Reactivity of mixed organozinc and mixed organocopper reagents: 6. Nickel-catalyzed coupling of methylarylzincs with primary alkyl halides; An atom-economic aryl-alkyl coupling

Article abstract of DOI:10.1016/j.tetlet.2011.10.083

A nickel-catalyzed process for the cross-coupling of mixed arylzincs and primary alkyl halides has been developed. The reaction of a methylarylzinc with a primary alkyl halide in THF in the presence of NiCl₂/PPh ₃ takes place with selective aryl transfer at room temperature in moderate yields. This protocol provides an atom-economic alternative to aryl-primary alkyl coupling using diarylzincs.

Full text of DOI:10.1016/j.tetlet.2011.10.083

Tetrahedron Letters 52 (2011) 7087–7090
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Tetrahedron Letters
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Reactivity of mixed organozinc and mixed organocopper reagents:
6. Nickel-catalyzed coupling of methylarylzincs with primary alkyl halides; an
atom-economic aryl–alkyl coupling
⇑
Özgen Ömür Pekel, Ender Erdik
Ankara University, Science Faculty, Beßsevler, Ankara 06100, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 July 2011
Revised 26 September 2011
Accepted 17 October 2011
Available online 20 October 2011
A nickel-catalyzed process for the cross-coupling of mixed arylzincs and primary alkyl halides has been
developed. The reaction of a methylarylzinc with a primary alkyl halide in THF in the presence of NiCl2/
PPh3 takes place with selective aryl transfer at room temperature in moderate yields. This protocol pro-
vides an atom-economic alternative to aryl–primary alkyl coupling using diarylzincs.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Alkylarylzincs
Mixed diorganozincs
Alkylation
Triphenylphosphine
Organozinc reagents of the type R2Zn are widely used organo-
metallic reagents due to their high reactivity, ease of preparation,
and high tolerance to many functional groups.1,2
nucleophiles and/or alkyl electrophiles and they have been sum-
marized in reviews devoted to coupling of organometallics with or-
ganic electrophiles7 and with alkyl electrophiles,8–10 and
organozincs11 and alkyl organometallics with organic electro-
philes12 and with alkyl electrophiles.13
According to our literature survey during our continuing work
on the reactivity and controlling factors of the group selectivity
of mixed organozinc reagents,14–17 the use of mixed diorganozincs
(RRRTZn) in the Pd- or Ni-catalyzed coupling reactions with organic
electrophiles is quite limited. The reaction of mixed alkylzinc re-
agents containing Me3SiCH2 as the residual group with allylic
phosphates under CuCN catalysis4j and with activated alkyl halides
in the presence of Ni catalysis has been reported.18 Mixed isopro-
pylalkenylzincs have been found to react with heteroatom electro-
philes such as R3SnCl and Ph2PCl and alkyl halides in the presence
of CuCN catalysis as alkenyl selective reagents.3f
Motivated by our early success in using mixed diorganozincs for
atom-economic acylation15 and amination16 of diorganozincs, we
decided to investigate the synthetic applicability of aryl–alkyl
Negishi cross-coupling of mixed alkylarylzincs with primary alkyl
halides in the presence of nickel catalysis. Palladium catalysis in
Negishi cross-coupling reactions is well-developed,19–22 however,
nickel catalysis has recently become important.11 It is known that
aryl nucleophiles are generally less reactive in cross-coupling reac-
tions with alkyl halides, however, they undergo fewer side reac-
tions due to lack of hydrogens.9 We postulate that the alkyl
nucleophile in the mixed alkylarylzinc reagent does not couple,
but may facilitate the coupling reaction. On the other hand, the
However, one drawback of this procedure is that only one of the
organic groups can be transferred efficiently to the substrate. In or-
der to achieve atom-economic reactions of diorganozincs, mixed
diorganozincs (R1R2Zn) in which one of the R groups has a lower
rate of transfer than the others have been developed.3 Methyl,
ethyl, and tert-butyl groups were found to react more slowly than
other alkyl, alkenyl, and aryl groups.3a–e Mixed diorganozincs
RRRTZn composed of one transferable group RT together with the
residual group RR have recently proved to be synthetically useful.4
Trimethylsilylmethyl (Me3SiCH2),4a neopentyl (tert-BuCH2), and
neophyl (PhMe2CH2) groups4b have been reported by Knochel
et al. as excellent residual groups.
Diorganozincs are also good reaction partners for Negishi cross-
coupling reactions with organic electrophiles in the presence of Pd
or Ni catalysis and provide a very popular method for forming new
C–C bonds.1,5,6 However, coupling with sp3carbon-containing
organozinc nucleophiles and/or sp3carbon-containing electro-
philes with b-hydrogen atoms still represent a difficult class of
coupling partners due to b-hydride elimination in the intermediate
alkyl metal complexes leading to alkenes as the main products or
side products (Scheme 1). Recently, several Ni and Pd catalyst sys-
tems have been reported for the successful coupling of alkyl
⇑
Corresponding author. Tel.: +90 312 212 6720/1031; fax: +90 312 223 23 95.
E-mail address: erdik@science.ankara.edu.tr (E. Erdik).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.083

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Ö. Ömür Pekel, E. Erdik / Tetrahedron Letters 52 (2011) 7087–7090
Scheme 1. General mechanism for transition metal catalyzed cross-coupling reactions of organozinc reagents with electrophiles. Catalytic cycle steps: (a) oxidative addition,
(b) transmetallation, (c) reductive elimination, (d) and (e) b-hydride elimination in the case of sp3 carbon containing electrophiles and organozinc nucleophiles.
formation of sp2carbon–sp3carbon bonds has been generally per-
formed using alkylzinc reagents and aryl/alkenyl halides.9,11,12,20,21
There are a few reports on the alternative coupling using aryl/alke-
nylzinc reagents and alkyl halides via potential b-hydride elimina-
tion.8–11 Thus, we aimed to develop suitable reaction conditions for
selective aryl transfer in the cross-coupling of mixed arylzincs with
primary alkyl halides using Ni catalysts.23,24
Here, we describe our progress toward achieving a simple Ni
catalyst system for the atom economic cross-coupling of mixed
alkylarylzincs with primary alkyl halides with selective aryl
transfer.
They are thought to facilitate the reductive elimination from the
intermediate oxidative addition product over the potentially com-
peting b-hydride elimination by removing electron density from
the metal center. We initiated our experiments by evaluating Ni(a-
cac)2 as the catalyst for the coupling of n-BuPhZn (1ac) in THF and
in THF/NMP (2:1) (entries 1 and 2). The yield was quite low in THF.
In THF/NMP (2:1), the yield increased to 48%, and the yields of the
individual products 3a (R1 = n-Bu) and 4 (R2 = Ph) were 19% and
29%, respectively. We also observed that reaction at room temper-
ature for about 1 h gave the highest yield although the Negishi
reaction is known to take place at lower temperatures.
First, we investigated the effect of the reaction parameters on
the group transfer selectivity of n-butylphenylzinc (1ac) in the
nickel-catalyzed alkylation with n-pentyl bromide and iodide 2
as a model coupling reaction (1).
For comparison, the transfer ability of the n-Bu group in n-
Bu2Zn (1a2) and in Ph2Zn (1c2) in THF/NMP (2:1) was 16% (entry
3) and 47% (entry 4), respectively. Thus, using an N-donor solvent
resulted in the same transfer ability of the n-Bu group, but lower
transfer of the Ph group in the mixed diorganozinc, n-BuPhZn.
The coupling in THF/NMP (2:1) was re-examined in the presence
of 4-fluorostyrene (20 mol %), however, the coupling was less effi-
cient and gave a lower 23% yield (entry 5), with transfer of only the
Ph group, unexpectedly. Increasing the amount of 4-fluorostyrene
(1 equiv) did not change the outcome of the coupling (entry 6).
The background alkylation yield of Ph2Zn (1c2) under the same
conditions was higher (entry 7). To our delight, the use of
Ni(PPh3)2Cl2 as the catalyst for the alkylation of n-BuPhZn (1ac) re-
sulted in a 57% yield with only Ph group transfer (entry 8).
Before screening Lewis bases as cosolvents, we determined the
coupling yields of n-Bu2Zn (1a2) and Ph2Zn (1c2) in the presence of
Ni(PPh3)2Cl2 catalysis. Not surprisingly, alkylation of 1a2 took
place, but with a low 11% yield (entry 9) and alkylation of 1c2 gave
a somewhat higher 67% yield (entry 10) than that of n-BuPhZn
(1ac). Coupling was significantly less efficient in THF/NMP (2:1),
THF/TMEDA (2:1) and THF/DMPU (2:1) (entries 11–13), possibly
due to the presence of PPh3 as a Lewis base as well as the N-donor
solvent.
We also used NiCl2 as the catalyst to determine the effect of
PPh3 as an additive instead of a ligand on the Ni catalyst in the cou-
pling of n-BuPhZn (1ac). We optimized the catalyst and additive
concentration at 10 mol % and coupling gave a 43% yield with the
transfer of only Ph group (entry 14). Background coupling yields
with n-Bu2Zn (1a2) and Ph2Zn (1c2) under the same conditions
were 8% and 52%, respectively (entries 15 and 16). Coupling of n-
butylphenylzinc (1ac) did not result in a decreased yield compared
to the coupling of diphenylzinc with respect to the error limit of GC
analysis (10%).
Ni catalyst
n-BuPhZn þ n-PentX
!
n ꢀ C9H20 þ Ph-n-Pent
4
3
1ac
2
THF
X ¼ Br; I
ð1Þ
We carried out the coupling reaction by adding n-pentyl iodide
(2) to the catalyst system in THF or in THF:cosolvent and then add-
ing n-butylphenylzinc (1ac). The relative transfer ability of n-Bu
and Ph groups was determined from the GC yields of coupling
products 3 and 4 using authentic samples. We used magnesium
based organozinc reagents and prepared the mixed diorganozinc
by reacting phenylmagnesium bromide with n-butylzinc chloride
(Method A1) and also by reacting n-butylmagnesium bromide with
phenylzinc chloride (Method A2). However, we found that the
group originally attached to Zn (n-Bu or Ph) did not affect the
group transfer selectivity. The coupling with n-pentyl iodide gave
a higher yield than that of n-pentyl bromide and we therefore
decided to focus our studies on pentyl iodide. The effect of the Ni
catalyst, cosolvent and additive (promoter) on the yields and rela-
tive transfer ability of the n-Bu and Ph groups in the coupling of n-
BuPhZn with n-pentyl iodide in THF are given in Table 1. We also
determined the background yields, that is, alkylation yields of n-
Bu2Zn (1a2) and Ph2Zn (1c2) under the same conditions.
We carried out the alkylation of n-BuPhZn (1ac) in THF, (i) using
Ni(acac)2 (acac = acetylacetonate), Ni(PPh3)2Cl2 and NiCl2 as cata-
lysts, (ii) using a coordinating solvent, such as NMP (N-methyl-2-
pyrrolidinone), TMEDA (N,N,N0,N0-tetramethylethylenediamine),
and DMPU (N,N-dimethylpropyleneurea), and (iii) using an addi-
tive, that is, 4-fluorostyrene. It has been reported that 4-fluorosty-
rene10,11,25 and 4-(trifluoromethyl)styrene10,11,26 can be used as
promoters in the coupling of organozinc reagents with alkyl elec-
trophiles leading to considerable improvements in the coupling.
Before investigating the scope of the coupling partner in the
NiCl2/PPh3 catalyzed aryl–alkyl coupling of n-butylarylzinc

Ö. Ömür Pekel, E. Erdik / Tetrahedron Letters 52 (2011) 7087–7090
7089
Table 1
Organic group transfer ability in the Ni-catalyzed coupling of n-butylphenylzinc (1ab) with n-pentyl iodide (2) in THF. Effect of the catalyst, solvent and additivea,b,c
Entry
1
Catalyst
Solvent
Additive
Total yield (%)d
3a:4e
1
2
3
4
5
6
7
8
1ac
1ac
1a2
1c2
1ac
1ac
1c2
1ac
1a2
1c2
1ac
1ac
1ac
1ac
1a2
1c2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
THF
—
—
—
—
11
48
16
47
23
20
37
57
11
67
43
37
45
43
8
27:73
40:60
THF:NMP (2:1)
THF:NMP (2:1)
THF:NMP (2:1)
THF:NMP (2:1)
THF:NMP (2:1)
THF:NMP (2:1)
THF
4-Fluorostyrene (20 mol %)
4-Fluorostyrene (1 equiv)
4-Fluorostyrene (1 equiv)
—
—
—
—
—
0:100
0:100
Ni(PPh3)2Cl2
Ni(PPh3)2Cl2
Ni(PPh3)2Cl2
Ni(PPh3)2Cl2
Ni(PPh3)2Cl2
Ni(PPh3)2Cl2
0:100
9
THF
THF
10
11
12
13
14
15
16
THF:NMP (2:1)
THF:TMEDA (2:1)
THF:DMPU (2:1)
THF
THF
THF
0:100
0:100
0:100
0:100
—
f
NiCl2
PPh3 (10 mol %)
PPh3 (10 mol %)
PPh3 (10 mol %)
f
NiCl2
f
NiCl2
52
a
n-BuPhZn (1ac) was prepared using Method A1 (see text) at ꢀ20 °C
b
Molar ratio of 1:2 was optimized as 2:1. A freshly prepared THF solution of 1 was added to a mixture of 2 and catalyst in solvent at 0 °C and the reaction carried out at
room temperature.
c
Catalyst was optimized as 20 mol %.
The sum of the GC yields of 3 and 4 determined from the mean value of three or four experiments.
The ratio of GC yield of 3 to 4.
Catalyst was optimized at 10 mol %.
d
e
f
reagents, we examined the methyl group as a residual group (Table
2). Methylphenylzinc (1bc) coupled with n-pentyl iodide (2) in a
much higher yield than that of n-butylphenylzinc (1ac) in the pres-
ence of NiCl2 (10 mol %) and PPh3 (10 mol %) (entry 1). Loading a
higher amount of catalyst system (entries 2 and 3) did not change
the yield. The use of THF/NMP (2:1) as solvent in the catalysis with
NiCl2 (10 mol %)/PPh3 (1 equiv) (entry 4) or with NiCl2 (20 mol %)/
PPh3 (20 mol %) (entry 5) decreased the coupling yield, as ex-
pected. Using a lower amount of PPh3 (entries 6 and 7) led to some-
what decreased yields. Tri-n-butylphosphine as an additive
(1 equiv) resulted in an extremely low 2% yield. The reactions were
carried out at room temperature for 1 h (optimized conditions) and
coupling at ꢀ10 °C resulted in a 54% yield after a reaction time of
2–3 h. However, we observed that carrying out the coupling at
40 °C gave an optimized 66% yield in 5 min (entry 8). Thus, 1 equiv
of the phenyl group in mixed methylphenylzinc (1bc) can lead to
aryl–alkyl coupling in the presence of NiCl2 (10 mol %) and PPh3
(10 mol %) in 63% yield. This is higher than the 57% yield obtained
using n-BuPhZn in the presence of Ni(PPh3)2Cl2 (20 mol %). A re-
duced catalyst loading is used even if the coupling efficiency was
almost same within the error limits of GC analysis.
We applied our Ni-catalyzed aryl–primary alkyl coupling condi-
tions using aryl nucleophiles of methylarylzinc reagents (catalyst
system: 10 mol % NiCl2/10 mol % PPh3 in THF at room temperature)
to a series of methyl (substituted phenyl) zinc reagents and n-alkyl
iodides (Table 3). n-Alkyl iodides (C5–C10) reacted with aryl nucle-
ophiles of methylarylzincs to give coupled products in moderate
yields. As aryl nucleophiles, tolyl, and phenyl nucleophiles contain-
ing –I, +M type functional groups (–OMe) were examined. How-
ever, we found that these conditions did not tolerate a –I, ꢀM
type functional group (–COMe) on the phenyl nucleophile and cou-
pling did not take place. We employed C5, C4 and C10 alkyl iodides
as primary alkyl electrophiles. Neopentyl iodide gave the coupling
product, albeit in a low yield.
Table 3
Ni-catalyzed coupling of methylarylzincs with primary alkyl iodides in THFa
Table 2
Effect of the additive on the phenyl transfer ability in the NiCl2-catalyzed coupling of
methylphenylzinc with n-pentyl iodide in THF and THF:NMP (2:1)a
Entry
R
R1
Yield of 4 (%)b
1
2
3
4
5
6
7
8
Ph
n-C5H11
n-C5H11
n-C5H11
n-C5H11
n-C5H11
n-C5H11
n-C5H11
n-C4H9
63
69
66
52
54
Entry
[NiCl2] (mol %)
Solvent
[PPh3] (mol %)
Yield of 4 (%)b
4-MeC6H4
3-MeC6H4
4-MeOC6H4
3-MeOC6H4
4-MeCOC6H4
3-MeCOC6H4
Ph
Ph
Ph
Ph
1
2
3
4
5
6
7
8
10
20
20
10
20
10
10
10
THF
THF
THF
THF:NMP (2:1)
10
20
1 equiv
1 equiv
20
15
5
10
63
63
63
36
37
60
56
66c
c
—
—
c
THF:NMP (2:1)
THF
THF
THF
58
50
59
15
9
10
11
n-C7H15
n-C10H21
neo-C5H11
a
Molar ratio of 1bc:2 was 2:1. For the preparation of 1bc and the coupling
a
b
c
reaction, see Ref. 27.
For a representative coupling procedure, see reference 29.
Yields were determined by GC.
No reaction was observed.
b
GC yield.
c
The reaction was carried out at 40 °C for 5 min.

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Ö. Ömür Pekel, E. Erdik / Tetrahedron Letters 52 (2011) 7087–7090
7. Knochel, P.; Thaler, T.; Diene, C. Isr. J. Chem. 2010, 50, 547–557.
In conclusion, we have established a new and simple Ni-cata-
8. Rudolph, A.; Lautens, M. Angew. Chem., Int. Ed. 2009, 48, 2656–2670.
9. Frisch, A. C.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 674–688.
10. Netherton, M. R.; Fu, G. C. Adv. Synth. Catal. 2004, 346, 1525–1532.
11. Phapale, V. B.; Cardenas, D. J. Chem. Soc. Rev. 2009, 38, 1598–1607.
12. Jana, R.; Pethak, T. D.; Sigman, M. S. Chem. Rev. 2011, 111, 1417–1492.
13. Cardenas, D. J. Angew. Chem., Int. Ed. 2003, 42, 384–387.
14. Erdik, E.; Pekel, Ö. Ö. J. Organomet. Chem. 2008, 693, 338–342.
15. Erdik, E.; Pekel, Ö. Ö. Tetrahedron Lett. 2009, 50, 1501–1503.
16. Erdik, E.; Pekel, Ö. Ö.; Kalkan, M. Appl. Organomet. Chem. 2009, 23, 245–248.
17. Erdik, E.; Özkan, D. J. Phys. Org. Chem. 2009, 12, 1148–1154.
18. Jensen, A. E.; Knochel, P. J. Org. Chem. 2002, 67, 79.
lyzed protocol for the cross-coupling of mixed methylarylzincs with
primary alkyl iodides27 leading to an atom-economic alternative to
aryl–primary alkyl coupling using diarylzincs. We are working to
probe the generality of the mixed arylzinc–alkyl coupling reaction
with respect to the coupling of aryl nucleophiles containing a wide
range of functional groups and also the coupling of activated alkyl
electrophiles such as benzyl, allyl, and a-carbonylalkyl halides.
Acknowledgment
19. Organ, M. G.; Avola, S.; Dubovyk, I.; Hadei, N.; Kantchev, E. A. B.; O’Brien, C. J.;
Volante, C. Chem. Eur. J. 2006, 12, 4749–4755. and references cited therein.
20. Çalımsız, S.; Organ, M. Chem. Commun. 2011, 47, 5181–5183. and references
cited therein.
21. Joshi-Pangu, A.; Ganesh, M.; Biscoe, M. R. Org. Lett. 2011, 13, 1218–1221.
22. Achonduh, G. T.; Hadei, N.; Volante, C.; Avola, S.; O’Brien, C. J.; Organ, M. G.
Chem. Commun. 2010, 46, 4109–4111. and references cited therein.
23. Note. The use of PEPPSI as a Pd catalyst in the coupling of n-BuPhZn (1ac) with
n-pentyl iodide 2 did not give selective Ph group transfer. The coupling yield in
We thank the Turkish Scientific and Technical Research Council,
Grant No. TBAG 106T644 for financial support.
References and notes
THF/NMP (2:1) was 67% with
a 3:4 molar ratio of 20:80. However, the
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Reagents in Organic Synthesis; New York: CRC Press, 1996.
background coupling yield with Ph2Zn was 72%.26
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Sciences, 2011.
25. Giovanni, R.; Knochel, P. J. Am. Chem. Soc. 1998, 120, 11186.
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Radinov, R. N. J. Am. Chem. Soc. 1993, 115, 1593–1594; (o) Srebnik, M.
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26. Jensen, A. E.; Dohle, W.; Knochel, P. Tetrahedron 2000, 46, 4197.
27. Typical procedure for the coupling of methylarylzincs with primary alkyl
iodides: All reactions were carried out in oven-dried glassware under a positive
pressure of nitrogen using standard syringe-septum cap techniques.28 For the
preparation of methylarylzinc reagents (aryl: C6H5, MeC6H4, MeOC6H4),
arylzinc chlorides were reacted with methylmagnesium chloride. Arylzinc
chloride was prepared by addition of arylmagnesium bromide (2 mmol) to
ZnCl2 (2 mmol) in THF (4 ml) at ꢀ20 °C and stirring at that temperature for
15 min. To freshly prepared arylzinc chloride (2 mmol), methylmagnesium
chloride (2 mmol) was added and the mixture was stirred at ꢀ20 °C for another
15 min. For the preparation of methylarylzinc reagents (aryl: 4-MeCOC6H4, 3-
MeCOC6H4), arylmagnesium bromides were reacted with methylzinc
chloride.26 Arylmagnesium bromide (2 mmol) was prepared by addition of
isopropylmagnesium bromide (2.1 mmol) to a solution of aryl iodide (2 mmol)
in THF (4 ml) at ꢀ15 °C and stirring at that temperature for 1 hour to complete
the Br/Mg exchange.29 Arylmagnesium bromide (2 mmol) solution was added
to methylzinc chloride (2 mmol), freshly prepared by addition of
methylmagnesium bromide (2 mmol) to ZnCl2 (2 mmol) in THF (4 ml) at
ꢀ20 °C and the mixture was stirred at that temperature for 15 min. For the
alkyl coupling reaction of methylarylzincs,
a mixture of NiCl2 (10 mol %,
0.013 g), PPh3 (10 mol %, 0.0263) and primary alkyl iodide in THF (2 ml) was
cooled to 0 °C and freshly prepared methylarylzinc (2 mmol) was added
slowly. The reaction mixture was stirred at room temperature for 1 h and then
hydrolyzed by addition of 1 M HCl and subsequently extracted with Et2O. The
combined ethereal solutions were washed with aq NaHCO3 solution, dried and
aliquots were analyzed by GC.
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