Comparison of benzene, nitrobenzene, and dinitrobenzene 2-arylsulfenylpyrroles

Article abstract of DOI:10.1021/jo070493r

(Chemical Equation Presented) The effectiveness of the 2,4- dinitrobenzenesulfenyl and 4-nitrobenzenesulfenyl groups as masking and directing groups at the 2-position of pyrrole has been investigated and compared to that of 2-phenylthiopyrrole. The presen

Full text of DOI:10.1021/jo070493r

Many synthetic routes involving the pyrrolic unit require the
controlled introduction of substituents via electrophilic substitu-
tion.11 Success in this regard relies upon successful direction
of incoming substituents and the ability to control the extent of
reactivity. Such control has most commonly been achieved by
the use of carboxylates at the 2-position which serve to both
protect the pyrrolic unit, through their electron-withdrawing
ability and formal carbamate character through resonance, and
direct electrophilic substitution.4,12 Although much practiced,
removal of a carboxy moiety from the 2-position of pyrroles is
often difficult and requires harsh conditions. In addressing the
limitations of carboxylates as protecting groups for pyrroles,
electron-rich sulfenyl groups have recently been demonstrated13
to block the pyrrolic 2-position and activate, rather than protect,
the pyrrolic ring. A variety of sulfenyl groups were investigated
(Figure 1, R ) CH3, CH2CH3, (CH2)9, Ph), and the utility of
the activated pyrroles in acylation reactions was established, as
well as the removal of the sulfenyl group using Raney nickel.
The realization that only blocking/masking the 2-position is
necessary, rather than electronically protecting the N atom
through the traditional use of electron-withdrawing groups, has
highlighted the fact that synthetic pyrrole chemistry, although
aged, is far from mastered.
Comparison of Benzene, Nitrobenzene, and
Dinitrobenzene 2-Arylsulfenylpyrroles
Jose R. Garabatos-Perera, Benjamin H. Rotstein, and
Alison Thompson*
Department of Chemistry, Dalhousie UniVersity, Halifax,
NoVa Scotia B3H 4J3, Canada
alison.thompson@dal.ca
ReceiVed March 8, 2007
The effectiveness of the 2,4-dinitrobenzenesulfenyl and
4-nitrobenzenesulfenyl groups as masking and directing
groups at the 2-position of pyrrole has been investigated and
compared to that of 2-phenylthiopyrrole. The presence of
the nitro group(s) enhances stability of the corresponding
pyrrole toward acid and does not significantly decrease the
ability of the pyrrolic unit to undergo electrophilic aromatic
substitution reactions in the form of formylation, nitration,
and condensation with aldehydes. The synthetic utility of
2-(2,4-dinitrobenzenesulfenyl)pyrrole was demonstrated
through the synthesis of meso-substituted dipyrromethanes.
The sulfoxides 2-(2,4-dinitrobenzenesulfinyl)pyrrole and
2-(4-nitrobenzenesulfinyl)pyrrole underwent neither formy-
lation nor nitration, and the increasing presence of nitro
groups within the moiety at the 2-position resulted in
decreased stability under acidic conditions.
FIGURE 1. 2-(Arylsulfenyl)pyrroles.
We previously reported on the effectiveness of 2,4-dini-
trobenzenesulfinyl and 2,4-dinitrobenzenesulfonyl units at the
2-position of pyrrole and demonstrated the removal of these
substituents under mild deprotection conditions.14 Following
Lindsey’s report concerning the activation and masking of
pyrroles using 2-sulfenyl groups, we herein report the reactivity
of 2 and 3, pyrroles substituted at the 2-position by nitroben-
zenesulfenyl groups. The nitro groups, although electron-
withdrawing, do not significantly reduce the reactivity of
pyrroles 2 and 3 compared to that of 1 and are found to impart
stability in air and acid, as well as to increase crystallinity.
The reactivity of pyrroles 1-3 under Vilsmeier-Haack
formylation12 conditions was investigated to determine the
Pyrrolic molecules exhibit a wide variety of electronic and
optical properties, and the pyrrolic unit is essential within the
synthesis of many natural products, new materials, and improved
pharmaceuticals.1-5 As such, the preparation and manipulation
of functionalized pyrroles is of increasing importance.1,6-10
(7) Fu¨rstner, A. Angew. Chem., Int. Ed. 2003, 42, 3582-3603.
(8) D’Alessio, R.; Bargiotti, A.; Carlini, O.; Colotta, F.; Ferrari, M.;
Gnocchi, P.; Isetta, A. M.; Mongelli, N.; Motta, P.; Rossi, A.; Rossi, M.;
Tibolla, M.; Vanotti, E. J. Med. Chem. 2000, 43, 2557-2565.
(9) O’Hagen, D. Nat. Prod. Rep. 2000, 17, 435-446.
(1) Sternberg, E. D.; Dolphin, D.; Bru¨ckner, C. Tetrahedron 1998, 54,
4151-4202.
(2) Taylor, E. C., Jones, R. A., Eds. Pyrroles; John Wiley & Sons: New
York, 1990.
(3) Ketcha, D. M. Progress in Heterocyclic Chemistry; Gribble, G. W.,
Gilchrist, T. L., Eds.; Pergamon Press: New York, 2001; Vol. 13.
(4) Jones, A. R., Bean, G. P., Eds. The Chemistry of Pyrroles; Academic
Press: London, 1977.
(5) Ferreira, V. F.; de Souza, M. C. B. V.; Cunha, A. C.; Pereira, L. O.
R.; Ferreira, M. L. G. Org. Prep. Proced. Int. 2001, 33, 411-454.
(6) Melvin, M. S.; Tomlinson, J. T.; Saluta, G. R.; Kucera, G. L.;
Lindquist, N.; Manderville, R. A. J. Am. Chem. Soc. 2000, 122, 6333-
6334.
(10) Sato, A.; McNulty, L.; Cox, K.; Kim, S.; Scott, A.; Daniell, K.;
Summerville, K.; Price, C.; Hudson, S.; Kiakos, K.; Hartley, J. A.; Asao,
T.; Lee, M. J. Med. Chem. 2005, 48, 3903-3918.
(11) Jolicoeur, B.; Chapman, E. E.; Thompson, A.; Lubell, W. D.
Tetrahedron 2006, 62, 11531-11563.
(12) Paine, J. B., III. In The Porphyrins; Dolphin, D., Ed.; Academic
Press: London, 1978; Vol. I, Chapter 4.
(13) Thamyongkit, P.; Bhise, A. D.; Taniguchi, M.; Lindsey, J. S. J.
Org. Chem. 2006, 71, 903-910.
(14) Thompson, A.; Butler, R. J.; Grundy, M. N.; Laltoo, A. B. E.;
Robertson, K. N.; Cameron, T. S. J. Org. Chem. 2005, 70, 3753-3756.
10.1021/jo070493r CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/18/2007
7382
J. Org. Chem. 2007, 72, 7382-7385

TABLE 1. Formylation of 2-Arylsulfenylpyrroles
pyrrole
selectivitya
yield (%)b
FIGURE 2. 2-(Arylsulfinyl)pyrroles.
1
2
3
1:0
1:0
27:1
75
76
67
demonstrate that the presence of the nitro group(s) does not
cause significant reduction in reactivity.
a Ratio of 2-substituted cf. 3-substituted product. b Isolated yields.
Having established that the presence of the nitro group(s)
does not diminish the reactivity of 2-arylsulfenylpyrroles toward
electrophilic substitution reactions, we investigated the relative
acid stabilities of 1-6. The studies were carried out by adding
a known amount of CF3CO2D to a stock solution of the
appropriate pyrrole and 1,4-dichlorobenzene (internal standard)
in CD2Cl2. Similar conditions, using CH3CO2D in place of CF3-
CO2D, have been previously used to investigate the extent of
deuteration of 2-alkylsulfenyl- and 2-phenylsulfenyl-substituted
pyrroles.13 As 2-phenylthiopyrrole was reported to be poorly
affected by deuterated acetic acid (very slow rates of deutera-
tion), we turned to the stronger trifluoroacetic acid (deuterated)
in order to assess the stability limits of arylsulfenylpyrroles
bearing nitro groups: we felt that the nitro derivatives would
be more stable to acidic conditions, hence our choice to use
TFA instead of acetic acid. Equivalents of the deuterated acid
were added at 30 min intervals to a maximum of 5.0 equiv,
and 1H NMR spectra were recorded 10 min after each addition.
Comparison of the signal integrals to that of the internal
standard, along with observations of new signals indicative of
decomposition, revealed the degree of robustness of the pyrroles
under acidic conditions. Interestingly, the nitro-substituted
2-arylsulfenylpyrroles 2 and 3 were still intact after the addition
of 5.0 equiv of CF3CO2D, while 1 decomposed after the addition
of 2.0 equiv, thereby supporting our laboratory observations
regarding the stability of 1. Indeed, in our hands, 1 was unstable
in air and was thus protected as its N-tosyl derivative,18 for ease
of manipulation, and then deprotected with base immediately
before use.19 Furthermore, 1 was prepared from 2-thiocyanato-
pyrrole using phenyl magnesium bromide according to Campiani
et al.,20 and as indicated by Lindsey.13 In our hands, 2-thiocy-
anatopyrrole decomposed very readily and was also extremely
liable to pass through multiple layers of latex gloves to cause
stains and discomfort of the skin. No such difficulties were
encountered with the nitro derivatives 2 and 3 which were
prepared by reaction of pyrrole with the corresponding sulfenyl
chloride.14 Evidently, the presence of electron-withdrawing nitro
groups in the arylsulfenyl unit increases the stability of the
pyrrolic core toward acidic conditions and supports the concept
that basicity and nucleophilicity, although often correlated, are
independent phenomena. For the 2-arylsulfinyl derivatives 4-6,
the opposite trend was observed compared to sulfides 1-3.
Indeed, 4 (no nitro groups, decomposition after 5.0 equiv of
CF3CO2D added) was more resistant to acid-catalyzed decom-
position than 6 (two nitro groups, decomposition after 2.0 equiv
of CF3CO2D added).
TABLE 2. Nitration of 2-Arylsulfenylpyrroles
pyrrole
T (°C)
time
yield (%)a
1
1
2
3
0
-5
rt
30 min
30 min
1 h
19
28
16
35
rt
1 h
a Isolated yields.
effects of the nitro substituents toward electrophilic aromatic
substitution of the pyrroles. Although large excesses of reagents
are often used for preparative electrophilic substitution reactions
of pyrroles, only 1.5 equiv of the Vilsmeier-Haack reagent was
used in our studies so that tangible differences in reactivity could
be detected (Table 1). Interestingly, both 2-(4-nitrobenzene-
sulfenyl)pyrrole (2) and 2-(2,4-dinitrobenzenesulfenyl)pyrrole
(3) gave formylation yields similar to that of 2-phenylthiopyrrole
(1), revealing that the presence of the nitro group(s) does not
significantly decrease the tendency of the corresponding 2-ar-
ylsulfenylpyrrole to undergo formylation. Only the 2-substituted
(R-product) was observed for 1 and 2 (as determined by analysis
of TLC and isolated products), and 3 yielded trace amounts of
3-formyl-5-(2,4-dinitrosulfenyl)pyrrole, assigned using two-
dimensional NMR experiments (NOESY, HMQC, and HMBC).
The excellent directing ability of the phenylsulfenyl, 4-nitroben-
zenesulfenyl, and 2,4-dinitrobenzenesulfenyl groups for formy-
lation at the vacant R-position is a useful feature of these
masking groups.11
The 2-arylsulfinylpyrroles 4-6 (Figure 2), prepared by
oxidation of 1-3 using m-CPBA, were completely unreactive
under Vilsmeier-Haack formylation conditions (1.5 equiv). This
is presumably due to the considerably greater electron-
withdrawing nature of the sulfoxide functionality compared with
that of the sulfide.15
To investigate the reactivity of pyrroles 1-6 toward nitration,
these compounds were treated with 1.1 equiv of HNO3 in Ac2O.
The reactivity trends observed for formylation were mirrored
with the sulfides 1-3 giving similar yields for nitration (Table
2), and only the 5-nitration product was observed. Once again,
the sulfoxides 4-6 were completely unreactive even after
extended reaction times. As for other nitration reactions,16,17
yields for the nitration of 1-3 were modest and the reactions
did not proceed at all cleanly. Nevertheless, these results further
To determine the nature of the observed acid-induced
decomposition of 1-6, and cognizant of the potential for
(18) Zonta, C.; Fabris, F.; Lucchi, O. D. Org. Lett. 2005, 7, 1003-1006.
(19) Kakushima, M.; Frenette, R. J. J. Org. Chem. 1984, 49, 2025-
2027.
(20) Campiani, G.; Nacci, V.; Bechelli, S.; Ciani, S. M.; Garofalo, A.;
Fiorini, I.; Wikstrom, H.; de Boer, P.; Liao, Y.; Tepper, P. G.; Cagnotto,
A.; Mennini, T. J. Med. Chem. 1998, 41, 3763-3772.
(15) Hansch, C.; Leo, A.; Taft, R. W. Chem. ReV. 1991, 91, 165-195.
(16) Artico, M. In Pyrroles; Jones, A. R., Ed.; Wiley: New York, 1990;
Vol. 1, Chapter 3.3.
(17) Jones, A. R., Bean, G. P., Eds. The Chemistry of Pyrroles; Academic
Press: London, 1977; Chapter 4.
J. Org. Chem, Vol. 72, No. 19, 2007 7383

TABLE 3. Treatment of 1-6 with TFA
TABLE 4. Synthesis of Dipyrromethanes
product ratio of
2- and 3-substituted
pyrrolesa
pyrrole
T (°C)
1
1
2
2
3
4
4
5
5
6
6
25
84
25
84
84
25
84
25
84
25
84
dec
dec
1:1
dec
1:4
1:0
dec
1:6
1:5
dec
dec
a Ratio determined from 1H NMR spectra of crude reaction mixtures;
dec ) decomposed.
a Isolated yields.
2-arylsulfenyl- and 2-arylsulfinylpyrroles to rearrange to their
respective 3-substituted derivatives,21,22 we investigated prepara-
tive-scale exposure of these compounds to TFA. Pyrroles 1-6
were thus mixed with a 1:1 mixture of TFA and DCE and stirred
for 2 h at 25 or 84 °C (Table 3). Subsequent concentration to
dryness and dissolution in deuterated DMSO, ensuring that all
material was dissolved, allowed analysis of the crude reaction
utility of nitro-containing arylsulfenylpyrroles. Typically, the
condensation was performed with a 2:1 ratio of 3/benzaldehyde
in CH2Cl2 containing TFA (0.05 M) at reflux temperature (Table
4), and dipyrromethanes were isolated in yields that are
comparable to those reported using 1.13 With only stoichiometric
amounts of 3 required for the preparation of reasonable yields
of meso-substituted dipyrromethanes, the route is efficient in
pyrrole and, again, the presence of the nitro groups does not
significantly affect the nucleophilicity of the pyrrolic ring.
However, pyrrole 3 did not react with the electron-rich aldehydes
mesitaldehyde and p-anisaldehyde. All of the isolated dipyr-
romethanes were indefinitely stable to air and moisture. Depro-
tection of 1,9-bis(2,4-dinitrobenzenesulfenyl)-5-phenyldipyr-
romethane was achieved in 50% unoptimized yield by removal
of the nitrobenzenesulfenyl groups through hydrodesulfurization
with Raney nickel complex, akin to the literature method for
the removal of alkyl- and arylsulfenyl masking groups.13
The studies reported herein further the scope of arylsulfe-
nylpyrroles containing nitro groups. 2-(2,4-Dinitrobenzenesulfe-
nyl)pyrrole and 2-(4-nitrobenzenesulfenyl)pyrrole are stable
masked pyrroles that exhibit similar reactivity to 2-phenylthi-
opyrrole but with much enhanced stabilities toward acid and
toward decomposition in air. Importantly, the presence of the
nitro groups within the 2-arylsulfenyl moiety does not signifi-
cantly diminish the nucleophilicity of the corresponding pyrrole.
Furthermore, the presence of nitro groups significantly augments
the crystallinity of 2-arylsulfenylpyrroles and generally enhances
air stability and ease of isolation. Arylsulfinylpyrroles, both with
and without nitro substituents, are unreactive toward formylation
and nitration, and with increasing nitro substitution, these
sulfoxides become less stable to acidic conditions.
1
products by H NMR spectroscopy. As observed during the
NMR scale experiments described above, 1 was unstable under
acidic conditions, even at 25 °C, and neither 2- nor 3-substituted
pyrroles were apparent in the crude reaction mixture. The
mononitro derivative 2 gave a 1:1 mixture of the 2- and
3-substituted products at 25 °C and only decomposed material
at 84 °C. In contrast, the dinitro derivative 3 gave a 1:4 mixture
of 2- and 3-(2,4-dinitrobenzene)sulfenylpyrroles, respectively,
after treatment for 2 h at 84 °C. These results indicate that both
the 2- and 3-substituted pyrroles show enhanced stability with
increasing nitro substitution. The sulfinylpyrrole 4 was resistant
to rearrangement at 25 °C, and only decomposition products
were apparent after 2 h at 84 °C. The mononitrosulfinyl
derivative 5 underwent significant rearrangement at both tem-
peratures, and the dinitrosulfinyl analogue 6 only decomposed
under acidic conditions, further supporting the determination
that with increasing nitro substitution the sulfinylpyrroles
become more unstable to acidic conditions. These preparative-
scale experiments allowed a distinction to be made between
rearrangement (2-substituted pyrroles to 3-substituted pyrroles)
and general decomposition. However, whether decomposition
is due to the instability of the 2-substituted starting material or
the 3-substituted rearranged product is difficult to assess
especially since we were unable to chromatographically separate
the two.
The reactivity of 3 in the synthesis of meso-substituted
dipyrromethanes, common precursors to porphyrinic com-
pounds, was examined in order to further assess the synthetic
Experimental Section
(21) Carmona, O.; Greenhouse, R.; Landeros, R.; Muchowski, J. M. J.
Org. Chem. 1980, 45, 5336-5339.
(22) DeSales, J.; Greenhouse, R.; Muchowski, J. M. J. Org. Chem. 1982,
47, 3668-3672.
General Procedure for Formylation. To DMF (1.5 equiv) at
0 °C under N2 was added POCl3 (1.5 equiv) dropwise. After stirring
at 100 °C for 15 min (to ensure the complete formation of the
7384 J. Org. Chem., Vol. 72, No. 19, 2007

POCl3-DMF complex), a solution of the pyrrole (1.0 equiv) in
1,2-dichloroethane was added at 0 °C. The reaction mixture was
heated at reflux for the appropriate amount of time (1.0-1.5 h),
and then hydrolysis was performed by the addition of an aqueous
solution of NaOAc. The reaction mixture was then stirred at reflux
temperature for 1 h, before being allowed to cool and then extracted
three times with ether. The combined organic layers were washed
three times with saturated Na2CO3 (aq) and once with brine, before
being dried over MgSO4 and filtered. The solvent was removed
under reduced pressure, and the crude product was purified using
column chromatography.
General Procedure for Isomerization Experiments. A solution
of the pyrrole (1.0 equiv) in a 1:1 mixture of TFA (37 equiv) and
ClCH2CH2Cl was stirred at the appropriate temperature (25 or
84 °C) for 2 h. After removal of the solvent in vacuo, analysis of
the mixture using 1H NMR spectroscopy gave the relative ratio of
2- and 3-isomers.
General Procedure for 1,9-Bis(2,4-dinitrobenzenesulfenyl)-
dipyrromethanes. A solution of 2-(2,4-dinitrobenzenesulfenyl)-
pyrrole (3) (2 equiv), aldehyde (1 equiv), and TFA in degassed
CH2Cl2 was stirred at reflux temperature for the appropriate amount
of time (20-48 h). To the resulting mixture, 0.1 N NaOH (50 mL)
was added at 25 °C. The organic phase was washed with 0.1 N
NaOH (3 × 50 mL) and H2O (3 × 50 mL) before being dried over
MgSO4 and filtered. The solvent was removed under reduced
pressure to give the crude product which was purified using column
chromatography.
General Procedure for Nitration. A solution of the pyrrole (1.0
equiv) in Ac2O was treated with a cold (0 °C) solution of 70%
HNO3 (1.1 equiv) in Ac2O. After stirring at the appropriate
temperature (0-25 °C) for the appropriate amount of time (0.5-
1.0 h), the reaction mixture was poured onto ice and treated with
solid Na2CO3 until pH 7. Extraction of the aqueous solution three
times with ether followed by washing of the combined organic
fractions with brine until pH 7, drying over MgSO4, filtration, and
removal of the solvent under reduced pressure gave the crude
product which was purified using column chromatography.
General Procedure for Acid Stability Studies. Pyrrole (53
µmol) and 1,4-dichlorobenzene (20 µmol, 0.003 g) were dissolved
in CD2Cl2 (600 µL). The solution was then transferred, with
Acknowledgment. This work was supported by the Natural
Sciences and Engineering Research Council of Canada (NSERC)
and AstraZeneca.
Supporting Information Available: Synthetic procedures and
characterization data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
filtration if necessary, into an NMR tube, and H NMR spectra
were acquired every 30 min for a duration of 2.5 h. Following the
acquisition of each of the first five spectra, CF3CO2D (4.1 µL, 53
µmol) was added to the tube, followed by thorough mixing via
shaking.
JO070493R
J. Org. Chem, Vol. 72, No. 19, 2007 7385