Bromo-nitro substitution on a tertiary α carbon - A previously uncharacterized facet of the Kornblum substitution

Article abstract of DOI:10.1039/c5ra14798k

Sodium nitrite in dimethylformamide substitutes nitro for bromine alpha to an amide carbonyl in high yield at a tertiary site. Hammett plots show a strongly positive ρ value (+0.67), indicating a negatively-charged transition state, in contrast to the typical S_N1/S_N2 mechanism domain for Kornblum substitutions. 2015

Full text of DOI:10.1039/c5ra14798k

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Bromo–nitro substitution on a tertiary a carbon—a
previously uncharacterized facet of the Kornblum
substitution†
Cite this: RSC Adv., 2015, 5, 76401
*
Matthew J. Leonard,‡ Peter G. McKay and Anthony R. Lingham
Received 26th July 2015
Accepted 3rd September 2015
Sodium nitrite in dimethylformamide substitutes nitro for bromine alpha to an amide carbonyl in high yield
at a tertiary site. Hammett plots show a strongly positive r value (+0.67), indicating a negatively-charged
transition state, in contrast to the typical SN1/SN2 mechanism domain for Kornblum substitutions.
DOI: 10.1039/c5ra14798k
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to prepare an a-nitroisobutyranilide (2) in order to perform an
alternative synthesis of the hydantoin anti-baldness compound
RU58841, a process that we published in 2014.10 The reaction
was simple and performed in high yield with low cost materials
(Fig. 3).
Introduction
The Kornblum substitution is the replacement of a halogen on
an organic compound by a nitro group by using sodium nitrite
(NaNO2) as a nitrite source and DMF as a solvent. The reaction
proceeds in high yields at room temperature and does not
require anhydrous conditions. It was discovered and widely
characterized by Nathan Kornblum (Fig. 1) at Purdue University,
Indiana in the 1950s.1–3
In 1991 Noboru Ono published a textbook that summarized
the key methods for the preparation of nitro compounds4 fol-
lowed by an updated version in 2001 (ref. 5) (while writing this
book, Ono collaborated with Kornblum, who was late in his
career and died shortly aer). Ono named the substitution “the
Kornblum reaction” in both the 1991 and 2001 versions.4,5
However, in 2002 the term “Kornblum reaction” was used by
Mamedov et al. to refer to the Kornblum oxidation,6 which is a
different reaction that was also elucidated by Kornblum. Yet a
third reaction has also been named aer Kornblum, namely the
Kornblum–DeLaMare rearrangement.7 We propose that the X–
NO2 substitution that was characterized by Kornblum be
described as the ‘Kornblum substitution’. We here discuss and
further characterize the Kornblum substitution.
We had discovered that it was possible to do a Kornblum
substitution on the a-bromoisobutyranilide (1) when we
observed that the product of 1 treated with NaNO2 in DMF
appeared as an M-89 signal on a GC-MS. We found that an aryl
isocyanate (Ar–NCO) was forming with the loss of 2-nitro-
propane under the high temperature conditions of the GC-MS
injector port, but that at room temperature the a-bromoisobu-
tyranilide (1) readily formed the a-nitroisobutyranilide (2),
which could be crystallized by the addition of water.
We note that among Kornblum's original writings on the
topic, in one paper Kornblum described the substitution as
occurring on primary and secondary carbons alpha to a
carbonyl.11 He subsequently placed a patent on this process for
the preparation of a-nitroesters from a-haloesters which
included an example of a tertiary nitro compound – the prepa-
ration of ethyl a-nitroisobutyrate (4) from ethyl a-bromoisobu-
tyrate (3)12 (Fig. 4).
The example in this patent of a tertiary halo–nitro substitu-
tion alpha to a carbonyl seems to have remained unnoticed; in
1971 Sayo et al. used a longer four-step synthesis to achieve a
The Kornblum substitution was summarized by Ono and
others as occurring on primary and secondary halogeno
compounds, but not tertiary where a HX elimination product is
consistently observed4,5,8,9 (Fig. 2). Kornblum's original obser-
vations2 support this view.
However, we have found that the Kornblum substitution
does proceed on a tertiary centre that is alpha to an anilide
carbonyl group. We have hence used the Kornblum substitution
RMIT University, 1 Bowen street, Melbourne 3001, Australia. E-mail: Matthew.
Leonard742@gmail.com
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c5ra14798k
‡ The following content is taken, in part, from the PhD thesis of the primary
author, Matthew Leonard.
Fig. 1 Nathan Kornblum.
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Fig. 2 The Kornblum substitution.
Fig. 3 An a-nitroisobutyranilide from an a-bromoisobutyranilide.
library of a-nitroisobutyranilides,13 which could have been done paper2 to prepare ethyl a-nitroisobutyrate (4) from ethyl a-bro-
in two steps if they had used the pathway shown in Fig. 3.
moisobutyrate (3); in 1977 Gelbard and Colonna15 carried out
The Kornblum substitution was subsequently performed on the Kornblum substitution on tertiary halo ethyl esters in order
a tertiary alpha carbon twice more by other workers, neither of to characterize the effectiveness of a new type of nitrite resin.
whom commented on the novelty of the substitution's occur- These three reports have gone generally unnoticed by the
ring at a tertiary halo carbon. In 1957 Kissinger and Ungnade14 organic synthesis community; later publications in the 1990s
stated that they followed Kornblum's method from his 1956 and 2000s still regarded the Kornblum substitution as not
Fig. 4 Preparation of ethyl a-nitroisobutyrate from Kornblum's 1957 patent.12
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Fig. 5 Chloro–thiocyanate substitution as observed by Glushkov et al.22
proceeding on a tertiary centre.16–18 Kornblum spoke entirely in that the attacking nucleophile bridges the carbonyl and the
terms of SN2 and SN1 mechanisms, and the general belief is that alpha carbon (and, by the principle of microscopic reversibility,
a bromo–nitro substitution will not proceed at such sites due to the leaving group must also bridge both positions).70 This
steric hindrance on the tertiary carbon, which impedes an SN2 mechanism has been supported by recent computational
pathway.19 It does encourage SN1, but the nitrite ion is an studies,71–73 some of which suggest that there is a bifurcation in
ambident nucleophile,20 and SN1 substitution by nitrite is the potential energy surface aer the transition state, a situa-
known usually to involve nucleophilic attack by the harder tion in which conventional transition state theory breaks down
oxygen atom (acting under charge control21), giving an alkyl and molecular dynamics may become important.74–77 It has also
nitrite product (R–O–N]O).8 SN2, on the other hand, sees been suggested that substitution is by SN1 reaction, and that
nucleophilic attack occur from the soer nitrogen atom (under this is accelerated by neighbouring group participation by the
orbital control) to furnish an alkyl nitro compound (R–NO2).8 carbonyl, creating a 2H-oxirenium cation,78 or by prior enoli-
The concept that an SN1 or an SN2 process will control the sation on the other side, creating an allylic system;79 other
product of an attack by an ambident nucleophile has been suggestions include via a carbene produced from an enolate,67
called “Kornblum's rule”.20
and through nucleophilic attack at the halogen.32,41,67 Evidence
A 1997 paper by Glushkov and co-workers22 shows evidence for each mechanism, and against other mechanisms, has been
that Kornblum's rule does not apply to tertiary halo carbons found by different workers in different reactions, and many
with an alpha carbonyl. The authors expected that Kornblum's writers give evidence that different mechanisms dominate in
rule would see thiocyanate ions (SCNꢀ) attacking the carboca- different circumstances.23,32,55,73
tion from a tertiary halo compound in an SN1 manner to form
In most papers Kornblum generally described the substitu-
an isothiocyanate (R–NCS), but instead from their substrates tion as SN2, but in one paper he described it as more SN2 than
they observed thiocyanate products (Rʹ–SCN) (Fig. 5), which are SN1 in nature, but with properties of both.80 As the substitu-
the expected result of an SN2 substitution (attack by the more tion's proceeding on a tertiary centre is at odds with Kornblum's
polarizable atom on the ambident nucleophile).
stated SN2 mechanism, we suspected that a different mecha-
Glushkov et al. postulated that the destabilizing effect of an nism was operative. We have therefore prepared a library of a-
alpha carbonyl prevented the formation of a carbocation and nitroisobutyranilides to show prima facie trends of the rate of
caused their substitution to occur by an SN2 process.22 Their Br–NO2 substitution, and to prepare Hammett plots from the
language, like many others', suggests that they consider SN1 and rate data to indicate any charge in the transition state that
SN2 to be the only two options.
would hint at the mechanism.
It has been frequently noted that nucleophilic substitution
reactions alpha to a carbonyl show atypical properties.23,24 They
are, in particular, unusually fast,25–31 though how much so
depends on the nucleophile and other circumstances.32–40
Various mechanistic reasons have been proposed for this. Some
authors argue that addition takes place initially at the carbonyl,
followed by either a 1,2-shi of the nucleophile to the alpha
position,41–47 or, alternatively, formation of an epoxide that
reacts with further nucleophile at the alpha position.40,48–55
Other authors reject this and contend that the reacting nucle-
ophile makes an ordinary SN2-like attack at the carbon bearing
the leaving group, but is assisted by interaction with carbonyl
p* antibonding orbitals that temporarily accept electron
density (oen described as conjugation with the p orbitals or
the p system, or as an enolate-like transition state),34,37,38,56–65 or
alternatively by purely electrostatic effects.23,66–69 More recently a
halfway position between these two extremes has been urged:
Results and discussion
In order to prepare a library of a-bromoisobutyranilides,
anilines of varied substitution were selected with both greater
and lesser electron withdrawing capacity than R ¼ phenyl and
also aniline itself (Table 1). The library of a-bromoisobutyr-
anilides were then each exposed to a 10 : 1 molar ratio of
sodium nitrite to reactant compound using DMF as solvent at
ambient temperature. The rate of conversion was monitored by
taking hourly aliquots for GC-MS analysis. It was observed that
the more electron-withdrawn the compound, the faster the
bromo–nitro substitution took place.
As well as a-bromoisobutyranilides, which have an aryl
group beyond the amide nitrogen, two compounds with an alkyl
group in place of the aryl, n-butyl and benzyl, were also
prepared, and found to undergo bromo–nitro substitution but
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Table 1 a-Bromoisobutyranilides monitored for their rate of Br–NO2
substitution
but its rate of Br–NO2 substitution to give 36 could be easily
monitored. It is therefore included in the graph to show the
additional increase in rate when the compound's R group had
the electron withdrawing capacity of two nitro groups and, as
expected, it proceeds much faster than the mono-nitros and the
CN/CF3 substituted compounds (1).
Some general trends in the bromo–nitro substitution were
immediately apparent before any calculations were applied to
the data. The rst principle that overrides all others is that the
reaction goes faster when the R group is more electron with-
drawing, no matter how the R group is congured. Changes
such as switching between ortho, meta and para substituted
groups have a comparatively small effect on rate.
An overview of the rate data is shown in Fig. 6. The %
substrate is plotted logarithmically: most compounds showed
close to pseudo-rst order behaviour. The sodium nitrite was
present in ten-fold excess; it has limited solubility in DMF and
excess solid was present. The solution was rapidly stirred,
keeping the nitrite concentration constantly near saturation.
Approximate straight lines of best t are shown.
It was observed that reactions of ortho substituted a-bro-
moisobutyranilides proceeded faster than the equivalent meta
or para isomers for the three substituents, methoxy, chloro and
nitro, for which we had data. It may be that a substituent on the
aryl ring closer to the site of halo–nitro substitution facilitates
the substitution through some form of steric acceleration. This
is shown in Fig. 7–9.
Bromo
Nitro
compound compound R-Substituents
p-Cyano-m-
triuoromethyl
H
1
2
5
6
7
8
p-Methyl
9
10
12
14
16
18
20
22
24
26
28
30
32
o-Carboethoxy
o-Nitro
m-Nitro
p-Nitro
o-Bromo
o-Chloro
m-Chloro
p-Chloro
o-Methoxy
m-Methoxy
p-Methoxy
Benzyl in place
of phenyl
n-Butyl in place
of phenyl
2,4-Dinitro
11
13
15
17
19
21
23
25
27
29
31
33
35
34
36
at a much reduced rate compared with the aryl compounds. An
additional a-bromoisobutyranilide with 2,4-dinitro substitution
(35) was not characterized due to extreme difficulty of isolation
Fig. 6 Substitution rate for tertiary a-bromoisobutyranilides.
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the ortho position gives signicantly faster reaction than chloro
in the ortho position. As bromo and chloro are quite similar
except for size, it appears that in this case we are observing
steric facilitation of the nearby substitution by the larger bromo
group managing to outweigh the normally stronger effect of rate
increasing with electronegativity.
This contrasts with reported observations that ortho
substituted phenacyl bromides are less reactive in nucleophilic
substitution by pyridine or t-butylamine.41,42,65
Br–NO2 substitution at low nitrite concentration
Our reaction conditions used saturated sodium nitrite in DMF.
To investigate the dependence of the rate on nitrite concentra-
tion, we sought to increase the solubility of nitrite ions in DMF by
using a co-solvent. Kornblum reported that the addition of 8%
urea to the DMF dissolved far more NaNO2 which further
increased the rate of substitution.11 When we tried the reaction
this way we observed a slight reduction in rate, and saw no
increase in solubility. We are puzzled by Kornblum's use of urea.
He may have intended it to react with free nitrous acid81 (which he
discussed as responsible for the degradation of the desired nitro
products), but there may have been reaction with some nitrite.
Therefore we instead used a low concentration experiment to
compare the substitution rate of 1 / 2 in a saturated solution
of NaNO2 in DMF with rates observed in solutions that con-
tained only 75% and 50% the concentration of a saturated
NaNO2 solution. The reaction rate was lowered under these
conditions (Fig. 10).
Fig.
7
Substitution
rate
for
methoxy
substituted
a-
bromoisobutyranilides.
The rate varied much less between the three chloro
substituted compounds than it did for the nitro and methoxy
compounds. The difference could be steric, or perhaps due to
nitro and methoxy's capability for hydrogen bonding; both can
bend with free rotation and contain free electron pairs.
However, one exception to the rst principle of increased
rate with more electron-withdrawing R groups is that bromo in
This change in rate is evidence against an SN1 mechanism as
the rate-limiting step of an SN1 reaction would be the formation
of a cationic intermediate, independent of the presence of
nitrite ions. This clearly cannot be an exclusive SN1 process and
we can declare that the nitrite must be taking part in the rate-
limiting step.
Hammett plots
First-order plots of ln(%substrate) against time were prepared
for the reactions of the compound library. The slope of these is
ꢀk0, where k0 is the pseudo-rst-order rate constant. As has been
mentioned, a dilution experiment showed that the reaction rate
depends also on nitrite concentration, so these reactions are
Fig.
8
Substitution
rate
for
chloro
substituted
a-
bromoisobutyranilides.
Fig. 9 Substitution rate for nitro substituted a-bromoisobutyranilides. Fig. 10 Effect of nitrite concentration on 1 / 2 reaction rate.
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Fig. 11 Hammett plot.
only pseudo rst order due to the nitrite concentration's Hammett plot against ordinary s values (from benzoic acid Ka
remaining effectively constant throughout the reaction. The values) gave a t that was not terribly good (R2 ¼ 0.92). A plot
nitrite concentration was the same in each experiment: ꢁ5 using s+ values84 (based on benzylic SN1 solvolysis, with a
mmol of the a-bromoisobutyranilide reactant (1–2 g) with positive charge next to the ring), which have strong through-
NaNO2 (4.00 g, 44.9 mmol) in 40 mL of DMF.
conjugation effects with electron-donating substituents gave a
Data and plots for individual compounds are shown in the much worse t (R2 ¼ 0.76). We then tried sꢀ values,§ originally
ESI,† with linear regression analysis. The linearity of these rst based on phenol Ka values, so a negative charge next to the ring
order plots is reasonably good, except for the fastest reactions, and strong through-conjugation effects with electron-
especially 1 / 2. In many cases, however, there was some withdrawing substituents: this gave the best t of all (R2
noticeable deviation from linearity or accuracy at the longer time 0.99) and a r of +0.67: in the phenol acidity standard r is 2.01.
scales and using the earlier portion of the data (never fewer than This result implies that not only does this reaction have a
¼
nine data points) gave more accurate linearity and improved the negative charge on the transition state, but that charge can
R2 value considerably (these are shown in the ESI†). As well as the readily conjugate onto the ring.
usual decline of analytical accuracy at lower concentrations, a
A combined Hammett plot of both meta and para substituted
ꢀ
ꢀ
small amount of the formed nitro product may degrade by further compounds, using smeta and spara values,{ gave R2 ¼ 0.992
reaction with nitrite ions via a nitroso intermediate to produce and a r value of 0.68 (Fig. 11).
the alkyl nitrite by-product (a process described by Kornblum82).
The positive r implies a mechanism in which the nucleo-
The k0 values obtained from these graphs for the meta and para phile attacks rst, before the leaving group leaves. One might
substituted anilides were used to construct Hammett plots. The think that the large r and the correlation with sꢀ implies the
meta examples, when plotted (as log10 k0/k0H) against ordinary
smeta values83 (which are based on Ka values for benzoic acids),
ꢀ
§ We have normally used the preferred sp values of Hansch, Leo and
gave a reasonable t (R2 ¼ 0.97) and showed a positive r value of
ꢀ
colleagues.85,86 However there is disagreement concerning the best value of sp
for methoxy. Hansch et al. prefer ꢀ0.26, which is essentially sp (ꢀ0.27); but this
and similar values are only obtained when the anilinium acidity is used as the
basis of measurement. When using aqueous phenols, p-methoxyphenol's acidity
requires a sp in the range ꢀ0.10 to ꢀ0.135,87–92 and these values give the best
0.70, indicating that the transition state develops a negative
charge relative to the starting species in the rate-determining step.
The para substituted compounds are more complex to
consider because ‘through conjugation’ is possible, where a
canonical form can be drawn that puts the charge right at the
para position and potentially on the substituent itself. A
ꢀ
t to our data.
ꢀ
ꢀ
{ We used Chuchani and Frohlich's values of sm and sp for methoxy92 and
ꢀ
ꢀ
Zeng's values of sm for chloro and nitro.93 The remaining sp values are from
Hansch, Leo and colleagues.85,86
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Fig. 12 Planar and conjugated anilide p system.
negative charge that forms must be on the nitrogen, but this pushing the nitro to do a 1,2-shi onto the adjacent atom
isn't necessarily so. In anilides there is strong p character in the (like a semipinacol rearrangement), displacing the halogen
nitrogen–carbonyl bond and therefore the whole group has a p (which may leave rst to give either a carbocation or an
system that is planar with and conjugated with the aromatic epoxide). [cf. (ref. 41–47)] (Fig. 13).
ring's p system (Fig. 12).
(2) In the rate-determining step nitrite adds to the
Therefore the negative charge that forms could be on the carbonyl as nitrite, forming a negative oxygen. The carbonyl
amide carbonyl, or on the position a to the carbonyl, as even re-forms, pushing the nitrite nitrogen onto the adjacent atom
there it will be conjugated with the ring (cf. hydrolysis of cin- in a four-centre reaction and displacing the halogen (which
namic esters, which has r ¼ 1.27.).
may leave rst to give either a carbocation or an epoxide)
If the mechanism started with deprotonation of the amide (Fig. 14).
NH, where would it go next? One can only imagine forming an
(3) The negative oxygen formed in possibilities 1 or 2 could
a-lactam, which would surely break open at the carbonyl. In any form an epoxide by displacing the adjacent bromide (which may
case, that mechanism wouldn't be available when the starting leave rst), then more nitrite could add at the other side of the
compound was an a-bromoester, and we know they also epoxide. The carbonyl re-forms, pushing off the rst nitrite. [cf.
react.1,12 Hence it appears that it must start with at least partial (ref. 40 and 48–55)] (Fig. 15).
addition at the carbonyl, or formation of an enolate. This
provides several possibilities, each of which has several sub- alpha carbon. Some electron density temporarily resides in the
possibilities: carbonyl p* antibonding orbital. The nucleophile nally
(4) The nitrite nucleophile bridges the carbonyl and the
(1) In the rate-determining step nitrite adds to the carbonyl displaces bromide in an SN2-like attack. [cf. (ref. 70–73)]
as nitro, forming a negative oxygen. The carbonyl re-forms (Fig. 16).
Fig. 13 Possible mechanism number one.
Fig. 14 Possible mechanism number two.
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Fig. 15 Possible mechanism number three.
(5) The rate-determining step is nucleophilic attack by
None of these options can be ruled out completely. The
nitrite (through nitrogen) at the bromine, with enolate as plausibility of mechanism 4 is supported by the molecular
leaving group and forming nitryl bromide. The enolate formed computations on reactions of (non-tertiary) a-halo carbonyls
could then react with the nitryl bromide to form the nitro with nucleophiles,71–73 and by an observation of stereospecic
product.
substitution with second-order kinetics at a tertiary centre
Fig. 16 Possible mechanism number four.
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Fig. 17 Possible mechanism number five.
alpha to a carbonyl.94 The report from Edwards and Grieco for a experiment ruled out this proposal as the reaction proceeded at
long time remained an isolated witness, but is now joined by the same rate in the absence of oxygen.
recent evidence of denite stereoinversion in tertiary a-chlor-
oesters reacted with azide, thiols and uoride.95,96 The bridging
lowers the energy of the transition state, and, by delivering the
Conclusions
nucleophile to the right position, may overcome the steric
problems of tertiary SN2. The r value is similar to the values (ca.
The Kornblum substitution has been robust from its inception
and the few rules that govern it are widely known; mainly that it
1.05) obtained from reaction of phenacyl chlorides with
proceeds with primary or secondary but not tertiary carbons. We
carboxylate, which were interpreted as supporting a bridging
have re-addressed these rules for the examples shown here
mechanism,70 though the same paper references other
where the substitution is seen to proceed on tertiary halo-
substitutions of phenacyl halides in which the r value was
carbons that are a to a carbonyl (Fig. 17), albeit probably by a
much less.
different mechanism to the standard Kornblum substitution
(Fig. 18).
However mechanism 5 is the only mechanism of these in
which a full negative charge is directly part of the p system,
Many earlier researchers discussed substitution mecha-
supporting maximum through-resonance. Although nucleo-
nisms in terms of a comparison between SN1 and SN2, a
philic attack on halogen as a means to substitution was
dichotomy that implied that these are the only two possibili-
considered by some early researchers32,41,67 it rarely appears in
ties,103,104 and Kornblum himself wrote this way when discus-
modern papers, though it is very similar to what happens in the
sing the reaction presented above.1,22,105 However, this type of
specic reduction of a-halo carbonyls by so nucleophiles.97 For
Kornblum substitution does not behave like the usual SN1 or
SN2 and it adds to the growing repertoire of substitutions that
do not t into the simple SN1/SN2 model that earlier researchers
had leaned upon.106
example, it is commonly accepted that the a-halogenation of
carbonyl compounds proceeds by the reaction of enol or enolate
with molecular bromine, displacing bromide anion [cf. (ref. 98
and 99)]. This reaction is known to be reversible, so the prin-
Further, the reaction represents a good way to prepare alpha-
ciple of microscopic reversibility requires that the reduction of
nitro ketones, esters and amides which are versatile building
blocks in organic synthesis as the nitro group may be reduced to
an amino group. The preparation of our library of a-nitro-
a-bromo carbonyl compounds by reaction with bromide occur
by attack by bromide at the bromine, as has been pointed out by
Altschul and Bartlett100 and Newman.101 Nitryl bromide is
isobutyranilides using the Kornblum substitution represents a
known to form and last for up to 30 min under some
far more convenient route to these compounds than what has
been reported previously.13 Ono quoted the Kornblum substi-
conditions.102
tution as high yielding for primary and secondary alkyl halides
(50–70%), but low yielding (0–5%) for tertiary alkyl halides.4,5
Br–NO2 substitution in the absence of O2
It has been suggested to us that as the reactions were carried out We may now add to this that the Kornblum substitution is very
under air this substitution may be proceeding by means of a high yielding (70–99%) for tertiary alkyl halides alpha to an
radical mechanism involving elemental oxygen (O2). A later anilide carbonyl.
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Fig. 18 Kornblum substitution on a tertiary a-carbon.
Acylation reactions
Experimental section
The library of reactant compounds was prepared by reacting
anilines (or in two cases, benzylamine and n-butylamine) with
a-bromoisobutyryl bromide. All reactions were carried out at
room temperature using ꢁ21.5 mmol (1.5–4 g) of the reactant
amine, dissolved in 1,2-dichloroethane (35 mL). Oven-dried
K2CO3 (3.00 g, 21.7 mmol) was added, then a 5% molar excess
of a-bromoisobutyryl bromide was added last, dropwise. The
ask was sealed and the reaction allowed to stir overnight at 700
rpm. The following morning the solvent was removed by rotary
evaporation, and the residue was partitioned between ethyl
acetate and water. The ethyl acetate fraction was dried (MgSO4),
evaporated, and the residue, if solid, recrystallized from
methanol.
General
IR spectra were measured from 4000–650 cmꢀ1 using a Varian
1000 FTIR spectrometer with a diamond Attenuated Total
Reectance (ATR) attachment. Reaction rate was monitored
using a Varian CP-3800 gas chromatograph equipped with an
SGE Analytical Science BPX5 column (column width 0.25 mm,
lm width 0.25 mm) which was adjoined to a Varian Saturn
2200 GC/MS/MS. Accurate mass spectra were measured using a
Waters GCT Premier HR-TOFMS equipped with an Agilent
7890 GC column. NMR spectra were obtained using a Bruker
Avance 300 MHz spectrometer. Chemical shis in 1H NMR
spectra are relative to chloroform at 7.24 ppm; in 13C NMR
spectra are relative to the central peak of deuterochloroform at
77.5 ppm.
Rather than using IUPAC names, we have named the
compounds as a-bromoisobutyranilides and a-nitro-
isobutyranilides in order to match the names given to them by
Sayo et al.13 who have earlier reported the synthesis of some of
the compounds in this category. Seven of the a-nitro-
isobutyranilides prepared by Sayo et al. have been prepared by
our new method. Table 2 compares our measured melting
points to those of Sayo et al.
p-Cyano-m-triuoromethyl-a-bromoisobutyranilide (1). p-
Cyano-m-triuoromethylaniline (3.96 g, 21.3 mmol) gave 7.02 g
(21.1 mmol, 99% yield) of pure p-cyano-m-triuoromethyl-a-
bromoisobutyranilide (1).
Characterization data for 1 are provided in our 2014 publi-
cation10 where it is given the correct IUPAC name of “2-bromo-
N-[4-cyano-3-(triuoromethyl)phenyl]-2-methylpropanamide”.
a-Bromoisobutyranilide (5). Aniline (2.00 g, 21.5 mmol) gave
4.04 g (16.8 mmol, 78% yield) of pure a-bromoisobutyranilide
(5) as white needles that looked like shredded coconut, m.p. 89–
92 ꢂC; Rf ¼ 0.54 in 4 : 1 hexanes/EtOAc, 0.74 in 65 : 35 hexanes/
EtOAc and 0.95 in 1 : 1 hexanes/EtOAc; IR(cmꢀ1): 3275, 3042,
2993, 2924, 1660 (C]O), 1594, 1551, 1513, 1461, 1401, 1372,
1355, 1318, 1295, 1234, 1187, 1141, 962, 900, 862, 815, 767, 738,
Table 2 Comparison of a-nitroisobutyranilide melting points
1
677; H NMR (300 MHz, 26 mg: 0.4 mL CDCl3): d 2.06 (6H, s,
M.p.
CH3), d 7.15 (1H, tt, ArH4, J 2, J 8), d 7.36 (2H, tt, ArH3, J 2, J 8), d
7.54 (2H, dt, ArH2, J 2, J 8), d 8.46 (1H, br, s, NH); 13C NMR (75
MHz, 137 mg: 0.4 mL CDCl3): d 32.8 (s, C-3A/B), d 63.2 (s, C-2), d
120.3 (s, C-20), d 125.1 (s, C-40), d 129.3 (s, C-30), d 137.6 (s, C-10), d
170.2 (s, C-1); GC-(EI) TOF-HRMS: calcd m/z for C10H12NOBr:
241.0102, observed: 241.0095.
Compound R] (ꢂC)
Sayo et al.13
6
H
104–107 104–105
p-Me 115–118 115–116
8
14
m-
135–136 135–136
NO2
16
22
24
30
p-NO2 138–140 137.5–139
m-Cl 125–128 134.5–136
p-Cl 124–127 121–122.5
p-Methyl-a-bromoisobutyranilide (7). p-Toluidine (2.30 g,
21.5 mmol) gave 4.72 g (18.5 mmol, 86% yield) of pure p-methyl-
a-bromoisobutyranilide (7) as little amber prisms, m.p. 95–98
ꢂC; Rf ¼ 0.63 in 4 : 1 hexanes/EtOAc, 0.78 in 65 : 35 hexanes/
EtOAc and 0.93 in 1 : 1 hexanes/EtOAc; IR(cmꢀ1): 3297, 3195,
3032, 3006, 2984, 2919, 1652 (C]O), 1601, 1533, 1512, 1470,
1404, 1319, 1297, 1236, 1193, 1164, 1100, 1022, 1009, 946, 938,
893, 813, 767, 755, 696; 1H NMR (300 MHz, 35 mg: 0.4 mL
CDCl3): d 2.05 (6H, s, CH3), d 2.33 (3H, s, ArCH3), d 7.15 (2H, d,
ArH3, J 8), d 7.42 (2H, d, ArH2, J 8), d 8.40 (1H, br, s, NH); 13C
p-
69–71 73–74
OMe
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NMR (75 MHz, 135 mg: 0.4 mL CDCl3): d 21.2 (s, ArCH3), d 32.8 EtOAc and 0.93 in 1 : 1 hexanes/EtOAc; IR(cmꢀ1): 3406, 3115,
(s, C-3A/B), d 63.4 (s, C-2), d 120.3 (s, C-20), d 129.7 (s, C-30), d 134.8 2929, 2931, 1698 (C]O), 1612, 1596, 1534, 1496, 1404, 1334,
(s, C-10), d 135.1 (s, C-40), d 170.1 (s, C-1); GC-(EI) TOF-HRMS: 1300, 1243, 1194, 1177, 1142, 1101, 945, 882, 854, 831, 750, 691,
1
calcd m/z for C11H14NOBr: 255.0259, observed: 255.0254.
674; H NMR (300 MHz, 30 mg: 0.4 mL CDCl3): d 2.05 (6H, s,
o-Carboethoxy-a-bromoisobutyranilide (9). Ethyl anthrani- CH3), d 7.74 (2H, dt, ArH2, J 2, J 8), d 8.23 (2H, dt, ArH3, J 2, J 8), d
late (3.60 g, 21.8 mmol) gave 6.26 g (20.1 mmol, 92% yield) of 8.72 (1H, br, s, NH); 13C NMR (75 MHz, 122 mg: 0.4 mL CDCl3): d
pure o-carboethoxy-a-bromoisobutyranilide (9) as little amber 32.4 (s, C-3A/B), d 62.1 (s, C-2), d 119.7 (s, C-20), d 125.2 (s, C-30), d
prisms, m.p. 59–61 ꢂC; Rf ¼ 0.63 in 4 : 1 hexanes/EtOAc, 0.82 in 143.5 (s, C-10), d 144.1 (s, C-40), d 170.7 (s, C-1); GC-(EI) TOF-
65 : 35 hexanes/EtOAc and 0.95 in 1 : 1 hexanes/EtOAc; HRMS: calcd m/z for
IR(cmꢀ1): 3189, 3117, 3076, 2974, 2937, 1696 (C]O), 1680 285.9929.
C10H11N2O3Br: 285.9953, observed:
(C]O), 1605, 1592, 1467, 1449, 1365, 1298, 1271, 1239, 1199,
o-Bromo-a-bromoisobutyranilide (17). o-Bromoaniline (3.70
1170, 1144, 1105, 1086, 1050, 1016, 969, 947, 856, 763, 730, 700; g, 21.5 mmol) gave 6.79 g (21.3 mmol, 99% yield) of pure o-
1H NMR (300 MHz, 30 mg: 0.4 mL CDCl3): d 1.42 (3H, t, ethyl bromo-a-bromoisobutyranilide (17) as a clear, low-viscosity
CH3), d 2.07 (6H, s, CH3), d 4.42 (2H, q, ethyl CH2), d 7.12 (1H, td, amber oil; Rf ¼ 0.70 in 4 : 1 hexanes/EtOAc, 0.85 in 65 : 35
ArH4, J 2, J 8), d 7.56 (1H, td, ArH5, J 2, J 8), d 8.08 (1H, dd, ArH6, J hexanes/EtOAc and 0.96 in 1 : 1 hexanes/EtOAc; IR(cmꢀ1): 3352,
2, J 8), d 8.70 (1H, dd, ArH3, J 2, J 8), d 11.90 (1H, br, s, NH); 13
C
2984, 2934, 1685 (C]O), 1588, 1520, 1434, 1300, 1155, 1110,
NMR (75 MHz, 145 mg: 0.4 mL CDCl3): d 14.4 (s, ethyl CH3), d 1025, 939, 745, 683; 1H NMR (300 MHz, 144 mg: 0.4 mL CDCl3):
32.1 (s, C-3A/B), d 60.5 (s, C-2), d 61.8 (s, ethyl CH2), d 116.2 (s, C- d 2.06 (6H, s, CH3), d 7.01 (1H, td, ArH4, J 2, J 8), d 7.33 (1H, td,
20), d 120.5 (s, C-60), d 123.2 (s, C-40), d 131.2 (s, C-30), d 134.7 (s, C- ArH5, J 2, J 8), d 7.56 (1H, dd, ArH3, J 2, J 8), d 8.32 (1H, dd, ArH6, J
50), d 141.4 (s, C-10), d 168.3 (s, ester C]O), d 171.0 (s, C-1); GC- 2, J 8), d 9.04 (1H, br, s, NH); 13C NMR (75 MHz, 144 mg: 0.4 mL
(EI) TOF-HRMS: calcd m/z for C13H15NO3Br: 312.0235, observed: CDCl3): d 32.7 (s, C-3A/B), d 62.7 (s, C-2), d 114.4 (s, C-20), d 121.8
312.0222.
o-Nitro-a-bromoisobutyranilide (11). o-Nitroaniline (2.90 g, (s, C-10), d 170.3 (s, C-1); GC-(EI) TOF-HRMS: calcd m/z for
(s, C-60), d 125.9 (s, C-50), d 128.6 (s, C-30), d 132.6 (s, C-40), d 135.8
21.0 mmol) gave 5.83 g (20.4 mmol, 97% yield) of pure o-nitro-a-
bromoisobutyranilide (11) as bright yellow needles, m.p. 67–70
C
10H11NOBr2: 318.9207, observed: 318.9194.
o-Chloro-a-bromoisobutyranilide (19). o-Chloroaniline (2.75
ꢂC; Rf ¼ 0.61 in 4 : 1 hexanes/EtOAc, 0.80 in 65 : 35 hexanes/ g, 21.6 mmol) gave 5.23 g (18.9 mmol, 88% yield) of pure o-
EtOAc and 0.83 in 1 : 1 hexanes/EtOAc; IR(cmꢀ1): 3320, 3118, chloro-a-bromoisobutyranilide (19) as a clear, low-viscosity
2985, 1701 (C]O), 1606, 1584, 1544, 1496, 1458, 1427, 1391, amber oil; Rf ¼ 0.66 in 4 : 1 hexanes/EtOAc, 0.86 in 65 : 35
1374, 1335, 1268, 1221, 1145, 1112, 1077, 1044, 1009, 945, 891, hexanes/EtOAc and 0.96 in 1 : 1 hexanes/EtOAc; IR(cmꢀ1): 3365,
862, 787, 742, 681; 1H NMR (300 MHz, 32 mg: 0.4 mL CDCl3): d 2985, 2934, 1686 (C]O), 1593, 1514, 1439, 1304, 1154, 1111,
1
2.07 (6H, s, CH3), d 7.23 (1H, td, ArH4, J 2, J 8), d 7.68 (1H, td, 1054, 1034, 940, 746, 698; H NMR (300 MHz, 139 mg: 0.4 mL
ArH5, J 2, J 8), d 8.25 (1H, dd, ArH3, J 2, J 8), d 8.73 (1H, dd, ArH6, J CDCl3): d 2.04 (6H, s, CH3), d 7.04 (1H, td, ArH4, J 2, J 8), d 7.26
2, J 8), d 11.34 (1H, br, s, NH); 13C NMR (75 MHz, 138 mg: 0.4 mL (1H, td, ArH5, J 2, J 8), d 7.36 (1H, dd, ArH3, J 2, J 8), d 8.30 (1H,
CDCl3): d 32.2 (s, C-3A/B), d 60.7 (s, C-2), d 122.1 (s, C-30), d 124.0 dd, ArH6, J 2, J 8), d 9.04 (1H, br, s, NH); 13C NMR (75 MHz, 139
(s, C-40), d 126.1 (s, C-60), d 134.7 (s, C-10), d 136.1 (s, C-50), d 137.0 mg: 0.4 mL CDCl3): d 32.8 (s, C-3A/B), d 62.9 (s, C-2), d 121.5 (s, C-
(s, C-20), d 171.3 (s, C-1); GC-(EI) TOF-HRMS: calcd m/z for 60), d 124.0 (s, C-20), d 125.4 (s, C-50), d 128.0 (s, C-30), d 129.4 (s, C-
C
10H11N2O3Br: 285.9953, observed: 285.9949.
m-Nitro-a-bromoisobutyranilide (13). m-Nitroaniline (2.90 z for C10H11NOClBr: 274.9713, observed: 274.9710.
g, 21.0 mmol) gave 5.83 g (20.4 mmol, 97% yield) of pure m- m-Chloro-a-bromoisobutyranilide (21). m-Chloroaniline
40), d 134.7 (s, C-10), d 170.4 (s, C-1); GC-(EI) TOF-HRMS: calcd m/
nitro-a-bromoisobutyranilide (13) as yellowish shards, m.p. (2.75 g, 21.6 mmol) gave 5.88 g (21.3 mmol, 99% yield) of pure
98–101 ꢂC; Rf ¼ 0.44 in 4 : 1 hexanes/EtOAc, 0.69 in 65 : 35 m-chloro-a-bromoisobutyranilide (21) as white needles with a
hexanes/EtOAc and 0.92 in 1 : 1 hexanes/EtOAc; IR(cmꢀ1): slight redness to them, m.p. 91–95 ꢂC; Rf ¼ 0.53 in 4 : 1 hexanes/
3370, 3090, 2980, 2931, 1694 (C]O), 1590, 1525, 1484, 1418, EtOAc, 0.78 in 65 : 35 hexanes/EtOAc and 0.94 in 1 : 1 hexanes/
1392, 1374, 1349, 1315, 1298, 1243, 1152, 1108, 1079, 1007, EtOAc; IR(cmꢀ1): 3291, 2998, 2977, 2931, 1663 (C]O), 1593,
1
958, 893, 874, 813, 735, 673, 692, 673; H NMR (300 MHz, 45 1521, 1424, 1285, 1244, 1162, 1109, 919, 875, 860, 782, 758, 697,
1
mg: 0.4 mL CDCl3): d 2.06 (6H, s, CH3), d 7.51 (1H, t, ArH5, J 8), 682; H NMR (300 MHz, 31 mg: 0.4 mL CDCl3): d 2.06 (6H, s,
d 7.90 (1H, dd, ArH6, J 2, J 8), d 7.99 (1H, dd, ArH4, J 2, J 8), d CH3), d 7.14 (1H, dt, ArH4, J 2, J 8), d 7.28 (1H, t, ArH5, J 8), d 7.39
8.46 (1H, t, ArH2, J 2), d 8.66 (1H, br, s, NH); 13C NMR (75 MHz, (1H, dq, ArH6, J 2, J 8), d 7.70 (1H, t, ArH2, J 2), d 8.47 (1H, br, s,
138 mg: 0.4 mL CDCl3): d 32.4 (s, C-3A/B), d 61.9 (s, C-2), d 115.2 NH); 13C NMR (75 MHz, 136 mg: 0.4 mL CDCl3): d 32.8 (s,
(s, C-20), d 119.6 (s, C-40), d 126.1 (s, C-60), d 130.0 (s, C-50), d C-3A/B), d 62.9 (s, C-2), d 118.5 (s, C-60), d 120.5 (s, C-20), d 125.3 (s,
138.8 (s, C-10), d 148.7 (s, C-30), d 170.8 (s, C-1); GC-(EI) TOF- C-40), d 130.3 (s, C-50), d 135.1 (s, C-30), d 139.0 (s, C-10), d 170.6 (s,
HRMS: calcd m/z for C10H11N2O3Br: 285.9953, observed: C-1); GC-(EI) TOF-HRMS: calcd m/z for C10H11NOClBr: 274.9713,
285.9963.
p-Nitro-a-bromoisobutyranilide (15). p-Nitroaniline (2.90 g,
observed: 274.9686.
p-Chloro-a-bromoisobutyranilide (23). p-Chloroaniline (2.75
21.0 mmol) gave 5.35 g (18.7 mmol, 89% yield) of pure p-nitro-a- g, 21.6 mmol) gave 4.45 g (16.1 mmol, 75% yield) of pure p-
bromoisobutyranilide (15) as tiny yellow needles, m.p. 116–120 chloro-a-bromoisobutyranilide (23) as colourless needles, m.p.
ꢂC; Rf ¼ 0.40 in 4 : 1 hexanes/EtOAc, 0.67 in 65 : 35 hexanes/ 119–121 ꢂC; Rf ¼ 0.52 in 4 : 1 hexanes/EtOAc, 0.78 in 65 : 35
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hexanes/EtOAc and 0.91 in 1 : 1 hexanes/EtOAc; IR(cmꢀ1): 3285,
3188, 3122, 3071, 2988, 2941, 2895, 1656 (C]O), 1591, 1552,
1529, 1478, 1459, 1418, 1398, 1372, 1351, 1305, 1287, 1254,
1240, 1187, 1142, 1092, 1074, 999, 962, 914, 904, 888, 864, 854,
792, 704, 683; 1H NMR (300 MHz, 43 mg: 0.4 mL CDCl3): d 2.04
(6H, s, CH3), d 7.30 (2H, dt, ArH3, J 2, J 8), d 7.49 (2H, dt, ArH2, J
2, J 8), d 8.45 (1H, br, s, NH); 13C NMR (75 MHz, 157 mg: 0.4 mL
CDCl3): d 32.6 (s, C-3A/B), d 62.8 (s, C-2), d 121.7 (s, C-20), d 129.3
(s, C-30), d 130.1 (s, C-40), d 136.2 (s, C-10), d 170.3 (s, C-1); GC-(EI)
TOF-HRMS: calcd m/z for C10H11NOClBr: 274.9713, observed:
274.9706.
o-Chloro-a-bromoisobutyranilide (25). o-Methoxyaniline
(2.40 g, 21.6 mmol) gave 4.92 g (18.2 mmol, 84% yield) of pure o-
chloro-a-bromoisobutyranilide (25) as a clear, brown-metallic
oil; Rf ¼ 0.60 in 4 : 1 hexanes/EtOAc, 0.81 in 65 : 35 hexanes/
EtOAc and 0.93 in 1 : 1 hexanes/EtOAc; IR(cmꢀ1): 3380, 2983,
2936, 2839, 1677 (C]O), 1600, 1522, 1486, 1459, 1433, 1336,
1290, 1250, 1218, 1176, 1157, 1110, 1047, 1026, 940, 773, 744; 1H
NMR (300 MHz, 28 mg: 0.4 mL CDCl3): d 2.06 (6H, s, CH3), d 3.92
(3H, s, O–CH3), d 6.90 (1H, dd, ArH3, J 2, J 8), d 6.98 (1H, td, ArH5,
J 2, J 8), d 7.08 (1H, td, ArH4, J 2, J 8), d 8.33 (1H, dd, ArH6, J 2, J 8),
d 9.13 (1H, br, s, NH); 13C NMR (75 MHz, 133 mg: 0.4 mL CDCl3):
d 32.5 (s, C-3A/B), d 56.0 (s, O–CH3), d 62.8 (s, C-2), d 110.2 (s, C-
30), d 119.5 (s, C-60), d 121.0 (s, C-50), d 124.4 (s, C-40), d 127.4 (s, C-
10), d 148.5 (s, C-20), d 169.9 (s, C-1); GC-(EI) TOF-HRMS: calcd m/
z for C11H14NO2Br: 271.0208, observed: 271.0195.
N-Benzyl-a-bromoisobutyramide (31). Benzylamine (2.30 g,
21.5 mmol) gave 4.33 g (17.0 mmol, 79% yield) of pure N-benzyl-
a-bromoisobutyramide (31) as a ne white powder, m.p. 77–80
ꢂC; Rf ¼ 0.38 in 4 : 1 hexanes/EtOAc, 0.64 in 65 : 35 hexanes/
EtOAc and 0.90 in 1 : 1 hexanes/EtOAc; IR(cmꢀ1): 3300, 3065,
3030, 2973, 2939, 2920, 1642 (C]O), 1533, 1495, 1471, 1453,
1418, 1355, 1292, 1195, 1102, 1081, 1014, 922, 826, 752, 729,
699, 693; 1H NMR (300 MHz, 23 mg: 0.4 mL CDCl3): d 1.99 (6H,
s, CH3), d 4.47 (2H, d, CH2 J 8), d 7.02 (1H, br, s, NH), d 7.30 (2H,
m, ArH2), d 7.34 (2H, m, ArH3), d 7.36 (1H, m, ArH4); 13C NMR
(75 MHz, 125 mg: 0.4 mL CDCl3): d 32.7 (s, C-3A/B), d 44.5 (s,
CH2), d 62.9 (s, C-2), d 127.7 (s, C-20), d 127.8 (s, C-40), d 129.0 (s,
C-30), d 138.0 (s, C-10), d 172.2 (s, C-1); GC-(EI) TOF-HRMS: calcd
m/z for C11H14NOBr: 255.0259, observed: 255.0265.
a-Bromo-N-butylisobutyramide (33). n-Butylamine (1.60 g,
21.9 mmol) gave 3.05 g (13.8 mmol, 63% yield) of pure a-bromo-
N-butylisobutyramide (33) as a clear, pale yellow, low-viscosity
oil; IR(cmꢀ1): 3348, 2959, 2932, 2873, 1649 (C]O), 1528, 1465,
1437, 1370, 1301, 1282, 1225, 1190, 1112, 738; 1H NMR (300
MHz, 26 mg: 0.4 mL CDCl3): d 0.96 (3H, t, alkyl4 J 8), d 1.38 (2H,
sextet, alkyl3 J 8), d 1.54 (2H, sextet, alkyl2 J 8), d 1.97 (6H, s, CH3),
d 3.28 (2H, sextet, alkyl1 J 8), d 6.73 (1H, br, s, NH); 13C NMR (75
MHz, 147 mg: 0.4 mL CDCl3): d 13.9 (s, C-40), d 20.2 (s, C-30), d
31.5 (s, C-20), d 32.8 (s, C-3A/B), d 40.3 (s, C-10), d 63.3 (s, C-2), d
172.0 (s, C-1); GC-(EI) TOF-HRMS: calcd m/z for C8H16NOBr:
221.0415, observed: 221.0417.
m-Chloro-a-bromoisobutyranilide (27). m-Methoxyaniline
(2.40 g, 21.6 mmol) gave 5.44 g (20.1 mmol, 93% yield) of pure
m-chloro-a-bromoisobutyranilide (27) as white needles, m.p.
Substitution reactions
112–114 ꢂC; Rf ¼ 0.47 in 4 : 1 hexanes/EtOAc, 0.75 in 65 : 35 Unless otherwise stated, reactions were carried out at room
hexanes/EtOAc and 0.93 in 1 : 1 hexanes/EtOAc; IR(cmꢀ1): 3454, temperature using ꢁ5 mmol (1–2 g) of the reactant bromo
3340, 3003, 2961, 2942, 2897, 1660 (C]O), 1597, 1546, 1528, compound (1–2 g) with NaNO2 (4.00 g, 44.9 mmol) in DMF (40
1510, 1462, 1442, 1414, 1375, 1355, 1299, 1232, 1183, 1172, mL) and a magnetic stirrer at 700 rpm.
1141, 1111, 1032, 962, 902, 865, 823, 764; 1H NMR (300 MHz, 31
The rates were monitored by periodically removing 1 mL of
mg: 0.4 mL CDCl3): d 2.10 (6H, s, CH3), d 3.86 (3H, s, O–CH3), d the reacting mixture, placing it in dichloromethane (2 mL) and
6.75 (1H, dd, ArH4, J 2, J 8), d 7.05 (1H, dd, ArH6, J 2, J 8), d 7.30 washing with water (4 ꢃ 3 mL) in a 5 mL screw cap vial. The
(1H, dd, ArH5, J 2, J 8), d 7.37 (1H, t, ArH2, J 2), d 8.49 (1H, br, s, dichloromethane layer was then dried (MgSO4) and analysed by
NH); 13C NMR (75 MHz, 31 mg: 0.4 mL CDCl3): d 32.9 (s, C-3A/B), GC-MS.
d 55.7 (s, O–CH3), d 63.5 (s, C-2), d 105.8 (s, C-60), d 111.3 (s, C-20),
d 112.4 (s, C-40), d 130.1 (s, C-50), d 139.0 (s, C-10), d 160.6 (s, C-30), reaction by trial in an initial rough experiment.
The time between each aliquot was determined for each
d 170.3 (s, C-1); GC-(EI) TOF-HRMS: calcd m/z for C11H14NO2Br:
271.0208, observed: 271.0216.
For preparative reactions, apart from the preparation of 2,
which could be obtained by addition of water to the DMF
p-Chloro-a-bromoisobutyranilide (29). p-Methoxyaniline reaction mixture, the substitutions were worked up on
(2.40 g, 21.6 mmol) gave 5.80 g (21.4 mmol, 99% yield) of pure p- completion by the removal of DMF on a rotary evaporator with
chloro-a-bromoisobutyranilide (29) as white needles, m.p. 88– water bath at 70 ꢂC and vacuum rigorously kept at 25 Torr, with
89 ꢂC; Rf ¼ 0.46 in 4 : 1 hexanes/EtOAc, 0.72 in 65 : 35 hexanes/ Dow Corning high vacuum grease freshly applied to the joins
EtOAc and 0.91 in 1 : 1 hexanes/EtOAc; IR(cmꢀ1): 3319, 3007, and Keck clips used to hold the ask onto a non-reversible
2982, 2962, 2841, 1654 (C]O), 1601, 1539, 1508, 1468, 1444, splash-guard. The residue was partitioned between water and
1412, 1372, 1316, 1300, 1273, 1232, 1223, 1197, 1184, 1164, ethyl acetate and the ethyl acetate fraction was evaporated. Aer
1106, 1031, 952, 933, 890, 831, 809, 763, 751, 675; 1H NMR (300 TLC of the residue to determine a suitable eluent, the product
MHz, 25 mg: 0.4 mL CDCl3): d 2.07 (6H, s, CH3), d 3.82 (3H, s, O– was puried by column chromatography (40 mm diameter) on
CH3), d 6.90 (2H, dt, ArH3, J 2, J 8), d 7.45 (2H, dt, ArH2, J 2, J 8), d 43–60 m silica (ꢁ150 g) with pre-adsorption on ꢁ10 g of silica.
8.40 (1H, br, s, NH); 13C NMR (75 MHz, 25 mg: 0.4 mL CDCl3): d This method typically produced 800–1300 mg of highly pure
32.4 (s, C-3A/B), d 55.5 (s, O–CH3), d 63.3 (s, C-2), d 114.6 (s, C-30), nitro substitution product as observed by NMR.
d 121.8 (s, C-20), d 130.5 (s, C-10), d 156.8 (s, C-40), d 169.9 (s, C-1);
GC-(EI) TOF-HRMS: calcd m/z for C11H14NO2Br: 271.0208, Cyano-m-triuoromethyl-a-bromoisobutyranilide) (1.68 g, 5.03
p-Cyano-m-triuoromethyl-a-nitroisobutyranilide (2). 1 (p-
observed: 271.0197.
mmol) was added to NaNO2 and DMF. The reaction was worked
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up by addition of 20 mL of deionized water which caused the (s, C-2), d 118.9 (s, C-20), d 122.0 (s, C-60), d 125.2 (s, C-40), d 131.6
product to begin to precipitate. The ask was placed in a crystal (s, C-30), d 135.1 (s, C-50), d 139.8 (s, C-10), d 166.5 (s, C-1), d 168.2
fridge at 8 ꢂC overnight and then the crystals collected by (s, ester C]O); GC-(EI) TOF-HRMS: calcd m/z for C13H15N2O5:
¨
Buchner funnel ltration to give 1.88 g of intensely white needles 279.0981, observed: 279.0972.
2 to 10 mm in length. These were found to be p-cyano-m-tri-
o-Nitro-a-nitroisobutyranilide (12). 11 (o-Nitro-a-bromoiso-
uoromethyl-a-nitroisobutyranilide (2) which was co-crystallized butyranilide) (1.36 g, 4.74 mmol) gave 1000 mg (3.95 mmol, 83%
in a 1 : 1 ratio with DMF (86% yield when corrected for the DMF), yield) of pure o-nitro-a-nitroisobutyranilide (12) as a deep
ꢂ
m.p. 129–131 C. A DMF free version of 2 could be prepared by yellow, cauliower-shaped crystalline nuggets, m.p. 82–84 ꢂC; Rf
repeated liquid/liquid extraction using water/ethyl acetate which ¼ 0.38 in 4 : 1 hexanes/EtOAc, 0.70 in 65 : 35 hexanes/EtOAc
provides a white amorphous powder of the same m.p. Charac- and 0.90 in 1 : 1 hexanes/EtOAc; IR(cmꢀ1): 3392, 2924, 2854,
terization data for 2 are provided in our 2014 publication10 where 1706 (C]O), 1607, 1588, 1548, 1497, 1454, 1431, 1396, 1374,
it is given the correct IUPAC name of “N-[4-cyano-3-(tri- 1335, 1270, 1224, 1161, 1140, 1075, 898, 861, 854, 789, 742, 688;
uoromethyl)phenyl]-2-methyl-2-nitropropanamide”.
1H NMR (300 MHz, 18 mg: 0.4 mL CDCl3): d 2.00 (6H, s, CH3), d
a-Nitroisobutyranilide (6). 5 (a-Bromoisobutyranilide) (1.20 7.28 (1H, td, ArH4, J 2, J 8), d 7.70 (1H, tt, ArH5, J 2, J 8), d 8.27
g, 4.98 mmol) gave 870 mg (4.18 mmol, 84% yield) of pure a- (1H, dd, ArH3, J 2, J 8), d 8.71 (1H, dd, ArH6, J 2, J 8), d 11.09 (1H,
nitroisobutyranilide (6) as an extremely shiny crystalline powder br, s, NH); 13C NMR (75 MHz, 18 mg: 0.4 mL CDCl3): d 24.6 (s, C-
with a hint of orange, m.p. 104–107 ꢂC; Rf ¼ 0.32 in 4 : 1
3
A/B), d 91.6 (s, C-2), d 122.7 (s, C-30), d 124.9 (s, C-40), d 126.3 (s,
hexanes/EtOAc, 0.56 in 65 : 35 hexanes/EtOAc and 0.87 in 1 : 1 C-60), d 134.1 (s, C-10), d 136.5 (s, C-50), d 137.2 (s, C-20), d 165.9 (s,
hexanes/EtOAc; IR(cmꢀ1): 3256, 3199, 3136, 3076, 1655 (C]O), C-1); GC-(EI) TOF-HRMS: calcd m/z for C10H11N3O5: 253.0699,
1598, 1549, 1538, 1492, 1459, 1440, 1399, 1373, 1352, 1321, observed: 253.0705.
1
1266, 1233, 1189, 1143, 963, 894, 859, 752, 695, 666; H NMR
m-Nitro-a-nitroisobutyranilide (14). 13 (m-Nitro-a-bromoi-
(300 MHz, 26 mg: 0.4 mL CDCl3): d 1.94 (6H, s, CH3), d 7.17 (1H, sobutyranilide) (1.43 g, 4.74 mmol) gave 1028 mg (4.06 mmol,
tt, ArH4, J 2, J 8), d 7.34 (2H, tt, ArH3, J 2, J 8), d 7.48 (2H, dt, ArH2, 86% yield) of pure m-nitro-a-nitroisobutyranilide (14) as a pale
J 2, J 8), d 7.98 (1H, br, s, NH); 13C NMR (75 MHz, 26 mg: 0.4 mL yellow, clean looking crystalline powder, m.p. 135–136 ꢂC; Rf ¼
CDCl3): d 24.9 (s, C-3A/B), d 91.6 (s, C-2), d 120.8 (s, C-20), d 125.8 0.27 in 4 : 1 hexanes/EtOAc, 0.57 in 65 : 35 hexanes/EtOAc and
(s, C-40), d 129.5 (s, C-30), d 136.8 (s, C-10), d 164.7 (s, C-1); GC-(EI) 0.84 in 1 : 1 hexanes/EtOAc; IR(cmꢀ1): 3347, 3093, 2923, 2854,
TOF-HRMS: calcd m/z for C10H12N2O3: 208.0848, observed: 1659 (C]O), 1617, 1553, 1532, 1458, 1434, 1401, 1373, 1350,
208.0846.
1317, 1287, 1262, 1234, 1192, 1145, 1089, 1079, 970, 909, 882,
p-Methyl-a-nitroisobutyranilide (8). 7 (p-Methyl-a-bromoi- 856, 824, 809, 734, 693, 671; 1H NMR (300 MHz, 50 mg: 0.4 mL
sobutyranilide) (1.28 g, 5.02 mmol) gave 970 mg (4.37 mmol, d6-DMSO): d 1.93 (6H, s, CH3), d 7.67 (1H, t, ArH5, J 8), d 8.01 (1H,
87% yield) of pure p-methyl-a-nitroisobutyranilide (8) as orange dd, ArH6, J 2, J 8), d 8.07 (1H, dd, ArH4, J 2, J 8), d 8.61 (1H, t,
shards of various morphology, m.p. 115–118 ꢂC; Rf ¼ 0.38 in ArH6, J 2), d 10.40 (1H, br, s, NH); 13C NMR (75 MHz, 50 mg: 0.4
4 : 1 hexanes/EtOAc, 0.61 in 65 : 35 hexanes/EtOAc and 0.87 in mL d6-DMSO): d 24.6 (s, C-3A/B), d 92.5 (s, C-2), d 115.7 (s, C-20), d
1 : 1 hexanes/EtOAc; IR(cmꢀ1): 3274, 3120, 3042, 2993, 2924, 119.8 (s, C-40), d 127.4 (s, C-60), d 131.3 (s, C-50), d 140.2 (s, C-10), d
2893, 2860, 1660 (C]O), 1594, 1550, 1522, 1513, 1460, 1436, 148.8 (s, C-30), d 167.5 (s, C-1); GC-(EI) TOF-HRMS: calcd m/z for
1401, 1372, 1355, 1318, 1295, 1259, 1234, 1187, 1179, 1141, 961,
900, 862, 815, 770, 738, 678; 1H NMR (300 MHz, 21 mg: 0.4 mL
C
10H11N3O5: 253.0699, observed: 253.0694.
p-Nitro-a-nitroisobutyranilide (16). 15 (p-Nitro-a-bromoiso-
CDCl3): d 1.93 (6H, s, CH3), d 2.32 (3H, s, ArCH3), d 7.13 (2H, d, butyranilide) (1.43 g, 4.74 mmol) gave 980 mg (3.87 mmol, 82%
ArH3, J 8), d 7.35 (2H, d, ArH2, J 8), d 7.91 (1H, br, s, NH); 13C yield) of pure p-nitro-a-nitroisobutyranilide (16) as a ne, white
NMR (75 MHz, 42 mg: 0.4 mL CDCl3): d 21.3 (s, ArCH3), d 24.9 (s, uffy powder, m.p. 138–140 ꢂC; Rf ¼ 0.19 in 4 : 1 hexanes/EtOAc,
C-3A/B), d 91.6 (s, C-2), d 121.1 (s, C-20), d 129.9 (s, C-30), d 134.3 (s, 0.45 in 65 : 35 hexanes/EtOAc and 0.87 in 1 : 1 hexanes/EtOAc;
C-10), d 135.5 (s, C-40), d 164.9 (s, C-1); GC-(EI) TOF-HRMS: calcd IR(cmꢀ1): 3352, 1709 (C]O), 1615, 1597, 1547, 1506, 1464,
m/z for C11H14N2O3: 222.1004, observed: 222.1006.
1409, 1400, 1374, 1346, 1307, 1249, 1221, 1181, 1160, 1142,
o-Carboethoxy-a-nitroisobutyranilide (10). 9 (o-Carboethoxy- 1115, 898, 848, 829, 816, 752, 691; 1H NMR (300 MHz, 27 mg: 0.4
a-bromoisobutyranilide) (1.56 g, 5.00 mmol) gave 1381 mg (4.95 mL d6-DMSO): d 1.94 (6H, s, CH3), d 7.94 (2H, dt, ArH2, J 2, J 8), d
mmol, 99% yield) of pure o-carboethoxy-a-nitroisobutyranilide 8.29 (2H, dt, ArH3, J 2, J 8), d 10.50 (1H, br, s, NH); 13C NMR (75
ꢂ
(10) as white, amorphous powder, m.p. 84–87 C; Rf ¼ 0.43 in MHz, 27 mg: 0.4 mL d6-DMSO): d 24.5 (s, C-3A/B), d 92.5 (s, C-2), d
4 : 1 hexanes/EtOAc, 0.69 in 65 : 35 hexanes/EtOAc and 0.93 in 121.2 (s, C-20), d 125.7 (s, C-30), d 144.0 (s, C-40), d 145.1 (s, C-10), d
1 : 1 hexanes/EtOAc; IR(cmꢀ1): 3177, 3120, 3082, 2991, 1699 167.4 (s, C-1); GC-(EI) TOF-HRMS: calcd m/z for C10H11N3O5:
(C]O), 1685 (C]O), 1608, 1594, 1551, 1529, 1466, 1455, 1366, 253.0699, observed: 253.0702.
1351, 1303, 1277, 1251, 1238, 1182, 1139, 1090, 1016, 857, 763,
o-Bromo-a-nitroisobutyranilide (18). 17 (o-Bromo-a-bromoi-
1
700; H NMR (300 MHz, 25 mg: 0.4 mL CDCl3): d 1.42 (3H, t, sobutyranilide) (1.61 g, 5.02 mmol) gave 1082 mg (3.77 mmol,
ethyl CH3), d 1.98 (6H, s, CH3), d 4.41 (2H, q, ethyl CH2), d 7.16 75% yield) of pure o-bromo-a-nitroisobutyranilide (18) as an
(1H, td, ArH4, J 2, J 8), d 7.57 (1H, td, ArH5, J 2, J 8), d 8.08 (1H, dd, amber oil; Rf ¼ 0.48 in 4 : 1 hexanes/EtOAc, 0.69 in 65 : 35
ArH6, J 2, J 8), d 8.66 (1H, dd, ArH3, J 2, J 8), d 11.81 (1H, br, s, hexanes/EtOAc and 0.91 in 1 : 1 hexanes/EtOAc; IR(cmꢀ1): 3398,
NH); 13C NMR (75 MHz, 68 mg: 0.4 mL CDCl3/0.1 mL d6-DMSO): 3339, 2997, 2925, 1699 (C]O), 1590, 1548, 1519, 1464, 1436,
d 14.9 (s, ethyl CH3), d 24.3 (s, C-3A/B), d 62.5 (s, ethyl CH2), d 92.3 1398, 1373, 1346, 1299, 1237, 1207, 1167, 1143, 1121, 1047,
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1026, 896, 855, 750; 1H NMR (300 MHz, 26 mg: 0.4 mL CDCl3): d mmol, 71% yield) of pure o-methoxy-a-nitroisobutyranilide (26)
1.98 (6H, s, CH3), d 7.04 (1H, td, ArH4, J 2, J 8), d 7.34 (1H, td, as tiny, pretty, orange prisms or various morphology, m.p. 67–
ArH5, J 2, J 8), d 7.56 (1H, dd, ArH3, J 2, J 8), d 8.24 (1H, dd, ArH6, J 70 ꢂC; Rf ¼ 0.40 in 4 : 1 hexanes/EtOAc, 0.65 in 65 : 35 hexanes/
2, J 8), d 8.52 (1H, br, s, NH); 13C NMR (75 MHz, 66 mg: 0.4 mL EtOAc and 0.89 in 1 : 1 hexanes/EtOAc; IR(cmꢀ1): 3331, 3043,
CDCl3): d 24.9 (s, C-3A/B), d 91.4 (s, C-2), d 114.8 (s, C-20), d 122.6 3005, 2964, 2936, 2901, 2838, 1675 (C]O), 1594, 1553, 1521,
(s, C-60), d 126.8 (s, C-50), d 128.9 (s, C-30), d 132.8 (s, C-40), d 134.9 1493, 1460, 1432, 1403, 1375, 1357, 1322, 1287, 1262, 1220,
(s, C-10), d 164.9 (s, C-1); GC-(EI) TOF-HRMS: calcd m/z for 1177, 1142, 1112, 1042, 1025, 963, 899, 862, 849, 780, 748, 739,
C
10H11N2O3Br: 285.9953, observed: 285.9961.
o-Chloro-a-nitroisobutyranilide (20). 19 (o-Chloro-a-bro- s, CH3), d 3.91 (3H, s, O–CH3), d 6.90 (1H, dd, ArH3, J 2, J 8), d
724, 666; 1H NMR (300 MHz, 19 mg: 0.4 mL CDCl3): d 1.95 (6H,
moisobutyranilide) (1.38 g, 4.99 mmol) gave 955 mg (3.94 6.97 (1H, td, ArH5, J 2, J 8), d 7.10 (1H, td, ArH4, J 2, J 8), d 8.28
mmol, 79% yield) of pure o-chloro-a-nitroisobutyranilide (20) as (1H, dd, ArH6, J 2, J 8), d 8.62 (1H, br, s, NH); 13C NMR (75 MHz,
an amber oil; Rf ¼ 0.43 in 4 : 1 hexanes/EtOAc, 0.70 in 65 : 35 57 mg: 0.4 mL CDCl3): d 24.9 (s, C-3A/B), d 56.2 (s, O–CH3), d 91.6
hexanes/EtOAc and 0.90 in 1 : 1 hexanes/EtOAc; IR(cmꢀ1): 3352, (s, C-2), d 110.4 (s, C-30), d 120.3 (s, C-60), d 121.4 (s, C-50), d 125.3
2998, 2922, 2852, 1697 (C]O), 1594, 1549, 1518, 1467, 1441, (s, C-40), d 126.9 (s, C-10), d 148.7 (s, C-20), d 164.4 (s, C-1); GC-(EI)
1398, 1373, 1347, 1302, 1238, 1168, 1144, 1128, 1055, 1035, 897, TOF-HRMS: calcd m/z for C11H14N2O4: 238.0954, observed:
856, 751, 690; 1H NMR (300 MHz, 21 mg: 0.4 mL CDCl3): d 1.97 238.0952.
(6H, s, CH3), d 7.11 (1H, td, ArH4, J 2, J 8), d 7.30 (1H, td, ArH5, J
m-Methoxy-a-nitroisobutyranilide (28). 27 (m-Methoxy-a-
2, J 8), d 7.40 (1H, dd, ArH3, J 2, J 8), d 8.26 (1H, dd, ArH6, J 2, J 8), bromoisobutyranilide) (1.40 g, 5.15 mmol) gave 981 mg (4.12
d 8.58 (1H, br, s, NH); 13C NMR (75 MHz, 39 mg: 0.4 mL CDCl3): mmol, 80% yield) of pure m-methoxy-a-nitroisobutyranilide (28)
d 24.9 (s, C-3A/B), d 91.5 (s, C-2), d 122.2 (s, C-60), d 124.2 (s, C-20), d as a crystalline mass of orange tipped needles, m.p. 97–99 ꢂC; Rf
126.2 (s, C-50), d 128.2 (s, C-30), d 129.5 (s, C-40), d 133.8 (s, C-10), d ¼ 0.29 in 4 : 1 hexanes/EtOAc, 0.55 in 65 : 35 hexanes/EtOAc
164.7 (s, C-1); GC-(EI) TOF-HRMS: calcd m/z for C10H11N2O3Cl: and 0.85 in 1 : 1 hexanes/EtOAc; IR(cmꢀ1): 3276, 3223, 3154,
242.0458, observed: 242.0462.
3007, 2943, 2838, 1665 (C]O), 1614, 1597, 1539, 1489, 1451,
m-Chloro-a-nitroisobutyranilide (22). 21 (m-Chloro-a-bro- 1427, 1397, 1373, 1344, 1320, 1301, 1277, 1267, 1208, 1182,
moisobutyranilide) (1.38 g, 4.99 mmol) gave 1135 mg (4.68 1149, 1031, 953, 844, 788, 764, 749, 727, 686; 1H NMR (300 MHz,
mmol, 94% yield) of pure m-chloro-a-nitroisobutyranilide (22) 28 mg: 0.4 mL CDCl3): d 1.93 (6H, s, CH3), d 3.80 (3H, s, O–CH3),
as a light orange crystalline mass with multiple nucleation d 6.72 (1H, dd, ArH4, J 2, J 8), d 6.96 (1H, dd, ArH6, J 2, J 8), d 7.22
points, m.p. 125–128 ꢂC; Rf ¼ 0.47 in 4 : 1 hexanes/EtOAc, 0.72 (1H, t, ArH5, J 8), d 7.26 (1H, d, ArH2, J 2), d 7.98 (1H, br, s, NH);
in 65 : 35 hexanes/EtOAc and 0.89 in 1 : 1 hexanes/EtOAc; 13C NMR (75 MHz, 120 mg: 0.4 mL CDCl3): d 24.6 (s, C-3A/B), d
IR(cmꢀ1): 3385, 3188, 3122, 3071, 2988, 2941, 2895, 1656 (C] 55.5 (s, O–CH3), d 91.5 (s, C-2), d 106.8 (s, C-60), d 111.6 (s, C-20), d
O), 1590, 1552, 1528, 1478, 1459, 1418, 1398, 1372, 1351, 1304, 113.2 (s, C-40), d 130.0 (s, C-50), d 138.0 (s, C-10), d 160.4 (s, C-30), d
1287, 1254, 1240, 1231, 1187, 1142, 1092, 1074, 999, 914, 904, 165.2 (s, C-1); GC-(EI) TOF-HRMS: calcd m/z for C11H14N2O4:
888, 854, 791, 704, 682; 1H NMR (300 MHz, 18 mg: 0.4 mL 238.0954, observed: 238.0954.
CDCl3): d 1.82 (6H, s, CH3), d 6.99 (1H, d, ArH4, J 8), d 7.14 (1H,
p-Methoxy-a-nitroisobutyranilide (30). 29 (p-Methoxy-a-bro-
td, ArH5, J 2, J 8), d 7.43 (1H, d, ArH6, J 8), d 7.64 (1H, m, ArH2), d moisobutyranilide) (1.40 g, 5.15 mmol) gave 1078 mg (4.53
9.38 (1H, br, s, NH); 13C NMR (75 MHz, 18 mg: 0.4 mL CDCl3/2 mmol, 77% yield) of pure p-methoxy-a-nitroisobutyranilide (30)
drops d6-DMSO): d 24.7 (s, C-3A/B), d 91.2 (s, C-2), d 118.9 (s, C-60), as tiny, pretty, pale yellow needles, m.p. 69–71 C; Rf ¼ 0.16 in
ꢂ
d 121.0 (s, C-20), d 124.7 (s, C-40), d 129.8 (s, C-50), d 134.2 (s, C-30), 4 : 1 hexanes/EtOAc, 0.48 in 65 : 35 hexanes/EtOAc and 0.80 in
d 139.3 (s, C-10), d 165.8 (s, C-1); GC-(EI) TOF-HRMS: calcd m/z 1 : 1 hexanes/EtOAc; IR(cmꢀ1): 3346, 3003, 2961, 2939, 2898,
for C10H11N2O3Cl: 242.0458, observed: 242.0475.
2840, 1660 (C]O), 1597, 1545, 1530, 1510, 1462, 1440, 1414,
p-Chloro-a-nitroisobutyranilide (24). 23 (p-Chloro-a-bro- 1403, 1375, 1356, 1311, 1299, 1268, 1232, 1184, 1173, 1141,
moisobutyranilide) (1.38 g, 4.99 mmol) gave 1070 mg (4.41 1112, 1031, 962, 901, 863, 850, 824, 764; 1H NMR (300 MHz, 28
mmol, 88% yield) of pure p-chloro-a-nitroisobutyranilide (24) as mg: 0.4 mL CDCl3): d 1.92 (6H, s, CH3), d 3.79 (3H, s, O–CH3), d
a pale yellow, clean looking crystalline powder, m.p. 124–127 ꢂC; 6.86 (2H, d, ArH3, J 8), d 7.37 (2H, d, ArH2, J 8), d 7.87 (1H, br, s,
Rf ¼ 0.38 in 4 : 1 hexanes/EtOAc, 0.67 in 65 : 35 hexanes/EtOAc NH); 13C NMR (75 MHz, 120 mg: 0.4 mL CDCl3): d 24.9 (s, C-3A/
and 0.90 in 1 : 1 hexanes/EtOAc; IR(cmꢀ1): 3303, 3195, 3126, B), d 55.8 (s, O–CH3), d 91.5 (s, C-2), d 114.5 (s, C-30), d 122.9 (s, C-
3057, 3002, 2924, 2854, 1664 (C]O), 1599, 1547, 1533, 1492, 20), d 129.8 (s, C-10), d 157.5 (s, C-40), d 164.9 (s, C-1); GC-(EI) TOF-
1460, 1400, 1379, 1353, 1308, 1287, 1241, 1188, 1145, 1087, HRMS: calcd m/z for C11H14N2O4: 238.0954, observed: 238.0971.
1014, 960, 904, 864, 820, 747, 708, 695, 667; 1H NMR (300 MHz,
N-Benzyl-a-nitroisobutyramide (32). 31 (N-Benzyl-a-bromoi-
21 mg: 0.4 mL CDCl3): d 1.94 (6H, s, CH3), d 7.30 (2H, d, ArH3, J sobutyramide) (1.40 g, 5.47 mmol) was added to NaNO2 and
8), d 7.44 (2H, d, ArH2, J 8), d 8.01 (1H, br, s, NH); 13C NMR (75 DMF and the reaction heated at 120 ꢂC for 4 h. Aer cooling the
MHz, 21 mg: 0.4 mL CDCl3): d 25.0 (s, C-3A/B), d 91.7 (s, C-2), d standard workup method gave 952 mg (4.29 mmol, 78% yield)
122.3 (s, C-20), d 129.5 (s, C-30), d 131.0 (s, C-40), d 135.5 (s, C-10), d of pure N-benzyl-a-nitroisobutyramide (32) as white, crystalline,
164.8 (s, C-1); GC-(EI) TOF-HRMS: calcd m/z for C10H11N2O3Cl: cauliower-shaped nodules, m.p. 87–88 ꢂC; Rf ¼ 0.23 in 4 : 1
242.0458, observed: 242.0477.
hexanes/EtOAc, 0.49 in 65 : 35 hexanes/EtOAc and 0.76 in 1 : 1
o-Methoxy-a-nitroisobutyranilide (26). 25 (o-Methoxy-a-bro- hexanes/EtOAc; IR(cmꢀ1): 3295, 3088, 3028, 3003, 2930, 1652
moisobutyranilide) (1.40 g, 5.15 mmol) gave 868 mg (3.65 (C]O), 1547, 1496, 1453, 1427, 1405, 1374, 1356, 1312, 1288,
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1236, 1209, 1162, 1077, 1055, 1029, 1000, 865, 747, 732, 698, substitution reactions. Aliquots were taken at ꢁ1 h intervals to
1
671; H NMR (300 MHz, 19 mg: 0.4 mL CDCl3): d 1.85 (6H, s, obtain ve data points for each reaction; all een GC-MS
CH3), d 4.45 (2H, d, CH2 J 8), d 6.46 (1H, br, s, NH), d 7.22–7.37 sample vials were run on the same GC-MS on the same day.
(5H, m, ArH2ꢀ6); 13C NMR (75 MHz, 55 mg: 0.4 mL CDCl3): d
24.8 (s, C-3A/B), d 44.4 (s, CH2), d 91.0 (s, C-2), d 127.8 (s, C-20), d
128.1 (s, C-40), d 129.1 (s, C-30), d 137.5 (s, C-10), d 167.2 (s, C-1);
Acknowledgements
GC-(EI) TOF-HRMS: calcd m/z for C11H14N2O3: 222.1004, We wish to acknowledge and thank RMIT for the unwavering
observed: 222.1001.
support of the synthetic organic laboratory. We wish to thank
N-Butyl-a-nitroisobutyramide (34). 33 (N-Butyl-a-nitro- Frank Antolasic for assistance with mass spectrometry experi-
isobutyramide) (1.30 g, 5.86 mmol) was added to NaNO2 and ments. We wish to thank Steve Diver at the University of Buffalo
DMF and the reaction heated at 120 ꢂC for 4 h. Aer cooling the for suggesting the oxygen-free experiment.
standard workup method gave 653 mg (3.47 mmol, 59% yield)
of pure N-butyl-a-nitroisobutyramide (34) as orange, trans-
References
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1403, 1374, 1355, 1301, 1287, 1205, 1157, 867; 1H NMR (300
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