problem, tris(2-(2-methoxyethoxy)ethyl)amine (TDA) was
used in lieu of triethylamine.24 The use of this milder base
did not affect the stability of the resulting carbamate
products, and the Fmoc-protected amines 3g and 3h were
obtained in 83% and 67% yields (Table 3). TDA was also
employed for the cross-coupling of certain aryl triflates, as
it was found to improve the yields of the corresponding
carbamate products (Table 3, entries 3b, 3c, 3e).
Table 3. Synthesis of Aryl Carbamatesa,b
The synthesis of allyl carbamates typically requires the
use of allyl chloroformate or allyl alcohol as the sol-
vent, both of which are particularly hazardous substances.
Therefore, applying the developed methodology to the
synthesis of allyl carbamates would be advantageous, since
it requires only a slight excess of the nucleophile. Allyl-
esters and carbamates are known to easily undergo Pd(0)-
catalyzed deprotection25 in the presence of nucleophiles.
Formation of the palladium π-allyl complex from the allyl
carbamate generates the deprotonated carbamic acid,
which readily decarboxylates to give the free amine.26 To
circumvent the undesired π-allyl pathway, the reactive Pd(0)
species needed to be removed from the reaction mixture
prior to the addition of allyl alcohol. Filtration of the
reaction mixture through a plug of Celite or silica gel did
not remove the palladium species completely, which lead to
diminished yields of the allyl carbamates. We envisioned that
addition of an iodobenzene to the reaction mixture would
provide an operationally simple procedure to rapidly convert
the Pd(0) present to Pd(II), thus minimizing cleavage of the
allyl carbamates without significantly altering the reaction
conditions.27 Indeed, stirring the reaction mixture with 10
mol % of iodobenzene prior to the introduction of allyl
alcohol provided carbamates 3i and 3j in 63% and 67%
yields (Table 3) using only a 2-fold excess of the allyl alcohol.
In summary, we have shown that using alcohols as
nucleophiles in the Pd-catalyzed cross-coupling of aryl
chlorides and triflates with sodium isocyanate provides a
broadrangeofarylcarbamate productsingood yields. The
substrate scope of the direct isocyanate coupling producing
aryl isocyanates in situ was extended by using aryl triflates
instead of aryl chlorides, allowing for the use of alcohols and
thiols not compatible with cross-coupling conditions.
a Reaction conditions (isolated yields, average of 2 runs). Step 1: ArX
(1 mmol), NaOCN (2 mmol), Pd2dba3 (x mol %), L1 (y mol %), toluene
(2 mL). The Pd2(dba)3 and L1 were preheated in toluene at 120 °C for
3 min. Step 2: NuH (2 mmol), NEt3 (0.1 mmol). b Troc: 2,2,2-trichloro-
ethoxycarbonyl. Cbz: carboxybenzyl. Fmoc: fluorenylmethyloxycar-
bonyl. Alloc: allyloxycarbonyl. c NR3 = NEt3 (25 mol %). d Pd2dba3
(0.5mol%),L1 (1.2mol%). e Pd2dba3 (1mol%), L1 (2.4mol%). f NR3 =
TDA (10 mol %). g 130 °C. h Pd2dba3 (0.75 mol %), L1 (1.8 mol %).
i NaOCN (3 mmol), toluene (3 mL). Step 2: BnOH (3 mmol), NEt3
(0.2 mmol). j No NEt3 was used in Step 2. k 0.5 mmol scale. l Step 2: PhI
(0.1 mmol), 30 min at rt, then AllylOH (2 mmol), NEt3 (0.1 mmol).
examine the potential of accessing these building blocks
using our methodology, 5-chloro-2-methylphenyl trifluoro-
methanesulfonate was subjected to the one-pot two-step
procedure. The in situ generated aryl diisocyanate was
reacted with benzyl alcohol toafford the bis-Cbz-protected
dianiline in 85% yield (92%/each carbamate formed;
Table 3, entry 3f).
9-Fluorenylmethyl carbamate (Fmoc) is a protecting
group for amino acids widely used in peptide synthesis.
It can be easily cleaved by weak bases, such as piperidine
and triethylamine.23 Therefore, it is unsurprising that our
standard conditions that employed triethylamine led to
deprotection of the resulting carbamate and the formation
of anilines as the major products. To overcome this
Acknowledgment. We thank the National Institutes
of Health (GM58160) for financial support of this project.
N.H.P. acknowledges a National Science Foundation
Graduate Research Fellowship. This activity was sup-
ported in part by an educational donation provided by
Amgen. We thank James Colombe (M.I.T.) for helpful
discussions and the Pentelute group (M.I.T.) for help in
obtaining HRMS spectra. MIT has patents on the ligand used
in this paper from which S.L.B. receives royalty payments.
(23) Fields, G. B. In Methods in Molecular Biology, Vol. 35;
Pennington, M. W., Dunn, B. M., Eds.; Humana Press Inc.: Totowa,
NJ, 1994; pp 17À27.
(24) TDA has been previously shown to facilitate the cross-coupling
of aryl chlorides with sodium cyanate: Reference 16; Supporting
Information.
(25) Jellerichs, B. G.; Kong, J.-R.; Krische, M. J. J. Am. Chem. Soc.
2003, 125, 7758.
(26) As expected, the presence of palladium in the reaction medium
resulted in the deprotection and the formation of the corresponding
anilines, in spite of the relatively mild conditions employed for the
second step of the sequence (15 h at 45 °C).
Supporting Information Available. Experimental pro-
cedures, characterizations and spectral data for all com-
pounds. This material is available free of charge via the
(27) Palladium(0)-complexes bearing biarylphosphine supporting
ligands are known to undergo oxidative addition with sp2 carbonÀ
halogen bonds at room temperature. Halogen = Cl, Br: Wolfe, J. P.; Singer,
R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9550.
The authors declare the following competing financial interest(s):
MIT has patents on ligands that are described in the papers from which
S.L.B. receives royalty payments.
D
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