Rapid Mo(CO)6 catalysed one-pot deoxygenation of heterocyclic halo-benzyl alcohols with Lawesson's reagent

Article abstract of DOI:10.1016/j.tetlet.2005.01.012

A fast and efficient microwave promoted one-pot method for deoxygenation of heterocyclic halo-benzyl alcohols has been developed. The method does not cause dehalogenation of the substrates and provides the deoxygenated products in high yield after only 30 min.

Full text of DOI:10.1016/j.tetlet.2005.01.012

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1501–1504
Rapid Mo(CO)6 catalysed one-pot deoxygenation of
heterocyclic halo-benzyl alcohols with LawessonÕs reagent
Xiongyu Wu, A. K. Mahalingam and Mathias Alterman*
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, BMC, Uppsala University, PO Box 574,
SE-751 23 Uppsala, Sweden
Received 2 December 2004;revised 20 December 2004;accepted 6 January 2005
Available online 20 January 2005
Abstract—A fast and efficient microwave promoted one-pot method for deoxygenation of heterocyclic halo-benzyl alcohols has
been developed. The method does not cause dehalogenation of the substrates and provides the deoxygenated products in high yield
after only 30 min.
Ó 2005 Elsevier Ltd. All rights reserved.
Methods for selective replacement of hydroxyl groups
by hydrogen atoms are important in organic chemistry.1
Numerous methods have been developed for the deoxy-
genation of alcohols.1–9 Ionic reactions for deoxygen-
ation of alcohols have been reported,8,3 but the most
frequently used method is the radical Barton–McCom-
bie deoxygenation.9 Although many hydrogen donors
and radical carriers such as silanes, dialkyl phosphites
and hypophosphorous acid have been used as replace-
ments for the toxic organotin hydride the deoxygenation
method requires two steps, which results in tedious der-
ivatisation of the hydroxyl compound. In addition, the
Barton–McCombie method is also known to cause
dehalogenation.5 We here describe a fast and chemo-
selective Mo(CO)6 catalysed one-pot deoxygenation
method with LawessonÕs reagent.
OH
N
N
N
N
Br
Br
1a
2a
Scheme 1.
McCombie method.9 The S-methyldithiocarbonate
derivative of 1a was first synthesised in good yield. Tri-
butyltin hydride with AIBN as radical initiator was
applied to achieve the deoxygenation. After a reaction
time of 24 h the deoxygenated compound 2a was iso-
lated in a modest 20% yield. This unsatisfying result
encouraged us to search for a more efficient method
for deoxygenation of heterocyclic halo-benzyl alcohols.
In an ongoing medicinal chemistry program10,11 we were
interested in obtaining p-halo-benzyl heterocycles. Thus,
to access these structures we synthesised the secondary
alcohol 1a from the corresponding aldehyde, which after
deoxygenation should provide the target compound 2a
Alper and Blais14,15 and Luh and Wong16 have reported
the use of Mo(CO)6 as a convenient reagent for cleavage
of carbon–sulfur bonds, using an ethereal solvent as
hydrogen donor.17,18 Since, thiols are easily prepared
from their corresponding alcohols with LawessonÕs
reagent19 we were interested in evaluating if these two
reagents could be combined to give a one-pot deoxygen-
ation reaction suitable for our purposes. To increase the
speed of the reaction we decided to use controlled micro-
wave heating as the energy source.20
(Scheme 1).12 Initially we applied TFA/NaBH4 and
8
3
H3PO2/I2 as deoxygenation reagents, but neither of
these methods were able to give the deoxygenated prod-
uct 2a. Also the Wolf–Kishner13 reduction of the corre-
sponding ketone failed to give compound 2a. We
therefore focused on applying the two-step Barton–
The first attempt was performed by adding 0.5 equiv of
LawessonÕs reagent and 0.5 equiv of Mo(CO)6 to com-
pound 1a in dioxane. The reaction mixture was there-
after heated in a microwave cavity21 at 170 °C for
Keywords: Deoxygenation;Mo(CO) ;Lawesson Õs reagent.
Corresponding author. Tel.: +46 18 471 4905;fax: +46 18 471
4474;e-mail: mathias@orgfarm.uu.se
6
*
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.012

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X. Wu et al. / Tetrahedron Letters 46 (2005) 1501–1504
Table 1. Optimisation of the deoxygenation of compound 1aa
that a catalytic amount (5 mol %) was enough for the
process to proceed to completion (entry 3). Increasing
the reaction temperature to 180 °C did not improve
the outcome of the reaction, and with lower temperature
(160 °C) full conversion of the alcohol was not achieved
(entries 4 and 5). We also applied P2S5 as an alternative
to LawessonÕs reagent (entry 6). With P2S5 the reaction
gave full conversion, but unfortunately insoluble solids
were formed in the reaction mixture. This problem could
be the reason for the low isolated yield (51%). To exam-
ine if both the reagents were necessary for the deoxygen-
ation, one reagent at a time was excluded from the
reaction. Neither of the reactions in the absence of
Mo(CO)6 or LawessonÕs reagent gave the deoxygenated
product (entries 7 and 8).
Entry Mo(CO)6 LawessonÕs
Temperature Isolated
yield (%)
(equiv)
Reagent (equiv) (°C)
1
2
3
4
5
6
7
8
0.5
0.5
0.5
170
170
170
180
160
180
170
170
70
48
75
73
64
51
0
0.25
0.5
0.05
0.05
0.05
0.1
0.5
0.5
0.2 P2S5
0.5
0
0.05
0
0
a Reaction time 30 min.
30 min. The alcohol 1a was fully consumed and the
deoxygenated compound 2a was obtained in a 70% yield
(Table 1, entry 1). By reducing the amount of Lawes-
sonÕs reagent (0.25 equiv), full conversion was not
achieved and consequently the isolated yield of com-
pound 2a was decreased (entry 2). Systematic reduction
of the amount of Mo(CO)6 used in the reaction revealed
To examine the scope and limitations of this microwave
promoted deoxygenation method, a series of heterocy-
clic p-halo-benzyl alcohols were selected for evaluation.
The results are presented in Table 2. In the initial exper-
a
Table 2. One-pot deoxygenation with LawessonÕs reagent and Mo(CO)6
Entry
Alcohol
Product
Isolated yield (%)
OH
N
N
1
75
N
N
Br
Br
1a
OH
2a
N
N
2
3
4
5
6
7
78
80
52
46b
74
84
N
N
I
I
1b
OH
2b
2c
2d
2e
2f
N
N
N
Br
Br
Br
Br
Br
Br
1c
OH
N
N
S
S
N
N
N
N
N
N
Br
1d
OH
N
S
Br
Br
1e
OH
N
N
N
1f
OH
S
S
Br
Br
N
1g
2g
OH
S
8
15c
Br
1h
2h

X. Wu et al. / Tetrahedron Letters 46 (2005) 1501–1504
1503
Table 2 (continued)
Entry
Alcohol
Product
Isolated yield (%)
OH
N
N
9
95
N
N
N
Br
Br
Br
1i
1j
2i
OH
S
N
S
N
10
11
93
81
N
Br
Br
2j
OH
N
N
Br
1k
2k
a 0.5 mmol Alcohol, 0.05 equiv Mo(CO)6, 0.5 equiv LawessonÕs reagent, 2.5 mL dioxane, microwave heating: 170 °C, 30 min.
b 0.3 equiv Mo(CO)6.
c Dimerised product was isolated in 30% yield.
iment it was demonstrated that bromides were not af-
fected by the deoxygenation method, we therefore
wanted to investigate an iodide substrate (entry 2).
The more reactive iodide remained intact and the deoxy-
genated product was obtained in a good yield. The pyr-
idine derivative (entry 3) was also a good substrate for
the deoxygenation reaction, but the triazole compound
gave a moderate 52% yield (entry 4). When applying
the pyrazole as substrate (entry 5), full conversion was
not initially achieved. The amount of Mo(CO)6 was
therefore increased to 0.3 equiv and full conversion
was then obtained, affording the corresponding deoxy-
genated compound in 46% yield.
Mo(CO)6
Lawesson´s
reagent
d8-Dioxane
170 °C, 30 min
OH
N
N
N
N
Br
Br
1i
2i
Scheme 2.
(Scheme 2). In this reaction no incorporation of
deuterium was found in the product 2i (determined
by NMR and MS). This suggests that the source of
hydrogen is from the thiol or the initial hydroxyl group.
In summary, a fast microwave promoted deoxygenation
reaction utilising Mo(CO)6 and LawessonÕs reagent has
been developed. The method provides a simple one-
pot reaction for the direct removal of hydroxyl groups
without isolation of intermediate derivatives. The
reaction does not cause dehalogenation and is suitable
for nitrogen-containing substrates.
Introduction of sulfur to the heterocycle did not have a
negative impact on the yield, and the two thiazoles 2f
and 2g were obtained in good yields (entries 6 and 7).
With the electron rich thiophene substrate the result
was very poor (15%), due to a competing dimerisation
reaction that could not be suppressed. Both benzoimidaz-
ole 1i and benzothiazole 1j gave excellent yields of the cor-
responding deoxygenated compounds (entries 9 and 10).
The substrate in entry 11 possessed an extra CH2 next to
the alcohol, resulting in the formation of the olefinic
product derived from abstraction of the b-hydrogen.
General procedure: A process vial (5 mL) was charged
with 1 (0.5 mmol), Mo(CO)6 (6.6 mg, 0.025 mmol),
LawessonÕs reagent (50.5 mg, 0.25 mmol) and dioxane
(2.0 mL). The vessel was exposed to microwave heating
for 30 min at 170 °C. The reaction tube was thereafter
cooled to room temperature and the solvent was re-
moved under vacuum. The crude product was purified
on an aluminium oxide column with 2:8–3:7 acetone–
hexane to give compounds 2a–g,i–k. Compound 2h
was adsorbed on aluminium oxide and purified with
5:95 ethyl acetate–hexane.
In the experiment without LawessonÕs reagent (Table 1,
entry 8) it was confirmed that the reaction proceeds via
the thiol. We have also shown that Mo(CO)6 was neces-
sary for the reaction to give the dethio product (Table 1,
entry 7). The suggested mechanism for desulfurisation
with Mo(CO)6 is via radical formation.16 The radical
mechanism hypothesis was supported by the formation
of the dimeric product from the thiophene substrate
(Table 2, entry 8). It is known that the a-hydrogen of
ethereal solvents can be abstracted by a radical spe-
cies.17,18 To investigate the source of hydrogen in the
desulfurised product we used dioxane-d8 in the reaction
with compound 1i under the described conditions
Acknowledgements
We gratefully acknowledge financial support from the
Swedish foundation for Strategic Research (SSF). We
thank Biotage AB for providing the microwave
synthesiser.

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X. Wu et al. / Tetrahedron Letters 46 (2005) 1501–1504
Pettersson, A.;Nyberg, F.;Fa ¨ndriks, L.;Hallberg, A.;
Supplementary data
Alterman, M. J. Med. Chem. 2004, 47, 1536–
1546.
11. Wan, Y.;Wallinder, C.;Plouffe, B.;Beaudry, H.;Maha-
lingam, A. K.;Wu, X.;Johansson, B.;Holm, M.;Botoros,
M.;Karlen, A.;Pettersson, A.;Nyberg, F.;Fa ¨ndriks, L.;
NMR-data of all new compounds are provided in the
supplementary data file. Supplementary data associated
with this article can be found, in the online version at,
10.1016/j.tetlet.2005.01.012.
Gallo-Payet, N.;Hallberg, A.;Alterman, M.
Chem. 2004, 47, 5995–6008.
J. Med.
12. Barletta, G.;Chung, A. C.;Rios, C. B.;Jordan, F.;
Schlegel, J. M. J. Am. Chem. Soc. 1990, 112, 8144–
8149.
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