The development of efficient protocols for the palladium-catalyzed cyclization reactions of secondary amides and carbamates

Article abstract of DOI:10.1021/ol9905351

(equation presented) With the proper choice of palladium catalyst, ligand, and base, five-, six-, and seven-membered rings are formed efficiently from secondary amide or secondary carbamate precursors, offering significant improvements to currently existing methodology.

Full text of DOI:10.1021/ol9905351

ORGANIC
LETTERS
1999
Vol. 1, No. 1
35-37
The Development of Efficient Protocols
for the Palladium-Catalyzed Cyclization
Reactions of Secondary Amides and
Carbamates
Bryant H. Yang and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
SBUCHWAL@MIT.EDU
Received March 24, 1999
ABSTRACT
With the proper choice of palladium catalyst, ligand, and base, five-, six-, and seven-membered rings are formed efficiently from secondary
amide or secondary carbamate precursors, offering significant improvements to currently existing methodology.
We recently reported that aryl bromides with pendant
secondary amide groups could be cyclized to form tertiary
amides (Scheme 1).1 Some advantages of this palladium-
functional group tolerance. However, these cyclization
protocols typically employed high catalyst loadings and often
long reaction times were necessary. Furthermore, while this
methodology did allow for the formation of five- and six-
membered rings, preparation of seven-membered rings
proceeded in low overall yield. Motivated by an increased
understanding of Pd-catalyzed C-N bond-forming reactions,2
we undertook a reinvestigation of this problem.
Scheme 1
The conditions which we previously reported for the
cyclization of secondary amides involved the use of Pd2-
(dba)3 (10 mol % Pd), (o-tolyl)3P, or (2-furyl)3P as ligand
(20 mol %) and K2CO3 or Cs2CO3 as base (1.4 equiv) in
toluene at 100 °C for 8-91 h.1 Using, among others, ligands
used recently in the corresponding amination chemistry,3
(2) (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc.
Chem. Res. 1998, 31, 805. (b) Yang, B. H.; Buchwald, S. L. J. Organomet.
Chem. 1999, 576, 121. (c) Hartwig, J. F. Angew. Chem., Int. Ed. Engl.
1998, 37, 2090.
catalyzed approach were that the cyclization reactions
occurred under fairly mild conditions and displayed good
(3) (a) Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc.
1996, 118, 7215. (b) Sadighi, J. P.; Harris, M. C.; Buchwald, S. L.
Tetrahedron Lett. 1998, 39, 5327.
(1) Wolfe, J. P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron 1996, 21,
7525.
10.1021/ol9905351 CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/17/1999

these same transformations can now be achieved in higher
yield and with decreased quantities of catalyst (3.3 mol %
Pd and 5.0 mol % ligand). For instance, the use of (()-
MOP as ligand and K2CO3 as base was effective for the
preparation of lactam 5a (82% isolated yield, Table 1, entry
1) and lactam 5b (94% yield, entry 2).4 In conjunction with
Cs2CO3 as base, the use of (()-MOP also proved optimal
for preparation of the seven-membered lactam 5c (88%
isolated yield, entry 3). These results all compare favorably
to our previous report,1 where 5a was produced in only 59%
yield and the preparation of 5b required a reaction time of
91 h. In that report, attempted synthesis of seven-membered
lactam 5c proceeded in only 5% yield, affording either
unreacted starting material or debrominated material instead.
Table 1. Cyclization of Secondary Amides and Secondary
Carbamates
Similar results were obtained for the cyclization of
acetamides 2a-2c (entries 4-6).5 Although excellent yields
were reported previously for the cyclization of 2a using (2-
furyl)3P as ligand, high catalyst loadings were necessary (10
mol % Pd).1 Furthermore, formation of the six-membered
ring 6b was sluggish (44% isolated yield),1 and no product
was detected in the attempted cyclization of 2c. We have
now found that cyclization of 2a can be readily accomplished
using DPEphos (10)4,6 as ligand and Cs2CO3 as base (87%
isolated yield). Amide 6b could be prepared in 92% yield
using (()-BINAP as ligand and Cs2CO3 as base. And while
the preparation of 6c (90% yield) requires 36 h using
Xantphos6 (11) as ligand, the inaccessibility of this product
by our previous method1 makes this an attractive procedure.
The cyclization of secondary carbamates (Table 1, entries
7-12) is not only a logical extension of the intramolecular
cyclization of acetamides but it has already been applied in
total synthesis.7 From the same primary amine precursors
of acetamides 2a-2c, both the N-tert-butoxycarbonyl (3a-
3c) and N-carbobenzyloxy (4a-4c) derivatives were pre-
pared. As would be expected, yields for analogous cycliza-
tions (i.e. 3a f 7a vs 4a f 8a) were comparable when the
(4) Optically active MOP, (()-BINAP, and DPEphos (vide infra) are
commercially available from Strem Chemical Co. (()-MOP is prepared
from a literature procedure. See: (a) Uozumi, Y.; Hayashi, T. J. Am. Chem.
Soc. 1991, 113, 9887. (b) Kurz, L.; Lee, G.; Morgans, D. Jr.; Waldyke, M.
J.; Ward, T. Tetrahedron Lett. 1990, 31, 6321.
(5) Prepared using the procedures described in ref 1. In each case, the
crude primary amine precursor was prepared by lithium aluminum hydride
reduction of the corresponding nitrile. Small amounts (2-7%) of debro-
mination can also occur during the reduction step. Substrates 1-4 are
therefore contaminated with small amounts of the corresponding debromi-
nated material. The debrominated byproduct is not believed to affect the
efficiency of the cyclization step, and it is easily removed by flash column
chromatography after the cyclization step.
a Unless indicated otherwise, all reactions were conducted at 0.2-
0.3 M in starting substrate. b Reaction was run at 0.06 M in starting
substrate, using 5.0 mol % Pd(OAc)2 and 7.5 mol % ligand.
(6) Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; van
Leeuwan, P. W. N. M.; Goubitz, K.; Fraanje, J. Organometallics 1995, 14,
3081.
(7) He, F.; Foxman, B. M.; Snider, B. B. J. Am. Chem. Soc. 1998, 120,
6417.
same ligand/base systems were utilized.8 Thus the five-
membered rings 3a and 4a were smoothly formed using Cs2-
36
Org. Lett., Vol. 1, No. 1, 1999

CO3 as base and DPEphos as ligand (entries 7 and 10).
Although the use of (()-BINAP/Cs2CO3 was ineffective for
the formation of five-membered rings, it is a useful system
for the preparation of six-membered rings, affording the
corresponding N-Cbz compound 7b in 92% isolated yield
and the analogous N-Boc substrate 8b in 81% isolated yield.
For formation of the seven-membered ring compounds 7c
and 8c, (()-MOP/Cs2CO3 is found to be an effective ligand/
base combination (79% and 85% yields, respectively).
The superiority of the ligands xantphos and MOP (relative
to BINAP and DPEphos) for cyclizations leading to seven-
membered rings is of some interest. The second ligating
group of both xantphos and MOP is less strongly bound to
palladium than that for either BINAP or DPEphos since the
OMe group on MOP is only weakly chelating and the
increased bite angle of Xantphos (relative to BINAP and
DPEphos) should result in an increased Pd-P bond length.6,9
We suggest that the availability of an open coordination site
may be important in the coordination of the secondary amide
to the putative Pd(II) oxidative addition complex to form an
eight-membered palladacycle intermediate. Since the forma-
tion of a six- or seven-membered palladacycle is presumably
a more facile process, an open coordination site may not be
necessary. This would explain why the more tightly bound
ligands BINAP and DPEphos are often suitable for the
formation of five- and six-membered ring products but not
seven-membered ring products.
In summary, we have shown that ligands capable of
chelation (i.e. bisphosphines or ligands with heteroatoms
capable of coordination) are in many instances useful ligands
for the palladium-catalyzed cyclization of secondary amides
and carbamates. Further studies, however, are necessary to
elucidate the mechanism of these reactions and to delineate
the effect that ligand structure, ligand electronics, and base
counterion have on these transformations.
(8) A general procedure for amide or carbamate cyclizations: a dry 25-
mL sealable Schlenk tube was charged with Pd(OAc)2 (3.2 mg, 0.014 mmol)
and (()-BINAP (13.4 mg, 0.022 mmol). The reaction vessel was evacuated
and flushed with argon. A solution of 4b (135 mg, 0.43 mmol) in toluene
(1 mL) was added via cannula. The mixture was heated under argon at 100
°C for 2 min to dissolve the solids. The reaction vessel was removed from
the oil bath, charged quickly with Cs2CO3 (196 mg, 0.60 mmol) and toluene
(0.3 mL), sealed with a Teflon screwcap, and heated at 100 °C until the
aryl bromide was consumed (24 h). The reaction mixture was cooled to rt,
filtered through a short plug of SiO2, and concentrated. The residue was
purified by flash column chromatography (9% EtOAc-hexanes) to afford
Acknowledgment. This research was funded by the
National Institutes of Health (GM58160). We also thank
Pfizer, Merck, and Novartis for additional support. B.H.Y.
gratefully acknowledges the NIH for a postdoctoral fellow-
ship (GM18588-02). We thank Dr. David Old, Mr. Joseph
Sadighi, and Ms. Michele Harris for samples of 9, 10, and
11, respectively.
1
8b (81 mg, 81% yield) as a colorless oil: H NMR (300 MHz, CDCl3) δ
7.63 (d, 1H, J ) 8.1 Hz), 7.4-6.9 (m, 3H), 3.71 (t, 2H, J ) 6.1 Hz), 2.74
(t, 2H, J ) 6.6 Hz), 1.90 (m, 2H), 1.52 (s, 9H); 13C NMR (75 MHz, CDCl3)
δ 153.9, 138.6, 129.9, 128.5, 125.7, 124.1, 123.2, 80.7, 44.6, 28.4, 27.5,
23.6; FTIR (neat) 1704 cm-1. Anal. Calcd for C14H19NO2: C, 72.07; H,
8.21. Found: C, 72.15; H, 8.33.
Supporting Information Available: Characterization
data for products 5-8 (6 pages). This material is available
free of charge via the Internet at http://pubs.acs.org.
(9) Kranenburg, M.; Delis, J. G. P.; Kamer, P. C. J.; van Leeuwen, P.
W. N. M.; Vrieze, K.; Veldman, N.; Spek, A. L.; Goubitz, K.; Fraanje, J.
J. Chem. Soc., Dalton Trans. 1997, 1839.
OL9905351
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