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Journal Name
Green Chemistry
COMMUNICATION
O
S
O
S
†
Electronic Supplementary Information (ESI) available: detailed
condition screening tables, experimental details, and 1H and 13C NMR
spectra of the products. See DOI: 10.1039/c000000x/
(2)
+
OH
Ph
t-Bu
N
Ph
t-Bu
NH2
N2, NaOH (1.0 equiv.)
H
1a
13
12
1
(a) P. T. Anastas and J. C. Warner, Green Chemistry:
(100% purity)
1) no additive, 100 oC, 12 h: 47%isol.
2) 2a (10 mol%), 100 oC, 12 h: 83%isol.
3) no additive, 125 oC, 12 h: 66%isol.
DOI: 10.1039/C4GC02542C
Practice, Oxford University Press, Oxford, England; New York,
1998; ( ) K. Sanderson, Nature, 2011, 469, 18.
) G. T. Brooks and T. R. Roberts, Pesticide Chemistry and
Bioscience, Royal Society of Chemistry, Cambridge, U.K., 1999; (
J. L. McGuire, Pharmaceuticals: Classes, Therapeutic Agents, Areas
of Application, Wiley-VCH, Weinheim, Germany, 2000, Vols. 1-4; (
R. Hili and A. K. Yudin, Nat. Chem. Bio. 2006, , 284; ( ) E. D. Cox
and J. M. Cook, Chem. Rev. 1995, 95, 1797; ( ) J. M. Humphrey and
A. R. Chamberlin, Chem. Rev. 1997, 97, 2243; ( ) C. Hansch, P. G.
Sammes and J. B. Taylor, Comprehensive Medicinal Chemistry
Pergamon Press, Oxford, 1990, Vol. 2, Chapter 7.1; ( ) E. E. Connor,
Sulfonamide Antibiotics Prim. Care Update Ob. Gyn. 1998, , 32; (
A. Kleemann, J. Engel, B. Kutscher and D. Reichert, Pharmaceutical
Substances, Synthesis, Patents, Applications, Thieme, Stuggart, 1999
) S.-Y. Park, P. Fung, N. Nishimura, D. R. Jensen, H. Fujii, Y. Zhao,
b
2
(
a
Consequently, upon generation, aldehyde 10 should quickly
condense with to give imine intermediates 11 (step iii),
which was further transfer hydrogenated by alcohols via TM-
free MPV-O process9-11 to give alkylated products
and
b
)
2-4
1
c
)
2
d
5-9
e
regenerate 10 (step iv) to finish the aldehyde-catalyzed
dehydrative N-alkylation cycle (cycle B).9a
f
,
As to cycle A, the reduced heterocylic amines 2’’
not be detected due to their instable nature. We suppose they
were oxidized by air to regenerate (step v) during the
workup. Because, we found heterocycle 14, an analogue of 2’’
4’’, could be easily oxidized to give aromatized 16 when it was
prepared in situ from 10a and 2-aminothiophenol 15 either
under air or under nitrogen (eq. 3, by in situ oxidation in the
reaction under air, or by oxidation during workup in the
reaction under nitrogen). Therefore, once generated, 2’’
may be oxidized by air to regenerate in reactions under air
(step v), which will further undergo alkylation to give products.
This well explains the higher yields of the products obtained
from reactions under air than under nitrogen, further supporting
cycle A in the proposed mechanism.
-4’’ could
g
5
h)
2-4
-
;
(
i
S. Lumba, J. Santiago, A. Rodrigues, T. F. Chow, S. E. Alfred, D.
Bonetta, R. Finkelstein, N. J. Provart, D. Desveaux, P. L. Rodriguez,
P. McCourt, J.-K. Zhu, J. I. Schroeder, B. F. Volkman and S. R.
Cutler, Science, 2009, 324, 1068.
-4’’
3
4
(
a
)
J. V. Metzger, Thiazoles and their Benzo Derivatives.
Comprehensive Heterocyclic Chemistry, Pergamon Press Ltd, New
York, 1984, vol. 6, pp. 235–331; ( ) X. Zhu, Q.-S. Yu, R. G. Cutler,
C. W. Culmsee, H. W. Holloway, D. K. Lahiri, M. P. Mattson and N.
H. Greig, J. Med. Chem., 2002, 45, 5090; ( ) S. D. Barchéchath, R. I.
2-4
b
c
Tawatao, M. Corr, D. A. Carson and H. B. Cottam, J. Med. Chem.
2005, 48, 6409.
,
SH
S
S
toluene
100 oC, 24 h
(3)
PhCHO +
Ph
Ph
(
a
) A. J. A. Watson and J. M. J. Williams, Science, 2010, 329, 635; (
T. D. Nixon, M. K. Whittlesey and J. M. J. Williams, Dalton Trans.
2009, 753; ( ) G. E. Dobereiner and R. H. Crabtree, Chem. Rev.
2010, 110, 681; ( ) G. Guillena, D. J. Ramón and M. Yus, Chem.
Rev., 2010, 110, 1611; ( ) K.-I. Fujita and R. Yamaguchi, Synlett,
2005, 560; ( ) T. Suzuki, Chem. Rev., 2011, 111, 1825; ( ) S. Bähn, S.
Imm, L. Neubert, M. Zhang, H. Neumann and M. Beller,
ChemCatChem, 2011, , 1853.
) M. H. S. A. Hamid, C. L. Allen, A. C. Maxwell, H. C. Maytum, A.
J. A. Watson and J. M. J. Williams, J. Am. Chem. Soc., 2009, 131
1766; ( ) Y. Zhang, X. Qi, X. Cui, F. Shi, and Y. Deng, Tetrahedron
Lett., 2011, 52, 1334; ( ) F. Li, H. Shan, Q. Kang and L. Chen, Chem.
Commun., 2011, 47, 5058; ( ) F. Li, H. Shan, L. Chen, Q. Kang and
P. Zou, Chem. Commun., 2012, 48, 603; ( ) F. Li, L. Chen, Q. Kang,
J. Cai and G. Zhu, New J. Chem., 2013, 37, 624.
) S. L. Feng, C. Z. Liu, Q. Li, X. C. Yu and Q. Xu, Chin. Chem.
Lett., 2011, 22, 1021; ( ) C. Liu, S. Liao, Q. Li, S. Feng, Q. Sun, X.
Yu and Q. Xu, J. Org. Chem., 2011, 76, 5759; ( ) X. Yu, C. Liu, L.
Jiang and Q. Xu, Org. Lett., 2011, 13, 6184; ( ) Q. Li, S. Fan, Q. Sun,
H. Tian, X. Yu and Q. Xu, Org. Biomol. Chem., 2012, 10, 2966; ( ) S.
Liao, K. Yu, Q. Li, H. Tian, Z. Zhang, X. Yu and Q. Xu, Org. Biomol.
Chem., 2012, 10, 2973; ( ) X. Yu, L. Jiang, Q. Li, Y. Xie and Q. Xu,
Chin. J. Chem., 2012, 30, 2322.
) L. Jiang, L. Jin, H. Tian, X. Yuan, X. Yu and Q. Xu, Chem.
Commun., 2011, 47, 10833; ( ) H. Tian, X. Yu, Q. Li, J. Wang and Q.
Xu, Adv. Synth. Catal., 2012, 354, 2671; ( ) B. Huang, H. Tian, S.
Lin, M. Xie, X. Yu and Q. Xu, Tetrahedron Lett., 2013, 54, 2861; (
b)
N
H
N
NH2
,
16
air: 93%; N2: 91%
15
14: analogue of 2''-4''
c
,
d
e
In conclusion, we have developed catalyst-free autocatalyzed
N-alkylation reactions of 2-aminobenzothiazoles, 2-
aminopyrimidines, and 2-aminopyrazine with primary and
secondary alcohols, providing an efficient, practical, and green
method for synthesis of the versatile heteroaryl amine
derivatives without using any external catalysts. Mechanistic
studies revealed that these interesting catalyst-free N-alkylation
reactions were induced by structure-dependent tautomeric
equilibriums of the heteroaryl amines through MPV-O transfer
hydrogenation of the imino tautomers by alcohols to give the
key initiating aldehydes, which then catalyzed the reactions to
complete to the give products. Further application and
extension of the catalyst-free alkylation reactions and deeper
mechanistic insights are underway.
f
g
3
5
6
(a
,
b
c
d
e
(
a
b
c
d
e
f
7
(a
Acknowledgments
b
c
We thank ZJNSF for Distinguished Young Scholars
(LR14B020002), NNSFC (20902070), and 580 Oversea Talents
Program of Wenzhou City for financial support.
d
)
E. Zhang, H. Tian, S. Xu, X. Yu and Q. Xu, Org. Lett., 2013, 15
2704.
,
8
9
Q. Xu and Q. Li, Chin. J. Org. Chem., 2013, 33, 18.
(
a
) Q. Xu, Q. Li and X. Zhu, J. Chen, Adv. Synth. Catal., 2013, 355
73; ( ) Q. Xu, J. Chen and Q. Liu, Adv. Synth. Catal., 2013
10 ( ) Q. Xu, J. Chen, H. Tian, X. Yuan, S. Li, C. Zhou and J. Liu,
Angew. Chem. Int. Ed., 2014, 53, 225; ( ) For a closely related
,
Notes and references
b
, 355, 697.
College of Chemistry and Materials Engineering, Wenzhou University,
Wenzhou, Zhejiang, 325035, China. E-mail: qing-xu@wzu.edu.cn; Fax:
(+)-86-577-86689302; Tel: (+)-86-138-57745327
a
b
ketone-initiated dehydrative alkylation of indole and pyrrole: X. Han
and J. Wu, Angew. Chem. Int. Ed., 2013, 52, 4637.
This journal is © The Royal Society of Chemistry 2012
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