Guanidine-catalyzed asymmetric trimethylsilylcyanation of carbonyl compounds

Article abstract of DOI:10.1002/adsc.200505161

Several kinds of modified guanidines were applied to the trimethylsilylcyanation of 3-phenylpropanal, cylohexanecarboxaldehyde, pivalaldehyde, and 4-phenyl-2-butanone. Good to moderate enantioselectivity was obtained, even on a ketonic substrate, when a C

Full text of DOI:10.1002/adsc.200505161

FULL PAPERS
DOI: 10.1002/adsc.200505161
Guanidine-Catalyzed Asymmetric Trimethylsilylcyanation of
Carbonyl Compounds
Yukari Kitani,a Takuya Kumamoto,a Toshio Isobe,b Keiko Fukuda,b
Tsutomu Ishikawaa,*
a
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi, Inage, Chiba 263-8522, Japan
Fax: (þ81)-43-290-2910, e-mail: benti@p.chiba-u.ac.jp
b
Central Research Laboratory, Shiratori Pharmaceutical Co. Ltd., 6-11-24 Tsudanuma, Narashino, Chiba 275-0016, Japan
Received: April 10, 2005; Accepted: July 23, 2005
Abstract: Several kinds of modified guanidines were (2S,3S,7S,8S)-tetraphenyl-1,4,8-triaza[2.2.0]bicyclo-
applied to the trimethylsilylcyanation of 3-phenylpro- oct-4-ene, was used as a base catalyst.
panal, cylohexanecarboxaldehyde, pivalaldehyde, and
4-phenyl-2-butanone. Good to moderate enantiose- Keywords: asymmetric catalysis; cyanotrimethylsi-
lectivity was obtained, even on a ketonic substrate, lane; guanidines; hydrocyanation; nitriles; organic cat-
when
a
C2-symmetrical
bicyclic
guanidine, alysis
Introduction
Results and Discussion
Hydrocyanation of carbonyl compounds with hydrogen In this study five modified guanidines, 1,[6a] 2,[6a] 3,[6b] 4,[6c]
cyanide (HCN), leading to a-hydroxy acids by hydroly- and 5, as shown in Figure 1, were examined in the TMS-
sis of the resulting addition products, is an important or- cyanation as catalysts.
ganic reaction for carbon-carbon bond formation.[1] Cy-
Corey et al.[8] had reported that a C2-symmetrical bi-
anotrimethylsilane (TMSCN)[2] can be used as the cyclic guanidine, (3S,7S)-1,4,6-triazabicylco[2.2.0]oct-
equivalent of HCN, in which a Lewis acid is basically 4-ene, acted as an effective organic base catalyst in the
needed as an additive in order to activate carbonyl sub- asymmetric Strecker reaction of diphenylmethylimino-
strates and the addition products are trimethylsilylated benzaldehyde with hydrogen cyanide (HCN) (96%
cyanohydrins (TMS-cyanohydrins). The use of chiral yield, 86% ee). Thus, a structurally-related C2-symmet-
additives leads to TMS-cyanohydrins with good asym- rical bicyclic guanidine 5 was newly designed and pre-
metric induction.[1b,3] Guanidines can be characterized pared from (1R,2S)-2-amino-1,2-diphenylethanol (6)
as superbases[4] in organic synthesis due to their strong
basicity.[5] We have explored the possibility of readily
available modified guanidines[6] as re-useable chiral su-
perbases in asymmetric synthesis.[7] The reaction of car-
bonyl compounds with TMSCN in the presence of a
modified guanidine was examined in the course of our
studies on guanidine chemistry and reasonable asym-
metric induction was observed when a newly prepared
C2-symmetrical bicyclic guanidine, (2S,3S,7S,8S)-tetra-
phenyl-1,4,8-triaza[2.2.0]bicyclooct-4-ene, was used as
a catalyst. In this paper we present the guanidine-cata-
lyzed asymmetric trimethylsilylcyanation (TMS-cyana-
tion) of carbonyl compounds.
Figure 1. Modified guanidines 1–5 used for TMS-cyanations.
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Yukari Kitani et al.
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Scheme 1. Preparation of the C2-symmetrical bicyclic guanidine 5.
Table 1. Preliminary trials for the guanidine-catalyzed TMS-cyanation of 3-phenylpropanal (14).
Run
Guanidine
Time [h]
15
Configuration
Yield [%][a]
ee [%][b]
1
2
3
4
5
1
2
3
4
5
2.5
2.0
2.0
2.0
2.5
95
94
97
95
96
3
1
3
5
12
S
R
S
S
S
[a]
1
Estimated by H NMR.
[b]
Determined by chiral HPLC. Conditions, column: DAICEL CHIRALCEL OD-H; solvent: n-hexane:2-propanol¼15: 1;
flow rate: 0.5 mL/min; detection: UV (254 nm); (R)-derivative: 8.2 min; (S)-derivative: 8.8 min.
in good total yield by application of 2-chloro-1,3-dime- deprotection of the ethoxycarbonyl function in 13 with
thylimidazolium chloride (DMC)-mediated reactions[9] sodium methoxide afforded the desired C2-symmetrical
in the key steps (Scheme 1). The amino alcohol 6 was bicyclic guanidine, (2S,3S,7S,8S)-tetraphenyl-1,4,8-tri-
smoothly converted to isothiocyanate 8 by treatment aza[2.2.0]bicyclooct-4-ene (5), in overall 42% yield.
with DMC[9a] after protection of the alcoholic function
At first the reaction of 3-phenylpropanal[3a,c,g,i,k] (14)
with t-butyldimethylsilyl(TBDMS)group. Modification with TMSCN in dichloromethane (CH2Cl2) was prelimi-
of the isothiocyanate function in 8 with ethoxycarbony- narily examined using modified guanidines (Table 1). A
lated (1S,2S)-1,2-diphenylethylenediamine 9 afforded a mixture of the aldehyde 14 (1 mol), TMSCN (1 mol),
thioamide derivative 10. The DMC-induced intramolec- and a guanidine (0.1 mol) in CH2Cl2 (0.25 mol/L) was
ular cyclization[9c] followed by deprotection of the silyl stirred at 08C until disappearance of 14 on TLC. The re-
group with tetrabutylammonium fluoride (TBAF) actions were smoothly completed within 2.5 h, but low
yielded a monocyclic guanidine 12. Treatment of 12 asymmetric inductions (up to 12% ee in run 5) were ob-
with methanesulfonyl chloride, in which intramolecular served in all cases. The absolute stereochemistry of the
substitution of the corresponding methanesulfonate in major enantiomer of the TMS-cyanohydrin 15 was de-
situ formed occurred, gave a bicyclic system 13. Finally, termined by chiral HPLC, even at the low ee achieved.
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Asymmetric Trimethylsilylcyanation of Carbonyl Compounds
FULL PAPERS
Table 2. The guanidine 5-catalyzed TMS-cyanation of 3-phenylpropanal (14) under modified conditions.
Run
Solvent
Temperature [ 8C]
Time [h]
15
Yield [%][a]
ee [%]
1b
2
3
4
5
CH2Cl2
THF
toluene
none
CH2Cl2
toluene
0
0
0
2.5
5.0
2.5
1.5
6.0
6.0
96
53
96
quant.
87
12
20
25
6
26
50
0
ꢀ78
6
ꢀ78
85
[a]
1
Estimated by H NMR.
The data cited from run 5 in Table 1.
[b]
Table 3. The TMS-cyanation of different carbonyl compounds in the presence of the guanidine 5.
Run
16
Temperature [ 8C]
Time [h]
17
Configuration
Yield [%][a]
ee [%]
1
2
3
a
b
c
ꢀ78
ꢀ40[d]
1.5
7.0
2.0
93
92
29
70[b]
43[c]
39
S
S
-
ꢀ78
[e]
[a]
1
Estimated by H NMR.
[b]
Determined by chiral HPLC after conversion of 17a to the benzoate. Conditions, column: DAICEL CHIRALPAK AD;
solvent: n-hexane:2-propanol¼100: 1; flow rate: 1.0 mL/min; detection: UV (254 nm); (R)-derivative: 8.4 min; (S)-deri-
vative: 9.1 min.
[c]
Determined by chiral HPLC after conversion of 17b to the benzoate. Conditions, column: DAICEL CHIRALPAK AD;
solvent: n-hexane:2-propanol¼150: 1; flow rate: 0.2 mL/min; detection: UV (254 nm); (R)-derivative: 37.1 min; (S)-deri-
vative: 43.5 min.
[d]
[e]
No reaction occurred at ꢀ788C.
Not determined.
No reaction occurred in the absence of a guanidine and and 3 vs. 6) and 50% ee was obtained with the use of tol-
no epimerization of the adduct was observed under the uene as solvent (run 6).
conditions used, indicating that guanidine plays the role
of a catalyst and that this addition reaction is kinetically TMS-cyanation under the estimated conditions using
controlled. different carbonyl substrates (Table 3). In the use of cy-
Finally the bicyclic guanidine 5 was applied to the
We next attempted reactions in the presence of the C2- clohexanecarbaldehyde[3b–e, g] (16a) not only satisfacto-
symmetrical bicyclic guanidine 5, which showed the best ry asymmetric induction (70% ee) but also smooth con-
ee among the guanidines examined, for optimization of version to the adduct (<1.5 h) was observed (run 1).
reaction conditions (Table 2). The use of tetrahydrofur- Smooth reaction, even when needing longer reaction
an (THF) (run 2) and toluene (run 3) as solvent in place times, was also observed in the case of pivalaldehy-
of CH2Cl2 led to slight improvements of asymmetric in- de[3b–e,j,k,n] (16b); however, the ee was 43% (run 2). In
duction, whereas lowering the ee was observed in the re- these cases the ee of the adduct was determined after
action without solvent in spite of a rate acceleration (run conversion to the corresponding benzoate.
4). The reactions at ꢀ788C, as expected, resulted in an
There are not so many examples[3j,l,m] on asymmetric
improvement of the asymmetric induction (run 1 vs. 5 TMS-cyanation of ketones to our knowledge. Thus, we
Adv. Synth. Catal. 2005, 347, 1653 – 1658
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tried the guanidine-catalyzed TMS-cyanation using 4- (1R,2S)-1-t-Butyldimethylsilyloxy-1,2-diphenyl-2-
phenyl-2-butanone (16c) as substrate (run 3). The reac- isothiocyanatoethane (8)
tion was carried out at ꢀ408C because of a lack of reac-
To a solution of the silyl ether 7 (15.1 g, 46. 2 mmol), carbon di-
sulfide (3.51 g, 46.2 mmol), and triethylamine (15.4 g,
tion at ꢀ788C. Although conversion was low (29%)
even after stirring for a longer time (21 h), moderate
asymmetric induction (39%) was observed.
152 mmol) in CH2Cl2 (100 mL) was added DMC (9.38 g,
55.5 mmol) and the whole was stirred at room temperature
for 1 h. After evaporation of the solvent the resulting insoluble
material was washed with hexane. The washings were com-
bined and evaporated. The residue was subjected to column
chromatography (hexane:ethyl acetate¼20:1) to afford 8 as
a colorless solid; yield: 14.1 g (82%); mp 37–408C; [a]D:
1
Conclusion
ꢀ32.3; H NMR: d¼ ꢀ0.47, ꢀ0.28 (each 3H, s, SiMe), 0.78
(9H, s, t-Bu), 4.77 (1H, d, J¼6.1 Hz, 1- or 2-H), 4.82 (1H, d,
J¼6.1 Hz, 2- or 1-H), 7.14–7.20 (4H, br s, ArH), 7.24–7.32
(6H, br s, ArH); 13C NMR: d¼ ꢀ5.49, ꢀ4.98, 17.98, 25.62,
68.18, 78.89, 127.10, 127.70, 128.03, 128.16, 128.25, 128.37,
In summary, it was found that a C2-symmetrical bicyclic
guanidine effectively catalyzed the asymmetric TMS-
cyanation of carbonyl substrates. Especially reasonable
ee was observed in cyclohexanecarbaldehyde (16a) and
moderate asymmetric induction was attained even in a
ketonic substrate. These guanidine-catalyzed asymmet-
ric TMS-cyanations could contribute to the develop-
ment of green chemistry,[10] because modified guani-
dines are considered to be re-useable (economically fa-
vored) and easily functionalizable (widely applicable)
artificial organic bases. Thus, further examination on
this guanidine chemistry is in progress in our laboratory.
135.87, 139.89; IR (KBr): nmax ¼2080 cmꢀ1
.
1-[(1R,2S)-(2-t-Butyldimethylsilyloxy-1,2-
diphenylethyl)]-2-[(1S,2S)-(1,2-diphenylethyl-2-
ethoxycarbonylamino)]thioamide (10)
A mixture of the isothiocyanate 8 (13.3 g, 36.0 mmol) and 2-
amino-1,2-diphenyl-1-ethoxycarbonylaminoethane (9; 10.2 g,
36.0 mmol) in CH2Cl2 (200 mL) was stirred at room tempera-
ture for 65 h. After evaporation of the solvent the residue
was subjected to column chromatography (hexane:ethyl
acetate¼5:1) to afford 10 as a colorless powder; yield: 22.0 g
(94%); mp 85–908C; [a]D: ꢀ52.1; 1H NMR[11]: d¼ ꢀ0.27,
ꢀ0.07 (each 3H, s, Me), 0.83 (9H, s, t-Bu), 1.18 (3H, br,
CH2CH3), 4.07 (2H, br, OCH2CH3), 4.73, 5.02 (each 1H, br,
CH), 5.63 (2H, br, CHꢁ2), 6.62 (1H, br, NH), 7.01 (10H, br
s, ArH), 7.17 (10H, br s, ArH); 13C NMR: d¼ ꢀ5.23, ꢀ4.83,
14.56, 18.08, 25.78, 60.40, 60.76, 61.42, 64.33, 126.71, 127.35,
127.47, 127.98, 128.57, 136.59, 138.10, 140.23, 157.52, 181,11;
Experimental Section
General
All melting points were measured on a Büchi 535 melting point
apparatus and are uncorrected. IR spectra were recorded on a
JASCO IR-700 spectrophotometer. 1H and 13C NMR spectra
were recorded in CDCl3 on a JEOL JNM GSX-300. Optical ro-
tationswere recorded inchloroform(c¼1.0) on a JASCO DIP-
140 digital polarimeter. Column chromatography was per-
formed on silica gel 60 (70–230 mesh, Merck).
IR (KBr): nmax ¼1690, 1530 cmꢀ1
.
(4S,5S)-2-[(1S,2R)-(2-t-Butyldimethylsilyloxy-1,2-
diphenylethyl)]imino-4,5-diphenyl-1-
ethoxycarbonylimidazolidine (11)
To a solution of the thioamide 10 (21.4 g, 32.8 mmol) and trie-
thylamine (9.94 g, 98.4 mmol) in acetonitrile (150 mL) was
added DMC (6.65 g, 39.4 mmol) and the whole was refluxed
for 17 h. After cooling the mixture was partitioned with
CH2Cl2. The residue obtained after conventional work-up
was subjected to column chromatography (hexane:ethyl
acetate¼5:1) to afford 11 as a colorless amorphous solid;
(1R,2S)-2-Amino-1-t-butyldimethylsilyloxy-1,2-
diphenylethane (7)
A mixture of (1R,2S)-2-amino-1,2-diphenylethanol (6; 10.0 g,
46.9 mmol), t-butylchlorodimethylsilane (7.07 g, 46.9 mmol),
triethylamine (4.74 g, 46.9 mmol), and 4-dimethylaminopyri-
dine (1.15 g, 9.38 mmol) in chloroform (200 mL) was stirred
at room temperature for 41 h and then heated (bath tempera-
ture, 408C) for 6 h with stirring. The mixture was washed with
H2O, dried over MgSO4, and evaporated. Purification of the
residue by column chromatography (CHCl3 :MeOH¼50:1)
afforded 7 as a colorless viscous oil; yield: 15.6 g (quant);
1
yield: 18.6 g (92%); [a]D: ꢀ21.0; H NMR: d¼ ꢀ0.20, ꢀ0.00
(each 3H, s, SiMe), 0.89 (9H, s, t-Bu), 0.95 (3H, t, J¼6.8 Hz,
CH2CH3), 3.99 (2H, q, J¼6.8 Hz, OCH2CH3), 4.74, 4.77
(each 2H, d, J¼4.1 Hz, CH), 5.22 (1H, dd, J¼8.6, 4.7 Hz, 4-
H), 5.23 (1H, d, J¼4.7 Hz, 5-H), 7.12–7.37 (20H, m, ArH),
7.95 (1H, br s, NH); 13C NMR: d¼ ꢀ5.31, ꢀ4.79, 13.83,
18.12, 25.83, 61.91, 63.14, 70.25, 73.94, 125.88, 126.12, 126.99,
127.12, 127.14, 127.20, 127.52, 127.58, 128.51, 128.52, 128.65,
138.43, 141.60, 142.58, 144.59, 152.78, 153.18; IR (KBr):
1
[a]D: ꢀ32.3; H NMR: d¼ ꢀ0.32, ꢀ0.25 (each 3H, s, SiMe),
0.75 (9H, s, t-Bu), 1.53 (2H, br s, NH2), 4.02, 4.63 (each 1H, d,
J¼6.5 Hz, 1-, 2-H), 7.13–7.30 (10H, br s, ArH); 13C NMR:
d¼ ꢀ5.55, ꢀ4.95, 18.01, 25.68, 62.90, 80.16, 127.10, 127.22,
127.48, 127.82, 127.94, 142.02, 142.66.
nmax ¼3370, 1710, 1640, 1520 cmꢀ1
.
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Asymmetric Trimethylsilylcyanation of Carbonyl Compounds
FULL PAPERS
(4S,5S)-4,5-Diphenyl-2-[(1S,2R)-(1,2-diphenyl-2-
hydroxyethyl)]imino-1-ethoxycarbonylimidazolidine
(12)
TMS-Cyanation of Cyclohexanecarbaldehyde (16a): 2-
Cyclohexyl-2-hydroxyacetonitrile (Typical Procedure)
Caution: TMSCN can be absorbed through the skin and is ex-
tremely toxic.
A
solution of the protected imidazolidine 11 (18.1 g,
A mixture of cyclohexanecarbaldehyde (16a; 0.05 mL,
0.41 mmol), TMSCN (0.05 mL, 0.38 mmol), and the guanidine
5 (17.5 mg, 0.04 mmol) in toluene (0. 5 mL) was stirred at 08C
for 1.5 h. After evaporation of the solvent, the residue was dis-
solved in ethyl acetate. The ethyl acetate solution was washed
with 10% aqueous HCl, dried over MgSO4, and evaporated to
dryness. Purification of the crude product by SiO2 column chro-
matography (hexane:ethyl acetate¼5:1) afforded 2-cyclohex-
yl-2-hydroxyacetonitrile; yield: 94.2 mg (82%). The ee was de-
termined by chiral HPLC after derivatization to the benzoate.
29.2 mmol) and a 1 M solution of tetrabutylammonium fluo-
ride (38.0 mL, 38.0 mmol) in tetrahydrofuran (76 mL) were
stirred at room temperature for 24 h. After partitioning with
CH2Cl2, the residue was subjected to column chromatography
(hexane:ethyl acetate¼3:1) to afford 12 as a colorless solid;
1
yield: 10.5 g (71%); mp 74–778C; [a]D: ꢀ54.8; H NMR: d¼
0.90 (3H, t, J¼7.0 Hz, CH2CH3), 3.93 (2H, m, OCH2CH3),
4.73, 4.83 (each 1H, d, J¼4.4 Hz, CH), 5.15 (1H, d, J¼
3.8 Hz, 5-H), 5.52 (1H, dd, J¼7.5, 3.8 Hz, 4-H), 7.06–7.39
(20H, m, ArH), 7.80 (1H, br s, NH); 13C NMR: d¼13.74,
62.20, 63.15, 70.47, 73.58, 78.40, 125.90, 126.13, 127.29, 127.46,
127.50, 127.56, 127.66, 127.72, 128.26, 128.74, 138.28, 139.82,
142.13, 143.77, 153.25, 154.34; IR (KBr): nmax ¼3340, 1710,
Acknowledgements
1640, 1530 cmꢀ1
.
This work was supported by a Grant-in-Aid for Scientific Re-
search (14370717) from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
(2S,3S,7S,8S)-6-Ethoxycarbonyl-2,3,7,8-tetraphenyl-
1,4,6-triazabicyclo[2.2.0]oct-4-ene (13)
References and notes
To a solution of the deprotected imidazolidine 12 (9.97 g,
19.7 mmol) and triethylamine (8.80 g, 87.1 mmol) in CH2Cl2
(100 mL) was added methanesulfonyl chloride (5.97 g,
33.4 mmol) and the whole was stirred at room temperature
for 24 h. After partitioning with CH2Cl2, acetonitrile was added
to the residue and the product 13 (3.04 g) was precipitated. The
filtrate was evaporated and the residue was subjected to col-
umn chromatography (hexane:ethyl acetate¼1 : 1) to afford
additional product 13 (5.60 g) as colorless solid; total yield:
8.64 g (90%); mp 162–1648C; [a]D: ꢀ25.2; 1H NMR: d¼1.17
(3H, t, J¼7.0 Hz, CH2CH3), 3.99, 5.36 (each 1H, d, J¼
8.8 Hz, CH), 4.14, 5.44 (each 1H, d, J¼2.4 Hz, CH), 4.24
(2H, m, OCH2CH3), 7.11–7.50 (20H, m, ArH); 13C NMR:
d¼14.23, 62.78, 64.33, 69.65, 72.94, 84.10, 126.02, 126.99,
127.08, 127.15, 127.91, 128.23, 128.32, 128.69, 128.88, 128.91,
129.22, 137.49, 139.01, 140.31, 142.75, 151.13, 159.56; IR
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(KBr): nmax ¼1720, 1660 cmꢀ1
.
(2S,3S,7S,8S)-2,3,7,8-Tetraphenyl-1,4,6-
triazabicyclo[2.2.0]oct-4-ene (5)
A solution of the protected bicyclic guanidine 13 (8.10 g,
16.6 mmol) and sodium methoxide (6.48 g, 119 mmol) in meth-
anol (32 mL) was stirred at room temperature for 1 h. After
partitioning with CH2Cl2, acetonitrile was added and the whole
was left to stand at ꢀ208C for 2 days. The precipitates were col-
lected by filtration to give 5 as a colorless solid; yield: 6.25 g
(91%); mp 157–1628C; [a]D: ꢀ158.0; 1H NMR: d¼4.05, 4.99
(each 2H, d, J¼5.5 Hz, CHꢁ2), 6.66 (1H, br, NH), 7.11–
7.14 (4H, m, ArH), 7.20–7.30 (16H, m, ArH); 13C NMR: d¼
67.72, 126.62, 127.27, 127.40, 127.95, 128.42, 128.62, 138.99,
142.78, 167.34; IR (KBr): nmax ¼1670 cmꢀ1; anal. calcd. for
C29H25N3: C 83.82, H 6.06, N 10.11; found: C 83.33, H 6.05, N
10.17.
Adv. Synth. Catal. 2005, 347, 1653 – 1658
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1657

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Adv. Synth. Catal. 2005, 347, 1653 – 1658