Mild Two-Step Conversion of Primary Amides to Alcohols by Reduction of Acylimidodicarbonates with Sodium Borohydride

Article abstract of DOI:10.1055/s-2003-42116

Di-tert-butyl acylimidodicarbonates, prepared from primary amides with two equivalents of di-tert-butyl dicarbonate under catalysis by 4- dimethylaminopyridine, readily undergo selective reductive cleavage of their acyl CO-N bonds by NaBH₄ to provide the corresponding alcohols in high yields.

Full text of DOI:10.1055/s-2003-42116

2386
LETTER
Mild Two-Step Conversion of Primary Amides to Alcohols by Reduction of
Acylimidodicarbonates with Sodium Borohydride
T
wo-Step Convers
l
ion of
f
mide
s
to
AlcR
a
Department of Biochemistry, University of Uppsala, Biomedical Center, PO Box 576, SE-751 23 Uppsala, Sweden
Fax +46(18)552139; E-mail: urbki@bmc.uu.se
b
Departamento de Quimica, Universidade do Minho, Gualtar, P-4700-320 Braga, Portugal
Received 8 September 2003
acylcarbamates. This effect has been measured for 2a
Abstract: Di-tert-butyl acylimidodicarbonates, prepared from pri-
mary amides with two equivalents of di-tert-butyl dicarbonate un-
der catalysis by 4-dimethylaminopyridine, readily undergo
selective reductive cleavage of their acyl CO-N bonds by NaBH4 to
provide the corresponding alcohols in high yields.
(R = Ph) using cyclic voltammetry (CV).1b
To study the reactivity of di-tert-butyl acylimidodicar-
bonates 2 in more detail with respect to reduction, several
compounds 2a–f listed in Table 1 have been prepared
from the corresponding amides 1.6 According to TLC the
syntheses of all went to completion within a maximum of
24 hours, which eliminated the need for chromatographic
purification of the products. These were all obtained as
highly lipophilic solids, some of which like 2e dissolved
easily in light petroleum and therefore occasionally were
difficult to recover by recrystallization. The variable
yields for individual compounds 2 reflect this fact rather
than low reactivity of some amides.
Key words: alcohols, amides, cleavage, reductions, sodium boro-
hydride
Recently, in connection with studies of model N-benzyl
acylcarbamates we observed that these substances under-
went regiospecific acyl CO-N reductive cleavage under
relatively mild conditions.1 In that context it occurred
to us that this reaction might be exploited for synthetic
purposes. As a continuation, we now present a simple
two-step procedure for conversion of primary amides to
alcohols based on similar principles. Rather few transfor-
mations of this kind involving hydrogenation, electro-
chemical and dissolving metal reduction and metal
hydride reagents have been reported in the literature.2
Some tertiary amides have recently been shown to under-
go notably mild reductive cleavage to alcohols by metal
hydride reagents.3
As a prelude to the preparative reduction experiments, at-
tempts were made to characterize the acylimidodicarbon-
ates 2 by CV. These experiments were performed in DMF
as described elsewhere.8 Although the activation potential
could not be determined for all compounds, in two cases
(for 2a and 2d) we could demonstrate that the introduction
of a second Boc group shifted the peaks by over 0.35 V to
less negative potential in comparison with the correspond-
ing N-benzyl acylcarbamates (Table 1).1a,8
As first shown by Grieco et al., secondary amides and lac-
tams undergo facile reaction with di-tert-butyl dicarbon-
ate (Boc2O) in the presence of 4-dimethylaminopyridine4
(DMAP) with formation of the corresponding acylcar-
bamates.5 Such compounds react with nucleophiles under
cleavage of their acyl-N bonds, as a consequence of which
the original amides can be converted to carbamates in two
steps. Similarly, primary amides 1 undergo substitution
with two equivalents of Boc2O in the presence of this cat-
alyst to give di-tert-butyl acylimidodicarbonates 2.6
Compounds 2 were reduced to alcohols 3 using an excess
of NaBH4 in EtOH on a 2–3 mmol scale with the simulta-
neous formation of an equivalent of HNBoc2.9 Although,
as demonstrated, the latter compound could generally be
efficiently separated from the desired alcohols by chroma-
tography on silica gel, in other cases due to the high lipo-
philicity of the products this turned out to be more
difficult and required rechromatography to provide pure
products, all of which have been described before. All re-
ductions with NaBH4 could be carried out at room temper-
ature except in the case of 2c. As reflected by its much
lower activation potential in comparison with 2a and 2d
(Table 1), it was less reactive and moderate heating was
therefore required. In this experiment also a side-product,
formed by the alternative cleavage of a Boc-group from
2c, could be isolated. Another triacylated ammonia deriv-
ative, NBoc3, known to undergo aminolysis,10 is also
cleaved to HNBoc2 by NaBH4 with high selectivity,
which exemplifies the dramatic shift in stability of Boc in
these compounds in comparison with simple carbam-
ates.11 Attempts to reduce 2c by cathodic electrolysis8 fur-
nished a complex mixture containing HNBoc2 but only
small amounts of 3c.
Compounds 2 behave as acylating agents,7 indicating a
significant further electron-withdrawing effect by the sec-
ond Boc group on nitrogen in comparison with that in
Scheme 1 Two-step conversion of primary amides via di-tert-butyl
acylimidodicarbonates to alcohols
SYNLETT 2003, No. 15, pp 2386–2388
0
1
.1
2
.2
0
0
3
Advanced online publication: 07.11.2003
DOI: 10.1055/s-2003-42116; Art ID: G22203ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Two-Step Conversion of Amides to Alcohols
2387
Reduction of the proline amide derivative 2f with both di- step. Among these amides are such containing additional
isobutylaluminium hydride and tri-tert-butoxy-alumini- ester, carbamate, alcohol and amino functions, some of
um hydride has previously been attempted but only which undergo additional reaction. As most functional
resulted in a meager (<10%) yield of a mixture of the cor- groups other than aldehydes and ketones are stable to
responding aldehyde and alcohol.7
NaBH4,13 the corresponding acylimidodicarbonates
should therefore normally be compatible with the mild re-
ducing agent used in the second step and provide alcohols
accordingly.
Concerning the scope of this two-step transformation
(Scheme 1), it can be mentioned that several amides 1
have been converted to di-tert-butyl acylimido-
dicarbonates7,12 2 using Boc2O/DMAP, so a fair amount
of information is already available with respect to the first
Table 1 Synthesis of di-tert-Butyl Acylimidodicarbonates 2 and their Reduction to Alcohols 3 by NaBH4
2
3
Amide 1/
Yielda (%) Spectral data of 2b
Mp (ºC)
Yielda
(%)
Spectral data of 3b
Solventc
–EP/V
Mp (ºC)
Benzamide (a)/A
77d
d = 1.38 (18 H), 7.47 (p t, J = 7 Hz, 2 H), n.d.e
d = 1.96 (br, 1 H), 4.66 (2 H), 7.26–7.39 (m,
59.5–60.5 7.60 (p t, J = 7 Hz, 1 H), 7.83 (p d, J = 7 oil
5 H); ca. 3338 (br), 1454, 1021, 735, 697 cm–1
1.56f
Hz, 2 H); 1765, 1740, 1702 cm–1
4-Nitrobenzamide
(b)/A
79g
d = 1.43 (18 H), 7.94 (p d, J = 8.4 Hz, 2
97
93–94
d = 2.18 (br, 1 H), 4.835 (2 H), 7.53 (d,
J = 8.9 Hz, 2 H), 8.21 (d, J = 8.8 Hz, 2 H);
3517, 1603, 1509, 1338, 1057, 736 cm–1
74.5–75.5 H), 8.32 (p d, J = 8.4 Hz, 2 H); 1782,
0.60, 1.01 1745, 1698, 1280 cm–1
4-Dimethylami-
nobenzamide (c)/B
95g
169–170
2.18
d = 1.38 (18 H), 3.08 (6 H), 6.65 (d,
54
d = 1.72 (br, 1 H), 2.93 (6 H), 4.54 (2 H), 6.71
(d, J = 8.7 Hz, 2 H), 7.22 (d, J = 8.7 Hz, 2 H)
N-Boc-4-dimethylaminobenzamide (side-
J = 9.1 Hz, 2 H), 7.76 (d, J = 9.1 Hz, 2 H); oil
1785, 1697, 1595, 1293, 1099 cm–1
12g
180 (dec) product): d = 1.53 (9 H), 3.04 (6 H), 6.65 (d,
J = 9.1 Hz, 2 H), 7.72 (d, J = 9.1 Hz, 2 H); EP/
V = –2.26 V
1-Naphthamide (d)/B 90g
d = 1.26 (18 H), 7.48 (dd, J1 = 8.2 Hz,
86/51
d = 1.95 (1 H), 5.09 (2 H), 7.41 (dd, J1 = 8.1
Hz, J2 = 7.1 Hz, 1 H), 7.47 (p d, J = 7 Hz, 1
H), 7.49 and 7.52 (2 × p dt, J1 = 7 Hz, J2 = 1.6
Hz, 1 H + 1 H), 7.79 (p d, J = 8 Hz, 1 H), 7.85
(p dd, J1 = 7.4 Hz, J2 = 2 Hz, 1 H), 8.06 (p d,
J = 8 Hz, 1 H); 3368–3308 (br), 1003, 800,
792, 774 cm–1
67.5–68.5 J2 = 7.2 Hz, 1 H), 7.54 and 7.60 (2 × p dt, 61–62
1.44
J1 = 7 Hz, J2 = 1.4 Hz, 1 H + 1 H), 7.79
(dd, J1 = 7.1 Hz, J2 = 1.2 Hz, 1 H), 7.89 (p
d, J = 8 Hz, 1 H), 8.00 (p d, J = 8.2 Hz, 1
H), 8.37 (p d, J = 8 Hz, 1 H); 1792, 1736,
1717, 1102 cm–1
Cyclohexanecarboxa- 74g
d = 1.17–1.36 and 1.41–1.51 (m, ca. 4 H), n.d.h
1.524 (18 H), 1.62–1.70 (m, ca. 2 H), 1.77 oil
and 1.81 (2 × p t, J = 3 Hz, 1 H + 1 H),
1.90 and 1.93 (2 × m, 1 H + 1 H), 3.16 (tt,
J1 = 11.3 Hz, J2 = 3.4 Hz, 1 H); 1777,
d = 0.88–0.98 (m, 2 H), 1.11–1.32 (m, 3 H),
1.43–1.53 (m, 1 H), 1.63 (1 H), 1.65–1.78 (m,
5 H), 3.44 (d, J = 6.3 Hz, 2 H); ca. 3290 (br),
2924, 2854, 1449, 1036 cm–1
mide (e)/B
67–67.5
–
1745, 1702 cm–1, estimated purity ≥95%
Boc-L-proline amide 85d
(f)/A 109–110
d = 1.42/1.45 (2 × s, 9 H), 1.53/1.56
(2 × s, 18 H), 1.81–2.06 and 2.22–2.35
(m, 4 H), 3.37–3.49 and 3.51–3.64 (m, 2
H), 5.11/5.19 (2 × dd, J1 = 8.9 Hz,
J2 = 3.5/2.7 Hz, 1 H); 1774, 1750, 1708,
1697 cm–1
84
d = 1.47 (9 H), 1.56 (m, 1 H), 1.81 (m, 2 H),
59.5–60i 1.99 (m, 1 H), 3.28–3.34 and 3.41–3.47 (m, 1
H + 1 H), 3.61 (br, 2 H), 3.95 (br, 1 H); 3438,
1664, 1412, 1049 cm–1
–
a Yields are not optimized.
b 1H NMR spectra recorded at 400 MHz in CDCl3. Proton signals are singlets, when not otherwise stated. Major/minor conformer. FT-IR
spectra recorded in KBr pellets (for 3a and 3e as films). Only carbonyl and hydroxyl and occasionally strongest bands given. Abbreviation:
p = perturbed.
c Solvents used in the preparation of 2: acetonitrile (A), dichloromethane (B).
d Previously described compound (ref.7).
e Twice chromatographed on silica gel with Et2O/light petroleum 1:4 (traces of HNBoc2 still visible).
f See ref.1b
g Novel compound with satisfactory C,H,N analysis.
h Chromatographed on silica with Et2O/CH2Cl2 1:15 but strongly contaminated with Boc-compound(s).
i [a]D25 –53.8 and [a]57825 –56.2 (c 1.0, MeOH), the former value in agreement with literature.
Synlett 2003, No. 15, 2386–2388 © Thieme Stuttgart · New York

2388
U. Ragnarsson et al.
LETTER
(8) Maia, H. L. S.; Monteiro, L. S.; Degerbeck, F.; Grehn, L.;
Ragnarsson, U. J. Chem. Soc., Perkin Trans. 2 1993, 495.
(9) Typical Reduction Procedure: A solution of 2c (732 mg, 2
mmol) in abs EtOH (12 mL) was treated with an excess of
NaBH4 (151 mg, 4 mmol) in one batch. After 20 h, when all
starting material had been consumed (TLC monitoring),
acetone (1 mL) was added, whereupon after 1 h the solvent
was evaporated. The obtained foam was dissolved in Et2O/
H2O, the aqueous phase backwashed once with Et2O and the
combined extracts dried (Na2SO4). After evaporation the
mixture was purified by chromatography on silica gel
(eluent: Et2O/CH2Cl2 1:15). HNBoc2 eluted first, followed
by pure 3c (298 mg, 97%); mp 91–92 °C; it was
recrystallized from Et2O/light petroleum.
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Acknowledgment
This work was supported by Magn. Bergvall’s stiftelse (U.R.), O.E.
och E. Johansson’s stiftelse and Helge Ax:son Johnson’s stiftelse
(L.G.) and FCT (Portugal) (L.S.M. and H.L.S.M.). U.R. also thanks
the RSC for a journals grant for international authors.
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Synlett 2003, No. 15, 2386–2388 © Thieme Stuttgart · New York