Synthesis of 2,3-disubstituted pyrroles from 3,N-dilithio-N-(tert-butyldimethylsilyl)-2-buten-1-amine

Article abstract of DOI:10.1021/jo015638n

N-(Trialkylsilyl)allylamines can be deprotonated at the cis-vinylic position to yield 3,N-dilithio-N-(trialkylsilyl)allylamines under mild conditions. N-(Trialkylsilyl)allylamines with terminal alkyl substituents were reported not to form dianions under t

Full text of DOI:10.1021/jo015638n

32
J . Org. Chem. 2002, 67, 32-37
Syn th esis of 2,3-Disu bstitu ted P yr r oles fr om
3,N-Dilith io-N-(ter t-bu tyld im eth ylsilyl)-2-bu ten -1-a m in e
Madeleine A. J acobson and Paul G. Williard*
Department of Chemistry, Brown University, Providence, Rhode Island 02912
Paul_Williard@brown.edu
Received March 20, 2001
N-(Trialkylsilyl)allylamines can be deprotonated at the cis-vinylic position to yield 3,N-dilithio-N-
(trialkylsilyl)allylamines under mild conditions. N-(Trialkylsilyl)allylamines with terminal alkyl
substituents were reported not to form dianions under the same conditions. During our investiga-
tions we found that N-(tert-butyldimethylsilyl)-2-buten-1-amine (1) is deprotonated under the
reaction conditions reported in the literature, but the resulting dianion is quenched by ethereal
solvents. Consequently, new reaction conditions were developed that allow the generation of stable
dianions from allylamines with terminal alkyl substituents. Thus, 2,3-disubstituted pyrroles hitherto
unattainable via this methodology were formed from 3,N-dilithio-N-(tert-butyldimethylsilyl)-2-buten-
1-amine (2) and various carbonyl electrophiles in good yields.
In tr od u ction
More recently some new methods have come to light, such
as the rhodium-catalyzed reaction of R-diazo ketoacyl
amides,14 the reaction of chromium carbene complexes
with 1-azadienes,15 the reaction of dichloroazodienes with
electron-rich olefins,16 and McMurry’s intramolecular
type II alkylidenation of acylamidocarbonyls.17 In addi-
tion, several reviews have recently been published on the
synthesis of pyrroles.18
Pyrroles represent an important class of heterocyclic
compounds.1,2 They are abundant in nature3 and are of
great interest as subunits for natural products.4 In
addition, substituted pyrroles often display biological
activity.1a,5 Pyrroles are also building blocks for por-
phyrins,2a,6 and polymers of pyrroles have found use as
conducting and nonlinear optics materials.7 Because of
their utility and interest there are numerous synthetic
pathways by which pyrroles can be synthesized.8 The
classical methods include the Hanzsch method using
chloroacetone and 3-amino ethyl crotonate,9 the Knorr10
and Paal-Knorr11 syntheses, as well as various 1,3-
dipolar cycloaddition reactions, such as the reaction of
nitrile ylides with alkynes,12 and reactions involving
substrates such as oxazolones, azalactones, and alkynes.13
2,3-Disubstituted pyrroles can be prepared by the
Trofimov reaction between appropriately substituted
oximes and ethyne,19 chloroethene,20 or 1,2-dichloroeth-
(8) (a) Patterson, J . M. Synthesis 1976, 5, 281. (b) J ones, R. A.; Bean,
G. P. The Chemistry of Pyrroles; Academic Press, Inc.: London, 1977.
(c) Bean, G. P. In The Chemistry of Heterocyclic Compounds; J ones,
A. R., Ed.; J ohn Wiley & Sons: New York, 1990; Vol. 48, Part 1,
Chapter 2, p 105. (d) Trofimov, B. A.; Mikhaleva, A. I. Heterocycles
1994, 37, 1193. (e) Enders, D.; Maassen, R.; Han, S.-H. Liebigs Ann
1996, 10, 1565. (f) J ones, G. B.; Chapman, B. J . In Comprehensive
Heterocyclic Chemistry; Bird, C. W., Ed.; Pergamon Press: Oxford,
1996; Vol. 2, p 1. (g) Black, D. St. C. In Comprehensive Heterocyclic
Chemistry; Bird, C. W., Ed.; Pergamon Press: Oxford, 1996; Vol. 2, p
39. (h) Sundberg, R. J . In Comprehensive Heterocyclic Chemistry; Bird,
C. W., Ed.; Pergamon Press: Oxford, 1996; Vol. 2, p 119. (i) Gribble,
G. W. In Comprehensive Heterocyclic Chemistry; Bird, C. W., Ed.;
Pergamon Press: Oxford, 1996; Vol. 2, p 207. (j) Gilchrist, T. L. J .
Chem. Soc., Perkin Trans. 1 1998, 615.
(9) (a) Hantzsch, A. Chem. Ber. 1890, 23, 1474. (b) Beelen van, D.
C.; Wolters, J .; Gen van der, A. Recl. Trav. Chim. Pays-Bas 1979, 98,
437.
(10) (a) Knorr, L. Ber. 1884, 17, 1635. (b) Knorr, L. Annalen 1886,
236, 290. (c) Kleinspehn, G. G. J . Am. Chem. Soc. 1955, 77, 1546.
(11) (a) Paal, C. Ber. 1885, 18, 367. (b) Knorr, L. Ber. 1885, 18, 1568.
(c) See ref 8b, Chapter 3.
(12) (a) Huisgen, R.; Stangl, H.; Sturm, H. J .; Wagenhofer, H. Angew.
Chem., Int. Ed. Engl. 1962, 1, 50. (b) Berre´e, F.; Marchand, E.; Morel,
G. Tetrahedron Lett. 1992, 33, 6155.
(13) (a) Bayer, H. O.; Gotthardt, H.; Huisgen, R. Chem. Ber. 1970,
103, 2356. (b) Huisgen, R.; Gotthardt, H.; Bayer, H. O.; Schaefer, F.
C. Chem. Ber. 1970, 103, 2611.
(14) Padwa, A.; Deen, D. C.; Hertzog, D. C.; Nadler, W. R.; Zhi, L.
Tetrahedron 1992, 48, 7565.
(15) Danks, T. N.; Velo-Rego, D. Tetrahedron Lett. 1994, 35, 9443.
(16) South, M. S.; J akuboski, T. L.; Westmeyer, M. D.; Dukesherer,
D. R. Tetrahedron Lett. 1996, 37, 1351.
(1) For biologically important pyrroles, see: (a) Lainton, J . A. H.;
Huffman, J . W.; Martin, B. R.; Compton, D. R. Tetrahedron Lett. 1995,
36, 1401. (b) de Leon, C. Y.; Ganem, B. Tetrahedron 1997, 53, 7731.
(c) Gupton, J . T.; Krumpe, K. E.; Burnham, B. S.; Dwornik, K. A.;
Petrich, S. A.; Du, K. X.; Bruce, M. A.; Vu, P.; Vargas, M.; Keertikar,
K. M.; Hosein, K. N.; J ones, C. R.; Sikorski, J . A. Tetrahedron 1998,
54, 5075. (d) J acobi, P. A.; Coutts, L. D.; Guo, J .; Hauck, S. I.; Leung,
S. H. J . Org. Chem. 2000, 65, 205.
(2) For the chemistry of macrocycles containing pyrrole units; see:
(a) Sessler, J . L.; Weghorn, S. J . Expanded, Contracted & Isomeric
Porphyrins; Pergamon Press: Oxford, 1997. (b) Thoresen, L. H.; Kim,
H.; Welch, M. B.; Burghart, A.; Burgess, K. Synlett 1998, 11, 1276.
(3) Pinder, A. R. In The Alkaloids; Grundon, M. F., Ed., The Royal
Chemical Society: London, 1982; Vol. 12, Chapter 2, p 35.
(4) See (a) Herbert, R. B. In The Alkaloids; Grundon, M. F., Ed.;
The Royal Chemical Society: London, 1982; Vol. 12, Chapter 1, p 1.
(b) Falk, H. The Chemistry of Linear Oligopyrroles and Bile Pigments;
Springer-Verlag: Wienna, 1989. (c) Biosynthesis of Tetrapyrroles;
J ordan, P. M., Ed.; Elsevier: Amsterdam, 1991.
(5) (a) Korostova, S. E.; Sobenina, L. N.; Nersterenko, R. N.; Aliev,
I. A.; Mikhaleva, A. I. Zh. Org. Khim. 1984, 1960; Chem. Abstr. 1985,
102, 131860. (b) Itoh, S.; Fukui, Y.; Haranou, S.; Ogino, M.; Komatsu,
M.; Ohshiro, Y. J . Org. Chem. 1992, 57, 4452. (c) Woo, J .; Sigurdsson,
S. T.; Hopkins, P. B. J . Am. Chem. Soc. 1993, 115, 3407.
(6) (a) Porphyrins and Metalloporphyrins; Smith, K. M., Ed.;
Elsevier: Amsterdam, 1975. (b) Franck, B.; Nonn, A. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1795.
(17) Furstner, A.; Bogdanovic, B. Angew. Chem., Int. Ed. Engl. 1996,
35, 2442.
(7) (a) Niziurski-Mann, R. E.; Cava, M. P. Heterocycles 1992, 34,
2003. (b) Naarmann, H.; Theophilou, N. In Electroresponsive Molecular
and Polymeric Systems; Skotheim, T. A., Ed.; Marcel Dekker Inc.: New
York, 1988; Vol. 1. (c) Bauerle, P. Adv. Mater. 1993, 5, 879.
(18) (a) Sundberg, R. J . Prog. Heterocycl. Chem. 1992, 4, 81. (b)
Gilchrist, T. L. Contemp. Org. Synth. 1994, 1, 205. (c) Sundberg, R. J .;
Nguyen, P. V. Prog. Heterocycl. Chem. 1994, 6, 110. (d) Gilchrist, T.
L. J . Chem. Soc., Perkin Trans. 1 1998, 615.
10.1021/jo015638n CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/08/2001

Synthesis of 2,3-Disubstituted Pyrroles
J . Org. Chem., Vol. 67, No. 1, 2002 33
Sch em e 1
is not surprising as the basicity of organolithiums is
known to increase with increasing substitution.24
The method of the previous investigators involved the
generation of dianion over a 48 h period, followed by
quenching with chlorotrimethylsilane. Over such a long
period of time the dianion would likely have been
reprotonated by the solvent to regenerate the lithium
amide of the starting amine. Consequently, the only
observed product was bis-N,N-disilylated crotylamine,22
misleadingly indicating lack of dianion formation. Our
experience suggested that dianion formation may be
complete as soon as 0.5 h after the addition of base.
Indeed, our NMR investigation into the reaction pro-
gress of the vinylic deprotonation of 1 in THF-d8 indicated
that dianion was completely formed after 90 min. This
dianionic species then went on to deprotonate solvent
(THF-d8) overnight to generate E-3-Deutero-N-lithio-N-
(tert-butyldimethylsilyl)-2-buten-1-amine (6). (Figures 2
and 3)
F igu r e 1. Central unit of 3,N-dilithio-N-(trialkylsilyl)allyl-
amines as observed by X-ray crystallography.
Sch em e 2
ane,21 in the presence of KOH or NaOH and elevated
temperatures, in yields around 40-50%. While 1,4-
conjugate addition reactions followed by cyclization nor-
mally lead to pyrroles containing electron-withdrawing
groups at the 3-position, the addition of enamines to
chloroacrylonitrile yields 2,3-disubstituted pyrroles.8c
In this paper we wish to present a synthesis of 2,3-
disubstituted pyrroles from a simple butenylamine pre-
cursor. Deprotonation of silyl-protected 2-E-buten-1-
amine with 3 equiv of n-butyllithium in benzene in the
presence of 1 equiv of THF at 60 °C to form the
3,N-dilithio species, followed by the addition of various
carbonyl compounds at 0 °C, gives 2,3-disubstituted
pyrroles in good yields (Scheme 1).
Attempts to generate useful amounts of the dianion
in nondeuterated THF or diethyl ether by varying the
reaction conditions failed, most likely because quenching
competes more effectively with dianion formation in
nondeuterated solvents. When the reaction was followed
by 1H NMR using benzene-d6 or toluene-d8 as the solvent,
none or only very small amounts of dianion were gener-
ated, even at elevated temperatures (+60 °C and +90
°C, respectively) and over extended periods of time. This
observation is in agreement with our previous experience
that the generation of dianions from N-(trialkylsilyl)-
allylamines in hydrocarbon solvents, such as pentane or
hexane, is sluggish at best and most often unsuccessful.
Upon addition of 1 equiv of THF, however, the reaction
proceeds smoothly, and the dianionic species is fully
generated at room temperature in less than 2 h (Scheme
4). This amount of THF appears to only catalyze the
formation of the vinylic anion and does not appear to
quench the formed dianion to any appreciable extent. The
reaction also proceeds to completion in the presence of
0.1 equiv of THF, but the rate of dianion formation is
reduced considerably. The mode of catalysis is currently
under investigation, as are attempts to crystallize the
dianionic species. It is interesting to note that the
Resu lts a n d Discu ssion
N-(Trialkylsilyl)allylamines can be deprotonated at the
cis-vinylic position to yield 3,N-dilithio-N-(trialkylsilyl)-
allylamines under surprisingly mild conditions (Scheme
2).22 We have characterized a series of such dianions by
X-ray crystallography23 (Figure 1), and the synthesis of
2-substituted pyrroles from the addition of dianions to
carbonyl electrophiles was reported in the literature.22
However, N-(trialkylsilyl)allylamines with terminal
alkyl substituents were reported not to form dianions
under the same conditions (i.e., 2 equiv of n-butyllithium,
in diethyl ether at 0 °C).22 During our investigations we
found that, contrary to previous reports, 1 is deproton-
ated under these reaction conditions, but the resulting
dianion is quenched by ethereal solvents (Scheme 3). This
increased basicity of the substituted vinyllithium species
1
equivalent H NMR experiment with 1 equiv of TMEDA,
instead of 1 equiv of THF, did not generate any discern-
ible amount of dianion.
Synthetically useful dianions of 1 can be generated
with 3 equiv of n-butyllithium and 1 equiv of THF in
benzene. The presence of dianion 2 can be confirmed by
GC/MS, after quenching a small aliquot of the reaction
mixture with D2O. The dianions react with carbonyl
electrophiles to yield 2,3-disubstituted pyrroles 3 (Scheme
1).
(19) For some examples, see: (a) Trofimov, B. A.; Korostova, S. E.;
Balabanova, L. N.; Mikhaleva, A. I. J . Org. Chem. USSR 1978, 14,
2018. (b) Korostova, S. E.; Mikhaleva, A. I.; Sobenina, L. N.; Shevchen-
ko, S. G.; Shcherbakov, V. V. Khim. Geterotsikl. Soedin. 1985, 11, 1501.
(20) For some examples, see (a) Aliev, I. A.; Zeinalova, S. N.;
Gasanov, B. R.; Mikhaleva, A. I.; Korostova, S. E. J . Org. Chem. USSR
1988, 24, 2198. (b) Aliev, I. A.; Mikhaleva, A. I.; Gasanov, B. R.;
Golovanova, N. I. Khim. Geterotsikl. Soedin. 1990, 10, 1337.
(21) For some examples, see: (a) Trofimov, B. A.; Mikhaleva, A. I.;
Vasil’ev, A. N.; Korostova, S. E.; Schevchenko, S. G. Khim. Geterotsikl.
Soedin. 1985, 1, 59. (b) Korostova, S. E.; Nesterenko, R. N.; Mikhaleva,
A. I.; Polovnikova, R. I.; Golovanova, N. I. Khim. Geterotsikl. Soedin.
1989, 7, 901.
The products are obtained as mixtures of the silylated
and desilylated 2,3-disubstituted pyrroles as detected by
(22) Burns, S. A.; Corriu, R. J . P.; Huynh, V.; Moreau, J . J . E. J .
Organomet. Chem. 1987, 333, 281.
(23) Williard, P. G.; J acobson, M. A. Org. Lett. 2000, 2, 2753.
(24) Sapse, A.-M.; Schleyer, P. von R. Lithium Chemistry: A
Theoretical and Experimental Overview; J ohn Wiley & Sons: New
York, 1995.

34 J . Org. Chem., Vol. 67, No. 1, 2002
J acobson and Williard
F igu r e 2. Generation and quenching of dianion 2. Reaction progress followed by 1H NMR in THF-d8 at 25 °C. Stacked NMR
spectra. A: Appearance of dianion and disappearance of monoanion as n-butyllithium is consumed. B: Deuteration of the dianion
to regenerate monoanionic lithium amide.
Sch em e 3
Sch em e 4
F igu r e 3. Generation and quenching of dianion 2. Reaction
progress followed by 1H NMR in THF-d8 at 25 °C. Plot of peak
areas as a function of time. / dianion (H-2), b monoanion (H-
2), O monoanion (H-3).
seen in reactions with amides. The reaction with N,N-
dimethylformamide (entry 9) proceeds readily and in high
yields, while the reaction with N,N-dimethylacetamide
(entry 10), N,N-diethylpropionamide (entry 11), and
1-methyl-2-pyrrolidinone (entry 12) give no pyrrole prod-
uct with recovery of starting amine. N,N,2-Trimethyl-
propionamide (entry 13) and N,N-dimethylbenzamide
(entry 14), on the other hand, give 87% and 89% of the
2,3-disubstituted pyrrole, respectively.
For entries 10-12, the R group is enolizable, while for
entries 9, 13, and 14 the R group is less so, or not at all.
If the electrophile is reactive enough, as in the case of
acid chlorides and anhydrides, addition of the dianion to
1
GC/MS, and confirmed by H NMR.25 Table 1 illustrates
some typical reactions and conversions. Acid chlorides
(entries 1 and 2), anhydrides (entries 3-5), and esters
(entries 6-8) all react readily, except for entry 6, ethyl
acetate. This entry’s lower yield is most likely due to a
competing reaction, namely enolization of the electrophile
by the dianionic species. This competing reaction is also
(25) Desilylation is presumed to occur by lithium siloxide elimination
from a cyclized intermediate as described in ref 22 and references
therein.

Synthesis of 2,3-Disubstituted Pyrroles
J . Org. Chem., Vol. 67, No. 1, 2002 35
Ta ble 1. P yr r ole F or m a tion fr om 2 a n d Va r iou s
Ta ble 2. P yr r ole F or m a tion fr om 2 a n d Va r iou s
Ca r bon yl Electr op h iles in Ben zen e a t 0 °C, Ar r a n ged by
R. Effect of th e Lea vin g Gr ou p
Ca r bon yl Electr op h iles in Ben zen e a t 0 °C
electrophile
pyrrole, % conversiona
R
X
R′ ) TBDMS
R′ ) H
total
CH3
CH3
CH3
CH3
Ph
Ph
Ph
Ph
Cl
54
54
27
0
46
65
71
46
NDb
NDb
NDb
0
54
28
54c
54c
27c
0d
100
93
OCOCH3
OCH2CH3
N(CH3)2
Cl
OCOPh
OCH2CH3
N(CH3)2
29
43
100
89
a
The % conversion was calculated based on unreacted N-(tert-
butyldimethylsilyl)-2-buten-1-amine as determined by GC/MS. The
presence of pyrrole product was confirmed by 1H NMR after
b
workup. Not detected. In this case the presence of unprotected
pyrrole product would not be detected by GC/MS; see footnote c.
c The limit of detection for the GC/MS was molecular weights of
100. Any formation of pyrroles (unprotected) with a molecular
weight less than this could therefore not be detected. In these cases
the total % conversion should be considered a lower limit for
d
possible yield of pyrrole product. 1 recovered.
Ta ble 3. Som e Rep r esen ta tive Exa m p les of Isola tion of
P yr r ole P r od u ct
a
The % conversion was calculated based on unreacted N-(tert-
butyldimethylsilyl)-2-buten-1-amine as determined by GC/MS. The
presence of pyrrole product was confirmed by 1H NMR after
workup. Not detected. The presence of unprotected pyrrole
b
R
electrophile
% yielda
product would not be detected by GC/MS; see footnote c. c The limit
of detection for the GC/MS was molecular weights of 100. Any
formation of pyrroles (unprotected) with a molecular weight less
than this could therefore not be detected. In these cases the total
% conversion should be considered a lower limit for possible yield
furan (3a )
Ph (3b)
Ph (3c)
ethyl 2-furoate
PhCOCl
(PhCO)2O
71
43b
41
46
Ph (3d )
PhCON(CH3)2
d
of pyrrole product. The balance of amine was converted to mono-
a
After purification by column chromatography, as described in
the Experimental Section. Yield based on N-(tert-butyldimethyl-
silyl)-2-buten-1-amine. After purification by preparative thin-
trifluoroacetylated (26%) and di-trifluoroacetylated (48%) N-(tert-
butyldimethylsilyl)-2-buten-1-amine. e 1 recovered.
b
layer chromatography, as described in the Experimental Section.
Yield based on N-(tert-butyldimethylsilyl)-2-buten-1-amine.
the carbonyl group, followed by cyclization to yield the
2,3-disubstituted pyrrole product dominates. If the elec-
trophile is less reactivesas in the case of esters (entry
6) and amides with enolizable protons (entries 10-12)s
enolization of the electrophile is the preferred reaction
pathway, and the reaction gives none or very little 2,3-
disubstituted pyrrole product. The amides (entries 10-
13)26 illustrate that the bulkier the R group, i.e., the
harder the R group is to enolize, the more pyrrole product
will be seen and vice versa. However, experiments using
trimethylacetyl chloride and trimethylacetic anhydride
indicate that if the R group is too bulky, much lower
yields and complex reaction mixtures are observed.
Consequently, sterically hindered carbonyls are expected
to give lower yields, regardless of their activity.
and anhydrides, give little or no amount of enolized
electrophile and consequently high yields of 2,3-disub-
stituted pyrrole. Less reactive carbonyls, such as esters
and amides, give more of the enolized electrophile and
lower yields of the 2,3-disubstituted pyrrole. For a
nonenolizable electrophile, such as R ) Ph, the nature
of the leaving group has little or no effect on the yield of
pyrrole product (Table 2).
In the final step, the mixtures of silylated and desi-
lylated pyrrole product were treated with tetrabutylam-
monium fluoride, and the resulting desilylated product
was purified by chromatography. Table 3 shows some
representative examples of isolation of 2,3-disubstituted
pyrroles, with yields varying from 41-71%.
We have here demonstrated the hitherto unknown
reactivity of N-(trialkylsilyl)allylamines with terminal
alkyl substituents to form dianionic species when exposed
to n-butyllithium in the presence of 1 equiv of THF in
benzene. These dilithiated species react with various
carbonyl electrophiles to form 2,3-disubstituted pyrroles
in good yields. We anticipate that highly substituted
pyrroles could be prepared from appropriately substituted
butenylamines. The mode of catalysis, which requires
For an enolizable electrophile (as R ) CH3) the nature
of the leaving group X greatly effects the yield (Table 2).
More reactive carbonyl compounds, such as acid chlorides
(26) When acrylamide (entry 15) was mixed with the dianion 2, a
white solid preciptated. GC/MS and 1H NMR indicated that most of
the dianion 2 remained in solution. The solid is likely polyacrylamide,
as the poylmerization of acrylamide in the presence of electrons is a
known phenomenon. Reaction of dianion 2 with acryloyl chloride
yielded a jellylike material and otherwise similar results. Most likely
a polymer was formed in this case as well.

36 J . Org. Chem., Vol. 67, No. 1, 2002
J acobson and Williard
The solvent was not evaporated, but the presence of amine
was confirmed by H NMR. The ether layer was used, as was,
in the next step.
THF to be present for the dianionic species to form, is
currently under investigation. We expect that THF-
induced changes in aggregation play an important role
in facilitating these reactions.27 In light of the inability
of TMEDA to catalyze this reaction, the possibility of a
unique aggregate with ethereal solvation is especially
intriguing. We are currently attempting to characterize
these interesting aggregates by X-ray crystallography
and NMR.
1
N-(ter t-Bu tyld im eth ylsilyl)-2-bu ten -1-a m in e (1). Tri-
ethylamine (11.0 g, 0.109 mol) was added to the ether layer
containing 9. tert-Butyldimethylsilyl chloride (16.3 g, 0.109
mol) dissolved in 40 mL of distilled diethyl ether was added
to the amine/triethylamine mixture. Within a few minutes, a
white solid precipitated. The reaction mixture was stirred at
room temperature for 12 h, and the presence of 1 was
confirmed by GC/MS. The reaction mixture was filtered
through florisil, and the filtrate was stirred with CaH2 for 4
h. Filtration, followed by fractional distillation (52 °C, 0.25
Exp er im en ta l Section
mmHg), resulted in 6.4 g (26% yield) of 1. FTIR (neat): ν (cm-1
)
Gen er a l. Diethyl ether and THF were distilled from
sodium/benzophenone under a nitrogen atmosphere. n-Buth-
yllithium was obtained from Aldrich Chemical Co. (2.5 M in
hexanes), and the exact concentration of the solution was
determined by direct titration with 2,5-dimethoxybenzyl al-
cohol in THF. All chemicals were purchased from Aldrich
Chemical Co. and distilled prior to use when appropriate.
Benzene and toluene were dried over CaH2 and distilled before
use. Deuterated NMR solvents were dried over 3 Å Linde
sieves prior to use. All reactions and NMR studies were carried
out under argon atmosphere, using flame-dried glassware.
Aldrich silica gel (70-230 mesh, 60 Å) and Analtech silica gel
thin layer plates (20 × 20 cm, 1000 µm) were used for
chromatography. GC analyses were performed on a Hewlett-
Packard 5890 series II gas chromatograph equipped with a
Hewlett-Packard 5972 mass selective detector. IR spectra were
recorded on a Perkin-Elmer 1600 FTIR. NMR spectra were
collected on Bruker DRX400 or DPX300 spectrometers operat-
ing at 400 and 300 MHz for 1H and 100 and 75 MHz for 13C
observation. The chemical shifts were referenced to CDCl3 (1H
7.27 ppm and 13C 77.23 ppm) as an internal standard. HRMS
were performed on a Kratos MS80RFA instrument.
3410, 2926, 2854, 1670. 1H NMR (CDCl3): δ 5.52 (m, 2H). 3.30
(m, 2H), 1.68 (m, 3H), 0.89 (s, 9H), 0.02 (s, 6H). 13C NMR
(CDCl3): δ -4.6, 18.0, 18.8, 26.1, 44.9, 124.4, 134.1. EIMS m/z
185 (6, M+), 170 (4), 128 (100), 99 (35). 73 (23), 59 (23). HRMS
calculated for C10H23NSi: 185.1599. Found: 185.1593.
Gen er a l P r oced u r e for th e P r ep a r a tion of Dia n ion 2
To F ollow th e Rea ction by NMR. n-Butyllithium (0.13
mmol) in hexanes was placed in a flame-dried NMR tube under
argon atmosphere. The hexanes were removed in vacuo, and
0.6 mL of THF-d8 was added. To this clear and colorless
solution (12 mg, 6.6 × 10-5 mol) was added 1.
Gen er a l P r oced u r e for th e Gen er a tion of Dia n ion 2
fr om 1. 1 (167 mg, 0.9 mmol) was weighed into a flask, and
3.4 mL of benzene was added. n-Butyllithium (1.8 mmol) was
added at 0 °C, followed by the addition of 1 equiv of dry THF.
The temperature was raised to +60 °C, and another 0.9 mmol
of n-butyllithium was added. The mixture was stirred at this
temperature for another 1 h. The presence of dianion was
confirmed by injecting a small aliquot of the reaction mixture
into D2O, extracting with hexanes, and detecting the M + 2
ion by GC/MS.
Gen er a l P r oced u r e for th e P r ep a r a tion of 2,3-Disu b-
stitu ted P yr r oles fr om 2. The electrophile (1.8 mmol) was
added dropwise to the dianion mixture at 0 °C. Solid electro-
philes were dissolved in 1 mL of benzene prior to addition.
The reaction mixture was allowed to warm to room temper-
ature and stirred for 2 h. The reaction mixture was poured
into water, and the aqueous layer was extracted with benzene
(3 × 5 mL). The combined organic layer was dried over Na2-
SO4 and the solvent evaporated to yield the crude 2,3-
disubstituted pyrroles.
Gen er a l P r oced u r e for Desilyla tin g N-(ter t-Bu tyld i-
m eth ylsilyl)p yr r oles. The crude mixture of silyl-protected
and non-silyl-protected pyrroles was dissolved in 3 mL of dry
THF. To this solution was added tetrabutylammonium fluoride
(1.4 mmol, 365 mg) dissolved in 3 mL of dry THF, and the
resulting slightly red liquid was stirred for 1 h at room
temperature. The reaction mixture was poured into saturated
aqueous NaHCO3, and the aqueous layer was extracted with
dichloromethane (3 × 5 mL). The combined organic layer was
dried over Na2SO4, and the solvents were evaporated to yield
the 2,3-disubstituted pyrroles as oils.
Som e Rep r esen ta tive Exa m p les of P u r ifica tion of 2,3-
Disu bstitu ted P yr r oles. 2-(2-Fu r yl)-3-m eth ylpyr r ole (3a).29
Crude 3a was purified by flash column chromatography using
1:9 dichloromethane:pentane, with 0.5% triethylamine, as the
eluent. 3a was subsequently isolated as a clear, colorless oil
in 71% yield. 1H NMR (CDCl3): δ 7.40 (dd, 1H, J ) 1.8 Hz,
0.8 Hz), 6.76 (m, 1H), 6.51 (dd, 1H, J ) 3.3 Hz, 1.8 Hz), 6.34
(dd, 1H, J ) 3.3 Hz, 0.8 Hz), 6.15 (m, 1H), 2.31 (s, 3H). 13C
NMR (CDCl3): δ 12.8, 103.1, 112.0, 112.1, 116.6, 117.7, 121.1,
140.2, 148.8. EIMS m/z 147 (100, M+), 118 (81), 104 (18), 91
(21). HRMS calculated for C9H9N: 147.0684. Found: 147.0683.
3-Meth yl-2-p h en ylp yr r ole (3b-d ).30 Prepared from ben-
zoyl chloride. The crude pyrrole was purified by preparative
thin-layer chromatography, using 1:2.3 acetone:hexanes as the
eluent. 3b was isolated as a colorless oil in 43% yield.
The synthesis of 2-E-buten-1-amine from 3-buten-2-ol was
adapted from literature procedures:28
2,2,2-Tr ich lor oa cetim id ic Acid 1-Meth yla llyl Ester (7).
NaH (1.4 g, 0.059 mol) was weighed into a flask, and 14 mL
of dry THF was added. This slurry was placed in an icebath
(at about 5 °C), and a solution of 3-buten-2-ol (18.6 g, 0.258
mol) in 25 mL of dry THF was added dropwise, with a syringe
pump. The temperature of the bath was maintained. After
stirring for 1 h, the solution was added to trichloroacetonitrile
(37.3 g, 0.258 mol) in 240 mL of dry THF at 0 °C, over the
course of 30 min. Stirring for 2 h, followed by evaporation of
the solvent, yielded a brown oil. This crude product was used
for the next step without further purification. 1H NMR
(CDCl3): δ 8.35 (br, 1H), 5.96 (ddd, 1H, J ) 17.3 Hz, 10.6 Hz,
5.6 Hz), 5.55 (m, 1H), 5.35 (dt, 1H, J ) 17.3 Hz, 1.3 Hz), 5.20
(dt, 1H, J ) 10.6 Hz, 1.3 Hz), 1.43 (d, 3H, J ) 6.55 Hz).
N-Bu t-2-en yl-2,2,2-tr ich lor oa ceta m id e (8). Crude 7 was
refluxed in 340 mL of toluene for 2 h, and the solvent was
evaporated. The crude product was purified by fractional
distillation (106 °C/0.25 mmHg) to yield 29.4 g (53%) as a white
solid, mp 28-29 °C. 1H NMR (CDCl3): δ 6.71 (br, 1H), 5.76
(dqt, 1H, J ) 15.3 Hz, 6.5 Hz, 1.3 Hz), 5.52 (dtq, 1H, J ) 15.2
Hz, 6.3 Hz, 1.6 Hz), 3.93 (m, 2H), 1.74 (ddt, 3H, J ) 6.5 Hz,
1.6 Hz, 1.3 Hz). 13C NMR (CDCl3): δ 18.1, 43.7, 93.0, 125.3,
130.8, 162.0. EIMS m/z 182 (16), 180 (25), 55 (100). HRMS
calculated for C6H8NOCl3Na: 237.9569. Found: 237.9567.
2-E-Bu ten -1-a m in e (9). A mixture of molten 8 (29.4 g,
0.136 mol) in 9 mL of DMF was added to 345 mL of 3 M KOH
in several portions over the course of 30 min, resulting in a
slightly exothermic reaction. After stirring at room tempera-
ture for 2 h, the reaction mixture was extracted with diethyl
ether (4 × 60 mL). The combined ethereal layer was washed
with brine (4 × 30 mL), dried over KOH pellets, and filtered.
(27) For reviews on R2NLi structures, see: (a) Gregory, K.; Schleyer,
P. v. R.; Snaith, R. Adv. Inorg. Chem. 1991, 37, 47. (b) Mulvey, R. E.
Chem. Soc. Rev. 1991, 20, 167. (c) Collum, D. B. Acc. Chem. Res. 1993,
26, 227. (d) Mulvey, R. E. Chem. Soc. Rev. 1998, 27, 339.
(28) (a) Overman, L. E. J . Am. Chem. Soc. 1976, 98, 2901. (b) J ordis,
U.; Grohmann, F.; Kuenburg, B. Org. Prepr. Proc., Int. 1997, 5, 549.
(29) Trofimov, B. A. Bull. Acad. Sci. USSR Div. Chem. Sci. 1979,
28, 2195.
(30) Thompson, T. W Chem. Commun. 1968, 532.

Synthesis of 2,3-Disubstituted Pyrroles
J . Org. Chem., Vol. 67, No. 1, 2002 37
Prepared from benzoic anhydride. Flash column chroma-
tography, using 1:4 dichloromethane:pentane, with 0.5% tri-
ethylamine as the eluent gave 3c as a colorless oil in 41% yield.
Prepared from N,N-dimethylbenzamide. Preparative thin-
layer chromatography, using 1:3.5 ethyl acetate:hexanes as
the eluent, followed by further purification by flash column
chromatography with 1:4 ethyl acetate:hexanes as the eluent,
gave 3d as a colorless oil in 46% yield.
HRMS calculated for C11H11N: 157.0891. Found 3b: 157.0894,
3c: 157.0888, 3d : 157.0894.
Ack n ow led gm en t. This work was supported by
PHS grant GM35980. HRMS were performed by Dr.
Tun-Li Shen, Brown University.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C NMR of
compounds 1, 3a , 3b, and 8. This material is available free of
charge via the Internet at http://pubs.acs.org.
1H NMR (CDCl3): δ 8.15 (br, 1H), 7.45 (m, 4H), 7.25 (m,
1H), 6.8 (t, 1H), 6.2 (t, 1H), 2.3 (s, 3H). 13C NMR (CDCl3): δ
12.8, 112.1, 116.2, 117.7, 126.0, 126.8, 128.5, 128.9, 133.8.
EIMS m/z 157 (75, M+), 156 (100), 128 (14), 77 (10), 51 (8).
J O015638N