Molecular iodine mediated cyclization reactions of 2-(1-alkynyl)benzylic alcohols to substituted indenones

Article abstract of DOI:10.1016/j.tetlet.2012.06.030

An efficient I₂-mediated approach to the synthesis of disubstituted indenones from readily available 2-alkynylbenzyl alcohols in the presence of H₂O has been developed. These results are different from the known iodocyclization react

Full text of DOI:10.1016/j.tetlet.2012.06.030

Tetrahedron Letters 53 (2012) 4402–4404
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Molecular iodine mediated cyclization reactions of 2-(1-alkynyl)benzylic
alcohols to substituted indenones
⇑
Chengyu Wang, Jingyu Yang, Xingcan Cheng, Ende Li, Yanzhong Li
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Institute of Medicinal Chemistry, Department of Chemistry, East China Normal University,
3663 North Zhongshan Road, Shanghai 200062, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient I2-mediated approach to the synthesis of disubstituted indenones from readily available 2-
alkynylbenzyl alcohols in the presence of H2O has been developed. These results are different from the
known iodocyclization reactions in which O-containing heterocycles are obtained.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 13 April 2012
Revised 4 June 2012
Accepted 8 June 2012
Available online 17 June 2012
Keywords:
2,3-Disubstituted indenones
Iodine-mediated reaction
2-(1-Alkynyl)benzylic alcohols
Cascade reactions
Molecular iodine has found wide utility in synthetic organic
chemistry,1 because it is a non-toxic, inexpensive and readily avail-
able reagent. Generally, it is utilized in effective iodocyclization
and cyclodehydroiodination reactions of tethered heteroatom-con-
taining alkynyl or alkenyl systems to heterocyclic compounds.
Many important heterocycles, such as furans,2 thiophenes,3 and
pyrroles4 etc,5 have been synthesized using this methodology.
For example, for the O-containing heterocycle formation, it is be-
lieved that the iodocyclization is realized by the nucleophilic attack
of the tethered oxygen atom to the activated alkyne moiety, and
the activation of the triple bond by molecular iodine is the key step
for the intramolecular cyclization (Scheme 1, Eq. 1). In the course
of our ongoing study on the development of new selective O-con-
taining heterocycle forming protocols,6 we found that 2-alkynylb-
enzyl alcohols7 could be efficiently converted into indenone
derivatives in the presence of iodine, which is in sharp contrast
to the known I2-mediated reactions (Scheme 1, Eq. 2). On the other
hand, indenone framework represents an important class of cyclic
molecules which are widely found in natural products,8 and sev-
eral efficient methodologies have been reported for the synthesis
of indenone derivatives.9 For example, metal-catalyzed annulation
of alkynes with o-halobenzaldehyde could be utilized as a facile
method for the synthesis of indenones.9b However, when unsym-
metrically substituted alkynes were employed, it usually afforded
a mixture of regioisomers. Thus the development of environmen-
tally friendly and less expensive protocols to indenones with
controllable substituent location is highly desirable. In this Letter,
we describe the I2-promoted cyclization of 2-alkynylbenzyl alco-
hols to indenone derivatives.
We began our investigation with (2-(hex-1-yn-1-yl)phenyl)
(phenyl) methanol (1a), which was synthesized according to the
reported method.7b The reaction of 1a in the presence of iodine
was selected as the prototypical case to screen the experimental
conditions. The results are shown in Table 1. When the reaction
was carried out using I2 (3 equiv) in THF at 50 °C, there is no forma-
tion of the iodocyclization product such as isochromene or iso-
benzofuran. Instead, an indenone derivative of 2a was produced
in 68% yield (Table 1, entry 1). However, 2a was contaminated with
small amount of byproduct, which was hard to purify. Changing
Known:
R1
R1
R1
O
I2/Base
OH
R2
O
and/or
(1)
(2)
iodocyclization
R2
I
I
R2
This work:
R1
R1
R1
O
+
I2/THF/H2O
OH
R2
R2
cyclization
H2O
Scheme 1.
R2
⇑
Corresponding author. Fax: +86 021 62233969.
E-mail address: yzli@chem.ecnu.edu.cn (Y. Li).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.030

C. Wang et al. / Tetrahedron Letters 53 (2012) 4402–4404
4403
Table 1
of water (THF/H2O = 30/1) gave the clean desired product in 77%
yield (Table 1, entry 4). Decreasing the amount of water gave the
similar result (Table 1, entry 5), while increasing the amount of
water afforded 2a in slightly lower yield with a prolonged reaction
time of 16 h (Table 1, entry 6). When 1.0 equiv of I2 was used in the
reaction, a much longer reaction time of 72 h was needed to afford
2a in 70% yield (Table 1, entry 7). ICl resulted a moderate yield
(49%) of 2a (Table 1, entry 11), and NIS gave no desired product
(Table 1, entry 12). The usage of dioxane instead of THF shortens
the reaction time but gave a lower yield of 64% (Table 1, entry
10). It was clear that the optimized reaction condition was to use
3.0 equiv of I2 as the reagent, a combined solvent (THF/H2O = 30/
1) at 50 °C (Table 1, entry 4).
With the optimal reaction conditions in hand, we next examined
the substrate scope of this new method for the synthesis of 2,3-
disubstituted indenones using a variety of 2-alkynylbenzylic alco-
hols 1 (Table 2). Firstly, we investigated the electronic effects of
the aromatic substituents on the benzylic carbon. It was found that
an electron-withdrawing (–Cl) aryl group afforded the correspond-
ing product 2b in 79% yield (Table 2, entry 2), even a strong elec-
tron-withdrawing like –CN aryl group gave good yield of the
indenone 2c (Table 2, entry 3). Electron-donating (–OMe) or
(–Me) aryl group resulted in 62% and 83% yields of the desired prod-
ucts, respectively, (Table 2, entries 4 and 5). Alkyl substituent as R1
such as methyl or benzyl also gave good results (Table 2, entries 6
and 7). Next, we investigated the substituent effect on the alkyne
terminus. When the triple bond substituted with a trimethylsilyl
Optimization studies for the formation of indenone 2a
OH
Ph
O
reagent
solvent
Ph
nBu
nBu
1a
2a
Entry Reagent
(equiv)
Solvent
THF
T (°C) Time
Yielda
(%)
(h)
1
2
3
4
5
6
7
8
9
I2 (3.0)
I2 (3.0)
I2 (30)
I2 (3.0)
I2 (3.0)
I2 (3.0)
I2 (10)
I2 (6.0)
I2 (5.0)
I2 (3.0)
50
70
50
50
50
50
50
rt
3
2
68b
—
Toluene
DCM
23
13
13
16
72
72
16
2
—
THF/H2O = 30/1
THF/H2O = 60/1
THF/H2O = 15/1
THF/H2O = 30/1
THF/H2O = 30/1
THF/H2O = 30/1
Dioxane/H2O = 30/
1
77
76
74
70
64
69
64
50
50
10
11
12
ICl (3.0)
NIS (3.0)
THF/H2O = 30/1
THF/H2O = 30/1
50
50
11
2
49
—
a
Isolated yield.
Containing small amount of byproduct.
b
the solvent to toluene or dichloromethane, no indenone formation
was observed (Table 1, entries 2 and 3). To our delight, the addition
Table 2
Synthesis of various 2,3-disubstituted indenones
Entry
Substrate
OH
R1
Conditiona
Time (h)
13
Product
Yieldb (%)
R1
O
nBu
1
1a: R1 = Ph
A
77
(2a)
nBu
2
3
4
5
6
7
R
1 = p-ClC6H4
1b
1c
1d
1e
1f
A
A
A
A
A
A
16
18
16
9
12
20
2b
2c
2d
2e
2f
79
66
62c
83
59
60
R1 = p-CNC6H4
R1 = p-MeOC6H4
R1 = p-MeC6H4
R1 = Me
R1 = Bn
1g
2g
OH
Ph
Ph
R2
8
1h: R2 = (CH2)2Ph
B
3
74
O (2h)
R2
9
10
11
12
R
2 = (CH2)2OBn
1i
1j
1k
1l
B
B
B
A
10
4
12
24
2i
45
R2 = TMS
R2 = tBu
R2 = Ph
2j (R2 = H)
58c
66d,e
40
2k
2l
OH
Ph
Ph
O
13
14
(1m)
(1n)
A
A
0.5
42
50
I
(3)
OH
Ph
Ph
O
MeO
MeO
MeO
MeO
nBu
9
(2n)
nBu
a
b
c
Condition A: 3.0 I2, 50 °C, THF:H2O = 30:1; condition B: 3.0 I2, 60 °C, dioxane:H2O = 30:1.
Isolated yield.
Dioxane:H2O = 15:1.
Dioxane:H2O = 60:1.
6.0 I2 was used.
d
e

4404
C. Wang et al. / Tetrahedron Letters 53 (2012) 4402–4404
Ph
Ph
O
Ph
50%NaBH4
Ph
1.0 BF3Et2O
Ph
CH3OH, 0 °C, 1h
CH2Cl2, rt, 20min
OH
2h
5h, 91%
4h
, 71%
Scheme 2.
group (1j) was employed, the I2-mediated reaction using THF and
H2O as solvent gave low yield of the corresponding desilylated
indenone product. Interestingly, the reaction took place smoothly
when dioxane was used instead of THF to give the corresponding
indenone in 58% yields (Table 2, entry 10). Substrate with a steri-
cally demanding substituent such as tert-butyl (1k) was also com-
patible under the reaction conditions, furnishing 2k in 66% yields
(Table 2, entry 11). The phenyl substituted 1l gave moderate yield
of 2l (Table 2, entry 12). It is worthy to note when substrate with
a cyclohexenyl group on the triple bond was employed, no desired
indenone but iodocyclization product 3 was obtained in moderate
yield (Table 2, entry 13). Substitution with bis-methoxy groups
on the parent phenyl ring gave 2n in 50% yield (Table 2, entry 14).
The utility of the thus formed indenone as useful synthetic
intermediate was investigated by simple reduction and Friedel-
Crafts reactions, which afforded tetracyclic compound 5h in good
yield under mild conditions (Scheme 2).
In conclusion, we have successfully developed an iodine medi-
ated efficient method for the synthesis of 2,3-disubstituted inde-
nones in the presence of H2O from 2-alkynylbenzyl alcohols, this
reaction is different from the reported iodocyclization reactions
which gave isochromene or isobenzofuran derivatives. Further
studies to make clear the reaction mechanism and applications of
this novel I2-mediated disubstituted indenone formation proce-
dure to extend the scope of synthetic utility of the reaction are un-
der progress in our group.
Supplementary data
Supplementary data (experimental details and spectroscopic
characterization of all new compounds) associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2012.06.030.
References and notes
1. For reviews, see: (a) Mphahlele, M. J. Molecules 2009, 14, 4814–4837; (b)
Mphahlele, M. J. Molecules 2009, 14, 5308–5322.
2. (a) Mancuso, R.; Mehta, S.; Gabriele, B.; Salerno, G.; Jenks, W. S.; Larock, R. C. J.
Org. Chem. 2010, 75, 897–901; (b) Liu, Y.; Zhou, S. Org. Lett. 2005, 7, 4609–4611;
(c) Liu, Y.; Song, F.; Cong, L. J. Org. Chem. 2005, 70, 6999–7002; (d) Chen, Z.;
Huang, G.; Jiang, H.; Huang, H.; Pan, X. J. Org. Chem. 2011, 76, 1134–1139.
3. (a) Flynn, B. L.; Flynn, G. P.; Hamel, E.; Jung, M. K. Bioorg. Med. Chem. Lett. 2001,
11, 2341–2343; (b) Ren, X. F.; Turos, E.; Lake, C. H.; Churchill, M. R. J. Org. Chem.
1995, 60, 6468–6483.
4. (a) Knight, D. W.; Redfern, A. L.; Gilmore, J. J. Chem. Soc., Perkin Trans. 1 2001,
2874–2883; (b) Knight, D. W.; Redfern, A. L.; Gilmore, J. J. Chem. Soc., Perkin
Trans. 1 2002, 622–628.
5. (a) Fischer, D.; Tomeba, H.; Pahadi, N. K.; Patil, N. T.; Yamamoto, Y. Angew. Chem.,
Int. Ed. 2007, 46, 4764–4766; (b) Kobayashi, K.; Hashimoto, K.; Shiokawa, T.;
Morikawa, O.; Konishi, H. Synthesis 2007, 6, 824–828; (c) Verma, A. K.; Aggarwal,
T.; Rustagi, V.; Larock, R. C. Chem. Commun. 2010, 46, 4064–4066; (d) Yue, D.;
Larock, R. C. Org. Lett. 2004, 6, 1037–1040; (e) Yue, D.; Ca, N. D.; Larock, R. C. J.
Org. Chem. 2006, 71, 3381–3388; (f) Yao, T.; Larock, R. C. J. Org. Chem. 2003, 68,
5936–5942; (g) Majumdar, K. C.; Sinha, B.; Ansary, I.; Chakravorty, S. Synlett
2010, 9, 1407–1411; (h) Shibahara, F.; Kitagawa, A.; Yamaguchi, E.; Murai, T.
Org. Lett. 2006, 8, 5621–5624.
6. (a) Xu, X.; Liu, J.; Liang, L.; Li, Y. Adv. Synth. Catal. 2009, 351, 2599–2604; (b) Li,
H.; Yang, J.; Liu, Y.; Li, Y. J. Org. Chem. 2009, 74, 6797–6801; (c) Xu, X.; Xu, X.; Li,
H.; Xie, X.; Li, Y. Org. Lett. 2010, 12, 100–103; (d) Yang, J.; Wang, C.; Xie, X.; Li, H.;
Li, E.; Li, Y. Org. Biomol. Chem. 2011, 9, 1342–1346.
7. For metal-catalyzed cyclization reactions of 2-alkynylbenzyl alcohols, see: (a)
Hashmi, A. S. K.; Schafer, S.; Wolfle, M.; Gil, C. D.; Fischer, P.; Laguna, A.; Blanco,
M. C.; Gimeno, M. C. Angew. Chem., Int. Ed. 2007, 46, 6184–6187; (b) Gabriele, B.;
Salerno, G.; Fazio, A.; Pittelli, R. Tetrahedron 2003, 59, 6251–6259.
8. (a) Ernst-Russell, M. A.; Chai, C. L. L.; Wardlaw, J. H.; Elix, J. A. J. Nat. Prod. 2000,
63, 129–131; (b) Lopes, L. M. X.; Yoshida, M.; Gottlieb, O. R. Phytochemistry 1984,
23, 2021–2024; (c) Anstead, G. M.; Ensign, J. L.; Peterson, C. S.;
Katzenellenbogen, J. A. J. Org. Chem. 1989, 54, 1485–1491.
9. (a) Larock, R. C.; Doty, M. J.; Cacchi, S. J. Org. Chem. 1993, 58, 4579–4583; (b)
Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106, 4644–4680. references cited therein;
(c) Miura, T.; Murakami, M. Org. Lett. 2005, 7, 3339–3341; (d) Tsukamoto, H.;
Kondo, Y. Org. Lett. 2007, 9, 4227–4230; (e) Morimoto, T.; Yamsaki, K.; Hirano,
A.; Tsutsumi, K.; Kagawa, N.; Kakiuchi, K.; Harada, Y.; Fukumoto, Y.; Chatani, N.;
Nishioka, T. Org. Lett. 2009, 11, 1777–1780; (f) Basavaiah, D.; Lenin, D. V. Eur. J.
Org. Chem. 2010 , 5650–5658. and references cited therein; (g) Dibe, D.; Toste, F.
D. J. Am. Chem. Soc. 2006, 128, 12062–12063; (h) Harada, Y.; Nakanishi, J.;
Fujihara, H.; Tobisu, M.; Fukumoto, Y.; Chatani, N. J. Am. Chem. Soc. 2007, 129,
5766–5771; (i) Kokubo, K.; Matsumasa, K.; Miura, M.; Nomura, M. J. Org. Chem.
1996, 61, 6941–6946; (j) Das, A.; Liao, H.-H.; Liu, R.-S. J. Org. Chem. 2007, 72,
9214–9218; (k) Pena, D.; Perez, D.; Guitian, E.; Castedo, L. Eur. J. Org. Chem. 2003,
1238–1243; (l) Alonso, D. A.; Najera, C.; Pacheco, M. C. Adv. Synth. Catal. 2002,
344, 172–183.
A typical procedure for the I2-mediated synthesis of 2-butyl-3-
phenyl-1H-inden-1-one (2a)9h
To a solution of (2-(hex-1-ynyl)phenyl)(phenyl)methanol (1a)
(132 mg, 0.5 mmol) in THF (3 mL) was added H2O (100 lL), I2
(381 mg, 1.5 mmol). The resulting solution was stirred at 50 °C
for 13 h. Then it was quenched with saturated Na2S2O3, extracted
with ethyl acetate, washed with saturated NaCl, and dried over
Na2SO4. The solvent was evaporated under reduced pressure and
the residue was purified by chromatography on silica gel to afford
2-butyl-3-phenyl-1H-inden-1-one (2a) (101 mg, 77%) as a yellow
oil. 1H NMR (300 MHz, CDCl3, Me4Si) d 0.84 (t, J = 7.2 Hz, 3H),
1.24–1.53 (m, 4H), 2.34 (t, J = 7.8 Hz, 2H), 6.98 (d, J = 7.2 Hz, 1H),
7.15–7.19 (m, 1H), 7.24–7.29 (m, 1H), 7.43–7.53 (m, 6H); 13C
NMR (75 MHz, CDCl3, Me4Si) d 13.69, 22.68, 22.94, 31.33, 120.38,
122.29, 127.68, 128.04, 128.65, 128.98, 130.89, 132.76, 133.06,
135.39, 145.78, 154.91, 198.24; HR-MS: m/z = 262.1356, Calcd for
C19H18O: 262.1358.
Acknowledgment
We are grateful to the National Natural Science Foundation of
China (No. 20872037) for financial support.