Nucleophilic aromatic substitution reactions of 1,2-dihydro-1,2-azaborine

Article abstract of DOI:10.1002/anie.201103192

Could go either way: The addition of nucleophiles to the parent 1,2-dihydro-1,2-azaborine and subsequent quenching with an electrophile generates novel substituted 1,2-azaborine derivatives (see scheme). Mechanistic studies are consistent with two distinc

Full text of DOI:10.1002/anie.201103192

DOI: 10.1002/anie.201103192
Heterocycles
Nucleophilic Aromatic Substitution Reactions of 1,2-Dihydro-1,2-
Azaborine**
Ashley N. Lamm, Edward B. Garner III, David A. Dixon, and Shih-Yuan Liu*
1,2-Dihydro-1,2-azaborine (1) is a benzene isostere in which a
present evidence that the substitution involves an addition-
elimination mechanism consistent with SNAr.
In our initial investigation, we discovered that when 1 was
treated with 1 equivalent of nBuLi in Et2O followed by
4 equivalents of trimethylsilyl chloride, the substituted het-
erocycle 2 was formed in 17% yield (Table 1, entry 1). A
=
À
C C unit of benzene is replaced with an isoelectronic B N
unit.[1,2] As part of our program to develop the basic science
Table 1: Optimization survey of SNAr reaction.[a]
and applications of 1,2-azaborine heterocycles,[3–6] we have
focused on expanding the scope of synthetically accessible
1,2-azaborines and investigating the aromatic character of this
family of heterocycles.
Entry
Solvent
Equiv of
nBuLi
T [8C]
Yield [%][b]
Among the four commonly investigated criteria for
aromaticity (structure, magnetism, energy, and reactivity),
we have determined that 1,2-azaborines exhibit delocalized
bonding,[7] have appropriate predicted NICS (À7.27 ppm;
nucleus-independent chemical shift) values,[8] and have an
experimentally determined resonance stabilization energy of
16.6 kcalmolÀ1,[9] which is consistent with significant aromatic
character. With regard to the reactivity criterion, Ashe and
co-workers have demonstrated that substituted 1,2-azabor-
ines undergo electrophilic aromatic substitution reactions.[10]
The parent 1,2-dihydro-1,2-azaborine (1) has recently been
isolated.[8] However, there have been no reactivity studies
performed on 1 to date. We are particularly interested in
investigating the reactivity of parent 1 for two reasons: 1) to
explore the fundamental reactivity differences between 1 and
benzene, and 2) to develop new synthetic methods to access
novel 1,2-azaborine derivatives. Herein we report that 1
readily undergoes nucleophilic aromatic substitution (SNAr)
reactions to furnish new 1,2-azaborine compounds. We also
1
2
3
4
5
6
7
8
9
Et2O
Et2O
Et2O
THF
pentanes
toluene
DME
Et2O
1
2
3
2
2
2
2
2
2
À30
À30
À30
À30
À30
À30
À30
25
17
94
71
67
11
53
86
46
77
Et2O
À78
[a] For reaction conditions see the Supporting Information. [b] Yields
determined by GC analysis of the reaction mixture versus pentadecane as
a calibrated internal standard. Yields are average of two runs.
DME=dimethoxy ether, THF=tetrahydrofuran, TMS=trimethlsilyl.
dramatic increase in product yield was observed when
2 equivalents of the nucleophile were used (entry 2). How-
ever, an additional increase in the amount of nucleophile used
led to a substantial decrease in product yield (entry 3). A
survey of solvents revealed that Et2O is the solvent of choice
among etheral and hydrocarbon solvents (entries 4–7 versus
entry 2). We also determined that the optimal temperature for
performing this substitution reaction is À308C; increasing or
lowering the reaction temperature resulted in diminished
yield of 2 (entries 8 and 9 versus entry 2).
[*] A. N. Lamm, Prof. Dr. S.-Y. Liu
Department of Chemistry, University of Oregon
Eugene, OR 97403-1253 (USA)
E-mail: lsy@uoregon.edu
The formation of compound 2 is consistent with a
nucleophilic aromatic substitution in which the hydride on
boron is serving as a leaving group. The ease with which this
substitution occurs (i.e., at À308C) is distinct from the
reactivity of benzene. The corresponding substitution reac-
tion with benzene typically requires a stronger nucleophile
(e.g., tBuLi) and much harsher conditions (e.g., reflux in
decalin at 1658C for 20 h).[11,12]
Having established the optimal reaction conditions for
this new substitution reaction, we then sought to expand its
substrate scope. As can be seen from Table 2, oxygen-based
nucleophiles are suitable for this reaction, including sodium
E. B. Garner III, Prof. Dr. D. A. Dixon
Department of Chemistry, Shelby Hall, University of Alabama
Tuscaloosa, AL 35487-0336 (USA)
[**] Correspondence concerning computational calculations should be
directed to David Dixon: dadixon@bama.ua.edu. Support for this
research has been provided by the National Science Foundation
(Grant DGE-0742540; A.N.L), the National Institutes of Health
(Grant R01-GM094541), the U.S. Department of Energy, and the
Robert Ramsay Foundation of The University of Alabama. We thank
Dr. A. J. V. Marwitz for helpful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103192.
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Communications
Table 2: Substrate scope of SNAr reaction.[a]
nisms 3 and 4, 1 equivalent of the nucleophile serves first as a
À
base to remove the N H proton to produce C. Subsequently
in Mechanism 3, the second equivalent of the nucleophile
À
displaces the B H bond (via a “di-anion”) to produce
À
M Nu
À
E X
Entry
Yield [%][b]
intermediate B. Alternatively, intermediate C can eliminate
a hydride to yield a “benzyne”-type 1,2-azaborine[14] which
then reacts with the nucleophile to produce B (Mechanism 4).
In our mechanistic studies we initially focused on the
reaction of 1 with nBuLi and TMSCl. To test the role of the
NH group, we synthesized the N-benzyl-protected 1,2-aza-
borine 3 [Eq. (1)], which was then subjected to the SNAr
reaction conditions (1 and 2 equivalents of nBuLi and
subsequent quenching with TMSCl). Interestingly, the sub-
stituted product 4 was not formed [Eq. (1)].[15] This exper-
imental observation is inconsistent with Mechanism 1, which
should be largely independent of the nature of the N sub-
stituent. We determined that 2 equivalents of nucleophile are
necessary to achieve a high yield of 2 [Eq. (2) versus (3)]. This
result is incompatible with Mechanism 2, which requires only
1 equivalent of the nucleophile. Furthermore, when 1 was
treated with 2 equivalents of nBuLi, a fine white powder
precipitated out of solution [Eq. (4)]. IR analysis of this
powder indicates formation of LiH.[16,17] The observation of
LiH is again inconsistent with Mechanism 2.
À
À
1
2
3
4
5
6
7
8
9
Na OtBu
H Cl
À
H Cl
63
79
81
80
98
59
71
89
67
60
À
K Oallyl
À
À
Li tBu
H Cl
À
À
Li nBu
H Cl
À
À
Li Ph
H Cl
À
À
BrMg vinyl
H Cl
À
H Cl
À
À
Li nBu
TMS Cl
À
À
Li nBu
Me I
À
À
10
Li nBu
H Cl
[a] For reaction conditions see the Supporting Information. [b] Yield of
isolated product. Average of two runs.
tert-butyloxide (entry 1) and potassium allyloxide (entry 2).
Carbon nucleophiles are very effective reaction partners.
Hindered branched (entry 3), less-hindered linear (entry 4)
sp3-hybridized organolithium reagents, as well as sp2-hybrid-
ized phenyllithium (entry 5) furnish the desired substituted
products in high yield. Grignard reagents also give the
corresponding products in moderate to good yield (entries 6
[13]
À
and 7). Noteworthy is the synthesis of B N styrene
À
(entry 6) and a novel B N tolan derivative (entry 7). The
scope with respect to the electrophile at the nitrogen position
includes H, TMS, Me, and Bn (entries 4, 8–10).
Scheme 1 illustrates four possible mechanistic scenarios
for the observed substitution reaction. Mechanism 1 involves
À
a simple displacement of the B H bond with the nucleophile
(via intermediate A) with subsequent intermolecular depro-
tonation by the released metal hydride and quenching with
the electrophile. In Mechanism 2, intermediate A releases H2
in an intramolecular fashion to generate intermediate B,
which is then quenched with the electrophile. In Mecha-
Whereas the experiments illustrated in equations (1)–(4)
are inconsistent with the proposed Mechanisms 1 and 2, they
are in agreement with Mechanisms 3 and 4. We were not
successful in trapping the “benzyne”-type 1,2-azaborine
intermediate using a number of trapping agents.[18] Therefore,
we used calculations to help determine the most likely
mechanism for the SNAr reaction. The computationally
determined energy diagram (Figure 1) at the G3MP2[19] plus
COSMO[20] level indicates that the formation of the “ben-
zyne”-type 1,2-azaborine is a high-energy process. In contrast,
the formation of the “di-anion” intermediate is energetically
very favorable. Based on all of the available data, we believe
Scheme 1. Possible reaction pathways of the substitution reaction.
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Angew. Chem. Int. Ed. 2011, 50, 8157 –8160

In summary, we have presented the
first reactivity study of 1,2-dihydro-1,2-
azaborine (1). We demonstrated that 1
can readily undergo nucleophilic aro-
matic substitution reactions under mild
reaction conditions, a reactivity pattern
that is distinct from its isostere benzene.
This new reactivity allows access to novel
À
1,2-azaborine structures, including a B N
tolan derivative. By using a combined
experimental
and
computational
approach, we determined the most likely
substitution mechanisms of 1 with both
carbon- and oxygen-based nucleophiles.
Current efforts are directed at utilizing
this reactivity for incorporating 1,2-aza-
borines into biologically relevant and
materials related molecules.
Figure 1. Calculated free energies in Et2O (G3MP2 + COSMO solvation model at the B3LYP-
DZVP2 level of theory, see the Supporting Information) of the proposed intermediates in the
SNAr reaction at 298 K.
that Mechanism 3 is the most likely mechanism for the
Experimental Section
Synthesis of compound 2: In a glove box, a 4 mL vial was charged with
a solution of 1 (0.020, 0.26 mmol), and ether (1.0 mL). nBuLi (1.6m in
Et2O, 0.320 mL, 0.510 mmol) was added to the solution at À308C, and
the mixture was allowed to stand at À308C for 3 h. Subsequently, a
cold solution of trimethylsilyl chloride (0.111 g, 1.02 mmol in 0.5 mL
Et2O) was slowly added to the reaction mixture. The resulting mixture
was allowed to stand for 1 h at À308C, and then warmed to room
temperature and stirred for an additional hour. At the conclusion of
the reaction, the mixture was concentrated under reduced pressure,
and the crude material was subjected to silica gel chromatography
using pentanes as the eluent, thus yielding 2 (0.047 g, 89%) as a clear
colorless oil.
conversion of 1 into 2.
À
The pKa value of the N H proton in 1,2-azaborines has
been determined to be approximately 26.[21] Alkoxide nucle-
À
ophiles are not basic enough to deprotonate the N H of 1.
Consequently, Mechanisms 3 and 4 cannot be used to explain
the SNAr reactivity with alkoxide nucleophiles (Table 2,
entries 1 and 2). To investigate the mechanism for oxygen-
based nucleophiles, we focused on the reaction of 1 with
NaOtBu and TMSCl. In this case, we determined that
1 equivalent of nucleophile is sufficient to furnish the
substituted product 5 in comparable yield as when 2 equiv-
alents of nucleophile were used [Eq. (5) versus Table 2,
1H NMR (500 MHz, C6D6): d = 7.59 (dd, 3JHH = 6.3, 4.8 Hz, 1H),
7.14 (d, 3JHH = 6.5 Hz, 1H), 7.03 (d, 3JHH = 11.1 Hz, 1H), 6.22 (d t,
3JHH = 1.18, 5.23 Hz, 1H), 1.71(m, 2H), 1.48 (m, 2H), 1.38 (t, JHH
=
3
8.3 Hz, 2H), 0.99 (t, JHH = 7.4 Hz, 3H), 0.17 ppm (s, 9H). 13C NMR
(125 MHz, C6D6): d = 143.2, 136.8, 130 (br), 111.3, 30.1, 26.4, 21 (br),
14.4, 1.5 ppm. 11B NMR (96.3 MHz, C6D6): d = 41.4 ppm. FTIR (thin
film) 2958, 2872, 1608, 1508, 1448, 1401, 1286, 1253, 1216, 1149, 1105,
1007, 991, 845, 765, 736, 685 cmÀ1. HRMS (EI) calcd for C11H22BNSi
[M+] 207.16146, found 207.16073.
3
entry 1]. Furthermore, the addition of NaOtBu to 1 results in
release of significant amount of gas consistent with H2
formation. Mechanisms 1 and 2 are both consistent with
these observations, the difference being whether H2 is
released in an intramolecular fashion (Mechanism 2) or
intermolecularly through the formation of NaH (Mecha-
nism 1). To address this, we added NaH to compound 6 and
then addition of TMSCl [Eq. (6)]; the starting material 6 was
Received: May 10, 2011
Published online: July 12, 2011
Keywords: aromatic substitution · aromaticity · boron ·
.
heterocycles · reaction mechanisms
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À
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