Direct, metal-free synthesis of benzyl alcohols and deuterated benzyl alcohols from p-toluenesulfonylhydrazones using water as solvent

Article abstract of DOI:10.1055/s-0031-1290372

A novel library of diverse alcohols was synthesized by metal-free couplings of diazoalkanes derived from p-toluenesulfonylhydrazones to water under reflux and microwave conditions, in high yields. In addition, this protocol was successfully applied in the synthesis of deuterium-labeled alcohols using deuterium oxide. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0031-1290372

PAPER
▌2237
paper
Direct, Metal-Free Synthesis of Benzyl Alcohols and Deuterated Benzyl
Alcohols from p-Toluenesulfonylhydrazones Using Water as Solvent
Metal-Free Synthesis of Alcohols from p-Toluenesulfonylhydrazones
Ángel García-Muñoz,a Aldo I. Ortega-Arizmendi,a Mario A. García-Carrillo,b Eduardo Díaz,b Nelly Gonzalez-Rivas,a
Erick Cuevas-Yañez*a
a
Centro Conjunto de Investigación en Química Sustentable UAEM-UNAM, Carretera Toluca-Atlacomulco Km 14.5, Toluca,
Estado de México, C.P. 50200, Mexico
b
Instituto de Química, UNAM, Circuito Exterior, Ciudad Universitaria, Coyoacán, México, D.F. 04510, Mexico
Fax +52(722)2175109; E-mail: ecuevasy@uaemex.mx
Received: 22.03.2012; Accepted after revision: 26.04.2012
times. The results are summarized in Table 1 and show
Abstract: A novel library of diverse alcohols was synthesized by
that after 24 hours alcohol 2 was obtained as the only re-
metal-free couplings of diazoalkanes derived from p-toluenesulfo-
action product in 85% yield.
nylhydrazones to water under reflux and microwave conditions, in
high yields. In addition, this protocol was successfully applied in
the synthesis of deuterium-labeled alcohols using deuterium oxide.
Table 1 Effect of Time on Alcohol Formation
K2CO3
Key words: alcohols, deuterated alcohols, p-toluenesulfonylhydra-
zones, coupling
OH
NNHTs
H2O
reflux
1
2
Entry
Time (h)
Yield (%) of 2
p-Toluenesulfonylhydrazones are interesting compounds
which have been used in many chemical transformations.
In particular, the generation of carbene/carbenoid inter-
mediates derived from p-toluenesulfonylhydrazones has
become an attractive method for coupling and C–C bond
formation in the last years. Recent work by Aggarwal,1
Barluenga and Valdés,2 Cheung,3 Yu,4 and Hamze,5 and
their co-workers, and also our group6 has demonstrated
that p-toluenesulfonylhydrazones might be an effective
source of diazoalkanes which represent the most impor-
tant carbenoid precursors in metal-catalyzed processes.
Moreover, a current trend in this area is the use of metal-
free conditions that provides a novel kind of C–C bond
coupling,7 as well as novel methods for the synthesis of
ethers8 and sulfides.9
1
2
3
4
5
6
2
4
35
50
65
72
85
83
8
12
24
48
In order to explore the reaction scope, several tosylhydra-
zones were reacted under similar conditions; the results
are presented in Table 2. In all cases, the corresponding al-
cohols were obtained in moderate to good yield. More
In connection with other studies, we required some non-
commercially available alcohols which we decided to pre-
pare from the corresponding carbonyl compounds using a
reductive carbene coupling approach. Although this ap-
proach is already known under classic photolytic condi-
tions,10 it has been considered only for mechanistic
studies because the reactions afford low yields and many
rearrangement side products. This fact inspired us to rein-
vestigate this process in order to find an efficient method-
ology for this transformation. Herein, a summary of our
successful endeavors in this area is described.
Table 2 Alcohols Prepared under Reflux Conditions
K2CO3
NNHTs
R2
OH
R2
H2O
reflux
R1
R1
Entry
R1
R2
Yield (%)
1
2
3
4
5
6
7
8
H
4-MeC6H4
Ph
85
45
40
66
63
60
62
62
H
H
4-ClC6H4
3-ClC6H4
4-Me2NC6H4
Ph
In a model study, 4-methylbenzaldehyde p-toluenesulfo-
nylhydrazone (1) was reacted with an excess of potassium
carbonate (3.5 equiv), and the resulting potassium salt was
treated with water at reflux temperature for different
H
H
Me
Me
H
SYNTHESIS 2012, 44, 2237–2242
Advanced online publication: 04.06.2012
4-MeOC6H4
2,6-Cl2C6H3
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1290372; Art ID: SS-2012-M0293-OP
© Georg Thieme Verlag Stuttgart · New York

2238
Á. García-Muñoz et al.
PAPER
Table 3 More Complex Alcohols Prepared under Reflux Conditions
Entry
Tosylhydrazone
Alcohol
MeO2C
HO
Yield (%)
NNHTs
OH
MeO2C
N
1
59
45
56
N
S
S
Bn
Bn
TsHNN
OH
NNHTs
2
3
N
S
N
S
Bn
Bn
NNHTS
OH
S
S
N
N
complex tosylhydrazones also gave alcohols (Table 3); These elements suggest that tosylhydrazone couplings to
only the starting material was recovered in some cases.
water could be a useful method for synthesizing alcohols
which minimizes the use of reducing agents. In addition,
this method is performed in water as solvent, avoiding the
use of additional organic solvents or special reaction con-
ditions.
The success of this process motivated us to explore alter-
native energy sources. Previous reports have shown that
microwave (MW) irradiation facilitates chemical process-
es.8 In our case, the use of microwave irradiation as an en-
ergy source resulted in increased reaction yields. One of the additional advantages that we found with this
Experiments demonstrated that the process is improved methodology is its application in the synthesis of deuteri-
through the use of microwave irradiation, showing shorter um-labeled alcohols from p-toluenesulfonylhydrazones
reaction times and almost quantitative yields (Table 4). and deuterium oxide instead of water. For this purpose,
Furthermore, rearrangements or other undesired products we carried out a series of preliminary experiments with
were not observed. At present, the use of microwave irra- deuterium oxide under reflux temperature conditions. The
diation in carbene insertions on O–H bonds has only been results (Table 5) indicated that the yields are similar to
used to prepare ethers; this is the first report of the synthe- those obtained using water as solvent.
sis of alcohols through a similar approach.
Table 5 Deuterium-Labeled Alcohols Prepared under Reflux Con-
ditions
Table 4 Alcohols Prepared under Microwave Conditions
K2CO3
D
OD
NNHTs
R2
NNHTs
R2
OH
R2
K2CO3, H2O
R1 R2
R1
MW, 130 °C
10 min
D2O
reflux
R1
R1
R1
R2
Yield (%)
Entry
R1
R2
Yield (%)
Entry
1
2
H
4-MeC6H4
Ph
99
94
95
92
89
95
99
99
80
89
89
97
99
1
2
3
4
5
6
H
Ph
82
90
55
65
60
70
H
H
4-MeC6H4
4-Me2NC6H4
4-ClC6H4
2,6-Cl2C6H3
Ph
3
H
4-ClC6H4
3-ClC6H4
4-Me2NC6H4
Ph
H
4
H
H
5
H
H
6
Me
Me
H
Me
7
4-MeOC6H4
2-MeOC6H4
4-FC6H4
4-BrC6H4
2-BrC6H4
4-Tol
In addition, we carried out insertion reactions of p-tolu-
enesulfonylhydrazones with deuterium oxide under mi-
crowave irradiation conditions, to obtain the
corresponding deuterium-labeled alcohols (Table 6). The
noteworthy fact in this case is that the process occurred in
higher yields than under conventional heating conditions.
To the best of our knowledge, this is the first example of
a selective deuterium labeling on the oxygen atom and the
C-1 atom in an alcohol in one step, which also displays a
novel metal-free method to prepare the labeled alcohols,
8
9
H
10
11
12
13
H
H
Me
Me
4-ClC6H4
Synthesis 2012, 44, 2237–2242
© Georg Thieme Verlag Stuttgart · New York

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Metal-Free Synthesis of Alcohols from p-Toluenesulfonylhydrazones
2239
in contrast to the traditional metal-catalyzed11 and metal
deuteride12 protocols.
reaction mixture was cooled to r.t. and the organic layer was sepa-
rated. The aqueous phase was extracted with CH2Cl2 (3 × 10 mL).
The organic phases were combined, dried over Na2SO4 and filtered.
The solvent was removed under reduced pressure and the final
product was purified by silica gel column chromatography (hex-
ane–EtOAc, 95:5).
Table 6 Deuterium-Labeled Alcohols Prepared under Microwave
Conditions
NNHTs
R2
K2CO3, D2O
D
OD
Synthesis of Alcohols under Microwave Irradiation Conditions;
General Procedure
R1
R1 R2
MW, 130 °C
30 min
A 5-mL microwave vial was charged with K2CO3 (241.5 mg, 1.75
mmol, 3.5 equiv), the corresponding tosylhydrazone (0.5 mmol),
H2O (5 mL) and a cylindrical magnetic stirring bar. The vessel was
sealed with a septum, placed into the microwave cavity of an Anton-
Paar microwave unit and irradiated to heat the reaction mixture at
130 °C. The total heating time was 10 min at 130 °C. When the re-
action was completed, the vial was cooled to r.t. The vial was then
opened and the contents were poured into a separating funnel. The
layers were separated and the aqueous phase was extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers were washed
with brine (20 mL), dried over Na2SO4 and filtered. The solvent was
removed under reduced pressure and the final product was purified
by silica gel column chromatography (hexane–EtOAc, 95:5).
Entry
R1
R2
Yield (%)
1
2
3
4
5
6
H
Ph
98
97
75
96
93
97
H
4-MeC6H4
4-Me2NC6H4
4-ClC6H4
2,6-Cl2C6H3
Ph
H
H
H
Me
p-Tolylmethanol (Tables 2 and 4, Entry 1)
Yields: 31 mg (85%, from 0.3 mmol of tosylhydrazone under reflux
conditions) and 60 mg (99%, from 0.5 mmol of tosylhydrazone un-
In summary, p-toluenesulfonylhydrazones are easily con-
verted into alcohols through a process that combines the der microwave conditions); white solid; mp 61 °C.
IR (ATR): 3267, 3049, 1618 cm–1.
1H NMR (500 MHz, CDCl3): δ = 2.26 (s, 3 H), 4.54 (s, 2 H), 7.08
(d, J = 7.5 Hz, 2 H), 7.16 (d, J = 7.0 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 21.30 (CH3), 65.36 (CH2), 127.27
(2 × CH), 129.38 (2 × CH), 137.51 (C), 138.07 (C).
use of water as a green solvent and microwave irradiation
as an alternative energy source. Thus, this reaction repre-
sents an alternative methodology for the synthesis of ben-
zyl alcohols from aldehydes and ketones which
complements the conventional reduction procedures
based on active metal or metal hydride reagents. In addi-
tion, this method was successfully extended to the synthe-
HRMS (EI): m/z calcd for C8H10O: 122.0732; found: 122.0735.
sis
of
deuterium-labeled
alcohols
from
p- Phenylmethanol (Tables 2 and 4, Entry 2)
Yields: 14.6 mg (45%, from 0.3 mmol of tosylhydrazone under re-
flux conditions) and 50.7 mg (94%, from 0.5 mmol of tosylhydra-
zone under microwave conditions); colorless oil.
toluenesulfonylhydrazones and deuterium oxide. This
route to alcohols is efficient and the simplicity of the
method should ensure a widespread application.
IR (ATR): 3326, 3088, 1611 cm–1.
1H NMR (500 MHz, CDCl3): δ = 4.60 (s, 2 H), 7.22 (m, 3 H), 7.29
(m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 65.49 (CH2), 127.15 (2 × CH),
127.81 (2 × CH), 128.72 (CH), 141.02 (C).
The starting materials were purchased from Aldrich Chemical Co.
and were used without further purification. p-Toluenesulfonylhy-
drazones were prepared according to the literature.1–3 Solvents were
distilled before use. Water was deionized using Millipore System
Direct-Q equipment. Silica gel (230–400 mesh) was purchased
from Merck. Silica plates of 0.20-mm thickness were used for thin-
layer chromatography. Melting points were determined with a
Fischer-Johns Scientific melting point apparatus and are uncorrect-
ed. 1H and 13C NMR spectra were recorded using a Bruker Avance
300-MHz or a Varian 500-MHz instrument. The chemical shifts (δ)
are given in ppm relative to TMS as internal standard (0.00). For an-
alytical purposes, the mass spectra were recorded on a Shimadzu
GCMS-QP2010 Plus or a JEOL JMS-5X 10217 spectrometer in the
EI mode (70 eV, 200 °C) via direct inlet probe [only the molecular
parent ions (m/z)]. IR spectra were recorded on a Nicolet Magna 55-
X FT instrument. The microwave-assisted reactions were per-
formed using an Anton-Paar Synthos 300 focused microwave unit
(constant factor of the microwave 1.214). The temperature was
monitored with an IR temperature sensor. In all experiments, the
microwave temperature was held constant. Reactions were carried
out in 5-mL glass vessels, which were sealed with a cap septum. The
specific reaction time corresponds to the total irradiation time.
HRMS (EI): m/z calcd for C7H8O: 108.0575; found: 108.0579.
(4-Chlorophenyl)methanol (Tables 2 and 4, Entry 3)
Yields: 17 mg (40%, from 0.3 mmol of tosylhydrazone under reflux
conditions) and 67.5 mg (95%, from 0.5 mmol of tosylhydrazone
under microwave conditions); white solid; mp 72 °C.
IR (ATR): 3270, 3259, 2955, 1592 cm–1.
1H NMR (500 MHz, CDCl3): δ = 4.64 (s, 2 H), 7.27 (d, J = 8 Hz, 2
H), 7.31 (d, J = 8 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 64.64 (CH2), 128.48 (2 × CH),
128.85 (2 × CH), 133.49 (C), 139.54 (C).
HRMS (EI): m/z calcd for C7H7ClO: 142.0185; found: 142.0187.
(3-Chlorophenyl)methanol (Tables 2 and 4, Entry 4)
Yields: 28.1 mg (66%, from 0.3 mmol of tosylhydrazone under re-
flux conditions) and 65.3 mg (92%, from 0.5 mmol of tosylhydra-
zone under microwave conditions); colorless oil.
IR (ATR): 3321, 3067 cm–1.
1H NMR (500 MHz, CDCl3): δ = 4.59 (s, 2 H), 7.15 (m, 1 H), 7.19
(m, 1 H), 7.21 (m, 1 H), 7.42 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 64.67 (CH2), 125.01 (CH),
Synthesis of Alcohols under Conventional Heating Conditions;
General Procedure
The appropriate tosylhydrazone (0.3 mmol) was added to a stirred
soln of K2CO3 (145.1 mg, 1.05 mmol, 3.5 equiv) in H2O (10 mL).
The resulting mixture was heated at reflux temperature for 24 h. The
127.12 (CH), 127.86 (CH), 129.98 (CH), 134.60 (C), 143.02 (C).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2237–2242

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Á. García-Muñoz et al.
PAPER
HRMS (EI): m/z calcd for C7H7ClO: 142.0185; found: 142.0188.
1H NMR (300 MHz, CDCl3): δ = 1.52 (d, J = 6.3 Hz, 3 H), 4.60 (s,
2 H), 4.95 (q, J = 6.3 Hz, 1 H), 5.21 (s, 2 H), 6.29 (s, 1 H), 6.81 (s,
1 H), 7.17 (m, 2 H), 7.27–7.30 (m, 3 H).
13C NMR (75 MHz, CDCl3): δ = 24.9 (CH3), 50.4 (CH2), 57.6
(CH2), 67.3 (CH), 101.9 (CH), 114.4 (CH), 127.5 (2 × CH), 127.6
(C), 128.1 (CH), 129.0 (2 × CH), 136.3 (C), 136.5 (C), 137.4 (C),
142.0 (C).
[4-(Dimethylamino)phenyl]methanol (Tables 2 and 4, Entry 5)
Yields: 28.5 mg (63%, from 0.3 mmol of tosylhydrazone under re-
flux conditions) and 67.2 mg (89%, from 0.5 mmol of tosylhydra-
zone under microwave conditions); colorless oil.
IR (ATR): 3239, 3093, 1614 cm–1.
1H NMR (500 MHz, CDCl3): δ = 2.90 (s, 3 H), 2.98 (s, 3 H), 4.48
(s, 2 H), 7.16 (d, J = 8.9 Hz, 2 H), 7.31 (d, J = 8.9 Hz, 2 H).
HRMS (EI): m/z calcd for C16H17NO2S: 287.0980; found:
287.0984.
13C NMR (125 MHz, CDCl3): δ = 40.43 (CH3), 40.87 (CH3), 53.90
(CH2), 111.76 (C), 128.82 (2 × CH), 134.43 (2 × CH), 152.26 (C).
1-Thieno[2,3-b]pyridin-5-ylethanol (Table 3, Entry 3)
Yield: 30.1 mg (56%); colorless oil.
IR (ATR): 3321, 3067, 1597 cm–1.
HRMS (EI): m/z calcd for C9H13NO: 151.0997; found: 151.0999.
1H NMR (300 MHz, CDCl3): δ = 1.54 (d, J = 6.3 Hz, 3 H), 5.04 (q,
J = 6.6 Hz, 1 H), 7.19 (d, J = 5.7 Hz, 1 H), 7.50 (d, J = 6.0 Hz, 1 H),
8.07 (d, J = 2.1 Hz, 1 H), 8.46 (d, J = 2.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 25.7 (CH3), 68.2 (CH), 121.6
(CH), 127.6 (CH), 128.2 (CH), 132.6 (C), 137.6 (C), 145.1 (CH),
160.6 (C).
1-Phenylethanol (Tables 2 and 4, Entry 6)
Yields: 21.9 mg (60%, from 0.3 mmol of tosylhydrazone under re-
flux conditions) and 57.9 mg (95%, from 0.5 mmol of tosylhydra-
zone under microwave conditions); colorless oil.
IR (ATR): 3364, 3086, 2973, 1601 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.39 (d, J = 4 Hz, 3 H), 4.59 (m,
1 H), 7.15–7.19 (m, 3 H), 7.42 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 21.81 (CH3), 65.40 (CH), 127.19
(2 × CH), 127.79 (CH), 128.73 (2 × CH), 141.30 (C).
HRMS (EI): m/z calcd for C9H9NOS: 179.0405; found: 179.0408.
(2-Methoxyphenyl)methanol (Table 4, Entry 8)
Yield: 68.3 mg (99%); colorless oil.
IR (ATR): 3366, 3066, 1690 cm–1.
HRMS (EI): m/z calcd for C8H10O: 122.0732; found: 122.0735.
1H NMR (500 MHz, CDCl3): δ = 3.33 (s, 3 H), 4.16 (s, 2 H), 6.33
(m, 1 H), 6.37 (m, 1 H), 6.44 (m, 1 H), 6.76 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 55.36 (CH2), 62.12 (CH3), 126.47
(CH), 128.68 (CH), 129.04 (CH), 129.60 (CH), 131.05 (C), 157.53
(C).
1-(4-Methoxyphenyl)ethanol (Tables 2 and 4, Entry 7)
Yields: 28.3 mg (62%, from 0.3 mmol of tosylhydrazone under re-
flux conditions) and 75.3 mg (99%, from 0.5 mmol of tosylhydra-
zone under microwave conditions); colorless oil.
IR (ATR): 3385, 3066, 1601 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.38 (d, J = 5 Hz, 3 H), 3.70 (s, 3
HRMS (EI): m/z calcd for C8H10O2: 138.0681; found: 138.0684.
H), 4.75 (m, 1 H), 6.78 (d, J = 8.6 Hz, 2 H), 7.20 (d, J = 8.7 Hz, 2
H).
(4-Fluorophenyl)methanol (Table 4, Entry 9)
Yield: 50.4 mg (80%); colorless oil.
13C NMR (125 MHz, CDCl3): δ = 25.18 (CH3), 55.43 (CH3), 70.09
(CH), 113.97 (2 × CH), 126.81 (2 × CH), 138.18 (C), 159.10 (C).
IR (ATR): 3220, 3011, 1605 cm–1.
HRMS (EI): m/z calcd for C9H12O2: 152.0837; found: 152.0839.
1H NMR (500 MHz, CDCl3): δ = 4.56 (s, 2 H), 6.96 (d, J = 8.5 Hz,
2 H), 7.25 (d, J = 8.2 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 64.76 (CH2), 115.68 (2 × CH),
(2,6-Dichlorophenyl)methanol (Table 2, Entry 8)
Yield: 32.7 mg (62%); white solid; mp 98 °C.
IR (ATR): 3321, 3067 cm–1.
1H NMR (500 MHz, CDCl3): δ = 4.97 (s, 2 H), 7.32 (m, 1 H), 7.35
128.97 (2 × CH), 136.72 (C), 164.09 (C).
HRMS (EI): m/z calcd for C7H7FO: 126.0481; found: 126.0485.
(m, 2 H).
(4-Bromophenyl)methanol (Table 4, Entry 10)
Yield: 82.7 mg (89%); white solid; mp 82 °C.
13C NMR (125 MHz, CDCl3): δ = 60.47 (CH2), 128.73 (2 × CH),
128.84 (CH), 136.22 (2 × C), 142.28 (C).
IR (ATR): 3311, 3075, 1592 cm–1.
HRMS (EI): m/z calcd for C7H6Cl2O: 175.9796; found: 175.9799.
1H NMR (500 MHz, CDCl3): δ = 4.53 (s, 2 H), 7.12 (d, J = 8.2 Hz,
2 H), 7.37 (d, J = 8.2 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 64.66 (CH2), 121.56 (C), 128.73
Methyl 6-Benzyl-2-(hydroxymethyl)-6H-thieno[2,3-b]pyrrole-
5-carboxylate (Table 3, Entry 1)
Yield: 53.4 mg (59%); colorless oil.
(2 × CH), 131.75 (2 × CH), 139.93 (C).
IR (ATR): 3600, 3022, 2953, 1696, 1517 cm–1.
HRMS (EI): m/z calcd for C7H7BrO: 185.9680; found: 185.9682.
1H NMR (300 MHz, CDCl3): δ = 3.83 (s, 3 H), 4.72 (s, 2 H), 5.29
(s, 2 H), 6.55 (s, 1 H), 7.22–7.32 (m, 5 H), 7.36 (s, 1 H).
(2-Bromophenyl)methanol (Table 4, Entry 11)
Yield: 82.9 mg (89%); white solid; mp 78 °C.
13C NMR (75 MHz, CDCl3): δ = 50.4 (CH2), 51.8 (CH3), 57.3
(CH2), 102.8 (CH), 125.5 (CH), 127.5 (2 × CH), 128.2 (CH), 128.4
(C), 128.8 (2 × CH), 135.2 (C), 139.8 (2 × C), 141.6 (C), 164.0 (C).
IR (ATR): 3297, 3207, 2955, 1966 cm–1.
1H NMR (500 MHz, CDCl3): δ = 4.67 (s, 2 H), 7.39 (m, 1 H), 7.45
(m, 1 H), 7.50 (m, 1 H), 7.65 (d, J = 7.8 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 65.25 (CH2), 127.33 (C), 127.84
(CH), 129.40 (CH), 130.29 (CH), 136.98 (CH), 139.90 (C).
HRMS (EI): m/z calcd for C16H15NO3S: 301.0773; found:
301.0776.
1-[6-Benzyl-5-(hydroxymethyl)-6H-thieno[2,3-b]pyrrol-2-
yl]ethanol (Table 3, Entry 2)
HRMS (EI): m/z calcd for C7H7BrO: 185.9680; found: 185.9685.
Yield: 38.8 mg (45%); colorless oil.
1-p-Tolylethanol (Table 4, Entry 12)
Yield: 65.9 mg (97%); colorless oil.
IR (ATR): 3346, 3096, 2920 cm–1.
IR (ATR): 3600, 3321, 3067 cm–1.
Synthesis 2012, 44, 2237–2242
© Georg Thieme Verlag Stuttgart · New York

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Metal-Free Synthesis of Alcohols from p-Toluenesulfonylhydrazones
2241
1H NMR (500 MHz, CDCl3): δ = 1.40 (d, J = 6.5 Hz, 3 H), 2.26 (s,
3 H), 4.78 (q, J = 6.4 Hz, 1 H), 7.08 (d, J = 7.6 Hz, 2 H), 7.18 (d,
J = 7.6 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 21.25 (CH3), 25.24 (CH3), 70.39
(CH), 125.51 (2 × CH), 129.31 (2 × CH), 137.28 (C), 143.04 (C).
13C NMR (125 MHz, CDCl3): δ = 21.42 (CH3), 65.03 (CDH),
127.42 (2 × CH), 129.51 (2 × CH), 137.69 (C), 138.07 (C).
HRMS (EI): m/z calcd for C8H8D2O: 124.0855; found: 124.0854.
[4-(Dimethylamino)phenyl][O,1-2H2]methanol (Tables 5 and 6,
Entry 3)
Yields: 25.3 mg (55%, from 0.3 mmol of tosylhydrazone under re-
flux conditions) and 57.4 mg (75%, from 0.5 mmol of tosylhydra-
zone under microwave conditions); colorless oil.
IR (ATR): 2330 cm–1 (O–D).
1H NMR (500 MHz, CDCl3): δ = 2.90 (s, 6 H), 4.50 (s, 1 H), 7.18
(d, J = 8.9 Hz, 2 H), 7.33 (d, J = 8.9 Hz, 2 H).
HRMS (EI): m/z calcd for C9H12O: 136.0888; found: 136.0891.
1-(4-Chlorophenyl)ethanol (Table 4, Entry 13)
Yield: 77.2 mg (99%); colorless oil.
IR (ATR): 3346, 3086, 1652 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.34 (d, J = 6.5 Hz, 3 H), 4.74 (q,
J = 6.4 Hz, 1 H), 7.27 (d, J = 8.6 Hz, 2 H), 7.72 (d, J = 8.6 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 25.40 (CH3), 69.83 (CH), 126.94
(2 × CH), 128.71 (2 × CH), 133.15 (C), 144.42 (C).
13C NMR (125 MHz, CDCl3): δ = 40.43 (2 × CH3), 53.90 (CDH),
111.76 (C), 128.82 (2 × CH), 134.43 (2 × CH), 152.26 (C).
HRMS (EI): m/z calcd for C9H11D2NO: 153.1121; found: 153.1125.
HRMS (EI): m/z calcd for C8H9ClO: 156.0342; found: 156.0348.
(4-Chlorophenyl)[O,1-2H2]methanol (Tables 5 and 6, Entry 4)
Yields: 28.1 mg (65%, from 0.3 mmol of tosylhydrazone under re-
flux conditions) and 69.1 mg (96%, from 0.5 mmol of tosylhydra-
zone under microwave conditions); colorless oil.
IR (ATR): 2325 cm–1 (O–D).
1H NMR (500 MHz, CDCl3): δ = 4.64 (s, 1 H), 7.29 (d, J = 8.3 Hz,
2 H), 7.32 (d, J = 8.3 Hz, 2 H).
Synthesis of Deuterium-Labeled Alcohols under Conventional
Heating Conditions; General Procedure
The appropriate tosylhydrazone (0.3 mmol) was added to a stirred
soln of K2CO3 (145.1 mg, 1.05 mmol, 3.5 equiv) in D2O (10 mL).
The resulting mixture was heated at reflux temperature for 24 h. The
reaction mixture was cooled to r.t. and the organic layer was sepa-
rated. The aqueous phase was extracted with CH2Cl2 (3 × 10 mL).
The organic phases were combined, dried over Na2SO4 and filtered.
The solvent was removed under reduced pressure and the final
product was purified by silica gel column chromatography (hex-
ane–EtOAc, 95:5).
13C NMR (125 MHz, CDCl3): δ = 64.64 (CDH), 128.48 (2 × CH),
128.85 (2 × CH), 133.49 (C), 139.54 (C).
HRMS (EI): m/z calcd for C7H5D2ClO: 144.0309; found: 144.0310.
(2,6-Dichlorophenyl)[O,1-2H2]methanol (Tables 5 and 6, Entry
5)
Synthesis of Deuterium-Labeled Alcohols under Microwave Ir-
radiation Conditions; General Procedure
A 5-mL microwave vial was charged with K2CO3 (241.5 mg, 1.75
mmol, 3.5 equiv), the corresponding tosylhydrazone (0.5 mmol),
D2O (2.5 mL) and a cylindrical magnetic stirring bar. The vessel
was sealed with a septum, placed into the microwave cavity of an
Anton-Paar microwave unit and irradiated to heat the reaction mix-
ture at 130 °C. The total heating time was 30 min at 130 °C. When
the reaction was completed, the vial was cooled to r.t. using a pro-
pelled air flow. The vial was then opened and the contents were
poured into a separating funnel. The layers were separated and the
aqueous phase was extracted with CH2Cl2 (3 × 10 mL). The com-
bined organic layers were washed with brine (20 mL), dried over
Na2SO4 and filtered. The solvent was removed under reduced pres-
sure and the final product was purified by silica gel column chroma-
tography (hexane–EtOAc, 95:5).
Yields: 32.0 mg (60%, from 0.3 mmol of tosylhydrazone under re-
flux conditions) and 82.8 mg (93%, from 0.5 mmol of tosylhydra-
zone under microwave conditions); colorless oil.
IR (ATR): 2324 cm–1 (O–D).
1H NMR (500 MHz, CDCl3): δ = 4.91 (s, 1 H), 7.32 (m, 2 H), 7.34
(m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 60.50 (CDH), 128.76 (2 × CH),
129.11 (CH), 131.34 (2 × C), 142.31 (C).
HRMS (EI): m/z calcd for C7H4D2Cl2O: 177.9919; found:
177.9921.
1-Phenyl[O,1-2H2]ethanol (Tables 5 and 6, Entry 6)
Yields: 26.0 mg (70%, from 0.3 mmol of tosylhydrazone under re-
flux conditions) and 60.1 mg (97%, from 0.5 mmol of tosylhydra-
zone under microwave conditions); colorless oil.
IR (ATR): 2325 cm–1 (O–D).
1H NMR (500 MHz, CDCl3): δ = 1.51 (s, 3 H), 7.36 (m, 2 H), 7.38
Phenyl[O,1-2H2]methanol (Tables 5 and 6, Entry 1)
Yields: 27.1 mg (82%, from 0.3 mmol of tosylhydrazone under re-
flux conditions) and 53.9 mg (98%, from 0.5 mmol of tosylhydra-
zone under microwave conditions); colorless oil.
IR (ATR): 2327 cm–1 (O–D).
1H NMR (500 MHz, CDCl3): δ = 4.67 (s, 1 H), 7.36 (m, 2 H), 7.37
(m, 3 H).
13C NMR (125 MHz, CDCl3): δ = 25.30 (CH3), 70.27 (CD), 125.64
(2 × CH), 127.74 (CH), 128.77 (2 × CH), 146.01 (C).
(m, 3 H).
13C NMR (125 MHz, CDCl3): δ = 64.97 (CDH), 127.30 (2 × CH),
127.95 (CH), 128.84 (2 × CH), 141.03 (C).
HRMS (EI): m/z calcd for C8H8D2O: 124.0855; found: 124.0858.
HRMS (EI): m/z calcd for C7H6D2O: 110.0699; found: 110.0702.
Acknowledgment
p-Tolyl[O,1-2H2]methanol (Tables 5 and 6, Entry 2)
Yields: 33.5 mg (90%, from 0.3 mmol of tosylhydrazone under re-
flux conditions) and 60.1 mg (97%, from 0.5 mmol of tosylhydra-
zone under microwave conditions); colorless oil.
Financial support from CONACYT (Project No. 135053) is grate-
fully acknowledged. The authors would like to thank Signa S.A. de
C.V., N. Zavala, A. Nuñez and L. Triana for technical support.
IR (ATR): 2325 cm–1 (O–D).
1H NMR (500 MHz, CDCl3): δ = 2.35 (s, 3 H), 4.62 (s, 1 H), 7.17
(d, J = 7.1 Hz, 2 H), 7.25 (d, J = 7.1 Hz, 2 H).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2237–2242

2242
Á. García-Muñoz et al.
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Synthesis 2012, 44, 2237–2242
© Georg Thieme Verlag Stuttgart · New York