Efficient activation of zinc: Application of the Blaise reaction to an expedient synthesis of a statin intermediate

Article abstract of DOI:10.1055/s-2004-831197

Efficient and practical in situ zinc activation was accomplished by treatment with catalytic amount of an organic acid. The protocol was applied successfully to the Blaise reaction of various nitriles. Noteworthy is the excellent Blaise transformation of (S)-4-chloro-3-trimethylsilyloxybutyronitrile (2b) into tert-butyl (S)-6-chloro-5-hydroxy-3-oxohexanoate (1), a key intermediate for the preparation of HMG-CoA reductase inhibitors (statins).

Full text of DOI:10.1055/s-2004-831197

PAPER
2629
Efficient Activation of Zinc: Application of the Blaise Reaction to an Expedient
Synthesis of a Statin Intermediate
a
a
a
a
a
a
A
H
pplication of
B
la
y
ise Reaction
u
to an Expedi
n
ent
S
ynthesis
i
of
a
S
k
tatin Intermediate Shin,* Bo Seung Choi, Ki Kon Lee, Hyeong-wook Choi, Jay Hyok Chang, Kyu Woong Lee,
a
b
Do Hyun Nam, No-Soo Kim*
a
Chemical Development Division, LG Life Sciences, Ltd./R&D, 104-1, Moonji-dong, Yusong-gu, Daejon 305-380, Korea
Faculty of Life Science Engineering, Youngdong University, San 12-1 Sulkye-ri Yeongdong-eup Yeongdong-gun Chungbuk, Korea
Fax +82(42)8665754; E-mail: hisin@lgls.co.kr
b
Received 21 May 2004; revised 4 June 2004
Abstract: Efficient and practical in situ zinc activation was accom-
plished by treatment with catalytic amount of an organic acid. The
protocol was applied successfully to the Blaise reaction of various
nitriles. Noteworthy is the excellent Blaise transformation of (S)-4-
chloro-3-trimethylsilyloxybutyronitrile (2b) into tert-butyl (S)-6-
chloro-5-hydroxy-3-oxohexanoate (1), a key intermediate for the
preparation of HMG-CoA reductase inhibitors (statins).
Key words: in situ zinc activation, Blaise reaction, statin interme-
diate
Scheme 1
results are gathered in Table 1. The Blaise reaction trans-
formation of benzonitrile and ethyl bromoacetate into eth-
The Blaise reaction (Scheme 1) was introduced to syn- yl benzoylacetate was used to gauge the effectiveness of
thetic organic chemists a century ago as an important the activation.
method for the preparation of b-keto esters and their pre-
cursors, b-aminoacrylates. However, in spite of its
Table 1 Effect of Acidity on the Activation of Zinc
straightforward introduction of versatile functionalities
from nitrile group, its use in organic chemistry was limit-
ed due to low yield, narrow scope, and undesired side re-
Entry Acid
pKa
Amount Conversiona,b
mol%) (%)
(
1
1
2
3
4
5
6
7
8
9
0
unactivated (control)
–
–
35
80
98
99
46
55
98
99
99
99
actions. These early problems were greatly improved by
2
Kishi’s modifications that use activated zinc prepared by
CH CO H
4.75
1.0
3
2
washing with a 3 N HCl solution and by adding the bro-
moacetate slowly to minimize self-condensation. Recent-
ClCH
2
CO H
2
2.85
0.23
1.0
3
4
ly, ultrasonic assistance and the use of added zinc oxide
CF CO H
1.0
3
2
have provided additional useful protocols for the Blaise
reaction.
CH SO H
–2.0
0.005
0.05
0.25
0.5
3
3
Although these modifications are significant improve-
ments over the original procedure, there is a substantial
need for further refinement of the reaction. A specific
shortcoming of the existing methods is the need for pre-
activation of the zinc. Also, optimal reaction conditions
typically require large excesses of zinc (usually 5–10
equiv) and of the bromoacetate (usually 3–5 equiv).
CH SO H
–2.0
–2.0
3
3
CH SO H
3
3
CH SO H
–2.0
3
3
CH SO H
–2.0
1.0
3
3
1
CF SO H
–13.0
1.0
3
3
In this paper, we describe a practical and simple execution
of the Blaise reaction using in situ activation of the zinc
metal.
a
The analyses were performed using GC: HP-5 column; injector:
2
80 °C; initial time and temp: 2 min and 50 °C; gradient: 10 °C/min;
final temp: 300 °C;, flow rate: 1 mL/min. Benzonitrile and ethyl ben-
zoylacetate were detected at 10.6 and 19.7 min, respectively.
Since aqueous hydrochloric acid wash is effective for zinc
activation removing the zinc oxide layer, it was thought
that an organic acid having a similar acidity would serve
b
All the reactions were quenched after 1.5 h and analyzed by GC.
the same function, and be compatible with the reaction We were delighted to have an immediate success. When 1
conditions. Based upon this assumption, various organic mol% of methanesulfonic acid was added for in situ acti-
5
,6
acids have been tested for in situ zinc activation and the vation of commercial zinc (5 equivalents), complete con-
version in the Blaise reaction of benzonitrile with ethyl
bromoacetate (4 equivalents) was observed by GC analy-
sis. Further optimization on the reduction of the use of
zinc and bromoacetate led to the conclusion that only 2
SYNTHESIS 2004, No. 16, pp 2629–2632
x
x.
x
x
.
2
0
0
4
Advanced online publication: 26.08.2004
DOI: 10.1055/s-2004-831197; Art ID: F07104SS
Georg Thieme Verlag Stuttgart · New York
©

2
630
H. Shin et al.
PAPER
equivalents of zinc and 1.6 equivalents of bromoacetate Table 2 The Blaise Reactions of Various Nitrilesa
are sufficient for complete conversion. The influence of
Entry Substrate
Product
Yield
the acidity and the stoichiometry of organic acids were
studied and it was found that the acidity of an organic acid
is critical for proper activation of zinc. Addition of acetic
acid provided 80% conversion (Table 1, entry 2), while
stronger acids such as chloroacetic, trifluoroacetic, meth-
anesulfonic, and trifluoromethanesulfonic acids led to
complete conversion. Using methanesulfonic acid as the
organic acid, we next examined the optimal amount of
acid required (Table 1, entries 5–8): A minimum of 0.25
mol% of methanesulfonic acid was necessary for com-
plete conversion (Table 1, entry 7). However, 0.5 mol%
of methanesulfonic acid (Table 1, entry 8) was generally
employed to ensure consistent results. We have also ob-
served that the Blaise reaction is quite tolerant of mois-
ture. We used commercial THF as solvent, which
contained 420 ppm of water by Karl Fisher titration. Even
THF with a water of up to 0.2% (wt/wt) gave consistently
successful results.
(
%)
1
77
86
2
3
4
5
66
91
75
The optimized Blaise reaction protocol was examined
with various nitriles and the results are summarized in
Table 2. Good to excellent isolated yields were observed
with aliphatic nitriles (Table 2, entry 1 and 2) as well as
benzylic nitriles (Table 2, entries 3 and 4). Aromatic ni-
triles also showed good yields regardless of their electron-
ic character.
6
7
67
77
85
Noteworthy is the conversion of (S)-4-chloro-3-trimethyl-
silyloxybutyronitrile (2b) to tert-butyl (S)-6-chloro-5-hy-
droxy-3-oxohexanoate (1), a key intermediate for the
8
7
preparation of HMG-CoA reductase inhibitors (Table 2,
entry 8 and Scheme 2). The known methods are based
upon the Claisen condensation of ethyl (S)-4-chloro-3-hy-
a
All the reactions were performed with 2 equiv of zinc and with slow
droxybutyrate with an excess of the lithium enolate of addition of 1.6 equiv of bromoacetate over 1 h. After addition, the
8
tert-butyl acetate and enzyme-mediated enantioselective mixture was refluxed for 0.5 h in THF.
9
reduction of tert-butyl 6-chloro-3,5-dioxohexenoate, re-
spectively. The former route is complicated by the forma-
tion of the side product 4. The latter method suffers the
limitation of being able to access only one of the two pos-
sible enantiomers.
Our route depicted in Scheme 2 eradicated the problems
associated with the precedents. Ring opening of (S)-epi-
1
0
chlorohydrin by sodium cyanide and subsequent protec-
tion of the secondary hydroxyl group by trimethylsilyl
1
1
group afforded (S)-4-chloro-3-trimethylsilyloxybuty-
ronitrile (2b) in good yield. At the epoxide opening stage,
maintaining the pH of the reaction in the range of 7.7 to
7
.9 was critical to the success of the reaction because un-
der more basic conditions the formation of 3-hydroxyglu-
taronitrile predominates. Blaise reaction of 2b with tert-
butyl bromoacetate provided the b-amino-a,b-unsaturated
ester intermediate 3, which was hydrolyzed by aqueous
HCl to cause concomitant hydrolysis of the enamine moi-
ety and deprotection of the trimethylsilyl group to afford
the b-keto ester 1 in 85% yield. Complete absence of the
Scheme 2
side product 4 clearly demonstrates the high functional Reagents and conditions: (a) NaCN, H SO , pH 7.7–7.9, –20 °C,
2
4
group compatibility of the optimized Blaise reaction con- 87%; (b) TMSCl, HMDS, 98%; (c) BrCH
ditions.
CO
Bu-t (1.6 equiv), Zn (2
2
2
equiv), MsOH (0.5 mol%), then 3 N HCl, 85%.
Synthesis 2004, No. 16, 2629–2632 © Thieme Stuttgart · New York

PAPER
Application of the Blaise Reaction to an Expedient Synthesis of a Statin Intermediate
2631
In conclusion, we have developed an efficient and practi- 13C NMR (100 MHz, CDCl
): d (keto form) = 195.6, 166.8, 140.0,
3
1
2
133.9, 132.3, 129.5, 127.5, 119.2, 61.5, 48.8, 14.0. d (enol form) =
cal in situ activation of zinc metal by treatment with an
catalytic amount of organic acid. The effectiveness of this
activation (use of 0.5 mol% of methanesulfonic acid)
leads to a significant reduction in the equivalents of zinc
and bromoacetate in the Blaise reaction to 2 and 1.6
equivalents, respectively. The established protocol was
successfully applied to the Blaise reactions of various ni-
1
1
72.6, 171.1, 135.8, 133.8, 131.2, 130.2, 127.3, 121.0, 93.2, 60.6,
4.3.
MS (ESI): m/z = 367 (2 M + Na), 195 (M + Na), 173 (M + H).
1
3
Ethyl 3-(3-Methoxyphenyl)- 3-oxopropionate
1
H NMR (400 MHz, CDCl ): d (keto form, 75%) = 7.50–7.35 (m, 3
3
H), 7.14 (m, 1 H), 4.21 (q, J = 7.2 Hz, 2 H), 3. 98 (s, 2 H), 3.86 (s,
triles and the expedient synthesis of tert-butyl (S)-6-chlo- 3 H), 1.26 (t, J = 7.2 Hz, 3 H). d (enol form, 25%) = 12.57 (s, 1 H),
ro-5-hydroxy-3-oxohexanoate (1).
7.50–7.35 (m, 3 H), 5.65 (s, 1 H), 4.27 (q, J = 7.2 Hz, 2 H), 3.84 (s,
3
H), 1.34 (t, J = 7.2 Hz, 3 H).
1
3
C NMR (100 MHz, CDCl ): d (keto form) = 192.4, 167.5, 160.0,
3
1
37.4, 129.8, 121.2, 120.4, 112.5, 61.5, 55.5, 46.1, 14.1. d (enol
b-Keto Esters; General Procedure
form) = 173.2, 171.3, 159.7, 134.9, 129.6, 118.5, 117.3, 111.2, 91.8,
To a stirred suspension of commercial zinc (zinc dust, <10 micron,
6
0.4, 55.4, 14.3.
Aldrich, 2.0 equiv) in THF (5 mL/g) was added MeSO H (1 mol%)
3
at r.t. The mixture was refluxed for 10 min and nitrile was added.
To the mixture was added ethyl bromoacetate (1.6 equiv) over 1 h
using syringe pump. After 30 min, the mixture was cooled to 0–5 °C
and aq 3 N HCl (4 mL/g) solution was added dropwise. After 3–24
h, all the organic volatiles are removed in vacuo and the remaining
mixture was extracted with EtOAc (10 mL/g). The separated organ-
ic layer was washed with H O, dried (MgSO ) and concentrated.
MS (ESI): m/z = 467 (2 M + Na), 245 (M + Na), 223 (M + H).
(S)-4-Chloro-3-hydroxybutyronitrile (2a)
To a stirred solution of NaCN (92.6 g, 1.89 mol) in H O (560 mL)
2
was added dropwise conc. H SO (92.0 g, 0.94 mol) over 1 h at
2
4
–25 °C to adjust the pH of the reaction mixture in the range of 7.7
to 7.9. To the mixture was added dropwise (S)-epichlorohydrin
(139.8 g, 1.51 mol). After 12 h, the formed solid was filtered and the
filtrate was extracted with CH Cl (370 g). Concentration of the
2
4
Column chromatography of the residue afforded the desired product
Table 2).
(
2
2
separated organic layer and vacuum distillation of the residue pro-
vided 157.5 g (87%) of 2a as a colorless oil; bp 110 °C/1 mmHg.
1
3
Ethyl 3-Oxoheptanoate
1
H NMR (400 MHz, CDCl ): d = 4.20 (q, J = 7.2 Hz, 2 H), 3.43 (s,
H), 2.54 (t, J = 7.2 Hz, 2 H), 1.59 (m, 2 H), 1.28 (t, J = 7.2 Hz, 3
H), 0.91 (t, J = 7.2 Hz, 3 H).
1
3
H NMR (400 MHz, CDCl ): d = 4.21 (m, 1 H), 3.71 (dd, J = 11.6,
3
2
4
6
.8 Hz, 1 H), 3.67 (dd, J = 11.6, 5.6 Hz, 1 H), 2.74 (dd, J = 16.8,
.0 Hz, 1 H), 2.69 (dd, J = 16.8, 6.4 Hz, 1 H), 2.61 (d, J = 5.6 Hz,
1
3
C NMR (100 MHz, CDCl ): d = 203.0, 167.3, 61.3, 49.3, 42.7,
5.5, 22.1, 14.1, 11.7, 13.8.
1 H).
3
2
13
C NMR (100 MHz, CDCl ): d = 117.0, 67.2, 47.2, 23.2.
3
MS (ESI): m/z = 367 (2 M + Na), 195 (M + Na), 173 (M + H).
EI-MS: m/z = 122 (M + H + 2), 120 (M + H), 81 (M + 2 – CH CN),
2
7
9 (M – CH CN).
1
4
2
Ethyl 3-Cyclopropyl-3-oxopropionate
1
H NMR (400 MHz, CDCl ): d = 4.21 (q, J = 7.2 Hz, 2 H), 3.57 (s,
H), 2.04 (m, 1 H), 1.29 (t, J = 7.2 Hz, 3 H), 1.12 (m, 2 H), 0.97
3
(
S)-4-Chloro-3-trimethylsilyloxybutyronitrile (2b)
2
To a stirred solution of 2a (150 g, 1.25 mol) in toluene (700 mL)
(
m, 2 H).
was added hexamethyldisilazane (HMDS, 121 g, 0.75 mol) at 0 °C.
To the mixture was added Me SiCl (6.9 g, 0.05 mol) and the mix-
ture was warmed to r.t. After 8 h, aq 10% NH Cl solution was added
1
3
C NMR (100 MHz, CDCl ): d = 202.8, 167.2, 61.3, 50.0, 20.7,
3
3
1
4.1, 11.7.
4
and the organic layer was separated. Concentration of the separated
organic layer provided 229.5 g (98%) of 2b as a colorless oil.
MS (ESI): m/z = 335 (2 M + Na), 179 (M + Na), 157 (M + H).
Ethyl 4-(3,4-Dimethoxyphenyl)-3-oxobutyrate15
1
H NMR (400 MHz, CDCl ): d = 4.12 (m, 1 H), 3.54 (dd, J = 11.4,
3
1
H NMR (400 MHz, CDCl ): d = 6.85–6.71 (m, 3 H), 4.17 (q,
4.8 Hz, 1 H), 3.48 (dd, J = 11.4, 7.2 Hz, 1 H), 2.70 (dd, J = 16.6,
4.6 Hz, 1 H), 2.62 (dd, J = 16.6, 6.6 Hz, 1 H), 0.21 (s, 9 H).
3
J = 7.2 Hz, 2 H), 3.87 (s, 6 H), 3.76 (s, 2 H), 3.44 (s, 2 H), 1.27 (t,
J = 7.2 Hz, 3 H).
13
C NMR (100 MHz, CDCl ): d = 116.8, 68.5, 46.5, 24.1, 0.0.
3
1
3
C NMR (100 MHz, CDCl ): d = 200.8, 167.1, 149.2, 148.4, 125.6,
3
EIMS: m/z = 367 (2 M – CH ), 284 (2 M + H – TMS – CN), 264 (2
M – H – TMS – CN – H O), 176 (M – CH ), 93 (M + H – TMS –
3
1
21.8, 112.5, 111.4, 61.4, 55.9, 49.6, 48.0, 14.1.
2
3
MS (ESI): m/z = 289 (M + Na), 267 (M + H).
CN), 75 (M + H – TMS – CN – H O), 73 (TMS).
2
1
5
Ethyl 4-(4-Methoxyphenyl)-3-oxobutyrate
tert-Butyl (S)-6-Chloro-5-hydroxy-3-oxohexanoate (1)
To a stirred suspension of commercial zinc dust (8.3 g, 126 mmol)
1
H NMR (400 MHz, CDCl ): d = 7.12 (m, 2 H), 6.87 (m, 2 H), 4.17
q, J = 7.2 Hz, 2 H), 3.80 (s, 3 H), 3.76 (s, 2 H), 3.43 (s, 2 H), 1.26
3
(
(
1
in THF (60 mL) was added MeSO H (60 mg, 0.6 mmol) at r.t. The
3
t, J = 7.2 Hz, 3 H).
3
mixture was refluxed for 10 min and (S)-4-chloro-3-trimethylsily-
loxybutyronitrile (2b; 12.0 g, 63 mmol) was added. To the mixture
was added tert-butyl bromoacetate (19.7 g, 101 mmol) over 1 h us-
ing a syringe pump. After 30 min, the mixture was cooled to 0–5 °C
and aq 3 N HCl (40 mL) was added dropwise. After 2 h, all the or-
ganic volatiles were removed in vacuo and the remaining mixture
was extracted with EtOAc (60 mL). The separated organic layer
was washed with H O, dried (MgSO ) and concentrated. Column
C NMR (100 MHz, CDCl ): d = 200.8, 167.1, 158.9, 130.6, 125.2,
3
1
14.3, 61.3, 55.2, 49.1, 48.1, 14.0.
MS (ESI): m/z = 495 (2 M + Na), 259 (M + Na), 237 (M + H).
Ethyl 3-(2-Bromophenyl)-3-oxopropionate13
H NMR (400 MHz, CDCl ): d (keto form, 60%) = 7.64–7.24 (m, 4
H), 4.18 (q, J = 7.2 Hz, 2 H), 4.02 (s, 2 H), 1.24 (t, J = 7.2 Hz, 3 H).
d (enol form, 40%) = 12.42 (s, 1 H), 7.64–7.24 (m, 4 H), 5.45 (s, 1
H), 4.27 (q, J = 7.2 Hz, 2 H), 1.34 (t, J = 7.2 Hz, 3 H).
1
3
2
4
chromatography (EtOAc–hexane, 1:3) of the residue afforded 12.1
25
9b
g (85%) of 1 as a viscous oil; [a] –24.4 (c = 1.0, CHCl ) {Lit.
D
3
25
[
a]D –24.9 (c = 1.4, CHCl )}.
3
Synthesis 2004, No. 16, 2629–2632 © Thieme Stuttgart · New York

2
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H. Shin et al.
PAPER
1
H NMR (400 MHz, CDCl ): d (enol form, 5%) = 12.40 (s, 1 H),
(6) (a) About 7–8 mol% of trimethylsilyl chloride was used for
the activation of zinc. Under these conditions, complete
conversion of the Blaise reaction of benzonitrile with ethyl
bromoacetate was observed. (b) For the Reformatsky
reaction, see: Picotin, G.; Miginiac, P. J. Org. Chem. 1987,
52, 4796. (c) For the reaction with ethyl formate, see:
Gawronski, J. K. Tetrahedron Lett. 1984, 25, 2605.
3
5
(
1
.01 (s, 1 H), 4.19 (m, 1 H), 3.62 (dd, J = 11.2, 4.8 Hz, 1 H), 3.58
dd, J = 11.2, 5.6 Hz, 1 H), 2.56 (m, 1 H), 2.48 (br s, 1 H), 2.46 (m,
H), 1.48 (s, 9 H). d (keto form, 95%) = 4.32 (m, 1 H), 3.62 (dd,
J = 11.2, 4.8 Hz, 1 H), 3.58 (dd, J = 11.2, 5.6 Hz, 1 H), 3.42 (s, 2
H), 3.00 (d, J = 3.2 Hz, 1 H), 2.91 (dd, J = 17.6, 4.4 Hz, 1 H), 2.85
(
dd, J = 17.6, 7.2 Hz, 1 H), 1.49 (s, 9 H).
1
3
(7) Istvan, E. S.; Deisenhofer, J. Nature 2001, 292, 1160.
C NMR (100 MHz, CDCl ): d (enol form) = 193.2, 166.1, 93.1,
3
(
8) (a) Nishiyama, A.; Inoue, K. US Patent 6340767, 2000;
Chem. Abstr. 2001, 134, 41920. (b) Kizaki, N.; Yamada, Y.;
Yasohara, Y.; Nishiyama, A.; Miyazaki, M.; Mitsuda, M.;
Kondo, T.; Ueyama, N.; Inoue, K. WO 2000008011, 2000;
Chem. Abstr. 2000, 132, 166230. (c) Mitsuda, M.;
7
5
9.2, 69.0, 49.0, 39.7, 28.3. (keto form) = 202.7, 166.0, 82.5, 67.4,
1.1, 49.0, 46.4, 28.0.
ESI-MS: m/z = 496 (2 M + Na + 2), 494 (2 M + Na), 261 (M + Na
2), 259 (M + Na).
+
Miyazaki, M.; Inoue, K. US Patent 6344569, 1999; Chem.
Abstr. 1999, 131, 310642. (d) Thottathil, J. K.; Pendri, Y.;
Li, W.-S.; Kronenthal, D. R. US Patent 5278313, 1994;
Chem. Abstr. 1994, 120, 217700. (e) Scheffler, J.-L.; Bette,
V.-B.; Mortreux, A.; Nowogrocki, G.; Carpentier, J.-F.
Tetrahedron Lett. 2002, 43, 2679.
HRMS-ESI: m/z calcd for C H ClO Na: 259.0713; found:
1
0
17
4
2
59.0712.
Acknowlegment
We thank Dr. Chris Melville for critical proof reading of the manus-
cript.
(
9) (a) Wolberg, M.; Hummel, W.; Wandrey, C.; Muller, M.
Angew. Chem. Int. Ed. 2000, 39, 4306. (b) Wolberg, M.;
Hummel, W.; Wandrey, C.; Muller, M. Chem.–Eur. J. 2001,
7
, 4562. (c) Wolberg, M.; Muller, M.; Hummel, W. WO
References
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(
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(
(
2) Hannick, S. M.; Kishi, Y. J. Org. Chem. 1983, 48, 3833.
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(12) (a) The activation method was applied successfully to the
Reformatsky reactions of benzaldehyde and nonanal with
ethyl bromoacetate (1.3 equiv) in benzene to provide 79%
and 78% of the corresponding b-hydroxy esters,
respectively. For the Reformatsky reaction, benzene was
found to be the choice of solvent. Use of THF has resulted in
low yield. (b) For similar conditions of the Reformatsky
reaction except zinc activation method, see: Frankenfeld, J.
W.; Werner, J. J. J. Org. Chem. 1969, 34, 3689.
(13) (a) Spitzmiller, E. R. J. Am. Chem. Soc. 1947, 69, 2013.
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(
(
1997, 38, 443.
5) (a) In the literature, iodine and 1,2-dibromoethane were used
as in situ zinc activators. However, iodine and 1,2-
dibromoethane were found to be deleterious for the Blaise
reaction of benzonitrile with ethyl bromoacetate. Only 30%
and 18% of respective conversion were observed. (b) For
the use of iodine, see: Zitsman, J.; Johnson, P. Y.
Tetrahedron Lett. 1971, 12, 4201. (c) For the use of 1,2-
dibromoethane, see: Gaudemar, M. Tetrahedron Lett. 1983,
(14) (a) Capozzi, G.; Roelens, S.; Talami, S. J. Org. Chem. 1993,
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