Electrophilic N-amination of two quinazoline-2,4-diones using substituted (Nitrophenyl)hydroxylamines

Article abstract of DOI:10.1021/op010239f

The preparation of a few (nitrophenyl)hydroxylamines and reaction with two quinazoline-2,4-diones is described. The electrophilic aminating agents were assessed in terms of yield for the N-amination of two quinazoline-2,4-diones and safety considerations for rapid scale-up. For the amination of the described system, the best yield and the highest onset temperature were found in the same aminating agent, specifically, (4-nitrophenyl)hydroxylamine.

Full text of DOI:10.1021/op010239f

Organic Process Research & Development 2002, 6, 230−233
Electrophilic N-Amination of Two Quinazoline-2,4-diones Using Substituted
(Nitrophenyl)hydroxylamines
David C. Boyles, Timothy T. Curran,* and Roger V. Parlett, IV
Pfizer Global Research and DeVelopment, Chemical Research and DeVelopment, 2800 Plymouth Road,
Ann Arbor, Michigan 48105, U.S.A.
Mark Davis and Frank Mauro
Pfizer Global Research and DeVelopment, Chemical Research and DeVelopment, Hazards EValuations Laboratory,
188 Howard AVenue, Holland, Michigan 49424, U.S.A.
Abstract:
The preparation of a few (nitrophenyl)hydroxylamines and
reaction with two quinazoline-2,4-diones is described. The
electrophilic aminating agents were assessed in terms of yield
for the N-amination of two quinazoline-2,4-diones and safety
considerations for rapid scale-up. For the amination of the
described system, the best yield and the highest onset temper-
ature were found in the same aminating agent, specifically,
(4-nitrophenyl)hydroxylamine.
Introduction
To rapidly supply material to support toxicological studies
of novel antibacterial agents, we had a need to prepare
3-amino-quinazoline-2,4-diones 1 and 2 (Figure 1). This
required the preparation of the corresponding imides 3 and
4 followed by N-amination. The aminating agent used by
discovery chemistry1 was O-(2,4-dinitrophenyl)hydroxyl-
amine 5.2 Due to potential safety concerns surrounding this
aminating agent, a sample was tested in our hazards
evaluation lab, and (dinitrophenyl)hydroxylamine 5 was
found to be quite energetic (vide infra; see Table 2).
Figure 1.
Scheme 1
More importantly the onset temperature was about 90 °C;
chemistry that had been done in-house using (dinitrophenyl)-
hydroxylamine 5 was reported to occur at 70-80 °C. These
issues caused us to look into the preparation and use of other,
readily available (nitrophenyl)hydroxylamines. We chose and
limited ourselves to substituted (nitrophenyl)hydroxylamines
as aminating agents because we thought that we could easily
evaluate them and readily prepare enough aminating agent
to fulfill the required immediate compound need. We chose
* Corresponding author information: Pfizer Global Research and Develop-
ment, Chemical Research and Development, 2800 Plymouth Road, Ann Arbor,
MI 48105. Telephone: 734-622-2433. Fax: 734-622-3294. E-mail: timothy.curran@
pfizer.com.
(1) Discovery Chemistry did not have any mishaps during the conduct of their
work. See: Bird, P.; Ellsworth, E. L.; Nguyen, D. Q.; Sanchez, J. P.;
Showalter, H. H. D.; Singh, R.; Stier, M. A.; Tran, T. P.; Watson, B. M.;
Yip, J. (Warner-Lambert Co.). 3-Aminoquinazolin-2,4-diones Antibacterial
Agents, WO 0153273, July 26, 2001. A detonation has been reported using
5 under basic conditions. See: Radhakrishna, A. S.; Loudon, G. M.; Miller,
M. J. J. Org. Chem. 1979, 44, 4836.
precursors to the aminating agents based on the cost,
commercial availability, and substrates that would produce
less energetic aminating agents.
Synthesis. The route to the aminating agents is shown in
Scheme 1. Although this is a known route to 8a and 5,2
several other N-Boc precursors and subsequent (nitrophenyl)-
hydroxylamines to our knowledge have not been reported.
Preparation of the (nitrophenyl)hydroxylamines involved
(2) Sheradsky, T.; Salemnick, G.; Nir, Z. Tetrahedron 1972, 28, 3833. For a
review on electrophilic aminations see: Tamura, Y.; Minamikawa, J.; Ikeda,
M. Synthesis 1977, 1.
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10.1021/op010239f CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/26/2002

Scheme 2
Table 2: DSC and ARC data on aminating agents
aminating onset temperature onset temperature
energy
agent
(ARC) (°C)
(DSC) (°C)
(DSC)b (J/g)
5
90
120
118
95
110a
-
128
119
124
2308c
1800c
1262
1291
1663
8a
8b
8c
8d
90
a This is the temperature at which the test cell burst, destroying our DSC
sensor. ARC measured ∆Pmax readings in excess of 20 000 psi/min for some
runs. b TNT is reported to have a measured decomposition energy of 4395 J/g
with an onset temperature of 250 °C.5 c Measured by ARC. This value is likely
less than the actual value because the decompositions out-ran the calorimeter
creating a nonadiabatic condition.
phenoxide on the quinazoline-2,4-dione heterocycle (Scheme
2). Byproduct 9b is also observed in the amination of 3 using
O-(2-methyl-4-nitrophenyl)hydroxylamine (8b), albeit in
lesser amounts. The 2-methyl and 2-chloro aminating agents
8b and 8c run a close second in yield. The reaction of the
monochlorinated reagent went smoothly at 50 °C in 3.5 h,
whereas the dichloro-aminating agent 8d promoted amination
in 2 h at that same temperature, but gave an inferior yield.
The increase in reactivity due to the addition of electron-
withdrawing substituents proved to also prevent the formation
of phenoxide addition products to the methoxy core 3; phenol
addition byproducts (i.e., 9a,b) were not observed using 8c,d.
A mixture of 8d/8e (85:15) was also used as an aminating
agent. Interestingly, examination of the crude reaction
mixture showed that 8d did the amination while 8e, the ortho-
substituted aminating agent, was left behind, unchanged.
Hazards Evaluation. The first aminating agent, O-(2,4-
dinitrophenyl)hydroxylamine (5) was initially subjected to
DSC (differential scanning calorimetry) analysis; this resulted
in the over-pressurization of the medium-pressure stainless
steel cell with enough force to shatter the ceramic sensor
and damage the surrounding oven. Testing was then con-
ducted in the ARC (accelerating rate calorimetry) using very
small sample sizes (0.25-0.5 g). All subsequent aminating
agents were evaluated by DSC and ARC. Dinitrophenylhy-
droxylamine 5 was found not to be shock-sensitive at 200
kg-cm. No other aminating agents were tested for shock
sensitivity. DSC and ARC data for these materials are
presented in Table 2. All aminating reagents prepared were
less energetic than O-(2,4-dinitrophenyl) hydroxylamine (5);
we were able to obtain data without destruction of the
instruments. Although the chloro-substituted phenyl hy-
droxylamines 8c and 8d were less energetic, their onset
temperatures were decreased. The 2-methylnitro-arene 8b
proved to be the least energetic and had a comparable onset
temperature to 8a. Unfortunately, for all aminating agents
tested, once reagent decomposition was initiated, a runaway-
reaction-scenario was created. We thought it best to go with
the O-(4-nitrophenyl)hydroxylamine (8a) because we could
work at about 50 °C less than the ARC onset temperature.
Nitrophenylhydroxylamine 8a also had a lower cost of
preparation in comparison to the other reagents, and we
Table 1: Amination of quinazolindiones 3 and 4
substrates for amination
aminating
agent
imide 3
imide 4
temperature, time, yield temperature, time, yield
8a
8b
8c
8d
72 °C, 2 h, 75%
72 °C, 2 h, 74%
50 °C, 3.5 h, 62%
50 °C, 3 h, 47%
-
72 °C, 2 h, 79%
72 °C, 2 h, 62%
50 °C, 3.5 h, 70%
50 °C, 3 h, 51%
50 °C, 3 h, 59%
8d/8e (85:15)
nucleophilic aromatic substitution of an N-Boc hydroxyl-
amine on the halonitro arene using KOH in EtOH or IPA.
Boc cleavage using TFA then rapidly gave the desired
phenylhydroxylamines 8a-e. Other acids were tried for this
deprotection including formic acid, methane sulfonic acid,
and HCl in Et2O but gave inferior yields (15-35%) to those
using TFA.
Aminations were initially done using NaH in a 1:1 mixture
of DMF3 and dioxane or THF, but K2CO3 was found to be
adequate for this reaction and was used in the amination
survey with reagents 8a-e on the quinazoline-2,4-diones 3
and 4. A polar solvent like DMF, DMA, or NMP is necessary
for the reaction to occur. Use of only dioxane or THF gave
no desired amination products. The survey was conducted
using 1 g of imide 3 or 4, 1.1 equiv of aminating agent (8a-
e), 1.5 equiv of K2CO3 in a 1:1 mixture of dioxane and DMF
at the temperatures and times shown. The products were
isolated by chromatography on SiO2. Results from this survey
are shown in Scheme 2 and Table 1.
The more reactive aminating agents allowed the reaction
to occur at lower temperature but gave diminished yield.
O-(4-Nitrophenyl)hydroxylamine (8a) was found to give the
best yield; although, with the more reactive methoxy core
3, a byproduct was generated in the 4-7% range (HPLC
area%).4 Byproduct 9a is due to attack of the resulting
(3) Mixtures of DMF and NaH have been reported to give spontaneous,
uncontrollable exotherms. See: Bretherick’s Handbook of ReactiVe Chemical
Hazards, 6th ed.; Butterworth-Heinemann Ltd.: Oxford, 1999; Vol. 1, pp
1604-1605
(4) Byproduct 9a was isolated, and NMR experiments proved adequate for
structural elucidation.
(5) Kohler, J.; Meyer, R. ExplosiVes, 4th ed.; VCH: Weinheim, 1993; pp 371-
374
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obtained a good yield of 1 and 2. This reagent was used to
prepare 1 and 2 on 0.5-0.75 mole scale without incident.
7.3 (d, 1H, J ) 2.5 Hz), 2.3 (s, 3H), 1.5 (s, 9H); EIMS m/e
(relative intensity) 267 (M-, 40), 152 (100).
N-Boc-(2-chloro-4-nitrophenyl)hydroxylamine (7c). Re-
action of 1,2-dichloro-4-nitrobenzene (6c, 20 g, 104 mmol)
in IPA with KOH and tert-butyl-N-hydroxy carbamate (16.1
g, 121 mmol, 1.2 equiv) gave after SiO2 plug filtration (20%
EtOAc/hexanes) 24.3 g, 81% yield of 7c as a yellow solid.
Conclusions
In conclusion, we have prepared and used a number of
phenylhydroxylamines to N-aminate quinazoline-2,4-diones
3 and 4 in good yield. The thermal analysis of the phenyl
hydroxylamines has been conducted to allow the determi-
nation of safe operating conditions for these aminating
agents.
1
For 7c: H NMR (CDCl3) 8.2 (d, 1H, J ) 2.5 Hz), 8.1 (dd,
1H, J ) 2.5, 9.2 Hz), 7.9 (bs, 1H), 7.3 (d, 1H, J ) 9.2 Hz),
1.5 (s, 9H); EIMS m/e (relative intensity) 287 (M-, 5), 172
(100).
N-Boc-(2,5-dichloro-4-nitrophenyl)hydroxylamine (7d).
Reaction of 1,2,5-trichloro-4-nitrobenzene (6d, 47.2 g, 208
mmol) in EtOH with KOH and tert-butyl-N-hydroxy car-
bamate (33.2 g, 226 mmol, 1.2 equiv) gave an 85:15 mixture
of p:o-substituted isomers. A portion of (4-nitrophenyl)-
hydroxylamine 7d was isolated by SiO2 chromatography
(10% EtOAc/hexanes) 18.4 g, 27% yield of 7d as a yellow
solid. An additional 43 g of a mixture of o- and p-isomers
64% was obtained. For 7d: 1H NMR (CDCl3) 8.1 (s, 1H),
7.8 (s, 1H), 7.7 (s, 1H), 1.5 (s, 9H); EIMS m/e (relative
intensity) 321 (M-, 80), 205 (100).
Experimental Section
The preparation of N-Boc(4-nitrophenyl)hydroxylamine
(7a) and O-(4-nitrophenyl)-hydroxylamine (8a) have been
previously reported.2 NMR data was recorded on Varian
Unity NMRs at 400 MHz. Mass spectra were recorded on
micromass platform LC. IR were recorded on a Biorad
FTS45 FTIR. CHN analyses were recorded on Lehman Labs
440. Melting points were recorded on a Thomas-Hoover
melting point apparatus and are uncorrected. DSC were
measured using sealed 120 uL medium-pressure stainless
steel crucibles in a Mettler DSC 821 and Mettler STAR
software. ARC data was measured using an A. D. Little
ARC-2000 accelerating rate calorimeter with a 1 in. diameter,
0.25 in. neck titanium bomb. Drop-weight tests were
performed using a Technoproducts ASTM standard drop-
weight tester under ASTM standard methods. EIHRMS
(electron impact high-resolution mass spectrum) were re-
corded on a VG 70-250-S.
General Procedure for the Preparation of Aminating
Reagents: Nucleophilic Aromatic Substitution and tert-
Butylcarbamate Cleavage. The N-Boc phenylhydroxyl-
amines 7a-e were either chromatographed or used crude in
the deprotection step. The phenylhydroxylamines 8a-e were
purified by recrystallization. The preparation of O-(2-methyl-
4-nitrophenyl)hydroxylamine (8b) is representative of the
substitution and Boc cleavage.
N-Boc-(2-Methyl-4-nitrophenyl)hydroxylamine (7b). A
mixture of KOH pellets (88%, 42.8 g, 0.67 mol, 1.3 equiv)
in EtOH (absolute, 875 mL) was prepared at room temper-
ature and stirred until the KOH dissolved (15 min). tert-
Butyl-N-hydroxy carbamate (106 g,0.80 mol, 1.6 equiv) was
added portionwise to give a yellow solution. To this mixture
was added a solution of 2-fluoro-5-nitrotoluene (6b, 79.9 g,
0.52 mol) in EtOH (absolute, 875 mL) rapidly. The resulting
solution became intensely orange. The reaction was then
warmed to 50 °C for 68 h (over weekend). The reaction
mixture was allowed to cool and concentrated in vacuo. The
resulting red oil was redissolved in EtOAc (800 mL) and
washed with NH4Cl solution (saturated, 800 mL). Phases
were separated and the aqueous phase extracted with EtOAc
(1 × 400 mL). The combined organic phases were washed
with brine (1 × 500 mL), dried (MgSO4), and filtered, and
the filtrate was concentrated in vacuo to give a yellow solid
which was dried (rt, 15 mmHg) to afford 7b as yellow solid,
138 g, quantitative crude. This was used without purification
in the subsequent step. For 7b: 1H NMR (CDCl3) 8.2 (bs,
1H), 8.0 (dd, 1H, J ) 2.5, 9 Hz), 7.9 (d, 1H, J ) 2.5 Hz),
(2-Methyl-4-nitrophenyl)hydroxylamine (8b). A solu-
tion of crude 7b (138 g, 0.52 mol) in CH2Cl2 (1.4 L) was
cooled to 5 °C and treated with TFA (180 mL) in one portion.
The resulting reaction mixture was allowed to warm to room
temperature with stirring for 16 h. The reaction mixture was
concentrated to give a dark, red oil. The oil was redissolved
in CH2Cl2 (800 mL) and washed with 10% Na2CO3. The
organic phase was dried (MgSO4) and filtered, and the filtrate
was concentrated in vacuo to give a beige solid. Recrystal-
lization from TBMe (600 mL) and heptane (1.6 L) gave 87
g of 8b as a beige solid; 61% yield. For 8b: mp ) 105-
1
107 °C; H NMR (CDCl3) 8.1 (dd, 1H, J ) 2.5, 9.0 Hz),
8.0 (d, 1H, J ) 2.5 Hz), 7.6 (d, 1H, J ) 9.0 Hz), 6.0 (bs,
2H), 2.2 (s, 3H); EIMS m/e (relative intensity) 169 (M+,
97), 138 (100); IR (neat) υmax 3325, 3259, 1587, 1492, 1480,
1336 cm-1. Anal. Calcd for C7H8N2O3: C, 50.00; H, 4.80;
N, 16.66. Found: C, 50.29; H, 4.73; N, 16.60.
(2-Chloro-4-nitrophenyl)hydroxylamine (8c). Reaction
of N-Boc-2-chloro-4-nitrophenyl)hydroxylamine (7c, 11.3 g,
39 mmol) with TFA (14 mL) in CH2Cl2 (130 mL) gave after
recrystallization from TBME/heptane 3.18 g, 43% yield, of
1
8c as a light brown solid. For 8c: mp ) 120-121 °C; H
NMR (DMSO-d6) 8.2 (m, 1H), 8.1 (m, 1H), 7.7 (d, 1H, J )
9.0 Hz), 7.6 (s, 2H); EIMS m/e (relative intensity) 187 (M-,
97), 172 (100); IR (neat) υmax 3340, 3106, 1583, 1510, 1468,
1336 cm-1. Anal. Calcd for C6H5ClN2O3: C, 38.22; H, 2.67;
N, 14.86. Found: C, 39.40; H, 2.95; N, 14.10. EIHRMS
(m/e) 187.9992 (M+) (C6H5ClN2O3 requires 187.9989; σ )
1.6 ppm)
(2,5-Dichloro-4-nitrophenyl)hydroxylamine (8d). Reac-
tion of N-Boc-(2,5-dichloro-4-nitrophenyl)hydroxylamine
(8d, 5.5 g, 17 mmol) with TFA (6 mL) in CH2Cl2 (55 mL)
gave after recrystallization from TBME/heptane 1.69 g, 45%
yield, of 8d as a light brown solid. For 8d: mp ) 117-118
1
°C; H NMR (CDCl3) 8.1 (s, 1H), 8.0 (s, 1H), 6.2 (s, 2H);
EIMS m/e (relative intensity) 206 (M- - NH2, 100); IR
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(neat) υmax 3340, 3106, 1583, 1510, 1468, 1336 cm-1. Anal.
Calcd for C6H4Cl2N2O3: C, 32.31; H, 1.81; N, 12.56.
Found: C, 32.62; H, 1.66; N, 12.39.
1.05 equiv) was added to the reaction mixture (an endotherm
of 2 °C resulted). After 2 h at 72 °C an additional portion of
aminating agent was added (12.3 g 0.08 mol, 0.1 equiv) and
heating continued for 20 h at which time the reaction was
judged complete (TLC, 50% EtOAc/hexanes). The reaction
mixture was allowed to cool. The solids which formed were
filtered and washed with THF (3 × 250 mL). The filtrate
was concentrated to about 1/10 volume (ca. 500 mL) in
vacuo. The concentrated solution was poured into ice (1 L)
and water (1.4 L) with stirring. Crystallization of the gooey
solid was initiated by adding 1 L of TBME to the mixture
with continued stirring for about 15 min, which afforded a
powdery beige solid. The solid was collected and washed
with water (2 × 300 mL). The crude solid was recrystallized
with IPA (1.5 L) and heptane (1.5 L), solid filtered off and
dried (15 mmHg, rt) to give pure 2 as a light brown solid,
166 g, 83%. For 2: mp ) 163-164 °C; 1H NMR (DMSO-
d6) 7.73 (t, 1H, J ) 9.3 Hz), 5.4 (s, 2H), 3.4 (m, 1H), 2.6 (t,
3H, J ) 3 Hz), 1.0 (m, 2H), 0.62 (m, 2H); 19F NMR -129
(m), -143 (m); IR (KBr) νmax 3333, 3244, 1716, 1637, 1474,
1410, 1308 cm-1. Anal. Calcd for C12H11F2N3O2: C, 53.93;
H, 4.15; N, 15.72. Found: C, 53.72; H, 4.10; N, 15.57.
General Procedure for Amination of Quinazoline-2,4-
diones 3 and 4 Using NaH and K2CO3. Preparation of
Hydrazides 1 and 2. 3-Amino-1-cyclopropyl-6,7-difluoro-
8-methoxy-1H-quinazoline-2,4-dione (1). A slurry of cyclic
imide 3 (150 g, 0.56 mol) in dioxane (1.3 L) and DMF (1.3
L) was cooled to 2 °C and treated portionwise with NaH
(60% in oil, 24.8 g, 1.1 equiv; 6 portions). After gas evolution
subsided, the reaction was warmed to room temperature then
further warmed to 72 °C and held at that temperature for 1
h. O-(4-nitrophenyl)hydroxylamine (8a; 96.4 g, 0.63 mol,
1.1 equiv) was added in one portion (resulted in a 2 °C
endotherm). After 4 h at 72 °C, additional aminating agent
(17.6 g, 0.11 mol, 0.2 equiv) was introduced. After stirring
for 20 h, the reaction was judged complete (TLC; 1:1 EtOAc/
hexanes). The reaction mixture was concentrated in vacuo
(remove dioxane and some DMF) then poured into water
(950 mL) and crushed ice (950 mL) with vigorous stirring.
The solid was collected and washed with water (1.5 L). The
solid was reslurried in water (2 L) and filtered. The resulting
solid was recrystallized from IPA (1.2 L) and heptane (1.4
L). The crystals were collected and dried to give 103 g, 65%.
For 1: mp 148-150 °C; 1H NMR (DMSO-d6) 7.7 (m, 1H),
5.5 (bs, 2H), 3.93 (s, 3H), 3.3 (m, 1H), 0.99 (m, 2H), 0.64
(m, 2H); 19F NMR -141 (m), -145 (m); IR (KBr) νmax 3359,
3251, 1729, 1658, 1482, 1407 cm-1. Anal. Calcd for
C12H11F2N3O3: C, 50.89; H, 3.91; N, 14.84. Found: C,
51.40; H, 4.13; N, 14.61.
Acknowledgment
We thank Dr. Davidson, Professor Rapoport, Dr. Ellsworth,
Dr. Sanchez, Dr. Showalter, M. Stier, and T. Tran for helpful
discussions during the conduct of this work. We also extend
our thanks to B. Leja and D. Greene for analytical support
for this project and Dr. Tobias for help in the determination
of 9a,b. For EIHRMS we thank J. Windak at the University
of Michigan.
3-Amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazo-
line-2,4-dione (2). A slurry of cyclic imide 4 (190 g, 0.754
mol) and K2CO3 (156 g, 1.13 mol, 1.5 equiv) in dioxane
(2.1 L) and DMF (2.1 L) was warmed to 72 °C for 30 min
then O-(4-nitrophenyl)hydroxylamine (8a, 122 g, 0.793 mol,
Received for review December 5, 2001.
OP010239F
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