Facile and efficient synthesis of (r)-4-(benzyloxy)-3-methylbutanenitrile: Toward developing a versatile chiral building block

Article abstract of DOI:10.1002/cjoc.201200517

A practical synthesis of (R)-4-(benzyloxy)-3-methylbutanenitrile, a potential chiral building block, from the corresponding α-keto ester in high yield and large scale was presented. A practical synthesis of (R)-4-(benzyloxy)-3-methylbutanenitrile, a potential chiral building block, from the corresponding α-keto ester in high yield and large scale was presented. Copyright

Full text of DOI:10.1002/cjoc.201200517

NOTE
DOI: 10.1002/cjoc.201200517
Facile and Efficient Synthesis of (R)-4-(Benzyloxy)-3-
methylbutanenitrile: Toward Developing a Versatile
Chiral Building Block
Song, Zijiea(宋子杰)
Shi, Yongb(史勇)
Jin, Ronghuaa(金荣华)
Lin, Jingronga(林静容)
Tian, Weisheng*,b(田伟生)
a Laboratory of Resource Chemistry, Shanghai Normal University, 100 Guiling Road, Shanghai 200234, China
b The Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
A practical synthesis of (R)-4-(benzyloxy)-3-methylbutanenitrile, a potential chiral building block, from the
corresponding α-keto ester in high yield and large scale was presented.
Keywords synthetic methods, rearrangement, (R)-4-(benzyloxy)-3-methylbutanenitrile, chiral building block
Introduction
a green oxidation process which also enabled the access
of (R)-methyl 5-(benzyloxy)-4-methyl-2-oxopentanoate
(1) in kilogram scale.[2] The functionalities of 1 offered
us unique opportunity to develop a series of chiral
building blocks. Herein, we set (R)-4-(benzyloxy)-3-
methyl-butanenitrile (2)[3] as our primary target because
the versatility and stability of CN group make it an ex-
cellent candidate as a chiral building block.
Chiral methyl units widely exist in many natural
products and pharmaceutical compounds, and chiral
pool strategy is one of the best options for introducing
such units. The access to suitable chiral building blocks
(natural or unnatural) is therefore of great interest. The
variety of terpenes (citronellal, menthol, pulegone etc.,
Figure 1) are great but their utilization is greatly limited
for the lack of flexibility.[1] Commercial Roche esters
are versatile but expensive, hence, cheaper succeda-
neum and derivatives are still in demand.
Experimental
(R)-Methyl
5-(benzyloxy)-2-(hydroxyimino)-4-me-
thylpentanoate (3)
To a solution of α-keto ester (1, 100 g, 0.40 mol) in
EtOH (400 mL) was added NH2OH•HCl (34.5 g, 0.50
mol, 1.25 equiv.) and NaOAc (41.0 g, 0.50 mol, 1.25
equiv.). The resulting mixture was warmed to reflux for
4 h and quenched with water (600 mL). The mixture
was extracted with ethyl acetate (300 mL×4), and the
combined organic phase was washed with brine, dried
over Na2SO4. Concentration under reduced pressure
afforded crude 3 (106 g, quantitative yield) as colorless
liquid which was used in next step without further puri-
fication. Rf＝0.40 (silica gel, EtOAc∶hexane, 1∶4);
R
R = CH2OH: (R)-(+)-citronellol
R = CHO: (R)-(+)-citronellal
R = CO2H: (R)-(+)-citronellic acid
OH
(+/-)-menthol
HO
OMe
O
O
(R/S)-Roche ester
(R)-(+)-pulegone
O
1
[α]2D7 －15.5 (c 1.23, CHCl3); H NMR (400 MHz,
RO
BnO
OMe
X
n
CDCl3) δ: 7.36—7.29 (m, 4H), 7.29—7.23 (m, 1H),
4.46 (s, 2H), 3.75 (s, 3H), 3.41—3.27 (m, 2H), 2.71 (dd,
J＝12.8, 7.4 Hz, 1H), 2.60 (dd, J＝12.8, 7.2 Hz, 1H),
2.32 (dq, J＝13.5, 6.8 Hz, 1H), 0.96 (d, J＝6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ: 164.27, 151.99, 138.49,
128.29 (2C), 127.53 (2C), 127.44, 75.75, 72.85, 52.49,
31.63, 29.47, 17.36; IR (KBr) v: 3277, 3031, 2956, 2930,
O
n = 0,1, 2
R = Bn, n = 0, X = CN (2)
a-keto ester (1)
Figure 1 Selected chiral methyl building blocks.
As a part of our project to exclude CrO3 from the
degradation of steroidal sapogenins, we have developed
*
E-mail: wstian@sioc.ac.cn
Received May 26, 2012; accepted June 14, 2012; published online XXXX, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200517 or from the author.
Chin. J. Chem. 2012, XX, 1—3
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Song et al.
NOTE
－
1
(R), 21.3 min (S) at 0.7 mL/min flow rate. The racemic
nitrile 2 was synthesized from 2-methylpropane-1,3-diol
according the procedure described in reference [3].
2872, 1728, 1630, 1214, 1151, 736 cm ; MS (ESI) m/z:
288.2 ([M＋Na]＋); HRMS (ESI) calcd for C14H19N-
ONa＋ 288.1206, found 288.1213.
(R)-Methyl 5-(benzyloxy)-4-methyl-2-(((methyl-
sulfonyl)-oxy)imino)pentanoate (5)
Results and Discussion
Beckmann-type reaction was hence chosen to
cleave C(1)—C(2) bond (Scheme 1, type II, Beckmann
fragmentation).[4] Ketoxime 3 was easily prepared by
treating α-keto ester with NH2OH•HCl in ethanol and
several typical conditions of Beckmann reaction were
examined thereafter (Table 1). As expected, treatment
of ketoxime 3 in acidic medium generated nitrile 2 as
the only identifiable compound in moderate yield (Table
1, Entries 1—3).
To a well-stirred solution of crude 3 (0.40 mol) in
dry CH2Cl2/Et3N (400 mL/220 mL) was added MsCl
(55 g, 0.48 mol, 1.2 equiv.) under a ice-water bath. Af-
ter stirring for 90 min at room temperature, the mixture
was quenched by adding water (500 mL). The resulting
biphasic system was separated and the aqueous phase
was extracted with CH2Cl2 (300 mL×3), and the com-
bined organic phase was washed with brine, dried over
Na2SO4. Concentration under reduced pressure afforded
crude 5 (136.4 g) as a dark red liquid which was used in
next step without further purification. Analytic sample
was obtained after flash column chromatography on
silica gel. Rf＝0.8 (silica gel, EtOAc∶hexane: 1∶4);
1H NMR (400 MHz, CDCl3) δ: 7.34—7.24 (m, 5H),
4.41 (d, J＝1.7 Hz, 2H), 3.72 (s, 3H), 3.39 (dd, J＝9.3,
4.6 Hz, 1H), 3.24 (t, J＝8.9 Hz, 1H), 3.14 (s, 3H), 2.76
(dd, J＝12.8, 8.5 Hz, 1H), 2.68 (dd, J＝12.8, 6.2 Hz,
1H), 2.34—2.22 (m, 1H), 0.96 (d, J＝6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ: 162.64, 160.77, 138.15,
128.37 (2C), 127.61, 127.56 (2C), 75.35, 72.92, 53.13,
36.81, 32.43, 32.15, 17.28; IR (KBr) v: 3030, 2958,
Scheme 1 Transformations of ketoxime 3
OH
type II cleavage
N
NH2OH
keto ester
BnO
OMe
EtOH, NaOAc
(1)
O
3
type I cleavage
BnO
NHR
(Beckmann rearrangement)
table 1
OCO2Me
N
N
BnO
BnO
OMe
－
1
2
2937, 2859, 1735, 1623, 1217, 1186, 1096, 523 cm ;
MS (ESI) m/z: 365.9 ([M＋Na]＋); HRMS (MALDI)
calcd for C15H21NO6SNa＋ 366.0994, found 366.0982.
4
O
(Beckmann fragmentation)
Table 1 Conditions for transforming ketoxime 3 into nitrile 2
(R)-4-(Benzyloxy)-3-methylbutanenitrile (2)
Entry
Condition
SOCl2 or POCl3, CH2Cl2, RT to reflux, 5 h Complex
Resultsa
To a well-stirred solution of sodium methoxide (22.6
g, 0.42 mol, 1.05 equiv.) in MeOH (400 mL) was added
crude 5 dropwise at －10 ℃ (ice/EtOH bath). A white
deposition (MsONa) was formed and the reaction com-
pleted after 90 min. The mixture was filtered and
washed with ethyl acetate, and then the filtrate was
concentrated and diluted with water (200 mL). The re-
sulting mixture was extracted with ethyl acetate (300
mL×4), and the combined organic phase was washed
with brine, dried over Na2SO4 and concentrated. Distil-
lation under reduced pressure (141 ℃, 8 mmHg) gave
nitrile 2 (63.2 g, 84%, 98.5% ee by HPLC analysis) as a
colorless liquid. Rf＝0.8 (silica gel, EtOAc∶hexane:
1
2
3
4
Ac2O, 4 mol/L HCl, EtOH, reflux, 6 h
12 mol/L HCl, MeOH, reflux, 5 h
64% 2
55% 2
C4F9SO2F, DBU, CH2Cl2, 0 ℃, 30 min
45% 2＋41% 4
a Isolated yield.
The reaction condition was further screened and the
balance of mass was finally realized when 3 was treated
with C4F9SO2F in the presence of DBU in dry CH2Cl2 at
0 ℃, providing nitrile 2 and methyl carbonate 4 in
comparable yield (Entry 4). The generation of 4 indi-
cated that an external nucleophilic attack at ester group
[C(1)] might greatly facilitate the decarboxylation and
the cleavage of N—O bond during the reaction, hence
provided us definite clue for further optimization.
As outlined in Scheme 2, ketoxime 3 was trans-
formed into stable methanesulfonate 5, and the latter
was treated with stoichiometric amount of sodium
methoxide in dry methanol under an ice-ethanol bath for
90 min to furnish the desired nitrile 2 smoothly in ex-
cellent yield (84%—86% from α-keto ester 1) and high
enantiomeric excess (98.5% for every batch, inherited
from 1). Although the scope of this reaction was not
expanded yet, the effectiveness and robustness of our
procedure were tested by running the reaction at 100 g
1
1∶5); b.p. 282 ℃; [α]2D8 ＋30.3 (c 1.01, CHCl3); H
NMR (400 MHz, CDCl3) δ: 7.39—7.27 (m, 5H), 4.52 (s,
2H), 3.47 (dd, J＝9.4, 4.7 Hz, 1H), 3.31 (dd, J＝9.2, 8.0
Hz, 1H), 2.51 (dd, J＝16.7, 5.3 Hz, 1H), 2.39 (dd, J＝
16.7, 7.0 Hz, 1H), 2.24—2.11 (m, 1H), 1.09 (d, J＝6.9
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 138.14,
128.50, 128.37, 127.92, 127.79, 127.66, 118.75, 73.24,
31.14, 21.37, 16.26; IR (film) ν: 3088, 3031, 2964, 2929,
－
1
2860, 2245, 1731, 1604, 1206, 739 cm ; MS (ESI) m/z:
212.1 ([M＋Na]＋). Anal. calcd for C12H15NO: C 76.2,
H 7.94, N 7.41; found C 76.00, H 8.09, N 7.32; HPLC
(chiral) Chiralpak AS-H at 23 ℃, λ ＝214 nm,
hexane∶isopropanol: 98∶2, retention times 19.6 min
2
www.cjc.wiley-vch.de
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, XX, 1—3

Facile and Efficient Synthesis of (R)-4-(benzyloxy)-3-methylbutanenitrile
Scheme 2 Synthesis of nitrile 2
of manipulation will make nitrile 2 a competitive re-
agent for synthetic chemists. Currently, derivation and
commercialization of ketoester 1 and nitrile 2 are ongo-
ing in our laboratory.
OMs
N
MsCl
Ketoxime
(3)
BnO
OMe
O
MeO-
MeONa
MeOH
106 g
5
References
OMs
[1] Wyatt, P.; Warren, S. Organic Synthesis: Strategy and Control,
Wiley, Chichester, 2007.
N
nitrile (2)
63 - 65 g
84% - 86% yield
98.5% ee
-CO(OMe)2
-MsONa
BnO
OMe
O-
[2] (a) Tian, W.-S.; Liu, S.-S.; Shen, J.-W. CN 1341603A, 2002; (b)
Tian, W.-S.; Liu, S.-S.; Qiu, B.-K.; Wu, X.-J. CN 1475494A, 2004;
(c) Tian, W.-S.; Zhang, S.-J.; Wang, Y. CN 102010336A, 2011; (d)
Tian, W.-S.; Shi, Y. Progress in Chemistry 2010, 22, 538 (in
Chinese).
MeO
6
scale for three times.
[3] (a) Ghosh, A. K.; Wang, Y.; Kim, J. T. J. Org. Chem. 2001, 66,
8973; (b) Ghosh, A. K.; Wang, Y. Tetrahedron Lett. 2000, 41, 2319.
[4] (a) Ferris, A.; Johnson, G.; Gould, F. J. Org. Chem. 1960, 25, 1813;
(b) Conley, R. T.; Lange, R. J. J. Org. Chem. 1963, 28, 210; (c)
Freeman, J. J. Org. Chem. 1961, 26, 3507; (d) Morita, K.-I.; Suzuki,
Z. J. Org. Chem. 1966, 31, 233.
Conclusions
We have developed a mild method for nitrile synthe-
sis from α-ketoester, by which we prepared (R)-4-(ben-
zyloxy)-3-methylbutanenitrile in large scale. The ease
(Lu, Y.)
Chin. J. Chem. 2012, XX, 1—3
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
3