A study on the phosphorylation of indole, imidazole, carbazole, and phenothiazine derivatives

Article abstract of DOI:10.1080/10426507.2012.668986

N-Heterocycles including indolecarbaldehyde, substituted benzimidazoles, and methylimidazole could be efficiently phosphorylated by diethyl chlorophosphate at room temperature in different solvents using alkali carbonate or triethylamine as the base. However, the phosphorylation of N-heterocycles with a lower reactivity at the NH function, such as carbazole and phenothiazine, could not be conducted to complete conversion under the conditions applied. Copyright

Full text of DOI:10.1080/10426507.2012.668986

This article was downloaded by: [University of Colorado - Health Science Library]
On: 01 October 2014, At: 10:55
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Phosphorus, Sulfur, and Silicon and the
Related Elements
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/gpss20
A Study on the Phosphorylation of
Indole, Imidazole, Carbazole, and
Phenothiazine Derivatives
Mátyás Milen a b , Péter Ábrányi-Balogh a , György Balogh a c , László
Drahos d & György Keglevich a
a Department of Organic Chemistry and Technology , Budapest
University of Technology and Economics , Budapest , Hungary
b EGIS Pharmaceuticals Plc. , Division for Chemical Research ,
Budapest , Hungary
c Gedeon Richter Plc. , Budapest , Hungary
d Hungarian Academy of Sciences , Chemical Research Center ,
Budapest , Hungary
Accepted author version posted online: 02 Mar 2012.Published
online: 19 Jun 2012.
To cite this article: Mátyás Milen , Péter Ábrányi-Balogh , György Balogh , László Drahos & György
Keglevich (2012) A Study on the Phosphorylation of Indole, Imidazole, Carbazole, and Phenothiazine
Derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements, 187:9, 1091-1100, DOI:
10.1080/10426507.2012.668986
To link to this article: http://dx.doi.org/10.1080/10426507.2012.668986
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.

This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &
Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Phosphorus, Sulfur, and Silicon, 187:1091–1100, 2012
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2012.668986
A STUDY ON THE PHOSPHORYLATION
OF INDOLE, IMIDAZOLE, CARBAZOLE,
AND PHENOTHIAZINE DERIVATIVES
1
1,3
Ma´tya´s Milen,1,2 Pe´ter Abra´nyi-Balogh, Gyo¨rgy Balogh,
´
La´szlo´ Drahos,4 and Gyo¨rgy Keglevich1
1Department of Organic Chemistry and Technology, Budapest University of
Technology and Economics, Budapest, Hungary
2EGIS Pharmaceuticals Plc., Division for Chemical Research, Budapest, Hungary
3Gedeon Richter Plc., Budapest, Hungary
4Hungarian Academy of Sciences, Chemical Research Center, Budapest, Hungary
GRAPHICAL ABSTRACT
Abstract N-Heterocycles including indolecarbaldehyde, substituted benzimidazoles, and
methylimidazole could be efficiently phosphorylated by diethyl chlorophosphate at room tem-
perature in different solvents using alkali carbonate or triethylamine as the base. However,
the phosphorylation of N-heterocycles with a lower reactivity at the NH function, such as car-
bazole and phenothiazine, could not be conducted to complete conversion under the conditions
applied.
Keywords N-heterocycles; phosphorylation; indoles; imidazoles; carbazole; phenothiazine
INTRODUCTION
There are many substrates with bioactivity among phosphoric acid derivatives.1–11
The diethylphosphoryl derivatives form a representative group as they may be valuable
intermediates in synthetic organic chemistry,12 or may be used as medicines or agrochemi-
cals. The two derivatives I and II shown below serve as antitumor13,14 and antimicrobal15
drug, respectively.
Received 16 December 2011; accepted 20 February 2012.
The authors are grateful to the Hungarian Scientific and Research Fund (OTKA K83118) for their support
to this project. This work is connected to the scientific program of the “Development of quality-oriented and
harmonized R+D+I strategy and functional model at BME” project. This project is supported by the New
´
Sze´chenyi Plan (Project ID: TAMOP-4.2.1/B-09/1/KMR-2010-0002).
Address correspondence to Gyo¨rgy Keglevich, Department of Organic Chemistry and Technology, Budapest
University of Technology and Economics, 1521 Budapest, Hungary. E-mail: gkeglevich@mail.bme.hu
1091

1092
M. MILEN ET AL.
In our earlier study, we described the N-alkylation of a few N-heterocycles.16 This
paper gives an account on our results on the phosporylation of indole-, imidazole-, and
benzimidazole derivatives, along with carbazole and phenothiazine. Obviously, a similar
reactivity of the NH moiety of the N-heterocycles was expected in phosphorylations as
compared to that in alkylations.
RESULTS AND DISCUSSION
The phosphorylation of a series of N-heterocycles was studied under different condi-
tions involving the application of the phase transfer catalytic and the MW techniques. Our
aim was to find the best set of conditions for the preparation of the phosphorylated species.
First, the reaction of indolecarbaldehyde with diethyl chlorophosphate was studied
(Scheme 1, Table 1).
Scheme 1
Carrying out the reaction using 1.1 equiv. of (EtO)2P(O)Cl in the presence of 1.2
◦
equiv. of K2CO3 in acetone at 26 C, the phosphorylation was complete after a 1 day
stirring (Table 1, Entry 1). The presence of tetrabutylammonium bromide (TBAB) was
harmful (Table 1, Entry 2). Applying Cs2CO3 instead of K2CO3, the phosphorylation was
complete already after 50 min stirring (Table 1, Entry 3). In the latter case, the isolated
Table 1 The phosphorylation of indolecarbaldehyde
Conversion
Base
Catalyst
Time
to 1 (%)a
Yield of 1 (%)
Entry
K2CO3
K2CO3
Cs2CO3
—
TBAB (10%)
—
24 h
24 h
50 min
97
55
100
not determined
not determined
93
1
2
3
aDetermined by LC-MS.

PHOSPHORYLATION OF N-HETEROCYCLES
1093
yield of the phosphorylated indole derivative 1 was 93%. Compound 1 has been previously
characterized only by melting point and 1H NMR data.17 We observed an 11–12 ◦C higher
melting point and characterized the product also by 31P and 13C NMR spectroscopy. The
different melting points may be the consequence of the different media (hexane–diisopropyl
ether vs. ethyl acetate17) used for recrystallization.
Our method is simpler than that described in the literature applying potassium tert-
butylate as the base and THF as solvent.17
It is noteworthy that after refluxing the components in acetone for 5 h, 1-ethyl-indole-
3-carbaldehyde 2 also appeared in the reaction mixture in a relative quantity of 10%.
Heterocycle 2 has been described in the literature.18 This minor component was
not isolated in pure form, however, its elemental composition was confirmed by HRMS
((M+H)+found = 174.0916, C11H12NO requires 174.0919). The ethylating ability of diethyl
chlorophosphate and analogous thio derivatives is well-known.19,20
Benzimidazole underwent quantitative phosphorylation with diethyl chlorophosphate
in the presence of Cs2CO3 in acetone after stirring at 26 ◦C for 20 min. The diethoxyphos-
phoryl benzimidazole 3a was isolated with a yield of 91%. According to a literature method,
the benzimidazole is first converted to the sodium salt by reaction with sodium methylate,
then the salt is phosphorylated to provide the product (3a) in a yield of 42%.21 One can
see that our method is simpler and more efficient. The phosphorylation was extended to
methyl-, dimethyl-, and trimethylbenzimidazole, to afford products 3b–d in 90–95% yield
(Scheme 2). Benzimidazole derivatives 3b–d are new. Compound 3a was described,21 but
no NMR characterization was provided.
Scheme 2
The use of alkali carbonates as a base is a better alternative than applying trialkyl-
amines. The use of the alkali carbonate/acetone system is “greener” than that of the trialkyl-
amine/aromatics or THF mixture.
Imidazole could also be phosphorylated under similar conditions, but during the work-
up procedure the phosphorylated imidazole decomposed. This decomposition is known

1094
M. MILEN ET AL.
from the literature.22–24 The unstable phosphorylated imidazole 3a could only be isolated
by Michalski et al. by distillation in high vacuum.25 Methylimidazole could also be phos-
phorylated, but in this instance, product 4 was more stable and could be identified by spectral
methods. The best method giving the phosphorylated imidazole 4 in a quantitative yield
involved the phosphorylation in THF in the presence of triethylamine at 26 ◦C (Scheme 3).
Product 4 is new.
Scheme 3
The next model to be studied was the phosphorylation of carbazole. Due to the
decreased reactivity of the NH moiety of carbazole, this reaction was investigated in a more
detailed way (Scheme 4, Table 2).
Scheme 4
◦
The use of 2 equiv. of (EtO)2P(O)Cl and 2 equiv. of sodium hydride at 110 C
(24 h) in toluene resulted in a conversion of 26%, that could be increased to 53% by applying
DMF as the solvent at the same temperature allowing a shorter reaction time (3.5 h) (Table 2,
Entries 1 and 2). Conducting the reaction in the presence of 2 equiv. of Cs2CO3 in acetone
at 26 ◦C or boiling acetonitrile the conversions were around 30% (Table 2, Entries 3 and 4).
The presence of a phase transfer catalyst, TBAB, did not have a positive impact on the
course of the reaction (Table 2, Entry 5). Under MW conditions in the presence of Cs2CO3
Table 2 Phosphorylation of carbazole under different conditions
Mode of
heating
Conversion
to 5 (%)a
Base
Catalyst
Solvent
T (◦C)
t (h)
Entry
NaH (2 equiv.)
NaH (2 equiv.)
—
—
—
—
PhMe
DMF
ꢀ
ꢀ
110
110
RT
82
82
100
100
26
3.5
24
24
24
1
26
53
32
29
28
21
5
1
2
3
4
5
6
7
Cs2CO3 (2 equiv.)
Cs2CO3 (2 equiv.)
Cs2CO3 (2 equiv.)
Cs2CO3 (2 equiv.)
Cs2CO3 (2 equiv.)
Me2CO
MeCN
MeCN
MeCN
MeCN
—
ꢀ
TBAB 10%
—
TBAB 10%
ꢀ
MW
MW
1
aDetermined by LC-MS.

PHOSPHORYLATION OF N-HETEROCYCLES
1095
in acetonitrile at 110 ◦C even lower conversions were observed, especially in the presence of
TBAB (Table 2, Entries 6 and 7). It was impossible to obtain the phosphorylated carbazole 5
in pure form due to its high instability. Our attempts of separation by chromatography failed.
Hence, product 5 was identified from the mixture of the best experiment (Table 2, Entry
2). It may not be without reason that the phosphorylated carbazole 5 was described without
characterization.26 Here, we provide for the first time NMR spectroscopic characterization
for the phosphorylated carbazole 5.
Preparation of the phosphorylated carbazole 5 was reported via the corresponding
potassium salt in acetonitrile. A yield of 97% was claimed, but no characterization of the
product was provided.26 We could not reproduce the results reported by the authors.
The last model was the phosphorylation of the not too reactive phenothiazine (Scheme
5, Table 3).
Scheme 5
Carrying out the phosphorylation in the presence of 2 equiv. of the acylating agent
and 2.5 equiv. of NaH in boiling toluene as the solvent, the conversion was only 20% after
24 h. The phosphorylated phenothiazine 6 (15%) and a by-product (5%) were present
in the reaction mixture beside the szarting phenothiazine (80%) (Table 3, Entry 1). The
◦
change in the solvent was again helpful. Reaction in DMF at 110 C for 24 h resulted in
a conversion of 66%. In the reaction mixture, the proportion of the desired product was
52% along with 14% of the by-product mentioned above (Table 3, Entry 2). Using boiling
acetonitrile, the conversion was 45% when Cs2CO3 was added as the base and the degree
of transformation was 60% when K2CO3 was applied with 10% of TEBAC. In these cases
no diethoxyphosphoryl-phenothiazine 6 was present in the reaction mixture. Instead, the
above mentioned by-product predominated (Table 3, Entries 3 and 4). After isolation and
spectroscopic identification, the by-product was found to be the ethylated phenothiazine 7.
Table 3 Phosphorylation of phenothiazine under different conditions
Composition (%)a
Base
Catalyst
Solvent
Mode of heating T (◦C) t (h) Phenothiazine
6
7
Entry
NaH
NaH
—
—
—
PhMe
DMF
MeCN
ꢀ
ꢀ
110
110
82
24
24
24
24
24
1
80
34
55
40
80
69
53
20
15
52 14
5
1
2
3
4
5
6
7
8
Cs2CO3
K2CO3
NaOH
Cs2CO3
Cs2CO3
K2CO3
ꢀ
—
—
—
—
—
—
45
60
20
31
47
80
TEBAC 10% MeCN
ꢀ
82
—
—
—
—
PhMe
MeCN
no solvent
no solvent
ꢀ
110
100
100
100
MW
MW
MW
1
1
aDetermined by LC-MS.

1096
M. MILEN ET AL.
The use of NaOH as base resulted again in the formation of the by-product 7 (Table 3, Entry
5). A similar outcome was experienced when the phosphorylation was attempted under MW
conditions (Table 3, Entries 6–8). The phosphorylated phenothiazine 6 decomposed on our
attempts to separate it from the other components. For this reason product 6 was identified
from the best experiment (Table 3, Entry 2). No data can be found on the preparation and
characterization of diethoxyphosphoryl-phenothiazine 6 in the literature. Here, we provide
for the first time at least a partial characterization of the phosphorylated phenothiazine 6.
It is noteworthy that the N-heterocycles studied revealed the same trend regarding
the reactivity of the NH unit in both phosphorylation and alkylation.16
In summary, indolecarbaldehyde, four benzimidazole derivatives, and methylimida-
zole were efficiently phosphorylated at room temperature in different solvents using alkali
carbonate or triethylamine as the base. Six phosphorylated N-heterocycles have been syn-
thesized and characterized; four of them are new and the remaining two were characterized
by NMR spectroscopy for the first time. However, the phosphorylation of N-heterocycles
with a lower reactivity at the NH function, such as carbazole and phenothiazine, could not
be accomplished quantitatively under the conditions applied. Due to the high degree of
instability, the phosphorylated carbazole and phenothiazine were characterized from the
reaction mixtures, thus, providing NMR spectroscopic data for these unstable species, for
the first time.
EXPERIMENTAL
Melting points were determined on a Kofler Boe¨tius micro-apparatus and were not
1
corrected. H NMR (500 MHz) and 13C NMR (125 MHz) spectra were recorded with a
Varian Unity Inova 500 MHz spectrometer. 1H NMR, 13C NMR, and 31P NMR spectra were
recorded with a Bruker Avance III spectrometer (400, 100, and 162 MHz, respectively) or
a Varian Mercury Plus 200 spectrometer (200, 50, and 80 MHz, respectively). CDCl3 was
used as solvent. Tetramethylsilane (TMS) and 85% H3PO4 were used as internal (1H, 13C)
and external (31P) standards, respectively. Chemical shifts (δ) and coupling constants (J)
are given in ppm and in Hz, respectively.
The MW-assisted reactions were carried out in a CEM Discover microwave reactor
equipped with a pressure controller using ca. 30 W irradiation power.
LC-MS experiments were carried out on an Agilent 1200 liquid chromatography
system connected with a 6120 MSD (Agilent Technologies). Analysis was performed at
40 ◦C on an Kinetex C18 column (5 cm × 2.1 mm, 2.6 µm) (Phenomenex) with a mobile
phase flow rate of 0.9 mL/min. Composition of eluent A was 0.1% (v/v) trifluoroacetic
acid in water (pH 1.9), eluent B was a 95:5 (v/v) mixture of acetonitrile, and water with
0.1% (v/v) trifluoroacetic acid. A fast linear gradient of 0–100% B was applied at a range
of 0–4 min, then 100% B kept for 3 min. The injection volume was set at 1 µL and the
sample concentration was uniformly 1.0 mg/mL (DMSO). The chromatographic profile was
registered at 240 nm. The MSD operating parameters were as follows: positive ionization
◦
mode, scan spectra from m/z 100 to 800, drying gas temperature 350 C, nitrogen flow
rate 12 L/min, nebulizer pressure 60 psi, quadrupole temperature 100 ◦C, capillary voltage
3000 V, fragmentor voltage 50 V.
Carefully dried solvents and reactants were used in the experiments. The alkali
carbonates were calcinated at 280 ◦C before use.

PHOSPHORYLATION OF N-HETEROCYCLES
1097
O,O-Diethyl (3-Formyl-1H-indol-1-yl)phosphonate (1)17
To a stirred slurry of 1H-indole-3-carbaldehyde (0.26 g, 1.8 mmol) and 0.70 g cesium
carbonate (2.16 mmol) in 10 mL of acetone was added 0.29 mL of diet◦hyl chlorophosphate
(0.34 g, 1.98 mmol) in one portion. The solution was stirred at 26 C until the starting
material disappeared (50 min). The reaction mixture was filtered, evaporated in vacuo, and
the residue was dissolved in dichloromethane. The solution was extracted with 10 mL of
water and the water phase was washed with dichloromethane (10 mL). The organic layer
was dried (MgSO4), the solvent was removed in vacuo, and the residual yellow oil was
recrystallized from hexane–diisopopyl ether. Yield: 0.47 g (93%); mp 68–69 ◦C [lit.17 57 ◦C
(ethyl acetate)]. 31P NMR (CDCl3, 80 MHz): δ = –4.6; 13C NMR (CDCl3, 125 MHz): δ =
185.4 (d, J = 1.0 Hz, CHO), 140.3 (d, J = 7.3 Hz, C ), 137.8 (C ), 126.8 (CH ), 125.5
(CH ), 124.3 (C ), 122.4 (CH ), 113.6 (CH ), 64.7 (d, J = 5.4 Hz, CH2), 15.8 (d, J
= 6.8 Hz, CH3); 1H NMR (CDCl3, 500 MHz): δ = 10.10 (s, 1H, CHO), 8.32 (d, J = 7.3
Hz, 1H, arom-H), 8.14 (d, J = 3.1 Hz, 1H, arom-H), 7.73 (t, J = 9.0 Hz, 1H, arom-H),
7.40–7.38 (m, 2H, arom-H), 4.31–4.25 (m, 2H, CH2), 4.13–4.08 (m, 2H, CH2), 1.32 (t, J =
7.1 Hz, 6H, CH3) [lit.17 1H NMR (CDCl3): δ = 9.95 (s, CHO), 7.0–8.2 (m, indolyl-H),
3.7–4.4 (m, CH2), 1.23 (t, J = 7 Hz, CH3)]; LC-MS: m/z 282 (M+H)+; (M+H)+
=
found
282.0899, C13H17NO4P requires 282.0895.
O,O-Diethyl (1H-Benzo[d]imidazol-1-yl)phosphonate (3a)21
To a stirred slurry of benzo[d]imidazole (0.21 g, 1.80 mmol) and 0.70 g of cesium
carbonate (2.16 mmol) in 10 mL of acetone was added 0.29 mL of diet◦hyl chlorophosphate
(0.34 g, 1.98 mmol) in one portion. The solution was stirred at 26 C until the starting
material disappeared (40 min). The reaction mixture was filtered, evaporated in vacuo, and
the residue was dissolved in dichloromethane. The solution was extracted with 10 mL of
water and the water phase was washed with dichloromethane (10 mL). The organic layer
was dried (MgSO4) and the solvent removed in vacuo. Yield: 0.41 g (91%), colorless oil.
31P NMR (CDCl3, 80 MHz): δ = –6.1; 13C NMR (CDCl3, 50 MHz): δ = 144.9 (d, J = 12.6
Hz, CH ), 144.4 (d, J = 7.2 Hz, C ), 133.0 (C ), 124.7 (CH ), 123.9 (CH ), 120.6
1
(CH ), 112.8 (CH ), 64.7 (d, J = 5.0 Hz, CH2), 15.8 (d, J = 6.9 Hz, CH3); H NMR
(CDCl3, 200 MHz): δ = 8.27 (s, 1H, CH=N), 7.85–7.82 (m, 1H, arom-H), 7.73–7.68 (m,
1H, arom-H), 7.40–7.35 (m, 2H, arom-H), 4.35–4.05 (m, 4H, CH2), 1.32 (t, J = 7.0 Hz,
6H, CH3); LC-MS: m/z 255 (M+H); (M+H)+
= 255.0900, C11H16N2O3P requires
found
255.0899.
The other benzimidazole derivatives were prepared analogously, except using 1.3
equivalent of Cs2CO3 and (EtO2P(O)Cl.
O,O-Diethyl (2-Methyl-1H-benzo[d]imidazol-1-yl)phosphonate (3b)
Yield: 0.43 g (90%); colorless oil. 31P NMR (CDCl3, 162 MHz): δ = –5.4; 13C NMR
(CDCl3, 100 MHz): δ = 154.2 (d, J = 6.6 Hz, CH ), 143.4 (C ), 135.6 (d, J = 7.2 Hz,
C ), 125.5 (CH ), 123.7 (d, J = 7.3 Hz, CH ), 119.1 (CH ), 113.6 (CH ), 65.2 (d, J
1
= 6.4 Hz, CH2), 64.4 (d, J = 5.1 Hz, CH2), 16.7 (CH3), 15.9 (d, J = 6.7 Hz, CH3); H
NMR (CDCl3, 400 MHz): δ = 7.81–7.80 (m, 1H, arom-H), 7.69–7.67 (m, 1H, arom-H),
7.30–7.27 (m, 2H, arom-H), 4.28–4.24 (m, 2H, CH2), 4.14–4.10 (m, 2H, CH2), 2.79 (s, 3H,

1098
M. MILEN ET AL.
CH3), 1.34 (t, J = 7.0 Hz, 6H, CH3); LC-MS: m/z 269 (M+H); (M+H)+found = 269.1056,
C12H18N2O3P requires 269.1055.
O,O-Diethyl (5,6-Dimethyl-1H-benzo[d]imidazol-1-yl)phosphonate (3c)
Yield: 0.48 g (95%); colorless oil. 31P NMR (CDCl3, 162 MHz): δ = –5.8; 13C NMR
(CDCl3, 100 MHz): δ = 143.6 (d, J = 7.3 Hz, CH ), 143.3 (d, J = 13.2 Hz, C ), 134.0
(C ), 133.0 (CH ), 131.5 (d, J = 5.3 Hz, CH=), 120.6 (CH ), 113.0 (CH ), 65.2 (d, J =
5.8 Hz, CH2), 64.5 (d, J = 5.1 Hz, CH2), 20.5 (CH3), 20.1 (CH3), 15.9 (d, J = 6.8 Hz,
CH3); 1H NMR (CDCl3, 400 MHz): δ = 8.14 (s, 1H, CH N), 7.58 (s, 1H, arom-H), 7.46
(s, 1H, arom-H), 4.30–4.23 (m, 2H, CH2), 4.13–4.08 (m, 2H, CH2), 2.40 (s, 3H, CH3), 2.38
(s, 3H, CH3), 1.38 (t, J = 7.1 Hz, 3H, CH3), 1.33 (t, J = 7.0 Hz, 3H, CH3); LC-MS: m/z
283 (M+H); (M+H)+
= 283.1211, C13H20N2O3P requires 283.1212.
found
O,O-Diethyl (2,5,6-Trimethyl-1H-benzo[d]imidazol-1-yl)phosphonate
(3d)
Yield: 0.51 g (95%); colorless oil. 31P NMR (CDCl3, 162 MHz): δ = –5.1; 13C NMR
(CDCl3, 100 MHz): δ = 141.8 (d, J = 13.7 Hz, C ), 134.1 (C ), 132.8 (CH ), 132.4
(CH ), 123.2 (C ), 119.3 (C ), 113.9 (C ), 65.2 (d, J = 5.9 Hz, CH2) 64.2 (d, J =
5.1 Hz, CH2), 20.4 (CH3), 20.0 (CH3), 16.6 (CH3), 16.0 (d, J = 6.6 Hz, CH3); 1H NMR
(CDCl3, 400 MHz): δ = 7.59 (s, 1H, arom-H), 7.42 (s, 1H, arom-H), 4.29–4.22 (m, 2H,
CH2), 4.12–4.08 (m, 2H, CH2), 2.74 (s, 3H, CH3), 2.37 (s, 3H, CH3), 2.35 (s, 3H, CH3),
1.38 (t, J = 7.0 Hz, 3H, CH3), 1.33 (t, J = 7.0 Hz, 3H, CH3); LC-MS: m/z 297 (M+H);
(M+H)+
= 297.1372, C14H22N2O3P requires 297.1368.
found
O,O-Diethyl (2-Methyl-1H-imidazol-1-yl)phosphonate (4)
2-Methyl-1H-imidazole (0.15 g, 1.8 mmol) and 0.25 mL of triethyamine (0.18 g,
1.8 mmol) were dissolved in 10 mL of anhydrous THF and 0.26 mL (1.8 mmol, 0.31 g)
◦
of diethyl chlorophosphate was added. After 20 min of stirring at 26 C the precipitate
was removed by filtration and the filtrate was concentrated. Yield: 0.39 g (99%); 31P NMR
(CDCl3, 162 MHz): δ = –5.2; 13C NMR (CDCl3, 100 MHz): δ = 148.2 (d, J = 5.0 Hz,
C ), 128.6 (d, J = 14.0 Hz, C ), 121.1 (d, J = 8.1 Hz, C ), 65.1 (d, J = 6.1 Hz, CH2),
64.5 (d, J = 5.2 Hz, CH2), 15.9 (d, J = 7.0 Hz, CH3), 15.1 (CH3); 1H NMR (CDCl3, 400
MHz): δ = 7.29 (s, 1H, arom-H), 6.99 (s, 1H, arom-H), 4.29–4.18 (m, 2H, CH2), 4.14–4.00
(m, 2H, CH2), 2.55 (s, 3H, CH3), 1.37 (t, J = 7.0 Hz, 6H, CH3); LC-MS: m/z 219 (M+H);
(M+H)+
= 219.0895, C8H16N2O3P requires 219.0899.
found
O,O-Diethyl (9H-Carbazole-9-yl)phosphonate (5) (Table 2, Entry 2)
To 0.24 g (1.4 mmol) of carbazole in 10 mL of dimethylformamide was added 0.14
g (3.5 mmol) of sodium hydride under N2 atmosphere. The mixture was heated to 110
◦C, and 0.42 mL (2.9 mmol) of diethyl chlorophosphate in 2 mL of dimethylformamide
was added dropwise. The content of the flask was stirred at this temperature for 3.5 h.
After filtration, the filtrate was concentrated to afford a mixture containing 53% of the
carbazolephosphate 5 and 47% of the starting carbazole. 31P NMR (CDCl3, 162 MHz):
δ = –2.8; 13C NMR (CDCl3, 100 MHz): δ = 128.1 (C ), 122.2 (CH ), 120.1 (CH ),

PHOSPHORYLATION OF N-HETEROCYCLES
1099
119.8 (CH ), 116.2 (C ), 110.6 (CH ), 63.6 (d, J = 4.5 Hz, CH2), 15.9 (d, J = 7.1
1
Hz, CH3); H NMR (CDCl3, 400 MHz): δ = 8,08–8.05 (m, 2H, arom-H), 8.03–8.00 (m,
2H, arom-H), 7.42–7.39 (m, 2H, arom-H), 7.23–7.19 (m, 2H, arom-H), 4.07–3.95 (m, 4H,
CH2), 1.26 (t, J = 7.1 Hz, 6H, CH3); LC-MS: m/z 304 (M+H); (M+H)+found = 304.1110,
C16H19NO3P requires 304.1103.
O,O-Diethyl (10H-Phenothiazine-10-yl)phosphonate (6) (Table 3,
Entry 2)
To 0.36 g (1.8 mmol) of phenothiazine in 10 mL of dimethylformamide was added
0.18 g (4.5 mmol) of sodium hydride under N2 atmosphere. The mixture was heated to 110
◦C and 0.52 mL (3.6 mmol) of diethyl chlorophosphate was added dropwise. The mixture
was stirred at this temperature for 1 day. Filtration and concentration of the filtrate yielded a
mixture containing 52% of product 6, 34% of the starting material, and 14% of by-product
7. 31P NMR (CDCl3, 162 MHz): δ = 0.1; 13C NMR (CDCl3, 125 MHz): δ = 141.7 (C ),
127.2 (CH ), 126.7 (CH ), 122.2 (CH ), 118.1 (C ), 116.8 (CH ), 62.0 (d, J = 5.9
1
Hz, CH2), 16.1 (d, J = 6.8 Hz, CH3); H NMR (CDCl3, 500 MHz): δ = 6.97–6.94 (m,
4H, arom-H), 6.81–6.78 (m, 2H, arom-H), 6.56–6.54 (m, 2H, arom-H), 4.08–3.98 (m, 4H,
CH2), 1.31 (t, J = 7.1 Hz, 6H, CH3); LC-MS: m/z 336 (M+H).
10-Ethyl-10H-phenothiazine (7)24 (Table 3, Entry 8)
To a mixture of 0.36 g (1.8 mmol) of phenothiazine and 0.50 g (3.6 mmol) of
potassium carbonate 0.52 mL (3.6 mmol) of diethyl chlorophosphate was added and the
reaction mixture was irradiated in the MW reactor at 100 ◦C for 1 h with stirring. The crude
product was extracted with 2 mL of acetonitrile, the acetonitrile solution was filtered, and
the solvent from the filtrate was evaporated to afford 0.33 g (80%) of ethylphenothiazine
7. 1H NMR (CDCl3, 500 MHz): δ = 7.13–7.10 (m, 4H), 6.88–6.83 (m, 4H), 3.92–3.87 (m,
2H), 1.39 (t, J = 7.0 Hz, 3H) [lit.27: 1H NMR (CDCl3): δ = 7.16–7.11 (m, 4H, arom-H),
6.88–6.85 (m, 4H, arom-H), 3.92 (m, 2H, CH2), 1.42 (t, 3H, CH3)]; LC-MS: m/z 228
(M+H).
REFERENCES
1. Eto, M. Organophosphorus pesticides. In: Organic and Biological Chemistry; CRC Press: Boca
Raton, 1974.
2. Van Wazer, J. R. Phosphorus and its Compounds, Vol. 2; Wiley-Interscience: New York, 1961.
3. Engel, R. Chem. Rev. 1977, 77, 349-367.
4. Kosolapoff, G. M. In: Organic Phosphorus Compounds, Vol. 6; Wiley-Interscience: New York,
1950; pp. 351-353.
5. Gryaznov, S.; Skorski, T.; Cucco, C.; Nieborowska-Skorska, M.; Chiu, C. Y.; Lloyd, D.; Chen,
J. K.; Koziolkiewiez, M.; Calabretta, B. Nucleic Acids Res. 1996, 24, 1508-1514.
6. Uhlmann, E.; Peyman, A. Chem. Rev. 1990, 90, 543-584.
7. Afarinkia, K.; Vinader, M. V. In: C. J. Moody (Ed.), Comprehensive Organic Functional Group
Transformations, Vol. 5; Acylphosphorus, -arsenic, -antimony and -bismuth functions. Pergamon:
London, 1995; pp. 393-407.
8. Savignac, P.; Iorga, B. Modern Phosphorus Chemistry; CRC Press: New York, 2003; pp. 319-404.
9. Denmark, S. E.; Stavenger, R. A. Accounts Chem. Res. 2000, 33, 432-440.
10. Westheimer, F. H. Science 1987, 235, 1173-1178.

1100
M. MILEN ET AL.
11. Di Novi, M.; Trainor, D. A.; Nakanishi, K. Tetrahedron Lett. 1983, 24, 855-858.
12. Yang, J.; Teng, Y.; Ara, S.; Rallapalli, S.; Cook, J. M. Synthesis 2009, 6, 1036-1040.
13. Leonova, E. S.; Makarov, M. V.; Rybalkina, E. Y.; Nayani, S. L.; Tongwa, P.; Fonari, A.;
Timofeeva, T. V.; Odinets, I. L. Eur. J. Med. Chem. 2010, 45, 5926-5934.
14. Das, S.; Das, U.; Sakagami, H.; Hashimoto, K.; Kawase, M.; Gorecki, D. K.; Dimmock, J. R.
Bioorg. Med. Chem. Lett. 2010, 20, 6464-6468.
15. Gupta, A. K.; Acharya, J.; Dubey, D. K.; Kaushik, M. P. Synth. Commun. 2007, 37, 3403-3407.
16. Milen, M.; Gru¨n, A.; Ba´lint, E.; Dancso´, A.; Keglevich, G. Synth. Commun. 2010, 40, 2291-2301.
17. Hoppe, I.; Scho¨llkopf, U. Liebigs Ann. Chem. 1984, 600-607.
18. Miranda, L. D.; Cruz-Almanza, R.; Pavon, M.; Alva, E.; Muchowski, J. M. Tetrahedron Lett.
1999, 40, 7153-7158.
19. Rani, B. R.; Bhalerao, U. T.; Rahman, M. F. Synth. Commun. 1990, 20, 3045-3052.
20. He, Z.-J.; Liu, J.-X.; Tang, C.-C. Synth. Commun. 1998, 28, 2769-2772.
21. Arbuzov, B. A.; Zoroastrova, V. M.; Sagitova, R. Kh. Bull. Acad. Sci. USSR, Div. Chem. Sci.
(Engl. Transl.) 1964, 13, 615-621.
22. Ranganathan, N.; Brinigar, W. S. J. Org. Chem. 1978, 43, 4853-4856.
23. Orth, E. S.; Wanderlind, E. H.; Medeiros, M.; Oliveira, P. S. M.; Vaz, B. G.; Eberlin, M. N.;
Kirby, A. J.; Nome, F. J. Org. Chem. 2011, 76, 8003-8008.
24. Basaif, S. A.; Williams, A. J. Org. Chem. 1988, 53, 2204-2209.
25. Dabkowski, W.; Michalski, J.; Radziejewski, C.; Skrypcynski, Z. Chem. Ber. 1982, 115, 1636-
1634.
26. Arbuzov, B. A.; Zoroastrova, V. M. Bull. Acad. Sci. USSR, Div. Chem. Sci. (Engl. Transl.) 1966,
15, 82-84.
27. Wu, T.-Y.; Tsao, M.-H.; Su, S.-G.; Wang, H. P.; Lin, Y.-C.; Chen, F.-L.; Chang, C.-W.; Sun, I.-W.
J. Braz. Chem. Soc. 2011, 22, 780-789.