Reduction of benzylic alcohols and α-hydroxycarbonyl compounds by hydriodic acid in a biphasic reaction medium

Article abstract of DOI:10.3762/bjoc.8.36

The synthetic protocol for the reduction of alcohols to hydrocarbons by using hydriodic acid, first described by Kiliani more than 140 years ago, was improved to be more applicable to organic synthesis. Instead of a strongly acidic, aqueous solution, a biphasic toluene-water reaction medium was used, which allowed the conversion of primary, secondary and tertiary benzylic alcohols, in good yields and short reaction times, into the corresponding hydrocarbons. Red phosphorous was used as the stoichiometric reducing agent. Keto, ester, amide or ether groups are tolerated, and catalytic amounts of hydriodic acid (0.2 equiv) in the presence of 0.6 equiv phosphorous are sufficient to achieve conversion.

Full text of DOI:10.3762/bjoc.8.36

Reduction of benzylic alcohols and α-hydroxy-
carbonyl compounds by hydriodic acid
in a biphasic reaction medium
Michael Dobmeier1, Josef M. Herrmann1, Dieter Lenoir2
and Burkhard König*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 330–336.
1Institute of Organic Chemistry, University of Regensburg, D-93040
Regensburg, Germany, Fax: +499419431717 and 2Helmholtz
Zentrum München, Ingolstädter Landstraße 1, D-85764 Neuherberg,
Germany
doi:10.3762/bjoc.8.36
Received: 29 December 2011
Accepted: 16 February 2012
Published: 02 March 2012
Email:
Burkhard König* - Burkhard.Koenig@chemie.uni-regensburg.de
Associate Editor: D. Y.-K. Chen
* Corresponding author
© 2012 Dobmeier et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
alcohols; catalysis; iodine; phosphorous reduction
Abstract
The synthetic protocol for the reduction of alcohols to hydrocarbons by using hydriodic acid, first described by Kiliani more than
140 years ago, was improved to be more applicable to organic synthesis. Instead of a strongly acidic, aqueous solution, a biphasic
toluene–water reaction medium was used, which allowed the conversion of primary, secondary and tertiary benzylic alcohols, in
good yields and short reaction times, into the corresponding hydrocarbons. Red phosphorous was used as the stoichiometric
reducing agent. Keto, ester, amide or ether groups are tolerated, and catalytic amounts of hydriodic acid (0.2 equiv) in the presence
of 0.6 equiv phosphorous are sufficient to achieve conversion.
Introduction
The reduction of hydroxy groups is a typical and important step mide substituent and subsequent catalytic reduction with H2/Pt
in the synthesis of complex natural products or drugs [1-4]. or the conversion into a tosylate and reduction with LiAlH4.
Functional-group tolerance during this reduction step is essen- The most commonly applied method is the Barton–McCombie
tial since various other groups are usually present. A number of reaction [14], due to its versatility and its very high functional-
synthetic procedures have been developed, which allow selec- group tolerance [15-18]. Although very general, the reaction has
tive reduction, but only a few one-step transformations are some drawbacks: The involved organotin hydrides are costly,
known, which use either titanium(III) [5-8] or different metal highly toxic [19-21] and often difficult to separate from the
complexes [9-13]. Most procedures require a sequence of steps, reaction products. Furthermore, secondary alcohols give best
e.g., the conversion of hydroxy groups into a chloride or bro- results, while others may react less efficiently.
330

Beilstein J. Org. Chem. 2012, 8, 330–336.
We have reinvestigated the long-known reduction of benzylic Results and Discussion
alcohols and α-hydroxycarbonyl compounds by hydriodic acid Initial investigations focused on simple benzylic alcohols
[22-32]. The method has been reported for a variety of alcohols, (Table 1, entries 1–3), which were converted in high to quanti-
but typically proceeds in aqueous solution and requires an tative yields into the corresponding alkanes. Carbonyl groups or
excess of HI or strong mineral acids such as phosphoric or amides in a benzylic position (Table 1, entries 4 and 6) and
sulfuric acid [33-35]. We describe a biphasic reaction medium aromatic hydroxy groups (Table 2, entry 7) or aromatic ethers
consisting of toluene and aqueous hydriodic acid. The phase (Table 1, entry 5) were not affected. Moreover, heterocycles
separation allows milder reaction conditions compared to the such as thiophene (Table 1, entry 7) were stable under these
classic Kiliani protocol and is more applicable to organic syn- conditions whereas furans (Table 1, entry 8) were decomposed
thesis.
due to ring opening. Benzylic alcohols were converted in good
Table 1: Reduction of benzylic alcohols to the corresponding alkanes.
Entry
Alcohol
Producta
Time [h]
Yield [%]
70b
1
2
2
3
0.5
96
0.25
100
4
5
6
1
0.5
1
80
92
82
7
8
9
0.5
1
62c
–
decomposition
0.25
74c
331

Beilstein J. Org. Chem. 2012, 8, 330–336.
Table 1: Reduction of benzylic alcohols to the corresponding alkanes. (continued)
10
0.5
49c
11
12
0.5
1.5
78
65
aAll products are known compounds described in the literature. The identities have been proven by proton NMR and mass analysis, which match the
literature data. bThe corresponding iodo compound was identified as a byproduct. cThe corresponding elimination product was obtained as a
byproduct.
to high yields to alkanes with increasing reactivity in the order stable alkene occurred. Propargylic alcohols (Table 2, entry 3
primary (2 h) < secondary (0.5–1 h) < tertiary alcohol (15–30 and 4) showed elimination or decomposed. In the case of flavin
min); carbonyl groups and ethers were tolerated. Diethyl tartrate (Table 2, entry 6), three hydroxy groups were reduced and one
was converted into diethyl succinate under the reaction condi- was converted into an iodo substituent.
tions given (Table 1, entry 12), but some of the material was
Alcohols other than those that were benzylic or α to carbonyl
lost due to ester hydrolysis.
groups were not converted into the corresponding alkanes, and
Allylic alcohols are completely consumed, but the corres- the reaction stopped at the iodoalkanes (Table 3). The reactiv-
ponding alkenes could not be isolated as pure products ity follows the order of primary < secondary < tertiary alcohols,
(Table 2). Mixtures of eliminiation and deoxygenation products, as expected for an SN1 reaction. The reduction potential of the
in some cases also rearangement of the deoxygenated product nonbenzylic iodoalkanes is not sufficient for reduction by
into the the more highly substitued, thermodynamically more hydriodic acid.
Table 2: Alcohols showing incomplete or unselective reaction with hydriodic acid and red phosphorous (3.0 equiv HI, 0.4 equiv Pred).
Entry
Alcohol
Product
Time [h]
Yield [%]
–
1
mixture of several products
1
2
3
mixture of several products
1
1
–
traces
4
decomposition
1
–
332

Beilstein J. Org. Chem. 2012, 8, 330–336.
Table 2: Alcohols showing incomplete or unselective reaction with hydriodic acid and red phosphorous (3.0 equiv HI, 0.4 equiv Pred). (continued)
5
6
7
decomposition
1
2
1
–
21
–
no conversion
Table 3: Alcohols yielding alkyl iodides with hydriodic acid and red
phosphorous.a
Entry
1
Alcohol
Product
Time [h] Yield [%]
8
98
2
3
8
83b
81c
20
a3 equiv HI, 0.4 equiv Pred. bSingle isomer. cProducts were analyzed
by gas chromatography; chlorobenzene was used as an internal stan-
dard.
Scheme 1: Mechanism of the alcohol reduction and recycling of
iodine.
comproportionation. We suggest a stepwise reduction by single
The mechanism of reduction by hydriodic acid consists of two electron transfer (SET) accompanied by the oxidation of I− to
steps (Scheme 1): The nucleophilic substitution of the hydroxy I2. The iodine, generated in the second step, is recycled by
group by iodide and the subsequent reduction of the alkyl iodide reduction with red phosphorous, regenerating hydriodic acid.
by hydriodic acid. The mechanistic details of the redox compro- Admittedly, the above-mentioned TEMPO adduct could also be
portionation of alkyl iodides and H–I have been strongly generated by nucleophilic substitution of the alkyl iodide with
debated in the literature [36-38]. However, the required reduced TEMPO. At least this would be another proof for the
benzylic or α-carbonyl position for the redox comproportiona- first reaction step. According to the redox equations of the reac-
tion indicates an intermediate with mesomeric stabilization due tion between iodine and red phosphorous, each mole of red
to the adjacent π-system. In a trapping experiment, using HI phosphorous is able to reduce at least 1.5 mol of iodine.
without phosphorous, diphenylcarbinol as the substrate and Catalytic amounts of hydriodic acid are therefore sufficient [28]
TEMPO as a trapping agent for radical intermediates, the for the reduction of the hydroxy group (Table 4), when excess
TEMPO adduct of diphenylcarbinol was detected by mass red phosphorous is added as a terminal reducing agent.
analysis. This indicates a radical mechanism of the redox However, depending on the amount of added hydriodic acid, the
333

Beilstein J. Org. Chem. 2012, 8, 330–336.
Table 4: Reduction of alcohols with catalytic amounts of hydriodic acid.
Entry Alcohol
Product
Time [h]
0.5
Yield [%]
82a
1
2
3
0.5
92b
98b
0.25
4
0.5
74b
a0.6 equiv HI, 0.4 equiv Pred. b0.1 equiv HI, 0.7 equiv Pred.
elimination of water may occur as an alternative reaction MgSO4 and filtered, and the solvent is removed. The crude
pathway. A low concentration of HI favors the elimination of product is purified by chromatography and spectroscopically
water, while higher HI concentrations lead to substitution and characterized.
reduction products.
For catalytic reactions of 1 mmol of the respective alcohol the
Conclusion
following amounts of hydriodic acid and Pred were used:
Toluene and aqueous hydriodic acid are a suitable biphasic (a) 0.6 mmol HI/0.4 mmol Pred, (b) 0.1 mmol HI/0.7 mmol Pred.
reaction mixture for the reduction of a range of benzylic alco-
hols. The two-phase system makes the Kiliani protocol more (E)-6-Methyl-1-phenylhept-4-en-3-ol (Table 2, entry 1): The
easily applicable to organic synthesis, as organic substrates and reaction was carried out under dry nitrogen atmosphere by
products dissolve in the organic phase and are separated from using standard Schlenk techniques. To a slurry of Mg powder
the mineral acids. The procedure allows the use of catalytic (0.67 g, 28 mmol) in dry THF (4 mL), 2 mL of a solution of
amounts of hydriodic acid and red phosphorous as the terminal 2-phenyl-1-bromethane (3.0 mL, 28 mmol) in dry THF (10 mL)
reductant. In the case of alcohols having no activation by adja- was added. The Grignard reaction was initiated by the addition
cent benzylic or carbonyl groups the reaction stops at the of iodine followed by sonication for several minutes. When the
corresponding alkyl iodide. A quantitative mass-efficiency exothermic reaction started the rest of the 2-phenyl-1-
analysis [39] of the reaction in comparison to tosylation/LAH, bromethane solution was added through a septum by syringe
Ti(III)-mediated and Barton–McCombie reduction revealed a over 15 min. After the addition, the reaction solution was heated
better atom economy and mass efficiency.
under reflux for 1 h to complete the reaction. The reaction solu-
tion was allowed to cool to rt before 4-methyl-2-pentenal
(2.3 mL, 20 mmol) was added dropwise. To complete the reac-
Experimental
Representative experimental procedure: The alcohol tion the solution was again heated under reflux for 1 h. The
(1 mmol, 1 equiv) is dissolved in 4 mL of toluene. Red reaction was quenched by the addition of HCl (2 M, 25 mL).
phosphorus (0.4 mmol), followed by concentrated hydriodic The aqueous phase was extracted with diethyl ether (3 ×
acid (57% w/w; 3.0 mmol, 3 equiv) is added and the reaction 15 mL). The combined organic phases were washed with satu-
mixture is heated to 80 °C for the stated time, allowed to cool to rated NaHCO3 (15 mL) and H2O (2 × 10 mL), and dried with
rt and quenched with Na2S2O3 (10 mL; 10% w/w) solution. MgSO4. The solvent was removed with a rotary evaporator. The
The aqueous phase is extracted with dichloromethane crude product was purified by flash chromatography (petro-
(3 × 10 mL), the combined organic phases are dried over leum ether/ethyl acetate 4:1, Rf 0.32; staining with vanillin solu-
334

Beilstein J. Org. Chem. 2012, 8, 330–336.
tion gave a blue spot). (E)-6-Methyl-1-phenylhept-4-en-3-ol was added dropwise. To complete the reaction the solution was
was isolated as a yellow oil in 74% yield (3.05 g, 14.9 mmol). again heated under reflux for 2 h. The reaction was quenched by
1H NMR (300 MHz, CDCl3) δ 7.33–7.14 (m, 5H), 5.63 (ddd, J the addition of HCl (2 M, 5 mL). The aqueous phase was
= 15.5, 6.4, 0.7 Hz, 1H), 5.44 (ddd, J = 15.5, 7.0, 1.2 Hz, 1H), extracted with diethyl ether (2 × 5 mL). The combined organic
4.13–4.01 (m, 1H), 2.79–2.59 (m, 2H), 2.39–2.21 (m, 1H), phases were washed with saturated NaHCO3 (3 mL), H2O (2 ×
1.97–1.72 (m, 2H), 1.58 (d, J = 2.7 Hz, 0.3H), 1.46 (d, J = 1.8 2.5 mL) and dried with MgSO4. The solvent was removed with
Hz, 1H), 1.00 (d, J = 6.8 Hz, 6H); 13C NMR (75 MHz, CDCl3) a rotary evaporator. The crude product was purified by flash
δ 139.6, 129.7, 128.5, 128.4, 125.8, 72.6, 38.8, 31.8, 30.7, 22.4, chromatography (petroleum ether/ethyl acetate 4:1, Rf 0.3;
21.3; EIMS m/z (%): 91.1 (100) [C7H7]+, 161.1 (81) [M − staining with vanillin solution gave a blue spot). 1-(4-
C3H7]+, 186.1 (5) [M − H2O]+, 204.2 [M]+∙; HRMS (m/z): [M]+ Methoxyphenyl)-2-phenylpropan-1-ol was isolated as a yellow
calcd for C14H20O, 204.1514; found, 204.1511.
oil in 57% yield (0.62 g, 2.6 mmol). Analytical data are iden-
tical with literature [41]. 1H NMR (300 MHz, CDCl3) δ
(E)-1-Phenylhex-4-en-3-ol (Table 2, entry 2): The reaction was 7.45–7.05 (m, 7H), 6.85–6.74 (m, 2H), 4.76 (d, J = 6.1 Hz, 1H),
carried out under a dry nitrogen atmosphere by using standard 3.78 (s, 3H), 3.09 (p, J = 6.9 Hz, 1H), 1.34 (d, J = 7.0 Hz, 3H);
Schlenk techniques. A solution (1 mL) of 2-phenyl-1- EIMS m/z (%): 137.1 (53) [M − C8H9]+, 224.1 (2) [M − H2O]+,
bromethane (1.35 mL, 10.0 mmol) in dry THF (10 mL) was 242.1 (1) [M]+∙.
added to Mg powder (0.25 g, 10 mmol). The Grignard reaction
was initiated by the addition of iodine followed by sonication 6,6-Dimethyl-2-phenylhept-4-yn-3-ol (Table 2, entry 4): The
for several min. When the exothermic reaction started the rest reaction was carried out under a dry nitrogen atmosphere by
of the 2-phenyl-1-bromethane solution was added through a using standard Schlenk techniques. The solution of 3,3-
septum by syringe over 15 min. After the addition, the reaction dimethyl-1-butyne (0.62 mL, 5 mmol) in dry THF (10 mL) was
solution was heated under reflux for 1 h to complete the reac- cooled to −78 °C. n-BuLi (1.6 M in hexane, 3.5 mL, 5.6 mmol)
tion. The reaction solution was allowed to cool to rt before was added dropwise through a septum by syringe. The reaction
crotonaldehyde (0.74 mL, 9.0 mmol) was added dropwise. To mixture was allowed to warm to rt before the solution of
complete the reaction the solution was again heated under 2-propionaldehyde (0.68 mL, 5 mmol) in dry THF (5 mL) was
reflux for 2.5 h. The reaction was quenched by the addition of added dropwise through a septum by syringe. This solution was
HCl (2 M, 10 mL). The aqueous phase was extracted with stirred for 4.5 h. The reaction was stopped by the addition of
diethyl ether (2 × 15 mL). The combined organic phases were H2O (10 mL). The aqueous phase was extracted with diethyl
washed with saturated NaHCO3 (5 mL), H2O (2 × 5 mL) and ether (3 × 15 mL), and the combined organic layers were dried
dried with MgSO4. The solvent was removed with a rotary with MgSO4. The solvent was removed with a rotary evapo-
evaporator. (E)-1-Phenylhex-4-en-3-ol was obtained in 96% rator. The crude product was purified by flash chromatography
yield (1.53 g, 8.69 mmol) in analytical purity. Analytical data (petroleum ether/ethyl acetate 4:1, Rf 0.42; staining with
were identical with the literature [40]. 1H NMR (300 MHz, vanillin solution gave a blue spot). 6,6-dimethyl-2-phenylhept-
CDCl3) δ 7.34–7.06 (m, 5H), 5.63 (dq, J = 15.3, 6.2 Hz, 1H), 4-yn-3-ol was isolated as a colorless oil in 46% yield (0.50 g,
5.48 (ddd, J = 15.3, 7.0, 1.4 Hz, 1H), 4.02 (q, J = 6.7 Hz, 1H), 2.3 mmol). 1H NMR (300 MHz, CDCl3) δ 7.40–7.19 (m, 5H),
2.73–2.56 (m, 2H), 1.67 (dd, J = 6.3, 0.7 Hz, 3H), 1.52 (s, 4.44 (dd, J = 7.4, 5.4 Hz, 1H), 3.03 (dd, J = 7.1, 5.4 Hz, 1H),
0.3H), 1.40 (s, 0.7H); EIMS m/z (%): 71.1 (100) [C4H7O]+, 1.67 (d, J = 5.4 Hz, 1H), 1.64 (d, J = 7.4 Hz, 1H), 1.39 (d, J =
91.1 (67) [C7H7]+, 105.1 (19) [M − C4H7O]+, 176.1 (50) [M]+. 7.1 Hz, 3H), 1.17 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 141.9,
128.8, 128.2, 127.0, 95.5, 78.1, 67.8, 67.5, 55.0, 46.1, 31.0,
1-(4-Methoxyphenyl)-2-phenylpropan-1-ol (Table 1, entry 5): 30.0, 16.3; EIMS m/z (%): 57.1 (36) [C4H9]+, 99.1 (100), 105.1
The reaction was carried out under a dry nitrogen atmosphere (20) [C8H10]+, 216.2 (7) [M]+∙.
by using standard Schlenk techniques. 1 mL of a solution of
4-bromo-1-methoxybenzene (0.62 mL, 5.0 mmol) in dry THF
Supporting Information
(10 mL) was added to Mg powder (0.12 g, 5.0 mmol). The
Grignard reaction was initiated by the addition of iodine fol-
Supporting Information File 1
lowed by sonication for several min. When the exothermic reac-
tion started the rest of the 4-bromo-1-methoxybenzene solution
was added through a septum by syringe over 15 min. After the
addition, the reaction solution was heated under reflux for 1 h to
complete the reaction. The reaction solution was allowed to
cool to rt before 2-phenylpropionaldehyde (0.60 mL, 4.5 mmol)
Spectroscopic data for the synthesis of some alcohols.
Quantitative mass efficiency analysis of four alternative
alcohol reduction reactions.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-36-S1.pdf]
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Beilstein J. Org. Chem. 2012, 8, 330–336.
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Acknowledgements
We thank the Fachagentur Nachwachsende Rohstoffe for finan-
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