Hydroalumination-triggered cyclization of silylated 1,3-dien-5-ynes to polysubstituted benzenes

Article abstract of DOI:10.1021/ol5022096

Regiocontrolled synthesis of polysubstituted benzenes from silylated 1,3-dien-5-ynes has been achieved by using diisobutylaluminum hydride (DIBAL-H). Hydroalumination of the alkyne moiety with DIBAL-H triggers the aromatic cyclization, which usually proce

Full text of DOI:10.1021/ol5022096

Letter
pubs.acs.org/OrgLett
Hydroalumination-Triggered Cyclization of Silylated 1,3-Dien-5-ynes
to Polysubstituted Benzenes
Hidenori Kinoshita, Takayuki Tohjima, and Katsukiyo Miura*
Department of Applied Chemistry, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakura-ku,
Saitama 338-8570, Japan
S
* Supporting Information
ABSTRACT: Regiocontrolled synthesis of polysubstituted benzenes from silylated 1,3-dien-5-ynes has been achieved by using
diisobutylaluminum hydride (DIBAL-H). Hydroalumination of the alkyne moiety with DIBAL-H triggers the aromatic
cyclization, which usually proceeds without rearrangement and loss of the existing substituents. The related unusual cyclizations
to different types of polysubstituted benzenes are also described.
olysubstituted benzene motifs appear ubiquitously in
various compounds from biologically active molecules to
adducts easily undergo geometrical isomerization leading to the
thermodynamically favored (E)-isomers.7 This information
promoted us to utilize the silicon-directed hydroalumination-
isomerization sequence for the preparation of trienylaluminums
having the same configuration as trienylpalladium intermediate
A. As shown in Scheme 2, we built up a working hypothesis to
P
functional molecular materials. Hence, much effort has been
devoted to synthetic methods for constructing polysubstituted
benzenes.1,2 During our campaign to develop effective access to
polysubstitued benzenes,3,4 we found that the Pd-catalyzed
intermolecular reaction of β-iodo-β-silylstyrenes with terminal
alkynes affords 1,2,3,5-tetrasubstituted benzenes efficiently
under mild reaction conditions.4 The [2 + 2 + 2] cycloaddition
has been proposed to proceed through 6π-electrocyclization of
trienylpalladium intermediate A (Scheme 1).5 Based on the
Scheme 2. Working Hypothesis for DIBAL-H-Promoted
Aromatic Cyclization
Scheme 1. Benzene Construction via 6π-Electrocyclization of
Trienylpalladium Intermediate
develop a new benzene-forming reaction. It consists of four
steps: regioselective hydroalumination of a silylated 1,3-dien-5-
yne 1, geometrical isomerization of the initial adduct to the
corresponding trienylaluminum intermediate B, disrotatory 6π-
electrocyclization of B,6 and aromatization of the resultant 5-
aluminocyclohexa-1,3-diene with elimination of DIBAL-H.
To explore our scenario, we commenced the optimization of
reaction conditions using silylated 1,3-dien-5-yne 1a (Table 1).8
Treatment of 1a with an equimolecular amount of DIBAL-H at
ambient temperature provided the desired tetrasubstituted
reaction mechanism, we envisioned that other metalated trienes
would also provide polysubstituted benzenes by a similar
reaction sequence involving disrotatory 6π-electrocyclization
and dehydrometalation. To ensure the feasibility, we attempted
the cyclization of trienylaluminums prepared from 1,3-dien-5-
ynes and diisobutylaluminum hydride (DIBAL-H).6 We report
herein that the hydroalumination-triggered reaction of silylated
1,3-dien-5-ynes is valuable for regioselective synthesis of
polysubstituted benzenes.
Hydroalumination of 1-silyl-1-alkynes with DIBAL-H takes
place in a syn-addition mode to give (Z)-1-alumino-1-silyl-1-
alkenes with high regioselectivity. In the absence of coordinative
solvents containing a heteroatom, the initially formed syn-
Received: July 26, 2014
Published: September 4, 2014
© 2014 American Chemical Society
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Letter
a
a
Table 1. Optimization of Reaction Conditions
Table 2. Scope and Limitations
b
DIBAL-H
(equiv)
temp
(°C)
2, yield
(%)
entry
Si
1
solvent
c
1
2
3
4
Me3Si
Me3Si
Me3Si
Me3Si
1a
1a
1a
1a
1.0
1.0
1.0
1.0
rt
50
hexane
hexane
THF
2a, 34
c
2a, 71
50
2a, 0
100
octane
2a,
c
b
74 (69)
c
5
6
7
8
Me3Si
Me3Si
Me3Si
Me3Si
Me3Si
Me3Si
Me3Si
Me3Si
Me3Si
Ph2MeSi
i-Pr3Si
H
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1.0
0
150
100
100
100
100
100
100
100
100
100
100
100
decane
octane
octane
octane
octane
octane
octane
octane
2a, 67
2a, 0
0.2
0.5
0.5
1.2
1.5
1.2
1.2
1.2
1.2
1.2
2a, trace
2a, 53
2a, 49
2a, 78
d
9
10
11
c
2a, 31
e
12
2a, 72
13
14
15
16
toluene 2a, 65
octane
octane
octane
2b, 53
2c, 0
2d, 0
a
Unless otherwise noted, all reactions were carried out with 1 (0.30
b
mmol) and DIBAL-H in solvent (0.30 mL) for 24 h. Isolated yield.
c
1
Determined by H NMR analysis using dibenzyl ether as an internal
d
e
standard. Me2AlH was used instead of DIBAL-H. The reaction time
was 12 h.
benzene 2a in only 34% yield even though 1a was consumed
completely (entry 1). The reaction at 50 °C formed 2a in 71%
yield (entry 2). In contrast, 1a was recovered intact when THF
was used as solvent (entry 3). A further elevation in reaction
temperature improved the yield to 74% (entry 4). However, the
yield of 2a decreased slightly at 150 °C (entry 5). In the absence
of DIBAL-H, dienyne 1a was recovered intact (entry 6). This
control experiment makes it clear that the present reaction is not
just a thermal electrocyclization of 1,3-dien-5-ynes.9 A reduced
amount of DIBAL-H (0.2 equiv) hardly promoted the cyclization
(entry 7). Use of 0.5 equiv of DIBAL-H or Me2AlH resulted in a
moderate yield of 2a (entries 8 and 9). These results are
indicative of no catalytic activity of these aluminum hydrides.
The reaction with 1.2 equiv of DIBAL-H gave the best result
(entry 10), while a further increase in amount of DIBAL-H
caused complex side reactions (entry 11). Shortening of the
reaction time brought a drop in yield (entry 12). Toluene was not
effective as solvent in promoting the present cyclization (entry
13). Modification of the silyl group of 1a strongly affected the
DIBAL-H-promoted cyclization. As shown in the reaction of 1b
(Si = Ph2MeSi), introduction of a bulky silyl group retarded the
cyclization (entry 14). With 1c, bearing a more hindered silyl
group (Si = i-Pr3Si), no desired product was detected with full
recovery of 1c (entry 15). Additionally, the reaction of the
nonsilylated substrate 1d resulted in a complex mixture of
unidentified products (entry 16).
With the optimized conditions in hand, we tested substrate
scope and limitations with various silylated 1,3-dien-5-ynes
(Table 2).8 First, we investigated the variation of reaction
efficiency by altering the substituent R4. Dienyne 1e, bearing a
cyclohexyl group as R4, was converted into 2e in 59% yield. The
structure of 2e was clearly confirmed by X-ray structure analysis
a
Unless otherwise noted, all reactions were carried out with 1 (0.30
mmol) and DIBAL-H (0.36 mmol) in octane (0.30 mL) at 100 °C for
b
c
d
24 h. Isolated yield. 2.5 equiv of DIBAL-H was used. The yield was
estimated by H NMR analysis using dibenzyl ether as an internal
standard.
1
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(entry 1). Introduction of isopentyl and benzyl groups as R4
succeeded in efficient cyclization to tetrasubstituted benzenes 2f
and 2g (entries 2 and 3). In contrast, 1,3-dien-5-ynes 1h and 1i,
bearing an oxygen-functionalized alkyl group, were cyclized
sluggishly even with 2.5 equiv of DIBAL-H (entries 4 and 5). A
complex mixture of unidentified products was formed in each
case. When alkyl chloride 1j (R4 = (CH2)3Cl) was treated with
DIBAL-H, dechlorinated product 2j was obtained in only 16%
isolated yield (entry 6). The sp3-carbon−chlorine bond was not
tolerant of the reaction conditions. Since the reaction of dienyne
1k (R4 = H) with DIBAL-H gave no desired product (entry 7),
the substituent R4 (R4 ≠ H) is essential for the aromatic
cyclization. Dienynes 1l and 1m, analogues of 1f by slight
modification in R1 and R2, were efficiently cyclized to the
corresponding tetrasubstituted benzenes (entries 8 and 9). It is
noteworthy that the sp2-carbon−chlorine bond of 1m was
compatible with the present cyclization.
We next turned our attention to the cyclization of 1,3-dien-5-
ynes having a different pattern of substitution. 1,2,3,4-
Tetrasubstituted dienyne 1n was smoothly converted into
pentasubstituted benzene 2n in high yield (entry 10).
Benzocycloheptane 2o was obtained from 1o in moderate
yield (entry 11). Intriguingly, the cyclization of dienyne 1p (R1 =
H) afforded 1,2,3,5-tetrasubstituted benzene 2p and its 1,2,4,5-
tetrasubstituted regioisomer 2q in moderate combined yield
(entry 12).10 Upon treatment with DIBAL-H, dienyne 1q (R2 =
H) did not turn into the expected product 2q. Instead, the
rearranged product 2p was formed in a rather low yield (entry
13). This result indicates that the substituent R2 (R2 ≠ H) is
crucial for an efficient cyclization.
DIBAL-H was found to have no catalytic activity (Table 1). This
discrepancy may be due to thermal decomposition and side
reactions of organoaluminum species under these conditions.
The rearranged cyclization of 1p and 1q can be explained by path
b, which consists of intramolecular carboalumination of the s-
cis,cis- or s-cis,trans-conformer of B, further carboalumination of
the cyclized intermediate C, ring-opening of cyclopropylcarbi-
nylaluminum D, and dehydroalumination of cyclohexadienyla-
luminum E. A similar reaction sequence has been proposed in
our pervious report on the dialkylaluminum hydride-promoted
cyclodimerization of silylated 1,3-enynes.3 The switch from path
a to path b is attributable to easy approach of the aluminum
moiety to the C1−C2 double bond in the absence of the
substituent R1 or R2. The rearranged cyclization suggests a
possibility that the aromatic cyclization of other substrates
bearing the same substituents as R1 and R2 proceeds via path b.
This path seems inconsistent with the fact that the substrates
bearing both substituents R1 and R2 are reactive toward the
aromatic cyclization because steric effects caused by these
substituents would retard the carboalumination steps. In
addition, the results shown in entries 12 and 13 of Table 2
indicate that the presence of R1 (R1 ≠ H) gives an ill effect on the
rearranged cyclization. At this stage, however, it is not clear which
path is mainly operative.12
To our surprise, the DIBAL-H-promoted reaction of dienyne
1r, bearing a tert-butyl group as R4, gave 1,3,5-trisubstituted
benzene 3 in quantitative yield with the loss of the 1-phenyl
group (Scheme 4). The structure of 3 was confirmed by
Scheme 4. Dephenylative Aromatization
As shown in Scheme 2, a plausible mechanism for the DIBAL-
H-promoted aromatization involves the 6π-electrocyclization of
trienylaluminum intermediate B followed by dehydroalumina-
tion. There are four possible planar conformations of the 6π-
electron system B, the s-cis,cis conformer of which is accessible to
the postulated 6π-electrocyclization (Scheme 3, path a).11 The
Scheme 3. Effects of Substituents and Plausible Mechanism
comparing the NMR data for the desilylated form of 3 with the
reported data for 3-tert-butylbiphenyl.13 To trace the eliminated
phenyl group, the reaction of 1r was conducted in a sealed tube at
100 °C for 24 h, and the reaction mixture was checked by GC
before and after quenching with methanol. This experiment
revealed that benzene was formed in 59% yield before quenching
and that the yield increased to 68% after quenching. Additionally,
treatment of the reaction mixture with iodine afforded
iodobenzene in 4% yield. On the basis of these observations, it
is likely that the reaction path forming 3 involves disrotatory 6π-
electrocyclization of the initially formed trienylaluminum
intermediate F without geometrical isomerization and the
elimination of a phenylaluminum speices (i-Bu2AlPh), that is, a
retro-carboalumination.14 The major part of i-Bu2AlPh would
suffer from thermal decomposition leading to benzene during the
reaction.
presence of the substituents R2 and R4 makes other conformers
unstable by steric repulsion between the aluminum moiety and
R2 or R4, and brings about conformational fixation of B to the s-
cis,cis conformation. This is a probable reason for the positive
effects of these substituents on the present cyclization. Although
the aromatization step by dehydroalumination gives a sense of
anticipation that DIBAL-H can work catalytically, in actual,
Dienynes 1s and 1t, bearing a methoxymethyl group, also
underwent an unexpected cyclization instead of the usual
cyclization to 2. Treatment of 1s and 1t with 2.5 equiv of
DIBAL-H provided benzyl-substituted benzenes 4s and 4t,
respectively, in good yield (Scheme 5, eq 1).15 A reduced amount
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Scheme 5. Aromatization via Non-6π-electrocyclization
REFERENCES
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of DIBAL-H (1.2 equiv) did not promote the cyclization of 1s at
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reaction of 1s with DIBAL-H (2.5 equiv) at 50 °C for 30 min
gave triene 5 in 68% with 32% recovery of 1s (Scheme 5, eq 2).
When the reaction mixture was subjected to 1H and 13C NMR
analyses before quenching with water, the NMR signals of
protons and carbons α to the ethereal oxygen appeared in lower
magnetic fields than those for 5. These observations indicate that
DIBAL-H is used not only for hydroalumination of the alkyne
part but also for coordination to the ethereal oxygen.
Considering the electrophilic activation of the allylic carbon
bearing a methoxy group, the formation of 4 can be rationalized
by intramolecular nucleophilic substitution of trienylaluminum16
intermediate G and subsequent aromatization via 1,3-hydrogen
shift.
Muller, H. Justus Liebigs Ann. Chem. 1960, 629, 222. (b) Eisch, J. J.;
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In summary, we developed the regiocontrolled synthesis of
polysubstituted benzenes from silylated 1,3-dien-5-ynes by using
DIBAL-H. Although this method for benzene construction is
rather limited in substrate scope, it enables the synthesis of
unsymetrically polysubstituted benzenes hardly obtainable by
the known methods. The introduction of a trimethylslilyl group
on the benzene ring serves to broaden the range of accessible
substituted benzenes on the basis of synthetic utility of
arylsilanes. In addition, the present study revealed some
interesting reactivities of organoalunimum reagents, which are
valuable for further development of aluminum-mediated
synthetic methods. Further study on the reaction mechanism is
underway.
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substrates in spite of all our efforts.
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ASSOCIATED CONTENT
* Supporting Information
■
(15) The structure of 4s was confirmed by leading 4s to 1-benzyl-2,3-
diethyl-5-(4′-phenyl)phenylbenzene (4s′) and analyzing its crystal
structure (CCDC 983140).
(16) For intermolecular nucleophilic substitution of vinylaluminum
speices, see: Zweifel, G.; Miller, J. A. Org. React. 1984, 32, 375.
S
Experimental procedures, characterization data, and crystallo-
graphic data for 2e (CCDC 983139) and 4s′ (CCDC 983140)
(CIF). This material is available free of charge via Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: kmiura@apc.saitama-u.ac.jp.
Notes
The authors declare no competing financial interest.
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