Deammoniative condensation of primary allylic amines with nonallylic amines

Article abstract of DOI:10.1002/cjoc.201400406

An unprecedented deammoniative condensation reaction of primary allylic amines with nonallylic amines has been developed through C-N bond cleavage. In the presence of 5 mol% palladium diacetate, 10 mol% 1,4-bis(diphenylphosphino) butane (dppb), and 5 mol% p-toluenesulfonic acid (TsOH), a range of α-unbranched primary allylic amines smoothly underwent deammoniative condensation with nonallylic amines in an α-selective fashion to give structurally diverse secondary and tertiary amines in good to excellent yields and E selectivity. Replacing dppb with racemic 2,2-bis(diphenylphosphino)-1,1- binaphthyl (BINAP) permitted the deammoniative condensation of enantioenriched α-chiral primary allylic amines with nonallylic amines to proceed with complete retention of configuration. Electrospray ionization (ESI) mass spectrometric analysis of the reaction mixture permitted the identification of some π-allylpalladium intermediates, and plausible mechanisms have been proposed to account for the regioselectivity and stereospecificity of the deammoniative condensation reaction. A range of enantioenriched primary allylic amines underwent palladium/acid-catalyzed direct substitution with nonallylic amines in a stereospecific manner. Copyright

Full text of DOI:10.1002/cjoc.201400406

FULL PAPER
DOI: 10.1002/cjoc.201400406
Deammoniative Condensation of Primary Allylic Amines with
Nonallylic Amines†
Yong Wang,a Manbo Li,a Xiantao Ma,a Congrong Liu,a,b Yonghong Gu,*,a and Shi-Kai Tian*,a
a Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China
b Department of Environmental Engineering, Nanjing Institute of Technology, Nanjing, Jiangsu 211167, China
An unprecedented deammoniative condensation reaction of primary allylic amines with nonallylic amines has
been developed through C－N bond cleavage. In the presence of 5 mol% palladium diacetate, 10 mol%
1,4-bis(diphenylphosphino)butane (dppb), and 5 mol% p-toluenesulfonic acid (TsOH), a range of α-unbranched
primary allylic amines smoothly underwent deammoniative condensation with nonallylic amines in an α-selective
fashion to give structurally diverse secondary and tertiary amines in good to excellent yields and E selectivity. Re-
placing dppb with racemic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) permitted the deammoniative
condensation of enantioenriched α-chiral primary allylic amines with nonallylic amines to proceed with complete
retention of configuration. Electrospray ionization (ESI) mass spectrometric analysis of the reaction mixture per-
mitted the identification of some π-allylpalladium intermediates, and plausible mechanisms have been proposed to
account for the regioselectivity and stereospecificity of the deammoniative condensation reaction.
Keywords amines, deammoniation, palladium, substitution, stereospecificity
Introduction
and tertiary allylic amines as allylic electrophiles,[4-6]
and only very recently it has witnessed the disclosure of
the allylic substitution reaction with primary allylic
amines, which exhibits much higher atom-economy
relative to that with commonly used allylic electro-
philes.[7] Thus, it is challenging, but rewarding with re-
gard to the exploration of new reactivity and selectivity,
to develop new nucleophilic substitution reactions of
allylic amines. Although in many cases the synthetic
routes to allylic amines are not shorter than that to ally-
lic halides and alcohol derivatives, chromatography can
often be avoided during the purification of allylic
amines. Owing to their basicity, allylic amines can be
easily purified using simple extractive procedures.[7]
Moreover, a number of racemic allylic amines can be
readily resolved by inexpensive tartaric acid,[7,8] and
consequently, optically active allylic amines can be eas-
ily prepared in large quantities.
Sporadic examples have shown that secondary and
tertiary allylic amines can undergo metal-catalyzed sub-
stitution with nonallylic amines (amine exchange)
[Scheme 1(a)]. As early as 1980, Trost and Keinan dis-
closed a Pd(PPh3)4-catalyzed exchange of 4,4'-dimeth-
oxybenzhydrylsorbylamine with benzylamine in the
presence of a stoichiometric amount of acetic acid.[5a]
Seventeen years later, Mortreux and coworkers reported
nickel- and palladium-catalyzed exchanges of N,N-
The nucleophilic substitution of allylic compounds is
extremely useful for the introduction of the allyl moiety
to target compounds, which permits a broad range of
transformations such as oxidation, reduction, and addi-
tion.[1] While allylic halides and sulfonates frequently
serve as reactive allylic electrophiles for the allylic sub-
stitution reaction in the absence of catalysts and addi-
tives, the employment of transition metals, particularly
palladium (the Tsuji-Trost reaction),[2] as catalysts per-
mits the allylic substitution reaction to proceed under
relatively mild conditions, and more importantly, ex-
tends the scope of electrophiles to allylic alcohols and
their derivatives such as carboxylates, carbonates, car-
bamates, phosphates, and epoxides. It is noteworthy that
the allylic substitution reaction is significantly affected
by the nature of the leaving groups of allylic electro-
philes, and consequently, the exploration of new allylic
electrophiles constitutes a promising strategy to address
certain reactivity, selectivity, and productivity issues.
In sharp contrast to allylic halides and alcohol de-
rivatives, allylic amines have rarely been employed di-
rectly as allylic electrophiles in the Tsuji-Trost reaction
through allylic C－N bond cleavage despite its wide
application in protective group chemistry.[3] Moreover,
previous reports focus on the employment of secondary
*
E-mail: ygu01@ustc.edu.cn; tiansk@ustc.edu.cn
Received June 22, 2014; accepted August 6, 2014; published online August 25, 2014.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201400406 or from the author.
Dedicated to Professor Chengye Yuan and Professor Li-Xin Dai on the occasion of their 90th birthdays.
†
Chin. J. Chem. 2014, 32, 741—751
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
741

Wang et al.
FULL PAPER
diethylallylamine with 10 equiv. of piperidine in the
presence of 5－50 equiv. of acetic acid.[5b] In 2002,
Hartwig and coworkers reported nickel- and palla-
dium-catalyzed exchanges of N-substituted 2-cyclo-
hexen-1-ylamines with primary and secondary nonally-
lic amines in the presence of 10 mol% trifluoroacetic
acid.[5c] Moreover, they observed the racemization of
(S)-N-(2-cyclohexen-1-yl)aniline under the exchange
conditions. In 2005, Yudin and Waston[5d] reported pal-
ladium-catalyzed exchanges of N,N-disubstituted
2-amino-2-methyl-3-butenes with secondary nonallylic
amines. In these reports, a large excess of nonallylic
amines were required for the sake of attaining high
conversion. Moreover, effective chirality transfer has
not been addressed.
velop a deammoniative condensation reaction of
α-unbranched primary allylic amines with nonallylic
amines, wherein chirality transfer was not involved. A
number of readily accessible palladium sources (5
mol%) and ligands were examined in the model reaction
of α-unbranched primary allylic amine 1a with nonally-
lic amine 2a in dioxane under a nitrogen atmosphere at
80 ℃ (Table 1, Entries 1－12). While most of the pal-
ladium sources and ligands failed to promote the desired
reaction, the use of Pd(OAc)2/dppb (1∶2) resulted in
the formation of tertiary amine 3a in 15% yield (Table 1,
Entry 10). Reasoning that the NH2 group in allylic
amine 1a might be activated by an acid facilitating
cleavage of the allylic C－N bond by the palladium
catalyst,[7] we examined a few Brønsted and Lewis acids
(5 mol%) and found that they dramatically affected
Scheme 1 Substitution of allylic amines with nonallylic amines
Table 1 Optimization of reaction conditionsa
(a) Previous reports (amine exchange):[5]
Pd source (5 mol%)
ligand (10 mol%)
NR3R4
R2
NR5R6
R2
NH2
O
O
NHR3R4
NHR1R2
+
NHR5R6
Ph
N
HN
2a
R1
R1
+
+
Ph
acid (5 mol%)
solvent, 80 o
C
1a
3a
Acid Solvent Yieldb/%
NR1R2
Me
Me
Entry Pd source
Ligand
NHR3R4
NR3R4
+
+
1
2
Pd(PPh3)4
Pd2(dba)3
none
none
none
none
none
none dioxane
none dioxane
none dioxane
none dioxane
none dioxane
none dioxane
none dioxane
none dioxane
none dioxane
none dioxane
none dioxane
none dioxane
PhCO2H dioxane
TsOH dioxane
B(OH)3 dioxane
ZnCl2 dioxane
AlCl3 dioxane
Bi2(SO4)3 dioxane
trace
0
Me
Me
(b) This work (deammoniative condensation):
NH2
3
Pd(PPh3)2Cl2
PdCl2
0
NR4R5
4
0
NHR4R5
5
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
0
R1
R3 +
R1
R3
+
NH3
c
R2
R2
6
PPh3
PCy3
trace
0
c
7
Reasoning that in the aforementioned reactions non-
allylic amines were generated as byproducts and they
could serve as nitrogen nucleophiles to compete with
the starting amines, we envisioned that the reaction effi-
ciency could be significantly improved by alternative
use of primary allylic amines as the allylic electrophiles,
yielding ammonia as a single byproduct, the extrusion
of which would constitute a key driving force for the
reaction to reach high conversion [Scheme 1(b)]. In the
course of exploring the synthetic utilities of C(sp3)-N
bond cleavage,[7,9] we found that palladium/acid was
able to catalyze the deammoniative condensation of
primary allylic amines with nonallylic amines (1.2
equiv.) in a stereospecific manner. The reaction exhibits
higher atom-economy than other relevant allylic subs-
titution[2] and the N-alkylation of primary allylic amines
(see below) for the synthesis of the same target amines,
and moreover, it complements known asymmetric
methods[10,11] in substrate scope via its unique ability to
prepare acyclic α-chiral secondary and tertiary allylic
amines with high optical purity starting from unsym-
metrical allylic electrophiles whose α-substituents are
different from γ-substituents.
8
(±)-BINAP
Xantphos
dppb
10
trace
15
0
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25e
TMEDA
(±)-BINOL
dppb
0
17
97d
24
trace
21
0
dppb
dppb
dppb
dppb
dppb
dppb
TsOH
DME
90
42
88
trace
trace
21
60
dppb
TsOH toluene
TsOH MeCN
dppb
dppb
TsOH
TsOH DMSO
TsOH EtOH
TsOH dioxane
DMF
dppb
dppb
dppb
a
Reaction conditions: amine 1a (0.50 mmol), amine 2a (0.60
mmol), Pd source (5 mol%), ligand (if any, 10 mol%), acid (if
any, 5 mol%), solvent (0.50 mL), 80 ℃, 10 min. b Isolated yield.
c 20 mol% ligand was used. d 98∶2 E/Z. e The reaction was per-
formed at 60 ℃.
Results and Discussion
At the outset we investigated the possibility to de-
742
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© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 741—751

Deammoniative Condensation of Primary Allylic Amines with Nonallylic Amines
the deammoniative condensation reaction (Table 1, En-
tries 13－18). To our delight, in the presence of 5 mol%
TsOH the reaction went to completion in only 10 min
and gave tertiary amine 3a in 97% yield with 98∶2 E/Z
selectivity (Table 1, Entry 14). Replacing dioxane with
other common solvents or lowering the temperature led
to the formation of the desired product in much lower
yields (Table 1, Entries 19－25).
Table 2 Deammoniative condensation of α-unbranche dprimary
allylic amines with nonallylic aminesa
Pd(OAc)2 (5 mol%)
dppb (10 mol%)
NH2
NRR'
R
N
R1
R1
+
H
R'
TsOH (5 mol%)
dioxane, 80 oC
R2
R2
2
3
1
Yieldb/
%
Entry
1, R1, R2
2, NRR'
3
E∶Zc
98∶2
In the presence of 5 mol% Pd(OAc)2, 10 mol% dppb,
and 5 mol% TsOH, a range of α-unbranched primary
allylic amines smoothly underwent deammoniative
condensation with nonallylic amines in an α-selective
fashion to give the desired secondary and tertiary
amines in good to excellent yields and E selectivity
(Table 2). In some cases TsOH was replaced with ZnCl2
and higher temperature was required in order to achieve
better yields (Table 2, Entries 5, 7, 8, 16, and 17). Both
alkyl- and arylamines served as suitable nitrogen nu-
cleophiles, and the β- and γ-positions of the
α-unbranched primary allylic amines could bear sub-
stituents such as aryl, heteroaryl, and alkyl groups. The
reaction tolerated functional groups such as nitrile,
chloro, and hydroxy groups. It is noteworthy that race-
mization was not observed in the deammoniative con-
densation reaction with optically active benzylic amines
2m and 2n (Table 2, Entries 13 and 14). When the
β-position of the α-unbranched primary allylic amine
was occupied by a substituent, significant geometric
isomerization was observed for the olefinic C＝C dou-
ble bond (Table 2, Entry 24). Such geometric isomeri-
zation was attributed to the π-σ-π-isomerization of the
π-allylpalladium intermediate generated from the palla-
dium catalyst and the allylic amine (see below).
1
2
1a, Ph, H
1a, Ph, H
1a, Ph, H
1a, Ph, H
1a, Ph, H
1a, Ph, H
2a, N(CH2CH2)2O 3a 97
2b, 1-Piperidinyl 3b 96 ＞99∶1
3
2c, N(CH2Ph)2 3c 78
2d, N(Me)CH2Ph 3d 88
98∶2
98∶2
4
5d
2e, N(Me)Ph
2f, NHPh
3e 84 ＞99∶1
3f 85 99∶1
6
HN
X
7d
8d
9
1a, Ph, H
1a, Ph, H
1a, Ph, H
1a, Ph, H
1a, Ph, H
1a, Ph, H
2g, X＝2-OMe 3g 82 ＞99∶1
2h, X＝2-CN 3h 67 ＞99∶1
2i, X＝4-OMe 3i 86
98∶2
10
11
12
2j, X＝4-Cl 3j 76 ＞99∶1
2k, NHCH2Ph 3k 60 ＞99∶1
2l, NHCHPh2 3l 70 ＞99∶1
NH
X
Ph
13
14
1a, Ph, H
1a, Ph, H
2m, X＝He
2n, X＝OH f
3m 62 ＞99∶1
3n 70 ＞99∶1
15
1a, Ph, H
2o,
3o 89
99:1
The standard reaction conditions were further ap-
plied to α-chiral primary allylic amine 4a, whose optical
purity was 97% ee. Whereas the deammoniative con-
densation of chiral amine 4a with amine 2k proceeded
in an α-selective fashion with retention of configuration
to give chiral amine 5a in 85% yield with extremely
high E selectivity, the optical purity of the product was
determined to be only 35% ee (Table 3, Entry 1). The
partial loss of enantiopurity could be attributed to the
generation of the π-allylpalladium intermediate that
would undergo racemization via Pd-Pd-exchange de-
pending on the nature of the ligand (see below).[2] To
achieve an effective chirality transfer, we surveyed a
few phosphine ligands and found that the use of racemic
BINAP as the ligand led to the formation of chiral
amine 5a in 84% yield with 97% ee (Table 3, Entry 3).
Moreover, no change was observed with the enantiopu-
rity of the product when prolonging the reaction time
from 1 to 3 h. Both optically active (R)-BINAP and
(S)-BINAP were examined for comparison. Although
the use of (R)-BINAP gave a much higher yield than
that of (S)-BINAP, in both cases the chirality was com-
pletely transferred with the same sense of chirality as
substrate 4a (Table 3, Entries 4 and 5). These results
indicated that the stereochemistry of the reaction was
N
16d 1b, 2-MeOC6H4, H
17d 1c, 4-MeOC6H4, H
18 1d, 4-CF3C6H4, H
19 1e, 1-Naphthyl, H
20 1f, 2-Thienyl, H
21 1g, 3-Pyridinyl, H
22 1h, Me(CH2)6, H
2o
3p 74 ＞99∶1
3q 98 ＞99∶1
3r 83 ＞99∶1
2o
2o
2o
2o
2o
2o
2o
2o
3s 84
3t 98
3u 83
94∶6
97∶3
97∶3
3v 64 ＞99∶1
3w 93
23g
1i, H, H
24
1j, Ph, Me
3x 97 84∶16
a Reaction conditions: amine 1 (0.50 mmol), amine 2 (0.60 mmol),
Pd(OAc)2 (5 mol%), dppb (10 mol%), TsOH (5 mol%), dioxane
(0.50 mL), 80 ℃, 10 min. b Isolated yield. c Determined by H
1
NMR spectroscopic analysis. d The reaction was performed with
5 mol% ZnCl2 instead of TsOH at 110 ℃ for 4 h. e 95% ee.
＞99% ee. g The reaction was performed in a sealed tube.
f
determined by the substrate rather than the ligand. Fi-
nally, we decided to use racemic BINAP, which is less
expensive than the optically active one, as the ligand
since it resulted in complete retention of configuration
as well as a good yield (Table 3, Entry 3).
Chin. J. Chem. 2014, 32, 741—751
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Wang et al.
FULL PAPER
Table 3 Survey of the ligandsa
Continued
Entry 4
2
5
Yieldd/%
eee/% Entry
Pd(OAc)2 (5 mol%)
ligand (10 mol%)
NH2
HN
Ph
Me
3
4a 2q 5c R＝H, R'＝(CH2)5Me
4a 2r 5d R＝H, R'＝Cy
96
87
92
82
69
90
97
97
97
97
97
97
NH2CH2Ph
+
Me
Ph
4a (97% ee)
Ph
TsOH (5 mol%)
dioxane, 80 o
C
4
5a
2k
5f
6 f
7f
8
4a 2f 5e R＝H, R'＝Ph
Entry
Ligand
dppb
Yieldb/%
E∶Zc
eed/%
35
4a 2d 5f R＝CH2Ph, R'＝Me
4a 2c 5g R＝R'＝CH2Ph
4a 2a 5h NRR'＝N(CH2CH2)2O
1
2
3
4
85
82
84
86
54
＞99∶1
＞99∶1
＞99∶1
＞99∶1
＞99∶1
Xantphos
0
(±)-BINAP
(R)-BINAP
(S)-BINAP
97
97
5
a
97
N
Reaction conditions: amine 4a (0.50 mmol), amine 2k (0.60
mmol), Pd(OAc)2 (5 mol%), ligand (10 mol%), TsOH (5 mol%),
dioxane (0.50 mL), 80 ℃, 1 h. b Isolated yield. c Determined by
1H NMR spectroscopic analysis. d Determined by HPLC analysis
on a chiral stationary phase.
R''
Ph
9
4a 2o 5i R''＝H
82
62
97
93
10g 4b 2o 5j R''＝Me
Cl
HN Ph
Me
11g
77
96
4c 2k 5k
In the presence of 5 mol% Pd(OAc)2, 10 mol% ra-
cemic BINAP, and 5 mol% TsOH, a range of unsym-
metrical α-chiral primary allylic amines (α-substituent ≠
γ-substituent) smoothly underwent deammoniative con-
densation with various primary and secondary nonally-
lic amines in an α-selective fashion to give structurally
diverse α-chiral amines in good to excellent yields with
complete retention of configuration (Table 4). In some
cases, the yields were enhanced significantly by replac-
ing TsOH with ZnCl2 and by prolonging the reaction
time from 1 to 10 h (Table 4, Entries 5－7). The α-, β-
and γ-positions of α-chiral primary allylic amines could
bear aryl and alkyl groups, and alkyl- and arylamines
served as suitable nitrogen nucleophiles.
12
80
90
4d 2o 5l
N
Me
HN Ph
Me
13g
14g
85
70
98
98
4e 2k 5m
Ph
Me
HN
Me
4f 2k
5nh
Ph
a Reaction conditions: amine 4 (0.50 mmol), amine 2 (0.60 mmol),
Pd(OAc)2 (5 mol%), racemic BINAP (10 mol%), TsOH (5
mol%), dioxane (0.50 mL), 80 ℃, 1 h. b Unless otherwise stated,
the reaction gave ＞99∶1 E/Z selectivity. c See below for the
assignment of the absolute configuration of products 5. d Isolated
yield. e Determined by HPLC analysis on a chiral stationary phase.
f The reaction was performed in the presence of 5 mol% ZnCl2
instead of TsOH for 10 h. g The reaction was performed for 4 h.
h 91∶9 E/Z.
Table 4 Deammoniative condensation of α-chiral primary ally-
lic amines with nonallylic aminesa-c
Pd(OAc)2 (5 mol%)
R
R'
NH2
R3
N
R
N
(±)-BINAP (10 mol%)
R1
+
H
R'
R1
R3
TsOH (5 mol%)
dioxane, 80 oC
R2
R2
4
2
5
NH2
Me
Cl
NH2
Me
NH2
R3
Ph
4a, R3 = Me (97% ee)
4b, R3 = Et (93% ee)
The regioselectivity depends largely on the structure
of the unsymmetrical α-chiral primary allylic amine.
Chiral amine 4g is a regioisomer of chiral amine 4a, and
they were expected to go through the same π-allyl-
palladium intermediate to give the same product in the
deammoniative condensation reaction with a nonallylic
amine. Indeed, the deammoniative condensation of
chiral amine 4g with amine 2o proceeded in a
γ-selective fashion to give chiral amine 5i in 90% yield
with complete retention of configuration (Scheme 2).
The γ-selectivity probably arises from both maximizing
conjugation and minimizing steric hindrance prior to the
attack of the nitrogen nucleophile on the π-allylpal-
ladium intermediate (see below).
4d (90% ee)
4c (96% ee)
NH2
Me
NH2
NH2
NH2
R
Ph
Me
Me
2p, R = Ph
2q, R = (CH2)3Me
4f (98% ee)
4e (98% ee)
2r
Entry 4
2
5
Yieldd/%eee/%
NRR'
Me
Ph
1
2
4a 2k 5a R＝H, R'＝CH2Ph
4a 2p 5b R＝H, R'＝(CH2)2Ph
84
95
97
97
744
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Chin. J. Chem. 2014, 32, 741—751

Deammoniative Condensation of Primary Allylic Amines with Nonallylic Amines
Scheme 2 Reactions of chiral amines 4g and 4h
To gain more insights into the reaction mechanism,
we carried out electrospray ionization (ESI) mass spec-
trometric analysis of the reaction mixture of amine 4a
and amine 2a in the presence of 5 mol% Pd(OAc)2, 10
mol% racemic BINAP, and 5 mol% TsOH, and tenta-
tively identified diallylic amine 6a, triallylic amine 7a,
and π-allylpalladiums 8a and 9a according to the high
resolution mass data (Table 5). These results indicate
that the allylic C－N bond of the allylic amine is
cleaved by a Pd(0) species, which is generated in situ
from Pd(OAc)2 through reduction with the amine sub-
strate and/or the phosphine ligand.[12]
NH2
Ph
R
4g, R = Me, 96% ee
4h, R = Ph, 98% ee
Pd(OAc)2 (5 mol%)
(±)-BINAP (10 mol%)
HN
TsOH (5 mol%)
dioxane, 80o
N
N
2o
R = Me
C
R = Ph
Ph
5o, 76%
Ph
Ph
Me
5i, 90%
> 99:1 E/Z, 96% ee
> 99:1 E/Z, 0% ee
Table 5 High resolution mass data
We also examined the reaction of a symmetrical
α-chiral primary allylic amine (α-substituent＝γ-sub-
stituent). Treatment of chiral amine 4h with amine 2o
under the standard reaction conditions led to the forma-
tion of racemic amine 5o in 76% yield (Scheme 2). The
complete loss of enantio purity was attributed to the
symmetry of the resulting π-allylpalladium intermediate
(see below).
Racemization was not observed with chiral amine 5h
when treating it with 5 mol% Pd(OAc)2, 10 mol% ra-
cemic BINAP, and 5 mol% TsOH, and moreover, the
addition of a nonallylic amine did not change the optical
purity of the remaining chiral amine. The extrusion of
ammonia, a gaseous byproduct, from the reaction mix-
ture was speculated to constitute a key driving force for
the deammoniative condensation reaction to go to com-
pletion. For comparison, we carried out the following
two experiments. Treatment of chiral amine 5h with 10
equiv. of ammonium bicarbonate, which decomposed to
generate ammonia at an elevated temperature, under the
standard reaction conditions resulted in the formation of
chiral amine 4a in only 15% yield with complete reten-
tion of configuration (Scheme 3). On the other hand, the
exchange reaction of chiral amine 5h with amine 2o (1
equiv.) proceeded in an α-selective fashion to give
chiral amine 5i in 42% conversion with complete reten-
tion of configuration. The conversion was unsatisfactory
because of the generation of amine 2a as a byproduct,
which served as a nitrogen nucleophile to compete ei-
ther with ammonia or with amine 2o during the reaction.
Entry Species
Formula
Mass (calcd) Mass (found)
1
2
3
4
[6a＋H]＋ C20H24N＋
[7a＋H]＋ C30H34N＋
278.19033
408.26858
278.18991
408.26718
876.21350
859.18909
8a
9a
C54H46NP2Pd＋ 876.21348
C54H43P2Pd＋
859.18693
On the basis of our experimental results and the
general mechanism of the Tsuji-Trost reaction,[2] we
propose the following catalytic cycles for the stereo-
specific deammoniative condensation of α-chiral pri-
mary allylic amines with nonallylic amines (Scheme 4).
The NH2 group in chiral amine 4 is activated by TsOH
and the allylic C－N bond is cleaved by a Pd(0) species,
PdLn, with inversion of configuration to give π-allylpal-
ladium 8, which releases ammonia to yield a more elec-
trophilic species, π-allylpalladium 9. The allylic carbon
of π-allylpalladium 9 is attacked by amine 2 with inver-
sion of configuration to give chiral amine 5 and concur-
rently regenerate Pd(0) to continue the catalytic cycle.
The double inversion of configuration leads to net
stereoretention. Moreover, the regioselectivity is deter-
mined by the steric and electronic properties of the R1
and R3 groups, and the attack of amine 2 on π-allylpal-
ladium 9 prefers to take place at the allylic position
having less steric hindrance and/or leading to a higher
degree of conjugation. If R1＝R3, the reaction would
lose optical purity completely because of the symmetry
of the π-allylpalladium intermediate. Although chiral
amine 4 can serve as a nitrogen nucleophile to attack
π-allylpalladium 9 to give diallylic amine 6, which un-
dergoes a similar reaction to give triallylic amine 7, both
amines are transformed into chiral amine 5 with reten-
tion of configuration through the intermediacy of
π-allylpalladium 9.
Scheme 3 Reaction of chiral amine 5h with ammonium bicar-
bonate or amine 2o
NH4HCO3
(10 equiv.)
NH2
Me
Ph
Pd(OAc)2 (5 mol%)
(±)-BINAP (10 mol%)
TsOH (5 mol%)
4a, 15%
>99:1 E/Z, 97% ee
O
N
dioxane, 80o C
Me
Ph
5h (97% ee)
HN
N
5i
2o (1 equiv.)
Ph
Me
5i:5h = 42:58
>99:1 E/Z, 97% ee
Chin. J. Chem. 2014, 32, 741—751
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
745

Wang et al.
FULL PAPER
Scheme 4 Proposed catalytic cycles
Conclusions
detection was monitored at 254 nm. The chiral HPLC
methods were calibrated with the corresponding racemic
mixtures. Optical rotations were measured on a polari-
meter with a sodium lamp at λ＝589 nm and reported as
[α]DT (c＝g/100 mL, solvent). Melting points are uncor-
rected.
All the starting amines are known compounds.
Amines 1a－1h and 1j and chiral amines 4a－4h were
prepared according to literature procedures.[7a-7c] The
rest of chemicals were purchased and used as received.
Abbreviations: Ac＝acetyl, BINAP＝2,2'-bis(diphe-
nylphosphino)-1,1'-binaphthyl, BINOL ＝ 1,1'-binaph-
thol, Cy ＝cyclohexyl, dba ＝dibenzylideneacetone,
DME ＝1,2-dimethoxyethane, DMF ＝N,N-dimethyl-
formamide, DMSO＝dimethylsulfoxide, dppb＝1,4-bis-
(diphenylphosphino)butane, TMEDA＝N,N,N',N'-tetra-
methylethylenediamine, Ts＝p-toluenesulfonyl, Xant-
phos ＝ 4,5-bis(diphenylphosphino)-9,9-dimethylxanth-
ene.
We have developed, for the first time, an efficient
deammoniative condensation reaction of primary allylic
amines with nonallylic amines in a highly regioselective
and stereospecific manner by taking advantage of
yielding ammonia as a single byproduct, the extrusion
of which constitutes a key driving force for the reaction
to reach high conversion. In the presence of 5 mol%
Pd(OAc)2, 10 mol% dppb, and 5 mol% TsOH, a range
of α-unbranched primary allylic amines smoothly un-
derwent deammoniative condensation with nonallylic
amines in an α-selective fashion to give structurally di-
verse secondary and tertiary amines in good to excellent
yields and E selectivity. Replacing dppb with racemic
BINAP permitted the deammoniative condensation of
α-chiral primary allylic amines with nonallylic amines
to proceed with complete retention of configuration. In
addition, ESI mass spectrometric analysis of the reac-
tion mixture allowed the identification of some
π-allylpalladium intermediates, and plausible mecha-
nisms have been proposed to account for the regioselec-
tivity and stereospecificity of the deammoniative con-
densation reaction. The current study not only signifi-
cantly extends the synthetic utilities of readily accessi-
ble primary allylic amines through C(sp3)－N bond
cleavage, but also provides a promising approach for the
development of atom-economic and selective allylic
substitution reactions.
General procedure for the deammoniative condensa-
tion of α-unbranched primary allylic amines with
nonallylic amines
A mixture of α-unbranched primary allylic amine 1
(0.50 mmol), nonallylic amine 2 (0.60 mmol), TsOH•
H2O (4.76 mg, 5 mol%), dppb (21.3 mg, 10 mol%), and
Pd(OAc)2 (5.61 mg, 5 mol%) in dioxane (0.50 mL) was
heated under nitrogen at 80 ℃ for 10 min. The mixture
was cooled to room temperature and purified by silica
gel chromatography, eluting with ethyl acetate/petro-
leum ether (1∶20－1∶2), to give amine 3. The E/Z
ratios of the products were determined by integrating
the vinyl proton signals in the 1H NMR spectra.
Experimental
General information
1H NMR and 13C NMR spectra were recorded using
tetramethylsilane as an internal reference. NMR multi-
plicities are abbreviated as follows: s＝singlet, d＝
doublet, t＝triplet, m＝multiplet. High pressure liquid
chromatography (HPLC) analyses were performed on
an instrument equipped with an isostatic pump using a
chiral stationary phase column (250 mm×4.6 mm) with
n-hexane/isopropanol as the mobile phase, and the UV
Analytical data for the new compounds are shown in
Table 2.
Amine 3p, colorless oil; 1H NMR (400 MHz, CDCl3)
δ: 7.47 (dd, J＝7.6, 1.6 Hz, 1H), 7.23－7.15 (m, 1H),
7.12－7.05 (m, 3H), 7.03－6.87 (m, 3H), 6.86－6.83
(m, 1H), 6.37 (dt, J＝16.0, 6.8 Hz, 1H), 3.81 (s, 3H),
3.66 (s, 2H), 3.33 (dd, J＝6.8, 1.2 Hz, 2H), 2.91 (t, J＝
6.0 Hz, 2H), 2.78 (t, J＝6.0 Hz, 2H); 13C NMR (100
746
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© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 741—751

Deammoniative Condensation of Primary Allylic Amines with Nonallylic Amines
MHz, CDCl3) δ: 156.6, 134.8, 134.2, 128.6, 128.5,
127.6, 127.4, 126.8, 126.6, 126.1, 125.9, 125.5, 120.7,
110.8, 61.3, 56.1, 55.4, 50.7, 29.1; HRMS (ESI) calcd
for C19H22ON＋ (M＋H)＋ 280.1696, found 280.1693.
Amine 3q, colorless oil; 1H NMR (400 MHz, CDCl3)
δ: 7.35－7.29 (m, 2H), 7.14－7.04 (m, 3H), 7.02－6.96
(m, 1H), 6.87－6.80 (m, 2H), 6.52 (d, J＝15.6 Hz, 1H),
6.21 (dt, J＝15.6, 6.8 Hz, 1H), 3.76 (s, 3H), 3.65 (s, 2H),
3.29 (dd, J＝6.8, 1.2 Hz, 2H), 2.90 (t, J＝6.0 Hz, 2H),
2.77 (t, J＝6.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ:
158.1, 133.6, 133.1, 131.4, 128.7, 127.6, 126.5, 125.5,
125.1, 124.5, 123.4, 113.0, 59.8, 54.9, 54.2, 49.6, 28.0;
HRMS (ESI) calcd for C19H22ON＋ (M＋H)＋ 280.1696,
found 280.1691.
126.3, 125.7, 123.5, 60.6, 56.1, 50.9, 29.0; HRMS (EI)
calcd for C17H18N2 (M) 250.1470, found 250.1468.
Amine 3v, colorless oil; 1H NMR (400 MHz, CDCl3)
δ: 7.15－7.05 (m, 3H), 7.05－6.98 (m, 1H), 5.70－5.61
(m, 1H), 5.56 (dt, J＝14.4,6.4 Hz, 1H), 3.62 (s, 2H),
3.16－3.06 (m, 2H), 2.91 (t, J＝6.0 Hz, 2H), 2.73 (t,
J＝6.0 Hz, 2H), 2.11－2.02 (m, 2H), 1.45－1.28 (m,
10H), 0.89 (t, J＝6.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ: 135.0, 134.5, 128.8, 126.8, 126.5, 126.2,
125.7, 60.8, 56.0, 50.6, 32.5, 32.0, 29.9, 29.4, 29.3, 29.2,
22.8, 14.3; HRMS (EI) calcd for C19H29N (M) 271.2300,
found 271.2285.
Amine 3x, obtained as a 84∶16 mixture of E/Z
1
isomers. Colorless oil; H NMR (400 MHz, CDCl3) δ:
Amine 3r, colorless oil; 1H NMR (400 MHz, CDCl3)
δ: 7.56 (d, J＝8.4 Hz, 2H), 7.47 (d, J＝8.4 Hz, 2H),
7.16－7.06 (m, 3H), 7.04－6.97 (m, 1H), 6.62 (d, J＝
16.0 Hz, 1H), 6.45 (dt, J＝16.0, 6.4 Hz, 1H), 3.68 (s,
2H), 3.34 (dd, J＝6.4, 0.8 Hz, 2H), 2.93 (t, J＝6.0 Hz,
2H), 2.79 (t, J＝6.0 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ: 140.6, 134.6, 134.2, 131.5, 130.0, 129.6,
7.36－7.27 (m, 4H), 7.21－7.16 (m, 1H), 7.11－7.06
(m, 3H), 7.01－6.93 (m, 1H), 6.49 (d, J＝1.2 Hz, 1H),
3.61 (s, 2H), 3.16 (d, J＝1.2 Hz, 2H), 2.88 (t, J＝6.0 Hz,
2H), 2.70 (t, J＝6.0 Hz, 2H), 1.95 (d, J＝1.2 Hz, 3H);
1
partial H NMR for the minor Z-isomer δ: 6.52 (s, 1H),
3.51 (s, 2H), 3.26 (d, J＝0.8 Hz, 2H), 2.82 (t, J＝6.0 Hz,
2H), 2.58 (t, J＝6.0 Hz, 2H), 1.98 (d, J＝1.6 Hz, 3H);
HRMS (EI) calcd for C19H21N (M) 263.1674, found
263.1666.
129.2, 128.8, 126.7, 126.6, 126.4, 125.8, 125.7 (q, JC
－
F
＝3.8 Hz), 60.6, 56.2, 51.0, 29.2; HRMS (EI) calcd for
C19H18NF3 (M) 317.1391, found 317.1393.
General procedure for the deammoniative condensa-
tion of α-chiral primary allylic amines with nonally-
lic amines (Table 4 and Scheme 2)
Amine 3s, obtained as a 94∶6 mixture of E/Z iso-
mers. Colorless oil; 1H NMR (400 MHz, CDCl3) δ: 8.13
(d, J＝8.4 Hz, 1H), 7.82－7.78 (m, 1H), 7.75 (d,
J＝8.4 Hz, 1H), 7.62 (d, J＝7.2 Hz, 1H), 7.55－7.39 (m,
3H), 7.34 (d, J＝15.6 Hz, 1H), 7.16－6.97 (m, 4H),
6.38 (dt, J＝15.6, 6.8 Hz, 1H), 3.73 (s, 2H), 3.43 (dd,
J＝6.8, 1.6 Hz, 2H), 2.93 (t, J＝5.6 Hz, 2H), 2.84 (t,
J＝5.6 Hz, 2H); Partial 1H NMR for the minor Z-isomer
δ: 6.15 (dt, J＝11.6, 6.4 Hz, 1H), 3.68 (s, 2H), 3.28 (dd,
J＝6.4, 1.6 Hz, 2H); HRMS (EI) calcd for C22H21N (M)
299.1682, found 299.1674.
A mixture of α-chiral primary allylic amine 4 (0.50
mmol), nonallylic amine 2 (0.60 mmol), TsOH•H2O
(4.76 mg, 5 mol%), racemic BINAP (31.1 mg, 10
mol%), and Pd(OAc)2 (5.61 mg, 5 mol%) in dioxane
(0.50 mL) was heated under nitrogen at 80 ℃ for 1.0 h.
The mixture was cooled to room temperature and puri-
fied by silica gel chromatography, eluting with ethyl
acetate/petroleum ether (1∶20－1∶2), to give chiral
amine 5.
Amine 3t, obtained as a 97∶3 mixture of E/Z iso-
mers. Colorless oil; 1H NMR (400 MHz, CDCl3) δ: 7.23
－7.18 (m, 2H), 7.13－7.03 (m, 4H), 7.01－6.95 (m,
1H), 6.57 (d, J＝16.0 Hz, 1H), 6.18 (dt, J＝16.0, 6.8 Hz,
1H), 3.64 (s, 2H), 3.26 (dd, J＝6.8, 1.2 Hz, 2H), 2.89 (t,
Analytical data for the new compounds are shown in
Table 4 and Scheme 2.
20
Chiral amine 5b, colorless oil; [α]D −70 (c 1.08,
CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.39－7.15 (m,
10H), 6.43 (d, J＝16.0 Hz, 1H), 6.05 (dd, J＝16.0, 8.0
Hz, 1H), 3.43－3.33 (m, 1H), 3.06－2.64 (m, 4H), 1.23
(d, J＝6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ:
140.0, 137.1, 134.1, 130.0, 128.7, 128.5, 127.3, 126.3,
126.2, 56.2, 48.8, 36.5, 22.0; HRMS (EI) calcd for
C18H21N (M) 251.1674, found 251.1673. The ee was
determined to be 97% by HPLC analysis (Chiralpak OJ,
λ＝254 nm, n-hexane/isopropanol＝95∶5, flow rate＝
1.0 mL/min): tR(minor)＝14.1 min, tR(major)＝11.3
min.
1
J＝6.0 Hz, 2H), 2.75 (t, J＝6.0 Hz, 2H); partial H
NMR for the minor Z-isomer δ: 5.81 (dt, J＝11.6, 6.4
Hz, 1H), 3.43 (dd, J＝6.4, 2.0 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ: 139.6, 134.6, 134.1, 128.6, 127.1,
126.7, 126.6, 126.1, 126.0, 125.6, 125.0, 121.8, 60.6,
56.0, 50.7, 29.0; HRMS (EI) calcd for C16H17NS (M)
255.1082, found 255.1075.
Amine 3u, obtained as a 97∶3 mixture of E/Z iso-
mers. Colorless oil; 1H NMR (400 MHz, CDCl3) δ: 8.63
－8.59 (m, 1H), 8.49－8.45 (m, 1H), 7.74－7.70 (m,
1H), 7.27－7.22 (m, 1H), 7.16－7.08 (m, 3H), 7.04－
6.99 (m, 1H), 6.60 (d, J＝16.0 Hz, 1H), 6.44 (dt, J＝
16.0, 6.4 Hz, 1H), 3.69 (s, 2H), 3.36 (dd, J＝6.4, 1.2 Hz,
2H), 2.94 (t, J＝6.0 Hz, 2H), 2.81 (t, J＝6.0 Hz, 2H);
Partial 1H NMR for the minor Z-isomer δ: 6.04 (dt, J＝
11.6, 6.8 Hz, 1H), 3.64 (s, 2H), 3.42 (dd, J＝6.8, 1.6 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ: 148.6, 148.4,
134.5, 134.1, 132.7, 132.5, 129.4, 129.2, 128.7, 126.6,
20
Chiral amine 5c, colorless oil; [α]D −76 (c 1.11,
CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.42－7.35 (m,
2H), 7.34－7.27 (m, 2H), 7.24－7.18 (m, 1H), 6.46 (d,
J＝16.0 Hz, 1H), 6.08 (dd, J＝16.0, 8.0 Hz, 1H), 3.39－
3.30 (m, 1H), 2.78－2.41 (m, 2H), 1.59－1.40 (m, 2H),
1.39－1.15 (m, 9H), 0.87 (t, J＝6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ: 137.2, 134.4, 129.8, 128.5, 127.3,
126.3, 56.4, 47.7, 31.8, 30.3, 27.1, 22.6, 22.0, 14.1;
Chin. J. Chem. 2014, 32, 741—751
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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747

Wang et al.
FULL PAPER
HRMS (EI) calcd for C16H25N (M) 231.1987, found
231.1999. The ee was determined to be 97% by con-
verting it to compound 5Bz-c (see below).
J＝16.0 Hz, 1H), 6.08 (dd, J＝16.0, 8.0 Hz, 1H), 3.85
(d, J＝13.2 Hz, 1H), 3.74 (d, J＝13.2 Hz, 1H), 3.49－
3.39 (m, 1H), 1.27 (d, J＝6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ: 140.5, 137.1, 135.3, 132.9, 129.7,
128.5, 128.3, 126.9, 126.8, 126.5, 55.5, 51.5, 22.1;
HRMS (EI) calcd for C17H18ClN (M) 271.1128, found
271.1122. The ee was determined to be 96% by con-
verting it to compound 5Bz-k (see below).
Chiral amine 5d, light yellow oil; [α]D20 −94 (c 1.01,
CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.40－7.35 (m,
2H), 7.33－7.27 (m, 2H), 7.25－7.18 (m, 1H), 6.44 (d,
J＝16.0 Hz, 1H), 6.07 (dd, J＝16.0, 8.0 Hz, 1H), 3.60－
3.49 (m, 1H), 3.41 (s, br, 1H), 2.56－2.48 (m, 1H), 2.01
－1.94 (m, 1H), 1.78－1.52 (m, 3H), 1.34－1.02 (m,
9H); 13C NMR (100 MHz, CDCl3) δ: 137.2, 134.9,
129.4, 128.5, 127.3, 126.3, 53.6, 52.6, 34.5, 33.3, 26.2,
25.3, 25.1, 22.5; HRMS (EI) calcd for C16H23N (M)
229.1830, found 229.1833. The ee was determined to be
97% by converting it to compound 5Bz-d (see below).
20
Chiral amine 5l, light yellow oil; [α]D −36 (c 1.00,
CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.81－7.77 (m,
3H), 7.74－7.73 (m, 1H), 7.64－7.60 (m, 1H), 7.48－
7.40 (m, 2H), 7.15－7.07 (m, 3H), 7.06－7.00 (m, 1H),
6.70 (d, J＝16.0 Hz, 1H), 6.43 (dd, J＝16.0, 7.6 Hz,
1H), 3.96－3.67 (m, 2H), 3.47－3.28 (m, 1H), 3.09－
2.78 (m, 4H), 1.41 (d, J＝6.4 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ: 134.5, 134.4, 133.6, 133.0, 132.4,
131.3, 128.7, 128.2, 127.9, 127.7, 126.8, 126.3, 126.1,
125.8, 125.6, 123.6, 62.1, 52.9, 47.4, 29.3, 17.8; HRMS
(EI) calcd for C23H23N (M) 313.1830, found 313.1812.
The ee was determined to be 90% by HPLC analysis
(Chiralpak AD, λ＝254 nm, n-hexane/isopropanol＝
99∶1, flow rate＝1.0 mL/min): tR(minor)＝12.4 min,
tR(major)＝10.2 min.
20
Chiral amine 5f, colorless oil; [α]D −81 (c 1.03,
CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.40－7.16 (m,
10H), 6.47 (d, J＝16.0 Hz, 1H), 6.31 (dd, J＝16.0, 7.2
Hz, 1H), 3.65 (d, J＝13.2 Hz, 1H), 3.52 (d, J＝13.2 Hz,
1H), 3.40－3.31 (m, 1H), 2.22 (s, 3H), 1.30 (d, J＝6.8
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 139.8, 137.3,
132.0, 130.8, 128.9, 128.5, 128.2, 127.3, 126.8, 126.3,
60.4, 58.3, 37.9, 17.0; HRMS (ESI) calcd for C18H22N＋
(M＋H)＋ 252.1747, found 252.1743. The ee was de-
termined to be 97% by HPLC analysis (Chiralpak OJ,
λ＝254 nm, n-hexane/isopropanol＝99∶1, flow rate＝
1.0 mL/min): tR(minor)＝8.7 min, tR(major)＝9.7 min.
Chiral amine 5i, light yellow oil; [α]D20 −50 (c 1.07,
CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.41－7.36 (m,
2H), 7.34－7.28 (m, 2H), 7.26－7.19 (m, 1H), 7.12－
7.05 (m, 3H), 7.04－6.99 (m, 1H), 6.52 (d, J＝16.0 Hz,
1H), 6.29 (dd, J＝16.0, 8.0 Hz, 1H), 3.86－3.67 (m,
2H), 3.37－3.22 (m, 1H), 2.99－2.71 (m, 4H), 1.36 (d,
Chiral amine 5m, light yellow oil; [α]D20 −25 (c 1.03,
CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.34－7.28 (m,
4H), 7.26－7.21 (m, 1H), 5.47 (dd, J＝15.6, 6.4 Hz,
1H), 5.25 (ddd, J＝15.6, 8.0, 1.2 Hz, 1H), 3.78 (d, J＝
13.2 Hz, 1H), 3.66 (d, J＝13.2 Hz, 1H), 3.19－3.10 (m,
1H), 2.00－1.87 (m, 1H), 1.78－1.60 (m, 4H), 1.34－
1.00 (m, 9H); 13C NMR (100 MHz, CDCl3) δ: 140.8,
137.5, 131.4, 128.4, 128.2, 126.8, 55.3, 51.3, 40.4, 33.2,
33.1, 26.2, 26.1, 22.2; HRMS (EI) calcd for C17H25N (M)
243.1987, found 243.1969. The ee was determined to be
98% by converting it to compound 5Bz-m (see below).
Chiral amine 5n, obtained as a 91∶9 mixture of E/Z
13
J＝6.4 Hz, 3H); C NMR (100 MHz, CDCl3) δ: 137.1,
135.1, 134.5, 132.3, 130.9, 128.7, 128.6, 127.4, 126.8,
126.3, 126.0, 125.6, 62.0, 53.0, 47.4, 29.4, 17.8; HRMS
(EI) calcd for C19H21N (M) 263.1674, found 263.1678.
The ee was determined to be 97% by HPLC analysis
(Chiralpak OD, λ＝254 nm, n-hexane/isopropanol＝
95∶5, flow rate＝1.0 mL/min): tR(minor)＝5.3 min,
tR(major)＝6.4 min.
20
1
isomers. Colorless oil; [α]D －24 (c 1.00, CHCl3); H
NMR (400 MHz, CDCl3) δ: 7.35－7.17 (m, 10H), 6.43
(s, 1H), 3.74 (d, J＝13.2 Hz, 1H), 3.63 (d, J＝13.2 Hz,
1H), 3.32－3.38 (m, 1H), 1.85 (d, J＝1.2 Hz, 3H), 1.23
1
(d, J＝6.8 Hz, 3H); Partial H NMR for the minor
20
Chiral amine 5j, light yellow oil; [α]D −16 (c 1.08,
Z-isomer δ: 6.47 (s, 1H); HRMS (EI) calcd for C18H21N
(M) 251.1674, found 251.1675. The ee was determined
to be 98% by converting it to compound 5Bz-n (see
below).
CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.40－7.36 (m,
2H), 7.32－7.26 (m, 2H), 7.22－7.17 (m, 1H), 7.11－
7.02 (m, 3H), 7.01－6.96 (m, 1H), 6.50 (d, J＝16.0 Hz,
1H), 6.18 (dd, J＝16.0, 8.8 Hz, 1H), 3.84－3.70 (m,
2H), 3.04－2.82 (m, 4H), 2.77－2.68 (m, 1H), 1.94－
1.78 (m, 1H), 1.70－1.56 (m, 1H), 0.94 (t, J＝7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ: 137.0, 135.3,
134.6, 132.8, 129.7, 128.6, 128.5, 127.3, 126.7, 126.3,
125.9, 125.5, 68.9, 53.0, 47.1, 29.5, 25.2, 11.0; HRMS
(EI) calcd for C20H23N (M) 277.1830, found 277.1827.
The ee was determined to be 93% by HPLC analysis
(Chiralpak AD-H, λ＝254 nm, n-hexane/isopropanol＝
99∶1, flow rate＝1.0 mL/min): tR(minor)＝7.4 min,
tR(major)＝4.4 min.
1
Racemic amine 5o, light yellow oil; H NMR (400
MHz, CDCl3) δ: 7.48－7.44 (m, 2H), 7.39－7.24 (m,
7H), 7.24－7.17 (m, 1H), 7.13－7.05 (m, 3H), 6.97－
6.93 (m, 1H), 6.62 (d, J＝16.0 Hz, 1H), 6.40 (dd, J＝
16.0, 8.8 Hz, 1H), 4.02 (d, J＝8.8 Hz, 1H), 3.80 (d, J＝
15.2 Hz, 1H), 3.60 (d, J＝15.2 Hz, 1H), 2.96－2.70 (m,
4H); 13C NMR (100 MHz, CDCl3) δ: 142.1, 136.9,
135.0, 134.6, 131.7, 131.2, 128.7, 128.6, 128.5, 127.9,
127.5, 127.3, 126.8, 126.4, 126.1, 125.6, 73.7, 54.7,
48.5, 29.1; HRMS (EI) calcd for C24H23N (M) 325.1830,
found 325.1838. The ee was determined to be 0% by
HPLC analysis (Chiralpak AD, λ＝254 nm, n-hexane/
isopropanol＝99∶1, flow rate＝1.0 mL/min): tR(1)＝
6.8 min, tR(2)＝8.0 min.
Chiral amine 5k, light yellow oil; [α]D20 −61 (c 1.05,
CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.55－7.51 (m,
1H), 7.36－7.29 (m, 5H), 7.26－7.12 (m, 3H), 6.87 (d,
748
www.cjc.wiley-vch.de
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 741—751

Deammoniative Condensation of Primary Allylic Amines with Nonallylic Amines
20
1
Benzoylation of chiral amines 5 for ee determination
yield. Colorless oil; [α]D −54 (c 1.07, CHCl3); H
NMR (400 MHz, CDCl3) δ: 7.56－7.12 (m, 14H), 6.86
－6.70 (m, 1H), 6.25－5.90 (m, 1H), 5.00－4.55 (m,
3H), 1.52－1.24 (m, 3H); 13C NMR (100 MHz, CDCl3)
δ: 172.5, 139.2, 136.9, 134.8, 133.1, 132.8, 129.6, 129.5,
128.8, 128.6, 127.5, 127.3, 127.0, 126.9, 126.4, 56.1,
44.8, 18.5; HRMS (EI) calcd for C24H22NOCl (M)
375.1390, found 375.1422. The ee was determined to be
96% by HPLC analysis (Chiralpak AD, λ＝254 nm,
n-hexane/isopropanol ＝ 90 ∶ 10, flow rate ＝ 1.0
mL/min): tR(minor)＝15.9 min, tR(major)＝21.4 min.
Amide 5Bz-m, prepared from chiral amine 5m in
81% yield. Colorless oil; [α]D20 −47 (c 1.02, CHCl3); 1H
NMR (400 MHz, CDCl3) δ: 7.48－7.18 (m, 10H), 5.55
－5.25 (m, 2H), 4.89－4.71 (m, 1H), 4.55－4.40 (m,
2H), 1.93－1.83 (m, 1H), 1.73－1.57 (m, 5H), 1.30－
1.05 (m, 6H), 1.03－0.92 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ: 172.4, 139.3, 138.4, 137.2, 129.3, 128.5,
128.3, 127.3, 126.8, 126.4, 56.0, 44.6, 40.4, 32.7, 26.1,
26.0, 18.8; HRMS (EI) calcd for C24H29NO (M)
347.2249, found 347.2273. The ee was determined to be
98% by HPLC analysis (Chiralpak AD, λ＝254 nm,
n-hexane/isopropanol＝95∶5, flow rate＝1.0 mL/min):
tR(minor)＝21.3 min, tR(major)＝30.5 min.
To a solution of chiral amine 5 (0.20 mmol) and
triethylamine (30.4 mg, 0.042 mL, 0.30 mmol) in di-
chloromethane (0.80 mL) at 0 ℃ was added dropwise
a solution of benzoyl chloride (33.7 mg, 0.028 mL, 0.24
mmol) in dichloromethane (0.20 mL). The mixture was
warmed to room temperature and stirred overnight. The
mixture was quenched with water (1.0 mL) and ex-
tracted with dichloromethane (5.0 mL), and the aqueous
layer was extracted with dichloromethane (3.0 mL). The
organic layers were combined, dried over sodium sul-
fate, and concentrated. The residue was purified by sil-
ica gel chromatography, eluting with ethyl acetate/pe-
troleum ether (1∶10－1∶5), to give amide 5Bz.
O
R
R'
R'
Ph
N
N
PhCOCl, NEt3
CH2Cl2
R1
R3
R1
R3
R2
5Bz
R2
5 (R = H)
O
Ph
O
R'
Cl Ph
Ph
N
N
Ph
Me
Me
5Bz-c, R' = (CH2)5Me
5Bz-d, R' = cyclohexyl
Amide 5Bz-n, prepared from chiral amine 5n in 90%
20
1
5Bz-k
Ph
yield. Colorless oil; [α]D −45 (c 1.00, CHCl3); H
NMR (400 MHz, CDCl3) δ: 7.55－7.15 (m, 15H), 6.41
(s, 1H), 5.15－4.85 (m, 1H), 4.60－4.35 (m, 1H), 4.32
－4.16 (m, 1H), 1.85－1.54 (m, 3H), 1.33 (d, J＝6.8 Hz,
3H);13C NMR (100 MHz, CDCl3) δ: 173.1, 139.3, 137.3,
129.4, 129.0, 128.6, 128.4, 128.2, 127.6, 127.4, 126.9,
126.8, 126.4, 60.6, 44.7, 17.6, 17.0; HRMS (EI) calcd
for C25H25NO (M) 355.1936, found 355.1956. The ee
was determined to be 98% by HPLC analysis (Chiralpak
AD, λ＝254 nm, n-hexane/isopropanol＝90∶10, flow
rate＝1.0 mL/min): tR(minor)＝13.4 min, tR(major)＝
17.5 min.
O
Ph
O
Ph
N
Ph
N
Me
Ph
Me
Me
5Bz-n
5Bz-m
Amide 5Bz-c, prepared from chiral amine 5c in 89%
20
1
yield. Colorless oil; [α]D −106 (c 1.07, CHCl3); H
NMR (400 MHz, CDCl3) δ: 7.48－7.22 (m, 9H), 7.27－
7.22 (m, 1H), 6.50－6.30 (m, 1H), 6.25－6.05 (m, 1H),
4.68－4.44 (m, 1H), 3.55－3.37 (m, 1H), 3.23－3.11
(m, 1H), 1.85－1.05 (m, 11H), 0.91－0.75 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ: 171.8, 137.5, 136.5, 130.9,
129.9, 129.2, 128.7, 128.5, 127.8, 126.4, 126.3, 55.7,
42.6, 31.5, 29.4, 27.0, 22.5, 18.7, 14.0; HRMS (EI)
calcd for C23H29NO (M) 335.2249, found 335.2260. The
ee was determined to be 97% by HPLC analysis
(Chiralpak AD, λ＝254 nm, n-hexane/isopropanol＝
95∶5, flow rate＝1.0 mL/min): tR(minor)＝13.8 min,
tR(major)＝16.5 min.
Assignment of the absolute configuration of chiral
amines 5
Chiral amines 5e and 5g are known compounds. The
absolute configuration of the rest of chiral amines 5
shown in Table 4 was determined by comparing their
chiral HPLC traces or specific optical rotations with the
authentic samples prepared by N-alkylation of chiral
amines 4. Shown below are the N-alkylation methods
we used to convert chiral amines 4 to chiral amines 5.
A mixture of chiral amine 4 (0.20 mmol) and car-
bonyl compound 12 (0.20 mmol) in methanol (2.4 mL)
was stirred at room temperature for 1.0 h, cooled to 0
℃, and added NaBH4 (3.78 mg, 0.10 mmol). The mix-
ture was stirred at room temperature for 1.0 h, added
water (10 mL), and extracted with ethyl acetate (10
mL×2). The organic extracts were combined, dried
over magnesium sulfate, and concentrated. The residue
was purified by silica gel chromatography, eluting with
ethyl acetate/petroleum ether (1∶20－1∶2), to give
chiral amine 5.
Amide 5Bz-d, prepared from chiral amine 5d in 84%
20
1
yield. Colorless oil; [α]D −88 (c 1.00, CHCl3); H
NMR (400 MHz, CDCl3) δ: 7.46－7.31 (m, 9H), 7.30－
7.21 (m, 1H), 6.55－6.35 (m, 2H), 4.45－4.05 (m, 1H),
3.45－3.10 (m, 1H), 1.85－1.45 (m, 10H), 1.20－0.98
(m, 3H); 13C NMR (100 MHz, CDCl3) δ: 171.2, 138.5,
137.0, 130.4, 128.8, 128.6, 128.5, 127.6, 126.5, 125.8,
31.4, 26.1, 25.3, 19.6; HRMS (EI) calcd for C23H27NO
(M) 333.2093, found 333.2096. The ee was determined
to be 97% by HPLC analysis (Chiralpak OD, λ＝254
nm, n-hexane/isopropanol ＝97 ∶3, flow rate ＝1.0
mL/min): tR(minor)＝13.3 min, tR(major)＝14.8 min.
Amide 5Bz-k, prepared from chiral amine 5k in 86%
Chin. J. Chem. 2014, 32, 741—751
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
749

Wang et al.
FULL PAPER
(a) Reductive amination
A mixture of chiral amine 4 (0.20 mmol),
1-(2-bromoethyl)-2-(bromomethyl)benzene (55.6 mg,
0.33 mL, 0.20 mmol), and potassium carbonate (553 mg,
4.0 mmol) in ethanol (2.0 mL) was heated under nitro-
gen at 80 ℃ for 3.0 h. The mixture was cooled to room
temperature and purified by silica gel chromatography,
eluting with ethyl acetate∶petroleum ether (1∶10), to
give chiral amine 5.
NH2
R3
R3
NaBH4, MeOH
R1
HN
R4
R1
Me
+
R4
O
R2
4a, 4c, 4e, or 4f
Me
12
R2
5a - 5d, 5k, 5m, or 5n
Entry 4
R1
Ph
Ph
Ph
Ph
R2 12
H 12a
H 12b
R3
Ph
R4
H
5
Yield/%
75
1
2
3
4
5
6
7
4a
4a
4a
4a
5a
Acknowledgement
CH2Ph
H 5b
5c
H 12d R3＝R4＝(CH2)5 5d
69
We are grateful for the financial support from the
National Natural Science Foundation of China (Nos.
21232007, 21202154 and 21172206) and the National
Key Basic Research Program of China (No.
2014CB931800).
H 12c (CH2)4Me
H
65
65
4c 2-ClC6H4 H 12a
Ph
Ph
Ph
H 5k
H 5m
H 5n
74
4e
4f
Cy
Ph
H 12a
63
Me 12a
76
References
(b) Nucleophilic substitution
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Me
HN
Ph
Me
N
Ph
CH3I, iPr2NEt
DMF
Ph
Ph
Me
5a
5f
A mixture of chiral amine 5a (47.5 mg, 0.20 mmol),
iodomethane (28.4 mg, 0.012 mL, 0.20 mmol), and
diisopropylethylamine (207 mg, 0.28 mL, 1.6 mmol) in
DMF (0.60 mL) was stirred at room temperature for 3.0
h. The mixture was purified by silica gel chromatogra-
phy, eluting with ethyl acetate/petroleum ether (1∶20),
to give chiral amine 5f (30.7 mg, 61%) as a colorless
oil.
(c) Disubstitution
O
O
NH2
Me
N
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Br
NaHCO3, PhMe
Br
Ph
Ph
Me
4a
5h
A mixture of chiral amine 4a (29.4 mg, 0.20 mmol),
1-bromo-2-(2-bromoethoxy)ethane (51.0 mg, 0.028 mL,
0.22 mmol), and sodium bicarbonate (37.0 mg, 0.44
mmol) in toluene (0.25 mL) was heated under nitrogen
at 115 ℃ for 23 h. The mixture was cooled to room
temperature and purified by silica gel chromatography,
eluting with ethyl acetate/petroleum ether (1∶2), to
give chiral amine 5h (34.8 mg, 80%) as a colorless oil.
NH2
K2CO3, EtOH
R2
+
R1
N
Br Br
4a, 4b, or 4d
R1
R2
5i, 5j, or 5l
Entry
4
R1
R2
5
Yield/%
1
2
3
4a
4b
4d
Ph
Ph
Me 5i
Et 5j
Me 5l
82
76
84
2-Naphthyl
750
www.cjc.wiley-vch.de
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 741—751

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Chem. Soc. 2012, 134, 20230; (b) Xie, Y.; Hu, J.; Wang, Y.; Xia, C.;
Huang, H. J. Am. Chem. Soc. 2012, 134, 20613; (c) Xie, Y.; Hu, J.;
Xie, P.; Qian, B.; Huang, H. J. Am. Chem. Soc. 2013, 135, 18327.
(Lu, Y.)
Chin. J. Chem. 2014, 32, 741—751
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