Catalysis of enantioselective [2+1]-cycloaddition reactions of ethyl diazoacetate and terminal acetylenes using mixed-ligand complexes of the series Rh2(RCO2)n (L*4-n). Stereochemical heuristics for ligand exchange and catalyst synthesis

Article abstract of DOI:10.1021/ja052254w

This paper describes the synthesis of mixed Rh₂(II) complexes containing bridging acetate and R,R-diphenyl-N-triflylimidazolidinone (DPTI) ligands (1,2, and 9-19), and their function as enantioselective catalysts for the conversion of ethyl diazoacetate and terminal acetylenes to chiral cyclopropenes. Of these catalysts, 1 and 10 functioned with the highest enantioselectivity, in accord with a mechanistic model in which one of the ligand bridges is broken in the intermediate Rh-carbene complex, The synthetic results allow conclusions with regard to kinetically and thermodynamically favored pathways for the synthesis of mixed acetate-DPTI complexes. A new C ₂-symmetric complex having only two anti-DTBTI bridges (23) is shown to be a highly effective chiral catalyst, as expected from the model.

Full text of DOI:10.1021/ja052254w

Published on Web 09/22/2005
Catalysis of Enantioselective [2+1]-Cycloaddition Reactions
of Ethyl Diazoacetate and Terminal Acetylenes Using
Mixed-Ligand Complexes of the Series Rh2(RCO2)n (L*4-n).
Stereochemical Heuristics for Ligand Exchange and Catalyst
Synthesis
Yan Lou, Travis P. Remarchuk, and E. J. Corey*
Contribution from the Department of Chemistry and Chemical Biology,
HarVard UniVersity, Cambridge, Massachusetts 02138
Received April 7, 2005; E-mail: corey@chemistry.harvard.edu
Abstract: This paper describes the synthesis of mixed Rh2(II) complexes containing bridging acetate and
R,R-diphenyl-N-triflylimidazolidinone (DPTI) ligands (1, 2, and 9-19), and their function as enantioselective
catalysts for the conversion of ethyl diazoacetate and terminal acetylenes to chiral cyclopropenes. Of these
catalysts, 1 and 10 functioned with the highest enantioselectivity, in accord with a mechanistic model in
which one of the ligand bridges is broken in the intermediate Rh-carbene complex. The synthetic results
allow conclusions with regard to kinetically and thermodynamically favored pathways for the synthesis of
mixed acetate-DPTI complexes. A new C2-symmetric complex having only two anti-DTBTI bridges (23) is
shown to be a highly effective chiral catalyst, as expected from the model.
The use of Rh2(II) salts, e.g., Rh2(OAc)4, as catalysts for C-C
bond formation in [2+1]-cycloaddition reactions of olefins (or
acetylenes) and R-diazo carbonyl compounds or in ring-forming
C-H insertion reactions of the latter represents an important
synthetic tool,1 made even more powerful by the development
of highly enantioselective versions using chiral Rh(II) catalysts.
The most effective of these chiral catalysts thus far have been
Rh2-bridged dimers having four identical chiral bridging ligands,
especially the ligands of McKervey/Davies (N-arylsulfonyl-
proline),1i,2 Doyle (chiral 2-oxopyrrolidines),1a,b,3 and Hashimoto/
Ikegami (N-phthaloyl-tert-butylglycine).1e,4 The rate-limiting
step for these catalytic reactions is the reaction of the R-diazo
carbonyl with the Rh(II) catalyst, forming N2 and a Rh(II)
carbenoid complex.5 The detailed nature of that complex and
the subsequent product-forming step, which are both crucial to
the understanding of the mechanistic basis for enantioselectivity,
have been obscure, although the assumption that the carbenoid
complex retains the framework of Rh2L4 has commonly been
made for symmetrically bridged catalysts.1,6 This assumption
has also been used in the latest computational studies of the
product-forming step.7,8 We recently have described a different
mechanistic model of the product-forming step with unsym-
metrically bridged catalysts which is based on the idea that the
Rh-carbenoid complex contains only three of the original ligand
bridges of the starting Rh(II) catalyst and that the reaction
proceeds by a [2+2]-cycloaddition of the CdC or CtC linkage
to Rh-carbenoid π-linkage.9,10 On the basis of this hypothesis,
we synthesized the chiral Rh(II) complex 1,10,11 having one
acetate and three R,R-diphenyl-N-triflylimidazolidinone (DPTI)
ligands, and compared it to the closely related complex with
(5) (a) Pirrung, M. C.; Morehead, A. T., Jr. J. Am. Chem. Soc. 1994, 116,
8991-9000. (b) Pirrung, M. C.; Morehead, A. T., Jr. J. Am. Chem. Soc.
1996, 118, 8162-8163. (c) Pirrung, M. C.; Liu, H.; Morehead, A. T., Jr.
J. Am. Chem. Soc. 2002, 124, 1014-1023. (d) Alonso, M. E.; Garc´ıa, M.
del C. Tetrahedron 1989, 45, 69-76.
(6) (a) Sheehan, S. M.; Padwa, A.; Snyder, J. P. Tetrahedron Lett. 1998, 39,
949-952. (b) Snyder, J. P.; Padwa, A.; Stengel, T.; Arduengo, A. J., III;
Jockisch, A.; Kim, H.-J. J. Am. Chem. Soc. 2001, 123, 11318-11319.
(7) (a) Nakamura, E.; Yoshikai, N.; Yamanaka, M. J. Am. Chem. Soc. 2002,
124, 7181-7192. (b) Yoshikai, N.; Nakamura, E. AdV. Synth. Catal. 2003,
345, 1159-1171.
(8) Nowlan, D. T., III; Gregg, T. M.; Davies, H. M. L.; Singleton, D. A. J.
Am. Chem. Soc. 2003, 125, 15902-15911. These workers have also
measured 12C/13C kinetic isotope effects for olefin cyclopropanation.
(9) For other studies of the conversion of acetylenes to cyclopropenes, see:
(a) Petiniot, N.; Anciaux, A. J.; Noels, A.; Hubert, A. J.; Teyssie, P.
Tetrahedron Lett. 1978, 1239-1242. (b) Doyle, M.; Protopopova, M.;
Mu¨ller, P.; Ene, D.; Shapiro, E. J. Am. Chem. Soc. 1994, 116, 8492-8498.
(c) Protopopova, M.; Doyle, M.; Mu¨ller, P.; Ene, D. J. Am. Chem. Soc.
1992, 114, 2755-2757. (d) Mu¨ller, P.; Imoga¨ı, H. Tetrahedron: Asymmetry
1998, 9, 4419-4428.
(10) Lou, Y.; Horikawa, M.; Kloster, R. A.; Hawryluk, N. A.; Corey, E. J. J.
Am. Chem. Soc. 2004, 126, 8916-8919.
(11) The structure of this catalyst was confirmed by single-crystal X-ray
diffraction analysis.
(1) For reviews, see: (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern
Catalytic Methods for Organic Synthesis with Diazo Compounds; John
Wiley: New York, 1998. (b) Doyle, M. P.; Ren, T. In Progress in Inorganic
Chemistry; Karlin, K. D., Ed.; John Wiley: New York, 2001; pp 113-
168. (c) Davies, H. M. L.; Beckwith, R. E. J. Chem. ReV. 2003, 103, 2861-
2908. (d) Forbes, D. C.; McMills, M. C. Curr. Org. Chem. 2001, 5, 1091-
1105. (e) Hashimoto, S. Farumashia 2001, 37, 1095-1097. (f) Doyle, M.
P.; Forbes, D. C. Chem. ReV. 1998, 98, 911-935. (g) Doyle, M. P.;
Protopopova, M. N. Tetrahedron 1998, 54, 7919-7946. (h) Kitagaki, S.;
Hashimoto, S. Yuki Gosei Kagaku Kyokaishi 2001, 59, 1157-1168. (i)
Davies, H. M. L.; Antoulinakis, E. G. J. Organomet. Chem. 2001, 617-
618, 47-55. (j) Davies, H. M. L. Eur. J. Org. Chem. 1999, 2459-2469.
(2) Kennedy, M.; McKervey, M. A.; Maguire, A. R.; Roos, G. H. P. J. Chem.
Soc., Chem. Commun. 1990, 361-362.
(3) (a) Doyle, M. P.; Brandes, B. D.; Kazala, A. P.; Pieters, R. J.; Jarstfer, M.
B.; Watkins, L. M.; Eagle, C. T. Tetrahedron Lett. 1990, 31, 6613-6616.
(b) Doyle, M. P.; Zhou, Q.-L.; Simonsen, S. H.; Lynch, V. Synlett 1996,
697-698. (c) Doyle, M. P.; Winchester, W. R.; Protopopova, M. N.; Mu¨ller,
P.; Bernardinelli, G.; Ene, D.; Motallebi, S. HelV. Chim. Acta 1993, 76,
2227-2235.
(4) Hashimoto, S.; Watanabe, N.; Ikegami, S. Tetrahedron Lett. 1990, 31,
5173-5174.
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A R T I C L E S
Lou et al.
four DPTI ligands (2)10,11 in the reaction of ethyl diazoacetate
with terminal acetylenes. The chiral complex 1 efficiently
solubility of Rh2(t-BuCO2)4 as compared to Rh2(OAc)4. Of great
interest was the finding that 5 catalyzed the formation of
S-cyclopropenes from ethyl diazoacetate with about the same
enantioselectivity as catalyst 1.10 These results are consistent
with a major reaction pathway via 6 (pivalate ligand possibly
bidentate), very analogous to that proposed for the reaction with
catalyst 1. As described previously, there seems to be no logical
explanation of the results obtained with catalyst 5 on the basis
of a tetra-bridged carbenoid intermediate since the upper right
quadrant of 5 is sterically the most accessible to the acetylene
and is also effectively achiral.
catalyzed the [2+1]-cycloaddition of ethyl diazo-
acetate to a variety of terminal acetylenes to form chiral (S)-
cyclopropenes with enantioselectivities ranging from 39:1 to
24:1. These enantioselectivities were higher than those obtained
There are some important points that should be noted with
regard to catalysts 1 and 5 and the tri-bridged carbenoid
complexes derived therefrom. With regard to 1, it is reasonable
to believe that the attack by ethyl diazoacetate occurs at the
rhodium having three oxygen substituents and one nitrogen
substituent (front Rh in 1), since that rhodium is sterically more
available than the other (rear Rh in 1). It is that selectivity which
accounts for the preferential formation of the carbenoid complex
3. With reference to catalyst 5, the two Rh centers are equivalent,
so it makes no difference which one attaches to the diazo ester.
However, the formation of assembly 6 requires that the Rh-
pivalate bond which breaks preferentially in the carbenoid
complex is that which is trans to an oxygen ligand rather than
to a nitrogen ligand. Alternatively, this preference may be
summarized by stating that the carbenoid is more stable when
there is an oxygen trans to the vacant Rh site than when there
is a nitrogen. Regardless of the descriptive mode, the preference
is a reasonable one, given that the driving force for bridge
cleavage is the tendency for minimization of the formal Rh
valance state in the carbenoid complex.
The present study was initiated with the following objec-
tives: (1) to probe further the mechanistic details of the product-
forming step in Rh(II)-catalyzed [2+1]-cycloaddition of ethyl
diazoacetate to terminal acetylenes; (2) to test the above-
described hypotheses regarding the basis for enantioselection
using Rh(II) complexes with chiral N-triflylimidazolones,
including DPTI and certain structural analogues; (3) to examine
the enantioselectivity of [2+1]-cycloaddition for the entire series
of mixed DPTI-carboxylate-containing Rh(II) complexes, i.e.,
the family Rh2(DPTI)n(RCOO)4-n; (4) to examine the factors
controlling ligand-exchange reactions of Rh2(II) complexes to
clarify the factors controlling the regio- and stereoselectivity;
and (5) to identify useful new Rh2(II) catalysts for enantio-
selective synthesis. The complex demands of rational design
of mixed-ligand Rh2(II) complexes have not previously been
met with unsymmetrical ligands such as DPTI. Further, very
little is known about the rational planning of syntheses of mixed
Rh2(II)-carboxylate γ-lactam complexes.
in parallel experiments using the Rh2(DPTI)4 catalyst 2 (ca. 9:1).
The excellent results obtained with catalyst 1 are in accord with
the triply bridged structure 3 for the Rh-carbenoid intermediate
and reaction with the terminal acetylenic substrate by a pathway
via assembly 4, in which the more labile acetate bridge to the
rhodium bearing the carbenoid fragment has been broken. The
nonbridging acetate ligand in 3 and 4 is arbitrarily shown as
monodentate, but it is likely to be attached to the rear rhodium
in a bidentate mode. The [2+2]-cycloaddition step 3 f 4
involves the energetically more stable arrangement of the
carbenoid fragment, HCCOOEt, with the bulky COOEt group
cis to the Rh-O bond and opposite the bulkier N-CHPh group.
The regiochemistry of the cycloaddition step is that expected
for the carbenoid carbon, being more electrophilic than rhodium.
In 3, the Rh bearing the carbenoid has additional electron density
in an orbital that can provide better Rh-carbenoid back-bonding
than with the corresponding Rh(II) tetra-bridged structure. Even
if the tetra-bridged structure were to predominate over the tri-
bridged structure at equilibrium, the reaction with the acetylene
would still proceed via 4 if the equilibration were relatively
rapid and the reactivity of 4 were greater than that of the
isomeric tetra-bridged intermediate.
The results obtained with 1 and 2 led us to prepare and
examine the behavior of a catalyst containing only two DPTI
ligands, specifically the dipivalate complex 5.10,11 The dipivalate
was chosen for 5 instead of the corresponding diacetate because
it could be prepared in much better yield due to the greater
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[2+
1]-Cycloadditions of Ethyl Diazoacetate and Acetylenes
A R T I C L E S
Synthesis of Mixed Complexes Rh2(OAc)n(OCOCF3)4-n
.
single-crystal X-ray diffraction analysis15,16 (crystallized from
CH3CN/C6H6). This preparative route takes advantage of the
more facile displacement of the trans-trifluoroacetate bridge in
Rh2(OCOCF3)3(OAc) by AcO- and also the obvious driving
force for displacement of the more stabilized trifluoroacetate
ion by the less stabilized acetate ion. The facile preparation of
the cis (7) and trans (8) isomers of Rh2(OAc)2(OCOCF3)2
provided both a heuristic for synthetic planning and two very
useful starting materials for the synthesis of mixed-ligand
Rh2(II) complexes.
Synthesis of Mixed-Ligand Rh2(II) Complexes with DPTI
and Acetate. There are 14 possible Rh2(II)-DPTI complexes,
including mixed-ligand complexes with acetate, having the
formula Rh2(OAc)n(DPTI)4-n. These are systematically dis-
played in Scheme 1 as a synthetic tree which shows the possible
pathways of formation by unidirectional ligand displacement.
We have been able to synthesize all but one of these, complex
20. The structures of complexes 11,11 1,10 15,11 19,11 and 210
were determined by single-crystal X-ray diffraction analysis,
as indicated in Scheme 1. Structure 10 is the acetate analogue
of pivalate 5, the structure of which was also determined by
X-ray analysis,10 and gave essentially identical ee values in
[2+1]-cycloaddition reactions with terminal acetylenes. The ee
values given in Scheme 1 represent those experimentally
determined for the various complexes as catalysts for the
reaction of ethyl diazoacetate and 1-heptyne in CH2Cl2 at 23
°C under the same standardized conditions. Structural assign-
ments to the remaining complexes in Scheme 1 will be discussed
below together with the method of synthesis.
We carried out initial studies on the synthesis of mixed-ligand
Rh2(II) complexes with acetate and trifluoroacetate ligands as
a simple model. The selection of this system was also guided
by some important findings of J. L. Bear and colleagues on the
reaction of Rh2(OAc)4 with trifluoroacetic acid.12,13 These
workers reported rate constants for the successive formation of
mono-, di-, tri-, and tetratrifluoroacetates to be in the ratio 1:2:
0.1 and 0.025.12 It was of great interest to us that whereas the
rate of the second exchange was somewhat faster than the first,
the third and fourth exchanges were progressively much slower.
Because of this, these researchers were able to isolate a pure
mixed complex of composition Rh2(OAc)2(OCOCF3)2, which
they considered to be the stereoisomer in which two identical
ligands are trans to one another. Upon reinvestigation of this
interesting reaction, we found that exposure of Rh2(OAc)4 to
excess CF3CO2H at 23 °C for 1.5-2 h produced this major
product which could be isolated in 51% yield after column
chromatography on silica gel.14 Recrystallization from 10%
A mixture of the three cis isomers of Rh2(OAc)2(DPTI)2, 10,
11, and 12, was synthesized in a logical way from the cis isomer
of Rh2(OAc)2(OCOCF3)2 (7) by reaction with the sodium salt
of DPTI (prepared by reaction of DPTI in THF with sodium
hexamethyldisilazane, NaN(TMS)2) in THF solution at 0 °C
for 2 h and at 23 °C for 12 h, as shown in Scheme 2. Purification
of the crude reaction product (ratio of 10, 11, and 12 ca. 4:2:1)
by chromatography on silica gel (5% CH3CN in CH2Cl2 for
elution) afforded the following isolated yields: 10, 43%; 11,
23%; and 12, 11%. The structure of 12 was obvious from the
NMR spectrum, which shows nonequivalent DPTI ligands (e.g.
two CF3 peaks in the 19F NMR spectrum in contrast to the
spectra 10 and 11, which show only a single sharp CF3 peak),
and from the fact that the cyclopropene that formed from ethyl
diazoacetate and 1-heptyne with 12 as catalyst was completely
racemic. A racemic product is to be expected since the Rh-
carbenoid intermediate from 12 is expected to be that in which
the carbene has attached to the Rh that initially had four oxygen
ligands (the sterically most accessible and the most Lewis acidic
Rh). Such a carbenoid clearly has a symmetric environment that
would not lead to enantioselection in [2+1]-cycloaddition
reactions. The structure of 10 follows logically not only by a
process of elimination but also from its identical catalytic
behavior with the dipivalate analogue 5, to which that structure
had been assigned unambiguously by X-ray analysis.10
CH3OH in CH2Cl2 afforded monoclinic crystals which were
subjected to X-ray crystallographic analysis and shown to be
the cis isomer of Rh2(OAc)2(OCOCF3)2 (7)15 rather than the
trans isomer.12 A simple explanation for this may be that the
acetate bridge which is trans to the relatively electronegative
trifluoroacetate in Rh2(OAc)3(OCOCF3) is bound more tightly
than the other two and thus is more difficult to protonate (in
the intermediate for ligand exchange, presumably having two
nonbridging axial CF3CO2 ligands coordinated to the tetra-
bridged Rh2(OAc)3(OCOCF3)) and to displace. In any event, it
is clear that the more electron-attracting CF3CO2 bridge
disfavors displacement of the trans-CH3CO2 bridge relative to
the two cis-CH3CO2 bridges.
These observations suggested a rational plan for the synthesis
of trans-Rh2(OAc)2(OCOCF3)2 (8) that proved to be successful.
Reaction of Rh2(OCOCF3)4 in CH3CN solution with 2 equiv
of n-Bu4N+OAc- at 0 °C afforded, after column chromatog-
raphy, 75% yield of 8, the structure of which was proven by
(12) Bear, J. L.; Kitchens, J.; Willcott, M. R., III. J. Inorg. Nucl. Chem. 1971,
33, 3479-3486.
(13) See also: Johnson, S. A.; Hunt, H. R.; Neumann, H. M. Inorg. Chem.
1963, 2, 960-962.
(14) Small amounts of Rh2(OCOCF3)3(OAc) and Rh2(OAc)3(OCOCF3) were
also isolated from the reaction mixture by chromatography.
(15) For details on the determination of structure by single-crystal X-ray
diffraction analysis, see Supporting Information.
(16) The only other reaction product was Rh2(OAc)3(OCOCF3).
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A R T I C L E S
Lou et al.
Scheme 1. Synthetic Tree for Sequential Formation of Rh2(OAc)n(DPTI)4-n Complexesa
a The ee values shown in Scheme 1 refer to those measured for the catalyzed addition of ethyl diazoacetate to 1-heptyne (CH2Cl2 at 23 °C). b At 40 °C
in CH2Cl2.
The cis-anti complexes 10 and 11 could also be prepared in
one step from Rh2(OAc)4 by heating with 2 equiv of DPTI-H
in chlorobenzene-acetic acid at reflux for 36 h. After chroma-
tography of the crude reaction product, 10 was obtained in 25%
isolated yield and 11 was obtained in 31% isolated yield. The
remaining rhodium is accounted for as Rh2(OAc)4 and Rh2-
(OAc)3(DPTI) under these conditions. The acetic acid cosolvent
minimizes the amount of Rh2(OAc)(DPTI)3 formed under these
conditions.
Scheme 2
Reaction of trans-Rh2(OAc)2(OCOCF3)2 (8) with Na+DPTI-
in THF at 23 °C gave cleanly trans-syn-Rh2(OAc)2(DPTI)2 (14).
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[2+
1]-Cycloadditions of Ethyl Diazoacetate and Acetylenes
A R T I C L E S
Table 1. Anionic Ligand Displacement of Acetate by DPTI Anion
in THF: Observed Ratio of Product to Remaining Starting Material
(9) as a Function of Time
The preferential formation of the trans-syn isomer 14 over the
trans-anti isomer 13, which is thermodynamically more stable
than 14, is especially interesting (see below). In the conversion
8 f 14, the anion of DPTI preferentially displaces trifluoro-
acetate rather than acetate because the former is a better leaving
group.
Since trans-anti-Rh2(OAc)2(DPTI)2 (13) was not available
from 8, an alternative route was devised for its synthesis starting
from the readily available 1. Upon heating of 1 with 10 equiv
of n-Bu4N+OAc- and 1 equiv of Rh2(OAc)4 in Et2O at reflux
for 12 h, trans-anti-Rh2(OAc)2(DPTI)2 could be obtained in 20%
isolated yield after chromatographic separation on silica gel.
t, min
9
10
11
12
13
14
10
30
60
120
180a
600b
1
1
1
1
1
1
0
0
0
0
0
0
0
0.03
0.20
0
0
0
0
0.15
0.49
0.02
0.04
0.09
0.13
0.31
0.03
0.05
0.12
0.19
0.53
0.02
0.03
0.05
0.06
0.10
a 1 (0.36) and 16 (0.03) also formed. b 1 (0.61) and 16 (0.16) also formed.
from the four equivalent ligands. We have never observed 20
as a reaction product, in all likelihood because that structure is
destabilized by strong steric repulsions between the substituents
on the four bridges and also destabilized electronically (see
below).
Enantioselectivity of the Reaction of Ethyl Diazoacetate
with 1-Heptyne as a Function of Catalyst Structure with
Complexes 1, 2, and 9-19. It is apparent from the data shown
in Scheme 1 that the highest enantioselectivities in the catalytic
test reaction of ethyl diazoacetate with 1-heptyne were observed
with catalysts 1 (95% ee) and 10 (91% ee), as expected for a
pathway via pre-transition-state complexes 4 and 6 (acetate
instead of pivalate), respectively, and as discussed in the
introductory section and in an earlier publication.10 The lower
enantioselectivities found for the catalyzed ethyl diazoacetate-
heptyne reactions using the rhodium complexes 11-19 and 2
(summarized in Scheme 1) are also consistent with the proposed
pathway. It is interesting that of all the Rh2(II) catalysts shown
in Scheme 1, the least reactive toward ethyl diazoacetate is the
cis-(2,2)-18, in which every Rh-O bond is trans to an Rh-N
bond. In the case of trans-anti-Rh2(OAc)2(DPTI)2 (13) as
catalyst, the 82:18 selectivity (64% ee) for formation of ethyl
(1S)-2-n-amyl-2-cyclopropenylcarboxylate from 1-heptyne and
ethyl diazoacetatesour mechanistic modelsrequires selectivity
in the cleavage of one acetate bridge in the intermediate
carbenoid (the upper acetate bridge of 13 in Scheme 1). This
point is discussed further in the last section of this paper. The
very low ee’s (0-5%) that result from the use of catalysts 12,
14, and 17 are predictable from the mechanistic model.
Preferred Pathways for the Formation of Rh2(OAc)n-
(DPTI)4-n Complexes by DPTI- Displacement of Acetate.
We have also carried out a kinetic investigation of selective
formation of mixed acetate-DPTI complexes of Rh(II) using
the displacement reaction of acetate by Na+DPTI- in THF
solution. The greater stability of AcO- vs DPTI- clearly
provides the driving force for this process. The reaction of
Rh2(OAc)n(DPTI)4-n with Na+DPTI- (from DPTI and sodium
hexamethyldisilazane) in THF at 50-60 °C was monitored by
HPLC analysis to determine quantitatively the rate of formation
of the new complexes formed by ligand displacement. The
complexes 9-19, 1, and 2 could all be distinguished by HPLC
analysis using a standard elution protocol.17 Some of the salient
results of this study are presented in Tables 1 and 2. A more
The remaining material from the reaction was the starting
complex Rh2(OAc)(DPTI)3 (1). Subsequent to the development
of this first preparation of 13, it was discovered that the same
compound could be made by isomerization of the less stable
14. Thus, upon heating of 14 in chlorobenzene solution at reflux
for 10 h, it was transformed into an 82:18 mixture of 13 and
14, respectively. The structures of 13 and 14 followed from 1H
and 19F NMR studies in the presence of pyridine.
Complex 13, in which the two DPTI ligands are in the trans-
anti relationship, coordinates with 1 equiv of pyridine to generate
a mono-pyridine adduct that exhibits four distinct methine
signals in the 1H NMR spectrum. With excess pyridine a
symmetrical bis-pyridine adduct is formed showing two methine
signals. In contrast, complex 14, in which the two DPTI ligands
are in a trans-syn relationship, coordinates with 1 equiv of
pyridine selectively to form a single mono-pyridine adduct that
shows two methine signals, as expected for the complex of
pyridine at the Rh having four oxygen ligands. The bis-pyridine
complex of 14 also shows two methine proton signals, as
expected for that structure. It is noteworthy that when 14 was
employed as catalyst in the [2+1]-cycloaddition of ethyl
diazoacetate to 1-heptyne, the cyclopropene carboxylic ester was
produced with only 5% ee, as expected for trans-syn-Rh2(OAc)2-
(DPTI)2.
The remaining rhodium-DPTI complexes that appear in
Scheme 1 were readily synthesized. Reaction of either complex
10 or 11 with Na+DPTI- in THF at 50 °C afforded 16, allowing
assignment of its structure. Complex 17 was similarly prepared
from 12 and Na+DPTI- in THF, which allowed assignment of
the structure 17. Complexes 18 and 19 were formed along with
2 by heating Rh2(OAc)4 with DPTI in chlorobenzene at reflux
in a Soxhlet apparatus containing a mixture of CaH2 and Celite
545 to remove HOAc from the reaction mixture. Chromatog-
raphy of the mixture furnished 2 as major product, lesser
amounts of 18, and an even smaller amount of 19. The structure
of 18 followed clearly from the 1H and 19F NMR spectra, which
showed two sets of peaks due to the two pairs of identical
ligands (i.e., those trans to each other). Structure 20, the only
remaining possibility, would show only a single set of peaks
(17) HPLC analysis was performed using a Microsorb MV silica column, 23
°C, detection at 254 nm, 1 mL/min flow rate, with the following solvent
mixtures: 20/78/2 EtOAc-hexanes-CH3CN (30 min); 80/18/2 EtOAc-
hexanes-CH3CN (30 min); then 20/78/2 EtOAc-hexanes-CH3CN (10
min). The retention times of the isomers in Scheme 1 were determined to
be as follows: 9, 51 min; 10, 39.8 min; 11, 40.5 min; 12, 41 min; 13, 22
min; 14, 25 min; 1, 15.2 min; 15, 13.7 min; 16, 10.3 min; 17, 30.3 min;
18, 10.0 min; 19, 6.1 min; 2, 10.8 min; (R,R)-DPTI, 7.0 min.
9
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A R T I C L E S
Lou et al.
Scheme 4. Other Pathways for Anionic Ligand Displacement of
Table 2. Anionic Ligand Displacement of Acetate by DPTI Anion
in THF: Observed Ratio of Product to Remaining Starting Material
(10, 11, or 12) as a Function of Time
Acetate by DPTI Anion in THF
a. From 10
b. From 11
t, min
10
1
16
11
16
2
60
180
1440
1
1
1
0
0
0.76
0.24
0.36
11.4
1
1
1
0
0.06
0.39
0
0
0.41
c. From 12
t, min
10
11
1
15
16
17
30a
60a
0
0.01
0.02
1
1
1
0.08
0.09
0.12
0.47
0.46
0.49
3.2
3.4
3.5
0.88
0.97
0.95
180a
a No 12 remaining.
Scheme 3. Kinetically Preferred Pathways for Anionic Ligand
Displacement of Acetate by DPTI Anion in THF
that 16 can undergo an interesting isomerization to 1 and that
1 is converted preferentially to 2. This isomerization of 16 to 1
indicates that it is possible for DPTI- to displace itself and to
do so in a way that effects a syn/anti stereomutation. The
behavior of the cis-syn-Rh2(OAc)2(DPTI)2 complex 12 is also
interesting. Upon heating with Na+DPTI- in THF, it is rapidly
isomerized to the clearly more stable P-cis-anti complex 11,
another example of stereomutation by DPTI- at a rate that is
fast relative to displacement of AcO-.
Our kinetic studies have also revealed a number of inter-
conversions that result from slower pathways for nucleophilic
displacement of acetate by DPTI- in Rh(II) complexes. These
slower pathways are summarized in Scheme 4. In addition to
the isomerization process that converts 12 to 11, 12 undergoes
displacement to form 15 and 17. The trans-syn complex 14 also
is subject to isomerization to form the trans-anti complex 13
that then goes on to 15 by acetate displacement. It is of
considerable interest that trans-syn-Rh2(OAc)2(DPTI)2 (14) is
less stable than the trans-anti isomer 13 because this difference
in stability must be associated with intrinsically less favored
bonding for DPTI ligands that are syn to one another as
compared to anti since steric destabilization cannot be a factor
here.18 Our failure to synthesize complex 20 may be due to the
occurrence in 20 of both electronic destabilization of the type
operating in 14 and steric repulsion.
General Aspects of Rh2(II) Ligand-Exchange Reactions.
The results described above on the displacement of acetate in
Rh2(II) complexes by Na+DPTI- in THF at 50-60 °C point to
some significant trends with regard to preferred pathways. First,
the formation of cis-anti arrangements of DPTI ligands appears
to be favored. Second, the displacements are kinetically
controlled at low conversions. Third, Na+DPTI- can also cause
isomerization of unstable to more stable structures in the Rh2-
(OAc)2(DPTI)2 series, for example the conversion of 12 to 11,
or 14 to 13.
extensive summary of the data appears in the Supporting
Information. From perusal of the information in Tables 1 and
2, it is evident that certain regio- and stereochemical preferences
exist for the ligand displacement reactions and that some
products are preferred over the other possibilities that are
summarized in Scheme 1. These kinetically favored reaction
pathways are shown in Scheme 3. Starting from Rh2(OAc)3-
(DPTI), the Rh2(OAc)2(DPTI)2 isomers 10, 11, and 12, all of
which have a cis arrangement of ligands (two bridges are cis if
they are at 90° angles to one another), are favored over the
trans isomers 13 and 14. At long reaction times 13 and 14
appear, evidently as secondary products formed by isomerization
of 10, 11, and/or 12. The Rh2(OAc)2(DPTI)2 isomers 10 and
11 are both converted preferentially to 16 by acetate displace-
ment. Complex 16 is then preferentially converted to 2 by
displacement of acetate by DPTI-. Our analyses also revealed
The conventional method of synthesis of Rh2(II) complexes
with chiral ligands involves the thermal reaction of an achiral
rhodium carboxylate, usually Rh2(OAc)4, with the chiral ligand
(18) It is possible that the trans-anti arrangement of DPTI ligands is energetically
more favorable than the trans-syn alternative in Rh2(II) complexes because
the former allows the two Rh centers to have the same electron density
and effective charge.
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[2+
1]-Cycloadditions of Ethyl Diazoacetate and Acetylenes
A R T I C L E S
Scheme 5
in refluxing solvent (e.g., C6H6 or C7H8). We have used this
method extensively to synthesize Rh2(DPTI)4 and Rh2(OAc)-
(DPTI)3 complexes, generally using C6H5Cl as solvent at reflux
with external CaH2-Celite 545 for continuous removal of
HOAc. Careful study of this thermal process by HPLC analysis
of reaction mixtures as a function of time has demonstrated that
this method generally leads to near-equilibrium mixtures of
products (see Supporting Information).
Studies on trans-anti-Rh2(OAc)2(DTBTI)2. As indicated in
Scheme 1, trans-anti-Rh2(OAc)2(DPTI)2 (13) catalyzes the
reaction of ethyl diazoacetate and 1-heptyne to form ethyl (1S)-
2-n-amyl-2-cyclopropenylcarboxylate of 64% ee (82:18 selectiv-
ity). Because this enantioselection can be explained by a
preference for pre-transition-state assembly 21 over the alterna-
tive 22, we were interested in testing whether the difference in
stability of 21 and 22 (or their bidentate acetate equivalents)
could be magnified by replacing the phenyl groups in catalyst
13 by the bulkier tert-butyl group, as shown in structure 23.
Table 3. Cyclopropenation of Ethyl Diazoacetate and Terminal
Alkynes Catalyzed by 23
entry
R
T,
°
C
yield, %
ee, %a
1
2
3
4
CH3(CH2)4
CH3(CH2)4
t-Bu
23
0
0
87
84
81
78
89
91
90
93
MeOCH2
0
a Enantiomeric excess was determined by GC using a γ-TA column.10
As expected from our mechanistic model, trans-anti-Rh2-
(OAc)2(DTBTI)2 (23) afforded substantially better enantiose-
lectivity than trans-anti-Rh2(OAc)2(DPTI)2 (13) for the reaction
of ethyl diazoacetate with 1-alkynes. Table 3 summarizes the
data obtained with catalyst 23 and three different alkynes which
show enantioselectivities of approximately 20:1 for each case.
We believe that these results provide additional evidence in
support of a pre-transition-state model analogous to 21 (for the
DPTI series).
Conclusions. The major objective of this work was the
investigation of the synthesis and catalytic properties of a series
of complexes of the type Rh2(OAc)n(ligand)4-n. Both cis- and
trans-Rh2(OAc)2(OCOCF3)2 have been synthesized, analyzed
to demonstrate structure, and applied as starting materials to
the synthesis of chiral Rh2(II) complexes. Thirteen of the
complexes Rh2(OAc)n(DPTI)4-n, whose structures are system-
atically displayed in Scheme 1, have been made and character-
ized structurally and then applied as catalysts to determine their
effectiveness in the synthesis of chiral ethyl 2-n-amyl-2-
cyclopropenylcarboxylate from 1-heptyne and ethyl diazoacetate.
As predicted from the mechanistic model described in the
introduction, complexes 1 and 10 excel with regard to enanti-
oselectivity, complexes 12, 14, 17, and 19 are poor, and 2, 11,
13, 15, 16, and 18 are mediocre (64-80% ee). Also as expected
from the mechanistic model, trans-anti-Rh2(OAc)2(DTBTI)2
(23) gave much better enantioselectivity (91%) than the DPTI
That replacement would be expected to disfavor a pathway via
the tert-butyl analogue of 22 vs that via the tert-butyl analogue
of 21 for two reasons: (1) the steric repulsion between the
acetylenic R group and tert-butyl in the analogue of 22 should
be considerably greater than for phenyl in 22 and (2) the steric
repulsion between the nonbridging acetate ligand in the tert-
butyl analogue of 22 would be greater than for phenyl in 22.
Consequently, we have synthesized the trans-anti complex 23,
which we designate herein as trans-anti-Rh2(OAc)2(DTBTI)2,
where DTBTI stands for the ligand (R,R)-4,5-di-tert-butyl-N-
triflylimidazolinone (25). The synthesis of the (R,R)-ligand 25
was carried out from (1R,2R)-1,2-di-tert-butylethylenediamine
(24).19 The route of synthesis is outlined in Scheme 5. The
reaction of trans-Rh2(OAc)2(OCOCF3)2 with Na+DTBTI- in
THF at 23 °C gave a mixture of trans-anti-Rh2(OAc)2(DTBTI)2
(23) and trans-syn-Rh2(OAc)2(DTBTI)2 in a ratio of ca. 1:2.20
Pure 23 was obtained by chromatography of this mixture on
silica gel (26% yield, unoptimized).21
(21) The structures of 23 and trans-syn-Rh2(OAc)2(DTBTI)2 were determined
by X-ray diffraction analysis. Interestingly, the latter forms only a mono-
complex with either MeOH or pyridine, as shown by X-ray or 1H NMR
spectral analysis, respectively.
(22) After this paper was submitted for publication, a Communication appeared
in which 12,13C kinetic isotope effects were measured for Rh2(OAc)4 and
Rh2(OAc)(DPTI)3 as catalysts for the reaction of N2CHCOOEt with
1-pentyne. See: Nowlan, D. T.; Singleton, D. A. J. Am. Chem. Soc. 2005,
127, 6190-6191. These results and theoretical calculations were claimed
to support the pathway involving tetrabridged Rh-carbenoid species,
contrary to our proposal.10 In our opinion, neither the kinetic isotope effect
data nor the theoretical calculations provide an adequate basis for favoring
one pathway over the other.
(19) Diamine 24 was prepared in this laboratory in 1988 by Dr. Po-Wei Yuen
by addition of tert-butylmagnesium chloride and the Schiff base of
benzylamine, glyoxal, followed by debenzylation with H2 and Pd-C
catalyst, and then resolution with R,R-tartaric acid, a method subsequently
developed also by Roland et al. (Roland, S.; Mangeney, P.; Alexakis, A.
Synthesis 1999, 228-230).
(20) As described above, the corresponding reaction in the DPTI series gave
selectively trans-syn-Rh2(OAc)2(DPTI)2 (14).
9
J. AM. CHEM. SOC. VOL. 127, NO. 41, 2005 14229

A R T I C L E S
Lou et al.
analogue 13 (64% ee). Preferred stereochemical pathways were
identified for the anionic displacement of acetate by Na+DPTI-
in the synthesis of the complexes shown in Scheme 1. This work
provides a basis for more rational planning of the stereocon-
Supporting Information Available: Synthetic procedures and
characterization data for the new Rh2(II) complexes reported
herein (PDF); X-ray crystallographic data for compounds 1, 2,
7, 8, 11, 15, 19, 23, and trans-syn-Rh2(OAc)2(DTBTI)2 (CIF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
trolled synthesis of complexes of the series Rh2(OAc)n-
22
(ligand)4-n
.
Acknowledgment. We are grateful to Drs. Richard Staples
and Robin Kloster for the X-ray crystallographic data.
JA052254W
9
14230 J. AM. CHEM. SOC. VOL. 127, NO. 41, 2005