A general method for the one-pot reductive functionalization of secondary amides

Article abstract of DOI:10.1021/jo502929x

A one-pot reaction for the transformation of common secondary amides into amines with C-C bond formation is described. This method consists of in situ amide activation with Tf₂O-partial reduction-addition of C-nucleophiles. The method is general in scope, which allows employing both hard nucleophiles (RMgX, RLi) and soft nucleophiles, as well as enolates. With the use of soft nucleophiles, the reaction proceeded with high chemoselectivity at a secondary amide in the presence of ester, cyano, nitro, and tertiary amide groups.

Full text of DOI:10.1021/jo502929x

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Note
A General Method for the One-pot Reductive
Functionalization of Secondary Amides
Pei-Qiang Huang, Ying-Hong Huang, Kai-Jiong Xiao, Yu Wang, and Xiao-Er Xia
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 05 Feb 2015
Downloaded from http://pubs.acs.org on February 6, 2015
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A General Method for the One-pot Reductive Functionalization of
Secondary Amides
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Pei-Qiang Huang,*,a,b Ying-Hong Huang,a,‡ Kai-Jiong Xiao,a,‡ Yu Wang,a and
Xiao-Er Xiaa
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a Department of Chemistry and Fujian Provincial Key Laboratory of Chemical
Biology, Collaborative Innovation Centre of Chemistry for Energy Materials, College
of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005,
P. R. China
b State Key Laboratory of Applied Organic Chemistry Lanzhou University, Lanzhou
730000, P. R. China
Email: pqhuang@xmu.edu.cn.
‡ Y.-H. H. and K.-J. X. contributed equally to this work
In Memory of Professor Dr. Bertrand Castro
ABSTRACT: A one-pot reaction for the transformation of common secondary amides
into amines with C-C bond formation is described. This method is consisted of in situ
amide activation with Tf2O – partial reduction – addition of C-nucleophiles. The
method is general in scope, which allows employing both hard nucleophiles (RMgX,
RLi) and soft nucleophiles, as well as enolates. The reaction proceeded with high
chemoselectivity at secondary amide in the presence of ester, cyano, nitro and tertiary
amide groups.
Due to the high stability and easy availability of amides,1a secondary amides1b-e
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constitute a class of versatile synthetic intermediates in organic synthesis2 and serve
as valuable directing group in both modern C-H activation/ functionalization3 and
classical C-H lithiation/ functionalization reactions.4 Since directing groups
themselves seldom constitute a part of the target molecules, it is highly desirable to
develop one-pot methods for their transformations into useful functional groups such
as amines. However, little attention has been paid to the subsequent step-economical5
transformations of the directing groups (amide groups) after C-H
functionalizations.3a,4b Moreover, amino group plays a pivotal role for the bioactivity
of pharmaceuticals and alkaloids.6 Thus, there are multiple and urgent demands for
methods allowing one-pot transformation of secondary amides into amines with C-C
bond formation.
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However, in contrast to that of tertiary amides,7-10 the one-pot reductive alkylation of
secondary amides remains a formidable challenge. Except for stepwise methods,11 the
reported one-pot methods only involve reductive di-allylation,12a-c Schwartz
reagent-mediated reductive cyanation of secondary lactams,12d,e and reductive
allylation of secondary amides.9b In 2012, our group disclosed a general method for
the one-pot reductive alkylation of secondary amides,13 which is based on the amide
activation with trifluoromethanesulfonic anhydride (Tf2O)14/ 2-fluoropyridine
(2-F-Py)15–organocerium reagent addition - reduction sequence (Scheme 1, Method
A). However the issue of chemoselectivity, one of the key challenges in modern
organic synthesis,16 has not yet been addressed in our previous method.13,17 Thus, the
development of a chemoselective alternative yet complementary partial reduction –
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nucleophilic addition approach (Scheme 1, Method B) is highly desirable, which has
been explored and the results are reported herein.
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Scheme 1. Complementary Approaches for the General One-pot Reductive
Alkylation of Secondary Amides
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Recently,18a we have demonstrated that secondary amides, after activation with Tf2O,
can be reduced by NaBH4 under mild conditions to give amines.18 Lately, we have
developed the first one-pot reductive coupling reaction of secondary amides,19 which
is based on the activations of secondary amides, partial reduction with triethylsilane
(Et3SiH)20 and Kagan reagent (SmI2)-mediated reductive coupling reactions. On the
basis of these precedents, a more general one-pot reductive functionalization of
secondary amides consisting of amide activation - partial reduction - addition of
organometallic reagent was envisioned, and the reductive n-butylation of N-benzyl
undecanamide 1a was selected for screening reaction conditions (Table 1, entry 1).
The optimal conditions were defined as: successive treatment of amide 1a with
2-F-Py (1.2 equiv), Tf2O (1.1 equiv) and Et3SiH (1.1 equiv) at 0 °C, followed by
addition of BF3OEt2 (1.5 equiv) and n-butyl Grignard reagent (4.0 equiv) at 0 °C for
2 h. In such a manner, amine 2a was obtained in 90% yield. It is worth to note that in
the absence of BF3OEt2, the product was obtained in a low yield (20%).
Scheme 2. One-pot Reductive Butylation of Amide 1a
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With the optimal conditions defined, the scope of the reaction was examined, and the
results are summarized in Table 1. Similar to the reductive n-butylation of 1a (Table 1,
entry 1), n-butylation of aliphatic amides 1b and 1c produced the corresponding
amines in 92% and 81% yield, respectively. The lower yield of 2c compared with
those of 2a and 2b is attributable to the volatility of the amine. Benzamides and
p-methylbenzamide reacted similarly to give amines 2d-g in 82-83% yields (entries
4-7). The reaction worked well with amides bearing different N-alkyl groups ranging
from primary (Bn, n-Bu, Me) to secondary (i-Pr, c-hex) alkyl groups. The reductive
alkylation of amide 1a with Grignard reagents prepared from primary alkyl (entry 1),
primary alkenyl (entry 8), and secondary alkyl (entry 9) halides worked similarly to
give the corresponding amines 2a, 2h, and 2i in 90-94% yields. Ethyl, benzyl, and
allyl magnesium bromides also reacted smoothly to give the corresponding amines
2j-n (entries 10-14). The reaction was shown to tolerate para-methoxy and
para-bromo substituents on the phenyl ring of benzamides (68% and 62%, entries 15
and 16). It is noteworthy that, besides Grignard reagents, organolithium reagents can
also serve as effective nucleophiles in the reductive functionalization (entries 17-20).
In particular, reductive alkynylation proceeded smoothly to give the corresponding
propargylamines 2q-s (entries 18-20), which are important structural motifs in natural
products and pharmaceuticals, and are versatile synthetic intermediates.21 Surprisingly,
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attempted introduction of simple ethenyl, ethynyl, and phenyl groups were at current
stage unsuccessful (entries 21 and 22). Significantly, reductive functionalization of 1a
with enolate derived from ethyl acetate underwent smoothly to give -aminoester 2t
in 82% yield (entry 23), thus providing an alternative method for the synthesis of
biologically important -amino acids.22
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Table 1. One-pot Reductive Functionalization of Secondary Amides with
Organometallic Reagents and Enolate
Entry Amide
R1
n-C10H21
n-C11H23
Me
R2
RM
Yield (%)a
2a: 90
2b: 92
2c: 81
2d: 89
2e: 82
2f: 83
1.
2.
3.
4.
5.
6.
7.
Bn
n-BuMgBr
n-BuMgBr
n-BuMgBr
n-BuMgBr
n-BuMgBr
n-BuMgBr
n-BuMgBr
1a
1b
1c
1d
1e
1f
n-Bu
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n-Bu
Me
Ph
Ph
Ph
c-hex
c-hex
4-Me-C6H
2g: 90
1g
4
8.
n-C10H21
Bn
Bn
2h: 94
2i: 92
2j: 81
2k: 85
1a
1a
1f
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n-C10H21
Ph
c-hexMgBr
EtMgBr
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11.
c-hex
c-hex
Ph
BnMgBr
1f
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12.
13.
14.
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16.
Me
c-hex
Ph
c-hex
c-hex
c-hex
c-hex
BnMgBr
2l: 79
2m: 77
2n: 87
2o: 68
1c
1h
1f
BnMgBr
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4-Br-C6H4
4-MeO-C6
H4
n-BuMgBr
n-BuMgBr
n-BuLi
1i
c-hex
2p: 62
1j
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20.
Ph
c-hex
c-hex
c-hex
c-hex
2f: 75
2q: 76
2r: 72
2s: 81
1f
1f
Ph
Me
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4-Me-C6H
4
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Ph
c-hex
c-hex
ndb
nd
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1f
Ph
PhMgBr
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n-C10H21
Bn
1a
2t: 82
a Isolated yield. b No desired product isolated.
Having demonstrated the viability of the present method for the one-pot reductive
alkylation of the C-H functionalization products, we next focused on issue of the
chemoselective reductive alkylation of secondary amides. To simplify the problem,
para-substituted benzamide derivatives were selected as substrates.10d,11e To further
explore the functional group tolerance, use of softer carbon nucleophiles was
investigated. As can be seen from Table 2, reductive allylation of 1a with
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allyltributyltin proceeded smoothly to give 2u in 90% yield (Table 2, entry 1). For
p-substituted benzamides bearing functional groups ranged from methoxyl, ester,
cyano to nitro, the reductive allylation reactions proceeded chemoselectively on the
secondary amide, producing the corresponding amines in good yields (entries 2-5). At
appropriate activation temperatures, the reductive alkylation of secondary amides
proceeded chemoselectively in the presence of tertiary amide, which remained intact
(entry 6). When using 5.0 mol equiv of allyltributyltin, the di-sec-amide underwent
bis-reductive allylation to give diamine 2aa in 89% yield (entry 7). The reaction was
incompatible with acetyl group (entry 8). Attempted addition of allyltrimethylsilane
(entry 9) failed to give the desired product, instead, after work up,
p-methoxybenzaldehyde was isolated in an 86% yield. Use of TMSCN as the carbon
nucleophile also afforded the desired -amino nitrile 2ab in 53% yield (entry 10).
Encouraged by these results, we next turned to the more challenging chemoselective
reductive alkylation of alicyclic amido ester 1q. To our delight, the reductive
allylation of amido ester 1q proceeded uneventfully to give the amino ester 2ac in
88% yield (entry 11). It is worthy of mentioning that N-α-allyl secondary amines are
in turn useful substrates for the synthesis of N-heterocycles for which a number of
methods have been developed.23
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Table 2. Reductive Functionalization of Secondary Amides with Soft Carbon
Nucleophiles
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Entry Amide
R1
R2
Nu (3 eq.)
Yield (%)a
2u: 90
2v: 87
1.
2.
3.
4.
5.
6.
n-C10H21
4-MeO-C6H4
4-MeO2C-C6H4
4-NC-C6H4
Bn
1a
1j
c-hex
c-hex
c-hex
c-hex
c-hex
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1k
1l
2w: 87
2x: 83
4-O2N-C6H4
2y: 81
1m
1n
4-Et2NC(O)-C6H4
2z: 77b
7.
1o
2aa: 89
ndc
8.
4-Ac-C6H4
4-MeO-C6H4
4-MeO-C6H4
c-hex
c-hex
c-hex
1p
1j
1j
9.
Ndd
10.
TMSCN
2ab: 53
11.
1q
2ac: 88
a Isolated yield. b Amide 1n was activated at 78 °C, 20 min; then 20 °C, 20 min;
and 0 °C 10 min. c No desired product was observed. d No desired product was
observed, instead, after work up, p-methoxybenzaldehyde was isolated in an 86%
yield.
To establish a tighter linkage between the present method with the secondary
amide-directed C-H activation methodology, some substrates and/ or products of C-H
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functionalization were tested for the reductive alkylation. We first examined the
reaction of amide 1r, prepared by Beak’s amide directed C-H alkylation.4b Following
the general procedure, the reductive alkylation proceeded smoothly to give the
expected amine 2ad in 84% yield as a 1: 1 diastereomeric mixture (Table 3, entry 1).
N-Methyl and N-iso-propyl benzamides 1e and 1s are substrates used by Nakamura
and Daugulis for the C-H activation and functionalization.3a,c Their reductive
n-butylation proceeded smoothly to give amines 2e and 2ae in 82% and 80% yield,
respectively (Table 3, entries 2 and 3). Subjection of benzamide 1t, a C-H
functionalization product prepared by Nakamura’s method,3c to the reductive
alkylation also gave amine 2af in 77% yield (entry 4).
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Table 3. Reductive Functionalization of Some C-H Functionalization Products/
Starting Materials
Entry Amide
R1
R2
RM
Yield (%)a
1.
1rb
2ad: 84 (dr = 1:1)c
2e: 82
2.
3.
4.
1ed
1sd
1tb
Ph
Me
i-Pr
i-Pr
n-BuMgBr
n-BuMgBr
4-Me-C6H4
2-Et-C6H4
2ae: 80
2af: 77
a Isolated yield. b C-H functionalization product. c The diastereomer ratio determine by
1H NMR. d C-H functionalization starting material.
In plausible mechanism for the one-pot reductive functionalization of secondary
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amides is depicted in Scheme 3. The IR evidence gained by Movassaghi,15 and our
previous supporting results19b allow us to suggest the formation of nitrinium ion
intermediate A along with 2-fluoropyridinium salt B upon treatment of secondary
amides with Tf2O. The highly electrophilic nitrinium ion intermediate A is reduced
with Et3SiH to give imine C. A proton exchange between the protonated 2-F-pyridine
B and more basic imine C results in iminium ion D and regenerates 2-F-pyridine. The
iminium ion D consumes an equivalent of nucleophile by proton exchange to yield
back imine C. The low reactivity of imines towards Grignard reagents is well-known.
Thus, the employment of a Lewis acid is necessary to convert the imine C to the
reactive chelating species E, which is subjected to nucleophilic addition to yield the
desired amine 2. The proton exchange between iminium ion D and non-basic
nucleophiles is less evident. However, this is supported by the fact that in the absence
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of BF3 OEt2 reductive allylation of 1a, and reductive cyanation of 1j gave the
corresponding products 2u and 2ab in only 12% and 20% yield, respectively, whereas
.
in the presence of BF3 OEt2, the yields are 90% (Table 2, entry 1) and 53% (Table 2,
entry 10), respectively.
Scheme 3. Plausible Mechanism for the One-pot Reductive Functionalization of
Secondary Amides
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Compared with our previous reductive alkylation method (Method A in Scheme 1),
the advantages of the present method reside in its chemoselectivity. In fact, attempted
reductive butylation of benzamide 1u by Method A was unsuccessful (Scheme 4).
Attempted deaminative butylation19b of benzamide 1v with organocerium reagent
produced only a trace of the desired ketone 2ah. In addition, for stereoselective
reductive alkylation of substrates bearing chiral elements, it can be expected that two
methods, with inversed order of addition of two nucleophiles, will give
complementary stereochemical outcomes.
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Scheme 4. Unsuccessful Chemoselective Reductive Butylation of 1u and 1v by
Method A.
Conclusion
In summary, we have developed a new and general method for the one-pot reductive
functionalization of secondary amides, which is complementary to the method we
developed recently.13 This method allows using a variety of nucleophiles including
hard nucleophiles such as RMgX and RLi, and soft nucleophiles such as TMSCN,
allyltributyltin as well as enolate. The reaction tolerates many sensitive functional
groups, and a number of functional groups bearing amines have been synthesized in
one-pot. The method has been applied to the transformations of selected C-H
functionalization products (1r, 1t) and C-H functionalization starting materials (1e,
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1s). We thus established a connection with the C-H functionalization products, which
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Experimental Section
Mass spectra were recorded on a LC-MS apparatus. HRFABMS spectra were
recorded on a 7.0 T FT-MS. H NMR and 13C NMR spectra were recorded on
1
instruments (400 and 100 MHz, respectively). Chemical shifts (δ) are reported in ppm
and respectively referenced to internal standard Me4Si and solvent signals (Me4Si, 0
1
ppm for H NMR and CDCl3, 77.0 ppm for 13C NMR). Infrared spectra were
measured using film KBr pellet techniques. Silica gel (300-400 mesh) was used for
flash column chromatography (FC), eluting (unless otherwise stated) with ethyl
acetate/ hexane mixture. Trifluoromethanesulfonic anhydride (Tf2O) was distilled
over phosphorus pentoxide and was stored for no more than a week before redistilling.
All other commercially available compounds were used as received. Dry
dichloromethane was distilled over calcium hydride under Argon. All reactions were
carried out under Argon. All the Grignard reagents were titrated immediately before
use.24
General procedure for the one-pot transformation of secondary amides 1 into
secondary amines 2.
Into a dry 10-mL round-bottom flask equipped with a stirring bar were added
successively an amide (1.0 mmol, 1.0 equiv), 4 mL of anhydrous dichloromethane
and 2-fluoropyridine (116.5 mg, 103 μL, 1.2 mmol, 1.2 equiv.). After being cooled to
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0 °C, trifluoromethanesulfonic anhydride (Tf2O) (310 mg, 185 μL, 1.1 mmol, 1.1
equiv) was added dropwise via a syringe at 0 °C and the reaction was stirred for 20
min. To the resulting mixture, triethylsilane (Et3SiH) (128 mg, 176 μL, 1.1 mmol, 1.1
equiv) was added dropwise at 0 °C and the reaction was stirred for 10 min. The
mixture was allowed to warm-up to room temperature and stirred for 5 h. After being
cooled to 0 °C, BF3·Et2O (213 mg, 185 μL, 1.5 mmol, 1.5 equiv) was added, and the
reaction mixture was stirred for 30 min. RMgX or RLi (4.0 mmol, 4.0 equiv) or
allyltributyltin (3.0 mmol, 3.0 equiv) was added dropwise to the resultant mixture at
0 °C. Then the reaction mixture was warmed slowly to rt. and stirred for 2 h. The
reaction was quenched with a saturated aqueous solution of ammonium chloride and
extracted with dichloromethane (3  5 mL). The combined organic layers were dried
over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash column chromatography on silica gel to afford the
desired amine 2.
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N-Benzylpentadecan-5-amine (2a)
Following the general procedure, the reductive alkylation of amide 1a (275 mg, 1.0
mmol) with nBuMgBr gave, after flash column chromatography on silica gel (eluent:
EtOAc/ n-hexane = 1/ 50), amine 2a (285 mg, yield: 90%). Colorless oil; IR (film)
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
max: 3349, 3026, 2924, 1494, 1454, 697 cm-1; H NMR (400 MHz, CDCl3) 
0.84-0.93 (m, 6H), 1.21-1.35 (m, 19H), 1.37-1.46 (m, 5H), 2.48-2.57 (m, 1H), 3.75 (s,
13
2H), 7.20-7.34 (m, 5H) ppm; C NMR (100 MHz, CDCl3)  14.1 (2C), 22.7, 23.0,
25.7, 27.9, 29.3, 29.6, 29.7 (2C), 29.9, 31.9, 33.7, 34.0, 51.2, 56.8, 126.7, 128.1 (2C),
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128.3 (2C), 141.1 ppm; HRMS (ESI) calcd for [C22H40N]+ (M+H+): 318.3155; found:
318.3156.
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N-Butylhexadecan-5-amine (2b)
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Following general procedure, the reductive alkylation of amide 1b (255 mg, 1.0 mmol)
with nBuMgBr gave, after flash column chromatography on silica gel (eluent: EtOAc/
n-hexane = 1/ 20), the known amine 2b13 (273 mg, 92%). Colorless oil. IR (film) max
:
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3390, 2956, 2923, 2854, 1466, 1113 cm-1; H NMR (400 MHz, CDCl3)  0.85-0.95
13
(m, 9 H), 1.22-1.50 (m, 30 H), 2.40-2.49 (m, 1 H), 2.56 (t, J = 7.1 Hz, 1H) ppm; C
NMR (100 MHz, CDCl3)  14.0, 14.1, 20.6, 22.6, 23.0, 25.7, 28.0, 29.3, 29.6 (3C),
29.6 (2C), 30.0, 31.9, 32.6, 33.8, 34.1, 46.9, 57.6 ppm; MS (ESI) m/z 298 (M+H+,
100%); HRMS (ESI) calcd for [C20H44N]+ (M+H+): 298.3468; found: 298.3466.
N-(Hexan-2-yl)cyclohexanamine (2c)
Following the general procedure, the reductive alkylation of amide 1c (141 mg, 1.0
mmol) with nBuMgBr gave, after flash column chromatography on silica gel (eluent:
EtOAc/ n-hexane = 1/ 30), amine 2c (148 mg, yield: 81%). Colorless oil; IR (film)
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
max: 3304, 2954, 2927, 2853, 1450, 1377, 1112 cm-1; H NMR (400 MHz, CDCl3) 
0.89 (t, J = 6.9 Hz, 3H), 1.01 (d, J = 6.1 Hz, 3H), 0.92-1.46 (m, 11H), 1.56-1.64 (m,
1H), 1.67-1.76 (m, 2H), 1.80-1.94 (m, 2H), 2.44-2.54 (m, 1H), 2.70-2.80 (m, 1H) ppm;
13C NMR (100 MHz, CDCl3)  14.0, 21.0, 22.9, 25.2, 25.3, 26.1, 28.3, 33.9, 34.5,
37.3, 49.3, 53.4 ppm; MS (ESI) m/z 184 (M+H+, 100%); HRMS (ESI) calcd for
[C12H26N]+ (M+H+): 184.2060; found: 184.2063.
N-Butyl-1-phenylpentan-1-amine (2d)
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Following general procedure, the reductive alkylation of amide 1d (177 mg, 1.0 mmol)
with nBuMgBr gave, after flash column chromatography on silica gel (eluent: EtOAc/
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n-hexane = 1/ 20), the known amine 2d13 (195 mg, 89%). Colorless oil. IR (film) max
:
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3320, 3083, 3062, 3025, 2957, 2928, 2858, 1493, 1454, 1125, 701 cm-1; H NMR
(400 MHz, CDCl3)  0.84 (t, J = 7.3 Hz, 3H), 0.86 (t, J = 7.3 Hz, 3H), 1.08-1.46 (m,
8H), 1.54-1.78 (m, 2H), 2.34-2.43 (m, 2H), 3.53 (dd, J = 7.6, 6.2 Hz, 1H), 7.18-7.34
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(m, 5H) ppm; C NMR (100 MHz, CDCl3)  13.9 (2C), 20.4, 22.7, 28.5, 32.4, 38.0,
47.4, 63.6, 126.7, 127.1 (2C), 128.2 (2C), 144.7 ppm; MS (ESI) m/z 220 (M+H+,
100%); HRMS (ESI) calcd for [C15H26N]+ (M+H+): 220.2060; found: 220.2058.
N-Methyl-1-phenylpentan-1-amine (2e)
Following general procedure, the reductive alkylation of amide 1e (135 mg, 1.0 mmol)
with nBuMgBr gave, after flash column chromatography on silica gel (eluent: EtOAc/
n-hexane = 1/ 20), the known amine 2e13 (145 mg, 82%). Colorless oil. IR (film) max
:
3301, 3083, 3062, 3025, 2956, 2930, 2857, 2788, 1493, 1453, 1134, 701 cm-1; H
1
NMR (400 MHz, CDCl3)  0.84 (t, J = 7.2 Hz, 3H), 1.06-1.33 (m, 4H), 1.55-1.80 (m,
13
3H), 2.26 (s, 3H), 3.38 (dd, J = 7.7, 6.2 Hz, 1H), 7.20-7.34 (m, 5H) ppm; C NMR
(100 MHz, CDCl3)  13.9, 22.6, 28.5, 34.4, 37.6, 65.5, 126.8, 127.2 (2C), 128.2 (2C),
144.1 ppm; MS (ESI) m/z 178 (M+H+, 100%); HRMS (ESI) calcd for [C12H20N]+
(M+H+): 178.1590; found: 178.1586.
N-(1-Phenylpropan-2-yl)cyclohexanamine (2f)
Following general procedure, the reductive alkylation of amide 1f (203 mg, 1.0 mmol)
with nBuMgBr gave, after flash column chromatography on silica gel (eluent: EtOAc/
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n-hexane = 1/ 20), the known amine 2f13 (203 mg, 83%). Colorless oil. IR (film) max
:
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3304, 3043, 2957, 2933, 2861, 1458, 1289, 1241, 1165, 639 cm-1; 1H NMR (400 MHz,
CDCl3)  0.81 (t, J = 7.2 Hz, 3H), 0.90-1.38 (m, 7H), 1.48-1.62 (m, 3H), 1.68-1.84 (m,
2H), 2.00-2.25 (m, 4H), 2.50-2.62 (m, 1H), 4.11-4.18 (m, 1H), 4.15 (dd, J = 10.8, 4.2
Hz, 1H), 7.38-7.50 (m, 5H), 7.93 (br s, 1H) ppm; 13C NMR (100 MHz, CDCl3)  13.6,
22.0, 24.3, 24.5, 24.6, 27.4, 27.8, 29.9, 33.6, 55.3, 60.5, 128.0 (2C), 129.5, 129.6 (2C),
133.9 ppm; MS (ESI) m/z 246 (M+H+, 100%); HRMS (ESI) calcd for [C17H28N]+
(M+H+): 246.2216; found: 246.2214.
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N-(1-p-Tolylpentyl)cyclohexanamine (2g)
Following general procedure, the reductive alkylation of amide 1g (217 mg, 1.0 mmol)
with nBuMgBr gave, after flash column chromatography on silica gel (eluent: EtOAc/
n-hexane = 1/ 20), the known amine 2g13 (233 mg, 90%). Colorless oil. IR (film)

max: 3314, 3039, 3015, 2926, 2853, 1512, 1449, 1124, 818 cm-1; 1H NMR (400 MHz,
CDCl3)  0.83 (t, J = 7.1 Hz, 3H), 0.96-1.32 (m, 9H), 1.48-1.72 (m, 6H), 1.93-2.02 (m,
1H), 2.19-2.28 (m, 1H), 2.34 (s, 3H, CH3), 3.70 (dd, J = 7.6, 6.4 Hz, 1H), 7.12 (d, J =
8.2 Hz, 2H), 7.09-7.18 (m, 4H) ppm; 13C NMR (100 MHz, CDCl3)  13.9, 21.1, 22.7,
24.8, 25.2, 26.1, 28.7, 32.8, 34.6, 38.5, 53.4, 59.4, 127.0 (2C), 128.9 (2C), 136.1,
141.9 ppm; MS (ESI) m/z 260 (M+H+, 100%); HRMS (ESI) calcd for [C18H30N]+
(M+H+): 260.2373; found: 260.2375.
N-Benzylhexadec-1-en-6-amine (2h)
Following the general procedure, the reductive alkylation of amide 1a (275 mg, 1.0
mmol) with 4-pentenylmagnesium bromide gave, after flash column chromatography
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on silica gel (eluent: EtOAc/ n-hexane = 1/ 10), amine 2h (309 mg, yield: 94%).
Colorless oil. IR (film) max: 3345, 3059, 3034, 2930, 2859, 1644, 1458, 910, 736,
703 cm-1; 1H NMR (400 MHz, CDCl3)  0.88 (t, J = 6.8 Hz, 3H), 1.22-1.32 (m, 16H),
1.38-1.46 (m, 6H), 2.00-2.08 (m, 2H), 2.50-2.58 (m, 1H), 3.75 (s, 2H), 4.92-5.04 (m,
2H), 5.75-5.87 (m, 1H), 7.19-7.36 (m, 5H) ppm; 13C NMR (100 MHz, CDCl3)  14.1,
22.7, 24.9, 25.6, 29.3, 29.6, 29.6 (2C), 29.9, 31.9, 33.4, 33.9, 34.0, 51.2, 56.6, 114.4,
126.8, 128.2 (2C), 128.3 (2C), 138.9, 141.0 ppm; HRMS (ESI) calcd for [C23H40N]+
(M+H+): 330.3155; found: 330.3155.
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N-Benzyl-1-cyclohexylundecan-1-amine (2i)
Following the general procedure, the reductive alkylation of amide 1a (275 mg, 1.0
mmol) with cyclohexylmagnesium bromide gave, after flash column chromatography
on silica gel (eluent: EtOAc/ n-hexane = 1/ 10), amine 2i (316 mg, yield: 92%).
Colorless oil. IR (film) max: 3361, 3092, 3066, 3021, 2918, 2851, 1457, 736, 695
1
cm-1; H NMR (400 MHz, CDCl3)  0.92 (t, J = 6.8 Hz, 3H), 1.03-1.52 (m, 23H),
1.65-1.85 (m, 6H), 2.30-2.38 (m, 1H), 3.74-3.83 (m, 2H), 7.24-7.40 (m, 5H) ppm; 13C
NMR (100 MHz, CDCl3)  14.1, 22.7, 26.4, 26.8 (2C), 26.8, 29.0, 29.2, 29.3, 29.6,
29.7 (2C), 30.0, 30.9, 31.9, 40.8, 52.0, 62.0, 126.7, 128.2 (2C), 128.3 (2C), 141.3 ppm;
HRMS (ESI) calcd for [C24H42N]+ (M+H+): 344.3312; found: 344.3314.
N-(1-Phenylpropyl)cyclohexanamine (2j)
Following the general procedure, the reductive alkylation of amide 1f (203 mg, 1.0
mmol) with EtMgBr gave, after flash column chromatography on silica gel (eluent:
EtOAc/ n-hexane = 1/ 30), amine 2j (176 mg, yield: 81%). Colorless oil; IR (film)
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max: 3497, 3062, 2929, 2857, 1607, 1492, 1456, 1289, 1242, 1167, 763, 703 cm-1; 1H
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NMR (400 MHz, CDCl3)  0.79 (t, J = 7.4 Hz, 3H), 0.98-1.42 (m, 5H), 1.54-2.10 (m,
7H), 2.41-2.50 (m, 1H), 3.91 (dd, J = 9.8, 4.8 Hz, 1H), 5.41 (br s, 1H), 7.32-7.44 (m,
5H) ppm; 13C NMR (100 MHz, CDCl3)  10.4, 24.5, 24.8, 25.2, 29.0, 29.8, 31.9, 54.6,
61.6, 127.6 (2C), 128.2, 128.9 (2C), 138.3 ppm; MS (ESI) m/z 218 (M+H+, 100%);
HRMS (ESI) calcd for [C15H24N]+ (M+H+): 218.1903; found: 218.1904.
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N-(1,2-Diphenylethyl)cyclohexanamine (2k)
Following the general procedure, the reductive alkylation of amide 1f (203 mg, 1.0
mmol) with BnMgBr gave, after flash column chromatography on silica gel (eluent:
EtOAc/ n-hexane = 1/ 30), the known amine 2k25a (237 mg, yield: 85%). Colorless oil;
IR (film) max: 3326, 3083, 3061, 3026, 2925, 2851, 1494, 1452, 1264, 1120, 742, 700
cm-1; 1H NMR (400 MHz, CDCl3)  0.76-1.16 (m, 5H), 1.44-1.88 (m, 5H), 2.18-2.27
(m, 1H), 2.82-2.97 (m, 2H), 4.05 (dd, J = 7.8, 6.3 Hz, 1H) 7.07-7.13 (m, 2H),
,
7.15-7.26 (m, 4H), 7.28-7.31 (m, 4H) ppm; 13C NMR (100 MHz, CDCl3)  24.7, 25.1,
26.0, 32.6, 34.7, 45.6, 53.4, 61.1, 126.2, 126.8, 127.2 (2C), 128.2 (2C), 128.2 (2C),
129.2 (2C), 140.0, 144.5 ppm; MS (ESI) m/z 280 (M+H+, 100%); HRMS (ESI) calcd
for [C20H26N]+ (M+H+): 280.2060; found: 280.2053.
N-(1-Phenylpropan-2-yl)cyclohexanamine (2l)
Following the general procedure, the reductive alkylation of amide 1c (141 mg, 1.0
mmol) with BnMgBr gave, after flash column chromatography on silica gel (eluent:
EtOAc/ n-hexane = 1/ 30), amine 2l (172 mg, yield: 79%). Colorless oil; IR (film)

max: 3311, 3084, 3061, 3026, 2925, 2852, 1601, 1495, 1451, 1140, 744, 670 cm-1; 1H
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NMR (400 MHz, CDCl3)  1.05 (d, J = 6.3 Hz, 3H), 0.86-1.30 (m, 5H), 1.54-1.74 (m,
3H), 1.80-1.95 (m, 2H), 2.52-2.64 (m, 2H), 2.80 (dd, J = 13.3, 6.3 Hz, 1H), 3.05-3.14
(m, 1H), 7.15-7.32 (m, 5H) ppm; 13C NMR (100 MHz, CDCl3)  20.5, 25.1, 25.2,
26.0, 33.1, 34.2, 43.6, 50.9, 53.5, 126.1, 128.3 (2C), 129.3 (2C), 139.4 ppm; MS (ESI)
m/z 218 (M+H+, 100%); HRMS (ESI) calcd for [C15H24N]+ (M+H+): 218.1903; found:
218.1908.
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N-(1-Cyclohexyl-2-phenylethyl)cyclohexanamine (2m)
Following general procedure, the reductive alkylation of amide 1h (209 mg, 1.0 mmol)
with BnMgBr gave, after flash column chromatography on silica gel (eluent: EtOAc/
n-hexane = 1/ 20), the known amine 2m13 (219 mg, 77%). Colorless oil. IR (film) max
3323, 3083, 3061, 3025, 2923, 2851, 1493, 1449, 1120, 744, 699 cm-1; 1H NMR (400
MHz, CDCl3)  0.76-1.28 (m, 10H), 1.34-1.85 (m, 11H), 2.21-2.31 (m, 1H), 2.53 (dd,
:
J = 13.2, 7.8 Hz, 1H), 2.63-2.71 (m, 1H), 2.77 (dd, J = 13.2, 5.4 Hz, 1H), 7.16-7.30 (m,
5H) ppm; 13C NMR (100 MHz, CDCl3)  25.1, 26.1, 26.6, 26.7, 26.8, 28.8, 29.1, 33.6,
34.2, 38.3, 41.0 (2C), 54.7, 61.4, 125.8, 128.2 (2C), 129.2 (2C), 140.6 ppm; MS (ESI)
m/z 286 (M+H+, 100%); HRMS (ESI) calcd for [C20H32N]+ (M+H+): 286.2529; found:
286.2530.
N-(1-Phenylbut-3-enyl)cyclohexanamine (2n)
Following the general procedure, the reductive alkylation of amide 1f (203 mg, 1.0
mmol) with allylmagnesium bromide gave, after flash column chromatography on
silica gel (eluent: EtOAc/ n-hexane = 1/ 30), the known amine 2n25b (199 mg, yield:
87%). Colorless oil; IR (film) max: 3368, 3061, 3024, 2926, 2852, 1491, 1450, 1114,
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759, 702 cm-1; H NMR (400 MHz, CDCl3)  0.92-1.20 (m, 5H), 1.48-1.71 (m, 4H),
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1.92-2.00 (m, 1H), 2.21-2.29 (m, 1H), 2.30-2.44 (m, 2H), 3.84 (dd, J = 7.6, 6.1 Hz,
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1H), 5.00-5.11 (m, 2H), 5.63-5.76 (m, 1H), 7.20-7.34 (m, 5H) ppm; C NMR (100
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MHz, CDCl3)  24.9, 25.2, 26.1, 32.9, 34.7, 43.5, 53.5, 59.0, 117.3, 126.7, 127.1 (2C),
128.2 (2C), 135.7, 144.7 ppm; MS (ESI) m/z 230 (M+H+, 100%).
N-[1-(4-Bromophenyl)pentyl]cyclohexanamine (2o)
Following general procedure, the reductive alkylation of amide 1i (281 mg, 1.0 mmol)
with nBuMgBr gave, after flash column chromatography on silica gel (eluent: EtOAc/
n-hexane = 1/ 20), the known amine 2o13 (220 mg, 68%). Colorless oil. IR (film) max
:
3323, 3018, 2925, 2852, 1589, 1483, 1449, 1125, 1009, 822 cm-1; 1H NMR (400 MHz,
CDCl3)  0.83 (t, J = 7.1 Hz, 3H), 0.90-1.32 (m, 9H), 1.48-1.70 (m, 6H), 1.90-1.98 (m,
1H), 2.14-2.23 (m, 1H), 3.70 (dd, J = 7.2, 6.8 Hz, 1H), 7.13-7.18 (m, 2H), 7.40-7.45
(m, 2H) ppm; 13C NMR (100 MHz, CDCl3)  13.9, 22.6, 24.8, 25.1, 26.1, 28.5, 32.9,
34.7, 38.5, 53.6, 59.2, 120.2, 128.9 (2C), 131.3 (2C), 144.3 ppm; MS (ESI) m/z 324
(M+H+, 100%); HRMS (ESI) calcd for [C17H27BrN]+ (M+H+): 324.1321; found:
324.1321 and 326.1306.
N-[1-(4-Methoxyphenyl)pentyl]cyclohexanamine (2p)
Following general procedure, the reductive alkylation of amide 1j (233 mg, 1.0 mmol)
with nBuMgBr gave, after flash column chromatography on silica gel (eluent: EtOAc/
n-hexane = 1/ 20), the known amine 2p13 (170 mg, 62%). Colorless oil. IR (film) max
:
1
3323, 3061, 3028, 2996, 2926, 2852, 1510, 1463, 1246, 1039, 831 cm-1; H NMR
(400 MHz, CDCl3)  0.83 (t, J = 7.1 Hz, 3H, CH3), 0.96-1.32 (m, 9H), 1.50-1.72 (m,
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6H), 1.93-2.01 (m, 1H), 2.18-2.27 (m, 1H), 3.69 (dd, J = 7.2, 6.8 Hz, 1H, CH), 3.80 (s,
3H, CH3), 6.83-6.89 (m, 2H), 7.15-7.21 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3) 
14.0, 22.7, 24.9, 25.2, 26.2, 28.7, 32.9, 34.7, 38.5, 53.4, 55.2, 59.0, 113.6 (2C), 128.1
(2C), 137.0, 158.3 ppm; MS (ESI) m/z 276 (M+H+, 100%); HRMS (ESI) calcd for
[C18H30NO]+ (M+H+): 276.2322; found: 276.2325.
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N-(1-Phenylpropan-2-yl)cyclohexanamine (2q)
Following general procedure, the reductive alkylation of amide 1f (203 mg, 1.0 mmol)
with lithium phenylacetylide gave, after flash column chromatography on silica gel
(eluent: EtOAc/ n-hexane = 1/ 20), the known amine 2q13 (219 mg, 76%). Colorless
oil. IR (film) max: 3391, 3059, 2923, 2850, 1598, 1489, 1449, 1263, 1112, 756, 692
cm-1; 1H NMR (400 MHz, CDCl3)  1.12-1.36 (m, 5H), 1.57-1.66 (m, 1H), 1.70-1.89
(m, 3H), 1.96-2.06 (m, 1H), 2.80-2.90 (m, 1H), 4.90 (s, 1H), 7.26-7.39 (m, 6H),
7.43-7.49 (m, 2H), 7.55-7.61 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3)  24.7, 25.0,
26.1, 32.6, 33.9, 51.5, 54.3, 85.0, 89.8, 123.2, 127.5 (2C), 127.6, 128.0, 128.2 (2C),
128.5 (2C), 131.7 (2C), 141.0 ppm; MS (ESI) m/z 290 (M+H+, 100%); HRMS (ESI)
calcd for [C21H24N]+ (M+H+): 290.1903; found: 290.1907.
N-(4-Phenylbut-3-yn-2-yl)cyclohexanamine (2r)
Following the general procedure, the reductive alkylation of amide 1c (141 mg, 1.0
mmol) with lithium phenylacetylide gave, after flash column chromatography on
silica gel (eluent: EtOAc/ n-hexane = 1/ 30), amine 2r (163 mg, yield: 72%).
Colorless oil; IR (film) max: 3305, 3079, 3054, 2927, 2852, 1597, 1489, 1449, 1125,
755, 691 cm-1; 1H NMR (400 MHz, CDCl3)  0.97-1.38 (m, 5H), 1.43 (d, J = 6.8 Hz,
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3.84 (q, J = 6.8 Hz, 1H), 7.26-7.32 (m, 3H), 7.38-7.44 (m, 2H) ppm; C NMR (100
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MHz, CDCl3)  22.9, 24.8, 25.2, 26.1, 32.5, 34.4, 42.4, 54.4, 82.5, 92.2, 123.4, 127.8,
128.2 (2C), 131.6 (2C) ppm; MS (ESI) m/z 228 (M+H+, 100%); HRMS (ESI) calcd
for [C16H22N]+ (M+H+): 228.1747; found: 228.1744.
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N-[1-(p-Tolyl)non-2-yn-1-yl]cyclohexanamine (2s)
Following the general procedure, the reductive alkylation of amide 1g (217 mg, 1.0
mmol) with 1-nonynyllithium gave, after flash column chromatography on silica gel
(eluent: EtOAc/ n-hexane = 1/ 10), amine 2s (252 mg, yield: 81%). Brown oil. IR
(film) max: 3328, 2930, 2847, 1507, 1453, 1113, 811, 715 cm-1; 1H NMR (400 MHz,
CDCl3)  0.90 (t, J = 6.9 Hz, 3H), 1.11-1.97 (m, 18H), 2.21-2.27 (m, 2H), 2.33 (s, 3H),
2.69-2.78 (m, 1H), 4.61 (br s, 1H), 7.14 (d, J = 7.9 Hz, 2H), 7.38 (d, J = 7.9 Hz, 2H)
ppm; 13C NMR (100 MHz, CDCl3)  14.0, 18.8, 21.0, 22.6, 24.8, 25.0, 26.1, 28.5,
28.8, 31.3, 32.7, 33.8, 50.8, 54.1 80.6, 85.1, 127.3 (2C), 129.0 (2C), 136.9, 138.8 ppm;
HRMS (ESI) calcd for [C22H34N]+ (M+H+): 312.2686; found: 312.2685.
Ethyl 3-(benzylamino)tridecanoate (2t)
Following the general procedure, the reductive alkylation of amide 1a (275 mg, 1.0
mmol) with EA enolate gave, after flash column chromatography on silica gel (eluent:
EtOAc/ n-hexane = 1/ 5), amine 2ab (284 mg, yield: 82%). Colorless oil. IR (film)

max: 3345, 3063, 3025, 2963, 2930, 2855, 1735, 1453, 1184, 735, 694 cm-1; 1H NMR
(400 MHz, CDCl3)  0.88 (t, J = 6.8 Hz, 3H), 1.20-1.36 (m, 21H), 1.38-1.57 (m, 2H),
1.69 (br s, 1H), 2.44 (d, J = 6.2 Hz, 2H), 2.97-3.06 (m, 1H), 3.78 (s, 2H), 4.13 (q, J =
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7.1 Hz, 2H), 7.16-7.38 (m, 5H) ppm; 13C NMR (100 MHz, CDCl3)  14.1, 14.2, 22.7,
25.6, 29.3, 29.5, 29.6 (2C), 29.7, 31.9, 34.3, 39.4, 51.0, 54.3, 60.2, 126.8, 128.1 (2C),
128.3 (2C), 140.6, 172.6 ppm; HRMS (ESI) calcd for [C22H38NO2]+ (M+H+):
348.2897; found: 348.2892.
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N-Benzyltetradec-1-en-4-amine (2u)
Following the general procedure, the reductive alkylation of amide 1a (275 mg, 1.0
mmol) with AllylSnBu3 gave, after flash column chromatography on silica gel (eluent:
EtOAc/ n-hexane = 1/ 20), amine 2t (271 mg, yield: 90%). Colorless oil. IR (film)
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
max: 3365, 3067, 3029, 2955, 2922, 2855, 1457, 73, 736, 690 cm-1; H NMR (400
MHz, CDCl3)  0.88 (t, J = 6.9 Hz, 3H), 1.20-1.50 (m, 18H), 2.12-2.32 (m, 2H),
2.56-2.65 (m, 1H), 3.77 (s, 2H), 5.04-5.12 (m, 2H), 5.72-5.85 (m, 1H), 7.20-7.35 (m,
5H) ppm; 13C NMR (100 MHz, CDCl3)  14.1, 22.7, 25.7, 29.3, 29.6 (3C), 29.9, 31.9,
33.9, 38.3, 51.2, 56.2, 117.1, 126.8, 128.1 (2C), 128.3 (2C), 135.8, 140.8 ppm; HRMS
(ESI) calcd for [C21H36N]+ (M+H+): 302.2842; found: 302.2844.
N-[1-(4-Methoxyphenyl)but-3-en-1-yl]cyclohexanamine (2v)
Following the general procedure, the reductive alkylation of amide 1j (233 mg, 1.0
mmol) with AllylSnBu3 gave, after flash column chromatography on silica gel (eluent:
EtOAc/ n-hexane = 1/ 50), amine 2u (255 mg, yield: 87%). Colorless oil. IR (film)
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
max: 3328, 3071, 2996, 2926, 2847, 1611, 1511, 1466, 1241, 1103, 827 cm-1; H
NMR (400 MHz, CDCl3)  0.94-1.18 (m, 5H), 1.44-1.71 (m, 4H), 1.91-2.00 (m, 1H),
2.20-2.29 (m, 1H), 2.30-2.40 (m, 2H), 3.80 (s, 3H), 3.76-3.83 (m, 1H), 4.99-5.10 (m,
13
2H), 5.62-5.75 (m, 1H), 6.86 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 8.6 Hz, 2H) ppm; C
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NMR (100 MHz, CDCl3)  24.9, 25.2, 26.1, 32.9, 34.7, 43.5, 53.4, 55.2, 58.3, 113.6
(2C), 117.2, 128.0 (2C), 135.8, 136.7, 158.4 ppm; HRMS (ESI) calcd for
[C17H26NO]+ (M+H+): 260.2009; found: 260.2009.
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Methyl 4-[1-(cyclohexylamino)but-3-en-1-yl]benzoate (2w)
Following the general procedure, the reductive alkylation of amide 1k (261 mg, 1.0
mmol) with AllylSnBu3 gave, after flash column chromatography on silica gel (eluent:
EtOAc/ n-hexane = 1/ 20), amine 2v (241 mg, yield: 84%). Colorless oil. IR (film)

max: 3324, 3083, 2976, 2926, 2847, 1723, 1611, 1433, 1279, 1109, 769, 703 cm-1; 1H
NMR (400 MHz, CDCl3)  0.92-1.18 (m, 5H), 1.30-1.70 (m, 4H), 1.89-1.98 (m, 1H),
2.16-2.26 (m, 1H), 2.28-2.43 (m, 2H), 3.90 (s, 3H), 3.87-3.93 (m, 1H), 5.01-5.11 (m,
13
2H), 5.61-5.74 (m, 1H), 7.40 (d, J = 8.3 Hz, 2H), 7.99 (d, J = 8.3 Hz, 2H) ppm; C
NMR (100 MHz, CDCl3)  24.8, 25.1, 26.1, 32.9, 34.7, 43.3, 51.9, 53.9, 59.0, 117.8,
127.1 (2C), 128.7, 129.6 (2C), 135.1, 150.4, 167.1 ppm; HRMS (ESI) calcd for
[C18H26NO2]+ (M+H+): 288.1958; found: 288.1962.
4-[1-(Cyclohexylamino)but-3-en-1-yl]benzonitrile (2x)
Following the general procedure, the reductive alkylation of amide 1l (228 mg, 1.0
mmol) with AllylSnBu3 gave, after flash column chromatography on silica gel (eluent:
EtOAc/ n-hexane = 1/ 10), amine 2w (211 mg, yield: 83%). Colorless oil. IR (film)

max: 3328, 3075, 3046, 2926, 2847, 2221, 1607, 1263, 732 cm-1; 1H NMR (400 MHz,
CDCl3)  0.94-1.20 (m, 5H), 1.40-1.74 (m, 4H), 1.87-1.97 (m, 1H), 2.14-2.23 (m, 1H),
2.25-2.40 (m, 2H), 3.90 (dd, J = 7.8, 5.7 Hz, 1H), 5.03-5.12 (m, 2H), 5.60-5.74 (m,
13
1H), 7.45 (d, J = 8.2 Hz, 2H), 7.61 (d, J = 8.2 Hz, 2H) ppm; C NMR (100 MHz,
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CDCl3)  24.8, 25.1, 26.0, 32.9, 34.7, 43.3, 54.0, 59.0, 110.5, 118.2, 119.0, 127.9 (2C),
132.1 (2C), 134.6, 150.9 ppm; HRMS (ESI) calcd for [C17H22N2]+ (M+H+): 255.1856;
found: 255.1857.
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N-[1-(4-Nitrophenyl)but-3-en-1-yl]cyclohexanamine (2y)
Following the general procedure, the reductive alkylation of amide 1m (248 mg, 1.0
mmol) with AllylSnBu3 gave, after flash column chromatography on silica gel (eluent:
EtOAc/ n-hexane = 1/ 10), amine 2x (222 mg, yield: 81%). Yellow oil. IR (film) max
:
3328, 3071, 2925, 2851, 1607, 1524, 1346, 857, 694 cm-1; H NMR (400 MHz,
CDCl3)  0.94-1.18 (m, 5H), 1.44-1.74 (m, 4H), 1.88-1.98 (m, 1H), 2.15-2.24 (m, 1H),
2.25-2.43 (m, 2H), 3.96 (dd, J = 7.8, 5.7 Hz, 1H), 5.04-5.12 (m, 2H), 5.62-5.75 (m,
1
13
1H), 7.52 (d, J = 8.7 Hz, 2H), 8.18 (d, J = 8.7 Hz, 2H) ppm; C NMR (100 MHz,
CDCl3)  24.8, 25.1, 26.0, 32.9, 34.7, 43.3, 54.1, 58.8, 118.3, 123.5 (2C), 127.9 (2C),
134.5, 146.9, 153.1 ppm; HRMS (ESI) calcd for [C16H23N2O2]+ (M+H+): 275.1754;
found: 275.1758.
4-[1-(Butylamino)but-3-en-1-yl]-N,N-diethylbenzamide (2z)
Following the general procedure, change the activated procedure into: amide 1n was
activated at 78 °C, stirred for 20 min. then keeping 20 °C for 20 min, and 0 °C 10
min. The reductive alkylation of amides 1n (276 mg, 1.0 mmol) with AllylSnBu3 gave,
after flash column chromatography on silica gel (eluent: EtOAc/ n-hexane = 1/ 2),
amine 2y (232 mg, yield: 77%). Colorless oil. IR (film) max: 3320, 3083, 2959, 2926,
1
2864, 1636, 1466, 1300, 1101, 840 cm-1; H NMR (400 MHz, CDCl3)  0.86 (t, J =
7.4 Hz, 3H), 1.13 (br s, 3H), 1.19-1.35 (m, 5H), 1.37-1.47 (m, 2H), 1.66 (br s, 1H),
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2.31-2.47 (m, 4H), 3.28 (br s, 2H), 3.55 (br s, 2H), 3.66 (dd, J = 7.4, 6.1 Hz, 1H),
5.02-5.13 (m, 2H), 5.64-5.77 (m, 1H), 7.34 (s, 4H) ppm; 13C NMR (100 MHz, CDCl3)
 12.8, 13.9, 14.2, 20.4, 32.2, 39.2, 42.9, 43.2, 47.4, 62.4, 117.6, 126.4 (2C), 127.1
(2C), 135.2, 135.8, 145.4, 171.3 ppm; HRMS (ESI) calcd for [C19H31N2O]+ (M+H+):
303.2431; found: 303.2429.
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1,1'-(1,4-Phenylene)bis(N-butylbut-3-en-1-amine) (2aa)
Following the general procedure, the reductive alkylation of amide 1o (276 mg, 1.0
mmol) with AllylSnBu3 gave, after flash column chromatography on silica gel (eluent:
EtOAc/ n-hexane = 1/ 10), amine 2z (292 mg, yield: 89%). Colorless oil. IR (film)
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
max: 3324, 3075, 2959, 2926, 2868, 2851, 2810, 1644, 1466, 1122, 927 cm-1; H
NMR (400 MHz, CDCl3)  0.86 (t, J = 7.3 Hz, 6H), 1.24-1.47 (m, 8H), 1.53-1.72 (m,
2H), 2.33-2.49 (m, 8H), 3.62 (dd, J = 7.3, 6.3 Hz, 2H), 5.00-5.13 (m, 4H), 5.64-5.79
(m, 2H), 7.24 (s, 4H) ppm; 13C NMR (100 MHz, CDCl3)  13.9 (2C), 20.4 (2C), 32.2
(2C), 42.9 (2C), 47.4 (2C), 62.4 (2C), 117.3 (2C), 127.0 (4C), 135.6 (2C), 142.6 (2C)
ppm; HRMS (ESI) calcd for [C22H37N2]+ (M+H+): 329.2951; found: 329.2956.
2-(Cyclohexylamino)-2-(4-methoxyphenyl)acetonitrile (2ab)
Following the general procedure, the reductive alkylation of amide 1j (233 mg, 1.0
mmol) with TMSCN gave, after flash column chromatography on silica gel (eluent:
EtOAc/ n-hexane = 1/ 5), amine 2aa (129 mg, yield: 53%). Colorless oil. IR (film)

max: 3338, 3071, 2996, 2926, 2847, 2221, 1511, 1466, 1241, 827 cm-1; 1H NMR (400
MHz, CDCl3)  1.07-1.38 (m, 5H), 1.59-1.67 (m, 1H), 1.70-1.82 (m, 3H), 1.93-2.03
(m, 1H), 2.79-2.90 (m, 1H), 3.81 (s, 3H), 4.78 (s, 1H), 6.91 (d, J = 8.7 Hz, 2H), 7.42
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(d, J = 8.7 Hz, 2H) ppm; C NMR (100 MHz, CDCl3)  24.2, 24.6, 25.9, 31.9, 33.8,
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51.0, 54.7, 55.3, 114.2 (2C), 119.5, 128.4 (2C), 131.9, 159.9 ppm; HRMS (ESI) calcd
for [C15H21N2O]+ (M+H+): 245.1648; found: 245.1647.
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Methyl 3-[(1-phenylbut-3-en-1-yl)amino]propanoate (2ac)
Following the general procedure, the reductive alkylation of amide 1q (207 mg, 1.0
mmol) with AllylSnBu3 gave, after flash column chromatography on silica gel (eluent:
EtOAc/ n-hexane = 1/ 2), amine 2ac (205 mg, yield: 88%). Colorless oil. IR (film)

max: 3332, 3079, 3025, 2976, 2942, 2922, 2843, 1727, 1445, 1167, 765, 711 cm-1; 1H
NMR (400 MHz, CDCl3)  1.93 (br s, 1H), 2.31-2.52 (m, 4H), 2.64-2.77 (m, 2H),
3.62-3.70 (m, 4H), 5.01-5.13 (m, 2H), 5.65-5.78 (m, 1H), 7.20-7.37 (m, 5H) ppm; 13C
NMR (100 MHz, CDCl3)  34.5, 42.7, 43.0, 51.5, 62.3, 117.5, 127.0, 127.1 (2C),
128.2 (2C), 135.3, 143.6, 173.2 ppm; HRMS (ESI) calcd for [C14H19NNaO2]+
(M+Na+): 256.1308; found: 256.1303.
N-Isopropyl-6-phenylhept-1-en-4-amine (2ad)
Following the general procedure, the reductive alkylation of amide 1r (205 mg, 1.0
mmol) with AllylSnBu3 gave, after flash column chromatography on silica gel (eluent:
EtOAc/ n-hexane = 1/ 5), amine 2ad (194 mg, dr = 1:1, yield: 84%). Colorless oil. IR
(film) max: 3320, 3083, 3067, 3025, 2959, 2930, 2868, 1453, 1379, 1176, 765, 703
cm-1; 1H NMR (400 MHz, CDCl3)  0.89 (d, J = 6.3 Hz, 3H), 1.01 (d, J = 6.3 Hz, 3H),
1.23 (d, J = 7.0 Hz, 3H), 1.48-1.57 (m, 1H), 1.67-1.77 (m, 1H), 2.04-2.19 (m, 2H),
2.44-2.52 (m, 1H), 2.74-2.85 (m, 1H), 2.86-2.96 (m, 1H), 4.98-5.10 (m, 2H),
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5.64-5.78 (m, 1H), 7.14-7.22 (m, 3H), 7.25-7.32 (m, 2H) ppm; C NMR (100 MHz,
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CDCl3)  23.0, 23.2, 23.9, 36.7, 38.8, 43.4, 45.2, 51.7, 117.2, 125.9, 127.1 (2C), 128.3
(2C), 135.4, 147.4 ppm; HRMS (ESI) calcd for [C16H26N]+ (M+H+): 232.2060; found:
232.2055.
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N-Isopropyl-1-(p-tolyl)pentan-1-amine (2ae)
Following the general procedure, the reductive alkylation of amide 1s (177 mg, 1.0
mmol) with nBuMgBr gave, after flash column chromatography on silica gel (eluent:
EtOAc/ n-hexane = 1/ 20), amine 2ae (175 mg, yield: 80%). Colorless oil. IR (film)

max: 3316, 3046, 2955, 2926, 2859, 1462, 1375, 1176, 818 cm-1; 1H NMR (400 MHz,
CDCl3)  0.83 (t, J = 7.1 Hz, 3H), 0.92 (d, J = 6.3 Hz, 3H), 1.00 (d, J = 6.3 Hz, 3H),
1.06-1.13 (m, 1H), 1.20-1.30 (m, 3H), 1.51-1.61 (m, 1H), 1.65-1.80 (m, 2H), 2.33 (s,
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3H), 2.54-2.62 (m, 1H), 3.63 (dd, J = 8.0, 5.9 Hz, 1H), 7.08-7.16 (m, 4H) ppm; C
NMR (100 MHz, CDCl3)  13.9, 21.0, 21.9, 22.7, 24.2, 28.6, 38.4, 45.4, 60.0, 127.0
(2C), 128.9 (2C), 136.2, 141.8 ppm; HRMS (ESI) calcd for [C15H26N]+ (M+H+):
220.2060; found: 220.2061.
1-(2-Ethylphenyl)-N-isopropyl-3-methylbut-3-en-1-amine (2af)
Following the general procedure, the reductive alkylation of amide 1t (191 mg, 1.0
mmol) with 2-methylallylmagnesium chloride gave, after flash column
chromatography on silica gel (eluent: EtOAc/ n-hexane = 1/ 20), amine 2af (178 mg,
yield: 77%). Colorless oil. IR (film) max: 3316, 3067, 3021, 2963, 2930, 2868, 1657,
1
1470, 1445, 1371, 898, 753 cm-1; H NMR (400 MHz, CDCl3)  0.95 (d, J = 6.3 Hz,
3H), 1.02 (d, J = 6.3 Hz, 3H), 1.26 (t, J = 7.6 Hz, 3H), 1.77 (s, 3H), 2.18-2.30 (m, 2H),
2.52-2.63 (m, 1H), 2.64-2.81 (m, 2H), 4.22 (dd, J = 8.7, 4.9 Hz, 1H), 4.80-4.88 (m,
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The Journal of Organic Chemistry
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2H), 7.13-7.24 (m, 3H), 7.56-7.62 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3)  15.6,
22.0, 22.3, 24.3, 25.2, 46.0, 47.3, 52.1, 113.2, 126.0, 126.4, 126.4, 128.4, 141.1, 142.6,
143.0 ppm; HRMS (ESI) calcd for [C16H26N]+ (M+H+): 232.2060; found: 232.2059.
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Acknowledgment: The authors are grateful for financial support from the National
Natural Science Foundation of China (21332007 and 21472153) and the Program for
Changjiang Scholars and Innovative Research Team in University of Ministry of
Education, China.
Supporting Information Available: 1H and 13C NMR spectra of all products. This
material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: pqhuang@xmu.edu.cn.
Author Contributions
‡ Y.-H. H. and K.-J. X. contributed equally to this work.
Notes
The authors declare no competing financial interest.
References
1. For a recent review on the recent developments in amide synthesis, see: (a) Lanigan, R. M.;
Sheppard, T. D. Eur. J. Org. Chem. 2013, 7453. (b) Yoo, W.-J.; Li, C.-J. J. Am. Chem. Soc.
2006, 128, 13064. (c) Nordstrøm, L. U.; Vogt, H.; Madsen, R. J. Am. Chem. Soc. 2008, 130,
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