Cross-coupling for cross-conjugation: Practical synthesis and Diels-Alder reactions of [3]dendralenes

Article abstract of DOI:10.1021/ol7021998

(Chemical Equation Presented) The parent [3]dendralene and 2-substituted [3]dendralenes are made easily through cross-coupling reactions. Contrary to some earlier reports, [3]dendralene is sufficiently stable to be handled using standard synthetic methods

Full text of DOI:10.1021/ol7021998

ORGANIC
LETTERS
2007
Vol. 9, No. 23
4861-4864
Cross-Coupling for Cross-Conjugation:
Practical Synthesis and Diels
−Alder
Reactions of [3]Dendralenes
Tanya A. Bradford,† Alan D. Payne,† Anthony C. Willis,†,‡
Michael N. Paddon-Row,*,§ and Michael S. Sherburn*,†,¶
Research School of Chemistry, The Australian National UniVersity,
Canberra ACT 0200, Australia, and School of Chemistry,
The UniVersity of New South Wales, Sydney, NSW 2052, Australia
sherburn@rsc.anu.edu.au (synthetic); m.paddonrow@unsw.edu.au (computational)
Received September 6, 2007
ABSTRACT
The parent [3]dendralene and 2-substituted [3]dendralenes are made easily through cross-coupling reactions. Contrary to some earlier reports,
[3]dendralene is sufficiently stable to be handled using standard synthetic methods. These compounds allow the one-step stereoselective
construction of polycyclic frameworks through reactions with dienophiles. Site selectivity and stereoselectivity in Diels−Alder reactions with
dienophiles are generally not influenced by the nature of the [3]dendralene’s 2-substituent; these features can, however, be influenced with
Lewis acids.
Dendralenes are acyclic cross-conjugated oligoalkenes with
great potential in synthesis.1 The preparation of the simplest
member of the family, [3]dendralene, 1, was first reported
in 1955.2 Some groups contend that the hydrocarbon is too
prone to polymerization to be synthetically useful.3 Other
groups have reported that [3]dendralene can be isolated,
participates in [4 + 2] cycloadditions with electron-poor
dienophiles at room temperature,4 and undergoes relatively
clean Diels-Alder dimerization at elevated temperatures.5
[3]Dendralene has eight sites for substitution and annel-
ation (Figure 1). Synthetic methods for the preparation of
[3]dendralenes monosubstituted at the central methylene (i.e.,
4) have been reported,6 and the synthetic potential of these
trienes has been exploited in elegant investigations by Fallis7
and others.8 Reports have also recently appeared on the
† The Australian National University.
§ The University of New South Wales.
¶ ARC Centre of Excellence for Free Radical Chemistry and Biotech-
nology.
‡ To whom correspondence should be addressed regarding X-ray crystal
structures. E-mail: willis@rsc.anu.edu.au.
(4) Cadogan, J. I. G.; Cradock, S.; Gillam, S.; Gosney, I. J. Chem Soc.,
Chem. Commun. 1991, 114-115.
(5) Trahanovsky, W. S.; Koeplinger, K. A. J. Org. Chem. 1992, 57,
4711-4716.
(1) (a) Hopf, H. In Organic Synthesis Highlights V; Schmalz, H.-G.,
Wirth, T., Eds.; Wiley-VCH: Weinheim, Germany, 2003; pp 419-427.
(b) Hopf, H. Classics in Hydrocarbon Chemistry: Syntheses, Concepts,
PerspectiVes; Wiley-VCH: Weinheim, Germany, 2000. (c) Hopf, H. Angew.
Chem., Int. Ed. 2001, 40, 705-707. (d) Hopf, H. Angew. Chem., Int. Ed.
Engl. 1984, 23, 948-960.
(2) (a) Blomquist, A. T.; Verdol, J. A. J. Am. Chem. Soc. 1955, 77, 81-
83. (b) Bailey, W. J.; Economy, J. J. Am. Chem. Soc. 1955, 77, 1133-
1136.
(6) (a) Woo, S.; Squires, N.; Fallis, A. G. Org. Lett. 1999, 1, 573-575.
(b) Chin, C. S.; Lee, H.; Park, H.; Kim, M. Organometallics 2002, 21,
3889-3896. (c) Miller, N. A.; Willis, A. C.; Paddon-Row, M. N.; Sherburn,
M. S. Angew. Chem., Int. Ed. 2007, 46, 937-940.
(7) (a) Woo, S.; Legoupy, S.; Parra, S.; Fallis, A. G. Org. Lett. 1999, 1,
1013-1016. (b) Clay, M. D.; Riber, D.; Fallis, A. G. Can. J. Chem. 2005,
83, 559-568.
(3) (a) Wada, E.; Nagasaki, N.; Kanemasa, S.; Tsuge, O. Chem. Lett.
1986, 1491-1494. (b) Hosomi, A.; Masunari, T.; Tominaga, Y.; Yanagi,
T.; Hojo, M. Tetrahedron Lett. 1990, 31, 6201-6204.
(8) (a) Kwon, O.; Park, S. B.; Schreiber, S. L. J. Am. Chem. Soc. 2002,
124, 13402-13404. (b) See ref 6c.
10.1021/ol7021998 CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/11/2007

either the union of ethenyl- and 1,3-butadien-2-yl units [Table
1, paths (i) and (ii)] or the functionalization of a pre-formed
[3]dendralene system [paths (iii) and (iv)].
Table 1. The Four Cross-Coupling Approaches to
2-Substituted [3]Dendralenes
Figure 1. The parent [3]dendralene and its three monosubstituted
analogues. The 2-substituted system (highlighted) is the subject of
the present study.
synthesis and cycloaddition reactions of [3]dendralenes
comprising endocyclic and semicyclic diene units.9-14 In
contrast, monosubstituted [3]dendralenes 2 and 3 are very
poorly represented in the literature.
In fact, none of the published reports of 2-substituted
[3]dendralenes 3 describe either general or practical
syntheses.15-24 Herein we describe straightforward procedures
for the multigram-scale synthesis of an extensive range of
2-substituted [3]dendralenes by way of Tamao-Kumada-
Corriu25,26 or Negishi27,28 cross-couplings. The routes involve
entry
product
3a
3b
3b
3b
3b
3c
3d
3e
3f
3g
1 (R ) H)
methoda
M
X
yield (%)
1
2
3
4
5
6
7
8
9
(i)
(i)
MgCl
MgCl
ZnBr
MgBr
ZnBr
MgBr
MgBr
ZnBr
MgCl
ZnBr
MgBr
Cl
Br
I
Cl
I
Cl
Cl
I
Br
Cl
Cl
65 (87b)
79
60
76
67
(31b)
68
40
38
40
(30b)
(ii)
(iii)
(iv)
(ii)
(iii)
(iv)
(i)
(9) (a) Bra¨se, S.; de Meijere, A. Angew. Chem., Int. Ed. Engl. 1995, 34,
2545-2547. (b) Bra¨se, S.; Wertal, H.; Frank, D.; Vidovic´, D.; de Meijere,
A. Eur. J. Org. Chem. 2005, 4167-4178.
(10) (a) Brummond, K. M.; Chen, H.; Sill, P.; You, L. J. Am. Chem.
Soc. 2002, 124, 15186-15187. (b) Brummond, K. M.; You, L. Tetrahedron
2005, 61, 6180-6185.
(11) Shibata, T.; Takesue, Y.; Kadowaki, S.; Takagi, K. Synlett 2003,
268-270.
10
11
(iv)
(ii)
(12) Kang, B.; Kim, D.-h.; Do, Y.; Chang, S. Org. Lett. 2003, 5, 3041-
3043.
(13) Ahmed, M.; Atkinson, C. E.; Barrett, A. G. M.; Malagu, K.;
Procopiou, P. A. Org. Lett. 2003, 5, 669-672.
(14) Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 1346-1352.
(15) Gajewski, J. J.; Shih, C. N. J. Org. Chem. 1972, 37, 64-68.
(16) Kleijn, H.; Westmijze, H.; Meijer, J.; Vermeer, P. Recl. TraV. Chim.
Pays-Bas 1983, 102, 378-380.
(17) Hopf, H.; Gottschild, D.; Lenk, W. Isr. J. Chem. 1985, 26, 79-87.
(18) Kanemasa, S.; Sakoh, H.; Wada, E.; Tsuge, O. Bull. Chem. Soc.
Jpn. 1985, 58, 3312-3319.
(19) Djahanbini, D.; Cazes, B.; Gore, J. Tetrahedron 1987, 43, 3441-
3452.
(20) Zefirov, N. S.; Kuznetsova, T. S.; Gromov, A. V.; Kozhushkov, S.
I.; Vatlina, L. P.; Kozlovskii, V. I. Zh. Org. Khim. 1990, 26, 1432-1437.
(21) Lukin, K. A.; Timofeeva, A. Y.; Zefirov, N. S. Zh. Org. Khim. 1990,
26, 1888-1891.
(22) Kimura, M.; Tanaka, S.; Tamaru, Y. J. Org. Chem. 1995, 60, 3764-
3772.
a Reagents and conditions. (i) and (iii): Ni(dppp)Cl2 (1-3 mol %), THF,
-20 to 25 °C, 2-20 h; (ii) and (iv): Pd(PPh3)4 (1-3 mol %), THF, -78
to 25 °C, 20 h. b Triene obtained as a solution in THF/light petroleum. Yield
1
estimated by H NMR spectroscopy.
Thus, [3]dendralenes substituted at the 2-position with
alkyl, halogen, aryl, alkoxy, and carboxy groups are readily
prepared by the simple cross-coupling procedures listed in
Table 1. Paths (iii) and (iv) require the key electrophile
2-chloro[3]dendralene 3a, which was prepared in high yield
by Tamao-Kumada-Corriu coupling between the chloro-
prene Grignard reagent 5 and excess 1,1-dichloroethylene 6
(X ) R ) Cl) (Table 1, entry 1). 2-Chloro[3]dendralene 3a
was readily converted into ca. 0.5 M THF solutions of its
corresponding Grignard reagent 11 (M ) MgCl) through
reaction with activated Mg powder. Attempts to generate
more concentrated solutions of this Grignard reagent were
met with dimerization of the chloride precursor. The organo-
zinc analogue 11 (M ) ZnBr) was accessed simply by
transmetalation of the Grignard reagent with zinc dibromide.
Dienic and trienic nucleophiles and electrophiles 5, 7, 9, and
(23) Liu, G.; Lu, X. Org. Lett. 2001, 3, 3879-3882.
(24) (a) Valentic´, N. V.; Vitnik, Z.; Kozhushkov, S. I.; de Meijere, A.;
Usˇc´umlic´, G. S.; Juranic´, I. O. J. Serb. Chem. Soc. 2003, 68, 67-76. (b)
Valentic´, N. V.; Usˇc´umlic´, G. S. J. Serb. Chem. Soc. 2003, 68, 525-534.
(c) Valentic´, N. V.; Vitnik, Z.; Kozhushkov, S. I.; de Meijere, A.; Usˇc´umlic´,
G. S.; Juranic´, I. O. J. Mol. Struct. 2005, 744-747, 901-908.
(25) (a) Corriu, R. J. P.; Masse, J. P. J. Chem. Soc., Chem. Commun.
1972, 144-144. (b) Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem.
Soc. 1972, 94, 4374-4376.
(26) Recent reviews: (a) Negishi, E.-i.; Zeng, X.; Tan, Z.; Qian, M.;
Hu, Q.; Huang, Z. Palladium- or Nickel-Catalyzed Cross-Coupling with
Organometals Containing Zinc, Aluminum, and Zirconium: The Negishi
Coupling. In Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de
Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, Germany, 2004;
Vol. 2, pp 815-889. (b) Knochel, P.; Sapountzis, I.; Gommermann, N.
Carbon-Carbon Bond-Forming Reactions Mediated by Organomagnesium
Reagents. In Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de
Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, Germany, 2004;
Vol. 2, pp 671-698. (c) Takahashi, T.; Kanno, K.-i. In Modern Organo-
nickel Chemistry; Tamaru, Y., Ed.; Wiley-VCH: Weinheim, Germany,
2005; Chapter 2, pp 41-55.
(28) Recent reviews: (a) Negishi, E.-i. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E.-i., Ed.; Wiley-Interscience:
New York, 2002; Vol. 1, Part III, pp 215-1119. (b) Knochel, P.; Calaza,
M. I.; Hupe, E. Carbon-Carbon Bond-Forming Reactions Mediated by
Organozinc Reagents. In Metal-Catalyzed Cross-Coupling Reactions, 2nd
ed.; de Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, Germany,
2004; Vol. 2, pp 619-670. (c) See ref 26a. (d) Negishi, E.-i.; Hu, Q.; Huang,
Z.; Qian, M.; Wang, G. Aldrichimica Acta 2005, 38, 71-88.
(27) King, A. O.; Okukado, N.; Negishi, E.-i. J. Chem. Soc., Chem.
Commun. 1977, 683-684.
4862
Org. Lett., Vol. 9, No. 23, 2007

11 require coupling partners, and the availability of such
compounds is a major factor in determining the synthetic
pathway of choice [Table 1, reactions (i)-(iv)]. For example,
some 2-substituted [3]dendralenes are most easily accessed
through path (iii) (Table 1, entries 4 and 7). In cases where
path (iii) would require a nucleophile with functionality
incompatible with a Grignard reagent, path (iv) is the method
of choice (Table 1, entries 8 and 10). A direct comparison
of the four approaches (Table 1, entries 2-5) demonstrates
that 2-phenyl[3]dendralene 3b can be made with roughly the
same ease.
Table 2. Diels-Alder Reactions of 2-Substituted
[3]Dendralenes with N-Methylmaleimidea
Since it is evident that some cross-conjugated oligoalkenes
are more stable than others,29 the thermal stability of these
[3]dendralenes was investigated. It was found that the parent
[3]dendralene 1 and its 2-substituted congeners 3a-g can
be handled in the laboratory without special precautions.
These compounds can be stored neat or in solution at
-20 °C for several weeks. The degradation half-lives of
these dendralenes at 120 °C were found to be in the range
of 1-30 h.30
Thus far, the main synthetic interest in [3]dendralenes
stems from their participation in diene-transmissive Diels-
Alder (DTDA) sequences.31 This involves the cycloaddition
of a dienophile to one of the [3]dendralene’s conjugated
butadienes, which in turn generates a new semicyclic 1,3-
diene capable of undergoing a second cycloaddition event
to generate a decalin ring system. 2-Substituted [3]den-
dralenes are interesting since there is an issue of site
selectivity in their cycloadditions with dienophiles (Table
2). In the only previous report of a 2-substituted [3]den-
dralene reacting with dienophiles, Tsuge observed a single
product 14f, when 3f was treated with N-methylmaleimide
(NMM).18 Would the nature of the 2-substituent influence
the site selectivity of dienophile addition to a [3]dendralene?
In our hands, when exposed to excess NMM at room
temperature, trienes 3 furnished a mixture of three prod-
ucts: diastereomeric bisadducts 14 and 15, and monoadduct
16.32 The bisadducts result from an initial addition to the
less substituted 1,3-butadiene moiety of 3 (i.e., diene A),
and the monoadduct 16 is the product of addition to the more
substituted diene of 3 (i.e., diene B). Bisadduct 14 was the
major product from all these reactions, irrespective of the
nature of the substituent. The π-diastereofacial selectivity
seen during the conversion of 13 f 14 + 15 is in the range
of 5:1 f 9:1. As is evident upon following these reactions
entry
R
14:15:16
yield (%)
1
2
3
4
Cl
Ph
Me
61:12:27
58:6:36
56:8:36
65:7:28
65:7:28
81:10:9
68:8:24
90:10:0
65
90
64
67
90
41
66
66
p-(MeO)C6H4
p-(NO2)C6H4
OEt
CO2Me
H
5
6b
7
8c
a Triene 3 (1 molar equiv), NMM (5 molar equiv), CHCl3, 25 °C, 18 h.
b Triene 3 (1 molar equiv), NMM (5 molar equiv), CaH2 (0.33 mol equiv),
CH2Cl2, 25 °C, 72 h. Tsuge reports a single product 14f for this reaction.18
c Cadogan reports a single product 14h for the reaction between [3]den-
dralene (1) and (N-H)-maleimide.4
Thus, NMM addition to diene A occurs with similar ease to
the addition to its daughter adduct 13. At ambient temper-
ature and pressure, monoadduct 16, with its inside diene
substituent, resists further reaction. Compound 16d can be
coerced into cycloaddition with NMM at high pressure (19
kbar, 25 °C), however, to give the two diastereomeric
bisadducts 17d and 18d (83%, 17d:18d ) 70:30).
1
by H NMR, triene 3, monoadduct 13, and bisadducts 14
and 15 are all present in the reaction mixture, even after the
consumption of relatively small amounts (ca. 10%) of 3.
It is clear from inspection of the data presented in Table
2 that the diene site selectivity of 2-substituted [3]dendralenes
is not significantly influenced by the nature of the substituent.
In their study with 2-ethoxy[3]dendralene, Tsuge et al.18
suggest that the preference for dienophile addition to the less
substituted diene is the result of a ground state destabilization
of the s-cis conformation of the 2,3-disubstituted diene of
dendralene 3f. Computational modeling of the reaction of
2-chloro[3]dendralene (3a) with NMM at the B3LYP/6-
31G(d) level of theory shows that the ground state interaction
identified by Tsuge operates in the transition state. Four
(29) (a) We recently demonstrated that [4]dendralene (i.e., 2-vinyl[3]-
dendralene) is stable: Payne, A. D.; Willis, A. C.; Sherburn, M. S. J. Am.
Chem. Soc. 2005, 127, 12188-12189. (b) Some other substituted [3]den-
dralenes readily polymerize: Nu¨ske, H.; Bra¨se, S.; Kozhushkov, S. I.;
Noltemeyer, M.; Es-Sayed, M.; de Meijere, A. Chem.sEur. J. 2002, 8,
2350-2369.
(30) Solutions (0.2 M) of dendralenes in C6D6 containing an internal
standard were held at 120 °C in sealed tubes. Consumption of the triene
1
was measured by H NMR analysis.
(31) For a review of sequences of Diels-Alder reactions, see: Winkler,
J. D. Chem. ReV. 1996, 96, 167-176.
(32) Where detectable, all cycloadditions involving NMM dienophiles
were found to proceed exclusively through the endo-mode.
Org. Lett., Vol. 9, No. 23, 2007
4863

endo-transition structures (TSs) for each of the two possible
diene sites were located, all of which differ in the conforma-
tion of the olefinic substituent about the 1,3-butadiene
reaction site. The lowest free energy (298 K) TS for initial
cycloaddition to (2-chlorovinyl)butadiene A and to (2-chloro-
3-vinyl)butadiene B are depicted in Figure 2.
reactions of 2-substituted [3]dendralenes, these features can
be manipulated by altering the reaction conditions (Scheme
1). Thus, whereas the treatment of 3b with NMM gave 14b,
Scheme 1. Effect of Lewis Acids on Selectivity of the Diels-
Alder Reaction of 2-Phenyl[3]dendralene (3b) with NMM
Figure 2. B3LYP/6-31G(d) optimized Diels-Alder endo-TSs for
cycloadditions of NMM to diene A (left) and diene B (right) of
2-chloro[3]dendralene (3a). NMe H atoms have been omitted for
clarity. All distances are in angstroms.
15b, and 16b in a 58:6:36 ratio (Table 2, entry 2), exposure
to NMM•2EtAlCl2 results in two products, 14b and 15b, in
a ratio of 33:66. Hence, complete site selectivity for the less
substituted diene of the cross-conjugated triene is achieved
by promoting the cycloaddition with EtAlCl2. Furthermore,
the Lewis acid brings about a reversal of the inherent
π-diastereofacial selectivity of the second cycloaddition.
Investigations into both the origins and applications of these
intriguing findings are underway.
The nonparticipating olefinic substituents in both TSs are
twisted out-of-plane with respect to the attached double bond
component of the reacting diene. It is noteworthy that the
nonreacting 1,3-butadiene moieties adopt skewed s-cis
conformations.33 The free energy (298 K) of the TS involving
diene A is 4.9 kJ mol-1 lower than that of diene B, which
equates to a predicted product ratio of 88:12 (coincidentally,
inclusion of all eight TSs gives the same product ratio). This
value is in fair agreement with the experimentally determined
ratio of 73:27 (Table 2, entry 1). Inspection of the nonbond-
ing Cl‚‚‚H/C distances between C2 and C3 butadiene
substituents (depicted in blue in Figure 2) suggests that the
TS involving diene B (on the right) suffers greater steric
congestion compared to diene A.34 Evidently, the electronic
influences of the substituents examined in the present study
do not overcome this steric effect.
Acknowledgment. Funding from Australian Research
Council (ARC) is gratefully acknowledged, as are generous
computing time allocations from the Australian Partnership
for Advanced Computing (APAC) and the Australian Centre
for Advanced Computing and Communications (ac3).
Supporting Information Available: Full experimental
procedures; computational details; atomic displacement el-
lipsoid plots for compounds 14a and 14d (CCDC numbers
1
654085 and 654086, respectively); H and/or 13C NMR
spectra of compounds 1, 3a-g, 13a,b,d, 14a-h, 15a-h,
16a-g, 17d, and 18d. This material is available free of
charge via the Internet at http://pubs.acs.org.
While the nature of the substituent does not significantly
influence the site selectivity or stereoselectivity of the DTDA
OL7021998
(33) Tsuge and co-workers propose a skewed s-trans conformation of
the nonreacting 1,3-butadiene moiety.18 Gas phase electron diffraction
measurements indicate that [3]dendralene adopts a conformation consisting
of a planar s-trans-1,3-butadiene with the 2-vinyl group skewed 40° out of
plane: Almenningen, A.; Gatail, A.; Grace, D. S. B.; Hopf, H.; Klaeboe,
P.; Lehrich, F.; Nielsen, C. J.; Powell, D. L.; Tratteberg, M. Acta Chem.
Scand. 1988, A42, 634-650. [4]Dendralene behaves similarly, adopting
an s-trans, s-trans, skew conformation according to calculations: Palmer,
M. H.; Blair-Fish, J. A.; Sherwood, P. J. Mol. Struct. 1997, 412, 1-18.
(34) Although the Cl‚‚‚H and Cl‚‚‚C distances in the two TSs depicted
in Figure 2 are not strikingly different, significantly stronger steric
compression energy will develop in the TS involving addition to diene B
(right) compared to diene A (left). This is because the interatomic distances
lie within the sum of the van der Waals radii: Cl + C ) 3.8 Å and Cl +
H ) 3.0 Å. Thus, the distances lie on the steep side of the van der Waals
curve, and only a small change in distance can lead to a large change in
energy.
4864
Org. Lett., Vol. 9, No. 23, 2007