Triflic anhydride mediated synthesis of 3,4-dihydroquinazolines: A three-component one-pot tandem procedure

Article abstract of DOI:10.1039/c9ob01596e

A one-pot three-component tandem reaction involving a key Pictet-Spengler-like annulation step has been developed, providing an efficient method for the synthesis of 3,4-dihydroquinazolines in moderate to good yields from amides, aldehydes, and amines. The multicomponent triflic anhydride mediated reaction tolerates the installation of numerous functional groups, affording extensive diversity about the heterocyclic scaffold.

Full text of DOI:10.1039/c9ob01596e

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Triflic anhydride mediated synthesis of
3,4-dihydroquinazolines: a three-component
Cite this: DOI: 10.1039/c9ob01596e
one-pot tandem procedure†
Christina L. Magyar, Tyler J. Wall, Steven B. Davies, Molly V. Campbell,
Haven A. Barna, Sydney R. Smith, Christopher J. Savich and R. Adam Mosey
*
A one-pot three-component tandem reaction involving a key Pictet–Spengler-like annulation step has
been developed, providing an efficient method for the synthesis of 3,4-dihydroquinazolines in moderate
to good yields from amides, aldehydes, and amines. The multicomponent triflic anhydride mediated reac-
tion tolerates the installation of numerous functional groups, affording extensive diversity about the
heterocyclic scaffold.
Received 18th July 2019,
Accepted 8th August 2019
DOI: 10.1039/c9ob01596e
rsc.li/obc
Spengler-like annulation reaction.12 The Pictet–Spengler reac-
tion is a well-established method of carbon–nitrogen bond
Introduction
The 3,4-dihydroquinazoline scaffold is an important structural formation that involves intramolecular attack of an arene to a
feature common to natural products and synthetic compounds tethered iminium species.13 The reaction is commonly used
with known pharmacological properties. Naturally occurring for the installation of a cyclic amine present in partially satu-
vasicine (I, Fig. 1), for example, is an alkaloid found in rated heterocyclic ring systems including tetrahydroisoquino-
Adhatoda vasica and Peganum harmala plants that has been lines and tetrahydro-β-carbolines. An analogous Pictet–
used medicinally for centuries to treat respiratory ailments.1 Spengler-like synthesis of the partially saturated 3,4-dihydro-
Biological properties exhibited by members of this compound quinazoline heterocyclic ring, which contains an amidine
class include antiparasitic (e.g. II),2 antifungal (e.g. III),3 antitu- rather than an amine, requires the generation and subsequent
mor (e.g. IV),4 and antiviral (e.g. V)5 activities, among others intramolecular annular capture of
a N-amidinyliminium
(Fig. 1).6 Interest in this heterocyclic scaffold has led to the species. Such an approach has previously been investigated by
development of numerous synthetic methods for its construc- the Katritzky12a and El Efrit12b groups, whose studies involved
tion. Common methods of 3,4-dihydroquinazoline synthesis in situ generation of aryllithium imidates followed by treat-
include reduction of quinazoline7 or quinazolinone8 com- ment with imines (Scheme 1a). While the lithiated intermedi-
pounds, condensation-type reactions of ortho-amino benzyl- ates successfully capture imines, the potential molecular diver-
amines with carbonyl derivatives,9 and ring formation via sity about the resultant heterocyclic scaffold is limited by the
addition of nucleophiles to carbodiimide intermediates,10 as
well as unique multicomponent one-pot methods.11 Despite
numerous available methodologies for the synthesis of
3,4-dihydroquinazolines, many suffer from common draw-
backs including costly or lengthy syntheses, issues which have
hampered exploration of diversity among members of this
compound class.
A much less frequently encountered approach to 3,4-di-
hydroquinazoline synthesis involves construction of the
scaffold’s heterocyclic ring through an intramolecular Pictet–
Department of Chemistry, Lake Superior State University, Sault Sainte Marie,
MI 49783, USA. E-mail: rmosey@lssu.edu
†Electronic supplementary information (ESI) available. CCDC 1862436. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c9ob01596e
Fig. 1 Biologically active 3,4-dihydroquinazolines.
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Table 1 Optimization of reaction conditionsa
Entry
Base
Temp. (°C)
Yieldb (%)
1c,d
2d
3
4
5
6
7
8
9
2-Chloropyridine
2-Chloropyridine
2-Chloropyridine
2-Fluoropyridine
Pentafluoropyridine
2-Methoxypyridine
Pyridine
−10
−10
−10
−10
−10
−10
−10
−10
−41
−78
−41
−41
36
56
61
45
38
0
21
34
84
70
64
85
None
2-Chloropyridine
2-Chloropyridine
2-Chloropyridine
2-Chloropyridine
Scheme 1 New Pictet–Spengler-like approach for 3,4-dihydroquina-
zoline synthesis.
10
11e
12f
incompatibility of the strongly nucleophilic intermediates and
the reagents used to generate them with many organic func-
tional groups. Therefore, a Pictet–Spengler-type approach to
the synthesis of this scaffold which obviates the use of metals
would permit access to increasingly diverse members of this
compound class. Herein we report
a metal-free Pictet–
Spengler-like synthesis of 3,4-dihydroquinazolines using com-
mercially or readily available N-aryl amides, amines, and alde-
hydes in one-pot Tf2O-mediated tandem reaction (Scheme 1b).
a Conditions: 1 (1.0 mmol), benzylamine (1.1 mmol), benzaldehyde
(1.1 mmol), 4 Å mol sieves (1.0 g), CH2Cl2 (10.0 mL), rt, 18 h; then
base (1.2 mmol), Tf2O (1.1 mmol), temperature; then rt, 24 h.
b Isolated yield. c 4
Å
mol sieves were not added. d N-
Benzylidenebenzylamine (1.1 mmol) was used instead of benzylamine
Results and discussion
and benzaldehyde. e Reflux during final step. f 48 h for final step.
The synthesis of 3,4-dihydroquinazolines via a metal-free
Pictet–Spengler-like annulation required a reliable method for
the generation of the N-amidinyliminium annulation precur-
sor (e.g. 1b, Scheme 2). We investigated the synthesis of this
precursor, and the ensuing annulation, via established Tf2O-
mediated N-aryl amide dehydration14 to generate 1a followed
by imine addition (Scheme 2). Indeed, treatment of amide 1
with Tf2O and 2-chloropyridine (2-ClPyr) followed by
N-benzylidenebenzylamine afforded 3,4-dihydroquinazoline 2
in 36% yield (Table 1, entry 1), the structure of which was con-
firmed by single crystal X-ray analysis. The reaction yield was
improved through addition of 4 Å molecular sieves (Table 1,
entry 2), conditions which reduced amide recovery resulting
from hydrolysis of water-sensitive intermediates 1a and 1b.
Next, molecular sieve-promoted in situ imine generation15 was
pursued under similar conditions, whereby the required imine
was to be formed from the corresponding amine and aldehyde
prior to amide dehydration. True to design, stirring a mixture
of benzylamine, benzaldehyde, and amide 1 in CH2Cl2 with
4 Å molecular sieves prior to treatment with Tf2O and 2-ClPyr
afforded 2 in 61% yield (Table 1, entry 3). Additional screening
efforts were then performed to reveal optimal conditions for
our one-pot multicomponent reaction. Desired 3,4-dihydroqui-
nazoline 2 was obtained in the presence and absence of a
variety of pyridine bases (Table 1, entries 3–8), with the use of
2-ClPyr (entry 3) providing the greatest product yield. The
temperature at which 2-ClPyr and Tf2O were added was found
to be important, as optimal yields were observed when
addition occurred at −41 °C (Table 1, entry 9). Further modifi-
cations to reaction conditions, such as heating to reflux
Scheme 2 Tandem assembly of 3,4-dihydroquinazolines.
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instead of room temperature after addition of Tf2O (Table 1, 4c were prepared in moderate to good yields, whereas the yield
entry 11) or allowing the reaction to proceed longer (Table 1, of fluoro alkoxy derivative 4d was markedly lower, even when
entry 12) did not provide substantial increases in product the reaction proceeded for an additional 24 hours after the
yield.
addition of Tf2O. The use of amides bearing alkyl substituted
With optimal conditions identified, exploration of the reac- N-arenes also led to moderate yields of desired 3,4-dihydroqui-
tion scope initiated with examination of the amide component nazoline products, with products of monoalkylated N-aryl
(Table 2). Concerning N-arene substitution, the general trend amides being formed in lower yields than those from the di-
observed was that the use of amides bearing electron rich alkylated counterparts (4e vs. 4f–4h). A single regioisomer
N-arenes led to higher product yields when compared to the product was routinely isolated in these reactions even though
use of electron poor N-arenes, a result of enhanced nucleophi- the formation of an additional regioisomer product in most
licity of the N-arene ring leading to an increase in the rate of reactions was possible, an outcome that was likely driven by
the Pictet–Spengler-like annulation step. Alkoxy derivatives 4a– steric factors. In order to assess the effect of steric interactions
on reaction regioselectivity, N-aryl amide 3h bearing two
different substituents (methyl and isopropyl) meta to the
amide nitrogen was prepared. When submitted to reaction
Table 2 Synthesis of 3,4-dihydroquinazolines through variation of the
starting amidea
conditions, the amide was converted to a mixture of regio-
isomers 4ha and 4hb (2.7 : 1 ratio),16 in which the major
product resulted from annulation from the less sterically con-
gested carbon ortho to the nitrogen on the amide N-arene.
Lastly, an amide bearing a nucleophilic heterocycle rather
than a substituted benzene was used to install a core thio-
phene unit in 4i. Diversification at the C2 position (e.g. R2) was
also investigated through variation of the amide acyl group.
Nearly all tested amides, including those bearing alkyl, aryl,
and heteroaryl acyl groups, were successfully integrated into
the product scaffolds in moderate to good yields without issue
(e.g. 4j–4q). However, incorporation of very bulky groups at this
position proved to be challenging. Comparison of 4m and 4n
revealed the more sterically demanding o-toluyl substituent
was installed in a lower yield than the p-toluyl group.
Furthermore, the use of amides bearing the larger mesityl or
tert-butyl groups in the same position provided no observable
products.
Structural diversity at the N3 position was explored through
the use of various amines (Table 3). Linear and branched alkyl
groups were readily introduced at the N3 position through the
addition of alkanamines (5a–5d). However, similar to at the C2
position, the incorporation of the large tert-butyl group was
unsuccessful (e.g. 5e). These results demonstrate that the
approach of the imine towards the intermediate generated
from amide dehydration (e.g. 1a) is sensitive to steric inter-
actions and becomes unfavorable when attempting to insert
bulky groups at the C2 and N3 positions. An alkoxyamine was
also installed at the N3 position (e.g. 5f) through the use of
O-benzylhydroxylamine. Lastly, aromatic and heteroaromatic
substituents were incorporated from the use of corresponding
amines (5g–5i). The insertion of the 4-anisyl and the 3-pyridyl
groups from the parent amines proceeded smoothly (5g and
5h, respectively). However, the use of aniline did not provide
any product under the optimized reaction conditions.
Modification of reaction conditions to include the use of
2-fluoropyridine (2-FPyr) instead of 2-ClPyr was thus investi-
gated as a means of generating the highly electrophilic nitri-
lium intermediate during amide dehydration.17 Under the
modified conditions with 2-FPyr, aniline was successfully
installed to yield desired 5i. The use of 2-FPyr was also investi-
a Conditions: 3 (1.0 mmol), benzylamine (1.1 mmol), benzaldehyde
(1.1 mmol), 4 Å mol sieves (1.0 g), CH2Cl2 (10.0 mL), rt, 18 h; then
2-ClPyr (1.2 mmol), Tf2O (1.1 mmol), −41 °C; then rt, 24 h. Isolated
yield. b 48 h for final step.
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Table 3 Variation of the amine and aldehyde componentsa
5k). However, the observed reduction in yield was likely not
due to steric factors alone, as modulation of the electronics at
this position revealed that reaction yields are decreased by the
use of electron rich aldehydes compared to electron deficient
aldehydes (e.g. 5l vs. 5m). These results are in line with a
Pictet–Spengler mechanism of ring formation, in which the
electronic character installed in the cyclization precursor inter-
mediate (e.g. 1b, Scheme 2) from the aldehyde component
modulates the rate of capture by the N-arene nucleophile.
Incorporation of electron deficient aldehydes enhances the
electrophilicity of the cyclization precursors, thereby resulting
in higher reaction yields. Additional substituents were also
installed at the C4 position including heteroaromatic groups
(e.g. 5n and 5o) and an ester (5p). Finally, the use of aliphatic
aldehydes in the reaction was pursued. The use of pivaldehyde
provided C4-alkyl product 5q in moderate yields, whereas the
use of isobutyraldehyde provided very little of desired product
5r. Similarly low yields were observed when additional alde-
hydes bearing an alpha hydrogen, such as hexanal, hydrocin-
namaldehyde, and isovaleraldehyde were tested in the reac-
tion. We postulate that the drop in yields when using these
aldehydes is likely due to deprotonation of the alpha hydrogen
of the iminium intermediates under the basic reaction con-
ditions to generate enamines,18 which would lack the requisite
reactivity to undergo annulation.
Generation and subsequent intramolecular capture of a
Pictet–Spengler-like precursor is required for successful syn-
thesis of 3,4-dihydroquinazolines under our studied reaction
conditions. Our results demonstrate installation of an imine
subsequent to amide dehydration as an efficient method of
achieving this transformation (e.g. Scheme 3, Path A). We also
sought to determine whether the Pictet–Spengler-like annula-
tion pathway might be occurring through an amidine inter-
mediate. Throughout our studies, amidines were identified in
many reaction mixtures following aqueous workup. The ami-
dines were presumed to have formed from attack of the amide
dehydration intermediate by an amine19 rather than an imine
a Conditions: 1 (1.0 mmol), amine (1.1 mmol), aldehyde (1.1 mmol),
4 Å mol sieves (1.0 g), CH2Cl2 (10.0 mL), rt, 18 h; then 2-ClPyr
(1.2 mmol), Tf2O (1.1 mmol), −41 °C; then rt, 24 h. Isolated yield.
b 48 h for final step. c 2-FPyr used instead of 2-ClPyr.
gated in reactions wherein products were unable to be syn-
thesized due to steric interactions (e.g. 5e), but those attempts
proved to be unsuccessful.
Variation of the aldehyde component was then investigated
as a means of synthesizing 3,4-dihydroquinazolines differing
at the C4 position (Table 3). The use of substituted benzal-
dehydes readily provided products with substituted phenyl
groups at this position. While alkyl groups about the phenyl
group were tolerated, increases in steric bulk at the ortho posi-
tion of the C4 phenyl substituent provided lower product
yields than the phenyl substituent itself (compare 2 to 5j and Scheme 3 Investigation of reaction pathway.
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due to incomplete imine formation prior to treatment with
Tf2O or through hydrolysis of unreacted Pictet–Spengler-like
annulation precursor present at the time of workup. The pres-
ence of amidines in the reaction mixtures also presented an
alternative reactive pathway for product formation involving
initial generation of an amidine followed by reaction with an
aldehyde to generate the annulation precursor (Scheme 3, Path
B). To test this alternative pathway, amidine 6 was prepared
from amide 3j through treatment with Tf2O and 2,6-lutidine
followed by benzylamine (Scheme 3).20 Isolated 6 was then
treated with benzaldehyde, 2-ClPyr, and 4 Å molecular sieves
in CH2Cl2 to mimic optimized reaction conditions, but no
desired product was observed. Furthermore, additional reac-
tion conditions were evaluated, including variations in base
(including base-free and acidic conditions), solvent, and temp-
erature. Under none of the tested conditions was any 3,4-dihy-
droquinazoline 4j ever observed, indicating that contributions
to reaction yields from a reaction pathway involving an
amidine intermediate is unlikely under our multicomponent
reaction conditions.
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Conclusion
In conclusion, we have developed an efficient one-pot pro-
cedure for the synthesis of diverse 3,4-dihydroquinazolines via
a Tf2O-mediated tandem assembly of amides, amines, and
aldehydes. The reaction involves a key Pictet–Spengler-like
annulation step under metal-free conditions for the formation
of the partially saturated heterocyclic ring. Further studies con-
cerning the scope and synthetic applications of this chemistry,
as well as biological properties of 3,4-dihydroquinazoles, are
underway in our laboratory.
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There are no conflicts to declare.
Acknowledgements
We thank Grace Hubbell and Travis Quevillon for assistance
with the synthesis of starting materials. We also thank Richard
Staples of Michigan State University for assistance recording
X-ray data and Judy Westrick, director of the Lumigen
Instrumentation Center at Wayne State University, for assistance
recording HRMS data. This work was supported by funding
from the National Institutes of Health (1R03AI126233-01) and
the National Science Foundation (MRI award 1626523).
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