Tandem Ir-catalyzed allylic substitution reaction of allyl sulfinates and isomerization

Article abstract of DOI:10.1021/ol902873q

(Chemical Equation Presented) An efficient method for the synthesis of trisubstituted vinyl sulfones is reported. Using the [lr(COD)Cl] ₂/phosphoramidite ligand (L1)/DBU, trisubstituted vinyl sulfones could be synthesized from allyl sulfinates

Full text of DOI:10.1021/ol902873q

ORGANIC
LETTERS
2010
Vol. 12, No. 4
800-803
Tandem Ir-Catalyzed Allylic Substitution
Reaction of Allyl Sulfinates and
Isomerization
Qing-Long Xu, Li-Xin Dai, and Shu-Li You*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
slyou@mail.sioc.ac.cn
Received December 13, 2009
ABSTRACT
An efficient method for the synthesis of trisubstituted vinyl sulfones is reported. Using the [Ir(COD)Cl]2/phosphoramidite ligand (L1)/DBU,
trisubstituted vinyl sulfones could be synthesized from allyl sulfinates in high yields as exclusively E isomers.
Sulfones have received much attention in both organic and
medicinal chemistry because of their versatile synthetic
utilities and interesting biological activities.1-3 Particularly,
substituted vinyl sulfones are known for biological activities
such as being potent inhibitors for many types of cysteine
proteases.2 Synthetically, substituted vinyl sulfones are
widely used as Michael acceptors or dienophiles in cycload-
dition reactions.4 More recently, there have been several
reports on the utilization of substituted vinyl sulfones in
catalytic enantioselective processes, providing efficient syn-
theses of optically active sulfones.5-7 Consequently, the
development of efficient synthesis of substituted vinyl
sulfones has attracted considerable attention in both organic
synthesis and the pharmaceutical industry. To date, there have
been many reports on the synthesis of vinyl sulfones;1,8
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10.1021/ol902873q  2010 American Chemical Society
Published on Web 01/26/2010

however, the synthesis of multisubstituted vinyl sulfones in
a stereoselective manner is still challenging and highly
desirable.9
and the highest yield (92%) was obtained in dioxane at 100
°C (entries 8-12, Table 1).
Table 1. Optimization of the Conditions for Ir-Catalyzed Allylic
Substitution of 1a and Isomerization with Ligand L1a
Figure 1. Ir-catalyzed allylic substitution reaction of allyl
sulfinate.
entry
base
solvent
time (h) convn (%)b yield (%)c
1
2
3
DBU
Et3N
K3PO4
THF
THF
THF
38
48
48
48
48
36
25
36
60
20
36
9
>95
82
NR
NR
As part of our research program to develop Ir-catalyzed
allylic substitution reactions,10 we recently attempted the
synthesis of optically pure allyl sulfones via Ir-catalyzed
allylic substitution of allyl sulfinates (Figure 1). However,
when the reaction of allyl sulfinate 1a and [Ir(COD)Cl]2/
ligand L1 (Figure 2) was carried out,11 surprisingly, the
substituted vinyl sulfone 3a was obtained in good yield
exclusively as an E isomer. The formation of 3a is likely
through the isomerization of the desired allyl sulfone 2
(Figure 1). Given the importance for the stereoselective
synthesis of trisubstituted vinyl sulfones, we report our results
on this subject here.
4
Cs2CO3 THF
28
33
5
BSA
DBU
-
DBU
DBU
DBU
DBU
DBU
THF
THF
THF
toluene
CH3CN
Et2O
CH2Cl2
dioxane
trace
6d
7
NR
77
82
87
67
90
8
9
10
11
12e
>95
a Reaction conditions: 2 mol % of [Ir(COD)Cl]2, 4 mol % of L1, 0.2
mmol of 1a in 2 mL of solvent. Determined by H NMR of the crude
reaction mixture. c Isolated yields. d 20 mol % of DBU was used. e At 100
°C. BSA ) N,O-Bis(trimethyl)acetamide.
b
1
Under the above conditions (entry 12, Table 1), different
ligands were evaluated, and the results are summarized in
Table 2. Most ligands could be used in this reaction but with
relatively low conversion. The reaction with ligand L8, the
diastereomer of L1, led to the formation of 3a in 85% yield
(entry 8, Table 2). Notably, the reaction in the presence of
DBU only without Ir catalyst also proceeded slowly, afford-
ing 10% conversion.
Under the optimized reaction conditions [2 mol % of
[Ir(COD)Cl]2, 4 mol % of L1, 1.0 equiv of DBU, dioxane,
100 °C], various substrates were carried out to test the
generality of the reaction. As summarized in Table 3, both
aryl (phenyl, tolyl) and aliphatic (tert-butyl) sulfinates could
be used in the reaction. For the phenyl sulfinate, aryl-bearing
Figure 2. Different ligands used in the reaction.
We began our study by examining different bases, and
DBU (1 equiv) was found to be the optimal base, affording
3a in 82% yield (entry 1, Table 1). Reducing the loading of
DBU led to a significant decrease of the conversion, and no
product was formed in the absence of DBU (entries 6 and
7, Table 1). Various solvents such as THF, toluene, CH3CN,
ether, CH2Cl2, and dioxane were all tolerated in the reaction,
(11) For reviews: (a) Miyabe, H.; Takemoto, Y. Synlett 2005, 1641. (b)
Takeuchi, R.; Kezuka, S. Synthesis 2006, 3349. (c) Helmchen, G.; Dahnz,
A.; Du¨bon, P.; Schelwies, M.; Weihofen, R. Chem. Commun. 2007, 675.
(d) Helmchen, G. Iridium Complexes in Organic Synthesis; Oro, L. A.,
Claver, C., Eds.; Wiley-VCH: Weinheim, Germany, 2009; p 211. For recent
examples: (e) Schelwies, M.; Du¨bon, P.; Helmchen, G. Angew. Chem., Int.
Ed. 2006, 45, 2466. (f) Kazmaier, U.; Stolz, D. Angew. Chem., Int. Ed.
2006, 45, 3072. (g) Weihofen, R.; Tverskoy, O.; Helmchen, G. Angew.
Chem., Int. Ed. 2006, 45, 5546. (h) Lyothier, I.; Defieber, C.; Carreira,
E. M. Angew. Chem., Int. Ed. 2006, 45, 6204. (i) Defieber, C.; Ariger, M. A.;
Moriel, P.; Carreira, E. M. Angew. Chem., Int. Ed. 2007, 46, 3139. (j) Ueno,
S.; Hartwig, J. F. Angew. Chem., Int. Ed. 2008, 47, 1928. (k) Polet, D.;
Rathgeb, X.; Falciola, C. A.; Langlois, J. B.; Hajjaji, S. E.; Alexakis, A.
Chem.sEur. J. 2009, 15, 1205. (l) Gnamm, C.; Krauter, C. M.; Bro¨dner,
K.; Helmchen, G. Chem.sEur. J. 2009, 15, 2050. (m) Gnamm, C.; Bro¨dner,
K.; Krauter, C. M.; Helmchen, G. Chem.sEur. J. 2009, 15, 10514. (n)
Stanley, L. M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2009, 48, 7841. (o)
Madrahimov, S. T.; Markovic, D.; Hartwig, J. F. J. Am. Chem. Soc. 2009,
131, 7228. (p) Stanley, L. M.; Hartwig, J. F. J. Am. Chem. Soc. 2009, 131,
8971.
(9) For a Fe-catalyzed allylic substitution of sodium sulfinate: Jegelka,
M.; Plietker, B. Org. Lett. 2009, 11, 3462. After the submission of our
manuscript (10/13/2009), Ueda and Hartwig reported an Ir-catalyzed allylic
substitution with sodium sulfinates affording chiral allylic sulfones without
the use of extra base: Ueda, M.; Hartwig, J. F. Org. Lett. 2010, 12, 92.
(10) (a) He, H.; Zheng, X.-J.; Li, Y.; Dai, L.-X.; You, S.-L. Org. Lett.
2007, 9, 4339. (b) Liu, W.-B.; He, H.; Dai, L.-X.; You, S.-L. Org. Lett.
2008, 10, 1815. (c) Liu, W.-B.; He, H.; Dai, L.-X.; You, S.-L. Synthesis
2009, 2076. (d) He, H.; Liu, W.-B.; Dai, L.-X.; You, S.-L. J. Am. Chem.
Soc. 2009, 131, 8346.
Org. Lett., Vol. 12, No. 4, 2010
801

Table 2. Screening Different Ligandsa
Table 4. Ir-Catalyzed Allylic Substitution of Sodium
Arylsulfinates and Isomerizationa
entry
ligand
convn (%)
yield (%)
90
1
2
3
4
5
6
7
8
9b
L1
L2
L3
L4
L5
L6
L7
L8
none
>95
33
43
33
25
30
20
>95
10
entry
R1
5a, Ph
R2
yield (%)b
1
2
3
4
5
6
4a, Ph
3a, 92
3n, 96
3o, 65
3d, 75
3b, 94
3g, 85
85
5a, Ph
5a, Ph
5a, Ph
5a, Ph
4b, p-MeOC6H4
4c, 1-thienyl
4d, p-CF3C6H4
4e, n-Pr
a Reactions were conducted under the conditions of entry 12, Table 1.
b Reaction with DBU only in the absence of Ir catalyst.
5b, p-MeC6H4
4a, Ph
a Reaction conditions: 2 mol % of [Ir(COD)Cl]2, 4 mol % of L1, 0.3
mmol of 4 and 0.2 mmol of 5 in 2 mL of CH2Cl2. b Isolated yields.
electron-withdrawing substituents and aliphatic allyl alcohol
derived sulfinates could all be tolerated, generally in good
to excellent yields (entries 1-6, Table 3). However, when
electron-donating groups containing aryl allyl sulfinates were
attempted, the pure substrates were difficult to obtain due to
the instability of these substrates on the silica gel column.
Therefore, the intermolecular reaction between allyl carbon-
ates and sodium sulfinates was explored to access these
products.
aryl and aliphatic ones. Both sodium benzenesulfinate and
sodium p-methylbenzenesulfinate were tolerated in the reac-
tion.
To gain insight into the reaction mechanism, cross
experiments have been carried out by subjecting an equimolar
amount of 1a and 5b to the reaction conditions (eq 1, Scheme
1). Two products 3a and 3g were obtained with the ratio
Table 3. Substrate Scope for Tandem Ir-Catalyzed Allylic
Scheme 1. Cross Experiments
Substitution of Allyl Sulfinates and Isomerizationa
entry
1
R1
R2
yield (%)b
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
Ph
Ph
Ph
Ph
Ph
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
t-Bu
Ph
n-Pr
3a, 92
3b, 92
3c, 90
3d, 82
3e, 73
3f, 93
3g, 92
3h, 30
3i, 90
3j, 96
3k, 96
3l, 91
3m, 78
p-BrC6H4
p-CF3C6H4
Et
p-FC6H4
Ph
62/38, determined by 1H NMR of the crude reaction mixture.
These results exclude the rearrangement pathway for the
current reaction. The different distribution of the two products
is likely due to the poor solubility of sodium p-methylben-
zensulfinate. To test this hypothesis, the reaction of 1g and
5a was carried out under the same reaction conditions. As
expected, two products 3a and 3g (3a/3g ) 28/72) were
obtained with the reversed ratio (eq 2, Scheme 1).
n-Pr
9
p-BrC6H4
p-FC6H4
Ph
n-Pr
p-BrC6H4
10
11
12
13
1j
1k
1l
t-Bu
t-Bu
1m
a Reaction conditions: 2 mol % of [Ir(COD)Cl]2, 4 mol % of L1, 0.2
mmol of 1 in 2 mL of dioxane. b Isolated yields.
In addition, when sulfone 6 and DBU were heated at 100
°C in dioxane for 1 h, complete isomerization to 3b was
observed (Scheme 2). These results suggest that DBU is
responsible for the isomerization process.
In summary, we have found an efficient stereoselective
synthesis of trisubstituted vinyl sulfones. The tandem reaction
involving Ir-catalyzed allylic substitution of allyl sulfinate
and isomerization allows ready access to trisubstituted vinyl
After optimizing the reaction conditions, we found that
the intermolecular reactions proceeded smoothly in refluxing
dichloromethane, leading to sulfones 3 in good yields. As
summarized in Table 4, the intermolecular reaction is suitable
for not only the electron-donating groups bearing aryl allyl
sulfinates but also the electron-withdrawing groups bearing
802
Org. Lett., Vol. 12, No. 4, 2010

process make the current reaction potentially useful in
organic synthesis.
Scheme 2. DBU-Catalyzed Isomerization
Acknowledgment. We thank the NSFC (20872159,
20821002, 20932008) and National Basic Research Program
of China (973 Program 2009CB825300) for generous
financial support.
Supporting Information Available: Experimental pro-
cedures and characterization of the products 3. This material
is available free of charge via the Internet at http://pubs.acs.org.
sulfones either from an intramolecular reaction of allyl
sulfinates or from the intermolecular reactions between allyl
carbonates and sodium sulfinates. The ready availability of
the starting materials, mild conditions, and atom-economical
OL902873Q
Org. Lett., Vol. 12, No. 4, 2010
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