Highly regioselective synthesis of 3,4-disubstituted 1H-pyrrole

Article abstract of DOI:10.1021/jo991531c

A highly regioselective method for the synthesis of 3,4-disubstituted 1H-pyrroles has been developed employing the ipso-directing property of a trimethylsilyl group. As a key starting material in this study, the known 3,4-bis(trimethylsilyl)-1H-pyrrole (3), was protected with carefully chosen groups, namely tert-butoxycarbonyl, N,N-dimethylaminosulfonyl, p- toluenesulfonyl, and triisopropylsilyl. A highly regioselective monoiodination of these 1-protected pyrroles was achieved by reaction with iodine - silver trifluoroacetate at low temperatures. Subsequent palladium- catalyzed cross-coupling reactions afforded 1-protected-4-substituted 3- trimethylsilyl-1H-pyrroles, which again underwent further room-temperature ipso-iodination and palladium-catalyzed cross-coupling reactions to provide symmetrical and unsymmetrical 1-protected-3,4-disubstituted 1H-pyrroles. Deprotection of 1-(tert-butoxycarbonyl) and 1-(N,Y-dimethylaminosulfonyl) groups was found to be nontrivial. The 1-(p-toluenesulfonyl) protecting group was eventually proved to be superior to other protection groups, because it was readily removed after stepwise ipso monoiodinations and palladium- catalyzed cross-coupling reactions.

Full text of DOI:10.1021/jo991531c

3274
J . Org. Chem. 2000, 65, 3274-3283
High ly Regioselective Syn th esis of 3,4-Disu bstitu ted 1H-P yr r ole†,1
J ian-Hui Liu, Ho-Wai Chan, and Henry N. C. Wong*
Department of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories,
Hong Kong SAR, China
Received September 29, 1999
A highly regioselective method for the synthesis of 3,4-disubstituted 1H-pyrroles has been developed
employing the ipso-directing property of a trimethylsilyl group. As a key starting material in this
study, the known 3,4-bis(trimethylsilyl)-1H-pyrrole (3), was protected with carefully chosen groups,
namely tert-butoxycarbonyl, N,N-dimethylaminosulfonyl, p-toluenesulfonyl, and triisopropylsilyl.
A highly regioselective monoiodination of these 1-protected pyrroles was achieved by reaction with
iodine-silver trifluoroacetate at low temperatures. Subsequent palladium-catalyzed cross-coupling
reactions afforded 1-protected-4-substituted 3-trimethylsilyl-1H-pyrroles, which again underwent
further room-temperature ipso-iodination and palladium-catalyzed cross-coupling reactions to
provide symmetrical and unsymmetrical 1-protected-3,4-disubstituted 1H-pyrroles. Deprotection
of 1-(tert-butoxycarbonyl) and 1-(N,N-dimethylaminosulfonyl) groups was found to be nontrivial.
The 1-(p-toluenesulfonyl) protecting group was eventually proved to be superior to other protection
groups, because it was readily removed after stepwise ipso monoiodinations and palladium-catalyzed
cross-coupling reactions.
In tr od u ction
electrophilic aromatic substitution reactions as well as
lithiation reactions of pyrrole rings occur predominantly
at the R-position.7 Selective substitutions at one or more
of the â-positions have been generally believed to be a
challenging goal in many synthetic programs. In the
literature, several approaches to 3,4-disubstituted pyr-
roles have been recorded,8 but it appears that they are
less versatile for the realization of more elaborate sub-
stitution patterns.
The use of silicon in organic synthesis has attracted a
great deal of interest because of the unusual properties
that silicon conveys to organic molecules.9 The ability of
silicon to stabilize a carbocation at the â-position, known
The syntheses of pyrroles are by all means an attrac-
tive area in heterocyclic chemistry,2 due primarily to the
fact that many pyrroles are subunits of natural products3
and some are the building blocks for porphyrin synthe-
sis.4 In particular, 3,4-disubstituted 1H-pyrroles have
generated considerable interest owing to their remark-
able diversity of biological activity.5 A number of these
compounds have been shown to possess antidiabetic,6a
fungicidal,6b or antibacterial6c properties. However, it is
also noteworthy that the 3,4-disubstituted pyrrole system
is probably the most difficult to be prepared since most
† Dedicated to the memory of Professor Ta-shue Chou, Institute of
Chemistry, Academia Sinica, Taipei.
(1) (a) Preliminary results have been published; see: Chan, H.-W.;
Chan, P.-C.; Liu, J .-H.; Wong, H. N. C. J . Chem. Soc., Chem. Commun.
1997, 1515-1516. (b) Taken in part from the Ph.D. theses of H.-W.
C.; J .-H. L. The Chinese University of Hong Kong, 1997 and 1999,
respectively.
(2) Patterson, J . M. Synthesis 1976, 281-304. J ones, R. A.; Bean,
G. P. The Chemistry of Pyrroles; Academic Press: London, 1977. J ones,
G. B.; Chapman, B. J . In Comprehensive Heterocyclic Chemistry; Bird,
C. W., Ed.; Pergamon Press: Oxford, 1996; Vol. 2, pp 1-38. Black, D.
St. C. In Comprehensive Heterocyclic Chemistry; Bird, C. W., Ed.;
Pergamon Press: Oxford, 1996; Vol. 2, pp 39-118. Sundberg, R. J . In
Comprehensive Heterocyclic Chemistry; Bird, C. W., Ed.; Pergamon
Press: Oxford, 1996; Vol. 2, pp 119-206. Gribble, G. W. In Compre-
hensive Heterocyclic Chemistry; Bird, C. W., Ed.; Pergamon Press:
Oxford, 1996; Vol. 2, pp 207-257.
(3) Inter alia, see: (a) Herbert, R. B. In The Alkaloid; Grundon, M.
F., Ed.; Chemical Society: London, 1982; Vol. 12. (b) Falk, H. The
Chemistry of Linear Oligopyrroles and Bile Pigments; Springer-
Verlag: Berlin, 1989. (c) Biosynthesis of Tetrapyrroles; J ordan, P. M.,
Ed.; Elsevier: London, 1991.
(4) Porphyrins and Metalloporphyrins; Smith, K. M., Ed.; Elsevier:
Amsterdam, 1975. Franck, B.; Nonn, A. Angew. Chem., Int. Ed. Engl.
1995, 34, 1795-1811. Sessler, J . L.; Weghorn, S. J . Expanded,
Contracted and Isomeric Porphyrins; Pergamon Press: Oxford, 1997.
(5) Meanwell, N. A.; Romine, J . L.; Rosenfeld, M. J .; Martin, S. W.;
Trehan, A. K.; Wright, J . J . K.; Malley, M. F.; Gougoutas, J . Z.;
Brassard, C. L.; Buchanan, J . O.; Federici, M. E.; Fleming, J . S.;
Gamberdella, M.; Hartl, K. S.; Zavoico, G. B.; Seiler, S. M. J . Med.
Chem. 1993, 36, 3884-3903.
(6) (a) Holland, G. F. U. S. Patent 4,282,242, 1981; Chem. Abstr.
1981, 95, 187068e. (b) Nippon Soda Co., Ltd. J apanese Patent 81 79,-
672, 1981; Chem. Abstr. 1981, 95, 187069f. (c) Umio, S.; Kariyone, K.
J apanese Patent 68 14,699, 1968; Chem. Abstr. 1969, 70, 87560z.
(7) Anderson, H. J .; Loader, C. E.; Xu, R. X.; Leˆ, N.; Gogan, N. J .;
McDonald, R.; Edwards, L. G. Can. J . Chem. 1985, 63, 896-902
(8) (a) Gabel, N. W. J . Org. Chem. 1962, 27, 301. (b) van Leusen, A,
M.; Siderius, H.; Hoogenboom, B. E.; van Leusen, D. Tetrahedron Lett.
1972, 5337-5340. (c) Groves, J . K.; Cundasawmy, N. E.; Anderson,
H. J . Can. J . Chem. 1973, 51, 1089-1098. (d) Ichimura, K.; Ichikawa,
S.; Iwamura, K. Bull. Chem. Soc. J pn. 1976, 49, 1157-1158. (e) van
Nispen, S. P. J . M.; Mensink, C.; van Leusen, A. M. Tetrahedron Lett.
1980, 21, 3723-3726. (f) Muchowski, J . M.; Naef, R. Helv. Chim. Acta.
1984, 67, 1168-1172. (g) Magnus, P.; Danikiewicz, W.; Katoh, T.;
Huffman, J . C.; Folting, K. J . Am. Chem. Soc. 1990, 112, 2465-2468.
(h) Shum. P. W.; Kozikowski, A. P. Tetrahedron Lett. 1990, 31, 6785-
6788. (i) Alvarez, A.; Guzma´n, A.; Ruiz, A.; Velarde, E.; Muchowski,
J . M. J . Org. Chem. 1992, 57, 1653-1656. (j) van Leusen, D.; van
Echten, E.; van Leusen, A. M. J . Org. Chem. 1992, 57, 2245-2249. (k)
Ho-Hoang, A.; Fache, F.; Lemaire, M. New J . Chem. 1992, 16, 1017-
1018. (l) Seino, H.; Ishii, Y.; Hidai, M. J . Am. Chem. Soc. 1994, 116,
7433-7434. (m) Cooper, J . M.; Morris, D. G.; Ryder, K. S. J . Chem.
Soc., Chem. Commun. 1995, 697-698. (n) Sugihara, Y.; Miyatake, R.;
Murata, I. Imamura, A. J . Chem. Soc., Chem. Commun. 1995, 1249-
1250. (o) Seino, H.; Ishii, Y.; Sasagawa, T.; Hidai, M. J . Am. Chem.
Soc. 1995, 117, 12181-12193. (p) Head, N. E.; Turner, J . J . Org. Chem.
1995, 60, 4302-4304. (q) ten Have, R.; Leusink, F. R.; van Leusen, A.
M. Synthesis 1996, 871-876. (r) Pavri, N. P.; Trudell, M. L. J . Org.
Chem.. 1997, 62, 2649-2651. (s) Scheffer, J . R.; Ihmels, H. Liebigs
Ann. 1997, 1925-1929. (t) Merz, A.; Meyer, T. Synthesis 1999, 94-
99. (u) Zelikin, A.; Shastri, V. R.; Lange, R. J . Org. Chem. 1999, 64,
3379-3380. (v) Donohoe, T. J .; Harji, R. R.; Cousins, R. P. C. Chem.
Commun. 1999, 141-142. (w) Shiraishi, H.; Nishitani, T.; Nishihara,
T.; Sakaguchi, S.; Ishii, Y. Tetrahedron 1999, 55, 13957-13964.
(9) Perrin, C. L. J . Org. Chem. 1971, 36, 420-425. Hartshorn, S. R.
Chem. Soc. Rev. 1974, 3, 167-192. Eaborn, C. J . Organomet. Chem.
1975, 100, 43-57. Ha¨bich, D.; Effenberger, F. Synthesis 1979, 841-
876.
10.1021/jo991531c CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/29/2000

Synthesis of 3,4-Disubstituted 1H-Pyrrole
J . Org. Chem., Vol. 65, No. 11, 2000 3275
as the â-effect,10 has been widely used in most reactions
that involve silicon-carbon bond cleavage, leading to the
ipso displacement of a silicon-contained group such as a
trimethylsilyl group by other substituents. These sub-
stitution-desilylation reactions were first used for the
regiospecific synthesis of several interesting disubstituted
benzene derivatives.11 Recently, the successful conver-
sions of 3,4-bis(trimethylsilyl)furan (1)12 to 3,4-disubsti-
tuted furans and 3,4-bis(trimethylsilyl)thiophene (2)13 to
3,4-disubstituted thiophenes have been achieved in our
laboratory involving the concomitant duties of a silyl
group both as a protecting group and as an ipso director.
The similarities of furan and thiophene to pyrrole
prompted us to investigate the synthesis of 3,4-bis-
(trimethylsilyl)-1H-pyrrole (3), to which different sub-
stituents may be introduced into the â-carbons of the
pyrrole ring through stepwise halodesilylation and sub-
sequent palladium-catalyzed cross-coupling reactions. It
is anticipated that 3 might offer a general entry toward
the synthesis of symmetrical and unsymmetrical 3,4-
disubstituted-1H-pyrroles.
Sch em e 1a
a
Reagents and conditions: (i) n-BuLi, THF, -78 °C, 20 min;
(ii) i-Pr3SiCl, -78 °C, 30 min, -78 °C to rt, 15 min, 95%; (iii) NaH,
DMF, 0 °C, 2 h; (iv) ClSO2NMe2, 0 °C to rt, 2 h, 97%.
spectrum will become possible. In our special case, the
choice of protecting group was restricted to those that
do not require acidic conditions for group introduction
as well as group removal because 3 undergoes even a
facile ipso protodesilylation in dilute aqueous HCl. In the
literature, two kinds of pyrrole protections are known,
i.e., electron-donating protecting groups and electron-
withdrawing groups. The latter is much superior to the
former, due to its ability to reduce the electron density
of the π-excessive pyrrole system, thereby increasing the
stability of the pyrrole ring. In our previous study,1,14 tert-
butoxycarbonyl and p-toluenesulfonyl groups were chosen
as protecting groups for this purpose. The tert-butoxy-
carbonyl group (Boc) can easily be introduced and re-
moved.18 The toluenesulfonyl group (Ts) can also be easily
introduced and is stable under a wide variety of reaction
conditions.19 In addition to tert-butoxycarbonyl and p-
toluenesulfonyl, triisopropylsilyl (TIPS) and N,N-di-
methylaminosulfonyl groups (DMAS) were also selected
for 1-protection. The use of triisopropylsilyl group for
pyrrole protection has been recorded,1,20 and its compat-
ibility with mild protection and deprotection conditions
encountered in substituted pyrrole synthesis has also
been demonstrated.20 Thus, protection of the nitrogen
atom of 3 was accomplished in 95% yield by the use of
iPr3SiCl and n-BuLi as base at -78 °C, as described by
Bray and co-workers,20 to afford 1-triisopropylsilyl-3,4-
bis(trimethylsilyl)-1H-pyrrole (4) (Scheme 1). Pyrrole 4
formed a colorless liquid at room temperature and was
extremely acid sensitive (vide infra). The two singlets at
δ 0.22 and 6.88 in its 1H NMR spectrum indicated its
high level of symmetry, and absorptions at δ 1.09 and
1.43 were due to the isopropyl protons. Unlike the other
three aforementioned protecting groups, to our best
knowledge, N,N-dimethylaminosulfonyl21 has never been
employed for pyrrole protection. The formation of 5 took
place smoothly by slow addition of a DMF solution of 3
to a cooled solution of NaH in the same solvent and was
followed by the addition of ClSO2NMe2 to furnish 5 in a
good yield (Scheme 1). The 1H NMR spectrum of 5 showed
a singlet at δ 2.81 for the six methyl protons of the N,N-
dimethylaminosulfonyl group.
The successful preparation1,14 of 3 and its protection14
with tert-butoxycarbonyl and p-toluenesulfonyl groups
were reported recently. The iodination of 1-protected 3,4-
bis(trimethylsilyl)-1H-pyrroles was also disclosed.1 Herein,
we would like to present details of the synthesis of some
structurally elaborate 1-substituted and 1-unsubstituted
3,4-disubstituted 1H-pyrroles.
Resu lts a n d Discu ssion
1. P r otection of 3,4-Bis(tr im eth ylsilyl)-1H-p yr r ole
(3). Our desired molecule 3 was obtained from 1-tri-
methylsilyl-2-aziridinecarbonitrile15 through a 1,3-dipolar
cycloaddition16 with bis(trimethylsilyl)acetylene.1,14 Due
to the π-excessive pyrrole’s acid sensitivity, high reactiv-
ity, and inferior stability,17 1-protection is therefore
required before further reactions. Moreover, by varying
the substituents on the nitrogen, a broad reactivity
(10) Ushakov, S. N.; Itenberg, A. M. Zh. Obshch. Khim. 1937, 7,
2495-2498; Chem. Abstr. 1938, 32, 20833. Bassindale, A. R.; Taylor,
P. G. In The Chemistry of Organosilicon Compounds; The Activating
and Directing Effects of Silicon; Patai, S., Rappoport, Z., Eds.; Wiley:
Chichester, 1989; Part 2, pp 893-964. Lambert, J . B. Tetrahedron
1990, 46, 2677-2689. White, J . M. Aust. J . Chem. 1995, 48, 1227-
1251. Lambert, J . B.; Zhao, Y.; Emblidge, R. W.; Salvador, L. A.; Liu,
X.-Y.; So, J .-H.; Chelius, E. C. Acc. Chem. Res. 1999, 32, 183-190.
(11) Fe´lix, G.; Dunogue`s, J .; Calas, R. Angew. Chem., Int. Ed. Engl.
1979, 18, 402-404.
(12) Ho, M. S.; Wong, H. N. C. J . Chem. Soc., Chem. Commun. 1989,
1238-1240. Song, Z. Z.; Zhou, Z. Y.; Mak, T. C. W.; Wong, H. N. C.
Angew. Chem., Int. Ed. Engl. 1993, 32, 432-434. Song, Z. Z.; Wong,
H. N. C. Liebigs Ann. Chem. 1994, 29-34. Song, Z. Z.; Wong, H. N. C.
J . Org. Chem. 1994, 59, 33-41. Song, Z. Z.; Ho, M. S.; Wong, H. N. C.
J . Org. Chem. 1994, 59, 3917-3926.
(13) Ye, X.-S.; Yu, P.; Wong, H. N. C. Liebigs. Ann. Recueil 1997,
459-466. Ye, X.-S.; Wong, H. N. C.; J . Org. Chem. 1997, 62, 1940-
1954.
The removal of the tert-butoxycarbonyl group from the
known 1-(tert-butoxycarbonyl)-3,4-bis(trimethylsilyl)-1H-
pyrrole (6)14 to form 3 was achieved efficiently by the use
of NaOMe in MeOH. Under these conditions, the two
trimethylsilyl groups of 6 remained intact. Likewise, the
p-toluenesulfonyl group can also be removed readily from
(18) Carpino, L. A.; Barr, D. E. J . Org. Chem. 1966, 31, 764-767.
Dhanak, D.; Neidle, S.; Reese, C. B. Tetrahedron Lett. 1985, 26, 2017-
2020.
(19) Sakakibara, S.; Fujii, T. Bull. Chem. Soc. J pn. 1969, 42, 1466.
(20) Bray, B. L.; Mathies, P. H.; Naef, R.; Solas, D. R.; Tidwell, T.
T.; Artis, D. R.; Muchowski, J . M. J . Org. Chem. 1990, 55, 6317-6328.
(21) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; Wiley: New York, 1999.
(14) Liu, J .-H.; Chan, H.-W.; Feng, X.; Wang, Q.-G.; Mak, T. C. W.;
Wong, H. N. C. J . Org. Chem. 1999, 64, 1630-1634.
(15) Tomiyama, Y.; Wakabayashi, S.; Yokota, M.; J . Med. Chem.
1989, 32, 1988-1996.
(16) La Porta, P.; Capuzzi, L.; Bettarini, F. Synthesis 1994, 287-
290.
(17) Smith, G. F. Adv. Heterocycl. Chem. 1963, 2, 287-309.

3276 J . Org. Chem., Vol. 65, No. 11, 2000
Liu et al.
Sch em e 2
Sch em e 5
Sch em e 3
displacement of both trimethylsilyl groups was possible
only when the reactions were carried out at room tem-
perature and in the presence of an excess of I2. Conse-
quently, the iododesilylation of the remaining trimeth-
ylsilyl group was always performed at room temperature
(vide infra).
It is obvious that the reactivity was affected by the
1-substituents. Pyrroles 4 and 8, bearing σ-donors at
their nitrogen atoms, were clearly more reactive than the
other three less electron-rich pyrroles. From the observed
reaction temperatures, it is likely that the relative order
of reactivity for these five 1-protecting groups is t-Bu ∼
i-Pr3Si > t-BuOCO > p-MeC6H4SO2 > SO2NMe2. This
trend is in full agreement with the electronic effect
exerted by these 1-substituents. The structures of 9-13
Sch em e 4
1
were unequivocally established by their H NMR spectral
data.
3. P r ep a r a tion of 3,4-Disu bstitu ted 1H-P yr r oles.
The iodo groups of 9-13 served as pivotal handles from
which many functional group conversions can be realized.
For example, pyrrole 11 was readily converted to its
cyano derivative 14 by reaction with KCN and Pd(OAc)2
under basic conditions (Scheme 5).23 The tert-butoxycar-
bonyl group was, however, also removed concomitantly.
Despite the fact that palladium-catalyzed cross-cou-
pling reactions have been widely used in organic syn-
thesis, the application of these coupling reactions on
pyrroles has not been studied in a systematic manner.
Herein our attention will be focused on the palladium-
catalyzed cross-coupling reactions.
(a ) 3,4-Disu bstitu ted 1H-P yr r oles fr om 1-(ter t-
Bu t oxyca r b on yl)-3-t r im e t h ylsilyl-4-iod o-1H -p yr -
r ole (11). The palladium-catalyzed cross-coupling strat-
egy between iodoarenes and terminal alkynes,24 alkenes,25
and areneboronic acid26 offered important routes for the
functionalization of pyrroles at their â-carbons. 1-(tert-
Butoxycarbonyl)-protected pyrrole 11 was first used for
this purpose. It was found that the palladium-catalyzed
Sonogashira reaction24 proceeded smoothly under mild
conditions. Four alkynyl-substituted pyrrole compounds
15-18 were prepared in good yields via treatment of the
iodide 11 with different terminal alkynes in the presence
of a catalytic amount of palladium(0), a secondary amine
1-(p-toluenesulfonyl)-3,4-bis(trimethylsilyl)-1H-pyrrole (7)14
by reaction with KOH in MeOH, affording the parent 3
in good yield (Scheme 2).
2. Iod in a tion of 1-P r otected 3,4-Bis(tr im eth ylsi-
lyl)-1H-p yr r oles. With 1-protected 3,4-bis(trimethylsi-
lyl)-1H-pyrroles 4, 5, 6, and 7 in hand, a practical avenue
toward 3,4-disubstituted 1H-pyrrole was therefore sought,
making use of repeated and stepwise ipso iodinations and
palladium-catalyzed cross-coupling reactions. Thus, as
depicted in Scheme 3, our initial attempt was to replace
one of the two trimethylsilyl groups with an iodo group
by employing the â-effect10 of the trimethylsilyl group.
Subsequently, 1-protected 3-trimethylsilyl-4-iodo-1H-pyr-
roles were converted through palladium-catalyzed cross-
coupling reactions to lead to 1-protected-4-substituted
3-trimethylsilyl-1H-pyrroles. The remaining trimethyl-
silyl group was expectedly replaced again by other
substituents through repeated iodination and cross-
coupling reactions to form 3,4-disubstituted-1H-pyrroles
after deprotection (Scheme 3).
The C-Si bond can be easily cleaved by I2 due to the
σ-donating character of a trimethylsilyl group,22 as well
as its â-effect.10 A direct iodination using iodine and silver
trifluoroacetate in THF at low temperature (usually -78
°C) was perfomed since furan 112 and thiophene 213 were
both iodinated under similar conditions. In this way,
efficient conversions of 1-protected 3,4-bis(trimethylsilyl)-
1H-pyrroles 4, 5, 6, 7, and 8 (prepared from a similar
route as that for 3) into regiospecific monoiodides 9-13
were achieved in acceptable yields within 1 h at low
temperature using I2/CF3CO2Ag as shown in Scheme 4.
It is worthy to note that in all cases only one trimethyl-
silyl group underwent iododesilylation at low tempera-
tures (-35 to -78 °C) when 1 equiv of I2 was used. The
(23) Takagi, K.; Okamoto, T.; Sakakibara, Y.; Ohno, A.; Oka, S.;
Hayama, N. Bull. Chem. Soc. J pn. 1975, 48, 3298-3301.
(24) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 4467-4470. Tilley, J . W.; Zawoiski, S. J . Org. Chem. 1988, 53,
386-390. Sonogashira, K. In Comprehensive Organic Synthesis; Pat-
tenden, G., Ed.; Pergamon Press: Oxford, 1991; Vol. 3, pp 521-549.
Rossi, R.; Carpita, A.; Bellina, F. Org. Prep. Proced. Int. 1995, 27, 129-
160.
(25) Heck, R. F. J . Am. Chem. Soc. 1968, 90, 5518-5526. Heck, R.
F. Org. React. 1981, 27, 345-390. Heck, R. F. Palladium Reagents in
Organic Syntheses; Academic Press: London, 1985. Crisp, G. T. Chem.
Soc. Rev. 1998, 27, 427-436.
(26) Suzuki, A. Acc. Chem. Res. 1982, 15, 178-184. Sharp, M. J .;
Snieckus, V. Tetrahedron Lett. 1985, 26, 5997-6000. Sato, M.;
Miyaura, N.; Suzuki, A. Chem. Lett. 1989, 1405-1408. Suzuki, A. Pure
Appl. Chem. 1991, 63, 419-422. Abe, S.; Miyaura, N.; Suzuki, A. Bull.
Chem. Soc. J pn. 1992, 65, 2863-2865. Suzuki, A. Pure Appl. Chem.
1994, 66, 213-222. Franc, C.; Denonne, F.; Cuisinier, C.; Ghosez, L.
Tetrahedron Lett. 1999, 40, 4555-4558.
(22) Miller, R. B.; Reichenbach, T. Tetrahedron Lett. 1974, 543-
546.

Synthesis of 3,4-Disubstituted 1H-Pyrrole
J . Org. Chem., Vol. 65, No. 11, 2000 3277
Sch em e 6
Sch em e 7a
as base, and CuI as cocatalyst (Scheme 6).27 The active
Pd(0) catalyst was generated in situ from Pd(PPh3)2Cl2
and CuI in diethylamine. It was recorded in the literature
that CuI facilitated alkynylation of the Pd(II) intermedi-
ate.28 The 1H and 13C NMR spectral assignments of
compounds 15, 16, 17, and 18 were straightforward, and
all significant absorptions were easily assigned.
The Heck reaction25 has become an invaluable method
for introducing ethenyl substituents including acrylate
ester moieties on heterocycles. 3-Trimethylsilyl-4-iodofu-
ran12 and 3-trimethylsilyl-4-iodothiophene13 readily re-
acted with alkyl acrylates, acrylonitrile, styrene, and
methyl vinyl ketone. However, such alkenylation of
pyrrole 11 was found to be very difficult under the
regular Heck reaction conditions, i.e., Pd(OAc)2 and PPh3
in triethylamine under reflux,29 in that pyrrole 11 failed
to form the acrylyl derivative from an excess of methyl
acrylate and Pd(OAc)2-PPh3 at 100-120 °C. Instead, it
gave only recovered pyrrole 11 and an intractable brown
viscous oil. Likewise, 11 did not give the alkenylpyrrole
derivatives through similar reactions with styrene or
methyl vinyl ketone. Eventually, it was discovered that
this drawback could be remedied by the use of PdCl2-
(PPh3)2. Thus, alkenylation of 11 with methyl acrylate
was achieved using the following procedure: an excess
of terminal alkene (14 equivalents) was added to a
refluxing mixture of 11 in Et3N and DMF containing a
catalytic amount of PdCl2(PPh3)2. By using this method,
several alkenylpyrroles 19-23 were obtained. The ster-
eochemistry of the products was different due to different
substrates.30 For example, with methyl acrylate and
methyl vinyl ketone, 11 gave exclusively the trans-
disubstituted alkenes 19 and 20, while reaction with
acrylonitrile gave a mixture of trans-21 as well as the
cis-21. A similar situation was also found for styrene; i.e.,
the gem-isomer 23 was obtained in addition to the trans
isomer 22. The structure of the trans double bond was
indicated by the much larger coupling constant (J ) 16
Hz) between the two trans protons in the 1H NMR
spectra of 19, 20, trans-21, and 22. The structure of the
terminal double bond of 23 was confirmed also by its
coupling constant (J ) 1.8 Hz) between the two meth-
ylidene protons in its 1H NMR spectrum. The cis-
disubstituted double bond of cis-21 was supported by the
characteristic coupling constant (J ) 11.7 Hz) between
the two cis-protons. The yields of these reactions were
usually low (Scheme 7).
a
Reagents and conditions: (i) CH2dCHCO2Me, PdCl2(PPh3)2,
Et3N, DMF, 100-120 °C, 5 h; (ii) CH2dCHCOMe, PdCl2(PPh3)2,
Et3N, DMF, 100-120 °C, 5-10 h; (iii) CH2dCHCN, PdCl2(PPh3)2,
Et3N, DMF, 110 °C, 11 h; (iv) CH2dCHPh, PdCl2(PPh3)2, Et3N,
DMF, 100-120 °C.
Sch em e 8
The reaction between areneboronic acid with aryl
halide in the presence of Pd(0) catalyst, referred to as
the Suzuki cross-coupling reaction,26 proved to be a very
efficient method for the synthesis of aryl-substituted
pyrroles. In this connection, Suzuki coupling reaction26
on pyrrole 11 was also performed. The cross-coupling
proceeded smoothly in boiling toluene as solvent and Pd-
(PPh3)4 as catalyst. Sodium carbonate (2 equiv) as base
was required to activate the palladium catalyst as well
as the areneboronic acids. The results obtained from a
variety of areneboronic acids are summarized in Scheme
8. Typically, the preparation of 1-(tert-butoxycarbonyl)-
3-trimethylsilyl-4-phenyl-1H-pyrrole (24) in a moderate
yield was based on the coupling of 11 with benzenebo-
ronic acid. Compounds 25, 26, and 27 were obtained in
a similar manner (Scheme 8).
Apart from the cross-coupling method, the iodo group
of pyrrole 11 could also be converted to other substituents
via an organometallic pathway.31 For instance, 11 was
able to undergo a rapid iodine-lithium exchange with
n-BuLi in THF, which was followed by the quenching
with H2O to generate the corresponding 1-(tert-butoxy-
carbonyl)-3-trimethylsilyl-1H-pyrrole (28) (Scheme 9). It
is believed that further manipulations of 28 may provide
a useful access to 3-substituted-1H-pyrroles.
(27) Tao, W.; Nesbitt, S.; Heck, R. F. J . Org. Chem. 1990, 55, 63-
69.
(28) Dieck, H. A.; Heck, R. F. J . Organomet. Chem. 1975, 93, 259-
263.
(29) Cabri, W.; Candiani, I.; Bedeschi, A. J . Org. Chem. 1992, 57,
3558-3563.
(30) Spencer, A. J . Organomet. Chem. 1983, 258, 101-108.
(31) Chen, W.; Cava, M. P. Tetrahedron Lett. 1987, 28, 6025-6026.

3278 J . Org. Chem., Vol. 65, No. 11, 2000
Liu et al.
Sch em e 9
Sch em e 11a
Sch em e 10
a
Reagents and conditions: (i) RCtCH, PdCl2(PPh3)2, CuI,
Et2NH, rt, 7 h; (ii) CH2dCHR, PdCl2(PPh3)2, Et3N, DMF, 125 °C,
1 h; (iii) ArB(OH)2, Pd(PPh3)4, 2 M Na2CO3, MeOH-PhMe, 90-
100 °C, 12 h.
Sch em e 12
After the first trimethylsily group had been replaced
by substituents, the remaining trimethylsilyl group of the
1-(tert-butoxycarbonyl)-protected pyrrole was subjected
to a second ipso iodination. After that, a subsequent
cross-coupling reaction might furnish ultimately 3,4-
disubstituted 1H-pyrroles. Compound 17 was first chosen
for further iodination. Nonetheless, the yields of the
second iodination were not consistent, being frequently
lower in large-scale iodination. In addition, the polarity
of the starting material 17 was almost the same as that
of the product, therefore making the chromatographic
purification rather difficult. The reaction conditions
(reaction time, solvent, temperature, silver catalyst) were
modified all to no avail. An excess of iodine or prolonged
reaction time only led to the decomposition of the starting
materials. A similar result was also observed for the
iodination of 24.
Reaction of pyrrole 10 with terminal acetylene under
standard Sonogashira conditions24 gave alkynylation
products 32 and 33. Pyrrole 10 was also able to couple
with terminal alkenes to form exclusively trans-alkenyl-
ation products 34 and 35.25 Under Suzuki conditions,26
the 4-aryl derivatives 36 and 37 were isolated in good
yields after purification by chromatography (Scheme 11).
The three types of palladium-catalyzed cross-couplings
were found to go to completion in much shorter reaction
times when compared to the 1-(tert-butoxycarbonyl)
analogues.
In view of this unfavorable outcome, an alternative
approach in which the order of functionalization was
reversed was examined. Thus, 17 was first deprotected
using NaOMe/MeOH to give 3-trimethylsilyl-4-pheny-
ethynyl-1H-pyrrole (29). Without isolation, iodination of
29 was achieved following the aforementioned routine to
afford 30. Palladium-catalyzed cross-coupling of 30, the
final step toward the desired 3,4-disubstituted pyrroles,
was successfully accomplished under the Sonogashira
conditions24 to provide 3,4-bis(phenylethynyl)-1H-pyrrole
(31) (Scheme 10). It is noteworthy that 30 decomposed
slowly upon purification on a silica gel column. For this
reason, this strategy appeared to be quite limited in
scope. At this juncture, a different approach was at-
tempted and will be discussed in the following section.
(b ) 3,4-Disu b st it u t ed 1H -P yr r oles fr om N,N-Di-
methyl-3-trimethylsilyl-4-iodo-1H-pyrrolesulfonamide
(10). Since the introduction of the second iodine atom
was apparently inaccessible in a clean manner via the
1-(tert-butoxycarbonyl)-protected pyrroles, we therefore
turned our attention to other protecting groups with the
conviction that 1-protecting groups could greatly influ-
ence pyrrole reactivities. Consequently, 1-(N,N-dimethyl-
aminosulfonyl)-protecting pyrrole 10 was selected espe-
cially for the iodination of its remainimg trimethylsilyl
group.
The next step was again the ipso iodination of the
remaining trimethylsilyl group. Although ipso iodinations
of the first trimethylsilyl group in 4-8 were carried out
at low temperatures (Scheme 4), the iodination of the
second trimethylsilyl group of 1-(N,N-dimethylaminosul-
fonyl)-protected pyrroles must be performed at room
temperature because of the strongly deactivating electron-
withdrawing property of the N,N-dimethylsilylsulfonyl
protecting group. Thus, treatment of the 4-alkenylpyrrole
34 with iodine and CF3CO2Ag at room temperature
resulted in an ipso iodination, furnishing the iodide 38.
The 4-aryl derivative 36 reacted similarly to afford 39
(Scheme 12). No trace of starting 34 and 36 was observed
on TLC plates, and the reactions were complete in a very
short time.
As expected, subsequent cross-coupling reactions pro-
ceeded very easily. For example, compound 38 was found
to undergo alkynylation with phenylacetylene in 73%
yield in 2-5 h at room temperature to afford 40.24 It also
readily underwent a Suzuki coupling reaction26 with
benzeneboronic acid to give phenylpyrrole 41 in 78%
yield. Likewise, compound 39 gave the corresponding
trimethylsilylethyne and 4-hydroxybutyne derivative 42
and 43 in 90% and 80% yield, respectively. Diarylpyrrole
44 was isolated in 86% yield by reaction of 39 with
benzeneboronic acid (Scheme 13).

Synthesis of 3,4-Disubstituted 1H-Pyrrole
J . Org. Chem., Vol. 65, No. 11, 2000 3279
Sch em e 13a
Sch em e 15a
a
Reagents and conditions: (i) Me3SiCtCH, PdCl2(PPh3)2, CuI,
Et2NH, rt, 14 h, 94%; (ii) CH2dCHCO2Me, PdCl2(PPh3)2, Et3N,
DMF, 100-120 °C, 1 h, 94%; (iii) ArB(OH)2, Pd(PPh3)4, 2 M
Na2CO3, MeOH-PhMe, 100-110 °C, 3 h.
a
Reagents and conditions: (i) PhCtCH, PdCl2(PPh3)2, CuI,
Et2NH, rt, 2-5 h, 73%; (ii) PhB(OH)2, Pd(PPh3)4, 2 M Na2CO3,
MeOH-PhMe, 110 °C, 2 h, 78%; (iii) RCtCH, PdCl2(PPh3)2, CuI,
Et2NH, rt, 4 h, 80%; (iv) PhB(OH)2, Pd(PPh3)4, 2 M Na2CO3,
MeOH-PhMe, 110 °C, 1.5 h, 86%.
dimethylaminosulfonyl group led us to examine other
protecting groups. A careful literature search revealed
that the p-toluenesulfonyl group appeared to be a good
substitute for the N,N-dimethylaminosulfonyl group. The
choice in favor of the p-toluenesulfonyl group as the
1-protecting group was due to the fact that an electron-
withdrawing p-toluenesulfonyl group, like the N,N-di-
methylaminosulfonyl group, should benefit the Heck
reaction as well as iodination reactions when compared
with the tert-butoxycarbonyl series. Moreover, unlike the
N,N-dimethylaminosulfonyl group, the p-toluenesulfonyl
group was often used for pyrrole protection, and because
of this a number of methods are available for its re-
moval.38
The same synthetic strategy used for 1-(N,N-dimethyl-
aminosulfonyl)-3,4-disubstituted-1H-pyrroles was carried
out. Thus, iodopyrrole 12 was converted to alkynylated
product 46 under standard Sonogashira conditions.24 The
3-alkenylated 47 and 3-arylated derivatives 48 and 49
were also readily obtained through Heck25 and Suzuki26
reactions in good yield, respectively (Scheme 15).
Similar to 1-(N,N-dimethylaminosulfonyl)-protected
pyrroles, the iodination of the remaining trimethylsilyl
group of 46 gave iodide 50 in a reasonable yield and in a
clean manner. As discussed previously, the displacement
of the second trimethylsilyl always required a much
higher reaction temperature than that of the first tri-
methylsilyl group. This particular characteristic is es-
sential to our program because only in this way unsym-
metrically 3,4-disubstituted 1H-pyrroles can be realized.
Compound 50 reacted with p-methoxybenzeneboronic
acid under Suzuki conditions26 to afford two products,
namely the normal 3,4-disubstituted 1-(p-toluenesulfo-
nyl)pyrrole 51 and the undesired bipyrrole 52. As pre-
dicted previously, the p-toluenesulfonyl group was easily
removed by treatment of 51 with KOH in MeOH, giving
53 in good yield (Scheme 16). On the other hand, 47 was
converted to 55 via 54 in a simple manner (Scheme 17).
From the iodinated compound 56, obtained in turn
from 48, two 1-(p-toluenesulfonyl)-3,4-disubstituted pyr-
roles 55 and 57 were obtained through Heck25 and
Suzuki26 reactions, respectively (Scheme 18). Deprotec-
tion of these 1-(p-toluenesulfonyl)-protected pyrroles was
Sch em e 14
The final step of our protocol required the deprotection
of the N,N-dimethylaminosulfonyl group from pyrroles
40-44. It is known that sulfonamides are among the
most stable of the N-protecting groups, and their removal
often requires drastic conditions, i.e., heating to reflux
in a strong acid32 or in a base.33 In addition, the N,N-
dimethylaminosulfonyl group is often used for imidazole
protection,34 and a survey of the literature revealed no
example for pyrrole protection. Only very recently have
some N-sulfonyl groups (N-methanesulfonyl, N-p-tolu-
enesulfonyl, and N-benzenesulfonyl) on pyrroles and
indoles been reported to be cleaved with TBAF in THF.35
Some other milder deprotection methods for N-sulfonyl
groups, such as Mg/MeOH36 or NaI/Me3SiCl,37 were also
recorded. However, treatment of the N,N-dimethylami-
nosulfonyl-protected pyrroles 40-44 with 2 equiv of
TBAF in THF at 60-70 °C failed to afford the desired
parent 3,4-disubstituted 1H-pyrroles except for 40, which
generated nonprotected 45 (Scheme 14). For the other
four protected pyrroles 41-44, alternate deprotection
procedures involving Mg/MeOH or NaI/Me3SiCl were also
unfruitful.
(c) 3,4-Disu bstitu ted 1H-P yr r oles fr om 1-(p-Tolu -
en esu lfon yl)-3-tr im eth ylsilyl-4-iodo-1H-pyr r ole (12).
The difficulties associated with the deprotection of N,N-
(32) Snyder, H. R.; Heckert, R. E. J . Am. Chem. Soc. 1952, 74, 2006-
2009.
(33) Sundberg, R. J .; Laurino, J . P. J . Org. Chem. 1984, 49, 249-
254.
(34) Carpenter, A. J .; Chadwick, D. J . Tetrahedron 1986, 42, 2351-
2358.
(35) Yasuhara, A.; Sakamoto, T. Tetrahedron Lett. 1998, 39, 595-
596.
(36) Okabe, K.; Natsume, M. Tetrahedron 1991, 47, 7615-7624.
(37) Sabitha, G.; Subba Reddy, B. V.; Abraham, S.; Yadav, J . S.
Tetrahedron Lett. 1999, 40, 1569-1570.
(38) Kocienski, P. J . Protecting Groups; Georg Thieme Verlag:
Stuttgart, 1994; pp 209-215.

3280 J . Org. Chem., Vol. 65, No. 11, 2000
Liu et al.
Sch em e 16
Sch em e 18a
a
Reagents and conditions: (i) I2, CF3CO2Ag, THF, rt, 1 h, 62%;
(ii) p-MeOC6H4B(OH)2, Pd(PPh3)4, 2 M Na2CO3, MeOH-PhMe,
100 °C, 2.5 h, 37%; (iii) CH2dCHCO2Me, PdCl2(PPh3)2, Et3N,
DMF, 100 °C, 50 min, 66%; (iv) KOH, MeOH, rt, 1 h, 95%; (v)
n-Bu4NF, THF, 60 °C, 3 h, 96%.
Sch em e 19
Sch em e 17
Sch em e 20a
a
Reagents and conditions: (i) n-BuLi, THF, HMPA, -78 °C;
(ii) MeI, -78 °C, 60%; (iii) PhCHO, -78 °C, 21%.
Sch em e 21a
accomplished successfully. The p-toluenesulfonyl group
was removed by treatment of 57 with KOH in MeOH to
afford 58 (Scheme 18). In order not to affect the meth-
oxycarbonyl, the protecting group of 55 was removed to
afford 59 under a milder condition, i.e., TBAF in THF
with heating at 60-70 °C (Scheme 18).
(d ) 3,4-Disu bstitu ted 1H-P yr r oles fr om 1-Tr iiso-
pr opylsilyl-3-tr im eth ylsilyl-4-br om o-1H-pyr r ole (60).
Although our initial plan to secure unsymmetrically 3,4-
disubstituted 1H-pyrroles by starting from the 1-(p-
toluenesulfonyl)-protected pyrroles was successful, we
also investigated the use of triisopropylsilyl as a protect-
ing group in the synthesis of 3,4-disubstituted-1H-pyr-
roles. In addition to the ipso iodination that afforded 9,
the trimethylsilyl group of 4 was also efficiently replaced
by a bromo group through the reaction with NBS at -10
°C (Scheme 19), providing bromide 60.
Lithiation of 60 at -78 °C and subsequent quenching
with either iodomethane or benzaldehyde gave 61 (60%)
and 62 (21%), respectively (Scheme 20).
As shown in Scheme 21, pyrrole 61 underwent further
regiospecific iodination at room temperature to yield
iodide 63, from which several palladium-catalyzed cross-
coupling reactions were carried out. For instance, com-
a
Reagents and conditions: (i) I2, CF3CO2Ag, THF, rt, 55%; (ii)
ArB(OH)2, Pd(PPh3)4, 2 M Na2CO3, MeOH-PhMe, 80 °C; (iii)
RCtCH, PdCl2(PPh3)2, CuI, Et2NH, rt.
pounds 64 and 65 were obtained from 63 via a Suzuki
reaction pathway.26 It is interesting to note that the
unprotected 64, namely 3-phenyl-4-methyl-1H-pyrrole,
was recently isolated from the cephalic extracts of the
ant Anochetus kempfi.39 Sonogashira reaction24 of 63 with

Synthesis of 3,4-Disubstituted 1H-Pyrrole
J . Org. Chem., Vol. 65, No. 11, 2000 3281
Sch em e 22
crepancy, the N,N-dimethylaminosulfonyl group can still
serve as a good 1-protecting group for access to 3,4-
disubstituted 1H-pyrroles when a more effective depro-
tection condition is uncovered. The p-toluenesulfonyl
group is by far the best protection group that led to
various parent 3,4-disubstituted 1H-pyrroles. The ad-
vantages of the p-toluenesulfonyl over triisopropylsilyl,
tert-butoxycarbonyl, and N,N-dimethylaminosulfonyl are
evident because it was compatible with easy experimen-
tal manipulation, reliable large-scale operation, and
chromatographic stability on silica gel.
four different terminal alkynse gave pyrroles 66-69,
respectively. Unfortunately, all attempts to react 63
under a variety of Heck reaction conditions25 failed.
Under usual workup procedures, it was observed that
all the triisopropylsilyl-protected pyrroles are relatively
less stable, as compared with their less electron-rich
analogues mentioned above. For example, the 1-triiso-
propylsilylpyrroles must be chromatographed on silica gel
columns in the presence of Et3N. A neat sample of 63
even turned dark upon keeping at room temperature.
4. Syn th esis of P yr r olebor oxin es. 3,4-Bis(trimeth-
ylsilyl)furan (1) was successfully converted to its borox-
ine, which was used as a key intermediate for the
realization of many 3,4-disubstituted furans.13 According
to the literature method,13 the reaction was performed
by adding BCl3 to a CH2Cl2 solution of the acid-sensitive
pyrrole 3. However, it was observed that the reaction
solutions immediately darkened as BCl3 was slowly
added to pyrroles 3 or 4 even at -78 °C. When 1-(tert-
butoxycarbonyl)-protected pyrrole 6 was used, the situ-
ation was improved to a certain extent in that only at
approximately 0 °C did the solution turned dark. The
protecting groups on the pyrroles apparently were able
to moderate their reactivities. In this connection, an
obvious choice would be the N,N-dimethylaminosulfonyl-
protected pyrrole 5. Therefore, pyrrole 5 was allowed to
react with BCl3 in a dilute CH2Cl2 solution at -78 °C.
After usual workup and purification by column chroma-
tography, 70 was obtained in a meager 23% yield,
together with a significant amount of 71 (34%) (Scheme
22). Due to its disappointing yield, it was concluded that
70 was not a suitable precursor for the synthesis of 3,4-
disubstituted-1H-pyrrole.
Exp er im en ta l Section
1-Tr iisop r op ylsilyl-3,4-bis(tr im eth ylsilyl)-1H-p yr r ole
(4). n-BuLi (1 mL, 1.6 mmol) was added to a stirred solution
of pyrrole 314 (0.3 g, 1.42 mmol) in THF (6.5 mL) at -78 °C.
Twenty minutes later, triisopropylsilyl chloride (0.3 mL, 1.42
mmol) was added and stirred for another 30 min. The reaction
mixture was warmed to room temperature over 15 min. Usual
workup (Et2O) gave 4 as a colorless oil (495 mg, 95%): 1H NMR
(CDCl3) δ 0.22 (s, 18H), 1.09 (d, J ) 7.4 Hz, 18H), 1.43 (sept,
J ) 7.4 Hz, 3H), 6.88 (s, 2H); 13C NMR (CDCl3) δ 1.03, 11.87,
17.90, 123.52, 133.58; MS m/z 367 (M+, 82); HRMS calcd for
C
19H41NSi3 367.2541, found 367.2552.
N,N-Dim eth yl 3,4-Bis(tr im eth ylsilyl)-1H-p yr r ole-1-su l-
fon a m id e (5). NaH (1.44 g, 36 mmol) was placed in a 250
mL three-necked flask fitted with a thermometer, and a
dropping funnel and was washed with hexanes (2 × 8 mL).
Then DMF (70 mL) was added. This NaH-DMF mixture was
cooled to 0 °C, and a solution of 3 (6.33 g, 30 mmol) in DMF
(50 mL) was added dropwise. After addition, the reaction was
stirred at 0 °C for 2 h. ClSO2NMe2 (3.22 mL, 30 mmol) in DMF
(50 mL) was added, and the mixture was stirred and simul-
taneously allowed to warm to room temperature in 2 h. The
resulting mixture was then poured into ice-water (250 mL),
and Et2O (300 mL) was added. The aqueous layer was
separated and washed with Et2O (2 × 200 mL). The combined
ethereal solution was washed with water (2 × 200 mL) and
brine (2 × 200 mL) and dried over MgSO4. After evaporation,
the residue was purified by chromatography on silica gel (400
g) eluted with hexanes/Et2O (10:1) to give 5 (9.27 g, 97%) as
1
white crystals: mp 109 °C; H NMR (CDCl3) δ 0.26 (s, 18H),
2.81 (s, 6H), 7.14 (s, 2H); 13C NMR (CDCl3) δ 0.51, 38.29,
125.89, 128.94; MS m/z 318 (M+, 55). Anal. Calcd for
C
12H26N2O2SSi2: C, 45.24; H, 8.23; N, 8.79. Found: C, 45.20;
H, 8.49; N, 8.85.
Dep r ot ect ion of 1-(ter t-Bu t oxyca r b on yl)-3,4-b is(t r i-
m eth ylsilyl)-1H-p yr r ole (6). A mixture of 614 (31 mg, 0.1
mmol) and NaOMe (11 mg, 0.2 mmol) in MeOH (3 mL) was
stirred at room temperature for 8 h to give white solids (17
mg, 80%): mp 115-118 °C; The 1H NMR spectrum was
identical to that of an authentic sample of 3.14
Con clu sion
Triisopropylsilyl, tert-butoxycarbonyl, p-toluenesulfo-
nyl, and N,N-dimethylaminosulfonyl were introduced to
the pyrrole nitrogen of 3 as protecting groups. 3,4-
Disubstituted 1H-pyrroles were synthesized through
stepwise and repeated iodination and palladium-cata-
lyzed cross-coupling reaction. Three drawbacks were
encountered in this study, namely, the Heck coupling
reaction, the ipso iodination to replace the second tri-
methylsily group, and the final deprotection step. Of
several alternatives we investigated, the tert-butoxycar-
bonyl group was unfavored both for the Heck reaction
and for the ipso iodination. The N,N-dimethylaminosul-
fonyl group gave acceptable results not only for the Heck
coupling but also for the ipso iodination. Nevertheless,
the deprotection of the N,N-dimethylaminosulfonyl group
was performed with great difficulties. Despite this dis-
Dep r otection of 1-(p-Tolu en esu lfon yl)-3,4-bis(tr im eth -
ylsilyl)-1H-p yr r ole (7). KOH (100 mg) was added to a
solution of 714 (13.9 mg, 0.04 mmol) in MeOH (1.5 mL). The
mixture was stirred at room temperature for 20 h. After
extraction with Et2O (10 mL), washing with H2O (5 mL),
drying (Na2SO4), filtration, and evaporation, the pale yellow
residue was crystallized from MeOH-H2O (5:1) to afford white
1
crystals (5 mg, 62%): mp 115-118 °C. The H NMR spectrum
was identical to that of an authentic sample of 3.14
1-(ter t-Bu tyl)-3,4-bis(tr im eth ylsilyl)-1H-p yr r ole (8). To
a solution of 1-(tert-butyl)-2-aziridinecarbonitrile16 (436 mg, 3.5
mmol) in xylene (18 mL) was added bis(trimethylsilyl)acetyl-
ene (780 mg, 4.6 mmol) at room temperature. This mixture
was refluxed under N2 for 18 h. The solvent was evaporated
in vacuo. The residue was taken up in Et2O, and the resulting
ethereal solution was filtered through Celite (2 cm). The
filtrate was concentrated and chromatographed on silica gel
(150 g) eluted with hexanes/Et2O (20:1) to afford 8 (744 mg,
79%) as colorless crystals: 1H NMR (CDCl3) δ 0.25 (s, 18H),
1.54 (s, 9H), 6.95 (s, 2H); 13C NMR (CDCl3) δ 1.33, 30.91, 54.68,
(39) J ones, T. H.; Flournoy, R. C.; Torres, J . A.; Snelling, R. R.;
Spande, T. F.; Garraffo, H. M. J . Nat. Prod. 1999, 62, 1343-1345.

3282 J . Org. Chem., Vol. 65, No. 11, 2000
Liu et al.
121.11, 127.29; MS m/z 267(M+, 77). Anal. Calcd for C14H29
NSi2: C, 62.85; H, 10.92; N, 5.23. Found: C, 62.85; H, 11.23;
N, 4.94.
-
gel (40 g) to give 24 (189 mg, 60%) as colorless crystals: 1H
NMR (CDCl3) δ 0.13 (s, 9H), 1.60 (s, 9H), 7.26-7.37 (m, 7H);
13C NMR (CDCl3) δ 0.07, 27.99, 83.72, 118.76, 121.85, 126.73,
126.93, 128.02, 128.69, 133.67, 136.72, 148.69; MS m/z 315
(M+, 8). Anal. Calcd for C18H25NO2Si: C, 68.53; H, 7.99; N,
4.44. Found: C, 68.75; H, 8.22; N, 4.43.
1-Tr iisop r op ylsilyl-3-t r im e t h ylsilyl-4-iod o-1H -p yr -
r ole (9). (Rep r esen ta tive Exa m p le of Iod in a tion : P r o-
ced u r e 1). A mixture of pyrrole 4 (73.4 mg, 0.2 mmol) and
CF3CO2Ag (44 mg, 0.2 mmol) dissolved in THF (5 mL) was
cooled to -78 °C, and I2 (50.8 mg, 0.2 mmol) in THF (2 mL)
was added dropwise. The reaction mixture was stirred for 1 h
at -78 °C under N2. The brown mixture was diluted with Et2O
(10 mL) and then filtered through Celite. The filteration was
washed successively with 50% aqueous Na2S2O3 (3 × 5 mL),
H2O (10 mL), and brine (10 mL) and dried over MgSO4. After
evaporation, the residue was subjected to column chromatog-
raphy (silica gel, 20 g) with hexanes as eluent to give 9 (72
mg, 85%) as a colorless oil: 1H NMR (CDCl3) δ 0.28 (s, 9H),
1.08 (d, J ) 7.4 Hz, 18H), 1.42 (sept, J ) 7.4 Hz, 3H), 6.62 (d,
J ) 2.1 Hz, 1H), 6.88 (d, J ) 2.1 Hz, 1H); 13C NMR (CDCl3) δ
-0.57, 11.62, 17.75, 68.85, 123.28, 130.68, 131.73; MS m/z 421
(M+, 12); HRMS calcd for C16H32INSi2 421.1112, found 421.1102.
3-Tr im eth ylsilyl-4-cya n o-1H-p yr r ole (14). A mixture of
11 (365 mg, 1 mmol), KCN (130 mg, 2 mmol), Pd(OAc)2 (2 mg,
0.01 mmol), KOH (8.4 mg, 0.15 mmol), and HMPA (5 mL) was
heated at 75 °C for 12 h under N2. After extraction with EtOAc
(2 × 20 mL), the organic layer was washed with H2O (35 mL),
dried (Na2SO4), and evaporated. The resulting residue was
chromatographed (hexanes/Et2O 1:1) on silica gel (40 g) to
afford 14 (90 mg, 55%) as colorless crystals: 1H NMR (CDCl3)
δ 0.30 (s, 9H), 6.79 (t, J ) 1.8 Hz, 1H), 7.41 (d, J ) 1.8 Hz,
1H), 9.30 (s, br, 1H); 13C NMR (CDC13) δ -0.93, 96.71, 118.15,
121.53, 124.99, 127.97; MS m/z 164 (M+, 49); HRMS calcd for
C8H13N2Si (MH+) 165.0842, found 165.0841.
1-(ter t-Bu t oxyca r b on yl)-3-t r im et h ylsilyl-1H -p yr r ole
(28). (Rep r esen ta tive Exa m p le of Lith ia tion a n d Su bse-
qu en t Nu cleop h ilic Su bstitu tion : P r oced u r e 5). To a
stirred solution of 11 (365 mg, 1 mmol) in dry THF (16 mL)
was added dropwise n-BuLi (0.75 mL, 1.2 mmol), and the
mixture was stirred for 1 h at -78 °C under N2. H2O (54 mL,
3 mmol) was added, and the mixture was stirred for an
additional 3.5 h until warmed to room temperature. After
extraction with Et2O (2 × 20 mL), washing with H2O (15 mL),
drying (Na2SO4), filtration, and evaporation, the residue was
chromatographed (hexane/CH2Cl2 30:4) on silica gel (40 g) to
give 28 (132 mg, 55%) as a colorless residue: 1H NMR (CDCl3)
δ 0.21 (s, 9H), 1.59 (s, 9H), 6.25 (dd, J ) 3.0, 1.5 Hz, 1H), 7.24
(d, J ) 1.5 Hz, 1H), 7.28-7.29 (m, 1H); 13C NMR (CDCl3) δ
-0.73, 27.90, 83.36, 115.95, 120.97, 122.09,125.15, 148.73; MS
m/z 239 (M+, 22); HRMS calcd for C12H21NO2Si (MH+) 240.1414,
found 240.1412.
3-Iod o-4-p h en yleth yn yl-1H-p yr r ole (30). A mixture of 17
(335 mg, 1 mmol) and NaOMe (0.2 g) was dissolved in MeOH
(5 mL) and stirred at room temperature for 6 h. After washing
(H2O), extraction (Et2O), and evaporation, the residue was
flash chromatographed (hexane/Et2O 5:2) on silica gel (5 g) to
afford 29 as a brown sticky oil, which was used without further
purification and identification. Compound 29 was dissolved
in THF (30 mL) and iodinated with I2 (400 mg, 1.57 mmol)
and CF3CO2Ag (363 mg, 1.65 mmol) at -78 °C for 2 h. The
crude residue was purified by chromatography on silica gel
(40 g, hexane/Et2O 7:2) to afford 30 (181 mg, 62% over two
1-(ter t-Bu t oxyca r b on yl)-3-t r im et h ylsilyl-4-t r im et h yl-
silyleth yn yl-1H-p yr r ole (15). (Rep r esen ta tive Exa m p le
of Son oga sh ir a Rea ction : P r oced u r e 2). PdCl2(PPh3)2 (70
mg, 0.1 mmol) and CuI (114 mg, 0.6 mmol) were added to a
solution of pyrrole 11 (365 mg, 1 mmol), trimethylsilylacetylene
(156 mg, 1.6 mmol), and Et2NH (3 mL). This mixture was
stirred for 24 h at room temperature under N2. The solvent
was evaporated, and the residue was purified by chromatog-
raphy on silica gel (20 g, hexanes) to give 15 (307 mg, 92%) as
1
steps) as a brown oil: H NMR (CDCl3) δ 6.83 (t, J ) 2.4 Hz,
1H), 7.02 (t, J ) 2.4 Hz, 1H), 7.32-7.58 (m, 5H), 8.39 (s, br,
1H); 13C NMR (CDCl3) δ 67.25, 84.04, 90.80, 110.75, 122.33,
123.27, 123.64, 127.79, 128.25, 131.31; MS m/z 293 (M+, 100).
Anal. Calcd for C12H8IN: C, 49.17; H, 2.75; N, 4.78. Found:
C, 49.15; H, 2.64; N, 4.67.
3-P h en yleth yn yl-4-(tr a n s-2-m eth oxyca r bon yleth en yl)-
1H-p yr r ole (45). A solution of 40 (36 mg, 0.1 mmol), TBAF
(0.2 mL, 0.2 mmol), and THF (3 mL) was stirred at 60 °C for
2 h. After extraction with EtOAc (2 × 10 mL), washing with
H2O (10 mL), drying (Na2SO4), filtration, and evaporation, the
residue was chromatographed (hexane/EtOAc 4:1) on silica gel
(20 g) to afford 45 (21 mg, 60%) as a yellow residue: 1H NMR
(CDCl3) δ 3.79 (s, 3H), 6.82 (d, J ) 15.9 Hz, 1H), 6.99 (t, J )
2.4 Hz, 1H), 7.07 (t, J ) 2.4 Hz, 1H), 7.33-7.37 (m, 3H), 7.51-
7.54 (m, 2H), 7.72 (d, J ) 15.9 Hz, 1H), 8.75 (s, br, 1H); 13C
NMR (CDCl3) δ 51.46, 83.44, 91.79, 104.19, 114.47, 121.01,
121.09, 123.66, 124.22, 127.86, 128.34, 131.18, 137.67, 168.76;
MS m/z 251 (M+, 12). Anal. Calcd for C16H13NO2: C, 76.48; H,
5.21; N, 5.57. Found: C, 76.22; H, 5.28; N, 5.37.
3-(p-Meth oxyp h en yl)-4-tr im eth ylsilyleth yln yl-1H-p yr -
r ole (53). Pyrrole 51 (42 mg, 0.1 mmol) was dissolved in THF
(2 mL) and MeOH (2 mL) containing KOH (0.2 g) at room
temperature for 2 h. The reaction was quenched by pouring
into H2O (15 mL) and extracted with Et2O (15 mL). The
residue after evaporation was chromatographed on silica gel
(15 g) eluted by hexane/Et2O (5:2) to give 53 (23 mg, 85%) as
a yellow oil: 1H NMR (CDCl3) δ 0.33 (s, 9H), 3.82 (s, 3H), 6.74
(t, J ) 2.1 Hz, 1H), 6.87 (d, J ) 8.4 Hz, 2H), 7.13 (t, J ) 2.1
Hz, 1H), 7.43 (d, J ) 8.4 Hz, 2H), 8.37 (s, br, 1H); 13C NMR
(CDCl3) δ -0.70, 55.26, 84.47, 88.75, 109.41, 113.89, 116.63,
120.58, 123.16, 123.96, 132.32, 158.90; MS m/z 269 (M+, 100).
Anal. Calcd for C16H19NOSi: C, 71.33; H, 7.11; N, 5.20.
Found: C, 71.55; H, 7.41; N, 5.16.
1
colorless crystals: mp 48-49 °C; H NMR (CDCl3) δ 0.22 (s,
9H), 0.28 (s, 9H), 1.59 (s, 9H), 7.12 (d, J ) 1.8 Hz, 1H), 7.45
(d, J ) 2.1 Hz, 1H); 13C NMR (CDCl3) δ -1.25, -0.14, 27.85,
84.10, 95.32, 100.49, 112.40, 124.80, 125.33, 147.96; MS m/z
335 (M+, 17). Anal. Calcd for C17H29NO2Si2: C, 60.84; H, 8.71;
N, 4.17. Found: C, 60.76; H, 9.01; N, 4.09.
1-(ter t-Bu t oxyca r b on yl)-3-t r im et h ylsilyl-4-(tr a n s-2-
m eth oxyca r bon yleth en yl)-1H-p yr r ole (19). (Rep r esen ta -
tive Exa m p le of Heck Cou p lin g Rea ction : P r oced u r e 3).
To a solution of 11 (365 mg, 1.0 mmol) in DMF (9 mL) were
added methyl acrylate (1.25 mL, 13.8 mmol), Et3N (4 mL), and
PdCl2(PPh3)2 (100 mg, 0.14 mmol) at room temperature. The
reaction mixture was refluxed at 100-120 °C under N2 with
stirring for 5 h. After extraction with Et2O (2 × 20 mL),
washing with H2O (15 mL), drying (Na2SO4), filtration, and
evaporation, the residue was chromatographed (hexanes/
EtOAc 5:2) on silica gel (40 g) to give 19 (107 mg, 33%) as a
colorless oil: 1H NMR (CDCl3) δ 0.27 (s, 9H), 1.59 (s, 9H), 3.76
(s, 3H), 6.19 (d, J ) 15.9 Hz, 1H), 7.20 (d, J ) 1.8 Hz, 1H),
7.58 (d, J ) 2.1 Hz, 1H), 7.61 (d, J ) 15.9 Hz, 1H); 13C NMR
(CDCl3) δ -0.41, 27.85, 51.42, 84.43, 116.33, 121.43, 122.35,
127.29, 138.90, 148.07, 167.62; MS m/z 323 (M+, 3). Anal. Calcd
for C16H25NO4Si: C, 59.41; H, 7.79; N, 4.33. Found: C, 59.34;
H, 8.04; N, 4.30.
1-(ter t-Bu toxyca r bon yl)-3-tr im eth ylsilyl-4-p h en yl-1H-
p yr r ole (24). (Rep r esen ta tive Exa m p le of Su zu k i Cou -
p lin g Rea ction : P r oced u r e 4). To a solution of 11 (365 mg,
1 mmol), benzeneboronic acid (122 mg, 1 mmol), and Pd(PPh3)4
(58 mg, 0.05 mmol) in MeOH-toluene (1:1, 3 mL) was added
a 2 M Na2CO3 solution (0.4 mL). The resulting mixture was
heated at ca. 100 °C for 4 h and then poured into ice-water
(10 mL). After extraction with Et2O (2 × 20 mL), washing with
H2O (15 mL), drying (Na2SO4), filtration, and evaporation, the
residue was chromatographed (1% Et2O in hexanes) on silica
3-(p-Meth oxyp h en yl)-4-p h en yl-1H-p yr r ole (58). This
compound was prepared from 57 (161 mg, 0.4 mmol) and KOH
(0.5 g) in a similar manner as described for 53 and purified
by chromatography on silica gel (25 g) eluted with hexanes/
Et2O (5:2) to afford 58 (95 mg, 95%) as a yellow residue: 1H
NMR (CDCl3) δ 3.88 (s, 3H), 6.90-6.96 (m, 4H), 7.26-7.40 (m,
7H), 8.38 (s, br, 1H); 13C NMR (CDCl3) δ 55.13, 113.59, 116.97,

Synthesis of 3,4-Disubstituted 1H-Pyrrole
J . Org. Chem., Vol. 65, No. 11, 2000 3283
117.23, 122.98, 123.24, 125.57, 128.12, 128.25, 128.41, 129.58,
°C. After the temperature was raised to 0 °C (ca. 6 h), the
reaction was quenched with H2O. After the usual workup
(Et2O), the residue was subjected to silica gel (60 g) chroma-
tography with hexanes/Et2O (1:1) as the eluent. The first
fraction contained 125 mg (23%) of white solids identified as
135.81, 157.74; MS m/z 249 (M+, 100); HRMS calcd for C17H15
-
NO 249.1148, found 249.1129.
3-P h en yl-4-(tr a n s-2-m eth oxyca r bon yleth en yl)-1H-p yr -
r ole (59). Pyrrole 55 (191 mg, 0.5 mmol) was deprotected with
TBAF (1 mL, 1 mmol) in the same manner as that for 40 and
purified by chromatography on silica gel (25 g) eluted with
hexanes/EtOAc (25:6) to give 59 (109 mg, 96%) as a yellow
residue: 1H NMR (CDCl3) δ 3.74 (s, 3H), 6.12 (d, J ) 15.9 Hz,
1H), 6.84 (t, J ) 2.4 Hz, 1H), 7.18 (t, J ) 2.4 Hz, 1H), 7.29-
7.43 (m, 5H), 7.76 (d, J ) 15.9 Hz, 1H), 8.67 (s, br, 1H); 13C
NMR (d6-acetone) δ 50.86, 113.03, 117.87, 118.71, 121.04,
125.84, 126.67, 128.96, 129.24, 136.15, 139.30, 168.04; MS m/z
227 (M+, 17). Anal. Calcd for C14H13NO2: C, 73.99; H, 5.77;
N, 6.16. Found: C, 73.71; H, 5.76; N, 6.05.
1-Tr iisop r op ylsilyl-3-t r im et h ylsilyl-4-b r om o-1H -p yr -
r ole (60).8h To a solution of 4 (36.7 mg, 0.1 mmol) in THF (2
mL) was added solid NBS (17.8 mg, 0.1 mmol) under N2 at
-10 °C, and the mixture was stirred for 2 h. After that,
aqueous 50% Na2S2O3 (3 mL) and Et2O (15 mL) were added.
The ethereal layer was separated, washed with H2O (2 × 5
mL), and dried over Na2SO4. After evaporation of the solvent,
the residue was chromatographed on silica gel (20 g, hexanes)
to give 60 (34.4 mg, 92%) as a colorless liquid: 1H NMR
(CDCl3) δ 0.27 (s, 9H), 1.09 (d, J ) 7.4 Hz, 18H), 1.40 (sept, J
) 7.4 Hz, 3H), 6.61 (d, J ) 2.2 Hz, 1H), 6.79 (d, J ) 2.2 Hz,
1H); 13C NMR (CDCl3) δ 0.63, 11.56, 17.73, 103.97, 120.21,
124.78, 130.69; MS m/z 375 (M+, 70).
1
70: mp 247 °C; H NMR (CDCl3) δ 0.41 (s, 9H), 2.85 (s, 6H),
7.13 (d, J ) 1.8 Hz, 1H), 7.99 (d, J ) 1.8 Hz, 1H); 13C NMR
(CDCl3) δ -0.30, 38.33, 119.16, 126.75, 128.08, 135.78. Borox-
ine 70 was not too stable for further identification. The second
fraction contained 134 mg (34%) of white solids identified as
1
71: mp 210 °C; H NMR (CDCl3) δ 2.84 (s, 18H), 6.80 (dd, J
) 3.0, 2.4 Hz, 3H), 7.16 (dd, J ) 3.0, 2.4 Hz, 3H), 7.77 (t, J )
1.5 Hz, 3H); 13C NMR (CDCl3) δ 38.31, 115.60, 116.72, 121.79,
131.24; MS m/z 600 (M+, 100). Anal. Calcd for C18H27B3N6-
O9S3: C, 35.99; H, 4.53; N, 14.00. Found: C, 35.91; H, 4.62;
N, 13.82.
Ack n ow led gm en t. The work described in this paper
was substantially supported by a grant from the Re-
search Grants Council of the Hong Kong Special Ad-
ministrative Region, China (Project No. CUHK 77/93E).
H.N.C.W. wishes to thank the Croucher Foundation
(Hong Kong) for a Croucher Senior Research Fellowship
(1999-2000).
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for the compounds prepared as well as the experimen-
tal procedures for the preparation of 10-13, 16-18, 20-23,
25-27, 31-44, 46-52, 54-57, and 61-69. This material is
available free of charge via the Internet at http://pubs.acs.org.
Tr is[1-(N,N-d im eth yla m in osu lfon yl)-4-tr im eth ylsilyl-
1H-p yr r ol-3-yl]bor oxin e (70) a n d Tr is[1-(N,N-d im eth yl-
a m in osu lfon yl)-1H-p yr r ol-3-yl]bor oxin e (71). To a solution
of 5 (637 mg, 2 mmol) in CH2Cl2 (80 mL) was added a solution
of BCl3 (2 mL) diluted with CH2Cl2 (35 mL) under N2 at -78
J O991531C