Pt-catalyzed cyclization/1,2-migration for the synthesis of indolizines, pyrrolones, and indolizinones

Article abstract of DOI:10.1021/ol0701971

(Chemical Equation Presented) Indolizine, pyrrolone, and indolizinone heterocycles are easily accessed via the Pt(II)-catalyzed cycloisomerization or a tandem cyclization/ 1,2-migration of pyridine propargylic alcohols and derivatives. This method provides an efficient synthesis of highly functionalized heterocycles from readily available substrates.

Full text of DOI:10.1021/ol0701971

ORGANIC
LETTERS
2007
Vol. 9, No. 6
1169-1171
Pt-Catalyzed Cyclization/1,2-Migration for
the Synthesis of Indolizines, Pyrrolones,
and Indolizinones
Cameron R. Smith, Eric M. Bunnelle, Allison J. Rhodes, and Richmond Sarpong*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
rsarpong@berkeley.edu
Received January 25, 2007
ABSTRACT
Indolizine, pyrrolone, and indolizinone heterocycles are easily accessed via the Pt(II)-catalyzed cycloisomerization or a tandem cyclization/
1,2-migration of pyridine propargylic alcohols and derivatives. This method provides an efficient synthesis of highly functionalized heterocycles
from readily available substrates.
The development of efficient and versatile strategies for the
synthesis of heterocycles continues to be of major signifi-
cance in synthetic organic chemistry.1 In this regard,
transformations that employ readily available substrates to
provide access to multiply functionalized heterocycles are
highly desirable. In the last two decades, the pharmacological
potential of indolizines and related derivatives has become
well recognized.2 As a result, a variety of methods for their
syntheses have emerged.3 However, there still remains a
significant need for more direct methods to afford function-
alized indolizine derivatives.
(e.g., 3), via the intermediacy of a zwitterion (2).4,5 On the
basis of this precedent, we reasoned that substrates such as
4 (Scheme 2), which possess a nitrogen nucleophile, could
provide a platform for metal-catalyzed cycloisomerizations
to access a range of nitrogen-containing heterocycles (e.g.,
6).
Optimization studies of this transformation began with
propargylic ester 7a (Table 1), which was easily prepared
(1) For a recent general review, see: Joule, J. A.; Mills, K. In
Heterocyclic Chemistry, 4th ed.; Blackwell Science Ltd.: Cambridge, MA,
2000.
Previously, we reported the Pt-catalyzed cyclization of an
acetate nucleophile (see 1, Scheme 1) onto an activated
alkyne to achieve the formation of pentannulated products
(2) Michael, J. P. Nat. Prod. Rep. 1999, 16, 675.
(3) For recent examples, see: (a) Kaloko, J., Jr.; Hayford, A. Org. Lett.
2005, 7, 4305. (b) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am.
Chem. Soc. 2001, 123, 2074. (c) Seregin, I. V.; Gevorgyan, V. J. Am. Chem.
Soc. 2006, 128, 12050. (d) Marchalin, S.; Baumlova´, B.; Baran, P.; Oulyadi,
H.; Da¨ıch, A. J. Org. Chem. 2006, 71, 9114.
(4) Bhanu Prasad, B. A.; Yoshimoto, F. K.; Sarpong, R. J. Am. Chem.
Soc. 2005, 127, 12468.
Scheme 1. Pt(II)-Catalyzed Pentannulation
(5) Metallocarbenoid intermediates, generated from 2, are believed to
be important in these transformations. See: (a) Mamane, V.; Gress, T.;
Krause, H.; Fu¨rstner, A. J. Am. Chem. Soc. 2004, 126, 8654. (b) Miki, K.;
Ohe, K.; Uemura, S. J. Org. Chem. 2003, 68, 8505. (c) Harrak, Y.;
Biaszykowski, C.; Benard, M.; Cariou, K.; Manetti, E.; Mourie´s, V.;
Dhimane, A.-L.; Fensterbank, L.; Malacria, M. J. Am. Chem. Soc. 2004,
126, 8656.
10.1021/ol0701971 CCC: $37.00
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would dictate the formation of this critical 1:1 Pt/PR3
complex, which led to the choice of 9 and 10 as additives.
Significant differences in reaction efficiency were also
observed upon exposure of internal alkyne substrates (e.g.,
7b) to various Pt(II)-catalyzed cycloisomerization conditions
as outlined in entries 5-11. Consistent with our initial
observations (entries 1-4), bulky phosphine additives pro-
vided conditions that produced higher yields of the desired
indolizine product (i.e., 8b, entries 6 and 7) as compared to
PtCl2 alone (entry 5).
The effect of phosphines 9 and 10 on reaction efficiency
was more pronounced at 40 °C. At this temperature, there
was no reaction with PtCl2 alone as the catalyst (entry 8),
whereas with 9 and 10 as additives (entries 9 and 10,
respectively), product formation was observed, with 9
proving to be optimal. Interestingly, indium trichloride also
catalyzes the transformation of 7b to 8b (entry 11) albeit in
lower overall yields. However, this catalyst was found to be
ineffective in the transformation of substrates possessing
terminal alkynes (e.g., 7a).
Scheme 2. Proposed Heterocycloisomerization
from pyridine-2-carboxaldehyde in two steps.6 Initial attempts
identified PtCl4 (entry 1) and PtCl2 (entry 2) to be suitable
catalysts that provide moderate yields of the desired C-1
substituted indolizine 8a at 70 °C.7
Table 1. Cycloisomerization of Terminal Alkyne Propargylic
Ester Substrates
a
Reaction conditions: 5 mol % of catalyst, 10 mol % of additive, 0.20
Figure 1. Pt(II)- and In(III)-catalyzed cycloisomerizations. Yields
are indicated for reactions using PtCl2 and InCl3 (in parentheses).
For a full description of reaction details, including the identity of
propargylic ester substrates, see Supporting Information.
M in benzene.
Furthermore, after a screen of various additives, we were
delighted to find that the addition of 10 mol % of the bulky,
electron-rich phosphine ligands 2-(di-tert-butylphosphino)-
biphenyl8 (9, entry 3) or 2-(dicyclohexylphosphino)biphenyl
(10, entry 4) to the reaction mixture with PtCl2 as catalyst
led to a significant increase in the yield of the indolizine
product 8a, with 10 proving to be superior (79% yield). The
utility of phosphine ligands in facilitating Pt(II)-catalyzed
reactions involving nitrogen nucleophiles is consistent with
recent observations made by Widenhoefer during studies of
the hydroamination of olefins.9 Importantly, for the hydro-
amination reactions reported by Widenhoefer, a 1:1 ratio of
Pt(II) salt to exogenous phosphine (Pt/PR3) was critical to
success.10 We reasoned that the use of bulky phosphines
As shown in Figure 1, a range of indolizine products are
easily obtained utilizing the optimized reaction conditions
with either Pt(II) (5 mol % of PtCl2, 10 mol % of 2-(di-tert-
butylphosphino)biphenyl (9), 0.2 M in PhH, 70 °C) or In-
(III) (5 mol % of InCl3, 0.2 M in PhH, 70 °C). The pivalate
protective group was found to be ideal (see 11-14), and a
range of alkyl-, cycloalkyl-, aryl-, and alkenyl-substituted
indolizines are readily obtained in modest to good yields.
Of note, silyl protective groups may be employed as
evidenced by the formation of silylated indolizine 15 in 57%
yield.11
On the basis of these initial studies, we hypothesized that
tertiary propargylic alcohol substrates such as 16 (Scheme
3) could provide a platform for metal-catalyzed cycloisomer-
izations that involve a 1,2-shift.12
This would provide access to a range of highly substituted
heterocycles. In a preliminary study, pyrrolone 19 was
(6) For details, see Supporting Information.
(7) Heating 7a without added catalyst at 120 °C over 48 h yielded minor
amounts of 8a (ca. 15% yield) along with significant byproducts. This points
to a slow and inefficient background reaction.
(8) (a) Tomori, H.; Fox, J. M.; Buchwald, S. L. J. Org. Chem. 2000, 65,
5334. (b) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2000, 122, 1360.
(9) (a) Bender, C. F.; Widenhoefer, R. A. J. Am. Chem. Soc. 2005, 127,
1070. (b) Qian, H.; Widenhoefer, R. A. Org. Lett. 2005, 7, 2635.
(10) Wang, X.; Widenhoefer, R. A. Organometallics 2004, 23, 1649.
Org. Lett., Vol. 9, No. 6, 2007
1170

Scheme 3. Tandem Cyclization/1,2-Migration of 16
Table 2. Pt-Catalyzed Formation of Indolizinones
formed in 71% yield upon treatment of hydrazone 16 with
PtCl2 (10 mol %) for 24 h at 100 °C. Presumably, this
conversion proceeds via initial formation of 17, which yields
18 upon proton transfer. An ensuing 1,2-shift of the ethyl
group affords 19.13
Despite our initial success in transforming 16 to pyrrolone
19, our general conditions proved to be ineffective at low
catalyst loadings for substrates that contain a pyridine
fragment. A screen of various additives, solvents, and
temperatures identified a set of optimized conditions (5 mol
% of PtCl2, 10 mol % of 2-(di-tert-butylphosphino)biphenyl,
0.1 equiv of Cs2CO3, 100 °C), which was readily applicable
to several tertiary propargylic alcohol substrates (20a-e,
Table 2) to provide the corresponding indolizinones (21a-
e) in modest to good yields. The addition of substoichio-
metric quantities of a base (Cs2CO3), which may facilitate
proton-transfer events prior to the 1,2-migration event, was
found to be critical.14 Importantly, preliminary results indicate
that the 1,2-migrations occur with high stereoselectivity as
evidenced by the efficient transfer of chirality in the
formation of enantioenriched indolizinone 21a (97% ee, eq
1) from 20a (99.9% ee).15,16
a
Cs2CO3 was not used as an additive.
metal-catalyzed cycloisomerization that allows access to
indolizines and indolizinones and for the first time highlights
the significant effect of bulky electron-rich phosphines on
these cycloisomerization transformations. Further studies to
probe the mechanisms of these transformations, broaden the
scope to include other examples of chirality transfer, and
identify conditions to shorten the reaction times are under-
way. Additionally, applications of these heterocycles in
natural product synthesis are currently ongoing and will be
reported in due course.
Acknowledgment. The authors would like to thank Ms.
Christina Kraml (AccelaPure Corp., Frick Lab Rm 201,
Princeton University, Princeton, NJ 08544) for enantioen-
riched samples of 20a and Johnson Matthey for a gift of
PtCl2. The authors are also grateful to UC Berkeley, Eli Lilly,
and GlaxoSmithKline for generous financial support.
Supporting Information Available: Experimental details
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
To the best of our knowledge, the work reported herein
represents the first examples of this mechanistically distinct,
(11) Previously, PtCl2 was reported to be an ineffective catalyst for the
cycloisomerization that results in 15. See ref 2c.
OL0701971
(12) For an example of R-hydroxyiminium 1,2-migration, see: Fenster,
M. D. B.; Patrick, B. O.; Dake, G. R. Org. Lett. 2001, 3, 2109.
(13) For examples using cyclic R-ketols, see: Kirsch, S. F.; Binder, J.
T.; Lie´bert, C.; Menz, H. Angew. Chem., Int. Ed. 2006, 45, 5878.
(14) The formation of a cesium alkoxide prior to 1,2-migration may also
be important.
(15) Enantioenriched 20a was obtained via preparative chiral column
chromatography of the racemate.6
(16) Efforts to delineate whether this transformation is stereospecific and
whether the loss of ee in forming enantioenriched 21a occurs via a
competing process are currently ongoing.
Org. Lett., Vol. 9, No. 6, 2007
1171