Miles et al.
TABLE 4. Average Bond Lengths and Bond Angles for Lewis
Acids and Their Complexes
of the promoter. Syn addition is assumed to occur by formation
and subsequent collapse of a metalloxy-halide ion pair. The anti
addition process most likely proceeds by a higher order
mechanism in which the oxocarbenium ion electrophile and
halide nucleophile undergo antiperiplanar bonding on opposite
faces of the double bond.
M-X bond
O-M bond
C-O-M
Lewis acid
lengtha (Å)
lengthb (Å)
angleb (deg)
TiCl4
TiBr4
BCl3
BBr3
SnCl4
SnBr4
AlCl3
ZrCl4
InCl3
2.18
2.31
1.75
1.87
2.33
2.46
2.06
2.32
2.46
2.14 ( 0.07
1.58 ( 0.02
2.30 ( 0.1
1.88 ( 0.09
125 ( 12
115 ( 3
127 ( 10
136 ( 4
Experimental Section
Representative Halo-Prins Cyclization Procedure: Method
A (15a and 15b). A solution of 1 (50 mg, 0.26 mmol) in CH2Cl2
(3 mL) was stirred and cooled at -78 °C as 1.0 M TiCl4 (0.26
mL, 0.26 mmol) in CH2Cl2 was added over 30 s. The resulting
yellow solution was stirred for 1 min at -78 °C after which a
solution of Et3N (175 µL, 1.3 mmol) and MeOH (60 µL, 1.3 mmol)
in CH2Cl2 (2 mL) was slowly added. The suspension was stirred
for 10 min, warmed to room temp, stirred for an additional 10 min,
and diluted in Et2O (25 mL). The organic phase was washed with
10% aq HCl (2 × 5 mL), satd NaHCO3 (5 mL), and satd NaCl (5
mL), dried (MgSO4), and concentrated under reduced pressure to
afford 57 mg of a yellow oil. GC and 1H NMR analyses established
the yield (70%) and cis/trans ratio of 10:1. 15a: 1H NMR (500
MHz, CDCl3) δ 0.81 (t, 1H, J ) 12.5 Hz), 0.85 (d, 3H, J ) 6.4
Hz), 0.88 (m, 1H), 0.91 (s, 3H), 0.96 (dd, 1H, J ) 10.1, 5.6 Hz),
1.19 (s, 3H), 1.57-1.62 (m, 2H), 1.66 (ddd, 1H, J ) 13.1, 3.6, 2.4
Hz), 1.76 (dd, 1H, J ) 15.0, 4.10 Hz), 1.78-1.87 (m, 2H), 1.87
(dd, 1H, J ) 15.3, 4.8 Hz), 2.06 (ddd, 1H, J ) 14.8, 3.6, 2.3 Hz),
2.15 (ddd, 1H, J ) 15.2, 3.0, 2.4 Hz), 2.41 (br s, 1H, exch. D2O),
4.53 (app. quint, 1H, J ) 3.9 Hz); 13C NMR (126 MHz, CDCl3) δ
22.0, 22.5, 24.4, 27.4, 32.9, 33.3, 36.0, 46.2, 47.4, 50.8, 50.9, 57.3,
72.0; IR (neat) νmax 3592, 3479, 2947, 2867, 1455, 1370, 1265,
1167, 1009 cm-1; MS (EI, 70 eV) m/z (rel intensity %) 230 (13),
215 (88), 195 (30), 177 (25), 161 (27), 153 (100), 145 (20), 112
(62), 95 (21), 83 (45). Recrystallization from hexane gave an
analytical sample: mp 63-65 °C; [R]24D ) +2.7 (c ) 1.0, CHCl3).
15b: 1H NMR (500 MHz, CDCl3) δ 0.88 (d, 3H, J ) 6.6), 0.91
(s, 3H), 0.95 (dd, 1H, J ) 12.6, 3.2 Hz), 0.98 (s, 3H), 1.03 (t, 1H,
J ) 13.1 Hz), 1.12 (s, 1H, exch. D2O), 1.31 (qd, 1H, J ) 13.0, 3.5
Hz), 1.52 (ddd, 1H, J ) 13.5, 3.9, 2.4 Hz), 1.52 (t, 1H, J ) 12.4
Hz), 1.57 (t, 1H, J ) 12.4 Hz), 1.62 (dq, 1H, J ) 13.5, 3.4 Hz),
1.65-1.74 (m, 1H), 1.79 (app d quint, 1H, J ) 12.9, 3.3 Hz), 1.99
(ddd, 1H, J ) 12.8, 3.9, 2.5 Hz), 2.12 (ddd, 1H, J ) 12.9, 4.0, 2.5
Hz), 4.38 (tt, 1H, J ) 12.1, 4.0); 13C NMR (126 MHz, CDCl3) δ
21.4, 22.0, 22.1, 27.6, 31.7, 35.3, 35.7, 50.0, 50.5, 51.0, 52.4, 54.6,
73.8; IR (neat) νmax 3567, 3483, 2948, 2869, 1456, 1368, 1240,
1028, 775; MS (EI, 70 eV) m/z (rel intensity) 230 (24), 215 (100),
195 (16), 177 (13), 161 (27), 153 (36), 137 (26), 112 (34), 81 (48).
Recrystallization from hexane gave an analytical sample: mp 61-
a Reference 26. b Reference 27.
octahedral geometry when coordinated to a Lewis base.
However, while the more Lewis acidic titanium reagents gave
syn addition products, the weaker Lewis acids SnCl4, SnBr4,
and ZrCl4 resulted in anti addition. The relatively weaker Lewis
acidities of the tin and zirconium halides28f result in slower rates
of cyclization and/or ion pair collapse, and thus, the higher order
pathway leading to anti addition predominates.
Complexes of AlCl3, BCl3, and BBr3 have pseudotetrahedral
geometry and relatively short bond lengths, but they gave
opposite stereochemistry in the halo Prins cyclizations. The
stronger Lewis acidities of the boron halides compared to those
of the corresponding aluminum halides are well documented,28f
which together with the smaller C-O-B bond angles of the
boron complexes, accounts for this apparent inconsistency. The
reaction temperature and reaction times with BCl3, BBr3, and
SnCl4 are similar (Table 3), implying comparable Lewis acidity
toward the carbonyl substrate. Thus, it is somewhat surprising
that boron halides are syn selective while SnCl4 is anti selective.
Presumably, the shorter bond lengths in the BX3 complexes and
ion pairs would place the halide ligands in closer proximity to
the syn face of the δ carbon than the Cl ligand would be in the
intermediates from SnCl4. Most of the relative rates for the metal
chlorides estimated from reaction times (Table 3) parallel the
electropositive character of the metals: TiCl4 > ZrCl4 and BCl3
> AlCl3 > GaCl3 > InCl3.28
Conclusions
The Lewis acid-mediated Prins cyclization of δ,ꢀ-unsaturated
ketones provides a promising method for stereocontrolled
synthesis of cis and trans bromo- and chlorocyclohexanols, and
hindered tertiary alcohols readily derived from them. The
capability to tolerate steric hindrance is illustrated by the syn
cyclization of enone 2 to chlorohydrin 21a in which hydroxyl,
chloro, and two methyl substituents occupy four of the five
available axial positions on the trans decalin nucleus. Consistent
syn selectivities were observed for cyclizations onto unsubsti-
tuted and δ-methyl substituted enones in the presence of TiCl4,
TiBr4, BCl3, and BBr3, while a variety of other Lewis acids
were trans selective. The slower cyclizations of enones bearing
methyl groups on the terminal carbon gave trans chlorohydrins.
The stereochemistry seems to correlate with the Lewis acidity
62 °C; [R]24 ) +5.2 (c ) 1.0, CHCl3).
D
Method B (22a and 22b). A slurry of finely crushed TiBr4 (0.58
g, 1.54 mmol) in CH2Cl2 (20 mL) was vigorously stirred at -78
°C as a solution of 1 (0.30 g, 1.54 mmol) in CH2Cl2 (3 mL) was
slowly added. After the solution was stirred at -78 °C for 15 min,
buffered methanolysis at 0 °C with Et3N (1.1 mL, 7.7 mmol) and
MeOH (0.31 mL, 7.7 mmol) in CH2Cl2 (3 mL) and ether extraction
as described above in method A afforded 0.41 g of a yellow oil.
1
GC and H NMR analyses on the crude product established the
yield (76%) and cis/trans ratio of 15:1. Purification by flash
chromatography on silica gel (98:2 hexane/Et2O) of the yellow oil
afforded 0.28 g (65%) of cis bromohydrin 22a as a colorless oil
that crystallized upon standing and 0.029 g (7%) of trans bromo-
hydrin 22b as a colorless oil that crystallized at 0 °C. 22a: 1H
NMR (500 MHz, CDCl3) δ 0.83 (app. q, 2H, J ) 12.4 Hz), 0.85
(d, 3H, J ) 6.4 Hz), 0.90 (s, 3H), 0.95 (app. q, 1H, J ) 4.7 Hz),
1.19 (s, 3H), 1.56 (qd, 1H, J ) 13.1, 3.2 Hz), 1.59 (dd, 1H, J )
6.4, 3.4 Hz), 1.65 (dt, 1H, J ) 13.3, 2.4 Hz), 1.79 (dm, 2H, J )
11.0 Hz), 1.86 (dd, 1H, J ) 15.0, 4.3 Hz), 2.01 (dd, 1H, J ) 15.4,
5.2 Hz), 2.17 (ddd, 1H, J ) 15.0, 4.7, 1.7 Hz), 2.21 (s, 1H), 2.25
(28) (a) Paul, R. C.; Dhindsa, K. S.; Ahluwalia, S. C.; Narula, S. P. Indian
J. Chem. 1970, 8, 549-551. (b) Cook, D. Can. J. Chem. 1963, 41, 522-
526. (c) Paul, R. C.; Ahluwalia, S. C.; Rehani, S. K.; Pahil, S. S. Indian J.
Chem. 1965, 3, 207-212. (d) Luo, Y.-R.; Benson, S. W. Inorg. Chem.
1991, 30, 1676-1677. (e) Laszlo, P.; Teston, M. J. Am. Chem. Soc. 1990,
112, 8750-8754. (f) Satchell, D. P. N.; Satchell, R. S. Chem. ReV. 1969,
69, 251-278.
1500 J. Org. Chem., Vol. 71, No. 4, 2006