Novel thermal iminocyclopropene rearrangements: regioselectivity in the synthesis of pyrroles

Article abstract of DOI:10.1016/j.tetlet.2006.05.185

A novel and readily available method for synthesis of pyrroles possessing substituents with various functional groups has been developed, by means of thermal iminocyclopropene rearrangements. It will provide a novel and readily available access to pyrrole

Full text of DOI:10.1016/j.tetlet.2006.05.185

Tetrahedron Letters 47 (2006) 5793–5796
Novel thermal iminocyclopropene rearrangements:
regioselectivity in the synthesis of pyrroles
Hiroyasu Sato and Kunio Hiroi*
Ohu University, The School of Pharmaceutical Sciences, Department of Synthetic Organic Chemistry, 31-1 Misumido,
Tomitamachi, Koriyama, Fukushima 963-8611, Japan
Received 4 April 2006; revised 24 May 2006; accepted 30 May 2006
Abstract—A novel and readily available method for synthesis of pyrroles possessing substituents with various functional groups has
been developed, by means of thermal iminocyclopropene rearrangements. It will provide a novel and readily available access to pyr-
roles under mild reaction conditions with simple procedures. The regioselectivity in this iminocyclopropene rearrangement was
disclosed.
Ó 2006 Elsevier Ltd. All rights reserved.
A cyclopropene skeleton exists at a rather highly acti-
vated energy level in its ground state, owing to its intrin-
sic severe steric strain, and, therefore, it has been well
known to be limited to access to it synthetically.1 Cur-
rently, a new and readily available method has been
communicated for access to cyclopropenes by the assis-
tance of rhodium catalysts.2 We wish to communicate
herein a novel, simple, and synthetically available ap-
proach to pyrroles involving substituents with various
functional groups under mild reaction conditions by
means of novel thermal rearrangements of iminocyclo-
propenes.3 Heterocyclic chemistry of pyrroles plays a
significant role in the areas of pharmaceutical sciences
and organic synthesis,4 ranging from medicines to mate-
rial sciences such as ligands in catalytic (asymmetric)
synthetic reactions.5
though by the assistance of an acid catalyst such as
ammonium chloride or hydrobromic acid.7
On the other hand, a cyclopropene ring can be shown to
be more reactive, due to the strain involved in the ring,
resulting in smooth opening of the ring under rather
mild reaction conditions, followed by rearrangement
or cycloaddition reactions to yield five-membered
carbo- or heterocycles, or other cyclic products.
An iminocyclopropene–pyrrole rearrangement, how-
ever, which has been developed by us, proceeds at much
lower reaction temperature (60–80 °C) without any
assistance by catalysts; the yield and regioselectivity of
the products depend upon the reaction solvent used
and the reaction temperature.
In comparison with cyclopropane chemistry, which has
had a long history of research of theoretical interest
and synthetic uses,6 especially in the pharmaceutical
area, a cyclopropene seems to be a more labile and reac-
tive chemical species, and therefore, we expect it might
be a more chemically interesting and synthetically useful
intermediate. For instance, for thermal cleavage of a
cyclopropane ring, rather or very severe heating at high
temperature is required normally. An iminocyclopro-
pane–dihydropyrrole rearrangement also needs heating
at considerably high temperature (130–140 °C) even
The thermal rearrangements of iminocyclopropenes
(imine IR: 1651 cmÀ1) into pyrroles were studied by
reacting ketoesters 1a2 with primary amines 2c in tolu-
ene at 40–110 °C in the presence of molecular sieves
˚
4 A to afford pyrroles 4c and 5c and the results are sum-
marized (Scheme 1 and Table 1).
As shown in Table 1, the highest yield (72%) of 4c and
5c was obtained with a 94:6 ratio of 4c and 5c, respec-
tively, by the reaction of 1 with 5.0 equiv of benzylamine
(2c) in toluene at 80 °C for 12 h in the presence of mole-
˚
cular sieves 4 A. Use of a lower amount of benzylamine
*
(3.0 equiv) in the above reaction gave 4c and 5c in 43%
yield with a lower ratio of 4c to 5c (80:20). The reaction
Corresponding author. Tel.: +81 24 932 8931; fax: +81 24 933
7372; e-mail: k-hiroi@pha.ohu-u.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.185

5794
H. Sato, K. Hiroi / Tetrahedron Letters 47 (2006) 5793–5796
R1
H3C
R2 NH2
+
CO2CH3
O
2a R2= p-EtOC6H4
2e R2= n-C4H9
1a R1= Ph
b
c
= p-FC6H4
= PhCH2
f
= i-Pr
= Ph
b
= p-FC6H4
g
c
= n-C6H13
d
= PhCH2CH2
d
e
= o-MeC6H4
= p-MeC6H4
R1
CO2CH3
CH3
CO2CH3
CH3
R1
+
R1
N
R2
N
CO2CH3
N
R2
R2
CH3
3a-q
4a-q
5a-q
3a R1= Ph, R2= p-EtOC6H4
3j
k
l
= p-FC6H4, = PhCH2
b
c
d
e
f
g
h
i
= Ph,
= Ph,
= Ph,
= Ph,
= Ph,
= p-FC6H4
= PhCH2
= PhCH2CH2
= n-C4H9
= i-Pr
= p-FC6H4, = PhCH2CH2
= p-FC6H4, = n-C4H9
= p-FC6H4, = i-Pr
m
n
o
p
q
= n-C6H13
,
= p-FC6H4
= i-Pr
= n-C6H13
,
= p-FC6H4, = Ph
= o-MeC6H4 = PhCH2
= p-MeC6H4 = PhCH2
= p-FC6H4, = p-EtOC6H4
= p-FC6H4, = p-FC6H4
Scheme 1.
Table 1. Studies on thermal rearrangements of iminocyclopropenes 3c into pyrroles (4c and 5c)
Entry
C6H5CH2NH2 (equiv)
Solvent
Temp (°C)
Time (hr)
4c:5ca
Yields (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1
3
5
5
5
5
5
5
5
5
5
5
5
5
Toluene
Toluene
Toluene
Toluene
Toluene
Benzene
Xylene
CHCl3
CH2Cl2
HMPA
CH3CN
DMA
60
60
40
60
80
Reflux
80
Reflux
Reflux
80
Reflux
80
39
17
20
14
12
12
12
12
24
12
12
12
12
12
83:17
80:20
91:9
93:7
94:6
94:6
97:3
93:7
98:2
15 (80)b
43
50
70
72
55
48
57
65c (33)b
52
54
35
23
29
91:9
74:26
31:69
23:77
23:77
DMSO
DMF
80
80
a The ratio was determined by 1H NMR analysis.
b Yields of the recovered starting material.
c A corrected yield based on the recovered starting material.
of 1a with a stoichiomeric amount of benzylamine pro-
vided products 4c and 5c in a poor yield (15%) with the
recovered starting material (80%).
corresponding pyrroles (4j, 4q and 5j, 5q) with a similar
ratio of 4 and 5, however the chemical yields were
dependent upon the stereoelectronic effects of the sub-
stituents. In the case of p-fluorophenyl (3j) or p-tolyl
(3q) group, the chemical yields were decreased (43%
and 18%) by lowering of reactivity of alkenyl carboca-
tions 6 due to stabilization by resonance effects by a p-
fluoro group or electron donating effects by a p-methyl
group in 6. On the other hand, in the case of 3p (o-tolyl
substituent), the reaction via 6 would be more preferable
giving high regioselectivity (>99:1), since another inter-
mediate (7) has severe steric hindrance between the
o-tolyl and the methyl ester groups.
Stereoelectronic effects of substituents on the cycloprop-
enes were studied (Table 2). Initially, effects of aromatic
substituents were examined using phenyl, p-tolyl, o-
tolyl, or p-fluorophenyl groups as a substituent. A
cyclopropene (3c) possessing a phenyl group as a
substituent on the ring underwent a smooth thermal
reaction (in toluene at 80 °C for 12 h) to give pyrroles
4c and 5c in good yields (72%). The reaction of p-substi-
tution models (3j and 3q) on the phenyl ring provided

H. Sato, K. Hiroi / Tetrahedron Letters 47 (2006) 5793–5796
Table 2. Thermal rearrangements of iminocyclopropenes 3 into pyrroles (4 and 5)
5795
Entry
R1
R2
Products
Ratio of 4:5a
Yields (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Ph
Ph
Ph
Ph
Ph
Ph
p-FC6H4
p-FC6H4
p-FC6H4
p-FC6H4
p-FC6H4
p-FC6H4
p-FC6H4
n-C6H13
n-C6H13
o-MeC6H4
p-MeC6H4
p-EtOC6H4
p-FC6H4
PhCH2
PhCH2CH2
n-C4H9
i-Pr
4a/5a
4b/5b
4c/5c
4d/5d
4e/5e
4f/5f
90:10
92:8
94:6
95:5
91:9
25:75
93:7
91:9
93:7
97:3
75
53
72
46
67
36
56
33
44
43
43
53
24
80
64
21
18
Ph
4g/5g
4h/5h
4i/5i
p-EtOC6H4
p-FC6H4
PhCH2
PhCH2CH2
n-C4H9
i-Pr
PhCH2
i-Pr
PhCH2
PhCH2
4j/5j
4k/5k
4l/5l
94:6
91:9
4m/5m
4n/5n
4o/5o
4p/5p
4q/5q
10:90
58:42
12:88
>99:1
95:5
a The ratio was determined by 1H NMR analysis.
In the case of 3n (n-hexyl substituent), the reaction via 6
would slightly decrease due to steric reason by the n-hex-
yl group to give pyrroles 4n and 5n with a ratio of 58:42,
respectively.
The structure of the products 4 and 5 was determined
by the NMR spectral analysis. The a-methylene of
benzyl group, methyl ester at C3 and methyl at C2
of 5c appear at 5.07, 3.67 and 2.45, respectively.8
The hydrogens at C5 of 5g and C4 of 4g appear at
6.68 and 6.74, respectively.9 The regiochemistry of 4g
was determined by NOE observed between a hydrogen
at C4 and a methoxy group, and also HMBC between
the hydrogen at C4 and the ester carbonyl carbon. The
regiochemistry of the product 4m and 5m was deter-
mined by NMR spectral analysis; the hydrogens at
C5 of 5m and C4 of 4m appear at 6.60 and 6.43,
respectively.9
Dramatic solvent effects were observed in the above
reaction (Table 1). We examined solvent effects, by
employing, instead of toluene, acetonitrile, chloroform,
dichloromethane, dimethyl sulfoxide (DMSO), N,N-
dimethylformamide (DMF), benzene, xylene, N,N-
dimethylacetamide (DMA), or HMPA as a solvent.
The results are summarized in Table 1. As listed in Table
1, it should be noted that inversion of the regioselectivity
in the product was observed, depending upon the sol-
vent used. With the use of a slightly or strongly polar
solvent such as acetonitrile, DMSO, or DMF, an
amount of 5c was increased in acetonitrile with a 74:26
ratio of 4c and 5c, and 5c was obtained as a major prod-
uct in DMSO, DMF and DMA with 23:77 to 31:69 ratio
of 4c and 5c, respectively, even though the yield was not
so high (54–23%). In another case using 3e in DMSO,
the inversion of regiochemistry in products was
observed with the same ratio (4e:5e = 8:92, 30% yield).
The experimental results obtained, including the regio-
selectivity and the solvent effects mentioned above, are
rationalized as follows. If the reaction proceeds via a
concerted mechanism, it will be particularly hard to
rationalize the dramatic solvent effects mentioned
above. Therefore, on the basis of this fact, we can
undoubtedly anticipate the existence of ionic intermedi-
ates such as 6 and 7, which are formed by fission of the
cyclopropene rings, followed by cyclization affording 4
and 5, respectively. In the cyclization, if the steric factors
are seriously important, the thermal reaction will
provide 5 as a major product. Otherwise, if the chemical
stability of the intermediary sp2 carbocation is a crucial
factor for cyclization, 4 will be provided as a major
product. Based on the results described earlier, it should
be concluded that the most important factor in this reac-
tion will be the stability of the sp2 carbocation produced.
So, with the use of DMSO and DMF as a solvent, steric
interference will be increased by solvation of the carbo-
cation coordinated with the anionic solvents to disturb
the reaction at the stage 6, and, therefore, the formation
of 5 will be preferred with the solvent. However, the
use of HMPA as a solvent was not effective for presen-
tation of high regioselectivity, due to decrease of the
coordination ability to alkenyl carbocations presumably
by the steric reason. The steric effects by N-substituent
(i-propyl) in the imino groups will be rationalized along
this line (Scheme 2).
Use of other primary amines (2a–g) (5.0 equiv), instead
of benzylamine, in the above reaction was studied under
the same reaction conditions (in toluene, 80 °C, and
12 h), and the results are listed in Table 2. It shows that
moderate yields of 4a–q and 5a–q were obtained with
high regioselectivity (75:25 to >99:1). The steric bulki-
ness of N-substituents at the imino groups seriously af-
fected the cyclization stage. We have studied the effects
of N-substituents in 3, changing the substituents such
as benzyl, phenethyl, p-methoxyphenyl, p-fluorophenyl,
n-butyl, i-propyl and phenyl groups. As we expected,
no big difference was observed in the series of aromatic
substituents and alkyl substituents. However, it should
be noted that the regiochemistry of the products was in-
versed in the case of i-propyl group as shown in Table 2.
An i-propyl group significantly affected the regiochem-
istry on cyclization, with the preferential formations of
5f over 4f (75:25) and 5m over 4m (90:10) (Table 2).

5796
H. Sato, K. Hiroi / Tetrahedron Letters 47 (2006) 5793–5796
R1
R1
R1
N
5
N
N
4
R2
R2
CO2CH3
CO2CH3
R2
CO2CH3
CH3
CH3
CH3
6
3
7
Scheme 2.
2–78; (b) Ma, S.; Zhang, J. J. Am. Chem. Soc. 2003, 125,
12386–12387.
4. Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chem-
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5. Cotisor, O.; Linert, W. Metal Mediated Template Synthesis
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6. (a) Meijere, A. de Angew. Chem., Int. Ed. Engl. 1979, 18,
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56; (c) Bookhart, M.; Studabaker, W. B. Chem. Rev. 1987,
87, 411–432.
Thus, we have developed a novel and readily available
method for synthesis of pyrroles with various groups
via thermal rearrangement of iminocyclopropenes into
pyrroles. We have determined the regiochemistry at
the cyclization by the effects of substituents in the sys-
tems, and disclosed regioselectivity and also dramatic
solvent effects in this rearrangement. Based on the regio-
chemical results, the reaction mechanism is discussed.
7. Acid-catalyzed thermal rearrangements of iminocyclopro-
panes see, (a) Stevens, R. V.; Fitzpatrick, J. M.; Kaplan,
M.; Zimmerman, R. L. J. Chem. Soc., Chem. Commun.
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Tetrahedron Lett. 1976, 3799–3802; Blake, K. W.; Gillies, I.;
Denney, R. C. J. Chem. Soc., Perkins Trans. 1 1981, 700–
702.
8. Gomez-Sanchez, A.; Stiefel, B. M.; Fernandez-Fernandez,
R. J. Chem. Soc., Perkin Trans. 1 1982, 441–447.
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Japanese Pharmaceutical Society, 2004, Osaka, Abstract