One-Pot Tandem Assembly of Amides, Amines, and Ketones: Synthesis of C4-Quaternary 3,4- And 1,4-Dihydroquinazolines

Article abstract of DOI:10.1021/acs.joc.0c01308

A multicomponent tandem assembly procedure for the synthesis of diverse C4-quaternary 3,4-dihydroquinazolines from amides, amines, and ketones has been developed. The one-pot reaction involves successive triflic anhydride mediated amide dehydration, ketimine addition, and Pictet-Spengler-like cyclization processes and affords products in up to 92% yield. Conversion of 3,4-dihydroquinazolines to the corresponding 1,4-dihydroquinazolines via a two-step N1 dealkylation and regioselective N3 functionalization protocol, including computational rationale for the observed regioselectivity, is also described.

Full text of DOI:10.1021/acs.joc.0c01308

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Article
One-Pot Tandem Assembly of Amides, Amines, and Ketones:
Synthesis of C4-Quaternary 3,4- and 1,4-Dihydroquinazolines
molly campbell, Alexei V. Iretskii, and R. Adam Mosey
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01308 • Publication Date (Web): 07 Aug 2020
Downloaded from pubs.acs.org on August 10, 2020
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One-Pot Tandem Assembly of Amides, Amines, and Ketones: Synthesis of
C4-Quaternary 3,4- and 1,4-Dihydroquinazolines
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Molly V. Campbell, Alexei V. Iretskii, and R. Adam Mosey*
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Department of Chemistry, Lake Superior State University, Sault Sainte Marie, MI 49783
*rmosey@lssu.edu
O
R5 R4
N
R5 R4
N
R3
R2
R5 R4
R3
R2
one-pot
synthesis
H2N
O
2 steps
R1
R1
N
N
R2
R1
R6
R4 = alkyl, aryl, ester
R5 = ketone, ester
N
H
R6 = alkyl, acyl
1,4-DHQs
3,4-DHQs
31 Examples, up to 92% yield
15 Examples
ABSTRACT: A multicomponent tandem assembly procedure for the synthesis of diverse C4-quaternary 3,4-
dihydroquinazolines from amides, amines, and ketones has been developed. The one-pot reaction involves successive
triflic anhydride mediated amide dehydration, ketimine addition, and Pictet-Spengler-like cyclization processes and
affords products in up to 92% yield. Conversion of 3,4-dihydroquinazolines to the corresponding 1,4-
dihydroquinazolines via a two-step N1 dealkylation and regioselective N3 functionalization protocol, including
computational rationale for the observed regioselectivity, is also described.
INTRODUCTION
Dihydroquinazolines (DHQs) are amidine-containing heterocycles found in natural products and in compounds of
medicinal importance.1 The DHQ motif exists in two forms which differ in the sites of saturation about the
heterocyclic ring (e.g. the 1,4- and 3,4-dihydro forms), and in the absence of a substituent on one of the ring nitrogens,
DHQ compounds may be found in both forms at equilibrium. The majority of known N-substituted DHQ syntheses
focus on the production of compounds with a tertiary C4 center, the sole sp3 hybridized carbon present in the scaffold.
The synthesis of N-substituted DHQs bearing quaternary C4 centers has been much less explored, with literature
reports of quaternary 1,4-DHQ scaffolds being particularly scant. Pioneering methods of N-substituted quaternary
DHQ synthesis involved transformation of quinazolines via treatment with alkyl halides following metal-mediated
quinazolinide anion generation to afford mixtures of 1,4- and 3,4-DHQs.2 Alternatively, quaternary 3,4-DHQs have
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been constructed from the corresponding tertiary counterparts through alkylation of select acidic substrates following
deprotonation with NaH.3 Other examples of quaternary 3,4-DHQ synthesis include addition of nitriles to
functionalized hydroxymethylanilines in the presence of acids,4 intramolecular attack of amidines onto tethered
alkenes,5 and Ugi multicomponent assembly,6 among others.7 A recent focus of quaternary DHQ synthesis has been
for the construction of natural products hinckdentine A8 and trigonoliimines A and B.9 The quaternary 3,4-DHQ
scaffold present in these alkaloids has been synthesized via intramolecular condensation reactions of
aminomethylanilines bearing preassembled quaternary centers,10 oxidation of tetrahydroquinazolines,11 or Strecker
assembly from o-ketoformanilides.12 Separate methods have arisen for the synthesis of related DHQs bearing an
additional heteroatom at the C4 center.13
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Previously we reported the synthesis of 3,4-DHQs through a triflic anhydride-mediated tandem assembly process
involving a key Pictet-Spengler-like annulation step (Scheme 1).14 The reaction involved in situ generation of imines
from aldehydes and amines, after which the imine became incorporated into the heterocyclic scaffold, with the starting
aldehyde’s carbon bulk making up the newly formed DHQ C4 carbon and its attached substituent (i.e. R4). Whereas
the use of imines in the reaction afforded compounds with tertiary C4 centers, an analogous reaction involving the
installation of ketimines15 would instead give rise to C4-quaternary 3,4-DHQs. Challenges for such a reaction were
envisioned to mirror those of traditional Pictet-Spengler methods of quaternary center formation, namely difficulty in
both the formation of ketiminium reaction intermediates and in cyclization to generate the new heterocyclic rings due
to enhanced steric bulk and reduced electrophilicity of ketimines relative to imines.16 However, overcoming these
challenges would permit direct access to diverse quaternary members of this compound class. Herein we report a one-
pot multicomponent synthesis of C4-quaternary 3,4-DHQs as well as selective conversion of 3,4-DHQs to the
corresponding 1,4-DHQs.
Scheme 1. Synthesis of 3,4-DHQs and 1,4-DHQs
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Previous work:
O
R4
R3NH2
R3
N
4 Å molecular sieves
then Tf2O, 2-ClPyr
R4
R1
H
R1
O
N
R2
C4-tertiary
3,4-dihydroquinazolines
N
H
R2
9
This work:
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O
R5 R4
R3NH2
R3
4 Å molecular sieves
then Tf2O, 2-ClPyr
R4
R1
R5
N
R1
O
N
R2
C4-quaternary
3,4-dihydroquinazolines
N
H
R2
R4 = alkyl, aryl, ester
R5 = ketone, ester
R5 R4
N
R5 R4
R3
R2
1. N3 dealkylation
N
R1
R1
2. regioselective N1
functionalization
N
N
R2
R6
C4-quaternary
1,4-dihydroquinazolines
R6 = alkyl, acyl
RESULTS AND DISCUSSION
The proposed synthesis of C4-quaternary 3,4-DHQs through a multicomponent tandem approach involved in situ
ketimine generation from a ketone and an amine (Scheme 2). The reaction was anticipated to proceed via addition of
the ketimine to an amide-derived reactive species such as 1a or 1b to form a ketiminium intermediate (e.g. 1c), which
would then undergo Pictet-Spengler-like cyclization to afford the quaternary product (e.g. 2). Conditions developed
by Movassaghi17, 18 for the synthesis of aromatic heterocycles were selected to facilitate the conversion of amides to
reactive pyridinium18 (e.g. 1a) and nitrilium19 (e.g. 1b) species through treatment with Tf2O and a pyridine base. Ethyl
benzoylformate was chosen as a ketone to test the proposed synthesis, as the ketone not only exhibits high
electrophilicity required for ketimine formation, but it also contains an ester which would act as a useful reactive
handle once incorporated into the DHQ scaffold. Initially, conditions similar to those previously used for the synthesis
of 3,4-DHQs from aldehydes were investigated.14 A mixture of amide 1, benzylamine, and ethyl benzoylformate was
stirred with molecular sieves in CH2Cl2 for 18 hours at room temperature followed by treatment with 2-chloropyridine
(2-ClPyr) and Tf2O at -41 °C. After warming to room temperature, the reaction stirred for an additional 24 hours to
afford quaternary compound 2 in 72% yield (Table 1, entry 1).20 The reaction yield was unchanged when 2-ClPyr
and Tf2O were instead added at -78 °C (entry 2). Variations in the pyridine base, including omission of a base (entries
3-8), revealed 2-fluoropyridine (2-FPyr) to provide higher yields of 2 (entry 3). The use of 2-FPyr with Tf2O during
amide dehydration is known to result in nitrilium formation (e.g. 1b, Scheme 2),19,21 which would presumably allow
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for better access of the ketimine to initiate nucleophilic addition. Modifications to the solvent type did not increase
reaction yield (entries 9 – 11), but changes in solvent volumes did have a measurable effect on the reaction outcome
(entries 3, 12 - 14). As a general trend, reaction yields increased with increasing concentration of the amide so long
as the amide was visibly soluble. The highest tested concentration where the amide was observed to be fully soluble
resulted in 86% yield of 2 (entry 13), whereas a more concentrated reaction gave a lower product yield (entry 14).
Interestingly, a similar product yield was observed when the base was exchanged with 2-ClPyr (entry 15) at the optimal
reaction concentration, indicating generation of the nitrilium intermediate is not as crucial for high reaction yields
when the rate of the bimolecular ketimine addition step is increased through solvent volume reduction. Lastly,
increasing the reaction time following amide dehydration was not found to alter reaction yields (entry 16).
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Scheme 2. C4-Quaternary 3,4-DHQ Tandem Assembly
2-ClPyr
Tf2O
N
Cl
OTf
Ph
O
N
1a
CO2Et
N
O
Ph
Ph
O
N
Ph
H
generated
1
in situ
2-FPyr
Tf2O
OTf
N
O
Ph
1b
CO2Et
Ph CO2Et
Pictet-Spengler-like
cyclization
Ph
OTf
Ph
N
Ph
N
O
N
Ph
O
N
Ph
1c
2
Table 1. Optimization of Reaction Conditionsa
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O
4
5
6
7
4 Å mol. sieves,
CH2Cl2, rt, 18 h
Ph
CO2Et
H2N
O
Ph
Ph CO2Et
N
Ph
then Tf2O (1.1 equiv.),
base (1.2 equiv.),
-41 °C to rt, 24 h
O
N
Ph
O
N
Ph
H
1
2
8
9
entry
1
base
conc. (M)b
0.05
yield (%)c
solvent
DCM
DCM
DCM
DCM
2-Chloropyridine
2-Chloropyridine
2-Fluoropyridine
2,6-Dichloropyridine
72
72
77
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2d
0.05
3
0.05
4
0.05
0.05
0.05
50
30
71
46
41
49
44
5
Pentafluoropyridine
2-Methoxypyridine
Pyridine
DCM
DCM
DCM
DCM
DCE
6
7
0.05
0.05
0.05
8
None
9
2-Fluoropyridine
2-Fluoropyridine
10
11
0.05
CHCl3
toluene
0.05
0.02
0.20
0.50
0.20
0.20
2-Fluoropyridine
2-Fluoropyridine
2-Fluoropyridine
2-Fluoropyridine
2-Chloropyridine
2-Chloropyridine
61
12
13
14
15
16f
62
DCM
86 (84)e
64
DCM
DCM
87 (85)e
86 (85)e
DCM
DCM
aConditions: 1 (1.0 mmol), benzylamine (1.1 mmol), ethyl benzoylformate (1.1 mmol), 4 Å mol. sieves (1.0 g),
CH2Cl2, rt, 18 hr; then base (1.2 mmol), Tf2O (1.1 mmol), -41 °C; then rt, 24 h. bAmide concentration. cNMR yield
d
e
f
with 1,3,5-trimethoxybenzene as internal standard. Base and Tf2O added at -78 °C. Isolated yield. 48 h for final
step.
With optimal reaction conditions identified, the reaction scope was then explored (Table 2). First, variations about
the nucleophilic anilide portion of the starting amides were investigated. Higher yields were observed when using
amides bearing electron rich anilides compared with electron poor anilides (compare 2 and 4a to 4c), a finding which
aligns with prior observations that Pictet-Spengler-like cyclization is promoted by increases in electron density about
the nucleophilic anilide ring.14 However, increases in electron density through incorporation of groups that also added
to steric bulk were found to negatively impact ring formation. The incorporation of a second methoxy group onto the
starting anilide ring in the meta position provided a lower yield than if only a single meta-methoxy group was present
(4a vs 2). Likewise, the use of an amide with a 3,5-dimethyl anilide ring provided 4b in only 27% yield. In general,
incorporation of bulky groups about the heterocyclic scaffold which interact with the newly forming quaternary center
led to lower reaction yields. Replacement of the anilide ring with the nucleophilic thiophene ring was also performed
to afford heterocycle 4d in good yields. The acyl portion of the amide was then varied (e.g. R2) to demonstrate alkyl
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(e.g. 4e – 4g) and aryl (e.g. 4h – 4j) group installation at this position. While all tested amide variants were converted
to corresponding products, aromatic amides provided higher yields than the alkyl counterparts. Modulation of the
amine component was also conducted, revealing that a range of alkyl and aryl amines are compatible with the reaction
(e.g. 4k – 4o). However, the proximity of the nitrogen atom and its carbon bulk to the new quaternary center in the
heterocyclic system makes it susceptible to steric effects, such that the use of a bulky amine like cyclohexylamine
(e.g. 4m) provides a low product yield.
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Next, the ketone component was investigated (Table 2). First, different aryl keto esters were evaluated in the reaction
(e.g. 4p – 4r). Electron deficient aryl groups were found to promote the reaction compared to electron rich arenes
(e.g. 4p vs 4q and 4r), with the enhancement of 4p formation likely occurring due to increased electrophilicity of the
Pictet-Spengler annulation precursor (e.g. 1c, scheme 2). Replacement of the aryl group with a heteroaromatic
thiophene ring resulted in the formation of 4s, although the product was formed in a much lower yield than when using
the aromatic counterparts. However, the quaternary center bearing the thiophene was installed in much higher yield
when the amine component was changed to p-anisidine (e.g. PMP group in 4t). Alkyl keto esters were also
successfully used in the reaction (e.g. 4u – 4x), whereby reaction yields were observed to degrade as bulkiness of the
alkyl group increased. Interestingly, incorporation of a tert-butyl ester (e.g. 4y) had no negative effect on reaction
yield, indicating that the bulky alkoxy group remains distal to reactive sites during the tandem assembly processes.
Lastly, dual ester functionalities were readily installed from the use of a keto diester (e.g. 4z). In addition to keto
esters, the reaction was also found to tolerate diketones (e.g. 5a – 5d). Addition of alkyl diketones 2,3-butanedione
and 2,3-hexanedione provided the corresponding DHQs bearing an alkyl group and a ketone at the quaternary center
in moderate yields (e.g. 5a and 5b, respectively). Interestingly, while two possible regioisomer products were
predicted to arise from the use of 2,3-hexanedione, the only product observed was that formed from ketimine
generation at the more sterically accessible C2 carbonyl.22 Aromatic functionalities were also installed at the
quaternary center via treatment with benzil (e.g. 5c) and with acenaphthoquinone (e.g. 5d), the latter of which resulted
in the formation of a spiro ring junction.
Table 2. Synthesis of Diverse C4-Quaternary 3,4-DHQs
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R5 R4
N
4 Å mol. sieves, CH2Cl2, rt, 18 h
O
O
R3
R2
R1
R1
H2N R3
then Tf2O, 2-Clpyr,
-41 °C to rt, 24 h
R4
R5
N
R2
N
H
1
3
4 - 5
or
7
8
O
Ph CO2Et
Ph
Ph CO2Et
Ph
Ph CO2Et
Ph
Ph CO2Et
Ph CO2Et
Ph
Ph CO2Et
F
S
N
N
N
N
Ph
N
N
Ph
9
O
N
Ph
N
Ph
O
N
Ph
N
Ph
O
N
O
N
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4a
4b
4c
4d
4e
4f
, 76%
, 27%
, 29%
, 79%
, 50%
, 49%
Ph CO2Et
Ph
Ph CO2Et
Ph
Ph CO2Et
Ph
Ph CO2Et
Ph
Ph CO2Et
C6H13
Ph CO2Et
N
N
N
N
N
N
S
O
N
O
N
O
N
O
N
O
N
Ph
O
N
Ph
4g
4h
4i
4j
4k
4l
, 48%
, 58%
, 77%
, 77%
, 78%
, 46%
O
F
F
O
F
Ph CO2Et
N
Ph CO2Et
N
Ph CO2Et
N
CO2Et
CO2Et
Ph
CO2Et
Ph
O
N
Ph
N
N
O
N
Ph
O
N
Ph
O
N
Ph
O
N
, 74%
Ph
O
N
Ph
O
N
Ph
4m
4n
4o
4p
4q
4r
, 55%
, 7%
, 49%
, 92%
, 36%
S
S
CO2Et
Ph
CO2Et
CO2Et
Ph
CO2Et
Ph
CO2Et
Ph
CO2Et
Ph
N
N
O
N
N
N
N
O
N
Ph
O
N
Ph
O
N
Ph
O
N
Ph
O
N
Ph
O
N
Ph
4s
4t
4u
4v
4w
4x
, 3%
, 5%
, 50%
, 22%
, 37%
, 21%
O
N
O
O
Ph CO2tBu
Ph
EtO2C CO2Et
Ph
Ph
Ph
O
N
N
Ph
N
Ph
N
Ph
N
Ph
Ph
O
N
Ph
O
N
Ph
O
N
Ph
O
N
Ph
O
N
Ph
O
N
4y
4z
5a
5b
5c
5d
, 35%
, 90%
, 81%
, 57%
, 40%
, 21%
aConditions: amide 1 or 3 (1.0 mmol), amine (1.1 mmol), ketone (1.1 mmol), 4 Å mol. sieves (1.0 g), CH2Cl2 (5.0
mL), rt, 18 h; then 2-ClPyr (1.2 mmol), Tf2O (1.1 mmol), -41 °C; then rt, 24 h. Isolated yield.
Once the scope of the quaternary 3,4-DHQ synthesis had been explored, attention was turned towards the synthesis
of 1,4-DHQs. Limited reports involving N1 functionalization of N-unsubstituted C4-quaternary DHQs describe
alkylation through treatment with methyl iodide23 and dimethyl sulfate.4a, 24 In these studies, alkylation was performed
with an excess of the alkylating agent, resulting in mixtures of N1 alkylation, N3 alkylation, and dialkylation. We
sought to convert 3,4-DHQs prepared in our studies to the corresponding 1,4-DHQs via N3 dealkylation and
subsequent N1 alkylation as a means of both accessing diverse 1,4-DHQs and for determining conditions which might
afford regioselectivity during alkylation. To this end, compound 2 was selected to undergo transformation through
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removal of the N3-benzyl substituent followed by alkylation with a benzyl halide (Scheme 3). The two-step reaction
sequence was anticipated to afford 7, the N1-benzyl regioisomer of 2, and selectivity of the alkylation reaction was to
be measured by observing the product ratio of 7 to 2, resulting from N1 and N3 alkylation, respectively. The benzyl
group was readily removed from 2 via hydrogenation to afford 6 in high yield. Alkylation of 6 with benzyl bromide
after deprotonation with NaH then provided 1,4-DHQ 7 in 78% yield20 without any of 2 being observed.
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Scheme 3. Conversion of 3,4-DHQs to 1,4-DHQs
cyclohexene
Pd/C cat.
Ph CO2Et
Ph
Ph CO2Et
N
N
EtOH, 85 °C
92%
O
N
Ph
O
N
H
Ph
2
6
Ph CO2Et
BnBr, NaH
N
DMF, rt
78%
O
N
Ph
Ph
7
The alkylation of 6 with benzyl bromide was modelled in order to better understand the observed reaction
regioselectivity (Scheme 4). The reaction involves initial deprotonation of 6 with NaH to generate anion 6a; the
approach of the alkyl halide towards the anion leads to transition states TS1 and TS2 in which the alkyl halide initiates
bond formation with the N3 and N1 positions, respectively. DFT calculations of all compounds and transition states
in DMF solution were performed at EDF2/6-31G* level of theory without symmetry constraints under SM8 continuum
solvation model using Spartan’18 (Wavefunction, Inc.) software suite. Under this level of theory, both 2 and 7 were
calculated to form exothermically (-105 and -113 kJ/mol, respectively) from the alkylation of 6a. Interestingly, an
activation energy of 72 kJ/mol in DMF was required to reach TS1, the transition state leading to 2, whereas a lower
activation energy of 55 kJ/mol in DMF was required to attain TS2 en route to 7. The difference of 17 kJ/mol between
the corresponding transition states indicates the lower activation energy of TS2 as the probable driving force for
selective N1 alkylation of 6a. Similar results of calculations were obtained for methyl iodide addition (C-PCM model,
the activation energy difference of 11 kJ/mol favoring the N1-methyl analog of 7),25 whereas the addition of methyl
bromide, based on the calculated data, should lead to a lower selectivity due to a smaller difference of the activation
energies (4 kJ/mol). The computational data suggests functionalization of deprotonated quaternary DHQs should
occur regioselectively at the N1 position through treatment with electrophiles of varying sizes.
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Scheme 4. Computational Rationale for Regioselective Alkylation
5
6
7
8
Ph CO2Et
Ph
Ph CO2Et
N
Ph CO2Et
N
N
O
N
Ph
O
N
Ph
O
N
Ph
2
6a
7
Ph
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TS1
6a
2
TS2
7
To explore the scope of 1,4-DHQ synthesis via regioselective functionalization, reactions involving combinations of
various DHQs and electrophiles were investigated (Table 3). First, 3,4-DHQs 4c, 4e, and 4z, which differ in the
substituents installed around the parent scaffold, were subjected to hydrogenation conditions to afford the
corresponding N3-dealkylated compounds (e.g. 8a – c, respectively). Subsequently, each was treated with NaH and
a slight excess of benzyl bromide (1.3 equivalents) to afford the anticipated N1-benzylated products in high yields (9a
– 9c). Next, the use of different alkyl halides was explored. Treatment of 6 with allyl bromide provided 9d in 72%
yield. Less reactive alkyl halides also resulted in formation of 1,4-DHQs, albeit in lower yields. A hexyl group was
introduced through the use of 1-bromohexane to generate 63% of 9e, while the cyclohexylmethyl group was installed
in 60% yield (e.g. 9f). The yield of 9e was increased to 78% when 1.0 equivalent of 1-iodohexane was used, while a
loss of yield was observed with the use of superstoichiometric amounts of the iodoalkane, presumably due to
overalkylation. Conversely, treatment with the less reactive 1-chlorohexane resulted in formation of 9e in less than
10% yield. Treatment with bulkier secondary alkyl halides 2-bromopropane and 2-iodopropane afforded 9g in similar
yields, which were lower than when using primary alkyl halides. Synthesis of N1-monomethylated product 9h22 in
82% yield was accomplished cleanly via treatment with 1.0 equivalent of methyl iodide with no N3-alkylated
regioisomer being observed, a finding in agreement with the abovementioned computational data. Moreover, the use
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of excess methyl iodide (3 equivalents) primarily afforded dialkylated dihydroquinazolinium salt 10. In addition to
alkyl halides, the use of electrophilic 1,3-propanesultone was also examined under the reaction conditions, leading to
the generation of sulfonic acid 11 in 55% yield. Finally, acylation was performed through treatment with acid
anhydrides or acid chlorides to generate N1-acylated products in moderate yields (e.g. 12a22 and 12b).
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Table 3. Scope of 1,4-DHQ Synthesisa
R3 CO2Et
N
R3 CO2Et
N
R
X
NaH, DMF
R1
R1
rt, 18 h
N
R
R2
N
R2
H
8
6
or
9 12
-
Ph CO2Et
N
Ph CO2Et
EtO2C CO2Et
N
F
N
O
N
Ph
O
O
N
O
O
N
Ph
Ph
9a
Ph
Ph
9b
9c
, 90%
, 72%
, 82%
Ph CO2Et
N
Ph CO2Et
N
Ph CO2Et
N
O
N
Ph
N
Ph
N
Ph
b
9d
9e
9f
, 60%
, 74%
, 63%, (78%)
Ph CO2Et
N
Ph CO2Et
N
Ph CO2Et
N
I
O
N
Ph
O
O
N
Ph
O
O
N
Ph
b
b
c
9g
9h
10
, 81%
, 22%, (21%)
, 82%
Ph CO2Et
N
Ph CO2Et
N
Ph CO2Et
N
N
Ph
N
Ph
O
N
Ph
Ph
O
O
HO3S
d
e
e
11
12a
12b
, 64%
, 55%
, 56%
aConditions: 6 or 8 (1.0 equiv.), NaH (1.2 equiv.), DMF, 0 °C, 30 min; then alkyl bromide (1.3 equiv.), rt, 18 h.
Isolated yield. bAlkyl iodide (1.0 equiv.) used. cMethyl iodide (3.0 equiv.) used. d1,3-Propanesultone (2.0 equiv.) used
instead of alkyl halide. eAcid chloride or acid anhydride (1.1 equiv.) used instead of alkyl halide.
Further exploration of quaternary 1,4-DHQ synthesis involved the installation of new fused rings about the N1-C2
portion of the scaffold (Scheme 5). Such ring systems were postulated to arise from tethered electrophiles at the C2
position that would undergo substitution by the N1 atom. Amides 13a and 13b, each bearing a chloroalkyl chain were
constructed to test this hypothesis. The use of each in multicomponent 3,4-DHQ syntheses with ethyl benzoylformate
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and benzylamine led to the assembly of multicyclic complexes 14a and 14b in which the halogen had been expelled
via intramolecular cyclization. Whereas prior use of chloroalkyl electrophiles for intermolecular substitution was
largely unsuccessful, providing low yields of 1,4-DHQs, the intramolecular substitution reactions worked very well.
Removal of the N3-benzyl substituents via hydrogenation then afforded multicyclic adducts 15a and 15b, in which
new 5 and 6 membered rings were incorporated, respectively.
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Scheme 5. Synthesis of Fused Tricyclic 1,4-DHQs
O
Ph CO2Et
Ph
O
CO2Et
H2N
n
Ph
Cl
4 Å mol. sieves,
CH2Cl2, rt, 18 h
N
Ph
O
then 2-ClPyr, Tf2O
-41 °C to rt, 24 h
O
N
N
H
Cl
n
13a
13b
14a
14b
, n = 1
, n = 2
, n = 1; 58%
, n = 2; 64%
Ph CO2Et
N
cyclohexene
Pd/C cat.
EtOH
O
N
85 °C, 18 h
n
15a
15b
, n = 1; 68%
, n = 2; 56%
CONCLUSIONS
In conclusion, we have developed an efficient one-pot procedure for the synthesis of C4-quaternary 3,4-DHQs via a
Tf2O-mediated tandem assembly of amides, amines, and ketones. We have also demonstrated conversion of 3,4-
DHQs to 1,4-DHQs through a two-step procedure involving N3 dealkylation followed by regioselective N1 alkylation
and acylation. The diverse functionalities installed about the ring systems through this chemistry are amenable to
further synthetic manipulation, allowing for even greater future diversity about this heterocyclic scaffold.
EXPERIMENTAL SECTION
General Experimental Information. Reactions were carried out in flame-dried glassware under nitrogen atmosphere.
All reactions were magnetically stirred and monitored by TLC on EMD Millipore silica gel 60F254 pre-coated glass
plates using UV light (254 nm) to visualize the compounds. Column chromatography was carried out on SiliaFlash
P60 (230 – 400 mesh) silica gel supplied by SiliCycle or on a Yamazen AKROS MPLC system using silica gel
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columns supplied by Yamazen Corporation. Infrared spectra were recorded on an Agilent Technologies Cary 630 FT-
IR spectrometer. Proton (1H NMR) and carbon (13C NMR) nuclear magnetic resonance spectra were recorded on a
Bruker Avance III 400 MHz spectrometer. The chemical shifts are given in parts per million (ppm) on the delta (δ)
scale. Tetramethylsilane (TMS) or the residual solvent peak was used as a reference value. High resolution mass
spectra were recorded at the LSSU Cannabis Center of Excellence on an Agilent 1290 Ultra-High Pressure Liquid
Chromatograph with a Time of Flight Mass Spectrometer (UHPLC-TOF). Melting points were obtained using a Mel-
Temp capillary melting point apparatus and are uncorrected. 2-Chloropyridine and 2-fluoropyridine were dried over
4 Å molecular sieves; all other solvents and chemicals were purchased from commercial vendors and were used
without additional purification. Amides 1, 3a-e, and 3h-j were prepared as previously reported.14
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General procedure for amide synthesis. To a mixture of an amine and triethylamine (TEA) in CH2Cl2, cooled to 0
°C in an ice bath, was added dropwise an appropriate acid chloride followed by 4-DMAP. The ice bath was removed,
and the reaction stirred at room temperature under N2 atmosphere for 18 h. The reaction mixture was washed with
saturated NaHCO3 solution (x3) and brine before being dried (Na2SO4) and concentrated. The crude product was then
purified either by crystallization or chromatography.
General procedure for 3,4-DHQ synthesis: A mixture of amide, amine, aldehyde, and 4 Å molecular sieves (~1 g
per mmol of amide) in CH2Cl2 was prepared and stirred for 18 h at room temperature under N2 atmosphere. The
reaction mixture was cooled to -41 °C in an acetonitrile/dry ice bath and was treated successively with 2-
chloropyridine followed by Tf2O. The reaction was then allowed to warm to room temperature and was stirred for 24
h. The molecular sieves were filtered from the reaction, and the filtrate was washed with saturated aqueous NaHCO3
solution before being dried (Na2SO4) and concentrated. The crude mixture was then purified via chromatography.
General procedure for 3,4-DHQ debenzylation: To a mixture of 3,4-DHQ in EtOH and cyclohexene was added
10% Pd/C, and the reaction was heated to 85 °C in a sealed vial set in an aluminum block heater for 18 h. The mixture
was cooled to room temperature and passed through a celite plug with EtOAc. The filtrate was concentrated, and the
residue was purified via trituration or chromatography.
General procedure for 1,4-DHQ synthesis: To a suspension of NaH (60% dispersion in mineral oil) in DMF, cooled
to 0 °C in an ice bath, was added N-unsubstituted 3,4-DHQ. The reaction stirred at 0 °C for 30 minutes before an
alkyl halide or acid anhydride was added. The ice bath was removed, and the reaction was stirred at room temperature
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for 18 h. The reaction was cooled in an ice bath and aqueous saturated NaHCO3 solution was added. The mixture
was extracted with CH2Cl2 (x3), and the pooled extracts were dried (Na2SO4) and concentrated. The remaining DMF
was removed azeotropically in vacuo with toluene, and the resulting residue was purified by chromatography.
7
8
9
Ethyl 3-benzyl-7-methoxy-2,4-diphenyl-3,4-dihydroquinazoline-4-carboxylate (2). Prepared according to the
general 3,4-DHQ synthesis protocol with 1 (0.227 g, 1.00 mmol), benzylamine (0.12 mL, 1.1 mmol), ethyl
benzoylformate (0.18 g, 1.1 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.11 mL, 1.2 mmol), and Tf2O (0.18 mL, 1.1
mmol). Following workup, the residue was purified by MPLC (0% - 1% MeOH in 95:5 CH2Cl2:ether as eluent) to
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afford the desired product (0.403 g, 85%) as a solid (m.p. = 133 - 136 °C). H NMR (400 MHz, CDCl3) δ 7.60 – 7.47
(m, 2H), 7.40 – 7.30 (m, 2H), 7.26 – 7.16 (m, 3H), 7.20 – 7.09 (m, 3H), 6.98 – 6.86 (m, 3H), 6.85 (d, J = 2.0 Hz, 1H),
6.73 (d, J = 8.7 Hz, 1H), 6.64 – 6.51 (m, 3H), 4.83 (d, J = 17.0 Hz, 1H), 4.40 – 4.14 (m, 2H), 4.01 (d, J = 17.0 Hz,
1H), 3.73 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.2, 160.2, 159.4, 143.3, 139.6,
138.8, 137.6, 130.5, 130.4, 128.5, 128.4, 128.0, 127.71, 127.65, 127.5, 126.02, 126.00, 118.6, 111.9, 107.4, 74.2, 62.1,
55.1, 52.0, 14.1; IR (neat): 3060, 2928, 1730, 1552, 1489, 1219, 1031 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd
for C31H29N2O3 477.2178; Found 477.2162.
Ethyl 3-benzyl-5,7-dimethoxy-2,4-diphenyl-3,4-dihydroquinazoline-4-carboxylate (4a). Prepared according to
the general 3,4-DHQ synthesis protocol with 3a (0.257 g, 1.00 mmol), benzylamine (0.12 mL, 1.1 mmol), ethyl
benzoylformate (0.18 g, 1.1 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.11 mL, 1.2 mmol), and Tf2O (0.18 mL, 1.1
mmol). Following workup, the residue was purified by MPLC (0% - 1% MeOH in 95:5 CH2Cl2:ether as eluent) to
afford the desired product (0.383 g, 76%) as a solid (m.p. = 101 - 104 °C). 1H NMR (400 MHz, CDCl3) δ 7.75 – 7.67
(m, 2H), 7.36 – 7.27 (m, 4H), 7.28 – 7.16 (m, 4H), 7.11 – 7.02 (m, 3H), 6.94 (d, J = 7.9 Hz, 2H), 6.55 (d, J = 2.4 Hz,
1H), 6.19 (d, J = 2.4 Hz, 1H), 4.62 (d, J = 17.4 Hz, 1H), 4.41 (d, J = 17.4 Hz, 1H), 3.96 (dq, J = 10.8, 7.1 Hz, 1H),
3.76 (s, 3H), 3.58 (dq, J = 10.8, 7.1 Hz, 1H), 3.54 (s, 3H), 1.05 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3)
δ 170.1, 160.6, 158.4, 155.8, 142.11, 142.07, 138.0, 136.8, 128.7, 128.1, 127.8, 127.7, 127.6, 127.5, 127.4, 126.5,
126.3, 108.1, 101.1, 96.8, 69.5, 61.4, 55.3, 55.2, 52.1, 13.7; IR (neat): 3058, 2935, 1735, 1597, 1552, 1213, 1150,
1042 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C32H31N2O4 507.2284; Found 507.2282.
Ethyl 3-benzyl-5,7-dimethyl-2,4-diphenyl-3,4-dihydroquinazoline-4-carboxylate (4b). Prepared according to the
general 3,4-DHQ synthesis protocol with 3b (0.225 g, 1.00 mmol), benzylamine (0.12 mL, 1.1 mmol), ethyl
benzoylformate (0.18 g, 1.1 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.11 mL, 1.2 mmol), and Tf2O (0.18 mL, 1.1
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mmol). Following workup, the residue was purified by flash chromatography (0% - 1% MeOH in 95:5 CH2Cl2:ether
as eluent) followed by additional flash chromatography (20% EtOAc in hexanes as eluent) to afford the desired product
(0.126 g, 27%) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.50 – 7.38 (m, 4H), 7.24 – 7.10 (m, 6H), 7.04 (d, J = 1.9 Hz,
1H), 6.97 – 6.88 (m, 3H), 6.68 (d, J = 2.0 Hz, 1H), 6.60 (dd, J = 8.0, 1.6 Hz, 2H), 4.71 (d, J = 17.1 Hz, 1H), 4.38 (dq,
J = 10.8, 7.1 Hz, 1H), 4.23 (dq, J = 10.8, 7.1 Hz, 1H), 4.05 (d, J = 17.1 Hz, 1H), 2.28 (s, 3H), 1.60 (s, 3H), 1.31 (t, J
= 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.1, 158.0, 142.4, 140.6, 139.2, 138.4, 137.6, 137.0, 130.6,
129.8, 128.5, 128.1, 128.0, 127.9, 127.8, 127.5, 126.1, 126.0, 123.8, 122.6, 73.4, 62.2, 51.8, 21.6, 20.8, 14.1; IR (neat):
3062, 2920, 1730, 1593, 1556, 1448, 1217, 1027 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C32H31N2O2
475.2386; Found 475.2383.
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Ethyl 3-benzyl-6-fluoro-7-methoxy-2,4-diphenyl-3,4-dihydroquinazoline-4-carboxylate (4c). Prepared according
to the general 3,4-DHQ synthesis protocol with 3c (0.246 g, 1.00 mmol), benzylamine (0.12 mL, 1.1 mmol), ethyl
benzoylformate (0.18 g, 1.1 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.11 mL, 1.2 mmol), and Tf2O (0.18 mL, 1.1
mmol). Following workup, the residue was purified by flash chromatography (100:3:1 CH2Cl2:ether:MeOH as eluent)
to afford the desired product (0.145 g, 29%) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.49 (dd, J = 6.5, 3.1 Hz, 2H),
7.34 – 7.29 (m, 2H), 7.27 – 7.21 (m, 3H), 7.22 – 7.12 (m, 3H), 6.99 – 6.87 (m, 4H), 6.60 – 6.50 (m, 3H), 4.81 (d, J =
16.9 Hz, 1H), 4.42 – 4.23 (m, 2H), 3.97 (d, J = 17.0 Hz, 1H), 3.88 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H); 13C{1H} NMR
(101 MHz, CDCl3) δ 172.1, 159.0 (d, 6JC-F = 2 Hz), 149.5 (d, 1JC-F = 243 Hz), 148.2 (d, 2JC-F = 12 Hz), 139.10, 139.08,
138.9, 137.4, 130.5, 128.7 (d, 3JC-F = 5 Hz), 128.4, 128.1, 127.9, 127.8, 127.6, 126.14, 126.08, 118.0 (d, 3JC-F = 6 Hz),
116.5 (d, 2JC-F = 21 Hz), 108.4 (d, 4JC-F = 2 Hz), 73.9 (d, 4JC-F = 1 Hz), 62.3, 56.0, 52.1, 14.2; IR (neat): 3060, 2932,
1731, 1504, 1219, 1023 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C31H28FN2O3 495.2084; Found 495.2086.
Ethyl 6-benzyl-5,7-diphenyl-1-thia-4,6-diaza-6,7-dihydroindene-7-carboxylate (4d). Prepared according to the
general 3,4-DHQ synthesis protocol with 3d (0.203 g, 1.00 mmol), benzylamine (0.12 mL, 1.1 mmol), ethyl
benzoylformate (0.18 g, 1.1 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.11 mL, 1.2 mmol), and Tf2O (0.18 mL, 1.1
mmol). Following workup, the residue was purified by flash chromatography (100:5 CH2Cl2:ether as eluent) to afford
the desired product (0.356 g, 79%) as a solid (m.p. = 123 - 125 °C). 1H NMR (400 MHz, CDCl3) δ 7.52 – 7.38 (m,
4H), 7.27 – 7.12 (m, 7H), 6.99 (d, J = 5.3 Hz, 1H), 6.97 – 6.85 (m, 3H), 6.55 (d, J = 6.7 Hz, 2H), 4.82 (d, J = 17.0 Hz,
1H), 4.43 – 4.26 (m, 2H), 4.03 (d, J = 17.0 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
171.6, 158.1, 145.3, 139.0, 138.8, 137.3, 130.0, 129.1, 128.6, 128.1, 127.9, 127.8, 127.6, 126.11, 126.09, 125.6, 123.6,
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119.9, 73.5, 62.3, 52.0, 14.2; IR (neat): 3029, 2958, 1730, 1556, 1446, 1221, 1019 cm-1; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C28H25N2O2S 453.1637; Found 453.1635.
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Ethyl 3-benzyl-7-methoxy-2-methyl-4-phenyl-3,4-dihydroquinazoline-4-carboxylate (4e). Prepared according to
the general 3,4-DHQ synthesis protocol with 3e (0.166 g, 1.00 mmol), benzylamine (0.12 mL, 1.1 mmol), ethyl
benzoylformate (0.18 g, 1.1 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.11 mL, 1.2 mmol), and Tf2O (0.18 mL, 1.1
mmol). Following workup, the residue was purified by flash chromatography (100:3:1 CH2Cl2:ether:MeOH as eluent)
to afford the desired product (0.206 g, 50%) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.37 – 7.31 (m, 2H), 7.19 – 7.05
(m, 6H), 6.94 – 6.89 (m, 2H), 6.73 (d, J = 2.6 Hz, 1H), 6.60 (d, J = 8.6 Hz, 1H), 6.52 (dd, J = 8.7, 2.7 Hz, 1H), 4.79
(d, J = 17.7 Hz, 1H), 4.33 – 4.14 (m, 3H), 3.80 (s, 3H), 2.22 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 171.9, 160.3, 158.7, 142.8, 140.2, 138.2, 130.3, 130.1, 128.4, 128.2, 127.8, 126.6, 125.6, 118.4, 111.6,
106.5, 74.5, 62.1, 55.3, 52.2, 23.9, 14.1; IR (neat): 3060, 2980, 1730, 1590, 1562, 1493, 1215, 1198, 1151, 1027 cm-
1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H27N2O3 415.2022; Found, 415.2017.
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N-(3-Methoxyphenyl)butanamide (3f). Prepared according to the general amide synthesis protocol with m-anisidine
(1.12 mL, 10.0 mmol), TEA (1.70 mL, 12.2 mmol), butyryl chloride (1.13 mL, 11.0 mmol), 4-DMAP (0.012 g, 0.10
mmol), and CH2Cl2 (50 mL). After workup, the residue was purified by flash chromatography (20% EtOAc in hexanes
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as eluent) to afford the desired product (1.570 g, 82%) as a waxy solid (m.p. = 30 – 33 °C). H NMR (400 MHz,
CDCl3) δ 8.65 (s, 1H), 7.33 (t, J = 2.2 Hz, 1H), 7.14 (t, J = 8.1 Hz, 1H), 7.07 (dt, J = 8.2, 1.3 Hz, 1H), 6.61 (ddd, J =
8.1, 2.5, 1.1 Hz, 1H), 3.69 (s, 3H), 2.31 (dd, J = 8.0, 7.0 Hz, 2H), 1.71 (h, J = 7.4 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 172.5, 160.0, 139.6, 129.5, 112.5, 109.9, 106.0, 55.1, 39.4, 19.2, 13.7. The NMR
spectral data are consistent with those reported in the literature.26
Ethyl 3-benzyl-7-methoxy-4-phenyl-2-propyl-3,4-dihydroquinazoline-4-carboxylate (4f). Prepared according to
the general 3,4-DHQ synthesis protocol with 3f (0.193 g, 1.00 mmol), benzylamine (0.12 mL, 1.1 mmol), ethyl
benzoylformate (0.18 g, 1.1 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.11 mL, 1.2 mmol), and Tf2O (0.18 mL, 1.1
mmol). Following workup, the residue was purified by flash chromatography (100:5:1 CH2Cl2:ether:MeOH as eluent)
to afford the desired product (0.217 g, 49%) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.31 – 7.25 (m, 2H), 7.13 – 7.05
(m, 6H), 6.90 – 6.85 (m, 2H), 6.75 (d, J = 2.7 Hz, 1H), 6.59 (d, J = 8.7 Hz, 1H), 6.50 (dd, J = 8.7, 2.7 Hz, 1H), 4.82
(d, J = 18.0 Hz, 1H), 4.32 – 4.12 (m, 3H), 3.80 (s, 3H), 2.45 (ddd, J = 14.3, 10.1, 5.2 Hz, 1H), 2.35 (ddd, J = 14.3,
10.3, 6.2 Hz, 1H), 1.97 – 1.72 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (101 MHz,
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CDCl3) δ 172.1, 160.7, 160.3, 142.9, 140.4, 138.5, 130.4, 130.2, 128.2, 128.0, 127.6, 126.5, 125.5, 118.0, 111.6, 106.5,
74.2, 62.0, 55.3, 51.3, 38.0, 20.9, 14.13, 14.11; IR (neat): 3060, 2928, 1731, 1558, 1493, 1213, 1200, 1034 cm-1;
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C28H31N2O3 443.2335; Found 443.2339.
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N-(3-Methoxyphenyl)cyclohexanecarboxamide (3g). Prepared according to the general amide synthesis protocol
with m-anisidine (1.12 mL, 10.0 mmol), TEA (1.70 mL, 12.2 mmol), cyclohexanecarbonyl chloride (1.47 mL, 11.0
mmol), 4-DMAP (0.012 g, 0.10 mmol), and CH2Cl2 (50 mL). After workup, the residue was purified by
recrystallization from EtOAc and hexanes to afford the desired product (1.635 g, 70%) as a solid (m.p. = 94 – 97 °C).
1H NMR (400 MHz, CDCl3) δ 7.37 (t, J = 2.1 Hz, 1H), 7.22 – 7.13 (m, 2H), 6.94 (dd, J = 8.0, 2.1 Hz, 1H), 6.64 (dd,
J = 8.3, 2.5 Hz, 1H), 3.80 (s, 3H), 2.22 (tt, J = 11.7, 3.5 Hz, 1H), 1.95 (dd, J = 12.7, 3.4 Hz, 2H), 1.88 – 1.78 (m, 2H),
1.75 – 1.65 (m, 1H), 1.54 (qd, J = 12.2, 10.7, 5.8 Hz, 2H), 1.38 – 1.17 (m, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
174.4, 160.2, 139.4, 129.6, 111.6, 110.2, 105.2, 55.3, 46.7, 29.7, 25.7. The NMR spectral data are consistent with
those reported in the literature.27
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Ethyl 3-benzyl-2-cyclohexyl-7-methoxy-4-phenyl-3,4-dihydroquinazoline-4-carboxylate (4g). Prepared
according to the general 3,4-DHQ synthesis protocol with 3g (0.233 g, 1.00 mmol), benzylamine (0.12 mL, 1.1 mmol),
ethyl benzoylformate (0.18 g, 1.1 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.11 mL, 1.2 mmol), and Tf2O (0.18
mL, 1.1 mmol). Following workup, the residue was purified by flash chromatography (100:3:1 CH2Cl2:ether:MeOH
as eluent) to afford the desired product (0.282 g, 58%) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.28 (dd, J = 7.7, 2.0
Hz, 2H), 7.14 – 7.05 (m, 6H), 6.87 (dd, J = 7.7, 1.8 Hz, 2H), 6.73 (d, J = 2.6 Hz, 1H), 6.54 (d, J = 8.6 Hz, 1H), 6.47
(dd, J = 8.6, 2.7 Hz, 1H), 4.83 (d, J = 18.0 Hz, 1H), 4.31 – 4.07 (m, 3H), 3.80 (s, 3H), 2.36 (ddd, J = 11.5, 8.3, 3.2 Hz,
1H), 2.25 – 2.16 (m, 1H), 1.94 – 1.74 (m, 2H), 1.73 – 1.62 (m, 1H), 1.62 – 1.48 (m, 3H), 1.30 – 1.14 (m, 5H), 1.01 –
0.86 (m, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.3, 163.6, 160.2, 143.2, 140.8, 139.0, 130.3, 130.1, 128.1, 128.0,
127.6, 126.4, 125.5, 118.1, 111.4, 106.8, 74.3, 61.9, 55.3, 50.9, 42.2, 31.4, 30.3, 26.6, 26.0, 25.8, 14.2; IR (neat): 2926,
1731, 1556, 1202, 1029 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C31H35N2O3 483.2648; Found 483.2651.
Ethyl 3-benzyl-2-(m-fluorophenyl)-7-methoxy-4-phenyl-3,4-dihydroquinazoline-4-carboxylate (4h). Prepared
according to the general 3,4-DHQ synthesis protocol with 3h (0.246 g, 1.00 mmol), benzylamine (0.12 mL, 1.1 mmol),
ethyl benzoylformate (0.18 g, 1.1 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.11 mL, 1.2 mmol), and Tf2O (0.18
mL, 1.1 mmol). Following workup, the residue was purified by flash chromatography (20% EtOAc in hexanes as
eluent) to afford the desired product (0.380 g, 77%) as a solid (m.p. = 124 - 127 °C). 1H NMR (400 MHz, CDCl3) δ
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7.39 – 7.34 (m, 2H), 7.29 (d, J = 7.7 Hz, 1H), 7.24 – 7.11 (m, 5H), 7.00 – 6.87 (m, 4H), 6.84 (d, J = 2.6 Hz, 1H), 6.72
(d, J = 8.7 Hz, 1H), 6.63 – 6.55 (m, 3H), 4.75 (d, J = 16.9 Hz, 1H), 4.40 – 4.19 (m, 2H), 4.01 (d, J = 16.9 Hz, 1H),
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3.78 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.2, 162.3 (d, JC-F = 247 Hz), 160.3,
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126.1, 123.6 (d, JC-F = 3 Hz), 118.6, 115.6 (d, JC-F J = 21 Hz), 115.1 (d, JC-F = 23 Hz), 112.3, 107.5, 74.3, 62.3,
55.2, 52.0, 14.1; IR (neat): 2924, 1730, 1556, 1485, 1224, 1031 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C31H28FN2O3 495.2084; Found 495.2090.
Ethyl 3-benzyl-7-methoxy-2-(p-methoxyphenyl)-4-phenyl-3,4-dihydroquinazoline-4-carboxylate (4i). Prepared
according to the general 3,4-DHQ synthesis protocol with 3i (0.257 g, 1.00 mmol), benzylamine (0.12 mL, 1.1 mmol),
ethyl benzoylformate (0.18 g, 1.1 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.11 mL, 1.2 mmol), and Tf2O (0.18
mL, 1.1 mmol). Following workup, the residue was purified by flash chromatography (100:10:1 CH2Cl2:ether:MeOH
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as eluent) to afford the desired product (0.389 g, 77%) as a foamy solid (m.p. = 60 - 64 °C). H NMR (400 MHz,
CDCl3) δ 7.50 – 7.43 (m, 2H), 7.34 – 7.29 (m, 2H), 7.18 – 7.07 (m, 3H), 6.96 – 6.87 (m, 3H), 6.85 (d, J = 2.7 Hz, 1H),
6.77 (d, J = 8.8 Hz, 2H), 6.69 (d, J = 8.7 Hz, 1H), 6.61 – 6.54 (m, 3H), 4.87 (d, J = 17.0 Hz, 1H), 4.40 – 4.19 (m, 2H),
3.98 (d, J = 16.9 Hz, 1H), 3.78 (s, 3H), 3.71 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
172.5, 160.2, 159.8, 159.3, 143.5, 139.7, 139.1, 130.6, 130.5, 130.1, 129.3, 128.4, 127.7, 127.6, 126.0, 126.0, 118.7,
113.5, 111.8, 107.3, 74.2, 62.1, 55.2, 52.0, 14.2; IR (neat): 3060, 2935, 1730, 1552, 1491, 1247, 1219, 1031 cm-1;
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C32H31N2O4 507.2284; Found 507.2288.
Ethyl
3-benzyl-7-methoxy-4-phenyl-2-(2-thienyl)-3,4-dihydroquinazoline-4-carboxylate
(4j).
Prepared
according to the general 3,4-DHQ synthesis protocol with 3j (0.233 g, 1.00 mmol), benzylamine (0.12 mL, 1.1 mmol),
ethyl benzoylformate (0.18 g, 1.1 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.11 mL, 1.2 mmol), and Tf2O (0.18
mL, 1.1 mmol). Following workup, the residue was purified by flash chromatography (100:5 CH2Cl2:ether as eluent)
to afford the desired product (0.377 g, 78%) as a solid (m.p. = 112 - 115 °C). 1H NMR (400 MHz, CDCl3) δ 7.35 –
7.31 (m, 2H), 7.25 (dd, J = 3.7, 1.2 Hz, 1H), 7.22 (dd, J = 5.1, 1.2 Hz, 1H), 7.19 – 7.10 (m, 3H), 6.99 – 6.94 (m, 3H),
6.87 – 6.83 (m, 2H), 6.74 – 6.70 (m, 2H), 6.67 (d, J = 8.6 Hz, 1H), 6.57 (dd, J = 8.7, 2.7 Hz, 1H), 5.06 (d, J = 17.2
Hz, 1H), 4.37 – 4.19 (m, 2H), 4.08 (d, J = 17.2 Hz, 1H), 3.77 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 172.2, 160.3, 153.8, 143.2, 139.4, 138.8, 138.6, 130.6, 130.3, 128.6, 128.3, 127.9, 127.8, 127.4, 126.5,
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126.3, 126.2, 119.1, 112.4, 107.6, 74.7, 62.3, 55.3, 52.4, 14.3; IR (neat): 3068, 2935, 1731, 1586, 1552, 1495, 1450,
1219, 1154, 1033 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C29H27N2O3S 483.1742; Found 483.1740.
Ethyl 3-hexyl-7-methoxy-2,4-diphenyl-3,4-dihydroquinazoline-4-carboxylate (4k). Prepared according to the
general 3,4-DHQ synthesis protocol with 1 (0.228 g, 1.00 mmol), hexylamine (0.15 mL, 1.1 mmol), ethyl
benzoylformate (0.18 g, 1.1 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.11 mL, 1.2 mmol), and Tf2O (0.18 mL, 1.1
mmol). Following workup, the residue was purified by MPLC (30% - 50% EtOAc in hexanes as eluent) to afford the
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desired product (0.215 g, 46%) as an oil. H NMR (400 MHz, CDCl3) δ 7.63 – 7.58 (m, 2H), 7.53 – 7.48 (m, 2H),
7.45 – 7.31 (m, 6H), 6.77 (d, J = 2.7 Hz, 1H), 6.70 (d, J = 8.7 Hz, 1H), 6.52 (dd, J = 8.7, 2.7 Hz, 1H), 4.39 – 4.23 (m,
2H), 3.76 (s, 3H), 3.33 (ddd, J = 15.5, 11.3, 4.9 Hz, 1H), 2.69 (ddd, J = 15.1, 11.6, 4.7 Hz, 1H), 1.28 (t, J = 7.1 Hz,
3H), 0.95 – 0.80 (m, 3H), 0.69 – 0.41 (m, 8H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.9, 160.2, 158.8, 143.3, 141.4,
137.7, 130.6, 130.5, 128.6, 128.33, 128.26, 127.9, 127.7, 118.0, 111.8, 107.1, 73.8, 62.1, 55.2, 49.4, 30.4, 29.5, 25.9,
22.0, 14.2, 13.7; IR (neat): 3060, 2928, 1731, 1552, 1489, 1217, 1033 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd
for C30H35N2O3 471.2648; Found 471.2650.
Ethyl 3-(cyclohexylmethyl)-7-methoxy-2,4-diphenyl-3,4-dihydroquinazoline-4-carboxylate (4l). Prepared
according to the general 3,4-DHQ synthesis protocol with 1 (0.227 g, 1.00 mmol), cyclohexanemethylamine (0.14
mL, 1.1 mmol), ethyl benzoylformate (0.18 g, 1.1 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.11 mL, 1.2 mmol),
and Tf2O (0.18 mL, 1.1 mmol). Following workup, the residue was purified by MPLC (15% - 40% EtOAc in hexanes
as eluent) followed by additional purification by MPLC (0% - 40% EtOAc in CH2Cl2 as eluent) to afford the desired
product (0.233 g, 48%) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 6.9 Hz, 2H), 7.47 – 7.40 (m, 2H), 7.38 –
7.26 (m, 6H), 6.82 – 6.65 (m, 2H), 6.50 (dd, J = 8.8, 2.7 Hz, 1H), 4.32 – 4.12 (m, 2H), 3.72 (s, 3H), 3.44 (dd, J = 15.1,
7.3 Hz, 1H), 2.63 (dd, J = 15.1, 5.0 Hz, 1H), 1.37 – 1.24 (m, 4H), 1.19 (t, J = 7.1 Hz, 3H), 0.91 – 0.82 (m, 1H), 0.75
– 0.53 (m, 3H), 0.15 – -0.09 (m, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.1, 160.2, 159.4, 143.6, 141.0, 138.1,
131.2, 130.6, 128.61, 128.57, 128.4, 128.1, 127.8, 118.3, 111.7, 107.1, 74.2, 62.0, 55.2, 54.5, 37.4, 30.5, 30.4, 26.0,
25.8, 25.7, 14.1; IR (neat): 2924, 1731, 1551, 1489, 1217, 1150, 1031 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd
for C31H35N2O3 483.2648; Found 483.2641.
Ethyl 3-cyclohexyl-7-methoxy-2,4-diphenyl-3,4-dihydroquinazoline-4-carboxylate (4m). Prepared according to
the general 3,4-DHQ synthesis protocol with 1 (0.227 g, 1.00 mmol), cyclohexylamine (0.13 mL, 1.1 mmol), ethyl
benzoylformate (0.18 g, 1.1 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.11 mL, 1.2 mmol), and Tf2O (0.18 mL, 1.1
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mmol). Following workup, the residue was purified by flash chromatography (100:5:1 CH2Cl2:ether:MeOH as eluent)
followed by additional flash chromatography (20% EtOAc in hexanes) to afford the desired product (0.034 g, 7%) as
an oil. 1H NMR (400 MHz, CDCl3) δ 7.62 – 7.51 (m, 4H), 7.43 – 7.31 (m, 6H), 6.79 – 6.66 (m, 2H), 6.50 (dd, J = 8.7,
2.7 Hz, 1H), 4.27 (qd, J = 7.1, 2.0 Hz, 2H), 3.77 (s, 3H), 2.86 (td, J = 11.3, 7.2 Hz, 1H), 1.85 – 1.74 (m, 1H), 1.43 –
1.33 (m, 1H), 1.30 – 1.20 (m, 5H), 1.10 – 0.99 (m, 2H), 0.78 – 0.42 (m, 4H); 13C{1H} NMR (101 MHz, CDCl3) δ
171.7, 160.1, 158.7, 142.9, 141.6, 139.6, 130.8, 129.6, 128.6, 128.2, 127.8, 127.7, 118.4, 111.9, 107.1, 74.4, 63.0,
62.0, 55.3, 34.5, 33.4, 27.3, 27.1, 25.3, 14.1; IR (neat): 2924, 1733, 1541, 1489, 1264, 1141, 1036 cm-1; HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C30H33N2O3 469.2491; Found 469.2485.
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Ethyl 3-(m-fluorophenyl)-7-methoxy-2,4-diphenyl-3,4-dihydroquinazoline-4-carboxylate (4n). Prepared
according to the general 3,4-DHQ synthesis protocol with 1 (0.227 g, 1.00 mmol), 3-fluoroaniline (0.11 mL, 1.1
mmol), ethyl benzoylformate (0.18 g, 1.1 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.11 mL, 1.2 mmol), and Tf2O
(0.18 mL, 1.1 mmol). Following workup, the residue was purified by flash chromatography (20% EtOAc in hexanes
as eluent) followed by additional flash chromatography (100:3 CH2Cl2:ether as eluent) to afford the desired product
(0.237 g, 49%) as a foamy oil. 1H NMR (400 MHz, CDCl3) δ 7.73 – 7.57 (m, 2H), 7.29 – 7.03 (m, 8H), 6.94 (t, J =
1.5 Hz, 1H), 6.81 – 6.50 (m, 5H), 6.43 (tdd, J = 8.2, 2.5, 1.0 Hz, 1H), 4.42 – 4.23 (m, 2H), 3.81 (s, 3H), 1.25 (t, J =
7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.5, 161.7 (d, 1JC-F = 246 Hz), 160.2, 156.1, 143.7 (d, 3JC-F = 10
Hz), 142.9, 138.4, 137.3, 130.6, 129.8, 129.5, 129.0, 128.4 (d, 3JC-F = 9 Hz), 128.0, 127.8, 127.7, 125.6, 120.0, 116.8
(d, 2JC-F = 23 Hz), 112.7, 112.4 (d, 2JC-F = 21 Hz), 107.8, 74.6, 62.5, 55.3, 14.1; IR (neat): 3058, 2928, 1731, 1552,
1487, 1340, 1219, 1031 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C30H26FN2O3 481.1927; Found 481.1930.
Ethyl 7-methoxy-3-(p-methoxyphenyl)-2,4-diphenyl-3,4-dihydroquinazoline-4-carboxylate (4o). Prepared
according to the general 3,4-DHQ synthesis protocol with 1 (0.228 g, 1.00 mmol), p-anisidine (0.136 g, 1.1 mmol),
ethyl benzoylformate (0.18 g, 1.1 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.11 mL, 1.2 mmol), and Tf2O (0.18
mL, 1.1 mmol). Following workup, the residue was purified by flash chromatography (30% EtOAc in hexanes as
eluent) to afford the desired product (0.454 g, 92%) as a solid (m.p. = 74 - 76 °C). 1H NMR (400 MHz, CDCl3, heated
to 330 K) δ 7.63 – 7.56 (m, 2H), 7.23 – 7.17 (m, 2H), 7.16 – 7.03 (m, 6H), 6.92 (d, J = 2.6 Hz, 1H), 6.73 (broad s,
2H), 6.65 (d, J = 8.6 Hz, 1H), 6.58 (dd, J = 8.7, 2.6 Hz, 1H), 6.29 (d, J = 9.3 Hz, 2H), 4.29 (qq, J = 6.9, 3.7 Hz, 2H),
3.78 (s, 3H), 3.46 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.4, 160.3, 157.2, 156.8,
143.5, 139.1, 138.0, 135.2, 131.0, 130.8, 129.7, 129.5, 128.5, 127.7, 127.5, 127.5, 119.8, 112.9, 112.3, 108.0, 74.8,
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[M+H]+ Calcd for C31H28N2O4 493.2127; Found 493.2125.
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Ethyl 3-benzyl-4-(p-fluorophenyl)-7-methoxy-2-phenyl-3,4-dihydroquinazoline-4-carboxylate (4p). Prepared
according to the general 3,4-DHQ synthesis protocol with 1 (0.227 g, 1.00 mmol), benzylamine (0.12 mL, 1.1 mmol),
ethyl 4-fluorobenzoylformate (0.18 mL, 1.1 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.11 mL, 1.2 mmol), and
Tf2O (0.18 mL, 1.1 mmol). Following workup, the residue was purified by flash chromatography (100:5:2
CH2Cl2:ether:MeOH as eluent) to afford the desired product (0.366 g, 74%) as a solid (m.p. = 163 - 165 °C). 1H NMR
(400 MHz, CDCl3) δ 7.60 – 7.50 (m, 2H), 7.31 – 7.22 (m, 5H), 7.01 – 6.89 (m, 3H), 6.85 (d, J = 2.7 Hz, 1H), 6.77 (t,
J = 8.6 Hz, 2H), 6.69 (d, J = 8.7 Hz, 1H), 6.58 (dt, J = 8.8, 2.2 Hz, 3H), 4.86 (d, J = 17.0 Hz, 1H), 4.39 – 4.21 (m,
2H), 3.94 (d, J = 17.0 Hz, 1H), 3.79 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.1, 162.4
(d, 1JC-F = 249 Hz), 160.4, 159.5, 143.4, 138.8, 137.5, 135.6 (d, 4JC-F = 3 Hz), 132.6 (d, 3JC-F = 8 Hz), 130.4, 128.8,
128.3, 127.8, 127.7, 126.3, 126.0, 118.3, 114.5 (d, 2JC-F = 22 Hz), 112.2, 107.6, 73.6, 62.4, 55.3, 52.3, 14.2; IR (neat):
3058, 2937, 1730, 1552, 1489, 1221, 1163, 1033 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C31H28FN2O3
495.2084; Found 495.2078.
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Ethyl 3-benzyl-7-methoxy-4-(p-methoxyphenyl)-2-phenyl-3,4-dihydroquinazoline-4-carboxylate (4q). Prepared
according to the general 3,4-DHQ synthesis protocol with 1 (0.227 g, 1.00 mmol), benzylamine (0.12 mL, 1.1 mmol),
ethyl 4-methoxybenzoylformate28 (0.227 g, 1.1 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.11 mL, 1.2 mmol), and
Tf2O (0.18 mL, 1.1 mmol). Following workup, the residue was purified by flash chromatography (100:3:1
CH2Cl2:ether:MeOH as eluent) followed by additional flash chromatography (85:15:3 hexanes:EtOAC:TEA as eluent)
to afford the desired product (0.183 g, 36%) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.54 – 7.46 (m, 2H), 7.28 – 7.17
(m, 5H), 7.01 – 6.87 (m, 3H), 6.84 (d, J = 2.7 Hz, 1H), 6.75 (d, J = 8.7 Hz, 1H), 6.67 – 6.55 (m, 5H), 4.79 (d, J = 16.9
Hz, 1H), 4.42 – 4.19 (m, 2H), 3.99 (d, J = 16.9 Hz, 1H), 3.80 (s, 3H), 3.71 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 172.6, 160.2, 159.5, 159.5, 143.4, 139.1, 137.6, 131.9, 131.6, 130.6, 128.6, 128.1, 127.8,
127.6, 126.1, 126.1, 118.7, 113.0, 112.0, 107.3, 73.7, 62.2, 55.3, 55.2, 52.1, 14.2; IR (neat): 2922, 1730, 1552, 1489,
1256, 1034 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C32H31N2O4 507.2284; Found 507.2278.
Ethyl
3-benzyl-7-methoxy-2-phenyl-4-(2,4-xylyl)-3,4-dihydroquinazoline-4-carboxylate
(4r).
Prepared
according to the general 3,4-DHQ synthesis protocol with 1 (0.228 g, 1.00 mmol), benzylamine (0.12 mL, 1.1 mmol),
ethyl 2,4-dimethylbenzoylformate28 (0.227 g, 1.1 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.11 mL, 1.2 mmol),
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and Tf2O (0.18 mL, 1.1 mmol). Following workup, the residue was purified by flash chromatography (100:5:2
CH2Cl2:ether:MeOH as eluent) followed by additional flash chromatography (30% EtOAc in hexanes as eluent) to
afford the desired product (0.277 g, 55%) as a solid (m.p. = 146 - 149 °C). 1H NMR (400 MHz, CDCl3) δ 7.70 – 7.63
(m, 2H), 7.38 – 7.24 (m, 3H), 7.14 (d, J = 7.9 Hz, 1H), 7.01 – 6.89 (m, 2H), 6.85 (t, J = 7.4 Hz, 2H), 6.76 (dd, J = 5.7,
3.0 Hz, 2H), 6.56 – 6.47 (m, 2H), 6.44 (d, J = 6.8 Hz, 2H), 4.94 (d, J = 16.3 Hz, 1H), 4.42 – 4.20 (m, 2H), 3.97 (d, J
= 16.4 Hz, 1H), 3.76 (s, 3H), 2.21 (s, 3H), 1.71 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
172.5, 160.1, 160.0, 142.3, 139.8, 138.6, 138.0, 137.8, 134.4, 133.7, 130.7, 129.7, 128.7, 128.4, 128.1, 127.3, 127.0,
126.2, 125.8, 118.5, 112.2, 107.5, 74.5, 62.2, 55.2, 52.7, 22.3, 20.8, 14.1; IR (neat): 3034, 2928, 1728, 1552, 1489,
1215, 1148, 1031 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C33H33N2O3 505.2491; Found 505.2492.
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Ethyl
3-benzyl-7-methoxy-2-phenyl-4-(2-thienyl)-3,4-dihydroquinazoline-4-carboxylate
(4s).
Prepared
according to the general 3,4-DHQ synthesis protocol with 1 (0.229 g, 1.01 mmol), benzylamine (0.12 mL, 1.1 mmol),
ethyl thiophene-2-glyoxylate28 (0.204 g, 1.1 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.11 mL, 1.2 mmol), and
Tf2O (0.18 mL, 1.1 mmol). Following workup, the residue was purified by flash chromatography (100:5:1
CH2Cl2:ether:MeOH as eluent) followed by additional flash chromatography (85:15:5 cyclohexane:EtOAc:TEA) to
afford the desired product (25.3 mg, 5%) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.32 (m, 2H), 7.26 (dd, J =
5.1, 1.2 Hz, 1H), 7.24 – 7.16 (m, 3H), 7.10 (dd, J = 3.7, 1.2 Hz, 1H), 7.01 – 6.96 (m, 3H), 6.94 (d, J = 8.7 Hz, 1H),
6.87 (dd, J = 5.1, 3.7 Hz, 1H), 6.83 (d, J = 2.7 Hz, 1H), 6.78 – 6.72 (m, 2H), 6.62 (dd, J = 8.7, 2.7 Hz, 1H), 4.69 (d, J
= 16.8 Hz, 1H), 4.38 – 4.16 (m, 3H), 3.81 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.2,
160.5, 159.1, 144.5, 142.5, 138.6, 137.5, 130.1, 129.8, 128.5, 128.0, 127.7, 127.6, 127.5, 126.6, 126.3, 125.9, 118.4,
112.3, 107.7, 71.0, 62.6, 55.3, 52.2, 14.1; IR (neat): 3062, 2939, 1731, 1586, 1554, 1489, 1444, 1383, 1217, 1154,
1031 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C29H27N2O3S 483.1742; Found 483.1746.
Ethyl 7-methoxy-3-(p-methoxyphenyl)-2-phenyl-4-(2-thienyl)-3,4-dihydroquinazoline-4-carboxylate (4t).
Prepared according to the general 3,4-DHQ synthesis protocol with 1 (0.228 g, 1.00 mmol), p-anisidine (0.137 g, 1.11
mmol), ethyl thiophene-2-glyoxylate28 (0.202 g, 1.10 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.11 mL, 1.2 mmol),
and Tf2O (0.18 mL, 1.1 mmol). Following workup, the residue was purified by MPLC (30% - 50% EtOAc in hexanes
as eluent) to afford the desired product (0.251 g, 50%) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.56 – 7.50 (m, 2H),
7.20 – 7.11 (m, 4H), 7.02 – 6.98 (m, 2H), 6.90 (d, J = 8.7 Hz, 1H), 6.86 – 6.70 (m, 3H), 6.63 (dd, J = 8.7, 2.6 Hz, 1H),
6.41 (d, J = 8.9 Hz, 2H), 4.31 – 4.13 (m, 2H), 3.81 (s, 3H), 3.57 (s, 3H), 1.17 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101
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MHz, CDCl3) δ 170.8, 160.5, 157.5, 156.6, 143.7, 141.6, 136.8, 134.7, 130.2, 130.0, 129.4, 128.9, 128.7, 127.8, 127.5,
125.7, 118.7, 113.0, 112.8, 107.7, 71.4, 62.7, 55.4, 55.1, 14.0; IR (neat): 3060, 2960, 1735, 1651, 1508, 1489, 1351,
1247, 1033 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C29H27N2O4S 499.1692; Found 499.1689.
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Ethyl 3-benzyl-7-methoxy-4-methyl-2-phenyl-3,4-dihydroquinazoline-4-carboxylate (4u). Prepared according to
the general 3,4-DHQ synthesis protocol with 1 (0.227 g, 1.00 mmol), benzylamine (0.12 mL, 1.1 mmol), ethyl
pyruvate (0.12 mL, 1.1 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.11 mL, 1.2 mmol), and Tf2O (0.18 mL, 1.1
mmol). Following workup, the residue was purified by MPLC (40% - 65% EtOAc in hexanes as eluent) to afford the
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desired product (0.091 g, 22%) as an oil. H NMR (400 MHz, CDCl3) δ 7.49 – 7.44 (m, 2H), 7.31 – 7.27 (m, 3H),
7.23 – 7.12 (m, 4H), 7.06 (dd, J = 8.0, 1.4 Hz, 2H), 6.82 (d, J = 2.7 Hz, 1H), 6.68 (dd, J = 8.6, 2.7 Hz, 1H), 4.81 (d, J
= 17.6 Hz, 1H), 4.29 (d, J = 17.6 Hz, 1H), 4.16 (qd, J = 7.1, 5.5 Hz, 2H), 3.80 (s, 3H), 1.84 (s, 3H), 1.23 (t, J = 7.1
Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.9, 160.3, 160.2, 142.8, 139.6, 137.3, 128.8, 128.4, 128.3, 127.5,
126.8, 125.9, 125.8, 118.1, 112.3, 108.5, 65.6, 62.0, 55.3, 52.0, 24.3, 14.1; IR (neat): 3056, 2980, 1728, 1552, 1489,
1226, 1144, 1100, 1027 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H27N2O3 415.2022; Found 415.2024.
Ethyl 3-benzyl-7-methoxy-2-phenyl-4-propyl-3,4-dihydroquinazoline-4-carboxylate (4v). Prepared according to
the general 3,4-DHQ synthesis protocol with 1 (0.228 g, 1.01 mmol), benzylamine (0.12 mL, 1.1 mmol), ethyl 2-
oxovalerate (0.16 mL, 1.1 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.11 mL, 1.2 mmol), and Tf2O (0.18 mL, 1.1
mmol). Following workup, the residue was purified by MPLC (30% - 55% EtOAc in hexanes as eluent) to afford the
desired product (0.170 g, 37%) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.35 (dd, J = 6.6, 3.0 Hz, 2H), 7.25 – 7.18
(m, 3H), 7.15 – 7.03 (m, 5H), 6.88 (d, J = 8.6 Hz, 1H), 6.78 (d, J = 2.7 Hz, 1H), 6.63 (dd, J = 8.5, 2.7 Hz, 1H), 4.43
(s, 2H), 4.07 (dq, J = 10.8, 7.1 Hz, 1H), 3.87 (dq, J = 10.8, 7.1 Hz, 1H), 3.77 (s, 3H), 2.30 – 2.10 (m, 2H), 1.56 – 1.28
(m, 2H), 1.12 (t, J = 7.1 Hz, 3H), 0.78 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.2, 160.0, 159.2,
142.8, 137.8, 137.5, 128.5, 128.2, 127.9, 127.5, 127.1, 126.9, 125.5, 116.1, 112.4, 108.6, 70.4, 61.8, 55.2, 52.2, 39.7,
16.9, 14.0, 13.8; IR (neat): 3062, 2928, 1728, 1554, 1493, 1232, 1142, 1031 cm-1; HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C28H31N2O3 443.2335; Found 443.2337.
Ethyl
3-benzyl-4-isopropyl-7-methoxy-2-phenyl-3,4-dihydroquinazoline-4-carboxylate
(4w).
Prepared
according to the general 3,4-DHQ synthesis protocol with 1 (0.228 g, 1.00 mmol), benzylamine (0.12 mL, 1.1 mmol),
ethyl dimethylpyruvate (0.16 mL, 1.1 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.11 mL, 1.2 mmol), and Tf2O (0.18
mL, 1.1 mmol). Following workup, the residue was purified by MPLC (14% - 35% EtOAc in hexanes as eluent) to
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afford the desired product (0.092 g, 21%) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.31 – 7.23 (m, 2H), 7.22 – 7.12
(m, 3H), 7.10 – 6.97 (m, 5H), 6.84 (d, J = 2.7 Hz, 1H), 6.76 (d, J = 8.6 Hz, 1H), 6.65 (dd, J = 8.6, 2.7 Hz, 1H), 4.84
(d, J = 17.1 Hz, 1H), 4.26 (d, J = 17.2 Hz, 1H), 4.02 (dq, J = 10.8, 7.1 Hz, 1H), 3.81 (s, 3H), 3.70 (dq, J = 10.9, 7.2
Hz, 1H), 2.73 (hept, J = 6.8 Hz, 1H), 1.25 (d, J = 6.8 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H), 0.97 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 170.9, 159.9, 158.9, 143.1, 138.1, 137.2, 128.7, 128.0, 127.8, 127.6, 126.8, 126.6,
126.3, 115.5, 111.9, 108.4, 74.0, 61.7, 55.2, 54.4, 39.3, 18.5, 17.5, 13.6; IR (neat): 3058, 2928, 1730, 1552, 1491,
1226, 1036 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C28H31N2O3 443.2335; Found 443.2328.
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Ethyl 3-benzyl-7-methoxy-2-phenyl-4-(tert-butyl)-3,4-dihydroquinazoline-4-carboxylate (4x). Prepared
according to the general 3,4-DHQ synthesis protocol with 1 (0.227 g, 1.00 mmol), benzylamine (0.12 mL, 1.1 mmol),
ethyl 3,3-dimethyl-2-oxobutanoate29 (0.178 g, 1.1 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.11 mL, 1.2 mmol),
and Tf2O (0.18 mL, 1.1 mmol). Following workup, the residue was purified by flash chromatography (100:3:1
CH2Cl2:ether:MeOH as eluent) to afford the desired product (0.015 g, 3%) as an oil. 1H NMR (400 MHz, CDCl3) δ
7.36 – 7.31 (m, 2H), 7.21 – 7.13 (m, 3H), 7.05 – 6.99 (m, 3H), 6.93 – 6.86 (m, 3H), 6.71 – 6.68 (m, 2H), 5.05 (d, J =
17.6 Hz, 1H), 4.16 (d, J = 17.6 Hz, 1H), 4.04 (dq, J = 10.8, 7.1 Hz, 1H), 3.84 (s, 3H), 3.62 (dq, J = 10.9, 7.2 Hz, 1H),
1.26 (s, 9H), 0.87 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.3, 159.7, 158.8, 143.5, 138.4, 136.9,
129.0, 128.3, 127.92, 127.91, 127.7, 126.6, 126.4, 115.5, 111.4, 108.2, 76.2, 61.3, 56.9, 55.3, 45.1, 26.3, 13.3; IR
(neat): 2926, 1733, 1551, 1491, 1210, 1154, 1034 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C29H33N2O3
457.2491; Found 457.2495.
tert-Butyl 3-benzyl-7-methoxy-2,4-diphenyl-3,4-dihydroquinazoline-4-carboxylate (4y). Prepared according to
the general 3,4-DHQ synthesis protocol with 1 (0.227 g, 1.00 mmol), benzylamine (0.12 mL, 1.1 mmol), tert-butyl
benzoylformate30 (0.227 g, 1.1 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.10 mL, 1.2 mmol), and Tf2O (0.18 mL,
1.1 mmol). Following workup, the residue was purified by flash chromatography (100:5:1 CH2Cl2:ether:MeOH as
eluent) to afford the desired product (0.455 g, 90%) as a solid (m.p. = 147 - 150 °C). 1H NMR (400 MHz, CDCl3) δ
7.54 – 7.47 (m, 2H), 7.40 – 7.35 (m, 2H), 7.26 – 7.21 (m, 3H), 7.19 – 7.10 (m, 3H), 6.97 – 6.87 (m, 3H), 6.84 (d, J =
2.7 Hz, 1H), 6.67 (d, J = 8.7 Hz, 1H), 6.59 – 6.53 (m, 3H), 4.80 (d, J = 17.0 Hz, 1H), 4.00 (d, J = 16.9 Hz, 1H), 3.81
(s, 3H), 1.45 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.3, 160.0, 159.5, 143.3, 140.0, 139.1, 137.6, 130.8,
130.7, 128.5, 128.3, 128.0, 127.8, 127.6, 127.5, 126.1, 126.0, 119.0, 111.8, 107.1, 83.2, 74.6, 55.3, 52.2, 28.0; IR
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(neat): 3062, 2976, 1726, 1554, 1489, 1265, 1241, 1154, 1034 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C33H33N2O3 505.2491; Found 505.2488.
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Diethyl 3-benzyl-7-methoxy-2-phenyl-3,4-dihydroquinazoline-4,4-dicarboxylate (4z). Prepared according to the
general 3,4-DHQ synthesis protocol with 1 (0.227 g, 1.00 mmol), benzylamine (0.12 mL, 1.1 mmol), diethyl
ketomalonate (0.17 mL, 1.1 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.10 mL, 1.2 mmol), and Tf2O (0.18 mL, 1.1
mmol). Following workup, the residue was purified by flash chromatography (25% EtOAc in hexanes as eluent) to
afford the desired product (0.382 g, 81%) as a solid (m.p. = 141 - 143 °C). 1H NMR (400 MHz, CDCl3) δ 7.43 – 7.38
(m, 2H), 7.28 – 7.22 (m, 3H), 7.15 – 7.07 (m, 3H), 7.06 – 6.99 (m, 3H), 6.84 (d, J = 2.6 Hz, 1H), 6.72 (dd, J = 8.7,
2.7 Hz, 1H), 4.67 (s, 2H), 4.17 (dq, J = 10.8, 7.1 Hz, 2H), 3.93 (dq, J = 10.8, 7.1 Hz, 2H), 3.79 (s, 3H), 1.15 (t, J = 7.1
Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 168.9, 160.6, 158.4, 142.1, 137.7, 136.5, 128.9, 128.4, 128.2, 128.0,
127.6, 126.8, 126.7, 113.2, 112.7, 108.2, 74.5, 62.6, 55.3, 53.7, 13.8; IR (neat): 3064, 2880, 1735, 1558, 1493, 1254,
1224, 1034 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C28H29N2O5 473.2076; Found 473.2072.
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1-(3-Benzyl-7-methoxy-4-methyl-2-phenyl-3,4-dihydroquinazolin-4-yl)-1-ethanone (5a). Prepared according to
the general 3,4-DHQ synthesis protocol with 1 (0.227 g, 1.00 mmol), benzylamine (0.12 mL, 1.1 mmol), 2,3-
butanedione (0.10 mL, 1.1 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.11 mL, 1.2 mmol), and Tf2O (0.18 mL, 1.1
mmol). Following workup, the residue was purified by MPLC (50% - 70% EtOAc in hexanes as eluent) to afford the
desired product (0.220 g, 57%) as a solid (m.p. = 147 - 149 °C). 1H NMR (400 MHz, CDCl3) δ 7.59 – 7.44 (m, 2H),
7.29 (t, J = 3.2 Hz, 3H), 7.15 (dt, J = 13.4, 6.6 Hz, 3H), 7.01 (t, J = 7.7 Hz, 3H), 6.86 (d, J = 2.7 Hz, 1H), 6.69 (dd, J
= 8.5, 2.7 Hz, 1H), 4.83 (d, J = 17.5 Hz, 1H), 4.23 (d, J = 17.5 Hz, 1H), 3.78 (s, 3H), 2.14 (s, 3H), 1.70 (s, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 205.9, 160.7, 160.6, 143.4, 139.5, 137.1, 129.1, 128.5, 128.4, 127.7, 127.0, 125.8,
125.4, 117.6, 112.5, 109.0, 70.2, 55.3, 51.7, 24.6, 21.9, IR (neat): 3058, 2954, 1713, 1549, 1485, 1275, 1146, 1068,
1029 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C25H25N2O2 385.1916; Found 385.1912.
1-(3-Benzyl-7-methoxy-4-methyl-2-phenyl-3,4-dihydroquinazolin-4-yl)-1-butanone (5b). Prepared according to
the general 3,4-DHQ synthesis protocol with 1 (0.227 g, 1.00 mmol), benzylamine (0.12 mL, 1.1 mmol), 2,3-
hexanedione (0.14 mL, 1.1 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.11 mL, 1.2 mmol), and Tf2O (0.18 mL, 1.1
mmol). Following workup, the residue was purified by MPLC (0% - 20% EtOAc in hexanes as eluent) to afford the
desired product (0.165 g, 40%) as a solid (m.p. = 117 - 119 °C). 1H NMR (400 MHz, CDCl3) δ 7.59 – 7.49 (m, 2H),
7.35 – 7.28 (m, 3H), 7.23 – 7.12 (m, 3H), 7.08 – 6.97 (m, 3H), 6.85 (d, J = 2.7 Hz, 1H), 6.69 (dd, J = 8.6, 2.7 Hz, 1H),
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4.86 (d, J = 17.5 Hz, 1H), 4.22 (d, J = 17.5 Hz, 1H), 3.81 (s, 3H), 2.53 (ddd, J = 17.2, 7.8, 6.8 Hz, 1H), 2.40 (ddd, J =
17.2, 7.6, 6.5 Hz, 1H), 1.70 (s, 3H), 1.57 – 1.43 (m, 2H), 0.77 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3)
δ 208.5, 160.8, 160.5, 143.6, 139.7, 137.1, 129.1, 128.5, 128.4, 127.8, 126.9, 125.8, 125.4, 117.6, 112.4, 108.8, 70.0,
55.4, 51.7, 38.4, 21.9, 17.6, 13.6; IR (neat): 3058, 2924, 1713, 1552, 1489, 1273, 1146, 1029 cm-1; HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C27H29N2O2 413.2229; Found 413.2230.
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(3-Benzyl-7-methoxy-2,4-diphenyl-3,4-dihydroquinazolin-4-yl)phenylformaldehyde (5c). Prepared according to
the general 3,4-DHQ synthesis protocol with 1 (0.228 g, 1.00 mmol), benzylamine (0.12 mL, 1.1 mmol), benzil (0.233
g, 1.1 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.11 mL, 1.2 mmol), and Tf2O (0.18 mL, 1.1 mmol). Following
workup, the residue was purified by MPLC (25% - 50% EtOAc in hexanes as eluent) to afford the desired product
(0.108 g, 21%) as a solid (m.p. = 118 - 120 °C). 1H NMR (400 MHz, CDCl3) δ 7.67 – 7.60 (m, 2H), 7.50 – 7.43 (m,
2H), 7.43 – 7.34 (m, 3H), 7.31 – 7.16 (m, 8H), 6.94 – 6.88 (m, 1H), 6.88 – 6.81 (m, 4H), 6.50 (dd, J = 8.8, 2.7 Hz,
1H), 6.37 (d, J = 7.3 Hz, 2H), 4.65 (d, J = 16.9 Hz, 1H), 4.03 (d, J = 16.9 Hz, 1H), 3.75 (s, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 198.9, 160.3, 159.9, 144.5, 138.7, 138.7, 137.5, 137.2, 131.7, 131.4, 129.7, 129.2, 128.9, 128.6, 128.1,
128.0, 127.9, 127.8, 127.5, 126.1, 126.0, 116.1, 112.1, 108.2, 78.5, 55.2, 52.7, IR (neat): 3062, 2932, 1679, 1582,
1549, 1487, 1277, 1156, 1033 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C35H29N2O2 509.2229; Found
509.2224.
3'-Benzyl-7'-methoxy-2'-phenyl-3'H-spiro[acenaphthene-1,4'-quinazolin]-2-one (5d). Prepared according to the
general 3,4-DHQ synthesis protocol with 1 (0.227 g, 1.00 mmol), benzylamine (0.12 mL, 1.1 mmol),
acenaphthoquinone (0.201 g, 1.10 mmol), CH2Cl2 (5.0 mL), 2-chloropyridine (0.11 mL, 1.2 mmol), and Tf2O (0.18
mL, 1.1 mmol). Following workup, the residue was purified by MPLC (45% - 65% EtOAc in hexanes as eluent) to
afford the desired product (0.170 g, 35%) as a solid (m.p. = 126 - 129 °C). 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J =
8.2 Hz, 1H), 7.95 (d, J = 7.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.73 (dd, J = 8.1, 7.0 Hz, 1H), 7.59 – 7.45 (m, 4H),
7.31 – 7.23 (m, 3H), 7.01 – 6.88 (m, 4H), 6.71 (d, J = 7.0 Hz, 2H), 6.30 (dd, J = 8.6, 2.7 Hz, 1H), 5.84 (d, J = 8.6 Hz,
1H), 4.25 (d, J = 16.4 Hz, 1H), 3.99 (d, J = 16.4 Hz, 1H), 3.72 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 201.7,
160.3, 159.5, 143.0, 142.0, 139.0, 137.6, 137.2, 132.0, 130.21, 130.16, 129.1, 128.8, 128.6, 128.3, 127.8, 127.5, 127.0,
126.9, 126.1, 125.7, 116.9, 112.1, 109.4, 73.1, 55.3, 52.5; IR (neat): 3027, 2926, 1724, 1552, 1489, 1344, 1275, 1150,
1031 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C33H25N2O2 481.1916; Found 481.1920.
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Ethyl 7-methoxy-2,4-diphenyl-3,4-dihydroquinazoline-4-carboxylate (6). Prepared according to the general 3,4-
DHQ debenzylation protocol with 2 (2.182 g, 4.58 mmol), EtOH (8 mL), cyclohexene (20 mL), and 10% Pd/C (0.621
g). After workup, the residue was triturated with ether, and the solid was collected by filtration to afford the desired
product (1.634 g, 92%) as a solid (m.p. = 159 - 161 °C). 1H NMR (400 MHz, CDCl3) δ 7.96 – 7.89 (m, 2H), 7.52 –
7.32 (m, 8H), 6.95 (d, J = 8.6 Hz, 1H), 6.91 (d, J = 2.7 Hz, 1H), 6.62 (dd, J = 8.6, 2.7 Hz, 1H), 6.13 (s, 1H), 4.42 –
4.20 (m, 2H), 3.83 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.7, 160.2, 153.7, 143.8,
143.0, 135.2, 130.9, 129.5, 128.7, 128.6, 128.4, 127.5, 127.0, 116.2, 112.1, 108.6, 66.7, 62.4, 55.3, 14.2; IR (neat):
3358, 3060, 2976, 1728, 1593, 1560, 1465, 1208, 1103, 1023 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C24H23N2O3 387.1709; Found 387.1715.
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Ethyl 1-benzyl-7-methoxy-2,4-diphenyl-1,4-dihydroquinazoline-4-carboxylate (7). Prepared according to the
general 1,4-DHQ synthesis protocol with 6 (83.3 mg, 0.22 mmol), benzyl bromide (29 µL, 0.29 mmol), NaH (11.0
mg, 0.28 mmol), and DMF (1.5 mL). After workup, the residue was purified by MPLC (31% - 52% EtOAc in hexanes
as eluent) to afford the desired product (79.4 mg, 78%) as a solid (m.p. = 112 - 114 °C). 1H NMR (400 MHz, CDCl3)
δ 7.53 – 7.45 (m, 2H), 7.41 – 7.25 (m, 8H), 7.12 – 6.98 (m, 4H), 6.75 (d, J = 7.6 Hz, 2H), 6.61 (dd, J = 8.6, 2.4 Hz,
1H), 6.48 (d, J = 2.5 Hz, 1H), 4.79 (s, 2H), 4.35 (dq, J = 10.7, 7.1 Hz, 1H), 4.22 (dq, J = 10.8, 7.1 Hz, 1H), 3.70 (s,
3H), 1.26 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 173.1, 159.5, 155.9, 144.3, 138.5, 136.8, 135.8,
129.5, 128.8, 128.8, 128.4, 127.9, 127.9, 127.14, 127.10, 126.5, 116.8, 108.2, 100.6, 69.2, 61.8, 55.2, 51.2, 14.2; IR
(neat): 3058, 2924, 1728, 1612, 1504, 1366, 1210, 1029 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C31H29N2O3
477.2178; Found 477.2174.
Ethyl 6-fluoro-7-methoxy-2,4-diphenyl-3,4-dihydroquinazoline-4-carboxylate (8a). Prepared according to the
general 3,4-DHQ debenzylation protocol with 4c (0.135 g, 0.41 mmol), EtOH (2 mL), cyclohexene (4 mL), and 10%
Pd/C (0.094 g). The reaction mixture was passed through a silica plug (10% MeOH in EtOAc as eluent) instead of a
celite plug, and the concentrated filtrate was purified by MPLC (10% ether in CH2Cl2 as eluent) to afford the desired
product (0.082 g, 74%) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.91 (dd, J = 7.9, 1.8 Hz, 2H), 7.50 – 7.32 (m, 8H),
6.98 (d, J = 8.2 Hz, 1H), 6.79 (d, J = 12.0 Hz, 1H), 6.13 (s, 1H), 4.39 – 4.21 (m, 2H), 3.90 (s, 3H), 1.27 (t, J = 7.1 Hz,
3H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.4, 153.2 (d, 6JC-F = 2 Hz), 149.7 (d, 1JC-F = 243 Hz), 148.1 (d, 2JC-F = 12
Hz), 142.4, 139.4 (d, 3JC-F = 3 Hz), 135.0, 130.9, 128.8, 128.7, 128.6, 127.3, 126.9, 115.7 (d, 3JC-F = 7 Hz), 115.6 (d,
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2JC-F = 21 Hz), 109.5 (d, JC-F = 2 Hz), 66.4 (d, JC-F = 2 Hz), 62.6, 56.1, 14.1; IR (neat): 3379, 3060, 2976, 1731,
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1599, 1497, 1476, 1444, 1228, 1094 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H22FN2O3 405.1614; Found
405.1612.
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Ethyl 1-benzyl-6-fluoro-7-methoxy-2,4-diphenyl-1,4-dihydroquinazoline-4-carboxylate (9a). Prepared according
to the general 1,4-DHQ synthesis protocol with 8a (65.5 mg, 0.16 mmol), benzyl bromide (25 µL, 0.21 mmol), NaH
(8.0 mg, 0.20 mmol), and DMF (2.0 mL). After workup, the residue was purified by MPLC (32% - 53% EtOAc in
hexanes as eluent) to afford the desired product (57.5 mg, 72%) as a solid (m.p. = 189 - 192 °C). 1H NMR (400 MHz,
CDCl3) δ 7.57 – 7.50 (m, 2H), 7.43 – 7.27 (m, 8H), 7.15 – 7.07 (m, 3H), 6.85 (d, J = 11.7 Hz, 1H), 6.79 (dd, J = 7.8,
1.8 Hz, 2H), 6.51 (d, J = 7.4 Hz, 1H), 4.82 (s, 2H), 4.34 (dq, J = 10.8, 7.1 Hz, 1H), 4.23 (dq, J = 10.8, 7.1 Hz, 1H),
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3.73 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.7, 156.0, 148.8 (d, JC-F = 242 Hz),
147.1 (d, 2JC-F = 12 Hz), 143.7, 136.6, 135.6, 133.8 (d, 3JC-F = 3 Hz), 129.7, 128.9, 128.6, 128.5, 128.1, 127.8, 127.4,
127.3, 126.6, 116.5 (d, 3JC-F = 6 Hz), 115.5 (d, 2JC-F = 21 Hz), 100.4 (d, 4JC-F = 2 Hz), 69.0, 61.9, 56.3, 51.7, 14.2; IR
(neat): 3062, 2935, 1728, 1621, 1515, 1448, 1221, 1031 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C31H28FN2O3
495.2084; Found 495.2089.
Ethyl 7-methoxy-2-methyl-4-phenyl-1,4-dihydroquinazoline-4-carboxylate (8b). Prepared according to the
general 3,4-DHQ debenzylation protocol with 4e (0.195 g, 0.47 mmol), EtOH (3 mL), cyclohexene (4 mL), and 10%
Pd/C (0.098 g). After workup, the residue was purified by MPLC (8% - 35% MeOH in EtOAc as eluent) to afford
the desired product (0.128 g, 84%) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.43 – 7.28 (m, 5H), 6.94 (d, J = 8.6 Hz,
1H), 6.69 (s, 1H), 6.57 (dd, J = 8.6, 2.7 Hz, 1H), 5.63 (broad s, 1H), 4.36 – 4.18 (m, 2H), 3.79 (s, 3H), 2.17 (s, 3H),
1.26 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 172.1, 160.3, 154.8, 142.8, 140.9, 129.8, 128.6, 128.4,
127.4, 114.0, 111.9, 106.1, 66.7, 62.5, 55.4, 21.7, 14.1; IR (neat): 3351, 2978, 1731, 1593, 1484, 1204, 1219, 1124,
1021 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C19H21N2O3 325.1552; Found 325.1557.
Ethyl 1-benzyl-7-methoxy-2-methyl-4-phenyl-1,4-dihydroquinazoline-4-carboxylate (9b). Prepared according to
the general 1,4-DHQ synthesis protocol with 8b (70.0 mg, 0.22 mmol), benzyl bromide (33 µL, 0.28 mmol), NaH
(10.5 mg, 0.26 mmol), and DMF (2.0 mL). After workup, the residue was purified by MPLC (0% - 1% MeOH in
EtOAc as eluent) to afford the desired product (73.2 mg, 82%) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.34 – 7.18
(m, 8H), 7.06 – 6.97 (m, 3H), 6.55 (dd, J = 8.6, 2.4 Hz, 1H), 6.28 (d, J = 2.5 Hz, 1H), 4.93 (d, J = 2.7 Hz, 2H), 4.28
(qq, J = 10.8, 7.1 Hz, 2H), 3.63 (s, 3H), 2.27 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
173.1, 159.6, 153.0, 144.4, 138.4, 136.5, 129.1, 128.9, 127.8, 127.7, 127.3, 127.0, 125.8, 115.5, 107.4, 99.8, 68.6,
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61.7, 55.2, 49.4, 22.4, 14.1; IR (neat): 3056, 2973, 1726, 1636, 1610, 1504, 1383, 1288, 1206, 1027 cm-1; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C26H27N2O3 415.2022; Found 415.2019.
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Diethyl 7-methoxy-2-phenyl-3,4-dihydroquinazoline-4,4-dicarboxylate (8c). Prepared according to the general
3,4-DHQ debenzylation protocol with 4z (0.205 g, 0.437 mmol), EtOH (2 mL), cyclohexene (4 mL), and 10% Pd/C
(0.0.97 g). After workup, the residue was purified by MPLC (30% - 50% EtOAc in hexanes as eluent) to afford the
desired product (0.128 g, 84%) as an oil. 1H NMR (400 MHz, CDCl3, 330 K) δ 7.89 (broad s, 2H), 7.64 – 7.30 (m,
4H), 6.88 (broad s, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.32 (broad s, 1H), 4.27 (qd, J = 7.1, 2.4 Hz, 4H), 3.79 (s, 3H), 1.27
(t, J = 7.1 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 168.9, 161.0, 152.7, 143.9, 135.2, 130.9, 128.7, 126.9, 112.2,
109.9, 66.7, 62.8, 55.4, 14.0; IR (neat): 3353, 3060, 2980, 1730, 1620, 1478, 1249, 1210, 1049 cm-1; HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C21H23N2O5 383.1607; Found 383.1612.
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Diethyl 1-benzyl-7-methoxy-2-phenyl-1,4-dihydroquinazoline-4,4-dicarboxylate (9c). Prepared according to the
general 1,4-DHQ synthesis protocol with 8c (81.0 mg, 0.21 mmol), benzyl bromide (33 µL, 0.28 mmol), NaH (10.2
mg, 0.26 mmol), and DMF (2.0 mL). After workup, the residue was purified by MPLC (45% - 70% EtOAc in hexanes
as eluent) to afford the desired product (90.0 mg, 90%) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.55 – 7.47 (m, 2H),
7.40 – 7.30 (m, 4H), 7.27 – 7.08 (m, 5H), 6.64 (dd, J = 8.7, 2.4 Hz, 1H), 6.37 (d, J = 2.5 Hz, 1H), 4.82 (s, 2H), 4.28
(q, J = 7.1 Hz, 4H), 3.65 (s, 3H), 1.29 (t, J = 7.1 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 169.6, 160.1, 156.8,
138.0, 136.8, 135.9, 129.7, 129.6, 128.6, 128.48, 128.45, 127.3, 126.3, 111.4, 108.7, 100.8, 70.7, 62.0, 55.2, 51.3,
14.1; IR (neat): 2983, 1733, 1616, 1508, 1374, 1269, 1219, 1053 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C28H29N2O5 473.2076; Found 473.2073.
Ethyl 1-allyl-7-methoxy-2,4-diphenyl-1,4-dihydroquinazoline-4-carboxylate (9d). Prepared according to the
general 1,4-DHQ synthesis protocol with 6 (85.8 mg, 0.22 mmol), allyl bromide (25 µL, 0.29 mmol), NaH (10.4 mg,
0.26 mmol), and DMF (2.0 mL). After workup, the residue was purified by MPLC (20% - 40% EtOAc in hexanes as
eluent) to afford the desired product (70.1 mg, 74%) as a solid (m.p. = 106 - 109 °C). 1H NMR (400 MHz, CDCl3) δ
7.53 – 7.47 (m, 2H), 7.43 – 7.20 (m, 8H), 6.97 (d, J = 8.6 Hz, 1H), 6.64 (dd, J = 8.6, 2.4 Hz, 1H), 6.55 (d, J = 2.4 Hz,
1H), 5.47 (ddt, J = 17.2, 10.2, 5.0 Hz, 1H), 5.03 (dq, J = 10.6, 1.6 Hz, 1H), 4.97 (dq, J = 17.1, 1.6 Hz, 1H), 4.33 (dq,
J = 10.8, 7.1 Hz, 1H), 4.27 – 4.16 (m, 3H), 3.79 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
173.1, 159.6, 155.7, 143.9, 138.5, 135.8, 133.2, 129.5, 129.0, 128.7, 128.3, 127.9, 127.8, 127.0, 117.2, 117.1, 108.1,
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100.6, 69.3, 61.6, 55.3, 49.9, 14.2; IR (neat): 3058, 2980, 1724, 1610, 1501, 1446, 1364, 1206, 1170, 1027 cm-1;
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C27H27N2O3 427.2022; Found 427.2022.
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Ethyl 1-hexyl-7-methoxy-2,4-diphenyl-1,4-dihydroquinazoline-4-carboxylate (9e). Prepared according to the
general 1,4-DHQ synthesis protocol with 6 (86.0 mg, 0.22 mmol), 1-bromohexane (40 µL, 0.29 mmol), NaH (10.4
mg, 0.26 mmol), and DMF (2.0 mL). After workup, the residue was purified by MPLC (15% - 35% EtOAc in hexanes
as eluent) to afford the desired product (65.7 mg, 63%) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.53 – 7.47 (m, 2H),
7.42 – 7.19 (m, 8H), 6.95 (d, J = 8.5 Hz, 1H), 6.66 (dd, J = 8.5, 2.4 Hz, 1H), 6.62 (d, J = 2.4 Hz, 1H), 4.32 (dq, J =
10.8, 7.1 Hz, 1H), 4.21 (dq, J = 10.8, 7.1 Hz, 1H), 3.83 (s, 3H), 3.71 – 3.52 (m, 2H), 1.32 – 1.23 (m, 5H), 1.09 – 1.00
(m, 2H), 0.97 – 0.77 (m, 4H), 0.74 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 173.2, 159.7, 156.3, 143.9,
138.5, 135.9, 129.5, 129.1, 128.9, 128.3, 127.79, 127.76, 127.0, 118.0, 107.8, 100.1, 69.3, 61.6, 55.4, 46.9, 31.2, 28.0,
25.8, 22.3, 14.2, 13.9; IR (neat): 3060, 2928, 1728, 1610, 1500, 1446, 1366, 1211, 1172, 1113, 1027 cm-1; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C30H35N2O3 471.2648; Found 471.2659.
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Ethyl 1-(cyclohexylmethyl)-7-methoxy-2,4-diphenyl-1,4-dihydroquinazoline-4-carboxylate (9f). Prepared
according to the general 1,4-DHQ synthesis protocol with 6 (85.3 mg, 0.22 mmol), bromomethyl cyclohexane (40 µL,
0.29 mmol), NaH (10.5 mg, 0.26 mmol), and DMF (2.0 mL). After workup, the residue was purified by MPLC (20%
- 40% EtOAc in hexanes as eluent) to afford the desired product (64.4 mg, 60%) as an oil. 1H NMR (400 MHz, CDCl3)
δ 7.46 (dd, J = 7.1, 2.6 Hz, 2H), 7.43 – 7.35 (m, 3H), 7.35 – 7.26 (m, 4H), 7.24 – 7.18 (m, 1H), 6.97 (d, J = 8.6 Hz,
1H), 6.68 (dd, J = 8.6, 2.4 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 4.33 (dq, J = 10.9, 7.1 Hz, 1H), 4.21 (dq, J = 10.9, 7.1
Hz, 1H), 3.85 (s, 3H), 3.48 (dd, J = 14.5, 6.0 Hz, 1H), 3.36 (dd, J = 14.5, 7.2 Hz, 1H), 1.55 – 1.20 (m, 8H), 1.09 –
0.73 (m, 4H), 0.54 (qd, J = 12.2, 3.3 Hz, 1H), 0.36 – 0.21 (m, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 173.3, 159.6,
156.4, 144.1, 138.7, 136.0, 129.4, 129.3, 128.8, 128.3, 127.8, 127.7, 127.1, 117.8, 107.6, 100.2, 69.1, 61.7, 55.4, 53.2,
36.2, 30.5, 30.3, 26.1, 25.7, 14.2; IR (neat): 3058, 2920, 1726, 1610, 1502, 1446, 1372, 1202, 1172, 1027 cm-1; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C31H35N2O3 483.2648; Found 483.2655.
Ethyl 1-isopropyl-7-methoxy-2,4-diphenyl-1,4-dihydroquinazoline-4-carboxylate (9g). Prepared according to the
general 1,4-DHQ synthesis protocol with 6 (77.0 mg, 0.20 mmol), 2-bromopropane (24 µL, 0.26 mmol), NaH (9.9
mg, 0.25 mmol), and DMF (2.0 mL). After workup, the residue was purified by MPLC (20% - 40% EtOAc in hexanes
as eluent) to afford the desired product (17.9 mg, 21%) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.63 – 7.58 (m, 2H),
7.43 – 7.33 (m, 5H), 7.33 – 7.27 (m, 2H), 7.26 – 7.20 (m, 1H), 6.91 (d, J = 8.6 Hz, 1H), 6.85 (d, J = 2.4 Hz, 1H), 6.66
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