Highly efficient and chemoselective acetalization and thioacetalization of aldehydes catalyzed by propylphosphonic anhydride (T3P) at room temperature

Article abstract of DOI:10.1016/j.tetlet.2012.07.052

Propylphosphonic anhydride (T3P), a low toxic peptide coupling agent, has been demonstrated to be an efficient catalyst for the chemoselective acetalization and thioacetalization of aldehydes in the presence of ketones. Cyclic and acyclic acetals of diverse aldehydes were obtained in good to excellent yields at room temperature in the presence of a catalytic amount of T3P.

Full text of DOI:10.1016/j.tetlet.2012.07.052

Tetrahedron Letters 53 (2012) 5030–5033
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Tetrahedron Letters
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Highly efficient and chemoselective acetalization and thioacetalization of
aldehydes catalyzed by propylphosphonic anhydride (ÒT3P) at room
temperature
John Kallikat Augustine a, , Agnes Bombrun b, Wolfgang H. B. Sauer b, Pujari Vijaykumar a
⇑
a Syngene International Ltd, Biocon Park, Plot Nos. 2 & 3, Bommasandra IV Phase, Jigani Link Road, Bangalore 560 099, India
b Merck Serono SA, 9 Chemin des Mines, 1202 Geneva, Switzerland
a r t i c l e i n f o
a b s t r a c t
Propylphosphonic anhydride (ÒT3P), a low toxic peptide coupling agent, has been demonstrated to be an
efficient catalyst for the chemoselective acetalization and thioacetalization of aldehydes in the presence
of ketones. Cyclic and acyclic acetals of diverse aldehydes were obtained in good to excellent yields at
room temperature in the presence of a catalytic amount of T3P.
Article history:
Received 15 June 2012
Revised 10 July 2012
Accepted 11 July 2012
Available online 20 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Acetalization
Propylphosphonic anhydride (ÒT3P)
Thioacetalization
Chemoselective
Catalyst
The protection of carbonyl compounds plays a vital role during
multistep syntheses in organic and medicinal chemistry. Among
carbonyl protecting procedures, acetalization and thioacetalization
are extensively used methods for protecting aldehydes and
ketones.1 In general, they are prepared by the reaction of carbonyl
compounds with an alcohol or thiol in the presence of a Brønsted
or Lewis acid catalyst.2 However, only a few of these methods have
demonstrated chemoselective protection of aldehydes in the pres-
ence of ketones3 and the existing methods suffer from the practical
limitations such as high catalyst loading, limited substrate scope,
and use of toxic reagents. Further, a lot of these methods required
refluxing temperatures to facilitate the complete reaction.3e,h Thus,
the development of efficient methods having broad substrate and
functional group tolerance for the chemoselective acetalization or
thioacetalization at room temperature is still vital.
Propylphosphonic anhydride (T3P) is an efficient and mild pep-
tide coupling reagent having low toxicity.4 Although T3P has been
widely used as a mild coupling reagent in peptide synthesis, new
applications have recently been developed for this reagent.5 In con-
tinuation to our studies on various applications of T3P,6 herein, we
report an efficient and mild procedure for acetalization and thioace-
talization of aldehydes using a catalytic amount of T3P. The method
is highly chemoselective, providing the selective acetalization of an
aldehyde in the presence of a ketone at room temperature.
A preliminary assessment established that T3P effectively cata-
lyzed the conversion of 4-chlorobenzaldehyde (1a) in methanol
into acetal 3a at reflux. Upon further optimization, we realized that
the reaction of 1a with methanol (2a) in the presence of T3P
(10 mol %; 50% solution in EtOAc) at room temperature for 4 h also
produced the desired dimethoxy acetal 3a in 94% isolated yield
(Table 1, entry 1). The scope and generality of the reaction was
then established by reacting structurally diverse aromatic, ali-
phatic, and unsaturated aldehydes with methanol at room temper-
ature for 4–7 h (Table 1). The results showed that excellent yields
of dimethoxy acetals were obtained (Table 1, entries 1–9) with T3P
as a catalyst. Further, the method has the ability to tolerate a vari-
ety of functionalities including acid sensitive groups (Table 1, entry
10) illustrating the mildness of the method.7 Under these reaction
conditions, the yield of the reaction did not change significantly
with aromatic aldehydes bearing electron withdrawing or electron
donating substituents on the ring, or with aliphatic aldehydes.8
Likewise, a hindered aldehyde did not behave differently, but affor-
ded the respective acetal in good yield (Table 1, entry 5).
Next, we investigated the scope of various alcohols tolerated by
acetalization mediated by T3P. As it was not optimum to use an ex-
cess of alcohol for each study, EtOAc was our solvent of choice that
facilitated complete dissolution of starting materials and ensured
an easy work up. Thus, a solution of 4-nitrobenzaldehyde (1b) in
EtOAc was treated with various alcohols (2.2 equiv) at room
⇑
Corresponding author. Tel.: +91 80 2808 3131; fax: +91 80 2808 3150.
E-mail addresses: john.kallikat@syngeneintl.com, john.kallikat@gmail.com
(J.K. Augustine).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.052

J. K. Augustine et al. / Tetrahedron Letters 53 (2012) 5030–5033
5031
Table 1
Table 2
T3P catalyzed acetalization: scope of aldehydes
T3P catalyzed acetalization: scope of alcohols
T3P (10 mol%)
T3P (10 mol%)
OMe
OMe
R
X R
X R
R
O2N
CHO
CHO
O2N
MeOH (5 vol)
ROH or RSH (2.2 equiv)
EtOAc, 3-5 h
1
3
RT, 4-7 h
1b
X = O, S
Entry
1
Substrate
Product
Yield (%)a
Entry Alcohol/thiol
Product
Yield
(%)a,b
CHO
OMe
OEt
OEt
OMe
94b
Cl
Cl
1a
1
2
Ethanol 2b
93
3a
O2N
CHO
OMe
OMe
3k
O2N
2
3
4
5
92
O
O
O2N
1b
3b
OMe
OMe
O
O
O
Isopropanol 2c
91
CHO
O2N
3l
NC
92
NC
1c
3c
3
4
1,2-Ethanediolc 2d
1,3-Propanediolc 2e
98
95
CHO
OMe
OMe
O2N
O2N
3m
O
HOOC
Cl
93
HOOC
Br
1d
3d
OMe
CHO
Br
3n
OMe
91c
Cl
O
3e
1e
Pinacolc 2f
91
O
O
O
5
Br
Br
O2N
O2N
O2N
3o
OMe
OMe
6
7
8
S
96
CHO
S
O
Ph
1-Phenyl-1,2-ethanediolc
2g
1f
CHO
3f
6
7
89
93
OMe
OMe
3p
O
O
93
O
1g
3g
1,2-Propanediolc 2h
1,2-Cyclohexanediolc 2i
1,3-Propanedithiolc 2j
Br
CHO
OMe
OMe
Br
3q
90c,d
N
N
1h
OMe
O
3h
O
S
OMe
OMe
OMe
8
9
94
95
CHO
CHO
O2N
O2N
3r
S
9
93
88
1i
3i
OMe
OMe
N
3s
boc
10
N
boc
a
b
c
Isolated yields.
Reaction took 3–5 h for completion.
1.2 equiv were used.
3j
1j
a
b
c
Isolated yields.
Reaction took 1 h for completion at reflux, and took 4 h at room temperature.
Reaction was completed in 7 h.
20 mol % of T3P was used.
d
primary, secondary, and tertiary alcohols.9 Besides, 1,2-diols gave
1,3-dioxolanes (Table 2, entries 3, 5–8)10 and 1,3-diols gave 1,3-
dioxanes (Table 2, entry 4), respectively, in good yields. Similarly,
1,3-propanedithiol underwent a smooth reaction to provide 1,3-
dithiane in good yield (Table 2, entry 9).11
temperature for 3–5 h (Table 2, entries 1–9) to give excellent yields
of corresponding acetals. The method was general with respect to

5032
J. K. Augustine et al. / Tetrahedron Letters 53 (2012) 5030–5033
Acetals and dithianes tolerate a broad range of basic, nucleo-
H
philic, reducing, and organometallic reagents. Dithianes are also
useful for the generation of masked carbonyl anions which are em-
ployed in Corey–Seebach reaction for C–C bond formation.12 As a
consequence, while demonstrating the chemoselectivity of this
method, we studied a competitive reaction of an aldehyde bearing
ketone functionality with a range of alcohols and thiols. Thus, 4-
acetylbenzaldehyde (1k) was treated with diverse alcohols and thi-
ols in the presence of a catalytic amount of T3P at room tempera-
ture (Table 3). After 4–6 h of reaction, the aldehyde group was
converted into its corresponding acetal or thioacetal in good to
excellent yields, while the ketone group remained unchanged even
after prolonged reaction time (Table 3, entries 1–7).
R1 OH
R
O
1
2
O
P
Pr
O
P
O
P
4
R1
R
Pr
O
O
O
O
Pr
H
O
P
Pr
HO
Pr
O
Pr
O
O
P
P
O
O
- OH
5
OH
Pr
O
The catalytic process involving T3P for the generation of acetals
could be explained by the transformations shown in Scheme 1. A
likely involvement of T3P (4) during the initiation of reaction be-
tween alcohol (2) and aldehyde (1) enhances the rate of formation
P
P
P
O
Pr
O
O
O
O
R
HO R1
R1
2
6
O
H
O
Pr
Table 3
7
T3P catalyzed chemoselective acetalization and thioacetalization
- H
O
T3P (10 mol%)
XR
CHO
R
3
O
R1
ROH or RSH (2.2 equiv)
XR
O
1k
EtOAc, RT
X = O, S
Yield (%)a,b
R1
Entry
1
Alcohol/thiol
Product
Scheme 1. Probable mechanistic pathway.
S
S
S
1,3-Propanedithiolc 2j
1,2-Ethanedithiolc 2k
1-Propanethiol 2l
96
of oxocarbenium ion 6 via intermediate 5. The nucleophilic attack
of a second molecule of alcohol on 6 produces acetal 3. The ‘open’
T3P (7) produced during the course of reaction cyclizes to regener-
ate the catalyst 4 (T3P), which in turn, promotes the catalytic cycle.
The transition state of an aldehyde after its reaction has a lower
energy than that of ketone due to steric crowding, and thus a ke-
tone exhibits a lower reactivity than aldehyde. Further, quantum
mechanical calculations (see, Supplementary data Table 4) find
the formation of intermediate 5 more favored for aldehydes than
for ketones which is in line with experimental findings: even in
the presence of a ketone, the reaction proceeds exclusively on
the aldehyde, producing only the relevant acetals/thioacetals.
In summary we have demonstrated the utilization of T3P, a low
toxic peptide coupling agent, as an efficient catalyst for the acetal-
ization or thioacetalization of aldehydes. The chemoselective ace-
talization or thioacetalization of an aldehyde in the presence of
ketone, the stability of acid-sensitive groups, easy workup proce-
dure, and the catalytic nature of the reagent make the present
methodology a practical alternative to the existing methodologies.
Besides, this procedure highlights the synthetic utility of T3P as a
versatile reagent in organic synthesis.
3t
O
O
S
2
3
94
89
3u
S
S
3v
O
Ph
S
Ph
S
4
Thiophenol 2m
95
3w
O
O
O
O
5
6
1,2-Ethanediolc 2d
1,3-Propanediolc 2e
95
96
3x
Supplementary data
O
Supplementary data (contains quantum mechanical calcula-
tions, copies of 1H NMR and 13C NMR for 3a–z, 3za and 3zb) asso-
ciated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2012.07.052.
O
O
3y
O
O
O
References and notes
7
Pinacolc 2f
91
1. (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd ed.;
John Wiley and Sons: New York, 1999; (b) Kocienski, P. J. Protecting Groups, 1st
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2. (a) Cameron, A. F. B.; Hunt, J. S.; Oughton, J. F.; Wilkinson, P. A.; Wilson, B. M. J.
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125; (d) Wenkert, E.; Goodwin, T. E. Synth. Commun. 1977, 7, 409; (e)
3z
a
b
c
Isolated yields.
Reaction took 4–6 h for completion.
1.2 equiv were used.

J. K. Augustine et al. / Tetrahedron Letters 53 (2012) 5030–5033
5033
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crude product was passed through a small plug of neutral alumina to afford the
dimethoxy acetals (3a–i) in good purity and yield.
8. Although, the less reactive aliphatic aldehydes such as n-octanal (1l) and
isovaleraldehyde (1m) could be converted into respective dimethoxy acetals on
reacting with methanol in the presence of T3P (10 mol %; 50% solution in
EtOAc) at room temperature, we were unable to isolate them in pure form
owing to their poor stability. However, 1l and 1m could easily be reacted with
pinacol at room temperature leading to the formation of more stable acetals
3za (93% yield) and 3zb (97% yield). Copies of 1H NMR and 13C NMR for
compounds 3za and 3zb are available in Supplementary data.
O
O
O
O
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3za
3zb
9. General procedure for the acetalization/thioacetalization: To
a mixture of
aldehyde (1, 0.01 mol) and an alcohol or thiol (2, 0.022 mol) in EtOAc
(10 mL) was added T3P (10 mol %, 50% solution in EtOAc). The resulting
reaction mixture was stirred at room temperature for 3–5 h. When the reaction
was completed (monitored by TLC), the mixture was cooled and washed with
saturated NaHCO3 solution and brine. The organic phase was dried over
anhydrous Na2SO4. The solvent was removed under reduced pressure and the
crude product was passed through a small plug of neutral alumina to afford the
acetals or thioacetals in good yield.
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Radhakrishnan, A. Tetrahedron 2009, 65, 9989; (b) Augustine, J. K.; Atta, R. N.;
Ramappa, B. K.; Boodappa, C. Synlett 2009, 3378; (c) Augustine, J. K.; Kumar, R.;
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Bombrun, A.; Mandal, A. B.; Alagarsamy, P.; Atta, R. N.; Selvam, P. Synthesis
2011, 1477; (e) Augustine, J. K.; Bombrun, A.; Venkatachaliah, S. Tetrahedron
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7. T3P catalyzed preparation of dimethoxy acetals (3a–i): a mixture of aldehyde (1,
0.01 mol), methanol (2a, 3–5 vol), and T3P (10 mol %, 50% solution in EtOAc)
was stirred at room temperature for 4–7 h. When the reaction was completed
(monitored by TLC), the solvent was removed under vacuum and the residue
was diluted with water (20 mL). The product was extracted with ethyl acetate
(2 Â 15 mL) and the combined organic extracts were washed with saturated
NaHCO3 solution (1 Â 10 mL) and brine. The organic phase was dried over
anhydrous Na2SO4. The solvent was removed under reduced pressure and the
10. General procedure for the preparation of 1,3-dioxolanes and 1,3-dithiolanes: To a
mixture of aldehyde (1, 0.01 mol) and 1,2-diol or 1,2-dithiol (2, 0.012 mol) in
EtOAc (10 mL) was added T3P (10 mol %, 50% solution in EtOAc). The resulting
reaction mixture was stirred at room temperature for 4–6 h. When the reaction
was completed (monitored by TLC), the mixture was cooled and washed with
saturated NaHCO3 solution and brine. The organic phase was dried over
anhydrous Na2SO4. The solvent was removed under reduced pressure and the
crude product was passed through a small plug of neutral alumina to give the
desired dioxolanes or dithiolanes in good yield.
11. General procedure for the preparation of 1,3-dioxanes and 1,3-dithianes: To a
mixture of aldehyde (1, 0.01 mol) and 1,3-diol or 1,3-dithiol (2, 0.012 mol) in
EtOAc (10 mL) was added T3P (10 mol %, 50% solution in EtOAc). The resulting
reaction mixture was stirred at room temperature for 4–6 h. When the reaction
was completed (monitored by TLC), the mixture was cooled and washed with
saturated NaHCO3 solution and brine. The organic phase was dried over
anhydrous Na2SO4. The solvent was removed under reduced pressure and the
crude product was passed through a small plug of neutral alumina to obtain
the desired dioxanes or dithianes in good yield.
12. (a) Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231; (b) Corey, E. J.; Seebach,
D. Angew. Chem., Int. Ed. Engl. 1965, 4, 1075; (c) Smith, A. B.; Xian, M. J. Am.
Chem. Soc. 2006, 128, 66.