N -acyl DBN tetraphenylborate salts as N -acylating agents

Article abstract of DOI:10.1021/jo202647f

Air-stable and crystalline N-acyl DBN tetraphenylborate salts have been synthesized from 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and the corresponding acyl chloride in the presence of sodium tetraphenylborate. The salts have been shown to be effective N-acylating agents, reacting with primary amines, secondary amines, and sulfonamides to form the corresponding N-acylated products in good yields. The DBN hydrotetraphenylborate byproduct can be conveniently removed by filtration, providing pure N-acylated products without the need for further purification. The N-acyl DBN tetraphenylborate salts are attractive alternatives to acyl halides as they can be stored in air without decomposition, avoid the production of free acid during acylation reactions, and can be used under more forcing thermal conditions.

Full text of DOI:10.1021/jo202647f

Article
pubs.acs.org/joc
N-Acyl DBN Tetraphenylborate Salts as N-Acylating Agents
James E. Taylor, Matthew D. Jones, Jonathan M. J. Williams, and Steven D. Bull*
Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, U.K.
S
* Supporting Information
ABSTRACT: Air-stable and crystalline N-acyl DBN tetraphenylbo-
rate salts have been synthesized from 1,5-diazabicyclo[4.3.0]non-5-
ene (DBN) and the corresponding acyl chloride in the presence of
sodium tetraphenylborate. The salts have been shown to be effective
N-acylating agents, reacting with primary amines, secondary amines,
and sulfonamides to form the corresponding N-acylated products in good yields. The DBN hydrotetraphenylborate byproduct
can be conveniently removed by filtration, providing pure N-acylated products without the need for further purification. The N-
acyl DBN tetraphenylborate salts are attractive alternatives to acyl halides as they can be stored in air without decomposition,
avoid the production of free acid during acylation reactions, and can be used under more forcing thermal conditions.
reagents have been developed to avoid the problems associated
with using acyl chlorides and acid anhydrides for acylation
reactions.
INTRODUCTION
■
Acylation reactions are one of the most significant and widely
used transformations in organic chemistry. For example, the
amide bond is ubiquitous throughout nature and is found in
many pharmaceutically active molecules, making the N-
acylation of amines to form amide products one of the most
frequently used reactions in drug synthesis.1,2 N-Acyl
sulfonamides are also an important class of compounds in the
medicinal and agrochemical industries, with many examples
having been reported to exhibit a diverse range of
pharmacological activities.3 N-Acyl sulfonamides are also widely
used as safety-catch linkers in solid support syntheses.4
Various synthetic protocols have been developed that employ
different acyl sources and catalysts to increase the rate of
acylation reactions.5 Of all the potential acyl sources, acyl
chlorides and acid anhydrides are currently the most widely
used. For example, the Schotten−Baumann reaction, first
described in 1884, between amines and acyl chlorides or acid
anhydrides in the presence of aqueous base is the foundation of
synthetic acylation reactions.6 Modern variations of the original
reaction can be performed in organic solvents and utilize acyl
transfer catalysts such as DMAP and its derivatives or Lewis
acid catalysts,7 although uncatalyzed versions in organic
solvents have also been reported.8
However, there are a number of problems associated with the
use of acyl chlorides and acid anhydrides in N-acylation
reactions. For example, reactions of amines with acyl chlorides
can be highly exothermic, while anhydrides can form imides as
side products when reacted with primary amines.9 Many acyl
chlorides are also air-sensitive and volatile and are hydrolyzed
by moisture to form acids, releasing HCl in the process. This
can not only render acyl chlorides practically difficult to use,
but can also cause problems when acid-sensitive functionality is
present within the reacting molecules. Additionally, many acyl
chlorides are synthesized from their corresponding carboxylic
acids, and while this is straightforward for simple substrates,
problems are often encountered in preparing acyl chlorides
from more complex substrates. Therefore, various alternative
The use of carboxylic acids as potential acyl sources, in
particular the coupling of amino acids for peptide synthesis, has
generated much interest. Direct reaction between an acid and
an amine usually results in salt formation rather than acylation,
and although acid-amine salts can be condensed at high
temperatures (110−180 °C),2k,10 the conditions are impractical
and often incompatible with the presence of other chemical
functionality. Consequently, numerous coupling reagents have
been developed that activate acids towards nucleophilic
addition by amines in a one-pot procedure. Coupling reagents
based on the use of carbodiimides, chloroformates, N-
acylimidazoles, phosphonium salts, pentafluorophenol, and
guanidinium salts are regularly used in peptide synthesis.11
Several other acyl sources have also been developed for the
N-acylation of amines.12 In particular, Katritzky and co-workers
have extensively researched the use of N-acyl benzotriazoles as
stoichiometric acylating agents.9,13 Their group has prepared a
large number of crystalline and stable N-acyl benzotriazoles by
reacting benzotriazole with the appropriate acyl chlorides.
Alternatively, they have developed methods of synthesizing N-
acyl benzotriazoles directly from the corresponding acids.14
These N-acyl benzotriazoles have been shown to react with a
number of different nucleophiles, including amines, hydroxyl-
amines, sulfonamides, oximes, thiols, and amino acids.
We have recently reported that the bicyclic amidine 1,5-
diazabicyclo[4.3.0]non-5-ene (DBN, 1) can catalyze the
regioselective Friedel−Crafts acylation of N-protected pyrroles
and indoles.15 While the mechanism of this process was being
investigated, a crystalline N-benzoyl DBN·BPh4 (3a) salt was
isolated (Scheme 1) by reacting DBN (1) with benzoyl
chloride (2a) in the presence of sodium tetraphenylborate, thus
Received: January 6, 2012
Published: February 13, 2012
© 2012 American Chemical Society
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Scheme 1. Formation of N-Benzoyl DBN·BPh4 (3a) from
Benzoyl Chloride (2a) and DBN (1)
Table 1. Synthesis of N-Acyl DBN·BPh4 Salts (3a−f) from
DBN (1) and Acyl Chlorides (2a−f)
providing structural information on the proposed key
intermediates in these acylation reactions.16
Consequently, due to the air-stable and crystalline nature of
this salt, it was decided to investigate whether other N-acyl
DBN·BPh4 salts could be prepared and determine whether they
could act as potential alternatives to acyl chlorides and acid
anhydrides for the N-acylation of amines to form amides.
RESULTS AND DISCUSSION
■
Initially, we investigated whether other stable N-acyl
DBN·BPh4 salts (3b−f) could be synthesized in a similar
manner to N-benzoyl DBN·BPh4 (3a) by adding DBN (1) to a
solution of the appropriate acyl chloride (2b−f) and sodium
tetraphenylborate in acetonitrile (Table 1).17 After removal of
the sodium chloride precipitate by filtration, the salts were
recrystallized from dichloromethane and hexane. Pleasingly,
this protocol allowed for simple isolation of air-stable and
crystalline N-acyl DBN·BPh4 salts of acetyl chloride (2b), o-
toluoyl chloride (2c), hydrocinnamoyl chloride (2d), and
sterically demanding pivaloyl chloride (2e) in high yields
(Table 1, entries 2−5). This protocol also worked well for the
more reactive ethyl chloroformate (2f), affording N-ethyl
carboxyl DBN·BPh4 (3f) as an air-stable powder in 95% yield
(Table 1, entry 6). All of the N-acyl DBN·BPh4 salts (3a−f)
were found to be bench-stable and could be stored and handled
in air without decomposition.18 This is in contrast to many of
the parent acyl chlorides used, especially acetyl chloride (2b)
and ethyl chloroformate (2f), which are water-sensitive and
decompose rapidly to release HCl upon contact with moisture
in the air. The ease of synthesis and favorable physical
properties of these N-acyl DBN·BPh4 salts potentially make
them valuable alternatives to acyl chlorides in acylation
reactions.
a
b
Yields by recrystallization from CH2Cl2 and hexane. Decomposition
observed.
i), with the results summarized in Table 2. The reactions of N-
acetyl DBN·BPh4 (3b) with p- and m-toluidine (4b and 4c)
proceeded well, enabling the amide products (5b and 5c) to be
isolated in 94% and 99% yields, respectively (Table 2, entries 2
and 3). However, reaction of the more sterically demanding o-
toluidine (4d) with N-acetyl DBN·BPh4 (3b) was unsuccessful,
with no amide product formed after 24 h (Table 2, entry 4).
Alkyl substitution in the para-position was tolerated, with p-tert-
butylaniline (4e) reacting smoothly to give the corresponding
amide 5e in 82% isolated yield (Table 2, entry 5). Halogen
substitution on the aniline reduced the conversion slightly, with
p-fluoroaniline (4f) reacting with N-acetyl DBN·BPh4 (3b) to
give 76% of the corresponding amide (5f) (Table 2, entry 6).
Reaction with electron-rich p-methoxyaniline (4g) proceeded
to completion, allowing N-(4-methoxyphenyl)acetamide (5g)
to be isolated in 74% yield (Table 2, entry 7). However, the
presence of a strongly electron-withdrawing group resulted in
no amide product being observed when p-nitroaniline (4h) was
used as a substrate (Table 2, entry 8). Pleasingly, the acylation
protocol was successfully applied to 4-aminopyridine (4i),
forming N-(pyridine-4-yl)acetamide (5i) in 81% yield (Table 2,
entry 9).
N-Acylation of Anilines. The acylation of aniline (4a)
using N-acetyl DBN·BPh4 (3b) was the first acylation reaction
to be investigated. An initial screen of solvents and conditions
revealed that N-acetyl DBN·BPh4 (3b) was soluble in
acetonitrile, dichloromethane, and tetrahydrofuran and that
its reaction with aniline (4a) in acetonitrile at 80 °C was
optimal. Therefore, aniline (4a) was added to 1.3 equiv of N-
acetyl DBN·BPh4 (3b) in acetonitrile and heated at 80 °C for
24 h, before being cooled to room temperature and
1
concentrated under reduced pressure. H NMR spectroscopic
analysis of the crude product showed that the reaction had
proceeded to 100% conversion. The reaction mixture could be
readily purified by dissolving the crude reaction product in
ethyl acetate and filtering off the insoluble salts, which were
shown to be a mixture of unreacted N-acetyl DBN·BPh4 (3b)
and DBN·HBPh4. The filtrate was then concentrated under
reduced pressure to give an analytically pure sample of N-
phenylacetamide (5a) in 90% yield without the need for
column chromatography (Table 2, entry 1). This successful
acylation protocol was then applied to a range of anilines (4b−
N-Acylation of Primary Amines. With conditions
established for the acylation of anilines and a convenient
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Table 2. N-Acylation of Anilines (4a−i) Using N-Acetyl
Table 3. Acylation of Primary Amines (6a−h) Using N-
a
a
DBN·BPh4 (3b)
Acetyl DBN·BPh4 (3b)
a
Reactions performed on a 0.5 mmol scale using 0.65 mmol of N-
b
acetyl DBN·BPh4 (3b). Determined by 1H NMR spectroscopic
analysis. Isolated yields in parentheses.
c
a
Reactions performed on a 0.5 mmol scale using 0.65 mmol of N-
product (7b) after 1 h (Table 3, entry 2). In this case it was
necessary to repeat the washing and filtration isolation
procedure to obtain a pure sample of N-phenethylacetamide
(7b) in 97% yield. The N-acylation of piperonylamine (6c) also
proceeded with complete conversion after 1 h, leading to the
isolation of the corresponding amide (7c) in 70% yield (Table
3, entry 3). The reaction of N-acetyl DBN·BPh4 (3b) with 4-
picolylamine (6d) was equally successful, giving N-(pyridin-4-
ylmethyl)acetamide (7d) in 78% isolated yield (Table 3, entry
4). 5-Methyl furfurylamine (6e) was also acylated smoothly,
forming the amide 7e in 97% yield (Table 3, entry 4). The
reaction of sterically demanding tert-butylamine (6f) with N-
acetyl DBN·BPh4 (3b) proceeded smoothly, forming N-(tert-
butyl)acetamide (7f) in 76% yield (Table 3, entry 6). The N-
b
acetyl DBN·BPh4 (3b). Determined by 1H NMR spectroscopic
analysis. Isolated yields in parentheses.
c
workup procedure in hand that enabled amide products to be
purified by filtration of excess DBN salts, the acylation of
primary amines was then investigated. Initially, benzylamine
(6a) was added to a solution of N-acetyl DBN·BPh4 (3b) in
1
acetonitrile and heated at 80 °C. After only 1 h H NMR
spectroscopic analysis showed complete conversion into amide,
allowing N-benzylacetamide (7a) to be isolated in 99% yield
(Table 3, entry 1). This acylation protocol was then applied to
a range of primary amines, the results of which are summarized
in Table 3. 2-Phenethylamine (6b) was successfully acylated
using N-acetyl DBN·BPh4 (3b), giving 100% conversion into
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acylation methodology was then applied to enantiomerically
pure (R)-α-methylbenzylamine ((R)-6g), to test whether the α-
stereocenter would be racemized under the reaction conditions
(Table 3, entry 7). (R)-N-(1-Phenethyl)acetamide ((R)-7g)
was obtained in a 66% yield after 1 h with the measured specific
rotation of +121 (c 0.97 g/100 mL in CHCl3) being
comparable with literature values for (R)-7g [[α]D25 = +127,
(c 1.0 g/100 mL in CH2Cl2)].19a N-Acetyl DBN·BPh4 (3b) was
then used to acylate (S)-phenylalanine methyl ester ((S)-6h),
affording the corresponding amide ((S)-7h) in 99% yield
(Table 3, entry 8). The specific rotation of amide (S)-7h [[α]D18
= +90 (c 0.68 g/100 mL in CHCl3)] was comparable with
literature values for (S)-7h [[α]D25 = +96 (c 1.0 g/100 mL in
CHCl3)]19b thus confirming that little racemization of the α-
stereocenter had occurred during the reaction.
Table 4. Acylation of Benzylamine (6a) Using Different N-
Acyl DBN·BPh4 Salts (3a−f)
a
We then investigated the use of the different N-acyl
DBN·BPh4 salts (3a−f) for the acylation of benzylamine
(6a). The reaction of N-benzoyl DBN·BPh4 (3a) with
benzylamine (6a) required 16 h to proceed to completion,
with N-benzyl benzamide (8a) being isolated in 78% yield
(Table 4, entry 1). The acylation of benzylamine (6a) with
sterically demanding N-o-toluoyl DBN·BPh4 (3c) was un-
successful, with no evidence of any amide formation after 16 h
(Table 4, entry 3). In contrast, the reactions of benzylamine
(6a) with both N-hydrocinnamoyl DBN·BPh4 (3d) and N-
pivaloyl DBN·BPh4 (3e) worked well, with both reactions
proceeding to complete conversion within 1 h to afford N-
benzyl-3-phenylpropanamide (8d) and N-benzylpivalamide
(8e) in 73% and 98% yield, respectively (Table 4, entries 4
and 5). Finally, reaction of benzylamine (6a) with N-ethyl
carboxyl DBN·BPh4 (3f) also proceeded to completion within
1 h, enabling the corresponding carbamate (8f) to be isolated
in 82% yield (Table 4, entry 6).
N-Acylation of Secondary Amines. Next, the use of N-
acetyl DBN·BPh4 (3b) for the acylation of secondary amines
(9a−h) to afford tertiary amides was investigated (Table 5).
First, it was found that N-benzyl-N-methylamine (9a) reacted
with N-acetyl DBN·BPh4 (3b) to give quantitative conversion
into amide product (10a) in 1 h (Table 5, entry 1). The N-
acylation protocol also worked well for N-benzyl-N-phenethyl-
amine (9b), giving N-benzyl-N-phenethylacetamide (10b) in
98% isolated yield (Table 5, entry 2). The reaction of N-acetyl
DBN·BPh4 (3b) with the more sterically demanding N-benzyl-
N-isopropylamine (9c) gave a lower 83% conversion, with the
amide product (10c) being isolated in 55% yield after the
standard workup procedure followed by an additional acid/base
wash to remove the excess amine (Table 5, entry 3). N,N-
Dibenzylamine (9d) also reacted slowly, with a reaction time of
16 h required to give complete conversion into tertiary amide
(10d) (Table 5, entry 4). It was found that 2 equiv of the cyclic
secondary amine pyrrolidine (9e) was required to consume 1
equiv of N-acetyl DBN·BPh4 (3b), allowing amide 10e to be
isolated in 88% yield (Table 5, entry 5). Next, piperazine (9f)
was reacted with 1 equiv of N-acetyl DBN·BPh4 (3b), forming
a single amide product (10f), with no bis-N,N′-acylated product
observed (Table 5, entry 6). As expected, morpholine (9g)
worked well as a substrate for acylation with N-acetyl
DBN·BPh4 (3b), affording 1-morpholinoethanone (10g) in a
97% isolated yield (Table 5, entry 7). Finally, N,O-
dimethylhydroxylamine hydrochloride (9h) was used as a
nucleophile in an attempt to form the corresponding Weinreb
amide. N-Hydrocinnamoyl DBN·BPh4 (3d) was employed
instead of N-acetyl DBN·BPh4 (3b) in order to increase the
a
Reactions performed using 0.5 mmol of benzylamine (6a) and 0.65
b
1
mmol of N-acyl DBN·BPh4. Determined by H NMR spectroscopic
analysis. Isolated yields in parentheses. 16 h reaction time.
c
d
molecular weight of the Weinreb amide formed and thus
facilitate its isolation during workup. An additional 1 equiv of
DBN (1) was also added to the reaction to liberate the
nucleophile (9h) from its hydrochloride salt. Pleasingly, the
reaction proceeded to completion in 1 h, allowing the Weinreb
amide 10h to be isolated in 80% yield after standard workup
followed by an additional acid/base wash to remove residual
DBN hydrochloride (Table 5, entry 8).
N-Acyl DBN·BPh4 Salts for the N-Acylation of
Sulfonamides. Because N-acetyl DBN·BPh4 (3b) had been
shown to be a highly efficient N-acylating agent for a wide
range of amines, it was decided to investigate its use for the
acylation of sulfonamides (Table 6). Initially, N-acetyl
DBN·BPh4 (3b) and benzenesulfonamide (11a) were heated
under the previously developed conditions for 16 h; however,
only 38% conversion into N-acetyl benzenesulfonamide (12a)
was observed. In an attempt to improve the conversion, the
reaction was repeated using 20 mol % DBN (1) as a catalyst.
Pleasingly, this resulted in 95% conversion into N-acetyl
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Table 5. Acylation of Secondary Amines (9a−h) Using N-
Table 6. Acylation of Sulfonamides (11a−h) Using N-Acetyl
a
a
Acetyl DBN·BPh4 (3b)
DBN·BPh4 (3b)
a
Reactions performed on a 0.5 mmol scale using 0.65 mmol of N-
b
1
acetyl DBN·BPh4 (3b) and 20 mol % DBN (1). Determined by H
NMR spectroscopic analysis. Isolated yields in parentheses.
c
using N-acetyl DBN·BPh4 (3b) and 20 mol % DBN (1) to give
their corresponding N-acetyl sulfonamides (12c and 12d) in
80% and 74% yield, respectively (Table 6, entries 3 and 4). The
reactions of N-acetyl DBN·BPh4 (3b) with less nucleophilic p-
nitrobenzenesulfonamide (11e) and p-chlorobenzenesulfona-
mide (11f) did not proceed as smoothly, with only 66% and
35% conversion into N-acetyl sulfonamides (12e and 12f)
observed, respectively (Table 6, entries 5 and 6). Acylation of
the secondary sulfonamide N-benzyl p-toluenesulfonamide
(11g) with N-acetyl DBN·BPh4 (3b) worked well, affording
N-acetyl N-benzyl p-toluenesulfonamide (12g) in 65% yield
after 16 h (Table 6, entry 7). However, the reaction of the more
sterically demanding N-hexyl p-toluenesulfonamide (11h) was
less successful, with only 42% conversion into N-acetyl
sulfonamide (12h) observed after 16 h (Table 6, entry 8).
a
Reactions performed on a 0.5 mmol scale using 0.65 mmol of N-
b
acetyl DBN·BPh4 (3b). Determined by 1H NMR spectroscopic
analysis. Isolated yields in parentheses. 16 h. Reaction using 2 equiv
of pyrrolidine (9e). Reaction performed using 0.5 mmol of N-acetyl
DBN·BPh4 (3b). Reaction performed using 0.65 mmol of N-
c
d
e
f
g
hydrocinnamoyl DBN·BPh4 (3d) and 0.6 mmol of DBN (1).
benzenesulfonamide (12a), which was isolated in 83% yield
after being purified by the standard workup procedure, followed
by an acid wash to remove the DBN (1) catalyst (Table 6,
entry 1). The successful acylation conditions using 20 mol %
DBN (1) were subsequently applied to the acylation of a
number of other sulfonamides. Methanesulfonamide (11b) was
found to be more reactive than benzensulfonamide (11a),
giving complete conversion into product (12b) within 16 h
(Table 6, entry 2). p-Toluenesulfonamide (11c) and p-
methoxybenzenesulfonamide (11d) were successfully acylated
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166.4, 165.2, 164.5, 163.9, 163.2, 136.2, 136.1, 126.2, 126.1, 126.1,
126.0, 122.2, 55.1, 43.9, 43.5, 35.5, 24.2, 18.6, 18.3; IR (film, cm−1)
νmax 1746 (CO), 1640, 1479, 1428; HRMS m/z (ES) 167.1198,
C9H15N2O [M]+ requires 167.1179.
CONCLUSIONS
■
In conclusion, a broad range of bench-stable and highly
crystalline N-acyl DBN·BPh4 salts have been synthesized, which
are easy to handle and do not react with moisture in air. The
utility of these N-acyl DBN·BPh4 salts for N-acylation reactions
with a range of amine nucleophiles has been demonstrated,
reacting with anilines, primary and secondary amines, and
sulfonamides to afford their corresponding N-acylated products
in high yields. The products can be isolated in pure form via a
simple workup procedure without the need for purification by
chromatography.
1-(o-Toluoyl)-2,3,4,6,7,8-hexahydropyrrolo[1,2-a]pyrimidine
Tetraphenylborate (N-o-Toluoyl DBN·BPh4) (3c). DBN (1) (0.62
mL, 5 mmol) was added dropwise to a solution of sodium
tetraphenylborate (1.71 g, 5 mmol) and o-toluoyl chloride (2c)
(0.68 mL, 5.2 mmol) in acetonitrile (25 mL) according to the general
procedure. The crude product was purified by recrystallization
(CH2Cl2/hexane), yielding the title compound (2.75 g, 98%) as
colorless crystals. Mp 173−176 °C; 1H NMR (300 MHz; CD3CN) δH
7.57−7.51 (1H, m, Tol-H), 7.44−7.35 (11H, m, 3 Tol-H and 8 BPh4-
H), 7.07 (8H, app t, J = 7.4 Hz, BPh4-H), 6.92 (4H, app t, J = 7.2 Hz,
BPh4-H), 3.65 (2H, app t, J = 7.7 Hz, H6), 3.50 (2H, app t, J = 5.6 Hz,
H2), 3.28 (2H, app t, J = 6.0 Hz, H4), 3.15 (2H, app t, J = 7.9 Hz, H8),
2.41 (3H, s, Tol-CH3), 2.09−1.89 (4H, m, H3 and H7); 13C{1H} NMR
(75 MHz, CD3CN) δC 171.6, 168.5, 165.8, 165.1, 164.4, 163.8, 137.9,
136.8, 136.7, 136.7, 136.7, 133.2, 132.9, 132.5, 128.2, 127.2, 126.7,
126.6, 126.6, 126.6, 122.8, 56.1, 45.7, 45.4, 35.7, 19.6, 19.5, 19.3; IR
(film, cm−1) νmax 1763 (CO), 1653, 1478, 1427; HRMS m/z (ES)
243.1516, C15H19N2O [M]+ requires 243.1492.
1-Hydrocinnamoyl-2,3,4,6,7,8-hexahydropyrrolo[1,2-a]-
pyrimidine Tetraphenylborate (N-Hydrocinnamoyl DBN·BPh4)
(3d). DBN (1) (1.19 mL, 10 mmol) was added dropwise to a solution
of sodium tetraphenylborate (3.42 g, 10 mmol) and hydrocinnamoyl
chloride (2d) (1.55 mL, 10.4 mmol) in acetonitrile (50 mL) according
to the general procedure. The crude product was purified by
recrystallization (CH2Cl2/hexane), yielding the title compound (4.23
g, 73%) as colorless crystalline plates. Mp 167−170 °C; 1H NMR (300
MHz; CD2Cl2) δH 7.41−7.34 (8H, m, BPh4-H), 7.33−7.21 (5 H, m,
Ph-H), 7.01 (8H, app t, J = 7.5 Hz, BPh4-H), 6.86 (4H, app t, J = 7.2
Hz, BPh4-H), 3.29 (2H, app t, J = 8.1 Hz, H6), 3.19 (2H, app t, J = 7.8
Hz, H2), 2.93 (2H, app t, J = 7.2 Hz, H4), 2.70 (2H, app t, J = 5.7 Hz,
H8), 2.58−2.53 (4H, m, CH2H2Ph), 1.93 (2H, app p, J = 7.9 Hz, H7),
1.36 (2H, app p, J = 5.8 Hz, H3); 13C{1H} NMR (75 MHz, CD2Cl2)
δC 173.3, 166.9, 165.7, 165.0, 164.4, 163.7, 140.2, 136.6, 129.5, 129.3,
127.5, 126.6, 126.5, 126.5, 126.5, 122.7, 55.6, 44.4, 43.2, 38.1, 36.0,
30.7, 19.0, 18.8; IR (film, cm−1) νmax 1742 (CO), 1634, 1436, 1427;
HRMS m/z (ES) 257.1643, C16H21N2O [M]+ requires 257.1654.
1-Pivaloyl-2,3,4,6,7,8-hexahydropyrrolo[1,2-a]pyrimidine
Tetraphenylborate (N-Pivaloyl DBN·BPh4) (3e). DBN (1) (0.62
mL, 5 mmol) was added dropwise to a solution of sodium
tetraphenylborate (1.71 g, 5 mmol) and pivaloyl chloride (2e) (0.64
mL, 5.2 mmol) in acetonitrile (25 mL) according to the general
procedure. The crude product was purified by recrystallization
(CH2Cl2/hexane), yielding the title compound (2.58 g, 98%) as
colorless crystals. Mp 157−158 °C; 1H NMR (300 MHz; CD3CN) δH
7.34−7.28 (8H, m, BPh4-H), 7.02 (8H, app t, J = 7.4 Hz, BPh4-H),
6.87 (4H, app t, J = 7.3 Hz, BPh4-H), 3.75 (2H, app t, J = 5.5 Hz, H2),
3.60 (2H, app t, J = 7.5 Hz, H6), 3.25 (2H, app t, J = 5.9 Hz, H4), 3.11
(2H, app t, J = 7.9 Hz, H8), 2.07−1.90 4H, m, H3 and H7), 1.34 (9H, s,
(CH3)3); 13C{1H} NMR (75 MHz, CD3CN) δC 181.3, 168.2, 165.7,
165.1, 164.4, 163.8, 136.7, 136.7, 126.6, 126.6, 126.6, 126.5, 122.8,
118.3, 56.1, 45.3, 44.9, 43.0, 34.8, 28.1, 19.8, 19.3; IR (film, cm−1) νmax
1718 (CO), 1642, 1470, 1426; HRMS m/z (ES) 209.1628,
C12H21N2O [M]+ requires 209.1649.
EXPERIMENTAL SECTION
■
General. All reactions were performed using starting materials
obtained from commercial sources without further purification and
using dry solvents under an atmosphere of nitrogen. 1H NMR spectra
were recorded at 300 MHz and 13C{1H} NMR spectra were recorded
at 75 MHz. Chemical shifts δ are quoted in parts per million and are
referenced to the residual solvent peak, and coupling constants, J, are
reported in Hertz (Hz). NMR peak assignments were confirmed using
2D 1H COSY where necessary. Infrared spectra were recorded as thin
films and were recorded with internal background calibration in the
range 600−4000 cm−1. High resolution mass spectra were recorded in
either positive or negative mode using electrospray (ES) ionization.
Specific rotations were recorded with a path length of 1 dm;
concentrations (c) are quoted in g/100 mL.
General Procedure for the Synthesis of N-Acyl DBN·BPh4
Salts (3a−f). Sodium tetraphenylborate (1 equiv) is added to a round-
bottom flask and purged with nitrogen. Dry acetonitrile (to make a 0.2
M solution of NaBPh4) and the appropriate acyl chloride (1.04 equiv)
are added, and the resulting solution is cooled to 0 °C. DBN (1) (1
equiv) is added dropwise, and a precipitate of sodium chloride begins
to form. The reaction is left to stir for 1 h before being warmed to
room temperature and filtered through a pad of Celite, washing
thoroughly with acetonitrile. The filtrate is concentrated under
reduced pressure, and the resulting N-acyl-DBN·BPh4 salt is purified
by recrystallization from dichloromethane and hexane.
1-Benzoyl-2,3,4,6,7,8-hexahydropyrrolo[1,2-a]pyrimidine
tetraphenylborate (N-Benzoyl DBN·BPh4) (3a). DBN (1) (1.85
mL, 15 mmol) was added dropwise to a solution of sodium
tetraphenylborate (5.13 g, 15 mmol) and benzoyl chloride (2a)
(1.81 mL, 15.6 mmol) in acetonitrile (75 mL) according to the general
procedure. The crude product was purified by recrystallization
(CH2Cl2/hexane), yielding the title compound (7.62 g, 93%) as a
1
colorless solid. Mp 117−119 °C; H NMR (300 MHz; CD3CN) δH
7.71 (3H, app d, J = 8.7 Hz, Ph-H), 7.57 (2H, app t, J = 7.7 Hz, Ph-H),
7.35−7.27 (8H, br s, BPh4-H), 7.02 (8H, app t, J = 7.4 Hz, BPh4-H),
6.87 (4H, app t, J = 7.1 Hz, BPh4-H), 3.75 (2H, app t, J = 7.6 Hz, H6),
3.65 (2H, app t, J = 5.5 Hz, H2), 3.40 (2H, app t, J = 5.8 Hz, H4), 3.19
(2H, app t, J = 7.7 Hz, H8), 2.17−1.93 (4H, m, H3 and H7); 13C{1H}
NMR (75 MHz, CD3CN) δC 171.6, 168.8, 165.7, 165.1, 164.4, 163.8,
136.7, 136.7, 134.6, 132.8, 130.1, 130.0, 126.6, 126.6, 126.6, 126.5,
122.8, 56.1, 46.9, 45.4, 35.2, 19.9, 19.5; IR (film, cm−1) νmax 1714
(CO), 1635, 1487; HRMS m/z (ES) 229.1342, C14H17N2O [M]+
requires 229.1336.
1-Ethyl Carboxyl-2,3,4,6,7,8-hexahydropyrrolo[1,2-a]-
pyrimidine Tetraphenylborate (N-Ethyl Carboxyl DBN·BPh4)
(3f). DBN (1) (0.62 mL, 5 mmol) was added dropwise to a solution of
sodium tetraphenylborate (1.71 g, 5 mmol) and ethyl chloroformate
(2f) (0.64 mL, 5.2 mmol) in acetonitrile (25 mL) according to the
general procedure. The crude product was purified by recrystallization
(CH2Cl2/hexane), yielding the title compound (2.45 g, 95%) as a
colorless powder. Mp 156−157 °C; 1H NMR (300 MHz; CD3CN) δH
7.27 (8H, br s, BPh4-H), 6.99 (8H, app t, J = 7.3 Hz, BPh4-H), 6.83
(4H, app t, J = 7.2 Hz, BPh4-H), 4.30 (2H, q, J = 7.1 Hz, OCH2CH3),
3.77−3.67 (4H, br m, H2 and H6), 3.41−3.30 (4H, br m, H4 and H8),
2.12−1.90 (4H, m, H3 and H7), 1.31 (3H, t, J = 7.1 Hz, OCH2CH3);
13C{1H} NMR (75 MHz, CD3CN) δC 168.7, 165.8, 165.1, 164.5,
1-Acetyl-2,3,4,6,7,8-hexahydropyrrolo[1,2-a]pyrimidine Tet-
raphenylborate (N-Acetyl DBN·BPh4) (3b). DBN (1) (1.19 mL, 10
mmol) was added dropwise to a solution of sodium tetraphenylborate
(3.42 g, 10 mmol) and acetyl chloride (2b) (0.74 mL, 10.4 mmol) in
acetonitrile (50 mL) according to the general procedure. The crude
product was purified by recrystallization (CH2Cl2/hexane), yielding
the title compound (4.72 g, 97%) as transparent crystalline plates. Mp
185 °C (dec); 1H NMR (300 MHz; CD2Cl2) δH 7.41−7.34 (8H, br s,
BPh4-H), 7.02 (8H, app t, J = 7.4 Hz, BPh4-H), 6.86 (4H, app t, J = 7.2
Hz, BPh4-H), 3.23 (2H, app t, J = 8.1 Hz, H6), 3.12 (2H, app t, J = 7.8
Hz, H2), 2.70 (2H, app t, J = 5.8 Hz, H4), 2.49 (2H, app t, J = 5.9 Hz,
H8), 2.02 (3H, s, COCH3), 1.87 (2H, app p, J = 8.0 Hz, H7), 1.34 (2H,
app p, J = 6.0 Hz, H3); 13C{1H} NMR (75 MHz, CD2Cl2) δC 170.9,
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163.8, 152.2, 136.8, 136.7, 136.7, 136.7, 126.7, 126.6, 126.6, 126.5,
122.8, 66.2, 56.5, 45.1, 44.0, 36.1, 19.1, 18.8, 14.3; IR (film, cm−1) νmax
1763 (CO), 1654, 1478; HRMS m/z (ES) 197.1277, C10H17N2O2
[M]+ requires 197.1285.
accordance with the literature.19c 1H NMR (300 MHz; CDCl3) δH
7.89 (1H, br s, NH), 7.46−7.41 (2H, m, Ar-H), 6.97 (2H, t, J = 8.6 Hz,
Ar-H), 2.13 (3H, s, COCH3); 13C{1H} NMR (75 MHz, CDCl3) δC
168.8, 159.5 (d, J = 242.6 Hz, FC), 134.1 (d, J = 2.9 Hz, FCCHCHC),
122.1 (d, J = 7.9 Hz, FCCHCH), 115.7 (d, J = 22.5 Hz, FCCH), 24.4;
HRMS m/z (ES) 154.0685, C8H9FNO [M + H]+ requires 154.0668.
N-(4-Methoxyphenyl)acetamide (5g). 4-Methoxyaniline (4g)
(0.062 g, 0.5 mmol) was added to a solution of N-acetyl DBN·BPh4
(3b) (0.316 g, 0.65 mmol) in acetonitrile (2 mL) and heated at 80 °C
for 24 h according to the general procedure. The crude product was
dissolved in ethyl acetate, and the excess salts were filtered off to give
the title compound (0.061 g, 74%) as a brown solid, with
spectroscopic data in accordance with the literature.19c 1H NMR
(300 MHz; CDCl3) δH 7.60 (1H, br s, NH), 7.39 (2H, d, J = 8.9 Hz,
Ar-H), 6.83 (2H, d, J = 8.9 Hz, Ar-H), 3.77 (3H, s, OCH3), 2.13 (3H,
s, COCH3); 13C{1H} NMR (75 MHz, CDCl3) δC 168.6, 156.5, 131.2,
122.1, 114.2, 55.6, 24.4; HRMS m/z (ES) 188.0716, C9H11NNaO2 [M
+ Na]+ requires 188.0687.
N-(Pyridin-4-yl)acetamide (5i). 4-Aminopyridine (4i) (0.047 g,
0.5 mmol) was added to a solution of N-acetyl DBN·BPh4 (3b) (0.316
g, 0.65 mmol) in acetonitrile (2 mL) and heated at 80 °C for 1 h
according to the general procedure. The crude product was dissolved
in ethyl acetate, and the excess salts were filtered off to give the title
compound (0.055 g, 81%) as a light brown solid, with spectroscopic
data in accordance with the literature.19e 1H NMR (300 MHz; CDCl3)
δH 9.72 (1H, br s, NH), 8.42 (2H, d, J = 6.3 Hz, py-CHCHN), 7.58
(2H, dd, J = 5.1, 1.3 Hz, py-CHCHN), 2.18 (3H, s, COCH3); 13C{1H}
NMR (75 MHz, CDCl3) δC 170.2, 150.1, 146.3, 114.0, 24.7; HRMS
m/z (ES) 137.0732, C7H9N2O [M + H]+ requires 137.0710.
General Procedure for the N-Acylation of Amines with N-
Acyl DBN·BPh4 Salts. The appropriate N-acyl-DBN·BPh4 (1.3 equiv,
0.65 mmol) is added to a carousel tube and purged with nitrogen. Dry
acetonitrile (2 mL) and the appropriate amine (1 equiv, 0.5 mmol) are
added, and the resulting solution is heated at 80 °C for the time
specified before being cooled to room temperature. The reaction
mixture is filtered before being concentrated under reduced pressure.
The crude product is suspended in the minimum amount of hot ethyl
acetate and allowed to cool before the mixture is filtered to remove the
remaining N-acyl-DBN salt and DBN·HBPh4. If necessary, the amide
can be further purified by dissolving in ethyl acetate and washing
successively with 1 M HCl, 1 M NaOH, and brine before being dried
over MgSO4, filtered, and concentrated under reduced pressure.
N-Phenylacetamide (5a). Aniline (4a) (0.05 mL, 0.5 mmol) was
added to a solution of N-acetyl DBN·BPh4 (3b) (0.316 g, 0.65 mmol)
in acetonitrile (2 mL) and heated at 80 °C for 24 h according to the
general procedure. The crude product was dissolved in ethyl acetate,
and the excess salts were filtered off to give the title compound (0.061
g, 90%) as a brown solid, with spectroscopic data in accordance with
the literature.19c 1H NMR (300 MHz; CDCl3) δH 7.89 (1H, br s, NH),
7.42 (2H, d, J = 7.9 Hz, Ph-H), 7.21 (2H, t, J = 7.6 Hz, Ph-H), 7.01
(1H, t, J = 7.4 Hz, Ph-H), 2.06 (3H, s, CH3); 13C{1H} NMR (75
MHz, CDCl3) δC 169.1, 138.0, 129.0, 124.4, 120.3, 24.5; HRMS m/z
(ES) 136.0765, C8H10NO [M + H]+ requires 136.0762.
N-(p-Tolyl)acetamide (5b). p-Toluidine (4b) (0.054 g, 0.5 mmol)
was added to a solution of N-acetyl DBN·BPh4 (3b) (0.316 g, 0.65
mmol) in acetonitrile (2 mL) and heated at 80 °C for 24 h according
to the general procedure. The crude product was dissolved in ethyl
acetate, and the excess salts were filtered off to give the title compound
(0.070 g, 94%) as a beige solid, with spectroscopic data in accordance
with the literature.19c 1H NMR (300 MHz; CDCl3) δH 8.01 (1H, br s,
NH), 7.38 (2H, d, J = 8.3 Hz, Tol-H), 7.08 (2H, d, J = 8.2 Hz, Tol-H),
2.29 (3H, s, Tol-CH3), 2.12 (3H, s, COCH3); 13C{1H} NMR (75
MHz, CDCl3) δC 168.9, 135.6, 133.9, 129.4, 120.3, 24.4, 20.9; HRMS
m/z (ES) 172.0761, C9H11NNaO [M + Na]+ requires 172.0738.
N-(m-Tolyl)acetamide (5c). m-Toluidine (4c) (0.054 mL, 0.5
mmol) was added to a solution of N-acetyl DBN·BPh4 (3b) (0.316 g,
0.65 mmol) in acetonitrile (2 mL) and heated at 80 °C for 24 h
according to the general procedure. The crude product was dissolved
in ethyl acetate, and the excess salts were filtered off to give the title
compound (0.074 g, 99%) as a beige solid, with spectroscopic data in
accordance with the literature.19c 1H NMR (300 MHz; CDCl3) δH
8.11 (1H, br s, NH), 7.28 (1H, s, Tol-H), 7.21 (1H, t, J = 8.3 Hz, Tol-
H), 7.07 (1H, t, J = 7.7 Hz, Tol-H), 6.81 (1H, d, J = 7.5 Hz, Tol-H),
2.20 (3H, s, Tol-CH3), 2.04 (3H, s, COCH3); 13C{1H} NMR (75
MHz, CDCl3) δC 169.1, 138.8, 138.1, 128.7, 125.1, 120.9, 117.3, 24.5,
21.5; HRMS m/z (ES) 150.0907, C9H12NO [M + H]+ requires
150.0914.
N-(4-(tert-Butyl)phenyl)acetamide (5e). 4-tert-Butylaniline (4e)
(0.080 mL, 0.5 mmol) was added to a solution of N-acetyl DBN·BPh4
(3b) (0.316 g, 0.65 mmol) in acetonitrile (2 mL) and heated at 80 °C
for 24 h according to the general procedure. The crude product was
dissolved in ethyl acetate, and the excess salts were filtered off to give
the title compound (0.078 g, 82%) as a beige solid, with spectroscopic
data in accordance with the literature.19d 1H NMR (300 MHz; CDCl3)
δH 7.81 (1H, br s, NH), 7.43 (2H, d, J = 8.5 Hz, Ar-H), 7.31 (2H, d, J
= 8.6 Hz, Ar-H), 2.14 (3H, s, COCH3), 1.29 (9H, s, (CH3)3); 13C{1H}
NMR (75 MHz, CDCl3) δC 168.8, 147.3, 135.4, 125.8, 120.0, 34.4,
31.5, 24.5; HRMS m/z (ES) 192.1403, C12H18NO [M + H]+ requires
192.1388.
N-Benzylacetamide (7a). Benzylamine (6a) (0.055 mL, 0.5
mmol) was added to a solution of N-acetyl DBN·BPh4 (3b) (0.316 g,
0.65 mmol) in acetonitrile (2 mL) and heated at 80 °C for 1 h
according to the general procedure. The crude product was dissolved
in ethyl acetate, and the excess salts were filtered off to give the title
compound (0.074 g, 99%) as a brown solid, with spectroscopic data in
accordance with the literature.2h 1H NMR (300 MHz; CDCl3) δH
7.26−7.16 (5H, m, Ph-H), 6.08 (1H, br s, NH), 4.30 (2H, d, J = 5.8
Hz, CH2N), 1.89 (3H, s, COCH3); 13C{1H} NMR (75 MHz, CDCl3)
δC 170.2, 138.4, 128.7, 127.9, 127.5, 43.7, 23.2; HRMS m/z (ES)
172.0755, C9H11NNaO [M + Na]+ requires 172.0738.
N-Phenethylacetamide (7b). 2-Phenethylamine (6b) (0.063 mL,
0.5 mmol) was added to a solution of N-acetyl DBN·BPh4 (3b) (0.316
g, 0.65 mmol) in acetonitrile (2 mL) and heated at 80 °C for 1 h
according to the general procedure. The crude product was dissolved
in ethyl acetate, and the excess salts were filtered off. The solution was
washed with brine before being dried over MgSO4 and concentrated to
give the title compound (0.079 g, 97%) as a brown oil, with
spectroscopic data in accordance with the literature.12f 1H NMR (300
MHz; CDCl3) δH 7.26−7.09 (5H, m, Ph-H), 5.47 (1H, br s, NH), 3.39
(2H, q, J = 6.9 Hz, NHCH2H2Ph), 2.71 (2H, t, J = 7.0 Hz,
NHCH2H2Ph), 1.81 (3H, s, COCH3); 13C{1H} NMR (75 MHz,
CDCl3) δC 170.3, 139.0, 128.8, 128.7, 126.6, 40.8, 35.7, 23.4; HRMS
m/z (ES) 186.0906, C10H13NNaO [M + Na]+ requires 186.0889.
N-(Benzo[d][1,3]dioxol-5-ylmethyl)acetamide (7c). Piperonyl-
amine (6c) (0.062 mL, 0.5 mmol) was added to a solution of N-acetyl
DBN·BPh4 (3b) (0.316 g, 0.65 mmol) in acetonitrile (2 mL) and
heated at 80 °C for 1 h according to the general procedure. The crude
product was dissolved in ethyl acetate, and the excess salts were
filtered off to give the title compound (0.068 g, 70%) as a light brown
solid, with spectroscopic data in accordance with the literature.19f 1H
NMR (300 MHz; CDCl3) δH 6.69−6.62 (3H, m, Ar-H), 6.00 (1H, br
s, NH), 5.85 (2H, s, OCH2O), 4.23 (2H, d, J = 5.6 Hz, CH2N), 1.92
(3H, s, COCH3); 13C{1H} NMR (75 MHz, CDCl3) δC 170.1, 148.0,
147.0, 132.3, 121.2, 108.5, 108.4, 101.2, 43.6, 23.3; HRMS m/z (ES)
194.0814, C10H12NO3 [M + H]+ requires 194.0817.
N-(4-Fluorophenyl)acetamide (5f). 4-Fluoroaniline (4f) (0.048
mL, 0.5 mmol) was added to a solution of N-acetyl DBN·BPh4 (3b)
(0.316 g, 0.65 mmol) in acetonitrile (2 mL) and heated at 80 °C for 24
h according to the general procedure. The crude product was dissolved
in ethyl acetate, and the excess salts were filtered off to give the title
compound (0.058 g, 76%) as a beige solid, with spectroscopic data in
N-(Pyridin-4-ylmethyl)acetamide (7d). 4-Picolylamine (6d)
(0.050 mL, 0.5 mmol) was added to a solution of N-acetyl DBN·BPh4
(3b) (0.316 g, 0.65 mmol) in acetonitrile (2 mL) and heated at 80 °C
for 1 h according to the general procedure. The crude product was
dissolved in ethyl acetate, and the excess salts were filtered off to give
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the title compound (0.059 g, 78%) as a yellow oil, with spectroscopic
data in accordance with the literature.19g 1H NMR (300 MHz; CDCl3)
δH 8.45 (2H, d, J = 6.1 Hz, py-CHCHN), 7.13 (2H, d, J = 5.9 Hz, py-
CHCHN), 6.83 (1H, br d, J = 7.0 Hz, NH), 4.35 (2H, d, J = 6.1 Hz,
CH2NH), 1.99 (3H, s, COCH3); 13C{1H} NMR (75 MHz, CDCl3) δC
170.6, 149.8, 147.9, 122.4, 42.4, 23.1; HRMS m/z (ES) 173.0709,
C8H10N2NaO [M + Na]+ requires 173.0691.
N-((5-Methylfuran-2-yl)methyl)acetamide (7e). 5-Methyl fur-
furylamine (6e) (0.056 mL, 0.5 mmol) was added to a solution of N-
acetyl DBN·BPh4 (3b) (0.316 g, 0.65 mmol) in acetonitrile (2 mL)
and heated at 80 °C for 1 h according to the general procedure. The
crude product was dissolved in ethyl acetate, and the excess salts were
filtered off to give the title compound (0.074 g, 97%) as an orange oil.
1H NMR (300 MHz; CDCl3) δH 6.14 (1H, br s, NH), 6.00 (1H, d, J =
2.9 Hz, OCCH), 5.80 (1H, d, J = 2.1 Hz, OCCH), 4.26 (2H, d, J = 5.4
Hz, CH2N), 2.17 (3H, s, CHCCH3), 1.90 (3H, s, COCH3); 13C{1H}
NMR (75 MHz, CDCl3) δC 170.0, 151.9, 149.4, 108.3, 106.3, 36.7,
23.1, 13.5; HRMS m/z (ES) 154.0885, C8H12NO2 [M + H]+ requires
154.0868.
N-Benzyl-3-phenylpropanamide (8d). Benzylamine (6a) (0.055
mL, 0.5 mmol) was added to a solution of N-hydrocinnamoyl
DBN·BPh4 (3d) (0.375 g, 0.65 mmol) in acetonitrile (2 mL), and the
resulting solution was heated at 80 °C for 1 h according to the general
procedure. The crude product was dissolved in ethyl acetate, and the
excess salts were filtered off. The solution was washed with 1 M HCl, 1
M NaOH, and brine before being dried over MgSO4, filtered, and
concentrated to give the title compound (0.087 g, 73%) as a colorless
solid, with spectroscopic data in accordance with the literature.2h 1H
NMR (300 MHz; CDCl3) δH 7.23−7.03 (10H, m, Ph-H), 5.78 (1H, br
s, NH), 4.28 (2H, d, J = 5.7 Hz, HNCH2Ph), 2.89 (2H, t, J = 7.6 Hz,
COCH2CH2Ph), 2.41 (2H, t, J = 7.6 Hz, COCH2CH2Ph); 13C{1H}
NMR (75 MHz, CDCl3) δC 172.1, 140.9, 138.3, 128.7, 128.6, 128.5,
127.8, 127.5, 126.3, 43.6, 38.5, 31.8; HRMS m/z (ES) 240.1375,
C16H18NO [M + H]+ requires 240.1388.
N-Benzylpivalamide (8e). Benzylamine (6a) (0.055 mL, 0.5
mmol) was added to a solution of N-pivaloyl DBN·BPh4 (3e) (0.343
g, 0.65 mmol) in acetonitrile (2 mL), and the resulting solution was
heated at 80 °C for 1 h according to the general procedure. The crude
product was dissolved in ethyl acetate, and the excess salts were
filtered off. The solution was washed with 1 M HCl, 1 M NaOH, and
brine before being dried over MgSO4, filtered, and concentrated to
give the title compound (0.094 g, 98%) as a pale yellow oil, with
spectroscopic data in accordance with the literature.19i 1H NMR (300
MHz; CDCl3) δH 7.27−7.15 (5H, m, Ph-H), 6.01 (1H, br s, NH), 4.34
(2H, d, J = 5.6 Hz, HNCH2Ph), 1.14 (9H, s, C(CH3)3); 13C{1H}
NMR (75 MHz, CDCl3) δC 178.4, 138.7, 128.7, 127.6, 127.4, 43.6,
38.7, 27.7; HRMS m/z (ES) 214.1194, C12H17NNaO [M + Na]+
requires 214.1203.
N-(tert-Butyl)acetamide (7f). tert-Butylamine (6f) (0.053 mL, 0.5
mmol) was added to a solution of N-acetyl DBN·BPh4 (3b) (0.316 g,
0.65 mmol) in acetonitrile (2 mL) and heated at 80 °C for 1 h
according to the general procedure. The crude product was dissolved
in ethyl acetate, and the excess salts were filtered off to give the title
compound (0.044 g, 76%) as a brown solid, with spectroscopic data in
accordance with the literature.19h 1H NMR (300 MHz; CDCl3) δH
5.44 (1H, br s, NH), 1.88 (3H, s, COCH3), 1.31 (9H, s, (CH3)3);
13C{1H} NMR (75 MHz, CDCl3) δC 169.7, 51.2, 28.8, 24.6; HRMS
m/z (ES) 116.1091, C6H14NO [M + H]+ requires 116.1075.
(R)-N-(1-Phenylethyl)acetamide ((R)-7g). (R)-α-Methyl benzyl-
amine ((R)-6g) (0.064 mL, 0.5 mmol) was added to a solution of N-
acetyl DBN·BPh4 (3b) (0.316 g, 0.65 mmol) in acetonitrile (2 mL)
and heated at 80 °C for 1 h according to the general procedure. The
crude product was dissolved in ethyl acetate, and the excess salts were
filtered off to give the title compound (0.054 g, 66%) as a brown solid,
Ethyl Benzylcarbamate (8f). Benzylamine (6a) (0.055 mL, 0.5
mmol) was added to a solution of N-ethyl carboxyl DBN·BPh4 (3f)
(0.336 g, 0.65 mmol) in acetonitrile (2 mL), and the resulting solution
was heated at 80 °C for 1 h according to the general procedure. The
crude product was dissolved in ethyl acetate, and the excess salts were
filtered off. The solution was washed with 1 M HCl, 1 M NaOH, and
brine before being dried over MgSO4, filtered, and concentrated to
give the title compound (0.073 g, 82%) as a pale yellow oil, with
spectroscopic data in accordance with the literature.19j 1H NMR (300
MHz; CDCl3) δH 7.45−7.20 (5H, m, Ph-H), 5.95 (1H, br s, NH), 4.29
(2H, d, J = 5.9 Hz, NCH2Ph), 4.08 (2H, q, J = 7.1 Hz, OCH2CH3),
1.18 (3H, t, J = 7.1 Hz, OCH2CH3); 13C{1H} NMR (75 MHz,
CDCl3) δC 157.2, 134.9, 128.8, 128.1, 127.6, 61.2, 45.2, 14.8.
N-Benzyl-N-methylacetamide (10a). N-Benzyl-N-methylamine
(9a) (0.065 mL, 0.5 mmol) was added to a solution of N-acetyl
DBN·BPh4 (3b) (0.316 g, 0.65 mmol) in acetonitrile (2 mL) and
heated at 80 °C for 1 h according to the general procedure. The crude
product was dissolved in ethyl acetate, and the excess salts were
filtered off to give the title compound (0.081 g, 99%) as a dark brown
oil, with spectroscopic data in accordance with the literature.12f The
with spectroscopic data in accordance with the literature.19a [α]D22
=
1
+121 (c 0.97 g/100 mL in CHCl3); H NMR (300 MHz; CDCl3) δH
7.28−7.19 (5H, m, Ph-H), 5.84 (1H, br s, NH), 5.03 (1H, p, J = 7.2
Hz, CHCH3), 1.88 (3H, s, COCH3), 1.39 (3H, d, J = 7.0 Hz,
CHCH3); 13C{1H} NMR (75 MHz, CDCl3) δC 169.3, 143.3, 128.8,
127.5, 126.3, 48.9, 23.5, 21.8; HRMS m/z (ES) 186.0922,
C10H13NNaO [M + Na]+ requires 186.0895.
(S)-Methyl 2-Acetamido-3-phenylpropanoate ((S)-7h). (S)-
Phenylalanine methyl ester ((S)-6h) (0.090 g, 0.5 mmol) was added to
a solution of N-acetyl DBN·BPh4 (3b) (0.316 g, 0.65 mmol) in
acetonitrile (2 mL) and heated at 80 °C for 1 h according to the
general procedure. The crude product was dissolved in ethyl acetate,
and the excess salts were filtered off to give the title compound (0.110
g, 99%) as a beige solid, with spectroscopic data in accordance with the
literature.19b [α]D18 = +90 (c 0.68 g/100 mL in CHCl3); 1H NMR (300
MHz; CDCl3) δH 7.24−7.16 (3H, m, Ph-H), 7.02 (2H, app d, J = 7.1
Hz, Ph-H), 6.04 (1H, br d, J = 7.3 Hz, NH), 4.80 (1H, dd, J = 13.6, 5.9
Hz, CHCHAHB), 3.64 (3H, s, OCH3), 3.07 (1H, dd, J = 13.9, 5.9 Hz,
CHCHAHB), 2.99 (1H, dd, J = 13.9, 5.9 Hz, CHCHAHB), 1.90 (3H, s,
COCH3); 13C{1H} NMR (75 MHz, CDCl3) δC 172.2, 169.8, 135.9,
129.3, 128.6, 127.2, 53.2, 52.4, 37.9, 23.1; HRMS m/z (ES) 222.1132,
C12H16NO3 [M + H]+ requires 222.1130.
1
product was analyzed as a 4:3 mixture of rotamers (25 °C). major H
NMR (300 MHz; CDCl3) δH 7.31−7.08 (5H, m, Ph-H), 4.50 (2H, s,
NCH2Ph), 2.83 (3H, s, NCH3), 2.07 (3H, s, COCH3); minor 1H
NMR (300 MHz; CDCl3) δH 7.31−7.08 (5H, m, Ph-H), 4.44 (2H, s,
NCH2Ph), 2.86 (3H, s, NCH3), 2.07 (3H, s, COCH3); major and
minor 13C{1H} NMR (75 MHz, CDCl3) δC 171.1, 170.8, 137.3, 136.5,
128.9, 128.6, 128.0, 127.6, 127.3, 126.3, 54.2, 50.6, 35.5, 33.7, 21.9,
21.5; HRMS m/z (ES) 186.0921, C10H13NNaO [M + Na]+ requires
186.0894.
N-Benzyl Benzamide (8a). Benzylamine (6a) (0.055 mL, 0.5
mmol) was added to a solution of N-benzoyl DBN·BPh4 (3a) (0.356
g, 0.65 mmol) in acetonitrile (2 mL), and the resulting solution was
heated at 80 °C for 16 h according to the general procedure. The
crude product was dissolved in ethyl acetate, and the excess salts were
filtered off to give the title compound (0.077 g, 78%) as a beige solid,
with spectroscopic data in accordance with the literature.2h 1H NMR
(300 MHz; CDCl3) δH 7.73−7.70 (2H, m, PhH), 7.43−7.18 (8H, m,
PhH), 6.36 (1H, br s, NH), 4.58 (2H, d, J = 5.7 Hz, CH2N); 13C{1H}
NMR (75 MHz, CDCl3) δC 167.4, 138.2, 134.4, 131.6, 128.8, 128.6,
128.0, 126.7, 126.1, 44.2; HRMS m/z (ES) 212.1067, C14H14NO [M +
H]+ requires 212.1075.
N-Benzyl-N-phenethylacetamide (10b). N-Benzyl-N-phenethyl-
amine (9b) (0.10 mL, 0.5 mmol) was added to a solution of N-acetyl
DBN·BPh4 (3b) (0.316 g, 0.65 mmol) in acetonitrile (2 mL) and
heated at 80 °C for 1 h according to the general procedure. The crude
product was dissolved in ethyl acetate, and the excess salts were
filtered off to give the title compound (0.124 g, 98%) as a dark brown
oil, with spectroscopic data in accordance with the literature.19k The
1
product was analyzed as a 1:1 mixture of rotamers (25 °C). H NMR
(300 MHz; CDCl3) δH 7.28−7.02 (20H, m, 4 Ph-H), 4.53 (2H, s,
NCH2Ph), 4.27 (2H, s, NCH2Ph), 3.49 (2H, t, J = 7.5 Hz,
NCH2CH2Ph), 3.34 (2H, t, J = 7.5 Hz, NCH2CH2Ph), 2.80−2.69
(4H, m, 2 NCH2CH2Ph), 2.04 (3H, s, COCH3), 1.93 (3H, s,
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COCH3); 13C{1H} NMR (75 MHz, CDCl3) δC 171.0, 170.8, 139.3,
138.2, 137.7, 136.8, 129.0, 128. 9, 128.8, 128.8, 128.7, 128.6, 128.2,
127.7, 127.5, 126.8, 126.4, 126.4, 52.7, 49.5, 48.3, 48.1, 34.9, 34.0, 21.9,
21.3; HRMS m/z (ES) 254.1545, C17H20NO [M + H]+ requires
254.1540.
N-Methoxy-N-methyl-3-phenylpropanamide (10h). N,O-Di-
methylhydroxylamine hydrochloride (9h) (0.049 g, 0.5 mmol) was
added to a solution of N-hydrocinnamoyl DBN·BPh4 (3d) (0.375 g,
0.65 mmol) and DBN (1) (0.070 mL, 0.6 mmol) in acetonitrile (2
mL) and heated at 80 °C for 1 h according to the general procedure.
The crude product was dissolved in ethyl acetate, and the excess salts
were filtered off. The solution was washed with 1 M HCl, 1 M NaOH,
and brine before being dried over MgSO4 and concentrated to give the
title compound (0.077 g, 80%) as a pale orange oil, with spectroscopic
data in accordance with the literature.19p 1H NMR (300 MHz; CDCl3)
δH 7.25−7.10 (5H, m, Ph-H), 3.53 (3H, s, OCH3), 3.11 (3H, s,
NCH3), 2.89 (2H, t, J = 7.8 Hz, CH2CH2Ph), 2.67 (2H, t, J = 7.8 Hz,
CH2CH2Ph); 13C{1H} NMR (75 MHz, CDCl3) δC 173.9 141.5, 128.6,
128.6, 126.2, 61.3, 34.0, 30.8; HRMS m/z (ES) 194.1209, C11H16NO2
[M + H]+ requires 194.1181.
General Procedure for the N-Acylation of Sulfonamides
with N-Acetyl DBN·BPh4. N-Acetyl DBN·BPh4 (3b) (1.3 equiv, 0.65
mmol) and the appropriate sulfonamide (1 equiv, 0.5 mmol) are
added to a carousel tube and purged with nitrogen. Dry acetonitrile (2
mL) and DBN (1) (20 mol %, 0.1 mmol) are added, and the resulting
solution is heated at 80 °C for 16 h before being cooled to room
temperature. The crude product is suspended in the minimum amount
of hot ethyl acetate and allowed to cool before the mixture is filtered to
remove the remaining N-acetyl-DBN salt and DBN·HBPh4.The filtrate
is then washed with NH4Cl and brine before being dried over MgSO4,
filtered, and concentrated under reduced pressure.
N-(Phenylsulfonyl)acetamide (12a). DBN (1) (0.01 mL, 0.1
mmol) and acetonitrile (2 mL) were added to the N-acetyl DBN·BPh4
(3b) (0.316 g, 0.65 mmol) and benzenesulfonamide (11a) (0.079 g,
0.5 mmol), and the resulting solution was heated at 80 °C for 16 h
according to the general procedure. The crude product was dissolved
in ethyl acetate, and the excess salts were filtered off. The solution was
washed with NH4Cl and brine before being dried over MgSO4,
filtered, and concentrated to give the title compound (0.083 g, 83%) as
a light brown solid, with spectroscopic data in accordance with the
literature.19q 1H NMR (300 MHz; CDCl3) δH 9.05 (1H, br s, NH),
7.99 (2H, d, J = 7.7 Hz, Ph-H), 7.59 (1H, t, J = 7.3 Hz, Ph-H), 7.49
(2H, t, J = 7.6 Hz, Ph-H), 2.00 (3H, s, COCH3); 13C{1H} NMR (75
MHz, CDCl3) δC 168.5, 138.6, 134.2, 129.2, 128.4, 23.7; HRMS m/z
(ES) 200.0384, C8H10NO3S [M + H]+ requires 200.0381.
N-Benzyl-N-isopropylacetamide (10c). N-Benzyl-N-isopropyl-
amine (9c) (0.080 mL, 0.5 mmol) was added to a solution of N-acetyl
DBN·BPh4 (3b) (0.316 g, 0.65 mmol) in acetonitrile (2 mL) and
heated at 80 °C for 1 h according to the general procedure. The crude
product was dissolved in ethyl acetate, and the excess salts were
filtered off. The solution was washed with 1 M HCl, 1 M NaOH, and
brine before being dried over MgSO4 and concentrated to give the title
compound (0.053 g, 55%) as a pale yellow oil. The product was
1
analyzed as a 4:3 mixture of rotamers (25 °C). major H NMR (300
MHz; CDCl3) δH 7.29−7.10 (5H, m, Ph-H), 4.79 (1H, h, J = 6.8 Hz,
CH(CH3)2), 4.38 (2H, s, CH2Ph), 1.93 (3H, s, COCH3), 1.01 (6H, d,
J = 6.8 Hz, CH(CH3)2); minor 1H NMR (300 MHz; CDCl3) δH 7.29−
7.10 (5H, m, Ph-H), 4.46 (2H, s, CH2Ph), 4.04 (1H, h, J = 6.7 Hz,
CH(CH3)2), 2.15 (3H, s, COCH3), 1.06 (6H, d, J = 6.7 Hz,
CH(CH3)2); major and minor 13C{1H} NMR (75 MHz, CDCl3) δC
171.5, 170.7, 139.7, 138.6, 128.8, 128.3, 127.2, 127.0, 126.6, 125.8,
49.8, 47.0, 45.5, 43.7, 22.7, 22.1, 21.5, 20.4; HRMS m/z (ES)
214.1221, C12H17NNaO [M + Na]+ requires 214.1203.
N,N-Dibenzylacetamide (10d). Dibenzylamine (9d) (0.10 mL,
0.5 mmol) was added to a solution of N-acetyl DBN·BPh4 (3b) (0.316
g, 0.65 mmol) in acetonitrile (2 mL) and heated at 80 °C for 16 h
according to the general procedure. The crude product was dissolved
in ethyl acetate, and the excess salts were filtered off to give the title
compound (0.084 g, 70%) as a pale yellow oil, with spectroscopic data
in accordance with the literature.19l 1H NMR (300 MHz; CDCl3) δH
7.32−7.06 (10H, m, PhH), 4.51 (2H, s, NCH2Ph), 4.35 (2H, s,
NCH2Ph), 2.13 (3H, s, COCH3); 13C{1H} NMR (75 MHz, CDCl3)
δC 171.3, 137.3, 136.4, 129.0, 128.7, 128.5, 128.5, 128.3, 127.7, 127.5,
126.4, 50.8, 48.0, 21.8; HRMS m/z (ES) 262.1213, C16H17NNaO [M
+ Na]+ requires 262.1208.
1-(Pyrrolidin-1-yl)ethanone (10e). Pyrrolidine (9e) (0.083 g, 1.0
mmol) was added to a solution of N-acetyl DBN·BPh4 (3b) (0.243 g,
0.5 mmol) in acetonitrile (2 mL) and heated at 80 °C for 1 h
according to the general procedure. The crude product was dissolved
in ethyl acetate, and the excess salts were filtered off to give the title
compound (0.05 g, 88%) as a yellow oil, with spectroscopic data in
accordance with the literature.19m 1H NMR (300 MHz; CDCl3) δH
3.34 (4H, app q, J = 6.7 Hz, CH2NCH2), 1.95 (3H, s, COCH3), 1.90−
1.75 (4H, m, NCH2CH2CH2); 13C{1H} NMR (75 MHz, CDCl3) δC
169.4, 47.5, 45.6, 26.2, 24.7, 22.6; HRMS m/z (ES) 136.0729
C6H11NNaO [M + Na]+ requires 136.0733.
1-(Piperazin-1-yl)ethanone (10f). Piperazine (9f) (0.043 g, 0.5
mmol) was added to a solution of N-acetyl DBN·BPh4 (3b) (0.243 g,
0.5 mmol) in acetonitrile (2 mL) and heated at 80 °C for 1 h
according to the general procedure. The crude product was dissolved
in ethyl acetate, and the excess salts were filtered off to give the title
compound (0.063 g, 99%) as a orange oil, with spectroscopic data in
accordance with the literature.19n 1H NMR (300 MHz; CDCl3) δH
3.55−3.51 (2H, m, CH2NCOCH3), 3.40−3.37 (2H, m,
CH2NCOCH3), 2.83−2.76 (4H, m, CH2NHCH2), 2.12 (1H, br s,
NH), 2.04 (3H, s, COCH3); 13C{1H} NMR (75 MHz, CDCl3) δC
169.1, 47.5, 46.3, 45.8, 42.5, 21.4; HRMS m/z (ES) 151.0868,
C6H12N2NaO [M + Na]+ requires 151.0847.
1-Morpholinoethanone (10g). Morpholine (9g) (0.044 mL, 0.5
mmol) was added to a solution of N-acetyl DBN·BPh4 (3b) (0.316 g,
0.65 mmol) in acetonitrile (2 mL) and heated at 80 °C for 1 h
according to the general procedure. The crude product was dissolved
in ethyl acetate, and the excess salts were filtered off to give the title
compound (0.063 g, 97%) as a brown oil, with spectroscopic data in
accordance with the literature.19o 1H NMR (300 MHz; CDCl3) δH
3.65−3.60 (4H, m, CH2OCH2), 3.57−3.54 (2H, m, CH2NCOCH3),
3.41 (2H, t, J = 4.8 Hz, CH2NCOCH3), 2.05 (3H, s, COCH3);
13C{1H} NMR (75 MHz, CDCl3) δC 169.2, 66.9, 66.6, 46.7, 41.8, 21.2;
HRMS m/z (ES) 152.0692, C6H11NNaO2 [M + Na]+ requires
152.0687.
N-(Methylsulfonyl)acetamide (12b). DBN (1) (0.01 mL, 0.1
mmol) and acetonitrile (2 mL) were added to the N-acetyl DBN·BPh4
(3b) (0.316 g, 0.65 mmol) and methanesulfonamide (11b) (0.048 g,
0.5 mmol), and the resulting solution was heated at 80 °C for 16 h
according to the general procedure. The crude product was dissolved
in ethyl acetate, and the excess salts were filtered off. The solution was
washed with NH4Cl and brine before being dried over MgSO4,
filtered, and concentrated to give the title compound (0.067 g, 98%) as
1
a deep purple oil. H NMR (300 MHz; CDCl3) δH 6.00 (1H, br s,
NH), 3.23 (3H, s, SO2CH3), 2.13 (3H, s, COCH3); 13C{1H} NMR
(75 MHz, CDCl3) δC 171.4, 41.3, 24.1; HRMS m/z (ES) 160.0029,
C3H7NNaO3S [M + Na]+ requires 160.0044.
N-Tosylacetamide (12c). DBN (1) (0.01 mL, 0.1 mmol) and
acetonitrile (2 mL) were added to the N-acetyl DBN·BPh4 (3b)
(0.316 g, 0.65 mmol) and p-toluenesulfonamide (11c) (0.086 g, 0.5
mmol), and the resulting solution was heated at 80 °C for 16 h
according to the general procedure. The crude product was dissolved
in ethyl acetate, and the excess salts were filtered off. The solution was
washed with NH4Cl and brine before being dried over MgSO4,
filtered, and concentrated to give the title compound (0.085 g, 80%) as
a brown solid, with spectroscopic data in accordance with the
literature.19q 1H NMR (300 MHz; CDCl3) δH 9.15 (1H, br s, NH),
7.86 (2H, d, J = 8.3 Hz, Tol-H), 7.27 (2H, d, J = 8.1 Hz, Tol-H), 2.37
(3H, s, Tol-CH3), 1.99 (3H, s, COCH3); 13C{1H} NMR (75 MHz,
CDCl3) δC 168.7, 145.4, 135.6, 129.8, 128.4, 23.6, 21.8; HRMS m/z
(ES) 214.0539, C9H12NO3S [M + H]+ requires 214.0533.
N-((4-Methoxyphenyl)sulfonyl)acetamide (12d). DBN (1)
(0.01 mL, 0.1 mmol) and acetonitrile (2 mL) were added to the N-
acetyl DBN·BPh4 (3b) (0.316 g, 0.65 mmol) and 4-methoxybenze-
nesulfonamide (11d) (0.094 g, 0.5 mmol), and the resulting solution
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Article
was heated at 80 °C for 16 h according to the general procedure. The
crude product was dissolved in ethyl acetate, and the excess salts were
filtered off. The solution was washed with NH4Cl and brine before
being dried over MgSO4, filtered, and concentrated to give the title
compound (0.085 g, 74%) as a brown solid, with spectroscopic data in
accordance with the literature.19q 1H NMR (300 MHz; CDCl3) δH
9.01 (1H, br s, NH), 7.92 (2H, d, J = 9.0 Hz, Ar-H), 6.93 (2H, d, J =
9.0 Hz, Ar-H), 3.81 (3H, s, OCH3), 1.99 (3H, s, COCH3); 13C{1H}
NMR (75 MHz, CDCl3) δC 168.6, 164.1, 130.8, 129.9, 114.3, 55.9,
23.6; HRMS m/z (ES) 230.0472, C9H12NO4S [M + H]+ requires
230.0487.
N-Benzyl-N-tosylacetamide (12g). DBN (1) (0.01 mL, 0.1
mmol) and acetonitrile (2 mL) were added to the N-acetyl DBN·BPh4
(3b) (0.316 g, 0.65 mmol) and N-benzyl-p-toluenesulfonamide (11g)
(0.131 g, 0.5 mmol), and the resulting solution was heated at 80 °C for
16 h according to the general procedure. The crude product was
dissolved in ethyl acetate, and the excess salts were filtered off. The
solution was washed with NH4Cl and brine before being dried over
MgSO4, filtered, and concentrated to give the title compound (0.099 g,
65%) as a beige solid, with spectroscopic data in accordance with the
literature.19r 1H NMR (300 MHz; CDCl3) δH 7.53 (2H, d, J = 8.4 Hz,
Tol-H), 7.31−7.17 (7H, m, Ar-H), 5.00 (2H, s, NCH2Ph), 2.34 (3H, s,
Tol-CH3), 2.20 (3H, s, COCH3); 13C{1H} NMR (75 MHz, CDCl3)
δC 170.5, 145.1, 136.8, 136.6, 129.9, 128.7, 128.1, 127.9, 49.6, 25.0,
21.7; HRMS m/z (ES) 304.1012, C16H18NO3S [M + H]+ requires
304.1007.
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ASSOCIATED CONTENT
* Supporting Information
■
S
1H and 13C{1H} NMR spectra of all N-acyl DBN·BPh4 salts
(3a−f); X-ray crystal structures and CIF files for N-benzoyl
DBN·BPh4 (3a) and N-hydrocinnamoyl DBN·BPh4 (3d). This
material is available free of charge via the Internet at http://
pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: S.D.Bull@bath.ac.uk
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We would like to thank the University of Bath for funding (to
J.E.T.).
■
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