Conversion of carbamates to amidosulfones and amides. Synthesis of the [14C]-labeled antiobesity agent Ro23-7637

Article abstract of DOI:10.1021/ol020062p

Matrix presented Carbamates of primary and secondary amines react with the dianion of methyl phenyl sulfone to yield amidosulfones. Alylation of the amidosulfone followed by reductive removal of the sulfonyl residue gives an amide.

Full text of DOI:10.1021/ol020062p

ORGANIC
LETTERS
2002
Vol. 4, No. 10
1803-1806
Conversion of Carbamates to
Amidosulfones and Amides. Synthesis
of the [14C]-Labeled Antiobesity Agent
Ro23-7637.
James D. White,* Paul R. Blakemore, and Selena Milicevic
Department of Chemistry, Oregon State UniVersity, CorVallis, Oregon 97331-4003
Satish C. Choudhry,* Joseph Cupano, and Lucia Serico
Chemical Synthesis, Non-Clinical DeVelopment, and Pre-Clinical Research and
DeVelopment, Hoffmann-La Roche Inc., Nutley, New Jersey 07110
james.white@orst.edu
Received March 21, 2002
ABSTRACT
Carbamates of primary and secondary amines react with the dianion of methyl phenyl sulfone to yield amidosulfones. Alylation of the amidosulfone
followed by reductive removal of the sulfonyl residue gives an amide.
Carbamates are widely used protecting groups for amines
because they are easily prepared and are stable to a broad
range of reagents used in synthesis yet can be removed under
conditions that release the parent amine cleanly and in high
yield.1 Certain carbamates such as the carbobenzyloxy (Cbz)
and tert-butoxycarbonyl (Boc) derivatives of amines have
played a pivotal role as protection devices in peptide
synthesis,2 but beyond the methods available for their
preparation and cleavage surprisingly little is known of their
more general chemical properties. For conversion of an amine
protected as its carbamate to an amide, conventional practice
holds that the carbamate is first removed and the liberated
amine is reacted with an acylating agent in a subsequent step.
An alternative means for accomplishing the same overall
transformation would, in principle, invoke nucleophilic attack
by an alkyl anion at the carbonyl group of the carbamate
with subsequent expulsion of an alkoxide. Ideally, the alkyl
group introduced in this manner should be capable of
modification, including further substitution, so that amides
directly from carbamates are not restricted to structures
carrying acyl appendages inherited solely from those alkyl
anions that are reactive with carbamates.
The dianion of methyl phenyl sulfone3 appeared to be a
good candidate for reaction with carbamates4 because (a)
this species is highly nucleophilic, (b) the resulting amido-
(3) White, J. D.; Avery, M. A.; Choudhry, S. C.; Dhingra, O. P.; Kang,
M.-c; Whittle, A. J. J. Am. Chem. Soc. 1983, 105, 6517.
(4) For other applications of this and related sulfonyl dianions in
synthesis, see: Eisch, J. J.; Dua, S. K.; Behrooz, M. J. Org. Chem. 1985,
50, 3674 and references therein.
(1) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; Wiley: New York, 1999; pp 503-547.
(2) Bodanszky, M. Principles of Peptide Chemistry; Springer-Verlag:
New York, 1984; p 99.
10.1021/ol020062p CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/17/2002

sulfone would be capable of further alkylation, and (c) the
sulfonyl substituent can be cleaved to produce an amide. This
sequence from carbamate to amide is outlined in Scheme 1,
Table 1. Preparation of Amidosulfones from Carbamates
Scheme 1
where alkylation of the intermediate amidosulfone anion
followed by reductive cleavage of the sulfone furnishes an
amide in which C1, C2, and the remaining carbons of the
acyl chain originate from three different sources. This feature
lends the method considerable versatility, for example, by
allowing the introduction of labeled carbon via the carbamate
carbonyl, the methyl group of methyl phenyl sulfone, or the
alkylating agent RX. To illustrate this point, a synthesis of
the antiobesity agent Ro23-76375 is described in which a
14C label is incorporated via isotopically enriched methyl
phenyl sulfone.6
Carbamates 1-13 were prepared from a variety of amines
by standard methods using either methyl or ethyl chloro-
formate, or in some cases di-tert-butyl dicarbonate.7 Methyl
and ethyl carbamate esters of secondary amines reacted
smoothly with the dilithio dianion of methyl phenyl sulfone
at 0 °C and gave amidosulfones in good yield (Table 1).
However, the reaction of methyl phenyl sulfonyl dianion with
tert-butyl carbamates was variable, yields with the Boc
derivatives of piperidine (2) and indoline (11) being low.
The N-Boc derivative of indole gave no amidosulfone but
instead returned the parent indole quantitatively. The car-
bamates 12 and 13 derived from ethylamine and n-propyl-
amine, respectively, reacted with the dianion of methyl
phenyl sulfone to give an amidosulfone only if the nitrogen
was first blocked as its N-trimethylsilyl derivative.8 In these
cases, the N-silyl group was introduced in situ and was
cleaved during workup.
The amidosulfone anion generated by addition of the
dianion of methyl phenyl sulfone to a carbamate can be
alkylated in situ with an alkyl halide (2 equiv), or the
(5) (a) Campfield, L. A.; Smith, F. J.; Mackie, G.; Tenenbaum, R.;
Sassano, M. L.; Mullin, J.; Kaiser, K.; Kierstead, R. W. Obes. Res. 1993,
3 Suppl 4, 5915. (b) Mullin, Jr., J. G.; Kierstead, R. W.; Triscari, J. U.S.
Patent 4632925, 1986.
(6) Choudhry, S. C.; Serico, L.; Liebman, A. A. Synth. Appl. Isotop.
Label. Comp. 1981, 218.
(7) Pope, B. M.; Yamamoto, Y.; Tarbell, D. S. Proc. Natl. Acad. Sci.
U.S.A. 1972, 69, 730.
(8) (a) Ghiron, C.; Piga, E.; Rossie, T.; Tamburini, B.; Thomas, R.
Tetrahedron Lett. 1996, 37, 3891. (b) Burkhart, J. P.; Holbert, G. W.;
Metcalf, B. W. Tetrahedron Lett. 1984, 25, 5267.
a Footnote: (1) the carboxylic acid was reacted with Et3N/Me3SiCl (12)
or with LDA/Me3SiCl (13) before exposure to the dianion of methyl phenyl
sulfone.
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Org. Lett., Vol. 4, No. 10, 2002

Table 2. Alkylation of Amidosulfones and Subsequent Reuctiona
a Footnotes: (1) the carboxylic acid was converted to its methyl ester with CH2N2 after alkylation; (2) mixture of two diastereomers (ratio not determined).
Org. Lett., Vol. 4, No. 10, 2002
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in comparable yields using the one-pot procedure. In the case
of the sulfone 21 derived from ephedrine, it was first
necessary to block the hydroxyl function (e.g., 25) for
successful C-alkylation. The amidosulfone 20 derived from
the ethyl carbamate of anabasine failed to undergo alkylation
R to the sulfonyl group, presumably because of competing
N-alkylation at the pyridine nucleus. Reductive removal of
the sulfonyl group from alkylated amidosulfones 26-39 was
carried out with either 6% sodium-amalgam in methanol
buffered with disodium hydrogen phosphate9 or with sa-
marium diiodide in a mixture of methanol and tetrahydro-
furan.10 In all cases, the yield of reduction product was
excellent.
Scheme 2
The ready availability of methyl phenyl sulfone bearing a
14C label in the methyl group11 makes the carbamate-to-amide
conversion an ideal sequence for incorporating isotopic
carbon. This is illustrated in a synthesis of [14C]-labeled
Ro23-7637 (54), an insulin-lowering antiobesity agent
(Scheme 2).5 Thus, piperidine 55 was converted to its ethyl
carbamate 56,5b and the latter was reacted with the dianion
of [14C]-methyl phenyl sulfone (specific activity ) 30 mCi/
mmol) to produce the monoanion of keto sulfone 57. The
latter was alkylated directly with 3-(7-bromoheptyl)pyridine
(58), prepared from 3-picoline by deprotonation of the methyl
substituent and alkylation with 1,6-dibromohexane, to yield
keto sulfone 59.5b After reductive removal of the sulfonyl
residue with sodium amalgam, 59 furnished [14C]-Ro23-7637
(54) in >98% radiochemical purity.
In summary, a method has been developed for the
conversion of carbamates of primary and secondary amines
to amides that does not require prior cleavage of the
carbamate. The method provides access to a wide variety of
amides through alkylation of an intermediate amidosulfone
and is especially well-suited to the introduction of an isotopic
label into the amide.
Acknowledgment. Financial support for this work from
the National Science Foundation (0076103-CHE) and Hoff-
mann-La Roche Inc. is gratefully acknowledged.
Supporting Information Available: A typical procedure
for the preparation of an amidosulfone from a carbamate,
alkylation of the amidosulfone, and reductive cleavage of
the sulfonyl group to an amide; characterization data for new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
amidosulfone can be isolated and alkylated in a separate step
with an alkyl halide (1 equiv) in the presence of a base (1
equiv). Thus, alkylation of the R anion of amidosulfones 14-
19 and 22, each prepared using potassium tert-butoxide in
THF, with a variety of alkylating agents in the presence of
tetra-n-butylammonium iodide gave a good yield of the
expected product in all cases (Table 2). Alkylation of 23
was carried out in DMF with potassium carbonate as the
base and gave clean C-alkylation with 1-iodobutane. The
alkylated amidosulfones 26, 31, and 32 were also prepared
OL020062P
(9) Trost, B. M.; Arndt, H. C.; Strege, P. E.; Verhoren, T. L. Tetrahedron
Lett. 1976, 3477.
(10) Molander, G. A.; Hahn, G. J. Org. Chem. 1986, 51, 1135.
(11) Choudhry, S. C.; Serico, L.; Cupano, J. J. Org. Chem. 1989, 54,
3755.
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Org. Lett., Vol. 4, No. 10, 2002