Efficient pyrrole synthesis using double nucleophilic addition to α,β-unsaturated imines with plural nucleophiles

Article abstract of DOI:10.1021/ol0615634

2,3,5-Trisubstituted pyrroles were prepared in a regioselective manner using the double nucleophilic addition of α,α-dialkoxy ketene silyl acetals and ketene sily thioacetals or trimethylsilyl cyanide to α,β-unsaturated !mines followed by acid-promoted cy

Full text of DOI:10.1021/ol0615634

ORGANIC
LETTERS
2006
Vol. 8, No. 16
3585-3587
Efficient Pyrrole Synthesis Using Double
Nucleophilic Addition to
r,â-Unsaturated Imines with Plural
Nucleophiles
Makoto Shimizu,* Atsushi Takahashi, and Shiho Kawai
Department of Chemistry for Materials, Graduate School of Engineering, Mie
UniVersity, Tsu, Mie 514-8507, Japan
mshimizu@chem.mie-u.ac.jp
Received June 26, 2006
ABSTRACT
2,3,5-Trisubstituted pyrroles were prepared in a regioselective manner using the double nucleophilic addition of
r,r-dialkoxy ketene silyl
acetals and ketene sily thioacetals or trimethylsilyl cyanide to
r,â-unsaturated imines followed by acid-promoted cyclization and oxidation
with DDQ. Using this methodology an imidazole glycerol phosphate dehydratase inhibitor (IGPDI) possessing a monopyrrole aldehyde moiety
was synthesized.
Widespread existence of biologically important pyrrole
derivatives1 coupled with the need to construct such a
skeleton in an efficient manner prompted us to explore a
new methodology.2 A potentially effective approach to
construct a pyrrole ring involves cyclization of γ-amino
carbonyl compounds followed by dehydrogenation. For the
synthesis of γ-amino carbonyl compounds, crucial intermedi-
ates in this strategy, nucleophilic addition to γ-oxoimines
constitutes a straightforward pathway. However, difficulty
has often been encountered for the synthesis of γ-oxoimines
due to susceptibility to hydrolysis and/or isomerization.3 For
circumvention of such a drawback of isolating relatively
unstable imine intermediates as well as use of an operation-
ally simple experimental procedure, we have recently
introduced a double nucleophilic addition reaction to R,â-
unsaturated imines.4 When R,R-dialkoxy ketene silyl acetal,
an acyl anion equivalent, is used as the first nucleophile,
this methodology offers a facile synthetic route to γ-amino
carbonyl synthons. This paper describes a straightforward
(1) (a) Annoura, H.; Tatsuoka, T. Tetrahedron Lett. 1995, 36, 413. (b)
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T.; Nishi, T. Tetrahedron Lett. 2001, 42, 5463.
10.1021/ol0615634 CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/08/2006

approach to γ-amino carbonyl compounds and the subsequent
transformation into 2,3,5-trisubstituted pyrroles (Scheme 1),
addition acceptors (Table 1, entries 1, 2, and 4). The best
diastereomeric excess was obtained using N-4-methoxycro-
tylidenimine (entry 4). Use of the 4-dimethylaminophenyl
derivative recorded both a decreased product yield and a
diastereomeric excess presumably due to the coordination
of the nitrogen atom of the 4-dimethylaminophenyl group
with AlCl3 (entry 6). We next examined use of ketene silyl
thioacetal 3 (Table 1, conditions B) or trimethylsilyl cyanide
4 (Table 1, conditions C) as the second nucleophile, with
ketene silyl acetal 2 as the first nucleophile to give the double
addition product 6 or 7, respectively. The reactions proceeded
regio- and chemoselectively. We found that the ketene silyl
acetal 2 underwent 1,4-addition, whereas the ketene silyl
thioacetal 3 or trimethylsilyl cyanide 4 underwent 1,2-
addition in a highly regioselective manner, where the only
byproduct obtained was a negligible amount of 1,2-addition
product derived from 1 with 2.
All the 1,4- and 1,2-addition products obtained were
converted readily into the corresponding multisubstituted
pyrroles via cyclization into dihydropyrrole with acids such
as H2SO4, methanesulfonic acid, and TFA followed by
dehydrogenation with DDQ (Table 2). Both steps proceeded
to give the products in high yield. Cyclization of the adduct
5b needed a slightly longer reaction time for completion in
Scheme 1. Present Strategy for the Synthesis of Pyrroles
which enables a six-step synthesis of imidazole glycerol
phosphate dehydratase inhibitors (IGPDIs) of herbicidal
activity.5
For the synthesis of γ-amino carbonyl compounds, an
initial reaction was carried out using imine 1 and ketene silyl
acetal 2 (3.0 equiv) in CH2Cl2 in the presence of aluminum
chloride (1.0 equiv) and MS 4Å containing H2O at -78 °C
to room temperature to give the double addition product 5
in good yield with syn-selectivity (Table 1, conditions A).
Table 1. Double Nucleophilic Addition to R,â-Unsaturated
Imines 1a
Table 2. Transformation into Dihydropyrrole and Pyrrolea
condi- time
tions (h) product (%)b syn:antic
entry R1
R2
1
2
3
4
5
6
7
8
9
Ph PMP
Ph Ph2CH
Ph 4-Me2NC6H4
Me PMP
A
A
A
A
B
B
B
B
C
C
8.5
9.5
13.0
9.5
11.5
14.0
14.0
14.0
17.0
16.0
5a
5b
5c
5d
6e
6f
6g
6h
7i
85
80
66
90
80
63
62
70
55
95
87:13
75:25
76:24
99: 1
90:10
55:45
85:15
67:33
94: 6
88:12
entry 5,6,7 dihydropyrrole (%)b time (h)c pyrrole (%)b
1
2
5a
5b
5c
5d
6e
6f
8a
8b
8c
8d
9e
9f
88
96
13.0
13.0
13.0
13.0
12.5
12.5
12.5
12.5
12.0
12.0
11a
11b
11c
11d
12e
12f
quant
95
Ph PMP
Ph 4-Me2NC6H4
Ph 2,4-(MeO)2C6H3
Me PMP
3
4
5
6
7
8
9
10
quant
69d
73
quant
66
62
93
97
69
74
80
Ph PMP
67e
10 Me PMP
7j
6g
6h
7i
9g
9h
10i
10j
79e
86
quante
86e
12g
12h
13i
a See typical procedure. b Isolated yields. c Determined by HPLC and/
or1H NMR.
7j
13j
a See typical procedure. b Isolated yields. c Time for dehydrogenation.
The 4-methoxyphenyl (PMP) or diphenylmethyl group at the
nitrogen atom was the substituent of choice for the double
d H2SO4:H2O ) 2:1. The reaction time was 6.5 h. e H2SO4:H2O ) 1:1.
3586
Org. Lett., Vol. 8, No. 16, 2006

the presence of a 2:1 mixture of H2SO4 and H2O (entry 4).
Regarding the instances where the cyclization was relatively
harsh, use of increased amounts of H2O improved the product
yields (entries 6, 7, 9, and 10). Subsequent dehydrogenation
with DDQ proceeded to give pyrroles in good to excellent
yields.
A similar cyclization into dihydropyrrole was effected by
TBAF, albeit in moderate yield, when the TMS ether
derivative 14 prepared from 1,2-bis(trimethylsiloxy)-1,2-
diethoxyethene was used (Scheme 2).
cyanide 4 were treated with N-4-methoxycrotylidenimine 1j
in the presence of AlCl3 to give the doubly alkylated product
7j in 95% yield (see Table 1, entry 10). Removal of the PMP
7
group was carried out by oxidation with PhI(OAc)2 followed
by the protection of the formed amine functionality with a
Boc group because of the difficulty in removing of PMP
group after cyclization into the pyrrole. The Boc-protected
double-addition product 15 was treated with MeSO3H and
DDQ to afford the pyrrole 16 in 92% yield (2 steps), where
the NH-free dihydropyrrole intermediate was not isolated.
Finally reduction of the cyano group with Raney-Ni W4 in
8
the presence of NaPH2O2 gave the desired monopyrrole
aldehyde 17 in 73% yield.
Scheme 2. Cyclization Effected by TBAF
In conclusion, we have found an efficient synthesis of
2,3,5-trisubstituted pyrroles in a regioselective manner using
the double nucleophilic addition to R,â-unsaturated aldi-
mines. The synthetic utility of the methodology was dem-
onstrated in the construction of various types of pyrroles, in
particular the IGPDI 17. This strategy for the preparation of
pyrroles may be applied to the synthesis of multisubstituted
derivatives of useful bioactivity.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Culture, Sports, Science, and Technology, Japan.
As an application of the present methodology, a synthesis
of the IGPDI 17 possessing herbicidal activity6 was carried
out (Scheme 3). The ketene silyl acetal 2 and trimethylsilyl
Supporting Information Available: Experimental pro-
cedures and product characterization. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
OL0615634
Scheme 3. Synthesis of IGPDI
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