Sulfur ylides 12. Optically active keto stabilized sulfur ylide obtained from L-proline: Synthesis and study

Article abstract of DOI:10.1023/A:1022131201542

Optically active keto stabilized sulfur ylide was synthesized from L-proline. The reactions of the ylide with methyl acrylate and methyl vinyl ketone afforded 1,2-disubstituted cyclopropanes. In the case of acrylonitrile, a mixture of 1,2- and 1,1-disubstituted cyclopropanes was obtained. Acylation of the ylide with acetic anhydride gave twice stabilized sulfur ylide.

Full text of DOI:10.1023/A:1022131201542

2230
Russian Chemical Bulletin, International Edition, Vol. 51, No. 12, pp. 2230—2233, December, 2002
Organic Chemistry
Sulfur ylides
12.* Optically active keto stabilized sulfur ylide obtained from Lꢀproline:
synthesis and study
ꢀ
S. N. Lakeev, I. Z. Mullagalin, F. Z. Galin, I. O. Maidanova, and M. F. Abdullin
Institute of Organic Chemistry, Ufa Research Center of the Russian Academy of Sciences,
71 prosp. Oktyabrya, 450054 Ufa, Russian Federation.
Fax: +7 (347 2) 35 6066. Eꢀmail: galin@anrb.ru, irina_m@anrb.ru
Optically active keto stabilized sulfur ylide was synthesized from Lꢀproline. The reactions
of the ylide with methyl acrylate and methyl vinyl ketone afforded 1,2ꢀdisubstituted cycloproꢀ
panes. In the case of acrylonitrile, a mixture of 1,2ꢀ and 1,1ꢀdisubstituted cyclopropanes was
obtained. Acylation of the ylide with acetic anhydride gave twice stabilized sulfur ylide.
Key words: Lꢀproline, keto stabilized sulfonium ylide, cyclopropanation, rearrangement,
acylation.
In continuation of the studies1—8 aimed at synthesizꢀ
sulfonium salt 7 in 55% yield. Deprotonation of salt 7
with a mixture of a saturated solution of K2CO3 and 12.5 M
NaOH leads to an optically active keto stabilized ylide 1
in 98% yield. In ylide 1, the negative charge at the ylide C
atom is delocalized over the carbonyl group; as a result,
the absorption band of this group is shifted to longer
wavelengths (1565 cm–1).
We proposed a more efficient method for the synthesis
of ylide 1 via catalytic decomposition of diazo ketone 4
with rhodium acetate in the presence of Me2S; the yield
of ylide 1 was 50%. This method makes it unnecessary to
obtain bromo ketone and sulfonium salt and deprotonate
the latter (the overall yield was 40%).
ing sulfonium ylides from amino acids, we obtained optiꢀ
cally active keto stabilized sulfur ylide 1 from Lꢀproline
(Scheme 1) and studied its reactions with activated oleꢀ
fins and acetic anhydride.
The reaction of protected Lꢀproline 2 with ClCO2Me
affords a mixed anhydride 3, which reacts with an etheꢀ
real solution of CH2N2 to give diazo ketone 4 in 78%
yield. Acylation of CH2N2 with acid chloride 5 proved to
be less efficient (the yield of diazo ketone 4 was 56%).
The IR spectrum of compound 4 contains an absorption
band at 2140 cm–1 characteristic of a diazo group. The
reaction of diazo ketone 4 with aqueous HBr affords
αꢀbromomethyl ketone 6, which reacts with Me2S to give
Ylide 1 is easily cyclopropanated with activated oleꢀ
fins. The reaction of ylide 1 with methyl vinyl ketone
affords a 1 : 2 mixture of cisꢀ and transꢀisomers 8 in 80%
* For Part 11, see Ref. 1.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2071—2074, December, 2002.
1066ꢀ5285/02/5112ꢀ2230 $27.00 © 2002 Plenum Publishing Corporation

Sulfur ylide from Lꢀproline
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 12, December, 2002 2231
Scheme 1
Scheme 2
from the relative intensities of two singlets at δH 3.60 and
1
3.80 for the methoxycarbonyl protons in the H NMR
spectrum.
Scheme 3
Previously,10 it was shown that cyclopropanation of
acrylonitrile with a sulfur ylide obtained from Nꢀphthaloꢀ
ylꢀβꢀalanine is accompanied by rearrangement into 1,1ꢀdiꢀ
substituted cyclopropane. In the case of ylide 1, cycloꢀ
propanation of acrylonitrile affords a 1 : 3 mixture of
1,2ꢀ (10a) and 1,1ꢀdisubstituted cyclopropanes (10b)
(Scheme 4). In the 13C NMR spectrum of the mixture
obtained, two triplets for methylene C atoms at δC 21.72
and 21.61 and a singlet for the quaternary C atom at
δC 17.42 were unambiguously assigned to the 1,1ꢀisomer
10b. Signals for the cyclopropane C atoms in the 1,2ꢀisoꢀ
mer 10a appear as two doublets at δC 24.46 and 6.98 and a
triplet at δC 16.42. The ratio of isomers 10a and 10b was
determined from the relative intensities of two multiplets
at δH 3.55 (10b) and 3.75 (10a) for the CH2N protons of
the pyrrolidine ring in the 1H NMR spectrum.
Reagents and conditions: a) BzCl, NaOH, ∼20 °C, 75%;
b) (COCl)2/DMF, CH2Cl2, ∼20 °C; c) CH2N2, CH2Cl2,
–5 °C, 56%; d) ClCO2Me/Et3N, Et2O, ∼20 °C; e) CH2N2,
Et2O, 78%; f ) HBr, CH2Cl2, ∼20 °C, 74%; g) Me2S, Me2CO,
∼20 °C, 55%; h) K2CO3, NaOH, CHCl3, –5 °C, 98%;
i) Rh2(OAc)4, Me2S, CH2Cl2, 40 °C, 50%.
Scheme 4
yield (Scheme 2). The ratio of the isomers was deterꢀ
mined from the intensities of signals at δH 2.15 and 2.25
1
for the acetyl protons in the H NMR spectrum. The
higherꢀfield signal corresponds to the cisꢀisomer, which is
due to the 1,2ꢀsynꢀinteraction of the oxo group with the
protons of the acetyl group.9
The reaction of ylide 1 with methyl acrylate in MeCN
at 80 °C gave a 1 : 1 mixture of cisꢀ and transꢀisomers
of methyl cyclopropanecarboxylate 9 in 80% yield
(Scheme 3). The ratio of the isomers was determined
Acylation of ylide 1 with acetic anhydride in toluene
affords twice stabilized ylide 11 (Scheme 5). In its IR
spectrum, the absorption band of the CO group bound
to the ylide C atom is shifted to longer wavelengths
(1580 cm–1) compared to the starting ylide 1. The
13C NMR spectrum shows a signal for the ylide C atom at

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Russ.Chem.Bull., Int.Ed., Vol. 51, No. 12, December, 2002
Lakeev et al.
δC 86.2. In the 1H NMR spectrum, a signal at δH 2.35 for
the acetyl group is most characteristic.
yield of compound 4 was 1.37 g (56%). Found (%): C, 63.87;
H, 5.63; N, 17.05. C13H13N3O2. Calculated (%): C, 64.19;
H, 5.39; N, 17.27. IR, ν/cm–1: 1705, 1776, 2140. 1H NMR
(CDCl3), δ: 1.75—1.93, 2.05—2.31, 3.50—3.71 (all m, 2 H each,
CH2); 4.71 (t, 1 H, CH, J = 5.4 Hz); 5.61 (s, 1 H, CH);
7.30—7.60 (m, 5 H, Ar). 13C NMR (CDCl3), δ: 25.04, 28.86,
50.52, 53.05, 63.29, 127.41, 128.32, 130.36, 136.04, 170.04,
193.52.
Scheme 5
1ꢀBenzoylꢀ2ꢀbromoacetylpyrrolidine (6). A 48% solution of
HBr (10 mL) was added at 0 °C to a stirred solution of diazo
ketone 4 (2.43 g, 10 mmol) in 20 mL of CH2Cl2. After gas
evolution ceased, the reaction mixture was stirred for an addiꢀ
tional 0.5 h. The mixture was warmed to ∼20 °C and poured into
10 mL of water. The organic layer was separated, washed with
5% Na2CO3, and dried over MgSO4. The solvent was removed,
and the residue was chromatographed on SiO2 in a short column
with chloroform—acetone (9 : 1) as the eluent to give comꢀ
pound 6 (2.19 g, 74%) as a light yellow oil. Found (%): C, 52.57;
H, 4.55; Br, 26.75; N, 4.65. C13H14BrNO2. Calculated (%):
C, 52.72; H, 4.76; Br, 26.98; N, 4.73. IR, ν/cm–1: 1700, 1780.
1H NMR (CDCl3), δ: 1.73—1.90, 2.15—2.29, 3.45—3.61,
4.00—4.20 (all m, 2 H each, CH2); 4.72 (t, 1 H, CH, J =
7.2 Hz); 7.30—7.60 (m, 5 H, Ar). 13C NMR (CDCl3), δ: 25.43,
29.97, 33.31, 49.92, 62.85, 126.84, 127.96, 130.20, 134.79,
169.27, 200.30.
1ꢀBenzoylꢀ2ꢀ(dimethylsulfonioacetyl)pyrrolidine bromide (7).
A solution of bromo ketone 6 (2.96 g, 10 mmol) and Me2S
(1.86 g, 30 mmol) in 7 mL of Me2CO was stirred at ∼20 °C in the
presence of 4A molecular sieves and left for ∼14 h. The salt that
formed was filtered off and washed with Me2CO to give comꢀ
pound 7 (1.97 g, 55%) as white crystals, m.p. 107—110 °C.
Found (%): C, 50.15; H, 5.55; Br, 21.75; N, 3.65; S, 8.71.
C15H20BrNO2S. Calculated (%): C, 50.28; H, 5.63; Br, 22.31;
N, 3.91; S, 8.95. IR, ν/cm–1: 1615, 1690. 1H NMR (CF3COOH),
δ: 1.80—2.00, 2.25—2.30 (both m, 2 H each, CH2); 2.90, 3.00
(both s, 3 H each, SMe2); 3.55—3.61 (m, 2 H, CH2); 4.85 (t,
1 H, CH, J = 7.1 Hz); 5.15 (m, 2 H, CH2); 7.20—7.50 (m, 5 H,
Ar). 13C NMR (CF3COOH), δ: 25.12, 25.29, 28.67, 52.15, 53.39,
66.38, 127.68, 129.25, 129.66, 133.42, 173.43, 181.22.
Experimental
IR spectra were recorded on URꢀ20 and Specord Mꢀ80 inꢀ
struments (in Vaseline oil). 1H and 13C NMR spectra were reꢀ
corded on a Bruker AMꢀ300 spectrometer (300 and 75 MHz,
respectively) with Me4Si as the internal standard. Specific rotaꢀ
tion was determined on a Perkin—Elmer 241 MC polarimeter.
Specific rotation is expressed in deg mL g–1 dm–1; the concenꢀ
tration of solutions is expressed in g (100 mL)–1; wavelength is
589 nm. The course of the reaction was monitored by TLC on
Silufol UVꢀ254 plates (Czech Republic); visualization under
UV light or with ninhydrin. The reaction products were isolated
by column chromatography on silica gel. Diethyl ether was dried
over KOH and distilled. Solvents (Me2CO, CH2Cl2, CHCl3,
and MeCN) were distilled over P2O5. Methyl acrylate, acryloꢀ
nitrile, and methyl vinyl ketone were purified by distillation.
Toluene was refluxed and distilled over sodium; Me2S was dried
over 4A molecular sieves. LꢀProline (pure grade, Reanal Co.)
and benzoyl chloride (pure grade, Shostka Chemical Plant) were
used as purchased.
NꢀBenzoylꢀLꢀproline (2) was obtained in 75% yield accordꢀ
ing to the known procedure; its spectroscopic characteristics are
identical with the literature data.11
1ꢀBenzoylꢀ2ꢀ(2ꢀdiazoꢀ1ꢀoxoethyl)pyrrolidine (4). A. To a susꢀ
pension of NꢀbenzoylꢀLꢀproline 2 (2.19 g, 10 mmol) in 90 mL of
dry diethyl ether ClCO2Me (0.85 mL, 11 mmol) was added in
one portion at 20 °C. The reaction mixture was stirred for 0.5 h.
Triethylamine (1.4 mL, 11 mmol) was added in two portions
spaced at 0.5 h, and stirring was continued for an additional
0.5 h. The precipitate of Et3N•HCl that formed was filtered off.
An ethereal solution of CH2N2 obtained from nitrosomethylurea
(NMU) (2 g, 20 mmol) was added dropwise at 0 °C to the stirred
filtrate. The reaction mixture was left at 0 °C for 12 h. The
solvent was removed to give diazo ketone 4 (1.89 g, 78%) as a
heavy light yellow oil.
1ꢀBenzoylꢀ2ꢀ(dimethylsulfuranylideneacetyl)pyrrolidine (1).
A. A saturated solution of K2CO3 (1.74 mL) and 12.5 M NaOH
(0.3 mL) was added in one portion at 0 °C to a stirred suspension
of salt 7 (1.07 g, 3 mmol) in 5 mL of CHCl3. The reaction
mixture was stirred for 15 min and then warmed to ∼20 °C. The
organic layer was separated and dried over K2CO3. The solvent
was removed to give ylide 1 as a light yellow oil. The yield of
18
compound 1 was 0.81 g (98%), [α]D –150.4 (c 0.1, CHCl3).
Found (%): C, 65.05; H, 6.55; N, 5.15; S, 10.91. C15H19NO2S.
Calculated (%): C, 64.95; H, 6.90; N, 5.05, S, 11.56. IR, ν/cm–1
:
B. One drop of DMF and then (COCl)2 (2.5 g, 20 mmol) in
10 mL of CH2Cl2 were added at 0 °C to a stirred solution of
NꢀbenzoylꢀLꢀproline 2 (2.19 g, 10 mmol) in 35 mL of CH2Cl2.
The mixture was warmed to ∼20 °C and stirred until gas evoluꢀ
tion ceased. The solvent was removed. Crude 1ꢀbenzoylpyrꢀ
rolidineꢀ2ꢀcarbonyl chloride (5) was immediately used in the
reaction with CH2N2. A solution of acid chloride 5 (2.38 g,
10 mmol) in 20 mL of CH2Cl2 was added dropwise at –5 °C to
40 mL of an ethereal solution of CH2N2 obtained from NMU
(4 g, 40 mmol), and the reaction mixture was stirred at –5 °C for
0.5 h. The solvent was removed, and diazo ketone 4 was purified
by column chromatography in chloroform—acetone (9 : 1). The
1565, 1645. 1H NMR (CDCl3), δ: 1.72—1.89, 2.05—2.19
(both m, 2 H each, CH2); 2.59 (s, 6 H, SMe2); 3.48—3.71 (m,
2 H, CH2); 4.09 (t, 1 H, CH, J = 15 Hz); 4.50 (s, 1 H, CH);
7.30—7.60 (m, 5 H, Ar). 13C NMR (CDCl3), δ: 25.21, 28.30,
29.72, 50.43, 52.46, 66.07, 226.95, 127.71, 129.67, 137.30,
170.14, 188.19.
B. A solution of diazo ketone 4 (0.39 g, 1.6 mmol) in 7 mL of
CH2Cl2 was added dropwise over 0.5 h to a stirred solution of
Me2S (0.5 g, 8 mmol) and Rh2(OAc)4 (0.0007 g, 0.016 mmol) in
15 mL of CH2Cl2. The reaction mixture was refluxed until gas
evolution ceased. The course of the reaction was monitored by
TLC in CHCl3—Me2CO (9 : 1); visualization with ninhydrin.

Sulfur ylide from Lꢀproline
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 12, December, 2002 2233
The completion of the reaction was concluded from the absence
of the diazo ketone. The reaction mixture was washed with
water and dried over Mg2SO4; the solvent was removed. The
yield of ylide 1 was 0.22 g (50%).
compound 11 was 0.27 g (95%). Found (%): C, 63.21; H, 6.42;
N, 4.23; S, 9.78. C17H21NO3S. Calculated (%): C, 63.92;
H, 6.63; N, 4.39; S, 10.04. IR, ν/cm–1: 1580, 1650. 1H NMR
(CDCl3), δ: 1.85—2.10 (m, 4 H, 2 CH2); 2.35 (s, 3 H, Me);
3.05, 3.10 (both s, 3 H each, SMe2); 3.50—3.80 (m, 2 H, CH2);
5.45 (t, 1 H, CH, J = 7.05 Hz); 7.30—7.60 (m, 5 H, Ar).
13C NMR (CDCl3), δ: 25.42, 26.11, 26.82, 27.21, 31.95, 63.50,
86.23, 127.0, 128.02, 129.74, 136.51, 169.12, 170.29, 176.12.
Cyclopropanation (general procedure). An olefin (1.5 mmol)
was added to a solution of ylide 1 (0.28 g, 1 mmol) in 5 mL of
MeCN. The reaction mixture was refluxed for 2 h. The solvent
was removed, and the residue was chromatographed on Al2O3 in
a short column (chloroform—acetone (9 : 1) as the eluent).
2ꢀ(2ꢀAcetylcyclopropanecarbonyl)ꢀ1ꢀbenzoylpyrrolidine (8)
was obtained as a light yellow oil. The yield of compound 8
was 0.23 g (80%). Found (%): C, 71.25; H, 6.35; N, 4.33.
C17H19NO3. Calculated (%): C, 71.56; H, 6.71; N, 4.91. IR,
ν/cm–1: 1660, 1705, 1720. 1H NMR (CDCl3), δ: 1.40—1.55,
1.80—1.95 (both m, 2 H each, CH2); 2.15 (s, 3 H, COMe, cis);
2.25 (s, 3 H, COMe, trans); 2.30, 2.84 (both m, 1 H each, CH);
3.50 (m, 2 H, CH2); 4.65 (m, 1 H, CH); 7.30—7.60 (m, 5 H,
Ar). 13C NMR (CDCl3), δ: 18.01, 18.17, 25.30, 27.64, 28.04,
28.27, 30.44, 30.58; 32.02, 50.08, 65.62, 126.79, 128.08, 130.03,
135.66, 169.44, 205.55, 205.76.
Methyl 2ꢀ(1ꢀbenzoylpyrrolidineꢀ2ꢀcarbonyl)cyclopropaneꢀ
carboxylate (9) was obtained as a light yellow oil. The yield of
compound 9 was 0.24 g (80%). Found (%): C, 67.55; H, 6.25;
N, 4.05. C17H19NO4. Calculated (%): C, 67.76; H, 6.36; N, 4.65.
IR, ν/cm–1: 1650, 1730, 1750. 1H NMR (CDCl3), δ: 1.28—1.51
(m, 2 H, CH2); 1.85 (m, 1 H, CH); 1.95—2.05, 2.15—2.41
(both m, 2 H each, CH2); 2.50—2.60 (m, 1 H, CH); 3.45—3.55
(m, 2 H, CH2); 3.60 (s, 3 H, CO2Me, cis); 3.80 (s, 3 H, CO2Me,
trans); 4.85 (m, 1 H, CH); 7.30—7.60 (m, 5 H, Ar). 13C NMR
(CDCl3), δ: 17.09, 17.37, 23.76, 24.09, 25.35, 26.37; 26.49;
28.27, 50.15, 52.12, 65.65, 127.19, 128.20, 130.13, 135.93,
169.58, 172.54, 204.94.
This work was financially supported by the Ministry of
Industry, Science, and Technology of the Russian Fedꢀ
eration (State Contract No. 41.002.1.1.1401).
References
1. S. N. Lakeev, I. Z. Mullagalin, F. Z. Galin, I. O. Maidanova,
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Khim., 2002, 951 [Russ. Chem. Bull., Int. Ed., 2002, 51, 1035].
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G. A. Tolstikov, Izv. Akad. Nauk, Ser. Khim., 1999, 2100
[Russ. Chem. Bull., 1999, 48, 2077 (Engl. Transl.)].
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Tolstikov, Izv. Akad. Nauk, Ser. Khim., 1998, 2376 [Russ.
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Nauk, Ser. Khim., 1997, 2008 [Russ. Chem. Bull., 1997, 46,
1904 (Engl. Transl.)].
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Nauk, Ser. Khim., 1996, 165 [Russ. Chem. Bull., 1996, 45,
156 (Engl. Transl.)].
6. S. N. Lakeev, F. Z. Galin, L. M. Khalilov, and G. A.
Tolstikov, Izv. Akad. Nauk, Ser. Khim., 1992, 720 [Bull.
Russ. Acad. Sci., Div. Chem. Sci., 1992, 41, 566 (Engl.
Transl.)].
7. G. A. Tolstikov, F. Z. Galin, S. N. Lakeev, L. M. Khalilov,
and V. S. Sultanova, Izv. Akad. Nauk SSSR, Ser. Khim.,
1990, 612 [Bull. Acad. Sci. USSR, Div. Chem. Sci., 1990, 39,
535 (Engl. Transl.)].
8. L. M. Khalilov, V. S. Sultanova, S. N. Lakeev, F. Z. Galin,
L. F. Chertanova, and G. A. Tolstikov, Izv. Akad. Nauk
SSSR, Ser. Khim., 1991, 2298 [Bull. Acad. Sci. USSR, Div.
Chem. Sci., 1991, 40, 2011 (Engl. Transl.)].
9. R. Glaser, M. A. Bernstein, and A. Balan, Magn. Res. Chem.,
1991, 29, 766.
2ꢀ(1ꢀBenzoylpyrrolidineꢀ2ꢀcarbonyl)cyclopropaneꢀ1ꢀcarboꢀ
1
nitrile (10a). H NMR (CDCl3), δ: 3.75 (m, 2 H, CH2N); 4.95
(m, 1 H, CHN); 7.30—7.60 (m, 5 H, Ph). 13C NMR (CDCl3),
δ: 6.98, 16.42, 24.46, 25.08, 28.25, 50.26, 65.92, 119.68, 127.28,
127.42, 128.38, 130.55, 135.48, 135.58, 169.86, 203.63.
1ꢀ(1ꢀBenzoylpyrrolidineꢀ2ꢀcarbonyl)cyclopropaneꢀ1ꢀcarboꢀ
1
nitrile (10b). H NMR (CDCl3), δ: 3.55 (m, 2 H, CH2N); 5.05
(m, 1 H, CHN); 7.30—7.60 (m, 5 H, Ph). 13C NMR (CDCl3),
δ: 17.42, 21.61, 21.72, 25.56, 28.45, 50.03, 64.89, 120.27, 127.28,
127.42, 128.38, 130.55, 135.48, 135.58, 169.63, 199.42.
The mixture of nitriles 10a and 10b was obtained as a light
yellow oil. The total yield was 0.21 g (82%). Found (%): C,
71.54; H, 5.95; N, 10.15. C16H16N2O2. Calculated (%): C, 71.62;
H, 6.01; N, 10.44. 10a + 10b: IR, ν/cm–1: 1650, 1730, 2260.
1ꢀBenzoylꢀ2ꢀ(2ꢀdimethylsulfuranylideneꢀ1,3ꢀdioxobutyl)pyrꢀ
rolidine (11). Ylide 1 (0.28 g, 1 mmol) was dissolved under
heating in 8 mL of dry toluene to give a yellow solution. Acetic
anhydride (0.11 g, 1 mmol) was added dropwise, and the resultꢀ
ing colorless solution was refluxed for 1 h. The solvent was
removed to give ylide 11 as a light yellow oil. The yield of
10. G. A. Tolstikov, F. Z. Galin, and S. N. Lakeev, Izv. Akad.
Nauk SSSR, Ser. Khim., 1990, 1187 [Bull. Acad. Sci. USSR,
Div. Chem. Sci., 1990, 39, 1008 (Engl. Transl.)].
11. M. F. Ancell and S. S. Brown, J. Chem. Soc., 1957, 1788.
Received February 11, 2002;
in revised form May 29, 2002