Cyclization reactions of homopropargyl azide derivatives catalyzed by PtCl4 in ethanol solution: Synthesis of functionalized pyrrole derivatives

Article abstract of DOI:10.1021/ol062249c

PtCl₄-catalyzed cyclization reactions of homopropargyl azide derivatives to pyrrole rings were investigated. Using ethanol as solvent with 2,6-di-tert-butyl-4-methylpyridine as the base was found to be the best set of conditions for effecting this ring-closing reaction. These reaction conditions can be applied to the preparation of functionalized pyrrole derivatives, with no effect on the functional groups.

Full text of DOI:10.1021/ol062249c

ORGANIC
LETTERS
2006
Vol. 8, No. 23
5349-5352
Cyclization Reactions of Homopropargyl
Azide Derivatives Catalyzed by PtCl4 in
Ethanol Solution: Synthesis of
Functionalized Pyrrole Derivatives
Kou Hiroya,*,† Shigemitsu Matsumoto,† Masayasu Ashikawa,†
Kentaro Ogiwara,† and Takao Sakamoto†,‡
Graduate School of Pharmaceutical Sciences, Tohoku UniVersity, Aoba-ku,
Sendai 980-8578, Japan
hiroya@mail.tains.tohoku.ac.jp
Received September 11, 2006
ABSTRACT
PtCl4-catalyzed cyclization reactions of homopropargyl azide derivatives to pyrrole rings were investigated. Using ethanol as solvent with
2,6-di-tert-butyl-4-methylpyridine as the base was found to be the best set of conditions for effecting this ring-closing reaction. These reaction
conditions can be applied to the preparation of functionalized pyrrole derivatives, with no effect on the functional groups.
Carbon-nitrogen bond formation reactions are an important
tool in the synthesis of biologically active heterocyclic
substances.1 In our efforts directed toward the development
of new synthetic methods for obtaining heterocyclic com-
pounds, we had previously reported effective methods for
the synthesis of substituted indole derivatives, catalyzed by
Cu(II) salts2 or Pd(PPh3)4-methyl propiolate complex.3
Intermolecular nucleophilic addition reactions of the nitrogen
atom to the alkyne moiety, that do not conjugate to the sp2-
or sp-hybridized carbon, tend to be difficult, apparently due
to the low reactivity of the alkyne group. Until now,
cyclization reactions, which involve the formation of carbon-
nitrogen bonds, catalyzed by early transition metal or
organolanthanoide complexes have been well investigated.1,4
In addition, examples for the same type reactions catalyzed
by late transition metal complex, which contain, e.g., Pd,
Au, Ag, Cu, and Ru, also have been reported.1,5 In spite of
the powerful catalytic properties of Cu(II) salts2 and Pd-
(PPh3)4-methyl propiolate complex,3 the cyclization reac-
tions of 1 to 2 could not be effected, and starting material
was recovered quantitatively (Scheme 1). After several
attempts, we found that the cyclization reaction of 1 was
† Graduate School of Pharmaceutical Sciences, Tohoku University
‡ Tohoku University 21st Century COE Program “Comprehensive
Research and Education Center for Planning of Drug Development and
Clinical Evaluation”, Sendai 980-8578, Japan.
(4) (a) Molander, G. A.; Romero, J. A. C. Chem. ReV. 2002, 102, 2161-
2185. (b) Li, C.; Thomson, R. K.; Gillon, B.; Patrick, B. O.; Schafer, L. L.
Chem. Commun. 2003, 2462-2463. (c) Pohlki, F.; Doye, S. Chem. Soc.
ReV. 2003, 32, 104-114. (d) Molander, G. A.; Hasegawa, H. Heterocycles
2004, 64, 467-474. (e) Doye, S. Synlett 2004, 1653-1672. (f) Lauterwasser,
F.; Hayes, P. G.; Bra¨se, S.; Piers, W. E.; Schafer, L. L. Organometallics
2004, 23, 2234-2237. (g) Hultzsch, K. C.; Hampel, F.; Wagner, T.
Organometallics 2004, 23, 2601-2612. (h) Heutling, A.; Pohlki, F.;
Bytschkov, I.; Doye, S. Angew. Chem., Int. Ed. 2005, 44, 2951-2954.
(5) (a) Esseveldt, B. C. J. v.; Vervoort, P. W. H.; Delft, F. L. v.; Rutjes,
F. P. J. T. J. Org. Chem. 2005, 70, 1791-1795. (b) Zhang, L.; Kozmin, S.
A. J. Am. Chem. Soc. 2005, 127, 6962-6963. (c) Chang, S.; Lee, M.; Jung,
D. Y.; Yoo, E. J.; Cho, S. H.; Han, S. K. J. Am. Chem. Soc. 2006, 128,
12366-12367.
(1) (a) Mu¨ller, T. E.; Beller, M. Chem. ReV. 1998, 98, 675-703. (b)
Hosokawa, T. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E.-i., Ed.; de Meijere, A., associate Ed.; John Wiley &
Sons, Inc.: New York, 2002; Vol. 2, pp 2211-2244. (c) Alonso, F.;
Beletskaya, I. P.; Yus, M. Chem. ReV. 2004, 104, 3079-3159.
(2) (a) Hiroya, K.; Itoh, S.; Sakamoto, T. J. Org. Chem. 2004, 69, 1126-
1136. (b) Hiroya, K.; Itoh, S.; Ozawa, M.; Kanamori, Y.; Sakamoto, T.
Tetrahedron Lett. 2002, 43, 1277-1280. (c) Hiroya, K.; Itoh, S.; Sakamoto,
T. Tetrahedron 2005, 61, 10958-10964.
(3) (a) Hiroya, K.; Matsumoto, S.; Sakamoto, T. Org. Lett. 2004, 6,
2953-2956. (b) Hiroya, K.; Matsumoto, S.; Ashikawa, M.; Kida, H.;
Sakamoto, T. Tetrahedron 2005, 61, 12330-12338.
10.1021/ol062249c CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/14/2006

necessary in 1,2-dichloroethane was presumed to be due to
low solubility of PtCl4 (Table 1, entry 1). This problem was
Scheme 1. Cyclization Reactions of the Tosylamide 1 System
Table 1. Cyclization Reactions Catalyzed by PtCl4 or PtCl2
entry
Pt catalyst
solvent
time (h)
yield (%)
1
2
3b
4
5
6
7b
PtCl4
PtCl4
PtCl4
PtCl4
PtCl2
PtCl2
PtCl2
ClCH2CH2Cl
EtOH
EtOH
tert-BuOH
ClCH2CH2Cl
EtOH
16
9
1
24
24
24
24
70
65
79
2 (58)a
10 (76)a
21 (67)a
40 (48)a
catalyzed by platinum catalyst, recently reported to be an
activator of π-bonds (Scheme 1).6,7
Disappointingly, it was found that the PtCl4-catalyzed
cyclization reaction can only be applied to a limited number
of substrates, due to the instability of the enamine moiety
of the products. However, in the process of surveying new
substrates and catalyst systems, we unexpectedly found that
homopropargyl azide derivatives could be converted to
pyrrole rings in the presence of catalytic amounts of PtCl4,
in 70% yield (Scheme 2). While we were working on
EtOH
a The numbers in parentheses are yields of recovered 3. b The reactions
were started after stirring the platinum catalyst in ethanol for 1 h at 50 °C.
resolved by changing the solvent to ethanol (Table 1, entry
2). Surprisingly, the reaction rate was much improved by
stirring the solution of PtCl4 in ethanol for 1 h at 50 °C before
adding the substrate (Table 1, entry 2 vs 3). The requirement
of the induction period for obtaining higher catalytic activities
suggested the possibility that initially added PtCl4 is trans-
formed to other active species.
Scheme 2. PtCl4-Catalyzed Cyclization Reaction of
Homopropargyl Azide Derivatives
In 1974, Hass and Hauthal reported that ethanol was
oxidized by PtCl4 to produce PtCl2, acetaldehyde, and
hydrogen chloride.10 Noting from our results that tert-butanol
was not an effective solvent (Table 1, entry 4), we speculated
that perhaps the active species in ethanol is PtCl2, which
could be generated in situ. However, when the reaction was
performed in the presence of commercially available PtCl2,
completely different results were obtained than from the
reaction with PtCl4. Namely, the reaction rates were much
slower in either dichloroethane or ethanol, and the rates could
not be improved, even with an induction period (as in entry
3). Furthermore, the reaction did not proceed to completion
even after 24 h (Table 1, entries 5, 6, and 7). From these
results, it is obvious that PtCl4 in ethanol is being converted
into a species other than PtCl2. However, the true active
species cannot be identified at the present time. On the other
hand, since it is difficult to imagine that Pt(IV) could be
reduced to Pt(II) in dichloroethane, the structure of the
catalyst may vary depending upon the solvent used.
optimizing our reaction conditions, Toste’s research group
published a paper describing nearly identical reactions,
including the conversion of homopropargyl azide derivatives
to substituted pyrroles in the presence of catalytic amounts
of (dppm)Au2Cl2 and AgSbF6 in dichloromethane under mild
conditions.8 Toste’s group proposed a reaction mechanism
in which gold(I) induces activation of the alkyne toward
nucleophilic addition of the proximal nitrogen atom of the
azide. Herein, we describe a simpler catalytic system for
efficient pyrroles synthesis as Toste’s reaction.9
Optimization of the Pt-catalyzed reactions began with the
selection of the solvent. The long reaction time (16 h)
(6) Pt(II) catalyst: (a) Nakamura, I.; Bajracharya, G. B.; Wu, H.; Oishi,
K.; Mizushima, Y.; Gridnev, I. D.; Yamamoto, Y. J. Am. Chem. Soc. 2004,
126, 15423-15430. (b) Harrison, T. J.; Dake, G. R. Org. Lett. 2004, 6,
5023-5026. (c) Fu¨rstner, A.; Davies, P. W.; Gress, T. J. Am. Chem. Soc.
2005, 127, 8244-8245. (d) Nakamura, I.; Mizushima, Y.; Yamamoto, Y.
J. Am. Chem. Soc. 2005, 127, 15022-15023. (e) Fu¨rstner, A.; Davies, P.
W., J. Am. Chem. Soc. 2005, 127, 15024-15025. (f) Oh, C. H.; Reddy, V.
R.; Kim, A.; Rhim, C. Y. Tetrahedron Lett. 2006, 47, 5307-5310.
(7) Pt(IV) catalyst: (a) Pastine, S. J.; Youn, S. W.; Sames, D. Org. Lett.
2003, 5, 1055-1058. (b) Pastine, S. J.; Sames, D. Org. Lett. 2003, 5, 4053-
4055. (c) Pastine, S. J.; Youn, S. W.; Sames, D. Tetrahedron 2003, 59,
8859-8868.
(9) For recent examples on the pyrrole synthesis, see: (a) Kamijo, S.;
Kanazawa, C.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127, 9260-9266.
(b) Lu, L.; Chen, G.; Ma, S. Org. Lett. 2006, 8, 835-838. (c) Binder, J. T.;
Kirsch, S. F. Org. Lett. 2006, 8, 2151-2153. (d) Harrison, T. J.; Kozak, J.
A.; Corbella-Pane´, M.; Dake, G. R. J. Org. Chem. 2006, 71, 4525-4529
and references cited therein. (e) Freifeld, I.; Shojaei, H.; Langer, P. J. Org.
Chem. 2006, 71, 4965-4968. (f) Seregin, I. V.; Gevorgyan, V. J. Am. Chem.
Soc. 2006, 128, 12050-12051. (g) Wan, X.; Xing, D.; Fang, Z.; Li, B.;
Zhao, F.; Zhang, K.; Yang, L.; Shi, Z. J. Am. Chem. Soc. 2006, 128, 12046-
12047.
(10) (a) Hass, D.; Hauthal, T. Z. Chem. 1975, 15, 33-34. (b) Hass, D.;
Hauthal, T. Z. Chem. 1975, 15, 65-66. (c) Labinger, J. A.; Herring, A.
M.; Lyon, D. K.; Luinstra, G. A.; Bercaw, J. E. Organometallics 1993, 12,
895-905.
(8) Gorin, D. J.; Davis, N. R.; Toste, F. D. J. Am. Chem. Soc. 2005,
127, 11260-11261.
5350
Org. Lett., Vol. 8, No. 23, 2006

decomposition even under weakly acidic conditions. In fact,
when the reaction was applied to 5, the pyrrole 6 gradually
decomposed over the long course of the reaction time.
Because the possibility for generation of hydrogen chloride
could not be ruled out, we next ran the reaction in the
presence of a variety of bases. The addition of either the
inorganic base Cs2CO3 or the proton-sponge completely
inhibits the reaction (Table 2, entries 2 and 3). On the other
hand, in the presence of a bulkier base, such as 2,6-di-tert-
butyl-4-methylpyridine, the stoichiometry of the reaction was
much improved over that obtained in the reaction run in the
absence of base [Table 2, entry 1 (5 + 6 ) 67%) vs 4 (5 +
6 ) 87%)], although the reaction rate was slightly sup-
pressed. Finally, the reaction could be run to completion by
increasing the amount of both PtCl4 and the base to provide
the pyrrole 6 in 72% yield.
Table 2. Cyclization Reactions in the Presence of Basea
PtCl4
entry (mol %)
base (mol %)
yield (%)
1
2
3
4
5
5
5
5
5
15
50 (17)b
0 (68)b
0 (91)b
Cs2CO3 (20)
proton-sponge (20)
2,6-di-tert-butyl-4-methylpyridine (20) 43 (44)b
2,6-di-tert-butyl-4-methylpyridine (60) 72
a For all entries, 5 and the base were added after the solution of PtCl4 in
ethanol was stirring for 1 h at 50 °C. b The numbers in parentheses are
yields of recovered 5.
Having established the reaction conditions, we next applied
it to other substrates with a variety of functional groups,
producing the results compiled in Table 3. The reaction
conditions have to be modified slightly, depending on the
Since pyrroles are π-electron-rich heteroaromatic com-
pounds, it is known that the pyrrole ring may be prone to
Table 3. Platinum-Catalyzed Cyclization Reactionsg
a PtCl4 (5 mol %) and 2,6-di-tert-butyl-4-methylpyridine (20 mol %) in 0.1 M substrate concentration in ethanol. b PtCl4 (15 mol %) and 2,6-di-tert-
butyl-4-methylpyridine (60 mol %) in 0.1 M substrate concentration in ethanol. c PtCl4 (5 mol %) and 2,6-di-tert-butyl-4-methylpyridine (20 mol %) in 0.03
M substrate concentration in ethanol. d PtCl4 (15 mol %) and 2,6-di-tert-butyl-4-methylpyridine (60 mol %) in 0.01 M substrate concentration in ethanol.
e The number in parentheses was the yield of the reaction in 1,2-dichloroethane. f The number in parentheses was the yield of the recovered starting material.
g For all entries, both substrate and base were added after stirring the solution of PtCl4 in ethanol for 1 h at 50 °C.
Org. Lett., Vol. 8, No. 23, 2006
5351

structure of the substrate, in order to obtain maximum
chemical yield. Namely, the substrate bearing the phenyl-
ethynyl group is the most reactive and just 5 mol % of PtCl4
and 20 mol % of 2,6-di-tert-butyl-4-methylpyridine are
enough to afford the product in good yield (Table 3, entry
1). Substrates with an alkyl group substituted on the alkyne
terminal (Table 3, entry 3), as well as compounds with silyl
ether (Table 3, entry 4), hydroxyl (Table 3, entry 2), and
ethoxycarbonyl groups (Table 3, entry 5), gave the corre-
sponding pyrrole rings in reasonable yields under standard
reaction conditions (15 mol % of PtCl4 and 60 mol % of
2,6-di-tert-butyl-4-methylpyridine, 0.1 M solution of the
azide in ethanol). The amino group in the substrate must be
protected in order to obstruct complexation between the
amino group and PtCl4. In our case, N-Boc tosylamide was
used as the protecting group; however, partial elimination
of the Boc group in the product was observed under standard
reaction conditions. This side reaction was avoided by
diluting the reaction mixture from 0.1 to 0.03 M solution
(Table 3, entry 6).
of the acyclic starting materials. However, diluting the
reaction conditions proved effective for such substrates. In
these cases, 0.01 M proved to be the best concentration for
the substrate, and the corresponding pyrroles 16, 18, and 20
were afforded in reasonable yields (Table 3, entries 7, 8,
and 9).
Importantly, these reaction conditions can be carried out
under aerobic condition for phenyl-substituted pyrrole syn-
theses (Table 3, entries 1, 7, and 9). For theses substrates,
the solvent (ethanol) also can be used without any purifica-
tion. However, decomposition of the pyrroles during the
reactions for the other substrates was observed (Table 3,
entries 3 and 6).
One possibility for the mechanism of this cyclization
reaction may be the same as that proposed by Toste.8
However, we observed that the azide group was completely
decomposed under the cyclization reaction conditions.12
Thus, another pathway cannot be ruled out. Clarification of
the mechanism, further improvement of the conditions, and
applications to the synthesis of biologically active pyrrole-
containing compounds are currently underway in our labora-
tory.
It is known that terminal alkynes react with organic azides
to produce triazole compounds.11 In our reactions, we
observed low yields of the products under standard reaction
conditions, presumably due to intermolecular polymerization
Acknowledgment. This research was supported by a
Grant-in-Aid for Scientific Research (B) from Japan Society
for the Promotion of Science (JSPS) (to T.S.).
(11) (a) Mock, W. L.; Irra, T. A.; Wepsiec, J. P.; Manimaran, T. L. J.
Org. Chem. 1983, 48, 3619-3620. (b) Lewis, W. G.; Green, L. G.;
Grynszpan, F.; Radic´, Z.; Carlier, P. R.; Taylor, P.; Finn, M. G.; Sharpless,
K. B. Angew. Chem., Int. Ed. 2002, 41, 1053-1055. (c) Rostovtsev, V. V.;
Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002,
41, 2596-2599. (d) Wang, Z.-X.; Qin, H.-L. Chem. Commun. 2003, 2450-
2451.
(12) The reaction of (4-azidobutyl)benzene in the presence of 15 mol %
of PtCl4 and 60 mol % of 2,6-di-tert-butyl-4-methylpyridine, which was
stirred in EtOH for 1 h at 50 °C before adding the substrate, at 50 °C gave
the starting material in 80% yield and the complete decomposition of the
starting material was observed in the presence of 100 mol % of PtCl4 and
2,6-di-tert-butyl-4-methylpyridine.
Supporting Information Available: Experimental detail
for the synthesis of the homopropargyl azide derivatives, a
general experimental procedure for the cyclization reaction,
and spectroscopic data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL062249C
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