Application of daugulis copper-catalyzed direct arylation to the synthesis of 5-aryl benzotriazepines

Article abstract of DOI:10.1021/ol900103a

A method for the direct arylation of benzotriazepines is reported, employing an aryl iodide as the coupling partner, copper iodide as the catalyst, and lithium tert-butoxide as the base. A variety of electron-rich, electron-poor, and sterically hindered aryl iodides are compatible with the reaction conditions. The arylation reaction can also be performed outside a glovebox in air without a significant decrease in yield. Furthermore, convenient microwave conditions for carrying out this transformation are reported.

Full text of DOI:10.1021/ol900103a

ORGANIC
LETTERS
2009
Vol. 11, No. 7
1511-1514
Application of Daugulis
Copper-Catalyzed Direct Arylation to the
Synthesis of 5-Aryl Benzotriazepines
Sirilata Yotphan, Robert G. Bergman,* and Jonathan A. Ellman*
Department of Chemistry, UniVersity of California and DiVision of Chemical Sciences,
Lawrence Berkeley National Laboratory, Berkeley, California 94720
rbergman@berkeley.edu; jellman@berkeley.edu
Received January 17, 2009
ABSTRACT
A method for the direct arylation of benzotriazepines is reported, employing an aryl iodide as the coupling partner, copper iodide as the
catalyst, and lithium tert-butoxide as the base. A variety of electron-rich, electron-poor, and sterically hindered aryl iodides are compatible
with the reaction conditions. The arylation reaction can also be performed outside a glovebox in air without a significant decrease in yield.
Furthermore, convenient microwave conditions for carrying out this transformation are reported.
Benzodiazepines and benzotriazepines are classes of non-
aromatic heterocycles that have emerged as privileged
pharmacophore stuctures due to their wide-ranging biological
activities.1 Examples of well-known benzodiazepines include
Valium (diazepam), Librium (chlordizepoxide), Xanax (al-
prazolam), and Ativan (lorazepam).2 In addition, a number
of benzotriazepines are currently being evaluated in clinical
trials.3 As a consequence, strategies for the rapid synthesis
and functionalization of these classes of compounds are of
considerable interest to both academic and industrial re-
searchers.4
We have previously reported on the Rh-catalyzed direct
functionalization of a range of nitrogen heterocycles,5 with
many of these transformations documented to proceed via
Rh-bound N-heterocyclic carbene (NHC) intermediates. We
speculated that benzodiazepines and triazepines should be
capable of forming NHC-metal complexes and were able
to isolate and characterize a 1,4-benzodiazepine NHC-Rh
complex.6 However, we were not able to achieve the Rh-
catalyzed direct arylation of either 1,4-benzodiazepines or
triazepines under a wide range of reaction conditions and
therefore focused on alternative transition metal catalysts for
the direct arylation of these classes of heterocycles. Herein
we report that benzotriazepines can be efficiently arylated
via Cu-catalysis.7,8
(1) (a) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.;
Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson,
P. S. J. Med. Chem. 1988, 31, 2235. (b) Patchett, A. A.; Nargund, R. P.
Annu. Rep. Med. Chem. 2000, 35, 289.
(2) For recent reviews, see: (1) Leonard, B. E. Hum. Psycopharmacol.
Clin. Exp. 1999, 14, 125. 2 Fryer, R. I. Bicyclic Diazepines. The Chemistry
of Heterocyclic Compounds; Wiley: New York, 1991; Chapter 7.
(3) (a) McDonald, I. M.; Austin, C.; Buck, I. M.; Dunstone, D. J.; Gaffen,
J.; Griffin, E.; Harper, E. A.; Hull, R. A. D.; Kalindjian, B.; Linney, I. D.;
Low, C. M. R.; Patel, D.; Pether, M. J.; Raynor, M.; Roberts, S. P.; Shaxted,
M. E.; Spencer, J.; Steel, K. O. M.; Sykes, D. A.; Wright, P. T.; Xun, W.
J. Med. Chem. 2007, 50, 4789. (b) McDonald, I. M.; Black, J. W.; Buck,
I. M.; Dunstone, D. J.; Griffin, E. P.; Haper, E. A.; Hull, R. A. D.;
Kalindjian, B.; Lilley, E. J.; Linney, I. D.; Pater, M. J.; Roberts, S. P.;
Shaxted, M. E.; Spencer, J.; Steel, K. I. M.; Sykes, D. A.; Walker, M. K.;
Watt, G. F.; Wright, L.; Wright, P. T.; Xun, W. J. Med. Chem. 2007, 50,
3101.
(4) For recent references, see: (a) Bunin, B. A.; Ellman, J. A. J. Am.
Chem. Soc. 1992, 114, 10997. (b) Tucker, H.; Le Count, D. J. In
ComprehensiVe Heterocyclic Chemistry II; Katrizky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Elsevier: Amsterdam, 1996; Vol. 9, p 151. (c) del
Pozo, C.; Macias, A.; Alonso, E.; Gonzalez, J. Synthesis 2004, 16, 2697.
(d) Neamati, N.; Turpin, J. A.; Winslow, H. E.; Chrisensen, J. L.;
Williamson, K.; Orr, A.; Rice, W. G.; Pommier, Y.; Garofalo, A.; Brizzi,
A.; Campiani, G.; Fiorini, I.; Nacci, V. J. J. Med. Chem. 1999, 42, 3334.
(e) Nadin, A.; Sanchez Lopez, J. M.; Owens, A. P.; Howells, D. M.; Talbot,
A. C.; Harrison, T. J. Org. Chem. 2003, 68, 2844. (f) Spencer, J.; Chowdhry,
B. Z.; Mallet, A. I.; Rathnam, R. P.; Adatia, T.; Bashall, A.; Rominger, F.
Tetrahedron 2008, 64, 6082
.
10.1021/ol900103a CCC: $40.75
Published on Web 03/04/2009
2009 American Chemical Society

The direct arylation of benzotriazepine 1a was intially
explored using copper catalysts according to the conditions
reported by Daugulis and co-workers for the direct arylation
of aromatic C-H bonds, CuI (10 mol %), LiOtBu (2 equiv),
and PhI (3 equiv) in DMF at 140 °C.9,10 Under these
conditions arylated product 2a was obtained in a promising
40% isolated yield (Table 1), although the reaction time
Table 2. Effect of Copper Source and Phenyl Halide Coupling
Partnera
Table 1. Effect of Catalyst Loading and Temperaturea
entry
Cu catalyst
PhX
% yield
1
2
3
4
5
6
7
8
9
None
CuCl2
CuBr2
Cu(OAc)2
CuCl
CuBr
CuOAc
CuI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhBr
PhCl
0
55
57
42
65
66
58
79
5b
0
entry
catalyst loading
temperature (°C)
% yield
CuI
CuI
1
2
3
4
5
6
7
8
10%
10%
1.0 equiv
1.0 equiv
2.0 equiv
20%
140
140
140
140
140
140
100
rt
36 (40b)
5c
10
a Conditions: benzotriazepine substrate (1 equiv), PhX (3 equiv), Cu catalyst
(20 mol %), LiOtBu (2 equiv). Yields determined by GC integration relative
to hexamethylbenzene as an internal standard. b Reaction time ) 24 h.
19c
99 (98b)
100
79 (75b)
16
Without copper, no reaction was observed (entry 1). Interest-
ingly, both Cu(I) and Cu(II) catalysts could be employed in
this transformation. However, Cu(I) complexes tended to
result in higher yields. Consistent with Daugulis’s observa-
tions for the arylation of aromatic heterocycles, only aryl
iodides are effective coupling partners, with aryl bromides
and chlorides giving little or no product (entries 9 and 10).
This result suggests that this method should be useful for
the chemoselective arylation at iodide-substituted centers
when other halogen substituents are present (vide infra).
Upon examining different bases and solvents (Table 3),
LiOtBu and DMF were found to be optimal. Stronger bases
20%
20%
5
a Conditions: benzotriazepine substrate (1 equiv), PhI (3 equiv), LiOtBu
(2 equiv). Yields were determined by GC integration relative to hexam-
ethylbenzene as an internal standard. b Isolated yield. c Reaction time ) 30
min.
necessary for complete conversion (12 h) (entry 1) was longer
than that reported by Daugulis for the arylation of azoles
(10-30 min) (entry 2).
To increase product yield, we first examined catalyst
loading and temperature (Table 1). The use of stoichiometric
CuI resulted in quantitative conversion of the benzotriazepine
1a to the arylated product 2a (entries 4 and 5). Decreasing
the amount of CuI negatively affects the yield of the arylated
product, as does lowering the reaction temperature (entries
6-8). With the aim of developing a catalytic direct arylation,
we chose 20 mol % of the copper catalyst and 140 °C for
further evaluation of reaction parameters.
Table 3. Effect of Base and Solventa
In this survey, we first examined the effect of copper
source and the electrophilic coupling partner (Table 2).
entry
base
solvent
% yield
(5) (a) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res.
2008, 41, 1013. (b) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. J. Am.
Chem. Soc. 2007, 129, 5332. (c) Berman, A. M.; Lewis, J. C.; Bergman,
1
2
3
4
5
6
7
8
LiOtBu
NaOtBu
KOtBu
LDA
Na2CO3
Cs2CO3
K3PO4
LiOtBu
LiOtBu
LiOtBu
LiOtBu
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
THF
79
15
10
7
R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 14926
.
(6) Gribble, M. W.; Ellman, J. A.; Bergman, R. G. Organometallics
2008, 27, 2152.
(7) For recent reviews on C-H functionalization of heterocycles, see:
(a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107, 174. (b)
Seregin, I. V.; Gevorgyan, V. Chem. Soc. ReV. 2007, 36, 1173. (c) Campeau,
L.-C.; Fragnou, K. Chem. Commun. 2006, 1253.
(8) See Supporting Informationfor experimental details of substrate
preparation and screening of reaction conditions.
(9) (a) Do, H.-Q.; Kashif Khan, R. M.; Daugulis, O. J. Am. Chem. Soc.
2008, 130, 15185. (b) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2008,
0b
0b
15b
52
60
36b
8
9
10
11
dioxane
toluene
130, 1128. (c) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404
.
a Conditions: benzotriazepine substrate (1 equiv), PhI (3 equiv), CuI
(20 mol %), base (2 equiv). Solvent (1.0 M benzotriazepine substrate). Yields
were determined by GC integration relative to hexamethylbenzene as an
internal standard. b Reaction time ) 24 h.
(10) For other reports on copper-catalyzed and copper-mediated C-H
bond functionalization and C-C bond formation of heterocycles, see: (a)
Besselievre, F.; Piguel, S.; Mahuteau-Betzer, F.; Grierson, D. S. Org. Lett.
2008, 10, 4029. (b) Yoshizumi, T.; Tsurugi, H.; Satoh, T.; Miura, M.
Tetrahedron Lett. 2008, 49, 1598
.
1512
Org. Lett., Vol. 11, No. 7, 2009

resulted in significantly lower yields as well as starting
material decomposition (entries 2-4). Either no reaction or
low conversion was observed when weaker bases were
employed (entries 5-7). The mechanism of this direct
arylation reaction is likely to be similar to that previously
reported by Daugulis and co-workers for the Cu-catalyzed
arylation of aromatic C-H bonds, wherein the base is
necessary for deprotonation/metalation.9 Weaker bases such
as K3PO4, which is effective for the direct arylation of azoles
and polyfluoroarenes, did not work well for benzotriazepine
substrates presumably because of the much higher pKa value
of the benzotriazepine sp2 C-H bond. For this heterocycle
class, the stronger base, LiOtBu, as well as prolonged
reaction times, are apparently necessary for deprotonation/
metalation. A variety of solvents were evaluated with LiOtBu
as the base and in all cases resulted in much poorer
conversion relative to DMF (entries 8-11).
electron-poor and electron-rich aryl iodides to give benzo-
triazepines 2g, 2h, and 2j and benzotriazepines 2b, 2c, 2f,
and 2i, respectively. Ortho-substituted aryl iodides could also
be coupled in high yields (benzotriazepines 2c and 2f). Good
functional group compatibility was observed with alkoxy (2f),
chloro (2h), nitro (2j), and pyridyl (2l) groups all being
compatible with the reaction conditions. Although 2-iodopy-
ridine coupled in only modest yields with 20 mol % CuI,
the yield of 2l could be significantly improved by employing
stoichiometric quantities of CuI. A vinyl iodide was also
coupled (2k) with stoichiometric CuI resulting in a doubling
of the yield relative to that obtained when 20 mol % CuI
was used. The N-Bn-protected benzotriazepine substrate was
also an effective reaction partner in this transformation (2m).
In contrast, benzotriazepines with free N-H groups, e.g., 1
(R ) H), are not effective substrates as a result of competitive
N-arylation.
Using the optimal reaction conditions the scope of the
catalytic direct arylation reaction was next examined (Scheme
1). Benzotriazepine 1a could be successfully coupled to both
We also found that this reaction can be conducted outside
of the glovebox in air without significantly decreasing the
yield of product (Scheme 2). Moreover, microwave irradia-
Scheme 1.
Benzotriazepine Direct Arylation Substrate Scopea
Scheme 2. Arylation Reaction Outside of Glovebox
tion could be used to shorten reaction times (Table 4). With
this method of heating, 1 equiv of CuI is optimal, and at
this stoichiometry, complete conversion is observed within
1 h at 140 °C (entry 5).
Table 4. Microwave-Assisted Benzotriazepine Arylationa
entry
catalyst loading
conditions
% yielda
1
2
3
4
5
20%
20%
20%
20%
140 °C, 12 h
150 °C, 6 h
160 °C, 1 h
200 °C, 30 min
140, 1 h
62
57
51
33
1 equiv
98 (99b)
a Conditions: benzotriazepine substrate (1 equiv), aryl iodide (3 equiv),
CuI (20 mol %), LiOtBu (2 equiv). Reported yields are isolated yields.
Yields in parentheses are isolated yield when employing 1 equiv of CuI.
a Conditions: benzotriazepine substrate (1 equiv), PhI (3 equiv), LiOtBu
(2 equiv). Yields are GC yields determined by integration relative to
hexamethylbenzene as an internal standard. b Isolated yield.
Org. Lett., Vol. 11, No. 7, 2009
1513

In conclusion, we have developed an efficient Cu-
catalyzed protocol for the direct arylation of benzotriaz-
epines, a class of heterocycles that are actively being
investigated as drug candidates. This is the first example
of the copper-mediated coupling of nonaromatic hetero-
cycles. The transformation can be conducted either under
inert atmosphere or in air and can be conveniently
performed using microwave irradation. Further studies to
expand substrate scope to benzodiazepines and other
benzazepine derivatives are currently underway.
Energy Research, Office of Basic Energy Sciences, Chemical
Sciences Division, U.S. Department of Energy under contract
DE-AC02-05CH11231 (to R.G.B.). We thank Dr. Ashley
M. Berman (University of California Berkeley) for helpful
discussions.
Supporting Information Available: Full experimental
details and characterization for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This work was supported by the NIH
grant GM069559 (to J.A.E.) and by the Director, Office of
OL900103A
1514
Org. Lett., Vol. 11, No. 7, 2009