Boron in disguise: The parent fused BN indole

Article abstract of DOI:10.1021/ja205779b

"Fused" BN indoles are an emerging class of boron-containing indole mimics, featuring geometric structure and electophilic aromatic substitution reactivity similar to those of indoles but exhibiting distinct electronic structure, leading to unique optoele

Full text of DOI:10.1021/ja205779b

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Boron in Disguise: The Parent “Fused” BN Indole
Eric R. Abbey, Lev N. Zakharov, and Shih-Yuan Liu*
Department of Chemistry, University of Oregon, Eugene, Oregon 97403-1253, United States
S Supporting Information
b
Scheme 1. Synthesis of Parent BN Indole 3a
ABSTRACT: “Fused” BN indoles are an emerging class of
boron-containing indole mimics, featuring geometric struc-
ture and electophilic aromatic substitution reactivity similar
to those of indoles but exhibiting distinct electronic struc-
ture, leading to unique optoelectronic properties. Herein we
report the synthesis of the parent N-H BN indole and provide a
head-to-head comparison of the structural features, pKa values,
and optoelectronic properties of this hybrid organic/inor-
ganic indole with the classic natural indole.
ndole (1a) is a heterocycle of great importance to biological
systems. Within proteins, the redox-active indole side chain of
I
Our initial attempts at removing the N-t-Bu group from 3b to
access the parent 3a were not successful. We then chose tert-
butyldimethylsilyl (TBS) as an alternative N-protecting group.18
Thus, treatment ofN-allylethylenediamine (5) withn-BuLi followed
by quenching with TBSCl provided 6 in 87% yield (Scheme 1).
Condensation of diamine 6 with in situ-generated allylboron di-
chloride afforded heterocycle 7 in 57% yield. Subsequent ring-
closing metathesis with Grubbs’s first-generation catalyst pro-
vided the bicyclic product 8. Oxidative dehydrogenation of 8 with a
catalytic amount of Pd/C in perfluorodecalin furnished the fully
aromatic N-TBS BN indole 3c. We found perfluorodecalin to be
a more convenient solvent than decane that was used in the syn-
thesis of 3b, because the product can be isolated via biphasic ex-
traction with cold THF. Interestingly, X-ray diffraction (XRD)
studies of crystals isolated from the crude reaction mixture revealed
an almost parallel (3.7°) π-complex of the product 3c with per-
tryptophan is one of the primary charge carriers involved in elec-
tron transfer.1,2 The optical properties of indole make trypto-
phan one of the principal intrinsic fluorophores in protein fluo-
rescence analysis.3,4 The electron-rich aromatic indole core in
tryptophan is also responsible for tryptophan’s ability to partici-
pate in a wide range of inter- and intramolecular interactions
(e.g., cationÀπ and πÀπ interactions).5 Indole is the biosyn-
thetic parent to the essential amino acid tryptophan, the neuro-
transmitters serotonin6 and melatonin,7 and the auxin plant hor-
mones,8 and it remains a prominent structural feature in drug
design.9 Expansion of the diversity available to indole-based struc-
tures through BN/CC isosterism10 is in part driven by potential
therapeutic11 and analytical motives enabled by boron12 and has
produced the phenylenediamine family of 1,3,2-benzodiazabor-
olines 2 (“external” BN indoles)13,14 and the recently reported
“fused” BN indoles 3, containing the 1,2-dihydro-1,2-azaborine
(4)15 core.
fluoronaphthalene Fnap (3c Fnap, Table 1), with an interplanar
3
distance of 3.524 Å.19 Silica gel chromatography allowed isola-
tion of clean 3c. Deprotection of the N-TBS group of 3c with
TBAF afforded the target parent BN indole 3a in 55% yield. To
the best of our knowledge, BN indole 3a is the only example of a
natural product isostere (i.e., isoelectronic and isostructural to a
natural product (e.g., indole)) containing an sp2-type BN bond
pair.20,21
With 3a in hand, we began characterization of the structural,
optical, and physical features of the new heterocycle. X-ray-quality
crystals of 3a had a disordered structure, with a unit cell (cell
volume 662.42 Å3, space group Pna2(1)) identical to that of the
similarly disordered indole 1a.22 Given our fortuitous discovery
Our group recently found that the “fused” BN indole 3b displays
reactivity similar to that of indole 1b in electrophilic aromatic
substitution (EAS) reactions.16 This is in contrast to the family of
1,3,2-benzodiazaborolines 2, which have not been shown to
undergo EAS reactions at the five-membered ring. While N-t-Bu-
BN indole 3b closely mimics indole’s chemistry at the C2ÀC3
bond, it does not contain a free N-H fragment, an important
feature in the biochemistry of indole and its derivatives.17 We
now report the synthesis of the parent N-H BN indole 3a, with an
in-depth comparison to its carbonaceous counterpart 1a.
of the crystalline π-complex 3c Fnap, we attempted co-crystal-
3
lization of the parent 3a with perfluoronaphthalene. X-ray-quality
crystals of 3a Fnap were obtained through slow evaporation
3
from CH2Cl2 but unfortunately were also disordered. Screening
Received: June 21, 2011
Published: July 13, 2011
r
2011 American Chemical Society
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|

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Table 1. Bond Length Comparison: π-Complexes of BN Indoles and Indole
Figure 1. Cyclic voltammograms of BN indole 3a and indole 1a (0.08 M
TBAOTf in CH3CN at glassy carbon electrode; scan rate, 50 mV/s).
other electron-deficient aromatics, we successfully obtained a non-
disordered XRD structure by complexation with ethyl 4-chloro-3,5-
Figure 2. Normalized absorption (dotted line) and emission (solid line)
spectra of BN indole 3a (red) and indole 1a (black) and photophysical data
for 3a and 1a in CH3CN. aLiterature value, see ref 30. bLiterature value, see
ref 29.
dinitrobenzoate (Ar). The orange 1:1 complex 3a Ar shows evi-
3
dence of πÀπ stacking in the solid state, with an interplanar
distance of 3.268 Å and an almost parallel (1.2°) relationship.
These structural features are consistent with a charge-transfer
complex, and the interplanar distance is slightly shorter than the
range of spacings found in the indoleÀpicric acid π-complex
compared to indole 1a; it is also consistent with reported observa-
tions on BN arenes in comparison to their organic analogues.28
We also determined the absorption and emission properties of
BN indole 3a in direct comparison to indole 1a (Figure 2). Indole’s
absorbance maximum was found at λ = 268 nm in CH3CN,
whereas BN indole’s absoption maximum is bathochromically
shifted to λ = 293 nm (Figure 2). The fluorescence spectrum of
1a in CH3CN showed an emission peak at λem = 315 nm. In
contrast, BN indole’s λem appears at 360 nm. Thus, BN indole 3a
displays a larger Stokes shift (6350 cmÀ1) than its carbonaceous
counterpart 1a (5570 cmÀ1). The red-shifted absorbance and
emission bands of 3a in comparison to those of 1a are consistent
with a smaller HOMOÀLUMO gap in 3a vs 1a. The fluores-
cence quantum yield of 3a (Φ = 0.08) is lower than that exhibited
by indole 1a (Φ = 0.32),29 as is the molar absorptivity (ε = 6400
1a Pic23 and other related structures (3.3À3.5 Å).24 A qualita-
3
tive comparison of the parent “fused” BN indole complex 3a Ar
3
with 1a Pic reveals striking similarities.25 However, Bond 4 in 3a
3
is relatively short and Bond 9 relatively long compared to those in
1a (Table 1). A shorter Bond 4 in BN indole 3a vs 1a is consistent
with a smaller atomic radius of nitrogen versus carbon.26 A longer
Bond 9 in 3a vs 1a is likely the consequence of the larger atomic
radius of boron versus carbon.26 All three structures are highly
planar, with bond lengths consistent with aromatic delocaliza-
tion. All three indoles exhibit a relatively short C(2)ÀC(3) bond
length (Bond 3), which shows significant double bond character
and is responsible for much of indole’s unique chemistry.
Cyclic voltametry reveals some of the electronic differences
between heterocycles 1a and 3a. BN indole 3a has an irreversible
oxidation wave, peaking at 1.04 V, compared to 1.18 V measured
for indole 1a vs SCE (Figure 1). Both oxidations are irreversible
and show evidence of polymerization at the electrode, consistent
with previously reported CV measurements of indole.27 The
lower oxidation potential measured for 3a is consistent with a
higher energy HOMO and more electron-rich character of 3a
vs 8200 MÀ1 cmÀ1 30 respectively).
,
The N-H functionality is a critical component of indole-
containing biomolecules.17 While we previously established that
N-t-Bu-BN indole 3b displays the same regioselectivity as indole
in EAS reactions,16 the chemistry of the N-H of BN indole 3a
remained unexplored. We sought to estimate the pKa of the N-H
proton in 3a through a series of 1H NMR bracketing experiments.
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dx.doi.org/10.1021/ja205779b |J. Am. Chem. Soc. 2011, 133, 11508–11511

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Table 2. pKa Bracketing Experiments for 3a
’ AUTHOR INFORMATION
Corresponding Author
lsy@uoregon.edu
’ ACKNOWLEDGMENT
Support has been provided by the National Institutes of
Health (National Institute of General Medical Sciences, Grant
R01-GM094541). This material is based upon work supported
by the National Science Foundation under Award No. DGE-
072540 (E.R.A.). We thank Chris Weber for cyclic voltametry
measurements and sharing his expertise in electrochemistry.
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’ ASSOCIATED CONTENT
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