Asymmetric allenylation of aliphatic aldehydes catalyzed by a chiral formamide

Article abstract of DOI:10.1016/S0957-4166(98)00290-0

(S,S)-N,N-Bis(α-methylbenzyl)formamide in combination with HMPA catalyzes the allenylation of aliphatic aldehydes with propargyltrichlorosilane with good enantioselectivity (up to 95% e.e.).

Full text of DOI:10.1016/S0957-4166(98)00290-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2889–2894
Asymmetric allenylation of aliphatic aldehydes catalyzed by a
chiral formamide
Katsuhiko Iseki,∗ Yoshichika Kuroki and Yoshiro Kobayashi
MEC Laboratory, Daikin Industries, Ltd, Miyukigaoka, Tsukuba, Ibaraki 305-0841, Japan
Received 29 June 1998; accepted 17 July 1998
Abstract
(S,S)-N,N-Bis(α-methylbenzyl)formamide in combination with HMPA catalyzes the allenylation of aliphatic
aldehydes with propargyltrichlorosilane with good enantioselectivity (up to 95% e.e.). © 1998 Elsevier Science
Ltd. All rights reserved.
1. Introduction
The present paper discloses the first catalytic enantioselective allenylation of aldehydes.1 N,N-
Dimethylformamide (DMF) is an effective Lewis base that catalyzes some important reactions such as
allylation2 and allenylation3 of carbonyl compounds. We have previously succeeded in the asymmetric
allylation of aliphatic aldehydes with allyl- and crotyltrichlorosilanes mediated by the chiral DMF
analog, (S,S)-N,N-bis(α-methylbenzyl)formamide 1.4 The present addition of a propa-1,2-dienyl group
to aliphatic aldehydes is carried out enantioselectively using the chiral catalyst 1 in combination with the
additive, hexamethylphosphoramide (HMPA).
2. Results and discussion
Treatment of cyclohexanecarboxaldehyde 2a with 1.5 equiv. of a mixture of propargyl- and allenyl-
trichlorosilanes (3:4=75:25)5 in the presence of catalyst 1 (20 mol%) and HMPA (100 mol%) in
dichloromethane at −78°C for 14 days produced (S)-enriched propa-1,2-dienyl carbinol 5a in 71%
yield with 79% e.e. (Table 1, entry 1).6 However, propargyl carbinol 6a was obtained in only a
small amount (5a:6a=98:2), suggesting that formamide 1 catalyzes reaction of the aldehyde with
allenylsilane 4 very sluggishly.7 Although a decrease in the amount of catalyst 1 (10 mol%) retained
∗
Corresponding author. Tel: 81-298-58-5060; fax: 81-298-58-5082; e-mail: iseki@mec.daikin.co.jp
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00290-0

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Table 1
Asymmetric allenylation of aliphatic aldehydes 2 with propagyltrichlorosilane 3 catalyzed by
formamide 1
the enantioselectivity (entry 2, 79% e.e.), the absence of HMPA markedly suppressed it (entry 3, 43%
e.e.).8 Hydrocinnamaldehyde 2b and 2-ethylbutanal 2c provided the corresponding propa-1,2-dienyl
carbinols, 5b and 5c, with an enantiomeric excess of 79% and 77%, respectively (entries 4 and 5).
The highest enantioselectivity was attained with 2,2-dimethylpropanal 2d (entry 6, 95% e.e.). With
heptanal 2e, the reaction in acetone was found to be more effective in terms of enantioselectivity than
that in dichloromethane (entry 7, 56% e.e.).9 A typical aromatic aldehyde, benzaldehyde 2f, gave the
corresponding alcohol 5f in essentially racemic form (entry 8).10,11
In conclusion, we have succeeded in the first catalytic enantioselective allenylation of aliphatic
aldehydes using the chiral formamide 1. Attempts are presently being made to improve the allenylation,
especially the catalytic activity,12 and to apply the catalyst 1 to other catalytic asymmetric reactions.
3. Experimental
3.1. General
All reactions were carried out under an argon atmosphere with magnetic stirring in oven-dried glass-
ware. Dichloromethane and acetone were distilled from CaH2 and K2CO3, respectively, immediately
before use. Other solvents and reagents were used as supplied or purified. Anhydrous MgSO4 was used
as the drying agent. TLC was carried out with pre-coated Kieselgel 60F254 plates (Merck). Silica gel
60 (Merck, 230–400 mesh) was used for column chromatography. GLC analysis was carried out on a
Shimadzu GC-17A instrument using a J&W Scientific (30 m×0.25 mm) DB-1 capillary column whose
film thickness was 0.25 µm. Liquid chromatographic analysis was performed on a Shimadzu LC-10A
at 254 nm using a chiral column (Daicel Chiralcel OD-H and AD columns). Optical rotations were
measured at 589 nm using a 1.0 dm cell with a total volume of 1 mL on a JASCO DIP-370 polarimeter.

K. Iseki et al. / Tetrahedron: Asymmetry 9 (1998) 2889–2894
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Melting points were measured on a Yanaco MP-500D micro melting point apparatus and are uncorrected.
Infrared spectra were taken either neat or as KBr pellets on a Perkin–Elmer 1600 FT-IR. Absorption
1
was expressed in reciprocal centimeters (cm−1). H NMR and 13C NMR spectra were recorded at 200
1
MHz and 50 MHz, respectively, on a Varian Gemini-200 instrument. H NMR signals were expressed
in parts per million (ppm) downfield from TMS as the internal standard (δ). 13C NMR spectra were
given with CHCl3 (77.0 ppm) as the internal standard. Coupling constants are in hertz. CDCl3 served
as solvent for 1H and 13C NMR. Low- and high-resolution mass spectral analyses were performed at 70
eV electron-impact (EI) using a Kratos CONCEPT-1H double-focusing magnetic sector spectrometer.
Elemental analysis was carried out at the Toray Research Center, Inc., Tokyo.
3.2. Materials
(S,S)-Bis(α-methylbenzyl)amine was purchased from AZmax Co. Ltd., Chiba, Japan. Acetic formic
anhydride was prepared according to reported procedures.13
3.3. Preparation of (S,S)-N,N-bis(α-methylbenzyl)formamide 1
To a solution of (S,S)-bis(α-methylbenzyl)amine (5 g, 22.2 mmol) in dichloromethane (50 mL) was
added dropwise acetic formic anhydride (96% purity, 5.1 g, 55.6 mmol) at room temperature. After
stirring for 1 h, the reaction was quenched with saturated aqueous NaHCO3 (50 mL). The organic layer
was separated and the aqueous phase extracted with dichloromethane (2×50 mL). The combined extracts
were washed with brine and dried. After evaporation of the solvent, the residue was purified by flash
chromatography (SiO2, EtOAc:n-hexane=1:3) and recrystallized from Et2O:n-hexane to give 1 (5.5 g,
25
98% yield) as colourless needles: m.p. 80.2–81.8°C; [α]D −214.1 (c 1.02, CHCl3); IR (KBr): 2976,
1
1645, 1248, 697 cm−1; H NMR (CDCl3): δ 1.67 (d, J=7.2 Hz, 3H), 1.71 (d, J=7.2 Hz, 3H), 4.50 (q,
J=7.2 Hz, 1H), 5.69 (q, J=7.2 Hz, 1H), 7.30–6.78 (m, 10H), 8.33 (s, 1H); 13C NMR (CDCl3): δ 17.1,
22.4, 50.7, 52.9, 126.7, 127.4, 127.7, 128.1, 128.3, 139.8, 141.0, 162.6; MS: m/z 253 [M+], 148, 120,
105; anal. calcd for C17H19NO: C, 80.6; H, 7.6; N, 5.5. Found: C, 80.6; H, 7.5; N, 5.5.
3.4. Preparation of propargyltrichlorosilane 3
A mixture of trichlorosilane (25 g, 184.6 mmol), propargyl chloride (13.4 mL, 184.6 mmol) and Et2O
(150 mL) was added dropwise to a suspension of CuCl (1.83 g, 18.5 mmol) and Et3N (24.4 mL, 175.4
mmol) in Et2O (150 mL) at room temperature. After 16 h at this temperature, the reaction mixture was
filtered. Distillation of the filtrate gave a mixture of 3 and 4 (3:4=75:25, 6.65 g, 21%) at 55–58°C/85 torr.
1
3: H NMR (CDCl3): δ 2.11 (t, J=3.0 Hz, 1H), 2.42 (d, J=3.0 Hz, 2H); 13C NMR (CDCl3): δ 15.4,
71.3, 109.2; MS: m/z 176 [M+], 174 [M+], 172 [M+]; HRMS calcd for C3H3Cl3Si [M+]: 171.9070.
Found: 171.9073.
1
4: H NMR (CDCl3): δ 4.92 (d, J=6.8 Hz, 2H), 5.33 (t, J=6.8 Hz, 1H); 13C NMR (CDCl3): δ 74.1,
84.4, 216.4; MS: m/z 176 [M+], 174 [M+], 172 [M+]; HRMS calcd for C3H3Cl3Si [M+]: 171.9070.
Found: 171.9077.

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3.5. General procedure for the preparation of 3,5-dinitrobenzoate derivatives of propa-1,2-dienyl
carbinols 5
To a solution of an optically active propa-1,2-dienyl carbinol 5 (65 µmol) in dichloromethane (2 mL)
were added Et3N (0.5 mL, 3.59 mmol), 3,5-dinitrobenzoyl chloride (77 mg, 0.33 mmol), and a catalytic
amount of 4-dimethylaminopyridine at room temperature. The reaction mixture was stirred for 18 h,
poured into ice water and extracted with Et2O. The combined extracts were washed with 0.5 N HCl,
saturated aqueous NaHCO3 and brine, dried and filtered. After evaporation of the solvent, a solution of
the residue in dichloromethane was passed through a short silica gel column. The 3,5-dinitrobenzoate was
recovered completely by elution with dichloromethane and the combined fractions were concentrated in
vacuo. The obtained residue was analyzed by HPLC using a chiral column (Daicel Chiralcel OD-H and
AD columns) to determine the enantiomeric excess.
3.6. Typical procedure for allenylation catalyzed by the chiral formamide 1. (S)-1-Cyclohexylbuta-2,3-
dien-1-ol 5a
To a solution of cyclohexanecarboxaldehyde 2 (112 mg, 1.0 mmol), catalyst 1 (50.7 mg, 0.2 mmol)
and HMPA (175 µL, 1.0 mmol) in dichloromethane (2 mL) was added dropwise a mixture of 3 and 4
(263 mg, 1.5 mmol) at −78°C. After stirring at −78°C for 14 days, the reaction mixture was poured into
an ice-cooled mixture of Et2O (30 mL) and saturated aqueous NaHCO3 (30 mL) and stirred for 15 min.
The organic layer was separated and the aqueous phase extracted with Et2O (2×30 mL). The combined
organic extracts were dried (MgSO4) and concentrated in vacuo. The oily residue was purified by flash
chromatography (SiO2, EtOAc:n-hexane=1:20) to afford 5a and 6a (5a:6a=98:2, 108 mg, 71% yield) as
a colourless oil. [α]D24 +10.5 (c 1.02, benzene) (79% e.e.); IR (neat): 3360, 2924, 1955, 1450, 1015, 841
1
cm−1; H NMR (CDCl3): δ 0.82–1.91 (m, 11H), 1.75 (s, 1H), 3.92 (ddt, J=2.2, 6.6, 6.6 Hz, 1H), 4.83
(dd, J=2.2, 6.5 Hz, 2H), 5.21 (dt, J=6.5, 6.6 Hz, 1H); 13C NMR (CDCl3): δ 26.1, 26.5, 28.3, 28.6, 44.1,
74.0, 77.1, 93.2, 112.3, 207.2; MS: m/z 152 [M+], 113, 95; HRMS calcd for C10H16O [M+]: 152.1201.
Found: 152.1196. HPLC analysis of the corresponding 3,5-dinitrobenzoate: tR (retention time) (minor),
4.1 min (10.4%); tR (major), 7.7 min (89.6%) (Chiralcel AD, n-hexane:EtOH=9:1, 2.0 mL/min). Elution
with n-hexane:EtOAc (3:1) recovered the chiral formamide 1 (49.1 mg) without racemization.
3.7. 6-Phenylhexa-1,2-dien-4-ol 5b
23
Compound 5b (5b:6b=99:1, 71%) was obtained by the same procedure as 5a: a colourless oil; [α]D
−2.4 (c 1.41, CHCl3) (79% e.e.); IR (neat): 3384, 2928, 1955, 1716, 1454, 700 cm−1; 1H NMR (CDCl3):
δ 1.69 (d, J=4.9 Hz, 1H), 1.93 (dt, J=7.6, 7.7 Hz, 2H), 2.77 (dt, J=4.4, 7.7 Hz, 2H), 4.12–4.30 (m, 1H),
4.91 (dd, J=2.5, 6.5 Hz, 2H), 5.31 (dt, J=6.5, 6.8 Hz, 1H), 7.12–7.39 (m, 5H); 13C NMR (CDCl3): δ 31.7,
39.0, 68.9, 77.8, 94.7, 125.9, 128.4, 128.5, 141.8, 207.1; MS: m/z 174 [M+], 156, 91; HRMS calcd for
C12H14O [M+]: 174.1045. Found: 174.1042. HPLC analysis of the corresponding 3,5-dinitrobenzoate:
tR (major), 16.7 min (89.5%); tR (minor), 22.0 min (10.5%) (Chiralcel AD, n-hexane:EtOH=9:1, 1.0
mL/min).
3.8. 5-Ethylhepta-1,2-dien-4-ol 5c
23
Compound 5c (5c:6c=96:4, 70%) was obtained by the same procedure as 5a: a colourless oil; [α]D
+38.8 (c 0.90, CHCl3) (77% e.e.); IR (neat): 3360, 2963, 1956, 1461, 1021, 841 cm−1; 1H NMR (CDCl3):

K. Iseki et al. / Tetrahedron: Asymmetry 9 (1998) 2889–2894
2893
δ 0.92 (t, J=7.3 Hz, 6H), 1.20–1.60 (m, 5H), 1.62 (s, 1H), 4.13–4.28 (m, 1H), 4.86 (dd, J=2.2, 6.4 Hz,
2H), 5.23 (dt, J=6.4, 6.9 Hz, 1H); 13C NMR (CDCl3): δ 11.5, 11.6, 21.5, 21.8, 47.1, 71.2, 77.3, 93.3,
208.9; MS: m/z 140 [M+], 125, 111, 101; HRMS calcd for C9H16O [M+]: 140.1201. Found: 140.1208.
HPLC analysis of the corresponding 3,5-dinitrobenzoate: tR (minor), 4.2 min (11.6%); tR (major), 7.8
min (88.4%) (Chiralcel AD, n-hexane:EtOH=20:1, 2.0 mL/min).
3.9. 5,5-Dimethylhexa-1,2-dien-4-ol 5d
The 3,5-dinitrobenzoate of compound 5d (5d:6d=94:6, 55%) was obtained by the same procedure
24
as 5a: [α]D +78.5 (c 0.87, CHCl3) (95% e.e.); IR (KBr): 3103, 2969, 1732, 1548, 1345, 1278, 1167
1
cm−1; H NMR (CDCl3): δ 1.08 (s, 9H), 4.78–4.97 (m, 2H), 5.25–5.42 (m, 2H), 9.15–9.25 (m, 3H);
13C NMR (CDCl3): δ 25.7, 35.3, 77.1, 81.9, 87.2, 122.3, 129.3, 134.3, 148.6, 161.7, 209.2; MS: m/z 320
[M+], 305, 281, 195; HRMS calcd for C15H16N2O6 [M+]: 320.1008. Found: 320.1013. HPLC analysis
of the 3,5-dinitrobenzoate: tR (minor), 14.3 min (2.7%); tR (major), 15.8 min (97.3%) (Chiralcel OD-H,
n-hexane:EtOH=20:1, 1.0 mL/min).
3.10. Deca-1,2-dien-4-ol 5e
Compound 5e (5e:6e=93:7, 37%) was obtained by the same procedure as 5a, except using acetone
25
instead of dichloromethane: a colourless oil; [α]D +4.1 (c 0.93, CHCl3) (56% e.e.); IR (neat): 3334,
1
2929, 1957, 1467, 841 cm−1; H NMR (CDCl3): δ 0.88 (t, J=6.7 Hz, 3H), 1.20–1.65 (m, 10H), 1.69
(s, 1H), 4.10–4.23 (m, 1H), 4.85 (dd, J=2.4, 6.8 Hz, 2H), 5.24 (dt, J=6.3, 6.8 Hz, 1H); 13C NMR
(CDCl3): δ 14.1, 22.6, 25.4, 29.2, 31.8, 37.5, 69.7, 77.4, 94.9, 206.9; MS: m/z 154 [M+], 139, 115, 84,
70; HRMS calcd for C10H18O [M+]: 154.1358. Found: 154.1354. HPLC analysis of the corresponding
3,5-dinitrobenzoate: tR (minor), 11.8 min (21.8%); tR (major), 13.7 min (78.1%) (Chiralcel OD-H, n-
hexane:EtOH=20:1, 1.0 mL/min).
3.11. 1-Phenylbuta-2,3-dien-1-ol 5f
23
Compound 5f (5f:6f=96:4, 59%) was obtained by the same procedure as 5a: a colourless oil; [α]D
0.0 (c 0.65, CHCl3) (0% e.e.); IR (neat): 3380, 1955, 1452, 1024, 850, 700 cm−1; 1H NMR (CDCl3): δ
2.14 (s, 1H), 4.94 (dd, J=2.2, 6.5 Hz, 2H), 5.23–5.33 (m, 1H), 5.46 (dt, J=6.5, 6.5 Hz, 1H), 7.23–7.60
(m, 5H); 13C NMR (CDCl3): δ 72.0, 78.2, 95.2, 126.1, 127.8, 128.5, 142.8, 207.0; MS: m/z 146 [M+],
145, 108, 77; HRMS calcd for C10H10O [M+]: 146.0732. Found: 146.0736.
References
1. For enantioselective allenylation using a stoichiometric amount of chiral ligands, see: (a) Boldrini, G. P.; Lodi, L.;
Tagliavini, E.; Tarasco, C.; Trombini, C.; Umani-Ronchi, A. J. Org. Chem. 1987, 52, 5447–5452. (b) Corey, E. J.; Yu,
C.-M.; Lee, D.-H. J. Am. Chem. Soc. 1990, 112, 878–879.
2. (a) Kobayashi, S.; Nishio, K. Tetrahedron Lett. 1993, 34, 3453–3456; (b) Kobayashi, S.; Nishio, K. Synthesis 1994,
457–459; (c) Kobayashi, S.; Nishio, K. J. Org. Chem. 1994, 59, 6620–6628; (d) Wang, Z.; Wang, D.; Sui, X. J. Chem.
Soc., Chem. Commun. 1996, 2261–2262.
3. Kobayashi, S.; Nishio, K. J. Am. Chem. Soc. 1995, 117, 6392–6393.
4. Iseki, K.; Mizuno, S.; Kuroki, Y.; Kobayashi, Y. Tetrahedron Lett. 1998, 39, 2767–2770.
5. Reaction of propargyl chloride with trichlorosilane in the presence of CuCl and Et3N in Et2O at room temperature for 16
h generated 3 selectively (3:4=86:14); see Ref. 3. However, the distillation (55–58°C/85 torr) from the reaction mixture
caused the isomerization between 3 and 4 (3:4=75:25).

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6. The absolute configuration of the major enantiomer was determined to be S by comparison of the [α]D value with reported
24
data. Observed [α]D value of 5a with 79% e.e.: [α]D +10.5 (c 1.02, benzene). For (R)-enriched alcohol 5a (85% e.e.),
see: Lautens, M.; Delanghe, P. H. M. J. Am. Chem. Soc. 1994, 116, 8526–8535; [α]D −10.2 (c 2.1, benzene).
7. Kobayashi and Nishio have shown that 3 and 4 react with aldehydes in DMF to afford 5 and 6, respectively; see Ref. 3.
8. The reason why HMPA improves the enantioselectivity remains unclear. Both HMPA and 1 may coordinate with 3 to
generate a hexavalent silicate.
9. The allenylation of 2e using 40 mol% of 1 and 200 mol% of HMPA in dichloromethane at −78°C for 7 days gave 5e
in 74% yield with 28% ee (5e:6e=99:1). Acetone provides higher enantiomeric excesses than dichloromethane in the
allenylation of straight-chain aldehydes.
22
10. For (S)-enriched alcohol 5f (47% e.e.), see Ref. 1a; [α]D +45.6 (c 1.2, CCl4).
11. Although HMPA itself catalyzes the allenylation of aromatic aldehydes at −78°C, 1 is not effective in terms of
enantioselectivity even in the absence of HMPA; see Ref. 4.
12. The present allenylation is very sluggish at −78°C. Elevating the temperature improves the reaction rate but dramatically
suppresses the enantioselectivity; the allenylation of 2a in the presence of 1 (40 mol%) and HMPA (200 mol%) was carried
out at −40°C for 7 days to afford (S)-5a (5a:6a=91:9) in 84% yield with 19% e.e.
13. Krimen, L. I. Organic Synthesis; John Wiley: New York, 1988; Collect. Vol. 6, pp. 8–9.