Ruthenium-catalyzed stereoselective intramolecular carbenoid C-H insertion for β- and γ-lactam formations by decomposition of α-diazoacetamides

Article abstract of DOI:10.1021/ol050003m

(Chemical Equation Presented) An operationally simple catalytic system based on [RuCl₂(p-cymene)₂] was developed for stereoselective cyclization of α-diazoacetamides by intramolecular carbenoid C-H insertion, and β-lactams were produ

Full text of DOI:10.1021/ol050003m

ORGANIC
LETTERS
2005
Vol. 7, No. 6
1081-1084
Ruthenium-Catalyzed Stereoselective
Intramolecular Carbenoid C H Insertion
for - and -Lactam Formations by
Decomposition of -Diazoacetamides
−
â
γ
r
Matthew Kwok-Wai Choi, 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
wyyu@hku.hk
Received January 3, 2005
ABSTRACT
An operationally simple catalytic system based on [RuCl2(p-cymene)2] was developed for stereoselective cyclization of
r-diazoacetamides by
intramolecular carbenoid C
reactions can be performed without the need for slow addition of diazo compounds and inert atmosphere. With
the carbenoid insertion was directed selectively to aromatic C H bond leading to -lactam formation (>95% yield).
−H insertion, and
â
-lactams were produced in excellent yields and >99% cis-stereoselectivity. The Ru-catalyzed
r
-diazoanilides as substrate,
−
γ
Transition metal-catalyzed intramolecular carbenoid C-H
insertion by decomposition of R-diazocarbonyl compounds
constitutes a powerful strategy for construction of carbocyclic
and heterocyclic compounds.1 A notable example is the
dirhodium(II,II) carboxylate-catalyzed decomposition of
R-diazoacetamides for stereoselective preparation of â- and
γ-lactams,1b-e which are prevalent structures in natural
products and many pharmaceuticals.2 However, apart from
rhodium, few transition metal complexes are known to
exhibit comparable reactivities for catalytic carbenoid C-H
insertion reaction.3
The use of ruthenium complexes as catalysts for stereo-
selective C-C bond formation is receiving current attention.4
We previously showed that ruthenium porphyrins5 are
effective catalysts for cyclization of tosylhydrazones via
intramolecular carbenoid C-H insertion to afford cis-
disubstituted dihydrobenzofurans and â-lactams in excellent
yields and cis-stereoselectivity.6 With an objective to develop
(3) A recent report on Cu-catalyzed carbenoid C-H insertion, see: Diaz-
Requejo, M. M.; Belderrain, T. R.; Nicasio, M. C.; Trofimenko, S.; Perez,
P. J. J. Am. Chem. Soc. 2002, 124, 896.
(4) (a) Naota, T.; Takaya, H.; Murahashi, S.-I. Chem. ReV. 1998, 98,
2599. (b) Trost, B. M.; Toste, F. D.; Pinkerton, A. B. Chem. ReV. 2001,
101, 2067.
(5) For selected examples of ruthenium porphyrin catalyzed carbenoid
reactions, see: (a) Simonneaux, G.; Galardon, E.; Paul-Roth, C.; Gulea,
M.; Masson, S. J. Organomet. Chem. 2001, 617, 360. (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) Zhou, C.-Y.; Yu, W.-Y.; Che, C.-M. Org. Lett. 2002, 4,
3235. (d) Zhou, C.-Y.; Chan, P. W. H.; Yu, W.-Y.; Che, C.-M. Synthesis
2003, 9, 1402. (e) Li, G.-Y.; Chen, J.; Yu, W.-Y.; Hong, W.; Che, C.-M.
Org. Lett. 2003, 5, 2153. (f) Li, Y.; Chan, P. W. H.; Zhu, N.-Y.; Che,
C.-M.; Kwong, H.-L. Organometallics 2004, 23, 54.
(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. (f)
Davies, H. M. L.; Beckwith, R. E. J. Chem. ReV. 2003, 103, 2861.
(2) (a) Sunagawa, M.; Sasaki, A. Heterocycles 2001, 54, 497. (b) Singh,
G. S. Tetrahedron 2003, 59, 7631. (c) Elassar, A. Z. A.; El-Kair, A. A.
Tetrahedron 2003, 59, 8463.
(6) (a) Cheung, W.-H.; Zheng, S.-L.; Yu, W.-Y.; Zhou, G.-C.; Che, C.-
M. Org. Lett. 2003, 5, 2535. (b) Zheng, S.-L.; Yu, W.-Y.; Xu, M.-X.; Che,
C.-M. Tetrahedron Lett. 2003, 44, 1445.
10.1021/ol050003m CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/10/2005

Table 1. Ruthenium-Catalyzed Intramolecular Carbenoid C-H Insertion of R-Diazoacetamides
a Reaction conditions: A mixture of diazo compound (0.1 mmol) and [RuCl2(p-cymene)]2 (0.5 mol %) was stirred in toluene at 70 °C in an open
b
atmosphere unless otherwise noted. Isolated yield. c Yields determined by 1H NMR analysis of the crude reaction mixture. d Reaction performed under N2
atmosphere. e [RuCl2(p-cymene)]2 loading ) 2.5 mol %.
enantioselective carbenoid reactions, the rather laborious
procedure required for structural modification of the por-
phyrin ligands prompted us to search for some non-
porphyrin-based ruthenium systems that would be more
amenable to structural variation. In developing operationally
simple and practical protocols for catalytic carbenoid trans-
formations, we now report that [RuCl2(p-cymene)]2 can
mediate catalytic intramolecular carbenoid C-H insertion
reactions by decomposition of R-diazoacetamides. The
â-lactam products were obtained in >90% yield with remark-
able stereoselectivity (>99% cis). There are extensive reports
describing [RuCl2(p-cymene)]2 as a catalyst for a variety of
reactions such as transfer hydrogenation,7a,b alkene meta-
thesis,7c,d aerobic oxidation,7e and alkene cyclopropanation.7f-h
As yet, however, examples for [RuCl2(p-cymene)]2-catalyzed
carbenoid C-H insertion are unprecedented in the literature.
Treatment of N-p-chlorobenzyl-N-tert-butyl-R-ethoxycar-
bonyl-R-diazoacetamide (1a, 0.1 mmol) with [RuCl2(p-
cymene)]2 (0.5 mol %) in toluene (10 mL) at 70 °C under
an argon atmosphere afforded N-tert-butyl-cis-1-ethoxycar-
bonyl-2-p-chlorophenyl-â-lactam (2a) in quantitative yield
after 0.5 h (Table 1, entry 1). No trans-â-lactam product
was detected by 1H NMR analysis of the crude mixture. The
1
stereochemistry of the cis-â-lactam was established by H
NMR spectroscopy.
Without [RuCl2(p-cymene)]2 as catalyst, no â-lactam
formation was observed and the starting 1a was quantitatively
recovered. It is noteworthy that the cis-stereoselectivity
observed in this work is comparable to that for the ruthenium
porphyrin-catalyzed aryl tosylhydrazone cyclizations. Ac-
cording to the literature, dirhodium-catalyzed decompositions
of R-diazoacetamides are known to favor trans-â-lactam
formation.8
Presumably, the â-lactam formation is mediated by a
reactive ruthenium carbene species, which undergoes car-
benoid insertion to the benzylic C-H bond. In this work,
when [RuCl2(p-cymene)]2 was reacted with diphenyldiaz-
omethane (4 equiv) in toluene at 70 °C under nitrogen,
complete decomposition of the diazo compounds resulted
affording tetraphenylethylene in 83% yield. However, at-
tempts to isolate the putative ruthenium carbene complex
were futile. Previously, Nishiyama and co-workers reported
that [RuCl2(p-cymene)]2 reacted with vinyl diazoacetate to
generate a π-allyl ruthenium complex, which was structurally
characterized by X-ray crystallography.9
(7) See for examples: (a) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya,
T.; Noyori, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 285. (b) Jiang, Y.;
Jiang, Q.; Zhang, X. J. Am. Chem. Soc. 1998, 120, 3817. (c) Hafner, A.;
Muhlebach, A.; van der Schaaf, P. A. Angew. Chem., Int. Ed. Engl. 1997,
36, 2121. (d) Furstner, A.; Picquet, M.; Bruneau, C.; Dixneuf, P. H. J. Chem.
Soc., Chem. Commun. 1998, 1315. (e) Choi, E.; Lee, C.; Na, Y.; Chang, S.
Org. Lett. 2002, 4, 2369. (f) Nishiyama, H.; Itoh, Y.; Sugawara, Y.;
Matsumoto, H.; Aoki, K.; Itoh, K. Bull. Chem. Soc. Jpn. 1995, 68, 1247.
(g) Simal, F.; Jan, D.; Demonceau, A.; Noels, A. F. Tetrahedron Lett. 1999,
40, 1653. (h) Leadbeater, N. E.; Scott, K. A.; Scott, L. J. J. Org. Chem.
2000, 65, 3231.
(8) (a) Padwa, A.; Austin, D. J.; Price, A. T.; Semones, M. A.; Doyle,
M. P.; Protopopova, M. N.; Winchester, W. R.; Tran, A. J. Am. Chem.
Soc. 1993, 115, 8669. (b) Yoon, C. H.; Zaworotko, M. J.; Moulton, B.;
Jung, K. W. Org. Lett. 2001, 3, 3539.
(9) Nishiyama, H.; Konno, M.; Aoki, K.; Davies, H. M. L. Organome-
tallics 2002, 21, 2536.
1082
Org. Lett., Vol. 7, No. 6, 2005

According to earlier reports,5,7f-h,10 slow addition of
R-diazo compounds and inert atmosphere were often neces-
sary for ruthenium-catalyzed carbenoid transformations. The
slow addition procedure is to avoid/minimize the diazo
coupling reaction. In this work, we found that the [RuCl2-
(p-cymene)]2-catalyzed intramolecular carbenoid C-H inser-
tion reaction could be performed without using the slow
addition procedure or an inert atmosphere. For example,
heating a mixture of 1a (0.1 mmol) and [RuCl2(p-cymene)]2
(0.5 mol %) at 70 °C in open atmosphere (i.e., without Ar/
N2 protection) furnished cis-â-lactam in quantitative yield
within 0.5 h (Table 1, entry 1). No diazo coupling products
Scheme 1. Proposed Reactive Conformations for Cyclization
of R-Diazoacetamide 1g
1
bonds) is similar to the related systems with [Rh2(CH3CO2)4]
as catalyst.8
(fumarate/maleate) were detected by H NMR analysis.
Employing the reaction conditions: Ru (1 mol %), toluene,
70 °C, other ruthenium complexes such as [RuII(TTP)(CO)]
[H2TPP ) meso-tetrakis(p-tolyl)porphyrin], [RuII(salen)-
(PPh3)2] [salen ) N,N′-bis(2,4-dibromosalicyclidene)-1,2-
cyclohexanediamine)], [RuII(6,6′-Cl2-bpy)2(H2O)2] (CF3SO3)2
(6,6′-Cl2-bpy ) 6,6′-dichloro-2,2′-bipyridine),11 [RuII(PPh3)2-
Cl2], and [Ru(COD)Cl2]n (COD ) 1,8-cyclooctadiene) failed
to effect catalytic cyclization of 1a with complete recovery
of the starting material. Under an inert atmosphere,
[Cp*RuCl2]2 (Cp* ) pentamethylcyclopentadienyl) was
found to catalyze cyclization of 1a to give cis-lactam 2a
exclusively in 96% yield (NMR) within 2 h. However, when
the identical reaction was conducted in an open atmosphere,
the cis-lactam product was obtained in only 62% yield at
80% substrate conversion after 5 h of reaction.
Using 1f as substrate and [RuCl2(p-cymene)]2 as catalyst
(0.5 mol %), a mixture of trans-γ-lactam 3 (51%) and cis-
â-lactam 2f (15%) was produced after 16 h of reaction (Table
1, entry 6).12 Again, no trans-â-lactam product was detected
1
by H NMR analysis of the crude reaction mixture. The
trans-stereochemistry of γ-lactam 3 was established by a 2D-
NOESY NMR study (see the Supporting Information).
With [RuCl2(p-cymene)]2 (2.5 mol %) in toluene at 70
°C for 2 h, R-diazoacetamide 1g containing a benzyl and a
phenylethylene group underwent intramolecular carbenoid
C-H insertion reaction to afford trans-γ-lactam 4 and cis-
â-lactam 2g in 53 and 28% yield, respectively (Table 1, entry
7). Similar results were obtained when [Rh2(CH3CO2)4] was
employed as a catalyst (0.1 mol %) in CH2Cl2 at reflux under
N2. Assuming metal-carbenoids are being generated as active
intermediates, the formation of γ- and â-lactams can be
explained by the presence of two reactive conformations as
depicted in Scheme 1.13
We also explored carbenoid insertion into aromatic C-H
bonds.14 When R-diazoanilides 1h and 1i were treated with
[RuCl2(p-cymene)]2 (2.5 mol %) in toluene at 70 °C for 16
h, effective carbenoid C-H insertion into the p-methoxy-
phenyl group was observed, and γ-lactams 5 and 6 were
isolated in 97 and 92% yields respectively (Table 1, entries
8 and 9). However, using [Rh2(CH3CO2)4] as catalyst (CH2-
Cl2 at reflux, 16 h), the analogous reactions yielded trans-
â-lactams (57% for 1h; 87% for 1i) and γ-lactams (43% for
1h; 15% for 1i).
In this work, common solvents such as toluene, CHCl3,
CH2Cl2, acetone, EtOAc, and THF could be utilized without
prior treatment for the cyclization of 1a with >95% yields
and complete cis-selectivity being attained in most cases (see
the Supporting Information). However, when DMF, CH3-
CN, and MeOH were used as solvent, no substrate conversion
was observed within 3 h.
The scope of the [RuCl2(p-cymene)]2-catalyzed intramo-
lecular carbenoid C-H insertion has been explored and the
results are depicted in Table 1. Analogous to 1a, other
N-para-Y-substituted benzyl-N-tert-butyl R-diazoacetamides
[Y ) H (1b), OMe (1c)] were converted to the corresponding
cis-â-lactams (99% NMR yields) under the Ru-catalyzed
conditions (entries 2 and 3). Even so, the catalytic reaction
of R-diazoketone 1d was found to give trans-lactam 2d
exclusively in quantitative yield (entry 4). With N,N-
diisopropyl substituted R-diazoacetamide 1e as substrate, the
Ru-mediated carbenoid insertion was directed to the methine
(tertiary) C-H bond furnishing â-lactam 2e in 89% isolated
yield (entry 5). No γ-lactam due to insertion at the primary
C-H bond was detected by 1H NMR analysis. The observed
reactivity preference (i.e., tertiary C-H > primary C-H
For the Ru-catalyzed reaction of R-diazoanilides, complete
substrate consumption was observed within 2 h based on
TLC monitoring. However, 1H NMR analysis of the reaction
mixtures revealed a complicated spectrum. This finding
suggested that decarboxylation of the putative R-ethoxycar-
bonyl γ-lactam may involve several undefined chemical
(12) For comparison, we also performed the identical reaction using
[Rh2(CH3CO2)4] as catalyst by employing a reported protocol:8a 1f (0.1
mmol), Rh (0.1 mol %), CH2Cl2, N2, reflux; an equimolar mixture of â-
and γ-lactams was obtained in 96% overall yield.
(10) Selected examples: (a) Lo, W.-C.; Che, C.-M.; Cheng, K.-F.; Mak,
T. C. W. Chem. Commun. 1997, 1205, (b) Galardon, E.; Maux, P. L.;
Simmoneaux, G. Chem. Commun. 1997, 927. (c) Simal, F.; Jan, D.;
Demonceau, A.; Noels, A. F. Tetrahedron Lett. 1999, 40, 1653. (d) Baratta,
W.; Herrmann, W. A.; Kratzer, R. M.; Rigo, P. Organometallics 2000, 19,
3664. (e) Uchida, T.; Irie, R.; Katsuki, T. Tetrahedron 2000, 56, 3501.
(11) (a) Che, C.-M.; Leung, W.-H. J. Chem. Soc., Chem. Commun. 1987,
1376. (b) Lau, T.-C.; Che, C.-M.; Lee, W.-O.; Poon, C.-K. J. Chem. Soc.,
Chem. Commun. 1988, 1406.
(13) (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) Doyle, M. P.;
Taunton, J.; Pho, H. Q. Tetrahedron Lett. 1989, 30, 5397.
(14) (a) Hrytsak, M.; Durst, T. J. Chem. Soc., Chem. Commun. 1987,
1150. (b) Nakatani, K. Tetrahedron Lett. 1987, 28, 165. (c) Doyle, M. P.;
Shanklin, M. S.; Pho, H. Q.; Mahapatro, S. N. J. Org. Chem. 1988, 53,
1017. (d) Babu, S. D.; Hrytsak, M. D.; Durst, T. Can. J. Chem. 1989, 67,
1071. (e) Etkin, N.; Babu, S. D.; Fooks, C. J.; Durst, T. J. Org. Chem.
1990, 55, 1093.
Org. Lett., Vol. 7, No. 6, 2005
1083

Scheme 2
Scheme 3. Regioselective Carbenoid Insertion to Aromatic
C-H Bond
â-lactam 2a exclusively in 80% isolated yield. By means of
1H NMR analysis with Eu(hfc)3 as shift reagent, the optical
purity of trans-2a was determined to be 50%ee (Scheme 3).
Identical results (trans-2a: 72% yield, 53%ee) were obtained
when treating 1a with [RuCl2(L*)(C2H4)] as catalyst. Using
the “[RuCl2(p-cymene)]2 + L*” protocol, reactions of other
diazoacetamides 1b and 1c furnished the corresponding
â-lactams in moderate enantioselectivities (41%ee for trans-
2b and 53%ee for trans-2c; see Table S2, Supporting
Information). Yet, the cyclization of 1c also gave the cis-
â-lactam as a minor product (8% isolated yield), and the
optical purity of the cis-2c was determined to be 55%ee
(Table S2, Supporting Information). The factors governing
the stereo- and enantioselectivities for the present Ru-
catalyzed carbenoid C-H insertion are under investigation.
species. Nevertheless, heating the reaction mixtures for an
additional 14 h yielded the γ-lactams exclusively in quantita-
tive yields based on NMR analysis.
The regioselectivity observed in the Ru-catalyzed aromatic
C-H insertion reactions (Scheme 2) can be explained by
the putative ruthenium carbenoid preferring to react via
conformer A rather than conformer B due to reduced
nonbonded interactions between the alkyl chain and the
carbonyl group.
The asymmetric synthesis of â-lactams has been a subject
of extensive investigation.1,15 In this work, we have examined
enantioselective cyclization of R-diazoacetamides catalyzed
by [RuCl2(p-cymene)]2 in the presence of a chiral pyridine
bis(oxazoline) ligand L* (Scheme 3). Earlier work by
Nishiyama and co-workers showed that chiral [RuCl2(L*)-
(C2H4)] complexes are effective catalysts for enantioselective
alkene cyclopropanations.7f
Acknowledgment. This work is supported by the Areas
of Excellence Scheme established under the University
Grants Committee of the Hong Kong Special Administrative
Region, China (AoE/P-10/01), The University of Hong Kong
(University Development Fund), and the Hong Kong Re-
search Grants Council (HKU7026-03P).
Treatment of 1a with [RuCl2(p-cymene)]2 (5 mol %) and
L* (10 mol %) in toluene at 70 °C for 72 h produced trans-
(15) (a) Doyle, M. P.; Protopopova, M. N.; Winchester, W. R.; Daniel,
K. L. Tetrahedron Lett. 1992, 33, 7819. (b)Watanabe, N.; Anada, M.;
Hashimoto, S.; Ikegami, S. Synlett 1994, 1031. (c) Anada, M.; Hashimoto,
S. Tetrahedron Lett. 1998, 39, 79. (d) Anada, M.; Watanabe, N.; Hashimoto,
S. Chem. Commun. 1998, 1517. (e) Anada, M.; Hashimoto, S. Tetrahedron
Lett. 1998, 39, 9063. (f) Anada, M.; Watanabe, O. M.; Kitagaki, S.;
Hashimoto, S. Synlett 1999, 11, 1775.
Supporting Information Available: Detail experimental
procedures and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
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