Electrophilic ipso-cyclization of N-(p-methoxyaryl)propiolamides involving an electrophile-exchange process

Article abstract of DOI:10.1021/jo8018297

(Chemical Equation Presented) A novel electrophilic ipso-cyclization involving an electrophile-exchange process has been developed. In the presence of CuX (X = I, Br, SCN) and electrophilic fluoride reagents, a variety of N-(p-methoxyaryl)propiolamides an

Full text of DOI:10.1021/jo8018297

Electrophilic ipso-Cyclization of N-(p-Methoxyaryl)propiolamides
Involving an Electrophile-Exchange Process
Bo-Xiao Tang,† Qin Yin,† Ri-Yuan Tang,‡ and Jin-Heng Li*,†,‡
Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research, Hunan Normal
UniVersity, Changsha 410081, China, and College of Chemistry and Materials Science, Wenzhou
UniVersity, Wenzhou 325035, China
jhli@hunnu.edu.cn
ReceiVed August 15, 2008
A novel electrophilic ipso-cyclization involving an electrophile-exchange process has been developed.
In the presence of CuX (X ) I, Br, SCN) and electrophilic fluoride reagents, a variety of
N-(p-methoxyaryl)propiolamides and 4-methoxyphenyl 3-phenylpropiolate were cyclized to selectively
afford the corresponding spiro[4.5]decenones in moderate to good yields. It is noteworthy that two
azaquaternary tricyclic products were synthesized through a two-step pathway involving an electrophilic
ipso-cyclization and then an intramolecular Heck reaction.
Introduction
method is worked via two pathways: (1) between a alkyne and
an o-arene substitute to construct benzo-heterocycle and benzo-
carbocycle compounds,1,2 and (2) between a alkyne and an ipso-
arene substitute to construct spirocycle compounds.3 However,
only four papers have been reported on the electrophilic
cyclization by the latter pathway.3 Moreover, the electrophiles
are limited to halogens, such as ICl, I2, NIS (N-iodosuccimide),
and Br2, in all cases. In the presence of halogen electrophiles,
4-(p-substituted aryl)-1-alkynes underwent the electrophilic ipso-
Recently, the electrophilic cyclization method has been proven
to be a powerful tool for the synthesis of highly functionalized
heterocyclic and carbocyclic compounds.1-3 Generally, the
† Hunan Normal University.
‡ Wenzhou University.
(1) For reviews, see: (a) Frederickson, M.; Grigg, R. Org. Prep. Proced.
Int. 1997, 29, 33. (b) Frederickson, M.; Grigg, R. Org. Prep. Proced. Int. 1997,
29, 63. (c) Martins da Silva, F.; Jones, J., Jr.; De Mattos, M. C. S. Curr. Org.
Synth. 2005, 2, 393.
(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. (b) Zhang, X.; Larock,
R. C. J. Am. Chem. Soc. 2005, 127, 12230. (c) Yu, Q.-F.; Zhang, Y.-H.; Yin,
Q.; Tang, B.-X.; Tang, R.-Y.; Zhong, P.; Li, J.-H. J. Org. Chem. 2008, 73, 3658.
(d) Tang, B.-X.; Tang, D.-J.; Tang, S.; Yu, Q.-F.; Zhang, Y.-H.; Liang, Y.; Zhong,
P.; Li, J.-H. Org. Lett. 2008, 10, 1063.
(4) (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) Hesse, M. Alkaloide,
Verlag Helvetica Chimica Acta: Zu¨rich, Switzerland, 2000. (c) Yoneda, K.;
Yamagata, E.; Nakanishi, T.; Nagashima, T.; Kawasaki, I.; Yoshida, T.; Mori,
H.; Miura, I. Phytochemistry 1984, 23, 2068. (d) Sakamoto, K.; Tsujii, E.; Abe,
F.; Nakanishi, T.; Yamashita, M.; Shigematsu, N.; Izumi, S.; Okuhara, M. J.
Antibiot. 1996, 49, 37. (e) Biard, J. F.; Guyot, S.; Roussakis, C.; Verbist, J. F.;
Vercauteren, J.; Weber, J. F.; Boukef, K. Tetrahedron Lett. 1994, 35, 2691. (f)
Blackman, A. J.; Li, C.; Hockless, D. C. R.; Skelton, B. W.; White, A. H.
Tetrahedron 1993, 49, 8645. (g) Du, Y.; Lu, X. J. Org. Chem. 2003, 68, 6463,
and references cited therein. (h) Amagata, T.; Minoura, K.; Numata, A. J. Nat.
Prod. 2006, 69, 1384. (i) Greger, H. Planta Med. 2006, 72, 99. (j) Zhao, Y.-M.;
Gu, P.; Tu, Y.-Q.; Fan, C.-A.; Zhang, Q. Org. Lett. 2008, 10, 1763, and references
cited therein.
(2) For selected papers on the electrophilic iodocyclizations of alkynes, see:
(a) Zhang, X.; Campo, M. A.; Yao, T.; Larock, R. C. Org. Lett. 2005, 7, 763.
(b) Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 1432. (c) Yao, T.; Campo,
M. A.; Larock, R. C. J. Org. Chem. 2005, 70, 3511. (d) Yue, D.; Yao, T.; Larock,
R. C. J. Org. Chem. 2005, 70, 10292. (e) Yue, D.; Yao, T.; Larock, R. C. J.
Org. Chem. 2006, 71, 62. (f) Hu, T.; Liu, K.; Shen, M.; Yuan, X.; Tang, Y.; Li,
C. J. Org. Chem. 2007, 72, 8555. (g) Pattarozzi, M.; Zonta, C.; Broxterman,
Q. B.; Kaptein, B.; De Zorzi, R.; Randaccio, L.; Scrimin, P.; Licini, G. Org.
Lett. 2007, 9, 2365. (h) Worlikar, S. A.; Kesharwani, T.; Yao, T.; Larock, R. C.
J. Org. Chem. 2007, 72, 1347. (i) Ciochina, R.; Grossman, R. B. Chem. ReV.
2006, 106, 3963. (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. (k) Fischer, D.; Tomeba,
H.; Pahadi, N. K.; Patil, N. T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2007, 46,
4764. (l) Barluenga, J.; Vazquez-Villa, H.; Ballesteros, A.; Gonzalez, J. M. J. Am.
Chem. Soc. 2003, 125, 9028. (m) Barluenga, J.; Vazquez-Villa, H.; Ballesteros,
A.; Gonzalez, J. M. Org. Lett. 2003, 5, 4121. (n) Barluenga, J.; Trincado, M.;
Rubio, E.; Gonzalez, J. M. Angew. Chem., Int. Ed. 2003, 42, 2406. (o) Barluenga,
J.; Trincado, M.; Rubio, E.; Gonzalez, J. M. Angew. Chem., Int. Ed. 2006, 45,
3140. (p) Barluenga, J.; Palomas, D.; Rubio, E.; Gonzalez, J. M. Org. Lett. 2007,
9, 2823. (q) Garud, D. R.; Koketsu, M. Org. Lett. 2008, 10, 3319.
9008 J. Org. Chem. 2008, 73, 9008–9011
10.1021/jo8018297 CCC: $40.75 2008 American Chemical Society
Published on Web 10/17/2008

ipso-Cyclization of N-(p-Methoxyaryl)propiolamides
TABLE 1. Screening Optimal Conditionsa
TABLE 2. Electrophilic ipso-Cyclization of
4-(p-Methoxyarylalkynes (1) with CuI (2a) and F1a
F+
yield (%)b
entry reagent 1
Z
R
R′
C6H5
C6H5
C6H5
4-MeC6H4
2-MeC6H4
4-MeOC6H4
4-NO2C6H4
4-AcC6H4
Thien-2-yl
CH3
product yield (%)b
entry
CuX
t (°C)
1
2
3
4
1b
1c
1d
1e
1f
NH
H
H
H
H
H
H
H
H
H
H
H
6
7
8
16
trace
93
1
2
3
4
CuI (2a)
CuI (2a)
CuI (2a)
CuI (2a)
CuI (2a)
CuI (2a)
CuI (2a)
CuI (2a)
r.t
F1
F1
F1
F1
F2
s
F1
F1
F1
F1
F2
trace (3)
60 (3)
87 (3)
76 (3)
74 (3)
0 (3)
70 (3)
69 (3)
86 (4)
13 (5)
51 (5)
NAc
NBn
NMe
NMe
NMe
NMe
NMe
NMe
NMe
NMe
60
90
110
90
90
90
90
90
90
90
9
90
82
78
45
48
63
41
32
5
10
11
12
13
14
15
16
17
18
5
6
7
8
1g
1h
1i
6
7c
8d
9
9
1j
CuBr (2b)
CuSCN (2c)
CuSCN (2c)
10
11
12
13
1k
1l
1m
1n
10
11
n-C5H11
NMe MeO C6H5
C6H5
trace
45
a Reaction conditions: 1 (0.2 mmol), CuX (3 equiv), F+ (1.5 equiv),
O
H
and MeCN (1 mL). b Isolated yield. F+ (1.0 equiv). d CuI (2 equiv).
c
a Reaction conditions: 1 (0.2 mmol), CuI (2a; 3 equiv), F1 (1.5
equiv), and MeCN (1 mL) at 90 °C for 6 h. b Isolated yield.
halocyclization reaction smoothly to give the corresponding
spiro[4.5]trienes in good yields.3a-c Very recently, we have
reported that para-unsubstituted arylalkynes could also undergo
the electrophilic ipso-iodocyclization with NIS and HOAc to
selectively afford spiro[4.5]trienyl acetates in moderate to good
yield.3d Importantly, these spirocyclic compounds are pharma-
cologically important compounds that widely occur in nature
products as well as are often utilized as intermediates in organic
synthesis.4 Thus, the development of alternative electrophilic
ipso-cyclization routes including new electrophiles to the
synthesis of spirocyclic compounds is still interesting. Initially,
we expected to induce a fluoride onto the spiro[4.5]decene
skeleton using electrophilic fluoride reagents, but all the
experiments failed. Accidently, we found that the electrophilic
ipso-cyclization reaction could take place with CuX (CuI, CuBr,
and CuSCN) combined with the electrophilic fluoride reagents.5
Here, we wish to report our detailed results (eq 1).
of 3 was enhanced sharply to 60% at 60 °C and the highest
yield was obtained at 90 °C (entries 2 and 3). N-Fluoro-N′-
(chloromethyl)triethylenediamine bis(tetrafluoroborate) F2, an-
other electrophilic fluoride reagent, was also evaluated, and it
was less effective than F1 (entry 5). Note that no reaction was
observed without any electrophilic fluoride reagents (entry 6).
Subsequently, the amount of both CuI and F1 was tested, and
it turned out that 3 equiv of CuI and 1.5 equiv of F1 provided
the best results (entries 3, 7, and 8). Finally, a series of salts
were also examined by reacting with amide 1a in the presence
of the electrophilic fluoride reagents (entries 9-11).6 We were
happy to observe that both CuBr (2b) and CuSCN (2c) were
highly active for the reaction. It is noteworthy that in the
presence of F1 the reaction of amide 1a with CuBr (2b) provides
satisfactory yield (entry 9), but F2 affords better results than
F1 in the reaction of amide 1a with CuSCN (2c) (entry 11).
With the standard reaction conditions in hand, we then used
the CuI/F1 system to explore the scope of amides (Table 2).
The results showed that a variety of amides were suitable
substrates to react with CuI (2a) and F1 in moderate to good
yields, and the substitutes on the nitrogen, the terminal of Ct C
bond, or aromatic ring affected the reaction to some extent. In
the presence of CuI (2a) and F1, amide 1b bearing a free N-H
group underwent the electrophilic ipso-iodocyclization reaction
in 16% yield (entry 1), and the reaction of amide 1c, having an
N-acetyl group, was unsuccessful (entry 2). To our delight,
substrate 1d with an N-benzyl group afforded the target product
(8) in good yield (entry 3). Subsequently, the substitutes, either
aryl or alkyl, at the terminal Ct C bond were investigated. We
found that several functional groups, such as methyl, methoxy,
nitro, and acetyl, on the aryl ring were tolerated well, and the
yields were reduced to some extent in the presence of the
electron-withdrawing group. While amide 1e bearing a methyl
group, for instance, was treated with 2a and F1 in 90% yield
Results and Discussion
As shown in Table 1, N-(4-methoxyphenyl)-N-methyl-3-
phenylpropiolamide (1a) was used as the starting substrate to
explore the optimal conditions.5 We found that the reaction
temperature has a fundamental influence on the reaction (entries
1-4). Only a trace amount of the target product 3 was observed
from the reaction of amide 1a with CuI (2a) and an electrophilic
fluoride reagent F1, 1-fluoro-2,4,6-trimethylpyridinium tet-
rafluoroborate, at room temperature (entry 1), whereas the yield
(5) For a paper on the X-/F+ electrophile-exchange process, see: Syvret,
R. G.; Butt, K. M.; Nguyen, T. P.; Bulleck, V. L.; Rieth, R. D. J. Org. Chem.
2002, 67, 4487.
(6) Other salts, including CuBr2, CuCl, CuCl2, CuCN, KBr, NaCl, and
NaNO2, were also examined, and they were less effective. The detailed data are
summarized in the Supporting Information.
J. Org. Chem. Vol. 73, No. 22, 2008 9009

Tang et al.
TABLE 3. Electrophilic ipso-Cyclization of
SCHEME 1. Synthesis of Azaquaternary Tricyclic Products
4-(p-Methoxyarylalkynes (1) with CuBr (2b) and F1a
entry
reagent 1
R
R′
C6H5
2-MeC6H4
4-MeOC6H4
product
yield (%)b
1
2
3
1d
1f
1g
Bn
CH3
CH3
19
20
21
84
71
71
a Reaction conditions: 1 (0.2 mmol), CuBr (2b; 3 equiv), F1 (1.5
equiv), and MeCN (1 mL) at 90 °C for 6 h. b Isolated yield.
SCHEME 2. A Possible Mechanism
TABLE 4. Electrophilic ipso-Cyclization of
4-(p-Methoxyarylalkynes (1) with CuBr (2c) and F2a
entry
reagent 1
R
R′
C6H5
2-MeC6H4
4-MeOC6H4
product
yield (%)b
1
2
3
1d
1f
1g
Bn
CH3
CH3
22
23
24
57
43
59
a Reaction conditions: 1 (0.2 mmol), CuSCN (2c; 3 equiv), F2 (1.5
equiv), and MeCN (1 mL) at 90 °C for 6 h. b Isolated yield.
with Pd(OAc)2 and TBAB (n-tetrabutylammonium bromide) to
give two azaquaternary tricyclic products 26 and 27 in good
total yield.
A working mechanism as outlined in Scheme 2 was proposed
on the basis of the reported mechanism and the present
results.1-3,5 First, a new electrophilic X cation is formed in situ
by exchange with an electrophilic fluoride reagent.5 Subse-
quently, the electrophilic X cation reacts with the alkyne moiety
to afford the onium intermediate A, followed by the intramo-
lecular electrophilic ipso-cyclization of intermediate A to form
intermediate B, and then intermediate C. Finally, attack of
intermediate C by the nucleophilic reagents occurs to cleave
the O-CH3 bond and generate the target product.
(entry 4), the yield was decreased to 45% in the reaction of
amide 1h having a nitro group (entry 7). Interestingly, a
heterocyclic amide 1j also underwent reaction with 2a and F1
smoothly to afford the corresponding product 14 in 63% yield
(entry 9). It was encouraging to discover that alkylalkynes 1k
and 1l were also suitable substrates for the reaction with 2a
and F1 (entries 10 and 11). Unfortunately, attempts at cyclization
of amide 1m bearing an o-methoxy group on the N-aryl ring
only afforded a trace amount of the target product 17 under the
standard reaction conditions (entry 12). It is worth noting that
ester 1n also undergoes the reaction with 2a and F1 successfully
in 45% yield (entry 13).
Conclusion
In summary, we describe here the first example of the
electrophilic ipso-cyclization reaction involving an electrophile-
exchange process. In the presence of CuX (X ) I, Br, SCN)
and electrophilic fluoride reagents, a variety of N-(p-meth-
oxyaryl)propiolamides and 4-methoxyphenyl 3-phenylpropiolate
were cyclized to selectively afford the corresponding spiro[4.5]-
decenones in moderate to excellent yields. Noteworthy is that
two azaquaternary tricyclic products are synthesized in two
steps. Work to probe the detailed mechanism and apply the
reaction in organic synthesis is currently underway.
Subsequently, we turned our attention to apply both the CuBr/
F1 system and the CuSCN/F2 system in the electrophilic ipso-
cyclization reaction with amides 1 (Tables 3 and 4). As
demonstrated in Table 3, the reactions of amides 1d, 1f, and
1g with CuBr (2b), respectively, were conducted smoothly in
the presence of F1 to generate the target products in good yields.
Substrate 1g bearing an o-methyl group, for instance, underwent
the electrophilic ipso-bromocyclization reaction with 2a and F1
smoothly in 71% yield (entry 2 in Table 3). Next, the reactions
of amides 1 with CuSCN (2c) and F2 were also evaluated as
listed in Table 4. To our delight, amides 1d, 1f, or 1g were
reacted with CuSCN (2c) and F2 successfully to afford the target
products in moderate yields (entries 1-3 in Table 4).
The azaquaternary tricyclic skeleton is widely observed in
nature products, particularly in alkaloids.4 Consequently, we
decided to construct this kind of alkaloid skeleton (Scheme 1).
In the presence of the CuBr/F1 system, substrate 1o was cyclized
to afford the corresponding product 25 in 80% yield. The
product 25 then underwent the intramolecular Heck reaction
Experimental Section
Typical Experimental Procedure of the Electrophilic ipso-
Cyclization Reaction. A mixture of amide 1 (0.2 mmol), CuX (X
) I, Br, SCN; 3 equiv), and electrophilic fluoride reagent (1.5 equiv)
was stirred in CH3CN (1 mL) at 90 °C for 6 h under nitrogen
protection until complete consumption of starting material as
monitored by TLC and GC-MS analysis. After the reaction was
finished, diethyl ether was poured into the mixture, then filtered
9010 J. Org. Chem. Vol. 73, No. 22, 2008

ipso-Cyclization of N-(p-Methoxyaryl)propiolamides
and evaporated under vacuum. The residue was purified by flash
column chromatography (hexane/ethyl acetate) to afford the desired
product.
1716, 1663; LRMS (EI 70 eV) m/z (%) 405 (M+ + 2, 15), 403
(M+, 14), 0.324 (39), 129 (100); HRMS (EI) for C22H1479BrNO2
(M+) calcd 403.0208, found 403.0207.
N-Methyl-3-bromo-4-phenyl-1-azaspiro[4.5]-deca-3,6,9-trien-2,8-
dione (4). White solid, mp 163.5-164.1 °C (uncorrected); 1H NMR
(500 MHz) δ 7.43-7.36 (m, 5H), 6.55 (d, J ) 10.5 Hz, 2H), 6.50
(d, J ) 10.5 Hz, 2H), 2.95 (s, 3H); 13C NMR (125 MHz) δ 183.6,
165.7, 151.2, 144.1, 133.3, 130.1, 130.0, 128.6, 127.7, 119.7, 68.2,
26.6; IR (KBr, cm-1) 1701, 1670; LRMS (EI 70 eV) m/z (%) 331
(M+ + 2, 25), 329 (M+, 25), 250 (42), 129 (100); HRMS (EI) for
C16H1279BrNO2 (M+) calcd 329.0051, found 329.0051.
Typical Experimental Procedure of the Intramolecular Heck
Reaction. A mixture of substrate 25 (0.15 mmol), Pd(OAc)2 (5 mol
%), TBAB (1 equiv), and Et3N (2 equiv) was stirred in DMF (1
mL) at 120 °C for 1.5 h under the nitrogen protection until complete
consumption of starting material as monitored by TLC and GC-
MS analysis. After the reaction was finished, diethyl ether was
poured into the mixture, then washed with water. The organic layer
was dried with anhydrous Na2SO4 and evaporated under vacuum.
The residue was purified by flash column chromatography (hexane/
ethyl acetate) to afford the desired product 26 and 27.
6-Bromo-5-phenyl-1H-pyrrolo[2,1-e]phenanthridine-2,7(9H,13bH)-
dione (27). White solid, mp 208.5-211.9 °C (uncorrected); 1H NMR
(500 MHz) δ 7.51-7.47 (m, 3H), 7.36-7.34 (m, 2H), 7.24-7.22
(m, 3H), 7.19-7.17 (m, 1H), 6.54 (d, J ) 10.0 Hz, 1H), 6.23 (d,
J ) 10.0 Hz, 1H), 5.34 (d, J ) 17.5 Hz, 1H), 4.38 (d, J ) 17.5
Hz, 1H), 3.62 (s, 1H), 2.91 (d, J ) 17.0 Hz, 1H), 2.27 (d, J ) 17.0
Hz, 1H); 13C NMR (125 MHz) δ 194.9, 163.5, 155.7, 143.5, 135.0,
132.3, 132.2, 131.4, 130.1, 129.2, 127.9, 127.3, 127.0, 126.6, 120.6,
100.0, 66.3, 41.5, 40.4, 39.2; IR (KBr, cm-1) 1716, 1684; LRMS
(EI 70 eV) m/z (%) 407 (M+ + 2, 58), 405 (M+, 56), 0.326 (100),
129 (74); HRMS (EI) for C22H1679BrNO2 (M+) calcd 405.0364,
found 405.0364.
Acknowledgment. We would like to thank the Specialized
Research Fund for the Doctoral Program of Higher Education
(No. 20060542007), National Natural Science Foundation of
China (No. 20572020), and New Century Excellent Talents in
University (No. NCET-06-0711) for financial support.
6-Bromo-5-phenyl-9H-pyrrolo[2,1-e]phenanthridine-2,7-dione (26).
1
White solid, mp 247.2-249.3 °C (uncorrected); H NMR (500
MHz) δ 7.53-7.51 (m, 1H), 7.45-7.37 (m, 5H), 7.33 (t, J ) 4.0
Hz, 1H), 7.05-7.03 (m, 2H), 6.75 (d, J ) 10.0 Hz, 1H), 6.40 (d,
J ) 2.0 Hz, 1H), 6.26-6.23 (m, 1H), 5.21 (d, J ) 15.0 Hz, 1H),
4.18 (d, J ) 15.5 Hz, 1H); 13C NMR (125 MHz) δ 184.1, 171.3,
157.3, 150.7, 145.9, 136.1, 132.8, 131.5, 131.0, 130.0, 129.3, 129.1,
Supporting Information Available: General experimental
procedures, characterization data for compounds 3-6, 8-16,
and 18-28, and copies of spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
128.8, 128.6, 128.4, 126.2, 125.0, 121.1, 72.2, 44.9; IR (KBr, cm-1
)
JO8018297
J. Org. Chem. Vol. 73, No. 22, 2008 9011