Dibutyltin dimethoxide-catalyzed cyano transfer to aldehydes and imines

Article abstract of DOI:10.1002/adsc.201000409

A novel reaction involving cyano transfer from benzophenone cyanohydrin to aldehydes and imines was realized by using dibutyltin dimethoxide as a catalyst. Various cyanohydrins and α-amino nitriles were obtained in moderate to high yields by this reaction. Ketimines also showed remarkable reactivity as cyano acceptors under conventional reaction conditions. This catalytic reaction was further applied to a three-component condensation reaction of aldehydes, aniline, and benzophenone cyanohydrin in the presence of Drierite. Copyright

Full text of DOI:10.1002/adsc.201000409

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DOI: 10.1002/adsc.201000409
Dibutyltin Dimethoxide-Catalyzed Cyano Transfer to Aldehydes
and Imines
Akira Yanagisawa,a,* Takuya Matsumoto,a Naoyuki Kushihara,a
and Kazuhiro Yoshidaa
a
Department of Chemistry, Graduate School of Science, Chiba University, Inage, Chiba 263-8522, Japan
Fax : (+81)-43-290-2789; e-mail: ayanagi@faculty.chiba-u.jp
Received: May 25, 2010; Revised: September 13, 2010; Published online: November 12, 2010
Abstract: A novel reaction involving cyano transfer
from benzophenone cyanohydrin to aldehydes and
imines was realized by using dibutyltin dimethoxide
as a catalyst. Various cyanohydrins and a-amino ni-
triles were obtained in moderate to high yields by
this reaction. Ketimines also showed remarkable re-
activity as cyano acceptors under conventional reac-
tion conditions. This catalytic reaction was further
applied to a three-component condensation reac-
tion of aldehydes, aniline, and benzophenone cya-
nohydrin in the presence of Drieriteꢀ.
tone cyanohydrin has been achieved in the presence
of triethylamine as catalyst.[6] Here we describe a
novel reaction involving the cyano transfer from ben-
zophenone cyanohydrin to aldehydes and imines cata-
lyzed by dibutyltin dimethoxide (Scheme 1).
We have previously found that dibutyltin oxide acts
as a catalyst in the allyl transfer reaction of tertiary
homoallylic alcohols with aldehydes in which a cata-
lytic amount of an allylic tin species is generated in
situ.[7] We envisioned that Bu2SnO would also catalyze
the cyano transfer to aldehydes if a tin cyanide spe-
cies were formed from a ketone cyanohydrin, accord-
ing to a similar catalytic mechanism to that for the
Keywords: aldehydes; a-amino nitriles; cyanation;
cyanohydrins; imines; tin
Table 1. Screening of tin catalysts for the cyano transfer
from benzophenone cyanohydrin to benzaldehyde.[a]
The cyanation of aldehydes and imines is a conven-
ient method for preparing cyanohydrins and a-amino
nitriles, respectively, which are further transformed
into synthetically useful compounds, such as a-hy-
droxy carboxylic acids and a-amino acids.[1] As a cy-
anating agent, trimethylsilyl cyanide (Me3SiCN) is fre-
quently utilized in the reaction with aldehydes to
afford trimethylsilylated cyanohydrins.[2] Besides
Me3SiCN, acetone cyanohydrin is known as a useful
cyanide source. For example, acetone cyanohydrin un-
dergoes cyano transfer to aldehydes in the presence
Entry
Catalyst
Temp. [oC]
t [h]
Yield[b] [%]
1
Bu2SnO
Bu2SnBr2
Bu2SnBr2
100
3
<1
<1
<1
66
2
r.t.–120
r.t.–70
r.t.
24
26
20
32
3[c]
4
Bu2Sn
Bu2Sn
ACHTUNGTRENNUNG
A
5[d]
r.t.–120
<1
[a]
Unless otherwise noted, the reaction was performed
using tin catalyst (10 mol%), benzophenone cyanohydrin
(2 equiv.), and benzaldehyde (1 equiv.) in dry toluene at
the specified temperature for 3–32 h.
Isolated yield.
THF was used as solvent.
of a catalytic amount of an oxovanadium(V)ACTHNUTRGNEUG(N salen)
complex.[3] Zirconium alkoxide complexes[4] and orga-
nosamarium complexes[5] have also been employed as
catalysts. In addition, acetone cyanohydrin is applica-
ble to the cyano transfer reaction with imines. Indeed,
a three-component Strecker-type reaction with ace-
[b]
[c]
[d]
Acetone cyanohydrin was used as cyanide source.
Scheme 1. Bu2SnACHTUNGTRENNUNG(OMe)2-catalyzed cyano transfer from benzophenone cyanohydrin to aldehydes and imines.
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Dibutyltin Dimethoxide-Catalyzed Cyano Transfer to Aldehydes and Imines
allyl transfer reaction.[7] We attempted to react ben-
zaldehyde with benzophenone cyanohydrin in the
presence of Bu2SnO in toluene at 1008C for 3 h, but
were not able to obtain the target benzaldehyde cya-
nohydrin at all (entry 1, Table 1). Then, we tested the
catalytic ability of Bu2SnBr2, which effectively catalyz-
es the trimethylsilylcyanation of aldehydes,[8] but the
reaction did not proceed in both toluene and THF
Table 3. Screening of organotin dimethoxide catalysts for
the cyano transfer from benzophenone cyanohydrin to
benzaldehyde.[a]
(entries 2 and 3). Surprisingly, Bu2SnACTHUNTRGENNG(U OMe)2 promot-
Entry
R
X
Yield [%][b]
ed the cyano transfer.[9] When benzaldehyde was
treated with two equivalents of benzophenone cyano-
hydrin under the influence of 10 mol% of
1
Me
Bu
Bu
Ph
Cl
Br
–
Cl
Br
84
72
74
45
76
2
3[c]
4
Bu2SnACHTUNGTRENNUNG(OMe)2 in toluene at room temperature for
20 h, the desired adduct was formed in 66% yield
(entry 4). Employment of acetone cyanohydrin in
place of benzophenone cyanohydrin resulted in a sig-
nificant deceleration of the cyano transfer (entry 5).
In order to improve the chemical yield, we next ex-
amined solvent effects (Table 2). Among the solvents
used, diethyl ether gave a better result than toluene
(compare entry 4 with entry 1). Dichloromethane,
THF, and acetonitrile were less effective solvents in
the present cyanation (entries 2, 3, and 5).
5
Bn
[a]
Unless otherwise noted, the reaction was performed
using R2SnX2 (10 mol%), MeONa (20 mol%), benzophe-
none cyanohydrin (2 equiv.), and benzaldehyde (1 equiv.)
in dry diethyl ether at room temperature for 20 h.
Isolated yield.
[b]
[c]
Commercial Bu2Sn
ACHTUNGERTN(NUNG OMe)2 was used as an organotin di-
methoxide catalyst.
The alkyl substituents of an organotin dimethoxide notin dimethoxide also efficiently catalyzed the reac-
are considered to affect its electronic and/or steric tion (entry 5), whereas Ph2Sn(OMe)2 afforded the de-
AHCTUNGTRENNUNG
properties. Thus, we further carried out the screening sired product in low yield (entry 4). Based on these
of organotin dimethoxides, that were generated in situ results, we concluded that commercial dibutyltin di-
from the corresponding dialkyltin dihalides (X=Cl or methoxide is the tin catalyst of choice because its cat-
Br) and sodium methoxide, in the reaction involving alytic activity is almost equivalent to that of the in
cyano transfer from benzophenone cyanohydrin to situ generated dialkyltin dimethoxide, and it is easy to
benzaldehyde in diethyl ether (Table 3). As a result, handle.
Me2Sn
Bu2Sn(OMe)2 (compare entry 1 with entry 2). There performed the cyano transfer from benzophenone cy-
seems to be essentially no difference in reactivity be- anohydrin to various aldehydes. The results are sum-
tween commercially available Bu2Sn(OMe)2 and the marized in Table 4. Not only aromatic aldehydes but
A
With the optimized catalyst and solvent in hand, we
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
in situ prepared one (entries 2 and 3). A bulky orga- an a,b-unsaturated aldehyde and aliphatic aldehydes
also underwent the cyanation under conventional re-
action conditions and the corresponding cyanohydrins
were obtained in moderate to high yields. The sub-
Table 2. Solvent effect on the cyano transfer from benzo-
ACHTUNGTRENNUNG
stituent at the para-position of benzaldehyde to a
large extent influenced its reactivity (compare en-
tries 2–4 with entry 1). As for the p-trifluoromethyl
derivative, the isolated yield of the product reached
90% (entry 3). In the reaction with cinnamaldehyde, a
1,2-adduct was formed predominantly (entry 9).
ACHTUNGTRENNUNG
The above-mentioned results further prompted us
to use Bu2SnACHTNUTRGNEUNG(OMe)2 as a catalyst for the cyano trans-
Entry
Solvent
Yield [%][b]
fer from benzophenone cyanohydrin to aldimines.
Treatment of N-benzylideneaniline (1 equiv.) with
benzophenone cyanohydrin (2 equiv.) in the presence
of dibutyltin dimethoxide (10 mol%) in diethyl ether
at 408C for 20 h gave the target a-amino nitrile in
94% combined yield (Table 5, entry 1). Then, we at-
tempted the cyanation of diverse aldimines under
these reaction conditions and Table 5 shows selected
examples. Worthy of note is that the reaction with
electron-rich imines gave reactivities that were higher
1
2
3
4
5
toluene
CH2Cl2
THF
Et2O
MeCN
66
58
42
74
58
[a]
The reaction was performed using Bu2SnACTHNUTRGENUG(N OMe)2
(10 mol%), benzophenone cyanohydrin (2 equiv.), and
benzaldehyde (1 equiv.) in a specified dry solvent at
room temperature for 20 h.
[b]
Isolated yield.
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Table 4. Bu2Sn
ACHTUNGTRENNUNG(OMe)2-catalyzed cyano transfer from benzo-
ketimines derived from ketones and aniline under the
conventional reaction conditions (408C, 20 h) and
found that their reaction with benzophenone cyano-
hydrin proceeded smoothly to afford the desired
products in satisfactory yields (Scheme 2).
phenone cyanohydrin to various aldehydes.[a]
We further applied the present catalytic process to
a three-component cyano transfer from benzophe-
none cyanohydrin to in situ generated aldimines. The
three-component coupling procedure that employs a
cyanide source, an aldehyde, and an amine is superior
to the two-component one that employs a cyanide
source and an imine because the former does not re-
quire the tedious preparation of imines and is applica-
ble to unstable imines. Under the typical reaction
conditions for the two-component coupling proce-
dure, good chemical yields were obtained when a mix-
ture of benzophenone cyanohydrin (2 equiv.), an alde-
hyde (1 equiv.), and aniline (1 equiv.) was treated with
Entry
R
Yield [%][b]
1
2
3
4
5
6
7
8
Ph
74
65
90
29
50
84
59
32
45
90
64
87
4-NO2C6H4
4-CF3C6H4
4-MeOC6H4
2-MeOC6H4
1-naphthyl
2-naphthyl
2-thienyl
(E)-PhCH=CH
PhCH2CH2
n-C5H11
9
10
11
12
10 mol% of Bu2SnACHTNUGTRNEUNG(OMe)2 in the presence of Drier-
iteꢀ as a drying agent in ether at 408C for 20 h (en-
tries 1 and 2 in Table 6).
c-C6H11
[a]
The reaction was performed using Bu2SnACTHNUTRGENUG(N OMe)2
A plausible catalytic mechanism for the cyano
transfer to aldehydes is illustrated in Figure 1. First of
(10 mol%), benzophenone cyanohydrin (2 equiv.), and al-
dehyde (1 equiv.) in dry ether at room temperature for
20 h.
Isolated yield.
all, Bu2SnACTHUGNTERNNU(G OMe)2 reacts with benzophenone cyanohy-
[b]
drin to yield the tin alkoxide of cyanohydrin 1 and
MeOH. Tin alkoxide 1 then coordinates with alde-
hyde 2 to afford the tin alkoxide-aldehyde complex 3.
This is followed by the intramolecular cyano transfer
to the aldehyde to give the tin alkoxide of cyanohy-
drin 4 and benzophenone. Finally, protonation of tin
alkoxide 4 with benzophenone cyanohydrin results in
the formation of the desired product 5 and the regen-
eration of the tin alkoxide of cyanohydrin 1.
Table 5. Bu2Sn
ACHTUNGTRENNUNG(OMe)2-catalyzed cyano transfer from benzo-
phenone cyanohydrin to various aldimines.[a]
In summary, we have presented an example of a
Entry
R1
R2
Yield [%][b] cyano transfer from benzophenone cyanohydrin to al-
dehydes and imines catalyzed by Bu2SnACTHNUTRGEN(NUG OMe)2. The
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
94
main features of the present reaction are as follows:
(i) it employs readily available chemicals and can pro-
vide various cyanohydrins and a-amino nitriles in
high yields of up to 99%; (ii) ketimines can be also
converted into the corresponding a-aminonitriles by
applying this reaction; and (iii) a three-component
coupling procedure has been developed for a-amino-
nitrile synthesis as a more efficient alternative.
4-MeOC6H4
2-MeOC6H4
4-CF3C6H4
1-naphthyl
2-furyl
4-MeOC6H4
Ph
Ph
>99
>99
73
86
96
93
97
83
4-BrC6H4
4-MeOC6H4
4-BrC6H4
[a]
The reaction was performed using Bu2SnACTHNUTRGENUG(N OMe)2
(10 mol%), benzophenone cyanohydrin (2 equiv.), and al-
dimine (1 equiv.) in dry diethyl ether at 408C for 20 h.
Isolated yield.
Experimental Section
[b]
General Remarks
Column chromatography was conducted with 63–230 mesh
silica gel. All experiments were carried out under an atmos-
phere of standard grade argon gas (oxygen <10 ppm). Ben-
zophenone cyanohydrin was prepared by treating benzophe-
none with trimethylsilyl cyanide in the presence of a catalyt-
ic amount of ZnI2 in CH2Cl2 followed by acid hydrolysis
(3N HCl/THF).[10] Aldimines were prepared from the corre-
than that of the reaction with N-benzylideneaniline
(compare entries 2, 3, and 8 with entry 1) and an
almost quantitative yield was attained in the case of
4-MeO and 2-MeO derivatives (entries 2 and 3). In
contrast, electron-deficient imines gave the corre-
sponding cyanated products in low yields (entries 4
and 9). Furthermore, we investigated the reactivity of sponding aldehydes and amines in the presence of anhy-
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Dibutyltin Dimethoxide-Catalyzed Cyano Transfer to Aldehydes and Imines
Scheme 2. Bu2SnACHTUNGTRENNUNG(OMe)2-catalyzed cyano transfer from benzophenone cyanohydrin to ketimines.
Table 6. Three-component cyano transfer from benzophe-
none cyanohydrin to in situ generated aldimines catalyzed
Typical Experimental Procedure for Cyano Transfer
from Benzophenone Cyanohydrin to Aldehydes:
Synthesis of 2-Hydroxy-2-phenylacetonitrile (entry 4
in Table 2, entry 3 in Table 3, entry 1 in Table 4)[11]
by Bu2SnACHTUNGTRENNUNG
(OMe)2.[a]
A
mixture of benzophenone cyanohydrin (209.2 mg,
1.0 mmol) and benzaldehyde (51 mL, 0.50 mmol) was dis-
solved in dry diethyl ether (2 mL) under an argon atmos-
phere. To the resulting solution was added dibutyltin di-
methoxide (11.5 mL, 0.050 mmol) at room temperature.
After stirring for 20 h at this temperature, the mixture was
concentrated under vacuum. The residual crude product was
purified by column chromatography on silica gel to afford 2-
hydroxy-2-phenylacetonitrile; yield: 49.0 mg (74%).
Entry
R
Yield [%][b]
1
2
Ph
78
72
(E)-PhCH=CH
[a]
The reaction was performed using Bu2SnACTHNUTRGENUG(N OMe)2
(10 mol%), benzophenone cyanohydrin (2 equiv.), alde-
hyde (1 equiv.), aniline (1 equiv.), and Drieriteꢀ (5 equiv.)
in dry ether at 408C for 20 h.
Typical Experimental Procedure for Cyano Transfer
from Benzophenone Cyanohydrin to Imines:
Synthesis of 2-(N-Anilino)-2-phenylacetonitrile
(entry 1 in Table 5)[12]
[b]
Isolated yield.
A
mixture of benzophenone cyanohydrin (209.2 mg,
1.0 mmol) and N-benzylideneaniline (90.6 mg, 0.50 mmol)
was dissolved in dry diethyl ether (2 mL) under an argon at-
mosphere. To the resulting solution was added dibutyltin di-
methoxide (12.0 mL, 0.052 mmol) at room temperature.
After stirring for 20 h at 408C, the mixture was concentrated
under vacuum. The residual crude product was purified by
column chromatography on silica gel to afford 2-(N-anili-
no)-2-phenylacetonitrile; yield: 97.9 mg (94%).
Typical Experimental Procedure for Three-
component Cyano Transfer from Benzophenone
Cyanohydrin to in situ Generated Aldimines:
Synthesis of 2-(N-Anilino)-2-phenylacetonitrile
(entry 1 in Table 6)[12]
A mixture of benzaldehyde (51 mL, 0.50 mmol), aniline
(46 mL, 0.50 mmol), and Drieriteꢀ (340.4 mg, 2.5 mmol) in
dry diethyl ether (2 mL) was stirred under an argon atmos-
phere at room temperature for 30 min. To the resulting solu-
tion were added benzophenone cyanohydrin (209.2 mg,
1.0 mmol) and dibutyltin dimethoxide (12.0 mL, 0.052 mmol)
in that order. After stirring for 20 h at 408C, the mixture
was concentrated under vacuum. The residual crude product
was purified by column chromatography on silica gel to
afford 2-(N-anilino)-2-phenylacetonitrile; yield: 81.5 mg
(78%).
Figure 1. Plausible catalytic mechanism for the cyano trans-
fer to aldehydes catalyzed by Bu2Sn(OMe)2.
AHCTUNGTRENNUNG
drous MgSO4 in dry THF. Other chemicals were used as
purchased.
Caution! HCN is generated through the present catalytic
reactions
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Akira Yanagisawa et al.
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Acknowledgements
a catalytic addition of Me3SiCN to ketones, see: d) Y.
Li, B. He, X. Feng, G. Zhang, Synlett 2004, 1598; e) B.
He, Y. Li, X. Feng, G. Zhang, Synlett 2004, 1776; f) F.-
X. Chen, X. Feng, Synlett 2005, 892; g) L. Wang, X.
Huang, J. Jiang, X. Liu, X. Feng, Tetrahedron Lett.
2006, 47, 1581. For a catalytic Strecker reaction using
Me3SiCN, see: h) Y. Wen, Y. Xiong, L. Chang, J.
Huang, X. Liu, X. Feng, J. Org. Chem. 2007, 72, 7715.
[3] A. Watanabe, K. Matsumoto, Y. Shimada, T. Katsuki,
Tetrahedron Lett. 2004, 45, 6229.
This work was supported by a Grant-in-Aid for Scientific Re-
search on Priority Area “Advanced Molecular Transforma-
tions of Carbon Resources” from the Ministry of Education,
Culture, Sports, Science and Technology, Japan. We also
thank Professor Takayoshi Arai at Chiba University for help-
ful discussions.
[4] T. Ooi, K. Takaya, T. Miura, H. Ichikawa, K. Maruoka,
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Adv. Synth. Catal. 2010, 352, 2918 – 2922