WO2018080897A1

WO2018080897A1 - PD-CATALYZED γ-C(SP3)-H ARYLATION / HETEROARYLATION OF FREE AMINES

Info

Publication number: WO2018080897A1
Application number: PCT/US2017/057434
Authority: WO
Inventors: Jin-Quan Yu
Original assignee: Scripps Research Institute
Current assignee: Scripps Research Institute
Priority date: 2016-10-24
Filing date: 2017-10-19
Publication date: 2018-05-03
Anticipated expiration: 2019-04-24
Also published as: US10759743B2; US20190241508A1; CN110121492B; CN110121492A

Abstract

Pd(II)-catalyzed g-G(sp3)-H arylation or heteroarylation of primary amines is realized by using 2-hydroxynicotinaldenyde as a catalytic transient directing group. Importantly, the catalyst and the directing group loading can be lowered to 2% and 4% respectively, thus demonstrating high efficiency of this newly designed transient directing group. Heterocyclic aryl iodides are also compatible with this reaction. Furthermore, swift synthesis of 1,2,3,4-tetrahydronaphthyridine derivatives is accomplished using this reaction.

Description

Pd-catalyzed γ-0(«ρ³)-Η Ar lation / HeteroarySaison of Free Amines

CROSS-REFERENCE TO RELATED APPLICATION This application claims the priority of U.S. provisional application serial number 62/41 1 ,978, filed October 24, 2016, the disclosure of which is incorporated by reference herein in its entirety.

STATEMENT OF GOVERNMENT SUPPORT

This invention was made with government support under 2R01 G 08401 9 awarded by the National Institutes of Health. The government has certain rights in the invention.

BACKGROUN

in the past decade, directed C-H activations have been extended to a wide range of ^'synthetically useful substrates and transformations.¹ Nevertheless, the covalenl installation and removal of directing groups often poses a major obstacle for their synthetic applications, in addition to adding two steps to -the .synthetic sequence, the reaction conditions for these steps are sometimes incompatible with labile functionalities on advanced synthetic intermediates.

Thus, developing catalytic directing groups that can transiently bond to the substrate for C-H activation and subsequently dissociate reversibly is: highly desirable. This strategy has been successfully applied in a number of R {i)~catalyzed C.(sp²)-H activations.² Recently, our group discovered that simple amino acids can serve as an effective transient directing group for Pd(ii)-catalyzed G(sp³)-H funetionalization of aldehydes and ketones via a reversible imine linkage, thus demonstrating the feasibility of using transient directing groups for Pd(li) catalysts, although the loading of directing groups is still high (4Q%).³ Notably, the bidentate coordination system provided by the imine moiety and the weakly coordinating carb^'oxylic acid points to a new direction for our long search of transient directing groups that assist the activation of C{sp^:-)-H bonds (Scheme 1 (2)),

Following the success of identifying a transient directing group for ketones, we- wondered whether similar approach could be applied for the activation of free amines. Amines are ubiquitous structural motifs In compounds with pharmaceutical, agroc-hemicai and agricultural importance,⁴ While site-selective C-H ^'funetionalization of free aliphatic amine is highly desirable as it enables rapid late-stage modifications and derivations, this proces is traditionally difficult due to the formation of the unreactive Pd{RNH_z)_zX₂ complexes,⁵ as. well as the vulnerability of amines towards a-oxidation and efectrophiies.⁶ Nevertheless, numerous methods have been developed for the C~H iunciionaJization of amines with various protecting groups.⁷"⁸ An interesting b-O-H functionalization of free secondary amines (R2NH) has also been reported, although bulky a-quaternary center is required for this reaction. '⁰

SUMMARY

In various embodiments, the invention provides a method for P d (I t ^catalyzed g-C(sp³)- H aryiafton or heteroaryiation of a primary amine having a y-hydrogen atom, using an effective amount of a catalytic transie m ula IDG

(TOG)

wherein Y ss N or CX₄; and

Xi, X2, Xg, and X₄ each independently is alkyl, aryl, haloaikyl, alkyiamlno, or alkoxyl; or wherein any single pair of Xi and X₂, of 2 and X3, and of Xs and > when present, together with the ring to which they are bonded, forms a fused 5-, 6-, or 7-rnembered cycioaikyi ring;

the method comprising contacting a primary amino compound of formula (I)

wherein Ri R2 , R¾ and R₄ each independently is hydroge or alkyl, or wherein Ra and

R₄ together with the atoms to which they are bonded form, a cycioaikyi,

and an aryl iodide (Arl) or a heteroaryl iodide (HeiAri), respectively, which can be unsubstituied or can be substituted with one or more independently selected an/I, afkyl, halo, nifro, haloaikyl, alkoxyi, aikoxycarbonyl, or earboxaldehyde groups;

in the presence of an effective amount of paiiadium(ii) acetate, Pd{ii)(OAc)2, and in the presence of an effective amount of transient directing group TDG, to provide a product of formula (H)

wherein AH signifies an aryi or a heteroaryi group.

Further, the invention provides, in various embodiments, a method wherein the compound of formula (li) is further N-protected with a t-butoxycarbonyl (tBoc) group by contacting the compound of formula (if) and t-butoxycarbonyianhydride, to give a compound of formula (!!!)

For instance, the TOG can be 2-hydfoxynicptinaidehyde (TDG4).

in various embodiments, the primary amino compound of formula (!) can be contacted with an aryi iodide and group AH in the compound of formula (II) can be aryl. More specifically, the reaction milieu can further comprise silver trlfiuoroacetate. More specifically, the group AH in the. compound of formula (!!!) can be aryl.

In various embodiments, the primary amino compound of formula (I) can be contacted with a heteroaryi iodide and group AH in the compound of formula (it) can be heteroaryi. More specifically, the reaction milieu can further comprise silver trif!uoroaeetate or pyridone, or both. More specifically, ^'the group AH in the compound of formula (III) can be heteroaryi.

In various embodiments, the compound of formula (II) or of formula (ill) can be any of the examples provided, wherein group AH is aryi or is heteroaryi

DETAILED DESCRIPTION

Herein, we report an efficient Pd-eatalyzed C-H arylation or heteroarylaiion reaction- of free primary amines with aryl Iodide as coupling partners under air using a catalytic transient directing group. This development, -in combination with our previous transient directing group for ketone substrates,³ identifies irnine and weakly coordinating carboxylai© or its surrogate as privileged structural motifs, for efficient transient directing groups, Scheme 1 compares this known ketone y-sp3- arylation .proced.ure(1 ) with the method disclosed and claimed herein (2).

Using 2-hydroxynicotmaidahyde as a catalytic transient directing group, arylation of the y-carbon atom of an alkyiamlno substrate having a γ-hydrogen atom can be achieved in good yield. Scheme 1

Boc Protection

inspired by Jun's Rh(i)-cataiyzed aidehydic -C-H activation using a reversible

imine/pyridine directing group.,²⁸ we have previously investigated the development of imine/c iral oxazoiine^1'1 transient directing groups for asymmetric C-H activation of ketones and amines without -success. Recently, Dong's group reported an interesting example of g-arylaiion of free primary amines via in situ generation of an imine directing group with stoichiometric 8- formyiquino!ine.¹²

However, this method is mostly limited to amines containing a-sufastsfuents and requires using highly active aryi iodonium ArzlBf4 salts as coupling partners. The use of glovebox is also necessary, presumably to prolong the lifetime, of the stoichiometric imines, From our previous studies on imine/oxazoiine and imine/pyridine transient directing groups, we believe that these strongly coordinating transient directing groups have two fundamental disadvantages for rendering the directing group catalytic: undesired strong bischeiation of .amiho/oxazolirte or pyridine with Pd(i!) prevents the required formation of the imine linkage: the imjne/oxazoline or pyridine bischeiation with Pd(ii), even if generated, is not sufficiently reactive for developing highly effective catalytic directing groups.

Since the combination of the imine moiety and the weakly coordinating carboxyl grou constitutes an efficient transient directing group for ketones (Eq 1 ), we envisioned a-keto acids could form similar transient Intermediates upon condensation with amine substrates (Table 1 ). Gyclohexyiamine was chosen as model substrate due to its abundancy and relative high -boiling point. Boc protectiors of the arylated amin was performed for ease of separation and analysis. Our initial experimental exploration was largely based on our previous reaction conditions.³ 10 eq of HzO was added to facilitate the imine hydrolysis after C-H activation. We were encouraged to find that trace amount of ary!ated product 2ai».was detected with g!yoxy!ic acid (TDG1).¹³ Siight!y improved yield was obtained when g^'lyoxylic acid was replaced with the more stable henylglyoxylic acid (TDG2), Gratifying!y,. replacing the carboxyi group with an acidic phenol afforded the desired product in 62% yield (TDG3). Since; 2-hydroxypyridine (pyridone) has been used: as carboxyi surrogate in our previous !lgand design for mete-C-H activation,¹⁴ we tested commerciall available 2-hydraxynieoitnaidehyde as the catalytic transient directing group. To our delight, the reaction proceeded to completion and afforded 2a-i¾ in 94% yield (T0G4). introducing an electron-withdrawing CF₃ group to the hydroxy p rid ne directing group reduced the yield (TD6S). TD66 was completely unreaeiive, which suggests that the 7- membered ring bischeiation is not reactive. Other bidentate coordination systems such as the imine/pyridine and Imine/quinoline systems provided negligible yieids regardless the involvement of the S-membered or the 6~memhered ring bischeiation (TOG7-8), confirming the importance of the weakly coordinating anionic hydroxyi group.

Table 1. Development of the Transient Directing Gm p^{s b}

ID mo!% Pd(OAc)₂

20 moi% TDG

2 eq. Ari 1) 2 HCt

2 eq. AgTFA 2) ION NaQH, Ar

HFlP;HQAc = i^'9:1 [0.2 NT BocjO Ar s 4-C0₂MePh

1a 1 0 e ^'Hs 120 2a₁₉

Conditions: 1a (0.2 mmo!), ·4-0^'(¼ βΡΜ {0.4 mmol), Pd{QAc]₂ (10 moi%), TDG (20 moi%), AgTFA (0.4· mm©!), HHP/HOAc = 19/1 (1.0 tnl), ¾0 (2.0 mmol), 120 °C, 12 . Yields were determined by ¹ H N R analysis of the crude reaction mixture using GHaBfc as the interna! standard.

.A series of control experiments were aiso conducted, The reaction did not proceed in. the absence of the transient directing group. Simple 2-hydroxypyridine did not. give any product, which confirms the importance of the imine generation. Furthermore, the bidentate chelation mode of the imine and hydroxy! moieties in TDG4 was also shown to be crucial in this reaction as changing their spatial arrangements provided trace products (TDG 9). With the optimized conditions in hand, we next investigated the scope of the aryi iodide coupling partners. We were pleased to find that Y~C(sp³)~H aryiation of 1a with a vast variety of aryi iodides proceeded smoothly to provide an efficient access of 3-ar l cyctohexyiamines with good to excellent yields (Table 2), which were found to be applicable in the synthesis of potent antitumor reagents,¹⁵ Simple iodobenzene and various other methyl and phenyl substituted aryi iodides are well tolerated, affording the desired products in excellent yields (2ai-2a_S). Electron rich aryl iodides with alkoxy substituents afforded the corresponding products in good yields (2ae-2a¾). Halogenaied aryi iodides containing flupro, chloro and brorrso substituents are also tolerated {2as^«2aii, 2an-2a«,). When i ,3-diiodohenzene was employed as the- coupling partner, only one iodide was activated (2a<?j Electron deficient aryi iodides bearing trifiuoromethyi, nitro, methyl ketone and ester substituents are all well tolerated, providing consistently good to excellent yields (2ais-2an, 2ai»). Notably, reactive aldehyde functionality on the aryl iodide remained intact during the reaction (2aig}. Furthermore, stericaily demanding aryl iodides bearing substitutions at the ortho position are also compatible with this protocol (2a_?< 2a₉, 2a«). While aryiation of cyclohexy!a mine with heterocyclic aryi iodide; gave less than 10% yield, acyclic aikyl amine displayed excellent compatibility ^'with a range of heteroary! iodides. Pyridine based aryl iodides with different substitutions such as-fluoro, chloro, bromo and t ifiuoromethyi groups at different positions are well tolerated, providing 50-70% yields .(2bt-2be, 2be). Even electron donating methoxy group is also compatible (2b?). Various other thiophene, quinoiine and qusf oxaiine based heterocyclic aryl iodides are also tolerated, providing moderate yields

Table 2. Scope of Ary! Iodide Coupling Partners³

"Conditions: la-b {0.2 mmoi), Arl (0.4 mmot}, Pcl(OAc)j (10 moi.%), TDG4 {20 mq!%),. AgTFA (0.4 mmoi), HF!P/HOAc 19/1 (1.0 mL), H2O (2,0 mmoi), 120 "C, 12 h. isolated yields, < 30 °C, 48h.

Next we surveyed the amine scope of this g-C(sp³)~H aryiatson. We were pleased to find thai our protocol was applicable to a variety of free aliphatic amines. The aryjatlon of methyl C- H bonds in simple free aliphatic amines such as propylamine, isobutylamine, and 2- methylbutylamlne proceeded selectively at the g position with good yields (2c«e). Aliphatic amines bearing one or two methyl groups at the a-substitutron are also well tolerated (2f*g). in comparison to aliphatic amines with a~substiiuent, those without a-suhsiituent are usually more difficult substrates in C-H activations,¹⁶ which presumably attributes to both the lack of the Thorpe-ingoid effect and the increased susceptibility to oxidation and etectrophiies. However, our system Is effective in both a-substituted and non-substituted substrates. Various

functionalities such as phenyl, ether and even additional free amine (the. di-free amine was used in 2j and subsequently di-Boc protected) are compatible with this catalytic system, providing the corresponding products in moderate yields (2 -j). Furthermore, methylene C-H arylations of both cyclic and acyclic substrates are achieved. Simple acyclic aliphatic amines of different lengths and bearing methyl a-substitution. proceeded with moderate to good efficiencies (2k-l, 2m). Cyclic amines such. as cyclopentyi- and cyelooctyi- amines are also tolerated, affording the desired products as a single disastereomer (2n-o).

To demonstrate the synthetic utility of this reaction, we were pleased to find that the catalyst and directing group loading can be lowered to sub 5%, thus rendering the transient directing group catalytic {Scheme 2a). When the reaction was scaled up to 2 mmo!, the catalyst and template could be further lowered to 2% and 4% respectively. The desired pure arylated free amine product could be obtained in 61 % isolated yield following simple acid-base extraction protocols without any further purification (Scheme 2b). Furthermore, the C-H aryJaiibn of 1b with 2-fluoro-4-iodopyridine provides a facile access to 1 ,2,3,4-ietrahydrona.phthyridi.ne

derivatives, which exhibit important biological activities.¹⁷ $ΝΑΓ of amine to the pyridyl fluoride spontaneously took place in a one-pot fashion without any reaction work up, affording 2q in 70% isolated yield (Scheme 2c).

Scheme 2. Scale up Reaction and Synthetic Applications

2 moi% Pd(OAc]₂

4 mol% T064

2 eq. Art

Ar

2 eq. AgTFA Ar = 4-C0₂MePh

1a HFIP:HOAc = 19: 1 [0.2M] 2p

10 eq. H₂0, 130 ^PC, 48h

2 mmoi 61% yield

in conclusion, we have developed an unprecedented Pd(ll)-catalyzed g-C(sp³)-H arylation of aliphatic amines with aryl iodides as the coupling partners using a commercially available catalytic transient directing group. Methyl as well as cyclic and acyclic methylene C~H bonds were functionalized with good efficiencies. Notably, this catalytic system works we!j with aiiphatic amines bearing no substituent and one or two substituenis at the a position, in addition, straightforward ring closure by amine nucleophilic addition provides convenient access to valuable heterocyclic motif of 1 ,2₍3,4-tetrahydronaphthyridfne,

Table 3. Scope of A!kyi Amines³'*

Conditions: 1c-o (0.2 mmol), 4^CQ.MePh1 (0. mmol}, Pd{DAc {10. mo!%), TDG4 {20 mol%), AgTFA (0.4 mmoi). HFIP/HOAc - 19/1 (1.0 ml.}, H₂0 (2,0 mmol), 120 °G, 12 ft. "isolated yields. ^c90 "C. ^SO mol% TDG4. ^e 50 °C, HFIP/HOAc = 2: , 30 eq HzO. in the various embodiments of the heteroarylaiion reaction analogous to the above- described aryiation reaction, the^■ following scheme illustrates the method. The reaction can be carried out using TDG and slive triffuoroacetate, as described above, further in the presence of pyridine, In the condensation of an amino compound possessing a γ-hydrogen atom and a heteroaryl iodide as shown in Schem 3, below. Scheme 3: HeteroaryiatiQn reaction

54%

Condlitio s: Gydofiexyi amine (0 1 mmoi); Heferoary! Iodides (3:2 mmoi), Pd(OAc)₂.(0.01 mmoi),

TDG (0.02 mmoi), pyridone (0 05 mmoi}, AgOTFA {0,3 rnma!), H₂0 {1.0 mmoi), HRP (1 JO itiL),_.

150 °C, 12 h. After the .completion of the reaction , the amine product was protected with Boc₂0

Various heteroaryjiodides can b© used in this reaction, for example as shown in Tab! wherein group R can be any of aryl, alkyl, halo, nitre, haioaikyi, aikoxyl, alkoxycarbonyl, or carboxaldehyde groups.

Table 4: Heteroar i iodide reagents

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(13) While we are submitting this manuscript, g-aryiation of alkyi amines using transient directing group TOG1 was reported: Y. Liu, H. Ge. Nature Chem. 2016, .advance online publication. do!:1Q,1038 nchem.28G6. This transient directing, group is largely limited to amines containing a-quaternary centers and not compatible with acyciie methylene C-H bonds.

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1.3 (16) In most cases, directed C(sp³)-H^■functionaiizatipn only applies for amines bearing a- substftuent, see ref 7-8. Reduced yields were obtained with amines bearing no a~$ubstituent in ref. 7f, 7g, 71, 8G, 1 1 & 13.

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All patents and publications referred to herein are incorporated by reference herein to the same extent as if each Individual publication was specifically and individually indicated to be incorporated by reference in its entirety.

Exam l

1 < General information

2-hydroxynicotinaldehyde was purchased from Combi-blocks and used directly in the reactions. Amines, solvents and other chemicals were obtained from Sigma-A!drich, Acros and Alfa Aesar, and used directly without further purification. Analytical thin layer chromatography was performed on 0.25 mm silica gel 60-F254. Visualization was carried out with UV light and.

Vogel's permanganate. Preparative TIC was performed on 1 ,0 mm silica gel (Analtech).

Columns for flash chromatography (f C) contained silica gel {32~83μ, Dynamic Adsorbents, Inc.}.. ¹H NMR spectra were recorded on Bruker AV-400 instrument (400 MHz) or Varian Inova 400 (400 MHz), Bruker PRX-690 instrument (600 MHz). Chemical shifts were quoted in parts per million (ppm) referenced to 0.0 ppm for tetra methyl si lane. ¹³C NMR spectra were recorded on Bruker DRX-600 instrument (^'150 MHz), and were fully decoupled by broad band proton decoupling. Chemical shifts were reported in ppm referenced to the center line of a triplet at 77.0 ppm of CDCI3, High-resolution mass spectra (HRMS) were recorded on an Agilent Mass spectrometer using ESI-TQF (electrospray ionization-fime of flight). 2. Experimental Section

2.1 Solvent Screening

erstry Solvent NSvlR Yield (%)

1 DCE trace

2 toluene <5_:

3 dtoxane trace

4 MeCN NR

5 HFIP 58

6 AcOH 34

7 HFfP HOAc {2:1} 52

8 BFSP:HGAc (9 1 ) 65

9 HFIP; HGAc {19:1} 88

10 HFIP:HQAc {19:1} +10 equiv H₂0 94 (m

Reaction conditions: 1a (0.2 mmol), 4-(C0₂Me)Ph-i (2.0 equiv}, Pd(OAc}₂ (10

•mo!%), TDG4 (20 moi }, AgTFA (2.0 ©quw), solvents (10 ml), 120 12 h.

^Isolated yield.

2,2 General Procedure for Pd-Cafaly¾ed Y-C{sp³) H Aryiation of Free Amsrses Ussrs Transient D rect ng Group G

equ v. ₂ ,

To an oven dried microwave tube (5 ml) equipped with a magnetic stir bar was added Pd(OAc)a (4.5mg, 0.02 mmol, 10 mo1%), transient directing group (TDG4, 4.9rng_f 0.02 mmol, 20 moi%), Arl (0.4^■mmof), AgTFA (0.4 mmof) and solvent (HFlP/KOAc - 19/1, 1,0 ml ), followed by the free amine substrate (0,2 mmo!}, and H2O (36 uL). The tube was capped and covered with safety shield. Then the mixture vvas stirred at room temperature for 10 mins before- heating to 120 °C for 12 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature and the dark brown suspension was passed through a pad of Celite and washed with THF (1.0 mL 3).. The THF solutions were combined and concentrated under vacuum. Then THF (0.8 mL) and HCI (2 , 0.8 mL) were added to the residue and the mixture was stirred at rt for 1 h. The mixture was subsequently basified with NaOH (TO M, 0.4 mL) (Checked with pH paper) and BocjO (4.0 eq.) was added. The brown solution was then vigorously stirred at room temperature for 4 hr. Ethyl Acetate (2.0 mL) was added and well mixed. The top organic layer was separated and passed through a pad of Silica (3 cm). The remaining aqueous layer was further extracted with ethyl acetate (2.0 mL*3), Every time the organic extract was passed through the above pad of Silica. All the organic extracts were collected, combined in a vial and evaporated under reduced pressure and the resulting mixture was purified by prep TLC or flash column chromatography (Hex/EA ~ 3/1 )

tert-but≠ (3-phenylcycJohexyl)carbamate (2a,)

Following the general procedure, compound 2ai was obtained as a single diastereomer (cis) and a white soild (47.4 mg, 88% yield) after purification by preparative TLC (eiuertt:

hexane/EtOAc = 5/1 ). H NMR (6G0 MHz, CDC ) δ 7,31 7.26 (m,. 2H)_y 7.21 - 7.16 (m, 3H),

4.43 (s, 1Ή), 3,66 - 3.50 ( , 1 H), 2.62 (tt, J ~ 12.3, 3,4 Hz, 1 H), 2.19 - 2.23 (m, 1H), 2.09 - 2.01 (m, 1 H), 1..95 - 1.82 {nv2H), 1.47 - 1 .51 (ro, 10H), 1 .34 {qd, J ~ 12.6, 3.4 Hz, 1 H)_; 1 .23 (q, J - 12.0 Hz, 1H), 1.10 (qd, J ~ 12.5, 3.8 Hz_> 1 H). «C NM (151 MHz, CDCb) δ 165.16, 146.27, 128.38, 126.74, 126,09, 79.11 , 50,03, 43.25, 41.43, 33.21 , 33.12, 28.42, 25,20. HRM^'S (ESI- TOF) Gated for Ci₇H₂₅NO¾N P+Naf: 298.1778; found; 298,1777.

ierf-butyl (3-(p-toiyi)cycSohexyi)carbamat© {2&z} Following the genera! procedure, compound 2a¾ was obtained as a single diastereomer (cis) and a white solid (52.6 mg, 91% -yield) after purification by preparative TLC (e!uent:

hexan.es/EtOAq = 5/1). W MSVlR {600 MHz, CDCig) 7.12 - 7.08 (m, 4H), 4.43 (d, J - 8,8 Hz..1 H), 3,57 (s, 1H 2.59 (it J - 12.4, 3,4 Hz, H), 2.31.(s,.3H), 2.21 -2.12 ^'(m, 1H), 2.04 {dtfdd, J~ 9.0, 5.5, 3.7, 1.8 Hz, 1H), 1.91 -1.80{m,.2H), 1.85 -1.46 {m, 1Ή), 1.-45 (s, 9H), 1.32 (qd, J~ 12.8, 3,5 Hz, 1H), 1.21 (q,. J = 12,1 Hz, 1H), 1.08 (qd, J - 12,5, 3.8 Hz, 1H).¹³C MMR{151 MHz, CDCIa) δ 155. 5, 43.33, 135,53, 129.05, 126.59, 79.09, 50.05, 42.81, 41.52, 33,23, 28.42,

found:312.1927

fsif-buiyi {3- m-toIyS}cycIohexyl)carfoamate (2a3)

Following the general procedure, compound 2a*;. was obtained as a single diastereomer (cis) and a white solid (52.7 mg, 91% yield) after purification by preparative TLC (eluent:

hexane/EiOAc -.5/1 ), Ή N^'MR (600 MH2, CDGb) δ 7,17 (t, J = 7.8 Hz, H), 7.02 - 6,98 (m, 3H), 4.56-4,37 (rfi, 1H), 3.57 (d, J - 11.1 Hz, 1H), 2.58 (tt, J~ 12,3, 3.3 Hz, 1H), 2.32 (s, 3H), 2.18 (d, J~ 12.4 Hz, 1H),-2,04.<dddt, J ~ 10,6, 5,6, 3.7, 1.9 Hz, 1H), 1,91 ~ 1.81 (m, 2H), 1.48- 1.51 (m, 11 H), 1.33 (qd, J~ 12,8, 3.6 Hz, 1H), 1.22.(q, J~ 1:2.0 Hz, 1H), 1.09 (qd, J- 12.5, 3,9 Hz, 1H).¹³C NMR (151 MHz, CDGb) δ 155.16, 146.25, 137.86, 128.27, 127.59, 126.83, 123.72, 79.07, 50.04, 43.19, 41.45, 33.21, 33.11, 28.44, 25.21, 21.46, HRMS (ESi-TOF) Gated

G eHjy OjNa [M+Na]⁺; 312.1934: found: 312.1930.

tBrt-buiyl (3»(3_s5-dimethyphenyl)cyciohexyi)carbamate (2 4)

Following the general procedure, compound 2BA was obtained as a single diastereomer (cis) and a white solid (53.4 mg, 88% yield) after purification by preparative TLC (eluen hexane/BOAc = 5/1 ), ¹H NMR {600 MHz, pDC^'b) δ 6.84 ~ 6.79 (rn, 3H), 4.42 (s, 1H), 3.56 (s, 1H), 2.55 (it, J = 12,5, 3.5 Hz, 1H), 2.28 {s, 6H), 2.19 -2.14 (m. W), 2.08 - 2.00 (m, 1H), 1.91 - 1.80 (m, 2H), 1 -52 - 1.45 <m, 1H), 1.43 (s, 9H), 1.33 (qd, J= 12,7, 3.5 Ηζ,ΙΗ), 1.21 (q, J - 12.1 Hz,.1H), 1.08 (qd. J = 12.5, 3.9 Hz, IN). «C NMR {151 MHz, CDC!₃).6 155.16, 146.29, 137.80, 127.74, 124.60, 79.07, 50.07, 43.13, 41.49, 33.24, 33.11, 28.44, 25.22, 2133. HRMS (ESi- TOF) Gated for QuHaNOaNa M+Na : 326.2091: found: 326.2084.

ferf-butyi (3-{[1 ,1 ^!-bip enyll-4-yl)cycf ohexyljcarbamate (2a&)

Foilowiog the general procedure, compound 2as was obtained as a single diastereomer (cis) and a white solid (58.3 mg, 83% yield) after purification by preparative TLC (eluent:

bexane/EfOAc = 5/1 ).¹H UMR (500 MHz, CDCI3) δ 7.57 (dd, J = 8-2, 1 .4 Hz, 2H), 7.52 (d, J - 8.0_. Hz, 2H), 7.41 ((, J * 7.6 Ηζ·, 2H), 7.34 - 7.29 (m, 1Ή), 7.26 (d, J = 8.1 Hz, 2H), 4,45 (d, J - 7.7 Hz, 1H), 3.80 (s, 1H), 2.67 {it J - 12,3, 3.3 Hz, 1H), 2.23 (d, J ~ 12.3 Hz, 1H), 2.10 - 2,02 (m, 1H), 1.9G. (tq, J = 9.5_> 3.4 Hz, 2H>, 1.57 - 1.48 (m, -1H), 1.44^■ (s, 9H>, 1.41 - 1 ,32 (m, IN), 1.26 (q, J = 12.1 Hz, 1H), 1.11 (qd, J = 12.5, 3.7 Hz, 1H). ¹ C NMR (151 MHz, CDCf₃) δ 155.16, 145.38, 141.01 , 139.04, 128.69, 127.16, 127.11 , 12.7.01 , 126,99, 79.13, 50.02, 42,89, 41.42, 33.19, 33.11, 28.43, 25.20. HRMS (ESi-TOF) Caicd for CaaH^NOz a . [M+Na]*: 374.2091; found: 374.2086.

tert-bulyi (3~{4-methoxypheny!)cyc hexy!}carbarT5aie (2^'δδ)

Foiiowing the general procedure, compound 2a§ was obtained as a single diastereomer (cis) and a white solid (48.9 mg, 80% yield) after purification by preparative TLC (eiuerrt:

hexane/EtOAc * 5/1 ). Ή NMR (600 M:Hz, CDCI₃) 6 7.13 - 7.07 (m, 2H), 6.86 - 6,80 (m, 2H), 4,45 (s, 1H), 3.78 (s, 3H), 3.64 - 3,49 (m, H), 2.57 (tt, J = 12,3, 3.5. Hz, 1 H), 2.16 (d, J = 12.4 Hz, 1_.H), 2.03 (dtd, J =11.8, 3.8, 1,8 Hz, 1H), 1.91 -1.78 (m, 2H), 155 ~~ 1.46 (m, 1H), 1.43 (s, 9H), 1.30 (qd, J= 12.9, 3,7 Hz, 1H), 1.18 (q, J = 12,1 Hz, 1H), 1.08 (qd, J ~ 12.5, 3.8 Hz, 1H). «G NM {151 MHz, CDCi₃) δ 157.85, 155.16, 138.54, 127.57, 1 3.74, 79.08_r 55:23, 50.04, 42.36, 41.69, 33.36, 33.19, 28.42, 25. 8. HRMS (ESI-TOf) Gated for C-,₈H₂7N0₃Na [ +Na]*: 328.1883; found; 328.1882.

^■fenf-b.utyi (3^2- ethoxypheny}eyclobexy!}carbamate (2a?)

Following the genera! procedure, compound 2a? was obtained as a single diastereomer (cis) and a white solid (39.7 mg, 65% yield) after purification by preparative TLC (eiuent;

hexane/EtQAc * 5/1 ). Ή NMR (600_. MHz, CDC!₃) δ 7.23 - 7.17 (m, 2H), 6.78 (dt, J - 7.5, 1.3 Hz, 1H)₅6,73 {dt, J ~ 7,6, 2.0 Hz, .1H), 4,44 (s, 1H), 3.79.(s_s.3H), 3.65 ~ 3.49 (m, 1Ή), 2.60 (tt, J - 12.3, 3,4 Hz, 1H), 2.19 (d, J = 2.3: Hz, 1H), 2.04 (dqt, J - 10.8, 3.5, 1.7 Hz, 1H), 1.93 - 1.81 (m, 2H).1.53- 1.40 (m, 10H), 1.33(qd, J- 12.6, 3.4 Hz, 1H),.1,22 (q, J = 12,0 Hz, 1Hj, 1.14- 1.04 (m, 1H).¹³C NMR (151 MHz, C.DC!₃) S 156.69, 155.15, 34.45..126.82, 126.48, 120.48, 110,40, 78.99, 55.31, 50.11, 39.95, 35.69, 33.57, 31,84, 28,44, 25,29. HRMS (ES!-TOF) Ca!cd for &₈H₂₇N0₃Na [M+Naf 328.1883; found; 328,1882.

feri-butyi (3-{2_J3-dsbydroben^o|b][1 ,4]dioxin~6-yI}cyclohexyt)carbamate (2 s

Fpi^'lowing the general procedure, compound 2as was obtained as a single diastereomer (cis) and a white solid (49.6 mg, 75% yield} after purification by preparative TLC (eluerrt:

he ane/EIOAc ^« 5/1).¹H NMR (600 MHz, CDCfe) δ 6.77 (d, J^« 8.2 Hz, 1H), 6.69 (d, J = 2.1 Hz, 1H), 6,66 (dd, J ~ 8.3, 2.1 Hz, 1Ή), 4.43 (d, J~ 8.2 Hz, 1H), 4,25-4.21 (m_s 4H), 3.55 (d, J ~ 11.1 Hz, 1H), 2.52 (tt, J* 1.2.4, 3.3 Hz, 1H), 2.15 (d, j« 12.4 Hz, 1H), 2.05 - 1.99 (m, 1H), 1.89 -1/?8(m, 2H), 1.50 -1.45 (m, 1H), 1.43 {$, 9H), 1.27 (qd, J = 12,8, 3.6 Hz, TH), 1.16 (q, J = 12.Θ Hz, 1H), 1.07 (qd, J = 12.5, 3.9 Hz, 1H).¹³C NMR (151 MHz, CDGfe) 5155.15, 143.26, 141.71, 139.84, 119,68, 116.99, 1 5-30, 77.24, 64.41 , 64,31 , 49.98, 42.47.41.56, 33.28, 33.18, 28,42, 25.13. HRMS (ESi-TOF) ^.Gated for -CigHayNCMMa [M+Na]⁺: 356.1832; found: 356,1826.

feff-butyl |3-(2-fluoropl eny!}cyciohexyf}Garbarnaie (2a₉)

Following the general procedure, compound_.2ag was obtained as a single diastereomer (cis) arsd a white solid (36.9 mg, 63% yield) after purification by preparative TLC (elueni:

■hexane/EtOAe^■ - 5/1).¹H NMR (600 MHz, CDCI3) δ 7.21 - 7,13 (m, 2H), 7.06 (t,J - 7.2 Hz, H), 6.99 (ddd, J ~ 9.6, 8.3, .2 Hz, 1 H), 4.55 - 4,36 (m, 1H)i3.59{s, 1 Ή), 2,95 (tt, J - 12.3, 3, Hz, 1H), 2.16 (dt J« 11.8, 3.7, 2.0 Hz, 1Ή), 2.09 - 2.02 (m, 1H), 1.89 (dp, J = 13.5, 3.4 Hz, 1H), 1.83 (did, J~ 13,0, 3.4, 1.7 Hz, 1H), 1.51 (qt, J- 13.3, 3.5 Hz, 1H), 1,44 (s, 9H), 1.37 (qd, J ~ 12.7, 3.5 Hz, 1 H), 1 ,31 (q, J ~ 11,9, 8.8 Hz, 1Ή), 1.12 (qd, J- 12.6, 3.9 Hz, 1 H).¹³C NMR (151 MHz, CDCf3) δ 160,92, 159.30, 154.66, 132.30 (d, J = 14.3 Hz), 127.27, 126,95 (d, J~ 8. Hz), 123,57 (d, J=« 3.7 Hz), 114,93 (d, J -22.3 Hz), 78.66, 49.45, 39.13, 35-98, 32,76, 27.96... 24.6.8.¹⁹F NMR. (400 MHz, CDC 13). δ -119.06 (s). RMS (ESi-TGF) Caicd for C ^FNGs a [M+Naf: 316.1683; found: 316.1679,

f erf-butyl {3-{4~chtorop ersyS}cyciohexyl)carba8Tiiate (2aie)

Following the genera! procedure, compound 2:a« was obtained as a single diastereomer (cis) and a white §olid {45.2 mg, 73% yieid) after purifiGation by preparative TIC (eiuent:

hexane/EIOAc ~ 5/1).¹H NMR (600 MHz, CDCis) δ 7.24 (d, J - 8,4 Hz, 2H), 7. 1 (d, J = 8.5 Hz, 2H), 4.45 (s, 1H), 3.57 (s, 1H), 2.60 (tt, J ~ 12.3, 3,4 Hz, H), 2.17 (d, J = 12,3 Hz, 1H), 2.03 (dtq, J= 10.7, 3.5, 1,8 Hz, 1H), 1.89 (dp, - 13.6, 3.4 Hz, 1H), 1.82 (d pd , J~ 10.0, 3.3, 2,1, 1.4 Hz, 1H), 1,49 (tt, - 13.3, 3.5 Hz, 1H), 1.43 (s, 9H), 1.34 -1.26 (m, 1H), 1.18 (q, J - 12.1 Hz, 1H), 1.09 (qd, J ^« 12.6, 8.9 Hz, 1H). ³C NMR (151 MHz, CDCi₃) δ 1.55.14, 144.69, 131.66, 128,46, 128.10, 79,19, 49.92, 42.64, 41.34, 33.10, 33.07, 28.42, 25.11. RMS (ESI-TOF) Calcd for.Ci₇H_¾Gi 0₂Na [M+Naf: 332,1388; found: 332.1382.

ie/t-foyty] (3-{2-bromophenyl)c¾'c?ohexyS)carbamate f2a-n)

Following the general procedure, compound 2a-n was obtained as a single -diastereomer (cis) and a white solid {43.1 mg, 61% yield) after purification by preparative TLC (eiuent:

hexane/EtOAo« -S/1). ¹H NMR (600 MHz, CDCfe) δ 7.53 (dd, J ~ 8.0, 1.3 Hz, 1H), 7.28-7.23 (m, 1H), 7.21 (dd, ^= 7.8, 1.8 Hz, 1H), 7.04 (td, J-~ 7.6, 1.8 Hz, 1H), 4.44 (s, 1H), 3.62 (s, 1.H_.J, 3.10 (t, J - 12,2 Hz, 1H), 2.20 (dti, J = 11 _;8, 3.8, 2.1 Hz, 1H), 2.08 (d, J ~ 12.6 Hz, IN), 1.94 - 1.84 (m, 2H), 1.54 (qt, J - 13.8, 3.7 Hz, 1H), 1.44 (s, 9H), 1.31 ~ 1.17 (m, 2H), 1.11 (qd, J~ 12.6, 3.8 Ηζ, Η).¹³C NMR (151 MHz, CDCb) δ 154,63, 144.20, 132.49, 127.10, 127.06, 126.66, 123,97, 78.68, 49,45, 41.44, 39.30, 32.83, 31,74, 27.98, 24.64. HR!vlS (ESi-TOF) Caicd for C.irH₂4Br 0₂Na P+ a]⁺: 376.0883; found: 334.0881.

feri-buiyi p^»(3~iGdop «riyI)cycSohsxyi)carbamae (2ai )

Following the general procedure, compound 2a« was obtained as & single diastereomer (cis) and a white solid (48,9 rag, 61% yield) after purification by preparative TLC (eiuent

hexane/EiOAc * 5/1), ¹H NMR (400 MHz, CDCi₃) δ 7.54 (d, J -1.8 Hz, 1H), 7.52 (dt, J~ 7.7, 1.4 Hz, 1H), 7.14 (dt, J* 7.7, 1,3 Hz, 1H), 7.01 (f, J~ 7.8 Hz, 1H), 4.44 (d, J ^~- 8.1 Hz, 1H), 3.65 - 3.49 (m, 1H), 2.56 (it, J = 12.4, 3.4 Hz, 1H), 2.1.8 (d, J =12.3 Hz, 1H), 2.07- 1.99 (m, 1_.H), .89 (dp, J - 13.6, 3.4 Hz, 1H), 1.85 - 1.81.{m, 1H), 1.48 (dt J =^· 13.7, 3.7 Hz, 1H), 1.44 (e, 9H), 1,-34:- 1.27 (m_s -1H), 1.19 (q, J ~ 12.1 Hz, 1H), 1.09 (qd, J ~ 12.6, 3,9 Hz, 1H).¹³C NMR (151 MHz, CDCb) δ 155.13, 148,67, 135.85, 130,17, 128.38, 126,20, 94,56, 79.20, 49.88, 43.24, 42,87, 41.19, 33.03, 28.42, 25,08, HRMS (ESI-TOF) Gated forCi_?H₂ lN0₂ a [M+Naf:

424.0744; found: 424.0746.

teri- utyt f3~3~chforo~4 IyorophenyS)cyG|ohexyl)carbamate (2a«)

Following the genera! procedure, compound 2&%% was obtained as a single diastereomer (cis) and a white solid (.48.4 mg, 74% yield) after purification by preparative TLC (elueni:

hexane/EfOAc ~ 4/ ). Ή NMR (600 MHz, CDCb) δ 7,23 ~ 7,18 (m, 1H), 7.07 - 7.01 (m, 2H), 4.45 (d, . J= 8.1 Hz. H), 3.57 (s, IN), 2.59 (it, J- 12.3, 3.3 Hz, 1H), 2,18,(d,J = 12.3 Hz, 1H), 2.03 (dtt, 10.4, 3,6, 1.9 Hz, IB), 1.90 (dp, J= 13.6, 3.4 Hz, 1H), 1.83.(dtt, . J = 11.8, 3.5, 1.8 Hz, 1H), 1,4-9 (it, J ~ 13.4, 3.6 Hz, 1H), 1.44 (s, 9H), 1.32 -1.24 {m, 1H), 1.17 (q, J~ 12.0 Hz, IN), 1,10(qd, 12.6, 3.9 Hz, 1H).¹³C NMR (151 MHz, CDCb) δ 157.31, 155,68, 155,15, 143.25 (d, J=3.2Hz , 128.70, 126.43 (d, j~6.8 Hz), 120.57 (d, J = 17.5 Hz), 116.32 (d, J~ 20.6 Hz), 79.26, 49.84, 42,33, 41.35, 33.15, 32.95, 28.-41, 25.03.^1SF NMR (400 MHz, CDCI3) δ ~ 11-9.9 (s). HRMS (ESI-TOF) Cased for Ci7H₂₃CIFN0₂Na [M+Na]⁺: 350.1294; found: 350.1288,

ferf-bu^'tyl (S^S^jS-irsfkioroprsenyljcycfohexy carbaniate {2an}

Foiiowing the general procedure, compound .2ai* was obtained as a single diastereomer (cis) and a white solid (34.2 mg, 52% yield) after purification by preparative TLC (eiuent:

hexane/EfOAc = 3/1 ). ^'1H NMR (500 MHz, CDCb) δ 6.82 ~ 6,75 (m, 2H), 4.51 - 4.32 {m, 1 H), 3.56 (S, 1Ή), 2.57 (it, J= 12,3, 3.4 Hz, 1H), 2,19 (d, J ~ 12.2 Hz, 1 H), 2.05 - 2.00 (m, 1H), 1.91 (dp, J- 13.6, 3.4 Hz, 1_.H), 1.82 (dtd, J*.11.6, 3,2, 1.6 Hz, 1H), 1,49 (ddd, J~ 13.4, 9.7, 3.6 Hz, 1H), 1.44 (s, 9H), 1 ,24 (qd, J ~ 12,9, 3.8 Hz, 1H), 1 ,18 ~ 1.04 (m, 2H), «Q NMR (.151 MHz, CDCb) δ 154.65, 151,44 (dd, J * 9,8, 4.2 Hz), 149.79 {dd, J - 9.7, 4.0 Hz), 141,97 (q, J * 6.4 Hz), 138.39 (1, 15.4 Hz), 136.69 (d. J ~ 15.5 Hz), 110.12 (dd, J^« 16.4, 4.1 Hz), 78.88, 87.51 , 49.24, 42,01, 0,6, 32.46, 27,94, 24.43.¹⁹F NMR (400 MHz, CDCb) δ -135.27 (d, J - 20-8 Hz), . 164.48 <t, J - 20.7 Hz). HRMS (ES1-T0F) Calcd for CiiHzzFaN z (Μ+Η]⁺: 330.1675; found: 330.1671 ,

ferf-butyj (3-{4-(triftuoromethyl ph«nyi)cyc!ohexyl)carbam3ie {2a_iS)

Following the general procedure, compound 2.a« was obtained as a si^'ngte diastefeomer (cis) and a white solid (56.9 mg, 83% yield) after purification by preparative TLC (e!uen

hexane/EtOAe = 4/1 }, H NMR {400 MHz, CDCi₃) δ 7.54 (d, ~ 8.1 Hz, 2H), 7.29 (d, = 8,0 Hz, 2H), 4,48 (d, ~ 8,3 Hz, 1 H), 3,60 (d, J = 11 ,6 Hz, 1H), 2,69 (tt, J = 12.3, 3.4 Hz, 1 H), 2,21 (ti, J = 12,3 Hz, 1Ή), 2.05 (6tt, ~ 12.5, 4.0, 2.0 Hz, 1Ή), 1.92 (dp, J ~ 13.5, 3.4 Hz, 1 H), 1.85 (dtt, J ~ 11.7, 3.5, 1.9 Hz, 1 H), 1.51 (qt, = 13.2, 3.7 Hz, 1 H), 1.44 (s, 9H), 1.35 (qd, J = 12.8. 3.6 Hz, 1Ή), 1.23 (q, J = 12.1 Hz, 1H), 1.13 (qd, - 12.6,_. 3.9 Hz, 1H_.)^'.¹³C NMR (151 MHz, GDCI₃) δ 154.69, 149.73, 127,96 (q, J * 32,4 Hz), 126.63, 124.86 (q, J = 3.7 Hz), 122.93, 78.78, 49,42, 42.66, 40.63, 32.54, 32.45, 27.94, 24.63. ¹⁹F^' NMR (400 MHz, CDCi₃) 5 -62.61 {s)> HRMS (ESi- TOF) Caicd for

[M^'+Na ; 366.1651 ; found: 366,1648.

fierMsutyf {3-(4-nitrop enyf}eyelohexyS)carfoamate (2ai₆)

Folio wing the general procedure, compound 2a½ was obtained as a single dsasiereomer (cis) and a white solid (46.7 mg, 73% ieid) after purification by preparative TLC (eiuent:

hexane/EtOAc = 4/1 ). ¹H NMR (600 MHz, CDCb) δ 8.15 (d, J = 8.7 Hz, 2.H), 7.37 - 7.32 (m, 2Ή), 4,49 {ύ, J ~ 8.1 Hz, 1 H), 3,61 (s, 1H), 2.75 (tt, J-~ 12.3, 3.4 Hz, 1H), 2.23 (d, J - 12.3 Hz, 1 H)_i: 2.06 (ddq, J = 12.6. 3.8. 1.9 Hz, 1 H). 1.94 (dp, J = 13.6, 3.4 Hz, 1 H), .87 (did, J ~ 15.1. 3.6, 2.0 Ηζ, ΊΗ), 1.53 (qt ^» 13.3, 3.6 Hz, 1 H), 1,44 (s, 9H), 1.36 (qd, J ~ 12.8, 3,6 Hz, 1H), 1.25 (q, J - 1_.2,1 Hz, 1 H), 1.15 (qd, J = 12.6, 3.9 Hz, 1Ή). ^1;3C NMR (151 MHz, CDCla) δ 155.14, 153.76, 146.44, 127.62, 123.75, 79,34, 49.78, 43,22, 40.87, 32.87, 32.81 , 28.41 , 25.04. HRMS (ESi-TOF) Gated

jM+Na : 343.1628; found: 343.1630.

ferf-bu tyl (3-(4~acety I pheny & |c c&o exyli ) ca rbam ate {2ai? )

Following the general procedure, compound 2ai? was obiained as a single diastereomer (cis) and a white solid (50.7 rng, 80% yield) after purification by preparative TLC (elueni:

hexane/EtOAc =^; 4/1), ¹H NMR (600 MHz, CDCfe) δ 7.89 (d, J = 8.3 Hz, 2H), 7,28 (ci, J = 8.3 Hz, 2H), 4.47 (s, 1 H), 3.60 (s, 1 H), .2,74 - 2.66 (m, 1.H), 2.58 (s, 3H), 2.21 (d, J ~ 12.3 Hz, 1H), 2.09 - 2.03 (m, 1 H), 1.92 (dp, J - 13.5, 3.4 Hz, 1H), 1 ,86 (dtt, J = 12.2, 4.2, 2.1 Hz, 1 H), 1.51 (qt, J = 13.2, 3.5 Hz, 1H), 1.44 (s, 9H), 1.36 (qd, J* 12.7, 3,5 Hz, 1 H), 1.25 (q, J = 12.1 Hz, 1 H), 1 ,13 (qd, J - 12.6, 3.9 Hz, 1 H), ¹³C NMR (151 MHz, CDG!₃) δ 107.35, 154,69, 151.37, 134,85, 128.16, 126.53, 78,78, 49.42, 42.85, 40.52, 32.58, 32.39, 27.95, 26.10, 24.65. HRMS (ESI-TOF) Caled for Ci₉H:₂7N0₃Na [ +Na]⁺: 340.1.883; found: 340.1879,.

terf-butyl (3- 3-formylphersy!)cycfoiisxyl)carbamat@ {2 s}

Following the general procedure, compound 2a« was obtained as a single diastereomer (cis) and a white solid (38.2 mg, 63% yield) after purification by preparative TLC .{eluerit:

hexane/ElOAc - 2/1), NMR (500 MHz, CDCI₃) δ 9.99 {s, 1 H), 7.71 (ddd, J = 8,6, 4.5, 2.2 Hz, 2H), 7.50 - 7.41 (m, 2H), 4,50 (d, J ~ 8.7 Hz, 1Ή), 3.69 - 3.53 (m, 1 H). 2.72 (it, J ~ 12.4, 3.3 Hz, 1H), 2.24 (d, J = 12.3 Hz, 1H), 2.06 (ddt, J ~ 8-6, 5.8, 3.0 Hz, IN), 1.97 - 1.84 (m, 2H), 1 ,57 - 1.48 (m, 1H), 1.44 (s, 9M), 1.40 - 1.33 (m, 1 H), 1.28 (qd, J = .6, 11.2, 3.2 Hz, 1 H), 1.14 _.(qd, J =^■ 12.5, 3.8 Hz, 1H). ¹³C NMR (151 MHz, CDC|₉) δ 192.52, 155.17, 147.30, 136.62, 33.37, 129.08, 128,06, 127.4.8, 79.23, 49.90, 42.93, 41.14, 33.04, 32.99, 28.42, 25.1 1. HRMS <ESI- TOF) Caicd for CiaHasNOa a *Na]⁺: 326.1727; found: 326.1725.

methyl 4-{3-{{feii-byfoKycarbony }amino)cyGlohexyl)ber5zoate (2aig)

Following the general procedure, compound 2a-i9 was obtained as a single diastereomer (cis) and a white solid (59.9 mg, 90% yield) after purification by preparative TLC {eluent:

hexane/EtOAc ~ 5/1 ). H_. NMR (400 MHz, CDCi₃) 5 7.98 - 7.93 (m, 2H), 7.26 - 7.24 (m, 2H), 4.47 (s, 1H), 3.90 (s, 3H), 3.59 (s, 1 H), 2.69 (ft, J = 12.2, 3.4 Hz, 1Ή), 2.20 (d, = 12,3 Hz, .H), 2.05 (did, J = 14.1 , 3.7, 1.9 Hz, 1 H), 1.95 - 1.82 (m, 2H), 1.54 - 1.47 (m, I H), 1.43 (s, 9H), 1.35 (qd, J - 12.8, ..3.6 Hz, IH), 1.24 ( ,. J = 12.1 Hz, 1 H), 1.12 (qd, J = 12.5, 3.8 Hz, 1 H). ¹³C HMH (151 MHz, CDCb) 5 167.07, 155.15, 151.55, 12979, 128.08, 126,81 , 79.22, 51.98, 49.90, 43,3.2, 41.02, 33,07, 32,88, 28,42, 25.12. HR S (ESi-TQF) .CalCd. for Ci₉H₂₇NC Na ( +Maf: 356.1832; found; 356. 833. The -stereochemistry was determined by 2D NGE analysis.

teri-butyS (2»((2~fluoropyrsdin-4-y!}methyl)bulyi}carbamaie (2bi)

Following the general procedure, compound .2bt was obtained as a white solid (37.2 mg, 68% yield) after purification by preparative TLC (eluent: hexane/EtOAc = 2/1 ), ¹H NMR (400 MHz, CDCia) 5 8.10 (d, J - 5.1 Hz, 1H), 7.00 (d, J =■ 5.1 Hz, 1H), 6.75 (s, 1H>, 4.56 (s, IH), 3:10 (ddt, J = 51.0, 13.6, 6.2 Hz, 2H), 2.68 -- 2.54 (m, 2H-), 1.82 (q, J - 6.6 Hz, H), 1 ,43 (s, 9H), 1.33 (p, J ~ 7.3 Hz, 2H), 0.93 (t, J - 7.4 Hz, 3H . ¹³C NMR (15 MHz, CDCI₃) 164.87, 163.29, 156.05, 147.33 (d, J = 15.4 Hz),- 122.20 (d, J - 3.8 Hz), 109.76 (d, J.- 36.3 Hz), 79.39, 43.22, 41.29, 37.42, 28.38, 23.92, 10.87. ⁹F NMR (400 MHz, C.DCb) 5 -69.39 (s). HRMS (ESI-TOF) Calcd for C 15H24F 2O2 p+H]^÷: 283. 816; found: 283.1810.

terf-buivS (2-{{2-chloropyndiii-4-y melhyl)butyl}carbafnate (Zbz)

Following the general procedure, compound Zbi was obtained as a white solid (41.1 mg, 69% yield) after purification by preparative TLC (eiuefit: hexane/EtOAc = 2/1).¹H NMR (500 MHz, CDCIaj 58:27 (dd, J~ 5.2, 1.2 Hz, 1H), 7.15 (s, 1H), 7.05 (d, J =5:1 Hz, 1H), 4.55 (s, 1H), 3.10 (deft; J ~ 55.6, 13.4, 6.2 Hz, ,2H), 2.56 ,(ddd, = 49.9, 13.9, 7.0 Hz, 2H), 1.80 (d.d,. J- 1.3.4, 8.8 Hz.-IH), 1.44 (s, 9H), 1.32 (p, J =7.2 Hz, 2H), 0.92 (id, J =7.4, 1,1 Hz, 3H). ³C NMR (151 MHz, CDC!a) δ 155.56, 152.96, 15.1.17, 148.99, 124.28, .122.81, 78.93, 42.72, 40.84, 38.80, 27.92, 23.43.10.40. H.RMS (ES1-TGF) Gated for CisHz C!NaOa (M+H.J*: 299.1521 ; found:

ieff-buty! (2-{(2>bromopyrldii -4-yl)methyl)butyS)cari5amaie (2fo_s)

Following the general procedure, compound 2 a was obtained as a white- solid (38.4 mg, 5.6% yield) after purification by preparative TLC (eluent; hexane/EiOAc = 2/1). \H N R (400 MHz, GDCIa) 8.25 (<J, J = 5.1 Hz, 1H), 7.31 (s, 1H)₍ 7.08 (d, J ~ 5.0 Hz, 1H), 4.56 {s, 1H), 3.10 (ddt, J ~ 57.4, 14.3, 6.1 Hz, 2H), 2.55 (odd, J~ 52.2, 13.9, 7.0 Hz, 2H), 1.82 - 1.76 (m, 1H), 1.44 fs, 9Ή), 1.32 (p, J * 7.2 Hz, 2H), 0.92 (t, J - 7.5 Hz, 3H).¹³G NMR (i51 Hz, CDCI₃) «C NMR (151 MHz, CDCI3) δ 156.03, 153,21, 149.88, 142.43, 128.56, 123.66, 79.41, 43.17, 41.32, 37.19, 28.39, 23.89, 10.86. HR.MS (ESi-TOF) Caicd forCi₅H2₄BrN₂0₂ [M+H]*: 343.1016; found:

343.1016.

ferf-butyl {2~((6-fSyoropyndin-3-yl)mei yi)buiy!carbamale (2b4)

Following the general procedure,^■com.pound.2b4 was obtained as a white, solid (37.8 mg, 67% yield) after purification by preparative TLC (eiuent: hexane/EtOAc^™ 2/1).¹H NMR (400 MHz, CDCia) δ 8.03 - 7.99 (m, 1H), 7.60 {dt, J - 8.4,4,3 Hz, 1.H), 6.86 (dd, ~8A, 2.9 Hz, 1H), 4.53 (s, 1H), 3,09 (ddd, J~ 35.8, 14.5, 7.9 Hz, 2H), 2.63 - 2:50 (m, 2H), .1.77^» 1.71 (m, 1H), 1.44 (s, 9H), 1.35 ~ 1.28 (m, 2H), 0.92 (t, J =7.5 Hz, 3H). ³C NMR (151 MHz, CDC1₃) 163.16, 161.59, 156.05, 147.55 (d, J ~ 14.2 Mz), 141,58 d, J = 7.6 Hz), 133.45 (d, J = 4.4 Hz), 109.09 (d, J = 37.3 Hz), 79.34, 43.00, 41.77, 34.07, 28.40, 23.68.^1SF MR (400 MHz, CDCia) δ -72,34 (s).

forCi₅H₂4FN₂0₂ [M+H]⁺: 283.1816; found: 283.18 .

ferf«butyi (2-{(0«ch!oropyrsdi!i-3«yi)meihyf)butyS}carbamate (2bs

Following the general procedure, compound 2b¾ was obtained as a white so!id (35.8 mg, 60% yield) after purification by preparative TLC (eiu^'ent: hexane/ELOAc ~ 2/1). H NMR (400 MHz, CDC ) δ 8.19 (d, J = 2.4 Hz, H), 7.53 - 7.42 (m, 1H>, 7,25 (d, J ~ 8.1 Hz, 1H), 4.55 (s, 1H), 3.09 (ddt, J = 44.7, 13.8, 6.0 Hz, 2H), 2.59 (dd, J = 14.1, 6.8 Hz, 1H), 2.52 (dd, J = 14.1 , 7.4 Hz, 1 H), 1.73 (d, J =^' 6,3 Hz, 1 H), 1.44 {s, 9H), 1.35 ~ 1.28 ( , 2H), 0.92 (I, J = 7,5 Hz, 3H). ³C

NMR (151 MHz, CDCI3) 5155.57, 149.60, 148.69, 138.88, 134.42, 123.43·, 78.88, 42.56, 41.21, 33.85, 27.92, 23.24, 10.41. HRMS: (ESi-TOF) Gated for Ci₅H2CI ₂02 [M+H.}⁺ 299.1521; found:

ferf-butyl (2~((8-Ghioro-5-(trjfluoromethyI)pyrsdin-3-yl5methyS b (2b₆) The general procedure was followed, except that the reaction was heated to.130 °C and stirred for 48h. Compound 2be was obtained as a white solid (42,5 mg, 58% yield) after purification by preparative TLC (eluenf: hexane/EtOAc = 2/1).¹H NMR (400 MHz, CDC!₃) δ 8.38 (d, J - 2,3 Hz, 1H), 7.82 (t J = 5.4 Hz, 1H), 4.54 (s, 1H), 3.22 - 2.95 (m, 2H), 2.69 (dd, J - 14.2,.6.8 Hz, 1H), 2.59 (dd, J « 14.2, 7.4 Hz, 1H), 1.77 ({, J¾ 6.5 Hz, 1H), 1,44 (s, 9H), 1.37 - 129 (ro, 2H), 0.9 (t, J ~ 7.5 Hz, 3H).¹³C NMR (151 MHz, CDCI3) δ 155:56, 152.14, 146.04, 136.56, 134,86, 124.3 (q, J - 33_. Hz), 121.73 ( J ^~ 273.2 Hz), 79.07, 42.43, 41.23, 33.77, 27,89, 23.32, 10.39. ⁹F NMR (400 MHz, CDCb) δ -63.86 (s). HRMS (ESf-TOF) Cefod fer CieHjaCiFaNsOa [M+Hf: 367.1395; found: 367.1392.

i@rf~buiyi (2~{{2-met oxypyridin-3-yi)niethyi)buiyS carbamate (2b?)

Following the general procedure, compound 2b? was obtained as a white solid {23,5 mg, 40% yieid) after purification by preparative TLC (eiuent; hexane/EtQAc ~ 2/1 ). H NMR (400 MHz, CDCia) 8.03 (dd, J - 5.1 , 1.8 Hz, 1 H), 7.38 (d, J = 7.2 Hz, 1 H), 6.82 (dd, J ~ 7.1 , 5.0 Hz, 1H), 4.76 (s, 1 H), 3,96 (s, 3H), 3.04 (dc!t, J/= 46.5, 13.2, 5.3 Hz, 2H), 2.53 (dd, J = 7.0, 3,0 Hz, 2H), 1.74 (p, J - 6.3 Hz, IB), . 1.. 4 (s, 9H), 1 .33 (p, J.^» 7.3. Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H ..¹³C NMR (15 MHz, CDCb) δ 16.2.10, 156,16, 144.47, 138.86, 123.19, 116.79, 78,92, 53.27, 42.89, 40.34, 31.97, 28.44, 24.51 , 11.16. HRMS (ESI-TOF) Calcd for Gtt>H₂eN₂0₃ a [M+Naf:

317.1836; found: 317.1831.

terf-butyl (2-i(6-(trifiyoromethyI)pyridin-2^«yS)metriyi)butyS)carbamaie (2b_B)

Following the general procedure, ^'compound 2be was obtained as a white solid (50.5 mg, 76% yieid) after purification by preparative TLC (eiuent: hex_.ane/EtOAc - 2/1 ). H NMR (400 MHz, CDC^'fe) 6 7,77 (t, J - 7,8 Hz, 1H), 7.52 - 7.49 (m, 1 H)_: 7.35 (d, J ^« 7.9 Hz, 1H), 5,05 (s, 1H), 3,22 - 3.09 (m, 1H), 3.02 (dt, J - 13.6, 6.6 Hz, I N), 2.9 - 2.78 (m, 2H), 2.03 (dh, J = ,0, 7.4, 6.7 Hz, 1 H), 1.43 (s, 9H), 1.38 - 1.2? (m, 2H), 0.95 (t, J 7.4 Hz, 3H), ³C NMR (151 MHz, CDC ) 5 161.30, 155.74, 147.13 (q, J= -34.2 Hz), 137.04, 126.00, 121 ,06 (q, J ~ 274.1 Hz), 117.24 (tt, J = 0.5 Hz), 78.42, 42.67, 39.94, 39.54, 27.92, 24.18, 10.73. ⁹F NMR (400 MHz, CDCb) δ -68.41 (s). HRMS (ESI-TOF) Calcd for CtsHzsFaNaOaNa [M+Naf: 355.1604; found; o . s 6Q3.

2

ferf-foutyl {2-{quinoHn-~3-yimethyl)buiy})c rbamat6 (2b^)

The general procedure was followed, except that the reaction was heated to 130 °C and stirred for 48h. Compound 2b» was obtained as a white solid- (27.0 rng, 43% yield) after purification by preparative TLC (eiuenf: exane EtQAc^■ ~ .2/1 )- ¹H NMR (400 MHz, CDCis) δ 8.7S (d, J = 2.3 Hz, 1-H), 8.12 - 8.06 (m, 1H), 7.96 - 7.88 (m, 1 H), 7.77 (dd, J = 8.2, 1.4 Hz, 1 H), 7.66 (ddd. J * 8.4, 6.9, 1 .5 Hz, 1 H), 7,53 {ddd, J ^~ 8.1 , 6.8, 1.2 Hz, 1H), 4.59 (s, 1 H), 3.24 ~ 3.02 (ra, 2H)„ .2.85 - 2.68 (m, -2H), 1.92 - 1.79 (m, 1 H), 1.43 (s, 9H), 1.37 {did, J = 14.5, 7.5, .5.7 Hz, 2H), 0,95 (i, J ~ 7.4 Hz, 3H). ¹¾^: N R (151 MHz, QDC!₃) 6 166.08, 152.17, 146.85, 1.35.14, 133.26, 129.12, 128.73, 128.06, 127.36, 126.64, 79.26, 43.21 , 41 .83, 35.42, 28,39, 23.79-, 10.93. HR S (ESI- TOF) Caicd for CieH^e aOa a p+Na]⁺: 337.1886; found: 337.1885,

tefi-butyl (2-{quino!?n-6-yimethyi)buiy.i)carbamate (2bto)

The general procedure- was followed, except that the reaction was heated to 130 °G and stirred for 48 . Compound Zbw Was^' obtained as a white solid (26.4 mg, 42% yield) after purification by preparative TLC (eiuenl: hexane/EtOAe ~ 2/1 ). ^i:H NMR (600 MHz, C^'DCI_a) δ 8.86 (dd, J = 4.3, 1.7 Hz, -1 H), 8.09 (dt, J = 8.1 , 1.2 Hz, 1 H), 8.04 (d, J ~ 8,6 Hz, 1 H-), 7.58 (d, J - 2,0 Hz, H), 7.55 (dd, J = 8.7, 1.9 Hz, 1 H), 7.38 {dd, J ~ 8.2, 4.2 Hz, 1 H), 4.55 (d, J - 7.0 Hz, TH), 3.14 (ridt, J * 39.9, 12.8, 5.9 Hz, 2H), 2.76 (t, ≠ 6.6 Hz, 2^'H), 1 -88 .(d, J = 6.5 Hz, 1 H), 1 .42 (s, 9H), 1.40 - 1 .34 (m, 2H), 0.95 (t, J - 7.4 Hz, 3H). ¹³C NMR (151 MHz, CDCia) δ 155.81 , 149.23, 146.59, 138.72, 135.20, 130.82, 128.80, 127.7.9, 128.62, 120.66, 78.68, 42,88, 41 .40, 37.74, 27.94, 23.54, 10.51 . HRMS (ESi-TOF) Ca-ted.for

337.1886; found: 337.1886.

ferf-butyi {2-{qutnoxalfn-e-yimeir3yl)bufy!)carbamate (2bn)

The general procedure was followed, except that the reaction was heated to 130 °C and stirred for 48h. Compound 2i>n was obtained as a white solid (27,7 mg, 44% yield) after purification by preparative TLC (eluenf; hexane/EtOAc = 2/ ). H NMR (400 MHz, CDCI₃) δ 8.81 (dd, J ^~ 11.8, 1 ,8 Hz, 2H), 8.04 (d, J = 8.6. Hz, 1 H}, 7.92 - 7.85 (m, 1H), 7.67 - 7.57 (m, 1.H), 4.56 (s, 1 H), 3.15 (dp, J ~ 26.5, 6.9, 6.4 Hz, 2H), 2.83 {qd, J ~ 13.9, 7.1 Hz, 2H), 1.92 (p_., J = 6.5 Hz, 1 H), 1.43 (s, 9H), 1.40 - 1.35 (m, 2H), 0,95 (t, J = 7.4 Hz, 3H). ^1SC NMR {151 MHz, CDCk) δ 155,59, 144.5 , 143.85, 143.00, 142.56, 141.33, 131.50, 128.80, 128.18, 78.76, 42.84, 41.37, 37,83, 27.93, 23.46, 10.48. HRMS (ESi-TOF) -Gated for G18H25N3O2N0 [M+Naj⁺: 338.1839; found;

fe i-butyf (2-{(5-acety!thiophen-2-yS)m®t yl)butyl}carbamate {2b¾}

Following the general procedure, compound 2fa« was obtained as a white solid (37.3 mg, 60% yield) after purification by preparative TLC (eiueni: bexane/BQAc ~ 2/1 ).¹H NMR {400 MHz, GDC (3) δ 7.53 (d, J * 3,7 Hz, 1 H), 6.84 (d, J■ 3.7 Hz, 1 H), 4.55 (s, 1 H), 3. 1 (did, J ~ 26.9, 13,5, 5.9 H2, 2H)-, 2.82 (qd, J - 14.9, 6.8 -Hz. 2H), 2.51 (s,.3H), 1.83 - 1.75 (m, 1 H), 1 ,44 (s, 9H), 1.40 - 1.33 (m, 2H), 0,94 (t, J ^ 7.5 Hz, 3H). ³C - NMR {151 MHz, CDCI3) δ 190.43, 156.07, 153,22, 142,56, 132.90, 126.86, 79.30, 43,06, 42.33, 32.64, 28.40, 26.48, 23.89, 10.96. HRMS (ESI-TOF) Caicd for C₁₆Ha₅N0₃S a [ +Na]⁺: 334.1447; found; 334,1 45.

me lhyl 4- 3-{{ieri-buioxycarbonyl)amino}propyl)benzoaie (2c)

Following the genera! procedure, compound 2c was obtained as a white solid (39.8 mg, 68% yield) after purification by preparative TLC (eluent: hexane/EtOAc =· 5/1 }, ¹H NMR (600 MHz, CDCis) 7.98 ~ 7.92 (m, 2H), 7.26 - 7.22 (m, 2H>, 3,90 (s_« 3H)₍ 3.15 (t, J ~ 7.0 Hz, 2H), 2,72 - 2.67 (m, 2H), 1.83 (p, J - 7.4 Hz, 2H), 1.44 (s, 9H). - ³C NMR (150 MHz, CDC!₃) δ 16.7.08, 155.95, 147.12, 129.78, 128.38, .27.96, 79.23, 51.99, 40.15, 33.17, 31 .46, 28.4 . HR S (ESS- [W+Naf : 316.1519; found: 316. 518.

methyl 4-{3-((i'e f-butoxycarbortyl}amtno)r2-methylpropyt)foenzoate (2d, Monoaryiation)

The general procedure was followed, except that the reaction was heated to 90 °C. Mono- and di-ary!ation compounds were obtained as white solids (20.9mg, 34% mor>o, 38% di, 72% total yield} after purification with preparative TLC (eluent: hexane/EtOAc - 5/1 ). ¹H NMR (600 MHz, CDCfe) S 7.98 - 7.93 (m, 2H), 7.24 - 7,20 {m, 2H), 4.58 (s, 1 H), 3.90 (s, 3H), 3.06 (ddi J = 66.9, 13.9, 6,5 Hz, 2H). 2.76 (s, 1 H), 2.41 (dd. 1 3,5, 8.7 Hz, 1 H), 2.01 - 1 .88 (m, 1Ή), 1.44 (s, 9H), 0.86 (d, J « 6,7 Hz, 3H). ¹³C NMR (151 MHz, CDCfe) δ 167,10, 158.04, 146.06, 129.65, 1.29.09, 127.99, 79.22, 52.00, 46.39, 40.86, 35.71 , 28,41 , 17,24. HRMS (ESf-TOF) Calcd for

*: 330.1676; found: 3.30.1676.

dimethyl 4₎4^*^2-(({tert-butoxycart onyi)amino)me hyf propane-1 ,3-diyl dlbenzoafe {2d, Dsary!ation)

The general procedure was followed, except that the reaction was heated to 90 °C. Mono- and di-arylation compounds were obtained as- white solids (34% mono, 33.5 mg, 38% di, 72% total yield) after purification with preparative TLG (eluent: hexane/EtOAc ~ 5/1 ), ¹H NMR (600 MHz:, CDCis) 7,97 - 7.93 (m, 4H), 7.20 (d, J - 8.0 Hz, 4H), 4.52 - 4,44 (m, 1 H), 3.90 (s, 6H), 3.08 {t, J - 6.3 Hz, 2H), 2.64 (ddd, J = 45,2, 13.9, 7.1 Hz, 4H), 2.21 {p, J = 7.0 Hz, 1 H), 1.42 (s, 9H). ¹³G NMR (151 MHz, CDC 1₃> δ 166.99, 155.98, 145.58, 129.80, 129.05, 128.21 , 79.35, 52.03, 43.59, 42.49, 38.36, 28.37. HRMS (ESi-TOF)^' Caicd for CasHaiNOeNa_. [M+Naj*: 464.2Q44; found:

methyl 4-{2«{|{feff-butoxyc3d>onyl}aminG)roethyl}butyi)benzoate (2e)

Following the general procedure, compound 2e was obtained as a white .solid (44.3 nig, 69% yield) after purification by preparative TLC (eiuent: hexane/EtOAc - 5/1 ). ^"Ή NMR (6D0 MHz, CDCI₃) δ 7.98 - 7.93 (m, 2H), 7.23 (d, J ~ 8.0 Hz, 2H), 4.50 (s, i H), ..3.90 (s, 3H), 3.09 (ddi, J. ~ 41.9, 13.5, 5.9 Hz, 2H), 2.63 (qd, J » 13,7, 7.1 Hz, 2H , 1.78 (p, J * 6.5 Hz, 1 H), 1.35 - 1.28 {m, 2H), 0.91 (i, J ~ 7.5 Hz, 3H). NMR (151 MHz, CDCk) δ 167.09, 156.04, 146.32, 129.68, 1-29.08, 127.95, 79.15, 51.99, 43.29, 41.87, 38.24, 28.40, 23.93, 10.93. HRMS (ESI-TOF) Calcd af: 344.1832; found: 344.1832.

methyi 4- -({feit--buioxycarbony!}am!no}buiyi)t)eni;oa e (2f)

The general procedure was followed, except that 50 mo % TDG4 was used. Compound 2f was obtained as a white solid (54.6 mg, 89% yield) after purification with preparative TLC (eluent: hexane/EtOAc = 5/1 ). Ή NMR (600 MHz, CDCfe) δ 7.98 - 7.92 (m, 2H), 7.25 (d, J = 8.2 Hz, 2H), 4,38 (s, H), 3,90 (s, 3H), 3.73 (d, J - 17.3 Hz, 1 H), 2.71 (id, J - 7.7, 4.8 Hz, 2H), 1.74 (dd, J = 8.7, 5.8 Hz,. 2H), 1.45 <s, 9H), 1.16 (d, J - 6.6 Hz, 3H). «C NMR ( 51 MHz, GDG ) δ 167.1 1 , 155.34, 147.51 , 129.76, 128.38, 127.86, 79,1.2, 51.97, 46,34, 38.79, 32.59, 28,43, 28.04, 21.38. HRMS (ESI-TOF) Calcd for Ci?H₂₅N0₄Na [M+Na]*: 330,1676; found: 330.1676.

methyl 4*(3«{{te^buioxycarbonyi)am§no)-3-mefhy!biityl} en203le (2g, Honoarylation) Following the general procedure, mono- and di-ary'ation compounds were obtained as white solids (10.3mg, 16% mono, 45% di, 61 % total yield) after purification with preparative TLC (eiuent: hexane/EtOAe ^» 5/1). ·Η NMR (600 MHz, CDCfe) δ 7,96 - 7.92 (m, 2H), 7.26 - 7.24 (m , 2H), 4,45 (s, 1 H), 3.90 (s, 3H), 2.67 - 2,59 (m, 2H), 1.99 (t, J ^~ 8.6 Hz, 2H),. 1.45 (s, 9H), 1.31 (s, 6H). ¹³C NMR (151 MHz, CDCfe) δ 166.69, 147.69, 129.27, 127.97, 127.26, 126.79, 78.37, 51.95, 51.50, 41.10, 30.49, 28,00, 27.01. HRMS

| +Na|⁺: 344.1832; found: 344.1825,

Following the general procedure, mono- and di-ar lation compounds were obtained as white solids (16% mono, 40-.9mg, 45% di, 61% total yield) after purification, with preparative TLC (eiuent: bexane/EtQAc= 5/1 ). H NMR (600 MHz, CDCI₃) 5 7.98 - 7.89 (m, 4H), 7.40 ~ 7.31 (m:₅ 4H), 4.26 (s, 1 H), 4.18 (t, - 6.7 Hz, 1 H), 3.88 (s, 6H), 2,59 (d, J - 6.7 Hz, 2H), 1.37 (s, 9H), 1.17 (&, 6H). ³C NMR (151 MHz, CDCfe) δ 166.86, 154.09, 150,23, 130.03, 128.27, 127.86, 127.25, 78.82, 52.80, 52.01 , 47.93, 44.23, 28.38. HRMS (ESl-TOF) Calcd for CjeHasNOeNa [M+ a]^*; 478.2200; found: 478.220 .

met l 4_^{3~((teff~buioxycarbonyl)am5riQ)-'2-p eny!propyi)ber5^oate (2h

Following the general procedure, compound 2ft was obtained as a white solid (44.3 rhg,_.60% yield) after purification by preparative TLC (eiuent: hexane EtOAc ^~ 5/1 ), H NMR (600 MHz, CDCfe) 7.85 (d, J - 7.9 Hz, 2H), 7.28 - 7.24 (m, 2H), 7.22- 7,1.8 (m, 1 H), 7.10 - 7.05 (m, 4H), 4.41 (8, 1H). 3.87 (s, 3H), 3,58 {p, J - 6.2 Hz, 1 H), 3,26 (ddd, J - 12.9, 8.4, 4.4 Hz, 1 H), 3.08 (d, J * 6.5 HZ, 1 H), ,3,03 (dd, J ~ 13.6, 6.0 Hz, 1 H), 2.90 (dd, J ~ 13,5, 8,7 Hz, 1 H), 1.39 (s, 9Ή). ⁵³C NMR { 151 MHz, CDCb) ³C NMR (151 MHz, CPCfe) δ 167.06, 155,84, 1.45.12, 141.38. 129,52, 129.06, 128.64, 127.98, 127.88, 126.93, 79.30, 51.95, 47.68, 45.51, 40.51 , 28.34. .HRMS (ES!- TOF) Ca!cd for C₂2H_2? Oa a [M+Na}⁺: 392.1832; found: 392.1832,

methyl 4-{3~f{fefi~bytoxyearbonyi)amino)-4-methoxybuty )ber^{zoate (21}

Following the general procedure, compound 2i was obtained as a white solid (34,4 mg, 51% yield) after purification by preparative TLC (eiuent: hexane/EtOAc = 5/1 ). H NM (600 MHz, CDCb) 7.95 (d, J = 8.0 Hz, 2H), 7.28 - 7.24 (m, 2H), 4.77 (d, J =^'7.8 Hz,. 1 H), 3,90 (d, J - 0.9 Hz, 3H), 3.76 {s, 1H), 3.39 (d, J 4.2 Hz, 2H), 3.33 (d, - 0.9 Hz, 3H),. 2.72 (dtd, J ~ 15.9, 14.0, 7.4 Hz, 2H), 1.93 - 175 (m, 2H), 1.45 (d, J = 0.9 Hz, 9H). ¹³C NMR (151. MHz, CDC ) 51.67.15, 155.63, 147.49, 129.75, 128.43, 127.87, 79.32, 74.54, 59.13, 51.99, 50.1 1 , 33.75, 32:58, 28.43.

sMa [M+Na]⁺: 360.1 81 ; found: 360,1781.

methyl 4^»(5^' {f6rf~but0xycarbon l}arrHno}^

benzoate (2j)

The general procedure was followed, except 8.0 eq of BocsO was used during the 80c

protection step. Compound 2j was obtained as a white soiid (41.4 mg, 46% yield) after purification by preparative TLC {eluenf: hexane/EtOAc = 5/1 ). ¹ H NMR (600 MHz, CDCb) δ 7.95 (d, J ^« 8,3 Hz, 2H), 7.22 (d, J 8.1 Hz, 2H), 4.58 (d, J = 29.1 Hz, 2H), 3.90 (s, 3H), 3.07 (t, J ~ 7,6 Hz, 4H), 2.62 (qd, J - 13.8, 7.2 Hz, -2H), 1.86 (p, J = 6.3 Hz, 1 H), 1.54 (s, 1 H), 1.43 (d, J ~ 3.3 Hz, 19H), 1.35 - 1 .23 (m, 2H). ¹³C NMR {151 MHz, CDCb) 6 167.02, 156, 19, 156.05,

145.91, 129.77, 129.04, 128.10, 79.31 , 79.07, 52.01 , 43.24, 40.54, 40.25, 38.69, 28.43., 28.29, 26.93. HRMS (ESI-TOF) Gated for C^H^OeNa j:M+Na}*: 473.2622; found: 473,2621 .

methyl 4~(4-{{ierf-butoxycarbonyl)amlF3o}butaf5~2-yiJbers2; sate (2k)

The genera! procedure was followed, except that the reaction was perforrned at 150 °C in

HF IP/HO Ac = 2/1. -solution {1.0 mL) with 30 eq. H₂0 additive (6.0 mmol). Compound 2jk was obtained as a white solid (40.5 mg, 66% yield} after purification with preparative TLC (eluent: hexane/EiOAc ~ 5/1 ). ¹ H. N MR {600 MHz, CDCi₃) δ 7.98 ~ 7.95 (m, 2H), 7.26 - 7.24 (m, 2H), 4.44 (s, 1H), 3.90 (s, 3H), 3..01 (did, J - 20.1 , 13.5, 12.6, 6.4 Hz, 2H), 2.82 (h, J ~ 7.1 Hz, 1 H), 1.84™ 1.73 (m, 2H), 1.42 (s, 9H}_» 1.28 (d, J ^«..6.-9 Hz, 3H), ¹³C R (151 MHz, CDC ) δ

167.05, 155.83, 152.14, 129.92, 128.19, 126.93, 79.18, 52.00, 39.00, 38.10, 37.76, 28.40, - for Ci:₇H₂₅N04 a [ +Naj⁺: 330.1676; found: 330.1676.

methyl 4-{1 -{{teri-butoxyGarbonyl)airs ino)ociari-3-y!)ber!Eoate (2I)

The general procedure was followed, except thai the reaction was performed at 150 °C in

HFiP/HOAc - 2/1 solution {1.0 mL) With .30 eq, H2O additive (6,0 mrnol),. Compound 21 was obtained as a white solid (31.2 mg, 43% yield) after purification with preparative TL.G (eluen hexane/EtOAc - 5/ ). H NMR (600 MHz, GDCI₃) δ 7.96 (ύ, J ~ 8.3 Hz, 2H), 7.21 (d, * 8.3 Hz, 2H), 4,42 (s, 1H), 3.90 (s, 3H), 2,93- (dtd. J ~ 19.4, 11.5, 10.2, 4.5 Hz, 2H), 2.62 (tt, J = 9.8, 5.2 Hz, H), 1.72 (ddi, 13.7, 9.6, 6.9 Hz, 1 H), .64 (ddi, J * 15.0, 10,0, 5.0. Hz, 1 H), 1.57 (qd, J = 9.5, 4.7 Hz, 1 H), 1.42 (s, 9H), -1.27 - 1.11- (m, .6H), 1.06 (dtd,. J ~ 14.8, 7.3, 4.5 Hz, 1H}, 0.84 - 0.80 (m, 3H), ¹³G NMR (151 MHz, CDCb) δ 167,09, 155.81 , 150.75, 129,85, 128.21, 127.59, 79.12, 51.99, 43.82, 39.01, 36,79, 36.57, 31.75, 28,39, 27.05, 22.48, 1 .00. HRMS {ESI-TOF} Gated

[M+NaF: 386.2302; found: 386.2302.

methyl 4~{4-((feft-buioxycarbonyS)amirso}pen an~2- J)berixoate (2m)

The general procedure was followed, except that SO mo!% TDG4 was used. Compound 2m was. obtained as a white solid (54.6 rng, 85% yield, 2.6/1 d.r.) after purification with preparative TIC (elgen hexane/EiOAc « 5/1 ). ¹H NMR (600 MHz, CDCi₃} δ 7.99 - 7,94: (m, 2H), 7.26 (del, J « 8.2, 4.7 Hz, 2H), 4.26 (dd, J ~ 18.0, 8.8 Hz, 1Ή), 3.90 (s, 3H), 3.52 (s, 1 H), 2,88 (di J - 14,0,

7.4 Hz, I N), 1.66 (td. J * 8.4. 4,4 Hz, 2H), 1.43 (s, 9H), 1 .27 (dd, 6.9, 3,8 Hz, 3H), 1.08 (d,

6.5 Hz, 3H). ¹³C NMR (151 MHz, COC ) δ 166.63, 154.56, 151 .99, 129.38, 127.63, 126.60, 126,43, 78.51 , 51.49, 45.24, 44.40, 36.50, 27.95. HR S (ESI-TOF) Calcd for C1SH27NO4 3 [M+Naf: 344.1832; found: 344.1832.

methyl 4~(3~((ierf~ utoxycarbonyi)araino}cycto ef ty!)benzoate (2n)

The general procedure was followed, except thai 50 mol% TDG4 was used. Compound 2n was obtained as a white s iid (26.1 mg, 41 % yield, single diastereonisr (cis)) after purification with preparative TIC (eluent: hexane/EtOAc = 5/1 ). ^'1 H NMR (600 MHz, CDCi₃) δ 7,96 (d, J = 8,3 Hz, 2H), 7.28 (d, J « 8.3 Hz, 2H), 4.62 (s, 1 H), 4.10 (s, 1Ή), 3.90 (s, 3H), 3.12 (ddd, J = 17.4, 10,3, 7.5 Hz, 1 H), 2.53 (dt, J - 13,2, .6.9 Hz, 1 H), 2.21 - 2.07 (m, 2H},_: 1.76 (did, J == 12.8, .9.9, 9,4, 6.9 Hz, 1H), 1.66 - 1 ,59 {m, 1Ή), 1.45 {s, 9H). ^1¾C NMR (151 MHz, CDCfe) δ 166.58, 155,01 , 150.1 5, 129.29, 127,55, 126,48, 78.80, 51.54, 43.36, 41.26, 32,45, 31 ,38, 27.97. HRMS (ESI- TOF) Caicd for GieHisNC Na [M+Na]⁺: 342.1676; found; 342.1676. The stereochemistry was determined by 2D NOE analysis.

me l 4-(3-{(feri^»butoxycar onyl}aniino)cyefooctyi)benzoate (2o, Monoaryfatron)

Following the genera! procedure, mono- and di-arylatson compounds were obtained as white solids (23.8m^'g, 33% mono, 43% d^'t, 76% iota! yield) after purification with preparative TIC _.{eiuen Hexane/EtOAc =-6/1 ). ¹H NMR (600 MHz, CDCi₃) δ 7.94 (d, J ~ 8.3 Hz, 2R), 7.24 (d, J = 8.3 Hz, 2H), 4.50 (s, 1H), 3.90 (s, 3H), 3.83 (s, 1 H), 2.91 (s, 1H), 2.00 ~ 1.91 (m, 3H), 1.90 ~ 1.74 (m, 3H), 1.65 (td, J = 14.7,. 11.8, 8.1 Hz, 6H), 1.41 {$, 9H), "C NMR (151 MHz, CDC!s) δ 167.11 , 154.95, 154.81 , 129.84, 127.72, 126.81 , 79.10, 51.96, 50.71 , 44.02, 41.42, 35.09, 33.35, 28.44, 26.95, 24.32, 22.43. HRMS (ESI-TOF) Cased for C¾H₃iN:0«Na [M+Na :

384.2145; found: 384,2144. The stereochemistry' was determined by 2D NQE analysis.

dimethyl 4,4V{3-{{ferf^utoxy ar onyl}amm (2o,

Diaryiation).

Following the genera! procedure, mono- and di-ary!ation compounds were obtained as white solids (33% mono, 42.6mg, 43% di, 76% total yse!d) after purification with preparative TLC

(eiuent: hexane/ElOAc = 5/1). ^"H NMR. (600 MHz, CDCI₃) 6 7.99 - 7,94 (m, 4H), 7.30 » 7.24 (m, 4H), 4.54 (s, 1 H), 3.90 (s, 6H), 3.79 (d, J - 31.2 Hz, 1 H), 3.12 {«, 2H}, 2.15 - 1.86 (m, 8H), 1.77 <qd, J ~ 10,6, 9.9, 4.5 Hz, 2H), 1.36 (s, 9H}.. ¹³C NMR (151 MHz, CDCI₃) δ 167.04, 154.62, 154.51 , 129.94, 127.88, 126.85, 79,25, 52.00, 42.73, 42.16, 35.77, 28.37, 23.37. HRMS (ESI- TOF) Calcd for 02eH₃?NOsNa M+ a]⁺: 518.2513; found: 518.2513, The stereochemistry was- determined by 2D NOE analysis. Large Scale Reaction with the Production of Free Aryiateti Amine

methyl 4-{3-amsnocyciohe¾y§)benzoate (2p)

The general procedure for setting up the reaction was followed. After the reaction, the mixture was cooled to room temperature, filtered through Celite and mixed with 11V1 aqueous HCi {2,0 ml.}. After being stirred at room temperature for 30 min, the mixture was transferred to a separate funnel and the organic phase was discarded. The water phase was washed with

CH₂Ci2 (5,0 ml), basified by 4M aqueous NaOH until pH > 12 and extracted with CH₂Ci₂ (4 * 15,0 ml). The combined organic phase was dried over ajSO* and concentrated in Vacuo to obtain the pure product without any further purification as a pale yellow oil (.284.3mg, 61% yield). ¹M N R (600 MHz, CDQfe) δ 7.99 - 7.93 (m, 2H), 7.28 - 7.23 (m, 2H), 3.89 (s, 3H), 2.81 (it, J - 11.1 , 3,9 H2..-1 H), 2.64 (it, J = 12.2, 3.4 Hz, 1 H), 2.02 (dtt, J = 14.2, 3.8, 1.6 Ηζ, 1 Η)> 1,9.7 - 1.91 (m, 1H), 1.89 (dp, J ~ 13,2, 3.3 Hz, 1 H), 1 ,84 (dddd, J ~ 14.5, 5.1 , 3,3, 1.7 Hz, 1 H), ,46 (qt, J = 13,1 , 3.4 Hz, 2H), 1.35 (id, J 12.6, 3.5 Hz, 1 H), 1.27 (td, J = 12.3, 11 ,0 Hz, 1 H), 1 ,10 (tdd, J - 12.8, 11.2, 3.7 Hz, 1 H). '¾ NMR (151 MHz, C-DCI5) 5 166,62, 151.69, 129.30, 127.49, 126,36, 51.49, 50.34, 43.70, .42.97, 35.76, 32.77, 24,76. HRMS (ESi-TOF) Caicd for

Ci₄Hi₉ 0₂ a [M+Naf: 256.1313; found; 256,1314.

2.4 Synthesis of 1 ,2,3,4-tetrahydronaphthyfsdine

3-ethyi-1 ,2,3,4-tetrahydro-l ,8~n8pMhyrsd»ne ( q)

Following the general procedure before Boc protection workup, 1 ,2,3,4-tetmhydronaphthyridlne was obtained as a; brown .solid (22.7mg, 70%) after purification with preparative TLC (eiuent: hexane/EtQAc ^» 1/1 ). W MR (600 MHz, CDQfe) δ 7,72 - 7.66 (m, 1H), 7,19 (dq, ~ 7.2, 1.3_: Hz, 1H), 7.08· (s, 1H), 6.44 (dd, J = 7.1 , 5.5 Hz, 1 H),. 3.48 (did, J = 11 ,9, 3.8, 2.0 Hz, 1H), 3.03 (dd, J - 11.9, 9.4 Hz, 1H), 2.78 (ddd, J ~ 15,9, 4.5. 2.0 Hz, 1H), 2.39 (ddt, ~ 15.9, 10.3, 1,2 Hz, 1H), 1.77 (tdt, J * 14,0, 6.8, 4.2 Hz, 1H), 1.38 (dq, J - 14..3, 7.3 Hz; 2H), 0.98 (t, J 7; 5 Hz, 3H). ¹³C MR (151 MHz, CDCIs) 5 55.35, 44.01 , 136.90, 1 17.6.1 , 1 1 1.21 , 45,71 32:46, 3 .99, 25,46, 10.99. HRMS (ESi-TOF) Calcd for Ci_DHi₄N₂Na [M+Naf: 185.1049; found: 185,1049.

C-H ^' Heteroarylation

To a long 20 m\ reaction tube charged with -a magnetic stirring bar was added Pd(OAe)2 (2.3 mg, 0,01 mrnol), 2-ch!oro-6-bydroxyben2aidehyde (3.1 mg, 0.02 mm !), pyndone (8,1 mg, 0.05 mmoi), AgGTFA (86.3 mg, 0.3 mmoi), Heteroaryi iodide (0.2. mmgl), cyciohexylamine (1 .5 uL, 0.1 mmoi) and H2Q (18 uL), The tube was well sealed and stirred at room temperature for 5 mine before moving to a 150 °C heating plate. After 12h, the reaction was coo ed to room temperature and EtO^'H (2,0 ml) was added. The mixture was filtered through a pad of Celit (3 cm) and washed with EtOH (1,0 mL * 3). The filtrates were combined and evaporated under vacuum.

Boc Protection

The residue was dissolved in THF (1.0 mL) and HCI_taci,) (2N, 0.5 mL) was added. The brown mixture was stirred at room temperature for 1 h, NapH(_$a.) (10 , 0,2 ml) was slowly added to the mixture under an ice-water bath. Then di-feri-butoxycarbonyl anhydride Βο¾0 (0.1 mL)_. was added. The mixture was allowed to warm up to room temperature and stirred overnight. Ethyl acetate (1 ,0 mL) was added and the top layer (organic layer) was taken and passed through a plug of silica (3 cm). Ethyl acetate (2,0 mL ^χ 3) was used to extract the remaining aqueous layer and washed through the above silica. The filtrate was combined and evaporated to afford the crude Boc protected amine. The residue was applied to column chromatography to get the pure compound.

Claims

What is claimed is:

1. A method for Pd( ii)-catalyzed g~C(sp )-H aryiation or heieroaryiaiion of a primary amine having a y-hydrogen atom, using an effective amount of a catalytic transient directing group of formula TDG

wherein Y is N or CX4; and

Xi , , X-3, and X each Independently is aikyi, aryi, haloalkyi, alkyiamino, or alkoxyl; or wherein any single pair of i and Xa, of Xa and X3, and of X3 and X4 when present, -together with the ring to which they are bonded, forms a fused 5-, 6-,· or 7-membered cycioa!kyi ring;

the method comprising contacting a primary amino compound of formula (!)

wherein i R₂ , R3, and R¾ each independently is hydrogen or aikyi, or wherein f¾ and i¾ together with the atoms to which they are bonded form a cycloalkyl,

and an aryl iodide (Ari) or a heteroaryi iodide (HetAr!), respectively, which can be un substituted or can be substituted with one or more independently selected aryi, aikyi, halo, nitro, haloalkyl, alkoxyl, aikoxycar on^'yl, or carboxaldebyde groups;

in a reaction milieu comprising the presence of an effective amount- of pa!iadiuro(il) acetate, Pd{l i)(OAc)2, and in the presence of an effective amount of transient directing group TDG, to provide a product of formula (it)

wherein: AH Signifies an aryl o a heteroaryi group.

2. The method of claim 1 , wherein the compound_. of formula (Π) is further -protected with a t-butoxyparbonyf (tBoc) _.group, by contacting the compound of formula (If) and t~

bytoxyearbohylanhydride, to give a compound of formula (Hi)

3. The method of claim 1 , wherein TDG is 2~hydroxynicotinaidehyc e (TDG4).

4. The method, of claim 1,. wherein the primary amino compound of formula (I.) is contacted with an ary! iodide and group AH in the compound of formula (If) is aryt.

5. The method of claim 4, wherein the reaction milieu further comprises silver

trrfluoroacetate.

6. The method of claim 2, wherein group AH in the compound of formula (ill) is ary!.

7. The method of claim: 1 , wherein the primar amino compound of formula (!) is contacted with a heferoaryl iodide and group AH in the compound of formula. (II) is heteraaryl

8. The method of claim 7 wherein the reaction milieu further comprises silver

trif!uoroacetate or pyridone, or both.

9. The method of claim 2, wherein group AH in the compound of formula (III) is. heferoaryl.

The method of claim 6 wherein the compound of formula (Hi) is any one of

The method of claim 9, wherein the compound of formula (IS) is any one of

fo₉,43%^c 2b₁₀, 42%^c 2b , 44%° 2h₁₂, 60%