Directed ortho lithiation of N-tert-butylbenzenesulfinamide

Article abstract of DOI:10.1081/SCC-100103334

Introducing the sulfinamide group as a new useful ortho-directing group, we are presenting the synthesis of a series of ortho-substituted N-tert-butylbenzenesulfinamides via directed lithiation of the title compound and subsequent quenching of the dilithiated intermediates with various electrophiles.

Full text of DOI:10.1081/SCC-100103334

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DIRECTED ORTHO
LITHIATION OF N-TERT-
BUTYLBENZENESULFINAMIDE
Peter Stanetty a & Thomas Emerschitz a
a Institute of Organic Chemistry , Vienna
University of Technology, Getreidemarkt 9,
Vienna, A-1060, Austria
Published online: 09 Nov 2006.
To cite this article: Peter Stanetty & Thomas Emerschitz (2001) DIRECTED ORTHO
LITHIATION OF N-TERT-BUTYLBENZENESULFINAMIDE, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry,
31:6, 961-968, DOI: 10.1081/SCC-100103334
To link to this article: http://dx.doi.org/10.1081/SCC-100103334
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SYNTHETIC COMMUNICATIONS, 31(6), 961–968 (2001)
DIRECTED ORTHO LITHIATION OF
N-TERT-BUTYLBENZENESULFINAMIDE
Peter Stanetty* and Thomas Emerschitz
Institute of Organic Chemistry, Vienna University of
Technology, Getreidemarkt 9, A-1060 Vienna, Austria
ABSTRACT
Introducing the sulfinamide group as a new useful ortho-
directing group, we are presenting the synthesis of a series of
ortho-substituted N-tert-butylbenzenesulfinamides via direc-
ted lithiation of the title compound and subsequent quenching
of the dilithiated intermediates with various electrophiles.
In the last two decades directed ortho-metalation has become a strat-
egy of increasing importance for the construction of various aromatic sub-
stitution patterns as well as in the synthesis of aromatic and heteroaromatic
ring systems.1 As carboxamides and sulfonamides are among the best and
most commonly used directing groups, it could be assumed that the sulfin-
amide group should have similar directing properties, however, the latter
has not received methodological attention. Recently, Katritzky et al.2
reported a single example where N-phenyl-benzenesulfinamide was used in
an ortho-lithiation reaction. In the present paper we are reporting the first
results of our investigations concerning the application of the N-tert-butyl-
sulfinamide group as an ortho-directing group.
The sulfinamide group can be introduced into aromatic compounds by
several methods.3 The most important approach starts with the sodium or
* Corresponding author. E-mail: pstanett@pop.tuwien.ac.at
961
Copyright & 2001by Marcel Dekker, Inc.
www.dekker.com

962
STANETTY AND EMERSCHITZ
lithium salt of benzenesulfinic acid. The sodium benzenesulfinate is commer-
cially available, lithium salts can easily be obtained by reaction of aryl-
lithium compounds with sulfur dioxide in dry diethyl ether or THF.
Treatment of these sulfinates with thionyl chloride in dry petroleum ether4
gave a sufficiently pure sulfinyl chloride, which was then reacted with
2 equiv. of tert-butylamine in dry dichloromethane according to Chiang
et al.5 Alternatively, the N-t-butylsulfinamide group was also introduced
directly by addition of phenyllithium of N-sulfinyl-tert-butylamine, which
is easily available by reaction of tert-butylamine with N-(chlorosulfinyl)-
imidazole.6 A similar addition reaction has been described by Gilman and
Morris7a as well as Klamann et al.7b using Grignard reagents and
N-sulfinylaniline.
Compared to similar directed metalation groups the tert.-butylsulfina-
mide group is very sensitive to hydrolysis, but careful work-up leads to
products which can easily be purified by column chromatography or recrys-
tallization.
A representative series of products (2) obtained by applying an opti-
mized lithiation procedure to the N-tert-butylbenzenesulfinamide is listed in
the following Table.
When DMF was applied, the resulting product was identified as the
cyclic half aminal 3a, which is the more stable ring-chain tautomer.
In the case of CO2 as the electrophile, aqueous HCl had to be used in
the work-up procedure; thus the sulfinamide moiety was hydrolyzed to the
sulfinic acid 3b (see below).
As the hydrolysis of the imine 2f could not be accomplished without
concommitant cleavage of the sulfinamide group, the ketone 2e was

ORTHO LITHIATION
963
Table. Reaction of Dilithiated Sulfinamide 1 with Various Electrophiles
Entry
Electrophile
Product
R
Yield (%)
1tBuNCO
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
CONHtBu
CONHPh
CONMe2
CONEt2
C(Ph)=O
C(Ph)=NH
CH(Ph)-OH
C(Ph)2-OH
CH(3-Py)-OH
I
92
62
60
63
60
72
77
74
81
63
87
68
75
PhNCO
ClCONMe2
ClCONEt2
PhCONMe(OMe)
PhCN
PhCHO
PhCOPh
3-PyCHO
1
0
I
2j
2k
2l
2
11
12
1
Cl3C-CCl3
TosN3
Cl
N3
SiMe3
3
3SiCl Me
2m
prepared by reaction with N-methoxy-N-methyl-benzamide (‘‘Weinreb-
Amide’’) according to literature procedures.8
Being interested in the exploitation of these results towards the syn-
thesis of heterocyclic ring systems, we are continuing to investigate the scope
and limitations of the applicability of sulfinamides as directed metalation
groups in our laboratory.
EXPERIMENTAL SECTION
Melting points were determined with a Kofler hot-stage apparatus and
are uncorrected. NMR-spectra were recorded on a Bruker AC 200 FT
NMR spectrometer using TMS as internal standard.
General Procedure
N-tert-Butylbenzenesulfinamide (1.0 g) 1 was dissolved in dry tetrahy-
drofuran (50 mL) under nitrogen and cooled to ꢀ30ꢁC. n-BuLi (2.2 equiv.,
2.5 M in hexane) was added dropwise, and the reaction mixture warmed to

964
STANETTY AND EMERSCHITZ
room temperature over a period of 2 h. Then it was recooled to ꢀ78ꢁC, and
the electrophile {1.2 equiv., solids (entries 8, 11) dissolved in THF (10 mL)}
was added via syringe. The resulting mixture was stirred for 3–4 h and
allowed to warm to room temperature again. Then it was hydrolyzed with
100 mL of an aqueous solution of ammonium chloride (approx. 10%) and
extracted twice with ethyl acetate (50 mL). The combined extracts were
washed with water and dried over sodium sulfate. After removal of the
solvent in vacuo the residue was purified by flash column chromatography
(silica gel, hexane/ethyl acetate 2:1; entries 3, 4, 10–13) or trituration with
isopropyl ether (entries 1, 2, 5–9).
2-(1,1-Dimethylethyl)-2,3-dihydro-3-hydroxy-benzisothiazole-1-oxide
(3a)
Yield: 85%, colorless crystals, m.p. 95–98ꢁC. 1H NMR (CDCl3):
ꢀ ¼ 1.59 (s, 9H, C(CH3)3), 5.99 (bs, 1H, OH), 7.50–7.60 (m, 3H, arom. H),
7.68–7.74 (m, 2H, arom. H); 13C NMR (CDCl3): ꢀ ¼ 30.5 (q, C(CH3)3), 56.2
(s, C(CH3)3), 86.9 (d, CHOH), 123.8, 124.9, 129.7, 131.5, 141.4, 143.6. Anal.
calcd. for C11H15NO2S (225.31) C 58.64; H 6.71; N 6.22. Found C 58.53; H
6.61; N 6.14.
2-Sulfinobenzoic Acid (3b)
Modified work-up: The reaction mixture was hydrolyzed with 50 mL
of 2N HCl and extracted twice with 50 mL of ethyl acetate. The combined
organic layers were washed with water and dried over sodium sulfate. After
evaporation of the solvent the residue was triturated with isopropyl ether.
Yield: 81%, colorless crystals, m.p. 108–111ꢁC. 1H NMR (DMSO-d6):
ꢀ ¼ 7.65 (t, 1H, J ¼ 7 Hz), 7.80 (t, 1H, J ¼ 7 Hz), 7.96 (d, 1H, J ¼ 7 Hz), 8.09
(d, 1H, J¼7 Hz); 13C NMR (DMSO-d6): ꢀ ¼ 123.8, 129.7, 130.8, 131.4,
132.8, 150.2, 167.1. Anal. calcd. for C7H6O4S (186.19) C 45.16; H 3.25.
Found C 45.31; H 3.25.
N-(1,1-Dimethylethyl)-2-[(1,1-dimethylethyl)aminosulfinyl]-
benzamide (2a)
Yield: 92%, colorless crystals, m.p. 137–140ꢁC. 1H NMR (DMSO-d6):
ꢀ ¼ 1.25 (s, 9H, C(CH3)3), 1.38 (s, 9H, C(CH3)3), 5.69 (bs, 1H, NH),
7.41–7.65 (m, 3H, NH þ arom. H), 7.90–8.0 (m, 2H, arom. H); 13C NMR
(DMSO-d6): ꢀ ¼ 28.6, 30.3 (q, C(CH3)3), 50.9, 53.4 (s, C(CH3)3), 124.0,

ORTHO LITHIATION
965
128.3, 129.3, 129.7, 136.0, 145.4, 166.3. Anal. calcd. for C15H24N2O2S
(296.43) C 60.78; H 8.16; N 9.45. Found C 60.96; H 8.38; N 9.39.
2-[(1,1-Dimethylethyl)aminosulfinyl]-N-phenylbenzamide (2b)
Yield: 62%, colorless crystals, m.p. 142–145ꢁC. 1H NMR (DMSO-d6):
ꢀ ¼ 1.22 (s, 9H, C(CH3)3), 7.03–7.50 (m, 6H, NHþarom. H), 7.70 (d, 1H,
arom. H), 7.90–8.05 (m, 3H, arom. H), 8.19–8.29 (m, 1H, arom. H);
13C NMR (DMSO-d6): ꢀ ¼ 27.1(q, C( CH3)3), 50.8 (s, C(CH3)3), 119.6,
123.1, 123.5, 125.6, 127.6, 128.0, 129.4, 132.2, 140.0, 140.4, 196.4. Anal.
calcd. for C17H20N2O2S (316.42) C 64.53; H 6.37; N 8.85. Found C 64.32;
H 6.21; N 8.60.
2-[(1,1-Dimethylethyl)aminosulfinyl]-N,N-dimethylbenzamide (2c)
Yield: 60%, colourless crystals, m.p. 87–90ꢁC. 1H NMR (DMSO-
d6) ꢀ ¼ 1.21 (s, 9H, C(CH3)3), 2.80, 2.97 (2s, 6H, CH3), 6.20 (bs, 1H, NH),
7.33 (d, 1H, J ¼ 7.7 Hz), 7.50–7.67 (m, 2H), 7.94 (d, 1H, J ¼ 7.7 Hz);
13C NMR (DMSO-d6): ꢀ ¼ 30.2 (q, C(CH3)3), 34.2, 38.2 (q, CH3), 53.1(s,
C(CH3)3), 125.0, 126.8, 128.7, 130.0, 135.4, 144.1, 167.9. Anal. calcd. for
C13H20N2O2S (268.38) C 58.18; H 7.51; N 10.44. Found C 58.10; H 7.58; N
10.23.
2-[(1,1-Dimethylethyl)aminosulfinyl]-N,N-diethylbenzamide (2d)
Yield: 63%, colorless crystals, m.p. 101–104ꢁC. 1H NMR (DMSO-d6):
ꢀ ¼ 1.07 (t, 3H, CH3), 1.19 (t, 3H, CH3), 1.21 (s, 9H, C(CH3)3), 2.94–3.21(m,
2H, CH2), 3.23–3.60 (m, 2H, CH2), 7.32 (d, 1H, J ¼ 6.4 Hz), 7.50–7.68 (m,
2H), 7.97 (d, 1H, J ¼ 6.4 Hz); 13C NMR (DMSO-d6): ꢀ ¼ 13.1, 13.7 (2q,
CH2CH3), 30.3 (q, C(CH3)3), 38.9, 43.3 (2t, CH2CH3), 53.4 (s, C(CH3)3),
124.7, 126.3, 128.9, 130.1, 135.3, 143.8, 167.5. Anal. calcd. for
C15H24N2O2S (296.43) C 60.78; H 8.16; N 9.45. Found C 60.59; H 8.05; N
9.41.
N-(1,1-Dimethylethyl)-2-(phenylcarbonyl)-benzenesulfinamide (2e)
Yield: 60%, colorless crystals, m.p. 158–161ꢁC. 1H NMR
(CDCl3): ¼ 1.03 (s, 9H, C(CH3)3), 3.74 (bs, 1H, NH), 7.38–7.70 (m, 6H,

966
STANETTY AND EMERSCHITZ
arom. H), 7.8 (d, 2H, arom. H, J ¼ 7 Hz), 8.1(d, 1H, arom. H, J ¼ 7 Hz);
13C NMR (CDCl3): ꢀ ¼ 30.0 (q, C(CH3)3), 54.3 (s, C(CH3)3), 125.5, 128.4,
128.7, 129.9, 130.1, 130.3, 133.4, 136.8, 137.7, 146.1, 195.1. Anal. calcd. for
C17H19NO2S (301.41) C 67.74; H 6.35; N 4.65. Found C 67.93; H 6.42; N
4.54.
N-(1,1-Dimethylethyl)-2-(iminophenylmethyl)-benzenesulfinamide (2f)
Yield: 72%, colorless crystals, m.p. 132–135ꢁC. H NMR (CDCl3):
1
ꢀ ¼ 1.52 (s, 9H, C(CH3)3), 7.50–8.02 (m, 9H, arom. H); 13C NMR
(CDCl3): ꢀ ¼ 33.3 (q, C(H3)3), 56.0 (s, C(CH3)3), 122.7, 125.6, 128.8,
128.9, 130.4, 131.5, 131.8, 132.3, 132.5, 143.6, 164.9. Anal. calcd.
for C17H20N2OS (300.42) C 67.97; H 6.71; N 9.32. Found C 68.19; H
6.52; N 9.24.
N-(1,1-Dimethylethyl)-2-(hydroxyphenylmethyl)-benzenesulfinamide (2g)
Yield: 77%, colorless crystals, m.p. 132–140ꢁC (diast. mixture).
1H NMR (CDCl3): ꢀ ¼ 1.43 (s, 9H, C(CH3)3), 4.0 (bs, 1H, OH), 6.27 (s,
1H, CH), 7.15–7.50 (m, 8H, arom. H), 8.02 (d, 1H, arom. H, J ¼ 7 Hz);
13C NMR (CDCl3): ꢀ ¼ 31.0 (q, C(CH3)3), 55.6 (s, C(CH3)3), 70.0 (d,
CHOH), 123.9, 127.1, 127.8, 128.5, 128.6, 128.7, 131.6, 142.0, 142.1,
143.6. Anal. calcd. for C17H21NO2S (303.42) C 67.29; H 6.98; N 4.62.
Found C 67.57; H 7.09; N 4.58.
N-(1,1-Dimethylethyl)-2-(hydroxydiphenylmethyl)-benzenesulfina-
mide (2h)
Yield: 74%, colorless crystals, m.p. 120–128ꢁC (decomp.). H NMR
1
(CDCl3): ꢀ ¼ 1.28 (s, 9H, C(CH3)3), 3.86 (bs, 1H, OH), 6.60 (bs, 1H, NH),
6.80 (d, 1H, arom. H, J ¼ 8.6 Hz), 7.24–7.38 (m, 11H, arom. H), 7.49 (t, 1H,
arom. H, J ¼ 8.6 Hz), 8.10 (d, 1H, arom. H, J ¼ 8.6 Hz); 13C NMR (CDCl3):
ꢀ ¼ 30.4 (q, C(CH3)3), 55.3 (s, C(CH3)3), 81.7 (s, COH), 125.5, 127.1, 127.4,
127.6, 127.8, 127.9, 128.0, 128.2, 130.3, 131.0, 145.2, 145.4, 145.5, 147.8.
Anal. calcd. for C23H25NO2S (379.52) C 72.79; H 6.64; N 3.69. Found C
72.70; H 6.76; N 3.65.

ORTHO LITHIATION
967
N-(1,1-Dimethylethyl)-2-[hydroxy(3-pyridyl)methyl]-
benzenesulfinamide (2i)
Yield: 81%, colorless crystals, m.p. 138–146ꢁC (diast. mixture).
1H NMR (DMSO-d6): ꢀ ¼ 1.12, 1.31 (s, 9H, C(CH3)3), 6.03–6.28 (m, 3H),
7.29–7.39 (m, 1H), 7.48–7.80 (m, 3H, arom. H), 7.90–8.03 (m, 1H),
8.40–8.52 (m, 2H, arom. H); 13C NMR (DMSO-d6): ꢀ ¼ 29.6, 29.9 (q,
C(CH3)3), 53.1, 53.2 (s, C(CH3)3), 65.7, 67.1 (2d, CHOH), 122.4, 122.7,
122.8, 123.0, 125.8, 127.1, 127.3, 127.8, 130.1, 130.2, 133.7, 134.0, 138.9,
139.1, 140.4, 140.9, 142.3, 143.4, 147.3, 147.8, 147.9. Anal. calcd. for
C16H20N2O2S (304.41) C 63.13; H 6.62; N 9.20. Found C 63.18; H 6.66; N
9.03.
N-(1,1-Dimethylethyl)-2-iodobenzenesulfinamide (2j)
Yield: 63%, colorless crystals, m.p. 125–128ꢁC. H NMR (CDCl3):
1
ꢀ ¼1.43 (s, 9H, C(CH3)3), 3.49 (bs, 1H, NH), 7.16 (td, 1H, J¼7.6 Hz,
1.7 Hz), 7.54 (td, 1H, J ¼ 7.6 Hz, 1.3 Hz), 7.84 (dd, 1H, J¼7.6 Hz, 1.3 Hz),
7.98 (dd, 1H, J ¼ 7.6 Hz, 1.7 Hz); 13C NMR (CDCl3): ꢀ ¼ 30.8 (q, C(CH3)3),
54.6 (s, C(CH3)3), 125.5, 128.8, 132.2, 139.8, 148.5. Anal. calcd. for
C10H14INOS (323.19) C 37.16; H 4.37; N 4.33. Found C 37.17; H 4.52; N
4.35.
2-Chloro-N-(1,1-dimethylethyl)-benzenesulfinamide (2k)
Yield: 87%, colorless crystals, m.p. 120–123ꢁC. H NMR (CDCl3):
1
ꢀ ¼ 1.41 (s, 9H, C(CH3)3), 3.65 (bs, 1H, NH), 7.17–7.33 (m, 2H, arom. H),
7.42–7.50 (m, 1H, arom. H), 7.97–8.03 (m, 1H, arom. H); 13C NMR
(CDCl3): ꢀ ¼ 30.8 (q, C(CH3)3), 54.6 (s, C(CH3)3), 125.3 127.3, 130.1,
131.9, 144.1. Anal. calcd. for C10H14ClNOS (231.75) C 51.83; H 6.09; N
6.04. Found C 52.01; H 6.02; N 6.04.
2-Azido-N-(1,1-dimethylethyl)-benzenesulfinamide (2l)
Yield: 68%, yellow crystals, m.p. 115–118ꢁC. 1H NMR (CDCl3):
ꢀ ¼ 1.40 (s, 9H, C(CH3)3), 3.72 (bs, 1H, NH), 7.17–7.33 (m, 2H), 7.50 (t,
1H, J ¼ 9 Hz), 7.95 (d, 1H, J ¼ 9 Hz); 13C NMR (CDCl3): ꢀ ¼ 30.8 (q,
C(CH3)3), 54.3 (s, C(CH3)3), 118.8, 125.0, 125.1, 131.9, 137.0, 137.1. Anal.

968
STANETTY AND EMERSCHITZ
calcd. for C10H14N4OS (238.31) C 50.40; H 5.92; N 23.51. Found C 50.35; H
5.92; N 23.27.
N-(1,1-Dimethylethyl)-2-(trimethylsilyl)-benzenesulfinamide (2m)
Yield: 75%, colorless crystals, m.p. 94–97ꢁC. 1H NMR (CDCl3):
ꢀ ¼ 0.40 (s, 9H, Si(CH3)3), 1.40 (s, 9H, C(CH3)3), 3.58 (bs, 1H, NH), 7.43
(t, 1H, J ¼ 7 Hz), 7.52–7.61 (m, 2H), 8.19 (d, 1H, J ¼ 7 Hz); 13C NMR
(CDCl3): ꢀ ¼ 0.6 (q, Si(CH3)3), 30.9 (q, C(CH3)3), 54.9 (s, C(CH3)3), 122.2,
130.0, 130.2, 134.7, 137.4, 154.0. Anal. calcd. for C13H23NOSSi (269.48) C
57.94; H 8.60; N 5.20. Found C 58.17; H 8.49; N 5.22.
REFERENCES AND NOTES
1. For excellent reviews, see Gschwend, H.W.; Rodriguez, H.R. Org.
React. (N.Y.), 1979, 26, 1; Beak, P.; Snieckus, V. Acc. Chem. Res.
1982, 15, 306; Narasimhan, N.S.; Mali, R.S. Synthesis 1983, 957;
Snieckus, V. J. Heterocycl. Chem. 1984, 95; Snieckus, V. Bull. Soc.
Chim. Fr. 1988, 67; Snieckus, V. Chem. Rev. 1990, 90, 879–933.
2. Katritzky, A.R.; Lue, P. J. Org. Chem. 1990, 55, 74–78.
3. Muth, F. In Methods of Organic Chemistry (Houben-Weyl) Vol. 9;
Muller, E. Ed.; Thieme: Stuttgart, 1955; pp. 299–342; Krauthausen, E.
In Methods of Organic Chemistry (Houben-Weyl), Supplement E11;
Klamann, D. Ed.; Thieme: Stuttgart, 1985; pp. 618–664.
4. Kurzer, F. J. Chem. Soc. 1953, 549–556; Organic Syntheses Coll. Vol.
IV, 1963, 937–939.
5. Chiang, Y.H.; Luloff, J.S.; Schipper, E. J. Org. Chem. 1969, 34,
2397–2401; Douglass, I.B.; Farah, B.S. J. Org. Chem. 1958, 23,
805–807; Raiford, L.C.; Hazlet, S.E. J. Am. Chem. Soc. 1935, 57,
2172–2174.
6. Kim Y.H.; Shin, J.M. Tetrahedron Lett. 1985, 26, 3821–3824.
7. (a) Gilman, H.; Morris, H.L. J. Am. Chem. Soc. 1926, 48, 2399–2404.
(b) Klamann, D.; Sass, C.; Zelenka, M. Chem. Ber. 1959, 92, 1910–1912.
8. Nahm, S.; Weinreb, S.M. Tetrahedron Lett. 1981, 22, 3815–3818.