The synthesis of optically active P-heterocycles

Article abstract of DOI:10.1002/hc.20599

Optically active 1-alkoxy- and 1-amino- 3-phospholene oxides were synthesized by the reaction of the corresponding 1-chloro-3-phospholene oxides with (1 R,2S,5R)-(-)menthol and (S)-(-)-α- phenylethylamine. The 3-methyl-3-phospholene oxides were subjected to dichlorocyclopropanation under liquid-liquid phase transfer catalytic conditions to afford the 3-phosphabicyclo[3.1.0]hexane 3-oxides as a mixture of four diastereomers. Thermolysis of the menthyl-phosphabicyclohexane oxides led to the corresponding 1 2-dihydrophosphinine oxide as a diastereomeric mixture of two double-bond isomers. As a result of additional steps, the dichlorocarbene addition reaction of the 1-menthyl- 3,4-dimethyl-3-phospholene oxide resulted in eventually, the formation of a 4-dichloromethylene-1,4-dihydrophosphinine oxide.

Full text of DOI:10.1002/hc.20599

Heteroatom Chemistry
Volume 21, Number 4, 2010
The Synthesis of Optically Active
P-Heterocycles
Gyo¨rgy Keglevich,1 Judit Dvorszki,1 Vikto´ria Ujj,1,2 and
Krisztina Luda´nyi3,4
1Department of Organic Chemistry and Technology, Budapest University of Technology
and Economics, 1521 Budapest, Hungary
2Research Group of the Hungarian Academy of Sciences at the Department of Organic Chemistry
and Technology, Budapest University of Technology and Economics, Budapest, Hungary
3Department of Pharmaceutics, Faculty of Pharmacy, Semmelweis University, 1092 Budapest,
Hungary
4Hungarian Academy of Sciences, Chemical Research Center, 1525 Budapest, Hungary
Received 9 February 2010; revised 10 March 2010
INTRODUCTION
ABSTRACT: Optically active 1-alkoxy- and 1-amino-
3-phospholene oxides were synthesized by the re-
action of the corresponding 1-chloro-3-phospholene
oxides with (1R,2S,5R)-(–)menthol and (S)-(–)-α-
phenylethylamine. The 3-methyl-3-phospholene oxides
were subjected to dichlorocyclopropanation under
liquid–liquid phase transfer catalytic conditions to
afford the 3-phosphabicyclo[3.1.0]hexane 3-oxides
These days the P-heterocyclic discipline is of in-
creasing importance [1,2]. The P-heterocycles are
used as building blocks in synthetic organic chem-
istry, as catalysts, as ligands in transition metal
complexes, and as biologically active substrates [1–
3]. The most easily available 3-phospholene oxides
served well as starting materials for six-membered
P-heterocycles [4,5]. A two-step ring enlargement in-
cluding 3-phosphabicyclo[3.1.0]hexane 3-oxides as
the intermediates made available 1,2-dihydro- and
1,2,3,6-tetrahydrophosphinine oxides [4,5]. Other
derivatives including 1,4-dihydrophosphinine oxides
were also synthesized [5]. All of the P-chiral hetero-
cycles prepared were racemates [4,5]. Petrusiewicz
and his co-workers were the first who devel-
oped methods for the synthesis of optically active
P-heterocycles [6–13]. Fogassy et al. including one
of the authors of this paper have recently elabo-
rated the simple resolution of 3-phospholene oxides
via molecule complexes and coordination complexes
[14–17]. Ring enlargement of the antipodes of the 3-
phospholene oxides may obviously lead to optically
active 1,2-dihydrophosphinine oxides.
as
a mixture of four diastereomers. Thermol-
ysis of the menthyl-phosphabicyclohexane oxides
led to the corresponding 1,2-dihydrophosphinine
oxide as a diastereomeric mixture of two double-
bond isomers. As a result of additional steps, the
dichlorocarbene addition reaction of the 1-menthyl-
3,4-dimethyl-3-phospholene oxide resulted in even-
tually, the formation of a 4-dichloromethylene-1,4-
ꢀ
C
dihydrophosphinine oxide.
2010 Wiley Periodicals,
Inc. Heteroatom Chem 21:271–277, 2010; Published on-
line in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hc.20599
Correspondence to: Gyo¨rgy Keglevich; e-mail: keglevich@mail
.bme.hu.
Contract grant sponsor: Hungarian Scientific and Research
Fund.
In this paper, we describe the preparation of
optically active 3-phospholene oxides by substitu-
tion at the phosphorus atom and their conversion
Contract grant number: OTKA K067679.
2010 Wiley Periodicals, Inc.
c
ꢀ
271

272 Keglevich et al.
26°C
OH
Cl
Cl
Cl
H
Cl
H
Me
O
Me
Me
6
3
H
5
4
1
TEBAC
NaOH / H2O
4
5
3
2
Me
2
1
TEA
P
P
P
+
O
O
O
O
O
PhMe
2'
2'
CHCl3
1'
6'
3'
4'
1'
6'
3'
4'
H
H
H
5'
5'
26°C
Me
OH
Me
Me
Me
Me
SOCl2
3a
4Aa
4Ba
26°C
CHCl3
P
P
H2N
Cl
Cl
H
Cl
H
Cl
H
O
O
Cl
Me
1
2
Me
Me
6
Me
5
4
1
TEBAC
NaOH / H2O
4
5
3
2
2
1
3
(2 eq.)
PhMe
P
P
P
H
H
H
+
O
O
O
NH
Me
NH
Me
NH
Me
CHCl3
1'
4'
1'
4'
2'
3'
2'
3'
3b
4Ab
4Bb
SCHEME 1
to 3-phosphabicyclo[3.1.0]hexane 3-oxides, as well
as 1,2- and 1,4-dihydrophosphinine oxides.
the C-chiral center, or fixed C-chiral centers in the
nucleophilic reactants.
Then 3-methyl-3-phospholene oxide 3a was sub-
jected to ring enlargement by the “dichlorocar-
bene” method [4]. According to this method, in
the first step, dichlorocarbene, generated from chlo-
roform by aqueous NaOH under phase transfer
catalytic conditions, was added on the double
bond of the phospholene oxide (3a). Both diastere-
omers of the phospholene oxide (3a) afforded the
3-phosphabicyclo[3.1.0]hexane 3-oxide (4a) as a
mixture of A and B isomers; consequently, the
dichlorocarbene adduct (4a) was obtained as a mix-
ture of four isomers (Scheme 1). The assignment of
the stereostructures to isomers A and B is tentative.
Partial separation of the diastereomers was possible;
column chromatography led to a fraction consisting
of 50% of 4A1a and 50% of 4A2a.
RESULTS AND DISCUSSION
In our efforts to synthesize optically active
P-heterocycles, we utilized (1R,2S,5R)-(–)-menthol
and (S)-(–)-α-phenylethylamine as the chiral-
building blocks. 1-Hydroxy-3-methyl-3-phospholene
oxide 1 was converted to the corresponding phos-
phinic chloride (2) by reaction with thionyl chlo-
ride in chloroform. Intermediate
2 was then
reacted with (1R,2S,5R)-(–)-menthol and (S)-(–)-α-
phenylethylamine in toluene, using triehylamine or
one more equivalent of the chiral amine itself as the
base to give cycloalkyloxy- and aminophospholene
oxides 3a and 3b, respectively (Scheme 1). The sub-
stituted phospholene oxides (3a and 3b) were ob-
tained as a 1:1 mixture of two diastereomers due
to the P-chirality of chlorophospholene oxide 2 and
Dichlorocyclopropanation
of
phenylethy-
laminophospholene oxide 3b was also accomplished
R
O
R
O
R
O
R
O
H
H
.
3a
0.5
+
P
+
P
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O
O
O
O
OH HO
OH HO
.
( )-3a ( )-I
(+)-3a
R,R =
R = Me [( )-I ] ;
[ ( )-II ]
.
( )-3a ( )-II
SCHEME 2
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Optically Active P-Heterocycles 273
under liquid–liquid phase transfer catalytic con-
ditions. In this case, the corresponding dichloro-
carbene adduct (4b) was again formed as four
isomers (Scheme 1), but probably due to hydrolytic
side-reactions the yield was moderate. In the
earlier described liquid–liquid phase dichloro-
cyclopropanation reaction of 1-diethylamino-3-
methyl-3-phospholene oxide, the diastereomer
containing the dichlorocyclopropane ring and
the oxygen of the P=O moiety in the trans dis-
position was assumed to be the major isomer
[18].
are in any case formed as a ca 3:1 mixture of two
double-bond isomers [4,5].
Beside the optically active 3-methyl-3-
phospholene oxides (3a and 3b), the analogous
3,4-dimethyl-3-phospholene oxides (8a and 8b)
were also prepared. In this instance, however, the
corresponding phosphinic chloride 7 was obtained
from 1-ethoxy-3,4-dimethyl-3-phospholene oxide
6 by a reaction with phosphorus pentachloride.
Reaction of intermediate 7 with (1R,2S,5R)-(–)-
menthol and (S)-(–)-α-phenylethylamine provided
phospholene oxides 8a and 8b, respectively, as
single isomers (Scheme 4).
The diasteromers of racemic 1-[(1ꢁ R,2ꢁ S,5ꢁ R)-
menthyloxy]-3-methyl-3-phospholene oxide 3a were
separated by the method elaborated by us for the res-
olution of 3-phospholene 1-oxide derivatives [14,15].
According to this method, 0.5 equiv of (–)-TADDOL
derivative I or II was added to the ethyl acetate
solution of menthyloxy-phospholene oxide 3a. Af-
ter the addition of hexane to the hot solution, the
supramolecular formation (–)-3a·(–)-I or (–)-3a·(–)-
II precipitated. After the first and second recrystal-
lization, complex (–)-3a·(–)-I was obtained in a yield
of 64% with an ee of 90% and in a yield of 25%
with an ee of >99%, respectively. Recrystallization
of complex (–)-3a·(–)-II led to a 45% yield and 90%
ee. Hence, the use of TADDOL I was more efficient
than “spiro TADDOL” II. The phospholene oxide
(–)-3a was regenerated by flash column chromatog-
raphy of the supramolecular complexes (–)-3a·(–)-I
and (–)-3a·(–)-II.
The treatment of phospholene oxide 8a with
NaOH/H2O-chloroform under phase transfer cat-
alytic conditions resulted, eventually 4-dichloro-
methylene-1,4-dihydrophosphinine
oxide
12a
(Scheme 4). The reaction sequence followed an ear-
lier protocol [4,19], according to which the primarily
formed dichlorocarbene adduct (in the present case
9a) is not stable under the conditions of the reaction
and undergoes a spontaneous cyclopropane ring
opening to afford and 1,4-dihydrophosphinine oxide
(in this case 10a). Then, the dihydrophosphinine
oxide may be the subject of a second series of trans-
formation with the excess of the reagents present
to give a 1,4-dihydrophosphinine oxide (in this case
12a) via the corresponding dichlorocarbene adduct
(in this case 11a) (Scheme 4). The difference in
the stability of monomethyl-phosphabicyclohexane
4 and that of dimethyl derivative 9 is the conse-
quence of the number of the methyl groups on the
skeleton. The special opening of the cyclopropane
ring in intermediate 11 to result in an exocyclic
4-dichloromethylene group is also the consequence
of the additional methyl group. The novel mech-
anism is under evaluation by quantum chemical
calculations [20].
In the next stage, we carried out the second
step of the ring enlargement, that is the thermal
opening of the dichlorocyclopropane ring. Thermol-
ysis of the 3-phosphabicyclo[3.1.0]hexane 3-oxide 4a
was accomplished in boiling toluene in the pres-
ence of 1 equiv of triethylamine to furnish the 1,2-
dihydrophosphinine oxide 5a as a ca 3:1 mixture of
double-bond isomers A and B (Scheme 3). It is worth
mentioning that the diastereomeric composition of
the starting material (4a) did not complicate the sit-
uation, as the dihydrophosphinine oxides of type 5
The new 3-phospholene oxides 3a, 3b, 8a, and
8b, 3-phosphabicyclo[3.1.0]hexane oxides 4a and
4b, dihydrophosphinine oxides 5a and 12a were
1
characterized by 31P, 13C, and H NMR, as well as
mass spectroscopical methods.
In conclusion, eight new optically active
P-heterocycles comprising four 3-phospholene ox-
ides, two 3-phosphabicyclo[3.1.0]hexane 3-oxides, a
1,2- and a 1,4-dihydrophosphinine oxide have been
described that can be used as P-ligands after deoxy-
genation.
Cl
Cl
Me
Me
4
4
5
6
3
2
3
2
5
C
TEA
110°
6
1
1
P
P
4Aa + 4Ba
+
O
O
O
O
PhMe
H
H
EXPERIMENTAL
Me
Me
1
The 31P, 13C, and H NMR spectra were taken on a
5Aa
5Ba
Bruker DRX-500 spectrometer operating at 202.4,
125.7, and 500 MHz, respectively. Chemical shifts
SCHEME 3
Heteroatom Chemistry DOI 10.1002/hc

274 Keglevich et al.
Cl
Me
Cl
Me
TEBAC
NaOH / H2O
61°
Me
C
Me
Me
Y
Me
Me
O
Me
PCl5
YH
3
2
1
CHCl3
HCl
CHCl3
P
P
P
P
O
OEt
Cl
O
O
Y
Y = menthyl
6
7
8
9a
Cl
Cl
Cl
Y
Cl
P
Cl
Cl
Me
.
.
CCl2
Me
Me
Me
Me
Me
4
3
2
HCl
1
P
P
O
Y
O
O
Y
10a
11a
12a
H
NH
Me
O
2'
1'
6'
3'
4'
H
(a),
(b)
Y =
5'
1'
2'
3'
4'
Me
SCHEME 4
ꢁ
ꢁ
are downfield relative to 85% H3PO4 and TMS. The
couplings are given in hertz. Mass spectrometry was
performed on a ZAB-2SEQ instrument.
21.0 (CHCH3), 22.0 (CHCH3), 23.1 (C3 ), 25.8 (C5 ),
31.5 (CHMe2), 32.6 (J = 88.4, C5),c 34.0 (J = 92.5,
d
e
ꢁ
ꢁ
ꢁ
C2), 34.1 (C4 ), 43.5 (C6 ), 48.5 (J = 6.3, C2 ), 76.7
f
ꢁ
(J = 7.5, C1 ), 120.5 (J = 10.7, C4), 136.4 (J = 16.8,
C3)g.
Synthesis of 1-[(1R,2S,5R)-Menthyloxy]-3-
methyl-3-phospholene 1-oxide (3a)
a−gmay be reversed
Resolution of 1-[(1ꢁ R, 2ꢁS, 5ꢁR-Menthyloxy]-3-
methyl-3-phospholene 1-oxide (3a) using
(–)-TADDOL (I)
To 13.2 g (100.0 mmol) of 1-hydroxy-3-methyl-3-
phospholene 1-oxide (1) in 40 mL of chloroform,
9.0 mL (124.0 mmol) of thionyl chloride was added
and the solution was stirred for 16 h. After evap-
oration of the volatiles, the residue was taken up
in 300 mL of toluene. To the solution so obtained,
13 mL (102.0 mmol) of triethylamine and 15.6 g
(100 mmol) of (1R,2S,5R)-(–)-menthol were added
and the mixture was stirred at 26◦C for 16 h. After
filtration, the product was purified by column chro-
matography (silica gel, 2% methanol in chloroform)
to give 13.5 g (50%) of 3a as a 1:1 mixture of two
diastereomers.
To 0.21 g (0.77 mmol) of racemic 1-[(1ꢁ R,2ꢁ S,5ꢁ R)-
menthyloxy]-3-methyl-3-phospholene oxide (3a)
and 0.18 g (0.38 mmol) of (–)-TADDOL (I) in 0.2 mL
of hot ethyl acetate, 2 mL of hexane was added.
After the addition, colorless crystals of the com-
plex started to appear immediately. After 2 h, the
crystals were separated by filtration to give 0.20 g
(71%) of complex [(–)-3a·(–)-I] with an ee of 71%.
The complex was further purified by two recrystal-
lizations from ethyl acetate–hexane (0.2 mL/1 mL)
to afford complex (–)-3a·(–)-I in a yield of 64%
with an ee of 90% and in a yield of 25% with
an ee of >99%, respectively. Column chromatogra-
phy (silica gel, chloroform-methanol) of the com-
plex regenerated 18 mg (25%) of the enantiomer-
ically pure (–)-1-[(1ꢁ R,2ꢁ S,5ꢁ R)-menthyl]-3-methyl-3-
[α]2D5 = −44.4 (c 1, CHCl3); 1H NMR (CDCl3)
ꢁ
δ 0.82 (d, J = 6.6, 3H, C5 CH3), 0.92 (d, J = 6.6,
6H, CH(CH )2), 1.80 (s, 3H, C3 CH3), 2.30 2.60 (m,
3
4H, CH2PCH2), 4.15–4.35 (m, 2H, OCH), 5.52 (d,
J = 35.4, 1H, C4H); HRMS, [M + H]+found = 271.1810,
C15H28O2P requires 271.1827.
Isomer A: 31P NMR (CDCl3) δ 73.28; 13C NMR
phospholene 1-oxide [(–)-(3a)]; ee >99%; [α]2D5
−77.6 (c 0.4, CHCl3); 31P NMR (CDCl3) δ 73.2.
=
(CDCl3) δ 15.9 (C5 CH3),a 20.7 (J = 3.6, C3 CH3),b
ꢁ
ꢁ
ꢁ
21.0 (CHCH3), 22.0 (CHCH3), 23.1 (C3 ), 25.8 (C5 ),
c
ꢁ
31.4 (J = 88.9, C5), 31.5 (CHMe2), 34.1 (C4 ), 35.3 (J
Synthesis of 1-[(1S)-1-Phenylethylamino]-3-
methyl-3-phospholene l-oxide (3b)
d
e
ꢁ
ꢁ
= 92.0, C2), 43.5 (C6 ), 48.5 (J = 6.3, C2 ), 76.7 (J =
f
g
ꢁ
7.5, C1 ), 120.2 (J = 11.1, C4), 136.4 (J = 16.8, C3) .
Isomer B: 31P NMR (CDCl3) δ 73.33; 13C NMR
To 6.6 g (50.0 mmol) of 1-hydroxy-3-methyl-3-
phospholene 1-oxide (1) in 20 mL of chloroform,
(CDCl3) δ 16.0 (C5 CH3),a 20.9 (J = 3.6, C3 CH3),b
ꢁ
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Optically Active P-Heterocycles 275
4.5 mL (62.0 mmol) of thionyl chloride was added
and the solution was stirred for 16 h. After evap-
oration of the volatiles, the residue was taken up
in 150 mL of toluene. To the solution so obtained,
13 mL (102.0 mmol) of (S)-α-phenylethylamine was
added and the mixture was stirred for 16 h. After
filtration, the product was purified by column chro-
matography (silica gel, 3% methanol in chloroform)
to give 8.8 g (75%) of 3b as a 1:1 mixture of two
diastereomers.
CH2PCH2), 4.15–4.35 (m, 2H, OCH); HRMS, [M +
H]+found = 285.1964, C16H30O2P requires 285.1983.
Synthesis of 1-[(1S)-1-Phenylethylamino)]-3,4-
dimethyl-3-phospholene 1-oxide (8b)
To 0.80 g (4.6 mmol) of l-ethoxy-3,4-dimethoxy-3-
phospholene 1-oxide (6) in 20 mL of chloroform,
1.0 g (4.9 mmol) of phosphorus pentachloride was
added and the mixture was kept at reflux for 6 h. Af-
ter filtration and evaporation of the volatiles, phos-
phinic chloride 7 was dissolved in 20 mL of toluene.
To the solution so obtained, 1.2 mL (9.2 mmol) of
(S)-α-phenylethylamine was added and the mixture
was stirred for 16 h. After filtration, the product was
purified by column chromatography (silica gel, 3%
methanol in chloroform) to give 0.93 g (81%) of 8b as
colorless oil. [α]2D5 = +103.0 (c 0.4, CH2Cl2); 31P NMR
(CDCl3) δ 55.3; 13C NMR (CDCl3) δ 16.1 (CHCH3),
[α]2D5 = −26.8(c 2, CHCl3); 1H NMR (CDCl3) δ
1.52 (d, 3H, J = 6.6, CHCH3), 1.68 and 1.70 (s,
3H, C3 CH3, isomer A and B), 2.00–2.55 (m, 4H,
CH2PCH2), 2.91 (bs, 1H, NH), 4.30–4.50 (m, 1H, CH),
5.44 (d, J = 33.6, 1H, C4H), 7.20–7.39 (m, 5H, Ar);
HRMS, [M + H]f+ound = 236.1192, C13H19NOP requires
236.1204.
Isomer A: 31P NMR (CDCl3) δ 62.0; 13C NMR
(CDCl3) δ 20.1 (CHCH3),a 25.5 (J = 3.1, C3 CH3),b
31.9 (J = 81.4, C2),c 34.6 (J = 85.2, C5),d 50.2
16.3 (CHCH3), 25.8 (J = 6.2, C3 CH3), 36.9 (J = 83.5,
e
f
∗
ꢁ
ꢁ
(CHMe), 120.2 (J = 9.5, C3), 125.6 (C2 ), 126.7 (C4 ),
∗
ꢁ
C5), 37.6 (J = 83.2, C2), 50.6 (CHMe), 125.7 (C2 ),
∗
g
∗
ꢁ
ꢁ
128.1 (C3 ), 136.3 (J = 11.1, C4), 145.0 (C1 ); may
be reversed.
∗
ꢁ
ꢁ
126.9 (C4 ), 127.4 (J = 11.6, C3), 128.3 (C3 ), 145.1
∗
1
ꢁ
(J = 2.9, C1 ), may be reversed; H NMR (CDCl3)
Isomer B: 31P NMR (CDCl3) δ 62.5; 13C NMR
(CDCl3) δ 20.3 (CHCH3),a 25.6 (J = 3.3, C3 CH3),b
32.4 (J = 81.2, C2),c 35.2 (J = 84.3, C5),d 50.4
δ 1.51 (d, J = 6.6, 3H, CHCH ), 1.52 (s, 3H, CH3),
3
1.59 (s, 3H, CH3), 2.08–2.25 (m, 2H, CH2), 2.30–2.52
(m, 2H, CH2), 2.88 (bs, 1H, NH), 4.31–4.51 (m, 1H,
e
f
∗
ꢁ
ꢁ
(CHMe), 120.3 (J = 9.3, C3), 125.6 (C2 ), 126.7 (C4 ),
CH), 7.20–7.39 (m, 5H, Ar). HRMS, [M + H]f+ound
=
∗
g
∗
ꢁ
ꢁ
128.1 (C3 ), 136.1 (J = 11.2, C4), 145.0 (C1 ); may
be reversed.
250.1347, C14H21NOP requires 250.1361.
a−gmay be reversed.
Synthesis of 6,6-Dichloro-3-[(1R,2S,5R)-
menthyloxy]-1-methyl-3-phosphabicyclo-
[3.1.0]hexane 3-oxide (4a)
Synthesis of 1-[(1R,2S,5R)-Menthyloxy]-3,4-
dimethyl-3-phospholene 1-oxide (8a)
To 0.80 g (4.6 mmol) of 1-ethoxy-3,4-dimethoxy-3-
phospholene 1-oxide (6) in 20 mL of chloroform,
1.0 g (4.9 mmol) of phosphorus pentachloride was
added and the mixture was kept at reflux for 2.5 h.
After filtration and evaporation of the volatiles, phos-
phinic chloride 7 was dissolved in 20 mL of toluene.
To the solution so obtained, 0.65 mL (4.7 mmol) of
triethylamine and 0.79 g (5.1 mmol) of (1R,2S,5R)-
(–)-menthol were added and the mixture was stirred
for 16 h. After filtration, the product was purified
by column chromatography (silica gel, 2% methanol
in chloroform) to give 1.3 g of 8a as colorless oil.
[α]2D5 = −104.0 (c 0.4, CH2Cl2); 31P NMR (CDCl3) δ
To the mixture of 2.0 g (7.4 mmol) of 1-[(1R,2S,5R)-
menthyloxy]-3-methyl-3-phospholene 1-oxide (3a)
and 0.20 g (0.80 mmol) of TEBAC in 40 mL of chlo-
roform, a solution of NaOH (5.5 g of NaOH in 7 mL
of water) was added dropwise and the mixture was
kept at reflux for 3 h. The mixture was cooled to 26◦C,
filtrated, the organic phase separated and made up
to its original volume. To the solution, 0.10 g (0.40
mmol) of TEBAC and 5.5 g of NaOH in 7 mL of wa-
ter were added and the mixture was kept at reflux
for 3 h. The mixture was cooled and filtrated; the
organic phase was separated and concentrated. The
crude product so obtained was purified by column
chromatography (silica gel, 2% methanol in chloro-
form) to give 0.50 g (19%) of 4a consisting of iso-
mers A1 (30%), A2 (29%), B1 (21%), and B2 (20%)
as a colorless oil. Repeated chromatography led to a
fraction containing only isomers A1 (50%) and A2
(50%). [α]2D5 = −46.0 (c 1, CHCl3); HRMS, [M +
H]+found = 353.1176, C16H28Cl2O2P requires 353.1204
for the 35Cl isotopes.
66.6; 13C NMR (CDCl3) δ 15.7 (C5 CH3), 16.2 (J =
ꢁ
4.2, CH3), 16.4 (J = 4.0, CH3), 20.6 (CHCH3), 21.7
ꢁ
ꢁ
(CHCH3), 22.8 (C3 ), 25.6 (C5 ), 31.2 (CHMe2), 33.8
ꢁ
(C4 ), 36.1 (J = 91.4, C5), 37.3 (J = 93.4, C2), 43.2
ꢁ
ꢁ
ꢁ
(C6 ), 48.2 (J = 6.3, C2 ), 76.2 (J = 7.4, C1 ), 127.0 (J
= 13.1, C3), 127.3 (J = 12.7, C4); 1H NMR (CDCl3) δ
ꢁ
0.81 (d, J = 6.8, 3H, C5 CH3), 0.91 (d, J = 6.0, 6H,
CH(CH )2), 1.72 (s, 6H, C3 CH3), 2.32–2.60 (m, 4H,
3
Heteroatom Chemistry DOI 10.1002/hc

276 Keglevich et al.
Isomer A1: 31P NMR (CDCl3) δ 81.0; 13C NMR
CH CH3), 72.4 (J = 13.7, C6), 125.7 (Cβ), 127.3 (Cδ),
1
ꢁ
128.6 (Cγ), 144.9 (J = 3.2, Cα); H NMR (CDCl3) δ
(CDCl3) δ 15.7 (C5 CH3), 20.8 (CHCH3), 21.7
A
B
ꢁ
1.52 (s, 3H, C1 CH3), 1.55 (d, J = 6.9, 3H, CH CH3),
7.27 7.38 (m, 5H, Ar).
(J = 7.8, C1 CH3), 21.9 (CHCH3), 22.9 (C3 ), 25.9
C
ꢁ
(C5 ), 27.7 (J = 91.0, C2), 31.1 (J = 12.6, C1), 31.4
Isomer B: 31P NMR (CDCl3) δ 75.9; 13C NMR
(CDCl3) δ 21.3 (J = 7.3, C1 CH3), 27.2 (J = 84.1,
C4), 26.0 (J = 5.4, CH CH3), 31.5 (J = 86.4, C2),
31.9 (J = 12.3, C1), 33.3 (J = 11.1, C5), 50.4 (J = 1.3,
CH CH3), 72.5 (J = 12.6, C6), 126.0 (Cβ), 127.4 (Cδ),
(CHMe2), 32.5 (J = 94.3, C4),E 33.3 (J = 12.4, C5),D
F
ꢁ
ꢁ
ꢁ
34.0 (C4 ), 42.9 (C6 ), 48.3 (J = 5.9, C2 ), 72.2 (J =
14.1, C6).
Isomer A2: 31P NMR (CDCl3) δ 81.1; 13C NMR
ꢁ
(CDCl3) δ 15.7 (C5 CH3), 20.8 (CHCH3), 21.8
1
A
B
ꢁ
128.6 (Cγ ), 144.8 (J = 3.4, Cα); H NMR (CDCl3) δ
(J = 7.5, C1 CH3), 21.9 (CHCH3), 22.8 (C3 ), 25.9
C
ꢁ
1.52 (s, 3H, C1 CH3), 1.55 (d, J = 6.9, 3H, CH CH3),
7.27–7.38 (m, 5H, Ar).
(C5 ), 26.7 (J = 92.2, C2), 31.1 (J = 12.6, C1), 31.4
(CHMe2), 32.6 (J = 12.6, C5),D 33.5 (J = 91.0, C4),E
ꢁ
ꢁ
ꢁ
Isomer C: 31P NMR (CDCl3) δ 74.2.
Isomer D: 31P NMR (CDCl3) δ 74.9.
F
34.0 (C4 ), 43.0 (C6 ), 48.3 (J = 5.9, C2 ), 72.2 (J =
14.1, C6).
A−Fmay be reversed.
Isomer B1: 31P NMR (CDCl3) δ 85.7; 13C NMR
Synthesis of 3- and 5-Methyl-4-chloro-1-[(1R,2S,
5R)-menthyloxy]-1,2-dihydrophosphinine
1-oxides (5Aa and 5Ba)
(CDCl3) δ 15.8 (C5 CH3),a 21.0 (CHCH3), 21.6
ꢁ
b
c
d
ꢁ
(J = 7.7, C1 CH3), 21.9 (CHCH3), 22.9 (C3 ), 25.8
f
e
ꢁ
(C5 ), 27.0 (J = 88.9, C2), 31.1 (J = 12.7, C1), 31.6
(CHMe2),g 32.6 (J = 90.9, C4),h 32.7 (J = 10.8, C5),i
A mixture of 3.3 g (9.4 mmol) of dichlorcyclopropane
derivative 4a consisting of isomers A1 (30%), A2
(29%), B1 (21%), and B2 (20%) and 1.4 ml (10.0
mmol) of triethylamine in 50 mL of dry toluene was
stirred at the boiling point for 10 h. Then the pre-
cipitated salt was filtered off and the filtrate concen-
trated in vacuum. The crude product so obtained was
purified by repeated column chromatography ((1)
3% methanol in chloroform and (2) ethyl acetate–
hexane 3:1, using silica gel as the absorbent) to
give 1.8. g (61%) of the title product 5a as a mix-
ture of four isomers (5Aa1: 34%, 5Aa2: 42%, 5Ba1:
13%, and 5Ba2 11%). [α]2D5 = −57.0 (c 1.0, CHCl3);
HRMS, [M + H]+found = 317.1447, C16H27ClO2P re-
quires 317.1437 for the 35Cl isotope.
j
k
ꢁ
ꢁ
ꢁ
34.0 (C4 ), 43.6 (C6 ), 48.7 (J = 6.0, C2 ), 72.0 (J =
12.3, C6)l .
Isomer B2: 31P NMR (CDCl3) δ 86.2; 13C NMR
(CDCl3) δ 15.9 (C5 CH3),a 21.0 (CHCH3), 21.5 (J
ꢁ
= 7.9, C1 CH3),b 22.0 (CHCH3), 23.0 (C3 ), 25.3
c
d
ꢁ
e
f
ꢁ
(J = 91.4, C2), 25.9 (C5 ), 31.1 (J = 12.7, C1), 31.5
(CHMe2),g 31.8 (J = 92.8, C4),h 32.4 (J = 11.2, C5),i
j
k
ꢁ
ꢁ
ꢁ
34.0 (C4 ), 43.5 (C6 ), 48.6 (J = 5.8, C2 ), 72.1 (J =
12.1, C6)l .
a−lmay be reversed.
Synthesis of 6,6-Dichloro-3-[(1S)-
l-phenylethylamino]-1-methyl-3-
phosphabicyclo[3.1.0]hexane 3-oxide (4b)
For major isomers 5Aa1 and 5Aa2: 31P NMR
To the mixture of 4.0 g (17.0 mmol) of 1-[(1S)-1-
phenylethylamino]-3-methyl-3-phospholene 1-oxide
(3b) and 1.36 g (6.0 mmol) of TEBAC in 80 mL of
chloroform, a solution of 26.0 g of NaOH in 28 mL
of water was added dropwise and the mixture was
kept at reflux for 3 h. The mixture was cooled and fil-
trated; the organic phase was separated and concen-
trated. The crude product so obtained was purified
by column chromatography (silica gel, 2% methanol
in chloroform) to give 1.0 g (19%) of 4b, consisting of
isomers A (36%), B (26%), C (29%), and D (9%) as a
colorless oil. Repeated chromatography led to a frac-
tion containing only isomers A (60%) and B (40%).
(CDCl3) δ 31.0 (34%) and 31.2 (42%); 13C NMR
ꢁ
(CDCl3) δ 15.78, 15.85 (C5 ∗ CH3), 20.8 (CHCH3), 21.8
ꢁ
(CHCH3), 22.8, 22.9 (C3 ), 23.4 (J = 10.4) (C3 CH3),
∗
ꢁ
ꢁ
25.5, 25.8 (C5 ), 31.5 (CHMe2), 33.9 (C4 ), 34.0 (J =
ꢁ
99.8), 34.9 (J = 100.2) (C2), 43.67, 43.9 (C6 ), 48.3
ꢁ
(J = 7.1), 48.4 (J = 7.0) (C2 ), 76.8 (J = 7.2), 77.0
ꢁ
(J = 7.5) (C1 ), 119.6 (J = 121.2), 120.8 (J = 121.0)
(C6), 123.3, (J = 21.9) (C3), 131.9 (J = 8.6), 132.2
1
(J = 8.9) (C4), 143.9, 144.6 (C5); H NMR (CDCl3)
δ 0.76 (d, J = 6.0), 0.83 (d, J = 5.6, 3H) (CHCH3),
0.92 (d, J = 5.5, CH(CH3)2), 2.03 (s, C3 CH3), 6.07
2
3
(t, JPH
=
3 JHH = 10.0, C6H), 6.70 (dd, JPH = 39.6,
3 JHH = 12.8, C5H); ∗tentative assignment.
[α]2D5 = −8.3 (c 1.3, CHCl3); HRMS, [M + H]+found
=
For minor isomers 5Ba1 and 5Ba2: 31P NMR
318.0586, C14H19Cl2NOP requires 318.0581 for the
35Cl isotopes.
(CDCl3) δ 30.1 (13%) and 30.2 (11%); 13C NMR
ꢁ
(CDCl3) δ 15.6, 15.85 (C5 CH3), 20.9 (CHCH3), 21.9
Isomer A: 31P NMR (CDCl3) δ 75.7; 13C NMR
(CDCl3) δ 21.7 (J = 7.1, C1 CH3), 25.6 (J = 85.9,
C4), 26.2 (J = 5.3, CH CH3), 31.7 (J = 12.6, C1),
32.8 (J = 84.9, C2), 33.2 (J = 10.6, C5), 50.3 (J = 1.4,
(CHCH3), 22.7, 22.8 (C3 ), 24.6 (J = 5.6), 24.8 (J
∗
ꢁ
ꢁ
= 5.8) (C5 CH3), 25.4, 25.7 (C5 ), 28.4 (J = 99.0),
∗
ꢁ
29.1 (J = 100.4) (C2), 31.5 (CHMe2), 33.9 (C4 ),
ꢁ
ꢁ
43.71 (C6 ), 48.4 (J = 7.0), 48.5 (J = 10.8) (C2 ), 76.6
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Optically Active P-Heterocycles 277
ꢁ
(J = 4.0), 76.7 (J = 4.0) (C1 ), 118.9 (J = 125.8),
REFERENCES
120.0 (J = 126.1) (C6), 123.4 (J = 8.0), 123.8 (J =
10.5) (C3), 131.2 (J = 2.0), 131.5 (J = 2.0) (C4), 149.8
(J = 1.6), 150.7 (J = 1.6) (C5); 1H NMR (CDCl3) δ 0.92
[1] Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. (Eds.).
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[2] Mathey, F. (Ed.). Phosphorus-Carbon Heterocyclic
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Amsterdam, 2001.
∗
(d, J = 5.5, CH(CH3)2), 2.12 (s, C5 CH3); tentative
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[3] Quin, L. D. A Guide to Organophosphorus Chemistry;
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[4] Keglevich, G. Synthesis 1993, 931.
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dihydrophosphinine l-oxide (12a)
To the mixture of 0.76 g (2.7 mmol) of 1-[(1R,2S,5R)-
menthyloxy]-3,4-dimethyl-3-phospholene l-oxide (8)
and 0.035 g (0.15 mmol) of TEBAC in 5 mL of chlo-
roform, a solution of 4.0 g (0.10 mol) of NaOH in
4 mL of water was added dropwise and the mixture
was kept at reflux for 3 h. The mixture was cooled to
26◦C and filtrated; the organic phase was separated
and concentrated. The crude product so obtained
was purified by column chromatography (silica gel,
2% methanol in chloroform) to give 0.33 g (33%) of
12a as a colorless oil.
[α]2D5 = −59.6 (c 1.0, CHCl)3; 31P NMR (CDCl3)
δ 18.0; 13C NMR (CDCl3) δ 15.8 (C5 CH3 ), 20.8
ꢁ
ꢁ
ꢁ
(CHCH3), 21.7 (CHCH3)), 22.7 (C3 ), 23.4 (J = 16.3,
ꢁ
C3 CH3), 23.6 (J = 16.0, C5 CH3), 25.1 (C5 ), 31.4
ꢁ
ꢁ
ꢁ
(CHMe2), 33.8 (C4 ), 43.3 (C6 ), 48.5 (J = 6.5, C2 ), 77.3
ꢁ
(J = 7.5, C1 ), 122.7 (J = 128.0, C2), 122.8 (J = 130.1,
[15] Nova´k, T.; Ujj, V.; Schindler, J.; Czugler,
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C6), 123.8 (J = 4.2, CCl2), 136.5 (J = 24.4, C4), 154.3
(J = 15.2, C3, C5); 1H NMR (CDCl3) δ 0.76 (d, 3H, J =
ꢁ
6.9, C5 CH3), 0.89 (d, 3H, J = 7.0, CH(CH )2), 0.91
3
(d, 3H, J = 6.4, CH(CH )2), 2.32 (s, 6H, C3 CH3), 4.02
3
(dq, J1 = 9.8, J2 = 4.5, 3H, OCH), 5.99 (d, J = 10.5,
1H, C2H), 6.03 (d, J = 10.6, 1H, C6H); HRMS, [M +
H]+found = 377.1214, C18H28Cl2O2P requires 377.1204.
[17] Ujj, V.; Bagi, P.; Schindler, J.; Madara´sz, J.; Fogassy,
E.; Keglevich, G. Chirality, in press.
´
[18] Keglevich, G.; Kova´cs, A.; To´´ke, L.; Ujsza´szy, K.;
ACKNOWLEDGMENT
Argay, G.; Czugler, M.; Ka´lma´n, A. Heteroatom Chem
1993, 4, 329.
´
G. K. is indebted to Dr Tibor Nova´k, Ada´m Bo´dis,
and Dr Andrea Kere´nyi for participating in a part of
the project.
´
[19] Keglevich, G.; Szo¨llo´´sy, A.; To´´ke, L.; Fu¨lo¨p, V.;
Ka´lma´n, A. J Org Chem 1990, 55, 6361.
[20] Mucsi, Z.; Keglevich, G., in preparation.
Heteroatom Chemistry DOI 10.1002/hc