A new application of diphenylphosphorylazide (DPPA) reagent: Convenient transformations of quinolin-4-one, pyridin-4-one and quinazolin-4-one derivatives into the 4-azido and 4-amino counterparts

Article abstract of DOI:10.1016/j.tetlet.2004.04.032

Herein, we describe a transformation of the oxo-function of a series of quinolin/pyridin/quinazolin-4-ones into 4-azido and thence into 4-amino derivatives in moderate yields by a very short and convenient new procedure using DPPA (diphenylphosphoryl azide) as reagent. A mechanism for this interesting new application of DPPA is suggested based on the identification of some of the intermediates.

Full text of DOI:10.1016/j.tetlet.2004.04.032

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4241–4243
A new application of diphenylphosphorylazide (DPPA) reagent:
convenient transformations of quinolin-4-one, pyridin-4-one and
quinazolin-4-one derivatives into the 4-azido and 4-amino
counterpartsq
Alexander Aizikovich,a Vladimir Kuznetsov,a Sofia Gorohovsky,a Amalia Levy,a
Simha Meir,a Gerardo Bykb and Garry Gellermana,*
aCompugen Ltd, Chemistry Division, 11 Ha’Amal St., P.O. Box 3066, Ashkelon 78785, Israel
bLaboratory of Peptidomimetics and Genetic Chemistry, Department of Chemistry, Bar Ilan University, 52900 Ramat Gan, Israel
Received 11 January 2004; revised 2 April 2004; accepted 7 April 2004
Abstract—Herein, we describe a transformation of the oxo-function of a series of quinolin/pyridin/quinazolin-4-ones into 4-azido
and thence into 4-amino derivatives in moderate yields by a very short and convenient new procedure using DPPA (diphenyl-
phosphoryl azide) as reagent. A mechanism for this interesting new application of DPPA is suggested based on the identification of
some of the intermediates.
Ó 2004 Elsevier Ltd. All rights reserved.
Heterocyclic aromatic aza-compounds, especially pyr-
idine, quinoline and quinazoline derivatives, are widely
used in organic synthesis and chemical technology. One
of the best methods for synthesizing their amino deriv-
atives starts from the corresponding oxy-counterparts
and involves a two step process:1;2 the oxo derivative is
first transformed into a leaving group such as tosyl oxy
or halogen followed by reaction with an azide anion.
Catalytic reduction of the azido-derivatives obtained,
results in the desired amines in good yield.1;2 In our
continuing efforts to introduce exhaustive substitution
into constrained heterocyclic scaffolds, we have focused
on the introduction of amino groups into quinolin-4-
ones, pyridin-4-ones and quinazolin-4-ones.
conditions.3;4 It has been also applied as a peptide
coupling reagent5 and for transformation of alcohols
into amines.6 Nevertheless, to our knowledge, its reac-
tivity towards heterocyclic oxo aromatics, that can be in
equilibrium with their phenol tautomers, has not been
investigated. We have reacted a variety of quinolin/
pyridin/- and quinazolin-4-ones with DPPA in DMF at
100 °C for 24 h and obtained, in one-pot, the corre-
sponding azido-derivatives in moderate yields (see
Scheme 1 and Table 1).
The moderate yields can be explained firstly, as a result of
steric hindrance at position 4 caused by substitution at
position 3 and secondly, in terms of the low stability of
aromatic azides, which undergo slow degradation espe-
cially at high temperature. The lowest yield was observed
for the reaction of 2,3-diphenylquinolin-4-one (Table 1,
entry 5, 22%). The reactions were followed by HPLC–MS
DPPA has been developed and extensively used to
transform acids into acyl azide intermediates, which
undergo Curtius rearrangement under appropriate
N3
N
O
aromatic system
Keywords: DPPA; Azide; Quinolin-4-one; Pyridin-4-one; Quinazolin-
4-ol.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.04.032
* Corresponding author. Tel.: +972-353-18325; fax: +972-353-51250;
e-mail: garyg@compugen.co.il
DPPA/DMF
100 °C
N
H
Scheme 1.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.032

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A. Aizikovich et al. / Tetrahedron Letters 45 (2004) 4241–4243
Table 1. Azides and amines synthesized using DPPA as reagent
Precursor
OH
#
Azide
Yield (%)
61
#
Amine
Yield (%)
84
N3
NH2
1
9
N
H
O
N
H
O
N
H
O
O
N3
NH2
S
S
S
2
55
10
88
N
H
N
N
O
N3
N
NH2
N
MeOOC
MeO
MeOOC
MeO
MeOOC
MeO
3
4
64
74
11
12
84
98
N
H
Ph
Ph
Ph
O
N3
N
NH2
N
H
Ph
Ph
N
Ph
NH2
O
N3
MeO
Ph
Ph
MeO
Ph
Ph
MeO
Ph
Ph
5
6
22
48
13
14
97
97
N
H
N
N
O
N3
N
NH2
MeOOC
Ph
Pr
MeOOC
Ph
Pr
MeOOC
Ph
Pr
N
H
N
Pr
Pr
Pr
O
N3
NH2
7
8
45
––
15
16
83
N
H
COOEt
N
N
CO2Et
N
COOEt
Pr
Pr
Pr
O
NH2
N3
N
NH
N
63 (overall
yield)
N
N
analysis, which allowed the clear identification of a
phosphoric ester intermediate formed from the DPPA
and the oxo function in the early part of the reactions
(entries 1, 3–7).6 We suggest that this intermediate is
further attacked by the azide anion to generate azido
derivatives, with elimination of phosphate, mediated by a
sp3 intermediate in an addition–elimination pathway.
Continuing the reactions beyond 24 h brought about an
accelerated degradation of the azide products with a
concomitant decrease in yields. When the reaction was
performed on 2,4-dioxo derivatives (Table 1, entry 1) the
azide was obtained regioselectively leaving the 2-oxo
group intact. The nonreactivity of the 2-oxo position was
confirmed when we tried to perform the reaction on
quinolin/pyridin-2-ones without success (data not
shown). 4H-Thieno[3,2-b]pyridin-7-one (Table 1, entry
2) reacted readily with DPPA to give the corresponding
azide derivative. Interestingly, 4-aminoquinazoline 16
can be obtained in one-pot and in good yield (63% overall
yield) without isolation of the azide intermediate 8. Thus,
amines can be directly obtained in higher yields without
isolation of the intermediate azides. All the azides were
transformed into amines using regular catalytic hydro-
genation conditions, in high yields (Table 1, entries 9–16).
In conclusion, we have demonstrated a new application
of DPPA for the transformation of various pyridin-4-
ones, quinazolin-4-ones and quinolin-4-ones into their
corresponding azides and thence into amines.
Extension of this approach to other oxy heterocycles is
currently being investigated.

A. Aizikovich et al. / Tetrahedron Letters 45 (2004) 4241–4243
4243
1. Experimental
1.1. Synthesis of azides 1–8
1.4. 4-Amino-6,8-dimethyl-2-phenyl-quinoline (12)
The product was isolated without special purification.
1
Analytical HPLC (tR): 6.17 min; H NMR(300 MHz,
1 mmol of the 4-oxo precursor and 1.1 mmol of DPPA
were dissolved in 5 mL DMF, 1.3 mmol of triethylamine
was added and the mixture was heated to 100 °C with
stirring under argon for 24 h. After cooling, the DMF
was evaporated under vacuum and the resulting crude
oil was purified by HPLC except for azide 8, which was
directly reduced without isolation. (One typical example
is given, for physical data of other products see Sup-
plementary information.)
DMSO-d6, d ppm): 2.42 (s, 3H); 2.67 (s, 3H); 6.63 (s, 2H,
NH2); 7.10 (s, 1H, 3-H); 7.34 (s, 1H, 5-H); 7.41–7.50 (m,
4H of Ph); 7.77 (s, 1H, 7-H); 8.09–8.11 (m, 2H of Ph).
13C NMR(600 MHz, CDCl d ppm), 155 (2-C); 146 (9-
3
C); 152 (10-C); 140 (4-C); 134–137 (6-C, 8-C); 132 (7-C);
129 (40-C); 126 (10-C); 119 (20-C); 117 (5-C); 98 (3-C); 22
(Me); 18 (Me). MS (m=z): 249 [MHþ]. HRMS (electron
spray) calcd for C17H16N2: 248.131301 and found:
248.131349.
1.2. Synthesis of amines 9–16
Acknowledgements
Azide 1–7 or crude 8 (0.5 mmol) was dissolved in 10 mL
methanol under argon, the solution was degassed twice
in vacuo and 30 mg of Pd/C was added. Reduction was
carried out under hydrogen for 24 h. The Pd/C was
removed by passage through Celite and the methanol
evaporated in vacuo. (One typical example is given, for
physical data of other products see Supplementary
information.)
We wish to thank Dr. Evgeny Mizerichin, Alexander
Rozovsky and to Andrey Finkelman for their help in
purifications and analysis. Prof. Gerardo Byk is
indebted to the ‘Marcus Center for Medicinal Chemis-
try’ and to the Ygal Alon Foundation.
1.3. 4-Azido-6,8-dimethyl-2-phenyl-quinoline 4
References and notes
The product was purified by preparative HPLC (RP-18).
Elution started with petroleum ether and ended with
petroleum ether/ethyl acetate (70:30 v/v) and used a
linear gradient at a flow rate of 100 mL/min (cycle time
25 min). Analytical HPLC (tR): 9.84 min; 1H NMR
(300 MHz, DMSO-d6, d ppm): 2.47 (s, 3H); 2.75 (s, 3H);
7.48–7.59 (m, 4H Ph and 7-H); 7.65 (s, 1H, 5-H); 7.94 (s,
1H, 3-H); 8.32–8.35 (m, 2H Ph). 13C NMR(600 MHz,
CDCl3, d ppm), 155 (2-C); 142 (9-C); 141 (10-C); 138 (4-
C); 137–137 (6-C, 8-C); 132 (7-C); 130 (40-C); 129 (10-C);
127 (20-C); 117 (5-C); 106 (3-C); 22 (Me); 18 (Me). MS
(electron spray, m=z): 275 [MH]þ.
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