New procedure for the preparation of highly sterically hindered alkenes using a hypervalent iodine reagent

Article abstract of DOI:10.1039/b414959a

A method to construct the olefinic bond in overcrowded alkenes using hypervalent iodine reagent was discussed. In the process, the diazo compound was made to react in a 1,3-dipolar cycloaddition with thioketone to form two isomeric thiadiazolines, which were unstable. A single isomer of episulfide was formed, since the methyl substituent blocks ring closure on one side of the molecule of the essentially flat thiocarbonyl yielded moiety. The method is very efficient because it allows selective coupling reaction and facilitates purification of the desired product.

Full text of DOI:10.1039/b414959a

View Article Online / Journal Homepage / Table of Contents for this issue
C O M M U N I C A T I O N
New procedure for the preparation of highly sterically hindered
alkenes using a hypervalent iodine reagent†
Matthijs K. J. ter Wiel, Javier Vicario, Stephen G. Davey, Auke Meetsma and Ben L. Feringa*
Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute, University of
Groningen, Nijenborgh 4, 9747 AG, Groningen, The Netherlands. E-mail: Feringa@chem.rug.nl;
Fax: +31 50 363 4296; Tel: +31 50 363 4278
Received 28th September 2004, Accepted 20th October 2004
First published as an Advance Article on the web 10th November 2004
New methodology is described to construct the olefinic
bond in overcrowded alkenes using a hypervalent iodine
reagent, and applied in the synthesis of molecular motors.
atom is then performed by reaction with copper powder or
triphenylphosphine to yield the desired alkene. It was established
that the elimination of nitrogen in the thiadiazoline was followed
by a conrotatory ring closure to form the corresponding
episulfide.6
The design of nanomechanical devices via a bottom-up ap-
proach, elegantly illustrated in the recent examples of molecular
machines,1 demands for new synthetic methodology to construct
such complex molecular systems. Accordingly, we have focused
on the development of molecular switches and motors based
on sterically overcrowded alkenes.2 Besides the challenge to
synthesize these highly overcrowded alkenes, control of steric
hindrance at the central olefinic bond is a crucial parameter for
the motor function. A key feature of the light-driven molecular
motors is that they are capable of repeated unidirectional
rotation around their central double bond functioning as the
axis of rotation. This rotation takes place in four steps as two
photoisomerization steps are each followed by a thermal helix
inversion step.3 However, in the so-called first generation of this
type of molecules the rate determining thermal isomerization
steps are slow at room temperature. The replacement of the
two six-membered rings of the original molecular motor by
two five-membered rings in 1 led to a significant increase of
the speed of rotation due to a decrease in steric hindrance.4
In this paper we present new methodology to prepare sterically
overcrowded alkenes 2, with distinct upper and lower halves and
which contain in the upper half a five-membered ring bearing the
stereocentre needed to control the direction of rotation (Fig. 1).
Apart from the effectiveness in olefin formation due to the
gradual build-up of steric hindrance in the molecule, a major
advantage of the reaction is the selective coupling of two non-
identical halves which is not easily accomplished with, for
example, the McMurry reaction. Of major importance for the
development of functionalized molecular motors and switches
is the tolerance of the olefination reaction towards a variety of
functional groups.10
However, the diazo–thioketone coupling method for the
preparation of target structures 2, starting from hydrazone 4 and
thioketones 7, failed to provide any of the desired episulfides
8 (Scheme 1). We found that the approach we commonly
use for similar compounds employing silver(I) oxide as the
oxidant was not successful.11,12 This prompted an investigation
of other oxidizing agents. Based on earlier investigations, the
use of hypervalent iodine compounds13 such as 5 seemed to
be particularly promising.14 Only recently, similar hypervalent
iodine reagents have attracted conderable interest in a number
of synthetic applications.15 Indeed, reaction at low temperature
(−50 ◦C) in DMF resulted in formation of the diazo compound
6, as was deduced from the slightly red color of the solution.
Upon addition of thioxanthone 7a (Y = O), the evolution
of nitrogen gas was observed and after workup episulfide 8a
(Y = O) was obtained in good yield. To extend the scope of
the reaction and to test the applicability of reagent 5, various
thioketones 7a–g were used in the coupling reaction. Moderate
Fig. 1 Molecular motors 1 and 2 containing either one or two
five-membered rings with a stereocentre.
Where most olefination reactions fail to provide such severely
hindered molecules we rely on the diazo–thioketone coupling,
more commonly referred to as the Barton–Kellogg5,6 reaction,
to prepare sterically overcrowded alkenes. The reaction was
introduced in 1920 by Staudinger7 and intensively used in
the group of Scho¨nberg.8 The power of this method is that
steric strain is gradually introduced into the molecule in a
two fold extrusion process.9 In the first step of the reaction,
a diazo compound and a thioketone react in a 1,3-dipolar
cycloaddition in which a thiadiazoline is formed. In most cases
this thiadiazoline is thermally unstable and rapidly eliminates
nitrogen to form an episulfide. Extrusion of the remaining sulfur
† Electronic supplementary information (ESI) available: experimental
procedures for compounds 4, 7f, 8a–g, and 2a–g; crystal data for 8a. See
http://www.rsc.org/suppdata/ob/b4/b414959a/
Scheme 1 The modified diazo–thioketone coupling for the synthesis of
overcrowded alkenes.
2 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 8 – 3 0
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

View Article Online
Table 1 Episulfides 8a–g and alkenes 2a–g
Y
R
8
Yield (%)a
2
Yield (%)a
O
S
H
H
H
H
H
OMe
NO2
a
b
c
d
e
f
63
58
79
44
48
89
63
a
b
c
d
e
f
87
87
90
81
81
82
87
C(CH3)2
CH CH
—
O
S
=
g
g
a Isolated yields, see ref. 17.
to excellent yields were obtained for the various episulfides, as
depicted in Table 1.
Desulfurization of the episulfides 8 was performed preferably
by reaction with excess triphenylphosphine in refluxing p-xylene.
Although the desulfurization of episulfide 8a could be performed
with copper powder, removal of the side products could only
be achieved with considerable effort. Much more convenient
was the use of triphenylphosphine, which cleanly converted
the episulfides 8a–g to the corresponding alkenes. In case of
alkenes 2a, 2b, 2c and 2d it was impossible to separate the
excess triphenylphosphine by column chromatography. In order
to facilitate the purification of these alkenes, this crude reaction
mixture was stirred overnight in the presence of excess methyl
iodide in p-xylene. Despite the additional reaction with methyl
iodide, the reaction sequence was efficient and the conversion
of the episulfides to the corresponding alkenes proceeded in
all cases in yields exceeding 80%. Surprisingly, the episulfides
8a–8d were obtained as single isomers. To determine the actual
structure of the isomer obtained in the stereoselective diazo–
thioketone coupling, crystals suitable for X-ray crystallographic
analysis were grown by slow diffusion of acetonitrile into a
solution of 8a in chloroform (Fig. 1 and Fig. 2).16
Scheme 2 Reaction of diazo compound 6 and thioketone 7a to form
episulfide 8a via the intermediacy of thiadiazoline 9 and thiocarbonyl
ylide 10.
the synthesis of overcrowded alkenes and molecular motors.
There are two important advantages of this procedure over the
McMurry reaction. First of all, this procedure allows selective
coupling of different upper and lower halves without formation
of homocoupled products. This is not only more efficient from
a synthetic point of view, but also facilitates purification of the
desired products. Secondly, many substituted thioketones are
available, which allows selective functionalization of the desired
motor molecules with substituents that would not have been
tolerated by the McMurry reaction. In conclusion, this new
method not only allows the synthesis of new molecular motors,
but is also highly efficient in the construction of severely hindered
non-symmetric alkenes.
Financial support from the Netherlands Foundation for
Scientific Research (NWO-CW, MKJtW), the Basque Country
Government (JV), and the EU Project on Molecular Level De-
vices and Machines HPRN-CT-2000-00029 (SGD) is gratefully
acknowledged.
References and notes
1 V. Balzani, A. Credi, F. M. Raymo and J. F. Stoddart, Angew. Chem.,
Int. Ed., 2000, 39, 3348.
2 B. L. Feringa, N. Koumura, R. A. van Delden and M. K. J. ter Wiel,
Appl. Phys. A., 2002, 75, 301.
3 N. Koumura, R. W. J. Zijlstra, R. A. van Delden, N. Harada and
B. L. Feringa, Nature, 1999, 401, 152.
4 M. K. J. ter Wiel, R. A. van Delden, A. Meetsma and B. L. Feringa,
J. Am. Chem. Soc., 2003, 125, 15076.
5 (a) D. H. R. Barton and B. J. Willis, J. Chem. Soc., Chem. Commun.,
1970, 1225; (b) D. H. R. Barton, E. H. Smith and B. J. Willis, J. Chem.
Soc., Chem. Commun., 1970, 1226;(c) D. H. R. Barton and B. J. Willis,
J. Chem. Soc., Perkin Trans. 1, 1972, 305.
Fig. 2 PLUTO drawing of episulfide 8a.
6 (a) R. M. Kellogg, Tetrahedron, 1976, 32, 2165; (b) J. Buter, S.
Wassenaar and R. M. Kellogg, J. Org. Chem., 1972, 37, 4045–4060.
7 H. Staudinger and J. Siegwart, Helv. Chim. Acta, 1920, 3, 833.
8 For example:(a) A. Scho¨nberg, D. Cernik and W. Urban, Ber. Dtsch.
Chem. Gess. B, 1931, 64, 2577; (b) A. Scho¨nberg and E. Frese, Chem.
Ber., 1968, 101, 701.
9 For a review concerning organic extrusion reactions, see: F. S. Guziec
and L. J. Sanfilippo, Tetrahedron, 1988, 44, 6241.
10 For example, the strong reducing conditions in the McMurry reaction
are not compatible with a nitro-group.
11 N. Koumura, E. M. Geertsema, M. B. van Gelder, A. Meetsma and
B. L. Feringa, J. Am. Chem. Soc., 2002, 124, 5037.
12 Presumably due to the low stability of 6 and the low rate of oxidation
by Ag2O, this approach is not effective..
It is evident from the structure shown that the methyl
substituent and the naphthalene moiety are oriented in the same
direction in order to diminish the steric strain in the molecule.
Although the syn-orientation of the sulfur atom with respect
to the methyl substituent might be surprising, this is a direct
consequence of the reaction mechanism shown in Scheme 2.
In the first step of the reaction sequence (Scheme 2), the diazo
compound 6 reacts in a 1,3-dipolar cycloaddition with thioke-
tone 7a. Although there could be a stereochemical preference
in this reaction it is anticipated that two isomeric thiadiazolines
9 are formed. These thiadiazolines are thermally unstable and
even at low temperatures nitrogen evolution is observed, to form
a thiocarbonyl ylide 10. Since the methyl substituent blocks
ring closure on one side of the molecule of the essentially flat
thiocarbonyl ylide moiety, a single isomer of episulfide 8a is
formed.
13 Encyclopedia of Reagents for Organic Synthesis, ed. L. A. Paquette,
Wiley, New York, 1995, vol. 6, p. 3982.
14 (a) P. A. S. Smith and E. M. Bruckmann, J. Org. Chem., 1974, 39,
1047; (b) L. Lapatsanis, G. Milias and S. Paraskewas, Synthesis, 1985,
513.
15 (a) M. E. Furrow and A. G. Myers, J. Am. Chem. Soc., 2004, 126,
12222; (b) K. C. Nicolaou, C. J. N. Mathison and T. Montagnon,
J. Am. Chem. Soc., 2004, 126, 5192.
Although further optimization of the reaction conditions
might be achieved, these results represent a major advance in
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 8 – 3 0
2 9

View Article Online
16 Crystal data for 8a, C27H20OS, Mr = 392.52, orthorhombic, P212121,
ability. CCDC reference number 251068. See http://www.rsc.org/
suppdata/ob/b4/b414959a/ for crystallographic data in .cif format.
17 The compounds showed spectroscopic and analytical data in ac-
cordance with the structures. See the electronic supplementary
information† for typical procedures.
˚
a = 6.4273(3), b = 15.6636(7), c = 18.9920(9) A, V = 1912.01(16)
3
A , Z = 4, Dc = 1.363 g cm−3, k (Mo–Ka) = 0.71073 A, l =
1.86 cm−1, F(000) = 824, T = 100 K, GoF = 0.956, wR(F2) =
0.773 for 4735 reflections with F0 ≥ 4d(F0) criterion of observ-
˚
˚
3 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 8 – 3 0