Sequential assembly strategy for tetrasubstituted olefin synthesis using vinyl 2-pyrimidyl sulfide as a platform

Article abstract of DOI:10.1021/ja045858t

We have developed a programmable and diversity-oriented synthetic scheme for tetrasubstituted olefins through a site-selective and sequential assembly of π-components onto a C=C core of vinyl 2-pyrimidyl sulfide. Noteworthy features are that (i) all components assembled stem from readily available organic halides or their Grignard reagents, (ii) the installation at the desired position can be achieved by the addition of the components in the appropriate order, and (iii) simple alteration of addition order in the sequence results in the production of all possible regio- and stereoisomers of multisubstituted olefins. Copyright

Full text of DOI:10.1021/ja045858t

Published on Web 09/04/2004
Sequential Assembly Strategy for Tetrasubstituted Olefin Synthesis Using
Vinyl 2-Pyrimidyl Sulfide as a Platform
Kenichiro Itami,* Masahiro Mineno, Nobuhiro Muraoka, and Jun-ichi Yoshida*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto UniVersity,
Nishikyo-ku, Kyoto 615-8510, Japan
Received July 9, 2004; E-mail: itami@sbchem.kyoto-u.ac.jp; yoshida@sbchem.kyoto-u.ac.jp
Table 1. One-Pot Double Mizoroki-Heck Reaction of 1 with Aryl
The regio- and stereoselective synthesis of multisubstituted
olefins is one of the most challenging subjects in organic synthesis.
In particular, the development of a general method for the synthesis
of tetrasubstituted olefins with four different substituents has been
a formidable challenge for chemists for years.1 Moreover, in view
of potential use as functional materials, an extended π-system based
on tetrasubstituted olefin structure (tetraarylethenes) would be an
interesting target.2 We envisaged that the sequential assembly
(installations) of π-components, such as aryl groups, onto a CdC
core of an ethylene derivative substituted by a suitable heteroatom
(E) would be a straightforward strategy for multisubstituted olefin
synthesis. Because of the presence of such a heteroatom (E), the
three C-H bonds (one R-C-H and two â-C-H bonds) and C-E
bonds are nonequivalent, thereby distinguishable in principle toward
π-component assembling reactions. This strategy differs from the
classical olefin synthesis as exemplified by the Wittig reaction and
its analogues that connect two components with the creation of a
CdC bond, where the selectivity (stereoselectivity) would be
dependent on existing substituent(s). As an assembling-site-
controlling heteroatom (E), we paid particular attention to sulfur
because of the rich chemistry of organosulfur compounds. We
herein report a general method for the synthesis of tetrasubstituted
olefins using vinyl 2-pyrimidyl sulfide (1) as a platform, realizing
our concept.
Iodides
run
Ar1
Ar2
2 (yield, %)
1a
2a
3a
4a
5a
6a
7
phenyl (a)
phenyl (a)
2aa (93)
2bb (90)
2cc (81)
2dd (91)
2ee (92)
2ff (95)
2ab (90)
2ad (88)
2ae (88)
2da (94)
2de (89)
2ea (86)
2ed (86)
2ef (90)
2gd (89)
2ge (94)
2gf (92)
2-methylphenyl (b)
3-methylphenyl (c)
4-methylphenyl (d)
4-methoxyphenyl (e)
1-naphthyl (f)
phenyl (a)
phenyl (a)
phenyl (a)
4-methylphenyl (d)
4-methylphenyl (d)
4-methoxyphenyl (e)
4-methoxyphenyl (e)
4-methoxyphenyl (e)
3-thienyl (g)
2-methylphenyl (b)
3-methylphenyl (c)
4-methylphenyl (d)
4-methoxyphenyl (e)
1-naphthyl (f)
2-methylphenyl (b)
4-methylphenyl (d)
4-methoxyphenyl (e)
phenyl (a)
4-methoxyphenyl (e)
phenyl (a)
4-methylphenyl (d)
1-naphthyl (f)
8
9
10
11
12
13
14
15
16
17
4-methylphenyl (d)
4-methoxyphenyl (e)
1-naphthyl (f)
3-thienyl (g)
3-thienyl (g)
a Reactions were performed at 80 °C with 2.0 equiv of aryl iodides.
selectively onto 1 (runs 7-17). Thus, a toluene solution of 1 (1.0
equiv), Ar1-I (1.0 equiv), Et3N (3.0 equiv), and Pd[P(t-Bu)3]2 (5
mol %) was stirred at 60 °C for 3 h to afford monoarylated vinyl
sulfide in situ. Thereafter, Ar2-I (1.0 equiv) was added to the
solution, and the mixture was stirred for an additional 15-24 h at
90 °C to give doubly arylated product 2. The regio- and stereose-
lectivities of double MHR are greater than 95% as determined by
NMR analysis.
Having established an efficient component assembling method
at â-C-H bonds, we next embarked on the assembly of the third
component at the R-C-H bond of 2. After many experiments, we
found that this could be achieved by the R-lithiation/cross-coupling
sequence of 2 (Table 2). Thus, a THF solution of 2 was treated
with t-BuLi (2.2 equiv) to afford R-lithiated species with tert-butyl
group installed onto pyrimidine ring.8 The use of an equimolar
amount of t-BuLi only resulted in the alkylation onto pyrimidine
ring. Since R-lithiation does not take place without the pyrimidyl
group under otherwise identical conditions, we suppose that the
2-pyrimidyl group is also acting as a directing group in the
R-lithiation of such sterically congested alkenyl sulfides.
As a π-component installation method at â-C-H bond of vinyl
sulfide, we investigated the Pd-catalyzed Mizoroki-Heck reaction
(MHR). Since there is only one example in the literature possibly
reflecting the low reactivity of vinyl sulfide toward MHR,3 we
began by exploring a highly reactive vinyl sulfide as well as a
catalyst. After extensive screening, we found that appending the
catalyst-directing4 2-pyrimidyl group5 on sulfur enormously en-
hances the reactivity of vinyl sulfide toward MHR. In addition, we
found the Pd/P(t-Bu)3 system6 to be a highly active MHR catalyst
in our synthesis. Moreover, because of the presence of catalyst-
directing 2-pyrimidyl group on sulfur, hard-to-achieve double MHR7
has been accomplished, which allows us to install two components
at two â-C-H bonds in one pot.
The results of one-pot double MHR of vinyl 2-pyrimidyl sulfide
(1) with aryl iodides are shown in Table 1. Various electronically
and structurally diverse aryl iodides can be applied in this reaction
to give â,â-diarylvinyl sulfides 2. The yields are greater than 90%
in many cases even using equimolar quantity of each reagent.
Moreover, it is also possible to install different aryl groups
The successive π-component assembling at R-position was
accomplished by cross-coupling reaction (CCR) of the thus-obtained
organolithiums with aryl halides under the influence of Pd(PPh3)4/
CuI catalyst. The use of Cu cocatalyst is essential in this CCR.
The treatment of the resultant crude solution with DDQ resulted in
9
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J. AM. CHEM. SOC. 2004, 126, 11778-11779
10.1021/ja045858t CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Synthesis of 3 through R-Lithiation/Cross-Coupling of 2
Scheme 1
run
2
Ar3
3 (yield, %)
1
2
3
4
5
6
2aa
2ae
2de
2ed
2ed
2ff
4-methoxyphenyl (e)
4-methylphenyl (d)
phenyl (a)
phenyl (a)
1-naphthyl (f)
3aae (82)
3aed (78)
3dea (82)
3eda (70)
3edf (65)
3ffd (55)
(5ade, 5aed, 5dae, 5dea, 5ead, and 5eda) that are possible from a
set of three aryl groups (a, d, and e) by changing the applying
order of those aryl groups into the reaction sequence.
4-methylphenyl (d)
In summary, we have developed a programmable and diversity-
oriented synthetic scheme for tetrasubstituted olefins through a site-
selective and sequential assembly of π-components onto a CdC
core of vinyl 2-pyrimidyl sulfide (Scheme 1). Noteworthy features
are that (i) all components assembled stem from readily available
organic halides or their Grignard reagents, (ii) the installation at
the desired position can be achieved by the addition of the
components in the appropriate order, and (iii) simple alteration of
addition order in the sequence results in the production of all
possible regio- and stereoisomers of multisubstituted olefins. As
well as applications to pharmaceutical chemistry, we feel that the
present strategy should find many uses for combinatorial lead-
structure identification and optimization in the development of
functional organic materials where the structure-property relation-
ships are often not predictable. The investigations in this line as
well as expanding the applicable components assembled are
currently ongoing in our laboratory.
Table 3. Synthesis of Tetraarylethenes 4 and Triarylethenes 5
run
sulfide
Ar4
product (yield, %)
1a
3aae
3aae
3aed
3dea
3eda
3edf
3edf
3edf
3ffd
2ab
2dd
2cc
2ee
2ff
2gd
2ge
2gf
phenyl (a)
2-naphthyl (h)
4-methylphenyl (d)
4-fluorophenyl (i)
4-fluorophenyl (i)
phenyl (a)
2-naphthyl (h)
2-thienyl (j)
phenyl (a)
4aaea (72)
4aaeh (46)
4aedd (40)
4deai (52)
4edai (42)
4edfa (22)
4edfh (14)
4edfj (21)
4ffda (31)
5abe (58)
5ddb (62)
5cch (66)
5eei (85)
5ffd (67)
5gdk (63)
5gel (52)
5gfm (58)
5ade (76)
5aed (69)
5dae (62)
5dea (73)
5ead (76)
5eda (81)
2a
3a
4a
5a
6a
7a
8a
9a
10b
11b
12b
13b
14b
15b
16b
17b
18b
19b
20b
21b
22b
23b
4-methoxyphenyl (e)
2-methylphenyl (b)
2-naphthyl (h)
Acknowledgment. This work was supported by a Grant-in-Aid
for Scientific Research from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan.
4-fluorophenyl (i)
4-methylphenyl (d)
9-phenanthryl (k)
3,4-(methylenedioxy)phenyl (l)
3-methoxyphenyl (m)
4-methoxyphenyl (e)
4-methylphenyl (d)
4-methoxyphenyl (e)
phenyl (a)
Supporting Information Available: Experimental procedures and
analytical and spectroscopic data of compounds (PDF, CIF). This
material is available free of charge via the Internet at http://pubs.acs.org.
2ad
2ae
2da
2de
2ea
References
(1) Recent successful synthesis of tetrasubstituted olefins: (a) Zhou, C.;
Emrich, D. E.; Larock, R. C. Org. Lett. 2003, 5, 1579. (b) Itami, K.; Kamei,
T.; Yoshida, J. J. Am. Chem. Soc. 2003, 125, 14670.
(2) For a review on functional materials based on stilbenoid structures, see:
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P. G.; Morera, E.; Ortar, G. Tetrahedron Lett. 1992, 33, 3073. (b) Badone,
D.; Guzzi, U. Tetrahedron Lett. 1993, 34, 3603. (c) Larhed, M.; Andersson,
C. M.; Hallberg, A. Tetrahedron 1994, 50, 285. (d) Itami, K.; Nokami,
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M.; Hallberg, A. J. Am. Chem. Soc. 2003, 125, 3430.
4-methylphenyl (d)
phenyl (a)
2ed
a Reaction conditions: 3, Ar4MgBr (3.0 equiv), Pd2(dba)3 (5 mol %),
toluene, 90 °C, 20 h. b Reaction conditions: 2, Ar4MgBr (3.0 equiv),
Pd[P(t-Bu)3]2 (5 mol %), toluene, 60 °C, 15 h.
the regeneration of the pyrimidine ring (oxidation) to finally provide
R,â,â-triarylated vinyl sulfides 3 in good yields with virtually
complete retention of stereochemistry.
(5) The corresponding phenyl, 2-pyridyl, and pyrazyl analogues exhibited
lower reactivity toward Mizoroki-Heck reactions.
(6) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989.
(7) (a) Bra¨se, S.; de Meijere, A. In Handbook of Organopalladium Chemistry
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(b) Nilsson, P.; Larhed, M.; Hallberg, A. J. Am. Chem. Soc. 2001, 123,
8217. (c) Reference 4d.
(8) R-Lithiation of vinyl sulfides: Oshima, K.; Shimoji, K.; Takahashi, H.;
Yamamoto, H.; Nozaki, H. J. Am. Chem. Soc. 1973, 95, 2694.
(9) (a) Okamura, H.; Miura, M.; Takei, H. Tetrahedron Lett. 1979, 43. (b)
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(10) The stereochemistry was determined by X-ray analysis of 5gel.
As for the final π-component assembling method at the remaining
C-S bond of R,â,â-triarylated vinyl sulfides 3, we found that CCR
with Grignard reagents (Ar4MgBr)9 under the influence of Pd
catalyst is particularly effective. As listed in Table 3, a number of
tetrasubstituted olefins 4 were prepared in moderate to good yields
with virtually complete retention of stereochemistry (runs 1-9).
When â,â-diarylated vinyl sulfides 2 were used as coupling partners,
trisubstituted olefins 5 could also be prepared in a regio- and
stereoselective fashion (runs 10-23).10 In the triarylethene synthesis,
we also demonstrated the preparation of all stereo- and regioisomers
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