H. Zipse, P. Knochel et al.
THF, in which the lithium atom can safely be assumed to
completely fill its first coordination shell, no large prefer-
ence for equatorial isomer trans-(eq)-4 can be found. How-
ever, this result is in clear contrast to the trapping experi-
ments performed at À1008C in Et2O/hydrocarbon solvents,
thus demonstrating a large or exclusive preference for equa-
torial isomers. Because the experimentally observed strong
stereochemical preference for equatorially substituted trans-
(eq)-4 may be due to aggregates that are formed at low tem-
peratures in weakly coordinating solvents, calculations were
also performed on the respective cyclohexyllithium aggre-
gates. A comparison of the gas-phase stabilities of dimers
yllithium reagents, whereas they displayed a stabilization
effect on 2-substituted neomenthyllithium neomen-(ax)-10.
An invertive reactivity pathway was found for the reaction
of thermodynamically less-stable axially substituted cyclo-
hexyllithium cis-(ax)-4 with organotin halides.
Experimental Section
Preparation of cis-(ax)-1:
A 1.0m solution of I2 (1.2 equiv, 15.2 g,
60 mmol) in CH2Cl2 (60 mL) was prepared in a flame-dried, Ar-flushed
Schlenk flask that was equipped with a stirrer bar and the solution was
cooled to 08C by using a Huber T100 cryostat. PPh3 (1.2 equiv, 15.7 g,
60 mmol) was added portion-wise and the resulting suspension was stir-
red for 1 h, before N-methyl-imidazole (1.2 equiv, 4.79 mL, 60 mmol) was
added. The reaction mixture became a bright-yellow suspension and
trans-4-(tert-butyl)cyclohexanol (1.0 equiv, 7.81 g, 50 mmol) was added
portion-wise. The resulting mixture was stirred for 15 h at 08C, before
being quenched with a saturated solution of NaHSO3 (50 mL). The
phases were separated and the aqueous phase was extracted with CH2Cl2
(3ꢃ50 mL). The combined organic layers were dried over Na2SO4 and
ACHTUNGTRENNUNG(trans-(eq)-4)2 and ACHTUNGTRENNUNG(cis-(ax)-4)2 only shows a small prefer-
ence (4.72 kJmolÀ1) for the equatorial isomer (Table 5,
entry 3). The hexameric structures found for nBuLi[20] (from
n-hexane) and cyclohexyllithium[21] (from benzene) indicate
that even-higher aggregates can easily be formed in less-
polar solvents. Therefore, equatorial/axial preference was
also explored for the hexameric form of cyclohexyllithium.
Despite the fact that this system now lacks the tBu anchor
at the 4-position of the cyclohexane ring, nevertheless, these
results are expected to be relevant to the substituted system.
The results obtained at the B3LYP or MP2 levels of theory
are quite clear about the strong preference for the all-equa-
the solvents were removed on
a rotary evaporator (358C, 8 mbar,
<30 min). The crude mixture was purified by column chromatography on
silica gel (i-hexane), the solvents were removed on a rotary evaporator
(358C, 8 mbar, <30 min), and the product was placed under high vacuum
(ꢃ10À3 mbar) at 308C to remove cyclohexene and any elimination by-
products. Neat cis-1-(tert-butyl)-4-iodocyclohexane (cis-(ax)-1) was ob-
tained as a white solid (7.5 g, 56% yield, d.r. 98:2). 1H NMR (599 MHz,
CDCl3): d=4.89 (br s, 1H), 2.13 (d, J=14.0 Hz, 2H), 1.68–1.62 (m, 2H),
1.60–1.47 (m, 4H), 1.08 (tt, 1J=11.5 Hz, 2J=3.3 Hz, 1H), 0.90 ppm (s,
9H); 13C NMR (151 MHz, CDCl3): d=47.8, 37.9, 36.9, 32.6, 27.4,
23.3 ppm; IR (ATR): n˜ =2956 (s), 2939 (vs), 2921 (m), 2885 (m), 2863
(m), 2845 (m), 2832 (m), 1482 (w), 1472 (w), 1444 (w), 1430 (m), 1418
(m), 1390 (w), 1366 (m), 1350 (w), 1308 (m), 1243 (m), 1232 (m), 1186
(s), 1016 (m), 996 (m), 851 (m), 764 (w), 652 nm (m); MS (70 eV, EI): m/
z (%): 266 (8) [M]+, 140 (11), 139 (100), 123 (15), 83 (47), 81 (21), 69
(17), 67 (18), 57 (69), 55 (17), 41 (14); HRMS (EI): m/z calcd for
C10H19I: 266.0531; found: 266.0530.
torial isomer, ACHTUNGTRENNUNG(trans-(eq)-18)6, over the all-axial isomer, ACHTUNGTERN(NUGN cis-
(ax)-18)6, in agreement with the conformation found in the
hexameric X-ray crystal structure.[21] The large energy differ-
ence of 71.3 kJmolÀ1 in favor of
ACHTNUTRGENNG(U trans-(eq)-18)6 implies a
preference of 11.9 kJmolÀ1 for the equatorial orientation in
each of the six monomers (Table 5, entry 4). Compared to
the equatorial/axial energy differences for the respective
tert-butyl-cyclohexyllithium monomers (trans-(eq)-4 and cis-
(ax)-4) and dimers (ACHTUNTRGENNUG(trans-(eq)-4)2 and ACHUTNGTERN(NNGU cis-(ax)-4)2), this
Preparation of cis-(ax)-5a: A solution of n-hexane /Et2O (3:2, 5.5 mL)
was prepared in a flame-dried, Ar-flushed Schlenk flask that was equip-
ped with a stirrer bar and the solution was cooled to À1008C by using a
Huber T100 cryostat. tBuLi (2.2 equiv, 1.3m in n-hexane, 0.84 mL,
1.1 mmol) was added by syringe. After 5 min, a 1.0m solution of cis-4-
tert-butyl-cyclohexyl iodide (cis-(ax)-1, 1.0 equiv, 134 mg, 0.5 mmol) in n-
hexane/Et2O (3:2, 0.5 mL) was added. The reaction mixture was
quenched after 4–5 s with neat S2Me2 (4 equiv, 0.18 mL, 2 mmol). After
stirring for 5 min at À1008C, a saturated aqueous solution of NH4Cl
(2 mL) was added. After warming to RT, the phases were separated and
the aqueous phase was extracted with Et2O (3ꢃ5 mL). The combined or-
ganic phase was dried over Na2SO4 and the solvents were evaporated.
Purification of the crude oil by column chromatography on silica gel
(i-hexane) provided thioether cis-(ax)-5a (68 mg, 73% yield, d.r. 90:10).
1H NMR (300 MHz, CDCl3): d=3.03 (br s, 1H), 2.06 (s, 3H), 1.95 (d, J=
14.1 Hz, 2H), 1.66 (tt, 1J=13.4 Hz, 2J=3.7 Hz, 2H), 1.59–1.49 (m, 2H),
1.49–1.34 (m, 2H), 1.07–0.96 (m, 1H), 0.86 ppm (s, 9H); 13C NMR
(75 MHz, CDCl3): d=48.4, 44.3, 32.6, 31.1, 27.5, 21.9, 14.8 ppm; IR
(ATR): n˜ =2938 (vs), 2930 (vs), 2864 (m), 2846 (m), 1478 (m), 1467 (m),
1440 (m), 1393 (w), 1365 (s), 1312 (m), 1263 (m), 1237 (w), 1227 (w),
1214 (m), 1024 (w), 865 (w), 770 (w); MS (70 eV, EI): m/z (%): 186 (8)
[M]+, 175 (28), 147 (25), 83 (10), 57 (22); HRMS (EI): m/z calcd for
C11H22S: 186.1442; found: 186.1443.
result implies that the state of aggregation may be a key de-
terminant for the stereochemical preference in substituted
cyclohexyllithiums.
Conclusion
In summary, we have described a practical preparation of
stereodefined cyclic secondary alkyllithium reagents from
their corresponding organic iodides. This stereoretentive
method allowed a detailed study of the thermodynamic sta-
bilities, stereochemical behavior, and reactivities of a wide
range of axially and equatorially substituted cyclohexyllithi-
um reagents.
Thus, it was possible to stereospecifically synthesize vari-
ous cis- and trans-cyclohexane derivatives by quenching with
several classes of electrophiles. We also found a clear ten-
dency of equilibration towards the equatorially substituted
lithium compounds. This thermodynamic phenomenon can
be explained by the formation of highly aggregated organo-
lithium species that display a large energy difference be-
tween the all-equatorial and all-axial species, as confirmed
by ab initio calculations. Polar solvents, such as THF, sped
up the equilibration process for axial 4-substituted cyclohex-
Preparation of trans-(eq)-5a: A solution of n-hexane/Et2O (3:2; 5.5 mL)
was prepared in a flame-dried, Ar-flushed Schlenk tube that was equip-
ped with a stirrer bar and the solution was cooled to À1008C by using a
Huber T100 cryostat. tBuLi (2.2 equiv, 1.3m in n-hexane 0.84 mL,
1.1 mmol) was added by syringe. After 5 min, a 1.0m solution of trans-4-
tert-butyl-cyclohexyl iodide (trans-(eq)-1, 1.0 equiv, 134 mg, 0.5 mmol) in
4620
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 4614 – 4622