of the base and reaction conditions these impurities were nearly
eliminated. Thus, substituting pyridine for triethylamine and
with reverse addition of the amine to SOCl2, the isolated yield
of 20 increased significantly ( ~ 98%). A variety of oxidation
conditions were screened for the oxidation of 20 to 22 to avoid
decomposition due to over oxidation, partial deprotection (e.g.,
Boc), or hydrolytic cleavage (Scheme 5). Among them, NaIO4/
RuCl3 conditions proved superior, and the desired dioxides
22a,b were isolated in excellent yield ( > 94%) as off-white
solids.
Nucleophilic displacement of the cyclic sulfamidates 22a,b
with the benzoate protected pyrrolidinol 67 and removal of
protecting groups were straightforward and efficient. Both
protected substrates 22a,b coupled easily at room temperature
with the aminobenzoate 6. The sulfamic acids 23a,b could be
isolated in 60–70% recrystallized yield as the stable zwitterions;
hydrolysis8 with acid then gave the desired amines 24a,b
quantitatively.9 The Boc protecting group was also removed
under these conditions and provided the primary amine 24b
directly. Removal of the Cbz group of 24a also produced 24b
cleanly under transfer hydrogenation conditions.
A variety of palladium/ligand combinations under a wide
range of conditions were explored for the key amination
sequence. The palladium-mediated coupling of the benzylamine
24b with the aryl bromide 25 using a Pd(OAc)2/BINAP catalyst
system provided 27 in a modest yield ( ~ 39%).10 Interestingly,
the Pd2(dba)3/(o-biphen)P(t-Bu)2 combination proved to be
effective only when the corresponding aryl chloride 26 was
used (ca. 42%).1,2 Reductive alkylation in the presence of
paraformaldehyde, using NaBH4/Lewis acids or aqueous for-
maldehyde/sodium triacetoxyborohydride or NaH2PO3 combi-
nations showed some product but the alkylations were not
complete even after prolonged reaction time with excess
reagent. However, the combination of paraformaldehyde,
NaCNBH3, TMSCl and MgSO4 was effective in producing the
desired N-methylated product 28 (55%). Since hydrolysis and
salt formation of 28 to 1 in one pot has been demonstrated,11 the
present efforts concluded a synthesis of 1.
In summary, we have developed an efficient synthesis of CJ-
15,161 involving Pd-catalyzed aryl amination as the key-step.
The described approach is amenable for multigram-scale
preparation of 1. The direct amination of 4-halobenzamide12 as
the halide counterpart, and efficient preparation of the substrate
amine by dual protection/activation involving oxathiazolidine
formation are two noteworthy transformations of the synthetic
scheme and may find broader application for the preparation of
other N-aryl 1,2-diamines.
We sincerely thank Professors Steven Ley (Cambridge) and
David Collum (Cornell) for helpful discussions.
Notes and references
1 (a) J. F. Hartwig, Angew. Chem., Int. Ed. Engl., 1998, 37, 2046–2067;
(b) J. F. Hartwig, M. Kawatsura, S. I. Hauck, K. H. Shaughnessy and L.
M. Alcazar-Roman, J. Org. Chem., 1999, 64, 5575–5580; (c) B. H.
Yang and S. L. Buchwald, J. Organomet. Chem., 1999, 576, 125–146;
(d) J. P. Wolfe and S. L Buchwald, J. Org. Chem., 2000, 65, 1144–1157;
(e) J. P. Wolfe, H. Tomori, J. P. Sadighi, J. Yin and S. L. Buchwald, J.
Org. Chem., 2000, 65, 1158–1174 and references therein.
2 C. Dai and G. C. Fu, J. Am. Chem. Soc., 2001, 123, 2719 and references
therein.
3 S. R. Anderson, J. T. Ayers, K. M. DeVries, F. Ito, D. Mendenhall and
B. C. Vanderplas, Tetrahedron: Asymmetry, 1999, 10, 2655–2663.
4 G. A. M. Giardina, L. F. Raveglia, M. Grugni, H. M. Sarau, C. Farina,
A. D. Medhurst, D. Graziani, D. B. Schmidt, R. Rigolio, M. Luttmann,
S. Cavagnera, J. J. Foley, V. Vecchietti and D. W. P. Hay, J. Med.
Chem., 1999, 42, 1053–1065.
5 A similar mechanism was proposed for the formation of 2-oxazolidone
from b-iodourethane, see: C. Heathcock and A. Hassner, Angew. Chem.,
1963, 344.
6 For a report on direct synthesis of sulfamidate using sulfuryl chloride,
see: D. Alker, K. J. Doyle, L. M. Harwood and A. McGregor,
Tetrahedron: Asymmetry, 1990, 1, 877–880.
7 For some recent accounts of nucleophilic ring opening of cyclic
sulfamidates with different nucleophiles, see: (a) L. Wei and W. D.
Lubell, Org. Lett., 2000, 2, 2595–2598; (b) M. Atfani, L. Wei and W. D.
Lubell, Org. Lett., 2001, 3, 2965–2968; (c) M. K. Pound, D. L. Davies,
M. Pilkington, M. M. de Pina Vaz Sousa and J. D. Wallis, Tetrahedron
Lett., 2002, 43, 1915–1918.
8 Hydrolysis of sulfamic acid in aqueous acid is believed to proceed
through an A2 mechanism, see: G. A. Benson and W. J. Spillane, Chem.
Rev., 1980, 80, 151.
9 For some recent examples of acid-hydrolysis of sulfamic acids, see; M.
Okuda and K. Tomioka, Tetrahedron Lett., 1994, 35, 4585–4586; M. E.
Van Dort, Y. W. Jung, P. S. Sherman, M. R. Kilbourn and D. M.
Wieland, J. Med. Chem., 1995, 38, 810–815; B. M. Kim and S. M. So,
Tetrahedron Lett., 1998, 39, 5381–5384.
10 The yields are lower with benzoate protected substrate 26a due to
competing hydrolysis of the starting amine. With silyl protection the
yields were in the range 80–90%.
11 Personal communication; M. Couturier, M. Andreson, J. Tucker, CRD,
Pfizer, manuscript under preparation.
12 A. Klapars, J. C. Antilla, X. Huan and S. L. Buchwald, J. Am. Chem.
Soc., 2001, 123, 7727–7729. For some rare examples of use of amide as
substrate in Pd chemistry, see: (a) Y. D. Ward and V. Farina,
Tetrahedron Lett., 1996, 37, 6993; (b) C. A. Willoughby and K. T.
Chapman, Tetrahedron Lett., 1996, 37, 7181; (c) A. Batch and R. H.
Dodd, J. Org. Chem., 1998, 63, 872; (d) J. T. Link, B. Sorensen, G. Liu,
Z. Pei, E. B. Reilly, S. Leitza and G. Okasinski, Bioorg. Med. Chem.
Lett., 2001, 11, 973.
Scheme 5 Reagents and conditions: (i) CbzCl, CH2Cl2, 89%; (ii) SOCl2,
Et3N, CH2Cl2, ~ 80%; (iii) SOCl2, py, CH2Cl2, ~ 90%; (iv) RuCl3, NaIO4,
CH3CN, H2O, 0 °C to RT, 1 h, > 90%; (v) 6, Et3N, EtOAc, 60–70%; (vi)
2 M HCl, MTBE; (vii) HCO2NH4, Pd/C, THF, quant.; (viii) Pd(OAc)2,
BINAP, Cs2CO3, toluene, 100 °C, 39%; (ix) Pd2(dba)3, (o-biphen)P(t-Bu)2,
Cs2CO3, toluene, 100 °C, 42%; (x) (CHO)n, NaCNBH3, TMSCl, MgSO4,
55%; (xi) aq. NaOH, IPA, then benzoic acid, 81%.
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