A Divergent Nickel-Catalyzed Synthesis of Quinazolinediones and Benzoxazinone Imines

Article abstract of DOI:10.1055/s-0037-1610140

During exploration of the nickel(0)-catalyzed reaction of isocyanates and isatoic anhydrides, it was found that changes in the substitution pattern of the isocyanate led to constitutionally isomeric quinazolinediones [quinazoline-2,4(1 H,3 H)-diones] or benzoxazinone imines [2-imino-1,2-dihydro-4 H -3,1-benzoxazin-4-ones]. Ligand and solvent screening experiments allowed for identification of conditions that could lead to each constitutional isomer in good to excellent levels of selectivity and yield. Comprehensive characterization of the previously poorly characterized benzoxazinone imines is also provided.

Full text of DOI:10.1055/s-0037-1610140

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–I
special topic
A
en
W. Wertjes et al.
Special Topic
Synthesis
A Divergent Nickel-Catalyzed Synthesis of Quinazolinediones and
Benzoxazinone Imines
William Wertjesa
Sloan Ayersa
O
O
Qi Gaob
N
O
O
Eric M. Simmonsa
Gregory L. Beutner*a
PPh2
PHOX
R
N
O
N
PPh2
PPh2
O
N
N
O
0
0
0
0
0-
0
0
1
8-
7
7
9
1-
4
0
4
R
N
XANTPHOS
O
CH3
a Chemical and Synthetic Development, Bristol-Myers Squibb
Company, One Squibb Drive, New Brunswick, NJ 08903-0191,
U.S.A.
R'
Ni(cod)2
THF, 60 °C
Ni(cod)2
PhCH3, 80 °C
O
R
N
CH3
R'
CH3
O
C
gregory.beutner@bms.com
b Drug Product Sciences and Technology, Bristol-Myers Squibb
Company, One Squibb Drive, New Brunswick, NJ 08903-0191,
U.S.A.
R'
Dedicated to Prof. Scott Denmark on his birthday.
Published as part of the Special Section dedicated to Scott E. Denmark on the occasion of his 65th birthday
Received: 21.03.2018
Accepted after revision: 09.04.2018
Published online: 17.05.2018
Early studies defined the scope and potential of this
chemistry, more recent work has set the stage for the syn-
thesis of more complex nitrogen-containing heterocycles.
For example, Matsubara and co-workers first demonstrated
that isatoic anhydrides can serve as highly functionalized
4π-components, allowing access to quinolones followed by
the work of Yang and co workers on the synthesis of indoles
in high yields using simple nickel(0) catalysts.5
DOI: 10.1055/s-0037-1610140; Art ID: ss-2018-c0192-st
Abstract During exploration of the nickel(0)-catalyzed reaction of iso-
cyanates and isatoic anhydrides, it was found that changes in the substi-
tution pattern of the isocyanate led to constitutionally isomeric
quinazolinediones [quinazoline-2,4(1H,3H)-diones] or benzoxazinone
imines [2-imino-1,2-dihydro-4H-3,1-benzoxazin-4-ones]. Ligand and
solvent screening experiments allowed for identification of conditions
that could lead to each constitutional isomer in good to excellent levels
of selectivity and yield. Comprehensive characterization of the previ-
ously poorly characterized benzoxazinone imines is also provided.
Table 1 References to Metal-Catalyzed [2+2+2] Heterocycle Synthesis
R1
O
R2
R4
O
R2
R1
R2
R3
Key words quinazolinedione, benzoxazinone, nickel, cycloaddition
N
R2
O
C
N
[2+2+2]
R1
R2
N
R4
N
R1
R1
Transition-metal-catalyzed [2+2+2] cycloadditions are a
powerful strategy for construction of complex aromatic
rings starting from simple and readily available precursors.1
Although much early work focused on alkynes as 2π-com-
ponents, the reactivity of nitriles was soon realized, allow-
ing for access to pyridines.2 Continuing exploration of hetero-
atom containing 2π components slowly gained momentum,
allowing for the synthesis of a wide range of nitrogen-con-
taining heterocycles. At present, the scope of the reaction
includes isocyanates, carbodiimides, and sulfur-containing
heterocumulenes3 as competent substrates.
The synthesis of common heterocycles such as pyri-
dines, pyridones, pyrimidinediones, and their conjugated
analogues has been explored with a variety of metal pre-
cursors including cobalt, iridium, nickel, rhodium, rutheni-
um, and iron among others (Table 1).6–18 In some cases,
achiral examples have been realized (yellow), while in oth-
ers chiral ligands (green) have made possible the synthesis
of axially chiral heterocycles with high levels of selectivity.4
However, clearly gaps still remain (red).
R4
R2
R1
N
cycloaddition
R3
N
R4
O
Pyridines
Pyridones
Pyrimidinediones
Co
ref. 6
ref. 7
Ir
ref. 8
ref. 9
Ni
Rh
Ru
Fe
ref. 10
ref. 13
ref. 16
ref. 18
ref. 11
ref. 14
ref. 17
ref. 12
ref. 15
Recently, we faced the challenge of preparing an axially
chiral quinazolinedione as part of an ongoing drug discov-
ery program.19 Inspired by examples of the synthesis of
closely related pyridones via metal-catalyzed cycloaddi-
tions (Scheme 1, eq. 1), we wondered if a similar disconnec-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

B
W. Wertjes et al.
Special Topic
Synthesis
tion could be employed to construct quinazolinediones
through a catalytic cycloaddition between an isatoic anhy-
dride and an isocyanate (Scheme 1, eq. 2).
R
O
N
R
O
Ni(cod)2 (5 mol%)
XANTPHOS (5 mol%)
O
N
(1)
+
N
C
O
2-MeTHF
60 °C
H
O
H
N
O
O
CH3
CH3
R = H or substituent
(previous work
see ref. 20)
1
2
3
O
O
O
(1.2 equiv)
Ni(cod)2
R'
R'
P(c-C6H11
)
3
N
R
O
H3C
NiLn
(1)
O
N
PhCH3, 80 °C
24 h
N
N
R
+
N
R
R'
– CO2
CH3
O
R'
CH3
O
H3C
Ni(cod)2 (5 mol%)
XANTPHOS (5 mol%)
O
3ab
O
O
MW: 280.12 g/mol
N
C
O
Ni0Ln
(2)
O
(2)
N
2-MeTHF
60 °C
N
O
+
CH3
+
O
R'
CH3
OCN
N
R
O
H3C
O
N
R
O
R'
1a
2b
(1.2 equiv)
N
N
Scheme 1 Proposed Ni-catalyzed synthesis of quinazolinediones
CH3
CH3
4ab
MW: 280.12 g/mol
In an earlier communication we described the success-
ful demonstration of this transformation using the Ni(0)–
XANTPHOS catalyst system (Scheme 2, eq. 1).20 The reac-
tion performed well in the case of alkyl isocyanates as well
as ortho- and unsubstituted aryl isocyanates. We next
wanted to explore the reactions of ortho,ortho-disubstitut-
ed aryl isocyanates, since the resulting ortho,ortho-disub-
stituted N-aryl-quinazolinediones would be of interest due
to their known biological activity.21 Based on the good to
excellent yields we had obtained with a range of aryl isocy-
anates, we did not anticipate significant challenges when
moving to these more hindered substrates. But addition of a
second ortho-substituent to the aryl isocyanate altered the
reaction outcome in an unexpected manner. As reported
herein, further investigations of impurities formed in those
studies led to the discovery of a divergent, ligand-controlled
synthesis of two distinct heterocycles, quinazolinediones
and benzoxazinone imines, starting from a single set of
starting materials.
Scheme 2 Ni(0)-catalyzed reactions of isocyanates and isatoic anhy-
drides
Upon consideration of the reaction mechanism, we hy-
pothesized that due to steric constraints, it was possible
that insertion could occur across the distal C=O bond of the
isocyanate rather than the hindered C=N bond. The result-
ing product would be a benzoxazinone imine. Based on a
review of the literature,22 the formation of this heterocycle
did not seem unreasonable, but further study was needed
to confirm this hypothesis due to the dearth of existent
structural information on benzoxazinone imines. Growth of
single crystals for X-ray diffraction analysis finally secured
identification of this new product as a constitutional iso-
mer of the desired quinazolinedione, the benzoxazinone
imine 4ab (Figure 1).23
In initial experiments with isatoic anhydride (1a) and
2,6-dimethylphenyl isocyanate (2b) under the standard
conditions
using
bis(cycloocta-1,5-diene)nickel(0)
[Ni(cod)2] and XANTPHOS, we obtained a small amount of
the desired product 3ab (Scheme 2, eq. 2). Significant
amounts of a second compound were also formed. LC-
HRMS revealed that this byproduct had an identical ele-
mental composition to the desired product. This byproduct
was isolated and its structure was probed by various spec-
Figure 1 ORTEP diagram (50% ellipsoid probability) of benzoxazinone
imine 4ab
1
troscopic techniques. H and 13C NMR spectroscopy and IR
The X-ray structure revealed several interesting features
of this heterocycle. It presents a Z-imine with the N-aryl
group forming a dihedral of 76.1° with the main ring sys-
tem. The C=N bond is 1.260(2) Å, and the ester group is dis-
torted with an O–C–O angle of 127.8(2)°. With the struc-
ture confirmed, we completed NMR assignments for 3ab
and 4ab as shown in Table 2.
spectroscopy revealed only subtle differences between 3ab
1
and the unknown H-13C HMBC spectra showed identical
C–H connectivity in the two products. 1H-15N HMBC spectra
revealed a substantial chemical shift difference was ob-
served between the two products (δ = 164.7 vs 196.9), but
this did not allow for unambiguous identification of the un-
known structure.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

C
W. Wertjes et al.
Special Topic
Synthesis
Table 2 13C and 15N NMR Data for 3ab and 4ab
sults observed with XANTPHOS, solvent choice appeared to
have little effect on conversion or selectivity with P,N
ligands and THF was selected for further development.
14
13
O
15
16
O
19
14
3
6
3
6
19
11
N
10
2
7
2
7
13
12
1
12
1
15
16
4
5
4
5
O
17
Table 3 Ligand Screening for Formation of 3ab and 4ab
10
8
N
8
N
O 18
N
17
18
11
H3C
9
9
O
O
3ab
4ab
N
O
CH3
Position
δC
δN
δC
δN
N
O
N
O
CH3
Ni(cod)2 (5 mol%)
ligand (5 mol%)
CH3
1
160.5
114.8
128.0
123.0
135.8
115.0
141.0
157.7
109.7
129.5
121.8
137.4
114.0
143.4
3ab
1a
2
solvent
60 °C, 16 h
+
+
3
H3C
O
N
H3C
O
4
OCN
5
CH3
N
6
CH3
CH3
4ab
2b
(1.2 equiv)
7
8
114.2
164.7
96.3
Entry
Ligand
Solvent
Conv. (%)a
Ratioa 3ab/4ab
9
30.7
32.5
1
2
3
4
5
6
7
8
9
10
XANTPHOS
DPEPhos
DPPE
PhCH3
93
14
1
44:56
50:50
67:33
98:2
10
149.4
140.9
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
THF
11
196.9
12
134.4
135.3
128.1
128.2
17.2
143.3
128.3
127.4
122.3
18.0
DPPP
18
7
13, 17
14, 16
15
DPPB
94:6
DPPF
16
29
9
75:25
92:8
BISBI
18, 19
DBFPhos
DPPEpy
PHOX
94:6
>99
>99
>99:1
>99:1
With the identity of the constitutional isomer con-
firmed, we next attempted to identify orthogonal reaction
conditions that would lead to selective formation of the
benzoxazinone and quinazolinedione products. Work by
Belmont and co-workers has demonstrated the potential of
ligand control over cyclization of amides in a rhodium-cata-
lyzed reaction, producing related heterocyclic constitution-
al isomers.24 Ligand and solvent screening in the reaction
between 1a and 2b (Table 3)25 showed that XANTPHOS was
unique in its ability to generate significant amounts of the
benzoxazinone 4ab, particularly in non-polar solvents such
as toluene (entry 1). Closely related ligands, including DPE-
Phos and other large bite angle bis-phosphines,26 gave low-
er reactivity and favored formation of quinazolinedione 3ab
when compared to XANTPHOS (entries 2–8). The highest
selectivity was observed with P,N chelating ligands such as
DPPEpy27 and PHOX28 which gave complete selectivity for
formation of 3ab (entries 9 and 10). In contrast to the re-
a Calculated based on HPLC area percent of 1a, 3ab, and 4ab adjusted for
UV response factors.
After a brief examination of reaction temperature, we
arrived at conditions which could provide the desired
quinazolinedione or benzoxazinone in moderate to excel-
lent yields (Table 4). Use of the achiral PHOX ligand provid-
ed high levels of selectivity for the quinazolinediones 3 (en-
tries 1–5) while XANTPHOS was optimal for synthesis of
the benzoxazinones 4 (entries 6–10). In the case of the
Ni(0)-XANTPHOS-catalyzed process, selectivity was signifi-
cantly lower than with the PHOX ligand but appeared to
improve as the steric demands of the isocyanate increased
(entry 10). The hindered tert-butyl isocyanate (2g) yielded
quinazolinedione 3ag in high yield using the PHOX ligand
(Scheme 3); however, no reaction of 1a and 2g was ob-
served with XANTPHOS.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

D
W. Wertjes et al.
Special Topic
Synthesis
Table 4 Reaction Scope for Formation of 3 and 4
3 and 4. IR spectroscopy showed that 3 had a clear band at
~1720 cm–1, while 4 exhibited a distinctive band at higher
frequency (~1765 cm–1). Finally, several significant differ-
ences were observed in the NMR spectra, namely the 15N
chemical shift for N-11 (δ = ~165 vs ~197 for 3 vs 4, respec-
tively) and the 13C chemical shift for C-10 (δ = ~150 vs ~141
for 3 vs 4, respectively). MS analysis did not provide a con-
sistent method for differentiating between the two consti-
tutional isomers. Only in the cases of the more sterically
hindered benzoxazinones 4ac–4af, MS/MS facilitated iden-
tification of the structure due to the loss of CO2 in the major
molecular fragment.
R
O
N
N
R'
O
O
N
R
CH3
Ni(cod)2 (5 mol%)
ligand (5 mol%)
O
3ab–af
N
C
O
solvent (0.28 M)
60–80 °C
+
O
R'
O
CH3
R
O
1a
2b–f
(1.2 equiv)
N
N
CH3
R'
We monitored the progress of the reaction using HPLC
analysis with two substrates to probe for differences which
might explain formation of the different heterocycles
(Scheme 4). In the presence the Ni(0)–XANTPHOS complex,
the reaction of mono-ortho-substituted isocyanate 2a was
found to be significantly faster than that of di-ortho-substi-
tuted isocyanate 2b (compare green and purple trace).
None of benzoxazinone 4aa derived from mono-ortho-sub-
stituted isocyanate 2a was detected at any point during the
reaction.
4ab–af
PPh2
N
O
PPh2
PPh2
O
XANTPHOS
PHOX
Entry
2
Conv.a (%)
[Ratio 3/4]
Yieldb (%)
3
4
1
2
3
4
5
6
7
8
9
10
Me, Me (2b)
Et, Et (2c)
>99c [>99:1]
>99c [>99:1]
>99c [>99:1]
95c [>99:1]
87c [>99:1]
90d [25:75]
88d [50:50]
84d [33:67]
73d [33:67]
91d [1:99]
83 (3ab)
91 (3ac)
87 (3ad)
96 (3ae)
76 (3af)
15 (3ab)
37 (3ac)
20 (3ad)
13 (3ae)
–
–
–
–
–
–
i-Pr, i-Pr (2d)
Me, i-Pr (2e)
Me, t-Bu (2f)
Me, Me (2b)
Et, Et (2c)
53 (4ab)
56 (4ac)
46 (4ad)
52 (4ae)
80 (4af)
i-Pr, i-Pr (2d)
Me, i-Pr (2e)
Me, t-Bu (2f)
a. Based on HPLC area percent of 3 and 4.
b Based on isolated material.
c PHOX, THF, 60 °C, 4 h.
d XANTPHOS, toluene, 80 °C, 4 h.
O
N
O
Ni(cod)2 (5 mol%)
PHOX (5 mol%)
N
C
O
O
N
O
THF (0.28 M)
60 °C, 6 h
N
O
CH3
CH3
1a
2g
(1.2 equiv)
3ag
88% yield
Scheme 3 Reaction of isatoic anhydride with tert-butyl isocyanate
Scheme 4 Kinetic analysis of the reactions of 2a and 2b
Consideration of the series of compounds as a whole re-
vealed some systematic differences between heterocycles 3
and 4, consistent with previous observations from the liter-
ature.29 All benzoxazinones 4 were significantly less polar
than the corresponding quinazolinediones 3, allowing for
easy separation by chromatography. UV-VIS spectroscopy
revealed a clear and systematic bathochromic shift between
In contrast, under identical reaction conditions, the
disubstituted isocyanate 2b exhibited stalling that was co-
incident with a shift in the product selectivity towards 4ab
(red trace). Initial selectivity between 4ab and 3ab was
nearly 1:1 but shifted to 4:1 by the time the reaction had
stalled at ~50% conversion after 3 h. This could signify a
change in the resting state of the nickel catalyst or it could
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

E
W. Wertjes et al.
Special Topic
Synthesis
suggest an equilibrium between 3 and 4. Investigation of
Table 5 Equilibration Studies on 4ab
this reaction mixture by 31P NMR did show a change in the
O
R
30
catalyst resting state from Ni(XANTPHOS)2 to a new, un-
O
Me
O
identified signal coincident with the reaction stalling. This
new species appeared to be catalytically inactive since ad-
dition of fresh substrates did not lead to any additional
product formation or change in product selectivity.
N
N
N
R'
N
O
CH3
Me
Ni(cod)2 (5 mol%)
ligand (5 mol%)
CH3
4ab
3ab–ac
4ab–ac
+
+
To test whether the formation of 3 and 4 is reversible in
the Ni(0)–XANTPHOS catalyzed reaction, a series of experi-
ments was designed in which benzoxazinone 4ab was re-
subjected to the reaction conditions. Earlier studies demon-
strated that benzoxazinones were the kinetic products of
the reaction between anthranilic acids and isocyanates.31
The benzoxazinones could then be converted into the ther-
modynamically favored quinazolinediones by prolonged
heating in the presence of a Brønsted acid through a process
similar to the Chapman rearrangement.32 Control experi-
ments in this system revealed that equilibration between 4
and 3 did not occur upon heating alone or in the presence
of Ni(cod)2 or ligand individually. However, in the presence
of ligated nickel complexes, reversibility was observed un-
der mild conditions (Table 5). Benzoxazinone 4ab was com-
pletely converted into quinazolinedione 3ab in less than 1 h
in the presence of both the Ni(0)–PHOX and Ni(0)–XANTPHOS
catalysts (entries 1 and 2). Although this result seems at
odds with the high selectivity for the benzoxazinones 4 ob-
served with the Ni(0)–XANTPHOS complex, catalyst de-
composition during the actual reaction may prevent full
equilibration to 3, consistent with the results of the 31P
NMR monitoring of the reaction (vide supra).
To gain additional insights into the equilibration mecha-
nism, we repeated the experiments in the presence of iso-
cyanate 2c to probe for the formation of cross-over prod-
ucts (entries 3 and 4). With the Ni(0)–PHOX catalyst, less
than 1% of the isomeric cross-over products derived from
incorporation of 2c were observed. In contrast significant
amounts of 3ac/4ac were formed using the XANTPHOS cat-
alyst in the presence of 2c.
Considering these results a mechanism can be proposed
for the reaction to rationalize formation of the benzoxazi-
nones (Scheme 5). The pre-formed Ni(XANTPHOS)2 com-
plex i is the catalyst resting state and undergoes dissociative
ligand exchange to give the isocyanate-bound complex ii
and free XANTPHOS. This species ii is then in equilibrium
with two other catalytic intermediates iii and iv. For unhin-
dered isocyanates, binding of a second molecule of isocya-
nate leads to the inactive, off-cycle intermediate iii. Alter-
natively, binding of isatoic anhydride leads to the produc-
tive complex iv. This complex iv can then undergo insertion
in the acyl C–O bond of the isatoic anhydride with release of
carbon dioxide to give complex v. The nickel(II) center in v
can bind to either the distal C=O or the proximal C=N bond,
depending on the steric demands of the aryl group. The
O
solvent (0.28 M)
Et
R
O
OCN
N
N
Et
CH3
R'
2c
Entry
Methoda
Additive
3ab
4ab
3ac
4ac
(%)b
(%)b
(%)b
(%)b
1
2
3
A
B
A
none
100
0
0
0
0
0
none
100
0
0
+ 2c (1.2
99.4
0.4
0.2
equiv)
4
B
+ 2c (1.2
54.6
7.5
27.5
10.4
equiv)
a Method A: PHOX, THF, 60 °C, 1 h; B: XANTPHOS, toluene, 80 °C, 1 h.
b Reported values are HPLC area percent.
product determining step likely arises from this isocyanate-
bound intermediate v in the final insertion and reductive
elimination. This final reductive elimination is reversible,
allowing for equilibration between the benzoxazinone
imine and quinazolinedione isomers. Matsubara and co-
workers have ascribed selectivity in the nickel(0)-catalyzed
reaction of unsymmetrical alkynes and isatoic anhydrides5c
to minimization of steric interactions in related intermedi-
ates prior to reductive elimination.33 The fact that forma-
tion of the benzoxazinone imine, which requires insertion
into the distal C=O bond of the isocyanate, is sensitive to the
steric demands of the pendant aryl group is consistent with
this computational analysis.
In conclusion, we have discovered a novel and divergent
method for synthesis of quinazolinediones or benzoxazi-
none imines starting from readily available isatoic anhy-
drides and ortho-disubstituted aryl isocyanates. Ligand
choice in this nickel(0)-catalyzed reaction is critical and
XANTPHOS was shown to be unique in its ability to form
the benzoxazinone imine. Switching to the PHOX ligand al-
lowed for synthesis of the constitutionally isomeric
quinazolinediones in excellent yields and selectivities. Al-
though we are unable at this point to completely rationalize
this intriguing change in selectivity, this work demon-
strates the utility of iterative rounds of reaction screening
to develop truly general processes and highlights the op-
portunities that a ‘failed’ reaction can present for new dis-
coveries.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

F
W. Wertjes et al.
Special Topic
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.12 (m, 3 H), 3.25 (sept, J = 7.0 Hz, 1
H), 2.36 (s, 3 H), 1.26 (d, J = 7.0 Hz, 6 H).
13C{1H} NMR (100 MHz, CDCl3): δ = 142.7, 133.4, 130.0, 127.8, 125.7,
Ar
O
N
L
L
L
L
L
L
C
Ar
N
Ni0
Ni0
C
O
124.2, 123.6, 29.4, 22.8, 18.9.
N
Ar
O
N
i
O
O
iii
Me
L
L
Ar
3-(2,6-Dimethylphenyl)-1-methylquinazoline-2,4(1H,3H)-dione
(3ab); Typical Procedure 1 (TP1)
O
N
C
O
Ar
Ar
O
N
C
N
L
L
N
C
O
Ni(cod)2 (40 mg, 0.141 mmol, 0.05 equiv) and PHOX (47 mg, 0.141
mmol, 0.05 equiv) were combined and dissolved in THF (5 mL). The
mixture was stirred for 10 min to give a dark green solution. This
solution was then added to a suspension of 1a (0.5 g, 2.82 mmol, 1.0
equiv) and 2,6-dimethylphenyl isocyanate (2b; 0.476 mL, 3.38 mmol,
1.2 equiv) in THF (5 mL). The vial was capped and heated to 60 °C for 4
h, or until full conversion was observed by HPLC analysis. Concentra-
tion of the resulting brown solution followed by direct purification by
chromatography (silica gel) gave 3ab (0.65 g, 83%) as a white crystal-
line solid; Rf = 0.50 (hexanes/EtOAc 7:3); mp 183 °C (DSC).
Ni0
Me
O
O
N
ii
Ar
Me
N
O
Ar
C
O
N
Ar
N
Ni
L
L
O
O
C
Ni0
Ln
N
O
R
O
IR (solid state): 1719, 1707, 1660, 1606, 1499, 1480, 1448, 1424,
1380, 1344, 1329, 1316, 1262, 1189, 1170, 1146, 1113 cm–1
.
O
O
O
1H NMR (400 MHz, CDCl3): δ = 8.29 (d, J = 7.6 Hz, 1 H), 7.77 (t, J = 7.3
N
C
Ni
Hz, 1 H), 7.29 (m, 3 H), 7.19 (d, J = 7.2 Hz, 2 H), 3.68 (s, 3 H), 2.13 (s, 6
H).
13C{1H} NMR (100 MHz, CDCl3): δ = 161.0, 150.1, 141.1, 135.4, 135.3,
134.0, 129.4, 128.8, 128.5, 123.0, 115.7, 113.7, 30.9, 17.7.
Ar
N
Ln
N
iv
R
CO2
v
HRMS: m/z [M + H]+ calcd for C17H17N2O2: 281.1285; found: 281.1290.
Scheme 5 Proposed reaction mechanism
UV (MeCN): λ = 223, 246, 314 nm.
3-(2,6-Diethylphenyl)-1-methylquinazoline-2,4(1H,3H)-dione
(3ac)
Required reagents, chemicals, and solvents were purchased from
commercial vendors and used without additional purification. 1-
Methyl-3,1-benzoxazine-2,4-dione (1a) was crystallized prior to use
as follows: The crude material was slurried in DMAc (5 mL/g) and
heated to 60 °C to generate a solution. To this was slowly added water
(2.5 mL/g). The resulting slurry was allowed to cool to r.t. and age for
several hours before filtration, washing twice with 2 mL/g water and
then drying under an N2/vacuum sweep overnight. The crude, com-
mercial material could be used for the reaction, but led to lower
yields. Anhydrous, degassed solvents were used for all reactions. The
presence of BHT as inhibitor was not found to be detrimental to reac-
tivity or selectivity. All reactions were prepared and performed in an
inert atmosphere glovebox.
Following TP1: Ni(cod)2 (40 mg, 0.141 mmol, 0.05 equiv), PHOX (47
mg, 0.141 mmol, 0.05 equiv), 1a (0.5 g, 2.82 mmol, 1.0 equiv), and
2,6-diethylphenyl isocyanate (2c; 0.585 mL, 3.38 mmol, 1.2 equiv)
were combined in THF (10 mL) and heated to 60 °C for 4 h before di-
rect purification by chromatography (silica gel) to yield 3ac (0.79 g,
91%) as a white crystalline solid; Rf = 0.61 (hexanes/EtOAc 7:3); mp
135 °C (DSC).
IR (solid state): 1710, 1660, 1604, 1482, 1460, 1421, 1378, 1324,
1313, 1290, 1259, 1184, 1162, 1142, 1116 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.29 (dd, J = 8.2, 1.5 Hz, 1 H), 7.76 (dt,
J = 7.6, 1.5 Hz, 1 H), 7.38 (t, J = 7.6 Hz, 1 H), 7.32 (m, 2 H), 7.25 (m, 2 H),
3.86 (s, 3 H), 2.42 (q, J = 7.6 Hz, 4 H), 1.16 (t, J = 7.6 Hz, 6 H).
2-Isopropyl-6-methylphenyl Isocyanate (2e)
13C{1H} NMR (100 MHz, CDCl3): δ = 161.5, 150.6, 141.1, 140.7, 135.4,
The 2-isopropyl-6-methylaniline (5.0 g, 33.5 mmol, 1.0 equiv) and
Me3N (4.7 mL, 33.5 mmol, 1.0 equiv) were dissolved in EtOAc (50 mL)
and cooled in an ice bath. To this was added a solution of triphosgene
(4.6 g, 15.1 mmol, 0.45 equiv) in EtOAc (50 mL) via a dropping funnel
over 10 min. The bath was then removed and the thick suspension
was stirred at r.t. for 1 h. The mixture was then filtered through Celite
and the cake washed with EtOAc. The combined organics were
washed with water (100 mL) and 0.2 M pH 8 sodium phosphate buffer
(2 × 100 mL) (a mildly basic buffer wash is required to decompose re-
sidual triphosgene which can inhibit the reaction) and then dried
(Na2SO4), filtered, and concentrated to give 2e (4.78 g, 82%, 95 wt% by
NMR) as a tan oil. The isocyanate was of acceptable quality to be used
without further purification.
132.8, 129.5, 129.1, 126.4, 123.0, 115.7, 113.7, 30.9, 24.0, 13.8.
HRMS: m/z [M + H]+ calcd for C19H21N2O2: 309.1598; found: 309.1602.
UV (MeCN): λ = 223, 246, 313 nm.
3-(2,6-Diisopropylphenyl)-1-methylquinazoline-2,4(1H,3H)-di-
one (3ad)
Following TP1: Ni(cod)2 (40 mg, 0.141 mmol, 0.05 equiv), PHOX (47
mg, 0.141 mmol, 0.05 equiv), 1a (0.5 g, 2.82 mmol, 1.0 equiv), and
2,6-diisopropylphenyl isocyanate (2d; 0.72 mL, 3.38 mmol, 1.2 equiv)
were combined in THF (10 mL) and heated to 60 °C for 4 h before di-
rect purification by chromatography (silica gel) to yield 3ad (0.82 g,
87%) as a white crystalline solid; Rf = 0.71 (hexanes/EtOAc 7:3); mp
195 °C (DSC).
IR (toluene): 2293, 2270 cm–1
.
IR (solid state): 1712, 1661, 1606, 1480, 1465, 1420, 1376, 1364,
1340, 1322, 1308, 1290, 1258, 1184, 1163, 1144, 1116 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

G
W. Wertjes et al.
Special Topic
Synthesis
1H NMR (400 MHz, CDCl3): δ = 8.24 (dd, J = 8.4, 1.5 Hz, 1 H), 7.76 (dt, J
= 7.3, 1.5 Hz, 1 H), 7.44 (t, J = 7.9 Hz, 1 H), 7.31 (m, 4 H), 3.67 (s, 3 H),
2.66 (sept, J = 6.7 Hz, 2 H), 1.18 (d, J = 6.8 Hz, 6 H), 1.16 (d, J = 6.8 Hz, 6
H).
IR (solid state): 1700, 1652, 1606, 1497, 1481, 1464, 1418, 1394,
1365, 1344, 1323, 1276, 1253, 1234, 1191, 1168, 1146, 1118 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.07 (d, J = 7.6 Hz, 1 H), 7.60 (t, J = 7.6
Hz, 1 H), 7.19 (t, J = 7.6 Hz, 1 H), 7.10 (d, J = 8.2 Hz, 1 H), 3.50 (s, 3 H),
1.76 (s, 9 H).
13C{1H} NMR (100 MHz, CDCl3): δ = 161.7, 150.8, 145.5, 141.1, 135.4,
131.0, 129.6, 129.5, 124.0, 123.0, 115.7, 113.7, 31.0, 29.0, 24.0, 23.9.
HRMS: m/z [M + H]+ calcd for C21H25N2O2: 337.1911; found: 337.1916.
13C{1H} NMR (100 MHz, CDCl3): δ = 163.7, 151.7, 140.1, 134.2, 128.3,
122.3, 118.2, 113.0, 62.0, 30.6, 29.7.
UV (MeCN): λ = 221, 246, 314 nm.
HRMS: m/z [M + H]+ calcd for C13H17N2O2: 233.1285; found: 233.1287.
UV (MeCN): λ = 222, 247, 315 nm.
3-(2-Isopropyl-6-methylphenyl)-1-methylquinazoline-
2,4(1H,3H)-dione (3ae)
(Z)-2-[(2,6-Dimethylphenyl)imino]-1-methyl-1,2-dihydro-4H-3,1-
Following TP1: Ni(cod)2 (40 mg, 0.141 mmol, 0.05 equiv), PHOX (47
mg, 0.141 mmol, 0.05 equiv), 1a (0.5 g, 2.82 mmol, 1.0 equiv), and 2-
isopropyl-6-methylphenyl isocyanate (2e; 0.61 mL, 3.38 mmol, 1.2
equiv) were combined in THF (10 mL) and heated to 60 °C for 4 h be-
fore direct purification by chromatography (silica gel) to yield 3ae
(832 g, 96%) as a white crystalline solid; Rf = 0.56 (hexanes/EtOAc
7:3); mp 143 °C (DSC).
benzoxazin-4-one (4ab); Typical Procedure 2 (TP2)
Ni(cod)2 (162 mg, 0.564 mmol, 0.05 equiv) and XANTPHOS (334 mg,
0.564 mmol, 0.05 equiv) were combined and dissolved in toluene (20
mL). The mixture was stirred for 10 min to give a bright orange solu-
tion. This solution was then added to a suspension of 1a (2.0 g, 11.3
mmol, 1.0 equiv) and 2,6-dimethylphenyl isocyanate (2b; 1.9 mL,
13.5 mmol, 1.2 equiv) in toluene (10 mL). The flask was capped with a
septum and needle vent and heated to 80 °C for 4 h, or until full con-
version was observed by HPLC analysis. Concentration of the resulting
brown solution followed by direct purification by chromatography
(silica gel) gave 4ab (1.67 g, 53%) as a white crystalline solid; Rf = 0.70
(hexanes/EtOAc 7:3); mp 165 °C (DSC).
IR (solid state): 1715, 1701, 1658, 1610, 1479, 1422, 1378, 1344,
1325, 1313, 1293, 1261, 1185, 1171, 1161, 1145, 1126 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.30 (d, J = 7.9 Hz, 1 H), 7.74 (t, J = 7.4
Hz, 1 H), 7.35 (m, 4 H), 7.19 (d, J = 7.0 Hz, 1 H), 3.68 (s, 3 H), 2.72 (sept,
J = 6.7 Hz, 1 H), 2.14 (s, 3 H), 1.21 (d, J = 6.7 Hz, 3 H), 1.19 (d, J = 6.7 Hz,
3 H).
13C{1H} NMR (100 MHz, CDCl3): δ = 161.3, 150.4, 145.8, 141.0, 135.3,
135.0, 132.5, 129.3, 129.0, 128.2, 124.0, 122.9, 115.6, 113.7, 30.8, 28.6,
23.8, 23.7, 17.9.
IR (solid state): 1764, 1667, 1607, 1589, 1492, 1467, 1421, 1368,
1339, 1323, 1271, 1254, 1241, 1210, 1170, 1148, 1125 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.05 (d, J = 7.3 Hz, 1 H), 7.7 (t, J = 8.2
Hz, 1 H), 7.14 (m, 2 H), 7.04 (m, 2 H), 6.90 (t, J = 7.3 Hz, 1 H), 3.72 (s, 3
H), 2.15 (s, 6 H).
13C{1H} NMR (100 MHz, CDCl3): δ = 157.9, 143.7, 142.7, 140.7, 137.2,
130.7, 128.6, 127.7, 122.9, 121.9, 113.0, 110.2, 32.6, 18.4.
HRMS: m/z [M + H]+ calcd for C19H21N2O2: 309.1598; found: 309.1603.
UV (MeCN): λ = 221, 245, 315 nm.
HRMS: m/z [M + H]+ calcd for C17H17N2O2: 281.1285; found: 281.1289.
3-(2-tert-Butyl-6-methylphenyl)-1-methylquinazoline-
2,4(1H,3H)-dione (3af)
UV (MeCN): λ = 233, 264, 343 nm.
Following TP1: Ni(cod)2 (40 mg, 0.141 mmol, 0.05 equiv), PHOX (47
mg, 0.141 mmol, 0.05 equiv), 1a (0.5 g, 2.82 mmol, 1.0 equiv), and 2-
tert-butyl-6-methylphenyl isocyanate (2f; 0.64 g, 3.38 mmol, 1.2
equiv) were combined in THF (10 mL) and heated to 60 °C for 4 h be-
fore direct purification by chromatography (silica gel) to yield 3af
(0.69 g, 76%) as a white crystalline solid; Rf = 0.62 (hexanes/EtOAc
7:3); mp 156 °C (DSC).
(Z)-2-[(2,6-Diethylphenyl)imino]-1-methyl-1,2-dihydro-4H-3,1-
benzoxazin-4-one (4ac)
Following TP2: Ni(cod)2 (81 mg, 0.282 mmol, 0.05 equiv), XANTPHOS
(167 mg, 0.282 mmol, 0.05 equiv), 1a (1.0 g, 5.7 mmol, 1.0 equiv), and
2,6-diethylphenyl isocyanate (2c; 1.2 mL, 6.8 mmol, 1.2 equiv) in tol-
uene (20 mL) were heated to 80 °C for 4 h before purification by chro-
matography (silica gel) to yield 4ac (975 mg, 56%) as a white crystal-
line solid; Rf = 0.78 (hexanes/EtOAc 7:3); mp 127 °C (DSC).
IR (solid state): 1703, 1658, 1608, 1483, 1452, 1425, 1378, 1325,
1312, 1294, 1260, 1178, 1151, 1138, 1118 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.30 (dd, J = 8.2, 1.8 Hz, 1 H), 7.75 (dt,
J = 8.5, 1.5 Hz, 1 H), 7.46 (d, J = 8.2 Hz, 1 H), 7.31 (m, 3 H), 7.20 (d, J =
8.2 Hz, 1 H), 3.67 (s, 3 H), 2.03 (s, 3 H), 1.27 (s, 9 H).
13C{1H} NMR (100 MHz, CDCl3): δ = 162.2, 151.0, 146.5, 140.9, 136.4,
135.4, 132.8, 129.4, 129.0, 128.8, 126.9, 123.0, 115.9, 113.7, 36.0, 31.9,
30.9, 18.2.
IR (solid state): 1760, 1668, 1606, 1589, 1483, 1454, 1414, 1368,
1335, 1320, 1269, 1245, 1199, 1164, 1145, 1124 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.04 (d, J = 7.9 Hz, 1 H), 7.71 (t, J = 8.2
Hz, 1 H), 7.14 (m, 2 H), 7.07 (m, 2 H), 7.00 (m, 1 H), 3.71 (s, 3 H), 2.49
(q, J = 7.6 Hz, 4 H), 1.17 (t, J = 7.6 Hz, 6 H).
13C{1H} NMR (100 MHz, CDCl3): δ = 157.9, 143.7, 141.6, 140.9, 137.2,
134.2, 130.7, 125.8, 123.2, 121.8, 113.0, 110.2, 32.5, 24.9, 14.0.
HRMS: m/z [M + H]+ calcd for C20H23N2O2: 323.1754; found: 323.1755.
UV (MeCN): λ = 220, 247, 316 nm.
HRMS: m/z [M + H]+ calcd for C19H21N2O2: 309.1598; found: 309.1603.
UV (MeCN): λ = 233, 264, 344 nm.
3-tert-Butyl-1-methylquinazoline-2,4(1H,3H)-dione (3ag)
Following TP1: Ni(cod)2 (81 mg, 0.282 mmol, 0.05 equiv), PHOX (94
mg, 0.141 mmol, 0.05 equiv), 1a (1.0 g, 5.64 mmol, 1.0 equiv), and
tert-butyl isocyanate (2f; 0.78 mL, 6.77 mmol, 1.2 equiv) were com-
bined in THF (10 mL) and heated to 60 °C for 6 h before direct purifi-
cation by chromatography (silica gel) to yield 3ag (1.16 g, 89%) as a
white crystalline solid; Rf = 0.88 (hexanes/EtOAc 7:3); mp 108 °C
(DSC).
(Z)-2-[(2,6-Diisopropylphenyl)imino]-1-methyl-1,2-dihydro-4H-
3,1-benzoxazin-4-one (4ad)
Following TP2: 81 mg Ni(cod)2 (0.282 mmol, 0.05 equiv), XANTPHOS
(167 mg, 0.282 mmol, 0.05 equiv), 1a (1.0 g, 5.7 mmol, 1.0 equiv), and
2,6-diisopropylphenyl isocyanate (2d; 1.4 mL, 6.8 mmol, 1.2 equiv) in
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

H
W. Wertjes et al.
Special Topic
Synthesis
toluene (20 mL) were heated to 90 °C for 4 h before purification by
chromatography (silica gel) to yield 4ad (867 mg, 46%) as a white
crystalline solid; Rf = 0.82 (hexanes/EtOAc 7:3); mp 146 °C (DSC).
Acknowledgment
The authors would like to thank Dr. Matthew Winston for helpful dis-
cussions and Dr. Robert Waltermire for supporting this work.
IR (solid state): 1765, 1665, 1606, 1587, 1484, 1457, 1376, 1358,
1339, 1320, 1270, 1246, 1194, 1173, 1146, 1124 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.05 (d, J = 8.0 Hz, 1 H), 7.72 (t, J = 8.2
Hz, 1 H), 7.13 (m, 4 H), 7.07 (m, 1 H), 3.73 (s, 3 H), 2.94 (sept, J = 6.7
Hz, 2 H), 1.20 (d, J = 6.7 Hz, 12 H).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610140.
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
13C{1H} NMR (100 MHz, CDCl3): δ = 157.8, 143.8, 140.3, 140.2, 138.8,
137.2, 130.7, 123.5, 122.9, 121.8, 113.0, 110.2, 32.5, 28.7, 23.3.
HRMS: m/z [M + H]+ calcd for C21H25N2O2: 337.1911; found: 337.1913.
References
UV (MeCN): λ = 233, 264, 345 nm.
(1) (a) Thakur, A.; Louie, J. Acc. Chem. Res. 2015, 48, 2354.
(b) Kumar, P.; Louie, J. In Transition-Metal-Mediated Aromatic
Ring Construction; Tanaka, K., Ed.; Wiley: New York, 2013, Chap.
2, 37. (c) Saito, S. In Modern Organonickel Chemistry; Tamaru, Y.,
Ed.; Wiley-VCH: Weinheim, 2005, Chap. 6, 171.
(2) Varela, J. A.; Saá, C. Chem. Rev. 2003, 103, 3787.
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Nishiyama, H.; Itoh, K. J. Am. Chem. Soc. 2005, 127, 605.
(Z)-2-[(2-Isopropyl-6-methylphenyl)imino]-1-methyl-1,2-dihy-
dro-4H-3,1-benzoxazin-4-one (4ae)
Following TP2: Ni(cod)2 (81 mg, 0.282 mmol, 0.05 equiv), XANTPHOS
(167 mg, 0.282 mmol, 0.05 equiv), 1a (1.0 g, 5.7 mmol, 1.0 equiv), and
2-isopropyl-6-methylphenyl isocyanate (2e; 1.22 mL, 6.76 mmol, 1.2
equiv) in toluene (20 mL) were heated to 80 °C for 4 h before purifica-
tion by chromatography (silica gel) to yield 4ae (905 mg, 52%) as a
white crystalline solid; Rf = 0.76 (hexanes/EtOAc 7:3); mp 118 °C
(DSC).
(4) (a) Amatore, M.; Aubert, C. Eur. J. Org. Chem. 2015, 265.
(b) Reissig, H.-U.; Zimmer, R. In Science of Synthesis;
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l
Molander,
G.-A., Ed.; Thieme: Stuttgart, 2006, 371.
IR (solid state): 1756, 1667, 1607, 1558, 1486, 1473, 1460, 1440,
(5) (a) Sun, M.; Ma, Y.-N.; Li, Y.-M.; Tian, Q.-P.; Yang, S.-D. Tetrahe-
dron Lett. 2013, 54, 5091. (b) Nakai, K.; Kurahashi, T.;
Matsubara, S. Chem. Lett. 2013, 42, 1238. (c) Yoshino, Y.;
Kurahashi, T.; Matsubara, S. J. Am. Chem. Soc. 2009, 131, 7494.
(6) (a) Gutnov, A.; Heller, B.; Fischer, H.-J.; Drexler, A.;
Spannenberg, D.; Sundermann, C.; Sundermann, B. Angew.
Chem. Int. Ed. 2004, 43, 3795. (b) Wakatsuki, Y.; Yamazaki, H.
Tetrahedron Lett. 1973, 14, 3383.
1420, 1369, 1333, 1320, 1268, 1242, 1198, 1163, 1145, 1123 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.05 (d, J = 7.6 Hz, 1 H), 7.72 (t, J = 7.9
Hz, 1 H), 7.14 (m, 3 H), 7.04 (d, J = 7.3 Hz, 1 H), 6.99 (t, J = 7.6 Hz, 1 H),
3.72 (s, 3 H), 3.01 (sept, J = 7.3 Hz, 1 H), 2.14 (s, 3 H), 1.20 (d, J = 6.7 Hz,
6 H).
13C{1H} NMR (100 MHz, CDCl3): δ = 157.9, 143.7, 141.5, 140.6, 139.1,
137.2, 130.7, 128.4, 127.6, 123.2, 123.0, 121.8, 113.0, 110.2, 32.6, 28.6,
23.2, 18.5.
(7) Hong, P.; Yamazaki, H. Synthesis 1977, 50.
(8) Onodera, G.; Shimizu, Y.; Kimura, J.; Kobayashi, J.; Ebihara, Y.;
Kondo, K.; Sakata, K.; Takeuchi, R. J. Am. Chem. Soc. 2012, 134,
10515.
HRMS: m/z [M + H]+ calcd for C19H21N2O2: 309.1598; found: 309.1599.
UV (MeCN): λ = 231, 266, 342 nm.
(9) Onodera, G.; Suto, M.; Takeuchi, R. J. Org. Chem. 2012, 77, 908.
(10) McCormick, M. M.; Duong, H. A.; Zuo, G.; Louie, J. J. Am. Chem.
Soc. 2005, 127, 5030.
(11) (a) Duong, H. A.; Cross, M. J.; Louie, J. J. Am. Chem. Soc. 2004,
126, 11438. (b) Hoberg, H.; Oster, B. W. J. Organomet. Chem.
1982, 234, C35.
(12) (a) Duong, H. A.; Louie, J. Tetrahedron 2006, 62, 7552.
(b) Hoberg, H.; Oster, B. W. J. Organomet. Chem. 1983, 252, 359.
(13) Kashima, K.; Teraoka, K.; Uekusa, H.; Shibata, Y.; Tanaka, K. Org.
Lett. 2016, 18, 2170.
(14) Tanaka, K.; Wada, A.; Noguchi, K. Org. Lett. 2005, 7, 4737.
(15) Kondo, T.; Nomura, M.; Ura, Y.; Wada, K.; Mitsudo, T. Tetrahe-
dron Lett. 2006, 47, 7107.
(16) Yamamoto, Y.; Okuda, S.; Itoh, K. Chem. Commun. 2001, 1102.
(17) Yamamoto, Y.; Takagishi, H.; Itoh, K. Org. Lett. 2001, 3, 2117.
(18) (a) Spahn, N. A.; Nguyen, M. H.; Renner, J.; Lane, T. K.; Louie, J.
J. Org. Chem. 2017, 82, 234. (b) Knoch, F.; Kremer, F.; Schmidt,
U.; Zenneck, U.; Le Floch, P.; Mathey, F. Organometallics 1996,
15, 2713.
(19) Watterson, S. H.; De Lucca, G. V.; Shi, Q.; Langevine, C. M.; Liu,
Q.; Batt, D. G.; Bertrand, M. B.; Gong, H.; Dai, J.; Yip, S.; Li, P.;
Sun, D.; Wu, D.-R.; Wang, C.; Zhang, Y.; Traeger, S. C.; Pattoli, M.
A.; Skala, S.; Cheng, L.; Obermeier, M. T.; Vickery, R.; Discenza, L.
N.; D’Arienzo, C. J.; Zhang, Y.; Heimrich, E.; Gillooly, K. M.;
Taylor, T. L.; Pulicicchio, C.; McIntyre, K. W.; Galella, M. A.;
(Z)-2-[(2-tert-Butyl-6-methylphenyl)imino]-1-methyl-1,2-dihy-
dro-4H-3,1-benzoxazin-4-one (4af)
Following TP2: Ni(cod)2 (40 mg, 0.141 mmol, 0.05 equiv), XANTPHOS
(84 mg, 0.141 mmol, 0.05 equiv), 1a (0.5 g, 2.82 mmol, 1.0 equiv), and
2-tert-butyl-6-methylphenyl isocyanate (2f; 0.64 g, 3.38 mmol, 1.2
equiv) in toluene (10 mL) were heated to 80 °C for 4 h before purifica-
tion by chromatography (silica gel) to yield 4af (724 mg, 80%) as a
white crystalline solid; Rf = 0.76 (hexanes/EtOAc 7:3); mp 173 °C
(DSC).
IR (solid state): 1761, 1659, 1607, 1583, 1508, 1482, 1471, 1455,
1426, 1368, 1336, 1319, 1301, 1268, 1243, 1213, 1184, 1169, 1145,
1125 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.04 (d, J = 7.9 Hz, 1 H), 7.71 (t, J = 8.3
Hz, 1 H), 7.22 (d, J = 7.9 Hz, 1 H), 7.14 (m, 2 H), 7.07 (d, J = 7.3 Hz, 1 H),
6.93 (t, J = 7.6 Hz, 1 H), 3.75 (s, 3 H), 2.11 (s, 3 H), 1.36 (s, 9 H).
13C{1H} NMR (100 MHz, CDCl3): δ = 157.8, 143.7, 142.4, 140.3, 140.1,
137.2, 130.7, 128.9, 128.4, 124.0, 122.7, 121.8, 113.0, 110.1, 35.0, 32.4,
30.1, 18.6.
HRMS: m/z [M + H]+ calcd for C20H23N2O2: 323.1754; found: 323.1758.
UV (MeCN): λ = 233, 265, 347 nm.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

I
W. Wertjes et al.
Special Topic
Synthesis
Tebben, A. J.; Muckelbauer, J. K.; Chang, C.; Rampulla, R.;
Mathur, A.; Salter-Cid, L.; Barrish, J. C.; Carter, P. H.; Fura, A.;
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(23) CCDC 1541563 contains the supplementary crystallographic
data for this paper. The data can be obtained free of charge from
The
Cambridge
Crystallographic
Data
Centre
via
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I