Bronsted acid TfOH-mediated [3 + 2] cycloaddition reactions of diarylvinylidenecyclopropanes with nitriles

Article abstract of DOI:10.1021/jo800390c

(Chemical Equation Presented) Diarylvinylidenecyclopropanes undergo a [3 + 2] cycloaddition reaction with MeCN in the presence of Bronsted acid TfOH to give the corresponding 3,4-dihydro-2H-pyrrole derivatives 2 in moderate to excellent yields under reflu

Full text of DOI:10.1021/jo800390c

Brønsted Acid TfOH-Mediated [3 + 2] Cycloaddition Reactions of
Diarylvinylidenecyclopropanes with Nitriles
Wei Li and Min Shi*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
mshi@mail.sioc.ac.cn
ReceiVed February 17, 2008
Diarylvinylidenecyclopropanes undergo a [3 + 2] cycloaddition reaction with MeCN in the presence of
Brønsted acid TfOH to give the corresponding 3,4-dihydro-2H-pyrrole derivatives 2 in moderate to
excellent yields under reflux within a short time. As for the diarylvinylidenecyclopropane substrate
containing a strongly electron-donating methoxy group on the benzene ring, the reaction leads to the
formation of a different type of 3,4-dihydro-2H-pyrrole derivatives 4 under the same conditions.
SCHEME 1. [3 + 2] Photocycloaddition of
Diarylvinylidenecyclopropanes with Nitriles via
Photoinduced Electron Transfer
Introduction
Cycloaddition reactions of compounds containing highly strained
cyclopropane ring moieties with nitriles have been the focus of
organic synthesis for more than two decades.1 Generally, these
cycloadditions can proceed quickly upon photoirradiation1a–c or
by the treatment with strong Lewis or Brønsted acids1d–g along
with the release of ring strain. Diarylvinylidenecyclopropanes
(VDCPs) 1 are one of the most remarkable organic compounds
known since they have an allene moiety connected by a cyclo-
propane ring, and yet they are thermally stable and reactive
substances. Many pioneering studies have been done involving
mechanistic, theoretical, spectroscopic, and synthetic studies.1b,2,3
For example, Mizuno and co-workers have reported a [3 + 2]
photocycloaddition of diarylvinylidenecyclopropanes with organic
carbonitriles via photoinduced electron transfer in the presence of
Mg(ClO4)2 and 9,10-dicyanoanthracene (DCA) (Scheme 1).1b This
interesting excited state reaction is fairly effective for the construc-
tion of 3,4-dihydro-2H-pyrrole derivatives containing an allene
moiety, although it is only suitable for the diarylvinylidenecyclo-
propanes containing a methoxy group on the benzene ring.
In this paper, we wish to report the Brønsted acid TfOH-
mediated ground state cycloaddition of a variety of diarylvi-
nylidenecyclopropanes (VDCPs) 1 with nitriles to give the
corresponding 3,4-dihydro-2H-pyrrole derivatives 2 or 4 in good
to excellent yields under mild conditions.
Results and Discussion
* To whom correspondence should be addressed. Fax: 86-21-64166128.
(1) (a) Herbertz, T.; Roth, H. D. J. Am. Chem. Soc. 1996, 118, 10954–10962.
(b) Mizuno, K.; Nire, K.; Sugita, H.; Otsuji, Y. Tetrahedron Lett. 1993, 34,
6563–6566. (c) Weng, H. X.; Sheik, Q.; Roth, H. D. J. Am. Chem. Soc. 1995,
117, 10655–10661. (d) Gridnev, I. D.; Shastin, A. V.; Balenkova, E. S.
Tetrahedron 1991, 47, 5577–5584. (e) Yu, M.; Pagenkopf, B. L. J. Am. Chem.
Soc. 2003, 125, 8122–8123. (f) Yu, M.; Pagenkopf, B. L. Org. Lett. 2003, 5,
5099–5102. (g) Huang, J. W.; Shi, M. Synlett 2004, 2343–2346.
Initial examination was performed using diphenylvinylidenecy-
clopropane 1a as the substrate in the presence of trifluoromethane-
sulfonic acid CF3SO3H (TfOH) (pKa ) 4.2 in acetic acid at 20
°C)4 in MeCN to develop the optimal conditions, and the results
of these experiments are summarized in Table 1. We found that
the corresponding 3,4-dihydro-2H-pyrrole derivative 2a was pro-
10.1021/jo800390c CCC: $40.75
Published on Web 05/01/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 4151–4154 4151

Li and Shi
TABLE 1. Brønsted Acid TfOH-Mediated [3 + 2] Cycloaddition
of Diphenylvinylidenecyclopropane 1a with MeCN under Various
Conditions
TABLE 2. Brønsted Acid TfOH-Mediated [3 + 2] Cycloaddition
of a Variety of Diarylvinylidenecyclopropanes 1 with MeCN under
Reflux
entrya
R1/R2
time/min
yield of 2b/%
1
2
3
4
5
6
7
8c
p-MeC6H4/p-MeC6H41b
p-FC6H4/p-FC6H41c
p-ClC6H4/p-ClC6H41d
p-MeC6H4/p-C6H51e
m,p-di-Me2C6H3/C6H51f
p-ClC6H4/C6H51g
5
5
5
5
5
5
5
10
2b,90
2c,71
2d,70
2e,90
2f,94
2g,75
2h,56
2i,17
entrya
x
temp/°C
time/min
yield of 2ab/%
1
2
3
1.0
1.5
1.0
1.5
0.5
1.5
1.0
0.5
rt
rt
50
50
15
15
15
5
60
5
49
55
90
93
54
91
93
67
4
o-MeC6H4/MeC6H41h
p-ClC6H4/o-ClC6H41i
5c
6
50
reflux
reflux
reflux
a Reaction conditions: VDCP (0.18 mmol) was dissolved in dry
MeCN under argon atmosphere, TfOH (1.0 equiv) was added, and then
the reaction mixture was refluxed for 5 min. b Isolated yield. c See
Scheme 2.
7
5
390
8d
a Reaction conditions: VDCP (0.18 mmol) was dissolved in dry
MeCN (2 mL) under argon atmosphere, TfOH (x equiv) was added, and
then the mixture was stirred at different temperatures for different times.
b Isolated yield. c 40% of 1a was recoverd. d 32% of 1a was recovered.
SCHEME 2. Unexpected Reaction of
Diarylvinylidenecyclopropane 1i with MeCN Promoted by
TfOH
duced under various conditions in MeCN in moderate to high
yields. For example, using 1.0 and 1.5 equiv of TfOH as a promoter
at room temperature (20 °C), the reaction proceeded smoothly to
give 2a in 49 and 55% yield within 15 min, respectively (Table 1,
entries 1 and 2). Increasing the reaction temperature to 50 °C
accelerated the reaction rate, affording 2a in 90% yield within 15
min with 1.0 equiv of TfOH and in 93% yield within 5 min with
1.5 equiv of TfOH (Table 1, entries 3 and 4). In the presence of
0.5 equiv of TfOH, the reaction became sluggish to produce 2a in
54% yield along with the recovery of 40% of 1a even after
extending the reaction time to 60 min (Table 1, entry 5). Under
reflux in MeCN, 2a was produced in 91 and 93% yield in the
presence of 1.5 and 1.0 equiv of TfOH within 5 min, respectively
(Table 1, entries 6 and 7). When using 0.5 equiv of TfOH as a
promoter under reflux in MeCN, 2a was formed in 67% by
extending the reaction time to 390 min (Table 1, entry 8). These
results indicated that the best reaction conditions are to carry out
the reaction in MeCN under reflux in the presence of 1.0 equiv of
TfOH.
having a moderately electron-donating methyl group on the
benzene ring, the corresponding 3,4-dihydro-2H-pyrrole deriva-
tives 2b, 2e, 2f, and 2 h were obtained in high yields (Table 2,
entries 1, 4, 5, and 7). Adding a moderately electron-withdraw-
ing chloro or fluoro atom on the benzene ring of symmetrical
diarylvinylidenecyclopropanes 1c and 1d as well as unsym-
metrical diarylvinylidenecyclopropane 1g afforded the corre-
sponding 3,4-dihydro-2H-pyrrole derivatives 2c, 2d, and 2g in
moderate yields (Table 2, entries 2, 3, and 6). Interestingly, when
using unsymmetrical diarylvinylidenecyclopropane 1i bearing
an ortho-chloro atom on the benzene ring as the substrate, the
yield of the expected product 2i was only 17% (Table 2, entry
8) along with another unexpected product 3 in 53% yield, which
is derived from a Ritter reaction process (Scheme 2).1g,5
A plausible mechanism for this Brønsted acid TfOH-mediated
[3 + 2] cycloaddition of diarylvinylidenecyclopropane 1 with
With these optimized reaction conditions identified, we next
examined the cycloaddition of a variety of diarylvinylidenecy-
clopropanes 1 with MeCN. The results are shown in Table 2.
As for symmetrical diarylvinylidenecyclopropane 1b and un-
symmetrical diarylvinylidenecyclopropanes 1e, 1f, and 1 h
(2) (a) Poutsma, M. L.; Ibarbia, P. A. J. Am. Chem. Soc. 1971, 93, 440–450.
(b) Smadja, W. Chem. ReV. 1983, 83, 263–320. (c) Hendrick, M. E.; Hardie,
J. A.; Jones, M., Jr. J. Org. Chem. 1971, 36, 3061–3062. (d) Sugita, H.; Mizuno,
K.; Saito, T.; Isagawa, K.; Otsuji, Y. Tetrahedron Lett. 1992, 33, 2539–2542.
(e) Mizuno, K.; Sugita, H.; Kamada, T.; Otsuji, Y. Chem. Lett. 1994, 44, 9–
452, and references cited therein. (f) Sydnes, L. K. Chem. ReV. 2003, 103, 1133–
1150. (g) Akasaka, T.; Misawa, Y.; Ando, W. Tetrahedron Lett. 1990, 31, 1173–
1176. (h) Mizuno, K.; Sugita, H.; Isagawa, K.; Goto, M.; Otsuji, Y. Tetrahedron
Lett. 1993, 34, 5737–5738. (i) Mizuno, K.; Sugita, H.; Hirai, T.; Maeda, H.
Chem. Lett. 2000, 1144–1145. (j) Mizuno, K.; Nire, K.; Sugita, H.; Maeda, H.
Tetrahedron Lett. 2001, 42, 2689–2692. (k) Mizuno, K.; Maeda, H.; Sugita, H.;
Nishioka, S.; Hirai, T.; Sugimoto, A. Org. Lett. 2001, 3, 581–584. (l) Mizuno,
K.; Sugita, H.; Hirai, T.; Maeda, H.; Otsuji, Y.; Yasuda, M.; Hashiguchi, M.;
Shima, K. Tetrahedron Lett. 2001, 42, 3363–3366. (m) Maeda, H.; Zhen, L.;
Hirai, T.; Mizuno, K. ITE Lett. Batteries, New Technol. Med. 2002, 3, 485–488.
(n) Xu, G.-C.; Liu, L.-P.; Lu, J.-M.; Shi, M. J. Am. Chem. Soc. 2005, 127, 14552–
14553. (o) Shi, M.; Lu, J.-M.; Xu, G.-C. Tetrahedron Lett. 2005, 46, 4745–
4748. (p) Li, Q.-J.; Shi, M.; Timmons, C.; Li, G.-G. Org. Lett. 2006, 8, 625–
628. (q) Shi, M.; Lu, J.-M. Synlett 2005, 2352–2356. (r) Lu, J.-M.; Shi, M. Org.
Lett. 2007, 9, 1805–1808. (s) Lu, J.-M.; Shi, M. Org. Lett. 2006, 8, 5317–5320.
(t) Shi, M.; Li, W. Tetrahedron 2007, 63, 6654–6660.
(3) For the synthesis of vinylidenecyclopropanes, please see: (a) Isagawa,
K.; Mizuno, K.; Sugita, H.; Otsuji, Y. J. Chem. Soc., Perkin Trans. 1 1991,
2283–2285, and references cited therein. (b) Al-Dulayymi, J. R.; Baird, M. S.
J. Chem. Soc., Perkin Trans. 1 1994, 1547–1548. The other papers related to
vinylidenecyclopropanes: (c) Maeda, H.; Hirai, T.; Sugimoto, A.; Mizuno, K. J.
Org. Chem. 2003, 68, 7700–7706. (d) Pasto, D. J.; Brophy, J. E. J. Org. Chem.
1991, 56, 4556–4559. (e) Pasto, D. J.; Miles, M. F. J. Org. Chem. 1976, 41,
425–432. (f) Pasto, D. J.; Miles, M. F.; Chou, S.-K. J. Org. Chem. 1977, 42,
3098–3101. (g) Pasto, D. J.; Borchardt, J. K.; Fehlper, T. P.; Baney, H. F.;
Schwartz, M. E. J. Am. Chem. Soc. 1976, 98, 526–529. (h) Pasto, D. J.; Chen,
A. F.-T.; Ciurdaru, G.; Paquette, L. A. J. Org. Chem. 1973, 38, 1015–1026. (i)
Pasto, D. J.; Borchardt, J. K. J. Am. Chem. Soc. 1974, 96, 6937–6943.
4152 J. Org. Chem. Vol. 73, No. 11, 2008

Brønsted Acid TfOH-Mediated [3 + 2] Cycloaddition
SCHEME 3. Proposed Mechanism for the [3 + 2]
Cycloaddition Reaction
SCHEME 4. Proposed Mechanism for the Ritter Reaction
of 1i with MeCN
TABLE 3. Brønsted Acid TfOH-Promoted [3 + 2] Cycloaddition
of Diphenylvinylidenecyclopropane 1j with Nitriles
MeCN is shown in Scheme 3. First, there is an equilibrium
between intermediates A1, A1′, and A1′′ in the reaction of
acetonitrile and TfOH according to previous literature.6a,b
Intermediate A1 undergoes an electrophilic attack to the far
position of allene moiety from the aryl groups (noted as f) of
diarylvinylidenecyclopropane 1 to afford the corresponding
cyclopropane ring-opened cationic intermediate B, which un-
dergoes the subsequent intramolecular cyclization reaction to
give cationic intermediate C. Treatment of C with Na2CO3
furnishes 3,4-dihydro-2H-pyrrole derivative 2 (Scheme 3). This
proposed mechanism could explain why 1 equiv or more of
TfOH is required in above reaction to produce 2 in good yield.
To further clarify the reaction mechanism, we conducted the
addition of 0.18 mmol of TfOH to 2.0 mL of MeCN under reflux
for 15 min followed by removal of the solvent in vacuo. The
IR spectrum of the residue did not contain an absorption band
at 2245 cm-1 [ν(CN) of nitrile]6a but gave a weakly broad
absorption band at 2500 cm-1 and two strong absorption bands
at 3327 and 3210 cm-1, respectively,6b suggesting the existence
of intermediates A1 and A1′ as shown in Scheme 3.6 Adding
Et2O to the residue afforded many white precipitates which
could be recrystallized from MeOH/Et2O to give intermediate
A2 as shown in Scheme 3 as well by comparing its IR spectrum
with the literature value.6b The resulting precipitates could also
promote the cycloaddition of 1a with MeCN (as a solvent) to
provide 2a in moderate yield, although a prolonged reaction
time is required (eq 1). All of these facts indicated that the
intermediates A1 and A1′ are active species in this reaction.
entrya
RCN
yield of 4b/%
1
2
3
4
5
MeCN
4a,94
4b,75
4c,58
4d,64
4e,72
nPrCN
PhCH2CN
PhCn
CH2dCHCN
a Reaction conditions: VDCP (0.1 mmol) was dissolved in dry RCN
(2 mL) under argon atmosphere, TfOH (1.0 equiv) was added, and then
the reaction mixture was refluxed for 5 min. b Isolated yield.
corresponding cationic intermediate D.7Intermediate D is cap-
tured by MeCN to give the cationic intermediate E, which is
hydrolyzed by water to furnish the product 3 (Scheme 4).
Electron-deficient diarylvinylidenecyclopropane 1i and the ortho-
chloro group on the benzene ring can sterically and electronically
retard the reaction with cationic intermediate A. Therefore,
proton-induced intramolecular rearrangement takes place pref-
erentially to give cationic intermediates D and E as well as the
subsequent Ritter reaction product 3.
Moreover, using di(4-methoxyphenyl)vinylidenecyclopropane
1j as the substrate to react with MeCN in the presence of 1.0
equiv of TfOH under reflux,8 we found that 3,4-dihydro-2H-
(4) (a) Koppel, I. A. Taft, R. W. Anvia, F. Zhu, S. Hu, L. Sung, K.
DesMarteau, D. D. Yagupolskii, L. M. Yagupolskii, Y. L. Ignat’ev, N. V.
Kondratenko, N. V. Volkonskii, A. Y. Vlasov, V. M. Notario, R. Maria, P. J. Am.
Chem. Soc. 1994, 116, 3047–3057. (b) Foropoulus, J. DesMarteau, D. D Inorg.
Chem. 1984, 23, 3720–3723. H2SO4: pKa ) 7.0 in acetic acid at 20 °C.
(5) (a) Ritter, J. J. J. Am. Chem. Soc. 1952, 74, 763–765. (b) Krimel, L. I.
Org. React. 1969, 17, 215. (c) Bishop, R.; Hawkins, S. C.; Ibana, I. C. J. Org.
Chem. 1988, 53, 427–430.
A2 (1.0 equiv)
1a.
8 2a
(1)
82 °C, MeCN, 30 min, 71 %
(6) (a) Booth, B. L.; Noori, G. F. M. J. Chem. Soc., Perkin Trans. 1. 1980,
2894–2900. (b) Muhannad, I. A.; Brian, L. B.; Ghazi, F. M. N.; Fernanca,
J. R. P. P. J. Chem. Soc., Perkin Trans. 1 1983, 1075–1082. (c) Ruske, W. In
Friedel-Crafts and Related Reactions; Olah, G. A., Ed.; Wiley: New York,
1964; Vol. 111, part I, p 383. (d) Jeffrey, E. A.; Satchell, D. P. N. J. Chem. Soc.
B 1966, 579–586.
As to the Ritter reaction product 3 in the reaction of
diarylvinylidenecyclopropane 1i with MeCN, a plausible mech-
anism is shown in Scheme 4. Instead of Brønsted acid TfOH
being captured by MeCN, 1i is first protonated by TfOH at the
near position of the allene moiety from the aryl groups (noted
as n) along with the cyclopropane ring opening to give the
(7) This cationic intermediate is exactly a long-lived cyclopropylcarbinyl
cation. Olah, G. A.; Reddy, V. P.; Prakash, G. K. S. Chem. ReV. 1992, 92, 69–
95.
J. Org. Chem. Vol. 73, No. 11, 2008 4153

Li and Shi
SCHEME 5. Proposed Mechanism for the [3 + 2] Cycloaddition Reaction of 1j with Nitriles
SCHEME 6. Reduction of 2a with NaBH4 and Pd/H2 in
Methanol
The cycloaddition product 2a of 1a with MeCN could be
converted to the corresponding pyrrolidine 5 in 60% yield by
reduction with NaBH4 in methanol (Scheme 6).1b Moreover,
with 10% Pd/C in methanol under hydrogen gas atmosphere,
2a was transformed to the corresponding 3,4-dihydro-2H-pyrrole
6 in 70% yield (Scheme 6).9
In conclusion, we disclosed a [3 + 2] cycloaddition reaction
using VDCPs 1 with nitriles promoted by Brønsted acid TfOH
in this paper. In this transformation, the corresponding 3,4-
dihydro-2H-pyrrole derivatives 2 or 4 can be obtained in
moderate to excellent yields under mild conditions within short
reaction time. A considerable range of aromatic group substi-
tuted VDCPs 1 has been examined in the reaction. These
processes provide an efficient route to the synthesis of different
3,4-dihydro-2H-pyrrole derivatives according to different sub-
strates. Moreover, pyrrolidine derivatives 5 and 6 were obtained
in good yields by the further transformations of the cycloadduct
2a. Efforts are underway to elucidate the mechanistic details
and the scope and limitations of this reaction in the laboratory.
pyrrole derivative 4a with an isopropylidene group on the five-
membered ring was formed in 94% yield rather than the
“normal” product containing an allene moiety such as 2a-2i
(Table 3, entry 1). In addition, 1j can react smoothly with
various nitriles to give the corresponding 3,4-dihydro-2H-pyrrole
derivatives as 4b, 4c, 4d, and 4e in good yields (Table 3, entries
2-5). This interesting different reaction capability with nitriles
may be due to the strongly electron-donating methoxy groups
on the benzene rings of 1j.
A plausible mechanism for the [3 + 2] cycloaddition reaction
of 1j with nitriles mediated by TfOH is shown in Scheme 5.
As in Scheme 3, RCN is first protonated by Brønsted acid TfOH
to give the corresponding cationic intermediate A1.6 Intermedi-
ate A1 undergoes an electrophilic attack to the middle position
of allene moiety (noted as m) of 1j to give the corresponding
intermediate F, which immediately undergoes a ring-opening
process to afford cationic intermediate G. Intramolecular
cyclization takes place to give cationic intermediate H, which
furnishes the corresponding product 4 through neutralization
with Na2CO3 (Scheme 5). The strongly electron-donating
methoxy groups on the benzene rings of 1j increases the electron
density at the middle position of the allene moiety, facilitating
the electrophilic attack of cationic intermediate A. Therefore,
the reaction takes place in a different pathway.
Experimental Section
General Procedure for the Cycloaddition of 1a-1h with
MeCN. Under an argon atmosphere, diarylvinylidenecyclopropane
(VDCP) (0.18 mmol) was dissolved in MeCN (2.0 mL), and then
the mixture was heated to the reflux temperature. To the resulting
18 µL solution of TfOH (1.0 equiv) was added, and reaction
mixtures were stirred for 5-15 min. The reaction was quenched
by addition of anhydrous Na2CO3. After the solid was filtrated off,
the solution was washed with CH2Cl2 (2 × 10 mL). The combined
organic phases were concentrated in vacuo, and the residue was
purified by a flash column chromatography on silica gel column
with petroleum ether/EtOAc (3:1) as an eluent.
Acknowledgment. We thank the Shanghai Municipal Com-
mittee of Science and Technology (04JC14083, 06XD14005),
and the National Natural Science Foundation of China (20472096,
203900502, 20672127, and 20732008).
Supporting Information Available: Detailed experimental
1
procedures, H and 13C NMR spectra for the cycloadducts 2
and 4, Ritter reaction product 3, and the reduction products 5
and 6. This material is available free of charge via the Internet
at http://pubs.acs.org.
(8) The normal reaction product such as 2j (an analogue of 2a) was not
detected at room temperature.
(9) Cromble, L.; Fernando, C. E. C. J. Chem. Res. Miniprint. 1998, 7, 1501–
1518.
JO800390C
4154 J. Org. Chem. Vol. 73, No. 11, 2008