Electrophilic aromatic substitutions of aryltrifluoroborates with retention of the BF3- group: Quantification of the activating and directing effects of the trifluoroborate group

Article abstract of DOI:10.1021/ja4017655

Kinetics and mechanisms of transition-metal free reactions of furyl, thienyl and indolyl trifluoroborates with benzhydrylium (Ar₂CH ⁺) and iminium (Me₂N⁺=CHR) ions have been investigated. In contrast to common belief, substitutions at CH positions are often faster than ipso-substitutions of the BF₃K group, because BF₃K activates the position attached to boron by a factor of 10 ³-10⁴ while adjacent CH positions are activated by factors of 10⁵-10⁶. Several reactions that have previously been interpreted as ipso-substitutions actually proceed via initial substitution at a vicinal or remote CH position, followed by protodeborylation. If the proton released during electrophilic substitution at a CH position is trapped by a base, the BF₃^- group can be preserved. Remote reactions of heteroaryl trifluoroborates with iminium ions provide straightforward access to novel zwitterionic ammonium or iminium trifluoroborates, which have been characterized by single-crystal X-ray analyses.

Full text of DOI:10.1021/ja4017655

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Article
Electrophilic Aromatic Substitutions of Aryltrifluoroborates
3–
with Retention of the BF Group: Quantification of the
Activating and Directing Effects of the Trifluoroborate Group
Guillaume Berionni, Varvara Morozova, Maximilian Heininger, Peter Mayer, Paul Knochel, and Herbert Mayr
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja4017655 • Publication Date (Web): 27 Mar 2013
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Electrophilic Aromatic Substitutions of Aryltrifluoroborates
with Retention of the BF3– Group: Quantification of the
Activating and Directing Effects of the Trifluoroborate Group
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Guillaume Berionni, Varvara Morozova, Maximilian Heininger, Peter Mayer, Paul Knochel, Herbert
Mayr*
Department Chemie, Ludwig–Maximilians–Universität München, Butenandtstr. 5–13 (Haus F), 81377 München (Germany)
Supporting Information Placeholder
ABSTRACT: Kinetics and mechanisms of transition–metal free reactions of furyl, thienyl and indolyl trifluoroborates with
benzhydrylium (Ar2CH+) and iminium (Me2N+=CHR) ions have been investigated. In contrast to common belief, substitutions at
CH–positions are often faster than ipso–substitutions of the BF3K group, because BF3K activates the position attached to boron by a
factor of 103–104 while adjacent CH–positions are activated by factors of 105–106. Several reactions which have previously been
interpreted as ipso–substitutions actually proceed via initial substitution at a vicinal or remote CH position, followed by
–
protodeborylation. If the proton released during electrophilic substitution at a CH position is trapped by a base, the BF3 group can
be preserved. Remote reactions of heteroaryl trifluoroborates with iminium ions provide straightforward access to novel zwitterionic
ammonium or iminium trifluoroborates, which have been characterized by single–crystal X–ray analyses.
We have now quantified the activating effects of the BF3K group
INTRODUCTION
on vicinal and more remote positions in indoles, furans,
benzofurans and thiophenes and report that it is even possible to
preserve the BF3 group when the proton released during an
electrophilic substitution at a CH position is trapped by a Brønsted
base.
We will show how these data can be used for predicting scope and
limitations of uncatalyzed electrophilic aromatic substitutions of
Palladium and rhodium catalyzed couplings of arylborates with
electrophiles belong to the most important family of CC–bond
forming reactions.1 Transition–metal free reactions of aryl and
heteroaryl˗borates with electrophiles (E+), e.g., halogenations,2
Michael additions,3 borono Mannich,4 and Friedel˗Crafts
reactions5 are also known, and most of them have been reported to
proceed via substitution of the BX3– group (Eq 1).
–
aryltrifluoroborates with
a variety of electrophiles including
iminium ions (Me2N+=CHR).
(1)
RESULTS AND DISCUSSION
Reactions of benzhydrylium ions 1 with indolyl trifluoroborates
2a˗e. NMR and X˗ray analyses of the products obtained from the
reactions of the p˗dimethylamino substituted benzhydrylium
tetrafluoroborate 1f˗BF4– (Table 1) with the indolyl trifluoroborates
2a or 2b revealed that the electrophilic attack did not occur at the
ipso˗position. Scheme 1 shows that the C3 substituted indole 4
was formed in high yield when 2a or 2b were combined with the
However, several examples of such reactions have recently been
found which do not regioselectively proceed at the ipso˗position.6
Ortho and more remote (e.g. para) electrophilic substitution
reactions of arylborates have been observed,7 but seldom with
retention of the boron group.8 Although organotrifluoroborates
have been gaining increasing importance in recent years because of
–
their compatibility with
a
variety of reaction conditions,1,9
benzhydrylium salt 1f˗BF4 in acetonitrile in the absence of base
(Scheme 1, middle).
electrophilic aromatic substitution reactions of aryl and heteroaryl
trifluoroborates salts with retention of the BF3K substituent have to
our knowledge not been reported so far.
In recent work, we have quantified the ipso˗activating effect of
several boron substituents and found that the trifluoroborate
substituent is a strong ipso˗activating group that increases the
nucleophilic reactivity of the furan ring (Eq 1, Ar = furan) by a
factor of 104.10
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Table 1. Structures, max in CH3CN, and electrophilicity
parameters E for the benzhydrylium ions 1a–j (Ar2CH+X–) used as
1
2
˗
reference electrophiles in this work.11a c, 12
3
4

max / nm
E
5
6
7
8
X = OMe, Y = Me
X = Y = OMe
1a
1b
478
500
1.48
0.00
1c
524
–1.36
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X = Y = N(Me)CH2CF3
X = Y = N(CH2CH2)2O
X = Y = NMe2
1d
1e
1f
586
611
605
612
–3.85
–5.53
–7.02
–7.69
Figure 1. ORTEP drawing (50% probability ellipsoids) of 3.
Selected interatomic distances (Å) and angles (deg): C2–B1 =
X = Y = N(CH2)4
1g
13
…
1.611, C2–N1 = 1.402, C2–C3 = 1.378 and C10–H F1 = 131.40.
1h
620
–8.22
In the absence of base, the benzhydrylium salt 1f˗BF4– reacted with
N˗Boc protected indol˗2˗yl trifluoroborates 2c and 2d at their
3–position to yield the zwitterionic ammonium difluoroborates 6
and 7, respectively (Scheme 2), indicating that the electrophilic
1i (n = 2)
1j (n = 1)
642
632
–9.45
–10.04
–
attack occurred exclusively in vicinal position to the BF3 group.
Interestingly, the released proton led to cleavage of the t˗butyl
group and formation of an unprecedent 1,4,2˗oxazaborolidine ring
as shown in the X˗ray structure of 7 (Figure 2), rather than to the
cleavage of the BF3K group as in 4.7a,13 In the presence of NEt3, the
indoles 2c,d reacted in the same way as 2a,b and gave the
ammonium trifluoroborates 8 and 9 in good yields (Scheme 2).
Scheme 1. Friedel–Crafts reactions of the benzhydrylium salt 1f–
BF4– with potassium indol–2–yl trifluoroborate 2a and indol–5–yl
trifluoroborate 2b in the absence and presence of NEt3 at 20 °C.
Scheme 2. Reactions of N–Boc–indol–2–yl trifluoroborates 2c and
2d with 1f–BF4– in the absence and presence of NEt3 at 20 °C.
The assumption that these reactions proceed via initial attack of
the benzhydrylium salt 1f˗BF4 at the 3–position of the indoles 2a
–
and 2b, followed by protodeborylation, was confirmed by the
exclusive formation of the triethylammonium salts 3 and 5
(Scheme 1) when the reactions were performed in the presence of
triethylamine, which scavenges the protons released during the
electrophilic attack at C–3. The X˗ray structure of the ammonium
indol˗2˗yl trifluoroborate 3 depicted in Figure 1 shows an
…
intermolecular N4–H F3 hydrogen bond (2.488 Å) between the
–
ammonium hydrogen and one of the fluorine atoms of the BF3
substituent, as well as an intramolecular C10–H F1 interaction
(2.272 Å, not shown in Figure 1) which may stabilize the
compound.13,14 The triethylammonium trifluoroborate 5 was less
stable than 3 and undergoes a slow retro Friedel–Crafts reaction
with formation of 2b within several days in CD3CN.14
…
Figure 2. ORTEP drawing (50% probability ellipsoids) of the
zwitterion 7. Selected interatomic distances (Å) and angles (deg)
C2–B1 = 1.605, B1–O1 = 1.564, O1–C27 = 1.317, C27–N1 =
1.365, N1–C2 = 1.415, C22–N3 = 1.382, C14–N2 = 1.480 and
N1–C2–B1 = 103.84, C2–B1–O1 = 99.32, B1–O1–C27 = 111.69,
O1–C27–N1 = 110.52, C27–N1–C2 = 114.58.13,14
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As summarized in Scheme 3, the initially formed Wheland
mechanistic proposal is supported by the observation that
1
2
3
4
5
6
7
intermediate of these reactions can rapidly be deprotonated by a
Brønsted base to yield the C3–substituted indol–2–yl
trifluoroborates; when no base is available, the protons released
from the Wheland intermediate led to a fast protodeborylation
reaction if R = Me or removal of the tert–butyl group and
subsequent cyclization to give an oxazaborolidine ring if R = Boc
(Scheme 3, bottom).
protodeborylation, i.e. the formation of 13, is fully suppressed
when the reaction is carried out in the presence of 10 equivalents
of 2,6–lutidine, and 14 is thus produced in 90% yield.
Scheme 5. Reactions of the fur–2–yl trifluoroborate 2h with the
benzhydrylium salt 1f–BF4– at 20 °C in MeCN.
8
9
Scheme 3. Mechanistic proposal for the reactions of indolyl
trifluoroborates with electrophiles E+.
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In contrast to 2c and 2d, neither the N–Boc protected indol˗3˗yl
trifluoroborate 2e nor the parent N˗tert˗butoxycarbonyl indole 2f
(not shown in Scheme 4) reacted with 1f˗BF4 under these
–
conditions (MeCN, 20 °C, 3 h). However, 2e reacted smoothly
with the more electrophilic p˗methoxy–substituted benzhydrylium
–
The formation of 13 and 14 from fur–3–yl trifluoroborate 2i and
1f˗BF4– can be explained analogously (Scheme 6).
tetrafluoroborate 1b˗BF4 to yield the ipso˗substitution product 10
quantitatively. The benzofuran–2–yl trifluoroborate 2g, a structural
–
analogue of 2c, also reacted with 1b˗BF4 to yield the C3–
Scheme 6. Reactions of the fur–3–yl trifluoroborate 2i with the
benzhydrylium salt 1f–BF4– at 20 °C in MeCN.
substituted product 11 and traces of the disubstituted benzofuran
12. As in the reactions of the indoles 2a˗d, also in 2g the BF3K
group fails to direct benzhydrylium salts 1 to the borylated
position.
Scheme 4. Reactions of potassium N–Boc–indol–3–yl
trifluoroborate 2e and benzofuran–2–yl trifluoroborate 2g with
1b–BF4– at 20 °C in MeCN.
Treatment of the thiophene 2j with one equivalent of the
–
benzhydrylium salt 1f˗BF4 in acetonitrile at ambient temperature
gave 59% of the 2,3–disubstituted thiophene 17 (Scheme 7). We
have to assume that 17 is not generated directly, however, because
–
it was not observable after 30 min, when 2j and 1f˗BF4 were
combined in the presence of 10 equivalents of 2,6–lutidine.
Instead, the formation of the trisubstituted thiophene 16 was
1
derived from the H NMR spectrum with a singlet absorption at
 6.80 ppm for the thiophene ring (See SI, p. S19), which was
observed after 30 min.
Scheme 7. Reactions of the potassium thien–2–yl trifluoroborate 2j
–
with the benzhydrylium salt 1f–BF4 at 20 °C in CD3CN in the
absence and presence of 2,6–lutidine.
Reactions of benzhydrylium ions 1 with furyl and thienyl
trifluoroborates 2h˗j. The potassium fur–2–yl trifluoroborate 2h
reacted with 1f˗BF4– in the absence of base to give a 1:7 mixture of
the mono– and di–substituted products 13 and 14, respectively
(Scheme 5). Since treatment of the monoalkylated furan 13 with
the benzhydrylium salt 1f˗BF4– did not yield 14 under the same
conditions, one can conclude that the disubstituted furan 14 is not
generated via 13 as an intermediate. We, therefore, suggest that 2h
is attacked at C5 by the benzhydrylium ion 1f to give the –adduct
15a which tautomerizes with formation of 15b. The
dimethylanilinium fragment in 15b is sufficiently acidic to affect
protodeborylation with formation of 13. Alternatively 15b reacts
with further 1f˗BF4– to give the 1,5–disubstituted furan 14. This
After evaporation of the excess of 2,6–lutidine and redissolution of
16 in CD3CN, a slow and quantitative conversion of 16 into 17
was observed, most probably via retro Friedel˗Crafts reaction
followed by irreversible ipso attack of the released benzhydrylium
ion 1f–BF4– at the C2 position of 2j.
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Page 4 of 8
As shown in the above examples, external bases are needed to trap
less than factor of 2 (Table 2), we conclude that also the
1
2
3
4
5
6
7
8
the products resulting from the initial attack of electrophiles at
unsubstituted positions of aryltrifluoroborates. Therefore, in earlier
investigations, which have been carried out in the absence of base,
remote substitution might have been elusive because the initially
generated products have either undergone retro Friedel–Crafts
reactions or protodeborylation yielding products which do not
show the site of initial attack.1,3,4 A similar behavior has previously
been reported for silylated and stannylated furans and
thiophenes.15 A rationalization for this behavior can be derived
from the following kinetic data.
coordination of the potassium counterion to the oxygen of the
N˗Boc group, which was observed in the solid state of indole 2e,13a
does not significantly influence the reactivities of the N˗Boc
protected indolyl˗trifluoroborates in dilute acetonitrile solution.
Table 2. Second˗order rate constants k2 for the reactions of the
benzhydrylium salts 1a–j (Ar2CH+X–, concentration ≈ 10–5 M) with
the heteroarenes 2a–k (concentration range: 10–4 – 10–3 M) in
CH3CN at 20 °C and the resulting reactivity parameters N and sN
of 2a–k. The arrows indicate the site of attack of Ar2CH+X–.
a
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Ar2CH+X–
˗nucleophiles 2
k2 / M–1 s–1
N, sN
Kinetic investigations. In order to quantify the activating effect of
the BF3K substituent on different positions of a –system, we
measured the kinetics of the reactions of the benzhydrylium ions
1a–j with the heteroarenes 2a–k spectrophotometrically (UV˗Vis),
by following the disappearance of 1 at their maximum wavelengths
max (Table 1). As discussed previously, benzhydrylium ions 1 are
suitable electrophiles for comparing nucleophiles of widely
differing reactivities, because variation of the substitution of 1 in
m˗ and p˗positions allows large variations in electrophilicity while
–
2a
1f–BF4
9.23 × 102 b 9.55, 1.16
–
1g–BF4
1.02 × 102
1.44 × 102 b
1.65 × 102 c
1.35 × 101
–
1h–BF4
2.92 × 101 b
1.31
–
1i–BF4
1j–BF4
–
2.81 × 10–1
–
˗
2b
2c
1e–BF4
1f–BF4
3.47 × 103
7.46 × 101
1.74 × 101
3.70
8.77, 1.09
6.46, 0.96
keeping the steric surroundings of the reaction centers constant.11a c
–
By using an excess of the nucleophiles 2a–k (10−200 equivalents),
pseudo first˗order conditions were achieved, as indicated by the
mono˗exponential decays of the absorbances of the benzhydrylium
ions 1 (Figure 3). The mono˗exponential decays showed that the
protons or BF3 released during the kinetics did not have an effect
on the kinetics. In all cases, the benzhydrylium ions 1 were
consumed completely, and plots of kobs (s–1) against the
concentrations of the heteroarenes 2 were linear with negligible
intercepts, as exemplified in the insert of Figure 3 for the reaction
of the indole 2a with 1g and shown in the SI for all other reactions.
–
1g–BF4
–
–
1h–BF4
–
1c–PF6
1d–BF4
5.56 × 104
1.40 × 102
2.09 × 102 b
8.24
–
1e–BF4
1.08 × 101 b
–
2d
1d–BF4
1e–BF4
6.86 × 103
4.18 × 101
6.82 × 101 d
1.25
7.10, 1.18
–
–
1f–BF4
2e
2f
–
1c–PF6
1d–BF4
2.13 × 103
1.79
4.06, 0.79
1.68, 1.26
–
1a–TfO–
1b–TfO–
1c–TfO–
1.09 × 104
1.03 × 102
2.87
–
2h
2i
1d–BF4
1e–BF4
4.95 × 101
2.32 e
5.99, 0.79
6.83, 0.93
–
–
1d–BF4
1e–BF4
1f–BF4
5.11 × 102
2.19 × 101
5.62 × 10–1 e
3.13 × 10–1
3.85 × 10–1
Figure 3. Exponential decay of the absorbance of cation 1g (7.2 ×
10–6 M) during the reaction with indole 2a (5.04 × 10–4 M) in
CH3CN at 20 °C in the presence of 1.0 equiv. of 2,6˗lutidine (kobs
= 6.43 × 10–2 s–1). Insert: Determination of the second–order rate
constant k2 from the dependence of kobs on the concentration of 2a
(k2 = 1.44 × 102 M–1 s–1).
–
–
1f–TfO–
–
1f–BPh4
–
2j
1d–BF4
1e–BF4
1f–BF4
1.12 × 103
5.53 × 101
1.56 e
4.33 × 103
1.05 × 102
1.27 × 102
7.32, 0.90
3.06, 1.19
–
The slopes of these plots gave the second˗order rate constants k2
listed in Table 2. As the addition of a large excess of 2,6˗lutidine
has no or only a minor effect on the second˗order rate constants k2
reported in Table 2 (examined for 2a, 2c, 2h, 2i, and 2j) and as the
change of the counteranions of the benzhydrylium ions 1 only
slightly affected the k2 values (examined for 2i and 2k), we conclude
that the formation of the Wheland intermediates is generally
rate˗determining. As the presence of 18˗crown˗6 ether affected the
rate constants of the reaction of the N˗Boc indole 2d with 1e by
–
2k
1b–TfO–
1c–TfO–
–
1c–PF6
a N and sN parameters of 2a–k derived from the linear plots of lg k2 vs. E
as shown in Figure 4, see the SI (p S39) for details; b With 1.0 equiv. of
c
d
2,6˗lutidine/2a; With 5.0 equiv. of 2,6˗lutidine/2a; With 1.0 equiv.
of 18˗crown˗6 ether/2d. e No base effect was observed when performing
the reaction with 1 to 10 equiv. of 2,6˗lutidine/(2h˗j).
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Scheme 9. Activation of different positions of furan by the BF3K
In Figure 4, the k2 values reported in Table 2 are plotted against the
group derived from the second˗order rate constants k2 (M–1 s–1,
from Table 2) for the reactions of furans with the cation 1d (E =
–3.85).
1
2
3
E values of the benzhydrylium ions 1 reported in Table 1 according
to the linear free˗energy relationship (2).11
lg k2 (20 °C) = sN(N + E)
(2)
4
5
6
7
8
In this correlation, k2 is the second˗order rate constant (in M–1 s–1),
E (electrophilicity parameter) measures the strengths of the
electrophiles, and N (nucleophilicity parameter) and sN (sensitivity)
are solvent˗dependent nucleophile˗specific reactivity parameters.11
9
10
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1j 1i
1h 1g 1f
1e
1d
1c
1b
1a
5
4
a Calculated with Eq (2) and the N and sN values from Ref. 11b; b From Ref.
10; c k2 is statistically corrected by a factor 2 for the furan 2o.
2c
2f
2d
2b
2k
2e
The comparisons in Schemes 8 and 9 show that the ipso˗activation
by the BF3K substituent is smaller than its vicinal or remote
activation. As the nucleophilicity N is defined as the intercept on
the abscissa of log k2 vs. E correlations (Figure 4), and the sensitivity
parameters sN can be neglected in qualitative analyses of
structure˗reactivity relationships, the scale depicted in Figure 5
renders a rough comparison of the reactivities of borylated and
non˗borylated heteroarenes.12
2a
3
2i
lg k2
2
2h
1
0
-1
-11
-9
-7
-5
-3
-1
1
Electrophilicity
Figure 4. Plots of the logarithms of the second˗order rate constants
lg k2 for the reactions of nucleophiles 2a–k with the benzhydrylium
ions 1a–j versus their electrophilicity parameters E [see Eq (2) and
Tables 1 and 2]. The correlation line for 2j is not shown for the
sake of clarity (See the SI, p S39 for details).
As the correlation lines for the indoles 2a˗f, the furans 2h˗i and the
thiophenes 2j˗k in Figure 4 are not strictly parallel, the relative
reactivities of the nucleophiles 2a˗k depend slightly on the
electrophile. We, therefore, selected the cation 1d as reference
electrophile for the quantitative structure˗reactivity analysis in
Schemes 8 and 9. The k2 ratios 2e/2f, 2c/2f and 2b/2n show that
BF3K enhances the nucleophilic reactivity of the C3 position of
indoles less when located in C3 (ipso) than when located in vicinal
(C2) or remote (C5) positions (Scheme 8).
Scheme 8. Second˗order rate constants k2 (M–1 s–1, from Table 2)
for the reactions of indoles with the cation 1d (E = –3.85) and
resulting activation of the C3 position by the BF3K group.
a Calculated with Eq (2) and N, sN values from Table 2; b From Ref. 11d.
The relative reactivities of the furans 2m/2l, 2i/2o and 2h/2o
(Scheme 9) also show that BF3K enhances the nucleophilic
reactivity of furans much more when located in remote positions
(activation > 105) than when located in the attacking (ipso) position
(≈ 104) as in 2m.
Figure 5. Comparison of the nucleophilicities of heteroaryl
trifluoroborates and of related heteroarenes.12 For N parameters of
indoles 2n–q, see ref. 11d and for the N˗Boc indole 2f see Table 2.
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Figure 5 shows that the N˗Boc group reduces the nucleophilic
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a)
reactivity of the C˗3 position of indole by roughly 4 orders of
magnitude (from N = 5.55 for 2q to N = 1.68 for 2f), whereas the
N˗methyl group induces only a slight activation of the C˗3 position
(N = 5.75 for 2n). The 104˗fold activation of the 3˗position of
indoles by a 2˗BF3K group, which was derived in Scheme 8, is
responsible for the fact that 2a (N = 9.55) has a similar
nucleophilicity as moderately active enamines (e.g. 2s in Figure 5).12
From the N parameter of the indole 2b (N = 8.77) one can further
derive that a 5˗BF3K substituent activates the 3˗position of indole
even more than a 5˗NH2 group (N = 7.22 for 2p) as replacement of
NH by NCH3 has little influence on reactivity (see above).
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Figure 5 shows that the strong vicinal˗activation of BF3K raises the
nucleophilic reactivities of the furans 2h and 2i above those of the
indoles 2n and 2q, which open new possibilities of transition
metal˗free reactions of such organotrifluoroborates with a variety of
electrophiles, some of which shall be discussed below.
Reactions of heteroaryltrifluoroborates with iminium ions. As
expected from its high N parameter, indolyl trifluoroborate 2a
reacts promptly with the Eschenmoser salt 18 (E = –6.69)11b,e and
with the Vilsmeier salt 19 (E = –5.77)11b,e at the C3 position
(Scheme 10). No external base was needed to preserve the
trifluoroborate group since intramolecular deprotonation of the
Wheland intermediate by the dimethylaminomethyl group is fast
during the formation of 20, and since fast elimination of HCl from
the Wheland intermediate generated from 2a and 19 yields the
stable zwitterion 21.
Figure 6 a) ORTEP view of the ammonium–trifluoroborate 20
(symmetry code i = –x, y, 0.5–z) and, b) ORTEP view of the
iminium–trifluoroborate 21; ellipsoids at the 50% probability
level.13 Selected interatomic distances (Å) and angles (deg) for 20:
C2–B1 = 1.621(4), N1–C2 = 1.383, C2–C3 = 1.388, C3–C10 =
1.487, C10–N2 = 1.514, N2….F1 = 2.811(3), N2….F1i = 2.878(3),
C3–C10–N2 = 113.38, C3–C2–B1 = 129.21. For 21: C2–B1 =
1.645, N1–C2 = 1.352, C2–C3 = 1.421, C3–C10 = 1.416, C10–
N2 = 1.304, C3–C10–N2 = 133.19, C3–C2–B1 = 132.92.
Scheme 10. Reactions of the potassium indol–2–yl trifluoroborate
2a with Eschenmoser salt 18 and Vilsmeier salt 19 in MeCN for 5
min at 20 °C.
Analogous reactions were observed when 5˗membered ring
heteroaryl˗trifluoroborates 2h˗j were treated with the iminium salts
18 and 19 (Table 3). Like benzhydrylium ions, the iminium salts 18
and 19 attacked the potassium furyl and thienyl trifluoroborates
2h˗j at remote positions of the BF3K group to yield the zwitterionic
ammonium trifluoroborates 23 and 25 and the iminium
trifluoroborates 22, 24 and 26 (Table 3).
Table 3. Products and yields of the reactions of furyl- and thienyl-
trifluoroborates 2h˗j with 18 and 19 at 20 °C in MeCN for 1 h.
Both, the ansa–ammonium borate 20 and the iminium borate 21
were characterized by single˗crystal X˗ray crystallography (Figure 6).
Intra and intermolecular N–H….F hydrogen bonding interactions
–
between the fluorine atoms of the BF3 group and the ammonium
hydrogen led to the formation of dimers with an intermolecular
4˗membered ring in the case of 20 (Figure 6a).16 An intramolecular
–
C10–H….F3 hydrogen bond between a fluorine atom of the BF3
group and the proton of the iminium moiety and a strong
electronic delocalization stabilize the hemicyanine 21 (Figure 6b).16
The trifluoroborates 20 and 21 are colorless, crystalline, air– and
water–stable compounds, which are highly soluble in polar solvents
and moderately soluble in nonpolar organic solvents as previously
reported for related compounds.16–18
a Fast decomposition prevented the characterization of this product.
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Gras, E. Org. Biomol. Chem. 2011, 9, 4714. (h) Ishikura, M. Heterocycles,
CONCLUSION
2011, 83, 247. (i) Lennox, A. J. J.; Lloyd–Jones, G. C. Isr. J. Chem. 2010, 50,
664. (j) Gillis, E. P.; Burke, M. D. Aldrichimica Acta, 2009, 42, 17.
(k) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829. (l) Fagnou, K.;
Lautens, M. Chem. Rev. 2003, 103, 169.
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Although the trifluoroborate group raises the nucleophilicity of the
carbon directly attached to the boron atom (ipso–activation) by a
factor of approximately 103–104, the activation of the vicinal or
more remote positions of a –system is even greater. Hence in
noncatalyzed reactions of aryl and heteroaryl trifluoroborates, the
BF3K group often directs electrophiles to adjacent or remote CH
positions and because the proton released during electrophilic
substitution at a CH position usually causes a subsequent
protodeborylation, the entering electrophile is often found at a
position different from that of the departing BF3K group.
When bases are present to trap the released protons, it is even
possible to isolate boron containing substitution products. With
iminium ions, the protons are trapped intramolecularly, opening a
new straightforward access to bifunctional ammonium and
iminium borates, with potential applications in catalysis and
molecular recognition.16,17 Further synthetic transformations, e.g.
cross–coupling reactions, with the borate substituent remaining in
these products are also feasible.19 Recent examples of unselective
and of remote substitutions of aryl and heteroaryl trifluoroborates
and trialkylborates6–8 can thus be rationalized.
(2) (a) Molander, G. A.; Cavalcanti, L. N. J. Org. Chem. 2011, 76, 7195.
(b) Akula, M. R.; Yao, M.–L.; Kabalka, G. W. Tetrahedron Lett. 2010, 51,
1170. (c) Yao, M.–L.; Reddy, M. S.; Yong, L.; Walfish, I.; Blevins, D. W.;
Kabalka, G. W. Org. Lett. 2010, 12, 700. (d) Cazorla, C.; Métay, E.;
Andrioletti, B.; Lemaire, M. Tetrahedron Lett. 2009, 50, 3936. (e) Kabalka,
G. W.; Mereddy, A. R. Tetrahedron Lett. 2004, 45, 343. For other types of
uncatalyzed SEAr reactions of organoborates with electrophiles, e.g. ipso–
nitration and ispo–sulfuration, see: (f) Molander, G. A.; Cavalcanti, L. N. J.
Org. Chem. 2012, 77, 4402. (g) Prakash, G. K. S.; Panja, C.; Mathew, T.;
Surampudi, V.; Petasis, N. A.; Olah, G. A. Org. Lett, 2004, 6, 2205. (h)
Kerverdo, S.; Gingras, M. Tetrahedron Lett. 2000, 41, 6053.
(3) Selected recent examples: (a) Wu, H.; Radomkit, S.; O’Brien, J. M.;
Hoveyda; A. H. J. Am. Chem. Soc., 2012, 134, 8277. (b) Pubill–Ulldemolins,
C., Bonet, A., Bo, C., Gulyás, H.; Fernández, E. Chem. Eur. J. 2012, 18,
1121. (c) Lee, K.–S.; Zhugralin, A. R.; Hoveyda, A. H. J. Am. Chem. Soc.
2009, 131, 7253.
(4) (a) Candeias, N. R.; Montalbano, F.; Cal, P. M. S. D.; Gois, P. M. P.
Chem. Rev. 2010, 110, 6169. (b) Vieira, A. S.; Ferreira F. P.; Fiorante, P. F.;
Guadagnin, R. C.; Stefani, H. A. Tetrahedron 2008, 64, 3306. (c) Chiu, C.–
W.; Gabbaï, F. P. J. Am. Chem. Soc. 2006, 128, 14248. (d) Tremblay–Morin,
J.–P.; Raeppel, S.; Gaudette, F. Tetrahedron Lett. 2004, 45, 3471.
(e) Harwood, L. M.; Currie, G. S.; Drew, M. G. B.; Luke, R. W. A. Chem.
Commun. 1996, 1953. For transition–metal free reactions of organoborates
with oxonium ions and other cationic electrophiles, see also: (f) Clausen, D.
J.; Floreancig, P. E.; J. Org. Chem., 2012, 77, 6574. (g) Vo, C.–V. T.;
Mitchell, T. A.; Bode, J. W. J. Am. Chem. Soc. 2011, 133, 14082.
(h) Larouche–Gauthier, R.; Elford, T. G.; Aggarwal, V. K. J. Am. Chem. Soc.
2011, 133, 16794. (i) Mitchell, T. A.; Bode, J. W. J. Am. Chem. Soc. 2009,
131, 18057.
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ASSOCIATED CONTENT
Experimental procedures, product characterizations, kinetic
experiments, copies of all NMR spectra and crystallographic data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
(5) (a) Kim, J.; Movassaghi, M. J. Am. Chem. Soc. 2011, 133, 14940.
(b) Lee, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129, 15438.
(c) Negishi, E.–i.; Abramovitch, A.; Merrill, R. E. J. Chem. Soc. Chem. Comm.
1975, 138.
(6) Examples of not fully ipso–regioselective reactions of arylborates with
electrophiles are reported ref. 2a, 5a, 7a–c and 7e–g.
Corresponding Author
Herbert.Mayr@cup.uni–muenchen.de
Homepage: http://www.cup.lmu.de/oc/mayr
Notes
(7) (a) Ishikura, M.; Kato, H. Tetrahedron, 2002, 58, 9827. (b) Ishikura,
M.; Agata, I.; Katagiri, N. J. Heterocycl. Chem. 1999, 36, 873. (c) Ishikura,
M.; Terashima, M. J. Heterocycl. Chem. 1994, 31, 977. (d) Ishikura, M.;
Kamada, M.; Oda, I.; Ohta, T.; Terashima, M. J. Heterocycl. Chem. 1987, 24,
377. (e) Negishi, E.–i.; Merrill, R. E.; Abramovitch, A.; Campbell, D. P.
Bull. Korean Chem. Soc. 1987, 8, 424. (f) Levy, A. B. Tetrahedron Lett. 1979,
20, 4021. (g) Marinelli, E. R.; Levy, A. B. Tetrahedron Lett. 1979, 20, 2313.
(h) Utimoto, K.; Okada, K.–I.; Nozaki, H. Tetrahedron Lett. 1975, 16, 4239.
(i) Negishi, E.–i.; Merrill, R. E. J. Chem. Soc. Chem. Comm. 1974, 860. (j)
Example of remote chlorination reactions of heteroaryl trifluoroborates are
also reported in ref. 2a.
(8) For electrophilic aromatic substitutions of aryl borates and boronates
with retention of the boron group, see: (a) Bartolucci, S.; Bartoccini, F.;
Righi, M.; Piersanti, G. Org. Lett. 2012, 14, 600 (b) Appukkuttan, P.;
Dehaen, W.; Van der Eycken, E. Chem. Eur. J. 2007, 13, 6452. (c) Isaad, J.;
El Achari, A. Tetrahedron 2011, 67, 4939. (d) Olah, G. A.; Piteau, M.; Laali,
K.; Rao, C. B.; Farooq, O. J. Org. Chem. 1990, 55, 46. See also ref. 7a–d and
f–i.
(9) For transition–metal–free reactions of aryltrifluoroborates with
retention of the BF3K group, see: (a) Molander, G. A.; Ajayi, K. Org. Lett.
2012, 14, 4242. (b) Molander, G. A.; Febo–Ayala, W.; Jean–Gérard, L. Org.
Lett. 2009, 11, 3830. (c) Molander, G. A.; Cooper, D. J. J. Org. Chem. 2008,
73, 3885. (d) Molander, G. A.; Ham, J.; Canturk, B. Org. Lett. 2007, 9, 821.
(e) Molander, G. A.; Cooper, D. J. J. Org. Chem. 2007, 72, 3558. (f)
Molander, G. A.; Ellis, N. M. J. Org. Chem. 2006, 71, 7491. (g) Molander,
G. A.; Ham, J. Org. Lett. 2006, 8, 2767. (h) Molander, G. A.; Petrillo, D. E.
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Support of this work has been provided by the Alexander von
Humboldt Foundation (grant for G. B.), the Deutsche
Forschungsgemeinschaft (SFB 749) and the Fonds der Chemischen
Industrie. We thank Dr. A. R. Ofial and Dr. B. Maji (Munich) for
their help during the preparation of the manuscript. Prof. F.
Terrier (Versailles, France) and Dr. S. Lakhdar (Caen, France) are
acknowledged for helpful discussions.
ABBREVIATIONS
Boc, t–butoxycarbonyl
MeCN, acetonitrile
REFERENCES
(1) For recent reviews on organotrifluoroborates, see: (a) Darses, S.;
Genet, J.–P. Chem. Rev. 2008, 108, 288. (b) Molander, G. A.; Ellis, N. Acc.
Chem. Res. 2007, 40, 275. (c) Stefani, H. A.; Cella, R.; Vieira, A. S.
Tetrahedron 2007, 63, 3623. (d) Darses, S.; Genet, J.–P. Eur. J. Org. Chem.
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D. G. in Boronic Acids: Preparation and Applications in Organic Synthesis,
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(f) Yamamoto, Y. Heterocycles, 2012, 85, 799. (g) Bonin, H.; Delacroix, T.;
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a recent synthesis of
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organotrifluoroborates under non–etching conditions, see: (i) Lennox, A. J.
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Aldridge, S.; Fallis, I. A.; Jones, C.; Ooi, L.–L. Angew. Chem., Int. Ed. 2005,
44, 3606. Also see ref. 18.
1
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(17) For potential applications of ammonium and iminium borates in
molecular recognition and in catalysis, see: (a) Oishi, S.; Saito, S. Angew.
Chem., Int. Ed. 2012, 51, 5395. (b) Gott, A. L.; Piers, W. E.; Dutton, J. L.;
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Leskelä, M.; Repo, T.; Pyykkö, P.; Rieger, B. J. Am. Chem. Soc. 2008, 130,
14117. (f) Zhu, L.; Shabbir S. H.; Gray, M.; Lynch, V. M.; Sorey, S.; Anslyn,
E. V. J. Am. Chem. Soc. 2006, 128, 1222.
(11) (a) Mayr, H.; Ofial, A. R. Pure Appl. Chem. 2005, 77, 1807. (b) Mayr,
H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66. (c) Mayr, H.; Bug,
T.; Gotta, M. F.; Hering, N.; Irrgang, B.; Janker, B.; Kempf, B.; Loos, R.;
Ofial, A. R.; Remennikov, G.; Schimmel, H. J. Am. Chem. Soc. 2001, 123,
9500. (d) Lakhdar, S.; Westermaier, M.; Terrier, F.; Goumont, R.;
Boubaker, T.; Ofial, A. R.; Mayr, H. J. Org. Chem. 2006, 71, 9088. (e) Mayr,
H.; Ofial, A. R. Tetrahedron Lett. 1997, 38, 3503.
(12) Database for N, sN and E parameters and references to original
literature: www.cup.uni–muenchen.de/oc/mayr/DBintro.html.
(13) CCDC numbers for compound 3: 874120, for 7: 881210 (only one
of the two symmetrically independent molecules is depicted in Figure 2), for
20: 874121 and for 21: 912272. These supplementary crystallographic data
can be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif. For the indole 2e see: (a)
Berionni, G.; Mayer, P.; Mayr, H. Acta Crystallogr., Sect. E: Struct. Rep. Online
2012, 68, m551.
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(18) The hydrolyses and stabilities of organotrifluoroborates have
recently been studied : (a) Lennox, A. J. J.; Llyod–Jones G. C. J. Am. Chem.
Soc. 2012, 134, 7431. (b) Ting, R.; Harwig, C. W.; Lo, J.; Li, Y.; Adam, M.
J.; Ruth, T. J.; Perrin, D. M. J. Org. Chem. 2008, 73, 4662.
(19) For recent examples of cross–coupling reactions of alkyl–
ammonium trifluoroborates, including their internal salts, see:
(a) Colombel, V.; Presset, M.; Oehlrich, D.; Rombouts, F.; Molander, G. A.
Org. Lett. 2012, 14, 1680. (b) Fleury–Brégeot, N.; Raushel, J.; Sandrock, D.
L.; Dreher, S. D.; Molander, G. A. Chem. Eur. J. 2012, 18, 9564.
(c) Molander, G. A.; Beaumard, F. Org. Lett. 2011, 13, 1242. (d) Raushel, J.;
Sandrock, D. L.; Josyula, K. V.; Pakyz, D.; Molander, G. A. J. Org. Chem.
2011, 76, 2762. (e) Luisi, R.; Giovine, A.; Florio, S. Chem. Eur. J. 2010, 16,
2683. (f) Molander, G. A.; Cooper, D. J. J. Org. Chem. 2008, 73, 3885.
(g) Batey, R. A., Quach, T. D. Tetrahedron Lett. 2001, 42, 9099.
(14) The intramolecular C10–H10…F1–B1 interaction in zwitterions 3,
8, 9 and 21 also exists in CD3CN solution as illustrated by the deshielding
of the benzhydryl proton H10 ( > 6.20 ppm) as compared to the non–
borylated compound 4 ( = 5.44 ppm) and 10 ( = 5.46 ppm) or to the
compound 5 where there is no H10…F interaction ( = 5.47 ppm). See also:
(a) Desiraju, G. R. Angew. Chem., Int. Ed. 2011, 50, 52. (b) Mayr, H.; Ofial,
A. R.; Würthwein, E.–U.; Aust, N. C. J. Am. Chem. Soc. 1997, 119, 12727.
(15) (a) Herrlich, M.; Hampel, N.; Mayr, H. Org. Lett. 2001, 3, 1629. (b)
Herrlich, M.; Mayr, H.; Faust, R. Org. Lett. 2001, 3, 1633.
(16) For related zwitterionic ammonium trifluoroborates, see:
(a) Batsanov, A. S.; Hérault, D.; Howard, J. A. K.; Patrick, L. G. F.; Probert,
M. R.; Whiting, A. Organometallics 2007, 26, 2414. (b) Coghlan, S. W.;
Giles, R. L.; Howard, J. A. K.; Patrick, L. G. F.; Probert, M. R.; Smith, G.
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