Nickel-Catalyzed Synthesis of Quinazolinediones

Article abstract of DOI:10.1021/acs.orglett.7b00052

A nickel(0)-catalyzed method for the synthesis of quinazolinediones from isatoic anhydrides and isocyanates is described. High-throughput ligand screening revealed that XANTPHOS was the optimal ligand for this transformation. Subsequent optimization studies, supported by kinetic analysis, significantly expanded the reaction scope. The reaction exhibits a case of substrate inhibition kinetics with respect to the isocyanate. Preliminary results on an asymmetric synthesis of atropisomeric quinazolinediones are reported.

Full text of DOI:10.1021/acs.orglett.7b00052

Letter
pubs.acs.org/OrgLett
Nickel-Catalyzed Synthesis of Quinazolinediones
Gregory L. Beutner,* Yi Hsiao, Thomas Razler, Eric M. Simmons, and William Wertjes
Chemical and Synthetic Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey 08903-0191,
United States
S
* Supporting Information
ABSTRACT: A nickel(0)-catalyzed method for the synthesis of
quinazolinediones from isatoic anhydrides and isocyanates is
described. High-throughput ligand screening revealed that
XANTPHOS was the optimal ligand for this transformation.
Subsequent optimization studies, supported by kinetic analysis,
significantly expanded the reaction scope. The reaction exhibits a
case of substrate inhibition kinetics with respect to the isocyanate.
Preliminary results on an asymmetric synthesis of atropisomeric quinazolinediones are reported.
ickel(0)-catalyzed cycloadditions of unsaturated organic
compounds comprise a large family of reactions that give
Scheme 2. Synthetic Routes to Quinazolinediones
N
access to unsaturated five- and six-membered rings.1 When one of
the components is an isocyanate, these transformations allow
access to a broad range of heterocycles including pyridones,2
pyrimidiones,2a,3 amides,4 imides,5 and hydantoins.6 The
reactions proceed via interaction of a nickel(0) complex with
two π-bonds, leading to the formation of an aza-nickelacycle, as
exemplified by intermediate i in the synthesis of pyridones from
alkyne and isocyanate coupling partners (Scheme 1, eq 1).7
Scheme 1. Nickel(0)-Catalyzed Reactions with Isocyanates
of isatoic anhydrides makes it an excellent choice for preparation
of these compounds. However, in the case of the desired N-
arylquinazolinediones where a potential chiral axis exists between
N3 and the pendant aryl ring, such methods provide little
opportunity for asymmetric induction. The synthesis of
quinazolinediones in the presence of copper or palladium
catalysts starting from o-bromobenzoates may provide options
through introduction of a chiral ligand, but these methods have
not been demonstrated for the synthesis of the N-arylquinazo-
linediones of interest.11
Recognizing the broad utility of isatoic anhydrides as an entry
point to the synthesis of quinazolinediones, we hypothesized that
a nickel-catalyzed process could be developed to prepare these
heterocycles from isatoic anhydrides and isocyanates (Scheme 2,
eq 4). The asymmetric synthesis of 2-pyridones from aryl
isocyanates has been achieved using rhodium or iridium
catalysis,12 but no similar atropisomer selective reactions are
known for nickel. In addition, although isocyanates have been
used in a number of nickel(0)-catalyzed processes, reactivity with
Recently, it has been demonstrated that a similar nickelacycle ii
can be accessed through decarboxylative insertion of a nickel(0)
complex into an isatoic anhydride (eq 2),8 which can
subsequently react with alkynes or alkenes to form quinolone
and indole products depending on the reaction conditions.
As part of an ongoing drug discovery program, we became
interested in the synthesis of N-arylquinazolinediones.9 Several
methods exist for the preparation of these heterocycles following
a simple disconnection that leads back to an o-amino benzoic acid
derivative, generally an isatoic anhydride (Scheme 2, eq 3).10
Ring opening with an amine, followed by cyclization with a
carbonylating agent (e.g., carbonyldiimidazole, phosgene), leads
to formation of the quinazolinedione in good yields. The
simplicity of this reaction and the ready availability of awide range
Received: January 6, 2017
© XXXX American Chemical Society
A
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Letter
isatoic anhydrides has not been demonstrated. In this report, we
describe the development of a nickel(0)-catalyzed synthesis of
quinazolinediones from isocyanates and isatoic anhydrides.
Initial screening of the test reaction between N-methylisatoic
anhydride (1a) and o-tolyl isocyanate (2a) using nickel(0) bis-
cyclooctadiene (Ni(cod)2) was conducted in 96-well plate format
to rapidly assay a diverse set of ligands (Table 1).13 Monodentate
Table 2. Effect of Isocyanate Stoichiometry
a
a
entry isocyanate (equiv) conv (3 h, %) conv (20 h, %) yield (%)
Table 1. Results of Achiral Ligand Screening
1
2
3
4
5
6
2a (1.2)
2b (1.2)
2b (2.4)
2b (0.6)
2b (1.2)
2b (1.2)
98
10
4
>99
22
13
54
67
97
98
ND
ND
ND
ND
83
48
54
93
b
c
a
Conversions are calculated on the basis of HPLC area % of 1a and
a
entry
ligand
conv (%)
bite angle16 (deg)
b
2a,b, adjusted for UV response factors. Addition of 2b completed in
two portions of 0.60 equiv. Slow addition of 2b over 1 h.
c
1
PPh3
PCy3
IPr
41
18
39
43
92
48
25
40
36
40
32
48
79
NA
NA
NA
NA
102
105
83
2
3
4
SIPr
isocyanate 2b. To our surprise, XANTPHOS was again identified
as the optimal ligand with few other ligands showing sufficiently
high reactivity to warrant further investigation. Since the Ni(0)−
XANTPHOS catalyst showed different performance at a
screening scale when compared to the gram scale for the reaction
of 1a and 2b, we sought to understand this difference and, thus,
extend the reactivity of our initial screening hit. However,
examination of overall reaction concentration, addition order,
temperature, presence of cyclooctadiene (COD), and headspace
volume showed that none of these factors had a significant
influence on the efficiency of the Ni−XANTPHOS-catalyzed
process at larger scales.
5
XANTPHOS (4)
DPEPhos
DPPE
6
7
8
DPPP
92
9
DPPB
97
11
11
12
13
DPPF
99
BISBI
120
134
NA
DBFphos
PHOX
a
Conversions are calculated on the basis of HPLC area % of 1a and
2a, adjusted for UV response factors.
It was not until we began to investigate the stoichiometry of the
process that a path forward was identified. Based on concerns
about the stability of the isocyanate,17 the loading of the
isocyanate was varied. Although larger amounts of isocyanate did
not lead to improved conversions, lower amounts did (entries 2−
4). On the basis of this result, portionwise addition was explored,
which led to a further increase in conversion. Finally, slow
addition of isocyanate 2b over 1 h led to very high conversions,
comparable to what had originally been observed at the screening
scale (entry 6). This result suggested that having excess
isocyanate relative to catalyst may lead to catalyst inhibition,
possibly due to formation of an inactive, off-cycle intermediate
bound to excess isocyanate. Although it was unclear at this stage
why this change allowed us to translate the screening scale results
to preparative scale, we elected to use this slow-addition method
to continue exploring the reaction scope.
As shown in Figure 1, the slow addition protocol greatly
broadened the reaction scope but was not required in all cases.
Curiously, it appeared that the more sterically hindered
isocyanates were more reactive. The slow addition protocol
allowed for the synthesis of quinazolinediones devoid of ortho-
substituents on the aryl ring as well as alkyl isocyanates, opening
access to a small family of natural products.10a,18 In contrast to the
broad scope of isocyanates that could be employed, the isatoic
anhydride component showed more significant limitations that
could not be overcome by the slow addition protocol or
reoptimization of the ligand. Although substitution on the distal
aryl ring was tolerated, changes to the N1-substituent were not. In
the case of the parent isatoic anhydride (R″ = H) and the N-
benzyl isatoic anhydride, no reaction was observed, even using
slow addition or higher temperatures in toluene. Some reactivity
was observed in the case of the N-phenyl- and N-isopropylisatoic
ligands typically used in this class of transformations gave poor
conversion (entries 1−4). Bidentate ligands gave better results,
with XANTPHOS being the optimal ligand in terms of reaction
conversion (entry 5).14 Examination of the closely related
DPEPhos showed poor results, suggesting that the rigid
conformation of XANTPHOS was critical toward attaining
high reactivity (entry 6). A survey of bidentate ligands with a
broad range of bite angles did not reveal any distinct trend
(entries 7−12), consistent with the hypothesis that rigidity,
rather than bite angle, is responsible for the high performance of
XANTPHOS in this transformation. The only ligand that gave
comparable reactivity to XANTPHOS was the phosphino-
oxazoline ligand PHOX (entry 13). The success of the PHOX
ligand was encouraging since a wide variety of chiral phosphino-
oxazolines are available, while chiral analogues of XANTPHOS
are not readily available.15 Additional solvent screening using
XANTPHOS at a preparative scale revealed that noncoordinat-
ing solvents such as toluene gave high conversions, while more
polar solvents such as N,N-dimethylacetamide showed lower
levels of reactivity. Additionally, a 1:1 XANTPHOS/Ni ratio was
found to be optimal, with excess ligand leading to significantly
lower reaction rates.
Having identified the optimal reaction conditions, we moved
to evaluate the reaction scope at a gram scale. Initial results for the
reaction between 1a and 2a were excellent, but examination of
additional substrates immediately revealed some limitations
(Table 2, entries 1, 2). Surprisingly, the reaction of phenyl
isocyanate (2b) showed a dramatic loss in reactivity. At this point,
we suspected that the initial choice of substrates for ligand
screening might have led to a ligand with poor generality;
therefore, the original ligand set was re-examined using phenyl
B
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Letter
of isocyanate. The data fit nicely to a substrate inhibition model19
where binding of one molecule of isocyanate to nickel would lead
to an active catalyst and binding of the second isocyanate would
lead to an inactive complex, competing with productive binding
of the isatoic anhydride.
We propose the mechanism depicted in Scheme 3 to account
for these observations. Ni(XANTPHOS)2 (5)14,20 undergoes a
Scheme 3. Proposed Mechanism for Catalyst Activation
dissociative ligand exchange with isocyanate to generate the
active intermediate 6. This proposal is consistent with the
negative impact of excess XANTPHOS on reaction rate.
Productive binding of the isatoic anhydride to 6 would generate
7, which could then proceed on to the rate-determining carbon−
oxygen bond-insertion step.21 If binding of an additional
isocyanate to 6 competes with the isatoic anhydride it would
lead to an inactive, off-cycle intermediate 8. The scenario sets up a
competition between active complex 6 and inactive complex 8. In
the complex 6, the presence of an ortho-substituent may disfavor
η2-binding of a second isocyanate in favor of a more compact,
single-point binding to the isatoic anhydride.22 The general form
of this mechanism shows a number of similarities with the
proposed mechanism of nickel(0)-catalyzed cycloadditions
between alkynes and isatoic anhydrides, including the hypothesis
that it is an alkyne-bound nickel(0) catalyst which is the active
catalyst intermediate.23
Having gained some knowledge of the scope and type of ligand
required for the transformation to proceed, the asymmetric
version of the process was investigated. A chiral ligand screen was
undertaken, favoring P,N ligands such as phosphino-oxazoline
ligands,24 but representatives from other chiral ligand classes
were also examined. Reactions were run at 40 °C using 1b and 2d
to minimize the chance of racemization in the product 3bd
through rotation of the carbon−nitrogen chiral axis. As expected,
chiral P,N ligands such as SL-N003 and SIPHOX gave moderate
to good levels of selectivity (Scheme 4).13 This is consistent with
the observations of Murakami and co-workers who found PHOX
ligands optimal in a related nickel(0) catalyzed transformation.3b
In summary, we have developed a nickel(0)-catalyzed
synthesis of quinazolinediones from readily available isatoic
anhydrides and isocyanates. Leveraging the power of ligand
screening, both achiral and chiral ligands were found that
promotes this transformation. Despite encountering some initial
limitations in terms of scope, high yields could be obtained with a
broad range of substrates by employing a slow addition protocol.
The rationale behind the need for slow addition of the isocyanate
Figure 1. Reaction scope with the Ni(0)−XANTPHOS catalyst system.
anhydrides, but even at 100 °C in toluene, conversions could not
be driven beyond 50% after 16 h.
Although a solution to the initial limitations on the substrate
scope had been found, we remained curious about the sluggish
reactivity of the less hindered isocyanates like phenyl isocyanate
2b. We sought to gain additional information about the reaction
through a combination of spectroscopic and kinetic studies. 31
P
NMR studies were not revealing since the catalyst resting state
appeared to be Ni(XANTPHOS)2 (5). Several transient species
were observed, but only at low levels, and they could not be
identified. Kinetic studies of the reaction of 1a and 2a based on
HPLC analysis of reaction aliquots provided more information.13
A curious rate dependence was observed with respect to the
isocyanate 2a (Figure 2). Two kinetic regimes are clear: one at
low concentrations of 2a where the rate is increasing with the
concentration of isocyanate and a second at higher concen-
trations of 2a where the rate is decreasing with the concentration
Figure 2. Dependence of initial rate on concentration of 2a and fitting to
a substrate inhibition model (d[3aa]/dt = k4K1K3[Ni]0[1a][2a]/(1 +
K1([2a]/[4]) + K1K3[1a][2a] + K1K2[2a]2)) shown in Scheme 3.
C
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Letter
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Scheme 4. Asymmetric Synthesis of Quinazolinedione 3bd
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(13) See the Supporting Information for a description and results.
(14) The unique reactivity of XANTPHOS in Ni(0) systems has been
observed previously: (a) Staudaher, N. D.; Stolley, R. M.; Louie, J. Chem.
Commun. 2014, 50, 15577. (b) Kumar, P.; Prescher, S.; Louie, J. Angew.
Chem., Int. Ed. 2011, 50, 10694.
is explained through substrate inhibition of the nickel(0) catalyst
by unproductive binding of a second molecule of isocyanate to a
key catalyst intermediate. It is anticipated that the clues provided
in these studies about the key factors affecting this fruitful class of
reactions can aid in its extension to even more complex and
challenging substrates.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00052.
1
Experimental procedures, characterization data, and H
and 13C NMR data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: gregory.beutner@bms.com.
ORCID
Gregory L. Beutner: 0000-0001-8779-1404
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Mr. Sloan Ayers (BMS) for assistance with MS and
NMR analysis, Dr. Matthew Winston (BMS) for helpful
discussions, and Dr. Robert Waltermire (BMS) for supporting
this work.
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