Selective monoalkylation of phosphorus-substituted CH acids with (bromomethyl)- And 1,4-bis(bromomethyl)benzenes

Article abstract of DOI:10.1023/B:RUCB.0000024852.47670.5d

C-Alkylation of phosphorus-substituted CH acids with various substituted (bromomethyl)arenes under phase transfer catalysis conditions (K ₂CO₃/MeCN) proceeds with high selectivity (75-100%) as monoalkylation.

Full text of DOI:10.1023/B:RUCB.0000024852.47670.5d

Russian Chemical Bulletin, International Edition, Vol. 53, No. 1, pp. 219—227, January, 2004
219
Selective monoalkylation of phosphorusꢀsubstituted
CH acids with (bromomethyl)ꢀ and 1,4ꢀbis(bromomethyl)benzenes
I. L. Odinets,ꢀ O. I. Artyushin, S. V. Lenevich, G. V. Bodrin, K. A. Lyssenko,
I. V. Fedyanin, P. V. Petrovskii, and T. A. Mastryukova
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5085. Eꢀmail: odinets@ineos.ac.ru
CꢀAlkylation of phosphorusꢀsubstituted CH acids with various substituted (bromoꢀ
methyl)arenes under phase transfer catalysis conditions (K2CO3/MeCN) proceeds with high
selectivity (75—100%) as monoalkylation.
Key words: CH acids, phosphorylacetonitriles, thiophosphorylacetonitriles, alkylation,
(bromomethyl)benzene, 1,4ꢀbis(bromomethyl)benzene, phase transfer catalysis, Xꢀray difꢀ
fraction analysis.
CꢀAlkylation of various types of CH acids, including
phosphorus(IV)ꢀsubstituted CH acids, using various bases
and heterophase systems finds wide application in preꢀ
parative organic chemistry for modifying the structures of
starting substrates1,2 and is, apparently, one of the most
extensively studied reactions proceeding under phase
transfer catalysis (PTC) conditions. It should also be noted
that alkylation of CH acids is the reaction, in which phase
transfer catalysis has been discovered for the first time.
These reactions proceed readily with benzyl halides posꢀ
sessing higher electrophilicity compared to aliphatic priꢀ
mary haloalkanes, due to which even their chlorineꢀsubꢀ
stituted derivatives can be used,3,4 although such examples
are few in number. In particular, the reaction of dimethylꢀ
amide of cyanomethylphosphonic acid with benzyl chloꢀ
ride in the NaOH (50%)/CH2Cl2 system proceeded with
rather high selectivity as Cꢀmonoalkylation (71% yield).3
C,CꢀDialkylation of diethoxyphosphorylacetonitrile with
benzyl chloride (46% yield) and its paraꢀfluorineꢀsubstiꢀ
tuted derivative (70% yield) was carried out under condiꢀ
tions of ionꢀpair extraction (12.5 M NaOH/TEBA,*
60 °C).4 As for alkylation of phosphorusꢀsubstituted
CH acids with poly(halomethyl)arenes, only exhausꢀ
tive cycloalkylation of (thio)phosphorylacetonitriles
with hexakis(bromomethyl)benzene in the K2CO3
(or Cs2CO3)/MeCN—DMSO system (95 : 5) was deꢀ
scribed. The latter reaction gave rise to a mixture of geoꢀ
metric isomers of 2,5,8ꢀtris[diphenyl(thio)phosphoryl]ꢀ
2,3,4,5,6,7,8,9ꢀoctahydroꢀ1Hꢀcyclopenta[e]ꢀasꢀindaꢀ
ceneꢀ2,5,8ꢀtricarbonitrile (trisꢀphosphorylated triꢀ
indanes).5
by varying the type of phase transfer systems.3,4,6 Hence,
it was of interest to examine the possibility of the
use of disubstituted (halomethyl)arenes, for exꢀ
ample, 1,4ꢀbis(bromomethyl)benzene, as synthons for the
preparation of new types of functionalized macrocycles
(Scheme 1). Such compounds with the exocyclic P atom
attached to the macrocyclic core are of interest as chelatꢀ
ing and extractive agents, which is able not only to be
coordinated at the P=X group but also to form guest—host
inclusion compounds as well as precursors of new types of
phosphine ligands for metal complex catalysis.
Scheme 1
X = O, S; Y = CN, COOR, C(O)R; R1, R2 = OAlk, Alk, Ar
We used the phaseꢀtransfer catalyzed reaction of
diphenylphosphorylacetonitrile (1a) with benzyl bromide
(2a) as a model process for determining the conditions for
the reaction proceeding as dialkylation. We chose subꢀ
strate 1a as the CH acid because phosphorylacetonitriles
(Horner—Emmons reagents) and their thiophosphoꢀ
rylated analogs are readily available and are not tend to
exhibit dual reactivity in PTC reactions.
It is well known that alkylation of CH acids can
be directed toward either selective monoꢀ or dialkylation
* TEBA is triethylbenzylammonium chloride.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 209—217, January, 2004.
1066ꢀ5285/04/5301ꢀ0219 © 2004 Plenum Publishing Corporation

220
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 1, January, 2004
Odinets et al.
It appeared that the reactions of compounds 1a and 2a
of the MeCN—DMSO solvent mixture (9 : 1) led to an
increase in the percentage of the double alkylation prodꢀ
uct to 25%, whereas the yields of compounds 4a,b, correꢀ
spondingly, decreased.
readily proceeded at ∼20 °C with the use of potassium
carbonate as the base and MeCN as the organic phase to
give (regardless of the ratio between the starting reagents)
the corresponding monobenzylꢀsubstituted derivative 3
in high yield (Scheme 2). An increase in the temperature
(MeCN, 80 °C) leads only to a decrease in the reaction
time but does not change the direction of the reaction.
An analogous result was obtained with the use of an
MeCN—DMSO mixture (in ratios from 9 : 1 to 8 : 2) as
the organic phase.
The reactions of nitriles 1a,b with 2ꢀdiphenylꢀ
phosphorylmethyl(bromomethyl)benzene (2c) in the
K2CO3/MeCN system proceeded exclusively as monoꢀ
alkylation (Scheme 4). When DMSO was used as the
solvent for substrate 1a, the direction of the reaction perꢀ
sisted and the overall rate of the process only slightly
increased (in both systems, product 6a was prepared in
approximately equal yields). According to the 31P NMR
spectroscopic data, the reaction of nitrile 1b in DMSO
afforded a mixture consisting of the starting compound 1b
(36%), product 6b (36%), and 2ꢀpropenenitrile 7 (28%).
The latter product was, evidently, generated due to elimiꢀ
nation of the diphenylthiophosphoryl fragment from 6b.
(E)ꢀ3ꢀ{2ꢀ[(Diphenylphosphoryl)methyl]phenyl}propꢀ2ꢀ
enenitrile (7) was isolated from the reaction mixture in
the individual state in low yield by fractional crystalliꢀ
zation.
Scheme 2
It is known that the reactions of compound 1a with
α,ωꢀdihaloalkanes,7 α,ψꢀdihaloalkanes,8 and hexaꢀ
kis(bromomethyl)benzene5 in the K2CO3/DMSO system
proceed as exhaustive cycloalkylation. However, in our
study, the reactions afforded only 23% of the correspondꢀ
ing dialkylation product (according to the 31P NMR specꢀ
troscopic data) even with the use of this heterophase sysꢀ
tem and an excess of benzyl bromide.
Scheme 4
Although the reactions of diphenylphosphorylacetoꢀ
nitrile (1a) and its thiophosphoryl analog 1b with the use
of oꢀcyanoꢀsubstituted (bromomethyl)benzene 2b as an
electrophilic component also proceeded predominantly
as monoalkylation (the yields of compounds 4a,b were
higher than 75%), double alkylation products 5a,b were
generated (in 15—17% yields) already in a soft phase transꢀ
fer system, such as K2CO3/MeCN (Scheme 3). The use
X = O (a), S (b)
i. X = O, S; K2CO3/MeCN or X = O; K2CO3/DMSO.
ii. X = S, K2CO3/DMSO
Scheme 3
Apparently, high selectivity of the reactions of phosꢀ
phorylꢀ and thiophosphorylacetonitriles with various
(bromomethyl)benzenes in the K2CO3/MeCN system
is attributed not to steric factors or thermodynamic
favorability of the monoalkylation product but to low soluꢀ
bility of primary Cꢀalkylation products in MeCN, due to
which they are removed from the reaction sphere. In parꢀ
ticular, compounds 4a,b produced in the reaction with
2ꢀ(bromomethyl)benzonitrile (2b) have the highest soluꢀ
bility in MeCN, and it is this reaction that proceeded with
the lowest selectivity. The above assumption is supported
also by a decrease in selectivity of the reaction with benzyl
bromide (see Scheme 2) in the presence of DMSO as the
organic phase, because product 3 is more soluble in DMSO
than in MeCN. Since 2ꢀ(diphenylphosphoryl)ꢀ and
2ꢀ(diphenylthiophosphoryl)ꢀ3ꢀ{2ꢀ[(diphenylphosphoꢀ
X = O (a), S (b)

Selective monoalkylation of Pꢀsubstituted CH acids Russ.Chem.Bull., Int.Ed., Vol. 53, No. 1, January, 2004
221
ryl)methyl]phenyl}propanenitriles 6a,b have low solubilꢀ
ity even in DMSO, the nature of the solvent has no effect
on the selectivity of their reactions. Low solubility in
MeCN makes it possible to isolate easily the final solid
product by filtration after the addition of water to the
reaction mixture. It should be noted that this treatment
often affords products as stable hydrates, which are only
sometimes destroyed upon subsequent recrystallization
from nonaqueous solvents.
Therefore, in attempting to perform double alkylation
of phosphorylꢀ and thiophosphorylacetonitriles 1a—d with
1,4ꢀbis(bromomethyl)arenes 9a,b, which could afford
macrocycles in a substantially dilute reaction mixture, we
prepared products of double monoalkylation at both
bromomethyl fragments of the electrophilic component
in high yields* (the reagent ratio was 2 : 1) (Scheme 5).
A change in the reagent ratio has no effect on the reaction
pathway and only hinders isolation of the target products.
to give the corresponding diphosphorylated derivatives
11a,b. However, in this case, the reagent ratio 8 : 9 =
1.2 : 1 appeared to be most efficient, because the phaseꢀ
transfer catalyzed reaction was accompanied by partial
hydrolysis of the ester fragment in ester 8 and the reꢀ
sulting diphenylphosphorylacetic acid did not undergo
CHꢀalkylation.
In this case, the reaction products are also poorly
soluble in MeCN. After aqueous treatment of the mixꢀ
ture, these products can easily be isolated by filtration as
crystal hydrates of individual compounds; impurities of
the unconsumed starting reagents, potassium carbonate,
and small amounts of byꢀproducts (for example, hydrolyꢀ
sis products of ester 8) can be removed by washing with
either water or MeCN. In some cases, crystal hydrate can
be decomposed and water of crystallization can be reꢀ
moved upon subsequent recrystallization.
The compositions and structures of all the comꢀ
pounds synthesized were confirmed by elemental analysis
1
data (Table 1) and the IR and H, 31P, and 13C NMR
Scheme 5
spectra (Tables 2 and 3). In addition, the structure of
2ꢀ[2ꢀcyanoꢀ2ꢀ(diphenylphosphoryl)ethyl]benzonitrile
(4a) was established by singleꢀcrystal Xꢀray diffraction
analysis. The overall view of molecule 4a is shown in
Fig. 1. Selected bond lengths and bond angles are given
in Table 4. In the crystal, the cyano group in the α posiꢀ
tion with respect to the P atom (at the C(1) atom)
has a synperiplanar conformation relative to the phosꢀ
phoryl group; the O(1)—P(1)—C(1)—C(9) torsion
angle is 68°. The P(1)—C(1)—C(2)—C(3) fragꢀ
ment adopts an antiperiplanar conformation (the
P(1)—C(1)—C(2)—C(3) torsion angle is –172.8°). The
cyanoꢀsubstituted phenyl group is nearly orthogonal to
the latter fragment (the C(1)—C(2)—C(3)—C(8) torsion
angle is –102.5°). Hence, the conformation of molecule
4a in the crystal excludes the formation of intramolecular
contacts of the cyano substituent (C(10)N(2)) of the pheꢀ
nyl ring with both the αꢀH(1) atom and the H atoms of
the P(O)Ph2 group.
Analysis of the crystal packing demonstrated that the
molecules are linked in chains extended along the crystalꢀ
lographic c axis via strong C—H...O contacts involving
the H(1) atom (C(1)...O(1´), 3.151(3) Å; H(1)...O(1),
2.17 Å; C(1)—H(1)—O(1), 149°) and the H(16) atom
(C(16)...O(1´), 3.390(3) Å; H(16)...O(1), 2.31 Å;
C(1)—H(1)—O(1), 173°). These chains, in turn, are
linked via C—N...H contacts (C(21)...N(2´), 3.416(3) Å;
H(21)...N(2´), 2.49 Å; C(21)—H(21)—N(2´), 163°) in a
layer parallel to the bc plane, the phenyl groups forming a
hydrophobic coating of the layer (Fig. 2).
9: R3 = H (a), Me (b)
Comꢀ
pound
1a
1b
1c
R1
R2
R3
X
Y
Ph
Ph
Ph
EtO
Ph
Ph
Ph
Ph
Ph
Ph
EtO
Ph
Ph
Ph
Ph
EtO
EtO
Ph
Ph
Ph
Ph
Ph
—
—
—
—
—
O
S
CN
CN
CN
CN
COOEt
CN
CN
CN
CN
CN
O
O
O
O
S
O
S
O
O
O
O
1d
8
10a
10b
10c
10d
10e
10f
11a
11b
H
H
Me
Me
Me
Me
H
EtO
EtO
Ph
CN
COOEt
COOEt
Ph
Me
It should also be noted that ethyl diphenylphosphorylꢀ
The IR spectra of compounds 3, 6a,b, and 10a—f have
characteristic CN stretching bands in the region of
2230—2240 cm–1 and CH2 bending bands at
1437—1445 cm–1. In the spectra of compounds 4a,b and
5a, each cyano group appears as an individual absorption
acetate (8) reacted with compounds 9a,b in a similar way
* The use of a 5—10 mol.% phase transfer catalyst, for example
TEBA, Bu4NHSO4, or Bu4NCl, appeared to be most efficient in
the reacitons of thiophosphorylacetonitriles.

222
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 1, January, 2004
Odinets et al.
Table 1. Yields, melting points, elemental analysis data, and results of IR spectroscopy for compounds 3—7, 10, and 11
Comꢀ
pound
Yielda
(%)
M.p./°C
(solvent)
Found
Calculated
Molecular
formula
IR, ν/cm–1
ν(P=O) ν(CH2)b
(%)
N
ν(CN)
(11: ν(C=O)) (ν(P=S))
С
H
3
97 (83) 174—175 (hydrate);
195—196 (EtOH)
76.16 5.54 4.21
76.12 5.47 4.23
74.11 4.63 8.07
74.15 4.81 7.86
70.92 4.69 7.41
70.95 4.60 7.52
76.01 4.42 8.36
76.42 4.70 8.91
72.27 5.23 2.41
72.46 5.54 2.49
C21H18NOP
2240
1190, 1215 1437
4а
67 (54)
77 (65)
17 (10)
88 (71)
79 (64)
27 (15)
87 (74)
181 (EtOH)
C22H17N2OP
2230, 2240 1198, 1225 1445
4b
133 (EtOH)
C22H17N2SP
2232, 2240 (675)
1445
5a
212—213 (MeOH)
278 (MeCN—H2O)
C30H22N3OP
2235, 2240 1195, 1215 1442
6a
C34H29NO2P2•H2O
C34H29NOP2S•H2O
C22H18NOP
2235
2235
2210
1187, 1190 1437
1195 (620) 1432
6b c
7 d
135—136
(MeCN—H2O)
225 (decomp.)
(MeOH)
70.15 5.37
70.45 5.39
—
76.35 5.58 3.88
76.96 5.28 4.08
70.44 4.85 4.54
70.69 4.53 4.58
70.18 5.01 4.35
70.01 4.87 4.55
73.88 5.73 4.22
73.95 6.01 4.31
70.21 5.71 3.84
70.40 5.72 4.11
65.74 7.01 4.58
65.67 6.71 4.71
56.40 7.24 5.31
56.24 7.47 5.47
1190
1195
(628)
1442
1445
1440
10a
10b
10с
10d
10e
10f
11a e
11b
310 (EtOH)
C36H30N2O2P2•1.5H2O 2240
C36H30N2P2S2 2230
80 (55) 255 (CH2Cl2—Et2O)
100 (92)
100 (87)
100 (83)
95 (86)
92 (76)
95 (70)
266 (MeCN—H2O)
C40H38N2O2P2•0.5H2O 2237
C40H38N2S2P2•0.5H2O 2237
C32H38P2O6N2•0.5H2O 2241
1205, 1183 1438
164
(658)
1260
1437
1443
(CH2Cl2—MeCN)
248—249
(MeCN—H2O)
173—174
(CH2Cl2—pentane)
247—248 (EtOH)
C24H38N2P2O2
C40H40O6P2•H2O
C44H48O6P2
2240
1722
1720
1262, 1251, 1440
1231
1204, 1187, 1436
1183
68.82 5.88
68.96 6.08
71.37 6.61
71.92 6.58
—
265—266 (THF)
—
1198, 1215 1435
a The yields are given according to the 31P NMR spectroscopic data, the yields of the compounds isolated are given in parentheses.
b Bending vibrations.
c Found (%): P, 11.07. Calculated (%): P, 10.69.
d
ν(C=C) = 1620 cm–1
.
e Found (%): P, 8.82. Calculated (%): P, 8.89.
band. In the spectrum of compound 7 containing the
cyanovinyl fragment, the CN absorption band is shifted
to longer wavelengths (2210 cm–1), and the absorption
mixtures of meso and d,l forms, the signals of the stereoꢀ
isomers in the 31P NMR spectra of most of the comꢀ
pounds in solutions in CDCl3 coincide with each other,
and two individual singlets are observable in the spectra
measured in DMSOꢀd6. Nevertheless, several sets of charꢀ
acteristic signals corresponding to stereoisomers are obꢀ
served in some 13C NMR spectra even in solutions in
CDCl3. It should be noted that the 31P NMR spectrum of
a solution (in CDCl3) of compound 10e, in which the
P atoms are also asymmetric, shows two pairs of signals.
The distance between the signals of isomers 10eꢀA and
10eꢀB is about 1 ppm, whereas the distances for the meso
and d,l forms are as small as hundredths of ppm.
band of the C=C double bond is observed at 1620 cm–1
.
In the spectra of compounds 11 containing the carboꢀ
alkoxy group, the C=O absorption band is observed in the
characteristic region of 1720—1725 cm–1. The P=O abꢀ
sorption band, whose position varies depending on the
number of the P—C bonds at the P atom, often has two
maxima. For compound 6a, these bands correspond, apꢀ
parently, to absorption of two different phosphoryl fragꢀ
ments. In the spectra of other compounds, these bands
belong, presumably, to two different stereoisomers.
In spite of the fact that compounds 10 and 11 contain
two asymmetric C atoms (except for compound 10e with
four asymmetric centers) and are generated as statistical
In the 13C NMR spectra, the signal of the C atom
bound to the P atom appears as a characteristic doublet at
δ 30.3—37.3 (Y = CN) and 49.5—51.0 (Y = COOAlk,

Selective monoalkylation of Pꢀsubstituted CH acids Russ.Chem.Bull., Int.Ed., Vol. 53, No. 1, January, 2004
Table 2. Parameters of the 31P{1H} and 1H NMR spectra of compounds 3—7, 10, and 11
223
Comꢀ
pound
31P NMR, δ
CDCl3 DMSO
1H NMR (CDCl3), δ (J/Hz)
3
27.78
27.95
46.28
—
2.83 (ABX system, 1 H, HB (CH2), 2JH,H = 13.6, 3JP,H = 11.6, 3JH,H = 7.6); 3.42
(ABX system, 1 H, HA (CH2), 2JP,H = 11.6, 3JH,H = 7.6); 3.57 (m, 1 H, CHP(O),
2JP,H =16.8); 7.22—7.34, 7.43—7.68, 7.80—7.91, 7.99—8.01 (all m, 5 H + 6 H + 2 H +
2 H, Ph)
4a
4b
3.19—3.27, 3.40—3.47 (both m, 2 H each, CH2); 3.83 (appeared as dt, 1 H, CHCN,
3JP,H = 3JH,H = 12.4, 3JH,H = 4.4); 7.38 (t, 1 H, Ar, 3JH,H = 7.6); 7.42 (d, 1 H, Ar,
3JH,H = 7.6); 7.55—7.60 (m, 1 H + 4 H, Ar + mꢀH (Ph)); 7.62—7.66 (m, 1 H + 2 H,
Ar + pꢀH (Ph)); 7.93—8.01 (m, 4 H, oꢀH (Ph))
3.25 (m, 1 H, ABX system, CH2, 2JH,H = 14.0, 2JP,H = 12.0, 3JH,H = 7.6); 3.35 (m, 1 H,
ABX system, CH2, 2JH,H = 14.0, 2JP,H = 10.5, 3JH,H = 4.6); 4.09 (appeared as dt, 1 H,
CHCN, 3JP,H = 3JH,H = 12.0, 3JH,H = 4.6); 7.38 (t, 1 H, Ar, 3JH,H = 7.6); 7.47 (d, 1 H,
Ar, 3JH,H = 7.6); 7.55—7.63 (m, 2 H + 6 H, Ar + mꢀH, pꢀH (Ph)); 8.00—8.08 (m, 4 H,
oꢀH (Ph))
—
5a
26.08
—
—
3.46—3.60 (m, 4 H, CH2Ar); 7.28—7.27, 7.35—7.43, 7.49—7.55, 8.06—8.11 (all m, 6 H +
4 H + 4 H + 4 H, Ar + Ph)
5b
53.20
—
—
2
6a*
29.34, 29.90 2.92—3.02 (m, 2 H, CH2CH); 3.58 (t, 1 H, CH2P(O), 2JP,H = JH,H = 15.0); 3.87 (dd, 1 H,
CH2P(O)); 5.31—5.37 (m, 1 H, CH); 6.73 (d, 1 H, Ar, 3JH,H = 7.6); 6.97 (t, 1 H, Ar,
3JH,H = 7.6); 7.13 (t, 1 H, Ar, 3JH,H = 7.6); 7.20—7.25, 7.44—7.52, 7.60—7.69, 7.84—7.92,
7.98—8.02 (all m, 21 H, 3 H + 3 H + 9 H + 4 H + 2 H, Ar + Ph)
6b*
—
48.74 (P=S), 2.86—2.89, 2.96—3.00 (both m, 1 H each, CH2CH); 3.57, 3.88 (both t, 1 H each, CH2Р(О),
29.88 (P=O) 2JP,H = 2JH,H = 14.8); 5.78—5.82 (m, 1 H, CH); 6.72 (d, 1 H, Ar, 3JH,H = 7.4); 6.97 (t, 1 H,
3
Ar, JH,H = 7.4); 7.40 (t, 1 H, Ar, 3JH,H = 7.4); 7.10—7.22, 7.51—7.71, 7.85—7.89,
7.99—8.05, 8.15—8.20 (all m, 21 H, 3 H + 3 H + 9 H + 4 H + 2 H, Ar + Ph)
7
28.92
—
3.71 (d, 2 H, CH2Р(О), 2JP,H = 13.6); 5.52 (d, 1 H, CH=); 7.17 (d, 1 H, Ar, 3JH,H = 7.6);
3
7.25 (t, 1 H, Ar, JH,H = 7.4); 7.35 (d, 1 H, Ar, 3JH,H = 7.6); 7.44—7.50, 7.52—7.59,
7.64—7.73 (all m, 12 H, CH= + Ar + Ph)
10а
10b
27.77
45.60
29.57, 29.55 2.75—2.85, 3.33—3.41 (both m, 2 H each, CH2); 3.49—3.58 (m, 2 H, CHCN); 7.18 (s, 4 H,
C6H4); 7.50—8.05 (m, 20 H, 4 Ph)
48.32
2.87—2.95, 3.40—3.48 (both m, 2 H each, CH2); 3.66—3.77 (m, 2 H, CHCN); 7.35 (s, 4 H,
C6H4); 7.60—7.71 (m, 12 H, mꢀH, pꢀH (Ph)); 7.97, 8.16 (both dd, 4 H each, oꢀH (Ph),
3JР,H = 13.6, 3JH,H = 7.2)
10с
10d
28.19,
28.11
29.81, 29.69 2.13 (s, 12 H, Me); 3.15—3.25, 3.32—3.35 (both m, 2 H each, CH2); 3.45—3.55 (m, 2 H,
CH); 7.50—7.69 (m, 12 H, mꢀH, pꢀH (Ph)); 7.85—7.92, 8.05—8.12 (both m, 8 H, oꢀH (Ph))
45.88
49.52, 49.50 2.10 (s, 12 H, Me); 3.15—3.35 (m, 4 H, CH2); 3.52—3.68 (m, 2 H, CH); 7.48—7.65 (m, 12 H,
mꢀH, pꢀH (Ph)); 7.85—7.90, 8.12—8.17 (both m, 4 H each, oꢀH (Ph))
10еꢀA** 34.10,
34.13
33.12
20.05
1.37—1.44 (t, 6 H, CH3CH2, 3JH,H = 6.8); 2.10 (A), 2.15 (B) (s, 12 H, CH3Ar); 2.92—3.10
(m, 2 H, CH2CH); 3.18—3.24 (m, 3 H, CH2CH + CH); 3.36—3.48 (m, 1 H, CH); 4.09—4.21
34.13
10еꢀB** 33.09,
(А), 4.21—4.37 (В) (m, 4 H, OCH2); 7.54—7.70 (m, 6 H, mꢀH, pꢀH (Ph)); 7.89—8.00
(m, 4 H, oꢀH (Ph))
33.12
10f
11а
11b
18.09
1.39 (t, 6 H, CH3CH2, 3JH,H = 6.8); 1.40 (t, 6 H, CH3CH2, 3JH,H = 7.2); 2.27 (s, 12 H,
2
CH3Ar); 3.03 (ABX system, 2 HA, CH2Ar, 2JH,H = 12.0, JP,H = 23.2, 3JH,H = 4.0);
3.20—3.28 (m, 2 HB, CH2Ar); 3.37—3.46 (m, 2 H, CH); 4.22—4.36 (m, 8 H, OCH2CH3)
29.42
26.95 (br.)
—
0.76 (t, 6 H, CH3CH2, 3JH,H = 6.8); 3.06 (ABX system, 2 HA, CH2Ar, 2JH,H = 14.1,
2JP,H = 9.4, 3JH,H = 2.9); 3.20—3.28 (m, 2 HB, CH2Ar); 3.65—3.80 (m, 6 H, OCH2 + CH);
6.97 (s, 4 H, C6H4); 7.44—7.54, 7.81—7.90 (both m, 12 H + 8 H, 4 Ph)
0.71 (t, 6 H, CH3CH2, 3JH,H = 7.2); 2.00 (s, 12 H, CH3Ar); 3.13—3.19 (m, 2 H, CH2CH);
3.46—4.02 (m, 8 H, CH2CH + OCH2 + CH); 7.43—7.53, 7.78—7.83, 7.94—8.00 (all m,
12 H + 4 H + 4 H, 4 Ph)
29.82,
29.67
1
* The H NMR spectrum was recorded in DMSOꢀd6.
** In the 1H NMR spectrum, most of the signals for the isomers A and B overlap with each other.

224
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 1, January, 2004
Odinets et al.
Table 3. Parameters of the 13C NMR spectra (δ, J/Hz) of compounds 3, 4a,b, 10a,c,d,e,f, and 11a,b
Comꢀ C(2)
C(1)
(d)
C(3)
(d)
C(4)
(d)
CAr
(s)
R1R2 a
R3
pound
(d)
3
3
31.80
35.98
(1JP,C
61.1)
117.03
136.25
(3JP,C
10.8)
127.44,
129.045
128.89, 129.01 (both d, mꢀC (Ph), JP,C = 12.4);
130.17 (d, P—C, 1JP,C = 93.1); 131.18 (d, P—C,
1JP,C = 93.3); 131.14 (d, oꢀC (Ph), 2JP,C = 9.6);
131.94 (d, oꢀC (Ph), 2JP,C = 8.4); 133.04, 136.25
(both s, pꢀC (Ph))
—
=
=
=
=
=
=
=
b
4a
30.45
31.42
31.48
(2JP,C = (1JP,C
5.6);
31.42
(2JP,C = (1JP,C
5.6)
25.8
(2JP,C = (1JP,C
34.54
(1JP,C
59.8)
115.57
(2JP,C
5.2)
139.63
(3JP,C
11.2)
128.17,
130.74,
133.02,
133.23
128.25 (d, P—CAr, 1JP,C = 104.0); 129.67 (d, P—C,
1JP,C = 106.0); 128.93 (d, mꢀC (Ph), 3JP,C = 12.8);
129.08 (d, mꢀC (Ph), JP,C = 12.4); 131.17
117.17
=
=
=
3
2
(d, oꢀC (Ph), JP,C = 9.6); 131.40 (d, oꢀC (Ph),
2JP,C = 9.2); 133.10 (s, pꢀC (Ph))
4b
37.30
(1JP,C
46.6)
115.59
(2JP,C
5.6)
139.64
(3JP,C
12.8)
128.26,
131.17,
133.10,
133.30
128.16 (d, P—CAr, 1JP,C = 66.2); 128.98 (d, P—C,
1JP,C = 65.8); 128.11 (d, mꢀC (Ph), 3JP,C = 12.8);
117.36 b
128.88 (d, mꢀC (Ph), 3JP,C = 12.4); 131.65 (d, oꢀC (Ph),
2JP,C = 10.4); 131.75 (d, oꢀC (Ph), JP,C = 10.8);
2
132.72, 132.74 (both s, pꢀC (Ph))
3
10a
36.01
116.96
(2JP,C
3.0);
116.98
(2JP,C
2.2)
116.99
(2JP,C
3.4);
116.96
(2JP,C
3.4)
116.70
(2JP,C
5.9);
116.64
(2JP,C
135.77
(3JP,C
11.1);
135.79
(3JP,C
11.1)
132.27
(3JP,C
10.3)
129.29,
129.35
128.89 (d, mꢀC (Ph), JP,C = 12.4); 129.02 (d, mꢀC (Ph),
—
2
=
=
=
3JP,C = 13.4); 131.13 (d, oꢀC (Ph), JP,C = 9.5); 131.93
61.0);
35.79
(d, oꢀC (Ph), 2JP,C = 9.1); 132.94, 133.08 (both s,
pꢀC (Ph))
=
=
60.7)
33.43
10c
10d
133.44
128.88 (d, mꢀC (Ph), 3JP,C = 12.3); 129.80 (d, P—C,
16.88
16.15
2
=
=
1JP,C = 100.1); 131.14 (d, oꢀC (Ph), JP,C = 9.6);
5.2)
60.3)
131.93 (d, oꢀC (Ph), 2JP,C = 9.0); 132.94, 133.08
(both s, pꢀC (Ph))
=
26.65
(2JP,C = (1JP,C
5.4)
35.95
131.90
(3JP,C
12.4);
131.83
(3JP,C
133.56
(br)
127.93 (d, P—C, 1JP,C = 81.4); 127.90 (d, P—C,
1JP,C = 81.2); 128.81 (d, mꢀC (Ph), 3JP,C = 12.6);
=
=
=
3
45.4)
128.91, 128.93 (both d, mꢀC (Ph), JP,C = 12.7);
130.12, 130.15 (both d, P—C, 1JP,C = 83.7); 131.24
2
=
=
(d, oꢀC (Ph), JP,C = 10.4); 132.36 (d, oꢀC (Ph),
5.9)
12.3)
2JP,C = 10.1); 132.45, 132.48, 132.77, 132.80
(all pꢀC (Ph))
10eꢀA 26.88
30.28
115.59
(2JP,C
9.0);
115.63
(2JP,C
128.81
(3JP,C
13.2)
133.15,
134.54
(br)
16.35 (d, СН3СН2О, 3JP,C = 4.5); 63.64 (d, СН3СН2О, 16.81
(2JP,C = (1JP,C
3.8);
26.92
(2JP,C = (1JP,C
=
=
=
=
2JP,C = 6.8); 64.06 (d, СН3СН2О, 2JP,C = 7.0);
126.24 (d, P—CPh, 1JP,C = 100.6); 127.56 (d, P—CPh
1JP,C = 96.4); 132.22 (d, mꢀC (Ph), 3JP,C = 11.1);
(br)
138.9);
30.25
,
=
=
132.24 (d, mꢀC (Ph), 3JP,C = 11.6); 132.27 (d, oꢀC (Ph),
2
3.4)
139.0)
33.04
8.9)
2JP,C = 9.7); 132.53 (d, oꢀC (Ph), JP,C = 9.8); 133.24,
133.26 (both s, pꢀC (Ph)
10eꢀB 26.11
116.18
(2JP,C
9.2);
116.22
(2JP,C
128.77
(3JP,C
13.2)
133.53
16.36 (d, СН3СН2О, 3JP,C = 4.4); 16.39 (d, СН3СН2О, 16.64
(2JP,C = (1JP,C
3.5)
=
=
=
(J = 2.8); JP,C = 4.8); 62.38 (d, СН3СН2О, 2JP,C = 6.5); 62.50
(br)
3
91.1);
33.62
(1JP,C
91.1)
133.42
(d, СН3СН2О, 2JP,C = 6.4); 126.23 (d, P—CPh
,
(J = 2.0) 1JP,C = 98.6); 127.54 (d, P—CPh, 1JP,C = 95.4); 131.98
3
=
(d, mꢀC (Ph), JP,C = 11.3); 132.24 (d, mꢀC (Ph),
3JP,C = 11.2); 133.54, 133.56 (both s, pꢀC (Ph))
8.4)
(to be continued)

Selective monoalkylation of Pꢀsubstituted CH acids Russ.Chem.Bull., Int.Ed., Vol. 53, No. 1, January, 2004
Table 3 (continued)
225
Comꢀ C(2)
C(1)
(d)
C(3)
(d)
C(4)
(d)
CAr
(s)
R1R2 a
R3
pound
(d)
10f
27.01
30.33
115.63
(2JP,C
9.1)
168.63
(2JP,C
2.0)
132.29
(3JP,C
13.3)
136.90
(3JP,C
13.4)
133.33
16.22, 16.24 (both d, СН3СН2ОР, 3JP,C ≈ 1); 63.69 (d,
СН2ОР, 2JP,C = 6.7); 64.12 (d, СН2ОР, 2JP,C = 6.8)
16.86
(2JP,C = (1JP,C
=
=
=
=
=
=
3.0)
11a c 31.51
138.2)
50.97
(1JP,C
56.8)
3
128.50
128.19 (d, mꢀC (Ph), JP,C = 12.1); 128.47 (d, mꢀC (Ph),
—
3JP,C = 11.6); 130.17 (d, P—C, 1JP,C = 93.1); 131.18 (d,
P—C, 1JP,C = 93.3); 131.00 (d, oꢀC (Ph), 2JP,C = 9.2);
2
131.40 (d, oꢀC (Ph), JP,C = 9.3); 131.96, 131.98 (both s,
pꢀC (Ph))
3
11b d 26.67
49.63
(1JP,C
57.8);
49.54
(1JP,C
59.35)
169.31
133.29
(3JP,C
11.2)
132.81
128.27 (d, mꢀC (Ph), JP,C = 11.9); 128.33 (d, mꢀC (Ph), 16.73
3JP,C = 11.8); 130.19 (d, P—C, 1JP,C = 102.5);
=
=
=
131.20 (d, P—C, 1JP,C = 101.6); 131.10 (d, oꢀC (Ph),
2JP,C = 8.9); 131.50 (d, oꢀC (Ph), JP,C = 9.2); 131.90,
2
132.01 (both br.s, pꢀC (Ph))
a In the JMODECHO NMR spectrum, the signals of the quaternary C atoms of the Ph—P fragment are not always observable due to
low solubility of hydrates of these compounds.
b R3 = 2ꢀCN.
c C(3)(O)OR: 13.31 (Me), 60.90 (OCH2).
d C(3)(O)OR: 13.24 (Me), 60.89 (OCH2).
11a,b). In the spectra of compounds 10c—e, which differ
Interestingly, the constant 1JP,C for the methine C atom is
1
only in the nearest environment about the P atom, the
substantially smaller than JP,C for the C atoms in the
1
spinꢀspin coupling constant JP,C changes in going from
substituents R1 and R2 directly bound to the P atoms. The
signals of the methylene C atom are observed as a singlet
the compounds bearing the P=O group to their thioꢀ
phosphoryl analogs as well as with increasing number of
P—C bonds in the molecule (i.e., in going from phosꢀ
phonates to phosphinates and then to phosphine oxides).
2
(3, 4a,b, and 11a) or a doublet with JP,C ≈ 3.0—5.6 Hz.
In most cases, the signals for the stereoisomers are identiꢀ
cal in both the position and spinꢀspin constant. It should
H(14)
H(15)
C(15)
C(14)
N(1)
C(9)
C(13)
H(13)
H(16)
C(12)
H(12)
C(16)
H(7)
H(8)
C(11)
C(1)
C(7)
H(1)
C(2)
C(6)
C(8)
C(3)
O(1)
H(6)
H(2B)
P(1)
H(18)
C(5)
H(5)
C(4)
C(17)
C(10)
H(2A)
C(18)
N(2)
H(22)
C(19)
H(19)
C(22)
C(21)
H(21)
C(20)
H(20)
Fig. 1. Overall view of molecule 4a.

226
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 1, January, 2004
Odinets et al.
Table 4. Selected bond lengths (d) and bond angles (ω) in molꢀ
ecule 4a
ABX system, and the corresponding spinꢀspin coupling
constants can be estimated only in some cases.
To summarize, Cꢀalkylation of phosphorusꢀcontaining
CH acids with various substituted (bromomethyl)arenes
using PTC (K2CO3/MeCN) proceeds selectively as monoꢀ
alkylation. The selectivity decreases as the solubility of
the reaction product increases, for example, in the reacꢀ
tions of compound 2b with phosphorylꢀ and thiophosꢀ
phorylacetonitriles in MeCN or with the use of DMSO as
a coꢀsolvent.
Bond
d/Å
Angle
ω/deg
P(1)—O(1)
P(1)—C(1)
P(1)—C(11)
P(1)—C(17)
N(1)—C(9)
N(2)—C(10) 1.137(3)
C(1)—C(9) 1.470(3)
C(4)—C(10) 1.429(3)
1.469(1)
1.842(2)
1.790(2)
1.802(2)
1.134(3)
O(1)—P(1)—C(1)
113.70(9)
O(1)—P(1)—C(11) 113.40(9)
O(1)—P(1)—C(17) 111.9(1)
C(11)—P(1)—C(1) 107.23(9)
C(17)—P(1)—C(1) 102.92(9)
C(11)—P(1)—C(17) 107.00(9)
C(9)—C(1)—C(2)
C(9)—C(1)—P(1)
C(2)—C(1)—P(1)
N(1)—C(9)—C(1)
110.8(2)
110.5(1)
110.2(1)
178.5(2)
Experimental
The NMR spectra were recorded on Bruker WPꢀ200SY and
Bruker AMXꢀ400 instruments in CDCl3 and C6D6 using the
residual signals of protons of the deuterated solvent as the interꢀ
nal standard (1H and 13C) or 85% H3PO4 as the external standard
(31P). The 13C NMR spectra were measured using JMODECHO;
the signals of the C atoms bearing odd and even numbers of
protons have opposite polarities. The IR spectra were recorded
on a MagnaꢀIR750 (Nicolet) Fourierꢀtransform spectrometer
(spectral resolution was 2 cm–1; 128 scans) in KBr pellets.
The starting phosphorylacetonitriles were prepared by the
Arbuzov rearrangement of the corresponding esters of trivalent
phosphorus acids under the action of chloroacetonitrile accordꢀ
ing to a known procedure.9 The corresponding thiophosphorylꢀ
acetonitriles were synthesized by the reactions of phosphoryl
derivatives with Lawesson's reagent.9 2ꢀ(Bromomethyl)benzoꢀ
nitrile (2b) was synthesized according to a known procedure; its
N(2)—C(10)—C(4) 178.7(3)
also be noted that in the compounds containing two Ph
substituents at the P atom, these phenyl rings are generꢀ
ally magnetically nonequivalent and each ring is characꢀ
terized by its own set of signals of the corresponding
C atoms. The spectrum of compound 10e containing four
asymmetric centers is substantially complicated.
1
The H NMR spectra of the compounds under study
are consistent with the aboveꢀdescribed structures, the
protons of the methylene unit always being magnetically
nonequivalent. The presence of stereoisomers generally
leads to complication of the characteristics pattern of an
H(16)
H(21)
H(1)
O(1)
N(2)
Fig. 2. Fragment of the crystal packing of compound 4a illustrating a C—H...Oꢀ and C—H...Nꢀbonded layer projected perpendicular
to the plane of the layer.

Selective monoalkylation of Pꢀsubstituted CH acids Russ.Chem.Bull., Int.Ed., Vol. 53, No. 1, January, 2004
227
physicochemical characteristics are identical with those pubꢀ
lished in the literature.10
was >95%. Generally, the crude products contained water of
crystallization. Analytically pure samples were prepared by reꢀ
crystallization.
2ꢀMethylbenzyl(diphenyl)phosphine oxide. A mixture of
1ꢀ(bromomethyl)ꢀ2ꢀmethylbenzene (17.7 g, 0.095 mol) and ethyl
diphenylphosphinite (23.0 g, 0.1 mol) in xylene (25 mL) was
heated at 136—140 °C for 1 h. The reaction mixture was conꢀ
centrated to oneꢀhalf of the initial volume and the hot residue
was diluted with an excess of hexane. The precipitate that formed
was filtered off, recrystallized from benzene, washed on a filter
with pentane, and dried in vacuo to prepare the target phosphine
oxide in a yield of 27.2 g (93.0%), m.p. 142—143 °C. Found (%):
C, 78.60; H, 6.30; P, 10.10. C20H19OP. Calculated (%): C, 78.42;
Xꢀray diffraction study of compound 4a (C22H17N2OP,
M = 356.35). At 298 K, crystals are monoclinic, space group
C2/c, a = 34.222(4) Å, b = 9.875(1) Å, c = 11.324(1) Å,
β = 95.214(2)°, V = 3810.9(7) Å3, µ = 1.56 cm–1, Z = 8 (Z´ = 1),
dcalc = 1.242 g cm–3. The intensities of 11780 reflections were
measured on an automated Smart 1000 CCD diffractometer at
298 K (λMoꢀKα radiation, graphite monochromator, ω scanꢀ
ning technique, 2θmax = 55°), and 4376 independent reflections
(Rint = 0.0297) were used in calculations. The structure was
solved by direct methods and refined by the fullꢀmatrix leastꢀ
squares method against F2 in the anisotropicꢀisotropic approxiꢀ
mation using the SHELXTL PLUS program package. The
H atoms were revealed from difference electron density syntheꢀ
ses and refined using the riding model. The final reliability facꢀ
tors were as follows: wR2 = 0.1237, GOF = 1.097 based on all
reflections (R1 = 0.0543 was calculated using 3046 reflections
with I > 2σ(I )).
1
H, 6.25; P, 10.11. 31P{1H} NMR (CDCl3), δ: 30.02. H NMR
2
(CDCl3), δ: 2.13 (s, 3 H, Me); 3.65 (d, 2 H, PCH2, JP,H
=
14.0 Hz); 6.92—7.00 (m, 2 H, Ar); 7.07—7.10 (m, 2 H, Ar);
7.40—7.45 (m, 4 H, mꢀH (PPh)); 7.48—7.53 (m, 2 H;
pꢀH (PPh)); 7.64—7.73 (m, 4 H, oꢀH (PPh)).
2ꢀ(Bromomethyl)benzyl(diphenyl)phosphine oxide (2c).
NꢀBromosuccinimide (7.9 g, 0.044 mol) and a catalytic amount
of a mixture of benzoyl peroxide and AIBN were added with
stirring to a solution of 2ꢀmethylbenzyl(diphenyl)phosphine
oxide (see above) (12.5 g, 0.041 mol) in CCl4 (200 mL) on
irradiation with a tungsten lamp. The reaction mixture was reꢀ
fluxed for 1 h. The resulting solid compound was filtered off and
washed with warm CCl4 (2×40 mL). The precipitate on a filter
was additionally thoroughly washed with hot water (∼200 mL),
dried in air, and recrystallized from a benzene—EtOH mixture.
An additional portion of the precipitate that formed upon conꢀ
centration of the filtrate was recrystallized from the same solꢀ
vent mixture. The total yield of the target product was 11.2 g
(71.2%), m.p. 200—202 °C. Found (%): C, 62.70; H, 4.73;
Br, 20.73; P, 8.07. C20H18BrOP. Calculated (%): C, 62.36;
H, 4.71; Br, 20.74; P, 8.04. 31P{1H} NMR (CDCl3), δ: 29.89.
This study was financially supported by the Russian
Foundation for Basic Research (Project No. 02ꢀ03ꢀ33073)
and the Grant from the President of the Russian Federaꢀ
tion (the Program "Leading Scientific Schools," Project
No. NShꢀ1100.2003.3).
References
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sis, 2nd Ed., Verlag Chemie, Weinheim, 1985.
2. M. I. Kabachnik and T. A. Mastryukova, Mezhfaznyi kataliz
v fosfororganicheskoi khimii [Phase Transfer Catalysis in Orꢀ
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3. J. Blanchard, N. Collognon, Ph. Savignac, and N. Normant,
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4. R. K. Singh, Synthesis, 1986, 762.
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Korlyukov, P. V. Petrovskii, G.ꢀV. Roeschenthaler, and T. A.
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Zh. Obshch. Khim., 1996, 66, 44 [J. Gen. Chem. USSR, 1996,
66 (Engl. Transl.)].
2
1H NMR (CDCl3), δ: 3.85 (d, 2 H, PCH2, JP,H = 13.2 Hz);
4.65 (s, 2 H, CH2Br); 6.77 (d, 1 H, Ar, 3JH,H = 7.6 Hz); 7.03 (t,
1 H, Ar, 3JH,3H = 7.6 Hz); 7.15 (t, 1 H, Ar, 3JH,H = 7.6 Hz); 7.30
(d, 1 H, Ar, JH,H = 7.6 Hz); 7.43—7.48 (m, 4 H, mꢀH (PPh));
7.52—7.55 (m, 2 H, pꢀH (PPh)); 7.69 (dd, 4 H, oꢀH (PPh),
3JH,H = 7.6 Hz, 3JP,H = 11.6 Hz).
Monoalkylation of phosphorylꢀ and thiophosphorylacetoꢀ
nitriles with (bromomethyl)benzenes (general procedure). A mixꢀ
ture of the corresponding phosphorylꢀ or thiophosphorylꢀ
acetonitrile 1 (1 equiv., 4.15 mmol), K2CO3 (4 equiv., 2.30 g,
16.60 mmol), and benzyl bromide 2 (1 equiv., 4.15 mmol) or
bis(bromomethyl)arene 9a,b (0.5 equiv., 2.07 mmol) in MeCN
was stirred at ∼20 °C for 18—20 h. The course of the reaction
was monitored by 31P NMR spectroscopy. Then the reaction
mixture was concentrated to oneꢀhalf of the initial volume and
diluted with a twofold volume of water. For compounds 4a,b
and 11b, the organic layer was separated and the aqueous layer
was twice extracted with CH2Cl2. The combined extracts were
dried with Na2SO4 and filtered. The filtrate was concentrated to
dryness and the residue was recrystallized from EtOH (4a,b) or
its mixture with THF (11b). The first portion of crystals after
recrystallization of the crude mixture, which was prepared by
the reactions of 1a with 2b, from MeOH presented dialkylated
product 5a. Its yield and physicochemical parameters are given
in Table 1. In the case of compounds 3, 6a,b, 10a—f, and 11a,
the reaction product that precipitated upon aqueous treatment
was filtered off and dried in air. According to the 1H and
31P NMR spectroscopic data, the purity of the crude product
10. R. C. Fuson, J. Am. Chem. Soc., 1926, 48, 833.
Received July 24, 2003;
in revised form October 21, 2003