Highly diastereoselective Csp3 -Csp 2 Negishi cross-coupling with 1,2-, 1,3- and 1,4-substituted cycloalkylzinc compounds

Article abstract of DOI:10.1038/nchem.505

Stereoselective functionalizations of organic molecules are of great importance to modern synthesis. A stereoselective preparation of pharmaceutically active molecules is often required to ensure the appropriate biological activity. Thereby, diastereoselective methods represent valuable tools for an efficient set-up of multiple stereocentres. In this article, highly diastereoselective Csp³ Negishi cross-couplings of various cycloalkylzinc reagents with aryl halides are reported. In all cases, the thermodynamically most-stable stereoisomer was obtained. Remarkably, this diastereoselective coupling was successful not only for 1,2-substituted cyclic systems, but also for 1,3- and 1,4-substituted cyclohexylzinc reagents. The origin of this remote stereocontrol was investigated by NMR experiments and density functional theory calculations. A detailed mechanism based on these experimental and theoretical data is proposed.

Full text of DOI:10.1038/nchem.505

ARTICLES
PUBLISHED ONLINE: 17 JANUARY 2010 | DOI: 10.1038/NCHEM.505
Highly diastereoselective Csp3–Csp2 Negishi
cross-coupling with 1,2-, 1,3- and 1,4-substituted
cycloalkylzinc compounds
Tobias Thaler1, Benjamin Haag1, Andrei Gavryushin1, Katrin Schober2, Evelyn Hartmann2,
Ruth M. Gschwind2, Hendrik Zipse1, Peter Mayer3 and Paul Knochel1
*
Stereoselective functionalizations of organic molecules are of great importance to modern synthesis. A stereoselective
preparation of pharmaceutically active molecules is often required to ensure the appropriate biological activity. Thereby,
diastereoselective methods represent valuable tools for an efficient set-up of multiple stereocentres. In this article, highly
diastereoselective Csp3 Negishi cross-couplings of various cycloalkylzinc reagents with aryl halides are reported. In all
cases, the thermodynamically most-stable stereoisomer was obtained. Remarkably, this diastereoselective coupling was
successful not only for 1,2-substituted cyclic systems, but also for 1,3- and 1,4-substituted cyclohexylzinc reagents. The
origin of this remote stereocontrol was investigated by NMR experiments and density functional theory calculations. A
detailed mechanism based on these experimental and theoretical data is proposed.
alladium-catalysed Csp3 cross-coupling reactions are impor- (Table 1, entries 2 and 3). Cross-coupling with heteroarylbromides,
tant methods for preparing complex organic molecules1–11
.
either electron-poor (such as 5-bromopyrimidine) or electron-rich
The possibility of forming these C–C bonds in a stereocon- (such as ethyl 5-bromofuroate), led to the desired alkylated
trolled manner further increases their synthetic potential12–14
P
.
adducts 10 and 11 with d.r. ¼ 98:2 (Table 1, entries 4 and 5). The
Thus, a number of chiral ligands for asymmetric palladium- and method was extended to isopulegylzinc chloride (1b), which under-
nickel-catalysed cross-couplings have been developed success- went highly diastereoselective cross-coupling reactions with methyl
fully15–23. In their pioneering work, Hayashi, Kumada and co- 4-iodobenzoate (8b, 72%, d.r. .99:1), 4-iodoanisole (5b, 71%, d.r.
workers showed that secondary alkylmagnesium and -zinc reagents .99:1) and 3-iodo-2-cyclohexenone29 (9b, 64%, d.r. ¼ 99:1)
allow the preparation of chiral cross-coupling products18,22,23. The (Table 1, entries 6–8). In all cases, the thermodynamically favoured
zinc or magnesium organometallics used in these reactions are con- diastereomer was formed, as shown by X-ray analysis (see
figurationally labile and subject to epimerization at the carbon–metal Supplementary Information).
bond. Herein, we report highly diastereoselective Negishi cross-
couplings24 on various substituted cycloalkylzinc reagents. These gave 12 (Table 2). The methyl group is less bulky than an isopropyl
an unexpected remote 1,3- and 1,4-stereocontrol. group and its steric influence may be expected to be less pro-
This method was extended to 2-methylcyclohexylzinc chloride
In our initial experiments, we prepared menthylzinc halides 1a and nounced. Even so, a high diastereoselectivity was observed when
2 either by treating menthylmagnesium chloride25 (3a) with zinc chlor- 12 was reacted with methyl 4-iodobenzoate in the presence of
ide (1.1 equiv., tetrahydrofuran (THF), 25 8C, ten minutes, 81%) or Pd(dba)2 and S-Phos at 225 8C, and the cross-coupling product
by the reaction of neomenthyl iodide26 (4) with zinc powder and 13 was obtained with 82% yield and d.r. ¼ 99:1 (Table 2, entry 1).
lithium chloride27 (THF, 25 8C, six hours, 78%) (Table 1).
Rearrangement reactions, such as those observed by Molander
The resulting menthylzinc reagents 1a and 2 were then subjected and co-workers30, can be largely avoided at this low temperature.
to palladium-catalysed cross-couplings with aryl halides at room Remarkably, we found that similarly high stereoselectivities were
temperature. Pd(PPh3)4 or Pd(dibenzylideneacetone)2 (Pd(dba)2) obtained with cyclohexylzinc reagents bearing substituents at pos-
with dicyclohexyl(20,60-dimethoxybiphenyl-2-yl)phosphine (S- ition 4, such as zinc compounds 14a and 14b, or at position 3,
Phos (ref. 28)) (1:1) were used as catalysts. To our delight, the such as 17a–17c. Owing to the remoteness of the substituents a
trans-cross-coupling products were obtained with high diastereo- large steric effect is not expected. Therefore, we subjected 4-methyl-
meric purities (diastereomeric ratio (d.r.) ¼ 96:4 to ꢀ99:1) and cyclohexylzinc chloride (14a) to a Negishi cross-coupling with
63–81% yields (Table 1). Thus, the reaction of menthylzinc chloride methyl 4-iodobenzoate (Pd(PPh3)4, 2 mol%, 25 8C, 15 hours).
1a with 4-iodoanisole in the presence of Pd(dba)2 (1 mol%) and The cross-coupling product 15a was obtained with a high diastereo-
S-Phos (1 mol%, 25 8C, four hours) in a mixture of THF and meric ratio of 92:8 (Table 2, entry 2). By screening several catalyst
N-ethyl-2-pyrrolidone (NEP) (6 vol%) furnished the arylated systems and reaction conditions, it was further possible to
menthyl-derivative 5a in 78% yield and d.r. .99:1 (Table 1, entry 1). increase this diastereoselectivity to d.r. ¼ 95:5 (for details see the
Similarly, the cross-coupling reactions with 1-chloro-4-iodobenzene Supplementary Information). A 2:1 combination of tris(2,4,6-tri-
and 1-iodo-3-(trifluoromethyl)benzene produced the expected methoxyphenyl)phosphine (TMPP)31 and PdCl2 was found to be
products 6a and 7a with d.r. ¼ 98:2 and 96:4, respectively the most diastereoselective catalyst system. Using these conditions,
1Department Chemie und Biochemie, Ludwig-Maximilians-Universita¨t Mu¨nchen, Butenandtstrasse 5-13, Haus F, 81377 Mu¨nchen, Germany, 2Institut fu¨r
Organische Chemie, Universita¨t Regensburg, Universita¨tsstrasse 31, 93040 Regensburg, Germany, 3Department Chemie und Biochemie, Ludwig-
Maximilians-Universita¨t Mu¨nchen, Butenandtstrasse 5-13, Haus D, 81377 Mu¨nchen, Germany. e-mail: paul.knochel@cup.uni-muenchen.de
*
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Table 1 | Cross-coupling products obtained with menthyl-
and isopulegylzinc halides (the major diastereomers are
shown).
Table 2 | Cross-coupling products obtained with 2-, 4- and
3-substituted cyclohexylzinc halides (the major
diastereomers are shown).
Ar-I (0.7 equiv.)
Pd(dba)2 (1 mol%),
S-Phos (1 mol%)
R-I,
Me
Me
Pd(dba)2 (1 mol%)
S-Phos (1 mol%)
Ar
ZnCl
ZnCl2
THF, NEP (6 vol%),
–25 °C, 12 h,
then –15 °C, 6 h
MgCl
ZnCl
R
THF, 25 °C,
10 min
THF, NEP (6 vol%),
25 °C, 4–6 h
or –10 °C, 15 h
12
13
3a (menthyl)
3b (isopulegyl)
1a, 1b: 81%
5a, 5b, 6a, 7a, 8b, 9b
R1
R2
R2
R1
Ar-I (0.7 equiv.)
(TMPP)2PdCl2 (2 mol%)
Ar-I (0.7 equiv.)
(TMPP)2PdCl2 (2 mol%)
Hetaryl-Br
Pd(PPh3)4 (5 mol%)
Zn, LiCl
THF, NEP (6 vol%),
–10 °C, 12–15 h
THF, NEP (6 vol%),
–10 °C, 12–15 h
THF, 25 °C,
6 h
ZnCl
Ar
THF, NEP (10 vol%),
25 °C, 15 h
Hetaryl
I
ZnI–LiCl
ZnCl
Ar
17a R2 = Me
17b R2 = i-Pr
17c R2 = CF3
18a–18c, 19a, 19b, 20a,
22a, 22b, 23a, 23b
14a R1 = Me
14b R1 = t-Bu
15a, 15b, 16b
4
2: 78%
10, 11
Entry
Product
Yield (%)*, Entry
d.r.†
Product
Yield (%)*,
d.r.†
Entry
Product
Yield (%)*, Entry
d.r.†
Product
Yield (%)*,
d.r.†
Me
82, 99:1‡
8
85, 95:5**
1
5
CO2Me
1
Me
N
O
CO2Et
78, .99:1
81, 98:2‡
CF3
13
OMe
21a
11
5a
Me
i-Pr
2
84, 95:5
89, 92:8§
9
70, 96:4#
2
3
4
6
CF3
CO2Me
Cl
19b
71, 98:2
72, .99:1
8b
6a
CO2Me
15a
7
t-Bu
i-Pr
CF3
3
59, 95:5
10
86, 96:4
OMe
63, 96:4
71, .99:1
7a
5b
CO2Me
18b
CO2Me
8
15b
O
N
76, 98:2‡
64, 99:1§
N
t-Bu
i-Pr
4
60, 94:6
11
71, 95:5
9b
10
In the equations shown, a double bond with a dashed line indicates a single bond or a double bond
according to the structures given in the table. *Isolated yield of analytically pure product.
†Determined by capillary GC analysis before and after purification. ‡Pd(PPh3)4 (5 mol%) was
used as catalyst. §The cross-coupling reaction was carried out at 210 8C.
Me
O
22b
CF3
16b
18a
19a
Me
i-Pr
5
77, 97:3
96:4k
12
71, 97:3#
4-substituted cyclohexylzinc chlorides, such as 14a and 14b,
furnished the thermodynamically favoured trans-4-substituted
products (15a, 15b and 16b) with diastereoselectivities up to 95:5
(Table 2, entries 2–4).
CO2Et
96:4}
CO2Me
23b
Similarly, 3-substituted cyclohexylzinc chlorides (17a–17c) pro-
vided the cis-cross-coupling products (18a–18c, 19a, 19b, 20a, 21a,
22b and 23b) with d.r. up to 97:3 (Table 2, entries 5–13). The rela-
tive stereochemistry of 18a was determined by X-ray analysis (see
Supplementary Information). The diastereoselectivities were not
affected by the bulkiness or the nature of the ring substituents.
For example, the cross-couplings of 3-methylcyclohexyl- (17a), 3-
isopropylcyclohexyl- (17b) and 3-trifluoromethylcyclohexylzinc
chloride (17c) with methyl 4-iodobenzoate furnished the respective
products 18a, 18b and 18c with similar diastereoselectivities (d.r. ¼
96:4 to 97:3; Table 2, entries 5, 10 and 13). Indeed, these stereo-
selective Negishi cross-coupling reactions could be extended to
various cyclic systems, including cyclopentanes, bicyclic com-
pounds and steroids (Fig. 1). Thus, cross-coupling of 2-isopropyl-
cyclopentylzinc chloride (24) (prepared from 1-chloro-2-
isopropylcyclopentane (25) via magnesium insertion and trans-
metallation with ZnCl2) with methyl 4-iodobenzoate furnished
selectively the trans-product 26 (96%, d.r. ¼ 96:4). An excellent
Me
CF3
6
7
70, 96:4# 13
74, 96:4
CF3
CO2Me
18c
Me
81, 95:5**
O
20a
*Isolated yield of analytically pure product. †Determined by capillary GC analysis before and after
purification. ‡5% of regioisomer detected. §The reaction was performed at room temperature using
Pd(PPh3)4 (2 mol%) as catalyst. kd.r. obtained when a large excess (5 equiv.) of electrophile was
used. }d.r. obtained when a large excess (5 equiv.) of zinc reagent was used. #The reaction was
carried out at 25 8C. **The reaction was carried out with 3-methylcyclohexylzinc iodide
(prepared via zinc insertion) at room temperature using Pd(PPh3)4 (5 mol%) as catalyst.
126
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ARTICLES
I
CO2Me
Pd(dba)2 (1 mol%)
i-Pr
i-Pr
i-Pr
CO2Me
1. Mg, THF
S-Phos (1 mol%)
Cl
ZnCl
THF, NEP (6 vol%),
25 °C, 15 h
2. ZnCl2,THF
25
24: 67%
26: 96%, d.r. 96:4
Me
Me
Me
I
CO2Me
Pd(dba)2 (1 mol%)
S-Phos (1 mol%)
Me
Me
Me
Me
Me
Me
1. Mg, THF
Cl
THF, NEP (6 vol%),
–25 °C, 15 h
2. ZnCl2, THF
CO2Me
ZnCl
28
27: 62%
29: 65%, d.r. 95:5
Me
Me
I
OMe
Me
Me
Me
Pd(dba)2 (1 mol%)
S-Phos (1 mol%)
Me
Me
Me
Me
Me
,
THF, NEP (6 vol%)
25 °C, 8 h
H
H
H
H
ClZn
MeO
30
31: 86%, d.r. 97:3
Figure 1 | Diastereoselective cross-coupling with various cycloalkylzinc reagents. The thermodynamically most-stable diastereomers were obtained
in Negishi-type cross-couplings between 1,2-substituted cyclopentyl-, isopinocampheyl- and cholesterylzinc reagents and aryl iodides (Ar–I).
Diastereoselectivities were determined by capillary GC analysis (26 and 29) or by 1H NMR spectroscopic analysis (31). The relative stereochemistry
of 31 was determined by X-ray analysis (see Supplementary Information).
H
Me
ZnCl
H
H
ZnCl
Me
Me
ZnCl
H
H
eq-14a(trans)
ax-14a(cis)
eq-14a(cis)
L
L
L
PdL2
Ar Pd
L
X
Fast
Ar Pd
X
Slow
Slow
Ar Pd
X
Ar-X
L
L
32
32
32
H
H
L
Me
H
PdL2Ar
Me
PdAr
Me
PdL2Ar
H
L
eq-33(trans)
ax-33(cis)
eq-33(cis)
Reductive elimination
Reductive elimination
Ar
Me
Me
Ar
H
trans-34
cis-34
Figure 2 | Mechanistic proposal for the diastereoselective cross-coupling of substituted cycloalkylzinc reagents with aryl iodides. The diastereomeric
organozinc complexes eq-14a(trans), ax-14a(cis) and eq-14a(cis) are in equilibrium. Transmetallation occurs preferentially between the aryl–palladium
complex 32 and the organozinc reagent eq-14a(trans), which leads to the thermodynamically most-stable palladium complex eq-33(trans) in which all non-
hydrogen substituents of the cyclohexyl ring occupy equatorial positions. The formation of the palladium complexes ax-33(cis) and eq-33(cis) is disfavoured
for steric reasons. Reductive elimination furnishes the trans-product trans-34 selectively.
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ARTICLES
Table 3 | Conformational analysis of the diastereomeric zinc and palladium complexes based on DFT calculations.
298
eq–ax
298
Entry
Organozinc complexes, DG
and DE0,eq–ax
Organopalladium complexes, DG
and DE0,eq–ax
eq–ax
(kcal mol21)*
(kcal mol21)*
THF
Cl
THF
PMe3
Me
PMe3
Ph
Me
THF
Zn
Me
Pd
Me3P
Pd
Me3P
Zn
Ph
THF
Me
Cl
1
eq-12
ax-12
eq-35
ax-35
20.55, 21.29
24.85, 25.02
THF
THF
Cl
Zn
PMe3
Ph
THF
PMe3
Ph
Me
Zn
Pd
THF
Pd
Me3P
Cl
2
Me
Me
Me3P
Me
eq-17a
ax-17a
eq-36
ax-36
20.68, 0.10
22.88, 22.59
THF
PMe3
Ph
THF
PMe3
Cl
THF
Zn
Pd
Pd
Me3P
Zn
Ph
THF
Me
Me
Me3P
Cl
Me
Me
3
4
5
eq-14a
ax-14a
eq-37
ax-37
20.51, 20.04
22.08, 22.37
Me
Ph
Cl
Me3P
Pd
i-Pr
THF
Me
THF
Me3P Pd PMe3
Zn
Ph
PMe3
Zn
i-Pr
i-Pr
THF
THF
Me
Me
Cl
i-Pr
eq-1a
ax-1a
eq-38
ax-38
20.77, 20.36
29.84, 210.08
i-Pr
i-Pr
H
PMe3
Cl
H
i-Pr
i-Pr
PMe3
Cl
Zn
Pd Ph
PMe3
THF
THF
Zn
Pd
THF
THF
Ph
H
H
PMe3
trans-25
cis-25
trans-39
cis-39
20.43, 0.10
25.54, 25.03
*Calculated energetic difference (B3LYP/631SVP) between the thermodynamically lowest conformers of the two diastereomers.
diastereoselectivity was also observed with isopinocampheylzinc mixture may be responsible for this fast equilibration. The transme-
chloride (27) (prepared from isopinocampheyl chloride32 (28)) tallation of the zinc reagent eq-14a(trans) with ArPdL2X (32),
which gave the arylated product 29 (65%, d.r. ¼ 95:5). Finally, the cho- obtained by Pd(0)-insertion into an aryl halide (Ar-X), preferentially
lesterylzinc chloride 30 (prepared from cholesteryl chloride33) was led to the palladium intermediate eq-33(trans) provided that
arylated with 4-iodoanisole to give the steroid 31 (86%, d.r. ¼ 97:3). the transmetallation occurred with retention of the configuration38.
The performance of cross-coupling reactions with 17a using a The alternative formation of the palladium intermediates ax-33(cis)
large excess (5 equiv.) of methyl 4-iodobenzoate or the zinc and eq-33(cis) is disfavoured for steric reasons. In both of these
reagent 17a (5 equiv.) also led to the cross-coupling product 18a conformers either the palladium moiety or the methyl group occupies
with diastereoselectivities similar to those under standard conditions the axial position. This results in repulsive interactions with the
(0.7 equiv. of the electrophile) (d.r. ¼ 96:4 compared to 97:3; see bulky phosphine ligands on the palladium (as shown by density
Table 2, entry 5)34. Based on these observations, we propose a ten- functional theory (DFT) calculations, see below). After reductive
tative mechanism in which the conformers and both diastereomers elimination the trans-product trans-34 was obtained selectively
of the cyclohexylzinc complex (eq-14a(trans), ax-14a(cis) and from eq-33(trans) (Fig. 2).
eq-14a(cis), Fig. 2) (where the ax/eq notation describes the position
To obtain an insight into the energetic differences between the
of the metal substituent and the cis/trans notation describes the palladium intermediates of type 33 and to verify our mechanistic
relative stereochemistry of the metal and the methyl substituents proposal, we used DFT to carry out a conformational analysis
on the cyclohexyl ring) are in equilibrium. Although the carbon– on the respective organozinc and organopalladium complexes.
zinc bond is reported to be stable configurationally35,36, it was Comparison of the energetically lowest conformers showed that
shown that the presence of metallic salts facilitates its epimeriza- only small and insignificant thermodynamic differences exist
tion37 and the presence of PdX2, MgX2, ZnX2 or LiCl in the reaction between the diastereomeric cycloalkylzinc chloride complexes
128
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ARTICLES
a
b
Hα
H
Heq
OMe
OMe
XmLnPd
~
MeO
P PdCl2
Me
Hα
Heq
Hax
3
2
Me
Hax
Hax
H
H
)
(30 mol%
d8-THF, –10 °C
Heq
Me
PdLnXm
ZnCl
17a
40
2.5
2.0
Figure 3 | NMR studies on the transmetallation of 3-methylcyclohexylzinc chloride (17a) to give (TMPP)2PdCl2. a,b, A one-dimensional section from the
1H31P-HMBC spectrum (a) shows the proton signals from the palladium intermediate (see 33 in Fig. 2). The most intense of the cyclohexyl signals at
d ¼ 2.8 ppm represents the methine signal that shows the strongest coupling with the phosphorus atom of the TMPP ligand (3JHP). The neighbouring
methylene protons show signals in the region from d ¼ 1.4 ppm to 1.7 ppm with lower intensities (4JHP). 3JHH-coupling of 11 Hz (+0.5 Hz) in the methine signal,
which corresponds to a coupling of axial protons, identifies the structure to be of type 40 in which the palladium moiety occupies the equatorial position (b).
(less than 0.77 kcal mol21 in free energy for zinc complexes 1a, 12,
14a, 17a and 25; Table 3) (for details see the Supplementary
Information). However, the corresponding organopalladium com-
plexes (35–39) show a significant change in thermodynamic energies
Methods
Preparation of 1-((1R,2R,5R)-2-isopropenyl-5-methylcyclohexyl)-4-
methoxybenzene (5b). A dry and argon-flushed 10 ml Schlenk tube, equipped
with a magnetic stirring bar and a septum, was charged with ZnCl2 (1.2 mmol,
1.2 ml of a 1.0 M THF solution) and NEP (0.12 ml, 10 vol%). A solution of
that favour the diastereomers with all substituents in equatorial pos-
itions. The calculations demonstrate that considerable repulsive inter-
actions between the substituents on the cycloalkyl moiety and the
phosphine ligands on palladium increase the energy gap between
the diastereomeric complexes up to 9.84 kcal mol21 in free energy
(Table 3). This energy increase becomes experimentally significant
isopulegylmagnesium chloride (0.62 M in THF, 1.0 mmol, 1.61 ml) in THF was
added at 25 8C. The reaction mixture was stirred for ten minutes. In a second dry and
argon-flushed 10 ml Schlenk flask, a solution of Pd(dba)2 (0.01 mmol, 5.75 mg),
S-Phos (0.01 mmol, 4.11 mg) and 4-iodoanisole (0.7 mmol, 0.164 g) in THF
(0.7 ml) was stirred for five minutes and the organozinc reagent was added.
The reaction progress was monitored by gas chromatography (GC) analysis.
Conversion was complete after six hours. The reaction mixture was quenched with
and accounts for the diastereoselectivities observed in the cross- saturated NH4Cl(aq) solution (2 ml), and water was added (2 ml). The phases were
separated and the aqueous phase extracted with Et2O (3 ꢁ 10 ml). The combined
organic layers were dried over Na2SO4 and the solvents were evaporated. The crude
product was purified via column chromatography (SiO2, n-pentane:Et2O 40:1).
The arylated product 5b (121 mg) was obtained as a colourless oil in
71% yield (d.r. . 99:1).
The preparation of 5b is representative for the cross-coupling of menthyl-,
isopulegyl-, isopinocampheyl-, cholesteryl-, 2-methylcyclohexyl- and
isopropylcyclopentylzinc reagents. The respective reaction temperatures are
indicated in Tables 1 and 2, and in Fig. 1.
coupling reactions. For instance, complex ax-37, which has a
methyl substituent in the axial position, is strongly disfavoured
compared with eq-37 by 2.08 kcal mol21, which explains why the
cross-coupling reaction only proceeds via intermediate eq-37 (or
via eq-33(trans) and not via ax-33(cis) or eq-33(cis) in Fig. 2).
To substantiate the results from the theoretical calculations,
which suggested that the diastereoselectivity results from a fast
transmetallation of the cycloalkylzinc reagent to the palladium
complex, we carried out NMR studies on the reaction of 3-methyl-
cyclohexylzinc chloride (17a) with (TMPP)2PdCl2 in d8-THF
(0.3 M) at 210 8C (Fig. 3).
Preparation of methyl 4-(cis-3-isopropylcyclohexyl)benzoate (18b). A dry and
argon-flushed 10 ml Schlenk tube, equipped with a magnetic stirring bar and a
septum, was charged with 1.2 ml (1.2 mmol) of a solution of ZnCl2 in THF (1.0 M)
and NEP (0.12 ml, 10 vol%). A solution of 3-isopropylcyclohexylmagnesium
chloride (0.70 M in THF, 1.0 mmol, 1.43 ml) in THF was added at 25 8C.
The reaction mixture was stirred for ten minutes. In a second dry and argon-
flushed 10 ml Schlenk flask, a solution of TMPP2PdCl2 (0.02 mmol, 25 mg)
Many signals of several zinc species (17a and aggregates) and
palladium complexes were detected in the NMR spectra. However,
using 1H31P heteronuclear multiple bond correlation (HMBC)
analysis, only one 31P chemical shift simultaneously displayed and methyl 4-iodobenzoate (0.7 mmol, 0.183 g) in THF (0.7 ml) was prepared and
cross-signals with the cyclohexyl and aromatic 1H-signals. This
shows that only one palladium intermediate was present in a detect-
able amount. J-coupling between the proton signals in the cyclo-
hexyl ring identified the intermediate as a structure of type 40
(Fig. 3) in which the palladium occupies the equatorial position
(3JHH-coupling was detected at 11 Hz (+0.5 Hz), which corre-
sponds to a coupling of axial protons; for details and spectra see
the Supplementary Information). These results confirm the confor-
mational preferences of the tentative mechanism proposed in Fig. 2.
In summary, we have shown that Csp3–Csp2 cross-coupling reac-
tions of variously substituted six- and five-membered cycloalkylzinc
reagents proceed with high diastereoselectivities. The best rational-
ization is to assume an equilibration of the zinc reagents and
preferential formation of the most-stable eq-palladium intermediate
cooled to 210 8C. Subsequently, the organozinc reagent was added slowly. The
reaction progress was monitored by GC analysis. Conversion was complete after
12 hours. The reaction mixture was quenched with saturated NH4Cl(aq) solution
(2 ml), and water was added (2 ml). The phases were separated and the aqueous
phase extracted with Et2O (3 ꢁ 10 ml). The combined organic layers were dried over
Na2SO4 and the solvents were evaporated. The crude product was purified via
column chromatography (SiO2, n-pentane:Et2O 30:1). The arylated product
18b (140 mg) was obtained as a colourless oil in 86% yield (d.r. ¼ 96:4). The
preparation of 18b is representative for the cross-coupling of 3- and 4-substituted
cyclohexylzinc reagents, for which the respective reaction temperatures are
indicated in Table 2.
DFT calculations. These were carried out using the Gaussian03 Rev.B.04 program
package39 with the non-local hybrid B3LYP exchange-correlation functionals40–43
.
The basis set, denoted as 631SVP, consists of the Ahlrich def2-SVP all-electron basis
set44 for zinc atoms, all-electron and ECP for palladium atoms and the 6-31G(d,p)
basis set45–47 for other atoms (see Supporting Information for full details of the
(for example, eq-33(trans)), as supported by DFT calculations and computational study).
NMR experiments. Further mechanistic studies and applications to
more functionalized ring systems and heterocycles are being inves-
tigated in our laboratories.
Received 21 August 2009; accepted 27 November 2009;
published online 17 January 2010
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129
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.505
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Acknowledgements
We thank the European Research Council, the Fonds der Chemischen Industrie, the
Sonderforschungsbereich 749 and the Deutsche Forschungsgemeinschaft for financial
support. We also thank Evonik Degussa GmbH, BASF AG, W. C. Heraeus GmbH,
Chemetall GmbH and Solvias AG for generous gifts of chemicals.
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Author contributions
T.T. and A.G. planned, conducted and analysed the experiments. B.H. and H.Z. planned
and analysed the DFT calculations. B.H. conducted the DFT calculations. T.T., K.S., E.H.
and R.M.G. planned and conducted the NMR experiments. K.S., E.H. and R.M.G. analysed
the NMR experiments. P.M. performed the X-ray analysis. P.K. designed and directed the
project and wrote the manuscript, with contributions from T.T., B.H. and R.M.G. All
authors except P.M. contributed to discussions.
Additional information
The authors declare no competing financial interests. Supplementary information and
chemical compound information accompany this paper at www.nature.com/
naturechemistry. Reprints and permission information is available online at http://npg.nature.
com/reprintsandpermissions/. Correspondence and requests for materials should be
addressed to P.K.
25. Beckmann, J., Dakternieks, D., Draeger, M. & Duthie, A. New insights into the
classic chiral Grignard reagent (1R,2S,5R)-menthylmagnesium chloride. Angew.
Chem. Int. Ed. 45, 6509–6512 (2006).
130
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