Solvent-Controlled, Tunable β-OAc and β-H Elimination in Rh(III)-Catalyzed Allyl Acetate and Aryl Amide Coupling via C-H Activation

Article abstract of DOI:10.1021/acs.orglett.6b01566

The Heck reaction between arenes and allyl acetate has led to cinnamyl derivatives and allyl products depending on the regioselectivity of β-elimination. The regioselectivity can be controlled by the solvent in the Rh(III)-catalyzed arene-allyl acetate coupling via C-H activation: (1) in THF, cinnamyl derivatives via β-H elimination were generated; (2) in MeOH, allyl products via β-OAc elimination were produced. Both routes have advantages such as excellent γ-selectivity toward allyl acetate, good to excellent yields, and broad substrate scope.

Full text of DOI:10.1021/acs.orglett.6b01566

Letter
pubs.acs.org/OrgLett
Solvent-Controlled, Tunable β‑OAc and β‑H Elimination in Rh(III)-
Catalyzed Allyl Acetate and Aryl Amide Coupling via C−H Activation
Huimin Dai, Chao Yu, Zihao Wang, Hong Yan,* and Changsheng Lu*
State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing,
Jiangsu 210023, China
S
* Supporting Information
ABSTRACT: The Heck reaction between arenes and allyl acetate has led to
cinnamyl derivatives and allyl products depending on the regioselectivity of
β-elimination. The regioselectivity can be controlled by the solvent in the
Rh(III)-catalyzed arene−allyl acetate coupling via C−H activation: (1) in
THF, cinnamyl derivatives via β-H elimination were generated; (2) in
MeOH, allyl products via β-OAc elimination were produced. Both routes
have advantages such as excellent γ-selectivity toward allyl acetate, good to
excellent yields, and broad substrate scope.
rene−alkene coupling is one of the most commonly used
regioselectivity,13 stereoselectivity,14 structural control,15 phys-
ical properties,16 and so on. Herein we report solvent-tunable
β-elimination in Rh(III)-catalyzed coupling of arenes and allyl
esters, which is based on amide-directed C−H activation. By
solvent control, different selectivity in β-elimination has been
reached: (1) in THF, cinnamyl derivatives by β-H elimination
were isolated; (2) in MeOH, allylation products by β-OAc
elimination were obtained. Both pathways share the advantages
such as excellent γ-selectivity toward allyl acetate, good to
excellent yields, and broad substrate scope. Moreover, both
products are of high value in organic synthesis and biochemical
studies.17−19
A
and well-developed reactions in organic synthesis,1,2
among which dehydrogenative cross-coupling by C−H
activation of arenes is the most convenient and economical
strategy because it avoids prefunctionalization.3−5 The
coupling-partner alkenes have been expanded from electron-
deficient alkenes to aliphatic olefins and styrenes, whereas allyl
esters still remain challenging because of the lack of fine-
tunability of issues such as (i) metal-selective insertion (internal
vs terminal), (ii) divergence of β-elimination (β-OAc vs β-H),
and (iii) competitive regioselectivity in β-elimination (allylic vs
styrenyl) (Scheme 1).6−11 Gratefully, a breakthrough in
To optimize the reaction conditions, our study was initiated
by using amide 1a and allyl acetate as the model substrates
(Table 1). First, different catalysts were examined with MeOH
as the solvent and AgOAc as the additive. Both [Cp*RhCl2]2
and [(η6-cymene)RuCl2]2 led to 4a with excellent β-OAc
elimination, and the former could give rise to yields of up to
99% (entries 1 and 3). However, Cp*CoI2(CO) was inactive
(entry 2). Then the effect of different solvents was investigated
(entries 4−13). An additional product 3aa was generated by β-
H elimination in solvents other than MeOH or MeCN. The
newly formed alkenyl group adopts the E-type conformation, as
confirmed by 1H NMR spectroscopy. Furthermore, 1a
exhibited excellent selectivity toward the γ-site of allyl acetate.
The −N(H)OMe group behaves as an internal oxidant here.
THF was the best solvent for the formation of 3aa (entry 10),
but [(η6-cymene)RuCl2]2 was inactive in THF (entry 13).
Additives were also screened. Ag2CO3 was found to be slightly
better than AgOAc (entry 14 and Table S1). When the catalyst
loading was increased to 3 mol %, the yield of 3aa was
improved to 67% (entry 15). Notably, the addition of 4 Å
molecular sieves improved both the yield and selectivity, which
Scheme 1. Oxidative Heck Reaction between Arenes and
Allyl Acetate
selective β-H elimination has been achieved by the pioneering
work on Pd catalysis (Scheme 1a).7,8 However, high temper-
ature and excess arene are needed for all of the reactions
because of the absence of directing groups. Moreover, the
regioselectivity on the arenes is quite low except for special
arenes8 such as thiophene. In terms of selective β-OAc
elimination (Scheme 1c,d9), some effective reactions under
Rh,10 Ru,11 and other metal catalysis12 have been published.
Nonetheless, how to tune the regioselectivity of β-elimination
through simple manipulation of the reaction conditions has not
been reported yet.
Solvents are known to play very important roles in chemical
processes. Significant influences have been disclosed in
Received: May 31, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01566
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Letter
a
a
Table 1. Optimization of the Reaction Conditions
Table 3. Scope of Amides
b
yield (%)
entry
1
catalyst
solvent
MeOH
additive
3aa
4a
99
[Cp*RhCl2]2
Cp*CoI2(CO)
[(η6-cymene) RuCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[(η6-cymene) RuCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
0
0
c
2
MeOH
MeOH
MeCN
DCE
0
79
c
3
0
4
5
0
88
17
<10
28
23
<10
46
22
32
0
69
6
DCM
PhMe
DMF
27
7
62
8
66
9
DMSO
THF
43
10
11
12
19
1,4-dioxane
Et2O
<10
<10
12
c
13
THF
14
THF
49
67
74
0
15
c
15
d
THF
19
16
THF
18
17
MeOH
98
a
Unless otherwise noted, the reactions were carried out in refluxing
solvent (2 mL) containing 1a (33.0 mg, 0.2 mmol), 2a (45 μL, 2.5
equiv), catalyst (1.5 mol %), and additive (20 mol %) for 12 h.
b
c
d
Isolated yields. Using 3 mol % catalyst. Using 3 mol % catalyst and
60 mg of 4 Å molecular sieves.
might be attributed to the removal of generated MeOH (entry
16). In MeOH, Ag2CO3 performed as well as AgOAc (entry
17). Therefore, Ag2CO3 was finally chosen as the additive in
the solvent-controlled reaction. Of note, the reaction is water-
sensitive but not air-sensitive.
Different allyl electrophiles were screened as well (Tables 2
and S3). The activity of those allyl reagents varied with the
Table 2. Scope of Allyl Resources
a
b
The optimized standard conditions were used. Ratios were
c
determined by H NMR spectroscopy. 3fa6/3fa2 = 2/1; 4f6/4f2 =
4/5. 36 h. No reaction.
1
d
e
leaving group. In THF, 2a was the only suitable candidate,
affording a 74% yield. However, the reaction could not proceed
through β-H elimination with 2e−g (Table S3, entries 5−7). In
MeOH, all of the tested allyl reagents were active. 2e gave a
yield lower than 10%, but 2a and 2d were able to yield 4a
almost quantitatively. Therefore, 2a was chosen to explore the
reactivities of different amides.
With the optimized conditions in hand, amides bearing
varying functional groups were investigated (Table 3). To our
delight, the solvent-dependent reaction can tolerate not only
substituents such as halogens and PhO− but also those such as
cyano, nitro, oximido, and heterocycles. In THF, all of the
substrates preferred β-H rather than β-OAc elimination,
although the selectivity was not ideally perfect. Furthermore,
they all exhibited excellent selectivity toward the γ-site of allyl
acetate. The yields are moderate to good but comparatively
lower for the electron-deficient substrates (e.g., 1e and 1h) and
for the substrates containing a heterocycle (e.g., 1o and 1p).
Notably, the −N(H)OMe group serves as not only a directing
group but also an internal oxidant. Once reduced to a primary
amine, it loses the directing function, thereby avoiding the
follow-up alkenylation. Because of steric hindrance, 1f−h
preferred the alkenylation at the 6-position. Additionally, Z-
isomer products were observed in the cases of electron-
deficient substrates, especially those containing electron-
withdrawing groups at the meta position. The Z-isomer
products could be transformed to corresponding E isomers
by prolonging the reaction time.
In MeOH, all of the substrates exhibited an exclusive
preference for β-OAc elimination, and good to excellent yields
were obtained. However, 1p and 1q led to 4p and 4q,
respectively, in only moderate yields because of double-bond α-
B
DOI: 10.1021/acs.orglett.6b01566
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isomerization of the allylation products. Those terminal allyl
products can be further transformed to substituted alkenes
through olefin metathesis20 (Scheme 2).
Me-1i was not reactive in either MeOH or THF (Scheme S6),
the Rh(III) catalyst should be directed by the anionic nitrogen
to activate the ortho C−H bond to generate I, as shown in
Scheme 5. Furthermore, H/D scrambling was observed at the
Scheme 2. Substituted Alkenes Derived from Allylation
Products through Olefin Metathesis
Scheme 5. Proposed Mechanism
On the basis of this solvent-dependent approach, not only
the products of single β-OAc or β-H elimination but also those
products obtained by both types of eliminations can be
produced. For example, 6i could be prepared by cascade
alkenylation in a one-pot reaction (Scheme 3).
Scheme 3. One-Pot Preparation of 6i
ortho site next to the amide group of the products when 1h
reacted in MeOD or THF/D2O (Schemes S7 and S8), and
thus, the C−H bond activation is reversible. The kinetic isotope
effect was measured as 2.1 in MeOH and 1.8 in THF,
respectively (Scheme S9), so the C−H bond activation is the
rate-determining step in both solvents. The double bond of allyl
acetate inserts into the C−Rh bond in I to give II.10−12 Then
the reaction proceeds in different pathways depending on the
solvent: (1) in THF, the reaction prefers to produce 3ia
through β-H elimination; (2) in MeOH, the reaction entirely
goes through β-OAc elimination. The difference might be
caused by solvents that affect the coordination sphere of the Rh
center in II as well as the stability of the intermediates III and
IV after β-elimination.
We tested further transformations of the two types of
solvent-tunable reaction products. 3aa could lead to azide-
substituted olefin product 7a (Scheme 4a) and 3-methylenei-
Scheme 4. Transformations of 3aa
In conclusion, solvent-tunable β-elimination in Rh(III)-
catalyzed coupling of arenes and allyl acetate through C−H
activation has been realized: (1) in THF, cinnamyl derivatives
by β-H elimination were generated; (2) in MeOH, allyl
products by β-OAc elimination were obtained. Both routes lead
to good to excellent yields with broad substrate scope under
mild conditions.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01566.
soindolin-1-one derivative 8a (Scheme 4b) under the catalysis
of Pd(PPh3)4 based on the Tsuji−Trost reaction.19 4a could be
transformed to 3,4-dihydroisoquinolin-1(2H)-one derivatives
9aa−ac when halogenated reagents were used;21 products 9
also could be prepared in one pot using 1a as the starting
material (Table 4).
■
S
Experimental procedures and full characterization details,
To understand the mechanism behind this interesting
reaction, some control experiments were conducted. Since
1
including H and 13C NMR and HRMS spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Table 4. One-Pot Synthesis of Dihydroisoquinolinones
*E-mail: hyan1965@nju.edu.cn.
*E-mail: luchsh@nju.edu.cn.
Notes
The authors declare no competing financial interest.
X
halogenated reagents
9, yield (%)
Cl
Br
I
NCS
NBS
NIS
9aa, 45
9ab, 78
9ac, 86
ACKNOWLEDGMENTS
This work was supported by the National Natural Science
Foundation of China (21271102, 21472086, and 21531004)
■
C
DOI: 10.1021/acs.orglett.6b01566
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Letter
and the National Basic Research Program of China
(2013CB922101).
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