Electronic effects in the Pt-catalyzed cycloisomerization of propargylic esters: Synthesis of 2,3-disubstituted indolizines as a mechanistic probe

Article abstract of DOI:10.1021/ol701973s

(Chemical Equation Presented) The initial 5-exo versus 6-endo cyclization of the acyl group onto the activated alkyne of propargylic esters has been found to be dependent on electronic effects of the acyl, alkyne, and propargylic carbon substituents. Thes

Full text of DOI:10.1021/ol701973s

ORGANIC
LETTERS
2007
Vol. 9, No. 22
4547-4550
Electronic Effects in the Pt-Catalyzed
Cycloisomerization of Propargylic
Esters: Synthesis of 2,3-Disubstituted
Indolizines as a Mechanistic Probe
Alison R. Hardin and Richmond Sarpong*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
rsarpong@berkeley.edu
Received August 11, 2007
ABSTRACT
The initial 5-exo versus 6-endo cyclization of the acyl group onto the activated alkyne of propargylic esters has been found to be dependent
on electronic effects of the acyl, alkyne, and propargylic carbon substituents. These electronic effects control the ratio of 2,3-disubstituted
versus 1,3-disubstituted indolizine products formed when substrates bearing pyridines at the alkyne terminus are used.
Cycloisomerization transformations involving the activation
of alkynes using late transition metals (e.g., Ru, Pt, Ag, and
Au) are a very active area of current research in synthetic
organic chemistry.1 A subset of these reactions involving
propargylic esters2 have undergone a renaissance in the past
decade, building on the pioneering studies of Ohloff and
Rautenstrauch using Zn(II) and Pd(II) salts, respectively.3
The proposed mechanisms by which these cycloisomeriza-
tions proceed are mostly supported by empirical observations
and may involve zwitterion, metallocarbenoid, or allene type
intermediates as outlined in Scheme 1. However, a univer-
sally predictive model that delineates the role of catalysts
Scheme 1. Potential Cycloisomerization Mechanisms
(1) For a recent review, see: Fu¨rstner, A.; Davies, P. W. Angew. Chem.,
Int. Ed. 2007, 46, 3099.
and the electronic effects the alkyne substituents have in
funneling a substrate through a specific reactive intermediate
to product has yet to emerge.4 This shortcoming highlights
the importance of initiating investigations that employ
(2) For related reviews, see: (a) Marion, N.; Nolan, S. P. Angew. Chem.,
Int. Ed. 2007, 46, 2750. (b) Miki, K.; Uemura, S.; Ohe, K. Chem. Lett.
2005, 34, 1068. (c) Mendez, M.; Mamane, V.; Fu¨rstner, A. Chemtracts
Org. Chem. 2003, 16, 397. For examples of Au- and Pt-catalyzed acyloxy
migrations of propargylic esters, see: (d) Wang, S.; Zhang, L. J. Am. Chem.
Soc. 2006, 128, 8414. (e) Mamane, V.; Gress, T.; Krause, H.; Fu¨rstner, A.
J. Am. Chem. Soc. 2004, 126, 8654. (f) Fehr, C.; Galindo, J. Angew. Chem.,
Int. Ed. 2006, 45, 2901. (g) Cho, E. J.; Kim, M.; Lee, D. Eur. J. Org.
Chem. 2006, 3074.
(4) Important advances have been made in identifying metal salts and
ligand combinations and alkyne substituents that may exert influence on
the course of the reaction; see for example: (a) Marion, N.; de Fre´mont,
P.; Lemie´re, G.; Stevens, E. D.; Fensterbank, L.; Malacria, M.; Nolan, S.
P. Chem. Commun. 2006, 2048. (b) Barluenga, J.; Riesgo, L.; Vicene, R.;
Lo´pez, L. A.; Toma´s, M. J. Am. Chem. Soc. 2007, 129, 7772.
(3) (a) Strickler, H.; Davis, J. B.; Ohloff, G. HelV. Chim. Acta 1976, 59,
1328. (b) Rautenstrauch, V. J. Org. Chem. 1984, 49, 950.
10.1021/ol701973s CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/11/2007

different metal complexes and propargylic ester substrates
in an effort to understand the mechanisms of these processes.
A particularly successful approach to control initial 5-exo
versus 6-endo nucleophilic attack of the ester carbonyl onto
the alkyne (see 1 f 2 versus 1 f 6) is the introduction of
substituents to electronically modulate the alkyne reactivity.4b,5
While propargylic esters bearing terminal alkynes typically
undergo 5-exo-dig cyclization using Ru, Pt, or Au catalysts,6
internal alkynes bearing alkyl or aryl7 substituents usually
undergo 6-endo-dig cyclization. Malacria was the first to
report that ester substituents at the alkyne terminus lead
exclusively to initial 5-exo-dig cyclization using PtCl2 as the
catalyst.5 We have recently shown that this strategy is
effective for the synthesis of indenes (e.g., 9, Scheme 2) using
propargylic ester substrates such as 7.8
cyclization due to the electron-withdrawing capability of the
2-substituted pyridine at the alkyne terminus. Backbonding
from the metal center (see 11) was expected to yield
metallocarbenoid 12, which upon cyclization (via the inter-
mediacy of zwitterion 13) would yield 2,3-disubstituted
indolizine 14 following proton transfer. Alternatively, in Path
B, initial 6-endo-dig cyclization (should the pyridine sub-
stituent exert electronic effects similar to a phenyl group)
would furnish allene 15, which would react further (via 16)
to form 1,3-disubstituted indolizine 17.
Our group has recently reported a cycloisomerization
transformation for the synthesis of 1,3-disubstituted indol-
izines such as 17.9 However, general methods to synthesize
2,3-disubstituted indolizines (e.g., 14) are limited. Given the
existing challenge of regioselective functionalization of
indolizines,10 the transformation of 10 f 14 would be
especially significant.
The propargylic ester substrate 18a (Table 1), which was
prepared in a one-pot sequence in high overall yield from
Scheme 2. Pt-Catalyzed Indene Formation
Table 1. Optimization Studies
Herein, we report a novel mode of reactivity of propargylic
ester substrates bearing pyridine substituents at the alkyne
terminus that undergo cycloisomerization to produce highly
functionalized indolizine products. During the course of these
studies, we have discovered remote electronic effects of
substituents at the propargylic position to be important in
biasing initial 5-exo versus 6-endo cyclization.
yield (%)
entry substrate catalyst
ligand
additive (ratio 19:20)a
1
2
3
4
5b
6b
7b
18a
18a
18a
18b
18b
18b
18b
PtCl2
PtCl2
PtCl2
PtCl2
PtCl2
PtCl2
PtI2
-
PPh3
-
-
-
-
Lil
LiCl
-
10
-
For example, two possible cycloisomerization pathways
are open to propargylic ester substrate 10 (Scheme 3). Path
P(C6F5)3
P(C6F5)3
P(C6F5)3
P(C6F5)3
P(C6F5)3
42 (3:1)
64 (9:1)
61 (15:1)
42 (9:1)
82 (18:1)
Scheme 3. Proposed 1,3- and 2,3-Disubstituted Indolizine
Formation
a Ratio determinations were made by comparison of 1H NMR resonances.
b Reaction conducted at 80 °C.
the corresponding pyridine acetylene, was used in our initial
optimization studies.11 Using previous Pt(II)-catalyzed cy-
cloisomerization studies from our laboratories as a starting
point, we investigated the effect of combinations of platinum
salts, solvents, and reaction conditions on the efficiency of
the indolizine-forming transformation.
The best initial results were obtained with PtCl2 as a
catalyst and benzene as the solvent, which gave a 10%
conversion with the majority of the mass balance accounted
(8) Prasad, B. A. B.; Yoshimoto, F. K.; Sarpong, R. J. Am. Chem. Soc.
2005, 127, 12468.
A is predicated on the basis of our previous cycloisomer-
ization studies, whereby 10 could undergo initial 5-exo-dig
(9) (a) Smith, C. R.; Bunnelle, E. M.; Rhodes, A. R.; Sarpong, R. Org.
Lett. 2007, 9, 1169. (b) A related report recently appeared: Seregin, I. V.;
Schammel, A. W.; Gevorgyan, V. Org. Lett. 2007, 9, 3433.
(10) (a) Park, C. H.; Ryabova, V.; Seregin, I. V.; Sromek, A. W.;
Gevorgyan, V. Org. Lett. 2004, 6, 1159. (b) Sawada, K.; Okada, S.; Kuroda,
A.; Watanabe, S.; Sawada, Y.; Tanaka, H. Chem. Pharm. Bull. 2001, 49,
799. (c) Ostby, O. B.; Dalhus, B.; Gundersen, L.-L.; Rise, F.; Bast, A.;
Haenen, G. R. M. M. Eur. J. Org. Chem. 2000, 22, 3763.
(5) Cariou, K.; Mainetti, E.; Fensterbank, L.; Malacria, M. Tetrahedron
2004, 60, 9745.
(6) (a) Miki, K.; Ohe, K.; Uemura, S. Tetrahedron Lett. 2003, 44, 2019.
(b) Miki, K.; Ohe, K.; Uemura, S. J. Org. Chem. 2003, 68, 8503.
(7) For earlier discussions, see: (a) Cho, E. J.; Kim, M.; Lee, D. Org.
Lett. 2006, 8, 5413. (b) Marion, N.; Diez-Gonza´lez, S.; de Fre´mont, P.;
Noble, A. R.; Nolan, S. P. Angew. Chem., Int. Ed. 2006, 45, 3647.
(11) For complete synthesis details, see Supporting Information.
4548
Org. Lett., Vol. 9, No. 22, 2007

for by starting material (Table 1, entry 1). With the goal of
using phosphine additives to modulate the reactivity of the
Pt catalysts, we surveyed a range of phosphines including
JohnPhos, 2-dicyclohexylphosphino biphenyl,12 and PPh3
(entry 2) as additives. Each of these cases returned the
starting material. However, with the electron-deficient tris-
(pentafluorophenyl)phosphine as an additive,13 a significant
increase in yield (42%, entry 3) of indolizine products was
observed, albeit as a 3:1 mixture comprising regioisomeric
indolizines 19a and 20a.14 The acyl substituent also emerged
as an important parameter with pivalates (see 18b, entry 4)
giving significantly better selectivities and yields as compared
to acetates (18a, entry 3).
Table 2. Effect of Substitution at the Propargylic Position
Our continuing studies have sought to minimize the
regioisomeric mixture of products (i.e., 19 versus 20). By
analogy to the course of reaction of ester-terminated alkyne
substrates (see Scheme 2), we hypothesized that a more
electron-deficient pyridine fragment would favor an initial
5-exo-dig cyclization, which would lead predominantly to
the desired 2,3-disubstituted indolizines via an overall 1,2-
acyl shift. With this goal in mind, we surveyed a range of
Lewis acids as additives, which could in theory accept
electron density from the pyridine by coordination to the
nitrogen atom. A variety of Lewis acid additives including
InCl3, Yb(OTf)3, TMSCl, and AlCl3 as well as protic acids
such as HCl led predominantly to decomposition. By
contrast, we were gratified to find that LiI gave an improved
15:1 ratio of 19b/20b at 80 °C (entry 5). Encouraged by
this result, other lithium salts such as LiCl (entry 6) were
investigated as additives, but these did not show any added
improvement. These results indicated that the iodide coun-
terion was playing a crucial role. Thus, we attempted the
reaction with PtI2, which gave an excellent yield and ratio
favoring 19b (entry 7).
The cycloisomerization reaction proved to be general for
a range of substrates employing the optimized conditions of
10 mol % of PtI2, 20 mol % of P(C6F5)3, 0.10 M in PhH at
100 °C for 24 h, as illustrated in Table 2. In general,
substrates bearing alkyl substituents at the propargylic
position (e.g., R ) i-Bu or cyclohexyl) were unproductive
and led predominantly to decomposition. However, with
t-butyl or cyclopropyl substituents, a mixture of indolizine
products was obtained in low yield (entries 1 and 2,
respectively). Alkenyl substituents provided good yields and
a high ratio favoring the desired indolizine (entries 3-5).
Aromatic substituents at the propargylic position generally
served as the best substrates for these reactions as evidenced
by the exceptional product ratios and yields (e.g., entry 11).
A qualitative examination of our observations up to this
stage suggests that substituents at the propargylic position
that stabilize developing cationic character promote the
formation of the 2,3-disubstituted indolizine products (pre-
a Ratio determinations were made by comparison of 1H NMR resonances.
sumably by favoring the 5-exo-dig cyclization pathway). To
more closely probe this observation, several substrates
possessing electronically differentiated aryl groups were
prepared (entries 12a-e, Table 2). While electron-neutral
(entry 12a) and electron-donating substituents (entry 12b)
gave good yields and high ratios favoring the desired
indolizine, electron-withdrawing groups led to diminished
yields and lower product ratios (entries 12c-e). To the best
of our knowledge, this study serVes as the first inVestigation
of electronic effects at the propargylic position on the course
of cycloisomerizations of propargylic esters.
In addition to the dramatic effect of electronics at the
propargylic position on observed product ratios, we have also
found that the introduction of an electron-rich acyl group
(p-methoxybenzoyl) in place of the pivalate has a significant
effect. For example, ratios of >20:1 (67% yield) and 13:1
(56% yield) were obtained using 21b and 21d as substrates,
respectively (Scheme 4; compare to 21a and 21c, which
possess pivalate groups).
(12) (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.
(13) For an example of the use of P(C6F5)3 as a ligand in Pt(II)-catalyzed
cycloisomerizations, see: Hours, A. E.; Snyder. J. K. Tetrahedron Lett.
2006, 47, 675.
(14) The regioisomers 19 and 20 were inseparable by column chroma-
tography. The major isomer (19) was identified using nOe studies.
Org. Lett., Vol. 9, No. 22, 2007
4549

of propargylic esters on the electronic effects of the sub-
stituent at the propargylic position. Electron-donating groups
favor 5-exo-dig cyclization, whereas more of the product
resulting from initial 6-endo-dig cyclization is observed with
electron-withdrawing groups. Additionally, the acyl group
electronics influence the mode of cyclization. Using pyridine-
terminated propargylic ester substrates, a novel cycloisomer-
ization reaction for the synthesis of 2,3-disubstituted indoliz-
ines has been developed. Our current efforts are focused on
probing the mechanisms of these transformations further and
applying our methods to the synthesis of other heterocycles.
Scheme 4. Effect of Acyl Substituent
Acknowledgment. The authors are grateful to UC
Berkeley, GlaxoSmithKline, Johnson Matthey, and Boe-
hringer Ingelheim for support of this research.
With regard to the mechanism of these indolizine-forming
reactions, several preparative experiments have provided
additional insight. Using deuterated propargylic ester 24
(Scheme 5) as the substrate, indolizine 25-d was obtained
Note Added after ASAP Publication. In Table 1, entry
7 of column 3 (catalyst) was incorrect in the version
published ASAP September 11, 2007; the corrected version
was published ASAP September 13, 2007.
Scheme 5. Crossover Experiment with Cycloisomerization
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.
Substrates
OL701973S
(16) The rates of reaction of 24-d and 18b were judged to be comparable.
(17) Although further empirical evidence points to Path A (see Scheme
1) as being operative (ref 18), an alternate pathway involving conversion
of, e.g., 18b to 19b via allene 26 and zwitterion 27 as intermediates cannot
be unambiguously discounted.
with 60% deuterium incorporation at C-1.15 This observation
supports the propargylic position as the source of the C-1
proton.
Furthermore, a crossover experiment employing 24-d and
18b led to all four possible deutero and protio products (as
identified by 1H NMR), giving support to an intermolecular
mechanism for proton transfer.16,17
In our hands, catalysts such as CuI and CuCl, which have been reported to
promote isomerizations related to 18b f 26 f 27 (refs 19 and 20), led
only to decomposition. Furthermore, 1H NMR and preparative monitoring
of these reactions did not identify a discrete intermediate such as 26.
(18) Our proposed mechanism is supported by the reaction of tertiary
propargylic ester 28, which yields 30 under our reaction conditions.
In conclusion, we have shown for the first time a marked
dependence of the initial metal-catalyzed mode of cyclization
(19) Sromek, A. W.; Kel’in, A. V.; Gevorgyan, V. Angew. Chem., Int.
Ed. 2004, 43, 2280.
(15) Subsequent studies have shown that the proton at C-1 is readily
exchangeable. Complete loss of deuterium from this position occurs upon
purification of 25-d on SiO2.
(20) (a) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem.
Soc. 2001, 123, 2074. (b) Schwier, T.; Sromek, A. W.; Yap, D. M. L.;
Chernyak, D.; Gevorgyan, V. J. Am. Chem. Soc. 2007, 129, 9868.
4550
Org. Lett., Vol. 9, No. 22, 2007