The N-Aryl aminocarbonyl ortho-substituent effect in Cu-catalyzed aryl amination and its application in the synthesis of 5-substituted 11-Oxo-dibenzodiazepines

Article abstract of DOI:10.1021/ol202721h

Double amination of ortho-substituted aryl bromides proceeded under mild conditions to afford 5-substituted 11-oxo-dibenzodiazepines, which revealed that there is a strong ortho-substituent effect caused by N-aryl aminocarbonyl groups during copper-cataly

Full text of DOI:10.1021/ol202721h

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6422–6425
The N-Aryl Aminocarbonyl
ortho-Substituent Effect in Cu-Catalyzed
Aryl Amination and Its Application in the
Synthesis of 5-Substituted
11-Oxo-dibenzodiazepines
Xiaoqiong Diao,† Lanting Xu,† Wei Zhu, Yongwen Jiang,‡ Haoyang Wang,‡
Yinlong Guo,‡ and Dawei Ma*,‡
Department of Chemistry, Fudan University, Shanghai 200433, China, and State Key
Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Madw@mail.sioc.ac.cn
Received October 11, 2011
ABSTRACT
Double amination of ortho-substituted aryl bromides proceeded under mild conditions to afford 5-substituted 11-oxo-dibenzodiazepines, which
revealed that there is a strong ortho-substituent effect caused by N-aryl aminocarbonyl groups during copper-catalyzed aryl amination.
A considerable number of bioactive compounds contain
an 11-oxo-dibenzodiazepine moiety, including the clinical
antidepressant dibenzepin (1, Figure 1), nonpeptidyl en-
dothelin receptor antagonist 2,1 histone deacetylase inhi-
bitor 3,2 muscarinic acetylcholine receptor modulator 4,3
potent and selective Chk-1 inhibitor5,4 and potential agent
for the treatment of angiogenesis-related indications 6.5
The classical approach for assembling these compounds is
dependent on the selective alkylation1À3 of 1,6-unsubstituted
11-oxo-dibenzodiazepines of general structure 8. These tri-
cyclic heterocycles typically require several steps for their
preparation, beginning with the copper-catalyzed coupling
reactions of anthranilic acids with 2-halonitrobenzenes (or
2-halobenzoic acids with o-phenylendiamines).1À6 The clas-
sical approach suffers both from length of sequence from
commercially available starting materials and generally
(6) (a) Giani, R. P.; Borsa, M.; Parini, E.; Tonon, G. C. Synthesis
1985, 550. (b) Al-Tel, T. H.; Al-Qawasmeh, R. A.; Schmidt, M. F.; Al-
Aboudi, A.; Rao, S. N.; Sabri, S. S.; Voelter, W. J. Med. Chem. 2009, 52,
† Fudan University.
ꢀ
6484. (c) Leyva-Perez, A.; Cabrero-Antonino, J. R.; Corma, A. Tetra-
‡ Chinese Academy of Sciences.
hedron 2010, 66, 8203.
(1) Murugesan, N.; Gu, Z.; Lee, V.; Webb, M. L.; Liu, E. C.-K.;
Hermsmeier, M.; Hunt, J. T. Bioorg. Med. Chem. Lett. 1995, 5, 253.
(2) Binaschi, M.; Boldetti, A.; Gianni, M.; Maggi, C. A.; Gensini, M.;
Bigioni, M.; Parlani, M.; Giolitti, A.; Fratelli, M.; Valli, C.; Terao, M.;
Garattini, E. ACS Med. Chem. Lett. 2010, 1, 411.
(7) (a) Ma, D.; Lu, X.; Shi, L.; Zhang, H.; Jiang, Y.; Liu, X. Angew.
Chem., Int. Ed. 2011, 50, 1118. (b) Ma, D.; Geng, Q.; Zhang, H.; Jiang,
Y. Angew. Chem., Int. Ed. 2010, 49, 1291. (c) Ma, D.; Xie, S.; Xue, P.;
Zhang, X.; Dong, J.; Jiang, Y. Angew. Chem., Int. Ed. 2009, 48, 4222.
(d) Wang, B.; Lu, B.; Jiang, Y.; Zhang, Y.; Ma, D. Org. Lett. 2008, 10,
2761. (e) Zou, B.; Yuan, Q.; Ma, D. Org. Lett. 2007, 9, 4291. (f) Zou, B.;
Yuan, Q.; Ma, D. Angew. Chem., Int. Ed. 2007, 46, 2598.
(3) Eberlein, W. G.; Trummlitz, G.; Engel, W. W.; Schmidt, G.;
Pelzer, H.; Mayer, N. J. Med. Chem. 1987, 30, 1378.
(4) Wang, L.; Sullivan, G. M.; Hexamer, L. A.; Hasvold, L. A.;
Thalji, R.; Przytulinska, M.; Tao, Z.-F.; Li, G.; Chen, Z.; Xiao, Z.; Gu,
W.-Z.; Xue, J.; Bui, M.-H.; Merta, P.; Kovar, P.; Bouska, J. J.; Zhang,
H.; Park, C.; Stewart, K. D.; Sham, H. L.; Sowin, T. J.; Rosenberg, S. H.;
Lin, N.-H. J. Med. Chem. 2007, 50, 4162.
(8) For selected recent examples from other groups, see: (a) Liu, X.;
Fu, H.; Jiang, Y.; Zhao, Y. Angew. Chem., Int. Ed. 2009, 48, 348. (b) Bao,
W.; Liu, Y.; Lv, X.; Qian, W. Org. Lett. 2008, 10, 3899. (c) Coste, A.;
Toumi, M.; Wright, K.; Razafimahaleo, V.; Couty, F.; Marrot, J.;
Evano, G. Org. Lett. 2008, 10, 3841. (d) Martin, R.; Rodrı
´
guez, R.;
(5) Hansen, A. J.; Jorgensen, T. K.; Olsen, U. B. WO 2000032193, 2000.
Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 7079.
r
10.1021/ol202721h
Published on Web 11/16/2011
2011 American Chemical Society

moderate yields of the diaryl amine alkylation steps due to
poor amine reactivity.1À3,5
Scheme 1. CuCl-Catalyzed Coupling Reactions of Benzylamine
with Different ortho-Substituted Aryl Bromides
During our investigations on the development of new
copper-catalyzed coupling reactions for heterocycle
synthesis,7À9 we became interested in the potential double
coupling reactions of dibromides 9 with primary amines.
Such transformations would provide an alternative and
direct pathway for preparing 5-substituted 11-oxo-diben-
zodiazepines 7. In subsequent studies, we discovered that
N-aryl aminocarbonyl groups greatly promoted the copper-
catalyzed coupling of aryl halides with amines. This effect
allows formation of 5-substituted 11-oxo-dibenzodiaze-
pines via double amination under very mild conditions.
A complete account of our results is provided herein.
have stronger ortho-substituent effects than amido groups.
To verify this hypothesis, we conducted a series of control
experiments. When 2-bromo-N-phenylbenzamide 11a was
treated with 1 mol % CuCl and benzylamine for 10 h at
room temperature, anthranilamide 12a was isolated in
93% yield withcomplete consumption of starting material.
In contrast, no conversion was observed when 2-bromo-
benzamide 11b and 2-bromoacetanilide 13 were subject to
the same reaction conditions. These results clearly demon-
strate that N-phenyl aminocarbonyl groups are more
powerful directors for amination than acetamido10 and
simple aminocarbonyl groups.11 Interestingly, under the
same conditions, 2-bromo-N-benzylbenzamide 11c under-
went approximately 95% conversion to give 12c with 84%
yield, indicating that N-substituents might have dramatic
influence on the ortho-substituent effect of aminocarbonyl
groups in general. This hypothesis was further supported
by comparing the reactivity of N-(4-chlorophenyl)-substi-
tuted bromide 11d and N-(4-methoxyphenyl)-substituted
bromide 11e, which gave 84 and 40% coupling yields after
8 h at room temperature, respectively. Additionally, cou-
pling reaction of dibromide 14 with benzylamine afforded
amination product 15 exclusively, whereas no conversion
was observed in case of bromide 16 as a coupling partner.
The reactivity difference between these two substrates
clearly indicated that the mild coupling conditions resulted
from the ortho-substituent effect but not the simple induc-
tive effect of the N-phenyl aminocarbonyl groups.
Figure 1. Structures of bioactive 11-oxodibenzodiazepines and
methods for their preparation.
When model dibromide 9a (Scheme 1) was subjected to
experimental coupling conditions with benzylamine and
CuCl at room temperature in DMF, we were surprised to
isolate the open anthranilamide 10a in 86% yield. This
result suggested that N-aryl aminocarbonyl groups might
Returning to the monocoupling product 10a, we sought
to find suitable conditions to complete our initially desired
(9) For recent reviews, see: (a) Evano, G.; Blanchard, N.; Toumi, M.
Chem. Rev. 2008, 108, 3054. (b) Ma, D.; Cai, Q. Acc. Chem. Res. 2008,
41, 1450. (c) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48,
6954. (d) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2010, 13. (e) Sperotto,
E.; Klink, G. P. M; Koten, G.; Vries, J. G. Dalton Trans. 2010, 39, 10338.
(10) (a) Cai, Q.; Zou, B.; Ma, D. Angew. Chem., Int. Ed. 2006, 45,
1276. (b) Xie, X.; Chen, Y.; Ma, D. J. Am. Chem. Soc. 2006, 128, 16050.
(11) (a) Xu, W.; Jin, Y.; Liu, H.; Jiang, Y.; Fu, H. Org. Lett. 2011, 13,
1274. (b) Zhao, H.; Fu, H.; Qiao, R. J. Org. Chem. 2010, 75, 3311.
Org. Lett., Vol. 13, No. 24, 2011
6423

cyclization. When 20 mol % of CuCl was used, the desired
cyclization product 7a could be isolated with 22% yield
(Table 1, entry 1). We then focused our attention on using
ligands to promote the cyclization.9 Introducing L-proline
to the reaction mixture was found to be ineffective for this
coupling reaction (Table 1, entry 2). However, improved
yields were observed when trans-4-hydroxy-L-proline and
N,N-dimethylglycine were utilized (Table 1, entries 3 and 4).
Our best result was obtained when 1,10-phenanthroline
was employed (Table 1, entry 5). Further investigation
revealedthatinthiscase, thecatalytic loading necessaryfor
timely reaction completion could be reduced to 10 mol %
if the reaction temperature was raised to 50 °C (Table 1,
entry 6).
Table 2. CuCl-Catalyzed Formation of 11-Oxodibenzodiaze-
pines from Dibromidesa
Table 1. Condition Screening for Cyclization of Aryl Bromide
10aa
entry
ligand
yieldb (%)
1
2
3
4
5
6
22
trace
41
L-proline
trans-4-hydroxy-L-proline
N,N-dimethylglycine
1,10-phenanthroline
1,10-phenanthroline
85
93
90c
a Reaction conditions: 10a (0.5 mmol), CuCl (0.1 mmol), ligand (0.2
mmol, 0.1 mmol for entry 5), K3PO4 (1.5 mmol), DMF (1 mL), rt (or 50
°C for entry 6), 24 h. b Isolated yield. c 0.05 mmol of CuCl and 0.05 mmol
of ligand were used.
The combination of CuCl and 1,10-phenanthroline was
then examined for direct conversion of dibromides 9 into
5-substituted 11-oxo-dibenzodiazepines, and the results
are summarized in Table 2. To our delight, this catalytic
system performed well for this transformation, providing
the desired tricyclic heterocycles in 52À82% yield. From
methylamine and n-propylamine, dibenzodiazepines 7b
and 7c were isolated with 73% yield (Table 2, entries 1
and 2), which couldbe usedfor synthesizing antidepressant
dibenzepin 1, histone deacetylase inhibitor 32 and non-
peptidyl endothelin receptor antagonist 2,1 respectively.
Using N1,N1-dimethyl-propane-1,3-diamine as a coupling
partner, the muscarinic acetylcholine receptor modulator
43 was directly obtained in 80% yield (Table 2, entry 3).
Furthermore, coupling of 3-aminopropan-1-ol with 9a
produced dibenzodiazepine 7d (Table 2, entry 4), a suitable
precursor for the preparation of bioactive compound 6.5
Four other functionalized amines were also found to be
applicable in this process, affording the corresponding
products 7eÀh, all in good yields (Table 2, entries 5À8).
a Reaction conditions: 9 (0.5 mmol), amine (0.55 mmol), CuCl (0.05
mmol), 1,10-phenanthroline (0.05 mmol), K3PO4 (1.5 mmol), DMF
(1 mL), rtÀ50 °C, 24À36 h. b 0.1 mol CuCl was used, and the reaction
was carried out at rt.
Further explorations indicated that introducing func-
tional groups at both aromatic rings was possible, as
evidenced by the successful generation of dibenzodiaze-
pines 7iÀm from the corresponding elaborated dibromides
6424
Org. Lett., Vol. 13, No. 24, 2011

(Table 2, entries 9À13). In the case of 7m, relatively low
yield was observed because of incomplete cyclization
(Table 2, entry 13). We reasoned that this problem resulted
from the fluorine-induced poor nucleophilicity of aniline
intermediate in the second coupling step. A similar pro-
blem was also observed in the formation of pyridine
embodied tricyclic heterocycle 7n (Table 2, entry 14). The
wide range of examples taken together leads us to conclude
that the present method should allow for the preparation
of a wide range of 5-substituted 11-oxo-dibenzodiazepines.
In conclusion, we have revealed that N-substituted
aminocarbonyl groups possess a strong ortho-substituent
effect, allowing the ligandless CuCl-catalyzed coupling of
2-bromo-N-phenylbenzamides and primary amines at
room temperature with a low catalyst loading. On the basis
of this observation, we have developed a facile method
for assembling 5-substituted 11-oxo-dibenzodiazepines via
double aryl amination.12 The mild conditions and conve-
nient availability of the starting materials make this
approach very competitive in the synthesis of these biolo-
gically important heterocycles. The detailed coupling reac-
tion mechanism behind this ortho-substituent effect and
its further applications in organic synthesis are actively
investigated, and the results will be disclosed in due course.
Acknowledgment. The authors are grateful to the Min-
istry of Science and Technology (Grant 2009ZX09501-00)
and Chinese Academy of Sciences and National Natural
Science Foundation of China (Grants 20632050 & 20921091)
for their financial support.
Supporting Information Available.
Experimental
procedures and copies of 1H NMR and 13C NMR spectra
for all new products. This material is available free of
charge via the Internet at http://pubs.acs.org.
(12) For an example on Pd-catalyzed double aryl amination, see:
Nozaki, K.; Takahashi, K.; Nakano, K.; Hiyama, T.; Tang, H.-Z.;
Fujiki, M.; Yamaguchi, S.; Tamao, K. Angew. Chem., Int. Ed. 2003, 42,
2051.
Org. Lett., Vol. 13, No. 24, 2011
6425