Electrophilic carbocyclization of aryl propargylic alcohols: A facile synthesis of diiodinated carbocycles and heterocycles

Article abstract of DOI:10.1021/ol1029194

Diiodinated carbocycles and oxygen heterocycles can be readily synthesized by electrophilic carbocyclization of aryl propargylic alcohols in moderate to good yields under mild conditions. The resulting diiodide can be further exploited by subsequent oxidi

Full text of DOI:10.1021/ol1029194

ORGANIC
LETTERS
2011
Vol. 13, No. 4
684–687
Electrophilic Carbocyclization of Aryl
Propargylic Alcohols: A Facile Synthesis
of Diiodinated Carbocycles and
Heterocycles
Hai-Tao Zhu, Ke-Gong Ji, Fang Yang, Li-Jing Wang, Shu-Chun Zhao, Shaukat Ali,
Xue-Yuan Liu, and Yong-Min Liang*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, and State Key
Laboratory of Solid Lubrication, Lanzhou Institute of Chemical Physics, Chinese
Academy of Science, Lanzhou 730000, P.R. China
liangym@lzu.edu.cn
Received December 2, 2010
ABSTRACT
Diiodinated carbocycles and oxygen heterocycles can be readily synthesized by electrophilic carbocyclization of aryl propargylic alcohols in
moderate to good yields under mild conditions. The resulting diiodide can be further exploited by subsequent oxidizing and coupling reactions.
Both the iodine anion and cation generated from I2 are used effectively. The presence of a trace amount of water is essential for this electrophilic
cyclization.
Recently, the intramolecular electrophilic cyclization of
nucleophiles, such as oxygen, nitrogen, sulfur, phosphorus,
and also sp2 or sp3 hybridized carbon, with alkynes has
proven to be an effective method for the synthesis of carbo-
cyclic and heterocyclic compounds.1-11 Many important
heterocycles and carbocycles, such as furans,1 benzo[b]-
furans,2 pyrroles,3 indoles,4 isoquinolines,5 quinolines,6
benzo[b]thiophenes,7 phosphaisocoumarins,8 naphthols,9
(1) (a) Kruglov, A. A. Zh. Obshch. Khim. 1937, 7, 2605. (b) Huang,
X.; Fu, W.; Miao, M. Tetrahedron Lett. 2008, 49, 2359. (c) Zhou, H.;
Yao, J.; Liu, G. Tetrahedron Lett. 2008, 49, 226. (d) Liu, Y.; Zhou, S.
Org. Lett. 2005, 7, 4609. (e) Bew, S. P.; Knight, D. W. J. Chem. Soc.,
Chem. Commun. 1996, 1007. (f) El-Taeb, G. M. M.; Evans, A. B.;
Knight, D. W.; Jones, S. Tetrahedron Lett. 2001, 42, 5945. (g) Sniady,
A.; Wheeler, K. A.; Dembinski, R. Org. Lett. 2005, 7, 1769. (h) Liu,
Y.-H.; Song, F.-J.; Cong, L. Q. J. Org. Chem. 2005, 70, 6999.
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Chem. 1999, 52, 767. (b) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.;
Moro, L. Synlett 1999, 1432. (c) Arcadi, A.; Cacchi, S.; Di Giuseppe, S.;
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Larock, R. C. J. Org. Chem. 2005, 70, 10292. (e) Mehta, S.; Waldo, J. P.;
Larock, R. C. J. Org. Chem. 2009, 74, 1141.
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Angew. Chem., Int. Ed. 2003, 42, 2406. (b) Amjad, M.; Knight, D. W.
Tetrahedron Lett. 2004, 45, 539. (c) Yue, D.; Larock, R. C. Org. Lett.
2004, 6, 1037.
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2973. (b) Huang, Q. H.; Hunter, J. A.; Larock, R. C. J. Org. Chem. 2002,
67, 3437. (c) Fischer, D.; Tomeba, H.; Pahadi, N. K.; Patil, N. T.; Huo,
Z.; Yamamoto, Y. J. Am. Chem. Soc. 2008, 130, 15720. (d) Yamamoto,
Y.; Gridnev, I. D.; Patil, N. T.; Jin, T. Chem. Commun. 2009, 5075.
(e) Fischer, D.; Tomeba, H.; Pahadi, N. K.; Patil, N. T.; Yamamoto, Y.
Angew. Chem., Int. Ed. 2007, 46, 4764. (f) Huo, Z.; Tomeba, H.;
Yamamoto, Y. Tetrahedron Lett. 2008, 49, 5531.
(3) (a) Yoshida, M.; Al-Amin, M.; Shishido, K. Tetrahedron Lett.
2009, 50, 6268. (b) Knight, D. W.; Redfern, A. L.; Gilmore, J. J. Chem.
Soc., Perkin Trans. 1 2001, 2874. (c) Knight, D. W.; Redfern, A. L.;
Gilmore, J. J. Chem. Soc., Perkin Trans. 1 2002, 622.
r
10.1021/ol1029194
Published on Web 01/20/2011
2011 American Chemical Society

naphthalenes,10 and indenes11 have been accessed using
this protocol. However, the electrophilic carbocyclization
with allenes has often been considered to be less attractive
due to the lack of efficient control of the regio- and stereo-
selectivity.12 Not long ago, Barluenga and co-workers re-
ported an interesting carbocyclization of allenes to haloge-
nated dihydronaphthalene in the presence of electrophiles.
But the use of expensive I(py)2BF4, and the relatively low
temperature make this approach a bit limited synthetically.13
Table 1. Optimization of the Electrophilic Cyclization of
1,3-Diphenylprop-2-yn-1-ola
entry
solvent
I2 (equiv)
time (h)
yield (%)b
1
2
CH3NO2
1.2
1.5
2.0
3.0
2.0
2.0
2.0
2.0
2.0
2.0
0.5
0.5
0.5
0.5
6.0
0.5
0.5
0.5
0.5
0.5
51
63
70
69
63
52
48
7
Scheme 1. Design of an Electrophile-Promoted Domino Process
CH3NO2
3
CH3NO2
4
CH3NO2
5
CH3NO2
6
CH2Cl2
7
CH3CN
8
ClCH2CH2Cl
1,4-dioxane
(CH3CH2)2O
9
nr
nr
1 0
a All reactions were run under the following conditions, unless
otherwise indicated: 0.3 mmol of 1a with 2.0 equiv of I2 in 5 mL of wet
CH3NO2 at room temperature. b nr = no reaction.
On the basis of our previous work, we have found that in
the presence of protons, substrate A loses a hydroxyl group
to afford the intermediate propargyl carbocations B. B, in
resonance with allene cation C, reacts with an iodide anion
to give D, which can be activated by an iodide cation
(Scheme 1a).14 We envisioned that aryl propargylic alcohols
could also undergo the same transformation in the presence
of iodine and then can cyclize to give diiodinated carbo-
cycles (Scheme 1 b). Herein, we report an effective method
for the synthesis of five- and six-membered carbocyclic rings
and seven-membered heterocyclic rings in the presence of I2.
Our initial study began with 1,3-diphenylprop-2-yn-1-ol
(1a) (0.3 mmol) and 1.2 equiv of I2 in wet CH3NO2 at room
temperature; to our delight, the desired product, 2,3-
diiodo-1-phenyl-1H-indene (2a), was isolated in 51% yield
after 0.5 h (Table 1, entry 1). On increasing the amount of
I2 to 1.5 equiv, a 63% yield of 2a was obtained after 0.5 h
(Table 1, entry 2). On further increasing the amountof I2 to
2.0equiv, a 70% yield of 2awas obtained(Table1, entry3).
Increasing the amounts of I2 to 3.0 equiv gave the slightly
decreased yield of 69% (entry 4). Prolonging the reaction
time to 6 h decreased the yield to 63% (entry 5). The study of
the influence of different reaction media showed that CH2Cl2,
ClCH2CH2Cl, and CH3CN were less effective (entries 6-8),
whereas 1,4-dioxane and diethyl ether proved to be ineffective
(entries 9 and 10). The optimum reaction conditions thus
developed are the following: 1.0 equiv of 1a and 2.0 equiv I2 in
CH3NO2 (5.0 mL) at room temperature.
Afterhaving establishedthe optimizedconditionsforthe
present reaction, various 1,3-diphenylprop-2-yn-1-ol deriv-
atives 1a-j were subjected to the above conditions, as de-
picted in Table 2. Thus, the tandem carbon-carbon bond
formations of 1,3-diphenylprop-2-yn-1-ol derivatives 1a-j
proceeded smoothly to provide the corresponding prod-
ucts 2a-j in moderate to good yields. The reaction could
tolerate various substituents on the aromatic R2 groups.
Electron-withdrawing aryl groups showed a bit better
result than those with electron-rich groups in this tandem
reaction (entries 2-6). Interestingly, substrates like 1h-j
with aliphatic groups also gave the corresponding 2,3-
diiodocarbocyclic compounds 2h-j in moderate yields.
Noteworthily, we also investigated the reaction of 5
mmol of 1a in the presence of 2.0 equiv of I2; the desired
product 2,3-diiodo-1-phenyl-1H-indene was obtained in
64% yield after 1 h. Furthermore, when using IBr as the
electrophilic reagent, substrates 1,3-diphenylprop-2-yn-1-ol (1a)
and 1-(4-methoxyphenyl)-3-phenylprop-2-yn-1-ol (1b) can also
afford the desired products 3-bromo-2-iodo-1-phenyl-1H-
indene (5a) and 3- bromo-2-iodo-1-(4-methoxyphenyl)-1H-
indene (5b) in 68% and 87% yield, respectively (Scheme 2).
(6) (a) Zhang, X.; Campo, M. A.; Yao, T.; Larock, R. C. Org. Lett.
2005, 7, 763. (b) Zhang, X.; Yao, T.; Campo, M. A.; Larock, R. C.
Tetrahedron 2010, 66, 1177. (c) Huo, Z.; Gridnev, I. D.; Yamamoto, Y.
J. Org. Chem. 2010, 75, 1266.
(7) (a) Flynn, B. L.; Verdier-Pinard, P.; Hamel, E. Org. Lett. 2001, 3,
651. (b) Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67, 1905. (c) Hessian,
K. O.; Flynn, B. L. Org. Lett. 2003, 5, 4377.
(8) (a) Peng, A. Y.; Ding, Y. X. Org. Lett. 2004, 6, 1119. (b) Peng,
A. Y.; Ding, Y. X. Tetrahedron 2005, 61, 10303.
(9) (a) Zhang, X.; Sarkar, S.; Larock, R. C. J. Org. Chem. 2006, 71,
236. (b) Barluenga, J.; Vazque-Villa, H.; Merino, I.; Ballesteros, A.;
Gonzalez, J. M. Chem.;Eur. J. 2006, 12, 5790.
(10) Barluenga, J.; Vazquez-Villa, H.; Ballesteros, A.; Gonzalez,
J. M. Org. Lett. 2003, 5, 4121.
(11) (a) Khan, Z. A.; Wirth, T. Org. Lett. 2009, 11, 229. (b) Bi, H.-P.;
Guo, L.-N.; Duan, X.-H.; Gou, F.-R.; Huang, S.-H.; Liu, X.-Y.; Liang,
Y.-M. Org. Lett. 2007, 9, 397.
(12) (a) Li, J.; Kong, W.; Yu, Y.; Fu, C.; Ma, S. J. Org. Chem. 2009,
74, 8733. (b) Ma, S. Acc. Chem. Res. 2009, 42, 1679. (c) Li, W.; Shi, M.
J. Org. Chem. 2008, 73, 6698.
(13) Barluenga, J.; Campos-Gomez, E.; Minatti, A.; Rodriguez, D.;
Gonzalez, J. M. Chem.;Eur. J. 2009, 15, 8946.
(14) (a) Ji, K.-G.; Zhu, H.-T.; Yang, F.; Shaukat, A.; Xia, X.-F.;
Yang, Y.-F.; Liu, X.-Y.; Liang, Y.-M. J. Org. Chem. 2010, 75, 5670.
(b) Ji, K.-G.; Shu, X.-Z.; Zhao, S.-C.; Zhu, H.-T.; Niu, Y.-N.; Liu,
X.-Y.; Liang, Y.-M. Org. Lett. 2009, 11, 3206. (c) Ji, K.-G.; Zhu, H.-T.;
Yang, F.; Shu, X.-Z.; Zhao, S.-C.; Shaukat, A.; Liu, X.-Y.; Liang, Y.-M.
Chem.;Eur. J. 2010, 16, 6151.
Org. Lett., Vol. 13, No. 4, 2011
685

Table 2. Synthesis of 2,3-Diiodophenylindenes 2 from 1,3-Di-
phenylprop-2-yn-1-ol Derivatives 1 a
Scheme 2. Synthesis of Funtionalized Indenes
a All reactions were run under the following conditions, unless
otherwise indicated: 0.3 mmol of 1 with 2.0 equiv of I2 in 5 mL of
CH3NO2 at room temperature. b Isolated yield. c The reaction was
carried out at 40 °C.
Table 3. Synthesis of 2,3-Diiodophenyldihydronaphthalene 3
from 1,4-Diphenylbut-2-yn-1-ol Derivatives 1a
To explore the scope of this carbocyclization further, we
also investigated a range of 1,4-diphenylbut-2-yn-1-ol deriv-
atives 1k-p. Substrates such as 1,4-diphenylbut-2-yn-1-ol
(1k) led to the desired product 2,3-diiodo-1-phenyl-1,4-
dihydronaphthalene (3k) in 78% yield under the optimized
condition (Table 3, entry 1). Substituted aryl propargylic
acohols 1l-p were also employed in the reaction, and the
corresponding six-membered ring products 3l-p were iso-
lated in moderate yields.
Seven-membered heterocyclic rings are important inter-
mediates for the synthesis of pharmaceuticals and biolog-
ically active molecules.15 Constructing seven-membered
rings through transition metal-catalyzed cyclizations has
been accessed.16 However, successful examples for the pre-
paration of polyoxacyclic ring systems induced by iodine
are rarely reported, possibly because of the disadvanta-
geous influence of both entropic and enthalpic factors, as
well as both electronic and steric effects. Thus, we designed
the reaction of substrate 4- phenoxy-1-phenylbut-2-yn-
1-ol (1q) in the presence of I2 to construct an important
entry
substrate
R1 = H, R2 = Ph
R1 = H, R2 = p-MeOC6H4
R1 = H, R2 = m-MeOC6H4
R1 = H, R2 = o-MeOC6H4
R1 = H, R2 = benzo[1,3]dioxole
R1 = H, R2 = p-ClC6H4
product
yield (%)b
1
2
3
4
5
6
3k
3l
78
57
48
61
75
52
3m
3n
3o
3p
a All reactions were run under the following conditions, unless
otherwise indicated: 0.3 mmol of 1 with 2.0 equiv of I2 in 5 mL CH3NO2
at room temperature. b Isolated yield.
polycyclic structure. To our delight, the desired product
3,4-diiodo-5-phenyl-2,5-dihydrobenzo[b]oxepine (4q) was
obtained in 57% yield at 80 °C (Table 4, entry 1). The
molecular structure of the representative product 4q was
determined by X-ray crystallography (Figure 1). Substi-
tuted phenoxyl substrates 1r and 1s led to desired products
4r and 4s in 58% and 72% yield, respectively. Substrates
such as 1u, 1v, and 1w, having p-chloro, p-methoxyphenyl,
and p-bromo substituents, produced 44%, 62%, and 54%
yields of seven-membered diiodinated oxacyclic com-
pounds, respectively.
(15) (a) Rujirawanich, J.; Gallagher, T. Org. Lett. 2009, 11, 5494.
(b) Batchelor, R.; Harvey, J. E.; Northcote, P. T.; Teesdale-Spittle, P.;
Hoberg, J. O. J. Org. Chem. 2009, 74, 7627. (c) Furuta, H.; Hasegawa,
Y.; Mori, Y. Org. Lett. 2009, 11, 4382. (d) Coulter, M. M.; Dornan,
P. K.; Dong, V. M. J. Am. Chem. Soc. 2009, 131, 6932. (e) Hashimoto,
T.; Naganawa, Y.; Maruoka, K. J. Am. Chem. Soc. 2009, 131, 6614.
(16) (a) Shin, S.; Gupta, A. K.; Rhim, C. Y.; Oh, C. H. Chem.
Commun. 2005, 4429. (b) Hildebrandt, D.; Huggenberg, W.; Kanthak,
M.; Ploger, T.; Muller, I. M.; Dyker, G. Chem. Commun. 2006, 2260.
(c) Kim, N.; Kim, Y.; Park, W.; Sung, D.; Gupta, A. K.; Oh, C. H. Org.
Lett. 2005, 7, 5289. (d) Padwa, A.; Fryxell, G. E.; Zhi, L. J. Am. Chem.
Soc. 1990, 118, 3100. (e) Feldman, K. S. Tetrahedron Lett. 1983, 24,
5585.
Our study has also shown that the dihydronaphthalene
3k can be oxidized to 2,3-diiodo-1-phenylnaphthalene
(5k) by 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in
686
Org. Lett., Vol. 13, No. 4, 2011

various palladium-catalyzed processes. For example, the
Sonagashira coupling of 2,3-diiodo-1-phenylnaphthalene
(5k) afforded the corresponding product 2,3-bis((4-methoxy-
phenyl)ethynyl)-1-phenylnaphthalene (6k), which may find
utility as fluorescent materials, in 49% yield (Scheme 3).
Table 4. Synthesis of 3,4-Diiodophenyldihydrobenzo[b]-
oxepines 4 from 4-Phenoxy-1-phenylbut-2-yn-1-ol Derivatives 1a
Scheme 3. Palladium-Catalyzed Sonogashira Coupling
Reaction
a All reactions were run under the following conditions, unless other-
wise indicated: 0.3 mmol of 1 with 2.0 equiv of I2 in 5 mL of CH3NO2 at
80 °C. b Isolated yield.
93% yield after 18 h. A standard feature of this process is
the fact that the dihalogenated carbocyclic compounds pro-
duced by iodocyclization can be further exploited by using
In conclusion, an efficient synthesis of substituted diha-
logenated 1H-indenes, dihydronaphthalenes, anddihydro-
benzo[b]oxepines in moderate yields from simple aryl pro-
pargylic alcohols under mild reaction conditions has been
developed. The dihalogenated moiety can be readily in-
troduced into the carbocycle and heterocycle in a position
not easily obtained previously. The resulting diiodinated
products can be used toprepare more complex products by
using known organopalladium chemistry. In this reaction,
both halogen atoms, such as I and Br, are used effectively
and trace amounts of water are necessary. Further studies
on electrophilic cyclizations of propargylic alcohols are in
progress in our laboratory.
Acknowledgment. We thank the National Science Foun-
dation (NSF-21072080) for financial support. We acknowl-
edge National Basic Research Program of China (973
Program) 2010CB833203.
Supporting Information Available. Detailed experimen-
1
tal procedure and copies of H NMR and 13C NMR
spectra of all compounds and X-ray data of 4q in CIF
format. This material is available free of charge via the
Internet at http://pubs.acs.org.
Figure 1. Structure of 4q.
Org. Lett., Vol. 13, No. 4, 2011
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