Isocyanide cyclization reactions: 4-methylene-4H-benzo[d][1,3]oxazine, 3-benzyl-4-methylene-3,4-dihydroquinazolines and 3-(4-benzyl)-3H-quinazolin-4- ones - Experiment and theory

Article abstract of DOI:10.1002/ejoc.201300293

2-Isocyanoacetophenone (3a) was found to be an easily accessible starting material for the unexpected formation of various heterocyclic systems. Thus, a hitherto unknown rather unstable 4-methylene-4H-benzoxazine derivative 4, which could be characterized by NMR spectroscopy, was formed in situ by the reaction of 3a in the presence of weak acids. In the presence of benzylamines, a new class of 3,4-dihydroquinazoline derivatives 6 and their oxidation products, quinazolin-4-ones 9, were obtained. The starting materials and products were completely characterized by spectroscopic and X-ray analysis. The scope and limitations of these cyclization reactions were investigated under various reaction conditions. High-level quantum chemical calculations were carried out to elucidate the mechanisms leading to scaffolds 4 and 6. The calculations suggest that the formation of 4 and 6 involves the generation of an unusual six-membered N-heterocyclic carbene or its C-protonated form as a reaction intermediate, followed by tautomerisation. This mechanism might also be applicable to other isocyanide cyclization reactions. Copyright

Full text of DOI:10.1002/ejoc.201300293

FULL PAPER
DOI: 10.1002/ejoc.201300293
Isocyanide Cyclization Reactions: 4-Methylene-4H-benzo[d][1,3]oxazine, 3-
Benzyl-4-methylene-3,4-dihydroquinazolines and 3-(4-Benzyl)-3H-quinazolin-4-
ones – Experiment and Theory
Benedikt Neue,[a] Ralph Reiermann,[a] Roland Fröhlich,[a] Birgit Wibbeling,[a]
Klaus Bergander,[a] and Ernst-Ulrich Würthwein*[a]
Keywords: Isocyanides / Nitrogen heterocycles / Oxygen heterocycles / Cyclization / Reaction mechanisms / Density
functional calculations
2-Isocyanoacetophenone (3a) was found to be an easily ac- scopic and X-ray analysis. The scope and limitations of these
cessible starting material for the unexpected formation of
various heterocyclic systems. Thus, a hitherto unknown
rather unstable 4-methylene-4H-benzoxazine derivative 4,
which could be characterized by NMR spectroscopy, was
formed in situ by the reaction of 3a in the presence of weak
acids. In the presence of benzylamines, a new class of 3,4-
dihydroquinazoline derivatives 6 and their oxidation prod-
cyclization reactions were investigated under various reac-
tion conditions. High-level quantum chemical calculations
were carried out to elucidate the mechanisms leading to scaf-
folds 4 and 6. The calculations suggest that the formation of
4 and 6 involves the generation of an unusual six-membered
N-heterocyclic carbene or its C-protonated form as a reaction
intermediate, followed by tautomerisation. This mechanism
ucts, quinazolin-4-ones 9, were obtained. The starting mate- might also be applicable to other isocyanide cyclization reac-
rials and products were completely characterized by spectro-
tions.
terns. They were obtained during the attempted conversion
of ketone 3a with benzylic amines into the corresponding
imines (i.e., 7). In the absence of amines, under slightly
acidic conditions, 3a unexpectedly formed benzoxazine 4,
which explains the instability of this compound, and sug-
gests new synthetic applications of similar isocyanides.[4,5]
These experimental studies are augmented by high-level
quantum chemical studies into the possible mechanism of
these reactions. These quantum chemical studies focus on
intramolecular nucleophilic additions of oxygen and nitro-
gen nucleophiles to the carbon atoms of the isocyanides,
possibly after C-protonation under the reaction conditions.
We suggest the formation of unusual six-membered N-
heterocyclic carbene intermediates, or – which is more
likely – their protonated forms.
Introduction
Due to their unique ability to react both as an electro-
phile and a nucleophile at carbon, isocyanides are chemical
building blocks with a wide range of applications, especially
in heterocyclic chemistry.[1,2] In the course of our studies on
the cyclization reactions of aza-polyenyl anions, which led
to several new routes for the synthesis of 5-, 6-, 7-, and
even 14-membered heterocyclic ring systems,[3] we became
interested in benzyl imines 7, derived from 2-isocyanoaceto-
phenone 3a as the carbonyl component. We anticipated that
these imines (i.e., 7) could be used as precursors to the cor-
responding anions, which could undergo ring-closure reac-
tions to give heterocyclic compounds by a new anionic reac-
tion pathway. Compound 3a is known to be rather unstable,
and its reactivity has not yet been studied in detail. For
example, its reactions with amines are, to the best of our
knowledge, unknown.
Quinazoline-4-ones[6] and the less common 3,4-di-
hydroquinazolines[7] are of interest because of their mani-
fold medicinal and pharmacological applications. Various
derivatives of quinazolin-4-ones have previously been syn-
thesized by other routes.[8]
In this paper, we describe unexpected reactions leading
to various quinazoline derivatives 6 and their oxidation
products, quinazolin-4-ones 9, with unique substitution pat-
[a] Organisch-Chemisches Institut, Westfälische Wilhelms-
Universität,
Results and Discussion
Corrensstrasse 40, 48149 Münster, Germany
Fax: +49-251-83-39772
Synthesis and Properties of Isocyanide 3
E-mail: wurthwe@uni-muenster.de
Homepage: http://www.uni-muenster.de/Chemie/OC/research/
wue/euw.htm
The precursors for the reactions under study, 2-isocyano-
phenyl ketones 3a–c, were synthesized in two steps by modi-
fication of reported procedures starting from the respective
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300293.
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Isocyanide Cyclization Reactions
Scheme 1. Synthesis of 2-isocyanophenyl ketones 3.
primary amines (i.e., 1a–c).[9] The first step, a formylation mation), which reached a maximum concentration in our
reaction using formic acid, gave formamides 2a–c experiments after about 8–10 d of reaction time. All
(Scheme 1).
attempts to isolate the pure compound failed, but the NMR
Additionally to the reported experimental data for 2a spectra unambiguously confirmed the formation of 4. For
and 2c,[10] we were able to characterize the structures of 2a our investigation of the reaction mechanism (see below), we
and 2c by X-ray diffraction (Figure 1).[11] The molecular tested several solvents and reaction conditions. Dichloro-
structures of 2a and 2c are completely planar as a result methane turned out to be the best solvent. More strongly
of intramolecular hydrogen bonding (N1/N11–H···O2/O22, acidic conditions (POCl3 or HCl) led, as expected, to de-
1.939 Å for 2a and 1.964 Å for 2c). Characteristic bond composition, mostly into formamide 2 and black residues.
lenghts for 2a and 2c are as follows: 1.225(3) and Molecular sieves resulted in a slower conversion than that
1.2297(17) Å for C=O (ketone), 1.343(3) and 1.348(2) Å for seen with β-alanine. Triethylamine gave no reaction at all.
N–C (formamide), and 1.221(3) and 1.213(2) Å for C–O
(formamide). The X-ray structures indicate that the carb-
onyl and formamide functionalities of 2 are in close proxim-
ity, and this is also expected to be the case for the corre-
sponding isocyanides (i.e., 3), setting them up for intramo-
lecular reactions.
Scheme 2. Synthesis of 4-methylene-4H-benzo[d][1,3]oxazine (4)
from isocyanide 3a (left); compounds A as obtained by Kobayashi
et al.[13] (right).
Compound 4 is closely related to a compound reported
by Kobayashi et al.,[13] who identified 2-substituted 4-alk-
ylidene-4H-benzo[d][1,3]oxazines A after treatment of com-
pounds related to 3 with vinyl ethers under mildly acidic
conditions. The reaction reported here represents the basic
type of cyclization reaction of less stable isocyanides such
as 3, and as such, represents the “missing link” to other
isocyanide cyclizations as reported by Kobayashi[2] and
Figure 1. Molecular structures of compounds 2a and 2c (Schakal
plot).[12]
other groups.[4] Substituted derivatives of compounds 4
have been prepared by Saito et al. by Palladium-catalysed
cyclization of N-acyl-o-alkynylanilines.[14]
In the second step, compounds 2 were dehydrated using
phosphorus oxychloride to give isocyanides 3. Compounds
3a and 3c were obtained in high yield, whereas the reaction
sequence starting from 2-aminobenzophenone (1b) gave
only a small amount of the target compound (i.e., 3b).
Compounds 3 were oils that solidified below ca. –30 °C. We
were not able to obtain crystals suitable for X-ray diffrac-
tion.
Reactions of 3 with Amines: Synthesis of
Dihydroquinazolines 6 and Quinazoline-4-ones 9
Compounds 3a–c were treated with various primary
amines in the presence of molecular sieves.[15] Our initial
Compound 3a was reasonably stable at 0 °C, but it re- aim was the preparation of imines 7. However, the use of
acted within a few days after the addition of even weakly alkylamines such as methylamine, neopentylamine, or tert-
acidic compounds such as β-alanine to form black residues. butylamine in the presence of molecular sieves led only to
1
Intermediate H and 13C NMR spectra taken of a dilute inseparable mixtures. Benzylamines 5a–e were investigated
toluene solution of 3a with a small portion of β-alanine next. To our surprise, the reaction of isocyanide 3a with 5a–
indicated the predominant formation of 4-methylene-4H- e did not result in the formation of the expected condensa-
benzo[d][1,3]oxazine (4; Scheme 2 and Supporting Infor- tion products (i.e., 7; Scheme 3, Table 1). Instead, from 3a,
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4-methylene-3,4-dihydro-quinazoline products of type 6 with molecular sieves. Catalytic amounts of acid (p-tolu-
were obtained after crystallization under argon in moderate enesulfonic or camphorsulfonic acids) also facilitated the
to good yields. We assume that the initially targeted imines formation of compounds 6, whereas bases inhibited it. An
(i.e., 7) are involved as key intermediates in these reactions experiment using triethylamine as additional base resulted
(see mechanistic discussion below). The reaction of dimeth- in no reaction.
oxy-substituted compound 3c with benzylamines also gave
Crystals suitable for X-ray diffraction analysis were
the corresponding 3,4-dihydroquinazolines, which could be grown for 6a and 6d. The results confirmed the structures
identified in the crude mixtures by NMR spectroscopy and and gave us insight into the conformational properties of
mass spectrometry. Attempts to purify these products by these molecules (Figure 2).[11]
recrystallization failed. Column chromatography on silica
or aluminium oxide resulted in decomposition, mostly into
the corresponding formamide (i.e., 2c). From the type of
products obtained (i.e., 6), it is clear that the scope of this
ring-forming reaction is limited to aryl alkyl ketones. With
the rather unreactive diaryl ketone 3b, no reaction with
amines to give imines was observed, even when other
“smaller” amines (methylamine), harsher conditions
(Brønsted or Lewis acid catalysis), and higher temperatures
were used to promote the condensation reaction.
Figure 2. Molecular structure of compound 6d (Schakal plot).[12]
The 4-methylene-3,4-dihydroquinazoline framework of
6d is planar. The length of the imine bond N9–C10 is
1.281(3) Å, while the bond length C2–C11 is 1.325(3) Å.
Furthermore, the NMR spectra of 6 show some interesting
features. The signal of the proton at C10 is shifted remarka-
bly upfield (δ = 6.96 ppm for 6a) compared to what is usual
for imines.[16] The protons of the alkene functionality reso-
nate at δ = 3.66 (d) and 4.49 (m) ppm.
Oxidation of 6 to 9
Compounds 6a–e were found to be quite sensitive
towards oxidation. Thus, during column chromatography,
compounds 6a,d were transformed into 9a,d (Scheme 4), al-
beit in low yield. The structures of the oxidized products
were determined by 1D and 2D NMR spectroscopy and
Scheme 3. Formation of 6a–e by reaction of compounds 3a with mass spectrometry, and for 9d, the data were consistent
with data reported in the literature.[17] A related type of
benzylamines 5 (top). Compound 7 (middle). Compound 3b does
not react with amines 5 (bottom). For the substitution patterns, see
oxidation was reported by Kim et al.[18]
Table 1.
Table 1. Substitution patterns of compounds 5 and 6, and isolated
yields of 6.
R3
R4
Isolated yield
of 6 [%]
5a, 6a
5b, 6b
5c, 6c
5d, 6d
5e, 6e
H
CH3
Cl
OCH3
OCH3
H
H
H
H
75
77
31
31
24
Scheme 4. Oxidation of 6a,d to give compounds 9a,d.
OCH3
To investigate this oxidation reaction in more detail,
compounds 6a,d were stirred in a flask exposed to air for
Next, we focussed our attention on optimizing the condi- about 7 d. We observed a conversion into the respective
tions of the reaction of 3a with benzylamines to form prod- quinazolin-4-ones (i.e., 9a,d) with a yield of about 30% (de-
ucts 6. The best results were obtained in dichloromethane termined by NMR spectroscopy). Figure 3 shows the con-
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Isocyanide Cyclization Reactions
Figure 3. Reaction of 6a to form 9a in an NMR tube. Spectra were recorded after 24 h, 48 h, 120 h, and 168 h (solvent C6D6).
version of 6a into 9a, as monitored by 1H NMR spec- would be rather sensitive to an acidic environment. There-
troscopy. While the peaks of compound 6a decreased the fore, the results obtained from this series of calculations
signals for 9a (marked with a *) are increasing with time.
support the experimental data for the formation of this
The oxidized compounds were recrystallized from ethyl interesting enol ether 4, which, as an intermediate or if iso-
acetate. Compound 9a was isolated in 25% yield, and 9d lated, might be a useful building block in organic synthesis.
in 20% yield. It was also possible to obtain 9d by column
Secondly, we investigated the formation of 3-benzyl-4-
methylene-3,4-dihydroquinazoline (6a; Scheme 6). Here, we
assume that the condensation reaction of 3a with benzyl-
amine 5a first leads to intermediate 7. Taking 7 as the start-
ing point, we considered two pathways. The first one, in-
volving neutral imine 7, is based on an interaction between
the lone pair of the imine nitrogen and the isocyanide car-
bon atom. The intermediate in this reaction (i.e., 14) con-
tains an unusual and interesting six-membered-ring N-het-
erocyclic carbene moiety, and is about 15.1 kcalmol–1
higher in energy than 7. No similar cyclization of an iso-
cyanide to give such a rare six-membered N-heterocyclic
carbene is known, to the best of our knowledge.[21] The cal-
culated barrier for the ring-closure reaction is
16.9 kcalmol–1. As final step, we propose a (probably inter-
molecular) proton shift to give 6a, which is thermodynami-
cally favoured (by about –22.6 kcalmol–1) compared to 7.
These calculated data are in good agreement with the exper-
imental conditions used.
chromatography (SiO2, pentane/ethyl acetate). In this case,
1
9d was obtained in 10% yield. For the H and 13C NMR
spectra of pure compounds 9a,d in CD2Cl2, see Supporting
Information. Attempts to increase the conversion or yield
by filtration through SiO2 or by using DDQ as an oxidant
were not successful. Further studies to improve this oxi-
dation reaction are ongoing.
Reaction Mechanism
The unexpected formation of six-membered N,O and
N,N heterocyclic species starting from compounds 3
prompted us to investigate the possible reaction mecha-
nisms by quantum chemical calculations at the SCS-MP2/
6-311+G(d,p)//B3LYP/6-31+G(d),[19,20] level of theory.
At first, we studied the cyclization reaction of 3a to give
4 computationally (Scheme 5). The cyclization of the neu-
tral compound can be excluded, as the necessary intermedi-
ate carbene (i.e., 10) does not correspond to a local mini-
We also considered a proton-catalysed route. It involves
mum on the energy hypersurface. However, the proton-cata- the initial protonation of 7 to give the nitrilium ion (i.e.,
very exothermic cyclization reaction (by
lysed pathway (protonation at the isocyanide carbon atom 15).
A
to give 12, rather then at oxygen to give 11, lower line) is –43.2 kcalmol–1) with a small barrier (only 1.9 kcalmol–1)
quite exothermic (–16.8 kcalmol–1), and leads to 13 with a might lead to 16, which, upon deprotonation from the
very small activation barrier (2.5 kcalmol–1). Loss of a pro- methyl group, could produce 6a. The exothermic nature and
ton leads to the final product (i.e., 4). Based on chemical the low barrier of this pathway indicate that it should be a
intuition, it seems likely that compound 4, an enol ether, very attractive alternative to the neutral route. The neces-
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Scheme 5. Proposed mechanisms for the formation of compound 4 starting from isocyanide 3a. Carbene 10 does not correspond to a
minimum. The energies in upper line are relative to 3a, those in the lower line are relative to 12 [kcalmol–1], using SCS-MP2/6-
311+G(d,p)//B3LYP/6-31+G(d)+ZPE. The zero point energies were taken from the DFT calculations.
Scheme 6. Proposed mechanisms for the formation of compound 6a from the imine 7. The energies in the first line are relative to 7, those
in the lower line are relative to 15 [kcalmol–1], using SCS-MP2/6-311+G(d,p)//B3LYP/6-31+G(d)+ZPE. The zero point energies were
taken from the DFT calculations.
sary catalytic protons may come from the molecular sieves (such as 6), their oxidation products 9, and other related
under our experimental conditions.
systems that might be of interest with regard to pharmaco-
logical and medicinal applications. We are now investigating
the reactivity of the enamine functionality in compounds 6
and the suitability of these compounds for further modifi-
cations. In addition, we have investigated the mechanism for
the formation of compounds 4 and 6 by quantum chemical
calculations. The ring-closure reactions described here,
which are likely to be induced by protonation, are rare ex-
amples of the use of isocyanides in the synthesis of six-
membered heterocyclic rings. These results suggest that the
synthesis of other heterocycles, e.g., with different ring sizes,
could be achieved based on the mechanistic principles de-
veloped here.
Conclusions
2-Isocyanoacetophenone (3a) is a rather reactive sub-
stance. For example, it cyclizes intramolecularly in the pres-
ence of weak acids to form the hitherto unknown, rather
unstable 4-methylene-4H-benzo[d][1,3]oxazine (4). This is
the parent compound of various substituted derivatives
known in the literature. Furthermore it has been found that
reaction of compound 3a with various benzylamines in the
presence of molecular sieves leads to the unexpected forma-
tion of 3-benzyl-4-methylene-3,4-dihydroquinazolines 6a–e.
Surprisingly, imines 7 that would result from a condensa-
tion reaction were not observed. All compounds were com-
pletely characterized, and molecular structures of 6a and 6d
were determined by X-ray diffraction. Compounds 6 were
rapidly oxidized in air to give 3-(4-benzyl)-3H-quinazolin-
4-one derivatives 9a and 9d. Thus, this method opens new
pathways for the preparation of substituted 4-methylene-
Experimental Section
General Remarks: The following compounds were used as internal
references in 1H and 13C NMR spectroscopy: Tetramethylsilane
(1H; δ = 0.00 ppm), CD2Cl2 (1H; δ = 5.32 ppm), CDCl3 (1H; δ =
7.26 ppm), C6D6 (1H; δ = 7.16 ppm), CD2Cl2 (13C; δ = 53.8 ppm),
4H-benzo[d][1,3]oxazine (4) and quinazoline derivatives CDCl3 (13C; δ = 77.0 ppm), C6D6 (13C; δ = 128.1 ppm). If neces-
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Isocyanide Cyclization Reactions
sary, the experiments were carried out with the complete exclusion
of moisture. For the synthesis of 2a–c and 3a,b modified literature
procedures were used.[9] To the best of our knowledge, analytical
data for 2c are only partially reported in the literature.[10]
1-(2-Isocyano-phenyl)ethanone (3a): A solution of POCl3 (3.81 mL,
41.79 mmol) in dry THF (50 mL) was added dropwise to a mixture
of compound 2a (5.50 g, 33.70 mmol) and Et3N (22.76 mL,
163.81 mmol) in dry THF (50 mL) at –78 °C. The mixture was
stirred for 6 h at 0 °C, then it was poured into cold H2O (50 mL).
The mixture was extracted with diethyl ether (3ϫ 50 mL), and the
combined organic extracts were washed with H2O (2ϫ 50 mL) and
dried with MgSO4. Finally, the solvent was removed in vacuo to
give 3a (4.30 g, 29.62 mmol, 88%) as a dark brown oil. The product
was sufficiently pure to be used in further reactions.
N-(2-Acetylphenyl)formamide
(2a):
2-Aminoacetophenone
(13.50 mL, 111.10 mmol) was dissolved in toluene (50 mL) in a
round-bottomed flask. Formic acid (41.88 mL, 1.11 mol) was
added, and the mixture was heated at reflux for 4 h. The organic
phase was washed carefully with NaHCO3 (satd. aq.; 3ϫ 50 mL)
and dried with MgSO4. The solvent was removed under reduced
pressure, and the crude product was purified by recrystallization
from cyclohexane/dichloroethane (1:1) to give 2a (16.68 g,
102.20 mmol, 92%) as a colourless solid.
(2-Isocyanophenyl)(phenyl)methanone (3b): Analogously to the syn-
thesis of 3a, a solution of POCl3 (1.13 mL, 12.40 mmol) in dry
THF (50 mL) was added to a mixture of 2b (2.25 g, 10.00 mmol)
and Et3N (6.78 mL, 48.60 mmol) in dry THF (50 mL). After 4 h
at 0 °C, compound 3b (0.23 g, 1.10 mmol, 11%) was obtained.
X-ray Crystal Structure Analysis of 2a:[11] Formula C9H9NO2, M
= 163.17, slightly yellow crystal, 0.20ϫ0.10ϫ0.10 mm, a =
14.1429(7), b = 3.8805(2), c = 15.5216(9) Å, β = 110.896(2)°, V =
795.82(7) Å3, ρcalc = 1.362 gcm–3, μ = 0.097 mm–1, empirical ab-
sorption correction (0.981 Յ T Յ 0.990), Z = 4, monoclinic, space
group Pn (No. 7), λ = 0.71073 Å, T = 223(2) K, ω and φ scans,
4775 reflections collected (Ϯh, Ϯk, Ϯl), [(sinθ)/λ] = 0.67 Å–1, 3142
independent (Rint = 0.036) and 2838 observed reflections [IՆ
2σ(I)], 227 refined parameters, R = 0.049, wR2 = 0.116, max. (min.)
residual electron density 0.17 (–0.16) eÅ–3, hydrogen atoms at N1A
and N1B were refined freely, other hydrogen atoms were calculated
and refined as riding atoms.
1-(2-Isocyano-4,5-dimethoxyphenyl)ethanone (3c): Analogously to
the synthesis of 3a, POCl3 (3.85 mL, 42.16 mmol) was dissolved in
dry THF (50 mL). This solution was added to a stirred solution of
2c (7.59 g, 34.00 mmol) and Et3N (23.05 mL, 165.24 mmol) in dry
THF (50 mL). The reaction mixture was stirred overnight at room
temperature. Compound 3c (6.28 g, 30.60 mmol, 90%) was ob-
tained as a brown solid, m.p. 115 °C. IR (neat): ν = 2120 (m), 1668
˜
(m), 1639 (m), 1591 (m), 1512 (s), 1458 (m), 1449 (m), 1393 (m),
1362 (m), 1267 (s), 1260 (s), 1219 (s), 1146 (m), 1028 (m), 1022 (m)
cm–1. 1H NMR (300.13 MHz, CD2Cl2): δ = 2.68 (s, 3 H, CH3),
3.80 (s, 6 H, OCH3), 6.91 (s, 1 H, CHarom.), 7.28 (s, 1 H, CHarom.
)
ppm. 13C NMR (75.47 MHz, CD2Cl2): δ = 30.3 (CH3), 56.7
(OCH3), 56.9 (OCH3), 111.9 (CHarom.), 128.1, 150.0, 152.9, 169.9
(NC), 195.7 (CO) ppm. HRMS (ESI): calcd. for C11H12NO3
206.0812; found 206.0812.
N-(2-Benzoylphenyl)formamide (2b): Analogously to the synthesis
of 2a, 2-aminobenzophenone (0.56 g, 2.84 mmol) was dissolved in
toluene (10 mL). Then formic acid (1.07 mL, 28.40 mmol) was
added. After heating for 4 h under reflux, 2b (0.36 g, 1.83 mmol,
64%) was obtained as a slightly yellow solid.
4-Methylene-4H-benzo[d][1,3]oxazine (4): Compound 3a (1.500 g,
15.17 mmol) was dissolved in dry toluene (15 mL) and treated with
β-alanine (ca. 0.025 g) while stirring at room temperature. From
this dark brown solution samples of 0.8 mL were taken. Toluene
was removed from these samples in vacuo, and the residue was then
dissolved in C6D6 for NMR measuements. Typical NMR spectra
taken after 12, 48, and 140 h showed the conversion of 3a into
4, accompanied by increasing amounts of decomposition. NMR
N-(2-Acetyl-4,5-dimethoxyphenyl)formamide (2c): Analogously to
the synthesis of 2a, 1-(2-amino-4,5-dimethoxyphenyl)ethanone
(5.00 g, 9.61 mL, 25.61 mmol) and formic acid (9.66 mL,
256.10 mmol) were mixed in toluene (100 mL). The mixture was
heated for 4 h. The yellow precipitate was filtered and washed with
diethyl ether (about 50 mL). The filtrate was neutralized and
washed with NaHCO3 as described for the synthesis of 2a, to give
1
spectroscopic data after 10 d: H NMR (C6D6, 300.13 MHz): δ =
2c (4.52 g, 20.23 mmol, 79%), m.p. 171 °C. IR (neat): ν = 3221 (w),
˜
2
2
5
4.40 (d, J = 2.6 Hz, 1 H, CH2), 4.52 (dd, J = 2.6, J = 1.1 Hz, 1
3204 (w), 3150 (vw), 3121 (vw), 2995 (w), 2970 (vw), 2941 (w), 2887
(w), 2841 (vw), 1684 (m), 1638 (m), 1611 (m), 1578 (m), 1520 (s),
1476 (m), 1458 (m), 1450 (m), 1410 (m), 1389 (m), 1366 (m), 1337
(m), 1254 (vs), 1204 (vs), 1173 (m), 1128 (m), 1053 (s), 1034 (m),
1018 (m) cm–1. 1H NMR (300.13 MHz, C6D6): δ = 2.04 (s, 3 H,
CH3), 3.35 (s, 3 H, OCH3), 3.40 (s, 3 H, OCH3), 6.82 (s, 1 H,
5
H, CH2), 6.60 (d, J = 1.1 Hz, 1 H, CH=N), 6.80 (ddd, 1 H), 6.90
(ddd, 1 H, CHarom.), 7.10 (ddd, 1 H, CHarom.), 7.20 (ddd, 1 H,
CHarom.) ppm. 13C NMR (C6D6, 75.47 MHz): δ = 85.8 (CH2), 122.5
(Cipso), 122.9, 126.8, 128.1, 130.9 (CHarom.), 138.1 (Cipso), 148.5
(CH=N), 151.1 (Cquat.) ppm. For detailed spectra, see Supporting
Information
4
CHarom.), 7.87 (d, J = 1.8 Hz, 1 H, CHarom.), 8.81 (s, 1 H, CHO),
11.87 (br. s, 1 H, NH) ppm. 13C NMR (C6D6, 75.47 MHz): δ =
27.9 (CH3), 55.5 (OCH3), 56.2 (OCH3), 104.6 (Carom.), 115.1
(Carom.), 155.6 (Cipso), 159.9 (CO) ppm. HRMS (ESI): calcd. for
C11H13NO4Na 246.0737; found 246.0741.
General Procedure for the Synthesis of 3-Benzyl-4-methylene-3,4-di-
hydroquinazolines (6): Isocyanide 3a (1.00 equiv.) was dissolved in
dry CH2Cl2 in a Schlenk flask containing molecular sieves (4 Å).
Then, amine (1.02 equiv.) was added. The solution was stirred at
room temperature. After 18 h, the mixture was filtered through a
pad of Celite, which was then washed with dry CH2Cl2 (3ϫ
50 mL). The solvent was removed in vacuo, and the residue was
recrystallized to give the pure product. To prevent oxidation to 8,
recrystallization was performed either by slow evaporation of sol-
vent under vacuum or using an argon flow.
X-ray Crystal Structure Analysis of 2c:[11] Formula C11H13NO4, M
= 223.22, yellow crystal 0.35ϫ 0.27ϫ 0.13 mm, a = 14.5534(4), b
= 9.0344(3), c = 8.1465(2) Å, β = 97.135(2)°, V = 1062.82(5) Å3,
ρcalc = 1.395 gcm–3, μ = 0.107 mm–1, empirical absorption correc-
tion (0.964 Յ T Յ 0.986), Z = 4, monoclinic, space group P21/c
(No. 14), λ = 0.71073 Å, T = 223(2) K, ω and φ scans, 7810 reflec-
tions collected (Ϯh, Ϯk, Ϯl), [(sinθ) / λ] = 0.67 Å–1, 2547 indepen- 3-Benzyl-4-methylene-3,4-dihydroquinazoline (6a): Compound 3a
dent (Rint = 0.037) and 2212 observed reflections [IՆ 2σ(I)], 152
refined parameters, R = 0.049, wR2 = 0.136, max. (min.) residual
electron density 0.26 (–0.18) eÅ–3, the hydrogen atom at N11 was
refined freely, other hydrogen atoms were calculated and refined as
riding atoms.
(0.25 g, 1.72 mmol) was dissolved in dry CH2Cl2 (50 mL). Then,
benzylamine (0.20 mL, 1.76 mmol) was added to the stirred mix-
ture. The solvent was removed in vacuo, and recrystallization from
CH2Cl2 gave pure 6a (0.30 g, 1.28 mmol, 75%) as an orange solid,
m.p. 110–111 °C. IR (neat): ν = 3073 (vw), 3061 (vw), 3055 (vw),
˜
Eur. J. Org. Chem. 2013, 4944–4952
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4949

E.-U. Würthwein et al.
FULL PAPER
3032 (vw), 2997 (vw), 2988 (vw), 1692 (vw), 1676 (vw), 1624 (vs),
1603 (vs), 1593 (vs), 1572 (s), 1543 (w), 1522 (vw), 1489 (m), 1474
(m), 1454 (vs), 1425 (w), 1404 (m), 1383 (s), 1371 (vs), 1354 (s),
1333 (vw), 1315 (w), 1300 (w), 1275 (vw), 1261 (vw), 1225 (s), 1209
(w), 1015 (vs), 976 (m), 955 (m), 934 (w), 922 (w), 858 (w), 826
(vs), 818 (vs), 800 (vs), 772 (vs), 764 (vs), 716 (vs), 689 (s), 665 (m),
1
633 (w), 608 (s) cm–1. H NMR (CD2Cl2, 400.13 MHz): δ = 3.75
2
(d, J = 2.8 Hz, 1 H, CH2,olef.), 4.58–4.59 (m, 1 H, CH2,olef.), 4.70
3
(m), 1175 (m), 1157 (w), 1148 (w), 1126 (w), 1115 (s), 1074 (w), (s, 2 H, CH2), 7.16 (t, J = 7.6 Hz, 1 H, CHarom.), 7.23–7.35 (m, 6
1057 (w), 1028 (w), 974 (s), 941 (vw), 922 (s), 903 (w), 853 (m), 800
(vw), 779 (s), 758 (vs), 750 (vs), 735 (vs), 700 (vs), 694 (vs), 667
(vw), 644 (vw), 625 (m), 610 (vw) cm–1. 1H NMR (CD2Cl2,
300.13 MHz): δ = 3.66 (d, 3J = 3.0 Hz, 1 H, CH2,olef.), 3.90 (s, 2 H,
H, CHarom.), 7.41 (s, 1 H, CH=N), 7.57 (d, 3J = 8.0 Hz, 1 H,
CHarom.) ppm. 13C NMR (CD2Cl2, 100.61 MHz): δ = 46.2 (CH2),
80.3 (CH2,olef.), 123.2 (Cquat.), 126.8, 127.3, 128.6, 128.9, 129.1,
129.5, 130.6 (CHarom.), 133.9, 134.6, 140.2, 142.5, 142.9 (Cipso),
CH2), 4.48–4.50 (m, 1 H, CH2,olef.), 6.83–6.91 (m, 3 H, CHarom.), 148.3 (CH=N) ppm. HRMS (ESI): calcd. for C16H13ClN2H
3
6.96 (s, 1 H, CH=N), 6.97–7.13 (m, 4 H, CHarom.), 7.40 (dd, J = 269.0840; found 269.0840.
4
3
4
8.1, J = 1.5 Hz, 1 H, CHarom.), 7.62 (dd, J = 7.8, J = 1.2 Hz, 1
H, CHarom.) ppm. 13C NMR (C6D6, 75.47 MHz): δ = 53.4 (CH2),
79.8 (CH2,olef.), 123.0 (CHarom.), 123.5 (Cquat.), 126.4, 126.5, 127.6,
127.8, 129.0, 130.3 (CHarom.), 135.7, 140.2, 143.1 (Cipso), 147.9
(CH=N) ppm. HRMS (ESI): calcd. for C16H14N2H 235.1230;
found 235.1230. C16H14N2 (234.30): calcd. C 82.02, H 6.02, N
11.96; found C 81.74, H 5.85, N 11.57.
3-(4-Methoxybenzyl)-4-methylene-3,4-dihydroquinazoline
(6d):
Compound 3a (0.76 g, 5.20 mmol) was dissolved in dry CH2Cl2
(50 mL). Then, 4-methoxybenzylamine (0.69 mL, 5.30 mmol) was
added. Recrystallization from CH2Cl2 gave 6d (0.42 g, 1.60 mmol,
31%) as yellow crystals, m.p. 141–142 °C. IR (neat): ν = 3038 (vw),
˜
3007 (w), 2955 (w), 2936 (vw), 2835 (vw), 2363 (w), 2342 (vw), 1630
(s), 1611 (m), 1595 (s), 1587 (m), 1562 (m), 1547 (m), 1533 (w),
X-ray Crystal Structure Analysis of 6a:[11] Formula C16H16N2, M = 1508 (s), 1477 (m), 1460 (s), 1441 (w), 1425 (w), 1404 (m), 1373 (s),
234.29, yellow crystal 0.30ϫ 0.25 ϫ 0.25 mm, a = 9.680(1), b =
1364 (m), 1315 (m), 1292 (m), 1277 (w), 1238 (s), 1229 (s), 1206
(m), 1175 (s), 1152 (m), 1115 (w), 1101 (w), 1080 (w), 1055 (w),
1026 (m), 1011 (m), 980 (m), 962 (m), 928 (m), 910 (w), 887 (w),
878 (w), 856 (w), 837 (w), 816 (m), 779 (vs), 762 (vs), 746 (m), 712
6.179(1), c = 20.601(3) Å, β = 92.94(1)°, V = 1230.6(3) Å3, ρcalc
=
1.265 gcm–3, μ = 0.583 mm–1, empirical absorption correction
(0.845 Յ T Յ 0.868), Z = 4, monoclinic, space group P21/c (No.
14), λ = 1.54178 Å, T = 223(2) K, ω and φ scans, 8219 reflections
collected (Ϯh, Ϯk, Ϯl), [(sinθ) / λ] = 0.60 Å–1, 2110 independent
(Rint = 0.039) and 1902 observed reflections [IՆ 2σ(I)], 163 refined
parameters, R = 0.046, wR2 = 0.126, max. (min.) residual electron
density 0.11 (–0.14) eÅ–3, hydrogen atoms calculated and refined
as riding atoms.
1
(w), 696 (w), 687 (w), 669 (w), 650 (w), 627 (w), 608 (w) cm–1. H
2
NMR (CD2Cl2, 300.13 MHz): δ = 3.78 (s, 3 H, OCH3), 3.85 (d, J
= 2.7 Hz, 1 H, CH2,olef.), 4.60 (dd, 2J = 2.7, 5J = 0.9 Hz, 1 H,
CH2,olef.), 4.65 (s, 2 H, CH2), 6.87–6.92 (m, 2 H, CHarom.), 7.13–
7.27 (m, 4 H, CHarom.), 7.30–7.34 (m, 1 H, CHarom.), 7.34 (s, 1 H,
CH=N), 7.58 (d, 3J = 9.0 Hz, 1 H, CHarom.) ppm. 13C NMR
(CD2Cl2, 75.48 MHz): δ = 53.6 (CH2), 55.8 (OCH3), 80.0 (CH2,o-
lef.), 114.7, 123.2 (CHarom.), 123.5 (Cquat.), 126.6, 127.2 (CHarom.),
127.6 (Cipso), 128.5, (CHarom.), 140.3, 142.6 (Cipso), 148.4 (CH=N),
159.8 (Cipso) ppm. HRMS (ESI): calcd. for C17H16N2OH 265.1335;
found 265.1319.
3-(4-Methylbenzyl)-4-methylene-3,4-dihydroquinazoline (6b): Com-
pound 3a (0.28 g, 1.90 mmol) was dissolved in dry CH2Cl2
(50 mL). Then, 4-methylbenzylamine (0.25 mL, 1.94 mmol) was
added. Recrystallization from toluene gave 6b (0.36 g, 1.46 mmol,
77%) as a pale orange solid, m.p. 91–92 °C. IR (neat): ν = 3049
˜
(w), 3030 (w), 3013 (w), 3007 (w), 2924 (w), 2334 (w), 1674 (m), X-ray Crystal Structure Analysis of 6d:[11] Formula C17H16N2O, M
1630 (m), 1607 (m), 1595 (s), 1566 (m), 1516 (m), 1485 (m), 1474 = 264.32, yellow crystal 0.35ϫ 0.20ϫ 0.05 mm, a = 9.2898(2), b =
(m), 1462 (m), 1454 (m), 1396 (m), 1368 (s), 1312 (m), 1300 (m), 14.0573(4), c = 10.5040(3) Å, β = 94.694(1)°, V = 1367.11(6) Å3,
1273 (m), 1252 (m), 1223 (m), 1204 (m), 1182 (m), 1173 (m), 1155 ρcalc = 1.284 gcm–3, μ = 0.081 mm–1, empirical absorption correc-
(m), 1119 (m), 1103 (m), 1080 (m), 1038 (w), 1020 (m), 989 (w),
976 (w), 962 (m), 949 (m), 932 (m), 885 (w), 870 (w), 856 (m), 839 (No. 14), λ = 0.71073 Å, T = 223(2) K, ω and φ scans, 7577 reflec-
(w), 818 (m), 775 (s), 762 (s), 746 (vs), 698 (m), 669 (m), 662 (m),
tions collected (Ϯh, Ϯk, Ϯl), [(sinθ) / λ] = 0.66 Å–1, 3174 indepen-
tion (0.972 Յ T Յ 0.996), Z = 4, monoclinic, space group P21/c
652 (w), 640 (m), 627 (m), 611 (m), 592 (m), 583 (m), 571 (m), 563 dent (Rint = 0.035) and 2501 observed reflections [IՆ 2σ(I)], 182
1
(m), 552 (w), 546 (w), 538 (m), 528 (m), 511 (m) cm–1. H NMR
refined parameters, R = 0.061, wR2 = 0.143, max. (min.) residual
electron density 0.16 (–0.16) eÅ–3, hydrogen atoms calculated and
refined as riding atoms.
(CD2Cl2, 300.13 MHz): δ = 2.34 (s, 3 H, CH3), 3.82 (d, 2J = 2.6 Hz,
2
5
1 H, CH2,olef.), 4.58 (dd, J = 2.6, J = 0.9 Hz, 1 H, CH2,olef.), 4.68
(s, 2 H, CH2), 7.13–7.18 (m, 5 H, CHarom.), 7.23–7.27 (m, 1 H,
CHarom.), 7.30–7.36 (m, 1 H, CHarom.), 7.42 (s, 1 H, CH=N), 7.57
(dd, 3J = 8.0, 4J = 1.4 Hz, 1 H, CHarom.) ppm. 13C NMR (CD2Cl2,
75.47 MHz): δ = 21.3 (CH3), 54.1 (CH2), 80.0 (CH2,olef.), 123.2
(CHarom.), 123.5 (Cquat.), 126.7, 127.1, 127.2, 130.0, 130.5 (CHarom.),
132.8, 138.2, 140.4, 142.7 (Cipso), 148.5 (CH=N) ppm. HRMS
(ESI): calcd. for C17H16N2H 249.1386; found 249.1372.
3-(2,4-Dimethoxybenzyl)-4-methylene-3,4-dihydroquinazoline (6e):
Compound 3a (1.02 g, 5.00 mmol) was dissolved in dry CH2Cl2
(50 mL). Then, 3,4-dimethoxybenzylamine (0.77 mL, 5.10 mmol)
was added. Recrystallization from toluene/ethyl acetate gave 6e
(0.35 g, 1.20 mmol, 24%), m.p. 95 °C. IR (neat): ν = 2994 (w), 2947
˜
(w), 2845 (w), 2835 (w), 1626 (m), 1603 (m), 1589 (m), 1572 (m),
1506 (m), 1485 (m), 1462 (m), 1435 (m), 1412 (m), 1385 (m), 1377
(m), 1306 (m), 1283 (m), 1269 (m), 1231 (m), 1209 (vs), 1194 (m),
3-(4-Chlorobenzyl)-4-methylene-3,4-dihydroquinazoline (6c): Isocy-
anide 3a (0.74 g, 5.00 mmol) was dissolved in dry CH2Cl2 (50 mL), 1184 (m), 1161 (m), 1121 (m), 1103 (vs), 1078 (m), 1069 (w), 1038
and the mixture was stirred at room temp. Then, 4-chlorobenzyla-
mine (0.63 mL, 5.17 mmol) was added. Recrystallization from
CH2Cl2 gave 6c (0.42 g, 1.55 mmol, 31%) as a colourless solid, m.p.
(vs) cm–1. 1H NMR (400.13 MHz, CD2Cl2): δ = 3.78 (s, 3 H,
OCH3), 3.85 (s, 3 H, OCH3), 3.91 (d, 2J = 2.6 Hz, 1 H, CH=CH2),
4.56 (m, 1 H, CH=CH2), 4.61 (s, 2 H, CH2), 6.44–6.46 (m, 1 H,
3
118–119 °C. IR (neat): ν = 3258 (w), 3219 (w), 2999 (w), 2984 (w), CHarom.), 6.50 (d, J = 2.4 Hz, 1 H, CHarom.), 7.08–7.15 (m, 2 H,
˜
2812 (w), 2803 (w), 1614 (vs), 1597 (vs), 1570 (vs), 1522 (w), 1491
(vs), 1481 (vs), 1458 (s), 1452 (s), 1437 (w), 1418 (w), 1402 (m),
1387 (vs), 1356 (vs), 1298 (w), 1281 (w), 1234 (m), 1227 (m), 1207
(s), 1190 (w), 1159 (vs), 1130 (s), 1090 (vs), 1074 (s), 1053 (m), 1036
CHarom.), 7.29–7.22 (m, 1 H, CHarom.), 7.28–7.32 (m, 1 H, CHarom.),
7.39 (s, 1 H, CH=N), 7.56–7.58 (m, 1 H, CHarom.) ppm. 13C NMR
(100.62 MHz, CD2Cl2): δ = 49.3 (CH2), 55.9, 56.0 (OCH3), 79.1
(CH2,olef.), 99.0, 104.7 (CHarom.), 115.4 (Cquat.,ipso), 123.2 (CHarom.),
4950
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 4944–4952

Isocyanide Cyclization Reactions
[3]
123.5 (Cquat.,ipso), 126.4, 127.1, 129.6, 130.4 (CHarom.), 140.6, 142.8
(Cipso), 148.7 (CH=N), 159.1, 161.4 (Cipso) ppm. HRMS (ESI):
calcd. for C18H19N2O2 295.1441; found 295.1437.
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3-Benzylquinazolin-4(3H)-one (9a): Compound 6a (0.30 g,
1.28 mmol) was stirred in ethyl acetate under air for 7 d. Subse-
quent recrystallization from the same solvent gave 9a (0.08 g,
0.32 mmol, 25%) as yellow–orange crystals. The analytical data
corresponds to the literature.[17]
3-(4-Methoxybenzyl)-3H-quinazolin-4-one (9d)
Procedure 1: Compound 6d (0.26 g, 1.00 mmol) was stirred in ethyl
acetate under air for 7 d. Subsequent recrystallization from the
same solvent gave 9d (0.05 g, 0.20 mmol, 20%) as orange crystals.
[4]
Procedure 2: A cyclohexane/ethyl acetate solution (1:1) of 6d
(0.42 g, 1.60 mmol) was filtered through a short silica column un-
der air to allow the oxidation to take place. Compound 9d (0.04 g,
0.16 mmol, 10%) was obtained as orange crystals. Rf [SiO2, cyclo-
[5]
[6]
hexane/ethyl acetate (1:1)]: 0.27, m.p. 123–124 °C. IR (neat): ν =
˜
3069 (w), 3059 (w), 3034 (w), 3003 (w), 2982 (w), 2957 (w), 2930
(w), 2914 (w), 2837 (w), 2361 (vw), 2332 (vw), 1730 (w), 1663 (vs),
1607 (s), 1589 (m), 1570 (m), 1562 (m), 1510 (s), 1485 (m), 1472
(s), 1454 (m), 1447 (m), 1437 (m), 1422 (m), 1408 (m), 1389 (m),
1366 (s), 1356 (m), 1323 (m), 1312 (m), 1292 (s), 1244 (vs), 1202
(m), 1182 (s), 1165 (s), 1140 (m), 1103 (m), 1026 (s), 986 (m), 970
(m), 957 (m), 924 (m), 874 (m), 839 (m), 820 (s), 812 (s), 800 (m),
781 (m), 768 (vs), 748 (s), 716 (m), 692 (s), 664 (m), 656 (m), 633
(m), 608 (m) cm–1. 1H NMR (CD2Cl2, 400.13 MHz): δ = 3.77 (s, 3
H, CH3), 5.10 (s, 2 H, CH2), 6.85–6.90 (m, 2 H, CHarom.), 7.29–
7.33 (m, 2 H, CHarom.), 7.47–7.51 (m, 1 H, CHarom.), 7.66–7.69 (m,
1 H, CHarom.), 7.72–7.77 (m, 1 H, CHarom.), 8.11 (s, 1 H, CH=N),
[7]
[8]
8.26–8.29 (m,
1 H, CHarom.)
ppm. 13C NMR (CD2Cl2,
100.61 MHz): δ = 49.7 (OCH3), 55.8 (CH2), 114.7 (CHarom.), 122.9
(Cquat.), 127.1, 127.7, 128.0 (CHarom.), 128.7 (Cipso), 130.1, 134.6
(CHarom.), 147.1 (CH=N), 148.8, 160.1, 161.4 (Cquat.,ipso) ppm.
HRMS (ESI): calcd. for C16H14N2O2H 267.1128; found 267.1129.
C16H14N2O2 (266.29): calcd. C 72.16, H 5.30, N 10.52; found C
71.99, H 5.59, N 10.14.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of new compounds; total energies
(SCS-MP2/6-311+G(d,p)//B3LYP/6-31+G(d)+ZPE), Cartesian co-
ordinates (B3LYP/6-31+G(d))//B3LYP/6-31+G(d)), and numbers
of imaginary frequencies for the calculated structures; and graphi-
cal plots of the crystal structures.
[9]
Acknowledgments
[10]
[11]
a) S. D. Phillips, R. N. Castle, J. Heterocycl. Chem. 1980, 17,
1489–1495; b) N. R. Marquis, R. L. Vigdahl, DE 2152521 A1,
1970; c) J. L. Minielli, H. C. Scarborough, FR 3207 M, 1964.
Datasets were collected with Nonius KappaCCD diffractomet-
ers. In the case of Mo radiation, the diffractometer was
equipped with a rotating anode generator. Programs used: data
collection COLLECT (Nonius B. V., 1998), data reduction:
Denzo-SMN (Z. Otwinowski, W. Minor, Methods in Enzy-
mology 1997, 276, 307–326), absorption correction Denzo (Z.
Otwinowski, D. Borek, W. Majewski, W. Minor, Acta Crys-
This work was supported by the International Research Training
Group (IRTG) 1143 Münster–Nagoya, the Deutsche Forschungs-
gemeinschaft (DFG) and the Fonds der Chemischen Industrie,
Frankfurt, Germany.
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Received: February 27, 2013
Published Online: June 19, 2013
4952
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 4944–4952