Efficient Copper-Catalyzed Multicomponent Synthesis of N-Acyl Amidines via Acyl Nitrenes

Article abstract of DOI:10.1021/jacs.9b07140

Direct synthetic routes to amidines are desired, as they are widely present in many biologically active compounds and organometallic complexes. N-Acyl amidines in particular can be used as a starting material for the synthesis of heterocycles and have several other applications. Here, we describe a fast and practical copper-catalyzed three-component reaction of aryl acetylenes, amines, and easily accessible 1,4,2-dioxazol-5-ones to N-acyl amidines, generating CO₂ as the only byproduct. Transformation of the dioxazolones on the Cu catalyst generates acyl nitrenes that rapidly insert into the copper acetylide Cu-C bond rather than undergoing an undesired Curtius rearrangement. For nonaromatic dioxazolones, [Cu(OAc)(Xantphos)] is a superior catalyst for this transformation, leading to full substrate conversion within 10 min. For the direct synthesis of N-benzoyl amidine derivatives from aromatic dioxazolones, [Cu(OAc)(Xantphos)] proved to be inactive, but moderate to good yields were obtained when using simple copper(I) iodide (CuI) as the catalyst. Mechanistic studies revealed the aerobic instability of one of the intermediates at low catalyst loadings, but the reaction could still be performed in air for most substrates when using catalyst loadings of 5 mol %. The herein reported procedure not only provides a new, practical, and direct route to N-acyl amidines but also represents a new type of C-N bond formation.

Full text of DOI:10.1021/jacs.9b07140

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Article
Efficient Copper Catalyzed Multicomponent
Synthesis of N-acyl amidines via Acyl Nitrenes
Kaj M. van Vliet, Lara H. Polak, Maxime A. Siegler, Jarl Ivar
van der Vlugt, Célia Fonseca Guerra, and Bas de Bruin
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b07140 • Publication Date (Web): 29 Aug 2019
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Efficient Copper Catalyzed Multicomponent Synthesis of N-acyl am-
idines via Acyl Nitrenes
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Kaj M. van Vliet,[a] Lara H. Polak,[a] Maxime A. Siegler,[b] Jarl Ivar van der Vlugt,[a] Célia Fonseca
Guerra,[c][d] and Bas de Bruin*[a]
[a] Homogeneous, Supramolecular and Bio-inspired Catalysis Group (HomKat), van ’t Hoff Institute for Molecular Sciences
(HIMS), Universiteit van Amsterdam (UvA), Amsterdam 1012 WX, The Netherlands.
[b] Department of Chemistry, John Hopkins University, Baltimore, Maryland 21218, United States.
[c] Department of Theoretical Chemistry and Amsterdam Center for Multiscale Modeling, Vrije Universiteit Amsterdam
(VU), De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
[d] Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Nether-
lands.
ABSTRACT: Direct synthetic routes to amidines are desired, as they are widely present in many biologically active compounds
and organometallic complexes. N-Acyl amidines in particular can be used as a starting material for the synthesis of heterocycles
and have several other applications. Here, we describe a fast and practical copper catalyzed 3-component reaction of aryl acety-
lenes, amines and easily accessible 1,4,2-dioxazol-5-ones to N-acyl amidines, generating CO2 as the only by-product. Transfor-
mation of the dioxazolones on the Cu-catalyst generates acyl nitrenes that rapidly insert into the copper acetylide CuC bond rather
than undergoing an undesired Curtius rearrangement. For non-aromatic dioxazolones, [Cu(OAc)(Xantphos)] is a superior catalyst
for this transformation, leading to full substrate conversion within 10 minutes. For the direct synthesis of N-benzoyl amidine deriva-
tives from aromatic dioxazolones, [Cu(OAc)(Xantphos)] proved to be inactive, but moderate to good yields were obtained when
using simple CuI as the catalyst. Mechanistic studies revealed the aerobic instability of one of the intermediates at low catalyst
loadings, but the reaction could still be performed in air for most substrates when using catalyst loadings of 5 mol%. The herein
reported procedure does not only provide a new, practical and direct route to N-acyl amidines, but also represents a new type of
CN bond formation.
amidines remains an unsolved challenge. Current synthetic
INTRODUCTION
routes to N-acyl amidines usually rely on reactions of pre-
made primary amides with amino acetals49 or acylation of
amidines with stoichiometric coupling reagents.50–52 A direct,
atom-efficient synthetic strategy is thus desired.
Amidines are useful substrates with a variety of applica-
tions. The amidine structure in 1,8-diazabicyclo[5.4.0]un-dec-
7-ene (DBU) is used frequently as a non-nucleophilic base in
synthetic chemistry,1 and more complex amidines are even
considered to be “superbases”.2 Amidines also have been used
as ligands for organometallic complexes3 and as starting mate-
rial for the synthesis of N-heterocycles.4–10 The structure itself
is present in various natural products and biologically active
compounds such as Janoxapin, Pentamidine and Sildenafil
(see Figure 1).11,12
Multiple methods exist for the synthesis of amidines in gen-
eral, including the Pinner reaction,13 substitution of phenoxy-
imidates,14 Beckman-type rearrangements,15 dehydrogenative
coupling reactions,16,17 or by catalysis with palladium14,18–21 or
nickel,22 as well as some multi-component reactions.23–33
Chang developed strategies for the synthesis of sulfonated and
phosphorylated amidines via traditional click chemistry with
azides, followed by a thermal N2 exclusion, resulting in a net
coupling of a nitrene to an alkyne.29,34-45 However, the general
(kinetic) stability of most triazoles puts severe limitations to
the applicability of other azides, and this method also proved
to be unsuitable for the synthesis of N-benzoyl or N-acyl ami-
dines.45,46 Nicasio and Pérez showed that a copper catalyzed
reaction of acetylenes with N-aroyl or N-acyl azides produces
triazoles or oxazoles instead of N-acyl amidines.47,48 In fact,
development of direct methods for the synthesis of N-acyl
Figure 1. Several amidine compounds and their applications.
N-acyl amidines are a particularly interesting class of com-
pounds. They are important substructures in a variety of medi-
cines,53,54 and have been used as precursors for cyclization
reactions,50,53 as ligands for catalysts and other molecular
assemblies54 or as substrates for reductive alkylation.55 We
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therefore focused on developing a new method for the direct Inspired by the work of Wang on copper catalyzed carbene
insertion into CH bonds,82 we anticipated that acyl nitrenes
could be coupled to terminal alkynes as a new type of CN
bond formation. We envisioned that the activation of 1,4,2-
dioxazol-5-ones on copper acetylides could readily form an
acyl nitrene on copper that should rapidly insert into the CuC
bond to furnish a CN bond, avoiding decomposition by the
Curtius rearrangement and thus providing a direct route to
acylated amidines (Scheme 1, right).
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synthesis of N-acyl amidines via a one-pot multi-component
reaction.
Since our group is focusing on CH activation using metal-
locarbenes and metallonitrenes for the catalytic formation of
new CC and CN bonds,56–62 we considered that a related
acyl nitrene transfer strategy could be useful for the synthesis
of N-acyl amidines. However, realizing new strategies to con-
vert acyl nitrenes in a selective manner is rather troublesome.
While amides are amongst the most stable nitrogen containing
moieties, acyl nitrenes are intrinsically unstable. Even when
bound to a metal, alkyl migration via the Curtius rearrange-
ment generally rapidly leads to an isocyanate (Scheme 1,
left).63–65 Hence, in the context of seeking protocols to couple
acyl nitrenes to C-nucleophiles, such Curtius rearrangements
are undesired and thus represent a selectivity problem, in
particular for aliphatic acyl nitrenes. The barrier for this rear-
rangement is lower for aliphatic acyl nitrenes than for aro-
matic derivatives, and the intrinsic instability of aliphatic acyl
azides makes them challenging to isolate and unsuitable for
prolonged storage.
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RESULTS AND DISCUSSION
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In an initial attempt to couple acyl nitrenes to acetylenes, we
added dioxazolone 1a to a mixture of copper bromide, chloro-
form, phenylacetylene (2a) and diisopropylamine (3a) as a
base. The yellow color, typical for copper acetylide complex-
es, slowly turned dark green upon addition of the dioxazolone.
Analysis of the crude reaction mixture by mass spectrometry
suggested that a 3-component reaction had taken place.
Scheme 1. Acyl nitrene formation from 1,4,2-dioxazol-5-
ones, followed by an undesired metal induced Curtius
rearrangement (left) versus desired nitrene insertion into a
M-Cacetylide bond (right).
Figure 2. Ligands used in this work.
1H NMR analysis indeed confirmed the formation of the 3-
component reaction product 4aaa in 63% yield (Table 1). The
reaction thus readily gives access to this N-acyl amidine. To
optimize the reaction conditions, we explored the efficiency of
the reaction using different Cu(I) catalysts and different sol-
vents (ligands used in this study are shown in Figure 2). Most
copper salts worked equally well (Table 1, entries 1-5). The
[Cu(MeCN)4]+ salts appeared to work slightly better, which is
commonly observed for copper catalyzed reactions.83 We also
employed some well-defined Cu(I)-ligand complexes, includ-
ing complexes containing the Xantphos ligand (Xantphos =
4,5-bis(diphenylphosphino)-9,9-dimethylxan-thene) (Table 1,
entries 6-11).84–86 Surprisingly, while most complexes perform
poorly, [Cu(OAc)(Xantphos)] gave a very high selectivity.
The reaction works well in a variety of different solvents un-
der aerobic conditions at room temperature (Table 1, entries
12-19). Results obtained in toluene and ethyl acetate show that
the reaction is selective in both polar and apolar solvents. In
methanol and acetonitrile, the desired product was not ob-
served, which is suggestive of catalyst inhibition by coordina-
tion of these solvents to copper. In THF, however, full conver-
sion towards the product is observed. Excellent yield is ob-
tained with 5% catalyst loading (or more), but the yield drops
with lower catalyst loadings (Table 1, entries 20-24). Notably,
when the reaction is diluted 10 times, formation of the product
4aaa was not observed (Table 1, entry 25). Instead, 1,1-
diisopropyl-3-phenethylurea compound 5aa was formed,
indicating a Curtius rearrangement of the acyl nitrene. Replac-
ing the Xantphos ligand by ethylenebis(diphenylphosphine)
(dppe) or 2 equivalents of PPh3 results in a decreased yield of
4aaa (Table 1, entries 26-27).
In addition to the intrinsic instability of acyl nitrenes, efficient
formation of these reactive intermediates constitutes an additional
challenge. Conventional precursors used for metallonitrene chem-
istry are iminoiodinanes, haloamines, azides and hydroxyla-
mines,66 most of which are difficult to prepare, poorly soluble,
require elevated temperatures to activate or associated with selec-
tivity and sustainability issues. Cyclic nitrene precursors were
recently shown to be efficient nitrene precursors,67 which are
more practical. In particular, 1,4,2-dioxazol-5-ones are notewor-
thy acyl nitrene precursors in this perspective. They are stable
until at least 100 °C, have a low activation barrier upon coordina-
tion to a metal and produce only CO2 as a side product.68 They
can be synthesized by two practical steps from acids, esters or
acyl chlorides.69 Although these properties are known for over 50
years, these class of substrates only have become popular for
applications in catalysis since the work of Bolm in 2014.70
Still, the intrinsic instability of N-acyl metallonitrenes generated
from these substrates is a major issue. Successful approaches to
use N-acyl metallonitrenes in catalysis typically rely on directed
CH activation or generation of the acylnitrene on a metal center
already containing a pre-activated co-substrate.71–77
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Scheme 2. The desired catalyzed reaction vs. the uncata-
Table 1. Optimization of reaction conditions.
1
lyzed side reaction (urea formation).
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Catalyst (mol% Cu)
Solvent
Yield (%)
#
CuCl (10)
CuBr (10)
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
DCM
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1
2
63
The use of less equivalents of acetylene has a larger effect
on the yield than lowering the amount of diisopropylamine
(56% and 84% yield, respectively).When one equivalent of all
reactants was used we still obtained 70% of the N-acyl ami-
dine. It should be noted that a lower yield is obtained when
using just one equivalent of phenylacetylene in combination
with a higher concentration of diisopropylamine. This indi-
cates that fast formation of a copper acetylide species is im-
portant, and that this process must outcompete the diisoprop-
ylamine-assisted decomposition of the dioxazolone to obtain
high yields of the desired N-acyl amidine.
CuI (10)
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3
[Cu(NCMe)4]BF4 (10)
[Cu(NCMe)4]PF6 (10)
[Cu(TpBr3)(NCMe)] (10)
[Cu(TpMs)(THF)] (10)
[CuCl(IPr)] (10)
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0
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[CuI(Xantphos)] (10)
0
9
[Cu(OAc)(Xantphos)] (10)
[Cu(NCMe)2(Xantphos)]BF4 (10)
[Cu(OAc)(Xantphos)] (10)
[Cu(OAc)(Xantphos)] (10)
[Cu(OAc)(Xantphos)] (10)
[Cu(OAc)(Xantphos)] (10)
[Cu(OAc)(Xantphos)] (10)
[Cu(OAc)(Xantphos)] (5)
[Cu(OAc)(Xantphos)] (2)
[Cu(OAc)(Xantphos)] (1)
[Cu(OAc)(Xantphos)] (0.5)
[Cu(OAc)(Xantphos)] (0.1)
[Cu(OAc)(Xantphos)] (5)
[Cu(OAc)] + dppe (5)
[Cu(OAc)] + 2 PPh3 (5)
98
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25#
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Table 2. Scope of the [Cu(OAc)(Xantphos)] catalyzed
3-component reaction.
58 (97%*)
THF
95
EtOAC
DCE
92
74
Toluene
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
93
97
43 (94%*)
10 (19%*)
0
0
0 (98%*)
74%*
82%*
Reaction of 1a (0.5 mmol), 2a (2 eq.), 3a (2 eq.) and catalyst in
solvent (1 mL), stirred overnight in a closed 4 mL vial at room
temperature in air. Yields are determined by 1H NMR spectrosco-
py with 1,3,5-trimethoxybenzene as external standard. * Reac-
tions performed in a N2 filled glovebox. 10 mL of chloroform
was used. Full conversion to 1,1-diisopropyl-3-phenethylurea
#
§
was observed.
We hypothesized that aerobic oxidation of one or more re-
action intermediates could inhibit catalysis. Indeed, perform-
ing the reactions under an N2 atmosphere led to high yields of
the product (Table 1, entries 12, 21 and 25). Surprisingly,
without a catalyst full conversion of dioxazolone 1a to urea
5aa was observed in the presence of amine 3a at room tem-
perature. Further screening (see ESI) demonstrated that sec-
ondary amines are able to activate and decompose 1,4,2-
dioxazol-5-ones, resulting in the urea (Scheme 2). This side
reaction and the Curtius rearrangement catalyzed by an oxi-
dized copper complex likely explain the decreased yields
when using lower catalyst concentrations under aerobic condi-
tions (Table 1, entries 21-22).
Reaction of 1x (0.5 mmol), 2y (2 eq.), 3z (2 eq.) and
[Cu(OAc)(Xantphos)] (5 mol%) in CHCl3 (1 mL), stirred for 10
minutes in a closed 4 mL vial at room temperature. Isolated yields
#
are given. * Performed under an N2 atmosphere. quantitative
formation of product according to 1H NMR with 1,3,5-
trimethoxybenzene as internal standard. $ The urea was formed as
the main product.
The copper catalyzed 3-component reaction produces only
CO2 as a by-product. In view of the atom efficiency of the
process, we tested the efficacy of this reaction with a lower
ratio of phenylacetylene and diisopropylamine relative to the
dioxazolone substrate (see ESI).
Scope of the (Xantphos)Cu-catalyzed reaction
The catalytic reaction is not limited to the use of phe-
nylethyl dioxazolone 1a (Table 2), and actually has a relative-
ly large substrate scope. Longer dioxazolone substrates can be
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used without a decrease in yield (4baa-4daa), and double reaction. To verify our assumption, we further explored the
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bonds are tolerated as well (4eaa). The yield dropped signifi-
cantly for benzyl dioxazolone 1f and cyclohexyl dioxazolone
1g. Presumably, slower activation of the bulkier substrates on
the copper acetylide species leads to faster aerobic decomposi-
tion of the catalyst. The fact that under an atmosphere of N2
products 4faa and 4gaa are obtained in good yields supports
that hypothesis. An oxygen atom at the β-position of the diox-
azolone is deleterious for the yield, as 62% of urea 5ia was
obtained when 1i was used. We suspect that this is the result
of chelation of the substrate or product to copper, inhibiting
the formation of the acetylide on the metal. A first attempt to
apply another terminal alkyne, para-tolyl acetylene, in the
copper catalyzed 3-component reaction yielded only 35% of
N-acyl amidine 4aba. However, again under a protective at-
mosphere of nitrogen we observed high yields of the desired
product (see Table 2). Para-, meta- and ortho-tolyl acetylene
all gave a similar high yield, suggesting a negligible influence
of sterics at the acetylene (4aba-4ada). The electron-rich
4-ethynyl anisole gave slightly lower yields (4aea), which
could be a result of a lower acidity of the acetylene CH bond,
thus leading to less efficient formation of the copper acetylide
complex. When using an alkyl acetylene (2j), which is even
less acidic, product 4aja was not observed. Electron-
withdrawing phenyl acetylenes, on the other hand, were con-
verted with high efficiency (4afa-4aga). Even the use of het-
eroaromatic acetylenes 3-ethynylpyridine and 3-ethynyl-
thiophene resulted in efficient formation of the desired prod-
ucts 4aha and 4aja (79% and 98%, respectively).
effect of changing the steric bulk of the amine. Indeed, the less
bulky amines N-ethyl-iso-propylamine 3e and N-methyl-tert-
butylamine 3f do not result in any desired product formation,
while the bulkier amine N-ethyl-tert-butylamine 3g produced
the desired product 4aag in high yield (96%). The change
from 3f to 3g might seem abrupt, but note that in amine 3g the
ethyl group is pushed away from the tert-butyl group when
coordinated to Cu(I), thus making it much bulkier and hence a
weaker donor. The combined results suggest that smaller
amines poison the catalyst, while the bulkier amines fit poorly
in the “Xantphos pocket” resulting in negligible catalyst inhi-
bition and thus a high product yield (see Figure 3). Upon in-
creasing the steric bulk of the amine further, i.e. employing
2,2,6,6-tetramethylpiperidine (3i) as nucleophile, we observed
formation of the desired product as the enamine tautomer
(4aai, see ESI).
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Table 3. The scope of amines used for the
[Cu(OAc)(Xantphos)] catalyzed 3-component reaction
Figure 3. Proposed catalyst poisoning by small amine substrates.
.
Reaction of 1a (0.5 mmol), 2a (2 eq.), 3z (2 eq.) and
[Cu(OAc)(Xantphos)] (5 mol%) in CHCl3 (1 mL), stirred for 10
minutes in a closed 4 mL vial at r.t.. Isolated yields for 4aaz are
given. * A tautomer (enamine) was isolated.
Next, we explored the scope of using different amines as
coupling partners in reactions catalyzed by [Cu(OAc)-
(Xantphos)] (Table 3). We initially were disappointed to see
that benzylamine, isopropylamine and diethylamine did not
yield any N-acyl amidine (3b-3d). Dicyclohexylamine (3h),
however, did show a very high yield for the formation of the
desired product. We hypothesized that the less bulky amines
might coordinate too strongly to the copper atom, and compete
with coordination of the dioxazolone and thereby inhibit the
Figure 4. 31P NMR studies on the formation of [Cu(CCPh)(Xant-
phos)]. 31P NMR spectra measured under an N2 atmosphere in
CDCl3. (A) [Cu(OAc)(Xantphos)]; (B) [Cu(OAc)(Xantphos)]
with 40 equivalents phenylacetylene; (C) [Cu(OAc)(Xantphos)]
with 40 equivalents iPr2NH; [Cu(OAc)(Xantphos)] with 40 equiv-
alents or both phenylacetylene and iPr2NH under (D) air or (E)
N2; (F) [Cu(CCPh)(Xantphos)] formed from salt metathesis from
[CuCl(Xantphos)] and lithium phenylacetylide.
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Figure 5. Kinetic experiments and X-ray structure of the catalyst interacting with phenyl acetylene. We varied the concentration of the
catalyst and all three substrates, and calculated the slope of the steepest part in the graph as the reaction rate. These rates have been plotted
over the related concentration to give graphs A, B, C and D. Graph E shows the pressure during the reaction towards 4aaa for
[Cu(OAc)(Xantphos)] (red) and [Cu(NCMe)2(Xantphos)]BF4 (blue). F shows the crystal structure obtained by crystallization in the pres-
ence of acetylene, showing a H-bonding interaction with the acetate.
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Together with the formation of the acetylide complex, we
Mechanistic investigations
could always observe a broad peak at  = 13 ppm and free
Xantphos, which might result from clustering of copper spe-
cies. Dimers could be observed in mass spectrometry and
indication for the formation of [Cu3(CCPh)3-(Xantphos)2]
species was obtained by single crystal X-ray diffraction (low
quality data set; see ESI for a connectivity plot).
To get more insight into the reaction mechanism we investi-
gated the kinetics of the reaction, following the pressure build-
up caused by CO2 release during the reaction in a dedicated
closed system as a measure of the substrate conversion over
time.88,89 The observed rates are plotted as a function of the
concentrations of the catalyst and each of the substrates 1a, 2a
and 3a (Figure 5A-D).
To gain more information about the reaction mechanism, we
studied the formation of copper species with 31P NMR spec-
troscopy, investigated the kinetics of the reaction and per-
formed supporting DFT studies.
We used 31P NMR spectroscopy to study the formation of
[Cu(CCPh)(Xantphos)] under optimized reaction conditions,
both in air and under
a
nitrogen atmosphere.
[Cu(OAc)(Xantphos)] in CDCl3 gave a 31P NMR signal at  =
17 ppm (Figure 4A), which remained unchanged upon addi-
tion of phenylacetylene or diisopropylamine (Figure 4B/4C).
When both reactants were added to the solution of
[Cu(OAc)(Xantphos)] in CDCl3 in air, a new signal was ob-
served at  = +29 ppm, which corresponds to Xantphos-P-
dioxide, and a small broad peak at  = 13 ppm emerged as
well (Figure 4D). Under an N2 atmosphere, we did not observe
ligand oxidation and detected a new singlet at 15 ppm, along
with a signal at  = 19 ppm corresponding to free Xantphos
(Figure 4E). Coordination of Xantphos to copper acetylide or
salt metathesis of [CuCl(Xantphos)] with lithium phenylacety-
lide (Figure 4F) led to the same 31P NMR signal at  = 15
ppm, supporting the formation of [Cu(CCPh)(Xantphos)].
The reaction is clearly first order in both [catalyst] and [di-
oxazolone] and (nearly) zero order in [iPr2NH]. The rate de-
pendence of [PhCCH] (Figure 5C) is more complex, and sug-
gestive of saturation kinetics. This behavior is most likely
caused by a (slightly endergonic) pre-equilibrium between
[Cu(OAc)(Xantphos)] and [Cu(CCPh)(Xantphos)]. The exist-
ence of such an equilibrium could be confirmed by H/D ex-
change studies. Burk and coworkers showed with H/D scram-
bling that copper acetates and copper acetylides are in fast
equilibrium.90
In
a
similar
experiment,
using
Rapid
formation
of
copper
acetylide
complex
[Cu(OAc)(Xantphos)] as the catalyst, we also observed H/D
scrambling of phenylacetylene-D and 4-CF3-phenylacetylene
(see ESI for details). Combined with the 31P NMR studies
shown in Figure 4 and the small effect of [iPr2NH] on the rate,
the data suggest that this pre-equilibrium shifts towards the
acetylide complex in the presence of the amine.
[Cu(CCPh)(Xantphos)] upon addition of a base to a reaction
mixture containing both [Cu(OAc)(Xantphos)] and phenylace-
tylene is further associated with a characteristic color change
from colorless to bright yellow.87 The influence of air on the
yield of the catalytic reactions in case of lower catalyst load-
ings or when sterically more demanding dioxazolones are used
implies that [Cu(CCPh)(Xantphos)] reacts with water or diox-
ygen from air.
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Figure 6. DFT (B3LYP-D3-TZ2P) computed energies of the acyl nitrene activation and insertion.
From the catalyst screening studies presented in Table 1, it
is clear that the ‘unsaturated’ [Cu(NCMe)2(Xantphos)]BF4
complex is less selective than [Cu(OAc)(Xantphos)] for the
formation of the N-acyl amidine, indeed confirming that the
acetate plays a prominent role in the catalytic cycle. When
comparing the conversion over time between the reaction
The barriers of these transition states (from D) are very sim-
ilar (~ 7.5 kcal mol-1). The resulting intermediates, E for
TS2-1 and F for TS2-2, are different by only 3.5 kcal/mol and
connected by a low energy barrier transition state TS3 and
thus can both be present during the reaction. The undesired
Curtius rearrangement from intermediate D was calculated to
be ~3 kcal higher in energy than TS2-1 and TS2-2, which is in
line with the experimental observations (see ESI for further
details). For the protodemetalation of the vinylideneamide by
an incoming equivalent of acetylene, acetic acid or even diiso-
propylamine, many pathways can be considered from either E
or F. The protodemetalation was therefore not included in the
DFT studies.
catalyzed
by
[Cu(OAc)(Xantphos)]
and
the
[Cu(NCMe)2(Xantphos)]BF4 (Figure 5E) we observed a very
large difference in rate, confirming that the acetate is im-
portant for rapid formation of the acetylide complex.91 In fact,
the X-ray structure of the [Cu(OAc)(Xantphos)]-HCCPh ad-
duct, obtained by crystallization of [Cu(OAc)(Xantphos)] in
the presence of an excess of phenylacetylene, reveals a direct
hydrogen bonding (H-bonding) interaction between the cop-
per-bound 2-acetate fragment and the acidic proton of the
acetylene (Figure 5F).
Scheme 3. Proposed catalytic cycle.
Further mechanistic information was obtained using density
functional theory (DFT) calculations (Figure 6, see ESI for
details). While rapid formation of acetylide complex B was
observed experimentally during the NMR studies, DFT calcu-
lations show that the acetylene activation pre-equilibrium step
is endergonic by about +3 kcal/mol. This small discrepancy is
likely a medium effect, a result of the reaction being per-
formed under non-standard concentration conditions, or a
combination thereof.92 N-coordination and subsequent activa-
tion of the dioxazolone substrate on the Cu-center, leading to
CO2 dissociation, over TS1 produces acyl nitrene acetylide
intermediate D. Interestingly, two possible transition states
need to be considered for the CN bond formation step, in-
volving acyl nitrene insertion into the CuC bond of the acety-
lide fragment. In TS2-1, the acyl nitrene is 1-N coordinated
and CN coupling leads to a η1-N coordination of the amide
moiety. In TS2-2, the acyl nitrene coordinates in a 2-N,O
fashion and CN bond formation leads to a chelating coordi-
nation of the carbonyl and the triple bond.
The combined information gathered from the catalytic stud-
ies and the mechanistic investigations led us to the proposed
catalytic cycle shown in Scheme 3. The reaction sequence
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are easily accessible and only generates CO2 as by-product
involves activation of acetylene 2a by complex A to form
1
2
3
4
5
6
7
8
acetylide complex B, most likely assisted by the amine. Sub-
sequently, B activates the dioxazolone to form acyl nitrene
intermediate D, which leads to either E or F, followed by
protodemetalation to regenerate A and to form vinylidenea-
mide G. Finally, reaction of the amine with the electrophilic
intermediate G produces the N-acylamidine product 4.
under mild conditions, making this an attractive methodology
for both small and large scale organic synthesis.
ASSOCIATED CONTENT
Experimental procedures, kinetic experiments, NMR spectra,
crystallographic data and coordinates of calculated structures can
be found in the Supporting Information. This material is available
free of charge via the Internet at http://pubs.acs.org.
Table 4. Synthesis of N-benzoyl amidines from aryl-1,4,2-
dioxazol-5-ones catalyzed by CuI.
9
AUTHOR INFORMATION
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Corresponding Author
* b.debruin@uva.nl
Author Contributions
The manuscript was written through contributions of all authors.
Funding Sources
This research was supported by the Netherlands Organization for
Scientific Research (NWO), the Holland Research School of
Molecular Chemistry (HRSMC) and the UvA Research Priority
Area “Sustainable Chemistry”.
ACKNOWLEDGMENT
Reaction of 1a (0.5 mmol), 2a (2 eq.), 3z (2 eq.) and CuI (10
mol%) in CHCl3 (1 mL), stirred for 30 minutes in a closed 4 mL
vial at room temperature. Isolated yields are shown.
We would like to thank Lukas Wolzak, Eduard O. Bobylev and
Ed Zuidinga for the mass spectrometry measurements and Xavier
Caumes for leading us to the [Cu(OAc)(Xantphos)] complex.
Expanding the scope to benzoyl amidines using CuI
As shown in Table 2, phenyl dioxazolone 1h is not convert-
ed by [Cu(OAc)(Xantphos)], thus preventing the one-pot
3-component synthesis of benzoyl amidines when using this
catalyst. However, we argued that it might well be possible to
expand the substrate scope of the newly discovered one-pot
Cu-catalyzed 3-compentent reaction from alkyl dioxazoles to
aryl dioxazolones if we would use a less bulky Cu-catalyst.
Such reactions are desirable, as (just like for N-acyl amidines)
there were up until now no practical or high-yielding reactions
available for the efficient one-pot (multicomponent) synthesis
of benzoyl amidines. Sharpless and Chang published a method
to synthesize the corresponding amidine from a benzoyl azide,
but the desired compound was obtained in only very low yield
(9% based on 1H NMR spectroscopy).44 Hence, we considered
that it remained important to develop new catalytic methods to
convert aryl dioxazolones to benzoyl amidines. Therefore, we
decided to investigate the reactivity of less bulky, phosphine-
free copper salts in reactions using these substrates. Gratify-
ingly, CuI proved to be a suitable catalyst to extend the proto-
col to the synthesis of N-benzoyl amidine derivatives. Using
10 mol% of CuI as the catalyst and phenyl dioxazolone as the
substrate yielded the desired product in 68% isolated yield
(see Table 4). This method works for electron-rich as well as
electron-poor aryl dioxazolones (4jaa, 4kaa). The reaction
still seems to be affected by sterics, but o-phenyl dioxazolone
still produced 4laa in 34% isolated yield.
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