Selective synthesis of spiro[4,5]trienyl acetaes via an intramolecular electrophilic ipso-lodocyclization process

Article abstract of DOI:10.1021/ol703050z

A general and efficient intramolecular electrophilic ipso-iodocyclization of para-unactivated arylalkynes has been developed for the syntheses of spiro[4,5]trienyl acetaes. In the presence of NIS (N-iodosuccimide) and HOAC, para-unactivated arylalknes, including N-arylpropilamides and phenyln 3-phenylpropilate, underwent the intramolecular electrophilic ipso-iodocylization smoothly in moderate to good yields.

Full text of DOI:10.1021/ol703050z

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1063-1066
Selective Synthesis of Spiro[4,5]trienyl
Acetates via an Intramolecular
Electrophilic ipso-Iodocyclization
Process
Bo-Xiao Tang,† Dong-Jun Tang,† Shi Tang,†,‡ Quan-Fu Yu,† Yue-Hua Zhang,†
Yun Liang,† Ping Zhong,§ and Jin-Heng Li*,†,§
Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research,
Hunan Normal UniVersity, Changsha 410081, China, Technical Institute of Physics
and Chemistry, Chinese Academy of Scicence, Beijing 100080, China, and College of
Chemistry and Materials Science, Wenzhou UniVersity, Wenzhou 325035, China
jhli@hunnu.edu.cn
Received December 19, 2007
ABSTRACT
A general and efficient intramolecular electrophilic ipso-iodocyclization of para-unactivated arylalkynes has been developed for the synthesis
of spiro[4,5]trienyl acetates. In the presence of NIS (N-iodosuccimide) and HOAc, para-unactivated arylalkynes, including N-arylpropiolamides
and phenyl 3-phenylpropiolate, underwent the intramolecular electrophilic ipso-iodocyclization smoothly in moderate to good yields.
Electrophilic cylizations of arylalkynes have emerged as an
important topic in organic chemistry because their products,
heterocycles and carbocycles, have found widespread use
in the synthesis of natural and biologically active products.1,2
Currently, the vast majority of these electrophilic cyclization
methods are worked between alkyne and o-arene substitutions
to construct heterocycles and carbocycles.1 Recent work has
provided another novel route to these compounds by elec-
trophilic ipso-cyclization of arylalkynes (eq 1).2 In the
presence of halogen electrophiles, 4-(para-substituted aryl)-
1-alkynes underwent the electrophilic ipso-halocyclization
reaction smoothly to give azaspiro[4,5]trienones in good
yields. Unfortunately, the ipso-cyclization method is limited
to aryl compounds bearing some para substituents, such as
methoxy and N,N-dimethylamino groups, on the aryl rings.
Thus, alternative methods for the electrophilic ipso-cycliza-
tion of para-unactivated arylalkynes remain a challenging
task. After a series of trials, we were happy to find that
(1) For selected recent papers on the electrophilic iodocyclizations of
arylalkynes, see: (a) Zhang, X.; Campo, M. A.; Yao, T.; Larock, R. C.
Org. Lett. 2005, 7, 763-766. (b) Yao, T.; Larock, R. C. J. Org. Chem.
2005, 70, 1432-1437. (c) Yao, T.; Campo, M. A.; Larock, R. C. J. Org.
Chem. 2005, 70, 3511-3517. (d) Yue, D.; Yao, T.; Larock, R. C. J. Org.
Chem. 2005, 70, 10292-10296. (e) Yue, D.; Yao, T.; Larock, R. C. J.
Org. Chem. 2006, 71, 62-69. (f) Hu, T.; Liu, K.; Shen, M.; Yuan, X.;
Tang, Y.; Li, C. J. Org. Chem. 2007, 72, 8555-8558. (g) Pattarozzi, M.;
Zonta, C.; Broxterman, Q. B.; Kaptein, B.; De Zorzi, R.; Randaccio, L.;
Scrimin, P.; Licini, G. Org. Lett. 2007, 9, 2365-2368. (h) Worlikar, S. A.;
Kesharwani, T.; Yao, T.; Larock, R. C. J. Org. Chem. 2007, 72, 1347-
1353. (i) Ciochina, R.; Grossman, R. B. Chem. ReV. 2006, 106, 3963-
3986. (j) 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, 397-400. (k) Fischer, D.;
Tomeba, H.; Pahadi, N. K.; Patil, N. T.; Yamamoto, Y. Angew. Chem., Int.
Ed. 2007, 46, 4764-4766. (l) Barluenga, J.; Vazquez-Villa, H.; Ballesteros,
A.; Gonzalez, J. M. J. Am. Chem. Soc. 2003, 125, 9028-9029. (m)
Barluenga, J.; Vazquez-Villa, H.; Ballesteros, A.; Gonzalez, J. M. Org. Lett.
2003, 5, 4121-4123. (n) Barluenga, J.; Trincado, M.; Rubio, E.; Gonzalez,
J. M. Angew. Chem., Int. Ed. 2003, 42, 2406-2409. (o) Barluenga, J.;
Trincado, M.; Rubio, E.; Gonzalez, J. M. Angew. Chem., Int. Ed. 2006, 45,
3140-3143. (p) Barluenga, J.; Palomas, D.; Rubio, E.; Gonzalez, J. M.
Org. Lett. 2007, 9, 2823-2826.
† Hunan Normal University.
‡ Technical Institute of Physics and Chemistry.
§ Wenzhou University.
10.1021/ol703050z CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/15/2008

N-arylpropiolamides and phenyl 3-phenylpropiolate could
undergo the intramolecular electrophilic ipso-iodocycliza-
tion/nucleophilic addition process with NIS (N-iodosuccim-
ide) and HOAc to selectively afford spiro[4,5]trienyl ace-
tates in moderate to good yields (eq 2).3,4 This work now
presents the first examples for extending the electrophilic
ipso-cyclization of p-methoxyarylalkynes to para-unactivated
arylalkynes.
of NIS (entry 2). However, no desired ipso-cyclization
products were isolated in the presence of I2 (entry 3).
Subsequently, the temperature effect was investigated, and
it turned out that room temperature gave the better results
(entries 1 and 4). Although the reaction rate was enhanced
at 60 °C, the total yield was decreased. It is noteworthy that
no reaction is observed from the analogous amides with the
methyl group replaced by a hydrogen, acetyl, or allyl group
(entries 5-7). Finally, attempts at ipso-bromocyclization
reaction of amide 1a with NBS failed (entry 8).
N-Methyl-N,3-diphenylpropiolamide (1a) was chosen as
the starting substrate to screen the optimal reaction condi-
tions, and the results are summarized in Table 1. To our
Table 1. Screening Conditionsa
isolated yield (%)
These results prompted us to explore the scope of the
intramolecular ipso-iodocyclization reaction under the op-
timal conditions (Table 2). As shown in Table 2, a variety
entry
R
[I] (equiv) t (°C) time (h) cis-2
trans-3
1
2
3
4
5
6
7
8b
Me (1a)
Me (1a)
Me (1a)
Me (1a)
H (1b)
acetyl (1c) NIS (1.5)
allyl (1d) NIS (1.5)
Me (1a)
NIS (1.5)
ICl (1.5)
I2 (2.0)
NIS (1.5)
NIS (1.5)
25
25
25
60
25
25
25
3
3
3
0.6
3
43
38
trace
42
0
35
13
trace
18
0
0
0
0
Table 2. Intramolecular Electrophilic ipso-Iodocyclizations of
1 with NIS and HOAca
3
3
0
0
NBS (1.5) 25
3
0
a Reaction conditions: 1 (0.4 mmol) and HOAc (1 mL). b No bromo-
cyclization reaction was observed.
delight, the reaction of amide 1a with NIS in HOAc
proceeded selectively to afford the corresponding cis- and
trans-3-iodoazaspiro[4,5]trienyl acetates 2a in 43% and 35%
yields, respectively (entry 1).5 The yields of both cis- 2a
and trans-2a were reduced to some extent using ICl instead
isolated yield (%)
entry
R/R′
cis-2
50
trans-2
1
2
3
4
5
6
7
8
9
10
11
12
13
C6H5/2-Me (1e)
C6H5/3-Me (1f)
C6H5/2,5-diMe (1 g)
C6H5/2,3-diMe (1h)
C6H5/2-Cl (1i)
38
34
39
53
33
(2) (a) Appel, T. R.; Yehia, N. A. M.; Baumeister, U.; Hartung,
H.; Kluge, R.; Stro¨hl, D.; Fangha¨nel, E. Eur. J. Org. Chem. 2003, 47-53.
(b) Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2005, 127, 12230-
12231.
(3) For selected papers on the synthesis of the azaspiro[4,5]decane
skeleton by the intramolecular oxidative ipso-cyclization reactions of
aryls with nitrenium ions, see: (a) Miyazawa, E.; Sakamoto, T.;
Kikugawa, Y. J. Org. Chem. 2003, 68, 5429-5432. (b) Kikugawa, Y.;
Nagashima, A.; Sakamoto, T.; Miyazawa, E.; Shiiya, M. J. Org. Chem.
2003, 68, 6739-6744. (c) Dohi, T.; Maruyama, A.; Minamitsuji,
Y.; Takenaga, N.; Kita, Y. Chem. Commun. 2007, 1224-1226. (d)
Kawashima, T.; Naganuma, K.; Okazaki, R. Organometallics 1998, 17,
367-372.
(4) For selected papers on the synthesis of the spiro[4,5]decane skeleton
by the other methods, see: (a) Kende, A. S.; Koch, K. Tetrahedron Lett.
1986, 27, 6051-6054. (b) Haack, R. A.; Beck, K. R. Tetrahedron Lett.
1989, 30, 1605-1608. (c) Nagao, Y.; Lee, W. S.; Jeong, I.-Y.; Shiro, M.
Tetrahedron Lett. 1995, 36, 2799-2802. (d) Boyle, F. T.; Hares, O.;
Matusiak, Z. S.; Li, W.; Whiting, D. A. J. Chem. Soc., Perkin Trans. 1
1997, 2707-2711. (e) Blay, G.; Cardona, L.; Collado, A. M.; Garc´ıa, B.;
Morcillo, V.; Pedro, J. R. J. Org. Chem. 2004, 69, 7294-7302. (f) Pearson,
A. J.; Wang, X.; Dorange, I. B. Org. Lett. 2004, 6, 2535-2538. (g) Pigge,
F. C.; Coniglio, J. J.; Rath, N. P. Organometallics 2005, 24, 5424-5430.
(h) Pigge, F. C.; Coniglio, J. J.; Dalvi, R. J. Am. Chem. Soc. 2006, 128,
3498-3499.
48
30
48
50
C6H5/2-Br (1j)
C6H5/2-I (1k)
43
44
44
44
C6H5/2-CH3CO (1l)
4-MeC6H4/H (1 m)
4-MeOC6H4/H (1n)
4-MeCOC6H4/H (1o)
Me/H (1p)
trace
39
trace
35
47
18
trace
17
trace
45
H/H (1q)
trace
trace
a Reaction conditions: 1 (0.4 mmol), NIS (0.6 mmol), and HOAc (1
mL) at room temperature for 3 h.
of amides 1e-q were examined in the presence of NIS and
HOAc. The results demonstrated that several functional
groups, such as methyl, chloro, bromo, iodo, and methoxy
groups, on the aromatic ring of amides were tolerated well
under the standard conditions. First, a number of N-aryl
1064
Org. Lett., Vol. 10, No. 6, 2008

groups of the amides 1f-l were examined. We found that
N-methyl-N-aryl-3-phenylpropiolamides 1f-k, having electron-
donated groups on the N-aromatic ring, all work well with
NIS and HOAc, but amide 1l bearing an electron-withdraw-
ing group failed to generate the target ipso-iodocyclization
products. N-(2-Iodophenyl)-N-methyl-3-phenylpropiolamide
(1k), for instance, underwent the intramolecular ipso-
iodocyclization reaction with NIS and HOAc smoothly to
provide the cis- and trans-azaspiro[4,5]trienyl acetates 2k
in 44% and 44% yields, respectively (entry 7). However,
substrate 1l bearing a 2-acetyl group was not a suitable
substrate for the reaction. Subsequently, amides bearing some
substitutes at the terminal of alkyne were then investi-
gated. We found that amides 1m-n and 1p having the
4-methylphenyl, 4-methoxyphenyl or methyl group at the
terminal of alkyne, were treated with NIS and HOAc
smoothly in moderate to good yields (entries 9, 10, and 12),
whereas the reactions of substrates 1o and 1q, bearing an
4-acetylphenyl or a hydrogen group, was unsuccessful
(entries 11 and 13).
smoothly to afford the desired oxaspiro[4,5]trienyl acetate
2t in a good total yield (eq 5).
To elucidate the mechanism, a controlled reaction was
conducted under the standard conditions (Scheme 2). In the
Scheme 2. Two Controlled Reactions
presence of NIS and HOAc, a product identical to that in
previous papers2b was observed from the reaction of N-(4-
methoxyphenyl)-N-methyl-3-phenylpropiolamide (1u) with
NIS in HOAc.
A working mechanism as outlined in Scheme 3 was pro-
posed on the basis of the present results and the previously
As listed in Scheme 1, we were surprised to find that amide
1r, bearing an o-methoxy group on the N-aryl ring, could
also undergo the ipso-iodocyclization reaction with NIS in
Scheme 3. Working Mechanism
Scheme 1. ipso-Iodocyclization Reaction
reported mechanisms.1-3 Initially, the iodonium intermediate
A is generated by the interaction of the electrophilic NIS
with the alkyne moiety followed by the intramolecular
electrophilic ipso-cyclization of intermediate A to form
intermediate B.1,2 Finally, attack of intermediate B by the
nucleophilic HOAc occurs to afford both cis and trans
products 2.
In summary, we have developed a general and efficient
protocol for the intramolecular electrophilic ipso-cyclization
of para-unactivated arylalkynes. In the presence of NIS and
HOAc, N-arylpropiolamides and phenyl 3-phenylpropiolate
underwent the electrophilic ipso-cyclization reaction with
NIS followed by attack with HOAc to synthesize spiro[4,5]-
trienyl acetates in moderate to good yields. Importantly, we
have developed a novel route to the synthesis of new type
spiro[4,5]decane skeleton, and the known spiro[4,5]decane
skeleton is a prevalent motif in many naturally occurring
and biologically active compounds.6 Work to apply the
reaction in organic synthesis and develop more novel
intramolecular electrophilic ipso-cyclization processes is
currently underway.
HOAc smoothly to give N-methyl-3-phenyl-1-azaspiro[4,5]-
deca-3,6,8-trien-10-one (3r), not the target azaspiro[4,5]-
trienyl acetate 2r, in a 53% yield (eq 3). Subsequently, an
amine 1s and an ester 1t were also examined under the
standard conditions. Unfortunately, N-methyl-N-(3-phenyl-
prop-2-ynyl)benzenamine (1s) was observed to be an unsuit-
able substrate for the ipso-iodocyclization reaction under the
same conditions (eq 4). Note that the reaction of phenyl
3-phenylpropiolate (1t) with NIS and HOAc proceeds
(5) Interestingly, cis and trans isomers can be separated by flash column
chromatography using hexane/ethyl acetate as the eluent. The structure and
the cis and trans configuration of the products 2 were based upon the
chemical shift of the 8-proton by comparison with the authoritative data of
ref 2d and were unambiguously assigned by X-ray analysis of the product
cis-2i; see the Supporting Information.
Org. Lett., Vol. 10, No. 6, 2008
1065

Acknowledgment. We thank the Specialized Research
Fund for the Doctoral Program of Higher Education (No.
20060542007), National Natural Science Foundation of
China (No. 20572020), New Century Excellent Talents in
University (No. NCET-06-0711) and Fok Ying Tung Educa-
tion Foundation (No. 101012) for financial support.
(6) (a) Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.; Plavac, F.;
White, C. T. The Total Synthesis of Natural Products; Apsimon, J., Ed.;
Wiley-Interscience: New York, 1983; Vol. 5, pp 264-313. (b) Sakamoto,
K.; Tsujii, E.; Abe, F.; Nakanishi, T.; Yamashita, M.; Shigematsu, N.; Izumi,
S.; Okuhara, M. J. Antibiot. 1996, 49, 37-44. (c) Biard, J. F.; Guyot, S.;
Roussakis, C.; Verbist, J. F.; Vercauteren, J.; Weber, J. F.; Boukef, K.
Tetrahedron Lett. 1994, 35, 2691-2694. (d) Blackman, A. J.; Li, C.;
Hockless, D. C. R.; Skelton, B. W.; White, A. H. Tetrahedron 1993, 49,
8645-8656. (e) Du, Y.; Lu, X. J. Org. Chem. 2003, 68, 6463-6465 and
references cited therein. (f) Yoneda, K.; Yamagata, E.; Nakanishi, T.;
Nagashima, T.; Kawasaki, I.; Yoshida, T.; Mori, H.; Miura, I. Phytochem-
istry 1984, 23, 2068-2069. (g) Amagata, T.; Minoura, K.; Numata, A. J.
Nat. Prod. 2006, 69, 1384-1388.
Supporting Information Available: Analytical data and
spectra (1H and 13C NMR) for all products 2 and 3; typical
procedure for the intramolecular electrophilic ipso-iodocy-
clization reaction. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL703050Z
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Org. Lett., Vol. 10, No. 6, 2008