Pyridine stabilized oxiranyl remote anions

Article abstract of DOI:10.1016/j.tetlet.2009.04.106

The chemistry of oxiranyl remote anions derived from α,β-epoxypyridines is investigated. Deprotonation of α,β-epoxy pyridines at the β-position and reactions of the corresponding anions with a variety of electrophiles are found to be highly regioselective, possibly as a consequence of stabilization from the chelation between lithium and the pyridine moiety in the form of a five-membered cyclic intermediate.

Full text of DOI:10.1016/j.tetlet.2009.04.106

Tetrahedron Letters 50 (2009) 4217–4220
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Pyridine stabilized oxiranyl remote anions
Pattama Saisaha a, Chakkrapan Nerungsi a, Supitchaya Iamsaard a, Tienthong Thongpanchang a,b,
*
a Department of Chemistry and Center for Innovation in Chemistry, Faculty of Science, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand
b National Center for Genetic Engineering and Biotechnology, Thailand Science Park, Klong Luang, Patumthani 12130, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
The chemistry of oxiranyl remote anions derived from
a
,b-epoxypyridines is investigated. Deprotonation
Received 18 February 2009
Revised 10 April 2009
Accepted 28 April 2009
Available online 3 May 2009
of
a,b-epoxy pyridines at the b-position and reactions of the corresponding anions with a variety of
electrophiles are found to be highly regioselective, possibly as a consequence of stabilization from the
chelation between lithium and the pyridine moiety in the form of a five-membered cyclic intermediate.
Ó 2009 Elsevier Ltd. All rights reserved.
The chemistry of oxiranyl remote anions, although in its early
stage, has received significant attention due to unique and fasci-
nating chemical characteristics and its high potential as a new
approach towards substituted epoxides, which are key precursors
in natural products synthesis.1,2 As revealed in the literature, the
generation of oxiranyl remote anions and their reactions can be
exemplified as shown in Scheme 1. It was suggested that the stabil-
ity of the anions could be promoted by chelation between lithium
and the carbonyl oxygen of ketone 2,3 ester 4,1 lactone or imide 6,4
or the nitrogen of oxazoline 8.2 These groups apparently used lone
pair electrons to promote anion stabilization via chelation.
Pyridine is a fundamentally important heterocyclic aromatic
compound which has been used as a directing group in coordina-
tion chemistry.5 In principle, the pyridyl group attached to an
epoxide would also serve as a lithium-chelator and thus stabilize
the oxiranyl remote anion 10 (Scheme 1). To further extend the
chemistry and synthetic utility of the oxiranyl remote anion inter-
mediates, we report here our investigations on the pyridine stabi-
lized oxiranyl remote anion and its reactions with electrophiles.
In analogy to compound 1, epoxypyridine 9 in which the stabi-
lizing group is pyridine instead of a ketone was prepared following
the reaction summarized in Scheme 2. Treatment of 2-picoline 11
with n-BuLi then with PhCHO gave, after dehydration, alkene 13.
Two-step epoxidation of 13 with NBS in dioxane-H2O (2:1), fol-
lowed by base-induced epoxide ring closure gave the desired prod-
uct 9.
trophile, could be deduced by HMBC in which the key correlations
were those between Hy and pyridine carbons C3, C4 and C5 (Fig. 1).
In principle, two major factors that govern the regioselectivity
of the deprotonation could be envisioned; (i)
a-stabilization from
the phenyl group7 and/or (ii) b-stabilization through coordination
between the pyridine nitrogen and lithium in the form of a five-
membered cyclic chelate (intermediate 10, Scheme 1). To substan-
tiate the significance of each factor, the chemistry of the oxiranyl
remote anion derived from epoxypyridine 15 of which the phenyl
group was relocated to the
investigated.
a-position of the epoxypyridine was
Epoxypyridine 15 could be prepared straightforwardly via the
Corey-Chaykovsky reaction between 2-benzoylpyridine and trim-
ethylsulfoxonium iodide.8 Treatment of epoxy-pyridine 15 with
LTMP in the presence of a variety of electrophiles including TMSCl,
PhCOPh, MeCOMe and ClCO2Et yielded substituted products 16a–d
as summarized in Table 2.
Interestingly, the reaction provided the products in which the
substituents were oriented regioselectively syn to the pyridine
group as confirmed by NOESY experiments (Fig. 2). For example,
in the case of 16a, correlations between a methyl of the TMS group
and Ha and Hb of the pyridine ring as well as between Hy and HA of
the phenyl ring were observed. Moreover, the observation of the
disubstituted product 16d, entry 4, could be rationalized consider-
ing that the first deprotonation–substitution occurred at Hx (via
the b-anion, governed by the pyridine moiety), followed by depro-
Treatment of epoxypyridine 9 with lithium 2,2,6,6-tetrame-
thylpiperidide (LTMP) in the presence of a variety of electrophiles,
including TMSCl, EtI, MeCOMe, MeCONMe2 and cyclohexanone,
gave the substituted products 14a–e in moderate6 to good yields
as shown in Table 1. The regiochemistry of the substituted
products 14, wherein Hx was abstracted and replaced by an elec-
tonation–substitution at Hy (via the a-anion of the ester group).
The regiochemical outcomes of the aforementioned reactions
unambiguously demonstrate the significance of the chelation
effect from pyridine in the induction of the regioselectivity of
b-deprotonation. However, the decrease in yield compared between
thereaction of compounds 9 (Table 1) and 15 (Table 2) also alludes to
participation in anion stabilization of the phenyl group.
To establish that the regioselectivity of deprotonation in 9 was
indeed a consequence of the stabilization effect from pyridine
through chelation, cis-epoxide 20 was prepared. As shown in
* Corresponding author. Tel./fax:+66 2 201 5139.
E-mail address: tettp@mahidol.ac.th (T. Thongpanchang).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.106

4218
P. Saisaha et al. / Tetrahedron Letters 50 (2009) 4217–4220
Keto- stabilized
oxiranyl anion
Ester- stabilized
oxiranyl anion
Lactone- and Imide- stabilized
oxiranyl anion
Pyridine- stabilized
oxiranyl anion
Oxazoline- stabilized
oxiranyl anion
O
H
H
H
O
X
H
Ph
CO2CH3
O
H
O
Ph
H3CO2C
N
H
Y
O
H
N
O
H
O
O
H3C
H
Ph
Ph
5
1
3
9
7
X = O, Y = H2
X = N(CH2)2CH3, Y = O
X = N(CH2)3CH3, Y = O
O
Li
Li
O
H
Ph
X
O
H
CO2CH3
N
H
O
Ph
O
H
O
O
Li
Y
N
O
H3CO
O
Li
Li
Ph
Ph
H3C
4
2
6
8
10
Present Work
Ref. 3
Ref. 1
Ref. 4
Ref. 2
Scheme 1. Formation of remote stabilized oxiranyl anions.
Scheme 3, Wittig reaction of 18 with 2-pyridinecarboxaldehyde
yielded cis-adduct 19 in 64% yield. Alkene 19 was then subjected
to epoxidation with NBS, dioxane-H2O (2:1) and finally, base-cata-
lyzed epoxide ring closure, to afford the desired product 20 in 33%
yield.
deprotonation at Hx of epoxypyridine 9 was the result of the
chelation effect from the pyridine and lithium in the form of
five-membered cyclic intermediate, instead of the acidity of
protons Hx or Hy.
Treatment of epoxide 20 with LTMP and then quenching with
CD3OD yielded ketone 21 exclusively, without any deuterium
incorporation (Scheme 4). The regiochemistry of the product was
assigned by HMBC experiments of which correlations between
Table 1
Lithiation and substitution reactions of a,b-epoxypyridine 9
the
a-methylene proton and the phenyl carbons were observed
Hy
O
Hy
O
3 eq LTMP/ 3.6 eq electrophile
N
N
exclusively (Fig. 3).
º
Hx
E
THF/ -78 C/ 5 h
Formation of 21 could take place via a mechanism similar to
that reported by Hodgson et al.,9 as shown in Scheme 5. In this
case, due to the diminishing chelation by the pyridine moiety,
the regioselectivity of the deprotonation was thus influenced by
the acidity of protons Hx and Hy. Because of its greater acidity,10
9
14a-14e
Entry
1
Electrophile
TMSCl
Product (%yield)
proton abstraction from epoxide 20 occurred at the
a-position to
H
the pyridine group (Hy-abstraction). The lithiated species then
directed the addition of LTMP to the epoxide regioselectively at
the carbon adjacent to the pyridine group, leading to the epoxide
ring opening to afford dianion 22. Elimination of Li2O from dianion
22 gave enamine 23. Upon normal work-up, ketone 21, in which
the carbonyl group is adjacent to the pyridine group was thus
obtained. This finding confirmed that the highly regioselective
(94)
14a
N
O
TMS
H
O
N
2
3
4
Etl
14b (44)
Et
1. n-BuLi/ -78 ºC to 0 ºC
OH
H
1h
N
N
O
MeCOMe
MeCONMe2
14c
14d
(55)
(56)
2. PhCHO/ -78 ºC/ 5 h
N
CH3
HO
Me
11
12 (66%)
Me
p-TsOH/ toluene
H
reflux/ 6 h
H
N
O
Me
1. NBS/ dioxane-H2O/
rt/ 15 h
O
H
O
N
N
2. 1 N NaOH/ i-PrOH/
H
H
rt/ 5 h
N
O
H
5
Cyclohexanone
(67)
14e
HO
13 (96%)
Scheme 2. Preparation of epoxypyridine 9.
9 (59%)

P. Saisaha et al. / Tetrahedron Letters 50 (2009) 4217–4220
4219
n-BuLi
Ph3PCHPh
Ph3PCH2Ph Br
3
-78 ºC to rt/ 1 h
4
2
1
17
18
H
yH
O
N
H
H
TMS
N
CHO
-78 ºC to rt/ 5 h
H
H
14a
Figure 1. Key HMBC correlations in compound 14a.
1. NBS/ dioxane-H2O/
rt/ 15 h
H
H
H
O
H
N
N
2. 1 N NaOH/ i-PrOH/
rt/ 5 h
Table 2
Lithiation and substitution reactions of
a
,b-epoxypyridine 15
20 (33%)
19 (64%)
Scheme 3. Preparation of epoxypyridine 20.
3 eq LTMP/ 3.6 eq electrophile
THF/ -78 ºC/ 5 h
N
N
O
Hy
O
Hy
Hx
E
15
16a-16d
Entry
1
Electrophile
TMSCl
Product (%yield)
Hy
O
Hx
1. LTMP/ -78 ºC/ 30 min
N
N
2. CD3OD/ -78 ºC/ 5 h
O
N
O
16a
16b
16c
(73)
(77)
20
21 (75%)
TMS
H
Scheme 4. Deprotonation of epoxypyridine 20 with LTMP.
N
HO
2
3
4
PhCOPh
MeCOMe
ClCO2Et
O
H
3
Ph
Ph
4
2
H
H
1'
1
2'
3'
N
O
N
HO
Me
1'
(29)
(16)
O
H
2'
21
Me
Figure 3. Key HMBC correlations in ketone 21.
N
16d
O
N TMP
EtO2C
CO2Et
Li
Hy
O
Hx
LTMP/ -78 ºC
30 min
N
Hx
OLi
Hc
N
20
22
Hb
Ha
Hd
N
- Li2O
TMP
TMP =
O
HA
H3C Si
H3C
Hy
CH3
N
16a
work-up
N
Figure 2. Key NOE correlations in compound 16a.
O
21
23
In conclusion, this investigation has described the highly
regioselective formation of oxiranyl remote anions derived from
Scheme 5. Proposed mechanism for the generation of ketone 21.
a,b-epoxypyridines. It was also found that the stabilization from
the chelation between the lithium and the pyridine moiety in the
form of a five-membered cyclic intermediate played a key role in
the regioselectivity. In addition, the phenyl group at the b-position
of the a,b-epoxypyridine could also facilitate the formation of the
oxiranyl anion, thus enhancing the yields of the substituted
2,2,6,6-tetramethylpiperidine (0.32 mL, 1.90 mmol) in THF
(7 mL)) was added a solution of trans-2-(3-phenyloxiran-2-yl)pyr-
idine 9 (100.0 mg, 0.51 mmol) and freshly distilled trimethylsilyl
chloride (0.23 mL, 1.82 mmol) in THF (3 mL) at À78 °C. The reac-
tion mixture was stirred at À78 °C for 5 h before quenching with
saturated ammonium chloride solution. The crude mixture was
extracted with 20 mL CH2Cl2 thrice and the combined organic layer
was washed with H2O, dried over Na2SO4 and the mixture was
products.
General procedure for lithiation and substitution reactions of a,b-
epoxypyridine 9. To a solution of LTMP (1.52 mmol, generated
in situ from n-BuLi (1.33 N in hexanes, 1.14 mL, 1.52 mmol) and

4220
P. Saisaha et al. / Tetrahedron Letters 50 (2009) 4217–4220
evaporated to dryness. Purification by preparative thin layer chro-
matography (SiO2; 5% EtOAc/hexane) gave 2-(3-phenyl-3-(tri-
methylsilyl)oxiran-2-yl)pyridine 14a (129.5 mg, 0.48 mmol, 94%
yield) as a white solid. mp 48–51 °C. 1H NMR (300 MHz, CDCl3):
d À0.10 (s, 9H, Si(CH3)3), 4.24 (s, 1H, Hx), 7.32–7.39 (m, 2H,
1ArH, Hb), 7.42–7.47 (m, 2H, 2ArH), 7.53–7.59 (m, 3H, 2ArH, Hd),
7.80 (td, J = 7.68, 1.46 Hz, 1H, Hc), 8.74 (d, J = 4.87 Hz, 1H, Ha);
13C NMR (75 MHz, CDCl3): d À2.0, 63.2, 65.5, 121.6, 122.6, 126.0,
126.5, 128.0, 136.1, 142.7, 148.9, 156.9; IR (cmÀ1): 3057, 3023,
2900, 1590, 1568, 1494, 1471, 1446, 1432, 1247, 839, 776, 755,
703; exact mass: m/z [M+H+] found 270.1141.
article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.04.106.
References and notes
1. Lertvorachon, J.; Thebtaranonth, Y.; Thongpanchang, T.; Thongyoo, P. J. Org.
Chem. 2001, 66, 4692–4694.
2. (a) Capriati, V.; Degennaro, L.; Flavia, R.; Florio, S.; Luisi, R. Org. Lett. 2002, 4,
1551–1554; (b) Capriati, V.; Degennaro, L.; Florio, S.; Luisi, R.; Punzi, P. Org. Lett.
2006, 8, 4803–4806; (c) Florio, S.; Perna, F. M.; Luisi, R.; Barluenga, J.; Fananas,
F. J.; Rodriguez, F. J. Org. Chem. 2004, 69, 9204–9207.
3. Baramee, A.; Clardy, J.; Kongsaeree, P.; Rajviroongit, S.; Suteerachanon, C.;
Thebtaranonth, Y. Chem. Commun. 1996, 1511–1512.
4. Chaiyanurakkul, A.; Jitchati, R.; Kaewpet, M.; Rajviroongit, S.; Thebtaranonth,
Y.; Thongyoo, P.; Watcharin, W. Tetrahedron 2003, 59, 9825–9837.
5. (a) Itami, K.; Nokami, T.; Ishimura, Y.; Mitsudo, K.; Kamei, T.; Yoshida, J. J. Am.
Chem. Soc. 2001, 123, 11577–11585; (b) Fort, Y.; Rodriguez, A. L. J. Org. Chem.
2003, 68, 4918–4922.
Acknowledgements
6. Aside from TMSCl, the decrease in yield could also reflect the low-compatibility
nature of electrophiles with LTMP.
Fellowships from the Development and Promotion of Science
and Technology Talents program (DPST), the Royal Golden Jubilee
(RGJ) Scholarship and Post-Graduate Education and Research in
Chemistry (PERCH-CIC) for P.S., C.N. and S.I. and research support
from the Thailand Research Fund (RMU4980021) and from the
Commission on Higher Education, Ministry of Education are grate-
fully acknowledged.
7. For selected references on phenyl stabilized oxiranyl anions, see: (a) Capriati,
V.; Florio, S.; Luisi, R. Chem. Rev. 2008, 108, 1918–1942. and references cited
therein; (b) Capriati, V.; Florio, S.; Luisi, R. Synlett 2005, 1359–1369; (c)
Hodgson, D. M.; Gras, E. Synthesis 2002, 1625–1642; (d) Capriati, V.; Florio, S.;
Luisi, R.; Salomone, A. Org. Lett. 2002, 4, 2445–2448.
8. (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84, 867–868; (b). Synth.
Commun. 2003, 33, 2135–2143.
9. (a) Hodgson, D. M.; Bray, C. D.; Kindon, N. D.; Reynolds, N. J.; Coote, S. J.; Um, J.
M.; Houk, K. N. J. Org. Chem. 2009, 74, 1019–1028; (b) Hodgson, D. M.; Bray, C.
D.; Kindon, N. D. J. Am. Chem. Soc. 2004, 126, 6870–6871.
Supplementary data
10. Although the pKa of both Hx and Hy in this particular system has not been
reported, it could be postulated, based on the pKa of 2-methylpyridine and
toluene, that Hy is more acidic than Hx Fraser, R. R.; Mansour, T. S.; Savard, S. J.
Org. Chem. 1985, 50, 3232–3234.
Supplementary data (1H and 13C NMR spectra of compounds 9,
14a–e, 15, 16a–d, 20 and 21 are available) associated with this