Kulinkovich-type reactions of thioamides: Similar to those of carboxylic amides?

Article abstract of DOI:10.1039/c2cc31394d

The behaviour of thioamides under Kulinkovich-type conditions is compared with the known reactivity of carboxylic amides. Dramatic differences are disclosed. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc31394d

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COMMUNICATION
Kulinkovich-type reactions of thioamides: similar to those of carboxylic
amides?w
´
Ewelina Augustowska, Antoine Boiron, Jerome Deffit and Yvan Six*
Received 24th February 2012, Accepted 21st March 2012
DOI: 10.1039/c2cc31394d
The behaviour of thioamides under Kulinkovich-type conditions
is compared with the known reactivity of carboxylic amides.
Dramatic differences are disclosed.
Since the original report by the group of Kulinkovich in 1989,1
the transformations mediated by excess amounts of Grignard
reagents in the presence of alkoxytitanium(IV) species of the
type XTi(OiPr)3 (X = Cl, OiPr) have emerged as a family of
powerful reactions with remarkably broad scope.2 In particular, the
Kulinkovich–de Meijere cyclopropanation of carboxylic amides
can now be considered as the method of choice for the synthesis
of tertiary cyclopropylamines.2,3,4 The alkene ligand-exchange
version of this process is especially interesting, as it allows the
inter- or intra-molecular coupling of a carboxylic amide and
an olefin (Scheme 1).
Scheme 2 Comparison of the reactivities of amide 1aO and thioamide
The mechanism involves the formation of a titanacyclopropane
1aS under Kulinkovich-type conditions.
A resulting from the reaction of the Grignard reagent with the
starting titanium(IV) reagent. After ligand exchange with the olefin
partner, a new titanacyclopropane complex B is generated, which
then undergoes 1,2-insertion of the carbonyl group to afford an
oxatitanacyclopentane intermediate C. The following elementary
steps eventually deliver the aminocyclopropane product. The
reaction has been shown to be diastereospecific with respect to
the configuration of the alkene.5,6 In this context, we wondered
how thioamides would behave, under Kulinkovich-type conditions,
as compared with carboxylic amides. This communication is an
account of our preliminary results.
At first glance, the differences between the reactions of the
N-alkenylamide 1aO and the corresponding thioamide 1aS
under standard conditions could be judged as minor. The main
product is the aminocyclopropane 2a resulting from an intra-
molecular Kulinkovich–de Meijere reaction (Scheme 2). Besides
this transformation, the thioamide 1aS is also partly converted
into the cyclopentyl-substituted tertiary amine 3a or the cyclohexyl
derivative 4a depending on the Grignard reagent used, namely
cyclopentylmagnesium chloride or cyclohexylmagnesium chloride.
In contrast, the reactions of 1bO/1bS and the reactions of
1cO/1cS in the presence of styrene are clearly divergent: these
amides and the corresponding thioamides exhibit completely
orthogonal behaviours (Scheme 3). In fact, while the carboxylic
amide 1bO undergoes an intramolecular Kulinkovich–de Meijere
reaction to give the original 2-azabicyclo[5.1.0]octane 2b,7 no trace
of this compound is observed starting from the thioacetamide 1bS
Scheme 1 Kulinkovich–de Meijere reaction with ligand exchange.
Laboratoire de Synthe`se Organique DCSO, UMR 7652 CNRS/Ecole
Polytechnique, 91128 Palaiseau Cedex, France.
E-mail: six@dcso.polytechnique.fr; Fax: +33 (0)1 6933 5972;
Tel: +33 (0)1 6933 5979
w Electronic supplementary information (ESI) available: Experimental
procedures and characterisation data of the new compounds. See DOI:
10.1039/c2cc31394d
c
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Chem. Commun., 2012, 48, 5031–5033 5031

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Table 1 Titanium-mediated reductive alkylation of thioamidesa
Scheme 3 Amides vs. thioamides: examples of divergent reactions.
Conditions: Ti(OiPr)4 (1.5 equiv.), cC6H11MgCl (4.0 equiv.), THF,
0 to 20 1C.
and only the cyclohexane-substituted tertiary amine 4b is formed,
with moderate conversion. The reaction of the formamide 1cO and
styrene to form 2c had already been described by de Meijere et al.
under slightly different conditions.6 Our result is closely similar and
no reductive alkylation product 4c is formed. Conversely, using the
thioamide 1cS in place of 1cO, 4c is obtained in 65% yield and 2c is
not observed.
These examples convincingly suggest that the initially formed
titanacyclopropane A reacts much faster with thioamide functions
than with alkene groups. This is in sharp contrast with the known
reactivity of carboxylic amide and ester groups, which have been
demonstrated to be less reactive than terminal alkene functions
towards the intermediates involved in Kulinkovich-type reactions.8
As a logical consequence, we expected that the observed
reductive alkylation process could be generally performed in
the absence of an olefin reactant. The results, obtained from
several non-alkene thioamide substrates and presented in
Table 1, confirmed this hypothesis. In all cases, the expected
alkylated products 3–5 were obtained, generally in moderate
yields. The effect of the choice of the solvent was briefly
examined: while both tBuOMe and THF are suitable, cyclo-
hexane performs less well (entry 7) and, perhaps unsurprisingly,
dichloromethane is not compatible with the transformation
(entry 13). The three Grignard reagents employed, namely
isopropyl-, cyclopentyl- and cyclohexyl-magnesium chloride
give comparable yields. It is worthy of note that the thiolactams
1fS and 1gS perform significantly better than the acyclic
thioamides. The chiral substrate 1gS is converted into the
corresponding amines 4g and 5g with some diastereoselectivity
(entries 10–12). Interestingly, when the reaction of 1cS and
cyclohexylmagnesium chloride was quenched with D2O, 92%
deuterium incorporation was evidenced on the tertiary amine
product 4c, at the position shown (entry 4).9
a
Reaction conditions: Ti(OiPr)4 (1.5 equiv.), RMgCl (4.0 equiv.), in
b
the solvent indicated, at 20 1C or 0 to 20 1C, typically for 60 min. The
yields and, if relevant, the diastereoisomeric ratios (dr) have been
evaluated by NMR analysis of the crude products. The yields in
c
parentheses are given for the isolated products. The reaction was
d
quenched with D2O. Deuterium incorporation E 92%. The cis
diastereoisomer was obtained predominantly.
e
An equilibrium of the complex D with the metallated iminium
species E can then be invoked. Trapping of E by the Grignard
reagent would afford the a-metallated amine F. Upon hydrolysis
or deuteriolysis, this ultimate intermediate of the reaction would
then be transformed into the products 3–5. From the substrate
To explain the observed results, we propose a mechanism
whereby the starting thioamide 1 would react with the primary
titanacyclopropane intermediate A to give a thiatitanacyclo-
propane species D by a ligand exchange process (Scheme 4).
c
5032 Chem. Commun., 2012, 48, 5031–5033
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A metallative alkylation reaction is observed, with an important
competitive pathway being the production of a secondary amine.
The transformation is thought to operate via a thia-titana-
cyclopropane intermediate that can be trapped intramolecularly
by an olefin group placed at a suitable distance. We are currently
carrying out further investigations to get deeper insight into the
reaction mechanism, improve its efficiency and develop novel
extensions. Our results will be reported in due course.
We warmly thank Natalia Szwankowska and Aleksander
Przyby"a for their contribution to initial experiments. We are
grateful to Michel Levart for the MS and HRMS analyses of
´
our compounds. We also wish to thank Ecole Polytechnique
for the PhD grant of E. Augustowska and the CNRS for
financial support.
Notes and references
1 O. G. Kulinkovich, S. V. Sviridov, D. A. Vasilevskii and
T. S. Prityskaya, Zh. Org. Khim., 1989, 25, 2244–2245 (Russ. J.
Org. Chem., 1989, 25, 2027–2028).
Scheme 4 Proposed mechanism for the titanium-mediated transformation
of thioamides 1 into tertiary amines 3–5.
2 Recent reviews: (a) J. K. Cha and O. G. Kulinkovich, in
Organic Reactions, ed. S. E. Denmark, John Wiley & Sons, 2012,
vol. 77, ch. 1; (b) A. Wolan and Y. Six, Tetrahedron, 2010, 66, 15–61;
(c) A. Wolan and Y. Six, Tetrahedron, 2010, 66, 3097–3133.
3 Initial report: V. Chaplinski and A. de Meijere, Angew. Chem., 1996,
108, 491–492 (Angew. Chem., Int. Ed. Engl., 1996, 35, 413–414).
4 Dedicated review: A. de Meijere, S. I. Kozhushkov and
A. I. Savchenko, J. Organomet. Chem., 2004, 689, 2033–2055; see
also: A. de Meijere, V. Chaplinski, H. Winsel, M. Kordes,
B. Stecker, V. Gazizova, A. I. Savchenko, R. Boese and F. Schill
1aS, it is reasonable to invoke a competitive pathway giving
the bicyclic intermediate CaS by an intramolecular 1,2-insertion
of the terminal alkene side-chain into the metallacycle D. The
tentative titanium complex CaS would eventually afford 2a in the
same way as from the analogous sulfur-free species C (Scheme 1).
In the cases of the reaction of 1bS or the reaction of 1cS with
styrene, this alternative pathway is expected to be much slower
because it would involve the formation of a seven-membered ring
or an intermolecular process.
(nee Brackmann), Chem.–Eur. J., 2010, 16, 13862–13875.
´
5 (a) C. P. Casey and N. A. Strotman, J. Am. Chem. Soc., 2004, 126,
1699–1704; (b) N. Ouhamou and Y. Six, Org. Biomol. Chem., 2003,
1, 3007–3009.
To account for the rather modest yields obtained, one can
invoke a competitive direct addition of the Grignard reagent onto
the starting thioamide. Indeed, the main by-product generally
observed is the secondary amine 6 (produced in up to 37% yield).
Cyclohexylmethylketone is detected by NMR in the crude products
of the reactions carried out with cyclohexylmagnesium chloride
starting from the thioaceamide 1dS and 1eS. However, the rather
minor amounts of this ketone (8–15% yield) suggest that 6 could
also be formed by another mechanism, possibly by an elimination
elementary step, somewhere in a pathway following the formation
of D. In the case of the thiolactam reactants 1fS and 1gS, such a
process could be reversible, hence the better results obtained with
these compounds.
6 Examples involving disubstituted alkenes are few, because the formation
of the intermediate B is less favoured than in the case of monosubstituted
alkenes. See A. de Meijere, C. M. Williams, A. Kourdioukov, S. V.
Sviridov, V. Chaplinski, M. Kordes, A. I. Savchenko, C. Stratmann and
M. Noltemeyer, Chem.–Eur. J., 2002, 8, 3789–3801.
7 Very few compounds with this skeleton have been described.
Selected references: (a) L. Jerome, T. D. Sheppard, A. E. Aliev
and W. B. Motherwell, Tetrahedron Lett., 2009, 50, 3709–3712;
´
(b) A. Mallagaray, G. Domı
´
nguez, A. Gradillas and J. Pe
´
rez-
Castells, Org. Lett., 2008, 10, 597–600; (c) Y. S. Park and
P. Beak, Tetrahedron, 1996, 52, 12333–12350.
8 Selected references: (a) O. G. Kulinkovich, A. I. Savchenko,
S. V. Sviridov and D. A. Vasilevski, Mendeleev Commun., 1993,
230–231; (b) J. Lee, H. Kim and J. K. Cha, J. Am. Chem. Soc., 1996,
118, 4198–4199.
9 Attempted trapping of the final intermediate with benzaldehyde was
unsuccessful: the simple reductive alkylation product 4c was
obtained.
In summary, thioamides behave drastically differently
from carboxylic amides under Kulinkovich-type conditions.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 5031–5033 5033