Cobalt-Mediated Aldol-Type Reactions

Full text of DOI:10.1021/jo961905r

J . Org. Chem. 1997, 62, 1159-1163
1159
Sch em e 1
Coba lt-Med ia ted Ald ol-Typ e Rea ction s
Fulvia Orsini*
Dipartimento di Chimica Organica e Industriale,
via Venezian, 21-20133 Milano, Italy
Received October 8, 1996
We have already reported that a Co(0)-trimethylphos-
phine complex is an efficient mediator for one-pot Refor-
matsky-type reactions of halogen derivatives with car-
bonyl compounds to give secondary and tertiary alcohols.1
The investigation was extended to other low-oxidation-
state cobalt complexes, which have also proven effective,
with several advantages over the classical zinc-mediated
Reformatsky reaction,2 the most notable being the milder
conditions and the higher yields of addition products.3
We have now found that R-halo ketones react with
carbonyl compounds (ketones and aldehydes) in the
presence of low-oxidation-state cobalt complexes with
phosphines to yield aldols as shown in Scheme 1.
not observed, not even when aldehydes such as acetal-
dehyde or phenyl acetaldehyde were used. Aldols were
formed at the original site of the bromine atom and with
moderate to good diastereoselectivity, depending on both
the electrophile and on the bromo compound.
No appreciable differences have been observed when
trimethylphosphine is substituted with triphenylphos-
phine as a ligand-to-cobalt.5 The latter, more convenient
to use, had the added advantage that it could be
recovered at the end of the reaction.
The tested R-chloro ketones gave sluggish reactions
and significant amounts of the common side products
that plague typical aldol condensations such as polycon-
densation products. This problem, however, was over-
come by "in situ" conversion of chlorides to the corre-
sponding iodides in the presence of potassium iodide.
Iodides gave generally high yields of aldols.
Under the experimental conditions tested, threo selec-
tivity was generally observed with both bromo and iodo
ketones.6 The regioselectivity of this aldol reaction was
demonstrated by treatment of 3-iodobutan-2-one (pre-
pared in situ from 3-chlorobutan-2-one) with benzalde-
hyde to afford the expected â-hydroxy ketone without any
contamination of the regioisomer.
In order to improve the diastereoisomeric ratio and to
test a possible dependence from the reaction time, the
reaction between phenylacetaldehyde and R-bromo pro-
piophenone was investigated at long reaction time and
gave a higher yield of the threo aldol (Table 1, entry 10).
A time/diastereoisomeric ratio dependence was also
verified in the reaction between R-bromo propiophenone
and pivalaldehyde (Table 1, entry 7).
For one model system (R-bromopropiohenone and ben-
zaldehyde), the reaction was also carried out at different
temperatures (Table 2). In each case, the aldol was
obtained in good yield. Temperature, however, had a
significant effect on the diastereoselectivity of the reac-
tion, which proceeded smootly at low temperature (-78
°C) to give the erythro aldol as the major diastereoisomer.
The reactions also proceeded cleanly when carried out
with a 10/1 mole ratio of the organic reagents to cobalt,
in the presence of magnesium metal (Table 3). The fact
that the reaction can be carried out with a substoichio-
Resu lts a n d Discu ssion
Two series of experiments were carried out. In the
first, several combinations of R-halo ketones and carbonyl
compounds (ketone or aldehyde) were simultaneously
added via a “one pot” procedure to tetrakis(trimeth-
ylphosphine)cobalt(0), Co[P(CH3)3]4, in equimolar amounts.
The Co[P(CH3)3]4 was selected first because it is a well-
identified complex4 obtained by reducing a mixture of
anhydrous Co(II) chloride and trimethylphosphine (1:4
mole ratio) with magnesium metal in tetrahydrofuran.
Furthermore, it may be expected, by analogy with the
Reformatsky-type reactions,1 to undergo oxidative addi-
tion with R-halo ketones yielding intermediate species
capable of functioning as nucleophiles.
In the second series of experiments, most of the
reactions performed with Co[P(CH3)3]4 were investigated
by substituting trimethylphosphine with triphenylphos-
phine as a ligand-to-cobalt. This investigation had two
objectives: one was to explore if the properties of the
ligand could influence the effectiveness of the cobalt
complex in promoting aldol reactions. The other and
more specific objective was to find a ligand less toxic and
easier to handle with respect to trimethylphosphine.
The results obtained, summarized in Table 1, illustrate
some general features of this cobalt-mediated aldol
reaction.
Addition of R-bromo ketones to carbonyl compounds in
the presence of Co[P(CH3)3]4 resulted in the formation
of aldol products in high yields at a reaction temperature
(0 °C) convenient for preparative work. R,â-Unsaturated
aldehydes as cinnamaldehyde gave only 1,2-addition
product. Nonselective condensations (autocondensation
of the halo ketone or of the carbonyl electrophile) were
(5) The species formed from Co(II) by reduction with magnesium
metal in the presence of 4 equiv of triphenylphosphine was not isolated.
The course of the reduction with magnesium and of the addition to
carbonyl compounds suggests the formation of a Co(0) species. How-
ever, for correcteness, we will refer to it as a low-state-oxidation
complex.
* To whom correspondence should be addressed. Tel.: 02-2367588.
Fax: 02-2364369.
(1) Orsini, F.; Pelizzoni F.; Pulici, M.; Vallarino, L. M. J . Org. Chem.
1994, 59, 1-3.
(2) Orsini, F.; Pulici, M.; Vallarino. L. M. J . Organomet. Chem. 1995,
495, C1-C5.
(3) Orsini, F.; Pulici, M. Highlights on Recent Advancement on
Reformatsky-Type Reactions: the Cobalt Approach. In Trends in
Organometallic Chemistry; Research Trends Ed.; Trivandrum, India,
1994; Vol. 1, pp 625-667.
(4) (a) Klein, H. F. Angew. Chem. 1971, 83, 363. (b) Klein, H. F.;
Karsch, H. H. Chem Ber. 1975, 108, 944-955.
(6) The stereochemical assignment was based on the 1H NMR vicinal
coupling constant J 2,3 [J 2,3 (threo) > J 2,3 (erythro)]14 and on the 13C
NMR15 resonances of C2, C3, R1, assuming hydrogen-bonded structures
in a chair conformation with the maximum number of R substituents
equatorial. In the reaction between R-bromopropiophenone and piv-
alaldehyde the stereochemical assignment based on NMR data can be
misleading as the favored conformation in the threo isomer would place
the bulky tert-butyl group and the methyl group apart with, as a
consequence, a small H2-C-C-H3 angle.
S0022-3263(96)01905-6 CCC: $14.00 © 1997 American Chemical Society

1160 J . Org. Chem., Vol. 62, No. 4, 1997
Ta ble 1. Coba lt-Med ia ted Nu cleop h ilic Ad d ition of r-Ha lo Keton es to Ca r bon yl Com p ou n d sa
carbonyl compd L ) Me3P L ) Ph3P
yield (%) threo/erythrob time (min) yield (%) threo/erythrob time (min)
Notes
entry
R-halo ketone
R2
R3
1
2
3
4
5
6
7
8
9
R-bromoacetophenone
H
H
H
C6H5
C6H5
59c
85
90
90
90
120
60
120
30
57c
85
83
82
86
81
81e
88
87
90
90
120
120
90
90
120
50
60
120
60
480
120
4-methoxy-R-bromoacetophenone
4-methoxy-R-bromoacetophenone
4-methoxy-R-bromoacetophenone
R-bromopropiophenone
C6H5CHdCH 81d
-(CH2)5-
C6H5
C6H5CHdCH 78
(CH3)3C
-(CH2)5-
CH3
78
84
H
H
H
91/9
88/12
91/9
87/13
R-bromopropiophenone
R-bromopropiophenone
83e
R-bromopropiophenone
R-bromopropiophenone
H
H
87
90
80/20
88/12
120
480
80/20
70/30
90/10
10
R-bromopropiophenone
CH2Ph
11
12
1-bromo-3,3-dimethyl-butan-2-one
R-chloroacetophenone
H
H
C6H5
C6H5
85
120
480
180
480
120
480
180
480
180
83
mixturei
54d,f,j,l
13
14
15
2-chlorocyclohexanone
2-chlorocyclopentanone
3-chlorobutan-2-one
H
H
H
C6H5
C6H5
C6H5
25 [14]g-i,k
85f,j,l
90/10
75/25
77/23
79/21
20 [10]g-i,k
50 [25]f,g,j,l
mixturei
86f,j,l
65/35
a
b
The reactions were performed at 0 °C, if not otherwise stated. The stereochemistry was assigned from the coupling constant J 2,3 in
the 1H NMR spectrum14 and from the 13C NMR resonance of C2, C3.15 c Low recovery of crude material was observed. Yield determined
d
by 1H NMR. e Two diastereoisomers were obtained in 91/9 ratio. A longer reaction time (3 h) gave a 72/28 diastereoisomeric ratio. In
this case the stereochemical assigment is doubtful since the J 2,3 are very similar (2.0 and 3.5 Hz, respectively).6 f The reaction was
g
performed in the previous “in situ” formation of the corresponding iodo ketone in the presence of KI. Yields in brackets refer to the
h
product formed by water elimination from the hydroxilic function. Bis-adducts, from condensation on both R positions of the halo ketone,
were observed (∼20%).14 The reaction was performed at 25 °C. Reaction performed in the presence of dimethylformamide. Starting
i
j
k
l
benzaldehyde (33%) and dihydrobenzoin (meso and racemate, 30%) were recovered. Yield determined from R-chloro ketone.
Ta ble 2. In flu en ce of th e Tem p er a tu r e on th e Rea ction
tions (temperature, time of reaction, speed of stirring).
The reactions in the absence of cobalt were generally
slower, less reproducible, and required a variable period
of induction. Once started, the reactions afforded the
expected aldol, in variable amounts depending on the
organic reagents and on the speed of the reaction,
betw een r-Br om op r op iop h en on e a n d Ben za ld eh yd ea
T (°C)
time (h)
yield (%)
threo/erythro
0
-30
-78
1
3
5
84
84
82
91/9
88/12
30/70
1
accompanied by several byproducts (detected in the H
a
The reactions were carried out under stoichiometric conditions
with a 1/1 reagent-to-cobalt molar ratio.
NMR spectrum of the crude reaction mixture) and
occasionally by starting organic reagents. In one case,
when 1-bromo-3,3-dimethylbutan-2-one was used, no
reaction was observed.
metric amount of the Co-phosphine complex offsets the
disadvantage inherent in the use of trimethylphosphine.
In most cases Co[P(CH3)3]4 was therefore used to avoid
purification of the aldol from the phosphine at the end
of the reaction. In few cases, however, triphenylphos-
phine was also tested as a ligand-to-cobalt and gave
essentially the same results obtained with trimeth-
ylphosphine. The course and the end point of the
reaction were easily monitored by the alternation of the
yellow-brown color of the Co(0) complex and the deep
purple-blue color of the Co(II) complex during the addi-
tion of the R-halo ketone/carbonyl compound reagents.
The high yield of the aldol was obtained when the
reaction was worked up as soon as the organic reagents
were added, and the yellow-brown color of Co(0) complex
persisted for few minutes. Prolonged reaction times
served only to degrade the initially formed aldol to form
byproducts.
These results indicate that, in the absence of Co-
complex, magnesium alone is capable of giving â-hydroxy
ketones from carbonyl compounds and R-bromo ketones,
but a different composition of the reaction mixture is
generally observed under the same experimental condi-
tions. One more piece of evidence that might prove the
actual involvement of cobalt also under substoichiometric
conditions is the color of the solution that continuosly
and swiftly changes from yellow-brown (Co(0) complex)
to deep purple-blue (Co(II) complex) during the addition
of the organic reagents and that allows a timely visual-
ization of the end point of the reaction with minimization
of the byproducts. It is therefore reasonable to assume
that, as far as the reduction Co(II)/Co(0) is faster than
the reaction of magnesium with the R-halo ketone, the
soluble Co(0)-phosphine complex reacts with the R-halo
ketone before magnesium, which must work in the
heterogeneous phase. A cobalt species is no doubt
involved in the substoichiometric reaction of 1-bromo-
3,3-dimethylbutan-2-one with benzaldehyde.
To investigate whether an organomagnesium com-
pound might be involved,7 parallel experiments were
performed adding the R-bromo ketones and the carbonyl
compounds reported in Table 3 to magnesium alone in
tetrahydrofuran. The amounts of bromo ketone, alde-
hyde, and magnesium were the same in both series of
experiments, and so were the other experimental condi-
As observed for Co-mediated Reformatsky-type reac-
tions, the obtained results and the stoichiometry of the
reaction (1/1/1 ratio reagents/Co-complex)8 suggest a
mechanism involving the oxidative addition of the R-halo
ketone to the Co(0) complex to give a Co(II) intermediate
species. This is also supported, as mentioned above, by
(7) Preparation of the magnesium enolate from various 2-bromo-2-
alkyl-5,5′-dimethylcyclopentanones and R-bromo-R′-tert-butyl ketones
in ether-benzene solutions at reflux, followed by condensation with
carbonyl compounds was reported: Fellmann, P; Dubois, J . E. Tetra-
hedron 1978, 34, 1349-1357.
(8) A 1:1:0.5 organic reagents/Co ratio was also tested and produced
a ∼ 50% recovery of starting product.

Notes
J . Org. Chem., Vol. 62, No. 4, 1997 1161
Ta ble 3. Coba lt (Su bstoich iom etr ic Con d ition s) a n d Ma gn esiu m -Med ia ted Ad d ition of r-Br om o Keton es to Ca r bon yl
Com p ou n d s
carbonyl compd
entry
R-halo ketone
R2
R3
yield (%)
threo/erythroa
procedureb
time (min)
1
2
3
4
5
6
7
8
9
4-methoxy-R-bromoacetophenone
4-methoxy-R-bromoacetophenone
R-bromopropiophenone
R-bromopropiophenone
R-bromopropiophenone
R-bromopropiophenone
R-bromopropiophenone
R-bromopropiophenone
R-bromopropiophenone
R-bromopropiophenone
H
C6H5
C6H5
C6H5
C6H5
C6H5
(CH3)3C
(CH3)3C
80c
35d,e
84f
A
B
A
A
B
A
B
A
B
A
A
B
A
A
40
40
40
150
40
20
20
35
35
30
35
35
30
50
H
H
H
H
H
H
88/12
90/10
82/18
27g
66h
85c,i
40j,k
80l
-(CH2)5-
-(CH2)5-
CH2Ph
CH2Ph
CH2Ph
C6H5
75
10
H
H
H
H
95c
92c,l
62m
83n
83l
70/30
70/30
75/25
11
12
R-bromopropiophenone
1-bromo-3,3-dimethyl-butan-2-one
a
The stereochemistry was assigned from the coupling constant J 2,3 in the 1H NMR spectrum14 and from the 13C NMR resonance of
C2,C3.15 Procedure A (substoichiometric in Co(0) complex): the halo ketone and the carbonyl compound were added to the Co complex
b
in a 10/10/1 molar ratio at 0 °C, if not otherwise stated. Procedure B: the reaction was performed in the presence of magnesium alone
d
at 0 °C, if not otherwise stated. c Yield determined by 1H NMR. Yield of isolated products. e Benzyl alcohol (10%), dihydrobenzoin (meso
and racemate, 10%), starting reagents (30%), and other unidentified compounds were observed in the 1H NMR spectrum of the crude
g
product. f 1,3-Diphenyl-2-methyl-1,3-propanediol (4%) was obtained as a byproduct. Several byproducts were observed. One of them
h
i
was identified as 1,3-diphenyl-2-methyl-1,3-propanediol (15%). Starting reagents (31%) were recovered. Two diastereoisomers were
obtained in 91/9 ratio. In this case the stereochemical assigment is doubtful since the J 2,3 are very similar (2.0 and 3.5 Hz, respectively).6
j
k
Starting bromo ketone was observed in the 1H NMR spectrum. Two diastereoisomers were obtained in 91/9 ratio. A longer reaction
l
m
time (90 min) gave 65% yield of aldol (75/25 diastereoisomeric ratio). Triphenylphosphine was used as a ligand-to-cobalt. Several
n
unidentified products were detected in the 1H NMR spectrum. No reaction was observed in the presence of magnesium alone.
the typical purple-blue color of the tetrahedral Co(II)-
phosphine complex, which appears in the solution of
substoichiometric reactions.
The intermediate Co(II)-species could not be isolated
under the conditions of the reactions. Therefore, its
identity (C-metalated species or enolate) cannot be
determined with certainty.
However, the stereochemical outcome of the reactions
and the trends of the diastereoselection, similar for the
cobalt-mediated and for the magnesium-mediated reac-
tions,9 would suggest the involvement of a Co-enolate
and a chairlike six-membered transition state with the
metal bonded to the oxygen atoms of the enolate and the
carbonyl compound.
aldols. The most common method for generating a
metal-enolate is based on metal-hydrogen exchange.
Occasionally, oxidative metalations have been used:11
generally, in these cases activation of the metal was
essential for the success of the reaction.
The cobalt-mediated aldol reaction proceeds cleanly
and smoothly,12 requires no additives (acids or bases) and
no cosolvents, and does not need freshly distilled and
dried solvents.13 The fact that the solid, air-stable
triphenylphosphine can be used as a ligand-to-cobalt and
that the reactions can be carried out with a 10/1 molar
ratio of reagents-to-cobalt are added advantages. Finally,
with respect to other methods that involve oxidative
metalation, the use of a soluble Co(0) complex offsets the
disadvantages of heterogeneous reactions and activation
of the metal.
Con clu sion
In conclusion, this new procedure represents a valid
supplement to the existing procedures.
The aldol condensation is one of the most important
tools for C-C bond formation, and several methods were
developed to overcome the problems connected with this
fundamental reaction. The use of a preformed enolate
or enol ether of one of the components has been the most
successful.10 The former usually requires strictly anhy-
drous conditions, cosolvent (such as HMPT), bases, and,
in some cases, multistep procedures to achieve a good
stereoselectivity; the latter require Lewis acids to form
Exp er im en ta l Section
Gen er a l Meth od s. Trimethylphosphine (1 M solution in
tetrahydrofuran), triphenylphosphine, tetrahydrofuran (THF),
anhydrous, and tetrahydrofuran, ACS reagent, were purchased
from Aldrich and used as received. Anhydrous cobalt(II) chloride
was heated at 120-150 °C for 2 h prior to use. Magnesium
metal (as turnings) was activated by treatment with a solution
of 1,2-dichloroethane in THF, followed by washing with THF.
R-Chloro- and R-bromo ketones and carbonyl compounds were
purchased from Aldrich and used as received. R-Iodo ketones
were prepared from the corresponding R-chloro ketones by
reaction with KI in tetrahydrofuran-dimethylformamide and
directly used. Proton nuclear magnetic resonence (1H NMR)
spectra were obtained with Varian XL-200 and Bruker AC-300
instruments. Thin layer chromatography (TLC) was carried out
(9) The enolate structure was unambigously assigned for some
magnesium derivatives: Fellmann, P; Dubois, J . E. Tetrahedron Lett.
1977, 247-250.
(10) Mukayama, T. Org. React. 1982, 28, 203-331.
(11) For aldol-type reactions based on oxidative metalation of the
halo carbonyl compounds, see the following for examples. (a) Tita-
nium: Ishihara, T.; Yamanaka, T.; Ando, T. Chem. Lett. 1984, 1165-
1168. (b) Chromium: Dubois, J . E.; Axiotis, G.; Bertounesque, E.
Tetrahedron Lett. 1985, 26, 4371-4372. (c) Boron: Nozaki, K.; Oshima
K.; Utimoto, K. Tetrahedron Lett. 1988, 29, 1041-1044. (d) Alumi-
num: Matsubara, S.; Tsuboriwa, N; Morizava, Y.; Oshima K.; Nozaki,
H. Bull. Soc. Chim. J pn. 1984, 57, 3243-3246. (e) Tin: Mukaiyama,
T.; Harada, T. Chem. Lett. 1982, 161-164; Kato, J . I.; Mukaiyama, T.
Chem. Lett. 1983, 1727-1728. (f) Antimony: Huang, Y. Z.; Chen C.;
Shen, Y. J . Chem. Soc., Perkin Trans. 1988, 1, 2855-2859. (g)
Cerium: Fukuzawa, S.; Sumimoto, N.; Fijinama, T.; Sakai, S. J . Org.
Chem. 1990, 55, 1628-1631.
(12) Complexes of Co(II) acetate with 2,2′-bipyridine were reported
to promote aldol condensation of aldehydes with ketones in DMF at
80 °C for several hours to give R,â-unsaturated ketones: Irie, K;
Watanabe K. I. Bull. Chem. Soc. J pn. 1980, 53, 1366-1371.
(13) In one run the reaction of R-bromopropiophenone and benzal-
dehyde was performed in absolute tetrahydrofuran (0 °C, 1 h) and
afforded 86% of the expected aldol (91/9 threo/erythro diastereoisomeric
ratio).

1162 J . Org. Chem., Vol. 62, No. 4, 1997
Notes
on silica gel plates (60 F254, Merk); zones were detected visually
by ultraviolet irradiation (254 nm) or by spraying with methanol/
H2SO4 9:1 followed by heating at 100 °C.
All reactions were carried out at 25 °C in a dry nitrogen
atmosphere.
H, d, J ) 7.5 Hz), 2.45 (1 H, dq, J ) 7.0, 7.5, 7.5 7.5 Hz), 4.05 (1
H, d, J ) 7.0 Hz), 5.65 (1H, s), 7.2-7.4 (10 H).
Typ ica l P r oced u r e for th e Ma gn esiu m -Med ia ted Rea c-
tion s. To activated magnesium turnings (300 mg) in tetrahy-
drofuran (4 mL) was added a tetrahydrofuran solution (6 mL)
of R-bromopropiophenone (5 mmol) and benzaldehyde (5 mmol)
dropwise under stirring at 0 °C. The progress of the reaction
was monitored by TLC and compared with the reaction per-
formed in the presence of cobalt. After 40 min, the reaction
mixture was diluted with ethyl acetate, poured into crushed ice/
aqueous HCl, and extracted with ethyl acetate (3 × 15 mL). The
organic layers were collected, dried (Na2SO4), and evaporated
to dryness. The crude material was flash-chromatographed
(silica gel, ethyl acetate/n-hexane 20/80) and afforded 1-phenyl-
2-methyl-3-hydroxy-3-phenylpropan-1-one (66%, 82/18 threo/
erythro ratio) accompanied by starting bromo ketone (31%). In
one run a longer reaction time (3 h) afforded aldol (60%), starting
bromo ketone (20%), 1,3-diphenyl-2-methyl-1,3-propanediol (10%),
and dihydrobenzoin (meso and racemate 10%, identified by TLC
and 1H NMR analysis).
1-P h en yl-3-h ydr oxy-3-ph en ylpr opan -1-on e (en tr y 1, Table
1): colorless solid: mp ) 48-50 °C (diisopropyl ether) (lit.14 mp
) 50-53 °C); IR 1541, 1599, 1674, 3525, 3676 cm-1; 1H NMR δ
3.28 (1 H, s, disappears with D2O), 3.38 (2 H, d, J ) 6.5 Hz),
5.33 (1 H, dd, J ) 6.5, 6.5 Hz), 7.2-7.6 (8 H, m), 7.95 (2 H, dd,
J ) 8.6, 2.2 Hz); 13C NMR 48.07 (t), 70.71 (d), 126.42 (d), 128.32
(d), 2 × 128.82 ( d), 2 × 129.24 (d), 2 × 129.32 (d), 129.62 (d),
134.30 (d), 136.50 (s), 143.67 (s), 200.79 (s); MS m/ z 226 (M+),
208 (M+ - H2O), 120 (C6H5C(OH)dCH2), 105 (C6H5CO).
Anal. Calcd for C15H14O2: C, 79.62; H, 6.24. Found: C, 79.77;
H, 6.25.
The tetrakis(trimethylphosphine)cobalt(0), Co[P(CH3)3]4, was
prepared as previously reported1,4
P r ep a r a tion of th e Low -Va len t Coba lt-Tr ip h en ylp h os-
p h in e Com p lex. Activated magnesium turnings (500 mg),
anhydrous cobalt(II) chloride (130 mg, 1 mmol), and triphen-
ylphosphine (1.05 g, 4 mmol) were added to THF (4.0 mL). The
mixture was stirred until the original blue color turned to yellow-
brown. The clear supernatant was transferred by syringe to
another flask immediately before use.
Typ ica l P r oced u r e for th e Coba lt-Med ia ted Stoich io-
m etr ic Rea ction s. The filtered solution of the Co-phosphine
complex (1 mmol) was treated dropwise with a solution contain-
ing R-bromopropiophenone (1 mmol) and benzaldehyde (1 mmol)
in tetrahydrofuran (4 mL) at 0 °C. The progress of the reaction
was monitored by TLC (ethyl acetate/n-hexane 20/80). When
the organic reagents were no longer present, the solution was
diluted with ethyl acetate, poured into crushed ice/0.1 N HCl,
and extracted with ethyl acetate (3 × 15 mL). The combined
organic solutions were washed with water, dried (Na2SO4), and
evaporated to dryness. The crude material was flash chromato-
graphed over silica gel (ethyl acetate/n-hexane 15/85) and yielded
84% of 1-phenyl-2-methyl-3-hydroxy-3-phenylpropan-1-one (91/9
threo/erythro ratio).
Threo: IR 1480, 1545, 1590, 1673, 3482, 3598 cm-1; 1H NMR
δ 1.05 (3 H, d, J ) 7.5 Hz), 3.84 (1 H, dq, J ) 7.5, 7.5, 7.5, 7.5
Hz), 3.86 (1H, s, disappears with D2O), 4.98 (1 H, d, J ) 7.5
Hz), 7.17-7.78 (8 H, m), 7.98 d (2 H, d, J ) 8.0 Hz); 13C NMR:
16.27 (q), 48.67 (d), 77.45 (d), 127.43 (d), 128.53 (d), 4 × 129.10
( d), 2 × 129.24 (d), 2 × 133.86 (d), 137.62 (s), 143.01 ( s), 205.51
(s); MS m/ z 240 (M+), 222 (M+ - H2O), 207 (M+ - CH3), 105
(C6H5CO).
1-(4′-Meth oxyph en yl)-3-h ydr oxy-3-ph en ylpr opan on e (en -
tr y 2, Ta ble 1): colorless amorphous solid; IR 1515, 1578, 1602,
1670, 3510, 3666 cm-1; 1H NMR δ 3.29 (2 H, d, J ) 4.5 Hz), 3.5
(1 H, s, disappears with D2O, OH), 5.30 (1 H, t, J ) 4.5 Hz),
6.90 d (2 H, d, J ) 8.8 Hz), 7.15-7.5 (5 H, m), 7.90 (2 H, d, J )
8.8 Hz); 13C NMR 46.93 (t), 55.43 (q), 70.27 (d), 2 × 113.50 (d),
2 × 127.4 (d), 128.49 (d), 2 × 128.49 (d), 2 × 130.77 (d), 130.01
(s), 143.36 (s), 164.04 (s), 198.57 (s); MS m/ z 256 (M+), 238 (M+
- H2O), 150 (CH3OC6H5C(OH)dCH2), 135 (150 - CH3).
Anal. Calcd for C16H16O3: C, 74.98; H, 6.29. Found: C, 74.56;
H, 6.34.
Anal. Calcd for C16H16O2: C, 79.97; H, 6.71. Found: C, 79.51;
H, 6.24.
1
Erythro (detected in the H NMR and 13C NMR spectra of the
threo/erythro mixture): 1H NMR δ 1.21 (3 H, d, J ) 7.5 Hz),
3.71 (1 H, dq, J ) 4.0, 7.5, 7.5, 7.5 Hz), 3.86 (1 H, s, disappears
with D2O), 5.21 (1 H, d, J ) 4.0 Hz), 7.17-7.78 (8 H, m), 7.91 (2
H, d, J ) 8.0 Hz); 13C NMR 12.10 (q), 47.93 (d), 73.96 (d), 126.77
(d), 127.96 (d), 4 × 129.10 (d), 2 × 129.24 (d), 2 × 133.86 (d),
136.50 (s), 143.01 (s), 205.90 d (s).
1-(4′-Met h oxyp h en yl)-3-h yd r oxy-5-p h en ylp en t -4-en -1-
on e (en tr y 3, Ta ble 1): colorless solid: mp 76-78 °C (diiso-
propyl ether/ethyl acetate); IR 1512, 1576, 1603, 1668, 3517,
3673 cm-1 1H NMR δ 3.12 and 3.20 (2 H, AB system, J AB
; )
Typ ica l P r oced u r e for th e Coba lt-Med ia ted Su bsto-
ich iom etr ic Rea ction s. Triphenylphoshine (524 mg, 2 mmol)
was added to a mixture of activated magnesium turnings (300
mg) and anhydrous CoCl2 (65 mg, 0.5 mmol) in tetrahydrofuran
(4 mL). The reaction was stirred at room temperature until the
yellow-brown color of the low-oxidation-state cobalt complex
18.0, J AX ) 5.5, J BX ) 4.0 Hz), 3.61 (1 H, s, disappears with D2O),
3.86 (3 H, s), 4.93 (1 H, ddd, J ) 6.9, 5.5, 4.0 Hz), 6.32 (1 H, dd,
J ) 15.4, 6.9 Hz), 6.71 (1 H, d, J ) 15.4 Hz), 6.95 (2 H, d, J )
8.8 Hz), 7.20-7.40 (5H, m), 7.95 (2 H, d, J ) 8.8 Hz); 13C NMR
53.74 (t), 64.38 (d), 77.71 (q), 2 × 122.84 (d), 2 × 135.45 (d),
136.55 (d), 2 × 137.47 (d), 138.87 (s), 139.22 (d), 2 × 139.46 (d),
139.66 (d), 145.71 (s), 172.92 (s), 207.41 (s); MS m/ z 282 (M+),
264 (M+ - H2O), 150 (CH3OC6H5C(OH)dCH2), 135 (150 - CH3).
Anal Calcd for C18H18O3: C, 76.57; H, 6.43. Found: C, 76.77;
H, 6.45.
1-(4′-Meth oxyp h en yl)-3-(1"-h yd r oxycycloh exyl)p r op a n -
1-on e (en tr y 4, Ta ble 1): colorless prisms; mp 67-69 °C
(diisopropyl ether-ethyl acetate); IR 1500, 1545, 1590, 1670,
3483, 3679 cm-1; 1H NMR δ 1.25 (2 H, m), 1.45 (4 H, m), 1.75 (4
H, m), 3.05 (2 H, s), 3.85 (3 H, s), 3.85 (1 H, s, disappears with
D2O), 6.92 (2 H, d, J ) 9.5 Hz), 7.92 (2 H, d, J ) 9.5 Hz); 13C
NMR 22.12 (t), 2 × 25.92 (t), 2 × 37.96 (t), 47.25 (t), 55.60 (q),
71.01 (s), 2 × 113.93 (d), 2 × 130.61 (d), 130.61 (s), 164.02 (s),
200.53 (s). MS m/ z 248 (M+), 230 (M+ - H2O), 150 (CH3-
OC6H5C(OH)dCH2), 135 (150 - CH3), 107 (CH3OC6H5).
Anal. Calcd for C15H20O3: C, 72.55; H, 8.12. Found: C, 72.36;
H, 8.00.
developed. The mixture was then cooled at 0 °C, and
a
tetrahydrofuran solution (6 mL) of R-bromopropiophenone (5
mmol) and benzaldehyde (5 mmol) was added dropwise at 0 °C:
the speed of addition was modulated so as to preserve the
original brown color and reduce to a minimum the time of
development of the blue color (Co(II)-complex). At the end of
the reaction (40 min), indicated by the persistence for few
minutes of the yellow-brown color of the low-oxidation-state Co
complex, the reaction mixture was diluted with ethyl acetate,
poured into crushed ice/0.1 N HCl, and extracted three times
with ethyl acetate. The organic layers were collected, dried (Na2-
SO4), and evaporated to dryness. The crude 1-phenyl-2-methyl-
3-hydroxy-3-phenyl-propan-1-one did not require further puri-
fication (84% yield, 88/12 threo/erythro ratio by 1H NMR
analysis). In one run a longer reaction time (3 h) afforded the
aldol (27% yield) accompanied by several byproducts: one of
them was identified as 1,3-diphenyl-2-methyl-1,3-propandiol
(15% yield).
1,3-Dip h en yl-2-m eth yl-1,3-p r op a n ed iol: 1H NMR (main
diastereoisomer) δ 1.25 (3 H, d, J ) 7.5 Hz), 2.18 (1 H, ddq, J )
4.2, 7.0, 7.5, 7.5, 7.5 Hz), 4.70 (1 H, d, J ) 7.0 Hz), 5.02 (1H, d,
J ) 4.2 Hz), 7.2 - 7.4 (10 H); 13C NMR: 11.22 (q), 45.80 (d), 74.26
(d), 74.27 (d), 2 × 125.97 (d), 2 × 126.21 (d), 126.91 (d), 127.52
(d), 2 × 127.95 (d), 2 × 128.38 (d), 2 × 143.49 (s); MS m/ z 242
(M+), 224 (M+ - H2O), 209 (M+ - H2O, - CH3). Minor
diastereoisomer (detected in the 1H NMR spectrum): δ 1.22 (3
1-P h en yl-2-m eth yl-3-h ydr oxy-5-(4′-m eth oxyph en yl)pen t-
1-en -5-on e (en tr y 6, Ta ble 1). Threo: IR 1676, 1711, 3505
cm-1; 1H NMR δ 1.27 (3 H, d, J ) 7.3 Hz), 3.0 (1 H, s, disappears
with D2O), 3.71 (1 H, qd, J ) 7.3, 7.3, 7.3, 7.3 Hz), 4.60 (1 H, dd,
J ) 7.3, 7.3 Hz), 6.28 (1 H, dd, J ) 17.4, 7.3 Hz), 6.68 (1 H, d,
(14) House H. O.; Crumrine D. S.; Teranishi A. Y.; Olmstead H. D.
J . Am. Chem. Soc. 1973, 95, 3310-3324.
(15) Heathcock, C. H.; Pirrung, M. C.; Sohn, J . E. J . Org. Chem.
1979, 44, 4294-4299.

Notes
J . Org. Chem., Vol. 62, No. 4, 1997 1163
J ) 17.4 Hz), 7.20-7.65 (8 H, m), 8.00 (2 H, d, J ) 8.7 Hz); 13
C
Anal. Calcd for C17H18O2: C, 80.28; H, 7.13. Found: C, 80.15;
NMR 15.97 (q), 47.00 (d), 75.88 (d), 2 × 127.16 (d), 3 × 129.10
H, 7.12.
1
Erythro (detected in the H NMR and 13C NMR mixture): 1H
(d), 3 × 129.30 (d), 129.31 (d), 130.37 (d), 132.69 (d), 133.94 (d),
137.00 (s), 137.10 (s), 205.02 (s); MS m/ z 266 (M+), 248 (M+
H2O), 233 (248 - CH3), 134 (C6H5C(OH)dCHCH3), 105 (C6H5-
CO).
-
NMR δ 1.36 (3 H, d, J ) 7.0 Hz), 2.75 (1 H, s, disappears with
D2O), 2.78 and 2.84 (2 H, ABX system, J AB ) 13.9 Hz, J AX ) 7.4
Hz, J BX ) 6.8 Hz), 3.46 (1 H, dq, J ) 7.0, 7.0, 7.0, 3.7 Hz), 4.32
(1 H, ddd, J ) 7.4, 6.8, 3.7 Hz), 7.15-7.35 (5 H, m), 7.40-7.65
(3H, m), 7.85-7.95 (2H, m); 13C NMR 12.07 (q), 41.37 (t), 44.31
(d), 73.32 (d), 127.19 (d), 2 × 127.09 (d), 2 × 129.22 (d), 2 ×
129.34 (d), 129.36 (d), 129.95 (d), 134.02 (d), 138.94 (s), 138.95
(s), 205.77 (s).
Anal. Calcd for C18H18O2: C, 81.17; H, 6.81. Found: C, 81.41;
H, 6.74.
1
Erythro (detected in the H NMR and 13C NMR spectra of the
threo/erythro mixture): 1H NMR δ 1.32 (3H, d, J ) 7.3 Hz), 3.0
(1 H, s, disappears with D2O), 3.80 (1 H, m), 4.70 (1 H, m), 6.23
(1 H, dd, J ) 17.4, 7.3 Hz), 6.70 (1 H, d, J ) 17.4 Hz), 7.20-7.65
d (8 H, m), 7.80 (2 H, d, J ) 8.7 Hz); 13C NMR 12.44 (q), 46.12
(d), 72.91 (d), 127.16 (d), 127.18 (d), 128.38 (d), 3 × 129.10 (d),
2 × 129.30 (d), 129.31 (d), 130.37 (d), 132.69 (d), 133.94 (d),
137.00 (s), 137.10 (s), 205.02 (s).
1-ter t-Bu tyl-3-h yd r oxy-3-p h en ylp r op a n -1-on e (en tr y 11,
Ta ble 1): Colorless thick oil (lit.14 mp ) 22-23 °C); IR 1693,
3523 cm-1 1H NMR δ 1.14 (9 H, s), 2.88 (2 H, d, J ) 8.4 Hz),
;
3.55 (1 H, s, disappears with D2O), 5.15 (1 H, dd, J ) 8.4, 8.4
Hz), 7.25-7.40 d (5 H, m); 13C NMR 3 × 26.61 (q), 44.85 (s),
46.06 (t), 70.49 (d), 126.23 (d), 126.24 (d) 128.00 (d), 2 × 128.94
(d), 143.85 (s), 216.88 (s); MS m/ z 206 (M+), 189 (M+ - OH),
149 (M+ - C(CH3)3), 131 (149 - H2O), 107 (149 - CH2CO).
Anal. Calcd for C13H18O2 C, 75.69; H, 8.80. Found: C, 75.57;
H, 8.78.
1-P h en yl-2,4,4-tr im eth yl-3-h yd r oxyp en ta n -1-on e (en tr y
7, Ta ble 1). Major diastereoisomer: colorless thick oil; IR 1579,
1
1597, 1660, 3451 cm-1; H NMR δ 0.88 (9 H, s), 1.44 (3 H, d, J
) 7.5 Hz), 3.45 (1 H, d, J ) 2.0 Hz), 3.80 (1 H, dq, J ) 7.5, 7.5,
7.5, 2.0 Hz), 5.75 (1 H, s, disappears with D2O), 7.55 (2H, dd, J
) 8.1, 8.1 Hz), 7.55 (1H, dd, J ) 8.1, 8.1 Hz), 7.95 (2 H, d, J )
8.1 Hz); 13C NMR: 19.71 (q), 3 × 27.58 (q), 37.05 (s), 38.44 (d),
85.75 (d), 2 × 128.94 (d), 129.11 (d), 2 × 133.55 (d), 134.36 (s),
208.90 (s); MS m/ z 220 (M+), 203 (M+ - H2O), 205 (M+ - CH3),
203, 163 (M+ - C(CH3)3).
2-(1′-P h en yl-1′-h yd r oxym eth yl)cycloh exa n -1-on e14 (en -
tr y 13, Ta ble 1). Threo: IR 1496, 1602, 1699, 3529, 3648 cm-1
;
1H NMR δ 1.28 (2 H, m), 1.56 (2 H, m), 2.10 (2 H, m), 2.38 (2 H,
m), 2.61 (1 H, ddd, J ) 14.0, 8.4, 6.0 Hz), 3.45 (1 H, d, J ) 2.6
Hz, disappears with D2O), 4.70 (1 H, d, J ) 8.4 Hz), 7.15-7.45
(5 H, m); MS m/ z 204 (M+), 186 (M+ - H2O), 105 (C6H5CHO),
98 ((CH2)5CO).
Anal. Calcd for C14H20O2: C, 76.33; H, 9.15. Found: C, 76.12;
H, 9.12.
Minor diastereoisomer: colorless needles; mp ) 58-60 °C
1
Erythro (detected in the H NMR spectra of the threo/erythro
1
(diisopropyl ether); IR 1579, 1597, 1660, 3451 cm-1; H NMR δ
mixture): 1H NMR δ 1.28-2.8 (9H, m), 3.45 (1H, s, disappears
with D2O), 5.30 (1H, d, J ) 3.2 Hz), 7.0-7.5 (5H, m).
2-(1′-P h en yl-1′-h yd r oxym eth yl)cyclop en ta n -1-on e14 (en -
tr y 14, Ta ble 1). Threo: IR 1734, 3446, 3606 cm-1; 1H NMR δ
1.4-2.3 d (6 H, m), 2.48 (1 H, m) 2.70 (1H, s, disappears with
D2O), 4.70 (1 H, d, J ) 8.0 Hz), 7.2-7.4 (5 H, m); 13C NMR 23.28
(t), 27.40 (t), 38.27 (t), 55.90 (d), 75.60 (d), 127.17 (d), 128.53
(d), 128.87 (d), 129.87 (d), 132.89 (d), 143.59 (s), 220.99 (s); MS
m/ z 190 (M+), 172 (M+ - H2O), 130 (172 - CHCO), 107 (C6H5-
CHOH), 84 ((CH2)4CO).
0.99 (9 H, s), 1.25 (3 H, d, J ) 7.5 Hz), 3.73 (1 H, d, J ) 3.5 Hz),
3.72 (1 H, dq, J ) 7.5, 7.5, 7.5, 3.5 Hz), 5.75 (1 H, s, disappears
with D2O), 7.48 (2 H, d, J ) 8.1 Hz), 7.55 (1 H, d, J ) 8.1 Hz),
7.95 (2 H, d, J ) 8.1 Hz); 13C NMR 15.25 (q), 3 × 26.91 (q), 35.70
(s), 41.05 (d), 77.58 (d), 2 × 128.46 (d), 2 × 128.77 (d), 133.26
(d), 133.80 (s), 205.65 (s); MS m/ z 220 (M+), 205 (M+ - CH3),
163 (M+ - C(CH3)3), 134 (C6H5C(OH)dCHCH3), 105 (C6H5CO).
Anal. Calcd for C14H20O2: C, 76.33; H, 9.15. Found: C, 76.22;
H, 9.12.
1-P h en yl-3-(1′-h yd r oxycycloh exyl)-2-m et h ylp r op a n -1-
on e (en tr y 8, Ta ble 1): 1H NMR δ 1.25 (3 H, d, J ) 7.5 Hz),
1.2-1.7 (10 H, m), 3.52 (1 H, q, J ) 7.5, 7.5, 7.5, 7.5 Hz), 7.45 (2
H, dd, J ) 8.0, 8.0 Hz), 7.55 (1 H, dd, J ) 8.0, 8.0 Hz), 7.96 (2
H, dd, J ) 8.0, 8.0 Hz); 13C NMR 10.0 (q), 19.16 (t), 19.50 (t),
23.37 (t), 32.32 (t), 34.80 (t), 44.57 (d), 70.03 (s), 125.84 (d), 2 ×
126.31 (d), 129.51 (d), 131.10 (d), 134.57 (s), 205.39 (s); MS m/ z
232 (M+), 214 (M+ - H2O), 134 (C6H5C(OH)dCHCH3), 105 (C6H5-
CO).
1
Erythro (detected in the H NMR and 13C NMR spectra of the
threo/erythro mixture): 1H NMR δ 1.4-2.3 (6 H, m), 2.48 (1 H,
m), 2.70 (1H, s, disappears with D2O), 5.30 (1 H, d, J ) 4.0 Hz),
7.2-7.4 (5 H, m); 13C NMR 21.05 (t), 29.87 (t), 39.76 (t), 56.71
(d), 71.95 (d), 126.16 (d), 127.75 (d), 128.87 (d), 129.23(d), 131.06
(d), 143.59 (s), 220.99 (s).
4-P h en yl-4-h yd r oxy-3-m et h ylb u t a n -2-on e (E n t r y 15,
Ta ble 1). Threo: 1H NMR δ 0.80 (3 H, d, J ) 7.9 Hz), 2.15 (3
H, s), 2.80 (1 H, dq, J ) 9.5, 7.9, 7.9, 7.9 Hz), 3.6 (1 H, s,
disappears with D2O), 4.15 (1 H, d, J ) 9.5 Hz), 7.15 - 7.25 (5
H, m); 13C NMR 14.59 (q), 30.56 (q), 54.39 (d), 77.03 (d), 2 ×
127.32 (d), 128.48 (d), 2 × 129.01 (d), 142.75 (s), 213.97 (s); MS
m/ z 178 (M+), 160 (M+ - H2O), 117 (160 - CH3CO), 107 (C6H5-
CHOH).
1-P h en yl-2-m eth yl-3-h ydr oxybu tan -1-on e (en tr y 9, Table
1). Threo: 1H NMR δ 1.22 (3 H, d, J ) 7.9 Hz), 1.28 (3 H, d, J
) 7.9 Hz), 2.70 d (1 H, s, disappears with D2O), 3.40 (1 H, dq, J
) 7.9, 7.9, 7.9, 7.9 Hz), 4.08 (1 H, dq, J ) 7.9, 7.9, 7.9, 7.9 Hz),
13
7.22- 7.60 (3 H, m), 7.90 (2 H, d, J ) 9.8 Hz); C NMR 15.60
(q), 21.28 (q), 48.44 (d), 70.30 (d), 3 × 129.04 (d), 2 × 133.86 (d),
137.44 (s), 205.91 (s); MS m/ z 178 (M+), 160 (M+ - H2O), 145
(160 - CH3), 105 (C6H5CO).
Anal. Calcd for C13H14O2: C, 74.13; H, 7.92. Found: C, 74.0;
H, 7.90.
1
Erythro (detected in the H NMR and 13C NMR spectra of the
Anal. Calcd for C11H14O2: C, 74.13; H, 7.92. Found: C, 74.10;
H, 7.89.
threo/erythro mixture): 1H NMR δ 1.00 (3 H, d, J ) 7.9 Hz),
2.05 (3 H, s), 2.80 (1 H, dq, J ) 7.9, 7.9, 7.9, 4.2 Hz), 3.6 (1 H,
s, disappears with D2O), 4.35 (1 H, d, J ) 4.2 Hz), 7.15-7.25 (5
H, m); 13C NMR 11.08 (q), 30.06 (q), 54.13 (d), 73.84 (d), 2 ×
126.60 (d), 127.91 (d), 2 × 128.84 (d), 142.75 (s), 213.97 (s).
1
Erythro (detected in the H NMR and 13C NMR spectra of the
threo/erythro mixture): 1H NMR δ 1.21 (3 H, d, J ) 6.8 Hz),
1.27 (3 H, d, J ) 6.8 Hz), 2.70 (1 H, s, disappears with D2O),
3.42 (1 H, dq, J ) 6.8, 6.8, 6.8, 3.4 Hz), 4.22 (1 H, dq, J ) 6.8,
6.8, 6.8, 3.4 Hz), 7.22-7.60 (3 H, m), 7.92 (2 H, d, J ) 9.8 Hz);
13C NMR 12.02 (q), 20.97 (q), 46.69 (d), 68.18 (d), 3 × 129.30
(d), 2 × 133.97 (d), 136.84 (s), 205.91 (s).
Ack n ow led gm en t. Financial support by Consiglio
Nazionale delle Ricerche (CNR, Roma) through “Pro-
getto Finalizzato Chimica Fine II”, Centro di Studio Per
le Sostanze Organiche Naturali (CNR, Milano), are
MURST “Progetto Nazionale di Ricerca, 40%” is grate-
fully acknowledged. Prof. F. Pelizzoni (University,
Milano, Italy) and Prof. L. M. Vallarino (V.C.U., Rich-
mond VA) are gratefully acknowledged for helpful
discussions. Dr. M. Ferrari is gratefully acknowledged
for computer-aided literature research.
1-P h en yl-2-m eth yl-3-h yd r oxy-4-p h en ylbu ta n -1-on e (En -
1
tr y 10, Ta ble 1). Threo: H NMR δ 1.32 (3 H, d, J ) 7.0 Hz),
2.75 (1 H, s, disappears with D2O), 2.82 and 2.86 (2 H, ABX
system, J AB ) 13.5 Hz, J AX ) 7.2 Hz, J BX ) 6.0 Hz), 3.58 (1 H,
dq, J ) 7.0, 7.0, 7.0, 7.0 Hz), 4.19 (1 H, ddd, J ) 7.2, 7.0, 6.0
Hz), 7.15-7.30 (5 H, m), 7.40-7.60 (3H, m), 7.90-8.0 (2H, m);
13C NMR: 15.07 (q), 41.24 (t), 44.32 (d), 75.04 (d), 126.21 (d), 2
× 128.23 (d), 2 × 128.46 (d), 2 × 129.19 (d), 131.78 (d), 133.15
(d), 136.46 (s), 138.28 (s), 205.70 (s); MS m/ z 254 (M+ ), 236
(M+ - H2O), 221 (236 - CH3), 163 (M+ - C6H5CH2), 134
(C6H5C(OH)dCHCH3), 120 (C6H5CH2CHO), 105 (C6H5CO).
J O961905R