Molecular iodine mediated intramolecular cyclization: An efficient method for the synthesis of benzoxepine derivatives

Article abstract of DOI:10.1055/s-0029-1219825

A simple, efficient and cost effective method for a divergent synthesis of benzoxepine derivatives using a hitherto unreported, highly regioselective, tandem iodocyclization procedure is described.

Full text of DOI:10.1055/s-0029-1219825

LETTER
1407
Molecular Iodine Mediated Intramolecular Cyclization: An Efficient Method
for the Synthesis of Benzoxepine Derivatives
I
odine-Mediate
d
In
.
tramolecula
C
r
Cyclization . Majumdar,* Biswajit Sinha, Inul Ansary, Santanu Chakravorty
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
E-mail: kcm_ku@yahoo.co.in
Received 15 March 2010
from the toxicity of thiophenol. Recent activity in the
Abstract: A simple, efficient and cost effective method for a diver-
gent synthesis of benzoxepine derivatives using a hitherto unreport-
ed, highly regioselective, tandem iodocyclization procedure is
described.
study of biologically active oxepines and oxepanes has re-
quired the search for versatile, cost effective reagents and
simple reaction conditions for the synthesis of these het-
erocycles. During the last few years iodine has found wide
utility because it is an inexpensive, non-toxic and readily
available electrophilic reagent that enables iodocycliza-
tion reactions to generate compounds with synthetic and
biological applications.11 Iodocyclization of heteroatoms
with tethered alkynes has been found to be an effective
and high-yielding method of preparing a large number of
heterocyclic compounds, e.g., furans,12 pyrroles,13 in-
doles,14 benzo[b]furans15 and benzo[b]thiophenes.16 Iodo-
nium-promoted heteroannulations are quite attractive
because they offer an alternative protocol for the synthesis
of complex molecules that are not always accessible using
common organometallic reagents. Although many exam-
ples are available for the construction of five- and six-
membered heterocycles utilizing iodine-mediated cy-
clization, to our knowledge, the synthesis of medium-ring
heterocycles has not been reported so far. These findings
prompted us to undertake a study on iodine-mediated cy-
clizations for the synthesis of benzoxepine derivatives.
These would provide an alternative and easy procedure
for the construction of some benzoxepine skeletons,
which are present as a basic structural moiety in a number
of naturally occurring compounds. Herein we report the
results.
Key words: iodine, intramolecular cyclization, benzoxepine, elec-
trophile, 7-exo cyclization
A wide range of natural products possess a seven-mem-
bered oxacycle in their molecular architecture.1 More-
over, these units serve as target molecules in numerous
synthetic studies.2 The benz[b]oxepine ring system occurs
in a small number of biologically active natural products
isolated mainly from plant sources.3 Some of these com-
pounds exhibit oral hypotensive and antiulcer properties.4
The fungal metabolites pterulone and its analogue5 inhib-
its the eukaryotic respiratory chain at the NADH site of
the ubiquinone oxidoreductase, possesses potent antifun-
gal activity and are only weakly cytotoxic (Figure 1). On
the other hand, Pterulinic acid also exhibits significant an-
tifungal and either weak or no cytotoxic activity, and is an
effective inhibitor of eukaryotic respiration.6
O
Cl
Cl
OH
O
O
pterulone
pterulone analogue
The required precursors 3a–d for our present study were
synthesized in 67–83% yields by heating compounds 2a–
d to reflux with propargyl bromide in acetone in the pres-
ence of anhydrous K2CO3 and a catalytic amount of NaI
(Scheme 1). The compounds 2a–d were, in turn, prepared
by heating salicylaldehydes 1a–d to reflux in acetone in
the presence of anhydrous K2CO3. The hydroxy aldehydes
1a–d were prepared according to our earlier published
procedure.17
A 3:1 mixture of 7-exo cyclized diiodo product 4a18 and
uncyclized iodo derivative 5 were formed when a mixture
of compound 3a, molecular iodine (1 equiv) and NaHCO3
(1 equiv) were stirred at room temperature in anhydrous
acetonitrile for six hours. The 8-endo cyclized product 6
was not obtained (Scheme 2).
Cl
O
COOH
O
pterulinic acid
Figure 1
Many synthetic methods, including palladium-mediated
intramolecular Heck reaction,7 RCM8 and transition-met-
al-mediated cyclizations,9 have been utilized for the con-
struction of medium-sized heterocycles, especially
oxepines and oxocine derivatives. Recently we have suc-
cessfully synthesized medium-ring heterocycles based on
a sulfanyl radical addition and cyclization procedure,10
but sometimes these methods suffer from complex reac-
tion conditions, difficulty in separation of products and
Interestingly, the amount of iodine, as well as NaHCO3,
played important roles in this reaction. Using two equiva-
lents of iodine increased the amount of the uncyclized
iodo-derivative 5 to a 1:3 ratio at the expense of desired
SYNLETT 2010, No. 9, pp 1407–1411
Advanced online publication: 13.04.2010
DOI: 10.1055/s-0029-1219825; Art ID: G09110ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
0

1408
K. C. Majumdar et al.
LETTER
O
O
R
R
CHO
R
(i)
(ii)
O
3a–d
OH
1a R = t-Bu
OH
2a–d
1b R = Me
1c R = OMe
1d R = H
Scheme 1 Reagents and conditions: (i) anhyd acetone, anhyd K2CO3, reflux; (ii) propargyl bromide, anhyd acetone, anhyd K2CO3, NaI,
reflux.
O
I
O
O
I
O
H
H
I
(i)
I
O
O
O
4a
7-exo (major)
O
5
3a
6
I
minor
8-endo (not found)
Scheme 2 Reagents and conditions: (i) I2, NaHCO3, anhyd MeCN, r.t.
cyclized product. Similar results were obtained when two
equivalents of NaHCO3 was used. Increasing the amount
of both I2 and NaHCO3 drastically reduced the amount of
cyclized product. In acetonitrile as solvent, iodine acted
both as an electrophile and a nucleophile. To expand the
scope of our iodine-catalyzed process, the reaction was
carried out using the procedure stated above but adding a
small amount of methanol to give a reduced amount of di-
iodo product 4a and a small amount of a new 7-exo cy-
clized product 7a. This establishes the fact that, in this
system, iodine acts as an electrophile and methanol as a
nucleophile (Scheme 3).
Table 1 Optimization of I2-Mediated Reactions
Entry Electrophile Nucleophile Solvent
Product Yield
(%)b
(equiv)
I2 (1)
I2 (2)
I2 (3)
I2 (1)
I2 (1)
I2 (1)
I2 (1)
(equiv)
1a
2
–
MeCN
MeCN
MeCN
MeCN
4a
4a
4a
55
20
15
–
3
–
4
MeOH (1)
4a + 7a 25 + 10
4a + 7a 25 + 25
5
MeOH (10) MeCN
MeOH (20) MeCN
6a
7
7a
7a
50
45
MeO
MeOH
MeOH
O
O
a Optimized reaction conditions. In each case, 1 equiv of NaHCO3
H
(i)
was used.
O
b Isolated yields.
I
O
3a
7a
OCH2 protons. Moreover, the high d value and NOE cor-
relation confirmed that the double bond proton is in the
deshielded zone of the carbonyl oxygen of the COCH3
group. The seven-membered structure is also supported
by two doublet protons resonating at d = 4.79 ppm (Ha,
J = 9.1 Hz) and d = 5.18 ppm (Hb, J = 9.2 Hz), whereas in
case of the eight-membered ring, the proton at d = ~5.18
ppm would be expected to split in a more complex manner
(Figure 2).
Scheme 3 Reagents and conditions: (i) I2, NaHCO3, anhyd MeCN,
anhyd MeOH, r.t.
Using an increased amount of methanol increased the
amount of 7a. When 20 equivalents of methanol was used,
the reaction afford compound 7a and uncyclized iodo-
derivative 5 in an approximate 5:2 ratio, without any for-
mation of the cyclized diiodo product 4a. The results are
summarized in Table 1.
It was also noted that when the reaction was carried out
with the salicyladehyde derivatives containing an elec-
tron-withdrawing group, e.g., p-Cl and m-Cl, only uncyc-
When compounds 3b–d were treated under the optimized
reaction conditions either in acetonitrile or in an aceto-
nitrile–methanol mixture, the corresponding cyclized
products were obtained in 48–55% yields. The results are
summarized in Table 2.
NOE
NOE
Me
Hb
Ha
MeO
H
O
The structures of the cyclized products were determined
from their spectral and analytical data. The IR spectrum of
the cyclized product 7b showed a characteristic carbonyl
Me
H
H
I
O
1
peak at 1713 cm–1, whereas the H NMR spectrum re-
H
NOE
7b
vealed one triplet (J = 1.0 Hz) at d = 7.22 ppm (=CH, exo-
cyclic), indicating the long-range allylic coupling with
Figure 2
Synlett 2010, No. 9, 1407–1411 © Thieme Stuttgart · New York

LETTER
Iodine-Mediated Intramolecular Cyclization
1409
Table 2 Scope of the I2-Mediated Cyclization
Entry
Starting material
Product
Time (h)
6
Yield (%)
55
O
I
O
H
1
O
I
O
3a
4a
7a
4b
O
MeO
O
H
2
3
4
8
6
7
50
52
48
O
I
O
3a
O
O
I
O
H
O
I
O
3b
MeO
O
H
O
I
O
3b
7b
O
MeO
O
H
MeO
MeO
5
6
5
6
52
48
O
I
O
3c
7c
4c
O
I
O
H
O
I
O
3d
O
MeO
O
H
7
8
55
O
I
O
3d
7d
lized iodo-derivatives 5 were isolated without any b). The cyclization is supposed to proceed through the for-
cyclized products. On the other hand, substrate 3c did not mation of 1,2-diiodoalkenyl intermediates 11. Initially
give any cyclized product in the absence of methanol nu- formed diiodoalkenyl intermediates 11 may subsequently
cleophile.
undergo dehydroiodination under basic conditions to af-
ford the minor products 5. A less probable explanation for
the formation of products 4 proceeding through nucleo-
philic displacement of iodine from the envisioned di-
iodoalkenyl intermediates 11 by nucleophilic a-carbon
(relative to the carbonyl group) cannot be ruled out.
A probable mechanism for the iodine-mediated reaction is
depicted in Scheme 4. Cyclization might occur either
through ‘path a’ or ‘path b’. In case of the former, cycliza-
tion is assumed to proceed via activation of the carbon–
carbon triple bond of 3 by coordination to I+ and, subse-
quently, the remaining I– ion may attack the double bond From this study, it can be seen that the iodine-mediated
of 8 in a Michael fashion to form carbanions 10. Subse- cyclization protocol is very useful for the synthesis of
quent attack of the carbanions at the iodonium moiety in a more substituted benzoxepine derivatives; the presence of
7-exo-mode may afford the seven-membered oxepine de- iodine functionality on the heterocycles can easily be de-
rivatives 4; but the formation of products 5 could be ex- rivatized through a range of available procedures, espe-
plained by considering an alternative pathway (pathway cially metal-catalyzed C–C bond forming reactions.19
Synlett 2010, No. 9, 1407–1411 © Thieme Stuttgart · New York

1410
K. C. Majumdar et al.
LETTER
I
O
I
O
I
O
R
R
R
O
O
O
8
9
10
I
I
I
7-exo
path a
I2
8-endo
R
O
O
I
I
R
O
R
H
H
O
I2
3
I
I
O
O
4
6
path b
O
O
R
R
H
– HI
O
I
O
11
I
5
I
Scheme 4
L.; Dominguez, D.; Rodriguez, d. L. A.; Saa, J. M.; Suau, R.;
Tojo, E.; Vidal, M. C. Tetrahedron Lett. 1984, 25, 5933.
(f) Tojo, E.; Dominguez, D.; Castedo, L. Phytochemistry
1991, 30, 1005. (g) Stefinovic, M.; Snieckus, V. J. Org.
Chem. 1998, 63, 2808. (h) Yamaguchi, S.; Furihata, K.;
Miyazawa, M.; Yokoyama, H.; Hirai, Y. Tetrahedron Lett.
2000, 41, 4787. (i) Yamaguchi, S.; Tsuchida, N.; Miyazawa,
M.; Hirai, Y. J. Org. Chem. 2005, 70, 7505. (j) Sabui, S. K.;
Venkateswaran, R. V. Tetrahedron Lett. 2004, 45, 983.
(k) Engler, M.; Anke, T.; Sterner, O. J. Antibiot. 1997, 50,
330.
In conclusion, we have achieved an efficient and straight-
forward method for the construction of benzoxepine de-
rivatives through an iodine-mediated electrophilic
cyclization reaction. The procedure reported here is more
economical than alternative methods and avoids separa-
tion problems. Moreover, during the cyclization process,
the iodine atom is incorporated in the final compounds,
which are attractive for transformations into other substi-
tuted compounds. To the best of our knowledge, this type
of iodine-mediated, tandem reaction has not been previ-
ously reported.
(4) (a) Tretter, J. R. US Patent 3514449, 1970; Chem. Abstr.
1970, 73, 35404u. (b) Dictionary of Drugs, 1st ed.; Elks, J.;
Ganellin, C. R., Eds.; Chapman and Hall: London, 1990,
984.
(5) (a) Engler, M.; Anke, T.; Sterner, O.; Brandt, U. J. Antibiot.
1997, 50, 325. (b) Wijnberg, J. B. P. A.; van Veldhuizen, A.;
Swart, H. J.; Frankland, J. C.; Field, J. A. Tetrahedron Lett.
1999, 40, 5767.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
(6) Lin, Y. L.; Kuo, H. S.; Wang, Y. W.; Huang, S. T.
Tetrahedron 2003, 59, 1277.
We thank the DST (New Delhi) and CSIR (New Delhi) for financial
assistance. Three of us are grateful to the CSIR (New Delhi) (B.S.
and S.C.) and to the UGC (New Delhi) (I.A.) for their research fel-
lowships.
(7) (a) Di Fabio, R.; Micheli, F.; Baraldi, D.; Bertani, B.; Conti,
N.; Dal Forno, G.; Feriani, A.; Donati, D.; Marcchioro, C.;
Messeri, T.; Missio, A.; Pasquarello, A.; Pentassuglia, G.;
Pizzi, D. A.; Provera, S.; Quaglia, A. M.; Sabbatini, F. M.
Farmaco 2003, 58, 723. (b) Hayashi, M.; Sai, H.; Horikawa,
H. Heterocycles 1998, 48, 1331. (c) Majumdar, K. C.;
Chattopadhyay, B.; Ray, K. Tetrahedron Lett. 2007, 48,
7633. (d) Cropper, E. L.; Andrew, J. P.; White, A. F.; Hii,
K. K. J. Org. Chem. 2006, 71, 1732. (e) Arnold, L. A.; Luo,
W.; Guy, R. K. Org. Lett. 2004, 6, 3005. (f) Gibson, S. E.;
Jones, J. O.; Kalindjinan, S. B.; Knight, J. D.; Steed, J. W.;
Tozer, M. J. J. Chem. Soc., Chem. Commun. 2002, 1938.
(g) Alcaide, B.; Polanco, C.; Sierra, M. A. Eur. J. Org.
Chem. 1998, 2913. (h) Gibson, S. E.; Middleton, R. J.
J. Chem. Soc., Chem. Commun. 1995, 1743. (i) Majumdar,
K. C.; Chattopadhyay, B.; Sinha, B. Tetrahedron Lett. 2008,
49, 1319. (j) Majumdar, K. C.; Chattopadhyay, B. Synlett
2008, 979. (k) Majumdar, K. C.; Chattopadhyay, B. Curr.
Org. Chem. 2009, 13, 731. (l) Zeni, G.; Larock, R. C. Chem.
Rev. 2004, 104, 2285.
References and Notes
(1) (a) Faulkner, D. J. Nat. Prod. Rep. 1984, 1, 251. (b)Bruder,
M.; Haseler, P. L.; Muscarella, M.; Lewis, W.; Moody, C. J.
J. Org. Chem. 2010, 75, 353. (c) Yoshida, M.; Nakatani, K.;
Shishido, K. Tetrahedron 2009, 65, 5702.
(2) (a) Oishi, T.; Ohtsuka, Y. Stud. Nat. Prod. Chem.; Rahman,
A., Ed.; Elsevier: Amsterdam, 1989, 73. (b) Moody, C. J.
Stud. Nat. Prod. Chem.; Rahman, A., Ed.; Elsevier:
Amsterdam, 1989, .
(3) (a) Shamma, M. The Isoquinoline Alkaloids, Chemistry and
Pharmacology; Academic Press: New York, 1972, 153.
(b) Campello, M. J.; Castedo, L.; Sai, J. M.; Suau, R.; Vidal,
M. C. Tetrahedron 1981, 23, 239. (c) Ulubelen, A.; Goren,
N.; Tanker, N. J. Nat. Prod. 1985, 48, 6. (d) Gozler, B.
J. Nat. Prod. 1984, 47, 753. (e) Campello, M. J.; Castedo,
Synlett 2010, No. 9, 1407–1411 © Thieme Stuttgart · New York

LETTER
Iodine-Mediated Intramolecular Cyclization
1411
(8) (a) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199.
(b) Chattopadhyay, S. K.; Karmakar, S.; Biswas, T.;
Majumdar, K. C.; Rahaman, H.; Roy, B. Tetrahedron 2007,
63, 3919. (c) Villar, H.; Frings, M.; Bolm, C. Chem. Soc.
Rev. 2007, 36, 55. (d) Clark, J. S.; Grainger, D. M.; Ehkirch,
A. A.-C.; Blake, A. J.; Wilson, C. Org. Lett. 2007, 9, 1033.
(9) (a) Yet, L. Chem. Rev. 2000, 100, 2963. (b) Rosillo, M.;
Domínguez, G.; Casarrubios, L.; Pérez-Castells, J. J. Org.
Chem. 2005, 70, 10611. (c) Trost, B. M. In Homogeneous
Transition Metal Catalyzed Reactions; Moser, W. R.;
Slocum, D. W., Eds.; American Chemical Society:
Washington DC, 1992, Chap. 31, 463. (d) Coulter, M. M.;
Dornan, P. K.; Dong, V. M. J. Am. Chem. Soc. 2009, 131,
6932.
(13) (a) Knight, D. W.; Redfern, A. L.; Gilmore, J. J. Chem. Soc.,
Perkin Trans. 1 2001, 2874. (b) Knight, D. W.; Redfern,
A. L.; Gilmore, J. J. Chem. Soc., Perkin Trans. 1 2002, 622.
(14) (a) Flynn, B. L.; Flynn, G. P.; Hamel, E.; Jung, M. K.
Bioorg. Med. Chem. Lett. 2001, 11, 2341. (b) Ren, X.-F.;
Turos, E.; Lake, C. H.; Churchill, M. R. J. Org. Chem. 1995,
60, 6468. (c) Ren, X.-F.; Konaklieva, M. I.; Shi, H.; Dickey,
S.; Lim, D. V.; Gonzalez, J.; Turos, E. J. Org. Chem. 1998,
63, 8898.
(15) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L.
Synlett 1999, 1432.
(16) (a) Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67, 1905.
(b) Flynn, B. L.; Verdier-Pinard, P.; Hamel, E. Org. Lett.
2001, 5, 651.
(10) (a) Majumdar, K. C.; Debnath, P. Tetrahedron 2008, 64,
9799. (b) Majumdar, K. C.; Maji, P. K.; Ray, K.; Debnath,
P. Tetrahedron Lett. 2007, 48, 9124. (c) Majumdar, K. C.;
Mondal, S.; Ghosh, D. Tetrahedron Lett. 2010, 51, 348.
(11) (a) Mphahlele, M. J. Molecules 2009, 14, 4814. (b) Yue,
D.; Larock, R. Org. Lett. 2004, 6, 1037. (c) Halim, R.;
Scammells, P. J.; Flynn, B. L. Org. Lett. 2008, 10, 1967.
(d) Zhang, X.; Campo, M. A.; Yao, T.; Larock, R. C. Org.
Lett. 2005, 7, 763. (e) Alvaro, G.; Fabio, R. D.; Gualandi,
A.; Fiorelli, C.; Monari, M.; Savoia, D.; Zoli, L. Tetrahedron
2007, 63, 12446. (f) Amjad, M.; Knight, D. W. Tetrahedron
Lett. 2004, 45, 539. (g) Aillaud, I.; Bossharth, E.; Conreaux,
D.; Desbordes, P.; Monteiro, N.; Balme, G. Org. Lett. 2006,
8, 1113. (h) Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem.
2006, 71, 62.
(17) Majumdar, K. C.; Ansary, I.; Sinha, B.; Chattopadhyay, B.
Synthesis 2009, 3593.
(18) Compound 4a: A mixture of compound 3a (100 mg, 0.39
mmol), I2 (100 mg, 0.39 mmol), and anhyd NaHCO3 (33 mg,
0.39 mmol) was stirred in anhyd MeCN (10 mL) at r.t. for 6 h.
Then CH2Cl2 (50 mL) was added to the reaction mixture and
the organic phase was taken and washed successively with
10% aq sodium thiosulfate (20 mL), H2O (20 mL), brine (20
mL) and dried (Na2SO4). The solvent was removed under
reduced pressure and the crude product thus obtained was
purified by silica gel (230–400 mesh) column chroma-
tography (petroleum ether–EtOAc, 97:3) to give the
colorless gummy product 4a. Yield: 55%; IR (neat): 1710,
2927, 3066 cm–1; 1H NMR (400 MHz, CDCl3): d = 1.29 (s,
9 H), 2.21 (s, 3 H), 3.42 (d, J = 1.6 Hz, 1 H), 4.52 (d, J = 1.6
Hz, 1 H), 4.69 (s, 2 H), 6.78 (d, J = 8.8 Hz, 1 H), 7.18–7.20
(m, 2 H), 7.30 (dd, J = 8.4, 2.4 Hz, 1 H); 13C NMR (100
MHz, CDCl3): d = 24.8, 31.4, 34.3, 54.3, 63.2, 74.4, 82.1,
98.5, 111.7, 122.1, 123.6, 126.3, 144.8, 153.5, 204.6.
HRMS: m/z [M + K]+ calcd for C17H20I2O2: 548.9190;
found: 548.9190.
(12) (a) Bew, S. P.; Knight, D. W. J. Chem. Soc., Chem.
Commun. 1996, 1007. (b) El-Taeb, G. M. M.; Evans, A. B.;
Knight, D. W.; Jones, S. Tetrahedron Lett. 2001, 42, 5945.
(c) Sniady, A.; Wheeler, K. A.; Dembinski, R. Org. Lett.
2005, 7, 1769.
(19) Liu, W.; Zhou, S. Org. Lett. 2005, 7, 4609.
Synlett 2010, No. 9, 1407–1411 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.