Controlling selectivity in N-heterocycle directed borylation of indoles

Article abstract of DOI:10.1039/d1ob00018g

Electrophilic borylation of indoles with BX₃(X = Cl or Br) using directing groups installed at N1 can proceed at the C2 or the C7 position. The six membered heterocycle directing groups utilised herein, pyridines and pyrimidine, result in indole C2 borylation being the dominant outcome (in the absence of a C2-substituent). In contrast, C7 borylation was achieved using five membered heterocycle directing groups, such as thiazole and benzoxazole. Calculations on the borylation of indole substituted with a five (thiazole) and a six (pyrimidine) membered heterocycle directing group indicated that borylation proceedsviaborenium cations with arenium cation formation having the highest barrier in both cases. The C7 borylated isomer was calculated to be the thermodynamically favoured product with both five and six membered heterocycle directing groups, but for pyrimidine directed indole borylation the C2 product was calculated to be the kinetic product. This is in contrast to thiazole directed indole borylation with BCl₃where the C7 borylated isomer is the kinetic product too. Thus, heterocycle ring size is a useful way to control C2vs. C7 selectivity in N-heterocycle directed indole C-H borylation.

Full text of DOI:10.1039/d1ob00018g

Organic &
Biomolecular Chemistry
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Controlling selectivity in N-heterocycle directed
borylation of indoles†
Cite this: Org. Biomol. Chem., 2021,
9, 2949
1
S. A. Iqbal, K. Yuan, J. Cid,
J. Pahl and M. J. Ingleson
*
Electrophilic borylation of indoles with BX
3
(X = Cl or Br) using directing groups installed at N1 can
proceed at the C2 or the C7 position. The six membered heterocycle directing groups utilised herein, pyr-
idines and pyrimidine, result in indole C2 borylation being the dominant outcome (in the absence of a
C2-substituent). In contrast, C7 borylation was achieved using five membered heterocycle directing
groups, such as thiazole and benzoxazole. Calculations on the borylation of indole substituted with a five
(thiazole) and a six (pyrimidine) membered heterocycle directing group indicated that borylation proceeds
via borenium cations with arenium cation formation having the highest barrier in both cases. The C7 bory-
lated isomer was calculated to be the thermodynamically favoured product with both five and six mem-
bered heterocycle directing groups, but for pyrimidine directed indole borylation the C2 product was cal-
Received 5th January 2021,
Accepted 10th March 2021
3
culated to be the kinetic product. This is in contrast to thiazole directed indole borylation with BCl where
DOI: 10.1039/d1ob00018g
the C7 borylated isomer is the kinetic product too. Thus, heterocycle ring size is a useful way to control
rsc.li/obc
C2 vs. C7 selectivity in N-heterocycle directed indole C–H borylation.
In this case, regioselectivity stems from unfavourable inter-
actions between the pivaloyl Bu group and the C7-H, this
Introduction
t
9
Derivatives of the heterocycle indole are core motifs in a orients the Lewis basic carbonyl group closer to C7 than C2.
variety of bioactive compounds such as Hippadine, We were interested in probing the electrophilic C–H bory-
1
Chloropeptin I and Chuangxinmycin, while functionalised lation of indoles using heterocycle based directing groups
indoles also have been utilised in organic materials appli- installed on N1. Directing groups are necessary to overcome
2
cations. Therefore, the functionalisation of indole derivatives the C3 selectivity otherwise observed using BX
3
derived elec-
7
b
in a selective manner is important. An efficient route to gene- trophiles. Selectivity (C2 versus C7) in heterocycle directed
rate selectively functionalised heteroarenes, including indoles, borylation could vary depending on heterocycle ring size and
3
is directed C–H borylation, with the borylated products extre- heterocycle substituents. The targeted borylated products are
4
mely useful in synthesis. In the past decade directed electro- potentially of interest for use in synthesis and in their own
philic C–H borylation (e.g. Fig. 1A) has been widely used right as fused four coordinate boron containing materials.
3
c,5
including to form boron containing organic materials,
bory- Four-coordinate organoboron containing compounds are of
3
c
lated intermediates for synthesis, and boron containing bio- current interest, in part due to the incorporation of LB → BR3
3
c,6
active compounds.
directing groups installed on N1 can lead to C2 or C7 boryla- effective method to significantly lower the LUMO energy.
tion (Fig. 1B). High C7 selectivity was reported only recently, The incorporation of LB → B units into a π-conjugated system
Electrophilic borylation of indoles using (LB = Lewis base) units into conjugated materials being an
5
,10
7
8
by some of us, and concomitantly Shi, Houk and co-workers.
has been utilised to produce a range of materials (Fig. 1C)
Both groups used the N-pivaloyl directing group to achieve with interesting properties, such as: small HOMO–LUMO
5
,10
electrophilic C–H borylation of indoles with BBr , with this gaps; high photoluminescence quantum yields;
directing group providing good selectivity for the C7 position. thermal isomerisation
photo/
3
1
1
to name a few. Herein we demon-
strate that Lewis basic N-heterocycles installed on indole-N1
are viable directing groups for the selective electrophilic C–H
borylation of indoles at either the C2 or C7 position (Fig. 1,
bottom). Rational selection of the heterocyclic directing
group (by using a five membered or a six membered hetero-
cycle) enables the borylation reaction to be switched between
C2 and C7.
EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, EH9 3FJ, UK.
E-mail: michael.ingleson@ed.ac.uk
†
Electronic supplementary information (ESI) available: Full experimental and
computational details, copies of NMR spectra for isolated compounds and key
in situ NMR spectra. CCDC 2051058 and 2051059. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/d1ob00018g
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indole product observed by NMR spectroscopy was from C2
borylation (δ11B = 2.7 ppm); a minor product was observed at
ca. 10–15% conversion, which was tentatively assigned as the
C7 borylation product (δ11B = 5.9 ppm). This minor product
was not protonated 1 as the minor product resonances per-
sisted in the presence of the hindered base 2,6-ditertbutyl-4-
methylpyridine (DTP). Furthermore, it was not the Lewis
adduct, 1-BCl (inset Scheme 1), which was observed in reac-
3
tion mixtures analysed at short times (ca. 5 min) and had a
δ
11B = 7.2 ppm. The C2-borylated product, 2-Cl, displayed a
1
diagnostic singlet in the H NMR spectrum at 6.88 ppm (for
the C3-H) while the δ11B of 2.7 ppm is consistent with a four
coordinate boron centre. Highest conversions to 2-Cl at room
temperature were obtained in the presence of DTP. Notably,
3
heating the reaction of 1/BCl in a sealed tube (to prevent loss
of HCl) did not lead to any increase in the species assigned as
the C7 borylated product suggesting that C2-B to C7-B isomeri-
sation is not occurring under these conditions.
3
Addition of pinacol/NEt solutions to the crude reaction
mixtures containing 2-Cl also produced one major new bory-
lated indole with NMR spectroscopy consistent with 2-Pin
1
1
(
2
Scheme 1). The B NMR spectrum of 2-Pin showed a peak at
6 ppm, this resonance is shifted upfield relative to heteroaryl-
BPin species (∼31 ppm) presumably due to some N–B inter-
action with pyrimidine. Isolation of 2-Pin proved challenging
due to sensitivity towards protodeboronation, although the
Fig. 1 Directed electrophilic C–H borylation of 2-phenylpyridine (top, corresponding BPh
left) and N-pivaloyl indole at C7 (top, right). Photo/thermal induced iso-
compound, 2-Ph, was isolable. Borylation
3
led to exclusive (by NMR spectroscopy) for-
2
of 1 using BBr
merisation of 4-coordinate N–B–C compounds (middle, left). Selected
examples of 4-coordinate N–B–C compounds used in optoelectronic
applications (middle, right). This work: heterocycle directed electrophilic
C–H borylation at C2 or C7 (bottom).
mation of 2-Br with no C7-borylation observed in this case.
Compound 2-Br was converted to 2-Ph by addition of ZnPh
and into the 1,8-diaminonaphthalene derivative, 2-Dan, which
proved more robust to isolation than the pinacol congener.
The pyridyl analogue, 3 (Scheme 2), also was readily bory-
2
3
lated with BCl and analysis of this reaction revealed formation
of the C2 borylation product, 4-Cl, as the only observable bory-
Results and discussion
Indole C–H borylation with different directing groups
1
lated product by H NMR spectroscopy (singlet for C3-H
11
observed at 6.91 ppm is consistent with C2 borylation).
B
Since the key goal of this study was to understand selectivity in NMR spectroscopy again confirmed the presence of a four
directed borylation, it was important to determine C2 vs. C7
selectivity at the primary product stage (e.g. the BX boracycle
2
containing compound, X = Cl or Br). This was necessary as
subsequent functionalisation at boron, e.g. installation of
pinacol, has been observed to lead to isomerisation and/or
7
protodeboronation, with the latter more prevalent for the C2
1
2
isomer than the C7. During this work it was found in mul-
tiple borylation reactions that solid precipitated. This solid
could be an N → BX3 Lewis adduct, borylated products or
other species such as protonated starting material (with the
E
proton generated as the by-product from S Ar). Therefore to
determine the selectivity in the C–H borylation step reaction
mixtures were dried in-vacuo and a portion of the resultant
solid was dissolved for analysis by NMR spectroscopy. The dis-
cussion of borylation selectivity throughout is based on ana-
lysis of these fully homogeneous solutions.
N-Pyrimidine indole, 1, was combined with BCl
3
under a
Scheme 1 Pyrimidine directed borylation and subsequent functionali-
range of conditions (see ESI†). In all cases, the major borylated sation at boron.
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equiv. of BCl
3
at room temperature. This led to rapid boryla-
tion, with a new resonance at δ11B = 6.0 ppm, assigned as the
C7 borylated product 8-Cl. Protection at boron by addition of
pinacol/NEt enabled isolation of 8-Pin in 80% yield. The
3
observed δ11B for 8-BPin at 11.1 ppm indicated a significant N–
B interaction, with this chemical shift more comparable to 6-
Pin (containing a 6 membered boracycle) than 2-Pin (contain-
ing a five membered boracycle). The formation of 8-Cl con-
firmed the feasibility of N-heterocycle-directed indole C7 bory-
lation when functionalisation at the C2 site is blocked.
Furthermore, the δ11B of 8-Cl is very close to that of the minor
product observed during the borylation of 1, supporting the
assignment of this minor product as derived from C7-
borylation.
Scheme 2 Borylation of indole functionalised with a pyridine directing
group.
coordinate boron centre (δ11B = 3.0 ppm). Compounds 2-X and
4
-Cl were all bench stable indicating a strong N → B dative
bond. For 4-Cl, slow evaporation of solvent led to crystals suit-
able for X-ray diffraction analysis which confirmed the formu-
lation as the C2 borylated product (vide infra for further discus-
N-Heterocycle substituted indoles were targeted that would
undergo selective C7 borylation even when the C2 position is
not blocked. Thus, a 3-methyl pyridyl directing group was
installed on indole to give compound 9 (Scheme 5). It was
hypothesised that due to unfavourable interactions between
the C7-H and the pyridyl-methyl group the pyridyl would
rotate to position the methyl group closer to C2-H than C7-H.
This would orientate the Lewis basic N more towards C7 than
sion). Furthermore, addition of ZnPh to 4-Cl led to formation
2
of 4-Ph. It should be noted that no minor products derived
from C7 borylation were isolated during the purification of
compounds 2 and 4 by column chromatography.
Due to the absence of any definitively characterised six
membered boracycles from pyrimidine/pyridine directed C7-H
indole borylation, confirmation of the accessibility of six mem-
bered boracycles using these borylation conditions was sought
in a related system. Thus N-pyrimidine-carbazole, 5, a sub-
strate where no five membered boracycle is accessible, was syn-
C2. However, compound 9 underwent borylation with BCl to
3
form one major new borylated indole species consistent with
C2 borylation, 10-Cl, along with protonated 9 as the by-
product. Repeating borylation in the presence of the hindered
base DTP led to formation of 10-Cl as the only new indole con-
taining product, with no C7-borylated product, 11-Cl,
observed. While the δ11B of 10-Cl was observed at 2.5 ppm,
comparable to that for 2-Cl for example, 10-Cl proved much
more sensitive to protodeboronation than 2-X and 4-Cl. We
attribute this to the C7-H/Me interaction destabilising the N–B
dative bond in 10-Cl leading to more facile decomposition via
protodeboronation. Wang and co-workers have previously
thesised. Borylation of 5 with BCl
3
proceeded readily to form
6
-Cl. Addition of pinacol/NEt to 6-Cl yielded 6-Pin in 67% iso-
3
lated yield (Scheme 3). Compound 6-Pin proved more robust to
protic species than 2-Pin, consistent with the previously
reported relatively high sensitivity of C2/C3 borylated indoles
1
2
11
to protodeboronation. The δ B for 6-Pin (9.9 ppm) suggested
a stronger interaction between pyrimidine and the BPin unit
1
1
than that present in 2-Pin (δ B = 26 ppm), which may also
contribute to the enhanced stability of 6-Pin towards protic
species.
noted that weak dative bonds in related Ar B ← N containing
Following the successful formation of the six membered
boracycle in 6, an N-heterocycle-indole derivative, 7, that only
permits C7-borylation, due to blocking of the C2 position, was
synthesised (Scheme 4). Compound 7 was combined with 1.5
3
compounds leads to much less stable (with respect to protode-
boronation) compounds than those with stronger dative
1
3
bonds. The failure to observe any 11-Cl indicates the methyl
groups is not large enough to force 9 to adopt a geometry
where the pyridyl N is proximal to C7 (Scheme 4). This is con-
t
sistent with the requirement for bulkier groups, such as Bu in
Scheme 3 Pyrimidine directed carbazole borylation.
Scheme 4 Pyrimidine directed borylation of 2-methyl indole.
Scheme 5 3-Methyl pyridine directed C–H borylation of indole at C2.
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pivaloyl, in previously reported C7 selective indole electrophilic duced 17-X (X = Cl or Br) as the only observed product by NMR
borylation reactions. spectroscopy on addition of BX (Scheme 7). Slow cooling of a
3
A different approach to realise selective C7 borylation was DCM solution of 17-Cl yielded crystals suitable for X-ray diffr-
targeted, using five membered heterocyclic directing groups. It action analysis which further confirmed the formulation as
was hypothesised that replacing six-membered N-heterocycle the C7 borylated product (vide infra for discussion of metrics).
directing groups with five membered analogues, as in com- The reaction of 17-Cl with ZnPh yielded the C7-BPh product
2 2
pound 12 (Scheme 6), would disfavour C2 functionalisation. 17-Ph. The borylation of the benzothiazole derivative, 16, also
The greater strain expected in the product from C2 borylation, was achieved on addition of BX . However, the extremely low
3
1
3-Cl, due to the presence of the three fused five membered solubility of 18-X in chlorinated organic solvents meant that
rings, and the greater distortion expected during the C2 boryla- only 18-Ph could be characterised, so the selectivity in the bor-
tion process, would lead to higher energy barriers for C2 bory- ylation step for this compound cannot be readily determined.
lation relative to C7 borylation and a less stable borylated Nevertheless, borylation is likely also to be C7-selective by
product (for the C2 isomer 13-Cl relative to the C7 isomer 14- analogy to 12 and 15.
Cl).
In all the BPh products isolated in this work, there was a
2
1
1
Directed electrophilic borylation of 12 proved selective for significant N–B interaction as indicated by the B NMR
the C7 position with no C2 borylation observed by H NMR spectra (δ B in the region 0–2 ppm), which showed notice-
spectroscopy. C7 borylated product 14-Cl has an B resonance able upfield shifts relative to Ar B species. As expected, N →
1
11
1
1
3
2
at 6.2 ppm consistent with a four coordinate boron centre. BPh coordination modulates the electronic properties of the
Pinacol installation on to boron in 14-Cl could be performed substituted indoles, with the first reduction potential for the
and a modest yield (55%) of the C7-BPin product, 14-Pin, was BPh functionalised compounds being less negative by ca. 0.5
2
1
1
isolated (δ B 13.8 ppm). ZnPh
2
was utilised to install phenyl V than the non-borylated precursors, as observed previously
groups on boron in 14-Cl which enabled isolation of the C7- for related compounds.
1
1
Similar changes in the first
BPh product 14-Ph (Scheme 6). To the best of our knowledge, reduction process were observed on installation of BPh at C2
2
2
this is the first example of five membered heterocycle directing or C7.
groups being used to enable selective C7-H functionalisation
1
4
of indoles.
C7 selective indole borylation using BCl
Solid state structures
3
3
or BBr was also
observed with benzoxazole (15) and benzothiazole (16) as the Direct comparison of the solid state structures of a C2 and a
directing groups – thus it appears a general outcome with five C7 borylated product, 4-Cl and 17-Cl, is informative (Fig. 2).
membered heterocycle directing groups. Compound 15 pro- Both 4-Cl and 17-Cl feature effectively planar fused polycyclic
cores, with small angles between the planes of the five-mem-
bered ring in indole and the heterocyclic directing group (for
4-Cl = 3.50°, for 17-Cl = 7.44°). The boron atom in both are
4-coordinate, however the N2–B1 bond distance in 4-Cl is
1.589(2) Å, slightly longer than the analogous bond distance in
17-Cl (1.561(6) Å), possibly due to the greater strain in five-
membered boracycle. In contrast, the C–B distances are effec-
tively identical. Increased strain in 4-Cl also is indicated by 17-
Cl having a C7–B1–N2 angle of 107.7(4)° (close to the ideal for
a tetrahedral boron centre), while 4-Cl has a contracted com-
parable angle (N2–B1–C2 angle of 97.7(1)°) imposed by the five
Scheme 6 Thiazole directed borylation selectively at indole C7.
Fig. 2 Solid state structures of left, 4-Cl, and right 17-Cl, ellipsoids at
5
1
=
9
0% probability. Selected distances (Å) and angles (°) for 4-Cl: B1–N2 =
.589(2); C2–B1 = 1.587(2); B–Cl1 = 1.856(1), B1–Cl2 = 1.848(2); N1–C1
1.375(2) N1–C1–N2 = 109.7(1); N1–C2–B1 = 107.3(1); N2–B1–C2 =
7.7(1); C1–N2–B1 = 111.8(1). For 17-Cl: N2–B1 = 1.561(6); C7–B1 =
.595(7); B1–Cl1 = 1.875(6); B1–Cl2 = 1.861(6); N1–C1 = 1.334(5); N1–
1
C1–N2 124.0(4); C1–N2–B1 = 125.2(4); C7–B1–N2 = 107.7(4); C1–N1–
Scheme 7 Benzoxazole and benzothiazole directed borylation at C7.
C8 = 118.7(4).
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membered boracycle constructed of three shorter bonds (three with a short distance of 3.379 Å between stacked adjacent
CN bonds) and two longer bonds (the CB and NB bonds). In molecules, whereas no close face to face stacking is observed
the extended structure of 4-Cl face-to-face π stacking is seen in the extended solid state structure for 17-Cl.
3 2 2
Fig. 3 DFT calculated energy profiles for addition of BCl to 12 (a) and 1 (b) at M06-2X/6-311+G(d,p)//PCM (CH Cl ). Route for C2 borylation:
purple. C7: black. Values are for ΔG in kcal mol− , with ΔE provided in parentheses.
1
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DFT calculations
2 2
DFT calculations at the M06-2X/6-311+G(d,p)//(PCM(CH Cl ))
(PCM = polarisable continuum model) level were performed to
gain further insight into the origin of the C2 vs. C7 borylation
selectivity with five and six membered N-heterocycle directing
groups. The calculations indicated the mechanism of boryla-
tion is very similar irrespective of the heterocyclic directing
group employed, proceeding via borenium cation intermedi-
ates, with arenium cation formation being rate limiting. It
should be noted that the metrics for the five and six mem-
bered boracycles in the solid state structures of 4-Cl and 17-Cl
are closely comparable to the metrics of the boracycles in the
calculated C2-BCl and C7-BCl structures derived from pyrimi-
2
2
Fig. 4 Change in energy on distorting the N-heterocycle-indole 12/1
dine and thiazole directed indole borylation.
Addition of BCl
this step calculated to be exergonic by 12.8 kcal mol
Borenium cation (INT2) formation through halide transfer to a
from the optimised geometry (centre) to the geometry observed in the
to 12 forms complex INT1 (Fig. 3a), with key transition state for C2 (right) and C7 (left) borylation.
3
−1
.
−
second molecule of BCl
3
, forming [BCl
4
] , is then endergonic
(
by 4.3 kcal mol− relative to 12 + two equiv. BCl ), consistent
1
The borylation of 1 (Fig. 3b) follows a similar pathway to
3
with no borenium intermediates being observed by NMR spec- that of 12, although borenium cation formation is more ender-
troscopy. The formation of the arenium cation at C7 then pro- gonic starting from 1, possibly due to the lower basicity of pyri-
‡
ceeds through a 6-membered transition state, TS 1A, with an midine relative to thiazole (pK
values of the conjugate acids
a
−1
‡
overall energy barrier of 23.9 kcal mol from INT1. TS 1A leads are 1.3 and 2.5, respectively). While the relative energies of the
to arenium cation, INT3A, at which point there is a small energy two product isomers show the C7 product to be 2.2 kcal mol
barrier for deprotonation with [BCl ] as base. The formation of lower in energy than the C2 isomer (2-Cl), the reaction is pro-
−
1
−
4
the C7 borylated product, 14-Cl, and HCl is energetically down- ceeding under kinetic control (as observed in many other
−1
3c
hill by −15.8 kcal mol relative to 12 and BCl
. The mechanism N-directed borylation reactions using BX
3
3
)
to give the C2
has many similarities to that calculated for pivaloyl directed borylated product as the major product. However, the key tran-
7
,8
indole borylation, and an earlier study by Uchiyama and co- sition state for C2 borylation is only slightly lower in energy
1
5
‡
workers on imidazole directed electrophilic borylation.
relative to that for C7 borylation (compare TS 3A and 3B), con-
The observed C7 selectivity in the borylation of 12 is repro- sistent with the observed formation of minor amounts of a
duced by the calculations, with the formation of the C2 bory- product derived from 1 assigned as the C7-borylated product.
lated isomer having higher barriers throughout (e.g. energy of These observations are consistent with the documented
‡
‡
‡
TS 1B > TS 1A). Comparing the calculated structures for TS 1A kinetic preference for functionalisation of indoles at C2 in pre-
‡
and TS 1B with 12 (or INT2) shows that during borylation ference to C7 in the absence of other factors (e.g. ring strain as
there is a larger distortion of the thiazole-indole unit in TS 1B in 12 or steric bulk as in the pivaloyl functionalised indoles).
relative to 12 (or to INT2) than in TS 1A. This is demonstrated The smaller difference in ΔE between the key transition states
by the relative change in the N–C–N and C–N–B bond angles for determining C2 vs. C7 selectivity (e.g. ΔE between TS 1A/B
INT2 to TS 1B Δ = 7.38° and 9.27°, respectively), with a is > than ΔE between TS 3A/B) is due, at least in part, to a
smaller distortion in TS 1A relative to INT2 (for the equivalent smaller difference in the distortion energy of the
angles Δ = 2.2° and 0.95°). The different degrees of distortion N-heterocycle-indole units in the two borylation transition
leads to an energy difference of 3 kcal mol between the two states starting from 1 (Fig. 4 bottom) relative to that starting
geometries of the thiazole-indole unit in the respective tran- from 12 (Fig. 4 top). Thus, the relatively high distortion energy
sition states (Fig. 4). This presumably is a significant contribu- (14.4 kcal mol− ) of the thiazole-indole moiety in the key tran-
‡
‡
‡
‡
‡
(
‡
−
1
1
‡
‡
tor to the observed δΔE between TS 1A and TS 1B (2.5 kcal sition state for C2 borylation is a significant factor in the bory-
mol ).
−
1 16
This confirms that increasing distortion energy lation of 12 being selective for C7.
during C2 borylation by using five membered heterocycle
Finally, consistent with pivaloyl directed indole borylation,
directing groups is an effective route to enable highly selective the C7 borylated product is more stable than the C2 analogue
C7 functionalisation. It is also noteworthy that the C7 bory- in both the cases calculated herein. This is attributed to the
lated isomer, 14-Cl, is the kinetic and thermodynamic product 6-membered boracycle derived from C7 borylation having less
starting from 12, with a significant energy difference (6.8 kcal strain, as indicated by calculated C–B–N angles being close to
−
1
mol ) between 13-Cl and 14-Cl. This is presumably due to the 109°, whereas borylation at C2 to form a five-membered ring
greater strain present in the C2 borylated product (as exempli- gives calculated C–B–N angles of ca. 97°, significantly more
fied by N–C–N = 112.97° in the calculated structure of 13-Cl vs. acute than the optimal angle for a 4-coordinate boron com-
1
21.59° in that of 14-Cl).
pound. This is consistent with relative angles observed in the
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solid state structures of 4-Cl and 17-Cl. It is noteworthy that either the University of Manchester or the University of
the energy difference between 13-Cl and 14-Cl is considerably Edinburgh using electrospray or APCI ionisation modes. Cyclic
greater than that between the C2 and C7 pyrimidine isomers, voltammetry measurements were conducted under an N
again highlighting the greater impact on relative energies of atmosphere using a CH-Instrument 1110C Electrochemical/
2
the two isomers imposed by five membered directing groups.
Analyser potentiostat. THF (1 mM) was used as the solvent in
all cases and tetrabutylammonium hexafluorophosphate (0.1
M) was used as the electrolyte. A glassy carbon working elec-
trode was used and platinum wire as the counter and reference
Conclusions
electrodes. All potentials were calibrated against the ferrocene/
+
Modification of the heterocycle directing group installed at N1 ferrocenium (Fc/Fc ) redox couple.
on indoles can afford selective electrophilic borylation at
either the C2 or the C7 position. Six membered heterocyclic
Synthesis of 2-Br
directing groups lead to preferential C2 borylation using BX
with borylation calculated to proceed via a borenium cation 1 (0.039 g, 0.2 mmol) which was dissolved in DCM (0.7 mL).
mediated mechanism. Calculations indicate with a six mem- BBr (0.44 mL, 1 M in DCM) was added, the ampule was
3
,
To an ampule fitted with a J-Youngs tap was added compound
3
bered heterocycle directing group that C2 borylation is the sealed and the mixture was stirred at room temperature for
kinetically favoured pathway, but C7 borylation leads to the 0.5 hours. The solvent/volatiles were removed under vacuum
thermodynamic product. In contrast, five membered hetero- and the solid dried. The product was dissolved in DCM,
cycle directing groups lead to selective C7 borylation, with the passed through a filter and the volatiles were removed to give a
smaller internal angles in five membered rings resulting in solid which was washed with pentane and dried to give the
1
higher barriers to borylation at C2 relative to C7. Thus with pure product, 2-Br (0.054 g, 74%) as a yellow solid. H NMR
3
five membered heterocycle directing groups, C7 indole boryla- (500 MHz, CDCl ) δ 8.97 (dd, J = 4.7, 2.2 Hz, 1H), 8.82 (dd, J =
tion with BX3 is the kinetically and the thermodynamically 6.1, 2.3 Hz, 1H), 8.19–8.10 (m, 1H), 7.60 (dt, J = 7.4, 1.0 Hz,
1
3
1
favoured outcome. These results indicate that five membered 1H), 7.40–7.26 (m, 3H), 6.93 (d, J = 0.8 Hz, 1H). C{ H} NMR
heterocyclic directing groups have been overlooked as a means (126 MHz, CDCl ) δ 165.9, 151.8, 135.7, 132.7, 125.1, 124.8,
to target selective C7 functionalisation in directed indole func- 122.4, 114.8, 113.9, 113.3. B NMR (160 MHz, CDCl ) δ −6.82.
3
1
1
3
+
+
tionalisation. To date this area has been dominated by six- [Acc. Mass] calculated [M + H] : 363.92508, observed [M + H] :
membered heterocycle based directing groups and thus C2 363.92830.
1
7
functionalisation.
Synthesis of 2-Ph
To an ampule fitted with a J-Youngs tap was added compound
1
(0.030 g, 0.15 mmol) which was dissolved in o-DCB (0.5 mL).
BCl 1 M in hexanes (0.33 mL, 0.33 mmol) was added, the
tube was sealed and the mixture was heated to 80 °C for
Experimental
3
General
All reactions were performed under an inert atmosphere using 16 hours. The solvents and excess BCl were removed under
3
2
standard Schlenk techniques unless otherwise stated. All vacuum and ZnPh (0.077 g, 0.35 mmol) was added followed
chemicals were purchased from commercial sources and used by toluene (0.5 mL). The reaction mixture was stirred for 2
without further purification unless stated otherwise. BCl and days at room temperature. The product was purified by
3
BBr
3
solutions were transferred to Schlenks fitted with column chromatography on silica gel (EtOAc/petroleum ether)
1
J. Youngs valves prior to use. Dry solvents were obtained from to give 2-Ph (0.011 g, 22%) as a yellow solid. H NMR
an Inert PureSolv MD5 SPS machine or dried over CaH and (400 MHz, CDCl ) δ 8.90 (dd, J = 4.8, 2.3 Hz, 1H), 8.54 (dd, J =
2
3
stored over 3 Å molecular sieves. Bruker 300, Bruker 400 and 5.8, 2.3 Hz, 1H), 8.31–8.22 (m, 1H), 7.62–7.52 (m, 1H),
1
3
Bruker 500 MHz NMR spectrometers were used to obtain
C
7.42–7.31 (m, 4H), 7.29–7.26 (m, 2H), 7.25–7.16 (m, 6H), 7.11
1
1
11
13
1
{
H}, H and B NMR spectra. CDCl or CD Cl was used as (dd, J = 5.8, 4.8 Hz, 1H), 6.67 (d, J = 0.9 Hz, 1H). C{ H} NMR
3
2
2
the solvent in all cases and the residual CHCl
3
2 2
or CH Cl reso- (126 MHz, CDCl3) δ 163.3, 154.6, 152.4, 136.7, 133.0, 127.8,
1
3
1
1
11
nance was used as reference for C{ H} and H NMR spectra. 126.5, 123.9, 122.6, 120.8, 113.8, 113.6, 108.9.
B NMR
1
1
+
B NMR spectra were referenced to external BF -Et O. NMR (128 MHz, CDCl ) δ 0.36. [Acc. Mass] calculated [M + H] :
3
2
3
+
Spectroscopy was undertaken at room temperature (∼20 °C), 360.1667, observed [M + H] : 360.1655.
spin–spin J coupling constants are reported in hertz (Hz) and
Synthesis of 2-Dan
the chemical shifts δ are reported in ppm. C–B bonded and C–
1
3
13
1
(N)
3
C resonances were not detected in the C{ H} NMR To an ampule fitted with a J-Youngs tap was added compound
spectra presumably due to their being very broad resonances 1 (0.028 g, 0.14 mmol) which was dissolved in DCM (0.35 mL).
due to quadrupolar effects. Column chromatography was per- BBr (0.33 mL, 1 M in DCM) was added and the ampule was
3
formed on 40–63 µm silica gel manually or using
a
sealed and stirred at room temperature for 0.75 hours. The
CombiFlash NextGen 300+ Autocolumn system. Mass spec- solvent/volatiles were removed under vacuum and the product
trometry was performed by the mass spectrometry services at dried.
A
mixture of 1,8-diaminonapthalene (0.025 g,
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Paper
Organic & Biomolecular Chemistry
0
.14 mmol) in DCM (1 mL) and K CO (0.020 g, 0.7 mmol) in (0.018 g, 0.15 mmol) and NEt (0.21 mL, 1.5 mmol) were
2 3 3
H O (0.7 mL) was prepared and stirred vigorously for 1 hour added and the mixture was stirred for 1 hour. Volatiles were
2
and then added to the reaction ampule containing the bory- removed under vacuum and the crude product was purified by
lated indole at 0 °C, after stirring at 0 °C for 10 minutes the column chromatography on silica-gel (EtOAc: hexane) to yield
1
ampule was warmed to room temperature and stirred for a the pure product, 6-Pin (0.025 g, 67%) as a white solid.
further 2 hours. The reaction mixture was poured into a NMR (400 MHz, CD Cl
conical flask and dried over MgSO , the crude product was 8.3 Hz, 1H), 8.05 (d, J = 7.7 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H),
purified by column chromatography on silica-gel (EtOAc/pet- 7.75 (d, J = 7.2 Hz, 1H), 7.57–7.41 (m, 3H), 7.28 (t, J = 5.2 Hz,
H
2
2
) δ 9.10 (d, J = 5.2 Hz, 2H), 8.83 (d, J =
4
1
3
1
roleum ether) to give the pure product, 2-Dan (0.016 g, 31%) as 1H), 1.31 (s, 12H). C{ H} NMR (101 MHz, CD
2
Cl
2
) δ 156.8,
1
an off-white solid. H NMR (400 MHz, CDCl ) δ 8.77 (dd, J = 154.0, 141.5, 138.9, 129.9, 128.6, 127.2, 125.3, 124.6, 124.0,
.2, 0.9 Hz, 1H), 8.68 (d, J = 4.8 Hz, 2H), 7.66 (dt, J = 7.7, 1.1 120.8, 119.0, 119.0, 114.8, 81.4, 27.1. B NMR (128 MHz,
Cl ) δ 9.90. [Acc. Mass] calculated [M + H] : 372.1878,
2 2
H), 7.07 (dd, J = 8.3, 1.0 Hz, 2H), 7.04 (t, J = 4.7 Hz, 1H), 6.95 observed [M + H] : 372.1869.
3
1
1
8
+
Hz, 1H), 7.45–7.34 (m, 1H), 7.34–7.24 (m, 1H), 7.19–7.11 (m, CD
+
2
1
3
(
s, 1H), 6.32 (dd, J = 7.1, 1.0 Hz, 2H), 5.80 (br s, 2H, N–H
̲
C
1
Synthesis of 8-Pin
{
H} NMR (126 MHz, CDCl
3
1
1
1
1
14.7, 105.8. B NMR (128 MHz, CDCl ) δ 27.64. [Acc. Mass] 7 (0.042 g, 0.2 mmol) which was dissolved in DCM (1.6 mL).
3
+
+
calculated [M + H] : 362.15715, observed [M + H] : 362.15720.
3
BCl (0.3 mL, 1 M in DCM) was added and the ampule was
sealed and stirred at room temperature for 0.25 hours. The
volatiles were removed and the crude dried under vacuum.
Synthesis of 4-Cl
To an ampule fitted with a J-Youngs tap was added compound NEt
3
(0.42 mL, 3 mmol) was added followed by pinacol
3
(0.019 g, 0.10 mmol) which was dissolved in DCM (0.35 mL). (0.029 g, 0.24 mmol) and DCM (2.5 mL), the ampule was
BCl (0.33 mL, 1 M in DCM) was added to and the ampule was sealed and stirred for 1 h. The crude product was purified by
3
sealed and stirred at room temperature for 3 hours. The flash chromatography on silica gel (EtOAc/petroleum ether) to
1
solvent/volatiles were removed under vacuum until dryness to give the pure product (0.054 g, 80%) as a white solid. H NMR
give the pure product, 4-Cl (0.024 g, 87%) as a yellow solid. (400 MHz, CDCl ) δ 9.00 (d, J = 5.1 Hz, 2H), 7.55 (dd, J = 7.2,
3
Crystals were grown by slow evaporation of a DCM/pentane 1.3 Hz, 1H), 7.41–7.35 (m, 1H), 7.32–7.27 (m, 1H), 7.19 (t, J =
1
solution of the product. H NMR (400 MHz, CDCl
3
) δ 8.53 (d, J 5.1 Hz, 1H), 6.48–6.45 (m, 1H), 2.84 (d, J = 1.2 Hz, 3H), 1.31 (s,
1
3
1
=
(
5.8 Hz, 1H), 8.22–8.06 (m, 1H), 7.72–7.59 (m, 3H), 7.36–7.18 12H). C{ H} NMR (101 MHz, CDCl ) δ 156.2, 154.1, 139.9,
m, 3H), 6.91 (s, 1H). C{ H} NMR (126 MHz, CDCl
45.3, 142.3, 136.0, 132.7, 124.3, 123.7, 122.8, 118.4, 111.4,
10.7, 109.8. B NMR (128 MHz, CDCl ) δ 3.03. [Acc. Mass] 335.17996, observed [M] : 335.18117.
3
3
1
3
1
3
) δ 148.8, 138.0, 127.3, 126.5, 124.6, 118.9, 114.3, 111.5, 81.1, 26.8, 17.9.
1
1
+
1
1
3
B NMR (128 MHz, CDCl ) δ 11.19. [Acc. Mass] calculated [M]
1
1
+
+
+
calculated [M
+ Na] : 297.01281, observed [M + Na] :
Synthesis of 10-Cl
To an ampule fitted with a J-Youngs tap was added compound
(0.020 g, 0.1 mmol) and 2,6-di-tert-butyl-4-methylpyridine
To an ampule fitted with a J-Youngs tap was added compound (0.21 g, 0.01 mmol) which were dissolved in DCM (0.35 mL)
-Cl (0.056 g, 0.2 mmol) and ZnPh (0.100 g, 0.46 mmol) fol- followed by addition of BCl (3.2 eq., 1 M in DCM, 0.33 mL).
2
97.01270.
Synthesis of 4-Ph
9
4
2
3
lowed by toluene (1.5 mL). The ampule was sealed and the The mixture was stirred at room temperature for 3 hours after
reaction was stirred at room temperature for 16 hours. The which the solvent/volatiles were removed under inert con-
crude product was purified by column chromatography on ditions by vacuum and the product dried. Crude NMR spectra
3
silica-gel (EtOAc: petroleum ether) to give the pure product, 4- in CDCl showed the major product as 10-Cl (88% yield deter-
1
1
Ph (0.011 g, 15%) as a brown solid. H NMR (400 MHz, CDCl
3
)
mined by H NMR spectrosocpy. 55 mg crude solid obtained,
δ 8.34–8.30 (m, 1H), 8.10–8.00 (m, 1H), 7.80 (dt, J = 8.6, 1.1 Hz, 1 mg dissolved fully in CD Cl and 1 μL mesitylene internal
2
2
1
1
H), 7.77–7.66 (m, 1H), 7.66–7.53 (m, 1H), 7.35 (dd, J = 8.1, 1.5 standard added enabling yield determination). H NMR
Hz, 4H), 7.29–7.15 (m, 8H), 7.17–7.08 (m, 1H), 6.66 (d, J = 0.9 (500 MHz, CD Cl ) δ 8.43 (d, J = 5.7 Hz, 1H), 8.05–7.90 (m, 2H),
Hz, 1H). C{ H} NMR (126 MHz, CDCl ) δ 150.3, 143.9, 142.8, 7.68–7.53 (m, 1H), 7.34–7.21 (m, 3H), 6.91 (s, 1H), 2.98 (s,
2
2
1
3
1
3
1
1
1
1
3
36.9, 133.1, 132.8, 127.7, 126.2, 122.8, 121.9, 121.3, 117.3, 3H). B NMR (128 MHz, CDCl ) δ 2.45. [Acc. Mass] calculated
11.2, 109.6, 107.2. B NMR (128 MHz, CDCl ) δ 0.02. [Acc. [M] : 288.03869, observed [M] : 288.03925. C{ H} NMR spec-
3
Mass] calculated [M + H] : 359.17141, observed [M + H] : trum was not obtained due to poor solubility of 9-Cl.
1
1
+
+
13
1
+
+
3
59.17100.
Synthesis of 14-Ph
Synthesis of 6-Pin
BCl
pound 5 (0.024 g, 0.1 mmol) in DCM (1 mL) and the reaction BCl
mixture was stirred at room temperature for 1 hour. Pinacol and the mixture was stirred at 60 °C for 3 hours. The solvent
To an ampule fitted with a J-Youngs tap was added compound
3
(0.11 mL, 1 M in DCM) was added to a solution of com- 12 (0.029 g, 0.15 mmol) which was dissolved in DCM (0.4 mL).
(0.33 mL, 1 M in DCM) was added, the ampule was sealed
3
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and excess BCl were removed under vacuum and ZnPh
Paper
3
2
reaction mixture was heated to 60 °C for 2.75 hours, after
(0.077 g, 0.35 mmol) was added followed by DCM (1.5 mL). which it was cooled and the solvent/volatiles removed under
The reaction mixture was stirred for 1 hour at room tempera- vacuum and the solid dried to give 17-Cl (0.030 g, 73%) as a
1
3
ture. The solids were filtered off and the crude product was yellow solid. H NMR (500 MHz, CDCl ) δ 8.38 (m, J = 8.2, 1.3,
purified by column chromatography on silica gel (EtOAc/pet- 0.6 Hz, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.65 (dt, J = 8.3, 0.9 Hz,
roleum ether) to give the product, 14-Ph (0.035 g, 66%) as a 1H), 7.62–7.58 (m, 3H), 7.56–7.46 (m, 2H), 6.97 (d, J = 3.7 Hz,
1
13
1
white solid. H NMR (400 MHz, CDCl
3
) δ 7.37 (d, J = 4.0 Hz, 1H). C{ H} NMR (126 MHz, CDCl
3
) δ 149.9, 146.8, 134.3,
1
H), 7.35 (dd, J = 7.3, 1.5 Hz, 1H), 7.29 (m, 6H), 7.24–7.18 (m, 131.2, 129.9, 127.6, 127.5, 126.8, 126.4, 121.6, 119.9, 118.7,
1
3
1
11
5
H), 7.18–7.11 (m, 2H), 6.82 (dd, J = 7.5, 3.8 Hz, 2H). C{ H} 115.4, 111.3. B NMR (128 MHz, CDCl3) δ 3.92. [Acc. Mass]
+
+
3
NMR (101 MHz, CDCl ) δ 159.2, 137.2, 136.2, 133.7, 129.39, calculated [M] : 314.01795, observed [M] : 314.01728.
1
11
27.4, 125.9, 125.7, 125.4, 121.6, 117.9, 112.7, 108.8. B NMR
+
Synthesis of 18-Ph
(128 MHz, CDCl
3
) δ 0.22. [Acc. Mass] calculated [M + H] :
+
3
65.1278, observed [M + H] : 365.1269.
To an NMR tube fitted with a J-Youngs tap was added com-
pound 16 (0.0250 g, 0.1 mmol DCM (0.35 mL) was added fol-
Synthesis of 14-Pin
lowed by BBr
To an ampule fitted with a J-Youngs tap was added compound and the reaction mixed for 2 hours at room temperature fol-
2 (0.037 g, 0.18 mmol). DCM (0.4 mL) was added followed by lowed by 1 hour at 60 °C. The solvent/volatiles were removed
BCl (0.22 mL, 1 M in DCM). The ampule was sealed and the under vacuum and the crude material dried. ZnPh (20 mg,
3
(0.22 mL, 1 M in DCM), the tube was sealed,
1
3
2
reaction mixture was stirred for 3 hours at 60 °C after which 0.1 mmol) was added followed by DCM (1 mL), the tube was
the solvent/volatiles were removed under vacuum. NEt3 sealed and mixed overnight at room temperature. The product
(
0
0.38 mL, 2.7 mmol) was added followed by pinacol (0.021 g, was purified on silica-gel (EtOAc/petroleum ether) to give the
.18 mmol) and the reaction mixture was stirred vigorously pure product, 18-Ph (0.012 g, 29%) as a grey solid. H NMR
1
overnight at room temperature. The crude product was puri- (400 MHz, CDCl ) δ 7.73–7.68 (m, 1H), 7.60 (dt, J = 8.4, 0.7 Hz,
3
fied on silica-gel (EtOAc/petroleum ether) to give 14-Pin 1H), 7.44 (dd, J = 8.1, 1.5 Hz, 4H), 7.33–7.25 (m, 3H), 7.23–7.14
1
13
1
(
0.032 g, 55%) as an orange oil. H NMR (500 MHz, CDCl
3
) δ (m, 7H), 7.14–7.08 (m, 2H), 6.85 (d, J = 3.7 Hz, 1H). C{ H}
7
.83 (d, J = 4.0 Hz, 1H), 7.70 (d, J = 7.2 Hz, 1H), 7.54 (d, J = 7.8 NMR (126 MHz, CDCl ) δ 159.6, 144.7, 135.4, 133.8, 129.4,
3
Hz, 1H), 7.33 (t, J = 7.5 Hz, 1H), 7.29–7.18 (m, 1H), 6.96 (d, J = 127.5, 127.3, 126.5, 125.5, 125.5, 125.4, 125.2, 122.4, 122.2,
1
3
1
11
4
3
.0 Hz, 1H), 6.77 (d, J = 3.6 Hz, 1H), 1.37 (s, 12H). C{ H} 121.7, 117.8, 114.0. B NMR (128 MHz, CDCl ) δ 0.88. [Acc.
+
+
NMR (126 MHz, CDCl ) δ 161.1, 138.8, 136.5, 129.8, 127.1, Mass] calculated [M + H] : 415.14348, observed [M + H] :
B NMR 415.14370.
160 MHz, CDCl ) δ 13.75. [Acc. Mass] calculated [M + H] :
3
1
1
1
(
3
24.6, 123.8, 120.8, 111.4, 110.5, 81.3, 27.1.
+
3
+
27.1333, observed [M + H] : 327.1324.
Conflicts of interest
Synthesis of 17-Ph
There are no conflicts to declare.
To an NMR tube fitted with a J-Youngs tap was added com-
pound 15 (0.024 g, 0.1 mmol). DCM (0.35 mL) was added fol-
lowed by BCl
was sealed and heated to 60 °C for 2.75 hours after which it
was cooled and excess BCl and DCM were removed under
vacuum. ZnPh (0.050 g, 0.23 mmol) was added followed by
DCM (0.5 mL) and the reaction mixture was left overnight at
room temperature. The crude product was purified by column
3
1 M in DCM (0.22 mL, 0.22 mmol). The tube
Acknowledgements
3
This project has received funding from the European Research
Council (ERC) under the European Union’s Horizon 2020
research and innovation programme (grant agreement no
2
769599). We acknowledge SIRCAMS at University of Edinburgh
chromatography on silica gel (EtOAc/Hexanes) to give 17-Ph
for performing mass spectrometry and Dr G. Nichol for collect-
ing single crystal X-ray diffraction data.
1
(
0.026 g, 64%) as a white solid. H NMR (500 MHz, CDCl ) δ
3
7
.59–7.53 (m, 2H), 7.42–7.38 (m, 5H), 7.34–7.27 (m, 3H),
7
.25–7.18 (m, 6H), 7.17–7.11 (m, 2H), 6.89 (d, J = 3.6 Hz, 1H).
1
3
1
C{ H} NMR (126 MHz, CDCl ) δ 152.2, 146.9, 136.6, 134.0,
3
References
1
1
34.0, 129.7, 127.3, 126.5, 126.5, 126.1, 125.6, 125.0, 119.7,
1
1
18.3, 118.3, 114.1, 110.9. B NMR (160 MHz, CDCl
3
) δ 0.08.
1 (a) T. A. Shah, P. B. De, S. Pradhan and T. Punniyamurthy,
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+
[Acc. Mass] calculated [M + H] : 399.16632, observed [M + H] :
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99.16540.
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2 For select recent examples: (a) M. Liu, M. Shi and H. Meng,
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BCl (0.22 mL, 1 M in DCM). The ampule was sealed and the
3
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Paper
Organic & Biomolecular Chemistry
3
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