A convenient synthesis of bisamides with BF3 etherate as catalyst

Article abstract of DOI:10.1016/j.tet.2013.11.017

A convenient synthesis of bisamide from aldehyde and amide with BF ₃ etherate as catalyst was reported. Both aryl and aliphatic bisamides could be prepared with this procedure in high yield at room temperature and the catalyst loading as low as

Full text of DOI:10.1016/j.tet.2013.11.017

Tetrahedron 69 (2013) 11080e11083
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Tetrahedron
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A convenient synthesis of bisamides with BF3 etherate as catalyst
*
Yi Zhang, Zhihao Zhong, Yingmei Han, Ruirui Han, Xu Cheng
Institute of Chemistry and Biomedical Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210046, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 August 2013
Received in revised form 27 October 2013
Accepted 5 November 2013
Available online 15 November 2013
A convenient synthesis of bisamide from aldehyde and amide with BF3 etherate as catalyst was reported.
Both aryl and aliphatic bisamides could be prepared with this procedure in high yield at room tem-
perature and the catalyst loading as low as 0.5 mol % was achieved. Fine-tuned solvent was utilized for
both rapid conversion and simple isolation. Two CB2 receptor inverse agonists were synthesized with
this protocol in high yield.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Catalysis
Aminal
Aldehyde
Amide
Condensation
1. Introduction
this significant biological potency, the bisamides were also ap-
plied as the ligands in the Ullmann coupling reactions by Pan and
Aminal compounds have been applied in the treatment of
high blood pressure and arise the interests from synthetic com-
munity.1 Several enantioselective syntheses of acyclic and cyclic
aminal compounds were reported using organocatalysts by
Antilla,2 List,3 Rueping,4 and Tian groups,5 respectively. Recently,
Kesavan showed Lewis acid was highly stereoselective catalyst to
construct the cyclic aminal chiral center as well.6 Another type of
aminal compound, the methylidene bisamides bearing two gem-
amide units showed their application as a new class of CB2 re-
ceptor inverse agonist with high efficacy along with the signifi-
cant CB1/CB2 selectivity (Ki(CB1)/Ki(CB2)) as high as 235 folds.
Similar compound could inhibit the osteoclast formation with
co-workers.8
The first synthesis of gem-bisamide was achieved via conden-
sation reaction between aldehyde and amide in 1933 by Noyes.9
There were some good catalytic syntheses of bisamides employ-
ing Brønsted acids or Lewis acids as catalysts as well.10
Though with these progresses, there were still some challenges:
in some conversions utilizing different catalysts, for example,
H2SO4,10a supported sulfonic acid,10h p-TsOH, FeCl3$3H2O, ZnCl2,10f
and silica-supported BaCl2,10g elevated temperature was required.
So far, only TMSOTf7,10d was reported as catalyst to effect the con-
version at room temperature with 10 mol % loading, which limited
the scale-up regarding the catalyst cost. On the other hand, in the
solvent free version, the reactions still require the wet workup and
purification with organic solvent,10f,g which increased the overall E
factor.13 The substrate scope with good yield is still a major concern
in the catalysis system. The searching for an inexpensive catalyst for
room temperature reaction will also facilitate the syntheses of the
bisamides.
the IC72 of 0.1 mM. The computational studies show the scaffold is
important in terms of activity and selectivity (Fig. 1).7 Besides
We reasoned that the typical pKa values for the protonated al-
dehyde and amide are ꢀ1011 and ꢀ0.5,12 respectively, which sug-
gests the Brønsted acid is captured by amide instead of
the aldehyde. Thus the activation of aldehyde with minor part of
Brønsted acid incurs the elevated temperature frequently. So
our effort was focused on the Lewis acid catalyzed condensation of
aldehyde and amide (Scheme 1). Herein, we would like to report
our BF3 etherate catalysis for more efficient synthesis under mild
condition with simple workup for broad substrate range.
Fig. 1. The CB receptor inverse agonist with bisamide backbone.
* Corresponding author. Tel./fax: þ86 025 8468 7375; e-mail address: chengxu@
nju.edu.cn (X. Cheng).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.11.017

Y. Zhang et al. / Tetrahedron 69 (2013) 11080e11083
11081
For a straightforward reaction, it is ideal to get the pure product
from reaction mixture directly even without recrystallzation.17
Herein, the convenience of this protocol was demonstrated in
Fig. 2, where the reaction (entry 13) started as a reddish clear so-
lution of aldehyde, amide, and BF3 etherate in acetone and ended as
a white gel. The pure solid product 1a could be collected by simple
filtration.
Scheme 1. Catalyzing the reaction with Lewis acid.
2. Results and discussion
The initial study was to screen different kinds of Lewis acids
and solvents to identify the most reactive catalyst and medium
for the condensation and the results were summarized in Table 1
where p-fluorobenzaldehyde and benzamide were employed as
standard substrate. To achieve the mild condition, the reaction
was locked at room temperature with 10 mol % catalyst. Lewis
acids, such as Ti(OiPr)4, Mg(ClO4)2, Sc(OTf)3, Cu(OTf)2, CuBr, and
TiCl4 did not achieve any positive result (entries 1e6). Widely
applied AlCl3 (entry 7) gave only 25% yield. To our delight, BF3
etherate, a well-known14 and cheap15 Lewis acid, increased the
yield significantly to 47% in diethyl ether (entry 8). The following
solvent optimization revealed that the solubility of both sub-
strate and product play an important role in this process. It was
found when the substrate was well soluble and the product could
precipitate at low concentration, the reactivity, the ease of
workup by filtration, and the high purity of product could meet
together. Thus the toluene, DCM, THF, and ethyl acetate (entries
9e12) failed to obtain homogenous solution at the first stage, and
in turn diminished the yield and purity of final product. Mean-
while highly polar solvents, such as DMF and EtOH (entries 14 &
15) also failed to enhance the reaction due to their perfect sol-
ubility for both substrate and product. To our surprise, acetone,
a conventional aldol donor and a relatively green and healthy
solvent for room temperature reaction,16 boosted the yield to 82%
(entry 13).
Fig. 2. The product 1a was achieved as white gel.
Encouraged by these results, we explored a variety of alde-
hydes and amides with BF3 etherate as the catalyst (Table 2). The
aromatic aldehyde bearing electron-withdrawing group gave
faster conversion than 3-methoxysalicylaldehyde (1a vs 1h). The
aromatic aldehydes containing bromide were favored due to the
enhanced precipitation (1def). To our delight, several functional
groups, such as phenol and thiophenyl were well compatible
without significant impact on the yield (1hej). The electronic
effect on aromatic amide was also investigated and it was found
that both electron withdrawing (2aec) and electron donating
groups (3aec, 4a,b) benefit the reactivity. The amides, such as
cinnamide, acrylamide, phenylacetamide, and thienylacetamide
gave corresponding bisamide (5a,b, 6, 7aee, 8aee) as precipitate
with high yield. Meanwhile, the fully aliphatic amides reacted
with a variety of aldehydes, offering bisamides (9aee, 10a,b) in
the same manner.
Table 1
The screening for optimum catalyst and solventa
The catalytic efficiency of BF3 etherate was measured with the
reaction toward 7b employing catalyst loading from 10 mol % to
0.5 mol % at room temperature. It was clear that with extended
reaction time, 0.5 mol % catalyst worked well almost without any
compromise of productivity (Table 3).
To explore the scalability of this conversion, the preparation of
1m was scaled up to 1 mol with 1 mol % BF3 etherate as catalyst. The
reaction finished in 12 h in the yield of 82% and the product was
pure as well as that from the routine scale.
Entry
Catalyst
Solvent
Yieldb
1
2
3
4
5
6
7
8
Mg(ClO4)2
Ti(OiPr)4
Sc(OTf)3
Cu(OTf)2
CuBr
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Toluene
DCM
THF
N. D.
5%
N. D.
5%
A plausible mechanism for this conversion was illustrated in
Scheme 2. The cycle commences from the coordination of al-
dehyde to the BF3 and the activated carbonyl is attacked by the
amide to form the hemi aminal intermediate A in which the
hydroxyl is removed with the help of Lewis acid and gem-amide
group. In turn, the enamide ion pair intermediate B may react
with the second amide directly to give the bisamide in-
termediate C and yield the final bisamide after dehydration. On
the other hand the enamide ion pair intermediate B may de-
hydrate prior to the nucleophilic addition of the second amide
and gave the overall same product through intermediate D. In
the presence of hydrogen bonding acceptor and lone electron
pair donor, such as acetone and diethyl ether, the reaction be-
tween water and BF3 to form fluoroboric acid can be inhibited,
which ensures the BF3 enter the next catalytic cycle.
10%
N. D.
25%
47%
62%
53%
57%
48%
82%
25%
31%
TiCl4
AlCl3
BF3*OEt2
BF3*OEt2
BF3*OEt2
BF3*OEt2
BF3*OEt2
BF3$*OEt2
BF3*OEt2
BF3*OEt2
9
10
11
12
13
14
15
EA
Acetone
DMF
EtOH
a
4-Fluorbenzaldehyde (1.0 mmol), benzamide (2.0 mmol), 0.2 M for aldehyde in
solvent. Typical catalyst loading is 10 mol %. The reaction was carried out at room
temperature for 120 min.
b
Isolated yield by filtration for entries 7e15 and NMR yield for entries 2 and 4 and
in turn diminished the yield and purity of final product. Meanwhile highly polar
solvents, such as DMF and EtOH (entries 14 & 15) also failed to enhance the reaction
due to their perfect solubility for both substrate and product. To our surprise, ace-
tone, a conventional aldol donor and a relatively green and healthy solvent for room
temperature reaction,16 boosted the yield to 82% (entry 13).
As a demonstration, CB2 receptor inverse agonists 11 and 12
were synthesized with BF3 etherate as catalyst in ether, a solvent
fine-tuned for the product (Scheme 3). The reaction gave rise to the
target as precipitate in good to excellent yield.

11082
Y. Zhang et al. / Tetrahedron 69 (2013) 11080e11083
Table 2
Table 2 (continued)
The substrate scope with BF3 etherate as catalysta
Backbone
Compound number
Reaction time Yieldb
(min)
10a R¼Ph
10
180
75%
81%
10b R¼n-Bu
Backbone
Compound number
Reaction time Yieldb
(min)
a
Aldehyde (1.0 mmol), amide (2.0 mmol), and BF3 etherate (10 mol %) was stirred
in acetone at room temperature for the given time.
1a R¼4-FePh
120
90
200
60
180
160
120
400
50
82%
88%
72%
90%
82%
71%
68%
80%c
94%c
90%c
72%c
91%
86%
1b R¼2-FePh
b
Isolated yield by filtration.
Et2O was used instead of acetone to favor precipitation.
1c R¼2-ClePh
1d R¼4-BrePh
1e R¼3-BrePh
1f R¼2-BrePh
1g R¼Ph
c
Table 3
The catalyst loading experimenta
1h R¼2-OHe3-OMe-Ph
1i R¼thiophene-3-yl
1j R¼5-Brethiophene-2-yl
1k R¼Styrenyl
1l R¼Bn
40
120
60
1m R¼n-Bu
15
Entry
BF3*OEt2 loading
Reaction time (h)
Yieldb
2a R¼4-FePh
2b R¼4-BrePh
2c R¼Bn
300
120
25
71%
92%
93%
1
2
3
4
10%
0.5
6
15
23
94%
91%
91%
89%
5 mol %
2 mol %
0.5 mol %
a
Phenylacetaldehyde (1.0 equiv), phenylacetamide (2.0 equiv), 0.2 M for alde-
hyde in acetone at room temperature.
b
Isolated yield by filtration.
3a R¼4-BrePh
3b R¼Bn
30
40
30
90%
90%
93%
3c R¼n-Bu
4a R¼Bn
5
20
98%
98%
4b R¼n-Bu
5a R¼Bn
25
25
90%
90%
5b R¼n-Bu
6
200
81%
7a R¼2-BrePh
7b R¼4-BrePh
7c R¼2-FePh
7d R¼Bn
200
160
300
25
86%
78%
70%
94%
92%
Scheme 2. Plausible mechanism for the formation of bisamide.
7e R¼2-Pheethyl
25
8a R¼4-BrePh
45
30
45
50
36
92%
90%
92%c
88%c
91%
8b R¼Bn
8c R¼5-Brethiophene-2-yl
8d R¼Thiophene-3-yl
8e R¼n-Bu
9a R¼4-BrePh
180
400
240
30
71%
70%c
88%
89%c
75%
9b R¼2-OHe3-OMe-Ph
9c R¼Bn
9d R¼5-Brethiophene-2-yl
9e R¼n-Bu
30
Scheme 3. The synthesis of CB2 receptor inverse agonists.

Y. Zhang et al. / Tetrahedron 69 (2013) 11080e11083
11083
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In conclusion, we developed a mild, efficient, and convenient
procedure for bisamides using low-cost catalyst with substrate
scope from aromatic to aliphatic compounds at room tempera-
ture. The catalyst loading could be lowered to 0.5 mol % with
retained yield and the reaction could be scaled up to 1 mol. The
procedure was applied in the synthesis of two CB2 receptor in-
verse agonists.
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Acknowledgements
The Startup fundings (985) from Ministry of Education of Peo-
ple’s Republic of China and Jiangsu province are highly acknowl-
edged. Funding of National University Student Innovation Program
(G1310284037) for Z.Y., Z.Z.H., H.Y.M., and H.R.R. is highly
appreciated.
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Supplementary data
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The general procedure, analysis data of new compounds, and
NMR spectra. Supplementary data related to this article can be
found online at http://dx.doi.org/10.1016/j.tet.2013.11.017.
14. For some BF3 mediated reaction, see: (a) Fran, E.; Kardos, Z.; Wolfling, J.;
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15. 60 RMB, ca. 9.7 USD for 500 mL from Sinopharm, http://www.reagent.com.cn.
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