A facile synthesis of polysubstituted pyrroles

Article abstract of DOI:10.1021/ol006050q

(equation presented) α-Aminoalkylcuprates prepared from CuX·2LiCI (X = Cl, CN) and 1 equiv of an α-lithiocarbamate undergo conjugate addition reactions to α,β-alkynyl ketones in moderate to good yields, affording E:Z mixtures of α,β-enones. Treatment of the conjugate adducts with PhOH/TMSCI in CH₂CI₂ effected carbamate deprotection and cyclization to afford a flexible two-step synthesis of substituted pyrroles.

Full text of DOI:10.1021/ol006050q

ORGANIC
LETTERS
2000
Vol. 2, No. 15
2283-2286
A Facile Synthesis of Polysubstituted
Pyrroles
R. Karl Dieter* and Huayun Yu
Howard L. Hunter Chemistry Laboratory, Clemson UniVersity,
Clemson, South Carolina 29634-0973
dieterr@clemson.edu
Received May 11, 2000
ABSTRACT
r-Aminoalkylcuprates prepared from CuX‚2LiCl (X ) Cl, CN) and 1 equiv of an r-lithiocarbamate undergo conjugate addition reactions to
r,â-alkynyl ketones in moderate to good yields, affording E:Z mixtures of r,â-enones. Treatment of the conjugate adducts with PhOH/TMSCl
in CH Cl2 effected carbamate deprotection and cyclization to afford a flexible two-step synthesis of substituted pyrroles.
2
Pyrroles represent an important class of heterocyclic com-
pounds,1,2 and numerous synthetic routes exist for their
preparation.3 Many procedures, however, provide limited
access to pyrroles in terms of substituents and substitution
patterns. One broad strategy employs 1,4-conjugate addition
reactions to construct the carbon skeleton of the pyrrole
framework followed by cyclization reactions. Conjugate
addition reactions of R-aminoketones to acetylenic esters,
enamines to chloroacrylonitrile, betaines to activated alkynes,
R-amino acid derivatives to R,â-unsaturated esters or nitriles,
and R-azido esters to malononitriles4 afford pyrroles with a
wide range of substitution patterns.3a With the exception of
the chloroacrylonitrile procedure which affords 2,3-disub-
stituted pyrroles, these conjugate addition routes lead to
pyrroles containing electron-withdrawing groups (EWG) at
the 3-position (e.g., CN, CHO, CO2R, etc.). The conjugate
addition of isocyanide-derived carbanions stabilized with an
additional EWG to a variety of R,â-unsaturated functional
groups (e.g., ester, ketone, nitro, and sulfone) provides a
general route to substituted pyrroles containing an EWG.5
In some instances the EWG can be removed in a subsequent
step. Polysubstituted pyrroles are also available from transi-
tion metal intermediates (e.g, W,6a-c Cr,6c-d Zr,6e Ti6f),
reductive couplings,7 and aza Wittig reactions8 and by several
(5) For use of active methylene compounds containing an electron-
withdrawing group (EWG) and an isocyanide group, see: (a) Trudell, M.
L.; Pavri, N. P. J. Org. Chem. 1997, 62, 2649 (b) Katrizky, A. R.; Cheng,
D.; Musgrave, R. P. Heterocycles 1997, 44, 67. (c) Adamczyk, M.; Reddy,
R. E. Tetrahedron Lett. 1995, 36, 7983 and 9121. (d) Dijkstra, H. P.; ten
Have, R.; van Leusen, A. M. J. Org. Chem. 1998, 63, 5332. (e) Ono, N.;
Miyagawa, H.; Ueta, T.; Ogawa, T.; Tani, H. J. Chem. Soc., Perkin Trans.
1 1998, 1595. (f) Abel, v. Y.; Haake, E.; Haake, G.; Schmidt, W.; Struve,
D.; Walter, A.; Montforts, F.-P. HelV. Chem. Acta 1998, 81, 1978. (g) Di
Santo, R.; Costi, R.; Massa, S.; Artico, M. Synth. Commun. 1998, 28, 1801.
(6) For use of transition metal intermediates in polysubstituted pyrrole
synthesis, see: (a) Iwasawa, N.; Maeyama, K.; Saitou, M. J. Am. Chem.
Soc. 1997, 119, 1486. (b) Iwasawa, N.; Ochiai, T.; Maeyama, K. J. Org.
Chem. 1998, 63, 3164. (c) Aumann, R. Chem. Ber. 1993, 126, 2325. (d)
Danks, T. N.; Velo-Rego, D. Tetrahedron Lett. 1994, 35, 9443. (e) Dekura,
F.; Honda, T.; Mari, M. Chem. Lett. 1997, 825. (f) Gao, Y.; Shirai, M.;
Sato, F.; Tetrahedron Lett. 1996, 37, 7787.
(1) For biologically important pyrroles see: (a) Lainton, J. A. H.;
Huffman, J. W.; Martin, B. R.; Compton, D. R. Tetrahedron Lett. 1995,
36, 1401. (b) De Leon, C. Y.; Ganem, B. Tetrahedron 1997, 53, 7731. (c)
Jacobi, P. A.; Coutts, L. D.; Guo, J. S.; Hauck, S. I.; Leung, S. H. J. Org.
Chem. 2000, 65, 205. (d) Gupton, J. T.; Krumpe, K. E.; Burnham, B. C.;
Dwornik, K. A.; Petrich, S. A.; Du, K. X.; Bruce, M. A.; Vu, P.; Vargas,
M.; Keertikar, K. M.; Hosein, K. N.; Jones, C. R.; Sikorski, J. A.
Tetrahedron 1998, 54, 5075.
(2) (a) For the chemistry of macrocycles containing pyrrole units, see:
Sessler, J. L.; Weghorn, S. J. Expanded, Contracted & Isomeric Porphyrins;
Elsevier Science Ltd: Oxford, 1997. For pyrrole based dyes, see: Thoresen,
L. H.; Kim, H.; Welch, M. B.; Burghart, A.; Burgess, K. Synlett 1998,
1276.
(3) (a) Bean, G. P. In The Chemistry of Heterocyclic Compounds; Jones,
A. R., Ed.; Wiley: New York, 1990; Vol. 48, Part 1, Chapter 2, p 105. (b)
Gilchrist, T. L. J. Chem. Soc., Perkin. Trans. 1 1998, 615.
(4) Marco, J. L.; Martinez-Grau, A.; Martin, N.; Seoane, C. Tetrahedron
Lett. 1995, 36, 5393.
(7) (a) Fu¨rstner, A.; Weintritt, H.; Hupperts, A. J. Org. Chem. 1995, 60,
6637. (b) Quiclet-Sire, B.; The´venot, I.; Zard, S. Z. Tetrahedron Lett. 1995,
36, 9496.
(8) Katritzky, A. R.; Jiang, J.; Steel, P. J. J. Org. Chem. 1994, 59, 4551.
10.1021/ol006050q CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/29/2000

useful multistep pathways.9 Conjugate addition of R-amino-
alkylcuprates to alkynyl ketones followed by amine depro-
tection and cyclization (eq 1) provides a potential synthetic
reagents with acid chlorides.11 Lithiation of the tert-butyl-
dimethylsilyl ether of propargyl alcohol, quenching with
acetaldehyde, and subsequent oxidation [MnO2 (10 equiv),
CH2Cl2, 25 °C] of the resultant alcohol afforded alkynyl
ketone 9.12 The availability of several methods for the
preparation of R,â-alkynyl ketones allows for the introduction
of a wide range of substituents at positions 3 and 5 of the
pyrrole ring system.
The first step in this synthetic protocol involves the
conjugate addition of R-aminoalkylcuprates to alkynyl
ketones. Initial studies employing CuCN and 2 equiv of the
R-lithiocarbamate, generated via Beak’s deprotonation pro-
cedure13 [sec-BuLi, THF, -78 °C, 1 h], gave modest yields
of conjugate adducts as 1:1 to 3:1 mixtures of E:Z diaster-
eomers. Higher yields of conjugate adducts were obtained
with the cyanocuprate reagent (RLi + CuCN‚2LiCl) or an
organocopper reagent prepared from CuCl‚2LiCl and 1 equiv
of the R-lithio carbamate (Table 1). Presumably the latter
reagent involves either a chlorocuprate reagent (i.e., RCu-
ClLi) or is analogous to the RCu/TMEDA reagent reported
by Johnson.14 R-Aminoalkylcuprates prepared from tert-
butoxycarbonyl (Boc) protected N,N-dimethylamine, pyrro-
lidine, and piperidine underwent clean high yield conjugate
additions to methyl alkynyl ketones (Table 1, entries 1-2
and 6-9) but gave little to no conjugate addition with a
corresponding phenyl ketone (entry 5). The successful
route to polysubstituted pyrroles. Inability to control olefin
stereochemistry in the γ-amino-R,â-enone adduct could pose
serious problems unless both stereoisomers can be cyclized
to the corresponding pyrrole. In conjunction with our work
on N-Boc-protected R-aminoalkylcuprates,10 we have devel-
oped a versatile two-step synthesis of pyrroles that overcomes
these problems and that can accommodate a variety of
substituents and substitution patterns.
The alkynyl ketones 5-8 are readily available from
terminal acetylenes via reaction of alkynyl organozinc
Table 1. Reaction of R-Aminoalkylcuprates with R,â-ynones Followed by Deprotection and Cyclization to Pyrroles
a Boc-protected amines were deprotonated [sec-BuLi, THF, sparteine or TMEDA, -78 °C, 1 h] to form R-lithiocarbamates (RLi). b Treatment of RLi
with CuX‚2LiCl (X ) Cl, CN, -78 °C, 1 h, 1.0 equiv) gave the cuprate RCuXLi. c Enones generated from R-aminoalkylcuprates and alkynyl ketones [THF,
-78 °C to room temperature]. d Yields based upon isolated products purified by flash column chromatography unless otherwise noted. e E:Z isomer ratio
was determined by 1H NMR integration ratio and/or 13C peak heights. f Pyrroles were formed upon treatment of Boc-protected γ-aminoketones with PhOH
(30 equiv) and TMSCl (10 equiv) in CH2Cl2 at room temperature and gave satisfactory NMR, and 13C NMR, data. g Performed on a 5 mmol scale. h See
ref 17. i Yields determined by NMR using CH2Cl2 as internal standard. j Yield obtained from pure (E)-enone. k Yield obtained from pure (Z)-enone. l n )
1. m n ) 2. n Yield corresponds to the overall yield for conjugate addition and pyrrole formation. o Present as the major isomer in a 69:31 ratio with N-benzyl-
2-methyl-4-butylpyrrole. p Present as the major isomer in a 70:30 ratio (obtained in both THF and PhMe/THF) with N-benzyl-2-methyl-4-phenylpyrrole.
q Enolate anion generated by the conjugate addition reaction was quenched with N-bromosuccinimide (NBS).
2284
Org. Lett., Vol. 2, No. 15, 2000

conjugate addition to a tert-butyl ynone (entry 6) suggests
that the failure with phenyl ynones lies in electronic factors.
Steric factors did play a role with 4-trimethylsilyl-3-butyn-
2-one which failed to react with the cuprate derived from 1.
Although alkynyl ketone 9 gave modest yields (i.e., 46%)
of the conjugate adduct with the cuprate derived from 1,
5-chloro-3-butyn-2-one gave low yields (10%) of the 1,4-
addition product and the major products appeared to arise
via SN2′ substitution of the propargyl chloride. R-Amino-
alkylcuprates prepared from Boc-protected benzylic amines
also undergo a conjugate addition reaction to R,â-alkynyl
ketones (entries 10-11), permitting introduction of an
aromatic substituent at C2. Benzyl methyl carbamate 4
underwent competitive deprotonation at the methyl group,
giving a 70:30 mixture of the N-methyl and N-benzyl
pyrroles in both THF and toluene/THF (entries 10-11),
although previous reports noted a solvent dependence for
the regioisomeric deprotonation.15 Although these conjugate
addition reactions produced mixtures of E and Z diastereo-
mers that varied from experiment to experiment, the desired
Z isomer could not be selectively formed under a variety of
reaction conditions. The stereochemistry of the conjugate
adducts was established by difference NOE experiments on
the addition product of 1 and 6 (entry 2) and the configuration
of the other enones was assigned by analogy with the
chemical shifts of the olefinic protons.16 The proton absorp-
tion between δ 6.01-6.50 was assigned to the Z diastereomer
while the absorption between δ 5.87-6.07 was assigned to
the E diastereomer, consistent with previous observations
and consistent with the NOE experiments performed on the
isolated E and Z diastereomers obtained from carbamate 1
and ynone 6.
and methyl carbons, both regioisomeric pyrroles were
obtained, illustrating the effectiveness of the PhOH/TMSCl
carbamate deprotection-cyclization sequence. Elegant stud-
ies by Merrifield and co-workers has established that Boc
deprotection under these conditions is not effected by HCl
which is only slowly generated from PhOH/TMSCl and then
largely from the water present in commercial phenol. The
addition of Me3SiCl to PhOH in CH2Cl2 lowers the pKa from
10 (1 M PhOH in CH2Cl2) to 2 and the acidity of this
medium contributes to Boc cleavage which is second order
in phenol. Although Boc cleavage generates HCl as a
byproduct in the reaction medium, control experiments19
revealed that anhydrous HCl in CH2Cl2 (from AcCl and
MeOH, 10 mol %, 4 h) did not effectively promote Boc
cleavage. Although traces of HCl are sufficient to effect
isomerization of R,â-unsaturated ketones, the underlying
mechanism of this cyclization process which effectively
converts both the E and Z diastereomers to pyrroles remains
to be elucidated.19 The use of excess PhOH/TMSCl (30:10
equiv) posed difficulties in the workup and isolation of the
pyrrole products. Subsequent experimentation revealed that
the deprotection and cyclization could be effected with
reduced quantities of PhOH/TMSCl in identical yields.
Procedurally, the γ-amino enone (1 mmol) was dissolved in
dry CH2Cl2, PhOH (10 equiv) and TMSCl (3 equiv) were
added at room temperature, and the mixture was stirred at
room temperature (3 h). The reaction mixture was diluted
with ether and washed with 10% KOH to remove the phenol,
and the KOH washings were extracted with ether. Combina-
tion of the organic phases and concentration afforded the
crude products which were purified by flash chromatography
(silica gel). Reactions performed on a 6-7 mmol scale
generally gave higher yields than the 1 mmol scale reported
in Table 1. The relatively high yields of these cyclization
reactions suggested that both the Z and E diastereomers were
undergoing cyclization to the pyrrole under the reaction
conditions. This was confirmed by isolation of the individual
E and Z diastereomers obtained from 1 and 6 and conversion
of each isomer to the same pyrrole in nearly identical yields
(entries 3-4). These results indicate that the R,â-enones are
much more prone to isomerization under these reaction
conditions than the corresponding R,â-enoates.10c,19 The
PhOH/TMSCl protocol readily converted all of the γ-amino
Several efforts to effect Boc deprotection and pyrrole
formation were unsuccessful, giving either trace amounts of
product and starting material [CH2Cl2, concentrated HCl,
1-2 drops or anhydrous HCl (10 mol %) from AcCl and
MeOH] or complex mixtures containing no pyrrole
[TMSOTf (1.2 equiv), CH2Cl2, -20 °C, 4 h and acetyl
bromide (1.2 equiv), MeOH (5.0 equiv), CH2Cl2]. Treatment
of the conjugate adducts with PhOH/TMSCl18 in methylene
chloride effected deprotection of the amine and subsequent
cyclization to afford the desired pyrrole. When deprotonation
of carbamate 4 occurred competitively at both the benzylic
(9) (a) Arcadi, A.; Rossi, E. Tetrahedron 1998, 54, 15253. (b) Yasuda,
M.; Morimoto, J.; Shibata, I.; Baba, A. Tetrahedron Lett. 1997, 38, 3265.
(c) Aoyagi, Y.; Mizusaki, T.; Ohta, A. 1996, 37, 9205. (d) Barluenga, J.;
Toma´s, M.; Kouznetsov, V.; Sua´rez-Sobrino, A.; Rubio, E. J. Org. Chem.
1996, 61, 2185. (d) Katritzky, A. R.; Li, J. J. Org. Chem. 1996, 61, 1624.
(e) Nagafuji, P.; Cushman, M. J. Org. Chem. 1996, 61, 4999. (f) Hamby,
J. M.; Hodges, J. C. Heterocycles 1993, 35, 843.
(10) For conjugate addition reactions of R-aminoalkylcuprates, see: (a)
Dieter, R. K.; Alexander, C. W. Tetrahedron Lett. 1992, 33, 5693. (b) Dieter,
R. K.; Alexander, C. W. Synlett 1993, 407-409. (c) Dieter, R. K.; Velu, S.
E. J. Org. Chem. 1997, 62, 3798-3799. (d) Dieter, R. K.; Lu, K.
Tetrahedron Lett. 1999, 40, 4011. (e) Dieter, R. K.; Alexander, C. W.; Nice,
L. E. Tetrahedron 2000, 56, 2776.
(15) (a) Park, Y. S.; Boys, M. L.; Beak, P. J. Am. Chem. Soc. 1996,
118, 3757. (b) Schlosser, M.; Limat, D. J. Am. Chem. Soc. 1995, 117, 12342.
(c) Voyer, N.; Roby, J. Tetrahedron Lett. 1995, 36, 6627. (d) The isomeric
pyrroles were confirmed by GC-mass spectral analysis. Although appearing
as a single spot on TLC, N-benzyl-2-methyl-4-phenylpyrrole was cleanly
separated from its regioisomer by GC chromatography and displayed a
parent molecular ion at m/z 247 and a fragement ion at 91 m/z for the benzyl
cation. A 13C absorption at δ 50.5 was also observed for the benzylic CH2
group.
(16) Dieter, R. K.; Silks, L. A., III.; Fishpaugh, J. R.; Kastner, M. E. J.
Am. Chem. Soc. 1985, 107, 4679.
(17) Adachi, I.; Harada, K.; Miyazaki, R.; Kano, H. Chem. Pharm. Bull.
1974, 22, 61.
(11) Verkruijsse, H. D.; Heus-kloos, Y. A.; Brandsma, L. J. Organomet.
Chem. 1988, 338, 289.
(12) Obrecht, D. HelV. Chim. Acta 1989, 72, 447.
(13) (a) Beak, P.; Lee, W. K. Tetrahedron Lett. 1989, 30, 1197. (b) Beak,
P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109. (c) For a review, see: Beak,
P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan, S. Acc. Chem.
Res. 1996, 29, 552.
(18) Kaiser, E.; Sr.; Picart, F.; Kubiak, T.; Tam, J. P.; Merrifield, R. B.
J. Org. Chem. 1993, 58, 5167.
(19) While a referee suggested the possibility of E to Z isomerization
via sequential phenol 1,4-conjugate addition-elimination, control experi-
ments revealed that while anhydrous HCl (CH2Cl2, 10 mol %) failed to
cleave the Boc protecting group the E:Z ratio of the γ-amino-R,â-enone
from 1 and 6 changed from 71:29 to 37:63. Thus, the generation of HCl
during Boc deprotection appears sufficient to effect E to Z isomerization.
(14) Johnson, C. R.; Marren, T. J. Tetrahedron Lett. 1987, 28, 27.
Org. Lett., Vol. 2, No. 15, 2000
2285

enones to pyrroles in modest to good yields (Table 1), with
the exception of the conjugate adduct of alkynyl ketone 9
and the cuprate derived from 1 which gave only trace
amounts of the desired pyrrole.
may be used in a variety of transition metal coupling
reactions (e.g., Pd, Ni, Zn, Cu) or converted to lithium and
Grignard reagents for introduction of alkyl, aryl, alkenyl, or
alkynyl substituents at the bromine-bearing carbon atom.
This synthetic route to pyrroles provides opportunities for
introducing substituents at positions 1, 2, 3, and 5 of the
pyrrole ring (eq 1). Trapping of the intermediate allenyl
enolate would allow for the introduction of substituents at
the 4-position. Reaction of the R-aminoalkylcuprate derived
from 1 with ynone 5 followed by trapping with N-bromo-
succinimide afforded the R-bromo enone (Scheme 1) which
The recent development of R-aminoalkylcuprate chemistry
and the ready availability of ynones provides an efficient
two-step synthesis of polysubstituted pyrroles. This synthetic
strategy provides a rapid and efficient synthesis of 1,2-di-,
1,2,4-tri-, 1,2,5-tri-, and 1,2,3,5-tetrasubstituted pyrroles.
Trapping of the intermediate allenyl enolate generated in the
conjugate addition reaction leads to the bromopyrrole,
allowing substitution at all five positions of the pyrrole ring.
Utilization of ynals or monoprotected carbamates of primary
amines (leading to 1-unsubstituted pyrroles) are under
investigation and would increase the range of pyrrole
substitution patterns accessible by this methodology. The
only current limitation of this method for simple alkyl and
aryl substituents appears to be the synthesis of 2,5-diaryl-
pyrroles and the use of alkynyl ketones derived from
propargyl derivatives (e.g., propargyl halides and silyl ethers).
Scheme 1
Acknowledgment. This work was generously supported
by the National Institutes of Health (GM-60300-01). Several
initial experiments on the conjugate addition of R-amino-
alkylcuprates to alkynones were performed by Dr. Lois E.
Nice and are gratefully acknowledged.
could be cyclized to the bromopyrrole in 41% overall yield
(entry 12). Alternatively, bromination of ynone 5 [Br2,
CH2Cl2, -78 °C] afforded the trans-1,2-dibromoenone (76%
yield) which reacted with the R-aminoalkylcuprate to give
the same conjugate adduct in 37% yield. The bromopyrroles
OL006050Q
2286
Org. Lett., Vol. 2, No. 15, 2000