Electrophilic ipso-iodocyclization of N-(4-methylphenyl)propiolamides: Selective synthesis of 8-methyleneazaspiro[4,5]trienes

Article abstract of DOI:10.1021/jo800328a

(Chemical Equation Presented) A novel and selective method for the synthesis of 8-methylenespiro[4,5]trienes via intramolecular electrophilic ipso-iodocyclization of N-(4-methylphenyl)propiolamides has been developed. In the presence of ICl or I₂, 8-methylene-1-azaspiro[4,5]trienes were selectively prepared from the electrophilic ipso-iodocyclization of N-(4-methylphenyl)propiolamides in moderate to good yields.

Full text of DOI:10.1021/jo800328a

SCHEME 1
Electrophilic ipso-Iodocyclization of
N-(4-Methylphenyl)propiolamides: Selective
Synthesis of 8-Methyleneazaspiro[4,5]trienes
Quan-Fu Yu,† Yue-Hua Zhang,† Qin Yin,† Bo-Xiao Tang,†
Ri-Yuan Tang,‡ Ping Zhong,‡ and Jin-Heng Li*,†,‡
Key Laboratory of Chemical Biology & Traditional Chinese
Medicine Research (Ministry of Education), College of
Chemistry and Chemical Engineering, Hunan Normal
UniVersity, Changsha 410081, China, and College of
Chemistry and Materials Science, Wenzhou UniVersity,
Wenzhou 325035, China
N-methoxy-(4-substituted aryl)amides2a or N-phthalimido-3,4-
(4-halophenyl)propanamides,2b underwent the intramolecular
oxidative ipso-cyclization reactions to selectively give 1-
azaspiro[4,5]decanes in moderate to good yields. Recently, the
Fangha¨nel group3a and the Larock group3b independently de-
veloped another novel route to synthesize the spiro[4,5]trienones
by the intramolecular electrophilic ipso-cyclization of 4-(4-
methoxyaryl)-1-alkynes using ICl or I2/NaHCO3 system (eq 1
in Scheme 1). To the best of our knowledge, a methyl group as
an active para-group for the ipso-cyclization reaction still
remains an unexplored area. Here, we wish to report that 4-(p-
methylaryl)-1-alkynes could undergo the intramolecular ipso-
iodocyclization process with ICl or I2 to afford the corresponding
8-methylene-1-azaspiro[4,5]trienes in moderate to good yields
(eq 2).4
jhli@hunnu.edu.cn
ReceiVed February 12, 2008
A novel and selective method for the synthesis of 8-meth-
ylenespiro[4,5]trienes via intramolecular electrophilic ipso-
iodocyclization of N-(4-methylphenyl)propiolamides has
been developed. In the presence of ICl or I2, 8-methylene-
1-azaspiro[4,5]trienes were selectively prepared from the
electrophilic ipso-iodocyclization of N-(4-methylphenyl)pro-
piolamides in moderate to good yields.
The reactions of N-methyl-3-phenyl-N-p-tolylpropiolamide
(1a) with iodine reagents were conducted to screen the optimal
reaction conditions, and the results are summarized in Table 1.
No reaction was observed when amide 1a was treated with ICl
in MeCN at -78 °C (entry 1). To our delight, the target product
(2) For selected papers on the synthesis of the spiro[4,5]decane skeleton by
the intramolecular oxidative ipso-cyclization reactions of nitrenium ions, see:
(a) Kawashima, T.; Naganuma, K.; Okazaki, R. Organometallics 1998, 17, 376–
372. (b) Wardrop, D. J.; Basak, A. Org. Lett. 2001, 3, 1053–1056. (c) Miyazawa,
E.; Sakamoto, T.; Kikugawa, Y. J. Org. Chem. 2003, 68, 5429–5432. (d)
Kikugawa, Y.; Nagashima, A.; Sakamoto, T.; Miyazawa, E.; Shiiya, M. J. Org.
Chem. 2003, 68, 6739–6744. (e) Wardrop, D. J.; Landrie, C. L.; Ort´ız, J. A.
Synlett 2003, 1352–1354. (f) Wardrop, D. J.; Burge, M. S. J. Org. Chem. 2005,
70, 10271–10284. (g) Dohi, T.; Maruyama, A.; Minamitsuji, Y.; Takenaga, N.;
Kita, Y. Chem. Commun. 2007, 1224–1226.
The spiro[4,5]decane compounds are valuably synthetic
intermediates as well as prevalently structural units in many
naturally occurring and biologically active compounds.1 The
majorityofmethodsfortheselectivesynthesisofspiro[4,5]decanes
include the oxidative ipso-cyclization reactions of the corre-
sponding aryl nitrenium ions bearing an active para-group, such
as methoxy, hydroxyl, dimethylamino, or halo groups, by
hypervalent iodides.2–5 Kikugawa and co-workers, for example,
have reported that in the presence of hypervalent iodides a
variety of aryl nitrenium ions bearing methoxy, fluoro, chloro,
and bromo at the 4-position of the aromatic ring, such as
(3) (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.
(4) We have also developed a general and selective protocol for the synthesis
of spiro[4,5]trienyl acetates via an intramolecular electrophilic ipso-cyclization
of N-arylpropiolamides with NIS and HOAc, in which no active substitutes at
the para-position of the N-aryl ring were required; see: Tang, B.-X.; Tang, D.-
J.; Tang, S.; Yu, Q.-F.; Zhang, Y.-H.; Liang, Y.; Zhong, P. Org. Lett. 2008, 10,
1063–1066.
(5) For selected papers on the synthesis of the spiro[4,5]decane skeleton by
the other ipso-cyclization 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. (i) Zhdankin, V. V.; Stang, P. J.
Chem. ReV. 2002, 102, 2523–2584. (j) Wang, Z.; Xi, Z. Synlett 2006, 1275–
1277. (k) Liu, L.; Wang, Z.; Zhao, F.; Xi, Z. J. Org. Chem. 2007, 72, 3484–
3491.
† Hunan Normal University.
‡ Wenzhou University.
(1) Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.; Plavac, F.; White, C. T.
In The Total Synthesis of Natural Products; Apsimon, J., Ed.; Wiley-Interscience:
New York, 1983; Vol. 5, 264-313. (b) Yoneda, K.; Yamagata, E.; Nakanishi,
T.; Nagashima, T.; Kawasaki, I.; Yoshida, T.; Mori, H.; Miura, I. Phytochemistry
1984, 23, 2068–2069. (c) Sakamoto, K.; Tsujii, E.; Abe, F.; Nakanishi, T.;
Yamashita, M.; Shigematsu, N.; Izumi, S.; Okuhara, M. J. Antibiot. 1996, 49,
37–44. (d) Biard, J. F.; Guyot, S.; Roussakis, C.; Verbist, J. F.; Vercauteren, J.;
Weber, J. F.; Boukef, K. Tetrahedron Lett. 1994, 35, 2691–2694. (e) Blackman,
A. J.; Li, C.; Hockless, D. C. R.; Skelton, B. W.; White, A. H. Tetrahedron
1993, 49, 8645–8656. (f) Du, Y.; Lu, X. J. Org. Chem. 2003, 68, 6463–6465.
(g) Amagata, T.; Minoura, K.; Numata, A. J. Nat. Prod. 2006, 69, 1384–1388.
(h) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748–
8758.
3658 J. Org. Chem. 2008, 73, 3658–3661
10.1021/jo800328a CCC: $40.75 2008 American Chemical Society
Published on Web 04/01/2008

TABLE 1. Screening Optimal Conditionsa
treated with I2 afforded only 11% yield of the target product
2i, and with ICl did not work (entries 7 and 8). Similar results
were obtained using terminal alkyne 1n as the substrate (entries
13 and 14). To our delight, substrates bearing a methyl, electron-
withdrawing aryl, or electron-neutral aryl group at the terminal
of the Ct C bond of propiolamide all worked well with ICl or
I2 in moderate to good yields (entries 15-19). Unfortunately,
attempts at the electrophilic ipso-cyclization of amide 1s, having
an electron-donating aryl group at the terminal of propiolamide,
with either ICl or I2 failed (entries 20 and 21). The electrophilic
ipso-cyclization of N-(4-butylphenyl)-N-methyl-3-phenylpropi-
olamide (1t) with ICl also proceeded successfully in a 65%
yield, but the reaction of 1t with I2 provided a low yield (entries
22 and 23).
Other substrates, including amides 1u-v, amine 1w, and ester
1x, were further explored under the standard conditions, and
the results are summarized in Scheme 2. The results revealed
that 4-(p-methoxyaryl)-1-alkyne 1u was a suitable substrate to
undergo the electrophilic ipso-cyclization reaction with ICl or
I2 to give N-methyl-3-iodo-4-phenyl-1-azaspiro[4,5]-deca-3,6,9-
trien-8-one (2u) in good yields, which is similar to those of
Larock’s results (eq 3 in Scheme 2).3a However, N-methyl-3-
phenyl-N-o-tolylpropiolamide (1v) reacted with either ICl or I2
and afforded an ortho-cyclized product 3v, not the target ipso-
cyclized product (eq 4 in Scheme 2). Unfortunately, both amine
1w and ester 1x were found to be unsuitable substrates for
the reaction under the standard conditions (eqs 5 and 6 in in
Scheme 2).6
entry
R
[I]
H2O (mL)
t (°C)
-78
-25 to rt
time (h) yield (%)b
1
2
3
4
Me (1a) ICl
Me (1a) ICl
Me (1a) ICl
Me (1a) ICl
Me (1a) I2
Me (1a) I2
Me (1a) I2
Me (1a) NIS
s
s
1
1
1
0 (2a)
63 (2a)
81 (2a)
33 (2a)
88 (2a)
89 (2a)
48 (2a)
0 (2a)
trace (2a)
NR (2b)
trace (2b)
NR (2c)
trace (2c)
NR (2d)
48 (2d)
H2O (0.1) -25 to rt
H2O (0.3) -25 to rt
s
H2O (0.1) rt
s
s
1
5
rt
24
24
24
24
24
1
6
7c
8
rt
rt
9
Me (1a) NaIO H2O (0.1) rt
10
11
12
13
14
15
H (1b)
H (1b)
Ac (1c) ICl
Ac (1c) I2
Bn (1d) ICl
Bn (1d) I2
ICl
I2
H2O (0.1) -25 to rt
rt
H2O (0.1) -25 to rt
rt
H2O (0.1) -25 to rt
rt
s
24
1
24
1
s
s
24
a Reaction conditions: 1 (0.3 mmol), ICl (1.5 equiv) or I2 (2 equiv),
H2O and MeCN (3 mL). NR ) no reaction. b Isolated yield. c NaHCO3
(2 equiv) was added.
2a could be isolated in a 63% yield from the reaction of amide
1a with ICl at -25 °C for 0.5 h and then heating to room
temperature for another 0.5 h (entry 2). We found that the
amount of water affected the reaction to some extent. The yield
of 2a was enhanced to 81% in the presence of 0.1 mL of water,
whereas 0.2 mL of water provided only a 33% yield (entries 3
and 4). The results demonstrated that I2 was highly efficient
for the reaction with amide 1a to afford the desired product 2a
in an 88% yield at room temperature (entry 5), and identical
results were observed in the presence of 0.1 mL of H2O (entry
6). However, the yield of 2a was reduced to 48% in the presence
of NaHCO3 (entry 7; Larock’s conditions). No reaction was
observed at room temperature using NIS or NaIO as the iodine
source (entries 8 and 9).4 It was found that analogous amides
with the methyl group replaced by a hydrogen or an acyl group
were not suitable substrates for the reaction in the presence of
either I2 or ICl (entries 10-13). Identical results were observed
from the reaction of N-benzyl-3-phenyl-N-p-tolylpropiolamide
(1d) with ICl (entry 14). Gratifyingly, a 48% yield of the target
product 2d was isolated when amide 1d was treated with I2
(entry 15).
As listed in Table 2, a variety of N-methyl-p-tolylpropiola-
mides 1e-s were evaluated to explore the scope of the
electrophilic ipso-cyclization reaction under the standard condi-
tions. The results demonstrated that both the electronic effect
and the steric effect affected the reaction to some extent.
Initially, substitutes on the aromatic ring of the N-p-tolyl group
were tested. We found that a series of functional substitutes,
such as methyl, chloro, or bromo groups, were tolerated well.
N-(2-Bromo-4-methylphenyl)-N-methyl-3-phenylpropiola-
mide (1g), for instance, underwent the reaction with I2 smoothly,
providing a 91% yield (entry 4). Amide 1h, a bulky substrate,
was also reacted with ICl to afford the corresponding product
1h in quantitative yield, but with I2 gave only 40% yield (entries
5 and 6). Subsequently, substitutes at the terminal of the Ct C
bond of N-methyl-p-tolylpropiolamides were evaluated. The
results showed that terminal alkynes 1i and 1n were not suitable
for the reaction under the standard conditions. Substrate 1i
A working mechanism as outlined in Scheme 3 for the
electrophilic ipso-cyclization reaction is proposed on the basis
of the present results and the previously reported mechanisms.2,3,7
The iodonium intermediate A is readily generated by the
interaction of the electrophilic iodine reagent (ICl or I2) with
the alkyne moiety followed by the intramolecular ipso-electro-
philic cyclization reaction of intermediate A to form intermediate
B.2,3,6 Among the possible transition states of intermediate B,
intermediate C is the most stable transition state. Finally,
intermediate C undergoes the ꢀ-H elimination process to yield
the corresponding product 2.
In summary, we have developed a novel intramolecular
electrophilic ipso-cyclization reaction method for the synthesis
of 8-methyleneazaspiro[4,5]trienes. In the presence of ICl or
I2, a variety of N-(4-methylphenyl)propiolamides successfully
(6) For selected recent papers on the electrophilic iodocyclizations of alkynes,
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.
(7) The two reactions of amine 1w and ester 1x were determined by GC-
MS analysis. The results showed that no products were observed from the reaction
of 1w, but 1,2-diiodoalkene (p-tolyl 2,3-diiodo-3-phenylacrylate) was detected
from the reaction of 1x. Thus, we deduced that the electronic effect of the
substrates plays a crucial role in the reaction.
J. Org. Chem. Vol. 73, No. 9, 2008 3659

TABLE 2. Electrophilic ipso-Iodocyclization of N-Arypropiolamides (1)a,b
a Conditions A: 1 (0.3 mmol), MeCN (3 mL), ICl (1.5 equiv), and H2O (0.1 mL) at -25 °C (0.5 h) to room temperature (0.5 h). Conditions B: 1 (0.3
mmol), MeCN (3 mL), and I2 (2 equiv) at room temperature for 24 h. NR ) no reaction. b Isolated yield.
3660 J. Org. Chem. Vol. 73, No. 9, 2008

SCHEME 2. The ipso-Cyclization of Other Substratesa
products. Efforts to study the detailed mechanism and extend
the application of the ipso-cyclization transformations in organic
synthesis are underway in our laboratory.
Experimental Section
Typical Experimental Procedure for the ipso-Electrophilic
Cyclization of N-(4-Methylpheny)propiolamides with ICl: A
mixture of N-(4-methylaryl)propiolamides 1 (0.3 mmol), ICl (1.5
equiv), and H2O (0.1 mL) in MeCN (3 mL) was stirred at -25 °C
(0.5 h) to room temperature (0.5 h) until complete consumption of
starting material as monitored by TLC and GC analysis. Then the
mixture was washed with saturated NaS2O3 and extracted with
diethyl ether. The organic layers were dried with Na2SO3 and
evaporated under vacuum, and the residue was purified by flash
column chromatography to afford the pure product (hexane/ethyl
acetate).
Typical Experimental Procedure for the ipso-Electrophilic
Cyclization of N-(4-Methylphenyl)propiolamides with I2: A
mixture of N-(4-methylaryl)propiolamides 1 (0.3 mmol) and I2 (2
equiv) in MeCN (3 mL) and/or H2O (0.1 mL) was stirred at room
temperature for 24 h until complete consumption of starting material
as monitored by TLC and GC analysis. Then the mixture was
washed with saturated NaS2O3 and extracted with diethyl ether.
The organic layers were dried with Na2SO3 and evaporated under
vacuum, and the residue was purified by flash column chromatog-
raphy to afford the pure product (hexane/ethyl acetate).
a Conditions A: 1 (0.3 mmol), MeCN (3 mL), ICl (1.5 equiv), and H2O
(0.1 mL) at -25 °C (0.5 h) to room temperature (0.5 h). Conditions B: 1
(0.3 mmol), MeCN (3 mL), and I2 (2 equiv) at room temperature for 24 h.
N-Methyl 3-Iodo-4-phenyl-8-methylenespiro[4,5]triene (2a): Pale
1
yellow solid, mp 177.6-178.8 °C (uncorrected); H NMR (400
MHz) δ 7.47 (d, J ) 8.0 Hz, 2H), 7.36 (d, J ) 6.8 Hz, 3H), 6.58
(d, J ) 9.6 Hz, 2H), 5.44 (d, J ) 9.6 Hz, 2H), 5.20 (s, 2H), 2.87
(s, 3H); 13C NMR (100 MHz) δ 167.0, 162.2, 134.9, 133.3, 132.2,
SCHEME 3. A Working Mechanism
129.4, 128.3, 128.0, 126.1, 119.7, 96.0, 70.9, 26.4; IR (KBr, cm-1
)
1699, 1637, 1588; LRMS (EI, 70 eV) m/z (%) 375 (M+, 10), 248
(88), 129 (100); HRMS (EI) for C17H14INO (M+) calcd 375.0120,
found 375.0120.
Acknowledgment. We thank the Specialized Research Fund
fortheDoctoralProgramofHigherEducation(No.20060542007),
New Century Excellent Talents in University (No. NCET-06-
0711), and the National Natural Science Foundation of China
(No. 20572020) for financial support.
Supporting Information Available: General experimental
procedures, compounds 2 and 3v characterization data, and
copies of spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
underwent the electrophilic ipso-iodocyclization reaction to
selectively prepare 4-methyleneazaspiro[4,5]trienes in moderate
to excellent yields. Moreover, both an iodo and a methylene
group on these products provides an attractive and useful route
to introduce new groups for the synthesis of new bioactive
JO800328A
J. Org. Chem. Vol. 73, No. 9, 2008 3661