Concise palladium-catalyzed synthesis of dibenzodiazepines and structural analogues

Article abstract of DOI:10.1021/ja206229y

A general and highly efficient protocol for the synthesis of dibenzodiazepines and their structural analogues is reported. In the presence of catalytic quantities of palladium, readily accessible precursors are cross-coupled with ammonia and then spontaneously undergo an intramolecular condensation to form the corresponding dibenzodiazepines in one step. This new strategy is applicable to the construction of a wide variety of dibenzooxazepines and other structurally related heterocycles.

Full text of DOI:10.1021/ja206229y

COMMUNICATION
pubs.acs.org/JACS
Concise Palladium-Catalyzed Synthesis of Dibenzodiazepines and
Structural Analogues
Dmitry Tsvelikhovsky and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
S Supporting Information
b
Scheme 1. Pairs of Coupling Partners Traditionally Used for
Synthesis of Dibenzodiazepines
ABSTRACT: A general and highly efficient protocol for the
synthesis of dibenzodiazepines and their structural analo-
gues is reported. In the presence of catalytic quantities of
palladium, readily accessible precursors are cross-coupled
with ammonia and then spontaneously undergo an intra-
molecular condensation to form the corresponding diben-
zodiazepines in one step. This new strategy is applicable to
the construction of a wide variety of dibenzooxazepines and
other structurally related heterocycles.
harmacologically active dibenzodiazepines and their structural
P
analogues, dibenzooxazepines and dibenzo(di/ox)azepinones,1,2
account for a significant portion of widely prescribed azepine-
based drugs. Unfortunately, access to a large number of structural
derivatives of these heterocycles is hindered by their multistep
syntheses. Since the first reported synthesis of dibenzodiazepine
derivatives by Schmutz in 1964À67 (clozapine and loxapine;
Figure 1), limited progress has been made.3 Existing routes to
dibenzodiazepines (and their derivatives) generally rely on the
preparation of amide4 or lactam5 intermediates and subsequent
functionalization of the heterocyclic scaffold to introduce additional
substituents (Scheme 1). Such transformations typically require
harsh conditions, purification after each synthetic step, and the use of
protecting groups.1b,c,5c,6 Most previously reported synthetic path-
ways require reduction of a NO2 group and have limited functional
group compatibility, whereas coupling of substrates with two free
NH2 groups leads to a mixture of products. Thus, there is a need for
an efficient, concise, and general protocol to provide access to a
diverse range of dibenzodiazepine derivatives.
Scheme 2. Proposed Synthesis of Dibenzo(di/ox)azepines
and Dibenzo(di/ox)azepinones
Herein we report a versatile method for the synthesis of di-
benzodiazepine analogues via the formation of key precursor 1,
which is readily accessed by cross-coupling of o-carbonyl(anilines or
phenols) with 1,2-dihaloarenes (or their equivalents) (Scheme 2).7
This synthetic strategy is based on the notion that in the presence of
catalytic quantities of palladium, this precursor would generate
intermediate 2 via cross-coupling with ammonia8 and further spont-
aneously undergo an intramolecular condensation to form the
corresponding dibenzodiazepine 3 in one step (Scheme 2). We
also felt that this new strategy might be applicable to the construc-
tion of dibenzooxazepines (3; Y = O) or other structural analogues,
such as dibenzodiazepinones (4; Y = NH) and dibenzooxazepi-
nones (4; Y = O). To our knowledge, these constitute the first
application of the Pd-catalyzed coupling of ammonia in the
synthesis of complex heterocycles.8
Received: July 5, 2011
Figure 1. Pharmacologically active dibenzodiazepine derivatives.
Published: August 12, 2011
r
2011 American Chemical Society
14228
dx.doi.org/10.1021/ja206229y J. Am. Chem. Soc. 2011, 133, 14228–14231
|

Journal of the American Chemical Society
COMMUNICATION
Scheme 3. Optimization Study for the Synthesis of Dibenzodiazepines
Scheme 4. Plausible Pathways for the Formation of
Dibenzodiazepine
In order to test our hypothesis, aniline 5, which was prepared
in 94% yield via a CÀN coupling reaction7 of 2-aminobenzophenone
and 2-bromochlorobenzene, was selected as the diarylamine
precursor (Scheme 3). Initial studies were carried out on a 0.5
mmol scale at temperatures ranging from 80 to 110 °C using a
variety of palladium sources, bases, and phosphines.7a,8c We found
that an efficient catalyst for the desired transformation could be
formed from the combination of t-BuDavePhos (L3), Pd2(dba)3,
and NaOt-Bu at 85 °C. Other combinations of catalyst, ligand,
and base (Scheme 3a,b) led to the reduction of starting precursor
5 or gave low yields of the desired dibenzodiazepine 7. The use of
1,4-dioxane as the solvent provided the optimal yield of product
and allowed for a convenient protocol to be developed in which a
commercially available solution of ammonia (0.5 M in 1,4-
dioxane) could be used as the source of NH2.8a The optimal
range of equivalents of ammonia was broad (5À10 equiv;
Scheme 3c), which simplifies the experimental operation. The
highest conversion was achieved when 5 equiv of NH3 was
employed at a 0.1 M concentration of precursor.
dibenzodiazepine derivatives in good to excellent yields (Table 1).
Notably, both electron-rich and electron-deficient diarylamine
precursors were transformed efficiently. Under these conditions,
heterocycles such as diaxoles, thiols, and pyridines as well as
various functional groups were tolerated. Interestingly, our opti-
mized conditions failed to provide the desired dibenzodiazepine
products in the case of acetophenone-core precursors (R = Me).
However, we found that when the amount of ammonia was increased
to 7 equiv, the catalyst loading to 4 mol %, and the temperature to
120 °C, the desired transformation proceeded readily in the presence
of Cs2CO3, albeit in lower yields (products 9f and 9g; Table 1).
With suitable access to dibenzodiazepines in hand, we next
examined the scope of the reaction toformdibenzooxazepines. For
this transformation, the key diarylether precursors 12 were pre-
pared via copper-catalyzed CÀO cross-coupling reactions of
commercially available 2-carbonylphenols 10 and 1,2-dihaloarenes
11 (Table 2).7d As expected, in the presence of Pd2(dba)3, L3, and
base (NaOt-Bu or Cs2CO3), reactions of such precursors (both
electron-rich and electron-deficient) with ammonia afforded the
dibenzooxazepines as single products in good yields (Table 2).
As an expansion of this study, we next explored the pre-
paration of structurally related dibenzodiazepinones and
In principle, the reaction of precursor 5 with ammonia could
produce three possible reactive intermediates, 6aÀc (Scheme 4),
that could give rise to dibenzodiazepine 7. In order to differ-
entiate among these, the reaction was carried out under the
standard conditions but in the absence of molecular sieves.
Compound 6a was then isolated as the only observable intermedi-
ate, and the structure was assigned on the basis of its 1H and 13
C
NMR spectra and the results of elemental analysis. No evidence for
the presence of either a hemiaminal or an imine was detected. It
should be also noted that no diarylated product8 was formed under
the optimized conditions. Presumably, the intramolecular conden-
sation of intermediate 6a yields 7 faster than an additional
intermolecular Pd-mediated cross-coupling with 5 can occur.
We next prepared a range of diarylamine precursors 8 that
were subjected to our optimized conditions to provide a range of
14229
dx.doi.org/10.1021/ja206229y |J. Am. Chem. Soc. 2011, 133, 14228–14231

Journal of the American Chemical Society
COMMUNICATION
Table 1. Palladium-Catalyzed Synthesis of Dibenzodiazepines
Scheme 5. Formation of Dibenzodiazepinone
Conditions (yields are averages of two runs): a Precursor (1.0 mmol),
0.5 M ammonia solution in 1,4-dioxane (10 mL, 5.0 mmol), Pd2(dba)3
(0.015 mmol), L3 (0.05 mmol), NaOt-Bu (1.5 mmol), 85 °C, 2 h. b 5 h.
c Precursor (1.0 mmol), 0.5 M ammonia solution in 1,4-dioxane (14 mL,
7.0 mmol), Pd2(dba)3 (0.02 mmol), L3 (0.06 mmol), Cs2CO3 (4.0
mmol), 120 °C, 24 h. d See ref 9.
Table 3. Palladium-Catalyzed Synthesis of Dibenzodiazepi-
nones and Dibenzooxazepinonesa
Table 2. Palladium-Catalyzed Synthesis of Dibenzooxazepines
a Conditions (yields are averages of two runs): precursor (1.0 mmol),
0.5 M ammonia solution in 1,4-dioxane (14 mL, 7.0 mmol), Pd2(dba)3
(0.02 mmol), L3 (0.06 mmol), Cs2CO3 (4.0 mmol), 120 °C, 24 h.
dibenzooxazepinones via a tandem aminationÀcyclization ap-
proach. For this study, commercially available ethyl-2-amino-
benzoate and 1-bromo-2-chlorobenzene were chosen as test
substrates. Precursor 14 was then prepared via a CÀN cross-
coupling reaction and isolated in 88% yield (Scheme 5). In order
to prevent cleavage of the ester functional group, this precursor
was subjected to the ammonia coupling reaction conditions in
the presence of Cs2CO3 as the base. As a result, dibenzodiaze-
pinone 16 was obtained in 80% yield. On the basis of previous
observations, we envisioned that 16 could be generated in a
one-pot process via the intramolecular aminolysis of reactive
intermediate 15 formed from the cross-coupling of 14 with
ammonia (Scheme 5). To determine the nature of the inter-
mediate formed, precursor 14 was allowed to react under the
Conditions (yields are averages of two runs): a Precursor (1.0 mmol),
0.5 M ammonia solution in 1,4-dioxane (10 mL, 5.0 mmol), Pd2(dba)3
(0.015 mmol), L3 (0.05 mmol), NaOt-Bu (1.5 mmol), 85 °C, 5 h. b The
precursor can be prepared from 1,2-dibromobenzene or 1-bromo-2-
iodobenzene.
14230
dx.doi.org/10.1021/ja206229y |J. Am. Chem. Soc. 2011, 133, 14228–14231

Journal of the American Chemical Society
COMMUNICATION
optimized conditions for 6 h. Consequently, 15 was isolated in
47% yield, while no products other then 16 and precursor 14
were observed. It should be noted that neither strong base, acid,
nor metallic reagents were required to promote the cyclization of
15, representing a first case of direct aminolysis in the presence of
a catalytic amount of palladium.10 Further investigations using
several ester-functionalized precursors (prepared in the same way
as 14) were performed. As shown in Table 3, the cascade trans-
formations were successful and quite general, tolerating variation
of the substituents of the precursors and leading to the formation
of the expected heterocycles in high yields. We were also pleased to
find that substrates bearing a wide range of esters, such as tert-butyl,
ethyl and methyl, which significantly simplifies the synthetic
protocol with regards to the choice of available starting material.
In conclusion, we have developed a practical and general protocol
for the Pd-catalyzed synthesis of dibenzodiazepines and their struc-
tural analogues, an important class of heteroaromatic compounds.
This method was applicable to a wide variety of precursors, and good
yields of pure heterocycles were obtained. The synthetic advantage
of this route is exemplified by the successful preparation of these
compounds via the catalytic and shortest sequence reported to date
through the use of simple, easily accessible starting materials.
Schlingmann, G.; Janso, J. E.; Bernan, V.; Feng, X. D.; Carter, G. T. J. Nat.
Prod. 2004, 67, 1431. (f) McAlpine, J. B.; Banskota, A. H.; Charan, R. D.;
Schlingmann, G.; Zazopoulos, E.; Piraee, M.;Janso,J.;Bernan,V.S.;Aouidate,
M.; Farnet, C. M.; Feng, X. D.; Zhao, Z. Z.; Carter, G. T. J. Nat. Prod. 2008,
71, 1585. (g) Ratnayake, A. S.; Janso, J. E.; Feng, X.; Schlingmann, G.; Goljer,
I.; Carter, G. T. J. Nat. Prod. 2009, 72, 496. For pharmacological properties of
Sintamil, see:(h) David, J.; Grewal, R. S. Indian J. Exp. Biol. 1974, 12, 225.
(3) (a) Hunziker, F.; Kunzle, F.; Schmutz, J.; Schindler, O. Helv.
Chim. Acta 1964, 47, 1163. (b) Hunziker, F.; Fischer, E.; Schmutz, J.
Helv. Chim. Acta 1967, 50, 1588. (c) Schmutz, J.; Kunzle, F.; Hunziker,
F.; Gauch, R. Helv. Chim. Acta 1967, 50, 245.
(4) For reviews of the synthesis of dibenzodiazepines (and their
derivatives) via amide intermediates, see: (a) Noskov, V. G.; Noskova,
M. N.; Kruglyak, Y. L.; Strukov, O. G.; Bezrukov, A. P.; Kurochkin, V. K.
Pharm. Chem. J. USSR 1997, 31, 431. (b) Wardrop, A. W. H.; Sainsbury,
G. L.; Harrison, J. M.; Inch, T. D. J. Chem. Soc., Perkin Trans. 1 1976, 1279. (c)
Xu, X. X.; Guo, S.; Dang, Q.; Chen, J.; Bai, X. J. Comb. Chem. 2007, 9, 773.
(5) For reviews of the synthesis of dibenzodiazepines (and their
derivatives) via lactam intermediates, see: (a) Smits, R. A.; Lim, H. D.;
Stegink, B. R.; Bakker, A.; de Esch, I. J.; Leurs, R. J. Med. Chem. 2006,
49, 4512. (b) Su, J.; Tang, J.; McKittrick, B. A.; Burnett, D. A.; Zhang, H.;
Smith-Torhan, A.; Fawzi, A.; Lachowicz, J. Bioorg. Med. Chem. Lett.
2006, 16, 4548. (c) Joshua, A. V.; Sharma, S. K.; Strelkov, A.; Scott, J. R.;
Martin-Iverson, M. T.; Abrams, D. N.; Silverstone, P. H.; McEwan, A. J. B.
Bioorg. Med. Chem. Lett. 2007, 17, 4066. (d) Liao, Y.; Venhuis, B. J.;
Rodenhuis, N.;Timmerman, W.;Wikstrom, H.;Meier, E.;Bartoszyk, G. D.;
Bottcher, H.; Seyfried, C. A.; Sundell, S. J. Med. Chem. 1999, 42, 2235.
(6) (a) Shi, F. Q.; Xu, X.; Zheng, L. Y.; Dang, Q.; Bai, X. J.Comb. Chem.
2008, 10, 158. (b) Ottesen, L. K.; Ek, F.; Olsson, R. Org. Lett. 2006,
8, 1771. (c) Hasvold, L. A.; Wang, L.; Przytulinska, M.; Xiao, Z.; Chen, Z.;
Gu, W. Z.; Merta, P. J.; Xue, J.; Kovar, P.; Zhang, H.; Park, C.; Sowin, T. J.;
Rosenberg, S. H.; Lin, N. H. Bioorg. Med. Chem. Lett. 2008, 18, 2311. (d)
Fu, R.; Xu, X.; Dang, Q.; Bai, X. J. Org. Chem. 2005, 70, 10810. (e) Yang,
J. X.; Che, X.; Dang, Q.; Wei, Z. L.; Gao, S.; Bai, X. Org. Lett. 2005, 7, 1541.
(7) 2-Chlorophenyl trifluoromethanesulfonate also can be used as a
coupling partner (as shown in the Supporting Information). See: (a) Surry,
D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338. (b) Surry, D. S.;
Buchwald, S. L. Chem. Sci. 2011, 2, 27. (c) Hartwig, J. F. Angew. Chem., Int. Ed.
1998, 37, 2046. (d) Maiti, D.; Buchwald, S. L. J. Am. Chem. Soc. 2009,
131, 17423. (e)Fors, B. P.;Watson, D. A.;Biscoe, M. R.;Buchwald, S. L.J. Am.
Chem. Soc. 2008, 130, 13552. (f) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534.
(8) (a) Surry, D. S.; Buchwald, S. L. J. Am. Chem. Soc. 2007,
129, 10354. (b) Shen, Q. L.; Hartwig, J. F. J. Am. Chem. Soc. 2006,
128, 10028. (c) Lundgren, R. J.; Peters, B. D.; Alsabeh, P. G.; Stradiotto,
M. Angew. Chem., Int. Ed. 2010, 49, 4071.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, char-
b
acterizations, spectral data for all compounds, and complete ref 2a.
This material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
sbuchwal@mit.edu
’ ACKNOWLEDGMENT
This work was supported by an educational donation provided
by Amgen and from the National Institutes of Health (Grant
GM-58160), to whom we are grateful. We also thank FMC
Lithium for a generous gift of ClP(t-Bu) and Nippon Chemicals
for gifts of chemicals and unrestricted funds. We thank reviewer
3 for thoughtful and constructive comments and suggestions
concerning the mechanism of formation of 7.
(9) Replacing the chloride atom of the precursor used for the prepara-
tion of 9f (Table 1) by bromide while maintaining all of the other reaction
conditions constant provided a highly selective cyclization that gave
carbazole 9f1 in high yield (86%), completely suppressing the formation
of dibenzodiazepine 9f (for details, see the Supporting Information).
’ REFERENCES
(1) For recent reviews of the pharmacological activity of dibenzo-
diazepines and dibenzooxazepines, see: (a) Umemiya, H.; Fukasawa, H.;
Ebisawa, M.; Eyrolles, L.; Kawachi, E.; Eisenmann, G.; Gronemeyer, H.;
Hashimoto, Y.; Shudo, K.; Kagechika, H. J. Med. Chem. 1997, 40, 4222.
(b) Jiang, X. L.; Lee, G. T.; Prasad, K.; Repic, O. Org. Process Res. Dev. 2008,
12, 1137. (c) Ebisawa, M.; Umemiya, H.; Ohta, K.; Fukasawa, H.; Kawachi,
E.; Christoffel, G.; Gronemeyer, H.; Tsuji, M.; Hashimoto, Y.; Shudo, K.;
Kagechika, H. Chem. Pharm. Bull 1999, 47, 1778. (d) Sakaki, J.; Konishi, K.;
Kishida, M.; Gunji, H.; Kanazawa, T.; Uchiyama, H.; Fukaya, H.; Mitani,
H.; Kimura, M. Bioorg. Med. Chem. Lett. 2007, 17, 4808.
(2) For recent reviews of the pharmacological activity of dibenzodiaze-
pinones and dibenzooxazepinones, see: (a) Wang, L.; et al. J. Med. Chem.
2007, 50, 4162. (b) Klunder, J. M.; Hargrave, K. D.; West, M.; Cullen, E.; Pal,
K.; Behnke, M. L.; Kapadia, S. R.; McNeil, D. W.; Wu, J. C.; Chow, G. C. J.
Med. Chem. 1992, 35, 1887. (c) Lu, S. M.; Alper, H. J. Am. Chem. Soc. 2005,
127, 14776. (d) 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. (e) Charan, R. D.;
(10) Sabot, C.; Kumar, K. A.; Meunier, S.; Mioskowski, C. Tetra-
hedron Lett. 2007, 48, 3563 and references therein.
14231
dx.doi.org/10.1021/ja206229y |J. Am. Chem. Soc. 2011, 133, 14228–14231