Practical synthesis and reactivity of [3]dendralene

Article abstract of DOI:10.1021/jo9024557

(Chemical Equation Presented) Aconvenient and high-yielding three-step synthesis of the simplest branched triene, [3]dendralene, has been devised. The synthesis is robust and operationally simple, requiring no chromatography and involving no protecting gr

Full text of DOI:10.1021/jo9024557

pubs.acs.org/joc
synthetic route of the parent [3]dendralene 1 in solvent-free
Practical Synthesis and Reactivity of [3]Dendralene
form. We identify the mode of decomposition of the hydro-
carbon as a neat liquid, and its participation in new
Diels-Alder reactions and domino Diels-Alder sequences.
For more than 50 years the synthesis of 1 focused on
pyrolytic elimination methods (Scheme 1). The original pre-
paration by Blomquist and Verdol involved the flow tube
pyrolysis of a diacetate precursor at 485 °C.5 A short time later,
a significantly higher yielding procedure was reported by
Bailey and Economy involving pyrolysis of a triacetate pre-
cursor at 540 °C,6 which was later optimized (900 °C) by
Trahanovsky.7 The hydrocarbon has also been prepared
by pyrolysis of 1,2-di(acetoxymethyl)cyclobutane at 450-
485 °C;8 through Hoffman elimination of a tris(trimethyl-
ammonium hydroxide) precursor at 180 °C/12 Torr;9 by
electrocyclic ring-opening of vinyl cyclobutene at 335 °C;10
Tanya A. Bradford,† Alan D. Payne,† Anthony C. Willis,†
Michael N. Paddon-Row,*,‡ and Michael S. Sherburn*,†
†Research School of Chemistry, 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; m.paddonrow@unsw.edu.au
Received November 16, 2009
SCHEME 1. Existing Synthetic Routes to the Simplest Acyclic,
Branched Triene 1a
A convenient and high-yielding three-step synthesis of the
simplest branched triene, [3]dendralene, has been devised.
The synthesis is robust and operationally simple, requir-
ing no chromatography and involving no protecting
groups or specialized equipment, allowing the synthesis
of the volatile hydrocarbon in pure, solvent free form on a
multigram scale. The stability, dimerization when stored
neat, and Diels-Alder reactivity of [3]dendralene
including double cycloaddition sequences and catalytic
;
enantioselective variant are reported.
;
Dendralenes are acyclic, branched oligo-alkenes with
essentially untapped potential in synthesis.1 We recently
reported multigram scale synthetic preparations and char-
acterizations of [4]-, [5]-, [6]-, [7]-, and [8]dendralenes, and we
demonstrated that this family of fundamental hydrocarbons
exhibit alternation in behavior.2 In addition, we have shown
that both [4]dendralene3 and [5]dendralene4 serve as precur-
sors to polycyclic structures with natural product-like com-
plexity, through their propensity to undergo domino
sequences of pericyclic reactions. Herein we disclose a new
aSome yields are not disclosed in the original publications.
by acid-catalyzed elimination of a chloroether precursor at
140-160 °C;11 and by pyrolysis of 3-vinyl-3-sulfolene at 55012
(5) Blomquist, A. T.; Verdol, J. A. J. Am. Chem. Soc. 1955, 77, 81–83.
(6) Bailey, W. J.; Economy, J. J. Am. Chem. Soc. 1955, 77, 1133–1136.
(7) Trahanovsky, W. S.; Koeplinger, K. A. J. Org. Chem. 1992, 57, 4711–
4716.
*To whom correspondence should be addressed: M.S.S., synthetic;
M.N.P.-R., computational.
(8) (a) Blomquist, A. T.; Verdol, J. A. J. Am. Chem. Soc. 1955, 77, 1806–
1809. (b) Bailey, W. J.; Cunov, C. H.; Nicholas, L. J. Am. Chem. Soc. 1955,
77, 2787–2790.
(1) Reviews: (a) Hopf, H. Angew. Chem., Int. Ed. Engl. 1984, 23, 948–
960. (b) Hopf, H. Classics in Hydrocarbon Chemistry: Syntheses, Concepts,
Perspectives; Wiley-VCH: Weinheim, Germany, 2000; pp 253-260. (c) Hopf, H.
Angew. Chem., Int. Ed. 2001, 40, 705–707. (d) Hopf, H. In Organic Synthesis
Highlights V; Schmalz, H.-G., Wirth, T., Eds.; Wiley-VCH: Weinheim, Germany,
2003; pp 419-427.
ꢀ
(9) Martin, H.-D.; Eckert-Maksic, M.; Mayer, B. Angew. Chem., Int. Ed.
Engl. 1980, 19, 807–809.
(10) Vdovin, V. M.; Finkel’shtein, E. Sh; Shelkov, A. V.; Yatsenko, M. S.
Russ. Chem. Bull. 1986, 35, 2364–2366.
(11) Marathon Oil Co., Findlay, Ohio. Synthesis of Polyene Derivatives.
Netherlands Appl. NL6607062, Nov 25, 1966; Chem. Abstr. 1967, 66,
104644.
(2) Payne, A. D.; Bojase, G.; Paddon-Row, M. N.; Sherburn, M. S.
Angew. Chem., Int. Ed. 2009, 48, 4836–4839.
(3) Payne, A. D.; Willis, A. C.; Sherburn, M. S. J. Am. Chem. Soc. 2005,
127, 12188–12189.
(12) Cadogan, J. I. G.; Cradock, S.; Gillam, S.; Gosney, I. J. Chem. Soc.,
Chem. Commun. 1991, 114–115.
(4) Bojase, G.; Payne, A. D.; Willis, A. C.; Sherburn, M. S. Angew. Chem.,
Int. Ed. 2008, 47, 910–912.
(13) Fielder, S.; Rowan, D. D.; Sherburn, M. S. Angew. Chem., Int. Ed.
2000, 39, 4331–4333.
DOI: 10.1021/jo9024557
r
Published on Web 12/11/2009
J. Org. Chem. 2010, 75, 491–494 491
2009 American Chemical Society

Bradford et al.
JOCNote
and 450 °C.13 Hopf devised a route to 1 through the inter-
mediacy of 2-ethynyl-1,3-butadiene, which in turn was pre-
pared through both pyrolytic dehydration of an alcohol
precursor over molecular sieves (300 °C)14 and an ingenious
rearrangement of an allenyne isomer (500 °C).15
Since these syntheses require somewhat specialized labo-
ratory techniques and, in some cases, quite lengthy stepwise
syntheses of precursors, we recently developed one-step,
cross-coupling approaches to [3]dendralene 1 from commer-
cially available starting materials (chloroprene and vinyl
bromide) using standard laboratory methods.16 Despite
their simplicity and brevity, these recent approaches have
the drawback that they allow access to the hydrocarbon only
as a solution in THF. In light of the obvious need for solvent-
free, multigram samples of the hydrocarbon, we devised a
simple new route to [3]dendralene that employs standard
laboratory equipment. The new preparation of [3]dendra-
lene 1 is depicted in Scheme 2.
is stable and easily handled.12 In fact, the perceived instability
of the hydrocarbon has led to the development of synthetic
equivalents of the triene.19 To our knowledge, experimental
findings relating to the propensity of 1 to undergo dimerization
and/or polymerization have been reported in three papers.
In the first,5 1 was reported to form a gelatinous mass on storage
for 36 h at -5 °C and was also said to form a liquid dimer
(structure not identified) on standing at room temperature for
2 days. The second report noted the dimerization of the hydro-
carbon both during its formation through pyrolysis and
distillation (structure not identified).6 Trahanovsky7 describes
0.1-0.4 M solutions of the hydrocarbon in benzene as reason-
ably stable at room temperature and a dimerization in these
solutions over 22 h at 95 °C to produce a mixture of five
compounds. This last report identifies 6 as the major dimer.7
Since no data have been reported on the stability of the parent
hydrocarbon as a pure compound, we placed neat samples of
[3]dendralene in sealed glass ampules at 25 °C and its disap-
pearance was monitored by 1H NMR spectroscopy. Under these
conditions, [3]dendralene has a half-life of ca. 10 h and undergoes
a relatively clean dimerization to form Trahanovsky’s [4þ2]
adduct 6in 80% isolated yield after 4 weeks at room temperature
(Scheme 3).
SCHEME 2. The New Synthesis of [3]Dendralene
SCHEME 3. The Dimerization of [3]Dendralene
This approach is conceptually similar to our earlier, one-
step cross-coupling protocols in that it involves the union
of two and four carbon fragments, namely 2 and 3. The
alcohol 4, prepared according to the protocol described by
Nunomoto,17 and known18 bromide 5, can be stored over
extended periods without significant decomposition. The
triene-forming elimination step (5 f 1) is carried out by slow
addition of DBU to a solution of the bromide in DMSO held
at room temperature under a modest vacuum; the triene
distills as it is formed and is collected in a cold trap (see the
Experimental Section for details). We have prepared up to
5-g batches of the hydrocarbon of high (>95%) purity in this
manner. Due to the relatively unstable nature of the hydro-
carbon when stored neat (vide infra), we prescribe the
synthesis and storage of the bromide precursor 5 on large
scale and the conversion of this compound into 1 as required.
Nevertheless, when stored in ca. 1 M solutions in common
organic solvents, 1 was found to undergo only slight (<10%)
decomposition over a one-month period in a -20 °C freezer.
Contrasting reports on the stability of 1 have been re-
ported in the literature. Some have suggested that the
hydrocarbon is too prone to polymerization for it to be
synthetically useful19 and another notes that the compound
In principle, four distinct isomeric adducts may be formed,
6-9 (Scheme 4), which arise from permutations of the two
aspects of regioselectivity, specifically site selectivity and
orientational selectivity. Thus, either the inner (I) or outer
(O) alkene site of 1 can function as the dienophile, and the
dienophile and diene substituents can orient in either a
“para” (P) or “meta” (M) sense in the product. The reason
why 6 is the favored adduct may be nicely understood in
terms of a straightforward qualitative mechanistic analysis
advanced by Dewar et al.,20 which is remarkably successful
in predicting substituent effects on the regioselectivity of
Diels-Alder reactions. In this analysis, the Diels-Alder
transition state (TS) involving unsymmetrically substituted
diene and dienophile components is highly asynchronous
and has strong biradicaloid character. Consequently, it is
permissible, for qualitative purposes, to approximate the
biradicaloid TSs with the biradicals themselves, in which
case, the most favored TS is predicted to be that which
corresponds to the most stable biradical. Application of
the Dewar analysis to the [3]dendralene dimerization leads
to a comparison of the relative delocalization energies in the
four TS biradical analogues IP-Birad, IM-Birad, OP-Birad,
and OM-Birad (Scheme 4). IP-Birad is predicted to be the
most stable species because it possesses a pair of delocalized
pentadienyl radicals, whereas the others have either one
(IM-Birad and OP-Birad) or two (OM-Birad) less stable
allyl radicals.
(14) Priebe, H.; Hopf, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 286–287.
€
(15) Bader, H.; Hopf, H.; Jager, H. Chem. Ber. 1989, 122, 1193–1198.
(16) Bradford, T. A.; Payne, A. D.; Willis, A. C.; Paddon-Row, M. N.;
Sherburn, M. S. Org. Lett. 2007, 9, 4861–4864.
(17) Nunomoto, S.; Kawakami, Y.; Yamashita, Y. J. Org. Chem. 1983,
48, 1912–1914.
(18) Archer, D. A.; Bromidge, S. M.; Sammes, P. G. J. Chem. Soc., Perkin
Trans. 1 1988, 3223–3228.
(19) (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.
(20) Dewar, M. J. S.; Olivella, S.; Stewart, J. J. P. J. Am. Chem. Soc. 1986,
108, 5771–5779.
(21) This term was coined by Tsuge: Tsuge, O.; Wada, E.; Kanemasa, S.
Chem. Lett. 1983, 12, 239–242.
492 J. Org. Chem. Vol. 75, No. 2, 2010

Bradford et al.
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SCHEME 4. Qualitative Dewar Mechanistic Analysis of the
Dimerization of [3]Dendralenea
TABLE 1. DTDA Sequence of [3]Dendralene 1 with Maleimide
Dienophiles 10
entry
R
product ratio 11:12
isolated yield (%)
a
b
c
H
Me
Ph
87:13
90:10
91b:9
96:4
50a
66
91
80
d
t-Bu
aYield over two steps: N-H-maleimide adducts were converted
(K2CO3, MeI) into N-Me derivatives to assist isolation. X-ray of 11c
in SI.
b
SCHEME 5. Selective Monocycloadditions of 1 with Maleimide
Dienophiles 10
aThe asynchronous, biradicaloid TSs may be approximated by the
corresponding biradicals (Birad structures in center).
[3]Dendralene has been shown to undergo double
(diene-transmisive)21,22 cycloaddition reactions with maleic
anhydride,5,6 various quinones,6,12 N-phenyl-1,2,4-triazo-
line-3,5-dione,12 dimethylacetylenedicarboxylate,12 and male-
imide.12 The stereoselectivity of the last of these transforma-
tions is the only one previously reported: a single diastereomer
11a was reported from this reaction in 65% yield, with
product stereochemistry assigned on the basis of NOE data.
In our hands, under the reported conditions, an 87:13 mix-
ture of two diastereomers is generated from the reaction of
maleimide with [3]dendralene. The major diastereomer 11a
results from an endo-mode approach of the second male-
imide dienophile to the less sterically encumbered π-diastereo-
face of the bicyclic monoadduct. As might be anticipated, the
π-diastereofacial selectivity of this reaction is progre-
ssively improved in the dienophile series maleimide 10a <
N-methylmaleimide 10b < N-phenylmaleimide 10c < N-tert-
butylmaleimide 10d (Table 1). These reactions demonstrate
that, despite its propensity to react as a dienophile in dimeriza-
tion reactions, the hydrocarbon prefers to react with a more
activated, electron poor dienophile.
[3]Dendralene has also been shown to undergo a single
cycloaddition reaction with tetracyanoethylene in 92% yield,
followed by a second addition with PTAD.12 We find that
maleimide dienophiles 10 also participate in selective mono-
additions to [3]dendralene 1 in ca. 60-80% isolated yields by
mixing stoichiometric amounts of the hydrocarbon and
dienophile in toluene at ambient temperature (Scheme 5).
Evidently, monoadducts of [3]dendralene 13 are less reactive
toward dienophiles than is the triene.
TABLE 2. Monoaddition Reactions of [3]Dendralene 1 with Unsym-
metrical Dienophiles 14
entry
dienophile 14
yield (%)
a
b
c
d
e
R = OMe, R0 = H
R = Ot-Bu, R0 = H
R = OMe, R0 = Me
R = OEt, R0 = Me
R = Et, R0 = H
85
46
79
75
62
selective monoadditions to 1, resulting in the formation of
substituted semicyclic dienes 15, even in the presence of
excess dienophile (Table 2). In all cases, only the expected
“para” regiosiomer was detected.
The successful extension of these findings into an enantio-
selective process is presented in Scheme 6, wherein 16, amodified
version23 of Corey’s oxazaborolidinium catalysts,24 promotes
the monocycloaddition of methyl acrylate 14a to[3]dendralene1
(23) Catalyst 16, carrying 3,5-dimethoxyphenyl groups, has been found
to deliver higher enantioselectivities in Diels-Alder reactions than the
corresponding phenyl and 3,5-dimethylphenyl systems introduced by Corey:
Kwan, L. C. H.; Paddon-Row, M. N.; Sherburn, M. S.Unpublished results.
Once again, we find SnCl4 a useful Lewis acid activator of the oxazaboro-
lidine (see ref 26).
With the less reactive dienophiles methyl and tert-butyl
acrylate, methyl and ethyl methacrylate, and ethyl vinyl
ketone, 14a-e, Lewis acid activation also brings about
(22) For a review, see: Winkler, J. D. Chem. Rev. 1996, 96, 167–176.
(24) Corey, E. J. Angew. Chem., Int. Ed. 2009, 48, 2100–2117.
J. Org. Chem. Vol. 75, No. 2, 2010 493

Bradford et al.
SCHEME 7. Sequential DTDA Processes Involving
[3]Dendralene 1
JOCNote
SCHEME 6. Enantioselective Oxazaborolidinium Cation-
Catalyzed Diels-Alder Addition of [3]Dendralene 1 to Methyl
Acrylate 14a and Model Transition Structurea
aThis TS is based on the fully optimized TS for addition of butadiene to
methyl acrylate, to which the additional vinyl group in [3]dendralene has
been attached, without further optimization of the resulting structure.
Ar = 3,5-dimethoxyphenyl.
to form adduct 17 in a respectable 86% yield and 92% ee. The
absolute configuration of the major product 17 is assigned
on the basis of the pre-TS model proposed by Corey et al.,25
which has been verified by reliable quantum chemical calcula-
tions.26,27 A model TS for this cycloaddition is depicted in
Scheme 6. It is based on the B3LYP/6-32G(d)-optimized TS
for addition of butadiene to methyl acrylate27 and a vinyl group
has been attached to the butadiene moiety at the “para” position
with respect to the ester substituent. The marked bond-forming
asynchronicity is clearly evident in the case of butadiene, one
findings set the scene for applications of new DTDA additions
in synthesis: proof-of-principle results are depicted in
Scheme 7, which demonstrate the rapid stereoselective con-
struction of functionalized decalin frameworks 18 and 19.
Experimental Section
[3]Dendralene (1). DBU (15.0 mL, 101 mmol, 3.2 equiv) was
added dropwise to a stirred solution of 5-bromom-3-ethylene-
pent-1-ene 518 (5.0 g, 31 mmol, 1.0 equiv) in anhydrous DMSO
(12.5 mL) at room temperature under nitrogen. The flask was
equipped with a short path distillation apparatus and the
receiver flask was cooled to -78 °C. After 15 min, a vacuum
(60 mmHg) was applied for 1 h before increasing the vacuum (20
mmHg) for an additional hour. [3]Dendralene 1 was collected in
the cold trap as a colorless oil (2.0 g, 79%). The hydrocarbon is
stored as a 1 M PhMe or CH2Cl2 solution at -20 °C if not used
immediately. Characterization data for 1 matched those pre-
viously reported.13 1H NMR (300 MHz, CDCl3) δ 6.45 (2 H, dd,
J = 17.4, 11.1 Hz), 5.41 (2 H, br d, J = 17.4 Hz), 5.15 (2 H, br d,
J = 11.1 Hz), 5.15 (2 H, br s) ppm; 13C NMR (75 MHz, CDCl3)
δ 135.9 (C), 115.8 (2 ꢀ CH), 115.6 (2 ꢀ CH2), 110.5 (CH2) ppm.
˚
forming bond being advanced over the other by about 0.9 A.
Placement of the vinyl substituent at C2 of the diene will stabilize
the developing cationic charge in the diene component in the TS,
whereas attaching it at C3 will lead to little stabilization. This
explanation of orientational selectivity in Lewis acid promoted
reactions between 14 and 1 is analogous to that proposed above
for [3]dendralene dimerization, except that in this case it is more
appropriate to consider zwitterionic TS analogues rather than
biradical ones.
In summary, a new synthesis of [3]dendralene has been
developed. The approach allows access to solvent-free, multi-
gram quantities of the pure hydrocarbon without the need for
specialized equipment. The hydrocarbon undergoes relatively
clean Diels-Alder dimerization at ambient temperature when
stored neat. It also undergoes selective single and double
cycloaddition reactions with a wide range of alkenic dieno-
philes under catalyzed and uncatalyzed conditions. These
Acknowledgment. Funding from the Australian Research
Council (ARC) is gratefully acknowledged. We thank
Laurence C. H. Kwan (Australian National University) for a
sample of catalyst 16. M.N.P.-R. acknowledges computing
time from the Australian Partnership for Advanced Comput-
ing (APAC) awarded under the Merit Allocation Scheme.
(25) Ryu, D . H.; Lee, T. W.; Corey, E. J. J. Am. Chem. Soc. 2002, 124,
9992–9993.
(26) Paddon-Row, M. N.; Kwan, L. C. H.; Willis, A. C.; Sherburn, M. S.
Angew. Chem., Int. Ed. 2008, 47, 7013–7017.
(27) Paddon-Row, M. N.; Anderson, C. D.; Houk, K. N. J. Org. Chem.
2009, 74, 861–868.
Supporting Information Available: Experimental proce-
1
dures and characterization data, including H and 13C NMR
spectra, for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
494 J. Org. Chem. Vol. 75, No. 2, 2010