Journal of the American Chemical Society
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and rate of Pd–NCO formation decreases in the order Cl>Br>I.
Similar reactivity profiles have been demonstrated for other Cꢀ
N bondꢀforming processes when a weakly nucleophilic couꢀ
pling partner is used.16,22
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However, the use of these substitutes is often associated with a
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rowed substrate scope.
1
2
3
4
5
6
7
8
In summary, an efficient protocol for the synthesis of unꢀ
symmetrical ureas was developed which proceeds via a pallaꢀ
diumꢀcatalyzed crossꢀcoupling of aryl chlorides and triflates
with sodium cyanate. A second set of conditions was estabꢀ
lished which allowed for an expanded substrate scope with
respect to the electrophile via introduction of phenol to the
reaction mixture. Mechanistic studies conducted on this sysꢀ
tem suggest that transmetallation is the rateꢀlimiting step. Fiꢀ
nally, the first example of reductive elimination from an aryl
palladium isocyanate complex was demonstrated. Additional
studies on the role of phenol in promoting the reaction with
more sterically hindered and heterocyclic substrates are curꢀ
rently underway.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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28
29
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32
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34
35
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anions: Ushkov, A. V.; Grushin V. V. J. Am. Chem. Soc. 2011,
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(12) Paul, F.; Moulin, S.; Piechaczyk, O.; Le Floch, P.; Osborn, J. A.
J. Am. Chem. Soc. 2007, 129, 7294.
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(15) Oxidative addition complexes with L1 as the supporting ligand
have been previously synthesized in our laboratory and have
been shown to undergo fast aryl transfer to “C3” carbon of the
bottom ring of the biaryl ligand, leading to formation of
dearomatized Pd(II) complexes, where palladium is σꢀbound to
“C2” carbon of the bottom ring of the ligand and exhibits addiꢀ
tional interaction with “C3” moiety: Maimone, T.J.; Milner, P.J.;
Kinzel, T.; Zhang, Y.; Takase, M.K.; Buchwald, S.L. J. Am.
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(16) Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131,
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(17) Fors, B. P.; Dooleweerdt, K.; Zeng, Q.; Buchwald, S. L. Tetra-
hedron 2009, 65, 6576.
(18) (a) Ueda, S.; Su, M.; Buchwald, S. L. J. Am. Chem. Soc. 2012,
134, 700. (b) Kotecki, B. J.; Fernando, D. P.; Haight, A. R.;
Lukin, K. A. Org. Lett. 2009, 11, 947.
(19) Triethylamine was shown to facilitate the crossꢀcoupling step of
the sequence. The exact role of this additive remains unclear. It
may potentially increase the solubility of the cyanate salt.
(20) Biscoe, M. R.; Barder, T. E.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2007, 46, 7232.
(21) Fujita, K.; Yamashita, M.; Puschmann, F.; Martinez Alvarezꢀ
Falcon, M.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem. Soc.
2006, 128, 9044.
(22) Hicks, J. D.; Hyde, A. M.; Cuezva, A. C.; Buchwald, S. L. J.
Am. Chem. Soc. 2009, 131, 16720.
(23) Rigby, J. H. Synlett, 2000, 1.
(24) Clayden, J.; Donnard, M.; Lefranc, J.; Minassi, A.; Tetlow, D. J.
J. Am. Chem. Soc. 2010, 132, 6624.
(25) For another example where the beneficial effect of a phenoxide
additive was observed in a palladiumꢀcatalyzed crossꢀcoupling
reaction see: Martinelli, J. R.; Clark, T. P.; Watson, D. A.; Munꢀ
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8460.
SUPPORTING INFORMATION
Experimental procedures, characterizations, spectral data for all
compounds, and Xꢀray crystallographic (CIF) data for 2. This
material is available free of charge via the Internet at
AUTHOR INFORMATION
Corresponding Author
* sbuchwal@mit.edu
ACKNOWLEDGMENT
This work was supported, in part, by an educational donation
provided by Amgen and by the National Institutes of Health
(GM58160). The Varian 300 MHz and 500 MHz NMR spectromꢀ
eters used for portions of this work was purchased with funds
from the National Science Foundation (Grants CHE 9808061 and
DBI 9729592). The departmental Xꢀray diffraction instrumentaꢀ
tion was purchased with the help of funding from the National
Science Foundation (CHEꢀ0946721). We thank members of the
Dincă Laboratory for the help in obtaining IR spectra of complexꢀ
es 1 and 2.
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