Concise two-step solution phase syntheses of four novel dihydroquinazoline scaffolds

Article abstract of DOI:10.1016/j.tetlet.2010.05.108

Novel two-step solution phase protocols for the synthesis of dihydroquinazolines and fused dihydroquinazoline-benzodiazepine tetracycles are reported. The methodology employs the Ugi reaction to assemble the desired diversity and acid treatment enables ri

Full text of DOI:10.1016/j.tetlet.2010.05.108

Tetrahedron Letters 51 (2010) 3951–3955
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Concise two-step solution phase syntheses of four novel
dihydroquinazoline scaffolds
Justin Dietrich a,b,d, Christine Kaiser e, Nathalie Meurice d,e, Christopher Hulme a,b,c,d,
*
a College of Pharmacy, Department of Pharm/Tox, Divisions of Medicinal Chemistry & Organic Chemistry, University of Arizona, Tucson, AZ 85721, United States
b BIO5 Institute, University of Arizona, Tucson, AZ 85721, United States
c Department of Chemistry, University of Arizona, Tucson, AZ 85721, United States
d Southwest Comprehensive Center for Drug Discovery and Development, United States
e The Translational Genomics Research Institute (TGen), N 5th Street, Phoenix, AZ 85004, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel two-step solution phase protocols for the synthesis of dihydroquinazolines and fused dihydroqui-
nazoline-benzodiazepine tetracycles are reported. The methodology employs the Ugi reaction to assem-
ble the desired diversity and acid treatment enables ring-closing transformations. The protocols are
further facilitated by the use of microwave irradiation and n-butyl isocyanide to control the rate of each
ring-forming transformation.
Received 29 April 2010
Revised 21 May 2010
Accepted 23 May 2010
Available online 1 June 2010
Published by Elsevier Ltd.
1. Introduction
could be produced in two steps: an Ugi reaction with mono-Boc
protected 2-aminobenzylamines 5, supporting aldehydes 8, non-
The elucidation of the complete human genome in 20011 has re-
sulted in a dramatic increase in the demand for the identification of
small molecules to validate the pharmacological potential of new
macromolecular targets.2,3 In particular, isonitrile-based method-
ologies,4–6 followed by a variety of secondary ring-forming trans-
formations, have shown great utility in concisely producing
highly functionalized and drug-like scaffolds with high iterative
efficiency potential.7–9 Methodologies developed in this laboratory
have proven quite productive, delivering examples where initial
hits have progressed into clinical trials for the treatment of both
HIV infection10,11 and pre-term labor,12–15 importantly without
the need to ‘scaffold hop’. Recently, we have reported a contrite
two-step synthesis of triazabenzulenones16 that represents the
first post-condensation Ugi modification employing two internal
amino nucleophiles and a subsequent report that utilized micro-
wave irradiation with n-butyl isonitrile in place of a traditional ‘de-
signer convertible isonitrile,17 to form benzodiazepines and
diketopiperazines. Herein, we report two-step syntheses that yield
dihydroquinazolines 1 and 2 and fused dihydroquinazoline-benzo-
diazepine tetracycles 3 and 4, Figure 1. The tetracyclic scaffolds
represent a second example of a post-condensation Ugi modifica-
tion employing two internal amino nucleophiles and all four syn-
theses rely on the reduced reactivity of an n-butyl amide
carbonyl derived from n-butyl isonitrile relative to traditional con-
vertible isonitriles to ensure the correct sequence of ring-forming
events. It was envisioned that the dihydroquinazoline core
convertible isonitriles 7, and carboxylic acids 6 to yield the conden-
sation product 9 followed by acid-promoted deprotection and
cyclization. Both the 1,4-dihydroquinazoline (Scheme 1a, (10)
and 3,4-dihydroquinazoline (Scheme 1b, 12) scaffolds can be pro-
duced from the corresponding mono-protected 2-aminobenzyl-
amine input 5 or 11. We have previously demonstrated a similar
acid-promoted dehydration of an Ugi condensation product to gen-
erate an aromatic benzimidazole core16,18 and this Letter expands
the use of such methodology to obtain non-aromatic bicyclic rings
such as the dihydroquinazolines 1 and 2 with significantly differ-
ent physicochemical properties and spacial positioning of decorat-
ing functionality.
Optimal yields for the Ugi reaction were found to occur via
pre-formation of the Schiff base in methanol for 30 min, followed
by addition of the isonitrile and carboxylic acid inputs with sub-
sequent microwave irradiation at 100 °C for 10 min (isolated
yields 48–85%). The Ugi product was then treated with 10%
TFA/DCE (irradiated at 120 °C) to form the desired quinazoline
scaffolds 10 and 12 core in good yield (46–65% ꢀisolated overall
yield for two steps).19 With this protocol in hand, it was hypoth-
esized that addition of a second protected amine, through the use
of an N-Boc-protected anthranilic acid 13, would enable the for-
mation of novel fused dihydroquinazoline-benzodiazepines
(Schemes 2a and 2b, 14 and 15) after deprotection and two
sequential cyclization steps. However, addition of the bulky
Boc-protected amine group resulted in a dramatic decrease in
the yield of the Ugi reaction (<5%).
This effect was also observed in the 1,4-quinazoline series
with 2-chlorobenzoic acid (Fig. 3, 30). Circumventing this problem,
* Corresponding author. Tel.: +1 520 626 5322.
E-mail address: hulme@pharmacy.arizona.edu (C. Hulme).
0040-4039/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2010.05.108

3952
J. Dietrich et al. / Tetrahedron Letters 51 (2010) 3951–3955
R4
N
R4
N
R4
N
R2
R2
N
N
R1
N
R4
N
R2
H
N
NH
N
NH
R3
R1
HN
R3
R1
O
O
O
1
2
3
4
R1
O
Figure 1. Representative dihydroquinazoline bicyclic and tetracyclic scaffolds.
Boc
HN
Boc
N
O
N
R2
R1 CHO
R2
R4
O
H
MeOH, rt 1H
10% TFA/DCE
120ºC, 20 min
N
R4
8
H
NH2
N
5
N
µW 100ºC, 10 min
R2
R3
R1
R1 HN R3
R4 CO2H
R3
N
C
O
10
9
6
7
Scheme 1a.
R2
NH2
N
R4
R2
R1 CHO
O
R2
10% TFA/DCE
120ºC, 20 min
MeOH, rt 1H
µW 100ºC, 10 min
NH
Boc
R4
O
N
R1
O
11
Boc NH
N
HN
R3
R3
N
C
R4 CO2H
R1 HN R3
12
Scheme 1b.
Boc
HN
Boc
O
HN
Boc
H
O
N
N
H
1. DCM, MgSO
130ºC, 10 min µW
4
10% TFA, DCE,
130ºC, 20 min
O
N
NH2
N
2. DCM, 120ºC
10 min µW
56% yield
O
NH
OH
14
44%
HN
O
N
C
NH
Boc
13
Scheme 2a.
NHBoc
NH2
Boc
H
O
O
HN
N
10% TFA, DCE,
130ºC, 20 min
BocHN
1. DCM, MgSO
4
O
N
N
O
130ºC, 10 min µW
2. DCM, 120ºC
10 min µW
58% yield
O
NH
15
36%
OH
HN
N
C
NH
Boc
13
Scheme 2b.
pre-formation of the Schiff base in toluene under microwave
irradiation with removal of water (MgSO4) provided the Schiff base
in quantitative yields. Subsequent reaction in MeOH afforded the
desired Ugi product in 44% yield [note: observed by-products arose
from methanol addition to the Schiff base and the Passerini
reaction]. Interestingly, reactions in trifluoroethanol yielded simi-
lar results—a strategy that is often successful in reducing solvent
participation in the Ugi reaction. A modest improvement in yield
was observed by pre-forming the Schiff base in dichloromethane
in the presence of MgSO4 (microwave, 120 °C). Following the

J. Dietrich et al. / Tetrahedron Letters 51 (2010) 3951–3955
3953
addition of supporting reagents, the reaction was irradiated at
120 °C for 10 min with an acceptable improvement in yield (56%,
Scheme 2a). Removal of the two Boc groups, cyclo-dehydration
to the dihydroquinazoline core, and concomitant cyclization onto
the n-butyl amide afforded the desired fused 1,4-dihydroquinazo-
line-benzodiazepines 14 and 15 in acceptable yields upon simple
acid treatment and microwave irradiation.20 Not surprisingly, the
major side products of the cascade reaction were the benzodiaze-
pine trifluoroacetamide 16 (24% yield) and the bicyclic trifluoroac-
etamide 17 (13% yield), Figure 2.
The scope of the methodology was evaluated with a selection
of different reagents. Cyclization reactions of purified Ugi prod-
ucts were run in series on a Biotage Initiator 8 microwave and
were purified in a sequential manner on a Biotage Isolera 4 sys-
tem utilizing neutralized silica gel columns. The observed high
polarity of dihydroquinazolines can be attributed to their rela-
tively high pKa values (Table 1). Thirteen examples are presented
18 through 30 containing all four dihydroquinazoline cores with
isolated overall yields for the two-step procedure ranging from
21% to 64% Figure 3.
O
F
F
HN
F
O
N
16
24% yield
N
H
O
O
F
F
HN
N
F
N
O
NH
17
13% yield
Figure 2.
To demonstrate scaffold uniqueness, virtual libraries for 1
through 4 were enumerated (comprising scaffold 1—168 com-
pounds; 2—168 compounds, 3—144 compounds, 4—48 com-
pounds) and compared with the 375,000 compounds in the NIH
molecular libraries small molecule repository (MLSMR). A total of
1043 nearest neighbors were indentified and a principle compo-
nent analysis21 clearly demonstrates the unique diversity space
occupied by expanded libraries of the four scaffolds described
herein Figure 4.
In summary, we have reported concise two-step solution
phase syntheses that afford bicyclic dihydroquinazolines and
fused tetracyclic dihydroquinazoline-benzodiazepines, which are
under-represented in the literature and the MLSMR.22 With ame-
nability to high-throughput solution phase synthesis, it is ex-
pected that the methodology will be embraced by the lead
generation community.
Table 1
H
N
pKa = 5.14a
N
CH3
H
N
pKa = 6.57a
pKa = 7.84a
N
CH3
CH3
N
N
H
a
pKa values were estimated using ACD/pKa.
N
N
N
N
N
N
H
N
CH3
N
N
N
H
N
NH
N
N
O
NH
HN
HN
O
O
O
O
48%, 81%, 39%
82%, 78%, 64%
83%, 70%, 58%
80%, 60%, 48%
58%, 36%, 21%
18
19
20
21
22
N
N
N
N
N
N
N
N
N
N
O
CH3
NH
O
NH
O
H
N
NH
O
NH
O
O
O
O
78%, 78%, 61%
75%, 73%, 55%
78%, 72%, 56%
78%, 64%, 49%
56%, 44%, 25%
23
24
25
26
27
Cl
N
N
N
N
N
N
O
H
N
N
NH
NH
O
O
O
71%, 58%, 41%
85%, 58%, 50%
38%, 68%, 25%
28
29
30
Figure 3. Reported % yields = Ugi yield, cyclization yield, overall yield.

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J. Dietrich et al. / Tetrahedron Letters 51 (2010) 3951–3955
Figure 4.
was stirred at room temperature for 30 min followed by the addition of n-butyl
isocyanide (95 l, 0.900 mmol) and benzoic acid (110 mg, 0.900 mmol). The
Acknowledgments
l
reaction was then irradiated for 10 min at 100 °C. The solvent was evaporated
We would like to thank the Office of the Director, NIH, and the
National Institute of Mental Health for funding (1RC2MH090878-
01).
in vacuo, crude material taken up in 3 mL 10% EtOAc/Hexane and loaded onto a
12 g silica column with purification performed on
a 4
BiotageÒ Isolera
(gradient 10–20% EtOAc/hexane) to yield the desired Ugi product (344 mg,
0.738 mmol, 82% yield). The Ugi product was then taken up in 5 mL 10% TFA/
DCE, transferred to a 2–5 mL microwave vial and irradiated at 120 °C for
20 min. The reaction was then poured into a separatory funnel that contained
50 mL saturated sodium carbonate and 50 mL DCM. The organic layer was
collected and aqueous layer further extracted with DCM (50 ml). The combined
organics were dried over MgSO4, concentrated onto neutralized silica, and
purified on a Biotage Isolera (25 g neutralized column, 20% EtOAc/1.5% TEA/
hexane) to yield the desire 1,4-dihydroquinazoline product, N-butyl-2-(2-
phenylquinazolin-1(4H)-yl)pentanamide 20 (209 mg, 0.576 mmol, 64% yield).
1H NMR (300 MHz, CDCl3): 7.50 (dd, 2H, J = 1.8 Hz, J = 14.7 Hz), 7.31–7.45 (m,
3H), 7.12 (dt, 1H, J = 7.5 Hz, J = 0.9 Hz), 7.05 (dt, 1H, J = 0.9 Hz, J = 7.5 Hz), 6.98
(d, 1H, J = 5.4 Hz), 6.78 (d, 1H, J = 7.5 Hz). 6.45 (t, 1H, J = 5.4 Hz), 4.83 (d, 1H,
J = 18.6 Hz), 4.74 (d, 1H, J = 18.6 Hz), 4.25 (dd, 1H, J = 4.2 Hz, J = 10.2 Hz), 3.29
(m, 2H), 1.7–2.2 (m, 2H), 1.45–1.6 (m, 2H), 1.20–1.40 (m, 4H), 0.91 (t, 3H,
J = 4.5 Hz), 0.79 (t, 3H, J = 4.2 Hz). 13C NMR (75 MHz, CDCl3): 171.05, 158.18,
137.03, 136.62, 130.05, 129.09 (2C), 128.40 (2C), 127.32, 126.78, 124.66,
123.92, 116.74, 62.99, 49.30, 39.90, 31.91, 29.89, 20.52, 20.18, 14.14, 14.03.
20. General procedure for preparation of dihydroquinazoline-benzodiazepine
References and notes
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tetracycle 26: To
a
2.0–5.0 mL microwave vial was added
a solution of
butyraldehyde (246
l
l, 1.350 mmol) in DCM (3 ml), tert-butyl (2-
9. Hulme, C.; Dietrich, J. Mol. Divers. 2009, 13, 195–207.
10. Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51–80.
(aminomethyl)phenyl)carbamate (300 mg, 1.350 mmol), and MgSO4. The
reaction was sealed and irradiated for 10 min at 120 °C to yield the Schiff
base in quantitative yields (Rf 0.82, 25% EtOAc/Hex). n-Butylisocyanide (143 ll,
11. Hulme, C.; Maggiora, G. M. Curr. Opin. Chem. Biol. 2008, 12, 257–259.
12. Hulme, C.; Nixey, T. Curr. Opin. Drug Discov. Dev. 2003, 6, 921–929.
13. Liddle, J.; Allen, M. J.; Borthwick, A. D.; Brooks, D. P.; Davies, D. E.; Edwards, R.
M.; Exall, A. M.; Hamlett, C.; Irving, W. R.; Mason, A. M.; McCafferty, G. P.;
Nerozzi, F.; Peace, S.; Philp, J.; Pollard, D.; Pullen, M. A.; Shabbir, S. S.; Sollis, S.
L.; Westfall, T. D.; Woollard, P. M.; Wu, C.; Hickey, D. M. Bioorg. Med. Chem. Lett.
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1.350 mmol) and 2-((tert-butoxycarbonyl)amino)benzoic acid (320 mg,
1.350 mmol) were added and reacted at 120 °C under microwave irradiation.
The crude mixture was poured into a separatory funnel containing saturated
sodium bicarbonate and DCM. The organic layer was collected, dried, loaded
onto 2 g silica gel and purified on a Biotage Isolera (40 g column, gradient 10–
35% EtOAc/Hex) to yield the Ugi product (478 mg, 0.783 mmol, 58% yield). The
Ugi product was then taken up in 10% TFA/DCE (5 ml), transferred to a 2–5 mL
microwave vial and irradiated at 130 °C for 20 min. After heating, the reaction
was poured into
a separatory funnel that contained saturated sodium
carbonate (50 mL) and DCM (50 mL). The organic layer was collected and
then the aqueous layer was extracted twice more with DCM (2 Â 50 mL). The
combined organics were dried over MgSO4, concentrated onto neutralized
silica, and purified on a Biotage Isolera (25 g neutralized column, 50% EtOAc/
2.0% TEA/hexane) to yield the desire 3,4-dihydroquinazoline-benzodiazepine
15. Reiss, T. Trends Biotechnol. 2001, 19, 496–499.
16. Tempest, P.; Ma, V.; Thomas, S.; Hua, Z.; Kelly, M. G.; Hulme, C. Tetrahedron Lett.
2001, 42, 4959–4962.
17. Venter, J. C. et al Science 2001, 291, 1304–1351.
18. Wyatt, P. G.; Allen, M. J.; Borthwick, A. D.; Davies, D. E.; Exall, A. M.; Hatley, R.
J.; Irving, W. R.; Livermore, D. G.; Miller, N. D.; Nerozzi, F.; Sollis, S. L.;
Szardenings, A. K. Bioorg. Med. Chem. Lett. 2005, 15, 2579–2582.
19. General preparation of dihydroquinazolines, 19: To a solution of butyraldehyde
tetracyclic
product,
7-propyl-7,9-dihydrobenzo[5,6]-[1,4]diazepino[7,1-
b]quinazolin-6(5H)-one 27 (87 mg, 0.283 mmol, 21% yield). 1H NMR
(300 MHz, CDCl3): 8.65 (s, 1H), 8.08 (d, 1H, J = 7.2 Hz), 7.45 (t, 1H, J = 7.2 Hz),
7.2–7.4 (m, 3H), 7.1–7.2 (m, 1H), 7.10 (t, 1H (dd, 2H, J = 1.8 Hz, J = 14.7 Hz),
6.95–7.10 (m, 3H), 4.41 (d, 1H, J = 13.2 Hz), 4.27 (d, 1H, J = 13.2 Hz), 4.12 (t, 1H,
(164
ll, 1.800 mmol) in methanol (3 mL) in a 2.0–5.0 ml microwave vial was
added tert-butyl 2-aminobenzylcarbamate (200 mg, 0.900 mmol). The reaction

J. Dietrich et al. / Tetrahedron Letters 51 (2010) 3951–3955
3955
7.5 Hz), 1.8–2.1 (m, 2H), 1.2–1.5 (m, 4H), 0.95 (t, 3H, J = 7.2 Hz). 13C NMR
(75 MHz, CDCl3): 170.95, 143.533, 137.11, 132.12, 131.64, 129.16, 128.94,
126.07, 125.59, 125.46, 124.48, 122.63, 121.22, 56.41, 43.14, 27.79, 19.42,
14.32.
function as implemented in the nearest neighbor search tool in PowerMV
(distance threshold for library 1 and 2 = 0.5; library 3 = 0.29; library 4 = 0.4).
The libraries and the MLSMR subset (1571 compounds total) were imported
into MOE (Molecular Operating Environment v2009.11, Chemical Computing
Group) and represented by structural fingerprints (MACCS keys). Tanimoto
similarities were computed based on the MACCS keys, which generated a 1571
by 1571 matrix. The columns of the matrix were used as input for a principle
component analysis and the first three principle components were represented
graphically using MOE (Fig. 4).
21. In an exercise to demonstrate uniqueness, virtual libraries for all four scaffolds
were enumerated with Symyx Draw 3.2 (comprising scaffold 1—168
compounds; 2—168 compounds, 3—144 compounds, 4—48 compounds). The
parent structure of each compound was then compared with the 375,000
compounds available in the NIH molecular libraries small molecule repository
(MLSMR) described by pharmacophore fingerprints using PowerMV v0.61. A
total of 1043 similar compounds were selected using a Tanimoto Similarity
22. (a) Krasavin, M.; Busel, A.; Parchinsky, V. Tetrahedron Lett. 2009, 50, 5945–
5950; (b) Lygin, Alexander V.; de Meijere, Armin. Org. Lett. 2009, 11, 389–392.