Regiospecific formal [3 + 2] annulation of: Tert -propargyl alcohols with acyclic 1,3-diketones via the cycloisomerization of homoallenyl ketones

Article abstract of DOI:10.1039/c8ob02158a

A one-pot, regiospecific synthesis of dihydrofurans bearing a quaternary centre and tetrasubstituted furans is developed from the formal [3 + 2] annulation of tert-propargyl alcohols and 1,3-diketones under Ca(ii)/DBU conditions. The reaction proceeds through the S_N2^I mechanism to form homoallenyl ketone and a subsequent cycloisomerization to yield novel and new chemical entities of privileged scaffolds.

Full text of DOI:10.1039/c8ob02158a

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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ARTICLE
Regiospecific formal [3+2] Annulation of tert-Propargyl alcohols
with acyclic 1,3-diketones via the Cycloisomerization of
homoallenyl ketones
Received 00th January 20xx,
Accepted 00th January 20xx
Srinivasarao Yaragorla,*and P. Rajesh
DOI: 10.1039/x0xx00000x
www.rsc.org/
A one-pot, regiospecific synthesis dihydrofuransbearing a quaternary centreand tetrasubstituted furans is developed from
the formal [3+2] annulation oftert-propargyl alcohols and 1,3-diketones under Ca(II)/DBU conditions. The reaction
proceeds throughSN2Imechanism to form homoallenyl ketone and a subsequentcycloisomerization to yield a novel and
new chemical entities of privileged scaffolds.
catalyzed cycloisomerization of allenyl ketones to furan
derivatives, however,thisallenyl ketone was separately
Introduction
prepared
and
used
for
cyclization
(multi-step
Propargyl alcohols are versatile feedstock materials in organic
synthesis.1-3They contain multiple reactive sites,particularly
three electrophilic and one nucleophilic hydroxyl group and
hence considered asambident substrates.1-3 Therefore several
researchers explored this ambident nature of propargyl
alcohols by activating different reactive centresunder various
reaction conditions to generate a vast library of carbo- and
heterocyclic compounds.1-3 However, the reaction of these
propargyl alcohols with 1,3-dicarbonyl compounds is
particularly challenging and intriguing, owing to the reason
that both the substrates are ambiphilicin nature. Though a
good number of reports are available on the reaction of
propargyl alcohols with 1,3-dicarbonyl compounds, most of
synthesis).6Despite these reports, there is no single report
available on the annulation of tert-propargyl alcohols with 1,3-
dicarbonyl compounds through
a regiospecific SN2 type
mechanism to provide a regiodivergent synthetic protocol for
furans. In continuation of our research interests to explore the
ambident reactivity of propargyl alcohols,7 particularly towards
the annulation reactions, herein we report a Ca(II)-catalyzed
formal [3+2] annulation of tert-propargyl alcohols and 1,3-
diketones in one–pot (Figure 1).
R4
R4
O
O
O
OH
R2
R4
R3
R3
step-2
R1
SN
1
R1
R1
themproceed through
a
propargylic substitution with
step-1
R2
substitution at
propargylic carbon
R3
R2
diketonethrough the SN1 mechanism, followed by base
mediated a cyclization to afford the respective furan4 or pyran
derivatives5 (Figure 1).For example, secondary propargyl
alcohols were treated with 1,3-diketones in presence of a
suitable Lewis acid or a transition metal catalysts and or bases
to make the furan derivative through 5-exocyclization (Figure
1, condition-a).4It is also reported that tertiary propargyl
alcohols react with enols or enol equivalents in presence of
acid catalysts (along with bases in some cases) to give the
pyran derivatives through 6-endocyclization (Figure 1,
condition -b).5A couple of methods are available on the Au-
propargylic carbon
part of ring
(a) propargylic substitution via SN1 followed by cyclization
R3
R2
R2
R1
O
C
R2
R3
OH
R1
OH
R3
HO
R1
substitution
at acetylenic carbon
propargylic carbon
part of ring
(b) cyclizationvia allene to chromene
Me
R
Me
R
R2
R3
O
cyclo
isomerization
O
C
R2
O
R2
R3
R4
R4
R1
OH
R3
R
R4
R1
S
N2I
R1
substitution at
acetylenic carbon
propargylic carbon
out side the ring
(c) Single-Pot-Synthesis via SN2I, followed by Cycloisomerization of homoallenyl-
ketone (This Work)
Figure
1 Schematic representation of differences in the
regioselectivity between the previous (a,b) and current works (c).
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Table 2 Scope of Ca(II)-catalyzed regiospecific annulation of
and 2 a
1
The rationale for the regiodivergent one-pot annulation and
cycloisomerization is depicted in Figure 2.A nucleophilic
substitution of activated propargyl alcohol with 1,3-diketone
.
at the acetylenic car
bon takes place through SN2I mechanism
OH
R2
R3
R4
Me
O
R1
Me
10 mol% Ca(NTf2)2
DBU (3 eq.), DCE, rt
to furnish the allene intermediate, which follows regioselective
cyclization to yield the tetrasubstituted furan. This hypothesis
can also be supported by the popular concept of thehard-soft
acid-
base theory proposed by Pearson.8 The proposed reaction
R2
R3
O
O
R4
+
Me
(2a; R4=Me)
(2b; R4=OEt)
O
R1
(1)
(3)
path (SN2I) is favourable by soft-soft interactions to form the
allene intermediate9followed by hard-hard interactions of
carbonyl oxygen with acetylenic carbon (sp hybridized) of
allenyl ketone (Figure 2) to furnish the substituted furan
(Figure 2).
Me
Me
Me
Me
Me
Me
O
Ph
Me Me
O
Ph
Ph
O
O
O
O
3c
78%, 6 h
3b
79%, 5 h
3a
80%, 5 h
EtO
Ph
Me
O
Me
Me
Me
Me
Ph
Ph
Me
O
O
Ph
O
O
Figure 2 Rationale for our synthetic design
O
3f
79%, 6 h
3e
78%, 7 h
3d
79%, 7 h
scope at C4 (from alkyne substitution of 1)(3a to 3e)
Cl
Results and discussion
Table 1 Optimization of reaction conditions for the annulation of 1a
and 2a#
Ph
Ph
Me
O
Me
Me
O
Me
Ph
Ph
O
O
X-ray structure
of 3h
CCDC-1863704
3h
80%, 6 h
3g
F
F
MeO
78%, 5.5 h
Me
Me
Ent Catalyst (mol%)
ry
Base
(equiv.)
Reaction
conditions
DCE, rt, 24 h
Yield
3a(%)
0a
Me
Me
Me
Ph
Me
Me
O
1
2
3
4
Ca(OTf)2/Bu4NPF6
(10/10)
Ca(OTf)2/Bu4NPF6 DBU (1)
(10/10
Ca(OTf)2/Bu4NPF6 DBU (3)
(10/10)
Ca(NTf2)2/Bu4NP DBU (3)
F6(10/5)
Me
CH3
CH3
Ph
Ph
O
O
Ph
O
20b
37b
64
O
O
DCE, rt, 12 h
DCE, rt, 12 h
DCE, rt, 12 h
O
O
3i
3j
80%, 6 h
F
3k
78%, 6 h
Cl
3l
78%, 6 h
79%, 6 h
F
F
scope of substitutions on aryl rings at C5 (3f to 3l)
Ph
Ph
OEt
5
6
7
8
9
Ca(NTf2)2(10)
Ca(NTf2)2(20)
Ca(NTf2)2(5)
Ca(NTf2)2(10)
Ca(NTf2)2(10)
DBU (3)
DBU (3)
DBU (3)
DBU (1)
DABCO
(3)
DCE, rt, 6 h
DCE, rt, 6 h
DCE, rt, 6 h
DCE, rt, 6 h
DCE, rt, 12 h
80
80
71
68
55
Me
OEt
Ph
Me
Me
O
Me
Ph
Ph
O
O
O
O
O
3m
3n
3o
Cl
scope with β-keto esters
77%, 5.5 h
79%, 6 h
78%, 5.5 h
10 Ca(NTf2)2(10)
11 Mg(OTf)2/Bu4NP DBU (3)
F6 (10/10)
K2CO3 (3) DCE, rt, 12 h
DCE, rt, 12 h
45
35
aA mixture of
1 (1 equiv.), 2 (1.5 equiv.) was used, DBU was added after the
consumption of1 or after the formation of allene (monitored by TLC)
12 PTSA (10)
13 Ca(NTf2)2(10)
14 Ca(NTf2)2(10)
DBU (3)
DBU (3)
DBU (3)
DCE, rt, 12 h 56
CH3CN, rt, 12 h 40
The implementation of our hypothesis was commenced by
stirring a mixture of 1,1,3-triphenylprop-2-yn-1-ol (1a, 0.35
mmol),10 3-methylpentane-2,4-dione (2a,0.52 mmol) and 10
mol% Ca(OTf)2/Bu4NPF6in DCE at rt. This leads to the formation
of allene intermediate (1a2a) in 45% after 40 minutes, but not
the desired product (entry 1, Table 1). There is no further
change in the reaction even after continued for 24 h.
Presuming that a base is required for cyclization of this allene,
toluene, rt, 12
h
25
15 Ca(NTf2)2(10)
16 Ca(NTf2)2(10)
DBU (3)
DBU (3)
EtOH, rt, 12, h
neat, rt, 12 h
nr
50
#Reaction conditions: substrates 1a (0.35 mmol), 2a (0.52 mmol),
a
isolated yields. 3a was not formed but 45% of allene intermediate
(1a2a) formed, bremaining mixture contains allene and 1a. Base was
added after the formation of allene intermediate.
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we have added DBU (1 equiv) after the formation of allene
ARTICLE
(approximately 40 minutes, monitored by TLC) and found that Our attempts to minimize the loading of catalyst or base
the formation of desired dihydrofuran (3a) 1-(5-benzhydryl-3- (entries 7 and 8), and search for their alternatives by replacing
methyl-2-methylene-4-phenyl-2,3-dihydrofuran-3-yl)ethan-1-
DBU with other bases such as DABCO, K2CO3(entries 9, 10);and
one in 20% yield along with some unreactive allene and 1a replacing Ca(II) with Mg(II), PTSA and by substituting DCE with
(entry 2, Table 1).The coupling constant of olefinic protons of other solvents (acetonitrile, toluene and ethanol) or the
3a is (2.8 Hz) found to be in the range of geminal coupling. absence of solvent were unsuccessful (entries 9-16).
When DBU was added in 3 equiv. the reaction yield was Having established the standard (optimum) reaction
slightly improved to 37% (entry 3). An attempt with conditions (entry 5, Table 1) for the regiospecific annulation of
Ca(NTf2)2/Bu4NPF6 (10/5 mol%) gave us the encouraging yield 1a and 2a, we were keen to check the generality of this
of 3a in 64%, with DBU (3 equiv.) at rt after 12 h (entry 4). protocol. Accordingly, we prepared different propargyl
Interestingly the combination of 10 mol% Ca(NTf2)2/DBU (3 alcohols10 using a variety of terminal alkynes (keeping the
equiv) gave 80% of 3a at rt in 6 h (entry 5), further increase of benzophenone constant) such as 4-methylphenyl (1b), 4-
the catalyst loading was not helpful for the betterment of the butylphenyl
reaction yield (entry 6).11
acetylenes and treated them with 2a under standard reaction
Table 3 Scope of Ca(II)-catalyzed regiospecific [3+2] annulation condition and obtained the respective 2-methylene-2,3-
of dihydrofurans 3b 3e in good yields (Table 2). Next, we
and 1,3-diketones.a
(1c), 4-ethoxyphenyl (1d), cyclopropyl (1e)
1
-
examined the scope of the substitutions on propargylic
phenyls and realized that the substitutions are compatible
with the protocol and yielded the dihydrofurans 3f-3lin good
yields. The structural conformation of3h was further
supported by the single crystal X-ray data.12 Compound 3m
was prepared from 9-(phenylethynyl)-9H-fluoren-9-ol (1o) and
2a in 77% yield.The scope of ethyl 2-methyl-3-oxobutanoate
(
2b) as the nucleophilic partner was examined by synthesizing
the respective dihydrofurans 3n and 3o in good yields (Table
2).
Encouraged by this novel regiospecific annulation protocol of ynols
(1) with α-methyl-1,3-dicarbonyl compounds (2a, 2b), we aimed to
check whether a simple 1,3-diketone (without having methyl
substitution on α-carbon) such as acetylacetonecan react with ynols
in a similar way or not. Therefore a mixture of 1a, pentane-2,4-
dione (2c) and Ca(NTf2)2 (10 mol%) was stirred in DCE at rt for 50
min and added DBU (3 equiv.) and continued the reaction for 18 h
and obtained the desired furan 4a in 15 % yield along with diene
1a2c. The reaction yield was increased to 75% by refluxing it in DCE
for 18 h. In the next experiment, we refluxed 1a and 2c in
acetonitrile with 10 mol% of Ca(OTf)2/Bu4NPF6for 50 minutes and
added 3 equiv. DBU and obtained the yield of 4aby 80% after 8 h.
Therefore we considered this as the suitable condition and
extended this to check the generality of this protocol (Table 3). We
found that the annulation reaction of 2c was compatible with the
propargylic substitutions (of 1) such as diphenyl, dimethyl, phenyl-
methyl and cyclopropyl-methyl in providing the corresponding
furans with diversity at 5th position (4a to 4d) in good yields (Table
3). Also, the substitutions on the propargylic phenyl groups of 1
were tolerated by this protocoland furnished the respective tetra-
substituted furans 4e-4j in good yields.The structure of 4h was
further confirmed by the single crystal X-ray data.121-phenylbutane-
1,3-dione (2d) is proved as a good annulation partner with 1 and
furnished corresponding furan derivatives 4k-4min good yields.
Ethyl acetoacetate and methyl acetoacetatesalso participate in the
annulation with 1 under standard reaction conditionand yielded the
furans 4n to 4r in good yields (Table 3).
aA mixture of
1 (1 equiv.), 2 (1.5 equiv.) was used, DBU was added after the
consumption of 1 or after the formation of allene (monitored by TLC)
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CH3
O
Ph
Ph
Pd/C, H2, MeOH,
rt, 12 h, 78%
CH3
Ph
Ph
O
O
CH3
Ph
5
CH2
CH3
Ph
CH2
CH3
Ph
Ph
O
H3C
NaBH4, EtOH,
O
O
oC to rt, 3 h, 80%
3a
OH
CH3
Ph
6
Scheme 1. Functional group transformation of dihydrofuran 3a
Synthetic transformation of dihydrofuran 3a is depicted in the
Scheme 1, hydrogenation of exo-double bond (5% Pd/C, H2, MeOH)
gave the dihydrofuran derivative 5 in 78% yield. A reduction of
ketone functionality of 3a was also performed with NaBH4 to obtain
the alcohol 6 in 80% yield.
Scheme 3 Possible reaction mechanism
Scheme 2. Isolation of intermediates to propose the reaction
mechanism
Conclusions
Before proposing the reaction mechanism, we have isolated
the homo-allenyl ketone intermediate formed1a2a during the
synthesis of 3a by the annulation of 1a and 2a. Similarly, diene
intermediate 1a2c was isolated from the annulation reaction
of 1a and 2c during the synthesis of 4a (Scheme 2).
In conclusion, we have developed a facile Ca(II)-catalyzed
regiospecific [3+2] annulation of tert-propargyl alcohols and
acyclic 1,3-diketones. This approach is first and unique interms
of mode of annulation, which proceeds through the formation
of homo-allenyl ketone (SN2I) and regioselective
cycloisomerization to form structurally unique furans.
Dihydrofurans were synthesized at room temperature.
Intermediates were isolated in both the series and we have
demonstrated a couple of functional group transformations of
the dihydrofuran. Large substrate scope, good yields, use of
Ca(II) as the catalyst and one-pot reaction are some of the
highlights of this work. We strongly believe that this approach
will enable to explore the medicinal and material applications
of these new chemical entities (NCE) owing to their structural
uniqueness and ofcourse the privileged nature.
The possible reaction mechanism for the Ca(II)/DBU mediated
annulation of
1
and
2
is described in the Scheme 3. Initially,
the tautomer of
2
adds to the activated propargyl alcohol
through the SN2I mechanism, which is facilitated by the soft-
soft interactions and yields the kinetically stable homo-allenyl
ketone intermediate, allene-1. This allenyl intermediate
further reacts with DBU and gives enol intermediate (
then undergo cyclization ( ) and isomerization provides the
quaternary centred dihydrofuran . If there is no substitution
on the
-carbon (R4=H) of allene-1, it will undergo
isomerization to give a 1,6-conjugated system ( ). Then DBU
reacts with methyl ketone of and gives enol , which
subsequently undergoes cycloisomerization via 5-exo trig
A) which
B
3
α
C
C
D
Conflicts of interest
passion to furnish fully substituted furan 4.
There are no conflicts to declare.
Acknowledgements
This work is financially supported by SERB no-EMR/2016/4812
and CSIR no-02(333)/18/EMRII India. PR thanks CSIR for the
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C8OB02158A
Journal Name
ARTICLE
Regiospecific formal [3+2] Annulation of tert-Propargyl alcohols with acyclic 1,3-
diketones via the Cycloisomerization of homoallenyl ketones
Srinivasarao Yaragorla,* and P. Rajesh
A one-pot, regiospecific synthesis dihydrofurans bearing a quaternary centre and tetrasubstituted furans is developed from the formal [3+2] annulation of
tert-propargyl alcohols and 1,3-diketones under Ca(II)/DBU conditions. The reaction proceeds through SN2I mechanism to form homoallenyl ketone and a
subsequent cycloisomerization to yield a novel and new chemical entities of privileged scaffolds.
OH
R1
R2
R1
R2
R1
R2
Me
Me
O
O
Ca(II)/DBU
R4
+
CH2
R4
O
or
HO
R3
R4
R1
R3
R
R
R4
R3
if R3=H
C
R
R2
via homo-allenyl-enol
R
First-Regiodivergent approach 37 compounds
Isolation of intermediates;
Synthetic transformations
regiospecific [3+2] annulation
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