Stereoselective synthesis of activated cyclopropanes with an α-pyridinium acetamide bearing an 8-phenylmenthyl group as the chiral auxiliary

Article abstract of DOI:10.1016/j.tetlet.2004.03.044

The reaction between an α-pyridinium acetamide bearing an 8-phenylmenthyl group as the chiral auxiliary and β-substituted methylidenemalononitriles gave rise to trans-cyclopropanes with diastereomeric ratios of up to 98:2. For most of the reactions, the absolute stereochemistry of the major product was found to be opposite of that of the major products of the reaction of the corresponding ester series, which also utilized the 8-phenylmenthyl group.

Full text of DOI:10.1016/j.tetlet.2004.03.044

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3565–3568
Stereoselective synthesis of activated cyclopropanes with an
a-pyridinium acetamide bearing an 8-phenylmenthyl group as the
chiral auxiliary
a
a
Satoshi Kojima,a,b, Kyoko Hiroike and Katsuo Ohkata
*
aDepartment of Chemistry, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama, Hiroshima, Higashi 739-8526,
Japan
bCenter for Quantum Life Sciences, Hiroshima University, 1-3-1 Kagamiyama, Hiroshima, Higashi 739-8526, Japan
Received 14 February 2004; revised 4 March 2004; accepted 10 March 2004
Abstract—The reaction between an a-pyridinium acetamide bearing an 8-phenylmenthyl group as the chiral auxiliary and
b-substituted methylidenemalononitriles gave rise to trans-cyclopropanes with diastereomeric ratios of up to 98:2. For most of the
reactions, the absolute stereochemistry of the major product was found to be opposite of that of the major products of the reaction
of the corresponding ester series, which also utilized the 8-phenylmenthyl group.
Ó 2004 Elsevier Ltd. All rights reserved.
The high reactivity of cyclopropanes1 has been attrib-
uted to their strained nature, and due to this character,
certain cyclopropanes have been found to show bio-
activity2 and some others have been utilized as building
blocks en route to complex structures.3 Thus, the
asymmetric synthesis of cyclopropanes has been a well
examined subject.4 Although high levels of asymmetric
induction has been reported for catalytic reactions
involving metal-carbenoid reactions,4b;5 so far, satisfac-
tory results have been limited to cyclopropanes that are
not highly substituted. For cyclopropanes with multiple
numbers of electron-withdrawing groups that are viable
of further functionalization, not many examples are
known. For such type of cyclopropanes, the ylide
method, which usually utilizes ylides prepared from
sulfonium salts or chloromethylcarbonyl compounds, is
more commonly used.4b;6 Pyridinium ylides have also
been found to be applicable for cyclopropanation7 and
we have recently described the first asymmetric variant8
using an a-pyridinium acetate 1 bearing an 8-phenyl-
menthyl group9;10 as the chiral auxiliary (Scheme 1).
Using 1, moderate diastereoselectivities were observed in
4. We assumed that the first C–C bond formation
involved the Michael addition of the pyridinium ylide to
the substituted methylidenemalononitrile substrate.
Since the ylide from the a-pyridinium acetate is highly
NC CN
R
NC CN
C(O)XR*
R
CN
CN
Cl
base
O
+
+
R* =
N
solvent
XR*
C(O)XR*
R
Ph
4 trans-1R (X = O)
5 trans-1R (X = NH)
4 trans-1S (X = O)
5 trans-1S (X = NH)
1 (X = O)
2 (X = NH)
3
Scheme 1.
Keywords: Diastereoselective; Activated cyclopropane; 8-Phenylmenthylamine; Pyridinium ylide; Methylidenemalononitrile.
* Corresponding author at present address: Department of Chemistry, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama,
Higashi-Hiroshima 739-8526, Japan. Tel.: +81-82-424-7433; fax: +81-82-424-0747; e-mail: skojima@sci.hiroshima-u.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.044

3566
S. Kojima et al. / Tetrahedron Letters 45 (2004) 3565–3568
Table 1. Cyclopropanation using 3a (R ¼ Ph)
stabilized we reasoned that the observed moderate
selectivity was due to facile retro-Michael addition that
could intervene. In order to minimize this reverse reac-
tion, we envisioned that the use of amides in the place of
esters would be the solution. To this end, we prepared
the amide analog 2 and found that for certain substrates,
the selectivity could be raised, and also that the stereo-
chemistry of the major product became opposite of that
of the ester analog determined by X-ray structural
analysis. Herein we describe our results.
Entry
Base
Solvent
Temperature Yield
(%)
Dra
1
2
3
4
Et3N
LiH
DBU
CH2Cl2
CH2Cl2
CH3CN
Rt
Rt
86
97
0
62:38
64:36
––
Rt
0 °C
t-BuOK CH3CN
20
54:46
a Determined by 1H NMR of the crude product.
what sluggish and generally required room temperature
whereas 0 °C was sufficient for the ester series. To
establish the stereochemistry of the products, X-ray
structural analysis of the minor product, which formed
better-shaped crystals, was carried out. The absolute
stereochemistry was found to be trans-1S,17 the opposite
to that of the major 4-pyridyl substituted cyclopropane
diastereomer of the ester series (trans-1R), thus it fol-
lowed that the major phenyl substituted product (5a)
had the same stereochemistry as that in the ester series.
Although the amine analog of highly utilized 8-phenyl-
menthol would seemingly be useful as a chiral auxiliary,
only a single report on its use was seen in the literature
when we commenced on this project and that with no
details on its preparation.11 Thus, we initiated our
studies by examining methods of preparing 7 (Scheme
2). In analogy with the preparation of menthylamine
from natural menthone via dissolving metal reduction of
the oxime of menthone,12 8-phenylmenthone13 was
converted to its methoxyimine 6.14 Refluxing mixtures of
6 and sodium in absolute ethanol gave rise to diaste-
reomeric mixtures of the required amine 7 with ratios up
to 89:11. Ratios were typically over 80:20 and yields in
the range of 68–97%.15 The use of methanol in the place
of ethanol lead to substantially reduced yield, and the
use of Na with i-PrOH in toluene as in the synthesis of
the corresponding alcohol from menthone gave rise to
product in the ratio of only 67:33.13 The oxime of
8-phenylmenthone was also useful, giving amine 7 in
61% with 83:17 selectivity. Although the diastereomers
of 7 could be separated by slow and careful chroma-
tography, the mixture was typically used as is and con-
verted to chloroacetamide 8, which could be purified by
recrystallization.16 The NMR of 8 clearly indicated that
the amino group was oriented equatorial, and this was
confirmed by X-ray structural analysis of the minor
diastereomer 8-ax (axial N).17 The pyridinium salt 2 was
obtained upon treating 8 with pyridine neat.18
Since the selectivity was disappointing for 3a, we deci-
ded to examine the effect of solvent using the t-butyl
substituted methylidenemalononitrile (3b) as the sub-
strate with Et3N as base.19 As a result, high selectivities
(up to 2:98) were achieved with little dependence on the
nature of the solvent (Table 2). Although EtOH was
favorably used in previously reported examinations,7;8 it
was not effective here. Interestingly, the X-ray structural
analysis of the major product revealed that the major
product had stereochemistry opposite (trans-1S) to that
of the major Ph diastereomer of 5a, indicating that the
stereochemical course of the reaction had changed.17
As for substrates with aliphatic substituents, practically
no selectivity was observed for the one with the
unbranched n-butyl group (3d), whereas a ratio of 12:88,
which exceeds the best ratio (86:14) in the ester series,
was observed for that with a more sterically demanding
i-propyl group (3c) (Table 3). 1-Adamantyl substituted
In the case of the ester series, the diastereoselectivity for
the phenyl substituted substrate (3a) had been found to
vary in the range of 64:36–83:17 depending upon solvent
although practically no difference in selectivity was
observed with change of the base. Thus, these two
conditions were first examined. Using 3a with four dif-
ferent bases (Table 1), it was found that Et3N and LiH
functioned best for high yield, giving only the trans
substituted cyclopropane as in the case of the ester ser-
ies. However, the diastereoselectivity was found to be
low in comparison with the ester series, contrary to
expectations. The reaction itself was found to be some-
Table 2. Cyclopropanation using 3b (R ¼ t-Bu)
Entry
Base
Solvent
Temperature Yield
(%)
Dra
1
2
3
4
5
6
7
Et3N
LiH
CH2Cl2
CH2Cl2
CH3CN
THF
Rt
Rt
Rt
Rt
Rt
Rt
Rt
62
84
59
83
61
69
0
7:93
5:95
2:98
5:95
6:94
4:96
––
Et3N
Et3N
Et3N
Et3N
Et3N
Toluene
DMF
EtOH
a Determined by 1H NMR of the crude product.
O
(i)
(ii)
(iii)
(iv)
Cl
O
OMe
Cl
O
N
NH2
N
H
N
NHR*
Ph
Ph
Ph
Ph
6
7
8
2
Scheme 2. Reagents and conditions: (i) NH3OMeCl, pyridine, EtOH, 95%; (ii) Na, EtOH, reflux, 68–97%, up to 89:11; (iii) ClCH2COCl,
C6H5NMe2, ether, 87%, diastereomerically pure; (iv) pyridine, reflux, 97%.

S. Kojima et al. / Tetrahedron Letters 45 (2004) 3565–3568
Table 3. Cyclopropanation reaction with various substrates (RCH ¼ CXCN)
3567
Entry
Substrate
R
X
Base
Solvent
Temperature
Product
Yield (%)
Dra
1
3a
3b
3c
3c
3d
3d
3e
3e
3f
3f
3f
3g
3h
3h
3i
Ph
t-Bu
CN
CN
LiH
Et3N
LiH
CH2Cl2
CH3CN
CH2Cl2
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
CH2Cl2
CH2Cl2
CH3CN
CH2Cl2
CH2Cl2
CH3CN
CH2Cl2
CH3CN
CH2Cl2
CH3CN
Rt
Rt
5a
5b
5c
5c
5d
5d
5e
5e
5f
5f
5f
5g
5h
5h
5i
97
59
64:36
2:98
2
3
i-Pr
i-Pr
CN
CN
Rt
45
13
12:88
Nd
4
Et3N
Et3N
LiH
0 °C
0 °C
Rt
5
n-Bu
n-Bu
CN
CN
70
81
43:57
45:55
8:92
6
7
1-Adamantyl
1-Adamantyl
t-Bu
CN
CN
Et3N
Et3N
Et3N
LiH
Reflux
Reflux
Reflux
Reflux
Reflux
Rt
100
88
8
7:93
8:92
9
CO2Me
CO2Me
CO2Me
CN
83
62
10
11
12
13
14
15
16
17
18
t-Bu
t-Bu
5:95
7:93
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
78
52
4-Py
47:53
37:63
15:85
36:64
13:87
16:84
12:88
1-Naphthyl
1-Naphthyl
2-ClC6H4
2-ClC6H4
2,6-Cl2C6H3
2,6-Cl2C6H3
CN
CN
Rt
Rt
94
99
CN
CN
Rt
Rt
100
96
3i
5i
3j
CN
CN
Reflux
Rt
5j
100
50
3j
5j
a Determined by 1H NMR of the crude product.
€
New York, 1987; (b) Salaun, J. Chem. Rev. 1989, 89, 1247–
1270; (c) Carbocyclic Three- and Four-Membered Ring
Compounds; de Meijere, A., Ed. Houben-Weyl; Thieme:
Stuttgart, 1996; Vol. E17a–c.
3e and t-butyl substituted a-cyanoacrylate 3f were also
found to give high selectivity, even though higher reac-
tion temperatures were required. As for substrates with
aromatic groups, the one with the electronegative
4-pyridyl group (3g) turned out slightly to favor the
diastereomer bearing stereochemistry opposite to that of
the major diastereomer of 5a. Substrates with hindered
aromatic substituents also gave rise to the trans-1S
diastereomer with moderate diastereoselectivity (15:85–
12:88). Here, MeCN was clearly the better solvent. The
minor diastereomer of the 2-chlorophenyl product was
found to be trans-1R, thus implying that the major
product for substrates with bulky aromatic substituents
were all trans-1S.17
€
2. For reviews see: (a) Salaun, J. In Small Ring Compounds
in Organic Synthesis V. Topics in Current Chemistry;
Springer: Berlin, 2000; Vol. 207, pp 1–67; (b) Pietruszka, J.
Chem. Rev. 2003, 103, 1051–1070.
3. For reactions of cyclopropanes see: (a) Danishefsky, S.
Acc. Chem. Res. 1979, 12, 66–72; (b) de Meijere, A.
Angew. Chem., Int. Ed. Engl. 1979, 18, 809–826; (c) Wong,
H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C. Chem. Rev.
1989, 89, 165–198.
4. For reviews see: (a) Li, A.-H.; Dai, L.-X.; Aggarwal, V. K.
Chem. Rev. 1997, 97, 2341–2372; (b) Lebel, H.; Marcoux,
J.-F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103,
977–1050.
In summary, we have utilized the 8-phenylmenthylamine
chiral auxiliary for the cyclopropanation reactions of
pyridinium ylides to give products bearing three elec-
tron-withdrawing groups. High diastereoselectivity was
observed especially for bulky Michael acceptor reac-
tants, and the stereochemical course of the reaction
turned out to be opposite of that of the ester series.
Detailed studies of this reaction are currently in progress.
5. For a review see: Doyle, M. P.; Protopopova, M. N.
Tetrahedron 1998, 54, 7919–7946.
6. For catalytic asymmetric efforts see: (a) Arai, S.; Naka-
yama, K.; Ishida, T.; Shioiri, T. Tetrahedron Lett. 1999,
40, 4215–4218; (b) Papageorgiou, C. D.; Ley, S. V.;
Gaunt, M. J. Angew. Chem., Int. Ed. 2003, 42, 828–831.
7. (a) Shestopalov, A. M.; Sharanin, Y. A.; Litvinov, V. P.;
Nefedov, O. M. Zh. Org. Khim. 1989, 25, 1111–1112; (b)
Shestopalov, A. M.; Litvinov, V. P.; Rodinovskaya, L. A.;
Sharanin, Y. A. Izv. Acad. Nauk SSSR, Ser. Khim. 1991,
1, 146–155; (c) Litvinov, V. P.; Shestopalov, A. M. Zh.
Org. Khim. 1997, 33, 975–1014, and references cited
therein; (d) Vo, N. H.; Eyermann, C. J.; Hodge, C. N.
Tetrahedron Lett. 1997, 38, 7951–7954.
Acknowledgements
8. Kojima, S.; Fujitomo, K.; Shinohara, Y.; Shimizu, M.;
Ohkata, K. Tetrahedron Lett. 2000, 41, 9847–9851.
9. For reviews see: (a) Whitesell, J. K. Chem. Rev. 1992, 92,
953–964; (b) Jones, G. B.; Chapman, B. J. Synthesis 1995,
475–497; (c) Jones, G. B. Tetrahedron 2001, 57, 7999–
8016.
10. (a) Ohkata, K.; Miyamoto, K.; Matsumura, S.; Akiba,
K.-Y. Tetrahedron Lett. 1993, 34, 6575–6578; (b) Ohkata,
K.; Kubo, T.; Miyamoto, K.; Ono, M.; Yamamoto, J.;
Akiba, K.-Y. Heterocycles 1994, 38, 1483–1486; (c)
Takagi, R.; Kimura, J.; Shinohara, Y.; Ohba, Y.; Takez-
ono, K.; Hiraga, Y.; Kojima, S.; Ohkata, K. J. Chem.
Soc., Perkin Trans. 1 1998, 689–698; (d) Shinohara, Y.;
Ohba, Y.; Takagi, R.; Kojima, S.; Ohkata, K. Heterocycles
This work was supported in part by a Grant-in-Aid for
Scientific Research (No 14540497) from the Japan
Society for the Promotion of Science. We also
acknowledge the Natural Science Center for Basic
Research and Development of Hiroshima University for
machine time on analytical instruments.
References and notes
1. For general reviews on cyclopropanes see: (a) The Chem-
istry of the Cyclopropyl Group; Rappoport, Z., Ed.; Wiley:

3568
S. Kojima et al. / Tetrahedron Letters 45 (2004) 3565–3568
2001, 55, 9–12; (e) Takagi, R.; Nakamura, M.;
in ether (30 mL) was added chloroacetyl chloride (0.50 mL,
6.3 mmol). The reaction mixture was heated at reflux for
4 h, quenched with H2O and extracted with ether. The
combined organic extracts were washed with aq NaHCO3
and brine, dried (Na2SO4), and removed in vacuo. The
crude product was purified by silica gel column chroma-
tography (hexane/EtOAc ¼ 5:1) and recrystallization
(EtOH) to give 8 as needles (1.27 g, 87%): Rf ¼ 0:23
(hexane/EtOAc ¼ 5:1); 1H NMR (500 MHz, CDCl3) d
7.36–7.27 (m, 4H), 7.20–7.14 (m, 1H), 5.40 (d, J ¼ 9:1 Hz,
1H), 3.89 (ddd, J ¼ 11:3, 10.7, 3.4 Hz, 1H), 3.58 (d,
J ¼ 14:6 Hz, 1H), 3.38 (d, J ¼ 14:6 Hz, 1H), 2.01 (dq,
J ¼ 13:1, 3.4 Hz, 1H), 1.92 (ddd, J ¼ 11:9, 10.7, 3.4 Hz,
1H), 1.83–1.75 (m, 2H), 1.57–1.45 (m, 1H), 1.32 (s, 3H),
1.26 (dtd, J ¼ 13:1, 11.9, 3.4 Hz, 1H), 1.16 (s, 3H), 0.96
(dtd, J ¼ 13:1, 11.9, 3.4 Hz, 1H), 0.87 (d, J ¼ 6:7 Hz, 3H),
0.82 (ddd, J ¼ 13:1, 12.2, 11.3 Hz, 1H); 13C NMR
(125 MHz, CDCl3) d 163.8, 152.5, 128.5, 125.7, 124.8,
Hashizume, M.; Kojima, S.; Ohkata, K. Tetrahedron Lett.
2001, 42, 5891–5895; (f) Takagi, R.; Hashizume, M.;
Nakamura, M.; Begum, S.; Hiraga, Y.; Kojima, S.;
Ohkata, K. J. Chem. Soc., Perkin Trans. 1 2002, 179–190.
11. (a) Dieck, H. T.; Dietrich, J. Ang. Chem., Int. Ed. Engl.
1985, 24, 781–783; (b) Independent use has recently been
presented: Kosugi, Y.; Akakura, M.; Ishihara, K.
Abstracts of Papers, 83th Annual Spring Meeting of the
Chemical Society of Japan, Tokyo, 4H6-06, 2003.
12. (a) Wallach, O. Liebigs Ann. Chem. 1893, 276, 301; (b)
Feltkamp, H.; Friedrich, K.; Thanh, T. N. Liebigs Ann.
Chem. 1967, 707, 78–86.
13. Ort, O. Org. Synth. 1985, 65, 203–214.
14. A mixture of 8-phenylmenthone13 (1.41 g, 6.11 mmol),
O-methylhydroxylamine hydrochloride (0.87 g, 10.5
mmol), and pyridine (1.00 mL, 12.4 mmol) in EtOH
(18 mL) was heated at reflux for 3 h. After the solvents
were removed in vacuo, water and ethyl acetate were
added to the residue. The aqueous layer was extracted
with ethyl acetate. The combined organic extracts were
washed with brine, dried (Na2SO4), and removed in vacuo.
The residue was purified by silica gel column chromato-
graphy (hexane/EtOAc ¼ 30:1) to give 6 as a colorless oil
50.7, 43.8, 42.6, 39.6, 34.8, 31.7, 31.3, 26.9, 21.8, 21.1; IR
22
D
(Nujol) 3313, 1655, 1543, 1219, 775, 709, 613 cmꢀ1; ½aꢁ
þ61.3 (c 1.07, CHCl3); HRMS (EIþ) m=z calcd for
C18H26ClNO 307.1703, found 307.1692; Anal. Calcd for
C18H26ClNO: C, 70.22; H, 8.51; N, 4.55. Found: C, 70.31;
H, 8.74; N, 4.45; mp 126–131 °C.
1
(1.50 g, 95%): Rf ¼ 0:73 (hexane/EtOAc ¼ 5:1); H NMR
17. Crystallographic data for X-ray structures have been
deposited with the Cambridge Crystallographic Data
Centre as CCDC-231391 (8-ax), 231392 (5a-minor),
231393 (5b-major), and 231394 (5i-minor). Copies of
the data can be obtained free of charge on application
to CCDC, 12 Union Road, Cambridge CB12 1EZ, UK
(fax: +44-(0)1223-336033 or email: deposit@ccdc.cam.
ac.uk).
(500 MHz, CDCl3) d 7.38–7.34 (m, 2H), 7.30–7.24 (m,
2H), 7.17–7.12 (m, 1H), 3.74 (s, 3H), 3.00 (ddd, J ¼ 13:1,
4.3, 1.8 Hz, 1H), 2.42 (dd, J ¼ 11:3, 4.3 Hz, 1H), 1.71–1.54
(m, 3H), 1.52 (s, 3H), 1.44 (s, 3H), 1.40 (dd, J ¼ 13:1,
11.3 Hz, 1H), 1.33 (dtd, J ¼ 13:1, 11.3, 3.4 Hz, 1H), 0.96
(dtd, J ¼ 13:1, 11.3, 3.4 Hz, 1H), 0.91 (d, J ¼ 6:4 Hz, 3H);
13C NMR (125 MHz, CDCl3) d 159.3, 150.5, 127.6, 126.1,
125.2, 61.0, 52.8, 40.1, 34.5, 33.9, 33.1, 28.6, 26.8, 24.9,
18. A mixture of 8 (300.2 mg, 0.98 mmol) and pyridine
(1.00 mL, 12.4 mmol) was heated at 100 °C for 2 h. Then
the mixture was cooled to room temperature and ether was
added. The liberated solid was washed with ether, filtered,
and dried in vacuo to give 2 as a hygroscopic pale brown
solid (366.4 mg, 97%): 1H NMR (500 MHz, CDCl3) d 9.18
(d, J ¼ 5:5 Hz, 2H), 8.53 (d, J ¼ 9:8 Hz, 1H), 8.46 (t,
J ¼ 7:9 Hz, 1H), 8.03 (t, J ¼ 7:0 Hz, 2H), 7.41 (d,
J ¼ 7:3 Hz, 2H), 7.34 (t, J ¼ 7:6 Hz, 2H), 7.14 (t,
J ¼ 7:3 Hz, 1H), 5.64 (d, J ¼ 14:3 Hz, 1H), 4.66 (d,
J ¼ 14:3 Hz, 1H), 3.79 (ddd, J ¼ 11:3, 10.7, 3.4 Hz, 1H),
2.12 (ddd, J ¼ 12:2, 10.7, 3.4 Hz, 1H), 1.73 (dq, J ¼ 13:1,
3.4 Hz, 1H), 1.70–1.65 (m, 1H), 1.65–1.58 (m, 1H), 1.41–
1.32 (m, 1H), 1.36 (s, 3H), 1.27 (ddd, J ¼ 13:1, 12.2,
11.3 Hz, 1H), 1.18 (s, 3H), 1.12 (dtd, J ¼ 13:1, 12.2,
3.4 Hz, 1H), 0.91 (dtd, J ¼ 13:1, 12.2, 3.4 Hz, 1H), 0.82 (d,
J ¼ 6:4 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 161.4,
151.9, 145.7, 145.1, 128.1, 127.5, 125.6, 125.0, 61.7, 50.9,
49.5, 42.8, 40.1, 34.2, 31.9, 28.7, 27.0, 24.1, 21.7; IR
22.2; IR (neat) 1639, 1601, 1446, 1049, 872, 848, 775, 760,
22
D
702 cmꢀ1; ½aꢁ ꢀ27.9 (c 1.04, CHCl3); HRMS (EIþ) m=z
calcd for C17H25NO 259.1936, found 259.1936; Anal.
Calcd for C17H25NO: C, 78.72; H, 9.71; N, 5.40. Found: C,
79.00; H, 9.79; N, 5.43.
15. A solution of 6 (1.16 g, 4.48 mmol) in EtOH (5.80 mL) was
heated to reflux. Then Na (1.45 g, 63.1 mmol) and EtOH
(6.50 mL) were added. The reaction mixture was heated for
15 h, poured into ice and extracted with ether. The
combined organic extracts were washed with brine, dried
(Na2SO4), and removed in vacuo. The crude product was
purified by silica gel column chromatography (CH2Cl2/
MeOH/Et3N ¼ 40:2:1) to give 7 as a pale yellow oil (0.94 g,
91%, diastereomeric mixture 89:11). Further careful chro-
matography (CH2Cl2/MeOH/Et3N ¼ 60:2:1) gave pure 7 as
the slower eluting component: Rf ¼ 0:43 (CH2Cl2/
1
MeOH ¼ 10:1); H NMR (500 MHz, CDCl3) d 7.40–7.36
(m, 2H), 7.33–7.27 (m, 2H), 7.18–7.13 (m, 1H), 2.64 (ddd,
J ¼ 11:3, 10.1, 3.4 Hz, 1H), 1.82 (dq, J ¼ 13:1, 3.4 Hz, 1H),
1.74–1.67 (m, 2H), 1.65 (ddd, J ¼ 12:2, 10.1, 3.4 Hz, 1H),
1.46–1.35 (m, 1H), 1.38 (s, 3H), 1.22 (s, 3H), 1.11 (dtd,
J ¼ 13:1, 12.2, 3.4 Hz, 1H), 0.90 (dtd, J ¼ 13:1, 12.2,
3.4 Hz, 1H), 0.89–0.84 (m, 2H), 0.87 (d, J ¼ 6:4 Hz, 3H),
0.78 (ddd, J ¼ 12:8, 12.2, 11.3 Hz, 1H); 13C NMR
(125 MHz, CDCl3) d 152.9, 128.3, 125.4, 125.4, 54.2, 53.2,
(Nujol) 3375, 3182, 1674, 1632, 1562, 1292, 702, 675 cmꢀ1
;
22
D
½aꢁ ꢀ2.93 (c 2.24, CHCl3); HRMS (EIþ) m=z calcd for
C23H31ClN2O 386.2125, found 386.2144; Anal. Calcd for
C23H31ClN2OÆH2O: C, 68.21; H, 8.21; N, 6.92. Found: C,
68.46; H, 8.17; N, 6.81; mp 219–222 °C.
19. Typical procedure (5b): To a solution of 2 (53.2 mg,
0.14 mmol) in CH3CN (1.5 mL) was added Et3N (0.03 mL,
0.22 mmol), followed by a solution of 3b (14.4 mg,
0.11 mmol) in CH3CN (1.5 mL) at 0 °C. The mixture was
stirred for 17 h, during which time the mixture was allowed
to warm to room temperature. Usual workup and
46.6, 39.9, 35.3, 32.0, 30.6, 27.0, 22.7, 22.2; IR (neat) 3394,
22
1601, 1030, 833, 764, 702 cmꢀ1; ½aꢁ ꢀ33.6 (c 1.02, CHCl3);
D
HRMS (EIþ) m=z calcd for C16H25N 231.1987, found
231.1981. Anal. Calcd for C16H25N: C, 83.06; H, 10.89; N,
6.05. Found: C, 82.89; H, 10.87; N, 6.09.
chromatography
[silica
gel,
hexane/EtOAc ¼ 7:1,
16. To
a
4.78 mmol) and N,N-dimethylaniline (0.85 mL, 6.7 mmol)
solution of diastereomerically pure
7
(1.11 g,
Rf ¼ 0:43 (hexane/EtOAc ¼ 3:1)] gave a mixture of 5b
(25.5 mg, 59%, dr ¼ 2:98).