Electrophilic aromatic substitution of a BN indole

Article abstract of DOI:10.1021/ja107312u

We report the first examples of a "BN-fused" indole, and we demonstrate that this new family of unnatural indole derivatives undergoes electrophilic aromatic substitution (EAS) reactions with the same regioselectivity as its organic analogue. Competition

Full text of DOI:10.1021/ja107312u

Published on Web 11/02/2010
Electrophilic Aromatic Substitution of a BN Indole
Eric R. Abbey, Lev N. Zakharov, and Shih-Yuan Liu*
Department of Chemistry, UniVersity of Oregon, Eugene, Oregon 97403, United States
Received August 13, 2010; E-mail: lsy@uorgon.edu
Scheme 2. Synthesis of N-t-Bu-BN-Indole 2
Abstract: We report the first examples of a “BN-fused” indole,
and we demonstrate that this new family of unnatural indole
derivatives undergoes electrophilic aromatic substitution (EAS)
reactions with the same regioselectivity as its organic analogue.
Competition experiments reveal that N-t-Bu-BN-indole is more
nucleophilic in EAS reactions than its carbonaceous counterpart.
X-ray structural analysis between BN indole and classic indole
highlights significant differences in bond distances, in particular
for bonds associated with the boron atom.
Indole1 is one of the most ubiquitous heterocyclic motifs in
nature. Due to the abundance of biologically active indole deriva-
tives,2 the indole ring system has become an important structural
component in drug discovery efforts. Consequently, the synthesis
and functionalization of indoles has been a major focus in research,
the expansion of the chemical space of accessible indole structures
being one of the goals.3 An alternative approach to expand structural
diversity is “elemental isosterism”. To this end, the BN/CC
isosterism has recently emerged as a viable strategy to create
biomimetic analogues of common structural units in organic
molecules (e.g., olefin,4 benzene,5 and indene6). Despite the recent
advances in this area, the elemental isosterism of the biologically
important indole has remained virtually unexplored. To date, the
only BN-substituted indoles are phenylenediamine-type heterocycles
containing an external BN unit as illustrated in 1 (Scheme 1).7,8
To the best of our knowledge, electrophilic aromatic substitution
(EAS), a crucial reaction of the biochemistry of indoles,9 has not
been demonstrated with these phenylenediamine-type BN indoles.
Herein we report the first example of a “BN-fused” indole (e.g.,
heterocycle 2 in Scheme 1), and we demonstrate that this new BN
indole undergoes EAS reactions with the same regioselectivity as
its organic analogue, N-t-Bu-indole 3.10
which is estimated to be orders of magnitude greater than in the
case of benzene.13 This is due to indole’s electron-rich nature, and
the high electron density at its 3-position is responsible for indole’s
regioselectivity toward EAS reactions. The bicyclic N-t-Bu-BN-
indole 2 consists of a six-membered 1,2-dihydro-1,2-azaborine
heterocycle14,15 and a five-membered 2,3-dihydro-1H-1,3,2-diaz-
aborole core (Scheme 3).16 Thus, we were particularly interested
in whether unnatural N-t-Bu-BN-indole 2 would display the classical
indole-type regioselectivity in EAS reactions (i.e., at the 3-position)
or substitution at the 7- and 5-positions,17 which have been
demonstrated to be most nucleophilic in monocyclic 1,2-azaborine
structures.18
Scheme 3. Regioselectivity in EAS Reactions of N-t-Bu-BN-Indole 2
We surveyed the EAS reaction of N-t-Bu-BN-indole 2 with a
variety of electrophiles. As can be seen from Table 1, bromination
of 2 occurred at the 3-position, yielding the brominated product
6a (Table 1, entry 1). The Mannich reaction of 2 with dimeth-
yliminium chloride provided our first BN indole alkaloid, N-t-Bu-
BN-gramine 6b, in 53% yield (Table 1, entry 2). Lewis acid
mediated Michael addition of 2 to cyclohexenone with zirconium
tetrachloride19 furnished 6c in 57% yield (Table 1, entry 3).
Deuterium exchange20 occurred in degassed 1:1 CD3OD/D2O
at 100 °C providing 6d in 39% isolated yield (Table 1, entry 4).
Friedel-Crafts acylation of 2 with acetyl chloride was ac-
complished in the presence of Et2AlCl21 to yield 6e (Table 1,
entry 5). In each case, we observed substitution at the 3-position
of 2. The H(2) and H(3) proton signals of 2 appear as one singlet
Scheme 1. A Novel BN Indole
Synthesis of N-t-Bu-BN-indole 2 begins with the condensation
of N-t-Bu-N′-allylethylenediamine with in situ generated allylboron
dichloride (Scheme 2), affording heterocycle 4 in 50% yield. Ring-
closing metathesis (RCM) with Grubbs first generation catalyst
provides the bicyclic 5 in 51% yield.11 The yield of the RCM step
can be improved to 79% using Schrock’s catalyst. Dehydrogenation
of precursor 5 to furnish the target compound 2 is accomplished in
the presence of Pd/C in refluxing decane.12
1
in H NMR (in CD2Cl2) integrating for two protons. Thus, we
determined the substitution pattern of EAS products by either
single crystal X-ray diffraction (e.g., for 6e) or NOESY
experiments (e.g., for 6a and 6c).22
With N-t-Bu-BN-indole 2 in hand, we then investigated its
reactivity toward EAS. Indole itself displays high EAS reactivity,
9
16340 J. AM. CHEM. SOC. 2010, 132, 16340–16342
10.1021/ja107312u  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 1. EAS Reactions of 2
a
1H NMR indicates ∼80% deuterium enrichment.
The modest yields of these reactions are likely due to side
reactions associated with the relatively acidic reaction conditions.
Indoles are known to undergo self-condensation reactions in the
presence of acids.23 We determined that N-t-Bu-BN-indole 2 forms
the B-methoxy-substituted trimer 7 (Figure 1) in acidic methanol
solution among other byproducts.24 In one instance, we were able
to isolate a single crystal of 7 and determine its structure by X-ray
crystallography.25,26 Although substituted at the nitrogen and at
the C(3) position, the structure of 7 provides us with the first glimpse
into the bonding of BN indoles fused at the BN unit. Comparing
the intraring bond distances of the six-membered ring of 7 and a
B-diphenylamino-substituted 1,2-azaborine A (Figure 1),27 the most
noticeable difference is observed in the BsN bond distances. In
the fused bicyclic BN indole 7 the B(1)sN(2) distance (1.463(2)
Å) is longer than the corresponding BsN bond in a monocyclic
1,2-azaborine (1.446(2) Å). This is likely due to the better π-overlap
between the “exocyclic” nitrogen atom in 7 (i.e., N(1)) versus that
in A. It is also consistent with the shorter N(1)sB(1) distance in 7
(1.440(2)Å) compared to the BsN(exocyclic) bond length of
1.486(2)Å in A. We are also interested in comparing the BN indole
structure 7 with its carbonaceous counterpart. The typical bond
distances of a 1,3-dialkylsubstituted indole are illustrated in the
bottom right corner of Figure 1 (structure B).28 The most significant
differences in bond distances are directly associated with the
replacement of the CdC bond in B with a BsN unit. Due to the
larger covalent radius of boron,29 the B(1)sC(7) (1.509(2) Å) and
B(1)sN(1) (1.440(2) Å) bond lengths are significantly longer (by
∼0.1 Å) than those in indole B. On the other hand, presumably
due to the slightly smaller covalent radius of the nitrogen (vs
carbon),29 the N(2)sC(4) (1.370(2) Å) and N(2)sC(3) (1.404(2)
Å) distances are shorter than the corresponding bonds in B, although
this difference is less pronounced (i.e., shorter by only ∼0.02 Å).
Thus, while BN indoles are geometrically similar in shape compared
to natural indoles, the differences in bonding (e.g., bond lengths
and electronic structure) could potentially lead to significantly
different biological activity.
Figure 1. ORTEP illustrations, with thermal ellipsoids drawn at the 35%
probability level, of 7 and 6e.
at the C(3) position, significant changes in bond distances are
observed compared to 7. The N(1)-C(2) (1.363(2)Å), C(2)-C(3)
(1.372(2) Å), and the B(1)-N(2) bond distances in 6e are consistent
with a significant contribution of structure 6e′.
In order to probe the effect of the BN/CC isosterism of indoles
on the reactivity in EAS reactions, we performed competition
experiments between N-t-Bu-BN-indole 2 and its corresponding
carbonaceous analogue 3. Protection of the pyrrolic nitrogen with
an N-tert-butyl group allows the reactivity of the 3-position to be
evaluated without the influence of an indole N-H. Using 1 equiv
of each indole 2 and 3 and 0.5 equiv of electrophile (E+
)
dimethyliminium chloride) in CD2Cl2, we observed only EAS
products associated with N-t-Bu-BN-indole 2, with indole 3
remaining intact (Scheme 4).30 We hypothesize that N-t-Bu-BN-
indole 2 exhibits greater enamine character in the pyrrolic ring and
is therefore more nucleophilic than indole 3.
Scheme 4. EAS Competition Experiment with Dimethyliminium
Chloride As the Electrophile
In summary, we synthesized the first examples of BN-fused
indole derivatives. We also demonstrated that this new family of
BN indoles undergoes EAS reaction with classical indole-type
regioselectivity at the 3-position. Competition experiments revealed
that N-t-Bu-BN-indole 2 is more nucleophilic in EAS reactions than
its carbonaceous counterpart. Single crystal X-ray structure analysis
showed that while BN indoles are similar in shape compared to
classical indoles, significant differences in bond distances, in
particular those associated with the boron atom, are observed. Our
work lays the synthetic foundation for BN-substituted unnatural
products containing the indole motif and highlights the potential
We were also very pleased to discover that acylated BN indole
6e forms crystalline solids suitable for single crystal X-ray
diffraction analysis. The structure of 6e is illustrated in Figure 1
(top right). Because of the electronic impact of the acetyl substituent
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C O M M U N I C A T I O N S
(9) For a review of tryptophan biosynthesis, see: Raboni, S.; Bettati, S.;
Mozzarelli, A. Cell. Mol. Life Sci. 2009, 66, 2391–2403.
(10) Fletcher, A. J.; Bax, M. N.; Willis, M. C. Chem. Commun. 2007, 45, 4764–
4766.
of BN/CC isosterism as a general strategy in expanding the chemical
space of biologically active molecules.
Acknowledgment. Support has been provided by the University
of Oregon, Medical Research Foundation of Oregon, and 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.).
(11) Ashe, A. J., III; Fang, X. A. Org. Lett. 2000, 2, 2089–2091.
(12) Marwitz, A. J. V.; Abbey, E. R.; Jenkins, J. T.; Zakharov, L. N.; Liu, S.-
Y. Org. Lett. 2007, 9, 4905–4908.
(13) Sundberg, R. J. In Best Synthetic Methods, Indoles; Academic Press: San
Diego,1996; pp 1-6.
(14) For an overview, see: (a) Bosdet, M. J. D.; Piers, W. E. Can. J. Chem.
2009, 87, 8–29. (b) Liu, Z.; Marder, T. B. Angew. Chem., Int. Ed. 2008,
47, 242–244.
(15) Marwitz, A. J. V.; Matus, M. H.; Zakharov, L. N.; Dixon, D. A.; Liu,
S.-Y. Angew. Chem., Int. Ed. 2009, 48, 973–977.
Supporting Information Available: Experimental procedures and
compound characterization data (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
(16) For an overview on 2,3-dihydro-1H-1,3,2-diazaboroles, see: Weber, L.
Coord. Chem. ReV. 2001, 215, 39–77.
(17) Pan, J.; Kampf, J. W.; Ashe, A. J., III. Org. Lett. 2007, 9, 679–681.
(18) To the best of our knowledge, EAS reactions have not been demonstrated
with 2,3-dihydro-1H-1,3,2-diazaboroles.
(19) Kumar, V.; Kaur, S.; Kumar, S. Tetrahedron Lett. 2006, 47, 7001–7005.
(20) Lane, B. S.; Brown, M.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050–
8057.
References
(1) (a) Baeyer, A. Liebigs. Ann. Chem. 1866, 140, 295–296. (b) Baeyer, A.;
Emmerling, A. Chem. Ber. 1869, 2, 679–683.
(2) For leading references, see: (a) O’Connor, S. E.; Maresh, J. J. Nat. Prod.
Rep. 2006, 23, 532–547. (b) Gul, W.; Hamann, M. T. Life Sci. 2005, 78,
442–453.
(21) Okauchi, T.; Itonaga, M.; Minami, T.; Owa, T.; Kitoh, K.; Yoshino, H.
Org. Lett. 2000, 2, 1485–1487.
(22) The determination of the substitution pattern for 6b and 6d were made by
inference.
(23) Smith, G. F. AdV. Heterocycl. Chem. 1963, 2, 300–309.
(24) Ishii, H.; Murakami, K.; Sakurada, E.; Hosoya, K.; Murakami, Y. J. Chem.
Soc., Perkin Trans. 1 1988, 2377–2385.
(3) (a) Cacchi, S.; Fabrizi, G. Chem. ReV. 2005, 105, 2873–2920. (b) Humphrey,
G. R.; Kuethe, J. T. Chem. ReV. 2006, 106, 2875–2911.
(25) Correspondence concerning X-ray crystallography should be directed to
Lev Zakharov. E-mail: lev@uoregon.edu.
(4) (a) Zhou, H. B.; Nettles, K. W.; Bruning, J. B.; Kim, Y.; Joachimiak, A.;
Sharma, S.; Carlson, K. E.; Stossi, F.; Katzenellenbogen, B. S.; Greene,
G. L.; Katzenellenbogen, J. A. Chem. Biol. 2007, 14, 659–669. (b) Ito, H.;
Yumura, K.; Saigo, K. Org. Lett. 2010, 12, 3386–3389.
(26) Although we have determined that trimer 7 is the major product in the
acid catalyzed trimerization of 2, we were not able to isolate 7 cleanly.
See Supporting Information for details.
(5) Liu, L.; Marwitz, A. J. V.; Matthews, B. W.; Liu, S. Y. Angew. Chem.,
(27) Abbey, E. R.; Zakharov, L. N.; Liu, S.-Y. J. Am. Chem. Soc. 2008, 130,
7250–7252.
Int. Ed. 2009, 48, 6817–6819.
(6) Ashe, A. J., III; Yang, H.; Fang, X.; Kampf, J. W. Organometallics 2002,
22, 4578–4580. (b) Fang, X.; Yang, H.; Kampf, J. W.; Holl, M. M. B.;
Ashe, A. J., III. Organometallics 2006, 25, 513–518.
(7) For pioneering work in this area, see: (a) Ulmschneider, D.; Goubeau, J.
Chem. Ber. 1957, 90, 2733–2738. (b) Goubeau, J.; Schneider, H. Liebigs
Ann. Chem. 1964, 675, 1–9.
(28) For a representative example, see the structure published in: Evans, D. A.;
Scheidt, K. A.; Fandrick, K. R.; Lam, H. W.; Wu, J. J. Am. Chem. Soc.
2003, 125, 10780–10781.
(29) Pyykko¨, P.; Atsumi, M. Chem.sEur. J. 2009, 15, 12770–12779.
(30) See Supporting Information for details.
(8) For an overview, see: Weber, L. Coord. Chem. ReV. 2008, 252, 1–31.
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