Intermolecular Diels-Alder Cycloaddition/Cross-Coupling Sequences of 2-Bromo-1,3-butadienes

Article abstract of DOI:10.1021/acs.orglett.9b04567

2-Bromo-1,3-butadienes are demonstrated to be effective substrates for tandem Diels-Alder/transition metal cross-coupling reaction sequences. Intermolecular cycloaddition of a 2-bromo-1,3-diene with activated dienophiles proceeded under Lewis acid catalys

Full text of DOI:10.1021/acs.orglett.9b04567

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Letter
Intermolecular Diels−Alder Cycloaddition/Cross-Coupling
Sequences of 2‑Bromo-1,3-butadienes
∥
∥
̈
Hans Choi, Harry J. Shirley, Harry R. M. Aitken, Tim Schulte, Tilo Sohnel, Paul A. Hume,
Margaret A. Brimble,* and Daniel P. Furkert*
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ABSTRACT: 2-Bromo-1,3-butadienes are demonstrated to be
effective substrates for tandem Diels−Alder/transition metal cross-
coupling reaction sequences. Intermolecular cycloaddition of a 2-
bromo-1,3-diene with activated dienophiles proceeded under Lewis
acid catalysis in generally high yields with good to excellent endo
diastereoselectivity. The resulting vinyl bromide cycloadducts
underwent subsequent Stille and Suzuki cross-couplings under standard conditions in good yields. Both the Diels−Alder and
cross-coupling steps were highly tolerant of a range of functionalities and protecting groups. The use of the bromine substituent as
both a cycloaddition directing group and cross-coupling nucleofuge avoids extra steps required to install and remove the more
commonly used silyl enol ethers and enol sulfonates for each transformation and gives full control of the alkene regiochemistry
throughout the reaction sequence. The 2-bromo-1,3-dienes were conveniently prepared in three steps from readily available
aldehydes and established as hydrolytically stable and practical synthetic intermediates.
iels−Alder cycloaddition1 is a powerful synthetic tool for
subsequent conversion to an enol sulfonate cross-coupling
partner.
2
Dthe stereoselective construction of complex structures.
In principle, 2-halogenated 1,3-butadienes are viable
substrates for tandem Diels−Alder/cross-coupling sequences;
vinyl halides are standard substrates for transition-metal-
catalyzed cross-coupling, and some Diels−Alder reactions of
halogenated dienes are known. The latter include examples
involving 2-chloro-1,3-butadienes11 or chloro- or iodo-
substituted heterocyclic dienes.12 Cycloadditions of bromi-
nated 1,3-butadienes are more widely reported, often in the
context of brominated heterocyclic dienes13 or the intra-
molecular Diels−Alder (IMDA) reactions of brominated
trienes toward natural product frameworks.14 In some cases
the bromine substituent plays a pivotal role in directing the
cycloaddition stereoselectivity.14f,15a Intermolecular examples
of Diels−Alder reactions of linear 2- or 3-bromo-1,3-
butadienes appear to be very rare in the literature (Scheme
1A).15 Furthermore, to our knowledge only one example of a
2-bromo-1,3-butadiene Diels−Alder/cross-coupling sequence
has been reported, and this example involved a heterocyclic
diene rather than a linear diene (Scheme 1B).16 In the course
of our own studies, it appeared that a tandem Diels−Alder/
cross-coupling sequence would advantageously simplify the
approach required for the synthesis of several natural product
Despite this utility, it is less employed in applied fields such as
medicinal chemistry than the high stereocontrol and increase
in molecular complexity might suggest.3 This may be due to
the variables involved, including reaction component selection,
orbital electronics, catalyst, and potential for later trans-
formations. As a result, identification of cycloaddition partners
demonstrating predictable and reliable reactivity remains an
ongoing challenge. Additionally, Diels−Alder strategies incor-
porating a second reliable synthetic step in a tandem sequence
are an area of current interest,4 especially for access to complex
and diverse molecular scaffolds to drive drug discovery.5
Transition-metal-catalyzed cross-couplings have emerged as
suitable partners for these sequences in tandem with the
Diels−Alder reaction. The challenge in their synthetic
application involves identification of suitable diene substituents
that satisfy the reactivity and regioselectivity requirements for
both the cycloaddition and cross-coupling steps (Scheme 1). A
number of 2-substituted 1,3-butadiene systems have been
investigated for their utility in tandem Diels−Alder/cross-
coupling sequences, most notably including preparatively
useful examples based on boron6,7 and silicon8,9 and some
less-investigated examples such as iodonium salts and organo-
indium species.10 The 2-substituted 1,3-butadiene substrate
class are of particular importance as they enable full control of
the alkene position through the tandem sequence without the
additional steps or alkene regioisomers potentially encountered
with the use of more activated dienes (e.g., 2-silyloxy-1,3-
butadienes) that involve the intermediacy of a ketone and
Received: December 19, 2019
https://dx.doi.org/10.1021/acs.orglett.9b04567
© XXXX American Chemical Society
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A

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a
Scheme 1. 2-Bromodienes: Cycloaddition/Cross-Coupling
Scheme 2. Synthesis of 2-Bromo-1,3-butadienes 6a−g
a
Reagents and conditions: (a) TiCl4, 3, CH2Cl2, −78 °C, 10 h, 84%;
(b) 4, Sn, HBr, Et2O/H2O (1:1), rt, 3 h, 79%; (c) MsCl, Et3N,
DMAP, CH2Cl2, 3 h; (d) DBU, PhMe, 75 °C, 3 h, 97% (over two
steps). Yields for 6b−g over two steps from the corresponding
aldehydes are shown. See the Supporting Information for details.
was then taken forward to probe the feasibility of the
cycloaddition.
Initial attempts to effect the Diels−Alder reaction of
bromodiene 6a and acrolein in the presence of boron
trifluoride etherate or copper(II) triflate in dichloromethane
gave no reaction (Scheme 3). In contrast, the use of tin
tetrachloride gave the separable cycloaddition adducts cis/
endo-7a and trans/exo-7b in 78% yield (dr 2:1). The major
product was assigned as cis/endo on the basis of a NOESY
correlation between the indicated cis ring protons in 7a that
was not observed in the trans/exo isomer 7b. A series of related
dienophiles including methacrolein, methyl acrylate, methyl
vinyl ketone, and acrylonitrile were also found to afford the
corresponding cycloadducts 8−11 in good yields. Boron
trifluoride etherate proved to be the most generally effective
Lewis acid for the transformation, although the diastereose-
lectivity, reaction conditions, and reaction times varied slightly
according to the substrates (see the Supporting Information
for additional details). In general, the cis/endo isomers were
observed to predominate, although the relative amount of the
thermodynamically favored trans/exo isomer28 formed was
found to increase significantly at higher reaction temperatures.
Additional reactions of 2-bromodiene 6a with the dienophile
generated in situ from Meldrum’s acid and formaldehyde or
with benzoquinone also delivered the corresponding cyclo-
adducts 12 and 13 in high yields.
Further structural confirmation of the cycloadduct relative
stereochemistry was obtained from an X-ray structure of cis/
endo isomer 11. In addition, benzoyl deprotection of
cycloadduct 9 (dr 1.3:1) delivered separable cyclized cis/endo
lactone 14 and noncyclized trans/exo alcohol 15 in 37% and
31% yield, respectively (Scheme 4). Diels−Alder reaction of 5-
hydroxy-2-bromo-1,3-diene 16 and methyl acrylate directly
afforded a mixture of the same products, endo-lactone 14
(84%) and exo-alcohol 15 (10%) (dr 8.4:1), in nearly
quantitative combined yield.
frameworks. Although the use of 2-substituted butadiene
systems based on boron or silicon had merit, their stability
toward standard transformations, including aqueous base, was
uncertain. After consideration of the above literature, we were
encouraged to investigate 2-bromo-1,3-butadiene systems
(Scheme 1C). A variety of methods have been employed for
the preparation of 2- and 3-bromo-1,3-butadienes, including
Wittig olefination of α-bromoaldehydes,17 vinyl halide
formation from α,β-unsaturated ketones,18 ring opening of
dibromocyclopropanes,19 Suzuki coupling of dibromoalkenes
prepared via Corey−Fuchs-type sequences,14f and bromina-
tion/rearrangement of N-allylhydrazones.20 Approaches based
on halogenation−elimination of α-allenic systems (boronic
esters,21 alcohols,22 and acetates23) have also been reported. In
our view, however, none of these methods appeared to be
optimal for a robust modular approach.
Identification of a general route to 2-bromo-1,3-butadienes
began with Lewis acid-catalyzed addition of bromoallylsilane
324 to aldehyde 2,25 affording homoallylic alcohol 5 in high
yield (Scheme 2). Alcohol 5 was also available via addition of
significantly less expensive 2,3-dibromopropene (4)26 to
aldehyde 2 using the tin-mediated method described by
Otera,27 which proved to be reliable on a multigram scale.
Mesylation/elimination proceeded readily to give bromodiene
6a in excellent yield exclusively as the E isomer (J = 14.7 Hz).
Diene 6a was stable toward long-term storage at 4 °C as a 0.2
M solution in dichloromethane, although some polymerization
of the isolated compound was observed upon storage without
solvent. To demonstrate that the chemistry was generally
applicable for the synthesis of 2-bromo-1,3-butadienes, addi-
tional compounds 6b−g were prepared, including those with
OTIPS (6c, 6d) and OPMB (6e, 6f) groups and the Roche
ester-derived diene 6f. All of these compounds proved similarly
stable as 6a, with the exception of 6b, which was observed to
decompose upon isolation as previously reported.18 Diene 6a
All of the cycloadditions were found to proceed with
complete selectivity for a single regioisomer. Inspection of a
representation of the calculated HOMO for 2-bromodiene 6a
(Scheme 5) revealed a larger orbital coefficient localized on C1
of the diene π system.29 Interestingly, the presence of the
B
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Scheme 3. Diels−Alder Cycloadditions of 2-Bromo-1,3-butadiene 6a
Scheme 4. Direct Lactonization to cis/endo-14
Table 1. Diels−Alder Cycloaddition of 2-Bromodiene 6a
and N-Phthalimido Enal 17
temp.
(°C)
time
(h)
yield
(%)
a
entry
LA
solvent
dr
1
2
3
4
5
6
BF3·OEt2
BF3·OEt2
BF3·OEt2
TiCl4
TiCl4
TiCl4
−78
0
50
−78
0
CH2Cl2
CH2Cl2
PhMe
CH2Cl2
CH2Cl2
PhMe
3
3
3
18
18
10
n.d.
10:1
5:1
≥19:1
≥19:1
5:1
trace
42
47
81
88
Scheme 5. Representation of the HOMO of 2-Bromodiene
6a
50
67
a
endo:exo; n.d. = not determined.
to undergo transition-metal-catalyzed cross-coupling was next
confirmed (Scheme 6, top). As expected, cyclohexenyl
bromide 11a was smoothly transformed into the expected
vinyl derivative 19 under standard Stille coupling conditions in
86% yield. The Suzuki coupling of 7a with phenylboronic acid
also proceeded uneventfully, affording 20 in good yield
without loss of stereochemical integrity.
The synthetic utility of the vinyl bromide handle for
elaboration of complex natural product intermediates was
exemplified by further transformations of the N-phthalimido
cycloadduct 18a (Scheme 6, bottom). Deprotection of the
amine group with hydrazine hydrate led to the direct formation
of spirocyclic aldimine 21, which then underwent subsequent
Stille coupling with either vinyl- or allyltributylstannane to
afford olefins 22 and 23 in 53% and 59% yield, respectively.
Alternatively, conversion of the aldehyde function of N-
phthalimido cycloadduct 18a to give the corresponding alkyne
24 using the Seyferth−Gilbert reagent (25) could also be
carried out in excellent yield. Uneventful removal of the N-
phthalimide protecting group was then followed by gold-
catalyzed intramolecular hydroamination32 to give spirocyclic
ketimine 26. Finally, Stille coupling again proceeded readily
under standard conditions to install the exocyclic vinyl group
of 27. These synthetic sequences illustrate the compatibility of
bromine substituent appears to twist the diene slightly out of
coplanarity.
To further probe the scope of the 2-bromobutadiene Diels−
Alder cycloaddition, the reaction of 6a and N-phthalimido enal
1730 was also investigated (Table 1). This system has potential
utility for the synthesis of natural product frameworks,
including the pro-apoptotic and HIV-1-active spirocyclic
imine algal metabolite portimine.31 In this case, although the
use of boron trifluoride etherate afforded the endo cycloadduct
18a in moderate yield with reasonable stereoselectivity,
titanium tetrachloride proved to be more successful, giving
18a in high yield as essentially a single diastereoisomer after a
brief optimization. The endo relative stereochemistry of 18a
was unambiguously confirmed by X-ray crystallography.
With 2-bromobutadiene systems established as useful
substrates for regio- and stereoselective intermolecular
Diels−Alder reactions, the ability of the resulting cycloadducts
C
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three steps from readily available aldehydes and established as
hydrolytically stable and practical synthetic intermediates.
Scheme 6. Elaboration and Cross-Coupling of Diels−Alder
a
Cycloadducts
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04567.
Experimental procedures, characterization data, and
NMR spectra for all new compounds (PDF)
Accession Codes
CCDC 1972112 and 1972898 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
e-mailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Margaret A. Brimble − School of Chemical Sciences and
Maurice Wilkins Centre for Molecular Biodiscovery, The
University of Auckland, Auckland 1010, New Zealand;
orcid.org/0000-0002-7086-4096; Email: m.brimble@
auckland.ac.nz
Daniel P. Furkert − School of Chemical Sciences and Maurice
Wilkins Centre for Molecular Biodiscovery, The University of
Auckland, Auckland 1010, New Zealand; orcid.org/0000-
0001-6286-9105; Email: d.furkert@auckland.ac.nz
a
Reagents and conditions: (a) H2NNH2·H2O, MeOH, reflux, 2 h,
Authors
56%; (b) vinyltributylstannane, Pd2(dba)3, CsF, [tBu3PH]BF4, DMF,
100 °C, 18 h, 53%; (c) allyltributylstannane, Pd2(dba)3, CsF,
[tBu3PH]BF4, DMF, 100 °C, 18 h, 59%; (d) dimethyl (diazomethyl)-
phosphonate (25), NaHMDS, THF, −78 °C, 0.5 h, 87%; (e) (i)
H2NNH2·H2O, MeOH, reflux, 2 h; (ii) Au(PPh3)Cl, AgSbF6, Et3N,
MeCN, 95 °C, 0.5 h, 86% over two steps; (f) vinyltributylstannane,
Pd2(dba)3, CsF, [tBu3PH]BF4, DMF, 100 °C, 18 h, 68%.
Hans Choi − School of Chemical Sciences, The University of
Auckland, Auckland 1010, New Zealand
Harry J. Shirley − School of Chemical Sciences, The University
of Auckland, Auckland 1010, New Zealand
Harry R. M. Aitken − School of Chemical Sciences, The
University of Auckland, Auckland 1010, New Zealand
Tim Schulte − School of Chemical Sciences, The University of
Auckland, Auckland 1010, New Zealand
̈
Tilo Sohnel − School of Chemical Sciences, The University of
the vinyl bromide cycloadducts with a wide range of reaction
conditions and the tolerance of the cross-coupling step for a
diverse selection of sensitive functionalities, including ester,
aldehyde, and imine groups.
Auckland, Auckland 1010, New Zealand
Paul A. Hume − School of Chemical and Physical Sciences,
Victoria University of Wellington, Wellington 6012, New
Zealand
In summary, 2-bromo-1,3-butadiene systems have been
demonstrated to be highly effective substrates for tandem
Diels−Alder/cross-coupling reaction sequences. Intermolecu-
lar cycloaddition of 2-bromodienes with a variety of activated
dienophiles was shown to proceed in generally high yields with
good to excellent endo diastereoselectivity. The resulting vinyl
bromide cycloadducts readily underwent subsequent Stille and
Suzuki cross-couplings under standard conditions. Importantly,
both the Diels−Alder and cross-coupling steps were highly
tolerant of a range of functionalities and protecting groups,
which should enable the application of this methodology in
diverse synthetic contexts. The use of the bromine substituent
as both a directing group for cycloaddition and a nucleofuge
for cross-coupling avoids extra steps required to install more
commonly used silyl enol ethers and enol sulfonates for each
transformation and gives full control of the alkene
regiochemistry throughout the reaction sequence. The 2-
bromo-1,3-dienes themselves were conveniently prepared in
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.9b04567
Author Contributions
∥H.C. and H.J.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the Royal Society of New Zealand for
funding support (Marsden Grant UOA1422) and Tania
Groutso (UoA) for assistance with crystallography.
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