Rh/Lewis Acid Catalyzed Regio-, Diastereo- and Enantioselective Addition of 2-Acyl Imidazoles with Allenes

Article abstract of DOI:10.1002/cjoc.201700596

A highly regio-, diastereo- and enantioselective addition of 2-acyl imidazoles or 2-acyl pyridines with allenes promoted by Rh/Lewis acid synergistically catalytic system is described. This atom economic approach leads to the formation of the branched allylic alkylated products including acyclic quaternary all-carbon stereogenic centres in good yields with good to excellent diastereo- and enantioselectivities. Kinetic studies reveal that the rate-determining step in this process is the oxidative addition of Rh(I) with C—H bond.

Full text of DOI:10.1002/cjoc.201700596

Rh/Lewis Acid Catalyzed Regio-, Diastereo- and Enantioselective
Addition of 2-Acyl Imidazoles with Allenes
Pranjal P. Bora,‡ Gui-Jun Sun,‡ Wei-Feng Zheng, and Qiang Kang*
Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, Fujian Institute of Research on the Struc-
ture of Matter, Chinese Academy of Sciences, 155 Yangqiao Road West, Fuzhou, 350002, P. R. China
A highly regio-, diastereo- and enantioselective addition of 2-acyl imidazoles or 2-acyl pyridines with allenes
promoted by Rh/Lewis acid synergistically catalytic system is described. This atom economic approach leads to the
formation of the branched allylic alkylated products including acyclic quaternary all-carbon stereogenic centres in
good yields with good to excellent diastereo- and enantioselectivities. Kinetic studies reveal that the
rate-determining step in this process is the oxidative addition of Rh(I) with C-H bond.
Keywords rhodium, allene, enantioselective, Lewis acid, allylation
Introduction
stable rhodacycle with rigid framework could facilitate
the enantio-induction of this transformation. To examine
our hypothesis, 2-acyl imidazole[16] 2a was selected as
model substrate for the asymmetric coupling with al-
lene.[17]
Transition metal catalyzed allylic alkylation is con-
sidered as one of the most standout success of transition
metal catalysis, enjoys tremendous popularity for the
construction of carbon-carbon bonds along with wide
applications in the synthesis of numerous pharmaceuti-
cal and natural products.[1] Although a myriad of pow-
erful methods including the asymmetric versions have
been developed by varying the substrates, nucleophiles
and metal complexes over the years,[2-5] these methods
are less attractive in terms of atom economy, requires
specially designed substrates and generates waste.
Scheme 1 Rh-catalyzed approaches towards asymmetric allyla-
tion with allenes
Following on the pioneering work by the Trost[6] and
Yamamoto[7] with palladium catalysts, Breit and
co-workers[8-10] developed a series of rhodium-catalyzed
pro-nucleophile addition reactions to allenes and termi-
nal alkynes towards enantio-enriched branched allylic
products, which can be regarded as atom-economic al-
ternatives to traditional allylic substitution.[11] This
strategy was successfully explored towards a number of
asymmetric C-X (O, N, S) bonds formation to achieve
enantio-enriched branched allylic products (Scheme 1).
However, rhodium catalyzed asymmetric addition of
carbon pronucleophiles to allenes remains a formidable
challenge,[12] which might be due to the relatively weak
acidity of C-H bond, hindering the oxidative addition
with rhodium complexes.[13]
To address the above challenge, we envisioned to ac-
tivate the carbon pronucleophile by: (a) employing
compatible Lewis acid[14] to improve the acidity of C-H
bond; (b) installing an appropriate chelating group[15] to
form relative stable rhodacycle to facilitate the oxidative
addition of C-H with the Rh(I) complex. Further, we
have also anticipated that the formation of relatively
Experimental
In a 10 mL flame dried schlenk tube fitted with a
rubber septum and magnetic bar, 2-acyl imidazole (0.15
mmol, 1 equiv) was added and put on vacuum and
backfilled with argon for three times. Then, the schlenk
tube was transferred to glove box and [Rh(COD)Cl]2 (3
mg, 0.006 mmol, 4 mol%), (S)-SEGPHOS (11 mg,
0.018 mmol, 12 mol%) and Yb(OTf)3·H2O (9 mg, 0.015
mmol, 10 mol%) were added. The tube was then re-
moved from the glove box and 0.75 mL of anhydrous
dichloroethane (DCE) and allene (0.3 mmol, 2.0 equiv)
were added by syringe under a flow of argon and stirred
o
at 40 C for 48-72 hours. After completion of the reac-
tion (as monitored by TLC analysis), the reaction mix-
ture was directly purified with column chromatography
*
E-mail: kangq@fjirsm.ac.cn.
Received ((will be filled in by the editorial staff)); accepted ((will be filled in by the editorial staff)); published online XXXX, 2017.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.2017xxxxx or from the author. ((Please delete
if not appropriate.)).
‡ These authors contributed equally to this work.
This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which
may lead to differences between this version and the Version of Record. Please cite this
article as doi: 10.1002/cjoc.201700596
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on silica gel, eluting with 0-7% EtOAc in PE (elution
gradient).
idazoles with different N-substitution afforded the de-
sired branched allylic products (3a-3c, Scheme 2) in
good yields with excellent enantioselectivities
(93:7-96:4 er). Similarly, 2-acyl imidazoles with either
electron-rich or electron-poor aryl groups also furnished
the corresponding products (3d-3g, 3h) in good yields
with consistently high enantioselectivities. In addition,
2-acyl imidazoles incorporating 2-naphthyl or thienyl
group were similarly good coupling partners to afford 3i
(77% yield, 86:14 dr, 98:2 er) and 3j (96% yield, 88:12
dr, 95:5 er), respectively. Notably, ether and alkyl sub-
stituted 2-acyl imidazoles were also tolerated in our op-
timal reaction conditions to give the corresponding ad-
duct with slightly decreased enantioselectivities (3k and
3l). In addition to cyclohexylallene, other α-alicyclic
allenes were also proved to be excellent coupling part-
ners to afford the desired allylic products in high yields
with excellent enantioselectivities (3m and 3n, Scheme
2). Linear-alkyl-substituted allenes and allenes with
different functional group such as free alcohol, cyano,
ester, pththalimino also performed well under the opti-
mal reaction conditions in terms of yields and enanti-
oselectivities (3o-3t), however relatively lower dia-
stereoselectivities were observed.
Results and Discussion
We emanated our study by exploring effective com-
bination of chiral ligand, Lewis acid and reaction condi-
tions for the regio-, diastereo- and enantioselective cou-
pling of cyclohexylallene 1a and 2-acyl imidazole 2a
(Table 1). In the presence of 4 mol% of [Rh(COD)Cl]2,
12 mol% of (R)-BINAP and 10 mol% of Yb(OTf)3·H2O,
the reaction of 1a and 2a in DCE at 70 oC took place to
furnish the branched allylic product 3a in 84% yield
with 78:22 dr and 82:18 er (entry 1, Table 1). Encour-
aged by this promising result, we screened various
phosphine ligands (entries 2-4). Among the ligands
tested, (S)-SEGPHOS was found to be most competent,
affording 3a in 89% yield with 80:20 dr and 93:7 er
(entry 3). Pleasingly, lowering the reaction temperature
to 40 oC led to improved diastereo- and enantioselectiv-
ity (85:15 dr, 93:7 er, entry 5). Following further
screening of chiral ligands, Lewis acids, solvents and
metal catalysts (see Supporting Information for more
details, Table S1-S4). Lewis acids such as Sc(OTf)3,
In(OTf)3, Mg(OTf)2 and Cu(OTf)2 have no significant
impact on the outcome of the title reaction. The optimal
reaction conditions were identified as following: 4
mol% of [Rh(COD)Cl]2, 12 mol% of (S)-SEGPHOS
and 10 mol% of Yb(OTf)3·H2O in DCE (0.2 M) at 40
oC.
Scheme 2 Rh-catalyzed approaches towards asymmetric allyla-
tion with allenesa
Table 1 Optimization of reaction conditionsa
O
Cy
R3 = Ph, 3a, 86% yield, 85:15 dr, 93:7 er
Me, 3b, 72% yield, 84:16 dr, 95:5 er
iPr, 3c, 91% yield, 85:15 dr, 96:4 er
N
N
N
N
Ph
R3
3a-3c
MeO
R2
=
O
Cy
Me
OMe
R2
3d, 84% yield,
3e, 88% yield,
3f, 78% yield,
88:12 dr, 96:4 er
iPr
90:10 dr, 96:4 er
94:6 dr, 97:3 er
F3C
MeO
3g, 82% yield,
3h, 67% yield,
3i, 77% yield,
80:20 dr, 96:4 er
72:28 dr, 95:5 er
86:14 dr, 98:2 er
O
Me
S
MeO
Entry
Ligand
Yield (%)b
dr c
erd
3k, 68% yield,
86:14 dr, 90:10 er
3l, 44% yield,
72:28 dr, 91:9 er
3j, 96% yield,
75:25 dr, 95:5 er
84
76
89
78:22
77:23
80:20
79:21
18:82
19:81
93:7
1
2
3
4
5
(R)-BINAP
O
R1
R1
=
Cy
(R)-TolBINAP
(S)-SEGPHOS
(S)-DM-SEGPHOS
N
N
Ph
3m, 79% yield,
83:17 dr, 94:6 er
3n, 80% yield,
90:10 dr, 97:3 er
3o, 87% yield, 60:40 dr
94:6 & 90:10 er
iPr
O
90
86
83:17
93:7
N
O
HO
MeO2C
N
(S)-SEGPHOS
85:15
3q, 75% yield, 60:40 dr
90:10 & 88:12 er
3r
3p, 76% yield, 55:45 dr
, 40% yield, 58:42 dr
93:7 & 89:11 er
3s, 91% yield, 62:38 dr
91:9 & 88:12 er
aReaction conditions: 1a (0.2 mmol), 2a (0.1 mmol),
[Rh(COD)Cl]2 (4 mol%), ligand (12 mol%) and Yb(OTf)3·H2O
(10 mol%) in DCE (1 mL) at 70 C for 48 h under argon, unless
otherwise noted. b Isolated yield. c Diastereoselectivity (dr) was
determined by H NMR analysis of the crude reaction mixture.
Enantioselectivity (er) of the major diastereomers were deter-
mined by HPLC analysis. e Carried out at 40 C. 0.5 mL DCE
92:8 & 88:12 er
R1
R1
=
O
N
o
N
R2
3t, 94% yield, 60:40 dr
92:8 & 90:10 er
iPr
R2 = 4-CH3C6H4
1
d
aReaction conditions:
1
(0.3 mmol),
2
(0.15 mmol),
o
f
[Rh(COD)Cl]2 (4 mol%), (S)-SEGPHOS (12 mol%) and
Yb(OTf)3·H2O (10 mol%) in DCE (0.75 mL) at 40 oC for 48-72 h
under argon. Yield of isolated products were reported. Diastere-
oselectivity (dr) was determined by 1H NMR analysis of the
crude reaction mixture. Enantioselectivity (er) of the major dia-
stereomers were determined by HPLC analysis.
was used.
With the optimized conditions in hand, the scope of
the reaction with regard to both the 2-acyl imidazoles
and allenes were examined (Scheme 2). The 2-acyl im-
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Then, we sought to examine different chelating
groups for this transformation (Scheme 3). Pleasingly,
the reaction of 2-acyl pyridine 4a with cyclohexylallene
1a proceeded smoothly to afford the desired branched
allylic product 5a in 77% yield, 94:6 dr and 99:1 er. The
2-acyl pyridines with methyl in the pyridine moiety also
delivered the corresponding product 5b in 68% yield
with 99:1 er. Moreover, benzimidazole and 2-thiazole
were found to be good chelating group for the title reac-
tion, affording the corresponding products with excel-
lent diastereo- and enantioselectivities (5c and 5d).
However, 1-acyl pyrazole could not be tolerated under
the optimized conditions, the reaction with cyclohexyl-
allene led to the formation of a complex mixture with-
out detecting the formation of 5e. The absolute configu-
ration of major diastereomer of product 5b was con-
firmed by a single-crystal X-ray analysis (for details,
see the Supporting Information).[18]
Scheme 4 Synthesis of acyclic all-carbon quaternary centresa
aReaction conditions:
6
(0.3 mmol),
2
(0.15 mmol),
[Rh(COD)Cl]2 (4 mol%), (S)-SEGPHOS (12 mol%) and
Yb(OTf)3·H2O (10 mol%) in DCE (0.75 mL) at 40 oC for 48-72 h
under argon. Yield of isolated products were reported. Diastere-
oselectivity (dr) was determined by 1H NMR analysis of the
crude reaction mixture. Enantioselectivity (er) were determined
by HPLC analysis.
To illustrate the potential synthetic application of
this protocol, further transformation of the product was
carried out. The imidazole moiety could be easily trans-
ferred to other functional groups. For example, the re-
moval of the imidazole moiety of 3i worked smoothly,
resulting in ketone 8 (major diastereomer) in 50% yield
without loss in enantiomeric excess (Scheme 5).
Scheme 3 Investigation of effect of chelating groupsa
[Rh(COD)Cl]2 (4 mol %)
O
Cy
O
(S)-SEGPHOS (12 mol %)
R1
+
Cy
X
X
Yb(OTf)3•H2O (10 mol %)
DCE, 40 oC, 48-72 h
R1
1a
4
5
O
Cy
O
Cy
O
Cy
N
N
N
N
Me
Ph
Ph
Ph
Me
5b, 68% yield,
92:8 dr, 99:1 er
5c, 53% yield,
96:4 dr, 99:1 er
Scheme 5 Synthetic transformation of product 3i
5a, 51% yield,
94:6 dr, 99:1 er
O
Cy
O
Cy
N
N
N
S
Ph
Ph
5e, n.d.b
5d, 75% yield,
94:6 dr, 96:4 er
aReaction conditions: 1a (0.3 mmol),
4
(0.15 mmol),
A plausible mechanism is shown in Scheme 6. Lewis
acid and chelation assisted oxidative C-H addition of
2-acyl imidazole to Rh(I) via a transient species A, gen-
erates a Rh(III)-H intermediate B. Then, hydromet-
alation of the allene with intermediate B leads to the
formation of intermediate C,[21] which might be attacked
by another molecule of 2-acyl imidazole or perform
reductive elimination to furnish the branched product 3.
[Rh(COD)Cl]2 (4 mol%), (S)-SEGPHOS (12 mol%) and
Yb(OTf)3·H2O (10 mol%) in DCE (0.75 mL) at 40 oC for 48-72 h
under argon. Yield of isolated products were reported. Diastere-
oselectivity (dr) was determined by 1H NMR analysis of the
crude reaction mixture. Enantioselectivity (er) were determined
by HPLC analysis. bFormation of unidentified complex mixture.
Next, we wished to explore our approach for the
asymmetric synthesis of synthetically challenging acy-
clic quaternary all-carbon stereogenic centres (Scheme
4). In order to achieve enantioselective formation of
acyclic quaternary all-carbon stereogenic centres, the
catalytic systems need to overcome the high degree of
steric repulsion between the carbon substituents along
with the conformational control.[19,20] Gratifyingly, the
coupling reactions of 1-methyl-1-cyclohexyl allene 6
with various of 2-acyl imidazoles 2 furnished 7a-7d in
55-71% yield with 94:6-97:3 er.
Scheme 6 Proposed mechanism
Control Experiments. To gain a better understand-
ing of the mechanistic details of this reaction, several
control experiments (Scheme 7) and initial rate kinetics
experiments were performed. The coupling reaction of
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1
cyclohexylallene and 2-acyl imidazole 2a did not pro-
ceed in the absence of Lewis acid (eqn 1, Scheme 7),
suggesting that the Lewis acid is an indispensable com-
ponent of the catalytic system. Similarly, the reaction of
cyclohexylallene and substrate 4f without chelating
group also failed to proceed, which affirmed the requi-
site of chelating group for the title reaction (eqn 2,
Scheme 7). From these two experiments it appears that
both the Lewis acid and chelating group in pronucleo-
phile synergistically assist the reaction to proceed. An
isotope-labeling experiment was performed with
[D2]2-acylimidazole and cyclohexylallene under the
optimal reaction conditions (eqn 3, Scheme 7). The
deuterium incorporation was observed only at the inter-
nal position of the alkene (see Supporting Information
for more details).
was conducted. The H NMR spectrum (263K) of the
o
reaction after 10 minutes reaction at 30 C showed a
major Rh-H species at δ = -16.3 ppm, which indicates
the oxidative addition of the C-H bond to the rhodium.
-4
y = 1.64x + 1.58326,
-5
2
R
= 0.99156
-6
-7
-8
-5.5
-5.0
-4.5
-4.0
ln[Rh]
Scheme 7 Control experiments
Figure 1 Plot of initial rate versus [Rh] (M).
-5.0
y = 1.0338x - 4.73888,
2
R
= 0.92162
-5.5
-6.0
-6.5
-7.0
-7.5
-2.5
-2.0
-1.5
ln[2c]
-1.0
-0.5
Figure 2 Plot of initial rate versus [2-acyl imidazole 2c] (M).
Kinetic experiments and NMR Monitoring Ex-
periment. Moreover, initial rate kinetic experiments
were performed to elucidate the reaction order for the
Rh catalyst and for both the allene and 2-acyl imidazole
by in situ 1H NMR spectroscopy. The reaction appeared
to have a first-order dependence on the Rh precatalyst
and substrate 2c (Figure 1-2), and a nearly zero-order
dependence on substrate 1a (Figure 3, see Supporting
Information for more details). The first-order depend-
ence on the Rh catalyst and substrate 2c indicates that
Rh and 2c are involved in rate-limiting step. The ze-
ro-order dependence of the substrate 1a shows that sub-
strate incorporation into the catalytic cycle is not
rate-limiting. These experiments are consistent with a
pathway wherein the rate-determining step occurs prior
to intermediate B addition to the allene. Moreover, as
shown in Scheme 8, a primary KIE of 2.45 was found
for 2-acyl imidazole with proton vs deuterium labels at
the α-carbonyl position. To investigate if the oxidative
addition of Rh(I) with C-H bond is rate-limiting, we
performed a Hammett plot study of para-substituted
2-acyl imidazoles (Figure 4), in which electron-donating
substrate led to a higher initial rate. These investigations
provide insight that the oxidative addition of Rh(I) with
C-H bond might be rate-determining step under these
catalytic conditions. The NMR monitoring experiment
of stoichiometric amount of 2-acyl imidazole with
-7.0
-6.8
y = 0.00815x -6.20625,
2
-6.6
-6.4
-6.2
-6.0
-5.8
-5.6
R
= 0.98074
-2.5
-2.0
-1.5
-1.0
-0.5
ln[1a]
Figure 3 Plot of initial rate versus [allene 1a] (M).
0.30
OMe
X = OMe, Me, H;
0.25
y = -0.94235x - 0.00635
X= H, F, Cl, CF
3
2
0.20
0.15
0.10
0.05
0.00
-0.05
R
= 0.97316
Me
y = -0.07724x - 0.00422
H
F
2
R
= 0.95639
CF
3
Cl
-0.3 -0.2 -0.1 0.0 0.1 0.2 0.3 0.4 0.5 0.6
σ
[Rh(COD)Cl]2, Sc(OTf)3 and (S)-SEGPHOS in CDCl3
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X.–L.; Dai, L.-X. J. Am. Chem. Soc. 2001, 123, 7471-7472; (b)
Zhang, P.; Brozek, L. A.; Morken, J. P. J. Am. Chem. Soc. 2010, 132,
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Scheme 8 Control experiments
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Conclusions
In summary, we have successfully demonstrated an
atom economic approach for asymmetric allylic alkyla-
tion of 2-acyl imidazoles or 2-acyl pyridines with al-
lenes promoted by the combination of rhodium and
Lewis acid catalysis. The reaction produced the
branched allylic alkylated products in good yields with
good to excellent diastereo- and enantioselectivities.
This approach was also explored for the enantioselec-
tive construction of synthetically challenging acyclic
quaternary all-carbon stereogenic centres. The mecha-
nistic studies including of control experiments and ini-
tial rate kinetic experiments indicate that 1) both the
Lewis acid and chelating group assisted C-H oxidative
addition to Rh-complex is a key step to accomplish the
anticipated coupling; 2) the oxidative addition of Rh(I)
with C-H bond might be rate-determining step under the
optimal reaction conditions. Further extension of the
protocol with other coupling partners are currently un-
derway in our laboratory.
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Acknowledgement
We thank Prof. Daqiang Yuan (Fujian Institute of
Research on the Structure of Matter, Chinese Academy
of Sciences) for his kind help in an X-ray analysis. This
work was supported by the Strategic Priority Research
Program of the Chinese Academy of Sciences, Grant No.
XDB20000000 and 100 Talents Programme of the Chi-
nese Academy of Sciences.
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Entry for the Table of Contents
Page No.
Title Rh/Lewis Acid Catalyzed Regio-,
Diastereo- and Enantioselective Addi-
tion of 2-Acyl Imidazoles with Allenes
A highly regio-, diastereo- and enantioselective addition of 2-acyl imidazoles or 2-acyl
pyridines with allenes promoted by Rh/Lewis acid synergistically catalytic system is
described which leads to the formation of the branched allylic alkylated products in-
cluding acyclic quaternary all-carbon stereogenic centres in good yields with good to
excellent diastereo- and enantioselectivities.
Pranjal P. Bora,‡ Gui-Jun Sun,‡
Wei-Feng Zheng, and Qiang Kang*
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