Tandem one-pot synthesis of α-(aminomethylene)-γ-butyrolactones via regioselective epoxide ring-opening with the Blaise reaction intermediate

Article abstract of DOI:10.1016/j.tetlet.2010.10.108

A novel tandem one-pot method for the synthesis of α-aminomethylene- γ-butyrolactone derivatives has been developed through the regioselective epoxide opening reactions with the Blaise reaction intermediates, generated by the reaction of a Reformatsky rea

Full text of DOI:10.1016/j.tetlet.2010.10.108

Tetrahedron Letters 51 (2010) 6893–6896
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Tandem one-pot synthesis of
a-(aminomethylene)-c-butyrolactones via
regioselective epoxide ring-opening with the Blaise reaction intermediate
Young Ok Ko a, Yu Sung Chun a, Youngmee Kim a, Sung Jin Kim a, Hyunik Shin b, , Sang-gi Lee a,
⇑
⇑
a Department of Chemistry and Nano Science (BK21), Ewha Womans University, Seoul 120-750, Republic of Korea
b Chemical Development Division, LG Life Science, Ltd/R&D, Daejeon 350-380, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel tandem one-pot method for the synthesis of
a
-aminomethylene-
c
-butyrolactone derivatives has
Received 17 September 2010
Revised 19 October 2010
Accepted 22 October 2010
Available online 28 October 2010
been developed through the regioselective epoxide opening reactions with the Blaise reaction interme-
diates, generated by the reaction of a Reformatsky reagent with nitriles. Formation of a modified Blaise
reaction intermediate by the addition of a stoichiometric amount of n-BuLi followed by slow addition
of epoxide is required for the good yield of c-butyrolactones.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Tandem reaction
Blaise reaction intermediate
Epoxide opening
Butyrolactone
Regioselectivity
Tandem and cascade reactions have attracted significant atten-
tion because of their undeniable benefits such as atom economy
and one-pot operation with maximization of molecular complex-
icity. Indeed, the device and implementation of tandem reactions
are challenging facets and have become increasingly important in
organic synthesis.1 We have recently interested in the application
of the Blaise reaction intermediate 2,2 generated by nucleophilic
addition of a Reformatsky reagent to nitriles, for tandem bond
Re-catalyzed cross-coupling of nitrile with lactones is the only
general one-pot method for this class of compounds.7 In this con-
text, our tandem process not only discloses the distinctive reac-
tivity profile of the Blaise reaction intermediate in the epoxide
ring-opening reaction but also provides a new method to synthe-
size b-substituted 3 or
c-substituted a-aminomethylene-c-buty-
rolactone derivatives 4 from nitriles in one-pot manner.
Initially, we anticipated that the Blaise reaction intermediate
could act as a nucleophile in the epoxide ring-opening since it
can be considered as a nitrogen isostere of the zinc enolate of the
b-ketoesters.8 In this scenario, we assumed that the zinc(II) com-
plex 2 may act dual functions as a Lewis acid to activate the epox-
ide ring and as a nucleophile. We commenced our investigation
with the Blaise reaction intermediate 2a (R1 = Ph, R = Et), formed
formations, and demonstrated its nucleophilic nature:
a-carbon
and/or b-nitrogen act as nucleophilic sites allowing tandem syn-
thesis of
a a
-acylated,3a,b -vinylated b-enaminoesters,3c and 2-
pyridones.3d As the result of our continued research on the Blaise
reaction intermediate, we report herein a novel tandem one-pot
synthesis of b-substituted 3 or
ene- -butyrolactones 4 via regioselective epoxide opening reac-
tion with the Blaise reaction intermediate 2 (Scheme 1).
-Lactones are ubiquitous in many natural products and bio-
c-substituted a-aminomethyl-
c
c
logically active compounds, and also used as a versatile building
block for the synthesis of a wide range of bioactive compounds.4
Although a variety of synthetic routes have been developed,5
nucleophilic epoxide ring-opening with enolates followed by
intramolecular transesterification is the most general synthetic
O
H2N
O
R1
O
CO2R
ZnBr
Br
R2
or
Zn
3
R2
R1 CN
HN
R1
O
method for
c
-butyrolactones.6 However, in the literature, there
-aminom-
-butyrolactones from nitriles: the recently developed
O
1
H2N
R1
are very limited precedents for one-pot synthesis of
a
OR
ethylene-
c
2
O
R2
4
⇑
Corresponding authors. Tel.: +82 2 3277 4505; fax: +82 2 3277 3419 (S.-g.L.).
E-mail address: sanggi@ewha.ac.kr (S.-g. Lee).
Scheme 1. Strategy for the tandem one-pot synthesis of c-butyrolactones.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.108

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Y. O. Ko et al. / Tetrahedron Letters 51 (2010) 6893–6896
(>98% conversion by GC) by the reaction of benzonitrile (1a) with a
Reformatsky reagent generated in situ from ethyl bromoacetate
(1.5 equiv) and zinc (3.0 equiv) in THF. To this solution was added
styrene oxide (1.2 equiv) at 0 °C, and the reaction continued for
24 h at room temperature to afford, after workup with satd NH4Cl
Br
Bu
Zn
Zn
HN
O
HN
O
nBuLi
LiBr
Ph
OEt
Ph
OEt
O
2a
O
2a'
aqueous solution, the b-phenyl substituted a-aminomethylene-c-
Ph
Ph
butyrolactone 3a in 43% yield with exclusive regioselectivity re-
sulted from the epoxide ring-opening at the more substituted car-
bon (entry 1, Table 1).
NH
O
NH
O
O
To improve the moderate yield, we first varied the reaction
temperature. Unfortunately, the yield was gradually dropped as
the reaction temperature increased resulting 3a in 38% at room
temperature (entry 2, Table 1) and in 31% at THF reflux temper-
ature (entry 3, Table 1). Addition of Lewis acidic ZnBr2 or pro-
longed addition of epoxide did not improve the yield (entries 4
and 5, Table 1). Under these reaction conditions, all epoxide
was consumed, but the Blaise reaction intermediate was always
remained. This observation suggested that the epoxide may react
with other nucleophiles such as Ia and EtOZnBr, which may be
generated during the reactions. The lactonization reaction of the
initially formed Ia may compete with epoxide ring-opening reac-
tion affording oligomers. In addition, EtOZnBr, generated after
lactonization of Ia, could also react with epoxide (Scheme 2). To
solve this problem, we added an equivalent amount of nBuLi to
generate the butylzincate 2a0 via ligand exchange with zinc bro-
mide. With this zinc species, the EtOZnBu would be generated
after lactonization, and then the proton exchange between II
and EtOZnBu could produce the non-nucleophilic Bu–H and eth-
oxyzincate IIIb, which can be converted into product 3a after
workup with satd NH4Cl aqueous solution (Scheme 2). Thus,
1.0 equiv of nBuLi was added to the Blaise reaction intermediate
at 0 °C, and then styrene oxide was added at 35 °C. After 12 h,
the product 3a was obtained in a slightly increased yield of 50%
(entry 6, Table 1). When the epoxide (3.0 M in THF) was added
over 12 h, the yield increased further to 58% (entry 7, Table 1).
Eventually, we found that slow addition of epoxide at 45 °C is
critical for lactone ring formation, and thus, desired product 3a
could be obtained in 70% yield by addition of epoxide at 45 °C
for 12 h (entry 8, Table 1).8 However, addition of epoxide at
THF reflux temperature decreased the yield slightly to 65% (entry
9, Table 1). Moreover, as we observed in our previous tandem
Ph
OEt
Ph
OEt
Ph
OZnBr
oligomers
O
OZnBu
Ph
Ph
Ib
Ia
EtOZnBu
EtOZnBr
O
Ph
O
HN
Ph
HN
Ph
O
O
Ph
Ph
II
II
EtOZnBu
EtOZnBr
Bu-H
EtOH
Br
EtO
Zn
Zn
O
O
O
O
HN
Ph
HN
H2N
Ph
workup
workup
O
O
Ph
Ph
Ph
IIIb
Ph
3a
IIIa
Scheme 2. Proposed mechanism for epoxide opening with the Blaise reaction
intermediate 2a and the ligand exchanged butylzincate 2a0.
acylation reactions,3a the addition of other non-nucleophilic
strong bases such as NaHMDS (entry 10, Table 1) or BuLi (entry
t
11, Table 1) did not provide any beneficial effect on the Blaise
reaction intermediate toward epoxide ring-opening.
Under the optimized reaction conditions9 the generality of this
tandem reaction has been investigated with aromatic and aliphatic
nitriles to open the styrene oxide. As shown in Table 2, the Blaise
Table 1
Condition optimization for the tandem one-pot synthesis of b-phenyl substituted
c
-butyrolactone 3a via epoxide ring-opening with the Blaise reaction intermediatea
O
Zn (3.0 equiv)
BrCH2CO2Et
(1.5 equiv)
O
Br
H2N
Ph
Ph
Zn
(1.2 equiv)
O
Ph CN
HN
Ph
O
additive
temp (oC)
time (h)
THF, reflux,
1 h (>98%)
1a
Ph
OEt
3a
2a
Entry
Additive
Temp (°C)
Addition time (h)
Reaction time (h)
Yield (%)c
1
2
3
4
5
—
—
—
0
rt
Reflux
0
35
35
35
45
Reflux
45
—
—
—
—
12
—
12
12
12
12
12
24
12
12
12
12
3
12
12
12
12
12
43
38
31
40
37
50
58
70
65
37
55
ZnBr2 (30 mol %)
—
6b
7b
8b
9b
10b
11b
nBuLi (1.0 equiv)
nBuLi (1.0 equiv)
nBuLi (1.0 equiv)
nBuLi (1.0 equiv)
NaHMDS (1.0 equiv)
tBuLi (1.0 equiv)
45
a
b
c
Reaction carried out with 5.0 mmol scale of 1a and zinc was pre-activated with 5 mol % of methanesulfonic acid in THF reflux.
Additive was added at 0 °C.
Isolated yield after column chromatography.

Y. O. Ko et al. / Tetrahedron Letters 51 (2010) 6893–6896
6895
Table 2
Table 3
Condition optimization for the tandem one-pot synthesis of b-phenyl substituted
c
-
Condition optimization for the tandem one-pot synthesis of c-substituted c-
butyrolactone 3 via styrene oxide ring-opening with the Blaise reaction intermediatea
butyrolactone 4 via epoxide ring-opening with the Blaise reaction intermediate 2aa
nBuLi
(1.0 equiv)
0oC, 30 min
Zn (3.0 equiv)
Bu
Zn (3.0 equiv)
BrCH2CO2Et
(1.5 equiv)
nBuLi (1.0 equiv)
0 oC, 30 min
O
Br
BrCH2CO2Et
(1.5 equiv)
H2N
Ph
O
Zn
H2N
R1
Zn
HN
Ph
O
O
R1 CN
Ph CN
1a
HN
R1
O
O
THF, reflux,
1 h (>98%)
O
then
O
then
THF, reflux,
1 h (>98%)
1
OEt
R2
4
OEt
2a
R2
Ph
3
2
Ph
(1.2 equiv)
45 oC, 12 h
(1.2 equiv)
45 oC, 12 h
Entry
1
Epoxide
4
Yieldb (%)
Entry
1
3
Yieldb (%)
O
O
O
O
H2N
H2N
CN
BnO
4a (73)
O
1
2
3b (72)
Ph
1b
OBn
4a
O
Ph
O
O
H2N
Ph
H2N
CN
CN
C8H17
O
2
3
4b (57)
O
3c (72)
3d (61)
1c
C8H17
4b
Ph
H2N
O
H2N
Ph
O
O
F
O
O
4c (38)
3
1d
4c
Ph
F
a
O
O
Reaction carried out with 5.0 mmol scale of 1a and zinc was pre-activated with
5 mol % of methanesulfonic acid in THF reflux.
CN
H2N
b
O
4
5
6
7
3e (51)
3f (68)
3g(42)
3h(57)
Isolated yield after column chromatography.
O
1e
Ph
(Fig. 1).10 The electronic and steric properties of the substituent
showed marginal effect on the yield (entries 1–3, Table 2). With
aliphatic nitriles, the Blaise reaction intermediate formed from ste-
rically less demanded propionitrile 1f (entry 5, Table 2) showed
higher yield than that obtained from sterically bulky isovaleronit-
rile 1g (entry 6, Table 2).
We next investigate the aliphatic epoxides with the Blaise reac-
tion intermediate 2a (Table 3). In contrast to the styrene oxide, the
alkylsubstituted ethylene oxides are opened at sterically less de-
CH3CH2 CN
O
H2N
1f
O
Ph
O
O
H2N
H2N
CN
O
1g
Ph
Ph
CN
1h
manded terminal carbon to afford the c-substituted c-butyrolac-
O
tones as determined by X-ray analysis of 4a ( Fig. 1).11 These
results imply that the regioselectivity of epoxide ring-opening with
the Blaise reaction intermediate is dependent on the nature of
epoxides, that is, in styrene oxide, the regioselectivity of the nucle-
ophilic attack of the Blaise reaction intermediate was determined
by their electronic property, whereas steric factor is more domi-
nant in alkylsubstituted ethylene oxides. Even though the yield
was low, the less reactive cyclohexene oxide can also be opened
with the Blaise reaction intermediate to afford the cyclic lactone
4c.
Ph
Ph
Reaction carried out with 5.0 mmol scale of 1 and zinc was pre-activated with
a
5 mol % of methanesulfonic acid in THF reflux.
b
Isolated yield after column chromatography.
reaction intermediates, formed from all aromatic and aliphatic ni-
triles with a Reformatsky reagent, reacted with styrene oxide at
more substituted carbon to afford the corresponding b-substituted
In summary, we have developed a novel tandem one-pot meth-
od for the synthesis of b-substituted or
ethylene)- -butyrolactones through the regioselective epoxide
a
-aminomethylene-c-butyrolactones in moderate to good yields.
The structures of 3 were unambiguously determined by 1H and
13C NMR analyses as well as X-ray analyses of 3a and 3d
c-substituted a-(aminom-
c
Figure 1. X-ray structures of 3a, 3d, and 4a.

6896
Y. O. Ko et al. / Tetrahedron Letters 51 (2010) 6893–6896
Kitajima, M.; Kogure, N.; Nonato, M. G.; Takayama, H. J. Nat. Prod. 2010, 73,
1453.
ring-opening reaction with the Blaise reaction intermediate, where
the regioselectivity of epoxide ring-opening was largely deter-
mined by the steric and electronic nature of epoxide. A modifica-
tion of the addition of a stoichiometric amount of n-BuLi to the
Blaise reaction intermediate increased its reactivity toward the
5. Selected paper, see: (a) Movassaghi, M.; Jacobsen, E. N. J. Am. Chem. Soc. 2002,
124, 2456; (b) Gutierrez, J. L. G.; Jimenez-Cruz, F.; Epinosa, N. R. Tetrahedron
Lett. 2005, 46, 803; (c) Cho, C. S.; Shim, H. S. Tetrahedron Lett. 2006, 47, 3835; (d)
Dias, L. C.; de Castro, I. B. D.; Steil, L. J.; Augusto, T. Tetrahedron Lett. 2006, 47,
213; (e) Capuzzi, M.; Gambacotrta, A.; Gasperi, T.; Loreto, M. A.; Tardella, P. A.
Eur. J. Org. Chem. 2006, 5076; (f) Dohi, T.; Takenaga, N.; Goto, A.; Maruyama, A.;
Kita, Y. Org. Lett. 2007, 9, 3129; (g) Ramachandran, P. V.; Garrett, G.; Pratihar, D.
Org. Lett. 2007, 9, 4753; (h) Malkov, A. V.; Friscourt, F.; Bell, M.; Swarbrick, M.
epoxide opening reaction and lactonization to provide
a-(aminom-
ethylene)- -lactones efficiently. Further applications of the Blaise
c
reaction intermediate to other conceivable reactions are underway
and will be reported in due course.
ˇ
´
E.; Kocovsky, P. J. Org. Chem. 2008, 73, 3996; (i) Park, H. S.; Kwon, D. W.; Lee, K.;
Kim, Y. H. Tetrahedron Lett. 2008, 49, 1616.
6. (a) Taylor, S. K. Tetrahedron 2000, 56, 1149. and references therein; (b)
Domingo, L. R.; Gil, S.; Parra, M.; Segura, J. Molecules 2008, 13, 1303.
7. Takaya, H.; Ito, M.; Murahashi, S.-I. J. Am. Chem. Soc. 2009, 131, 10824.
8. When the reaction mixture was workedup with 3 N aqueous HCl solution, the
Acknowledgments
This work was supported by the Korea Research Foundation
(KRF-20090070898 and KRF-20090063004), the Seoul R&D fellow-
ship for Y. O. Ko, and RP-supporting from Ewha Womans Univer-
sity for Y. S. Chun.
a
-benzoylated b-phenyl-
previously reported that reaction of ethyl acetoacetate with styrene oxide in
the presence of sodium ethoxide afforded a mixture of b-phenyl- and -phenyl
substituted -acetyl- -butyrolactones in 45% and 55% yield, respectively, see:
Reitz, D. B. J. Org. Chem. 1979, 44, 4707.
9. Typical experimental procedure: to a stirred suspension of zinc dust (Aldrich,
10 m, 1.0 g, 15.3 mmol) was added 6 mol % of methanesulfonic acid in
c-butyrolactone was isolated in 68% yield. It has been
c
a
c
l
Supplementary data
anhydrous THF (2.5 mL). After 10 min reflux, benzonitrile 1a (0.8 mL,
7.6 mmol) was added. While maintaining reflux temperature, ethyl
bromoacetate (1.26 mL, 11.4 mmol) was added over 1 h by using a syringe
pump, and the reaction mixture was refluxed for 1 h. The reaction mixture was
cooled to 0 °C, and an equivalent amount of n-BuLi (4.75 mL of 1.6 M in hexane
solution, 7.6 mmol) was added at 0 °C. The 3.0 M solution of styrene oxide
(1.05 mL, 7.6 mmol) in THF was added slowly for 12 h at 45 °C. The reaction
was quenched with aqueous satd NH4Cl solution at room temperature, and
extracted with ethyl acetate (3 ꢀ 20 mL). The combined organic layer was dried
with MgSO4, filtered, and concentrated. The residue was purified by silica
chromatography to afford 3a (1.41 g, 70%).
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.10.108.
References and notes
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Brasche, G.; Gericke, K. Domino Reactions in Organic Synthesis; Wiley-VCH:
Weinheim, 2006; (c) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem.,
Int. Ed. 2006, 45, 7134; (d) Fürstner, A. Angew. Chem., Int. Ed. 2009, 48, 1364; (e)
Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. Rev. 1996, 96, 195.
2. (a) Blaise, E. E. C. R. Hebd. Seances Acad. Sci. 1901, 132, 478; (b) Blaise, E. E. C. R.
Hebd. Seances Acad. Sci. 1901, 132, 987; (c) Rathke, M. W.; Weipert, P. In Zinc
Enolates: The Reformatsky and Blaise Reaction in Comprehensive Organic
Reactions; Trost, B. M., Ed.; Pergamon: Oxford, 1991; Vol. 2, pp 277–299; (d)
Rao, H. S. P.; Rafi, S.; Padmavathy, K. Tetrahedron 2008, 64, 8037.
3. (a) Chun, Y. S.; Lee, K. K.; Ko, Y. O.; Shin, H.; Lee, S.-g. Chem. Commun. 2008,
5098; (b) Ko, Y. O.; Chun, Y. S.; Park, C.-L.; Kim, Y.; Shin, H.; Ahn, S.; Hong, J.;
Lee, S.-g. Org. Biomol. Chem. 2009, 7, 1132; (c) Chun, Y. S.; Ko, Y. O.; Shin, H.; Lee,
S.-g. Org. Lett. 2009, 11, 3414; (d) Chun, Y. S.; Ryu, K. Y.; Ko, Y. O.; Hong, J. Y.;
Hong, J.; Shin, H.; Lee, S.-g. J. Org. Chem. 2009, 74, 7556.
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Med. Chem. 2005, 5, 239; (b) González, A. G.; Silva, M. H.; Padrón, J. I.; León, F.;
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Samerasekera, R. Chem. Biodivers. 2009, 6, 1453; (f) Oliver, C. M.; Schaefer, A. L.;
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10. Crystal data for 3a (CIF deposition number: CCDC793437):
C17H15NO2,
momoclinic, P21/c, a = 6.0057(9) Å, b = 10.3248(15) Å, c = 22.742(3) Å,
V = 1407.8(4) Å3, Z = 4, Dc = 1.252 g/m3, F(0 0 0) = 560,7721 independent
collections with I/2
crystallographic analysis were measured on
diffractometer using graphite-monochromate Mo KR (k 0.71073 Å) and
scans in the range of h, 1.79 < h < 26.00. Crystal data for 3d (CIF deposition
number: CCDC 793438): 17H14FNO2, momoclinic, P21/c, a = 13.707(3) Å,
b = 9.6840(19) Å, c = 11.622(2) Å, V = 1437.9(5) Å3, Z = 4, Dc = 1.309 g/m3,
F(0 0 0) = 592,7634 independent collections with I/2 (I) (R1 = 0.0560,
wR2 = 0.1453), GOF (F2) = 0.945 data for crystallographic analysis were
measured on Bruker SMART APX diffractometer using graphite-
monochromate Mo KR (k 0.71073 Å) and -2 scans in the range of h,
1.59 < h < 26.00. Structure was solved and refined by using the SHEL V6.12.
11. Crystal data for 4a (CIF deposition number: CCDC 793436): 18H17NO3,
r
(I) (R1 = 0.0366, wR2 = 0.0531), GOF (F2) = 0.600 data for
a
Bruker SMART APX
-2
x
C
r
a
x
C
momoclinic, P21/c, a = 12.320(2) Å, b = 10.1168(16) Å, c = 12.1529(19) Å,
V = 1512.8(4) Å3, Z = 4, Dc = 1.297 g/m3, F(0 0 0) = 624,7619 independent
collections with I/2
crystallographic analysis were measured on
diffractometer using graphite-monochromate Mo KR (k 0.71073 Å) and
r
(I) (R1 = 0.0566, wR2 = 0.1605), GOF (F2) = 1.062 data for
a
Bruker SMART APX
-2
x
scans in the range of h, 2.61 < h < 26.00. Structure was solved and refined by
using the SHEL V6.12.