Rearrangement of 2,5-bis(silylated)-N-boc pyrroles into the corresponding 2,4-species

Article abstract of DOI:10.1021/jo901956a

(Chemical Equation Presented) The rearrangement of 2,5-bis(silylated)-N-Boc pyrroles in their 2,4-isomers is shown to proceed under mild acidic conditions. A reasonable mechanism, based on literature as well as experiments, is proposed to rationalize this

Full text of DOI:10.1021/jo901956a

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particularly interesting as potential precursors of the corre-
Rearrangement of 2,5-Bis(silylated)-N-Boc Pyrroles
into the Corresponding 2,4-Species
sponding 2,4-diaryl species7 through palladium-catalyzed
desilylative coupling reactions.8 The access to 2,4-disubsti-
tuted pyrroles from the corresponding 2,5-compounds was
reported via the acid-catalyzed R to β migration of acyl,9
sulfinyl,10 bromo or chloro,11 and enol12 substituents. Such a
transformation involves, as mentioned in the latter publica-
tion, the formation of a transient β cation by protonation of
the pyrrole ring at the R position prior to rearrangement. The
well-known ability of silicon to stabilize carbocations at the
β positions could favor such a rearrangement in the silylpyr-
role series and open an access to the aforementioned
2,4-disilylated species. The present paper deals with our first
investigations concerning this transformation.
Jean-Hugues Mirebeau, Mansour Haddad,
ꢀ
Martin Henry-Ellinger, Gerard Jaouen, Julien Louvel, and
Franck Le Bideau*
Laboratoire Charles Friedel, UMR 7223, Ecole Nationale
ꢀ
Superieure de Chimie de Paris, 11 rue Pierre et Marie Curie,
75231 Paris Cedex 05, France
franck-lebideau@enscp.fr
Received September 11, 2009
In connection with our interest in the synthesis of pyrro-
lylrhenium complexes,13 we reported the synthesis of a new
monodimethylphenylsilyl-substituted pyrrole according to a
procedure reported in the literature for the corresponding
trimethylsilyl compound.14 This procedure, modified by the
addition of 2 equiv of lithium 2,2,6,6-tetramethylpiperidine
(LTMP) and of the appropriate silylating agent (Scheme 1),
gave the desired disilylated compounds 2a-d in good yields
(70-86%) from the commercialy available N-Boc pyrrole 1.
The rearrangement of 2,5-bis(silylated)-N-Boc pyrroles
in their 2,4-isomers is shown to proceed under mild acidic
conditions. A reasonable mechanism, based on literature
as well as experiments, is proposed to rationalize this
transformation.
SCHEME 1. Synthesis of 2,5-Bis(silylated)-N-Boc Pyrroles
2a-d
Since the middle of the 1980s, there has been an interest in
the 2,3-, 3,4-, and 2,4-regioisomers of the 2,5-bis(silylated)
pyrroles. In 1985, Barton et al. studied the rearrangement of
2,5-bis(trimethylsilyl) pyrrole under irradiation1 and showed
that it led to a mixture of the corresponding 2,3- and 3,4-
species. Recently, Wong et al. have reported an efficient
synthesis of 3,4-bis(trimethylsilyl) pyrroles via a [2 þ 3]
cycloaddition of cyanoaziridines on the bis(trimethylsilyl)
acetylene,2 studied their reactivity,3 and used them as pre-
cursors of an uncommon 3,4-didehydro-1H-pyrrole4 and in
an elegant synthesis of Lukianol A.5 Concerning the 2,4-
bis(silylated) pyrroles, they were only reported as byproducts
in modest yields (24-55%) in this latter publication and in
the electrophilic substitution of N-substituted pyrroles
(10-18%).6 Nevertheless, these 2,4-regioisomers could be
The yield obtained (85%) for compound 2a is better than
that previously reported (68%) following another route
1
involving two steps.15 While the H NMR spectra of com-
pounds 2 in C6D6 show characteristic singlets for the iden-
tical protons of the ring between 6.6 and 6.7 ppm, their 1H
NMR spectra in CDCl3 point out the existence of mixtures of
compounds 2 and the rearranged products 3 (Scheme 2) in
(1) Barton, T. J.; Hussmann, G. P. J. Org. Chem. 1985, 50, 5881–5882.
(2) Chan, H.-W.; Chan, P.-C.; Liu, J.-H.; Wong, H. N. C. Chem.
Commun. 1997, 1515–1516.
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H. N. C. J. Org. Chem. 1999, 64, 1630–1634.
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(6) Frick, U.; Simchen, G. Synthesis 1984, 929–930.
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S. L.; Wannamaker, M. W.; Watson, B. T. J. Am. Chem. Soc. 1989, 111, 776–
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Chem. 1992, 45, 1167–1178. (e) Nitta, M.; Kobayashi, T. Chem. Lett. 1983,
1715–1718.
(8) Hiyama, T. J. Organomet. Chem. 2002, 635, 58–61.
(9) Carson, J. R.; Davis, N. M. J. Org. Chem. 1981, 46, 839–843.
(10) Carmona, O.; Greenhouse, R.; Landeros, R.; Muchowski, J. M.
J. Org. Chem. 1980, 45, 5336–5339.
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(b) Choi, D.-S.; Huang, S.; Huang, M.; Barnard, T. S.; Adams, R. A.;
Seminario, J. M.; Tour, J. M. J. Org. Chem. 1998, 63, 2646–2655. (c) Zonta,
C.; Fabris, F.; De Lucchi, O. Org. Lett. 2005, 7, 1003–1006.
(12) Trofimov, B. A.; Petrova, O. V.; Sobenina, L. N.; Ushakov, I. A.;
Mikhaleva, A. I.; Rusakov, Y. Y.; Krivdin, L. B. Tetrahedron Lett. 2006, 47,
3645–3648.
(13) Mirebeau, J.-H.; Le Bideau, F.; Marrot, J.; Jaouen, G. Organome-
tallics 2008, 27, 2911–2914.
(14) Hasan, I.; Marinelli, E. R.; Chang Lin, L.-C.; Fowler, F. W.; Levy,
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Published on Web 10/15/2009
DOI: 10.1021/jo901956a
r
2009 American Chemical Society

Mirebeau et al.
JOCNote
variable proportions according to the concentration used
to prepare the analytical samples and the quality of the
deuterated solvent. These latter compounds are character-
ized by two doublets at 6.44-6.47 and 7.26-7.44 ppm in
CDCl3 with a small coupling constant (4J = 1.5 Hz).
TABLE 1. Optimization Process for the Rearrangement of 2b (The
Proportions of Compounds 2b, 3b, 4b, and 5b Are Determined on the Basis
of the 1H NMR Spectra of the Crude Reaction Mixtures)
entry
HCl (equiv)
2b
3b
4b
5b
1
2
3
4
0.15
0.33
1.30
3.30
2%
94%
96%
92%
67%
3%
2%
4%
5%
1%
2%
4%
28%
SCHEME 2. Rearrangement of 2a-d in CDCl3
reaction mixtures showed traces of the only monodesilylated
product 4d in the rearrangement of 2d, while 3a (respec-
tively, 3c) was obtained along with 4a (9%) and 5a (8%)
(respectively, 4c (12%) and 5c (8%)). Compounds 4a14 and
5a3 were identified on the basis of the 1H NMR data reported
in the literature,14 whereas 4c and 4d were synthesized as
mentioned earlier in the text (vide supra). The 1H NMR data
of 5a and 5c were deduced from the crude reaction mixture
spectra.
From a mechanistic standpoint, this rearrangement could
be reasonably explained by the following steps (Scheme 4).
The first carbocation intermediate 6, which is favored by the
well-known β effect,16 could be the result of the protonation
of compound 2 in the R position as previously advanced for
other substituents.9-12 The rearrangement of this entity,
through a stabilized bridged form 7,17 could give the carbo-
cation 8 and the isolated products 3 after deprotonation and
aromatization. To validate the first step of this mechanism,
deuterium chloride was added to a solution of 2b in CDCl3.
After 5 min at room temperature, the 1H NMR spectra
showed the presence of the rearranged product 3b (67%),
unreacted compound 2b (1%), and a new compound (32%,
singlet at 6.84 ppm) resulting from the incorporation of
deuterium at the C5 position. The formation of 3b in that
case can be explained both by the residual acidity of CDCl3
as well as by the generation of Hþ during the process. This
rearrangement is not reversible because compound 3b gave
no starting material in acidic conditions and the 3,4-bis-
(silylated) species were never observed in our case.
Because deuterated chloroform frequently contains traces
of hydrochloric acid, a solution of 2,5-bis(triethylsilyl)-
N-Boc pyrrole 2b in chloroform (0.04 M) was acidified with
the same acid for the optimization process (Scheme 3 and
Table 1). Hydrochloric acid (0.15-3.30 equiv) in chloroform
was added to a solution of 2b in chloroform and stirred for
5 min before quenching with water. The 1H NMR spectra of
the crude reaction mixture thus obtained showed the exis-
tence of two new products 4b and 5b, resulting from proto-
desilylation. Compound 4b was independently synthesized
as previously mentioned for the monophenyldimethylsilyl-
N-Boc pyrrole (vide supra, see Supporting Information for
the synthesis of 4b-d) to confirm its structure, while the
structure of its regioisomer 5b was assigned on the basis of
the 1H NMR spectra of the crude reaction mixture obtained
with an excess of hydrochloric acid (Table 1, entry 4). These
two compounds differ by the nature of their chemical shifts
as well as the coupling constants of the ring protons. The
monosilylated pyrrole 4b presents, as the result of the nitro-
gen influence, only one deshielded proton (7.43 ppm in
C6D6) at the C5 position, while its analogue 5b has two
deshielded protons (7.59 and 7.40 ppm in C6D6) in positions
2 and 5. Furthermore, compound 4b possesses three pro-
tons associated with a 3JH-H coupling constant (3JH3-H4
=
3JH4-H5 = 3 Hz), while compound 5b has only two protons
involved with such a coupling constant (3JH4-H5 = 3 Hz).
Increasing the number of equivalents of HCl relative to 2b
(Table 1, entries 1-4) progressively increased the byproduct
formation at the expense of the desired product 3b. Despite
many attempts varying the reaction conditions (temperature,
solvent, concentration) or the nature of the acid used
(AcOH, PTSA), we were unable to direct the reaction toward
the formation of the sole product 3b. The best conditions
(entry 2) led to the formation of 3b in 80% yield along with an
unseparable mixture of 4b and 5b.
SCHEME 4. A Reasonable Mechanism
SCHEME 3. Acid-Catalyzed Rearrangement of 2b
By analogy with the phenylsulfinyl migration reported by
Carmona et al.,10 the present rearrangement might proceed
To illustrate the scope of this rearrangement, the current
study was carried out with the compounds 2a, 2c, and 2d in
similar conditions (see Supporting Information). The re-
arranged products were thus obtained after purification by
flash chromatography in good yields (74% for 3a, 70% for
(16) Bassindale, A. R.; Glynn, S. J.; Taylor, P. G. In The Chemistry of
Organosilicon Compounds. Activating and Directing Effects of Silicon; Patai,
S., Rappoport, Z., Eds.; Wiley: Chichester, UK, 1998; Vol. 2, pp 355-430.
(17) Lambert, J. B.; Zhao, Y.; Emblidge, R. W.; Salvador, L. A.; Liu,
J.-H. S.; Chelius, E. C. Acc. Chem. Res. 1999, 32, 183–190.
1
3c, and 91% for 3d). The H NMR spectra of the crude
J. Org. Chem. Vol. 74, No. 22, 2009 8891

Mirebeau et al.
JOCNote
by dissociation of 6 to the silylium ion and pyrrole 4 followed
by recombination into 8 (Scheme 5). This hypothesis was
discarded by carrying out the rearrangement of 2a in CDCl3
in the presence of 3 equiv of N-Boc pyrrole 1. This experi-
ment showed no product resulting from a crossover process
(monosilylated species), and only the rearranged product 3a
(19%), unreacted compound 1, and 2a (6%) were observed.
Finally, the formation of the intermediate 7 would be
favored by the release of the steric strain between the Boc
substituent and the migrating silyl group (Scheme 4). This
hypothesis was corroborated by the acid-catalyzed rearran-
gement of the methyl 2,5-bis(trimethylsilyl)-1H-pyrrole-
1-carboxylate 9 incorporating a less hindered N-protecting
group, which led, in the acidic reaction conditions used for
2a, to only 10% conversion in the rearranged product 105
(Scheme 6).
Experimental Section
General Procedure for the Synthesis of Compounds 2a-d: A
solution of 2,2,6,6-tetramethylpiperidine (TMP) (7.9 mmol) in
THF (15 mL) was cooled to -78 °C, and n-butyllithium (7.8
mmol, 1.6 M in hexane) was slowly added, keeping temperature
under -65 °C. The resulting mixture was allowed to stir for
30 min at -78 °C. N-Boc pyrrole (N-acetyl pyrrole for 9)
(3 mmol) in THF (15 mL) was then slowly added. The resulting
mixture was allowed to stir for 1.5 h at -78 °C, and the
appropriate silyl chloride (silyl triflate in the t-Bu(Me)2Si) (7.8
mmol) was slowly added. The crude reaction mixture was stirred
for 30 min at -78 °C then for 2 h at room temperature. The
reaction mixture was diluted with ether (50 mL) and poured into
water (50 mL). The aqueous layer was extracted with ether (3 ꢀ
30 mL), and the resulting organic layers were dried over MgSO4
and evaporated under vacuum. The crude mixture was purified
by flash chromatography using pentane as eluent.
tert-Butyl 2,5-bis(triethylsilyl)-1H-pyrrole-1-carboxylate 2b:
70% yield; colorless oil; 1H NMR (300 MHz, C6D6) δ 6.69
(s, 2H), 1.44 (s, 9H), 1.1-0.9 (m, 30H) ppm; 13C NMR (75 MHz,
C6D6) δ 152.5, 137.0, 126.3, 85.1, 28.3, 8.1, 4.9 ppm; MS m/z
[M þ H]þ 396, [M - C4H8 þ H]þ 340; IR (KBr) ν = 2954,
2874,1729, 1340, 1005, 729 cm-1. Anal. Calcd for C21H41NO2-
Si2: C, 63.74; H, 10.44. Found: C, 63.75; H, 10.13.
SCHEME 5. Crossover Experiment
General Procedure for the Synthesis of Compounds 3a-d: A
solution of HCl (18 μL, 35% w/w for 2a or 9, 30 μL, 35% w/w for
2b and 2d, 45 μL, 35% w/w for 2c) in CHCl3 (15 mL) was added
to compounds 2a-d or 9 (1 mmoL) in CHCl3 (10 mL). The
resulting mixture was allowed to stir at room temperature for
5 min and diluted into ether (100 mL). Water (50 mL) was added
to the crude reaction mixture. Aqueous layer was extracted with
ether (3 ꢀ 25 mL). The organic layers were dried over MgSO4
and evaporated under vacuum. The resulting oil was purified by
flash chromatography using pentane as eluent to give 3a-d and
unseparable mixtures of the monosilylated products 4a-d and
5a-d.
SCHEME 6. Steric Hindrance Influence on the Rearrangement
tert-Butyl 2,4-bis(triethylsilyl)-1H-pyrrole-1-carboxylate 3b:
80% yield; colorless oil; 1H NMR (300 MHz, CDCl3) δ 7.34 (d,
J = 1.5 Hz, 1H), 6.46 (d, J = 1.5 Hz, 1H), 1.60 (s, 9H), 1.0-0.7
(m, 30H) ppm; 13C NMR (75 MHz, CDCl3) δ 149.8, 132.2, 130.5,
130.3, 118.4, 83.1, 28.2, 7.9, 7.7, 4.2, 3.9 ppm; IR (NaCl) ν =
In conclusion, the present work deals with a mild access to
2,4-bis(silylated)-N-Boc pyrroles via an acid-catalyzed re-
arrangement of the corresponding 2,5-species. Despite many
attempts based on the work of Pierrat et al.18 and using
compound 3a as a reagent, we were not able to perform the
palladium-catalyzed process leading to the 2,4-bis(aryl) pyr-
roles. The pyrrole heterocycle is a rather π excessive system,
and the absence of reaction under these conditions could be
expected due to a probable too weak polarization of the
C-Si bond. We are consequently working on the substitu-
tion of our silyl subtituents by silanolates which are more
prone to such a transformation.19
2953, 2875, 1742, 1357, 1290, 1219, 1158, 1103, 1007, 732 cm-1
;
MS m/z [M þ H]þ 396, [M - C4H8 þ H]þ 340; HRMS m/z calcd
for C21H42NO2Si2þ 396.2754, found 396.2751.
ꢁ
Acknowledgment. Financial support from the Ministere
de la Recherche (S.M. grant) and the Centre National de la
Recherche Scientifique are gratefully acknowledged.
Supporting Information Available: General procedures,
1
characterization of compounds and H NMR and 13C NMR
(18) Pierrat, P.; Gros, P.; Fort, Y. Org. Lett. 2005, 7, 697–700.
(19) Denmark, S. E.; Baird, J. D.; Regens, C. S. J. Org. Chem. 2008, 73,
1440–1455.
spectra of compounds 2a-d, 3a-d, 4b-d, and 9. This material is
available free of charge via the Internet at http://pubs.acs.org.
8892 J. Org. Chem. Vol. 74, No. 22, 2009