The: Z -enoate assisted, Meyer-Schuster rearrangement cascade: Unconventional synthesis of α-arylenone esters

Article abstract of DOI:10.1039/c6cc06639a

Br?nsted acid promoted nucleophilation of propargylic alcohols during the Meyer-Schuster rearrangement (M-S) has been introduced. A novel concept of reverse polarization of the M-S intermediate allenyl cation has been realized by employing a cis-enoate as

Full text of DOI:10.1039/c6cc06639a

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ARTICLE
The Z-enoate Assisted, Meyer-Schuster rearrangement Cascade:
Unconventional Synthesis of α-arylenone esters
Prabhakararao Tharraa and Beeraiah Baire*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Bronstead acid promoted nucleophilation of proaprgylic aclohols during Meyer–Schuster rearrangement (M-S) has been
introduced. A novel convept of reverse polarization of the M-S intermediate allenyl cation has been realized by employing
cis-enoate assisted strategy. This idea is well demonstrated by the metal free synthesis of complex, highly functionalized
cyclic as well as acyclic α−arylenones. The synthetic importance of the derived products was highlighted by the efficient
conversion to biologically relevant molecules such as pyrazoles and 4,5-seco-abietane.
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Propargylic alcohols are one of the most useful building blocks electrophilic central carbon of the allene
with two functional groups available to the synthetic chemists. catalyzed hydrolysis of the resulting alkoxyfuran 7’ gives the
Among various useful reactions of propargylic alcohols,1 the 1,4-ketoester
with the in situ reduction of initial double
Meyer–Schuster (M-S) rearrangement to enones is bond.
7, followed by acid
8
a
transformation of significant synthetic potential in organic
synthesis.2 This rearrangement involves an isomerization of a
A) Meyer-Schuster rearrangements
Acid or
transition
metal
OH
R2
R2 R1
E+
propargylic alcohol
1 to enone product 2 via 1,3-transposed
R3
R3
•
R1
OH
R3
O
R2
electrophile
R1
E
catalyst
allenol 3 (Scheme 1-A1). The M–S rearrangement can be
1
3
nucleophilic
centre
E = H; 2
promoted by the use of transition metal catalysts, Lewis acids
and Brønsted acids.2c Recently, an intercepted Meyer–Schuster
rearrangement was developed to broaden the synthetic utility
of this classical process.3 Accordingly, the key protonation step
E = aryl, alkyl; 4
1) E+ = H+; classical M-S rearrangement
2) E+ = Ar+, alkyl+ ; Electrophilic Intercepted M-S rearrangement
(known with Au, Cu, and InCl3 metal catalysts)7a-c
was replaced by the reaction of the allenol
electrophile (E+), to generate
-functionalized enone systems
(Scheme 1-A2).4,5 This strategy is applied for the synthesis of
3 with an
B) New strategy: Reverse polarization in Meyer-Schuster rearrangement
α
4
electrophilic
centre
OH
R2
R2 R1
Acid
Nu-H
α
-
R3
R3
R1
R3
O
•
R2
nucleophile
R1
Nu
aryl or alkyl enones 4, employing transition metal (Au, Cu, In)
catalysts and boronic acids,6a hyper valent iodonium salts,6b
and diazonium salts,6c as electrophilic reagents.
O
LG
1
5
(LG = leaving group)
R
Scheme 1 (a) Classical functionalization of propargylic alcohols via Meyer-Schuster
rearrangements and b) Our nucleophilic intercepted Meyer-Schuster rearrangement
In contrast to these electrophilic interception approaches,
we designed a conceptually novel, metal free, nucleophilic
interception strategy (Scheme 1B). To achieve this goal, it was
Overall the assisting nucleophile, viz., the ester
functionality is retained (though the double bond is reduced)
and two other nucleophiles i.e., second nucleophile and water
has been added. This approach provided us an opportunity to
uncover; unconventional modes of reactivity of propargylic
alcohols, and one of the developments is presented in this
necessary to alter the electronic properties of the allenol
from being nucleophilic to an electrophilic species ( ), so that
nucleophiles can easily be added. To invert electronic
properties of the allenol into an electrophilic species , we
chose an intramolecular nucleophilic assistance strategy
(Scheme 2). Accordingly, we propose that cis-enoate
(assisting nucleophile) on the alkyne terminal of a propargylic
alcohol would assist the initially formed allenyl cation, to
2
5
2
5
manuscript as Z-enoate assisted, intercepted
M–S
a
rearrangement approach for the synthesis of complex 1,4-
α-
arylenone esters.
6
generate the cyclic oxonium ion 7. Next, addition of the
participating nucleophile (2nd nucleophile) on to now the
R1
R1
R1
R2
R2
OH
R2
Acid
R1
R2
Nu
NuH
Nu
•
2nd NuH
H2
O
O
O
solvent
O
O
OR
OR
electrophilic
carbon
6
O
OR
cyclic-oxonium ion
OR
1,4-enone-ester
8
assisting
7
7'
alkoxyfuran
nucleophile
2nd NuH = ArH (this manuscript)
Scheme 2 Design for a Z-enoate assisted, nucleophilic intercepted M-S rearrangement
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To evaluate our hypothesis, we identified Z-enoate-
Journal Name
With an optimized condition in hand, we next turned our
propargylic alcohol 9a as a representative substrate, which attention to assess the scope and limitations of this new
possesses an internal aromatic group as the secondary process. At first the non-aromatic functionality at the
nucleophile. When 9a was treated with 0.25 eq., of p-toluene propargylic position was varied (Scheme 3). We were pleased
sulfonic acid (pTSA), at 0 °C to RT in CH2Cl2, there was no to find that, the nucleophilic arylative M-S rearrangement was
reaction observed and most of the 9a was recovered after 24 h smooth and efficient across a broad range of substituents 9b-h
(Table 1, entry 1). To our delight, when the reaction was under the optimized reaction conditions. Various acyclic
carried out at 55 °C, the expected intramolecular arylation substituents (ethyl, butyl, iso-propyl), cyclic systems, phenyl,
product, dihydro-naphthalene 10a was isolated in 80% yield vinyl, and allyl groups were compatible to provide access to a
along with 10% of corresponding acid 11a, after 1.5 h (entry 2). diverse array of functionalized dihydronaphthalene keto-esters
Encouraged by this initial result, next we turned our attention 10b-h
.
To unambiguously confirm the structure of the
naphthalene derivatives, X-ray diffraction analysis was
performed for compound 10f 8
for optimized reaction conditions.
.
Table 1 Reaction optimization study
a
Scheme 3 Substrate scope study for propargylic alcohols: All reactions were carried
out on 0.1-0.2 mmol of 9b-h; b yields are after purification; c MsOH (0.25 eq), 0 °C.
Next, we performed a scope study for the intramolecular
aromatic nucleophiles to generate diversely functionalized
dihydronaphthalene derivatives (Scheme 4). Synthetically
useful functional groups like OH, OMe and halogens on
aromatics were found to be compatible with the reaction
conditions and afforded the dihydrohanpthalenes 13a-i
and -naphthalenes were also employed as nucleophiles to
access isomeric phenanthrene derivatives 13j 13k
respectively. In case of -naphthalene, the reaction was very
. α-
β
&
a All the reactions were carried out on 0.1 mmol of 9a in 4 mL of CH2Cl2; b yields
c
d
β
after purification; 65% of 9a; with 0.75 eq. of BiCl3, 20% of 10a and 55% of
recovered 9a, after 3.5 days at 55 °C; e there was no reaction at RT; f 48% of 9a.
regio-selective to provide the product 13k via electrophilic
attack of the α-carbon.
When the amount of pTSA was increased to 0.5 eq., a drop
in yield of the 10a was observed (entry 3). With 1.3 eq. of
pTSA, at 55 °C (entry 4) the cascade process was faster and as
efficient as 0.25 equivalents. Surprisingly, with the MsOH7
(0.25 eq.), the reaction was clean at 0 °C to RT (entry 5) to
provide 10a in 75% yield along with 8% of 11a. There was no
noticeable improvement upon changing temperature of the
reaction and amount of MsOH (entries 6 & 7). More weaker
trifluoro- and cyano acetic acids, resulted in poor yields of 10a
after 2 days at 55 °C (entries 12 & 13). With the stronger TfOH
(0.25 eq.) the transformation was smooth, but relatively less
efficient (entry 8). We also evaluated various Lewis acids such
as BiCl3, AlCl3, and InCl3. First case (entry 9) even after 4 days
only about 7% of 10a was isolated along with 65% of
recovered 9a. With AlCl3 there was no clean reaction. InCl3
promoted the expected reaction to give 60% of 10a but took
0.75 eq. of acid and 25 h at 55 °C. After evaluating several
Brønsted and Lewis acids, pTSA found to be the best acid for
this transformation.
Scheme 4 Scope study for intramolecular aromatic nucleophiles and linkers
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In continuation, we have also studied different linkers with
In continuation, we also employed several unsymmetrical
oxygen and nitrogen atoms (N-Ts) in place of all carbon linker propargylic alcohols 18a-e in the bimolecular process (Scheme
and obtained corresponding benzopyrene and 6). All the substrates resulted in an inseparable mixture of E-
dihydroquinoline derivatives 13l and 13m respectively. and Z- -arylated enones 19a-e in good yields, along with
α
Having demonstrated the metal free, nucleophilic arylative minor amounts of corresponding acids. Interestingly, in most
M-S rearrangement on a broad range of intramolecular of the cases the E-isomer was identified as the major
aromatic nucleophiles, we also aimed to develop a bimolecular compound.10
process for the unconventional synthesis of α−aryl-acyclic- Ultimately, the synthetic value of any developed strategy
enones employing benzenoids and hetero-aromatics as lies in the ability of the synthesized compounds to serve as
intermolecular nucleophiles (Scheme 5).
precursors for molecules with medicinal and biological
importance. To highlight this, here we have shown
transformation of one of the acyclic-enone 16g to the
corresponding pyrazole 21 (Scheme 7, eq. 1). Pyrazoles are a
class of compounds shown to exhibit anti-cancer activity.11
Upon refluxing 16g with p-toluyl-hydrazine in ethanol for 3
days resulted in the formation of 21 in good yield.
Scheme 7 Synthetic applications of the synthesized α-arylenone products
Scheme
5 Development of a bimolecualr process and scope study for the
Next we converted one of the bicyclic 1,4-keto-ester 10a
into the functionalized carbocyclic system 23 presented in
various 4,5-seco-abietans,12 e.g., prionoid D, employing a two-
step aromatization-MeLi addition protocol (Scheme 7, eq.2).
Accordingly, the keto-ester 10a upon treatment with DDQ
underwent the aromatization to give 22 in 90% yield. Addition
of excess of MeLi to the keto-ester 22 resulted in the
formation of tert-alcohol 23 in excellent yield.
intermolecular nucleophiles with symmetrical propargylic alcohol
For this purpose, we chose a symmetric propargylic aclohol
15.
Divergently functionalized, synthetically versatile
aromatics9 such as phenols, furans, thiophenes, naphthols, and
indoles were added very efficiently to provide access to
complex
α-aryl-enones 16a-l. It is noteworthy here that, this
strategy avoids the use of commonly employed electrophilic
hyper valent iodonium salts, boronic acids and diazonium salts,
and can serve as a complimentary methodology for the
CO2Et
CO2Et
Ar-H
Ar-H = 1,3,5-trimethoxybenzene
MsOH
(1.3 equiv.)
synthesis of α-aryl-acyclic-enones.
DCM, 0
C
EtO2C
via 26'
24 h, 56%
24
Ar 25
OH
RO
O
G
G
RO
RO2C
O
Assisting
Acid
G
nucleophile
X
X
R2
R2
X
26
R2
OH
27
A
aromatic
nucleophile
RO
H2O
RO
R
3
1
O
2
H+
O
O
H+
O
R2
28
O
4
R2
5
H2O
H+
H+
R2
29
G
G
G
X
30
X
X
Scheme 8 Proposed mechanism
Scheme 6 Bimolecualr process with unsymmetrical propargylic alcohols
Finally to get evidence for the involvement of the
carboxylate group, the trans-enoate-propargylic alcohol 24
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3
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of 29 by water affords the end product dienone 30
.
In conclusion, we developed a novel strategy of
nucleophilation of propargylic alcohols via an intercepted
Meyer-Schuster rearrangement. A new concept of cis-enoate
assisted M-S rearrangement for the reverse polarisation of
propargylic alcohols was introduced. This strategy was
demonstrated by the cascade nucleophilic arylation of
propargylic alcohols via M-S arrangement under metal free
conditions. This process found very broad scope for
propargylic alcohols, aromatic nucleophiles and linkers. The
synthetic utility of the methodology was shown by efficient
synthesis of biologically relevant pyrazoles and carbocyclic
systems of 4,5-seco-abietane natural products.
4
We thank DST-INDIA for the financial support through
CHY/16-17/343/DSTX/BEER grant. P.T. thanks the CSIR, New
Delhi, India, for a fellowship. We thank Mr. Ramkumar for
single crystal X-ray analysis.
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Notes and references
7
In the literature, we found the following pKa values: for
MsOH: –1.9 (water) and +9.97 (acetonitrile); for TsOH: –0.6
(water) and +8.45 (acetonitrile). So, MsOH is weaker than
pTSA in organic solvents like acetonitrile, whereas it is
opposite in water.
Crystallographic data information for keto-ester 10f has been
deposited with the Cambridge Crystallographic Data Centre
with CCDC1451186 number. Further details were given in
ESI.
(a) After screening MsOH and pTSA under various conditions,
the reaction was found to be smooth with 1.3 eq. of MsOH.
(b) 5 equivalents of aromatic nucleophile found to give the
α-arylenones as sole products without any leftover starting
alcohol 15.
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