A direct phosphine-mediated synthesis of pyrroles from acid chlorides and α,β-unsaturated imines

Article abstract of DOI:10.1021/ol900185n

A one-step method to assemble pyrroles from α,β-unsaturated imines and acid chlorides has been developed. This reaction is mediated by triphenylphosphine, which eliminates phosphine oxide to allow cyclization. This reaction has been employed to access a d

Full text of DOI:10.1021/ol900185n

ORGANIC
LETTERS
2009
Vol. 11, No. 6
1369-1372
A Direct Phosphine-Mediated Synthesis
of Pyrroles from Acid Chlorides and
r,ꢀ-Unsaturated Imines
Yingdong Lu and Bruce A. Arndtsen*
Department of Chemistry, McGill UniVersity, 801 Sherbrooke Street W., Montreal QC
H3A 2K6, Canada
bruce.arndtsen@mcgill.ca
Received January 28, 2009
ABSTRACT
A one-step method to assemble pyrroles from r,ꢀ-unsaturated imines and acid chlorides has been developed. This reaction is mediated by
triphenylphosphine, which eliminates phosphine oxide to allow cyclization. This reaction has been employed to access a diverse range of
pyrroles via modulation of the two building blocks and applied as well to the synthesis of lukianol A.
Pyrroles have found utility in such diverse fields as medicinal
chemistry, materials science, polymer synthesis, and metal-
coordinating ligands and as synthetic building blocks.
Examples of these include various anti-inflammatory agents,1
antitumor agents,2 the blockbuster drug atorvastatin calcium,
commonly known as Lipitor,3 poly(pyrrole)-based conjugated
materials,4 and numerous natural products.5 This utility has
made the design of efficient routes to prepare pyrroles an
area of active research. Traditional methods for pyrrole
synthesis include the Hantzsch,6 Knorr,7 and Paal-Knorr8
syntheses.9 However, these methods can be limited by the
multistep syntheses often needed for their precursors and
sometimes harsh conditions. As such, a range of new
synthetic routes, including multicomponent coupling reac-
tions10 and metal-catalyzed syntheses,11 have been devel-
(5) For examples, see: (a) Gilchrist, T. L. J. Chem. Soc., Perkin Trans.
1999, 1, 2849–2866. (b) Boger, D. L.; Boyce, C. W.; Labroli, M. A.; Sehon,
C. A. J. Am. Chem. Soc. 1999, 121, 54–62. (c) Fan, H.; Peng, P.; Hamann,
M. T.; Hu, J.-F. Chem. ReV. 2008, 108, 264–287. (d) Morris, C. J.; Phillips,
A. J. Nat. Prod. Rep. 2008, 25, 95–117. (e) Baran, S. P.; O’Malley, P. D.;
Zografos, L. A. Angew. Chem., Int. Ed. 2004, 43, 2674–2677. (f) McArthur,
A. K.; Mitchell, S. S.; Tsueng, G.; Rheingold, A.; White, D. J.; Grodberg,
J.; Lam, K. S.; Potts, B. C. J. Nat. Prod. 2008, 71, 1732–1737. (g) Bode,
H. B.; Irschik, H.; Wenzel, S. C.; Reichenback, H.; Mu¨ller, R.; Ho¨fle, G.
J. Nat. Prod. 2003, 66, 1203–1206.
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M. J. J. Med. Chem. 1996, 38, 3895–3901. (b) Harrak, Y.; Rosell, G.;
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2007, 15, 4876–4890. (c) Ushiyama, S.; Yamada, T.; Murakami, Y.;
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(6) Hantzsch, A. Ber. Dtsch. Chem. Ges. 1890, 23, 1474–1483.
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(8) Paal, C. Chem. Ber. 1885, 18, 367–370.
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10.1021/ol900185n CCC: $40.75
Published on Web 02/17/2009
2009 American Chemical Society

Scheme 1
.
Phosphonite-Mediated Dipolar Cycloaddition to
Pyrroles
Figure 1. An approach to pyrroles from imines and acid chlorides.
oped, many of which can provide easy access to these
products. Nevertheless, there remains a need for methods to
synthesize pyrroles in an efficient fashion, especially those
that employ simple building blocks and a minimal number
of overall synthetic steps.
Our postulated mechanism for this reaction is shown in
Scheme 2. This is based upon the potential of phosphines to
undergo Micheal-type 1,4-addition to in situ generated R,ꢀ-
unsaturated iminium salts 2,14 rather than the 1,2-addition
we have previously noted with simple imines. Upon in situ
deprotonation, an intramolecular Wittig-type reaction would
allow cyclization and the generation of pyrroles.
Toward this end, we have recently reported that phospho-
nites can mediate the multicomponent coupling of imines,
acid chlorides, and alkynes to generate pyrroles in one pot
and from readily available building blocks (Scheme 1).12
Although this approach is effective, the reaction can be
limited by the necessary use of electron-withdrawing units
on the alkyne (e.g., the 3- and/or 4-pyrrole positions) and
poor regiocontrol with similarly sized alkyne substituents.
Both of these factors arise from the mechanism of pyrrole
formation, which involves a 1,3-dipolar cycloaddition reac-
tion to the in situ generated 1. In considering approaches to
address this issue, one possibility would be to change the
mechanism of phosphine-mediated pyrrole formation. The
role of phosphine in this chemistry is ultimately to remove
oxygen from the acid chloride as phosphine oxide, which is
liberated upon dipolar addition (Scheme 1). In principle, this
dipolar cycloaddition pathway can be avoided by instead
employing simple R,ꢀ-unsaturated imines. The latter are
readily available by simple aldol reactions followed by imine
formation and can potentially serve the same overall role as
imines and alkynes. As described below, these studies have
led to the design of a new, one-step route to generate
pyrroles. Although phosphines have been previously em-
ployed to mediate cyclizations to form pyrroles,13 to our
knowledge this is the first to employ such simple building
blocks: R,ꢀ-unsaturated imines and acid chlorides (Figure
1). In addition to its efficiency, the pyrroles are formed with
perfect regiocontrol, with a diverse range of substituents, and
employ only simple PPh3 to mediate the reaction.
Scheme 2
.
Postulated Mechanism for PPh3-Mediated Pyrrole
Synthesis
The results of our first attempt at this reaction were
promising. When the reaction of imine 3 and aroyl chloride
was carried out with PPh3 and NEt3 base, pyrrole was formed
within 15 min (Table 1, entry 1), albeit in 52% yield.
1
Monitoring this reaction by H and 31P NMR spectroscopy
reveals that the low yield of pyrrole resulted from two issues:
the incomplete reaction between the iminium salt and PPh3
(resulting in 2 at the end of the reaction) and the formation
of ca. 20% of a phosphorus-containing byproduct. The latter
is preliminarily characterized to be the phosphorus-ylide
(11) Recent examples: (a) Mihovilovic, M. D.; Stanetty, P. Angew.
Chem., Int. Ed. 2007, 46, 3612–3615. (b) D’Souza, D. M.; Mueller, T. J. J.
Chem. Soc. ReV. 2007, 36, 1095–1108. (c) Dhawan, R.; Arndtsen, B. A.
J. Am. Chem. Soc. 2004, 126, 468–469. (d) Nishibayashi, Y.; Yoshikawa,
M.; Inada, Y.; Milton, D. M.; Hidai, M.; Uemura, S. Angew. Chem., Int.
Ed. 2003, 42, 2681–2684. (e) Braun, R. U.; Zietler, K.; Muller, T. J. J.
Org. Lett. 2001, 3, 3297–3300. (f) Gorin, D. J.; Davis, N. R.; Toste, F. D.
J. Am. Chem. Soc. 2005, 127, 11260–11261. (g) Declerk, V.; Ribiere, P.;
Martinez, J.; Lamaty, F. J. Org. Chem. 2004, 69, 8372–8381. (h) Kamijo,
S.; Kanazawa, C.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127, 9260–
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(13) For the synthesis of pyrroles via aza-Wittig reagents and other
phosphine-mediated pyrrole syntheses, see: (a) Eguchi, S. ARKIVOC 2005,
2, 98–119. (b) Palacios, F.; Alonso, C.; Aparicio, D.; Rubiales, G.; de los
Santos, M. J. Tetrahedron 2007, 63, 523–575. (c) Katritzky, A.; Jiang, J.
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F.-P.; Schwartz, U. M.; Maib, P.; Mai, G. Liebigs Ann. Chem. 1990, 1037–
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G. J. Org. Chem. 2004, 69, 4913–4924. (d) Espenlaub, S.; Gerster, H.;
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12367.
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Org. Lett., Vol. 11, No. 6, 2009

Table 1. Development of a PPh3-Mediated Pyrrole Synthesisa
Table 2. Diversity of Pyrroles Available from Imines and Acid
Chloridesa
entry
base
additive
yield (%)
1b
2
3
4
5
NEt3
NEt3
NEt3
DBU
NEt3
NEt3
NEt3
52
71
86
85
78
52
61
Bu4NI
Bu4NI
Bu4NBr
NaI
6
7
KI
a Imine (94 mg, 0.40 mmol), 4-nitro-benzoychloride (89 mg, 0.48
mmol), PPh3 (157 mg, 0.60 mmol), base (0.60 mmol), and additive (0.40
mmol) in 1 mL of CH3CN. b 0.40 mmol PPh3.
resulting from 1,2-addition to the R,ꢀ-unsaturated imine (4),15
which cannot undergo intramolecular cyclization. Although
the use of a slight excess of PPh3 can eliminate 2 and increase
pyrrole yield (entry 2, 71%), this still results in the formation
of 4.
It is established that anions can play a role in addition to
iminium salts, with soft ions favoring conjugate addition.16
As such, a range of softer halide additives were examined
in the reaction, for their ability to stabilize the positive charge
at the ꢀ-position of 2. Whereas metal iodide salts did not
improve the yield, the addition of soluble Bu4NI led to the
elimination of 4 (<5%) and the formation of pyrrole in near
quantitative yield. In addition to triethylamine, the stronger
base DBU is also viable in this reaction (entry 4). Overall,
this provides a high yield, one-step synthesis of pyrroles from
R,ꢀ-unsaturated imines and acid chlorides.
This reaction employs substrates (imines and acid chlo-
rides) and reagents (triphenylphosphine and DBU) that are
all readily available. As such, it is a reaction that is both
straightforward to perform and readily diversified. For
example, as shown in Table 2, various aryl (electron-rich or
-poor), heteroaryl, hydrogen, and alkyl substituents can be
incorporated into R3 or R4 on the imine (entries 1-7). A
similar range of alkyl, aryl, or protecting groups (benzyl,
allyl) can also be employed on the imine nitrogen. In addition
to aryl- and alkyl-acid chlorides, R-ester-substituted acid
chlorides (entries 9 and 10) and even chloroformates (entry
8) can be used in this chemistry. The latter allows the
generation of 2-alkoxy-substituted pyrroles. A range of
functional groups can be used in each of these positions,
such as nitro, ester, ether, and halo units. Together, this
provides straightforward access to a diverse range of pyrroles,
with phosphine oxide and amineHCl salt the only byproducts.
Substituents can have a dramatic influence on the rate of
the coupling. For example, with electron-rich R4 or electron-
a Imine (0.40 mmol), acid chloride (0.40 mmol), Bu4NI (148 mg, 0.40
mmol), PPh3 (156 mg, 0.60 mmol), and DBU (90 mg, 0.60 mmol) in 1 mL
of CH3CN, rt, 18 h. b 65 °C for 18 h.
poor R5, the products are formed at ambient temperature,
whereas the opposite (electron-poor R4 or -donating R5)
significantly slows the reaction and requires high tem-
perature to go to completion (entries 2, 6, 8). These are
likely the effect of the intramolecular Wittig reaction,
(15) Complex 4 cannot be isolated from the reaction mixture; however,
its spectroscopic data (e.g., 31P NMR δ 12.6 ppm) is directly analogous to
that noted for similar R-amide-substituted phosphorus-ylides.12
(16) (a) Shiao, M.-J.; Chia, W.-L.; Peng, C. -J.; Shen, C.-C. J. Org.
Chem. 1993, 58, 3162–3164. (b) Yamaguchi, R.; Nakazono, Y.; Matsuki,
T.; Hata, E.; Kawanisi, M. Bull. Chem. Soc. Jpn. 1987, 60, 215–222.
Org. Lett., Vol. 11, No. 6, 2009
1371

chloride approach can be directly applied to these products,
allowing the assembly of the pyrrole core 5 in one pot from
the R,ꢀ-unsaturated aldehyde (65% yield), which can be
subsequently converted to the target.20 As far as we are
aware, this represents one of the most straightforward
approaches to these products and is also well-suited for the
construction of new variants of lukianol derivatives.
Scheme 3. Synthesis of Lukianol A
In conclusion, we have described a new synthesis of
pyrroles directly from simple R,ꢀ-unsaturated imines and acid
chlorides, mediated by triphenylphosphine. This reaction
proceeds via an intramolecular Wittig reaction pathway and
provides one-step access to a diverse range of pyrrole
products. The application of this chemistry to access biologi-
cally relevant pyrrole-based products, as well as other classes
of heterocycles, is currently underway.
where electron-poor carbonyl and electron-rich ylides
accelerate coupling.17
As an illustration of the potential utility of this reaction,
we have examined its application to the synthesis of lukianol
pyrroles. These products, such as lukianol A, have been
found to have activity against human epidermatoid
carcinoma.5c,18,19 As shown in Scheme 3, this imine/acid
Acknowledgment. We thank the National Science and
Engineering Research Council (Canada) Discovery and
AGENO programs for support of this research.
Supporting Information Available: Synthesis and char-
acterization of products. This material is available free of
charge via the Internet at http://pubs.acs.org.
(17) Speziale, A.; Bissing, D. E. J. Am. Chem. Soc. 1963, 85, 3878–
3884.
(18) Yoshida, W. Y.; Lee, K. K.; Carrol, A. R.; Scheuer, P. J. HelV.
Chem. Acta 1992, 75, 1721–1725
.
(19) For alternative routes, see: (a) Fu¨rstner, A.; Weintritt, H.; Hupperts,
A. J. Org. Chem. 1995, 60, 6637–6641. (b) Hinze, C.; Kreipl, A.; Terpin,
A.; Steglich, W. Synthesis 2007, 608–612. (c) Smith, A. J.; Ng, S.; White,
J. Org. Biomol. Chem. 2006, 4, 2477–2482. (d) Kim, S.; Son, S.; Kang, H.
OL900185N
Bull. Korean Chem. Soc. 2001, 22, 1403–1406
.
(20) Steps c-f follow the protocol developed by Fu¨rstner in ref 19a.
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Org. Lett., Vol. 11, No. 6, 2009