The unexpected formation of P-ylide in the reaction of 3-azido 1,4-benzodiazepine with tricyclohexylphosphine

Article abstract of DOI:10.1007/s11172-015-0849-y

Reaction of substituted 3-azido 1,4-benzodiazepine with tricyclohexylphosphine is not the Staudinger reaction and unexpectedly results in P-ylide of 1,4-benzodiazepine. This is the first example of organic azides exhibiting the pseudo halide properties in the reactions of trivalent phosphorus compounds.

Full text of DOI:10.1007/s11172-015-0849-y

Russian Chemical Bulletin, International Edition, Vol. 64, No. 1, pp. 233—236, January, 2015
233
The unexpected formation of Рꢀylide in the reaction
of 3ꢀazido 1,4ꢀbenzodiazepine with tricyclohexylphosphine
Yu. G. Gololobov,a† I. Yu. Krasnova,а S. V. Barabanov,а I. V. Fedyanin,а S. A. Andronati,b and V. I. Pavlovskiib
aA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (495) 135 5085. Еꢀmail: irina7krasnova@yandex.ru
bA. V. Bogatsky PhysicoꢀChemical Institute, National Academy of Sciences of Ukraine,
86 Lyustdorfskaya doroga, 65080 Odessa, Ukraine
Reaction of substituted 3ꢀazido 1,4ꢀbenzodiazepine with tricyclohexylphosphine is not the
Staudinger reaction and unexpectedly results in Pꢀylide of 1,4ꢀbenzodiazepine. This is the first
example of organic azides exhibiting the pseudo halide properties in the reactions of trivalent
phosphorus compounds.
Key words: tricyclohexylphosphine, triethylphospine, 3ꢀazidoꢀ7ꢀbromoꢀ5ꢀphenylꢀ1,2ꢀdiꢀ
hydroꢀ3Нꢀ1,4ꢀbenzodiazepinꢀ2ꢀone, Staudinger reaction, phosphorus ylides, phosphorus imides.
Substituted 1,4ꢀbenzodiazepines are widely used in
medicine1 and studying the transformation of these
heterocycles is promising from the viewpoint of the synꢀ
thesis of novel valuable substances. We have recently synꢀ
thesized phosphorylated 1,4ꢀbenzodiazepines bearing the
Р—С,2 Р—О,3 and P—S3 bonds. For the synthesis of phosꢀ
phorylated 1,4ꢀbenzodiazepines with the N—C bond at
the 3ꢀposition of the heterocycle, we applied the Staudinger
reaction4 (Scheme 1). The synthesis of 1,4ꢀbenzodiazepine
derivatives bearing the C—N—P fragment is promoted by
the fact that some 3ꢀaminoꢀsubstituted 1,4ꢀbenzodiazepines
are effective analgesics.5 Reaction of organic azides with
a variety of trivalent phosphorus compounds 1, first deꢀ
scribed in the beginning of the 20th century, in all docuꢀ
mented cases6,7 resulted in phosphorus imides, the valuꢀ
able reagents in the synthesis of functionally substituted
amines, nitrogen heterocycles, and a number of other
nitrogenꢀcontaining compounds.
by the electronic and spatial parameters of the substituꢀ
ents at both the trivalent phosphorus atom and azide nitroꢀ
gen atom. The bulky substituents at the nitrogen and phosꢀ
phorus atoms stabilize intermediates 2 obtained in some cases
in individual state.6,7 Triazenes 2 with less bulky substituents
at the phosphorus and nitrogen atoms are decomposed
with evolution of nitrogen to give imides 3 (see Scheme 1).
Due to the reversibility of the first stage of the transformation,
decomposition of triazenes 2 to the starting reagents is also
possible. It should be noted that depending on the nature
of substituents at the nitrogen and phosphorus atoms, imꢀ
ides 3 can be converted into other phosphorus compounds
with the Р—N bond. Thus, the reaction of Oꢀmethyldiꢀ
phenylphosphinite (4) with azide 5 (Scheme 2) in THF
(used without drying) yields 1,4ꢀbenzodiazepine 6 arising
apparently from hydrolysis of the initially formed imide 7.
Crystal structure of phosphorylated 1,4ꢀbenzodiazepine 6
was studied by Xꢀray diffraction analysis (Fig. 1). Selected
bond lengths are given in Table 1.
Investigation of the reactions of triethylꢀ and tricycloꢀ
hexylphosphine with 3ꢀazidoꢀ1,4ꢀbenzodiazepine 5 makes
Scheme 1
Table 1. Selected bond lengths for compound 6
Bond
d/Å
Bond
d/Å
Br(1)—C(6)
P(1)—O(2)
P(1)—N(1)
P(1)—C(16)
P(1)—C(22)
N(1)—C(1)
C(1)—C(2)
1.8981(16)
1.4882(12)
1.6543(14)
1.7965(16)
1.8049(16)
1.4533(19)
1.535(2)
O(1)—C(2)
N(2)—C(2)
N(2)—C(3)
C(3)—C(8)
C(8)—C(9)
N(3)—C(9)
N(3)—C(1)
1.2207(19)
1.360(2)
1.408(2)
1.404(2)
1.486(2)
1.286(2)
1.456(2)
The first stage of the Staudinger reaction is a reversible
formation of triazenes 2, stability of which is determined
† Deceased.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 0233—0236, January, 2015.
1066ꢀ5285/15/6401ꢀ0233 © 2015 Springer Science+Business Media, Inc.

234
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 1, January, 2015
Gololobov et al.
Scheme 2
the Staudinger pattern to give imide 8 (Scheme 3). Howꢀ
ever, the result of the reaction of tricyclohexylphosꢀ
phine with azide 5 was very surprising. Mixing the toluene
solutions of tricyclohexylphosphine and azide 5 results in
deep coloring of the reaction mixture and gradually preꢀ
cipitation of analytically pure compound. According to
IR spectroscopy, structure of the product in solid state
corresponds to ylide 9а; however, in solution (СDСl3)
NMR spectroscopy reveals zwitterionic structure 9b.
Scheme 3
it possible to evaluate the effect of spatial structure on the
direction of the reaction. It was found that the reaction of
triethylphosphine with azide 5 proceeds according to
C(12)
C(11)
Br(1)
C(6)
C(5)
C(13)
C(14)
C(7)
C(4)
C(8)
H(2)
C(10)
C(3)
C(2)
N(2)
C(9)
Cy is cyclohexyl.
C(15)
C(2)
NMR (1Н, 31Р) and IR spectra of ylide 9а synthesized
following a conventional "salt" method from chloride 10
(via salt 11) (Scheme 4) and by the reaction of tricycloꢀ
hexylphosphine and azide 5 (see Scheme 3) coincide.
The formation of ylide 9a by the reaction of azide 5
with tricyclohexylphosphine can be explained by the inꢀ
creased mobility of the azido group of heterocycle 5 locatꢀ
ed at the  position to the imine nitrogen. This group
readily eliminates on treatment with relatively nucleophilic
tricyclohexylphosphine (Scheme 5).
This suggestion favors the reaction to proceed by path b
(see Scheme 5). It is noteworthy that according to 31Р NMR
data, the reaction by path a to give small amounts of
imide 13 (via triazene 12) cannot be excluded. However,
attempted isolation of imide 13 failed. Since decomposiꢀ
tion of triazenes 2 is an intramolecular process6 (see
Scheme 1), the spatial effects of the substituents play
a significant role in stabilization and, consequently, in
decomposition of triazenes 2. It is known that in some
N(3)
O(1)
C(1)
N(1)
C(22)
C(27)
C(26)
H(1)
O(2)
C(25)
P(1)
C(23)
C(21)
C(24)
C(16)
C(17)
C(18)
C(20)
C(19)
Fig. 1. Crystal structure of compound 6. Thermal ellipsoids are
drawn at 50% probability level.

PꢀYlide formation under Staudinger conditions
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 1, January, 2015
235
Scheme 4
hexylphosphine and HN3 and thus transforms by the
Staudinger reaction4 into imide 16. Compound 16 was
identified in the reaction mixture by 31Р NMR spectroꢀ
scopy ( 45.7) (cf. Ref. 8).
In summary, we found a new reaction in the course of
which the azido group exhibits pseudo halide properties,
i.e., the reaction of 3ꢀazidoꢀ7ꢀbromoꢀ5ꢀphenylꢀ1,2ꢀdiꢀ
hydroꢀ3Нꢀ1,4ꢀbenzodiazepinꢀ2ꢀone (5) with tricycloꢀ
hexylphosphine. It is obvious that this property can be
explained by both the increased mobility of the azido group
of heterocycle 5 due to the effect of the imine nitrogen and
the effect of the bulky substituents at the phosphorus atom
impeding decomposition of triazene 12 with evolution of
nitrogen to give imide 13. The obtained results suggest
that the presence of the appropriate substituents in azides
and phosphines would favor the Staudinger reaction4 givꢀ
ing rise not only to the formation of phosphorus imides
but also to phosphorus ylides in other cases as well.
Experimental
NMR spectra were recorded with a Bruker Avanceꢀ400 inꢀ
strument (working frequency of 400.1 (1H), 100.68 (13С), 162
(
31Р) MHz). The chemical shifts are given in the  scale relative
to the residual solvent signal (1H, 13С) and 85% H3PO4 (31Р). IR
spectra were obtained on a Nicolet MagnaꢀIRꢀ750 Fourierꢀtransꢀ
form infrared spectrometer. The reactions were carried out unꢀ
der dry argon. Triethylphosphine and tricyclohexylphosphine
(Aldrich) were used as purchased.
cases triazenes 2 are very stable and cannot be converted
into imides 3 even upon heating above 150 С. Treatment
of salt 14 (see Scheme 5, path b) with another mol of
tricyclohexylphosphine leads to ylide 9a. Indeed, carrying
out the reaction in 2ꢀfold excess of tricyclohexylphosphine
notably increases the yield of ylide 9a. Tricyclohexylphosꢀ
phine ammonium salt 15 is in equilibrium with tricycloꢀ
3ꢀAzidoꢀ7ꢀbromoꢀ5ꢀphenylꢀ1,2ꢀdihydroꢀ3Нꢀ1,4ꢀbenzodiꢀ
azepinꢀ2ꢀone (5). To a stirred suspension of NaN3 (0.85 g,
13.3 mmol) in DMF (7 mL), a solution of chloride1 10 (3 g,
Scheme 5

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Russ.Chem.Bull., Int.Ed., Vol. 64, No. 1, January, 2015
Gololobov et al.
8.6 mmol) in DMF (30 mL) was added dropwise at room temꢀ
perature under argon. The reaction is exothermic and during
addition of chloride 10 the reaction temperature slowly rose to
32 С. The mixture was stirred for 4 h and then kept for 16 h. The
mixture was diluted with water (20ꢀfold excess), the precipitate
formed was collected by filtration and washed twice with water.
Crystallization from toluene afforded product 5 in the yield of
53%. M.p. 214 С. Found (%): C, 50.71; H, 2.74; N, 19.64;
Br, 22.42. C15H10BrN5O. Calculated (%): C, 50.56; H, 2.81;
N, 19.66; Br, 22.44. IR (KBr), /cm–1: 1708 (С=O), 2114 (N3).
1Н NMR (DMSOꢀd6), : 4.84 (s, 1 H, CHN3); 7.23—7.83 (m, 8 H,
Ar); 11.14 (s, 1 H, NH).
with anhydrous diethyl ether to give analytically pure ylide 9а
(120 mg). Spectral data of the samples obtained by methods A
and B coincide.
Xꢀray diffraction analyses of compound 6 was performed with
an automatized Bruker Smart Apex II diffractometer (graphite
monochromator, (MoꢀK) = 0.71073 Å,  scan mode, step of
0.55, exposure time of 30 s for a frame). Colorless crystals
(C27H21BrN3O2P, M = 530.35 g mol–1) at 120 K triclinic, space
–
group P1, a = 9.7976(5) Å, b = 10.6784(5) Å, c = 11.5284(6) Å,

= 85.2570(10),  = 84.2580(10),  = 80.9670(10),
V = 1182.44(10) Å3, Z = 2, dcalc = 1.490 g cm–3. Corrections for
absorption and other systematic errors were made with SADABS
program based on the intensities of equivalent reflections. For
further calculations, 6885 independent reflections (Rint = 0.0271)
from 25109 measured reflections were used. The structure was
solved by direct method; nonꢀhydrogen atoms were refined
anisotropically by fullꢀmatrix least squares against F2hkl. Hydroꢀ
gen atoms bonded to nitrogen atoms were located from a differꢀ
ence Fourier synthesis and refined isotropically. Other hydrogen
atoms were positioned geometrically and refined using a riding
model. The final residual factors are as follows: R1 = 0.0306
7ꢀBromoꢀ3ꢀdiphenylphosphinoylaminoꢀ5ꢀphenylꢀ1,2ꢀdihyꢀ
droꢀ3Нꢀ1,4ꢀbenzodiazepinꢀ2ꢀone (6). To an iceꢀcold solution of
methyl alcohol (6 mL, 1.2 mmol) in toluene (13 mL), a solution
of chlorodiphenylphosphine (0.25 mL, 1.38 mmol) in toluene
(3 mL) was added dropwise. After 40 min stirring, azide 5 (440 mg,
1.2 mmol) was added as a solid. The obtained mixture was heatꢀ
ed at 60 С for 40 min and then kept at room temperature for
12 h. The collected precipitate was analytically pure product 6
(300 mg, 48%). Crystals suitable for Xꢀray diffraction were obꢀ
tained by crystallization from MeCN—DMF (3 : 1). M.p. 245 С.
Found (%): Р, 5.66. C27H21BrN3РO2. Calculated (%): Р, 5.70.
IR (KBr), /cm–1: 1706 (С=O), 1606 (С=N), 3346 (NH).
31Р NMR (DMSOꢀd6), : 23.45. 1Н NMR (DMSOꢀd6), :
4.72—4.76 (m, 1 H, CHNP); 6.43—7.97 (m, 8 H, Ar); 11.01
(s, 1 H, NH).
(based on 5696 measured reflections with I > 2(I)), wR2
=
= 0.0750, and GOF = 0.984. The structure was solved and reꢀ
fined using the SHELX version 2009 9.13 software.9 The strucꢀ
ture is deposited with the Cambridge Crystallographic Data Center
(CCDC 1035289) and available free of charge via the Internet at
https://summary.ccdc.cam.ac.uk/structureꢀsummaryꢀform.
5
7ꢀBromoꢀ5ꢀphenylꢀ3ꢀ[(triethylꢀ ꢀphosphanilydene)amino]ꢀ
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 13ꢀ03ꢀ90406)
and the State Fund for Fundamental Research of Ukraine
(Project No. F53.3/009).
2,3ꢀdihydroꢀ1Нꢀ1,4ꢀbenzodiazepinꢀ2ꢀone (8). To a solution of
azide 5 (400 mg, 1.1 mmol) in toluene (8 mL), triethylphosphine
(2.2 mL, 2.2 mmol) was added at 70 С. The reaction was heated
at 70 С until evolution of nitrogen ceased (1 h). Reaction mixꢀ
ture was diluted with petroleum ether (15 mL), white precipitate
formed was collected (523 mg). Recrystallization from ethyl acꢀ
etate afforded colorless imide 7 in the yield of 41%. M.p. 240 С.
Found (%): P, 6.94. C21H25BrN3OP. Calculated (%): P, 6.95.
IR (KBr), /cm–1: 1666 (С=O). 31Р NMR (DMSOꢀd6), : 41.23.
1Н NMR (DMSOꢀd6), : 1.01 (m, 9 H, 3 Ме); 2.02—2.11
(m, 6 H, 3 СН2); 5.44 (s, 1 H, CHNP); 6.41—7.64 (m, 8 H, Ar);
10.55 (s, 1 H, NH).
References
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5
7ꢀBromoꢀ5ꢀphenylꢀ3ꢀ(tricyclohexylꢀ ꢀphosphanilylidene)ꢀ
1Нꢀ1,4ꢀbenzodiazepinꢀ2ꢀone (9а). А. To a solution of azide 5
(600 mg, 1.6 mmol) in toluene (12 mL), a 1 М solution of triꢀ
cyclohexylphosphine (3.2 mmol) in toluene (4 mL) was added at
70 С. The mixture was heated at 70 С until evolution of nitroꢀ
gen ceased (1 h). After 48 h, red precipitate was collected. Yield
495 mg (53%). M.p. 258—260 С. Found (%): C, 66.74; H, 6.85;
N, 5.10. C33H41BrN2OP. Calculated (%): C, 66.89; H, 6.92;
N, 4.73. IR (KBr), /cm–1: 1613 (С=N), 1571 (С=O). 31Р NMR
(СDCl3), : 28.3. 1Н NMR (DMSOꢀd6), : 1.31—2.92 (m, 30 H,
3 (CH2)5); 2.83 (m, 3 Н, СН); 5.50 (d, 1 H, CHP, JH,P = 4.50 Hz);
6.54—7.58 (m, 8 H, Ar).
6. Yu. G. Gololobov, I. N. Zhmurova, L. F. Kasukhin, Tetraꢀ
hedron, 1981, 37, 437.
B. To a solution of crude chloride 10 (0.55 g, 1.6 mmol) in
toluene (12 mL), a solution of tricyclohexylphosphine (0.9 g,
3.2 mmol) in toluene was added. After 1 h, reaction mixure was
diluted with diethyl ether (20 mL), precipitated formed (120 mg)
was filtered off. The filtrate was concentrated in vacuo followed
by addition of acetone (5 mL) and 10% aqueous NaOH to the
residue. Red precipitate formed was extracted with CH2Cl2, exꢀ
tracts were dried with sodium sulfate, and the solvent was reꢀ
moved in vacuo to dryness. Red solid residue was washed twice
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48, 1353.
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Received July 21, 2014;
in revised form October 13, 2014