Ruthenium(II) porphyrin-catalyzed amidation of aromatic heterocycles

Article abstract of DOI:10.1021/ol049232j

(Equation Presented) Ruthenium(II) porphyrin-catalyzed amidation of aromatic heterocycles with iminoiodanes under mild conditions (CH ₂Cl₂, 4 A molecular sieves, ultrasound, 40°C) was achieved in moderate to good yields (up to 84%) and conversions (up to 99%). Only the N,N-ditosylamidated product was obtained for reactions involving heteroarenes, where X = O, S, or NTs. N-Alkyl- and N-aryl-substituted pyrroles, on the other hand, were shown to give the 3,4-diaminated adduct.

Full text of DOI:10.1021/ol049232j

ORGANIC
LETTERS
2
004
Vol. 6, No. 14
405-2408
Ruthenium(II) Porphyrin-Catalyzed
Amidation of Aromatic Heterocycles
2
Ling He, Philip Wai Hong Chan, Wai-Man Tsui, Wing-Yiu Yu, and Chi-Ming Che*
Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of
Molecular Technology for Drug DiscoVery and Synthesis, The UniVersity of Hong
Kong, Pokfulam Road, Hong Kong, P. R. China
cmche@hku.hk
Received April 27, 2004
ABSTRACT
2 2
Ruthenium(II) porphyrin-catalyzed amidation of aromatic heterocycles with iminoiodanes under mild conditions (CH Cl , 4 Å molecular sieves,
ultrasound, 40 °C) was achieved in moderate to good yields (up to 84%) and conversions (up to 99%). Only the N,N-ditosylamidated product
was obtained for reactions involving heteroarenes, where X ) O, S, or NTs. N-Alkyl- and N-aryl-substituted pyrroles, on the other hand, were
shown to give the 3,4-diaminated adduct.
2
Transition metal-catalyzed nitrene insertion into C-H bonds
advances, examples of amidation of aromatic C(sp )-H bonds
are sparse in the literature. A recent notable achievement is
that of P e´ rez and co-workers showing that copper(I)-
homoscorpionate complexes can effect benzene amidation
1-6
is increasingly attractive as a C-N bond formation strategy.
2
3
4
Innovative works by Breslow, M u¨ ller, and Du Bois showed
that dirhodium(II,II) complexes with bridging carboxylate
ligands and derivatives are effective catalysts for amidation
6
by PhIdNTs in moderate yields. In the present work, we
describe amidation of C(sp )-H bonds of heteroarenes such
3
2
of saturated C(sp )-H bonds using N-(p-toluenesulfonyl)-
imino-phenyliodinane (PhIdNTs) or “PhI(OAc)
2
+ NH
2
-
as furan, pyrrole and thiophene using ruthenium(II) porphyrin
as a catalyst and PhIdNTs as a nitrogen source. Although
reactions of these heterocycles with metallocarbenoids to give
cyclopropanes are known, examples of protocols for cata-
lytic amidation of heteroarenes have limited precedent in the
literature. It is well-known that amino-functionalized het-
SO R” (usually R ) Ar) as a nitrogen source. Studies in
2
our laboratory demonstrated that highly enantioselective
amidation of saturated C-H bonds can be accomplished
7
5
using chiral ruthenium porphyrin catalysts. Despite these
(1) (a) M u¨ ller, P. In AdVances in Catalytic Processes; Doyle, M. P., Ed.;
JAI Press: Greenwich, CT, 1997; Vol. 2, p 113. (b) Jacobsen, E. N. In
ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yama-
moto, H., Eds.; Springer-Verlag: Berlin, 1999; Vol. 2, p 607. (c) M u¨ ller,
P.; Fruit, C. Chem. ReV. 2003, 103, 2905 and references therein.
(5) (a) Au, S.-M.; Huang, J.-S.; Yu, W.-Y.; Fung, W.-H.; Che, C.-M. J.
Am. Chem. Soc. 1999, 121, 9120. (b) Zhou, X.-G.; Yu, X.-Q.; Huang,
J.-S.; Che, C.-M. Chem. Commun. 1999, 2377. (c) Liang, J.-L.; Yu, X.-Q.;
Che, C.-M. Chem. Commun. 2002, 124. (d) Liang, J.-L.; Yuan, S.-X.; Huang,
J.-S.; Yu, W.-Y.; Che, C.-M. Angew. Chem., Int. Ed. 2002, 41, 3465.
(6) D ´ı az-Requejo, M. M.; Belderra ´ı n, T. R.; Nicasio, M. C.; Trofimenko,
S.; P e´ rez, P. J. J. Am. Chem. Soc. 2003, 125, 12078.
(7) Selected examples: (a) Doyle, M. P.; Chapman, B. J.; Hu, W.;
Peterson, C. S.; McKervey, M. A.; Garcia, C. F. Org. Lett. 1999, 1, 1327
and references therein. (b) Hughes, C. C.; Kennedy-Smith, J. J.; Trauner,
D. Org. Lett. 2003, 5, 4113.
(
2) (a) Breslow, R.; Gellman, S. H. Chem. Commun. 1982, 1400. (b)
Breslow, R.; Gellman, S. H. J. Am. Chem. Soc. 1983, 105, 6728. (c) Yang,
J.; Weinberg, R.; Breslow, R. Chem. Commun. 2000, 531.
(
3) Nageli, I.; Baud, C.; Bernardinelli, G.; Jacquier, Y.; Moran, M.;
M u¨ ller, P. HelV. Chim. Acta 1997, 80, 1087.
4) (a) Espino, C. G.; Du Bois, J. Angew. Chem., Int. Ed. 2001, 40, 598.
b) Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am. Chem. Soc.
001, 123, 6935.
(
(
2
1
0.1021/ol049232j CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/08/2004

erocycles are prevalent in many natural and therapeutic
products of biological significance.8
Scheme 1
Figure 1. Perspective view of 1. Selected bond lengths (Å) and
angles (deg): O(5)-C(1) 1.347(3), N(1)-C(1) 1.404(3), S(1)-
N(1) 1.689(2), C(1)-C(2) 1.334(4), C(2)-C(3) 1.447(5), S(1)-
N(1)-S(2) 122.7(1), C(2)-C(1)-N(1) 128.9(3), C(1)-C(2)-C(3)
At the outset of this study, we found that ultrasound
treatment of furan (1 equiv) with 10 mol % [Ru (TTP)(CO)]
II
[
(
H
2
(TTP) ) meso-tetrakis(tolyl)porphyrin] and PhIdNTs
11
103.1(3).
9
1.5 equiv) in CH
2 2
Cl containing 4 Å molecular sieves at
4
0 °C gave N,N-ditosylamido-2-furan (1) in 73% isolated
10
yield (Table 1, entry 1). The molecular structure of 1 has
the monotosylated amide (i.e., N-furan-2-yl-tolylsulfonamide)
was not detected.
The reason for formation of the N,N-ditosylamidated
product remains ill understood. However, attempts to obtain
the putative monotosylated compound were futile. For
example, conducting the above catalytic reaction in the
presence of a proton source such as TsOH (1.5 equiv) led to
compound 1 in a trace amount (<5%), and no N-furan-2-
yl-tolylsulfonamide was found.
Table 1. Optimization of Reaction Conditionsa
It is noteworthy that employment of both the ultrasound
and Ru catalyst for the amidation reaction was essential. As
shown in Table 1, conducting the reactions without ultra-
sound treatment afforded 1 in lower yields of 41 and 43%
(entries 2 and 5). No conVersion of furan was obserVed in
the absence of ruthenium(II) porphyrin catalyst eVen though
temp
(ïC)
catalyst loading
(mol %)
entry
1c
2
3c,d
4c
5
6
7e
product
% yieldb
40
40
40
40
40
65
40
10
10
10
2
2
2
1
1
1
1
1
1
2
73
41
10
40
43
45
63
ultrasound treatment was employed. A lower product yield
II
(
36%) was obtained on changing the [Ru (TTP)(CO)]
10
II
catalyst to [Ru (F20-TPP)(CO)] [H (F20-TPP) ) meso-
2
a
All reactions were performed in CH2Cl2 for 2 h with a catalyst:
heteroarene:PhIdNTs ratio of 1:1:5 in the absence of ultrasound. Isolated
yield based on the amount of heteroarene consumed. Reaction conducted
with ultrasound treatment. Reaction conducted with 5 equiv of PhIdNTs.
tetrakis(pentafluorophenyl)porphyrin] at a lower catalyst
loading of 5 mol %. In addition, reaction with excess PhId
NTs (5 equiv) was found to be detrimental to product yield,
with 1 being obtained in only 10% yield (entry 3). Furan
amidation with N-(p-nitrophenylsulfonyl)imino-phenyliodi-
b
c
d
e
Reaction conducted with PhIdNNs.
II
nane (PhIdNNs) as a nitrene source and [Ru (TTP)(CO)]
1
1
been established by X-ray crystal analysis (Figure 1).
as a catalyst (10 mol %) can also be accomplished, furnishing
sulfonamide 2 in 63% yield (entry 7). The analogous
ultrasound-assisted reaction of furan with PhIdNTs and
[Rh (CH CO ) ] as a catalyst gave 1 in only 21% yield in
1
Analysis of the crude reaction mixture by H NMR spec-
troscopy and mass spectrometry revealed that 1 was the sole
product. Under our experimental conditions, formation of
2
3
2 4
our hands. Trace quantities of 1 were obtained when the
Rh (CH CO ]-catalyzed reaction was performed without
ultrasound.
In this work, catalytic amidation reactions of some
substituted aromatic heterocycles have also been examined.
The results are summarized in Table 2.
(
8) Selected examples: (a) Lipshutz, B. H. Chem. ReV. 1986, 86, 795.
[
2
3
2 4
)
(
2
1
b) Reymond, J. L.; Pinkerton, A. A.; Vogel, P. J. Org. Chem. 1991, 56,
128. (c) Bossio, R.; Marcaccini, S.; Pepino, R.; Torroba, T. J. Org. Chem.
996, 61, 2202. (d) Marcotte, F.-A.; Rombouts, F. J. R.; Lubell, W. D. J.
Org. Chem. 2003, 68, 6984.
9) Amount of 4 Å molecular sieves employed is equivalent to the amount
by mass) of PhIdNTs used.
(
(
(
10) See Supporting Information for full experimental details.
Subjecting methyl 2-furoate and benzofuran to the protocol
(
11) See Supporting Information. Also, CCDC 219719-219720 contain
II
the supplementary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or
from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
“
ultrasound + [Ru (TTP)(CO)] (10 mol %) + 1.2 equiv of
2 2
PhIdNTs” in CH Cl at 40 °C gave the corresponding N,N-
ditosylamides 3 and 4 in low yields (<20%). However,
1
223 336033; e-mail: deposit@ccdc.cam.ac.uk).
2406
Org. Lett., Vol. 6, No. 14, 2004

furnishing 5 in 57% yield based on 56% substrate conversion,
and 6 in trace amounts for the analogous reaction with
thiophene.
II
Table 2. [Ru (TTP)(CO)]-Catalyzed Amidation of Aromatic
a
Heterocycles with PhIdNTs
Treatment of N-phenylimidazole under the conditions
II
“
ultrasound + [Ru (TTP)(CO)] (10 mol %) + 1.5 equiv of
PhIdNTs” in CH
2 2
Cl at 40 °C, gave rise to a ylide product
8
in 91% yield (entry 8 of Table 2); no amidation product
1
was observed by H NMR analysis of the crude reaction
mixture. Structural determination of 8 was made on the basis
1
13
of H and C NMR spectroscopy and X-ray crystal analysis
1
1
(
see Supporting Information).
II
Under the conditions [Ru (TTP)(CO)] (10 mol %),
PhIdNTs (5 equiv), CH Cl , 40 °C and ultrasound, catalytic
2
2
amidation of N-alkyl- and N-aryl-substituted pyrroles was
achieved and 3,4-diaminated pyrroles 9-15 were obtained
in good to excellent yields (up to 87%) and conversions
(Table 3, entries 1-7). In a few cases, reactions conducted
II
Table 3. [Ru (TTP)(CO)]-Catalyzed Amidation of
N-Substituted Pyrroles with PhIdNTsa
a
Reactions were performed in CH2Cl2 under ultrasound with 4 Å
II
entry
R
product
% yieldb
% conversionc
molecular sieves at 40 °C for 2 h with a [Ru (TTP)(CO)]:heteroarene:
PhIdNTs ratio of 1:10:50. Isolated yield based on the amount of
heteroarene consumed. Values in parentheses denote substrate conversion
determined by GC analysis. Reaction conducted with 1.2 equiv of
PhIdNTs. Reaction conducted with [Ru (F20-TTP)(CO)] (5 mol %) as a
catalyst. Obtained along with 1-phenylisatin in 9% yield. g Reaction
conducted with 1.5 equiv of PhIdNTs.
b
c
1
2
3
4
5
6
7
Me
C H
(o-Me)C H4
(p-Me)C6H4
(p-OMe)C6H4
(p-F)C6H4
9
68
82
60
84
81
50
87
99
99
99
99
99
99
60
d
10
11
12
13
14
15
6
5
e
II
6
f
(p-NO2)C6H4
increasing the amount of PhIdNTs to 5 equiv was found to
afford 3 and 4 in moderate to good substrate yields (up to
a
Reactions were performed in CH2Cl2 under ultrasound with 4 Å
II
molecular sieves at 40 °C for 2 h with a [Ru (TTP)(CO)]:pyrrole:PhIdNTs
b
ratio of 1:10:50. Isolated yield based on the amount of heteroarene
5
8%) and substrate conversions (entries 2 and 4). For
consumed. c Substrate conversion determined by GC analysis.
II
amidation of methyl 2-furoate, when [Ru (F20-TPP)(CO)]
5 mol %) was employed as a catalyst, 3 was obtained in
0% yield with 65% substrate conversion (entry 3). In
comparison, amidation of methyl 2-furoate with [Rh (CH
CO ] as a catalyst gave 3 in trace quantities, and the
(
4
with no Ru catalyst showed that diaminopyrroles 9-11 and
4 could also be obtained, albeit in lower yields of 18-
4%. In this work, amidation of N-methyl- and N-p-
2
3
-
1
5
2 4
)
analogous reaction of benzofuran afforded 4 in 14% yield
and 61% substrate conversion.
2 3 2 4
fluorophenylpyrrole with [Rh (CH CO ) ] as a catalyst
afforded 9 and 14 in 64 and 30% yields, respectively. Under
our experimental conditions, formation of either the 3-monoa-
midated or N,N-tosylamidated products were not detected
by H and C NMR analysis. Moreover, amidation of
N-phenylpyrrole with an equimolar amount of PhIdNTs was
found to give 10 exclusively in 21% yield based on 40%
substrate conversion.
With N-phenylindole as a substrate, the Ru-catalyzed
amidation with 1.5 equiv of PhIdNTs afforded N-monoto-
sylamide 5 as a 1: 1 mixture of 2- and 3-regioisomers in
1
13
6
4% yield (entry 5 of Table 2). The same reaction treated
with 5 equiv of PhIdNTs, however, preferentially gave
-phenylisatin in 77% yield. Reaction of thiophene under
1
these conditions, on the other hand, furnished N,N-ditosyl-
amide 6 in 33% yield with 56% substrate conversion (entry
In this work, we have also examined the “NH
2
Ts +
PhI(OAc) ” protocol for catalytic amidation of heteroarenes.
2
II
6). Similarly, reaction of N-tosylpyrrole was found to give
Treatment of methyl 2-furoate with [Ru (TTP)(CO)] (1.5
mol %), NH Ts (1 equiv), and PhI(OAc) (1 equiv) in 1,2-
the N,N-ditosylamide 7 in 80% yield but with a lower
2
2
substrate conversion of 22% (entry 7). Analogous to the
findings described in earlier sections, [Rh (CH CO ) ] was
2 3 2 4
dichloroethane at 65 °C without ultrasound was found to
give ditosylamide 3 as the sole product in 60% yield with
found to be less effective for amidation of N-phenylindole,
2
15% substrate conversion. With NH Ns as a nitrogen source,
Org. Lett., Vol. 6, No. 14, 2004
2407

tometry under a variety of conditions, no amidation product
1
II
was detected by H NMR and TLC analyses of the crude
Table 4. [Ru (TTP)(CO)]-Catalyzed Amidation of
1
2
a
mixtures. On the basis of this finding, we surmise that the
involvement of a bis(imido)ruthenium(VI) species as a
reactive intermediate in the catalytic reactions is insufficient
to instigate insertion of “NTs” or “NNs” into the aromatic
C-H bond and that amidation could have occurred via an
in situ substrate activation step. In addition, the near
2 2
Heteroarenes with NH Ns and PhI(OAc)
quantitative recovery of 17 (97%) from its reaction with
II
“
NH
2
Ns + PhI(OAc)
2
” in the presence of [Ru (TTP)(CO)]
suggests that formation of the N,N-ditosylamidated product
is unlikely to come from consecutive tosylation of a
monosulfonamide species.
In summary, we describe the first metalloporphyrin-
catalyzed amidation of aromatic heterocycles under mild
conditions. Efforts are currently underway to examine the
scope of the present amidation protocol with respect to other
heteroarene substrates and the possible reaction mechanism.
a
All reactions were carried out in 1,2-dichloroethane with 4 Å molecular
b
sieves at 65 °C. Isolated yield based on the amount of heteroarene
consumed. Values in parentheses denote substrate conversion determined
by GC analysis. [Ru (TTP)(CO)]:heteroarene:NH2Ns:PhI(OAc)2
.5:100:100:100, 12 h. As described in footnote d but with 250 equiv of
NH2Ns and PhI(OAc)2. [Ru (TTP)(CO)]:heteroarene:NH2Ns:PhI(OAc)2 )
:50:100:100, 2 h.
c
d
II
)
e
1
f
II
1
Acknowledgment. We thank Dr. Nian-Yong Zhu for
assistance in solving the crystal structures reported in this
paper. This work is supported by the Area of Excellence
Scheme (AoE/P-10-01) established under the University
Grants Committee (HKSAR), the Hong Kong Research
Grants Council (No. 7099/00P), and the University Develop-
ment Fund of The University of Hong Kong.
up to 76% yield and 60% substrate conversion was achieved
for amidation of methyl 2-furoate (Table 4, entry 1).
Likewise, benzofuran was converted to its N-nosylamide 17
in 50% yield (80% substrate conversion) under similar
reaction conditions (entry 2), and thiophene was converted
to N,N-dinosylsulfonamide 18 in 60% yield (entry 3). Under
similar conditions, the analogous reactions of methyl 2-fu-
roate, benzofuran and thiophene conducted at a higher
catalyst loading of 10 mol % were found to give comparable
product yields and substrate conversions.
Supporting Information Available: Detailed experi-
mental procedures and characterization data, including X-ray
crystallographic analysis. This material is available free of
charge via the Internet at http://pubs.acs.org.
To probe the mechanism of the catalytic reactions, we
OL049232J
examined the stoichiometric amidation of furan and N-
VI
phenylpyrrole with [Ru (TMP)(NTs)
2
] (H
2
(TMP) ) meso-
(12) Reactions conducted in the presence of PhI(OAc)2 or benyzl peroxide
as an additive were found to give similar outcomes (i.e., reduction of
Ru(VI) to Ru(IV) with no amidation product detected). Also, see Supporting
Information for experimental details.
tetrakis(2,4,6-trimethylphenyl)porphyrin). While reduction of
Ru(VI) to Ru(IV) could be observed by UV/vis spectropho-
2408
Org. Lett., Vol. 6, No. 14, 2004