Direct Regioselective Alkylation of Non-Basic Heterocycles with Alcohols and Cyclic Ethers through a Dehydrogenative Cross-Coupling Reaction under Metal-Free Conditions

Article abstract of DOI:10.1002/ejoc.201700030

A metal-free, simple, and highly efficient method for the direct alkylation of non-basic heterocycles and basic ones with various alcohols and cyclic ethers has been developed based on an oxidative C–H activation process. The corresponding products were generated through a dehydrogenative C–C cross-coupling reaction in the presence of di-tert-butyl peroxide in good to high yields.

Full text of DOI:10.1002/ejoc.201700030

A Journal of
Accepted Article
Title: Direct Regioselective Alkylation of Non-Basic Heterocycles with
Alcohols and Cyclic Ethers through a Dehydrogenative Cross-
coupling Reaction under Metal-Free Conditions
Authors: Ebrahim Kianmehr, Maryam Fardpour, and Khalid
Mohammed Khan
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700030
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700030
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10.1002/ejoc.201700030
European Journal of Organic Chemistry
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Direct Regioselective Alkylation of Non-Basic Heterocycles with
Alcohols and Cyclic Ethers through a Dehydrogenative Cross-
coupling Reaction under Metal-Free Conditions
Ebrahim Kianmehr,* Maryam Fardpour and Khalid Mohammed Khan[b]
Dedication ((optional))
Abstract: A metal-free, simple and highly efficient method for the
direct alkylation of non-basic heterocycles as well as basic ones with
various alcohols and cyclic ethers has been developed based on an
oxidative C-H activation process. The corresponding products were
generated through a dehydrogenative C-C cross-coupling reaction in
the presence of di-tert-butyl peroxide in good to high yields.
coupling (CDC) reactions of (benzo)thiazoles with cyclic ethers
in the presence of K2S2O8 was developed by Jiang and co-
workers.[7] In 2014, MacMillan[8] reported direct α-arylation of
ethers with electron-deficient nitrogen-containing heteroarenes
through the combination of photoredox catalytic approach and
the Minisci Reaction. In 2015, Wang et. al.[9] explored the ortho-
alkylation of N-iminopyridinium ylides with simple alcohols and
ethers in the presence of benzoyl peroxide. In the same year,
Cai et. al.[10] reported a nickel-catalyzed CDC reaction of indoles
with 1,4-dioxane with a single example of benzofuran as the
substrate.
Introduction
Heteroaromatic moieties are doubtlessly of great importance
among pharmaceutical compounds as well as agricultural
chemicals and therefore are essential to life (Figure 1).[1] Over
the last decade, the direct C-H functionalization of heterocycles
in medicinal chemistry has received much attention.[2] Moreover,
generating a new C-C bond via the C-H activation of alcohols
and ethers has attracted much interest according to its simple
introduction of an oxygen-containing functional group into the
molecule which provides vital materials for the manufacturing of
fine
chemicals,
pharmaceuticals,
agrochemicals
and
fragrances.[3]
Figure 1. Examples of Bioactive Compounds with Non-Basic Nitrogen-Free
Heterocyclic Cores.
The field of coupling alcohols to heterocyclic bases was first
studied by Minisci[4] which describes the hydroxymethylation and
hydroxyethylation of 4-methylpyridine and 4-methylquinoline, in
the presence of peroxides and stoichiometric amounts of acid, in
moderate and low yields, respectively. In 2011, Li et. al.[5]
published
a
palladium-catalyzed coupling of quinoline,
isoquinoline and rac-Binap with simple alcohols and Wang et.
al.[6] reported a metal-free direct C-2 alkylation of azoles with
alcohols and ethers in the presence of tert-butyl hydroperoxide
(TBHP). In 2013, copper-catalyzed cross-dehydrogenative
[a]
[b]
School of Chemistry, College of Science, University of Tehran,
Tehran, Iran
E-mail: kianmehr@khayam.ut.ac.ir
http://schem.ut.ac.ir/en/~kianmehr
H. E. J. Research Institute of Chemistry, International Center for
Chemical and Biological Sciences, University of
Karachi, Karachi-75270, Pakistan
Supporting information for this article is given via a link at the end of the
Scheme 1. Represented Examples of Alkylation in the Literature
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10.1002/ejoc.201700030
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In 2016, DiRocoo et. al.[11] developed a photoredox-catalayzed
hydroxymethylation of heteroaromatic bases. In the same year,
Wu et. al.[12] reported a copper-mediated alkylation of furan and
thiophene derivatives with cyclic ethers. As mentioned above,
although tremendous progress has been made in this area
(Scheme 1), some drawbacks such as the requirement of
making pyridinium salts at the beginning of the reaction
procedure and the use of expensive transition-metal catalysts
still remain.
1, entries 1-5). Unfortunately, inorganic oxidants, such as
K2S2O8, Na2S2O8 and (NH4)2S2O8 were also ineffective in this
reaction and no desired 3b was isolated (Table 1, entries 6-8).
To our delight, an 81% yield of 3b was obtained with 4 equiv of
di-tert-butyl peroxide (DTBP) (Table 1, entry 9). The reaction
was not completed with less than 4 equiv of DTBP, while
increasing the amount of oxidant was not effective in achieving
higher yields, either (Table 1, entries 10 and 11). With respect to
the amount of oxidant used in the reaction, 4 equiv of DTBP was
found to be optimal. The excess amount of DTBP required in the
reaction might refer to the fact that at high temperatures, the
tert-butoxy radical can further fragment to acetone. The effect of
solvent on the model reaction was also examined. Among the
tested solvents, ethanol as well as the substrate, was the most
effective solvent (Table 1, entry 9). Chlorobenzene (PhCl), 1,2-
dichloroethane (DCE), benzene, toluene and dimethyl sulfoxide
(DMSO) were subsequently inferior (Table 1, entries 13-17).
Therefore, the corresponding alcohol or cyclic ether was chosen
as both the reactant and reaction medium considering its
environmentally friendliness, cost-effectiveness and high
efficiency.
The thiophene and furan cores are present as vital moieties in
many different biologically active compounds[13a,b] such as
compound A (Figure 1, GSH = Glutathione) which is an
antioxidant and compound B, known as an inhibitor of the
formation of sickled cells in blood.[13c,d] Despite the importance
of these heterocylic cores, the alkylation with simple alcohols
and ethers were rarely explored.[14] Therefore, development of
new methods for the direct alkylation of heterocycles with
alcohols and cyclic ethers is highly desirable. Herein, we report
a simple, efficient and regioselective metal-free CDC reaction of
non-basic heterocycles such as thiophenes and furans as well
as pyridines with alcohols and cyclic ethers to obtain
corresponding products in good to high yields.
Once the optimized reaction conditions were achieved, the
scope of the alcohol in the direct alkylation of thiophenes with a
variety of alcohols was investigated. As can be seen in Table 2,
the reaction of thiophenes could be performed with a variety of
aliphatic alcohols such as methanol, ethanol, n-propanol and 2-
propanol to produce the corresponding hydroxyalkylated
products 3a-l in good to high yields.
Results and Discussion
We chose 2-acetylthiophene (1a) and ethanol (2b) as the model
substrates to investigate the optimization of the reaction
conditions (Table 1). Based on the model reaction, several
oxidants, solvents and temperatures were investigated to gain
the optimized reaction conditions (see the Supporting
Information).
Amazingly, the reaction of 2-acetylthiophene with ethylene glycol
as a diol proceeded through a different path which gave 3e with
78% yield. Also, when 2-methyl-1-propanol was used as the
alcohol substrate, products 3k and 3l were obtained with 2-
acetylthiophene and 3-acetylthiophene in high yields,
respectively. However, when 2-phenyl ethanol and allyl alcohol
were used as the reactant, no desired products were obtained
(3m and 3n). Reaction of furan as another non-basic
heterocycle was also investigated and the corresponding
hydroxyalkylated products were obtained in good yields (Table
2, 3o-q).
Table 1. Optimization of the Reaction Conditions[a]
entry
oxidant (equiv)
solvent
Yield[b] (%)
1
2
TBHP (4)
BPO(4)
C2H5OH
C2H5OH
C2H5OH
trace
0
0
We next decided to try direct alkylation of 2-acetylthiophene with
cyclic ethers under the optimized reaction conditions. As can be
seen from Table 2, the reaction of 1,4-dioxane, tetrahydrofuran
and 1,3-dioxolane with 2-acetylthiophene smoothly generated
4a-c in high yields.
DDQ (4)
3
4
5
BQ (4)
CHP (4)
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
PhCl
0
trace
0
0
0
81
61
81
N.D.
70
66
61
52
43
6
7
8
9
10
11
12
13[c]
14[c]
15[c]
16[c]
17[c]
K2S2O8 (4)
Na2S2O8 (4)
(NH4)2S2O8 (4)
DTBP (4)
DTBP (2)
DTBP (6)
-
DTBP (4)
DTBP (4)
DTBP (4)
DTBP (4)
DTBP (4)
DCE
Benzene
Toluene
DMSO
[a] Reaction conditions: 2-acetylthiophene (0.3 mmol), ethanol (2.0 mL),
oxidant (4.0 equiv), sealed tube, 130 °C, air, 10 h. [b] Isolated yields. [c]
ethanol (0.5 mL), solvent (1.5 mL). N.D. = No Desired Product, DCE = 1,2-
dichloroethane, DMSO = dimethyl sulfoxide
As shown in Table 1, a variety of organic oxidants such as tert-
butyl hydroperoxide (TBHP), benzoyl peroxide (BPO), 2,3-
dichloro-5,6-dicyanobenzoquinone (DDQ), benzoquinone (BQ)
and cumene hydroperoxide (CHP) were totally insufficient (Table
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Table 2. Substrates Scope for Hydroxyalkylation of Non-Basic Nitrogen-Free
both 2- and 4-hydroxylated products were obtained. Gratifyingly,
a mixture of PhCl:DMSO with the ratio 2:1 gave the 2-
hydroxylated product (6b) smoothly in 75% yield and only a
trace amount of the 4-hydroxylated product (6b’) which was
indicated by TLC (see the Supporting Information). In
continuation of this investigation, as shown in Table 3, various 2-
Heterocycles with Alcohols and Cyclic Ethers via CDC Reaction[a]
phenylpyridines,
3-phenylpyridine
and
4-benzylpyridine
successfully generated the anticipated products 6a-m in good
yields. With 2-methyl-1-propanol as the alcohol substrate, the
products 6l and 6m were formed with 2-phenylpyridine and 3-
phenylpyridine in good yields, respectively. Unfortunately, with
unsubstituted pyridine and thiophene, the reaction didn’t lead to
the formation of desired products. Propitiously, and unlike the
previous reports based on radical addition to basic heterocyclic
cores,[15] the reaction proceeded smoothly with no need to take
extra steps to activate the heterocyclic substrate as pyridinium
salts or use any kinds of metal catalysts or even add acid
directly into the reaction medium to achieve the corresponding
products and therefore, high regioselectivity was obtained only
through using a convenient solvent-mixture. To prove the role of
DTBP as a free radical generator, a control reaction involving
the use of 2,6-di-tert-butyl-4-methylphenol (BHT) as a radical
scavenger was performed. When 1a was treated with 1 equiv of
butylated hydroxytoluene, no desired product 3b was
observed.[16]
Table 3. Substrates Scope for Hydroxyalkylation of Pyridines with Alcohols via
CDC Reaction[a]
[a] Reaction conditions: non-basic heterocycle (0.3 mmol), alcohol/cyclic ether
(2.0 mL), DTBP (4.0 equiv), sealed tube, 130 °C, air, 10 h. [b] non-basic
heterocycle (2 mmol).
With the satisfying results of the reaction between non-basic
heterocycles and alcohols/cyclic ethers in hand, we decided to
examine some basic heterocycles, too. We started the
investigation with 2-phenylpyridine (5a) and ethanol (2b)
(Scheme 2).
Scheme 2. Hydroxyethylation of 2-phenylpyridine
[a] Reaction conditions: substituted pyridine (0.3 mmol), alcohol (0.5 ml),
PhCl:DMSO (2:1) (1.5 ml), DTBP (0.4 equiv), sealed tube, 130 °C, air, 10 h. [b]
substituted pyridine (2 mmol).
Under the optimized reaction conditions for the alkylation of non-
basic heterocycles, a mixture of 6b:6b’ was obtained with
41:38% yield. After solvent screening, it was found that the
solvent has a crucial importance on the reaction regioselectivity.
When the reaction was carried out in toluene, DMSO and PhCl,
Based on the above results and the previous reports, a plausible
mechanism for this reaction is given in Scheme 3.[17] Initially, a
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analyses were performed on commercial plates bearing 0.25-mm layer of
Merck Silica gel 60 F254. The products were purified by Silica gel 60
PF₂₅₄ for preparative thin layer chromatography (Merck). 1H and 13C
NMR spectra were recorded on Bruker DPX 300, 400 and 500 MHz
spectrometers in CDCl3; δ in ppm and J in Hz. Mass spectrometry was
performed with an Agilent 5975C VL MSD (ion source: EI+, 70 eV,
230 °C). High resolution mass spectra were obtained with a Kratos
Concept IIH mass spectrometer.
homolytic cleavage of di-tert-butyl peroxide affords tert-butoxy
radical.[18] The obtained free radicals subsequently undergo
hydrogen atom abstraction from α-position sp3 C-H of alcohol.
The obtained radical C attacks the C-5 position sp2 C-H of 2-
acetylthiophene, producing the corresponding free radical D.
Finally, a hydrogen atom abstraction from radical D affords the
desired products 3a-l and 3o-q.
General procedure for the CDC reaction of non-basic heterocycles
with alcohols/ethers. A 10-mL sealable reaction tube equipped with a
magnetic stirrer bar was charged with non-basic heterocycle (1 equiv, 0.3
mmol), DTBP (4 equiv, 1.2 mmol) and alcohol/ether (2.0 mL). The tube
was then sealed and placed in an oil bath, which was preheated to
130 °C. After stirring the mixture at this temperature for 10 hours, it was
cooled to room temperature and diluted with ethyl acetate, washed with
brine and dried over anhydrous MgSO4. The organic layer was then
concentrated in vacuo. Finally, the resulting residue was subjected to
preparative thin layer chromatography plates [Hex/EtOAc, 3:1] to afford
the target CDC reaction products.
General procedure for the CDC reaction of substituted pyridines
with alcohols. A 10-mL sealable reaction tube equipped with a magnetic
stirrer bar was charged with substituted pyridine (1 equiv, 0.3 mmol),
DTBP (4 equiv, 1.2 mmol), alcohol (0.5 mL) and PhCl:DMSO (2:1) (1.5
mL). The tube was then sealed and placed in an oil bath, which was
preheated to 130 °C. After stirring the mixture at this temperature for 10
hours, the mixture was diluted with CH2Cl2 and washed with brine. The
organic layer was dried over anhydrous MgSO4, filtered and concentrated
in vacuo. Finally, the resulting residue was subjected to preparative thin
layer chromatography plates [Hex/EtOAc, 3:1] to afford the target CDC
reaction products.
Scheme 3. Proposed Reaction Mechanism
When ethylene glycol is used as the alcohol substrate, the
reaction proceeds through a different mechanism and leads to
the formation of 3e with (1,3-dioxolan-2-yl)methyl substituent at
C-5 position (Scheme 4). First, radical intermediate E is formed
under the reaction conditions[19] via hydrogen atom abstraction
from ethylene glycol by tert-butoxy radical. 2-acetylthiophene
undergoes the reaction with E to give 5-acetylthiophene-2-
carbaldehyde F. Then, a reaction between F and ethylene glycol
gives the corresponding product 3e.
1-(5-(hydroxymethyl)thiophen-2-yl)ethan-1-one (3a). The general
procedure was followed using 2-acetylthiophene (0.3 mmol, 38 mg),
DTBP (102 mg, 1.2 mmol), methanol (2.0 mL). Purification by preparative
thin layer chromatography plates (silica gel, Hex/EtOAc 3:1) gave the
final product 3a as a brown oil (38 mg, 82%); 1H NMR (500 MHz, CDCl3):
δ = 7.57 (d, J = 4 Hz, 1H), 7.01 (d, J = 4 Hz, 1H), 4.85 (s, 2H), 2.53 (s,
3H). 13C NMR (125 MHz, CDCl3): δ = 190.9, 153.5, 147.2, 132.5, 125.4,
60.2, 26.6. MS (EI): m/z (%) = 156 (80) [M]+, 141 (100), 127 (40), 113
(46), 97 (21), 85 (78), 69 (19), 57 (22), 43 (89). C7H8O2S (156.2): calcd.
C 53.82, H 5.16; found C 53.95, H 5.15.
1-(5-(1-hydroxyethyl)thiophen-2-yl)ethan-1-one (3b). The general
procedure was followed using 2-acetylthiophene (0.3 mmol, 38 mg),
DTBP (102 mg, 1.2 mmol), ethanol (2.0 mL). Purification by preparative
thin layer chromatography plates (silica gel, Hex/EtOAc 3:1) gave the
final product 3b as a brown oil (41 mg, 81%); 1H NMR (400 MHz, CDCl3):
δ = 7.58 (d, J = 4 Hz, 1H), 7.00 (d, J = 4 Hz, 1H), 5.11 (q, J = 6.6, 1H),
2.54 (s, 3H), 1.60 (d, J = 6.5, 3H). 13C NMR (100 MHz, CDCl3): δ = 190.9,
159.4, 142.78, 132.6, 123.9, 66.4, 26.6, 25.4. MS (EI): m/z (%) = 170
(35) [M]+, 155 (70), 127 (100), 111 (27), 85 (15), 65 (14), 43 (71).
C8H10O2S (170.23): calcd. C 56.45, H, 5.92; found C 56.32, H 5.95.
Scheme 4. Proposed Reaction Mechanism for Ethylene Glycol as the Alcohol
Substrate
Conclusions
In conclusion, we have developed a novel, simple, regioselective,
facile and highly efficient method for the direct C-2 alkylation of
non-basic nitrogen-free heterocycles as well as basic nitrogen-
containing ones like substituted pyridines with various alcohols
and cyclic ethers under metal- and acid-free reaction conditions
in the presence of di-tert-butyl peroxide to generate the
corresponding products in good to high yields.
1-(5-(1-hydroxypropyl)thiophen-2-yl)ethan-1-one (3c). The general
procedure was followed using 2-acetylthiophene (0.3 mmol, 38 mg),
DTBP (102 mg, 1.2 mmol), n-propanol (2.0 mL). Purification by
preparative thin layer chromatography plates (silica gel, Hex/EtOAc 3:1)
gave the final product 3c as a brown oil (42 mg, 77%); IR: ν = 3418, 2966,
2930, 2875, 16474, 1452, 13603, 1276, 1029, 973, 930, 811 (cm-1). 1H
NMR (500 MHz, CDCl3): δ = 7.56 (d, J = 4 Hz, 1H), 6.97 (d, J = 4 Hz, 1H),
4.84 (t, J = 6.5, 1H), 2.52 (s, 3H), 1.83 (m, 2H), 0.96 (t, J = 7.5 Hz, 3H).
13C NMR (125 MHz, CDCl3); δ = 190.6, 158.1, 142.8, 132.3, 124.3, 71.7,
32.2, 26.5, 9.6. MS (EI): m/z (%) = 184 (11) [M]+, 155 (85), 127 (18), 113
(15), 85 (16), 57 (11), 43 (100). C9H12O2S (184.26): calcd. C 58.67, H
6.56; found C 58.59, H, 6.59.
Experimental Section
General Information. Unless otherwise noted, materials obtained from
commercial suppliers (Merck and Sigma-aldrich) were used without
further purification. Solvents were freshly distilled prior to use. TLC
1-(5-(2-hydroxypropan-2-yl)thiophen-2-yl)ethan-1-one
general procedure was followed using 2-acetylthiophene (0.3 mmol, 38
mg), DTBP (102 mg, 1.2 mmol), 2-propanol (2.0 mL). Purification by
(3d).
The
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10.1002/ejoc.201700030
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preparative thin layer chromatography plates (silica gel, Hex/EtOAc 3:1)
= 5.0 Hz, 1H), 6.98 (d, J = 5.2 Hz, 1H), 4.83 (s, 2H). 13C NMR (125 MHz,
CDCl3): δ = 132.4, 130.9, 128.8, 125.4, 68.1. MS (EI): m/z (%) = 193 (15)
[M]+, 182 (11), 165 (22), 119 (100), 111 (12), 105 (28), 97 (14), 91 (67),
83 (14), 71 (13), 65 (20), 57 (23), 43 (21). C5H5BrOS (193.06) calcd. C
31.11, H 2.61; found C 31.12, H 2.61.
1
gave the final product 3d as a viscous brown oil (40 mg, 73%); H NMR
(400 MHz, CDCl3): δ = 7.52 (d, J = 4 Hz, 1H), 6.97 (d, J = 4 Hz, 1H), 2.50
(s, 3H), 1.65 (s, 6H).13C NMR (100 MHz, CDCl3); δ = 190.6, 141.5, 132.9,
124.2, 114.6, 71.1, 29.6, 25.8. MS (EI): m/z (%) = 184 (12) [M]+, 169 (37),
153 (45), 127 (18), 111 (24), 97 (10), 85 (24), 71 (30), 57 (46), 43 (100).
C9H12O2S (184.26): calcd. C 58.67, H, 6.56; found C 58.51, H 6.56.
1-(5-(1-hydroxy-2-methylpropan-2-yl)thiophen-2-yl)ethan-1-one (3k).
The general procedure was followed using 2-acetylthiophene (0.3 mmol,
38 mg), DTBP (102 mg, 1.2 mmol), 2-methyl-1-propanol (2.0 mL).
Purification by preparative thin layer chromatography plates (silica gel,
Hex/EtOAc 3:1) gave the final product 3k as a viscous brown oil (48 mg,
81%); 1H NMR (400 MHz, CDCl3): δ = 7.55 (d, J = 3.6 Hz, 1H), 6.92 (d, J
= 3.6 Hz, 1H), 3.58 (s, 2H), 2.48 (s, 3H), 1.37 (s, 6H). 13C NMR (100 MHz,
CDCl3). δ = 190.9, 162.6, 141.9, 132.8, 124.5, 72.8, 40.6, 26.4, 26.1. MS
(EI): m/z (%) = 198 (30) [M]+, 181 (10), 167 (100), 153 (19), 139 (34), 125
(30), 111 (20), 97 (27), 85 (14), 69 (10), 55 (14), 43 (74). C10H14O2S
(198.28) calcd. C 60.57, H 7.12; found C 60.73, H 7.15.
1-(5-(1,2-dihydroxyethyl)thiophen-2-yl)ethan-1-one (3e). The general
procedure was followed using 2-acetylthiophene (0.3 mmol, 38 mg),
DTBP (102 mg, 1.2 mmol), ethylene glycol (2.0 mL). Purification by
preparative thin layer chromatography plates (silica gel, Hex/EtOAc 3:1)
gave the final product 3e as a brown oil (49 mg, 78%); 1H NMR (400
MHz, CDCl3): δ = 7.57 (d, J = 3.6 Hz, 1H), 6.95 (d, J = 3.6 Hz, 1H), 5.14
(t, J = 4, 1H), 3.97 (m, 2H), 3.90 (m, 2H), 3.21 (d, J = 4, 2H), 2.54 (s, 3H).
13C NMR (100 MHz, CDCl3) δ = 190.5, 147.2, 143.6, 132.5, 128, 103,
65.2, 35.5, 26.6. MS (EI): m/z (%) = 212 (11) [M]+, 167 (13), 149 (14),
139 (20), 124 (11), 111 (14), 97 (30), 86 (13), 73 (100), 57 (18), 45 (85).
C10H12O3S (212.27): calcd. C 56.58, H 5.70; found C 56.77, H, 5.73.
1-(2-(1-hydroxy-2-methylpropan-2-yl)thiophen-3-yl)ethan-1-one (3l).
The general procedure was followed using 3-acetylthiophene (0.3 mmol,
38 mg), DTBP (102 mg, 1.2 mmol), 2-methyl-1-propanol (2.0 mL).
Purification by preparative thin layer chromatography plates (silica gel,
Hex/EtOAc 3:1) gave the final product 3l as a brown oil (48 mg, 80%); 1H
NMR (400 MHz, CDCl3): δ = 7.59 (d, J = 3.8 Hz, 1H), 6.96 (d, J = 3.8 Hz,
1H), 3.62 (s, 2H), 2.54 (s, 3H), 1.42 (s, 6H). 13C NMR (100 MHz, CDCl3):
δ = 191, 162.9, 141.7, 133, 124.5, 72.6, 40.5, 26.4, 26.2. MS (EI): m/z
(%) = 198 (15) [M]+, 167 (100), 153 (10), 139 (15), 125 (14), 111 (10), 97
(15), 91 (11), 65 (12), 43 (85). C10H14O2S (198.28): calcd. C 60.57, H
7.12; found C 60.65, H 7.09.
1-(2-(hydroxymethyl)thiophen-3-yl)ethan-1-one (3f). The general
procedure was followed using 3-acetylthiophene (0.3 mmol, 38 mg),
DTBP (102 mg, 1.2 mmol), methanol (2.0 mL). Purification by preparative
thin layer chromatography plates (silica gel, Hex/EtOAc 3:1) gave the
final product 3f as a brown oil (37 mg, 80%); 1H NMR (500 MHz, CDCl3):
δ = 7.57 (d, J = 3.5 Hz, 1H), 7.01 (d, J = 3.5 Hz, 1H), 4.85 (s, 2H), 2.53 (s,
3H). 13C NMR (125 MHz, CDCl3): δ = 191.1, 154.6, 148.7, 133.2, 124.1,
63.2, 25.2. MS (EI): m/z (%) = 156 (80) [M]+, 141 (100), 127 (36), 113
(42), 97 (13), 85 (72), 69 (16), 57 (13), 43 (51). C7H8O2S (156.20): calcd.
C 53.82, H 5.16; found C 53.96, H, 5.17.
1-(5-(hydroxymethyl)furan-2-yl)ethan-1-one
(3o).
The
general
1-(2-(1-hydroxyethyl)thiophen-3-yl)ethan-1-one (3g). The general
procedure was followed using 3-acetylthiophene (0.3 mmol, 38 mg),
DTBP (102 mg, 1.2 mmol), ethanol (2.0 mL). Purification by preparative
thin layer chromatography plates (silica gel, Hex/EtOAc 3:1) gave the
final product 3g as a brown oil (40 mg, 79%); 1H NMR (500 MHz, CDCl3):
δ = 7.56 (d, J = 4 Hz, 1H), 6.98 (d, J = 4 Hz, 1H), 5.09 (q, J= 6.5 Hz, 1H),
2.52 (s, 3H), 1.58 (d, J = 6.5 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ =
190.7, 159.4, 142.7, 132.4, 123.8, 66.3, 26.5, 25.3. MS (EI): m/z (%) =
170 (13) [M]+, 155 (27), 127 (70), 111 (11), 85 (10), 65 (13), 43 (100).
C8H10O2S (170.23): calcd. C 56.45, H 5.92; found C 56.61, H 5.91.
procedure was followed using 2-acetylfuran (0.3 mmol, 33 mg), DTBP
(102 mg, 1.2 mmol), methanol (2.0 mL). Purification by preparative thin
layer chromatography plates (silica gel, Hex/EtOAc 3:1) gave the final
product 3o as a brown oil (34 mg, 80%); 1H NMR (500 MHz, CDCl3): δ =
7.13 (d, J = 3.5 Hz, 1H), 6.43 (d, J = 3.5 Hz, 1H), 4.68 (s, 2H), 2.45 (s,
3H). 13C NMR (125 MHz, CDCl3): δ = 186.6, 158.9, 152.2, 118.5, 109.6,
57.5, 25.7; MS (EI): m/z (%) = 140 (60) [M]+, 125 (60), 111 (15), 97 (58),
81 (12), 69 (62), 51 (18), 43 (100). C7H8O3 (140.14) calcd. C 60.00, H
5.75; found C 59.84, H 5.77.
1-(5-(1-hydroxyethyl)furan-2-yl)ethan-1-one
(3p).
The
general
1-(2-(1-hydroxypropyl)thiophen-3-yl)ethan-1-one (3h). The general
procedure was followed using 3-acetylthiophene (0.3 mmol, 38 mg),
DTBP (102 mg, 1.2 mmol), n-propanol (2.0 mL). Purification by
preparative thin layer chromatography plates (silica gel, Hex/EtOAc 3:1)
gave the final product 3h as a brown oil (40 mg, 73%); 1H NMR (500
MHz, CDCl3): δ = 7.56 (d, J = 4 Hz, 1H), 6.97 (d, J = 4 Hz, 1H), 4.84 (t,
J= 6.5 Hz, 1H), 2.52 (s, 3H), 1.83 (m, 3H), 0.96 (t, J = 6.5 Hz, 3H). 13C
NMR (125 MHz, CDCl3): δ = 191.7, 157.2, 145.7, 133.1, 124.6, 73.7,
34.1, 26.6, 9.7. MS (EI): m/z (%) = 184 (13) [M]+, 155 (100), 141 (10),
127 (21), 113 (17), 85 (15), 57 (12), 43 (96). C9H12O2S (184.26): calcd. C
58.67, H 6.56; found C 58.50, H 6.55.
procedure was followed using 2-acetylfuran (0.3 mmol, 33 mg), DTBP
(102 mg, 1.2 mmol), ethanol (2.0 mL). Purification by preparative thin
layer chromatography plates (silica gel, Hex/EtOAc 3:1) gave the final
product 3p as a brown oil (37 mg, 81%); 1H NMR (400 MHz, CDCl3): δ =
7.14 (d, J = 3.5 Hz, 1H), 6.41 (d, J = 3.5 Hz, 1H), 4.93 (q, J =6.6 Hz, 1H),
2.47 (s, 3H), 1.58 (d, J = 6.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ =
186.7, 162.6, 151.7, 118.7, 107.5, 63.7, 25.8, 21.4. MS (EI): m/z (%) =
154 (25) [M]+, 139 (52), 121 (14), 111 (72), 97 (21), 83 (29), 69 (10), 55
(32), 43 (100). C8H10O3 (154.16): calcd. C 62.33, H 6.54; found C 62.41,
H 6.56.
1-(5-(1-hydroxypropyl)furan-2-yl)ethan-1-one (3q). The general
procedure was followed using 2-acetylfuran (0.3 mmol, 33 mg), DTBP
(102 mg, 1.2 mmol), n-propanol (2.0 mL). Purification by preparative thin
layer chromatography plates (silica gel, Hex/EtOAc 3:1) gave the final
product 3q as a brown oil (38 mg, 75%); IR 3449, 2966, 2934, 2877,
1668, 1514, 1359, 1294, 1204, 1098, 1020, 974, 804, 630 (cm-1); 1H
NMR (500 MHz, CDCl3) δ 7.13 (d, J = 3.5 Hz, 1H), 6.39 (d, J = 3.5 Hz,
1H), 4.67 (t, J = 6.5 Hz, 1H), 2.44 (s, 3H), 1.82 (m, 2H), 0.96 (t, J = 7.5,
3H); 13C NMR (125 MHz, CDCl3) δ 186.5, 162, 151.7, 118.5, 108.1, 69.1,
28.7, 25.7, 9.5; MS (EI) m/z (relative intensity %) 168 (16) [M]+, 151 (12),
139 (83), 125 (10), 111 (10), 97 (23), 69 (12), 57 (10), 43 (100). C9H12O3
(168.19): calcd. C 64.27, H 7.19; found C 64.07, H 7.17.
5-(hydroxymethyl)thiophene-2-carbonitrile
(3i).
The
general
procedure was followed using 2-thiophenecarbonitrile (0.3 mmol, 33 mg),
DTBP (102 mg, 1.2 mmol), methanol (2.0 mL). Purification by preparative
thin layer chromatography plates (silica gel, Hex/EtOAc 3:1) gave the
final product 3i as a yellow oil (31 mg, 75%); 1H NMR (400 MHz, CDCl3):
δ = 7.53 (d, J = 3.8 Hz, 1H), 7.00 (d, J = 3.8 Hz, 1H), 4.90 (s, 2H). 13C
NMR (100 MHz, CDCl3): δ = 152.9, 137.6, 132.4, 127.8, 124.5, 59.8. MS
(EI): m/z (%) = 139 (90) [M]+, 122 (43), 110 (100), 106 (21), 95 (11), 83
(23), 78 (11), 69 (27), 64 (18), 57 (27), 51 (15), 45 (35), 41 (15).
C6H5NOS (139.18) calcd. C 51.78, H 3.62, N 10.06; found C 51.89, H
3.64, N 10.10.
(3-bromothiophen-2-yl)methanol (3j). The general procedure was
followed using 3-bromothiophene (0.3 mmol, 49 mg), DTBP (102 mg, 1.2
mmol), methanol (2.0 mL). Purification by preparative thin layer
chromatography plates (silica gel, Hex/EtOAc 3:1) gave the final product
3j as a brown oil (40 mg, 70%); 1H NMR (400 MHz, CDCl3): δ = 7.29 (d, J
1-(5-(1,4-dioxan-2-yl)thiophen-2-yl)ethan-1-one (4a). The general
procedure was followed using 2-acetylthiophene (0.3 mmol, 38 mg),
DTBP (102 mg, 1.2 mmol), 1,4-dioxane (2.0 mL). Purification by
preparative thin layer chromatography plates (silica gel, Hex/EtOAc 3:1)
gave the final product 4a as a brown oil (51 mg, 80%); 1H NMR (400 MHz,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700030
European Journal of Organic Chemistry
Full Paper
CDCl3): δ = 7.57 (d, J = 4 Hz, 1H), 6.98 (d, J = 4 Hz, 1H), 4.83 (dd, J =
9.6 & 2.7 Hz, 1H), 3.94 (d, J = 2.8 Hz, 1H), 3.87 (m, 2H), 3.68 (m, 2H),
3.50 (m, 1H), 2.52 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 190.6, 149.8,
143.6, 132.2, 125, 73.6, 71.9, 66.8, 66.2, 26.7. MS (EI): m/z (%) = 212
(57) [M]+, 183 (12), 169 (17), 154 (29), 139 (100), 111 (218), 97 (14), 86
(26), 73 (15), 65 (11), 57 (10), 43 (60). C10H12O3S (212.27): calcd. C
56.58, H 5.70; found C 56.42, H 5.71.
1-(6-phenylpyridin-2-yl)butan-1-ol (6d). The general procedure was
followed using 2-phenylpyridine (0.3 mmol, 47 mg), DTBP (102 mg, 1.2
mmol), n-butanol (0.5 mL) and PhCl:DMSO (2:1) (1.5 mL). Purification by
preparative thin layer chromatography plates (silica gel, Hex/EtOAc 3:1)
gave the final product 6d as a brown oil (46 mg, 68%); IR: ν = 3408, 3060,
2956, 2869, 1575, 1450, 1407, 1307, 1116, 1072, 1029, 912, 815, 759,
1
694, 624 (cm-1). H NMR (400 MHz, CDCl3): δ = 7.99 (d, J = 8 Hz, 2H),
7.74 (t, J = 8 Hz, 1H), 7.62 (d, J = 8 Hz, 1H), 7.39 (m, 3H), 7.17 (d, J = 8
Hz, 1H), 4.80 (dd, J = 7.6 Hz,1H), 1.79 (m, 1H), 1.69 (m, 1H), 1.46 (m,
2H), 0.92 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ = 169.8,
161.8, 155.5, 137.8, 129.3, 128.7, 127, 119.1, 118.8, 72.1, 40.7, 18.5, 14.
MS (EI): m/z (%) 227 (10) [M]+, 210 (17), 196 (10), 184 (100), 169 (44),
153 (44), 127 (21), 77 (16). C15H17NO (227.30): calcd. C 79.26, H 7.54, N
6.16; found C 79.41, H 7.49, N 6.13.
1-(5-(tetrahydrofuran-2-yl)thiophen-2-yl)ethan-1-one
(4b).
The
general procedure was followed using 2-acetylthiophene (0.3 mmol, 38
mg), DTBP (102 mg, 1.2 mmol), tetra-hydrofuran (2.0 mL). Purification by
preparative thin layer chromatography plates (silica gel, Hex/EtOAc 3:1)
gave the final product 4b as a brown oil (48 mg, 81%); 1H NMR (400
MHz, CDCl3): δ = 7.57 (d, J = 4 Hz, 1H), 6.95 (d, J = 4 Hz, 1H), 5.13 (t, J
= 6.4 Hz, 1H), 4.04 (q, J = 6.8, 1H), 3.89 (q, J = 8.1, 1H), 3.07 (t, J = 7 Hz,
1H), 2.60 (s, 3H), 1.98 (m, 3H). 13C NMR (100 MHz, CDCl3): δ = 190.8,
157.3, 142.6, 132.6, 124.1, 76.7, 68.7, 34.8, 26.6, 25.8. MS (EI): m/z (%)
= 196 (72) [M]+, 179 (29), 153 (100), 111 (10), 71 (12), 43 (18).
C10H12O2S (196.27): calcd. C 61.20, H 6.16; found C 61.33, H 6.19.
(6-(3-methoxyphenyl)pyridin-2-yl)methanol
(6e).
The
general
procedure was followed using 2-(3-methoxyphenyl)pyridine (0.3 mmol,
56 mg), DTBP (102 mg, 1.2 mmol), methanol (0.5 mL) and PhCl:DMSO
(2:1) (1.5 mL). Purification by preparative thin layer chromatography
plates (silica gel, Hex/EtOAc 3:1) gave the final product 6e as a dark
yellow oil (45 mg, 70%); IR: ν = 3394, 2927, 1579, 1460, 1313, 1288,
1224, 1164, 1045, 993, 864, 783, 698, 624 (cm-1). 1H NMR (400 MHz,
CDCl3): δ = 7.71 (t, J = 7.6 Hz, 1H), 7.53 (m, 3H), 7.34 (t, J = 7.6 Hz, 1H),
7.13 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 7.6 Hz, 1H), 4.78 (s, 2H), 3.86 (s,
3H). 13C NMR (100 MHz, CDCl3): δ = 160, 158.4, 155.7, 148.6, 137.4,
129.7, 129.6, 120, 119.7, 114.7, 112.4, 63.9, 55.3. HRMS (ESI+):
calculated for C13H13O2N1 [M+]: 215.0946. found: 215.0957.
1-(5-(1,3-dioxolan-2-yl)thiophen-2-yl)ethan-1-one (4c). The general
procedure was followed using 2-acetylthiophene (0.3 mmol, 38 mg),
DTBP (102 mg, 1.2 mmol) and 1,3-dioxolane (2.0 mL). Purification by
preparative thin layer chromatography plates (silica gel, Hex/EtOAc 3:1)
gave the final product 4c as a brown oil (49 mg, 82%); 1H NMR (400 MHz,
CDCl3): δ = 7.17 (d, J = 4.5 Hz, 1H), 7.05 (d, J = 4.5 Hz, 1H), 5.08 (s, 1H),
4.12 (m, 2H), 4.05 (m, 2H), 2.56 (s, 2H). 13C NMR (100 MHz, CDCl3): δ =
190.6, 152.2, 143.9, 132.3, 125.4, 95.9, 65.3, 26.6. MS (EI): m/z (%) =
198 (13) [M]+, 184 (15), 167 (43), 149 (100), 127 (15), 113 (18), 97 (16),
83 (22), 71 (42), 57 (74), 43 (57). C9H10O3S (198.24): calcd. C 54.53, H
5.08; found C 54.38, H 5.11.
1-(6-(3-methoxyphenyl)pyridin-2-yl)ethan-1-ol (6f). The general
procedure was followed using 2-(3-methoxyphenyl)pyridine (0.3 mmol,
56 mg), DTBP (102 mg, 1.2 mmol), ethanol (0.5 mL) and PhCl:DMSO
(2:1) (1.5 mL). Purification by preparative thin layer chromatography
plates (silica gel, Hex/EtOAc 3:1) gave the final product 6f as a dark
yellow oil (49 mg, 72%); IR: ν = 3408, 2970, 2929, 2839, 1575, 1461,
1404, 1315, 1286, 1224, 1161, 1114, 1078, 1043, 875, 783, 700, 624
(6-phenylpyridin-2-yl)methanol (6a). The general procedure was
followed using 2-phenylpyridine (0.3 mmol, 47 mg), DTBP (102 mg, 1.2
mmol), methanol (0.5 mL) and PhCl:DMSO (2:1) (1.5 mL). Purification by
preparative thin layer chromatography plates (silica gel, Hex/EtOAc 3:1)
gave the final product 6a as a dark yellow oil (39 mg, 70%); IR: ν = 3433,
2922, 1577, 1448, 1049, 761, 696 (cm-1). 1H NMR (400 MHz, CDCl3): δ =
7.99 (d, J = 7.2Hz, 2H), 7.72 (t, J = 7.6 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H),
7.39 (m, 3H), 7.14 (d, J = 7.6, 1H), 4.80 (s, 2H). 13C NMR (100 MHz,
CDCl3): δ = 158.4, 156, 139.5, 138.7, 129.3, 128.8, 126.9, 119.1, 118.8,
63.8; HRMS (EI) m/z calculated for C12H11O1N1 [M]+: 185.0841. found:
185.0831.
1
(cm-1). H NMR (400 MHz, CDCl3): δ = 7.72 (t, J = 7.6 Hz. 1H), 7.55 (m,
3H), 7.35 (t, J = 8 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 6.95 (dd, J = 8 & 1.6,
1H), 4.92 (q, J = 6.4 Hz, 1H), 3.87 (s, 3H), 1.53 (d, J = 6.8 Hz, 3H). 13C
NMR (100 MHz, CDCl3): δ = 162.4, 160, 155.3, 140.1, 137.8, 129.7,
119.3, 119.2, 118.5, 114.8, 112.5, 68.4, 55.4, 24.2; HRMS (ESI+):
calculated for C14H15O2N1 [M+]: 229.1103. found: 229.1120.
1-(6-(m-tolyl)pyridin-2-yl)propan-1-ol (6g). The general procedure was
followed using 2-(m-tolyl)pyridine (0.3 mmol, 51 mg), DTBP (102 mg, 1.2
mmol), n-propanol (0.5 mL) and PhCl:DMSO (2:1) (1.5 mL). Purification
by preparative thin layer chromatography plates (silica gel, Hex/EtOAc
3:1) gave the final product 6g as an orange oil (50 mg, 73%). 1H NMR
(500 MHz, CDCl3): δ = 7.84 (s, 1H), 7.79 (d, J = 7.5 Hz, 1H), 7.72 (t, J =
8 Hz, 1H), 7.62 (d, J = 8 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.23 ( d, J = 8
Hz, 1H), 7.15 (d, J = 7.5 Hz, 1H), 4.84 (t, J = 6.5 Hz, 1H), 2.44 (s, 3H),
1.90 (m, 1H), 1.72 (m, 1H), 0.97 (t, J = 6.5 Hz, 3H). 13C NMR (125 MHz,
CDCl3): δ = 161.5, 158.8, 142.5, 142.2, 137.3, 129.8, 128.6, 127.6, 124,
118.8, 118.6, 73.4, 31.4, 21.5, 9.3. MS (EI): m/z (%) 227 (15) [M]+, 212
(34), 196 (74), 198 (100), 170 (43), 141 (15), 128 (10), 115 (15), 91 (23),
77 (10), 65 (15), 51 (10), 43 (10). C15H17NO (227.30): calcd. C 79.26, H
7.54, N 6.16; found C 79.38, H 7.52, N, 6.12.
1-(6-phenylpyridin-2-yl)ethan-1-ol (6b). The general procedure was
followed using 2-phenylpyridine (0.3 mmol, 47 mg), DTBP (102 mg, 1.2
mmol), ethanol (0.5 mL) and PhCl:DMSO (2:1) (1.5 mL). Purification by
preparative thin layer chromatography plates (silica gel, Hex/EtOAc 3:1)
gave the final product 6b as a dark orange oil (45 mg, 75%); IR 3396,
2974, 1577, 1448, 1402, 1112, 1074, 817, 761, 696 (cm-1). 1H NMR (400
MHz, CDCl3): δ = 8.00 (d, J = 7.2 Hz, 2H), 7.74 (t, J = 8 Hz, 1H), 7.62 (d,
J = 8 Hz, 1H), 7.39 (m, 3H), 7.18 (d, J = 8 Hz, 1H), 4.92 (q, J = 6.4 Hz,
1H), 1.53 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ = 162.5,
155.5, 138.3, 138, 129.3, 128.7, 126.9, 119, 118.3, 68.4, 24.1. HRMS
(ESI+): calculated for C13H13O1N1 [M+]: 199.0997. found: 199.1007.
1-(6-phenylpyridin-2-yl)propan-1-ol (6c). The general procedure was
followed using 2-phenylpyridine (0.3 mmol, 47 mg), DTBP (102 mg, 1.2
mmol), n-propanol (0.5 mL) and PhCl:DMSO (2:1) (1.5 mL). Purification
by preparative thin layer chromatography plates (silica gel, Hex/EtOAc
3:1) gave the final product 6c as a dark orange oil (45 mg, 71 %); IR: ν =
3406, 2966, 2927, 2873, 1575, 1452, 1409, 1083, 981, 813, 761, 694,
624 (cm-1). 1H NMR (400 MHz, CDCl3): δ = 7.99 (d, J = 7.2 Hz, 2H), 7.70
(t, J = 8 Hz, 1H), 7.60 (d, J = 8 Hz, 1H), 7.40 (m, 3H), 7.14 (d, J = 8 Hz,
1H), 4.72 (dd, J=7.2 Hz, 1H), 1.89 (m, 1H), 1.70 (m, 1H), 0.95 (t, J = 7.2,
3 H). 13C NMR (100 MHz, CDCl3): δ = 161.5, 155.6, 138.7, 137.4, 129.1,
128.7, 126.9, 118.8, 118.8, 73.4, 31.3, 9.3. MS (EI): m/z (%) = 213 (58)
[M]+, 198 (24), 196 (75), 184 (100), 169 (26), 154 (98), 127 (46), 102 (16),
78 (35), 51 (25), 40 (10). C14H15NO (213.28): calcd. C 78.84, H 7.09, N
6.57; found C 78.72, H 7.05, N 6.53.
(5-phenylpyridin-2-yl)methanol (6h). The general procedure was
followed using 3-phenylpyridine (0.3 mmol, 47 mg), DTBP (102 mg, 1.2
mmol), methanol (0.5 mL) and PhCl:DMSO (2:1) (1.5 mL). Purification by
preparative thin layer chromatography plates (silica gel, Hex/EtOAc 3:1)
gave the final product 6h as a brown oil (41 mg, 73%); IR: ν = 3192, 2922,
2854, 1595, 1473, 1442, 1375, 1072, 1016, 759, 692 (cm-1). 1H NMR
(300 MHz, CDCl3): δ = 8.84 (s, 1H), 8.15 (d, J = 7.5 Hz, 1H), 7.56 (m, 3H),
7.42 (m, 3H), 4.98 (s, 2H). 13C NMR (75 MHz, CDCl3): δ = 156.4, 142.5,
139.2, 135.3, 129.5, 129.3, 127.1, 122.8, 62.2. HRMS (ESI+): m/z
calculated for C12H11O1N1 [M+]: 185.0841. found: 185.0850.
1-(5-phenylpyridin-2-yl)ethan-1-ol (6i). The general procedure was
followed using 3-phenylpyridine (0.3 mmol, 47 mg), DTBP (102 mg, 1.2
mmol), ethanol (0.5 mL) and PhCl:DMSO (2:1) (1.5 mL). Purification by
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700030
European Journal of Organic Chemistry
Full Paper
preparative thin layer chromatography plates (silica gel, Hex/EtOAc 3:1)
gave the final product 6i as a brown oil (42 mg, 70%); 1H NMR (400 MHz,
CDCl3): δ = 8.78 (s, 1H), 7.90 (dd, J = 8 & 1.9 Hz, 1H), 7.60 (dd, J = 5 &
1.9 Hz, 2H), 7.49 (m, 2H), 7.39 ( m, 2H), 4.97 (q, J = 6.5 Hz, 1H), 1.57 (d,
J = 6.5 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ = 162, 146.5, 137.5,
135.44, 129.1, 128.1, 127.1, 119.8, 68.9, 24.2. MS (EI): m/z (%) = 199
(15) [M]+, 184 (100), 156 (92), 154 (45), 127 (26), 102 (10), 77 (15), 51
(11), 43 (10). C13H13NO (199.25): calcd. C 78.36, H 6.58, N 7.03; found
C 78.59, H 6.62, N 7.08.
Keywords: heterocycles • alcohols • alkylation • C-C coupling •
C-H activation
[1]
a) G. Eren, S. Unlu, M. Nunez, L. Labeaga, F. Ledo, A. Entrena, E.
Banoglu, G. Costantino and Sahin. M, Bioorg. Med. Chem. 2010, 18,
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1-(5-phenylpyridin-2-yl)propan-1-ol (6j). The general procedure was
followed using 3-phenylpyridine (0.3 mmol, 47 mg), DTBP (102 mg, 1.2
mmol), n-propanol (0.5 mL) and PhCl:DMSO (2:1) (1.5 mL). Purification
by preparative thin layer chromatography plates (silica gel, Hex/EtOAc
3:1) gave the final product 6j as a brown oil (45 mg, 71%); IR: ν = 3392,
2960, 2923, 2860, 1593, 1471, 1450, 1371, 1332, 1107, 1043, 977, 912,
844, 748, 688 (cm-1). 1H NMR (400 MHz, CDCl3): δ = 8.77 (s, 1H), 7.95
(dd, J = 8.4 & 1.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 2H), 7.45 (t, J = 7.6, 2H),
7.39 ( m, 2H), 4.80 (dd, J = 6.8 Hz, 1H), 1.90 (m, 1H), 1.76 (m, 1H), 0.95
(t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ = 160.4, 145, 136.6,
136, 129.2, 128.4, 127, 121, 73.3, 31.2, 9.5. HRMS (ESI+): calculated for
C14H15O1N1 [M]+: 213.1154. found: 213.1157.
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a) Li, Y, S. Yu, X. Wu, J. Xiao, W. Shen, Z. Dong and J. Gao, J. Am.
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Verlag: Berlin, 2012, p. 65; c) G. Q Lin, Q. D. You, J. F. Cheng, Chiral
1-(4-benzylpyridin-2-yl)ethan-1-ol (6k). The general procedure was
followed using 4-benzylpyridine (0.3 mmol, 51 mg), DTBP (102 mg, 1.2
mmol), ethanol (0.5 mL) and PhCl:DMSO (2:1) (1.5 mL). Purification by
preparative thin layer chromatography plates (silica gel, Hex/EtOAc 3:1)
gave the final product 6k as a brown oil (47 mg, 73%); 1H NMR (500 MHz,
CDCl3): δ = 8.40 (d, J = 5 Hz, 1H), 7.24 (m, 3H), 7.16 (d, J = 7.5 Hz, 2H),
7.09 (s, 1H), 6.99 (d, J = 5 Hz, 1H), 4.81 (q, J = 6.5 Hz, 1H), 3.97 (s, 2H),
1.46 (d, J = 6.5 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ = 163.3, 150.9,
148.1, 138.7, 129, 128.7, 126.7, 122.8, 120.1, 68.8, 41.3, 24.2. MS (EI):
m/z (%) = 213 (12) [M]+, 210 (23), 199 (100), 183 (15), 168 (23), 154 (11),
141 (10), 115 (10), 78 (11), 43 (10). C14H15NO (213.28): calcd. C 78.84,
H 7.09, N 6.57; found C 78.65, H 7.04, N 6.52.
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2-methyl-2-(6-phenylpyridin-2-yl)propan-1-ol
(6l).
The
general
procedure was followed using 2-phenylpyridine (0.3 mmol, 47 mg), DTBP
(102 mg, 1.2 mmol), 2-methyl-1-propanol (0.5 mL) and PhCl:DMSO (2:1)
(1.5 mL). Purification by preparative thin layer chromatography plates
(silica gel, Hex/EtOAc 3:1) gave the final product 6l as a brown oil (48 mg,
71%); IR: ν = 3386, 3062, 2962, 2869, 1573, 1448, 1267, 1043, 763, 698,
623 (cm-1). 1H NMR (400 MHz, CDCl3): δ = 7.91 (d, J = 7.2 Hz, 2H), 7.71
(t, J = 7.6 Hz, 1H), 7.56 (d, J = 8 Hz, 1H), 7.40 (m, 3H), 7.24 ( d, J = 8 Hz,
1H), 3.81 (s, 2H), 1.36 (s, 6H). 13C NMR (100 MHz, CDCl3): δ = 168.1,
160, 155.5, 138, 129.1, 128.9, 126.8, 118.8, 118.2, 72, 41.2, 25.7. MS
(EI): m/z (%) = 227 (10) [M]+, 222 (10), 210 (100), 208 (30), 197 (37), 196
(56), 182 (20), 169 (15), 154 (15), 127 (13), 91 (16), 76 (17), 57 (10).
C15H17NO (227.30): calcd. C 79.26, H 7.54, N 6.16; found C 79.45, H
7.59, N 6.12.
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2-methyl-2-(5-phenylpyridin-2-yl)propan-1-ol (6m). The general
procedure was followed using 3-phenylpyridine (0.3 mmol, 47 mg), DTBP
(102 mg, 1.2 mmol), 2-methyl-1-propanol (0.5 mL) and PhCl:DMSO (2:1)
(1.5 mL). Purification by preparative thin layer chromatography plates
(silica gel, Hex/EtOAc 3:1) gave the final product 6m as a brown oil (168
mg, 74%). 1H NMR (400 MHz, CDCl3): δ = 8.71 (d, J = 2.4 Hz, 1H), 7.86
(dd, J = 8.2 & 2.4 Hz, 1H), 7.56 (m, 2H), 7.43 (m, 2H), 7.39 (m, 2H), 3.81
(s, 2H), 1.40 (s, 6H). 13C NMR (100 MHz, CDCl3): δ = 167, 146.2, 137.5,
135.3, 134.2, 129.1, 128, 127, 120.3, 72.1, 41, 25.6. MS (EI): m/z (%) =
227 (20) [M]+, 210 (58), 196 (100), 182 (28), 154 (19), 127 (22), 102 (10),
77 (16), 51 (15), 41 (15). C15H17NO (227.30): calcd. C 79.26, H 7.54, N
6.16; found C 79.11, H 7.57, N 6.19.
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Acknowledgements
We gratefully acknowledge the financial support from the
Research Council of the University of Tehran.
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10.1002/ejoc.201700030
European Journal of Organic Chemistry
Full Paper
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700030
European Journal of Organic Chemistry
Full Paper
Full Paper
A metal-free direct alkylation of non-
basic nitrogen-free heterocycles as
well as basic nitrogen-containing ones
with alcohols and cyclic ethers in the
presence of di-tert-butyl peroxide is
described.
Cross Dehydrogenative Coupling,
Hydroxyalkylation
Ebrahim Kianmehr,* Maryam Fardpour
and Khalid Mohammed Khan
Page No. – Page No.
Direct Regioselective Alkylation of
Non-Basic and Basic Heterocycles
with Alcohols and Cyclic Ethers
through a Dehydrogenative Cross-
coupling Reaction under Metal-Free
Conditions
This article is protected by copyright. All rights reserved.