Bismuth triflate-catalyzed friedel-crafts acylations of sydnones

Article abstract of DOI:10.1080/00397911.2011.580070

Friedel-Crafts acylations of various 3-arylsydnones at the C4 position have been achieved in good yields using 4 equivalents of an alkyl anhydride and 25mol% each of bismuth triflate and lithium perchlorate in anhydrous acetonitrile at 95C. Acylations app

Full text of DOI:10.1080/00397911.2011.580070

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Bismuth Triflate–Catalyzed Friedel–Crafts
Acylations of Sydnones
Jennifer Mahoney a , Kenneth Turnbull a & Mark Cubberley a
a Chemistry Department, Wright State University, Dayton, Ohio, USA
Accepted author version posted online: 12 Jan 2012.Version of
record first published: 17 Aug 2012.
To cite this article: Jennifer Mahoney, Kenneth Turnbull & Mark Cubberley (2012): Bismuth
Triflate–Catalyzed Friedel–Crafts Acylations of Sydnones, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 42:21, 3220-3229
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Synthetic Communications1, 42: 3220–3229, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.580070
BISMUTH TRIFLATE–CATALYZED FRIEDEL–CRAFTS
ACYLATIONS OF SYDNONES
Jennifer Mahoney, Kenneth Turnbull, and Mark Cubberley
Chemistry Department, Wright State University, Dayton, Ohio, USA
GRAPHICAL ABSTRACT
Abstract Friedel–Crafts acylations of various 3-arylsydnones at the C4 position have been
achieved in good yields using 4 equivalents of an alkyl anhydride and 25 mol% each of
bismuth triflate and lithium perchlorate in anhydrous acetonitrile at 95 ꢀC. Acylations
appear to be faster with arylsydnones bearing electron-donating moieties and sterically
unencumbered anhydrides.
Keywords Acylation; Friedel–Crafts; mesoionic compounds; sydnones
INTRODUCTION
Discovered in 1935, sydnones are the most studied compounds of the meso-
ionic heterocycles.[1] Sydnones undergo a wide variety of transformations including
electrophilic aromatic substitution, metalation, 1,3-dipolar cycloaddition, and
cleavage with aqueous acids to afford hydrazines or heterocycles.[2–6]
Acylation of the sydnone ring at the C4 position has been achieved by a
number of methods; however, those reported to date have limited synthetic utility
in that they lack generality, employ relatively harsh conditions, and=or have poor
atom economy. For example, Greco and coworkers showed that 4-acylation could
be achieved in reasonable yields using alkyl acids and phosphorus pentoxide.[7] How-
ever, aryl acids were unreactive. Yashunskii and Vasil’eva reported that 4-acetyl-3-
phenylsydnone (2) could be prepared in reasonable yield from 3-phenylsydnone
(1) using acetic anhydride and boron trifluoride etherate, yet the generality of this
Received March 11, 2011.
Address correspondence to Mark Cubberley, Chemistry Department, Wright State University,
Dayton, OH 45435, USA. E-mail: mark.cubberley@wright.edu
3220

FRIEDEL–CRAFTS ACYLATIONS OF SYDNONES
3221
procedure has not been established.[8] Tien and coworkers demonstrated initially
that 4-acylation could be achieved in moderate yields using acetic anhydride and
phosphoric or perchloric acid.[9] In a subsequent study, Tien and coworkers reported
that 4-acylation could be achieved using only a catalytic amount of perchloric acid
under ultrasonication.[10] Although ultrasonication accelerated the acylation, a
high-power ultrasonicator had to be employed for only modest gains in product
yield. We showed that 4-acylation could be achieved in good yields using acetic
anhydride and Montmorillonite K-10 at 120 ꢀC.[11] However, acylation was sluggish
with a strong electron-withdrawing group ortho to the sydnone ring. Accordingly,
our interest in 4-acylsydnones (and diacylsydnones) as synthetic precursors to novel
sydnoquinolines has prompted us to find a more efficient acylation method.
In traditional Friedel–Crafts acylation reactions, the Lewis acid (e.g., AlCl3) is
added in stochiometric excess (often 6 equivalents). Aqueous workup of the reaction
destroys the Lewis acid, producing acidic waste. Alternatively, metal triflates (parti-
cularly Ln and Bi) have been reported to facillitate Friedel–Crafts acylations at cata-
lytic concentrations, often with lithium perchlorate serving as a co-catalyst.[12]
Stable to aqueous workup, these catalysts can be recovered and recycled. The aim
of the present work was to explore the utility of metal triflates in the synthesis of
4-acylsydnones.
RESULTS AND DISCUSSION
A Labmate parallel synthesizer (Advanced Chemtech) was used to probe the
reaction conditions by which 3-phenylsydnone (1) could be converted to 4-acetyl-3-
phenylsydnone (2) in the presence of acetic anyhydride, a metal triflate, and lithium
perchlorate (Scheme 1). Initial trials utilized minimal amounts of metal triflate=
lithium perchlorate (5 mol%) and a small excess of acetic anhydride in acetonitrile
as solvent at reaction temperatures of 20, 35, and 50 ꢀC in capped vials (Table 1).
Entries 1–18 are consistent with literature reports that bismuth triflate is more active
than scandium and ytterbium triflates.[12] Increased acylation was observed with
increasing molar percent of bismuth triflate=lithium perchlorate (entries 19–26)
and ultimately temperature until complete conversion of 3-phenylsydnone (1) to
4-acetyl-3-phenylsydnone (2) was observed with 20 mol% bismuth triflate=lithium
perchlorate and 3 to 4 equivalents of acetic anhydride at 70 ꢀC (entries 27 and 28).
It is also of note that the lithium perchlorate cocatalyst was necessary for acylation
to occur (entries 29 and 30).
Scheme 1. Acetylation of 3-phenylsydnone.

3222
J. MAHONEY, K. TURNBULL, AND M. CUBBERLEY
Table 1. Acetylation of 3-phenylsydnone with various metal triflate catalysts
LiClO4
Mol % (mol %) Eq. Ac2O Temp. (ꢀC)
Entry
M
Solvent
Time Conversion (TLC)
1
2
Bi
Bi
5
5
5
5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2
20
35
50
20
35
50
20
35
50
20
35
50
20
35
50
20
35
50
50
50
50
50
50
50
50
50
70
70
50
50
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
16 h
16 h
16 h
16 h
16 h
16 h
16 h
16 h
16 h
2 d
None
None
3
Bi
5
5
Trace
None
None
4
Sc
Sc
Sc
Yb
Yb
Yb
Bi
5
5
5
5
5
6
5
5
None
None
7
5
5
8
5
5
None
None
9
5
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
5
5
None
None
Bi
5
5
2 d
2 d
Bi
5
5
Trace
None
None
Sc
Sc
Sc
Yb
Yb
Yb
Bi
5
5
2 d
2 d
5
5
5
5
2 d
2 d
None
None
5
5
5
5
2 d
2 d
None
None
5
5
10
5
10
5
16 h
3 d
Partial
Partial
Partial
Partial
Partial
Partial
Partial
Partial
Complete
Complete
None
Bi
Bi
5
5
3
4 d
2 d
Bi
10
10
15
15
20
20
20
20
0
10
10
15
15
20
20
20
0
2
Bi
3
2 d
2 d
Bi
2
Bi
3
2 d
2 d
Bi
3
Bi
3
16 h
16 h
2 d
Bi
4
Bi
3
Bi
20
3
2 d
None
Because thin-layer chromatography (TLC) examination suggested that acyla-
tion occurred faster using 4 equivalents of acetic anhydride compared to 3 equiva-
lents, the reaction was scaled up accordingly using a sealed pressure tube and
20 mol% freshly prepared bismuth triflate,[13] 20 mol% lithium perchlorate, and 4
equivalents of acetic anhydride at 95 ꢀC. [Yields were much lower with commercial
Bi(OTf)3.] Surprisingly, acylation was incomplete in this scaled-up reaction after
16 h; however, when the cocatalyst concentration was increased to 25 mol%, acyla-
tion was complete in just 2 h (TLC examination). Filtration of the crude reaction
mixture through a plug of silica gel to remove baseline material provided colorless
crystals of 4-acetyl-3-phenylsydnone (2) in 93% yield. The infrared (IR) spectrum
of this material showed strong peaks at 1797 and 1666 cmꢁ1 for the sydnone car-
bonyl and the acetyl group, respectively. The higher frequency sydnone carbonyl
stretch [versus 1760 cmꢁ1 for 3-phenylsydnone (1)] is consistent with the sydnone
carbonyl in resonance with the C4 acetyl. The proton NMR spectrum showed a sing-
let at 2.53 ppm for the acetyl methyl group.

FRIEDEL–CRAFTS ACYLATIONS OF SYDNONES
3223
Table 2. Acetylation of 3-phenylsydnone with bismuth triflate: Effects of reaction
time, co-catalyst, and concentration
Entry
Bi(OTf)3 (mol %)a
LiClO4 (mol %)
Time (h)
Yieldb (%)
1
2
3
4
5
6
25
25
20
25
25
30
25
25
20
20
15
30
2
16
4
93
58
57
76
48
87
4
16
2
aThe Bi(OTf)3 in these studies was freshly prepared from triphenyl bismuthene.
bUnrecrystallized yield.
Additional trials explored the effect of longer reaction times and variations in
the cocatalyst concentrations (Table 2). Increasing reaction times generally had a
negative effect on yield, presumably due to sydnone cleavage in the increasingly
acidic reaction medium (entry 1 versus entry 2). Similarly, decreasing the concen-
tration of bismuth triflate from 25 mol% decreased the yield (entry 3). Decreasing
the concentration of the lithium perchlorate cocatalyst relative to bismuth triflate
(25 mol%) also decreased the yield (entries 4 and 5). This effect could highlight the
buffering capacity of the lithum perchlorate that hinders acidolysis of the sydnone
ring. Increasing the concentration of bismuth triflate beyond 25 mol% had little
effect on yield (entry 6 versus entry 1).
We then investigated the utility of this novel, catalytic acylation methodology
with other alkyl anhydrides (Scheme 2 and Table 3). Trifluoroacetic anhydride
(TFAA), although a more reactive electrophile than acetic anhydride, failed to react
with 3-phenylsydnone (1) after 16 h at 95 ꢀC. It is possible that the inductive effect of
the fluorines in TFAA inhibits complexation with bismuth triflate. Acylations of 1
Scheme 2. Acylation of phenylsydnone.
Table 3. Acylation of 3-phenylsydnone using bismuth triflate=lithium
perchlorate catalysis
R
Bi(OTf)3=LiClO4 (mol %)
Time (h)
Yield (%)
CF3
20
25
25
25
16
4
—
63
73
59
CH2CH3
CH2CH2CH3
CH(CH3)2
16
16

3224
J. MAHONEY, K. TURNBULL, AND M. CUBBERLEY
Scheme 3. Acetylation of 3-arylsydnones.
Table 4. Acetylation of 3-arylsydnones using bismuth triflate=lithium
perchlorate catalysis
R
Bi(OTf)3=LiClO4 (mol %)
Time (h)
Yield (%)
a
NO2
Cl
25
25
25
25
25
72
4.5
4
—
87
83
83
78
Br
CH3
2
0.5
OCH3
aAn additional equivalent of acetic anhydride and 10 mol % of Bi(OTf)3=
LiClO4 were added after 26 h.
with propanoic, butanoic, and isobutanoic anhydrides (to yield the corresponding
acylated sydnones 4–6) were successful but were increasingly sluggish in that order,
presumably due to steric hindrance caused by the longer alkyl side chains.
Our final efforts were directed toward the acylation of para-substituted 3-aryl-
sydnones 7–11 with acetic anhydride (Scheme 3 and Table 4). In general, these trans-
formations gave good yields of the corresponding acyl sydnones 12–16, and there
was a positive correlation between increased reaction rate and the electron-donating
capacity of the para-substituent. Accordingly, acylation of para-methoxyphenyl-
sydnone (11) [R ¼ CH3O] was complete in just 30 min while acylation of para-nitro-
phenylsydnone (7) [R ¼ NO2] was still incomplete after 72 h.
In summary, we have developed a novel Friedel–Crafts acylation methodology
for 3-arylsydnones using 4 equivalents of an alkyl anhydride and 25 mol% each of
bismuth triflate and lithium perchlorate in anhydrous acetonitrile at 95 ꢀC. This acy-
lation methodology has more synthetic utility than the acylation methods reported
to date in that it tolerates a number of alkyl anhydrides and para-substituted 3-aryl-
sydnones, employs milder reaction conditions, and has a better atom economy. The
further scope and limitations of this approach will be reported in due course.
EXPERIMENTAL
3-Phenylsydnone (1) and its para-substituted analogs 7–11 (R ¼ NO2, Cl, Br,
CH3, OCH3) were synthesized according to reported procedures.[14] Bismuth triflate

FRIEDEL–CRAFTS ACYLATIONS OF SYDNONES
3225
was synthesized from commercially available triphenyl bismuthene.[13] All other
starting reagents were purchased from commercial sources and used without further
purification. Melting points were determined on a Mel-Temp melting-point appar-
atus and are uncorrected. IR spectra were acquired on a Mattson Genesis II FTIR.
NMR spectra were acquired on a Bruker 300-MHz NMR spectrometer and are
reported relative to tetramethylsilane (TMS) as an internal standard. Mass spectral
(MS) peaks for known compounds 2, 13–16, and 4–6 are reported in Refs. 15 and 7,
respectively.
General Procedure for the Acylation of 3-Phenylsydnone (1)
3-Phenylsydnone (0.617 mmol), bismuth triflate (0.154 mmol), lithium per-
chlorate (0.154 mmol), and alkyl anhydride (2.45 mmol) were added to a pressure
tube containing acetonitrile (5 mL). The mixture was heated to 95 ꢀC in an oil bath
and was stirred until the reaction was complete (TLC evidence). Water (5 mL) was
added, and the mixture was cooled to room temperature over 5 min and extracted
with methylene chloride (3 ꢂ 10 mL). The combined extracts were dried and filtered,
and the filtrate was removed in vacuo. The resulting solid was eluted through a plug
of silica gel using methylene chloride to remove baseline material and=or recrystal-
lized from hot ethanol.
4-Acetyl-3-phenylsydnone (2)
Using 3-phenylsydnone (0.1000 g, 0.617 mmol), bismuth triflate (0.1012 g,
0.154 mmol), lithium perchlorate (0.0164 g, 0.154 mmol), acetic anhydride (232 mL,
2.45 mmol), and acetonitrile (5 mL) in the general procedure gave, after 2 h, the title
compound as colorless crystals (89 mg, 71%); characterization data (mp, IR, NMR)
were consistent with literature data.[15]
4-Propanoyl-3-phenylsydnone (4)
Using 3-phenylsydnone (0.1000 g, 0.617 mmol), bismuth triflate (0.1012 g,
0.154 mmol), lithium perchlorate (0.0164 g, 0.154 mmol), propionic anhydride
(318 mL, 2.48 mmol), and acetonitrile (5 mL) in the general procedure gave, after
4 h, the title compound as colorless crystals (85 mg, 63%); mp 92 ꢀC; lit.
92.5–94 ꢀC;[7] nmax (KBr): 3070, 2962, 2968, 2835, 1794, 1664, 1491, 1426, 1300,
1
1022, 962, 767, 689 cmꢁ1; H NMR (CDCl3): 7.7 (m 5H), 2.9 (q, 2H), 1.1 (t, 3H)
13
=
=
ppm; C NMR (CDCl3): 187.8 (C O), 166.1 (sydnone C O), 135.1, 132.3, 129.4,
124.9, 105.9 (sydnone C-4), 33.9, 7.1 ppm.
4-Butanoyl-3-phenylsydnone (5)
Using 3-phenylsydnone (0.1000 g, 0.617 mmol), bismuth triflate (0.1012 g,
0.154 mmol), lithium perchlorate (0.0164 g, 0.154 mmol), butyric anhydride
(404 mL, 2.47 mmol), and acetonitrile (5 mL) in the general procedure, followed by
washing the combined organic extracts with saturated aqueous potassium carbonate,
gave, after 16 h, the title compound as colorless crystals (105 mg, 73%); mp 62–64 ꢀC;

3226
J. MAHONEY, K. TURNBULL, AND M. CUBBERLEY
lit. 72.5–74 ꢀC;[7] nmax (KBr): 3067, 2964, 2931, 2873, 1760, 1664 (C O), 1512, 1424,
=
1306, 998 cmꢁ1; 1H NMR (CDCl3): 7.7 (m 5H), 2.9 (t, 2H), 1.7 (sex, 2H), 0.9 (t, 3H)
13
ppm; C NMR (CDCl3): 197.3 (C O), 166.0 (sydnone C O), 135.1, 132.3, 129.4,
124.9, 106.0 (sydnone C-4), 42.1, 16.8, 13.6 ppm.
=
=
4-Isobutanoyl-3-phenylsydnone (6)
Using 3-phenylsydnone (0.1000 g, 0.617 mmol), bismuth triflate (0.1012 g,
0.154 mmol), lithium perchlorate (0.0164 g, 0.154 mmol), isobutyric anhydride
(403 mL, 2.43 mmol), and acetonitrile (5 mL) in the general procedure gave, after
16 h, the title compound as colorless crystals (85 mg, 59%); mp 105–106 ꢀC; lit.
113.5–115 ꢀC;[7] nmax (KBr): 3024, 2973, 2934, 2876, 1775, 1673, 1422, 1298, 1169,
955, 765, 688 cmꢁ1 1H NMR (CDCl3): 7.7 (m 5H), 3.6 (sep, 1H), 1.1 (d, 6H)
;
13
=
=
ppm; C NMR (CDCl3): 191.7 (C O), 165.6 (sydnone C O), 135.2, 132.3, 129.6,
124.8, 105.5 (sydnone C-4), 37.0, 17.8 ppm.
4-Acetyl-3-(4-chlorophenyl)sydnone (13)
Using 3-(4-chlorophenyl)sydnone (0.1219 g, 0.617 mmol), bismuth triflate
(0.1012 g, 0.154 mmol), lithium perchlorate (0.0164 g, 0.154 mmol), acetic anhydride
(232 mL, 2.45 mmol), and acetonitrile (5 mL) in the general procedure gave, after
4.5 h, the title compound as colorless crystals (129 mg, 87%); characterization data
(mp, IR, NMR) were consistent with literature data.[15]
4-Acetyl-3-(4-bromophenyl)sydnone (14)
Using 3-(4-bromophenyl)sydnone (0.1438 g, 0.617 mmol), bismuth triflate
(0.1012 g, 0.154 mmol), lithium perchlorate (0.0164 g, 0.154 mmol), acetic anhydride
(232 mL, 2.45 mmol), and acetonitrile (5 mL) in the general procedure gave, after 4 h,
the title compound as colorless crystals (144 mg, 83%); characterization data (mp,
IR, NMR) were consistent with literature data.[15]
4-Acetyl-3-(4-tolyl)sydnone (15)
Using 3-(4-tolyl)sydnone (0.1089 g, 0.617 mmol), bismuth triflate (0.1012 g,
0.154 mmol), lithium perchlorate (0.0164 g, 0.154 mmol), acetic anhydride (232 mL,
2.45 mmol), and acetonitrile (5 mL) in the general procedure gave, after 2 h, the title
compound as colorless crystals (112 mg, 83%); characterization data (mp, IR, NMR)
were consistent with literature data.[15]
4-Acetyl-3-(4-methoxyphenyl)sydnone (16)
Using 3-(4-methoxyphenyl)sydnone (0.1185 g, 0.617 mmol), bismuth triflate
(0.1012 g, 0.154 mmol), lithium perchlorate (0.0164 g, 0.154 mmol), acetic anhydride
(232 mL, 2.45 mmol), and acetonitrile (5 mL) in the general procedure gave, after
0.5 h, the title compound as colorless crystals (113 mg, 79%); characterization data
(mp, IR, NMR) were consistent with literature data.[15]

FRIEDEL–CRAFTS ACYLATIONS OF SYDNONES
3227
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