Regio- and Enantioselective Rhodium-Catalyzed Allylic Alkylation of Racemic Allylic Alcohols with 1,3-Diketones

Article abstract of DOI:10.1021/jacs.8b05126

Highly regio- and enantioselective rhodium-catalyzed allylic alkylation of 1,3-diketones with racemic secondary allylic alcohols is reported. In the presence of a Rh-catalyst derived from the Carreira (P, olefin)-ligand and TFA as an additive, chiral branched α-allylated 1,3-diketones could be obtained in good to excellent yields, with excellent regio- and enantioselectivity (b/l > 19/1, 86-98% ee). The direct utilization of allyl alcohols as electrophiles represents an improvement from the viewpoint of an atom economy. Both aryl- and aliphatic-substituted allyl alcohols are suitable substrates with excellent reaction outcomes. This reaction features mild conditions, broad substrate scope, and readily available substrates.

Full text of DOI:10.1021/jacs.8b05126

Subscriber access provided by UNIVERSITY OF TOLEDO LIBRARIES
Article
Regio- and Enantioselective Rhodium-Catalyzed Allylic
Alkylation of Racemic Allylic Alcohols with 1,3-Diketones
Sheng-Biao Tang, Xiao Zhang, Hang-Fei Tu, and Shu-Li You
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b05126 • Publication Date (Web): 25 May 2018
Downloaded from http://pubs.acs.org on May 25, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 8
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Regio- and Enantioselective Rhodium-Catalyzed Allylic Alkyl-
ation of Racemic Allylic Alcohols with 1,3-Diketones
Sheng-Biao Tang,† Xiao Zhang,† Hang-Fei Tu,† and Shu-Li You*,†,‡
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
†
State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Insti-
tute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling
Lu, Shanghai 200032, China
‡
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), 300072, China
Supporting Information Placeholder
ABSTRACT: Highly regio- and enantioselective rhodium-catalyzed allylic alkylation of 1,3-diketones with racemic sec-
ondary allylic alcohols is reported. In the presence of a Rh-catalyst derived from the Carreira (P, olefin)-ligand and TFA as
additive, chiral branched α-allylated 1,3-diketones could be obtained in good to excellent yields, with excellent regio- and
enantioselectivity (b/l>19/1, 86-98% ee). The direct utilization of allyl alcohols as electrophiles represents an improvement
from the viewpoint of atom economy. Both aryl and aliphatic substituted allyl alcohols are suitable substrates with excel-
lent reaction outcomes. This reaction features mild conditions, broad substrate scope and readily available substrates.
INTRODUCTION
Transition-metal-catalyzed asymmetric allylic alkyla-
tion (AAA) reactions provide a straightforward and relia-
ble method to construct the allylic stereocenters.1 Howev-
er, the transition metals employed for AAA reactions
mainly focused on Pd,2 Ir3 and Cu4. The utilization of rho-
dium catalytic systems for asymmetric allylic alkylation
reaction remains underexplored.5,6-9 In this regard, Evans
and coworkers pioneered in rhodium-catalyzed allylic
alkylation reactions, and disclosed asymmetric reactions
employing enantioenriched chiral allylic substrates via
double-inversion process (eq 1, Scheme 1).10 In addition,
recent efforts from the Evans group led to elegant Rh-
catalyzed asymmetric allylic alkylation of prochiral nucle-
ophiles.11 In 2003, Hayashi et al reported a very impressive
asymmetric allylic alkylation with allylic acetates by a Rh-
Phox catalytic system (eq 2, Scheme 1).12 Kazmaier and
coworkers reported Rh-catalyzed asymmetric allylic al-
kylation reactions of chelated enolates with enantioen-
riched allyl phosphates, where excellent chiral transfer
was achieved.13 To be noted, the groups of Nguyen,14
Breit15, Vrieze16 and Guo17 reported asymmetric allylic
amination reactions with racemic allylic esters. Recently,
the pioneering work from the groups of Breit,18 Dong19
and Kang20 demonstrated that allenes and alkynes are
suitable allylic precursors to afford allylic alkylation prod-
ucts via Rh-catalytic system. However, the reactions with
aryl substituted substrates generally led to moderate en-
antioselectivity (eq 3, Scheme 1).18e
our results on Rh-(P, olefin) complex catalyzed asymmet-
ric allylic alkylation with secondary racemic allylic alco-
hols directly.
Scheme 1. Rh-catalyzed asymmetric allylic alkylation
of allylic esters or addition of allenes
RESULTS AND DISCUSSION
Optimization of the Reaction Conditions. We began
our study by testing the reaction between phenyl vinyl
carbinol (1a) and acetylacetone (2a) with the Rh catalyst
derived from [Rh(cod)Cl]2 and the Carreira P/olefin lig-
and22 (Table 1). In the presence of 2 mol % of [Rh(cod)Cl]2
and 5 mol % of (S)-L1, the reaction did not occur in
CH2Cl2 (entry 1). With 100 mol % Fe(OTf)2 as an additive,
the alkylation products (3a/4a) were obtained in 10/1 b/l
regioselectivity, with the isolation of 3a in 39% ee (entry
2). To our delight, with TFA as an additive, the desired
product 3a was obtained in 94% yield and 71% ee, with an
Considering the known reports are mainly limited with
the employment of activated allylic alcohol precursors
and allenes, the direct utilization of readily available al-
lylic alcohols will be highly desirable.21 Herein, we report
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 8
14
15
Rh1
Rh2
Rh3
Rh4
Rh2
Rh2
Rh2
THF
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
L1
L1
L1
L1
L2
L3
L4
TFA
TFA
TFA
TFA
TFA
TFA
TFA
62
95
-
> 19/1
35
95
-
excellent regioselectivity (b/l > 19/1) (entry 3). Next, sev-
eral Brønsted acids such as benzoic acid, TsOH,
(nBuO)2PO2H and TfOH were tested, and none of them
gave better results (entries 4–7). Furthermore, the sol-
vents were examined (entries 8-14), and the reaction in
Et2O led to excellent yield and high regio- and enantiose-
lectivity (94% yield, b/l > 19/1, 92% ee, entry 11). Different
rhodium precursors such as [Rh(C2H4)2Cl]2, [Rh(nbd)Cl]2,
and [Rh(cod)OTf]2 were examined in Et2O (entries 15-17).
The catalyst derived from [Rh(C2H4)2Cl]2 gave the best
results (95% yield, b/l > 19/1, 95% ee, entry 15). Further
examination of ligands L2-L4 afforded no better results
(entries 18-20). Notably, the loss of reactivity with the
catalyst derived from ligand L3 without an olefin moiety
indicated the active catalyst requires the P-olefin binding
mode. Finally, the optimal conditions were obtained as
following: (2 mol %) [Rh(C2H4)2Cl]2 and (5 mol %) (S)-L1
were stirred for 15 min in Et2O, followed by the addition
of substrates and TFA (25 mol %).
1
2
3
4
5
6
7
8
> 19/1
16
17
18
19
20
-
-
-
-
91
> 19/1
-
86
-
trace
82
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
> 19/1
76
aGeneral conditions: 1a (0.4 mmol), 2a (0.2 mmol), [Rh] (2
mol %), ligand (5 mol %), and additive (25 mol %) in solvent
(2.5 mL) at room temperature. bYield of isolated product.
cDetermined by H NMR analysis. dDetermined by HPLC
1
analysis. eFe(OTf)2 (100 mol %) was used. DME = 1,2-
dimethoxyethane. [Rh(nbd)Cl]2 = norbornadiene rhodium(I)
chloride dimer.
Table 1. Optimization of the reaction conditionsa
Reaction Scope. With the optimized reaction condi-
tions in hand, we next investigated the substrate scope
(Scheme 2). Various racemic aromatic allylic alcohols
were allowed to react with acetylacetone (2a). The sub-
strates bearing an electron-donating group (4-Me, 4-OMe,
3-OMe, 2-OMe) at the different positions of phenyl ring
led to their desired products in 90-95% yields, b/l > 19/1,
and 87-95% ee (3a-3e) in 10-24 h. The substrates with an
electron-withdrawing group (CF3, F, Cl, Br, I) on the phe-
nyl ring required prolonged reaction time, providing good
to excellent yields (88-94%) and enantioselectivity (91-97%
ee) (3f-3k). The well tolerance with Cl, Br, and I groups,
which are known to undergo diverse Pd-mediated trans-
formations, shows the advantage of Rh catalysis over Pd
catalysis and offers easy handles for further modification.
Moreover, the reactions of 2-naphthyl- and bipenyl-
substituted allyl alcohols proceeded smoothly leading to
the isolation of 3l and 3m in 85% yield with 91% ee and in
88% yield and 87% ee, respectively. The reaction of 2-
furanyl allyl alcohol proceeded in slightly decreased yield
(60%, 87% ee, 3n), likely due to the unstability of sub-
strate under acidic conditions. 2-Benzothiophenyl allylic
alcohol was also a suitable substrate, leading to product
3o in 88% yield and 93% ee.
en-
try
1
[Rh]
Rh1
Rh1
Rh1
Rh1
Rh1
Rh1
Rh1
Rh1
Rh1
Rh1
Rh1
Rh1
Rh1
sol-
vent
CH2Cl2
lig-
and
L1
additive
-
yield
(%)b
-
3a/4ac
-
ee
(%)d
-
2e
3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
Fe(OTf)2
TFA
85
94
93
10/1
39
71
> 19/1
> 19/1
> 19/1
-
4
PhCO2H
TsOH
67
69
-
5
82
6
(nBuO)2
PO2H
TfOH
trace
78
7
> 19/1
> 19/1
> 19/1
> 19/1
> 19/1
> 19/1
> 19/1
66
71
8
TFA
TFA
TFA
TFA
TFA
TFA
90
93
9
tolu-
ene
CHCl3
75
-
10
11
12
13
23
Et2O
94
92
92
86
89
tBuO-
Me
DME
90
ACS Paragon Plus Environment

Page 3 of 8
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aGeneral conditions:
1 (0.4 mmol), 2a (0.2 mmol),
[Rh(C2H4)2Cl]2 (3 mol %), L1 (7 mol %), and TFA (100 mol %)
in Et2O (2.5 mL) at room temperature. bIsolated yield.
1
cDetermined by H NMR analysis. dDetermined by HPLC
aGeneral conditions:
1 (0.4 mmol), 2a (0.2 mmol),
analysis.
Scheme 3. Scope of the aliphatic allylic alcoholsa-d
[Rh(C2H4)2Cl]2 (2 mol %), L1 (5 mol %), and TFA (25 mol %)
in Et2O (2.5 mL) at room temperature. bIsolated yield.
The scope of 1,3-diketones was then examined. The re-
sults are summarized in Scheme 4. The reaction of hep-
tane-1,3-diones with alcohol 1a gave product 3ab in 89%
yield and 92% ee. However, when the sterically more con-
gested derivative (R = tBu) was tested, the enantioselectiv-
ity was decreased (31% ee, 3ad, Scheme 4). The reaction of
the 1,3-diphenyl-1,3-propanedione afforded the branched
product 3ae in 96% yield and 88% ee. Excellent enanti-
oselectivity (87-93% ee) was obtained for the reactions of
α-branched 1,3-diketones (3af-3ah). Furthermore, the
reaction was performed on a gram-scale to give the isolat-
ed product in 75% yield (1.14 g) and 94% ee (3a, Scheme
4).
1
cDetermined by H NMR analysis. dDetermined by HPLC
analysis.
Scheme 2. Scope of the aromatic racemic allylic alco-
holsa-d
Next, aliphatic allylic alcohols were also explored
(Scheme 3), which were known as challenging substrates
in allylic substitution reactions catalyzed by other met-
als.23 Under the slightly modified conditions,
[Rh(C2H4)2Cl]2 (3 mol %)/(S)-L1 (7 mol %) and TFA (100
mol %), the reactions of aliphatic allyl alcohols could pro-
vide their corresponding alkylation products in high to
excellent selectivities and good yields (Scheme 3). With
substrates bearing longer alkyl chain substituents, the
yields and enantioselectivity of products were increased
(78-89% yields, 92-98% ee, 3p-3s). A variety of aliphatic
allylic alcohols which have different substituent in the
alkyl chain were allowed to react with acetylacetone (2a),
good yields and excellent enantioselectivity were obtained
(3t-3u). Of particular note, various generally labile func-
tional groups such as Br, N3, and benzoyl and ether were
well compatible, the alkylation products (3v-3y) were ob-
tained in excellent enantioselectivity (93-96% ee). Moreo-
ver, cyclopentyl and cyclohexyl substituted substrates also
worked well, yielding the alkylation products (3z-3aa) in
excellent regio- and enantioselectivity (89-90% ee).
aGeneral conditions: 1a (0.4 mmol),
2 (0.2 mmol),
[Rh(C2H4)2Cl]2 (2 mol %), L1 (5 mol %), and TFA (25 mol %)
in Et2O (2.5 mL) at room temperature. bIsolated yield.
1
d
cDetermined by H NMR analysis. Determined by HPLC
analysis. eGram scale: 1a (14 mmol), 2a (7 mmol),
[Rh(C2H4)2Cl]2 (3 mol %), L1 (7 mol %), and TFA (25 mol %)
in Et2O (80 mL) at room temperature for 72 h.
Scheme 4. Scope of 1,3-diketonesa-d
ACS Paragon Plus Environment

Journal of the American Chemical Society
gioselectivity and 1.2/1 dr by changing the acid promoter
Page 4 of 8
1
2
3
4
5
6
7
to one equivalent amount of Yb(OTf)3. The subsequent
decarboxylation occurred to generate 5a in 62% yield and
70% ee with an opposite configuration (S) (eq 2, Scheme
6). Similarly, dimethyl malonate was proved to be a viable
participate, leading to the alkylation product 3c' in good
yield, excellent regioselectivity and moderate enantiose-
lectivity (b/l > 19/1, 89% yield, 65% ee, eq 3, Scheme 6).
8
9
Transformations. To further demonstrate the utility
of this method, the transformations of the branched al-
lylated 1,3-diketones were conducted as shown in Scheme
7. Compound 3a could be condensed with hydroxylamine
and hydrazines, leading to their corresponding oxazole
(6a) and pyrazoles (7a-b), respectively, in excellent yields.
There is no erosion of the enantiomeric purity during the
transformations.
aGeneral conditions:
1
(0.4 mmol),
2
(0.2 mmol),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[Rh(C2H4)2Cl]2 (2 mol %), L1 (5 mol %), and TFA (25 mol %)
in Et2O (2.5 mL) at room temperature for 24-36 h; Then KOH
(0.8 mmol) and EtOH (5 mL) were added, and the mixture
o
b
c
was stirred at 70 C for 30 min. Isolated yield. Determined
by 1H NMR analysis. dDetermined by HPLC analysis.
Scheme 5. One-pot protocol of alkylation and
deacetylationa-d
The synthetically valuable unsaturated ketones could
be obtained from alcohols in a one-pot protocol including
sequential alkylation and deacetylation18e,24 (Scheme 5).
The enantiomeric purity of the deacetylation products
was well preserved from the alkylation products (5a-5e).
The absolute configuration of product 5a was determined
as R by comparing the optical rotation with that reported
in literature.25
Scheme 7. Transformations of product 3a
Kinetic Resolution Studies. Since the racemic allylic
alcohols were used, we became intrigued to investigate
the possible kinetic resolution involved. Accordingly, the
reactions were quenched at 2 h and 24 h, respectively, as
shown in Scheme 8. It was found the ee of the desired
product 3a remained excellent and unchanged in both
cases (95%) and the allylic alcohol 1a was recovered with
25% and 65% ee, respectively, which suggested the kinetic
resolution is occurring (eqs 1-2, Scheme 8). Meanwhile,
the reaction between the same equivalent amount of 1a
and 2a was tested, and 3a was obtained in 82% yield and
87% ee, indicating an overall dynamic kinetic resolution
process for the product formation (eq 3, Scheme 8).
aGeneral conditions: 1a (0.4 mmol), 2' (0.2 mmol),
[Rh(C2H4)2Cl]2 (2 mol %), L1 (5 mol %), and TFA (25 mol %)
or Yb(OTf)3 (100 mol %) in Et2O (2.5 mL) at room tempera-
ture; The decarboxylation condition: 3b' (0.1 mmol), KOH
(0.4 mmol) and EtOH/H2O = 1/1 (3 mL) were added, and the
o
b
c
mixture was stirred at 80 C for 1 h. Isolated yield. Dr and
b/l was determined by H NMR analysis. dDetermined by
1
HPLC analysis.
Scheme 6. Investigation of β-ketoesters and dimethyl
malonatea-d
Scheme 8. Kinetic resolution studies
In addition to 1,3-diketones, cyclic β-ketoester 2a' was
also well tolerated, furnishing the corresponding α-allyl β-
ketoester compound 3a' in 83% yield with 6/1 dr and the
ee for the major diastereoisomer was confirmed as 96%
(eq 1, Scheme 6). However, the reaction based on acyclic
β-ketoester 2b' did not proceed at all under the previously
optimized conditions. Finally, we found the desired prod-
uct 3b' could be obtained in 96% yield with excellent re-
Proposed Catalytic Cycle. Based on the experi-
mental observations, a plausible mechanism was pro-
posed in Scheme 9 by utilizing the formation of 3a as an
example. In the presence of catalytic amount of acid addi-
tive, the rhodium(I) species (A) undergoes oxidative addi-
tion to afford the corresponding (η3-allyl)rhodium(III)
species (B) with the release of one molecule water and
ACS Paragon Plus Environment

Page 5 of 8
Journal of the American Chemical Society
and the CAS (XDB20000000, QYZDYSSWSLH012) for gener-
ous financial support. Dr Sheng-Biao Tang thanks Phar-
maron for a postdoctoral fellowship.
conjugate base of the acid. Then, the acetylacetone (2a)
directly attacks the allyl fragment to deliver η2-allyl-
rhodium(I) species (C). The substitution of product (3a)
by allylic alcohol (1a) completes the catalytic cycle and
species A is regenerated for the next catalytic cycle
(Scheme 9).
1
2
3
4
REFERENCES
5
6
7
8
9
(1) For selected reviews, see: (a) Trost, B. M.; Van Vranken, D. L.
Asymmetric Transition Metal-Catalyzed Allylic Alkylations. Chem.
Rev. 1996, 96, 395. (b) Trost, B. M.; Crawley, M. L. Asymmetric Tran-
sition-Metal-Catalyzed Allylic Alkylations:ꢀ Applications in Total
Synthesis. Chem. Rev. 2003, 103, 2921. (c) Lu, Z.; Ma, S. Metal-
Catalyzed Enantioselective Allylation in Asymmetric Synthesis. An-
gew. Chem. Int. Ed. 2007, 47, 258. (d) Weaver, J. D.; Recio, A. III.;
Grenning, A. J.; Tunge, J. A. Transition Metal-Catalyzed Decarboxy-
lative Allylation and Benzylation Reactions. Chem. Rev. 2011, 111, 1846.
(e) Butt, N. A.; Zhang, W. Transition Metal-Catalyzed Allylic Substi-
tution Reactions With Unactivated Allylic Substrates. Chem. Soc. Rev.
2015, 44, 7929. For a book, see: (f) Transition Metal Catalyzed Enan-
tioselective Allylic Substitution in Organic Synthesis (Ed.: Kazmaier,
U.), Springer Heidelberg, 2012.
(2) For selected reviews, see: (a) Helmchen, G. Enantioselective
Palladium-Catalyzed Allylic Substitutions With Asymmetric Chiral
Ligands. J. Organomet. Chem. 1999, 576, 203. (b) Tenaglia, A.; Heu-
mann, A. Palladium-Catalyzed Enantioselective Organic Transfor-
mations. Angew. Chem. Int. Ed. 1999, 38, 2180. (c) Trost, B. M. Pd
Asymmetric Allylic Alkylation (AAA). A Powerful Synthetic Tool.
Chem. Pharm. Bull. 2002, 50, 1. (d) Kazmaier, U. Palladium Catalyzed
Allylic Alkylations of Nonstabilized Enolates. Curr. Org. Chem. 2003,
7, 317. (e) Trost, B. M. Asymmetric Allylic Alkylation, an Enabling
Methodology. J. Org. Chem. 2004, 69, 5813. (f) Jensen, T.; Fristrup, P.
Toward Efficient Palladium-Catalyzed Allylic C-H Alkylation. Chem.
Eur. J. 2009, 15, 9632. (g) Milhau, L.; Guiry, P. J. Palladium-Catalyzed
Enantioselective Allylic Substitution. Top. Organomet. Chem. 2011,
38, 95.
(3) For selected reviews, see: (a) Takeuchi, R.; Kezuka, S. Iridium-
Catalyzed Formation of Carbon-Carbon and Carbon-Heteroatom
Bonds. Synthesis 2006, 2006, (b elmchen, ahnz,
bon, chelwies, eihofen, Iridium-Catalysed Asymmet-
ricallylic Substitutions. Chem. Commun. 2007, 675. (c) Hartwig, J. F.;
Stanley, L. M. Mechanistically Driven Development of Iridium Cata-
lysts for Asymmetric Allylic Substitution. Acc. Chem. Res. 2010, 43,
1461. (d) Hartwig, J. F.; Pouy, M. J. Iridium-Catalyzed Allylic Substitu-
tion. Top. Organomet. Chem. 2011, 34, 169. (e) Liu, W.-B.; Xia, J.-B.;
You, S.-L. Iridium-catalyzed asymmetric allylic substitutions. Top.
Organomet. Chem. 2011, 38, 155. (f) Tosatti, P.; Nelson, A.; Marsden, S.
P. Recent Advances and Applications of Iridium-Catalysed Asym-
metric Allylic Substitution. Org. Biomol. Chem. 2012, 10, 3147. (g)
Helmchen, G. In Molecular Catalysis; Gade, L. H.; Hofmann, P., Ed.;
Wiley-VCH: Weinheim, 2014; pp 235-254. (h) Zhuo, C.-X.; Zheng, C.;
You, S.-L. Transition-Metal-Catalyzed Asymmetric Allylic Dearoma-
tization Reactions. Acc. Chem. Res. 2014, 47, 2558. (i) Hethcox, J. C.;
Shockley, S. E.; Stoltz, B. M. Iridium-Catalyzed Diastereo-, Enantio-,
and Regioselective Allylic Alkylation with Prochiral Enolates. ACS
Catal. 2016, 6, 6207. (j) Qu, J.; Helmchen, G. Applications of Iridium-
Catalyzed Asymmetric Allylic Substitution Reactions in Target-
Oriented Synthesis. Acc. Chem. Res. 2017, 50, 2539.
(4) For selected reviews, see: (a) Pineschi, M. Copper-Catalyzed
Enantioselective Allylic Alkylation Ring-Opening Reactions of Small-
Ring Heterocycles with Hard Alkyl Metals. New J. Chem. 2004, 28,
657. (b) Yorimitsu, H.; Oshima, K. Recent Progress in Asymmetric
Allylic Substitutions Catalyzed by Chiral Copper Complexes. Angew.
Chem. Int. Ed. 2005, 44, 4435. (c) Alexakis, A.; Bäckvall, J. E.; Krause,
N.; Pàmies, O.; Diéguez, M. Enantioselective Copper-Catalyzed Con-
jugate Addition and Allylic Substitution Reactions. Chem. Rev. 2008,
108, 2796. (d) Harutyunyan, S. R.; den Hartog, T.; Geurts, K.; Min-
naard, A. J.; Feringa, B. L. Catalytic Asymmetric Conjugate Addition
and Allylic Alkylation with Grignard Reagents. Chem. Rev. 2008, 108,
2824. (e) Falciola, C. A.; Alexakis, A. Copper-Catalyzed Asymmetric
Allylic Alkylation. Eur. J. Org. Chem. 2008, 2008, 3765. (f) Langlois,
J.-B.; Alexakis, A. Copper-Catalyzed Enantioselective Allylic Substitu-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 9. Proposed catalytic cycle
CONCLUSION
In conclusion, we realized a rhodium-catalyzed highly
regio- and enantioselective allylic alkylation reaction of
1,3-diketones, using unactivated allylic alcohols as elec-
trophiles for the first time. Catalytic amount of TFA as the
additive plays a key role for activating the alcohol and
achieving excellent enantioselective control. Both racemic
aromatic and aliphatic allylic alcohols were well tolerated
in this reaction, affording the alkylation products in good
to excellent yields with excellent regio- and enantioselec-
tivity. A wide range of functional groups are compatible
with the reaction conditions. The unsaturated ketones
were obtained from alcohols in a one-pot protocol as well.
The utilization of readily available allylic alcohols as the
starting materials and uniformly high regio- and enanti-
oselectivity for both aryl and aliphatic allylic alcohols
warrant the synthetic potentials of this method.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and compound characterization
data. This material is available free of charge via the in-
ternet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
E-mail: slyou@sioc.ac.cn.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the National Key R&D Program of China
(2016YFA0202900), the National Basic Research Program of
China (2015CB856600), NSFC (21332009, 21421091, 21572250),
Program of Shanghai Subject Chief Scientist (16XD1404300),
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 8
tion. Top. Organomet. Chem. 2011, 38, 235. (g) Pineschi, M.; Bussolo,
tiospecific and Regioselective Rhodium-Catalyzed Allylic Alkylation:
Diastereoselective Approach to Quaternary Carbon Stereogenic
Centers. Org. Lett. 2000, 2, 2213. (c) Evans, P. A.; Robinson, J. E. Re-
gio-and Diastereoselective Tandem Rhodium-Catalyzed Allylic Al-
kylation/Pauson-Khand Annulation Reactions. J. Am. Chem. Soc.
2001, 123, 4609. (d) Evans, P. A.; Uraguchi, D. Regio- and Enanti-
ospecific Rhodium-catalyzed Arylation of Unsymmetrical Fluorinat-
ed Acyclic Allylic Carbonates: Inversion of Absolute Configuration. J.
Am. Chem. Soc. 2003, 125, 7158. (e) Evans, P. A.; Leahy, D. K. Regiose-
lective and Enantiospecific Rhodium-Catalyzed Allylic Alkylation
Reactions Using Copper (I) Enolates: Synthesis of (-)-Sugiresinol
Dimethyl Ether. J. Am. Chem. Soc. 2003, 125, 8974. (f) Evans, P. A.;
Lawler, M. J. Regio- and Diastereoselective Rhodium-Catalyzed
llylic ubstitution with cyclic α-Alkoxy-Substituted Copper(I)
Enolates:ꢀ Stereodivergent Approach to 2,3,6-Trisubstituted Dihy-
dropyrans. J. Am. Chem. Soc. 2004, 126, 8642. (g) Evans, P. A.; Clizbe,
E. A.; Lawler, M. J.; Oliver, S. Enantioselective Rhodium-Catalyzed
Allylic Alkylation of Acyclic α-Alkoxy Aubstituted Ketones Using a
Chiral Monodentate Phosphite Ligand. Chem. Sci. 2012, 3, 1835. (h)
Evans, P. A.; Oliver, S.; Chae, J. Rhodium-Catalyzed Allylic Substitu-
tion with an Acyl Anion Equivalent: Stereospecific Construction of
Acyclic Quaternary Carbon Stereogenic Centers. J. Am. Chem. Soc.
2012, 134, 19314. (i) Evans, P. A.; Oliver, S. Regio- and Enantiospecific
Rhodium-Catalyzed Allylic Substitution with an Acyl Anion Equiva-
lent. Org. Lett. 2013, 15, 5626. (j) Turnbull, B. W. H.; Oliver, S.; Evans,
P. A. Stereospecific Rhodium-Catalyzed Allylic Substitution with
Alkenyl Cyanohydrin Pronucleophiles: Construction of Acyclic Qua-
ternary ubstituted α,β-Unsaturated Ketones. J. Am. Chem. Soc. 2015,
137, 15374. (k) Turnbull, B. W. H.; Chae, J.; Oliver, S.; Evans, P. A.
Regio- and Stereospecific Rhodium-Catalyzed Allylic Alkylation with
an Acyl Anion Equivalent: an Approach to Acyclic α-ternary β, γ-
Unsaturated Aryl Ketones. Chem. Sci. 2017, 8, 4001.
V. D. I.; Crotti, P. Copper-Catalyzed Divergent Kinetic Resolution of
Racemic Allylic Substrates. Chirality 2011, 23, 703. (h) Hornillos, V.;
Gualtierotti, J.-B.; Feringa, B. L. Asymmetric Allylic Substitutions
Using Organometallic Reagents. Top. Organomet. Chem. 2016, 58, 1.
For a recent book, see: (i) Copper-Catalyzed Asymmetric Synthesis.
Alexakis A.; Krause N.; Woodward S. (eds), Wiley, Weinheim, 2014.
(5) For selected reviews, see: (a) Oliver, S.; Evans, P. A. Transition-
Metal-Catalyzed Allylic Substitution Reactions: Stereoselective Con-
struction of α- and β-Substituted Carbonyl Compounds. Synthesis
2013, 45, 3179. (b) Koschker, P.; Breit, B. Branching Out: Rhodium-
Catalyzed Allylation with Alkynes and Allenes. Acc. Chem. Res. 2016,
49, 1524. (c) Haydl, A. M.; Breit, B.; Liang, T.; Krische, M. J. Alkynes
as Electrophilic or Nucleophilic Allylmetal Precursors in Transition
Metal Catalysis. Angew. Chem. Int. Ed. 2017, 56, 11312.
(6) For selected reviews on Mo-catalyzed AAA reactions, see: (a)
Belda, O.; Moberg, C. Molybdenum-Catalyzed Asymmetric Allylic
Alkylations. Acc. Chem. Res. 2004, 37, 159. (b) Moberg, C. Molyb-
denum-Catalyzed and Tungsten-Catalyzed Enantioselective Allylic
Substitutions. Top. Organomet. Chem. 2011, 38, 209. For selected
examples, see: (c) Trost, B. M.; Hachiya, I. Asymmetric Molyb-
denum-Catalyzed Alkylations. J. Am. Chem. Soc. 1998, 120, 1104. (d)
Glorius, F.; Pfaltz, A. Enantioselective Molybdenum-Catalyzed Allylic
Alkylation Using Chiral Bisoxazoline Ligands. Org. Lett. 1999, 1, 141.
(e) Trost, B. M.; Hildbrand, S.; Dogra, K. Regio- and Enantioselective
Molybdenum-Catalyzed Alkylations of Polyenyl Esters. J. Am. Chem.
Soc. 1999, 121, 10416. (f) Belda, O.; Kaiser, N.-F.; Bremberg, U.; Larhed,
M.; Hallberg, A.; Moberg, C. Highly Stereo- and Regioselective Al-
lylations Catalyzed by o− yridylamide Complexes: Electronic and
Steric Effects of the Ligand. J. Org. Chem. 2000, 65, 5868. (g) Trost, B.
M.; Zhang, Y. Mo-Catalyzed Regio-, Diastereo-, and Enantioselective
Allylic Alkylation of 3-Aryloxindoles. J. Am. Chem. Soc. 2007, 129,
14548. (h) Trost, B. M.; Miller, J. R.; Hoffman, C. M. A Highly Enan-
tio- and Diastereoselective Molybdenum-Catalyzed Asymmetric
Allylic Alkylation of Cyanoesters. J. Am. Chem. Soc. 2011, 133, 8165.
(7) For an early example on Tungsten-catalyzed AAA reactions,
see: Lloyd-Jones, G. C.; Pfaltz, A. Chiral Phosphanodihydrooxazoles
in Asymmetric Catalysis: Tungsten-Catalyzed Allylic Substitution.
Angew. Chem. Int. Ed. 1995, 34, 462.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(11) (a) Turnbull, B. W. H.; Evans, P. A. Enantioselective Rhodium-
Catalyzed Allylic Substitution with a Nitrile Anion: Construction of
Acyclic Quaternary Carbon Stereogenic Centers. J. Am. Chem. Soc.
2015, 137, 6156. (b) Wright, T. B.; Evans, P. A. Enantioselective Rho-
dium-Catalyzed llylic lkylation of rochiral α,α-Disubstituted
Aldehyde Enolates for the Construction of Acyclic Quaternary Stere-
ogenic Centers. J. Am. Chem. Soc. 2016, 138, 15303.
(8) For selected reviews on Ru-catalyzed AAA reactions, see: (a)
Bruneau, C.; Renaud, J.; Demerseman, B. Pentamethylcyclopentadi-
enyl-Ruthenium Catalysts for Regio- and Enantioselective Allylation
of Nucleophiles. Chem. Eur. J. 2006, 12, 5178. (b) Bruneau, C.; Renaud,
J.; Demerseman, B. Ruthenium Catalysts for Selective Nucleophilic
Allylic Substitution. Pure Appl. Chem. 2008, 80, 861. (c) Begouin, J.-
M.; Klein, J.; Weickmann, D.; Plietker, B. Allylic Substitutions Cata-
lyzed by Miscellaneous Metals. Top. Organomet. Chem. 2011, 38, 269.
For selected examples, see: (d) Matsushima, Y.; Onitsuka, K.; Kondo,
T.; Mitsudo, T. A.; Takahashi, S. Asymmetric Catalysis of Planar-
Chiral Cyclopentadienylruthenium Complexes in Allylic Amination
and Alkylation. J. Am. Chem. Soc. 2001, 123, 10405. (e) Onitsuka, K.;
Matsushima, Y.; Takahashi, S. Kinetic Resolution of Allyl Carbonates
in Asymmetric Allylic Alkylation Catalyzed by Planar-Chiral Cyclo-
pentadienyl-Ruthenium Complexes. Organometallics 2005, 24, 6472.
(f) Bayer, A.; Kazmaier, U. Highly Regioselective Ruthenium-
Catalyzed Allylic Alkylations of Chelated Enolates. Org. Lett. 2010, 12,
4960. (g) Kanbayashi, N.; Hosoda, K.; Kato, M.; Takii, K.; Okamura,
T. A.; Onitsuka, K. Enantio- and Diastereoselective Asymmetric
Allylic Alkylation Catalyzed by a Planar-chiral Cyclopentadienyl
Ruthenium Complex. Chem. Comm. 2015, 51, 10895.
(9) For selected examples on Platinum-catalyzed AAA reactions,
see: (a) Blacker, A. J.; Clark, M. L.; Williams, M. J.; Loft, M. S. First
Highly Enantioselective Allylic Alkylations Catalysed by Platinum
Complexes. Chem. Comm. 1999, 913. (b) Blacker, A. J.; Clarke, M. L.;
Loft, M. S.; Mahon, M. F.; Humphries, M. E.; Williams, J. M. Plati-
num-Catalysed Allylic Alkylation: Reactivity, Enantioselectivity, and
Regioselectivity. Chem. Eur. J. 2000, 6, 353.
(10) (a) Evans, P. A.; Nelson, J. D. Conservation of Absolute Con-
figuration in the Acyclic Rhodium-Catalyzed Allylic Alkylation Reac-
tion:ꢀ Evidence for an Enyl (σ + π Organorhodium Intermediate. J.
Am. Chem. Soc. 1998, 120, 5581. (b) Evans, P. A.; Kennedy, L. J. Enan-
(12) Hayashi, T.; Okada, A.; Suzuka, T.; Kawatsura, M. High Enan-
tioselectivity in Rhodium-Catalyzed Allylic Alkylation of 1-
Substituted 2-Propenyl Acetates. Org. Lett. 2003, 5, 1713.
(13) Kazmaier, U.; Stolz, D. Regio- and Stereoselective Rhodium-
Catalyzed Allylic Alkylations of Chelated Enolates. Angew. Chem. Int.
Ed. 2006, 45, 3072.
(14) For selected examples, see: (a) Arnold, J. S.; Nguyen, H. M.
Rhodium-Catalyzed Dynamic Kinetic Asymmetric Transformations
of Racemic Tertiary Allylic Trichloroacetimidates with Anilines. J.
Am. Chem. Soc. 2012, 134, 8380. (b) Arnold, J. S.; Cizio, G. T.; Heitz, D.
R.; Nguyen, H. M. Rhodium-Catalyzed Regio- and Enantioselective
Amination of Racemic Secondary Allylic Trichloroacetimidates with
N-methyl Anilines. Chem. Comm. 2012, 48, 11531. (c) Arnold, J. S.;
Nguyen, H. M. Rhodium-Catalyzed Asymmetric Amination of Allylic
Trichloroacetimidates. Synthesis 2013, 45, 2101. (d) Arnold, J. S.;
Mwenda, E. T.; Nguyen, H. M. Rhodium-Catalyzed Sequential Allylic
Amination and Olefin Hydroacylation Reactions: Enantioselective
Synthesis of Seven-Membered Nitrogen Heterocycles. Angew. Chem.
Int. Ed. 2014, 53, 3688. (e) Mwenda, E. T.; Nguyen, H. M. Enantiose-
lective Synthesis of 1, 2-Diamines Containing Tertiary and Quater-
nary Centers through Rhodium-Catalyzed DYKAT of Racemic Allylic
Trichloroacetimidates. Org. Lett. 2017, 19, 4814.
(15) Li, C.; Breit, B. Rhodium-Catalyzed Dynamic Kinetic Asymmet-
ric Allylation of Phenols and 2-Hydroxypyridines. Chem. Eur. J. 2016,
22, 14655. (b) Zhou, Y.; Breit, B. Rhodium-Catalyzed Asymmetric N-
H Functionalization of Quinazolinones with Allenes and Allylic Car-
bonates: The First Enantioselective Formal Total Synthesis of (-)-
Chaetominine. Chem. Eur. J. 2017, 23, 18156.
(16) Vrieze, D. C.; Hoge, G. S.; Hoerter, P. Z.; Van Haitsma, J. T.;
Samas, B. M. A Highly Enantioselective Allylic Amination Reaction
Using a Commercially Available Chiral Rhodium Catalyst: Resolution
of Racemic Allylic Carbonates. Org. Lett. 2009, 11, 3140.
ACS Paragon Plus Environment

Page 7 of 8
Journal of the American Chemical Society
(17) Liang, L.; Xie, M.-S.; Qin, T.; Zhu, M.; Qu, G.-R.; Guo, H.-M.
Regio- and Enantioselective Synthesis of Chiral Pyrimidine Acyclic
Nucleosides via Rhodium-Catalyzed Asymmetric Allylation of Pyrim-
idines. Org. Lett. 2017, 19, 5212.
1
2
3
4
5
6
7
8
(18) For selected examples, see: (a) Li, C.; Breit, B. Rhodium-
Catalyzed Chemo- and egioselective ecarboxylative ddition of β-
Ketoacids to Allenes: Efficient Construction of Tertiary and Quater-
nary Carbon Centers. J. Am. Chem. Soc. 2014, 136, 862. (b) Beck, T. M.;
Breit, B. Regioselective Rhodium-Catalyzed Addition of 1, 3-
Dicarbonyl Compounds to Terminal Alkynes. Org. Lett. 2016, 18, 124.
(c) Li, C.; Grugel, C. P.; Breit, B. Rhodium-Catalyzed Chemo- and
Regioselective Decarboxylative Addition of β-Ketoacids to Alkynes.
Chem. Comm. 2016, 52, 5840. (d) Beck, T. M.; Breit, B. Regioselective
Rhodium-Catalyzed Addition of β-Keto Esters, β-Keto Amides, and 1,
3-Diketones to Internal Alkynes. Eur. J. Org. Chem. 2016, 2016, 5839.
(e) Beck, T. M.; Breit, B. Regio- and Enantioselective Rhodium-
Catalyzed Addition of 1, 3-Diketones to Allenes: Construction of
Asymmetric Tertiary and Quaternary All Carbon Centers. Angew.
Chem. Int. Ed. 2017, 56, 1903.
(19) For selected examples, see: (a) Chen, Q.-A.; Chen, Z.; Dong, V.
M. Rhodium-Catalyzed Enantioselective Hydroamination of Alkynes
with Indolines. J. Am. Chem. Soc. 2015, 137, 8392. (b) Cruz, F. A.;
Chen, Z.; Kurtoic, S. I.; Dong, V. M. Tandem Rh-Catalysis: Decarbox-
ylative β-Keto acid and Alkyne Cross-Coupling. Chem. Commun.
2016, 5836. (c) Cruz, F. A.; Zhu, Y.; Tercenio, Q. D.; Shen, Z.; Dong, V.
M. Alkyne Hydroheteroarylation: Enantioselective Coupling of In-
doles and Alkynes via Rh-Hydride Catalysis. J. Am. Chem. Soc. 2017,
139, 10641. (d) Chen, Z.; Dong, V. M. Enantioselective Semireduction
of Allenes. Nat. Comm. 2017, 8, 784.
(20) (a) Zheng, W.-F.; Xu, Q.-J.; Kang, Q. Rhodium/Lewis Acid
Catalyzed Regioselective Addition of 1,3-Dicarbonyl Compounds to
Internal Alkynes. Organometallics 2017, 36, 2323. (b) Bora, P. P.; Sun,
G.-J.; Zheng, W.-F.; Kang, Q. Rh/Lewis Acid Catalyzed Regio-, Dia-
stereo- and Enantioselective Addition of 2-Acyl Imidazoles with
Allenes. Chin. J. Chem. 2018, 36, 20.
(21) For selected reviews, see: (a) Bandini, M. Allylic Alcohols: Sus-
tainable Sources for Catalytic Enantioselective Alkylation Reactions.
Angew. Chem. Int. Ed. 2011, 50, 994. (b) Bandini, M.; Cera, G.; Chi-
arucci, M. Catalytic Enantioselective Alkylations with Allylic Alco-
hols. Synthesis 2012, 44, 504. (c) Sundararaju, B.; Achard, M.; Bru-
neau, C. Transition Metal Catalyzed Nucleophilic Allylic Substitution:
Activation of Allylic Alcohols via π-Allylic Species. Chem. Soc. Rev.
2012, 41, 4467.
(22) Defieber, C.; Ariger, M. A.; Moriel, P.; Carreira, E. M. Iridium-
Catalyzed Synthesis of Primary Allylic Amines from Allylic Alcohols:
Sulfamic Acid as Ammonia Equivalent. Angew. Chem. Int. Ed. 2007,
46, 3139.
(23) (a) Roggen, M.; Carreira, E. M. Enantioselective Allylic Etheri-
fication: Selective Coupling of Two Unactivated Alcohols. Angew.
Chem. Int. Ed. 2011, 50, 5568. (b) Lafrance, M.; Roggen, M.; Carreira,
E. M. Direct, Enantioselective Iridium-Catalyzed Allylic Amination of
Racemic Allylic Alcohols. Angew. Chem. Int. Ed. 2012, 51, 3470. (c) Liu,
W.-B.; Reeves, C. M.; Stoltz, B. M. Enantio-, Diastereo-, and Regiose-
lective Iridium-Catalyzed Asymmetric Allylic Alkylation of Acyclic β-
Ketoesters. J. Am. Chem. Soc. 2013, 135, 17298.
(24) (a) Fujimoto, K.; Maekawa, H.; Matsubara, Y.; Nishiguchi, I.
Electrochemical Deacetylation of 1,3-Dicarbonyl Compounds. Chem.
Lett. 1996, 25, 143. (b) Kanojia, S. V.; Chatterjee, S.; Gamre, S.; Chat-
topadhyay, S.; Sharma, A. Asymmetric Synthesis of the Constitutive
C22-carboxylic Acid of Macroviracin A. Tetrahedron 2015, 71, 1732.
(25) Hamilton, J. Y.; Sarlah, D.; Carreira, E. M. Iridium-Catalyzed
Enantioselective Allyl-alkene Coupling. J. Am. Chem. Soc. 2014, 136,
3006.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 8
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8
ACS Paragon Plus Environment