Cationic chiral dirhodium carboxamidates are activated for lewis acid catalysis

Article abstract of DOI:10.1002/anie.200704618

(Chemical Equation Presented) The power of a positive charge: Oxidized chiral dirhodium carboxamidate salts increase the rate of reaction of selected aldehydes with the Danishefsky diene (hetero-Diels-Alder reaction) and with nitrones (1,3-dipolar cycload

Full text of DOI:10.1002/anie.200704618

Angewandte
Chemie
DOI: 10.1002/anie.200704618
Asymmetric Catalysis
Cationic Chiral Dirhodium Carboxamidates Are Activated for Lewis
Acid Catalysis**
Yuanhua Wang, Joffrey Wolf, Peter Zavalij, and Michael P. Doyle*
Dedicated to Professor Henri Brunner on the occasion of his 72nd birthday
Chiral dirhodium(II) carboxamidates have high potential for
enantioselective Lewis acid catalyzed reactions because they
hold the Lewis base, which is activated for reaction, at the
axial coordination site in close proximity to the ligand
attachments for chiral differentiation. As has already been
demonstrated for the hetero-Diels–Alder reaction
(Scheme 1)[1,2] and for trimethylsilylketene/glyoxal cycload-
dition,[3] the chiral environment around the axial coordination
suitable to catalysis by the cationic metal complex.[6] We
anticipated that cationic chiral RhII/RhIII compounds could
increase the closeness of association of the catalyst with Lewis
bases, increase the rate of reaction with selected substrates,
and enhance enantiocontrol.
Oxidation of dirhodium(II) (Rh24+) compounds is well
known,[6] but their Rh25+ counterparts have been produced in
the presence of either a less labile ligand such as halide[7] or by
using another transition metal such as AgI, CeIV, or CuII for
the oxidation,[6,8] none of which are amenable to the use of
5+
Rh2 complexes as catalysts without laborious separation or
further catalyst manipulation. However, we have recently
discovered that nitrosonium salts effect facile oxidation of
dirhodium(II) carboxamidates at room temperature to form
the corresponding RhII/RhIII salts quantitatively, evolving
nitric oxide in the process. These complexes exhibit a
characteristic electronic absorption near 1000 cmÀ1. A crystal
structure for the bis(acetonitrile) complex of [Rh2{(4S)-
meox}4]BF4 is shown in Figure 1.
Scheme 1. Hetero-Diels–Alder reaction catalyzed by chiral dirhodi-
um(II) carboxamidates. TMS=trimethylsilyl, TFA=trifluoroacetic acid.
site strongly influences enantiocontrol and also pushes the
product off the rhodium axial coordination site to provide
turnover numbers (TON) as high as 10000.
5+
To test the ability of chiral Rh2 carboxamidates to
enhance selectivity in Lewis acid catalyzed transformations
we turned our attention to the hetero-Diels–Alder reaction
and to [Rh2(mepy)4] as the catalyst. As has been reported,[1a]
the use of 1.0 mol% [Rh2(mepy)4] with p-nitrobenzaldehyde
and the Danishefsky diene (see Scheme 1) resulted in the
corresponding hetero-Diels–Alder product (53% yield) in
However, the Lewis acidity for dirhodium(II) carboxami-
dates is low compared to that of many other catalysts for these
reactions.[4] Suitable Diels–Alder, ene, and dipolar cyclo-
addition reactions, for example, show no catalytic activity
with chiral dirhodium(II) carboxamidates, even with a,a-
difluoro analogues of the mepy and meaz catalysts that were
developed to enhance Lewis acid association with Lewis
bases.[5] We have prepared cationic RhII/RhIII counterparts to
the moderately active chiral dirhodium(II) carboxamidates to
enhance the Lewis acidity of these chiral dirhodium catalysts.
Cationic metal complexes are now commonly used to achieve
rate and selectivity enhancements for those transformations
5+
73% ee; use of the corresponding Rh2 complex, [Rh2{(5S)-
mepy}4]BF4, produced the same product in 93% ee (Table 1).
With the slow-reacting benzaldehyde,[1b] [Rh2{(5S)-
[*] Dr. Y. Wang, P. Zavalij, Prof. M. P. Doyle
Department of Chemistry and Biochemistry
University of Maryland
College Park, MD 20742 (USA)
Fax: (+1)301-405-7058
E-mail: mdoyle3@umd.edu
Dr. J. Wolf
Laboratoire de Chimie de Coordination
205 route de Narbonne
31077 Toulouse Cedex 4 (France)
[**] We are grateful to the National Institutes of Health (GM 46503) and
the National Science Foundation for their generous support. J.W.
thanks the “Fonds Social EuropØen” for a fellowship.
Figure 1. ORTEP view of [Rh2{(4S)-meox}4]BF4 as its bis(acetonitrile)
complex. Ellipsoids are shown at 30% probability; hydrogen atoms
are omitted for clarity. Selected bond lengths [Š]: Rh-Rh 2.4600(3);
Rh-Nmeox 1.958, 1.960, 1.983, 2.010(5); Rh-O 2.031, 2.031, 2.045,
2.046(4); Rh-NCMe 2.214, 2.265(6).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2008, 47, 1439 –1442
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1439

Communications
mepy}4]BF4 provides a substantial rate enhancement. With
One of the significant challenges in asymmetric Lewis acid
catalysis is a 1,3-dipolar cycloaddition between nitrones and
enals[10–13] to form isoxazolidines. A variety of chiral catalysts
have been used for the transformation with methacrolein,
which occurs in variable yields, usually below room temper-
ature, with the use of 5–10 mol% of catalyst and excess
methacrolein (Table 2). Ruthenium and iron catalysts
(Table 2, entries 1–2) appear to favor the formation of
2,[10,11] and the only example of a nickel catalyst (Table 2,
entry 5, with chiral ligand 3, which is shown in Scheme 2)
shows complete selectivity for the formation of 2.[12] Chiral
dirhodium(II) carboxamidates have been unsuitable because
they lack catalytic activity (e.g., Table 2, entry 6). In contrast,
chiral Rh5+ carboxamidates show high catalytic activity
(Table 2, entry 7). [Rh2{(5S)-mepy}4]BF4 exhibited high regio-
selectivity for 2 with modest enantioselectivity. Increasing the
steric bulk of the ligand ester group from methyl (4+) to
isopropyl (5+)[9] and, reported for the first time, to (R)-
menthyl (6+) enhanced the enantioselectivity for 1, but not for
2, for which the ee value remained at nearly the same level
throughout the selection of dirhodium catalysts. Other chiral
cationic dirhodium carboxamidate catalysts, [Rh2{(4S)-
meox}4]BF4 and [Rh2{(4S)-meaz}4]BF4, gave regio-and enan-
tioselectivities that were lower than those from [Rh2{(5S)-
mepy}4]BF4. Results do not vary when the molar ratio of
methacrolein over the nitrone is varied from 1.4 to 10, and the
enantioselectivity is the same when the catalyst loading is
increased from 5 to 10 mol%. Furthermore, there is no
detectable variation of regioselectivity or enantioselectivity
ethyl glyoxylate, enantioselectivity rose from 20 to 74% ee
with the enantiomer of the same catalyst under the same
conditions, and the rate of reaction with [Rh2{(5S)-
mepy}4]BF4 is significantly faster than that with [Rh2{(5S)-
Table 1: Influence of the cationic dirhodium (5S)-mepy catalysts on
reactivity and selectivity in hetero-Diels–Alder reactions of the Dani-
shefsky diene with representative aldehydes.[a]
Aldehyde
Catalyst
Conv. [%][b]
ee [%][c]
p-NO2C6H4CHO
p-NO2C6H4CHO
C6H5CHO
[Rh2{(5S)-mepy}4]
[Rh2{(5S)-mepy}4]BF4
[Rh2{(5S)-mepy}4]
[Rh2{(5S)-mepy}4]BF4
[Rh2{(5S)-mepy}4]
[Rh2{(5S)-mepy}4]BF4
[Rh2{(5S)-mepy}4]PF6
[Rh2{(5S)-mepy}4]SbF6
53
70
<5
40
<10
100
100
100
73
93
–
88
20
74
76
76
C6H5CHO
EtOOCCHO
EtOOCCHO
EtOOCCHO
EtOOCCHO
[a] Reactions were performed with1.0 mol% catalyst at room temper-
ature in anhydrous dichloromethane with a reaction time of 24 h using
1
1.1 equiv diene. [b] Determined by H NMR analysis. [c] Determined by
HPLC on an OD-H or AD-H column.
mepy}4]. The estimated increase in rate by [Rh2{(5S)-
mepy}4]BF4 is at least a factor of ten. As can be seen from
5+
this data, the anion of the Rh2 complex has no measurable
effect on the enantioselectivity. In its use as a Lewis acid
5+
catalyst, coordination of the Rh2 complex with water was
expected to produce a protonic acid; to circumvent this
problem these reactions were performed in the presence of a
noncoordinating base.
À
À
with the anion of the cationic catalyst (BF4 vs. PF6 or
À
SbF6 ). Use of 2,6-di-tert-butylpyridine (DTBP) to remove
The oxidation of organic com-
pounds by dirhodium(II/III) car-
Table 2: Comparative influence of cationic dirhodium carboxamidate catalysts on reactivity and
selectivity in 1,3-dipolar cycloaddition reactions between C,N-diphenylnitrone and methacrolein.[a]
boxamidates was anticipated.
Indeed, we have known for many
5+
years that Rh2 complexes are
4+
reduced to Rh2 by diazoacetates,
and this is one of the factors that
allows dirhodium(II) catalysts to
be used with high TON.[9] How-
ever, we anticipated that there are
Entry
Catalyst
Mol%
T
[C8]
Yield
[%]
1/2[b]
1/2
ee [%][c]
other oxidizable substrates in
1
2
3
4
5
6
7
8
[CpRu{Ar2POCH*(Ph)C*H(Ph)OPAr2}][d]
[CpFe{Ar2POCH*(Ph)C*H(Ph)OPAr2}][d]
[Cp*Rh{Ph2PC*H(Me)CH2PPh2}][e]
[Cp*Rh{Ph2PC*H(Me)CH2PPh2}][e]
Ni(ClO4)2·6H2O+(R,R)-DBFOX/Ph( 3)[f]
[Rh2{(5S)-mepy}4] (4)
[Rh2{(5S)-mepy}4]BF4 (4-BF4)
[Rh2{(5S)-ippy}4]BF4 (5-BF4)
[Rh2{(5S,R)-menpy}4]SbF6 (6-SbF6)
[Rh2{(5S,R)-menpy}4]SbF6 (6-SbF6)[g]
[Rh2{(5S,R)-menpy}4]SbF6 (6-SbF6)[h]
5
5
5
5
10
5
5
5
5
5
À20
À20
À25
0
92
85
100
100
73
<5
80
64
40:60
20:80
63:37
53:47
0:100
3:97
13:87
12:88
33:67
37:63
24:76
94:76
91:87
90:75
85:68
–:96
22:20
30:64
63:71
88:67
94:71
95:53
5+
whose presence Rh2
will be
reduced to Rh24+; thus, one proce-
dural requirement of our investi-
gation has been to test the redox
stability of the reacting partners
RT
À20
À20
RT
RT
RT
5+
with the Rh2 catalyst. We have
found, for example, that [Rh2{(4S)-
meox}4]BF4 is reduced by the Dan-
ishefsky diene, and the rate of this
oxidation is competitive with ca-
talysis at temperatures above 408C.
In contrast, [Rh2{(5S)-mepy}4]BF4,
which has a much lower oxidation
potential (358 mV vs. 742 mV),[5] is
stable to reduction by the Dan-
ishefsky diene over long reaction
times.
9
10
11
88
90
95
1
RT
[a] Reactions were performed in anhydrous dichloromethane with a reaction time of 24 h using a slight
excess of methacrolein (1.4 equiv), 10 mol% 2,6-di-tert-butylpyridine, and 4-Š molecular sieves (0.5 g
per mmol of nitrone). [b] Yield determined by product mass and 1/2 ratio determined by 1H NMR
analysis of reaction mixture using easily distinguished aldehydic protons. [c] Determined by 1H NMR of
the diastereomeric imine protons formed from reaction of 1 and 2 with( S)-(À)-a-methylbenzylamine
(reference [11a]); racemic product was obtained by reaction withdirohdium caprolactamate.
[d] Reference [10a]. [e] Reference [11a]. [f] Reference [12]. [g] In situ generated catalyst. [h] Catalyst
generated in situ witha reaction time of 48 h.
1440 www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 1439 –1442

Angewandte
Chemie
Table 3: Nitrone substituent effects in [Rh2{(5S,R)-menpy}4]SbF6-cata-
lyzed 1,3-dipolar cycloaddition reactions between C-aryl-N-phenylni-
trones 7 and methacrolein.[a]
Entry
Ar in 7
Mol%
Yield [%]
8/9
8/9
ee [%]
1
2
3
p-NO2C6H4 (7a)
C6H5 (7b)
p-MeOC6H4 (7c)
p-MeOC6H4 (7c)
3,4-(MeO)2C6H3 (7d)
p-Me2NC6H4 (7e)
5
5
5
1
5
5
82
90
83
86
60
50
16:84
37:63
67:33
47:53
65:35
90:10
21:46
94:71
91:60
93:28
90:55
90:45
4[b]
5
6
[a] Reactions were performed in anhydrous dichloromethane with a
reaction time of 24 husing [Rh {(5S,R)-menpy}4]SbF6 as the catalyst, a
2
slight excess of methacrolein, 10 mol% 2,6-di-tert-butylpyridine, and 4-Š
molecular sieves (0.5 g per mmol of nitrone). Products were analyzed as
reported in Table 2. [b] Catalyst generated in situ witha reaction time of
48 h.
Scheme 2. Structures of catalysts/ligands in Table 2.
protonic acid does not affect the catalytic activity of the Rh5+
salt. In situ preparation of 6+ gave higher product yields and
selectivities and allowed this reaction to be performed with
only 1.0 mol% of catalyst (Table 2, entries 10 and 11), but the
background reaction forming 2 was more pronounced. The
(S)-menthyl diastereoisomer of 6+ gave the same product
outcome as 6+.
Experimental Section
A flask containing [Rh2{(5S,R)-menpy}4]SbF6 (11.95 mg, 7.61 mmol)
and 4-Š molecular sieves (75 mg) was evacuated and purged with
nitrogen. Anhydrous dichloromethane (0.5 mL) was added, and the
mixture was stirred for 10 min at room temperature before 2,6-tert-
butylpyridine (3.52 mL, 0.015 mmol) was added by microsyringe.
After stirring for another 10 min at room temperature, freshly
distilled methacrolein (0.013 mL, 0.152 mmol) was added, and the
resulting solution was stirred for 30 min. A solution of the C,N-
diphenylnitrone (30 mg, 0.152 mmol) in dichloromethane (1 mL) was
then added dropwise to the flask, and the solution was stirred at room
temperature for 24 h and monitored by TLC for complete consump-
tion of the nitrone. The mixture was loaded directly onto a short silica
gel column to remove the catalyst and was washed with CH2Cl2
(20 mL). The combined organic layer was evaporated to dryness. The
regioisomer ratio was determined on the reaction mixture by
1H NMR analysis. The reaction mixture was purified by flash
chromatography on silica gel (CH2Cl2) to afford an inseparable
mixture of the desired products (35.8 mg, 88%).
Early results from Kündig and co-workers[10a] in which an
electron-withdrawing substituent on the C-phenyl ring of
C,N-diphenylnitrone was reported to increase the regioselec-
tivity of 3,4-endo/3,5-endo products (8/9; Scheme 3) from
Scheme 3.
CCDC 661689 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
40:60 to 0:100 prompted us to examine the influence on
selectivity by C-aryl substituents of C-aryl-N-phenylnitrone in
reactions with methacrolein. Since catalyst 6+ provides high
enantiocontrol for 8 but not for 9, our goal was to use
substituent effects on nitrone 7 to direct reaction regioselec-
tivity toward 8, which was anticipated to be formed with high
enantioselectivity. Indeed, with 5.0 mol% [Rh2{(5S,R)-
menpy}4] at room temperature, use of 7a (Ar= p-NO2C6H4)
produced an increase in regioselectivity favoring 9, but
nitrone 7c with the p-methoxy substituent reversed the
selectivity, and the p-dimethylamino substituent (7e) gave 8
almost exclusively with similarly high enantioselectivity
(Table 3). The background reaction which forms 9, exclu-
sively, is obviously competitive with the use of 1 mol%
catalyst (Table 3, entry 4) in the reaction of 7c.
Received: October 6, 2007
Published online: January 10, 2008
Keywords: asymmetric catalysis · cycloaddition ·
.
hetero-Diels–Alder reactions · nitrones · rhodium
[1] a) M. P. Doyle, I. M. Phillips, W. Hu, J. Am. Chem. Soc. 2001,
123, 5366 – 5367; b) M. P. Doyle, M. Valenzuela, P. Huang, Proc.
Natl. Acad. Sci. USA 2004, 101, 5391 – 5395; c) M. P. Doyle, C.
Hedberg, W. Hu, A. Holmstrom, Synlett 2004, 2425 – 2428.
[2] M. Anada, T. Washio, N. Shimada, S. Kitagaki, M. Nakajima, M.
Shiro, S. Hashimoto, Angew. Chem. 2004, 116, 2719 – 2722;
Angew. Chem. Int. Ed. 2004, 43, 2665 – 2668.
[3] R. E. Forslund, J. Cain, M. P. Doyle, Adv. Synth. Catal. 2005, 347,
87 – 92.
[4] a) Lewis Acids in Organic Synthesis, Vols. 1 and 2 (Ed.: H.
Yamamoto), Wiley-VCH, New York, 2000; b) Hetero-Diels–
Alder Methodology in Organic Synthesis (Ed.: H. H. Wasser-
man), Academic Press, San Diego, CA, 1987.
In summary, we have developed a new class of chiral
catalysts for reactions that are promoted by Lewis acids.
These catalysts are cationic chiral dirhodium carboxamidates
that can be formed in situ and used with low catalyst loadings.
Further studies to develop cationic chiral dirhodium carbox-
amidate salts for Lewis acid catalyzed reactions are underway.
Angew. Chem. Int. Ed. 2008, 47, 1439 –1442
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
1441

Communications
[5] a) D. Timmons, M. P. Doyle in Metal Bonds Between Metal
[9] M. P. Doyle, M. A. McKervey, T. Ye, Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds, Wiley, New York,
1998.
[10] a) F. Viton, G. Bernardinelli, E. P. Kündig, J. Am. Chem. Soc.
2002, 124, 4968 – 4969; b) V. Alezra, G. Bernardinelli, C.
Corminboeuf, U. Frey, E. P. Kündig, A. E. Merbach, C. M.
Saudan, F. Viton, J. Weber, J. Am. Chem. Soc. 2004, 126, 4843 –
4853.
[11] a) D. Carmona, M. P. Lamata, F. Viguri, R. Rodriguiz, L. A. Oro,
A. I. Balana, F. J. Lahoz, T. Tejero, P. Merino, S. Franco, I.
Montesa, J. Am. Chem. Soc. 2004, 126, 2716 – 2717; b) D.
Carmona, M. P. Lamata, F. Viguri, R. Rodriguiz, L. A. Oro,
F. J. Lahoz, A. I. Balana, T. Tejero, P. Merino, J. Am. Chem. Soc.
2005, 127, 13386 – 13398.
Atoms, 3rd ed. (Eds.: F. A. Cotton, C. A. Murillo, R. A. Walton),
Springer Science and Business Media, New York, 2005, chap. 13;
b) M. P. Doyle, T. Ren in Progess in Inorganic Chemistry, Vol. 49
(Ed.: K. Karlin), Wiley, New York, 2001, pp. 113 – 168.
[6] a) T. Ohkuma, N. Utsumi, K. Tsutumi, K. Murata, C. Sandoval,
R. Noyori, J. Am. Chem. Soc. 2006, 128, 8724 – 8725; b) M.
Janka, W. He, A. J. Frontier, R. Eisenberg, J. Am. Chem. Soc.
2004, 126, 6864 – 6865; c) K. Mori, T. Hara, T. Mizugaki, K.
Ebitani, K. Kaneda, J. Am. Chem. Soc. 2003, 125, 11460 – 11461;
d) S. Kezuka, T. Ikeno, T. Yamada, Org. Lett. 2001, 3, 1937 –
1939.
[7] A. J. Catino, J. M. Nichols, R. E. Forslund, M. P. Doyle, Org.
Lett. 2005, 7, 2787 – 2790.
[8] H. T. Chifotides, K. R. Dunbar in Metal Bonds between Metal
Atoms, 3rd ed. (Eds.: F. A. Cotton, C. A. Murillo, R. A. Walton),
Springer Science and Business Media, New York, 2005, chap. 12.
[12] M. Shirahase, S. Kanemasa, Y. Oderaotoshi, Org. Lett. 2004, 6,
675 – 678.
[13] K. V. Gothelf, K. A. Jorgensen, Chem. Commun. 2000, 1449 –
1458.
1442
www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 1439 –1442