Convenient synthesis of polyfunctionalized β-fluoropyrroles from rhodium(II)-catalyzed intramolecular N-H insertion reactions

Article abstract of DOI:10.1021/ol0275670

(Matrix presented) Polyfunctionalized β-fluoropyrrole can be readily prepared from rhodium(II) acetate-catalyzed intramolecular N-H insertion reaction of δ-amino-γ,γ-difluoro-α-diazo-β -ketoesters. A cyanomethylene group can be introduced at C-3 of the py

Full text of DOI:10.1021/ol0275670

ORGANIC
LETTERS
2003
Vol. 5, No. 5
745-748
Convenient Synthesis of
Polyfunctionalized â-Fluoropyrroles from
Rhodium(II)-Catalyzed Intramolecular
N−H Insertion Reactions
Yanli Wang and Shizheng Zhu*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai, 200032, P. R. China
zhusz@pub.sioc.ac.cn
Received December 29, 2002
ABSTRACT
Polyfunctionalized â-fluoropyrrole can be readily prepared from rhodium(II) acetate-catalyzed intramolecular N−H insertion reaction of δ-amino-
γ,γ-difluoro-r-diazo-â-ketoesters. A cyanomethylene group can be introduced at C-3 of the pyrrole ring through the Wittig reaction of the
diazo compounds followed by rhodium(II)-catalyzed intramolecular N−H insertion reactions.
Replacement of hydrogen by fluorine in biologically active
molecules often yields analogues with improved reactivity
and selectivity due to the unique physical and chemical
properties of fluorine and C-F bond.1 Polysubstituted
pyrroles are highly biologically active molecules and con-
stitute important classes of natural products and synthetic
pharmaceuticals,2 and certain naturally occurring halopyrroles
exhibit a strong antibacterial activity.3 Therefore, it is
interesting to introduce fluorine into the pyrrole ring. In fact,
fluoropyrroles have been shown to be valuable targets for
elaboration to porphyrins4 and for the preparation of com-
pounds of agricultural and medicinal interest. There have
been several methods for synthesizing fluoropyrroles. (a) One
method is the introduction of fluorine into a preformed
pyrrole either by direct fluorination or by substitution of a
functional group. Xenon difluoride was used for direct
fluorination at the R-position of a 1-methylpyrrole unit in a
drug and was also used for fluorination at the R-position of
simple N-H pyrroles bearing electron-withdrawing groups
in the R′-position.5 The fluorodecarboxylation reaction of
R-pyrrole carboxylic acids with F-TEDA-BF4 gave the
corresponding R-fluoropyrroles in mild yields.6 â-Fluoro-
pyrrole could also be obtained via a modified Schiemann
(1) (a) Ramachandran, P. V. In Asymmetric Fluoroorganic Chemistry:
Synthesis, Applications, and Future Directions; ACS Symposium Series
746; American Chemical Society: Washington, DC, 2000. (b) Ojima, I.;
McCarthy, J. R.; Welch, J. T. In Biomedical Frontiers of Fluorine
Chemistry; ACS Symposium Series 639; American Chemical Society:
Washington, DC, 1996. (c) Kukhar’, V. P.; Soloshonok, V. A. In Fluorine-
containing Amino Acids: Synthesis and Properties. Wiley: New York, 1995.
(d) Welch, J. T. In SelectiVe Fluorination in Organic and Bioorganic
Chemistry; ACS Symposium Series 456; American Chemical Society:
Washington, DC, 1991. (e) Welth, J. T.; Eswarakrishnan, S. In Fluorine in
Bioorganic Chemistry; Wiley & Sons: New York, 1991.
(2) (a) Lehuede, J.; Fauconneau, B.; Barrier, L.; Ourakow, M.; Piriou,
A.; Vierfond, J.-M. Eur. J. Med. Chem. 1999, 34, 991. (b) Katritzky, A.
R.; Rees, C. W. In ComprehensiVe Heterocyclic Chemistry; Bird, C. W.,
Cheeseman, G. W. H., Eds.; Pregamon Press: Oxford; Vol. 4, p 370 and
references therein.
(3) Koyama, M.; Kodama, Y.; Tsurukoa, T.; Ezaki, N.; Niwa, T.; Inouye,
S. J. Antibiot. 1981, 34, 1569.
(4) (a) Ono, A.; Kawamura, H.; Maruyama, K. Bull. Chem. Soc. Jpn.
1989, 62, 3386. (b) Ando, A.; Shinada, T.; Kinishita, S.; Arimura, N.;
Koyama, M.; Nagai, T.; Miki, T.; Kumadaki, I.; Sato, H. Chem. Pharm.
Bull. Jpn. 1990, 38, 2175.
(5) Wang, J.; Scott, A. I. Tetrahedron Lett. 1994, 35, 3697.
(6) Wang, J.; Scott, A. I. J. Chem. Soc., Chem. Commun. 1995, 2399.
10.1021/ol0275670 CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/08/2003

reaction.7 Recently, Barnes and co-workers performed an
electrophilic fluorination at the â-position of 1-(triiso-
propylsilyl)pyrrole and a highly functionalized pyrrole with
N-fluorobenzenesulfonimide via their â-lithio derivatives.8
(b) Another method is the preparation of an acyclic precursor
and its subsequent cyclization. Burton synthesized 2,5-
disubstituted â-fluoropyrroles in high yields from the cy-
clization reaction of R,R-difluoro-iodo ketones under basic
conditions.9 (c) A third method is a one-step synthesis of
fluorinated pyrroles by 1,3-dipolar cycloaddition of fluorine-
containing compounds. Thermolysis of aziridine-2-carbox-
ylates in the presence of chlorotrifluoroethylene resulted in
3,4-difluoropyrroles.10 1,3-Dipolar reaction of ylide formed
from domino reactions of imines with difluorocarbene with
electron-deficient alkynes led to 2-fluoropyrrole derivatives.11
However, these methods still suffer from the disadvantage
of multistep preparation or limited application. A general
synthetic route to fluoropyrroles, particularly to those
containing additional functionality appropriate for subsequent
formation of biologically interesting molecules, is still not
available due to both the high reactivity of pyrroles toward
electrophiles and the oxidizing power of electrophilic
fluorinating reagents.
be obtained by simply treating it with 4 Å molecular sieves
in benzene for 1-2 h. Subsequent diazo transfer reaction of
3a-j with p-methylbenzenesulfonyl azide and triethylamine
yielded the corresponding δ-amino-γ,γ-difluoro-R-diazo-â-
ketoesters 4a-j in 71 to 90% yields, respectively. All of
the diazo compounds 4a-j were stable to purification by
silica gel chromatography.
After treating diazo compounds 4a-h with 0.5 mol %
rhodium(II) acetate in toluene at 80 °C for 30 min, TLC
and 19F NMR indicated the disappearance of the diazo
compounds along with formation of two new substrates. The
1H NMR and 19F NMR spectra showed that the crude
mixtures contained intramolecular N-H insertion products
5a-h and HF elimination products 6a-h (Scheme 2). Slow
Scheme 2
With increasing frequency, the intramolecular N-H inser-
tion reaction of diazo compounds catalyzed by a transition-
metal provides a powerful strategy for nitrogen heterocyclic
synthesis, especially five-membered nitrogen cycles.12 Here
we report a convenient and versatile method for the synthesis
of polyfunctionalized â-fluoropyrroles by Rh2(OAc)4-
catalyzed intramolecular N-H insertion reaction of di-
fluorinated diazo compounds.
Recently, we reported that the Zn-CuCl-promoted Re-
formatsky-imine addition reaction of 4-bromo-4,4-difluoro-
acetoacetate with aldimines provided efficient and practical
access to δ-amino-γ,γ-difluoro-â-ketoesters 3a-j (Scheme
1).13 Due to the strong electron-withdrawing ability of
conversion of 5a-h into 6a-h was observed upon standing
at room temperature. Moreover, conducting the reaction in
refluxing toluene converted 5a-h to 6a-h completely within
6-12 h. Thus, in the presence of 0.5 mol % rhodium (II)
acetate, 4a-h were first heated in toluene at 80 °C for 0.5
h, and then the reaction mixtures were refluxed in toluene
for another 6-12 h, giving â-fluoropyrroles 6a-h as the
sole products. The reaction time and yields of products 6a-h
are summarized in Table 1. Variation of R1 and R3 substit-
uents in 4a-h did not have a great effect on the yields; even
diazo compound 4f with R3 as a bulky 2-naphthyl could
generate the corresponding pyrrole 6f in 80% yield (Table
1, entry 6). However, in the case of the Rh2(OAc)4-catalyzed
reaction of 4h with R3 as a benzyl group, we could not detect
the C-H insertion intermediate 5h, but only the final pyrrole
product 6h (Table 1, entry 7). We assumed that the HF
elimination reaction proceeded more quickly in this case than
the other diazo compounds with the nitrogen atom substituted
by an aryl group since the electron density in the nitrogen
Scheme 1
(7) Onda, H.; Toi, H.; Ogoshi, H. Tetrahedron Lett. 1985, 26, 4221.
(8) McClinton, M. A.; McClinton, D. A. Tetrahedron 1992, 48, 6555.
(9) (a) Qiu, Z. M.; Burton, D. J. Tetrahedron Lett. 1994, 35, 4319. (b)
Qiu, Z. M.; Burton, D. J. Tetrahedron Lett. 1995, 36, 5119.
(10) (a) Leroy, J.; Rubinstein, M.; Wakselman, C. J. Fluorine Chem.
1984, 25, 255. (b) Leroy, J.; Wakselman, C. Tetrahedron Lett. 1994, 35,
8605.
(11) Novikov, M. S.; Khlebnikov, A. F.; Sidorina, E. S.; Kostikov, R.
R. J. Chem. Soc., Perkin Trans. 1 2000, 231.
(12) (a) Davies, F. A.; Fang, T. N.; Goswami, R. Org. Lett. 2002, 4,
1599. (b) Honma, T.; Tada, Y.; Adachi, I.; Igarashi, K. Heterocycles 1989,
629. (c) Moyer, M. P.; Feldman, P. L.; Rapoport, H. J. Org. Chem. 1985,
50, 5223.
difluoromethylene, the adjacent carbonyl to difluorometh-
ylene in 3a-h had a marked proclivity for becoming
hydrated. A complete dehydration of the substrates could
(13) Wang, Y. L.; Zhu, S. Z. Synthesis 2002, 13, 1813.
746
Org. Lett., Vol. 5, No. 5, 2003

difluorinated vinyldiazomethanes 7 in medium yields, exist-
ing as a mixture of (Z)-/(E)-isomers of the double bond
(Scheme 3). The configuration of the double bond in 7 was
Table 1. Rh2(OAc)4-Catalyzed Intramolecular N-H Insertion
Reactions of 4
entry
4
time (h)
pyrroles 6
yield (%)
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
12
20
10
12
9
10
10
10
6
6a
6b
6c
6d
6e
6f
91
95
93
92
90
93
91
93
Scheme 3
6g
6h
10
4j
4
atom of 4h was less delocalized. The mechanism for pyrrole
formation involved insertion of the rhodium carbenoid into
the adjacent N-H bond to first produce 4,4-difluoro-5-
phenylpyrrolidine-2-carboxylate 5, which then underwent HF
elimination promoted by the lone â-electron pair on the
nitrogen atom to yield the final pyrroles. All of the
â-fluoropyrroles were stable in air except substrate 6g with
R1 as a furyl substitutent, which gradually became brown
upon standing at room temperature. The formation of the
â-fluoropyrroles 6a-h was strongly supported by their NMR
spectroscopic data. In particular, the 19F NMR spectra (282
MHz, CDCl3) of 6a-h showed the indicative single peak
of a fluorine atom on the pyrrole ring in a narrow range
from δ -174 to -179 ppm. The 1H NMR spectra signal of
6a-h (300 MHz, CDCl3) indicated the identical 3-OH at δ
8.23-8.76 ppm. However, the reaction of diazo compounds
4i and 4j containing quaternary substitution at C-5 with 1
mol % Rh2(OAc)4 in toluene at 80 °C or reflux resulted in
a complex mixture of products that could not be character-
ized. We were unable to identify any of the products, making
it impossible to determine whether the products resulted from
decomposition of insertion products or the reaction took an
entirely different path.
determined by 1H NMR. The (Z)-isomer with difluorometh-
ylene and cyano group on the same side showed the signal
of an alkenyl proton at a lower field than that of the (E)-
isomer.15 The (Z)- and (E)-isomer of compound 7i could be
separated by column chromatography.
Treating vinyldiazomethanes 7e and 7h (R2 ) hydrogen
atom) with 1 mol % Rh2(OAc)4 in refluxing toluene provided
3-cyanomethylene-substituted pyrroles 8e and 8h in 94 and
85% yields, respectively (Scheme 4). The assignment of the
Scheme 4
The former rhodium(II)-catalyzed cyclization intra-
molecular N-H insertion reaction of δ-amino-γ,γ-difluoro-
R-diazo-â-ketoesters, however, does not allow the introduc-
tion of other substituents except for the hydroxyl group to
the C-3 position of the pyrrole ring. To elaborate the utility
of this method and introduce more useful functional groups
into the pyrrole ring, we further investigated the intra-
molecular N-H insertion reaction of vinyldiazomethanes.
Although the rhodium(II)-catalyzed intermolecular X-H (X
) O, N, S, Si, etc.) insertion reactions of vinyldiazoesters
have been previously studied,14 the intramolecular N-H
insertion reaction of vinylcarbenoids has not been reported
until now.
1
structure of 8e and 8h was based on their characteristic H
NMR and 13C NMR spectra. We believe that the reaction
proceeded via the insertion of vinylcarbenoids into the N-H
bond, double-bond migration into the cycle, and subsequent
HF elimination reaction. We also observed that the (Z)-
isomer of 7 reacted much faster than the (E)-isomer. This
was usually due to the weaker hindrance of the substituents
The Wittig reaction of diazo ketoesters 4e, 4h, and 4i with
Wittig reagent triphenylphosphoranylideneacetonitrile (Ph3Pd
CHCN) proceeded readily at 55 °C in toluene, affording
(14) (a) Landais, Y.; Planchenault, D. Synlett 1995, 1191. (b) Davies,
H. M. L.; Smith, H. D.; Korkov, O. Tetrahedron Lett. 1987, 28, 1853. (c)
Priyadarshanie, B.; Yannick, L.; Liliana, P.-R.; Denis, P.; Valery, W. J.
Org. Chem. 1997, 62, 1630.
(15) (a) Zhang, X. G.; Qing, F. L.; Yang, Y. G.; Yu, J.; Fu, X. K.
Tetrahedron Lett. 2000, 41, 2953. (b) Allmendinger, T.; Lang, R. W.
Tetrahedron Lett. 1991, 32, 339.
Org. Lett., Vol. 5, No. 5, 2003
747

on the double bond of the (E)-isomer with the ligands on
the catalyst.16
to cleave the C-F bond.18 Therefore, we assumed that 7i
first underwent rhodium (II)-catalyzed intramolecular N-H
insertion reaction, giving the difluorinated dihyropyrrole 9.
Then, the lone electron pair on the nitrogen of 9 led to the
defluorination-hydrolysis reaction to give final product 10.
In conclusion, we have demonstrated a concise and
efficient synthetic protocol for the synthesis of polyfunc-
tionalized â-fluoropyrrole from the rhodium(II) acetate-
catalyzed intramolecular N-H insertion reaction of δ-amino-
γ,γ-difluoro-R-diazo-â-ketoesters. The cyanomethylene group
was introduced at the C-3 position of the pyrrole ring through
the Wittig reaction of the diazo compounds followed by
intramolecular N-H insertion reactions. Hydrolysis of dif-
luoromethylene was observed when aromatization by loss
of HF was not possible. To our knowledge, the functional
substituent on the pyrrole ring could elaborate this kind of
compound as the precursors for the synthesis of fluoro-
analogues of pharmacophores bearing a pyrrole ring related
to the parent compounds.
However, decomposition of 7i containing quaternary
substitution at the 5-carbon in the presence of 1 mol %
Rh2(OAc)4 gave rise to different results (Scheme 4). After
TLC indicated the disappearance of the diazo compounds
and removal of the solvent, the 1H NMR, 19F NMR, and IR
spectra of the crude mixture indicated the formation of pyr-
rolidine 9. However, 9 underwent defluorination-hydrolysis
reaction leading to 10 when exposed to air or purified by
silica gel chromatography. The structure of 10 was deter-
1
mined from its 13C NMR, H NMR, and IR spectra and
further elucidated by X-ray diffraction (Figure 1). Alkyl
Acknowledgment. The authors thank the National Natu-
ral Science Foundation of China (NNSFC) (Nos. 20072049
and 20032010) and the Innovation Foundation of Chinese
Academy of Sciences for financial support. We thank Nicole
J. Bernshaw (CCS, University of Utah) for a critical reading
of the manuscript.
Supporting Information Available: Experimental pro-
cedures and characterization for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Figure 1.
fluorides are less reactive than other halides and do not react
readily in typical nucleophilic displacement reactions because
fluorine forms the strongest single bond with carbon and
because of the poor stability of fluoride as a leaving group.17
It is also reported that the â-electron pair on the atom (O, S,
N, etc.) or on the double bond could attack from the backside
OL0275670
(17) (a) Sharts, C. M.; Sheppard, W. A. In Organic Fluorine Chemistry;
W. A. Benjiamim, Inc.: New York, 1969. (b) Cottrell, T. L. In The Strengths
of Chemical Bonds, 2nd ed.; Butterloorths Scientific Publications: London,
1958.
(18) (a) Shi, G. Q.; Cai, W. J. Org. Chem. 1995, 60, 6289. (b) Tdannley,
R. L.; Taborsky, R. C. J. Org. Chem. 1957, 22, 77. (c) Barr, D. A.;
Haszeldine, R. N. J. Chem. Soc. 1956, 3416, 3428. (d) Bauks, R. E.; Chang,
W. M.; Hazseldine, R. N. J. Chem. Soc. 1962, 3407.
(16) Davies, Huw, M. L.; Ahmed, G.; Churchill, M. R. J. Am. Chem.
Soc. 1996, 118, 10774.
748
Org. Lett., Vol. 5, No. 5, 2003