LETTER
Synthesis of Benzyl Alcohol Building Blocks
125
Table 3 Aldehyde/Pinacol Borane Synthesis (continued)
investigating the feasibility of synthesising both the alde-
hyde analogue through a DMF quench and also the pina-
col borane by quenching with 2-isopropoxy-4,4,5,5-tetra-
methyl-1,3,2-dioxaborolane.
i) n-BuLi (1.1 equiv),
–78 °C, THF, 10 min
OTBDMS
OTBDMS
ii) E+ quench
R1
R1
Aldehydes 7a, 7b and 7d, and pinacol boranates 8c and 8d
have not been reported previously in the literature. Alde-
hyde 7c has been synthesised by using a similar method-
ology to that reported here with sec-butyllithium, but in a
moderate 47% yield.9 The synthesis of compounds similar
to pinacol boranes 8a and 8b have been reported in the
patent literature by using palladium cross-coupling chem-
istry.10,11
Br
R
6
7, R = CHO
8, R = pinacol
Entry Bromo derivative
Aldehyde or pinacol
Yield
(%)
OTBDMS
OTBDMS
NC
Utilisation of our general lithium–bromide exchange
methodology and quenching with the appropriate electro-
phile generated the desired aldehydes 7a–d and pinacol
boranes 8a–d in moderate to excellent yields (Table 3).
B
NC
8
80
O
O
Br
6d
We then turned our attention to the p-benzyl carboxylic
acid products 4a–c. The required bromo precursors 10a–c
were again synthesised through the same two-step proto-
col from readily available carboxylic acids 9a–c (Table
4). The cyano precursor was not commercially available
and thus was not included in this study.
8d
It can be seen that, in all cases, the synthesis of the carbox-
ylic acids occurred smoothly in moderate to excellent
yield.
Following on from the success of the carboxylic acid syn-
thesis, we decided to increase the scope of the reaction by
Lithium–bromide exchange at –78 °C followed by the
appropriate quench generated the carboxylic acid 4a–c,
aldehyde 11a–c, or pinacol borane 12a–c building blocks
in moderate to good yields (Table 5).
Table 4 Synthesis of Bromo Precursors
O
In conclusion, we have demonstrated an efficient three-
step protocol for the synthesis of highly useful benzyl al-
cohol building blocks bearing carboxylic acid, aldehyde
or pinacol borane motifs. This methodology has proven to
be robust, is higher-yielding than current synthetic ap-
proaches, and can be performed on a multigram scale.
OTBDMS
i) BH3⋅THF (2.2 equiv),
r.t., 24 h
OH
Br
Br
ii) imidazole, TBDMSCl,
DMF, r.t., 24 h
R
R
10
9
Entry Starting material
Bromo derivative
Yield (%)a
Supporting Information for this article is available online at
O
r
t
iornat
OTBDMS
OTBDMS
OH
1
2
3
Br
93
Br
References and Notes
(1) A Reaxys search of these meta/para carboxylic acid
scaffolds revealed several thousand hits.
(2) Greenspan, P.; Clark, K.; Cowen, S.; McQuire, R.; Farley,
D.; Quadros, E.; Coppa, D.; Zheng, Fang. Z.; Zhou, H.;
Doughty, J.; Toscano, K.; Wigg, A.; Zhou, S. Bioorg. Med.
Chem. Lett. 2003, 13, 4121.
(3) Balaji, K.; Schaschke, N.; Machleidt, W.; Catalfamo, M.;
Henkart, P. J. Exp. Med. 2002, 196, 493.
(4) Cao, J.; Soll, R. M.; Noronha, G.; Barrett, K.; Gritzen, C.;
Hood, J.; Mak, C. C.; McPherson, A.; Pathak, V. P.; Renick,
J.; Splittgerber, U.; Zeng, B. WO 2006/101977, 2006; Chem.
Abstr. 2006, 145, 377376.
(5) Charrier, J.-D.; Binch, H. M.; Hurley, D. J.; Cleveland, T.;
Joshi, P.; Fanning, L. T. D.; Pinder, J.; O’Donnell, M.;
Virani, A. N.; Knegtel, R. M. A.; Durrant, S. J.; Young, S.
C.; Pierre, H.; Kay, D.; Reaper, P. M. WO2011/143426,
2011; Chem. Abstr. 2011, 155, 657044.
10a
9a
O
OH
Br
93
90
Br
Cl
Cl
10b
9b
O
OTBDMS
OH
Br
Br
F
F
10c
9c
a Isolated yield over two steps.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 123–127