Reactivity of mixed organozinc and mixed organocopper reagents: 12. Three component reaction of mixed (n-alkyl)(diaryl)zincates, chloroformates and phosphines for the synthesis of esters

Article abstract of DOI:10.1016/j.jorganchem.2015.08.012

The reaction of mixed n-butyldiphenylzincate, n-BuPh₂ZnMgBr with ethyl chloroformate, ClCOOEt in the presence n-Bu₃P in THF takes place with quantitative yield and phenyl group transfer to give PhCOOEt. Ethoxycarbonylation of n-BuPh₂ZnMgBr is preferable to the reaction of PhMgBr forming ester and triphenylcarbinol and also to the reaction of triphenylzincate, Ph₃ZnMgBr for atom economy. Group selectivity in the phosphine catalyzed C-COOR coupling of n-BuPh₂ZnMgBr and n-Bu₂PhZnMgBr can be controlled by changing reaction parameters. n-Bu₃P catalyzed reaction of n-BuPh₂ZnMgBr with ClCOOEt takes place with phenyl selectivity whereas reaction of n-Bu₂PhZnMgBr with ClCOOPh results in n-butyl transfer. Catalysis by Ph₃P increases n-butyl group:phenyl group transfer ratio in the ethoxycarbonylation of both zincates. Selective transfer of aryl groups in n-Bu₃P catalyzed reaction of n-butyl(aryl)₂ZnMgBr reagents with ClCOOEt in THF provides a new procedure for the organometallic synthesis of arenecarboxylic acid ethyl esters at room temperature.

Full text of DOI:10.1016/j.jorganchem.2015.08.012

Journal of Organometallic Chemistry 799-800 (2015) 75e81
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Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Reactivity of mixed organozinc and mixed organocopper reagents: 12.
Three component reaction of mixed (n-alkyl)(diaryl)zincates,
chloroformates and phosphines for the synthesis of esters
*
€
Duygu Ozkan, Ender Erdik
Ankara University, Science Faculty, Bes¸evler, Ankara 06100, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of mixed n-butyldiphenylzincate, n-BuPh2ZnMgBr with ethyl chloroformate, ClCOOEt in the
presence n-Bu3P in THF takes place with quantitative yield and phenyl group transfer to give PhCOOEt.
Ethoxycarbonylation of n-BuPh2ZnMgBr is preferable to the reaction of PhMgBr forming ester and tri-
phenylcarbinol and also to the reaction of triphenylzincate, Ph3ZnMgBr for atom economy. Group
selectivity in the phosphine catalyzed CeCOOR coupling of n-BuPh2ZnMgBr and n-Bu2PhZnMgBr can be
controlled by changing reaction parameters. n-Bu3P catalyzed reaction of n-BuPh2ZnMgBr with ClCOOEt
takes place with phenyl selectivity whereas reaction of n-Bu2PhZnMgBr with ClCOOPh results in n-butyl
transfer. Catalysis by Ph3P increases n-butyl group:phenyl group transfer ratio in the ethoxycarbonylation
of both zincates. Selective transfer of aryl groups in n-Bu3P catalyzed reaction of n-butyl(aryl)2ZnMgBr
reagents with ClCOOEt in THF provides a new procedure for the organometallic synthesis of arene-
carboxylic acid ethyl esters at room temperature.
Received 11 May 2015
Received in revised form
24 June 2015
Accepted 18 August 2015
Available online 25 August 2015
Keywords:
Mixed triorganozincates
Chloroformates
Phosphines
Group selectivity
Esters
© 2015 Elsevier B.V. All rights reserved.
1. Introduction
RT(RR)2ZnM [19e25] are synthetically useful reagents.
In the group selectivity of mixed cuprates R1R2CuLi, the
Organozinc reagents [1e3] are widely used organometallic re-
agents in organic synthesis due to their increased reactivity in the
presence of transition metal and/or organic catalysis, availability of
a number of methods for their preparation and their compatibility
with many functional groups compared with organolithium and
Grignard reagents.
Triorganozincates, R3ZnM (M ¼ Li, MgX; X ¼ Br, Cl) represent a
class of organozinc reagents which are more reactive than dio-
rganozincs, R2Zn and organylzinc halides, RZnX. However, tri-
organozincates have not been used in organic synthesis [4e8] as
extensively as organozinc halides and diorganozincs.
The serious drawback in the synthetic use of R2Zn and R3ZnM
reagents is the transfer of only one of the R groups to the electro-
phile leading to the low atom-economy in their reactions. To avoid
this problem, mixed diorganozincs R1R2Zn [9e12] and mixed tri-
organozincates R1R22ZnM [13,14] have been developed, in which
one of the R groups has a higher transfer rate than the other one.
Mixed diorganozincs. RRRTZn [15e18] and triorganozincates,
commonly accepted hypothesis is that the group in R1R2CuLi that
has a stronger bond to Cu acts as the group of lower selectivity
[1,26e28].
In our serial work on the reactivity and group selectivity control
of mixed organozinc and copper reagents [29e39], we observed
that the group transfer of an organyl group as RT in mixed dio-
rganozincs R1R2Zn [29e31,34,35], diorganocuprates, R1R2CuM
(M ¼ MgBr [32,37,38], ZnCl [38]) and copper catalyzed mixed tri-
organozincates, R1R2ZnMgBr [33,37] can be controlled by changing
reaction parameters, i.e. counter ion, M, leaving group of the elec-
trophile, solvent, temperature, transition metal catalyst and organic
catalyst. We hypothesized that in reactions of mixed reagents,
R1R2Zn and R1R2CuM, R1 group can change not only the transfer
ability, but also the transfer rate of R2 group leading to different
reaction rate of mixed reagents than that of homo reagents R22Zn
and R22CuM [33,36,39]. We also developed new atom-economic
procedures for C-organyl [32e34,37], CeN [31] and CeCOR
[29,30,34] coupling reactions using mixed diorganozinc reagents,
RRRTZn. However, to the best of our knowledge, the reactivity and
group selectivity in reactions of mixed organozincates R1R22ZnM
(M ¼ Li, MgBr) has not been intensively investigated.
* Corresponding author.
E-mail address: erdik@science.ankara.edu.tr (E. Erdik).
http://dx.doi.org/10.1016/j.jorganchem.2015.08.012
0022-328X/© 2015 Elsevier B.V. All rights reserved.

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D. Ozkan, E. Erdik / Journal of Organometallic Chemistry 799-800 (2015) 75e81
Ester functionality is one of the most common functional groups
The inherent difficulty in the reaction of organozincate reagents
3 with chloroformate ester 1a is possible formation of ketones 7
and tert-alcohols 8 as side products (1). However, in the reaction of
homo and mixed zincates, ketones were not detected and the yield
of ter-alcohols, n-Bu3COH and Ph3COH did not exceed 10%.
and can be prepared using a number of metal free and metal
catalyzed methods [40,41]. However, to the best of our knowledge,
the use of CeCOOR coupling of organolithium, -magnesium and
-zinc reagents and diorganocuprates is very limited [42,43]. Due to
the importance of a selective acylation procedure for carbanions,
we focused our interest on the applicability of mixed R1R2Zn and
R1(R2)2ZnMgBr reagents for organometallic synthesis of esters.
Here, we report our progress on the control of group selectivity
of (n-alkyl)(aryl)2zincates in acylation with chloroformate esters,
ClCOOR and achieving a protocol for the conversion of CaryleZn
bond to CaryleCOOR bond.
(1)
As seen, much lower ethoxycarbonylation yields of n-Bu
group, i.e. 8% and 12% were obtained using mixed zincates 3ab2
and 3a2b respectively, compared to the yield obtained in the
reaction of homozincate 3a3, i.e. 43%. However, we were excited
by the ethoxycarbonylation yields of Ph group, i.e. 68% and 36%
using mixed zincates 3ab2 and 3a2b, respectively, which are
higher than the yield obtained in the reaction of homozincate
3b3, i.e. 22%. Next, expecting a change in n-Bu group or Ph group
transfer, we investigated the effect of transition metal catalysis
and organic catalysis on the group selectivities in the ethox-
ycarbonylation of 3ab2. As transition metal catalysts, a range of
Cu, Ag, Ni and Pd salts were screened (Table 1). The use of CuI as a
catalyst lowered the total yield to 24% in the reaction of 3ab2
(entry 5) and the yield was further decreased to 12% in the
presence of CuCN and CuBr.Me2S. The use of AgI or AgOCOCF3 as
a catalyst in the reaction of 3ab2 led to a modest yield of about
40% (entries 6 and 7) with phenyl selective coupling. NiCl2(PPh3)2
catalysis did not give a yield higher than 18% (entry 8). Ethox-
ycarbonylation in the presence of PdCl2 did not proceed to
completion with a yield of 44% (entry 9) and catalysis with
Pd(OAc)2 or PEPPSI-iPr resulted in inferior yields of 36% and 4%,
respectively with phenyl selectivity. Unreacted ethyl chlor-
oformate 1a was mostly recovered in transition metal-free and
catalyzed reactions of zincates.
2. Results and discussion
As a model reaction to investigate the group selectivity of mixed
R1R2Zn (2) and R1(R2)2ZnMgBr (3) reagents with chloroformates,
we chose n-butyl and phenyl groups in these reagents to transfer to
ethyl chloroformate, ClCOOEt (1a) in THF (Scheme 1). We also
investigated the reaction of homo diorganozincs and homo tri-
organozincates to compare with mixed reagents for atom-economy
in the synthetic application.
We
used
magnesium-based
diorganozincs
and
triorganozincates. For the preparation of mixed diorganozinc 2ab,
PhZnCl was allowed to react with n-BuMgBr in a one pot procedure
[30]. The same procedure can be also applied by reacting n-BuZnCl
with PhMgBr. Mixed triorganozincates 3ab2 and 3a2b
were also prepared easily using n-butyl- and phenylzinc reagents
and n-butyl- and phenyl Grignard reagents [34].
The original attachment of n-Bu or Ph groups to Zn or Mg does
not make a change on the transfer ability of these groups in mixed
diorganozincs and triorganozincates [34].
The reaction of homodiorganozincs, din-butylzinc (2a2),
diphenylzinc (2b2) and mixed n-butylphenylzinc (2ab) in ethox-
ycarbonylation with 1a did not take place and gave dramatically
low yields of 7e10% in the presence of CuI catalysis.
In studying the effects of organic catalysis on the group selec-
tivity of mixed triorganozincates in their reaction with 1a, we used
donor solvents as cosolvents in THF and Lewis bases as additives. In
ethoxycarbonylation of 3ab2 in THF, we used donor solvents, NMP,
diglyme, DMF and also TMEDA as cosolvents. The results showed
that increasing polarity of the solvent prevented the organyl groups
from transferring to C]O group resulting in yields lower than 5%.
The recovery of ethyl chloroformate 1a only in 20e40% yield sug-
gests a possible reaction between these N-donor and O-donor
solvents and 1a. In fact, it is known that tert-amines react with
chloroformate esters to give carbamates under appropriate condi-
tions [44]. However, we did not turn our attention to a possible
reaction of donor solvents with 1a.
We already found n-Bu3P and Ph3P as successful additives to
carry out the acylation of n-BuPhZn (2ab) in high yield with com-
plete n-Bu group transfer and developed a phosphine catalyzed
acylation of mixed (n-alkyl)phenylzincs with aromatic acyl chlo-
rides for the synthesis of n-alkylarylketones [30]. In acylation of
Grignard reagents [45] and diorganozincs [30] possible in situ for-
mation of acylphosphonium salts, (RCO)P4R3ClƟ have been re-
ported [30,45]. So expecting formation of a similar phosphonium
salt, (EtOOC)P4R3ClƟ from ClCOOEt (1a) and R3P, we tried phos-
phine catalysis to see if the yield increases and/or group selectivity
changes in ethoxycarboylation (Table 2). We observed that n-Bu3P
catalysis proceeded the reaction with a quantitative yield and
complete phenyl selectivity (entries 1 and 2) compared with
Scheme 1. Ethoxycarbonylation of homo and mixed diorganozincs, n-BuxPh2exZn
(x ¼ 0e2) (2) and mixed triorganozincates, n-BuxPh3ꢁxZnMgBr (x ¼ 0e3) (3).
First, we determined the effect of the reaction parameters on the
group selectivity of mixed triorganozincates, n-BuPh2ZnMgBr
(3ab2) and n-Bu2PhZnMgBr (3a2b) in their reaction with ethyl
chloroformate (1a) in THF. In the initial study, we determined the
background yields using homozincates, trin-butylzincate (3a3) and
triphenylzincate (3b3).
Table 1 summarizes the yields and group selectivities, i.e. n-Bu
group: Ph group transfer ratios in the ethoxycarbonylation of homo
zincates, 3a3 and 3b3 and mixed zincates, 3ab2 and 3a2b. Transfer
abilities of organyl groups were found by calculating the GC yields
of ketones using authentic samples of 6a and 6b. The reaction
temperature and time was optimized to be 25 ꢀC and 1 h, respec-
tively. The reaction of 3a3 gave the product ester 6a in 43% yield
whereas 3b3 afforded the ester 6b in a lower yield of 22% (entries 1
and 2).
Ethoxycarbonylation of mixed zincate 3ab2 resulted in a good
total yield of 76% with a 6a:6b ratio of 10:90 (entry 3). For the re-
action of mixed zincate 3a2b, a total yield of 48% was obtained with
a 6a:6b ratio of 25:75 (entry 4).

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77
Table 1
Optimization on the yield and organic group selectivity in the ethoxycarbonylation of n-butyl and phenyl Grignard reagents derived homo and mixed triorganozincates 3 with
1a in THF. Screening Cu, Ag, Ni and Pd catalysts.a,b
Entry
Zincate
Catalyst
Yield, %c
6a
Group selectivitye
6b
22
Totald
6a:6b
1
2
3
4
5
6
7
8
9
3a3
3b3
e
43
e
e
e
3ab2
3a2b
3ab2
3ab2
3ab2
3ab2
3ab2
e
76
48
24
41
43
8
10:90
25:75
12:88
7:93
9:91
0:100
9:91
e
CuI
AgI
Ag(OCOCF3)
NiCl2 (PPh3)2
PdCl2
44
a
The reactions were carried out according to the conditions indicated by the above equation. Molar ratio of 3:1a is 2:1.
All the data are average of five or six experiments.
GC yield of 6a in the reaction of 3a3 and 2a2 and GC yield of 6b in the reaction of 3b3.
The sum of GC yields of 6a and 6b in the reactions of 3ab2 and 3a2b.
The ratio of GC yields of 6a and 6b.
b
c
d
e
uncatalyzed reaction (Table 1, entry 3). Optimal amount of n-Bu3P
Mixed zincate 3a2b behaved similarly either in the presence of
10 mol% n-Bu3P or 50 mol % Ph3P catalysis and ethoxycarbonylation
yield increased (entries 6 and 7); however phenyl selectivity
decreased in the presence of n-Bu3P (entry 7) compared with
uncatalyzed reaction (Table 1, entry 4). For comparison with the
quantitative and phenyl selective n-Bu3P catalyzed ethox-
ycarbonylation of n-BuPh2ZnMgBr (3ab2), we also carried out the
reaction with Ph3ZnMgBr (3b3) and found 90% yield (entry 8). This
result clearly shows the atom-economic character of 3ab2 for Ph
catalyst was found to be 10 mol%. However, when 10 mol% of Ph3P
was used, both yield and phenyl selectivity decreased (entry 3). The
use of Ph3P in 25e50 mol% gave still inferior results on the yield and
phenyl selectivity (entries 4 and 5)compared to the outcome of the
reaction in the presence of n-Bu3P catalysis.
These results showed that n-Bu3P is superior to Ph3P in catalysis
for aryl selective ethoxycarbonylation of (n-alkyl)(aryl)2ZnMgBr
reagents with ClCOOEt 1a.
Table 2
Effect of N- and O-donor cosolvents and Lewis base additives on the yield and group selectivity in the ethoxycarbonylation of Grignard reagents derived triphenylzincate 3b3,
n-butyldiphenylzincate 3ab2 and din-butylphenylzincate 3a2b with 1a in THF.a,b
Entry
Zincate
Solventc/Additive
Total yield, %d
Group selectivitye
6a:6b
1
2
3
4
5
6
7
8
3ab2
3ab2
3ab2
3ab2
3ab2
3a2b
3a2b
3b3
THF/n-Bu3P (10 mol%)
THF/n-Bu3P (25 mol%)
THF/Ph3P (10 mol%)
THF/Ph3P (25 mol%)
THF/Ph3P (50 mol%)
THF/n-Bu3P (10 mol%)
THF/Ph3P (50 mol%)
THF/n-Bu3P (25 mol%)
98
100
47
61
74
73
67
90
4:96
5:95
18:82
39:61
43:57
27:73
43:57
e
a
The reactions were carried out according to the conditions indicated by the above equation. Molar ratio of 3:1a is 2:1.
All the data are average of five or six experiments.
THF:cosolvent ratio was optimized to be 2:1.
The sum of GC yields of 6a and 6b in the reactions of 3ab2 and 3a2b. GC yield of 6b in the reaction of 3a3.
The ratio of GC yields of 6a and 6b.
b
c
d
e

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After having established the optimal reaction conditions, we
explored the scope of the n-Bu3P catalyzed aryl selective ethox-
ycarbonylation of (n-butyl)(diaryl)zincates with ClCOOEt (1a) to
use in the organometallic synthesis of esters. The results are sum-
marized in Table 3. The problem was the isolation of the esters from
the product mixture due to the presence of triarylcarbinols as side
products although less than 10% yields. The chromatographic sep-
aration of an ester-alcohol mixture is known as a tedious and time
consuming procedure and the use of DES (deep-eutectic solvents)
have been reported for successful separation of esters from alcohols
[46]. DES are a new type of ionic solvents formed by mixing a
quaternary ammonium salt together with a hydrogen-bond-donor.
We used choline chloride:glycerol (1:2 equiv/1 equiv) for extraction
of product esters.
As seen, a range of aryl groups of (n-Bu)(FGeC6H4)ZnMgBr re-
agents were transferred selectively to ClCOOEt (1a) to afford the
desired products, FGeC6H4COOEt in modest to good yields. How-
ever, ethoxycarbonylation of Bre and EtOOCe substituted phenyl
groups failed to give the desired products in acceptable yields.
To further expand the application scope of the CeCOOR coupling
reactions of organozincates, we also moved our attention to the
effect of the eOR group of XCOOR reagents, as a new parameter on
the yield and group selectivity. For an initial study, we employed
phenyl chloroformate, ClCOOPh (1b) in n-Bu3P catalyzed reactions.
The yields and group selectivities in the phenoxycarbonylation of
homo and mixed zincates are given in Table 4. Phosphine catalyzed
reaction of zincates with 1b also proceeded smoothly and did not
go to completion after extended reaction time. It is quite interesting
that 1b enhanced n-butyl selectivity remarkably in the reaction
with mixed zincates. Mixed zincate, n-BuPh2ZnMgBr (3ab2) gave
87% yield and 9a:9b ratio of 54:46 in the reaction with ClCOOPh
(1b) (entry 3) compared toı 98% yield and 7a:7b ratio of 4:96 in the
reaction with ClCOOEt (Table 2, entry 1). Mixed zincate,
n-Bu2PhZnMgBr (3a2b) also led to 87% yield with n-butyl selectivity
(9a:9b ¼ 90:10) in the reaction with ClCOOPh (1b) (entry 4)
compared to 73% yield and 6a:6b ratio of 27:73 in the reaction with
ClCOOEt (1a) (Table 2, entry 6). Phenoxycarbonylation yield of n-Bu
group in homozincate, n-Bu3ZnMgBr (3a3) and Ph group in
homozincate, Ph3ZnMgBr (3b3) resulted in 42% and 76%, respec-
tively (Table 4, entries 1 and 2). These experiments also showed
the atom-economic character of the n-butyl selective reaction of
n-Bu2PhZnMgBr (3a2b) with 1b to give n-BuCOOPh.
Scheme 2. Ethoxycarbonylation of RMgBr (R ¼ n-Bu, Ph) reagents (4) and homo and
mixed diorganocuprates, n-BuxPh2ꢁxCuMgBr (x ¼ 0e2) (5).
group transfer in ethoxycarbonylation.
We also examined the reactivity of n-butyl and phenyl Grignard
reagents (4) and Grignard reagent derived diorganocuprates (5) in
ethoxycarbonylation with 1a aiming a comparison of their yield
and/or group selectivity with those of triorganozincates (3)
(Scheme 2). The difficulty is that formation of ketones and/or tert-
alcohols as side products appeared in the reaction of Grignard re-
agents and a product mixture of ester 6, ketone 7 and mostly tert-
alcohol 7 was obtained.
The results are summarized below:
The reaction of n-BuMgBr(4a) with 1a in THF resulted in 50%
yield of the product mixture containing 6a, n-Bu2CO and mostly
n-Bu3COH. The use of 10 mol% of CuI as a catalyst decreased the
yield of product mixture to 26%. R3P (R ¼ n-Bu, Ph) catalyzed re-
action led to 55% yield of product mixture. In the reaction of
PhMgBr (4b) with 1a, we found 55% of product mixture containing
6b, Ph2CO and mostly Ph3COH. However, catalytic reaction with
10 mol % CuI increased the yield to 70%, in sharp contrast to that
observed in the copper catalyzed reaction of n-BuMgBr (4a). n-Bu3P
catalysis also led to 70% yield of product mixture.
Treatment of 1a with pre-prepared din-butylcuprate,
n-Bu2CuMgBr (5a2) and diphenylcuprate, Ph2CuMgBr (5b2) resul-
ted in quite low yields of ethoxycarbonylation, i.e. 17% yield of 6a
and 30% yield of 6b, respectively. Phosphine catalysis did not lead to
any improvement uncatalyzed and phosphine catalyzed ethox-
ycarbonylation of mixed cuprate, n-BuPhCuMgBr (5ab) led to a
yield of 14% with n-Bu group selectivity.
In summary, it is obvious that for a clean and high yield
C
aryleCOOEt coupling, the use of Grignard reagent derived mixed
n-alkyldiarylzincates is preferable aryl Grignard reagents and
also to triarylzincates to avoid the waste use of an aryl group.
We were pleased to find that in the presence of phophine
catalysis, ClCOOEt (1a) and ClCOOPh (1b) are workable
Table 3
Trin-butylphosphine catalyzed ethoxycarbonylation of bromomagnesium n-butyldiarylzincates with ethyl chloroformate (1a) in THF at 25 ꢀC in 2 h.a
Entry
Coupling yield, %b,c
1
2
3
4
5
C6H5
4-MeC6H4
3-MeC6H4
3-MeOC6H4
4-tert-BuC6H4
b
78
81
64
58
75
c
d
e
f
a
b
c
Reactions were run with a 2:1 M ratio of 3:1a. For synthetic procedure, see Experimental Section.
Isolated yield. Average of at least two independent experiments.
The products were fully characterized by 1H NMR.

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D. Ozkan, E. Erdik / Journal of Organometallic Chemistry 799-800 (2015) 75e81
79
Table 4
Trin-butylphosphine catalyzed phenoxycarbonylation of Grignard reagents derived triphenylzincate (3b3), n-butyldiphenylzincate (3ab2) and din-butylphenylzincate 3a2b
with phenyl chloroformate 1b in THF.a,b
Entry
Zincate
Yield, %c
7a
Group selectivitye
7b
76
Totald
9a:9b
1
2
3
4
3a3
3b3
3ab2
3a2b
42
e
e
87
87
54:46
90:10
a
The reactions were carried out according to the conditions indicated by the above equation. Molar ratio of 3:1b is 2:1.
All the data are average of five or six experiments.
GC yield of 9a in the reaction of 3a3 and GC yield of 9b in the reaction of 3b3.
The sum of GC yields of 9a and 9b in the reactions of 3ab2 and 3a2b.
The ratio of GC yields of 9a and 9b.
b
c
d
e
n-alkyl(aryl)2ZnMgBr reagents give CaryleCOOEt coupling with
1a and (n-alkyl)2(aryl)ZnMgBr reagents give
CalkyleCOOPh
coupling in high yield at room temperature.
Depending on the catalytic formation of (ROOC)P4R3ClƟ ions as
oxycarbonylation reagents, we offer a catalytic cycle for R3P cata-
lyzed reaction of triorganozincates, R3ZnMgBr with ClCOOR1 to give
esters RCOOR1 (Scheme 3).
The structure of stoichiometric triorganozincates in solution has
been reported as solvent separated ion pairs (SSIP) or as contact ion
pairs (CIP) of Zn centered anions and counter cations R1R22ZnƟM4
(R1 ¼ R2 or R1sR2, M ¼ Li, MgBr) [1]. However, Nakamura et al.
reported that triorganozincates react as organyl nucleophiles, but
not as zinc centered nucleophiles [47]. Hevia et al. has revealed the
formation of solvent separated R3ZnMgBr structure,
[R3ZnƟMg2Cl34(THF)6] in the solid state and in solution [8,48].
Ishihara et al. recently postulated ion pairs as essential moiety of
zincate reagents in the reaction of homo and mixed zincates to
ketones [49].
Scheme 3. Proposed catalytic cycle for phosphine, R23P catalyzed carbonylation of
triorganozincates, R3ZnMgBr with chloroformates, ClCOOR1.
In the catalytic cycle, in step b, zincate anion R3ZnƟ moiety at-
tacks the in situ formed catalytic phosphonium salt A yielding
addition product B and R2Zn. In step c, B releases the product ester
and the catalyst to regenerate the phosphonium salt A in the
following step a.
However, we observed that phosphine catalyzed reactions of
mixed triorganozincates with haloformate esters takes place with
group selectivity, which depends on the reaction parameters. In the
n-Bu3P catalyzed reaction of n-BuPh2ZnMgBr (3ab2) and
n-Bu2PhZnMgBr (3a2b) with ClCOOEt (1a), complete and higher
phenyl selectivity is observed, respectively, whereas their reaction
with ClCOOPh (1b) results in higher and complete n-butyl selec-
tivity, respectively. It seems that the reaction of haloformate ester
with eOPh group increases n-Bu group:Ph group transfer ratio than
that observed in the reaction of haloformate ester with eOEt group.
In addition, Ph3P catalysis increases n-Bu group:Ph group transfer
ratio in the reaction of 3ab2 and 3a2b.
For a plausible explanation for dependence of group selectivity of
zincates 3ab2 and 3a2b to leaving groups, eOR in ClCOOR (R ¼ Et or
Ph) and also to phosphine catalysts, R3P (R ¼ n-Bu or Ph), we
assumed a six-membered ring chair conformation for coordination
of R3ZnMgBr to ClCOOR in the transition state C (Scheme 4) [16,50]..
Scheme 4. Catalytic intermediate A and transition state C in R23P catalyzed reaction of
R3ZnMgBr with ClCOOR1.
substrates to react with mixed zincates, n-alkyl(aryl)2ZnMgBr
and (n-alkyl)2(aryl)ZnMgBr in THF resulting in group selective
transfer of n-alkyl or aryl groups. In the presence of n-Bu3P,

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D. Ozkan, E. Erdik / Journal of Organometallic Chemistry 799-800 (2015) 75e81
THF at room temperature is a newly developed procedure
for the synthesis of esters using carbanions as
nucleophiles.
As magnesium prefers tetracoordination, we assume here the ester
group will not participate in the chelation [29]. In the transition
state C, RƟ(n-Bu or Ph) will attack to the C]O group of the phos-
phonium salt A to afford the addition product B coordinated to R2Zn.
We think it is most probable that in transition states n-Bu group,
being a smaller group will link Mg and Zn centers more easily than
Ph group as reported for other methyl(aryl)2zincates [51].
(iv) Further applications of mixed triorganozincate reagents for
C-COOR and C-CONR2 coupling and detailed mechanistic
work for group selectivity are currently underway in our
laboratories.
According to the model for 3ab2 the attack of only Ph group to
C]O group takes place yielding phenyl selectivity. For 3a2b, either
n-Bu or Ph group will have the chance to react resulting in a
decrease in phenyl coupling. In the case of the reaction with phenyl
haloformate, ClCOOPh (1b), due to a possible steric interaction of
eOPh group in pseudoaxial or pseudoequatorial position, n-Bu
group both in 3ab2 and in 3a2b will have more chance to attack
resulting in a higher n-Bu group Ph group transfer ratio in 3ab2 and
n-butyl selectivity in 3a2b. This explanation seems to explain the
observed differences in group selectivities of 3ab2 and 3a2b in their
reactions with haloformates, ClCOOR (R ¼ Et, Ph). For the increase
in n-Bu group:Ph group transfer ratio by using Ph3P instead of n-
Bu3P, we simply think that the attack of Ph group in both 3ab2 and
3a2b will not be easier due to the steric interaction of e4PR32 group
in this case.
4. Experimental
4.1. General
All reactions were carried out under a nitrogen atmosphere in
oven dried glassware using standard syringe-septum cap tech-
niques [52]. Quantitative GC analysis were performed on a Thermo
Finnigan gas chromatograph equipped with a 28-5 capillary col-
umn packed with phenylpolysiloxane using the internal standard
technique. THF was distilled from sodium benzophenone dianion.
Commercially available n-butyl bromide and aryl bromides were
obtained commercially and purified using literature procedures.
Grignard reagents were prepared in THF by standard methods.
ZnCl2 was dried under reduced pressure at 100 ꢀC and used as THF
solution.
n-Bu3ZnMgBr (1a3) and Ph3ZnMgBr (1b3) were prepared by
dropwise addition of 3 mol equiv of n-BuMgBr or PhMgBr,
respectively in THF to a solution of 1 mol equiv of ZnCl2 in THF at
15 ꢀC and stirring at that temperature for 15 min. In the preparation
of n-BuPh2ZnMgBr (1ab2) and n-Bu2PhZnMgBr (1a2b), freshly
prepared Ph2Zn and PhZnCl were used, respectively. Ph2Zn and
PhZnCl were prepared in THF by dropwise addition of 2 mol equiv
or 1 mol equiv of PhMgBr, respectively in THF to a solution of
1 mol equiv of ZnCl2 in THF at ꢁ15 ꢀC and stirring at that temper-
ature for 5 min. For the preparation of n-BuPh2ZnMgBr (1ab2)
1 mol equiv of n-BuMgBr was added to 1 mol equiv of Ph2Zn in THF
and for the preparation of n-Bu2PhZnMgBr (1a2b) 2 mol equiv of n-
BuMgBr was added to PhZnCl in THF, both at ꢁ15 ꢀC and stirring at
that temperature for 15 min.
3. Conclusions
With the aim of controlling the group selectivity and providing a
new method for CaryleCOOR coupling using mixed zincates, herein
we have demonstrated that:
(i) Among the organomagnesium, -copper and -zinc reagents,
reaction
of
mixed
triorganozincates,
R1R22ZnMgBr
(R1,R2 ¼ n-alkyl or aryl) with ClCOOR (R ¼ Et, Ph) in the
presence of phosphines are successful for R2eCOOR
coupling.
(ii) In phosphine catalyzed reaction of RR(RT)2ZnMgBr with
ClCOOR, group selectivity can be controlled by changing
reaction parameters. n-Bu3P catalyzed reaction of
n-BuPh2ZnMgBr with ClCOOEt takes place with high yield
and phenyl group transfer whereas reaction of
n-Bu2PhZnMgBr with ClCOOPh leads to high yield with
n-butyl group transfer. In addition, Ph3P catalysis increases
n-Bu group: Ph group transfer ratio in the reaction of both
n-BuPh2ZnMgBr n-Bu2PhZnMgBr. These findings also pro-
vide support for our hypothesis that the group selectivity of
mixed organozinc reagents depends on the reaction
parameters.
4.2. Typical procedure for the synthesis of ethyl arenecarboxylates
from bromomagnesium n-butyldiarylzincates and ethyl
chloroformate in the presence pf trin-butylphophine
In a two-necked flame-dried flask, mixed n-butyldiarylzinc
bromomagnesium reagent, n-BuR2ZnMgBr (1ab2
e
1af2)
(R ¼ C6H5 b, 4-MeC6H4 c, 3-MeC6H4 d, 4-MeOC6H4 e, 3-MeOC6H4)
(10 mmol) was freshly prepared as explained above for 3ab2. For
this purpose, the flask cooled to ꢁ15 ꢀC was charged with ZnCl2
(10 mmol) in THF (10 ml). Arylmagnesium bromide (20 mmol)
was added at ꢁ15 ꢀC. Following stirring for 15 min at that
(iii) Selective transfer of aryl group in n-Bu3P catalyzed reac-
tion of (n-butyl)(aryl)2ZnMgBr reagents with ClCOOEt in

€
D. Ozkan, E. Erdik / Journal of Organometallic Chemistry 799-800 (2015) 75e81
81
temperature, n-BuMgBr (10 mmol) in THF was added at ꢁ15 ꢀC
and heterogeneous solution of mixed zincate was stirred at that
temperature for 15 min. To the mixed zincate (10 mmol), first n-
Bu3P (2.5 mmol) and after stirring for 5 min, ethyl chloroformate
(2a) (5 mmol) was added dropwise. The reaction mixture was
stirred at room temperature for 2 h. The mixture was hydrolyzed
with H2O. The separated organic phase was washed with 6NHCl
to remove n-Bu3P. Aqueous phase was extracted three times with
Et2O. The combined ethereal solutions were washed with aq.
Na2CO3, dried over Na2SO4 and concentrated by rotary evapora-
tion. The ethereal solution was mixed with DES (choline
chloride:glycerol ¼ 1:2 equiv/equiv) (sample: DES ¼ 1:5 v/v) and
centrifuged four times. The upper product ester phase was
extracted with ethyl acetate and H2O. The solutions were
concentrated by rotary evaporation and subjected to silica gel
column chromatography with petroleum ether: ether (1:1) as
eluent to give product esters. Product esters were pure according
to GC and 1H NMR analysis. For the reusability of DES, H2O was
added to the lower ionic solvent phase and extracted with ethyl
acetate to remove the product ester. Subsequently, H2O was
removed by heating the DES solution at 140 ꢀC in an open vessel
for 2 h.
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For financial support for the project, we thank Turkish Scientific
and Technical Research Council (Grant No. TBAG 112T676) and
Ankara University Research Fund (Grant No. 13L4240005) Dr.
Duygu Ozkan also thanks Turkish Scientific and Technical Research
Council for a Ph. D. Scholarship.
[35] E. Erdik, M. Kalkan, J. Phys. Org. Chem. 26 (2013) 256.
€
[36] E. Erdik, D. Ozkan, React. Kinet. Mech. Catal. 108 (2013) 293.
€ €
€
[37] E. Erdik, F. Eroglu, M. Kalkan, O.O. Pekel, D. Ozkan, E.Z. Serdar, J. Organomet.
€
Chem. 745e746 (2013) 235.
€ €
[38] O.O. Pekel, E. Erdik, J. Organomet. Chem. 751 (2014) 644.
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