Formation of β-(diphenylphosphoryl)pyrroles via reactions of dibromocyclobutenylphosphine oxides with aniline

Article abstract of DOI:10.1016/j.tetlet.2013.01.067

1-Phenyl-2-methyl(phenyl)-4-(diphenylphosphoryl)pyrroles are obtained, unexpectedly instead of the 1-phenyl-4-methyl(phenyl)-2-(diphenylphosphoryl) pyrrole regioisomers from a series of reactions between 1,4-dibromo-2- methyl(phenyl)-4-diphenylphosphorylc

Full text of DOI:10.1016/j.tetlet.2013.01.067

Tetrahedron Letters 54 (2013) 1714–1717
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Formation of b-(diphenylphosphoryl)pyrroles via reactions
of dibromocyclobutenylphosphine oxides with aniline
Alexander S. Bogachenkov a, , Boris I. Ionin a, Gerd-Volker Röschenthaler b
⇑
a Department of Organic Chemistry, St. Petersburg Institute of Technology (Technical University), Moskovskii pr 26, 190013 St. Petersburg, Russia
b School of Engineering and Science, Jacobs University Bremen, Campus Ring 1, 28759 Bremen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
1-Phenyl-2-methyl(phenyl)-4-(diphenylphosphoryl)pyrroles are obtained, unexpectedly instead of the
Received 11 December 2012
Revised 29 December 2012
Accepted 16 January 2013
Available online 23 January 2013
1-phenyl-4-methyl(phenyl)-2-(diphenylphosphoryl)pyrrole regioisomers from
a series of reactions
between 1,4-dibromo-2-methyl(phenyl)-4-diphenylphosphorylcyclobutenes and aniline via nucleophilic
substitution accompanied by an allylic shift, subsequent retro electrocyclization and pyrrole ring closure.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Dibromocyclobutenes
Phosphorylated pyrroles
Nucleophilic substitution
Allylic shift
Prototropic shift
Pyrroles are widely used in synthetic organic chemistry and
material science.1,2 Among pyrrole derivatives, there are a large
number of known natural biologically active compounds and drugs.3
It is also known that phosphorylated heterocycles regulate impor-
tant biological functions.4 From this point of view, phosphorylated
pyrroles are of particular interest. While a number of methods
have already been documented for the preparation of 2-phosphono-
pyrroles,5 there appear to be a few practical procedures available
for the synthesis of 3-phosphonopyrroles. These are based
on the addition of enolates and enamines to phosphonoazoalkenes,6
Br
Br
R
Br
R
PPh2Cl;
Et3N
CH2Cl2
Br2
Ph
Ph
R
Br
OH
P
CH2Cl2
-HBr
O
PPh2
Br
O
1a: R = Me
1b: R = Ph
2a,b
3a,b
Br
R
Br
R
Br
R
Br
PhMe or MeNO2
Br
Br
Ph2P
PPh2
PPh2
5a,b
O
O
O
4a,b
6a
Scheme 1. Route to the synthesis of dibromocyclobutenylphosphine oxides.
⇑
Corresponding author. Tel.: +7 9111811069.
E-mail addresses: alexterve@gmail.com (A.S. Bogachenkov), borisionin@mail.ru (B.I. Ionin).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.067

A. S. Bogachenkov et al. / Tetrahedron Letters 54 (2013) 1714–1717
1715
Figure 1. X-ray crystal structure (ORTEP) of 7a-hydrate.
and nucleophilic addition of CH acids to azoalkenes7 or
ethynylphosphonates.8
transformation into cyclobutenes. In continuation of our interest
in the chemistry of cyclobutenylphosphine oxides, we report here
a study on the reactions of bromine-containing phosphorylcyclo-
butenes with aniline, which resulted in the discovery of a new
strategy for the preparation of b-(diphenylphosphoryl)pyrroles
through a series of one-pot reactions.
Recently we reported the synthesis of 2-chloro-3-tert-butyl-1-
dialkyl(aryl)phosphorylcyclobut-2-enes with the purpose of
investigating the potential reactivity of these compounds.9 How-
ever, we found that their double bond was poorly reactive towards
electrophilic reagents (bromination and epoxidation), and when
the reaction was carried out under harsh conditions, cleavage of
the cyclobutene ring occurred leading to the formation of the
original 1,3-butadiene, sometimes with its geometric isomer at
We applied our approach described earlier9 to the synthesis of
cyclobutene 5b possessing bromine atoms at the double bond
and the saturated carbon atom, which also bears a diphenylphos-
phoryl group (Scheme 1).
the 1-position.
A
sequence of transformations starting with
The starting c-bromopropargylic alcohols 1a,b and allenes 2a,b
propargylic alcohols allows the preparation of various sterically
hindered 1,3-butadienes, some of which underwent thermal
were prepared according to the literature procedure.10 Bromina-
tion of 2a led to stable salt 3a,10 whereas in the case of 2b, the
Figure 2. X-ray crystal structure (ORTEP) of 7b.

1716
A. S. Bogachenkov et al. / Tetrahedron Letters 54 (2013) 1714–1717
Br
R
Br
R
Br
R
Br
or
NHPh
NHPh
-HBr
PhNH2
Br
Ph2P
Ph2P
PPh2
O
O
O
5a,b
O
O
O
Ph2P
Ph2P
Br
Ph2P
Br
4
3
1,4-addition
2
-HBr
5
R
R
R
N
N
1
O
NH
Ph
Ph
Ph
Ph2P
Br
7a: R = Me
7b: R = Ph
1,2-addition
R
N
Ph
Scheme 2. Proposed mechanism for the formation of pyrroles 7a,b.
corresponding salt 3b decomposed immediately, even upon cool-
ing, with liberation of hydrogen bromide to form diene 4b.11 Heat-
ing the reaction mixture in refluxing toluene for about half an hour
afforded cyclobutene 5b. It is interesting to note that the salt 3a
was found to be sufficiently stable, so our attempts to isolate 4a
failed. We therefore decided to prepare 5a bypassing 4a, based
on the fact that oxophospholenic salts such as 3a decompose read-
ily in polar solvents such as nitromethane.12 Thus, heating 3a in
refluxing nitromethane followed by column chromatography affor-
ded an inseparable mixture of two isomeric cyclobutenes, 5a and
6a in a 1:1 ratio.
addition, a prototropic shift and hydrogen bromide elimination.
The structures of the formed pyrroles, together with the isolation
of two isomeric dibromocyclobutenes, 5a and 6a, point to the pos-
sibility of allylic nucleophilic substitution and allylic anionotropic
isomerization.
Acknowledgments
The authors gratefully acknowledge the assistance of Drs. Val-
entin I. Zakharov and Albina V. Dogadina (SPbSTI; Department of
Organic Chemistry) for NMR spectral analyses, Dr. Bassem Bassil
(Jacobs University, Bremen), and the Center for X-ray diffraction
studies (SPbSU) for XRD data.
All the cyclobutenes obtained seemed to be reactive in
nucleophilic substitution reactions due to the presence of the
bromine atom attached to a tertiary carbon atom. Actually, we
found that these compounds readily underwent
a thermal
Supplementary data
reaction with excess aniline, however, the reaction proceeded
unexpectedly, with the formation of 1-phenyl-2-methyl
(phenyl)-4-diphenylphosphoryl pyrroles 7a,b instead of the
expected 1-phenyl-4-methyl(phenyl)-2-diphenylphosphoryl
regioisomers.
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
01.067. These data include MOL files and InChiKeys of the most
important compounds described in this article.
The structures of the obtained pyrroles were confirmed unam-
biguously by XRD crystal structure analysis13 (Figs. 1 and 2). Com-
pound 7a was isolated as the monohydrate (7a-hydrate).
Obviously, the thermal reaction proceeds through nucleophilic
substitution combined with an allylic shift, with subsequent retro
electrocyclization of the cyclobutene intermediate. Pyrrole ring-
closure probably proceeds via the intramolecular Michael addition
of aniline to the double bond, activated by the phosphoryl group,
followed by a prototropic shift and hydrogen bromide elimination
(Scheme 2).
To the best of our knowledge, allylic rearrangement of cyclob-
utenyl halides has not previously been observed. Kiefer reported
that attempted isomerization of 3-bromo-3-methylcyclobutene
met with failure.14
Thus, we have described a novel allylic transformation of
bromocyclobutenes and have proposed a new approach to the syn-
thesis of pyrrole derivatives via a series of reactions between phos-
phorylated dibromocyclobutenes and aniline, which involves
nucleophilic substitution with double bond migration, Michael
References and notes
1. (a) Jones, R. A. Pyrroles, Part II: The Synthesis, Reactivity and Physical Properties of
Substituted Pyrroles; Wiley and Sons: New York, 1992; (b) Rivero, M. R.;
Buchwald, S. L. Org. Lett. 2007, 9, 973–976; (c) Russel, J. S.; Pelkey, E. T.; Yoon-
Miller, S. J. P. Prog. Heterocycl. Chem. 2011, 22, 143–180.
2. (a) Lee, C. F.; Yang, L. M.; Hwu, T. Y.; Feng, A. S.; Tseng, J. C.; Luh, T. Y. J. Am.
Chem. Soc. 2000, 122, 4992–4993; (b) Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1
2001, 2491–2515; (c) Della Pina, C.; Falletta, E.; Rossi, M. Catal. Today 2011,
160, 11–27.
3. Katritzky, A. R.; Rees, C. W. R. In Comprehensive Heterocyclic Chemistry;
Pergamon Press: Oxford, 1984; Vol. 4, p 340.
4. (a) Woodward, R. M.; Polenzani, L.; Miledi, R. Mol. Pharmacol. 1993, 43, 609–
625; (b) Van der Jeught, S.; Stevens, Ch. V. Chem. Rev. 2009, 109, 2672–2702.
5. (a) Palacios, F.; Ochoa de Retana, A. M.; Vélez del Burgo, A. J. Org. Chem. 2011,
76, 9472–9477; (b) Cal, D.; Zagorski, P. Phosphorus, Sulfur Silicon Relat. Elem.
2011, 186, 2295–2302.
6. (a) Haelters, J.-P.; Corbel, B.; Sturtz, G. Phosphorus, Sulfur Silicon Relat. Elem.
1989, 44, 53–74; (b) de los Santos, J. M.; Roberto Ignacio, R.; Aparicio, D.;
Palacios, F. J. Org. Chem. 2009, 74, 3444–3448.
7. Attanasi, O. A.; De Crescentini, L.; Foresti, E.; Gatti, G.; Giorgi, R.; Perrulli, F. R.;
Santeusanio, S. J. Chem. Soc., Perkin Trans. 1 1997, 1829–1835.
8. Larionov, O. V.; de Meijere, A. Angew. Chem., Int. Ed. 2005, 44, 5664–5667.

A. S. Bogachenkov et al. / Tetrahedron Letters 54 (2013) 1714–1717
1717
9. Bogachenkov, A. S.; Efremova, M. M.; Ionin, B. I. Tetrahedron Lett. 2012, 53,
2100–2102.
10. Saalfrank, R. W.; Welch, A.; Haubner, M.; Bauer, U. Liebigs Ann. 1996, 2, 171–
181.
1391, 1437, 1502, 1597, 1657, 1821, 1897, 1971, 2916, 3060, 3124, 3439, 3500.
1H NMR (400.13 MHz, CDCl3): d 2.16 (s, 3H, CH3), 6.18–6.22 (br m, 1H, C3-H),
4
3
6.96 (dd, 1H, C5-H, JHH 1.8 Hz, JHP 3.5 Hz), 7.24–7.29 (m, 2H, 2o-H, N(Ph)),
3
7.36–7.54 (m, 3H, N(Ph); 4m-H, 2p-H, P(Ph)), 7.80 (dd, 4H, 4o-H, P(Ph), JHH
11. Procedure for the synthesis of compounds 4b and 5b: To a stirred solution of
allene 2b (2.05 g, 5 mmol) in dry CH2Cl2 (20 ml) at 0 °C was slowly added
dropwise bromine (0.80 g, 5 mmol) such that the temperature did not exceed
4 °C. The mixture was allowed to warm to room temperature over 1 h with
stirring (TLC monitoring). The solvent was carefully removed by rotary
evaporation. The resulting yellow oil was chromatographed on silica gel
using a mixture of CH2Cl2/MeOH (99:1) as the eluent, to yield 4b. Next, 4b was
suspended in toluene (12 ml) and the suspension was heated until a clear
solution was obtained. This solution was heated at reflux for another 30 min
then cooled to room temperature during which 5b precipitated.
7.3 Hz, 3JHP 12.3 Hz). 13C NMR (100.61 MHz, CDCl3): d 12.8 (s, CH3), 111.2 (d, C3,
2JCP 10.1 Hz), 113.0 (d, C4, JCP 128.8 Hz), 125.8 (s, 2o-C, Ph(N)), 127.9 (s, p-C,
1
Ph(N)), 128.3 (d, 4m-C, Ph(P), 3JCP 13.1 Hz), 128.9 (d, C5, 2JCP 19.1 Hz), 129.3 (d,
4
2
2m-C, Ph(N)), 131.5 (d, 2p-C, Ph(P), JCP 1.0 Hz), 131.7 (d, 4o-C, Ph(P), JCP
10.1 Hz), 131.8 (d, C2, JCP 12.4 Hz), 134.1 (d, 2ipso-C, Ph(P), JCP 107.7 Hz),
3
1
139.1 (s, ipso-C, Ph(N)). 31P NMR (161.98 MHz, CDCl3): d 22.6. ESI-MS: calcd for
C
23H20NOP (7a): 358.1355; found: 358.1371 (M+H)+.
12. Angelov, C. M. Phosphorous, Sulfur Relat. Elem. 1983, 15, 177–193.
13. The X-ray crystal structure for compound 7a-hydrate has been deposited at the
Cambridge Crystallographic Data Centre and allocated the deposition number
ꢀ
Procedure for the synthesis of compounds 5a and 6a:
A
solution of
CCDC 910127. Formula: C23H22N1O2P1. Crystal system triclinic, space group P1.
oxophospholenic salt 3a (2.03 g, 4 mmol) in MeNO2 (20 ml) was heated at
reflux for 1 h (TLC monitoring). The solvent was removed under reduced
pressure to afford a yellow oily material, which was chromatographed on silica
gel using a mixture of CH2Cl2/MeOH (98:2) as the eluent, to yield a mixture of
5a and 6a (1:1).
Unit cell parameters: a = 10.372(4) Å, b = 10.495(4) Å, c = 10.806(5) Å,
a
= 61.841(10)°, b = 80.684(10)°, c
= 73.171(10)°, V = 992.3(7) Å3; T = 100(2) K;
Z = 2; q ; l a, k = 0.71073 Å); F(000) =
calc = 1.256 g cmÀ3 = 0.156 mmÀ1 (for MoK
396; full-matrix least-squares on F2; parameters = 248; restraints = 0;
R(all) = 0.0503; wR(all) = 0.1127; GooF(all) = 1.075.
Procedure for the synthesis of compounds 7a,b: A solution of 1.9 mmol of the
corresponding cyclobutene (a mixture of 5a and 6a, or 5b) in dry aniline (5 ml,
55 mmol) was heated at 160 °C for 0.5 h (TLC monitoring). The mixture was
cooled to room temperature. A precipitate formed which was filtered and
washed with CH2Cl2 (2 Â 5 ml). The combined filtrate and washings were
concentrated to afford a yellow oily material, which was chromatographed on
silica gel using a mixture of CH2Cl2/MeOH (99:1) as the eluent and increasing
the polarity gradually by adding MeOH, to yield 7a,b.
The X-ray crystal structure for compound 7b has been deposited at the
Cambridge Crystallographic Data Centre and allocated the deposition number
CCDC 910126. Formula: C28H22N1O1P1. Crystal system orthorhombic, space
group
P
212121. Unit cell parameters: a = 6.0991(7) Å, b = 16.4127(18) Å,
= 90°, b = 90°,
= 90°, V = 2108.8(4) Å3; T = 100(2) K; Z = 4;
calc = 1.321 g cmÀ3 = 0.151 mmÀ1 (for MoK
, k = 0.71073 Å); F(000) = 880;
least-squares on parameters = 280; restraints = 0;
F2;
c = 21.066(2) Å,
q
full-matrix
a
c
;
l
a
R(all) = 0.0751; wR(all) = 0.1056; GooF(all) = 0.982.
1-Phenyl-2-methyl-4-diphenylphosphoryl-1H-pyrrole monohydrate (7a-hydrate):
Yield 0.38 g (57%), colorless crystals, mp 58–61 °C, Rf = 0.26 (CH2Cl2/MeOH,
96:4). IR (KBr, cmÀ1): 608, 640, 734, 813, 956, 1029, 1069, 1119, 1165, 1210,
14. Kiefer, E. F. Ph.D. Thesis, California Institute of Technology, Pasadena,
California, 1961.