(+)-Camphor-derived amino alcohols as ligands for the catalytic enantioselective addition of diethylzinc to benzaldehydes

Article abstract of DOI:10.1016/S0957-4166(01)00295-6

1,7,7-Trimethyl-3-(pyrid-2-ylmethyl)bicyclo[2.2.1]heptan-2-ol 4 and its 2-phenyl, 2-methyl and 2-butyl analogs 5-7 were synthesized, characterized and used as ligands for the addition of diethylzinc to benzaldehydes. Best results were attained with 5 mol%

Full text of DOI:10.1016/S0957-4166(01)00295-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1771–1777
(+)-Camphor-derived amino alcohols as ligands for the catalytic
enantioselective addition of diethylzinc to benzaldehydes
Marta Nevalainen† and Vesa Nevalainen*
Department of Chemistry, PO Box 55, University of Helsinki, FIN-00014 Helsinki, Finland
Received 7 June 2001; accepted 26 June 2001
Abstract—1,7,7-Trimethyl-3-(pyrid-2-ylmethyl)bicyclo[2.2.1]heptan-2-ol 4 and its 2-phenyl, 2-methyl and 2-butyl analogs 5–7 were
synthesized, characterized and used as ligands for the addition of diethylzinc to benzaldehydes. Best results were attained with 5
mol% of amino alcohol trans-4 (2-exo,3-endo), in hexane/toluene at rt. Thus, (1S)-1-phenylpropanol was obtained in 96% yield
and 89% e.e. An increase of the size of the 2-substituent had a dramatic effect on enantioselectivity and yield. © 2001 Elsevier
Science Ltd. All rights reserved.
1. Introduction
The rigidity of camphor-based 1,4-amino alcohols has
been proven to efficiently control the addition of
organozinc reagents to aldehydes.6 As a continuation of
our ongoing research on the design and synthesis of
new and inexpensive chiral ligands for catalytic enan-
tioselective reactions,7 we decided to synthesize new
amino alcohols with the camphor skeleton. Herein, we
report the synthesis and characterization of a series of
2-(pyridylmethyl)borneols and isoborneols8 and their
use as precursors of chiral catalysts for the enantiose-
lective addition of diethylzinc to benzaldehyde.
Oguni and Omi first reported1 the ability of chiral
2-amino alcohols to catalyze the enantioselective addi-
tion of diethylzinc to benzaldehyde. After that report, a
wide variety of related reactions have been described in
the literature and excellent levels of enantioselection
have been achieved.2–8 2-Amino alcohols are particu-
larly suitable ligands for this reaction as they react with
dialkylzinc to give a zinc alkoxide. The zinc atom of the
zinc alkoxide then coordinates to the nitrogen of the
2-amino group, leading to the formation of a five-mem-
bered chelate. Both of the reaction mechanisms
suggested4 for the addition of alkylzinc reagents to
aldehydes are based on the formation of a Zn-chelate.
2. Results and discussion
The installation of a pyridylmethyl group at the alpha
position of the carbonyl group of (+)-camphor was
attained following the method described in the litera-
ture.9 Thus, the sodium enolate of camphor was reacted
with pyridine-2-carbaldehyde to give enone 29d (Scheme
1). Hydrogenation of 2 on Pd/C in ethanol rendered
ketone 3 as a 2:1 exo/endo mixture of diastereoisomers
(Scheme 1). That mixture can be isomerized to the endo
diastereoisomer by treatment with sodium methoxide in
methanol, as reported for the benzylidene analog of 3.9a
Although the catalytic properties of 2-amino alcohols
have been extensively studied,4 the utility of 3- or
4-amino alcohols2 as ligands for the addition of
diethylzinc to aldehydes is clearly less well understood.
Some 3- and 4-amino alcohols with rigid structures
have been reported to efficiently catalyze4–6 this reac-
tion. In those cases, the zinc atom is potentially part of
a six- or seven-membered ring. Such chelates seem to be
sufficiently stable due to the rigidity of the ligand that
limits the conformational freedom of the O- and N-
atoms.
Reduction of a 7.5:1 endo/exo mixture of ketone 3 with
LiAlH4 in THF afforded alcohol 4 as a ca. 1:1 mixture
of cis-/trans-diastereoisomers. The relative stereochem-
istry of the newly formed stereocenter was assigned on
* Corresponding author. Fax: +358
nevalainen@helsinki.fi
9 191 50466; e-mail: vesa.
† Present address: Laboratory of Organic Chemistry, Department of
Chemical Technology, Helsinki University of Technology, PO Box
6100, FIN-02015 Helsinki, Finland. E-mail: marta.nevalainen
@hut.fi
the basis of coupling constants (JH2 H3
benzylidene analog of 4 as a model.9a Thus, JH2 H3
13.6 Hz for 2-endo,3-endo, 12.4 Hz for 2-exo,3-exo and
,
), taking the
,
is
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00295-6

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M. Ne6alainen, V. Ne6alainen / Tetrahedron: Asymmetry 12 (2001) 1771–1777
Scheme 1. Synthesis of 3-(2-pyridylmethyl)borneols and -isoborneols 4–7.
4.0 Hz for 2-exo,3-endo. Separation of that mixture by
flash chromatography rendered cis-4 as a 3.2:1 mixture
of 2-endo,3-endo/2-exo,3-exo diastereoisomeric alco-
hols, and trans-4 (2-exo,3-endo) as a pure isomer
(Scheme 1).
the catalyst at various temperatures indicates that the
active center of the catalyst is conformationally stable.
In that light we conclude that fixing the conformation
of three bonds of a seven-membered Zn-chelate pro-
vides enough rigidity to achieve good catalytic perfor-
mance. A similar tolerance towards variations of
reaction parameters was observed with the catalyst
loading. Indeed, when the reaction was carried out at
40°C with only 1 mol% of ligand (entry 11), the
decrease in the yield and e.e. was almost negligible.
Lowering the amount of catalyst even further (to a level
of 0.1 mol%) had a negative effect on those parameters
(entry 12). However, the enantioselectivity of the reac-
tion decreased only by about 10%. A similar catalyst
behavior was observed by Hanyu et al.6f with their
camphane-based 1,4-amino alcohols, and by Knoll-
muller et al.6d with their (2-exo,3-exo)-2-hydroxy-3-(2-
aminoethyl) derivatives of (+)-camphor, in which the
amino group was not aromatic.
The small size of hydride allows both the endo and exo
diastereomers of endo-3 to be formed, the addition of
more bulky nucleophiles such as PhLi or MeLi failed.
However, the mentioned organometallic reagents added
to ketone exo-3 in polar solvents on the less hindered
endo side,10 affording alcohols 5 and 6 (Scheme 1). The
yields of these additions were low as expected,10 due to
steric hindrance on the carbonyl group. Moreover, a
competing base-promoted enolization takes place, as
indicated by the deep red colors of the reaction mix-
tures. In contrast to those results, the addition of BuLi
to a 2:1 exo/endo mixture of 3 in hexane provided an
inseparable mixture of diastereomeric alcohols 7. Prob-
ably, the exo attack was in that case possible as a result
of the increased nucleophilicity of BuLi in an apolar
solvent. When a 7.5:1 endo/exo mixture of 3 was
treated with EtMgBr in THF no ethyl addition product
was formed. Instead, cis-4 was obtained as a 6:1 mix-
ture of 2-endo,3-endo/2-exo,3-exo alcohols. Similar
reductions of hindered ketones have been described in
the literature.11 It is interesting to note that EtMgBr is
a more facially selective reducing agent than LiAlH4 for
the preparation of 2-endo,3-endo-4 via reduction of 3.
Ligand cis-4 showed a much poorer performance than
the trans isomer. Indeed, under the best reaction condi-
tions determined for trans-4 (2-exo,3-endo) (entry 1),
cis-4 (3.2:1 2-endo,3-endo/2-exo,3-exo mixture) pro-
vided (R)-1-phenylpropanol in 84% yield and 52% e.e.
(entry 2). When a 6:1 mixture of 2-endo,3-endo/2-exo,3-
exo-4 was used, the e.e. improved only slightly (entry
3). This result seems to indicate that 2-endo,3-endo-4
(less crowded) is significantly more active than the
2-exo,3-exo isomer (more crowded). Because 2-exo-OH
and 2-endo-OH derivatives of camphor are known to
produce opposite enantiomers of 1-phenylpropanol,4b,6d
and if 2-exo,3-exo-4 would be contributing to the e.e., a
clear change in enantioselectivity could be expected as a
result of lowering the amount of that ligand. (R)-1-
Phenylpropanol was obtained with ligand cis-4 (2-
endo,3-endo) [the opposite enantiomer was attained
with trans-4 (2-exo,3-endo)] probably because the side
of the C(2)ꢀOꢀZn plane exposed by the Zn-chelate to
the reagents for coordination is the opposite to that
Ligands 4–7 were subsequently used in the catalytic
addition of diethylzinc to benzaldehyde. The conditions
used and the results obtained are summarized in Table
1.
When trans-4 (2-exo,3-endo) (5 mol%) was used to
catalyze the addition of diethylzinc to benzaldehyde at
22°C, (S)-1-phenylpropanol was formed in 96% yield
and 89% e.e. (entry 1, Table 1). Those results did not
improve either by lowering (entry 9), nor by increasing
(entry 10) the temperature. This steady performance of

M. Ne6alainen, V. Ne6alainen / Tetrahedron: Asymmetry 12 (2001) 1771–1777
1773
Table 1. Enantioselective synthesis of 1-phenylpropanol via addition of diethylzinc to benzaldehyde catalyzed by the Zn-
chelates of ligands 4–7
Entry
R
Ligand (mol%)
T (°C)
t (h)
Solvent
Yielda (%)
Eeb (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
MeO
MeO
Cl
Cl
trans-4c (5)
cis-4e (5)
cis-4f (5)
5 (5)
6 (5)
22
22
22
22
22
22
22
22
−22
35
40
40
22
22
22
22
4
12
12
24
24
24
12
0.5
24
1
1
1
4
6
8
10
Hex./Tol.d
Tol.
Tol.
Tol.
Tol.
96
84
80
89 (S)
52 (R)
56 (R)
8 (R)
40 (1.3:1)g
52 (2.7:1)g
8 (S)
7 (5)
Tol.
Tol.
32 (1:1)g
86
14 (R)
87 (S)
88 (S)
87 (S)
87 (S)
86 (S)
76 (S)
78 (S)
22 (R)
87 (S)
54 (R)
trans-4c (2.5)
trans-4c (10)
trans-4c (5)
trans-4c (5)
trans-4c (1)
trans-4c (0.1)
trans-4c (5)
cis-4f (5)
Hex./Tol.d
Hex./Tol.d
Hex./Tol.d
Hex./Tol.d
Hex./Tol.d
Hex./Tol.d
Hex./Tol.d
Hex./Tol.d
Hex./Tol.d
98
93
98
97
81
90
79
92
9
10
11
12
13
14
15
16
trans-4c (5)
cis-4f (5)
88
a Isolated yield.
b Determined by HPLC (Chiralcel OD, hex./IPA 95:5, 1.0 mL/min, 254 nm; 1-phenylpropanol: tR (R)=11.3 min, tR (S)=12.2 min; 1-(p-MeO-
phenyl)propanol: tR (R)=13.7 min, tR (S)=14.9 min; 1-(p-Cl-phenyl)propanol: tR (R)=11.5 min, tR (S)=10.7 min).3e
c 2-exo,3-endo
d 1:1 mixture.
e 3.2:1 2-endo,3-endo/2-exo,3-exo mixture.
f 6:1 2-endo,3-endo/2-exo,3-exo mixture.
g Ratio 1-phenylpropanol/benzyl alcohol.
exposed in the case of ligand trans-4 (2-exo,3-endo).
This hypothesis is supported by the observed chirality
transfer from ligands cis- and trans-4, which is in
agreement with that reported for DAIB4a,b,c and other
(+)-camphor based catalysts.6d,e (−)-DAIB (exo-OH) as
well as trans-4 (2-exo,3-endo) catalyze the formation of
(S)-1-phenylpropanol as the major enantiomer, mean-
while (+)-DAIB (endo-OH) and 2-endo,3-endo-cis-4
favor the (R)-enantiomer.
zaldehyde. The presence of the electron donating
methoxy group did not alter the reaction yield, but
decreased the enantioselectivity of the reaction when
both trans- and cis-4 were used (entry 13 versus 1, and
14 versus 2). A chlorine atom at the 4-position of the
benzene ring had no effect on the yield or in the
selectivity of the reaction (entry 15 versus 1, and 16
versus 2).
The results obtained with ligands 5–7, which contain a
bulkier group (Ph, Me and Bu; entries 4–6, Table 1) on
C(2) are consistent with the poor performance of 2-
exo,3-exo-4 discussed above. When the Zn-chelates
derived from 5–7 were used as catalysts, both the
reaction yield and the enantioselectivity decreased dra-
matically. Furthermore, the bigger the 2-substituent,
the more benzyl alcohol formed (see Table 1). This
indicates that the active metal center of the catalyst is
too crowded and, therefore, it cannot coordinate simul-
taneously the reagent and the substrate. This conclu-
sion is in agreement with the observation made by
Hanyu et al.,6f that 2-endo-methyl,2-exo-hydroxyl sub-
stituted camphor 1,4-amino alcohol derivatives exhibit
a poor catalytic performance.
3. Conclusion
In summary, we have synthesized 5 new (+)-camphor-
based amino alcohols [cis- and trans-4 (2-exo,3-endo),
5–7, Scheme 1], and used them as ligands for the
enantioselective addition of diethylzinc to benzalde-
hydes (Table 1). The seven-membered Zn-chelate
derived from 2-exo,3-endo-4 gave the best chemical
yield and highest enantioselectivity (96 and 89%,
respectively), among the compounds studied. Because
1,4-amino alcohols 4–7 might serve as useful chiral
ligands for other types of enantioselective reactions,
further studies on those ligands for the purposes of
catalytic enantioselective synthesis are in progress. A
computational study on the properties of intermediates
of the reactions catalyzed by the diastereomeric Zn-
chelates discussed above will be published in due
course.
3-(Pyridylmethyl)borneols 4 were used also to catalyze
the addition of diethylzinc to p-MeO and p-Cl ben-

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M. Ne6alainen, V. Ne6alainen / Tetrahedron: Asymmetry 12 (2001) 1771–1777
4. Experimental
(13.3 g, 55.0 mmol, 28%). Rf=0.32 (silica, hex./AcOEt
6:1). [h]2D01=+267 (c 1.17, CHCl3) (Lit.9d +208 c M/100,
dioxan). H NMR (CDCl3): l 8.67 (m, 1H), 7.68 (ddd,
J=7.6 Hz, J=7.6 Hz, J=1.6 Hz, 1H), 7.38 (d, J=8.0
Hz, 1H), 7.18 (m, 1H), 7.17 (s, 1H), 3.75 (d, J=4.4 Hz,
1H), 2.21–2.12 (m, 1H), 1.82–1.74 (m, 1H), 1.52 (m,
2H), 1.04 (m, 3H), 1.02 (m, 3H), 0.83 (m, 3H). 13C
NMR (CDCl3): l 208.9, 152.2, 149.9, 145.8, 136.1,
126.0, 125.6, 122.5, 57.3, 49.4, 46.1, 30.7, 26.1, 20.8,
18.2, 9.3. HRMS calcd for M++H (C16H20NO)
242.1543; found 242.1539.
4.1. General
1H NMR spectra were recorded on a Varian spectrom-
eter at 400 MHz and are reported in ppm downfield
from SiMe4. J values are given in Hz. 13C NMR spectra
were recorded on a Varian spectrometer at 100 MHz.
HRMS were conducted on a Bruker BioApex 47e
Fourier transform ion cyclotron resonance mass spec-
trometer (ES+). Optical rotations were measured on a
Perkin–Elmer polarimeter at rt, using a cell of 1 dm of
length and u=598 nm. Data are reported as follows:
[h]tDemp (solvent, concentration in g/100 mL). HPLC
analyses were performed using a Waters system with
UV detector. The column, detector wavelength, flow
rate and solvents were as denoted. The retention times
(tR) for the enantiomers are reported. Melting points
(mp) were performed on a Gallenkamp apparatus,
using open capillary tubes. Values are given in degrees
Celsius (uncorrected). Analytical thin layer chromatog-
raphy (TLC) was performed on Merck silica gel plates
with QF-254 indicator. Visualization was accomplished
with UV light. Flash chromatography was performed
using Merck silica gel 60 (40–63 mm).
4.3. 1,7,7-Trimethyl-3-(pyrid-2-ylmethyl)bicyclo[2.2.1]-
heptan-2-one 3
In a 250 mL 3-necked round-bottomed flask under
argon was suspended 5% Pd/C (600 mg) in EtOH (150
mL). Enone 2 (6.0 g, 24.9 mmol) in EtOH (10 mL) was
added, argon was replaced by hydrogen and the mix-
ture was stirred at rt (balloon pressure) for 24 h. The
suspension was then filtered through a short pad of
Celite with the aid of EtOH (2×50 mL), and the solvent
was evaporated under reduced pressure. The residue
was purified by flash chromatography (silica, hex./
AcOEt 8:1 and 4:1). A clear oil was obtained (5.0 g,
20.6 mmol, 83%), which corresponded to the title com-
pound as a 2:1 exo:endo mixture of diastereoisomers.
Rf=0.11 (silica, hex./AcOEt 8:1). [h]2D0=+45.9 (c 1.30,
Solvents were dried using standard procedures.12 Cam-
phor and diethylzinc (1.1 M in tol.) were purchased
from Fluka. 2-pyridylcarbaldehyde and benzaldehyde
were obtained from Fluka and were distilled/purified
previous to use. Butyllithium (1.6 M in hexanes),
methyllithium (1.6 M in Et2O), EtMgBr (1.0 M in
THF) were purchased from Aldrich. All moisture-sensi-
tive reactions were performed in oven-dried glassware
(12 h, 120°C), which was allowed to cool to rt over
phosphorous pentoxide in a dessicator.
1
CHCl3). H NMR (CDCl3): l 8.54 (m, 1H), 7.60 (m,
1H), 7.17 (m, 1H), 7.12 (m, 1H), 7.17 (s, 1H), 3.35 and
3.26 (2dd, J=14.4 Hz, J=4.4 Hz and J=14.4 Hz,
J=5.2 Hz, 1H), 3.01 and 2.48 (m and dd, J=9.6 Hz,
J=4.0 Hz, 1H), 2.79–2.68 (m, 1H), 2.05–1.91 (m, 2H),
1.80–1.46 (m, 2H), 1.41–1.31 (m, 1H), 0.97, 0.95, 0.94,
0.93, 0.89 (5s, 9H). 13C NMR (CDCl3): l 220.6, 160.9,
160.3, 149.3, 136.3, 136.2, 123.1, 121.2, 58.7, 57.6, 54.6,
50.2, 47.1, 46.8, 46.3, 45.8, 39.8, 35.6, 31.2, 29.2, 29.3,
21.8, 20.4, 20.4, 19.6, 19.2, 9.5, 9.4. HRMS calcd for
M++H (C16H22NO) 244.1705; found 244.1695.
4.2. 1,7,7-Trimethyl-3-(pyrid-2-ylmethylidene)bicyclo-
[2.2.1]heptan-2-one 29d
In a 1 L three-necked round-bottomed flask under Ar
was placed camphor (30.0 g, 0.20 mol) in dry benzene
(300 mL). Sodium (5.0 g, 0.22 mol) was added and the
resulting mixture was heated under reflux for 18 h,
cooled to rt and the excess of sodium removed. The
reaction mixture was cooled to 0°C, 2-pyridylcarbalde-
hyde (28 mL, 0.29 mol) was added dropwise, stirring
was continued for 3 h at rt and then the dark red
solution was poured into water (500 mL). The layers
were separated and the aqueous phase extracted with
AcOEt (4×200 mL). The combined organic extracts
were washed with water (3×200 mL), dried (MgSO4),
filtered and the solvent removed under reduced pres-
sure. The crude was purified by flash chromatography
(silica, hex./AcOEt 7:1 and 3.2:1) to render a yellowish
semi-solid, which was dissolved in Et2O (200 mL) and
extracted with 3% HCl (4×50 mL). The acidic phase
was washed with Et2O (50 mL), basified with 5%
NaOH (200 mL) and extracted with Et2O (3×50 mL),
which was washed with H2O (3×50 mL), dried
(MgSO4), filtered and the solvent evaporated in vac-
4.4. Isomerization to the endo product
In a 250 mL round-bottomed flask under argon was
dissolved sodium (0.85 g, 37.0 mmol) in dry MeOH (75
mL). Ketone 3 (2:1 exo:endo mixture) (2.0 g, 8.2 mmol)
in dry MeOH (5 mL) was added and the resulting
mixture was heated under reflux (bath temperature:
80°C) for 24 h, cooled to rt, poured into a saturated
NH4Cl solution (400 mL) and extracted with Et2O
(4×150 mL). The combined organic extracts were
washed with H2O (3×100 mL), dried (MgSO4), filtered
and the solvent evaporated under reduced pressure. The
target was obtained as a clear oil (2.0 g, 8.2 mmol,
quant.) (7.5:1 endo:exo mixture). [h]2D0=+82.6 (c 1.38,
1
CHCl3). H NMR (CDCl3) l 8.53 (m, 1H), 7.60 (ddd,
J=7.6 Hz, J=7.6 Hz, J=2.0 Hz, 1H), 7.18 (d, J=8.0
Hz, 1H), 7.12 (m, 1H), 3.26 (dd, J=14.4 Hz, J=5.2 Hz,
1H), 3.02 (m, 1H), 2.72 (dd, J=14.4 Hz, J=10.0 Hz,
1H), 1.96 (m, 1H), 1.80–1.67 (m, 2H), 1.41–1.34 (m,
1H), 0.97 (s, 3H), 0.93 (s, 3H), 0.89 (s, 3H). 13C NMR
(CDCl3): l 220.5, 160.3, 149.3, 136.2, 123.1, 121.2, 58.7,
50.2, 46.3, 45.8, 35.6, 31.2, 20.4, 19.6, 19.2, 9.5.
uum.
1,7,7-Trimethyl-3-(pyrid-2-ylmethylidene)-bicy-
clo[2.2.1]heptan-2-one was obtained as a yellow liquid

M. Ne6alainen, V. Ne6alainen / Tetrahedron: Asymmetry 12 (2001) 1771–1777
1775
4.5. 1,7,7-Trimethyl-3-(pyrid-2-ylmethyl)bicyclo[2.2.1]-
heptan-2-ol 4
dried (MgSO4), filtered and the solvent evaporated
under reduced pressure. The residue was purified by
flash chromatography (silica, hex./AcOEt 4:1) render-
ing cis-4 as an oil (330 mg, 1.3 mmol, 46%) and a
mixture 6:1 2-endo,3-endo/2-exo,3-exo and recovered
starting material (300 mg, mmol, 43%). [h]2D0 +34.1 (c
1.59, MeOH).
In a 100 mL 3-necked round-bottomed flask under
argon was suspended LiAlH4 (0.5 g, 13.2 mmol) in dry
THF
(15
mL).
1,7,7-Trimethyl-endo-3-(pyrid-2-
ylmethyl)-bicyclo[2.2.1]heptan-2-one (3, 750 mg, 3.1
mmol) in dry THF (10 mL) was added dropwise, the
resulting mixture was stirred overnight at rt, cooled to
0°C, quenched slowly with 5% NaOH (30 mL), diluted
with Et2O (30 mL) and saturated with Na2SO4. The
resulting heterogeneous mixture was stirred for 15 min,
filtered with the aid of Et2O (3×10 mL), dried (MgSO4),
filtered and the solvent evaporated under reduced pres-
sure. The residue was purified by flash chromatography
(silica, hex./AcOEt 4:1 and 2:1). The cis isomer was
obtained as an oil (330 mg, 1.3 mmol, 44%) and a
mixture 3.2:1 2-endo,3-endo/2-exo,3-exo. The trans iso-
mer (2-exo,3-endo) was obtained as white waxy solid
(270 mg, 1.1 mmol, 36%).
4.7. 1,7,7-Trimethyl-2-phenyl-3-(pyrid-2-ylmethyl)-
bicyclo[2.2.1]heptan-2-ol 5
In a 25 mL two-necked round-bottomed flask under
argon was placed freshly distilled bromobenzene (1.05
mL, 10.0 mmol) in dry THF (4 mL). The solution was
cooled to −78°C, BuLi (1.6M in hexanes, 7.0 mL, 11.2
mmol) was added dropwise and stirring was continued
for 1 h. 1,7,7-Trimethyl-3-(pyrid-2-ylmethyl)-bicyclo-
[2.2.1]heptan-2-one 3 (7:3 exo:endo) (500 mg, 2.06
mmol) in dry THF (1 mL) followed dropwise and the
resulting solution was allowed to warm from −78°C to
rt overnight. The reaction mixture was treated with sat.
NH4Cl solution (10 mL), the layers were separated and
the aqueous phase was extracted with ether (3×5 mL).
The combined organic extracts were washed with brine
(20 mL), dried (MgSO4), filtered and the solvent evapo-
rated under reduced pressure. The residue was purified
by flash chromatography (silica, hex./AcOEt 10:1 and
5:1). The fraction containing the product was dissolved
in Et2O (15 mL) and extracted with 3% HCl (3×10 mL).
The acidic phase was washed with Et2O (5 mL),
basified with 5% Na2CO3 to pH=8 and extracted with
AcOEt (3×10 mL), which was washed with H2O (10
mL), dried (MgSO4), filtered and the solvent evapo-
rated in vacuum. 1,7,7-Trimethyl-2-phenyl-3-(pyrid-2-
ylmethylidene)-bicyclo[2.2.1]heptan-2-ol was obtained
as a white solid (120 mg, 0.37 mmol, 18%). Rf=0.46
(silica, hex./AcOEt 4:1). [h]2D0 +88.9 (c 0.27, CHCl3).
cis-4 (2-endo,3-endo): Rf=0.31 (silica, hex./AcOEt 2:1).
[h]2D0 +18.0 (c 0.82, MeOH). 1H NMR (CDCl3): l
8.45–8.42 (m, 1H), 7.64–7.59 (m, 1H), 7.17–7.10 (m,
2H), 6.50–6.20 (bs, 1H), 3.93 and 3.73 (dd and d,
J=9.6 Hz, J=1.6 Hz, and J=7.6 Hz, 1H), 3.51 and
3.29 (t, J=13.6 Hz and J=12.4 Hz, 1H), 2.79 and 2.44
(dd, J=13.6 Hz, J=2.4 Hz and J=13.2 Hz, J=2.0 Hz,
1H), 2.39–2.30 and 1.94–1.88 (m and ddd, J=12.8 Hz,
J=8.0 Hz and J=2.8 Hz, 1H), 2.17–2.11 and 1.75–1.68
(2m, 1H), 1.65–1.62 and 1.59–1.53 (2m, 2H), 1.28–1.14
and 1.08–0.96 (2m, 2H), 1.02, 0.92, 0.91, 0.87, 0.83 (5s,
9H). 13C NMR (CDCl3): l 163.1, 162.6, 148.3, 148.3,
137.3, 137.2, 123.1, 123.0, 121.1, 121.0, 80.3, 74.5, 52.8,
52.6, 51.0, 49.9, 49.4, 47.1, 47.0, 42.6, 39.6, 35.6, 33.8,
30.0, 25.6, 22.3, 21.9, 20.5, 20.0, 18.6, 14.4, 12.0.
HRMS calcd for M++H (C16H24NO) 246.1852; found
246.1852.
1
Mp=101–102°C. H NMR (CDCl3): l 7.84 (m, 1H),
7.46 (ddd, J=7.6 Hz, J=7.6 Hz, J=2.0 Hz, 1H), 7.37
(d, J=7.6 Hz, 2H), 7.09 (t, J=7.6 Hz, 2H), 7.02 (m,
1H), 6.80 (m, 1H), 7.76–6.66 (bs, 1H), 3.64 (t, J=13.2
Hz, 1H), 2.86 (dd, J=13.2 Hz, J=3.2 Hz, 1H), 2.57
(dd, J=12.8 Hz, J=3.2 Hz, 1H), 1.87–1.78 (m, 1H),
1.76 (d, J=4.4 Hz, 1H), 1.57 (s, 3H), 1.29–1.00 (m,
4H), 0.90 (s, 6H). 13C NMR (CDCl3): l 161.4, 147.6,
147.4, 136.9, 127.0, 126.6, 125.5, 122.8, 120.8, 84.5,
55.5, 53.9, 52.1, 51.3, 40.6, 30.5, 29.9, 23.7, 23.3, 10.3.
HRMS calcd for M++H (C22H28NO) 322.2156; found
322.2165.
trans-4 (2-exo,3-endo): Rf=0.10 (silica, hex./AcOEt
1
2:1). [h]2D0 +9.2 (c 0.79, MeOH). Mp 77–78°C. H NMR
(CDCl3): l 8.46 (m, 1H), 7.60 (ddd, J=7.6 Hz, J=7.6
Hz, J=1.6 Hz, 1H), 7.20 (d, J=7.6 Hz, 1H), 7.12–7.09
(m, 1H), 4.90–4.60 (bs, 1H), 3.33 (d, J=4.0 Hz, 1H),
3.00–2.87 (m, 2H), 2.62–2.56 (m, 1H), 1.66–1.62 (m,
3H), 1.45–1.39 (m, 1H), 1.16 (s, 3H), 1.05–1.00 (m, 1H),
0.94 (s, 3H), 0.88 (s, 3H). 13C NMR (CDCl3): l 161.9,
148.6, 136.3, 123.6, 121.0, 86.1, 49.8, 49.5, 47.8, 47.6,
39.4, 35.2, 20.7, 20.6, 19.8, 11.5. HRMS calcd for
M++H (C16H24NO) 246.1852; found 246.1852.
4.8. 1,7,7-Trimethyl-2-methyl-3-(pyrid-2-ylmethyl)-
bicyclo[2.2.1]heptan-2-ol 6
4.6. Reduction of 3 with ethylmagnesium bromide
In a 25 mL two-necked round-bottomed flask under
argon was dissolved 1,7,7-trimethyl-endo-3-(pyrid-2-
ylmethyl)-bicyclo[2.2.1]heptan-2-one 3, (700 mg, 2.9
mmol, 7.5:1 endo/exo mixture) in dry THF (7 mL) and
the contents of the flask were cooled to 0°C. EtMgBr
(1 M in THF, 3 mL, 3.0 mmol) was added dropwise,
the resulting mixture was stirred overnight at rt and
quenched with sat. NH4Cl solution (10 mL). The layers
were separated and the aqueous one extracted with
Et2O (3×5 mL). The combined organic extracts were
In a 100 mL 3-necked round-bottomed flask under
argon was placed MeLi (1.6 M in Et2O, 32.0 mL, 51.2
mmol) and 1,7,7-trimethyl-3-(pyrid-2-ylmethyl)-bicyclo-
[2.2.1]heptan-2-one 3 (7:3 exo:endo) (500 mg, 2.06
mmol) in dry THF (2 mL) was added dropwise and the
resulting solution was heated under reflux for 2 h and
stirred for an additional 16 h at rt. The reaction mix-
ture was cooled to 0°C, treated with sat. NH4Cl solu-
tion (20 mL), the layers were separated and the aqueous
phase was extracted with Et2O (3×20 mL). The com-

1776
M. Ne6alainen, V. Ne6alainen / Tetrahedron: Asymmetry 12 (2001) 1771–1777
bined organic extracts were washed with brine (20 mL),
dried (MgSO4), filtered and the solvent evaporated
under reduced pressure. The residue was purified by
flash chromatography (silica, hex./AcOEt 5:1) render-
ing the target as a clear oil that crystallizes slowly with
time (110 mg, 0.42 mmol, 21%). Rf=0.17 (silica, hex./
AcOEt 4:1). [h]2D0 +15.7 (c 0.43, CHCl3). Mp=85–86°C.
1H NMR (CDCl3): l 8.44 (m, 1H), 7.63 (ddd, J=7.6
Hz, J=7.6 Hz, J=2.0 Hz, 1H), 7.16 (d, J=7.6 Hz,
1H), 7.14–7.09 (m, 1H), 5.90–4.50 (bs, 1H), 3.49 (t,
J=13.0 Hz, 1H), 2.78 (dd, J=13.0 Hz, J=3.0 Hz, 1H),
1.76 (m, 1H), 1.66 (dd, J=13.0 Hz, J=3.0 Hz, 1H),
1.59–1.53 (m, 2H), 1.46–1.30 (m, 2H), 1.40 (s, 3H),
1.05–1.00 (m, 1H), 0.99 (s, 3H), 0.92 (s, 3H), 0.85 (s,
3H). 13C NMR (CDCl3): l 162.6, 148.0, 137.2, 123.3,
121.2, 80.6, 59.4, 52.9, 52.5, 49.4, 40.9, 30.8, 30.1, 28.4,
23.0, 10.2. HRMS calcd for M++H (C17H26NO)
260.2018; found 260.2009.
warm to rt, stirred for 30 min and brought to the
reaction temperature. The aldehyde (0.50 mmol) was
added dropwise, the reaction mixture was stirred for t h
and treated with 3% HCl (5 mL). The layers were
separated and the aqueous one extracted with Et2O
(3×5 mL). The combined organic extracts were washed
with H2O (15 mL), dried (MgSO4), filtered and con-
centrated under reduced pressure. The residue was
analyzed by HPLC (Chiralcel OD, hex./IPA 95:5,
1.0 mL/min, 254 nm; 1-phenylpropanol: tR (R)=11.3
min, tR (S)=12.2 min; 1-(p-MeO-phenyl)propanol:
t
R (R)=13.7 min, tR (S)=14.9 min; 1-(p-Cl-phenyl)propa-
1
nol: tR (R)=11.5 min, tR (S)=10.7 min) and H NMR.
Acknowledgements
The authors are grateful to Professor Pirjo Vainiotalo
for providing the HRMS of this work.
4.9. 1,7,7-Trimethyl-2-butyl-3-(pyrid-2-ylmethyl)bicyclo-
[2.2.1]heptan-2-ol 7
In a 25 mL two-necked round-bottomed flask under
argon was placed BuLi (1.6 M in hexanes, 7.0 mL, 11.2
mmol) and was cooled to −78°C. 1,7,7-Trimethyl-3-
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1
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NMR (CDCl3): l 8.59, 8.57 and 8.45 (m, 1H), 7.63–
7.55 (m, 1H), 7.17–7.01 (m, 2H), 4.80–4.40 (bs, 1H),
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1.00–0.76 (m, 12H). 13C NMR (CDCl3): l 163.8, 163.2,
162.8, 149.7, 149.3, 148.3, 136.9, 135.9, 135.8, 123.6,
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