Pyrrole syntheses based on titanium-catalyzed hydroamination of diynes

Article abstract of DOI:10.1021/ol0489088

(Equation Presented) Titanium-catalyzed hydroamination of 1,4- and 1,5-diynes by primary amines leads to imino-alkynes that undergo in situ 5-endo dig and 5-exo dig cyclization reactions, respectively. The products are 1,2,5-trisubsituted pyrroles accesse

Full text of DOI:10.1021/ol0489088

ORGANIC
LETTERS
2
004
Vol. 6, No. 17
957-2960
Pyrrole Syntheses Based on
Titanium-Catalyzed Hydroamination of
Diynes
2
Balasubramanian Ramanathan, Adam J. Keith, Douglas Armstrong, and
Aaron L. Odom*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824
odom@cem.msu.edu
Received June 10, 2004
ABSTRACT
Titanium-catalyzed hydroamination of 1,4- and 1,5-diynes by primary amines leads to imino-alkynes that undergo in situ 5-endo dig and 5-exo
dig cyclization reactions, respectively. The products are 1,2,5-trisubsituted pyrroles accessed directly from readily available diyne starting
materials.
New synthetic strategies for the generation of substituted
pyrroles are of continuous interest due to the ubiquity of
this heterocycle in natural products and pharmaceuticals.
prepared, inexpensive titanium catalysts Ti(NMe
2 2
) (dpma)
(A) and Ti(NMe (dmpm) (B) (Scheme 1) can be used in
2 2
)
1
the monohydroamination of 1,4- and 1,5-diynes, which then
undergo cyclization to the corresponding pyrroles. These
pyrrole syntheses are an expansion of CuCl-catalyzed 1,3-
diyne reactions with primary amines to generate similar
We have been exploring new reactions based on titanium-
catalyzed intermolecular hydroamination2,3 using a selection
of pyrrolyl-based ancillary ligands. In the course of previous
studies, new protocols for the synthesis of hydrazones,
7
products.
4
,5
6
(dpma) (A),8,9 which
L ancillary ligand set (Scheme 1), has been
examined for a variety of hydroamination applications by
our group. The H dpma ligand is prepared in a single step
indoles, and R,â-unsaturated iminoamines have been
2 2
The pyrrolyl-based catalyst Ti(NMe )
1
0
discovered. In this paper, it is reported that the readily
has an X
2
(
1) For reviews see: (a) Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1
999, 2849-2866. (b) Jones, R. A., Ed. Pyrroles, Chemistry of Heterocyclic
Compounds; Wiley: New York, 1990; Vol. 48.
2) For an excellent review on hydroamination, see: M u¨ ller, T. E.; Beller,
M. Chem. ReV. 1998, 98, 675-703.
3) For a few recent examples, see: (a) Shi, Y.; Ciszewski, J. T.; Odom,
2
1
by a Mannich reaction between 2 equiv of pyrrole, 2 equiv
(
11
of formaldehyde, and methylamine hydrochloride. The most
(
active catalyst known to date is the dipyrrolylmethane
A. L. Organometallics 2001, 20, 3967-3969. (b) Li, C.; Thomson, R. K.;
Gillon, B.; Patrick, B. O.; Schafer, L. L. Chem. Commun. 2003, 2462-
(7) For examples, see: (a) Chalk, A. J. Tetrahedron Lett. 1972, 13, 3487-
3490. (b) Chalk, A. J. Tetrahedron 1974, 30, 1387-1391. (c) Schulte, K.
E.; Reisch, J.; Walker, H. Chem. Ber. 1965, 98, 98-103. Also, see pages
222-223 of Part 1 in ref 1b.
2
463. (c) Siebeneicher, H.; Bytschkov, I.; Doye, S. 2003, 42, 3042-3044.
(d) Castro, I. G.; Tillack, A.; Hartung, C. G.; Beller, M. Tetrahedron Lett.
2
003, 44, 3217-3221. (e) Ong, T.-G.; Yap, G. P. A.; Richeson, D. S. J.
Am. Chem. Soc. 2003, 125, 8100-8101. (f) Ackermann, L.; Bergman, R.
G.; Loy, R. N. J. Am. Chem. Soc. 2003, 125, 11956-11963.
(8) Cao, C.; Ciszewski, J. T.; Odom, A. L. Organometallics 2001, 20,
5011-5013.
(4) Cao, C.; Shi, Y.; Odom, A. L. Org. Lett. 2003, 4, 2853-2856.
5) Khedkar, V.; Tillack, A.; Michalik, M.; Beller, M. Tetrahedron Lett
(9) Harris, S. A.; Ciszewski, J. T.; Odom, A. L. Inorg. Chem. 2001, 40,
1987-1988.
(
2
004, 45, 3123-3126.
6) Cao, C.; Shi, Y.; Odom, A. L. J. Am. Chem. Soc. 2003, 125, 2880-
881.
(10) Green, M. L. H. J. Organomet. Chem. 1995, 500, 127-148.
(11) Li, Y.; Turnas, A.; Ciszewski, J. T.; Odom, A. L. Inorg. Chem.
2002, 41, 6298-6306.
(
2
1
0.1021/ol0489088 CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/28/2004

Scheme 1
Scheme 2
complex Ti(NMe
2
)
2
(dmpm) (B), which is useful for more
demanding substrate combinations. Catalyst B (Scheme 1)
1
1
is believed to have an active species that has an η ,η -dmpm.
5
1
The η ,η -dmpm structure, where dmpm refers to 5,5-
dimethyldipyrrolylmethane, is found in the solid-state for the
1
2
complex. In other words, the active species may be an X
ancillary ligand set. The H dmpm ligand is readily prepared
by condensation of acetone and pyrrole.1
Initial investigations were based on the known cyclization
2
2
amine to a 1,5-diyne would generate a 5-iminoalkyne, which
could undergo 5-exo dig cyclization.
3
14-16
of imino alkynes to pyrroles.
The intended reaction types
are illustrated in Scheme 2. Using a 1,4-diyne, monohy-
droamination with Markovnikov selectivity would yield the
17
4-iminoalkyne, which could undergo 5-endo dig cyclization
to the pyrrole. Similarly, Markovnikov addition of a primary
An attempt to carry out the monohydroamination of 1,4-
(
12) Shi, Y.; Hall, C.; Ciszewski, J. T.; Cao, C.; Odom, A. L. Chem.
Commun. 2003, 586-587.
13) Littler, B. J.; Miller, M. A.; Hung, C.-H.; Wagner, R. W.; O’Shea,
D. F.; Boyle, P. D.; Lindsey, J. S. J. Org. Chem. 1999, 64, 1391-1396.
14) For recent examples of pyrrole syntheses from imino alkynes, see:
a) Cossy, J.; Poitevin, C.; Sall e´ , L.; Pardo, D. G. Tetrahedron Lett. 1996,
7, 6709-6710. (b) Tarasova, O. A.; Nedolya, N. A.; Vvedensky, V. Y.;
Brandsma, L.; Trofimov, B. A. Tetrahedron Lett. 1997, 38, 7241-7242.
c) Arcadi, A.; Anacardio, R.; D’Anniballe, G.; Gentile, M. Synlett 1997,
pentadiyne (1a) with 1 equiv of aniline was pursued using
A as a catalyst. The major product in the reaction had a
18
(
mass consistent with double hydroamination of pen-
1
9,20
(
tadiyne.
Data for the dihydroamination product matched
(
3
that for an authentic sample of 2,4-bis(phenylimino)pentane
(eq 1). This result suggests that the second hydroamination
is faster than either the first hydroamination or the 5-endo
dig cyclization.
(
1
1
315-1317. (d) Knight, D. W.; Redfern, A. L.; Gilmore, J. Chem. Commun.
998, 2207-2208. (e) Le, C.-F.; Yang, L.-M.; Hwu, T.-Y.; Feng, A.-S.;
Tseng, J.-C.; Luh, T.-Y. J. Am. Chem. Soc. 2000, 122, 4992-4993. (f)
It has been shown that hydroamination reactions catalyzed
Gabriele, B.; Salerno, G.; Fazio, A.; Bossio, M. R. Tetrahedron Lett. 2001,
by titanium are sensitive to the size of the alkyne substrate.4
4
4
2, 1339-1341. (g) Kim, J. T.; Gevorgyan, V. Org. Lett. 2002, 4, 4697-
699.
Consequently, use of one internal alkyne and one terminal
alkyne, or two internal alkynes on the 1,4-pentadiyne
framework, should significantly slow the second hydroami-
nation reaction relative to the 5-endo dig cyclization. As
shown in Table 1, this strategy has been successful and
allowed the synthesis of substituted pyrroles from 1,4-diynes.
(15) Similar cyclizations have been explored in indole synthesis. For
examples, see: (a) Fujiwara, J.; Fukutani, Y.; Sano, H.; Maruoka, K.;
Yamamoto, H. J. Am. Chem. Soc. 1983, 105, 7177-7179. (b) Rudisill, D.
E.; Stille, J. K. J. Org. Chem. 1989, 54, 5856-5866. (c) Larock, R. C.;
Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689-6690. (d) Kuyper, L. F.;
Baccanari, D. P.; Jones, M. L.; Hunter, R. H.; Tansik, R. L.; Joyner, S. S.;
Boytos, C. M.; Rudolph, S. K.; Knick, V.; Wilson, H. R.; Caddell, J. M.;
Friedman, H. S.; Comley, J. C. W.; Stables, J. N. J. Med. Chem. 1996, 39,
92-903. (e) McDonald, F. E.; Chatterjee, A. K. Tetrahedron Lett. 1997,
8, 7687-7690. (f) Larock, R. C.; Yam, E. K.; Refvik, M. D. J. Org. Chem.
998, 63, 7652-7662. (g) Xu, L.; Lewis, I. R.; Davidsen, S. K.; Summers,
J. B. Tetrahedron Lett. 1998, 39, 5159-5162. (h) Yasuhara, A.; Kanamori,
Y.; Kaneko, M.; Numata, A.; Kondo, Y.; Sakamoto, T. J. Chem. Soc., Perkin
Trans. 1 1999, 529-534. (i) Hiroya, K.; Itoh, S.; Ozawa, M.; Kanamori,
Y.; Sakamoto, T. Tetrahedron Lett. 2002, 43, 1277-1280. (j) Battistuzzi,
G.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Parisi, L. M. Org. Lett. 2002, 4,
For this initial study, benzylamine (H
2
NBn) and aniline were
8
3
1
used most often as the amine substrates. An additional
reaction with p-methoxybenzylamine (H NPMB) was inves-
2
tigated with one substrate.
Markovnikov addition is observed almost exclusively with
A as a catalyst when either benzylamine or aniline are used
1
355-1358. (k) Kamijo, S.; Jin, T.; Yamamoto, Y. Angew. Chem., Int.
Ed. 2002, 41, 1780-1782. (l) Barluenga, J.; Trincado, M.; Rubio, E.;
Gonzalez, J. M. Angew. Chem., Int. Ed. 2003, 42, 2406-2409. (m) van
Esseveldt, B. C. J.; van Delft, F. L.; de Gelder, R.; Rutjes, F. P. J. T. Org.
Lett. 2003, 5, 1717-1720.
(18) Trace of a product having a mass consistent with monohydroami-
nation was observed, but it is not known if it was cyclized to the pyrrole.
(19) For the synthesis of 1,4-diynes, see: Verkruijsse, H. D.; Hasselaar,
M. Synthesis 1979, 292-293.
(20) CAUTION: The starting materials for 1,4-diynes used in ref 19
are the propargyl tosylates. Explosions have resulted from purifying
propargyl tosylate and its derivatives by vacuum distillation.
(
16) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc.
001, 123, 2074-2075.
17) Baldwin, J. E.; Lusch, M. J. Tetrahedron 1982, 38, 2939-2947.
2
(
2958
Org. Lett., Vol. 6, No. 17, 2004

occurs with amination â to the phenyl group, which is
consistent with the observed regioselectivity for this diyne
substrate. In addition, hydroamination of 1-phenylpropyne
is generally more facile than hydroamination of dialkyl
substituted alkynes, e.g., 3-hexyne. Consequently, it is likely
that the regioselectivity for this substrate is due to kinetically
favored amination â to the phenyl group of 1-phenyl-1,4-
hexadiyne (1c).
Table 1. Examples of Pyrroles Synthesized by Diyne
Hydroamination
The titanium-based pyrrole synthesis of 3d provides an
interesting example for comparison with current and pro-
gressing ketone-based methodologies, e.g., Paal-Knorr
synthesis. Generally, unsymmetrical 1,4-diketones are rela-
tively difficult to access in a short synthetic sequence.
However, the diketone needed for the synthesis of 3d by
Paal-Knorr and its reaction with benzylamine were recently
2
1
reported. The diketone was prepared using a novel Pd-
catalyzed procedure from methyl vinyl ketone and benzylzinc
chloride. Overall, 3d was available in 54% yield over two
steps. Using the procedure of Verkruijsse to generate the
diyne and titanium hydroamination, we prepared the unsym-
metrical pyrrole 3d in the comparable yield of 41% in two
steps.
The cyclization of the imine derived from 1-phenyl-1,4-
hexadiyne (1c) was quite slow after the titanium-catalyzed
reaction when the amine substrate was aniline. To finish the
cyclization, Gevorgyan’s procedure using 30 mol % CuI in
the presence of triethylamine at 110 °C was employed prior
1
6
to workup. Interestingly, the addition of copper for the
cyclization was only required for 1-phenyl-2-benzyl-5-
methylpyrrole (3c) formation. The benzylamine and para-
methoxybenzylamine (PMB-NH
) cyclized under the hydroamination reaction conditions to
provide N-benzyl-2-benzyl-5-methylpyrrole (3d) and N-PMB-
2
) products (entries 4 and
5
2
-benzyl-5-methylpyrrole (3e).
Unlike 1,4-pentadiyne (1a), hydroamination of 1,5-hexa-
diyne (2a), which also has both alkynes terminal, did not
yield products from dihydroamination. Instead, the products
observed are the expected N-substituted 2,5-dimethylpyrroles
(3f and 3g). This is likely due to the more facile 5-exo dig
cyclization being faster than the hydroamination reaction.
Unlike the 1,4-diyne hydroaminations, no uncyclized prod-
ucts were observed by GC under the reaction conditions.
a
Temperature is 100 °C unless otherwise stated. Conditions A ) 10
2
2
mol % A. Conditions B ) 10 mol % B. b Bn is benzyl. c PMB is
p-methoxybenzyl. CuI added to aid in cyclization.
d
8
to hydroaminate 1-hexyne. Considering that the terminal
alkynes used here are not very sterically or electronically
different from 1-hexyne, the major product expected and
observed in all cases where a terminal alkyne was present is
due to Markovnikov addition.
The anticipated 5-endo dig cyclization occurred readily
with most 1,4-diyne substrates to generate pyrrole products.
In many cases, a product with the same mass as the expected
pyrrole and a different GC/MS retention time was observed,
which was presumably the uncyclized hydroamination
product.
Even though the imine product was not observed in the
hydroamination of 1,5-hexadiyne (2a), it is still likely that
the imine is an intermediate. The relevant ketone derivative
of this intermediate, hex-5-yn-2-one (4), was prepared
When hydroamination of the unsymmetrical bis(internal)-
diyne 1-phenyl-1,4-hexadiyne (1c) was attempted, entries
(
21) Yuguchi, M.; Tokuda, M.; Orito, K. J. Org. Chem. 2004, 69, 908-
14.
22) The same symmetrical pyrroles, 3f and 3g, have been generated
9
3-5 in Table 1, the reactions were apparently regioselective
(
and resulted in only one isomer of pyrrole. This is likely
due to selective hydroamination of the phenyl-bearing alkyne.
Hydroamination of similar substrates, e.g., 1-phenylpropyne,
using Paal-Knorr synthesis and reported repeatedly in the literature. In
typical examples, 3f and 3g were synthesized in 82 and 67% yields,
respectively. Wothius, E.; Vander Jagt, D.; Mels, S.; De Boer, A. J. Org.
Chem. 1965, 30, 190-193.
Org. Lett., Vol. 6, No. 17, 2004
2959

23
26
according to the literature procedure. Reaction of the ketone
with aniline (eq 2) in the absence of titanium leads to
formation of N-phenyl-2,5-dimethylpyrrole (3f) that is
spectroscopically identical to the product of 2a hydroami-
nation with aniline.
allene intermediates are disfavored. Experimentally, it has
been shown that 1-imino-2-alkynes require copper catalysis
to cyclize, which has been suggested to occur through allene
intermediates. Consequently, we currently favor either an
imine-yne or enamine-yne cyclization pathway for 1-imino-
1
6
3
-ynes. However, these details of the cyclizations are
As mentioned previously, if the alkyne is substituted with
one aryl group and one alkyl, the predominant product is
generally due to amination â to the aromatic substituent.
Likewise, hydroamination of 1,6-diphenyl-1,5-hexadiyne
currently under scrutiny, including the possible role of
titanium in the cyclizations.
Applications of this new pyrrole synthesis based on alkyne
hydroamination are currently under investigation. While
Paal-Knorr is likely to be the preferable methodology in
circumstances where the 1,4-diketone is readily available, it
is hoped that this new pyrrole synthesis will complement
existing procedures where unsymmetrical pyrroles are de-
sired. Many unsymmetrical 1,4-diynes can be prepared in
one or two steps from commercially available compounds
and may be as or more accessible than the corresponding
unsymmetrical 1,4-diketones in some cases. In addition, we
are investigating the use of this new methodology in the
synthesis of pyrroles where application of Paal-Knorr
synthesis may lead to unwanted side reactions. For example,
we are investigating the synthesis of R-vinylpyrroles using
diyne hydroamination, which if prepared using R,â-unsatur-
ated ketones may have problems with interfering Michael-
2b)24 with aniline resulted in clean, high-yield formation
(
2
5
of a single isomer, N-phenyl-2,5-dibenzylpyrrole (3h).
A few substrate combinations attempted did not result in
successful pyrrole syntheses. Treatment of 1,6-diphenyl-1,5-
hexadiyne (2b) with benzylamine gave no reaction with
catalysts A and B. Considering the harsh conditions required
for the aniline reaction with this diyne and that aniline
reactions are generally more facile than alkylamine, the lack
of reaction with benzylamine probably represents a limitation
in the activity of our current catalysts rather than an inherent
problem with the substrate combination. In addition, 1-phen-
yl-1,4-pentadiyne (1d) reactions with either aryl or alkyl-
amines (Equation 3) did not give the desired product, which
may be the result of facile oligomerization of this diyne
starting material.
2
7
addition side reactions.
Acknowledgment. The authors appreciate the financial
support of the donors of the Petroleum Research Fund,
administered by the American Chemical Society, the Office
of Naval Research, the National Science Foundation, and
the Department of EnergysDefense Programs. A.L.O. is an
Alfred P. Sloan Fellow. The authors thank Bill Wulff for
helpful discussions.
The cyclizations could occur though several different
routes defined by disparate tautomers. However, the cycliza-
tions are likely occurring through the Baldwin allowed
Supporting Information Available: Synthetic details and
characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
5-endo dig and 5-exo dig cyclizations, and it is unlikely that
allene intermediates are involved. The reason for this is that
17
the 5-endo trig and 5-exo trig cyclizations required for the
OL0489088
(
23) Davis, L. B.; Greenberg, S. G.; Sammes, P. G. J. Chem. Soc., Perkin
Trans. 1 1981, 1909-1912.
24) Lucht, B. L.; Mao, S. S. H.; Tilley, T. D. J. Am. Chem. Soc. 1998,
20, 4354-4365.
25) Pyrrole 3h did not appear in our literature searches. However, a
(26) Some 5-endo trig cyclizations are known. These often involve metal-
mediated processes. For examples, see: (a) Trost, B. M.; Bonk, P. J. J.
Am. Chem. Soc. 1985, 107, 1778-1781. (b) Auvray, P.; Knochel, P.;
Normant, J. F. Tetrahedron Lett. 1985, 26, 4455-4458. Also see ref 16.
(27) To generate an R-vinyl pyrrole using Paal-Knorr synthesis would
require reaction of an R,â-unsaturated ketone with an amine to generate
the corresponding imine, a reaction that is often complicated by competing
Michael addition. Hydroamination of the enyne can be used as an alternative
procedure to R,â-unsaturated imines. Cao, C.; Li, Y.; Shi, Y.; Odom, A. L.
Chem. Commun. In press.
(
1
(
comparison can be made with 1,2,5-tribenzylpyrrole, which has been
synthesized using Paal-Knorr in three steps from commercially available
compounds in 42% yield overall. Wilcox, A. L.; Bao, Y. T.; Loeppky, R.
N. Chem. Res. Toxicol. 1991, 4, 373-381. Our synthesis of 3h was
accomplished in 61% overall yield in two steps.
2960
Org. Lett., Vol. 6, No. 17, 2004