Atroposelectivity of reactions of benzylic metalated thiobenzamides and thionaphthamides

Article abstract of DOI:10.1002/ejoc.200300233

N,N-Dialkyl-2-methylbenzenecarbothioamides and naphthalenecarbothioamides were prepared by thionation of amides with Lawesson's reagent under unusual conditions. Their axial chirality was evidenced. Benzylic deprotonation of thioamides bearing N,N-diisopr

Full text of DOI:10.1002/ejoc.200300233

FULL PAPER
Atroposelectivity of Reactions of Benzylic Metalated Thiobenzamides
and Thionaphthamides
David Ach,[a] Vincent Reboul,[a] and Patrick Metzner*[a]
Keywords: Amides / Thionation / Thioamides / Metalation / Chirality
N,N-Dialkyl-2-methylbenzenecarbothioamides and naph-
ated aldehyde or ketone, and an imine) to afford diastereom-
thalenecarbothioamides were prepared by thionation of
eric adducts (up to 88:12 dr). This is the first report on atropo-
amides with Lawesson’s reagent under unusual conditions. selective C−C bond formation in the benzylic position of
Their axial chirality was evidenced. Benzylic deprotonation
of thioamides bearing N,N-diisopropyl groups with sec-bu-
tyllithium was selective. The resulting anions were reacted
with prochiral electrophiles (aromatic aldehydes, an unsatur-
thioamides.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
We have wished to investigate this possibility in the sulfur
series. Our interest arose from the need to explore new
structures as chiral auxiliaries for asymmetric syntheses and
the observation that the axially chiral compounds available
so far are almost all of the biaryl structure. Recent investi-
gations have brought the first successes with non-biaryl
compounds.[3,6,8Ϫ14] A great deal of information on atropi-
someric naphthamides is available from the work of
Clayden and his group.[6,15Ϫ19] This has constituted the
starting point of our investigation. We have anticipated that
thioamides might bring advantages or differences over the
oxygen analogues: (i) marked orthogonality, (ii) enhanced
barriers of rotation as suggested by data reported by
Mannschreck and co-workers,[20,21] (iii) easy benzylic met-
allation and stabilization of the anions formed (polariz-
ability of sulfur), (iv) specific behavior of the thioamide
group present in the products for further uses.
Molecules bearing an aromatic nucleus conjugated to an
acyclic π-system are not necessarily flat. Constraints to a
favorable complete orbital overlap with a planar arrange-
ment are encountered, for instance by introduction of an
ortho-substituent on the aromatic ring.[1Ϫ4] For 2-methyl-
benzamides 1 or naphthamides 3, a noticeable angle is ob-
served between the planes of the aromatic ring and that of
the amide.[5,6] We have shown[7] recently that this is in-
creased in the sulfur series: ortho-substituted N-thionaph-
thamides 4 (R1 ϭ H; R2 ϭ Me) exhibit almost complete
orthogonality between the two planes (Scheme 1). A struc-
tural consequence is the axial chirality along the CArϪC(ϭS)
bond. If the rotation barrier is high enough, enantiomers
will be observed.
In a previous article,[7] we have reported an approach
with secondary thiobenzamides and thionaphthamides.
Their geometrical structure was studied and their benzylic
metallation was selectively achieved, but no atroposelectiv-
ity could be observed. We now report our results with ra-
cemic tertiary thioamides.
Synthesis and Structure of Thiobenzamides and
Thionaphthamides
The most usual preparation of tertiary thioamides[22Ϫ24]
involves thionation of the amides with PϭS compounds,
either P4S10 or the Lawesson’s reagent,[25] which is more sol-
uble in organic solvents. With this latter reagent, we have
attempted to prepare thioamides 12؊18. The failures that
we have met revealed that the sulfurization reactions are
sensitive to steric hindrance, and this obliged us to under-
take an optimization work (Table 1).
Scheme 1. Atropisomeric amides and thioamides
[a]
´
Laboratoire de Chimie Moleculaire et Thio-organique (UMR
´
CNRS # 6507), ENSICAEN-Universite de Caen
´
6, Boulevard du Marechal Juin, 14050 Caen, France
Fax: (internat) ϩ 33-2/31452877
E-Mail: metzner@ismra.fr
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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DOI: 10.1002/ejoc.200300233
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Benzylic Metalated Thiobenzamides and Thionaphthamides
FULL PAPER
Entries 2Ϫ5). Use of toluene was also efficient for the
thionation reaction but only with ortho-unsubstituted N,N-
diisopropylamide as starting material. To the best of our
knowledge, they represent the first examples of N,N-diiso-
propylthioamides.
Table 1. Synthesis of thioamides 12؊18
The difficulties to operate under classical conditions are
related to the steric hindrance of the N,N-diisopropyl moi-
ety and probably also to the geometrical structure of the
starting material. The carbonyl group becomes less access-
ible when its plane becomes more orthogonal to the arene
ring, by introduction of an ortho substituent. Both faces of
the carbonyl are strongly hindered.
Finally, a complementary route for N,N-dimethyl and
N,N-diethyl thioamides was tested according to a method
reported by Fiandanese and co-workers:[26] metal-catalyzed
coupling of an arylmagnesium bromide with thiocarbamoyl
chlorides. We replaced [1,2-bis(diphenyl-phosphanyl)-
ethane]nickel() dichloride by cheaper bis(triphenylphos-
phane)nickel() dichloride and achieved efficient coupling
at room temperature, providing thioamides 17 and 18 in 80
and 71% yields (Table 1, Entries 6 and 7).
Having the expected thioamides in hands, we examined
their structures. We have first shown that tertiary thioam-
ides exhibit a chirality axis. We tested separation of enantio-
mers by liquid chromatography on a large variety of chiral
columns (Chiracel OB and AD from Daicel, Chirose N°2
C1 from Chiralsep and Nucleodex β-OH from Macherey-
Nagel), but we were unsuccessful. Then, we observed that
addition of 3 equiv. of a chiral shift reagent, (ϩ)-(S)-1-(9-
anthryl)-2,2,2-trifluoroethanol,[27] to thioamides 12, 13 and
15 (and also amide 7 for comparison) effected separation
1
of the ortho methyls on the aromatic ring in H NMR (a
mixture of diastereoisomer 51:49 was observed according
the integration).
This prompted us to quantify the barrier to rotation
along the chiral axis: the CArϪC(ϭS). Extensive analyses
Amides 5 and 7 were prepared by the standard reaction have been reported for benzamides and naph-
of acid chlorides with secondary amines (respectively di- thamides.[2,20,21] For thioamides, scant information[21] re-
methylamine and diisopropylamine) in quantitative yield. veals that barriers (∆G϶) are enhanced of 30Ϫ40 kJ/mol.
The crude materials were used for the next step (thion- We have examined the 1H NMR of thioamides 13 and 15 at
ation). Amides 8, 10 and 11 were prepared in two steps variable temperature. The sample was heated in [D6]DMSO
(Scheme 2): the first one involves the reaction between the until the coalescence of the two signals of the methyl group
benzoyl chloride or 1-naphthoyl chloride and the appropri- of isopropyl group. By heating at 140 °C, none of the pos-
ate amine to afford amides 6 and 9; then, the second one is sible rotations [CArϪC(ϭS) and NϪC(ϭS)] was attained
an ortho-metallation with sec-butyllithium and subsequent and experimental values could not be obtained. We esti-
alkylation with the appropriate electrophile: ethyl iodide (6 mated by calculation (Mac Spartan) that the rotation bar-
Ǟ 8 and 9 Ǟ 11) or methyl iodide (9 Ǟ 10).
riers along the chirality axis are 115 kJ/mol for N,N-diiso-
Reaction of amide 5 (Table 1, Entry 1), bearing an ortho propyl-2-methylbenzenecarbothioamide (13) and 145 kJ/
methyl group, with 0.6 equiv. of Lawesson’s reagent in THF mol for the analogous naphthalenecarbothioamide 15. The
at room temperature overnight, afforded the thioamide 12 values for the corresponding amides 7 and 10 are 71 kJ/mol
in 98% yield. Surprisingly, replacement of the N,N-dimethyl and 90 kJ/mol respectively. Therefore the rate of racemiz-
group by the N,N-diisopropyl one led to complete inhi- ation is predicted to be extremely slow in the synthetic ex-
bition of the thionation in the previous reaction conditions. perimental conditions.
Several conditions, as well as other methods, were tested
without success. Use of Lawesson’s reagent in more drastic
Metallation
conditions finally led to the expected conversion. Sulfuriz-
Conditions for deprotonation were tested at Ϫ78 °C
ation in 1,2,4Ϫtrichlorobenzene as solvent, at 165 °C, gave using sec-butyllithium (1.5 equiv.) with subsequent addition
thioamides 13, 14, 15 and 16, in acceptable yields (Table 1, of MeI. With N,N-dimethyl-2-methylbenzenecarbothio-
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D. Ach, V. Reboul, P. Metzner
FULL PAPER
Scheme 2. Synthesis of thiobenzamides and thionaphthamides
amide (12), 2-ethylbenzenecarbothioamide 17 was not ob-
To avoid this deprotonation, the N-methyl groups have
served and, instead, abstraction of an N-methyl proton been replaced by N-isopropyl ones. Thus, using the thioam-
took place, to give N-methyl-N-ethyl thioamide 20 in 11% ide 13, selective benzylic monodeprotonation was
a
yield (Scheme 3). The yield raised to 72% using 2.2 equiv. achieved and alkylation or silylation (with Me3SiCl) af-
of base and 1 equiv. of MeI. It is worthy to note that ad- forded expected thioamides 14 and 22 (Scheme 4).
dition of 2 equiv. of MeI led to bis(alkylated) thioamide 21
Atroposelectivity
in 71% yield, showing that a dianion 19 was produced. This
intermediate is probably stabilized by coordination of the
N,N-Diisopropyl-2-methylbenzenecarbothioamide
13
carbanion lithium atom with the sulfur atom of the thioam- was deprotonated under the same conditions, and was sub-
ide. There are precedents for deprotonation of N-Me groups sequently treated with a variety of prochiral electrophiles:
of amides[28,29] and some thioamides.[30,31]
aromatic aldehydes and Michael acceptors (Scheme 5 and
Scheme 3. Double deprotonation of N,N-dimethyl-2-methylbenzenecarbothioamide
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Benzylic Metalated Thiobenzamides and Thionaphthamides
FULL PAPER
stereoselectivity ((Table 2, Entries 1Ϫ3), whereas 4-methyl-
3-penten-2-one gave a dr of 82:18 (Table 2, Entry 4). Com-
parative experiments with naphthamide 10 led to com-
pounds 38؊41 with very low selectivities in all cases.
Scheme 4. Deprotonation of N,N-diisopropylthioamide 13
Table 2). Thioamides 23؊27, bearing a hydroxy group on
the newly created stereogenic center, were isolated in mod-
1
Scheme 6. Deprotonation and carbonyl compounds addition in the
naphthalene series
erate yields (Table 2, Entries 1Ϫ5). H NMR revealed the
presence of two diastereomers with a low selectivity (dr
54:46 to 67:33). In order to compare with the oxygen ana-
logues,[6,15] we have submitted amide 7 to the same sequence
(Table 2). Products 33؊37 were isolated in better yields and Table 3. Deprotonation of N,N-diisopropylthioamide 15 and amide
10 with s-BuLi (1.5 equiv., Ϫ78 °C, 2 h) and reaction of the anions
with electrophiles (1.5 equiv., Ϫ78 °C, 1 h)
with higher diastereoselectivities (up to 88:12).
Scheme 5. Benzylic deprotonation and alkylation of benzamide 7
and thiobenzamide 13
Table 2. Deprotonation of N,N-diisopropylthioamide 13 and amide
7 with s-BuLi (1.5 equiv., Ϫ78 °C, 2 h) and reaction of the anions
with electrophiles (1.5 equiv., Ϫ78 °C, 1 h)
[a]
Ref.[15]
We could separate a few pure diastereomers by chroma-
tography (28, 31) or by crystallization (minor 29 from ethyl
acetate). An interesting observation was made with thioam-
ides 28 and 29. The isolated major diastereoisomers were
1
placed in CDCl3 solutions and monitored by H NMR at
room temperature. A slow isomerization was observed for
28: a dr of 84:16 was monitored after 36 d and 59:41 after
62 d. The epimerization of 29 was even slower.
Another type of electrophile was used by Clayden and
co-workers,[15] leading to an excellent stereocontrol: imines.
N-Benzylidene-N-methylamine was reacted with the anion
of thioamide 15. It gave a good yield of amine 32 but a
largely decreased dr 65:35 (Table 3, Entry 5).
A second series was investigated with thionaphthamide
As this was the first time that some degree of atroposelec-
15 (Scheme 6 and Table 3). Aldehydes led to a very low tivity was observed for thioamides, we have attempted to
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D. Ach, V. Reboul, P. Metzner
FULL PAPER
at room temperature for 19 h. Purification by silica gel chromatog-
raphy (Rf ϭ 0.3) with petroleum ether/ethyl acetate (8:2) afforded
10.774 g (98%) of compound 12. After crystallization from ethyl
determine the relative configuration of the major dia-
stereomers (determined by the Clayden group[15] for amino
naphthamides 42, but not for hydroxy naphthamide 38).
Unfortunately, single crystals of pure diastereomers and
suitable for X-ray diffraction analysis have not been avail-
able.
1
acetate, green crystals were obtained. M.p. 60 °C. H NMR: δ ϭ
2.24 (s, 3 H, ArMe), 3.04 (s, 3 H, NMe2), 3.61 (s, 3 H, NMe2),
7.11Ϫ7.22 (m, 4 H, Ar-H) ppm. 13C NMR: δ ϭ 18.9 (ArMe), 42.3
(NMe2), 42.8 (NMe2), 125.2 (ArϪH), 126.2 (ArϪH), 128.1
(ArϪH), 130.4 (ArϪH), 131.5 (Ar-Me), 143.3 (ArϪCϭS), 201.1
(CϭS) ppm. MS (EI): m/z (%) ϭ 179 (100) [Mϩ·], 164 (33), 1135
(57), 91 (21).
Conclusion
N,N-Diisopropyl-2-methylbenzenecarbothioamide (13):
A stirred
This study and the previous one have demonstrated, for
the first time, that tertiary thioamides are prone to atropo-
selectivity.
Thiobenzamides and thionaphthamides were prepared by
thionating the amides with Lawesson’s reagent and con-
ditions were adapted for the hindered examples, bearing
N,N-diisopropyl groups. The enantiomeric forms could be
solution of Lawesson’s reagent (11.065 g, 27.4 mmol, 0.6 equiv.) in
1,2,4-trichlorobenzene (60 mL) was added cautiously to N,N-diiso-
propyl-2-methylbenzamide (7, 10.000 g, 45.6 mmol, 1 equiv.). The
reaction mixture was stirred at 165 °C for 16 h. Purification by
silica gel chromatography (Rf ϭ 0.3) with petroleum ether/ethyl
acetate (9:1) afforded 9.653 g (90%) of amide 13. After crystalliza-
1
tion from hexane, a yellow powder was obtained. M.p. 140 °C. H
monitored by complexation with a chiral shift agent. The NMR: δ ϭ 1.12 [d, J ϭ 6.7 Hz, 3 H, N(CHMe2)2], 1.21 [d, J ϭ
6.7 Hz, 3 H, N(CHMe2)2], 1.82 [br. s, 6 H, N(CHMe2)2], 2.30 (s, 3
H, ArMe), 3.96Ϫ4.02 [m, 2 H, N(CHMe2)2], 6.94Ϫ6.99 (m, 1 H,
Ar-H), 7.14Ϫ7.18 (m, 3 H, Ar-H) ppm. 13C NMR: δ ϭ 19.3
(CHMe), 19.6 (CHMe), 20.0 (CHMe), 20.7 (CHMe), 51.2
(CHMe), 56.9 (CHMe), 124.3 (ArϪH), 126.4 (ArϪH), 127.6
(ArϪH), 131.0 (ArϪH), 131.5 (Ar-Me), 145.3 (ArϪCϭS), 199.7
(CϭS). IR (KBr): ν˜ ϭ 2968, 1494, 1376, 1342, 1244, 1144 (νCϭS),
1116, 754 cmϪ1. MS (EI): m/z (%) ϭ 235 (21) [Mϩ·], 192 (10), 135
(100), 118 (25), 91 (10), 75 (32), 43 (17). C14H21NS (235.38): calcd.
C 71.43, H 8.99, N 5.95; found C 71.31, H 9.06, N 5.92.
rotation barriers along the chirality axis were estimated to
be very high.
Selective abstraction of the benzylic proton required the
use of N,N-diisopropylthioamides and was achieved in both
thiobenzamide and thionaphthamide series.
A number of prochiral electrophiles were reacted with the
intermediate anions: aromatic aldehydes, α-unsaturated al-
dehydes and a ketone, and an imine. CϪC Bond formations
were achieved.
The atroposelectivity varied to a large extent: from 55:45
up to 82:18. Despite some exceptions, the selectivity was
poorer as compared to the amide series.
Though the selectivities are not high, this is the first re-
port on atroposelective reactions with thioamides in a
benzylic position.
General Procedure for the Preparation of Thioamides 14, 15 and 16:
Preparation of the Amides 8, 10 and 11: A solution of benzoyl chlo-
ride or 1-naphthoyl chloride (1 equiv.) in diethyl ether was cooled
to 0 °C. A solution of the appropriate amine (2.5 equiv.) in diethyl
ether was added dropwise. The reaction mixture was stirred at room
temperature for 16 h. After completion of the reaction, the mixture
was quenched with water. The organic phase was washed twice with
a aqueous solution of HCl (1 ) and then with brine. The organic
phase was dried with magnesium sulfate and after filtration the
solvent was removed under reduced pressure. The amide was ob-
tained sufficiently pure for immediate further use (quantitative
yield).
Experimental Section
1
General Remarks: NMR spectra were measured in CDCl3. The H
NMR spectra were recorded at 250 MHz (Bruker DPX 250) and
the 13C NMR spectra at 62.9 MHz (Bruker DPX 250). The chemi-
cal shifts are expressed in ppm relative to tetramethylsilane as an
internal standard. The coupling constants J are in Hz. The FTIR
spectra were recorded with a Perkin؊Elmer 16 PC FTIR spec-
trometer. Mass spectra were determined with a Nermag Riber R 10
RH spectrometer (ISMRA, Caen) or a JEOL AX 500 spectrometer
(IRCOF, Rouen). Elemental analyses were carried out by ICSN
(CNRS, Gif-sur-Yvette) and by ISMRA (Caen). Melting points
were measured with a digital IA 9000 Electrothermal instrument.
All reactions were carried out under nitrogen. Tetrahydrofuran
(THF) was distilled from sodium/benzophenone, and petroleum
ether from P2O5. Commercial solutions of sec-butyllithium were
titrated before use, according to ref.[32] Isomer ratios were deter-
mined by 1H NMR of the crude product. The preparation of
thioamides 14, 16, 17, 18, and amides 33؊41 is reported in the
Supporting Information (see footnote on the first page of this arti-
cle).
A solution of the previous amide (1 equiv.) in THF was cooled to
Ϫ78 °C. A solution of sec-butyllithium in cyclohexane (1.1 equiv.)
was then added dropwise. The reaction mixture was stirred at Ϫ78
°C for 1 h. The appropriate electrophile (ethyl or methyl iodide)
(1.1 equiv.) was added dropwise, and the resulting mixture was
stirred at Ϫ78 °C for 30 min. After completion of the reaction,
the mixture was quenched with a saturated aqueous solution of
ammonium chloride. The mixture was extracted twice with di-
chloromethane. The combined organic phases were then washed
with brine and dried with magnesium sulfate. After filtration, the
solvent was removed under reduced pressure and a solid was ob-
tained. The amide was obtained sufficiently pure for immediate
further use.
Thionation of the Amides 8, 10 and 11: To a stirred solution of
Lawesson’s reagent (0.6 equiv.) in 1,2,4-trichlorobenzene was added
caustiously the amide (1 equiv.). The reaction mixture was stirred
at 165 °C for 24Ϫ144 h. After completion of the reaction, the sol-
vent was removed under reduced pressure and the residue was puri-
N,N,2-Trimethylbenzenecarbothioamide (12): A stirred solution of
Lawesson’s reagent (14.868 g, 36.8 mmol, 0.6 equiv.) in THF
(340 mL). was added cautiously to N-dimethyl-2-methylbenzamide fied by silica gel chromatography with petroleum ether/ethyl acetate
(5, 10.009 g, 61.3 mmol, 1 equiv.). The reaction mixture was stirred as eluent.
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Benzylic Metalated Thiobenzamides and Thionaphthamides
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N,N-Diisopropyl-2-methyl-1-naphthalenecarbothioamide (15): The
general procedure of thionation was applied to N,N-diisopropyl-2-
methyl-1-naphthalenecarboxamide (10, 2.301 g, 8.5 mmol), Lawes-
ArCH2Me), 2.56Ϫ2.63 (m, 2 H, ArCH2Me), 3.55 (s, 3 H, NMe),
3.26Ϫ3.35 (m, 1 H, NCH2Me), 3.42Ϫ3.51 (m, 1 H, NCH2Me),
7.02Ϫ7.26 (m, 4 H, Ar-H) ppm. 1H NMR [(E) isomer]: δ ؍ 1.37 (t,
son’s reagent (2.075 g, 5.1 mmol) and 1,2,4-trichlorobenzene J ϭ 7.1 Hz, 3 H, NCH2Me), 1.24 (t, J ϭ 7.5 Hz, 3 H, ArCH2Me),
(20 mL). Reaction time at 165 °C: 100 h. Purification by silica gel
chromatography with petroleum ether/ethyl acetate (9:1) afforded
0.976 g (40%) of compound 15. After crystallization from chloro-
form/hexane, a yellow solid was obtained. M.p. 151 °C. Rf ϭ 0.6
(petroleum ether/ethyl acetate, 8:2). 1H NMR: δ ϭ 1.04 [d, 3 H,
2.56Ϫ2.63 (m, 2 H, ArCH2Me), 2.96 (s, 3 H, NMe), 4.01Ϫ4.10 (m,
1 H, NCH2Me), 4.31Ϫ4.40 (m, 1 H, NCH2Me), 7.02Ϫ7.26 (m, 4
H, Ar-H) ppm. 13C NMR [(Z) ؉ (E) isomers]: δ ؍ 10.9, 13.7
(NCH2Me), 14.7, 14.8 (ArCH2Me), 25.6, 25.9 (ArCH2Me), 39.9,
40.8 (NMe), 49.0, 50.7 (NCH2Me), 125.2, 125.4, 126.3, 126.5,
J ϭ 6.6 Hz, N(CHMe2)2], 1.16 [d, 3 H, J ϭ 6.6 Hz, N(CHMe2)2], 128.5, 128.8, 128.9, 137.7, 138.0, 142.8, 143.2, 200.4, 200.7 (CϭS)
1.97Ϫ2.07 [2 br. s, 6 H, N(CHMe2)2], 2.47 (s, 3 H, ArMe),
ppm. MS (EI): m/z (%) ϭ 207 (82) [Mϩ·], 193 (20), 174 (100), 149
3.88Ϫ4.15 [m, 2 H, N(CHMe2)2], 7.28Ϫ7.81 (m, 6 H, Ar-H) ppm. (44), 134 (68), 115 (66), 105 (15), 91 (28), 58 (66). HMRS calcd.
13C NMR: δ ϭ 19.8 (ArMe), 20.0, 20.5, 20.9 [N(CHMe2)2], 51.4, for C12H17NS: 207.1082; found 207.1089.
57.7 [N(CHMe2)2], 125.2, 125.7, 126.9, 127.4, 128.3, 128.4, 129.0,
N,N-Diisopropyl-2-ethylbenzenecarbothioamide (14): The general
129.4, 132.6, 140.3, 198.4 (CϭS) ppm. IR (KBr): ν˜ ϭ 2966, 1455,
procedure was applied to N,N-diisopropyl-2-methylbenzenecarbot-
1376, 1138 (νCϭS) cmϪ1. MS (EI): m/z (%) ϭ 285 (8) [Mϩ·], 242(7),
hioamide (13, 103 mg, 0.44 mmol), sBuLi (404 µL of a 1.3  solu-
tion in cyclohexane, 0.53 mmol), methyl iodide (33 µL, 0.53 mmol)
and THF (5 mL). Reaction time after addition of base: 1 h. Purifi-
cation by silica gel chromatography (Rf ϭ 0.3 as starting material)
200 (11), 185 (100), 168 (54), 115 (27). C18H23NS (285.45): calcd.
C 75.74, H 8.12, N 4.91, S 11.23; found C 75.40, H 8.09, N 5.41,
S 10.98.
General Procedure for Single Deprotonation of Thioamides 12 and
13, and then Treatment with Electrophiles (Compounds 20؊22): A
solution of thioamides 12 or 13 (1 equiv.) in THF was cooled to
with petroleum ether/ethyl acetate (9:1) afforded 79 mg (yield: 72%)
of compound 14 as a yellow powder. The spectroscopic data were
identical to those previously reported.
Ϫ78 °C.
A
solution of sec-butyllithium in cyclohexane
N,N-Diisopropyl-2-(1-trimethylsilylmethyl)-1-benzenecarbo-
thioamide (22): The general procedure was applied to N,N-diisopro-
pyl-2-methylbenzenecarbothioamide (13, 285 mg, 1.21 mmol),
sBuLi (1.4 mL of a 1.3  solution in cyclohexane, 1.81 mmol), tri-
methylsilyl chloride (310 µL, 2.42 mmol) and THF (7 mL). Reac-
tion time after addition of base: 1 h. Purification by silica gel chro-
matography (Rf ϭ 0.7) with petroleum ether/ethyl acetate (8:2) af-
forded 281 mg (yield: 76%) of compound 22 as a green oil. (Z)/(E)
ratio ϭ 100:0. 1H NMR: δ ϭ 0.09 (s, 9 H, SiMe3), 1.00 [d, J ϭ
6.7 Hz, 3 H, N(CHMe2)2], 1.12 [d, J ϭ 6.7 Hz, 3 H, N(CHMe2)2],
1.72 [br. s, 6 H, N(CHMe2)2], 1.88Ϫ1.95 (AB, J ϭ 13.7 Hz, 2 H,
CH2), 3.81Ϫ3.99 [m, 2 H, N(CHMe2)2], 6.88Ϫ7.01 (m, 4 H, Ar-H)
ppm. 13C NMR: δ ϭ 0.3, 0.4, 1.6 (SiMe3), 19.3, 20.1, 20.6
[N(CHMe2)2], 23.1 (CH2), 51.0, 56.6 [N(CHMe2)2], 124.8, 125.2,
127.2, 129.3, 134.8, 144.4, 200.1 (CϭS) ppm. IR (KBr): ν˜ ϭ 3028,
1522, 1343, 1252 (νSiϪMe), 1154 (υCϭS), 846 (νSiϪMe) cmϪ1. MS
(EI): m/z (%) ϭ 307 (6) [Mϩ·], 292 (5), 264 (6), 207 (7), 222 (4),
207 (7), 174 (4), 135 (10), 117 (15), 73 (24), 45 (73), 43 (100).
(1.5Ϫ2.4 equiv.) was then added dropwise. The reaction mixture
was stirred at Ϫ78 °C for 30Ϫ60 min. The appropriate electrophile
(methyl iodide or trimethylsilyl chloride) was added dropwise and
the resulting mixture was stirred at Ϫ78 °C for 30 min. After ad-
dition of a saturated aqueous ammonium chloride solution, the
mixture was extracted twice with dichloromethane. The combined
organic phases were washed with brine and dried with magnesium
sulfate. After filtration, the solvent was removed under reduced
pressure, and the residue was purified by silica gel chromatography
with petroleum ether/ethyl acetate as eluent.
N-Ethyl-N-methyl-2-methylbenzenecarbothioamide (20): The gen-
eral procedure was applied to N,N-dimethyl-2-methylbenzenecar-
bothioamide 12 (98 mg, 0.55 mmol), sBuLi (1 mL of a 1.2  solu-
tion in cyclohexane, 1.20 mmol), methyl iodide (27 µL, 0.44 mmol)
and THF (5 mL). Reaction time after addition of base: 30 min.
Purification by silica gel chromatography with petroleum ether/
ethyl acetate (8:2) afforded 76 mg (yield: 72%) of compound 20 as
a green oil. Rf ϭ 0.6 (petroleum ether/ethyl acetate, 8:2). (Z)/(E)
ratio ϭ 52:48. 1H NMR [(Z) isomer]: δ ؍ 1.11 (t, J ϭ 7.1 Hz, 3
H, NCH2Me), 2.26 (s, 3 H, ArMe), 3.55 (s, 3 H, NMe), 3.31Ϫ3.49
(m, 2 H, NCH2Me), 7.02Ϫ7.21 (m, 4 H, Ar-H) ppm. 1H NMR
[(E) isomer]: δ ؍ 1.37 (t, J ϭ 7.1 Hz, 3 H, NCH2Me), 2.23 (s, 3 H,
ArMe), 2.97 (s, 3 H, NMe), 3.97Ϫ4.05 (m, 1 H, NCH2Me),
4.33Ϫ4.41 (m, 1 H, NCH2Me), 7.07Ϫ7.21 (m, 4 H, Ar-H) ppm.
13C NMR [(Z) ؉ (E) isomers]: δ ؍ 9.5, 12.1 (NCH2Me), 17.6,
17.9 (ArMe), 38.3, 38.8 (NMe), 47.5, 48.9 (NCH2Me), 123.7, 123.9,
124.9, 125.2, 126.8, 129.3, 130.1, 130.5, 141.9, 199.2, 199.3 (CϭS)
ppm. MS (EI): m/z (%) ϭ 193 (89) [Mϩ·], 178 (36), 135 (100), 91
(37), 58 (40). HMRS calcd. for C11H15NS: 193.0925; found
193.0938.
General Procedure for Single Deprotonation of Thioamides 13, 15
and Amides 7, 10 then treatment with Electrophiles (Compounds
23؊41): A solution of compounds 7, 10, 13 or 15 (1 equiv.) in THF
was cooled to Ϫ78 °C. A solution of sec-butyllithium in cyclohex-
ane (1.2Ϫ2 equiv.) was then added dropwise. The reaction mixture
was stirred at Ϫ78 °C for 2 h. The appropriate electrophile was
added dropwise, and the resulting mixture was stirred at Ϫ78 °C
for 1 h. After addition of a saturated aqueous ammonium chloride
solution, the mixture was extracted twice with dichloromethane.
The combined organic phases were washed with brine and dried
with magnesium sulfate. After filtration, the solvent was removed
under reduced pressure, and the residue was purified by silica gel
chromatography with petroleum ether/ethyl acetate as eluent.
N,2-Diethyl-N-methylbenzenecarbothioamide (21): The general pro-
cedure was applied to N,N-dimethyl-2-methylbenzenecarbothioam-
N,N-Diisopropyl-2-(2-hydroxyphenylethyl)benzenecarbothioamide
ide 12 (100 mg, 0.56 mmol), sBuLi (1.12 mL of a 1.2  solution in (23): The general procedure was applied to N,N-diisopropyl-2-
cyclohexane, 1.34 mmol), methyl iodide (70 µL, 1.12 mmol) and
THF (4 mL). Reaction time after addition of base: 30 min. Purifi-
methylbenzenecarbothioamide 13 (212 mg, 0.90 mmol), sBuLi (960
µL of a 1.4  solution in cyclohexane, 1.35 mmol), benzaldehyde
cation by silica gel chromatography (Rf ϭ 0.5) with petroleum (138 µL, 1.35 mmol) and THF (10 mL). The crude product con-
ether/ethyl acetate (8:2) afforded 83 mg (yield: 71%) of compound
tained two diastereoisomers (dr ϭ 55:45). Purification by silica gel
chromatography with petroleum ether/ethyl acetate (8:2 then 6:4)
21 as a green oil. (Z)/(E) ratio ϭ 52:48. 1H NMR [(Z) isomer]: δ ؍
1.11 (t, J ϭ 7.1 Hz, 3 H, NCH2Me), 1.24 (t, J ϭ 7.5 Hz, 3 H, afforded 147 mg (yield: 48%) of compound 23. After crystallisation
Eur. J. Org. Chem. 2003, 3398Ϫ3406
www.eurjoc.org  2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3403

D. Ach, V. Reboul, P. Metzner
from chloroform/hexane, a yellow solid was obtained. Minor and (m, 6 H, NCHMe2), 1.79 (br. s, 6 H, NCHMe2), 3.63Ϫ3.78 (m, 2
FULL PAPER
major diastereoisomers were not separated by chromatography or
H, CH2), 4.01Ϫ4.11 [m, 2 H, N(CHMe2)2], 6.61Ϫ6.65 (m, 1 H,
crystallisation. M.p. 113 °C. Rf ϭ 0.3 (petroleum ether/ethyl acet-
CHOH), 7.12Ϫ8.43 (m, 13 H, Ar-H) ppm. 13C NMR [major ؉
1
ate, 8:2). H NMR [major diastereoisomer]: δ ؍ 1.07Ϫ1.14 (m, 6 minor diastereoisomers]:
δ
ϭ
19.6, 20.0, 20.5, 20.8, 20.9
[N(CHMe2)2], 40.7, 40.8 (CH2), 50.9, 57.2 [N(CHMe2)2], 69.4
CH2), 3.92Ϫ4.09 [m, 2 H, N(CHMe2)2], 5.38 (dd, J ϭ 2.6, J ϭ [CHOH, (major)], 73.0 [CHOH, (minor)], 124.7, 124.8, 125.3,
H, NCHMe2), 1.85 (br. s, 6 H, NCHMe2), 2.71Ϫ3.01 (m, 2 H,
1
9.5 Hz, 1 H, CHOH), 6.98Ϫ7.47 (m, 9 H, Ar-H) ppm. H NMR
125.6, 127.1, 127.2, 127.8, 127.9, 128.2, 129.0, 129.1, 129.2, 129.3,
[minor diastereoisomer]: δ ؍ 1.07Ϫ1.14 (m, 6 H, NCHMe2), 1.85 129.4, 134.6, 135.0, 140.7, 145.4, 198.2 [(CϭS), (minor)], 199.6
(br. s, 6 H, NCHMe2), 2.71Ϫ3.01 (m, 2 H, CH2), 3.92Ϫ4.09 [m, 2 [(CϭS), (major)] ppm. IR (KBr): ν˜ ؍ 3305 (νOH), 2968, 2928, 1489,
H, N(CHMe2)2], 4.96 (dd, J ϭ 5.4, J ϭ 9.0 Hz, 1 H, CHOH), 1347, 1264, 1152 (νCϭS) cmϪ1. MS (EI): m/z (%) ϭ 441 (19) [Mϩ·],
6.98Ϫ7.47 (m, 9 H, Ar-H) ppm. 13C NMR [mixture of diastereoiso-
423 (42), 407 (36), 306 (100), 235 (60), 192 (95), 135 (55). HMRS
mers]: δ ؍ 20.62, 20.8, 21.1, 21.8, 22.8 [N(CHMe2)2], 44.6, 44.8 calcd. for C29H31NOS: 441.2126; found 441.2130.
(CH2), 52.8, 58.6 [N(CHMe2)2], 74.4 [CHOH, (major)], 77.2
N,N-Diisopropyl-2-(2-hydroxy-4-methylpent-3-enyl)benzenecarbo-
[CHOH, (minor)], 125.6, 125.9, 127.1, 127.3, 128.3, 128.5, 128.7,
128.8, 129.5, 129.9, 130.0, 130.1, 131.6, 132.7, 133.1, 133.9, 146.6,
147.1, 200.5 (CϭS) ppm. IR (KBr): ν˜ ؍ 3368 (νOH), 2968, 2930,
2364, 1494, 1446, 1376, 1342, 1246, 1144 (νCϭS) cmϪ1. MS (CI):
m/z (%) ϭ 342 (100) [M ϩ H] ϩ, 324 (18), 308 (20). HMRS calcd.
for C21H28NOS: 342.1892; found 342.1900.
thioamide (26): The general procedure was applied to N,N-diisopro-
pyl-2-methylbenzenecarbothioamide (13, 180 mg, 0.76 mmol),
sBuLi (820 µL of a 1.4  solution in cyclohexane, 1.14 mmol), dis-
tilled 3-methyl-2-propenal (220 µL, 2.28 mmol) and THF (10 mL).
The crude product contained two diastereoisomers (dr ϭ 54:46).
Purification by silica gel chromatography (Rf ϭ 0.2) with petroleum
ether/ethyl acetate (8:2) afforded 100 mg (yield: 41%) of compound
26 as a yellow oil. Minor and major diastereoisomers were not
N,N-Diisopropyl-2-(2-hydroxynaphthylethyl)benzenecarbothioamide
(24): The general procedure was applied to N,N-diisopropyl-2-
methylbenzenecarbothioamide (13, 253 mg, 1.1 mmol), sBuLi separated by chromatography. 1H NMR [major diastereoisomer]:
(1.0 mL of a 1.3  solution in cyclohexane, 1.30 mmol), 1-naph-
thaldehyde (440 µL, 3.2 mmol) and THF (10 mL). The crude prod-
uct contained two diastereoisomers (dr ϭ 58:42). Purification by
δ ؍ 1.07 (d, J ϭ 6.7 Hz, 3 H, NCHMe2), 1.11 (d, J ϭ 6.7 Hz, 3
H, NCHMe2), 1.72 (br. s, 6 H, CHϭCMe2), 1.74Ϫ1.80 (br. s, 6 H,
NCHMe2), 2.54Ϫ2.84 (m, 2 H, CH2), 3.96Ϫ4.02 [m, 2 H,
silica gel chromatography (Rf ϭ 0.4) with petroleum ether/ethyl N(CHMe2)2], 4.69 (td, J ϭ 8.7, 5.0 Hz, 1 H, CHOH), 5.24Ϫ5.26
1
acetate (8:2) afforded 206 mg (yield: 49%) of compound 24 as a
white solid. Minor and major diastereoisomers were not separated
by chromatography. M.p. 72 °C. 1H NMR [major diastereoisomer]:
(m, 1 H, CHϭCMe2), 6.95Ϫ7.34 (m, 4 H, Ar-H) ppm. H NMR
[minor diastereoisomer]: δ ؍ 1.18 (d, J ϭ 6.7 Hz, 3 H, NCHMe2),
1.19 (d, J ϭ 6.7 Hz, 3 H, NCHMe2), 1.65 (m, 6 H, CHϭCMe2),
δ ؍ 0.99Ϫ1.09 (m, 6 H, NCHMe2), 1.79 (br. s, 6 H, NCHMe2), 1.74Ϫ1.80 (br. s, 6 H, NCHMe2), 2.54Ϫ2.84 (m, 2 H, CH2),
2.74 (br. s, 1 H, OH), 2.90Ϫ3.22 (m, 2 H, CH2), 3.92Ϫ3.98 [m, 2 3.96Ϫ4.02 [m, 2 H, N(CHMe2)2], 4.95 (td, J ϭ 8.8, 4.5 Hz, 1 H,
H, N(CHMe2)2], 6.02Ϫ6.11 (m, 1 H, CHOH), 7.01Ϫ7.87 (m, 11 CHOH), 5.28Ϫ5.29 (m, 1 H, CHϭCMe2), 6.95Ϫ7.34 (m, 4 H, Ar-
1
H, Ar-H) ppm. H NMR [minor diastereoisomer]: δ ؍ 0.99Ϫ1.09
(m, J ϭ 6.7 Hz, 6 H, NCHMe2), 1.79 (br. s, 6 H, NCHMe2),
H) ppm. 13C NMR [major ؉ minor diastereoisomers]: δ ؍ 18.6,
18.9, 20.7, 26.1 (CHϭCMe2), 19.7, 20.0, 20.7 [N(CHMe2)2], 41.0,
2.90Ϫ3.22 (m, 2 H, CH2), 3.92Ϫ3.98 [m, 2 H, N(CHMe2)2], 4.35 41.2 (CH2), 51.4, 57.1 [N(CHMe2)2], 68.0 [(CHOH, (major)], 70.3
(d, J ϭ 4.5 Hz, 1 H, OH), 5.71Ϫ5.83 (m, 1 H, CHOH), 7.01Ϫ7.87 [(CHOH, (minor)], 124.5, 124.9, 126.9, 127.1, 127.5, 127.9, 128.0,
(m, 11 H, Ar-H) ppm. 13C NMR [major ؉ minor diastereoiso-
128.7, 130.6, 131.3, 132.0, 132.6, 134.7, 135.0, 145.4, 145.6 ppm.
mers]: δ ؍ 19.6, 20.0, 20.1, 20.6 [N(CHMe2)2], 42.3 (CH2), 51.5, IR (NaCl, film): ν˜ ؍ 3381 (νOH), 1530, 1447, 1395, 1212, 1181 (νCϭ
57.7 [N(CHMe2)2], 69.9 [CHOH, (major)], 73.7 [CHOH, (minor)],
S), 813 cmϪ1. MS (CI): m/z (%) ϭ 320 (81) [M ϩ H]ϩ, 302 (100),
123.5, 123.7, 123.8, 124.3, 124.6, 125.8, 125.9, 126.0, 126.2, 126.3, 286 (44). HMRS calcd. for C19H3ONOS: 320.2048 found 320.2050.
126.5, 127.3, 127.4, 127.5, 128.0, 128.4, 129.1, 129.4, 130.2, 130.7,
2-(2-Hydroxy-2,4-dimethylpent-3-enyl)-N,N-diisopropylbenzene-
carbothioamide (27): The general procedure was applied to N,N-
130.8, 131.9, 132.4, 133.0, 134.1, 134.2, 141.0, 141.5, 145.3, 145.6,
199.3 [(CϭS), (minor)], 202.1 [(CϭS), (major)] ppm. IR (KBr): ν˜ ؍
3372 (νOH), 2968, 2928, 1494, 1340, 1246, 1144 (νCϭS) cmϪ1. MS
(EI): m/z (%) ϭ 391 (33) [Mϩ·], 358 (59), 235 (94), 220 (45), 192
(81), 135 (93), 43 (100). C25H29NOS (391.57): calcd. C 76.68, H
7.46, S 8.19; found C 76.71, H 7.55, S 7.63.
diisopropyl-2-methylbenzenecarbothioamide
(13,
124 mg,
0.53 mmol), sBuLi (568 µL of a 1.4  solution in cyclohexane,
0.80 mmol), distilled 4-methyl-3-propen-2-one (121 µL, 1.05 mmol)
and THF (10 mL). The crude product contained two diastereoiso-
mers (dr ϭ 67:33). Purification by silica gel chromatography (Rf ϭ
0.4) with petroleum ether/ethyl acetate (8:2) afforded 67 mg (yield:
38%) of compound 27 as a yellow oil. Minor and major dia-
N,N-Diisopropyl-2-(2-hydroxyanthrylethyl)benzenecarbothioamide
(25): The general procedure was applied to N,N-diisopropyl-2-
methylbenzenecarbothioamide (13, 263 mg, 1.11 mmol), sBuLi stereoisomers were not separated by chromatography. 1H NMR
(1.2 mL of a 1.4  solution in cyclohexane, 1.67 mmol), 9-anthral-
dehyde (346 mg, 1.67 mmol) and THF (15 mL). The crude product
contained two diastereoisomers (dr ϭ 57:43). Purification by silica
gel chromatography with petroleum ether/ethyl acetate (8:2) af-
forded 191 mg (yield: 39%) of compound 25. After crystallisation
[major diastereoisomer]: δ ؍ 1.08 (d, J ϭ 6.6 Hz, 6 H, NCHMe2),
1.09 (d, J ϭ 6.6 Hz, 6 H, NCHMe2), 1.41 [s, 3 H, C(OH)Me], 1.71
(m, 6 H, CHϭCMe2), 1.76Ϫ1.87 (br. s, 6 H, NCHMe2), 2.83 and
2.90 (AB, J ϭ 13.8 Hz, 2 H, CH2), 3.46 (s, 1 H, OH), 3.89Ϫ4.00
[m, 2 H, N(CHMe2)2], 5.29 (br. s, 1 H, CHϭCMe2), 6.97Ϫ7.89 (m,
1
from ethyl acetate, a yellow solid was obtained. Minor and major 4 H, Ar-H) ppm. H NMR [minor diastereoisomer]: δ ؍ 1.17 (d,
diastereoisomers were not separated by chromatography or crystal-
lisation. Rf ϭ 0.3 (petroleum ether/ethyl acetate, 8:2). 1H NMR 1.38 [s, 3 H, C(OH)Me], 1.74 (m, 3 H, CHϭCMe2), 1.76Ϫ1.87 (br.
[major diastereoisomer]: δ ؍ 1.04Ϫ1.14 (m, 6 H, NCHMe2), 2.02 s, 6 H, NCHMe2), 1.88 (m, 3 H, CHϭCMe2), 2.79 and 2.99 (AB,
J ϭ 6.6 Hz, 6 H, NCHMe2), 1.19 (d, J ϭ 6.6 Hz, 6 H, NCHMe2),
(br. s, 6 H, NCHMe2), 3.05Ϫ3.21 (m, 2 H, CH2), 4.01Ϫ4.11 [m, 2 J ϭ 14.1 Hz, 2 H, CH2), 3.37 (s, 1 H, OH), 3.89Ϫ4.00 [m, 2 H,
H, N(CHMe2)2], 6.81Ϫ6.92 (m, 1 H, CHOH), 7.12Ϫ8.43 (m, 13 N(CHMe2)2], 5.42 (br. s, 1 H, CHϭCMe2), 6.97Ϫ7.89 (m, 4 H, Ar-
1
H, Ar-H) ppm. H NMR [minor diastereoisomer]: δ ؍ 1.04Ϫ1.14
H) ppm. 13C NMR [major ؉ minor diastereoisomers]: δ ؍ 19.2,
3404
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3398Ϫ3406

Benzylic Metalated Thiobenzamides and Thionaphthamides
FULL PAPER
19.3, 19.4, 20.0, 20.6 [N(CHMe2)2], 19.0, 27.9, 28.0 (CHϭCMe2), (%) ϭ 441 (4) [Mϩ·], 308 (11), 285 (60), 242 (42), 185 (36), 166
29.6, 32.3 [C(OH)Me], 45.4, 45.8 (CH2), 51.4, 56.2 [N(CHMe2)2], (51). HMRS calcd. for C29H31NOS: 441.2126; found 441.2154.
73.3 [C(OH)Me, (minor)], 74.3 [C(OH)Me, (major)], 124.6, 125.1,
2-(2-Hydroxy-4-methylpent-3-enyl)-N,N-diisopropyl-1-naphthalene-
carbothioamide (30): The general procedure was applied to N,N-
diisopropyl-2-methyl-1-naphthalenecarbothioamide (15, 160 mg,
0.56 mmol), sBuLi (650 µL of a 1.3  solution in cyclohexane,
0.84 mmol), distilled 3-methyl-2-propenal (86 µL, 0.84 mmol) and
THF (10 mL). The crude product contained two diastereoisomers
(dr ϭ 55:45). Purification by silica gel chromatography (Rf ϭ 0.3)
with petroleum ether/ethyl acetate (8:2) afforded 147 mg (yield:
126.9, 127.0, 127.4, 127.5, 131.2, 131.6, 131.9, 132.0, 132.6, 133.2,
133.5, 145.7 ppm. IR (NaCl, film): ν˜ ؍ 3348 (νOH), 3041, 2966,
2854, 1487, 1464, 1321, 1221, 1135 (νCϭS) cmϪ1. MS (CI): m/z
(%) ϭ 334 (41) [M ϩ H]ϩ, 3316 (100), 300 (27), 236 (16), 99 (12).
HMRS calcd. for C20H32NOS: 334.2205 found 334.2201.
2-(2-Hydroxyphenylethyl)-N,N-diisopropyl-1-naphthalenecarbo-
thioamide (28): The general procedure was applied to N,N-diisopro-
pyl-2-methyl-1-naphthalenecarbothioamide
(15,
69 mg, 70%) of compound 30 as a yellow oil. Minor and major dia-
0.24 mmol), sBuLi (230 µL of a 1.2  solution in cyclohexane, stereoisomers were not separated by chromatography. 1H NMR
0.28 mmol), benzaldehyde (25 µL, 0.24 mmol) and THF (5 mL).
The crude product contained two diastereoisomers (dr ϭ 60:40).
Purification by silica gel chromatography with petroleum ether/
[major diastereoisomer]: δ ؍ 1.12 (d, J ϭ 6.7 Hz, 3 H, NCHMe2),
1.15 (d, J ϭ 6.7 Hz, 3 H, NCHMe2), 1.76 (s, 3 H, CHϭCMe2) 1.77
(s, 3 H, CHϭCMe2), 1.90Ϫ1.96 (br. s, 6 H, NCHMe2), 2.75 (dd,
ethyl acetate (8:2) afforded 46 mg (yield: 49%) of compound 28. J ϭ 13.7, 9.0 Hz, 1 H, CH2), 2.96 (dd, J ϭ 13.7, 3.6 Hz, 1 H, CH2),
Minor (Rf ϭ 0.2, colourless oil) and major (Rf ϭ 0.3, white solid,
M.p. 123 °C.) diastereoisomers were separated by chromatography.
1H NMR [major diastereoisomer]: δ ؍ 1.02 (d, J ϭ 6.7 Hz, 3 H,
3.85Ϫ4.20 [2 br. s, 2 H, N(CHMe2)2], 5.09 (td, J ϭ 9.0, 3.6 Hz, 1
H, CHOH), 5.34Ϫ5.37 (m, 1 H, CHϭCMe2), 7.43Ϫ7.52 (m, 3 H,
Ar-H), 7.71Ϫ7.79 (m, 3 H, Ar-H) ppm. 1H NMR [minor dia-
NCHMe2), 1.09 (d, J ϭ 6.7 Hz, 3 H, NCHMe2), 1.96 (br. s, 3 H, stereoisomer]: δ ؍ 1.02 (d, J ϭ 6.7 Hz, 3 H, NCHMe2), 1.04 (d,
NCHMe2), 2.07 (br. s, 3 H, NCHMe2), 2.92 (dd, J ϭ 13.8, 9.0 Hz,
1 H, CH2), 3.20 (dd, J ϭ 13.8, 2.8 Hz, 1 H, CH2), 3.81Ϫ4.21 [m,
2 H, N(CHMe2)2], 5.52 (dd, J ϭ 9.0, 2.8 Hz, 1 H, CHOH),
6.75Ϫ7.91 (m, 11 H, Ar-H) ppm. 1H NMR [minor diastereoiso-
J ϭ 6.6 Hz, 3 H, NCHMe2), 1.70 (s, 3 H, CHϭCMe2), 1.71 (s, 3
H, CHϭCMe2), 1.97Ϫ2.05 (br. s, 6 H, NCHMe2), 2.78 (dd, J ϭ
13.7, 4.4 Hz, 1 H, CH2), 3.03 (dd, J ϭ 13.7, 9.5 Hz, 1 H, CH2),
3.85Ϫ4.20 [2 br. s, 2 H, N(CHMe2)2], 4.81 (td, J ϭ 9.5, 4.4 Hz, 1
mer]: δ ؍ 1.04 (d, J ϭ 6.5 Hz, 3 H, NCHMe2), 1.06 (d, J ϭ 6.5 Hz, H, CHOH), 5.34Ϫ5.37 (m, 1 H, CHϭCMe2), 7.43Ϫ7.52 (m, 3 H,
3 H, NCHMe2), 1.99 (br. s, 3 H, NCHMe2), 2.06 (br. s, 3 H, Ar-H), 7.71Ϫ7.79 (m, 3 H, Ar-H) ppm. 13C NMR [major ؉ minor
NCHMe2), 3.03 (dd, J ϭ 13.8, 3.9 Hz, 1 H, CH2), 3.21 (dd, J ϭ diastereoisomers]: δ ؍ 18.2, 18.6 (CHϭCMe2), 19.3, 19.9, 20.1
13.8, 10.6 Hz, 1 H, CH2), 3.81Ϫ3.88 [m, 1 H, [N(CHMe2)2], 4.29 [N(CHMe2)2], 25.7, 25.8 (CHϭCMe2), 41.2 (CH2), 51.0, 51.2, 57.4,
[br. s, 1 H, [N(CHMe2)2], 5.09Ϫ5.13 (m, 1 H, CHOH), 7.28Ϫ7.87
57.6 [N(CHMe2)2], 67.7 [CHOH, (minor)], 69.8 [CHOH, (minor)],
(m, 11 H, Ar-H) ppm. 13C NMR [major diastereoisomer]: δ ؍ 19.4, 125.0, 125.1, 125.7, 125.9, 126.5, 126.7, 126.9, 127.5, 127.6, 128.0,
20.0, 20.1, 20.4 [N(CHMe2)2], 43.6 (CH2), 51.0, 57.4 [N(CHMe2)2], 128.5, 128.9, 129.0, 132.4, 132.5, 134.0, 134.6, 140.5, 140.7, 127.8,
72.9 (CHOH), 125.0, 125.6, 125.9, 126.6, 126.7, 126.9, 127.1, 127.9, 127.9, 128.6, 128.7, 197.4 (CϭS) ppm. MS (EI): m/z (%) ϭ 369 (28)
128.0, 128.3, 128.4, 128.6, 129.0, 132.7, 140.4, 145.2 ppm. 13C
[Mϩ·], 285 (13), 269 (29), 242 (25), 141 (24), 43 (100). C23H31NOS
NMR [minor diastereoisomer]: δ ؍ 20.1 [N(CHMe2)2], 43.8 (CH2), (369.56): calcd. C 74.75, H 8.45, N 3.79, S 8.67; found C 74.85, H
75.5 (CHOH), 51.4, 60.0 [N(CHMe2)2], 124.9, 125.6, 125.8, 126.0,
8.51, N 4.19, S 8.49. IR (KBr): ν˜ ؍ 3418 (νOH), 2966, 2926, 1490,
126.9, 127.1, 127.2, 128.0, 128.2, 128.3, 128.4, 128.9, 132.5, 1144 (νCϭS) cmϪ1
145.9 ppm. IR (KBr): ν˜ ؍ 3318 (νOH), 3050, 2966, 1492, 1374,
.
1338, 1208, 1148 (νCϭS) cmϪ1. MS (EI): m/z (%) ϭ 391 (28) [Mϩ·],
285 (63), 242 (60), 185 (28), 105 (60), 77 (86), 43 (100). HMRS
calcd. for C25H29NOS: 391.1970 found 391.1902.
2-(2-Hydroxy-2,4-dimethylpent-3-enyl)-N,N-diisopropyl-1-naph-
thalenecarbothioamide (31): The general procedure was applied to
N,N-diisopropyl-2-methyl-1-naphthalenecarbothioamide
(15,
128 mg, 0.45 mmol), sBuLi (450 µL of a 1.3  solution in cyclohex-
ane, 0.58 mmol), distilled 4-methyl-3-propen-2-one (129 µL,
1.12 mmol) and THF (10 mL). The crude product contained two
2-(2-Hydroxynaphthylethyl)-N,N-diisopropyl-1-naphthalenecarbo-
thioamide (29): The general procedure was applied to N,N-diisopro-
pyl-2-methyl-1-naphthalenecarbothioamide
(15,
165 mg, diastereoisomers (dr ϭ 82:18). Purification by silica gel chromatog-
0.58 mmol), sBuLi (490 µL of a 1.3  solution in cyclohexane, raphy (Rf ϭ 0.4) with petroleum ether/ethyl acetate (8:2) afforded
0.63 mmol), 1-naphthaldehyde (118 µL, 0.87 mmol) and THF
(10 mL). The crude product contained two diastereoisomers (dr ϭ
57:43). Purification by silica gel chromatography with petroleum
122 mg (yield: 71%) of compound 31 as a yellow oil. IR (KBr):
ν˜ ؍ 3362 (νOH), 3046, 2966, 1496, 1464, 1372, 1206, 1140 (νCϭS
cmϪ1. MS (EI): m/z (%) ϭ 383 (3) [Mϩ·], 365 (15), 322 (21), 285
)
ether/ethyl acetate (8:2) afforded 201 mg (yield: 79%) of compound (30), 185 (12), 43 (100). HMRS calcd. for C24H33NOS: 383.2283;
29. Minor and major diastereoisomers were not separated by chro-
matography. After crystallisation from ethyl acetate, the minor dia-
stereoisomer was obtained as a white solid. Minor Diastereoiso-
found 383.2205. Minor diastereoisomer and major diastereoisomer
were separated by chromatography. H NMR [major diastereoiso-
mer]: δ ؍ 1.01 (d, J ϭ 6.6 Hz, 3 H, NCHMe2), 1.11 (d, J ϭ 6.7 Hz,
1
mer: M.p. 203 °C. Rf ϭ 0.3 (petroleum ether/ethyl acetate, 7:3). 1H 3 H, NCHMe2), 1.48 [s, 3 H, C(OH)Me], 1.73 (d, J ϭ 1.1 Hz, 3 H,
NMR: δ ϭ 0.96 (d, J ϭ 6.7 Hz, 3 H, NCHMe2), 1.04 (d, J ϭ CHϭCMe2), 1.79 (d, J ϭ 0.7 Hz, 3 H, CHϭCMe2), 1.85Ϫ1.94
6.7 Hz, 3 H, NCHMe2), 1.96 (br. s, 6 H, NCHMe2), 2.07 (br. s,
(br. s, 6 H, NCHMe2), 3.00Ϫ3.11 (m, 2 H, CH2), 3.78 [br. s, 2 H,
6 H, NCHMe2), 3.28Ϫ3.34 (m, 2 H, CH2), 3.71Ϫ4.17 [m, 2 H, N(CHMe2)2], 5.38 (br. s, 1 H, CHϭCMe2), 7.43Ϫ7.80 (m, 6 H, Ar-
N(CHMe2)2], 4.55 (br. s, 1 H, OH), 5.91 (m, 1 H, CHOH), H) ppm. 1H NMR [minor diastereoisomer]: δ ؍ 0.98 (d, J ϭ
7.28Ϫ7.88 (m, 13 H, Ar-H) ppm. 13C NMR: δ ϭ 18.8, 19.1, 19.5,
6.6 Hz, 3 H, NCHMe2), 1.13 (d, J ϭ 6.6 Hz, 3 H, NCHMe2), 1.48
20.1 [N(CHMe2)2], 42.6 (CH2), 51.4, 57.8 [N(CHMe2)2], 73.3 [s, 3 H, C(OH)Me], 1.74 (br. s, 3 H, CHϭCMe2), 1.88Ϫ2.09 (m, 6
(CHOH), 123.0, 125.4, 125.9, 126.0, 126.1, 126.2, 126.9, 127.0, H, NCHMe2), 1.93 (br. S, 3 H, CHϭCMe2), 2.93 and 3.24 (AB,
128.1, 128.2, 128.3, 128.6, 129.2, 129.4, 129.7, 130.2, 132.6, 133.8,
141.0, 141.2, 197.7 (CϭS) ppm. IR (KBr): ν˜ ؍ 3362 (νOH), 3046, 1 H, CHϭCMe2), 7.44Ϫ7.53 (m, 3 H, Ar-H), 7.71Ϫ7.82 (m, 3 H,
2966, 1496, 1464, 1372, 1206, 1140 (νCϭS) cmϪ1. MS (EI): m/z Ar-H) ppm. 13C NMR [major diastereoisomer]: δ ؍ 19.2 (CHϭ
J ϭ 14.0 Hz, 2 H, CH2), 3.75 [br. s, 2 H, N(CHMe2)2], 5.50 (br. s,
Eur. J. Org. Chem. 2003, 3398Ϫ3406
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3405

D. Ach, V. Reboul, P. Metzner
FULL PAPER
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CMe2), 19.3, 19.5, 20.0, 20.6 [N(CHMe2)2], 28.0 (CHϭCMe2), 32.9
[CH(OH)Me], 46.0 (CH2), 51.7, 51.8 [N(CHMe2)2], 74.6
[C(OH)Me], 125.5, 126.0, 126.8, 127.0, 128.4, 128.7, 128.9, 130.0,
132.0, 132.9, 133.0, 141.1, 199.0 (CϭS) ppm. 13C NMR [minor
diastereoisomer]: δ ؍ 18.9 (CHϭCMe2), 19.4, 19.5, 20.6, 21.1
[N(CHMe2)2], 27.4 (CHϭCMe2), 29.4 [CH(OH)Me], 45.9 (CH2),
51.1, 51.9 [N(CHMe2)2], 73.2 [C(OH)Me], 125.2, 125.4, 125.8,
126.5, 126.6, 126.8, 127.9, 128.0, 128.8, 132.5, 133.5, 140.9, 198.2
(CϭS) ppm.
[6]
[7]
[8]
[9]
N,N-Diisopropyl-2-[2-(N-methylamino)phenylethyl)-1-naphthalene-
carbothioamide (32): The general procedure was applied to N,N-
diisopropyl-2-methyl-1-naphthalenecarbothioamide (15, 77 mg,
0.27 mmol), sBuLi (260 µL of a 1.2  solution in cyclohexane,
0.32 mmol), distilled N-benzylidene-methanimine (44 µL,
0.35 mmol) and THF (5 mL). The crude product contained two
diastereoisomers (dr ϭ 65:35). Purification by silica gel chromatog-
raphy with petroleum ether/ethyl acetate (8:2 then 5:5) afforded
71 mg (yield: 65%) of compound 32. After crystallisation from
ethyl acetate a white solid was obtained. Minor and major dia-
stereoisomers were not separated by chromatography or crystallis-
ation. M.p. 182 °C. 1H NMR [major diastereoisomer]: δ ؍ 1.00 (d,
J ϭ 6.6 Hz, 6 H, NCHMe2), 1.86Ϫ1.94 (br. s, 6 H, NCHMe2), 2.18
(s, 3 H, NHMe), 2.76Ϫ2.89 (m, 2 H, CH2), 3.72Ϫ3.89 [br. s, 2 H,
N(CHMe2)2], 4.08Ϫ4.12 (m, 1 H, CH), 7.06Ϫ7.53 (m, 11 H, Ar-H)
ppm. 1H NMR [minor diastereoisomer]: δ ؍ 1.08 (d, J ϭ 6.6 Hz, 3
H, NCHMe2), 1.09 (d, J ϭ 6.6 Hz, 3 H, NCHMe2), 1.97Ϫ2.14 (br.
s, 6 H, NCHMe2), 2.26 (s, 3 H, NHMe), 3.08Ϫ3.24 (m, 2 H, CH2),
3.91Ϫ4.12 [br. s, 2 H, N(CHMe2)2], 4.47Ϫ4.50 (s, 1 H, CH),
7.06Ϫ7.53 (m, 11 H, Ar-H) ppm. 13C NMR [major ؉ minor dia-
stereoisomers]: δ ؍ 19.4, 20.1, 20.5 [N(CHMe2)2], 34.6, 34.9
(NHMe), 41.8, 43.3 (CH2), 50.9, 57.3 [N(CHMe2)2], 63.7, 66.2
(CH), 125.8, 125.9, 126.6, 126.7, 126.9, 127.1, 127.2, 127.5, 127.7,
127.9, 128.0, 128.4, 128.5, 128.6, 132.7, 140.6, 140.7, 144.2, 197.5,
198.2 (CϭS) ppm. IR (KBr): ν˜ ؍ 3362 (νOH), 3046, 2966, 1496,
1464, 1372, 1206, 1140 (νCϭS), 808 cmϪ1. MS (EI): m/z (%) ϭ 404
(11) [Mϩ·], 285 (100), 270 (33), 242 (34), 185 (51), 120 (74). HMRS
calcd. for C26H32N2S: 404.2286; found 404.2200.
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Acknowledgments
ˆ
We gratefully acknowledge the ‘‘PunchOrga’’ Network (Pole Univ-
[25]
[26]
`
ersitaire Normand de Chimie Organique), the ‘‘Ministere de la Re-
´
cherche’’, CNRS, the ‘‘Region Basse-Normandie’’ and the Euro-
[27]
[28]
pean Union (FEDER funding) for financial support. We also
´
´
thank Prof. Nelly Ple, Alain Turck and Guy Queguiner (Rouen)
for fruitful discussions and collaboration, and Dr Abdelkrim Med-
dour and Prof. Jacques Courtieu (Orsay) for their kind assistance
in NMR analysis.
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J. H. Pink, N. Westlund, S. A. Yasin, Tetrahedron 1998, 54,
13277Ϫ13294.
Received April 15, 2003
3406
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3398Ϫ3406