Kinetic Resolution of Racemic Allylic Alcohols by Catalytic Asymmetric Substitution of the OH Group with Monosubstituted Hydrazines

Article abstract of DOI:10.1002/chem.201601747

A new strategy has been established for the kinetic resolution of racemic allylic alcohols through a palladium/sulfonyl-hydrazide-catalyzed asymmetric OH-substitution under mild conditions. In the presence of 1 mol % [Pd(allyl)Cl]₂, 4 mol % (S)-SegPhos, and 10 mol % 2,5-dichlorobenzenesulfonyl hydrazide, a range of racemic allylic alcohols were smoothly resolved with selectivity factors of more than 400 through an asymmetric allylic alkylation of monosubstituted hydrazines under air at room temperature. Importantly, this kinetic resolution process provided various allylic alcohols and allylic hydrazine derivatives with high enantiopurity.

Full text of DOI:10.1002/chem.201601747

A Journal of
Accepted Article
Title: Kinetic Resolution of Racemic Allylic Alcohols via Catalytic Asymmetric Sub-
stitution of the OH Group with Monosubstituted Hydrazines
Authors: Liang Yan; Jing-Kun Xu; Chao-Fan Huang; Zeng-Yang He; Ya-Nan Xu; Shi-
Kai Tian
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To be cited as: Chem. Eur. J. 10.1002/chem.201601747
Link to VoR: http://dx.doi.org/10.1002/chem.201601747
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Chemistry - A European Journal
10.1002/chem.201601747
Kinetic Resolution of Racemic Allylic Alcohols via Catalytic Asymmetric Substitution of the
OH Group with Monosubstituted Hydrazines
Liang Yan, Jing-Kun Xu, Chao-Fan Huang, Zeng-Yang He, Ya-Nan Xu, and Shi-Kai Tian*[a]
L. Yan, J.-K. Xu, C.-F. Huang, Z.-Y. He, Y.-N. Xu, Prof. Dr. S.-K. Tian
Department of Chemistry
University of Science and Technology of China
Hefei, Anhui 230026 (China)
E-mail: tiansk@ustc.edu.cn
Supporting information for this article is given via a link at the end of the document.
Abstract
A new strategy has been established for the kinetic resolution of racemic allylic alcohols through
palladium/sulfonyl hydrazide-catalyzed asymmetric substitution of the OH group under mild
conditions. In the presence of 1 mol% [Pd(allyl)Cl]2, 4 mol% (S)-SegPhos, and 10 mol%
2,5-dichlorobenzenesulfonyl hydrazide, a range of racemic allylic alcohols were smoothly resolved
with selectivity factors of up to > 400 via asymmetric allylic alkylation of monosubstituted
hydrazines under air at room temperature. Importantly, this kinetic resolution process provided
various allylic alcohols and allylic hydrazine derivatives with high enantiopurity.
Main text
Enantioenriched allylic alcohols serve as versatile building blocks in chemical synthesis.[1] Among
the great advances to access enantioenriched allylic alcohols, kinetic resolution of racemic ones has
emerged as a powerful strategy employed widely in asymmetric synthesis.[2] Technically speaking,
the kinetic resolution of racemic allylic alcohols has been accomplished by either epoxidation[3] or
electrophilic addition[4] of the C═C bond and by either acylation[5] or oxidation of the OH group
(Scheme 1).[6] With regard to racemic terminal allylic alcohols, their kinetic resolution has been
developed via iridium-catalyzed asymmetric substitution of the OH group.[7] In addition, racemic
allylic alcohols having -keto,[8] -ester,[9] or ′-ester groups[10] were reported to be resolved by
catalytic processes involving OH elimination or C═C bond hydrogenation. While some of these
methods are highly effective in resolving racemic allylic alcohols, it is still highly desirable to
develop new methods to expand the scope as well as improve the enantioselectivity. To this end, we
have developed a new strategy for efficient kinetic resolution of racemic allylic alcohols through
palladium/sulfonyl hydrazide-catalyzed asymmetric substitution of the OH group with
monosubstituted hydrazines under air at room temperature (Scheme 1). Decomposition of the
sulfonyl hydrazide into a sulfinic acid and a sulfonic acid is essential for the OH group to be
substituted smoothly through protonation.
Insert Scheme 1.
Despite the poor leaving ability and compatibility of the OH group, recent years have witnessed a
growing interest in the Tsuji-Trost reaction[11] of allylic alcohols.[12] Inspired by previous reports on
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the stereospecific intermolecular substitution of enantioenriched allylic alcohols[13] and the kinetic
resolution of racemic allylic alcohol derivatives using asymmetric Tsuji-Trost reaction,[14,15] we
decided to employ a chiral palladium complex to resolve racemic allylic alcohols despite the great
challenge in obviating racemization of π-allylpalladium intermediates as utilized in catalytic
asymmetric Tsuji-Trost reaction.[16] We selected carbazates (ROCONHNH2) as nucleophilic
components in the Tsuji-Trost reaction of allylic alcohols[17] and the expected kinetic resolution
would provide both allylic alcohols and protected allylic hydrazines in enantioenriched form.
Notably, very few methods are available to access enantioenriched allylic hydrazine derivatives,[13i,18]
which serve as useful building blocks in chemical synthesis.[19] Encouraged by our previous finding
that a stoichiometric sulfonyl hydrazide can accelerate the Tsuji-Trost reaction of allylic amines,[20]
we decided to survey some sulfonyl hydrazides to identify their abilities to promote the kinetic
resolution of racemic allylic alcohols with carbazates.
The model reaction of carbazate 2a with racemic allylic alcohol rac-1a proceeded sluggishly in the
presence of 1 mol% [Pd(allyl)Cl]2 and 4 mol% (S)-SegPhos in dioxane under air at room temperature
(Table 1, entry 1). Addition of 50 mol% sulfonyl hydrazide 3a dramatically accelerated the reaction,
and importantly, protected allylic hydrazine 4a was isolated in 42% yield with 95.1% ee and allylic
alcohol 1a was recovered in 47% yield with 94.8% ee, corresponding to a selectivity factor (s =
kfast/kslow) of 147 for the kinetic resolution (entry 2).[21] Moreover, the reaction exhibited exclusive α
selectivity and complete retention of the E-alkene geometry. To our surprise, decreasing the loading
of sulfonyl hydrazide 3a to 10 mol% not only resulted in good conversion but also improved the
enantioselectivity with an s factor of > 400 (entry 3). The reaction efficiency was affected
dramatically by the structure of the sulfonyl hydrazide and the use of a few other sulfonyl hydrazides
just led to lower enantioselectivity and/or poor reactivity (entries 4-7). The oxygen in the air proved
unnecessary for the reaction to occur but necessary for the high enantioselectivity according to the
control experiment performed under nitrogen (entry 8). However, pure oxygen atmosphere also
resulted in lower enantioselectivity (entry 9). The use of Pd(OAc)2 as a palladium source decreased
the enantioselectivity and even worse, the reaction failed to take place when using PdCl2 and
Pd2(dba)3 (entries 10-12). Replacing (S)-SegPhos with axially chiral bisphosphine ligands L2-5 gave
lower enantioselectivity and no desired product was detected in the reaction with chiral
monophosphine ligand L6 or the Trost ligand L7 (entries 13-18). Finally, we examined a number of
common solvents other than dioxane but found lower enantioselectivity and/or poor reactivity
(entries 19-22).
Insert Table 1.
In the presence of 1 mol% [Pd(allyl)Cl]2, 4 mol% (S)-SegPhos, and 10 mol% sulfonyl hydrazide 3a,
a range of racemic allylic alcohols were resolved through asymmetric allylation of carbazate 2a
under air at room temperature (Table 2, entries 1-22). In general, the reaction with allylic alcohols
having α-alkyl groups and γ-aryl (or γ-heteroaryl) groups proceeded with exclusive α selectivity and
complete retention of the E-alkene geometry and the racemic allylic alcohols were efficiently
resolved with s factors ranging from 20 to > 400 (entries 1-8 and 10-20). In contrast, lower but still
acceptable enantioselectivity was achieved when the α-substituents of allylic alcohols were aryl
groups (entries 9 and 22). Unlike the other cases, the allylic moiety of the π-allylpalladium
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intermediate generated from alcohol rac-1i is symmetrical, and consequently, the enantiopurity of
product 4i is independent on the enantioselective C─O bond cleavage and determined by the
stereoselective attack of the carbazate on the π-allylpalladium. Moreover, the kinetic resolution
process was successfully extended to an allylic alcohol having a γ-alkenyl group with excellent
enantioselectivity (entry 21). It is noteworthy that the regioselectivity in these cases is determined by
the nature of the α- and γ-substituents and the reaction prefers to occur at the allylic position leading
to a higher degree of conjugation, which is in accordance with a typical Tsuji-Trost reaction.[11]
Nevertheless, the reaction became sluggish with a (Z)-allylic alcohol such as
(Z)-4-phenylbut-3-en-2-ol, with a trisubstituted allylic alcohol such as 4,4-diphenylbut-3-en-2-ol, and
a cyclic allylic alcohol such as 2-cyclohexen-1-ol. On the other hand, the reaction proceeded well
with a few other carbazates and importantly, excellent enantioselectivity was achieved (entries
23-25). Further investigation revealed that a carbamyl hydrazine, an acyl hydrazide, and a
hydrazinylphosphonate were all able to serve as suitable nitrogen nucleophiles in the kinetic
resolution reaction of racemic allylic alcohols (entries 26-28). Taken together, this kinetic resolution
process permitted the preparation of various allylic alcohols and allylic hydrazine derivatives with
high enantiopurity.
Insert Table 2.
To gain insights into the reaction mechanism, we carried out electrospray ionization (ESI) mass
spectrometric analysis of the reaction mixture of alcohol rac-1a, carbazate 2a, 1 mol% [Pd(allyl)Cl]2,
4 mol% (S)-SegPhos, and 10 mol% sulfonyl hydrazide 3a. According to the high resolution mass
data, we tentatively assigned sulfinic acid 5a, sulfonic acid 6a, carbazate 7a, and π-allylpalladiums
8a and 8b (Figure 1).[22] We reasoned that π-allylpalladium 8a was generated by the coordination of
(S)-SegPhos to [Pd(allyl)Cl]2 and that π-allylpalladium 8b served as a key intermediate in the
Tsuji-Trost reaction (see below). While carbazate 7a could be generated directly from the reaction of
[Pd(allyl)Cl]2 with carbazate 2a,[23] sulfonyl hydrazide 3a could accelerate the formation of carbazate
7a and itself was converted to sulfinic acid 5a,[20] part of which was subsequently oxidized under air
to afford sulfonic acid 6a (see below).[24]
Insert Figure 1.
Both sulfinic acid 5a and sulfonic acid 6a were found to promote the kinetic resolution but with
much lower conversion and enantioselectivity relative to the reaction with sulfonyl hydrazide 3a [Eq.
(1)]. These results are in line with the lower enantioselectivity we observed when using a higher
loading of sulfonyl hydrazide 3a or performing the reaction under oxygen (Table 1, entries 2 and 9)
because sulfinic acid 5a and/or sulfonic acid 6a were generated in higher concentration. In contrast,
as demonstrated by the control experiment performed under nitrogen (Table 1, entry 8), lower
concentration of sulfinic acid 5a and/or sulfonic acid 6a also led to lower conversion and
enantioselectivity. Thus, it is plausible to conclude that the use of sulfonyl hydrazide 3a under air
could provide appropriate concentration of sulfinic acid 5a and/or sulfonic acid 6a to guarantee good
conversion and excellent enantioselectivity.
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[Pd(allyl)Cl]2 (1 mol%), (S)-SegPhos (4 mol%)
5a or 6a (10 mol%), air, dioxane, RT,11 h
(1)
4a
+
2a
rac-1a
1a
+
With 5a: C = 14.5%, s = 180
With 6a: C = 4.8%, s = 39
Based on the above experimental results and previous relevant studies, we propose the reaction
pathways as depicted in Scheme 2. The reaction is initiated by the decomposition of [Pd(allyl)Cl]2
with a monosubstituted hydrazine,[23] which provides Pd(0) and acids needed in the following
Tsuji-Trost reaction. Nucleophilic attack of hydrazine derivative 2 (or 3) on the allylic carbon in
[Pd(allyl)Cl]2 affords Pd(0), HCl, and hydrazine derivative 7 (or 9). Sulfonyl hydrazide 9 is subjected
to palladium-catalyzed aerobic oxidation to give sulfonyl diazene 10, a highly reactive electrophile
that undergoes the Tsuji-Trost reaction with monosubstituted hydrazine 2 to give hydrazine
derivative 7 and sulfinic acid 5.[20b] Further oxidation of sulfinic acid 5 gives sulfonic acid 6.[24] The
OH group of racemic allylic alcohol rac-1 is activated by HCl, sulfinic acid 5, and/or sulfonic acid 6,
and consequently, the allylic C─O bond is cleaved stereoselectively by chiral palladium(0) complex
PdL with inversion of configuration to give π-allylpalladium 8.[13g] Of course, the remaining alcohol
1 is enantioenriched due to the faster consumption of its enantiomer. Nucleophilic attack of
monosubstituted hydrazine 2 on the allylic carbon of π-allylpalladium 8 proceeds with inversion of
configuration to give allylic hydrazine derivative 4 and regenerate PdL along with the corresponding
acid to continue the catalytic cycle. Similar reaction of sulfonyl hydrazide 3 with π-allylpalladium 8
gives sulfonyl hydrazide 11, aerobic oxidation of which followed by oxidative addition with PdL
regenerates π-allylpalladium 8 having a sulfinate anion as a counteranion.
Insert Scheme 2.
In summary, we have developed a new strategy for the kinetic resolution of racemic allylic alcohols
through palladium/sulfonyl hydrazide-catalyzed enantioselective C─O bond cleavage under mild
conditions. In the presence of 1 mol% [Pd(allyl)Cl]2, 4 mol% (S)-SegPhos, and 10 mol%
2,5-dichlorobenzenesulfonyl hydrazide, a range of racemic allylic alcohols were smoothly resolved
with selectivity factors of up to > 400 via asymmetric allylic alkylation of monosubstituted
hydrazines under air at room temperature. Importantly, this kinetic resolution process proved useful
for the preparation of various allylic alcohols and allylic hydrazine derivatives with high
enantiopurity.
Acknowledgements
We are grateful for the financial support from the National Natural Science Foundation of China
(21472178 and 21232007), the National Key Basic Research Program of China (2014CB931800),
and Hefei Center for Physical Science and Technology (2014FXCX002).
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[15]For similar transition metal-catalyzed kinetic resolution of racemic allylic alcohol derivatives,
see: a) D. L. Hughes, M. Palucki, N. Yasuda, R. A. Reamer, P. J. Reider, J. Org. Chem. 2002, 67,
2762-2768; b) C. Fischer, C. Defieber, T. Suzuki, E. M. Carreira, J. Am. Chem. Soc. 2004, 126,
1628-1629; c) K. Onitsuka, Y. Matsushima, S. Takahashi, Organometallics 2005, 24, 6472-6474;
d) X.-B. Jiang, P. W. N. M. van Leeuwen, J. N. H. Reek, Chem. Commun. 2007, 2287-2289; e) D.
C. Vrieze, G. S. Hoge, P. Z. Hoerter, J. T. Van Haitsma, B. M. Samas, Org. Lett. 2009, 11,
3140-3142.
[16]a) D. Banerjee, K. Junge, M. Beller, Angew. Chem. 2014, 126, 13265-13269; Angew. Chem. Int.
Ed. 2014, 53, 13049-13053; b) X. Huo, G. Yang, D. Liu, Y. Liu, I. D. Gridnev, W. Zhang, Angew.
Chem. 2014, 126, 6894-6898; Angew. Chem. Int. Ed. 2014, 53, 6776-6780.
[17]S. Tšupova, U. Mäeorg, Org. Lett. 2013, 15, 3381-3383.
[18]a) T. Yamagishi, M. Ohnuki, T. Kiyooka, D. Masui, K. Sato, M. Yamaguchi, Tetrahedron:
Asymmetry 2003, 14, 3275-3279; b) R. J. Kloetzing, P. Knochel, Tetrahedron: Asymmetry 2006,
17, 116-123; c) D. Popa, R. Marcos, S. Sayalero, A. Vidal-Ferran, M. A. Pericàs, Adv. Synth.
Catal. 2009, 351, 1539-1556; d) H. Yuan, Z. Zhou, J. Xiao, L. Liang, L. Dai, Tetrahedron:
Asymmetry 2010, 21, 1874-1884; e) K. E. Lutz, R. J. Thomson, Angew. Chem. 2011,123,
4529-4532; Angew. Chem. Int. Ed. 2011, 50, 4437-4440; f) Y. Wang, J.-K. Xu, Y. Gu, S.-K. Tian,
Org. Chem. Front. 2014, 1, 812-816.
[19]a) B. F. Strick, D. A. Mundal, R. J. Thomson, J. Am. Chem. Soc. 2011, 133, 14252-14255; b) O.
Gutierrez, B. F. Strick, R. J. Thomson, D. J. Tantillo, Chem. Sci. 2013, 4, 3997-4003; c) J. C. T.
Reddel, K. E. Lutz, A. B. Diagne, R. J. Thomson, Angew. Chem. 2014, 126, 1419-1422; Angew.
Chem. Int. Ed. 2014, 53, 1395-1398.
[20]a) Y. Wang, Y.-N. Xu, G.-S. Fang, H.-J. Kang, Y. Gu, S.-K. Tian, Org. Biomol. Chem. 2015, 13,
5367-5371; b) T.-T. Wang, F.-X. Wang, F.-L. Yang, S.-K. Tian, Chem. Commun. 2014, 50,
3802-3805.
[21]For calculation of s factors, see: H. B. Kagan, J. C. Fiaud, Top. Stereochem. 1988, 18, 249-330.
As suggested by one reviewer, the exact s values were not given when they were > 400 because
of big errors.
[22]For details, see the Supporting Information.
[23]Y.-H. Su, Z. Wu, S.-K. Tian, Chem. Commun. 2013, 49, 6528-6530.
[24]A. Deavin, C. W. Rees, J. Chem. Soc. 1961, 4970-4973.
Scheme legends
Scheme 1. Strategies for the kinetic resolution of racemic allylic alcohols.
Scheme 2. Proposed reaction pathways.
Figure legends
Figure 1. Some intermediates and byproducts.
Tables
Table 1. Optimization of reaction conditions.[a]
Entry
R
[Pd]
L
Solvent
Yield [%][b]
1a 4a
ee [%][c]
C [%][d]
s[e]
3
1a
4a
7

Chemistry - A European Journal
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1
—
3a
3a
3b
3c
3d
3e
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
none
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
Pd(OAc)2
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
tetrahydrofuran
toluene
—
47
49
47
—
82
88
52
46
46
—
—
45
46
45
49
—
—
47
41
46
—
trace
42
44
42
trace
5
—
—
—
—
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L1
L1
L1
L1
2[f]
3
2,5-Cl2C6H3
2,5-Cl2C6H3
2,4,6-Me3C6H2
4-MeOC6H4
4-O2NC6H4
PhCH2
94.8
99.5
96.0
—
95.1
98.3
96.3
—
49.9
50.3
49.9
—
147
> 400
210
—
4
5
6
5.7
98.8
98.7
98.2
96.7
95.1
—
—
—
7
2
3.0
—
—
8[g]
9[h]
10
11
12
13
14
15
16
17
18
19
20
21
22
2,5-Cl2C6H3
2,5-Cl2C6H3
2,5-Cl2C6H3
2,5-Cl2C6H3
2,5-Cl2C6H3
2,5-Cl2C6H3
2,5-Cl2C6H3
2,5-Cl2C6H3
2,5-Cl2C6H3
2,5-Cl2C6H3
2,5-Cl2C6H3
2,5-Cl2C6H3
2,5-Cl2C6H3
2,5-Cl2C6H3
2,5-Cl2C6H3
38
40
48
0
72.0
98.7
99.4
—
42.3
50.5
51.1
—
239
300
230
—
PdCl2
Pd2(dba)3
0
—
—
—
—
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
46
49
48
47
0
97.1
94.6
99.6
91.7
—
86.2
86.1
82.8
92.7
—
53.0
52.4
54.6
49.7
—
57
48
64
86
—
0
—
—
—
—
48
52
48
trace
97.8
95.7
96.9
—
97.2
84.4
95.7
—
50.2
53.1
50.3
—
319
45
ethyl acetate
solvent[i]
191
—
[a] Reaction conditions: rac-1a (0.20 mmol), 2a (0.16 mmol), 3 (10 mol%), [Pd] (1 mol%), L (4
mol%), solvent (0.50 mL), air (1 atm), RT, 11 h. [b] Isolated yield. [c] Determined by HPLC analysis
on a chiral stationary phase. [d] C (conversion) = ee1a/(ee1a + ee4a). [e] s = ln[(1 - C)(1 - ee1a)]/ln[(1 -
C)(1 + ee1a)].[21] [f] 50 mol% 3a was used. [g] The reaction was run under nitrogen. [h] The reaction
was run under oxygen. [i] 1,2-Dichloroethane, acetonitrile, N,N-dimethylformamide, or dimethyl
sulfoxide. Ac = acetyl, dba = dibenzylideneacetone.
Table 2. Kinetic resolution of racemic allylic alcohols.[a]
Entry
R1
R2
R3
t [h] Yield [%][b] ee [%][c]
C [%][d] s[e]
1
2
4
1
4
1
4
1
2
3
Ph
Ph
Ph
CHMe2
Cbz
Cbz
Cbz
11
11
11
49
42
49
44
42
40
99.5
99.7
99.7
98.3 50.3
93.5 51.6
97.7 50.5
> 400
192
1a
1b
1c
2a
2a
2a
4a
4b
4c
cyclopentyl
cyclohexyl
> 400
8

Chemistry - A European Journal
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4
Ph
Me
Cbz
4
43
46
39
44
43
49
47
48
48
52
54
44
50
47
50
56
50
70
57
46
46
48
48
61
67
54
41
43
43
25
42
42
44
42
40
42
44
37
40
44
31
46
21
39
47
44
48
46
34
27
88.7
88.1
97.2
97.0
96.3
94.2
98.6
99.9
97.8
85.3
78.1
99.3
86.7
96.2
91.2
67.3
94.9
39.6
43.1
98.6
97.7
97.4
97.5
46.5
45.1
75.4 54.1
21
1d
1e
1f
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
4d
4e
5
Ph
CH2CHMe2
(CH2)7Me
CH2CH2Ph
CH2CH=CH2
Ph
Cbz
8
88.5 49.9
68.6 58.6
84.2 53.5
78.6 55.1
48
6
Ph
Cbz
6
22
4f
7
Ph
Cbz
8
48
1g
1h
1i
4g
4h
4i
8
Ph
Cbz
24
10
11
11
11
4
33
9
Ph
Cbz
52.7
—
—
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
4-FC6H4
4-ClC6H4
4-BrC6H4
4-NCC6H4
4-MeOC6H4
3-MeC6H4
2-MeOC6H4
1-naphthyl
2-naphthyl
2-furyl
3-thienyl
(E)-PhCH=CH
Me
CHMe2
CHMe2
CHMe2
CHMe2
CHMe2
CHMe2
CHMe2
CHMe2
CHMe2
CHMe2
CHMe2
CHMe2
Ph
Cbz
97.2 50.4
94.2 51.5
95.6 50.6
95.8 47.1
97.3 44.5
92.0 51.9
97.6 47.0
97.1 49.8
95.4 48.9
97.8 40.8
98.8 49.0
96.4 29.1
60.3 41.7
97.5 50.3
98.8 49.7
98.6 49.7
94.6 50.8
78.6 37.2
95.3 32.1
350
252
201
128
174
134
234
272
136
182
> 400
81
1j
4j
Cbz
1k
1l
4k
4l
Cbz
Cbz
1m
1n
1o
1p
1q
1r
1s
4m
4n
4o
4p
4q
4r
Cbz
11
11
14
14
16
24
12
18
11
9
Cbz
Cbz
Cbz
Cbz
Cbz
4s
Cbz
1t
4t
Cbz
1u
1v
1a
1a
1a
1a
1a
1a
4u
4b
4ab
4ac
4ad
4ae
4af
4ag
Cbz
6
Ph
CHMe2
CHMe2
CHMe2
CHMe2
CHMe2
CHMe2
Boc
393
> 400
> 400
158
13
Ph
Fmoc
CO2Et
CONHPh
COPh
PO(OEt)2
13
8
Ph
Ph
13
21
11
Ph
Ph
65
2g
[a] Reaction conditions: rac-1 (0.20 mmol), 2 (0.16 mmol), 3a (10 mol%), [Pd(allyl)Cl]2 (1 mol%),
(S)-SegPhos (4 mol%), dioxane (0.50 mL), air (1 atm), RT, 4-24 h. [b] Isolated yield. [c] Determined
by HPLC analysis on a chiral stationary phase. [d] C = ee1/(ee1 + ee4). [e] s = ln[(1 - C)(1 -
ee1)]/ln[(1 - C)(1 + ee1)]. Boc = tert-butoxycarbonyl, Cbz = benzyloxycarbonyl, Fmoc =
9-fluorenylmethoxycarbonyl.
Text for the Table of Contents
Eye-catching headline: Kinetic Resolution
Liang Yan, Jing-Kun Xu, Chao-Fan Huang, Zeng-Yang He, Ya-Nan Xu, and Shi-Kai Tian*
Kinetic Resolution of Racemic Allylic Alcohols via Catalytic Asymmetric Substitution of the
OH Group with Monosubstituted Hydrazines
9

Chemistry - A European Journal
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Insert TOC
A range of racemic allylic alcohols were resolved with selectivity factors of up to > 400 via
palladium/sulfonyl hydrazide-catalyzed asymmetric allylation of monosubstituted hydrazines under
air at room temperature (see scheme). The reaction provided various allylic alcohols and allylic
hydrazine derivatives with high enantiopurity.
Keywords: allylic alcohols • allylic hydrazines • kinetic resolution • palladium • sulfonyl hydrazides
10