A novel heterocumulenic Pauson-Khand reaction of alkynylcarbodiimides: A facile and efficient synthesis of heterocyclic ring-fused pyrrolinones

Article abstract of DOI:10.3987/COM-03-9726

The first examples of the heterocumulenic Pauson-Khand reaction are described. Alkynylcarbodiimides undergo an intramolecular Pauson-Khand cycloaddition upon heating in the presence of Mo(CO)₆ and DMSO to afford 4,5-dihydro-1H-pyrrolo[2,3-b]pyrrolin-2-ones and 1H-pyrrolo[2,3-b]indol-2-ones.

Full text of DOI:10.3987/COM-03-9726

HETEROCYCLES, Vol. 60, No. 5, 2003
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HETEROCYCLES, Vol, 60, No. 5, 2003, pp. 1045 - 1048
Received, 23rd January, 2003, Accepted, 28th February, 2003, Published online, 3rd March, 2003
A NOVEL HETEROCUMULENIC PAUSON-KHAND REACTION OF
ALKYNYLCARBODIIMIDES: A FACILE AND EFFICIENT SYNTHESIS
OF HETEROCYCLIC RING-FUSED PYRROLINONES
Takao Saito,* Masahiro Shiotani, Takashi Otani, and Satoshi Hasaba
Department of Chemistry, Faculty of Science, Tokyo University of Science,
Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Abstract – The first examples of the heterocumulenic Pauson-Khand reaction are
described. Alkynylcarbodiimides undergo an intramolecular Pauson-Khand
cycloaddition upon heating in the presence of Mo(CO)6 and DMSO to afford 4,5-
dihydro-1H-pyrrolo[2,3-b]pyrrolin-2-ones and 1H-pyrrolo[2,3-b]indol-2-ones.
The Pauson-Khand (P-K) reaction is a three-component reaction, formulated as a formal [2+2+1]
cycloaddition of an alkyne, an alkene, and carbon monooxide leading to a cyclopentenone,1 and has been
exploited extensively.2 Recently, allenes have also been utilized successfully in the P-K reaction to give
4- and/or 5-alkylidenecyclopentenones.3
Curiously, however, no examples of the use of a
heterocumulenic system in place of the allene component in either inter- or intramolecular P-K reaction
have been reported so far, despite the fact that it would constitute a novel and potent method for
straightforward construction of five-membered heterocycles or, in some cases, carbocycles in light of the
wide applicability and versatility imparted by this metal carbonyls-assisted cycloaddition. In this context,
we have succeeded in performing a heterocumulenic P-K cycloaddition which incorporates a
carbodiimide functionality and an internal alkyne moiety together with metal carbonyls. We report here
for the first time the heterocumulenic P-K reaction.4 The present P-K reaction also offers a novel and
efficient synthetic method for 4,5-dihydro-1H-pyrrolo[2,3-b]pyrrolin-2-ones and 1H-pyrrolo[2,3-b]indol-
2-ones.
In order to examine the feasibility of the heterocumulenic P-K reaction, we initially selected simple
alkynylcarbodiimides (5) as the key substrates. The carbodiimides (5) were readily prepared from
commercially available alkynols (1) by (a) tosylation, (b) nucleophilic substitution by an azide group, (c)
Staudinger reaction of azides (3) with triphenylphosphine, and by (d) aza-Wittig reaction of
iminophosphoranes (4) with isocyanates (Scheme 1).

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HETEROCYCLES, Vol. 60, No. 5, 2003
R1
R1
c
R1
R1
PPh3
d
a
R1
N C NR2
b
OH
OTs
N3
N
1
2
3
4
5
Scheme 1. Reagents and conditions: (a) TsCl, Et3N, CH2Cl2, 0 ˚C → rt, 3 h, (b) NaN3, DMF, rt, 3-12 h
(82-86 %, two steps), (c) Ph3P, benzene, 80 ˚C, 2 h, (d) R2NCO, benzene, rt, 1 h (27-54 %, two steps).
R1
Me
Me
R1
Mo(CO)6
Promoter
Mo(CO)6
DMSO
O
O
N
N
Ph
N
N
N
C
NR2
N
C
NPh
Toluene,
reflux, 1 h
R2
Toluene,
reflux, 1 h
6a
6
5
5a
Table 1. Efficiency of promoters in the
Pauson-Khand reaction of 5aa
Table 2. Heterocumulenic Pauson-Khand reaction of
alkynylcarbodiimides (5) to give pyrrolopyrrolones (6)a
Entry
R1
R2
Yield of 6a (%)b
Yield of 6 (%)b
Entry
Promoter
1
2
3
4
5
None
0
Trace
21
51
60
a
b
c
d
e
f
Me
Me
Me
Et
Et
Et
Ph
60
53
57
42
47
49
NMO
MeCN
DMF
p-Tol
p-ClC6H4
Ph
p-Tol
p-ClC6H4
DMSO
a) The reactions were carried out using 1.1
equiv. Mo(CO)6 and 5 equiv. promoters.
b) Isolated yield.
a) The reactions were carried out using 1.1 equiv
Mo(CO)6 and 5 equiv. DMSO.
b) Isolated yield.
With alkynylcarbodimides (5) in hand,we attempted the P-K reaction of 5a first using dicobaltoctacarbonyl.
Disappointingly, all attempts to carry out the P-K reaction under various conditions such as thermal
and/or promoter [N-methylmorpholine oxide (NMO),5 DMSO6]-assisted conditions were unsuccessful.†
However, the reactions using molybdenumhexacarbonyl2 in the presence of some promoters indeed
proceeded to yield the expected P-K product, 4,5-dihydro-1H-pyrrolo[2,3-b]pyrrolin-2-one (6a).7 The
representative results are shown in Table 1. Among the promoters tested under refluxing toluene for 1 h,
dimethyl sulfoxide8 was found to provide the best yield of 6a (60 %, Entry 5). The Mo(CO)6-mediated
P-K reaction procedure with the aid of DMSO under the same reaction conditions was also applied to
some other alkynylcarbodiimides (5b-f). The P-K reactions worked well to give 1H-pyrrolo[2,3-
b]pyrrolin-2-ones (6b-f) (Table 2),≠ suggesting that this P-K methodology seems to be promising for the
synthesis of variously substituted 4,5-dihydro-1H-pyrrolo[2,3-b]pyrrolin-2-ones.
In order to probe the generality of this carbodiimide-P-K methodology, we next investigated the reaction
of alkynylcarbodiimides (11) in which both carbodiimide and alkyne functionalities were each connected
with an ortho-phenylene group. Scheme 2 illustrates the preparation of alkynylcarbodiimides (11) from
commercially available o-iodoaniline (7) via (a) diazotization and azide-replacement, (b) Heck coupling
with an alkyne, followed by (c) Staudinger reaction with triphenylphosphine and (d) aza-Wittig reaction

HETEROCYCLES, Vol. 60, No. 5, 2003
1047
R1
R1
R1
I
a
I
b
d
c
N C NR2
NH2
PPh3
N3
N
N3
10
11
7
8
9
Scheme 2. Reagents and conditions: (a) i, NaNO2-aq. HCl, 5-10 ˚C, ii, NaN3, H2O, 5 ˚C, 2 h (84 %),
(b) HCCR1, PdCl2(PPh3)2, CuI, Et3N, CH2Cl2, rt, 1 h ( 99 %), (c) Ph3P, benzene,
rt, 1.5 h (71-95 %), (d) R2NCO, benzene, rt, 3-12 h (60-76 %).
with isocyanates. Treatment of carbodiimide (11a) with Mo(CO)6 in the presence of a promoter under
the same conditions above afforded 3-phenyl-1-propyl-1H-pyrrolo[2,3-b]indol-2-ones (12a) as the
expected P-K product (Table 3). Pentamethylene sulfide actually promoted the P-K reaction but was
less effective with either Mo(CO)6 or Co2(CO)8 contrary to our expectation (Entry 5).9 Again, DMSO
was found to be a good promoter in this reaction. The results of the DMSO-promoted Mo(CO)6-P-K
reactions of 11a-f are summarized in Table 4.≠ Although the Mo(CO)6-mediated P-K reaction of 11
having an unsubstituted acetylene (R1 = H) failed to afford compound (12) (R1 = H), the trimethylsilyl
group in 12d-f could be removed to provide 3-unsubstituted 1H-pyrrolo[2,3-b]indol-2-ones (12).
R1
Ph
R1
Ph
O
Mo(CO)6
DMSO
Mo(CO)6
DMSO
O
NR2
NPrn
N
N C NPrn
N C NR2
N
Toluene,
reflux, 1 h
Toluene,
reflux, 1 h
12
11a
11
12a
Table 3. Efficiency of promoters in the
Pauson-Khand reaction of 11aa
Table 4. Heterocumulenic Pauson-Khand reaction of
alkynylcarbodiimides (11) to give pyrroloindolones (12)a
Entry
R1
R2
Yield of 12a (%)b
Yield of 12 (%)b
Entry
Promoter
1
2
3
4
5
None
NMO
DMF
DMSO
(CH2)5S
0
51
44
55
28
a
b
c
d
e
f
Ph
Ph
Ph
Me3Si
Me3Si
Me3Si
n-Pr
Ph
p-Tol
n-Pr
Ph
55
45
48
50
60
70
a) The reactions were carried out using 1.1
equiv. Mo(CO)6 and 5 equiv. promoters.
b) Isolated yield.
p-Tol
a) The reactions were carried out using 1.1 equiv. Mo(CO)6
and 5 equiv. DMSO.
b) Isolated yield.
In conclusion, we have developed a heterocucmulenic Pauson-Khand reaction for the first time. The
synthetic usefulness of this methodology was demonstrated in the facile and efficient synthesis of 4,5-
dihydro-1H-pyrrolo[2,3-b]pyrrolin-2-ones and 1H-pyrrolo[2,3-b]indol-2-ones by using alkynyl-
carbodiimides as the substrates in the intramolecular cycloaddition.
Further studies on the heterocucmulenic Pauson-Khand methodology to provide a variety of heterocycles
are under way.

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HETEROCYCLES, Vol. 60, No. 5, 2003
† Complexation of the alkyne moiety of 5a/11a with dicobaltoctacarbonyl seems to be successful, but
attempts to promote the cycloaddition resulted in decomposition
≠ The reaction in refluxing toluene gave the P-K products (6/12) albeit in relatively low yields (42-
70 %) accompanying polymerization or deterioration of 5/11, while in refluxing benzene (at about 80 ˚C)
the reaction hardly occurred.
REFERENCES AND NOTES
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(0.13 mL, 1.88 mmol) in toluene (5 mL) was heated under reflux (120 ˚C) for 1 h. After being
cooled, the mixture was evaporated and the residue was briefly chromatographed with
dichrolomethane as eluant on a short silica gel column and further purified by thin-layer silica gel
chromatography (50 v/v % AcOEt-hexane) to give 3-methyl-1-phenyl-4,5-dihydro-1H-pyrrolo[2,3-
1
b]pyrrolin-2-one (6a) (48 mg, 60 % yield); mp 94.2-94.8 ˚C; IR (KBr) 1728, 1540 cm-1; H NMR
(400 MHz, CDCl3) δ 2.03 (t, J = 2.2 Hz, 3H), 2.80 (ddq, J = 4.4, 4.4, 2.2, 2H), 4.36 (dd, J = 4.4, 4.4,
2H), 7.24-7.28 (m, 1H), 7.32-7.46 (m, 2H), 7.68-7.70 (m, 2H); 13C NMR (100 MHz, DEPT, CDCl3) δ
9.62 (q), 24.43 (t), 62.82 (t), 123.44 (dx2), 123.97 (s), 126.23 (d), 128.97(dx2), 134.50(s), 145.80(s),
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