An improved understanding of the reaction of bis(bromomethyl)quinoxaline 1-N-oxides with amines using substituent effects

Article abstract of DOI:10.1021/jo062380y

(Chemical Equation Presented) The reaction of bis(bromomethyl)quinoxaline N-oxides with amines is interesting from a reaction mechanism perspective and due to the reported biological activity of compounds in this general class. The complex mechanism of th

Full text of DOI:10.1021/jo062380y

An Improved Understanding of the Reaction of
Bis(bromomethyl)quinoxaline 1-N-Oxides with Amines Using
Substituent Effects
Kathryn M. Evans, Alexandra M. Z. Slawin, Tomas Lebl, Douglas Philp, and
Nicholas J. Westwood*
School of Chemistry and Centre of Biomolecular Sciences, UniVersity of St. Andrews,
North Haugh, St. Andrews, KY16 9ST, United Kingdom
njw3@st-andrews.ac.uk; dp12@st-andrews.ac.uk
ReceiVed NoVember 19, 2006
The reaction of bis(bromomethyl)quinoxaline N-oxides with amines is interesting from a reaction
mechanism perspective and due to the reported biological activity of compounds in this general class.
The complex mechanism of this reaction (particularly in the case of primary amines) is complicated
further when C6 or C7 substituted mono-N-oxides are considered. In this study, the synthesis and
subsequent characterization of a series of 2,3-bis(bromomethyl)quinoxaline 1-N-oxides is reported.
Experimental and computational evidence is used to show that the observed product ratios from the
reaction with diethylamine reflect the influence of both the C6/C7 substituent and the N-oxide functional
group on the initial nucleophilic substitution reaction.
Introduction
experimental evidence in support of a mechanism for this
transformation (Scheme 1). In addition, an explanation of why
3 reacts to form the disubstituted intermediate 4 rather than
undergoing a cyclization reaction was provided. We reasoned
that electrostatic repulsion between the N-oxide oxygen and the
departing bromine atom in 3 prevents access to the transition
state required for an intramolecular SN2 displacement. Com-
putational studies played an important role in supporting this
hypothesis.
Bis(bromomethyl)quinoxaline N-oxides are of interest due to
their known biological activity and chemical reactivity. For
example, di-N-oxides of general type 1 have been shown to
possess antibacterial and antiparasitic activity.1,2 2 has also been
shown to exhibit a selective biological activity profile across a
series of assays designed to probe host cell invasion by the
parasite Toxoplasma gondii. On inspection this is a surprising
result given that 2 appears to be a general alkylating agent. In
our initial studies on this system,3 we considered the possibility
that 2 exhibits this unexpected activity profile due to its
mechanism of reaction with amines. We reported the first
These studies also led to an interesting prediction about the
reaction of 2,3-bis(bromomethyl)quinoxaline 1-N-oxides (e.g.,
5) with amines (Scheme 2). In particular, we showed that
reaction of 5 with diethylamine led to the formation of two
products 6 and 7, in a ratio of 63:37 respectively. This ratio
has subsequently been shown by us to be relatively independent
of the nature of the solvent suggesting that hydrogen bonding
interactions between, for example, the oxygen of the N-oxide
functional group and the incoming nucleophile do not signifi-
cantly affect the outcome of this reaction (Scheme 2).4
(1) Similar compounds have also been shown to exhibit antibacterial
activity. McIlwain, H. J. Chem. Soc. 1943, 322-325. Kim, H. K.; Miller,
L. F.; Bambury, R. E.; Ritter, H. W. J. Med. Chem. 1977, 20, 557-560.
(2) Carey, K. L.; Westwood, N. J.; Mitchison, T. J.; Ward, G. E. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 7434-7438.
(3) Pearson, R. J.; Evans, K. M.; Slawin, A. M. Z.; Philp, D.; Westwood,
N. J. J. Org. Chem. 2005, 70, 5055-5061.
10.1021/jo062380y CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/04/2007
3186
J. Org. Chem. 2007, 72, 3186-3193

Reactions of Bis(bromomethyl)quinoxaline 1-N-Oxides
SCHEME 1. Reaction of 2 with an Excess of a Primary
SCHEME 3. Reaction of 8 with a Secondary Aminea
Amine, n-Butylaminea
a Reagents and conditions: (a) diethylamine (4 equiv), CDCl3, 25 °C,
74% isolated yield of 9 (20 mM). bAll values correspond to relative amounts
of 9 and 10.
a Reagents and conditions: (a) n-butylamine, CDCl3, 25 °C.
SCHEME 4. Concentration Dependence of the Reaction of
5 with Diethylamine
SCHEME 2. Reaction of 5 with a Secondary Amine
b
a From ref 3. Average of 8 data points.
In attempting to rationalize the observed product ratio we
made two assumptions: (1) initial displacement of the bromine
atom adjacent to the N-oxide functional group in 5 (C9-Br) led
exclusively to formation of the cyclized product 6 and (2) initial
displacement of the alternative bromine atom (C10-Br) afforded
the disubstituted product 7.3 If correct, these two assumptions
dictate that the observed product ratio directly reflects the ratio
of the initial attack of the nucleophile at C9 and C10 in 5. X-ray
crystallographic analysis of 5 showed that the C9-Br bond was
longer than the C10-Br bond supporting favored attack adjacent
to the N-oxide, culminating in preferential formation of the
cyclized product 6. While this explanation was initially gratify-
ing, we remained concerned about using a “ground state”
observation such as X-ray structure determined bond length to
rationalize the outcome of this reaction. In addition, a later
observation regarding the concentration dependence of the
a Reagents and conditions: (a) diethylamine (4 equiv), CDCl3, 25 °C.
reaction of 2,3-bis(bromomethyl)quinoxaline (8) with diethyl-
amine refocused our interest in this work (Scheme 3). Here we
provide a detailed study of the reaction of a series of 2,3-bis-
(bromomethyl)quinoxaline 1-N-oxides with diethylamine. Through
the study of substituent effects on product ratios coupled with
further computational studies we have gained a more detailed
mechanistic understanding of this reaction.
Results and Discussion
Assessing the Validity of Assumptions 1 and 2. Previously
(4) Raposo, C.; Wilcox, C. S. Tetrahedron Lett. 1999, 40, 1285-1288.
our studies showed that when carried out at an initial concentra-
J. Org. Chem, Vol. 72, No. 9, 2007 3187

Evans et al.
FIGURE 1. Calculated structures (B3LYP/6-31G(d,p)) of transition states 14q and 15q leading to cyclized product 16 from intermediates 14 and
15, respectively. Transition state 14q is more stable by 1.39 kcal mol-1 at this level of theory. Carbon atoms are green, nitrogen atoms are blue,
oxygen atoms are red, bromine atoms are brown, and hydrogen atoms are light gray. Most hydrogen atoms have been omitted for clarity.
tion of 8 of 20 mM in CDCl3, 8 reacted with diethylamine to
give 9 as the only observed product.3 When this reaction was
repeated with increasing concentrations of 8 and diethylamine
in the same proportions, a mixture of two products 9 and 10
was obtained consistent with effective intermolecular competi-
tion over the previously dominant cyclization reaction
(Scheme 3). An analogous study with 5 showed a similar
trend (Scheme 4) consistent with a view that our previous
assumption 1 does not hold at higher reaction concentrations.
transition states for the cyclization reactions in each case. The
transition states required for cyclization were calculated at the
B3LYP/6-31G(d,p) level of theory by using the PCM solvation
model for CHCl3 (Figure 1). The transition states for the
cyclization reaction were located by generation of initial guesses
with use of the linear synchronous transit (LST) method and
refinement of these initial guesses at the HF/6-31G(d) level.
These transition states were then used as initial guesses for
refinement at the B3LYP/6-31G(d,p) level of theory. All
transition states were demonstrated to possess a single imaginary
vibration corresponding to the reaction coordinate. The results
obtained are summarized in Figure 1. It is striking that the
transition state structures are almost invariant with respect to
the substituent present (or, indeed, absent) at the C6 or the C7
position. In all cases, cyclization from C9 to C10 involves a
transition state that is less distorted (N-C-Br angles all around
166°) compared to those involving cyclization in the opposite
direction from C10 to C9 (N-C-Br angles all around 161°).
Examination of the view along the edge of the forming five-
membered ring emphasizes the structural differences in these
transition states (Figure 1). The distortion required to accom-
modate the electrostatic repulsion generated at the transition state
between the negatively charged oxygen atom of the N-oxide
and the departing bromide in a cyclization from C10 to C9 is
clearly evident. This repulsion results in significant distortion
of the five-membered ring in transition state 15q. By contrast,
the negatively charged oxygen atom of the N-oxide and the
departing bromide are on opposite sides of the molecule in 14q
and the transition state has a much less distorted geometry. These
It was reasoned that information on the validity of assumption
2 could potentially be obtained by carrying out the reaction of
5 with diethylamine at lower concentrations. However, even at
the lowest reaction concentrations that could be practically
studied the ratio of 6:7 remained constant, consistent with there
being no breakdown of assumption 2 even at low nucleophile
concentrations. We therefore concluded that provided a suitable
reaction concentration was selected, assumptions 1 and 2 both
hold and the ratio of 6:7 reflects the ratio of initial nucleophilic
attack at C9 and C10. The question remained, however, as to
why preferential attack at C9 was observed for 5.
Assumptions 1 and 2 Hold When Substituents Are Present
at C6/C7. Studying the dependence of the reaction of analogs
of 5 that are substituted at the C6/C7 position with diethylamine
was identified as a useful method of gaining further insight into
this potentially complex reaction. However, these studies were
only considered useful if assumptions 1 and 2 hold for the
modified substrates. It was therefore decided to assess compu-
tationally whether incorporation of C6/C7 substituents would
have a dramatic effect on the relative stabilities of the key
3188 J. Org. Chem., Vol. 72, No. 9, 2007

Reactions of Bis(bromomethyl)quinoxaline 1-N-Oxides
SCHEME 5. Synthesis of Substituted
Bis(bromomethyl)quinoxaline 1-N-Oxidesa
a Reagents and conditions: (a) Boc anhydride, DCM, rt, 2 d, quant. 23;
(b) H2, 10% Pd/C, MeOH, rt, 24 h, 99% 24; (c) SnCl2‚2H2O, EtOH, reflux,
93% 27; (d) 1,4-dibromo-2,3-butanedione, THF, 0 °C to rt, 12-27 h, 88-
95%; (e) mCPBA, DCM, rt/reflux, 24-48 h, 11-68%.
6, 11, and 12 (Figure 2A, see the Supporting Information for a
discussion of the NMR assignments).5 Interestingly, the signals
corresponding to 11 had reduced significantly by 27 min
(Figure 2B) and had disappeared within 47 min (Figure 2C)
accompanied over this time period by an increase in the signals
assigned to 6. This observation is consistent with a view that
11 was converted relatively rapidly to 6 in line with the
computational studies. In contrast, the size of the signals
corresponding to intermediate 12 was relatively static over a
much longer time period (Figure 2C). 12 only disappeared from
the reaction after approximately 6 h (Figure 2D) presumably
being converted to 6 as no signals corresponding to 7 were
observed in this experiment. The kinetic data obtained in this
experiment were used to estimate the relative rate of the two
cyclization reactions (11 or 12 to 6) with use of the kinetic
simulation package Gepasi.5 The calculations support a view
that the conversion of 12 to 6 is at least an order of magnitude
slower than the conversion of 11 to 6.5 Signals corresponding
to 11 and 12 were also observed when this experiment was
repeated with 5 at an initial concentration of 5 of 10 mM (data
not shown).
FIGURE 2. Reaction of 5 with limiting amounts of diethylamine in
1
CDCl3 monitored by H NMR: (A) t ) 7 min, (B) t ) 27 min, (C)
t ) 47 min, and (D) t ) 360 min. The asterisk indicates 13C satellites
of 5.
observations mirror the behavior of the unsubstituted system 5
(see table in Figure 1) and our previous work3 on related
systems.
The calculated energy difference (∆TSenergy) between the two
cyclization transition states for each substituent (table in
Figure 1) remains relatively constant as the substituent varies,
supporting a view that the relative rates of the two cyclization
reactions vary little with the substituent and hence the two
assumptions hold across the series of compounds studied. A
significant change in this calculated energy difference (and,
hence, in the relative rate of cyclization) would be expected if,
for example, one of the substituents dramatically facilitated the
cyclization reaction following attack at C9.5 One possible
explanation for the lack of a strong substituent effect on the
relative rates of the cyclization reactions is the relatively poor
overlap of the π-system of the quinoxaline 1-N-oxide with the
σ* orbital of the C-Br bond in the transition state for the
cyclization reactions. These computational studies therefore
suggest that, proVided the reactions of 5, 13, and 17-21 are
carried out at a suitably low concentration, any obserVed
dependence of product ratios on the substituent do not arise
from the failure of assumptions 1 or 2.
Interestingly, when the reaction of 13 with limiting quantities
of diethylamine was analyzed at an initial concentration of
13 of 10 mM, signals corresponding to the formation of two
intermediates were also observed (see the Supporting Informa-
1
tion for H NMR assignments). These intermediates behaved
analogously to 11 and 12, in that their relative stability with
respect to cyclization mirrored that observed in experiments with
5, again supporting the computational studies described above.5
Importantly, the fact that signals corresponding to intermediates
in the reactions of both 5 and 13 were observed to grow in
rapidly, plateau at low levels, and then decrease in intensity is
consistent with the initial nucleophilic substitution reactions
being rate-determining and hence important in determining the
Observation of Reaction Intermediates. In an attempt to
provide experimental evidence to support the above calculations,
1
a H NMR kinetic experiment was carried out on the reaction
of 5 with a limiting quantity of diethylamine (1 equiv) in CDCl3
at an initial concentration of 5 of 100 mM. This concentration
was chosen to maximize the signal from any reaction intermedi-
1
final product ratio. The low intensity of the H NMR signals
observed unfortunately made it very difficult to carry out a
computational simulation that led to sufficiently accurate relative
rates of the initial substitution reactions at C9 and C10 to be
informative.
1
ates. After 7 min post mixing three low-intensity sets of H
NMR signals were observed that were not present in the starting
sample of 5. These new signals were assigned to compounds
Observed Variation in the Product Ratio as a Function
of the Substituent. Having shown through a series of compu-
(5) For further details see the Supporting Information.
J. Org. Chem, Vol. 72, No. 9, 2007 3189

Evans et al.
TABLE 1. Product Distribution from Reaction of the Mono-N1-oxide 2,3-Bis(bromomethyl)quinoxaline Derivatives Bearing a C6/7 Substituent
with Diethylaminea,b
substituent
position
C9-Br bond
length (Å)
C10-Br bond
length (Å)
entry
compd
R
cyclizedc
disubstitutedc
1
2
3
4
5
6
17
18
19
20
13
21
NHBoc
NHBoc
Br
Br
NO2
NO2
6
7
6
7
6
7
nd
nd
nd
nd
61 (31)
68 (33)
55.5 (35)
57 (37)
14 (39)
12.5 (41)
39 (32)
32 (34)
44.5 (36)
43 (38)
86 (40)
87.5 (42)
1.979 (3)d
1.960 (18)
1.967 (3)
1.959 (3)
1.967(3)
1.964 (15)
1.961 (3)
1.960 (3)
a Reagents and conditions: (a) diethylamine (4 equiv), CDCl3, 25 °C. b All values are an average of between 4 and 24 datapoints and errors are (3 units.
nd ) not done. c Compound numbers shown in bold type. d Associated error shown in parentheses.
1
tational and H NMR kinetic studies that incorporation of a
substituent into 5 would not lead to a breakdown in assumptions
1 and 2, six analogues of 5 were prepared with substituents at
the C6 and C7 positions.
initial concentration of 20 mM. The results from these studies
are shown in Table 1.
The data showed a clear difference in the product ratio as a
function of the substituent, with the ratio of cyclized:disubsti-
tuted product decreasing as the electron-withdrawing nature of
the substituent increased. This trend was mirrored in both the
C6 and C7 series, with the results showing that there was little
dependence of the product ratio on the position of the substituent
(cf. entries 1 and 2).
Scheme 5 details how these analogues were prepared. With
the exception of the NHBoc substituted analogues 17 and 18,
the remaining isomeric pairs were separable by column chro-
matography. Subsequent analysis of the reaction of 13 and 17-
21 with diethylamine (4 equiv) was carried out in CDCl3 at an
Rationalization of the Observed Product Ratios. In our
previous studies with 5, the product ratio was rationalized based
on the observed C9-Br and C10-Br bond lengths. However,
this trend was not reproduced for 13, 20, and 21, where the
C9-Br and C10-Br bonds lengths determined from the crystal
structures did not vary as expected given the observed product
ratios (Table 1, entries 4-6). In addition, attempts to rationalize
the observed ratios by using 13C NMR shifts as a readout of
electron density at the C9 and C10 positions also failed.5-7
Our favored explanation for the observed variation in
chemical reactivity is best explained by initially considering the
reaction of 17 and 18, containing the electron-donating NHBoc
substituent. As the computational studies and 1H NMR support
the view that assumptions 1 and 2 hold for 17 and 18, the
observed product ratio reflects the relative ratio of initial
nucleophilic attack at the C9 and C10 positions. Given the
known electronic influence of an NHBoc substituent, it would
be expected that within the context of an SN2 reaction, the
transition states for the initial nucleophilic substitution reaction
would be more SN1-like with accumulation of positive charge
FIGURE 3. Schematic representation of a 2D energy surface illustrat-
ing the variation of the bond orders of the N-C and C-Br bonds in
the reaction of a benzylic bromomethylene group with amines. The
reaction coordinates are depicted for (i) the SN1 process (red solid line),
(ii) arbitrary reaction coordinates for the SN2 process (purple, green,
and blue lines), and (iii) the hypothetical limiting SN2 process (red
broken line). The transition states in the SN2 reactions are labeled aq
(N-C = C-Br), bq (N-C < C-Br), and cq (N-C , C-Br). The
image was adapted from refs 8 and 9.
(6) Cusack, K. P.; Arnold, L. D.; Barberis, C. E.; Chen, H.; Ericsson,
A. M.; Gaza-Bulseco, G. S.; Gordon, T. D.; Grinnell, C. M.; Harsch, A.;
Pellegrini, M.; Tarcsa, E. Bioorg. Med. Chem. Lett. 2004, 14, 5503-5507.
(7) Spencer, S. R.; Xue, L. A.; Klenz, E. M.; Talalay, P. Biochem. J.
1991, 273, 711-717.
3190 J. Org. Chem., Vol. 72, No. 9, 2007

Reactions of Bis(bromomethyl)quinoxaline 1-N-Oxides
SCHEME 6. Structures 43 (with Resonance Form) and 44
-withdrawing nature of the substituent. However, the position
(C6 or C7) of the substituent had only subtle effects on the
reaction outcome. A combination of experimental and compu-
tational analysis supports the view that, under the reaction
conditions used, the product ratio mirrored the relative propen-
sity of diethylamine to attack at C9 or C10 in the initial
nucleophilic substitution reaction. Rationalization of the results
by using ground state analysis of the reactants (X-ray crystal-
lography, 13C NMR) was not possible. However, the observed
variation in the product ratios as a function of the substituent
can be explained by considering the deviation from an ideal
SN2 reaction induced by the substituents and the ability of the
N-oxide functional group to stabilize positive charge that
develops at C9 in the transition state. These studies have
provided a detailed understanding of the mechanism of this
interesting chemical reaction and enabled us to provide an
improved explanation of the observed product ratio obtained
on reaction of 5 with diethylamine. Furthermore, these studies
will contribute to our attempts to explain the mode of action of
compounds of this general class.1-3
at either C9 or C10 (i.e., transition state cq, Figure 3).8
Comparison of the structures of the cations 43 (R ) NHCO2-
Me) and 44 (R ) NHCO2Me) intuitively suggests a preference
for the formation of a positive charge adjacent to the N-oxide
functional group in 43 due to the increased resonance stabiliza-
tion (Scheme 6). In line with the observed product ratio for 5,
it seems reasonable to propose that this is also the situation
when no C6/C7 substituent is present, i.e., the preference for
attack at C9 in 5 therefore results from the electronic influence
of the N-oxide functional group on the reaction mechanism
leading to most effective stabilization of developing positive
charge at C9 and hence preferred initial nucleophilic substitution
at this position leading to formation of 6 as the major product.
The question now becomes how can the observed change in
the major product on incorporation of the strongly electron-
withdrawing nitro functional group be rationalized (Table 1,
entries 5 and 6). One likely explanation that builds on the
arguments made above is that the perturbation caused by the
nitro group on the initial substitution reaction leads to a reduction
in the development of positive charge at the reactive centers
compared with the NHBoc and H substrates (i.e., the reaction
is more SN2-like, transition state aq, Figure 3). The influence
of the N-oxide functional group on the reaction as depicted in
Scheme 6 is essentially cancelled out and hence there is no
dominant reaction observed through C9. The fact that the
product resulting from C10 attack is the major product probably
reflects another bias of this system either due to steric impedance
to reaction at C9 compared with C10 or due to repulsion of the
incoming nucleophile at C9 by the N-oxide oxygen, which does
not occur at C10. In the case of the bromo-substituted series
(Table 1, entries 3 and 4), the electron-withdrawing nature of
the bromine substituent again modulates the influence of the
N-oxide functional group resulting in a situation where the
observed product ratios are consistent with less deviation from
an idealized SN2 transition state toward an SN1-mechanism as
compared with 5. In all cases, one possible explanation for the
insensitivity of the product ratio to the position of the substituent
is the relatively remote nature of the substituent from the reaction
center compared with, for example, analogous reactions of
benzyl halides.8
Experimental Section
General Methods. Unless otherwise noted, starting materials
and reagents were obtained from commercial suppliers and were
used without further purification. Dichloromethane (DCM) was
dried by heating under reflux over calcium hydride and distilled
under an atmosphere of nitrogen. mCPBA was purified by
dissolving in DCM and washing with an aqueous solution of
buffered KH2PO4 (1.0 M) at pH 7.4-7.5. The DCM phase was
then treated as for a separation. PE 40-60 refers to the fraction of
light PE 40-60 boiling in the range of 40-60 °C. Melting points
were recorded on an Electrothermal 9100 capillary melting point
apparatus. Values are quoted to the nearest 0.5 °C. IR spectra were
measured on a Perkin-Elmer Paragon 1000 FT-IR spectrometer.
1H NMR spectra were recorded at 300 and 500 MHz. 13C NMR
spectra were recorded at either 75 or 125 MHz. J values are quoted
in Hz. Low- and high-resolution mass spectral analyses were
recorded in either EI, CI, or ES operating in positive ion mode.
tert-Butyl 4-Amino-3-nitrophenylcarbamate (23). 23 was
prepared by a procedure reported by Smith et al.10 Di-tert-
butyldicarbonate (48.0 g, 0.22 mol) was added to a solution of
2-nitro-p-phenylenediamine (30.6 g, 0.20 mol) in anhydrous DCM
(1.00 L) at room temperature, under nitrogen. After being stirred
for 2 d the reaction mixture was diluted with DCM (1.00 L) and
washed with 10% w/v aqueous NaHCO3 solution (2 × 500 mL).
The organic phase was washed with brine (500 mL) and the
combined aqueous phases extracted with DCM (2 × 500 mL). The
combined organic phases were dried (MgSO4) and concentrated in
vacuo. Drying under vacuum at 50 °C gave 23 as a bright orange
solid (50.7 g, 0.20 mol, quant.); mp 135.0-137.0 °C. IR (NaCl,
Nujol) νmax: 3500, 3381, 3335, 1691, 1531, 1252, 1218, 1161, 887,
822, 747 cm-1. 1H NMR (300 MHz, DMSO-d6): δ 9.28 (br s, 1H),
3
4
8.20 (br s, 1H), 7.40 (dd, J ) 9.1 Hz, J ) 2.5 Hz, 1H), 7.25 (s,
2H), 6.95 (d, 3J ) 9.1 Hz, 1H), 1.46 (s, 9H). 13C NMR (75.5 MHz,
DMSO-d6): δ 152.8 (C), 142.3 (C), 129.3 (C), 128.5 (CH), 128.2
(C), 119.4 (CH), 112.6 (CH), 79.0 (C), 28.0 (3 × CH3). MS-EI+
(m/z) 253 ([M]+•, 4%), 197 (45), 153 (25). HRMS-EI+ (m/z) calcd
for C11H15N3O4 [M]+• 253.1063, found 253.1063. Anal. Calcd for
C11H15N3O4: C, 52.17; H, 5.97; N, 16.59. Found: C, 52.39; H,
6.07; N, 16.35.
Conclusion
Bis(bromomethyl)quinoxaline 1-N-oxides containing a sub-
stituent at either the C6 or C7 position have been synthesized
and their reactivity with diethylamine assessed. While in all
cases two products were formed, the ratio of the two products
varied significantly depending on the electron-donating or
tert-Butyl 3,4-Diaminophenylcarbamate (24). A 250 mL round-
bottomed flask equipped with 23 (4.00 g, 15.8 mmol) and 10%
Pd/C (0.80 g) was purged with nitrogen. MeOH (60.0 mL) was
(8) Shpan’ko, I. V.; Korostylev, A. P.; Rusu, L. N. J. Org. Chem. USSR
(Transl.) 1984, 20, 1881-1888.
(9) Scudder, P. H. Electron Flow in Organic Chemistry; John Wiley &
Sons, Inc.: New York, 1992.
(10) Smith, D. M.; McFarlane, M. D.; Moody, D. J. J. Chem. Soc., Perkin
Trans. I 1988, 691-696 and references cited therein.
J. Org. Chem, Vol. 72, No. 9, 2007 3191

Evans et al.
added with stirring and the flask covered in foil. The flask was
then purged with hydrogen and a hydrogen balloon introduced that
was replaced a further 3 times. After 24 h of stirring at room
temperature the reaction mixture was filtered over Celite washing
with MeOH (300 mL). Removal of the solvent in vacuo afforded
the desired product 24 as an off-white crystalline solid (3.50 g,
15.7 mmol, 99%) that was used without any further purification.
IR (NaCl, Nujol) νmax: 3410-3215, 1725, 1700, 1610, 1521, 1243,
1166, 1059, 850, 810-720 cm-1. 1H NMR (300 MHz, CDCl3): δ
>180 °C dec. IR (NaCl, Nujol) νmax: 3450, 1597, 1561, 1355, 830,
774, 672 cm-1. H NMR (300 MHz, CDCl3): δ 8.73 (br d, J )
1.8 Hz, 1H), 7.92 (m, 2H), 4.98 (s, 2H), 4.74 (s, 2H). 13C NMR
(75.5 MHz, CDCl3): δ 152.9 (C), 142.1 (C), 139.1 (C), 136.7 (C),
135.9 (CH), 131.4 (CH), 125.6 (C), 122.0 (CH), 30.0 (CH2), 20.5
(CH2). MS-ES+ (m/z) 435 ([M + Na]+, 2 × 81Br + 79Br, 74), 433
([M + Na]+, 2 × 79Br + 81Br, 100). HRMS-ES+ (m/z) calcd for
C10H779Br81Br2N2ONa [M + Na]+ 434.7965, found 434.7955.
HRMS-ES+ (m/z) calcd for C10H779Br281BrN2ONa [M + Na]+
432.7986, found 432.7980. Anal. Calcd for C10H7Br3N2O: C, 29.23;
H, 1.72; N, 6.82. Found: C, 29.49; H, 1.43; N, 6.60. The structure
was also confirmed by X-ray crystallographic analysis.5 2,3-Bis-
(bromomethyl)-6-bromoquinoxaline 1,4-dioxide12 was also collected
as a bright yellow crystalline solid (184 mg, 0.43 mmol, 55%).
1
4
3
3
6.92 (br s, 1H), 6.59 (d, J ) 8.2 Hz, 1H), 6.50 (dd, J ) 8.2 Hz,
4J ) 2.3 Hz, 1H), 6.37 (br s, 1H), 3.23 (br s, 4H), 1.49 (s, 9H). 13
C
NMR (75.5 MHz, CDCl3): δ 153.1 (C), 135.7 (C), 131.5 (C), 129.9
(C), 117.2 (CH), 110.5 (CH), 108.0 (CH), 80.0 (C), 28.3 (3 × CH3).
General Procedure for the Preparation of the C6-Substituted
2,3-Bis(bromomethyl)quinoxalines: 2,3-Bis(bromomethyl)-6-
bromoquinoxaline (28). A solution of 1,4-dibromo-2,3-butanedione
(529 mg, 2.17 mmol) in anhydrous THF (20 mL) was added
dropwise to a solution of 2711 (398 mg, 2.13 mmol) in anhydrous
THF (20 mL) at 0 °C over 15 min with stirring. The reaction was
warmed to room temperature and stirred for a further 27 h. After
concentration in vacuo, the crude material was redissolved in DCM
(100 mL) and partitioned between 10% w/v aqueous NaHCO3
solution (200 mL) and DCM (300 mL). The organic phase was
washed with brine (100 mL), dried (MgSO4), filtered, and concen-
trated in vacuo to give a pale brown solid. Purification by flash
column chromatography on silica gel (EtOAc:PE 40-60, 1:9) gave
28 as a white crystalline solid (736 mg, 1.86 mmol, 88%); mp
143.0-144.0 °C. IR (KBr) νmax: 3090, 3027, 2968, 1597, 1476,
General Procedure for Reactions of 2,3-Bis(bromomethyl)-
quinoxalines with Diethylamine. To a solution of the quinoxaline
derivative (0.5 mL of a 40 mM solution in CDCl3) was added a
solution of diethylamine (0.5 mL of a 120 mM solution in CDCl3)
in an NMR tube at 25 °C and the mixture was then monitored by
300 MHz 1H NMR. The excess of diethylamine was used to drive
the reactions to completion, in order to assist interpretation of the
1H NMR spectra.
2,2-Diethyl-2,3-dihydro-1H-pyrrolo[3,4-b]-7-bromoquinoxa-
lin-2-ium Bromide 4-Oxide (35). 35 was prepared according to
the general procedure with 19 and diethylamine. Reaction was
scaled up 6-fold for full analysis. 35 was collected following
crystallization to yield a white crystalline solid (16 mg, 0.04 mmol,
35%); mp >195 °C dec. IR (NaCl, Nujol) νmax: 3458, 1597, 1571,
1368, 1107, 820, 743, 723 cm-1. 1H NMR (300 MHz, DMSO-d6):
1419, 1357, 1211, 939, 833, 799, 722, 638, 603, 569, 426 cm-1
.
4
3
4
1H NMR (300 MHz, CDCl3): δ 8.24 (d, J ) 2.1 Hz, 1H), 7.92
δ 8.49 (d, J ) 2.1 Hz, 1H), 8.42 (d, J ) 9.2 Hz, 1H), 8.06 (dd,
3J ) 9.2 Hz, 4J ) 2.1 Hz, 1H), 5.26 (s, 2H), 5.23 (s, 2H), 3.72 (q,
3J ) 7.1 Hz, 4H), 1.31 (t, 3J ) 7.1 Hz, 6H). 13C NMR (75.5 MHz,
DMSO-d6): δ 153.8 (C), 146.1 (C), 135.5 (C), 133.4 (C), 133.4
(CH) 131.6 (CH), 125.6 (C), 119.7 (CH), 65.4 (CH2), 62.0 (CH2),
57.7 (2 × CH2), 8.4 (2 × CH3); MS-ES+ (m/z) 324 ([M - Br]+,
81Br, 87%), 322 ([M - Br]+, 79Br, 100). HRMS-ES+ (m/z) calcd
for C14H1881BrN3O [M - Br]+ 324.0535, found 324.0538. HRMS-
ES+ (m/z) calcd for C14H1879BrN3O [M - Br]+ 322.0555, found
322.0552.
3
3
4
(d, J ) 8.9 Hz, 1H), 7.85 (dd, J ) 8.9 Hz, J ) 2.1 Hz, 1H),
4.89 (s, 4H). 13C NMR (75 MHz, CDCl3): δ 151.8 (C), 151.1 (C),
142.0 (C), 140.2 (C), 134.4 (CH), 131.3 (CH), 130.2 (CH), 125.1
(C), 30.2 (CH2), 30.1 (CH2); MS-ES+ (m/z) 399 ([M + H]+, 3 ×
81Br, 23%), 397 ([M + H]+, 2 × 81Br + 79Br, 95), 395 ([M + H]+,
2 × 79Br + 81Br, 100), 393 ([M + H]+, 3 × 79Br, 25). Anal. Calcd
for C10H7Br3N2: C, 30.42; H, 1.79; N, 7.09. Found: C, 30.50; H,
1.60; N, 6.94.
General Procedure for the Oxidation of 2,3-Bis(bromometh-
yl)quinoxalines: 2,3-Bis(bromomethyl)-6-bromoquinoxaline 1-Ox-
ide (19). To a solution of 28 (312 g, 0.79 mmol) in anhydrous
DCM (20.0 mL) was added purified mCPBA (1.02 g, 5.93 mmol)
with stirring. After 34 h at room temperature the reaction mixture
was diluted with DCM (20.0 mL) and washed with 10% w/v Na2-
CO3 solution (3 × 20 mL). The organic phase was dried (MgSO4),
filtered, and concentrated in vacuo to give a yellow solid.
Purification by flash column chromatography on silica gel
(EtOAc:PE 40-60, 1:19 to 1:9) gave 19 as a pale yellow solid (37
mg, 0.09 mmol, 18%); mp 144.5-146.0 °C. IR (NaCl, Nujol)
(3-(Diethylaminomethyl)-6-bromoquinoxalin-2-ylmethyl)di-
ethylamine 1-Oxide (36). 36 was recovered from the filtrate in
1
the presence of diethylamine. H NMR (300 MHz, DMSO-d6): δ
3
4
8.36 (d, J ) 9.2 Hz, 1H), 8.32 (d, J ) 2.1 Hz, 1H), 7.94 (dd,
3J ) 9.2 Hz, J ) 2.1 Hz, 1H), 4.24 (s, 2H), 4.06 (s, 2H), 2.63-
4
2.49 (m, 8H), 0.95 (t, 12H). 1H NMR (300 MHz, CDCl3): δ 8.40
(d, 3J ) 9.2 Hz, 1H), 8.23 (d, 4J ) 2.1 Hz, 1H), 7.72 (dd, 3J ) 9.2
4
Hz, J ) 2.1 Hz, 1H), 4.28 (s, 2H), 4.10 (s, 2H), 2.65-2.54 (m,
8H), 1.02-0.97 (m, 12H). 13C NMR (75.5 MHz, CDCl3): δ 158.9
(C), 143.6 (C), 141.7 (C), 134.7 (C), 132.7 (CH), 131.9 (CH), 125.0
(C), 121.0 (CH), 57.6 (CH2), 47.2 (CH2), 47.0 (2 × CH2), 46.5
(2 × CH2), 11.3 (2 × CH3), 11.0 (2 × CH3). MS-ES+ (m/z) 397
([M + H]+, 81Br, 79%), 395 ([M + H]+, 79Br, 100), 379
([M - OH]+, 81Br, 54), 395 ([M - OH]+, 79Br, 55), 324 ([M -
NEt2]+, 81Br, 28), 322 ([M - NEt2]+, 79Br, 32), 308 ([M - O -
NEt2]+, 81Br, 56), 306 ([M - O - NEt2]+, 79Br, 83). HRMS-ES+
(m/z) calcd for C18H2781BrN4ONa [M + Na]+ 419.1245, found
419.1262. HRMS-ES+ (m/z) calcd for C18H2779BrN4ONa [M +
Na]+ 417.1266, found 417.1264.
ν
max: 3450, 1595, 1567, 1351, 1204, 1168, 1107, 1057, 823, 774,
1
4
683, 670 cm-1. H NMR (300 MHz, DMSO-d6): δ 8.40 (d, J )
3
3
4
2.1 Hz, 1H), 8.36 (d, J ) 9.2 Hz, 1H), 8.02 (dd, J ) 9.2 Hz, J
) 2.1 Hz, 1H), 5.00 (s, 2H), 4.99 (s, 2H). H NMR (300 MHz,
1
3
4
CDCl3): δ 8.39 (d, J ) 9.2 Hz, 1H), 8.23 (d, J ) 2.0 Hz, 1H),
7.80 (dd,3J ) 9.2 Hz, 4J ) 2.0 Hz, 1H), 4.96 (s, 2H), 4.73 (s, 2H).
13C NMR (75.5 MHz, CDCl3): δ 153.8 (C), 143.9 (C), 138.8 (C),
135.3 (C), 134.2 (CH), 132.2 (CH), 126.8 (C), 120.7 (CH), 29.9
(CH2), 20.6 (CH2). MS-ES+ (m/z) 435 ([M + Na]+, 2 × 81Br +
79Br, 79), 433 ([M + Na]+, 2 × 79Br + 81Br, 100). HRMS-ES+
(m/z) calcd for C10H779Br81Br2N2ONa [M + Na]+ 434.7965, found
434.7953. HRMS-ES+ (m/z) calcd for C10H779Br281BrN2ONa
[M + Na]+ 432.7986, found 432.7975. The structure was also
confirmed by X-ray crystallographic analysis.5 2,3-Bis(bromo-
methyl)-7-bromoquinoxaline 1-Oxide (20). 20 was also collected
as a white crystalline solid (30 mg, 0.07 mmol, 14%); mp
Acknowledgment. We acknowledge the input of an excel-
lent reviewer who’s suggestion it was to carry out the experi-
ments using limiting concentrations of diethylamine that are
described above and provided strong experimental evidence to
support the computational work. We would like to acknowledge
the assistance of Mrs. M. Smith for NMR, Mrs. C. Horsburgh
(11) Rangarajan, M.; Kim, J. S.; Sim, S-P.; Liu, A.; Liu, L. F.; La Voie,
E. J. Bioorg. Med. Chem. 2000, 8, 2591-2600.
(12) Musatova, I. S.; Elina, A. S.; Solov’eva, N. P.; Polukhina, L. M.;
Moskalenko, N. Y.; Pershin, G. N. Pharm. Chem. J. 1983, 17, 779-784.
3192 J. Org. Chem., Vol. 72, No. 9, 2007

Reactions of Bis(bromomethyl)quinoxaline 1-N-Oxides
materials and products, including 1H and 13C NMR spectra for the
reaction of 17/18 with diethylamine, and Cartesian coordinates and
total energies for the optimized structures of the calculated transition
states. This material is available free of charge via the Internet at
http://pubs.acs.org.
for HRMS analysis, and Mrs. S. Williamson for elemental
analysis. Financial support from BBSRC (No. 02/A1/B/08395
(KME), NIH (No. R01A1054961), and the Royal Society (NJW
fellowship) is gratefully acknowledged.
Supporting Information Available: General experimental
procedures and spectral data for previously unreported starting
JO062380Y
J. Org. Chem, Vol. 72, No. 9, 2007 3193