N-heterocyclic carbenes mediated cyano-phosphorylation of ketones

Article abstract of DOI:10.1016/j.tetlet.2013.08.073

Cyanation-O-protection reaction of ketones with different cyanide sources catalyzed by N-heterocyclic carbenes is reported. Under the catalysis of 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene, various ketones coupled with diethyl cyanophosphonate to p

Full text of DOI:10.1016/j.tetlet.2013.08.073

Tetrahedron Letters 54 (2013) 5861–5864
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Tetrahedron Letters
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N-heterocyclic carbenes mediated cyano-phosphorylation of ketones
⇑
⇑
⇑
Lin He , Jing Zhang, Ye-Cheng Fan, Guang-Fen Du , Jie Zhang, Bin Dai
Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan and School of Chemistry and Chemical Engineering, Shihezi University, Xinjiang 832003, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Cyanation-O-protection reaction of ketones with different cyanide sources catalyzed by N-heterocyclic
carbenes is reported. Under the catalysis of 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene, various
ketones coupled with diethyl cyanophosphonate to produce cyanohydrin-O-phosphates with a quatern-
ary carbon center in moderate to excellent yield. Furthermore, the reaction can be scaled-up easily and
high yield maintained.
Received 24 June 2013
Revised 10 August 2013
Accepted 20 August 2013
Available online 31 August 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
N-heterocyclic carbene
Cyanation-O-protection reaction
Ketone
Diethyl cyanophosphonate
Cyanohydrin-O-phosphonate
Introduction
Cyanohydrin-O-phosphates are valuable building blocks in syn-
thetic chemistry.5 Lithium diisopropylamine,6 lithium cyanide7
Cyanohydrins are versatile synthetic intermediates in organic
synthesis,1 and much efforts have been devoted to synthesizing
these target molecules.2 However, the intrinsic instabilities of
cyanohydrins or their trimethylsilyl derivatives restrains the
potential application. Therefore, one-pot procedures for protected
cyanohydrins have been developed using different cyanide sources
instead of TMSCN, such as alkyl cyanoformates, acyl cyanide and
diethyl cyanophosphonate.3 Recently, we have developed
cyanoethoxycarbonylation and cyanocarbonylation of aldehydes
catalyzed by N-heterocyclic carbenes (NHCs) under mild
conditions.4 However, the more challenging process for NHCs-
catalyzed cyano-O-protection of unactivated ketones remains
untouched.
and triethylamine8 catalyzed synthesis of racemic cyanohydrin-
O-phosphates have been documented. However, some of them re-
quired high catalyst loading, large excess of cyanide reagents, or
harsh reaction conditions. In particular, lithium cyanide itself is a
toxic reagent. Therefore, the development of efficient and ‘green’
methods for the synthesis of cyanohydrin-O-phosphates is of great
importance. Recently, Aoyama and co-workers reported that NHCs
promoted cyano-phosphorylation of aldehydes.9 However, when
ketones were used instead of aldehydes, only trace amount of pro-
ducts was obtained. In line with our continued interest of NHCs
catalysis,10 we herein report a NHC catalyzed cyano-phosphoryla-
tion of simple ketones, which provide the phosphonates nitriles in
high yields.
O
HO
NC OP(O)(OEt)2
20% HCl
reflux, 12 h
COOH
Me
O
P
OEt
5 mol% IPr
Me
Me
EtO
CN
+
toluene, rt, 4h
O2N
8o, 0.58g, 70%
O2N
O2N
4.3 mmol
6.4 mmol
8l, 1.4g, 99%
Scheme 1. The utility of NHC catalyzed cyano-phosphorylation of ketone.
⇑
Corresponding authors.
E-mail address: helin@shzu.edu.cn (L. He).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.073

5862
L. He et al. / Tetrahedron Letters 54 (2013) 5861–5864
Table 1
O
P
Evaluation of reaction conditionsa
EtO
Ar
CN
N
N
OEWG
CN
OEt
Ar
Ar
O
NHC, solvent
EWG
CN
+
EtO
P O
CN
OEt
O
(I)
6a
7
8
R1
R2
N
Ar
N
R1
EWG = CO2Et, P(O)(OEt)2, COMe
CN
R2
Cl-
Ar
Cl-
Ar
(II)
R1
O
OP(O)(OEt)2
R2 CN
N
N
N
Ar
N
OEt
N
N
Ar
Ar
Ar
O
P
OEt
2
1
3
Ar
Ar
Ar=2,6-(i-Pr)2C6H3
N
N
Ar=1,3,5-Me3C6H2
Ar=2,6-(i-Pr)2C6H3
Scheme 2. Proposed mechanism.
Cl
N
I-
R
N
Ph
OH
S
N
N
Results and discussion
5
4
Initially, the cyano-O-protection reaction of cyclohexanone
with several different cyanide sources was examined. To our de-
light, under the catalysis of 5 mol % 1,3-bis(2,6-diisopropyl-
phenyl)imidazol-2-ylidene (IPr),11 cyclohexanone can couple
with ethyl cyanoformate or diethyl cyanophosphonate smoothly
in THF, resulting in the corresponding product in good yield (Table
1, entries 1, 2). However, acetylcyanide was not suitable for the
reaction (Table 1, entry 3). The solvent effects were briefly exam-
ined, and toluene turned out to be a better choice (Table 1, entries
4–9). Using diethyl phosphorocyanidate as the cyanide source, the
reaction reached a full conversion within 8 h, and 8a was obtained
in quantitative yield (Table 1, entry 8). NHCs generated in situ from
precursors 2 or 3 can promote the reaction efficiently (Table 1, en-
tries 10, 11). However, the catalysts derived from 4 or 5 showed
low catalytic efficiency (Table 1, entries 12, 13). Keeping 1 as the
catalyst, lowering the catalyst loading to 1 mol %, 8a was still ob-
tained in high yield (Table 1, entry 14).
Entry
EWG
Solvent
Catalyst
Yieldb (%)
1
2
3
4
5
6
7
8
CO2Et
P(O)(OEt)2
COCH3
CO2Et
P(O)(OEt)2
COMe
CO2Et
P(O)(OEt)2
COCH3
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
THF
THF
THF
1, (5 mol %)
1, (5 mol %)
1, (5 mol %)
1, (5 mol %)
1, (5 mol %)
1, (5 mol %)
1, (5 mol %)
1, (5 mol %)
1, (5 mol %)
2, KOt-Bu
85
75
<10
49
77
46
<10
99
43
64
DCM
DCM
DCM
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
9
10c
11c
12c
13c
14
3, KOt-Bu
4, KOt-Bu
5, KOt-Bu
1, (1 mol %)
61
<10
<10
85
a
b
c
Compound 6a (1.0 equiv.), 7 (1.5 equiv), solvent: 2.0 mL, rt.
Isolated yields.
Using 6 mol % NHC-precursors and 5 mol % base.
With the optimal reaction conditions in hand (Table 1, entry
8), the scope of the reaction was next examined,12 and the re-
sults were summarized in Table 2. Both cyclic and acyclic ali-
phatic ketones were suitable substrates for the reaction (Table
2, entries 1–5). 4-Methylcyclohexanone coupled with diethyl
cyanophosphonate smoothly, giving the corresponding product
8b as the major diastereo isomer (Table 2, entry 2), and similar
selectivity was also observed by Nájera and co-workers.8 For lin-
ear aliphatic ketones, increasing the chains from methyl to n-
propyl, led to no obvious changes of the reactivities (Table 2, en-
tries 3–5). However, when ketone 6f was employed, which con-
Based on the previous work of NHCs-catalyzed cyanoethoxy-
carbonylation,4a a possible mechanism of current reaction was
illustrated (Scheme 2). The attack of NHC on diethyl cyanophosph-
onate would lead to the formation of intermediate I, followed by
cyanation of the ketone with a simultaneous protection of the
hydroxide group, and release NHC for the next catalytic cycle.
Conclusions
tains
a bulky tert-butyl group, the yield was decreased
In summary, we have demonstrated an efficient protocol for the
cyano-phosphorylation of ketones. The mild reaction conditions
and generally broad substrate scope of the current system provide
a valuable approach for the synthesis of cyanohydrin-O-phos-
phates with quaternary carbon centers. Moreover, the reaction
can be scaled up easily and relatively important reagents can be
obtained after simply manipulation, which hint a potential applica-
tion in pharmaceutical chemistry.
dramatically (Table 2, entry 6). When the unactive acetophenone
was introduced to the reaction, only low yield was obtained (Ta-
ble 2, entry 7). As expected, the introduction of electron-with-
drawing groups on the phenyl ring of the acetophenone
derivatives can enhance their reactivities dramatically, and the
corresponding products were obtained in good to excellent
yields (Table 2, entries 8–13). Similarly, the reaction of 2,2,2-tri-
fluoroacetophenone proceeded the reaction smoothly to give the
desired product in quantitative yield (Table 2, entry 14).
Acknowledgements
The reaction could be conveniently conducted on gram-scale
and high yield was still maintained. Furthermore, the resulting
cyanohydrin-O-phosphate 8l could be easily converted to
This work was supported by the National Natural Science Foun-
dation of China (No. 21262027) and the Team Innovation Project of
Shihezi University (No. 2011ZRKXTD-04).
a
-hydroxycarboxylic acid 8o in good yield under acidic conditions
(Scheme 1).9

L. He et al. / Tetrahedron Letters 54 (2013) 5861–5864
5863
Table 2
NHCs-catalyzed cyano-phosphorylation of ketonesa
R1
R2
O
P
OEt
O
OP(O)(OEt)2
CN
IPr, toluene, rt
EtO
CN
+
R1
R2
8
7
6
Entry
1
Ketones
Time (h)
Product
Yieldb (%)
CN
O
8
99
OP(O)(OEt)2
8a
H
CN
O
2
8
99c
Me
OP(O)(OEt)2
8b
O
O
O
O
NC
NC
NC
NC
OP(O)(OEt)2
3
4
5
24
24
24
78
70
68
8c
8d
8e
OP(O)(OEt)2
OP(O)(OEt)2
OP(O)(OEt)2
6
24
24
<10
38
8f
O
NC
OP(O)(OEt)2
7d
8g
O
O
NC
NC
NC
OP(O)(OEt)2
OP(O)(OEt)2
OP(O)(OEt)2
8d
9e
10
24
24
3
63
75
99
Br
8h
8i
Br
Cl
Cl
O
Cl
Cl
NC
8j
Cl
Cl
O
OP(O)(OEt)2
11
12
2
4
99
99
F3C
F3C
8k
8l
O
O
NC
NC
OP(O)(OEt)2
O2N
O2N
O2N
O2N
OP(O)(OEt)2
13
14
4
1
99
99
8m
O
NC
OP(O)(OEt)2
CF3
CF3
8n
a
b
c
Compound 6a (0.5 mmol), 7 (0.75 mmol), 5 mol % IPr, solvent: 2.0 mL, rt.
Isolated yields.
Isolated as a mixture of isomers (cis/trans = 6:1), determined by 1H NMR analysis.
d
e
Using 20 mol % IPr.
Using 10 mol % IPr.

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L. He et al. / Tetrahedron Letters 54 (2013) 5861–5864
other recent papers, see: (e) Enders, D.; Niemeier, O.; Balensiefer, T. Angew.
Supplementary data
Chem., Int. Ed. 2006, 45, 1463; (f) Takikawa, H.; Hachisu, Y.; Bode, J. W.; Suzuki,
K. Angew. Chem., Int. Ed. 2006, 45, 3492; (g) Dirocco, D. A.; Oberg, K. M.; Dalton,
D. M.; Rovis, T. J. Am. Chem. Soc. 2009, 131, 10872; (h) Li, G.-Q.; Dai, L.-X.; You, S.
L. Org. Lett. 2009, 11, 1623–1625; (i) DiRocco, D. A.; Rovis, T. J. Am. Chem. Soc.
2011, 133, 10402; (j) Bugaut, X.; Liu, F.; Glorius, F. J. Am. Chem. Soc. 2011, 133,
8130; (k) Sun, F.-G.; Sun, L.-H.; Ye, S. Adv. Synth. Catal. 2011, 353, 3134.
5. (a) Schrader, T. Chem. Eur. J. 1997, 3, 1273; (b) Schrader, T. Angew. Chem. 1995,
107, 1001. Angew. Chem., Int. Ed. 1995, 34, 917.; (c) Johnson, D. V.; Griengl, H.
Tetrahedron 1997, 53, 617; (d) Sawada, D.; Shibasaki, M. Angew. Chem., Int. Ed.
2000, 39, 209; (e) Sawada, D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2000,
122, 10521; (f) Duquette, J.; Zhang, M.; Zhu, L.; Reeves, R. S. Org. Process Res.
Dev. 2003, 7, 285; (g) Breuer, M.; Ditrich, K.; Habicher, T.; Hauer, B.; Kebeler,
M.; Stürmer, R.; Zelinski, T. Angew. Chem., Int. Ed. 2004, 43, 788.
6. Harusawa, S.; Yoneda, R.; Kurihara, T.; Hamada, Y.; Shioiri, T. Chem. Pharm. Bull.
1983, 31, 3932.
7. Yoneda, R.; Harusawa, S.; Kurihara, T. J. Org. Chem. 1827, 1991, 56.
8. Baeza, A.; Nájera, C.; Sansano, M. J. ARKIVOC 2005, ix, 353.
9. Fukuda, Y.; Maeda, Y.; Kondo, K.; Aoyama, T. Chem. Pharm. Bull. 2006, 54, 397.
10. (a) Cai, Z. H.; Du, G. F.; Dai, B.; He, L. Synthesis 2012, 5, 694; (b) Fan, Y.-C.; Du,
G.-F.; Sun, W.-F.; Kang, W.; He, L. Tetrahedron Lett. 2012, 53, 2231; (c) Wang, X.
B.; Zou, X. L.; Du, G. F.; Liu, Zh. Y.; Dai, B. Tetrahedron 2012, 68, 6498; (d) Zou, X.
L.; Du, G. F.; Sun, W. F.; He, L.; Ma, X. L.; Gu, C. Z.; Dai, B. Tetrahedron 2013, 69,
607.
11. Arduengo, A. J., III; Krafczyk, R.; Schmutzler, R. Tetrahedron 1999, 55, 14523.
12. General procedure for IPr-catalyzed cyano-phosphorylation reaction: IPr was
added to a solution of ketone 6 (0.5 mmol) and diethyl cyanophosphonate 7
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.08.
073.
References and notes
1. (a) Green, T. W.; Wuts, P. G. M. Protecting Groups in Organic Synthesis, 3rd ed.;
John Wiley & Sons: New York, 1999; (b) Rasmussen, J. K.; Heilmann, S. M.;
Krepski, L. R. In Advances in Silicon Chemistry; Larson, G. L., Ed.; ; Jai Press:
Greenwich CT, 1991; Vol. 1, p 75.
2. (a) Veum, L.; Kuster, M.; Telalovic, S.; Hanefeld, U.; Maschmeyer, T. Eur. J. Org.
Chem. 2002, 1516; (b) Lundgren, S.; Wingstrand, E.; Moberg, C. Adv. Synth.
Catal. 2007, 349, 364; (c) Khan, N. H.; Kureshy, R. I.; Abdi, S. H. R.; Agrawal, S.;
Jasra, R. V. Coord. Chem. Rev. 2008, 252, 593.
3. (a) Demir, A. S.; Aybey, A.; Emrullahoglu, M. Synthesis 2009, 1655; (b)
Yamagiwa, N.; Abiko, Y.; Sugita, M.; Tian, J.; Matsunaga, S.; Shibasaki, M.
Tetrahedron: Asymmetry 2006, 17, 566; (c) Baeza, A.; Casas, J.; Nájera, C.;
Sansano, J. M.; Saá, J. M. Angew. Chem., Int. Ed. 2003, 42, 3143; (d) Baeza, A.;
Casas, J.; Nájera, C.; Sansano, J. M.; Saá, J. M. Chem. Eur. J. 2005, 3849; (e) Abell, J.
P.; Yamamoto, H. J. Am. Chem. Soc. 2009, 131, 15118; (f) Aoki, S.; Kotani, S.;
Sugiura, M.; Nakajima, M. Tetrahedron Lett. 2010, 51, 3547; (g) Khan, N. H.;
Agrawal, S.; Kureshy, R. I.; Abdi, S. H. R.; Pathak, K.; Bajaj, H. C. Chirality 2010,
22, 153; (h) Zhang, Z. P.; Wang, Z.; Zhang, R. Z.; Ding, K. L. Angew. Chem., Int. Ed.
2010, 49, 6746.
(0.75 mmol, 114.0 lL) in dry toluene (2.0 mL) under nitrogen, and the resulting
mixture was stirred at room temperature until full consumption of the starting
ketone indicated by TLC. The solvent was removed under reduced pressure and
the crude material was purified by column chromatography (PE–EtOAc, 3:1) to
afford the pure cyanohydrin-O-phosphate.
4. (a) Zhang, J.; Du, G.-F.; Xu, Y.-K.; He, L.; Dai, B. Tetrahedron Lett. 2011, 52, 7153;
For reviews of NHCs catalysis, see: (b) Enders, D.; Niemeier, O.; Henseler, A.
Chem. Rev. 2007, 107, 5606; (c) Grossmann, A.; Enders, D. Angew. Chem., Int. Ed.
2012, 51, 314; (d) Bugaut, X.; Glorius, F. Chem. Soc. Rev. 2012, 41, 3511; For