Iridium-catalyzed enantioselective allylic substitution of o -allyl carbamothioates

Article abstract of DOI:10.1021/jo1006152

(Figure presented) With an [Ir(COD)Cl]₂/phosphoramidite ligand system, an allylic substitution of O-allyl carbamothioates was developed. The reaction proceeded in the favor of branched products with up to 93:7 branched-to-linear ratio, affording chiral S-allyl carbamothioates with up to 95% ee.

Full text of DOI:10.1021/jo1006152

pubs.acs.org/joc
stitution reactions.2 Despite the impressive progress to date,
Iridium-Catalyzed Enantioselective Allylic
Substitution of O-Allyl Carbamothioates
the construction of a carbon-sulfur bond in Ir-catalyzed
allylic substation reactions is less explored. Several transi-
tion metal complexes such as those using Pd,3 Ru,4 Rh,5 Fe,6
and Ni7 have been explored as suitable catalysts for allylic
substitution in the formation of carbon-sulfur bonds. No-
Qing-Long Xu, Wen-Bo Liu, 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
€
tably, Gais and Bohme have reported the enantioselective O,
S-rearrangement of racemic O-allylic thiocarbamates, pro-
viding enantioenriched allylic sulfur compounds.3e Given the
successful application of iridium catalysts for the allylic
substitution reactions of heteroatom nucleophiles,8,9 we
envisaged that iridium-catalyzed allylic substitution reaction
with a sulfur nucleophile would provide an efficient access to
chiral sulfur-containing compounds, which are highly im-
portant synthetic intermediates.10 During our recent studies
toward this goal using Ir-catalyzed allylic substitution reac-
tion of allyl sulfinates, trisubstituted vinyl sulfones were
obtained as a result of the subsequent isomerization.11
Simultaneously, an elegant protocol, developed by Ueda
and Hartwig, afforded the enantioenriched allylic sulfones
in excellent yields and ees.12
slyou@mail.sioc.ac.cn
Received March 31, 2010
To continue the development of asymmetric synthesis of
enantioenriched chiral sulfur compounds, we recently found
(4) Kondo, T.; Morisaki, Y.; Uenoyama, S.; Wada, K.; Mitsudo, T.
J. Am. Chem. Soc. 1999, 121, 8657.
(5) (a) Leong, P.; Lautens, M. J. Org. Chem. 2004, 69, 2194. (b) Zaitsev,
A. B.; Caldwell, H. F.; Pregosin, P. S.; Veiros, L. F. Chem.;Eur. J. 2009, 15,
6468.
(6) Jegelka, M.; Plietker, B. Org. Lett. 2009, 11, 3462.
(7) Yatsumonji, Y.; Ishida, Y.; Tsubouchi, A.; Takeda, T. Org. Lett.
2007, 9, 4603.
With an [Ir(COD)Cl]2/phosphoramidite ligand system, an
allylic substitution of O-allyl carbamothioates was devel-
oped. The reaction proceeded in the favor of branched
products with up to 93:7 branched-to-linear ratio, afford-
ing chiral S-allyl carbamothioates with up to 95% ee.
(8) Allyic 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) Lipowsky, G.; Helmchen, G. Chem. commun.
2004, 116. (e) Weihofen, R.; Dahnz, A.; Tverskoy, O.; Helmchen, G. Chem.
Commun. 2005, 3541. (f) Welter, C.; Dahnz, A.; Brunner, B.; Streiff, S.;
Du1bon, P.; Helmchen, G. Org. Lett. 2005, 7, 1239. (g) Leitner, A.; Shu, C.;
Hartwig, J. F. Org. Lett. 2005, 7, 1093. (h) Miyabe, H.; Yoshida, K.;
Yamauchi, M.; Takemoto, Y. J. Org. Chem. 2005, 70, 2148. (i) Singh,
O. V.; Han, H. J. Am. Chem. Soc. 2007, 129, 774. (j) Yamashita, Y.;
Gopalarathnam, A.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 7508.
(k) Lee, J. H.; Shin, S.; Kang, J.; Lee, S.-g. J. Org. Chem. 2007, 72, 7443.
(l) Pouy, M. J.; Leitner, A.; Weix, D. J.; Ueno, S.; Hartwig, J. F. Org. Lett.
2007, 9, 3949. (m) Spiess, S.; Welter, C.; Franck, G.; Taquet, J.-P.; Helmchen,
G. Angew.Chem., Int. Ed. 2008, 47, 7652. (n) Stanley, L. M.; Hartwig, J. F.
J. Am. Chem. Soc. 2009, 131, 8971. (o) Pouy, M. J.; Stanley, L. M.; Hartwig,
Iridium-catalyzed asymmetric allylic substitution has
emerged asone ofthe most efficientmethods toformcarbon-
carbon and carbon-heteroatom bonds, particularly due to
its high regioselectivity and excellent enantioselectivity.1
Studies by Hartwig and Helmchen demonstrated cyclome-
talated iridium as the active catalytic species, which further
provided the basis for asymmetric Ir-catalyzed allylic sub-
(1) For reviews, see: (a) Miyabe, H.; Takemoto, Y. Synlett 2005, 1641.
(b) Takeuchi, R.; Kezuka, S. Synthesis 2006, 3349. (c) Helmchen, G.; Dahnz,
ꢀ
J. F. J. Am. Chem. Soc. 2009, 131, 11312. (p) Weix, D. J.; Markovic, D.;
Ueda, M.; Hartwig, J. F. Org. Lett. 2009, 11, 2944. (q) Gnamm, C.; Krauter,
€
A.; Dubon, P.; Schelwies, M.; Weihofen, R. Chem. Commun. 2007, 675.
€
C. M.; Broner, K.; Helmchen, G. Chem.;Eur. J. 2009, 15, 2050. (r) Gnamm,
(d) Helmchen, G. In Iridium Complexes in Organic Synthesis; Oro, L. A., Claver,
C., Eds.; Wiley-VCH: Weinheim, Germany, 2009; p 211.
€
C.; Brodner, K.; Krauter, C. M.; Helmchen, G. Chem.;Eur. J. 2009, 15,
(2) (a) Bartels, B.; Garcıa-Yebra, C.; Rominger, F.; Helmchen, G. Eur. J.
Inorg. Chem. 2002, 2569. (b) Kiener, C. A.; Shu, C.; Incarvito, C.; Hartwig,
J. F. J. Am. Chem. Soc. 2003, 125, 14272. (c) Madrahimov, S. T.; Markovic,
D.; Hartwig, J. F. J. Am. Chem. Soc. 2009, 131, 7228. (d) Spiess, S.; Raskatov,
€
J. A.; Gnamm, C.; Brodner, K.; Helmchen, G. Chem.;Eur. J. 2009, 15,
11087.
10532. (s) Farwick, A.; Helmchen, G. Org. Lett. 2010, 12, 1108. (t) He, H.;
Liu, W.-B.; Dai, L.-X.; You, S.-L. Angew.Chem., Int. Ed. 2010, 49, 1496.
ꢀ
(9) Allylic etherification: (a) Lopez, F.; Ohmura, T.; Hartwig, J. F. J. Am.
Chem. Soc. 2003, 125, 3426. (b) Shu, C.; Hartwig, J. F. Angew.Chem., Int. Ed.
2004, 43, 4794. (c) Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E. M.
J. Am. Chem. Soc. 2004, 126, 1628. (d) Lyothier, I.; Defieber, C.; Carreira,
E. M. Angew. Chem., Int. Ed. 2006, 45, 6204. (e) Kimura, M.; Uozumi, Y.
J. Org. Chem. 2007, 72, 707. (f) Miyabe, H.; Yoshida, K.; Yamauchi, M.;
Takemoto, Y. J. Org. Chem. 2007, 72, 2148. (g) Ueno, S.; Hartwig, J. F.
Angew.Chem., Int. Ed. 2008, 47.
(10) For a review: (a) Fuchs, P. L.; Braish, T. F. Chem. Rev. 1986, 86, 903.
For selected examples: (b) Trost, B. M.; Organ, M. G.; Odoherty, G. A.
J. Am. Chem. Soc. 1995, 117, 9662. (c) Teall, M.; Oakley, P.; Harrison, T.;
Shaw, D.; Kay, E.; Elliott, J.; Gerhard, U.; Castro, J. L.; Shearman, M.; Ball,
R. G.; Tsou, N. N. Biol. Med. Chem. Lett. 2005, 15, 2685. (d) Peschiulli, A.;
Procuranti, B.; O’Connor, C. J.; Connon, S. J. Nat. Chem. 2010, 2, 380.
(11) Xu, Q.-L.; Dai, L.-X.; You, S.-L. Org. Lett. 2010, 12, 800.
(3) Selected examples: (a) Trost, B. M.; Krische, M. J.; Radinov, R.;
€
Zanoni, G. J. Am. Chem. Soc. 1996, 118, 6297. (b) Bohme, A.; Gais, H.-J.
Tetrahedron: Asymmetry 1999, 10, 2511. (c) Trost, B. M.; Crawley, M. L.;
Lee, C. B. J. Am. Chem. Soc. 2000, 122, 6120. (d) Vasen, D.; Salzer, A.;
Gerhards, F.; Gais, H.-J.; Bieler, N. H.; Togni, A. Organometallics 2000, 19,
€
€
539. (e) Gais, H.-J.; Bohme, A. J. Org. Chem. 2002, 67, 1153. (f) Lussem,
B. J.; Gais, H.-J. J. Org. Chem. 2004, 69, 4041. (g) Liao, M.; Duan, X.; Liang,
Y. Tetrahedron Lett. 2005, 46, 3469. (h) Tsarev, V. N.; Konkin, S. I.;
Shyryaev, A. A.; Davankov, V. A.; Gavrilov, K. N. Tetrahedron: Asymmetry
2005, 16, 1737. (i) Trost, B. M.; Crawley, M. L.; Lee, C. B. Chem.;Eur. J.
2006, 12, 2171. (j) Overman, L. E.; Roberts, S. W.; Sneddon, H. F. Org. Lett.
2008, 10, 1485.
(12) Ueda, M.; Hartwig, J. F. Org. Lett. 2010, 12, 92.
DOI: 10.1021/jo1006152
r
Published on Web 05/27/2010
J. Org. Chem. 2010, 75, 4615–4618 4615
2010 American Chemical Society

Xu et al.
JOCNote
TABLE 1. Optimization of Conditions for Ir-Catalyzed Allylic Substitu-
tion of 1a using L1a
FIGURE 1. Ligands used in the present work.
entry
base
time (h) conv (%)b 2a/3ab 2a, yield (%)c ee (%)d
1
2
3
4
5
6
7
8
36
36
36
36
36
21
23
19
24
23
12
12
36
12
12
25
80/20
83
TABLE 2. Screening Different Solvents and Ligandsa
entry ligand solvent conv (%)b 2a/3ab 2a, yield (%)c ee (%)d
K3PO4
Cs2CO3
DBU
DBN
BSA
Et3N
DIEA
DABCO
KOAc
KOAc
KOAc
NR
NR
NR
NR
12
18
17
26
35
25
49
51
57
1
2
3
4
5
6
7
8
9
10
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
toluene
THF
CH2Cl2
dioxane
DME
CH3CN
DMF
dioxane
dioxane
dioxane
80
>95
>95
>95
83/17
75/25
26/74
81/19
77/23
54
57
19
63
84
88
2
90
87
20
25
20
40
60
54
72
70
82/18
83/17
84/16
62/38
86/14
78/22
85/15
82/18
75/25
80/20
82
90
85
90
90
87
92
90
88
88
50
9
NR
NR
59
39
30
10
11e
12f
>95
90
71
79/21
73/27
74/26
87
93
80
13g KOAc
14f,g KOAc
15g,h KOAc
94
>95
aReactions were conducted under the conditions of entry 14, Table 1.
50
1
c
bDetermined by H NMR of the crude reaction mixture. Yield of 2a.
aReaction conditions: 2 mol % of [Ir(COD)Cl]2, 4 mol % of L1,
dDetermined by chiral HPLC analysis.
0.2 mmol of 1a, and 100 mol % of base in THF (2 mL). bDetermined by
1H NMR of the crude reaction mixture. Yield of 2a. Determined by
chiral HPLC analysis. eReflux condition. f200 mol % of KOAc was used.
g4 mol % of [Ir(COD)Cl]2 and 8 mol % of L1 were used. h400 mol % of
KOAc was used.
c
d
Under the above conditions (entry 14, Table 1), further
studies on the effect of solvents and ligands were carried out.
The results are summarized in Table 2. Various solvents
(toluene, CH2Cl2, dioxane, and DME) could be tolerated in
the reaction (entries 1-5, Table 2), but the regioselectivity is
poor in CH2Cl2. Moreover, reactions in acetonitrile and
DMF failed to give any product (entries 6 and 7, Table 2).
The best result was obtained in dioxane in terms of the
isolated yield of 2a (63%) and enantioselectivity (90% ee).
In dioxane, different ligands were evaluated (Figure 1). The
results suggested that ligands L2-L4 could be employed in
the reaction, albeit with relatively lower yields in comparison
with L1 (entries 8-10, Table 2).
that Ir-catalyzed allylic substitution of O-allyl carbamothio-
ates could afford chiral S-allyl carbamothioates with up to
95% ee. The reaction proceeded in an atom-economical
fashion with moderate to excellent regioselectivities. Herein,
we report the detailed studies.
Under the optimized reaction conditions [4 mol % of
[Ir(COD)Cl]2, 8 mol % of L1, 200 mol % of KOAc, dioxane,
50 °C], a wide range of substrates were tested to examine the
scope of this reaction. The results are shown in Table 3.
Various O-allyl carbamothioates derived from aryl allyl
alcohols bearing either electron-withdrawing groups
(p-CF3, p-Br) or electron-donating groups (p-Me, p-OMe)
could react well, affording the desired products in up to 90%
yield and 90% ee for 2 (entries 1-8, Table 3). It is worth
noting that the enantioselectivity of bulky 1-naphthyl-
substituted carbomothioate 1i sharply decreased, and only
20% ee was obtained (entry 9, Table 3). When O-allyl
carbamothioates derived from alkyl allyl alcohols, the sub-
stitution products were obtained in up to 91% yield but
with decreased regioselectivity (entries 10-12, Table 3). As
to substituents attached to the nitrogen, both phenyl and
aliphatic (n-butyl, Bn) groups could be tolerated in the
reaction. Notably, substrate 1m featuring dialkylated nitro-
gen group could also give rise to its desired product in 85%
yield and 95% ee (entry 13, Table 3). Although only moder-
ate regioselectivities were obtained, all of the branched
products could be easily separated from their linear isomers
using column chromatography except 2m.
In our initial investigation, O-cinnamyl butylcarbamothi-
oate 1a was chosen as the model substrate to optimize the
reaction conditions. The results are summarized in Table 1.
With [Ir(COD)Cl]2 (2 mol %)/L1 (4 mol %) as the cata-
lyst (Figure 1), the reaction in THF at 50 °C without
additional base proceeded in 25% conversion with moderate
branched-to-linear ratio (80:20) (entry 1, Table 1). Surpris-
ingly, the addition of K3PO4, Cs2CO3, DBU, and DBN
as bases completely inhibited the reaction (entries 2-5,
Table 1). Among a series of other bases tested, KOAc
showed a superior result, affording the corresponding pro-
duct 2a in 35% yield with 90% ee (entries 6-10, Table 1).
Notably, by increasing the catalyst loading and base simul-
taneously (4 mol % [Ir(COD)Cl]2 and 200 mol % KOAc),
the isolated yield of 2a was improved to 57% with 88% ee
(entry 14, Table 1).
4616 J. Org. Chem. Vol. 75, No. 13, 2010

Xu et al.
JOCNote
TABLE 3. Substrate Scope for Ir-Catalyzed Allylic Substitution of
SCHEME 2. Crossover Experiment of 1d and 1f
O-Allyl Carbamothioatesa
yield
ee
entry
1
2/3b
(%)c (%)d
1
2
3
4
5
6
7
8
1a: R1=Ph, R2=n-Bu, R3=H
81/19
90
68
80
52
61
66
80
62
74
79
91
89
85
90
90
85
93
64
89
86
63
20
89
56
84
95
1b: R1=p-CF3C6H4, R2=n-Bu, R3=H 74/26
1c: R1=p-BrC6H4, R2=n-Bu, R3=H
1d: R1=p-MeC6H4, R2=n-Bu,R3=H
62/38
93/7
1e: R1=p-MeOC6H4, R2=n-Bu, R3=H 61/39
1f: R1=Ph, R2=Bn, R3=H
86/14
65/35
78/22
82/18
61/39
61/39
60/40
70/30
1g: R1=p-MeC6H4, R2=Bn, R3=H
1h: R1=Ph, R2=Ph, R3=H
9
1i: R1=1-naphthyl, R2=n-Bu, R3=H
1j: R1=n-Pr, R2=n-Bu, R3=H
1k: R1=n-Pr, R2=Ph, R3=H
1l: R1=n-Pr, R2=Bn, R3=H
1m: R1=Ph, R2, R3=-(CH2)5-
10
11
12
13
coordination between the Ir-allyl complex and sulfur-con-
taining nucleophile.
aGeneral conditions: 4 mol % of [Ir(COD)Cl]2, 8 mol % of L1, 0.2
mmol of 1, and 200 mol % of KOAc in dioxane (2 mL). bDetermined by
1H NMR of the crude reaction mixture. cYields of 2 and 3. dDetermined
by chiral HPLC analysis.
In summary, we have developed an iridium-catalyzed
allylic substitution reaction that affords branched S-allyl
carbamothioates with moderate to excellent yields, enantio-
selectivities, and regioselectivities. The readily available
catalyst, facile transformation of the products, and the atom-
economical process make the current methodology poten-
tially useful in organic synthesis.
SCHEME 1. Crossover Experiment of 1a and 4
Experimental Section
General Procedure for Ir-Catalyzed Allylic Substitution of
O-Allyl Carbamothioates. To a dry Schlenk tube filled with argon
were added [Ir(COD)Cl]2 (5.4 mg, 0.008 mmol), phosphora-
midite ligand L1 [O,O0-(S)-(1,10-dinaphthyl-2,20-diyl)-N,N0-di-
(S,S)-[phenylethylphosphoramidite] (8.6 mg, 0.016 mmol),
THF (1 mL), and propylamine (0.7 mL) were added. The
reaction mixture was heated at 50 °C for 30 min, and then
the volatile solvents were removed under vacuum to give a
yellow solid. Then, O-allyl carbamothioate 1 (0.20 mmol),
KOAc (39.2 mg, 0.40 mmol), and 1,4-dioxane (2.0 mL) were
added. The reaction mixture was heated at 50 °C until the
carbamothioate was fully consumed (monitored by TLC).
Then the crude reaction mixture was filtrated with Celite and
washed with EtOAc. The filtrate was concentrated under
reduced pressure. The crude residue was purified by silica
gel column chromatography (petroleum ether/ethyl acetate) to
give the desired products. The ratio of regioisomers (bra-
nched to linear 2/3) was determined by 1H NMR of the
crude reaction mixture. For 1a, 90% yield, 2a/3a = 81:19.
Data for 2a: 72% yield, clear oil, 90% ee [Daicel CHIRAL-
PAK AD-H (0.46 cm ꢀ 25 cm); n-hexane/2-propanol = 90:10;
To determine the absolute configuration of the product,
an X-ray crystallographic analysis of enantiopure bromine-
containing compound 2c showed the configuration as S (see
the Supporting Information for details).
To gain insights into the reaction mechanism, a crossover
experiment has been carried out by subjecting an equimolar
amount of 1a and 4 to the standard reaction conditions
(Scheme 1). As determined by 1H NMR, the branched
products 2a/2d were isolated in 60% yield with the ratio
4.5:1, and the linear products 3a/3d were isolated in 20%
yield with the ratio 3.3:1. The formation of products 2d and
3d excludes the rearrangement pathway, while the dominant
formation of 2a (3a) over 2d (3d) indicates the existence of
coordination between the Ir-allyl complex and sulfur-con-
taining nucleophile. This likely contributes to the relatively
low regioselectivity and enantioselectivity of the current
reaction.
In addition, a crossover experiment between 1d and 1f has
been carried out (Scheme 2). As determined by 1H NMR or
HPLC, all possible eight products could be obtained. The
products derived from the same O-allyl carbamothioate
were favorably formed. This experiment also excludes
the rearrangement pathway and suggests the existence of
flow rate = 0.7 mL/min; detection wavelength = 214 nm; tR
=
16.70 (minor), 21.50 (major) min]. [R]20 = -240.0 (c 0.5,
D
CHCl3). 1H NMR (300 MHz, CDCl3) δ 7.36-7.22 (m, 5H),
6.15 (ddd, J = 6.6, 9.9, 16.8 Hz, 1H), 5.29-5.16 (m, 4H),
3.30-3.24 (m, 2H), 1.52-1.42 (m, 2H), 1.37-1.25 (m, 2H), 0.90
(t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 165.6, 140.1,
137.5, 128.6, 128.1, 127.3, 116.5, 51.3, 41.1, 31.6, 19.9, 13.6; IR
(film) vmax (cm-1) 3308, 3030, 2960, 2933, 2874, 1654, 1521,
1494, 1206, 986, 921, 840, 698; EI-MS (m/z) 249 (Mþ, 1), 150
(37), 117 (100), 115 (35), 91 (10), 77 (2); HRMS (EI) exact mass
calcd for C14H19NOS [M]þ 249.1187, found: 249.1191. Data for
3a: 18% yield, white solid. 1H NMR (400 MHz, CDCl3) δ
7.35-7.18 (m, 5H), 6.54 (d, J = 16.0 Hz, 1H), 6.23 (dt, J = 7.2,
J. Org. Chem. Vol. 75, No. 13, 2010 4617

Xu et al.
JOCNote
16.0 Hz, 1H), 5.52 (br s, 1H, NH), 3.73 (d, J = 7.2 Hz, 2H), 3.28
(m, 2H), 1.52-1.45 (m, 2H), 1.37-1.28 (m, 2H), 0.90 (t, J = 7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.4, 136.6, 132.4,
128.4, 127.5, 126.3, 125.5, 41.2, 32.5, 31.6, 19.8, 13.6; IR (film)
vmax (cm-1) 3290, 2961, 2938, 2873, 1662, 1633, 1525, 1398,
1214, 968, 744, 692; EI-MS (m/z) 249 (Mþ, 14), 150 (18), 117
(100), 115 (26), 91 (8), 57 (8). Anal. Calcd. for C14H19NOS: C,
67.43; H, 7.68; N, 5.62. Found: C, 67.29; H, 7.50; N, 5.51. Mp
100-102 °C.
Acknowledgment. We thank the National Natural Science
Foundation of China (20872159, 20821002, 20932008) and
National Basic Research Program of China (973 Program
2009CB825300) for generous financial support.
Supporting Information Available: Experimental proce-
dures and characterization of the products 2 and 3, including
CIF file. This material is available free of charge via the Internet
at http://pubs.acs.org.
4618 J. Org. Chem. Vol. 75, No. 13, 2010