Efficient synthesis of 1,3,5-trisubstituted (pyrrol-2-yl)acetic acid esters via dual nucleophilic reactions of sulfonamides or carbamate with 4-trimethyl-siloxy-(5E)-hexen-2-ynoates: Lewis acid catalyzed SN1 and intramolecular Michael addition

Article abstract of DOI:10.1021/ol0616485

Carbamates or sulfonamides have proven to regioselectively attack 2-propynyl-allyl hybrid cations, generated by the action of TMSOTf on 4-(trimethylsioxy)hex-5-en-2-ynoates, to afford conjugated 6-aminohex-4-en-2- ynoates in which an intramolecular amino-

Full text of DOI:10.1021/ol0616485

ORGANIC
LETTERS
2006
Vol. 8, No. 17
3881-3884
Efficient Synthesis of
1,3,5-Trisubstituted (Pyrrol-2-yl)acetic
Acid Esters via Dual Nucleophilic
Reactions of Sulfonamides or
Carbamate with
4-Trimethyl-siloxy-(5E)-hexen-2-ynoates:
Lewis Acid Catalyzed SN1 and
Intramolecular Michael Addition
Teruhiko Ishikawa,* Toshiaki Aikawa, Shinichiro Watanabe, and Seiki Saito*
Department of Medical and Bioengineering Science, Graduate School of Natural
Science and Technology, Okayama UniVersity, Tsushima, Okayama, Japan 700-8530
seisaito@biotech.okayama-u.ac.jp
Received July 5, 2006
ABSTRACT
Carbamates or sulfonamides have proven to regioselectively attack 2-propynyl-allyl hybrid cations, generated by the action of TMSOTf on
4-(trimethylsioxy)hex-5-en-2-ynoates, to afford conjugated 6-aminohex-4-en-2-ynoates in which an intramolecular amino-Michael reaction took
place, leading to pyrrole frameworks. In particular, the sulfonamides gave 1-sulfonylpyrroles in one pot.
Because of their important roles in nature1 and broad utility
in both pharmaceuticals2 and materials science,3 pyrroles
have been among the most attractive molecules in chemistry
and biology. Such characteristics have made the molecules
significant synthetic targets and, therefore, have continued
to give chemists incentive in exploring novel methods for
their preparations.4 However, with regard to general methods
for synthesizing (pyrrol-2-yl)acetic acid esters in one step,
only two methods leading to 1,3,4-trisubstituted derivatives
have been available.5 This strongly motivated us to approach
the synthesis of pyrroles of this class, and we have succeeded
in realizing one-pot preparation of 1,3,5-trisubstituted (pyrrol-
2-yl)acetic acid esters (3) from 4,6-disubtituted ethyl 4-tri-
methylsiloxy-5-hexen-2-ynoates (1)6 and sulfonamides (2)
by the action of catalytic trimethylsilyl trifluoromethane-
sulfonate (TMSOTf, 20 mol %; CH2Cl2; -30 °C to rt; 1-3
h) (Scheme 1). The process involves the formation of
2-propynyl-allyl hybrid cations (I1) that undergo SN1 reaction
attacking 2 with exclusive geometrical and regiochemical
selectivity to result in the formation of 6-sulfonylamido-(4Z)-
hexen-2-ynoates (5). Because of their convenient spatial
arrangement, 5 can smoothly undergo Michael addition to
(1) (a) Gilchrist, T. L. Heterocyclic Chemistry, 3rd ed.; Addison-Wesley
Longman: Essex, 1997; pp 192-209. (b) Joule, J. A.; Mills, K. Heteocyclic
Chemistry, 4th ed.; Blackwell Science: Oxford, 2000; pp 237-272. See
also, e.g.: Mourabit, A. A.; Potier, P. Eur. J. Org. Chem. 2001, 237-243.
(2) For blockbuster drugs of substituted pyrroles, see, e.g.: Thompson,
R. B. FASEB J. 2001, 15, 1671-1675. See also refs 14 and 15.
(3) For a recent review, see, e.g.: Jeppesen, J. O.; Becher, J. Eur. J.
Org. Chem. 2003, 3245-3266.
10.1021/ol0616485 CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/21/2006

reactive cation I1 but should not deactivate the Lewis acid
employed for cation generation. Furthermore, after being
embedded in 5, the nitrogen atom must exert enough
nucleophilicity to make the following intramolecular Michael
addition possible to give the second intermediate I2. A
sulfonyl group in 2 plays an important role in this context.
It would reduce the nitrogen Lewis basicity and increase the
acidity of the N-H bond in 5, which is responsible for the
appropriateness of 2 as a dual nucleophile in this process.
Indeed, normal primary amines or carboxamides were totally
ineffective in this transformation, probably as a result of the
deactivation of the catalyst TMSOTf by their strong Lewis
basicity. When benzyl carbamate was used in place of 2,
SN1-type amination took place but the expected Michael
addition was not effected at all (vide infra) probably because
of lack of requisite N-H acidity.
Scheme 1
Thus, combinations of 1a-e and 2a-e8 led to a variety
of (pyrrol-2-yl)acetic acid esters (3a-o) as summarized in
Table 1. As mentioned above, the olefinic geometries in 5
Table 1. One-Pot Pyrrole Synthesis
the second products (I2) followed by facile isomerization
resulting with 3. Because 1a-j were readily prepared by
the reaction of enones 4 and lithium acetylide of ethyl
propiolate followed by silylation with very high R1 or R2
tolerance,7 the requisite preparation of 1 did not impose any
problem on the whole process.
The use of 2 as an N-nucleophile is a crucial choice. This
N-nucleophile would surely be attacked by the highly
(4) For recent leading references of pyrrole synthesis using alkyne
derivatives, see: (a) Larionov, O. V.; de Meijere, A. Angew. Chem., Int.
Ed. 2005, 44, 5664-5667. (b) Kamijo, S.; Kanazawa, C.; Yamamoto, Y.
J. Am. Chem. Soc. 2005, 127, 9260-9266. (c) Ohri, R. V.; Radosevich, A.
T.; Hrovat, K. J.; Musich, C.; Huang, D.; Holman, T. R.; Toste, F. D. Org.
Lett. 2005, 7, 2501-2504. (d) Tejedor, D.; Gonza´lez-Cruz, D.; Garc´ıa-
Tellado, F.; Marrero-Tellado, J. J.; Rodr´ıguez, M. L. J. Am. Chem. Soc.
2004, 126, 8390-8391. (e) Ramanathan, B.; Keith, A. J.; Armstrong, D.;
Odom, A. L. Org. Lett. 2004, 6, 2957-2960. (f) Dhawan, R.; Arndtsen, B.
A. J. Am. Chem. Soc. 2004, 126, 468-469. (g) Gabriele, B.; Salerno, G.;
Fazio, A. J. Org. Chem. 2003, 68, 7853-7861. (h) Nishibayashi, Y.;
Yoshikawa, M.; Inada, Y.; Milton, M. D.; Hidai, M.; Uemura, S. Angew.
Chem., Int. Ed. 2003, 42, 2681-2684. (i) Kim, J. T.; Kel’in, A. V.;
Gevorgyan, V. Angew. Chem., Int. Ed. 2003, 42, 98-101. (j) Yoshida, M.;
Kitamura, M.; Narasaka, K. Bull. Chem. Soc. Jpn. 2003, 76, 2003-2008.
(k) Gabriele, B.; Dalerno, G.; Fazio, A.; Campana, F. B. Chem. Commun.
2002, 1408-1409. (l) Kel’in, A. V.; Srmek, A. W.; Gevorgyan, V. J. Am.
Chem. Soc. 2001, 123, 2074-2075. (m) Lee, C.; Yang, L.; Hwu, T.; Feng,
A.; Tseng, V.; Luh, T. J. Am. Chem. Soc. 2000, 122, 4992-4993.
(5) See refs 4d and 4j; ref 4k is also concerned with (pyrrol-2-yl)acetic
acids synthesis, which however required several steps.
(6) For a series of research concerned with this system, see: (a) Ishikawa,
T.; Okano, M.; Aikawa, T.; Saito, S. J. Org. Chem. 2001, 66, 4635-4642.
(b) Ishikawa, T.; Aikawa, T.; Mori, Y.; Saito, S. Org. Lett. 2003, 5, 51-
54. (c) Ishikawa, T.; Aikawa, T.; Mori, Y.; Saito, S. Org. Lett. 2004, 6,
1369-1372. (d) Ishikawa, T.; Manabe, S.; Aikawa, T.; Kudo, T.; Saito, S.
Org. Lett. 2004. 6, 2361-2364.
(7) Ten substrates (1a-j) were prepared as follows: to a solution of
ethyl propiolate in THF was added BuLi at -78 °C, and the mixture was
stirred at that temperature for 15 min. To this mixture was added enone at
-78 °C followed by stirring at -78 - 0 °C for 4.5 h. After the usual
workup, the alcohol product was purified by column chromatography and
silylated in the usual way (TMS-Cl, imidazole, THF, 0 °C to rt, 0.5 h) to
give 1, which was purified by column chromatography prior to use. The %
yields of 1 depended on the structure of enones. For the experimental detail
and spectroscopic data, see Supporting Information.
are required to be Z for the ensuing conjugated addition to
occur. In the case of benzyl carbamate the reaction stopped
at the stage of SN1 to give (Z)-6-(N-cbz)amino-4-hexen-2-
(8) These sulfonamides are commercially available.
3882
Org. Lett., Vol. 8, No. 17, 2006

ynoates (6a-f) (Table 2) in which such stereochemical
outcomes were observed with perfect (Z)-control without
exception.9
It should be also mentioned that the involvement of a TMS
ether in 1 may be crucial for the generation of I1 intermediate
(Scheme 1). When a trimethylsilyl cation released from the
catalyst can coordinate to the oxygen atom of 1 to which a
TMS group attaches, a (CH3)3Si-O-Si(CH3)3 bond can be
temporally generated with a bond angle of around 140° or
more (Scheme 2) judging from reported bond angle value
(144°) of disiloxane (H3Si-O-SiH3).12
Table 2. Carbamate as a Nucleophile: Two-Step Pyrrole
Synthesis
Scheme 2
entry
1
6 (yield)
7 (yield %)
1
2
3
4
5
6
7
8
1a
1b
1c
1f
1g
1h
1i
6a (53)
6b (58)
6c (82)
6d (86)
6e (57)
6f (53)
6g (9)
7a: R1 ) Ph; R2 ) Me (87)
7b: R1 ) Ph; R2 ) i-Pr (96)
7c: R1 ) Ph; R2 ) Ph (75)
7d: R1 ) 4-MeOPh; R2 ) i-Pr (94)
7e: R1 ) 4-ClPh; R2 ) i-Pr (78)
7f: R1 ) c-C6H11; R2 ) 4-MeOPh (53)
- (R1 ) c-C6H11; R2 ) Ph)
Such a situation would result in an increase in the more
sterically demanding nature of the 1,1,1,3,3,3-hexamethyl-
disiloxane (HMDSLOX) unit for the thus-generated oxonium
ion intermediate shown in Scheme 2, and thus the leaving
group ability of the HMDSLOX unit would become enough
to generate I1 under the given reaction conditions. On the
other hand, the thus-released HMDSLOX molecule has very
low nucleophilicity in a general sense13 so that 11 could not
return to 1 any more. The reaction of I1 with nucleophiles
leads to 3 or 6 accompanied by the formation of TfOH, which
might partly play a role of generating I1 by protonation. The
contribution of this kind, however, might be very low because
extremely low yield of 3h was observed when TfOH was
used in place of TMSOTf though it could not completely be
ruled out. Rather importantly we should recognize that the
HMDSLOX thus-released play a significant role to regenerate
the catalyst (TMSOTf) through the reaction with TfOH,
leaving behind trimethylsilanol as a byproduct which may
be so less nucleophilic that can attack I1: no formation of
products such as a conjugated 1-(trimethylsiloxy)enyne [an
enyne product with a TMSO-substituent in place of a
RSO2N(H)- or (cbz)N(H)-group in 5 or 6] was observed.
In summary, we have developed a novel, metal-free, Lewis
acid catalyzed synthesis of 1,3,5-trisubstituted (pyrrol-2-yl)-
acetic acid esters 3 and 7 from commercially available
inexpensive compounds of structural diversity. A series of
reactions involving TMSOTf coordination to 1, generation
of I1, an SN1 process, and intramolecular Michael addition
is kinetically tuned to proceed in a one-pot process. We can
use readily available enones, propiolate esters, and aryl- (or
alkyl-) sulfonamides or benzyl carbamate as starting com-
1j
6h (-)
- (R1 ) c-C6H11; R2 ) Me)
The data in Table 2 clearly indicate some limitations of
the present transformation. If R1 is an aryl group, R2 is
allowed to be an aryl or aliphatic group (entries 1-5),
whereas if R1 is an aliphatic group, R2 must be an aryl group
bearing an electron-donating substituent on the ring (entries
6 and 7). When both R1 and R2 groups are aliphatic (entry
8), desilylated substrate was recovered as an alcohol.
Although, unlike sulfonylamides, the (N-cbz)amino group
did not have enough nucleophilicity to attack the conjugated
triple bond, the desired transformation smoothly took place
to afford (N-cbz)pyrroles (7a-f) in acceptable yields on
treatment with NaH in THF (Table 2).
Not only an SN1 strategy other than SN210 but also the
use of N-nucleophiles of low Lewis basicity such as 2 or
benzyl carbamate should be a key to success for synthesizing
5 or 6. The less sterically demanding nature of an alkyne
group, as well as observed regiochemistry-controlling ability
of I1 in terms of the position of highest positive charge
density,11 would be responsible for the construction of the
conjugated 1-amino-(2Z)-en-4-yne framework, the requisite
for successful ensuing intramolecular Michael addition and
thus for the accomplishment of the whole pyrrole synthesis.
(9) For discussion about stereocontrol of this kind, see ref 6.
(10) It used to be the case that the synthesis of (Z)-(2-en-4-ynyl)amines
similar to 5 or 6 involved bromination (PBr3) of the corresponding (Z)-2-
en-4-yn-1-ols and subsequent SN2 reactions with amines or Mitsunobu
reactions of the alcohols. In addition, the syntheses of the alcohols were
specified to individual methods according to both kind and position of
desired substituents: Koerner, M.; Rickborn, B. J. Org. Chem. 1989, 54,
9-10.
(12) Shambayati, S.; Blake, J. F.; Wierschke, S. G.; Jorgensen, W. L.;
Schreiber, S. L. J. Am. Chem. Soc. 1990, 112, 697-703 and references
cited therein.
(13) For discussion about the lower basicity of disiloxane, see ref 12
and references therein.
(11) Elucidation of the exact nature of the observed exclusive regiose-
lectivity of this SN1 process must wait for future studies.
Org. Lett., Vol. 8, No. 17, 2006
3883

the nitrogen atom and have been known to exert anti-HIV
activity as non-nucleoside, reverse transcriptase inhibitors.15
Therefore, it is no exaggeration to say that the present
synthetic method deserves consideration when we contem-
plate the synthesis of (pyrrol-2-yl)acetic acid esters because
it offers vast opportunities commensurate with modern
synthetic criteria with respect to structural diversity16 and
chemical efficiency.17
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research on Priority Areas “Advanced
Molecular Transformations of Carbon Resources” from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy, Japan.
Supporting Information Available: Representative ex-
perimental procedures, physical properties and NMR charts.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Figure 1. Examples of (pyrrol-2-yl)acetic acid derivatives including
those bearing arenesulfonyl groups on the nitrogen atom: anti-
inflammatory drugs and candidates for anti-HIV drugs.
OL0616485
ponents. As shown in Figure 1, both tolmetin and zomepirac
are typical (pyrrole-2-yl)acetic acid derivatives and are
known as an anti-inflammatory drugs14 that are clinically
useful. Some pyrroles also shown in Figure 1 are (pyrrole-
2-yl)acetic acid derivatives bearing arenesulfonyl groups on
(15) Some 1-sulfonylryrroles exert anti-HIV activity as non-nucleoside,
reverse transcriptase inhibitors. See: (a) Artico, M.; Silvestri, R.; Massa,
S.; Loi, A. G.; Corrias, S.; Piras, G.; Colla, P. L. J. Med. Chem. 1996, 39,
522-530 and references therein. (b) Silvestri, R.; Artico, M.; Martino, G.
D.; Novellino, E.; Greco, G.; Lavecchia, A.; Massa, S.; Loi, A. G.;
Doratiotto, S.; Piras, G.; Colla, P. L. Bioorg. Med. Chem. 2000, 2305-
2309.
(14) For clinically useful pharmaceuticals featuring (pyrrol-2-yl)acetic
acid, see: Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D. In
Pharmaceutical Substances, 3rd ed.; Thieme: Stuttgart, New York, 1999.
(16) Schreiber, S. L. Science 2000, 287, 1964-1969.
(17) Trost, B. M. Science 1991, 254, 1471-1477.
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