1750 J . Org. Chem., Vol. 67, No. 6, 2002
Ren and Crudden
138.95, 128.29, 127.53, 127.40, 76.28, 70.10, 45.95, 35.49,
28.09, 27.66, 24.29, 21.06.
determined to be 32:68 in favor of the cis isomer by analyzing
crude mixture using (1H NMR). The cis and trans isomers
could be separated by column chromatography eluting with
49:1 hexane/EtOAc.
The aldehyde is not stable enough to be characterized by
elemental analysis or HRMS. The analysis was carried out on
the corresponding acid. cis-(2-Ben zyloxy)cycloh exyla cetic
a cid : IR (neat) 3030, 1700 cm-1; 1H NMR (400 MHz) (CDCl3)
δ 10.62 (brs, 1H), 7.35-7.27 (m, 5H), 4.60 (d, J ) 12.0 Hz,
1H), 4.40 (d, J ) 11.6 Hz, 1H), 3.62 (dt, J ) 2.8, 5.6 Hz, 1H),
2.59 (dd, J ) 7.2, 16.0 Hz, 1H), 2.33 (dd, J ) 6.8, 15.6 Hz,
1H), 2.16-2.06 (m, 1H), 1.98-1.88 (m, 1H), 1.66-1.30 (m, 7H);
13C {1H} NMR (100-MHz) (CDCl3) δ 177.85, 138.76, 128.31,
127.58, 127.45, 76.22, 70.21, 37.35, 36.32, 28.04, 27.39, 24.35,
20.85; HRMS (EI, 70 eV) calcd for M+ 248.1412, found
248.1393.
c i s -(3-t er t -B u t y ld i m e t h y ls i lo x y )c y c lo h e x y la c e t -
a ld eh yd e (17a -cis): IR (neat) 1724 cm-1; 1H NMR (400-MHz)
(CDCl3) δ 9.78 (t, J ) 2.4 Hz, 1H), 3.59 (tt, J ) 4.0, 10.4 Hz,
1H), 2.36 (dd, J ) 2.0, 6.8 Hz, 2H), 2.01-1.83 (m, 3H), 1.80-
1.71 (m, 1H), 1.70-1.63 (m, 1H), 1.37-1.14 (m, 2H), 1.12-
1.02 (m, 1H), 0.91-0.88 (m, 10H); 0.07 (s, 3H), 0.06 (s, 3H);
13C {1H} NMR (100 MHz) (CDCl3) δ 202.29, 70.88, 50.87, 42.64,
35.65, 31.95, 31.26, 25.86, 23.81, 18.16, -4.59, -4.64; HRMS
(EI, 70 eV) calcd for M+ - C4H9 199.1154, found 199.1164.
t r a n s-(3-t er t -Bu t yld im e t h ylsiloxy)cycloh e xyla ce t -
a ld eh yd e (17a -tr a n s): IR (neat) 1724 cm-1 1H NMR (400
;
tr a n s-(2-Ben zyloxy)cycloh exyla cet a ld eh yd e
(13c-
tr a n s): IR (neat) 1724 cm-1; H NMR (400 MHz) (CDCl3) δ
9.71 (dd, J ) 2.0, 3.2 Hz, 1H), 7.38-7.28 (m, 5H), 4.59 (d, J )
11.2 Hz, 1H), 4.39 (d, J ) 11.2 Hz, 1H), 3.01 (ddd, J ) 4.0, 9.6
Hz, 9.6 Hz, 1H), 2.60 (ddd, J ) 3.6, 7.2, 16.0 Hz, 1H), 2.25-
2.19 (m, 2H), 2.09-2.04 (m, 1H), 1.83-1.77 (m, 2H), 1.72-
1.65 (m, 1H), 1.32-1.20 (m, 3H), 1.16-1.04 (m, 1H); 13C {1H}
NMR (100 MHz) (CDCl3) δ 202.54, 138.36, 128.37, 127.99,
127.60, 81.65, 70.40, 48.52, 39.39, 37.92, 31.06, 25.43, 24.66.
The aldehyde is not stable enough to be characterized by
elemental analysis or HRMS, the analysis was carried out on
the corresponding acid. tr a n s-(2-Ben zyloxy)cycloh exyla ce-
1
MHz) δ 9.74 (t, J ) 2.8 Hz, 1H), 4.04 (m, 1H), 2.47-2.35 (m,
1H), 2.27-2.24 (m, 2H), 1.84-1.56 (m, 4H), 1.50-1.42 (m, 1H),
1.40-1.31 (m, 1H), 1.24-1.16 (m, 1H), 1.07-0.95 (m, 1H), 0.90
(s, 9H); 0.05 (s, 6H); 13C {1H} NMR (100 MHz) (CDCl3) δ
202.96, 66.62, 50.82, 40.29, 33.26, 32.55, 26.83, 25.79, 19.88,
18.05, -4.89, -4.92; HRMS (EI, 70 eV) calcd for M+ - C4H9
199.1154, found 199.1151.
3-Meth oxym eth oxycycloh exyla ceta ld eh yd e (17b). Hy-
droformylation of 3-methylene-1-methoxymethoxycyclohexanol
(16b) (507 mg, 3.25 mmol) was carried out in the presence of
[Rh(COD)Cl]2 (15.5 mg, 0.031 mmol) at room temperature for
64 h in a fashion analogous to that used for 2-methylene-1-
benzylcyclohexanol (12c). An internal NMR standard (p-
nitrotoluene) was added to measure the conversion (100%) and
NMR yield (70%). The diastereoselectivity was determined to
be 42:58 in favor of the cis isomer by analyzing crude mixture
(1H NMR). The cis and trans isomers could be separated by
column chromatography eluting with 9:1 hexane/EtOAc.
cis-(3-Meth oxym eth oxy)cycloh exyla ceta ld eh yd e (17b-
cis): IR (neat) 1728 cm-1; 1H NMR (400 MHz) (CDCl3) δ 9.77
(t, J ) 2.0 Hz, 1H), 4.68 (s, 2H), 3.54 (tt, J ) 4.4, 10.8 Hz,
1H), 3.37 (s, 3H), 2.37 (dd, J ) 2.0, 6.4 Hz, 2H), 2.08-1.90 (m,
3H), 1.84-1.77 (dp, J ) 3.6, 13.6 Hz, 1H), 1.73-1.65 (m, 1H),
1.39-1.27 (tq, J ) 3.6, 13.2 Hz, 1H), 1.24-1.12 (m, 1H), 1.08-
0.99 (q, J ) 12.0 Hz, 1H); 0.97-0.87 (dq, J ) 3.6, 12.0 Hz,
1H); 13C {1H} NMR (100 MHz) (CDCl3) δ 201.99, 94.52, 75.13,
55.16, 50.86, 39.50, 32.49, 32.07, 31.24, 23.80; HRMS (EI, 70
eV) calcd for M+ - C2H5O 141.0915, found 141.0918.
tic a cid : IR (neat) 3036, 1708 cm-1 1H NMR (400 MHz)
;
(CDCl3) δ 10.82 (brs, 1H), 7.36-7.28 (m, 5H), 4.68 (d, J ) 11.6
Hz, 1H), 4.45 (d, J ) 11.2 Hz, 1H), 3.08 (ddd J ) 4.4, 10.0,
10.0 Hz, 1H), 2.70 (dd, J ) 5.6, 15.6 Hz, 1H), 2.26-2.14 (m,
2H), 1.98-1.80 (m, 3H), 1.70-1.62 (m, 1H), 1.30-1.22 (m, 3H),
1.15-1.02 (m, 1H); 13C {1H} NMR (100 MHz) (CDCl3) δ 177.52,
138.22, 128.38, 127.87, 127.64, 81.73, 70.44, 40.31, 38.66,
31.60, 30.87, 25.34, 24.59; HRMS (EI, 70 eV) calcd for M+
248.1412, found 248.1396.
2-Me t h oxye t h oxym e t h oxycycloh e xyla ce t a ld e h yd e
(13e). Hydroformylation of 2-methylene-1-methoxyethoxymeth-
oxycyclohexanol (12e) (96.6 mg, 0.482 mmol) was carried out
in the presence of Rh(COD)2BF4 (2.4 mg, 0.0059 mmol) at room
temperature for 6 h in a fashion analogous to that used for
2-methylene-1-benzylcyclohexanol (12c). An internal NMR
standard (p-nitrotoluene) was added to measure the conversion
(42%) and NMR yield (41%). The diastereoselectivity was
determined to be 27:73 in favor of the trans isomer by
tr a n s-(3-Meth oxym eth oxy)cycloh exylacetaldeh yde (17b-
1
1
tr a n s): IR (neat) 1726 cm-1; H NMR (400 MHz) (CDCl3) δ
analyzing crude mixture using 400 H NMR. The cis and trans
9.76 (t, J ) 2.4 Hz, 1H), 4.68(d, J ) 0.8 Hz, 2H), 3.90 (m, 1H),
3.39 (s, 3H), 2.42-2.28 (m, 3H), 1.92-1.64 (m, 4H), 1.58-1.50
(m, 1H), 1.45-1.36 (m, 1H), 1.29-1.20 (m, 1H), 1.12-1.00 (m,
1H); 13C {1H} NMR (100 MHz) (CDCl3) δ 202.53, 94.68, 71.33,
55.23, 50.69, 37.23, 32.24, 30.20, 27.19, 20.26; HRMS (EI, 70
eV) calcd for M+ - C2H5O 141.0915, found 141.0913.
isomers could be separated by column chromatography eluting
with 85:15 hexane/EtOAc.
t r a n s-(2-Me t h o x y e t h o x y m e t h o x y )c y c lo h e x y la c e t -
a ld eh yd e (13e-tr a n s): IR (neat) 1724 cm-1 1H NMR (400
;
MHz) (CDCl3) δ 9.73 (dd, J ) 1.6, J ) 3.2 Hz, 1H), 4.81 (d, J
) 7.2 Hz, 1H), 4.64 (d, J ) 7.2 Hz, 1H), 3.70-3.67 (m, 2H),
3.58-3.55 (m, 2H), 3.41 (s, 3H), 3.22 (dt, J ) 4.0, 10.0 Hz,
1H), 2.59 (ddd, J ) 3.2, 6.8, J ) 16.0 Hz, 1H), 2.26-2.15 (m,
2H), 2.07-1.96 (m, 1H), 1.85-1.76 (m, 2H), 1.71-1.64 (m, 1H),
1.32-1.06 (m, 4H); 13C {1H} NMR (100 MHz) (CDCl3) δ 202.60,
93.93, 80.22, 71.73, 67.25, 59.01, 48.32, 39.07, 31.99, 31.87,
25.32, 24.57; HRMS (EI, 70 ev) calcd for M+ - C2H3O 187.1334,
found 187.1324.
c i s -(2-M e t h o x y e t h o x y m e t h o x y )c y c l o h e x y l a c e t -
a ld eh yd e (13e-cis): IR (neat) 1724 cm-1; 1H NMR (400 MHz)
(CDCl3) δ 9.80 (t, J ) 2.0 Hz, 1H), 4.77 (d, J ) 7.2 Hz, 1H),
4.70 (d, J ) 7.2 Hz, 1H), 3.76 (dt, J ) 3.2, 6.0 Hz, 1H), 3.73-
3.70 (m, 2H), 3.56 (t, J ) 4.4 Hz, 2H), 3.41 (s, 3H), 2.63 (ddd,
J ) 1.6, 6.4, 16.8 Hz, 1H), 2.36 (ddd, J ) 2.4, 7.2, 16.8 Hz,
1H), 2.29-2.21 (m, 1H), 1.87-1.78 (m, 1H), 1.62-1.32 (m, 7H);
13C {1H} NMR (100 MHz) (CDCl3) δ 202.72, 93.88, 75.04, 71.77,
67.13, 59.05, 45.82, 35.32, 29.04, 27.66, 24.01, 21.23; HRMS
(EI, 70 eV) calcd for M+ 230.1524, found 230.1518.
3-t er t -Bu t yld im e t h ylsiloxycycloh e xyla ce t a ld e h yd e
(17a ). Hydroformylation of 3-methylene-1-tert-butyldimeth-
ylsiloxylcyclohexanol (16a ) (626.0 mg, 2.77 mmol) was carried
out in the presence of Rh(COD)2BF4 (12.5 mg, 0.031 mmol) at
room temperature for 64 h in a fashion analogous to that used
for 2-methylene-1-benzylcyclohexanol (12c). An internal NMR
standard (p-nitrotoluene) was added to measure the conversion
(100%) and NMR yield (100%). The diastereoselectivity was
Ack n ow led gm en t. The Natural Sciences and En-
gineering Research Council of Canada (NSERC) is
gratefully acknowledged for support of this research in
terms of equipment and operating grants to C.M.C.
UNB is thanked for providing a Wiesner Award to L.R.
BioChem Pharma is also thanked for a scholarship to
L.R. Dr. Kazunori Hirabayashi and Mr. Timothy Lewis
are thanked for experimental efforts. Professors David
Magee, David Forbes, and Ilhyong Ryu and an anony-
mous reviewer are thanked for valuable suggestions.
Su p p or tin g In for m a tion Ava ila ble: Tables containing
yields and diastereomeric ratios for optimization of reaction
conditions in the hydroformylation of 9 and 12c. The effect of
parameters such as temperature, pressure, type and equiva-
lents of phosphine additives, CO/H2 ratios, and total pressure
are included. Spectroscopic data are included for trans-(2-
acetoxy)cyclohexylacetaldehyde (13a -tr a n s), trans-(2-meth-
oxymethoxy)cyclohexylacetic acid (from 13d -tr a n s), cis-(2-tert-
butyldimethylsiloxy)cyclohexylacetic acid (from 13f-cis), and
trans-(2-tert-butyldimethylsiloxy)cyclohexylacetic acid (from
13f-tr a n s). This material is available free of charge via the
Internet at http://pubs.acs.org.
J O001751M