One-pot transition-metal-free synthesis of dibenzo[b,f]oxepins from 2-halobenzaldehydes

Article abstract of DOI:10.1021/ol302371s

A one-pot transition-metal-free, base-mediated synthesis of dibenzo[b,f]oxepins was developed. The reaction of 2-halobenzaldehydes with (2-hydroxyphenyl)acetonitriles proceeds via a sequential aldol condensation and intramolecular ether formation reaction in the presence of Cs₂CO ₃ and molecular sieves in toluene.

Full text of DOI:10.1021/ol302371s

ORGANIC
LETTERS
2012
Vol. 14, No. 19
5102–5105
One-Pot Transition-Metal-Free Synthesis
of Dibenzo[b,f]oxepins from
2‑Halobenzaldehydes
Young Lok Choi,†,§ Hye Sun Lim,†,‡ Hwan Jung Lim,† and Jung-Nyoung Heo*,†,‡
Medicinal Chemistry Research Center, Korea Research Institute of Chemical
Technology, 141 Gajeong-ro, Daejeon 305-600, Korea, Department of Chemistry,
Korea University, 145 Anam-ro, Seoul 105-600 Korea, and Graduate School of
New Drug Discovery and Development, Chungnam National University,
99 Daehak-ro, Daejeon 305-764, Korea
heojn@krict.re.kr
Received August 26, 2012
ABSTRACT
A one-pot transition-metal-free, base-mediated synthesis of dibenzo[b,f]oxepins was developed. The reaction of 2-halobenzaldehydes with
(2-hydroxyphenyl)acetonitriles proceeds via a sequential aldol condensation and intramolecular ether formation reaction in the presence of
Cs2CO3 and molecular sieves in toluene.
Dibenzo[b,f]oxepin is an important motif in natural and
medicinal compounds (Figure 1). Recently, pacharin (1)
and bauhiniastatins 1À4 (2) were isolated from the plant
Bauhinia purpurea, and these compounds were shown to
significantly inhibit cancer cell growth.1 These compounds
are similar tothe naturalproducts bauhinoxepinB (3)2 and
artocarpol A (4),3 which have been shown to exhibit anti-
mycobacterial and anti-inflammatory activities, respectively.
Notably, molecules containing the dibenzo[b,f]oxepin
moiety have received considerable interest from the medici-
nal community due to these compounds’ potent biological
properties, such as antipsychotic,4 antidepressant,5 anti-
hypertensive,6 antiestrogenic,7 anti-inflammatory,8 and
insecticidal activities.9 For example, compound 5 is a
nonpeptide angiotensin II receptor antagonist that can reg-
ulate blood pressure and electrolyte homeostasis.6 CGP 3466
(6) exhibits strong neuroprotective activity as the result of its
ability to prevent neuronal apoptosis in the adult brain.10
Synthetic methodologies for the construction of a
dibenzo[b,f]oxepin scaffold have been focused primar-
ily on the combination of Ullmann coupling and the
† Korea Research Institute of Chemical Technology.
§ Korea University.
‡ Chungnam National University
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Anjaneyula, A. S. R.; Reddy, A. V. R.; Reddy, D. S. K.; Cameron,
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r
10.1021/ol302371s
Published on Web 09/17/2012
2012 American Chemical Society

transition-metal-free synthesis of dibenzo[b,f]oxepin from
2-halobenzaldehyde and (2-hydroxyphenyl)acetonitrile.18
At the outset, we envisioned two possible routes for the
one-pot synthesis of dibenzo[b,f]oxepin in which the cou-
pling partners, aryl halides and phenols, are switched, as
illustrated in Table 1.
Table 1. One-Pot Synthesis of Dibenzo[b,f]oxepina
Figure 1. Dibenzo[b,f]oxepins in natural and medicinal
compounds.
entry
X (7 or 12)
pathway
temp (°C)
yield (%)b
FriedelÀCrafts reaction.4d,5,8,11 For example, Paduraru
and Wilson published a synthesis of artocarpol A and D
analogs following this strategy.12 In addition, the nucleo-
philic aromatic substitution reaction (SNAr) has been widely
used for the formation of biaryl ethers.6,10a,13 Simultaneously,
the ring expansion route from xanthenes has been reported,
employing WagnerÀMeerwein rearrangement14 or Mn-
(III)-based oxidative radical rearrangement.15 Guy et al. des-
cribed the synthesis of dibenzo[b,f]oxepin based on a sequen-
tial Heck reaction and Pd-catalyzed etheration.16 However,
these strategies typically require lengthy reaction steps, yield
products with low regioselectivities, and are compatible with
few functional groups. As part of a research program to
develop a one-pot metal-catalyzed reaction/aldol condensa-
tion reaction,17 we sought to develop an efficient synthesis of
dibenzo[b,f]oxepin via a one-pot Cu-catalyzed aryl ether
formation/aldol condensation reaction. Serendipitously, we
observed that the formation of dibenzo[b,f]oxepin occurred
even in the absence of a copper catalyst. Herein, wereportthe
1
2
3
4
5
6
7
8
F (7a)
A
A
A
A
B
B
B
B
130
130
130
130
150
150
150
150
98
96
95
93
59
49
46
21
Cl (7b)
Br (7c)
I (7d)
F (12a)
Cl (12b)
Br (12c)
I (12d)
a Reaction conditions: (Pathway A) halobenzaldehyde 7 (0.36 mmol,
1.2 equiv), phenylacetonitrile 8a (0.3 mmol), Cs2CO3 (0.6 mmol), pyridine
(3 mL), 4 h; (Pathway B) benzaldehyde 11 (0.36 mmol, 1.2 equiv), phenyl-
acetonitrile 12 (0.3mmol),Cs2CO3 (0.9mmol),pyridine(3mL),4h.b Isolated
yield.
Table 2. Isomerization of the Nitrile Groupa
(10) (a) Zimmermann, K.; Waldmeier, P. C.; Tatton, W. G. Pure
Appl. Chem. 1999, 71, 2039–2046. (b) Zimmermann, K.; Roggo, S.;
Kragten, E.; Furst, P.; Waldmeier, P. Bioorg. Med. Chem. Lett. 1998, 8,
time
(h)
yield
(%)b
ratio of
10c/13cc
entry
solvent
additive
€
1195–1200. (c) Sagot, Y.; Toni, N.; Perrelet, D.; Lurot, S.; King, B;
Rixner, H.; Mattenberger, L.; Waldmeier, P. C.; Kato, A. C. Br. J.
Pharmacol. 2000, 131, 721–728.
(11) (a) Manske, R. H. F.; Ledingham, A. E. J. Am. Chem. Soc. 1950,
72, 4797–4799. (b) Olivera, R.; SanMartin, R.; Churruca, F.; Domınguez,
´
1
2
3
4
5
pyridine
pyridine
toluene
toluene
toluene
À
4
4
4
4
83
1:1
NDd
88
1:0.2
1:0.2
1:0
˚
MS (4 A)
À
˚
˚
MS (4 A)
72
93
MS (4 A)
24
1:0
E. J. Org. Chem. 2002, 67, 7215–7225.
(12) Paduraru, M. P.; Wilson, P. D. Org. Lett. 2003, 5, 4911–4913.
(13) (a) Hoyer, H.; Vogel, M. Monatch. Chem. 1962, 93, 766–774. (b)
Samet, A. V.; Marshalkin, V. N.; Lyssenko, K. A.; Semenov, V. V. Russ.
Chem. Bull. Int. Ed. 2009, 58, 347–350.
(14) (a) Storz, T.; Vangrevelinghe, E.; Dittmar, P. Synthesis 2005,
2562–2570. (b) Anet, F. A. L.; Bavin, P. M. G. Can. J. Chem. 1957, 35,
1084–1087. (c) Bavin, P. M. G.; Bartle, K. D.; Jones, D. W. J. Hetero-
cycl. Chem. 1968, 5, 327–330. (d) Hess, B. A., Jr.; Bailey, A. S.;
Boekelheide, V. J. Am. Chem. Soc. 1967, 89, 2746–2747.
a Reaction conditions: halobenzaldehyde 7f (0.36 mmol, 1.2 equiv),
phenylacetonitrile 8a (0.3 mmol), Cs2CO3 (0.6 mmol), MS (4 A, 300 mg),
solvents (3 mL). b Isolated yield. c 1H NMR ratio of 10c and 13c. d Not
determined.
(15) (a) Cong, Z.; Miki, T.; Urakawa, O.; Nishino, H. J. Org. Chem.
2009, 74, 3978–3981. (b) Nishino, H.; Kamachi, H.; Baba, H.; Kurosawa,
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B. T.; Heo, J.-N. Org. Lett. 2008, 10, 3543–3546. (c) Choi, Y. L.; Yu,
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Org. Lett., Vol. 14, No. 19, 2012
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Table 3. Scope of the One-Pot Synthesis of Dibenzo[b,f]oxepina
a Reaction conditions: halobenzaldehyde 7 (0.72 mmol, 1.2 equiv), phenylacetonitrile 8 (0.6 mmol), Cs2CO3 (1.2 mmol, 2.0 equiv), molecular sieves
(4 A, 300 mg), toluene (3 mL), 130 °C, 24 h. b Isolated yield. c Reaction temperature of 150 °C. d Reaction time of 48 h.
Based on the electronic properties of the substrates, we
thought that pathway A would be favored, primarily due
to both the higher nucleophilicity of phenol 8a and the
increased electrophilicity of halobenzaldehydes 7. After
screening numerous reaction conditions for pathway A
using 2-bromobenzaldehyde (7c), we found that Cs2CO3 in
pyridine at 130 °C gave the best result (Table 1, entry 3).
Other halo-substituents (7aÀb, d) for the ether formation
gave similar results, producing 10a with excellent yields
(entries 1, 2, and 4). Surprisingly, aldol condensation was
faster than aryl ether formation, a result that was con-
firmed by the isolation of intermediate 9under mild reaction
conditions. As expected, pathway B was less effective and
provided less of the desired product, 10a, with yields in the
range of 21% to 59% (Table 1, entries 5À8), even at a higher
reaction temperature of 150 °C. A comparison of the reac-
tion yields from halo-substituted benzaldehydes 12aÀd indi-
cated a significant halogen dependence in the following
order: F > Cl ≈ Br > I. We believe that this observation
supports the hypothesis that the aryl ether formation pro-
ceeds via the SNAr mechanism.19
(18) For a review of the transition-metal-free reaction, see: (a)
Shirakawa, E.; Hayashi, T. Chem. Lett. 2012, 41, 130–134. For recent
representative examples of the CÀO bond formation, see: (b) Jalalian,
N.; Ishikawa, E. E.; Silva, L. F., Jr.; Olofsson, B. Org. Lett. 2011, 13,
1552–1555. (c) Li, F.; Wang, Q.; Ding, Z.; Tao, F. Org. Lett. 2003, 5,
2169–2171. (d) Liu, Z.; Larock, R. C. Org. Lett. 2004, 6, 99–102. For
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CÀN bond formation, see: (e) Thome, I.; Bolm, C. Org. Lett. 2012, 14,
1892–1895. (f) Shi, L.; Wang, M.; Fan, C.-A.; Zhang, F.-M.; Tu, Y.-Q.
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Ramon, D. J.; Yus, M. J. Org. Chem. 2011, 76, 654–660.
While exploring the substrate scope, we found that
the reaction of 2,5-dibromobenzaldehyde (7e) with 8a
5104
Org. Lett., Vol. 14, No. 19, 2012

provided a ∼1:1 mixture of the cyclized products 10b and
13b due to the concomitant isomerization of the nitrile
group, as depicted in Table 2.20
With a highly efficient protocol in hand, our attention
turned to the formal synthesis of the angiotensin II
antagonist 5 on a gram scale (Scheme 1).6
The structure of 10b was clearly elucidated by X-ray
crystallography. When using 7f with a 5-chloro substitu-
ent, nitrile migration also occurred to give a mixture of 10c
and 13c21 in a similar ratio (Table 2, entry 1). We first
thought that the nitrile migration would be caused by H2O
formed during the aldol condensation. Consequently, the
reaction of 7f with 8a in the presence of molecular sieves
resulted in the suppression of the nitrile migration, yielding
products in a 1:0.2 ratio (entry 2). When the solvent was
changed to toluene, the migration still occurred but at a
reduced ratio (entry 3). Finally, we were pleased to find
that the use of molecular sieves in toluene could completely
prevent this migration, although the reaction was slower
(entries 4À5).
Scheme 1. Synthesis of the Key Intermediate 17 of Compound 5
To further extend the scope, the optimized protocol was
employed to obtain various dibenzo[b,f]oxepins from a
broad range of substituted 2-bromo- and 2-chlorobenzal-
dehydes and (2-hydroxyphenyl)acetonitriles. A variety of
both electron-withdrawing and -donating substituents
were well tolerated, and the results are summarized in
Table 3. Whenhighly electron-rich dimethoxyand dioxalyl
groups were used, an elevated reaction temperature was
needed for complete conversion (entries 7À8 and 14). It is
noteworthy that sterically hindered o-methyl and o-methoxy
groups could be added with excellent yields, although a
longer reaction time at a higher temperature was required
for these reactions (entries 12À14 and 15À17). Notably,
the use of aryl bromides or chlorides such as 7 is important
because most of these compounds are commercially avail-
able at low cost or can be easily prepared.
The requisite starting phenylacetonitrile 8c was easily
prepared using straightforward methodologies from ben-
zoic acid 14. The methylation of 14 followed by the
reduction of the corresponding methyl ester provided
benzyl alcohol 15 with an excellent yield.22,23 The sequen-
tial brominationÀcyanization of 15 produced (2-methoxy-
phenyl)acetonitrile 16 with a 87% yield.24 The demethyla-
tion of 16 with NaCN provided phenol 8c,25 which was
subjected to the optimized one-pot base-mediated cycliza-
tion to furnish dibenzo[b,f]oxepin 17 with a good yield.
Thus, the key intermediate 17 was prepared in six steps
with a 56.6% overall yield.26
In summary, we developed a one-pot transition-metal-
free, base-mediated synthesis of dibenzo[b,f]oxepins from
substituted 2-halobenzaldehydes and (2-hydroxyphenyl)-
acetonitriles. Importantly, this protocol is applicable to a
wide range of 2-bromo- and 2-chloro-substituted benzal-
dehydes. Additionally, we demonstrated the synthesis of
the key intermediate 17 on a gram scale. Further applica-
tions of this method for the synthesis of medicinally useful
compounds are currently being investigated.
(19) For reviews of SNAr ether formation: (a) Bunnett, J. F.; Zahler,
R. E. Chem. Rev. 1951, 49, 273–412. (b) Parker, A. J. Chem. Rev. 1969,
69, 1–32. (c) Sawyer, J. S. Tetrahedron 2000, 56, 5045–5065.
(20) Isomerization of nitrile: (a) Ayub, K.; Zhang, R.; Robinson,
S. G.; Twamley, B.; Williams, R. V.; Mitchell, R. H. J. Org. Chem. 2008,
73, 451–456. (b) Feng, L; Kumar, D.; Kerwin, S. M. J. Org. Chem. 2003,
68, 2234–2242.
(21) Dibenzo[b,f]oxepins 13c was identical with the synthetic com-
pound, which was obtained in 92% yield by the reaction of 7c with 8e
under the optimized conditions.
(22) (a) Snider, B. B.; Gao, X. J. Org. Chem. 2005, 70, 6863–6869. (b)
Itoh, Y.; Kitaguchi, R.; Ishikawa, M.; Naito, M.; Hashimoto, Y. Bioorg.
Med. Chem. 2011, 19, 6768–6778.
(23) Gensini, M.; Altamura, M.; Dimoulas, T.; Fedi, V.; Giannotti,
D.; Giuliani, S.; Guidi, A.; Harmat, N. J. S.; Meini, S.; Nannicini, R.;
Pasqui, F.; Tramontana, M.; Triolo, A.; Maggi, C. A. ChemMedChem
2010, 5, 65–78.
(24) Kelley, J. L.; Linn, J. A.; Selway, J. W. T. J. Med. Chem. 1989,
32, 1757–1763.
(25) McCarthy, J. R.; Moore, J. L.; Cregge, R. J. Tetrahedron Lett.
1978, 52, 5183–5186.
Acknowledgment. Financial support provided by the
KRICT and Ministry of Knowledge Economy, Korea is
gratefully acknowledged.
Supporting Information Available. Experimental pro-
cedures and NMR spectra for all compounds, including a
CIF file of 10b. This material is available free of charge via
the Internet at http://pubs.acs.org.
(26) According to the procedure reported by Kiyama and co-workers
(ref 6), the intermediate 17 was prepared from 3-methylphenol and
2-chloro-5-nitrobenzaldehyde in 12 steps with a 12.8% overall yield.
The authors declare no competing financial interest.
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