Identifying the roles of amino acids, alcohols and 1,2-diamines as mediators in coupling of haloarenes to arenes

Article abstract of DOI:10.1021/ja5101036

Coupling of haloarenes to arenes has been facilitated by a diverse range of organic additives in the presence of KO^tBu or NaO^tBu since the first report in 2008. Very recently, we showed that the reactivity of some of these additives (e.g., compounds 6 and 7) could be explained by the formation of organic electron donors in situ, but the role of other additives was not addressed. The simplest of these, alcohols, including 1,2-diols, 1,2-diamines, and amino acids are the most intriguing, and we now report experiments that support their roles as precursors of organic electron donors, underlining the importance of this mode of initiation in these coupling reactions.

Full text of DOI:10.1021/ja5101036

Article
pubs.acs.org/JACS
Identifying the Roles of Amino Acids, Alcohols and 1,2-Diamines as
Mediators in Coupling of Haloarenes to Arenes
†
†
†
†
†
Shengze Zhou, Eswararao Doni, Greg M. Anderson, Ryan G. Kane, Scott W. MacDougall,
‡
,†
,†
Victoria M. Ironmonger, Tell Tuttle,* and John A. Murphy*
†WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, United
Kingdom
‡
GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom
*
S Supporting Information
ABSTRACT: Coupling of haloarenes to arenes has been
facilitated by a diverse range of organic additives in the presence
t
t
of KO Bu or NaO Bu since the first report in 2008. Very recently,
we showed that the reactivity of some of these additives (e.g.,
compounds 6 and 7) could be explained by the formation of
organic electron donors in situ, but the role of other additives was
not addressed. The simplest of these, alcohols, including 1,2-diols,
1
,2-diamines, and amino acids are the most intriguing, and we now
report experiments that support their roles as precursors of
organic electron donors, underlining the importance of this mode
of initiation in these coupling reactions.
1
7,33
INTRODUCTION
derived from imidazolium salts, e.g., 7,
directly by electron transfer.
would function
■
1
Formation of biphenyls is of great importance both in industry
Organic electron donors have been studied intensively in
and in academic chemistry. It has normally been achieved
through coupling of arenes with the help of costly transition-
metal catalysts. In pharmaceutical chemistry, purification of
products from transition-metal impurities is necessary and is
time-consuming, so development of alternative coupling routes
is extremely worthwhile. Along these lines, Itami et al.
48−60
recent years.
These range from TTF 24 through TDAE 25
to more recent examples 28−32. In each case, an electron-rich
alkene is present (shown in blue in Figure 2) that is substituted
by multiple electron-releasing groups. When electron transfer
occurs, the resulting radical cation [or dication, following
transfer of two electrons] is stabilized by these groups.
Additional driving force results from formation of new aromatic
rings in the oxidized forms of most of these donors. Recently,
we reported that organic electron donors, e.g., 28, can act as
initiators in coupling reactions between haloarenes and
2
3
reported in 2008 the “transition-metal-free” coupling of
iodobenzenes with pyrazine and pyridine in the presence of
KO Bu. This was followed by a large number of reports
t
4−36
of
couplings of halobenzenes 1 with arenes or styrenes using
t
t
51
KO Bu or NaO Bu in the presence of a range of organic
arenes, forming aryl radicals by electron transfer to the
5
2,60n
additives 6−23 depicted in Figure 1. (In addition, a series of
related couplings promoted by KO Bu has also emerged.
haloarene. Donor 28
is formed in situ by treatment of
t
37−47
t
)
precursor salt 26 with KO Bu. This affords an N-heterocyclic
carbene 27; attack of the carbene on the imidazolium salt
within 27 gives an intermediate that, on deprotonation, affords
A number of authors suggested that the products arose from
reactions where aryl radicals were featured as intermedi-
2
,4,7,9
61
ates.
Studer and Curran presented an overview of the
tetraazafulvalene electron donor 28. In this and related
1
2
area and proposed that after addition of the aryl radical, 3, to
reactions, the electron donor simply needs to initiate the aryl
radical formation; the subsequent chain reaction (Scheme 1) is
quite efficient, and so only an extremely low concentration of
electron donor needs to be produced for a successful coupling
reaction to be seen.
We proposed similarly that imidazolium salts 7 could form
tetraazafulvalene donors with KO Bu in the presence of a trace
of BuOH as a proton source. Additionally, we showed that
when the additive 6, phenanthroline, was present, it was
an arene, deprotonation of the resulting cyclohexadienyl radical
was achieved by the metal butoxide. The product would be 5,
the radical anion of a biaryl, which could then transfer an
electron to another molecule of halobenzene to form the biaryl
product 2, together with a new aryl radical 3, in a chain reaction
4
51
t
(
Scheme 1).
t
17
The mode of initiation of the reaction for most of these
compounds, i.e., the origin of the initial aryl radicals, remained
unknown, although a number of authors suggested that
complexes formed between the metal alkoxide and additives
Received: October 1, 2014
4
,9,35
such as phenanthroline 6
or N-heterocyclic carbenes
©
XXXX American Chemical Society
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Figure 2. Organic electron donors.
although the reaction is much more sluggish. Traces of benzyne
are known to be formed from reaction of butoxides with
appropriate halobenzenes. We proposed that, in the absence
Figure 1. Selected organic additives that facilitate coupling of
haloarenes to arenes in the presence of KO Bu or NaO Bu.
9,18
t
t
of additives to underpin electron-transfer chemistry, benzyne
was formed and reacted as a diradical, initiating the formation
of aryl radicals shown in Scheme 1. The propagation of the
cycle within that scheme then secures the conversion to
Scheme 1
51
product.
However, that still leaves a bewildering diversity of additive
molecules, including 8−22 that facilitate the coupling reactions,
32
and where the mode of action is not understood. These
include amino acids, where some examples are reported to be
highly effective, while others were not at all effective. Notably,
the secondary amino acids (those featuring secondary amines)
sarcosine, 8, and proline, 9, were reported as highly active and
22
much more so than primary amino acids. Any explanation
2
8
7,24
must take account of this. Alcohols, including 1,2-diols,
and 1,2-diamines,
7
,24
also feature prominently in the list. This
paper addresses the role of amino acids and derivatives as well
as alcohols, 1,2-diols and 1,2-diamines, and proposes a unifying
mechanism of action for the generation of radicals from these
additives.
t
converted by KO Bu into an organic electron donor, and
similarly when pyridine was used as solvent in the presence of
t
51
RESULTS AND DISCUSSION
KO Bu, organic electron donors were formed. The organic
electron donors convert the haloarene into an aryl radical and a
halide anion, thereby initiating the cycle shown in Scheme 1.
The feasibilities of the observed reactions were supported by
computational results. (The computational studies also showed
that previously proposed electron transfer to iodobenzene from
■
Amino Acids and their Derivatives. Looking at amino
acids, the first point to establish was whether they indeed
reacted by electron transfer under the conditions of the
coupling reaction, as with our previous donor precursors, or by
other routes. For this, we used 2,6-dimethyliodobenzene 33 as
our diagnostic substrate (Scheme 2). This compound gives a
characteristic ratio (approximately 4:1) of biphenyl 35 and 2,6-
dimethylbiphenyl 34 by electron-transfer chemistry, as seen in
t
4,9,35
a complex of KO Bu with phenanthroline
would be
43
51
prohibitively endergonic. ) Further investigation showed
that the coupling of iodobenzene to benzene with KO Bu
t
51
occurs even in the absence of helpful additives like 28 and 6,
our recent work. The 2,6-dimethylphenyl radical 36 is
B
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Scheme 2
sterically hindered, and this particularly slows its attack on the
π-system of benzene that leads to formation of a C−C bond en
route to 34. In contrast, it can react more easily by hydrogen-
atom abstraction from benzene to form a phenyl radical 38
(
together with the volatile meta-xylene 37). The phenyl radical
then takes the place of the 2,6-dimethylphenyl radical 36 in
carrying out coupling to benzene, leading to formation of
biphenyl 35. This indirect process is less efficient than that seen
with less hindered iodobenzenes, and so while the yields of
coupled product with unhindered iodobenzenes are high with
efficient electron donors, they are routinely lower with this
substrate, affording a mixture of 34 and 35 typically in about
2
5% combined yield. This does not detract from the value of
substrate 33 as a diagnostic tool; it is not susceptible to
benzyne formation and therefore is an unambiguous reporter of
electron transfer. Moreover, as seen in the literature and as will
be shown below, less hindered aryl halides provide excellent
yields in coupling reactions with many types of initiator
discussed here.
In the following experiments, 2,6-dimethyliodobenzene 33 (1
mmol) was used as the haloarene in benzene as solvent with
t
KO Bu (2 equiv) and additive (0.2 equiv), unless otherwise
stated. (For additives with an X−H bond, where X is a
t
heteroatom, e.g., carboxylic acids or alcohols, 3 equiv of KO Bu
were used.) The reactions were all performed under identical
conditions of time and temperature, and the mass of 2,6-
dimethylbiphenyl 34 + biphenyl 35 is noted below in brackets
as ‘a’; in experiments where low amounts of these products
were produced, the reactions generally afforded high
percentages of recovered starting material, and in each
experiment this percentage is reported below as ‘b’. The
theoretical yield, based on a 1:4 ratio of the coupled products is
Figure 3. Additives tested as precursors to electron donors through
reaction of substrate 33.
predicted, gave no product (a = <0.5, b = 92%). If the amino
acids had an alternative general mode of activity that did not
rely on deprotonation of the α-carbon, for example, through
1
60 mg, so the “effective” electron donors gave ‘a’ >25 mg with
t
this hindered substrate, and reactions that gave 0−0.5 mg of
coupled products were classified as “not active” by electron-
transfer initiation. A blank reaction where KO Bu was added to
formation of a coordination complex with KO Bu, followed by
direct electron transfer from the butoxide anion, then coupling
products might have been expected when 41 was used as
organic additive. Interestingly, the N,N-dimethylglycine 42 gave
no product (a = <0.5, b = 94%), and this suggested that a
double deprotonation of this amino acid, as in 40, was more
difficult to achieve, perhaps for steric reasons. However, it was
notable that glycine 43 (a = 14; b = 76%) showed some
electron-transfer activity under our conditions.
The fact that secondary amino acids 8 and 9 were effective,
while tertiary amino acid 42 was not, suggested that the single
N-alkyl substitution of the secondary amino acids was useful
and important. For now, our minds focused on ways in which
the N-monosubstitution of amino acids might assist the
coupling reactions. A literature search showed that condensa-
tion of amino acids can occur simply on heating. Condensation
t
the substrate in the absence of additives gave a minute amount
(
<0.5 mg) of coupled products. It might be imagined that this
background reactivity should be 0 rather than <0.5 mg, but it is
clear that a very small amount of background reaction arises
from other less prevalent pathways.
62
The two amino acid test cases, sarcosine 8 (a = 44, b = 25%)
and proline 9 (a = 32, b = 54%) (Figure 3), were indeed able to
bring about the coupling reaction (with substrate 33 in benzene
as solvent), and so we interpret their reactions as being due to
electron transfer. The simplest source of electron transfer
would be the enolate of these amino acids, present as a
dianionthe dianion of sarcosine is shown as 39. To test this,
the C,C-dimethylamino acid 41 was tested and, as would be
C
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of secondary amines with carboxylic acids forms linear N-alkyl
donor to another molecule of iodobenzene 66, thereby forming
ketone product 69 (Scheme 3). The authors reported that this
63
amides or cyclic piperazinedione dimers, simply on heating.
t
In our hands, heating of the amino acids with KO Bu in
benzene at 150 °C did not afford detectable amounts of
condensation products, such as piperazinediones, but being
aware that even trace amounts of reactive compounds could
form and could initiate coupling chemistry through efficient
chain reactions, we explored the chemistry of piperazinediones,
prepared by other routes. Under the conditions of the coupling
reaction, N,N′-dialkyl piperazinedione 44 behaved as a good
electron donor (a = 45, b = 22%), while 47, an analogue
featuring free N−H groups, which would form from the
primary amino acid, glycine, was totally ineffective (a = <0.5, b
Scheme 3
=
92%). In this compound, 47, competition between
deprotonation of the CH2 protons and an amide N−H
would be in play, and the experiments agree with expectations
that the amide N−H is more acidic. In the resulting amide
anion, 48, the CH would not be deprotonated, and no
64
2
electron-rich alkene would form. Hence no electron transfer
would be observed. Thus, deprotonation of N,N′-dialkylpiper-
azinediones may be relevant to the special success of secondary
amino acids in facilitating the coupling reactions, but the minor
reactivity arising from primary amino acid glycine 42 cannot be
due to such a piperazinedione and may instead result from
formation of a small amount of dianion of glycine 43. Cyclic
piperazinedione 44 likely forms electron-rich enolate, 45, but
we also considered the possible formation of low concen-
trations of the anti-aromatic dianion in 46, which could be an
even more powerful electron donor. Computational studies
chemistry can be accelerated by photoactivation. Recently, the
team of Rossi has elegantly developed room-temperature
47
methods to extend this chemistry, but they have also achieved
the photoactivated coupling of haloarenes to arenes in the
t
27
presence of KO Bu in DMSO as solvent.
To see if enolates of simple esters and ketones would behave
as electron donors for the coupling of iodoarenes to arenes,
under our conditions in the nonpolar solvent benzene and in
the absence of photoactivation, they were now tested in the
coupling reaction between iodoarene 33 and benzene (Figure
(
see Supporting Information) showed that the structure 46
would indeed be planar and hence qualify as being anti-
aromatic. This should make it an exceptionally strong electron
donor. To calibrate the reactivity of 44 in the presence of
3
=
). Cyclopentanone 53 (a = 42, b = 0%) and pinacolone 54 (a
32, b = 3%) were active in this electron-transfer reaction.
Bearing in mind that π-releasing substituents on the α-carbon
should also assist, compounds 55−58 were investigated. Of
these esters, the α-ethoxy 56 (a = 44, b = 0%) and α,α-diethoxy
57 (a = 35, b = 0%) esters were most successful. The simpler
esters, ethyl acetate 55 (a = 19, b = 41%), and γ-butyrolactone
58 (a = 9, b = 74%), which would afford less electron-rich
enolates, were less effective.
The examples above shed light on the ability of a broad range
of enolates to act as electron-donor initiators in the coupling
reactions. As mentioned, the yields are low when using
substrate 33 relative to normal substrates, because of steric
hindrance. Accordingly we now investigated what happens with
normal substrate p-iodotoluene 70 (Figure 4). In this case,
small amounts of coupling reaction can occur through the
benzyne route, as seen in the blank reaction (inset, Figure 4)
where no additive is present, where 4% of the coupling product
71 was isolated. In contrast, reagents that afforded greater than
80% yield of p-methylbiphenyl 71 by electron transfer include
sarcosine 8, proline 9, N,N′-di-n-propylpiperazinedione 44 and
esters 55−57. Although mechanisms have not yet been
discussed for diamines (see below), the diamines 72 and 73
were also highly effective initiators in these coupling
t
KO Bu, we also prepared 49 which can only form a mono-
enolate, to check for differences from 44. Piperazinedione 49
worked as efficiently (a = 53, b =15%) as 44, so dianion
formation, as in 46, is not required. If disalt 46 can be formed, it
should be an excellent electron donor compared to monosalt
45 and capable of initiating the coupling of tougher substrates
than iodobenzenes. Accordingly, we tested 44 on chloroarene
5
8
substrates but saw no coupling reactivity under our standard
conditions. The final piperazinedione prepared was 50, an
analogue of 49 but featuring a single free carboxamide N−H.
Consistent with results from the other N−H containing
piperazinedione, 47, this final example again showed no activity
(
a = <0.5, b = 93%). Accordingly, the presence of an amide N−
51
H seems to decrease or remove electron-transfer-initiated
coupling activity completely. To explore whether a simple N-
alkylamide could trigger the coupling reactions in the presence
of KO Bu, the N′,N′-dimethylcarboxamide, 51, was tested,
t
giving moderate electron-transfer activity (a = 22, b = 57%).
This was similar to N-methylpyrrolidone 52 (a = 18, b = 52%).
Regardless of whether uncondensed amino acid derivatives
or derivatives of condensation products like piperazinediones
are involved, the electron-rich component that is formed
following base treatment in both cases is an enolate. Here
reference must be made to literature precedents by Scamehorn
5,7,24
reactions.
Alcohols and 1,2-Diols. To test whether these substrates
reacted by electron transfer, our first experiments studied cis-
1,2-dihydroxycyclohexane 59 and trans-1,2-dihydroxycyclohex-
6
5
and Bunnett, developing from findings of Rossi and
6
6
7
Bunnett, who reported that the enolate of pinacolone 67
reacted by electron transfer with iodobenzene 66 in DMSO as
solvent to form a phenyl radical 38; that radical coupled with a
further molecule of enolate 67 in a classic example of the SRN1
reaction, forming radical anion 68; in turn, 68 acted as electron
ane 60, using substrate 33 in benzene as solvent (Scheme 2).
These experiments duly formed coupled products 34 + 35 (a =
32, b = 0% for 59; a = 64, b = 0% for 60), showing that both
isomers operate as efficient electron donors. Cis- and trans-4-t-
butylcyclohexanol 61 (a = 10, b = 50%) and 62 (a = 5, b =
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Scheme 4
Figure 4. Coupling reactions of p-iodotoluene 70 with benzene,
facilitated with various additives. Yields in the parentheses are isolated
yields of 71. *Reacting for 5 h gave 89%; **reacting for 5 h gave 86%.
5
0%), respectively, as well as cyclohexanol 63 (a = 7, b = 50%)
behaved as less effective donors. The mechanism by which
alcohols and diols might initiate couplings by electron transfer
was now considered. One possibility involved transformation of
the alcoholate to an enolate. If so, then electron-transfer
pathways mentioned above would be accessible to the enolates.
For these cyclohexanols, enolate formation could come about
after oxidation of the alcoholate to the ketone, followed by
deprotonation. Conversion of alkoxides to ketones is normally
associated with the aluminum alkoxide in the Oppenauer
oxidation and features hydride ion delivery to an electrophile (a
67
ketone or aldehyde). Woodward showed that this chemistry
could also be triggered by KO Bu in toluene, although this
t
reaction has rarely been used since his work.
We examined a blank reaction of cis-tert-butylcyclohexanol
1 in benzene in the presence of KO Bu by NMR spectroscopy
t
6
(
Scheme 4). This very rapidly gave rise to a mixture of the cis-
1 and trans-62 diols as the major components, together with a
small amount of tert-butylcyclohexanone 75 (ratio:
.00:6.54:0.32). The fact that the mixture was not converted
exclusively to the ketone implies that delivery of the hydride by
4 or 76 to the ketone carbonyl group once formed, as in
complex 78, is easier than deprotonation by the alkoxide of
6
reaction of KH with ketone 75; the enolate formation was
1
verified by quenching a small aliquot with D O, and this gave
2
1
rise to monodeuterated 75-d . The isolated enolate was indeed
7
shown to trigger coupling reactions with benzene of substrates
33 and 78. (Details are included in the Supporting Information
file).
t
68
BuOH or 4-tert-butylcyclohexanol to form H2 (for computa-
tional support, see Supporting Information). When the trans-
tert-butylcyclohexanol 62 was treated similarly with KO Bu, it
The experiments were repeated with cis- and trans-cyclo-
hexane-1,2-diols 59 and 60. Treatment of cis-cyclohexane-1,2-
diol 59 at 130 °C with KO Bu afforded a mixture of both diols
and 2-hydroxycyclohexanone 80. The latter was isolated as its
2,4-dinitrophenylhydrazone 82. This compound is not stable
when exposed to air, undergoing oxidation, over some hours, of
the alcohol group to a ketone 83, which was also characterized
and compared to a sample prepared by an independent route.
t
t
also gave rise to the same mixture of 61, 62, and 75, although in
slightly different ratio (ratio: 1.00:8.63:0.11). This supports the
idea that the intermediate ketone is formed, which can act as
67
precursor to the enolate 77 as electron donor. To verify that a
structurally determined enolate can bring about such reactions,
enolate 77 was also formed separately and isolated, following
E
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Comparing the reactivity of the diol isomers 59 and 60 with
cyclohexanols 61−63 in the coupling reactions, the diols are far
more reactive. This could be explained if the reactive initiator
for radical formation is the enediolate 85 (a dianion resulting
from deprotonation of the hydroxyl group in 85 is also
conceivable) rather than the less electron-rich eneolate 84. The
former, 85, should be more electron-rich and more reactive
than its regioisomer, 84.
Scheme 5
1
,2-Diamines. Finally, we considered amines and 1,2-
diamines. Simple amine 64 showed no electron-transfer activity
Figure 3, a = <0.5, b = 92) in the coupling reaction with
(
substrate 33. However, in complete contrast, N,N′-dimethyle-
thylenediamine 65 was an effective donor (Figure 3, a = 46, b =
0), and Figure 4 shows that cyclohexane-1,2-diamines, 72 and
73, were among the most effective additives in promoting the
coupling of aryl halide 70 to benzene. In the coupling reaction
triggered by N,N′-dimethylethylenediamine 65 and by cyclo-
hexane-1,2-diamines 72 and 73, successful coupling reactions
are accompanied by formation of colored reaction mixtures,
indicative of the formation of conjugated substances, and so we
began to consider whether conversion of the diamines to
electron donors might be analogous to the oxidation of diols 59
and 60. However, all attempts by us to isolate discrete products
t
in blank reactions of KO Bu with these amines in benzene led
to no success.
Looking at relevant cases in the literature where dehydrogen-
ation of amines occurs under basic conditions, it is known that
magnesium diisopropylamide 86 can expel hydride to form an
6
9−72
imine 87.
In our case, with potassium butoxide as the base,
the equilibrium for formation of the amide anion KNHR is
expected to be very unfavorable from a simple primary amine,
although it might well be more favorable for a 1,2-diamine.
However, it has been shown that ethylenediamine 88, on
73
treatment with base, affords pyrazine radical anion 89, and
this likely results from condensation reactions with imines that
72
are initially formed through loss of hydride.
If such reactions are occurring under our conditions with
vicinal diamines, they may lead to a complex mixture of
condensed or uncondensed enamine-type products, present at
low concentration, each of which could function by electron
transfer. However, the necessary gate to those substances would
be formation of an imine through expulsion of hydride. This
could then undergo further deprotonation to afford an enamine
salt. The simplest scenario (no condensations) is represented in
Scheme 5 with transformation of diamine 90 to representative
imine 91 that on deprotonation gives electron-rich alkene 92.
Loss of hydride to form the imine is likely to have a very high
activation barrier and likely to be the rate-determining step in
formation of the initiating electron donor(s). (We emphasize
that we are speaking about the slow step in the process of
forming the initiator, not the slow step in the main chain
reaction shown in Scheme 1.) We proposed to test for this
using deuterium-labeled analogs of diamine 90.
In detail, our plan was to prepare the unlabeled N,N′-
dimethylethylenediamine 90 by an efficient route that could be
adapted to the synthesis of deuterated analogues in good yield.
If hydride loss is associated with the rate-determining step for
the formation of the initiator, then changing the relevant C−H
to C−D should slow down the formation of the initiator(s).
Conducting parallel reactions with deuterated and undeuter-
ated additives under the same conditions and for a given period
should result in formation of less initiator in the deuterated
case, and therefore a smaller number of radical chains would
have initiated in the deuterated amine case, resulting in much
less effective arene−arene coupling under defined conditions.
The synthesis that we developed for this purpose is shown in
Scheme 5, starting with potassium phthalimide, 93. Using this
route, the unlabeled diamine 90, the tetradeutero 100,
hexadeutero 99, and decadeutero 101 analogues were all
prepared. (Where deuterium analogues were prepared, d -1,2-
4
dibromoethane and/or d -iodomethane were used in place of
3
their non-deuterated counterparts in Scheme 5). The diamines
90, 99−101 were then tested side-by-side in four parallel
reactions of identical scale and under identical conditions. The
conditions were chosen through preliminary work with the
unlabeled diamine 90, using a relatively mild temperature (110
°C) and short reaction time (4 h) to give just about half of the
F
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normal conversion from substrate 33. Stopping short of full
conversion was important in allowing realistic assessment of
differences between the isotopomers. Under these conditions
the products (34 + 35) isolated from the four reactions were:
Scheme 6
1
6 mg from 90, 10 mg from 99, 0.5 mg from 100, and <0.5 mg
from 101 (see Supporting Information for additional tests at
35 °C). These reactions clearly show that a primary isotope
1
effect is in place for breakage of a methylene C−H(D) bond
here, so that formation of the active promoter(s) of the
coupling reaction definitely involves cleavage of a C−H/C−D
bond in the rate-determining step. Given that (i) these coupling
reactions operate through electron transfer, as seen in the
conversion of substrate 33, and therefore that electron donors
require to be prepared in situ; (ii) when the coupling reactions
with diamines are successful, the reaction mixtures become
brown-colored, indicating the formation of conjugated
compounds (in this respect, the reactions of additives 90 and
9
9 contrast with the additives 100 and 101, where no color
developed); (iii) there is literature precedent for conversion of
diamine 88, under basic conditions, to a pyrazine radical
7
3
anion; and (iv) deuterium isotope effects are observed, when
conducting the coupling of 33 in benzene, particularly for
labeled methylene groups in N,N′-dimethylethylenediamine,
9
0, the most satisfactory conclusion is that these reactions are
initiated by organic electron donors that are formed following
oxidation of the amines under basic conditions. The results are
definitely not consistent with a simple complexation of
potassium tert-butoxide followed by electron loss from the
4
3
butoxide.
The difference in yield in these reactions, notably the
difference in yield between using 99 and using 101 reflects
differences in concentration of the electron donors, which may
be 20-fold less in the labeled reactions. This does not mean that
a kinetic isotope effect of 20 or more is associated with the
breaking of a methylene C−H bond here, since the active
electron donor(s) may be formed in a scheme where two or
more imine-derived molecules play a role, e.g., in forming a
dihydropyrazine donor.
CONCLUSIONS
■
At the end of 2013, many organic additives were known to
trigger coupling of haloarenes to arenes in the presence of
t
t
KO Bu or NaO Bu, but their modes of action were unknown. In
51
our earlier paper, we showed that fully characterized organic
electron donors like 28 can initiate the coupling reactions
t
between haloarenes and arenes in the presence of KO Bu in
benzene as solvent. We also proposed and presented evidence
that the couplings that were facilitated by N-heterocyclic
carbenes, by phenanthroline, or by pyridine as solvent or that
used pyridines or pyrazines as substrates were all due to the in
situ formation of organic electron donors. Now, we present
evidence that amino acids also act as precursors to organic
electron donors, which are likely to be enolates, and that this
chemistry, conducted in benzene, builds on the observations of
electron donors under the conditions of the coupling reactions.
Comparison between deuterium labeled analogues and
unlabeled diamine 90 shows that C−H bond cleavage within
the diamines is absolutely required for the synthesis of the
electron donor initiator(s), and we propose that electron-rich
enamines or related compounds, such as their deprotonated
analogues, e.g., 92, are the active electron donors.
With this foundation now in place, a number of the
remaining mysteries relating to coupling reactions, facilitated by
organic additives, can be addressed predictively. Deprotonation
of macrocyclic pentapyridone 17 would afford 102, where the
amide enolate linked to two enamine structures is shown in
6
5,66
Scamehorn and Bunnett
for S 1 reactions that had been
RN
conducted in DMSO; the special effectiveness of amino acids
that feature secondary amines may be due to intermolecular
condensation reactions of amino acids to form cyclic N,N-
dialkylpiperazinediones or related compounds.
We present direct evidence in favor of oxidation of 1,2-diols
and alcohols to ketones under the conditions of our coupling
reactions, with the ketones acting as precursors of electron-rich
6
7
enolates. 1,2-Diamines are also shown to be precursors to
G
dx.doi.org/10.1021/ja5101036 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
blue, would be a candidate electron donor (Scheme 6).
Similarly deprotonation of porphyrin 18 would produce an
electron-rich structure; the doubly deprotonated porphyrin
shown as 103 is likely to be a superb electron donor. Thermal
(14) Rueping, M.; Leiendecker, M.; Das, A.; Poisson, T.; Bui, L.
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1
5,74,75
decarboxylation of salt 20 would afford carbene 104.
2
(
012, 48, 2033−2035.
17) Chen, W.-C.; Hsu, Y.-C.; Shih, W.-C.; Lee, C.-Y.; Chuang, W.-
H.; Tsai; Chen, P. P.-Y.; Ong, T.-G. Chem. Commun. 2012, 48, 6702−
704.
Combination of carbene 104 with its protonated form 105
would afford the highly electron-rich structure 106 that can
become an aromatic bis-quinolinium salt 107 on losing two
electrons. Compounds 21 and 22 can be deprotonated to afford
the organic electron donors 108 and 109. Many other organic
structures can therefore be predicted to be able to initiate C−C
coupling reactions. Since they are simply initiators for the
efficient radical chains shown in Scheme 1, the important point
is that they do not need to be formed in high yield; formation
reactions that would afford far less than 1% of the initiating
electron donors are quite likely to be able to trigger excellent
yields of coupled products.
6
(
18) Pieber, B.; Cantillo, D.; Kappe, O. C. Chem.−Eur. J. 2012, 18,
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(19) Bhakuni, B. S.; Kumar, A.; Balkrishna, S. J.; Sheikh, J. A.; Konar,
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(
2
(
911−3914.
21) De, S.; Ghosh, S.; Bhunia, S.; Sheikh, J. A.; Bisai, A. Org. Lett.
012, 14, 4466−4469.
22) Tanimoro, K.; Ueno, M.; Takeda, K.; Kirihata, M.; Tanimori, S.
J. Org. Chem. 2012, 77, 7844−7849.
23) Wang, L. G.; Yan, G. B.; Zhang, X. Y. Chin. J. Org. Chem. 2012,
(
ASSOCIATED CONTENT
Supporting Information
■
32, 1864−1871.
*
S
(24) Wu, Y.; Wong, S. M.; Mao, F.; Chan, T. L.; Kwong, F. Y. Org.
Lett. 2012, 14, 5306−5309.
Additional examples and experimental procedures as well as
analytical, spectroscopic and computational data are provided.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(25) Zhao, H.; Shen, J.; Guo, J.; Ye, R.; Zeng, H. Chem. Commun.
2
(
3
(
1
(
4
(
013, 49, 2323−2325.
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9, 2983−2985.
29) Kumar, A.; Bhakuni, B. S.; Prasad, Ch.; Durga, S.; Kumar, S.;
Kumar, S. Tetrahedron 2013, 69, 5383−5392.
30) De, S.; Subhadip, M.; Mishra, S.; Kakde, B. N.; Dey, D.; Bisai, A.
J. Org. Chem. 2013, 78, 7823−7844.
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AUTHOR INFORMATION
■
Corresponding Authors
John.Murphy@strath.ac.uk
Tell.Tuttle@strath.ac.uk
Notes
(
The authors declare no competing financial interest.
(
2
(
ACKNOWLEDGMENTS
■
We thank EPSRC (current grant number EP/K033077/1) and
GlaxoSmithKline and the University of Strathclyde for funding.
High-resolution mass spectra were obtained at the EPSRC
National Mass Spectrometry Centre, Swansea.
2
013, 15, 6102−6105.
(33) Ghosh, D.; Lee, J.-Y.; Liu, C.-Y.; Chiang, Y.-H.; Lee, H. M. Adv.
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