Palladium-Catalyzed Synthesis of Allylic Ureas via an Isocyanate Intermediate

Article abstract of DOI:10.1002/ejoc.201600149

A palladium-catalyzed coupling of allylic carbonates with trimethylsilylisocyanate to provide allylic isocyanates is reported. Amines are added in a second step to yield allylic ureas in this one-pot procedure. Use of a bidentate phosphine ligand with a large bite angle was found to be important in this transformation. The scope of allylic carbonates has been examined, as well as amines compatible with these reaction conditions.

Full text of DOI:10.1002/ejoc.201600149

DOI: 10.1002/ejoc.201600149
Communication
Pd Catalysis
Palladium-Catalyzed Synthesis of Allylic Ureas via an Isocyanate
Intermediate
Lucien P. Jay[a] and Timothy J. Barker*[a]
Abstract: A palladium-catalyzed coupling of allylic carbonates with a large bite angle was found to be important in this trans-
with trimethylsilylisocyanate to provide allylic isocyanates is re-
ported. Amines are added in a second step to yield allylic ureas
in this one-pot procedure. Use of a bidentate phosphine ligand
formation. The scope of allylic carbonates has been examined,
as well as amines compatible with these reaction conditions.
Introduction
butyl carbonate (Table 1). We initially examined the bidentate
ligand, Xantphos, given the precedent for its use in palladium-
allylic substitutions.[10,11] We were gratified to observe complete
conversion of the carbonate to the isocyanate when using tri-
methylsilylisocyanate as the source of cyanate (entry 1). No re-
action was observed with sodium or potassium cyanate as the
nucleophile (entries 2 and 3). The use of the soluble tetrabutyl-
ammonium cyanate also provided no reaction (entry 4). The
reaction was found to work best in CH2Cl2 when compared with
reactions performed in THF, toluene, or acetonitrile (entries 5–
7). No reaction was observed with cinnamyl bromide and cinna-
There are few reliable reactions that incorporate a cyanate
(NCO–) ion into organic molecules, despite isocyanates being
versatile intermediates in organic synthesis. The most straight-
forward approach to incorporate a cyanate would be in a sub-
stitution reaction with an alkyl halide. While there are examples
of alkali metal cyanates reacting as nucleophiles with alkyl hal-
ides, the resulting alkyl isocyanate products trimerize readily
under the reaction conditions.[1] A milder method to yield allylic
isocyanates is the substitution of allylic halides with silver cyan-
ate, but there are limitations to the examples reported.[2] Conse-
quently, alkyl isocyanates are typically synthesized from addi-
tion of phosgene to an amine[3] or Curtius rearrangements of
acyl azides,[4] or by Hofmann rearrangements of primary
amides.[5] These methods suffer from the use of hazardous rea-
gents or limited substrate scope.
Table 1. Optimization of Isocyanate Formation.[a]
Recently, there have been several examples of transition
metal-catalyzed coupling between a cyanate anion and an aryl
electrophile.[6] Kianmehr reported a copper-catalyzed coupling
of potassium cyanate and arylboronic acids in alcohol solvents
that resulted in aryl carbamate products.[7] Buchwald disclosed
a palladium-catalyzed coupling between sodium cyanate and
aryl chlorides and triflates for the synthesis of aryl ureas.[8] Palla-
dium-catalyzed allylic substitution reactions have become a
powerful method to form carbon–carbon and carbon–nitrogen
bonds under mild reaction conditions.[9] We envisioned a palla-
dium-catalyzed reaction employing allylic carbonate electro-
philes with a cyanate source to produce allylic isocyanates.
Entry
Change from Standard Conditions
Conversion [%]
1
2
3
4
5
6
7
8
None
100
0
0
0
40
6
0
0
0
20
0
0
8
7
3
0
58
83
NaOCN instead of TMSNCO
KOCN instead of TMSNCO
Bu4N(OCN) instead of TMSNCO
THF instead of CH2Cl2
Toluene instead of CH2Cl2
Acetonitrile instead of CH2Cl2
Cinnamyl bromide instead of 1
Cinnamyl acetate instead of 1
Cinnamyl methyl carbonate instead of 1
No Xantphos
0.12 equiv. of Xantphos
PPh3 instead of Xantphos
DPPE instead of Xantphos
BINAP instead of Xantphos
DPPF instead of Xantphos
DPEPhos instead of Xantphos
No molecular sieves
9
10
11
12
13
14
15
16
17
18
Results and Discussion
We began our investigations by examining cyanate anion sour-
ces in the presence of a palladium catalyst and cinnamyl tert-
[a] Department of Chemistry and Biochemistry, College of Charleston
66 George St., Charleston, SC 29424, USA
E-mail: barkertj@cofc.edu
http://chemistry.cofc.edu/index.php
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600149.
[a] Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, DPPE =
1,2-bis(diphenylphosphino)ethane, BINAP = 2,2′-bis(diphenylphosphino)-1,1′-
binaphthyl, DPPF = 1,1′-bis(diphenylphosphino)ferrocene, DPEPhos = bis-
[(2-diphenylphosphino)phenyl] ether.
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Communication
myl acetate, revealing that the choice of leaving group was im-
Next, the substrate scope was evaluated with regard to the
portant for this reaction (entries 8–9). Use of cinnamyl methyl allylic carbonate (Table 3). Substitution on the aromatic ring of
carbonate as the substrate resulted in a complex reaction mix- cinnamyl tert-butyl carbonate with electron-donating (3h) and
ture (entry 10). The reaction was sensitive to the ligand/Pd ratio electron-withdrawing groups, including a chloride (3k), was
with a 2:1 ratio of Xantphos/Pd completely inhibiting the reac- well-tolerated, providing the urea product in good yields. Allyl
tion (entry 12). While examining other bidentate phosphine li- tert-butyl carbonate was also an effective substrate providing
gands, a correlation was observed between the bite angle and the desired urea 3i in 64 % yield. Substitution with phenyl at
conversion to product in this reaction (entries 1, 14–17).[11] the 2-position of the allyl carbonate provided a lower yield of
Xantphos (bite angle 114°) gave full conversion to product urea 3l. Other substitution on the allylic carbonate was not tol-
while DPEPhos (bite angle of 102°) was the only other ligand erated with crotyl tert-butyl carbonate and 2-methallyl tert-
examined to give a significant conversion (58 %) to product.[11] butyl carbonate providing no reaction under the optimized
With both of these ligands, the reaction was completely select- conditions. Preliminary results heating crotyl tert-butyl carb-
ive for the linear isocyanate product. The addition of molecular onate in 1,2-dichloroethane and employing an allylpalladium
sieves was found to be necessary to ensure full conversion of chloride dimer as a precatalyst did not provide any improve-
the product reproducibly (entry 18). Allowing reactions to con- ment in reactivity for this substrate and other branched sub-
tinue longer than 2 hours did not improve the conversion un- strates.
der any of the modified conditions. Significant decomposition
of the isocyanate 2 was observed after 12 hours by H NMR of
Table 3. Substrate scope of allylic carbonate.
1
the unpurified reaction mixture.
Given the instability of the isocyanate, we sought to trap
this intermediate with an amine nucleophile after the complete
conversion of the carbonate to yield a urea product (Table 2).
After allowing 2 hours for formation of the isocyanate, addition
of 1.5 equiv. of amine provided full conversion to the urea after
an additional hour. With additional optimization, it was found
that only 1.5 equiv. of trimethylsilylisocyanate were needed in
the first step. The scope of amines was evaluated in the second
step of this two-step, one-pot transformation (Table 2). Primary
amines, such as benzylamine, provided the urea product in
great yield (85 %) over the two steps. The sterically bulky tert-
butylamine provided a 64 % yield of the urea product. Second-
ary amines including the bulky diisoproplyamine provided the
urea product in good yield (84 %) as well. Aromatic amines
were less reactive under these reaction conditions, but were
briefly examined due to the presence of arylamine moieties in
biologically active ureas.[12–16] Employing p-anisidine provided
the desired urea product in a 44 % yield after allowing 12 h for
the second step of the reaction. The instability of the isocyanate
under the reaction conditions is likely contributing to the di-
minished yield in this example.
A proposed catalytic cycle for formation of the isocyanate is
shown in Scheme 1 based on the similar reactivity of trimethyl-
silylazide.[9] Trimethylsilylazide has been identified as a soft nu-
cleophile in transition-metal-catalyzed allylic substitution reac-
tions. Soft nucleophiles attack on the carbon of the allylpalla-
dium intermediate as shown in Scheme 1.[9] Initial oxid-
ative addition of the allylic carbonate forms intermediate A.
Table 2. Substrate scope of amine in two-step, one-pot procedure.
Amine
Product
Yield [%]
BnNH2
tBuNH2
allylNH2
(iPr)2NH
C5H10NH (piperidine)
(Et)2NH
p-CH3OC6H4NH2
3a
3b
3c
3d
3e
3f
85
64
72
84
69
73
44
[a]
3g
[a] 12 h reaction time in the second step.
Scheme 1. Proposed catalytic cycle.
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Communication
Decarboxylation of the intermediate forms palladium tert- ton is also acknowledged for financial support. The NMR spec-
butoxide intermediate B, which is in equilibrium with the η3- trometer at the College of Charleston is supported by the Na-
allylpalladium species C. Dissociation of the alkoxide from Pd tional Science Foundation under Grant No. 1429308. Dr. John
may activate the trimethylsilylisocyanate for nucleophilic attack Greaves and Dr. Beniam Berhane (University of California, Irvine)
on an η3-allylpalladium D to provide the desired product and are acknowledged for mass spectrometry data.
regenerate palladium(0).
Keywords: Palladium · Allylic substitution · Isocyanate ·
Urea · Allylic compounds
Conclusions
A new palladium-catalyzed synthesis of allylic isocyanates from
the corresponding carbonate and trimethylsilylisocyanate has
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was developed for the synthesis of ureas by the addition of an
amine in the second step. The substrate scope, with regard to
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optimized conditions. Future studies will focus on expanding
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Experimental Section
1-Benzyl-3-cinnamylurea (3a): Representative procedure: Acti-
vated
4 Å molecular sieves, tris(dibenzylideneacetone)dipalla-
dium(0)-chloroform adduct (12 mg, 0.012 mmol, 0.03 equiv.), and
Xantphos (16 mg, 0.030 mmol, 0.075 equiv.) were added to a flame
dried 10 mL round-bottomed flask. The reaction was placed under
an atmosphere of Ar. Cinnamyl tert-butyl carbonate (68 mg,
0.40 mmol, 1 equiv.) was added as a solution in 3 mL of CH2Cl2.
Trimethylsilyl isocyanate (82 μL, 0.60 mmol, 1.5 equiv.) was added
by syringe and the reaction was stirred at room temp. After 2 h,
benzylamine (66 μL, 0.60 mmol, 1.5 equiv.) was added by syringe
to the orange reaction mixture and the reaction was stirred for an
additional hour. The reaction mixture was concentrated in vacuo
and purified by silica gel column chromatography (dry loading) us-
ing a gradient 4:1 hexanes/EtOAc to 1:1 hexane/EtOAc to provide
3a (90 mg, 85 %) as a white solid.
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Supporting Information (see footnote on the first page of this
article): Experimental details and characterization data for products
1
and copies of H and 13C NMR spectra of all reported products.
Acknowledgments
The College of Charleston Undergraduate Research and Crea-
tive Activities office is acknowledged for a summer undergradu-
ate research fellowship grant for L. P. J.. The College of Charles-
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Received: February 10, 2016
Published Online: March 22, 2016
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