Titanium(IV) Chloride-Mediated Stereoselective α-Alkylidenation to Efficiently Assemble Multisubstituted 1,3-Dienes

Article abstract of DOI:10.1002/adsc.201601025

A direct access to multisubstituted 1,3-dienes by α-exclusive alkylidenation of crotonic derivatives has been developed. This protocol, mediated by titanium tetrachloride chelation, features excellent regio- and stereoselectivity, mild reaction conditions, easy operation and wide substrate scope. Conversions of the derived dienes to other useful molecules were also explored. (Figure presented.).

Full text of DOI:10.1002/adsc.201601025

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DOI: 10.1002/adsc.201601025
Titanium(IV) Chloride-Mediated Stereoselective a-Alkylidena-
tion to Efficiently Assemble Multisubstituted 1,3-Dienes
Rengwei Sun,a Wei Song,a Chunmei Ma,a Huiwen Zhang,a and Xinhong Yua,*
a
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology,
Shanghai 200237, Peopleꢀs Republic of China
Fax : (+86)-21-6425-1033; phone: (+86)-21-6425-2604; e-mail: xhyu@ecust.edu.cn
Received: September 14, 2016; Revised: October 31, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201601025.
Abstract: A direct access to multisubstituted 1,3-
dienes by a-exclusive alkylidenation of crotonic de-
rivatives has been developed. This protocol, mediat-
ed by titanium tetrachloride chelation, features ex-
cellent regio- and stereoselectivity, mild reaction
conditions, easy operation and wide substrate scope.
Conversions of the derived dienes to other useful
molecules were also explored.
dressed under thermodynamic conditions.[10] However,
the direct a-condensation is less common.
The only direct a-C alkenylation by an aldol-type
reaction was reported in 1931[11] by refluxing crotonic
anhydride with benzaldehyde in the presence of trie-
thylamine to afford a-vinylcinnamic acid in 17–40%
yield, which is known as the Perkin reaction. Howev-
er, the need for preparing the corresponding anhy-
dride beforehand and the modest yield are disadvan-
tageous. Alternatively, use of the strong base LDA-
HMPA has addressed the issue of a-selectivity to
some degree, giving good yields and selectivity.[9a,12]
Nevertheless, a separate elimination step is needed,
apart from the strong base and extreme low tempera-
ture (À788C) required (Scheme 1). The limitations of
the aforementioned methods such as the need for an-
Keywords: alkylidenation; conjugated dienes; regio-
selectivity; titanium(iv) chloride; vinylogous aldol
condensation
Multisubstituted conjugated dienes are versatile hydride pre-preparation, relatively low yields and de-
building blocks as shown in Diels–Alder reactions,[1] manding reaction conditions prompted us to explore
[4+1][2] and [4+2][3] cycloadditions, thermal ring annu- a further superior protocol.
lations,[4] etc.[5] Synthetic protocols to produce such
To the best of our knowledge, the direct g-conden-
dienes have been widely explored[6] including, but not sation of crotonates has been well established, while
limited to, elimination, reduction, alkene metathesis, a-condensation still largely remains unexplored. To
metal-mediated coupling reactions, Wittig–Horner re- meet this challenge, we wanted to use the TiCl4/Et3N
actions, aldol condensation, isomerization of unconju- system to regio- and stereoselectively mediate the
gated dienes, rearrangement of allenes or alkynes, al- aldol condensation–dehydration between aldehydes
kylidenation with metal-carbene complexes and many 1 and crotonate derivatives 2. This elegant protocol
multistep reactions.
offered the target compound with great convenience
Among these methods, the aldol condensation[7] has at ambient temperature from readily available materi-
largely attracted our attention due to its green fea- als. By virtue of its simple procedure, good produc-
tures, which could afford a,b-unsaturated carbonyls tion, wide scope and scalable operation, this method
from inexpensive and readily available aldehydes or should find widespread applications.
ketones. However, harsh conditions and modest yields
Our investigation was initiated using the reaction of
have obstructed its extensive application. Moreover, 3,4-dimethoxybenzaldehyde 1a and methyl crotonate
the regioselective control becomes quite a challenge 2a with various Lewis acid/base/solvent combinations
when vinylogy is involved.[8] Typically, the non-direc- at room temperature (Table 1). A careful conditions
tive vinylogous aldol reaction (VAR) leads to a mix- screen revealed that the reaction worked efficiently in
ture of a-adduct and g-adduct.[9] Much work has been dichloromethane when 2.0 equiv. of titanium tetra-
done concerning the issue of regioselectivity. Gratify- chloride and no less than 3.0 equiv. of triethylamine
ingly, the direct g-condensation between aromatic al- were used. The excess base would make little differ-
dehydes and crotonic derivatives has been well ad- ence while an overload of Lewis acid will give rise to
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Table 1. Optimization of the reaction conditions.[a]
No. LA/Base
Sol-
vent
E/
Yield[c]
[%]
(equiv.)
Z[b]
1
2
3
4
5
6
7
8
9
AlCl3 (2.0)/Et3N (2.0)
TiCl4 (2.0)/Et3N (2.0)
FeCl3 (2.0)/Et3N (2.0)
ZnCl2 (2.0)/Et3N (2.0)
CuCl2 (2.0)/Et3N (2.0)
TiCl4 (3.0)/Et3N (3.0)
TiCl4 (1.0)/Et3N (1.0)
TiCl4 (1.0)/Et3N (2.0)
TiCl4 (2.0)/Et3N (3.0)
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
–
–
–
–
–
–
–
–
messy
28
N.R.
N.R.
N.R.
46
trace
<20
DCM 87:13 78
DCM 85:15 77
DCM 88:12 52[d]
10 TiCl4 (2.0)/Et3N (5.0)
11 TiCl4 (2.0)/(n-Pr)3N 3.0)
(
12 TiCl4 (2.0)/DBU (3.0)
13 TiCl4 (2.0)/N,N-diethylaniline
(3.0)
DCM
DCM
–
–
N.R.
N.R.
14 TiCl4(2.0)/DIPEA (3.0)
15 TiCl4 (2.0)/TEMED (1.5)
16 TiCl4 (2.0)/PBu3(3.0)
17 TiCl4 (2.0)/PPh3(3.0)
18 TiCl4 (2.0)/Et3N (3.0)
19 TiCl4 (2.0)/Et3N (3.0)
20 TiCl4 (2.0)/Et3N (3.0)
21 TiCl4 (2.0)/Et3N (3.0)
22 TiCl4 (2.0)/Et3N (3.0)
23 TiCl4 (2.0)/Et3N (3.0)
DCM
DCM
DCM
DCM
DCE
PhCl
–
–
–
–
–
–
–
–
–
–
messy
N.R.
N.R.
N.R.
26[d]
<10
N.R.
N.R.
trace
N.R.
THF
PhMe
CHCl3
CCl4
Scheme 1. Brief overview on the a-condensation of vinylo-
gous carbonyls.
[a]
Reaction conditions: 1 mmol 1a, 1 mmol 2a in 8 mL sol-
vent stirred in an ice bath and then addition of base/
Lewis acid.
Determined by NMR.
Isolated yield.
by-products, in contrast, an inadequate amount of
Lewis acid or base would afford incomplete conver-
sion. When a similar base, DIPEA was adopted in-
stead of Et3N, the reaction became messy. A mecha-
nism accounting for the formation of aldehydes with
extended vinylogy has been disclosed,[13] while causes
for the formation of other by-products await further
study.
[b]
[c]
[d]
Incomplete conversion. N.R.=no reaction.
showed considerable reactivity. The reaction also ex-
Having the optimized conditions in hands, we hibited impressive robustness when naphthalene or
began to explore the substrate scopes of aldehydes heteroaromatic rings like furan and thiophene were
and crotonates. Over 30 compounds were obtained introduced. Cinnamaldehydes are also workable
via this method in moderate to high yields (up to albeit with diminished E/Z selectivity and conversion
95%) with excellent stereoselectivities (>99:1 in most ratio. Gratifyingly, even aliphatic aldehydes could act
cases).
in this condensation. To overcome the poor chemose-
As is shown in Figure 1, the reaction exhibited lectivity of aliphatic aldehydes bearing active a-H
good compatibility with a wide range of functional atoms, pivaldehyde 3av and ethyl glyoxalate 3au were
groups on varied substitutional sites, except for un- adopted and the reaction gave the desired products in
protected hydroxy or amino groups. A series of ortho- good yields. Furthermore, condensation of formates
, meta-, and para-substituted arylaldehydes proceeded with crotonates could offer an elegant access to some
smoothly under the standard conditions. Although the 1-alkoxy-butadiene-2-carboxylates 3aq and 3ar.[14] In-
reaction preferred electron-rich arylaldehydes, alde- spired by this encouraging result, we subsequently
hydes bearing electron-withdrawing groups also tried dimethylformamide but this did not work at all,
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Figure 1. Scope of aldehydes. E/Z ratio determined by H NMR; isolated yield and configuration of the major isomer are
shown.
since the DMF would give a complex upon addition Among all the variations of crotonates, methyl (E)-
of TiCl4.[15]
hex-2-enoate 3m show the least stereoselectivity.
Subsequently, the feasibility of various substituted Gratifyingly, an alternative process was established to
crotonates was examined (Figure 2), and all kinds of make up for this shortage. By employing methyl (E)-
crotonates proved to be efficient in this protocol. Par- hex-2-enoate 1m instead of the hex-3-enoate 1l we
ticularly, the double bond migration strategy worked could obtain the desired product with improved yield
well in exo/endo double bond migration 3fa–3ha. and stereoselectivity. However, crotonamide would
1
Figure 2. Scope of substituted crotonates. E/Z ratio determined by H NMR; isolated yield and configuration of the major
isomer are shown.
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give a messy product with only traces of the desired
Since arylaldehyde is prone to dehydration so as to
product. Additionally, an intramolecular version of reach a conjugated system, we could hardly observe
this protocol was examined (3wc). The strained transi- the pre-dehydration intermediate A. However, we
ent state would account for this poor yield. Mean- were delighted to obtain such an intermediate be-
while, this protocol is not suitable for extended vinyl- tween the condensation of pivaldehyde and methyl
1
ogy, various conditions were tested for the condensa- crotonate 4av. Particularly, H NMR of the intermedi-
tion of sorbate but the materials remained intact.
ate shows a nearly 1:1 diastereoisomer ratio and the
Our proposed mechanism is illustrated in final product is 9:1 in E/Z selectivity. In a control ex-
Scheme 2, crotonate is deprotonated and coordinates periment, this pre-dehydration intermediate could
with titanium tetrachloride. The aldehyde, crotonate successfully convert into the final product 3av in
anion and titanium cation form the Zimmerman– a yield of 82% (Scheme 3).
Traxler transient, in which the planes of aldehyde and
crotonate are largely parallel to each other so that the
p orbital could constitute a new C–C bond. Thus, the
regioselectivity is explained. On the other hand, keep-
ing the bulky substituent of the aldehyde and the
alkyl chain of crotonate in an equatorial bond would
contribute to a more stable transitional state. Such
a preference would account for the stereoselectivity.
To further support this envisaged mechanism, efforts
Scheme 3. Control experiment: intermediate conversion.
were made to capture intermediates.
This condensation has also been proved to be an ef-
ficient process for scaling-up. A multigram-scale con-
densation of methyl crotonate (1a, 30 mmol, 3.05 g)
with benzaldehyde (2b, 30 mmol, 3.20 g) gave the de-
sired product (3ab, 4.04 g, E/Z=91:9) with little varia-
tion in yield and E/Z selectivity in comparison with
the 1 mmol scale reaction (3ab, 76%, E/Z=89:11).
The application of our protocol in the synthesis of
versatile derivatives was pursued, and herein illustrat-
ed by the convenient access to 2-vinyl-1H-indole-3-
carboxylate 5ai[16] and a series of cyclopentene-fused
rings (Scheme 4). With a nitro present next to the
formyl group, 3ai could easily convert to 5ai when
heated in P(OEt)3. Vinylindoles like this could be
used in the Diels–Alder reaction as a diene to prepare
many indole alkaloids.[17] Likewise, compounds with
pre-installed halogen or methoxy substituents next to
the formyl group are likely to react with the vinyl
chain under versatile conditions to form thiophene
and furan derivatives.[18]
Indenes are widely used as ligands and functional
materials due to their physical and biological proper-
ties. Herein, our readily prepared 1-aryl-3-carboxy-
lates were applied in the synthesis of indenes and cy-
clopentene-fused polycyclic systems.[19] Especially,
substrates bearing a ring like 3fa–3ha would offer
novel spiroindenes.
Up to date, the complex regiochemical issues in-
volved in the vinylogous aldol reaction remain largely
unexplored. Indeed, the site- and stereopredictable
aldol condensation of aldehydes with vinylogous car-
bonyls could be easily achieved via the aid of chelat-
ing titanium tetrachloride. Moreover the TiCl4/Et3N
system has long been used in aldol and related con-
densation reactions, and the Zimmerman–Traxler
transient state has also been proposed for stereocon-
trolled aldol condensation products.[20] However, this
Scheme 2. Proposed mechanism and transition state.
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TiCl4 (0.22 mL, 2 mmol) and the mixture was stirred for fur-
ther 2–8 h at room temperature. When the reaction was
complete as confirmed by TLC, the mixture was diluted
with saturated aqueous NaCl and the organic layer was sep-
arated. The organic phase was washed with brine and water.
It was then dried over anhydrous Na2SO4 and evaporated
under reduced pressure to afford the crude product, which
was purified by flash chromatography (petroleum ether/
ethyl acetate) to afford the product corresponding 1,3-diene
(3).
Procedure for the Synthesis of Methyl 2-Vinyl-1H-
indole-3-carboxylate (4ai)
A slightly modified procedure was used.[14] Methyl (E)-2-(2-
nitrobenzylidene)but-3-enoate (3ai, 1 mmol, 235 mg) was
dissolved in 2 mL of triethyl phosphite and heated at 1408C
for 5 h. Excess triethyl phosphite was removed under re-
duced pressure and the residue was chromatographed over
silica gel using PE/EA=3:1 as an eluent with 4ai as the only
product, yield: 76%; yellow solid.
Procedure for the Synthesis of Cyclopentene-Fused
Rings (6)
To a solution of the corresponding 1-aryldiene (3,1 mmol) in
5 mL dichloromethane was added concentrated sulfuric acid
(1 mmol, 1.0 equiv.) or the equivalent amount of TiCl4 and
the mixture stirred at room temperature for 1 h. On comple-
tion the reaction was quenched with 10 mL water and ex-
tracted with solvent. The Na2SO4-dried organic phase was
evaporated under reduced pressure and the residue was
chromatographed over silica gel using PE/EA ca 10:1 as an
eluent to afford product 6.
Scheme 4. Application of the a-alkylidenation-derived
dienes.
is the first report on the use of TiCl4/Et3N in a vinylo-
gous aldol condensation for both regio- and stereose-
lectivity.
Acknowledgements
This work was financially supported by National Natural Sci-
ence Foundation of China (No. 21476078) and Science and
Technology Commission of Shanghai Municipality (No.
12431900902).
In summary, we herein have reported the first ex-
ample of a TiCl4/Et3N-mediated a-exclusive conden-
sation of various aldehyde with a,b-unsaturated car-
boxylates under mild conditions in good yields (up to
95%) and stereoselectivities (>99:1 in most cases).
The usefulness has been illustrated by the synthesis of
vinylindole and novel indenes. This scalable protocol
offers a direct access to a variety of multisubstituted
1,3-dienes with great simplicity from readily available
starting materials. Further applications of these novel
types of dienes are under study in our laboratory.
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COMMUNICATIONS
Titanium(IV) Chloride-Mediated Stereoselective a-
Alkylidenation to Efficiently Assemble Multisubstituted 1,3-
Dienes
7
Adv. Synth. Catal. 2016, 358, 1 – 7
Rengwei Sun, Wei Song, Chunmei Ma, Huiwen Zhang,
Xinhong Yu*
Adv. Synth. Catal. 0000, 000, 0 – 0
7
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!