Iridium-catalyzed, regio- and enantioselective allylic substitution with aromatic and aliphatic sulfinates

Article abstract of DOI:10.1021/ol9023248

"Chemical Equation Presented" The iridium-catalyzed allylation of sodium sulfinate to form branched allylic sulfones is reported. The reactions between various sodium sulfinates and achiral allylic carbonates occur in good yields, with high selectivity fo

Full text of DOI:10.1021/ol9023248

ORGANIC
LETTERS
2010
Vol. 12, No. 1
92-94
Iridium-Catalyzed, Regio- and
Enantioselective Allylic Substitution with
Aromatic and Aliphatic Sulfinates
Mitsuhiro Ueda and John F. Hartwig*
Department of Chemistry, UniVersity of Illinois, 600 South Matthews AVenue,
Urbana, Illinois 61801
jhartwig@illinois.edu
Received October 27, 2009
ABSTRACT
The iridium-catalyzed allylation of sodium sulfinate to form branched allylic sulfones is reported. The reactions between various sodium
sulfinates and achiral allylic carbonates occur in good yields, with high selectivity for the branched isomer, and high enantioselectivities (up
to 98% ee).
Asymmetric allylic substitution catalyzed by transition-metal
complexes has become a powerful method for the enanti-
oselective construction of carbon-heteroatom and carbon-
carbon bonds.1 Despite the value of thioethers, sulfoxides,
and sulfones as chiral building blocks for the synthesis of
natural products and pharmaceutical intermediates,2 the
construction of carbon-sulfur bonds by allylic substitution
with high regio- and enantioselectivity has not been well
developed.
Sodium p-toluenesulfinate is known to serve as a nucleo-
phile in palladium-catalyzed allylic substitution reactions.3
Moreover, the sulfone product of this reaction is an important
building block because it is equivalent to a thioether,4 and
allylic sulfones are known to undergo olefin cross-metath-
esis.5 However, few allylations of sulfinates to form chiral,
branched products have been reported.6 Most often, reactions
of linear, monosubstituted allylic carbonates form achiral
linear sulfonate products.7
(1) (a) Trost, B. M.; VanVranken, D. L. Chem. ReV. 1996, 96, 395. (b)
Trost, B. M. Acc. Chem. Res. 1996, 29, 355. (c) Trost, B. M.; Crawley,
M. L. Chem. ReV. 2003, 103, 2921. (d) Graening, T.; Schmalz, H. G. Angew.
Chem., Int. Ed. 2003, 42, 2580. (e) Trost, B. M. J. Org. Chem. 2004, 69,
5813. (f) Takeuchi, R.; Kezuka, S. Synthesis 2006, 3349. (g) Helmchen,
G.; Dahnz, A.; Dubon, P.; Schelwies, M.; Weihofen, R. Chem. Commun.
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Churchill, M. R. J. Org. Chem. 1995, 60, 6468. (e) Trost, B. M.; Organ,
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15, 2685.
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2000, 122, 6120. (b) Felpin, F.-X.; Landais, Y. J. Org. Chem. 2005, 70,
6441. (c) Chandrasekhar, S.; Jagadeshwar, V.; Saritha, B.; Narsihmulu, C.
J. Org. Chem. 2005, 70, 6506.
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Commun. 1989, 298. (c) Somasundaram, N.; Pitchumani, K.; Srinivasan,
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K.; Mathis, C. A. J. Chem. Soc., Chem. Commun. 1994, 761.
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H.; Gais, H. J. Tetrahedron: Asymmetry 1995, 6, 643. (c) Trost, B. M.;
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10.1021/ol9023248  2010 American Chemical Society
Published on Web 12/02/2009

The high regioselectivity of iridium catalysts for formation
of branched products, along with the with high enantiose-
lectivity from reactions of heteroatom nucleophiles8-10
provides the potential that conditions with such a catalyst
can be developed for formation of chiral, branched allylic
sulfones from reactions of linear allylic esters and alkali metal
sulfinates (eq 1). Here, we report highly regio- and enanti-
oselective iridium-catalyzed reactions of a series of allylic
carbonates with various sodium sulfinates. These reactions
occur with high selectivities and yields with both aliphatic
and aromatic methyl carbonates and with both aliphatic and
aromatic sulfinates.
allylic ester to the 16-electron species formed by dissociation
of this bound olefin.10 We, therefore, began our investigations
of the allylation of sulfinates by testing whether metalacycle
1a would catalyze the reaction of sodium benzenesulfinate
with methyl cinnamyl carbonate to form allylic substitution
products. First, we investigated conditions involving an
organic and an aqueous phase with tetraoctylammonium
bromide as phase transfer agent to address the low solubility
of sodium benzenesulfinate in organic solvents. This initial
investigation showed that the sulfonated product 4a forms
in 80% yield with 87% ee and 98:2 branched-to-linear ratio
(entry 1, Table 1) when the reaction is conducted under
biphasic conditions.
Table 1. Effect of Solvents on the Ir-Catalyzed Allylation of
Sodium Benzenesulfinate 2a at Room Temperaturea
We recently introduced the single-component, metalacyclic
iridium complex 1 as an efficient catalyst for enantioselective
allylic amination (Figure 1).9 This complex is an 18-electron
entry
solvent
yield (%)b
4a:5ac
ee (%)d
1e
2
3
4
5
6
CH2Cl2/H2O (3:1)
DMF
80
95
89
89
65
78
98:2
>99:1
>99:1
>99:1
>99:1
>99:1
87
63
93
91
94
92
THF
CH2Cl2
1,4-dioxane
DME
a General conditions: 0.6 mmol 2a, 0.5 mmol 3a, 0.01 mmol 1a in 2
mL of solvent. b Isolated yield of 4a. c Determined by 1H NMR analysis of
the crude reaction mixture. d Determined by chiral HPLC analysis, see
Supporting Information for details. e 6 mol % tetraoctylammonium bromide
was added as phase-transfer catalyst.
Figure 1. Phosphoramidite ligands and structures of cyclometalated,
However, studies of reactions in several organic solvents
in the absence of an aqueous phase showed that the aqueous
phase and phase-transfer agent are unnecessary to achieve
acceptable rates, yields, and selectivities. Reactions con-
ducted in various organic solvents occurred with high
enantioselectivity, regioselectivity,11 and yield within 16 h
under mild conditions, despite the low solubility of sodium
benzenesulfinate in organic solvents (entry 3-6).
Finally, to improve this process further, we investigated
the effects of temperature, the identity of the leaving group
on the allylic carbonate, the identity of the aryl groups in
the catalyst, and the identity of the solvent on yield and
selectivity. Reactions conducted at 50 °C occurred in higher
yield than those conducted at room temperature, but the
enantioselectivity was lower (entry 1, Table 2). Reactions
of isopropyl or tert-butyl cinnamyl carbonates (entries 2 and
3) occurred in yields and enantioselectivities that are lower
than those of methyl cinnamyl carbonate, and experiments
with catalysts containing different aryl groups on the amino
substituent showed that reactions conducted with catalyst 1b
five-coordinate Ir catalysts.
species, but it contains a labile ethylene ligand that allows
initiation of the catalytic cycle by oxidative addition of the
(7) (a) Chandrasekhar, S.; Jagadeshwar, V.; Saritha, B.; Narsihmulu,
C. J. Org. Chem. 2005, 70, 6506. (b) Liao, M. C.; Duan, X. H.; Liang,
Y. M. Tetrahedron Lett. 2005, 46, 3469. (c) Felpin, F. X.; Landais, Y. J.
Org. Chem. 2005, 70, 6441. (d) Uozumi, Y.; Suzuka, T. Synthesis 2008,
1960.
(8) Amination: (a) Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2002,
124, 15164. (b) Shu, C.; Leitner, A.; Hartwig, J. F. Angew. Chem., Int. Ed.
2004, 43, 4797. (c) Miyabe, H.; Matsumura, A.; Moriyama, K.; Takemoto,
Y. Org. Lett. 2004, 6, 4631. (d) Leitner, A.; Shekhar, S.; Pouy, M. J.;
Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 15506. (e) Weihofen, R.; Dahnz,
A.; Tverskoy, O.; Helmchen, G. Chem. Lett. 2005, 3541. (f) Miyabe, H.;
Yoshida, K.; Yamauchi, M.; Takemoto, Y. J. Org. Chem. 2005, 70, 2148.
(g) Singh, O. V.; Han, H. J. Am. Chem. Soc. 2007, 129, 774. (h) Pouy,
M. J.; Leitner, A.; Weix, D. J.; Ueno, S.; Hartwig, J. F. Org. Lett. 2007, 9,
3949. (i) Yamashita, Y.; Gopalarathnam, A.; Hartwig, J. F. J. Am. Chem.
Soc. 2007, 129, 7508. Etherification: (j) López, F.; Ohmura, T.; Hartwig,
J. F. J. Am. Chem. Soc. 2003, 125, 3426. (k) Shu, C.; Hartwig, J. F. Angew.
Chem., Int. Ed. 2004, 43, 4794. (l) Lyothier, I.; Defieber, C.; Carreira, E. M.
Angew. Chem., Int. Ed. 2006, 45, 6204. (m) Ueno, S.; Hartwig, J. F. Angew.
Chem., Int. Ed. 2008, 47, 1928.
(9) (a) Stanley, L. M.; Hartwig, J. F. J. Am. Chem. Soc. 2009, 131,
8971. (b) Weix, D. J.; Markovic´, D.; Ueda, M.; Hartwig, J. F. Org. Lett.
2009, 11, 2944. (c) Pouy, M. J.; Stanley, L. M.; Hartwig, J. F. J. Am. Chem.
Soc. 2009, 131, 11312.
(10) Markovic´, D.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 11680.
(11) None of the minor isomer from addition to the terminus of the
allyl group was observed in the crude NMR spectrum.
Org. Lett., Vol. 12, No. 1, 2010
93

Table 2. Effect of Leaving Group and Solvent on the
Table 3. Ir-Catalyzed Allylation of Various Sodium Sulfinatesa
Ir-Catalyzed Allylation of Sodium Benzenesulfinate 2a at 50 °Ca
entry
R
solvent
THF
THF
THF
yield (%)b
4a:5ac
ee (%)d
1
2
3
4e
5
6
7
8
9
Me
i-Pr
t-Bu
Me
Me
Me
Me
Me
Me
95
78
61
99
82
89
NR
84
92
97:3
94:6
93:7
90:10
97:3
98:2
91
67
74
85
76
93
entry
R1
R2
4
yield (%)b 4:5c ee (%)d
THF
1
2
3
4
5
6
7
8
9e
Ph
Ph
Ph
4a
92
95
95
92
77
86
99
91
85
95
99
91
97:3
99:1
94:6
99:1
99:1
99:1
99:1
99:1
95:5
>99:1
>99:1
>99:1
94
89
92
94
93
97
98
91
86
92
93
95
toluene
EtOAc
MeCN
DME
4-MeOC6H4 4b
4-MeC6H4 Ph
4-MeC6H4 Me
4-MeC6H4 n-Pr
4-MeC6H4 i-Pr
4-MeC6H4 Cy
4-MeC6H4 PhC2H4
4c
4d
4e
4f
4g
4h
95:5
97:3
90
94
1,4-dioxane
a General conditions: 0.6 mmol 2a, 0.5 mmol 3, 0.01 mmol 1a in 2 mL
of solvent. b Isolated yield of 4a. c Determined by 1H NMR analysis of the
crude reaction mixture. d Determined by chiral HPLC analysis, see
Supporting Information for details. e 1b as catalyst was used.
4-ClC6H4 4-MeOC6H4 4i
10e Me
11e i-Pr
12e Cy
4-MeOC6H4 4j
4-MeOC6H4 4k
4-MeOC6H4 4l
occurred in excellent yield but with moderate regio- and
enantioselectivity (entry 4). High enantioselectivity was
maintained at 50 °C when reactions were conducted in
dioxane, and they occurred with yields and regioselectivities
that were equal or higher than those in other organic solvents
(entries 5-9). Thus, reactions conducted in 1,4-dioxane at
50 °C with catalyst 1a were shown to occur with the best
balance of yield, regioselectivity, and enantioselectivity and
would allow for the substitutions to be conducted with less
reactive aliphatic nucleophiles and electrophiles.
Table 3 summarizes the scope of the reactions conducted
under the optimized conditions described in entry 9 of Table
2. The reaction of electron-rich carbonate 3b occurred in
high yield (entry 2). Likewise, the reactions of the more
electron-rich of the aromatic sulfinates 2b occurred in higher
yield than those of the electron-neutral sodium benzene-
sulfinate 2a (entry 3). Most striking, the reaction of aliphatic
allylic carbonates occurred with complete regioselectivities
and high enantioselectivities (entry 4-8). Often iridium-
catalyzed allylic substitutions of aliphatic allylic carbonates
in the presence of catalyst 1a occur with regioselectivities
that are good but not as high as that observed with the
sulfinate nucleophile.
The reactions of allylic carbonates with a variety of sodium
sulfinates were also investigated. The reactions of electron-
poor sodium aromatic sulfinates 2c and 3b occurred with
somewhat lower regio- and enantioselectivity than reactions
of sodium benzene sulfonate. However, the sodium salts of
aliphatic sulfinates 2d-2f reacted with the p-methoxy-
substituted cinnamyl carbonate 3b with exceptionally high
regioselectivity, high yield, and high enantioselectivity. These
reactions of sulfinates 2d-f required 2.0 equiv of sulfinates,
perhaps because of the low reactivity of aliphatic sulfinates
as nucleophile (entries 10-12).
a General conditions: 0.6 mmol 2, 0.5 mmol 3, 0.01 mmol 1a in 2 mL
of dioxane. Results are an average of two runs. b Isolated yield of 4.
c Determined by 1H NMR analysis of the crude reaction mixture. d Determined
by chiral HPLC analysis, see Supporting Information for details. e 1.0 mmol
of 2 was used.
The absolute configurations of the reaction products 4e
and 4f were determined by comparison of the specific
rotations of the products with literature data.6a,12 Reactions
conducted with the catalyst derived from the (S,S,S)-
phosphoramidite generate the (R)-sulfonate. The stereochem-
istry of these reactions parallels that of the reactions of amine
nucleophiles9 in the presence of the same Ir catalysts.
In summary, we have developed regio- and enantioselec-
tive iridium-catalyzed allylations of sodium sulfinates to
produce branched substitution products. Notable features of
these reactions include high regio- and enantioselectivity of
the process with a broad range of allylic carbonates and
sodium sulfinates. We are currently investigating applications
of this process that would exploit the unique features of
chiral, nonracemic, allylic sulfones.
Acknowledgment. We acknowledge financial support
from the NIH (R37GM055382 to J.F.H.) and a gift of
[Ir(cod)Cl]2 from Johnson-Matthey. M.U. thanks JSPS for a
fellowship.
Supporting Information Available: Experimental pro-
cedures and product characterization. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
OL9023248
(12) Hiroi, K.; Kitayama, R.; Sato, S. J. Chem. Soc., Chem. Commun.
1983, 1470
.
94
Org. Lett., Vol. 12, No. 1, 2010