N-acyl 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) tetraphenylborate salts as O-acylating agents

Article abstract of DOI:10.1016/j.tetlet.2012.05.108

Air-stable and crystalline N-acyl DBN tetraphenylborate salts have been shown to be effective O-acylating agents, reacting with both primary and secondary alcohols to give the corresponding esters in good yields. In the case of diols, the N-acyl DBN·BPh₄ salts have been shown to acylate regioselectively the primary alcohol functionality in the presence of a secondary alcohol. The DBN hydrotetraphenylborate side product can be readily removed by filtration, providing the ester products without the need for further purification.

Full text of DOI:10.1016/j.tetlet.2012.05.108

Tetrahedron Letters 53 (2012) 4074–4076
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Tetrahedron Letters
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N-Acyl 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) tetraphenylborate salts as
O-acylating agents
⇑
James E. Taylor, Jonathan M. J. Williams, Steven D. Bull
Department of Chemistry, University of Bath, Claverton Down, Bath, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Air-stable and crystalline N-acyl DBN tetraphenylborate salts have been shown to be effective O-acylating
agents, reacting with both primary and secondary alcohols to give the corresponding esters in good
yields. In the case of diols, the N-acyl DBNÁBPh4 salts have been shown to acylate regioselectively the pri-
mary alcohol functionality in the presence of a secondary alcohol. The DBN hydrotetraphenylborate side
product can be readily removed by filtration, providing the ester products without the need for further
purification.
Received 12 March 2012
Revised 14 May 2012
Accepted 23 May 2012
Available online 30 May 2012
Keywords:
Acylation
Alcohol
Ó 2012 Elsevier Ltd. All rights reserved.
Ester
DBN
Tetraphenylborate
Acyl chlorides and acid anhydrides are currently the most com-
monly used acyl sources in acylation reactions of alcohols. How-
ever, there are some limitations to the use of acyl chlorides and
acid anhydrides in synthesis. For example, the acylation reactions
of heteroatoms using acyl chlorides and acid anhydrides can be
highly exothermic.1 These processes also release acids, which can
cause problems with any acid-sensitive functionality present with-
in the reacting substrate. In addition, acyl chlorides of complex
substrates can be difficult to prepare, whilst simpler acyl chlorides
are often air-sensitive and volatile, which makes them practically
difficult to use. Base or Lewis acid catalysed O-acylation reactions
of alcohols using acyl chlorides or acid anhydrides can also suffer
from poor regioselectivity between primary and secondary
alcohols.2
The O-acylation of alcohols using carboxylic acids as sacrificial
acyl donors is also widely used, although forcing conditions are of-
ten required to drive the equilibrium towards formation of ester
products. Transesterification reactions are also commonly used,
with a number of different esters having been employed as sacrifi-
cial acyl donors.2,3 Various other alternative acyl sources have also
been developed for carrying out O-acylation reactions.4,5 For exam-
ple, Katritzky et al. have developed an extensive range of N-acyl
benzotriazoles as stoichiometric acylating agents.6 Some of these
N-acyl benzotriazoles have been used as O-acylating reagents for
trifluoroacetylations, the preparation of fluorescently labelled car-
bohydrates, and recently for the formation of depsipeptides and
oligoesters.7 Herein, we report the application of a new bench-sta-
ble and crystalline acyl source for the O-acylation of alcohols.
We previously reported that the bicyclic amidine 1,5-diazabicy-
clo[4.3.0]non-5-ene (DBN, 1) can be used to catalyse the Friedel–
Crafts acylation reaction of N-protected pyrroles and indoles.8,9
Whilst investigating the mechanism of this process, the X-ray crys-
tal structure of an N-acyl DBN tetraphenylborate salt was obtained,
providing structural information on the proposed intermediates in
these reactions. Subsequently, we found that a number of air-sta-
ble and highly crystalline N-acyl DBNÁBPh4 salts 3a–f could be pre-
pared in high yields by reacting DBN (1) with the corresponding
acyl chloride 2a–f in the presence of sodium tetraphenylborate
(Scheme 1).10,11
N-Acyl DBNÁBPh4 salts 3a–f were found to be highly efficient N-
acylating agents, reacting with a wide variety of anilines, primary
amines and secondary amines (Scheme 2a), as well as sulfonamides
(Scheme 2b) to form their corresponding N-acylated products in
high yields. It was found that the DBN hydrotetraphenylborate
side-product could be readily removed by filtration, providing
N
O
+
NaBPh4
MeCN, 0 °C, 1 h
N
−
+
N
BPh4
Cl
2a-f
R
N
O
R
1
3a-f
3a R = Me, 97%; 3b R = Ph, 93%; 3c R = o-Tol, 98%;
t
3d R = CH2CH2Ph, 73%; 3e R = Bu, 98%; 3f R = OEt, 95%
⇑
Corresponding author. Tel.: +44 1225 383551.
E-mail address: S.D.Bull@bath.ac.uk (S.D. Bull).
Scheme 1. Synthesis of N-acyl DBNÁBPh4 salts 3a–f from DBN (1) and acyl chlorides
2a–f.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.108

J. E. Taylor et al. / Tetrahedron Letters 53 (2012) 4074–4076
4075
Table 1
N
O
O
(a)
(b)
O-Acetylation of alcohols 4a–h using N-acetyl DBNÁBPh4 (3a) to afford esters 5a–ha
+
R1
MeCN
80 C, 1 24 h
R1
+
+
DBN⋅HBPh4
−
NH
R2
N
N
R
°
−
BPh4
R2
R
O
N
O
DBN (1) (20 mol%)
MeCN, 80 °C, 16 h
R1 = aryl, alkyl
+
R
OH
+
+ DBN⋅HBPh4
RO
R2 = H, alkyl, OMe
N
−
BPh4
3a
4a-h
5a-h
O
N
O
O
O
O
R1
O
+
DBN (1) (20 mol%)
S
S
R1
NH
R2
N
R2
R
+
+ DBN⋅HBPh4
N
−
Conversionb,c (%)
100 (88)
°
MeCN, 80 C, 16 h
Entry
1
Alcohol
Ester
BPh4
R
R1 = aryl, alkyl
O
R2 = H, alkyl
Ph
Ph
OH
Ph
Ph
O
5a
4a
Scheme 2. N-Acyl DBNÁBPh4 salts as N-acylating agents for (a) anilines, primary
amines and secondary amines and (b) for sulfonamides.
O
OH
2
100 (80)
100 (74)
100 (84)
100 (79)
4b
O
N-acylated products without the need for further purification.
These N-acyl DBNÁBPh4 salts are attractive alternatives to acyl ha-
lides and acid anhydrides as they can be stored in air without
decomposition, avoid the production of free acid during acylation
reactions, and can be used under forcing thermal conditions.10
Consequently, it was decided to investigate whether the N-acet-
yl DBNÁBPh4 salt (3a) could be applied to the O-acetylation of alco-
hols to form esters. Initially, benzyl alcohol (4a) and 1.3 equiv of N-
acetyl DBNÁBPh4 (3a) were heated in acetonitrile at 80 °C for 16 h,
in accordance with the optimal conditions developed for the N-
acylation of amines. However, 1H NMR spectroscopic analysis of
the crude reaction mixture showed only 36% conversion into ben-
zyl acetate (5a), with the remainder being unreacted starting
material (Scheme 3). In an attempt to improve the conversion,
the reaction was repeated using 20 mol % DBN (1) as a catalyst,
as this had previously been shown to increase the rate of sulfon-
amide N-acylation using N-acyl DBNÁBPh4 salts. Pleasingly, this re-
sulted in complete conversion of benzyl alcohol (4a) into benzyl
acetate (5a) within 16 h. The crude product could be readily puri-
fied by dissolving the reaction mixture in chloroform and filtering
off the insoluble salts, which were a mixture of unreacted N-acetyl
DBNÁBPh4 (3a) and DBNÁHBPh4. The filtrate was then washed with
NH4Cl and brine to remove the DBN (1) catalyst, providing pure
benzyl acetate (5a) in 88% yield without the need for chromato-
graphic purificiation.12
5b
O
OH
6
3
O
4c
6 5c
O
4d
O
5d
OH
4d
Et
Et
O
5
Ph
OH
OH
Ph
O
5e
4e
O
6
100 (63)
O
4
4
4f
5f
O
OH
O
7
8
100 (70)
0 (—)
4g
5g
OH
—
4h
The successful O-acylation protocol using 20 mol % DBN (1) was
then applied to a range of alcohols 4b–h, with the results summa-
rized in Table 1. The reaction of N-acetyl DBNÁBPh4 (3a) with 2-
phenethyl alcohol (4b) proceeded with complete conversion, en-
abling 2-phenethyl acetate (5b) to be isolated in 80% yield (Table 1,
entry 2). Acetylation of octanol (4c) also worked well, providing oc-
tyl acetate (5c) in 74% yield after the standard work-up procedure
(Table 1, entry 3). It was found that phenol (4d) was sufficiently
acidic to be acylated using N-acetyl DBNÁBPh4 (3a) without the
DBN (1) catalyst, giving phenyl acetate (5d) in 84% isolated yield
(Table 1, entry 4). Secondary alcohols could also be acylated using
N-acetyl DBNÁBPh4 (3a) and 20 mol % DBN (1), with the reactions of
both 1-phenyl-1-propanol (4e) and unsaturated 1-octen-3-ol (4f)
giving complete conversion into their corresponding esters 5e
and 5f in 79% and 63% yields respectively (Table 1, entries 5 and
6). The cyclic secondary alcohol, 1-indanol (4g) was also success-
a
Reactions performed on a 0.5 mmol scale using 0.65 mmol N-acetyl DBNÁBPh4
(3a) and 20 mol % DBN (1).
Determined by 1H NMR spectroscopic analysis.
b
c
Isolated yields in parentheses.
No DBN (1) required.
d
fully acetylated using N-acetyl DBNÁBPh4 (3a), providing the corre-
sponding acetate 5g in 70% isolated yield (Table 1, entry 7).
However, reaction of N-acetyl DBNÁBPh4 (3a) with the tertiary alco-
hol tert-butanol (4h) was unsuccessful, with 1H NMR spectroscopic
analysis of the crude material showing no evidence of any O-acet-
ylation having occurred (Table 1, entry 8). Attempts to promote the
reaction by using an excess of alcohol, or using tert-butanol (4h) as
solvent were also unsuccessful, with no O-acetylation observed in
either case.
The successful O-acetylation protocol using N-acetyl DBNÁBPh4
(3a) and 20 mol % DBN (1) was then applied to 1-phenyl-1,2-eth-
anediol (6) to investigate whether its primary alcohol functionality
could be acetylated regioselectively in the presence of a secondary
alcohol. In this case, one equivalent of N-acetyl DBNÁBPh4 (3a) was
used, rather than the 1.3 equiv used for the previous acetylations.
After the standard work-up procedure, 1H NMR spectroscopic anal-
ysis revealed that the reaction had proceeded to 84% conversion,
O
N
MeCN
80 °C, 16 h
+
+
+ DBN⋅HBPh4
Ph
OH
Ph
O
N −
BPh4
O
3a
4a
5a
No additive, 36% conversion
+ DBN (1) (20 mol%), 100% conversion
Scheme 3. O-Acetylation of benzyl alcohol (4a) using N-acetyl DBNÁBPh4 (3a).

4076
J. E. Taylor et al. / Tetrahedron Letters 53 (2012) 4074–4076
OH
OH
OAc
OAc
N
O
(a)
(b)
DBN (1) (20 mol%)
MeCN, 80 °C, 16 h
+
OH
OAc
OH
+
OAc
OBz
+
+
+
Ph
Ph
Ph
Ph
Ph
Ph
Ph
−
N
BPh4
7a
7b
7c
84% conversion
7a 7b 7c
= 76:12:12
3a
6
:
:
OH
OH
OBz
OBz
N
O
DBN (1) (20 mol%)
+
N
OH
OBz
OH
+
+
Ph
−
°
MeCN, 80 C, 16 h
BPh4
Ph
8a
8b
8c
60% conversion
3b
6
8a 8b 8c
= 86:8:6
:
:
Scheme 4. Acylation of 1-phenyl-1,2-ethanediol (6) using (a) N-acetyl DBNÁBPh4 (3a) and (b) N-benzoyl DBNÁBPh4 (3b).
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with 76% of the converted material being 2-hydroxy-2-phenethyl
acetate (7a) obtained from acetylation of the primary alcohol.
However, the reaction was not completely regioselective, as 12%
of the secondary ester 7b and 12% of the bis-acylated ester 7c were
also observed (Scheme 4a). It was found that using more sterically
demanding N-benzoyl DBNÁBPh4 (3b) as the acyl source improved
the regioselectivity of the acylation, with the primary ester 8a, sec-
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86:8:6 ratio, although the overall conversion was reduced to 60%
(Scheme 4b).
In conclusion, the bench-stable and highly crystalline N-acetyl
DBNÁBPh4 salt (3a) has been shown to be an efficient O-acetylating
agent for a range of primary and secondary alcohols. The ester
products can be isolated via a simple work-up procedure, without
the need for further purification by column chromatography. N-
Acetyl DBNÁBPh4 (3a) and N-benzoyl DBNÁBPh4 (3b) have also been
shown to acylate the primary alcohol functionality of diols that
5. For examples of enantiomerically pure acylating agents used in kinetic
resolution reactions, see: (a) Arseniyadis, S.; Valleix, A.; Wagner, A.;
Mioskowski, C. Angew. Chem. Int. Ed. 2004, 43, 3314–3317; (b) Kondo, K.;
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Katritzky, A. R.; Suzuki, K.; Wang, Z. Q. Synlett 2005, 1656–1665; (c) Katritzky,
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Zhang, Y. M.; Singh, S. K. Synthesis 2003, 2795–2798.
also contain
a secondary alcohol group with very high
regioselectivity.
7. (a) Avan, I.; Tala, S. R.; Steel, P. J.; Katritzky, A. R. J. Org. Chem. 2011, 76, 4884–
4893; (b) Katritzky, A. R.; Cusido, J.; Narindoshvili, T. Bioconjugate Chem. 2008,
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Acknowledgment
8. Taylor, J. E.; Jones, M. D.; Williams, J. M. J.; Bull, S. D. Org. Lett. 2010, 12, 5740–
5743.
9. Taylor, J. E.; Bull, S. D.; Williams, J. M. J. Chem. Soc. Rev. 2012, 41, 2109–2121.
10. Taylor, J. E.; Jones, M. D.; Williams, J. M. J.; Bull, S. D. J. Org. Chem. 2012, 77,
2808–2818.
J.E.T. gratefully acknowledges the University of Bath for the
award of a Ph.D. scholarship.
References and notes
11. General procedure for the synthesis of N-acyl DBNÁBPh4 salts 3a–f: NaBPh4
(1 equiv) was added to a round-bottom flask and purged with nitrogen. Dry
MeCN (to make a 0.2 M solution of NaBPh4) and the appropriate acyl chloride
(1.04 equiv) were added and the resulting solution cooled to 0 °C. DBN (1)
(1 equiv) was added dropwise and a precipitate of NaCl began to form. The
reaction was left to stir for 1 h before being warmed to room temperature and
filtered through a pad of CeliteÒ, washing thoroughly with MeCN. The filtrate
was then concentrated under reduced pressure and the resulting N-acyl
DBNÁBPh4 salt purified by recrystallization from CH2Cl2 and hexane.
12. General procedure for the O-acetylation of alcohols using N-acetyl DBNÁBPh4 (3a):
N-acetyl DBNÁBPh4 (3a) (1.3 equiv, 0.65 mmol) was added to a carousel tube
and purged with nitrogen. Dry MeCN (2 mL), the appropriate alcohol (1 equiv,
0.5 mmol) and DBN (1) (20 mol %, 0.1 mmol) were added and the resulting
solution heated at 80 °C for 16 h. After being cooled to room temperature, the
mixture was filtered and concentrated under reduced pressure. The crude
product was suspended in a minimum amount of hot CHCl3 and allowed to
cool before filtering off the insoluble salts. The filtrate was washed with
NH4Cl(aq) and brine before being dried over MgSO4, filtered, and concentrated
under reduced pressure.
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