Combining Isocyanides with Carbon Dioxide in Palladium-Catalyzed Heterocycle Synthesis: N3-Substituted Quinazoline-2,4(1H,3H)-diones via a Three-Component Reaction

Article abstract of DOI:10.1021/acscatal.7b01503

We report a Pd-catalyzed three-component reaction of 2-bromoanilines, carbon dioxide, and isocyanides. The combination of these two readily available C₁-reactants, featuring a huge difference in kinetic and thermodynamic stability, is hitherto unprecedented in transition-metal catalysis. With this one-pot three-component reaction, N3-substituted quinazoline-2,4(1H,3H)-diones are obtained in moderate to high yields in a completely regio- and chemoselective manner. Our approach easily allows variation of the arene and N3-substitution pattern of the desired heterocycle. The formal synthesis of different APIs illustrates its practical applicability. In addition, the methodology also allows for a convenient and selective ¹³C-labeling through the use of ¹³CO₂. This is illustrated for [2-¹³C]-2,4-dichloro-6,7-dimethoxyquinazoline synthesis, a key intermediate for several APIs.

Full text of DOI:10.1021/acscatal.7b01503

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Article
Combining Isocyanides with Carbon dioxide in Palladium-
Catalyzed Heterocycle Synthesis: N3-Substituted
Quinazoline-2,4(1H,3H)-diones via a Three-Component Reaction.
Pieter Mampuys, Helfried Neumann, Sergey Sergeyev, Romano V. A. Orru,
Haijun Jiao, Anke Spannenberg, Bert U. W. Maes, and Matthias Beller
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b01503 • Publication Date (Web): 07 Jul 2017
Downloaded from http://pubs.acs.org on July 7, 2017
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Combining Isocyanides with Carbon dioxide in Palladium-Catalyzed
Heterocycle Synthesis: N3-Substituted Quinazoline-2,4(1H,3H)-diones
via a Three-Component Reaction.
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Pieter Mampuys,‡ Helfried Neumann,† Sergey Sergeyev,‡ Romano V. A. Orru,ϒ Haijun Jiao,† Anke Span-
nenberg,† Bert U. W. Maes,‡,* and Matthias Beller†,*
‡ Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp, Belgium
† Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Strasse 29a, 18059 Rostock, Germany
ϒ Department of Chemistry & Pharmaceutical Sciences and Amsterdam Institute for Molecules, Medicines and Systems
(AIMMS), VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
ABSTRACT: We report a Pd-catalyzed three-component reaction of 2-bromoanilines, carbon dioxide and isocyanides. The combi-
nation of these two readily available C1-reactants, featuring a huge difference in kinetic and thermodynamic stability, is hitherto
unprecedented in transition metal catalysis. With this one-pot three-component reaction N3-substituted quinazoline-2,4(1H,3H)-
diones are obtained in moderate to high yields in a completely regio- and chemoselective manner. Our approach easily allows
variation of the arene and N3-substitution pattern of the desired heterocycle. The formal synthesis of different APIs illustrates its
practical applicability. In addition, the methodology also allows for a convenient and selective 13C-labelling through the use of
13CO2. This is illustrated for [2-13C]-2,4-dichloro-6,7-dimethoxyquinazoline synthesis, a key intermediate for several APIs.
Keywords: carbon dioxide; isocyanide; C1-reactants; Pd-catalysis; 13C-labelling
INTRODUCTION
The use of abundant, non-toxic and renewable CO2 in or-
ganic synthesis is of actual interest and continues to attract
attention of the scientific community.1 Despite the significant
advancements made in this area, especially by transition
metal-catalyzed reactions, the incorporation of carbon diox-
ide into heterocycles such as benzo-annulated heteroarenes
has been less explored.2 Other readily available C1-building
blocks, like isocyanides (RNC)3 and CO,4 have been well ex-
plored for this purpose. Obviously, the thermodynamic stabil-
ity and chemical inertness of CO2 is one reason for this strik-
ing difference. The combination of CO2 and RNC in a multi-
Scheme 1. Possible reaction products.
component reaction would be an attractive additional way to
efficiently synthesize heterocycles, as in such an approach a
carbonyl and imine moiety can be introduced simultaneously.
However, the combination of both in transition-metal cata-
lyzed reactions is still unprecedented.5 This is presumably due
to the difference in kinetic and thermodynamic stability of
both C1-reactants. Moreover, CO2 is a gas with a limited solu-
bility in organic solvents, which decreases with increasing
temperature, while RNC are liquids or solids which fully solu-
bilize, further reinforcing the challenge to combine both
reactants in a multicomponent synthesis.
For our method development studies, we selected the
coupling of 2-haloanilines (1) with isocyanides (2) and carbon
dioxide as a suitable model system (Scheme 1). While the
reaction of 2-haloanilines with RNC via double insertion is
known to construct 3-iminoindol-2-amines (6, Scheme 1,
route A),7a the three-component coupling with CO2 to con-
struct benzo-annulated heterocycles has not yet been report-
ed.6,7 Even when an effective catalytic system which suffi-
ciently activates CO2 and tunes the RNC insertion reactivity
can be identified still two reaction products can be obtained,
namely 2-amino-4H-benzo[d][1,3]oxazin-4-one (5)8 and
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Table 1. Model Reaction and Selected Optimization Dataa
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1
2
3
4
5
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7
8
9
CO2
(bar)
Time Yield 3a
(h)
Entry
Ligand
Base
T (°C)
Solvent
(%)b
1
2
BuPAd2 Cs2CO3
80
80
80
80
80
80
80
60
Toluene
Toluene
10
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10
10
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10
10
10
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10
20
5
4
37c
44
0
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Xphos
Dppe
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
NEt3
4
3
Toluene
4
4
/
Toluene
4
0d
Scheme 2. Examples of biologically active N3-substituted
quinazolin-4(3H)-ones and N1,N3-subsituted quinazoline-
2,4(1H,3H)-diones.
5
BuPAd2
BuPAd2
BuPAd2
Toluene
4
0
6
Toluene
4
0
7
Toluene
4
0
9e
4-imino-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one
(4)
8
BuPAd2 Cs2CO3
Toluene
4
5f
(Scheme 1, route B and C). Therefore, both regio- and
chemoselectivity in the reaction of 1 with the two C1-
reactants has to be controlled. As no examples of heterocy-
cles of type 4 could be found in the literature,9 a spontaneous
rearrangement into N3-substituted quinazoline-2,4(1H,3H)-
diones 3 via deprotonation by base was anticipated. This is
interesting as heterocycles 3 are an important class of com-
pounds, which are key intermediates for the synthesis of
biologically active N3-substituted quinazolin-4(3H)-ones and
N1,N3-disubstituted quinazoline-2,4(1H,3H)-diones (Scheme
2).10 Classical synthesis of N3-substituted quinazoline-
2,4(1H,3H)- diones11,12 are typically based on more toxic reac-
tants [e.g. CO, phosgene, phosgene derivatives (isocyanates,
chloroformates, Boc2O), azides]13 and often involve sub-
strates, requiring multistep synthesis resulting in a low overall
efficiency and a difficult variation of the substitution pattern
of the arene ring. Moreover, N-alkylation of quinazoline-
2,4(1H,3H)-diones results in a mixture of N-mono- and dial-
kylated reaction products.14 Only by transformation into the
corresponding 2,4-bis(trimethylsilyloxy)quinazoline selective
N-alkylation can be achieved.14b, 15 However, this occurs at the
N1 rather than the N3-position. In view of the above, the
envisioned synthesis of 3 via a three-component reaction of
two C1-reactants (CO2, RNC), featuring a low toxicity,16 and
readily available 2-haloanilines 1 is interesting from both a
fundamental and synthetic point of view.
9
BuPAd2 Cs2CO3 100
Toluene
4
10
11
12
13
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20
21
a
BuPAd2 Cs2CO3
BuPAd2 Cs2CO3
BuPAd2 Cs2CO3
BuPAd2 Cs2CO3
BuPAd2 Cs2CO3
BuPAd2 Cs2CO3
BuPAd2 Cs2CO3
BuPAd2 Cs2CO3
BuPAd2 Cs2CO3
BuPAd2 Cs2CO3
BuPAd2 Cs2CO3
80
80
80
80
80
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80
80
80
80
80
80
THF
4
65
79
8
1,4-dioxane
CH3CN
4
4
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
4
75
61
42
48
91 (94)g
0h
4
1
4
10
10
0
7
7
7
10
1
7
57i,j
60i,k
65g,l
24
20
BuPAd2
DBU
1
Reaction conditions: 1a (0.5 mmol, 1.0 equiv.), 2a (1.2
equiv.), Pd(OAc)2 (10 mol%), ligand (20 mol%), Cs2CO3 (2.0
equiv.), solvent (1.0 mL), CO2 (x bar), 80 °C, time. BuPAd2 = diad-
amantylbutylphosphine, XPhos
2′,4′,6′-triisopropylbiphenyl,
bis(diphenylphosphino)ethane.
=
2-dicyclohexylphosphino-
Dppe 1,2-
1H NMR yield using 1,3,5-
=
b
trimethoxybenzene as internal standard. Number in parenthesis
is isolated yield. c 55% conversion 1a. d Pd(OAc)2 and ligand were
omitted. e 40% conversion 1a. 99% conversion 1a. 60% of unde-
f
g
sired 6a was obtained. Pd(OAc)2 (3 mol%), BuPAd2 (6 mol%)
h
were used. Ar atmosphere (10 bar). 65% of undesired 6a was
formed. Pd(OAc)2 (1 mol%), BuPAd2 (2 mol%) were used. j 80%
i
conversion 1a. k 89% conversion of 1a. l 92% conversion of 1a.
RESULTS AND DISCUSSION
Interestingly, at 100 °C N-tert-butyl-3-(tert-butylimino)-
3H-indol-2-amine (6a) was the major compound (60%), while
at 80 °C only 3a was selectively formed (entries 1, 9). Howev-
er, at 60°C only a low conversion of 1a and yield of 3a was
observed (entry 8). Solvent screening revealed that 1,4-
dioxane is the optimal solvent for this transformation (entries
1, 10-12). A lower yield of 3a was obtained when the reaction
time was prolonged from 4 to 7 hours (entries 11, 16). On the
other hand, additional reduction of the Pd(OAc)2 and BuPAd2
loading to 3 and 6 mol%, respectively, delivered the desired
Initially, the synthesis of 3-tert-butylquinazoline-
t
2,4(1H,3H)dione (3a) from o-bromoaniline (1a), BuNC (2a)
and CO2 was investigated in the presence of several palladium
phosphine complexes (Table 1). In toluene BuPAd2 proved to
be a suitable ligand for Pd(OAc)2 (10 mol%) affording 3a in
moderate yields (entries 1-3). As expected, without catalyst
no 3a was obtained (entry 4). The use of Cs2CO3 was crucial as
other bases (e.g. K2CO3 and NEt3) or no base did not yield the
desired heterocycle 3a (entries 5-7). Besides the base, also
the reaction temperature turned out to be important.
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Table 2. 2-Bromoaniline (1) scope.a
ACS Catalysis
Table 3. Isocyanide (2) scope.a
1
2
3
4
5
6
7
8
9
Yield
(%)
Yield
(%)
Yield
(%)
Yield
(%)
Entry
1
Entry
9
Entry
1
Entry
5
94b
92d
3a
3i
3j
85b
78c
49b
83b
7b
7c
7d
85
71
65
7f
7g
7h
56
91
58
10
11
12
13
14
15
16
17
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19
20
21
22
23
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31
32
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2
3
4
5
3b 89b 10
3c 88b 11
3d 84b 12
3e 51c 13
2
3
6
7
3k
3l
4
7e
70
8
7i
67
a
Reaction conditions: 1a (0.5 mmol, 1.0 equiv.), 2 (1.2 equiv),
Pd(OAc)2 (3 mol%), BuPAd2 (6 mol%), Cs2CO3 (2.0 equiv.), 1,4-
dioxane (1.0 mL), CO2 (10 bar), 80 °C, 16 h. Isolated yield.
3m 96b
6
7
3f 85b 14
3n
55b
50c
66e
3g
15
3o
3p
73c
77c
8
3h 73b 16
Figure 1. Molecular structure of 7c in the crystal. Only one mole-
cule of the asymmetric unit is depicted. Displacement ellipsoids
are drawn at the 50% probability level. Hydrogen atoms (except
H1) are omitted for clarity.
a
Reaction conditions: 1 (0.5 mmol, 1.0 equiv.), 2a (1.2 equiv.),
Pd(OAc)2 (3 mol%), BuPAd2 (6 mol%), Cs2CO3 (2.0 equiv.), 1,4-
dioxane (1.0 mL), CO2 (10 bar), 80 °C. Isolated yield. b 7 h. c 16 h. d
3-tert-butylquinazoline-2,4-(1H,3H)-diones (3a-h) were ob-
tained in moderate to high yield. Even very electron-rich 2-
bromoanilines such as 1g could be employed. Similarly, mod-
erate, such as halogens (1i-m), and strong electron-
withdrawing substituents, as exemplified by a trifluoromethyl
(1o-p) and an acyl moiety (1n), gave the corresponding 3-tert-
butylquinazoline-2,4-(1H,3H)diones (3i-p) in a good yield.
Notably, the reaction of 1a and 2a with CO2 could readily be
performed on 5 mmol scale.
e
5 mmol scale. Pd(OAc)2 (10 mol%), BuPAd2 (20 mol%), CO2 (2
bar), N2 (1 bar), 16 h.
3a in 94% isolated yield in 7 hours (entry 17). Further reduc-
tion of catalyst loading gave incomplete reaction (entry 19).
Interestingly, 3a could also be obtained at 1 bar of CO2, but a
slower conversion of 1a was then observed (entry 20). This
experiment shows that the chemoselectivity obtained is not
pressure related. When Ar was used as reaction atmosphere
instead of CO2, 6a was obtained as the only product in 65%
(entry 18). The full details of the optimization process can be
found in the SI.
Next, the scope of the reaction with respect to the RNC
reagent (2) was investigated with 1a as the coupling partner
(Table 3). Besides tBuNC (2a), other tertiary isocyanides (2b-c)
were well tolerated, even the very bulky 1-adamantyl isocya-
nide (2b). Reactions of isocyanides involving transition-metal
catalysis are often limited to tertiary RNC as primary and
secondary RNC have a more electrophilic isocyanide C- atom,
With the optimized reaction conditions in hand [1a (1.0
equiv.), 2a (1.2 equiv.), Pd(OAc)2 (3 mol%), BuPAd2 (6 mol%),
Cs2CO3 (2.0 equiv.), 1,4-dioxane (1.0 mL), CO2 (10 bar), 80 °C],
we evaluated the scope of the reaction (Table 2). First, 2a was
coupled with a variety of 2-bromoanilines (1). Substrates
bearing electron-donating (1a-h) substituents were well tol-
erated, irrespective of the position, and the corresponding
which increases their reactivity for insertion.3, Therefore,
we were pleased to observe that this novel three-component
17
reaction could be extended towards secondary (2d-f) and
3
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Considering that easily accessible 2a is a convertible RNC,
the tBu moiety in the N3-position of the reaction product can
also serve as a protecting group allowing initial selective N1-
functionalization, followed by N3-tBu cleavage with HCl yield-
ing N1-substituted quinazoline-2,4(1H,3H)-diones. This is
exemplified for the transformation of 3a into 9 (Scheme 3).
1
2
3
4
5
6
7
8
Scheme 3. Synthesis of 9 via N1-benzylation of 3a and N3-tBu
cleavage of 8.
Selective preparation of isotopically labelled APIs is an
important part for modern drug discovery processes (e.g. for
metabolic studies, internal standards). Readily available,
stable and safe C1 isotopically labelled reactants are ideal for
this purpose. In the past decade 13COgen and Sila13COgen,
both synthesized from 13CO2, have been developed by
Skrydstrup and co-workers as safe 13CO sources for labelling
through carbonylation.19 As 13CO2 is a non-toxic, non-
flammable and cheap carbonylating reactant (Scheme 5),
direct use without pre-transformation into 13CO releasing
reactants is interesting, whenever possible, and we therefore
examined its potential in our three-component protocol.20
2,4-Dichloro-6,7-dimethoxyquinazoline (11) was selected for
this purpose as it is an important precursor for well-known
APIs like Prazosin, Afluzosin and Doxazosin (Scheme 6).21 To
9
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Scheme 4. Synthesis of alkaloid 10 via methylation of 7i.
even primary RNC (2g-i) yielding the target compounds 7d-i
selectively in moderate to high yield, without the formation
of 6. The structures of all 3-substituted quinazoline-2,4-
(1H,3H)diones (3,7) were confirmed by 1H NMR, 13C NMR and
HRMS. Moreover, structures of 7b and 7c were unambiguous-
ly established by single-crystal X-ray measurements (see
Figure 1 and SI).
Many important active ingredients (AI) containing the
quinazoline-2,4(1H,3H)-dione scaffold have unsymmetrical
substitution patterns across the two nitrogen atoms (Scheme
2), which generally cannot be obtained selectively by a direct
alkylation reaction with RX on the parent N-unsubstituted
quinazolinedione core (vide supra). For such cases, our three-
component reaction provides an efficient solution as it direct-
ly delivers N3-subsituted quinazolin-2,4(1H,3H)-diones. A
subsequent alkylation at N1 can be easily performed under
standard alkylation conditions, as exemplified for the synthe-
sis of 8 from 3a (Scheme 3) and for alkaloid 1018 from 7i
(Scheme 4).
Scheme 5. 13C-carbonylating reactants.22
Scheme 6. Classical and three-component approach for 2,4-dichloro-6,7-dimethoxyquinazoline (11) synthesis.
4
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Scheme 7. Proposed mechanism for the synthesis of 3-substituted quinazoline-2,4(1H,3H)diones (3) from 2-bromoanilines (1),
R2NC (2) and CO2.
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obtain
[2-13C]-3-tert-butyl-5,6-dimethoxyquinazoline-
by nitrogen favouring formation of D and finally yielding N3-
subsituted quinazoline-2,4(1H,3H)-dione 3.
2,4(1H,3H)dione ([2-13C]-3g) a minimum amount of 13CO2
preferentially needs to be used. Moreover, challenging sub-
strate 1g is one of the least reactive under the standard con-
ditions of our protocol (Table 2, entry 7). Based on these
considerations, a higher catalyst loading and lower pressure
was selected for labelling. Flushing of the reactor was done
with N2 rather than 13CO2 to avoid spilling. Then, 2 bar of
13CO2 were introduced which gave 72% of [2-13C]-3g after 16
hours with 10% catalyst loading. Two bar 13CO2 corresponds
to only 4 equivalents and represents just 13% of the price of
all the components used in this reaction.22 Reaction of [2-13C]-
3g with POCl3 finally yields [2-13C]-2,4-dichloro-6,7-
dimethoxyquinazoline ([2-13C]-11) in 86% yield. Interestingly,
the classical routes reported for 11 also start from veratrole
and require more steps than our approach (Scheme 6).21,24-25
Moreover, 13C carbonylating agent NH213CONH2 (route A) is
much more expensive and NaO13CN (route B) is not commer-
cially available.
Several control experiments were performed to support the
proposed reaction mechanism. Rearrangement of 4 is sup-
ported by calculations which confirmed that 3 is thermody-
namic more stable (see SI). In addition, we performed an
experiment starting from N-benzyl-2-bromoaniline (1q) and
tert-butyl isocyanide (2a) under the standard conditions
(Scheme 8, A). In this case, 1-benzyl-4-tert-butylimino-1,4-
dihydro-2H-benzo[d][1,3]oxazin-2-one (4q) should be formed
in situ, which cannot rearrange by deprotonation. However,
this type of compounds is known to be unstable and suscep-
tible for hydrolysis.9 In accordance with this we obtained 68%
of N-tert-butyl-N´-benzyl-2-aminobenzamide (12). This prod-
uct is however not formed by a simple direct reaction of aryl
bromide 1q, 2a and water. Carbon dioxide is essential for this
transformation, as supported by a similar experiment under
Ar atmosphere yielding only N-benzylisatin (13) in 84%
(Scheme 8, B). 13 is obtained by hydrolysis of the initially
formed di-(tert-butylimino)isatin. Water in both experiments
comes from Cs2CO3 base. When we dried commercial Cs2CO3
and worked in dry dioxane a reduced amount of 12 was ob-
served under CO2 pressure in accordance with the presence
of a lower amount of water (Scheme 8, C). However, still no
4q could be isolated but instead 45% substrate 1q remained.
Clearly, water also influences the formation of intermediate
4. The reactions are very sensitive to the N-substituent of the
aniline as further exemplified using methyl (2-
bromophenyl)carbamate (1r) under Argon atmosphere. N-
tert-butyl-N´-(methoxycarbonyl)-2-aminobenzamide (14) was
obtained in this case and no isatin (Scheme 8, D), while N-
benzyl-2-bromoaniline (1q) only gave benzamide when work-
ing under CO2 atmosphere (Scheme 8, A and B). By perform-
ing an experiment with 13CO2 it could be proven that C2
comes from CO2, and not from hydrolysis of an imine built in
A plausible mechanism for the formation of 3 from 1 is
presented in Scheme 7. Oxidative addition of 2-
bromoanilines(1) to Pd0L yields complex A. R2NC (2) insertion
into Ar-PdII gives B.23 This complex is in equilibrium with di-
mer B2. A similar dimerization might take place in case of
complex A (not shown). Subsequent reaction with CO2 forms
palladacycle D. Reductive elimination delivers 4, which spon-
taneously rearranges into reaction product 3 under the basic
reaction conditions, and regenerates the active Pd0L complex.
Notably, chemoselectivity is determined in complex B where
a second isocyanide insertion is in competition with reaction
with CO2. Under Ar atmosphere only C can be formed finally
yielding 6. However, in the presence of CO2, the Lewis acidic
PdII centre in complex B activates CO2 for nucleophilic attack
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Scheme 9. Control experiments to check the stability of the
DBU salt of 2-bromophenylcarbamic acid (16).
CONCLUSIONS
In conclusion, we developed a novel three-component re-
action between readily available 2-bromoanilines, RNC and
CO2 affording N3-subsituted quinazoline-2,4-(1H,3H)-diones
in a single step. Our approach easily allows variation of the
arene moiety and the N3-position avoiding the use of more
toxic reactants typically involved in the classical routes. Be-
sides tertiary RNC the reaction also tolerates secondary and
primary RNC, which are often problematic in transition-metal
catalyzed reactions. The obtained N3-subsituted quinazoline-
2,4(1H,3H)-diones were easily post-functionalized, illustrating
the synthetic potential of our methodology. Also selective
labelling can be conveniently performed when using cheap
13CO2. The synthetic method disclosed provides the first ex-
ample in which a kinetic and thermodynamic unreactive (CO2)
and reactive (RNC) C1-reactant are successfully combined in a
transition metal-catalyzed three-component reaction. Even at
1 atm of CO2 complete regio- and chemoselectivity is ob-
served.
Scheme 8. Control experiments with N-benzyl-2-bromoaniline
(1q) and methyl (2-bromophenyl)carbamate (1r). Bn = benzyl.
via an isocyanide reactant (see Scheme 6 and SI). 31P NMR on
model complexes and the crude reaction mixture point to B2
as the resting state of the catalyst (see SI).
Concerning the order of the events in the catalytic cycle
there are two possible pathways, the one presented in
Scheme 7 where oxidative addition is occurring first followed
by R2NC insertion and subsequent reaction with CO2, or one
which starts with the formation of the cesium carbamate salt
of 2-bromoaniline (1a), CO2 and Cs2CO3. To find out whether
the latter is a viable reaction pathway, we performed some
model experiments to evaluate the stability of the 2-
bromophenylcarbamate salt (16). As it is easier to work with a
fully soluble organic base we decided to execute these exper-
iments with DBU, which was found to also be a suitable base
for our reaction protocol (Table 1, entry 21). When 2-
bromoaniline (1a) and 1 equiv. DBU were mixed in dioxane in
the presence of 1 atmosphere CO2 and stirred for 30 minutes
at rt, no DBU salt of 2-bromophenylcarbamic acid (16) was
formed (Scheme 9, A). Only 1a was fully recovered and 70%
ASSOCIATED CONTENT
Supporting Information. Detailed optimization data, experi-
mental procedures, characterization data and copies of NMR
spectra for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: bert.maes@uantwerpen.be
*E-mail: matthias.beller@catalysis.de
-
of the [DBUH+][HCO3 ] salt (15) was isolated.26 Even when
applying 40 bar of CO2 at 40 °C for 16 h a similar result was
obtained (Scheme 9, B). Therefore, we decided to also start
from a stable methyl carbamate precursor which upon hy-
drolysis could give access to 16. When methyl (2-
bromophenyl)carbamate (1r), 1 equiv. DBU and 1 equiv. wa-
ter were brought in dioxane and heated at 80 °C, 38% recov-
ered carbamate 1r, 61% 2-bromoaniline (1a) and 53%
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The research leading to these results has received funding from
the Innovative Medicines Initiative (www.imi.europa.eu) Joint
Undertaking under grant agreement n°115360, resources of
which are composed of financial contribution from the European
Union’s Seventh Framework Programme (FP7/2007-2013) and
EFPIA companies’ in kind contribution, FWO-Flanders (Project,
-
[DBUH+][HCO3 ] salt (15) were obtained (Scheme 9, C). These
experiments
point
to
a
very
unstable
2-
bromophenylcarbamate salt (16) and therefore it is unlikely
to be involved in our catalytic cycle.27
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Jiang, B. J. Org. Chem. 2015, 80, 5764-5770; (b) Zheng, Q.; Ding, Q.;
PhD fellowship and a travel grant for a research stay at LIKAT to
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Liu, X.; Zhang, Y.; Peng, Y. J. Organomet. Chem. 2015, 783, 77-82; (c)
Pandey, G.; Batra, S. RSC Adv. 2015, 5, 28875-28878; (d) Pandey, G.;
Bhowmik, S.; Batra, S. RSC Advances 2014, 4, 41433-41436; (e)
Sharma, S.; Jain, A. Tetrahedron Lett. 2014, 55, 6051-6054; (f)
Estévez, V.; Van Baelen, G.; Lentferink, B. H.; Vlaar, T.; Janssen, E.;
Maes, B. U. W.; Orru, R. V. A.; Ruijter, E. ACS Catal. 2013, 4, 40-43; (g)
Gu, Z.-Y.; Zhu, T.-H.; Cao, J.-J.; Xu, X.-P.; Wang, S.-Y.; Ji, S.-J. ACS Catal.
2013, 4, 49-52; (h) Qiu, G.; He, Y.; Wu, J. Chem. Commun. 2012, 48,
3836-3838; (i) Qiu, G.; Liu, G.; Pu, S.; Wu, J. Chem. Commun. 2012,
48, 2903-2905. (j) Van Baelen, G.; Kuijer, S.; Rýček, L.; Sergeyev, S.;
Janssen, E.; deKanter, F. J. J.; Maes, B. U. W.; Ruijter, E.; Orru, R. V. A.
Chem. Eur. J. 2011, 17, 15039-15044.
P. M.), VLAIO/Catalisti (ARBOREF), UAntwerpen (BOF) and the
Hercules foundation.
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(9)
Only
N1-alkylated
4-(arylimino)-1,4-dihydro-2H-
benzo[d][1,3]oxazin-2-ones, which can not undergo rearrangement
have been reported: Jadidi, K.; Ghahremanzadeh, R.; Mehrdad, M.;
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see: (a) Beutner, G. L.; Hsiao, Y.; Razler, T.; Simmons, E. M.; Wertjes,
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(H=4), Boc2O (H=3), isocyanates (e.g. tBuNCO (H=3)) and azides (H=4)
possess a high toxicity. Scale from 0 (low) to 4 (high).
(14) (a) Ismail, M. A. H.; Barker, S.; Abou El Ella, D. A.; Abouzid, K. A.
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t
(16) NFPA 704 Health (H) rating for CO2 (H=1) and RNC (e.g. BuNC
(H=2)) show a low toxicity. Scale from 0 (low) tot 4 (high).
(17) Delis, J. G. P.; Aubel, P. G.; Vrieze, K.; van Leeuwen, P. W. N. M.;
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Skrydstrup, T. J. Am. Chem. Soc. 2011, 133, 18114-18117. (c)
(24) (a) Lopez-Tapia, F.; Walker, K. A. M.; Brotherton-Pleiss, C.; Ca-
1
2
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Skrydstrup, T. J. Am. Chem. Soc., 2011, 133, 6061-6071.
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(21) Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D., In
Encyclopedia of Pharmaceutical Substances - 4th Edition, Georg
Thieme Verlag, Stuttgart/New York, 2001.
(22) Prizes taken from www.sigmaaldrich.com on 08/04/2017.
(23) For the mechanism of the synthesis of amides from RNC, water
and ArX, see: (a) Perego, L. A.; Fleurat-Lessard, P.; El Kaïm, L.; Ciofini,
I.; Grimaud, L. Chem. Eur. J. 2016, 22, 15491-15500; (b) Liang, Y.; Ren,
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(25) Jones, G.; Stanforth, S. P. in Organic Reactions, John Wiley &
Sons, 2004.
(26) (a) Pérez, E. R.; Santos, R. H. A.; Gambardella, M. T. P.; de Mace-
do, L. G. M.; Rodrigues-Filho, U. P.; Launay, J.-C.; Franco, D. W., J.
Org. Chem. 2004, 69, 8005-8011; (b) Heldebrant, D. J.; Jessop, P. G.;
Thomas, C. A.; Eckert, C. A.; Liotta, C. L., J. Org. Chem. 2005, 70,
5335-5338.
(27) For aniline such a salt with CO2 and DBU has been recently
described, see: Carrera, G. V. S. M.; da Ponte, M. N.; Branco, L. C.
Tetrahedron 2012, 68, 7408-7413.
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TOC graphics
O
Pd(OAc)2 (3 mol %)
R
N
C
R
O
Br
BuPAd2 (6 mol %)
N
R1
R1
+
Cs2CO3 (2.0 equiv)
1,4-dioxane
80 °C, 7-16 h
NH2
N
CO2
H
(24 examples)
up to 96%
CO and phosgene free route
Regio- and chemoselective reaction with 2 different C1-reactants
Selective 13C-labelling using 13CO2
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Scheme 1. Possible reaction products.
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Scheme 2. Examples of biologically active N3-substituted quinazolin-4(3H)-ones and N1,N3-subsituted
quinazoline-2,4(1H,3H)-diones.
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Figure 1. Molecular structure of 7c in the crystal. Only one molecule of the asymmetric unit is depicted.
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Scheme 3. Synthesis of 9 via N1-benzylation of 3a and N3-tBu cleavage of 8.
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Scheme 4. Synthesis of alkaloid 10 via methylation of 7i.
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Scheme 5. 13C-carbonylating reactants
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Scheme 6.Classical and three-component approach for 2,4-dichloro-6,7-dimethoxyquinazoline (11)
synthesis.
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Scheme 7. Proposed mechanism for the synthesis of 3-substituted quinazoline-2,4(1H,3H)diones (3) from 2-
bromoanilines (1), R2NC (2) and CO2.
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Scheme 8. Control experiments with N-benzyl-2-bromoaniline (1q) and methyl (2-bromophenyl)carbamate
(1r). Bn = benzyl.
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Scheme 9. Control experiments to check the stability of the DBU salt of 2-bromophenylcarbamic acid (16).
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