Mechanistic study of a complementary reaction system that easily affords quinazoline and perimidine derivatives

Article abstract of DOI:10.1002/ejoc.201402854

A new reaction between 2-aminobenzophenone and thiourea in dimethyl sulfoxide (DMSO) has been developed that primarily affords 4-phenylquinazoline as a single product. This reaction is also applicable, in general, to the reactions between thiourea and conformation-restricted β-amino ketones, such as 1-aminoanthracene-9,10-dione and 1-amino-9H-fluoren-9-one, to prepare perimidine derivatives. Experimental data is consistent with our computational study on the thermal decomposition of thiourea to form hydrogen sulfide and carbodiimide. This reaction involves a coupling between 2-aminobenzophenone and carbodiimide generated in situ from thiourea to form 4-phenylquinazolin-2(1H)-imine intermediate, and the generation of sulfur-containing reducing agent from hydrogen sulfide and DMSO, which reduces 4-phenylquinazolin-2(1H)-imine to 4-phenyl-1,2-dihydroquinazolin-2-amine. Elimination of ammonia from the latter yields 4-phenylquinazoline.

Full text of DOI:10.1002/ejoc.201402854

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DOI: 10.1002/ejoc.201402854
Mechanistic Study of a Complementary Reaction System that Easily Affords
Quinazoline and Perimidine Derivatives
Zerong Daniel Wang,*[a] Joshua Eilander,[a] Motoko Yoshida,[b] and Tianzhi Wang[c]
Keywords: Synthetic methods / Nitrogen heterocycles / Solvent effects / Reactive intermediates / Reaction mechanisms
A new reaction between 2-aminobenzophenone and thio-
urea in dimethyl sulfoxide (DMSO) has been developed that
primarily affords 4-phenylquinazoline as a single product.
This reaction is also applicable, in general, to the reactions
between thiourea and conformation-restricted β-amino
ketones, such as 1-aminoanthracene-9,10-dione and 1-
amino-9H-fluoren-9-one, to prepare perimidine derivatives.
Experimental data is consistent with our computational study
on the thermal decomposition of thiourea to form hydrogen
sulfide and carbodiimide. This reaction involves a coupling
between 2-aminobenzophenone and carbodiimide gener-
ated in situ from thiourea to form 4-phenylquinazolin-2(1H)-
imine intermediate, and the generation of sulfur-containing
reducing agent from hydrogen sulfide and DMSO, which re-
duces 4-phenylquinazolin-2(1H)-imine to 4-phenyl-1,2-di-
hydroquinazolin-2-amine. Elimination of ammonia from the
latter yields 4-phenylquinazoline.
ethyl bromoacetate,[16] or with aldehyde and ammonium
acetate in the presence of an oxidizing agent.[17]
Introduction
Several years ago, we studied the reactions between α-
amino acids and thiourea in the absence of solvent and
found that this led to the formation of 2-thiohydantoins
with very high yields from α-amino acids of nonpolar side
chains.[18] We then extended this reaction to β-amino
acids, i.e., anthranilic acids, to afford 2-thioxo-2,3-di-
hydroquinazolin-4(1H)-ones.[19] In both cases, white fumes
were observed when the mixture of thiourea and amino acid
was heated at temperatures above 170 °C, which has been
reported to be ammonium thiocyanate (NH4SCN).[20] In
contrast, when we extended the reaction between anthra-
nilic acid and thiourea to include the reaction between 2-
aminobenzophenone and thiourea above 170 °C, a very
complex reaction was observed, from which three major
components were identified with molecular weights of 358,
360, and 360. Among them, the most abundant product
had molecular weight of 358, which is most likely (5Z,11Z)-
6,12-diphenyldibenzo[b,f][1,5]-diazocine arising from the di-
meric cyclization of 2-aminobenzophenone itself. The other
two components, both with molecular weight of 360, are
presumably the reduced products from the cyclic dimer by
Substituted quinazolines have been identified with a vari-
ety of biological activities, such as analgesic,[1] antibacte-
rial,[2] antibiotic,[1b] anticonvulsant,[1a,2b,3] antidepressant,[4]
anti-inflammatory,[1a,3,5] antihypertensive,[1b,3] antimalari-
al,[2a,6] antineoplastic,[2a] and antitumoral,[1b,7] among
others. Especially, 4-substituted quinazolines, for example
4-aryl-quinazolines, have antiplasmodial activity[8] and are
EGFR tyrosine kinase inhibitors,[9] CNS depressants,[10]
and antibiotics against methicillin-resistant Staphylococcus
aureus and vancomycin-resistant Enterococcus faecalis.[11]
Likewise, perimidines, being fused quinazoline derivatives,
have also displayed important biological activities.[12] In ad-
dition, with an extended aromatic system, perimidines also
have important application in the dye/pigment industry.[13]
Because of their great potential and wide range of applica-
tions, the synthetic methods available for these heterocycles
have been explored extensively. In general, 4-phenylquinaz-
olines are prepared from 2-aminobenzophenones (ABPs)
and formamide in the presence of BF3·Et2O[14] or formic
acid,[15] or from the reaction of ABP with urotropine and
[a] Department of Chemistry, School of Science and Computer
Engineering, University of Houston-Clear Lake,
2700 Bay Area Boulevard, Houston, TX 77058, USA
E-mail: wang@uhcl.edu
http://prtl.uhcl.edu/portal/page/portal/SCE/Natural_Sciences/
chemistryprogram
[b] Sekisui Specialty Chemicals America, LLC,
900 Gemini Ave., Suite A, Houston, TX 77058, USA
[c] Sealy Center for Structural Biology & Molecular Biophysics,
University of Texas Medical Branch,
Galveston, TX 77555, USA
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402854.
Scheme 1. The reaction between 2-aminobenzophenone and thio-
urea.
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Z. D. Wang, J. Eilander, M. Yoshida, T. Wang
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Scheme 2. The expected products from the reaction between 2-aminobenzophenone and thiourea.
thiourea. However, when the same reaction was carried out
If thiourea is not the species to directly react with 2-
in dimethyl sulfoxide (DMSO), either heated on a hotplate aminobenzophenone to form 4-phenylquinazoline, then
or under microwave irradiation, a clean reaction affording what is the actual reactive species? What is the mechanism
4-phenylquinazoline was established,[21] leading to an in- of this reaction?
crease of molecular weight only by 9, as shown in Scheme 1.
This reaction appears to be very important from both
experimental and mechanistic points of view. First, this re-
action provides a practical method to prepare 4-substituted
Results and Discussion
quinazoline derivatives, especially the 4-aryl-quinazolines,
The reaction between 2-aminobenzophenone and thio-
in high yields with an easy workup process, because most urea in DMSO forms a complementary system that cleanly
of tested reactions are clean, with barely noticeable affords 4-phenylquinazoline. In this reaction, DMSO, which
amounts of reaction intermediates that ultimately trans- is used as the reaction solvent, apparently also plays an im-
form into products as the reaction proceeds to completion. portant role because only a trace amount of 4-phenylquin-
Secondly, the reaction mechanism is intriguing to our chem- azoline was identified when the reaction was carried out in
istry intuition. According to the mechanism outlined in the absence of solvent where both 2-aminobenzo-
Scheme 2, a product of either 4-phenylquinazolin-2-amine, phenone and thiourea melt above 170 °C. Similarly, when
4-phenylquinazolin-2(1H)-thione or 4-phenylquinazolin-2- the same reaction is carried out in other solvents of high
thiol, rather than 4-phenylquinazoline is expected. How- boiling points, such as N,N-dimethylformamide (DMF) or
ever, this mechanism (both path a and b) is inconsistent ethylene glycol, almost no 4-phenylquinazoline can be de-
with the experimental results. For example, none of the pre- tected either. Therefore, DMSO is a complementary solvent
dicted reaction intermediates or products that are stable or for this reaction. Figure 1 illustrates the progress of the re-
relatively stable with molecular weights corresponding to action between 2-aminobenzophenone and thiourea at
238, 255 and 256 were observed by GC/MS analysis of the 155 °C in DMSO as tracked by GC/MS analysis.
reaction mixture at different time intervals before the com-
The identity of 4-phenylquinazoline from this reaction
pletion of the reaction. Furthermore, neither 4-phenylquin- was fully confirmed by MS spectrometry, 1H and 13C NMR
azolin-2-amine nor 4-phenylquinazolin-2-thiol break down spectroscopy, and X-ray crystallography. The X-ray crystal-
into 4-phenylquinazoline, as a simultaneous cleavage of two lographic image of 4-phenylquinazoline is displayed in Fig-
bonds to eliminate a single sulfur atom or NH fragment ure 2. The reactions between thiourea and ten other substi-
will be involved, which is impracticable.
tuted 2-aminophenyl aryl ketones that afford substituted 4-
2
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Formation of Quinazoline and Perimidine Derivatives
Figure 1. GC analysis of the reaction mixture formed upon reaction between 2-aminobenzophenone and thiourea in DMSO at 155 °C.
All samples were prepared by dissolving 5 μL of reaction mixture in 350 μL of EtOAc containing 2% of n-hexadecane as internal
standard. GC conditions: 100 °C (1 min)Ǟ250 °C (1.5 min) at 20 °C/min. Acetone is occasionally visible (seen here in the chromatogram
obtained at 4 h), which was used to wash the needle before sample was injected. (A) GC spectrum of the reaction mixture before heat
was applied, in which thiourea is barely noticeable due to its high polarity and thermal instability, and 2-aminobenzophenone is detected
at a retention time of 8.025 min. Additionally, n-hexadecane as the internal standard (6.283 min), reaction solvent (DMSO), and the
solvent for GC analysis (EtOAc) also appear in the GC spectra. (B) GC spectrum of reaction mixture after heating for 1.5 h, in which a
new peak appears at a retention time of 8.352 min, corresponding to 4-phenylquinazoline. Two tiny peaks have been identified at retention
times of 8.485 and 8.823 min, as shown in (B) and (C), both with molecular weights of 221, which disappear as the reaction proceeds to
completion. (D) GC spectrum of the reaction mixture after being heated for 5 h.
aryl-quinazolines are summarized in Table 1. Furthermore, low solubility of 4-phenylquinazolines in water vs. the mis-
seven conformation-restricted β-amino ketones, such as 1- cibility of water with DMSO and the side products decom-
aminoanthracene-9,10-dione and 1-amino-9H-fluoren-9- posed directly from thiourea. Therefore, pure 4-phenylquin-
one, readily undergo analogous reactions with thiourea to azolines could be obtained by simple filtration of crystalline
form perimidine derivatives; these reactions are listed in products followed by water wash. Alternatively, the prod-
Table 2. The successful transformation of 2-aminophenyl ucts can be extracted between ethyl acetate (EtOAc) and
aryl ketones into substituted quinazoline and perimidine water and further purified by column chromatography to
derivatives establishes the generality of this reaction.
remove minor contaminants that have been identified as di-
Additional features of this reaction include the crys- methyl disulfide, dimethyl trisulfide, and even sulfur, which
talliferous property of 4-phenylquinazolines when the reac- are complementarily formed in this reaction system from
tion mixtures are cooled to room temperature, and the very thiourea and DMSO.
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Z. D. Wang, J. Eilander, M. Yoshida, T. Wang
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Table 1. The reactions of thiourea with 2-aminophenyl ket-
ones.
Figure 2. The X-ray crystal structure of 4-phenylquinazoline.
CCDC-996112 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
It is known that neat thiourea undergoes thermal decom-
position in two stages, as indicated by thermogravimetric
analysis (TGA).[22] Although thiourea starts to decompose
at temperatures above 170 °C, over 80% of weight loss actu-
ally occurs at temperatures above 220 °C,[20,23] and the pre-
dominating products from the thermal decomposition of
thiourea between 220–240 °C are ammonia and carbon di-
sulfide.[20,24]
To investigate the mechanism of the reaction between 2-
aminobenzophenone and thiourea in DMSO, we have per-
formed a computational study for thermal decomposition
of thiourea in the gas phase.[25] The computational results
indicate that the predominant products from thermal de-
composition of thiourea around 170 °C are the pairs of
hydrogen sulfide and carbodiimide (H2S + HN=C=NH),
and possibly also include ammonia and isothiocyanic acid
(NH3 + HN=C=S), the latter pair combines to form ammo-
nium thiocyanate. The formation of hydrogen sulfide and
carbodiimide has relatively lower activation energy than the
formation of ammonia and isothiocyanic acid, indicating
that H2S and carbodiimide are kinetically favored products.
However, this computational result is only supported by the
formation of guanidinium thiocyanate during the decompo-
sition of thiourea.[20]
It is possible that thermal decomposition of thiourea
takes place at lower temperature in polar solvents such as
DMSO than in the gas phase reaction, which also forms
hydrogen sulfide and carbodiimide, as well as NH3 and
HN=C=S as the favored products. If isothiocyanic acid is
the species that reacts with 2-aminobenzophenone, such re-
action will also form the reaction intermediates with molec-
ular weights of 238 and 256, as illustrated in Scheme 3.
It has been reported that the reaction between 2-amino-
5-chloro-benzophenone and chlorosulfonyl isocyanate gives
6-chloro-4-phenylquinazolin-2(1H)-one.[26] A similar reac-
tion of aminobenzophenone with benzoyl isothiocyanate[27]
or triphenylphosphine thiocyanate[28] led to the formation
of 4-phenylquinazolin-2(1H)-thione. These experiments
indicate that 4-phenylquinazolin-2(1H)-thione, with a mo-
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Formation of Quinazoline and Perimidine Derivatives
Table 2. Reactions forming perimidine derivatives.
lecular weight of 238, is stable and can be isolated. How-
ever, GC/MS analysis of the reaction mixture between thio-
urea and 2-aminobenzophenone at different time intervals
did not identify any components with the molecular weights
predicted in Schemes 2 and 3, except for 221, indicating that
neither thiourea nor isothiocyanic acid is the species in-
volved in the formation of 4-phenylquinazoline from 2-
aminobenzophenone.
To further prove that 4-phenylquinazoline is not formed
from 2-aminobenzophenone and isothiocyanic acid, we car-
ried out the reaction between 2-aminobenzophenone and
4-cyanophenyl isothiocyanate, and the reaction between 2-
aminobenzophenone and 4-methoxyphenyl isothiocyanate
in DMSO at 150 °C. To our surprise, 4-cyanophenyl iso-
thiocyanate decomposed completely in DMSO after the re-
action mixture has been heated for 2 h, affording a small
Scheme 3. The reaction mechanism between 2-aminobenzo-
phenone and isothiocyanic acid.
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Figure 3. GC analysis of the reaction between 2-aminobenzophenone and 4-cyanophenyl isothiocyanate.
portion of 4-cyanoaniline (Figure 3). In comparison, 4- DMSO. In both cases, 2-aminobenzophenone remains un-
changed throughout the heating process, as shown in Fig-
ures 3 and 4. Such experimental results repeatedly indicate
that isothiocyanate is not likely the reactive species in the
formation of 4-phenylquinazoline.
methoxyphenyl isothiocyanate can survive slightly longer
heating time than 4-cyanophenyl isothiocyanate, because a
tiny amount of this compound can still be detected after the
mixture with 2-aminobenzophenone was heated for 5.5 h.
However, no 4-methoxyaniline was detected in this mixture,
Given the computational results that H2S and
and the amount of 4-methoxyphenyl isocyanate seems to HN=C=NH are the kinetically favored products, we would
increase slightly, possibly from the reaction between 4- argue that carbodiimide could be the real species that reacts
methoxyphenyl isothiocyanate and residual moisture in with 2-aminobenzophenone to form 4-phenylquinazolin-
Figure 4. GC analysis of the reaction between 2-aminobenzophenone and 4-methoxyphenyl isothiocyanate.
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Formation of Quinazoline and Perimidine Derivatives
2(1H)-imine as the reaction intermediate with a molecular BTMSC, the reduction of 4-phenylquinazolin-2(1H)-imine
weight of 221, which can tautomerize to 2-amino-4-phenyl- is retarded. Therefore, it is reasonable that only a tiny
quinazoline, also with a molecular weight of 221. It is the amount of 4-phenylquinazoline could be detected when the
hydrogen sulfide that reacts with DMSO to form other mixture of 2-aminobenzophenone and BTMSC was heated
sulfur-containing molecules, such as methanethiol, which at 145 °C for 40 h in the sealed tube.
functions as the reducing agent to reduce 4-phenylquinazol-
If a reducing agent were indeed necessary for this reac-
in-2(1H)-imine to 4-phenyl-1,2-dihydroquinazolin-2-amine tion, the addition of reducing agent would promote the for-
that then evolves ammonia to afford 4-phenylquinazoline. mation of 4-phenylquinazoline. As expected, the addition
This hypothesis is based on the experimental result that of sulfur-containing reducing agents such as mercapto-
methanethiol, dimethyl sulfide, dimethyl disulfide, dimethyl ethanol or dithiothreitol (DTT) to the reaction mixture of
trisulfide, and even dimethyl tetrasulfide have been detected 2-aminobenzophenone and BTMSC does promote the for-
by GC/MS analysis of the reaction mixture. Hydrogen sulf- mation of 4-phenylquinazoline, and the product is notice-
ide itself might also function as the reducing agent. Our able even when the mixture is heated for only 110 min.
study on the simple decomposition of thiourea in DMSO Furthermore, the presence of acid, such as H2SO4 or AlCl3,
alone also indicates the formation of methanethiol, di- can additionally facilitate the formation of 4-phenylquin-
methyl sulfide, and up to dimethyl tetrasulfide, implying a azoline, especially when AlCl3 is added. This is because acid
stand-alone reaction between thiourea and DMSO, which helps the decomposition of BTMSC to simple carbodi-
generates sulfur-containing reducing species that are neces- imide. When AlCl3 is added to the reaction mixture, a fume
sary for the formation of 4-phenylquinazoline. This new forms immediately; presumably, AlCl3 is converted into
mechanism, which is consistent with experimental results, is HCl and the remaining moisture is removed. When twice
illustrated in Scheme 4.
the amount of BF3·Et2O with respect to AlCl3 was added
To probe this mechanism, N,NЈ-dicyclohexylcarbodi- to the reaction between 2-aminobenzophenone and
imide (DCC) and N,NЈ-bistrimethylsilyl carbodiimide BTMSC in DMSO in the presence of 2-mercaptoethanol,
(BTMSC), which are both commercially available, were lower amounts of 4-phenylquinazoline were detected under
tested with 2-aminobenzophenone in DMSO at 145 °C. The the same conditions. This may be for two reasons: the rela-
[29]
reaction from DCC did not give 4-phenylquinazoline even tively low acidity of BF3·Et2O with respect to AlCl3 and
after the reaction mixture has been heated for 40 h in a the boiling point of BF3·Et2O (126.9 °C), which is lower
sealed tube under microwave irradiation. However, the reac- than the reaction temperature so that a large portion of
tion between 2-aminobenzophenone and BTMSC, al- BF3·Et2O might remain in the gas phase instead of
though not an efficient reaction compared with that with being involved in the reaction. H2SO4 is not as efficient as
thiourea, does form detectable amounts of 4-phenylquinaz- AlCl3 because some water is also added when H2SO4 is
oline when the reaction mixture was heated at the same added.
temperature for 14 h, as shown in Figure 5. These results
In addition, the reaction between 2-aminobenzophenone
are reasonable because both carbodiimides are more bulky and BTMSC in the presence of nickel sulfide (Ni3S2) forms
than the simplest carbodiimide generated in situ from lower amounts of 4-phenylquinazoline than those in the
thiourea, making it more difficult for them to react with 2- presence of thiols due to the very low solubility of Ni3S2 in
aminobenzophenone. Given its weak C–Si bond, BTMSC DMSO. In this case, the addition of H2SO4 quickly helps
can decompose to the simplest carbodiimide, leading to re- the formation of the final product, presumably due to the
action conditions similar to those with thiourea, thus formation of H2S. All these experimental results, in combi-
BTMSC is superior to DCC. However, because hydrogen nation with the detection of (HOCH2CH2S)2 in the reaction
sulfide or other sulfur-containing molecules that can func- mixture when 2-mercaptoethanol is present, support the
tion as reducing agent are absent in the reaction of proposed mechanism that the intermediate 4-phenylquin-
Scheme 4. Proposed mechanism for the formation of 4-phenylquinazoline from 2-aminobenzophenone.
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Figure 5. GC analysis of the reactions of 2-aminobenzophenone with BTMSC or cyanamide.
azolin-2(1H)-imine is reduced to 4-phenyl-1,2-dihydroquin- the reaction intermediate 4-phenylquinazolin-2(1H)-imine,
azolin-2-amine, which then decomposes to the final prod- as predicted in Scheme 4. In comparison, the presence of
uct.
two equivalents of H2SO4 will also promote the reaction
Even for the reaction between 2-aminobenzophenone between 2-aminobenzophenone and thiourea, but this is
and thiourea, the presence of a trace amount of AlCl3 facili- less efficient for the formation of 4-phenylquinazoline than
tates the reaction, which almost reaches completion in 2 h, performing the reaction in the presence of AlCl3, possibly
whereas the same reaction in the presence of twice the due to the trace amount of water in H2SO4, because water
amount of BF3·Et2O yields less 4-phenylquinazoline, also would react with carbodiimide to afford urea. The observed
indicating that BF3·Et2O is inferior to AlCl3. By contrast, acceleration of the reaction in the presence of acid is proba-
the same reaction conducted in DMSO in the absence of bly due to the protonation of the imine intermediate, which
AlCl3 requires 5 h to complete, as shown in Figure 1. becomes more electrophilic than the neutral imine species.
Furthermore, a tiny peak formed by a substance with mo- Apparently, the reduction of the protonated imine interme-
lecular weight of 221 is detected by GC, corresponding to diate is faster than the reduction of neutral imine species.
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Formation of Quinazoline and Perimidine Derivatives
Conversely, the outcome of the same reaction performed
As shown in Tables 1 and 2, the reaction between thio-
under basic conditions (e.g., in the presence of 3 equiv. urea and 2-aminophenyl aryl ketones or the conformation-
KOH), in which only a limited amount of product can be restricted β-amino ketones is a general reaction in DMSO.
identified, further demonstrates the promoting effect of Furthermore, the reaction is suitable for β-amino ketones
acid on the formation of 4-phenylquinazoline. This is be- containing either a free amino group or a protected amino
cause KOH reacts with H2S to form K2S or KSH, both of group, because both N-methyl and N-acetyl groups in reac-
which are more nucleophilic, rather than remaining as the tants have been removed from the corresponding nitrogen
reducing agent under acidic conditions. Even if meth- atoms in the final products. In the case of 5-chloro-2-(N-
anethiol forms from the reaction between thiourea and methyl)-aminobenzophenone, a trace amount of 6-chloro-
DMSO, it might also react with KOH to form KSMe in- 1-methyl-4-phenylquinazolin-2(1H)-imine was successfully
stead of functioning as the reducing agent. More import- isolated and characterized, which provides direct support
antly, 1,3,5-triazine-2,4,6-triamine has been detected under for the proposed mechanism that is illustrated in Scheme 4.
these conditions; that is, the trimerization product of car- Due to the methyl group at the nitrogen atom, the reduction
bodiimide. The presence of this compound clearly supports of the imine intermediate and elimination of methylamine
the formation of carbodiimide. This is possibly the first di- instead of ammonia, as in the reactions of other 2-amino-
rect experimental evidence to support the computational re- benzophenones (Table 1), from the reduced intermediate to
sult for the formation of carbodiimide from thiourea de- form 6-chloro-4-phenylquinazoline are relatively slow, so
composition. Furthermore, 4-phenylquinazolin-2(1H)-one that this imine intermediate can be isolated by preparative
has been detected, which might be the hydrolyzed product TLC. A trace amount of 6-chloro-1-methyl-4-phenylquin-
of 4-phenylquinazolin-2(1H)-imine due to the retardation azolin-2(1H)-one has also been isolated and characterized,
of its reduction into 4-phenyl-1,2-dihydroquinazolin-2- which is presumably hydrolyzed from the imine intermedi-
amine in the absence of reducing agent.
ate during isolation by TLC.
It should be pointed out that this reaction is unique to
The reaction becomes extremely slow when it is heated
the solvent of DMSO, due to the formation of meth- at a temperature below 110 °C; presumably, decomposition
anethiol, dimethyl sulfide, dimethyl disulfide, etc. Some of of thiourea is very difficult at that temperature.
these sulfur-containing molecules naturally function as re-
ducing agents to reduce 4-phenylquinazolin-2(1H)-imine.
Conclusions
On the other hand, the reaction intermediate, i.e., 4-phenyl-
quinazolin-2(1H)-imine formed from 2-aminobenzophen-
one and carbodiimide, further oxidizes the reductive thio-
species and promotes the formation of such thio-species.
Therefore, the reaction between thiourea and 2-amino-
benzophenone and its unique solvent (i.e., DMSO) form
a complementary reaction system that nicely captures the
carbodiimide generated in situ from thiourea as the carbon
source to form the pyrimidine ring in quinazoline deriva-
tives. For comparison, when thiourea and 2-aminobenzo-
phenone are heated in DMF at a similar temperature range,
both 1,3,5-triazine-2,4,6-triamine and the cyclic dimer of 2-
aminobenzophenone were identified as the major products.
Even when the reaction mixture was heated in DMF for
24 h, only a trace amount of 4-phenylquinazoline was
formed due to the lack of sulfur-containing reducing agents
in the absence of DMSO.
A unique reaction system has been established that is ap-
plicable for the preparation of 4-arylquinazoline and perim-
idine derivatives. The reaction is the first example of the use
of carbodiimide generated in situ as the carbon source for
the newly formed pyrimidine moiety in both quinazoline
and perimidine derivatives. The mechanism and the trap-
ping of carbodiimide in the form of 1,3,5-triazine-2,4,6-tri-
amine support our early computational study for the ther-
mal decomposition of thiourea, which concluded that
carbodiimide and H2S are the major products of thiourea
at its first stage of decomposition.
Experimental Section
Summary of Scientific Instruments: A Biotage Initiator I microwave
was used for heating of reaction solutions under microwave irradia-
tion. All reaction solutions heated either under thermal heating or
by microwave irradiation were analyzed with an Agilent GC/MS
instrument, consisting of a 7890A GC system, a 5975C XL MSD
Additionally, a potential competing reaction to form 4-
phenylquinazoline involving cyanamide (NH2CN) has been
tested. Our computational results indicate that cyanamide,
as the structural isomer of carbodiimide, is not likely the with Triple-Axis Detector, a 7683B series injector and a HP
desktop computer operated under Windows XP. The 1H and 13C
product of thermal decomposition of thiourea due to the
very high activation energy.[25] In fact, the reaction between
NMR spectra (in CDCl3, TMS as the internal standard) were mea-
sured primarily at 750 MHz, and occasionally at 800 MHz with
2-aminobenzophenone and cyanamide under exactly the
a Bruker spectrometer located at the Sealy Center for Structural
same conditions to that of BTMSC gives a barely observ-
Biology & Molecular Biophysics, University of Texas Medical
able amount of 4-phenylquinazoline, even in the presence
Branch, Galveston, TX 77555, USA. High-resolution mass spectra
of mercaptoethanol (Figure 5). This is because the addition
(HRMS) were recorded with a LC/MS (ESI-TOF) system funded
of an amino group to the cyano group will break a triple
by the National Science Foundation (NSF 0958901) using water/
bond. This experimental result indicates that cyanamide is
less likely to be the species involved in the formation of 4-
phenylquinazoline.
acetonitrile as solvent with 0.1% trifluoroacetic acid added as the
protonation source, so that all compounds were detected as proton-
ated ions under positive mode.
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Pages: 12
Z. D. Wang, J. Eilander, M. Yoshida, T. Wang
FULL PAPER
General Procedure under Microwave Irradiation: To a 5 mL Biotage
reaction vial were added a small magnetic stirring bar, (2-amino-
phenyl) (4Ј,5Ј-dimethoxy-2-methylphenyl) ketone (19.2 mg), thio-
urea (20.5 mg, 3 equiv.) and DMSO (1.0 mL). The vial was sealed
and the solution was heated at 150 °C for 7 h in a Biotage micro-
wave reactor. The solution became brown and a precipitate formed
upon cooling to room temperature. The solution was heated at
150 °C under microwave irradiation for an additional 16 h, then an
aliquot (5 μL) of the solution was added to EtOAc (350 μL) for
GC/MS analysis, and the remaining solution was directly loaded
on a TLC plate for purification (hexane/EtOAc, 1:2). The scratched
silica gel powder was extracted with acetone (10 mL) and the acet-
one solution was dried on a rotary evaporator to afford 4-(2Ј-
methyl-4Ј,5Ј-dimethoxyphenyl)quinazoline (13.8 mg, 69.6%) as a
white powder. Rf = 0.30 (hexane/EtOAc, 1:2). 1H NMR (CDCl3,
750 MHz, TMS as internal standard): δ = 9.41 (s, 1 H, H-2), 8.14
115.7, 31.3 ppm. HRMS (ESI-TOF): m/z calcd. for C15H12ClN2O+
[M + H]+ 271.0633; found 271.0775.
General Procedure under Thermal Conditions: To a 125 mL flask,
were added
a magnetic stirring bar, 2-aminobenzophenone
(3.003 g), thiourea (3.4815 g, 3 equiv.), and DMSO (10 mL). The
solution was heated at 150 °C for 8 h, and the progress of the reac-
tion was monitored by GC/MS analysis periodically. The solution
was cooled to room temperature and EtOAc (30 mL) was used to
transfer the reaction mixture into a 125 mL separating funnel. The
solution was washed with water and the solvent was evaporated to
afford a residue (3.30 g). A sample of the residue (ca. 0.2 g) was
purified by thin-layer column chromatography (hexane/EtOAc, 2:1)
and further purified by recrystallization from EtOAc. The crystal
was submitted for X-ray crystallographic analysis.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of crystal information for 4-phenylquinazoline, GC/
MS analyses of the individual reaction solutions, 1H, 13C NMR
and HRMS characterization of purified reaction products and in-
termediates.
(d, J7,8 = 8.3 Hz, 1 H, H-8), 7.92 (ddd, J6,7 = 8.8, J7,8 = 6.9, J5,7
=
1.4 Hz, 1 H, H-7), 7.75 (dd, J5,6 = 8.0, J5,7 = 0.5 Hz, 1 H, H-5),
7.58 (ddd, J6,7 = 8.5, J5,6 = 6.9, J6,8 = 1.1 Hz, 1 H, H-6), 6.88 (s, 1
H), 6.86 (s, 1 H), 3.97 (s, 3 H, OMe), 3.86 (s, 3 H, OMe), 2.09 (s,
3 H, Me) ppm. 13C NMR (CDCl3, 187.5 MHz): δ = 169.72, 154.70,
150.53, 149.68, 146.94, 133.90, 128.90, 128.74, 128.32, 127.80,
127.31, 124.30, 113.49, 112.61, 56.07 (OMe), 56.00 (OMe), 19.47
Acknowledgments
+
(Me) ppm. HRMS (ESI-TOF): m/z calcd. for C17H17N2O2 [M +
H]+ 281.1285; found 281.1314.
This work was partially supported by the Robert Welch Foundation
(departmental grants BC-0022 and BC-1586), by the National
Science Foundation (NSF) (grant number 0958901) and by the
University of Houston-Clear Lake (FRSF grant). The authors
thank Dr. Jack Lu at UHCL and Dr. James Korp at University
of Houston for helping to characterize the X-ray structure of 4-
phenylquinazoline at MRSEC/TCSUH Shared Experimental Facil-
ities supported by NSF and the Texas Center for Superconductivity
at University of Houston.
Preparation of 6-Chloro-4-phenylquinazoline from 5-Chloro-2-(meth-
ylamino)benzophenone: To a 10 mL Biotage reaction vial were
added a small magnetic stirring bar, 5-chloro-2-(methylamino)
benzophenone (0.6343 g), thiourea (0.5902, 3 equiv.) and DMSO
(4.0 mL). The vial was sealed and placed into the microwave reac-
tor, and the solution was heated at 150 °C for 15 h. After cooling
to room temperature, the brownish solid was vacuum filtered,
washed with water and air-dried to afford the crude product
(0.618 g, 93.8%) as a solid. GC analysis indicated that the solid
contained 92% 6-chloro-4-phenylquinazoline, which displayed the
same retention time as the material formed directly from 2-amino-
5-chlorobenzophenone.
[1] a) V. Alagarsamy, D. Shankar, V. R. Solomon, R. V. Sheorey,
P. Parthiban, Acta Pharm. 2009, 59, 75–88; b) S. Mehta, N.
Swarnkar, M. Vyas, J. Vardia, P. B. Punjabi, S. C. Ameta, Bull.
Korean Chem. Soc. 2007, 28, 2338–2342.
A small fraction of the solid (0.10 g) was dissolved in acetone
(1 mL) and loaded on to a 20ϫ 20 cm preparative TLC plate
(1 mm thick, SiO2), and then developed by hexane/EtOAc (2:1).
Besides the known 6-chloro-4-phenylquinazoline as the major
product [85.2 mg; Rf = 0.61 (hexane/EtOAc, 2:1)], 6-chloro-1-
methyl-4-phenylquinazolin-2(1H)-imine [2.7 mg, Rf = 0.92 (hexane/
EtOAc, 2:1)], and 6-chloro-1-methyl-4-phenylquinazolin-2(1H)-one
[2.6 mg, Rf = 0.13 (hexane/EtOAc, 2:1)] were also obtained as white
solids. Both were characterized by NMR and HRMS analysis as
detailed below.
[2] a) W. T. Ashton, F. C. Walker, J. B. Hynes, J. Med. Chem. 1973,
16, 694–697; b) A. Kamal, K. L. Reddy, V. Devaiah, N. Shank-
araiah, M. V. Rao, Mini-Rev. Med. Chem. 2006, 6, 71–89.
[3] D. J. Connolly, D. Cusack, T. P. O’Sullivan, P. J. Guiry, Tetrahe-
dron 2005, 61, 10153–10202.
[4] K. Spirkova, S. Stankovsky, Chem. Heterocycl. Compd. 1995,
31, 1217–1218.
[5] A. Baba, N. Kawamura, H. Makino, Y. Ohta, S. Taketomi, T.
Sohda, J. Med. Chem. 1996, 39, 5176–5182.
[6] Y. Gama, I. Shibuya, M. Simizu, Chem. Pharm. Bull. 2002, 50,
1517–1519.
6-Chloro-1-methyl-4-phenylquinazolin-2(1H)-imine:
1H
NMR
[7] A. E. Wakeling, A. J. Barker, D. H. Davies, D. S. Brown, L. R.
Green, S. A. Cartlidge, J. R. Woodburn, Breast Cancer Res.
Treat. 1996, 38, 67–73.
[8] P. Verhaeghe, N. Azas, M. Gasquet, S. Hutter, C. Ducros, M.
Laget, S. Rault, P. Rathelot, P. Vanelle, Bioorg. Med. Chem.
Lett. 2008, 18, 396–401.
[9] Y. Kitano, T. Suzuki, E. Kawahara, T. Yamazaki, Bioorg. Med.
Chem. Lett. 2007, 17, 5863–5867.
[10] R. K. Goel, V. Kumar, M. P. Mahajan, Bioorg. Med. Chem.
Lett. 2005, 15, 2145–2148.
(CDCl3, 800 MHz, TMS as internal standard): δ = 8.46 (br. s, 1 H,
NH), 7.58 (dd, J1 = 8.0, J2 = 1.6 Hz, 2 H), 7.54 (tt, J1 = 7.2, J2 =
0.8 Hz, 1 H), 7.47 (ddd, J1 = 8.0, J2 = 7.2, J3 = 1.6 Hz, 2 H), 7.43
(d, J = 2.0 Hz, 1 H), 7.34 (dd, J1 = 9.6, J2 = 3.2 Hz, 1 H), 6.71 (d,
J = 9.6 Hz, 1 H), 2.96 (s, 3 H, N-Me) ppm. 13C NMR (CDCl3,
201 MHz): δ = 198.3, 151.2, 139.8, 134.9, 134.0, 131.1, 128.9, 128.3,
118.2, 117.9, 112.7, 29.6 ppm. HRMS (ESI-TOF): m/z calcd. for
C15H13ClN3 [M + H]+ 270.0793; found 270.0864.
+
[11] A. K. Parhi, Y. Zhang, K. W. Saionz, P. Pradhan, M. Kaul, K.
Trivedi, D. S. Pilch, E. J. LaVoie, Bioorg. Med. Chem. Lett.
2013, 23, 4968–4974.
[12] a) D. R. Panchasara, S. Pande, E-J. Chem. 2009, 6 (Suppl. 1),
S91–S96; b) K. C. Liu, H. S. Huang, L. T. Fan, Zhonghua
Yaoxue Zazhi 1993, 45, 511–518; c) D. R. Luthin, A. K. Rab-
novich, D. R. Bhumralkar, K. L. Youngblood, R. A. Bychow-
6-Chloro-1-methyl-4-phenylquinazolin-2(1H)-one:
1H
NMR
(CDCl3, 800 MHz, TMS as internal standard): δ = 7.83 (d, J =
2.4 Hz, 1 H), 7.73–7.71 (m, 3 H), 7.60 (tt, J1 = 7.9, J2 = 1.3 Hz, 1
H), 7.56 (tt, J1 = 7.5, J2 = 1.2 Hz, 2 H), 7.36 (d, J = 9.6 Hz, 1 H),
3.78 (s, 3 H, N-Me) ppm. 13C NMR (CDCl3, 201 MHz): δ = 173.7,
155.3, 142.7, 135.8, 135.3, 130.9, 129.6, 129.0, 128.6, 127.8, 116.7,
10
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Formation of Quinazoline and Perimidine Derivatives
ski, D. S. Dhanoa, J. M. May, Bioorg. Med. Chem. Lett. 1999,
9, 765–770.
[13] a) K. Hirokawa, K. Anazawa, Y. Ito, M. Tian, S. Nakaso, S.
Hasegawa, T. Matsubara, M. Furuki, M. Watanabe, T. Miyah-
ara, U. S. Pat. Appl. Publ. 201001
[14] C.-H. Yang, K.-H. Fang, W.-L. Su, S.-P. Wang, S.-K. Su, I.-W.
Sun, J. Organomet. Chem. 2006, 691, 2767–2773.
[15] A. Byford, P. Goadby, M. Hooper, H. V. Kamath, S. N. Kulk-
arni, Indian J. Chem. 1988, 27B, 396–397.
[23]
[24]
S. Wang, Q. Gao, J. Wang, J. Phys. Chem. B 2005, 109, 17281–
17289.
a) J. Madarász, G. Pokol, J. Therm. Anal. Calorim. 2007, 88,
329–336; b) H. Krall, J. Chem. Soc. Trans. 1913, 103, 1378–
1391.
D. Z. Wang, M. Yoshida, B. George, Comput. Theor. Chem.
2013, 1017, 91–98.
a) A. Barthel, L. Trieschmann, D. Stroehl, R. Kluge, G.
Boehm, R. Csuk, Arch. Pharm. (Weinheim, Germany) 2009,
342, 445–452; b) A. Kamal, K. R. Rao, P. B. Sattur, Synth.
Commun. 1980, 10, 799–804.
[25]
[26]
[16] N. Blazevic, M. Oklobdzija, V. Sunjic, F. Kajfez, D. Kolbah,
Acta Pharm. Jugoslavica 1975, 25, 223–230.
[17] S. K. Panja, S. Saha, RSC Adv. 2013, 3, 14495–14500.
[18] Z. D. Wang, S. O. Sheikh, Y. Zhang, Molecules 2006, 11, 739–
750.
[27] E. Altmann, R. Beerli, M. Gerspacher, J. Renaud, S. Weiler, L.
Widler, PCT Int. Appl., WO 2004056365A2, July 08, 2004.
[28] Y. Tamura, T. Kawasaki, M. Tanio, Y. Kita, Synthesis 1979,
120–121.
[29] a) G. Hilt, F. Pünner, J. Möbus, V. Naseri, M. A. Bohn, Eur. J.
Org. Chem. 2011, 5962–5966; b) P. Laszlo, M. Teston, J. Am.
Chem. Soc. 1990, 112, 8750–8754.
[19] Y. Zhang, K. Massey, Z. Wang, in: The 233rd ACS National
Meeting, Chicago, Illinois, 2007; Post 217.
[20] V. P. Timchenko, A. L. Novozhilov, O. A. Slepysheva, Russ. J.
Gen. Chem. 2004, 74, 1046–1050.
[21] Z. D. Wang, PCT Int. Appl. WO 2012/151141 A2, November
8, 2012.
[22] L. Stradella, M. Argentero, Thermochim. Acta 1993, 219, 315–
323.
Received: July 2, 2014
Published Online: ᭿
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Date: 14-10-14 13:16:01
Pages: 12
Z. D. Wang, J. Eilander, M. Yoshida, T. Wang
FULL PAPER
Nitrogen Heterocycles
Z. D. Wang,* J. Eilander, M. Yoshida,
T. Wang .......................................... 1–12
Mechanistic Study of a Complementary
Reaction System that Easily Affords Quin-
azoline and Perimidine Derivatives
Keywords: Synthetic methods / Nitrogen
heterocycles / Solvent effects / Reactive in-
termediates / Reaction mechanisms
The mechanism of a novel reaction to form
substituted quinazoline and perimidine de-
rivatives has been elucidated. This reaction
involves the thermal decomposition of
thiourea to form carbodiimide and H2S,
the former couples with 2-aminobenzo-
phenone to form 4-phenylquinazolin-
2(1H)-imine intermediate, which is then
reduced and converted into 4-phenylquin-
azoline.
12
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