Pt(II)-catalyzed synthesis of 1,2-dihydropyridines from aziridinyl propargylic esters

Article abstract of DOI:10.1021/ol070658i

Pt(II)-catalyzed cycloisomerization of aziridinyl propargylic esters affords 1,2-dihydropyridines with regiodefined installation of substituents. A mild conversion of the 1,2-dihydropyridines to the corresponding substituted pyridines as well as chirality

Full text of DOI:10.1021/ol070658i

ORGANIC
LETTERS
2007
Vol. 9, No. 11
2167-2170
Pt(II)-Catalyzed Synthesis of
1,2-Dihydropyridines from Aziridinyl
Propargylic Esters
Massoud Motamed, Eric M. Bunnelle, Surendra W. Singaram, and
Richmond Sarpong*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
rsarpong@berkeley.edu
Received March 20, 2007
ABSTRACT
Pt(II)-catalyzed cycloisomerization of aziridinyl propargylic esters affords 1,2-dihydropyridines with regiodefined installation of substituents. A
mild conversion of the 1,2-dihydropyridines to the corresponding substituted pyridines as well as chirality retention from the aziridinyl propargylic
ester substrates have been demonstrated.
Nitrogen-containing heterocycles comprise a large percentage
of natural products and pharmaceutically important small
molecules.1 Methods directed toward the synthesis of aza-
heterocycles continue to be an important undertaking, and
general strategies for the regio- and stereocontrolled intro-
duction of substituents remain a challenge. Dihydropyridines
(DHPs) have long been recognized as versatile synthetic
intermediates2 that provide ready access to a variety of sub-
stituted nitrogen-containing heterocycles such as piperidines
(by reduction)3 or to pyridines (by oxidation).4 Historically,
1,4-dihydropyridines (1,4-DHPs) have been the most studied,
whereas 1,2-DHPs have received relatively little attention.
This has stemmed primarily from the ease with which these
compounds can be accessed from pyridinium salts by
nucleophilic addition at C(4) and the emergence of Hantzsch-
type 1,4-DHPs as important calcium channel blockers.5 The
majority of synthetic approaches to 1,2-DHPs has also relied
on nucleophilic addition into N-alkyl or N-acylpyridinium
salts.6,7 Unfortunately, regioisomeric mixtures of addition
products (at the 2, 4, or 6 position) are often obtained if
unsymmetrically substituted pyridinium salts, especially those
that do not bear a substituent at the C(4) position, are
employed.8 More recently, other strategies for the synthesis
of 1,2-DHPs have emerged that address some of these
limitations.9 Because of the lack of general methods for the
regioselective synthesis of highly functionalized 1,2-DHP
derivatives, their synthetic and biological potential remains
largely unexplored. As such, there is a continued need for
the development of more functional-group-tolerant methods
that avoid the use of organolithium or Grignard reagents to
access 1,2-DHPs as well as general strategies that afford
access to bicyclic 1,2-DHPs.
We envisioned that 1,2-DHPs (e.g., 5a, Scheme 1) could
be realized from aziridinyl propargylic esters (see 1a) via a
(1) (a) Cordell, A. B. The Alkaloids: Chemistry and Biology; Elsevier
Science: San Diego, CA, 2003; Vol. 60. (b) Hesse, M. Alkaloids: Nature’s
Curse or Blessing?; WILEY-VCH: Weinheim, 2003.
(2) Lavilla, R. J. Chem. Soc., Perkin Trans. 1 2002, 1141-1156.
(3) For an example, see: Charette, A. B.; Grenon, M.; Lemire, A.;
Pourashraf, M.; Martel, J. J. Am. Chem. Soc. 2001, 123, 11829-11830.
(4) Chai, L. Z.; Zhao, Y. K.; Sheng, Q. J.; Liu, Z.-Q. Tetrahedron Lett.
2006, 47, 9283-9285.
(5) For a review, see: Gaudio, A. C.; Korolkovas, A.; Takahata, Y. J.
Pharm. Sci. 1994, 83, 1110-1115.
(6) For a review, see: Stout, D. M.; Meyers, A. I. Chem. ReV. 1982, 82,
233-243.
(7) Comins, D. L.; Hong, H.; Salvador, J. M. J. Org. Chem. 1991, 56,
7197-7199. See also ref 3.
(8) For examples, see: (a) Sundberg, R. J.; Hamilton, G.; Trindle, C. J.
Org. Chem. 1986, 51, 3672-3679. (b) Bennasar, M. L.; Roca, R.; Monerris,
M.; Juan, C.; Bosch, J. Tetrahedron 2002, 58, 8099-8106.
(9) (a) Ichikawa, E.; Suzuki, M.; Yabu, K.; Albert, M.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 11808-11809. (b) Brunner,
B.; Stogaitis, N.; Lautens, M. Org. Lett. 2006, 8, 3473-3476.
10.1021/ol070658i CCC: $37.00
© 2007 American Chemical Society
Published on Web 04/24/2007

overcome the following challenges: (1) oxidation of dihy-
dropyridines in the presence of air;12 (2) the nucleophilicity
of the aziridine nitrogen had to be tempered to allow for an
initial interaction of the activated Pt(II)-bound alkyne and
the propargylic ester (see 1af2) without competing nitrogen
addition to the alkyne;13 and (3) the reactivity of the aziridine
nitrogen had to be tuned to allow for its addition to the
metallocarbenoid functionality of 3 to afford 4 en route to
5a. Importantly, this addition should be rapid relative to a
potential vinyl aziridine rearrangement of 3.14
Scheme 1. Proposed Formation of 1,2-Dihydropyridines
Table 1. Pt(II)-Catalyzed 1,2-Dihydropyridine Synthesisa
Pt(II)-catalyzed cascade sequence. Thus, formation of zwit-
terion 2 from 1a via a 5-exo-dig cyclization of the ester
carbonyl functionality onto the alkyne and subsequent
rearrangement could afford metallocarbenoid 3. The strained
[3.1.0] bicycle 4 could then result from nucleophilic attack
of the aziridinyl nitrogen on the metallocarbenoid functional-
ity. At this stage, irreversible valence bond isomerization
coupled with the strain-release fragmentation of the aziridine
was expected to produce 1,2-DHP 5a.
The expectation that 5a could be formed from 1a is
supported by our recent report of a Pt(II)-catalyzed method
for the synthesis of acyloxycyclopentenones (e.g., 9, Scheme
2) using epoxide-bearing propargylic ester substrates (6).10
Scheme 2. Epoxide Fragmentation/Pentannulation Reaction
Our earlier investigations on the formation of 9 from 6
support a mechanism involving the intermediacy of 3(2H)-
pyran 7 and oxatriene 8. However, unlike 3(2H)-pyrans,
which are prone to oxa-6π-electrocyclic ring opening11 and
usually exist in equilibrium with the dienone or dienal
valence bond isomer, 1,2-DHPs are relatively robust. As
such, we hoped to identify optimal conditions for their
synthesis from aziridinyl propargylic esters without compet-
ing ring-opening reactions.
a
Standard conditions: 10 mol % of PtCl2, 0.2 M in PhMe at 100 °C
b
over 3 h. Isolated yields after column chromatography are reported.
The aziridinyl propargylic ester substrates (see Table 1)
were prepared by acylation of the corresponding aziridine
propargylic alcohols, which were available from the aziri-
dinyl aldehyde via a highly diastereoselective (>95:5 dr) 1,2-
To test the viability of our approach to 1,2-DHPs, a
judicious choice of protecting group had to be made to
(12) Olah, G. A.; Hunadi, R. J. J. Org. Chem. 1981, 46, 715-718.
(13) We have recently described that other nitrogen nucleophiles (e.g.,
pyridinyl nitrogens) add faster to activated alkynes relative to the propargylic
carboxylate. See: Smith, C. R.; Bunnelle, E. M.; Rhodes, A. J.; Sarpong,
R. Org. Lett. 2007, 9, 1169-1171.
(14) For a recent discussion of vinyl aziridine rearrangements, see: Ohno,
H. In Aziridines and Epoxides in Organic Synthesis; Yudin, A. K., Ed.;
WILEY-VCH: Weinheim, 2006; pp 37-72.
(10) Pujanauski, B. G.; Prasad, B. A. B.; Sarpong, R. J. Am. Chem. Soc.
2006, 128, 6786-6787.
(11) For a discussion of pyran chemistry, see: ComprehensiVe Hetero-
cyclic Chemistry; Katrizky, A. R., Rees, C. W., Eds.; Pergamon: Oxford,
1984; Vol. 3, pp 737-874.
2168
Org. Lett., Vol. 9, No. 11, 2007

addition15 of the corresponding alkynyllithium or Grignard.16
We were gratified to find that under Pt(II) catalysis (10 mol
% of PtCl2, 0.2 M in PhMe, 100 °C, 3 h) a range of aziridinyl
propargylic esters afforded the expected 1,2-DHP products
in moderate to good yields.
As detailed in Scheme 3, several acylated aziridines were
subjected to the standard reaction conditions and yielded the
1,2-DHPs (17a-d) as the major product after column
chromatography (65-74% yield). An X-ray crystal structure
of 1,2-DHP 17c (Figure 1)20 provides further support for the
As shown in Table 1, acetates, para-chlorobenzoate,
pivalate, and benzoate propargylic esters can be employed
(entries 1a-d). The permissibility of the nucleophile at the
propargylic position is further highlighted by the reaction
of trichloroacetimidate 10 (entry 2) to afford 11 in 56% yield.
To the best of our knowledge, this constitutes the first report
of the use of a trichloroacetimidate in a Pt(II)-catalyzed
cycloisomerization reaction.17 In addition, internal alkynes
bearing cyclopropyl or phenyl substituents at the alkyne
terminus (entries 3a and b, respectively) as well as cyclic
substrates (entry 4) readily participate in this transformation
to give good isolated yields (62-76%) of the desired 1,2-
DHP product.
In an effort to expand the scope of the substrates that
participate in this reaction, other substituents at the aziridine
nitrogen were explored. The N-acyl substrates (16a-d,
Scheme 3) were considered in a preliminary study.16 On the
Figure 1. ORTEP structure of 1,2-dihydropyridine 17c with
ellipsoids shown at the 50% probability level.
assigned structure of the 1,2-DHP products that result from
the preferred mode of cyclization of the N-acyl aziridine
substrates.
Scheme 3. Pt(II)-Catalyzed Cycloisomerization of Acylated
Aziridine Substrates
Under the standard reaction conditions, the Pt(II)-catalyzed
transformation of substrates possessing alkyl substitution on
the aziridine nitrogen (e.g., benzyl) has led to complex
mixtures of products from which none of the desired 1,2-
DHPs could be isolated. Presumably, the enhanced basicity
of the aziridine lone pair leads to competing nonproductive
pathways. This supports our identification of the aziridine
protecting group as an important parameter in the design of
substrates for this reaction.21
Although ample literature precedent exists for the conver-
sion of 1,2-DHPs to pyridines, the conditions required for
these processes often involve the use of strong oxidants or
acids.22 We envisioned that our 1,2-DHP products may
provide a suitable synthetic starting point to highly substituted
pyridines under mild conditions. In a preliminary study, 5b
was readily converted in 79% yield to hydroxy pyridine 20
upon treatment with potassium trimethylsilanoate (TMSOK)
at room temperature over 3 h (Scheme 4). Access to 20 now
sets the stage for further functionalization (e.g., by activation
of the hydroxyl group by triflation, followed by organo-
metallic coupling).
basis of literature precedent, which highlights the ambident
nucleophilicity of acylated aziridines,18 we hypothesized that
the presumed metallocarbenoid intermediate could lead to
1,2-DHP 17 or amide-incorporated heterocycle 18 products.
Although 17 would arise via the initially proposed mecha-
nism in which the aziridine nitrogen engages the metallo-
carbenoid intermediate (Scheme 1), 18 could be formed
through a pathway involving the nucleophilic addition of the
N-acyl carbonyl to the metallocarbenoid intermediate.19
(19) Mechanistically, this could proceed as illustrated below.
(15) A chelation-controlled 1,2-addition initially proposed to explain the
high diastereoselectivity has recently been called into question. See: (a)
Righi, G.; Piertrantonio, S.; Bonini, C. Tetrahedron 2001, 57, 10039-10046.
And: (b) Schomaker, J. M.; Geiser, A. R.; Huang, R.; Borhan, B. J. Am.
Chem. Soc. 2007, 129, 3794-3795.
(16) See Supporting Information for a detailed description for the
synthesis of the substrates.
(17) PtCl2 has been used to catalyze the Overman rearrangement of
trichloroacetimidates. See: Jaunzeme, I.; Jirgensons, A. Synlett 2005, 2984-
2986.
(18) Mente, P. G.; Heine, H. W.; Scharoubim, G. R. J. Org. Chem. 1968,
33, 4547-4548.
(20) Crystallographic data have been deposited in the Cambridge
Crystallographic Data Centre (CCDC #637309). Refinement data are
provided in the Supporting Information.
(21) The possibility of reduced stability of N-alkyl 1,2-dihydropyridines
relative to N-tosyl or N-acyl 1,2-dihydropyridines under the reaction
conditions may also contribute to the lack of success of this reaction.
Org. Lett., Vol. 9, No. 11, 2007
2169

opening/ring-closing processes) under our reaction condi-
tions. With access to highly enantioenriched 1,2-DHPs now
defined, the diastereoselective functionalization of these
compounds should provide stereoselective access to a range
of important azaheterocycles. These efforts are currently
under investigation.
Scheme 4. Conversion of 1,2-Dihydropyridines to Pyridines
In conclusion, we report a novel Pt(II)-catalyzed cyclo-
isomerization strategy for the synthesis of 1,2-DHPs that
achieves the regiodefined installation of substituents using
readily prepared aziridinyl propargylic ester substrates. In
addition, a mild conversion of the 1,2-DHPs to the corre-
sponding substituted pyridines as well as high levels of
chirality retention from the aziridinyl propargylic ester
substrates have been demonstrated. Efforts to further expand
the scope of these transformations to include other examples
of chirality retention and the identification of other modes
of cyclization of the aziridinyl propargylic ester substrates
are underway in our laboratories.
We next investigated chirality retention in converting
the aziridinyl propargylic ester substrates to the 1,2-DHP
products. As shown in Scheme 5, enantiopure 1a23 is
Scheme 5. Chirality Retention in the Formation of
1,2-Dihydropyridines
Acknowledgment. The authors are grateful to UC
Berkeley, GlaxoSmithKline, Johnson Matthey, and
Boehringer-Ingelheim for support of this research and to Ms.
Christina Kraml (AccelaPure Corp., Frick Lab Rm 201,
Princeton University, Princeton, NJ 08544) for enantiopure
samples of 5a. The authors also thank Drs. Fred Hollander
and Hye Jin Choi (UC Berkeley) for crystallographic data.
transformed in 70% yield with only a minor loss of
enantiomeric excess to the corresponding highly enantio-
enriched 1,2-DHP 5a.
This result attests to the stability of the 1,2-DHP com-
pounds toward epimerization (e.g., via subsequent ring-
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.
(22) For a recent example, see: Lemire, A.; Grenon, M.; Pourashraf,
M.; Charette, A. B. Org. Lett. 2004, 6, 3517-3520.
(23) Enantiopure 1a was obtained by preparative chiral column
HPLC of the racemate. For more information, see the Supporting Informa-
tion.
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Org. Lett., Vol. 9, No. 11, 2007