Electrophilic tetraalkylammonium nitrate nitration. II. Improved anhydrous aromatic and heteroaromatic mononitration with tetramethylammonium nitrate and triflic anhydride, including selected microwave examples

Article abstract of DOI:10.1021/jo026202q

A new one-pot nitration employing tetramethylammonium nitrate and trifluoromethanesulfonic anhydride in dichloromethane to provide a ready source of the nitronium triflate nitrating agent is presented. Rapid and selective nitration with a variety of aromatic and heteroaromatic substrates is achieved resulting in the synthesis of several novel organic compounds. A distinct advantage is the removal of undesired byproducts by aqueous workup. This very mild nitration permits large-scale syntheses and gives high isolated product yields that often require no further purification. This tetramethylammonium nitrate-based nitration also has been applied to microwave-assisted conditions, and the results with several compounds are outlined.

Full text of DOI:10.1021/jo026202q

Electr op h ilic Tetr a a lk yla m m on iu m Nitr a te Nitr a tion . II. Im p r oved
An h yd r ou s Ar om a tic a n d Heter oa r om a tic Mon on itr a tion w ith
Tetr a m eth yla m m on iu m Nitr a te a n d Tr iflic An h yd r id e, In clu d in g
Selected Micr ow a ve Exa m p les†
Scott A. Shackelford,* Mark B. Anderson, Lance C. Christie, Thomas Goetzen,
Mark C. Guzman, Martha A. Hananel, Wayne D. Kornreich, Haitao Li, Ved P. Pathak,
Alex K. Rabinovich, Ranjan J . Rajapakse, Larry K. Truesdale, Stella M. Tsank, and
Haresh N. Vazir
Pfizer Global Research and Development, La J olla Laboratories, 3550 General Atomics Court,
San Diego, California 92121-1194
scott.shackelford@pfizer.com.
Received J uly 16, 2002
A new one-pot nitration employing tetramethylammonium nitrate and trifluoromethanesulfonic
anhydride in dichloromethane to provide a ready source of the nitronium triflate nitrating agent
is presented. Rapid and selective nitration with a variety of aromatic and heteroaromatic substrates
is achieved resulting in the synthesis of several novel organic compounds. A distinct advantage is
the removal of undesired byproducts by aqueous workup. This very mild nitration permits large-
scale syntheses and gives high isolated product yields that often require no further purification.
This tetramethylammonium nitrate-based nitration also has been applied to microwave-assisted
conditions, and the results with several compounds are outlined.
In tr od u ction
used 94% HNO3 with triflic anhydride 2 to produce 3.4
Subsequently reported was a convenient in situ genera-
tion of 3 by reacting commercially available organic
tetraalkylammonium nitrate salts, tetrabutyl- 1b and
tetraethylammonium nitrate 1c, with 2 in CH2Cl2 to
effect saturated heterocycle ring N-atom nitration and
bromobenzene mononitration.5,6
Using commercially available reagent 1a offers a
distinct advantage over the previously reported higher
1b and 1c homologues because pure nitrated product 6
is isolated more easily.5,6 When 1a with 2 generate
nitrating agent 3, hydrophilic byproduct 4a also results,
which is removed during aqueous workup. Reagents 1b
and 1c produce less hydrophilic byproducts 4b and 4c;
however, these remain during aqueous workup, and
column chromatographic separation of 4b or 4c from the
desired product 6 is necessary.5,6 Reactions of NH4NO3
with 2 in CH2Cl2 or CH3NO2 required no column chro-
matographic separation but gave inconsistent results and
lower product yields.5
A convenient one-pot nitration reaction using tetra-
methylammonium nitrate 1a and trifluoromethanesulfon-
ic (triflic) anhydride 2 in dichloromethane readily gener-
ates the nitronium triflate (NO2OTf) 3 nitrating agent.
The addition of an aromatic substrate 5 to the in situ-
generated nitronium triflate 3 effects an anhydrous
electrophilic nitration that is both selective and amenable
to large-scale synthesis efforts. Reactions are conducted
from -78 °C to room temperature and at reflux with less
activated reactants (Scheme 1). A simple aqueous workup
removes the ionic tetramethylammonium triflate salt 4a
and triflic acid byproducts. Subsequent in vacuo solvent
removal gives the mononitrated product 6 in high isolated
yield and purity. Further purification often is unneces-
sary, and some products are analytically pure.
Hygroscopic nitronium triflate 3 initially was synthe-
sized by reacting anhydrous HNO3,1 N2O5,2 or NO2Cl3
with triflic acid. Because of its hygroscopicity, 3 is formed
in situ as a nitrating agent in an appropriate organic
solvent. An initial report on aromatic mononitration
described the formation of 3 in situ by reacting anhydrous
HNO3 with two moles of triflic acid in CH2Cl2, CCl4,
CFCl3, or pentane solvent.1 A later aromatic nitration
Five novel nitroaromatic compounds, including two
heterocycles, are reported using using reactant 1a to
generate nitrating reagent 3. Also discussed are the
directional effects, substituent compatibility, product
selectivity, and purity, as well as direct scale-up results
available from this nitration. Some parametric studies
† Portions of this article comprised part of a presentation at the 2nd
Conference on Coherent Synthesis: Advances in Productive Chemistry
Development, San Diego, CA, May 29-31, 2002.
(1) Coon, C. L.; Blucher, W. C.; Hill M. E. J . Org. Chem. 1973, 38,
4243-4248.
(2) Schmeisser, M.; Sartori, P.; Lippsmeir, B. Z. Naturforsch. 1973,
28b 573-574.
(3) Yarbro, S. K.; Noftle, R. E. J . Fluorine Chem. 1975, 6, 187-189
and references therein.
(4) Umemoto, T.; Ishihara, S. Tetrahedron Lett. 1990, 31, 3579-
3582.
(5) Shackelford, S. A.; Sharts, C. M.; Adams, C. M. 11th Rocky
Mountain Regional Am. Chem. Soc. Mtg., Albuquerque, NM, J uly 10-
12, 1992.
(6) Adams, C. M.; Sharts, C. M.; Shackelford, S. A. Tetrahedron Lett.
1993, 34, 6669-6671.
10.1021/jo026202q CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/12/2002
J . Org. Chem. 2003, 68, 267-275
267

Shackelford et al.
SCHEME 1. Ar om a tic a n d h eter oa r om a tic com p ou n d s 5 (A ) C, N, O, S), r in g size ) 5 a n d 6, p lu s R gr ou p s
a s seen in 5-45
TABLE 1. (CH3)4NNO3-Ba sed Nitr a tion of
Mon osu bstitu ted Ben zen es (7.5 m m ol Sca le)
The earlier anhydrous HNO3 and triflic acid nitration
procedure gives a similar isomeric product distribution
with toluene 5c (o/m/p) ) 62/1/37) and 5f (o/m/p ) 14.3/
85.6/0.1).1 A 1:2 HNO3/H2SO4 mixed acid nitration of 5c
also provides a similar o/m/p isomeric distribution (62/
5/33).9 Proton NMR analyses of the isolated products from
reactants 5a -d and 5f-h show very clean compounds
with little or no byproduct formation. Some unidentified
byproduct was seen in the isolated isomeric product
mixture of benzaldehyde 5e.
These same reaction conditions were also applied to
multiple-substituted benzenes (Table 2). Isolated product
purities seen in Table 2, and all subsequent tables, were
determined by HPLC at a 220 nm UV wavelength
detection. Purities determined by 1H NMR are specifically
noted.
isolated
o/m/p
isomers time
(%)
reactant
R group
conversion
(%)a
yield
(%)
no.
product
(h)
-OCH3
-OH
5a
5b
5c
5d
5e
5f
100
100
100
95
ND
ND
ND
71
6a
6b
6c
6d
6e
6f
6f
6g
6h
97
74
99
90
70
68
68
52
89b
63/5/32
90/0/10
62/0/38
33/0/67
31/63/6
8/88/4
7/89/4
16/78/6
13/84/3
24
23
24
26
97
24
48
26
102
-CH3
-Br
-CHO
-CF3
-CF3
5f
5g
-COOH
-SO2CH3 5h
57
a
ND ) not determined because of reactant volatility and its
b
loss during solvent removal. Actual yield in a pure isolated
mixture contained only reactant (43%) and product isomers (57%).
The only previous synthesis of 12 by direct nitration
used fuming nitric acid at 5 °C for 1 h and gave a 70%
isolated product yield before further purification.10 The
ratio of products 10a and 10b from 9 reveals that the
sterically crowded position between 1,3-disubstituted
methoxy groups is hardly attacked when less hindered
sites are available. With no alternative, nitration
readily occurs between two 1,3-positioned methoxy groups
with reactant 13 giving product 14. Product 14 repre-
sents an unreported compound. As seen in the nitra-
tion of 13, increasing the number of equivalents of 3
can drive reactions to completion. A slower reaction
warming profile was used in the latter two nitrations of
13.11
The General Procedure for this nitration scales directly
from 7.5 to 100 mmol by a proportional increase of
reagents and solvent while keeping reaction times the
same (Table 3). The addition time of 2 into the CH2Cl2
suspension of 1 to generate 3 may be increased to
dissipate a mild exotherm. Isolated product purities and
yields compare favorably with those obtained using
standard nitration methods. Our nitration of 4-tert-
butyltoluene 15 on an 86 mmol scale exclusively produced
presented suggest optimum reaction times for complete
reactant conversion in both the conventional benchtop
and microwave-assisted nitrations.
Resu lts a n d Discu ssion
Ar om a t ic Nit r a t ion . A wide scope of monosubsti-
tuted benzenes can be nitrated under the mild condi-
tions this 1a -based anhydrous nitration reaction allows
(Table 1). Nitrations were conducted with 1.05 equiv of
3 as described by the General Procedure (Experimental
Section). These nitration conditions are compatible
with many pendant electron-donating and withdrawing
substituents found on the benzene ring, including un-
saturated cyano, aldehyde, and ester functional groups.
Table 1 reflects the regiospecificity found with mono-
substituted benzenes. Isomeric percentages were deter-
mined by proton NMR on the isolated products. Aniline
gave no nitrated product, and nitrobenzene showed a
trace of m-dinitrobenzene. These exploratory reactions
were not optimized because our goal was to assess
comparative substituent compatibility, directing effects,
and compound reactivity.
The pronounced ortho-nitration (o/p ) 90/10) with
phenol 5b may result from the electrophilic nitronium
cation interacting with the lone pair electrons on the
oxygen atom of the directing hydroxyl group.7a,8 IPSO
addition followed by a 1,2-migration also would predict
the same result.7b The two nitrations of R,R,R-trifluoro-
toluene 5f confirm the reproducibility of this reaction.
(9) Roberts, J . D.; Caserio M. C. Modern Organic Chemistry; W. A.
Benjamin, Inc.: New York, 1967; p 545.
(10) Garg, H. G.; Singh, P. P. J . Chem. Soc. C 1969, 607.
(11) Reactant 13 (Table 2). The first two runs are described in the
General Procedure. Replacing the CO2/acetone bath with
a CO2/
acetonitrile cold bath for 2.5 h (from -49.6 to -35.0 °C) produced the
best result (run 3). This bath then was allowed to warm to 9.0 °C over
the next 2.5 h before removal; the reaction then was stirred another
48 h at room temperature. In the large-scale nitrations with 13, 17,
and 19, the CO2/acetone bath remained for 1 h, was replaced with a
CO2/acetonitrile bath (ca. -45 °C) for 3 h, and then was permitted to
warm unattended to room temperature over the next 48 h. For
compound 15, the CO2/acetone bath was removed immediately, and
the reaction was stirred for 24 h. For compound 11 (large scale), the
CO2/acetone bath was left in place to warm unattended to room
temperature over the next 23 h.
(7) (a) March, J . Advanced Organic Chemistry: Reactions, Mecha-
nisms, and Structure, 1st ed.; McGraw-Hill: New York, 1968; p 388.
(b) March, J . Advanced Organic Chemistry: Reactions, Mechanisms,
and Structure, 4th ed.; Wiley & Sons: New York, 1992; pp 512-513.
(8) Strazzolini, P.; Giumanini, A. G.; Scuccato, M. J . Org. Chem.
1998, 63, 952-958.
268 J . Org. Chem., Vol. 68, No. 2, 2003

Tetraalkylammonium Nitrate Nitration
TABLE 2. (CH3)4NNO3-Ba sed Nitr a tion of Mu ltip le-Su bstitu ted Ben zen es (7.5 Mm ol Sca le)
a
b
NO2OTf equivalents ) 1.05 relative to reactant 13. NO2OTf equivalents ) 1.50 relative to 13.
TABLE 3. (CH3)4NNO3-Ba sed Nitr a tion a t La r ge-Sca le (86 to 100 Mm ol Sca le)
a
Determined by NMR analysis.
J . Org. Chem, Vol. 68, No. 2, 2003 269

Shackelford et al.
SCHEME 2
the 4-tert-butyl-2-nitrotoluene isomer 16a . Electrophilic
nitration of 15 with NO2BF4 in tetramethylenesulfone
gave 5% of the other tert-butyl-3-nitrotoluene isomer
16b.12
The nearly equal presence of isomers 27 and 28 also was
unexpected. If the cyano group meta-directing influence
were significant, isomer 27 would predominate.
An excellent selectivity also was obtained in the
nitration of 2,4-dimethoxybenzonitrile 17. Only the novel,
unreported 2,4-dimethoxy-5-nitrobenzonitrile 18 isomer
was obtained. Efficient stirring was necessary for opti-
mum yields and purity, so a mechanical stirrer rather
than magnetic stirring was used in most large-scale
reactions. Nitration of 15 using a magnetic stirring bar
selectively provided product 16a . Isolated product 16a
was reduced to its aniline analogue without purification.
Reactant 19 gave an exceptional yield and purity of 20.
Reactant 21 gave a second example of preferred ortho-
nitration relative to its pendant methylsufonamide sub-
stituent by forming an isomeric mixture containing 95%
22a and 5% 22b (Scheme 2). The familiar fuming HNO3/
acetic anhydride nitration gave only the para-isomer 22b.
This nitration reaction normally affords monosubsti-
tuted nitroaromatic products. Two specific electron-rich
aromatic substrates under the General Procedure condi-
tions unexpectedly gave isomeric mixtures that contained
some dinitro-substituted products.
Heter oa r om a tic Nitr a tion . Although the heterocy-
clic aromatic ring is less susceptible to electrophilic
substitution, this nitration reaction was extended to
heteroaromatic compounds. Initially, the General Proce-
dure reaction conditions were applied and then modified
as necessary.
Reactant 2-chloro-4,6-dimethoxypyrimidine 30 formed
2-chloro-4,6-dimethoxy-5-nitropyrimidine 31 in an ex-
ceptionally high isolated yield and purity (Table 4). An
increase from 1.05 to 1.50 equiv of 3 effected a complete
conversion to product 31. The nitration of 30 also scales
easily from 7.5 mmol of 30 (1.31 g) to 2864 mmol (500 g)
with little reduction in isolated product yield and purity.
Product 31 was analytically pure as isolated and repre-
sents an unreported compound.
The nitration 2,4,6-trimethoxyacetophenone 23 repro-
ducibly gave products devoid of the acetyl group (eq 1).
While N-atom nitration via nitrative deacetylation occurs
with saturated N-acetylated heterocycles with 3,6 forma-
tion of 25 by an aromatic C-atom nitrative deacetylation
was not expected, because the two mechanisms would
differ substantially.
Nitrating agent 3 usually is generated in situ over a
1.5 h in CH2Cl2 solvent followed by addition of reactant
5 (Scheme 1). If 5 contains no substituent groups
susceptible to attack by the triflic anhydride 2, a mixture
of 1 and 5 can be treated with 2 (Alternative Method).
The alternate method also used heptane to effect pre-
cipitation of product 31 from CH2Cl2 solvent to produce
the slightly lower 83% yield. A second crop then gave a
comparable overall product yield. The thermal stability
and impact initiation properties of 31 suggest that one
should exercise care in the heating, handling, and storage
of this and other nitrated heterocyclic compounds.13
Reactant 2,4,6-trimethoxypyrimidine 32 can be ni-
trated to 2,4,6-trimethoxy-5-nitropyrimidine 33 in a high
isolated yield and purity (Table 4). Previously, product
33 was synthesized by the methanolysis of 2,4,6-trichloro-
Dinitration also occurred with 2,3-dimethoxybenzoni-
trile 26 using 1.5 equiv of 3 (eq 2). Unlike its two isomers
17 and 19, a 100% conversion of 26 gave an isolated
mixture consisting of 24% dinitro-substituted product 29.
(13) High-pressure DSC thermal screening of 31 at a 10 °C/min
temperature rise gave decomposition between 200 and 250 °C. Impact
sensitivity initiation resulted in a 20-30 J impact energy. When
reacting, handling, or isolating 31, temperatures probably should not
exceed 100 °C.
(12) Olah, G. A.; Kuhn, S. J . J . Am. Chem. Soc. 1964, 86, 1067-
1070.
270 J . Org. Chem., Vol. 68, No. 2, 2003

Tetraalkylammonium Nitrate Nitration
TABLE 4. (CH3)4NNO3-Ba sed Nitr a tion of Tr isu bstitu ted P yr im id in es 30 a n d 32
a
b
Alternative Method. Recrystallized product. c Determined by NMR analysis.
TABLE 5. (CH3)4NNO3-Ba sed Nitr a tion of F u r a n a n d Th iop h en e Der iva tives 34, 36, a n d 38
a
b
Only isomer 35a appeared in a proton NMR using CDCl3 solvent. Determined by NMR analysis.
5-nitrobenzene.14 Our results represent the first synthesis
of 33 by direct nitration.
The analogous methyl thiophene-2-carboxylate 36 af-
forded two 5-nitro- 37a and 4-nitro-substituted 37b
isomeric products in a 91% combined, isolated yield
(Table 5). A reported nitration of 36 conducted with
fuming HNO3 in concentrated H2SO4 from -20 to 0 °C
gave a 50/50 mixture of 37a and 37b.17 A 50 year old
reference describes the nitration of 36 with HNO3 in
acetic acid from 3 to 30 °C giving a 53% yield of 37a after
methanol recrystallization.18 A 66-67 °C melting point
was reported with no spectral data.
Unexpectedly, an attempted nitration of methyl 5-(chlo-
romethyl)-2-furoate 38 resulted in a 71% conversion to
a single oxidized product, methyl 5-formyl-2-furanoate,
39 without ring nitration (Table 5). Only unreacted 38
and product 39 were found in the isolated product
mixture from oxidation of the chlorinated “benzylic-like”
Nitration of methyl 2-furoate 34 produced a good yield
of isomers 35a and 35b with a 99% combined HPLC
purity (Table 5). Recrystallization from methanol/water
gave an overall 61-66% product yield of pure isomer 35a .
Previously, compound 34 has been nitrated with acetyl
nitrate at temperatures from -10 to -5 °C to give seven
different products with isomer 35a comprising 26% of the
product mixture.15 More recently, a two-pot nitration
using fuming nitric acid in acetic anhydride at -5 °C was
described that gave a 91% yield of 35a following an
extractive workup, filtration through a silica gel pad, and
a methanol recrystallization.16
(14) Cherkasov, V. M.; Remennikov, G. Ya.; Kisilenko, A. A. Chem.
Heterocycl. Compd. (Engl. Transl.) 1982, 526-529.
(15) Kolb, V. M.; Darling, S. D.; Koster, D. F.; Meyers, C. Y. J . Org.
Chem. 1984, 49, 1636-1639.
(16) Padwa, A.; Dimitroff, M.; Waterson, A. G.; Tianhua, W. J . Org.
Chem. 1997, 62, 4088-4096.
(17) Elliott, R. L.; O’Hanlon, P. J .; Rogers, N. H. Tetrahedron 1987,
43, 3295-3302.
(18) Guathier, B.; Maillard, J . Ann. Pharm. Fr. 1953, XI, 509-522.
J . Org. Chem, Vol. 68, No. 2, 2003 271

Shackelford et al.
TABLE 6. P a r a m etr ic (CH3)4NNO3-Ba sed Nitr a tion In vestiga tion of 2,6-Diflu or op yr id in e 40a
a
RT ) room temperature.
TABLE 7. P a r a m etr ic (CH3)4NNO3-Ba sed Nitr a tion of 3,5-Dim eth ylisoxa zole 42
position. Product 39 was authenticated by comparison
with a known sample. The potential scope and synthetic
usefulness of this result is being evaluated.
conversion of concentrated (1.09 M) 40 to 41 at room
temperature over 24 h suggests that a longer reaction
time would provide a complete reaction.
The complete conversion of 2,6-difluoropyridine 40 to
2,6-difluoro-3-nitropyridine 41 presented a challenge.
Previously, compound 41 has been synthesized from the
analogous chlorinated reactant, 2,6-dichloro-3-nitropy-
ridine, to produce 41 in an 81% yield.19 A stringent direct
nitration of 40 using concentrated H2SO4 and 100%
HNO3 gave 41 in a 78% yield.20 Direct nitration of 40 for
24 h with another nitronium salt, NO2BF4 in refluxing
CH2Cl2, gave a 20% yield of product 41.21
Our initial attempts to nitrate reactant 40 with the
General Procedure (0.25 M 40) converted only 50-67%
to product 41 (Table 6). Other unidentified byproduct(s)
also were observed.
Two General Procedure modifications effected a com-
plete conversion (Table 6). First, this reaction was
conducted at a 4.4-fold increase in reactant 40 concentra-
tion (1.09 M). Second, the reaction was stirred at reflux
instead of room temperature. A 100% reactant 40 conver-
sion was achieved in 8 h. Following aqueous workup, the
directly isolated 98% yield of product 41 proved to be
analytically pure by C, H, F, and N analysis.22 Extended
reaction times of 16 and 24 h had no deleterious effect
on the product 41 yield and purity. The clean 78%
With a more activated aromatic ring, 3,5-dimethyl-
isoxazole 42 formed 3,5-dimethyl-4-nitroisoxazole 43 in
100% conversion using the more dilute (0.19 M 42), room
temperature General Procedure conditions (Table 7). A
6-fold concentration increase in reactant 42 (1.13 M)
produced a comparable product 43 yield and purity. Both
conditions gave analytically pure isolated product 43.
Curiously, employing this concentrated reactant condi-
tion at reflux repeatedly gave a 95% conversion of 42
regardless of reaction time. Extended reflux reaction
times had no deleterious effect on product yield or
isolated purity. Product 43 obtained by reflux conditions
was analytically pure when treated for several hours in
a 45 °C vacuum oven.
Nitration of the less activated methyl 5-methylisox-
azole-3-carboxylate 44 under comparable General Pro-
cedure conditions with 0.23 M reactant gave an 86%
conversion to product 45 (Table 8). Again, only desired
product 45 and 14% unconverted reactant 44 were in the
isolated mixture. A 5-fold increase in reactant 44 con-
centration and refluxing the stirred reaction for 24 h gave
a 100 % isolated yield of analytically pure product 45.
Product 45 is an unreported compound.
(19) Radl, S.; Hradil, P. Collect. Czech. Chem. Commun. 1991, 56,
2420-2429.
(22) While compound 41 shows a propensity to retain trace amounts
of CH2Cl2 solvent and still give analytically pure analyses, this residual
solvent retention was not seen with the other nitrated products
investigated.
(20) Mutterer, F.; Weiss, C. D. Helv. Chem. Acta 1976, 59, 229-
235.
(21) Duffy, J . L.; Laali, K. K. J . Org. Chem. 1991, 56, 3006-3009.
272 J . Org. Chem., Vol. 68, No. 2, 2003

Tetraalkylammonium Nitrate Nitration
TABLE 8. (CH3)4NNO3-Ba sed Nitr a tion of Meth yl-5-m eth ylisoxa zole-3-ca r boxyla te 44
a
Determined by NMR analysis.
TABLE 9. Micr ow a ve-Assisted (CH3)4NNO3-Ba sed
Nitr a tion of a 2,6-Diflu or op yr id in e 40
The reaction vessel was vented and resealed, and run 6
was reinitiated with no further pressure anomaly.
Several conclusions are drawn from Table 9. The
nitration is complete after no more than 15 min of
irradiation (runs 1 and 3). The temperature and number
of equivalents of nitrating agent 3 have a distinct effect
in driving the reaction to completion (runs 2-4 and 7-9).
Higher temperature reactions for longer periods of time
appear to have no significant deleterious effect on product
yield or purity (runs 5-7).
This microwave-assisted nitration successfully was
scaled 15.8 times larger with 40 using a 250 mL reaction
vessel (Table 10). After aqueous workup, a quantitative
8.89 g yield of 98% analytically pure product 41 was
obtained. Table 10 compares the smaller and larger scale
15 min microwave-assisted reactions with the 8 h large-
scale conventional benchtop nitration conducted at reflux
(Table 6).
irradiation
time
% isolated
conversion
(%)
yield
run no. equiv of 3 temp
(min)
(purity)
1
2
3
4
5
6
7
8
9
1.3
1.3
1.3
1.3
1.5
1.5
1.5
1.5
1.5
60 °C
60 °C
60 °C
100 °C
110 °C
100 °C
100 °C
60 °C
10/5
15/5
30
15/15
10/5
10/5
10/5
10/5
10/5
91
96a
91
75
97
92
100
100b
100
96
91 (98)
91 (98)
91 (98)
85
80 °C
100
94 (100)
a
b
Momentary temperature spike to ca. 125 °C. Initial pressure
Four other compounds were nitrated under small-scale
microwave conditions with excellent results (Table 11).
The distribution of nitrated ortho-, meta-, and para-
nitromethylphenyl sulfone isomers 6h , obtained at a high
reactant 5h concentration, is similar to that obtained
with the General Procedure conditions (Table 1). An
elemental analysis of the isomeric product mixture 6h
obtained at 80 °C was consistent with the C7H7NO4S
formulation of the three mononitrated isomers. The
isomeric o/m/p percentages for mixture 6h were assigned
by proton NMR using data reported for pure isomers.23a,b
A total conversion with very high yields of analytically
pure nitrated heteroaromatic products 31, 43, and 45
occurred with pyrimidine 30, as well as isoxazoles 42 and
44, respectively, with isolated yields and purities com-
parable to those of our conventional benchtop nitrations
(Tables 4, 7, and 8). Small-scale microwave nitration of
44 gave 0.64 g of product 45 (Table 11). A large-scale
nitration of 44 using the Ethos microwave instrument
afforded a quantitative 5.03 g isolated yield of analyti-
cally pure 45.
spike greater than 20 bar.
Micr ow a ve-Acceler a t ed Nit r a t ion . Microwave-
assisted reaction conditions were applied to this tetra-
methylammonium nitrate-based nitration. Reactions were
conducted under an N2 gas in sealed reaction vessels at
high reactant concentrations (1.09-1.15 M) with 1.5
equiv of 3 and reaction temperatures above the CH2Cl2
solvent boiling point. A Personal Microwave “Smith
Creator” apparatus was used in all small-scale reactions.
Two large-scale nitrations were conducted in a Milestone
“Ethos” oven. Reagent 3 was generated first by reacting
1 and 2 at room temperature for at least 1.5 h before
adding reactant 5 and initiating microwave irradiation.
To ensure adequate mixing of the reactant suspension,
small-scale microwave nitrations were conducted in two
irradiation steps. Time entries in Tables 9 and 11,
separated by a forward slash, denote the two-step
microwave irradiations that sandwich reaction vessel
hand agitation or magnetic stirring to ensure adequate
reaction suspension mixing.
The optimum microwave nitration conditions needed
for a 100% conversion of 2,6-difluoropyridine 40 to
analytically pure isolated product 41 appear in run 9 of
Table 9.
Su m m a r y
Our use of inexpensive tetramethylammonium nitrate
1 with trifluoromethanesulfonic anhydride 2 to generate
the nitronium triflate 3 in situ with CH2Cl2 solvent
introduces a convenient, new one-pot nitration for
aromatic and heteroaromatic compounds 5. Advanta-
When a rapid temperature rise to ca. 125 °C occurred
in run 2, microwave irradiation was manually stopped,
and the sample was cooled below 60 °C. The microwave
was restarted, and no further exotherm resulted. Micro-
wave irradiation in run 6 initially produced a very rapid
pressure increase. An equipment safety feature auto-
matically stopped the reaction at a pressure of 20 bar.
(23) (a) Caccamese, S.; Finocchiaro, P.; Maravigna, P.; Montaudo,
G.; Recca A. Gazz. Chim. Ital. 1977, 107, 163-169. (b) Montaudo, G.;
Finocchiaro, P.; Trivellone, E.; Bottino, F.; Maravigna, P. J . Mol. Struct.
1973, 16, 299-306.
J . Org. Chem, Vol. 68, No. 2, 2003 273

Shackelford et al.
TABLE 10. Con ven tion a l Ben ch top a n d Micr ow a ve-Assisted Nitr a tion of 2,6-Diflu or op yr id in e 40a
a
Note: all samples of isolated product 41 were analytically pure by C, H, F, and N analysis.
TABLE 11. Micr ow a ve-Assisted (CH3)4NNO3-Ba sed Nitr a tion of Oth er Ar om a tics
a
b
Percentage of o/m/p isomers: 16/80/4. Percentage of o/m/p isomers: 17/79/4. c Total of all three o/m/p isomers.
tant. Elemental analyses were conducted by Atlantic Microlab,
Inc., Norcross, GA, or Quantitative Technologies, Inc., White-
house, NJ . The term “isolated product” refers to the product
obtained directly from reaction workup without any additional
purification. Where more or less than 7.50 mmol of reactant 5
was nitrated using the General Procedure, all amounts were
scaled directly by the same factor, including workup quantities.
Reactant 2 addition times were adjusted as necessary.
geously, simple aqueous workup removes primary byprod-
ucts from the desired isolated product 6. Compared with
traditional literature nitrations, improved isolated prod-
uct yield, isomer selectivity, and purity often result using
this nitration reaction. Directly isolated products fre-
quently require no further purification, and many were
found to be analytically pure.
Complete reactant conversion to mononitrated prod-
ucts can be effected with a wide scope of electron-rich to
electron-deficient compounds by optimizing reactant
concentration, temperature, and time. Both conventional
benchtop and microwave-assisted reaction procedures are
suitable for this nitration. Particularly noteworthy is the
demonstrated ease and safety of our nitration reaction
on a 1 to 500 g scale. Two known compounds were
obtained for the first time by direct nitration, and five
novel, unreported nitrated aromatic and heteroaromatic
compounds were synthesized and characterized.
Gen er a l P r oced u r e. Under a N2 gas blanket at room
temperature, between 2.26 and 2.39 g (8.01-8.47 mmol) of 2
were added dropwise to a stirred suspension of 1.12 g (7.89
mmol) 96% tetramethylammonium nitrate 1 in 20 mL of DCM
with a slight temperature rise.24 The addition funnel was
rinsed with 8 mL of anhydrous DCM that was added to the
reaction suspension. After stirring for at least 1.5 h at room
temperature, the stirred suspension was cooled in a CO2/
acetone bath. To the stirred nitronium triflate suspension was
added dropwise 7.50 mmol of aromatic substrate 5 dissolved
in 10 mL of DCM while keeping the reaction temperature at
-65.0 °C or lower. The addition funnel was then rinsed with
2 mL of anhydrous DCM that was added to the stirred reaction
suspension giving a 0.19 M reactant concentration. The
reaction suspension was kept under N2. The cooling bath could
then be removed; some reactions proceeded more cleanly if the
bath remained and gradually warmed unattended to room
temperature.25 The stirred reaction was quenched with 15 mL
of 5% aqueous NaHCO3 to give an aqueous layer of pH 8 (with
Exp er im en ta l Section
Gen er a l Con sid er a tion s. All NMR spectra were obtained
at 300 MHz. Use of FI/MS, GC/MS, or ES/MS analyses was
compound dependent. FTIR data were obtained as KBr pellets
or as thin film deposits using the attenuated total reflectance
method. Unless stated otherwise, product purities were de-
termined by HPLC/UV at 220 nm. Anhydrous, low-water, or
reagent-grade dichloromethane (DCM) solvent was used as
received. Both the tetramethylammonium nitrate (96%) and
trifluoromethanesulfonic anhydride were used as received.
Millimole calculations reflect the stated purity of each reac-
(24) The small-scale (7.50 mmol) reactions used a 6-12 min addition
time with a resultant 2-3 °C temperature rise. The larger scale (86-
100 mmol) reactions used a 12-20 min addition time with a corre-
sponding 3-5 °C temperature rise. The maximum temperature
occurred 25-40 min after addition was begun. Exothermicity during
this addition presented no serious issue.
274 J . Org. Chem., Vol. 68, No. 2, 2003

Tetraalkylammonium Nitrate Nitration
acidic compounds 5b, 5g, and 11, water was substituted to
keep an acidic pH). The lower DCM layer was separated and
washed with 5 × 25 mL of H2O. The combined H2O washes
were back-extracted with 25 mL of DCM. The two combined
DCM portions were dried over MgSO4. DCM removal by rotary
evaporation gave the isolated product 6.
1,4-Dim eth oxy-2-n itr oben zen e (8). Small Scale. Reacted
1.04 g (7.50 mmol) 7 with 1.05 equiv of 3 in 40 mL of DCM
(0.19 M 15) for 17 h to obtain an isolated yield of 0.97 g (71%):
FW ) 183.1; 1H NMR (DMSO-d6) δ 7.46 (s, 1H), 7.28 (m, 2H),
3.93 (s, 3H), 3.86 (s, 3H); GC/MS (CI, m/z) 183 (M+ and base
peak); FTIR (KBr) 3071, 3024, 2982, 2946, 2844, 1528, 1355
cm-1; mp uncorrected, (crude ) 68.6-70.0 °C), (HPLC purified
) 70.8-71.2 0 °C), lit. mp ) 71-73 °C,26a 68-70 °C,26b 71 °C.26c
Anal. Calcd for C8H9NO4: C, 52.46; H, 4.95; N, 7.65. Found:
C, 52.55; H, 4.94; N, 7.63.
colored oil: FW ) 160.1; 1H NMR (DMSO-d6) δ 8.94 (over-
lapped dd, 3H), 7.45 (d, 3H); FTIR (ATR film) 3018, 1534, 1348
cm-1; HPLC purity analysis ) 99.4%; GC/MS (CI, m/z) 161
(M+ + 1). Anal. Calcd for C5H2F2N2O2: C, 37.52; H, 1.26; F,
23.74; N, 17.50. Found: C, 37.69; H, 1.26; F, 23.92; N, 17.34.
Micr ow a ve-Assisted Sm a ll-Sca le P r oced u r e: 2-Ch lor o-
4,6-d im et h oxy-5-n it r op yr im id in e (31). A 5 mL Personal
Microwave reaction vessel with a stir bar was charged with
0.72 g (5.07 mmol) of 96% 1 and 1 mL of DCM. Under N2,
1.50-1.58 g (5.32-5.60 mmol) of 2 was added to the suspen-
sion with a capillary pipet followed by 1 mL of DCM. The
reaction vessel was stoppered, and the suspension was stirred
at room temperature for 1.5 h. To this stirred suspension of 3
under N2 were added 0.60 g (3.44 mmol) of 30 and 1 mL of
DCM (1.15 M 30). The crimp-sealed vessel contents briefly
were stirred and then irradiated at 60 °C for 10 min. The vessel
was removed and stirred and then irradiated for another 5
min. The cooled reaction contents were quenched by being
added to 25 mL of 5% aqueous NaHCO3 to give an aqueous
layer with a pH ) 8. The vessel was rinsed with 10 mL of
DCM and then 25 mL of H2O, and both were added to the
stirred NaHCO3 solution. The DCM layer was separated and
washed with 5 × 10 mL of H2O. The combined H2O portions
were back-extracted with 10 mL of DCM. The two DCM
portions were combined and dried over MgSO4. DCM removal
by rotary evaporation followed by room temperature vacuum
oven drying gave 0.69 g (91%) of white solid isolated product
2,6-Dim eth oxy-3-n itr oben zon itr ile (20). Large Scale.
Reacted 16.82 g (100.0 mmol) 19 (97%) with 1.50 equiv of 3 in
400 mL of DCM (0.25 M 19) for 1 h in a dry ice/acetone bath,
3 h in a dry ice/acetonitrile bath, and 48 h at room tempera-
ture11 to obtain an isolated yield of 20.85 g (100%): FW )
1
208.2; H NMR (DMSO-d6) δ 8.34 (d, 1H), 7.18 (d, 1H), 4.04
(s, 6H); FI/MS (APCI, m/z) 209 (M+ + 1), 208 (M+), 179 (base
peak); GC/MS (CI, m/z) 208 (M+), 178 (base peak); FTIR (ATR
film) 3096, 2995, 2955, 2884, 2852, 2236, 1584, 1520, 1353
cm-1; HPLC purity analysis ) 96.7%. A second nitration of
19 on the same scale using a 44 h reaction time at room
temperature11 gave isolated product 20: HPLC purity analysis
) 97.2%. Recrystallized from methanol. Anal. Calcd for
C9H8N2O4: C, 51.93; H, 3.87; N, 13.46. Found: C, 52.11; H,
3.90; N, 13.46.
1
31: FW ) 219.6; H NMR (DMSO-d6) δ 4.06 (s, 6H); GC/MS
(CI, m/z) 220 (M+ + 1 and base peak); HPLC purity ) 100%;
FTIR (ATR) 3045, 3017, 2958, 2942, 2885, 1529, 1376 cm-1
.
Anal. Calcd for C6H6ClN3O4: C, 32.82; H, 2.75; Cl, 16.15; N,
19.14. Found: C, 33.00; H, 2.70; Cl, 16.36; N, 19.20.
Mod ified Con cen tr a ted P r oced u r e: 2,6-Diflu or o-3-n i-
tr op yr id in e (41). Under N2 in a 100 mL three-necked reaction
flask fitted with a H2O-cooled reflux condenser and containing
3.49 g (24.60 mmol) of 96% 1 in a 10 mL DCM suspension,
7.04 g (24.96 mmol) of neat 2 was added via capillary pipet
followed by 2 mL of DCM. The suspension was stirred at room
temperature for 1.5 h. Reactant 5 (1.89 g, 16.4 mmol) was
added directly to a magnetically stirred suspension via capil-
lary pipet at room temperature followed by 3 mL of DCM. The
reaction was stirred under reflux for 8 h. The cooled reaction
was quenched by adding 42 mL of 5% NaHCO3 to bring the
aqueous layer to pH 8. The DCM layer was separated and
washed with 5 × 50 mL of H2O. The combined H2O portions
were back-extracted with 15 mL of DCM. The two DCM
portions were combined and dried over MgSO4. Solvent
removal by rotary evaporation and drying for 46 min in a room
temperature vacuum oven gave 2.58 g (99%) of 41 as a golden-
Ack n ow led gm en t. The authors thank Dr. Cathy
1
Moore for key H NMR discussions, Dr. Eric Milgram
for the ES/MS analyses, Dr. Manuel Ventura and Ms.
Catherine Pham for GC/MS assistance, Mr. Michael
Greig for ANCI/MS analyses, and Dr. Eric Sun for an
authentic sample of compound 39. Ms. Christine Au-
rigemma, Mr. Kevin Fiori, Ms. Lola Posey, Ms. Phuong
Tran, Ms. Xiaobing Xiong, and Mr. William Farrell
assisted with and conducted HPLC purity analyses. Mr.
Andrew Anderson provided FTIR assistance. Mr. J ames
Grant assisted with key library searches. Dr. Klaus
Dress verified German journal translations. Mr. Bruce
Fan obtained thermal analysis data. Mr. J ohn Porter
arranged for melting point determinations.
(25) Compounds 7 and 9 reacted immediately at CO2/acetone bath
temperature. Compounds 11, 13, 17, and 19 appeared to react slightly
above -50 °C. More deactivated compounds 5d -h reacted only slowly
at room temperature. For these, reactants could be added at room
temperature.
(26) The three most recently reported melting points for 16 are found
in the following references: (a) Sankararaman, S.; Kochi, J . K. Recl.
Trav. Chim. Pays-Bas 1986, 105, 278-285. (b) Errazuriz, B.; Tapia,
R.; Valderrama, J . A. Tetrahedron Lett. 1985, 26, 819-822. (c)
Rajamohan, K.; Rao, N. V. S. Indian J . Chem. 1973, 11, 1076-1077.
Su p p or tin g In for m a tion Ava ila ble: Small and large-
scale conventional benchtop plus microwave irradiation pro-
cedures, reaction conditions, and spectral characterization of
products 10a , 10b, 12, 14, 16a , 18, 22a , 22b, 31, 33, 35a , 35b,
37a , 37b, 39, 41, 43, 45, and 46o/m /p . This material is
available free of charge via the Internet at http://pubs.acs.org.
J O026202Q
J . Org. Chem, Vol. 68, No. 2, 2003 275