Influence of catalytic system composition on formation of adamantane containing ketones

Article abstract of DOI:10.1016/j.tet.2004.10.059

The preparation of non-symmetrical ketones by the reaction of acyl chlorides and the corresponding Grignard reagents in the presence of catalytic amounts of metal halides is described. The composition of catalyst has a great influence on the yield of the required ketone as well as on side product formation. For each catalytic system, the yield of ketone and the number of side products changes with the time of addition of the Grignard reagent. We examined the influence of both factors in our model reaction of adamantane-1-carbonyl chloride with ethylmagnesium bromide and discussed the possible mechanisms from this point of view. We have found ZnCl₂, MnCl₂, AlCl ₃ and CuCl to be active catalytic components and developed very efficient, cheap and fast methods for the preparation of alkyl adamantyl ketones. The procedure was also tested for the synthesis of other alkyl aryl ketones. Graphical Abstract.

Full text of DOI:10.1016/j.tet.2004.10.059

Tetrahedron 61 (2005) 83–88
Influence of catalytic system composition on formation of
adamantane containing ketones
*
´ ´ˇ
Robert Vıcha and Milan Potacek
´ˇ ´
Department of Organic Chemistry, Faculty of Science, Masaryk University Brno, Kotlarska 2, 611 37 Brno, Czech Republic
Received 21 June 2004; revised 1 October 2004; accepted 21 October 2004
´
Dedicated to Professor Milan Kratochvıl on his 80th birthday
Abstract—The preparation of non-symmetrical ketones by the reaction of acyl chlorides and the corresponding Grignard reagents in the
presence of catalytic amounts of metal halides is described. The composition of catalyst has a great influence on the yield of the required
ketone as well as on side product formation. For each catalytic system, the yield of ketone and the number of side products changes with the
time of addition of the Grignard reagent. We examined the influence of both factors in our model reaction of adamantane-1-carbonyl chloride
with ethylmagnesium bromide and discussed the possible mechanisms from this point of view. We have found ZnCl2, MnCl2, AlCl3 and
CuCl to be active catalytic components and developed very efficient, cheap and fast methods for the preparation of alkyl adamantyl ketones.
The procedure was also tested for the synthesis of other alkyl aryl ketones.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
procedure can be improved using only a catalytic amount of
the metal halide but in this case the rate of addition of the
organomagnesium reagent was found to be important.6
One of the most important strategies to obtain a new
carbon–carbon bond at a carbonyl group is a nucleophilic
substitution of a good leaving group using an organo-
metallic reagent (Scheme 1). Several modifications of the
general procedure where an organometallic reagent reacts
with acyl chlorides were studied1–3 or used in synthesis4,5
recently.
2. Results and discussion
A few years ago, Cahiez and Laboue6 described the
preparation of various ketones using acyl chlorides and
Grignard reagents in the presence of a catalytic amount of
manganese chloride and copper(I) chloride. They optimized
the rate of Grignard reagent addition to obtain the best yield
of the required ketone. For any other than the optimal rate,
the observed yields of the ketone decreased as the amount of
tertiary alcohol formed increased. In this work, we carried
out a number of experimental conditions for selected
catalytic systems to discover the best combination of
metals. This study led to the discovery of a new, efficient
method for the preparation of adamantyl ketones. Our data
from the reaction of Grignard reagents with adamantyl-1-
carbonyl chloride (1) with similar manganese–copper
catalysts are in good agreement with the observation of
Cahiez and Laboue6 (see Table 1, entries 8–13). The best
yield (82%) we obtained when the addition took about
56 min. Surprisingly, we did not detect a significant
amount of tertiary alcohol 4 anytime† and the main
Scheme 1.
Typically, ‘soft’ organometallic reagents containing copper,
zinc, manganese, etc. are used to support substitution of a
good leaving group and to avoid the successive addition of
an organometallic compound to an unsaturated carbonyl
group. It is interesting that good yields of ketones can also
be obtained when in situ transmetallation is carried out since
this means that the Grignard reagent reacts with the acyl
chloride in the presence of a suitable metal halide. This
Keywords: Ketones synthesis; Catalyst composition influence; 1-Adaman-
tyl; Grignard reagent.
* Corresponding author. Tel.: C420-549496615; fax: C420-549492688;
e-mail: potacek@chemi.muni.cz
† However, when the structure of Grignard reagent used eliminates the
reduction of ketone, the corresponding tertiary alcohol was present.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.059

´ ´ˇ
R. Vıcha, M. Potacek / Tetrahedron 61 (2005) 83–88
84
Table 1. Catalyst composition influence on the yield of ketone 2 and side-products distribution
A
B
Time (min)
Ca 2
Composition of crude productb
2
5
3
4
0
1
2
3
4
5
6
7
4.4
17.0
30.9
39.9
65.2
91.5
173.5
53
59
59
60
61
57
60
74.1
90.6
88.6
84.3
82.8
78.3
69.6
2.0
5.8
9.3
13.9
16.0
20.9
28.2
23.1
3.4
2.0
1.6
1.1
0.7
1.7
0.8
0.2
0.1
0.2
0.1
0.1
0.5
MnCl2$CuCl
AlCl3$CuCl
8
9
10
11
12
13
2.8
18.5
37.4
55.8
75.5
100.0
38
49
73
82
77
55
74.8
84.6
94.7
97.8
88.0
87.6
0.3
0.6
5.0
1.3
12.0
12.4
24.9
14.8
0.3
0.9
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
14
15
16
17
18
19
20
21
0.25
12.2
35.3
47.9
58.7
66.3
90.0
105.4
95
73
53
52
57
59
53
51
O99.5
91.6
87.0
86.0
85.0
84.0
81.0
78.0
0.0
8.4
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
13.0
14.0
15.0
16.0
19.0
22.0
ZnCl2$CuCl
22
23
24
25
26
27
28
4.5
15.8
29.6
44.8
66.9
82.9
105.9
82
80
79
80
81
76
74
98.4
98.3
97.4
96.2
95.1
93.9
93.2
0.8
1.2
2.0
3.3
4.5
5.8
6.5
0.7
0.5
0.5
0.4
0.4
0.3
0.3
0.1
0.0
0.1
0.0
0.0
0.0
0.0
AlCl3
29
30
31
32
33
34
35
36
0.3
10.4
19.1
31.7
47.1
67.8
87.0
119.4
49
55
57
56
53
47
50
41
97.0
90.6
89.5
86.6
85.6
77.0
75.4
68.7
1.9
8.5
9.6
13.4
14.4
22.8
24.5
30.8
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
1.1
0.9
0.7
0.0
0.0
0.2
1.0
0.5
CuCl
37
38
39
40
41
42
43
0.3
8.4
77
82
80
78
82
81
74
95.5
98.5
98.0
97.9
94.1
92.2
92.9
0.3
1.3
1.5
1.5
5.5
7.7
6.9
2.9
0.2
0.5
0.6
0.4
0.1
0.3
0.0
0.0
0.0
0.0
0.0
0.0
0.0
15.1
31.2
42.9
60.7
93.5
MnCl2$AlCl3
45
46
47
48
49
50
4.15
14.0
31.4
58.6
70.1
68
71
67
64
56
46
94.9
97.5
96.7
91.7
89.5
78.7
0.3
0.6
1.4
7.5
9.9
20.9
4.3
1.8
1.7
0.9
0.6
0.3
0.4
0.1
0.2
0.0
0.0
0.0
132.6
AZcatalyst, BZentry number, CZyield.
a Determined by GC with cyclohexanone as an internal standard.
b Determined by GC (relative %).
side product at high addition rate was the secondary
alcohol 3 arisen from reduction of ketone 2. Furthermore,
at a low addition rate we detected the ethyl adamantane-1-
carboxylate 5 as the main side product. There are two
possible routes to ester 5. The first one is reaction
between the acyl chloride and the corresponding
alcoholate coming from impurities in the starting
material (ethyl bromide) for Grignard reagent prep-
aration. This pathway is proved by reactions where
several different Grignard reagents were used and always
the relevant ester was detected as well as the ketone.
Nevertheless, this possibility cannot explain the increasing
amount of ester with a prolonged time of addition. Thus,
another pathway based on acylative cleavage of diethyl
ether7–11 is unambiguously present. The reaction pathways
Scheme 2. Supposed reaction pathways leading to main components of
crude products. (a) Ethylmagnesium bromide substitution of chlorine, (b)
Grignard reagent addition to carbonyl, (c) reduction of carbonyl group by
Grignard reagent, (d) acylative cleavage of diethyl ether.

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R. Vıcha, M. Potacek / Tetrahedron 61 (2005) 83–88
85
leading to the most important side products are shown in
Scheme 2.
In case when no catalyst was used, the ketone 2 yield does
not change significantly and for all the rates of the Grignard
reagent addition varies around 60%. The distribution of
products after reaction using MnCl2/CuCl catalyst is very
similar to that without any catalyst. The amount of ester 5 in
the non-catalyzed reaction is even higher than that in the
reaction catalyzed by manganese (compare entries 6 and
13). Use of aluminium trichloride with copper chloride
(entries 14–21) led to a completely different situation. The
highest ketone 2 yield (95%) was observed for the shortest
addition time (entry 14) and for any lower rate of addition
the yields were rapidly decreased.
Scheme 3. Proposed mechanism of ketone 2 formation based on Lewis acid
activated acyl chloride reaction with organocuprate.
Good yields (about 80%) were obtained when ZnCl2 was
used together with CuCl. They are nearly independent of the
time of addition (entries 22–26). A small decrease of ketone
2 yield (caused by ester formation) was observed only for
longer times of addition (entries 27 and 28).
organocuprate 6 is regenerated. Such a system can operate
efficiently only when conversion of alkylcopper into 6 by
action of Grignard reagent is sufficiently fast and when 6
reacts again very quickly with the activated acyl chloride
rather than with other electrophiles present in the reaction
mixture. The second assumption is acceptable because
activated acyl chloride seems to be the most electrophilic
species in the mixture.
Sets of experiments where AlCl3 (entries 29–36) and CuCl
(entries 37–43) were used separately show that the influence
of addition time with the AlCl3 catalyst has no significant
influence on the yield. However, the presence of CuCl
increases ketone 2 yield for all rates by about 20% in
comparison with the non-catalyzed reactions.
Finally, we tested our new method in the synthesis of several
ketones to eliminate the possible specific influence of the
bulky adamantane moiety. These results are summarized in
Table 2. In all the cases we obtained the expected ketones in
good or excellent yields. It should be mentioned tertiary or
secondary alcohols were not detected in any cases and the
corresponding amounts of unreacted carboxylic acids were
recovered (except acetic, propionic and pivalic acid).
In the case of AlCl3 catalyst, no significant amount of alcohols
was detected in the product although the yield of ketone 2 was
not higher than 60%. Appropriate unreacted starting material
was recovered after hydrolysis and identified as adamantane-
1-carboxylic acid. Finally, manganese chloride instead of
copper chloride was used (entries 45–50) but the reactions
were less successful. The best yield (71%) of ketone 2 in this
case was obtained for 14 min lasting addition.
3. Conclusion
A new, efficient, cheap and fast method for the synthesis of
non-symmetrical ketones has been developed. In comparison
with other methods, this one involves easily accessible
reagents and provides very good yields. Ketones are obtained
within 10 min at 10 8C and no special conditions or work-up
procedures are required. In addition, no undesirable alcohols
were present in crude product. Non-substituted ketones are
produced very efficiently but the full scope of our reaction
procedure remains a question for further research.
We can conclude, that the best result was observed when the
strongest Lewis acid was used together with the most
efficient organometallic reagent (formed in situ via
transmetallation). This assertion is in good agreement with
the trends indicated in Table 1. AlCl3 as well as CuCl used
separately decrease the amount of secondary alcohol, which
is formed when excessive amount of Grignard reagent is
present and that reacts not only with acyl chloride but
consequently also with the already formed ketone 2. When
AlCl3 and CuCl are used together, the absence of secondary
alcohol 3 at all addition rates implies the presence of a
mechanism that consumes Grignard reagent very rapidly,
and so undesirable reductions or additions can not occur.
4. Experimental
4.1. General data
A reasonable explanation of our results leads to the
formulation of a mechanism based on two joint cycles
(Scheme 3). In the first cycle, aluminium trichloride reacts
with acyl chloride to produce an acyl chloride–trichloro-
aluminium complex.12,13
All reactions were carried out under an argon atmosphere.
Solvents were dried by the standard methods and were
freshly distilled before use. LiCl, MnCl2, ZnCl2 were
purchased from Fluka Co. and were dried before use under
vacuum at 160 8C for 2 h. AlCl3 was obtained from Merck.‡
CuCl was prepared from CuSO4 via reduction by K2S2O5
in the presence of NaCl and was dried in the same way as
This activated alkyl carbonyl then interacts with organo-
copper compound 6 to produce the expected ketone 2,
EtCu$MgX2 and regenerated aluminium trichloride. In the
second joint cycle EtCu$MgX2 is alkylated by another
molecule of Grignard reagent and the reactive
‡ We used freshly crushed pale yellow coarse-grained crystals. White
powder available from other sources was not suitable for our purpose
(poor solubility).

´ ´ˇ
R. Vıcha, M. Potacek / Tetrahedron 61 (2005) 83–88
86
Table 2. Summarized results of acyl chlorides reaction with organomagnesium compounds catalyzed by AlCl3$CuCl
R0
R
Product
Yield (%)
91a
94b
89a
77a
87a
80a
96a
67b
87a
a Isolated yields of purified product.
b Determined by GC.
the other chlorides. The white powder obtained can be
stored under an argon atmosphere for several months.§
Melting points are uncorrected. NMR spectra were
recorded at 300 (1H) and 75.5 (13C) MHz (Bruker AM-
300) or 500 (1H) and 125.8 (13C) MHz (Bruker DRX-500)
respectively, using solvent as an internal standard. The
IR spectra were recorded with FT-IR instrument Genesis
ATI. GC analyses were run on a Shimadzu GC-17A
instrument.
Ethylmagnesium bromide was prepared by refluxing ethyl
bromide (10.90 g, 0.1 mol) with an excess of magnesium
turnings (3.16 g, 0.13 mol) in diethyl ether.14 The concen-
tration of clear solution was determined by acid/base
titration15 before use.
§ Commercial CuCl purchased from Fluka containing traces of CuCl2
(colored light green) was not suitable for our experiments. It is not
completely soluble in THF and caused low reproducibility and increasing
amount of secondary alcohols.

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R. Vıcha, M. Potacek / Tetrahedron 61 (2005) 83–88
87
4.2. General procedure for ketone preparation
was washed twice with solution of K2CO3 (20 mL, 1 M
solution) and with brine (20 mL) and dried over Na2SO4.
Colorless crystals obtained after solvent removing were
crystallized from hexane to yield 2.03 g of alcohol 4 (88%),
mp 67–69 8C, lit.21 68–69 8C. NMR data correspond with
literature.21
Into a dry three-necked flask equipped with a magnetic
stirring bar, thermometer and rubber septum, lithium
chloride (5 mL of 0.03 M solution in THF) was transferred
and the corresponding metal halide (0.075 mmol) was
added and dissolved. Into the obtained clear solution,
adamantane-1-carbonylchloride (1) (0.5 g, 2.5 mmol) was
added and solution was stirred for 5 min. Then, Grignard
reagent (2.5 mmol, 2 mL in ether) was added for the
required time period using a syringe pump. After complete
addition, the reaction mixture was quenched with hydro-
chloric acid (10 mL, 1 M solution). The water layer was
extracted three times with 10 mL of diethyl ether. The
collected organic layers were washed twice with potassium
carbonate solution (10 mL, 1 M), once with ammonium
chloride solution (10 mL, 3 M) and dried over sodium
sulfate overnight. The solution was filtered from Na2SO4
and diluted to 50 mL with diethyl ether. The yield of ketone
2 and the composition of the crude product were then
determined by gas chromatography. Cyclohexanone was
used as an internal standard.
4.2.5. Ethyl adamantane-1-carboxylate (5). The above
title compound was prepared according to literature
procedure22 from adamantane-1-carboxylic acid (2.5 g,
0.014 mol). It was refluxed for 2 h in ethanol (20 mL,
0.343 mol) in the presence of catalytic amount of H2SO4.
Crude product was purified by column chromatography
(silica gel, chloroform) to yield 2.5 g of ester (86%) as a
colorless liquid. Spectral data correspond with literature.23
4.2.6. 3,5-Dimethyladamantane-1-yl ethyl ketone. The
above title compound was prepared by the same procedure
like the ketone 2. Colorless liquid was obtained after
purification of the crude product by column chromato-
graphy (silica gel, 11% ethyl acetate/hexane); [Found: C,
81.8; H, 11.1. C15H24O requires C, 81.76; H, 10.98%];
nmax(KBr) 2944–2844 (br), 1701, 1455, 1375, 1357, 1333,
1260, 1208, 1159, 1126, 1094, 1027, 895, 842, 804, 700,
514 cmK1; dH (500 MHz, CDCl3) 2.39 (2H, q, JZ7.2 Hz,
COCH2CH3); 2.04–2.07 (1H, m, Ad); 1.57 (2H, m, Ad);
1.31–1.39 (4H, m, Ad); 1.28 (4H, m, Ad); 1.05–1.12 (2H, m,
Ad); 0.94 (3H, t, JZ7.2 Hz, COCH2CH3); 0.78 (6H, s, Ad-
Me,); dC (75.5 MHz, CDCl3) 216.2, 51.0, 48.5, 44.8, 43.1,
37.3, 31.1, 30.8, 29.6, 29.5, 8.1.
4.2.1. Adamantane-1-carbonyl chloride (1). Into a
suspension of adamantane-1-carboxylic acid (25.0 g,
0.126 mol) in toluene (32 mL) at 70 8C, SOCl2 (19.6 g,
0.164 mol) was added dropwise. The reaction mixture was
stirred at this temperature for 8 h. Then dry toluene (30 mL)
was added, the mixture was heated up and the SOCl2/
toluene azeotrope (30 mL) was distilled out. This procedure
was repeated three times. Finally, 20 mL of solvent was
distilled out, the residue was cooled down and allowed to
crystallize at K15 8C. Pale yellow needles obtained were
filtered and dried in a stream of an inert gas (yield 22.3 g,
89%, mp 47–48 8C, lit.16 mp 49–51 8C). NMR data
correspond with literature.16
4.2.7. 1-Adamantyl 4-methylphenyl ketone. The above
title compound was prepared by the same procedure like the
ketone 2. Colorless crystals were obtained after purification
of the crude product by crystallization from methanol, mp
61–63 8C; [Found: C, 85.0; H, 8.8. C18H22O requires C,
84.99; H, 8.72%]; nmax(KBr) 2943–2846(br), 1657, 1606,
1452, 1342, 1271, 1238, 1176, 1103, 991, 928, 833, 812,
737, 607 cmK1; dH (300 MHz, CDCl3) 7.53 (2H, m, Ph);
7.19 (2H, m, Ph); 2.39 (3H, m, Ad); 2.04–2.08 (9H, m, Ph-
CH3, Ad); 1.77 (6H, m, Ad); dC (75.5 MHz, CDCl3) 209.5,
140.9, 136.8, 128.8, 127.8, 47.1, 39.5, 36.8, 28.5, 21.6.
4.2.2. 1-Adamantyl ethyl ketone (2). Used as a standard
sample was prepared by the way described above scaled up
to 25 mmol of starting acyl chloride 1. AlCl3 and CuCl
were used as catalysts. Colorless flat crystals were
obtained after crystallization from ethanol/water (4.3 g,
89%, mp 31–33 8C, lit.17 31–32 8C). NMR data correspond
with literature.18
Acknowledgements
4.2.3. 1-(1-Adamantyl)propan-1-ol (3). Ketone 2 (1.32 g,
7 mmol) was treated with LiAlH4 (0.2 g, 5 mmol) in 20 mL
of dry diethyl ether at room temperature for 24 h according
to literature procedure.19 The reaction mixture was
quenched by addition of 30% aq. KOH solution (20 mL).
The resulting white suspension was filtered and washed with
diethyl ether. The combined organic phases were washed
with water and dried over Na2SO4. The solvent was
removed and colorless needles were obtained in amount
of 1.2 g (92%), mp 84–86 8C, lit.20 mp 85–86 8C). NMR
data correspond with literature.20
This work was supported by Ministry of Industry of the
Czech Republic, Grant No. PZ-CH/25.
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