Sydnone ring as an ortho-director of lithiation, 3: One-pot regiospecific o-acylation andsubsequent sydnone 4-substitution

Article abstract of DOI:10.1080/00397910802664251

Readily available 3-phenylsydnone (1) reacts with n-butyllithium/N,N, N′,N′-tetramethylethylenediamine (TMEDA) to form the dilithio species 2, which can be acylated regiospecifically at the ortho-aryl position using N-methoxy-N-methylamides (Weinreb's ami

Full text of DOI:10.1080/00397910802664251

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Sydnone Ring as an ortho-
Director of Lithiation, 3: One-
Pot Regiospecific o-Acylation
and Subsequent Sydnone 4-
Substitution
Kenneth Turnbull a & Douglas M. Krein a
a Chemistry Department , Wright State University ,
Dayton, Ohio, USA
Published online: 14 Jul 2009.
To cite this article: Kenneth Turnbull & Douglas M. Krein (2009) Sydnone Ring as an
ortho-Director of Lithiation, 3: One-Pot Regiospecific o-Acylation and Subsequent
Sydnone 4-Substitution, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 39:16, 2852-2858, DOI:
10.1080/00397910802664251
To link to this article: http://dx.doi.org/10.1080/00397910802664251
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Synthetic Communications1, 39: 2852–2858, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802664251
Sydnone Ring as an ortho-Director of Lithiation,
3: One-Pot Regiospecific o-Acylation
and Subsequent Sydnone 4-Substitution
Kenneth Turnbull and Douglas M. Krein
Chemistry Department, Wright State University, Dayton, Ohio, USA
Abstract: Readily available 3-phenylsydnone (1) reacts with n-butyllithium=
N,N,N0,N0-tetramethylethylenediamine (TMEDA) to form the dilithio species
2, which can be acylated regiospecifically at the ortho-aryl position using
N-methoxy-N-methylamides (Weinreb’s amides) followed by reaction with a
second, more reactive electrophile at the sydnone C-4 position. Asymmetrically
substituted arylsydnones 7 are obtained in 57–86% yield.
Keywords: Acylation, lithiation, mesoionic compounds, sydnones
Some years ago, we reported the first utilization of the sydnone ring as a
director of ortho-lithiation using n-butyl lithium (Scheme 1).[1,2] Therein,
3-phenylsydnone (1) reacted with 2.2 equivalents of n-BuLi in the
presence of N,N,N0,N0-tetramethylethylenediamine (TMEDA), and sub-
sequent treatment with a variety of electrophiles gave the corresponding
disubstituted sydnones 3 in 85–93% yield, presumably via the dilithio
intermediate 2. Having established that dilithiation was possible, we were
interested to see whether the site of electrophilic substitution could be
controlled. The pKa of the sydnone ring proton had been estimated to
be approximately 18–20,[3] and accordingly, it appeared likely that, in
2, the anion at the ortho-position would be considerably more reactive
than that on the sydnone ring. Selectivity for the ortho-position was of
considerable interest because much of our previous work had utilized
Received October 10, 2008.
Address correspondence to Kenneth Turnbull, Chemistry Department, Wright
State University, Dayton, OH 45435, USA. E-mail: kenneth.turnbull@wright.edu
2852

Sydnone Ring as an ortho-Director of Lithiation
2853
Scheme 1. Asymmetric substitution of 3-phenylsydnone.
ortho-substituted arylsydnones as precursors to differently substituted
sydnones,[4] fused ring sydnones,[5] or to various heterocycles.[6] Indeed,
complete selectivity for the ortho-aryl position was realized using methyl
iodide as electrophile [3-(2-tolyl)sydnone resulted]; however, extension to
the preparation of other ortho-alkyl sydnones was problematic because
ethyl iodide did not react under these conditions, presumably because of
competitive elimination. The most consistent results were obtained using
a weak electrophile such as an N-methoxy-N-methylamide (Weinreb’s
amide) 4,[7] and the corresponding o-acyl arylsydnones 6 were obtained
in 40–90% yield (Scheme 1). The success of this approach relied not only
on the greater nucleophilicity of the ortho-anion (in 2) but also on the key
characteristic of such reactions, namely that after initial attack of the
ortho-anion upon the amide, in the resultant intermediate (cf. 5), effective
complexation of the lithio intermediate prevented further reaction with
excess organolithium reagent or the anion on the sydnone ring because
the carbonyl group was not ‘‘revealed’’ until after workup. We were inter-
ested in the possibility that after selective reaction of the dianion 2 with a
Weinreb’s amide, it might be possible to react the resultant sydnone
carbanion 5 with a more reactive electrophile, yielding 7 on workup. This
possibility was particularly intriguing because in 1993 we had shown
that o-acyl-4-bromosydnones 7 (E ¼ Br) react with HBr to form novel
1-bromocarbonyl indazoles.[6b] However, the utility of this transforma-
tion was hampered by the relative inaccessibility of the starting bromo
species 7 (E ¼ Br). We now report that the latter (and related species 7,
E ¼ I, SiMe3, SPh, CHO) can be prepared in good yield (57–86%) in a
one-pot process starting from readily available 3-phenylsydnone (1).

2854
K. Turnbull and D. M. Krein
Table 1. Reactions of 3-phenylsydnone (1) with BuLi=TMEDA and Weinreb’s
amides followed by a second electrophile to afford 7a–i
Entry
7
R (in 4 and 7)
Eþ
E (in 7)
Yield (%)
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
g
h
i
C6H5
TMSCl
TMSCl
MSCl
TMSCl
TMSCl
Br2
TMS
TMS
TMS
TMS
TMS
Br
71
61
63
59
57
84
74
82
86
4-BrC6H4
4-MeOC6H4
CH3
ClCH2
C6H5
C6H5
I2
I
C6H5
C6H5
PhSSPh
DMF
SPh
CHO
Thus, treatment of 1 with 2.2 equivalents of n-butyllithium in tetra-
hydrofuran (THF) and TMEDA at ꢀ78ꢁC, followed by a Weinreb’s
amide and a second electrophile [Br2, I2, Me3SiCl, PhSSPh, or dimethyl-
formamide (DMF)], provides an attractive avenue to otherwise difficultly
accessible 4-substituted o-acylarylsydnones 7. The initial part of the study
was conducted using different Weinreb’s amides followed by the same
second electrophile, namely, chlorotrimethylsilane, and the resultant pro-
ducts, 7a–e, were obtained in 57–71% yield (Table 1, entries 1–5). With the
generality of the process established using differently functionalized
Weinreb’s amides, we elected to maintain the same Weinreb’s amide 4
(R¼Ph) and vary the second electrophile (Br2, I2, PhSSPh, or DMF).
The resultant products, 7f–i, were obtained in 74–86% yield (Table 1,
entries 6–9). The identities of the products were confirmed by satisfactory
combustion analyses, the presence of the sydnone C¼O stretching vibra-
tion at ꢂ1750 cmꢀ1 in their infrared (IR) spectra, and the expected chemi-
cal shifts and splitting patterns in their proton and carbon NMR spectra.
Overall, we have developed a useful, one-pot preparation of
4-substituted ortho-acyl or aroyl phenylsydnones 7 from readily available
3-phenylsydnone (1), and we intend to explore further the scope and
limitations of the present discovery.
EXPERIMENTAL
General Procedure for the Preparation of 4-Substituted 3-(2-(Acyl or
Aroyl)phenyl)sydnones 7
To a stirred solution of 3-phenylsydnone (1) (0.25 g, 1.54 mmol) in dry
THF (150 mL) at ꢀ78ꢁC under an atmosphere of dry nitrogen gas,

Sydnone Ring as an ortho-Director of Lithiation
2855
TMEDA (0.29 mL, 1.93 mmol) and then n-butyllithium (2.19 mL,
3.39 mmol, 1.55 M in hexane) were added dropwise. After 0.5 h, the app-
ropriate N-methoxy-N-methylamide 4 (1.77–1.85 mmol) was added to
the golden-yellow solution, and after an additional 1–2 h, the second elec-
trophile (1.85 mmol for entries 1 and 2 or 1.93 mmol for entries 3–9) was
added. After warming to 0ꢁC over 2 h, the mixture was quenched with
aqueous hydrochloric acid (100 mL, 10% v=v) and then extracted with
dichloromethane (3 ꢃ 100 mL). The combined organic extracts were dried
(MgSO4), and the solvent was removed in vacuo to afford the corres-
ponding o-acylated 4-substituted sydnone 7 as a dark oil. The latter
was triturated with hexane=ether (1:1, v:v) (for 7a, only), and the residual
oil was purified by column chromatography (silica gel, dichloromethane
as eluant) followed by recrystallization from dichloromethane=hexane
(for 7a–e, h) or dichloromethane=benzene=hexane (for 7f, g, i) to afford
colorless crystals.
3-(2-Benzoylphenyl)-4-trimethylsilylsydnone (7a)
Using N-methoxy-N-methylbenzamide (4, R¼Ph) (0.293 g, 1.77 mmol)
and chlorotrimethylsilane (0.201 g, 1.85 mmol) in the general procedure
gave the title compound (0.372 g), mp 150–152ꢁC. Found: C, 64.06; H,
5.45; N, 8.38. Calc. for C18H18N2O3Si: C, 63.88; H, 5.36; N, 8.28. nmax
(KBr): 3067, 2965, 1729, 1663, 1400, 1277, 932, 847, 702 cmꢀ1 1H
;
NMR (200 MHz, CDCl3): d 0.12 (s, 9H), 7.42–7.73 (m, 9H); 13C NMR
(CDCl3): ꢀ1.92 [Si(CH3)3], 107.73 (sydnone C-4), 126.90, 128.53,
129.99, 130.22, 131.32, 131.55, 133.98 (aromatic CH), 134.45, 135.84,
135.95 (aromatic quaternary C), 173.07 (sydnone C¼O), 192.41 (ketone
C¼O) ppm.
3-(2-(4-Bromobenzoyl)phenyl)-4-trimethylsilylsydnone (7b)
Using N-methoxy-N-methyl-4-bromobenzamide (4, R¼4-BrC6H4) (0.431 g,
1.77 mmol) and chlorotrimethylsilane (0.201 g, 1.85 mmol) in the general
procedure gave the title compound (0.390 g), mp 133–134ꢁC. Found: C,
51.94; H, 4.03; N, 6.71. Calc. for C18H17BrN2O3Si: C, 51.81; H, 4.11;
N, 6.71. nmax (KBr): 3065, 2959, 1730, 1663, 1582, 1385, 1274, 929,
1
846, 770 cmꢀ1; H NMR (200 MHz, CDCl3): d 0.09 (s, 9H), 7.57–7.74
(m, 8H); 13C NMR (CDCl3): ꢀ1.72 [Si(CH3)3], 107.88 (sydnone C-4),
125.21, 127.05, 131.42, 131.65, 131.95, 135.48 (aromatic CH), 129.66,
132.58, 134.28, 134.38 (aromatic quaternary C), 172.97 (sydnone
C¼O), 191.34 (ketone C¼O) ppm.

2856
K. Turnbull and D. M. Krein
3-(2-(4-Methoxybenzoyl)phenyl)-4-trimethylsilylsydnone (7c)
Using N-methoxy-N-methyl-4-methoxybenzamide (4, R¼4-MeOC6H4)
(0.361 g, 1.85 mmol) and chlorotrimethylsilane (0.209 g, 1.93 mmol) in
the general procedure gave the title compound (0.358 g), mp 128–
130ꢁC. Found: C, 61.84; H, 5.36; N, 8.21. Calc. for C19H20N2O4Si: C,
61.94; H, 5.47; N, 7.60. nmax (KBr): 3071, 2968, 1733, 1655, 1599, 1396,
1
1264, 931, 848 cmꢀ1; H NMR (200 MHz, CDCl3): d 0.14 (s, 9H), 3.87
(s, 3H), 6.91 (d, 2H), 7.65–7.75 (m, 6H); 13C NMR (CDCl3): ꢀ1.98
[Si(CH3)3], 55.54 (OCH3), 107.72 (sydnone C-4), 113.86, 126.82, 129.89,
130.58, 131.50, 132.50 (aromatic CH), 128.75, 130.26, 136.45, 164.34 (aro-
matic quaternary C), 173.10 (sydnone C¼O), 190.75 (ketone C¼O) ppm.
3-(2-Acetylphenyl)-4-trimethylsilylsydnone (7d)
Using N-methoxy-N-methylacetamide (4, R¼Me) (0.191 g, 1.85 mmol)
and chlorotrimethylsilane (0.209 g, 1.93 mmol) in the general procedure
gave the title compound (0.251 g), mp 93–94ꢁC. Found: C, 56.63; H,
5.84; N, 10.02. Calc. for C13H16N2O3Si: C, 56.50; H, 5.84; N, 10.14. nmax
(KBr): 3065, 2965, 1769, 1685, 1487, 1382, 1256, 1128, 1008, 841 cmꢀ1; 1H
NMR (200 MHz, CDCl3): d ꢀ0.14 (s, 9H), 1.82 (s, 3H), 7.60–7.74 (m, 4H);
13C NMR (CDCl3): 0.67 [Si(CH3)3], 26.04 (COCH3), 111.01 (sydnone
C-4), 114.31, 125.10, 130.04, 132.29 (aromatic CH), 132.97, 145.84 (aro-
matic quaternary C), 163.41 (sydnone C¼O), 196.70 (ketone C¼O) ppm.
3-(2-Chloroacetylphenyl)-4-trimethylsilylsydnone (7e)
Using 2-chloro-N-methoxy-N-methyl-acetamide (4, R¼ClCH2) (0.255 g,
1.85 mmol) and chlorotrimethylsilane (0.209 g, 1.93 mmol) in the general
procedure gave the title compound (0.271 g), mp 121–122ꢁC. Found: C,
50.19; H, 4.90; N, 9.07. Calc. for C13H15ClN2O3Si: C, 50.24; H, 4.86;
N, 9.01. nmax (KBr): 3066, 2974, 2936, 1733, 1710, 1600, 1498, 1408,
1
1347, 1223, 845, 768 cmꢀ1; H NMR (200 MHz, CDCl3): d 0.08 (s, 9H),
4.59 (s, 2H), 7.59–7.99 (m, 4H); 13C NMR (CDCl3): ꢀ2.37 [Si(CH3)3],
46.50 (CH2), 107.44 (sydnone C-4), 128.31, 130.11, 132.76, 133.54 (aro-
matic CH), 132.35, 134.22 (aromatic quaternary C), 176.75 (sydnone
C¼O), 191.70 (ketone C¼O) ppm.
3-(2-Benzoylphenyl)-4-bromosydnone (7f)
Using N-methoxy-N-methylbenzamide (4, R¼Ph) (0.306 g, 1.85 mmol)
and bromine (0.308 g, 1.93 mmol) in the general procedure gave the title

Sydnone Ring as an ortho-Director of Lithiation
2857
compound (0.445 g), mp 164–166ꢁC. Found: C, 51.96; H, 2.64; N, 8.11.
Calc. for C15H9BrN2O3: C, 52.20; H, 2.63; N, 8.12; nmax (KBr): 3066,
1730, 1661, 1595, 1421, 1275, 1207, 1026, 930, 703 cmꢀ1 1H NMR
;
(200 MHz, CDCl3): d 7.54–7.69 (m, 5H), 7.93–8.04 (m, 4H); 13C NMR
(CDCl3): 88.08 (sydnone C-4), 127.43, 128.70, 129.37, 131.09, 132.93,
134.04, 135.32 (aromatic CH), 131.32, 134.26, 164.65 (aromatic quatern-
ary C), 165.06 (sydnone C¼O), 191.75 (ketone C¼O) ppm.
3-(2-Benzoylphenyl)-4-Iodosydnone (7g)
Using N-methoxy-N-methylbenzamide (4, R¼Ph) (0.306 g, 1.85 mmol)
and iodine (0.489 g, 1.93 mmol) in the general procedure gave the title
compound (0.449 g), mp 186–188ꢁC. Found: C, 45.83; H, 2.38; N, 7.29.
Calc. for C15H9IN2O3: C, 45.94; H, 2.31; N, 7.14. nmax (KBr): 3065,
1708, 1663, 1597, 1445, 1273, 1200, 1022, 930, 704 cmꢀ1 1H NMR
;
(200 MHz, CDCl3): d 7.49–7.91 (m, 9H); 13C NMR (CDCl3): 58.29 (syd-
none C-4), 127.11, 128.08, 129.10, 130.61, 132.01, 132.15, 132.75, 133.36,
134.28, 135.17 (aromatic C), 168.14 (sydnone C¼O), 191.80 (ketone
C¼O) ppm.
3-(2-Benzoylphenyl)-4-phenylthiosydnone (7h)
Using N-methoxy-N-methylbenzamide (4, R¼Ph) (0.306 g, 1.85 mmol)
and diphenyl disulfide (0.421 g, 1.93 mmol) in the general procedure gave
the title compound (0.473 g), mp 142–144ꢁC. Found: C, 67.46; H, 3.71;
N, 7.50. Calc. for C21H14N2O3S: C, 67.37; H, 3.77; N, 7.48. nmax (KBr):
3072, 1749, 1657, 1596, 1446, 1386, 1279, 1239, 1036, 699 cmꢀ1; 1H NMR
(200 MHz, CDCl3): d 7.22 (s, 5H), 7.38–7.44 (m, 4H), 7.66–7.76 (m, 5H);
13C NMR (CDCl3): 101.56 (sydnone C-4), 126.99, 127.59, 128.55, 128.79,
129.48, 129.70, 131.05, 131.88, 132.16, 133.88 (aromatic CH), 132.27,
133.17, 135.40, 135.76 (aromatic quaternary C), 167.78 (sydnone C ¼ O),
192.40 (ketone C¼O) ppm.
3-(2-Benzoylphenyl)-4-formylsydnone (7i)
Using N-methoxy-N-methylbenzamide (4, R¼Ph) (0.306 g, 1.85 mmol)
and N,N-dimethylformamide (0.141 g, 1.93 mmol) in the general proce-
dure gave the title compound (0.368 g), mp 137–138ꢁC. Found: C,
65.03; H, 3.39; N, 9.43. Calc. for C16H10N2O3: C, 65.31; H, 3.43; N,
9.52. nmax (KBr): 3103, 3041, 1796, 1660, 1595, 1447, 1381, 1278, 932,
1
703 cmꢀ1; H NMR (200 MHz, CDCl3): d 7.48–7.81 (m, 9H), 9.41 (s, 1H);

2858
K. Turnbull and D. M. Krein
13C NMR (CDCl3): 105.97 (sydnone C-4), 124.63, 126.95, 128.64, 129.89,
130.22, 131.44, 132.42, 133.91, 134.61, 135.78 (aromatic C), 166.16 (sydnone
C¼O), 174.82 (aldehyde C¼O), 192.54 (ketone C¼O) ppm.
REFERENCES
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ortho-director of lithiation, 2: Dilithiation of 3-phenylsydnone and regio-
specific o-aryl acylation using N-methoxy-N-methylamides. Tetrahedron Lett.
1998, 39, 1509.
2. Turnbull, K.; Krein, D. M. The sydnone ring as an ortho-director of lithiation:
Dilithiation of 3-phenylsydnone and trapping by electrophiles. Tetrahedron
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