One-pot synthesis of 2-arylquinazolines and tetracyclic isoindolo[1,2-a]quinazolines via cyanation followed by rearrangement of ortho-substituted 2-halo-N-arylbenzamides

Article abstract of DOI:10.1002/adsc.201400505

The one-pot synthesis of substituted 2-arylquinazoline derivatives and tetracylic isoindolo[1,2-a]quinazoline via cyanation followed by rearrangement of ortho-substituted 2-halo-N-arylbenzamides is described. Using dimethyl sulfoxide (DMSO) as the solvent

Full text of DOI:10.1002/adsc.201400505

FULL PAPERS
DOI: 10.1002/adsc.201400505
One-Pot Synthesis of 2-Arylquinazolines and Tetracyclic
Isoindolo[1,2-a]quinazolines via Cyanation Followed by
Rearrangement of ortho-Substituted 2-Halo-N-arylbenzamides
Sachin D. Gawande,a Manoj R. Zanwar,a Veerababurao Kavala,a Chun-Wei Kuo,a
R. R. Rajawinslin,a and Ching-Fa Yaoa,*
a
Department of Chemistry, National Taiwan Normal University, 88, Sec. 4, Tingchow Road, Taipei, Taiwan 116, R.O.C.
E-mail: cheyaocf@ntnu.edu.tw
Received: May 22, 2014; Revised: July 29, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400505.
Abstract: The one-pot synthesis of substituted 2-aryl- nylquinazoline and long-chain 2-phenyl-4-styrylqui-
quinazoline derivatives and tetracylic isoindolo[1,2- nazoline derivatives were produced in moderate to
a]quinazoline via cyanation followed by rearrange- good yields using DMSO as the solvent. However,
ment of ortho-substituted 2-halo-N-arylbenzamides is various tetracyclic isoindole fused quinazoline deriv-
described. Using dimethyl sulfoxide (DMSO) as the atives were obtained in good yields when 1,4-dioxane
solvent, the cleavage of the tetracyclic isoindole was used as the solvent.
fused quinazoline leads to the formation of 2-arylqui-
nazoline derivatives. When 1,4-dioxane is used as the
solvent, tetracyclic isoindole fused quinazolines are Keywords: 2-arylquinazolines; C C bond formation;
produced in good yield. A wide range of products, in- copper catalysts; isoindolo[1,2-a]quinazolines; rear-
À
cluding 2-phenylquinazolin-4-amine, 4-methyl-2-phe- rangement
Introduction
properties such as anticonvulsant, antibacterial, anti-
viral, antitubercular, antiplasmodial, anticancer and
The synthesis of nitrogen heterocycles via transition topoisomerase I inhibitory activities.[2] In addition to
metal-mediated cross-coupling reactions has become 2-arylquinazolines, tetracyclic isoindolo[1,2-a]quinazo-
an area of interest. This may be due to the fact that line derivatives are ubiquitous structural motifs and
traditional synthetic methods are often laborious and possess excellent biological activities. A structural an-
the desired products are produced in relatively lower alogue such as batracylin has potent activity against
yields. Syntheses of these nitrogen heterocycles via colon carcinomas, cisplatin- and doxorubicin-resistant
copper-catalyzed and copper-mediated C C and C N tumors. A luotonin derivative was also reported to be
bond coupling reactions are very popular. Copper cat- effective against leukemia cells. Recent reports indi-
alysts are inexpensive, less toxic and the use of air- cate that tryptanthrin can be used effectively as a che-
sensitive and expensive ligands that are used with pal- motherapeutic agent in the treatment of sleeping dis-
ladium and other metal complex-based methodologies orders.[3] During our literature review we found very
can be avoided. Furthermore, applications of such few reports on the synthesis of isoindolo[1,2-a]quina-
copper-mediated handy protocols on 2-haloarylbenz- zoline derivatives.[4] Numerous approaches are avail-
À
À
ACHTUNGTRENNUNGamide derivatives with structural changes at the able for the synthesis of 2-arylquinazoline deriva-
amidic position leads to the formation of multicyclic tives.[5] However, the synthesis of 2-arylquinazoline
fused rings via multibond formation. Structural motifs derivatives is a cumbersome task, since it involves
such as dibenzoxazepinones, indoloquinolines and tet- either the use of starting materials such as 2-(amino-
racyclic fused N-heterocyclic compounds can be easily methyl)aniline, benzimidamide, which are not readily
synthesized using these methodologies, compared to available, or the use of dangerous peroxides or haz-
traditional multistep synthesis.[1]
ardous reagents.[6] We wish to report herein on the
2-Arylquinazolines are an important class of struc- solvent-dependent one-pot synthesis of multi-substi-
tural motifs that possess remarkable pharmacological tuted 2-arylquinazoline and tetracyclic isoindolo[1,2-
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Sachin D. Gawande et al.
Table 1. Optimization of reaction conditions.
a]quinazoline derivatives via cyanation followed by
rearrangement of the resulting ortho-substituted 2-
halo-N-arylbenzamide.
Results and Discussion
Our group previously reported on numerous proto-
cols for the synthesis of medicinally active N-hetero-
cycles.[7] In a continuation of this interest, we noted
the recently published articles on copper-catalyzed re-
actions of ethyl cyanoacetate and ethyl 2-(2-bromo-
benzamido)benzoate for the synthesis of isoquinoli-
no[2,3-a]quinazolinones by Fu and co-workers[8a] and
Pal and co-workers.[8b] Based on these reports, we hy-
pothesized that the reaction of 1a with CuCN would
first undergo cyanation followed by cyclization in the
À
presence of an amidic N H, which would lead to the
formation of the tetracyclic compound 2a (Scheme 1).
Furthermore, the hydroxy group can be easily func-
Scheme 1. Synthesis of tetracyclic compound 2a from 1a.
tionalized using various protocols. To investigate this
hypothesis, we treated 1a in the presence of CuCN in
DMSO and K2CO3 as a base at 1008C. The reaction
resulted in multiple spots on TLC after 2 h, however,
when the reaction was continued for a period of up to
16 h, a new compound was observed with a higher Rf
than the starting material (Table 1, entry 1). The com-
pound was isolated and purified by column chroma-
tography. Further characterization by 1H NMR,
13C NMR, LR-MS, HR-MS, single crystal X-ray dif-
fraction revealed that the compound was 2-phenylqui-
nazoline (3a, Figure 1) and not compound 2a
(Scheme 1).
[a]
[b]
Reactions were performed on 0.5 mmol of 1a, CuCN
(1 equiv.) and base (2.5 equiv,).
Yields refer to isolated and purified compounds.
Interestingly, the combination of such a strained
five-membered ring and a strong base leads to base-
À
catalyzed cleavage of the C N bond in compound 2a.
Moreover, further decarboxylation resulted in the for-
mation of compound 3a (Scheme 1). To our knowl-
edge, such types of cleavages have not been reported
in the literature. This motivated us to study this reac-
tion further.
To optimize the reaction conditions, we increased
the reaction temperature from 1008C to 1208C and
then to 1358C. An elevation in the temperature re-
Figure 1. X-ray crystal structure of 3a (ORTEP diagram).[9]
sulted in an increase in yield to 24% and 74%, respec- provement in yield (entry 4). Next, various inorganic
tively (Table 1, entries 2 and 3). However, a further bases such as Na2CO3, NaHCO3, K3PO4, Cs2CO3 we
increase in temperature failed to result in any im- examined for the reaction (entries 5–8) but these re-
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One-Pot Synthesis of 2-Arylquinazolines and Tetracyclic Isoindolo[1,2-a]quinazolines
Table 2. Synthesis of 2-arylquinazolines from various 2-halo-
benzamides.
sulted in either a lower yield of the desired product
or no product being formed. Furthermore, the use of
organic bases also resulted in lower yields of com-
pound 3a (entries 9–11). Based on this information, it
was concluded that K2CO3 was the preferred base for
use in this transformation. Different solvents were
then examined. However, we found that the product
was formed in DMF and DMA but afforded a lower
yield of 3a (entries 12 and 13).
We next examined the use of refluxing 1,4-dioxane
as the solvent for 12 h. Interestingly, a highly polar
compound was produced, as evidenced by its TLC
properties. The compound was isolated and purified.
1H NMR, 13C NMR, LR-MS, HR-MS data revealed
that the compound formed was a tetracyclic isoindole
fused quinazoline (2a) and was produced in 79%
yield (entry 14). Further screening of the reaction
using other solvents such as acetonitrile and ethanol
failed to improve product yield (entries 15 and 16).
Fine tuning of organic and inorganic bases also failed
to improve reaction yield (entries 17–22). Finally,
based on the optimization study, the reaction of 1a
with 1 equivalent of CuCN using K2CO3 as a base in
1,4-dioxane at 1018C were the optimal conditions for
the preparation of tetracyclic isoindole fused quinazo-
line (2a) and the reaction with K2CO3 as a base and
DMSO as a solvent at 1358C were the optimized con-
ditions for the preparation of 2-phenylquinazoline
(3a).
After optimizing the reaction conditions, the scope
of the reaction was studied, first with unsubstituted
ring A and ring B substituted compounds with alde-
hyde, ketone and cyanide groups at the ortho posi-
tion. The reaction of CuCN with a model substrate 1a
containing an aldehyde at the ortho position afforded
the 2-phenylquinazoline derivative (3a) in 74% yield
(entry 1, Table 2). However, the reaction of CuCN
with 1b and 1c bearing ketone and cyanide groups at
the ortho position yielded 4-methyl-2-phenylquinazo-
line 3b and 2-phenylquinazolin-4-amine 3c in 77%
and 57% yields, respectively, with longer reaction
times. The longer reaction time for compounds 3b
and 3c may be due to the less electrophilic nature of
the ketone and the nitrile functional groups. Next,
electron-donating amides were examined. The reac-
tion afforded the corresponding quinazoline deriva-
tives in moderate to good yields but a longer reaction
time was needed in most cases (entries 4 to 9). Sur-
prisingly, the reaction with N-(2-cyanophenyl)-2-iodo-
4,5-dimethoxybenzamide (1h) reached completion
within 9 h, producing
a product yield of 74%
(entry 8). Furthermore, a similar trend was observed,
when electron-withdrawing amide-containing sub-
strates were used in the reaction. Nitro-substituted
amides formed the corresponding 2-arylquinazoline
derivatives in good yields, but a longer reaction time
was needed (entries 10–12).
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As an expansion of this study, we further explored
the scope of the protocol with amidic linkages using
chalcone derivatives as depicted in Scheme 2. The re-
action of CuCN with the unsubstituted chalcone
amide (1o) resulted in the formation of the corre-
sponding 2-aryl-4-styrylquinazoline (3o) in 73% yield.
In the case of an electron-donating substituent on the
chalcone, the yield of the respective compound 3p
was reduced to 67% and a longer reaction time was
needed. However, an electron-withdrawing substitu-
ent on the chalcone (1q) resulted in a slightly in-
creased product yield and a reduced reaction time for
the synthesis of 4-(4-chlorostyryl)-2-phenylquinazo-
line (3q).
Table 2. (Continued)
Furthermore, we used the optimum reaction condi-
tions to check the scope of the tetracyclic isoindole
fused quinazoline, as depicted in Table 3. First, the re-
action was screened when the ring B contained alde-
hyde, ketone and cyanide groups at the ortho posi-
tion. The reaction of N-(2-formylphenyl)-2-iodoben-
zamide (1a) with CuCN in 1,4-dioxane afforded the
hydroxy-substituted tetracyclic isoindole fused quina-
zoline derivative in 79% (entry 1). Whereas, when
a ketone group was located at the ortho position, the
corresponding tetracyclic derivative (2b) was obtained
in good yield. The lower yield of compound 2c was
observed, when the reaction was carried out with the
[a]
Reactions were performed on 0.5 mmol of 1, CuCN
(1 equiv.) and K2CO3 (2.5 equiv.) at 1358C.
Yields refer to isolated and purified compounds.
[b]
ortho-cyano-substituted
N-(2-phenyl)-2-iodobenz-
AHCTUNGTREGUNaNN mide as a substrate (entry 3). Further, when ring A
However, the use of electron-withdrawing amides contained an electron-donating dioxymethylene
afforded better product yields than electron-donating group, the reaction produced a moderate yield of the
amides. The reaction also proceeded when amides desired product (2r) and a slightly longer reaction
bearing bromo and bulkier naphthyl groups were time was needed (entry 4). However, electron-with-
used, resulting in the formation of the corresponding drawing bromo substituents on ring A and ring B af-
products 3m and 3n in good yield.
forded moderate yields of compounds 2m and 2s. Fur-
Scheme 2. Synthesis of 2-aryl-4-styrylquinazoline derivatives from 2-halo-N-arylbenzamide.
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One-Pot Synthesis of 2-Arylquinazolines and Tetracyclic Isoindolo[1,2-a]quinazolines
Table 3. Synthesis of isoindole fused quinazolines from vari-
ous 2-halobenzamides.
AHCTUNGTREGcNNNU lization via the nucleophilic addition of the imine ni-
trogen to the aldehyde functionality to produce the
tetracyclic compound 2. The tetracyclic compound 2
then undergoes decarboxylation in the presence of
the base to form compound 3.
To support our proposed mechanism, we carried
out, two control experiments. In the first experiment,
we carried out the reaction of 1b with CuCN and po-
tassium carbonate in 1,4-dioxane as the solvent to
obtain 2b. After the complete conversion of 1b to the
tetracyclic compound 2b, which was confirmed by
TLC, DMSO was then added and the reaction mix-
ture heated at 1108C. The reaction produced 3b in
51% yield after 16 h of reaction (Scheme 4).
In the second control experiment, we treated the
tetracyclic compound 2a with potassium carbonate in
the absence copper in DMSO as the solvent at 1358C.
Under these conditions, we observed the conversion
of 2a into the corresponding 2-phenylquinazoline de-
rivative in 50% yield (Scheme 5).
The findings from the control experiments indicate
that the formation of 2-phenylquinazoline derivative
from the thermal decomposition of tetracyclic com-
pound is facilitated by the base.
Conclusions
In conclusion, we report on the synthesis of a series
of substituted 2-arylquinozaline derivatives and tetra-
cyclic isoindolo[1,2-a]quinazoline derivatives in mod-
erate to good yield in a one-pot process simply by
changing solvent and temperature. A novel base-cata-
lyzed cleavage of tetracyclic isoindolo[1,2-a]quinazo-
lines was observed during the synthesis of the 2-aryl-
quinazolines. Furthermore, the syntheses of 2-arylqui-
nazolin-4-amine and 2-phenyl-4-styrylquinazoline
were achieved very efficiently compared to currently
used methods. Good yields of the tetracyclic isoindo-
lo[1,2-a]quinazoline derivatives were achieved by
using 1,4-dioxane as the solvent.
[a]
Reactions were performed on 0.5 mmol of 1, CuCN
(1 equiv.) and K2CO3 (2.0 equiv.) at 1018C.
Yields refer to isolated and purified compounds.
Inseparable mixture
[b]
[c]
Experimental Section
General Procedure for the Synthesis of Substituted 2-
Halo-N-arylbenzamides (1a–s)
thermore, the protocol failed to form compound 2k,
when the strong electron-withdrawing nitro-substitut-
ed 1k was used as a substrate.
A plausible mechanism for the formation both 2
and 3 is depicted in Scheme 3. The reaction is initiat-
ed by the formation of intermediate I through cyana-
tion in the presence a base and CuCN, which may un-
dergo intramolecular cyclization via the nucleophilic
addition of the amidic nitrogen to the cyanide func-
tionality to generate the imine intermediate II. This
In a stir-bar-equipped flame-dried 50-mL round-bottom
flask containing 2-halobenzoic acid (A) (4 mmol), SOCl2
(2 mL) was carefully added, dropwise, followed by adding
one drop of DMF. The reaction mixture was then stirred at
808C for 3 h. The reaction mixture was then evaporated
under reduced pressure at 40–458C to remove excess SOCl2.
The resulting acid chloride was diluted in DCM (15 mL)
and then added dropwise to an ice-cold solution of substitut-
ed aniline (B) (6 mmol) and pyridine (3 mL) in DCM
intermediate further undergoes an intramolecular cy- (10 mL). The reaction mixture was then allowed to warm to
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Scheme 3. Plausible mechanism for the synthesis of compound 2 and 3.
Typical Procedure for the Synthesis of Isoindole
Fused Quinazoline Derivatives (2a–c, 2m, 2r and 2s)
In an oven-dried, 10-mL round-bottom flask equipped with
magnetic stirrer was added 1a (0.5 mmol), CuCN
(1.0 equiv.), K2CO3 (2.5 equiv.) in 1.4-dioxane (2 mL). The
reaction mixture was then stirred at 1018C under a nitrogen
atmosphere. After completion of the reaction, as deter-
mined by TLC, the reaction mixture was allowed to cool to
room temperature. The crude reaction mixture was then pu-
rified by column chromatography without workup using di-
chloromethane-methanol as the eluent to yield compound
2a.
Scheme 4. Control experiment 1.
Spectral Data for Compounds
2-Phenylquinazoline (3a): Yield: 74%; white solid; mp 100–
1018C; FT-IR (KBr): n=1641 cmÀ1 1H NMR (400 MHz,
;
CDCl3): d=9.09 (brs, 1H), 8.62–8.64 (m, 2H), 8.11 (d, J=
8.4 Hz, 1H), 7.90–7.95 (m, 2H), 7.63 (t, J=7.5 Hz, 1H),
7.52–7.58 (m, 3H); 13C NMR (100 MHz, CDCl3): d=161.3,
160.7, 151.0, 138.3, 134.3, 130.8, 128.9, 128.83, 128.80, 127.5,
127.3, 123.8; LR-MS (EI): m/z (relative intensity)=207
(100) [M+H]+, 314 (100); HR-MS (MALDI): m/z=
207.0924, calcd. for C14H11N2 [M+H]+: 207.0922.
Scheme 5. Control experiment 2.
4-Methyl-2-phenylquinazoline (3b): Yield: 77%; yellow
solid; mp 88–908C; FT-IR (KBr): n=1635 cmÀ1 1H NMR
;
room temperature with stirring overnight. After completion
of the reaction as determined by TLC analysis, the reaction
mixture was evaporated under reduced pressure and the res-
idue poured on crushed ice (50 g). The resulting solid was
washed with excess of ice-cold water to afford the pure com-
pound 1a–s.
(400 MHz, CDCl3): d=8.62–8.64 (m, 2H), 8.08–8.11 (m,
2H), 7.85–7.89 (m, 1H), 7.56–7.61 (m, 2H), 7.51–7.54 (m,
2H), 3.03 (s, 3H); 13C NMR (100 MHz, DMSO-d6): d=
168.4, 160.3, 150.6, 138.5, 133.6, 130.5, 129.4, 128.73, 128.71,
127.0, 125.1, 123.2, 22.2; LR-MS (ESI): m/z (relative intensi-
ty)=220 (100) [M]+, 204 (40); HR-MS: m/z=220.1003,
calcd. for C15H12N2 [M]+: 220.1000.
Typical Procedure for the Synthesis of 2-
Arylquinazolines (3a–q)
2-Phenylquinazolin-4-amine (3c): Yield: 57%; yellow
solid; mp 144–1458C; FT-IR (KBr): n=3470, 3350, 1644,
In an oven-dried, 10-mL round-bottom flask equipped with
a magnetic stirrer, 1a (0.5 mmol), CuCN (1.0 equiv.), K2CO3
(2.5 equiv.) in DMSO (2 mL) were added. The reaction mix-
ture was then stirred at 1358C under a nitrogen atmosphere.
After completion of the reaction, as determined by TLC,
the reaction mixture was allowed to cool to room tempera-
ture. The crude reaction mixture was then purified by
column chromatography without work-up using hexane-
ethyl acetate as the eluent to yield compound 3a.
1250 cmÀ1 1H NMR (400 MHz, CDCl3): d=8.51 (d, J=
;
6.7 Hz, 2H), 7.97 (d, J=8.3 Hz, 1H), 7.73–7.80 (m, 2H),
7.44–7.51 (m, 4H), 5.72 (bs, 2H); 13C NMR (100 MHz,
CDCl3): d=162.1, 159.7, 150.4, 138.6, 132.9, 129.9, 128.2,
127.8, 127.7, 125.2, 123.6, 113.3; LR-MS (ESI): m/z (relative
intensity=222 (100) [M+H]+, 189 (20); HR-MS: m/z=
222.1023, calcd. for C14H12N3 [M+H]+: 222.1031.
2-(4-Methoxyphenyl)quinazoline (3d): Yield: 70%; white
solid; mp 92–948C; FT-IR (KBr): n=1650, 1240, 1125 cmÀ1
;
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1H NMR (400 MHz, CDCl3): d=9.42 (bs, 1H), 8.59 (d, J=
8.6 Hz, 2H), 8.05 (d, J=8.4 Hz, 1H), 7.86–7.90 (m, 1H),
7.57 (t, J=7.4 Hz, 1H), 7.06 (d, J=8.7 Hz, 2H), 3.90 (s,
3H); 13C NMR (100 MHz, CDCl3): d=162.1, 161.1, 160.6,
151.1, 134.2, 131.0, 130.4, 128.7, 127.3, 126.9, 123.6, 114.2,
55.6; LR-MS (ESI): m/z (relative intensity)=237 (100) [M+
H]+, 179 (20); HR-MS: m/z=237.1022, calcd. for C15H13N2O
[M+H]+: 237.1028.
1H), 8.82 (d, J=8.8 Hz, 2H), 8.37 (d, J=8.8 Hz, 2H), 8.14
(d, J=8.4 Hz, 1H), 7.96–8.00 (m, 2H), 7.71(t, J=7.5 Hz,
1H); 13C NMR (100 MHz, CDCl3): d=160.9, 159.0, 150.8,
149.4, 144.0, 134.8, 129.6, 129.1, 128.5, 127.4, 124.1, 124.0;
LR-MS (EI): m/z (relative intensity)=251 (100) [M]+, 205
(40); HR-MS: m/z=251.0690, calcd. for C14H9N3O2 [M]+:
251.0695.
4-Methyl-2-(4-nitrophenyl)quinazoline (3k): Yield: 79%;
red solid; mp 174–1768C; FT-IR (KBr): n=3468, 1636, 1520,
2-(4-Methoxyphenyl)-4-methylquinazoline (3e): Yield:
75%; yellow solid; mp 68–708C; FT-IR (KBr): n=1648,
1350 cmÀ1 1H NMR (400 MHz, CDCl3): d=8.81 (d, J=
;
1220, 1130 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=8.60 (d,
8.9 Hz, 2H), 8.35 (d, J=8.9 Hz, 2H), 8.10–8.15 (m, 2H),
7.93 (t, J=7.6 Hz, 1H), 7.67 (t, J=7.6 Hz, 1H), 3.05 (s, 3H);
13C NMR (100 MHz, DMSO-d6): d=168.9, 158.0, 150.3,
149.2, 144.3, 134.2, 129.6, 129.5, 128.1, 125.2, 123.8, 123.4,
22.2; LR-MS (MALDI): m/z (relative intensity)=265 (100)
[M+H]+, 220 (28); HR-MS: m/z=265.0846, calcd. for
C15H11N3O2 [M]+: 265.0851.
J=8.6 Hz, 2H), 8.04 (t, J=7.2 Hz, 2H), 7.83 (t, J=7.6 Hz,
1H), 7.53 (t, J=7.5 Hz, 1H), 7.04 (d, J=8.6 Hz, 2H), 3.89
(s, 3H), 2.99 (s, 3H); 13C NMR (100 MHz, DMSO-d6): d=
168.2, 161.9, 160.2, 150.6, 133.6, 131.2, 130.4, 129.6, 125.2,
122.9, 114.1, 55.6, 22.2; LR-MS (MALDI): m/z (relative in-
tensity)=251 (100) [M]+, 221 (65); HR-MS: m/z=251.1191,
calcd. for C16H15N2O [M+H]+: 251.1184.
2-(4-Nitrophenyl)quinazolin-4-amine (3l): Yield: 73%);
dark yellow solid; mp 220–2228C; FT-IR (KBr): n=3470,
2-(4-Methoxyphenyl)quinazolin-4-amine (3f): Yield: 54%;
yellow solid; mp 179–1818C; FT-IR (KBr): n=3470, 3350,
3350, 1641, 1520, 1350 cmÀ1 1H NMR (400 MHz, DMSO-
;
1641, 1250, 1220, 1130 cmÀ1
;
1H NMR (400 MHz, DMSO-
d6): d=8.66 (d, J=8.6 Hz, 2H), 8.35 (d, J=8.6 Hz, 2H),
8.28 (d, J=8.2 Hz, 1H), 8.00 (bs, 2H), 7.81 (bs, 2H), 7.53 (s,
1H); 13C NMR (100 MHz, CDCl3): d=162.3, 157.8, 150.1,
148.3, 144.6, 133.3, 128.8, 127.9, 126.0, 123.6, 123.5, 113.4;
LR-MS (MALDI): m/z (relative intensity)=267 (100) [M]+,
221 (45); HR-MS: m/z=267.0893, calcd. for C14H10N4O2
[M+H]+: 267.0882.
d6): d=8.41 (d, J=8.6 Hz, 2H), 8.22 (d, J=8.1 Hz, 1H),
7.70–7.77 (m, 4H), 7.42 (t, J=6.9 Hz, 1H), 7.04 (d, J=
8.6 Hz, 2H), 3.83 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
d=161.9, 160.9, 159.5, 150.3, 132.9, 130.9, 129.4, 127.3, 124.7,
123.6, 113.5, 113.0, 55.2; LR-MS (MALDI): m/z (relative in-
tensity)=251 (100) [M+H]+; HR-MS: m/z=252.1142,
calcd. for C15H14N3O [M+H]+:252.1137.
2-(4-Bromophenyl)-4-methylquinazoline (3m): Yield:
76%; yellow solid; mp 105–1078C; FT-IR (KBr): n=1636,
2-(3,4-Dimethoxyphenyl)-4-methylquinazoline (3g): Yield:
57%; yellow solid; mp 179–1818C; FT-IR (KBr): n=1650,
585 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=8.52 (d, J=
1
1156, 1239 cmÀ1; H NMR (400 MHz, CDCl3): d=8.27 (dd,
8.4 Hz, 2H), 8.05–8.10 (m, 2H), 7.82 (t, J=7.6 Hz, 1H), 7.65
(d, J=8.4 Hz, 2H), 7.60 (t, J=7.5 Hz, 1H), 3.01 (s, 3H);
13C NMR (100 MHz, CDCl3): d=168.6, 159.5, 150.6, 137.5,
133.9, 131.9, 130.4, 129.5, 127.3, 125.4, 125.2, 123.3, 22.2;
LR-MS (ESI): m/z (relative intensity)=298 (98) [M]+,
300(100); HR-MS (ESI): m/z=298.0111, calcd. for
C15H11BrN2 [M]+: 298.0106.
J=8.44, 1.76 Hz, 1H), 8.22 (d, J=1.52 Hz, 1H), 8.05 (t, J=
6.9 Hz, 2H), 7.84 (t, J=7.96 Hz, 1H), 7.54 (t, J=7.6 Hz,
1H), 7.01 (d, J=8.4 Hz, 1H), 4.07 (s, 3H), 3.98 (s, 3H), 2.99
(s, 3H); 13C NMR (100 MHz, CDCl3): d=168.2, 160.0, 151.5,
150.7, 149.3, 133.6, 131.4, 129.2, 126.6, 125.2, 122.9, 122.2,
111.5, 111.1, 56.2, 56.2, 22.2; LR-MS (ESI): m/z (relative in-
tensity)=281 (100) [M+H]+, 220 (40); HR-MS: m/z=
281.1284, calcd. for C17H17N2O2 [M+H]+: 281.1290.
4-Methyl-2-(naphthalen-1-yl)quinazoline
77%; white solid; mp 119–1218C; FT-IR (KBr): n=1645,
1537, 1357 cmÀ1 1H NMR (400 MHz, CDCl3): d=8.66 (d,
(3n):
Yield:
2-(Benzo[d][1,3]dioxol-5-yl)quinazolin-4-amine
Yield: 74%; white solid; mp 193–1958C; FT-IR (KBr): n=
3470, 3350, 1641, 1250, 1150 cmÀ1 1H NMR (400 MHz,
(3h):
;
J=8.4 Hz, 1H), 8.15–8.20 (m, 3H), 7.99 (d, J=8.2 Hz, 1H),
7.92–7.96 (m, 2H), 7.68 (t, J=7.7 Hz, 1H), 7.63 (t, J=
7.7 Hz, 1H), 7.53–7.56 (m, 2H), 3.09 (s, 3H); 13C NMR
(100 MHz, CDCl3): d=168.6, 162.9, 150.3, 136.8, 134.4,
134.0, 131.5, 130.3, 129.5, 129.4, 128.6, 127.6, 126.9, 126.2,
126.0, 125.5, 125.2, 122.8, 22.2; LR-MS (MALDI): m/z (rela-
tive intensity)=271 (100) [M+H]+; HR-MS: m/z=
271.1241, calcd. for C19H14N2 [M+H]+: 271.1235.
;
DMSO-d6): d=8.21 (d, J=8.0 Hz, 1H), 8.07 (d, J=8.0 Hz,
1H), 7.93 (s, 1H), 7.70–7.76 (m, 4H), 7.43 (t, J=7.1 Hz,
1H), 7.01 (d, J=8.2 Hz, 1H), 6.10 (bs, 2H); 13C NMR
(100 MHz, CDCl3): d=161.9, 159.6, 150.4, 148.9, 147.4,
132.9, 132.8, 127.5, 124.8, 123.5, 122.4, 113.1, 107.9,
107.6,101.3; LR-MS (MALDI): m/z (relative intensity)=266
(100) [M+H]+, 243 (30); HR-MS: m/z=266.0935, calcd. for
C15H11N3O2 [M+H]+: 266.0930.
(E)-2-Phenyl-4-styrylquinazoline (3o): Yield: 73%; yellow
solid; mp 138–1408C; FT-IR (KBr): n=3480, 1545, 1378,
6,7-Dimethoxy-2-phenylquinazoline (3i): Yield: 67%;
white solid; mp 176–1788C; FT-IR (KBr): n=1635, 1230,
719 cmÀ1 1H NMR (400 MHz, CDCl3): d=8.76 (d, J=
;
7.3 Hz, 2H), 8.46 (d, J=15.4 Hz, 1H), 8.27 (d, J=8.3 Hz,
1H), 8.10 (d, J=8.4 Hz, 1H), 7.96 (d, J=15.4 Hz, 1H), 7.87
(t, J=7.7 Hz, 1H), 7.77 (d, J=7.4 Hz, 2H), 7.53–7.61 (m,
4H), 7.42–7.50 (m, 3H); 13C NMR (100 MHz, CDCl3): d=
162.1, 160.3, 152.2, 139.6, 138.7, 136.3, 133.6, 130.6, 129.8,
129.5, 129.1, 128.8, 128.7, 128.2, 127.0, 124.0, 121.8, 121.1;
LR-MS (ESI): m/z (relative intensity)=308 (100) [M]+, 307
(80); HR-MS: m/z=308.1317, calcd. for C22H16N2 [M]+:
308.1313.
1140 cmÀ1 1H NMR (400 MHz, CDCl3): d=9.23 (bs, 1H),
;
8.55 (d, J=8.3 Hz, 2H), 7.48–7.55 (m, 3H), 7.38 (m, 1H)
7.11 (s, 1H), 4.09 (s, 3H), 4.04 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=160.2, 157.3, 156.5, 150.6, 148.8, 138.6, 130.3,
128.8, 128.3, 119.6, 107.1, 104.2, 56.7, 56.4; LR-MS (EI): m/z
(relative intensity)=266 (100) [M]+, 265 (80); HR-MS:
m/z=266.1049, calcd. for C16H14N2O2 [M]+: 266.1055.
2-(4-Nitrophenyl)quinazoline (3j): Yield: 73%; dark
yellow solid; mp 218–2208C; FT-IR (KBr): n=3439, 3400,
(E)-4-[2-(Benzo[d][1,3]dioxol-5-yl)vinyl]-2-phenylquina-
zoline (3p): Yield: 67%; yellow solid; mp:169–1718C; FT-IR
1520, 1350 cmÀ1 1H NMR (400 MHz, CDCl3): d=9.52 (s,
;
Adv. Synth. Catal. 0000, 000, 0 – 0
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Sachin D. Gawande et al.
1
(KBr): n=1643, 1230, 1150, 1140 cmÀ1; H NMR (400 MHz,
DMSO-d6): d=164.6, 152.7, 151.5, 144.1, 130.6, 129.1, 128.2,
127.8, 127.0, 126.0, 125.0, 114.1, 103.1, 101.7, 81.3, 33.2; LR-
MS (ESI): m/z (relative intensity)=309 (100) [M+H+], 291
(82); HR-MS: m/z=309.0871, calcd. for C17H13N2O4 (M+
H+): 309.0875.
CDCl3): d=8.71 (d, J=6.8 Hz, 2H), 8.37 (d, J=15.3 Hz,
1H), 8.26 (d, J=8.3 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 7.86
(t, J=7.5 Hz, 1H), 7.78 (d, J=15.4 Hz, 1H), 7.52–7.61 (m,
4H), 7.29 (s, 1H), 7.23 (d, J=8.0 Hz, 1H), 6.88 (d, J=
8.0 Hz, 1H), 6.02 (s, 2H); 13C NMR (100 MHz, CDCl3): d=
162.2, 160.3, 152.2, 149.3, 148.6, 139.4, 138.8, 133.6, 130.9,
130.5, 129.5, 128.8, 128.7, 126.9, 124.2, 124.0, 121.8, 119.2,
108.9, 106.8, 101.7; LR-MS (EI): m/z (relative intensity)=
352 (100) [M+], 351 (60); HR-MS: m/z=352.1209, calcd. for
C23H16N2O2 [M+]: 352.1212.
9-Bromo-5-hydroxy-5-methylisoindolo[2,1-a]quinazolin-
11(5H)-one (2m): Yield: 66%; white solid; mp 166–1688C;
FT-IR (KBr): n=3379, 717 cmÀ1
;
1H NMR (400 MHz,
DMSO-d6): d=8.46 (d, J=8.2 Hz, 1H), 7.10 (s, 1H), 8.01–
8.03 (m, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.65 (d, J=7.4 Hz,
1H), 7.42 (t, J=7.5 Hz, 1H), 7.31 (t, J=7.5 Hz, 1H), 6.51
(bs, 1H), 1.59 (s, 3H); 13C NMR (100 MHz, DMSO-d6): d=
163.7, 143.8, 136.9, 133.2, 132.3, 130.3, 128.3, 127.9, 127.2,
126.1, 125.9, 125.7, 123.7, 114.6, 81.5, 33.2; LR-MS (ESI): m/
z (relative intensity)=343 (100) [M+H+], 345 (95); HR-
MS: m/z=343.0078, calcd. for C16H12N2O2 (M+H+):
343.0082.
(E)-4-(4-Chlorostyryl)-2-phenylquinazoline (3q): Yield:
76%; yellow solid; mp 150–1528C; FT-IR (KBr): n=1635,
715 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=8.71 (d, J=
8.2 Hz, 2H), 8.37 (d, J=15.4 Hz, 1H), 8.24 (d, J=8.3 Hz,
1H), 8.09 (d, J=8.4 Hz, 1H), 7.85–7.92 (m, 2H), 7.68 (d, J=
8.4 Hz, 2H), 7.53–7.61 (m, 4H), 7.43 (d, J=8.4 Hz, 2H);
13C NMR (100 MHz, CDCl3): d=161.7, 160.3, 152.3, 138.7,
138.1, 135.6, 134.8, 133.7, 130.7, 129.6, 129.4, 129.3, 128.8,
128.7, 127.1, 123.9, 121.8, 121.6; LR-MS (EI): m/z (relative
intensity)=342 (100) [M+], 341 (75); HR-MS: m/z=
342.0922, calcd. for C22H15ClN2 (M+): 342.0924.
3-Bromo-5-hydroxy-5-methylisoindolo[2,1-a]quinazolin-
11(5H)-one (2s): Yield: 60%; white solid; mp 174–1768C;
FT-IR (KBr): n=3570, 3348 cmÀ1
;
1H NMR (400 MHz,
DMSO-d6): d=8.42 (d, J=8.8 Hz, 1H), 7.97 (d, J=7.4 Hz,
1H), 7.91 (d, J=7.3 Hz, 1H), 7.84 (t, J=7.4 Hz, 1H), 7.75–
7.80 (m, 2H), 7.60 (dd, J=8.8 Hz, 1.8 Hz, 1H), 1.60 (s, 3H);
13C NMR (100 MHz, DMSO-d6): d=165.0, 144.2, 134.4,
133.2, 132.9, 131.1, 131.0, 130.4, 129.8, 129.6, 123.5, 121.9,
117.3, 116.8, 81.2, 33.1; LR-MS (ESI): m/z (relative intensi-
ty)=342 (100) [M+], 344 (95); HR-MS: m/z=342.0006,
calcd. for C16H11N2O2 (M+): 342.0004.
5-Hydroxyisoindolo[2,1-a]quinazolin-11(5H)-one
(2a):
Yield: 79%; white solid; mp 151–1528C; FT-IR (KBr): n=
3379 cmÀ1; H NMR (400 MHz, DMSO-d6): d=8.48 (d, J=
1
8.2 Hz, 1H), 7.97 (d, J=7.3 Hz, 1H), 7.93 (d, J=7.2 Hz,
1H), 7.78–7.88 (m, 2H), 7.53 (d, J=7.4 Hz, 1H), 7.40 (d, J=
7.7 Hz, 1H), 7.31 (t, J=7.4 Hz, 1H), 6.72 (d, J=7.3 Hz,
1H), 6.17 (d, J=7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3);
d=165.1, 146.4, 134.2, 133.3, 132.8, 131.4, 131.1, 128.7, 127.9,
125.4, 123.5, 123.4, 121.8, 114.7, 76.9; LR-MS (ESI): m/z
(relative intensity)=251 (100) [M+H+]; HR-MS (ESI):
m/z=249.0665, calcd. for C15H9N2O2 (MÀHÀ): 249.0664.
5-Hydroxy-5-methylisoindolo[2,1-a]quinazolin-11(5H)-
one (2b): Yield: 72%; white solid; mp 180–1828C; FT-IR
Acknowledgements
Financial support for this work by the Ministry of Science
and Technology of the Republic of China (NSC 100-2113M-
003-008-MY3), National Taiwan Normal University
(99T3030-2, 99-D, 100-D-06) and Instrumentation Centre at
National Taiwan Normal University is gratefully acknowl-
edged. The authors are grateful to Mr. Ting-Shen Kuo, Ms.
Hsiu-Ni Huan and Ms. Chiu-Hui He for providing X-ray,
mass and NMR spectral data presented in this paper.
(KBr): n=3467 cmÀ1 1H NMR (400 MHz, DMSO-d6): d=
;
8.50 (d, J=8.1 Hz, 1H), 7.98 (d, J=7.3 Hz, 1H), 7.93 (d, J=
7.2 Hz, 1H), 7.78–7.87 (m, 2H), 7.65 (d, J=7.4 Hz, 1H),
7.42 (t, J=7.4 Hz, 1H), 7.30 (t, J=7.4 Hz, 1H), 6.48 (s, 1H),
1.59 (s, 3H); 13C NMR (100 MHz, CDCl3): d=165.1, 144.4,
134.2, 133.3, 132.7, 131.1, 130.5, 128.2, 128.0, 127.1, 125.4,
123.4, 121.8, 114.5, 81.3, 33.2; LR-MS (ESI): m/z (relative
intensity)=251 (100) [M+H+], 247 (39); HR-MS (ESI):
m/z=265.0977, calcd. for C16H13N2O2 (M+H+): 265.0977.
5-Iminoisoindolo[2,1-a]quinazolin-11(5H)-one (2c): Yield:
63%; white solid; mp 178–1808C; FT-IR (KBr): n=
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(t, J=7.5 Hz, 1H), 7.64–7.66 (m, 1H), 7.51–7.57 (m, 2H),
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J=7.6 Hz, 1H), 7.36–7.40 (m, 3H), 7.26 (t, J=7.4 Hz, 1H),
6.41 (s, 1H), 6.27 (s, 2H), 1.57 (s, 3H); 13C NMR (100 MHz,
isoindolo[2,1-
;
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Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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FULL PAPERS
10 One-Pot Synthesis of 2-Arylquinazolines and Tetracyclic
Isoindolo[1,2-a]quinazolines via Cyanation Followed by
Rearrangement of ortho-Substituted 2-Halo-N-
arylbenzamides
Adv. Synth. Catal. 2014, 356, 1 – 10
Sachin D. Gawande, Manoj R. Zanwar,
Veerababurao Kavala, Chun-Wei Kuo, R. R. Rajawinslin,
Ching-Fa Yao*
10
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!