Palladium-Catalyzed N-Arylation of Amines and Amides with Aryltrimethylgermanes

Article abstract of DOI:10.1055/s-0035-1562104

Described herein is a novel palladium-catalyzed C-N bond-formation reaction employing aryltrimethylgermanes as the new arylating reagents. Primary/secondary amines or even amides could be smoothly arylated to provide the corresponding N-arylation products in moderate to excellent yields.

Full text of DOI:10.1055/s-0035-1562104

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
Q. Zhang et al.
Letter
Synlett
Palladium-Catalyzed N-Arylation of Amines and Amides with
Aryltrimethylgermanes
Qiang Zhang*
Cunfang Liu
Juan Shi
Pd(OAc)2 (5 mol%)
Ph3P (5 mol%)
NaOAc
R1
N
R2
Me
Ge Me
Me
H
N
R3
R2
R1
+
toluene, 100 °C, 12 h
Qiong Xu
R1 = aryl, alkyl, acyl, H
2 = aryl
R3 = aryl
24 examples
moderate to excellent yield
Lingxia Jin*
Chaibin Zhao
Tianlei Zhang
R
School of Chemistry and Environmental Science, Shaanxi University of
Technology, Shaanxi Province Key Laboratory of Catalytic Fundamentals
& Applications, Hanzhong, 723001, P. R. of China
zhangqiang22@126.com
jinlingxia1982@126.com
Received: 03.03.2016
Accepted after revision: 01.04.2016
Published online: 04.05.2016
synthesis. An alternative to such a transformation is the use
of organogermane, which eliminates the purification diffi-
culties associated with organoboron reagents, as well as the
toxic byproducts along with the use of organolead and or-
ganotin6 compounds. As far as we know, germanium, ele-
ment 32, has lower carbon–metal bond energy and a larger
covalent radius than the silicon counterpart in group IVA
(group 14). Thus germylated arenes7 are more susceptible
to electrophilic substitution reactions than arylsilane8 ana-
logues. However, examples of employing organogermanes
in N-arylation reaction have not yet been reported to date.
Herein, we describe, for the first time, a palladium-cata-
lyzed N-arylation of amines and amides employing aryl-
trimethylgermanes as substrates.
In the beginning, aryltrimethylgermane compounds
were synthesized7 via the corresponding bromobenzene
through Grignard reaction. Then phenyltrimethylgermane
(2a) and morpholine were used as substrates, and a series
of catalysts, bases, and solvents were employed for optimi-
zation of reaction conditions. Since ligands always play a
key role9 in transition-metal-catalyzed chemistry, we firstly
focused on the screening of ligands. In this transformation,
bidentate phosphine ligands such as dppp, dppe, dppb, and
dppf were proven to be less effective than the monodentate
phosphine ligand Ph3P.
DOI: 10.1055/s-0035-1562104; Art ID: st-2016-w0152-l
Abstract Described herein is a novel palladium-catalyzed C–N bond-
formation reaction employing aryltrimethylgermanes as the new ary-
lating reagents. Primary/secondary amines or even amides could be
smoothly arylated to provide the corresponding N-arylation products in
moderate to excellent yields.
Key words N-arylation, amine, amide, aryltrimethylgermane
Owing to the ubiquity and diverse biological activities,
N-containing molecules are of utmost importance. The con-
struction of the C–N bond is of significant importance1 as it
paves the ways to the introduction of nitrogen in organic
entities. Despite the significant achievements in this field,
the construction of the C–N bond is still a major challenge
for organic chemists. Thus, the development of more appli-
cable methodologies toward the formation of C–N bonds2
in an expedient fashion is still highly desirable. As the key
components featuring the N-containing molecules, amines,
and amides are ubiquitous structural motifs1a that have
been widely found in many biologically active entities.
Thus, syntheses of these compounds have attracted signifi-
cant interest in organic community and pharmaceutical in-
dustry. During the last decade, significant advancement has
been made. Notably, among all the methods developed, the
palladium-catalyzed Buchwald–Hartwig amination3,4 be-
tween aryl halides with amines has received the most at-
tention in this arena because of its high efficacy and good
substrate spectrum. Noteworthy, organoboron reagents5
have recently been employed as the arylating agents for the
metal-catalyzed C–N bond-formation event because of
their indisputable advantages of relative stability under air
and moisture conditions, commercial availability, good
functional-group compatibility, low toxicity, and ease of
To our delight, Ph3P could promote N-arylation of phen-
yltrimethylgermane to provide the desired product with
17% yield. Then we embarked on the examination of differ-
ent solvents. Xylene, dioxane, and 1,2-dimethoxyethane
(DME) gave inferior yields or delivered no product (Table 1,
entries 1–4). When using 5 mol% of Pd(OAc)2 as the cata-
lyst, 5 mol% Ph3P as the ligand, and 2.0 equivalents of K2CO3
as the base at 100 °C in toluene under argon atmosphere
produced the target product in 26% yield (Table 1, entry 3).
Among all the bases, NaOAc was the best base, and the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
Q. Zhang et al.
Letter
Synlett
Table 1 Screening of Parameters in the N-Arylation Reactiona
Table 2 N-Arylation of the Amines and Amides with PhGeMe3
a
[Pd] (5 mol%)
Ph3P (5 mol%)
base
Pd(OAc)2 (5 mol%)
Ph3P (5 mol%)
H
N
R1
N
R2
Me
Ge Me
Me
Me
NaOAc
H
+
O
N
+
Ge Me
Me
N
R2
R1
solvent
100 °C, 24 h
toluene, 100 °C, 12 h
O
1a
2a
3a
3
1
2a
Entry
Pd source
Base
K2CO3
Solvent
xlyene
Yield (%)b
Entry
1
Product
Yield (%)b
94
1
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
PdCl2
<5
<5
26
<5
76
65
94
47
37
68
<5
31
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
NaOAc
KF
dioxane
toluene
DME
N
3
O
3a
4
5
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
2
3
4
75
77
64
N
6
3b
7
8
9
K3PO4
NaOAc
NaOAc
NaOAc
9
N
3c
10
11
PdCl2(dppf)
Pd(PPh3)4
a Reaction conditions: morpholine (1a , 104.4 μL, 1.2 mmol), phenyl-
trimethylgermane (2a, 194.9 mg, 1.0 mmol), Pd source (5 mol%), Ph3P
(13.1 mg, 5 mol%), toluene (2.0 mL), under argon atmosphere at 100 °C for
12 h.
N
H
3d
b Isolated yield.
O
5
6
7
37
56
66
N
H
product was isolated in 94% yield (Table 1, entry 7). The
Pd(OAc)2 exhibited the highest catalytic activity among Pd-
Cl2, Pd(OAc)2, PdCl2(dppf), and Pd(PPh3)4. Further increasing
or decreasing the amount of Ph3P in the system did not in-
crease the yield. It was worth pointing out that rigorous ex-
clusion of air/moisture is not required in these transforma-
tions. Thus, we established the optimized reaction condi-
tions as follows: amine or amide 1a (1.2 mmol),
phenyltrimethylgermane (2a, 1.0 mmol), Pd(OAc)2 (5
mol%), Ph3P (5 mol%), NaOAc (164.1 mg, 2.0 mmol), toluene
(2.0 mL), 100 °C, 12 hours.
3e
O
N
H
3f
N
H
3g
NH
8
9
84
83
81
With the optimized conditions in hand, a variety of
amines including primary and secondary aliphatic amines
as well as anilines were systematically examined to explore
the extent of the reaction. As expected, a variety of amines
could be well tolerated in the reaction providing the N-ary-
lation products in moderate to excellent yields. Anilines
were expected to be good cross-coupling substrates under
the model conditions to provide the diarylamines in good
yields. It is worth noting that the hindrance of amines and
amides had obvious effects on this reaction. For example, 3l
and 3n were only isolated in 47% and 57% yield, respectively,
while 3h and 3m were formed in 84% and 87% yield, respec-
tively (Table 2, entries 8, 12, 13, 14). Interestingly, the 4-
chlorobenzenamine 1j could also be employed as the quali-
fied substrate in the reaction and keep the chloro group un-
touched (Table 2, entry 10).
3h
NH
3i
Cl
NH
10
3j
OMe
11
75
HN
3k
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

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Table 2 (continued)
Entry
Pd(OAc)2 (5 mol%)
Ph3P (5 mol%)
NaOAc
H
N
Product
Yield (%)b
PhNH2
+
ArGeMe3
Ar
toluene, 100 °C, 12 h
1i
2
3
NH
12
47
H
H
N
H
N
N
3l
3p 85%
3l 77%
3h 87%
MeO
NH
H
N
H
N
13
14
15
87
57
35
H
N
3m
OMe
MeO
H
OMe
3m 84%
3n 73%
N
3q 81%
H
N
H
N
H
N
OMe
3n
F
Cl
N
3s 77%
3t n.r.
3r 88%
NH
Scheme 1 N-Arylation of PhNH2 with aryltrimethylgermane
3o
a Reaction conditions: amine or amide 1 (1.2 mmol), phenyltrimethylger-
mane (2a, 194.9 mg, 1.0 mmol), Pd(OAc)2(11.2 mg, 5 mol%), Ph3P (13.1
mg, 5 mol%), NaOAc (164.1 mg, 2.0 mmol), toluene (2.0 mL), under argon
atmosphere at 100 °C for 12 h.10
L2Pd
reductive elimination
b Isolated yield.
A
R1
R2
ArGeMe3
2
Ar
N
3
We next employed aryltrimethylgermanes possessing
electron-donating groups or sterically hindered substrates
to further expand the scope of the reaction. As expected, all
reactions proceeded smoothly under our optimum condi-
tions and no obvious electronic effect except highly hin-
dered aryltrimethylgermane (Scheme 1). Of particular note,
a mono substitution in the ortho position of aryltrimethyl-
germane reduced reactivity slightly. 4-Chloroaniline (1j)
and 4-chlorophenyl- trimethylgermane (2j) could proceed
smoothly with 3j to afford 3s in good yield and keep the
chloro group untouched (Table 2, entry 10, Scheme 1).
To understand the mechanism in more detail, the crude
reaction mixture between morpholine and phenyltrimeth-
ylgermane under optimized reaction conditions was exam-
ined by GC–MS. It showed that the 1,1′-biphenyl and as the
byproduct was produced in situ except the 4-arylated
phenylmorpholine and the reactants. Based upon the above
experimental results, a plausible mechanism is outlined in
Scheme 2. The catalytic cycle may contain three steps: 1)
L2Pd A undergoes transmetalation to form ArPdL2 B, which
may produce the byproduct Ar–Ar through cross-coupling
reaction; 2) ArPdL2 B exchange the partner with R1R2NH to
form intermediate C; 3) intermediate C deliver the reduc-
tive elimination product 3, and the true catalytic species A
is regenerated.2a
transmetalation
R1
R1
ArGeMe3
L
Ar-PdL2
Ar-Ar
Ar-Pd
N
side reaction
B
L
C
H
N
ligand exchange
R1
R2
1
Scheme 2 A plausible mechanism
In conclusion, we describe for the first time a mild pal-
ladium-catalyzed N-arylation reaction of amines and am-
ides via ArGeMe3, The catalytic system provides N-arylation
products in moderate to excellent yields. The reaction has a
wide scope of substrate including amides, primary and sec-
ondary or aliphatic and aromatic amines, and may provide
potential opportunities in the N-arylation of nitrogen-con-
taining compounds. The applications of aryltrimethylger-
mane are the focus of ongoing efforts under way in our lab-
oratory and will be reported in due course.
Acknowledgment
We thank the Shaanxi Province Education Ministry Research Founda-
tion (No. 15JK1161), the National Natural Science Foundation of Chi-
na (No. 21502109), and the Introducing Talents Foundation of
Shaanxi University of Technology (No. SLGKYQD2-09), as well as the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

D
Q. Zhang et al.
Letter
Synlett
Brainstorm Project on Social Development by Department of Science
and Technology of Shaanxi Province (No. 2015SF270) for financial
support.
Salam, N.; Mondal, P.; Roy, A. S.; Ghosh, K.; Tuhinac, K. J. Mol.
Catal. A: Chem. 2014, 387, 7. (e) Chan, D. M. T.; Monaco, K. L.;
Wang, R. P.; Winters, M. P. Tetrahedron Lett. 1998, 39, 2933.
(f) Batey, R. A.; Quach, T. D. Org. Lett. 2003, 5, 4397. (g) Kantam,
M. L.; Venkanna, G. T.; Sridhar, C.; Sreedhar, B.; Choudary, B. M.
J. Org. Chem. 2006, 71, 9522.
Supporting Information
(5) (a) Mitchell, T. N. In Metal-Catalyzed Cross-Coupling Reactions;
Vol. 1; de Mejijere, A.; Diederich, F., Eds.; Wiley-VCH: Wein-
heim, 2004, 125–162. (b) Kwong, F. Y.; Klapars, A.; Buchwald, S.
L. Org. Lett. 2002, 4, 581. (c) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-
F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805. (d) Hartwig, J. F.
Angew. Chem. Int. Ed. 1998, 37, 2046. (e) Kumari, A. S.; Pathak,
D. D. Tetrahedron Lett. 2015, 56, 4135. (f) Quach, T. D.; Batey, R.
A. Org. Lett. 2003, 5, 4397. (g) Poonam, R.; Rajendra, S. Tetrahe-
dron Lett. 2014, 55, 5256. (h) Batey, R. A.; Quach, T. D. Org. Lett.
2003, 5, 4397.
(6) Anctil, E. J. G.; Snieckus, V. In Metal-Catalyzed Cross-Coupling
Reactions; Vol. 2; de Mejijere, A.; Diederich, F., Eds.; Wiley-VCH:
Weinheim, 2004, 761–814.
(7) (a) Moerlein, S. M. J. Org. Chem. 1987, 52, 664. (b) Zhang, Z.;
Pitteloud, J.-P.; Cabrera, L.; Liang, Y.; Toribio, M.; Wnuk, S. F.
Org. Lett. 2010, 12, 816.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562104.
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References and Notes
(1) (a) Lawrence, S. A. Amines: Synthesis, Properties, and Applica-
tion; Cambridge University Press: Cambridge, 2004. (b) Quan,
M. L.; Lam, P. Y. S.; Han, Q.; Pinto, D. J. P.; He, M. Y.; Li, R.; Ellis, C.
D.; Clark, C. G.; Teleha, C. A.; Sun, J.-H.; Alexander, R. S.; Bai, S.;
Luettgen, J. M.; Knabb, R. M.; Wong, P. C.; Wexler, R. R. J. Med.
Chem. 2005, 48, 1729. (c) Barchéchath, S. D.; Tawatao, R. I.; Corr,
M.; Carson, D. A.; Cottam, H. B. J. Med. Chem. 2005, 48, 6409.
(d) Voets, M.; Antes, I.; Scherer, C.; Müller-Vieira, U.; Biemel, K.;
Barassin, C.; Marchais-Oberwinkler, S.; Hartmann, R. W. J. Med.
Chem. 2005, 48, 6632. (e) Davey, D. D.; Adler, M.; Arnaiz, D.;
Eagen, K.; Erickson, S.; Guilford, W.; Kenrick, M.; Morrissey, M.
M.; Ohlmeyer, M.; Pan, G.; Paradkar, V. M.; Parkinson, J.;
Polokoff, M.; Saionz, K.; Santos, C.; Subramanyam, B.; Vergona,
R.; Wei, R. G.; Whitlow, M.; Ye, B.; Zhao, Z. S.; Devlin, J. J.;
Phillips, G. J. Med. Chem. 2007, 50, 1146. (f) Ullmann, F. Ann.
1904, 232, 38. (g) Fanta, P. E. Chem. Rev. 1946, 38, 139.
(h) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4,
581. (i) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453.
(2) (a) Hartwig, J. F. Palladium-Catalyzed Amination of Aryl Halides
and Related Reactions in Handbook of Organopalladium Chemis-
try for Organic Synthesis; Vol. 1; Negishi, E. I., Ed.; Wiley-Inter-
science: New York, 2002, 1051.2. (b) Muci, A. R.; Buchwald, S. L.
Practical Palladium Catalysts for CAN and CAO Bond Formation,
In Topics in Current Chemistry; Vol. 219; Miyaura, N., Ed.;
Springer: Berlin, 2002, 133. (c) Fagan, P. J.; Hauptman, E.;
Shapiro, R.; Casalnuovo, A. J. Am. Chem. Soc. 2000, 122, 5043.
(d) Rao, K. S.; Wu, T.-S. Tetrahedron 2012, 68, 7735. (e) Lin, B.;
Liu, M.; Ye, Z.; Ding, J.; Wu, H.; Cheng, J. Org. Biomol. Chem.
2009, 7, 869.
(8) (a) Song, R. J.; Deng, C. L.; Xie, Y. X.; Li, J. H. Tetrahedron Lett.
2007, 48, 7845. (b) Lam, P. Y. S.; Deudon, S.; Averill, K. M.; Li, R.;
He, M. Y.; DeShong, P.; Clark, C. G. J. Am. Chem. Soc. 2000, 122,
7600.
(9) Zhang, Q.; Chen, J.; Liu, M.; Wu, H.; Cheng, J.; Qin, C.; Su, W.;
Ding, J. Synlett 2008, 935.
(10) Representative Procedure
A Schlenk reaction tube was charged with phenyltrimethylger-
mane (2a, 194.9 mg, 1.0 mmol), 4-methoxyaniline (1m, 147.9
mg, 1.2 mmol), Pd(OAc)2 (11.2 mg, 5 mol%), Ph3P (13.1 mg, 5
mol%), NaOAc (164.1 mg, 2.0 mmol), toluene (2.0 mL), under
argon atmosphere at 100 °C for 12 h. After completion of the
reaction, as indicated by TLC, the reaction mixture was
extracted with Et2O (3 × 10 mL). The combined organic layer
was washed by water and dried by Na2SO4. The solvent was
removed in vacuo, and the residue was purified by a short
column chromatography (silica gel 300–400 mesh, PE–EtOAc =
8:1) to give 3m in 87% isolated yield (173 mg); mp 102–103 °C.
4-Methoxy-N-Phenylaniline (3m)
1H NMR (300 MHz, CDCl3): δ = 7.25–7.18 (m, 3 H), 7.09–7.05 (m,
2 H), 6.92–6.83 (m, 4 H), 5.49 (s, 1 H), 3.81 (s, 3 H). 13C NMR (75
MHz, CDCl3): δ = 135.7, 129.3, 124.3, 122.2, 119.5, 115.6, 114.6,
114.1, 55.6. MS (EI): m/z = 212. Anal. Calcd for C13H13NO: C,
78.35; H, 6.59; N, 7.02. Found: C, 78.22; H, 6.41; N, 6.95.
(3) (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc.
Chem. Res. 1998, 31, 805. (b) Hartwig, J. F. Angew. Chem. Int. Ed.
1998, 37, 2046.
(4) (a) Kumari, A. S.; Pathak, D. D. Tetrahedron Lett. 2015, 56, 4135.
(b) Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 4397. (c) Poonam,
R.; Rajendra, S. Tetrahedron Lett. 2014, 55, 5256. (d) Islam, S. M.;
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D