Formation of C=N bonds by the release of H2: A new strategy for synthesis of imines and benzazoles

Article abstract of DOI:10.1039/c3ob40388b

A new strategy for synthesis of imines using the approach of release of H₂ has been developed. This oxidant- and acceptor-free Pd/C catalysis protocol is further applied to synthesis of benzoxazoles, benzimidazoles, and benzothiazoles through a one-pot cascade reaction with notably high yields. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob40388b

Organic &
Biomolecular Chemistry
View Article Online
View Journal
COMMUNICATION
Formation of CvN bonds by the release of H2: a new
strategy for synthesis of imines and benzazoles†
Cite this: DOI: 10.1039/c3ob40388b
Received 22nd February 2013,
Accepted 22nd April 2013
Xukang Jin, Yuxiao Liu, Qiongqiong Lu, Dejun Yang, Jiangkai Sun,
Shuangshuang Qin, Jingwu Zhang, Jiaxuan Shen, Changhu Chu and Renhua Liu*
DOI: 10.1039/c3ob40388b
www.rsc.org/obc
A new strategy for synthesis of imines using the approach of markedly different synthetic strategies. However, the catalytic
release of H2 has been developed. This oxidant- and acceptor-free systems were mainly applicable to the dehydrogenation of
Pd/C catalysis protocol is further applied to synthesis of benzox- alcohols to the carbonyl compounds. No dehydrogenations of
azoles, benzimidazoles, and benzothiazoles through a one-pot amines to the imines and benzazoles with the release of H2
cascade reaction with notably high yields.
have been reported to date. Herein we reported an innovative
dehydrogenation method for the synthesis of imines as well as
benzoxazoles, benzimidazoles, and benzothiazoles with the
release of H2 in the presence of Pd/C without any oxidants and
hydrogen acceptors.
Introduction
The initial attempt toward the investigation is to develop an
efficient transfer hydrogenation process using benzylamine as
the hydrogen donor. During the condition screens, however,
we were surprised to find that Pd/C could catalytically dehydro-
genate benzylamine to benzylidenebenzylamine in the
absence of any oxidants and hydrogen receptors when N,N-
dimethylacetamide (DMA) was used as the solvent. By closely
analyzing the reaction mixtures, we did not detect any hydro-
genated products derived from DMA. These results implied
that the hydrogen parted from the substrate formed H2. To
verify the prediction of generation of H2 during the reaction,
we detected the gas generated in the reaction with GC. The
results shown in Fig. 1 clearly demonstrated the generation of
H2 during the reactions.
The construction of a new chemical bond is of paramount
importance in synthetic organic chemistry. In recent years,
direct bond construction strategies that promote atom
economy and avoid pre-functionalization of the substrates
have attracted much attention due to the rising demand of
green chemistry.1 Among them, the formation of a new bond
with liberation of H2 has emerged as an attractive and challen-
ging goal.2 These H2-liberation bond constructions are particu-
larly interesting both in organic synthesis and in hydrogen
production. In organic synthesis, the H2-liberation bond con-
struction methodology for organic synthesis largely dispenses
with the need for pre-functionalization of the substrates, and
therefore could significantly simplify and shorten the syn-
thesis route for target compounds. In hydrogen production,
although it has long been known that most of the organics are
hydrogen rich, the potential of organic compounds as a hydro-
gen source for green hydrogen production until now has been
undeveloped. In this light, the H2-liberation bond construction
methods provide a promising approach to the exploitation of
H2 from organic compounds through organic synthetic pro-
cesses. Thus several research groups have recently reported the
synthesis of carbonyl compounds,2a–g esters,2h–j acetals,2h
imines,2k and amides2l–o with the release of H2 as the con-
current product. These methods unlock opportunities for
Department of Chemistry, East China University of Science and Technology, Meilong
Road 130, Shanghai 200237, China. E-mail: liurh@ecust.edu.cn;
Fig. 1 GC H2 detection for the dehydrogenation of benzylamines. A: the
mixture of hydrogen gas and air. B: the gas sample from the reaction system
(reaction conditions: 1 mmol benzylamine, 2% mmol Pd/C, 120 °C, 30 min, 2 ml
DMA, N2 balloon. Some air infiltrated into the gas sample during sampling).
Fax: (+86) 21-64250627
†Electronic supplementary information (ESI) available: Experimental procedures
and characterization data for imines and benzazoles (benzoxazoles, benzimi-
dazoles, and benzothiazoles). See DOI: 10.1039/c3ob40388b
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem.

View Article Online
Communication
Organic & Biomolecular Chemistry
promote the desired dehydrogenation transformation and the
bases employed were deleterious to the dehydrogenations.
Thus we chose to implement the dehydrogenation reactions
only using Pd/C as the catalyst without any oxidants and accep-
tors. Definitely, all the reactions were carried out under an
atmosphere of high pure N2 (N2 balloon), and the reaction
mixtures have been thoroughly degassed before the reactions.
As revealed in Table 2, benzylic primary amines were
smoothly converted into the desired imines with very high con-
versions and yields. The dehydrogenation reaction was applied
to secondary amines (Table 2, entries 3 and 4). In the case of
tetrahydroquinoline, the dehydrogenation reaction produced
quinoline in near quantitative yields. As such, dehydrogena-
tion of dibenzylamine to the imine showed very high conver-
sion and yield. Dehydrogenations of cross coupling amines
were also tested. The results showed that near 100% benzyl
amine substrates were converted and high yields of target com-
pounds were reached. De-amination of amine 1 to the corres-
ponding methylbenzenes was observed under such reaction
conditions. This may be attributed to de-amination of benzyl
amines with H2 in the presence of Pd/C.
When the dehydrogenation was carried out with benzyl
amine and 2-aminophenol as the substrates under the reaction
conditions, we were surprised to find that the main product
was one benzoxazole. The generation of the benzoxazole was
attributed to a one-pot cascade reaction through the dehydro-
genation, cyclization and aromatization. The result is of great
interest because the compounds with five-membered hetero-
atomic (O, N, S) aromatic ring skeletons are widely found in
natural products, synthetic pharmaceutical, and agrochemical
compounds.7 Furthermore, these compounds have versatile
pharmacological properties and broad ranges of biological
functions such as antitumor, anticancer, and antibacterial
activities.8 A survey of the literature reveals that no such H2-lib-
eration methods for synthesis of benzoxazoles, benzimid-
azoles, and benzothiazoles have hitherto been reported. One
of the most general strategies towards the preparation of 2-sub-
stituted benzoxazoles could be described as oxidative cycliz-
ation of phenolic Schiff bases derived from the condensation
of 2-aminophenols and aldehydes (Scheme 2, classical
routes).9 These methods require stoichiometric or excess
amounts of oxidants or hydrogen acceptors to aromatize the
five-membered heteroatomic ring intermediates. For example,
very recently, Nguyen and the co-workers10 have reported the
synthesis of 2-arylbenzoxazoles using benzylamines and 2-sub-
stituted anilines as the substrates and stoichiometric amounts
of S8 as the hydrogen acceptors. However, the method gene-
rated harmful H2S gas as the by-product (Scheme 2, Nguyen’s
work). Thus our unexpected findings that benzoxazoles could
be prepared with Pd/C in the absence of oxidants and
hydrogen acceptors suggested that we may develop an innova-
tive method for synthesis of these useful compounds, and
therefore prompted us to further investigate the synthesis of
benzoxazoles, benzimidazoles, and benzothiazoles with this
H2 liberation catalytic system. The results collected in Table 3
demonstrated that the Pd/C catalyst system could efficiently
Scheme 1 Different pathways for the synthesis of imines.
Imines are useful compounds in laboratory and industrial
synthetic processes.3 The traditional methods for synthesis of
imines involve the condensation of carbonyl compounds with
amines in the presence of an acid catalyst. An alternative to
preparation of imines is oxidative dehydrogenation of primary
amines,4 secondary amines,5 and in situ dehydrogenation of a
mixture of amines and alcohols.2k,6 However, most of these
methods for synthesis of imines required an oxidant or a
hydrogen acceptor to perform the reactions (Scheme 1). Only
two examples involving dehydrogenation of alcohols to the
carbonyl compounds with release of hydrogen gas, following
the dehydrate reaction with amines to the imines have been
reported.2k,6a Thus we perceive that further investigation and
development of our findings of direct dehydrogenation of
amines to the imines with loss of hydrogen gas in the absence
of any oxidants and acceptors is both academically and practi-
cally interesting.
Results and discussion
Our investigation began with benzylamine as a typical sub-
strate and 10 wt% Pd/C as the catalyst and DMA as the solvent
for optimization of the reaction conditions. The results are
summarized in Table 1. A variety of acids such as TsOH and
bases (DBU, K2CO3, KOH, and CH3ONa) were screened for
their ability to promote the dehydrogenation reaction. The
results showed that the acidic additives tested were unable to
Table 1 Optimization for the dehydrogenated self-coupling of benzylaminea
Entry
Solvent
Pd/C (equiv.)
T (°C)
Yieldb (%)
1
2
3c
4
5
6
7
8
9
p-Xylene
C2H4Cl2
DMF
DMA
DMA
DMA
DMA
DMA
DMA
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.025
0.1
80
80
80
21
30
39
40
56
72
73
60
67
80
100
120
140
120
120
a Reaction conditions: 1 mmol benzylamine, 2 ml solvent, 2 h, N2
atmosphere. b Determined by GC analysis using n-dodecane as the
internal standard. c N-Benzylformamide was detected in the reaction
solution.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Communication
Table 2 Dehydrogenation of cross coupling amines catalyzed by Pd/Ca
Entry
1
Amine 1
Amine 2
Product
Time (h)
2
Yieldb (%)
72
2
2
89
3
4
5
91
98
20
5
6
14
16
85
78
7
8
6
9
83
75
9
5
9
74
72
10
11
12
7
86
77
12
a Reaction conditions: 1 mmol amine 1 (or 1 mmol amine 1 and 5 mmol amine 2), 5 mol% Pd/C (10 wt%), 120 °C, 2 ml DMA, N2 atmosphere.
b Determined by GC analysis using n-dodecane as the internal standard, and all products were identified by GC-MS.
convert a wide range of benzyl amines and o-phenylenedi-
amines (2-aminophenols or 2-aminothiophenols) to the benza-
zole compounds with high isolated yields in a one-pot
procedure. Key to the newly developed dehydrogenation
process is the findings that the reactions proceed well without
any oxidants or hydrogen acceptors. Furthermore, the
approach to benzazoles dispenses with the need of pre-prepa-
ration of the Schiff bases. It is noteworthy that the substrates
containing the groups that were susceptible to oxidation,
which are problematic in oxidative aromatization protocols,
seldom interfered with the catalytic dehydrogenation reaction.
In all reactions, we could detect the imine intermediates
during the reaction procedures. When benzaldehydes were
Scheme 2 Different pathways for the 2-arylbenzoxazole formation.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem.

View Article Online
Communication
Organic & Biomolecular Chemistry
intermediate, an iminium ion complex B; decomposition of B
generated C and D. C is a key intermediate, and the release of
H2 from C is the most important step toward the dehydrogena-
tion reactions. C is guessed to have similar chemical properties
with the intermediate H2Pd(0) derived from H2 and Pd/C.
Table 3 One-pot synthesis of benzoxazoles, benzimidazoles, and benzothi-
azoles catalyzed by Pd/Ca
Conclusions
Entry
1 or 2
3
Time (h)
4b (%)
In conclusion, we have developed an oxidant- and H-acceptor-
free heterogeneous catalysis protocol for the dehydrogenation
of amines into imines with liberation of H2 using Pd/C. This
catalytic process has dual functions: organic synthesis and
hydrogen production. Of particular interest is that the catalytic
system can further be applied to synthesis of benzoxazoles,
1
2
3
4
5
6
7
8
R = H (1)
R = CH3 (1)
R = F (1)
R = t-Bu (1)
R = OCH3 (1)
R = H (1)
R = CH3 (1)
R = F (1)
X = NCH3
X = NCH3
X = NCH3
X = NCH3
X = NCH3
X = O
X = O
X = O
X = S
X = S
X = S
X = S
X = NCH3
X = NCH3
X = NCH3
X = NCH3
X = O
X = O
X = O
X = O
X = S
24
24
24
24
24
30
30
30
28
28
28
28
14
14
14
14
16
16
16
16
13
13
13
13
75
86
92
90
85
77
86
70
85
93
95
70
benzimidazoles, and benzothiazoles through
a one-pot
cascade reaction with notably high yields. To the best of our
knowledge, this is the first report for synthesis of imines as
well as benzoxazoles by means of release of H2 without resort-
ing to oxidants or hydrogen acceptors. A plausible overall
mechanism described here is expected to help to tailor other
catalysts and substrates, so as to develop more efficient cataly-
tic processes for organic synthesis and hydrogen production.
9
R = H (1)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
R = CH3 (1)
R = t-Bu (1)
R = OCH3 (1)
R = H (2)
85
R = F (2)
87c
80c
85c
78
R = CH3 (2)
R = OCH3 (2)
R = H (2)
R = F (2)
88c
85c
92c
82
R = CH3 (2)
R = OCH3 (2)
R = H (2)
R = F (2)
R = CH3 (2)
R = OCH3 (2)
Acknowledgements
X = S
X = S
X = S
90c
88c
89c
This work was supported by grants from the National Natural
Science Foundation of China (No. 21072055) and the National
High Technology Research and Development Program of
China (863 Program) (No. 2008AA06Z306).
a Reaction conditions: 2 mmol 1 and 1 mmol 3 (1 mmol 2 and 1 mmol
3), 5 mol% Pd/C, 120 °C, 2 ml DMA, N2 atmosphere. b Isolated yields.
c GC yields.
Notes and references
used in place of benzylamines, the dehydrogenation reactions
achieved the conversion of the substrates to the corresponding
benzoxazoles, benzimidazoles, and benzothiazoles with the
same high yields (Table 3).
With reference to the mechanism of dehydrogenation of
tertiary amines and the release of H2 with Pd black,11 a plaus-
ible overall mechanism of this catalytic dehydrogenation can
be described in Scheme 3. The reactions proceeded with initial
coordination of the nitrogen lone pair to metal palladium(0)
followed by metal insertion into the adjacent C–H bond to
form A, which then came to rapid equilibrium with a key
1 K. Godula and D. Sames, Science, 2006, 312, 67.
2 (a) R. Kawahara, K. Fujita and R. Yamaguchi, J. Am. Chem.
Soc., 2012, 134, 3643; (b) K. Fujita, N. Tanino and
R. Yamaguchi, Org. Lett., 2007, 9, 109; (c) K. Fujita,
T. Yoshida, Y. Imori and R. Yamaguchi, Org. Lett., 2011, 13,
2278; (d) W. Fang, Q. Zhang, J. Chen, W. Deng and
Y.
Wang,
Chem.
Commun.,
2010,
46,
1547;
(e) T. Mitsudome, Y. Mikami, K. Ebata, T. Mizugaki,
K. Jitsukawa and K. Kaneda, Chem. Commun., 2008, 4804;
(f) T. Mitsudome, Y. Mikami, H. Funai, T. Mizugaki,
K. Jitsukawa and K. Kaneda, Angew. Chem., Int. Ed., 2008,
47, 138; (g) S. Musa, I. Shaposhnikov, S. Cohen and
D. Gelman, Angew. Chem., Int. Ed., 2011, 50, 3533;
(h) C. Gunanathan, L. J. W. Shimon and D. Milstein, J. Am.
Chem. Soc., 2009, 131, 3146; (i) J. Zhang, G. Leitus, Y. Ben-
David and D. Milstein, J. Am. Chem. Soc., 2005, 127, 10840;
( j) M. Nielsen, H. Junge, A. Kammer and M. Beller, Angew.
Chem., Int. Ed., 2012, 51, 5711; (k) B. Gnanaprakasam,
J. Zhang and D. Milstein, Angew. Chem., Int. Ed., 2010, 49,
1468; (l) B. Gnanaprakasam, E. Balaraman, Y. Ben-David
and D. Milstein, Angew. Chem., Int. Ed., 2011, 50, 12240;
(m) B. Gnanaprakasam and D. Milstein, J. Am. Chem. Soc.,
Scheme 3 Proposed mechanism for the synthesis of imines.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Communication
2011, 133, 1682; (n) C. Gunanathan, Y. Ben-David and
D. Milstein, Science, 2007, 317, 790; (o) H. Zeng and
Z. Guan, J. Am. Chem. Soc., 2011, 133, 1159; (p) M. Montag,
J. Zhang and D. Milstein, J. Am. Chem. Soc., 2012, 134,
10325; (q) S. W. Kohl, L. Weiner, L. Schwartsburd,
L. Konstantinovski, L. J. W. Shimon, Y. Ben-David,
M. A. Iron and D. Milstein, Science, 2009, 324, 74;
(r) R. Yamaguchi, C. Ikeda, Y. Takahashi and K. Fujita,
J. Am. Chem. Soc., 2009, 131, 8410.
E. L. Stone, T. D. Bradshaw, M. F. G. Stevens and
A. D. Westwell, J. Med. Chem., 2006, 49, 179; (c) M. Hranjec,
M. Kralj, I. Piantanida, M. Sedic, L. Suman, K. Pavelic and
G. Karminski-Zamola, J. Med. Chem., 2007, 50, 5696;
(d) M. C. Van Zandt, M. L. Jones, D. E. Gunn, L. S. Geraci,
J. H. Jones, D. R. Sawicki, J. Sredy, J. L. Jacot,
A. T. DiCioccio, T. Petrova, A. Mitschler and A. D. Podjarny,
J. Med. Chem., 2005, 48, 3141.
8 (a) J. A. Grobler, G. Dornadula, M. R. Rice, A. L. Simcoe,
D. J. Hazuda and M. D. Miller, J. Biol. Chem., 2007, 282,
8005; (b) J. Easmon, G. Pürstinger, K.-S. Thies,
G. Heinisch and J. Hofmann, J. Med. Chem., 2006, 49,
6343; (c) S. Aiello, G. Wells, E. L. Stone, H. Kadri,
R. Bazzi, D. R. Bell, M. F. G. Stevens, C. S. Matthews,
T. D. Bradshaw and A. D. Westwell, J. Med. Chem., 2008,
51, 5135.
9 (a) M. Pizzetti, E. D. Luca, E. Petricci, A. Porcheddu and
M. Taddei, Adv. Synth. Catal., 2012, 354, 2453;
(b) H. Sharghi, M. H. Beyzavi and M. M. Doroodmand,
Eur. J. Org. Chem., 2008, 4126; (c) W.-J. Yoo, H. Yuan,
H. Miyamura and S. Kobayashi, Adv. Synth. Catal., 2011,
353, 3085; (d) Y.-X. Chen, L.-F. Qian, W. Zhang and B. Han,
Angew. Chem., Int. Ed., 2008, 47, 9330; (e) K. Bahrami,
M. M. Khodaei and A. Nejati, Green Chem., 2010, 12, 1237;
(f) K. Bahrami, M. M. Khodaei and F. Naali, J. Org. Chem.,
2008, 73, 6835; (g) M. Wu, X. Hu, J. Liu, Y. Liao and
G.-J. Deng, Org. Lett., 2012, 14, 2722; (h) Y.-P. Zhu, F.-C. Jia,
M.-C. Liu and A.-X. Wu, Org. Lett., 2012, 14, 4414;
(i) G. A. Molander and K. Ajayi, Org. Lett., 2012, 14, 4242;
( j) A. J. Blacker, M. M. Farah, M. I. Hall, S. P. Marsden,
O. Saidi and J. M. J. Williams, Org. Lett., 2009, 11, 2039;
(k) Y. Kawashita, N. Nakamichi, H. Kawabata and
M. Hayashi, Org. Lett., 2003, 5, 3713; (l) Y. Shiraishi,
Y. Sugano, S. Tanaka and T. Hirai, Angew. Chem., Int. Ed.,
2010, 49, 1656.
3 (a) R. W. Layer, Chem. Rev., 1963, 63, 489; (b) S. F. Martin,
Pure Appl. Chem., 2009, 81, 195.
4 (a) S. Kodama, J. Yoshida, A. Nomoto, Y. Ueta, S. Yano,
M. Ueshima and A. Ogawa, Tetrahedron Lett., 2010, 51,
2450; (b) R. D. Patila and S. Adimurthy, Adv. Synth. Catal.,
2011, 353, 1695; (c) M. Largeron and M.-B. Fleury, Angew.
Chem., Int. Ed., 2012, 51, 5409; (d) F. Su, S. C. Mathew,
L. Möhlmann, M. Antonietti, X. Wang and S. Blechert,
Angew. Chem., Int. Ed., 2011, 50, 657; (e) X. Lang, H. Ji,
C. Chen, W. Ma and J. Zhao, Angew. Chem., Int. Ed., 2011,
50, 3934; (f) W. He, L. Wang, C. Sun, K. Wu, S. He, J. Chen,
P. Wu and Z. Yu, Chem.–Eur. J., 2011, 17, 13308; (g) L. Liu,
S. Zhang, X. Fu and C.-H. Yan, Chem. Commun., 2011, 47,
10148; (h) G. Chu and C. Li, Org. Biomol. Chem., 2010, 8,
4716; (i) Z. Hu and F. M. Kerton, Org. Biomol. Chem., 2012,
10, 1618.
5 (a) K. C. Nicolaou, C. J. N. Mathison and T. Montagnon,
Angew. Chem., Int. Ed., 2003, 115, 4211; (b) H. Choi and
M. P. Doyle, Chem. Commun., 2007, 745; (c) K. C. Nicolaou,
C. J. N. Mathison and T. Montagnon, J. Am. Chem. Soc.,
2004, 126, 5192; (d) G. Jiang, J. Chen, J.-S. Huang and
C.-M. Che, Org. Lett., 2009, 11, 4568.
6 (a) Y. Shiraishi, M. Ikeda, D. Tsukamoto, S. Tanakab and
T. Hiraia, Chem. Commun., 2011, 47, 4811; (b) L. Jiang,
L. Jin, H. Tian, X. Yuan, X. Yu and Q. Xu, Chem. Commun.,
2011, 47, 10833; (c) M. S. Kwon, S. Kim, S. Park, W. Bosco,
R. K. Chidrala and J. Park, J. Org. Chem., 2009, 74, 2879; 10 T. B. Nguyen, L. Ermolenko, W. A. Dean and A. Al-
(d) L. Blackburn and R. J. K. Taylor, Org. Lett., 2001, 3,
1637.
7 (a) M. L. McKee and S. M. Kerwin, Bioorg. Med. Chem.,
2008, 16, 1775; (b) C. G. Mortimer, G. Wells, J.-P. Crochard,
Mourabit, Org. Lett., 2012, 14, 5948.
11 (a) S.-I. Murahashi, T. Hirano and T. Yano, J. Am. Chem.
Soc., 1978, 100, 348; (b) S.-I. Murahashi and T. Watanable,
J. Am. Chem. Soc., 1979, 101, 7429.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem.