Domino Heck-C-H activation reaction of unsymmetrically substituted [3]cumulene

Article abstract of DOI:10.1039/b607684j

The Heck reaction of an unsymmetrically substituted [3]cumulene has been investigated. Although a carbonyl conjugated alkene is present, the arylpalladium species selectively inserts into the C3-4 double bond, and a subsequent C-H activation reaction with a neighboring phenyl group gives the indene derivatives with a tetrasubstituted olefin moiety. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b607684j

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Domino Heck–C–H activation reaction of unsymmetrically substituted
[3]cumulene{
Takumi Furuta,*a Tomohiro Asakawa,a Mie Iinuma,a Satoshi Fujii,b Kiyoshi Tanakaa and Toshiyuki Kan*a
Received (in Cambridge, UK) 31st May 2006, Accepted 17th July 2006
First published as an Advance Article on the web 3rd August 2006
DOI: 10.1039/b607684j
The Heck reaction of an unsymmetrically substituted [3]cumu-
lene has been investigated. Although a carbonyl conjugated
alkene is present, the arylpalladium species selectively inserts
into the C3–4 double bond, and a subsequent C–H activation
reaction with a neighboring phenyl group gives the indene
derivatives with a tetrasubstituted olefin moiety.
Cumulene derivatives have attracted a lot of attention due to their
high reactivity and unique chemical behavior1 as nucleophiles,
electrophiles, and occasionally dienophiles. Most investigations on
reactivity have focused on symmetrically substituted cumulene
Fig. 1 Domino Heck–C–H activation reaction of 1.
derivatives possessing the same substituents on both sides of the
molecule,2,12 but reports on the reactivity of unsymmetrically
substituted cumulene derivatives are limited.3
and phenyl iodide with 10 mol% of Pd(OAc)2 and i-Pr2NEt,
the reaction proceeded smoothly to afford indene derivative 5a as
an E–Z mixture in 54% yield (entry 1). Using 2.0 equivalent of
phenyl iodide improved the chemical yield (entry 2),{ but adding
more phenyl iodide did not afford a remarkable improvement
(entry 3).8
We have recently demonstrated the reaction behavior of
2-methyl-5,5-diphenylpenta-2,3,4-trienal (1),4 a stable unsymme-
trically substituted [3]cumulene, in Diels–Alder (DA) and Friedel–
Crafts reactions.5 That study has revealed that the distinct double
bonds, which possess different electronic and steric properties,
show completely different reactivities. The DA reaction of 1 with
cyclopentadiene selectively occurs on the C2–3 double bond to
afford tetrasubstituted allenyl adducts. In sharp contrast, the
Friedel–Crafts reaction with electron-rich hetero-aromatics yields
tetrasubstituted conjugated dienes via a conjugate addition–
protonation on C3–4.
Table 1 Domino Heck–C–H activation reactions of cumulene 1
As part of our continuing investigations on the reaction
behavior of 1 in transition metal catalyzed transformations, we
have explored the Heck reaction. Initially, we expected a reactivity
similar to the DA reaction might provide allene 3 via insertion of
an arylpalladium species into the carbonyl conjugated C2–3
double bond6 (path a) and successive b-hydride elimination of 2.
However, the reaction unexpectedly afforded 2,3-diaryl indene
derivative 5. This product is explained by a reaction that proceeds
through a domino process, which includes the selective insertion of
the arylpalladium species at the C3–4 double bond (path b) and a
further C–H activation reaction7 with a neighboring phenyl moiety
to palladacycle 4 (Fig. 1). Herein, we report the details of this
domino Heck–C–H activation reaction.
Yielda Ratiob
Entry Ar-X
Equiv. t/h Product (%)
(Z : E)
1c
2
3
4
5
6
7
8
PhI
PhI
PhI
PhBr
1.0
2.0
3.0
1.0
2
1
1
3
1
1
1
1
5a
5a
5a
—
5b
5c
5d
5e
54
3.7 : 1.0
59 (69)d 3.6 : 1.0
61
—
46
39
66
55
3.4 : 1.0
—
3.6 : 1.0
2.4 : 1.0
4.3 : 1.0
2.7 : 1.0
R = OMe 2.0
R = OMs 2.0
R = NO2 2.0
R = Br
2.0
We initially surveyed the appropriate conditions for the Heck
reaction with a variety of aryl halides (Table 1). Upon treating 1
9
10
11
R = OMe 2.0
R = OMs 2.0
R = NO2 2.0
2
1
1
5f
5g
5h
47
62
47
2.3 : 1.0
2.3 : 1.0
2.5 : 1.0
aDepartment of Synthetic Organic & Medicinal Chemistry, School of
Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka,
422-8526, Japan. E-mail: furuta@u-shizuoka-ken.ac.jp;
kant@u-shizuoka-ken.ac.jp; Fax: +81-54-264-5745;
a
b
Isolated yields of E–Z mixtures. Determined by integration of the
Tel: +81-54-264-5742
bDepartment of Physical Biochemistry, School of Pharmaceutical
Sciences, University of Shizuoka, 52-1 Yada, Shizuoka, 422-8526, Japan
{ This paper is dedicated to the memory of the late Prof. Kiyoshi Tanaka,
who passed away December 8, 2004.
1H NMR spectrum. The reaction mixture was heated to 100 uC.
c
d
Calculated by integration of the 1H NMR spectrum of the crude
reaction material using dimethyl oxalate as an internal standard.
3648 | Chem. Commun., 2006, 3648–3650
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Functionalized phenyl iodides were also applied to this reaction
(entries 5–11). The reaction with p-methoxyphenyl iodide gave the
corresponding indene derivative 5b in 46% yield (entry 5).9 In
addition, aryl iodides with electron-withdrawing groups were
compatible. Although p-mesyloxyphenyl iodide gave a moderate
result (entry 6),9 a nitro substituent increased the yield to 66%
(entry 7). Because phenyl bromide did not react (entry 4), the
transformation with p-bromophenyl iodide afforded 5e without
bromo substituent loss (entry 8).
Aryl iodides with both electron-releasing and withdrawing
groups at the meta-position also yielded the corresponding
products in moderate yields (entries 9–11).
The aromatic region in the NMR spectra for products 5a–5h
was highly overlapped, which made structural confirmations and
stereochemistry determinations of the tetrasubstituted double
bond problematic. Therefore, we prepared cumulene 8, an
appropriate substrate for structural determination that produced
simple NMR signals for the domino products.
Scheme 2 NOE correlations of (E)- and (Z)-9.
Cumulene 8 was prepared in a similar manner to 1.4 Lithiation
of 2-methyl-1-butene-3-yne (6) with n-BuLi and subsequent
addition of 4,49-dimethylbenzophenone afforded the alkynyl
alcohol. Without further purification, oxidation of the double
bond with dimethyldioxirane gave alkynyl epoxide 7 in 74% yield
in two steps. Treatment of 7 with BF3?Et2O afforded desired
cumulene derivative 8 (Scheme 1).
As expected, the domino reaction of 8 with p-nitrophenyl iodide
proceeded smoothly to give an E–Z mixture of 9, which had much
simpler signals in the aromatic region than 5a due to both the
methyl and nitro substituents on the phenyl rings. Therefore, a
complete assignment of each signal was possible. The NOE
correlations between the aromatic (Ha) and the methyl protons
and between the aromatic (Hb) and the formyl proton clearly
indicate that the Z-isomer on the tetrasubstituted olefin is the
major product. On the other hand, NOEs between Hc and the
formyl proton, and between Hd and the methyl protons were
observed in the E-isomer (Scheme 2).
Fig. 2 ORTEP drawing of (Z)-9 with thermal ellipsoids at the 20%
probability level.
successively cyclized to give indene derivative 5 via reductive
elimination of the palladium intermediate.
It is noteworthy that the direction of addition of the
arylpalladium iodide to 1 is also regioselective, in which the
palladium(II) and aryl group are positioned at C3 and C4,
respectively, in 10.
Moreover, X-ray crystallographic analysis of 9, which includes
the stereochemistry, was unambiguously determined as shown in
Fig. 2.10§
Scheme 3 depicts a plausible mechanism for the domino Heck–
C–H activation reaction. The first crucial step of the Heck reaction
is insertion of arylpalladium iodide into the C3–4 double bond to
give intermediate 10.11,12 Because b-hydride elimination of 10 is
not accessible, C–H activation of the neighboring phenyl moiety
proceeds smoothly to afford six-membered palladacycle 4, which is
Scheme 1 Reagents and conditions: (a) n-BuLi, Et2O, 250 uC, 30 min,
then 4,49-dimethylbenzophenone, 250 uC, 24 h; (b) dimethyldioxirane, rt,
1 h, 74% (2 steps); (c) BF3?Et2O, THF, 278 uC, 3 h, 58%.
Scheme 3 Plausible reaction pathway of Heck–C–H activation reaction.
Chem. Commun., 2006, 3648–3650 | 3649
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R 5 0.1183, wR2[F2] 5 0.3072 for 833 unique reflections. CCDC 609878.
For crystallographic data in CIF or other electronic format see DOI:
10.1039/b607684j
Multiple aryl modified tetrasubstituted alkenes have attracted a
lot of attention as key structural elements for bioactive
compounds. One of the most prominent examples of such a
molecule is tamoxifen,13 which is a clinically used drug for breast
cancer. The Heck–C–H activation reaction of unsymmetrically
substituted cumulenes described here might be useful and valuable
for constructing such bioactive tetrasubstituted alkenes with
appropriate functional groups on both the aromatic and alkene
moieties. These bioactive tetrasubstituted alkenes may be key
substituents for the interaction with receptors and pivotal in
further chemical transformations. Moreover, products 5a–5h and 9
could be recognized as conformationally locked analogs of
tamoxifen, in which one of the aromatic rings is fixed as the
partial structure of the indene framework. Using these indene
derivatives as bioprobes for tamoxifen related nuclear receptor is
also interesting.
1 One of the most prominent examples is shown in the neocarzinostatin
chromophore in which the biradical species generated by a Bergman
type cycloaromatization of the enyne[3]cumulene plays a key role in its
potent anti-tumor activity. See: (a) I. Saito, K. Yamaguchi, R. Nagata
and E. Murahashi, Tetrahedron Lett., 1990, 31, 7469; (b) A. G. Myers
and P. S. Dragovich, J. Am. Chem. Soc., 1993, 115, 7021; (c) A. L. Smith
and K. C. Nicolaou, J. Med. Chem., 1996, 39, 2103.
2 (a) A. Roedig and G. Zaby, Chem. Ber., 1980, 113, 3342; (b)
J. K. Crandall, D. M. Coppert, T. Schuster and F. Lin, J. Am.
Chem. Soc., 1992, 114, 5998; (c) N. Suzuki, M. Nishiura and
Y. Wakatsuki, Science, 2002, 295, 660; (d) N. Suzuki, Y. Fukuda,
C. E. Kim, H. Takahara, M. Iwasaki, M. Saburi, M. Nishiura and
Y. Wakatsuki, Chem. Lett., 2003, 32, 16; (e) P.-H. Liu, L. Li, J. A. Webb,
Y. Zhang and N. S. Goroff, Org. Lett., 2004, 6, 2081.
3 (a) J. G. Garcia, B. Ramos, L. M. Pratt and A. Rodriguez, Tetrahedron
Lett., 1995, 36, 7391; (b) J. M. Aurrecoechea, E. Pe´rez and M. Solay,
J. Org. Chem., 2001, 66, 564. See also ref. 2a.
4 X. Wang, B. Ramos and A. Rodriguez, Tetrahedron Lett., 1994, 35,
6977.
In summary, we have found a unique Heck–C–H activation
reaction of 1, which provides indene derivatives with both a
functionalized aryl and tetrasubstituted alkene moieties.
Furthermore, studies which introduce heteroaromatics such as
indole and pyrrole to 1 as well as the biological evaluation of the
products are currently under investigation.
5 T. Asakawa, M. Iinuma, T. Furuta, S. Fujii, T. Kan and K. Tanaka,
Chem. Lett., 2006, 35, 512.
6 It has been reported that the carbonyl conjugated double bond is more
reactive than the sterically similar isolated double bonds toward the
Heck reaction. This suggests that the reactivity of the C2–3 double bond
might be higher than that of the C3–4 or C4–5 double bond in 1. See
R. F. Heck, Org. React., 1989, 27, 345.
Notes and references
7 For reviews on C–H activation reaction, see: (a) A. E. Shilov and
G. B. Shul’pin, Chem. Rev., 1997, 97, 2879; (b) S. Ma and Z. Gu,
Angew. Chem., Int. Ed., 2005, 44, 7512; (c) K. Godula and D. Sames,
Science, 2006, 312, 67.
8 Addition of a phosphine ligand such as P(o-tol)3 was ineffective.
9 Increasing the amount of aryl iodides to a ten times higher concentration
afforded biaryl derivatives 11 and 12 as side products.
{ Typical procedure for domino Heck–C–H activation reaction (Table 1,
entry 2):
Iodobenzene (91 mL, 0.81 mmol), Pd(OAc)2 (9.2 mg, 41 mmol), and
i-Pr2NEt (0.21 mL, 1.2 mmol) were added to a solution of 1 (100 mg,
0.41 mmol) in CH3CN (4 mL) under an argon atmosphere. The mixture
was stirred at 80 uC for 1 h and then evaporated. The mixture was washed
with saturated aqueous NH4Cl and brine, extracted with CH2Cl2, dried
over MgSO4, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (n-hexane–AcOEt, 9 : 1) to afford 2-
(2,3-diphenyl-1H-inden-1-ylidene)propanal (5a) (78 mg, 59%, E : Z 5 1.0 :
3.6) as a red solid.
Duplicate reaction was performed to obtain the conversion. The yield
was calculated by the 1H NMR integration of the crude residue using
dimethyl oxalate as an internal standard.
10 Considering that the chemical shift of the Z-isomer aldehyde proton
of 9 shifts to a higher-field compared to the corresponding E-isomer due
to the anisotropic shielding of the neighboring p-nitrophenyl moiety
(Fig. 2), the major isomer of 5a–5h should be the Z-isomer.
11 Allene derivative 3 was not observed, suggesting that the insertion of
arylpalladium iodide into the C2–3 double bond, which leads to
palladium intermediate 2, does not occur (Fig. 1).
12 Considering a previous report, in which the indene derivative was
prepared by a related Heck–C–H activation reaction of tetraphenylbu-
tatriene with phenyl iodide, the central and isolated C3–4 double bond
might be the most reactive in [3]cumulene derivatives in a Heck reaction.
See G. Dyker, S. Borowski, G. Henkel, A. Kellner, I. Dix and P.
G. Jones, Tetrahedron Lett., 2000, 41, 8259.
1H NMR (270 MHz, CDCl3, E–Z mixture): d 5 1.65 (E-isomer) (s,
CH3), 2.50 (Z-isomer) (s, CH3), 7.2–7.9 (m, Ar), 9.52 (Z-isomer) (s, CHO),
10.88 (E-isomer) (s, CHO). 13C NMR (68 MHz, CDCl3, E–Z mixture):
d 5 14.1, 14.2, 121.2, 121.4, 126.2, 126.4, 126.6, 126.8, 127.3, 127.5, 127.6,
127.8, 128.0, 128.1, 128.2, 128.3, 128.5, 128.6, 128.9, 129.1, 129.2, 129.5,
129.95, 130.00, 130.1, 132.3, 133.6, 136.7, 136.8, 137.4, 137.8, 143.6, 145.9,
152.0, 192.5, 193.0. IR (neat, cm21) 1659. FAB-MS m/z 323 (M + H)+. HR
MS calcd for C24H19O (M + H)+ 323.1436, found 323.1450.
§ Crystallographic data for 9: C26H21NO3, M 5 395.46, triclinic, space
¯
˚
˚
˚
˚
group P1 (#2), T 5 298 K, a 5 10.7108(14) A, b 5 11.2338(13) A,
˚
c 5 10.2696(12) A, a 5 96.444(10)u, b 5 110.963(9)u, c 5 110.197(9) A,
3
V 5 1043.0(2) A , Z 5 2, D 5 1.259 g cm , l (Cu Ka) 5 1.54178 A,
23
˚
13 A. S. Levenson and V. C. Jordan, Eur. J. Cancer, 1999, 35, 1628.
3650 | Chem. Commun., 2006, 3648–3650
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