Revisiting Allylic Coupling of Grignard Reagents: Nano Copper Catalyzed One-Pot α-Selective Aryl-Allyl Coupling

Full text of DOI:10.1080/00304948.2017.1374104

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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Revisiting Allylic Coupling of Grignard Reagents:
Nano Copper Catalyzed One-Pot α-Selective Aryl-
Allyl Coupling
Melike Kalkan, Ender Erdik & Özgen Ömür Pekel
To cite this article: Melike Kalkan, Ender Erdik & Özgen Ömür Pekel (2017) Revisiting
Allylic Coupling of Grignard Reagents: Nano Copper Catalyzed One-Pot α-Selective Aryl-
Allyl Coupling, Organic Preparations and Procedures International, 49:5, 459-466, DOI:
10.1080/00304948.2017.1374104
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Date: 03 October 2017, At: 15:06

Organic Preparations and Procedures International, 49:459–466, 2017
Copyright Ó Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2017.1374104
Revisiting Allylic Coupling of Grignard Reagents:
Nano Copper Catalyzed One-Pot a-Selective
Aryl-Allyl Coupling
€
Melike Kalkan, Ender Erdik, and Ozgen Omur Pekel
€
€
Department of Chemistry, University of Ankara, 06100 Ankara, Turkey
Transition metal catalyzed allylation of organometallic compounds is one of the most
valuable methodologies for the formation of C-C bonds.1-9 Due to their easy preparation,
high reactivity and functional group tolerance, allylation reactions of Grignard
reagents10-14 and diorganozincs15-17 have been exploited for mediating regioselective and
enantioselective allylic coupling. Among various catalytic methods Cu-catalyzed non-
symmetric8,11,18-29 and asymmetric allylation8,11,18,24,30–39 of Grignard reagents have
attracted much attention. The regioselectivity of allylic coupling depends on the type of
Grignard reagent, the allylic partner, Cu(I) catalyst and organic catalyst, if necessary, as
well as on the reaction parameters.18-29 Various stereoselective procedures have also
been developed using chiral ligands on Cu(I) catalyst.8,18,24,30–39
Our group recently reported a series of Cu and Ni catalyzed synthetic40-43 and mech-
anistic experiments44,45 about the reactivity, chemoselectivity and regioselectivity of
alkylzinc halide40, dialkylzinc41-43 and diarylzinc41–43 reagents in their allylic coupling
reactions. We also explored allylation of mixed (alkyl)(aryl)zinc reagents with our
increasing interest in atom-economic reactions.41–43,45
In our program, we also investigated Cu(I) catalyzed magnesium-Barbier type
allylic coupling of alkyl Grignard reagents46 in order to develop an easier and less
time-consuming procedure compared with classical coupling. Classical reactions are
carried out in two steps, i. e., firstly, the Grignard reagent is prepared; and, secondly,
the necessary amount of Grignard reagent is used for the reaction with the electro-
phile. In the Barbier type reaction, magnesium is allowed to react with organyl
halide and electrophile in one pot, that is, the electrophile is reacted with in situ pre-
pared Grignard reagent. We demonstrated that CuCN catalyzed alkyl-allyl coupling
can be carried out under magnesium-Barbier conditions with comparable yields and
regioselectivities to classical CuCN catalyzed allylation of alkyl Grignard reagents
with g-selectivity.
This promising result on the Barbier type g-allylation of alkyl Grignard
reagents encouraged us to further investigate the synthetic potential of aryl
Grignard reagents in regioselective allylation under Barbier conditions. To the best
of our knowledge, there are no reports on allylic coupling of in situ prepared aryl
Received March 12, 2017; in final form April 17, 2017.
Address correspondence to Melike Kalkan, Department of Chemistry, University of Ankara,
06100 Ankara, Turkey. E-mail: melike.kalkan@ankara.edu.tr
459

460
Kalkan et al.
Grignard reagents, although a high number of papers have appeared on the regiose-
lective allylic coupling of classically prepared Grignard reagents.25–29 Herein, we
report details of our work on the succesful a-selective one-pot allylation of aryl
Grignard reagents.
As a model reaction, we chose allylation of in situ prepared phenylmagnesium bro-
mide with E-crotyl chloride. We carried out initial studies to optimize the reaction condi-
tions, finding the effects of reaction parameters (solvent, transition metal catalyst, organic
catalyst). Depending on our previous experience on Barbier type allylation of alkyl
Grignard reagents,46 solutions of bromobenzene 1a and E-crotyl chloride 2a in THF were
added to Mg separately, but at the same rate (Scheme 1). Unfortunately, one hour reaction
of 2 mmol PhBr in THF, 1 mmol E-crotyl chloride in THF and 1.2 mmol Mg at room
temperature resulted in a low yield (28%) although the a:g ratio (86 :14) was of potential
use.
Scheme 1 One pot allylation of phenylmagnesium bromide 1a with E-crotyl chloride 2a in THF.
However, using the same stoichiometry of coupling partners in classical type ally-
lation (i.e., 2 mmol PhMgBr and 1 mmol E-crotyl chloride) gave a high yield (98%)
with a-selectivity. Thus Barbier type aryl-allylation is not succesful compared with
classical allylation. However, with our interest in developing a new milder and easier
allylation procedure for aryl Grignard reagents, we persevered with Barbier type ally-
lation. We turned our attention to the in situ formation rate of Grignard reagent in the
presence of a coupling partner. In fact, in situ Grignard reagent is generally succes-
fully used in reactions with carbonyl compounds.10,47–50 However, in in situ coupling
reactions, a lower formation rate of Grignard reagent as electrophilic partner may lead
to a lower yield of cross coupled product. So we tried to control in situ formation of
phenyl Grignard reagent in the allylation. For this purpose, the aryl halide in THF
was added dropwise to Mg and the mixture was stirred for 7–10 minutes. During the
stirring, the heat evolving was controlled by cooling the flask. The slow consumption
of Mg in the flask indicated the formation of Grignard reagent. Following this the
allylic partner in THF was added dropwise to react with the in situ formed phenyl
Grignard reagent. Stirring the mixture at room temperature for 3 hours took place
with 60% yield and with good a-selectivity under the optimized 7.5 : 9 : 5 ratio of
PhBr: Mg: E-crotyl chloride (Table 1, entry 1).
With this good result in hand, we investigated the solvent and catalyst effect on the
yield and regioselectivity of the one-pot allylation of PhMgBr. A screen of HMPA as a
N-donor solvent and Lewis base reagent as additive showed that the yield did not increase
much in the presence of HMPA in 4 : 1 ratio of THF: HMPA, but a-selectivity decreased
(entry 2). Decreasing this ratio to 2 : 1 decreased the yield to 39% and the a:g ratio
changed to 44:56. However, in the presence of a 1:1 ratio of HMPA, the reaction did not
take place (entries 3 and 4). The use of urotropine and 2,2 0-bipyridyl were tested as Lewis
bases and their optimized (5% mol) addition led to lower yields and unchanged a-selec-
tivity (entries 5 and 6).
The effect of transition metal catalysis on the allylation of PhMgBr under classi-
cal conditions was also investigated; and for this purpose CuI, Cu(acac)2 and the

Revisiting Allylic Coupling of Grignard Reagents
461
Table 1
Regioselectivity in the One Pot Allylation of PhBr 1a with E-crotyl Chloride 2a in THF
in the Presence a N-donor Solvent and Lewis Bases and in the Presence of Cu and Ni
Catalystsa,b
Regioselectivityd
Coupling
yield,%c
Entry
Solvent
Catalyst
3a:4a
1
2
THF
—
—
60
68
39
—
50
43
70
66
49
81
92:8
79:21
44:56
—
THF:HMPA (4:1)
THF:HMPA (2:1)
THF:HMPA (1:1)
THF:Urotropinee
THF:2,2 0-Bipiridyle
THF
3
—
4
—
—
5
90:10
91:9
91:9
6
—
7
CuI, 4 mol %
Cu(acac)2, 4 mol %
Nano NiOf, 4 mol %
Nano CuOf, 4 mol %
8
THF
THF
89:11
88:12
93:7
9
10
THF
aThe data are averages of at least two independent experiments. bMolar ratio of 1a: Mg: 2a was
optimized to be 7.5 : 9 : 5. THF solution of 1a was added dropwise to Mg and after stirring for
10 min, THF solution of 2a was added dropwise. The mixture was stirred for 3 hours. cThe sum of
GC yields of a-coupling product 3a and g-coupling product 4a. The stereomer ratio E:Z in 3a is
not lower than 9:1. dThe ratio of GC yield of 3a and 4a. e5% mol equiv. vs 2a was used. fNanopow-
der, <50 nm particle size, Aldrich.
inexpensive nano catalysts CuO and NiO were employed in the reaction. In recent
years, metal nanoparticle catalysis has become of tremendous interest and this area
is expanding dramatically. Cu and Cu-based nanopaticles have generated a great
deal of interest as catalysts.51 With the optimized 4 mol % of CuI and 2 mol % of
Cu(acac)2, somewhat higher yields of 70% and 66%, respectively, were obtained
(entries 6 and 7). The use of 4 mol % nano NiO led to a lower 49% yield (entry 8).
However, nano CuO catalyzed allylation provided the highest yield (81%) and
a-selectivity (entry 9).
Intrigued by the milder one-pot conditions of aryl-allyl coupling, we decided to
explore the synthetic scope of the reaction with respect to aryl Grignard reagents
and allylic substrates. For this purpose, we first investigated allylation of a series of
aryl Grignard reagents. The results are given in Table 2. Synthetic a-transfer of a
wide range of aryl groups was obtained. As seen, alkyl substituted phenyl (entries 2,
3 and 4), methoxyphenyl (entries 5 and 6), aryl substituted phenyl (entry 10), dime-
thylaminophenyl (entry 12) and even bromo substituted phenyl (entries 7 and 8)
were allylated smoothly and provided the expected good to high yields with high
a-selectivity. Allylation of 1-naphthylmagnesium bromide (entry 9) was also
achieved in high yield. However, allylation of (4-vinyl)phenylmagnesium bromide
(entry 11) and 2-thienylmagnesium bromide (entry 13) were low due to the
formation of side products.

462
Kalkan et al.
Table 2
Scope of Aryl Bromides in the Nano CuO Catalyzed One Pot Coupling of
Arylmagnesium Bromides with E-crotyl Chloride in THFa,b
Regioselectivityd
3:4
No.
R
Coupling yield,%c
1
2
C6H5-
81
74
94
84
77
72
55
52
81
74
17
62
30
93:7
91:9
91:9
92:8
94:6
91:9
69:31
94:6
95:5
93:7
94:6
81:17
93:7
4-CH3-C6H4-
4-t-Bu-C6H4-
4-C2H5-C6H4-
3-CH3O-C6H4-
4-CH3O-C6H4-
3-Br-C6H4-
3
4
5
6
7
8
4-Br-C6H4-
1-Naphthyl-
9
10
11
12
13
4- C6H4-C6H5-
4- CH2DCH-C6H4-
4-(CH3)2N- C6H4-
2-Thienyl
b
aThe data are averages of at least two independent experiments. Molar ratio of 1: Mg: 2a was
optimized to be 7.5 : 9 : 5. THF solution of 1 was added dropwise to Mg and after stirring for
10 min, THF solution of 2a was added dropwise. The mixture was stirred for 3 hours. cThe sum of
GC yields of a-coupling product 3 and g-coupling product 4. The stereomer ratio E:Z in 3a is not
lower than 9:1. dThe ratio of GC yield of 3 and 4.
Next, we screened a series of g-substituted and g,g-disubstituted allylic electrophiles
in the one pot a-selective allylation of aryl Grignard reagents. The results are given in
Table 3. Allylation of E-crotyl bromide, 2b, i.e., the use of bromide instead of chloride as
a leaving group, did not change the yield and selectivity (entry 2). Among cinnamyl sub-
strates, allylation of E-cinnamyl chloride, 2c gave a good yield with somewhat lower
a-selectivity (entry 3); however E-cinnamyl acetate, 2d did not lead to a good yield,
although the selectivity was high (entry 4). Among g,g-disubstituted allylic substrates
tested, the yield and a-selectivity was found high only in the allylation of prenyl chloride
(1-chloro-3-methyl-2-butene), 2e (entry 5); but prenyl acetate, 2f, resulted in a low yield
and selectivity (entry 6). Allylation of geranyl acetate, 2g did not give a good yield as
expected from the acetate group as leaving group (entry 7).
In conclusion, we have developed a novel practical and easy route for a-selective
allylation of aryl Grignard reagents. The one-pot reaction of in situ formed aryl Grignard
reagents with g-substituted and g,g-disubstituted allylic halides at room temperature in
THF in the presence of nano CuO catalysis leads to high yields of aryl-allyl coupling
with high a-selectivity. Further studies to extend the scope of this method are currently
underway in our laboratory.

Revisiting Allylic Coupling of Grignard Reagents
463
Table 3
Scope of Allylic Substrates in the Nano CuO Catalyzed One Pot Coupling of
Arylmagnesium Bromides in THFa,b
Regioselectivityd
3:4
Entry
Allylic substrate
Coupling yield,%c
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
81
82
70
24
71
11
25
93:7
90:10
64:36
92:8
100:0
55:45
100:0
2g
b
aThe data are averages of at least two independent experiments. Molar ratio of 1a: Mg: 2a-g
was optimized to be 7.5: 9: 5. THF solution of 1a was added dropwise to Mg and after stirring for
10 min, THF solution of 2a-g was added dropwise. The mixture was stirred for 3 hours. cThe sum
of GC yields of a-coupling product 3 and g-coupling product 4. The stereomer ratio E:Z in 3a is
not lower than 9:1. dThe ratio of GC yield of 3 and 4.
Experimental Section
All reactions were carried out in oven-dried glassware under a positive pressure of nitro-
gen using standard syringe-septum cap techniques.52 GC analyses were performed on a
Thermo Finnigan gas chromatograph equipped with a ZB-5 capillary column packed
with phenylpolysiloxane at 70–250ꢀC using the internal standard technique.THF was dis-
tilled from sodium benzophenone dianion. Mg turnings for Grignard reagents and nano
CuO (ALDRICH, ˂50 nm) were used without further purification. Commercially avail-
able aryl halides RBr [R D C6H5, FG-C6H4 (FG D 4-CH3, 4-t-Bu, 4-C2H5, 3-CH3O,
4-CH3O, 3-Br, 4-Br, 4-C6H5, 4-CH2 D CH, 4-(CH3)2N), 1-naphthyl, 2-thienyl] and allylic
compounds were purified using literature procedures.53
A three-necked flame-dried flask equipped with a reflux condenser, two dropping
funnels and a magnetic stirrer was charged with Mg (9 mmol, 0.210 g) at room tempera-
ture. A solution of an aryl halide (7.5 mmol) in THF (7 mL) was added dropwise. Follow-
ing the formation of in situ aryl Grignard reagent, the formation rate was controlled by
cooling the flask whenever necessary for about 10 minutes. CuO (0.1 mmol, 0.008 g)
was added immediately. Then, the allylic halide (5 mmol) in THF (2 mL) was added

464
Kalkan et al.
dropwise to the stirred mixture at room temperature. The reaction mixture was stirred at
room temperature for 3–4 hours. After addition of internal standard (nonane), the mixture
was hydrolyzed with 15 mL saturated NH4Cl solution. The aqueous phase was extracted
with ether and aliquots were analyzed with GC to determine the coupling yield
and a-product:g-product ratio for aryl-allyl coupling. The products were identified by
matching their retention times with those of authentic samples.
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