Cyclic acetal formation between 2-pyridinecarboxyaldehyde and γ-hydroxy-α,β-acetylenic esters

Article abstract of DOI:10.1016/j.tetlet.2008.09.008

A new transformation between 2-pyridinecarboxyaldehyde and γ-hydroxy-α,β-acetylenic esters to form highly functionalized cyclic acetals was discovered. This transformation proceeds under very mild conditions without any additives and is promoted by the basic nature of the pyridine ring.

Full text of DOI:10.1016/j.tetlet.2008.09.008

Tetrahedron Letters 49 (2008) 6550–6552
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Tetrahedron Letters
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Cyclic acetal formation between 2-pyridinecarboxyaldehyde
and
c-hydroxy-
a,b-acetylenic esters
*
Sami Osman, Kazunori Koide
Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A new transformation between 2-pyridinecarboxyaldehyde and
c-hydroxy-a,b-acetylenic esters to
Received 12 August 2008
Accepted 2 September 2008
Available online 6 September 2008
form highly functionalized cyclic acetals was discovered. This transformation proceeds under very mild
conditions without any additives and is promoted by the basic nature of the pyridine ring.
Ó 2008 Elsevier Ltd. All rights reserved.
Electron-deficient propargylic alcohols such as
c
-hydroxy-
a
,b-
plished by Kwon et al. under phosphine catalysis.17 These exam-
ples demonstrate the importance of cyclic acetals in organic
synthesis.
We speculated that the weakly basic pyridine nitrogen atom
could transiently deprotonate the hydroxy group of alcohol 4, pro-
moting addition to the aldehyde (Scheme 1b). The resulting hemi-
acetal anion could then undergo a conjugate addition toward the
alkenyl esters are important intermediates in organic synthesis
due to their potential for further functionalization.1–4 As such,
development of new synthetic methodologies toward the prepara-
tion of these important synthetic intermediates is of interest to
many research groups including ours. For example, we showed
that highly functionalized
c-hydroxy-a,b-acetylenic esters could
be prepared by the coupling of aldehydes, ketones, or epoxides
with silver acetylides in the presence of Cp2ZrCl2 and AgOTf.5,6
The Trost group later developed an enantioselective method to
a,b-acetylenic esters to form product 5 with the indicated cis rela-
tionship of the pyridine and phenyl group and the trans olefin. This
could explain why 3- or 4-pyridinecarboxyaldehyde did not react.
prepare these compounds.7
precursors for -hydroxy-
esters,9,10 and trans-
-oxo-
tory, -hydroxy-a,b-alkenyl esters played a pivotal role in the syn-
c
-Hydroxy-
,b-alkenyl esters,8 cis-
,b-alkenyl esters.9,11,12 In our labora-
a
,b-acetylenic esters are
c
a
c
-oxo- ,b-alkenyl
a
c
a
(a)
CO2Me
c
Cp2ZrCl2
thesis of FR901464.13–15 While studying the scope of zirconium/
silver-promoted alkynylation of aldehydes and ketones, we found
the interesting reactivity of 2-pyridinecarboxyaldehyde toward
+
Ag
CO2Me
N
CH2Cl2
N
CHO
OH
Not isolated
3
1
2
c-hydroxy-a,b-acetylenic esters, which is the subject of this Letter.
In our efforts to develop zirconium/silver-promoted alkynyl-
(b)
N
ations of functionalized carbonyl compounds with silver acetylides,6
the coupling between 2-pyridinecarboxyaldehyde (1) and Ag–
C„C–CO2Me (2) in the presence of Cp2ZrCl2 gave an intractable
mixture (Scheme 1a). We hypothesized that the expected product
3 could react with 1, thereby producing the mixture. To test this
hypothesis, a mixture of 4 and 1 (1:1, 0.3 M each) was stirred at
23 °C in CH2Cl2 for 4 d (Scheme 1b). These reaction conditions pro-
duced the highly functionalized product 5 in 65% yield, whose
structure was confirmed by X-ray crystallography (Fig. 1). Interest-
ingly, compound 4 did not react with either 3- or 4-pyridinecarbo-
xyaldehyde. Similar compounds were produced by Evans et al. by
using alcohol substrates and potassium t-butoxide with an alde-
hyde to form 6-membered cyclic acetals.16 Another work to form
a very similar 6-membered ring 1,3-dioxan-4-ylidenes was accom-
OH
CH2Cl2
Ph
+
O
O
N
1
CHO
23 °C
48 h
CO2Me
Ph
CO2Me
4
5
65% yield
HN
O
NH
N
O
O
H
O
O
O
Ph
Ph
H
OMe
Ph
CO2Me
OMe
O
O
* Corresponding author. Tel.: +1 412 624 8767; fax: +1 412 624 8611.
E-mail address: koide@pitt.edu (K. Koide).
Scheme 1. (a) Attempted alkynylation. (b) Plausible mechanism for the cyclic
acetal formation.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.008

S. Osman, K. Koide / Tetrahedron Letters 49 (2008) 6550–6552
6551
Table 2
Reaction of 2-pyridinecarboxyaldehyde with
c
-hydroxy-
a
,b-acetylenic esters
OH
MeOH
23 °C
N
+
R
O
O
N
1
CHO
CO2Me
R
CO2Me
(1.2 equiv)
Entry
1
R
Time (d)
5.3
Yielda (%)
84 (60)
2
3
4
5
2.9
2.8
3.2
2.9
79 (61)
82 (60)
99 (83)
82 (65)
Figure 1. ORTEP representation of 5.
O2N
F3C
The selectivity for the trans olefin geometry may occur because the
lone pair electrons on the oxygen of the acetal and oxygen of the
ester carbonyl repel each other if the olefin were cis.24 The phenyl
and pyridine rings are cis to each other possibly because as the alk-
oxide attacks in a 1,4-fashion, both rings prefer to be in the pseu-
MeO
F
25,26
do-equatorial positions.
Although the reaction proceeded in CH2Cl2, we asked if other
solvents would be more suitable. Solvents were screened by 1H
NMR analysis in the respective deuterated solvent. Compounds 1
and 4 were dissolved in each of the deuterated solvents listed in
Table 1, with a final reaction concentration of 0.5 M (with respect
to the alkyne) in the presence of Bn2O as an internal standard, and
the reactions were monitored at 23 °C. After 25 h in CD2Cl2, 33% of
4 was consumed. In C6D6 and CD3OD, 38% and 44% conversion of 4
was observed, respectively. The reaction solution in CH2Cl2 turned
black after approximately 1 d, which may be a sign of polymeric
material being formed from the alkynoate; a similar observation
was noted by Garcia-Tellado and co-workers in their domino pro-
cess approach for their synthesis of 1,3-dioxolane.18 This probable
polymeric material production was dramatically reduced when
switching to MeOH as a solvent.
6
7
1.9
76 (40)
O
2.8
5.9
88 (67)
47 (34)
8
a
Yields for major diastereomer are shown in (). The yields of combined diaste-
reomers are listed outside ().
We then studied the reactivity of this novel 2-pyridylacetal
functionality. Standard hydrogenolysis conditions with Pd/C and
H2 reductively cleaved one of the two acetal C–O bonds to form
ether 7 in 40% yield as a mixture of tautomers (Scheme 2), with
the rest being the starting material. Structurally similar compound
has been shown to behave as an anti-ischemic and anti-hyperten-
sive activity,23 indicating that this synthetic method may provide a
library of compounds closely related to these anti-ischemic and
anti-hypertensive drugs. Hydrogenation with Pt/C reduced the pyr-
idine ring to form amine 8 in 33% yield with the rest being the
starting material. Similar results were obtained when palladium-
black was used. From these results, it is concluded that unlike
benzyl ethers, pyridylmethyl ethers are difficult to cleave under
the typical hydrogenolysis conditions. Acetal 6a was inert toward
acidic conditions (e.g., CSA and TFA) presumably because the pro-
tonated pyridine destabilizes the carbocation at the benzylic posi-
tion. Attempts to methylate the pyridine nitrogen with MeI and
treating with base gave no sign of reaction besides partial methyl-
ation of the nitrogen.19 Conjugate reduction of enoate 6a with
We next examined the scope of the reaction of 2-pyridinecarb-
oxyaldehyde with various
c-hydroxy-a,b-acetylenic esters in
MeOH. As can be seen in Table 2, the reaction is well-tolerable in
the presence of cyclohexyl (entry 1) and aromatic side chains (en-
tries 2–7) and even proceeds with the bulky t-butyl group (entry
8). With respect to the aromatic side chains, both electron-donat-
ing and electron-withdrawing substituents are withstood in the
reaction and proceed with similar yield.
Table 1
Solvent effect
OH
N
O
23 °C
25 h
Ph
+
O
N
CHO
CO2Me
20
NiCl2Á6H2O and NaBH4 resulted in 9 as a mixture of two separa-
CO2Me
Ph
ble diastereomers. The major diastereomer was isolated in 30%
yield. The remaining is a mixture of a minor amount of different
diastereomer and the unreacted starting material.
4
1
(1.2 equiv)
Entry
Solvent
% Conversion (by 1H NMR)
In conclusion, we have discovered an interesting reactivity
between 2-pyridinecarboxyaldehdye and c-hydroxy-a,b-acetylenic
esters. The reactions were promoted by the basicity and proximity
of the pyridine group. The acetal product 6a represents the reactiv-
ity of these acetal compounds under various reaction conditions.
Although these results indicate that reaction conditions are needed
1
2
3
4
5
CDCl3
CD2Cl2
C6D6
DMSO-d6
CD3OD
20
33
38
5
44
[4] = 0.5 M. Bn2O (0.5 mmol) was used as an internal standard.

6552
S. Osman, K. Koide / Tetrahedron Letters 49 (2008) 6550–6552
Supplementary data
N
NH
N
O
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.09.008.
a. H2,
b. H2,
Pt/C
O
OH
O
O
O
Pd/C
R
CO2Me
R
R
References and notes
CO2Me
CO2Me
7
6a
8
1. Mikami, K.; Yoshida, A. Tetrahedron 2001, 57, 889–898.
2. Molander, G. A.; St. Jean, D. J. J. Org. Chem. 2002, 67, 3861–3865.
3. Trost, B. M.; Crawley, M. L. J. Am. Chem. Soc. 2002, 124, 9328–9329.
4. Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2002, 124, 5025–5036.
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6. Shahi, S. P.; Koide, K. Angew. Chem., Int. Ed. 2004, 43, 2525–2527.
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9.
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11. Sonye, J. P.; Koide, K. Org. Lett. 2006, 8, 199–202.
N
O
.
c. NiCl2 6H2O,
NaBH4, H2
O
CO2Me
R
N
O
O
R=
R
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CO2Me
9
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Scheme 2. Derivatizations of 6a. Reagents and conditions: (a) H2, Pd/C (10 mol %),
EtOAc, 23 °C, 44 h, 40%; (b) H2, Pt/C (10 mol %), EtOAc, 23 °C, 22 h, 33%; (c)
NiCl2Á6H2O (7.0 equiv) NaBH4 (7.0 equiv), H2, MeOH, 23 °C, 46.5 h, 30%.
16. Evans, D. A.; Gauchet-Prunet, J. A. J. Org. Chem. 1993, 58, 2446–2453;
Applications of this Evans method include Rotulo-Sims, D.; Prunet, J.
Org. Lett. 2007, 9, 4147–4150; Hunter, T. J.; O’Doherty, G. A. Org. Lett.
2001, 9, 2777–2780; Denmark, S. E.; Fujimori, S. J. Am. Chem. Soc. 2005,
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to use the pyridine acetals as protecting groups, the acetals provide
an interesting scaffold for diversity-oriented synthesis21 because
this moiety has been shown to be important in biologically active
molecules.22,23
19. Katritzky, A. R.; Fan, W.-Q.; Li, Q.-L. Tetrahedron Lett. 1987, 28, 1195–1198.
20. Russell, T. W.; Duncan, D. M.; Hansen, S. C. J. Org. Chem. 1977, 42, 551–552.
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Acknowledgments
22. Kuruvilla, F. G.; Shamji, A. F.; Sternson, S. M.; Hergenrother, P. J.; Schreiber, S. L.
Nature 2002, 416, 653–657.
23. Campbell, S. F.; Cross, P. E.; Stubbs, J. K. U.S. Patent 4515799, May 7, 1985.
24. Kwon et al. observed similar trans selectivity in Ref. 17.
25. We presume the relation between the pyridinyl and the different R groups in
Table 2 is cis.
Financial support was provided by the NIH (R01CA120792). We
thank Dr. Damodaran Krishnan, Dr. Steve Geib, and Dr. John Wil-
liams for assisting with NMR, X-ray, and mass spectroscopic anal-
yses, respectively. We also would like to thank Mr. Christopher
Meta, Mr. John Sonye, and Dr. Shatrughan Shahi for preliminary
experiments.
26. The relationship between the phenyl and pyridine group and olefin geometry
of the other minor diastereomer was not determined.