A versatile synthesis of polysubstituted pyrroles

Article abstract of DOI:10.1016/S0040-4039(01)01203-5

The aldol products formed by the reaction between α-(N-benzyl or N-Cbz)amino aldehydes and lithium enolates of various ketones, were subjected to hydrogenolysis to give polysubstituted pyrroles in good yields (50-91%). The scope and limitations of this me

Full text of DOI:10.1016/S0040-4039(01)01203-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6027–6030
A versatile synthesis of polysubstituted pyrroles
Bharat Lagu,* Meng Pan and Michael P. Wachter
The R. W. Johnson Pharmaceutical Research Institute, Route 202, PO Box 300, Raritan, NJ 08869, USA
Received 27 June 2001; accepted 6 July 2001
Abstract—The aldol products formed by the reaction between a-(N-benzyl or N-Cbz)amino aldehydes and lithium enolates of
various ketones, were subjected to hydrogenolysis to give polysubstituted pyrroles in good yields (50–91%). The scope and
limitations of this methodology are explored. © 2001 Elsevier Science Ltd. All rights reserved.
Pyrroles have been used as a pharmacophore by many
research laboratories, which has led to development of
new methodologies for the synthesis of pyrroles.1 Dur-
ing the course of a program targeted towards the
synthesis of anti-inflammatory agents, an easy access
to polyalkylated pyrroles, which did not bear electron-
withdrawing groups, was warranted. A majority of the
known synthetic routes were found to be of limited
utility as they either lead to pyrroles bearing electron-
withdrawing groups or were not amenable for incor-
poration of a variety of alkyl or aryl substituents on
the pyrrole ring.2,3
2,5-diaryl pyrroles were thought to be limitations of
this synthetic route.
We were intrigued by the elegant synthesis of pyrroles
reported by Cushman and coworkers which utilizes aldol
products formed by the reaction between (N-Boc)-a-
amino aldehydes and ketones (Eq. (2)).5 Some notewor-
thy features of this synthetic route are the ready
availability of the starting materials, mild conditions and
the number of substituents at R1, R2 and R3 that can be
accessed. However, the yields were rather modest (5–
40%) and in all cases pyrroles with alkyl substituents on
the nitrogen could not be accessed by this route.6 A
possible explanation for the low yields could be a rapid
polymerization of the resulting pyrroles under the acidic
conditions employed. We reasoned that if one could
replace the tert-butoxycarbonyl group on the nitrogen
with another protecting group that can be removed under
relatively neutral conditions, the yields of pyrroles could
be improved and allow for a number of substituents to
be introduced on the pyrrole nitrogen.
A novel synthesis of polysubstituted pyrroles was
reported recently by Dieter and Yu via conjugate
addition of a-amino-alkylcuprates to alkynyl ketones
followed by amine deprotection and cyclization (Eq.
(1)).4 However, the need to synthesize alkynyl ketones,
the possibility of obtaining regioisomers when R1 and
R2 are unsymmetrical, and the inability to synthesize
R3
R1 R2
N
R1 R2
1. sec-BuLi
PhOH
O
R2
R4
N
(1)
N
TMSCl
2. CuCN.2LiCl
Boc R3 R4
Boc
3.
R3
COR4
R1
41-85%
Li
O
R2
R3
O
OH O
R2
cat. HCl
R1
R1
R3
(2)
H
R3
R1
N
HN
NH R2
Boc
Boc
Boc
5-40% yield
* Corresponding author. Tel.: 908-704-4291; fax: 908-526-6469; e-mail: blagu@prius.jnj.com
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01203-5

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B. Lagu et al. / Tetrahedron Letters 42 (2001) 6027–6030
HO
R1
R3
R4
O
OH O
R3
Li
O
R1
R2
R1
R2
R3
Hydrogenation
H
R4
R4
O
NH
N
N
R2
Ph
Ph
2
1
R3
HO
R1
HO
R1
R3
R4
R3
R4
H
– H2O
-H
R1
R4
N
N
N
R2
R2
R2
5
3
4
Scheme 1.
A benzyl group was considered as a potential replace-
ment for the tert-butoxycarbonyl group on the nitrogen
of the a-amino aldehydes to be used in the aldol
reactions. Aldol reactions of a-(N,N-dibenzyl)amino
aldehydes or a-(N,N-dibenzyl)amino ketones have been
reported by a number of groups.7 We speculated that
deprotection of the benzyl groups could lead to forma-
tion of an iminium ion (3) which could undergo a
deprotonation to provide an enamine (4) (Scheme 1).
The enamine can then undergo dehydration to yield
pyrrole (5).
The required a-(N,N-dibenzyl)amino aldehydes were
synthesized by Swern oxidation of the b-(N,N-dibenz-
yl)amino alcohols which were obtained from the com-
mercially available b-amino alcohols.8 The a-(N,N-
dibenzyl)amino aldehydes were reacted with lithium
enolates of various ketones at −78°C to obtain the
corresponding aldol products in 70–90% yield. The
aldol products, when subjected to standard hydrogena-
tion conditions (1 atm of H2 in the presence of palla-
dium black in methanol, 1–4 h), gave the corresponding
pyrroles 6–15 in good yields (Table 1).9,10 It is evident
Table 1.

B. Lagu et al. / Tetrahedron Letters 42 (2001) 6027–6030
6029
that various substituents, including the sterically
demanding tert-butyl group, are tolerated at the 2-, 3-
and 5-positions of the pyrroles. The synthetic method-
ology is flexible enough to yield a variety of substituent
combinations and 1,2-di-, 1,2,3-tri-, 1,2,5-tri- and
1,2,3,5-tetra-substituted pyrroles can be synthesized.
Pyrroles fused to carbocyclic rings (8 and 10) can also
be accessed using this synthetic route.
group and a benzyl group (18) or between a carboben-
zyloxy group and a benzyl group11 (12, Table 2, entry
5) to achieve chemoselective removal of one of the
protecting groups. In contrast, when a chemoselective
removal of the p-methoxybenzyl group was attempted
by ceric ammonium nitrate (Eq. (3)),12 formation of
pyrrole 12 was evident only by mass spectroscopy and
thin layer chromatography of the reaction mixture.
Attempts to isolate the pyrrole were unsuccessful. This
result highlights the mild conditions reported in this
letter. Pyrrole without a substituent on the nitrogen
(19) could not be synthesized by the methodology.
When N-benzyl prolinal was used as the a-amino alde-
hyde (entry 7), 6-methyl-5-phenyl-2,3-dihydro-1H-
pyrrolizine (20) was formed in 52% isolated yield.
The methodology described herein allows for the intro-
duction of a number of alkyl and aryl substituents on
the nitrogen of pyrroles (Table 2, 12 and 16–18) that
cannot be readily synthesized using known procedures.
In addition, we were able to exploit the differences in
the rates of hydrogenation between a p-methoxybenzyl
Table 2.

6030
B. Lagu et al. / Tetrahedron Letters 42 (2001) 6027–6030
OH
O
CH3
4582–4593; (e) DeLaszlo, S. E.; Mantlo, N. B.; Ponti-
cello, G. S.; Selnick, H. G.; Liverton, N. J. WO 97/05878
(Feb. 20, 1997).
Ceric ammonium nitrate
CH3CN-H2O
Ph
Ph
N
N
CH3
Ph
PMB
(3)
12
2. (a) Bean, G. P. In The Chemistry of Heterocyclic Com-
pounds; Jones, A. R., Ed.; Wiley: New York, 1990; Vol.
48, Part 1, Chapter 2, p. 105; (b) Sundberg, R. J. Prog.
Heterocyclic Chem. 1994, 6, 110.
Ph
Observed by mass spectroscopy
and TLC. Decomposed during work-up
3. For examples of pyrroles without electron-withdrawing
groups, see: (a) Lee, C. W.; Chung, Y. J. Tetrahedron
Lett. 2000, 41, 3423–3425; (b) Vessels, J. T.; Janicki, S.
Z.; Petillo, P. A. Org. Lett. 2000, 1, 73–76; (c) Trost, B.
M.; Keinan, E. J. Org. Chem. 1980, 45, 2741–2746.
4. Dieter, R. K.; Yu, H. Org. Lett. 2000, 2, 2283–2286.
5. (a) Cushman, M.; Nagafuji, P. J. Org. Chem. 1996, 61,
4999–5003; (b) Konieczny, M. T.; Cushman, M. Tetra-
hedron Lett. 1992, 33, 6939–6940.
6. Intermediates similar to the aldol products (i.e. g-acetam-
ido-b-hydroxy ketones) have been synthesized from isox-
azolines and were converted into 1-acetyl-2-aryl pyrroles.
See: (a) Ghabrial, S. S.; Thomsen, I.; Torssell, K. B. G.
Acta Chem. Scand. Ser. B 1987, 41, 426–434; (b) Mukerji,
S. K.; Sharma, K. K.; Torssell, K. B. G. Tetrahedron
1983, 39, 2231–2235.
A brief survey of other hydrogenation conditions
revealed that palladium black can be replaced with 10%
Pd–C or Pd(OH)2 as catalysts for the removal of the
benzyl group. The pH of the reaction mixture under
standard hydrogenation conditions was around 7.
Addition of a trace of acetic acid (<5 mL) shortened the
reaction time significantly while the addition of K2CO3
was found to hinder the rate of debenzylation. Pyrroles
can also be obtained in comparable yields under trans-
fer hydrogenation conditions with ammonium for-
mate,13 cyclohexadiene14 or formic acid15 as the
hydrogen donors.
The possible limitation of the methodology described
herein could be that the presence of certain functional
groups (e.g. mercaptans, thioethers, halogens or nitro
group) will not be tolerated due to possible poisoning
of the catalyst, dehalogenation or reduction under the
hydrogenation conditions.
7. Reetz, M. T. Chem. Rev. 1999, 99, 1121–1162 and refer-
ences cited therein.
8. Reetz, M. T.; Drews, M. W.; Schmitz, A. Angew. Chem.,
Int. Ed. Engl. 1987, 26, 1141.
9. The polysubstituted pyrroles were prone to polymeriza-
tion as evidenced by a change in the appearance of the
purified products over time (colorless oil turning pink in
a few hours).3c An internal standard was used to estimate
the yields in an accurate manner.
Thus, a versatile synthesis of polysubstituted pyrroles
was accomplished from the aldol product of a reaction
between a suitably protected aldehyde and an enolate.
The salient features of the synthetic methodology are:
(1) the flexibility to synthesize pyrroles with various
substituents at the 1-, 2-, 3-, and 5-positions; (2) a wide
selection of substituents that can be accessed from
commercially available ketones and amino acids; and
(3) use of mild reaction conditions. Further modifica-
tions of this methodology and applications to biologi-
cally important compounds are currently under
investigation.
10. Synthesis of 17 (typical procedure): To a cold solution
(ice bath) of 4-(benzylphenylamino)-3-hydroxy-2-methyl-
1-phenylbutan-1-one (50 mg, 0.14 mmol) in
5 mL
CD3OD was added Pd black (40 mg) and a balloon filled
with H2 was placed on top of the flask. After about 2 h,
the catalyst formed clumps and TLC (10% EtOAc/Hex)
1
and H NMR of the supernatant solution indicated that
the reaction was complete. Then tert-butyl-1-pyrrolecar-
boxylate (23.3 mL, 0.14 mmol) was added and the reac-
tion mixture was stirred for 5 min. Yield was determined
based on integration of pyrrole peaks of the product and
the internal standard between 5.8 and 7.0 ppm in 1H
NMR.
Acknowledgements
The authors thank Dr. William Murray for his support.
References
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