Rhodium Complex-Catalyzed Reaction of Isonitriles with Carbonyl Compounds: Catalytic Synthesis of Pyrroles

Article abstract of DOI:10.1021/ol0069296

(Matrix Presented) Low-valent rhodium complexes are efficient catalysts for the activation of α-C-H bond of isonitriles. Addition of isonitriles to carbonyl compounds proceeds under mild and neutral conditions to give the corresponding α,β-unsaturated for

Full text of DOI:10.1021/ol0069296

ORGANIC
LETTERS
2
001
Vol. 3, No. 3
21-424
Rhodium Complex-Catalyzed Reaction of
Isonitriles with Carbonyl Compounds:
Catalytic Synthesis of Pyrroles
4
Hikaru Takaya, Sachiko Kojima, and Shun-Ichi Murahashi*
Department of Chemistry, Graduate School of Engineering Science, Osaka UniVersity,
1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan
mura@chem.es.osaka-u.ac.jp
Received November 28, 2000
ABSTRACT
Low-valent rhodium complexes are efficient catalysts for the activation of r-C−H bond of isonitriles. Addition of isonitriles to carbonyl compounds
proceeds under mild and neutral conditions to give the corresponding r,â-unsaturated formamides. Catalytic synthesis of pyrroles can be
performed by cyclocondensation of isonitriles with 1,3-dicarbonyl compounds.
We have been investigating transition-metal-catalyzed C-H
bond activations induced by R-heteroatom effects. Upon
carbon-carbon bond at the R-position of isonitriles under
neutral conditions. Herein, we wish to report that rhodium-
catalyzed addition of isonitriles to carbonyl compounds
occurs to give the corresponding R,â-unsaturated formamides
(eq 1) and also the application of this method for catalytic
synthesis of pyrroles from 1,3-dicarbonyl compounds and
isonitriles (eq 2).
1
treatment with low-valent transition-metal complexes, activa-
2
3,4
tions of R-C-H bond of amines and nitriles can be
performed efficiently. In the case of nitriles, the activated
intermediates can be trapped with electrophiles to form
carbon-carbon bonds at the R-position of nitriles under
neutral and mild reaction conditions. This concept led us to
find rhodium-catalyzed activation of C-H bonds R to
isonitriles which have strong coordination ability toward
metals (Scheme 1). Capture of the R-metalated intermediate
Scheme 1
thus formed with electrophiles such as carbonyl compounds
provides a highly useful method for the formation of a
In the presence of 5 mol % of rhodium carbonyl complex,
Rh (CO) (1), the reaction of isonitriles such as ethyl
4
12
isocyanoacetate (2) with ketones took place to give the
corresponding R,â-unsaturated formamides, which are con-
(
1) For a review on C-H activations by the R-heteroatom effect, see:
Murahashi, S.-I.; Naota, T. Bull. Chem. Soc. Jpn. 1996, 69, 1805.
2) (a) Murahashi, S.-I.; Hirano, T.; Yano, T. J. Am. Chem. Soc. 1978,
(
1
00, 348. (b) Murahashi, S.-I.; Watanabe, T. J. Am. Chem. Soc. 1979, 101,
(4) (a) Naota, T.; Taki, H.; Mizuno, M.; Murahashi, S.-I. J. Am. Chem.
Soc. 1989, 111, 5954. (b) Murahashi, S.-I.; Naota, T.; Taki, H.; Mizuno,
M.; Takaya, H.; Komiya, S.; Mizuho, Y.; Oyasato, N.; Hiraoka, M.; Hirano,
M.; Fukuoka, A. J. Am. Chem. Soc. 1995, 117, 12436. (c) Takaya, H.; Naota,
T.; Murahashi, S.-I. J. Am. Chem. Soc. 1998, 120, 4244.
7
429.
(3) For reviews on C-H activations of nitriles, see: (a) Murahashi, S.-
I.; Takaya, H. Acc. Chem. Res. 2000, 33, 225. (b) Naota, T.; Murahashi,
S.-I.; Takaya, H. Chem. ReV. 1998, 98, 2599.
1
0.1021/ol0069296 CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/16/2001

sidered to be important precursors of N-formylamino acid
ethyl esters. Representative results of the formation of R,â-
of isonitriles because of their stronger coordination ability
to metals. Rhodium carbonyl complex Rh (CO)12 (1) has
4
5
8
unsaturated formamides are shown in Table 1 (entries 1 and
proven to be the best catalyst among the catalysts examined.
Mononuclear rhodium hydride complexes such as RhH(CO)-
3 3 3 4
(PPh ) and RhH(PPh ) are also good catalysts and gave
the formamide 3 in 77% and 70% yields, respectively.
Importantly, the present reaction can be applied to the
catalytic synthesis of pyrroles upon treatment with 1,3-
dicarbonyl compounds. Pyrroles are one of the most impor-
tant classes of heterocyclic compounds, because these are
readily conducted to important compounds such as porphy-
Table 1. Rhodium-Catalyzed Reactions of Ethyl
Isocyanoacetate (2) with Carbonyl Compoundsa
9
10
rins and polypyrroles. Pyrroles have been conventionally
prepared by base-promoted reactions: (i) cyclocondensation
of primary amines with 1,4-dicarbonyl compounds (Paal-
11
Knorr synthesis), (ii) cyclocondensation of R-aminoketones
or R-oximesters with 1,3-dicarbonyl compounds (Knorr
11
synthesis), and (iii) reactions of isonitriles with nitoroolefins
1
2
(
Barton synthesis); however, these methods are composed
of more than two reactions and require stoichiometric
amounts of strong bases which produce significant amounts
of waste salts. Some examples of catalytic synthesis of
13
pyrroles have been reported; however, development of new
catalytic methods which proceed highly efficiently and
selectively under neutral conditions still remained to be
explored.
In the presence of catalyst 1, cyclocondensation of ethyl
isocyanoacetate (2) with various 1,3-dicarbonyl compounds
proceeds to give the corresponding ethyl pyrrole-2-carboxy-
lates highly selectively (Table 1). When 2,4-pentanedione
was used, the condensation product, 3,5-dimethylpyrrole-2-
carboxylate (4), was obtained exclusively in 84% yield (entry
3
). The resultant pyrroles could be readily isolated by short-
pass column chromatography or bulb-to-bulb distillation as
an analytically pure product. Importantly, a medium-gram
scale reaction can be also employed to give 4 in 81% yield.
The rhodium-catalyzed reactions gave 2,3,4,5-tetrasubstituted
pyrroles in moderate yields (5a; 68%, 5b; 52%) (entry 4),
although poor yields have been obtained by conventional
1
1c
methods with strong bases (10-45%).
The efficiency of the present reaction is demonstrated by
regioselective synthesis of pyrroles, which are nearly unac-
cessible by conventional methods such as Knorr synthesis.
The cyclocondensation of 2 with asymmetric 1,3-dicarbonyl
a
A mixture of 1,3-dicarbonyl compound (2.0 mmol), ethyl isocyanoac-
etate (2) (1.0 mmol), and Rh4(CO)12 (1) (0.0075 mmol, 3 mol% based on
Rh) in dry toluene (0.5 mL) was stirred under an argon atmosphere for 4
h at 80 °C. Isolated yield based on 2. Reaction temperature, 25 °C.
b
c
1
3
compounds (R * R in eq 2) gives pyrroles regioselectively
on the basis of either steric effects or electronic effects. Thus,
2). The reaction of 2 with ketones induced by stoichiometric
(8) Bancroft, G. M.; Garrod, R. E. B.; Maddock, A. G.; Mays, M. J.;
amounts of strong bases such as butyllithium has been
reported to give the corresponding formamides. It is
noteworthy that the products derived from R-C-H activation
of carbonyl compounds are not formed, although carbonyl
Prater, B. E. J. Am. Chem. Soc. 1972, 94, 647.
6
(9) Kim, J. B.; Adler, A. D.; Longo, F. R.; Paine, J. B. In The Porphyrins;
Dolphin, D., Ed.; Academic Press: New York, 1978; Vol. 1, pp 85-234.
(10) Jones, R. A. In The Chemistry of Heterocyclic Compounds, Vol.
4
8, Pyrroles, Part 2; Taylor, E. C., Ed.; Wiley: New York, 1990.
(11) (a) Jackson, A. H.; Smith, K. H. In The Total Synthesis of Natural
a
compounds generally show lower pK values than those of
Products; ApSimon, J., Ed.; Wiely: New York, 1973; Vol. 1, pp 143-
278. (b) Jones, R. A.; Bean, G. P. In The Chemistry of Pyrroles; Blomquist,
A. T., Wasserman, H. H., Eds.; Academic Press: London, 1977. (c)
Patterson, J. M. Synthesis 1976, 281.
7
the corresponding isonitriles. This result suggests that the
C-H activation occurs chemoselectively at the R-position
(
12) (a) Barton, D. H. R.; Zard, S. Z. J. Chem. Soc., Chem. Commun.
(
5) (a) Noyori, R.; Ohta, M.; Hisiao, Y.; Kitamura, M.; Ohta, T.; Takaya,
1985, 1098. (b) Barton, D. H. R.; Kervagoret, J.; Zard, S. Z. Tetrahedron
1990, 46, 7587.
(13) (a)Murahashi, S.-I.; Shimamura, T.; Moritani, I. J. Chem. Soc.,
Chem. Commun. 1974, 931. (b) Utimoto, K.; Miwa, H.; Nozaki, H.
Tetrahedron Lett. 1981, 22, 4277. (c) Chatani, N.; Hanafusa, T. J. Org.
Chem. 1991, 56, 2166. (d) Tsutsui, H.; Narasaka, K. Chem. Lett. 1999, 45.
H. J. Am. Chem. Soc. 1986, 108, 7117. (b) Kitamura, M.; Hsiao, Y.; Noyori,
R.; Takaya, H. Tetrahedron Lett. 1987, 28, 4829.
(
6) Sch o¨ llkopf, U.; Gerhart, F.; Schr o¨ der, R. Angew. Chem., Int. Ed. Engl.
969, 8, 672.
7) Castejon, H. J.; Wiberg, K. B. J. Org. Chem. 1998, 63, 3937.
1
(
422
Org. Lett., Vol. 3, No. 3, 2001

the reaction of 2 with benzoylacetone gave the corresponding
pyrrole 6a selectively (6a/6b ) 88/12) (entry 5). The
structure of the isomer 6a was determined by NOE experi-
3-fluoro-2,4-pentanedione gave 3-fluorinated pyrrole 9 (entry
8). Regioselective synthesis of fluorinated pyrroles can be
also performed. The reaction of 2 with 2,2-dimethyl-
6,6,7,7,8,8,8-heptafluoro-3,5-octanedione gave 5-tert-butyl-
substituted pyrrole 10 exclusively (entry 9).
14
ments and X-ray structure analysis (Figure 1). The reaction
The mechanism for the present reaction can be rationalized
by assuming the R-C-H activation of isonitriles shown in
Scheme 2. Coordination of isonitrile 2 to the low-valent
Scheme 2
Figure 1. The X-ray structure of 6a.
of 2 with 1,1,1-trimethyl-2,4-pentanedione gave 5-tert-butyl-
substituted regioisomer 7 exclusively (entry 6). It is note-
worthy that ethyl 2,4-dioxovalerate, which has an electron-
withdrawing ester group, gave 3-ethoxycarbonyl-substituted
regioisomer 8 exclusively (entry 7). The structure of isomer
rhodium complexes RhL
n
3
(L ) CO, RNC, PR ) gives
8
was unequivocally determined by X-ray structural analysis
isonitrile complex 11, and subsequent C-H activation at the
R-position of isonitriles could occur to afford isocyanoalkyl-
rhodium intermediate 12. Insertion of the carbonyl com-
pounds to the rhodium-carbon bond of 12 followed by either
reductive elimination or protonation would give 13 and 11
to complete the catalytic cycle. Dehydration and hydration
would give the formamide 14 under the reaction conditions.
In the case of the reaction of 1,3-dicarbonyl compounds,
intermediate 15 will be formed in place of 14. Rhodium-
1
4
(Figure 2). The resultant pyrroles thus obtained can be
1
9
promoted decarbonylation of formamide 15 followed by
cyclocondensation of enamino intermediate 16 would give
the corresponding pyrrole 17 (Scheme 3). The rhodium-
Scheme 3
Figure 2. The X-ray structure of 8.
catalyzed decarbonylation was confirmed by decarbonylation
readily converted to the corresponding porphyrins. Actually,
octamethylporphyrin was readily obtained from ethyl 3,4,5-
of N-phenylformamide. In the presence of 5 mol % of
15
(16) For the synthesis of fluorinated pyrroles, see: (a) Kaesler, R. W.;
Legoff, E. J. Org. Chem. 1982, 47, 4779. (b) Ogoshi, H.; Homma, M.;
Toi, H.; Aoyama, Y. Tetrahedron Lett. 1983, 24, 929. (c) Burton, D. J.;
Qiu, Z.-M. Tetrahedron Lett. 1994, 35, 4319. (d) Wang, J.; Scott, A. I.
Tetrahedron 1994, 50, 6181. (e) Leroy, J.; Wakselman, C. Tetrahedron
Lett. 1994, 35, 8605.
(17) (a) Onda, H.; Toi, H.; Aoyama, Y.; Ogoshi, H. Tetrahedron Lett.
1985, 26, 4221. (b) Tsuchiya, S.; Seno, M. Chem. Lett. 1989, 263. (c)
Woller, E. K.; DiMagno, S. G. J. Org. Chem. 1997, 62, 1588. (d) Leroy,
J.; Bondon, A.; Toupet, L.; Rolando, C. Chem. Eur. J. 1997, 3, 1890. (e)
Murahashi, S.-I.; Naota, T.; Komiya, N. Tetrahedron Lett. 1995, 36, 8059
and references therein.
trimethylpyrrole-2-carboxylate (5a) by the literature method.
The efficiency of the present reaction is highlighted by
16
the synthesis of fluorinated pyrroles, which are currently
the subject of much attention as important building blocks
17
for the synthesis of fluorinated porphyrins and biologically
1
8
active substances. Thus, the cyclocondensation of 2 with
(
14) For details see, the Supporting Infromation.
(15) Paine, J. B., III.; Kirshner, W. B.; Moskowitz, D. W.; Dolphin, D.
J. Org. Chem. 1976, 41, 3857.
(18) Welch, J. T. Tetrahedron 1987, 43, 3123.
Org. Lett., Vol. 3, No. 3, 2001
423

catalyst 1, decarbonylation of N-phenylformamide proceeds
to give aniline nearly quantitatively under similar reaction
conditions. The observed regioselectivity could be ascribed
to the selective addition of 12 to the carbonyl group of the
The present rhodium complex-catalyzed reactions of
isonitriles will provide wide scope of both catalytic trans-
formations of isonitriles and new methods for the catalytic
synthesis of pyrroles. The key step of the present reaction is
the activation of the R-C-H bond of isonitriles induced by
3
1
1,3-dicarbonyl compounds. When R is larger than R , the
addition of the bulky isocyanoalkylrhodium intermediate 12
1,3
the R-heteroatom effect.
1
proceeds at the less hindered carbonyl group adjacent to R ,
3
giving a pyrrole which has bulky substituent (R ) at the
Acknowledgment. This work was supported by the
Research for the Future Program, The Japan Society for the
Promotion of Science, and a Grant-in-Aid for Scientific
Research, the Ministry of Education, Science, Sports, and
Culture, Japan. The authors thank DAIKIN INDUSTRIES,
LTD., and Dr. Yoshichika Kuroki for a generous gift of
3-fluoro-2,4-pentanedione.
5-position. Thus, the reactions of 2 with benzoylacetone and
pivaloylacetone proceed selectively to give 6a and 7,
1
3
respectively. On the other hand, when R is larger than R
and an electron-withdrawing group, selective addition to the
1
carbonyl group adjacent to R would occur predominantly
because of its high electrophilicity, giving a pyrrole which
1
has a bulky and electron-withdrawing substituent (R ) at the
3-postion. Actually, selective formation of 8 was observed
in the reaction of 2 with ethyl 2,4-dioxovalerate. Predominant
formation of 10, which has a bulky tert-butyl substituent at
Supporting Information Available: Experimental pro-
cedures, full characterization for all compounds, and crystal-
lographic data for 6a and 8. This material is available free
charge via the Internet at http://pubs.acs.org.
5-position and a strongly electron-withdrawing heptafluo-
ropropane substituent at the 3-position, is compatible with
the mechanism.
(19) Zahalka, H. A.; Alper, H. Tetrahedron Lett. 1987, 28, 2215.
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