Novel solid state reduction of organic functional groups on solid support (Merrifield's resin)

Article abstract of DOI:10.1055/s-1999-2758

Reduction of organic functional groups viz. aldehydes, ketones, esters and epoxides is achieved on solid support in solid state for the first time using NaBH₄ and LiAlH₄ under solvent free conditions.

Full text of DOI:10.1055/s-1999-2758

LETTER
1061
Novel Solid State Reduction of Organic Functional Groups on Solid Support
(Merrifield’s Resin)#
S. Chandrasekhar*, Abbas Raza, M. B. Padmaja
Indian Institute of Chemical Technology, Habsiguda, Uppal Road, Hyderabad-500 007, India
Fax +91 (91) 407173387; E-mail: srivaric@iict.ap.nic.in
Received 12 April 1999
MeOH) to afford methyl-3-hydroxy butanoate 1b (entry1)
Abstract: Reduction of organic functional groups viz. aldehydes,
in 81% yield. A similar result was obtained in reduction of
ketones , esters and epoxides is achieved on solid support in solid
pyruvic acid supported (entry 2) on Merrifield’s resin as
an ester.
state for the first time using NaBH4 and LiAlH4 under solvent free
conditions.
Key words: combinatorial chemistry, epoxides, carbonyl com- In the third instance the p-hydroxy-benzaldehyde support-
pounds, reduction, solid state, solid support
ed on resin when treated with NaBH4 in solid state, fur-
nished p-hydroxy benzyl alcohol 3b (entry 3) after
cleavage from resin using trifluro acetic acid (TFA). Sim-
ilarly, the epoxy functionalized resin, (entry 4) when treat-
ed with LiAlH4 for 6 hrs followed by TFA cleavage
yielded 1,10-undecanediol 4b in 60% isolated yield. Also
the ester linked epoxy resin (Entry 5) when treated with
LiAlH4 in one pot directly yielded the 1,10-undecane diol.
Organic reactions are conventionally carried out in solu-
tion phase. However, Toda et al have unequivocally
proved that, reactions proceed with equal ease and some-
times better in solid state as well.1 This is exemplified by
achieving various Functional Group Transformations
(FGT) in solid state.2 This solution free chemistry offers
some advantages over solution chemistry especially in ob-
taining better selectivities since molecules in a crystal are
arranged tightly and regularly. When more selective reac-
tion in the solid state is required, the host-guest technique
is applicable.3 The recently explored combinatorial chem-
istry,4 the backbone of which involves insoluble polymers
as solid supports, surprisingly are carried out in solvents.
Our interest in development of new reactions in solid
state5 has prompted us to examine whether the solid state
organic chemistry can be applied to polymer supported
(Merrifield and related resins) chemistry. Herein, we re-
port our new findings in the area of Solid State Solid Sup-
ported (SSSS) Chemistry, wherein a few organic
functionalities such as epoxides (eq. 1) and carbonyl com-
pounds including ester (eq. 2) were reduced with ease.
In conclusion, a novel SSSS reduction of organic func-
tional groups is reported wherein no solvent has been used
during the reaction course. This method once adopted
should offer few advantages especially during cleavage
step and also during reduction of carbonyl functionalities
wherein methanol has to be used as solvent (methanol is
found to have low swelling factor7) in combination with
NaBH4.
Typical experimental procedure:
A. Reduction of 3 with NaBH4:
To the potassium salt of para hydroxybenzaldehyde pre-
pared from K2CO3 (0.828 g, 6 mmol) and para hydroxy-
benzaldehyde (0.488 g, 4 mmol) in DMF was added
Merrifield’s resin (2 g, 2 mmol) in small portions. The
mixture was shaken at room temperature for 4 h. The resin
was filtered, washed with 5% HCl (10 mL) water (3 x 20
mL), acetone (2 x 20 mL) and ether (2 x 20 mL). The
resin was dried in vacuum to yield 2.205 g of 3.
IR (KBr): u=1032, 1246, 1693 cm-1
To resin 3 (2.200 g) was added NaBH4 (0.185 g, 5 mmol)
under N2 atmosphere. The contents were shaken for 6 h.8
The resultant solid was washed with water (2 x 20 mL),
acetone (2 x 20 mL), CH2Cl2 (2 x 20 mL) and ether
(2 x 20 mL). The resin was dried in vacuum to yield 2.198
g of 3a.
The commercially available lithium salt of acetoacetic
acid6 was loaded onto Merrifield’s resin by shaking the
lithium salt of the acid and resin in DMF. After filtration
and drying, solid resin was mixed thoroughly with solid
sodium borohydride and kept on mechanical shaker in a
stoppered round bottom flask at room temperature for 6
hrs. The resultant solid was washed with water, methanol,
acetone, dried and subjected to trans-esterification (Na/
IR (KBr): u=3300, 3100 cm-1
To resin 3a (2.190 g) in DCM was added 20% TFA in
CH2Cl2 (20 mL). The contents were shaken for 15 min and
filtered. The resin was washed with DCM (2 x 20 mL).
Combined filtrates were concentrated to give 4-Hydroxy
benzyl alcohol 3b (0.146 g) in 58.8% yield.
Synlett 1999, No. 07, 1061–1062 ISSN 0936-5214 © Thieme Stuttgart · New York

1062
S. Chandrasekhar et al.
LETTER
ture. Resin was carefully collected and washed with 10%
NaHCO3 solution (2 x 20 mL), water (2 x 20 mL), acetone
(2 x 20 mL), CH2Cl2 (2 x 20 mL) and ether (2 x 20 mL).
The resin was dried in vacuum to yield 2.298 g of resin 4.
IR (KBr): u=1245 cm-1.
To resin 4 (2.298 g) was added LiAlH4 (0.222 g, 6 mmol)
under N2 atmosphere. The contents were shaken for 6 h.8
Moist ether was added to the reaction mass. The resin was
carefully washed with 5% HCl (10 mL), water (2 x 20
mL), acetone (2 x 20 mL) and ether (2 x 20 mL). The res-
in was dried under vacuum to yield 2.256 g of 4a. (IR
(KBr): u=3665, 3050 cm-1)
To resin 4a (2.256 g) was added 30% TFA in CH2Cl2 (20
mL). The contents were shaken for 15 min and filtered.
The resin was washed with DCM (2 x 20 mL). Combined
filtrates were concentrated to give 1,10-undecandiol 4b
(0.228 g) in 60% yield.
Mass (M+) :188, 1H NMR (CDCl3): d 1.15 (d, 3H), 1.24-
2.65 (m, 16H), 3.55 (t, 2H, J = 5 Hz), 3.60-3.71 (m, 1H).
Acknowledgement
A.R thanks INSA, New Delhi and MBP thanks CSIR, New Delhi
for financial assistance.
References and Notes
(#) IICT Communication No. 4103.
(1) (a) Toda, F. Acc. Chem. Ress 1995, 28, 480 (b) Toda, F.; Koji,
K.; Yagi, M. Angew. Chem. Int. Ed. Engl. 1989, 28, 320.
(2) (a) Toda, F.; Kanemoto, K. Hetrocycles 1997, 185. (b) Toda,
F.; Imai, N. J. Chem. Soc. Perkin Trans. I 1994, 2673. (c)
Toda, F.; Tanaka, K.; Sekikawa, A. J. Chem. Soc., Chem.
Commun. 1987, 279. (d) Toda, F.; Yagi, M.; Kiyoshige, K. J.
Chem. Soc., Chem. Commun. 1988, 958.
(3) (a) Breslow, R. Acc. Chem. Res. 1995, 28, 146. (b) Toda, F.;
Tanaka, K. Tetrahedron Lett. 1988, 29, 557.
(4). (a) Gordon, E.M.; Barret, R.W.; Dower, W.J.; Fodor, S.P.;
Gallop, M.A. J. Med. Chem. 1994, 37, 1385. (b) Booth, S.;
Hermkens, P.H.H.; Ottenheijm, H.C.J.; Rees, D.C.
Tetrahedron 1998, 54, 15385
1
Mass (M+)124, H NMR (CDCl3): d=4.39 (s, 2H), 4.91
(br, s, 1H), 6.71 (d, 2H), 7.15 (d, 2H).
(5) (a) Chandrasekhar, S.; Uma, G.; Takhi, M. Tetrahedron Lett.
1997, 38, 8089. (b) Chandrasekhar, S.; Subba Reddy, B.V.
Synlett. 1998, 851.
B. Reduction of 4 with LiAlH4:
To the sodium salt of undecenol prepared from undecenol
(1.020 g, 6 mmol) and NaH (0.384 g, 16 mmol) in DMF
was added Merrifield's resin (3 g, 3 mmol) at 0 °C. The
contents were shaken at room temperature for 4 h. The
resin was washed with ethyl acetate (3 x 20 mL), water
(3 x 20 mL), acetone (2 x 20 mL), CH2Cl2 (2 x 20 mL)
and ether (2 x 20 mL). The resin was dried in vacuum to
yield 3.434 g of polymer bound undecenol.
(6) Acetoacetic acid lithium salt is obtained from Aldrich. Chem.
Co. (a) Merrifield, R.B. J. Am. Chem. Soc. 1963, 85, 2149. (b)
Merrifield’s Resin is obtained from Alderich Chem. Co.
(7) Encyclopedia of Polymer Science and Engineering, 2nd Ed.
"A Wiley-Interscience publication" V. Kudela, Vol. 7, p798.
(8) Prior to washings a small portion of reaction mixture was
subjected to IR spectroscopy using KBr pellet. The absence of
carbonyl peak was observed for 3a and broad hydroxy peak
(3050, 3665 cm-1) was observed for 4a. Prior grinding
reduction agents and resin is not desirable.
IR (KBr): u=1138 cm-1.
Polymer bound undecenol (2.5 g) was taken in CH2Cl2
and m-CPBA (0.415 g, 3 mmol) was added to it at 0 °C
and the contents were shaken for 12 h at room tempera-
Article Identifier:
1437-2096,E;1999,0,07,1061,1062,ftx,en;L00399ST.pdf
Synlett 1999, No. 07, 1061–1062 ISSN 0936-5214 © Thieme Stuttgart · New York