Ruthenium porphyrin catalyzed intramolecular carbenoid C-H insertion. Stereoselective synthesis of Cis-disubstituted oxygen and nitrogen heterocycles

Article abstract of DOI:10.1021/ol034806q

(Matrix presented) A ruthenium porphyrin-catalyzed stereoselective intramolecular carbenoid C-H insertion is described. Using [Ru ^II(TTP)(CO)] as catalyst, aryl tosylhydrazones are converted to 2,3-dihydrobenzofurans, 2,3-dihydroindoles, and β-lactams in good yields and remarkable cis selectivity (up to 99%). Enantioselective synthesis of 2,3-dihydrobenzofurans is also achieved with [Ru^II(D ₄-Por*)(CO)] as catalyst, and up to 96% ee is attained.

Full text of DOI:10.1021/ol034806q

ORGANIC
LETTERS
2003
Vol. 5, No. 14
2535-2538
Ruthenium Porphyrin Catalyzed
Intramolecular Carbenoid C−H Insertion.
Stereoselective Synthesis of
Cis-Disubstituted Oxygen and Nitrogen
Heterocycles
,†
Wai-Hung Cheung,† Shi-Long Zheng,† Wing-Yiu Yu,* Guo-Chuan Zhou,† 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, and Shanghai-Hong Kong Joint Laboratory on
Chemical Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Feng Lin Road, Shanghai 200032, China
cmche@hku.hk
Received May 12, 2003
ABSTRACT
A ruthenium porphyrin-catalyzed stereoselective intramolecular carbenoid C−H insertion is described. Using [RuII(TTP)(CO)] as catalyst, aryl
tosylhydrazones are converted to 2,3-dihydrobenzofurans, 2,3-dihydroindoles, and â-lactams in good yields and remarkable cis selectivity (up
to 99%). Enantioselective synthesis of 2,3-dihydrobenzofurans is also achieved with [RuII(D -Por*)(CO)] as catalyst, and up to 96% ee is attained.
4
Transition-metal-catalyzed carbenoid insertion into a satu-
rated C-H bond is an appealing methodology for construc-
tion of carbon-carbon bonds and natural product synthesis.1
The carbenoid C-H insertions have proven to be a unique
and effective strategy for stereo- and enantioselective
synthesis of five- and four-membered heterocycles.1 Signifi-
cant advances in this area have been made with the Rh-/
Cu-catalyzed decomposition of R-diazo esters, and highly
reactive metal-carbenes are postulated.2,3
Metalloporphyrins for catalytic carbenoid transformations
are receiving growing attention;4,5 in particular, ruthenium
porphyrins4a-d,f-h,5a,c represent a new class of highly robust
catalysts with superior stability (Figure 1). Importantly,
† The University of Hong Kong.
‡ Chinese Academy of Sciences.
(1) For reviews, see: (a) Taber, D. F. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, U.K.,
1991; Vol. 3, p 1045. (b) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern
Catalytic Methods for Organic Synthesis with Diazo Compounds; John
Wiley & Sons: New York, 1998. (c) Doyle, M. P.; Forbes, D. C. Chem.
ReV. 1998, 98, 911. (d) Pfaltz, A. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springler-Verlag: New
York, 1999; Vol. 2, p 513. (e) Lydon, K. M., McKervey, M. A. In
ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yama-
moto, H., Eds.; Springler-Verlag: New York, 1999; Vol. 2, p 539.
(2) For isolation of a stable rhodium carbenoid complex, see: Snyder,
J. P.; Padwa, A.; Stengel, T.; Arduengo, A. J., III; Jockisch, A.; Kim, H.-J.
J. Am. Chem. Soc. 2001, 123, 11318.
(3) For a theoretical study on rhodium-carbenoid, see: Nakamura, E.;
Yoshikai, N.; Yamanaka, M. J. Am. Chem. Soc. 2002, 124, 7181.
10.1021/ol034806q CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/11/2003

In this work, we employed aryl tosylhydrazones as
precursors for in situ generation of diazo compounds, where
handling or accumulation of unstable intermediates can be
avoided.10 Treating the sodium salt of 1a (1 mmol) with [RuII-
(TTP)(CO)] (1 mol %) and n-Bu4NBr (10 mol %) as phase-
transfer catalyst in toluene at 60-70 °C for 48 h afforded
dihydrobenzofuran 2a in 76% isolated yield (Table 1, entry
Table 1. Ru-Catalyzed Intramolecular Carbenoid C-H
Insertion
time yield
cis/
entry
Ru catalyst
PTC
T (°C) (h)
(%) transb
Figure 1. Ruthenium porphyrins.
1
2
3
4
5
6
7
[RuII(TTP)(CO)]
[RuII(TTP)(CO)]
[RuII(TTP)(CO)]
[RuII(TTP)(CO)]
[RuII(OEP)(CO)]
n-Bu4NBr 60-70 48 76 98:2
n-Bu4NBr 110 12
83 >99%c
BnEt3NCl 60-70 48
n-Bu4NBr 110
n-Bu4NBr 60-70 48
77
86
79
79
79
98:2
98:2
98:2
98:2
98:2
2
ruthenium porphyrins react with diazo compounds to afford
ruthenium-carbene complexes,6 some of which have been
structurally characterized.5b-d Here, we report an extensive
study on ruthenium porphyrin catalyzed cyclization of aryl
tosylhydrazones to form cis-2,3-disubstituted 2,3-dihydro-
benzofurans via carbenoid C-H insertion. In the course of
this study, Zheng et al.7 communicated the use of ruthenium
porphyrin for the synthesis of (()-epi-conocarpan. Dihydro-
benzofurans (e.g., lignans and neolignans) are widespread
in nature, and they exhibit a broad range of biological
activities including anticancer effects.8 In this report, we also
describe stereoselective synthesis of cis-disubstituted â-lac-
tams9 by employing the ruthenium-catalyzed protocol.
[RuII(p-F-TPP)(CO)] n-Bu4NBr 60-70 48
[RuII(3,4,5-MeO-
TPP)(CO)]
n-Bu4NBr 60-70 48
8
9
[RuII(TDCPP)(CO)] n-Bu4NBr 60-70 48
12
10
94:6
45:55
[RuII(TMP)(CO)]
n-Bu4NBr 60-70 48
a Isolated yield. b Determined by 1H-NMR. c R,R-d2-1a-Na as substrate,
cis-d2-2a was determined by NMR analysis.
1). 1H NMR analysis revealed that cis-disubstituted product
was predominantly formed (cis/trans ) 98:2) by comparing
the integral ratios of the methyl protons of the cis (0.78 ppm)
and trans isomers (1.38 ppm).11 Using benzyl R,R-d2-alcohol
(98% D), we prepared a deuterium-labeled 1a′. Under the
Ru-catalyzed conditions, facile cyclization of 1a′ to cis-
dihydrobenzofuran 2a′ (ca. 83% yield) was achieved exclu-
sively (Table 1, entry 2). On the basis of 1H NMR and mass
spectroscopic analyses, the deuterium content was conserved
after the cyclization reaction. The NMR spectrum of 2a′
unequivocally reveals that the deuterium atom at the C3
position originates from the benzylic C-D bond. This result
suggests that the Ru-catalyzed cyclization of aryl tosyl-
hydrazones involves cleavage of the benzylic C-H bond as
the principal step.
Other phase-transfer catalysts such as BnEt3NCl are
equally effective for the Ru-catalyzed cyclization of 1a (entry
3). Toluene was found to be the solvent of choice; using
other solvents such as CH2Cl2 and THF resulted in sluggish
reaction and low product yield (<6%) with >90% of the
starting hydrazone being recovered. It is well-known that
[Rh2(CH3CO2)4] is a highly effective catalyst for the analo-
gous C-H insertions. However, in this work, when the
(4) Works by others; see, for example: (a) Smith, D. A.; Reynolds, D.
N.; Woo, L. K. J. Am. Chem. Soc. 1993, 115, 2511. (b) Galardon, E.; Maux,
P. L.; Simonneaux, G. Chem. Commun. 1997, 927. (c) Frauenkron, M.;
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2000, 56, 615. (h) Hamaker, C. H.; Djukic, J.-P.; Smith, D. A.; Woo, L. K.
Organometallics 2001, 20, 5189. (i) Mirafzal, G. A.; Cheng, G.; Woo, L.
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T. C.-W. J. Chem. Soc., Chem. Commun. 1997, 1205. (b) Che, C.-M.;
Huang, J.-S.; Lee, F.-W.; Li, Y.; Lai, T.-S.; Kwong, H.-L.; Teng, P.-F.;
Lee, W.-S.; Lo, W.-C.; Peng, S.-M.; Zhou, Z.-Y. J. Am. Chem. Soc. 2001,
123, 4119. (c) Li, Y.; Huang, J.-S.; Zhou, Z.-Y.; Che, C.-M. J. Am. Chem.
Soc. 2001, 123, 4843. (d) Zheng, S.-L.; Yu, W.-Y.; Che, C.-M. Org. Lett.
2002, 4, 889. (e) Zhang, J.-L.; Che C.-M. Org. Lett. 2002, 4, 1911. (f)
Zhou, C.-Y.; Yu, W.-Y.; Che, C.-M. Org. Lett. 2002, 4, 3235.
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Wright, L. J.; J. Am. Chem. Soc. 1985, 107, 4570. (b) Collman, J. P.; Rose,
E.; Venburg, G. D. J. Chem. Soc., Chem. Commun. 1993, 934. (c) Park,
S.-B.; Sakata, N.; Nishiyama, H. Chem. Eur. J. 1996, 2, 203. (d) Galardon,
E.; Maux, P. L.; Toupet, L.; Simonneaux, G. Organometallics 1998, 17,
565. (e) Klose, A.; Solari, E.; Floriani, C.; Geremia, S.; Randaccio, L.
Angew. Chem. 1998, 110, 155; Klose, A.; Solari, E.; Floriani, C.; Geremia,
S.; Randaccio, L. Angew. Chem., Int. Ed. 1998, 37, 148.
(9) For an alternative approach for highly cis-selective â-lactam synthesis
using [2 + 2] cycloaddition, see: Taggi, A. E.; Hafez, A. M.; Wack, H.;
Young, B.; Ferraris, D.; Lectka, T. J. Am. Chem. Soc. 2002, 124, 6626 and
references therein.
(10) Aggarwal, V. K.; de Vicente, J.; Bonnert, R. V. Org. Lett. 2001, 3,
2785.
(7) Zheng, S.-L.; Yu, W.-Y.; Xu, M.-X.; Che, C.-M. Tetrahedron Lett.
2003, 44, 1445.
(8) (a) MacRae, W. D.; Towers, G. H. N. Phytochemistry 1984, 23, 1207.
(b) Ward, R. S. Nat. Prod. Rep. 1995, 183. (c) Ayers, A. C.; Loike, J. K.
Lignans: Chemical, Biological and Clinical Properties; Cambridge Uni-
versity Press: Cambridge, 1990.
(11) Snider, B. B.; Han, L.; Xie, C. J. Org. Chem. 1997, 62, 6978.
2536
Org. Lett., Vol. 5, No. 14, 2003

cyclization of 1a was conducted under the reaction condi-
tions: [Rh2(CH3CO2)4] (1 mol %), 1a (1 mmol) and n-Bu4-
NBr (10 mol %) in toluene at 60-70 °C, a mixture of cis-
and trans-2a (cis/trans ) 47:53) was obtained in only 21%
yield. Previously, Davies12a and Hashimoto12b independently
reported the chiral Rh-catalyzed enantioselective synthesis
of cis-2-aryl-3-methoxycarbonyl-2,3-dihydrobenzofurans by
intramolecular carbenoid C-H insertion strategy. According
to their reports, low temperature (-78 or -50 °C) was
employed to give a high degree of cis stereoselectivity.
Table 2. One-Pot Protocol for the Ru-Catalyzed Intramolecular
Carbenoid C-H Insertiona
In refluxing toluene (110 °C), the Ru-catalyzed cyclization
of 1a would attain complete substrate consumption within 2
h affording 2a in 86% yield (entry 4) with excellent cis
selectivity (cis/trans ) 98:2). In the absence of ruthenium
porphyrin catalyst, heating 1a in refluxing toluene led to
decomposition of the hydrazone without any formation of
the dihydrobenzofuran product.
Several ruthenium(II) porphyrins, [RuII(Por)(CO)], [H2-
Por: H2OEP ) octaethylporphyrin; H2-p-F-TPP ) meso-
tetrakis(p-fluorophenyl)porphyrin; H2-3,4,5-MeO-TPP ) meso-
tetrakis-(3,4,5-trimethoxyphenyl)porphyrin] were found to be
equally effective catalysts for the intramolecular carbenoid
C-H insertion, and 2a was isolated in 79-88% yields
(entries 5-7) and excellent cis selectivities (cis/trans ) 98:
2). And yet, when the sterically bulky [RuII(TDCPP)(CO)]
[H2TDCPP ) meso-tetrakis(2,6-dichlorophenyl)porphyrin]
was employed as catalyst, 2a was formed in only 12% yield
(entry 8) with a cis/trans ratio of 96:4. Likewise, with
[RuII(TMP)(CO)] [H2TMP ) meso-tetrakismesitylporphyrin]
as catalyst, 2a was formed in 10% yield and low cis
selectivity (cis/trans ) 45:55) (entry 9).
Reacting [RuII(TTP)(CO)] with sodium salt of benzo-
phenone tosylhydrazone (2 equiv) at ca. 65 °C in toluene
for 4 h under an argon atmosphere was found to give [(TTP)-
RudCPh2],5b which was characterized by 1H/13C NMR and
FAB-MS (see Supporting Information). An attempt to isolate
the carbenoid species derived from 1a with [OsII(TTP)(CO)]
was not successful; only the C-H insertion product was
obtained in 81% yield (Scheme 1).
a Reaction conditions: (1) LiHMDS (1.2 equiv) in THF, -78 °C, 30
min; (2) Ru catalyst, n-Bu4NBr, toluene MS4Å, 110 °C. b Isolated yield.
c Cis/trans ratio was determined by 1H NMR. d Modified reaction condi-
tions: 70 °C, 60 h.
containing two phenyl substituents, the reaction produced
trans-diphenyl-2,3-dihydrobenzofuran (2d) as the major
product (yield ) 78%; cis/trans ) 34:66; see entry 4).
Tosylhydrazones 1e,f containing aliphatic C-H bonds can
be readily converted to their corresponding dihydrobenzo-
furans (entries 5-6). This features a rare example of Ru-
carbenoid insertion into aliphatic C-H bond.
Scheme 1. Formation of [(TTP)RudCPh2] from the
Decomposition of Benzophenone Tosylhydrazone
It is reported that substrates such as 1g containing
electron-withdrawing ester substituents are not reactiVe for
the Rh-catalyzed carbenoid C-H insertion reaction.1a In this
work, with the [RuII(TTP)(CO)] catalyst, 1g was found to
undergo facile carbenoid C-H insertion, and 2g was
obtained in 66% yield with >99% cis selectiVity (entry 7).
However, under the Ru-catalyzed conditions, 1h containing
a CdC bond undergoes preferentially intramolecular cyclo-
propanation to give cyclopropane 2h in 56% yield (entry
8). No C-H insertion product was detected by H NMR
analysis of the crude reaction mixture.
The Ru-catalyzed intramolecular carbenoid C-H insertion
reaction is also effective for the formation of cis-disubstituted
The tosylhydrazone salt can be generated in situ10 by
reacting tosylhydrazone with a base, and a one-pot process
for the Ru-catalyzed intramolecular carbenoid C-H insertion
is developed. Several tosylhydrazone derivatives have been
employed to demonstrate the generality of the reaction.10 As
shown in Table 2, the reactions of aryl tosylhydrazones 1a-c
gave preferentially cis-disubstituted dihydrobenzofurans 2a-c
in good yields (entries 1-3). However, for substrate 1d
1
Org. Lett., Vol. 5, No. 14, 2003
2537

dihydroindoles. Treatment of N,N-dibenzyl-2-aminoaceto-
phenone tosylhydrazone 1i according to the one-pot protocol
furnished the product dihydroindole 2i in 78% isolated yield.
Again, >99% cis-selectivity was observed based on 1H NMR
analysis of the product (vicinal coupling constant ) 8.9
Hz).13 The high cis stereoselectivity is comparable to the
dihydrobenzofuran formation by the ruthenium-carbenoid
C-H insertion.
Table 3. One-Pot Protocol for the Ru-Catalyzed Cis-â-Lactam
Formationa
A wide variety of methods have been developed for the
preparation of â-lactam rings.14 Among them, the [Rh2(CH3-
CO2)4]-catalyzed carbenoid C-H insertion via decomposition
of R-diazo acetamides is a highly effective strategy for
making this important class of compounds.15 In this work,
we have also explored the Ru-catalyzed intramolecular
carbenoid C-H insertion protocol for construction of â-lac-
tam rings. Reaction of the N-benzyl-N-tert-butylacetamide
tosylhydrazone 3a under the Ru-catalyzed conditions gave
â-lactam 4a in 80% isolated yield after chromatographic
purification. The C-H insertion reaction proceeded with
remarkable cis-selectivity (>98%) since only cis-â-lactam
(vicinal coupling constants ) 5-6 Hz) was obtained based
1
on H NMR analysis. It is noteworthy that the analogous
rhodium(II) acetate catalyzed reactions are known to proceed
with trans selectivity,15a and no cis-lactams were produced.
Identical results were obtained with a series of ring-
substituted acetamide tosylhydrazones, and the cis-â-lactams
were furnished in 70-89% yields (see Table 3). The bulky
tert-butyl group was found to be essential for the success of
this transformation. When N,N-dibenzylacetamide tosyl-
hydrazone 3f was utilized as substrate, only N,N-dibenzy-
lacrylamide (Table 3, entry 6) was isolated in 70% yield and
no â-lactam was evident by 1H NMR analysis of the reaction
mixture.
Our preliminary study revealed that enantioselective car-
benoid C-H insertion can be achieved using chiral ruthenium
porphyrin as catalyst. Subjecting 1c to the Ru-catalyzed
conditions: [RuII(D4-Por*)(CO)] (D4-H2Por* ) 5,10,15,20-
tetrakis[(1S,4R,5R,8S)-1,2,3,4,5,6,7,8-octahydro-1,4:5,8-di-
methanoanthracene-9-yl]porphyrin)5a-b,16 (5 mol %), n-Bu4-
NBr (10 mol %) in toluene at 60-70 °C for 48 h, enantio-
a Reaction conditions: (1) LiHMDS (1.2 equiv) in THF, -78 °C, 30
min; (2) Ru catalyst (1 mol %), n-Bu4NBr, MS4Å, toluene, 110 °C, 4 h.
b Isolated yield. c >99% cis isomer was obtained and determined by 1H
NMR.
enriched 2c was obtained in 78% yield (>99% cis) and 96%
ee (see Supporting Information). The ee Value attained in
this work is among the best enantioselectiVity (94% ee)
reported by Hashimoto and co-workers using the chiral
rhodium catalyst.12 Further exploration of this methodology
for enantioselective carbon-carbon bond formation is un-
derway.
Acknowledgment. We acknowledge the support of the
Area of Excellence scheme (AoE/P-10/01) established under
the University Grants Committee of the Hong Kong Special
Administrative Region, China, The University of Hong Kong
(University Development Fund), and the Hong Kong Re-
search Grants Council (HKU7077/01P).
(12) (a) Davies, H. M. L.; Grazini, M. V. A.; Aouad, E. Org. Lett. 2001,
3, 1475. (b) Saito, H.; Oishi, H.; Kitagaki, S.; Nakamura, S.; Anada, M.;
Hashimoto, S. Org. Lett. 2002, 4, 3887.
(13) For C-H insertion, see: (a) Lim, H.-J.; Sulikowski, G. A.; J. Org.
Chem. 1995, 60, 2326. For other examples for preparation of cis-indole,
see: (b) Troin, Y.; Sinibaldi, M.-E.; Gramain, J.-C.; Rubiralta, M.; Diez,
A. Tetrahedron Lett. 1991, 32, 6129. (c) Wee, A. G. H.; Liu, B.; Zhang, L.
J. Org. Chem. 1992, 57, 4404.
(14) (a) Morin, R. B.; Gorman, M. Chemistry and Biology of â-Lactam
Antibiotics; Academic Press: New York, 1982. (b) Brown, A. G.; Roberts,
S. M. Recent AdVances in the Chemistry of â-Lactam Antibiotics; Royal
Society of Chemistry: London, 1985. (c) Durckheimer, W.; Blumbach, J.;
Lattrell, R.; Scheunemann, K. H. Angew. Chem., Int. Ed. Engl. 1985, 24,
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(15) (a) Doyle, M. P.; Shanklin, M. S.; Oon, S.-M.; Pho, H. Q.; van der
Heide, F. R.; Veal, W. R. J. Org. Chem. 1988, 53, 3384. (b) Anada, M.;
Watanabe, N.; Hashimoto, S.-I. Chem. Commun. 1998, 1517.
Supporting Information Available: Detailed experi-
mental procedures and characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL034806Q
(16) Enantioselective catalysis by [Ru(D4-Por*)(X)] complexes. see for
example: (a) Yu, W.-Y.; Che, C.-M. Pure Appl. Chem. 1999, 72, 281. (b)
Zhang, R.; Yu, W.-Y.; Lai, T.-S.; Che, C.-M. Chem. Commun. 1999, 1791.
(c) Zhang, R.; Yu, W.-Y.; Wong, K.-Y.; Che, C.-M. J. Org. Chem. 2001,
66, 8145. (d) Zhang, R.; Yu, W.-Y.; Sun, H.-Z.; Liu, W.-S.; Che, C.-M.
Chem. Eur. J. 2002, 8, 2495. (e) Liang, J.-L.; Yuan, S.-X.; Huang, J.-S.;
Yu, W.-Y.; Che, C.-M. Angew. Chem., Int. Ed. 2002, 41, 3465.
2538
Org. Lett., Vol. 5, No. 14, 2003