Metal-free reductive cleavage of N-O bonds in weinreb amides by an organic neutral super-electron donor

Article abstract of DOI:10.1055/s-2008-1078240

The scope of neutral organic super-electron donors as reducing agents has been extended to include the reductive cleavage of N-O bonds in Weinreb amides. This methodology proved to be applicable to a large array of substrates to afford their reduced counterparts in good to excellent yields. The variation in reactivity within the set of tested amides is rationalised. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078240

2132
LETTER
Metal-Free Reductive Cleavage of N–O Bonds in Weinreb Amides by an
Organic Neutral Super-Electron Donor
R
eductive Cle
y
W
e
l
v
midesby an
a
O
rganic Su
i
per-El
n
D
onor P. Y. Cutulic,a John A. Murphy,*a Hardeep Farwaha,a Sheng-Ze Zhou,a Ewan Chrystalb
a
WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, UK
Fax +44(141)5484822; E-mail: John.Murphy@strath.ac.uk
b
Syngenta, Jealott’s Hill International Research Centre, Bracknell RG42 6EY, UK
Received 2 June 2008
Dedicated to Sir Jack Baldwin on the occasion of his 70th birthday
Abstract: The scope of neutral organic super-electron donors as re-
ducing agents has been extended to include the reductive cleavage
of N–O bonds in Weinreb amides. This methodology proved to be
applicable to a large array of substrates to afford their reduced coun-
terparts in good to excellent yields. The variation in reactivity with-
in the set of tested amides is rationalised.
N
N
N
N
N
N
N
N
Me
Me
1
2
Key words: electron transfer, Weinreb amide, reduction, pyr-
idinylidene
I–
+N
I–
N+
N
N
NaH
DMF
The N–O bond is commonly encountered in organic
chemistry. It is most frequently encountered in N-meth-
oxy-N-methylamides, (Weinreb amides), which are very
well known and useful intermediates in organic synthe-
sis.1 Methodologies exist for the reduction of N–O bonds,
and usually feature the use of metal-based reducing
agents. For instance, N-hydroxy-2-azetidinones are re-
duced by TiCl3, but no reaction occurs with N-alkoxy-2-
azetidinone.2 Oxazine cycloadducts derived from mandel-
ic acid can also be reduced by catalytic hydrogenation,
Na/Hg or Mo(CO)6.3 Samarium(II) iodide has been used
to perform the reductive cleavage of N–O bonds in N-
alkoxytrifluoroacetamides.4 Yus et al. more recently pro-
posed a general procedure to perform reductive N–O bond
cleavage of Weinreb amides using a catalytic system fea-
turing Li and di-tert-butylbiphenyl.5a Birch conditions
have also been used by Cossy et al.5b
Me2N
NMe2
Me2N
NMe2
3
4
Scheme 1
Me
I
Et
1 (1.2 equiv)
DMF, 100 °C
N
N
88%
Ms
Ms
Me
Me
SO2Ph
SO2Ph
2 (3 equiv)
Me
Me
H
SO2Ph
97%
DMF, 110 °C
O
I
Me
Me
CO2H
Me
(i) 4 (1.5 equiv)
CO2Et
Me
r.t., DMF
O
O
O
Me
(ii) KOH, H2O
MeOH, 50 °C, 12 h
Me
83%
8%
In contrast to these metal-based reducing reagents, neu-
tral, organic, ground-state, super-electron donor reagents
have recently been developed within our research group.6–9
These are highly selective reducing agents and, being neu-
tral, operate under mild conditions. Donor 1 (Scheme 1)
effected single-electron transfer (SET) to aryl and alkyl
iodides, thereby generating the corresponding radicals,
which cyclised in the presence of appropriate trapping
groups, such as alkenes (Scheme 2).6 Recently, two more
powerful neutral ground-state electron donors 27 and 48,9
have been developed within our laboratories. These re-
agents can transfer two electrons to substrates, including
those that are more difficult to reduce. For instance, they
Scheme 2
convert aryl iodides into aryl anions7 and reductively
cleave selected sulfones and sulfonamides8,9 (Scheme 2).
Donor 4 is easily prepared by deprotonation of disalt 3. Its
scope as a powerful, neutral, ground-state electron donor
4 has so far been limited to the successful reductive cleav-
age of sulfones, aryl iodides, and alkyl halides. We were
keen to expand the scope of reductive cleavages that could
be performed. This paper presents the results of our study
on the reductive cleavage of N–O bonds of Weinreb
amides.
Weinreb amide substrates were easily synthesised, either
from the commercially available acid chloride counterpart
or from the commercially available carboxylic acid coun-
terpart that was firstly activated in situ with oxalyl chlo-
SYNLETT 2008, No. 14, pp 2132–2136
Advanced online publication: 31.07.2008
DOI: 10.1055/s-2008-1078240; Art ID: D19808ST
© Georg Thieme Verlag Stuttgart · New York
2
2
.0
8
.2
0
0
8

LETTER
Reductive Cleavage of Weinreb Amides by an Organic Super-Electron Donor
2133
ride and DMF, and N,O-dimethylhydroxylamine hy-
drochloride. Results of successful reductive N–O bond
cleavage of Weinreb amides (Scheme 3) are presented in
Table 1.
N
N
O
O
4
Me2N
NMe2
Me
R
N
R
NH
Me
DMF
OMe
Scheme 3
Table 1 Cleavage of Weinreb Amides by Donor 4 in DMF Solution
Entry
Reagent
Reaction conditions
Product
Yield (%)
O
O
4 (1.5 equiv)
r.t.
Me
NH
Me
N
OMe
X
X
1a
1b
1c
1d
X = H (LUMO 2.93 eV)
X = F
X = Cl
X = CN
X = H
X = F
X = Cl
X = CN
80
88
83
87
O
O
4 (1.5 equiv)
100 °C
Me
N
NH
Me
OMe
Y
Y
2a
2b
Y = OMe
Y = NMe2
Y = OMe
Y = NMe2
81
86
Me
H
N
O
O
N
Me
Me
4 (1.5 equiv)
OMe
3
4
92
91
r.t.
Me
N
H
N
O
O
OMe
4 (1.5 equiv)
r.t.
O
O
4 (1.5 equiv)
r.t.
Me
5
6
7
81
83
94
N
NH
Me
OMe
N
O
N
O
O
O
4 (1.5 equiv)
100 °C
N
NH
Me
MeO
Me
O
O
4 (1.5 equiv)
r.t.
Me
N
NH
OMe
Me
OMe
N
Me
NH
4 (1.5 equiv)
r.t.
Me
8
9
76
77
O
O
LUMO (3.89 eV)
O
O
Me
4 (1.5 equiv)
100 °C
N
OMe
NH
Me
LUMO (4.09 eV)
Synlett 2008, No. 14, 2132–2136 © Thieme Stuttgart · New York

2134
S. P. Y. Cutulic et al.
LETTER
Table 1 Cleavage of Weinreb Amides by Donor 4 in DMF Solution (continued)
Entry
10
Reagent
Reaction conditions
Product
Yield (%)
67
OMe
N
Me
NH
4 (1.5 equiv)
100 °C
Me
O
O
LUMO (4.05 eV)
LUMO (4.15 eV)
O
O
Me
4 (1.5 equiv)
100 °C
N
11
12
60
43
NH
Me
OMe
O
O
Me
4 (5 equiv)
100 °C
N
OMe
NH
Me
LUMO (5.27 eV)
The reductive cleavage of the N–O bonds of Weinreb
amides was successfully applied to a large range of sub-
strates. Furthermore, according to the substitution pattern,
tuning of the reaction conditions allowed complete reduc-
tive cleavage to be achieved. In the case of monoaromatic
system (Table 1, entries 1a–d), with or without an elec-
tron-withdrawing group in the para position, smooth N–
O bond cleavage was achieved at room temperature using
as little as 1.5 equivalents of electron donor 4. Reduced
product was isolated from the reaction mixture in very
high yields (80–88%) after aqueous workup and chroma-
tography. Nevertheless, when the same reaction condi-
tions were applied to electron-rich aromatic Weinreb
amides (Table 1, entries 2a and 2b), little conversion was
observed. Increasing the numbers of equivalents of elec-
tron donor 4 seemed to have little effect on conversion at
room temperature. However, increasing the temperature
from room temperature to 100 °C brought the reaction to
completion allowing isolation of the reduced amides in
very high yields (81–86%). Smooth reductive N–O bond
cleavages were also achieved for polycyclic aromatic
Weinreb amides at room temperature using 1.5 equiva-
lents of electron donor 4. Naphthalene- and anthracene-
derived Weinreb amides were successfully reduced to
their corresponding amides in excellent yields (Table 1,
entries 3 and 4). The reaction was also applied to heteroar-
omatic substrates. Reductive N–O bond cleavage oc-
curred at room temperature for the pyridine derivative
(entry 5), whereas, heating the reaction mixture at 100 °C
proved necessary to ensure complete conversion in the
case of the electron-rich furan derivative (Table 1, entry
6). When the carbonyl functional group was conjugated
with an alkene double bond, smooth reductive cleavage of
N–O bond was also possible and allowed isolation of the
corresponding reduced amide in excellent yield (Table 1,
entry 7). This methodology appears to be very specific,
with no reduction of the alkene double bond being ob-
served.
•
O–
O
O
SET
Me
Me
Me
–
R
N
R
N
R
N
•
OMe
OMe
OMe
5
6
7
•
MeO–
O–
O
O
SET
Me
Me
Me
R
N
H
R
N
R
N
10
9
8
Scheme 4
not conjugated to any p-system. Smooth reductive cleav-
age of the N–O bond was observed for the benzyl sub-
strate (Table 1, entry 8) at room temperature using as little
as 1.5 equivalents of electron donor 4 to afford its reduced
counterpart in high yield (76%). However, increasing the
length of the carbon chain made the reaction more diffi-
cult. For example, the reductive cleavage of N–O bonds of
Weinreb amides in entries 9–11 had to be performed at
high temperature to afford their reduced counterparts in
good yields, ranging from 60% to 77%. The reaction was
also successfully applied to an alkyl substrate (Table 1,
entry 12). However, in this case, 5 equivalents of 4 at
100 °C proved necessary to achieve the reductive N–O
bond cleavage to afford its reduced counterpart in modest
yield (43%).
With these results in mind, the general mechanism is pro-
posed in Scheme 3 for the reduction of Weinreb amides.
In the simplest scenario, single-electron transfer (SET)
from the neutral ground-state electron donor 4 to the
LUMO of the Weinreb amide p-system of the molecule 5
would occur. The LUMO of the Weinreb amide group is
principally p* in character, and the electron then requires
to be transferred to the s* the N–O bond giving rise to
cleavage of that bond. The result is an enolyl radical 8 that
can subsequently receive another electron from 4 by SET.
The arising enolate 9 abstracts a proton from the reaction
medium (see related paper in this issue) and subsequently
The reaction was also successfully applied to a range of
substrates where the Weinreb amide functional group is
Synlett 2008, No. 14, 2132–2136 © Thieme Stuttgart · New York

LETTER
Reductive Cleavage of Weinreb Amides by an Organic Super-Electron Donor
2135
N
N
Me2N
NMe2
4
O
N
Me
MeO
Table 1, entry 9
Figure 2 Proposed p-stacking interaction between donor 4 and
arene ring on substrate
Figure 1 LUMO for Weinreb amides (Table 1, entries 9 and 11)
Weinreb amide through a p-stacking interaction, an ad-
vantage that should become less apparent as the distance
between the amide and the aryl ring increased. Interest-
ingly, subtle mechanistic points of this type would not be
apparent if the reduction had been conducted by a more
powerful and less selective reducing agent.
rearranges to give, after workup and purification, reduced
compound 10 (Scheme 4).
The more electron-rich the carbonyl group, the more dif-
ficult the N–O bond reductive cleavage. Thus, the initial
electron transfer is the crucial step of this reaction. If the
first electron transfer from 4 to the Weinreb amide sub-
strate 5 is quite easy, then the reaction can be performed
easily using mild conditions. Otherwise, when the carbo-
nyl group is conjugated with an electron-rich group or not
conjugated, then the initial SET may be more difficult.
In conclusion, electron donor 4 carries out the reductive
cleavage of N-O bonds in Weinreb amides, and the reac-
tion was successfully applied to a large array of substrates.
The reactivity of these amides is intimately dependent on
their structure.
The most interesting facet, however, relates to the com-
parison between entries for the homologous amides in en-
tries 1a and 8–12 in Table 1. Inspection of the LUMO
Reduction of 4-Chloro-N-methoxy-N-methylbenzamide (Table
orbitals for these cases shows that the LUMO is associat- 1, entry 1c); Typical Procedure
In a centrifuge tube under argon at room temperature, precursor salt
ed with the arene ring (Figure 1). When this is conjugated
with the Weinreb amide, then the energy of the LUMO is
lowest (2.93 eV, see entry 1a, Table 1) among this series,
and cleavage occurs most easily. Inserting one methylene
group between the arene and the carbonyl (entry 8) in-
creases the LUMO to 3.89 eV, but the LUMO still spans
the Weinreb amide group to some extent as well as the
arene. Inserting two, three, and four methylenes between
the arene and the carbonyl group raises the LUMO to 4.09
eV, 4.05 eV, and 4.15 eV, respectively. In all of these cas-
es, the LUMO is associated with the arene p-system, but
not with the Weinreb amide group. Moving onto entry 12,
which features no arene, then the LUMO energy moves to
5.27 eV. The LUMO energy qualitatively correlates with
the ease of cleavage of the N–O bond. Thus it may be that,
where an aryl ring is present in a substrate, initial transient
electron transfer occurs to the arene, and this is passed on
intramolecularly to the Weinreb amide group. When an
aryl ring is not present, the electron transfer is more diffi-
cult, and the reaction requires more forcing conditions, is
less efficient, and affords a lower yield (entry 12). This is
therefore an interesting example of a neighbouring-group
electron-transfer effect, reminiscent of the amazing work-
ings of ribonucleotide reductases10 and certain peptides.11
3 (0.810 g, 1.5 mmol, 1.5 equiv) and NaH (0.6 g, 15 mmol, 15
equiv) were washed with anhydrous hexane (3×). Excess of hexane
was removed by a flow of argon. Anhydrous DMF (15 mL) was
then added to the resulting fine white powder and the mixture was
then stirred at r.t. under argon for 3 h. The resulting dark purple sus-
pension was then centrifuged and the upper liquid phase was trans-
ferred to 4-chloro-N-methoxy-N-methylbenzamide (0.199 g, 1
mmol, 1 equiv) via a cannula. The mixture was then stirred at r.t. un-
der argon overnight, after which it was then diluted with EtOAc
(100 mL) and washed with water (100 mL). The aqueous phase was
further extracted with EtOAc (2 × 50 mL). Combined organic phas-
es were then further washed with water (2 × 50 mL) and brine (50
mL). The resulting organic extract was finally dried over Na2SO4,
filtered and concentrated under reduced pressure. The residue was
then adsorbed onto silica and purified by flash chromatography
(CH2Cl2–EtOAc 95:5) to afford 4-chloro-N-methylbenzamide as a
fine white powder (0.141 g, 83%); mp 158-160 °C; IR (film): 3340,
3076, 2957, 1637, 1603, 1571, 1553, 1490, 1406, 1327, 1301, 1275,
1165, 1093 cm–1; 1H NMR (CDCl3, 400 MHz): d = 3.02 (d, J = 4.9
Hz, 3 H, CH3), 6.15 (br s, 1 H, NH), 7.39–4.43 (m, 2 H, Ar-H),
7.69–7.72 (m, 2 H, Ar-H); 13C NMR (CDCl3, 100 MHz): d = 26.9
(CH3), 128.3 (CH), 128.8 (CH), 133.0 (C), 137.6 (C), 167.2 (C); MS
(CI+): m/z (%) = 187 [M + NH4]+ (13), 172, [M + H]+ (28), 170 [M + H]+
(100), 136 (29), 93 (18); MS: m/z [M + H]+ calcd for C8H9ClNO
(35Cl): 170.0368; found: 170.0368.
Acknowledgment
An alternative rationalisation of the varying ease of reduc-
tion might arise from p-stacking of the donor 4 with the
arene group of a Weinreb amide (Figure 2). If electron
transfer to the arene were discounted, then the role of the
arene could be to retain the electron donor close to the
We thank Syngenta, Jealott’s Hill, and WestCHEM for funding. We
also thank ESPRC Mass Spectrometry Service Centre, Swansea for
High Resolution Mass Spectra.
Synlett 2008, No. 14, 2132–2136 © Thieme Stuttgart · New York

2136
S. P. Y. Cutulic et al.
LETTER
(4) Keck, G. E.; Wager, T. T.; McHardy, S. F. Tetrahedron
References
1999, 55, 11755.
(1) (a) Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun.
1982, 12, 989. (b) Nahm, S.; Weinreb, S. M. Tetrahedron
Lett. 1981, 22, 3815. (c) Aidhen, I. S.; Ahuja, J.
(5) (a) Yus, M.; Radivoy, G.; Alonso, F. Synthesis 2001, 914.
(b) Taillier, C.; Bellosta, V.; Meyer, C.; Cossy, J. Org. Lett.
2004, 6, 2145.
(6) Murphy, J. A.; Khan, T. A.; Zhou, S.; Thomson, D. W.;
Mahesh, M. Angew. Chem. Int. Ed. 2005, 44, 1356.
(7) Murphy, J. A.; Zhou, S.; Thomson, D. W.; Schoenebeck, F.;
Mahesh, M.; Park, S. R.; Tuttle, T.; Berlouis, L. E. A.
Angew. Chem. Int. Ed. 2007, 46, 5178.
(8) Schoenebeck, F.; Murphy, J. A.; Zhou, S.; Uenoyama, Y.;
Miclo, Y.; Tuttle, T. J. Am. Chem. Soc. 2007, 129, 13368.
(9) Murphy, J. A.; Garnier, J.; Park, S. R.; Schoenebeck, F.;
Zhou, S.-Z.; Turner, A. T. Org. Lett. 2008, 10, 1227.
(10) Stubbe, J.; Nocera, D. G.; Yee, C. S.; Chang, M. C. Y. Chem.
Rev. 2003, 103, 2167.
Tetrahedron Lett. 1992, 33, 5431. (d) Evans, D. A.; Kaldor,
S. W.; Jones, T. K.; Stout, T. J. J. Am. Chem. Soc. 1990, 112,
7001. (e) Selvamurugan, V.; Aidhen, I. S. Tetrahedron
2001, 57, 6065. (f) Mislin, G. A.; Burger, A.; Abdallah, M.
A. Tetrahedron 2004, 60, 12139. (g) Murphy, J. A.;
Commeureuc, A. G. J.; Snaddon, T. N.; McGuire, T. M.;
Khan, T. A.; Hisler, K.; Dewis, M. L.; Carling, R. Org. Lett.
2005, 7, 1427. (h) Kangani, C. O.; Kelley, D. E.; Day, B. W.
Tetrahedron Lett. 2006, 47, 6289. (i) Hisler, K.; Tripoli, R.;
Murphy, J. A. Tetrahedron Lett. 2006, 47, 6293.
(2) Mattingly, P. G.; Miller, M. J. J. Org. Chem. 1980, 45, 410.
(3) Ritter, A. R.; Miller, M. J. J. Org. Chem. 1994, 59, 4602.
(11) Giese, B. Bioorg. Med. Chem. 2006, 14, 6139.
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