Highly regioselective synthesis of fused seven-membered rings through copper-catalyzed cross-coupling

Article abstract of DOI:10.1039/c2cc37891d

A highly efficient protocol of copper catalysis for the one-pot synthesis of fused dibenzo[b,f][1,4]oxazepines is reported. The transformation involves a Smiles rearrangement, leading to the completely different regioselectivity from the classical cross-coupling. The easy reaction of aryl chlorides as substrates enhances the practical application of the methodology.

Full text of DOI:10.1039/c2cc37891d

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Highly regioselective synthesis of fused
seven-membered rings through copper-catalyzed
cross-coupling†
Peng Sang,a Ming Yu,a Hangfei Tu,a Jianwei Zouab and Yuhong Zhang*ac
Cite this: Chem. Commun., 2013,
49, 701
Received 31st October 2012,
Accepted 30th November 2012
DOI: 10.1039/c2cc37891d
www.rsc.org/chemcomm
A highly efficient protocol of copper catalysis for the one-pot
We herein report a highly regioselective synthesis of indole-
synthesis of fused dibenzo[b,f][1,4]oxazepines is reported. The fused dibenzo[b,f][1,4]oxazepines that involves the copper-
transformation involves a Smiles rearrangement, leading to the initiated C–N and C–O coupling of 2-(2-halophenyl)-1H-indoles
completely different regioselectivity from the classical cross- and 2-halophenols in one-pot. Aryl chlorides can be successfully
coupling. The easy reaction of aryl chlorides as substrates enhances applied to the synthesis of these seven-membered compounds,
the practical application of the methodology.
which enhances the practical application of the methodology.
Notably, this transformation involves Smiles rearrangement
Dibenz[b,f][1,4]oxazepine derivatives are pharmacologically active (1,5-hydrogen shift), which leads to the completely different
substances.1 In particular, heterocyclic ortho-fused dibenz- regioselectivity from the classical cross-coupling of copper
[b,f][1,4]oxazepines demonstrate valuable bioactivity, including catalysis.
antidepressive and anxiolytic activity,2 antiserotonergic and
Initially, we examined the reaction of 2-bromo-4-chlorophenol
antihistaminic effects.3 These compounds have been successfully (1a) and 2-(2-bromophenyl)-1H-indole (2a) with K3PO4 as
utilized for treating bronchial asthma and allergic bronchitis,4 the base and DMF as the solvent at 120 1C. We collected the
and they are useful progesterone receptor agonists.5 However, the product and we supposed that the product should be the
preparation of these seven-membered compounds usually needs cyclization compound 3a0 (Table 1). However, the result of
several steps and harsh reaction conditions. For example, X-ray crystallographic analysis for 3d (Fig. 1 and Table 2)
the synthesis of pyrrole ortho-fused dibenz[b,f][1,4]oxazepines revealed that a Smiles rearrangement occurred in this transforma-
requires five steps and caustic conditions.6 The search for new tion, and made the oxygen and chlorine atoms share an ortho-
and efficient strategies for the regioselective synthesis of this rather than the expected meta-relationship.
type of compounds is of great importance.
For this unprecedented reaction, a copper catalyst was
Copper-catalyzed C–O- and C–N-coupling reactions are absolutely required for the reaction (Table 1, entry 8). We
powerful tools in pharmaceutical synthesis and have been examined the efficiency of a number of Cu sources as shown in
extensively investigated in the last decade.7 Many heterocyclic Table 1. It was found that CuBr, CuCl, Cu(OAc)2, CuCO3ꢀCu(OH)2
molecules have been prepared by the use of the copper- and Cu(OTf)2 were active, but CuI afforded the highest yield
catalyzed coupling strategy.8 However, the application of copper (Table 1, entries 1–6). Ligands played a crucial role in the
catalyzed transformation for seven-membered heterocycles, reaction. CuI alone gave very low yield (Table 1, entry 7).
which are difficult to prepare owing to ring strain and trans- Significantly, the addition of dibenzoylmethane (dbm) led to
annular interactions,9 is rarely reported. In addition, the choice the formation of the product in 83% yield (Table 1, entry 1). The
of inexpensive but less reactive aryl chlorides as coupling generally used nitrogen-containing ligands in copper catalysis
partners still remains a challenge compared to the commonly such as L-proline and bipyridine showed a poor effect on the
used aryl bromides and aryl iodides.10
reaction. Of the bases tested, K3PO4 showed the best effect
(Table 1, entry 1). Cs2CO3 and K2CO3 gave the moderate yields
(Table 1, entries 9–10). No product was observed by the use of
KOAc (Table 1, entry 11). The effect of solvents on the reaction
was examined under the same reaction conditions (Table 1,
entries 12–15). DMF was the super solvent for the reaction
(Table 1, entry 1). The use of DMSO delivered the product with
moderate yield (Table 1, entry 12), and the reaction was
sluggish in PhMe, dioxane and MeCN (Table 1, entries 13–15).
a Department of Chemistry, Zhejiang University, Hangzhou 310027, China.
E-mail: yhzhang@zju.edu.cn
b Ningbo Institute of Technology, Zhejiang University, Ningbo 315104, China
c State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, China
† Electronic supplementary information (ESI) available: Experimental details.
CCDC 890740. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c2cc37891d
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 701--703 701

View Article Online
Communication
ChemComm
Table 1 Optimization of reaction conditionsa
The reaction afforded the highest yield when performed
at 120 1C (Table 1, entry 1). The temperature lower or higher
than that was deleterious to the reaction (Table 1, entries 16
and 17).
With the optimal reaction conditions in hand, the
coupling–annulation of variously substituted 2-halophenols
with 2-(2-bromophenyl)-1H-indole (2a) was examined as shown
in Table 2. For 2-iodophenol, the reaction can be easily per-
formed to afford the desired product 3b in excellent yield
(Table 2, entry 1). Encouraged by this successful coupling–
annulation using aryl iodide, we next studied the reaction of
2-bromophenol. To our delight, the desired product was also
obtained in moderate yield (Table 2, entry 2). Further study
showed that 2-bromophenol with the bromine group partici-
pated in the reaction even better to give the product 3c in good
yield (Table 2, entry 3). We conceived to further extend the
reaction to 2-chlorophenol and no reaction was observed. To
our delight, when 2-chlorophenol with electron-withdrawing
groups was used, the reaction could proceed easily to give the
products in moderate to good yields (Table 2, entries 4–7). As
for substitution patterns, 6-substituted 2-halophenol delivered
a relatively low yield compared with its 3- or 4-analogues
probably due to the steric hindrance (Table 3, entries 4–6).
On the other hand, too strong electron-withdrawing groups
showed lower reactivity (3f). We conceived to further extend
the reaction. The optimized conditions could also be applied
to 2-bromonaphthol to obtain the corresponding indole-fused
dibenzo[b,f][1,4]oxazepines derivative 3g (Table 2, entry 9).
We next examined the scope of variously substituted
2-(2-halophenyl)-1H-indoles as shown in Table 3. All of the
substrates provided good to excellent yields, showing good
functional group tolerance. A variety of substituted indoles
participated in the reaction smoothly to give the desired
products, including electron-withdrawing fluoro, chloro, and
bromo groups, as well as an electron-donating methyl group.
Indoles with the strong electro-withdrawing nitro group failed
to give the fused dibenzo[b,f][1,4]oxazepine product (Table 3,
3h–3k). For the C2-aromatic ring of indoles, iodide and bromide
Entry Cat.
Base
Solvent
Temp (1C) Yieldb (%)
1
2
CuI
CuBr
K3PO4
K3PO4
K3PO4
K3PO4
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
120
120
120
120
120
120
120
120
120
120
120
120
120
83
71
76
74
78
74
48
nr
79
74
0
77
nd
nd
Trace
76
74
3
4
CuCl
Cu(OAc)2
5
CuCO3ꢀCu(OH)2 K3PO4
6
Cu(OTf)2
CuI
—
K3PO4
K3PO4
K3PO4
Cs2CO3 DMF
K2CO3
KOAc
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
7c
8
9
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
10
11
12
13
14
15
16
17
DMF
DMF
DMSO
PhMe
Dioxane 120
MeCN
DMF
DMF
120
100
140
a
Reaction conditions: 2-bromo-4-chlorophenol (0.24 mmol),
2-(2-bromophenyl)-1H-indole (0.2 mmol), CuI (10 mol%), dbm (10 mol%),
base (3 equiv.), solvent (2 mL), N2, 12 h. Isolated yield. No dbm
was used in this reaction.
b
c
Fig. 1 The X-ray single crystal structure of product 3d.
Table 2 Variation of phenol ring substituentsa
Table 3 Variation of 2-(2-halophenyl)-1H-indole ring substituentsa
Entry
1 (Y/R1/R2/R3/R4)
3
Yieldb (%)
1
2
3
4
5
6
7
8
1b (I/H/H/H/H)
1c (Br/H/H/H/H)
1d (Br/H/Br/H/H)
1e (Cl/Cl/H/H/H)
1f (Cl/H/Cl/H/H)
1g (Cl/H/H/H/Cl)
1h (Cl/H/Br/H/H)
1i (Cl/H/CN/H/H)
3b
3b
3c
3d
3a
3e
3c
3f
90
58
91
82
88
41
79
29
Entry
2 (X/R5/Z)
3
Yieldb (%)
1
2
3
4
5
6
7
8
2b (I/H/C)
3a
3a
3a
3h
3i
3j
3k
3l
85
83
69
61
86
81
68
90
2a (Br/H/C)
2c (Cl/H/C)
2d (Br/Me/C)
2e (Br/F/C)
2f (Br/Cl/C)
2g (Br/Br/C)
2h (Br/H/N)
9
25
a
a
Reaction conditions: 1 (0.24 mmol), 2a (0.2 mmol), CuI (0.02 mmol),
Reaction conditions: 1a (0.24 mmol), 2 (0.2 mmol), CuI (0.02 mmol),
K3PO4 (0.6 mmol), dbm (0.02 mmol), DMF (2 mL) under N2.
Isolated yield.
K3PO4 (0.6 mmol), dbm (0.02 mmol), DMF (2 mL) under N2.
Isolated yield.
b
b
c
702 Chem. Commun., 2013, 49, 701--703
This journal is The Royal Society of Chemistry 2013

View Article Online
ChemComm
Communication
giving the product in good yields with high regioselectivity.
Exploration of this new strategy for the synthesis of other
interesting molecules is currently underway.
We gratefully acknowledge the National Basic Research
Program of China (No. 2011CB936003) and NSFC (No. 21072169)
for the financial support.
Notes and references
1 (a) J. M. Klunder, K. D. Hargrave, M. West, E. Cullen, K. Pal,
M. L. Behnke, S. R. Kapadia, D. W. McNeil, J. C. Wu, G. C. Chow
and J. Adams, J. Med. Chem., 1992, 35, 1887; (b) R. A. Smits,
H. D. Lim, B. Stegink, R. A. Bakker, I. J. P. de Esch and R. Leurs,
J. Med. Chem., 2006, 49, 4512; (c) R. Li, P. S. Farmer, J. Wang,
R. J. Boyd, T. S. Cameron, M. A. Quilliam, J. A. Walter and
S. E. Howlett, Drug Des. Discovery, 1995, 12, 337; (d) E. A. Hallinan,
T. J. Hagen, S. Tsymbalov, R. K. Husa, A. C. Lee, A. Stapelfeld and
M. A. Savage, J. Med. Chem., 1996, 39, 609; (e) E. A. Hallinan,
T. J. Hagen, S. Tsymbalov, A. Stapelfeld and M. A. Savage, Bioorg.
Med. Chem., 2001, 9, 1; ( f ) K. Nagarajan, J. David, Y. S. Kulkarni,
S. B. Hendi, S. J. Shenoy and P. Upadhyaya, Eur. J. Med. Chem. Chim.
Ther., 1986, 21, 21.
2 W. J. Van der Burg, Chem. Abstr., 1974, 81, 3986, DE2347727.
3 F. G. Sulman, Y. Pfeifer and E. Superstine, Arzneimittelforschung,
1981, 31, 109.
4 G. Walther, C. S. Schneider, K. H. Weber and A. Fuegner, Chem.
Abstr., 1982, 96, 6777, DE3008944.
5 P. P. M. A. Dols, B. J. B. Folmer, H. Hamersma, C. W. Kuil, H. Lucas,
L. Ollero, J. B. M. Rewinkel and P. H. H. Hermkens, Bioorg. Med.
Chem. Lett., 2008, 18, 1461.
6 A. F. Khlebnikov, M. S. Novikov, P. P. Petrovskii, J. Magull and
A. Ringe, Org. Lett., 2009, 11, 979.
7 (a) K. Kunz, U. Scholz and D. Ganzer, Synlett, 2003, 2428; (b) S. V. Ley
and A. W. Thomas, Angew. Chem., Int. Ed., 2003, 42, 5400.
8 For reviews and some selected examples, see: (a) D. Ma and Q. Cai,
Acc. Chem. Res., 2008, 41, 1450; (b) J. Lu, X. Gong, H. Yang and H. Fu,
Chem. Commun., 2010, 46, 4172; (c) S. Xu, J. Lu and H. Fu, Chem.
Commun., 2011, 47, 5596; (d) W. Xu, Y. Jin, H. Liu, Y. Jiang and
H. Fu, Org. Lett., 2011, 13, 1274; (e) A. K. Mandadapu, S. K. Sharma,
S. Gupta, D. G. V. Krishna and B. Kundu, Org. Lett., 2011, 13, 3162;
( f ) H. Fu and T. Liu, Synthesis, 2012, 2805; (g) P. Sang, Y. Xie,
J. Zou and Y. Zhang, Org. Lett., 2012, 14, 3894; (h) H. Xu and H. Fu,
Chem.–Eur. J., 2012, 18, 1180.
Scheme 1 Control experiments.
displayed higher reactivity than the corresponding aryl chloride
(Table 3, entries 1–3). Notably, 2-(2-bromophenyl)-1H-benzo-
[d]imidazole can also participate in the reaction easily with
2-bromo-4-chlorophenol to afford the imidazole-fused dibenzo-
[b,f][1,4]oxazepines derivative 3f in excellent yield (Table 2,
entry 8). It is noteworthy that the introduction of functional
groups, such as F, Cl, Br and CN, adds flexibility to further
elaborate the indole-fused dibenzo[b,f][1,4]oxazepine products
that are formed (3a, 3c–3f and 3h–3l).
Control experiments for the mechanistic studies were carried
out as shown in Scheme 1. When a mixture of 2-phenyl-1H-
indole (4a) and 2-bromo-4-chlorophenol (1a) was subjected to
the standard reaction conditions, no reaction was observed
(eqn (1)). This result reveals that the copper-catalyzed one-pot
reaction may first involve an Ullmann coupling between
2-(2-halophenyl)-1H-indoles and 2-halophenols. In contrast,
when 2-(2-bromophenyl)-1H-indole (2a) and 4-chlorophenol
(5a) were combined under identical conditions, the product
6a was obtained in 34% yield through the Ullmann coupling
and a Smiles rearrangement product 7a was obtained in 63%
yield (eqn (2)). We further treated 6a under standard condi-
tions, and 7a was afforded in 71% yield (eqn (3)). It is obvious
that this transformation involves Ullmann coupling and sub-
sequent Smiles rearrangement to give 7a. For our fused dibenzo-
[b,f][1,4]oxazepine products, the second Ullmann coupling occurs
after the Smile rearrangement to form the seven-membered ring.
Further studies to elucidate the detailed reaction mechanism are
ongoing in our laboratory.
9 For reviews and some selected examples, see: (a) U. Nubbemeyer,
Top. Curr. Chem., 2001, 216, 125; (b) M. E. Maier, Angew. Chem.,
Int. Ed., 2000, 39, 2073; (c) P. A. Evans and B. Holmes, Tetrahedron,
¨
1991, 47, 9131; (d) U. M. Lindstrom and P. Somfai, Chem.–Eur. J.,
¨
2001, 7, 94; (e) H. Bieraugel, T. P. Jansen, H. E. Schoemaker,
H. Hiemstra and J. H. van Maarseveen, Org. Lett., 2002, 4, 2673;
( f ) S. Derrer, J. E. Davies and A. B. Holmes, J. Chem. Soc., Perkin
Trans. 1, 2000, 2957.
10 For selected examples, see: (a) R. D. Rieth, N. P. Mankad,
E. Calimano and J. P. Sadighi, Org. Lett., 2004, 6, 3981; (b) H. A.
Chiong and O. Daugulis, Org. Lett., 2007, 9, 1449; (c) L. Ackermann,
R. Vicente and R. Born, Adv. Synth. Catal., 2008, 350, 741; (d) E. T.
Nadres, A. Lazareva and O. Daugulis, J. Org. Chem., 2010, 76, 471;
(e) S. Tamba, Y. Okubo, S. Tanaka, D. Monguchi and A. Mori, J. Org.
Chem., 2010, 75, 6998; ( f ) L. Ackermann and A. V. Lygin, Org. Lett.,
2011, 13, 3332; (g) T. Truong and O. Daugulis, J. Am. Chem. Soc.,
2011, 133, 4243; (h) T. Yamamoto, K. Muto, M. Komiyama,
J. Canivet, J. Yamaguchi and K. Itami, Chem.–Eur. J., 2011, 17, 10113.
In conclusion, we have developed a highly efficient method-
ology for synthesis of fused seven-membered rings from
2-(2-halophenyl)-1H-indoles and 2-halophenols in one-pot.
Notably, aryl chlorides can be successfully used as aryl substrates,
which makes the method more practical. This new transforma-
tion involves Ullmann coupling and Smiles rearrangement,
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 701--703 703