A catalytic and enantioselective cyclopropylation of aldehydes using dicyclopropylzinc

Article abstract of DOI:10.1039/a707315a

Enantioselective cyclopropylation of various aldehydes proceeds using dicyclopropylzinc in the presence of a catalytic amount of chiral amino alcohol or thiophosphoramidate with Ti(OPr¹)₄ to provide enantiomerically enriched cyclopropyl alkanols (up to 96.6% ee).

Full text of DOI:10.1039/a707315a

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A catalytic and enantioselective cyclopropylation of aldehydes using
dicyclopropylzinc
Takanori Shibata, Hayami Tabira and Kenso Soai*
Department of Applied Chemistry, Faculty of Science, Science University of Tokyo,
Kagurazaka, Shinjuku-ku, Tokyo, 162 Japan
Enantioselective cyclopropylation of various aldehydes
proceeds using dicyclopropylzinc in the presence of a cat-
alytic amount of chiral amino alcohol or thiophosphor-
amidate with Ti(OPri)4 to provide enantiomerically en-
riched cyclopropyl alkanols (up to 96.6% ee).
zinc bromide, cyclopropyl bromide and lithium under ultra-
sonic conditions [eqn. (1)]†,10
Li, ultrasonic
Et2O, 0 °C
(1)
+
ZnBr2
Br
Zn
2
The catalytic enantioselective addition of diorganozincs to
aldehydes is one of the most important methods for the synthe-
sis of optically active secondary alcohols.1 We have developed
highly efficient chiral catalysts for enantioselective alkylations,
namely chiral amino alcohols derived from norephedrines2 and
proline,3 and chiral cyclic diamines (piperazines).4 Moreover, we
found that the chiral thiophosphoramidate5 derived from nor-
ephedrine was also an effective catalyst in the enantioselective
alkylation using diethylzinc with the aid of Ti(OPri)4.6
We here report the first highly enantioselective cyclopropyl-
ation of aldehydes using dicyclopropylzinc.7 The cyclopropyl
group is of interest in synthetic methodologies.8 The enantio-
selective reduction of phenyl cyclopropyl ketones has been
reported to provide a chiral cyclopropyl alkanol9 but alkylation
is more convenient because various chiral cyclopropanols can
be obtained depending on the choice of aldehyde.
As a preliminary study, an enantioselective cyclopropyl-
ation of benzaldehyde was examined under several reaction
conditions using diphenyl(1-methylpyrrolidin-2-yl)methanol
(DPMPM) 1 and N-(O,O-dimethylthiophosphoryl)norephed-
rine (PHONE) 2 as chiral catalysts (Table 1).
Cyclopropylation proceeded in high yield (90.0%) and
optical yield (83.3% ee) by the use of 5 mol% of DPMPM 1 in a
mixed solvent of hexane and toluene (4:1.5) (Entry 1). Ee was
decreased in toluene-free solvent (Entry 2). Lowering the reac-
tion temperature (Ϫ18 ЊC) had almost no effect on optical yield
(Entry 3), but it was slightly improved by increasing the amount
of chiral catalyst (20 mol%) (Entry 4). Utilization of the lithium
salt of 1 gave the same result as that of 1 itself (Entry 5).
PHONE 2, the thiophosphoramidate of norephedrine, was very
† Dicyclopropylzinc is known to be prepared from the zinc chloride and
cyclopropyl Grignard reagent but in very low yield of ca. 10%.7 The
present method using lithium gave dicyclopropylzinc, which was puri-
fied by distillation, in an improved yield.
Dicyclopropylzinc was prepared in 30% isolated yield from
* E-Mail: ksoai@ch.kagu.sut.ac.jp
Table 1 Enantioselective cyclopropylation of benzaldehyde under various reaction conditions
chiral catalyst
OH
*
DPMPM 1 or
PHONE 2 – Ti(OPri)4
CHO
Zn
+
2
Ph
Ph
Ph
Ph
OH
Ph
Me
OMe
OMe
N
OH
N
HO
N
H
P
S
Me
Me
(S)-DPMPM 1
(R)-DPMPM 1
(1R,2S)-PHONE 2
Entrya
Chiral catalyst (equiv.)
Solventb
Temp./ЊC
Time/h
Yield (%)
Ee (%)c
1
2
3
4
(R)-1 (0.05)
(R)-1 (0.05)
(R)-1 (0.05)
(S)-1 (0.20)
(S)-1d (0.20)
2 (0.05)
Hex–Tol
Hex
Hex–Tol
Hex–Tol
Hex–Tol
Tol
0
0
Ϫ18
0
0
Ϫ30
Ϫ30
4
4
4
5
6
2
2
90.0
86.9
86.5
90.1
81.6
84.5
93.1
83.3 (S)
76.5 (S)
84.4 (S)
85.8 (R)
84.8 (R)
87.1 (R)
96.0 (R)
5
6e
7e
2 (0.15)
Tol
a Unless otherwise noted, molar ratio of aldehyde:dicyclopropylzinc was 1.0:3.0. b Hex = hexane, Tol = toluene. Ratio of mixed solvent Hex:Tol was
4:1.5. c Ee was determined by HPLC using a chiral column (Daicel Chiralcel OD, eluent: 2% propan-2-ol in hexane, flow rate: 1 ml minϪ1) and the
absolute configuration was determined by comparison of optical rotation in the literature [ref. 9(a)]. d Lithium alkoxide of 1 was used. e Molar ratio
of aldehyde:Ti(OPri)4 :dicyclopropylzinc was 1.0:1.2:3.0.
J. Chem. Soc., Perkin Trans. 1, 1998
177

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Table 2 Enantioselective cyclopropylation of various aldehydes
efficient than DPMPM 1 and very high optical yields (90.8–
96.6% ee) were observed in each reaction (Entries 1–4). In the
cases of cinnamaldehyde, the two methods gave almost the
same results (Entry 5). It appears that DPMPM 1 is suitable
for the cyclopropylation of aliphatic aldehydes, with the corre-
sponding cyclopropyl alkanols being obtained with moderate
ee (Entries 6 and 7).
+
RCHO
Zn
2
Method A: (1R,2S)-PHONE 2, Ti(OPri)4, –30 °C
Method B: (R)-DPMPM 1, 0 °C
We have developed a highly enantioselective cyclopropyl-
ation of aldehydes by dicyclopropylzinc with the use of a
catalytic amount of chiral catalysts. Various chiral cyclopropyl
alkanols were obtained from both aromatic and aliphatic alde-
hydes depending on the choice of catalyst. The present method
provides a convenient and direct route for the preparation of
optically active cyclopropyl alkanols.
OH
*
R
Entry
R
Methoda Time/h Yield (%) Ee (%)b
1
2
3
4
5
Ph
A
Bc
A
B
A
B
2
5
3
3
2
2
2
2
93.1
90.1
98.9
96.7
85.0
96.7
88.6
93.7
94.1
94.1
91.3
86.6
96.0
85.8
96.6
86.2
90.8
84.1
95.6
78.2
63.6
67.3
67.0
70.5d
Acknowledgements
Financial support by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Science, Sports and Culture
is gratefully acknowledged.
4-MeO-C6H4
4-Cl-C6H4
1-Naphthyl
A
B
PhCH᎐CH
A
B
1.5
1.5
1
᎐
References
6
7
PhCH2CH2
Cyclohexyl
Bc
B
1 (a) K. Soai and S. Niwa, Chem. Rev., 1992, 92, 833; (b) K. Soai and
T. Hayase, Yuki Gosei Kagaku Kyokaishi (J. Synth. Org. Chem. Jpn.),
1995, 53, 138; (c) K. Soai and T. Shibata, Yuki Gosei Kagaku
Kyokaishi (J. Synth. Org. Chem. Jpn.), 1997, 55, 994; (d) R. Noyori
and M. Kitamura, Angew. Chem., Int. Ed. Engl., 1991, 30, 49;
(e) P. Knochel and R. D. Singer, Chem. Rev., 1993, 93, 2117.
2 (a) K. Soai, S. Yokoyama, K. Ebihara and T. Hayasaka, J. Chem.
Soc., Chem. Commun., 1987, 1690; (b) K. Soai, S. Yokoyama and
T. Hayasaka, J. Org. Chem., 1991, 56, 4264; (c) K. Soai, T. Hayase,
K. Takai and T. Sugiyama, J. Org. Chem., 1994, 59, 7908.
3 (a) K. Soai and A. Ookawa, J. Chem. Soc., Chem. Commun., 1986,
412; (b) A. Ookawa and K. Soai, J. Chem. Soc., Perkin Trans. 1,
1987, 1465; (c) K. Soai, A. Ookawa, K. Ogawa and T. Kaba,
J. Chem. Soc., Chem. Commun., 1987, 467; (d) K. Soai, A. Ookawa,
T. Kaba and K. Ogawa, J. Am. Chem. Soc., 1987, 109, 7111.
4 (a) K. Soai, S. Niwa, Y. Yamada and H. Inoue, Tetrahedron Lett.,
1987, 28, 4841; (b) S. Niwa and K. Soai, J. Chem. Soc., Perkin Trans.
1, 1991, 2717.
5 (a) K. Soai, Y. Hirose and Y. Ohno, Tetrahedron: Asymmetry, 1993,
4, 1473; (b) K. Soai, Y. Ohno, Y. Inoue, T. Tsuruoka and Y. Hirose,
Recl. Trav. Chim. Pay-Bas, 1995, 114, 145.
6 (a) B. Schmidt and D. Seebach, Angew. Chem., Int. Ed. Engl.,
1991, 30, 99; (b) H. Takahashi, T. Kawakita, M. Ohno, M. Yoshioka
and S. Kobayashi, Tetrahedron, 1992, 48, 5691; (c) M. J. Rozema,
S. Achyutha Rao and P. Knochel, J. Org. Chem., 1992, 57, 1956.
7 K.-H. Thiele, S. Wilcke and M. Ehrhardt, J. Organomet. Chem.,
1968, 14, 13.
2
a Method A. Molar ratio of aldehyde:PHONE 2:Ti(OPri)4 :dicyclo-
propylzinc was 1.0:0.15:1.2:3.0. Method B. Molar ratio of
aldehyde:DPMPM 1:dicyclopropylzinc was 1.0:0.05:3.0. b Ee was
determined by HPLC using a chiral column. c 0.20 equiv. of DPMPM 1
was used. d Ee was determined as its benzoate by HPLC using a chiral
column.
effective with the aid of Ti(OPri)4 (Entry 6), especially when 15
mol% of 2 was used as a chiral catalyst. In this case 96.0% ee
was reached (Entry 7).
Various aldehydes were submitted to the enantioselective
cyclopropylation using PHONE 2 in coexistence of Ti(OPri)4
(Method A)‡ or DPMPM 1 (Method B)§ (Table 2). In the
cyclopropylation of aromatic aldehydes, PHONE 2 was more
‡ Typical experimental procedure for Method A (Table 2, Entry 1). A
toluene solution (2 ml) of (1R,2S)-PHONE 2 (41.3 mg, 0.15 mmol) and
Ti(OPri)4 (0.36 ml, 1.2 mmol) was stirred for 20 min at room tempera-
ture. The reaction vessel was cooled to Ϫ30 ЊC and a 1  toluene solu-
tion of dicyclopropylzinc (3 ml, 3 mmol) was injected into it. After the
reaction mixture was stirred for 20 min, a toluene solution (2 ml) of
benzaldehyde (106.1 mg, 1.00 mmol) was added at this temperature.
After the mixture was stirred for 2 h, the reaction was quenched by the
addition of sat. aq. NH4Cl (15 ml), then the mixture was filtered using
Celite and the filtrate was extracted with dichloromethane. The com-
bined extracts were dried over anhydrous sodium sulfate and evapor-
ated to dryness under reduced pressure. Purification of the crude prod-
uct on silica gel TLC (thin-layer chromatography) (eluent: CH2Cl2) gave
the pure cyclopropyl alkanol (137.9 mg, 0.931 mmol, 93.1%). Optical
purity was determined to be 96.0% ee by HPLC analysis.
8 The Chemistry of the Cyclopropyl Group, Parts
ed. Z. Rappoport, Wiley, New York, 1987.
1 and 2,
9 (a) C. W. Bradshaw, W. Hummel and C.-H. Wong, J. Org. Chem.,
1992, 57, 1532; (b) X. Zhang, H. Kumobayashi and H. Takaya,
Tetrahedron: Asymmetry, 1994, 5, 1179; (c) T. Nagata, K. D. Sugi,
T. Yamada and T. Mukaiyama, Synlett, 1996, 1076.
10 C. Petrier, J. C. S. Barbosa, C. Dupuy and J.-L. Luche, J. Org.
Chem., 1985, 50, 5761.
§ Typical experimental procedure for Method B (Table 2, Entry 1). To a
hexane solution (4 ml) of (R)-DPMPM 1 (26.8 mg, 0.10 mmol) and
benzaldehyde (52.7 ml, 0.50 mmol) was added a 1  toluene solution of
dicyclopropylzinc (1.5 ml, 1.5 mmol) at 0 ЊC. The quenching treatment
and purification was the same as that of Method A and gave pure
cyclopropyl alkanol (66.3 mg, 0.45 mmol, 90.1%). Optical purity was
determined to be 85.8% ee by HPLC analysis.
Paper 7/07315A
Received 9th October 1997
Accepted 18 November 1997
178
J. Chem. Soc., Perkin Trans. 1, 1998