Nickel-Catalyzed Reductive Etherification of Aldehydes at Room Temperature: C-O vs C-C Bond Formation

Article abstract of DOI:10.1021/acs.joc.7b02281

The reaction of secondary and tertiary benzyl alcohols activated by 2,4,6-trichloro-1,3,5-triazine (TCT) with aldehydes in the presence of NiCl₂·dmg as a precatalyst in ethylene glycol afforded ethers at room temperature. A selective C-O vs C-C bond formation was observed for the secondary and tertiary benzyl alcohols in comparison with primary ones.

Full text of DOI:10.1021/acs.joc.7b02281

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Note
Nickel-catalyzed Reductive Etherification of Aldehydes
at Room Temperature: C-O vs. C-C Bond Formation
Sajjad Rahimi, Farhad Panahi, Marzieh Bahmani, and Nasser Iranpoor
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02281 • Publication Date (Web): 28 Dec 2017
Downloaded from http://pubs.acs.org on December 29, 2017
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Nickel-catalyzed Reductive Etherification of Aldehydes at Room
Temperature: C-O vs. C-C Bond Formation
a
a,b
a
a,
Sajjad Rahimi, Farhad Panahi, * Marzieh Bahmani, and Nasser Iranpoor *
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a
Chemistry Department, College of Sciences, Shiraz University, Shiraz 71454, Iran
b
Mahshahr Campus, Amirkabir University of Technology, Mahshahr, Iran
ABSTRACT: The reaction of secondary and tertiary benzyl alcohols activated by 2,4,6-trichloro-
1
,3,5-triazine (TCT) with aldehydes in the presence of a NiCl .dmg as pre-catalyst in ethylene glycol
2
afforded ethers at room temperature. Selective C-O vs. C-C bond formation was observed for the
secondary and tertiary benzyl alcohols in comparison with primary ones.
Simple and efficient synthesis of ethers as an important class of organic compounds is still a subject
1
of broad attention. The most used etherification process relies on the Williamson method. In this
protocol, alcohols/phenols react with alkyl halides under very harsh and basic conditions. The
competing elimination in the case of secondary and tertiary halides and the use of basic conditions,
decrease the generality and functional group tolerance of the method. Also in this reaction, alkyl
halides as toxic and expansive material were employed. Acid-catalyzed condensation of alcohols is
another approach for the synthesis of ethers. This method also suffers from some limitations
including sensitivity to the steric bulk of the substrates, limitation to the synthesis of only
symmetrical ethers, and the use of harsh conditions which lead to the formation of byproducts such
2
as olefins. However, few selective methods have been developed for the synthesis of some ether
compounds .3-7
One of the most promising approaches on the synthesis of ethers is reductive coupling of
carbonyl compounds and silyl ethers in the presence of a hydrogen source and a Lewis catalyst.8
This strategy is efficiently suitable for the synthesis of unsymmetrical ethers. Silane-reductive
9
etherification is another version of this approach which silane was employed as reducing agent. In
this method, TMS-OTf was used as catalyst which is moisture sensitive with difficult handling. In
order to overcome the existing problems, other catalysts including, Cu(OTf)
2
,10a FeCl ,10b TMSI,8c
3
tris(pentafluorophenyl)borane,8h and RuHL
complex11 were used instead of TMS-OTf. In some
n
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cases the reductive etherification of carbonyl compounds was performed step-by-step with long
reaction times.8,10,12 This reaction has also been performed under the heterogeneous conditions and
1
3
14
H-Au(III) and Au/TiO
2
were reported as efficient catalysts for this purpose. A method was also
reported by Barluenga et al. on the metal-free reductive coupling of tosylhydrazones with alcohols
or phenols which is another route for reductive etherification of carbonyl compounds.15
0
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Previously, we reported the Ni-catalyzed coupling of benzylic substrates and aldehydes for one-
pot synthesis of benzylic alcohols.16 Also, we have illustrated the synthesis of amides using Ni-
1
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catalyzed reductive coupling of benzyl halides and carbodiimides. In this study we found that the
etherification of aldehydes could be accomplished simply at room temperature in ethylene glycol
(
EG) as both solvent and reducing agent (Scheme 1).
Scheme 1. Ni-catalyzed reductive etherification of aldehydes at room temperature using ethylene
glycol as reducing agent
As far as we know, there is no report in the literature on the Ni-catalyzed reductive
etherification of aldehydes.
The reaction conditions were optimized using a model reaction containing (1-
chloroethyl)benzene (1a) and benzaldehyde (2a). The obtained results of optimization study are
demonstrated in Table 1.
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Table 1. Optimization of the reaction conditions a
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Yield3a (%)b
Entry
Ni catalyst
Reductant
Zn
Solvent
EG
1
2
3
4
5
6
7
8
9
NiCl
NiCl
2
.5H
.5H
2
O
O
81
76
0
2
2
Mn
EG
None
Zn
EG
NiCl
NiCl
NiCl
NiCl
2
.5H
2
.5H
2
.5H
2
.5H
2
O
2
O
2
O
2
O
None
None
None
None
EG
EG
78
71
10
0
Glycerol
PEG-200
DMF
EG
NiBr
2
76
75
73
62
79
83
65
60c
NiCl
NiCl
NiCl
NiCl
2
(dppf)
EG
EG
1
1
1
0
1
2
2
2
2
(dppp)
EG
EG
(PPh
.glyme
.dmg
Ni(PPh (CO)
NiCl .dmg
3
)
2
EG
EG
EG
EG
13
NiCl
2
EG
EG
1
1
4
5
)
3 2
2
None
EG
DMF
EG
2
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NiCl
NiCl
2
.dmg
.dmg
EG
EG
EG
EG
84d
74e
1
2
a
Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), MgCl
2
(2.0 mmol), Reductant (3.0 mmol), [Ni]
(10 mol%), and solvent (3.0 mL). b Isolated yield. 5 mol% of catalyst was used. 12 mol% of
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e
catalyst was used. 8 mol% of catalyst was used.
As shown in Table 1, in the presence of Ni(II) pre-catalyst and Zn as reducing agent in ethylene
glycol as solvent, 81% of the corresponding ether was obtained (Table 1, entry 1). By change of
reducing agent to Mn, the reaction yield was decreased to 76%, demonstrating that Zn is more
efficient than Mn as reducing agent (Table 1, entry 2). In the absence of Ni catalyst, no product was
obtained representing that this is a Ni-catalyzed process (Table 1, entry 3).
Since, EG has already been used as reducing agent18 we decided to run the reaction in the
absence of metal reductant. Hopefully, the product in was obtained in remarkable yield of 87%
(Table 1, entry 4). In order to show the role of EG as reducing agent, different experiments were
conducted (Table 1, entries 5-7). For example, glycerol showed reductant activity and 71% of the
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ether product was produced, while in PEG-200 the reaction yield was decreased to 10 % and in
DMF no product was detected. Thus the existence of both Ni catalyst and EG as reducing agent for
this process is required. Considering the role of EG as both solvent and reducing agent, the
optimization study was continued.
Different Ni-catalysts21 were checked and NiCl
catalyst for this process (Table 1, entries 8-13). In order to show that this reaction proceeds
through a Ni(0)-catalyzed process, Ni(PPh (CO) was used as catalyst and 65% of the desired
.dmg was selected as the most efficient pre-
2
3
)
2
2
product was obtained (Table 1, entry 14). The amount of the pre-catalyst was also optimized and
10 mol% was recognized as the optimum amount (Table 1, entries 15-17). In this way, entry 13 of
Table 1 was selected as the most optimized condition for the Ni-catalyzed reductive etherification
of aldehydes.
We initially examined the reactivity of some other benzyl electrophiles toward the reductive
etherification reaction with benzaldehyde in order to benchmark their reactivity in this protocol
(Scheme 2).
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Scheme 2. Ni-catalyzed reductive etherification using different benzyl electrophiles
As shown in Scheme 2, it is possible to obtain the reaction yield of 83-84% using chloride,
bromide, tosylate and triflate electrophiles. No product formation was observed for benzyl alcohol
under our optimized conditions. Maximum reaction yield was observed for 2,4,6-tris(1-
phenylethoxy)-1,3,5-triazine (X for this substrate is considered OTA). This class of alkyl C-O
electrophiles is readily available and can be prepared in a single step by the reaction of alcohol with
2
,4,6-trichloro-1,3,5-triazine (TCT, cyanuric chloride).
TCT easily reacts with 3 equivalents of alcohol to produce 2,4,6-tris(alkoxy)-1,3,5-triazine
(
TAT). The C−O bond in TAT is longer than that alcohol, representing that TCT acts as a C−O bond
2
2
activating agent (Scheme 1). In fact, TAT is a alkyl C-O electrophile which can be used instead of
23
halides, allowing direct application of alcohols in organic reactions. In this study, TAT was used as
a new C-O electrophile in reductive coupling reaction with aldehydes and it was efficiently resulted
in the production of ether product.
However, what is interesting here is that, by use of primary benzyl alcohols, the obtained
product is not ether and instead an benzylic alcohol is produced (Scheme 3).
Scheme 3.Ni-catalyzed reductive coupling of activated primary benzyl alcohol by TCT and
benzaldehyde
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In fact, there is selectivity between the C-O and C-C bond formation reactions. In order to
confirm and generalize this observation, different primary, secondary and tertiary benzylic
substrates were reacted with different aldehydes and the obtained results confirmed our primary
observation. The obtained results demonstrated that under our optimized conditions, the reaction
of aromatic aldehydes with secondary and tertiary activated benzylic alcohols shows excellent C-O
bond formation selectivity and produces the corresponding ether (Scheme 4).
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Scheme 4. Products of nickel-catalyzed reductive coupling of primary, secondary and tertiary
benzylic C-O electrophiles and aldehydes. Reaction conditions: TAT (0.35 mmol), aldehyde (1.0
mmol), MgCl
2
(2.0 mmol), EG (3.0 mL), NiCl .dmg (10 mol%), rt, 24h.
2
As shown in Scheme 4, it is possible to synthesize different unsymmetrical ether compounds
through the reaction of aldehydes with secondary or tertiary benzyl alcohols. Aldehydes with both
electron-donating and electron-withdrawing groups underwent this reaction with secondary and
tertiary benzylic substrates and gave the ether product in moderate to good yields. Overall, this
methodology is suitable for the synthesis of bulky substituted benzylic ethers. Since benzyl ethers
can be used as protected group in multistep synthesis,24 our approach could have synthetic
significance for the protection of aldehyde groups. It should be mentioned that the direct
conversion of aldehyde group to ether moiety could be interesting with synthetic applications in
organic chemistry.
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Also, different primary benzylic substrates can be coupled with aldehydes in order to
synthesize diverse alcohol products (Scheme 4, products 4b-i). Infact, in this method there is a
competition between the nickel-catalyzed carbon-carbon bond formation reaction and the
reductive etherification by change of primary to secondary/tertiary benzylic substrates.
A series of competing experiments were also carried out to establish the selectivity trends
(
Scheme 5). First, a competing reaction was performed between a ketone (acetophenone) and
aldehyde in the reaction with 1-phenylethanol. It was found that no ether product was produced
with ketone under the optimized conditions. Additionally, we performed two other competing
experiments between aliphatic and aromatic aldehydes and found that benzaldehyde underwent
the etherification in the presence of butyraldehyde. Next, the experiment was performed between
allylic and benzylic substrates which led to the selective coupling of the benzylic substrate to
furnish the ether 3d in 76% yield. It seems that the allyl substrate forms an stable complex with Ni,
2
5
so that it can not react furture to produce the desired product. Finally, in a competing experiment
between the benzylic substrates and tert-butanol as a aliphatic alcohol, we exclusively observed
that tert-butanol cannot form ether under the optimized conditions. This observation refers to the
3
16
mechanistic aspect of the process, representing the existence of a η -bond nickel complex.
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CH3
O
Ph
N
Benzaldehyde (1 mmol)
Acetophenone (1 mmol)
H3C
CH3
O
O
3a: 73%
Aldehyde vs Ketone Substrate:
Ph
N
CH3
Ph
NiCl .dmg (10 mol%)
CH3 CH3
2
MgCl2 (2 mmol)
EG (3 mL), rt, 24h
N
O
O
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not observed
Ph
CH3
Butyraldehyde (1 mmol)
Benzaldehyde (1 mmol)
O
H C
3
O
N
3
p: 10%
CH3
N
N
CH3
Aliphatic vs Aromatic Aldehyde:
NiCl2.dmg (10 mol%)
MgCl2 (2 mmol)
CH3
Ph
O
O
Ph
O
EG (3 mL), rt, 24h
0
.35 mmol
3
a: 70%
CH3
O
O
CH3
O
N
N
CH3
F
not observed
N
O
F
CHO (1 mmol)
0
.35 mmol
Ph
Allylic vs Benzylic alcohol:
O
NiCl .dmg (10 mol%)
2
H C
3
O
MgCl2 (2 mmol)
F
EG (3 mL), rt, 24h
3
d: 76%
CH3
N
N
CH3
Ph
Ph
O
0
N
O
.35 mmol
Ph
CH3
H C
O
N
3
O
CH3
N
N
CH3
O N
2
3g: 70%
Ph
O
O
Ph
O2N
CHO (1 mmol)
Benzylic vs Aliphatic alcohol:
0.35 mmol
O
NiCl .dmg (10 mol%)
O
2
MgCl2 (2 mmol)
EG (3 mL), rt, 24h
O N
2
N
N
not observed
O
N
O
0
.35 mmol
Scheme 5. Competing experiments
In another experiment, the (benzyloxy)benzene was used instead of TBT and the reaction failed
to proceed (scheme 6). This experiment revealed that the triazine ring has an important role in the
activation of benzyl alcohols which this may be referred to the C-O bond activation function and
coordination of nitrogen atom to facilitate the Ni-catalyzed C-O bond cleavage.26
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Scheme 6. The role of triazine ring in activation of C-O bond and accomplish of reaction
It should be mentioned that, the residue of the reaction mixture after completion is cyanuric
2
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acid which was recovered from the reaction mixture. Also, in the absence of MgCl
2
, the reaction
yield was decreased significantly. This experiment show that MgCl
2
plays a key role in stabilization
of the active organometallic species during the reaction progress.28
Conclusion
In conclusion, we established a new and selective method for the reaction of benzylic electrophiles
with aldehydes using a Ni-catalyzed process. For primary substrates, the alcoholic products were
obtained via C-C coupling reactions, while for secondary and tertiary substrates; the preferred
product is ether through C-O bond formation reaction. The TCT reagent was used to activate the C-
O bond of benzyl alcohols to undergo in coupling reaction with aldehydes as benzyl C-O
electrophiles. Ethylene glycol was used as a green solvent and also as reducing agent to accomplish
the reaction under more environmentally friendly conditions. This nickel-catalyzed process opened
up a new way for synthesis of bulky substituted benzyl ethers and benzyl alcohols which could find
high potential application in organic synthesis.
Experimental Section
General. All of the commercial reagents and solvents were used without further purification.
Melting points were determined in open capillary tubes. FT-IR spectroscopy was employed for
characterization of the synthesized compounds using film KBr pellet techniques. NMR spectra were
acquired in DMSO-d with tetramethylsilane (TMS) as the internal standard. The sample was
6
analyzed by GC/MS for mass spectrometry and a microanalyzer for elemental analyses. Reaction
monitoring was accomplished by TLC on silica gel plates. Column chromatography was carried out
on columns of silica gel 60 (70−230 mesh).
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General procedure for Ni-catalyzed addition of benzyl alcohols to aldehydes using TCT
reagent. Into a flask (50 mL), a mixture of benzyl alcohol (1.0 mmol), and NaH (1.2 mmol) was
stirred in dry THF (5 mL) for 1h at room temperature. Then 0.35 mmol of TCT was added to the
reaction mixture and stirring was continued for 2 h. The precipitated solid was added to the
reaction mixture containing aldehyde (1.0 mmol), MgCl
2
(2.0 mmol), NiCl .dmg (10.0 mol%), and
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ethylene glycol (3.0 mL). The mixture was stirred at rt for 24h under these conditions. After
completion of the reaction as confirmed by TLC, ethyl acetate (25 mL) and water (25 mL) were
added to the reaction mixture. After separation of the organic layer from water, the aqueous phases
were extracted with ethyl acetate (2 x 25 mL) again. The combined organic layers were then dried
over anhydrous Na
2
SO , filtered and concentrated under vacuum to yield the crude product. The
4
crude product was purified by column chromatography (n-hexane/ethyl acetate) to obtain the
desired pure compound.
Typical procedure for large-scale Ni-catalyzed addition of benzyl alcohols to aldehydes using
TCT reagent . Into a conical flask (200 mL), a mixture of 4-methoxybenzyl alcohol (10 mmol), and
NaH (12 mmol) was stirred in dry THF (50 mL) for 2h at room temperature. Subsequently, 3.5
mmol of TCT was added to the reaction mixture and stirring was continued for 5h. The precipitated
solid was added to the reaction mixture containing 2-methoxybenzaldehyde (10 mmol), MgCl
2
(20
mmol), NiCl .dmg (1 mmol), and ethylene glycol (30 mL). The mixture was stirred at rt for 24h.
2
Afterward, ethyl acetate (300 mL) and water (300 mL) were added to the reaction mixture. The
organic layer was separated and the aqueous phases were extracted with ethyl acetate (2 x 50 mL)
again. The organic layer was dried over anhydrous Na
product it was purified by column chromatography using n-hexane/ethyl acetate (10:5) as eluent
= 0.42). Pure product was obtained in 74% (1.91 g) yield as light yellow oil.
2
SO and evaporated. In order to obtain pure
4
(
R
f
Spectral data for synthesized compounds
(
1-(benzyloxy)ethyl)benzene (3a). Light yellow oil, R
f
(n-hexane/EtOAc 10:1) = 0.66. Yield: 73%
1
(
155 mg). H NMR (250 MHz, CDCl
3
/TMS): δ (ppm) = 1.41 (d, J = 5 Hz, 3H), 4.22 (d, J = 12.5 Hz, 1H),
1
3
4
1
.36-4.47 (m, 2H), 7.18-7.31 (m, 10H). CNMR (62.5 MHz, CDCl
3
/TMS): δ (ppm) = 24.2, 70.3, 77.2,
26.3, 127.4, 127.5, 127.7, 128.3, 128.5, 138.6, 143.7. MS: m/z 212 (35, M+). Anal. Cal. For C15
16
H O
(212.28): C, 84.87; H, 7.60. Found: C, 84.80; H, 7.53.
1
-isopropyl-4-((1-phenylethoxy)methyl)benzene (3b). Pale yellow oil, R (n-hexane/EtOAc
f
1
10:1) = 0.60. Yield: 75% (190 mg). H NMR (250 MHz, CDCl
3
/TMS): δ (ppm) = 1.16 (d, J = 7.5 Hz,
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H), 1.40 (d, J = 7.5 Hz, 3H), 2.80-2,97 (m, 1H), 4.18 (d, J = 12.5 Hz, 1H), 4.33 (d, J = 12.5 Hz,1H),
1
3
4.43 (q, J = 7.5 Hz, 1H), 7.10-7.30 (m, 9H). CNMR (62.5 MHz, CDCl
3.8, 70.2, 77.2, 126.3, 126.4, 127.4, 127.8, 128.4, 136.4, 143.8, 147.8. MS: m/z 254 (65, M+), 255
12, M+1). Anal. Cal. For C18 22O (254.36): C, 84.99; H, 8.72. Found: C, 84.91; H, 8.65.
3
/TMS): δ (ppm) = 24.0, 24.3,
3
(
H
1
1
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1
1
1
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1
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1
-methoxy-4-((1-phenylethoxy)methyl)benzene (3c). Light yellow oil, R (n-hexane/EtOAc 10:2)
f
1
=
0.52. Yield: 72% (174 mg). H NMR (250 MHz, CDCl
3
/TMS): δ (ppm) = 1.38 (d, J = 7.5 Hz, 3H), 3.73
(
s, 3H), 4.15 (d, J = 10 Hz, 1H), 4.31 (d, J = 10 Hz, 1H), 4.41 (q, J = 7.5 Hz, 1H), 6.79 (d, J = 7.5 Hz, 2H),
1
3
7
.15-7.31 (m, 7H). CNMR (62.5 MHz, CDCl
3
/TMS): δ (ppm) = 24.2, 55.3, 69.9, 77.2, 113.7, 126.1,
127.4, 128.1, 128.5, 130.7, 143.8, 160.4. MS: m/z 242 (41, M+). Anal. Cal. For C16
18
H O
2
(242.31): C,
7
9.31; H, 7.49. Found: C, 79.25; H, 7.41.
1-fluoro-4-((1-phenylethoxy)methyl)benzene (3d). Colorless oil, R (n-hexane/EtOAc 10:2) =
f
1
0
.49. Yield: 76% (185 mg). H NMR (250 MHz, CDCl
3
/TMS): δ (ppm) = 1.32 (d, J = 7.5 Hz, 3H), 4.11
(
d, J = 10 Hz, 1H), 4.23 (d, J = 12.5 Hz, 1H), 4.34 (q, J = 7.5 Hz, 1H), 6.85 (t, J = 7.5 Hz, 2H), 7.10-7.23
1
3
/TMS): δ (ppm) = 24.9, 69.6, 77.3, 115.1 (d, 2JCF= 21.25 Hz), 126.3,
(m, 7H). CNMR (62.5 MHz, CDCl
27.6, 128.5, 129.4 (d, 3JCF = 8.12 Hz), 134.3 (d, 4JCF = 2.50 Hz), 143.5, 162.2 (1JCF = 243.75 Hz). MS:
m/z 230 (28, M+). Anal. Cal. For C15 15FO (230.27): C, 78.24; H, 6.57. Found: C, 78.18; H, 6.50.
3
1
H
1
-((1-phenylethoxy)methyl)-4-(trifluoromethyl)benzene (3e). Creamy white oil, R
f
(n-
/TMS): δ (ppm) = 1.32
d, J = 7.5 Hz, 3H), 4.11 (d, J = 10 Hz, 1H), 4.23 (d, J = 12.5 Hz, 1H), 4.34 (q, J = 7.5 Hz, 1H), 7.11-7.24
1
hexane/EtOAc 10:3) = 0.46. Yield: 72% (202 mg). H NMR (250 MHz, CDCl
3
(
(
1
3
m, 7H), 7.55 (d, J = 7.5 Hz, 2H). CNMR (62.5 MHz, CDCl /TMS): δ (ppm) = 24.3, 69.6, 77.5, 122.1,
3
125.1 (q, 3JCF = 3.75 Hz), 126.9, 127.9, 128.0, 130.0, 135.9, 143.4, 144.9. MS: m/z 280 (33, M+). Anal.
Cal. For C16 O (280.28): C, 68.56; H, 5.39. Found: C, 68.50; H, 5.31.
H F
15 3
4-((1-phenylethoxy)methyl)benzonitrile (3f). Colorless oil, R (n-hexane/EtOAc 10:3) = 0.43.
f
1
Yield: 70% (166 mg). H NMR (250 MHz, CDCl
3
/TMS): δ (ppm) = 1.43 (d, J = 7.5 Hz, 3H), 4.26-4.36
(
m, 2H), 4.43 (q, J = 7.5 Hz, 1H), 7.26-7.36 (m, 5H), 7.43 (d, J = 10 Hz, 2H), 7.58 (d, J = 7.5 Hz, 2H).
13CNMR (62.5 MHz, CDCl
3
/TMS): δ (ppm) = 24.3, 69.6, 77.4, 112.5, 118.6, 126.4, 127.9, 128.8, 129.4,
1
5
32.7, 142.6, 144.5. MS: m/z 237 (19, M+). Anal. Cal. For C16H15NO (237.29): C, 80.98; H, 6.37; N,
.90. Found: C, 80.90; H, 6.30; N, 5.84.
1
-nitro-4-((1-phenylethoxy)methyl)benzene (3g). Yellow oil, R (n-hexane/EtOAc 10:3) = 0.41.
f
1
Yield: 70% (180 mg). H NMR (400 MHz, CDCl
3
/TMS): δ (ppm) = 1.42 (d, J = 8.0 Hz, 3H), 4.64 (d, J =
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2.0 Hz, 1H), 4.74 (d, J = 12.0 Hz, 1H), 4.82 (q, J = 8.0 Hz, 1H), 7.22-7.30 (m, 5H), 7.44 (d, J = 8.0 Hz,
2H), 8.12 (d, J = 8.0 Hz, 2H). 13CNMR (100 MHz, CDCl
25.4, 127.0, 127.5, 128.5, 143.1, 145.5, 148.9. MS: m/z 257 (35, M+). Anal. Cal. For C15
257.28): C, 70.02; H, 5.88; N, 5.44. Found: C, 69.93; H, 5.81; N, 5.35.
3
/TMS): δ (ppm) = 25.1, 63.9, 70.5, 123.7,
1
H15NO
3
(
0
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(
(benzyloxy)methanetriyl)tribenzene (3h). Light yellow oil, R (n-hexane/EtOAc 10:2) = 0.57.
f
1
Yield: 68% (238 mg). H NMR (250 MHz, CDCl
3
/TMS): δ (ppm) = 4.08 (s, 2H), 6.99-7.31 (m, 14H),
/TMS): δ (ppm) = 65.8, 87.0, 127.1, 127.4, 127.9,
28.3, 128.8, 129.6, 139.2, 144.2. MS: m/z 350 (17, M+). Anal. Cal. For C26 22O (350.45): C, 89.11; H,
1
3
7
1
.42 (d, J = 7.5 Hz, 6H). CNMR (62.5 MHz, CDCl
3
H
6.33. Found: C, 89.02; H, 6.25.
(
((4-isopropylbenzyl)oxy)methanetriyl)tribenzene (3i). Dark brown oil, R
f
(n-hexane/EtOAc
1
1
0:2) = 0.55. Yield: 65% (255 mg). H NMR (250 MHz, CDCl
H), 2.73-2.89 (m, 1H), 4.05 (s, 2H), 7.09-7.24 (m, 13H), 7.42 (d, J = 7.5 Hz, 6H). CNMR (62.5 MHz,
/TMS): δ (ppm) = 24.1, 33.9, 65.6, 86.9, 125.9, 127.3, 127.9, 128.8, 129.6, 136.5, 144.2, 147.8.
MS: m/z 392 (23, M+). Anal. Cal. For C29 28O (392.53): C, 88.73; H, 7.19. Found: C, 88.65; H, 7.10.
3
/TMS): δ (ppm) = 1.16 (d, J = 7.5 Hz,
1
3
6
CDCl
3
H
(
((4-methoxybenzyl)oxy)methanetriyl)tribenzene (3j). White solid, R
f
(n-hexane/EtOAc 10:3)
1
= 0.48. Yield: 64% (243 mg). H NMR (250 MHz, CDCl
.79 (d, J = 7.5 Hz, 2H), 7.11-7.24 (m, 11H), 7.42 (d, J = 7.5 Hz,6H). CNMR (62.5 MHz, CDCl
δ (ppm) = 55.3, 65.4, 86.9, 113.7, 127.0, 127.2, 128.5, 128.7, 131.2, 144.2, 158.8. MS: m/z 380 (16,
M+). Anal. Cal. For C27 (380.48): C, 85.23; H, 6.36. Found: C, 85.16; H, 6.14.
3
/TMS): δ (ppm) = 3.70 (s, 3H), 4.01 (s, 2H),
1
3
6
3
/TMS):
24
H O
2
(
((4-(trifluoromethyl)benzyl)oxy)methanetriyl)tribenzene (3k). Creamy yellow oil, R
f
(n-
/TMS): δ (ppm) = 4.19
s, 2H), 6.92 (d, J = 7.5 Hz,2H), 7.14 (t, J = 7.5 Hz, 3H), 7.26 (t, J = 7.5 Hz, 6H), 7.39 (d, J = 7.5 Hz, 6H),
1
hexane/EtOAc 10:2) = 0.41. Yield: 61% (255 mg). H NMR (250 MHz, CDCl
3
(
13
/TMS): δ (ppm) = 64.9, 86.3, 122.7, 125.1 (q, 3JCF
=
7
3
C
.67 (d, J = 7.5 Hz, 2H). CNMR (62.5 MHz, CDCl
3
.75 Hz), 126.9, 127.9, 129.3, 130.0, 135.1, 142.9, 144.8. MS: m/z 418 (14, M+). Anal. Cal. For
O (418.45): C, 77.50; H, 5.06. Found: C, 77.42; H, 5.00.
27 21 3
H F
4
,4'-((benzyloxy)(phenyl)methylene)bis(methoxybenzene) (3l). Creamy white solid, R (n-
f
1
hexane/EtOAc 10:4) = 0.37. Yield: 63% (258 mg). H NMR (250 MHz, CDCl
3
/TMS): δ (ppm) = 3.63
(s, 6H), 4.07 (s, 2H), 6.72 (d, J = 10 Hz, 4H), 7.05-7.32 (m, 12H), 7.41 (d, J = 7.5 Hz, 2H). 13CNMR
62.5 MHz, CDCl /TMS): δ (ppm) = 55.2, 65.6, 86.4, 113.2, 126.8, 127.0, 127.1, 127.9, 128.2, 128.3,
(
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30.1, 136.4, 139.3, 145.2, 158.5. MS: m/z 410 (11, M+). Anal. Cal. For C28
H
26
O (410.50): C, 81.92;
3
H, 6.38. Found: C, 81.85; H, 6.31.
4
,4'-(((4-isopropylbenzyl)oxy)(phenyl)methylene)bis(methoxybenzene) (3m). Light yellow
1
oil, R
f
(n-hexane/EtOAc 10:4) = 0.35. Yield: 62% (280 mg). H NMR (250 MHz, CDCl
3
/TMS): δ (ppm)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
=
7
1.14 (d, J = 7.5 Hz, 6H), 2.67-2.85 (m, 1H), 3.64 (s, 6H), 4.04 (s, 2H), 7.72 (d, J = 10 Hz, 4H), 7.08-
.23 (m, 7H), 7.31 (d, J = 10 Hz, 4H), 7.42 (d, J = 7.5 Hz, 2H). 13CNMR (62.5 MHz, CDCl
/TMS): δ
3
(
ppm) = 24.1, 33.8, 55.1, 65.3, 86.2, 113.1, 126.3, 126.7, 127.0, 127.8, 128.2, 130.1, 136.3, 136.6,
45.2, 147.6, 158.4. MS: m/z 452 (27, M+). Anal. Cal. For C31 (452.58): C, 82.27; H, 7.13. Found:
C, 82.18; H, 7.05.
1
32
H O
3
4
,4'-(((4-methoxybenzyl)oxy)(phenyl)methylene)bis(methoxybenzene) (3n). Brown oil, R
f
(n-
/TMS): δ (ppm) = 3.71
s, 6H), 3.81 (s, 3H), 4.01 (s, 2H), 6.74-6.83 (m, 6H), 6.89 (d, J = 10 Hz, 2H), 7.32 (d, J = 10 Hz,4H),
1
hexane/EtOAc 10:4) = 0.33. Yield: 60% (264 mg). H NMR (250 MHz, CDCl
3
(
13
7
.39-7.53 (m, 5H). CNMR (62.5 MHz, CDCl /TMS): δ (ppm) = 55.5, 65.2, 86.4, 113.1, 113.14, 126.7,
3
128.4,129.1, 129.4, 129.7, 130.1, 136.4, 143.7, 158.4, 160.1. MS: m/z 440 (25, M+). Anal. Cal. For
(440.53): C, 79.07; H, 6.41. Found: C, 79.01; H, 6.33.
C
29 28
H O
4
4,4'-(phenyl((4-(trifluoromethyl)benzyl)oxy)methylene)bis(methoxybenzene) (3o). Creamy
1
yellow oil, R
f
(n-hexane/EtOAc 10:4) = 0.30. Yield: 60% (287 mg). H NMR (250 MHz, CDCl
3
/TMS): δ
(
ppm) = 3.63 (s, 6H), 4.13 (s, 2H), 6.71 (d, J = 7.5 Hz, 4H), 7.05-7.20 (m, 3H),7.28 (d, J = 10 Hz,4H),
1
3
7
.35-7.48 (m, 6H). CNMR (62.5 MHz, CDCl /TMS): δ (ppm) = 55.1, 64.9, 86.6, 113.2, 122.1, 125.1
3
(
q, 3JCF = 3.75 Hz), 126.9, 127.9, 128.0, 128.8, 129.3, 130.0, 135.9, 143.5, 144.8, 158.6. MS: m/z 478
(18, M+). Anal. Cal. For C29 (478.50): C, 72.79; H, 5.27. Found: C, 72.70; H, 5.17.
25 3
H F O
3
1
-(4-(Methylthio)phenyl)-2-phenylethanol (4a). Light brown oil, R
f
(n-hexane/EtOAc 10:2) =
1
0
2
3
.47. Yield: 86% (210 mg). H NMR (250 MHz, CDCl
3
/TMS): δ (ppm) = 1.97 (s, 1H), 2.40 (brs, 2H),
1
3
.89-2.92 (m, 3H), 4.74-4.79 (m, 1H), 7.08-7.22 (m, 9H). CNMR (62.5 MHz, CDCl
8.5, 46.1, 75.6, 128.4, 128.6, 131.96, 132.0, 132.1, 136.2, 137.0, 137.1. MS: m/z 244 (32, M+). Anal.
16OS (244.35): C, 73.73; H, 6.60; Found: C, 73.64; H, 6.52.
3
/TMS): δ (ppm) =
Cal. For C15
H
1
-(2-Methoxyphenyl)-2-(4-methoxyphenyl)ethanol (4b). Light yellow oil, R
f
(n-hexane/EtOAc
/TMS): δ (ppm) = 1.25 (s, 1H), 2.89-
.96 (m, 2H), 3.81-3.87 (m, 6H), 5.04 (s, 1H), 6.73-6.96 (m, 4H), 7.14–7.26 (m, 4H). 13CNMR (62.5
1
10:5) = 0.42. Yield: 78% (201 mg). H NMR (250 MHz, CDCl
3
2
MHz, CDCl /TMS): δ (ppm) = 43.2, 55.2, 55.5, 73.8, 110.2, 113.7, 120.4, 128.3, 128.5, 130.4, 130.7,
3
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32.3, 156.9, 158.4. MS: m/z 258 (19, M+). Anal. Cal. For C16
H
18
O (258.31): C, 74.39; H, 7.02;
3
Found: C, 74.31; H, 6.97.
5
-(1-Hydroxy-2-(4-isopropylphenyl)ethyl)-2-methoxyphenol (4c). Colorless oil,
f
R (n-
1
hexane/EtOAc 10:5) = 0.37. Yield: 81% (232 mg). H NMR (250 MHz, CDCl
3
/TMS): δ (ppm) = 1.23-
0
1
2
3
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8
9
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1
2
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0
1
.26 (m, 6H), 1.59 (s, 1H), 2.25 (s, 1H), 2.44-2.64 (m, 1H), 2.90 (s, 1H), 3.89 (s, 3H), 4.71 (s, 1H), 4.83
s, 1H), 6.98 (d, J = 10 Hz, 1H), 7.01-7.14 (m, 2H), 7.21.-7.31(m, 4H). 13CNMR (62.5 MHz,
CDCl /TMS): δ (ppm) = 24.0, 35.7, 45.0, 56.7, 74.8, 113.3, 115.6, 119.8, 126.6, 127.6, 134.7, 136.0,
45.1, 145.9, 150.4. MS: m/z 286 (30, M+). Anal. Cal. For C18 (286.37) C, 75.50; H, 7.74; Found:
C, 75.44; H, 7.68.
(
3
1
22
H O
3
4
-(2-Hydroxypentyl)benzonitrile (4d). Pale yellow oil, R (n-hexane/EtOAc 10:3) = 0.40. Yield:
f
1
68% (129 mg). H NMR (250 MHz, CDCl
3
/TMS): δ (ppm) = 0.84-0.88 (m, 3H), 1.53-1.60 (m, 4H),
1
3
1
.99 (s, 1H), 2.89-2.91 (m, 2H), 4.77 (s, 1H), 7.41 (d, J = 7.5 Hz, 2H), 7.59 (d, J =7.5 Hz, 2H). CNMR
62.5 MHz, CDCl /TMS): δ (ppm) = 13.7, 18.5, 36.5, 44.8, 71.6, 105.6, 118.3, 127.7, 128.9, 145.8. MS:
m/z 189 (71, M+). Anal. Cal. For C12 15NO (189.25): C, 76.16; H, 7.99; N, 7.40; Found: C, 76.11; H,
.92; N, 7.33.
(
3
H
7
1-(4-(Dimethylamino)phenyl)-2-(4-nitrophenyl)ethanol (4e). Yellow oil, R (n-hexane/EtOAc
f
1
1
0:3) = 0.34. Yield: 88% (252 mg). H NMR (250 MHz, CDCl
3
/TMS): δ (ppm) = 1.18 (s, 1H), 2.77-3.01
(
m, 8H), 4.73-4.79 (m, 1H), 6.61-6.68 (m, 2H), 7.07-7.09 (m, 2H), 7.65-7.72 (m, 2H), 8.04-8.08 (m,
1
3
2
1
H). CNMR (62.5 MHz, CDCl
3
/TMS): δ (ppm) = 40.1, 72.9, 111.6, 120.9, 123.6, 129.1, 130.5, 145.6,
48.0, 150.2. MS: m/z 286 (44, M+). Anal. Cal. For C16
18
H N
2
O
3
(286.33): C, 67.12; H, 6.34; N, 9.78;
Found: C, 67.19; H, 6.37; N, 9.85.
2
-(4-Nitrophenyl)-1-(thiophen-2-yl)ethanol (4f). Yellow oil, R
f
(n-hexane/EtOAc 10:3) = 0.33.
1
Yield: 79% (197 mg). H NMR (250 MHz, CDCl
3
/TMS): δ (ppm) = 1.18 (s, 1H), 3.00 (s, 2H), 5.13 (t, J=
1
3
7
.5 Hz, 1H), 7.15-7.30 (m, 4H), 7.44-7.48 (d, J = 10 Hz, 1H), 8.06 (d, J = 7.5 Hz, 2H). CNMR (62.5
MHz, CDCl
3
/TMS): δ (ppm) = 40.2, 69.1, 120.9, 123.6, 125.5, 127.2, 129.1, 143.3, 145.6, 148.0. MS:
m/z 249 (37, M+). Anal. Cal. For C12
H11NO
3
S (249.29): C, 57.82; H, 4.45; N, 5.62; Found: C, 57.75; H,
4
.41; N, 5.54.
2-(Furan-2-yl)-1-(thiophen-2-yl)ethanol(4g). Colorless oil, R (n-hexane/EtOAc 10:2) = 0.47.
f
1
Yield: 70% (136 mg). H NMR (250 MHz, CDCl
3
/TMS): δ (ppm) = 2.00 (s, 1H), 3.50-3.51 (m, 1H),
3
.56-3.58 (m, 1H), 4.97 (s, 1H), 6.73-6.94 (m, 5H), 7.15–7.18 (m, 1H). 13CNMR (62.5 MHz,
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CDCl
3
/TMS): δ (ppm) = 45.0, 76.2, 105.9, 109.4, 124.6, 126.6, 126.9, 141.6, 143.5, 155.2. MS: m/z
194 (63, M+). Anal. Cal. For C10
H
10
O S (194.25): C, 61.83; H, 5.19; S, 16.51, Found: C, 61.75; H, 5.12;
2
S, 16.44.
1-(4-Chlorophenyl)-2-(4-fluorophenyl)ethanol (4h). Pale yellow oil, R (n-hexane/EtOAc 10:3) =
f
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
0
.45. Yield: 87% (218 mg). H NMR (250 MHz, CDCl
3
/TMS): δ (ppm) = 1.94 (s, 1H), 2.75 (s, 1H), 2.83
13
(
s, 1H), 4.52 (s, 1H), 6.88-6.98 (m, 2H), 7.07-7.24 (m, 6H). CNMR (62.5 MHz, CDCl
3
/TMS): δ (ppm)
=
36.6, 64.2, 115.4, 128.1, 128.5, 129.8, 133.1, 134.5, 139.5, 160.9, 162.7. MS: m/z 250 (29, M+).
Anal. Cal. For C14 12ClFO (250.70): C, 67.07; H, 4.82. Found: C, 66.95; H, 4.74.
H
4
-(1-Hydroxy-2-mesitylethyl)benzonitrile (4i). Colorless oil, R
f
(n-hexane/EtOAc 10:3) = 0.38.
/TMS): δ (ppm) = 1.98 (s, 1H), 2.23-2.26 (m, 9H),
2.82 (s, 1H), 2.90 (s, 1H), 4.93 (s, 1H), 6.82 (s, 2H), 7.14 (d, J = 10 Hz, 2H), 7.48 (d, J = 7.5 Hz, 2H).
13CNMR (62.5 MHz, CDCl
/TMS): δ (ppm) = 20.9, 21.3, 40.9, 74.0, 108.6, 119.4, 125.5, 128.1, 130.1,
32.1, 139.0, 147.9, 159.8. MS: m/z 265 (25, M+). Anal. Cal. For C18 19NO (265.35): C, 81.47; H, 7.22;
1
Yield: 74% (196 mg). H NMR (250 MHz, CDCl
3
3
1
H
N, 5.28; Found: C, 81.40; H, 7.14; N, 5.20.
ASSOCIATED CONTENT
Supporting Information
1
13
Copies of H and C for all synthesized compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: iranpoor@susc.ac.ir.
*Email: panahi@shirazu.ac.ir.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
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Financial support from the research councils of Shiraz University and a grant from the Iran National
Elite Foundation are gratefully acknowledged.
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