Low-temperature deacylation of N-monosubstituted amides

Article abstract of DOI:10.1021/ol048852h

(Chemical Equation Presented) The (PhO)₃P-Cl₂ reagent, prepared in situ by titrating a solution of triphenyl phosphite with chlorine, is used to convert N-monosubstituted amides into their corresponding amines. The reaction, if compared to other traditional methods, shows the advantage of very mild conditions and low temperature (-30°C→rt).

Full text of DOI:10.1021/ol048852h

ORGANIC
LETTERS
2
004
Vol. 6, No. 22
885-3888
Low-Temperature Deacylation of
N-Monosubstituted Amides
3
†
‡
,†
Alberto Spaggiari, Larry C. Blaszczak, and Fabio Prati*
Dipartimento di Chimica, UniVersit a` di Modena e Reggio Emilia,
Via Campi 183-41100 Modena, Italy, and DiscoVery Chemistry Research and
Technologies, Eli Lilly and Company, Lilly Corporate Center,
Indianapolis, Indiana 46285
prati.fabio@unimore.it
Received June 17, 2004
ABSTRACT
The (PhO)
amides into their corresponding amines. The reaction, if compared to other traditional methods, shows the advantage of very mild conditions
and low temperature ( 30 rt).
3 2
P‚Cl reagent, prepared in situ by titrating a solution of triphenyl phosphite with chlorine, is used to convert N-monosubstituted
−
°Cf
Functional group interconversion is one of the most important
processes in organic synthesis. Transformation of amides into
their corresponding amines is a crucial example among such
interconversions due to the widespread use of amides as
amine protecting groups. The most common methods de-
scribed in the literature often involve harsh conditions such
as acid or base exposure at high temperature, involve
The first investigations into the chemistry of triphenyl
phosphite chlorine complex described its use for conversion
of simple alcohols to the corresponding alkyl chlorides. A
4
more complete study to better understand the nature of this
reaction focused specifically on applications in the field of
5
â-lactam antibiotics. In fact, when a solution of (PhO)
3
P in
dichloromethane is titrated with chlorine gas at -30 °C, a
distinctly new reagent is formed. The complex is stable
enough at this temperature to allow convenient and general
application in organic synthesis. However, despite several
efforts aiming to clarify the nature of these dihalotriphen-
1
multistep procedures, or deal with cumbersome reagent
2
,3
combinations. Hence, the need for milder, more selective
methods is clearly evident, especially when the substrates
are highly functionalized molecules that do not tolerate high
temperatures or harsh reagents. Here we describe a conve-
nient and general method for deacylation of N-monosubsti-
tuted amides under extremely mild conditions by means of
6
oxyphosphoranes, the exact nature of such compounds
7
remains, at present, uncertain. As part of our ongoing
(
4) (a) Coe, D. G.; Landauer, S. R.; Rydon, H. N. J. Chem. Soc. 1954,
281. (b) Rydon, H. N.; Tonge, B. L. J. Chem. Soc. 1956, 3043.
5) Hatfield, L. D.; Blaszczak, L. C.; Fisher, J. W. U.S. Patent 4,230,644,
2
triphenyl phosphite-chlorine complex (TPP‚Cl ).
2
(
†
Universit a` di Modena e Reggio Emilia.
Eli Lilly and Company.
1980. Hatfield, L. D.; Blaszczak, L. C.; Fisher, J. W. U.S. Patent 4,226,986,
1980.
‡
(
1) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J. Org. Chem. 1983, 48,
424.
2) Applegate, H. E.; Cimarusti, C. M.; Slusarchyk, W. A. Chem.
Commun. 1980, 7, 293.
3) (a) Hamilton, D. J.; Price, M. J. Chem. Commun. 1969, 8, 414. (b)
Sihlbom, L. Acta Chem. Scand. 1954, 8, 529.
(6) (a) Noack, E. Ann. 1883, 218, 85. (b) Ansch u¨ tz, R.; Emery, W. O.
Ann. 1887, 239, 312. (c) Ansch u¨ tz, R.; Emery, W. O. Ann. 1889, 253, 112.
(d) Foroman, J. P.; Lipkin, D. J. Am. Chem. Soc. 1953, 75, 3145. (e) Rydon,
H. N.; Tonge, B. L. J. Chem. Soc. 1956, 3043. (f) Tseng, C. K. J. Org.
Chem. 1979, 44, 2793. (g) Michalski, J.; Pakulski, M.; Skowronska, A. J.
Org. Chem. 1980, 45, 3122.
2
(
(
1
0.1021/ol048852h CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/06/2004

Scheme 1. Deacylation of a Cephalosporin V Derivative
research on the synthesis of new dual-action cephalosporins
as â-lactamase inhibitors, we applied the new reagent to a
phenoxyacetamido cephalosporin (cephalosporin V) deriva-
tive as shown in Scheme 1.
Figure 1. Examples of amides cleaved to their corresponding
amines by means of TPP‚Cl reagent.
5
A similar method using PCl as the oxophilic phosphorus
2
reagent has found application in medicinal chemistry, mainly
to remove the amide side chain in cephalosporins. However,
and THF are the preferred solvents. To this clear and almost
colorless solution is then added the substrate followed by
dropwise addition of an appropriate base (usually anhydrous
triethylamine or pyridine). The tertiary amine is used to
the hygroscopic PCl
side products are formed in the dark reaction mixture. Using
the TPP‚Cl instead, we performed the same reaction on a
5
is more cumbersome in practice and
8
2
cephalosporin V derivative, obtaining, in a one-pot synthesis,
the 7-amino derivative (as an easily filterable hydrochloride)
in 91% yield.
7
stabilize the kinetic intermediate; adventitious HCl acceler-
ates conversion to the thermodynamic form. The reaction is
left to stir at this temperature for 2 h. After the cold bath is
removed, a large excess of alcohol is added (usually
methanol, ethylene glycol, or isobutyl alcohol) to convert
the iminochloride intermediate into the corresponding imi-
noester derivative, which, in turn, undergoes hydrolytic
cleavage when treated with a mixture alcohol/water. In the
cases where the newly formed amine gave a sufficiently
insoluble hydrochloride, that product precipitates after the
first excess of alcohol was added. In the case of 1, in fact,
a conspicuous precipitation occurred after about 1 h from
the addition of isobutanol. In many other cases, however,
when the amine hydrochloride did not precipitate spontane-
ously, an extraction step was required. The final product was
Encouraged by the ease and convenience of this method,
which chemoselectively cleaves the amide side chain of the
sensitive cephalosporin without affecting the disubstituted
amide of the â-lactam ring, we sought to explore the
application of such a reaction as a general method for the
deacylation of N-monosubstituted amides. To assess the
generality of this deacylation method, we explored the same
reaction on a wide set of N-monosubstituted amides. By
varying either the acyl moieties (2-8) or the amine residue
(9-15), we explored aromatic, aliphatic, and aryl-aliphatic
amides, as well as a urethane (7) and an amino acid (15), as
reported in Figure 1.
A general procedure follows. The TPP‚Cl reagent is
2
generated in situ by bubbling chlorine gas into an anhydrous
9
recovered as a free base instead of a hydrochloride salt. In
all cases, however, the final amine was recovered free of all
byproducts (triphenyl phosphate and the residual ester), and
the final amine did not require any further purification. The
results, summarized in Table 1, show that in all the examined
solution of triphenyl phosphite at -30 °C. Dichloromethane
(
7) We found that this kind of (PhO)3P‚Cl2 reagent is substantially
different from that described in the prior art, to which previous literature is
4
31
referred. P NMR spectroscopy experiments were carried out by some
authors to observe the different chemical behavior of phosphorus, as well
as to monitor its change during the course of the reaction.6 Similar
experiments performed in our laboratory showed interesting results. In fact,
when the reagent was prepared by the action of chlorine gas in a solution
of (PhO)3P at -30 °C and the reaction was followed in an NMR tube, we
observed the disappearance of the (PhO)3P signal at 128.1 ppm, while new
signals at 7.4 ppm (intense) and -22.5 ppm (weak) appeared, as, however,
Tseng already reported in his work. These two signals ought to be referred
to as two distinct forms of the reagent; more precisely, the active form
seems to correspond to that resonating at 7.4 ppm (kinetic intermediate),
which, when the temperature is increased, slowly converts to the other form,
corresponding to the peak at -22.5 (thermodynamic product, not active).
The half-life of the kinetic form has been estimated to be about 8 h at
room temperature.
f
(9) Typical Experimental Procedure. In a 50 mL, three-necked, round-
bottom flask was dissolved 1.8 mL (6.7 mmol) of triphenyl phosphite in
15 mL of dry dichloromethane. The system was kept under argon and
magnetic stirring at -30 °C, and chlorine gas was then bubbled via a glass
septum, until the solution became bright yellow. The color was discharged
by adding a few drops of triphenyl phosphite, until the solution turned pale
yellow to almost colorless. The amide 12 (1000 mg, 6.1 mmol), dissolved
in 5 mL of dry dichloromethane, was added, and 960 µL (7.0 mmol) of
dry triethylamine was dropped in. The system was maintained at these
conditions for 2 h, and then the cold bath was removed and 1.6 mL (39.6
mmol) of dry methanol was added. After 5 h, the solvent was removed in
vacuo and replaced by 20 mL of a mixture methanol/water (1/1) and the
reaction was stirred for an additional 12 h period. The phase at the bottom
of the flask (triphenyl phosphate) was removed, and the remaining
homogeneous solution was acidified to pH about 3 by 10% HCl and
extracted with diethyl ether (2 × 20 mL). The aqueous phase was then
basified to about pH 11 with 10% NaOH and finally extracted with diethyl
ether (2 × 20 mL). The organic phases were pooled and dried over MgSO4,
filtered, and evaporated under reduced pressure, affording 652 mg of the
expected amine in 90% yield.
6f
(8) (a) Chauvette, R. R.; Hayes, H. B.; Huff, G. L.; Pennington, P. A. J.
Antibiot. 1972, 25, 248. (b) Lunn, W. H. W.; Burchfield, R. W.; Elzey, T.
K.; Mason, E. V. Tetrahedron Lett. 1974, 14, 1307. (c) Yamanaka, H.;
Chiba, T.; Kawabata, K.; Takasugi, H.; Masugi, T.; Takaya, T. J. Antibiot.
1
985, 38, 1738. (d) Gonz a` lez, M.; Rodr `ı guez, Z.; Tol o` n, B.; Rodr `ı guez, J.
C.; Velez, H.; Vald e´ s, B.; L o` pez, M. A.; Fini, A. Il Farmaco 2003, 58,
09.
4
3886
Org. Lett., Vol. 6, No. 22, 2004

Table 1. Results and Conditions for Deacylation of Amides
into Amines by Means of (PhO) P‚Cl Reagent
Scheme 3. Mild Conditions of Bischler-Napieralski-Type
Cyclization
3
2
amide
conditions*
yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
c
a
91 (as HCl salt)
90
80
70
72
74
87
96
72
76
73
90
81
70
these methyliminoesters proved to be extremely stable in the
reaction conditions and even under prolonged hydrolysis did
not convert into the expected amines.
Interestingly, when the same reaction was performed on
tryptamine acetamide (13), a dual behavior was observed.
In fact, we found that this substrate afforded the expected
amine (deacylation pathway) when sequentially treated with
b
b
b
b
d
d
b
d
d
b
d
d
e
0
1
2
3
2
TPP‚Cl and ethylene glycol (Table 1, compound 13) but
could also follow a different route (cyclization pathway)
when no alcohol was added. In the latter case, a ring was
formed leading to a â-carboline derivative, namely harma-
(
(
-)-14
+)-15
10
lane (Scheme 3, 13a), indicating that a Bischler-Napier-
95 (as HCl salt)
alski-type cyclization occurred on this electron-rich â-aryl-
ethylamine.
*
Solvent, base, alcohol: (a) THF, triethylamine, methanol; (b) CH2Cl2,
triethylamine, methanol; (c) CH2Cl2, pyridine, isobutanol; (d) CH2Cl2,
triethylamine, ethylene glycol; (e) THF, triethylamine, isobutanol.
Since this classically important reaction is usually per-
1
1
formed under severe conditions, needed for the formation
1
2
of the iminochloride as the key intermediate, we think that
a new method to carry out such a cyclization under very
mild conditions could be an attractive tool for synthesis of
heterocycles.
cases the amine was recovered in good to excellent yield,
thus indicating that this method can be usefully applied to
deacylate different kinds of variously substituted amides, as
well as to cleave urethanes (Table 1, compound 7). Impor-
tantly, no racemization occurred in deacylation of either (S)-
These experimental observations allow us to infer a
possible general mechanism for the process as depicted in
Scheme 4.
(
-)-14 or (S)-(+)-15, which afforded the expected amines
in unchanged enantiomeric composition (ee > 98%).
The most significant variable in the reaction conditions is
represented by the alcohol used to convert the iminochloride
into iminoester. We observed that methanol is the alcohol
of choice for general application, whereas isobutanol seems
to give better results when the product is highly insoluble,
as in cephalosporin 1. Ethylene glycol was particularly
efficient in the deacylation of amides 10 and 11 (Scheme
Scheme 4. General Deacylation Mechanism
2). When methanol was applied to these cases, the corre-
Scheme 2. Iminoester Formation
Preliminary results would suggest that bromine can be used
instead of chlorine during the preparation of the key reagent
(
10) Bal o` n, M.; Hidalgo, J.; Guardado, P.; Munoz, M. A.; Carmona, C.
J. Chem. Soc., Perkin Trans. 2 1993, 99.
11) See for some examples: (a) Itoh, N.; Sugasawa, S. Tetrahedron
957, 1, 45. (b) Kanaoka, Y.; Sato, E.; Yonemitsu, O.; Ban, Y. Tetrahedron
Lett. 1964, 35, 2419. (c) Bosch, J.; Domingo, A.; Linares, A. J. Org. Chem.
(
1
1
1
983, 48, 1075. (d) Rao, A. V. R.; Chavan, S. P.; Sivadasan, L. Tetrahedron
986, 42, 5071. (e) Torisawa, Y.; Hashimoto, A.; Nakagawa, M.; Hino, T.
Tetrahedron Lett. 1989, 30, 6549. (f) Sanchez-Sancho, F.; Mann, E.;
Herradon, B. Synlett 2000, 4, 509. For a review on these cyclization methods,
see also: Love, B. E. Org. Prep. Proced. Int. 1996, 28, 1.
sponding iminoesters were recovered in high yield, with no
evidence of the expected amines (Scheme 2). Once formed,
Org. Lett., Vol. 6, No. 22, 2004
3887

with triphenyl phosphite. In this view, in fact, a few tests
performed on selected substrates gave encouraging results,
even if yields appear slightly lower with respect to those
obtained using the original chlorine-based reagent.
Acknowledgment. We thank Eli Lilly and Company for
kindly providing a sample of cephalosporin derivative 1. We
also thank Dr. Maria Cecilia Rossi and Dr. Cinzia Restani
(Centro Interdipartimentale Grandi Strumenti at Universita`
di Modena e Reggio Emilia) for helpful assistance during
2
To summarize, TPP‚Cl chemistry can be successfully
applied to a wide range of amides, affording corresponding
amines in good to excellent yield. This represents an
interesting and new method for deacylating amides under
extremely mild conditions. Further extensions of this chem-
istry are currently under study in our laboratories.
31
P NMR and two-dimensional NMR experiments at 400
MHz Bruker NMR (financially supported by Fondazione
Cassa di Risparmio) and Prof. Franco Ghelfi (Universit a` di
Modena e Reggio Emilia) for providing chlorine delivery
plant. We also thank the NIH (Grant RO1 GM63815) for
financial support.
(
12) For syntheses of iminochlorides, see also: Kantlehner, W. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 6, pp 485-599.
OL048852H
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Org. Lett., Vol. 6, No. 22, 2004