An unusual behaviour of N-(tert-butoxycarbonyl)- and N-pivaloyl-(methylthio)anilines in metallation reactions

Article abstract of DOI:10.1016/S0040-4020(03)00347-8

The metallation reaction of N-Boc-and N-Piv-(methylthio)anilines are here described. The results show that N-Boc derivatives are metallated only by superbases to give products substituted at the thiomethylic group. N-Piv derivatives show a different behaviour: ortho-derivative is metallated by both butyllithium and superbase at the thiomethylic carbon atom, while para-derivative is metallated in ortho to the N-Piv group by butyllithium and at the thiomethylic carbon atom by superbase. The meta-derivative is metallated only by superbase at the thiomethylic carbon atom.

Full text of DOI:10.1016/S0040-4020(03)00347-8

Tetrahedron 59 (2003) 2893–2897
An unusual behaviour of N-(tert-butoxycarbonyl)- and N-pivaloyl-
(methylthio)anilines in metallation reactionsq
*
Maria Grazia Cabiddu, Salvatore Cabiddu, Enzo Cadoni, Stefania De Montis, Claudia Fattuoni
and Stefana Melis
*
Dipartimento di Scienze Chimiche, Cittadella Universitaria di Monserrato, S.S. 554 Bivio per Sestu, I-09042 Monserrato (CA), Italy
Received 28 November 2002; revised 7 February 2003; accepted 27 February 2003
Abstract—The metallation reaction of N-Boc-and N-Piv-(methylthio)anilines are here described. The results show that N-Boc derivatives
are metallated only by superbases to give products substituted at the thiomethylic group. N-Piv derivatives show a different behaviour: ortho-
derivative is metallated by both butyllithium and superbase at the thiomethylic carbon atom, while para-derivative is metallated in ortho to
the N-Piv group by butyllithium and at the thiomethylic carbon atom by superbase. The meta-derivative is metallated only by superbase at the
thiomethylic carbon atom. q 2003 Elsevier Science Ltd. All rights reserved.
Anilines bearing thiomethylic groups are useful building
blocks to synthesise biologically active molecules. In a
previous paper2 we showed that N,N-dimethyl-4-
(methylthio)aniline reacts with butyllithium to give
mixtures of products substituted at the arylic and the
thiomethylic hydrogen, while with superbases gives only
the product derived from the substitution of the thiomethylic
hydrogen. On the other side, ortho and meta isomers are
metallated only at the thiomethylic position with both
reagents.
compounds were quenched with carbon dioxide and
analysed by spectroscopic methods.
The metallation reactions were performed at various
temperatures (260, 240, 220, 210, 08C) at different
metallating reagent concentrations (2, 3, 4, 8 M equiv. of
organometallic reagent), with reaction times ranging from
30 min to 8 h. Contrary to our expectations, the reactions
performed on 1a–c gave only the starting material and a
small quantity (ca. 5%) of unidentifiable products. Then we
changed the metallating reagent employing the superbasic
mixture LICKOR (butyllithium and potassium tert-
butoxide). In this way (Scheme 1), all isomers afforded
products substituted at the thiomethylic position (3a–c,
respectively) with a yield of 70, 56, and 75%. The best
results were obtained using 4 M equiv. of LICKOR. Every
attempt to bimetallate the same substrates failed even using
6–8 M equiv. of metallating reagent.
Stanetty and co-workers reported the direct ortho-lithiation
of N-Boc-anilines, analyzing the best reaction conditions
(organolithium, solvent, temperature, reaction time) to
obtain the highest yield.3 Other papers4–8 described the
N-Boc group as a powerful ortho-directing group in the
metallation of arenes bearing various substituents.
In this work we examined the reactivity of N-Boc protected
anilines bearing a methylthio group in the ortho, meta, or
para position to test their relative directing power in the
annular metallation reaction, with the aim of further
functionalisation of these substrates after removal of the
Boc group.
In order to substitute one arylic hydrogen we tested the
pivaloyl protecting group because NHPiv is reported to act
All starting compounds were reacted with various alkyl-
lithium (butyllithium, tert-butyllithium): all metallated
q See Ref. 1.
Keywords: metallation; lithiation; thioethers; anilines.
*
Corresponding authors. Tel.: þ39-70-6754387; fax: þ39-70-6754388;
e-mail: scabiddu@unica.it
Scheme 1.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00347-8

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M. G. Cabiddu et al. / Tetrahedron 59 (2003) 2893–2897
Scheme 2.
as a more powerful ortho-directing group in metallation
reactions.9,10 The results (Scheme 2) showed that the ortho
isomer (2a) gives products deriving from the substitution of
one thiomethylic hydrogen with both organolithiums and
superbases. On the contrary, the para isomer (2c) is
metallated in ortho to the NHPiv group with butyllithium,
while the superbase leads to the substitution of one
thiomethylic hydrogen. Even with these compounds the
increase in the amount of organolithium does not signifi-
cantly affect the yield. Unexpectedly, 2b afforded only
starting material when treated with butyllithium, while
using the superbase we obtained the product 4b derived
from a thiomethylic substitution.
coordinating power than the thiomethyl group; on the
other side, the superbase selectively metallates the more
acidic thiomethylic group. The ortho isomer 2a, on the
contrary, is lithiated at the thiomethylic carbon even with
the organolithiums. This result can be accounted for by the
stabilisation of the thiomethyl carbanion by the adjacent
N-Piv group (Fig. 1).11
It is remarkable that all reactions require a great concen-
tration of metallating reagent: this phenomenon can be
explained in terms of competitive complexation processes,
due to the presence of many coordinating heteroatoms.
Moreover 1a, through its derivative 3a, shows to be a useful
precursor of 1,4-benzothiazines, as proved by the attainment
of compound 6 (Scheme 3).
In conclusion, examining the results it may be deduced that
the N-Boc interferes with the thiomethylic group inhibiting
the coordination and then the metallation cannot occur.
Only superbases are able to act on these substrates
abstracting the most acidic hydrogens, i.e. the thiomethylic
ones. In support of this hypothesis it can be noticed that the
N-Piv group, more effective than N-Boc to promote
coordinative processes, allows reactions not only with
superbase but even with organolithium. Moreover the
metallating reagents show different regioselectivity, as
expected: with 2c the organolithium selectively metallates
the position ortho to the N-Piv, due to its stronger
Scheme 3.
1. Experimental
1.1. General
1H NMR spectra were recorded on a Varian VXR-300
spectrometer with tetramethylsilane as internal reference.
IR spectra were recorded on a Perkin–Elmer 1310 grating
Figure 1.

M. G. Cabiddu et al. / Tetrahedron 59 (2003) 2893–2897
2895
spectrophotometer. The GC–MS analyses were performed
with a Hewlett–Packard 5989A GC–MS system with HP
5890 GC fitted with a capillary column (50 m£0.2 mm)
packed with DH 50.2 Petrocol (0.50 m film thickness). All
flash chromatography was on silica G60 (Merck) columns.
Microanalyses were carried out with a Carlo Erba 1106
elemental analyser. Melting points were obtained on a
Kofler hot stage microscope and are uncorrected.
yellow crystals, mp 109–1108C; [Found: C, 60.27; H, 7.09;
N, 5.88; S, 13.25. C12H17NO2S requires C, 60.22; H, 7.16;
N, 5.85; S, 13.40%]; nmax (CHCl3,) 3450 (NH), 1720 cm21
(CO); dH (300 MHz, CDCl3) 1.42 (9H, s, CCH3), 2.35 (3H,
s, SCH3), 6.60 (1H, s, NH, D2O exchangeable), 7.12 (2H, d,
J¼8.5 Hz, Ph), 7.21 (2H, d, J¼8.5 Hz, Ph); dc (75.4 MHz,
CDCl3) 17.0, 28.2, 80.5, 119.1, 128.4, 131.7, 136.1, 152.5;
m/z (EI) 239 (5, Mþ), 183 (36), 165 (8), 139 (18), 124 (26),
106 (3), 96 (5), 57 (100), 41 (69%).
1.2. Materials
1.2.4. 2,2-Dimethyl-N-[(2-methylthio)phenyl]propana-
mide (2a). To an ice-cooled solution of 2-(methylthio)-
benzenamine (10 g, 72 mmol) and triethylamine (11.8 g,
117 mmol) in dry tetrahydrofuran (100 mL) was added
dropwise under nitrogen a solution of 2,2-dimethylpro-
panoyl chloride (22.7 g, 188 mmol). The resulting mixture
was stirred at room temperature for 4 h, then the solvent was
removed in vacuo. The residue was diluted with dichloro-
methane and washed with 10% aqueous sodium hydroxide,
water and dried (Na2SO4). After the solvent was removed,
the residue was flash-chromatographed on silica gel column
with hexane/diethyl ether (6:1) as eluent to give the title
compound 2a (11.09 g, 69%) which was crystallised from
hexane as pale yellow crystals, mp 40–448C (lit.9 bp 85–
908C/0.005 mm Hg) [Found: C, 64.44; H, 7.61; N, 6.18; S,
14.21. C12H17NOS requires C, 64.53; H, 7.67; N, 6.25; S,
14.36%]; nmax (CHCl3,) 3360 (NH), 1695 cm21 (CO); dH
(300 MHz, CDCl3) 1.35 (9H, s, CCH3), 2.35 (3H, s, SCH3),
7.02 (1H, t, J¼7.5 Hz, Ph), 7.27 (1H, t, J¼7.8 Hz, Ph), 7.45
(1H, d, J¼7.6 Hz, Ph), 8.37 (1H, d, J¼8.4 Hz, Ph), 8.72
(1H, s, NH, D2O exchangeable); dc (75.4 MHz, CDCl3)
18.6, 27.4, 39.9, 120.1, 123.8, 125.0, 128.7, 132.8, 138.4,
176.3; m/z (EI) 223 (24, Mþ), 176 (83), 166 (7), 139 (30), 124
(37), 106 (9), 94 (7), 80 (8), 69 (4), 65 (8), 57 (100), 41 (37%).
Commercially available reagent-grade starting materials
and solvents were used. Solutions of butyllithium in hexane
and tert-butyllithium in pentane were obtained from Aldrich
Chemical Company and were analysed by the Gilman
double titration method before use.12 2-(Methylthio)-3-
(methylthio) and 4-(methylthio)aniline were purchased
(Aldrich).
1.2.1. N-(tert-Butoxycarbonyl)-2-(methylthio)benz-
enamine (1a). A solution of 2-(methylthio)benzenamine
(5 g, 36 mmol) in dry tetrahydrofuran (50 mL) was
blanketed with argon and then treated dropwise at room
temperature with a solution of tert-butylcarbonate (8.6 g,
40 mmol) in dry tetrahydrofuran (20 mL). When the
addition was complete the mixture was stirred for ca. 15 h
at 608C, cooled, diluted with diethyl ether (25 mL), washed
with 5% hydrochloric acid and then with aqueous sodium
carbonate. The ethereal solution was dried (Na2SO4) and
concentrated. The residue was flash-chromatographed on a
silica gel column using 20:1 hexane/ethyl acetate to give the
title compound 1a (5.77 g, 67%) as a yellow viscous oil;3
[Found: C, 60.15; H, 7.11; N, 5.78; S, 13.29. C12H17NO2S
requires C, 60.22; H, 7.16; N, 5.85; S, 13.40%]; nmax (neat)
3370 (NH), 1730 cm21 (CO); dH (300 MHz, CDCl3) 1.51
(9H, s, CCH3), 2.33 (3H, s, SCH3), 6.95 (1H, t, J¼7.3 Hz,
Ph), 7.24 (1H, t, J¼7.4 Hz, Ph), 7.43 (1H, d, J¼7.8 Hz, Ph),
7.61 (1H, s, NH, D2O exchangeable), 8.11 (1H, d,
J¼8.3 Hz, Ph); dc (75.4 MHz, CDCl3) 18.9, 28.2, 80.4,
118.7, 122.9, 124.0, 128.8, 133.1, 138.9, 152.6; m/z (EI) 239
(20, Mþ), 183 (51), 166 (10), 139 (53), 124 (37), 106 (12),
94 (11), 57 (100), 41 (47%).
In the same manner, starting from 3-(methylthio)- and
4-(methylthio)benzenamine, were prepared:
1.2.5. 2,2-Dimethyl-N-[(3-methylthio)phenyl]propan-
amide (2b). The residue was crystallised from aqueous
ethanol to give the title compound 2b (7.86 g, 71%) as a
white solid, mp 134–1368C; [Found: C, 64.58; H, 7.71; N,
6.21; S, 14.27. C12H17NOS requires C, 64.53; H, 7.67; N,
6.25; S, 14.36%]; nmax (Nujol,) 3280 (NH), 1645 cm21
(CO); dH (300 MHz, CDCl3) 1.31 (9H, s, CCH3), 2.48 (3H,
s, SCH3), 6.98 (1H, m, Ph), 7.20 (2H, m, Ph), 7.38 (1H, s,
NH, D2O exchangeable), 7.60 (1H, s, Ph); dc (75.4 MHz,
CDCl3) 15.6, 27.5, 39.6, 116.4, 117.5, 122.1, 129.1, 138.5,
139.5, 176.7; m/z (EI) 223 (12, Mþ), 139 (8), 123 (2), 106
(12), 85 (4), 77 (2), 57 (100), 41 (38%).
Analogously from 3-(methylthio)- and 4-(methylthio)-
benzenamine were prepared.
1.2.2. N-(tert-Butoxycarbonyl)-3-(methylthio)benz-
enamine (1b). The residue was crystallised from aqueous
ethanol to give the title compound 1b (5.85 g, 68%) as a
white solid, mp 74–768C; [Found: C, 60.11; H, 7.10; N,
5.80; S, 13.31. C12H17NO2S requires C, 60.22; H, 7.16; N,
5.85; S, 13.40%]; nmax (nujol) 3335 (NH), 1710 cm21 (CO);
dH (300 MHz, CDCl3) 1.51 (9H, s, CCH3), 2.47 (3H, s,
SCH3), 6.91 (1H, d, J¼7.8 Hz, Ph), 7.06 (1H, d, J¼7.5 Hz,
Ph), 7.18 (1H, t, J¼7.8 Hz, Ph), 7.26 (1H, s, Ph), 7.36 (1H, s,
NH, D2O exchangeable); dc (75.4 MHz, CDCl3) 15.5, 28.2,
80.5, 115.0, 115.9, 120.8, 129.1, 138.7, 139.3, 152.4; m/z
(EI) 239 (24, Mþ), 183 (58), 166 (7), 165 (7), 139 (24), 106
(32), 94 (3), 57 (100), 41 (37%).
1.2.6. 2,2-Dimethyl-N-[(4-methylthio)phenyl]propan-
amide (2c). The residue was crystallised from aqueous
ethanol to give the title compound 2c (13.50 g, 84%) as a
white solid, mp 143–1458C; [Found: C, 64.41; H, 7.60; N,
6.19; S, 14.24. C12H17NOS requires C, 64.53; H, 7.67; N,
6.25; S, 14.36%]; nmax (Nujol,) 3290 (NH), 1650 cm21
(CO); dH (300 MHz, CDCl3) 1.31 (9H, s, CCH3), 2.46 (3H,
s, SCH3), 7.23 (2H, d, J¼8.2 Hz, Ph), 7.35 (1H, s, NH, D2O
exchangeable), 7.47 (2H, d, J¼8.2 Hz, Ph); dc (75.4 MHz,
CDCl3) 16.7, 27.5, 39.5, 120.6, 127.9, 133.3, 135.6, 176.5;
m/z (EI) 223 (51, Mþ), 180 (2), 165 (2), 139 (30), 124 (31),
111 (2), 96 (3), 85 (5), 69 (3), 65 (2), 57 (100), 41 (25%).
1.2.3. N-(tert-Butoxycarbonyl)-4-(methylthio)benz-
enamine (1c). The residue was crystallised from aqueous
ethanol to give the title compound 1c (4.31 g, 50%) as pale

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1.3. General procedure for metallation with superbases
1.3.4. 2-({2-[(2,2-Dimethylpropanoyl)amino]phenyl}-
thio)acetic acid (4a). The residue was crystallised from
aqueous ethanol to give the title compound 4a (0.91 g, 68%)
as a white solid, mp 117–1218C; [Found C, 58.31; H, 6.34;
N, 5.18; S, 11.87. C13H17NO3S requires C, 58.40; H, 6.41;
N, 5.24; S, 11.99%]; nmax (CHCl3) 3370 (NH), 3060 (OH),
1710 and 1680 cm21 (CO); dH (300 MHz, CDCl3) 1.33 (9H,
s, CCH3), 3.56 (2H, s, SCH2), 7.05 (1H, t, J¼7.8 Hz, Ph),
7.34 (1H, t, J¼7.8 Hz, Ph), 7.56 (1H, d, J¼7.8 Hz, Ph), 8.32
(1H, d, J¼8.1 Hz, Ph), 9.13 (1H, s, NH, D2O exchangeable);
dc (75.4 MHz, CDCl3) 27.5, 38.8, 40.2, 121.2, 121.9, 124.5,
130.7, 135.9, 140.2, 173.7, 177.2; m/z (EI) 267 (10, Mþ),
176 (51), 165 (18), 136 (16), 124 (19), 109 (5), 93 (26), 57
(100), 41 (39%).
To a vigorously stirred solution of potassium tert-butoxide
(2.24 g, 20 mmol) and anhydrous tetrahydrofuran (25 mL) a
1.4 M solution of butyllithium in hexane (14.3 mL,
20 mmol) was added under argon at 2758C. After 15 min
a solution of the starting material (5 mmol) in anhydrous
tetrahydrofuran (25 mL) was added and stirring was
continued for 2 h at 2758C. The mixture was then poured
onto ca. 100 g of crushed solid carbon dioxide. After 24 h
the residue was treated with 10% aqueous NaHCO3 (10 mL)
and then with diethyl ether (20 mL). The alkali layer was
separated, washed with diethyl ether (3£10 mL) and then
acidified with 10% aqueous cold hydrochloric acid,
extracted with CHCl3 (3£10 mL), dried (Na2SO4) and
concentrated.
1.3.5. 2-({3-[(2,2-Dimethylpropanoyl)amino]phenyl}-
thio)acetic acid (4b). The residue was crystallised from
aqueous ethanol to give the title compound 4b (0.84 g, 63%)
as white crystals, mp 105–1078C; [Found C, 58.29; H, 6.36;
N, 5.15; S, 11.84. C13H17NO3S requires C, 58.40; H, 6.41;
N, 5.24; S, 11.99%]; nmax (CHCl3) 3250 (NH), 2740 (OH),
1730 and 1660 cm21 (CO); dH (300 MHz, CDCl3) 1.25 (9H,
s, CCH3), 3.61 (2H, s, SCH2), 7.08 (1H, d, J¼7.8 Hz, Ph),
7.16 (1H, t, J¼7.8 Hz, Ph), 7.31 (1H, d, J¼6.6 Hz, Ph), 7.58
(1H, s, Ph), 8.34 (1H, s, NH, D2O exchangeable); dc
(75.4 MHz, CDCl3) 28.1, 36.9, 40.2, 119.7, 122.1, 126.2,
130.0, 136.2, 139.0, 174.3, 178.2; m/z (EI) 267 (35, Mþ,),
223 (61), 183 (23), 164 (4), 138 (12), 108 (4), 94 (6), 57
(100), 41 (31%).
In this manner starting from 1a–c and 2a–c the following
compounds were obtained:
1.3.1. 2-({2-[(tert-Butoxycarbonyl)amino]phenyl}thio)-
acetic acid (3a). The residue was crystallised from aqueous
ethanol to give the title compound 3a (0.99 g, 70%) as pale
brown crystals, mp 112–1148C; [Found: C, 55.04; H, 5.98;
N, 4.90; S, 11.21. C13H17NO4S requires C, 55.11; H, 6.05;
N, 4.94; S, 11.32%]; nmax (CHCl3) 3500 (NH), 3370 (OH),
1720 cm21 (CO); dH (300 MHz, CDCl3) 1.53 (9H, s,
CCH3), 3.52 (2H, s, SCH2), 6.98 (1H, t, J¼7.5 Hz, Ph),
7.34 (1H, t, J¼7.2 Hz, Ph), 7.54 (1H, d, J¼7.8 Hz, Ph), 7.98
(1H, s, NH, D2O exchangeable), 8.14 (1H, d, J¼8.4 Hz, Ph);
dc (75.4 MHz, CDCl3) 28.3, 38.5, 80.9, 119.1, 120.3, 123.1,
130.8, 136.1, 140.5, 152.8, 174.9; m/z (EI) 283 (12, Mþ),
227 (21), 209 (12), 183 (16), 165 (16), 150 (9), 136 (34), 124
(26), 93 (47), 69 (25), 57 (100), 41 (80%).
1.3.6. 2-({4-[(2,2-Dimethylpropanoyl)amino]phenyl}-
thio)acetic acid (4c). The residue was crystallised from
aqueous ethanol to give the title compound 4c (0.87 g, 65%)
as yellow crystals, mp 165–1678C; [Found C, 58.33; H,
6.31; N, 5.18; S, 11.82. C13H17NO3S requires C, 58.40; H,
6.41; N, 5.24; S, 11.99%]; nmax (Nujol) 3320 (NH), 2640
(OH), 1730 and 1620 cm21 (CO); dH (300 MHz, DMSO-d6)
1.21 (9H, s, CCH3), 3.69 (2H, s, SCH2), 7.32 (2H, d,
J¼9.0 Hz, Ph), 7.61 (2H, d, J¼9.0 Hz, Ph), 9.22 (1H, s, NH,
D2O exchangeable); dc (75.4 MHz, DMSO-d6) 27.3, 36.4,
40.4, 120.9, 128.8, 129.8, 138.3, 170.8, 176.6; m/z (EI) 267
(31, Mþ), 183 (10), 165 (2), 150 (9), 124 (20), 108 (6), 91
(2), 57 (100), 41 (38%).
1.3.2. 2-({3-[(tert-Butoxycarbonyl)amino]phenyl}thio)-
acetic acid (3b). The residue was crystallised from aqueous
ethanol to give the title compound 3b (0.79 g, 56%) as a
pale brown solid, mp 122–1248C; [Found C, 55.02; H, 6.00;
N, 4.87; S, 11.19. C13H17NO4S requires C, 55.11; H, 6.05;
N, 4.94; S, 11.32%]; nmax (CHCl3) 3440 (NH), 3300 (OH),
1720 cm21 (CO); dH (300 MHz, CDCl3) 1.52 (9H, s,
CCH3), 3.67 (2H, s, SCH2), 7.06 (1H, m, Ph), 7.21 (2H, d,
J¼5.4 Hz, Ph), 7.26 (1H, s, Ph), 7.43 (1H, s, NH, D2O
exchangeable); dc (75.4 MHz, DMSO-d6) 28.1, 35.1, 79.2,
115.8, 117.3, 121.3, 129.3, 136.0, 140.1, 152.7, 170.4; m/z
(EI) 283 (20, Mþ), 227 (30), 224 (17), 183 (97), 166 (7), 164
(8), 150 (26), 138 (48), 124 (8), 109 (8), 94 (56), 80 (32), 65
(20), 57 (100), 41 (94%).
1.4. General procedure for metallation with
organolithium compounds
A vigorously stirred solution of starting material (5 mmol)
in anhydrous tetrahydrofuran (25 mL) was treated with a
1.4 M solution of n-butyllithium in hexane (14.3 mL,
20 mmol) at 08C under argon. After 2 h, the mixture was
poured onto ca. 100 g of crushed solid carbon dioxide. After
24 h the residue was treated with 10% aqueous sodium
bicarbonate (10 mL) and then with diethyl ether (20 mL).
The alkali layer was separated, washed with diethyl ether
(3£10 mL), and then acidified with cold concentrated
hydrochloric acid, extracted with diethyl ether (3£10 mL),
dried (Na2SO4), and concentrated.
1.3.3. 2-({4-[(tert-Butoxycarbonyl)amino]phenyl}thio)-
acetic acid (3c). The residue was crystallised from aqueous
ethanol to give the title compound 3b (1.05 g, 75%) as a
white solid, mp 153–1558C; [Found C, 55.05; H, 5.99; N,
4.85; S, 11.23. C13H17NO4S requires C, 55.11; H, 6.05; N
4.94; S, 11.32%]; nmax (Nujol) 3370 (NH), 2720 (OH),
1700 cm21 (CO); dH (300 MHz, DMSO-d6): 1.47 (9H, s,
CCH3), 3.65 (2H, s, SCH2), 7.28 (2H, d, J¼9.0 Hz, Ph), 7.40
(2H, d, J¼9.0 Hz, Ph), 9.39 (1H, s, NH, D2O exchangeable);
dc (75.4 MHz, DMSO-d6) 28.4, 36.8, 79.7, 119.1, 127.7,
130.7, 138.7, 153.1, 171.2; m/z (EI) 283 (6, Mþ), 227 (63),
209 (2), 183 (12), 168 (8), 164 (6), 136 (5), 124 (40), 108
(10), 96 (6), 69 (4), 57 (100), 41 (45%).
1a–c afforded only the starting material. The same results
were obtained performing the reaction at 260, 240, 220,
2108C. In the case of 2a the reaction, performed at 08C,
gave the products 4a in 55% yield. 2b afforded only the

M. G. Cabiddu et al. / Tetrahedron 59 (2003) 2893–2897
2897
starting material. In the case of 2c the following product was
obtained.
Cagliari (National Project ‘Stereoselezione in Sintesi
Organica, Metodologie ad Applicazioni’) and C.N.R.
(Italy) is gratefully acknowledged.
1.4.1. 2-[(2,2-Dimethylpropanoyl)amino]-5-(methyl-
thio)benzoic acid (5). The residue was crystallised from
aqueous ethanol to give the title compound 5 (0.87 g, 65%)
as pale brown crystals, mp 149–1508C; [Found C, 58.30; H,
6.33; N, 5.16; S, 11.85. C13H17NO3S requires C, 58.40; H,
6.41; N, 5.24; S, 11.99%]; nmax (CHCl3) 3510 (NH), 3320
and 3220 (OH) 1715 and 1670 cm21 (CO); dH (300 MHz,
CDCl3) 1.37 (9H, s, C–CH3), 2.51 (3H, s, SCH3), 7.51 (1H,
dd, J¼8.7, 2.4 Hz, Ph), 8.04 (1H, d, J¼2.1 Hz, Ph), 8.75
(1H, d, J¼9.0 Hz, Ph), 10.25 (1H, s, OH, D2O exchange-
able), 11.13 (1H, s, NH, D2O exchangeable); dc (75.4 MHz,
CDCl3); 16.7, 27.5, 40.4, 115.0, 121.3, 130.2, 132.3, 134.4,
139.8, 172.1, 178.2; m/z (EI) 267 (70, Mþ), 192 (12), 183
(71), 165 (56), 150 (8), 122 (10), 91 (8), 69 (6), 57 (100), 41
(68%).
References
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The same results were obtained performing the reactions
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product which was crystallised from aqueous ethanol to give
the title compound 6 (0.50 g, 86%) as pale brown needles,
mp 178–1798C (lit.13 mp 181–181.58C). The compound 6
is identical to the commercial product (Aldrich).
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`
Financial support from the Ministero dell’Universita e della
Ricerca Scientifica e Tecnologica, Rome, The University of
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