General and cost-effective synthesis of 1-heteroaryl/arylcycloalkylamines and their broad applications

Article abstract of DOI:10.1016/j.tet.2016.02.060

A general and cost-effective route has been developed to synthesize 1-heteroarylsubstituted cycloalkylamines from readily available heteroarylacetate in good yields. This synthesis features a LHMDS promoted cyclization and one-pot hydrolysis/Curtius rearr

Full text of DOI:10.1016/j.tet.2016.02.060

Accepted Manuscript
General and Cost-effective Synthesis of 1-Heteroaryl/arylcycloalkylamines and Their
Broad Applications
Dehui Zhang, Hongchao Zheng, Xiaodong Wang
PII:
S0040-4020(16)30122-3
10.1016/j.tet.2016.02.060
TET 27530
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 22 January 2016
Revised Date: 24 February 2016
Accepted Date: 25 February 2016
Please cite this article as: Zhang D, Zheng H, Wang X, General and Cost-effective Synthesis of 1-
Heteroaryl/arylcycloalkylamines and Their Broad Applications, Tetrahedron (2016), doi: 10.1016/
j.tet.2016.02.060.
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ACCEPTED MANUSCRIPT
Graphical Abstract
General and Cost-effective Synthesis of 1-
Heteroaryl/arylcycloalkyl-amines and Their
Broad Applications
Dehui Zhang, Hongchao Zheng and Xiaodong Wang*
Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina at Chapel Hill

ACCEPTED MANUSCRIPT
General and Cost-effective Synthesis of 1-
Heteroaryl/arylcycloalkylamines and Their Broad Applications
Dehui Zhang, Hongchao Zheng and Xiaodong Wang*
Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry,
Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
xiaodonw@unc.edu
ABSTRACT: A general and cost-effective route has been developed to synthesize 1-
heteroarylsubstituted cycloalkylamines from readily available heteroarylacetate in good yields. This
synthesis features a LHMDS promoted cyclization and one-pot hydrolysis/Curtius rearrangement. This
route can be easily carried out on multi-gram scale and be also used to prepare 1-arylsubstituted cyclo-
alkyl/cycloheteroalkylamines. 1-Heteroaryl/arylsubstituted cycloalkyl/cycloheteroalkylamines are ver-
satile building blocks and their applications in organic and medicinal chemistry have been demonstrated
in the synthesis of morpholine and N-methylpiperazine analogues and a known Rho kinase inhibitor
compound 9.
Keywords: pyridinylcycloalkyl amines, arylcycloalkyl amines, cyclization, quaternary carbon center,
one-pot hydrolysis/Curtius rearrangement
INTRODUCTION
Cycloalkyl rings are a fundamental building block in organic chemistry and key scaffold components in
medicinal chemistry.1 They permit exploration of molecular properties such as lipophilicity and confor-
mational constraint and can display substituents in multiple, dynamic orientations which can influence

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activity in bioassays, metabolic stability, and toxicity.2 1-Heteroaryl/arylcycloalkylamines are one of the
useful building blocks to introduce ring systems into final target molecules. However, their syntheses
can be challenging. So far, the most common synthetic route for 1-arylcycloalkylamines is from the cor-
responding acids, which are usually derived from their acetonitrile precursors.3-5 Due to the high toxicity
of the cyano starting material, such as NaCN, used to prepare these acetonitrile precursors, the applica-
tion of this method has been restricted in many aspects.6 Another method starts with 1-arylcycloalkanol.
After converting the alcohol to the azide by treatment with sodium azide in the presence of trifluoroace-
tic acid, a Raney-Nickel reduction provides the corresponding 1-arylcycloalkylamines.7 Since the start-
ing material 1-arylcycloalkanol is not readily available, especially for 1-heteroarylcycloalkanol, and the
hydrazoic acid generated in the reaction is explosive, this method has not been used broadly. A novel
methodology to prepare 1-arylcycloalkylamines from aromatic nitriles mediated by MeTi(Oi-Pr)3 or
Ti(Oi-Pr)4 was reported a few years ago8-9 in which the ring size of the cycloalkyl group is derived from
the Grignard reagents used in the reaction.9 This methodology is useful; however, the reaction is sensi-
tive to air and moisture due to the reactivity of Grignard reagents and has not been applied to heteroar-
omatic nitriles. Recently, we have discovered a general and cost-effective way to prepare 1-
pyridinylcycloalkyl amines from 2-pyridinylacetate. In this paper, we will demonstrate the scope of this
methodology and the wide application of the resulting products, 1-pyridinylcycloalkyl amines.
RESULTS AND DISCUSSION
As mentioned above, 1-pyridinylcycloalkyl amines are examples of heteroarylcycloalkylamines that are
versatile building blocks but are not commercially available. There is also no convenient and flexible
synthetic method available to enable their preparation. We decided to use compound 1a shown in
Scheme 1 as an example to explore possible synthetic routes. We reasoned that if we could obtain com-
pound 2a, Curtius rearrangement of 2a would yield the desired 1a. Compound 2a could possibly be syn-
thesized by a cyclization reaction via a double nucleophilic replacement of 1,4-dihalobutane by methyl
2

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2-(6-chloropyridin-3-yl)acetate in the presence of a base. The starting material methyl 2-(6-
chloropyridin-3-yl)acetate is readily available and inexpensive. In addition, the reactions proposed in the
sequence could be easily scaled up to multi-gram quantity.
Scheme 1. Retrosynthesis of compound 1a.
As a proof of concept, methyl 2-(6-chloropyridin-3-yl)acetate and 1,4-dibromobutane were used to test
the double nucleophilic replacement reaction10. After screening different reaction conditions, we found
this reaction went smoothly using lithium hexamethyldisilazide (LHMDS) as a base and THF as a sol-
vent at room temperature. Only trace amounts of the desired product 2a were formed if the commonly
used bases such as sodium hydroxide or sodium hydride were employed, even at elevated temperature
o
(100 C). The desired product 2a was obtained in good yield (64%) when methyl 2-(6-chloropyridin-3-
yl)acetate and 1, 4-dibromobutane were pre-mixed before the addition of LHMDS in two portions with
an interval of 6 hr. It is also worthwhile to note that dibromoalkanes instead of bromochloro-substituted
alkanes can be used for the reaction, which lowers the cost of the reagents and permits the reaction to
progress under milder reaction conditions.11
This reaction serves as a convenient way to form a quaternary carbon center with a five-membered ring
adjacent to a 2-pyridinyl group. To test how general this method is for preparation of other sized rings,
the scope of this reaction was explored under the optimized reaction conditions (Table 1).
Table 1. Cyclization Reactions
Ar
R
n Product Structure of 2 Yield (%)
3

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Me 3
63
2a
Me 1
Me 2
30
49
2b
2c
Me 4
Me 5
2d
2e
75
10
Bu 1
Bu 2
36a
69a
2f
2g
Bu 3
Bu 4
72
63
2h
2i
Me 3
Me 3
53a
63a
2j
2k
4

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Me 3
Me 3
Me 3
Me 5
81
2l
2m
2n
2o
72
40
51b
a
b
Isolated yield for two steps (cyclization and hydrolysis of the corresponding ester). 1-Bromo-2-(2-
bromoethoxy)ethane was used as a reagent.
As shown in Table 1, this method is general and can be used to install a quaternary carbon center con-
taining three, four, five, six, or seven-membered cycloalkyl or cycloheteroalkyl group adjacent to a het-
eroaryl or aryl group. The efficiency of this reaction is consistent with the expectation that five- and six-
membered rings are favored; and thus, compounds 2a, 2d, 2h and 2i were obtained in high yields. The
formation of three- (2b, 2f) and seven-membered rings (2e) under this reaction condition were less effi-
cient with 10-30% yields while the yields for forming four-membered rings (2c, 2g5) were moderate.
For 1-phenylsubstituted cycloalkylesters (compound 2f-2i), butyl esters were the preferred starting ma-
terials since they had a higher boiling point and were easily prepared. However, for compounds 2f and
2g, it was difficult to purify the products after the double nucleophilic replacement. Therefore, the free
acids were isolated instead after hydrolysis of the corresponding butyl esters by the treatment with sodi-
um hydroxide in methanol. 1-Alkylsubstituted cycloalkylcarboxylic acids are also valuable intermedi-
ates for further modification. A small substituent on the aryl group at meta- or orth- position such as me-
thyl group was well tolerated for this reaction to provide the desired products 2j and 2k with compara-
ble yields. Similarly, both 2j and 2k were isolated as free acids after the hydrolysis step due to the con-
tamination of some impurities in the corresponding esters after column chromatography purification.
5

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This reaction could also be applied to substrates containing other heterocycles at the 1-position, for ex-
ample, 3-pridinyl group (2l), 4-pyridinyl group (2m), and 2-thiazolyl group (2n). Furthermore, this reac-
tion could introduce not only the different-sized ring but also different type of the ring. For example, 4-
tetrahydropyran ring could be formed to yield the desired compound 2o in good yield.
Next, we tested how well Curtius rearrangement of the free acid would work to introduce an amino
group at the quaternary center. For compounds 2a-2e, 2h, 2i, 2l, 2m and 2o, the ester was hydrolyzed by
treatment with a 6.0 N NaOH solution in methanol to provide 1-arylsubstituted cycloal-
kyl/cycloheteroalkylcarboxylic acids in quantitive yields. Directly converting the carboxylic acids to the
corresponding amines under the commonly used Curtius rearrangement conditions (in toluene)12 only
produced the corresponding urea. Gratifyingly, the treatment of the acids with DPPA in dry t-BuOH and
in the presence of molecular sieves yielded the desired Boc-protected 1-arylsubstituted cycloal-
kyl/cycloheteroalkylamines (Table 2).
Table 2. Curtius rearrangement reactions.
Ar
R
n Product Structure of 3 Yield
By-
Structure of 4
Yield
(%)
(%)
Product
Me 3
Me 1
51
78
30
-
3a
3b
4a
-
-
6

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Me 2
Me 4
69
-
-
-
3c
27
58
3d
4d
Me 5
-
-
44
-
4e
H
H
1
2
83
85
-
-
-
-
-
-
3f
3g
Bu 3
Bu 4
49
-
31
80
3h
-
4h
4i
-
-
H
H
3
3
-
72
69
3j
3k
3l
4j
4k
4l
10
67
71
Me 3
Me 3
trace
trace
3m
4m
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Me 3
Me 4
90
-
-
-
-
3n
3o
4n
66
4o
Curtius rearrangement efficiency varies depending on the ring size of the cycloalkyl group due to the
steric effect. The larger ring of the cycloalkyl group shields the isocyanate group more efficiently from
the attack of nucleophiles. For example, in Table 2, for compounds bearing a cyclopropyl or cyclobutyl
ring, Boc-protected amines 3b, 3c, 3f,13 and 3g were the only products after the reaction. However, for
compounds having a cyclopentyl or cyclohexyl group, the corresponding isocyanates 4a, 4h, and 4d and
carbamoyl azide 4k were also isolated as byproducts. For 2e and 2i, isocyanides 4e and 4i were the only
products after the Curtius rearrangement while for 2j, carbamoyl azide 4j was the only product. These
isocyanides could be quantitatively converted to Boc-protected amines by heating at 150 °C for 6 hr in a
sealed tube using dry t-BuOH as a solvent and in the presence of 4 Å molecule sieves. Alternatively,
these isocyanates could be used as versatile building blocks for other transformations, such as chiral
urea formation (5) via a reaction between 4i with (S)-1-phenylethan-1-amine, as shown in Scheme 2.
However, for 2n, the decarboxylated product 3n was the only product under the Curtius rearrangement
condition. Interestingly, the Boc-protected amine 3o with a 4-tetrahydropyran ring at the quaternary cen-
ter was the only product while the stable isocyanate 4i was the only isolated product with a cyclohexyl
group at the same position under the same reaction condition.
Scheme 2. Synthesis of chiral urea analogue.
8

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The Boc protecting group could be removed by treatment with a 3.0 N HCl solution in MeOH at room
temperature to yield the desired compound 1 while the removal of the carbamoyl azide group required
concentrated HCl solution and higher reaction temperature (reflux in MeOH). As shown in Table 3, the
1-heteroaryl/1-arylsubstituted cycloalkyl/cycloheteroalkylamines were obtained in moderate to high
yields.
Table 3. Synthesis of 1-arylsubstitutedcycloalkyl amine 1
Ar
R
n Product Structure of 1 Yield (%)
Boc
3
98
1a
Boc
Boc
1
2
66
64
1b
1c
Boc
Boc
Boc
4
5
1
81
40
82
1d
1e
1f
9

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Boc
Boc
Boc
2
3
4
83
1g
1h
1i
76
71
NH(CO)N3
NH(CO)N3
Boc
3
3
3
3
4
72
77
99
97
99
1j
1k
1l
Boc
1m
1o
Boc
Most of 1-heteroaryl/arylsubstituted cycloalkyl/cycloheteroalkylamines have two functional groups, the
amino group and the halo atom on the aromatic/heteroaromatic ring, which could be further trans-
formed. Initially, we investigated the reactivity of the amino group. As shown in Scheme 3, a morpho-
line ring could be introduced in high yield by treating compound 1 with 1-bromo-2-(2-
bromoethoxy)ethane in the presence of DIPEA in a sealed tube; while the precedented reaction condi-
tions using K2CO3 as a base were not successful.14 However, neither of these reaction conditions were
able to introduce a piperazine or N-methylpiperazine ring into the molecule with bis(2-
10

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bromoethyl)amine, tert-butyl bis(2-bromoethyl)carbamate, or 2-bromo-N-(2-bromoethyl)-N-
methylethan-1-amine as starting materials. An alternative three-step reaction sequence (alkylation, me-
sylation and ring-closure) was used instead, as depicted in Scheme 3.
Scheme 3. Further transformation of 1.
As shown in Table 4, the ring size at the center did not affect the reaction to introduce a morpholine
ring; compounds 6a─6i were obtained in high yields. However, it played an important role in the reac-
tion to introduce a N-methylpiperazine ring; compounds 7b and 7d having the smallest cyclopropyl ring
were prepared with the highest yields while the yield was decreased for larger rings (comparing 7a, 7b
and 7c; 7d and 7e). For 6- and 7-membered ring, there was no reaction under the same reaction condi-
tion, probably due to the steric effect.
Table 4. Further transformation of 1
Ar
n Product Structure of product Yield (%)
3
6a
81
1
2
85
80
6b
6c
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4
5
93
6d
6e
86
1
2
6f
88
91
6g
3
4
83
80
6h
6i
3
31
7a
1
2
60
51
7b
7c
1
2
63
30
7d
7e
12

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In addition, the reactivity of the halo atom on the aromatic ring was explored. Compound 9 in Scheme 4
is a known Rho kinase inhibitor and Rho kinase is associated with cell migration.15 Blockade of Rho
kinase signaling has the potential to prevent cancer metastasis.16-17 Suzuki reaction between a readily
available boronic ester 8 with compound 1a proceeded smoothly under the normal reaction conditions18
and yielded compound 9 in 61% yield.
Scheme 4. The synthesis of Rho kinase inhibitor 9.
CONCLUSION We have developed a general and practical route to synthesize 1-
heteroaryl/arylsubstituted cycloalkyl/cycloheteroalkylamines from readily available heteroar-
yl/arylacetate, featuring a LHMDS promoted cyclization and one-pot hydrolysis/Curtius rearrangement.
A series of 1-pyridinylsubstituted and 1-phenylsubstituted cycloalkylamines were prepared efficiently.
The intermediates such as 1-heteroaryl/arylsubstituted cycloalkylcarboxylic acid, 1-
heteroaryl/arylsubstituted cycloalkylisocyanates hold great promise as versatile building blocks. Moreo-
ver, we have demonstrated further application of 1-heteroaryl/arylsubstituted cycloalkylamines as useful
building blocks for preparation of morpholine and N-methylpiperazine analogues and in the Suzuki
coupling reaction.
EXPERIMENTAL PROCEDURES
General Experimental Methods All reagents were commercially available and used without any fur-
ther purification. Microwave reactions were carried out using a Discover-S reactor with a vertically-
focused IR external temperature sensor and an Explorer 72 autosampler. The dynamic mode was used
to set up the desired temperature and hold time with the following fixed parameters: Prestirring, 1 min;
Pressure, 200 psi; Power, 200 W; PowerMax, off; Stirring, high. Flash chromatography was carried out
13

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on pre-packed silica gel disposable columns. A gradient from 0% to 100% ethyl acetate (100% to 0%
hexane) for nonpolar compounds and 20% methanol (100% to 80% CH2Cl2) for polar compounds were
used as elutes. Analytical thin-layer chromatography (TLC) was performed with silica gel 60 F254, 0.25
mm pre-coated TLC plates. TLC plates were visualized using UV254 or phosphomolybdic acid with
charring. All 1H NMR spectra were obtained with a 400 MHz spectrometer and 13C NMR spectra were
obtained with a 100 MHz spectrometer. MS was performed using an analytical instrument with the UV
detector set to 220 nm, 254 nm, and 280 nm, and a single quadrupole mass spectrometer using elec-
trospray ionization (ESI) source. Samples were injected (2 ꢀL) onto a 4.6 x 50 mm, 1.8 ꢀM, C18 col-
umn at room temperature. A linear gradient from 10% to 100% B (MeOH + 0.1% acetic acid) in 5.0
min was followed by pumping 100% B for another 2 or 4 minutes with A being H2O + 0.1% acetic acid.
The flow rate was 1.0 mL/min. High-resolution mass spectra were obtained using a liquid chromatog-
raphy-electrospray ionization and time-of-flight mass spectrometer.
Methyl 1-(6-chloropyridin-3-yl)cyclopentane-1-carboxylate (2a) (Procedure A): To a solution of
1,4-dibromobutane (4.88 g, 22.5 mmol) and methyl 2-(6-chloropyridin-3-yl)acetate (2.79 g, 15.0 mmol)
in THF (150 mL) was added a 1.0 M solution of LHMDS in THF (18.8 mL, 18.8 mmol) dropwisely at 0
oC. The reaction mixture was stirred at rt for 2.0 h, then was added a 1.0 M solution of LHMDS in THF
(18.8 mL, 18.8 mmol) slowly at rt. The reaction mixture was stirred at rt overnight, quenched with
brine, and extracted with ethyl acetate (30 mL, 3×). The combined organic layers were dried (MgSO4)
and concentrated under reduced pressure. The resulting residue was purified by column chromatography
with pre-packed silica gel disposable column to afford the title compound 2a (2.26 g, 63%) as a white
solid. mp: 47.8-49.0 oC. 1H NMR (400 MHz, CDCl3): δ 8.34 (d, J = 4.0 Hz, 1H), 7.60 (dd, J1 = 4.0 Hz,
J2 = 8.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 3.58 (s, 3H), 2.65-2.60 (m, 2H), 1.87-1.80 (m, 2H), 1.72-1.68
(m, 4H). 13C NMR (100 MHz, CDCl3): δ 175.1, 149.7, 148.3 (CH), 137.8, 137.6 (CH), 123.7 (CH), 56.8
(CH3), 52.6, 36.0 (2 × CH2), 23.4 (2 × CH2). HRMS (ESI) m/z: calcd for C12H15ClNO2: 240.0786
[M+H]+; found: 240.0789.
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Methyl 1-(6-chloropyridin-3-yl)cyclopropanecarboxylate (2b): The title compound (0.32 g, 30%)
1
was prepared according to the general procedure A as a colorless oil. H NMR (400 MHz, CDCl3): δ
8.33 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 3.62 (s, 3H), 1.66 (dd, J1 = 4.0 Hz, J2 =
8.0 Hz, 1H), 1.17 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 173.6, 151.5 (CH),
150.1, 141.0 (CH), 134.2, 123.7 (CH), 52.6 (CH3), 26.0, 16.3 (2 × CH2). HRMS (ESI) m/z: calcd for
C10H11ClNO2: 212.0473[M+H]+; found: 212.0479.
Methyl 1-(6-chloropyridin-3-yl)cyclobutanecarboxylate (2c): The title compound (0.55 g, 49%) was
prepared according to the general procedure A as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 8.28 (d,
J = 4.0 Hz, 1H), 7.53 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 3.63 (s, 3H), 2.89-2.80
13
(m, 2H), 2.50-2.42 (m, 2H), 2.15-2.05 (m, 1H), 1.95-1.84 (m, 1H). C NMR (100 MHz, CDCl3): δ
175.0, 149.7, 148.0 (CH), 138.1 (CH), 137.0, 123.8 (CH), 52.6 (CH3), 50.0, 32.1 (2 × CH2), 16.9 (CH2).
HRMS (ESI) m/z: calcd for C11H13ClNO2: 226.0629 [M+H]+; found: 226.0634.
Methyl 1-(6-chloropyridin-3-yl)cyclohexanecarboxylate (2d): The title compound (0.95 g, 75%) was
prepared according to the general procedure A as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 8.41 (d,
J = 4.0 Hz, 1H), 7.66 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 3.65 (s, 3H), 2.46 (d, J
= 12.0 Hz, 2H), 1.78-1.57 (m, 5H), 1.54-1.41 (m, 2H), 1.34-1.23 (m, 2H), 1.35-1.24 (m, 1H). 13C NMR
(100 MHz, CDCl3): δ 174.5, 149.9, 147.9 (CH), 138.0, 136.8 (CH), 123.9 (CH), 52.3 (CH3), 49.2, 34.2
(2 × CH2), 25.2 (2 × CH2), 23.2 (CH2). HRMS (ESI) m/z: calcd for C13H17ClNO2: 254.0942 [M+H]+;
found: 254.0947.
Methyl 1-(6-chloropyridin-3-yl)cycloheptanecarboxylate (2e): The title compound (0.13 g, 10%) was
prepared according to the general procedure A as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.31
(d, J = 4.0 Hz, 1H), 7.54 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 3.61 (s, 3H), 2.42-
2.34 (m, 2H), 2.03-1.95 (m, 2H), 2.64-1.46 (m, 8H). 13C NMR (100 MHz, CDCl3): δ 175.8, 149.5,
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147.8 (CH), 139.4, 136.8 (CH), 123.8 (CH), 52.6 (CH3), 52.3, 36.6 (2 × CH2), 29.2 (2 × CH2), 23.5 (2 ×
CH2). HRMS (ESI) m/z: calcd for C14H19ClNO2: 268.1099 [M+H]+; found: 268.1104.
1-(4-Bromophenyl)cyclopropane-1-carboxylic acid (2f): (Procedure B): To a solution of 1-bromo-2-
(2-bromoethoxy)ethane (1.3 g, 0.76 mL, 6.0 mmol) and 2-(6-chloropyridin-3-yl)acetate (686 mg, 4.0
mmol) in THF (40 mL)was added a 1.0 M solution of LHMDS in THF (5.0 mL, 5.0 mmol) dropwisely
at 0 oC. The reaction mixture was stirred at rt for 2.0 h, then was added a 1.0 M solution of LHMDS in
THF (5.0 mL, 5.0 mmol) slowly at rt. The reaction mixture was stirred at rt for 2 d, quenched with
brine, and extracted with ethyl acetate (30 mL, 3×). The combined organic layers were dried (MgSO4)
and concentrated under reduced pressure. The resulting residue was purified by column chromatography
with pre-packed silica gel disposable column to afford the desired ester with some impurities. A solution
of this ester in MeOH (1.0 mL) was added a 10.0 N solution of sodium hydroxide (2.0 mL, 20.0 mmol).
The reaction mixture was heated under reflux for 2 d. After cooling down to room temperature, the re-
sulting solution was washed with Et2O (10 mL, 3×). The aqueous layer was adjusted to pH 1.0 by add-
ing a 12 N HCl solution dropwisely. The resulting aqueous layer was extracted with Et2O (10 mL, 3×).
The combined organic layers were dried (Na2SO4) and concentrated to afford the title compound (0.43
g, 51%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.43 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz,
13
2H), 1.68 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 2H), 1.24 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 2H). C NMR (100
MHz, CDCl3): δ 180.5, 137.7, 132.2 (2 × CH), 131.4 (2 × CH), 121.5, 28.3, 17.4 (2 × CH2). HRMS
(ESI) m/z: calcd for C10H10BrO2: 240.9859 [M+H]+; found: 240.9859.
1-(4-Bromophenyl)cyclobutane-1-carboxylic acid (2g): The title compound (0.88 g, 69%) was pre-
o
1
pared according to the general procedure B as a white solid. mp: 113.6-114.6 C. H NMR (400 MHz,
CD3OD): δ 7.46 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 3.65 (s, 3H), 2.84-2.77 (m, 2H), 2.49-2.42
(m, 2H), 2.05-1.98 (m, 1H), 1.96-1.89 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 177.7, 143.3, 130.9 (2 ×
CH), 127.9 (2 × CH), 119.9, 51.9, 31.9 (2 × CH2), 15.9 (CH2). MS (ESI) m/z: calcd for C11H12BrO2:
255.0 [M+H]+; found: 255.0.
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Butyl 1-(4-bromophenyl)cyclopentanecarboxylate (2h): The title compound (1.2 g, 72%) was pre-
o
1
pared according to the general procedure A as a white solid. mp: 56.2-57.0 C. H NMR (400 MHz,
CDCl3): δ 7.40 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 3.99 (t, J = 8.0 Hz, 2H), 2.64-2.58 (m, 2H),
1.85-1.80 (m, 2H), 1.72-1.69 (m, 4H), 1.52-1.45 (m, 2H), 1.26-1.20 (m, 2H), 0.84 (t, J = 8.0 Hz, 3H).
13C NMR (100 MHz, CDCl3): δ 175.4, 142.5, 131.2 (2 × CH), 128.7 (2 × CH), 120.6, 64.8 (CH2), 58.8,
36.0 (2 × CH2), 30.5 (CH2), 23.5 (2 × CH2), 19.0 (CH2), 13.6 (CH3). HRMS (ESI) m/z: calcd for
C16H22BrO2: 325.0798 [M+H]+; found: 325.0796.
Butyl 1-(4-bromophenyl)cyclohexanecarboxylate (2i): The title compound (1.1 g, 63%) was prepared
1
according to the general procedure A as a colorless oil. H NMR (400 MHz, CDCl3): δ 7.43 (d, J = 8
Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 4.03 (t, J = 8.0 Hz, 2H), 2.45 (d, J = 12.0 Hz, 2H), 1.73-1.60 (m, 5H),
13
1.57-1.40 (m, 4H), 1.32-1.20 (m, 3H), 0.86 (t, J = 8.0 Hz, 3H). C NMR (100 MHz, CDCl3): δ 174.7,
143.0, 131.4 (2 × CH), 127.8 (2 × CH), 120.7, 64.6 (CH2), 50.5, 34.5 (2 × CH2), 30.5 (CH2), 25.5 (CH2),
23.5 (2 × CH2), 19.1 (CH2), 13.6 (CH3). HRMS (ESI) m/z: calcd for C17H24BrO2, 339.0954 [M+H]+;
found: 339.0953.
1-(o-Tolyl)cyclopentane-1-carboxylic acid (2j): The title compound (432 mg, 53% over 2 steps) was
o
1
prepared according to the general procedure B as a white solid. mp: 122.2-123.2 C. H NMR (400
MHz, CDCl3): δ 7.39-7.33 (m, 1H), 7.22-7.13 (m, 3H), 2.61-2.52 (m, 2H), 2.32 (s, 3H), 2.12-2.03 (m,
13
2H), 1.86-1.68 (m, 4H). C NMR (100 MHz, CDCl3): δ 182.6, 141.4, 136.7, 131.7 (CH), 126.9 (CH),
126.0 (CH), 125.8 (CH), 58.0, 36.7 (2 × CH2), 24.5 (2 × CH2), 21.0 (CH3). HRMS (ESI) m/z: calcd for
C13H15O2: 203.1072 [M-H]+; found: 203.1077.
1-(m-Tolyl)cyclopentane-1-carboxylic acid (2k): The title compound (480 mg, 63% over 2 steps) was
o
1
prepared according to the general procedure B as a white solid, mp: 127.4-128.6 C. H NMR (400
MHz, CDCl3): δ 7.24-7.19 (m, 3H), 7.11-7.05 (m, 1H), 2.71-2.62 (m, 2H), 2.36 (s, 3H), 1.98-1.87 (m,
13
2H), 1.81-1.70 (m, 4H). C NMR (100 MHz, CDCl3): δ 182.5, 142.7, 137.9, 128.2 (CH), 127.7 (CH),
17

ACCEPTED MANUSCRIPT
124.1 (CH), 58.8, 35.9 (2 × CH2), 23.5 (2 × CH2), 21.5 (CH3). HRMS (ESI) m/z: calcd for C13H15O2:
203.1072 [M-H]+; found: 203.1075.
Methyl 1-(pyridin-3-yl)cyclopentane-1-carboxylate (2l): The title compound (665 mg, 81%) was pre-
1
pared according to the general procedure A as a colorless oil. H NMR (400 MHz, CDCl3): δ 8.60 (s,
1H), 8.47-8.42 (m, 1H), 7.65-7.61 (m, 1H), 7.23-7.18 (m, 1H), 3.59 (s, 3H), 2.70-2.60 (m, 2H), 1.95-
1.83 (m, 2H), 1.77-1.67 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 175.6, 148.5 (CH), 148.0 (CH), 138.7,
134.4 (CH), 123.1 (CH), 57.3, 52.5 (CH3), 36.0 (2 × CH2), 23.5 (2 × CH2). HRMS (ESI) m/z: calcd for
C12H16NO2: 206.1181 [M+H]+; found: 206.1177.
Methyl 1-(pyridin-4-yl)cyclopentane-1-carboxylate (2m): The title compound (587 mg, 72%) was
1
prepared according to the general procedure A as a colorless oil. H NMR (400 MHz, CDCl3): δ 8.52-
8.46 (m, 2H), 7.23-7.18 (m, 2H), 3.59 (s, 3H), 2.62-2.52 (m, 2H), 1.94-1.82 (m, 2H), 1.76-1.64 (m, 4H).
13C NMR (100 MHz, CDCl3): δ 175.2, 152.0, 149.8 (2 × CH), 122.0 (2 × CH), 58.7, 52.5 (CH3), 35.8 (2
× CH2), 23.6 (2 × CH2). HRMS (ESI) m/z: calcd for C12H16NO2: 206.1181 [M+H]+; found: 206.1177.
Methyl 1-(thiazol-2-yl)cyclopentane-1-carboxylate (2n): The title compound (340 mg, 40%) was pre-
pared according to the general procedure A as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.68 (d, J
= 3.3 Hz, 1H), 7.24 (d, J = 3.3 Hz, 1H), 3.67 (s, 3H), 2.59-2.48 (m, 2H), 2.38-2.27 (m, 2H), 1.84-1.66
(m, 4H). 13C NMR (100 MHz, CDCl3): δ 174.3, 172.9, 142.2 (CH), 119.0 (CH), 59.2, 52.7 (CH3), 38.0
(2 × CH2), 24.5 (2 × CH2). MS (ESI) m/z: calcd for C10H14NO2S: 212.1 [M+H]+; found: 212.0.
Methyl 4-(6-chloropyridin-3-yl)tetrahydro-2H-pyran-4-carboxylate (2o): The title compound (552
mg, 51%) was prepared according to the general procedure A as white solid, mp: 61.3-62.5 oC. 1H NMR
(400 MHz, CDCl3): δ 8.40 (d, J = 4.0 Hz, 1H), 7.65 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 1H), 7.30 (d, J = 8.0
Hz, 1H), 3.93 (dt, J1 = 4.0 Hz, J2 = 12.0 Hz, 2H), 3.69 (s, 3H), 3.55 (dt, J1 = 2.0 Hz, J2 = 12.0 Hz, 2H),
2.53 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 2H), 1.96 (dd, J1 = 4.0 Hz, J2 = 12.0 Hz, 2H), 1.17 (dd, J1 = 4.0 Hz,
J2 = 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 173.6, 150.51, 147.59 (CH), 137.0 (CH), 136.5 (CH),
18

ACCEPTED MANUSCRIPT
124.2, 65.2, 52.7 (CH3), 47.1 (2 × CH2), 33.9 (2 × CH2). HRMS (ESI) m/z: calcd for C12H15ClNO3:
256.0740 [M+H]+; found: 256.0735.
tert-Butyl
(1-(6-chloropyridin-3-yl)cyclopentyl)carbamate
(3a)
and
2-chloro-5-(1-
isocyanatocyclopentyl)pyridine (4a): (Procedure C): A solution of 2a (2.26 g, 9.42 mmol) in MeOH
(19 mL) was added a 6.0 N solution of sodium hydroxide (9.42 mL, 56.5 mmol). The reaction mixture
was refluxed overnight and was added a 4.0 M HCl solution in dioxane (15.0 mL, 60 mmol) at rt. The
solvent was removed under reduced pressure. A solution of the residue in anhydrous t-BuOH (0.20 L)
with flame dried 4Å molecular sieve powder (1.0 g) was added diphenyl phosphorazidate (2.45 mL,
11.3 mmol) and triethylamine (2.64 mL, 18.8 mmol). The reaction mixture was stirred at rt for 1.0 h and
then heated under reflux overnight. The reaction mixture was filtered. The filtrate was concentrated un-
der reduced pressure. The resulting residue was purified by column chromatography with pre-packed
silica gel disposable column to afford the title compound 3a (1.42 g, 51%) and 4a (0.63 g, 30%). Com-
o
pound 3a: white solid. mp: 112.3-113.3 C; 1H NMR (400 MHz, CDCl3): δ 8.42 (d, J = 4.0 Hz, 1H),
7.70 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 4.89 (s, 1H), 2.35-2.01 (m, 2H), 2.00-1.93 (m, 2H),
1.87-1.80 (m, 4H), 1.34 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 154.3, 149.1, 147.1 (CH), 140.5, 137.0
(CH), 123.6 (CH), 79.9, 63.9, 39.4 (2 × CH2), 28.3 (2 × CH2), 22.9 (3 × CH3). HRMS (ESI) m/z: calcd
for C15H22ClN2O2: 297.1370, [M+H]+; found: 297.1364. Compound 4a: white solid. mp: 102.0-103.0
oC; 1H NMR (400 MHz, CDCl3): δ 8.48 (d, J = 4.0 Hz, 1H), 7.73 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 1H), 7.31
(d, J = 8.0 Hz, 1H), 2.26-2.18 (m, 2H), 2.07-1.91 (m, 6H).13C NMR (100 MHz, CDCl3): δ 150.5, 146.8
(CH), 137.9, 136.1 (CH), 130.0, 123.9 (CH), 69.5, 43.1 (2 × CH2), 23.0 (2 × CH2). HRMS (ESI) m/z:
calcd for C11H12ClN2O: 223.0633 [M+H]+; found: 223.0634. IR (film, cm-1): 2954, 2135 (N=C=O),
1698, 1588, 1541, 1487, 1460, 1201, 1079, 910.
tert-Butyl (1-(6-chloropyridin-3-yl)cyclopropyl)carbamate (3b): The title compound (1.1 g, 78%)
was prepared according to the general procedure C as a white solid. mp: 108.6-109.6 oC. 1H NMR (400
MHz, CDCl3): δ 8.26 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 5.30-5.24 (br, 1H), 1.40
19

ACCEPTED MANUSCRIPT
13
(s, 9H), 1.30 (s, 2H), 1.19 (s, 2H). C NMR (100 MHz, CDCl3): δ 151.2, 149.1, 147.2 (CH), 137.9,
136.4 (CH), 123.7 (CH), 80.0, 33.1, 28.3 (2 × CH2), 18.0 (3 × CH3). HRMS (ESI) m/z: calcd for
C13H18ClN2O2: 269.1051 [M+H]+; found: 269.1055.
tert-Butyl (1-(6-chloropyridin-3-yl)cyclobutyl)carbamate (3c): The title compound (0.97 g, 69%) was
o
prepared according to the general procedure C as a white solid. mp: 96.0-96.5 C. 1H NMR (400 MHz,
CDCl3): δ 8.44 (d, J = 4.0 Hz, 1H), 7.71 (m, 1H), 7.28 (d, J = 8.0 Hz, 1H), 5.20 (s, 1H), 2.55-2.44 (m,
13
4H), 2.18-2.14 (m, 1H), 1.93-1.88 (m, 1H), 1.28 (s, 9H). C NMR (100 MHz, CDCl3): δ 154.1, 149.4,
147.3 (CH), 140.3, 136.5 (CH), 123.6 (CH), 80.0, 57.0, 34.4 (2 × CH2), 28.3 (CH2), 15.4 (3 × CH3).
HRMS (ESI) m/z: calcd for C14H20ClN2O2: 283.1208 [M+H]+; found: 283.1213.
tert-Butyl (1-(6-chloropyridin-3-yl)cyclohexyl)carbamate (3d): The title compound (0.42 g, 27%)
o
1
was prepared according to the general procedure C as a white solid. mp: 94.2-95.2 C. H NMR (400
MHz, CDCl3): δ 8.43 (d, J = 4.0 Hz, 1H), 7.67 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 1H), 7.26 (d, J = 8.0 Hz,
1H), 4.88 (s, 1H), 2.19 (s, 2H), 1.72-1.65 (m, 7H), 1.32 (s, 9H), 0.83 (d, J = 4.0 Hz, 1H). 13C NMR (100
MHz, CDCl3): δ 153.9, 149.3, 147.3 (CH), 142.2, 136.0 (CH), 123.6 (CH), 79.7, 55.5, 36.1 (2 × CH2),
28.3 (2 × CH2), 25.1 (CH2), 21.7 (3 × CH3). HRMS (ESI) m/z: calcd for C16H24ClN2O2: 311.1521
[M+H]+; found: 311.1524.
tert-Butyl (1-(6-chloropyridin-3-yl)cycloheptyl)carbamate (3e) (Procedure D): A mixture of 4e
(0.13 g, 0.50 mmol) and flame-dried 4 Å molecule sieves powder (0.10 g) in tert-butyl alcohol (2.0 mL)
o
in a 10 mL sealed tube was heated at 150 C for 6 h. Then the reaction mixture was filtered through
celite at rt and washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure.
The resulting residue was purified by column chromatography with pre-packed silica gel disposable
column to afford the title compound 3e (0.16 g, 99%) as a white solid. mp: 82.5-84.0 oC. 1H NMR (400
MHz, CDCl3): δ 8.41 (d, J = 4.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 5.00 (s,
13
1H), 2.09-1.99 (m, 4H), 1.68-1.63 (m, 8H), 1.28 (s, 9H). C NMR (100 MHz, CDCl3): δ 154.1, 149.1,
20

ACCEPTED MANUSCRIPT
147.0 (CH), 143.2, 135.7 (CH), 123.5 (CH), 79.6, 59.2, 40.6 (2 × CH2), 28.5 (2 × CH2), 28.3 (2 × CH2),
22.7 (3 × CH3). HRMS (ESI) m/z: calcd for C17H25ClN2O2: 325.1677 [M+H]+; found: 325.1676.
tert-Butyl (1-(4-bromophenyl)cyclopropyl)carbamate (3f): The title compound (1.3 g, 83%) was pre-
o
1
pared according to the general procedure C as a white solid. mp: 127.5-127.8 C. H NMR (400 MHz,
CD3OD): δ 7.40 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 1.43 (s, 9H), 1.19 (d, J = 12.0 Hz, 4H).
13C NMR (100 MHz, CD3OD): δ 156.9, 143.1, 130.8 (2 × CH), 126.5 (2 × CH), 119.0, 78.9, 33.9, 27.3
(2 × CH2), 17.6 (3 × CH3). MS (ESI) m/z: calcd for C14H19 BrNO2: 312.1 [M+H]+; found: 312.1.
tert-Butyl (1-(4-bromophenyl)cyclobutyl)carbamate (3g): The title compound (1.4 g, 85%) was pre-
o
1
pared according to the general procedure C as a white solid. mp: 120.2-121.2 C. H NMR (400 MHz,
CDCl3): δ 7.45 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 2.51-2.39 (m, 4H), 2.19-1.98 (m, 1H),
1.91-1.77 (m, 1H), 1.36 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 153.9, 146.0, 130.6 (CH), 127.1 (CH),
119.5, 78.5, 58.3, 33.7 (2 × CH2), 27.3 (2 × CH2), 14.8 (3 × CH3). HRMS (ESI) m/z: calcd for
C15H20BrNO2Na: 348.0570 [M+Na]+; found: 348.0570.
tert-Butyl (1-(4-bromophenyl)cyclopentyl)carbamate (3h): The title compound (0.53 g, 31%) was
o
1
prepared according to the general procedure C as a white solid. mp: 106.2-107.2 C. H NMR (400
MHz, CDCl3): δ 7.41 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 4.91 (s, 1H), 2.31-2.03 (br, 2H),
2.01-1.94 (m, 2H), 1.87-1.77 (m, 4H), 1.36 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 154.2, 145.0, 131.0
(2 × CH), 127.5 (2 × CH), 120.1, 79.3, 65.5, 39.5 (2 × CH2), 28.3 (2 × CH2), 23.1 (3 × CH3). HRMS
(ESI) m/z: calcd for C16H2281BrNO2Na: 364.0706 [M+Na]+; found: 364.0705.
tert-Butyl (1-(4-bromophenyl)cyclohexyl)carbamate (3i): The title compound (0.18 g, 99%) was pre-
o
1
pared according to the general procedure D as a white solid. mp: 112.6-113.0 C. H NMR (400 MHz,
CDCl3): δ 7.42 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 4.82 (s, 1H), 2.17 (s, 2H), 1.75-1.55 (m,
8H), 1.31 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 153.9, 147.0, 131.2 (2 × CH), 127.0 (2 × CH), 120.1,
21

ACCEPTED MANUSCRIPT
79.2, 56.7, 36.3 (2 × CH2), 28.3 (2 × CH2), 25.3 (CH2), 22.0 (3 × CH3). HRMS (ESI) m/z: calcd for
C17H24BrNO2Na: 376.0883 [M+Na]+; found: 376.0882.
tert-Butyl (1-(m-tolyl)cyclopentyl)carbamate (3k) and (1-(m-tolyl)cyclopentyl)carbamoyl azide
(4k): The title compounds 3k (55 mg, 10%) and 4k (336 mg, 69%) were prepared according to the gen-
eral procedure D with 2.0 equivalent diphenyl phosphorazidate as white solids. 3k: mp: 112.6-113.1 oC.
1H NMR (400 MHz, CDCl3): δ 7.22-7.16 (m, 3H), 7.05-6.98 (m, 1H), 4.89 (br s, 1H), 2.34 (s, 3H),
2.30-2.10 (m, 2H), 2.08-1.95 (m, 2H), 1.90-1.73 (m, 4H), 1.39 (s, 9H). 13C NMR (100 MHz, CDCl3): δ
150.3, 141.8, 133.4, 123.9 (CH), 123.1 (CH), 122.4 (CH), 118.7 (CH), 75.0, 62.0, 35.7 (3 × CH3), 24.3
(2 × CH2), 19.3 (3 × CH3), 17.7 (2 × CH2). HRMS (ESI) m/z: calcd for C17H26NO2Na: 298.1783:
298.1783 [M+Na]+; found: 298.1778. 4k: mp: 127.1-128.4 oC. 1H NMR (400 MHz, CDCl3): δ 7.26-7.20
(m, 3H), 7.11-7.06 (m, 1H), 5.57 (br s, 1H), 2.38 (s, 3H), 2.37-2.32 (m, 2H), 2.13-2.03 (m, 2H), 1.88-
1.79 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 154.8, 144.1, 137.7, 128.1 (CH), 127.8 (CH), 126.5 (CH),
122.9 (CH), 67.0, 38.7 (2 × CH2), 22.9 (2 × CH2), 21.7 (CH3). HRMS (ESI) m/z: calcd for C13H17N4O:
245.1402 [M+H]+; found: 245.1397. IR (Microscope, cm-1): 3298, 2958, 2132 (N≡N), 1687 (C=O),
1520, 1452.
tert-Butyl (1-(pyridin-3-yl)cyclopentyl)carbamate (3l): The title compound (351 mg, 67%) was pre-
pared according to the general procedure C (NaOH hydrolysis at 50 oC overnight) as a white solid. mp:
103.2-103.7 oC. 1H NMR (400 MHz, CDCl3): δ 8.64 (d, J = 2.3 Hz, 1H), 8.43 (d, J = 4.5 Hz, 1H), 7.68
(dt, J1 = 2.0 Hz, J2 = 8.0 Hz, 1H), 7.20 (dd, J1 = 4.8 Hz, J2 = 8.0 Hz, 1H), 5.05 (br s, 1H), 2.35-2.10 (m,
13
2H), 2.05-1.95 (m, 2H), 1.90-1.72 (m, 4H), 1.34 (s, 9H). C NMR (100 MHz, CDCl3): δ 154.3, 147.6
(CH), 147.6 (CH), 141.0, 133.3 (CH), 122.8 (CH), 79.4, 64.4, 39.4 (3 × CH3), 28.3 (2 × CH2), 23.0 (2 ×
CH2). HRMS (ESI) m/z: calcd for C15H22N2O2: 263.1760 [M+H]+; found: 263.1757.
tert-Butyl (1-(pyridin-4-yl)cyclopentyl)carbamate (3m): The title compound (372 mg, 71%) was pre-
pared according to the general procedure C (NaOH hydrolysis at 50 oC overnight) as a white solid. mp:
22

ACCEPTED MANUSCRIPT
107.4-108.8 oC. 1H NMR (400 MHz, CDCl3): δ 8.51 (d, J = 5.4 Hz, 2H), 7.27 (d, J = 5.6 Hz, 2H), 5.09
(br s, 1H), 2.27-2.11 (m, 2H), 2.05-1.93 (m, 2H), 1.90-1.72 (m, 4H), 1.37 (s, 9H). 13C NMR (100 MHz,
CDCl3): δ 155.0, 154.3, 149.6 (2 × CH), 120.7 (2 × CH), 79.6, 65.3, 39.7 (3 × CH3), 28.3 (2 × CH2),
23.4 (2 × CH2). HRMS (ESI) m/z: calcd for C10H14NO2S: 263.1760 [M+H]+; found: 263.1758.
2-Cyclopentylthiazole (3n): The title compound (496 mg, 90%) was prepared according to the general
o
1
procedure C (NaOH hydrolysis at 50 C overnight) as a colorless oil. H NMR (400 MHz, CDCl3): δ
7.99 (d, J = 3.0 Hz, 1H), 7.47 (d, J = 2.8 Hz, 1H), 3.74 (quint, J = 8.5 Hz, 1H), 2.44-2.30 (m, 2H), 1.95-
13
1.70 (m, 6H). C NMR (100 MHz, CDCl3): δ 181.0, 136.8 (CH), 119.4 (CH), 41.8 (CH), 34.8 (2 ×
CH2), 25.4 (2 × CH2). HRMS (ESI) m/z: calcd for C8H12NS: 154.0690 [M+H]+; found: 154.0685.
tert-Butyl (4-(6-chloropyridin-3-yl)tetrahydro-2H-pyran-4-yl)carbamate (3o): The title compound
(1.03 g, 66%) was prepared according to the general procedure C as a white solid, mp: 162.0-163.0 oC.
1H NMR (400 MHz, CDCl3): δ 8.43 (d, J = 2.0 Hz, 1H), 7.67 (dd, J1 = 2.0 Hz, J2 = 8.0 Hz, 1H), 7.30 (d,
J = 8.0 Hz, 1H), 4.98 (br, 1H), 3.88 (dt, J1 = 4.0 Hz, J2 = 12.0 Hz, 2H), 3.77 (d, J = 12.0 Hz, 1H), 2.30-
2.04 (m, 4H), 1.37 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 153.9, 149.8, 147.2 (CH), 140.6 (CH), 136.0
(1 × CH), 135.9, 123.9, 77.3, 63.2 (2 × CH2), 53.4, 36.1 (2 × CH2), 28.3 (3 × CH3). HRMS (ESI) m/z:
calcd for C15H22ClN2O3: 313.1319 [M+H]+; found: 313.1314. IR (film, cm-1): 2954, 2135 (N=C=O),
1698, 1588, 1541, 1487, 1460, 1201, 1079, 910.
2-Chloro-5-(1-isocyanatocyclohexyl)pyridine (4d): The title compound (0.69 g, 58%) was prepared
according to the general procedure C as a white solid. mp: 148.0-150.0 oC. 1H NMR (400 MHz, CDCl3):
δ 8.49 (d, J = 4.0 Hz, 1H), 7.74 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 2.02-1.95
(m, 2H), 1.89-1.63 (m, 7H), 1.45-1.29 (m, 1H).13C NMR (100 MHz, CDCl3): δ 150.4, 146.6 (CH),
140.4, 135.8 (CH), 130.0, 123.9 (CH), 62.4, 39.8 (2 × CH2), 24.7 (2 × CH2), 22.2 (CH2). HRMS (ESI)
m/z: calcd for C12H14ClN2O: 237.0789 [M+H]+; found: 237.0790. IR (film, cm-1): 2937, 2861, 2144
(N=C=O), 1715, 1554, 1490, 1229, 1091, 914.
23

ACCEPTED MANUSCRIPT
2-Chloro-5-(1-isocyanatocycloheptyl)pyridine (4e): The title compound (0.55 g, 44%) was prepared
according to the general procedure C as a white solid. mp: 182.8-184.8 oC. 1H NMR (400 MHz, CDCl3):
δ 8.46 (d, J = 4.0 Hz, 1H), 7.72 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 2.03 (t, J =
13
8.0 Hz, 4H), 1.82-1.68 (m, 5H), 1.67-1.54 (m, 3H). C NMR (100 MHz, CDCl3): δ 150.2, 146.4 (CH),
141.8, 135.6 (CH), 123.8 (CH), 123.6, 65.7, 44.1 (2 × CH2), 27.6 (2 × CH2), 22.7 (2 × CH2). HRMS
(ESI) m/z: calcd for C13H16ClN2O: 251.0946 [M+H]+; found: 251.0951. IR (film, cm-1): 2926, 2858,
2257 (N=C=O), 1677, 1561, 1456, 1363, 1103, 1023, 825, 738.
1-Bromo-4-(1-isocyanatocyclopentyl)benzene (4h): The title compound (0.41 g, 31%) was prepared
according to the general procedure C as a white solid. mp: 102.5-104.5 oC. 1H NMR (400 MHz, CDCl3):
δ 7.30 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 8.0 Hz, 1H), 2.35 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 2H), 1.75-1.68
13
(m, 2H), 1.67-1.53 (m, 4H). C NMR (100 MHz, CDCl3): δ 159.1, 139.3, 130.5 (2 × CH), 127.5 (2 ×
CH), 120.2, 58.6, 34.5 (2 × CH2), 22.5 (2 × CH2). IR (film, cm-1): 2927, 2858, 2258 (N=C=O), 1679,
1533, 1457, 1364, 1238, 1102, 825, 735.
1-Bromo-4-(1-isocyanatocyclohexyl)benzene (4i): The title compound (1.1 g, 80%) was prepared ac-
1
cording to the general procedure C as a colorless oil. H NMR (400 MHz, CDCl3): δ 7.49 (dd, J1 = 4.0
Hz, J2 = 8.0 Hz, 1H), 7.35 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 1H), 1.95 (d, J = 12.0 Hz, 2H), 1.85-1.61 (m,
7H), 1.35-1.25 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 145.2, 131.5 (2 × CH), 126.6 (2 × CH), 123.2,
121.2, 63.8, 39.7 (2 × CH2), 24.9 (2 × CH2), 22.4 (CH2). IR (film, cm-1): 2935, 2861, 2253 (N=C=O),
1492, 1395, 1255, 1078, 1005, 898, 810, 704.
(1-(o-Tolyl)cyclopentyl)carbamoyl azide (4j): The title compound (351 mg, 72%) was prepared ac-
cording to the general procedure D with 2 equivalent diphenyl phosphorazidate (refluxing in t-BuOH
o
1
overnight) as a white solid, mp: 121.5-122.4 C. H NMR (400 MHz, CDCl3): δ 7.52-7.44 (m, 1H),
7.22-7.12 (m, 3H), 5.43 (br s, 1H), 2.56-2.46 (m, 2H), 2.45 (s, 3H), 2.20-2.07 (m, 2H), 1.90-1.70 (m,
13
4H). C NMR (100 MHz, CDCl3): δ 154.2, 141.2, 135.6, 132.4 (CH), 127.3 (2 × CH), 127.3, 125.5
24

ACCEPTED MANUSCRIPT
(CH), 67.3, 37.6 (2 × CH2), 22.9 6 (2 × CH2), 22.1 6 (2 × CH). HRMS (ESI) m/z: calcd for C13H17N4O:
245.1402 [M+H]+; found: 245.1396. IR (Microscope, cm-1): 3263, 2958, 2134 (N≡N), 1684 (C=O),
1531, 1456.
1-(6-Chloropyridin-3-yl)cyclopentanamine (1a): (Procedure E): Compound 3a (1.42 g, 4.73 mmol)
in a 3.0 N HCl solution in MeOH (10 mL) was stirred at rt for 24 h. The solvent was removed under re-
duced pressure. The resulting residue was then suspended in DCM and basified by a 2.0 N solution of
NaOH (20 mL). The organic phases were then separated and combined and dried by anhydrous magne-
sium sulfate. The solvent was then removed and the residue was purified by column chromatography
with pre-packed silica gel disposable column to afford the title compound 1a (1.12 g, 99%) as a brown
foam. 1H NMR (400 MHz, CD3OD): δ 8.63 (d, J = 4.0 Hz, 1H), 8.13 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 1H),
7.62 (d, J = 8.0 Hz, 1H), 2.41-2.27 (m, 4H), 2.04-1.87 (m, 4H). 13C NMR (100 MHz, CD3OD): δ 150.6,
147.2 (CH), 139.0 (CH), 135.7, 124.8 (CH), 64.3, 37.0 (2 × CH2), 22.3 (2 × CH2). HRMS (ESI) m/z:
calcd for C10H14ClN2: 197.0840 [M+H]+; found: 197.0847.
1-(6-Chloropyridin-3-yl)cyclopropanamine (1b): The title compound (0.80 g, 95%) was prepared ac-
cording to the general procedure E as a light brown foam. 1H NMR (400 MHz, CDCl3): δ 8.35 (s, 1H),
7.56 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 2.78 (s, 2H), 1.16 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 1H),
1.00 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 149.2, 147.4 (CH), 140.2, 136.4
(CH), 123.7 (CH), 34.4, 17.6 (2 × CH2). HRMS (ESI) m/z: calcd for C8H10ClN2: 169.0527 [M+H]+;
found: 169.0526.
1-(6-Chloropyridin-3-yl)cyclobutanamine (1c): The title compound (0.85 g, 93%) was prepared ac-
1
cording to the general procedure E as white foam. H NMR (400 MHz, CDCl3): δ 8.46 (d, J = 4.0 Hz,
1H), 7.72 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 2.54-2.47 (m, 2H), 2.22-2.15 (m, 2H), 2.08-1.97
13
(m, 1H), 1.99 (s, 2H), 1.79-1.74 (m, 1H). C NMR (100 MHz, CDCl3): δ 149.5, 147.1 (CH), 142.5,
25

ACCEPTED MANUSCRIPT
136.3 (CH), 123.8 (CH), 57.2, 37.1 (2 × CH2), 14.0 (2 × CH2). HRMS (ESI) m/z: calcd for C9H12ClN2:
183.0684 [M+H]+; found: 183.0689.
1-(6-Chloropyridin-3-yl)cyclohexanamine (1d): The title compound (1.0 g, 95%) was prepared ac-
cording to the general procedure E as a light brown foam. 1H NMR (400 MHz, CD3OD): δ 8.62 (d, J =
4.0 Hz, 1H), 8.08 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 2.57-2.49 (m, 2H), 2.02
13
(td, J1 = 4.0 Hz, J2 = 8.0 Hz, 1H), 1.81-1.73 (m, 2H), 1.61-1.51 (m, 1H), 1.50-1.32 (m, 3H). C NMR
(100 MHz, CD3OD): δ 151.5, 148.4 (CH), 138.3 (CH), 133.3, 124.6 (CH), 56.1, 33.7 (2 × CH2), 24.4 (2
× CH2), 21.3 (CH2). HRMS (ESI) m/z: calcd for C11H16ClN2: 211.0997 [M+H]+; found: 211.1002.
1-(6-Chloropyridin-3-yl)cycloheptanamine (1e): The title compound (1.1 g, 95%) was prepared ac-
cording to the general procedure E as a light brown foam. 1H NMR (400 MHz, CD3OD): δ 8.57 (d, J =
4.0 Hz, 1H), 8.02 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 2.56-2.47 (m, 2H), 2.17-
13
2.10 (m, 2H), 1.85-1.71 (m, 2H), 1.61 (m, 2H), 1.69-1.46 (m, 6H). C NMR (100 MHz, CD3OD): δ
151.3, 147.6 (CH), 137.7 (CH), 135.4, 124.5 (CH), 60.0, 37.3(2 × CH2), 28.4 (2 × CH2), 21.8 (2 × CH2).
HRMS (ESI) m/z: calcd for C12H18ClN2: 225.1153 [M+H]+; found: 225.1158.
1-(4-Bromophenyl)cyclopropanamine (1f): The title compound (1.0 g, 99%) was prepared according
1
to the general procedure E as a white foam. H NMR (400 MHz, CD3OD): δ 7.42 (d, J = 8.0 Hz, 2H),
7.25 (d, J = 8.0 Hz, 2H), 1.03 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 2H), 0.97 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 2H).
13C NMR (100 MHz, CD3OD): δ 145.3, 130.9 (2 × CH), 127.2 (2 × CH), 119.2, 35.5, 16.3 (2 × CH2).
HRMS (ESI) m/z: calcd for C9H11BrN: 212.0069 [M+H]+; found: 212.0074.
1-(4-Bromophenyl)cyclobutanamine (1g): The title compound (1.1 g, 98%) was prepared according to
the general procedure E as a white foam. 1H NMR (400 MHz, CD3OD): δ 7.64 (d, J = 8.0 Hz, 2H), 7.43
13
(d, J = 8.0 Hz, 2H), 2.78-2.71 (m, 2H), 2.64-2.58 (m, 2H), 2.27-2.16 (m, 1H), 1.98-1.89 (m, 1H). C
NMR (100 MHz, CD3OD): δ 139.1, 131.9 (2 × CH), 127.8 (2 × CH), 122.6, 58.4, 31.8 (2 × CH2), 13.1
(2 × CH2). HRMS (ESI) m/z: calcd for C10H13BrN: 226.0226 [M+H]+; found: 226.0228.
26

ACCEPTED MANUSCRIPT
1-(4-Bromophenyl)cyclopentanamine (1h): The title compound (1.1 g, 95%) was prepared according
1
to the general procedure E as a white foam. H NMR (400 MHz, CD3OD): δ 7.61 (d, J = 8.0 Hz, 2H),
7.46 (d, J = 8.0 Hz, 2H), 2.32-2.24 (m, 4H), 2.00-1.88 (m, 4H). 13C NMR (100 MHz, CD3OD): δ 139.5,
131.8 (2 × CH), 127.9 (2 × CH), 122.4, 65.7, 37.2 (2 × CH2), 22.4 (2 × CH2). HRMS (ESI) m/z: calcd
for C11H15BrN: 240.0382 [M+H]+; found: 240.0380.
1-(4-Bromophenyl)cyclophexanamine (1i): The title compound (1.2 g, 98%) was prepared according
to the general procedure E as a light brown foam. 1H NMR (400 MHz, CD3OD): δ 7.64 (d, J = 8.0 Hz,
2H), 7.54 (d, J = 8.0 Hz, 2H), 2.49 (dd, J1 = 4.0 Hz, J2 = 12.0 Hz, 2H), 1.97-1.90 (m, 2H), 1.76-1.72 (m,
13
2H), 1.60-1.53 (m, 1H), 1.49-1.35 (m, 3H). C NMR (100 MHz, CD3OD): δ 137.3, 132.0 (2 × CH),
128.4 (2 × CH), 122.7, 57.2, 34.0 (2 × CH2), 24.5 (2 × CH2), 21.5 (CH2). HRMS (ESI) m/z: calcd for
C12H14Br: 239.0253 [M-NH3+H]+; found 239.0259.
1-(o-Tolyl)cyclopentan-1-amine (1j) (Procedure F): A solution of 4j (1.0 mmol) in MeOH (1.0 mL)
was added a 12.0 N HCl solution (aq., 1.0 mL, 12.0 mmol) at rt. The resulting solution was heated under
reflux overnight. Upon evaporation of the solvent, the residue was dissolved in DCM (5.0 mL) and basi-
fied by a 10.0 N NaOH aqueous solution (2.0 mL). The aqueous layer was extracted with DCM (10 mL,
2×). The combined organic layers were dried (MgSO4) and concentrated. The residue was purified by
column chromatography with pre-packed silica gel disposable column to afford the title compound (135
mg, 77%) as a white foam. 1H NMR (400 MHz, CD3OD): δ 7.52-7.47 (m, 1H), 7.31-7.23 (m, 3H), 2.54
13
(s, 3H), 2.53-2.45 (m, 2H), 2.40-2.28 (m, 2H), 2.02-1.90 (m, 4H). C NMR (100 MHz, CD3OD): δ
138.0, 136.2, 132.8 (CH), 128.7 (CH), 127.2 (CH), 126.2 (CH), 67.3, 37.9 (2 × CH2), 22.5 (2 × CH2),
21.4 (CH3). HRMS (ESI) m/z: calcd for C12H18N: 176.1439 [M+H]+; found: 176.1434.
1-(m-Tolyl)cyclopentan-1-amine (1k): The title compound (126 mg, 72%) was prepared according to
the general procedure F as a white foam. 1H NMR (400 MHz, CD3OD): δ 7.38-7.31 (m, 3H), 7.25-7.20
13
(m, 1H), 2.40 (s, 3H), 2.37-2.23 (m, 4H), 2.06-1.84 (m, 4H). C NMR (100 MHz, CD3OD): δ 141.6,
27

ACCEPTED MANUSCRIPT
140.0, 130.4 (CH), 130.0 (CH), 127.8 (CH), 124.2 (CH), 67.5, 38.6 (2 × CH2), 23.9 (2 × CH2), 21.6
(CH3). HRMS (ESI) m/z: calcd for C12H18N: 176.1439 [M+H]+; found: 176.1434.
1-(Pyridin-3-yl)cyclopentan-1-amine (1l): The title compound (160 mg, 99%) was prepared according
1
to the general procedure E as a white foam. H NMR (400 MHz, CD3OD): δ 9.19 (d, J = 2.2 Hz, 1H),
13
9.01-8.93 (m, 2H), 8.25 (dd, J1 = 5.8 Hz, J2 = 8.3 Hz, 1H), 2.58-2.38 (m, 4H), 2.15-1.90 (m, 4H). C
NMR (100 MHz, CD3OD): δ 145.6 (CH), 141.7 (CH), 140.5 (CH), 140.4, 127.6 (CH), 64.4, 37.0 (2 ×
CH2), 22.4 (2 × CH2). HRMS (ESI) m/z: calcd for C10H15N2: 163.1235 [M+H]+; found: 163.1230.
1-(Pyridin-4-yl)cyclopentan-1-amine (1m): The title compound (157 mg, 97%) was prepared accord-
1
ing to the general procedure E as a white foam. H NMR (400 MHz, CD3OD): δ 9.00 (d, J = 6.8 Hz,
13
2H), 8.30 (d, J = 6.8 Hz, 2H), 2.45-2.35 (m, 4H), 2.15-1.97 (m, 4H). C NMR (100 MHz, CD3OD): δ
161.1, 142.1 (2 × CH), 124.8 (2 × CH), 65.9, 38.7 (2 × CH2), 23.6 (2 × CH2). HRMS (ESI) m/z: calcd
for C10H15N2: 163.1235 [M+H]+; found: 163.1230.
4-(6-Chloropyridin-3-yl)tetrahydro-2H-pyran-4-amine (1o): The title compound (1.25 g, 99%) was
1
prepared according to the general procedure E as a light brown foam. H NMR (400 MHz, CD3OD): δ
8.69 (d, J = 4.0 Hz, 1H), 8.19 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 3.98 (dt, J1 =
4.0 Hz, J2 = 12.0 Hz, 1H), 3.98 (td, J1 = 2.0 Hz, J2 = 12.0 Hz, 1H), 2.69-2.61 (m, 2 H), 2.35-2.26 (m,
2H); 13C NMR (100 MHz, CDCl3): δ 151.8, 148.7 (CH), 139.1 (CH), 132.2 (CH), 125.0, 63.1, 54.2 (2 ×
CH2), 33.7 (2 × CH2). HRMS (ESI) m/z: calcd for C10H14ClN2O: 213.0795 [M+H]+; found: 213.0790.
(S)-1-(1-(4-Bromophenyl)cyclohexyl)-3-(1-phenylethyl)urea (5): To a solution of 4i (0.14 g, 0.50
mmol) in toluene (1.0 mL) was added (S)-1-phenylethanamine (79 mg, 83 uL, 0.65 mmol). The reaction
o
mixture was heated at 110 C in a sealed tube for 12 h. The solvent was removed under reduced pres-
sure. The resulting residue was purified by column chromatography with pre-packed silica gel disposa-
ble column to afford the title compound 5 (0.15 g, 77%) as a white solid. mp: 210.0-210.2 oC. 1H NMR
(400 MHz, d6-DMSO): δ 7.39 (d, J = 8.0 Hz, 2H), 7.31-7.18 (m, 7 H), 6.37 (d, J = 8.0 Hz, 1H), 6.10 (s,
28