Solid-liquid phase alkylation of P=O-functionalized CH acidic compounds utilizing phase transfer catalysis and microwave irradiation

Article abstract of DOI:10.1002/hc.20673

Optimum conditions for the solid-liquid phase alkylation of methylenebis(diphenylphosphine oxide) (MBDPPO) and ethyl cyanomethylphosphonate (ECMP) were explored studying the role of phase transfer catalysis and microwave (MW) irradiation, as well as the e

Full text of DOI:10.1002/hc.20673

Heteroatom Chemistry
Volume 22, Number 2, 2011
Solid–Liquid Phase Alkylation of
P=O–Functionalized CH Acidic Compounds
Utilizing Phase Transfer Catalysis and
Microwave Irradiation
Gyo¨rgy Keglevich,1 Alajos Gru¨n,1,2 Zso´fia Blastik,1
and Istva´n Greiner3
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, 1521 Budapest, Hungary
3Gedeon Richter Plc., 1475 Budapest 10, PO Box 27, Hungary
Received 27 October 2010; revised 15 December 2010
INTRODUCTION
ABSTRACT: Optimum conditions for the solid–
liquid phase alkylation of methylenebis(diphenylphos-
phine oxide) (MBDPPO) and ethyl cyanomethylphos-
phonate (ECMP) were explored studying the role of
phase transfer catalysis and microwave (MW) irra-
diation, as well as the effect of the cation of the al-
kali carbonate. It was found that the alkylation of
MBDPPO may be best accomplished in acetonitrile,
in the presence of a quaternary ammonium salt and
Cs2CO3, while that of ECMP in the absence of catalyst
and solvent using K2CO3. MW irradiation was ben-
eficial in both cases. During the alkylation of ECMP,
by-products coming from the alcoholysis of the diethyl
Substituted CH-acidic compounds are important in-
termediates in the pharmaceutical industry. Substi-
tuted malonates are used in the synthesis of bar-
biturates that are hypnotics, whereas bisphosponic
derivatives are applied in the treatment of osteo-
porosis [1–5]. The C-alkylation of methylenebispho-
sphonates requires harsher conditions than that for
malonic or acetoacetic esters. The potassium salt
of tetraethylmethylenebisphosphonate was formed
by reaction with potassium in xylene [6], whereas
the sodium salt was formed by the interaction with
sodium hydride [7]. The salts so obtained were
reacted with alkyl halides to afford the alkylated
derivatives in variable yields [6,7]. Alkylations with
benzylic bromides and propargyl bromide were pre-
ceded by salt formation using sodium hydride as
shown in recent examples [8–10]. The alkylation
with propargyl bromide led to a mixture of mono-
and dialkylated products, which were impossible to
separate, and an alternative approach had to be elab-
orated for the monopropargylation [9,10].
ꢀ
C
ester were also identified. 2011 Wiley Periodicals, Inc.
Heteroatom Chem 22:174–179, 2011; View this article on-
line at wileyonlinelibrary.com. DOI 10.1002/hc.20673
Correspondence to: Gyo¨rgy Keglevich; e-mail: gkeglevich@
mail.bme.hu.
Contract grant sponsor: Scientific Research Fund (OTKA).
Contract grant numbers: K067679 and K83118.
With regard to “classical” CH-acidic com-
pounds, alkylation by the phase transfer catalytic
(PTC) method is an up-to-date procedure [11]. The
Contract grant sponsor: Richter Plc.
2011 Wiley Periodicals, Inc.
c
ꢀ
174

Solid–Liquiase Alkylation of P=O–Functionalized CH Acidic Compounds 175
TABLE 1 Benzylation of Bis(Diphenylphosphinyl)methane (1)
Δ or MW
T, t
Cs2CO3
O
O
O
PPh2
PPh2
PPh2
PPh2
TEBAC
+
BnBr
Bn
acetonitrile
O
1
2a
RX
Mode of Heating
T (◦C)
t (h)
TEBAC (10%)
Conversion (%)a
Yield of 2a (%)
Entry
BnBr
BnBr
BnBr
BnBr
BnBr
ꢀ
82
120
120
140
120
24
1.5
1.5
1.5
3
+
–
+
+
+
60
21
43
38
57
44
1
2
3
4
5
MW
MW
MW
MW
45
aOn the basis of 31P NMR.
combination of the PTC and the microwave (MW)
techniques may offer additional advantages [12].
We found that in the solid–liquid phase alkylation
of malonic, acetoacetic, and cyanoacetic esters, the
phase transfer catalyst may be substituted by MW
irradiation [13,14]. This method could also be ex-
tended to the ethylation of tetraethyl methylenebis-
phosphonate [15].
A few methylenebis(phosphine oxides) were
monomethylated in high yields [16]. Bis(diphenyl-
phosphinyl)methane, which is a rather hindered
substrate, could be alkylated via the potassium
salt [17]. At the same time, the alkylation of ethyl
cyanomethylphosphonate (ECMP), which is a mixed
CH acidic species, was carried out by forming the
salt by sodium hydride in DMF and reacting the salt
so formed with an alkyl halide [18], or by liquid–
liquid phase transfer catalysis applying aqueous al-
kali hydroxide as the base [19]. Alternative proce-
dures for the preparation of NCCHRP(O)(OEt)2 were
also described [20,21]. 2-Oxoalkanephosphonates
were alkylated via the sodium salt formed by reac-
tion with sodium hydride [22,23]. The structure and
synthetic use of α-phosphono carbanions (e.g., the
phosphonoacetate carbanion) were studied in detail
by Seyden-Penne and her coworkers. [24].
base. In boiling acetonitrile, in the presence of tri-
ethylbenzylammonium chloride (TEBAC), the con-
version was 60% after 1 day (Table 1, entry 1). We
expected a shorter reaction time under MW condi-
tions. Working at 120◦C, the conversion was 21%
after 1.5 h (Table 1, entry 2), but if there was 10%
TEBAC in the reaction mixture, the conversion was
43% (Table 1, entry 3). Allowing a 3-h reaction time,
a conversion of 57% could be achieved (Table 1,
entry 5). However, an increase in the reaction tem-
perature (120 → 140◦C) did not help (Table 1,
entry 4). The hindered model prevented more com-
plete conversions. From one of the best experiments
(Table 1, entry 5), the product (2a) was isolated by
chromatography in a yield of 45%.
Then the alkylation of bis(diphenylphosphinyl)
methane 1 by propyl and butyl bromide was stud-
ied. The experiments were carried out in the pres-
ence of TEBAC and Cs2CO3 in acetonitrile under
MW irradiation. Using propyl bromide and increas-
ing the temperature from 120 to 180◦C, the pro-
portion of the alkylated product (2b) was 30 and
47% (after a reaction time of 3 and 4 h, respec-
tively) (Table 2, entries 1 and 4). Entries 2 and 3 of
Table 2 represent intermediate cases. It can be seen
that the best conversions amounted to ∼64%, and
unidentified by-products were formed in a quantity
of up to 18%. Adopting the best set of parame-
ters (180◦C/4 h) for the preparation of the buthy-
lated bis(diphenylphosphinyl)methane (2c), its pro-
portion was 52% (Table 2, entry 5). Preparative
yields of products 2b and 2c were 40 and 46% af-
ter chromatography.
In this article, the effect of MW irradiation on the
PTC alkylation of bis(diphenylphosphinyl)methane
and ECMP is studied to find easily accomplish-
able and environment friendly efficient methods for
the synthesis of C-alkyl derivatives.
RESULTS AND DISCUSSION
Diethyl cyanomethylphosphonate (3) was ex-
pected to have a more enhanced reactivity toward
alkylation. The first experiments were carried out
in boiling acetonitrile for 1 day applying propyl
First the benzylation of bis(diphenylphosphinyl)
methane (1) was investigated. In all cases, acetoni-
trile was used as the solvent and Cs2CO3 as the
Heteroatom Chemistry DOI 10.1002/hc

176 Keglevich et al.
TABLE 2 Alkylation of Bis(Diphenylphosphinyl)Methane (1)
MW
T, t
Cs2CO3
O
O
O
PPh2
PPh2
PPh2
PPh2
TEBAC
+
RBr
R
acetonitrile
O
1
2
R = Pr, Bu
R = Pr (b), Bu (c)
Composition (%)a
RX
T (◦C)
t (h)
1
2
Other
Yield of 2 (%)
Entry
PrBr
PrBr
PrBr
PrBr
BuBr
120
140
160
180
180
3
3
4
4
4
62
46
38
36
26
30 (2b)
37 (2b)
44 (2b)
47 (2b)
52 (2c)
8
17
18
17
22
1
2
3
4
5
40
46
aOn the basis of 31P NMR.
bromide. Using K2CO3 and Cs2CO3, the conversions
were 47 and 93%, respectively, providing the propyl
product (4) in 45 and 84%, respectively (Table 2,
entries 1 and 3). The use of phase transfer cata-
lyst (TEBAC) led to decreased proportions of prod-
uct 4 and 31–37% of other components (Table 2,
entries 2 and 4). Hence, the presence of TEBAC is not
beneficial in the reaction under discussion. The MW
variations were accomplished at temperatures ≥100
for 1–2 h, in the absence of solvent. The best results
were obtained at 100◦C/2 h using K2CO3. In this case,
the conversion was 87%, and product 4 was present
in 70% in the reaction mixture (Table 3, entry 5).
The use of catalyst was disadvantageous (as above)
TABLE 3 Alkylation of Diethyl Cyanomethylphosphonate 3
MW or Δ
T, t
M2CO3
O
O
P(OEt)2
P(OEt)2
TEBAC
+
RBr
R
acetonitrile
CN
CN
(1.2 equiv.)
3
4
M = K, Cs
R = Pr, Bu
R = Pr (b), Bu (c)
Composition (%)a
Other Yield of 4 (%) Entry
RX
M
Mode of Heating T (◦C) t (h) Solvent TEBAC (10%)
3
4
PrBr
PrBr
PrBr
PrBr
PrBr
PrBr
PrBr
PrBr
PrBr
K
K
Cs
Cs
K
K
K
ꢀ
ꢀ
ꢀ
ꢀ
MW
MW
MW
MW
MW
ꢀ
MW
MW
MW
82
82
82
24
24
24
24
2
1
1
1
1
24
2
2
MeCN
MeCN
MeCN
MeCN
–
+
–
+
–
53 45 (4b)
26 37 (4b)
2
37
9
31
17
22
66
63
73
7
1
2
3
4
5
6
7
8
9
10
11
12
13
7
2
84 (4b)
67 (4b)
75
64
82
100
120
120
120
120
82
100
120
110
–
–
–
–
13 70 (4b)
20 58 (4b)
–
+
2
4
3
3
32 (4b)
33 (4b)
24 (4b)
90 (4c)
Cs
Cs
–
–
+
–
–
–
+
BuBr Cs
MeCN
82
59
BuBr
BuBr
BuBr
K
K
K
–
–
–
45 51 (4c)
20 65 (4c)
4
15
63
1
6
31 (4c)
aOn the basis of GC.
Heteroatom Chemistry DOI 10.1002/hc

Solid–Liquiase Alkylation of P=O–Functionalized CH Acidic Compounds 177
(Table 3, entries 6 and 7). Switching to the use of
the ester itself with the alcohol to furnish mixed ester
5 and 6.
Cs2CO3, the conversions were almost complete af-
ter 1 h, but by-products predominated over expected
product 4 (Table 3, entries 8 and 9). Product 4b was
isolated from the best experiments (Table 3, entries 3
and 5) in 75 and 64% yields after chromatography.
The alkylation of diethyl cyanomethylphospho-
nate 3 with butyl bromide led to similar results. Al-
most complete conversion could be attained in re-
fluxing acetonitrile, in the presence of Cs2CO3, but
the butylation was slow (Table 3, entry 10). Under
MW and solventless conditions, an irradiation of
120◦C/2 h seemed to be more suitable than 100◦C/2
h (Table 3, entries 11 and 12). In the latter case, the
conversion was 80% and the required product (4c)
was formed in 65% proportion. In the presence of
catalyst, less starting material (3) remained in the
mixture but the proportion of the by-products in-
creased to 63% (Table 3, entry 13). Preparative yields
of 4c were 82 and 59% from the best experiments
(Table 3, entries 10 and 12).
GC-MS analysis of the crude mixture of the ex-
periment covered by Table 3, entry 13 suggested that
the major by-products came from the single or dou-
ble alcoholysis of diethyl ester 4c. Moreover, ap-
plying the butyl bromide in 2.4 and 3.6 equivalent
quantities using TEBAC in 20 and 30%, respectively,
the relative proportions of monobutyl ester 5 and
dibutyl ester 6 were somewhat increased indicat-
ing the role of the quantity of the reactant (Table 4,
entries 1–3).
It can be seen that MW irradiation made possible
shorter reaction times. With regard to the alkylation
of the hindered bis(diphenylphosphinyl)methane 1
and the more reactive cyanomethylphosphonate, the
conditions required are different. In the previous
case, the use of solvent and catalyst is appropriate,
while in the latter instance, it is better not to apply
solvent and catalyst.
The alkylated products 2a–c and 4b were
mentioned in earlier literature [17,20,25–27], but
only 4b was characterized spectroscopically. Now,
alkyl-methylenebis(phosphine oxides) 2a–c and
cyanopentylphosphonate 4c were characterized by
31P, 13C, and 1H NMR, as well as mass spectral
methods.
In conclusion, it can be seen that the optimal
conditions for the solid–liquid phase C-alkylation of
P O-functionalized CH-acidic compounds are de-
pendent on the nature of the substrate. MW ir-
radiation was beneficial in all cases. The alkyla-
tion of bis(diphenylphosphinyl)methane could be
best accomplished in the presence of solvent and
catalyst using Cs2CO3, whereas the alkylation of
cyanomethylphosphonate was optimal in the ab-
sence of solvent and catalyst using K2CO3.
EXPERIMENTAL
General
The 31P, 13C, and 1H NMR spectra were obtained on
a Bruker DRX-500 spectrometer operating at 202.4,
125.7, and 500 MHz, respectively. Chemical shifts
are downfield relative to 85% H3PO4 or TMS. The
couplings are given in hertz. Mass spectrometry was
performed on a ZAB-2SEQ instrument.
Formation of the by-product 5 and 6 can be ex-
plained by assuming that water is released in the
reaction of hydrogen bromide (formed in the alkyla-
tion) with alkali carbonate under the circumstances
of the reaction that may lead to the partial hydrolysis
of the tetraethyl ester or the alkyl halide. Then, either
the acid function may react with the alkyl halide, or
TABLE 4 The Reaction of Diethyl Cyanomethylphosphonate 3 with Butyl Bromide under Solventless MW Conditions
MW
110°C/1 h
O
O
O
O
K2CO3
OEt
P(OEt)2
P(OEt)2
CN
P
P(OBu)2
TEBAC (10%)
OBu
+
Bu
CN
+
BuBr
Bu
+
Bu
CN
CN
3
4c
5
6
Composition (%)a
Quantity of BuBr (equiv)
Quantity of TEBAC (%)
3
4c
5
6
Other
Entry
1.2
2.4
3.6
10
20
30
6
0
0
31
20
14
31
38
37
8
21
25
24
21
24
1
2
3
aOn the basis of GC.
Heteroatom Chemistry DOI 10.1002/hc

178 Keglevich et al.
The MW-assisted reactions were carried out in a
CEM Discover MW reactor equipped with a pressure
controller using ca. 30 W irradiation.
CH2), 1.86 (m, 2H, CH2), 3.37–3.20 (m, 1H, CH),
7.36–7.24 (m, 12H, ArH), 7.70 (d, J = 7.4, 2H, ArH),
7.74 (d, J = 7.4, 2H, ArH), 7.87 (d, J = 7.5, 2H, ArH),
7.91 (d, J = 8.1, 2H, ArH); HRMS, M+found = 459.1640,
C28H29O2P2 requires 459.1643.
General Procedure for the Alkylation of
Bis(diphenylphosphinyl)methane 1 under MW
Conditions
1,1-Bis(diphenylphosphinyl)pentane (2c). Yield:
46%, mp. 204–205◦C, mp. [17] 204–206◦C; 31P NMR
(CDCl3) δ: 31.7; 13C NMR (CDCl3) δ: 13.3 (CH3), 22.3
(CH2), 25.9 (CH2), 32.5 (t, J = 5.3, CH2), 43.7 (t, J
= 57.1, CH), 128.3 (J = 12.1, Ar), 128.4 (J = 12.1,
Ar), 131.5 (Ar), 131.6 (J = 101.2, Ar), 131.6 (J = 9.6,
Ar), 131.6 (J = 9.4, Ar), 131.7 (Ar), 132.5 (dd, J =
99.8, J = 2.8, Ar); 1H NMR (CDCl3)δ: 0.49 (t, J = 7.3,
3H, CH3), 0.91 (m, 2H, CH2), 1.16 (m, 2H, CH2), 1.87
(m, 2H, CH2), 3.33–3.20 (m, 1H, CH), 7.35–7.24 (m,
12H, ArH), 7.71 (d, J = 7.9, 2H, ArH), 7.75 (d, J =
7.8, 2H, ArH), 7.88 (d, J = 7.7, 2H, ArH), 7.91 (d, J =
8.3, 2H, ArH); HRMS, M+found = 473.1800, C29H31O2P2
requires 473.1799.
The reaction components 0.20 g (0.48 mmol) of
bis(phosphinyl)methane 1, 0.58 mmol of alkyl halide
(benzyl bromide: 0.07 mL, propyl bromide: 0.05 mL,
butyl bromide: 0.06 mL), 0.16 g (0.48 mmol) of
Cs2CO3, and 0.01 g (0.05 mmol) of TEBAC along
with 5 mL of acetonitrile as the solvent were mea-
sured in a tube that was placed in the MW reactor
and was irradiated under pressure control by 30–
70 W at the appropriate temperature for the appro-
priate time. Then the mixture was filtered and the
solid was washed with 2 mL of ethyl acetate. Com-
bined organic phases were concentrated in vacuum,
and the residue so obtained was purified by column
chromatography (3% methanol in chloroform, silica
gel) to afford products 2a–c. For details, see Tables
1 and 2 and the list below.
The benzylation of 1 was also carried out us-
ing 0.20 g (0.48 mmol) of 1, 0.07 mL (0.58 mmol)
of benzyl bromide, 0.16 g (0.48 mmol) of Cs2CO3,
0.01 g (0.05 mmol) of TEBAC, and 5 mL of acetoni-
trile under traditional thermal conditions according
to Table 1, entry 1. The workup procedure was sim-
ilar to that described above.
The Best Procedure for the Propylation of Diethyl
Cyanomethylphosphonate 3 under Traditional Con-
ditions (Table 3, entry 3). The mixture of 0.25 g
(1.4 mmol) phosphonate 3, 0.15 mL (1.7 mmol) of
propyl bromide, 0.52 g (1.4 mmol) of Cs2CO3 in 5 mL
acetonitrile was heated at reflux for 24 h. The con-
tents of the flask were filtrated, the solid washed
with 2 mL of acetonitrile, and the combined organic
phases evaporated. The residue so obtained was pu-
rified by column chromatography (3% methanol in
chloroform, silica gel) to give 0.23 g (75%) of 4b.
1,1-Bis(diphenylphosphinyl)-2-phenylethane (2a).
Yield: 45%, mp. 218–219◦C, mp. [17] 217–218◦C; 31
P
NMR (CDCl3) δ: 31.6; 13C NMR (CDCl3) δ: 31.3 (CH2),
45.7 (t, J = 56.0, CH), 126.0 (Ar), 128.0 (Ar), 128.1
(J = 12.2, Ar), 128.2 (Ar), 128.4 (J = 12.2, Ar), 131.4
(J = 101.8, Ar), 131.4 (J = 9.2, Ar), 131.7 (dd, J =
100.0, J = 2.9, Ar) 131.5 (Ar), 131.6 (J = 8.3, Ar);
1H NMR (CDCl3) δ: 3.20 (dt, J = 15.5, J = 5.3, 2H,
CH2), 3.71 (tt, J = 15.9, J = 5.3, 1H, CH), 6.69 (d, J =
6.8, 2H, ArH), 6.96 (m, 3H, ArH), 7.14 (m, 4H, ArH),
7.38–7.24 (m, 4H, ArH), 7.61 (d, J = 7.8, 2H, ArH),
7.64 (d, J = 7.9, 2H, ArH), 7.87 (d, J = 7.7, 2H, ArH),
7.89 (d, J = 7.7, 2H, ArH); HRMS, M+found = 507.1653,
C32H29O2P2 requires 507.1643.
The Best Procedure for the Propylation of Diethyl
Cyanomethylphosphonate 3 under MW Conditions
(Table 3, entry 5). The mixture of 0.12 g (0.68 mmol)
of phosphonate 3, 0.07 mL (0.81 mmol) of propyl
bromide, and 0.09 g (0.68 mmol) of K2CO3 in a tube
was placed in the MW reactor and was irradiated
under pressure control by 30 W at 100◦C for 2 h. The
workingup procedure was similar described above
to give 0.096 g (64%) of 4b.
Diethyl 1-Cyanobutylphosphonate (4b). 31P
NMR (CDCl3) δ: 18.3, δP [20] 18.7; 13C NMR (CDCl3)
δ: 13.2 (CH2CH3), 16.4 (J = 4.9, OCH2CH3), 21.2
(J = 12.6, CH2), 28.9 (J = 4.4, CH2), 29.8 (J = 143.8,
CH), 63.7 (J = 6.9, OCH2), 64.0 (J = 7.0, OCH2),
1,1-Bis(diphenylphosphinyl)butane (2b). Yield:
40%, mp. 185–187◦C; 31P NMR (CDCl3) δ: 31.8; 13C
NMR (CDCl3) δ: 13.7 (s, CH3), 23.5 (t, J = 5.5, CH2),
28.1 (CH2), 43.3 (t, J = 57.2, CH), 128.1 (J = 12.1,
Ar), 128.2 (J = 12.2, Ar), 131.3 (Ar), 131.3 (J = 101.3,
Ar), 131.4 (J = 13.7, Ar), 131.4 (J = 15.9, Ar), 131.5
1
116.3 (J = 9.4, CN); H NMR (CDCl3) δ: 1.00 (dt,
J = 7.2, J = 1.6, 3H, CH3), 1.39 (t, J = 7.1, 3H, CH3),
1.40 (t, J = 7.1, 3H, CH3), 1.48–1.57 and 1.69–1.77
(m, 2H, CH2), 1.82–1.93 (m, 2H, CH2), 2.87–3.00 (m,
(Ar), 132.2 (dd, J = 102.6, J = 2.8, Ar); H NMR
1H, CH), 4.18–4.32 (m, 4H, OCH2); HRMS, Mf+ound
220.1103, C9H19NO3P requires 220.1103.
=
1
(CDCl3) δ: 0.53 (t, J = 7.3, 3H, CH3), 1.19 (m, 2H,
Heteroatom Chemistry DOI 10.1002/hc

Solid–Liquiase Alkylation of P=O–Functionalized CH Acidic Compounds 179
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Diethyl 1-Cyanopentylphosphonate (4c). Prod-
uct 4c was prepared by the MW method (Table 3,
entry 12). Yield: 59%; 31P NMR (CDCl3) δ: 18.23;
13C NMR (CDCl3) δ 13.7 (CH2CH3), 16.40 (J =
5.8, OCH2CH3), 16.42 (J = 5.8, OCH2CH3), 21.9
(CH2CH3), 26.7 (J = 4.4, CH2), 30.0 (J = 143.8, CH),
30.0 (J = 12.2, CH2), 63.7 (J = 6.9, OCH2), 64.1
(J = 7.9, OCH2), 116.3 (J = 9.3, NC); 1H NMR
(CDCl3) δ: 0.92 (t, J = 7.3, 3H, CH2CH2CH ), 1.37
3
(t, J = 7.0, 6H, OCH2CH ), 1.416–1.52 and 1.59–1.69
3
(m, 4H, CH2) 1.78–1.95 (m, 2H, CH2), 2.83–2.92 (m,
1H, CH), 4.19–4.25 (m, 4H, OCH CH3); [M + Na]+
2
found
= 256.1084, C10H20O3NPNa requires 256.1079.
Butyl, Ethyl 1-Cyanopentylphosphonate (5). 31P
NMR (CDCl3) δ: 18.22; [M + H]+found = 262.1577,
C12H25O3NP requires 262.1572.
Dibutyl1-Cyanopentylphosph+onate(6). 31P NMR
(CDCl3)δ: 18.29; [M
C14H29O3NP requires 290.1885.
+
H]found
=
290.1892,
ACKNOWLEDGMENTS
This work is connected to the scientific program of
the “Development of quality-oriented and harmo-
nized R+D+I strategy and functional model at BME”
project. This project is supported by the New Hun-
´
gary Development Plan (Project ID: TAMOP-4.2.1/
B-09/1/KMR-2010–0002).
[23] Clark, R. D.; Kozar, L. G.; Heathcock, C. H. Synthetic
Commun 1975, 5, 1.
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Heteroatom Chemistry DOI 10.1002/hc