Copper(II) tetrafluoroborate as a novel and highly efficient catalyst for acetal formation

Article abstract of DOI:10.1016/j.tetlet.2005.09.168

Commercially available copper(II) tetrafluoroborate hydrate has been found to be a highly efficient catalyst for dimethyl/diethyl acetal formation in high yields from aldehydes and ketones by reaction with trimethyl/triethyl orthoformate at room temperature and in short period. Acetalisation was carried out under solvent-free conditions with electrophilic aldehydes/ketones. For weakly electrophilic aldehydes/ketones (e.g., benzaldehyde, cinnamaldehyde and acetophenone) and for aldehydes having a substituent that can coordinate with the catalyst, the corresponding alcohol was used as solvent.

Full text of DOI:10.1016/j.tetlet.2005.09.168

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8319–8323
Copper(II) tetrafluoroborate as a novel and highly efficient
catalyst for acetal formation
Raj Kumar and Asit K. Chakraborti*
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER),
Sector 67, S.A.S.Nagar, Punjab 160 062, India
Received 24 July 2005; revised 23September 2005; accepted 28 September 2005
Available online 11 October 2005
Dedicated to Professor Mark S. Cushman
Abstract—Commercially available copper(II) tetrafluoroborate hydrate has been found to be a highly efficient catalyst for dimethyl/
diethyl acetal formation in high yields from aldehydes and ketones by reaction with trimethyl/triethyl orthoformate at room tem-
perature and in short period. Acetalisation was carried out under solvent-free conditions with electrophilic aldehydes/ketones. For
weakly electrophilic aldehydes/ketones (e.g., benzaldehyde, cinnamaldehyde and acetophenone) and for aldehydes having a substi-
tuent that can coordinate with the catalyst, the corresponding alcohol was used as solvent.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
tions. Thus, the development of an improved method
is still desirable.
Protection of aldehyde and ketone carbonyl groups is a
frequently desired exercise in organic synthesis as it is
often necessary to carry out a reaction on a multifunc-
tional substrate without affecting an aldehyde/ketone
group. One convenient method of protecting aldehydes
and ketones is to convert them into the corresponding
acetals.1 Acetalisation can be achieved by treatment
with alcohols in the presence of a protic1,2 or Lewis1,3
acid catalyst. A common regimen for acetal formation
is protic1,4 or Lewis1,5 acid catalysed reaction of alde-
hydes and ketones with trialkyl orthoformates. Other
methods use MeOH–PhSO2NHOH–MeONa,1b alkoxy-
silanes in the presence of TMSOTf,1b (EtO)3CH–
DDQ–EtOH6 and CAN–Na2CO3–ROH.7 However,
these methods have one or more drawbacks such as long
reaction times, high temperatures, use of costly re-
agents/catalysts, use of additional reagents, requirement
of special efforts for catalyst preparation, requirement of
stoichiometric amount of the catalysts, the need to use
special apparatus and moderate yields and side reac-
2. Results and discussions
When designing a new method, we realised that the use
of trialkyl orthoformates as the acetalisation agent in
the presence of a suitable transition metal catalyst
should constitute a better procedure operable under
mild conditions. The efficiency of the method would
depend upon the coordination property of the metal
catalyst to activate trialkyl orthoformate and/or the
carbonyl substrate. Recently, we have reported that
copper(II) tetrafluoroborate is an excellent catalyst for
electrophilic activation during acylation,8 diacetate for-
mation9 and thia-Michael addition10 reactions. In this
report, we disclose a highly efficient acetal formation
reaction catalysed by copper(II) tetrafluoroborate
(Scheme 1).
Various aldehydes and ketones were treated with tri-
methyl orthoformate in the presence of Cu(BF4)2ÆxH2O
Keywords: Dimethyl acetals; Diethyl acetals; Aldehydes; Ketones;
Copper(II) tetrafluoroborate hydrate; Catalyst; Trimethyl orthofor-
mate; Triethyl orthoformate.
R1
R2
R1 OR
R2
Cu(BF4)2.xH2O (1 mol%)
O
+ CH(OR)3
Neat or ROH, RT
OR
*
Corresponding author. Tel.: +91 0172 2214 682 686; fax: +91 0172
2214 692; e-mail: akchakraborti@niper.ac.in
Scheme 1. Cu(BF4)2ÆxH2O catalysed acetal formation.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.168

8320
R.Kumar, A.K.Chakraborti / Tetrahedron Letters 46 (2005) 8319–8323
formation was slow under neat conditions. However,
in these cases, the reactions proceeded well using MeOH
as solvent affording excellent yields (Table 2).
Table 1. Cu(BF4)2ÆxH2O catalysed dimethyl acetal formation from
aldehydes/ketones under solvent-free conditionsa
Entry Aldehyde/ketone
Time (min) Yield (%)b,c
CHO
R1
The phenyl/styryl groups in benzaldehyde, cinnamalde-
hyde and acetophenone made aldehyde/ketone carbonyl
less electrophilic due to resonance and inhibited the
effective formation of coordinate bonds with the cata-
lyst. For aldehydes bearing substituents that can coordi-
nate with the metal cation (e.g., OR, F, CN, NMe2, etc.)
no effective activation of trimethyl orthoformate by the
metal salt took place and acetal formation was retarded.
The moderate yield obtained with 4-dimethylamino-
benzaldehyde after 12 h (Table 2, entry 6) supported
the role of a coordinating effect of the substituent in
influencing acetal formation. Comparison of acetal for-
mation from 4-methylbenzaldehyde, 4-chlorobenzalde-
hyde and 4-nitrobenzaldehyde (Table 1, entries 1–3)
with those from 4-methoxybenzaldehyde, 4-fluorobenz-
aldehyde and 4-cyanobenzaldehyde (Table 2, entries 2–
4), respectively, highlighted the coordinating effect of
the substituents in the latter cases. The role of MeOH
may be explained by the fact that initial reaction of
R2
R3
R1 = R2 = H; R3 = Me
1
2
3
4
5
6
7
5
5
392
5
5
92
90
R1 = R2 = H; R3 = Cl
R1 = R2 = H; R3 = NO2
R1 = R2 = H; R3 = OCOPh
R1 = Br; R2 = R3 = H
R1 = Cl; R2 = R3 = H
R1 = R3 = H; R2 = NO2
91
88
90
92
5
8
CHO
8
9
15
85
CHO
15
2
82d
85
Table 2. Cu(BF4)2ÆxH2O catalysed dimethyl acetal formation from
10
11
Ph
Ph
CHO
CHO
aldehydes/ketones in dry MeOHa
Entry
Aldehyde/ketone
Time (min)
Yield (%)b,c
386
CHO
O
12
13
5
2
78
95
R
O
1
2
R = H
R = F
10
5
10
93d
95
3 R = CN
92
4
5
R = OMe
R = NMe2
20
12 h
91
58
a The aldehyde/ketone (2.5 mmol) was treated with CH(OMe)3
(2.0 equiv) in the presence of Cu(BF4)2ÆxH2O (1 mol %) at room
temperature (ꢀ25–30 ꢁC) under neat conditions.
CHO
b Isolated yield of the corresponding acetal.
c The products were characterised by IR, NMR.
d The reaction was carried out using 3equiv of CH(OMe) 3.
OMe
O
R
(1 mol %) at ꢀ25–30 ꢁC under neat conditions. The
reactions were monitored by IR and GCMS and the
optimum results are provided in Table 1. Substituted
benzaldehydes with Me, Cl, Br, NO2 and OCOPh
groups (entries 1–7), 1-naphthaldehyde (entry 8), 9-
anthraldehyde (entry 9), aryl alkyl aldehydes (entries
10 and 11) and saturated cyclic ketones (entries 12 and
13) afforded excellent results after 2–15 min. The reac-
tions could also be monitored visually: immediately
after the addition of the catalyst to the mixture of alde-
hyde and trimethyl orthoformate an exothermic reaction
takes place and the reaction mixture becomes homoge-
neous (for solid aldehydes) indicating completion of ace-
tal formation. In the case of 9-anthraldehyde, as the
product was solid, a small excess (3equiv) of trimethyl
orthoformate was required.
6
7
R = Me
R = c-C5H9
3 0
10
88
92
CHO
Ph
8
9
20
3
91
0
85
CHO
O
10
20
82
CHO
S
O
11
1.5 h
96
a The aldehyde/ketone (2.5 mmol) in dry methanol (1 mL) was treated
with CH(OMe)3 (2.0 equiv) in the presence of Cu(BF4)2ÆxH2O
(1 mol %) at room temperature (ꢀ25–30 ꢁC).
b Isolated yield of the corresponding acetal.
c The products were characterised by IR and NMR.
d A 36% yield was obtained on carrying out the reaction under neat
conditions.
In the cases of benzaldehyde, cinnamaldehyde, aceto-
phenone and aldehydes bearing substituents that are
capable of coordinating with the metal ion, the acetal

R.Kumar, A.K.Chakraborti / Tetrahedron Letters 46 (2005) 8319–8323
8321
MeO OMe
aldehyde with MeOH leads to the formation of a hemi-
MeO OMe
CHO
CHO
acetal, which undergoes nucleophilic attack on trimethyl
orthoformate complexed with Cu(BF4)2ÆxH2O and
results in acetal formation.4
CH(OMe)3
(5 mmol)
+
+
Cu(BF4)2.xH2O
(1 mol%)
NMe2
4
NMe2
2
Since there are limited reports for diethyl acetal forma-
tion,3e,f,4,5c–e,g we planned to evaluate the catalytic effi-
ciency of Cu(BF4)2ÆxH2O during the reaction of a few
representative aldehydes and ketones with triethyl
orthoformate (Table 3).
1
3
88%
12%
MeO
(2.5 mmol)
(2.5 mmol)
MeO OMe
Me
CHO
COMe
MeO
CH(OMe)3
(5 mmol)
+
+
Excellent results were obtained in each case. As
observed in the case of dimethyl acetal formation, the
reactions of benzaldehyde, cinnamaldehyde and aceto-
phenone required dry EtOH as solvent for diethyl acetal
formation.
Cu(BF4)2.xH2O
(1 mol%)
6
14%
1
5
3
86%
(2.5 mmol) (2.5 mmol)
MeO OMe
MeO OMe
CHO
CH(OMe)3
(5 mmol)
+
A comparison of the results of entries 1 and 6 (Table 2)
prompted us to study selective acetal formation during
intermolecular competition between benzaldehyde 1
and 4-dimethylaminobenzaldehyde 2. Thus, a mixture
of 1 (2.5 mmol) and 2 (2.5 mmol) in dry MeOH
(1 mL) was treated with trimethyl orthoformate
(5 mmol) in the presence of Cu(BF4)2ÆxH2O (1 mol %)
for 5 min at room temperature (Scheme 2). Excellent
selectivity was observed, (dimethoxymethyl)benzene 3
and 4-(dimethoxymethyl)-N,N-dimethylaniline 4 were
formed in a ratio of 88:12 (NMR). Similarly, the differ-
ence in the rate of reaction of 1 and acetophenone 5
(Table 2, compare the results of entries 1 and 11)
encouraged us to study the selectivity of acetal forma-
tion during inter- and intramolecular competition stud-
ies involving aldehyde and ketone carbonyl groups. The
Cu(BF4)2.xH2O
(1 mol%)
MeO
MeO
COMe
COMe
Me
7
9
8
77%
(2.5 mmol)
23%
Scheme 2. Cu(BF4)2ÆxH2O catalysed selective acetal formation during
inter- and intramolecular competition studies.
reaction of 1 (2.5 mmol) and 5 (2.5 mmol) with trimethyl
orthoformate (5 mmol) in dry MeOH (1 mL) in the pres-
ence of Cu(BF4)2ÆxH2O (1 mol %) at room temperature
for 5 min (Scheme 2) resulted in the formation of 3 and
2,2-dimethoxy-1-phenylethane 6 in a ratio of 86:14
(NMR). The reaction of 4-acetylbenzaldehyde
7
(2.5 mmol) with trimethyl orthoformate (5 mmol) in
MeOH (1 mL) in the presence of Cu(BF4)2ÆxH2O
(1 mol %) for 5 min at room temperature resulted
in the formation of 4-(dimethoxymethyl)acetophenone
Table 3. Cu(BF4)2ÆxH2O catalysed diethyl acetal formation from
aldehydes and ketonesa
Yield (%)b,c
8
and 2,2-dimethoxy-(40-dimethoxymethyl)-1-phenyl-
Entry
Aldehyde/ketone
Time (min)
ethane 9 in a ratio of 77:23(GCMS).
CHO
3. Conclusions
R
We have described herein the use of Cu(BF4)2ÆxH2O as a
highly efficient and reusable catalyst for dimethyl and
diethyl acetal formation at room temperature. The
advantages include, (i) the use of a cheap, easy to handle
and commercially available catalyst, (ii) room tempera-
ture reaction conditions, (iii) short reaction times, (iv)
80 high yields and (v) excellent chemoselectivity.
1
2
R = H
R = Me
10
3 95
5
93d
3 R = NO
95
92
d
2
CHO
Ph
4
5
10
3
CHO
Ph
0
O
6
7
375
4. Experimental
4.1. Typical procedure for acetal formation under neat
conditions
O
2 h
82d
To a magnetically stirred mixture of 4-methylbenzalde-
hyde (0.3g, 2.5 mmol) and trimethyl orthoformate
(0.53g, 5 mmol), Cu(BF 4)2ÆxH2O (6.0 mg, 0.025 mmol,
1 mol %) was added and the mixture was stirred at 25–
30 ꢁC until completion of the reaction (5 min, TLC,
IR). The mixture was diluted with saturated aq NaHCO3
(10 mL) and extracted with EtOAc (3 · 10 mL). The
a The aldehyde/ketone (1 equiv) was treated with CH(OEt)3 (2.0 equiv)
in the presence of Cu(BF4)2ÆxH2O (1 mol %) at rt (ꢀ25–30 ꢁC) in the
absence of solvent (except for entries 1, 5 and 7).
b Isolated yield of the corresponding acetal.
c The products were characterised by IR, NMR.
d The reaction was carried out in dry ethanol (1 mL).

8322
R.Kumar, A.K.Chakraborti / Tetrahedron Letters 46 (2005) 8319–8323
combined EtOAc extracts were washed with water (2 ·
10 mL), dried (Na2SO4) and concentrated under reduced
pressure to afford 4-(dimethoxy)methylbenzene (colour-
less oil, 0.415 g, 92%, entry 1, Table 1), IR (neat): 2936,
2828, 1618, 1447, 1353, 1201, 1105, 1054, 912,
100.86, 126.45, 128.02, 129.50, 129.65, 133.11, 135.28.
Anal. Calcd for C17H16O2: C, 80.93; H, 6.39. Found.
C, 80.96; H, 6.41. 3,4-(Dimethoxy)dimethoxymethylbenz-
ene (Table 2, entry 6): IR (neat): 2937, 2832, 1607,
1594, 1414, 1259, 1194, 1136, 1102, 990, 863, 863, 795,
807 cmꢁ1
;
1H NMR (300 MHz, CDCl3): d = 2.33 (s,
762 cmꢁ1 1H NMR (300 MHz, CDCl3): d = 3.32 (s,
.
3H), 3.30 (s, 6H), 5.35 (s, 1H), 7.15 (d, 2H, J = 7.6 Hz),
7.32 (d, 2H, J = 7.6 Hz); 13C NMR (75 MHz, CDCl3):
d = 21.2, 52.53, 103.16, 126.56, 128.81, 135.13, 138.06,
identical with an authentic sample.5e
6H), 3.88 (s, 3H), 3.90 (s, 3H), 5.33 (s, 1H), 6.84–6.97
(m, 1H), 6.98–6.99 (m, 2H). 13C NMR (75 MHz,
CDCl3): d = 52.34, 55.53, 102.86, 109.33, 110.40,
119.00, 126.48, 130.61, 148.64. Anal. Calcd for
C11H16O4 C, 62.25; H, 7.60. Found. C, 62.23; H, 7.63.
4-Cyclopentyloxy-3-methoxy dimethoxymethylbenzene
(Table 2, entry 7): IR (neat): 2954, 2829, 1607, 1510,
5. Representative experimental procedure for acetal
formation in the presence of solvent
1
1351, 1264, 1160, 1102, 1053, 988, 862, 804 cmꢁ1. H
NMR (300 MHz, CDCl3): d = 1.57–1.61 (m, 2H),
1.79–1.97 (m, 6H), 3.32 (s, 6H), 3.85 (s, 3H), 4.73–4.79
(m, 1H), 5.31 (s, 1H), 6.84 (d, 1H, J = 8.1 Hz), 6.93–
6.97 (m, 2H). 13C NMR (75 MHz, CDCl3): d = 24.03,
32.77, 52.75, 55.95, 80.32, 103.29, 110.10, 114.16,
119.07, 130.54, 147.73, 149.81. Anal. Calcd for
C15H22O4: C, 67.64; H, 8.33. Found. C, 67.63; H, 8.35.
To a magnetically stirred mixture of 4-cyanobenzalde-
hyde (0.327 g, 2.5 mmol) and trimethyl orthoformate
(0.53g, 5 mmol) in dry MeOH (1 mL), Cu(BF 4)2ÆxH2O
(6.0 mg, 0.025 mmol, 1 mol %) was added and the mix-
ture was stirred at 25–30 ꢁC until completion of the reac-
tion (10 min, TLC, IR). The reaction mixture was
diluted with saturated aq NaHCO3 (10 mL) and
extracted with EtOAc (3 · 10 mL). The combined
EtOAc extracts were washed with water (2 · 10 mL),
dried (Na2SO4) and concentrated under reduced pres-
sure to afford pure 4-(cyano)dimethoxymethylbenzene
(colourless oil, 0.407 g, 92%, entry 3, Table 2), IR (neat):
2938, 2832, 2229, 1353, 1209, 1101, 1057, 988, 822,
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.09.168.
556 cmꢁ1 1H NMR (300 MHz, CDCl3): d = 3.32 (s,
;
6H), 5.43(s, 1H), 7.50 (d, 2H, J = 8.3Hz), 7.68 (d,
2H, J = 8.3Hz); 13C NMR (75 MHz, CDCl3):
d = 52.56, 101.62, 112.14, 118.52, 127.45, 131.91,
143.10, identical with an authentic sample.2c
References and notes
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1
980, 755 cmꢁ1. H NMR (300 MHz, CDCl3): d = 3.35
(s, 6H), 5.55 (s, 1H), 7.14 (t, 1H, J = 7.5 Hz), 7.28 (t,
1H, J = 7.5 Hz), 7.52 (d, 1H, J = 7.6 Hz), 7.59 (d, 1H,
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1107, 1058, 981, 756 cmꢁ1
.
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.
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