3
À
Table 2: Diastereoselective C(sp ) C(sp) coupling of 3-substituted
cyclohexylzinc reagents.
modest diastereoselectivity (68:32 d.r.; Table 1, entry 1). On
switching to palladium catalysts, we found that the complex
[PdCl2(tmpp)2]
(tmpp = tris(2,4,6-trimethoxyphenyl)phos-
phine)[15] provided 4a with a high d.r. of 95:5. We also
observed the formation of some regioisomeric product
(ca. 4%).[16] This diastereoselectivity could be further
improved by replacing the phosphine ligand tmpp with
various bipyridines (6a,b; entry 3) and orthophenanthrolines
(7a–d; entry 4). The N ligands clearly proved to be superior.
The commercially available and inexpensive neocuproine[17]
(7b) combined excellent diastereoselectivity with the low
formation of regioisomers (< 2%). PdCl2 was found to be the
best Pd source and switching from Pd to Ni as the catalyst
resulted in a deterioration of the d.r. (87:13 d.r.; entry 7).
Bidentate N ligands are known to stabilize Pd0 more effi-
ciently than monodentate phosphines,[17b] thus leading to a
faster reductive elimination and minimizing unwanted
b-hydride elimination and the formation of regioisomeric
products.
Entry
Product
Yield [%][a]
d.r.[b]
1
2
3
4
4a: R=Ph
82
87
77
98:2
94:6
97:3
94:6
96:4[c]
4b: R=4-NC-C6H4
4c: R=(CH2)2OTBS
4d: R=TIPS
79
76[c]
5
6
4e: R=4-NC-C6H4
4 f: R=(CH2)2OTBS
85
74
95:5
97:3
The 3-substituted cyclohexylzinc reagent 1a was subse-
quently subjected to cross-coupling reactions with a range of
1-bromoalkynes 3a–d in the presence of the optimized
catalyst system (2 mol% PdCl2, 4 mol% 7b). The expected
thermodynamically preferred cis-1,3-disubstituted cyclohex-
ane derivatives[18] were obtained with good yields and
excellent diastereoselectivities (94:6 to 98:2 d.r.; Table 2,
entries 1–5). Bromoalkynes bearing aromatic (3a,b), aliphatic
(3c), and silyl moieties (3d) were successfully coupled.
Increasing the steric bulk of the substituent from iPr to tBu
on the cyclohexylzinc reagent did not have an effect on the
diastereoselectivity or yield (compare 4c (77%; 97:3 d.r.) and
4 f (74%; 97:3 d.r.); entries 3 and 6). Replacing the relatively
large iPr group with the sterically much less demanding
methyl group only led to a slight loss of diastereoselectivity
(compare 4a (82%; 98:2 d.r.) with 4g (79%; 96:4 d.r.);
entries 1 and 7). Functionalized cyclohexylzinc reagents
bearing an OTBS (OSiMe2tBu) functionality underwent the
palladium-catalyzed cross-coupling reactions with equally
high diastereoselectivities (96:4 to 98:2 d.r.; 4i,j; entries 9
7
8
4g: R=Ph
4h: R=4-NC-C6H4
79
88
96:4
96:4
9
10
4i: R=TIPS
4j: Ar=(CH2)2OTBS
81
94
98:2
96:4
[a] Yield of the isolated analytically pure product. [b] Determined by GC
analysis on a capillary column before and after purification. The
percentage of regioisomers produced as by-products was between 0–
5%. See the Supporting Information for details. [c] 6b (4 mol%) was
used. TIPS=triisopropylsilyl.
Steric interactions between the ligand on the palladium
center and the substituent on the cyclohexyl ring dictate the
stereochemical outcome of these diastereoselective cross-
coupling reactions. The stereocontrol is assumed to be
effected by a selective transmetalation step between the
respective cyclohexylzinc reagents and the alkynyl-
(bromo)palladium complex, which leads to the formation of
the thermodynamically most stable palladium intermediates.
Subsequent reductive elimination proceeds with retention of
configuration and furnishes the corresponding 1,3- and 1,4-
disubstituted products with high diastereoselectivity.[11]
and 10).
3
À
Next, we performed C(sp ) C(sp) coupling reactions with
the 4-substituted cyclohexylzinc reagents 2a–c (Table 2). To
our delight, the diastereoselectivity was as high as those
obtained for the coupling reactions of the 3-substituted
cyclohexylzinc iodides (94:6 to 98:2 d.r.; compare Tables 2
and 3), showing an excellent remote stereocontrol. In all
cases, the thermodynamically favored trans-1,4-disubstituted
cyclohexanes were preferentially formed (Table 3).[18] As for
the 3-substituted cyclohexylzinc reagents, the size of the
respective substituents only had a minor effect on the
diastereoselectivity. Thus, cyclohexylzinc reagent 2a bearing
a bulky tBu group furnished the coupling products 5a–d with
ꢀ 96:4 d.r. (Table 3, entries 1–4), while the coupling reactions
of the methyl-substituted zinc reagent 2b resulted in a slightly
lower d.r. of 95:5 (entries 5 and 6). Cross-coupling reactions
of the functionalized organozinc iodide 2c also proceeded
highly diastereoselectively (95:5 to 96:4 d.r.) to provide the
trans-configured products 5g–i in excellent yields (88–94%;
entries 7–9).
trans-1,4-Disubstituted cyclohexanes,[19] including their
alkynyl-substituted derivatives,[20] constitute important build-
ing blocks for liquid crystals because of their unique proper-
ties, such as low viscosity coefficients and higher optical
anisotropy. Our new coupling procedure offers a direct and
highly stereoselective route to such compounds (Table 3).
Supramolecular chirality can be induced in liquid crystals by
the use of chiral dopants.[21] Since menthyl-capped dopants[22]
have already been applied successfully to amplify chirality in
liquid crystals, we envisioned the synthesis of 8, which may
Angew. Chem. Int. Ed. 2011, 50, 2174 –2177
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2175