A stable intermediate: a new insight into the mechanism of Lewis acids-promoted formation of acylals from aldehydes

Article abstract of DOI:10.1016/j.tetlet.2007.01.007

Treatment of m-nitrobenzaldehyde with acetic anhydride in the presence of Lewis acids, such as InBr₃, ZnBr₂, Cu(OTf)₂, gives a stable intermediate at the initial stage of reaction. Based on this new organic compound characterized by X-ray single crystal diffraction, a new mechanism for Lewis acids-promoted formation of acylals from aldehydes is proposed. Exchange reaction with different ratio of acetic anhydride to propionic anhydride, in the presence of Lewis acids, is studied.

Full text of DOI:10.1016/j.tetlet.2007.01.007

Tetrahedron Letters 48 (2007) 3119–3122
A stable intermediate: a new insight into the mechanism of
Lewis acids-promoted formation of acylals from aldehydes
Liang Yin, Zhan-Hui Zhang and Yong-Mei Wang*
Department of Chemistry and the State Key Laboratory of Elemento-Organic Chemistry,
Nankai University, Tianjin 300071, PR China
Received 3 September 2006; revised 26 December 2006; accepted 4 January 2007
Available online 9 January 2007
Abstract—Treatment of m-nitrobenzaldehyde with acetic anhydride in the presence of Lewis acids, such as InBr3, ZnBr2, Cu(OTf)2,
gives a stable intermediate at the initial stage of reaction. Based on this new organic compound characterized by X-ray single crystal
diffraction, a new mechanism for Lewis acids-promoted formation of acylals from aldehydes is proposed. Exchange reaction with
different ratio of acetic anhydride to propionic anhydride, in the presence of Lewis acids, is studied.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The development of effective methods for selective pro-
tection and deprotection is currently of urgent impor-
tance in multistep organic synthesis. The protection of
aldehydes as acylals (1,1-diacetates) rather than acetals1
plays an important role in organic synthesis because of
their stability in neutral and basic medium2 and easy
conversion into parent aldehydes.3 In addition, acylals
are useful starting materials and intermediates in organ-
ic synthesis.4 Generally, 1,1-diacetates can be prepared
from aldehydes by treatment with acetic anhydride in
the presence of a suitable catalyst such as proton acids,
Lewis acids,5 heteropolyacids,6 solid acids7 and so on.8
Among these catalysts, Lewis acids enjoy a wide sub-
strate scope, mild conditions, good chemoselectivity
and excellent yields.
stage. Surprisingly in the reaction of m-nitrobenzalde-
hyde and acetic anhydride catalyzed by other Lewis
acids (XmYn), such as ZnBr2, Cu(OTf)2, 1 is also ob-
tained. A small quantity of 1 was separated by flash
chromatography12 and its molecular structure deter-
mined by X-ray crystallography (Chart 1). Furthermore,
1 can also react with acetic anhydride to produce 1,1-
diacetate in the presence of Lewis acids such as InBr3,
ZnBr2, Cu(OTf)2. Treatment of two molecules of alde-
hyde with one molecule of acetic anhydride under the
catalysis of a Lewis acid leads to the formation of 1 in
a reasonably high yield in ethyl acetate.13 In light of this
result, we think that 1 is a key intermediate in this
To the best of our knowledge, however, the mechanism
of the reaction catalyzed by Lewis acids between alde-
hydes and acetic anhydride is still unclear.9 Pinnick
and co-workers proposed an intermolecular mechanism
involving an intermolecular transfer of a second acetate
group after initial attack by acetic anhydride in the pres-
ence of FeCl3.10 Due to our continued interest in
InBr3,11 we have carried out a series of experiments to
get further insight into the mechanism for this reaction.
To our joy, the reaction of m-nitrobenzaldehyde and
acetic anhydride in the presence of 1 mol % InBr3 pro-
ceeded and afforded a stable compound 1 at the initial
*
Corresponding author. Tel./fax: +86 22 23502654; e-mail: ymw@
nankai.edu.cn
Chart 1. X-ray crystal structure of 1.
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.007

3120
L. Yin et al. / Tetrahedron Letters 48 (2007) 3119–3122
reaction and the reaction should be divided into two
processes. First, two m-nitrobenzaldehyde molecules
react with one acetic anhydride molecule to give one
molecule of 1 in the presence of Lewis acids. Another
acetic anhydride activated by Lewis acids then attacks
1 in the following step to afford 1,1-diacetate as the final
product (Scheme 1).
O
O
O
X Y
RCHO
m
n
R
O
RHC
O
X Y
m n
Based on the separated intermediate 1, the mechanism
of the formation of acylals is proposed in Scheme 2.
With the activation of carbonyl group of aldehyde by
coordinating its oxygen to Lewis acids (such as InBr3,
ZnBr2 or Cu(OTf)2), the transformation commences
with the reaction between two aldehyde molecules acti-
vated by Lewis acids and one acetic anhydride molecule.
The dissociation of Lewis acids from the original car-
bonyl group leads to a stable intermediate 2. We origi-
nally considered that 1,1-diacetate would be obtained
by the reaction of 1 and acetic anhydride in the absence
of Lewis acids. But GS analysis of a reaction mixture of
1 and acetic anhydride indicates that no 1,1-diacetate is
obtained in ethyl acetate while intermediate 1 is quanti-
tatively recovered instead. On the other hand, in the
presence of Lewis acids, such as ZnBr2, InBr3 or
Cu(OTf)2, TLC analysis indicates that 1 completely dis-
appeared in ethyl acetate and the corresponding 1,1-
diacetate is obtained nearly quantitatively, confirming
that Lewis acid is required to facilitate the following
process. Subsequent nucleophilic attack on 2 by acetic
anhydride activated by Lewis acids and near simulta-
neous dissociation of Lewis acids from the acetic anhy-
(CH CO) O
O
O
3
2
R
O
X Y
m
n
O
O
X Y
(CH CO) O
m
n
3
2
R
2
Scheme 2. Proposed mechanism of reaction between aldehyde and
acetic anhydride in the presence of Lewis acids.
dride generate 1,1-diacetate. Because of the similarities
between Lewis acids, it is reasonable to expect that this
reaction catalyzed by other Lewis acids will be quite
similar to InBr3, ZnBr2 or Cu(OTf)2-promoted
transformation.
To further verify our proposed mechanism, a variation
of the above reaction, in which a mixture of acetic anhy-
dride and propionic anhydride at a ratio of 1:1 is em-
ployed instead of acetic anhydride alone, is carried out
in the presence of different Lewis acids (Scheme 3).14
However, 3 and 4 have not been observed in the reac-
tions. When ZnBr2, InBr3 or Cu(OTf)2 are used as cat-
alysts at a substrate to catalyst ratio of 100:1, geminal
diacetate 5, mixed acetate/propionate 6 and geminal
dipropionate 7 are obtained in the ratio 27.0:49.7:23.3,
28.7:49.9:21.3 or 25.3:50.1:24.6, as determined by
CHO
NO
2
CHO
InBr , ZnBr or Cu(OTf)
2
(CH CO) O
3
2
3
2
NO
2
(CH3CO)2O
(C2H5CO)2O
O
Lewis acid
O
O
O
O
O
O C CH3
O C C2H5
O
O
O
O C CH3
O
O C C2H5
O
1
NO
2
4
3
InBr , ZnBr or Cu(OTf)
2
(CH CO) O
(CH3CO)2O
3
2
3
2
(CH3CO)2O
Lewis acid
(C2H5CO)2O
(C2H5CO)2O
Lewis acid
H
CH(OCOCH )
CH(COOCH3)2
H3COOC C COOC2H5
CH(COOC2H5)2
3 2
NO
2
5
7
6
Scheme 1. Conversion of m-nitrobenzaldehyde to corresponding 1,1-
diacetate in the presence of Lewis acids, such as InBr3, ZnBr2 or
Cu(OTf)2.
Scheme 3. Exchange reaction in the presence of Lewis acids (such as
InBr3, ZnBr2 and Cu(OTf)2).

L. Yin et al. / Tetrahedron Letters 48 (2007) 3119–3122
3121
a
Table 1. Exchange reaction in the presence of InBr3
In conclusion, a stable intermediate is separated and
characterized by X-ray crystallography in the reaction
of m-nitrobenzaldehyde with acetic anhydride using
Lewis acids as catalysts. Based on this finding, a plausi-
ble mechanism is reasonably proposed. Exchange reac-
tion, in the presence of Lewis acids, such as ZnBr2,
InBr3 or Cu(OTf)2, is studied in detail. In light of the
proposed mechanism, the inert nature towards acetic
anhydride of aromatic aldehydes with an amino group
can be reasonably explained.
Entry
Ratiob
5 (%)
6 (%)
7 (%)
1
2
3
4
5
6
7
10:1
5:1
2:1
1:1
1:2
79.7
65.9
42.6
22.4
9.9
18.5
31.0
45.3
51.4
44.1
27.1
16.2
1.8
3.1
12.1
26.2
46.0
70.0
82.6
1:5
1:10
2.8
1.2
a Benzaldehyde (10 mmol), acetic anhydride and propionic anhydride
(30 mmol), InBr3 (0.1 mmol).
b Ratio of acetic anhydride to propionic anhydride.
Acknowledgement
GC/MS, respectively. Furthermore, the mixtures of ace-
tic anhydride and propionic anhydride at different ratios
were also used to react with benzaldehyde in the pres-
ence of InBr3 (Table 1). It is evident that the concentra-
tion of 5 and 7 increases with enhancement of ratio of
corresponding anhydride to the other. However, with
the increasing ratio of one anhydride to the other, the
concentration of 6 firstly increases, but then begins to
decrease.
The authors thank the National Natural Science Foun-
dation of China (20472032) for financial support.
Supplementary data
X-ray single crystal diffraction data for 1 are available.
Supplementary data associated with this article can be
found in the online version at doi:10.1016/j.tetlet.
2007.01.007.
It has been reported that many catalysts are not suitable
for the preparation of gem-diacetates from aromatic
aldehydes with an amino group, such as p-(dimethyl-
amino) benzaldehyde, possibly due to the strong elec-
tron-donating dimethylamino group and the existence
of the quininoid structure with an aldehyde which de-
crease the reactivity of the aldehyde group.15 It is worth
noting that in the case of its protonated species, such as
N,N-dimethylammonium benzaldehyde, the reaction
progressed smoothly at room temperature to afford an
excellent yield of the corresponding gem-diacetate 9,
which was isolated as its free amine 8 after hydrogencar-
bonate workup (Scheme 4). However, we believe that
the stronger coordinating ability of an amino group
than a carbonyl group hinders the reaction. In spite of
the strongly electron-withdrawing nature of the N,N-
dimethylammonium ion, the reaction works well with-
out interfering of the amino functional group. Lewis
acids activate the carbonyl group of aldehyde and then
the transformation begins.
References and notes
1. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; John Wiley and Sons: New
York, 1999.
2. Gregory, M. J. J. Chem. Soc. B 1970, 1201–1207.
3. (a) Narayana, C.; Padmanabhan, S.; Kabalka, G. W.
Tetrahedron Lett. 1990, 31, 6977–6978; (b) Zhang, Z.-H.
Monatsh. Chem. 2005, 136, 1191–1195; (c) Perez, E. R.;
Marrero, A. L.; Perez, R.; Autie, M. A. Tetrahedron Lett.
1995, 36, 1779–1782; (d) Li, T.-S.; Zhang, Z.-H.; Fu, C.-G.
Tetrahedron Lett. 1997, 38, 3285–3288; (e) Jin, T.-S.; Ma,
Y.-R.; Zhang, Z.-H.; Li, T.-S. Synth. Commun. 1997, 27,
3379–3383; (f) Aggarwal, V. K.; Fonquerna, S.; Vernnall,
G. P. Synlett 1998, 849–850; (g) Ballini, R.; Bordoni, M.;
Bosica, G.; Maggi, R.; Sartori, G. Tetrahedron Lett. 1998,
39, 7587–7590; (h) Zolfigol, M. A.; Zebarjadian, M. H.;
Mohammadpoor-Baltork, I.; Shamsipur, M. Synth. Com-
mun. 2002, 32, 2803–2808; (i) Sartori, G.; Ballini, R.; Bigi,
F.; Bosica, G.; Maggi, R.; Righi, P. Chem. Rev. 2004, 104,
199–250.
4. (a) Sinder, B. B.; Amin, S. G. Synth. Commun. 1978, 8,
117–125; (b) Banks, R. E.; Miller, J. A.; Nunn, M. J.;
Stanley, P.; Weakley, T. J. R.; Ullah, Z. J. Chem. Soc.,
Perkin Trans. 1 1981, 1096–1102; (c) Trost, B. M.; Lee, J.
M.; Weiss, J. J. Am. Chem. Soc. 1995, 117, 7247–7248; (d)
Sydnes, L. K.; Sandberg, M. Tetrahedron 1997, 53, 12679–
12690; (e) Heerden, F. R.; Huyser, J. J.; Williams, D. B.
G.; Holzapfer, C. W. Tetrahedron Lett. 1998, 39, 5281–
5284; (f) Sandberg, M.; Sydnes, L. K. Tetrahedron Lett.
1998, 39, 6361–6364; (g) Sandbery, M.; Syndes, L. K. Org.
Lett. 2000, 2, 687–689; (h) Yadav, J. S.; Reddy, B. V. S.;
Reddy, G. S. K. K. Tetrahedron Lett. 2000, 41, 2695–2697;
(i) Trost, B. M.; Lee, C. J. Am. Chem. Soc. 2001, 123,
12191–12201.
CHO
CH(OCOCH )
3 2
(CH CO) O
3
2
InBr , 24 h
3
N(CH )
N(CH )
3 2
3 2
8 (0%)
CHO
CH(OCOCH )
3 2
(CH CO) O
3
2
InBr , 1 h
3
5. (a) Scriabire, I. Bull. Chem. Soc. Fr. 1961, 1194–1198; (b)
Michie, J. K.; Miller, J. A. Synthesis 1981, 824; (c)
Aggarwal, V. K.; Fonquerna, S.; Vennall, G. P. Synlett
1998, 849–850; (d) Chandra, K. L.; Saravanan, P.; Singh,
V. K. Synlett 2000, 359–360; (e) Yadav, J. S.; Reddy, B. V.
S.; Venugopal, C.; Ramalingam, T. Synlett 2002, 604–606;
NH(CH )
NH(CH )
3 2
3 2
Cl
Cl
9 (91%)
Scheme 4. Diacylation of p-(N,N-dimethylammonium) benzaldehyde
in the presence of InBr3.

3122
L. Yin et al. / Tetrahedron Letters 48 (2007) 3119–3122
(f) Roy, S. C.; Banerjee, B. Synlett 2002, 1677–1678;
Y.-M.; Liu, J.-Y.; Li, Y. Green Chem. 2004, 6, 563–565; (c)
Zhang, Z.-H.; Yin, L.; Li, Y.; Wang, Y.-M. Tetrahedron
Lett. 2005, 46, 889–893; (d) Zhang, Z.-H.; Yin, L.; Wang,
Y.-M. Adv. Synth. Catal. 2006, 348, 184–190.
(g) Karimi, B.; Ebrahiminan, G.-R.; Seradj, H. Synth.
Commun. 2002, 32, 669–673; (h) Yadav, J. S.; Reddy,
B. V. S.; Srinivas, C. Synth. Commun. 2002, 32, 1175–
1180; (i) Zhang, X.-Y.; Li, L.-J.; Zhang, G.-S. Green
Chem. 2003, 5, 646–648; (j) Karimi, B.; Maleki, J. J. Org.
Chem. 2003, 68, 4951–4954; (k) Smitha, G.; Reddy, C. S.
Tetrahedron 2003, 59, 9571–9576; (l) Ranu, B. C.; Dutta,
J.; Das, A. Chem. Lett. 2003, 32, 366–367; (m) Chakra-
borti, A. K.; Thilagavathi, R.; Kumar, R. Synthesis 2004,
831–833; (n) Aggen, D. H.; Arnold, J. N.; Hayes, P. D.;
Smoter, N. J.; Mohan, R. S. Tetrahedron 2004, 60, 3675–
3679; (o) Ghosh, R.; Maiti, S.; Chakraborty, A.; Halder,
R. J. Mol. Catal. A: Chem. 2004, 215, 49–53; (p) Bosco,
J. W. J.; Purkayastha, N.; Raju, B. R.; Saikia, A. K.
Synth. Commun. 2005, 35, 1301–1305; (q) Yang, S.-T.
J. Chem. Res. 2006, 199–202.
12. Separation of 1: A mixture of m-nitroaldehyde (1.511 g,
10 mmol), freshly distilled acetic anhydride (3.063 g,
30 mmol) and ZnBr2 (0.023 g, 0.1 mmol) was stirred at
room temperature. After 2 min, ethyl acetate (100 mL)
was added and the mixture was washed successively with
1 mol/L NaOH solution (2 · 20 mL), brine (10 mL) and
H2O (10 mL). The organic layer was separated and dried
over Na2SO4. Further purification was achieved by
column chromatograph on silica to give pure 1 (0.045 g,
1.8%). The crystals of 1 were obtained from a mixture of
dichloromethane and hexane. 1H NMR (300 MHz,
CDCl3, TMS): d 2.153 (s, 6H), d 7.250 (s, 2H), d 7.617
(t, J = 7.8 Hz, 2H), d 7.852 (dd, J = 1.2 Hz, 7.8 Hz, 2H), d
8.282 (dd, J = 1.2 Hz, 7.8 Hz, 2H), d 8.390 (s, 2H).
Elemental analysis: C18H16N2O9: Calcd: C, 53.47; H,
3.99; N, 6.93. Found: C, 53.52; H, 3.96; N, 7.01. CCDC
255816.
6. (a) Romanelli, G. P.; Thomas, H. J.; Baronetti, G. T.;
Autino, J. C. Tetrahedron Lett. 2003, 44, 1301–1303; (b)
Firouzabadi, H.; Iranpoor, N.; Nowrouzi, F.; Amani, K.
Tetrahedron Lett. 2003, 44, 3951–3954.
7. (a) Olah, G. A.; Mehrotra, A. K. Synthesis 1982, 962; (b)
Kumar, P.; Hegde, V. R.; Kumar, T. P. Tetrahedron Lett.
1995, 36, 601–602; (c) Pereira, C.; Guisnte, B.; Marcelo-
13. Treatment of two molecules of aldehyde with one molecule
of acetic anhydride catalyzed by Lewis acids in a low
concentration in ethyl acetate: A mixture of m-nitroalde-
hyde (0.302 g, 2 mmol), freshly distilled acetic anhydride
(0.102 g, 1 mmol) and InBr3 (0.035 g, 0.1 mmol) was
stirred in ethyl acetate (2 mL) at room temperature. After
12 h, evaporation of the solvent under reduced pressure
gave mixed products. Further purification was achieved by
column chromatograph on silica to give m-nitroaldehyde
´
Curto, M. J.; Carreyre, H.; Perot, G.; Guisnet, M.
Synthesis 1995, 1077–1078; (d) Ballini, R.; Bordoni, M.;
Bosica, G.; Maggi, R.; Sartori, G. Tetrahedron Lett. 1998,
39, 7587–7590; (e) Li, T.-S.; Zhang, Z.-H.; Gao, Y.-J.
Synth. Commun. 1998, 28, 4665–4671; (f) Li, Y.-Q. Synth.
Commun. 2000, 30, 3913–3917; (g) Li, Y.-Q.; Cheng, L.-H.
Chin. Chem. Lett. 2001, 12, 565–568; (h) Jankovicˇ, L.;
Komadel, P. J. Catal. 2003, 218, 227–233; (i) Jin, T.-S.;
Feng, G.-L.; Yang, M.-N.; Li, T.-S. Synth. Commun. 2004,
34, 1645–1651.
(0.139 g, 0.92 mmol),
(0.223 g, 0.88 mmol).
1 (0.012 g, 0.03 mmol), acylal
14. Typical exchange reaction: Benzaldehyde (1.060 g,
10 mmol) and ZnBr2 (0.023 g, 0.1 mmol) were added to
a mixture of acetic anhydride (1.021 g, 10 mmol) and
propionic anhydride (0.301 g, 10 mmol). The progress of
the reaction was monitored by TLC. After completion of
the reaction, ethyl acetate (100 mL) was added and the
mixture was washed successively with 1 mol/L NaOH
solution (2 · 20 mL), brine (10 mL) and H2O (10 mL). The
organic layer was separated and dried over Na2SO4.
Evaporation of the solvent under reduced pressure gave
mixed products, whose analysis by GC/MS shows the
ratio between 5, 6 and 7.
8. (a) Deka, N.; Kalita, D. J.; Borah, R.; Sarma, J. C. J. Org.
Chem. 1997, 62, 1563–1564; (b) Jin, T.-S.; Du, G.-Y.;
Zhang, Z.-H.; Li, T.-S. Synth. Commun. 1997, 27, 2261–
2266; (c) Karimi, B.; Seradj, H.; Ebrahimian, G. R. Synlett
2000, 623–624.
9. Patel, B. K.; Kavala, V. K. Eur. J. Org. Chem. 2005, 441–
451.
10. Kochhar, K. S.; Bal, B. S.; Deshpande, R. P.; Rajadh-
yaksha, S. N.; Pinnick, H. W. J. Org. Chem. 1983, 48,
1765–1767.
11. (a) Yin, L.; Zhang, Z.-H.; Wang, Y.-M.; Pang, M.-L.
Synlett 2004, 1727–1730; (b) Zhang, Z.-H.; Yin, L.; Wang,
15. Jin, T.-S.; Sun, G.; Li, Y.-W.; Li, T. S. Green Chem. 2002,
4, 255–256.