Exploring a benzyloxyaniline linker utilizing ceric ammonium nitrate (CAN) as a cleavage reagent: Solid-phase synthesis of N-unsubstituted β-lactams and secondary amides

Article abstract of DOI:10.1021/ol006766l

(equation presented) A novel benzyloxyaniline linker that uses ceric ammonium nitrate (CAN) as a cleavage reagent is described. Its application in the solid-phase synthesis of N-unsubstituted β-lactams and secondary amides furnishes compounds in moderate to excellent yield (45-91%) and high purity (93-99%).

Full text of DOI:10.1021/ol006766l

ORGANIC
LETTERS
2001
Vol. 3, No. 1
53-56
Exploring a Benzyloxyaniline Linker
Utilizing Ceric Ammonium Nitrate (CAN)
as a Cleavage Reagent: Solid-Phase
Synthesis of N-Unsubstituted â-Lactams
and Secondary Amides
Kirsteen H. Gordon and Shankar Balasubramanian*
UniVersity Chemical Laboratory, UniVersity of Cambridge, Cambridge CB2 1EW, U.K.
sb10031@cam.ac.uk
Received October 23, 2000
ABSTRACT
A novel benzyloxyaniline linker that uses ceric ammonium nitrate (CAN) as a cleavage reagent is described. Its application in the solid-phase
synthesis of N-unsubstituted â-lactams and secondary amides furnishes compounds in moderate to excellent yield (45−91%) and high purity
(93−99%).
There are a number of amide releasing linkers1 that have
been described that possess an amino group for incorporation
as -NHCO- into their products. Such linkers include Rink,2
Sieber amide,3 PAL,4 SASRIN,5 BAL,6 and MAMP.7 These
linkers rely on acid-induced SN1 cleavage mechanisms and
incorporate extended aromatic systems to stabilize the
resulting cations. A drawback of such systems is that their
amino groups are sterically hindered by methoxy groups
included in their aromatic systems. For example, the acylation
of Rink amide secondary amines with amino acids possessing
bulky side chains was reported to occur in only modest yields
(∼60%).8
is cleaved using ceric ammonium nitrate (Ce(NO3)6(NH4)2,
CAN). The linker has been designed for the release of
secondary amides and, in particular, â-lactams but will have
broader application. Monocyclic â-lactams such as the
nocardicins9 and monobactams10 are of interest as they have
been found to exhibit antibiotic properties. These compounds
can be synthesized by various routes, though the preparation
of a N-unsubstituted â-lactam is a common feature.8 In
solution-phase syntheses CAN has been utilized to remove
the p-methoxyphenyl group from the amide nitrogen of
â-lactams to generate their N-unsubstituted analogues.11,12
This reaction involves oxidation of the aromatic ring to
benzoquinone with the release of 1 mole equiv of MeOH
Herein we report a new amine linker of this category that
(1) Guillier, F.; Orain, D.; Bradley, M. Chem. ReV. 2000, 100, 2091-
2157.
(8) Chan, W. C.; White, P. D.; Beythien, J.; Steinauer, R. Chem.
Commun. 1995, 589-592.
(2) Rink, H. Tetrahedron Lett. 1987, 28, 3787-3790.
(3) Sieber, P. Tetrahedron Lett. 1987, 28, 2107-2110.
(4) Albericio, F.; Kneibcordonier, N.; Biancalana, S.; Gera, L.; Masada,
R. I.; Hudson, D.; Barany, G. J. Org. Chem. 1990, 55, 3730-3743.
(5) Mergler, M.; Nyfeler, R.; Tanner, R.; Gosteli, J.; Grogg, P.
Tetrahedron Lett. 1988, 29, 4009-4012.
(6) Jensen, K. J.; Alsina, J.; Songster, M. F.; Vagner, J.; Albericio, F.;
Barany, G. J. Am. Chem. Soc. 1998, 120, 5441-5452
(7) Brown, D. S.; Revill, J. M.; Shute, R. E. Tetrahedron Lett. 1998, 39,
8533-8536.
(9) Kamiya, T.; Aoki, H.; Mine, Y. In Chemistry and Biology of â-Lactam
Antibiotics; Morin, R. B., Gorman, M., Eds.; Academic Press: New York,
1982; Vol. 2, pp 166-224.
(10) Koster, W. H.; Cimarusti, C. M.; Sykes, R. B. In Chemistry and
Biology of â-Lactam Antibiotics; Morin, R. B., Gorman, M., Eds.; Academic
Press: New York, 1982; Vol. 3, pp 339-374.
(11) Fukuyama, T.; Frank, R. K.; Jewell, C. F. J. Am. Chem. Soc. 1980,
102, 2122-2123
(12) Kronenthal, D. R.; Han, C. Y.; Taylor, M. K. J. Org. Chem. 1982,
47, 2765-2768
10.1021/ol006766l CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/13/2000

and 1 mole equiv of product amide. Deprotection is typically
carried out in aqueous MeCN and is neither strongly acidic
or basic. The reaction is generally rapid, requiring only a
few minutes at room temperature, and exhibits high selectiv-
ity.10
Scheme 2. Solution-Phase Study of the CAN Cleavage
Reaction on the p-Benzyloxyphenyl Groupa
Exploitation of CAN in a solid-phase cleavage strategy
offers mild, rapid, and selective cleavage conditions. The
linker is based on resin bound aniline and is free from steric
hindrance and easy to prepare (Figure 1). The benzyloxy-
a (i) t-Hexenal (1 equiv), 4 Å molecular sieves, DCM, rt, 1 h;
(ii) Et3N (5 equiv), phenoxyacetyl chloride (2 equiv), DCM, 0 °C
to room temperature, 18 h, 67% for two steps; (iii) CAN (3 equiv),
MeCN/H2O (2:1), 0 °C to room temperature, 1 h, 59%.
ketene, selected to exclusively furnish cis â-lactam, to afford
4 (67%, Scheme 2).13 Lactam 4 was then reacted with CAN
(3 equiv) in aqueous MeCN at ambient temperature for 0.5
h. A TLC of the crude reaction mixture indicated the
presence of benzoquinone, which is a useful indicator for
the reaction and can be easily removed by extraction into
20% aqueous Na2SO3. Subsequent removal of the final traces
Figure 1. Linker construct that enables CAN cleavage.
1
of CAN (detected by H NMR spectroscopy) by filtration
aniline linker is also acid stable which contrasts with the
CAN or TFA cleavable benzyloxybenzylamine (BOBA)
linker.23
through a short plug of silica then furnished product 5 in
59% yield and greater than 95% purity (as judged by H
NMR spectroscopy).
1
The linker was synthesized in three high yielding steps
(Scheme 1) from p-aminophenol, which was first Boc-
Having demonstrated the ability of CAN to cleave the
p-benzyloxyphenyl group, the solid-phase synthesis of â-lac-
tams was examined. Although a number of papers have
described the solid-phase synthesis of these pharmacologi-
cally renowned compounds,14-17 only one has offered a route
to N-unsubstituted derivatives18 via the R-methyl-6-nitro-
veratrylamine photolabile linker.19 Resin 3 was therefore
condensed with an excess of trans-hexenal in DCM with 4
Å molecular sieves for 0.5 h and was washed with anhydrous
DCM. A second condensation step was utilized to ensure
complete imine formation for the subsequent cycloaddition
with ketene, formed in situ from phenoxyacetyl chloride and
Et3N. Successful conversion to the â-lactam was confirmed
by FTIR spectroscopy (υ cm-1 1753) and 13C gel-phase
NMR spectroscopy.
Scheme 1. Synthesis of p-Benzyloxyaniline Resina
a (i) Et3N (1 equiv), Boc2O (1 equiv), DMF, 12 h, 0 °C to room
temperature, 99%; (ii) NaH (3 equiv), 1 (3 equiv), DMF, 0 °C, 1
h then add to Br TentaGel resin (1 equiv), DMF, rt, 12 h, 97%;
(iii) 10% TFA/DCM, rt, 12 h then filter and wash with Et3N/DCM.
The cleavage conditions were next examined by treatment
of the resin bound â-lactam with either 5 or 10 equiv of
CAN for 0.5, 2, or 5 h at ambient temperature. The resins
were filtered and washed with several portions of DCM and
H2O, and the filtrates were extracted with DCM. The
combined organics were then washed with saturated
NaHCO3, 20% aqueous Na2SO3, and brine. FTIR spectros-
copy of all of the cleaved resins indicated quantitative release
(disappearance of the â-lactam carbonyl at 1753 cm-1), and
protected on the aniline nitrogen and then O-alkylated with
bromomethyl TentaGel resin (Novabiochem, 0.28 mmol/g).
A TentaGel resin was selected for this initial work for its
compatibility with the aqueous conditions required for CAN
cleavage. Boc deprotection and neutralization gave the free
amine resin 3 (97%, loading 0.28 mmol/g) as confirmed by
the complete disappearance of the Boc trimethyl peak at 28.5
ppm in the 13C gel-phase NMR spectrum.
To test whether CAN could cleanly remove the benzyl-
oxyphenyl group, a solution-phase model synthesis was
examined. Benzyloxyaniline, a resin mimic, was condensed
with trans-hexenal in DCM with 4 Å molecular sieves. trans-
Hexenal, an aldehyde with aliphatic carbons, was chosen to
facilitate reaction monitoring by 13C gel-phase NMR spec-
troscopy in the corresponding solid-phase reaction. The
resultant imine underwent cycloaddition with phenoxyacetyl
(13) Staudinger, H. Liebigs Ann. Chem. 1907, 51, 356.
(14) Singh, R.; Nuss, J. M. Tetrahedron Lett. 1999, 40, 1249-1252
(15) Schunk, S.; Enders, D. Org. Lett. 2000, 2, 907-910
(16) Pei, Y.; Houghten, R. A.; Kiely, J. S. Tetrahedron Lett. 1997, 38,
3349-3352.
(17) Gordon, K.; Bolger, M.; Khan, N.; Balasubramanian, S. Tetrahedron
Lett. 2000, in press.
(18) Ruhland, B.; Bhandari, A.; Gordon, E. M.; Gallop, M. A. J. Am.
Chem. Soc. 1996, 118, 253-254
54
Org. Lett., Vol. 3, No. 1, 2001

HPLC analysis of the resulting crude product 7a revealed 5
equiv of CAN for 0.5 h to be effective cleavage conditions.
When underivatized resin 3 was reacted with CAN (5 equiv)
in aqueous MeCN for 0.5 h, benzoquinone was detected in
the resin solvent, and a 13C gel-phase NMR spectrum
confirmed the formation of an alcohol resin
as described earlier. Following filtration through a short plug
of silica to remove the final traces of CAN, HPLC analysis
of the crude products showed high levels of purity (Table
1). The yields obtained were also good to excellent (45-
88%), with the lower yields deriving from the sterically
hindered aldehydes o-bromobenzaldehyde and trimethyl-
acetaldehyde. Their purity was not compromised, suggesting
that the reduction in yield was most likely due to either
incomplete imine formation or cycloaddition. This would
result in reversion to aniline resin 3 during washing and
release of MeOH, NH3 and benzoquinone during CAN
cleavage.
Having studied the conditions for â-lactam synthesis and
cleavage, an array of â-lactams was synthesized using six
aldehydes of varying stereoelectronic and steric character
(Table 1). The mechanism of the Staudinger reaction involves
The mechanism of CAN deprotection of the p-methoxy-
phenyl group from amides has not been studied. Experiments
on the oxidation of 1,4-dimethoxybenzenes and 1,4,5,8-
tetramethoxynaphthalenes to their quinones have, however,
shown that it is the aryl-oxygen bonds that are cleaved21 and
that 2 equiv of CAN are required.22 The proposed mechanism
thus involves two single electron oxidations of the electron
rich aromatic ring.22
Table 1. CAN Cleavage of â-Lactams
According to this mechanism cleavage of amide product
from the benzyloxyaniline linker is accompanied by the
release of 1 mole equiv of MeOH and benzoquinone, which
are easily removed under vacuum and by extraction into
Na2SO3, respectively. The amide product can therefore be
obtained pure, without need for chromatography.
In â-lactams, the amide bond is less electron-withdrawing
than in acyclic systems as a result of a decrease in
delocalization of the nitrogen lone pair. To explore whether
this effect is significant for CAN cleavage of the p-
benzyloxyphenyl group, the synthesis and release of an
acyclic secondary amide was investigated. Resin 3 was
reacted with p-nitrobenzaldehyde to furnish the correspond-
ing imine, which was reduced with NaBH4 to 8a (R1 )
p-nitrophenyl, Scheme 3). Subsequent acylation then fur-
7
R1
% puritya
% yieldb
a
b
c
d
e
f
CH3(CH2)2CHdCH-
4-nitrophenyl-
3-chlorophenyl-
2-bromophenyl-
(CH3)3C-
98
93
98
99
96
97
83
88
62
56
45
85
4-methoxyphenyl
a Determined by HPLC with UV detection at 220 nm. b Calculated from
the loading of resin 3.
initial nucleophilic attack of the imine nitrogen on the ketene
carbonyl to form a zwitterionic intermediate, which cyclizes
to form exclusively cis â-lactam, providing amines and acid
chlorides are chosen such that they do not stabilize the
zwitterionic charges.20 The stereoelectronic nature of the
aldehyde affects the nucleophilicity of the imine, with
electron-donating and electron-withdrawing groups favoring
and hindering reaction, respectively. In the second ring
closure step, however, this trend is reversed and electron-
withdrawing substituents are expected to enhance product
formation. p-Anisaldehyde and p-nitrobenzaldehyde were
therefore utilized to probe the sensitivity of the reaction to
electronic character, while m-chlorobenzaldehyde was in-
cluded as a “neutral” aldehyde being neither activated nor
deactivated. o-Bromobenzaldehyde and trimethylacetalde-
hyde were also examined in the array to test for any steric
effects in the reaction. Imine formation, for example, would
be expected to be more difficult with sterically hindered
carbonyl groups as would ring closure, which requires
reaction at the aldehyde carbonyl carbon.
Scheme 3. Synthesis and Release of Acyclic Secondary
Amides Using CAN as a Cleaving Agenta
a (i) R1CHO (10 equiv), 4 Å molecular sieves, DCM, rt, 0.5 h,
filter and wash with anhydrous DCM, repeat; (ii) NaBH4 (5 equiv),
MeOH/THF (1:1), rt, 10 h; (iii) DMAP (cat.), Et3N (5 equiv),
R2COCl (5 equiv), DCM, rt, 10 h; (iv) CAN (5 equiv), MeCN/
H2O (2:1), rt, 0.5 h.
13C gel-phase NMR and FTIR spectra of resins 6a-f were
obtained and indicated efficient transformations. Each of the
resins was cleaved with 5 equiv of CAN for 0.5 h at room
temperature, and the resin filtrates were extracted and washed
(19) Holmes, C. P.; Jones, D. G. J. Org. Chem. 1995, 60, 2318-2319
(20) Hegedus, L. S.; Montgomery, J.; Narukawa, Y.; Snustad, D. C. J.
Am. Chem. Soc. 1991, 113, 5784-5791
nished the acyclic amide 9a (R1 ) p-nitrophenyl, R2 ) CH-
(CH3)2), which was characterized by 13C gel-phase NMR and
Org. Lett., Vol. 3, No. 1, 2001
55

Utilization of p-anisaldehyde produced a complex mixture
of products, presumably as a result of the opportunity for
competitive p-methoxybenzyl cleavage. This result also
contrasts with that obtained for the p-anisaldehyde derived
â-lactam 7f and may be due to the fact that this would have
required cleavage of the â-lactam ring. p-Tolualdehyde was
investigated to test the applicability of the cleavage conditions
in the presence of a non-alkoxy-activated aromatic ring and
yielded product in high yield (91%) and purity (93%).
Table 2. CAN Cleavage of Secondary Amides
10
R1
R2
% puritya (% yield)b
a
b
c
d
e
4-NO2 phenyl-
4-Me phenyl-
2-Br phenyl-
(CH3)3C-
CH(CH3)2
CH(CH3)2
CH(CH3)2
Ph
96 (83)
93 (91)
94 (64)
95 (70)
c
4-MeO phenyl-
CH(CH3)2
a Determined by HPLC with UV detection at 220 nm. b Calculated from
To summarize, a new benzyloxyaniline linker utilizing
CAN as a cleavage reagent has been developed for the
synthesis and release of secondary amides, including â-lac-
tams. The linker can be prepared in three steps in high yield
(96%). Cleavage of the linker with CAN occurs rapidly (<0.5
h) in mild conditions (aqueous MeCN, room temperature)
and compounds of high purity (typically >90%) are obtained
after a simple extraction and filtration protocol. Application
of this strategy for the release of secondary amines is
currently under investigation.
the loading of resin 3. c Complex mixture of products produced.
FTIR spectroscopy. Exposure of resin 9a to the cleavage
conditions (5 equiv CAN, 0.5 h, room temperature) resulted
in 83% product in high purity (96%).
Four more aldehydes were examined, with trimethyl-
acetaldehyde and o-bromobenzaldehyde again being selected
to examine the steric influences in the system. In this scheme
the nature of the substituent at the imine carbon, deriving
from the aldehyde, was found to have less effect on the
efficiency of the reaction than in â-lactam synthesis as
products were generally obtained in higher yields (64-91%)
and purity (93-96%, Table 2). This suggests that it is the
cyclization step of â-lactam formation (rather than imine
formation) that is sensitive to steric encumbrance.
Acknowledgment. We thank the EPSRC (grant GRMO
4402). K.H.G. is a SCI Messel Scholar
Supporting Information Available: Experimental pro-
cedures and characterization data for 2, 3, 6a-f, 7a-f, 8a-
1
e, 9a-e and 10a-d. 13C NMR and H NMR spectra of 6a
(21) Jacob, P.; Callery, P. S.; Shulgin, A. T.; Castagnoli, N. J. Org. Chem.
1976, 41, 3627-3629.
(22) Tanoue, Y.; Terada, A. Bull. Chem. Soc. Jpn. 1988, 61, 2039-
2045.
and 7a, respectively. This material is available free of charge
via the Internet at http://pubs.acs.org.
(23) Aoki, Y.; Kobayashi, S. J. Comb. Chem. 1999, 1, 371-372.
OL006766L
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Org. Lett., Vol. 3, No. 1, 2001