Metal-Free Regioselective Cross Dehydrogenative Coupling of Cyclic Ethers and Aryl Carbonyls

Article abstract of DOI:10.1021/acs.joc.8b03048

A highly regioselective, efficient, and metal-free oxidative cross dehydrogenative coupling (CDC) of aryl carbonyls with cyclic ethers has been developed. This method offers easy access to substituted α-arylated cyclic ethers with a high functional group

Full text of DOI:10.1021/acs.joc.8b03048

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Article
Metal Free Regioselective Cross Dehydrogenative
Coupling of Cyclic Ethers and Aryl carbonyls
Kishor D Mane, Anagh Mukherjee, Kumar Vanka, and Gurunath M. Suryavanshi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03048 • Publication Date (Web): 15 Jan 2019
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The Journal of Organic Chemistry
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Metal-Free Regioselective Cross Dehydrogenative Coupling of Cyclic
Ethers and Aryl carbonyls
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Kishor D. Mane, †‡ Anagh Mukherjee, £‡ Kumar Vanka, £‡ and Gurunath Suryavanshi *†‡
†Chemical Engineering & Process Development Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road,
Pune-411008, India
£ Physical and Material Chemistry Division, CSIR-National Chemical Laboratory, Dr. Homi bhabha Road, Pune-411 008
‡Academy of Scientific and Innovative Research (AcSIR), New Delhi 110 025, India
KEYWORDS: Metal- free •
Regioselective • CDC • DFT
O
O
R1
R2
H
R1
R2
R1= H, CH2,
CH3, Ph
K2S2O8
O
( )n
X
CDC
NaOAc, Bu4NCl,
120 oC, 1-4 hr
H
O
( )n
X
37 examples
n= 1, 2
X=CH2, O
Metal Free
High Regioselective Reaction
Broad Substrate Scope
Yields up to 92%
ABSTRACT: A highly regioselective, efficient and metal free oxidative cross dehydrogenative coupling (CDC) of aryl carbonyls
with cyclic ethers has been developed. This method offers easy access to substituted α-arylated cyclic ethers with high functional
group tolerance in good to excellent yields. The regioselectivity of this CDC reaction was confirmed by density functional theory
(DFT) based calculations.
F
O
O
O
O
H
H
O
INTRODUCTION
O
F3C
Cl
Functionalized cyclic ethers are important scaffolds that are
found in a variety of natural products and pharmaceutical
ingredients.1 Generally, tetrahydrofuran (THF), 1,4-dioxane
and tetrahydropyrans (THP) are the examples of cyclic ethers.
These compounds show a broad spectrum of biological
O
O
O
Sesamin 2
Pesticide 1
O
O
O
O
O
2a
2b
activity, including antibacterial,
anti-inflammatory,
OH HO
Galbacin 3
anticancer, 2c-e, and antidiabetic.2f-g They have also been
employed in the synthesis of agricultural pesticide 1(figure 1).3
Lignin’s are the class of natural compounds that exclusively
contain substituted THF as a core unit.5 Examples of lignin’s
includes sesamin 2 and galbacin 3 (figure.1).These compounds
HO
OH
F
O
S
O
O
O
H
H
Me
N
N
N
O
F
H2N
Omarigliptin 5
4a
4b
are known to exhibit anticancer,
antioxidant,
anti-
properties.
Strebluslignanol F 4
4c
4d
inflammatory,
and
antiobesity
Strebluslignanol F 4, a natural product, contains 1, 4-dioxane
as core unit and shows potent anti-hepatitis B virus activity.5a
On the other hand, omaragliptin 5 is an oral antidiabetic drug
with substituted THP as the core moiety.5b
The formation of the C-C bond via C-H bond activation of
sp3, sp2 hybridised carbons as cross-coupling participants has
generated renewed attention over the last few decades.6a-b
However, sp3 C–H bond activation is a challenging task due to
their inertness, gained from high bond energy and high pKa
values. Hence, CDC reactions have attracted the attention of
organic chemists for the preparation of C-C bonds under metal
and metal-free conditions in academic as well as industrial
research.6c-f
Figure 1: Biologically Active Cyclic Ethers
After a careful survey of the literature, we realised that both
metal and metal-free approaches have been employed for the
oxidative cross dehydrogenative coupling of cyclic ethers with
arenes and heteroarenes. Some of these important methods
include the use of transition metals such as Cu (I) catalysed
cross coupling between substituted 1, 1’-diarylethenes and
cyclic ethers, 7 Cu (II) catalysed addition of α-oxyalkyl radical
8
to isoquinolinium salts and Fe (II) catalysed α-arylation of
cyclic and acyclic ethers with azoles.9 Also, Doyle and co-
workers have achieved α-arylation of cyclic ethers through Ni
(II) catalysed photoredox coupling between aryl halide and
cyclic ethers, as shown in Scheme 1.10
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Various electron deficient heterocyclic arenes were sub-jected
Page 2 of 9
equivalence of tetra butyl ammonium bromide (A) from 2 to 3
and refluxing at 120 oC, we obtained 57% yield of the desired
product (Table1, entry 3). When terta butyl ammonium
chloride (B) was used instead of tetra butyl ammonium
bromide (A) as an additive and the mixture refluxed for 4 h,
we got the expected product in 81% yield, which was a
significant improvement (Table1, entry 4) in comparison to
the first 3 entries (Table1, entry 1 to 3). It was also observed
that the reaction did not proceed in the absence of additive as
well as base (Table1, entry 5 & 6) and resulted in the recovery
of the starting material. By increasing the additive tetra butyl
ammonium chloride (B) from 3 to 4 equiv, we observed
increase in yields only by 4% (Table1, entry 7). Keeping the
tetra butyl ammonium chloride (B) (3 equiv), K2S2O8 (3 equiv)
constant
1
2
3
4
5
6
7
8
for α-arylation of cyclic and acyclic ethers under oxidative
metal-free conditions using a variety of oxidants such as
DTBP, TBHP, BPO and K2S2O8. These heterocycles contain
substituted pyridines,11 thiophenes,12 indoles,13 quinines,14
azoles15 and chromanes.16 Although these methods are
efficient towards yielding the CDC product, they are limited
to activated heterocyclic systems. Recently, Shirakawa et al.
reported base promoted oxidative dehydrogenative coupling
between a substituted benzene derivative and cyclic ethers, as
well as amides, in the presence of DTBP oxidant and NaOt-
Bu, base.17 Despite some advantages, the reaction suffers
from certain limitation’s such as, poor yields and poor
regioselectivity when electron withdrawing substituent’s were
present on the aryl rings.
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Table 1. Optimisation Conditions for Cross Dehydro-
genative Coupling
Doyle et.al.
Cl
Ac
O
O
1,4-Dioxane,
Photocatalyst (2 mol%)
Ni(cod)2 (10 mol%)
Oxidant, Base
Me
Me
Ac
O
1,4-Dioxane,K3PO4 ,
O
O
O
Additive, Time,
120 oC.
78% yield
6a
7a
S
O
D
Shirakawa et.al.
R
R
t-BuOOt-B (1 equiv)
NaOt-Bu (0.2- 2 equiv)
O
X
N
A. X= Br
B. X= Cl
C. X= F
OLi
O
THF, 120 oC, 24 h
-----------------------------------------------------------------------------------
F3C
This Work
Additive
K2S2O8 ( 3 eq),
O
O
NaOAc (2 eq),
Entry
1
Oxidant
Addtive
(equiv)
Base
(equiv)
Time
(h)
Yield
(%)a
R
R
( 3 equiv)
O
O
Bu4NCl ( 3 eq),
1,4-Dioxane,
120 oC,1-4 hr
K2S2O8
A (2)
NaOAc (2)
4
51
R= H, CH2,
CH3, Ph
2
3
4b
5
6
7
8
9
10
11c
12d
13
14
15
16
17
18
19
20
21
22
23
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
Na2S2O8
(NH4)2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
Oxone
A (2)
A (3)
B (3)
B (3)
-
B (4)
B (3)
B (3)
B (3)
B (3)
C (3)
B (3)
B (3)
B (3)
B (3)
-
NaOAc (2)
NaOAc (2)
NaOAc (2)
-
12
4
4
4
12
4
45
57
81
N.R.
N.R.
85
58-92 % yield
Scheme 1: Strategies for the α-Arylation of Cyclic Ethers
NaOAc (2)
NaOAc (2)
NaOAc (4)
NaOAc (2)
NaOAc (2)
NaOAc (2)
NaOAc (2)
K2CO3 (2)
NaOEt (2)
Cs2CO3 (2)
NaOtBu(2)
Bu4NOH
4
79
31
To overcome these shortcomings and inspired by metal free
our motive has been to develop a synthetic
method for the α-functionalisation of cyclic ethers with better
12
12
12
4
4
4
4
4
4
12
12
4
4
4
18
N.R.
N.R.
67
N.R.
70
N.R.
N.R.
N.R.
55
N.R.
17
approaches,
yields and regioselectivity (Scheme 1). Thus, we have
described the
metal free CDC reaction via Csp3–Csp2
coupling between various cyclic ethers and aromatic carbonyls
to generate a wide range of α-arylated cyclic ethers. The key
features of this reaction are: short reaction time, good to
excellent yields and high regioselectivity.
D (2)
D (2)
B (3)
B (3)
B (3)
B (3)
NaOAc (2)
-
NaOAc (2)
NaOAc (2)
NaOAc (2)
NaOAc (2)
RESULTS AND DISCUSSION
TBHP
DTBP
BPO
N.R.
Trace
N.R.
4
We have started our investigation, by taking acetophenone as
a model substrate and 1,4-dioxane as a coupling partner as
well as solvent. The results are summarised in Table 1.
[b] TBACl in 50% aq. solution. [c] Temp. 80 oC. [d]
Bu4NF.3H2O. N.R. = No Reaction.
Initially, when acetophenone 6a (1 equiv) and 1,4-dioxane
(30 equiv, also acts as solvent) are reacted at 120 °C in the
presence of oxidant K2S2O8 (3 equiv), tetra butyl ammonium
bromide (A) (2 equiv) as an additive and NaOAc (2 equiv), to
our delight we got the expected product 7a in 51% yield
within 4 h of reaction time (Table1, entry 1). When the
reaction time was increased from 4 h to 12 h, the yield of 7a
was reduced to 45%, as a result of decomposition of the
obtained product (Table1, entry 2). With increased
and increasing the stoichiometry of NaOAc (2 to 4 equiv) lead
to 79 % yield for the CDC product (Table 1, entry 8). In
continuation, the oxidant Na2S2O8 offers only 31% yield of the
desired product (Table 1, entry 9). No conversion was
observed using (NH4)2S2O8 (Table 1, entry 10). However, no
significant improvement was observed with the use of
different combinations of additives and bases. Instead, most of
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The Journal of Organic Chemistry
the attempts were not fruitful (Table 1, entry 11-23). However,
substituents at different positions on the aryl ketones,
providing the coupling products in moderate to good yields.
1
2
3
4
5
6
7
8
changing the bases didn’t lead to enhancement in the yields. In
order to examine the effect of atmospheric oxygen, the
reaction was conducted under inert atmosphere, which did not
affect the yield. In addition to this, the effect of the solvent
was also studied (see SI). Therefore, the best regioselectivity
and the highest yield of isolated product were achieved by
using K2S2O8 (3 equiv), terta butyl ammonium chloride (B) (3
Equiv) and NaOAc (2 equiv) for the reaction at 120 oC for 4 h
(Table1, entry 4).
With these optimized reaction conditions in hand (Table 1,
entry 4), the substrate scope of this unique transformation and
limitations of the CDC reaction were studied by evaluating a
variety of aryl carbonyls in order to investigate the generality
of this reaction.
When the
electron withdrawing and electron donating
groups were present at the position meta to the acetyl group
and the reaction done under optimised conditions, the desired
products were obtained in excellent yields (7b,7c,7f). The
unsubstituted acetophenone was subjected to the standard
reaction conditions with THP as a coupling ether, and gave the
desired product 7e in 66% yield. 1-Acetonaphthone also gave
the expected α-arylated products of different cyclic ethers with
excellent yields (7d, 7g, 7o). On the other hand, substituted
cyclic ketones such as indanone and tetralone resulted in
moderate yields of the products (7l-7n). It is noteworthy that
thioxanthone successively yielded CDC product 7k under
oxidation conditions without any adverse effect of the sulphur.
When acetophenone subjected under the standardized reaction
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Scheme 2: CDC Reaction between Aromatic Ketones and
conditions using 1,3-benzodioxole as
a
solvent, the
corresponding product 7r was formed in 58 % yield. Also,
acyclic ethers as coupling partners led to undesired
polymerisation. Unfortunately this approach failed to yield the
expected CDC products (7s-7x) when the reaction was carried
out on N-substituted aryl carbonyls and heterocyclic aryl
ketones.
Next, we examined the efficiency of substituted aldehydes
as coupling partners under the optimized experimental
conditions. Notably, it was observed that the rate of the CDC
reaction between benzaldehydes and cyclic ethers was faster
than for the aryl ketones.
O
K2S2O8 (3 equiv.),
NaOAc (2 equiv.)
O
H
R
R1
R
R
R1
OR
Solvent
R
TBACl (3 equiv.)
120 oC, 1-4h
6a - 6r
R1 = CH3,CH2,Ph
7a-7r
OR
-----------------------------------------------------------------------------------------------
O
O
O
Br
F
Me
Me
Me
Me
Me
O
O
O
O
O
O
7b
7c,
7d,
75%
, 80%
84%
Scheme 3: CDC Reaction between Aromatic Aldehydes
and Cyclic Ethers
O
O
O
Br
Me
O
O
O
O
O
K2S2O8 (3 equiv.),
NaOAc (2 equiv.)
H
R
7f
, 79%
H
H
R
R
7e
7g
, 82%
, 66%
O
R
OR
Solvent
O
S
TBACl (3 equiv.)
120 oC, 1-2 h
OR
8a 8m
9a 9m
-
-
O
O
O
O
-------------------------------------------------------------------------------------------
R
O
O
OMe
O
OMe
7h
7i,
, R= H, 72%
R= Br, 67%
, R= Cl, 61%
7h
XRD of
CCDC 1875062
R
7k
, 74%
H
H
H
7j
O
O
O
O
O
O
O
O
O
OMe
O
O
O
9a
9b
9c
9d
, 82%
, R= OMe, 79%
, R= Cl, 85%
, 92%
O
Br
7m
O
O
7n
, 62%
7l
, 67%
, 70%
O
R
OMe
O
O
O
H
F
H
H
O
H
R
Me
O
Me
O
Me
O
O
OMe
O
O
9e
9f
9g
9h
, 86%
OH
, 70%
, R= Cl, 89%
, R= OH, 71%
7p
7q
, R= OMe, 78%
, R= Br, 84%
7r
, 58%
7o
, 87%
O
O
O
O
R
R
7s,R= NO2, 0%
7t, R= NH2, 0%
7u,R=NHBn, 0%
7v, R= NBn2 0%
7w, R= NMe2, 0%
Me
H
Me
O
O
O
N
O
O
O
7x, 0%
9k, R = CN, 0%
9i
9j
, 80%
, 62%
Cyclic Ethers
9l, R = NO2, 0%
9m, R = CO2Et, 0%
Reaction condition: 6a (0.83 mmol), K2S2O8 (2.5 mmol),
TBACl (2.5 mmol 50% aq. solution), NaOAc (1.66 mmol),
1,4-Dioxane (3 ml) and Temp. 120 oC.
Reaction condition: 8a (0.73 mmol), K2S2O8 (2.20 mmol),
TBACl (2.20 mmol 50% aq. solution), NaOAc (1.47 mmol),
1,4-Dioxane (3 ml) at 120 oC.
As shown in scheme 2, the CDC reaction proceeds without
any difficulty for a wide range of substrates bearing various
Various substrates having electron-withdrawing substituents,
such as Cl, Br, and F groups on the aromatic ring of the
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aldehydes were efficiently reacted to produce the substituted
derivative 16 in quantitative yield. Subsequently, the same
compound 9d was converted into its 1,2-benzimidazole
derivative under the known protocol.19
In order to understand the mechanism of this CDC
reaction, we carried out control experiments (Scheme 6),
1
2
3
4
5
6
7
8
para-alkylated benzalehydes with excellent yields (Scheme 3,
entries 9b, 9e and 9g). Surprisingly, hydroxy substituted
benaldehydes also offer good yields of alkylated aryl
carbonyls under oxidative conditions (9h and 9i).
Benzaldehydes with different elec-tron donating substituents
also led to the corresponding product with good to excellent
yields. (9c, 9d & 9f). A reaction performed with 2,5-
dimethoxy benzaldehyde on a 6 mmol scale provided 9d in
79% yield. Cyano, nitro and carboxylate substituted aryl
derivatives were unable to give the desired product with our
optimized reaction conditions. (9k-m).
When benzil, α, α‘-dimethyl acetal was subjected to the
reaction under standard reaction condition, it gave unexpected
products. In THF, the acetal group remained unaffected,
whereas in 1,4-dioxane, it got deprotected to ketone (Scheme
4). An uncommon phenomenon that has been observed is that
the presence of bromine on the ortho or para position to the
aryl carbonyls delivers unexpected debrominated products, i.e.
14 and 9e, as shown in Scheme 4.
where two
equivalents of TEMPO (2,2,6,6-tetramethyl
piperidine-N-oxide) were added into the reaction system under
optimized reaction conditions. It was observed that the THF
radical coupled with TEMPO to from a TEMPO-THF adduct
18, instead of the expected product 7a. This indicates that the
reaction might be proceeding via the radical pathway. In the
second control experiment, when the reaction was performed
with p-substituted aryl ketone, we did not obtain the expected
ortho alkylated product 19.
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10
11
12
13
14
15
16
17
18
19
20
21
22
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Scheme 6: Control Experiments
O
O
N
K2S2O8 ( 3 eq )
NaOAc ( 2 eq )
1.
O
Me
O
N
O
TBACl ( 3 eq )
120 oC 2h
(2 eq.)
O
6a
18
Me
Scheme 4: Some Unexpected Result of CDC Reaction
O
2.
Standard Reaction
condition
Me
O
O
THF,
R
R
O
MeO
1.5h
OMe
19
R = Me, OMe, Cl
K2S2O8 (3 equiv),
NaOAc (2 equiv)
O
11
, 90 %
O
This indicates that the reaction regioselectively goes only to
O
MeO
O
OMe
TBACl (3 equiv.)
the para position. Based on the above control experiments and
1,4-
Dioxane
120 o
C
10
20, 21
the reported literature,
the possible catalytic cycle was
O
then initially proposed in scheme 7, as the α-oxyalkyl radical
O
12
, 61%
3h
O
R
K2S2O8 (3 equiv),
NaOAc (2 equiv)
O
Scheme 7: Expected Reaction Mechanism of Dehydro-
genative Coupling
Me
Me
R1
TBACl (3 equiv.)
120 oC, 3 h
O
13a
13b
, R=Br, R1=H 77%
, R=H, R1=Br 53%
14
TBACl
2-
2SO4
Sulfate
Radical
O
O
S2O8
O
Br
K2S2O8 (3 equiv),
NaOAc (2 equiv)
O
H
O
Me
H
O
O
HSO4
NaOAc
2-
O
O
SO4
Me
O
TBACl (3 equiv.)
120 oC, 1 h
F
9e
7a
Single
H
F
15
67%
Electron
Oxidation
21
O
O
H
HOAc
O
O
Me
22
oxyalkylradical
To show the utility of the reaction, the para-alkylated aryl
carbonyl derivatives were further functionalized under various
reaction conditions, as shown in scheme 5. The compound 9d
was subjected for the hydrogenation reaction using Pd/C; the
aldehyde group of 9d got reduced to methyl to give the
toluene
20
O
O
H
Me
O
21
Scheme 5: Synthetic Transformations of the Products
OMe
20 was generated via hydrogen atom abstraction from 1,4-
dioxane by persulfate.20 Then, this α-oxyalkyl radical 20
reacted with acetophenone 6a to generate the aryl radical
species 21. This was followed by single electron oxidation to
CH3
H2, Pd/C
O
OMe
MeOH
CHO
OMe
, 94%
OMe
21
O
form the aryl cation species 22. The aryl cationic species
16
O
O
further underwent aromatization to form the desired product
7a.
In order to elucidate the reasons behind the para product
being formed exclusively, quantum chemical calculations have
been done using density functional theory (DFT). (see SI for
more details, Fig. S1 and S2).
H
N
OMe
9d
O
Ref.19
O
MeO
N
o-Phenylene
diamine
17
, 78%
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The Journal of Organic Chemistry
CDCl3): δ 7.99 - 7.87 (m, J = 8.4 Hz, 2H), 7.54 - 7.39 (m, J = 8.0
CONCLUSION
1
2
3
4
5
6
7
8
Hz, 2H), 4.68 (dd, J = 2.3, 9.9 Hz, 1H), 3.98 - 3.94 (m, 1H), 3.92
(dd, J = 2.3, 11.1 Hz, 1H), 3.89 - 3.86 (m, 1H), 3.83 - 3.79 (m,
1H), 3.74 (dd, J = 3.1, 11.4 Hz, 1H), 3.41 (t, J = 10.9 Hz, 1H),
2.59 (s, 3H)). 13C{1H} NMR (126 MHz, CDCl3): δ 197.6, 143.4,
136.7, 128.4, 126.2, 77.3, 72.1, 66.9, 66.2, 26.5; HRMS (ESI) m/z
calculated for C12H15O3 [(M+H)+] 207.1016, found 207.1019.
1-(3-bromo-4-(1,4-dioxan-2-yl)phenyl)ethan-1-one
In conclusion, we have developed the first efficient and
metal free CDC reaction of aromatic carbonyls with inactive
cyclic ethers to give the desired p-alkylated aryl aldehydes and
ketones in good to excellent yields with high regioselectivity.
In addition, this reaction tolerates various functional groups
under oxidative conditions and can be applied to obtain a wide
range of substituted aromatic carbonyls. The utility of the
products of CDC were shown by converting them to
benzimidazole heterocycles and the toluene derivative.
o
(7b): white solid. Yield: 80% (114 mg); M.P.: 87-89 C. 1H
NMR (500MHz , CDCl3): δ 8.02 (d, J = 1.5 Hz, 1H), 7.83 (dd, J =
1.5, 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 4.92 (dd, J = 2.5, 9.7
Hz, 1H), 4.01 (dd, J = 2.5, 11.6 Hz, 1H), 3.91 (s, 1H), 3.90 - 3.88
(m, 1H), 3.77 - 3.74 (m, 1H), 3.69 - 3.63 (m, 1H), 3.15 (dd, J =
9.7, 11.6 Hz, 1H), 2.51 (s, 3H)). 13C{1H} NMR (126 MHz,
CDCl3): δ 196.3, 142.6, 137.8, 132.4, 128.2, 127.4, 122.0, 77.0,
9
Experimental Section
General Information:
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Solvents were purified and dried using standard procedures before
use. All air and moisture sensitive reactions were carried out in
flame dried glassware under a positive pressure of dry argon using
standard techniques. Commercially available chemicals were used
without further purification unless otherwise mentioned. For
moisture sensitive reactions, tetrahydrofuran (THF) and
dichloromethane (CH2Cl2) were dried using standard solvent
purification system. The following dry solvents are commercially
available and were used without further purification:
Acetonitrile: Acros Organics, 99.9% extra dry, over molecular
sieves. Ethanol: Acros Organics, 99.5% extra dry. Methanol:
Acros Organics, 99.8% extra dry, over molecular sieves.
Technical solvents for column chromatography were used after
simple distillation. The reactions were monitored by TLC
visualized by UV (254 nm) and/or with iodine. The purification
was done using column chromatography on silica 60 (Merck, 230-
400 mesh) with the indicated eluent mixtures (v/v).
Nuclear Magnetic Resonance Spectra were recorded at room
temperature on a Bruker AVHD-200, AVHD-400, AVHD-500
spectrometers in appropriate solvents using TMS as internal
standard or the solvent signals as secondary standards and the
chemical shifts are shown in δ scales. Coupling constants are
given in hertz (Hz) and the classical abbreviations are used to
describe the signal multiplicities. 1H NMR spectra were
calibrated to the residual proton signal of chloroform-d1 (δ = 7.27
ppm), 13C NMR spectra were referenced to the 13C triplet of
CDCl3 (δ = 77.16 ppm). Apparent multiplets which occur as a
result of coupling constant equality between magnetically non-
equivalent protons are marked as virtual (virt.). Following
abbreviations for single multiplicities were used: br – broad, s –
singlet, d – doublet, t – triplet, q – quartet, m – multiplet. High
Resolution Mass Spectra (HRMS) for all new compounds were
recorded on a ESI+ method and ORBITRAP mass analyzer
(Thermo Scientific Q-Exactive, Accela 1250 pump). All
chemicals are purchased from Sigma-Aldrich and used without
further purification.
70.5, 67.1, 66.3, 26.6;
HRMS (ESI) m/z calculated for
C12H14O3Br [(M+H)+] 285.0121, found 285.0127.
1-(4-(1,4-dioxan-2-yl)-3-fluorophenyl)ethan-1-one
o
(7c): white solid. Yield: 84% (136 mg); M.P.: 116-118 C. 1H
NMR (500 MHz, CDCl3): δ 7.72 - 7.78 (m, 1H), 7.57 - 7.66 (m,
2H), 4.97 (dd, J = 9.9, 2.3 Hz, 1H), 3.91 - 4.00 (m, 3H), 3.80 -
3.84 (m, 1H), 3.70 - 3.77 (m, 1H), 3.36 (dd, J = 11.4, 9.9 Hz, 1H),
2.59 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3): δ 196.4 , 160.4-
158.4 (d, JF-C = 247.96 Hz), 138.4-138.3 (d, JF-C = 6.68 Hz),
130.8-130.7 (d, JF-C = 14.31 Hz), 128.04-128.01 (d, JF-C = 3.81
Hz), 124.4, 114.8-114.6 (d, JF-C = 22.89 Hz ), 71.9 , 70.9, 67.2 ,
66.3, 26.6 ; HRMS (ESI) m/z calculated for C12H14O3F
[(M+H)+] 225.0921, found 225.0928.
1-(4-(1,4-dioxan-2-yl)naphthalen-1-yl)ethan-1-one
(7d): gummy liquid. Yield: 75% (113 mg). 1H NMR (200MHz ,
CDCl3): δ 8.87 - 8.64 (m, 1H), 8.15 - 8.05 (m, 1H), 7.93 (d, J =
7.6 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.66 - 7.51 (m, 2H), 5.43
(dd, J = 2.4, 9.7 Hz, 1H), 4.18 - 4.04 (m, 3H), 3.95 - 3.76 (m, 2H),
3.50 (dd, J = 10.0, 11.9 Hz, 1H), 2.75 (s, 3H). 13C{1H} NMR (126
MHz, CDCl3): δ 201.7, 138.7, 135.5, 130.4, 129.9, 127.7, 127.3,
126.6, 126.5, 122.5, 122.1, 74.7, 71.9, 67.2, 66.4, 29.8; HRMS
(ESI) m/z calculated for C16H17O3 [(M+H)+] 257.1172, found
257.1171.
1-(4-(tetrahydro-2H-pyran-2-yl)phenyl)ethan-1one
(7e)): whitish semisolid. Yield: 66% (112 mg). 1H NMR
(200MHz , CDCl3): δ 7.97 - 7.86 (m, J = 8.3 Hz, 2H), 7.49 - 7.38
(m, J = 8.2 Hz, 2H), 4.39 (d, J = 10.6 Hz, 1H), 4.17 (dd, J = 2.9,
10.9 Hz, 1H), 3.71 - 3.56 (m, 1H), 2.60 (s, 3H), 1.86 (d, J = 12.3
Hz, 1H), 1.75 - 1.47 (m, 5H). 13C{1H} NMR (101 MHz, CDCl3):
δ 197.9, 148.7, 136.1, 128.4, 125.8, 79.5, 68.9, 34.1, 26.6, 25.7,
23.9; HRMS (ESI) m/z calculated for C13H17O2 [(M+H)+]
205.1223, found 205.1222.
1-(3-bromo-4-(tetrahydro-2H-pyran-2-yl)phenyl)ethan-
1-one (7f): Clear oil. Yield: 79% (113 mg). 1H NMR (500MHz
, CDCl3): δ 8.08 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.0
Hz, 1H), 4.65 (d, J = 10.7 Hz, 1H), 4.16 (d, J = 11.1 Hz, 1H), 3.65
(t, J = 10.7 Hz, 1H), 2.57 (s, 3H), 2.03 (d, J = 13.4 Hz, 1H), 1.93
(br. s., 1H), 1.74 - 1.65 (m, 2H), 1.60 (d, J = 8.4 Hz, 1H), 1.31 -
1.24 (m, 1H). 13C{1H} NMR (126 MHz, CDCl3): δ 196.4, 147.7,
137.1, 132.3, 127.5, 127.4, 121.5, 78.9, 69.0, 32.6, 26.5, 25.7,
23.7; HRMS (ESI) m/z calculated for C13H16O2Br [(M+H)+]
283.0328, found 283.0333.
Typical Experimental Procedure for the Synthesis of 1-(4-
(1,4-dioxan-2-yl) phenyl) ethan-1-one (7a):
To a 25 mL round-bottom flask acetophenone 6a (0.833 mmol,
100 mg), K2S2O8 (2.5 mmol, 676 mg), tetrabutylammonium
chloride (TBACl, 2.5 mmol, 1.4 ml) and NaOAc (1.66 mmol, 136
mg) was taken in 1,4-dioxane (3 ml). The round-bottom flask was
equipped with a condenser and the resulting reaction mixture was
refluxed to 120 °C for 4 h, and the progress of the reaction was
monitored by TLC. Upon completion of the reaction, the reaction
mixture was dried under vacuum. Then the crude reaction mixture
was diluted with ethyl acetate (10 mL) and washed with brine.
Eluted with EtOAc (25 mL * 2). The organics was evaporated and
the crude residue was preadsorbed on silica gel and purified by
column chromatography (100-200 mesh silica Using 80/20
petroleum ether/ethyl acetate as the eluent to afford the
corresponding compound 7a in 81% yield.
1-(4-(tetrahydro-2H-pyran-2-yl)naphthalen-1-yl)ethan-
1-one (7g): Gummy oil. Yield: 82% (123 mg). 1H NMR
(400MHz , CDCl3): δ 8.78 (d, J = 7.9 Hz, 1H), 8.07 (d, J = 7.9
Hz, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.71 (d, J = 7.3 Hz, 1H), 7.62 -
7.51 (m, 2H), 5.09 (d, J = 11.0 Hz, 1H), 4.31 - 4.22 (m, 1H), 3.85
- 3.73 (m, 1H), 2.74 (s, 3H), 2.11 - 1.99 (m, 2H), 1.86 - 1.78 (m,
2H), 1.72 - 1.64 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3): δ
201.6, 143.8, 134.5, 130.2, 130.0, 128.0, 126.9, 126.3, 125.9,
1-(4-(1,4-dioxan-2-yl)phenyl)ethan-1-one (7a): white
solid. Yield: 81% (139 mg); M.P.: 91-93 oC. 1H NMR (500MHz ,
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The Journal of Organic Chemistry
Page 6 of 9
122.9, 121.0, 76.6, 69.0, 33.2, 29.7, 25.6, 23.8; HRMS (ESI) m/z
125.2, 123.6, 79.9, 68.6, 38.8, 34.3, 29.5, 29.4, 25.7, 23.0; HRMS
(ESI) m/z calculated for C14H17O2 [(M+H)+] 217.1223, found
217.1222.
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calculated for C17H19O2 [(M+H)+] 255.1380, found 255.1378
(4-(1,4-dioxan-2-yl)phenyl)(Phenyl)methanone(7h):
White solid. Yield: 72% (106 mg); M.P.: 70-72 oC. 1H NMR
(200MHz , CDCl3): δ 7.84 - 7.77 (m, 4H), 7.65 - 7.55 (m, 1H),
7.54 - 7.44 (m, 4H), 4.73 (dd, J = 2.7, 10.2 Hz, 1H), 4.01 - 3.93
(m, 2H), 3.92 - 3.85 (m, 1H), 3.85 - 3.69 (m, 2H), 3.48 (dd, J =
10.2, 11.5 Hz, 1H)). 13C{1H} NMR (101 MHz, CDCl3): δ 195.6,
142.5, 137.3, 137.0, 132.0, 129.9, 129.7, 128.0, 126.3, 125.6,
125.1, 77.1, 72.0, 66.7, 66.0; HRMS (ESI) m/z calculated for
C17H17O3 [(M+H)+] 269.1172, found 269.1174.
1-(4-(tetrahydrofuran-2-yl)naphthalen-1-yl)ethan-1-
one (7o): White solid. Yield: 87% (123 mg); M.P.: 65-67 oC. 1H
NMR (400 MHz, CDCl3): δ 8.80 (d, J = 8.5 Hz, 1H), 7.94 (d, J =
7.3 Hz, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 7.3 Hz, 1H),
7.52 - 7.65 (m, 2H), 5.61 - 5.76 (m, 1H), 4.20 - 4.37 (m, 1H), 4.06
(q, J = 7.7 Hz, 1H), 2.75 (s, 3H), 2.54 - 2.70 (m, 1H), 1.96 - 2.13
(m, 2H), 1.87 (dt, J = 12.5, 6.6 Hz, 1H). 13C{1H} NMR (101
MHz, CDCl3): δ 201.8, 144.9, 134.7, 130.6, 130.4, 128.5, 127.4,
126.8, 126.3, 123.4, 120.2, 77.7, 68.9, 34.0, 30.0, 25.9; HRMS
(ESI) m/z calculated for C16H17O2 [(M+H)+] 241.1223, found
241.1226.
1-(3-methoxy-4-(tetrahydrofuran-2-yl)phenyl)ethan-
1-one (7p): Clear oil. Yield: 78% (114 mg). 1H NMR (400MHz
, CDCl3): δ 7.48 - 7.43 (m, 2H), 7.38 (s, 1H), 5.09 (t, J = 7.0 Hz,
1H), 4.10 - 4.00 (m, 1H), 3.90 - 3.85 (m, 1H), 3.84 - 3.80 (m, 3H),
2.52 (s, 3H), 2.36 (dd, J = 6.7, 12.8 Hz, 1H), 1.88 (qd, J = 6.9,
14.2 Hz, 2H), 1.62 - 1.55 (m, 1H). 13C{1H} NMR (101 MHz,
CDCl3): δ 197.8, 156.2, 138.4, 137.0, 125.3, 121.6, 108.6, 75.8,
68.6, 55.4, 33.0, 26.5, 25.8; HRMS (ESI) m/z calculated for
C13H17O3 [(M+H)+] 221.1172, found 221.1177.
9
(4-(1,4-dioxan-2-yl)phenyl)(4-bromophenyl)methanone
(7i): White solid. Yield: 67% (89 mg); M.P.: 88-90 oC. 1H NMR
(200MHz , CDCl3): δ 7.81 - 7.74 (m, J = 8.3 Hz, 2H), 7.71 - 7.60
(m, 4H), 7.54 - 7.43 (m, J = 8.1 Hz, 2H), 4.73 (dd, J = 2.6, 10.0
Hz, 1H), 4.01 - 3.92 (m, 2H), 3.89 (d, J = 2.7 Hz, 1H), 3.84 - 3.69
(m, 2H), 3.46 (dd, J = 10.2, 11.6 Hz, 1H). 13C{1H} NMR (50
MHz, CDCl3): δ 194.5, 142.4, 136.1, 135.6, 131.0, 130.8, 129.4,
127.6, 126.9, 126.6, 125.5, 76.7, 71.6, 66.3, 65.7; HRMS (ESI)
m/z calculated for C17H16O3Br [(M+H)+] 347.0277, found
347.0285.
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(4-(1,4-dioxan-2-yl)phenyl)(4-
chlorophenyl)methanone (7j): White solid. Yield: 61% (85
mg); M.P.: 90-92 oC. 1H NMR (500 MHz, CDCl3): δ 7.75 (d, J =
8.4 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H), 7.48 (dd, J = 9.9, 8.4 Hz,
4H), 4.73 (dd, J = 10.3, 2.7 Hz, 1H), 3.97 - 4.00 (m, 1H), 3.90 -
3.95 (m, 2H), 3.82 - 3.86 (m, 1H), 3.76 (td, J = 11.3, 3.2 Hz, 1H),
3.47 (dd, J = 11.4, 10.3 Hz, 1H). 13C{1H} NMR (101 MHz,
CDCl3): δ 194.7, 142.7, 138.6, 136.5, 135.5, 131.1, 129.8, 128.3,
125.8, 77.1, 71.9, 66.7, 66.0; HRMS (ESI) m/z calculated for
C17H16O3Cl [(M+H)+] 303.0782, found 303.0789.
1-(3-bromo-4-(tetrahydrofuran-2-yl)phenyl)ethan-1-
1
one (7q): Clear oil. Yield: 84% (113 mg). H NMR (400 MHz,
CDCl3): δ 8.08 (d, J = 1.5 Hz, 1H), 7.86 (dd, J = 8.0, 1.5 Hz, 1H),
7.59 (d, J = 8.0 Hz, 1H), 5.15 (t, J = 7.1 Hz, 1H), 4.17 (td, J = 7.6,
6.1 Hz, 1H), 3.97 (q, J = 7.2 Hz, 1H), 2.51 - 2.64 (m, 4H), 1.98
(td, J = 14.0, 7.1 Hz, 2H), 1.65 (dd, J = 12.6, 7.6 Hz, 1H). 13C{1H}
NMR (126 MHz,CDCl3): δ 196.4, 148.5, 137.2, 132.4, 127.3,
126.6, 121.5, 79.7, 69.2, 33.2, 26.5, 25.7; HRMS (ESI) m/z
calculated for C12H14O2Br [(M+H)+] 269.0172, found 269.0178.
1-(4-(benzo[d][1,3]dioxol-2-yl)phenyl)ethan-1-one
(7r): white solid. Yield: 58% (116 mg); M.P.: 70-72 oC. 1H
NMR (500MHz, CDCl3): δ 8.04 (s, 1H), 8.02 (s, 1H), 7.70 (s,
1H), 7.68 (s, 1H), 7.01 (s, 1H), 6.89 (s, 4H), 2.63 (s, 3H). 13C{1H}
NMR (126 MHz, CDCl3): δ 197.5, 147.2, 140.9, 138.4, 128.6,
126.6, 121.9, 108.8, 108.7, 26.7; HRMS (ESI) m/z calculated for
C15H13O3 [(M+H)+] 241.0859, found 241.0864.
3-(1,4-dioxan-2-yl)-9H-thioxanthen-9-one (7k): White
o
1
solid. Yield: 74% (104 mg); M.P.: 163-165 C. H NMR (400
MHz, CDCl3): δ 8.54 - 8.66 (m, 2H), 7.56 - 7.66 (m, 3H), 7.46 -
7.53 (m, 1H), 7.42 (dd, J = 8.2, 1.8 Hz, 1H), 4.76 (dd, J = 10.1,
2.7 Hz, 1H), 3.91 - 4.05 (m, 3H), 3.85 (dd, J = 11.4, 2.7 Hz, 1H),
3.76 (td, J = 11.3, 3.4 Hz, 1H), 3.46 (dd, J = 11.9, 10.1 Hz, 1H).
13C{1H} NMR (101 MHz, CDCl3): δ179.7, 142.9, 137.6, 137.2,
132.3, 130.0, 129.8, 129.2, 128.8, 126.4, 126.0, 124.1, 123.2,
72.1, 67.0, 66.3; HRMS (ESI) m/z calculated for C17H15O3S
[(M+H)+] 299.0736, found 299.0733.
Typical Experimental Procedure for the Synthesis of 4-(1,4-
dioxan-2-yl)-3-methoxybenzaldehyde ( 9a ):
5-(1,4-dioxan-2-yl)-2,3-dihydro-1H-inden-1-one (7l):
To a 25 mL round-bottom flask 3-methoxybenzaldehyde 8a (0.73
mmol), K2S2O8 (2.20 mmol, 594 mg), tetrabutylammonium
chloride (TBACl, 2.20 mmol, 1.2 ml) and NaOAc (1.47 mmol,
121 mg) was taken in 1,4-dioxane (3 ml). The round-bottom flask
was equipped with a condenser and the resulting reaction mixture
was refluxed to 120 °C for 1.5 h, and the progress of the reaction
was monitored by TLC. Upon completion of the reaction, the
reaction mixture was dried under vacuum. Then the crude reaction
mixture was diluted with ethyl acetate (10 mL) and washed with
brine. Eluted with EtOAc (20 mL * 2). The organics was
evaporated and the crude residue was preadsorbed on silica gel
and purified by column chromatography (100-200 mesh silica
Using 85/15 petroleum ether/ethyl acetate as the eluent to afford
the corresponding compound 9a in 79% yield.
4-(1,4-dioxan-2-yl)-3-methoxybenzaldehyde (9a): Clear
oil. Yield: 79% (128 mg). 1H NMR (500 MHz, CDCl3): δ 9.97
(s, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.46 - 7.52 (m, 1H), 7.33 - 7.39
(m, 1H), 5.03 (dd, J = 9.7, 2.5 Hz, 1H), 4.02 (dd, J = 11.4, 2.7 Hz,
1H), 3.92 - 4.00 (m, 2H), 3.90 (s, 3H), 3.79 - 3.84 (m, 1H), 3.69 -
3.76 (m, 1H), 3.26 (dd, J = 11.3, 9.7 Hz, 1H). 13C{1H} NMR (126
MHz, CDCl3): δ 191.6, 156.2, 136.7, 133.8, 127.0, 124.4, 107.9,
72.6, 70.7, 67.1, 66.2, 55.3; HRMS (ESI) m/z calculated for
C12H15O4 [(M+H)+] 223.0965, found 223.0964.
o
White solid. Yield: 67% (110 mg); M.P.: 128-130 C. 1H NMR
(400 MHz, CDCl3): δ 7.50 - 7.70 (m, 2H), 7.39 (d, J = 6.7 Hz,
1H), 5.68 (d, J = 9.2 Hz, 1H), 3.92 - 4.08 (m, 3H), 3.82 (d, J =
11.0 Hz, 1H), 3.72 (td, J = 11.0, 3.7 Hz, 1H), 3.22 (t, J = 10.4 Hz,
1H), 3.05 - 3.17 (m, 2H), 2.58 - 2.83 (m, 2H). 13C{1H} NMR (101
MHz, CDCl3): δ 207.0, 155.7, 138.5, 134.6, 132.6, 125.9, 124.6,
73.2, 71.7, 67.0, 66.3, 36.6, 25.6; HRMS (ESI) m/z calculated for
C13H15O3 [(M+H)+] 219.1016, found 219.1018.
4-bromo-5-(tetrahydrofuran-2-yl)-2,3-dihydro-1H-
inden-1-one (7m): off white solid. Yield: 70% (93 mg); M.P.:
o
116-118 C. 1H NMR (200 MHz, CDCl3): δ 7.62 (d, J = 8.2 Hz,
1H), 7.39 (d, J = 8.1 Hz, 1H), 5.64 (t, J = 6.9 Hz, 1H), 4.06 (q, J =
7.1 Hz, 1H), 3.79 - 3.97 (m, 1H), 2.92 - 3.06 (m, 2H), 2.43 - 2.69
(m, 3H), 1.72 - 2.06 (m, 2H), 1.34 - 1.55 (m, 1H). 13C{1H} NMR
(126 MHz, CDCl3): δ 206.5, 155.1, 144.2, 137.1, 134.5, 125.2,
120.1, 76.4, 69.1, 36.4, 34.0, 26.9, 25.8; HRMS (ESI) m/z
calculated for C13H14O2Br [(M+H)+] 281.0172, found 281.0170.
6-(tetrahydrofuran-2-yl)-3,4-dihydronaphthalen-1(2H)-
one (7n): Clear oil. Yield: 62% (91 mg). 1H NMR (400 MHz,
CDCl3): δ 7.93 (d, J = 8.5 Hz, 1H), 7.13 - 7.24 (m, 2H), 4.85 (d, J
= 6.7 Hz, 1H), 4.04 (d, J = 7.9 Hz, 1H), 3.89 (d, J = 7.3 Hz, 1H),
2.85 - 2.97 (m, 2H), 2.52 - 2.64 (m, 2H), 2.21 - 2.36 (m, 1H), 2.01
- 2.13 (m, 2H), 1.91 - 2.00 (m, 2H), 1.65 - 1.79 (m, 1H). 13C{1H}
NMR (101 MHz, CDCl3): δ 197.9, 149.1, 144.4, 131.3, 127.0,
3-chloro-4-(1,4-dioxan-2-yl)benzaldehyde (9b): Pale
o
yellow solid. Yield: 85% (137 mg); M.P.: 72-74 C. 1H NMR
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(400MHz , CDCl3): 9.96 (s, 1H), 8.04 - 7.75 (m, 3H), 5.18 - 5.00
(m, 1H), 4.08 (d, J = 11.6 Hz, 1H), 4.04 - 3.93 (m, 2H), 3.84 (d, J
= 12.2 Hz, 1H), 3.75 (dd, J = 4.0, 10.1 Hz, 1H), 3.36 - 3.17 (m,
1H). 13C{1H} NMR (101 MHz, CDCl3): δ 190.1, 142.1, 136.5,
132.4, 129.6, 128.1, 127.9, 74.5, 70.1, 66.8, 66.0; HRMS (ESI)
m/z calculated for C11H12O3Cl [(M+H)+] 227.0469, found
227.0467.
4-(1,4-dioxan-2-yl)-2-methoxybenzaldehyde (9c): Clear
oil. Yield: 92% (150 mg). 1H NMR (500MHz , CDCl3): δ 10.43
(s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.04 (s, 1H), 6.95 (d, J = 8.0 Hz,
1H), 4.66 (dd, J = 2.7, 10.3 Hz, 1H), 3.98 - 3.93 (m, 4H), 3.91 (t, J
= 3.4 Hz, 1H), 3.89 - 3.87 (m, 1H), 3.83 - 3.79 (m, 1H), 3.76 -
3.72 (m, 1H), 3.41 (dd, J = 10.3, 11.4 Hz, 1H). 13C{1H} NMR
(126 MHz, CDCl3): δ 189.1, 161.7, 146.5, 128.3, 124.0, 117.9,
108.8, 77.1, 71.8, 66.6, 66.0, 55.4; HRMS (ESI) m/z calculated
for C12H15O4 [(M+H)+] 223.0965, found 223.0963.
Clear oil. Yield: 62% (98 mg). H NMR (200 MHz, CDCl3): δ
11.07 (s, 1H), 9.86 (s, 1H), 7.52 (d, J = 8.5 Hz, 1H), 6.89 - 7.07
(m, 2H), 4.92 (t, J = 7.1 Hz, 1H), 3.90 - 4.16 (m, 2H), 2.37 (dd, J
= 11.9, 6.3 Hz, 1H), 1.93 - 2.07 (m, 2H), 1.70 - 1.87 (m, 1H).
13C{1H} NMR (50 MHz, CDCl3): δ 195.3, 161.1, 153.7, 133.1,
119.0, 116.4, 113.5, 79.3, 68.4, 33.9, 25.2; HRMS (ESI) m/z
calculated for C11H12O3 [(M+H)+] 193.0859, found : 193.0858.
4-(1,4-dioxan-2-yl)-1-naphthaldehyde (9j): Clear oil.
Yield: 80% (131 mg). 1H NMR (200 MHz, CDCl3): δ 10.29 (s,
1H), 9.17 - 9.35 (m, 1H), 8.01 - 8.10 (m, 1H), 7.93 (d, J = 7.5 Hz,
1H), 7.82 (d, J = 7.5 Hz, 1H), 7.50 - 7.68 (m, 2H), 5.37 (dd, J =
9.9, 2.3 Hz, 1H), 3.98 - 4.11 (m, 3H), 3.73 - 3.84 (m, 2H), 3.41
(dd, J = 11.9, 9.9 Hz, 1H). 13C{1H} NMR (50 MHz, CDCl3): δ
192.7, 141.0, 135.7, 130.4, 130.0, 129.7, 128.0, 126.6, 125.1,
122.3, 122.2, 74.4, 71.5, 66.8, 66.0; HRMS (ESI) m/z calculated
for C15H14O3Na [(M+Na)+] 265.0835, found 265.0832.
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4-(1,4-dioxan-2-yl)-2,5-dimethoxybenzaldehyde (9d):
2,2-dimethoxy-2-phenyl-1-(4-(tetrahydrofuran-2-yl)
phenyl)ethan-1-one (11): White semisolid. Yield: 90% (114
mg). 1H NMR (400 MHz, CDCl3): δ 8.04 (d, J = 7.9 Hz, 2H),
7.61 (d, J = 7.3 Hz, 2H), 7.20 - 7.46 (m, 5H), 4.74 - 4.98 (m, 1H),
4.00 - 4.12 (m, 1H), 3.81 - 3.98 (m, 1H), 3.21 (s, 6H), 2.21 - 2.40
(m, 1H), 1.90 - 2.07 (m, 2H), 1.72 (dt, J = 12.4, 7.9 Hz, 1H).
13C{1H} NMR (50 MHz, CDCl3): δ 194.6, 148.8, 136.9, 133.0,
130.2, 128.8, 128.4, 126.9, 125.2 , 103.5, 80.1, 68.8, 50.0, 34.4,
25.9; HRMS (ESI) m/z calculated for C20H22O4Na [(M+Na)+]
349.1410, found 349.1406.
1-(4-(1,4-dioxan-2-yl)phenyl)-2-phenylethane-1,2-dione
(12): Yellow oil. Yield: 61% (70 mg). 1H NMR (500 MHz,
CDCl3): δ 7.97 (d, J = 7.6 Hz, 4H), 7.61 - 7.73 (m, 1H), 7.43 -
7.58 (m, 4H), 4.61 - 4.81 (m, 1H), 3.86 - 4.00 (m, 3H), 3.82 (d, J
= 10.7 Hz, 1H), 3.73 (td, J = 11.3, 2.9 Hz, 1H), 3.40 (t, J = 10.9
Hz, 1H). 13C{1H} NMR (50 MHz, CDCl3): δ 194.4, 194.0,
145.5, 134.9, 132.9, 132.5, 130.0, 129.9, 129.0, 126.6, 77.2, 72.1,
66.9, 66.3; HRMS (ESI) m/z calculated for C18H16O4Na
[(M+Na)+] 319.0941, found 319.0936.
1-(4-(tetrahydrofuran-2-yl)phenyl)ethan-1-one(14):
Clear oil Yield 77% (121 mg) & 53% (83 mg). 1H NMR
(400MHz , CDCl3): 7.93 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 8.5 Hz,
2H), 4.95 (t, J = 7.3 Hz, 1H), 4.14 - 4.07 (m, 1H), 3.97 (q, J = 7.3
Hz, 1H), 2.60 (s, 3H), 2.37 (dd, J = 6.4, 12.5 Hz, 1H), 2.02 (td, J =
7.0, 14.0 Hz, 2H), 1.81 - 1.74 (m, 1H). 13C{1H} NMR (101 MHz,
CDCl3): δ 197.8, 149.2, 136.1, 128.4, 125.6, 80.1, 68.9, 34.7,
26.6, 25.9. HRMS (ESI) m/z calculated for C12H14O2 [(M+H)+]
191.1067, found 191.1062.
Experimental Procedure for the synthesis of 2-(2,5-
dimethoxy-4-methylphenyl)-1,4-dioxane (16: Degassed
methanol (4.0 ml) was added to the mixture of Pd/C (10 wt %)
and 9d (0.3 mmol,76 mg ). After stirring under 1 atm pressure of
hydrogen for 12 h at room temperature, the reaction mixture was
filtered, and then evaporated under reduced pressure. The crude
product was then purified by flash column chromatography
(eluent: 90/10 pet.ether/ethyl acetate) to give hydrogenated
product 16 (67 mg) as a clear oil.
o
Yellow solid. Yield: 82% (124 mg); M.P.: 118-120 C. 1H NMR
(500 MHz, CDCl3): δ 10.43 (s, 1H), 7.27 (s, 1H), 7.19 (s, 1H),
4.98 (dd, J = 9.5, 2.3 Hz, 1H), 4.04 (dd, J = 11.3, 2.5 Hz, 1H),
3.96 - 3.99 (m, 1H), 3.92 - 3.96 (m, 4H), 3.82 (s, 3H), 3.79 - 3.81
(m, 1H), 3.69 - 3.76 (m, 1H), 3.22 (dd, J = 11.1, 9.9 Hz, 1H).
13C{1H} NMR (126 MHz, CDCl3): δ 189.2, 156.9, 149.9, 135.5,
123.8, 110.8, 108.1, 73.1, 70.9, 67.3, 66.4, 56.2, 55.7; HRMS
(ESI) m/z calculated for C13H17O5 [(M+H)+] 253.1071, found
253.1069.
3-fluoro-4-(tetrahydrofuran-2-yl)
benzaldehyde
(9e): Clear oil. Yield: 86% (135 mg) & 67% (105 mg). 1H NMR
(200MHz , CDCl3): 9.96 (s, 1H), 7.72 - 7.61 (m, 2H), 7.52 (d, J =
9.9 Hz, 1H), 5.16 (t, J = 7.1 Hz, 1H), 4.12 (q, J = 6.8 Hz, 1H),
4.03 - 3.87 (m, 1H), 2.59 - 2.39 (m, 1H), 2.09 - 1.93 (m, 2H), 1.75
(dd, J = 7.6, 12.1 Hz, 1H). 13C{1H} NMR (50 MHz, CDCl3): δ
190.7 , 162.3-157.3 (d, J = 248.82 Hz), 138.4-138.1 (d, J = 14.27
Hz), 137.0-136.9 (d, J = 6.22 Hz,), 127.4-127.3 (d, J = 4.39 Hz),
126.3-126.2 (d, J = 2.93 Hz,), 115.0-114.6 (d, J = 22.32 Hz), 74.9-
74.8 (d, J = 1.83 Hz), 68.8 , 33.4 , 25.9; HRMS (ESI) m/z
calculated for C11H12O2F [(M+H)+] 195.0816, found 195.0815.
3,5-dimethoxy-4-(tetrahydrofuran-2-yl)benzaldehydes
1
(9f): Clear oil. Yield: 70% (99 mg). HNMR (500MHz , CDCl3):
10.43 (s, 1H), 7.27 (s, 1H), 7.19 (s, 1H), 4.98 (dd, J = 2.3, 9.5 Hz,
1H), 4.04 (dd, J = 2.5, 11.3 Hz, 1H), 3.99 - 3.97 (m, 1H), 3.96 -
3.91 (m, 4H), 3.82 (s, 3H), 3.81 - 3.79 (m, 1H), 3.75 - 3.70 (m,
1H), 3.22 (dd, J = 9.9, 11.1 Hz, 1H). 13C{1H} NMR (101 MHz,
CDCl3): δ 191.4, 158.8, 136.2, 124.5, 104.9, 71.8, 68.7, 55.6,
29.9, 27.4; HRMS (ESI) m/z calculated for C13H17O4 [(M+H)+]
237.1121, found 237.1119.
3-chloro-4-(tetrahydrofuran-2-yl)benzaldehydes
(9g): Clear oil. Yield: 89% (134 mg). 1H NMR (400 MHz,
CDCl3): δ 9.86 (s, 1H), 7.75 (d, J=1.5 Hz, 1H), 7.60 - 7.70 (m,
2H), 5.14 (t, J=7.1 Hz, 1H), 4.03 - 4.17 (m, 1H), 3.90 (q, J=7.3
Hz, 1H), 2.50 (dd, J=12.5, 6.4 Hz, 1H), 1.83 - 2.02 (m, 2H), 1.51 -
1.65 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ 190.3, 148.2,
135.9, 132.0, 129.6, 127.9, 126.6, 77.4, 68.8, 32.7, 25; HRMS
(ESI) m/z calculated for C11H12O2Cl [(M+H)+] 211.0520, found
211.0519
3-hydroxy-4-(tetrahydrofuran-2-yl)benzaldehydes (9h):
Yellow oil. Yield: 71% (111 mg). 1H NMR (200 MHz, CDCl3): δ
9.98 (s, 1H), 9.80 (s, 1H), 7.20 - 7.46 (m, 2H), 7.10 (dd, J = 7.5,
1.8 Hz, 1H), 5.89 (dd, J = 9.6, 6.2 Hz, 1H), 4.09 - 4.35 (m, 1H),
3.77 - 4.04 (m, 1H), 2.49 - 2.70 (m, 1H), 1.96 - 2.23 (m, 2H), 1.63
- 1.84 (m, 1H). 13C{1H} NMR (50 MHz, CDCl3): δ 193.3, 157.2,
134.0, 128.5, 127.8, 124.7, 123.5, 80.2, 68.6, 32.9, 25.6; HRMS
(ESI) m/z calculated for C11H11O3 [(M-H)+] 191.0703, found
191.0702
2-(2,5-dimethoxy-4-methylphenyl)-1,4-dioxane
(16):
clear oil yield: 94% (71 mg). 1H NMR (400MHz, CDCl3): 6.89
(s, 1H), 6.59 (s, 1H), 4.95 - 4.82 (m, 1H), 3.92 - 3.83 (m, 3H),
3.75 (s, 3H), 3.72 - 3.62 (m, 5H), 3.22 (t, J = 10.4 Hz, 1H), 2.14
(s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 151.6, 149.2,
126.1, 124.1, 113.2, 108.8, 72.5, 71.2, 67.1, 66.1, 55.7, 55.6, 15.9;
HRMS (ESI) m/z calculated for
261.1097, found 261.1093.
C13H18O4Na [(M+Na)+]
Experimental Procedure for the synthesis of 2-(4-(1,4-
dioxan-2-yl)-2,5-dimethoxyphenyl)-1H-
benzo[d]imidazole (17): To a 25 mL round-bottom flask 4-
(1,4-dioxan-2-yl)-2,5-dimethoxybenzaldehyde (0.396 mmol,100
2-hydroxy-4-(tetrahydrofuran-2-yl)benzaldehydes (9i):
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The Journal of Organic Chemistry
Page 8 of 9
on lignans: natural products and synthesis. Nat. Prod. Rep. 2009, 26,
1251–1296, and references therein.
mg), o-phenylenediamine (0.396 mmol,42 mg), 30% H2O2 in
water (94 mg, 0.82 ml) and HCl 37% in water (50.5 mg, 0.15 ml )
was taken in acetonitrile (3 ml). After stirring for 1 h at rt the
reaction mixture was evaporated under reduced pressure, Then the
crude reaction mixture was diluted with ethyl acetate (10 mL) and
washed with brine. Eluted with EtOAc (15 mL * 2). The organics
was evaporated and the crude residue was preadsorbed on silica
gel and purified by column chromatography (100-200 mesh silica
Using 70/30 petroleum ether/ethyl acetate as the eluent to afford
the corresponding compound 17 in 78% yield as a white solid.
2-(4-(1,4-dioxan-2-yl)-2,5-dimethoxyphenyl)-1H-
benzo[d]imidazole (17): White solid. Yield: 78% (159 mg).
1H NMR (500 MHz, CDCl3): δ 10.80 (br. s., 1H), 8.08 (s, 1H),
7.84 (br. s., 1H), 7.52 (br. s., 1H), 7.13 - 7.35 (m, 3H), 5.05 (dd, J
= 9.7, 2.5 Hz, 1H), 4.07 - 4.13 (m, 4H), 3.96 - 4.05 (m, 2H), 3.95
(s, 3H), 3.82 - 3.87 (m, 1H), 3.74 - 3.81 (m, 1H), 3.31 (dd, J =
11.1, 10.3 Hz, 1H). 13C{1H} NMR (126 MHz, CDCl3): δ 151.1,
150.2, 149.6, 129.7, 122.6, 122.1, 118.9, 116.9, 110.7, 110.5,
110.3, 72.7, 71.0, 67.1, 66.2, 56.3, 55.8; HRMS (ESI) m/z
calculated for C19H21O4N2 [(M+H)+] 341.1496, found 341.1502.
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ASSOCIATED CONTENT
Supporting Information:
Analytical Data (1H, 13C, crystallographic data for compound 7h
and DFT Calculation Studies )
AUTHOR INFORMATION
Corresponding Author
* Phone: 020-2590-2547 Fax: 020-2590-2676
Email: gm.suryavanshi@ncl.res.in
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Sodium-Dependent Glucose Cotransporter
Restricted to the Intestinal Lumen, for the Treatment of Diabetes. J.
Med. Chem. 2017, 60, 710−721.
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Salunke, G. B. Preparation of benzaldehyde oxime ether and phenyl
alkyl ketone oxime ether compounds as pesticides. Patent No. JP
2014080385
1 (SGLT1) Inhibitor
(KDM and AM thank CSIR-New Delhi and UGC respectively for
providing fellowship. We acknowledge the Department of
Science and Technology DST for providing funds. We thank Dr
Rajesh Gonnade, CSIR-NCL, for providing the single crystal X-
ray dif-fraction data. K.V. is grateful to DST (EMR/2014/000013)
for providing financial assistance
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