Iron(III)-catalyzed nucleophilic substitution of the hydroxy group in benzoin by alcohols

Article abstract of DOI:10.1055/s-0031-1289738

The etherification reaction between benzoin derivatives and alcohols catalyzed by iron(III) proceeds in moderate to good yields. Other metal complexes showed either low reactivity or low chemoselectivity where oxidation of benzoin to benzil was a competing reaction. The iron source operated as a catalyst where 5 mol% of iron(III) generate the 2-alkoxy-1,2-diphenylethan-1-one in 50% yield. With an optimum of 25 mol% of catalyst, the desired ether was obtained in 85% yield. The etherification of benzoin and an alcohol proceed to generate the desired product in polar solvents such as 1,2-dichloroethane, whereas less polar solvents promote the competing oxidation to generate the benzil; polar coordinating solvents such as tetrahydrofuran inhibited the reaction. The efficiency of the reaction is found to be dependent on nucleophile where an optimum of 30 equivalents of alcohol was observed. With electron-donating substituents on the aromatic ring, the etherification was followed by oxidation to generate the benzil. Moderate yields of etherification product were obtained by monitoring the reaction progress with electron-rich substrates and quenching the reaction after two hours. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0031-1289738

PAPER
▌1213
paper
Iron(III)-Catalyzed Nucleophilic Substitution of the Hydroxy Group in
Benzoin by Alcohols
2-Alkoxy-1,2-diarylethan-1-ones by Nucleophilic Substitution
Anvar Mirzaei,a Srijit Biswas,b Joseph S. M. Samec*b
a
Islamic Azad University Sanandaj Branch, Department Of Chemistry, Kurdistan, Iran
b
Department of Biochemistry and Organic Chemistry, Uppsala University, Box 576, 751 23 Uppsala, Sweden
Fax +46(18)4713818; E-Mail: joseph.samec@biorg.uu.se
Received: 04.10.2011; Accepted after revision: 15.02.2012
separate step (Scheme 1).2 The substitution is then per-
formed in the presence of a stoichiometric amount of base.
This manipulation of the hydroxy group lowers the atom
economy and also the E-factor of the transformation.3
Abstract: The etherification reaction between benzoin derivatives
and alcohols catalyzed by iron(III) proceeds in moderate to good
yields. Other metal complexes showed either low reactivity or low
chemoselectivity where oxidation of benzoin to benzil was a com-
peting reaction. The iron source operated as a catalyst where 5
mol% of iron(III) generate the 2-alkoxy-1,2-diphenylethan-1-one in
50% yield. With an optimum of 25 mol% of catalyst, the desired
ether was obtained in 85% yield. The etherification of benzoin and
an alcohol proceed to generate the desired product in polar solvents
such as 1,2-dichloroethane, whereas less polar solvents promote the
competing oxidation to generate the benzil; polar coordinating sol-
vents such as tetrahydrofuran inhibited the reaction. The efficiency
of the reaction is found to be dependent on nucleophile where an op-
timum of 30 equivalents of alcohol was observed. With electron-
donating substituents on the aromatic ring, the etherification was
followed by oxidation to generate the benzil. Moderate yields of
etherification product were obtained by monitoring the reaction
progress with electron-rich substrates and quenching the reaction
after two hours.
R1OH
SOCl2
O
O
R3
R1Cl
R3
R2
R2
+
waste
+ base
OR1
OH
Scheme 1 Williamson etherification reaction
In this regard, catalysis based on a variety of transition
metals has been reported for the etherification to produce
unsymmetrical ethers.4,5 Several reports have recently
showed that iron(III) catalyses the etherification of allylic
and benzylic alcohols with primary and secondary ali-
phatic alcohols.6 However, the etherification of α-hy-
droxy carbonyls is still a challenging transformation.
Asensio and co-workers recently reported a gold(III)-cat-
alyzed etherification of primary and secondary benzylic
alcohols and also tertiary alkyl alcohols.7 The advantage
of the reported procedure was low catalyst loading, short
reaction times, and large substrate scope. However, ether-
ification of methyl mandelate, an α-hydroxy carbonyl,
generated a product that was unstable under the reaction
conditions employed. Abu-Omar and co-workers reported
a palladium(II)-catalyzed etherification of benzoin with
diphenylmethanol.8 In this case, the diphenylmethanol
acts as an electrophile, which limits the substrate scope to
benzylic ethers.
Key words: iron catalysis, Lewis acids, substitution, ethers, alco-
hols
Alkyl ethers of benzoin-like compounds (Figure 1) have
showed high activity towards inhibiting the 11βHSD1 re-
ceptor related to diseases such as diabetes, obesity, hyper-
lipidemia, hyperglycemia, hyperinsulinemia, hypertension,
and also glaucoma, osteoporosis, tuberculosis, dementia,
cognitive disorders, and depression.1 Considering this, the
development of a facile and straightforward methodology
for the synthesis of alkyl ethers of benzoin-like com-
pounds is essential.
O
R1
To our knowledge, there are no reports regarding success-
ful etherification reactions where the α-hydroxy carbonyl
compounds act as the electrophile. In this connection we
herein report a facile one-step protocol for the synthesis of
unsymmetrical ethers from aromatic α-hydroxy ketones
and alkyl alcohols.
R1
R1 = alkyl, alkoxy, halo
O
R2
R2 = alkyl
Figure 1 Biologically active alkyl ethers of benzoin1
In the initial stage of our study, we screened a number of
catalysts in the reaction between benzoin9,10 (1a) and bu-
tanol (2a) (Table 1). In contrast to other facile etherifica-
tions of benzylic alcohols, the α-keto substituent proved to
be more difficult. Catalysts based on rhenium(I)11 and in-
dium(III),12 that previously have been reported in the
etherification of benzylic alcohols were found to be unre-
active (entries 2 and 3). Also, the gold(III) catalyst report-
ed to promote etherifications of α-keto alcohols worked
In the standard protocol, the Williamson ether synthesis is
used to generate alkoxy ethers from α-hydroxy carbonyls
where the hydroxy group of the alcohol is transformed
into a better leaving group e.g. chloride or a tosylate in a
SYNTHESIS 42170012, 44,81213–1218
Advanced online publication: 27.03.2012
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DOI: 10.1055/s-0031-1289738; Art ID: SS-2012-N0511-OP
© Georg Thieme Verlag Stuttgart · New York

1214
A. Mirzaei et al.
PAPER
poorly in the etherification of 1a and generated the oxi- iron(III) chloride was considered to be the best choice for
dized 3a in only 4% yield (entry 8).6 Palladium(II)-cata- this reaction.
lyzed etherification of α-keto benzylic alcohols have been
After successfully choosing iron(III) chloride as the active
catalyst, we attempted to evaluate the optimum amount of
catalyst required for this transformation. Dry benzoin (1a,
1 mmol) and dry butanol (2a, 30 mmol) were added to a
reported to proceed smoothly when the α-keto benzylic al-
cohol operates as nucleophile.7 However, with benzoin as
electrophile only oxidized product was formed (entry 9).
Lewis acids based on chromium(II), zinc(II), bis-
Schlenk flask with iron(III) chloride (see Figure 2) in 1,2-
muth(III), and titanium(III) were also attempted without
dichloroethane (5 mL) under an atmosphere of nitrogen.
success.13 The most efficient catalysts for etherification of
The reactions were run for 24 hours at 80 °C and moni-
benzoin were two iron(III) sources (entries 11 and 13).6
tored by 1H NMR spectroscopy using ferrocene as an in-
Iron(III) chloride performed the etherification to generate
ternal standard. When 5 mol% iron(III) chloride was
the desired ether 3a with 47% conversion and 41% yield.
utilized, 48% conversion of etherification product 3a was
Iron(III) perchlorate performed the etherification to gen-
observed. This shows that the iron(III) is operating as a
erate the desired ether with 48% conversion and 28%
catalyst and not as a stoichiometric chlorinating reagent.
yield clearly showing that iron(III) is active in catalytic
Increasing the catalyst loading to 10 mol% gave 70%
yield of 3a. Above 10 mol% of catalyst loading, further
addition of iron(III) chloride only generated a stoichio-
metric increase in yield. Thus, 25 mol% of iron(III) chlo-
amounts. The aqueous complex of iron(III) chloride per-
formed poorly to generate the oxidized benzil (4) in 32%
yield (entry 12). A possible explanation is sensitivity to-
wards water. Accordingly, performing the etherification
ride generated 89% conversion to 3a. Above 25 mol% of
of 1a using dry iron(III) with addition of 0.3 equivalents
iron(III) chloride no further increase in the yield of 3a was
of water generated similar results. The Brønsted acid p-
observed. The remaining 11% was the corresponding ben-
toluenesulfonic acid was also examined, when using 10
mol% of p-toluenesulfonic acid, 55% conversion of 1a to
yield 31% of 3a was observed (entry 14). Anhydrous
zil (4).14
Table 1 Catalyst Screening in the Etherification of Benzoin by Bu-
tanola
O
O
O
[M] (5 mol%)
DCE, 80 °C
Ph
Ph
Ph
+
n-BuOH
+
Ph
Ph
Ph
OBu
OH
O
1a
2a
3a
4
Yieldb (%) of 3a
Entry
Catalyst
CrF2
Conv. (%)
1
2
0
0
0
0
ReMe(CO)5
InCl3
3
0
0
4
ZnBr2
0
0
5
ZnCl2
0
0
Figure 2 Dependence of iron(III) in the etherification of 1a (1
mmol) by 2a (30 mmol) with iron(III) chloride (DCE, 80 °C, 24 h)
6
TiF3
0
0
7
ZnI2
5
2
After optimization of the catalyst loading of iron(III) chlo-
ride required for the etherification, a number of dried sol-
vents were examined (Table 2). Running the reaction in
1,2-dichloroethane gave 100% conversion of starting ma-
terial to yield 89% of 3a (entry 1). Performing the reaction
in toluene also gave 100% conversion of starting material.
However, the chemoselectivity towards 3a was only 36%
and the rest was 4 (entry 2). Performing the reaction in
acetonitrile generated the desired etherification product in
60% yield (entry 3) whereas, the reaction in either tetrahy-
drofuran or n-pentane solvent gave poor results (entries 4
and 5). The catalyst dissolves readily in tetrahydrofuran
and the poor result could be explained by the competing
coordination of the oxygen of the solvent. Tetrahydrofu-
ran aside, the trend is that polar solvents perform better. A
8
NaAuCl4
PdCl2
20
20
5
4
9
trace
3
10
11
12
13
14
CuCl2
FeCl3
47
35
48
55
41
3
FeCl3·6H2O
Fe(ClO4)3
PTSA
28
31
a Reaction conditions: 1a (1 mmol), 2a (30 mmol), catalyst (5 mol%),
DCE (3.2 mL), 80 °C for 24 h.
b Reactions were monitored by 1H NMR spectroscopy using ferrocene
as internal standard.
Synthesis 2012, 44, 1213–1218
© Georg Thieme Verlag Stuttgart · New York

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2-Alkoxy-1,2-diarylethan-1-ones by Nucleophilic Substitution
1215
possible explanation is the presence of a carbocation inter- It should be pointed out in this connection that almost
mediate that is stabilized by the polar solvent.
100% conversion of the starting benzoin was observed in
all the cases. The remainder of the mass balance for low
yielding reaction always corresponded to the formation of
benzil by oxidation of benzoin.
Table 2 Solvent Dependence in the Iron(III)-Catalyzed Etherifica-
tion of Benzoina
O
O
O
The optimized reaction conditions from above with 30
equivalents of butanol in 1,2-dichloroethane were em-
ployed in the catalytic nucleophilic substitutions of vari-
ous aromatic benzoins (Table 3). In the standard reaction,
benzoin (1a) was etherified by butanol in 85% isolated
yield (89% conversion) within 11 hours (entry 1). When
the nucleophile was changed to propanol (2b), a similar
albeit lower yield was observed (entry 2). The sterically
hindered tert-butyl alcohol (2c) was reacted with benzoin
(1a) to generate the product 3c in low yield (entry 3). 1-
Phenylethanol (2d) generated product 3d in moderate
yield (entry 4). Substitution of the phenyl ring in the para-
position with an electron-donating methoxy substituent in
1b gave a remarkable effect in the efficiency; using the
standard procedure led to predominant oxidation to the
corresponding benzil with merely 10% yield of 3e after
ten hours. The reaction was carefully monitored, and after
two hours the reaction initially proceeded to 58% conver-
sion to 3e (entry 5). After this, the yield of 3e decreased
and the yield of the corresponding benzil increases. The
electron-donating methoxy substituent is known to pro-
mote oxidation in which iron(III) is reduced.14,15 This ex-
periment also shows that the electron-donating substituent
promotes the reversible reaction between etherification
product and carbocation intermediate or the alcohol. Sub-
stitution in para-position with electron-withdrawing fluo-
rine in 1c–e did not influence the reaction outcome
significantly and the etherification products 3f–h were
generated in good yields (entries 6–8). Exchanging one of
the phenyl groups in benzoin for a 3-furyl group in 1f led
to decreased reactivity (entry 9). A possible explanation is
that the electron-donating furyl substituent promotes a re-
versible etherification, in analogy to 4,4-dimethoxyben-
zoin (1b), to favor oxidation. When using the stronger
nucleophile thiobenzene, a disproportionation reaction
was observed. Benzamide and phenol showed no reactiv-
ity in the reaction with benzoin. The possible complex-
ation between phenolic OH and iron(III) might be the
reason why phenol is unreactive under this protocol.16 Nu-
cleophilic substitution of optically pure benzoin (R)-1a
was performed using butanol (2a) as nucleophile (Scheme
2); the product 3a obtained was completely racemic. This
observation supports a reaction mechanism in which a
free carbenium ion is generated.
FeCl3 (25 mol%)
solvent, 80 °C
Ph
Ph
Ph
n-BuOH
+
+
Ph
Ph
Ph
OBu
O
OH
4
3a
1a
2a
Entry Solvent
Temp (°C)
Conv. (%)
Yieldb (%)
3a
89
36
60
14
13
4
11
64
20
26
32
1
2
3
4
5
DCE
80
95
80
66
100
100
80
toluene
MeCN
THF
40
n-pentane 36
45
a Reaction conditions: 1a (1 mmol), BuOH (30 mmol), FeCl3 (25
mol%), solvent (3.2 mL), 24 h.
b Reactions were monitored by 1H NMR spectroscopy using ferrocene
as internal standard.
Using five equivalents of butanol (2a) lead to 50% forma-
tion to etherification product 3a (Figure 3). When the
amount of nucleophile was increased, higher yields of
etherification product 3a were observed. Performing the
etherification using ten equivalents of butanol (2a) leads
to 60% formation of the etherification product 3a. When
the reaction was performed using 20 equivalents of buta-
nol (2a), 75% conversion into 3a was observed. When 30
equivalents of butanol (2a) were used the reaction pro-
ceeded to 89% conversion into 3a. Above 30 equivalents
of butanol (2a), further improvement in generating 3a was
not observed.
O
O
FeCl3
Ph
Ph
+
n-BuOH
+
H2O
Ph
Ph
OH
(R)-1a 97% ee
OBu
3a 0% ee
2a
Figure 3 Dependence on butanol (2a) in the etherification of 1a (1
mmol) [FeCl3 (25 mol%), DCE, 80 °C, 24 h]
Scheme 2 Nucleophilic substitution of optically pure benzoin
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1213–1218

1216
A. Mirzaei et al.
PAPER
Table 3 Substituent Effect in the Etherification of Different Benzoinsa
O
O
FeCl3 (25 mol%)
80 °C, DCE
Ar2
Ar2
ROH
+
Ar1
1a–f
+
Ar1
H2O
OH
OR
2a–d
3a–i
Ar2
Ph
Entry
Electrophile 1
Ar1
Nucleophile 2
R
Product 3
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1b
1c
1d
1e
1f
Ph
2a
2b
2c
2d
2a
2a
2a
2a
2a
Bu
3a
3b
3c
3d
3e
3f
11
12
16
16
2
85
77
20
40
58
70
68
70
55
Ph
Ph
Pr
Ph
Ph
t-Bu
CHMePh
Bu
Ph
Ph
4-MeOC6H4
4-FC6H4
4-FC6H4
Ph
4-MeOC6H4
4-FC6H4
Ph
Bu
18
18
18
14
Bu
3g
3h
3i
4-FC6H4
3-furyl
Bu
Ph
Bu
a Reaction conditions: 1 (1 mmol), 2 (30 mmol), FeCl3 (25 mol%), DCE (3.2 mL), 80 °C.
b Yield refers to pure and isolated product.
To establish the generality of this reaction, we studied this the desired ether. Generation of racemic ether starting
reaction using 1,3-diketones as nucleophiles in place of from optically pure benzoin supports a reaction mecha-
alcohols under the same reaction conditions (Scheme 3). nism proceeding through a carbenium ion intermediate.
In situ oxidation of benzoin to benzil followed by conden- Replacing the nucleophile by 1,3-diketones yields the α,β-
sation between benzil and diketone took place to produce unsaturated tricarbonyl compounds in good yield.
the corresponding α,β-unsaturated tricarbonyl compounds
in good yield.5c,17 Acetylacetone (2e) produced the tricar-
bonyl compound 3j in 78% yield whereas, 69% formation
of 3k was observed employing ethyl acetoacetate (2f) as
nucleophile after 12 hours.
Solvents, reagents and chemicals were purchased from Aldrich. 1,2-
Dichloroethane was dried by distillation over anhydrous phospho-
rus pentoxide prior to use. All reactions were performed with oven-
dried glassware under a nitrogen atmosphere. The routine monitor-
ing of reactions was performed with silica gel pre-coated alumi-
num-backed plates, which were analyzed with iodine and/or UV
light. IR spectra were recorded using a Perkin-Elmer FT-IR spectro-
photometer. 1H and 13C NMR spectra were recorded using a Varian
300 (300 MHz) spectrometer on samples in CDCl3. Chemical shifts
are expressed in parts per million (ppm, δ) and are referenced to
CHCl3 (δ = 7.26 ppm) as an internal standard. All coupling con-
stants are absolute values and are expressed in Hz. High-resolution
mass spectral analyses (HRMS) were carried out on a micrOTOF
(Bruker) spectrometer using sodium formate. The molecular frag-
ments are quoted as the relation between mass and charge (m/z).
O
O
O
O
O
FeCl3 (25 mol%)
DCE, 80 °C, 12 h
R
Ph
+
R
Ph
Ph
Ph
OH
O
1a
2e R = Me
2f R = OEt
3j R = Me, 78%
3k R = OEt, 69%
Scheme 3 Direct substitution by diketone nucleophiles followed by
in situ oxidation
Compounds 3a,18 3b,18 3c,19 and 3d8a are known and their data cor-
respond with those reported in the literature. Compounds 3e, 3f, 3g,
3h, 3i, 3j and 3k are new and were fully characterized by 1H NMR,
13C NMR and IR spectroscopy and HRMS.
In conclusion, an iron(III)-mediated etherification proce-
dure of aromatic α-keto benzylic alcohols has been devel-
oped. Of the different catalysts screened, only iron(III)-
based catalysts showed high reactivity and selectivity to-
wards etherification products. Other metal complexes
were either unreactive or showed low chemoselectivity
where the corresponding benzil was a major side product.
The reaction outcome was dependent on both the concen-
tration of alcohol and iron(III). The electronic substituent
of the benzoin proved to be important. Electron-donating
substituents led to a competing oxidation to the corre-
sponding benzil after prolonged reaction time. Electron-
withdrawing substituents led to predominant formation of
2-Butoxy-1,2-diphenylethan-1-one (3a); Typical Procedure
Freshly distilled BuOH (2a, 2.22 g, 2.70 mL, 30 mmol) was added
to a mixture of benzoin (1a, 0.212 g, 1 mmol) and FeCl3 (0.040 g,
25 mol%) in anhyd DCE (3.2 mL) in an oven-dried Schlenk flask
under an atmosphere of N2 and the mixture was degassed for 5 min.
A reflux condenser was added to the Schlenk flask and the reaction
was refluxed for 11 h. The yield obtained was 89% [determined by
comparing the signal of ferrocene (δ = 4.18 ppm) and the benzylic
C–H (δ = 5.55 ppm)]. The soln was cooled to r.t. and the solvents
were evaporated under vacuum. The crude product was purified by
column chromatography (silica gel, hexanes–EtOAc, 30:1) to af-
ford 3a (220 mg, 85%) as white crystals.
Synthesis 2012, 44, 1213–1218
© Georg Thieme Verlag Stuttgart · New York

PAPER
2-Alkoxy-1,2-diarylethan-1-ones by Nucleophilic Substitution
1217
IR (KBr): 2953, 1718, 1694, 1677, 1597, 1448, 1106, 1027, 757 cm–1.
3JHH = 7.2 Hz, 2 H, 2 CH), 7.39 (d, 3JHH = 8.7 Hz, 2 H, 2 CH), 8.04
(d, 3JHH = 8.7 Hz, 2 H, 2 CH).
1H NMR (300 MHz, CDCl3): δ = 0.90 (t, 3JHH = 7.2 Hz, 3 H, CH3),
1.36–1.44 (m, 2 H, CH2), 1.62–1.68 (m, 2 H, CH2), 3.57 (t,
3JHH = 6.6 Hz, 2 H, OCH2), 5.55 (s, 1 H, CH), 7.31–7.40 (m, 6 H, 6
13C NMR (75 MHz, CDCl3): δ = 15.5 (CH3), 19.5 (CH2), 32.1
(CH2), 55.5 (OMe), 55.6 (OMe), 69.9 (OCH2), 85.3 (CH), 113.8 (2
CH), 114.3 (2 CH), 128.7 (2 CH), 129.4 (C), 129.4 (2 CH), 132.6
(C), 159.7 (C), 163.6 (C), 198.0 (C=O).
3
3
CH), 7.50 (d, JHH = 8.4 Hz, 2 H, 2 CH), 8.06 (d, JHH = 8.4 Hz, 2
H, 2 CH).
13C NMR (75 MHz, CDCl3): δ = 14.1 (CH3), 19.5 (CH2), 32.0
(CH2), 70.2 (OCH2), 85.9 (CH), 127.4 (2 CH), 128.4 (CH), 128.6 (2
CH), 129.0 (2 CH), 129.4 (2 CH), 133.4 (CH), 135.3 (C), 137.0 (C),
198.2 (C=O).
HRMS (ES+): m/z [M + H]+ calcd for C18H21O2: 269.1536; found:
269.1539.
HRMS (ES+): m/z [M + Na]+ calcd for C20H24NaO4: 351.1567;
found: 351.1576.
2-Butoxy-1,2-bis(4-fluorophenyl)ethan-1-one (3f)
White solid; yield: 213 mg (70%).
IR (KBr): 2959, 1694, 1678, 1597, 1500, 1410, 1224, 1154, 1092,
1014, 833, 800 cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.90 (t, 3JHH = 7.2 Hz, 3 H, CH3),
1.35–1.42 (m, 2 H, CH2), 1.62–1.66 (m, 2 H, CH2), 3.56 (t,
3JHH = 6.8 Hz, 2 H, OCH2), 5.43 (s, 1 H, CH), 7.02–7.11 (m, 4 H, 4
CH), 7.45 (dd, 3JHH = 8.9 Hz, 4JHF = 5.7 Hz, 2 H, 2 CH), 8.08 (dd,
3JHH = 9.0 Hz, 4JHF = 5.7 Hz, 2 H, 2 CH).
2-Propoxy-1,2-diphenylethan-1-one (3b)
White solid; yield: 196 mg (77%).
IR (KBr): 2962, 1693, 1676, 1597, 1579, 1448, 1105, 1075, 719
cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.94 (t, 3JHH = 7.2 Hz, 3 H, CH3),
1.65–1.70 (m, 2 H, CH2), 3.53 (t, 3JHH = 7.1 Hz, 2 H, OCH2), 5.56
(s, 1 H, CH), 7.32–7.51 (m, 6 H, 6 CH), 7.51 (d, 3JHH = 7.8 Hz, 2 H,
2 CH), 8.04 (d, 3JHH = 7.8 Hz, 2 H, 2 CH).
13C NMR (75 MHz, CDCl3): δ = 10.8 (CH3), 23.2 (CH2), 72.0
(OCH2), 85.0 (CH), 127.4 (2 CH), 128.5 (CH), 128.6 (2 CH), 128.9
(2 CH), 129.5 (2 CH), 133.4 (CH), 135.2 (C), 136.9 (C), 198.2
(C=O).
13C NMR (75 MHz, CDCl3): δ = 14.0 (CH3), 19.5 (CH2), 32.0
2
(CH2), 70.3 (OCH2), 85.7 (CH), 115.7 (d, JCF = 21.6 Hz, 2 CH),
2
3
116.0 (d, JCF = 21.6 Hz, 2 CH), 128.8 (d, JCF = 7.9 Hz, 2 CH),
131.2 (d, 4JCF = 2.9 Hz, C), 132.3 (d, 3JCF = 9.0 Hz, 2 CH), 132.7 (d,
4JCF = 3.1 Hz, C), 162.5 (d, JCF = 228.0 Hz, C), 165.5 (d,
1
1JCF = 236.0 Hz, C), 196.7 (C=O).
HRMS (ES+): m/z [M + Na]+ calcd for C18H18F2NaO2: 327.1167;
found: 327.1179.
HRMS (ES+): m/z [M + Na]+ calcd for C17H18NaO2: 277.1199;
found: 277.1206.
2-Butoxy-2-(4-fluorophenyl)-1-phenylethan-1-one (3g)
White solid; yield: 195 mg (68%).
2-tert-Butoxy-1,2-diphenylethan-1-one (3c)
White solid; yield: 54 mg (20%).
IR (KBr): 2860, 1743, 1588, 717 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.26 (s, 9 H, 3 CH3), 5.61 (s, 1 H,
IR (KBr): 2895, 1668, 1595, 1411, 1238, 1203, 1153, 878, 844, 714
cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.90 (t, 3JHH = 7.5 Hz, 3 H, CH3),
1.33–1.45 (m, 2 H, CH2), 1.60–1.67 (m, 2 H, CH2), 3.54 (t,
3JHH = 6.9 Hz, 2 H, OCH2), 5.52 (s, 1 H, CH), 7.05 (dd, 3JHH = 8.9
Hz, 3JHF = 8.4 Hz, 2 H, 2 CH), 7.38–7.54 (m, 5 H, 5 CH), 8.01 (d,
3JHH = 8.5 Hz, 2 H, 2 CH).
CH), 7.18–7.55 (m, 8 H, 8 CH), 8.04–8.09 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 27.9 (CH3), 76.1 (C), 79.6 (CH),
126.0 (CH), 127.4 (CH), 128.1 (CH), 128.6 (CH), 130.0 (CH),
132.9 (CH), 135.6 (C), 139.0 (C), 200.9 (C=O).
HRMS (ES+): m/z [M + Na]+ calcd for C18H20NaO2: 291.1361;
found: 291.1354.
13C NMR (75 MHz, CDCl3): δ = 14.1 (CH3), 19.5 (CH2), 32.1
2
(CH2), 70.2 (OCH2), 85.1 (CH), 115.4 (d, JCF = 21.3 Hz, 2 CH),
128.7 (2 CH), 129.1 (d, 3JCF = 8.2 Hz, 2 CH), 129.4 (2 CH), 132.7
(d, 4JCF = 3.1 Hz, C), 133.5 (CH), 135.0 (C), 162.8 (d, 1JCF = 245.5
Hz, C), 198.0 (C=O).
1,2-Diphenyl-2-(1-phenylethoxy)ethan-1-one (3d)
Yellowish oil; yield: 126 mg (40%).
IR (KBr): 2996, 1713, 1590, 1063, 717 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.50–1.53 (m, 3 H, CH3), 4.49–
4.59 (m, 1 H, CH), 5.47, 5.52 (s, 1 H, COCH), 7.25–7.40 (m, 13 H,
6 CH), 7.80 (d, 3JHH = 7.6 Hz, 2 H, 2 CH).
HRMS (ES+): m/z [M + Na]+ calcd for C18H19FNaO2: 309.1261;
found: 309.1260.
2-Butoxy-1-(4-fluorophenyl)-2-phenylethan-1-one (3h)
White solid; yield: 200 mg (70%).
13C NMR (75 MHz, CDCl3): δ = 23.8 (CH3), 24.1 (CH3), 81.4 (CH),
82.4 (COCH), 125.3 (CH), 126.4 (CH), 126.7 (CH), 127.1 (CH),
127.3 (CH), 127.9 (CH), 127.9 (CH), 128.2 (CH), 128.4 (CH),
128.5 (CH), 128.6 (CH), 128.7 (CH), 128.7 (CH), 129.0 (CH),
129.1 (CH), 129.8 (CH), 132.9 (CH), 133.1 (CH), 134.8 (CH),
142.4 (C), 142.7 (C), 198.7 (C=O).
IR (KBr): 2940, 1668, 1593, 1507, 1452, 1227, 1205, 1153, 846,
757, 714 cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.90 (t, 3JHH = 7.5 Hz, 3 H, CH3),
1.41–1.46 (m, 2 H, CH2), 1.63–1.68 (m, 2 H, CH2), 3.56 (t,
3JHH = 6.6 Hz, 2 H, OCH2), 5.46 (s, 1 H, CH), 7.06 (dd, 3JHH = 8.9
Hz, 3JHF = 8.4 Hz, 2 H, 2 CH), 7.30–7.50 (m, 5 H, 5 CH), 8.10 (dd,
3JHH = 9.0 Hz, 3JHF = 5.4 Hz, 2 H, 2 CH).
HRMS (ES+): m/z [M + Na]+ calcd for C22H20NaO2: 399.1361;
found: 399.1354.
13C NMR (75 MHz, CDCl3): δ = 14.0 (CH3), 19.5 (CH2), 32.0
2
(CH2), 70.3 (OCH2), 86.4 (CH), 115.7 (d, JCF = 21.6 Hz, 2 CH),
2-Butoxy-1,2-bis(4-methoxyphenyl)ethan-1-one (3e)
White solid; yield: 190 mg (58%).
127.0 (2 CH), 128.5 (CH), 129.0 (2 CH), 131.3 (d, 4JCF = 3.1 Hz, C),
132.4 (d, 3JCF = 9.3 Hz, 2 CH), 136.8 (C), 165.9 (d, 1JCF = 253.8 Hz,
C), 196.8 (C=O).
IR (KBr): 2933, 1682, 1679, 1600, 1573, 1462, 1305, 1250, 1167,
1100, 1028, 834, 790 cm–1.
HRMS (ES+): m/z [M + Na]+ calcd for C18H19FNaO2: 309.1261;
found: 309.1269.
1H NMR (300 MHz, CDCl3): δ = 0.90 (t, 3JHH = 7.2 Hz, 3 H, CH3),
1.38–1.42 (m, 2 H, CH2), 1.60–1.66 (m, 2 H, CH2), 3.55 (t,
3JHH = 6.9 Hz, 2 H, OCH2), 3.78 (s, 3 H, OMe), 3.84 (s, 3 H, OMe),
2-Butoxy-2-(2-furyl)-1-phenylethan-1-one (3i)
White solid; yield: 142 mg (55%).
3
5.47 (s, 1 H, CH), 6.84 (d, JHH = 7.2 Hz, 2 H, 2 CH), 6.88 (d,
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1213–1218

1218
A. Mirzaei et al.
PAPER
IR (KBr): 2940, 1668, 1595, 1506, 1232, 1205, 1153, 876, 848, 755,
714 cm–1.
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New York, 2001, 479–480.
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Pergamon Press: New York, 1979, 799–850.
1H NMR (300 MHz, CDCl3): δ = 0.90 (t, 3JHH = 7.5 Hz, 3 H, CH3),
1.60–1.62 (m, 2 H, CH2), 1.64–1.66 (m, 2 H, CH2), 3.56 (t,
3JHH = 6.8 Hz, 2 H, OCH2), 5.66 (s, 1 H, CH), 6.35 (dd, 3JHH = 4.1,
1.8 Hz, 1 H, CH), 6.40 (d, 3JHH = 2.7 Hz, 1 H, CH), 7.29–7.44 (m,
3 H, 3 CH), 7.56 (d, 3JHH = 2.7 Hz, 1 H, CH), 8.00 (d, 3JHH = 7.5 Hz,
2 H, 2 CH).
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Angew. Chem. Int. Ed. 2010, 49, 4993. (d) Quach, T. D.;
Batey, R. A. Org. Lett. 2003, 5, 1381. (e) Mann, G.;
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13C NMR (75 MHz, CDCl3): δ = 14.0 (CH3), 19.4 (CH2), 29.9
(CH2), 70.0 (OCH2), 79.0 (CH), 110.3 (CH), 111.0 (CH), 128.7 (2
CH), 129.3 (2 CH), 133.6 (CH), 135.1 (C), 135.3 (C), 143.5 (CH),
150.1 (C), 195.1 (C=O).
HRMS (ES+): m/z [M + Na]+ calcd for C16H18NaO3: 281.1148;
found: 281.1142.
3-Acetyl-1,2-diphenylpent-2-ene-1,4-dione (3j)
Yellowish oil; yield: 228 mg (78%).
IR (KBr): 1669, 1225, 951, 693 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.91 (s, 3 H, CH3), 2.69 (s, 3 H,
CH3), 7.19–7.25 (m, 3 H, CH), 7.32–7.39 (m, 4 H, CH), 7.44–7.48
(m, 3 H, CH).
13C NMR (75 MHz, CDCl3): δ = 15.0 (CH3), 31.2 (CH3), 121.7 (C),
125.0 (C), 125.4 (CH), 125.8 (CH), 128.4 (CH), 129.1 (CH), 129.5
(CH), 130.3 (CH), 130.7 (C), 134.3 (C), 147.3 (C=O), 157.7 (C=O),
196.1 (C=O).
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2009, 48, 9131. (e) Xiang, S.-K.; Zhang, L.-H.; Jiao, N.
Chem. Commun. 2009, 6487.
HRMS (ES+): m/z [M + Na]+ calcd for C19H16NaO3: 315.0997;
found: 315.1006.
Ethyl 2-Acetyl-4-oxo-3,4-diphenylbut-2-enoate (3k)
Yellowish oil; yield: 322 mg (69%).
IR (KBr): 1720, 1231, 1069, 699 cm–1.
(7) Cuenca, A. B.; Mancha, G.; Asensio, G.; Medio-Simón, M.
Chem.–Eur. J. 2008, 14, 1518.
1H NMR (300 MHz, CDCl3): δ = 1.07 (t, 3JHH = 7.2 Hz, 3 H, CH3),
2.72 (s, 3 H, CH3), 4.12 (q, 4JHH = 7.2 Hz, 2 H, CH2), 7.19–7.26 (m,
3 H, CH), 7.32–7.42 (m, 7 H, CH).
(8) (a) Miller, K. J.; Abu-Omar, M. M. Eur. J. Org. Chem. 2003,
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Organometallics 2005, 24, 2819.
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24, 2819.
13C NMR (75 MHz, CDCl3): δ = 14.0 (CH3), 14.1 (CH3), 60.1
(CH2), 116.0 (C), 122.6 (C), 125.4 (CH), 126.0 (CH), 128.1 (CH),
128.2 (CH), 128.7 (CH), 128.9 (CH), 130.1 (C), 130.8 (C), 147.6
(C=O), 158.5 (C=O), 164.3 (C=O).
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408.
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49, 1357.
HRMS (ES+): m/z [M + Na]+ calcd for C20H18NaO4: 345.1103;
found: 345.1117.
Acknowledgment
Financial support from Uppsala University, Kungliga Vetenskaps-
akademin, Byggmästare Olle Enqvists Stiftelse, and Magnus
Bergwalls Stiftelse is gratefully acknowledged. Dr Mirzaei thanks
the Islamic Azad University Sanandaj Branch for financial support.
Dr Biswas thanks the Wenner-Gren Foundation for support.
(16) Shriner, R. L.; Fuson, R. C.; Curtin, D. Y.; Morrill, T. C. The
Systematic Identification of Organic Compounds, 6th ed.;
Wiley: New York, 1980, 348.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.omnoinfrtIangiomnSionurpoatfrInt
g
iSutpor
(17) For Fe(III)-catalyzed direct substitution of alcohols by
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Synthesis 2012, 44, 1213–1218
© Georg Thieme Verlag Stuttgart · New York