Highly Z-selective synthesis of a,b-unsaturated nitriles using the Horner-Wadsworth-Emmons reaction

Article abstract of DOI:10.1016/j.tetlet.2013.02.020

A new HWE reagent, (o-tBuC6H4O)2P(O)CH2CN (2e), reacts with various types of aldehydes to give Z-a,bunsaturated nitriles with 86% to >99% Z-selectivity. Especially, the reaction of 2e with bulkier aldehydes, both aromatic and aliphatic, gave the Z-olefins with extremely high selectivity. The combination of t-BuOK and 18-crown-6 (1 equiv) is the base of choice for aromatic aldehydes and t-BuOK is generally the base of choice for aliphatic aldehydes.

Full text of DOI:10.1016/j.tetlet.2013.02.020

Tetrahedron Letters 54 (2013) 2026–2028
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Tetrahedron Letters
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Highly Z-selective synthesis of a,b-unsaturated nitriles using the
Horner–Wadsworth–Emmons reaction
⇑
Kaori Ando , Miho Okumura, Shigeo Nagaya
Department of Chemistry, Faculty of Engineering, Gifu University, Yanagido 1-1, Gifu 501-1193, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A new HWE reagent, (o-tBuC6H4O)2P(O)CH2CN (2e), reacts with various types of aldehydes to give Z-a,b-
Received 8 January 2013
Revised 30 January 2013
Accepted 6 February 2013
Available online 13 February 2013
unsaturated nitriles with 86% to >99% Z-selectivity. Especially, the reaction of 2e with bulkier aldehydes,
both aromatic and aliphatic, gave the Z-olefins with extremely high selectivity. The combination of
t-BuOK and 18-crown-6 (1 equiv) is the base of choice for aromatic aldehydes and t-BuOK is generally
the base of choice for aliphatic aldehydes.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
The HWE reaction
a,b-Unsaturated nitriles
Z-Selective
Stereoselectivity
Aldehydes
The stereochemistry of carbon–carbon double bonds is impor-
tant in exhibiting biological activity and other functionality. Fur-
thermore, alkenes are useful building blocks in stereo-specific
reactions for the construction of chiral centers, such as the Michael
reaction, chiral epoxidation, and dihydroxylation. Therefore, the
stereo-defined synthesis of carbon-carbon double bonds with high
selectivity is critically important. Although it is rather easy to obtain
the thermodynamically favored E-isomers, there are only a limited
number of methods for preparing the Z-isomers. During the course
of our study on the Z-selective Horner–Wadsworth–Emmons
(HWE) reactions, we prepared the reagent, (ArO)2P(O)CH2CO2Et 1,
methods are desirable, we decided to improve the Z-selective
HWE reagent 2a. In our study on the Z-selective HWE ester reagents
1, we found the ortho-substituted phenyl reagents (o-MeC6H4 and
o-iPrC6H4) to show higher Z-selectivity at low temperature. After
that, Touchard et al. reported improvement of the selectivity at
0 °C using the o-tBuC6H4 reagent.9,10 Here, we wish to report that
our new reagent (o-tBuC6H4O)2P(O)CH2CN 2e reacts with a variety
of aldehydes to give Z-a,b-unsaturated nitriles in high selectivity.
Diphenylphosphonoacetonitrile (2a) was readily prepared from
the reaction of acetonitrile and commercially available diphenyl
phosphorochloridate using 2 equiv of LDA in THF (Scheme 2). 2a
was obtained in 54% yield. This method is similar to Zhang’s meth-
od.5a The reagents 2b–2e were prepared in a similar way in 43–56%
yields using (ArO)2P(O)Cl, which were prepared from P(O)Cl3 and
2 equiv of ArOH and 2 equiv of Et3N in toluene in 78–88% yields ex-
cept for 3e (38% yield). Since the yield of 3e was low, the reagent 2e
was also prepared by the Arbusov reaction of phosphite 49 and bro-
moacetonitrile at 150 °C without solvent for 6 h in 51% yield. The
attempted synthesis of the p-ClC6H4 reagent from acetonitrile
and (p-ClC6H4O)2P(O)Cl was unsuccessful.
which gave Z-a,b-unsaturated esters highly selectively from the
reaction with aldehydes.1–3 We also prepared the reagent (PhO)2-
P(O)CH2CN 2a. Disappointingly, 2a reacted with aldehydes to give
a
,b-unsaturated nitriles with moderate Z-selectivity (80–83% Z for
3 examples) (Scheme 1).4 Later, Zhang et al. reported the synthesis
of 2a and the reaction with bulkier aldehydes such as pivalaldehyde
to give Z-a
,b-unsaturated nitriles highly selectively.5 However, the
reaction of 2a with benzaldehyde and less sterically hindered ali-
phatic aldehydes gave low selectivity (64–75% Z). The selective
preparation of monosubstituted Z-
a
,b-unsaturated nitriles have
The results of the HWE reaction of 2a–2e with benzaldehyde
are summarized in Table 1. After 2a was treated with t-BuOK in
THF at À78 °C for 15 min, the reaction with benzaldehyde was per-
formed at À78 °C. 5a was obtained in 97% yield and the Z/E ratio
was 80:2011 (entry 1). The same reaction at 0 °C gave lower
71:29 ratio (entry 2). The effect of base on the Z/E ratio was next
studied using Triton B, LDA, and NaH (entries 3–5). None of the
bases tested gave higher Z-selectivity compared with t-BuOK. Dis-
appointingly, the o-MeC6H4 reagent 2b and the o-iPrC6H4 reagent
also been reported by using the Peterson-type reaction,6 the Wit-
tig-type reaction,7 and other methods.8 Although some methods
gave monosubstituted Z-a,b-unsaturated nitriles highly selectively,
some require strong base or multi-step synthesis and some suffer
from substrate limitations. Since more general and practical
⇑
Corresponding author. Tel./fax: +81 58 293 2674.
E-mail address: ando@gifu-u.ac.jp (K. Ando).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.020

K. Ando et al. / Tetrahedron Letters 54 (2013) 2026–2028
2027
Table 2
1) base
(ArO)2P(O)CH2CN
The HWE reaction of 2e with aromatic aldehyde
R
CN
2) RCHO
Z
2
tBu
1) t-BuOK, THF
O
1 eq18-crown-6
O PCH2CN
R
CN
Scheme 1.
2 2e
2) RCHO
5
Z-
Entry
R
Condition
Yield
Z:E
1) 2 eq. LDA, THF, -78 °C, 15 min
(ArO)2P(O)CH2CN
CH3CN
1
2
3
4
5
6
7
8
9
Ph
À78 °C, 2 h
5a 78
5b 56
5b 79
5c 99
5d 84
5e 89
5f 79
5g 90
5g 79
5h 92
95:5
95:5
94:6
86:14
95:5
96:4
98:2
>99:1
93:7b
>99:1
yield
54%
2) (ArO)2P(O)Cl, -78 °C to 0 °C
p-MeC6H4
p-MeC6H4
p-MeOC6H4
p-ClC6H4
p-NO2C6H4
1-Naph
o-MeC6H4
o-MeC6H4
o-MeOC6H4
À78 °C, 4 h
a
b
c
d
e
2
Ar = Ph
À78 °C, 2 h to 0 °Ca
À78 to 0 °Ca
À78 °C, 2 h
3
= o-MeC6H4 56%
= o-iPrC6H4 50%
= p-MeOC6H4 43%
= o-tBuC6H4 46%
À78 °C, 2 h
À78 °C, 2 h to 0 °Ca
À78 °C, 2.5 h
À78 °C, 5 h
150 °C
(o-tBuC6H4O)2P(O)CH2CN
2e
(o-tBuC6H4O)2POEt + BrCH2CN
6 h
4
À78 to 0 °Ca
y. 51%
10
a
The reaction temperature was warmed over 1–2 h.
In the absence of 18-crown-6.
Scheme 2.
b
Table 1
The HWE reaction of 2 with benzaldehydea
proceeded slowly at À78 °C, Z-5f and Z-5h were obtained with
98:2 and >99:1 selectivity in good yields after warming up to
0 °C (entries 7 and 10). The reaction with o-methylbenzaldehyde
proceeded smoothly at À78 °C to give the olefin 5g with >99:1
Z-selectivity in 90% yield (entry 8). Even in the absence of
18-crown-6, Z-5g was obtained with 93:7 ratio (entry 9). These
successful results obtained from bulky aromatic aldehydes are
outstanding. We compared this nitrile HWE reaction with the ester
HWE reaction. When our ester reagent 1a1 was treated with NaH in
1) base, THF
(ArO)2P(O)CH2CN
Ph
CN
2) PhCHO
2
5a
Z-
Entry
2
Base
Condition
Yield (%)
Z:E
1
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2b
2c
2d
2e
2e
2e
2e
t-BuOK
t-BuOK
Triton B
LDA
À78 °C, 2 h
0 °C, 2 h
97
86
87
84
90
56
73
91
75
82
78
88
80:20
71:29
70:30
49:51
63:37
65:35
67:33
64:36
84:16
94:6
À78 °C, 2 h
À78 °C, 2 h
À78 °C, 2 h
À78 °C, 2.5 h
À78 °C, 2.5 h
À78 °C, 3 h
À78 °C, 2 h
À78 °C, 2 h
À78 °C, 2 h
À78 to 0 °C
NaHb
THF, the reaction with 1-naphthaldehyde gave Z-a,b-unsaturated
ester 6 with 93:7 Z-selectivity after aqueous work-up (Scheme 3).
However, the ratio was reduced to 79:21 after column chromatog-
raphy (silica gel/hexane–AcOEt (10:1)). The ratio was further
reduced to 56:44 by the treatment with silica gel in AcOEt for
30 min. On the other hand, the corresponding nitrile olefin was ob-
tained with 98:2 Z-selectivity after column chromatography. No
isomerization was detected in this case. Thus, a small nitrile group
can be useful for the preparation of sterically hindered synthetic
intermediates.
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOKb,c
t-BuOKc
NaH
10
11
12
95:5
64:36
a
b
c
Compound 2 was treated with base at À78 °C except for entries 5 and 10.
Compound 2 was treated with base at 0 °C.
1 equiv of 18-crown-6 was added.
The HWE reactions of 2e with various aliphatic aldehydes were
performed and the results are summarized in Table 3. Since the
reaction of 2e with aliphatic aldehydes hardly proceeded at
À78 °C, the reaction mixture was gradually warmed from À78 to
0 °C over 1–2 h after the addition of aldehydes. When 2e was trea-
ted with t-BuOK, the reaction with n-octanal gave 5i with 83:17 Z-
selectivity in 82% yield (entry 1). In the presence of 18-crown-6,
the selectivity was decreased (entry 2). By using NaH as base, the
selectivity was increased and the ratio 89:11 was obtained (entry
3). This selectivity was further improved to 90:10 by using 3 equiv
of NaH (entry 4).14 For the reaction with sterically more congested
aldehyde 7, t-BuOK was the base of choice. When the reaction was
performed at 0 °C using t-BuOK, 89:11 Z-selectivity was obtained
in 85% yield (entry 6). The reaction with an aldehyde having a sec-
ondary alkyl group, cyclohexanecarbaldehyde, was similarly per-
2c gave lower 65:35 and 67:33 ratios, respectively (entries 6 and
7). In order to see the electronic effect, the reactions of the p-
ClC6H4 reagent and the p-MeOC6H4 reagent 2d were planned.
Unfortunately, the p-ClC6H4 reagent was not obtained and 2d gave
low selectivity (entry 8). It seemed that the o-Me and o-iPr substit-
uents showed only an electron donating effect and their steric bulk
was not enough. Therefore, we prepared the o-tBuC6H4 reagent 2e.
Using the same condition as entry 1, the reaction of 2e gave a
slightly higher 84:16 ratio (entry 9). In the presence of 1 equiv of
18-crown-6, the selectivity was improved to 95:5 (entry 11). The
use of NaH as base resulted in low selectivity (entry 12). Thus,
the highest Z-selectivity was obtained using the reagent 2e and
t-BuOK as base in the presence of 18-crown-6 in THF at À78 °C.
We examined the HWE reaction of 2e with various aromatic
aldehydes in THF (Table 2).12 The reaction with p-methylbenzalde-
hyde at À78 °C was slow to give the olefin Z-5b in 56% yield with
95:5 ratio after 4 h (entry 2). When the reaction mixture was
warmed from À78 to 0 °C over 1–2 h, the yield was increased to
79% with slightly reduced 94:6 selectivity (entry 3). The reaction
with aldehydes having an electron withdrawing substituent, p-
1) NaH, THF, 0 °C
CO2Et
(PhO)2P(O)CH2CO2Et
2) 1-NaphCHO
-78 °C to 0 °C
1a
Z-6
y. 73% Z:E = 93:7
chlorobenzaldehyde
and
p-nitrobenzaldehyde,
proceeded
smoothly at À78 °C to give the Z-olefins 5d and 5e with 95:5 and
96:4 selectivity, respectively (entries 5 and 6). Bulky aromatic
aldehydes were good substrates for the reaction with 2e. Although
the reaction with 1-naphthaldehyde and o-methoxybenzaldehyde
silica gel
AcOEt, 30 min
column chromatography
79:21
56:44
Scheme 3.

2028
K. Ando et al. / Tetrahedron Letters 54 (2013) 2026–2028
Table 3
Supplementary data
The HWE reaction of 2e with aliphatic aldehydesa
tBu
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
02.020.
O
1) base, THF
2) RCHO
O2PCH2CN
R
CN
5
Z-
2e
Entry
RCHO
Base
Condition
Yield
Z:E
References and notes
1
2
3
4
5
6
7
8
9
10
11
12
13
14
n-Octanal
n-Octanal
n-Octanal
n-Octanal
7
t-BuOK
t-BuOKb
NaH
NaH (3 equiv)
NaH (3 equiv)
t-BuOK
NaH
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
À78 to 0 °C
À78 to 0 °C
À78 to 0 °C
À78 to 0 °C
À78 to 0 °C
0 °C, 2 h
À78 to 0 °C
À78 to 0 °C
0 °C, 2 h
25 °C, 2 h
0 °C, 2 h
À78 to 0 °C
À78 to 0 °C
À78 to 0 °C
5i 82
5i 47
5i 83
5i 95
5j 80
5j 85
5k 71
5k 74
5k 88
5k 85
5l 83
5m 70
5n 79
5o 84
83:17
77:23
89:11
90:10
76:24
89:11
76:24
85:15
87:13
85:15
97:3
1. (a) Ando, K. Tetrahedron Lett. 1995, 36, 4105–4108; (b) Ando, K. J. Org. Chem.
1997, 62, 1934–1939; (c) Ando, K. J. Org. Chem. 1998, 63, 8411–8416; (d) Ando,
K. J. Org. Chem. 1999, 64, 8406–8408; (e) Ando, K.; Oishi, T.; Hirama, M.; Ohno,
H.; Ibuka, T. J. Org. Chem. 2000, 65, 4745–4749.
2. For a computational investigation of the reaction mechanism, see: Ando, K. J.
Org. Chem. 1999, 64, 6815–6821.
3. For reviews: (a) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863–927; (b)
Ando, K. J. Synth. Org. Chem. Jpn. 2000, 58, 869–876.
4. Ando, K. unpublished results.
5. (a) Zhang, T. Y.; O’Toole, J. C.; Dunigan, J. M. Tetrahedron Lett. 1998, 39, 1461–
1464; The 12:1 Selectivity was reported for the reaction with a long chain
dialdehyde, (b) Stockman, R. A.; Sinclair, A.; Arini, L. G.; Szeto, P.; Hughes, D. L. J.
Org. Chem. 2004, 69, 1598–1602.
6. (a) Kojima, S.; Fukuzaki, T.; Yamakawa, A.; Murai, Y. Org. Lett. 2004, 6, 3917–
3920; (b) Yamakado, Y.; Ishiguro, M.; Ikeda, N.; Yamamoto, H. J. Am. Chem. Soc.
1981, 103, 5568–5570; (c) Haruta, R.; Ishiguro, M.; Furuta, K.; Mori, A.; Ikeda,
N.; Yamamoto, H. Chem. Lett. 1982, 1093–1096.
7
c-C6H11CHO
c-C6H11CHO
c-C6H11CHO
c-C6H11CHO
8
t-BuCHO
9
10
98:2
>99:1
>99:1
a
The reaction temperature was warmed over 1–2 h except for entries 6, 9–11.
1 equiv of 18-crown-6 was added.
b
7. (a) Fang, F.; Li, Y.; Tian, S.-K. Eur. J. Org. Chem. 2011, 1084–1091; (b) Kojima, S.;
Kawaguchi, K.; Matsukawa, S.; Uchida, K.; Akiba, K. Chem. Lett. 2002, 170–171.
8. (a) Tomioka, T.; Takahashi, Y.; Vaughan, T. G.; Yanase, T. Org. Lett. 2010, 12,
2171–2173; (b) Yazaki, R.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2009,
131, 3195–3197; (c) Sato, Y.; Niinomi, Y. J. Chem. Soc., Chem. Commun. 1982,
56–57.
Ph
Me CHO
OSiMe2tBu
CHO
CHO
CHO
10
OSiMe2tBu
7
8
9
9. Touchard, F. P.; Capelle, N.; Mercier, M. Adv. Synth. Catal. 2005, 347, 707–711.
10. For the amide reagents, (o-tBuC6H4O)2P(O)CH2CONR1R2, see: (a) Ando, K.;
Nagaya, S.; Tarumi, Y. Tetrahedron Lett. 2009, 50, 5689–5691; For the polymer-
supported reagents, see: (b) Ando, K.; Suzuki, Y. Tetrahedron Lett. 2010, 51,
2323–2325; For the intramolecular HWE reagents, see: (c) Ando, K.; Narumiya,
K.; Takada, H.; Teruya, T. Org. Lett. 2010, 12, 1460–1463; (d) Ando, K.; Sato, K.
Tetrahedron Lett. 2011, 52, 1284–1287.
11. The E:Z ratios were determined by integration of the vinyl proton signals in
400 MHz 1H NMR spectra of the crude reaction mixture. All the HWE products
described in this Letter except for 5j are known compounds. 1H NMR spectra
are identical to the reported values: Z-5a,6a E-5a,13a Z-5b,8a E-5b,13a Z-5c,6a E-
5c,13a Z-5d,6a E-5d,13a Z-5e,13b E-5e,13c Z-5f,7a E-5f,7a Z-5g,7a E-5g,13a Z-5h,6a E-
5h,6a Z-5k,6a E-5k,6a Z-5l,13d E-5l,13d Z-5m,6a E-5m,6a Z-5n,8a E-5n,8a Z-5o,6a E-
5o,6a Z-6,13e E-6.13f The NMR spectrum of 5i was not reported.4 Both 5i and 5j
were characterized by 400 MHz 1H NMR spectra, mass spectroscopy, and
HRMS.
12. A typical procedure for the Z-selective HWE reaction (entry 8 in Table 2): A
solution of 2e (0.30 mmol) and 18-crown-6 (0.105 g, 0.39 mmol) in THF (6 mL)
was treated with t-BuOK (0.045 g, 0.39 mmol) at 0 °C. 15 min later, the mixture
was cooled to À78 °C and o-methylbenzaldehyde (0.039 mL, 0.33 mmol) was
added. The resulting mixture was stirred at À78 °C for 2.5 h. The reaction was
quenched with aqueous NH4Cl, and the mixture was extracted with AcOEt
twice (7 and 4 mL). The combined extracts were washed with brine, dried
(MgSO4), and concentrated. After determining the Z/E ratio (>99:1) of the crude
mixture by 400 MHz 1H NMR, the olefin was isolated by flash chromatography
(hexane:AcOEt = 20:1) as a colorless oil (0.039 g, 90% yield) (Z/E = >99:1).
13. (a) Qin, C.; Jiao, N. J. Am. Chem. Soc. 2010, 132, 15893–15895; (b) Senra, J. D.;
Malta, L. F. B.; Souza, A. L. F.; Aguiar, L. C. S.; Antunes, O. A. C. Adv. Synth. Catal.
2008, 350, 2551–2558; (c) Shaaban, M. R.; Darweesh, A. F.; Dawood, K. M.;
Farag, A. M. ARKIVOC 2010, 208–225; (d) Grée, D.; Vallerie, L.; Grée, R.; Toupet,
L.; Washington, I.; Pelicier, J.-P.; Villacampa, M.; Pérez, J. M.; Houk, K. N. J. Org.
Chem. 2001, 66, 2374–2381; (e) Oyamada, J.; Kitamura, T. Chem. Commun.
2008, 4992–4994; (f) Ren, G.; Cui, X.; Yang, E.; Yang, F.; Wu, Y. Tetrahedron
2010, 66, 4022–4028.
formed by using t-BuOK and the reaction mixture was warmed to
0 °C to give 85:15 selectivity (entry 8). The highest selectivity was
obtained from the reaction at 0 °C (87:13) (entries 9 and 10). The
reaction with sterically more congested aldehyde 8 gave a much
higher 97:3 selectivity (entry 11). The reactions with the aldehydes
having tertiary alkyl group, pivalaldehyde, 1-methylcyclohexane-
carbaldehyde 9, and 2-methyl-2-phenylpropanal 10, were per-
formed by using t-BuOK at À78 to 0 °C. The Z-olefins 5m–5o
were obtained with 98:2, >99:1, and >99:1 selectivity in good
yields, respectively (entries 12–14).
In summary, we have developed a new HWE nitrile reagent, (o-
tBuC6H4O)2P(O)CH2CN (2e), which reacts with various types of
aldehydes to give Z-a,b-unsaturated nitriles with 86 to >99% Z-
selectivity. Especially, the reaction of 2e with the bulkier alde-
hydes, both aromatic and aliphatic, gave the Z-olefines with extre-
mely high selectivity. Since the nitrile group can be transformed to
various useful functional groups such as the aldehyde, the carbox-
ylic acid, and the amine, the present method will be of consider-
able utility in synthesis.
Acknowledgment
This work was partially supported by Grants-in-Aid for
Scientific Research from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
14. Pihko, P. M.; Salo, T. M. Tetrehedron Lett. 2003, 44, 4361–4364.