Ruthenium-catalyzed one-pot carbenoid N-H insertion reactions and diastereoselective synthesis of prolines

Article abstract of DOI:10.1021/ol800087p

Aryl- and aliphatic-substituted 3-hydroxyprolines and various other amino esters are conveniently prepared by [RuCI₂(p-cymene)] ₂-catalyzed one-pot intramolecular and intermolecular carbenoid N-H insertion reactions, respectively, and the prolines are formed with high diastereoselectivities. The catalytic reactions are tolerant toward air/moisture, and the product yields are insensitive to the organic solvents used.

Full text of DOI:10.1021/ol800087p

ORGANIC
LETTERS
2008
Vol. 10, No. 8
1529-1532
Ruthenium-Catalyzed One-Pot Carbenoid
H Insertion Reactions and
N−
Diastereoselective Synthesis of Prolines
Qing-Hai Deng,† Hai-Wei Xu,† Angella Wing-Hoi Yuen,‡ Zhen-Jiang Xu,*,† and
Chi-Ming Che*,†,‡
Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of
Organic Chemistry, The Chinese Academy of Sciences, 354 Feng Lin Road, Shanghai
200032, China, and Department of Chemistry and Open Laboratory of Chemical
Biology of the Institute of Molecular Techology for Drug DiscoVery and Synthesis, The
UniVersity of Hong Kong, Pokfulam Road, Hong Kong, China
cmche@hku.hk; xuzhenjiang@mail.sioc.ac.cn
Received January 16, 2008
ABSTRACT
Aryl- and aliphatic-substituted 3-hydroxyprolines and various other amino esters are conveniently prepared by [RuCl2(p-cymene)]2-catalyzed
one-pot intramolecular and intermolecular carbenoid insertion reactions, respectively, and the prolines are formed with high
N−H
diastereoselectivities. The catalytic reactions are tolerant toward air/moisture, and the product yields are insensitive to the organic solvents
used.
Metal-catalyzed carbenoid N-H insertion reactions are of
great utility for the generation of building blocks to be used
in the construction of natural products and other pharma-
ceuticals.1 Several decades ago, it was demonstrated that
transition-metal complexes such as those of Cu, Rh, and Fe
were effective catalysts for carbenoid N-H insertion reac-
tions. The first notable application of a metal-catalyzed
carbenoid N-H insertion2 was the synthesis of a bicyclic
â-lactam in 1978.3 Of the previously reported catalytic
reactions, relatively few have involved the use of ruthenium
complexes. Simonneaux and co-workers4 suggested that the
carbenoid species generated by the reaction between diaz-
oesters and ruthenium porphyrins may undergo N-H and
S-H insertion as well as alkene cyclopropanation. Zotto and
co-workers5 revealed that [RuCl(η5-C5H5)(PPh3)3]-catalyzed
(2) For reviews involving catalyzed diazo compound N-H insertion
reactions, see: (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds; Wiley: New York,
1998; Chapter 8.2. (b) Ye, T.; McKervey, M. A. Chem. ReV. 1994, 94,
1091. For recent examples, see: (c) Hrytsak, M.; Durst, T. Heterocycles
1987, 26, 2393. (d) Morilla, M. E.; Diaz-Requejo, M. M.; Belderrain, T.
R.; Nicasio, M. C.; Trofimenko, S.; Perez, P. J. Chem. Commun. 2002, 24,
2998. (e) Aviv, I.; Gross, Z. Synlett 2006, 6, 951. For example of highly
enantioselective metal-catalyzed intermoelcular carbenoid N-H insertion
reactions, see: (f) Liu, B.; Zhu, S.-F.; Zhang, W.; Chen, C.; Zhou, Q.-L. J.
Am. Chem. Soc. 2007, 129, 5834.
† Shanghai Institute of Organic Chemistry.
‡ The University of Hong Kong.
(1) (a) Salzmann, T. N.; Ratcliffe, R. W.; Christensen, B. G.; Bouffard,
F. A. J. Am. Chem. Soc. 1980, 102, 6161. (b) Aller, E.; Buck, R. T.;
Drysdale, M. J.; Ferris, L.; Haigh, D.; Moody, C. J.; Pearson, N. D.;
Sanghera, J. B. J. Chem. Soc., Perkin Trans. 1 1996, 2879. (c) Deng, G.;
Jiang, N.; Ma, Z.; Wang, J. Synlett 2002, 1913. (d) Dong, C.; Deng, G.;
Wang, J. J. Org. Chem. 2006, 71, 5560.
(3) Cama, L. D.; Christensen, B. G. Tetrahedron Lett. 1978, 19, 4233.
(4) (a) Galardon, E.; Maux, P. L.; Simonneaux, G. J. Chem. Soc., Perkin
Trans. 1 1997, 2455. (b) Galardon, E.; Maux, P. L.; Simonneaux, G.
Tetrahedron 2000, 56, 615.
10.1021/ol800087p CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/20/2008

N-H and S-H insertion reactions with diazoketones. Herein,
we show that the commerically available [RuCl2(p-cymene)]26
is an efficient catalyst for inter- and intramolecular carbenoid
N-H insertion reactions with diazocarbonyl compounds, and
that prolines can be obtained from [RuCl2(p-cymene)]2
catalyzed intramolecular carbenoid N-H insertion reactions
with high diastereoselectivities.
instability of the ruthenium catalyst and diazo compound in
aqueous medium.7 The reactions of different diazo com-
pounds with aniline were also investigated (Table 2). The
donor/acceptor-substituted carbenoid derived from ethyl
Table 2. [RuCl2(p-cymene)]2-Catalyzed Carbenoid N-H
We evaluated a number of Ru complexes for their ability
to catalyze carbenoid N-H insertion reaction between
aniline 1 (0.2 mmol) and ethyl phenyldiazoacetate 2 (0.2
mmol). The insertion reaction was effectively catalyzed by
[RuCl2(p-cymene)]2 (1 mol %) to afford ethyl 2-(pheny-
lamino)-2-phenylacetate 3 in 98% yield within 10 min
and by RuCl2(p-cymene)PPh3 to give the same product in
97% yield in 5 h. The dimeric coupling product, 2,3-
diphenyldiethyl ester, was not detected in any of the cases
examined. Under the same conditions, PPh3 alone and
[Ru(Por)CO] (Por ) TMP, 2,6-Cl2TPP) individually showed
no catalytic activities, and only the starting material could
be recovered (see the Supporting Information). We found
that reaction 1 was essentially insensitive to air, moisture
and the solvent used, as similar product yields were found
when the reaction was conducted in different organic
solvents, under an atmosphere of argon (anhydrous con-
ditions) or open to the atmosphere (Table 1). No reaction
Insertion Reaction of Aniline with Different Diazo Compounds
entrya
R
solvent
time
yieldb (%)
1c
2
3
Ph
Me
H
CH2Cl2
CH2Cl2
CH2Cl2
10 min
6 h
2 h
98
50
90
a Reaction conditions: 1 (0.2 mmol) and 2/2a/2b (0.2 mmol) were stirred
with 1 mol % catalyst in the solvent (4 mL) under reflux an atmosphere of
argon. b Isolated yield. c At room temperature.
phenyldiazoacetate afforded the product in 98% yield in 10
min, the less reactive acceptor-substituted carbenoid derived
from ethyl diazoacetate gave the product in 90% yield in 2
h. The reaction of the carbenoid derived from ethyl meth-
yldiazoacetate with aniline gave the product in only 50%
yield.8
[RuCl2(p-cymene)]2 was found to be the most effective
catalyst. Consequently, we investigated its ability to catalyze
the reactions between ethyl phenyldiazoacetate and a selec-
tion of anilines and amines (Table 3, reaction 2, entries 1-33;
Table S2 in the Supporting Information, entries 2-20) and
amides (Table 3, entries 34-36). The corresponding products
were obtained in up to 99% yield. In general, the reactions
with alkyl amines required a longer reaction time and higher
temperature than analogous reactions with aryl amines and
amides. This apparently correlates to the pKa (DMSO)
values, which are in the order: alkyl amines (pKa ∼44)>ary-
lamines (pKa 30-20)>/∼amides (pKa ∼23).9 A screening
of the solvents has been performed; we found that the less
reactive alkyl amines gave the highest product yields in
MeCN while no reaction for those alkyl amines were found
in CH2Cl2. The time for the completion of reaction 2 varied
from 15 min in the case of p-OMe aniline to <1 min in the
case of p-NO2 aniline at a high catalyst loading of 5.0 mol
% of [RuCl2(p-cymene)]2 and from 30 min in the case of
p-OMe aniline to 2 min in the case of p-NO2 aniline at a
catalytic loading of 1.0 mol %. At a low catalyst loading of
0.2 mol % of [RuCl2(p-cymene)]2, the time for the comple-
tion of reaction 2 varied from 6.5 h in the case of p-OMe
aniline to 5 min in the case of p-NO2 aniline (Table S3 in
the Supporting Information), consistent with the observation
that the pKa value of N-H moiety is an important factor
affecting the reaction.
Table 1. Solvent Effects for [RuCl2(p-cymene)]2-Catalyzed
Intermolecular Carbenoid N-H Insertion Reactions
open to the
under argon
atmosphere
time
(min)
yieldb
(%)
time
(min)
yieldb
(%)
entrya
solvent
toluene
ClCH2CH2Cl
MeCN
THF
CH2Cl2
H2O
1
2
3
4
5
6
30
15
10
15
10
94
97
96
97
98
e
15
15
15
15
10
93
95
94
96
98
24 h
a Reaction conditions: 1 (0.2 mmol) and 2 (0.2 mmol) were stirred with
1 mol % [RuCl2(p-cymene)]2 in CH2Cl2 (4 mL) at room temperature.
b Isolated yield. e No detectable reaction.
was observed when water was used as the solvent (Table 1,
entry 6); presumably, this is due to the insolubility and
(5) Zotto, A. D.; Baratta, W.; Rigo, P. J. Chem. Soc., Perkin Trans. 1
1999, 3079.
(6) Choi, M.-K.; Yu, W.-Y.; Che, C.-M. Org. Lett. 2005, 7, 1081.
(7) For catalysts that work in water, see: (a) Candeias, N. R.; Gois, P.
M. P.; Afonso, C. A. M. J. Org. Chem. 2006, 71, 5489. (b) Sutoh, T.;
Kondo, A.; Musashi, J. Tetrahedron 2004, 60, 5453. (c) Estevan, F.; Lloret.
J.; Sanau, M.; Ubeda, A. Organometallics 2006, 25, 4977. (d) Wurz, R. P.;
Charette, A. B. Org. Lett. 2002, 4, 4531.
(8) For the literatures on the reactivity of different carbenoids, see: (a)
Davies, H. M. L.; Beckwith, R. E. J. Chem. ReV. 2003, 103, 2861. (b)
Davies, H. M. L.; Nikolai, J. Org. Biomol. Chem. 2005, 3, 4176.
(9) http://www.chem.wisc.edu/areas/reich/pkatable,
(10) For examples of rhodium-catalyzed intramolecular carbenoid N-H
insertion, see: (a) Moyer, M. P.; Feldman, P. L.; Rapoport, H. J. Org. Chem.
1985, 50, 5223. (b) Garcia, C. F.; McKervey, M. A.; Ye, T. Chem. Commun.
1996, 12, 1465.
1530
Org. Lett., Vol. 10, No. 8, 2008

Table 3. [RuCl2(p-cymene)]2-Catalyzed Intermolecular
Carbenoid N-H Insertion Reactions with Amines and Amides
Table 4. Ru Complex-Catalyzed Intramolecular Carbenoid
N-H Insertion Reactions
yieldc
solvent time (h) cis/transb (%)
entrya
catalyst
1d
2
3
[RuCl2(p-cymene)]2 MeOH
[RuCl2(p-cymene)]2 THF
[RuCl2(p-cymene)]2 CH2Cl2
5
6
6
6
4
4
8
134:1
45:1
6:1
7:1
13:1
2:1
94
93
92
93
86
85
86
4
RuCl3· 3H2O
THF
5d
6d
7d
[Ru(CO)3Cl2]2
toluene
[Ru(2,6-Cl2TPP)CO] toluene
[Ru(TMP)CO] toluene
2:1
a Reaction conditions: 6a (0.2 mmol) were stirred with 1 mol % catalyst
in solvent (2 mL) at room temperature. b Determined by 1H NMR. c Isolated
yield based on 100% conversion. d Reaction was heated at 80 °C.
observed with MeOH. The diastereoselectivity given by
[RuCl2(p-cymene)]2 is higher than that of 1.5:1 and 6:1
catalyzed by Rh2(OAc)4 for similar reactions documented
in the literature (see data given in reference 11). RuCl3·nH2O
and [Ru(2,6-Cl2TPP)CO] catalyzed reaction 3 to give 7 with
cis/trans ratios of 7:1 and 2:1, respectively (Table 4, entries
4 and 6). Immediately after completion of the N-H
1
carbenoid insertions (as determined by H NMR analysis),
the ketone moieties were reduced by a direct addition of
NaBH4 to afford the corresponding substituted prolines 8
(Table 5). Only one isomer of 8 was obtained after this
reduction step, which was suggested to adopt a cis-cis
configuration by its NOE spectrum. The cis-cis configura-
tion of 8g was confirmed by X-ray crystallographic analysis
(see the Supporting Information).
a Reaction conditions: 4 (0.2 mmol) and 2 (0.2 mmol) were stirred with
1 mol % catalyst in CH2Cl2 (4 mL) at room temperature. b Isolated yield
based on 100% conversion. c See Table S3 in Supporting Information.
d Reaction performed in MeCN (1 mL) under reflux.
An elegant application of intramolecular N-H insertion10
c
is Davis’11a,
rhodium-catalyzed method for the syn-
A number of substrates, including both aryl (10 examples)
and aliphatic (3 examples) ones, were tested for intramo-
lecular carbenoid N-H insertions using [RuCl2(p-cymene)]2
as the catalyst. The results are shown in Tables 5 and 6.
Complete substrate conversion was found in all the cases
examined and the products were obtained in 85-95% yields
and in a cis-cis configuration. For reaction 5 (Table 6), the
Boc-protected group could be removed, after the reduction
step, by adding trifluoroacetic acid (TFA) to give 10, the
latter is a core structure commonly employed in the synthesis
of natural products.13 The configuration of 10 remains to be
cis-cis for R to be aryl or aliphatic group.
thesis of highly functionalized pyrrolidines. Even though a
number of structural variations have been achieved, one
drawback on the rhodium-catalyzed reactions was the
moderate diastereocontrol of the process. Therefore, we
decided to explore if ruthenium-catalyzed reactions could
improve the selectivity. In this work, we studied the catalytic
activity of [RuCl2(p-cymene)]2 toward intramolecular car-
benoid N-H insertion. Under similar reaction conditions,
we treated diazo compound 6a12 with a selection of ruthe-
nium catalysts. We quantified the amount of substituted
proline (3-carbonyl-1,5-diphenylpyrrolidine-2-carboxylic acid
methyl ester 7) formed (reaction 3) and examined the cis/
trans selectivity (Table 4).
The stereochemistry of 7 can be rationalized with reference
to the mechanism proposed by Doyle,2a,14 Taber,15 and
All the Ru catalysts depicted in Table 4, [RuCl2(p-
cymene)]2, RuCl3·nH2O, [Ru(CO)3Cl2]2, [Ru(2,6-Cl2TPP)-
CO], and [Ru(TMP)CO], catalyzed the intramolecular car-
benoid N-H insertion to give the proline product (cis major)
in a yield of 94%, 93%, 86%, 85%, and 86%, respectively
(Table 4, entries 1-6). Analogous to the results obtained
for the intermolecular carbenoid N-H insertions, [RuCl2(p-
cymene)]2 gave the highest product yield and also the highest
cis/trans ratio, 134:1, when MeOH was used as the solVent
(Table 4, entry 1). No competitive O-H insertion was
(11) (a) Davis, F. A.; Fang, T.; Goswami, R. Org. Lett. 2002, 4, 1599.
(b) Davis, F. A.; Yang, B.; Deng, J. J. Org. Chem. 2003, 68, 5147. (c)
Davis, F. A.; Deng, J. Tetrahedron 2004, 60, 5111.
(12) Doyle, M. P.; Kundu, K.; Russell, A. E. Org. Lett. 2005, 7, 5171.
(13) (a) Agami, C.; Platzer, N.; Puchot, C.; Sevestre, H. Tetrahedron
1987, 43, 1091. (b) Barrett, A. G. M.; Pilipauskas, D. J. Org. Chem. 1990,
55, 5194. (c) Mulzer, J.; Meier, A.; Buschmann, J.; Luger, P. J. Org. Chem.
1996, 61, 566.
(14) Doyle, M. P.; Westrum, L. J.; Wolthuis, N. E.; See, M. M.; Boone,
W. P.; Bagheri, V.; Pearson, M. M. J. Am. Chem. Soc. 1993, 115, 958.
(15) Taber, D. F.; You, K. K.; Rheingold, A. L. J. Am. Chem. Soc. 1996,
118, 547.
Org. Lett., Vol. 10, No. 8, 2008
1531

Table 5. [RuCl2(p-cymene)]2-Catalyzed Intramolecular
Carbenoid N-H Insertion Reactions for the Stereoselective
Synthesis of Phenyl-Substituted Prolines
Figure 1. Proposed structure of the reactive intermediate in the
Ru-catalyzed intramolecular carbenoid N-H insertion reaction.
entrya product
R1
R2
R3 timeb (h) yieldc (%)
The pure cis isomer of 1-(4-bromophenyl)-5-phenyl-
pyrrolidin-3-one ethyl ester that was obtained by recrystal-
lization interconverted gradually into the trans isomer in
solution under reflux. This change in stereochemistry is
attributed to an enolization, leading to the interconversion
of the cis to trans isomer in the reaction medium, which is
consistent with the results previously reported by Davis and
co-workers.11 In accordance with this finding, for the [Ru-
(CO)3Cl2]2-catalyzed intramolecular N-H insertion reaction
3 at 80 °C, the cis/trans ratio of product 7 decreased from
24:1 to 13:1 and further to 2:1 by increasing the reaction
time from 2 to 4 h and then 30 h (Table S4 in the Supporting
Information).
1
2
3
4
5
8a
8b
8c
8d
8e
8f
H
H
H
H
H
H
H
Me
Et
Et
Et
Et
Et
Et
Et
Et
4.5
2.5
2
2
2
2
3
4
5
89
85
95
92
94
94
86
93
90
88
87
o-Cl
m-Cl
p-Cl
H
6
p-Cl
p-Br
H
p-OMe
H
7
8
9
8g
8h
8i
H
p-Me
H
p-OMe Et
Me
10
11d
8j
8a
6
6
H
H
a Reaction conditions: 6 (0.2 mmol) was stirred with 1 mol % catalyst
in MeOH (2 mL). NaBH4 was added to the system after the diazo compound
was completely consumed. b The duration of the first step (i.e., the carbenoid
N-H insertion). c Isolated yield. d Reaction opened to the atmosphere.
The catalytic processes described in the present work can
be scaled up to gram scale with little effect on the overall
product yield or stereochemistry. R-(Phenylamino)benzene-
acetic acid ethyl ester was obtained in 98% yield by reacting
aniline (1.5 g, 8.0 mmol) with ethyl phenyldiazoacetate in
the presence of [RuCl2(p-cymene)]2 (0.1 mol %) in CH2Cl2
for 4.5 h. The phenyl-substituted 3-hydroxy-1,5-diphenylpyr-
rolidine-2-carboxylic acid methyl ester 8a was obtained in
91% yield by treating the diazocarbonyl compound 6a (1.0
g, 3.1 mmol) with [RuCl2(p-cymene)]2 (1.0 mol %) in MeOH
for 5.5 h.
Table 6. [RuCl2(p-cymene)]2-Catalyzed Intramolecular
Carbenoid N-H Insertion Reactions for the Stereoselective
Synthesis of Aliphatic and Phenyl-Substituted Prolines
In conclusion, we have established a convenient and
efficient protocol for carbenoid N-H insertion reactions
using the commerically available ruthenium catalyst [RuCl2-
(p-cymene)]2. The catalysis is tolerant toward oxygen and
moisture in the atmosphere. This new protocol offers direct
access to prolines with high stereoselectivities by one pot
intramolecular carbenoid N-H insertion reactions.
entrya
product
R1
R2
time (h)
yieldb (%)
1
2
3c
10a
10b
10c
Boc
Boc
Boc
Ph
2
2.5
2.5
87
85
84
t-Bu
cyclohexyl
a Reaction conditions: 9 (0.2 mmol) was stirred with 3 mol % catalyst
in MeOH. NaBH4 was added to the reaction mixture after the diazo
compound was completely consumed. b Isolated yield. c Reaction performed
in CH2Cl2.
Acknowledgment. This work was supported by The
University of Hong Kong (University Development Fund),
the Hong Kong Research Grants Council (HKU 7012/05P),
and the University Grants Committee of the Hong Kong SAR
of China (Area of Excellence Scheme, AoE/P-10/01). Q.H.
Deng and H.W. Xu thank the Croucher Foundation of Hong
Kong for a postgraduate studentship.
Davis.11b The carbomethoxy group at C-2 is forced into
the axial position by the metal (Figure 1). This is fol-
lowed by either a very fast or concerted proton trans-
fer, leading to the formation of product in a cis configur-
ation. As depicted in Table 4, lower cis/trans ratios were
found when [Ru(CO)3Cl2]2 or [Ru(2,6-Cl2TPP)CO] was used
as the catalyst, and the reactions catalyzed by these two
ruthenium complexes were observed only at temperature
g80 °C.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL800087P
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Org. Lett., Vol. 10, No. 8, 2008