Cu(OAc)2-mediated cross-coupling reaction of benzophenone N,N,N-trimethylhydrazonium salts and aryl boronic acids

Article abstract of DOI:10.1071/CH12350

Cu(OAc)₂-mediated coupling of benzophenone N,N,N- trimethylhydrazonium salts and aryl boronic acids proceeded to afford N-aryl imines.

Full text of DOI:10.1071/CH12350

CSIRO PUBLISHING
Aust. J. Chem. 2012, 65, 1687–1690
Communication
http://dx.doi.org/10.1071/CH12350
Cu(OAc)2-Mediated Cross-Coupling Reaction
of Benzophenone N,N,N-Trimethylhydrazonium
Salts and Aryl Boronic Acids
A B
,
A
A
Mitsuru Kitamura,
Yu Tokuda, Norifumi Tashiro,
A
and Tatsuo Okauchi
A
Department of Applied Chemistry, Kyushu Institute of Technology, 1-1 Sensuicho,
Tobata, Kitakyushu, 804-8550, Japan.
B
Corresponding author. Email: kita@che.kyutech.ac.jp
Cu(OAc)2-mediated coupling of benzophenone N,N,N-trimethylhydrazonium salts and aryl boronic acids proceeded to
afford N-aryl imines.
Manuscript received: 24 July 2012.
Manuscript accepted: 11 September 2012.
Published online: 15 October 2012.
Recent progress on the synthesis of aryl amines based on the
metal-catalyzed C-N bond formation reaction is remarkable.[1]
In general, aryl halides and nucleophilic amino compounds are
used in the C-N bond formation reaction. For the synthesis of
protected primary aryl amines, N-H imine (C ¼ NH, such as 2) is
an efficient nitrogen donor because the coupling product, N-aryl
imine 3, is stable under various conditions and is easily trans-
formed to the corresponding primary amine 4 under mild acidic
conditions (Scheme 1, strategy A).[2,3] The metal-catalyzed
cross-coupling of imines having a leaving group at the imino-
nitrogen (e.g. 5: C ¼ N-Y, where Y is a leaving group) and an
aryl metal species 7 is an alternative method for the synthesis of
N-aryl imine 3 (strategy B); however, this strategy has not been
well examined partly because of few studies on the oxidative
addition of 5 to the metal complex (5 þ M1- 6).[4] Recently,
Benzophenone (8a) and several methoxy-substituted benzophe-
nones 8b–d were transformed to N,N-dimethylhydrazones 9 in
moderate to high yields (Me2N-NH2, cat AcOH, in a sealed tube
at 1408C) (Runs 1–4). Interestingly, 2,5-dimethoxy benzophe-
none 8e was not converted to the corresponding hydrazone 9e
under the reaction conditions (Run 5). Successively, hydrazones
9a–c were converted to N,N,N-trimethylhydrazonium iodide
10a–c by reacting with MeI in a sealed tube (Runs 1–3).[9]
Benzophenone N,N,N-trimethylhydrazonium hexafluoropho-
sphate (11) was prepared from iodide 10a by treating with
NH4PF6 [NH4PF6 (1.5 equiv), CH2Cl2, H2O, rt, 10 h, 98 %].
Next, the metal-mediated coupling of diaryl ketone N,N,N-
trimethylhydrazonium salts and aryl boronic acids was exam-
ined (Table 2). The reaction products were determined after
evaporation of the reaction mixture and separation by silica gel
column chromatography.
the Cu-catalyzed coupling of benzophenone oxime
5
(Y ¼ OCOC6F5 or OAc) and aryl boronic acid 7 (M2 ¼ B(OH)2)
was reported.[5,6] This reaction proposed the intermediacy of
alkylidene aminocuprate 6 formed by the oxidative addition
of oximes to a copper complex.[4,6]
Initially, we attempted to couple benzophenone N,N,N-
trimethylhydrazonium iodide (10a) and p-tolylboronic acid
(12a) in the presence of a metal catalyst in 1,4-dioxane at
708C (Table 2, Runs 1–13). Although no coupling product
was formed by the treatment of either Pd(0) or Pd(II) metal
catalyst [Pd(PPh3)4, Pd2(dba)3 þ [1,10-bis(diphenylphosphino)
ferrocene] (dppf), Pd2(dba)3 þ [1,3-Bis(diphenylphosphino)
propane] (dppp), or Pd(OAc)2], the desired imine 14a was
obtained in 29 % when 10 mol-% Pd(PPh3)4 and 1.2 equiv of
Cu(OAc)2 were used (Run 1). By adding dppp or dppf as a ligand
in the catalyst system of Pd(0)-Cu(OAc)2, the yield of imine 14a
increased to 44 and 54 %, respectively (Runs 3 and 4). By
treating either with Cu(II) or Cu(I) salts such as Cu(OAc)2 or
Cu(OAc), N-aryl imine 14a was obtained in 44 and 40 % yield,
respectively, which suggested that the same active copper
species formed from both Cu(OAc)2 and Cu(OAc) in the
coupling reaction conditions (Runs 4 and 5, respectively).[10]
By the combined use of Cu(OAc)2 and Cu, N-aryl imine 14a
formed in 38 % yield (Run 6). Cu(I) thiophene-2-carboxylate
Previously, we reported the amino-Heck reaction (Narasaka-
Heck reaction)[4c,7] of g,d-unsaturated ketone N,N,N-
trimethylhydrazonium salts to give pyrroles.[8] This reaction is
proposed to be initiated by oxidative addition of a N,N,N-
trimethylhydrazonium salt to a palladium(0) complex, resulting
in the formation of an alkylideneaminopalladium(II) species.
This result suggested that the N,N,N-trimethylhydrazonium salt
could be used as an imino donor 5 similar to the oxime for the
synthesis of N-aryl imine 3 by strategy B as shown in Scheme 1.
Thus, we decided to examine the metal-mediated coupling of N,
N,N-trimethylhydrazonium with aryl boronic acid. In this letter,
we describe the outcome of this investigation.[9]
Benzophenone N,N,N-trimethylhydrazonium iodide deriva-
tives 10 were prepared from corresponding ketones 8 in two
steps, using a modification to Smith’s procedure[9] (Table 1).
Journal compilation Ó CSIRO 2012
www.publish.csiro.au/journals/ajc

1688
M. Kitamura et al.
Strategy A
Strategy B
Ph
Y
1
Ar-X
N
N
A series of arylboronic acids were then subjected to the
optimized conditions (Run 13) with benzophenone N,N,N-
trimethylhydrazonium iodide 10a (Runs 16–19). When
o-tolylboronic acid was used, the coupling product 14b was
obtained in 54 % yield (Run 16). The reaction with phenyl-
boronic acid having an electron-deficient group such as a cyano
group did proceed, giving coupling product 14c; however, the
yield was 10 % and benzophenone (8a) was formed in 40 %
yield (Run 17). In the reaction of o- or p-methoxyphenylboronic
acid, the coupling product was obtained in 35 and 24 % yield,
respectively (Runs 18 and 19).
The reaction of methoxy-substituted benzophenone hydra-
zonium salts with p-tolylboronic acid (12a) was also examined
(Runs 20 and 21). Hydrazonium salt 10b (Ar1 ¼ 4-MeOC6H4)
reacted smoothly to give the corresponding imine 14f in 60 %
yield (Run 20). In the reaction of tetramethoxy hydrazonium salt
10c (Ar1 ¼ 3,4-(MeO)2C6H3), ketone 8c was formed as a major
product and the coupling product 14 g was obtained in 36 %
yield (Run 21).
M1
Ph
5
M1
Ar-M1-X
H
N
Y
M1
Ph
ϩ base
Ph
Ph
base•HX
Ar
6
2
Ph
M1
Ar-M2
7
N
N
Ph
Ph
Ph
M1
Ar
M2-Y
H3Oϩ
4
Ar–NH2
Ph
3
Scheme 1. Metal-catalyzed synthesis of N-Aryl imines 3.
In the Cu(OAc)2-mediated coupling of diaryl ketone N,N,N-
trimethylhydrazonium salts 10 and aryl boronic acids 12, the
formation of diaryl ketone 8, hydrazone 9, and aryl amine 15 was
observed in some case. Ketone 8 could be formed by the
hydrolysis of the coupling product 14, hydrazonium salt 10,
or imino metal species such as 6 as depicted in Scheme 1,
although the actual reaction mechanism is unclear. Hydrazone 9
presumably formed by demethylation as a result of attack of
nucleophilic materials such as Iꢀ in the reaction mixture. Aryl
amine 15 was supposedly formed by the hydrolysis of the
coupling product 14.
Table 1. Preparation of benzophenone N,N,N-trimethylhydrazonium
salts 10
ϩ
IϪ
NH2–NMe2
cat. CH3CO2H
NMe2
Ar1
NMe3
O
N
N
Me-I
Ar1
Ar1
Ar1
Ar1
Ar1
sealed tube
140ЊC
sealed tube
cond. bB
8
9
10
cond. aA
Run Ar1
CondA Yield of 9
CondB
Yield of 10
[%]C
[%]C
In conclusion, we have developed a copper-mediated
coupling of N,N,N-trimethylhydrazonium salts and aryl boronic
acids to give N-aryl imines. The formation of N-aryl imine 14
suggested that N(sp2)–N(sp3) bond cleavage had occurred by the
aid of a copper complex, and thus, formed an alkylidene amino
copper species such as 6 coupled with aryl boronic compounds.
We could demonstrate the N-N bond cleavage and its applica-
tion in the synthesis of nitrogen-containing compounds.[12]
N,N-Dialkylhydrazones and N,N,N-trialkylhydrazonium salts
are often used as the corresponding carbonyl compounds;[13]
we showed that N,N,N-trimethylhydrazonium salt could be used
as the nitrogen donor (ammonia equivalent) and expand the
chemistry of hydhydrazonium salt. Further studies on the scope
and the mechanism of the reaction are currently in progress.
1
2
3
4
5
a: C6H5
b: 4-MeOC6H4
15 h
15 h
91
90
38
54
0
1008C, 10 min
608C, 10 min
408C, 10 min
1008C, 20 min
–
71
61
50
0
c: 3,4-(MeO)2C6H3 18 h
d: 2,4-(MeO)2C6H3 13 h
e: 2,5-(MeO)2C6H3 96 h
AMolar ratio: 8/NH2-NMe2/CH3CO2H ¼ 1/3/0.1.
BMolar ratio: 9/MeI ¼ 1/3.
CIsolated yields.
(CuTC) showed almost the same reactivity to Cu(OAc)
and Cu(OAc)2 (Run 7).[11] As shown in Run 8, the use of
a catalytic amount of Cu reagent was ineffective in forming
14a. The counter anion of the Cu reagent was found to be
important for the coupling. Copper halides were ineffective in
forming imine 14a regardless of the use of Cu(II) or Cu(I)
(Runs 9–11). Addition of dppf was also effective in the coupling
reaction with Cu(OAc)2, and afforded imine 14a in 60 %
yield (Run 13).
Next, various p-tolylboronic acid derivatives were examined
under Cu(OAc)2-mediated reaction conditions. The coupling
reaction of boronic acid esters (p-tolylboronic acid ester of
propylene glycol, 2,2-dimethylpropylene glycol, pinacol, and
catechol) did not proceed at all. The coupling of potassium
p-tolyltrifluoroborate (13) proceeded, but the yield of 14a was
lower than that obtained by the reaction with boronic acid 12a
(Table 2, 13 versus 14).
Experimental
Typical Procedure for the Synthesis Diarylketone
N,N,N-Trimethylhydrazonium Salts Table 1, Run 1)
A mixture of benzophenone N,N-dimethylhydrazone 9a (1.0 g,
4.5 mmol) and iodomethane (1.9 g, 13 mmol) in ethanol in a
sealed tube was stirred for 10 min at 1008C. After the reaction
mixture was cooled to room temperature, volatile materials were
removed under vacuum and the crude materials were purified by
recrystallization (hexane, ethanol) to afford pure benzophenone
N,N,N-trimethylhydrazonium iodide 10a in 71 % yield.
Typical Procedure for the Cu(OAc)2-Catalyzed Coupling
Reaction of Benzophenone N,N,N-Trimethylhydrazonium
Salts and Aryl Boronic Acids (Table 2, Run 13)
In the Pd(0)-catalyzed amino-Heck reaction of N,N,N-
trimethylhydrazonium salt, a poorly nucleophilic anion such as
BFꢀ4 and PFꢀ6 was found to be suitable as the counter anion of the
salts.[8] However, in the Cu(OAc)2-mediated coupling reaction,
hexafluorophosphate 11 was not suitable as shown in Run 15.
A mixture of benzophenone N,N,N-trimethylhydrazonium
iodide (10a, 0.5 mmol), p-tolylboronic acid (12a, 0.60 mmol),
Cu(OAc)2 (0.6 mmol), and dppf (0.05 mmol) in dry 1,4-dioxane
under a nitrogen atmosphere was stirred for 1 h at 708C. After

Cross-Coupling of Trimethylhydrazonium Salt
1689
Table 2. Metal-catalyzed coupling of benzophenone N,N,N-trimethylhydrzonium salts and aryl boronic acid derivativesA
ϩ
NMe3
X–
Ar2
Ar1
Ar2-B(OH)2
or
NMe2
12
N
N
O
N
Metal cat.
Ar2
15
Ϫ
NH2
ϩ
ϩ
ϩ
ϩ
Ar1
Ar1
Ar1
Ar1
Ar1
Ar1
Ar1
70ЊC
1,4-dioxane
p-Tol-BF3K 13
14
8
9
10 (X ϭ I)
11 (X ϭ PF6
)
Run Ar1
10 or 11 Ar2
12 or 13 Metal cat. (equiv)
Time [h]
Yield [%]B
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
11
p-Tol
12a
12a
12a
12a
12a
12a
12a
12a
12a
12a
12a
12a
12a
13
Pd(PPh3)4 (0.01), Cu(OAc)2 (1.2)
1.5
3
3
1
1
1
3
4
4
4
4
1
1
2
1
1
1
1
1
2
2
14a 29
14a 44
14a 54
14a 44
14a 40
14a 38
14a 36
8a 65 9a 2
8a 32 9a 5
8a 40 9a 5
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
o-Tol
Pd2(dba)3 (0.005), Cu(OAc)2 (1.2), dppp (0.02)
Pd2(dba)3 (0.005), Cu(OAc)2 (1.2), dppf (0.02)
Cu(OAc)2 (1.2)
8a 23 9a 2 15a 2
8a 36 9a 1
Cu(OAc) (1.2)
Cu(OAc) (0.6), Cu (0.6)
CuTC (1.2)
8a 22
8a 56 9a 7 15a 1
Cu(OAc)2 (0.1)
14a trace 8a 15
8a 9
CuI (1.2)
10 Ph
CuCl (1.2)
8a 57
11 Ph
CuCl2 (1.2)
8a 13
12 Ph
Cu(OAc)2 (1.2), PPh3 (0.2)
Cu(OAc)2 (1.2), dppf (0.1)
Cu(OAc)2 (1.2), dppf (0.1)
Cu(OAc)2 (1.2)
14a 49
14a 60
14a 29
8a 11 9a 7
13 Ph
8a 28 9a8
14 Ph
8a 15 9a 8 15a 13
15 Ph
12a
12b
14a trace 8a 12
14b 54 9a 28
16 Ph
10a
10a
10a
10a
10b
Cu(OAc)2 (1.2), dppf (0.1)
Cu(OAc)2 (1.2), dppf (0.1)
Cu(OAc)2 (1.2), dppf (0.1)
Cu(OAc)2 (1.2), dppf (0.1)
Cu(OAc)2 (1.2), dppf (0.1)
Cu(OAc)2 (1.2), dppf (0.1)
17 Ph
p-(CN)C6H4 12c
o-(MeO)C6H4 12d
p-(MeO)C6H4 12e
14c 10
14d 35
14e 24
14f 60
14g 36
8a 40 9a 19
8a 23 9a 27
8a 20 9a 15
8b 17
18 Ph
19 Ph
20 4-MeOC6H4
p-Tol
p-Tol
12a
12a
21 3,4-(MeO)2C6H3 10c
8c 50
AThe reaction was conducted with 10 or 11 (0.5 mmol), aryl boronic acid derivative (12 or 13, 1.2 equiv), and metal catalyst in 1,4-dioxane (1 mL) at 708C.
BIsolated yields.
the reaction mixture was cooled to room temperature, volatile
materials were removed under vacuum and the crude materials
were purified by flash column chromatography (SiO2, hexane/
ethyl acetate ¼ 20/1) to give N-diphenylmethylen-4-
methylphenylamine 14a (60 %), benzophenone (8a, 28 %), and
hydrazone 9a (8 %).
[3] Recently, several direct syntheses of primary amines by the
metal catalyzed C-N bond formation with NH3 have been reported.
(a) G. D. Vo, J. F. Hartwig, J. Am. Chem. Soc. 2009, 131, 11049.
doi:10.1021/JA903049Z
(b) L. Jiang, X. Lu, H. Zhang, Y. Jiang, D. Ma, J. Org. Chem. 2009, 74,
4542. doi:10.1021/JO9006738
(c) H.-J. Xu, Y.-F. Liang, Z.-Y. Cai, H.-X. Qi, C.-Y. Yang, Y.-S. Feng,
J. Org. Chem. 2011, 76, 2296. doi:10.1021/JO102506X
[4] Oxidative addition of oximes: (a) C. M. P. Ferreira, M. F. C. Guedes da
Silva, V. Y. Kukushkin, J. J. R. Frau´sto da Silva, A. J. L. Pombeiro,
J. Chem. Soc., Dalton Trans. 1998, 325. doi:10.1039/A707213I
(b) A. Tillack, P. Arndt, A. Spannenberg, R. Kempe, U. Rosenthal,
Z. Anorg. Allg. Chem. 1998, 624, 737. doi:10.1002/(SICI)1521-3749
(199804)624:4,737::AID-ZAAC737.3.0.CO;2-L
Supplementary Material
General experimental details and physical data including 1H/13C
NMR charts for benzophenone N,N,N-trimethylhydrazonium
iodide 10a–10c and selected coupling products 14a, 14f, 14g are
available on the Journal’s website.
(c) H. Tsutsui, K. Narasaka, Chem. Lett. 1999, 28, 45. doi:10.1246/
CL.1999.45
(d) H. Tsutsui, M. Kitamura, K. Narasaka, Bull. Chem. Soc. Jpn. 2002,
75, 1451. doi:10.1246/BCSJ.75.1451
Acknowledgements
This research was partially supported by a Grant-in-Aid for Scientific
ResearchfromtheMinistry ofEducation, Science, SportsandCulture, Japan.
(e) M. Kitamura, Y. Shintaku, D. Kudo, T. Okauchi, Tetrahedron Lett.
2010, 51, 4890. doi:10.1016/J.TETLET.2010.07.055
Oxidative addition of azines: (f) G. Erker, W. Fro¨mberg, C. Kru¨ger,
E. Raabe, J. Am. Chem. Soc. 1988, 110, 2400. doi:10.1021/
JA00216A011
References
[1] Selected reviews: (a) S. L. Buchwald, C. Mauger, G. Mignani,
U. Scholz, Adv. Synth. Catal. 2006, 348, 23. doi:10.1002/ADSC.
200505158
(b) J. F. Hartwig, Acc. Chem. Res. 2008, 41, 1534. doi:10.1021/
AR800098P
(g) T. Zippel, P. Arndt, A. Ohff, A. Spannenberg, R. Kempe,
U. Rosenthal, Organometallics 1998, 17, 4429. doi:10.1021/
OM980466E
(h) A. Zimniak, G. Bakalarski, J. Mol. Struct. 2001, 597, 211.
doi:10.1016/S0022-2860(01)00604-4
(c) D. S. Surry, S. L. Buchwald, Angew. Chem. Int. Ed. 2008, 47, 6338.
doi:10.1002/ANIE.200800497
˚
[2] (a) J. P. Wolfe, J. Ahman, J. P. Sandighi, R. A. Singer, S. L. Buchwald,
Tetrahedron Lett. 1997, 38, 6367. doi:10.1016/S0040-4039(97)01465-2
(b) R. A. Singer, S. L. Buchwald, Tetrahedron Lett. 1999, 40, 1095.
doi:10.1016/S0040-4039(98)02642-2
[5] M. Kitamura, G. Hattori, K. Narasaka, Abstract of Papers, 85th Annual
Meeting of The Chemical Society of Japan, Yokohama, The Chemical
Society of Japan: Tokyo, 2005; Abstract 3A6–46.
(c) G. Mann, J. F. Hartwig, M. S. Driver, C. Ferna´ndez-Rivas,
J. Am. Chem. Soc. 1998, 120, 827. doi:10.1021/JA973524G
[6] S. Liu, Y. Yu, L. S. Liebeskind, Org. Lett. 2007, 9, 1947. doi:10.1021/
OL070561W

1690
M. Kitamura et al.
[7] (a) M. Kitamura, K. Narasak, Chem. Rec. 2002, 2, 268. doi:10.1002/
TCR.10030
(b) K. Narasaka, M. Kitamura, Eur. J. Org. Chem. 2005, 4505.
doi:10.1002/EJOC.200500389
[8] M. Kitamura, H. Yanagisawa, M. Yamane, K. Narasaka, Heterocycles
(c) P. Y. S. Lam, C. G. Clark, S. Saubern, J. Adams, M. P. Winters,
D. M. T. Chan, A. Combs, Tetrahedron Lett. 1998, 39, 2941.
doi:10.1016/S0040-4039(98)00504-8
(d) Recent selected reports: L. Naya, M. Larrosa, R. Rodriguez,
J. Cruces, Tetrahedron Lett. 2012, 53, 769. doi:10.1016/J.TETLET.
2011.11.144
2005, 65, 273. doi:10.3987/COM-04-10280
[9] Direct reaction of N,N,N-trialkyl hydrazonium salts and Grignard
reagents/alkyl lithium reagents, see: (a) P. A. S. Smith, H. H. Tan,
J. Org. Chem. 1967, 32, 2586. doi:10.1021/JO01283A050
(b) P. A. S. Smith, C. R. Messing, J. Org. Chem. 1988, 53, 2959.
doi:10.1021/JO00248A011
[10] Cu-mediated coupling of aryl boronic acid and amines. Initial reports:
(a) D. M. T. Chan, K. L. Monaco, R.-P. Wang, M. P. Winters,
Tetrahedron Lett. 1998, 39, 2933. doi:10.1016/S0040-4039(98)
00503-6
(e) N. Matsuda, K. Hirano, T. Satoh, M. Miura, Angew. Chem. Int. Ed.
2012, 51, 3642. doi:10.1002/ANIE.201108773
(f) R. P. Rucker, A. M. Whittaker, H. Dang, G. Lalic, Angew. Chem.
Int. Ed. 2012, 51, 3953. doi:10.1002/ANIE.201200480
[11] Cu(I) thiophene-2-carboxylate: G. Allred, L. S. Liebeskind,
J. Am. Chem. Soc. 1996, 118, 2748. doi:10.1021/JA9541239
[12] For the N(sp3)-N(sp3) bond cleavage of hydrazine, Q. Tang,
C. Zhang, M. Luo, J. Am. Chem. Soc. 2008, 130, 5840 and references
cited therein. doi:10.1021/JA711153B
(b) D. J. Cundy, S. A. Forsyth, Tetrahedron Lett. 1998, 39, 7979.
doi:10.1016/S0040-4039(98)01735-3
[13] R. Lazny, A. Nodzewska, Chem. Rev. 2010, 110, 1386. doi:10.1021/
CR900067Y