Addition/elimination reactions of ethylsulfonyl pyridines: Stereoselective synthesis of vinylpyridine allylic alcohols

Article abstract of DOI:10.1016/j.tetlet.2012.12.049

2-(Phenylsulfonyl)ethyl pyridines can be coupled with aldehydes leading directly to sulfone-eliminated vinylpyridine allylic alcohols. These products are obtained in good yield and with high levels of stereocontrol.

Full text of DOI:10.1016/j.tetlet.2012.12.049

Tetrahedron Letters 54 (2013) 715–717
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Addition/elimination reactions of ethylsulfonyl pyridines: stereoselective
synthesis of vinylpyridine allylic alcohols
⇑
Gregory W. O’Neil , Nathan D. Drake, Jennifer M. Storvick
Department of Chemistry, Western Washington University, Bellingham, WA 98225, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
2-(Phenylsulfonyl)ethyl pyridines can be coupled with aldehydes leading directly to sulfone-eliminated
vinylpyridine allylic alcohols. These products are obtained in good yield and with high levels of
stereocontrol.
Received 8 December 2012
Accepted 17 December 2012
Available online 21 December 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Pyridine
Sulfone
Addition/elimination
Stereoselective
Heterocycle
The pyridine scaffold is common to a range of important biolog-
ically active compounds,1 ligands for catalysis,2 and various func-
tional materials.3 Recently our group became interested in
suggesting that deprotonation occurs selectively adjacent to the
sulfone.13 Surprisingly, however, in addition to this product we also
obtained small amounts of allylic alcohol 6. Herein we describe the
optimization of this process as a general and stereoselective
synthesizing
a family of marine alkaloids that included the
2-substituted pyridine derivative pulo’upone (1) (Fig 1).4 This com-
pound and the related metabolites haminol A (2) and B (3) have
been shown to act as alarm pheromones5 for the host mollusk
and display a range of noteworthy antimicrobial activities.6 One
strategy that was pursued for pyridine installation and construc-
OR
0
0
tion of the D2 ,3 alkene present in 1 was a classical Julia–Lythgoe
olefination.7 This was envisioned to occur by addition of pyridyl
sulfone 4 into a suitable aldehyde coupling partner.
haminol A (R = H, 2)
N
3
haminol B (R = Ac, )
O
Julia olefination
To that end, 48 was prepared uneventfully via sulfone displace-
ment of the tosylate derived from commercially available
2-(2-hydroxyethyl)-pyridine (Scheme 1).9 Prior to attempting the
coupling, it was recognized that 4 contains two sets of protons with
similar acidities. For instance one can find reports estimating the
pKa of both methyl phenylsulfone10 and 2-picoline11 as 31. Thus it
was not clear if deprotonation would occur adjacent to the sulfone
as is required for the Julia olefination. The reaction was therefore
performed on a model system using benzaldehyde and n-butyllith-
ium (n-BuLi) as base. Pyridylsulfone 4 was treated with 1.2 equiv of
n-BuLi at ꢀ78 °C which immediately gave a bright red colored
solution, characteristic of the 2-picolyllithium anion.12 Nonetheless,
benzaldehyde was added after stirring at this temperature for
30 min and the reaction was quenched after 1 h. The major product
H
N
N
4
SO2Ph
H
1
pulo'upone ( )
Figure 1. Pyridine-containing marine alkaloid natural products.
1. TsCl, pyr.
H H
2. PhSO2Na, NaI
DMF, 70 °C
(80%, 2-steps)
N
OH
N
SO2Ph
4
H H
similar pKa
1.2 eq BuLi
SO2Ph
was in fact
a stereoisomeric mixture of hydroxysulfones 5,
+
Ph
Ph
then PhCHO
N
N
5 (65%)
6 (10%)
OH
OH
⇑
Corresponding author. Tel.: +1 360 650 6283; fax: +1 360 650 2826.
E-mail address: oneil@chem.wwu.edu (G.W. O’Neil).
Scheme 1. Attempted Julia olefination with pyridyl sulfone 4.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.049

716
G. W. O’Neil et al. / Tetrahedron Letters 54 (2013) 715–717
N
SO2Ph
N
SO2Ph
SO2Ph 1.2 eq BuLi
SO2Ph
SO2Ph
BuLi
D2O
N
N
SO2Ph
D
(~20%)
(1 eq)
N
N
N
4
18
16
17
7
SO2Ph
N
SO2Ph
(E:Z >10:1)
BuLi
(2.2 eq)
PhCHO
(58%)
PhCHO
−SO2Ph
then H2O
Ph
OH
Ph
Ph
N
N
19
20
8
O
6
OH
Scheme 4. Deuterium labeling studies and reactivity of a 4-substituted pyridyl
Scheme 2. Proposed formation of 6 by addition/elimination.
sulfone.
coupling method for the synthesis of vinylpyridine allylic alcohols
of type 6.
1 equiv of n-butyllithium followed by quenching with D2O which
gave 17 with exclusive deuterium incorporation adjacent to the
sulfone. This result suggested that 16 might also be amenable to
this type of sequence, the selective formation of anion 18 prevent-
ing any competing nonproductive elimination of the sulfone group
prior to coupling. Indeed, further deprotonation with n-butyllith-
ium gave presumably dianion 19 that then added regioselectively
to benzaldehyde with concomitant elimination to produce the
trans-pyridyl alcohol 20 as a single stereoisomer by 1H NMR, albeit
in slightly lower yield than observed for the 2-series.
The prevalence of pyridine and in particular vinylpyridines in
important natural and synthetic compounds continues to drive
the development of novel methods for the synthesis of this struc-
tural motif.20 While metal-catalyzed direct pyridine alkenylation
processes have recently emerged for this purpose,21 these typically
require more specialized substrates and costly transition metals
while other reactions such as olefin metathesis have proven less
effective.22 Aside from the pyridyl sulfone and aldehyde coupling
partners, this novel addition/elimination sequence requires
n-butyllithium as the only other reagent. Additionally it is opera-
tionally simple, occurs relatively rapidly at low temperatures and
delivers coupled products in good yield and with high levels of ste-
reocontrol. It is anticipated that this general strategy will extend to
other ethylsulfone-substituted heterocycles with similar acidity
characteristics23 which can first be screened using the deuterium
labeling experiment described. Along with additions to carbonyls,
a variety of sulfone-alkylations24 are also known that might be
adapted for this sequence. Current efforts are aimed at better
understanding the mechanism for this transformation and extend-
ing this protocol as a general method for heterocycle incorporation
into more complex systems with applications to biologically rele-
vant molecules.
Compound 6 was thought to be the result of an addition/elimi-
nation sequence14 from dianion 7, generated by the slight excess
(1.2 equiv) of n-butyllithium that had been used (Scheme 2).
2-Picolyl lithium is well known and has been shown to exist to a
significant extent as the N-anion.15 Substituted 2-picolyl dianions
have also been described and used in synthesis,16 albeit not of this
particular arrangement. It therefore seems likely that dianion 7
added regioselectively to benzaldehyde generating intermediate
alkoxide 8 that then undergoes elimination of the phenyl sulfone,
followed by quenching to give 6.
Supportive of this mechanism, simply increasing the amount of
butyllithium, and therefore presumably the amount of dianion 7,
greatly increased the isolated yield of 6 (Scheme 3). The reaction ap-
pears to be quite general and operationally simple: deprotonation of
4 with 2.2 equiv of n-BuLi followed by addition of an aldehyde and
reaction at ꢀ78 °C with brief warming to ensure complete elimina-
tion gave good yields of a range of coupled products (6, 9–15). These
include aryl, alkyl, and dienyl allylic alcohols with exclusive trans-
alkene geometry as observed by 1H NMR analysis. The reaction gave
pyridyl alcohols 12 and 1317 with good Felkin control18 while Roche
ester derived products 14 and 15 were obtained with little to no
selectivity as expected.19 It is noteworthy that no double addition
is observed, due to the rapid beta-elimination of the sulfone group
post mono-acylation. This allows for the use of excess aldehyde
without the possibility of any potentially unwanted incorporation
of the electrophile adjacent to the pyridine (Scheme 4).
The 4-substituted pyridyl sulfone 16 was expected to exhibit a
similar acidity profile to 4.11 To test this, 16 was treated with
SO2Ph 2.2 eq BuLi
R
Acknowledgments
N
N
4
then RCHO
6 9 15
(E)- ,
-
OH
via
Financial support from Western Washington University, M.J.
Murdock Charitable Trust and Research Corporation departmental
development Grant, and the National Science Foundation (CHE-
1151492) is gratefully acknowledgd.
SO2Ph
N
7
Supplementary data
n-pent
OH
Ph
OH
N
N
N
N
Supplementary data (complete analytical data and experimen-
tal procedures for compounds 4, 6, 9–17, and 20) associated with
this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2012.12.049.
9 (72%)
6 (68%)
10 (78%)
OH
dr 6:1
dr 3:1 OTBS
Me
Ph
Ph
N
CH3
N
12
( )- (75%)
13 (70%)
OH
11 (67%)
OH
References and notes
OH
Me
Me
1. Review: (a) Lukevits, É. Chem. Heterocycl. Compd. 1995, 31, 639; Recent
example: (b) Santos, V. A. F. F. M.; Regasini, L. O.; Nogueira, C. R.; Passerini, G.
D.; Martinez, I.; Bolzani, V. S.; Graminha, M. A. S.; Cicarelli, R. M. B.; Furlan, M. J.
Nat. Prod. 2012, 75, 991.
2. Select example: Desimoni, G.; Faita, G.; Quadrelli, P. Chem. Rev. 2003, 103, 3119.
3. Recent example: Bayazit, M. K.; Clarke, L. S.; Coleman, K. S.; Clarke, N. J. Am.
Chem. Soc. 2010, 132, 15814.
OPMB
OTBS
N
N
14 (65%)
15 (73%)
OH
OH
Scheme 3. Scope of pyridyl sulfone addition/elimination sequence.

G. W. O’Neil et al. / Tetrahedron Letters 54 (2013) 715–717
717
4. (a) Coval, S. J.; Scheuer, P. J. J. Org. Chem. 1985, 50, 3024; (b) Carter, K. P.; Moser,
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(b) Labelle, M.; Belley, M.; Gareau, Y.; Gauthier, J. Y.; Guay, D.; Gordon, R.;
Grossman, S. G.; Jones, T. R.; Leblanc, Y. Bioorg. Med. Chem. Lett. 1995, 5, 283; (c)
Jackson, R. H.; Morrissey, M. M.; Sills, M. A.; Jarvis, M. F. J. Pharmacol. Exp. Ther.
1992, 262, 80.
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Chem. I. E. 2010, 49, 1115; (b) Murakami, M.; Hori, S. J. Am. Chem. Soc. 2003, 125,
4720; (c) Kanyiva, K. S.; Nakao, Y.; Hiyama, T. Angew. Chem. I. E. 2007, 46, 8872;
(d) Kanyiva, K. S.; Nakao, Y.; Hiyama, T. J. Am. Chem. Soc. 2008, 130, 2448; (e)
Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130, 9254; Pyridine 3-
alkenylation: (f) Ye, M.; Gao, G.-L.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 6964.
22. Storvick, J. K.; Ankoudinova, E.; King, B. R.; Van Epps, H.; O’Neil, G. W.
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8. Previous synthesis: (a) Achmatowicz, O.; Maruszewska-Wieczorkowska, E.;
Michalski, Y. Rocz. Chemii 1955, 29, 1029–1039
(b) For an alternative synthesis see Supplementary data.
9. Brandl, T.; Hoffmann, R. W. Eur. J. Org. Chem. 2002, 2613.
10. Bordwell, F. G.; Van der Puy, M.; Vanier, N. R. J. Org. Chem. 1976, 41, 1885.
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12. Buemel, O. F.; Smith, W. N.; Rybalka, B. Synthesis 1974, 43.
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Fraser, R. R.; Mansour, T. S.; Savard, S. J. Org. Chem. 1985, 50, 3232.
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17. The stereochemistry of alcohol 13 was determined by detailed NMR analysis
after conversion to the corresponding acetal:
OTBS
1. TBAF
H
O
N
N
2. CSA,
C(OMe)2Me2
H
O
OH
(70%, 2-steps)
nOe
See Supplementary data for details.