Design of chiral boronate-substituted acrylanilides. Self-activation and boron-transmitted 1,8-stereoinduction in [4+2] cycloaddition

Article abstract of DOI:10.1016/S0022-328X(03)00400-5

The [4+2] cycloaddition of ortho-boronoanilide dienophile 4 with cyclopentadiene was found to proceed faster than both its para isomer 8 and the unsubstituted derivative 6, thereby confirming that self-activation by internal coordination is operative in the case of 4. Chiral boronic esters derivatives 9-13 provided a small level of remote 1,8-stereoinduction transmitted through a putative tetrahedral stereogenic boronate complex. These results show that dialkoxyboronic esters can operate as weak, internal Lewis acids and activate carbonyl-containing functionalities in cycloaddition reactions.

Full text of DOI:10.1016/S0022-328X(03)00400-5

Journal of Organometallic Chemistry 680 (2003) 263Á270
/
www.elsevier.com/locate/jorganchem
Design of chiral boronate-substituted acrylanilides.
Self-activation and boron-transmitted 1,8-stereoinduction in
[4ꢀ
/
2] cycloaddition
Jason W.J. Kennedy, Dennis G. Hall *
Department of Chemistry, University of Alberta, W5-07 Chemistry Building, Edmonton, Alberta, Canada T6G 2G2
Received 4 March 2003; accepted 17 April 2003
On the occasion of Professor Frederick Hawthorne’s 75th birthday
Abstract
The [4ꢀ
isomer 8 and the unsubstituted derivative 6, thereby confirming that self-activation by internal coordination is operative in the case
/2] cycloaddition of ortho-boronoanilide dienophile 4 with cyclopentadiene was found to proceed faster than both its para
of 4. Chiral boronic esters derivatives 9Á13 provided a small level of remote 1,8-stereoinduction transmitted through a putative
/
tetrahedral stereogenic boronate complex. These results show that dialkoxyboronic esters can operate as weak, internal Lewis acids
and activate carbonyl-containing functionalities in cycloaddition reactions.
# 2003 Elsevier B.V. All rights reserved.
Keywords: Lewis acids; DielsÁ/Alder reactions; Boronate esters; Substituent effects; Chiral auxiliaries; Stereoselective synthesis; Remote
stereoinduction
1. Introduction
diols as boronate substituents, however, constitutes a
potentially significant advantage in the use of boronic
Borate esters have long been used to activate and even
influence the regioselectivity of phenoxy-derivatized
esters as Lewis acids for cycloadditions and other
reactions. This article describes the design, synthesis
and evaluation of several chiral boronate-substituted
acrylamide dienophiles [6].
quinones as dienophiles in [4ꢀ2] cycloadditions [1].
/
For example, through transesterification of the phenolic
substituent in juglone, a modified dienophile is formed
as a borate ester that can coordinate one of the quinone
carbonyls and act as an internal Lewis acid to activate
the dienophile component (Fig. 1). We envisaged that a
similar concept could be extended to the useful class of
acrylate dienophiles. We were particularly interested in
investigating the potential role of a chiral boronic ester
as an internal activator and as a source or a transmitter
2. Results and discussion
2.1. Synthesis of a boronate-substituted acrylanilide
dienophile
The ideal boronate-substituted acrylamide would be
stable, and conjugated in such a way as to be easily
hydrolyzed from the resulting cycloadducts to provide
enantioenriched product. Due to the superior stability of
aromatic boronates and the facilitated cleavage of
anilides over the corresponding saturated amides, we
decided to first consider borono-anilides of type I (Fig.
1). Thus, the pinacolboronate-substituted dienophile 4
required for studying the carbonyl activating effect of
of remote stereoinduction [2,3] in a model DielsÁAlder
/
reaction using modified acrylamide dienophiles of type I
(Fig. 1). Dialkoxyboronic esters are a priori very weak
Lewis acids [4,5]. The possibility of employing chiral
* Corresponding author. Tel.:
4928231.
E-mail address: dennis.hall@ualberta.ca (D.G. Hall).
ꢀ
/
1-780-4923141; fax:
ꢀ/1-780-
0022-328X/03/$ - see front matter # 2003 Elsevier B.V. All rights reserved.
doi:10.1016/S0022-328X(03)00400-5

264
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/
Table 1
Relative speed and endo/exo ratios from DielsÁAlder reactions of 4
/
and 6 a
Fig. 1. Internal activation via boronic ester coordination.
the boronic ester was easily prepared in four steps from
phenylboronic acid (Scheme 1).
Nitration of phenylboronic acid [7] followed by
hydrogenation of the isolated ortho isomer [8] yielded
aminoboronic acid 2. Esterification of the boronic acid
with pinacol furnished boronate 3, which was reacted
with acryloyl chloride to provide acrylanilide 4. The
corresponding dienophile 6 lacking the boronate group
was also made as a reference compound [9] for a
qualitative comparison of relative reaction rates in a
Time (h)
6
4
s.m.:adduct
endo:exo
s.m.:adduct
endo:exo
1
6
No reaction
1:0.4
1:5
2.7:1
2.5:1
2.8:1
3.8:1
1.2:1
1:13
3.8:1
4.3:1
48
model DielsÁAlder reaction with cyclopentadiene.
/
a
Ratios of starting materials (s.m.) and cycloadducts were mea-
sured by 1H-NMR spectroscopy on the crude reaction mixtures.
2.2. Comparative kinetic studies
To probe the effect of the boronate substituent, the
[4ꢀ2] cycloaddition of dienophiles 4 and 6 with
/
cyclopentadiene was studied by measuring ratios of
1
starting materials to cycloadducts by H-NMR analysis
on crude reaction mixtures. Although dienophile 4 is
more sterically hindered, the data show that it does react
noticeably faster than 6 and with increased endo/exo
selectivity in the resulting adducts 5 (Table 1). These
results are consistent with a small self-activation effect
by internal coordination between the boronic ester and
the carbonyl group in dienophile 4. To rule out the
possibility that the activation may be due to the
electron-withdrawing effect of the boronate group on
the reactivity of the acrylamide dienophile, a competi-
tive kinetic experiment was performed whereby 4 and
the corresponding para-substituted isomer 8 were al-
lowed to react simultaneously with excess cyclopenta-
diene (Scheme 2). The proportion of components in the
reaction mixture showed the faster consumption and
Scheme 2.
conversion to cycloadducts of 4 compared to 6. This
result further confirms that self-activation by internal
coordination is operative in the case of ortho-substituted
dienophile 4.
2.3. Investigation of remote stereochemical induction in
the cycloadducts
We then turned our attention towards evaluating the
appealing possibility that internal coordination could
serve at communicating stereochemistry in a long-range
fashion. There are very few examples of remote stereo-
induction beyond a 1,7 relative relationship between the
Scheme 1.

J.W.J. Kennedy, D.G. Hall / Journal of Organometallic Chemistry 680 (2003) 263Á
/
270
265
inducing center and the reactive one [2]. In the present
case, 1,8-stereoinduction (as measured between the
closest carbon atoms in the dienophilic component
and the chiral boronate substituent in the absence of
coordination) could be transmitted via internal carbonyl
coordination to the boron atom. In this way, the
resulting tetrahedral boronate, rendered stereogenic at
boron, would involve a temporary situation of 1,4-
stereoinduction. We imagined that known diol boronate
auxiliaries such as pinanediol, 1,2-dicyclohexyl-1,2-etha-
nediol [10], 1,4-dimethoxy-1,1,4,4-tetraphenyl-2,3-buta-
nediol [11], and Hoffmann’s camphor-based diol [12]
could be tested. Thus, the chiral dienophiles 9, 11, and
12 (Fig. 2) were assembled from the corresponding free
boronic acids and enantiopure diols in a manner
analogous to 4.
Scheme 3.
Attempts to evaluate Hoffmann’s diol in this chem-
istry were not successful. The corresponding acrylanilide
13 was prepared in very low yield and, surprisingly, did
Table 2
Level of remote 1,8-stereoinduction in the DielsÁ
between 9Á
12 and cyclopentadiene a
/Alder reaction
not readily undergo DielsÁ/Alder reaction with cyclo-
/
pentadiene.
The novel methylated analogue of 9, pinanediol
boronate 10, was synthesized starting with the palla-
dium-catalyzed borylation of aryl bromide 14 [13],
followed by transesterification of the resulting boronic
ester 15 with pinanediol to give 16 (Scheme 3). The latter
intermediate was hydrogenated and reacted with acry-
loyl chloride to provide acrylamide dienophile 10 in
moderate yield.
Unfortunately, the level of 1,8-stereoinduction ob-
served in these compounds was quite low, and the
highest value of 28% diastereomeric excess originated
from the exo cycloadduct of dienophile 11 (Table 2).
The selectivities observed in the endo cycloadducts were
uniformly poor. The higher selectivity of the exo
addition pathway in the approach of cyclopentadiene
Dienophile Yield
endo:exob De (endo) (%)
De (exo) (%)
9
10
94
56
46
72
2.0:1
1.5:1
1.4:1
3.7:1
8
5
5
0
6
9
6
9
11
18
28
22
18
22
11 c
12
(100) d 1.7:1
12 e
12 f
(73) d
(85) d
1.9:1
2.4:1
(ꢁ
6) g
/
a
Dienophile and cyclopentadiene refluxed in toluene (0.1 M)
overnight with BHT except as noted.
b
Ratios of cycloadducts were measured from representative signals
by 1H-NMR spectroscopy on the crude reaction mixtures.
c
Reaction performed at room temperature in CH2Cl2 for 3 days.
d
Yields in brackets are percent conversions determined from 1H-
NMR spectroscopy of the crude mixture.
e
Reaction performed at room temperature.
Reaction performed at room temperature in CH2Cl2.
Preference is for the opposite isomer compared to the reaction in
f
g
toluene.
to the S-cis acrylamide is consistent with the higher
steric demand of the methylene unit compared to the flat
diene moiety. An inspection of the X-ray crystal
structure of dienophile 9, displayed as an ORTEP
diagram in Fig. 3, [14] may provide some insight
towards explaining these results. Although the 11B-
NMR data did not show evidence for strong coordina-
tion (perhaps it is a dynamic process in solution), in the
solid state structure the boronic ester is firmly coordi-
nated to the acrylanilide carbonyl to form a tetrahedral
boronate [15]. In this structure, the ester substituents
appear to be too distant from the dienophile to allow
effective transmission of stereochemistry. Specifically in
the case of 9, which provided diastereoselectivities below
10%, Fig. 3 shows that the bulkiest part of the
pinanedioxy group, the gem-dimethyl bridge, is oriented
Fig. 2. Chiral 2-boronoacrylanilides.

266
J.W.J. Kennedy, D.G. Hall / Journal of Organometallic Chemistry 680 (2003) 263Á270
/
3. Conclusion
This work shows that non-activated dialkoxyboronic
esters can operate as weak, internal Lewis acids and
activate carbonyl-containing functionalities towards
cycloaddition reactions. This moderate activation was
clearly shown to be a result of the internal coordination
of the carbonyl and the boron. This coordination was
also shown to exist in the solid state by X-ray crystal-
lography. We further showed that chiral boronates can
induce selectivity in these cycloadditions in an example
of 1,8-stereoinduction transmitted through a putative
tetrahedral stereogenic boronate complex. Even if the
observed diastereoselectivities were quite low, the fact
that an auxiliary which is so remote from the reaction
centre can have an effect at all is quite remarkable.
Although the current system would need to be rede-
signed in order to find general applicability, these results
validate this concept of internal activation and may pave
the way to significant advances in the future.
Fig. 3. X-ray structure of acrylanilide 9 [14].
away from the reaction center. This arrangement leaves
only the C3 hydrogen and the C2 methyl as discriminat-
ing groups for effecting diastereofacial selectivity. Inter-
estingly, this observation suggested that the replacement
of hydrogen for a bulkier group at C16 of the aromatic
ring (ortho to the boronic ester) could induce a
preference for a different boronate configuration. Such
an arrangement could place the bulk of the pinane
group syn to the acrylamide moiety, or at least tip over
the gem-dimethyl bridge closer to the reaction center to
potentially allow a more effective transfer of chirality. In
order to help in understanding the steric effect of the
4. Experimental
4.1. General
Tetrahydrofuran was distilled from sodium/benzo-
phenone ketyl. Toluene and CH2Cl2 were distilled over
CaH2. 2-Nitrophenylboronic acid and 4-aminophenyl-
boronic acid hydrochloride pinacol ester were purchased
from Combi-Blocks Inc. and used as received. 1,4-
Dimethoxy-1,1,4,4-tetraphenyl-2,3-butanediol was pre-
pared according to the literature procedure [11]. All
other chemicals were purchased from either the Aldrich
Chemical Company or Caledon Chemicals and used as
received. Thin layer chromatography data was per-
formed on Merck Silica Gel 60 F254 plates and were
visualized with UV light and 1% KMnO4(aq). NMR
spectra were recorded on Bruker AM 300, Bruker AM
200, Varian INOVA-300, INOVA-400 or INOVA-500
instruments. The residual solvent protons (1H) or the
solvent carbons (13C) were used as internal standards.
boronate ester on the diastereoselectivity of the DielsÁ
/
Alder reaction, qualitative molecular modeling analysis
of 9 and 10 was carried out based on the crystal
structure of 9 [16]. The resulting models showed that
while the added methyl group in 10 does indeed tip the
pinane-unit closer to the reaction centre, the effect is
very small and the chiral auxiliary remains quite remote
from the acrylamide (Fig. 4). Unfortunately, the experi-
mental results from the DielsÁAlder reaction of 10
/
clearly confirmed that this additional methyl group is
not sufficient to allow for high selectivities with these
substrates. Molecular modeling analysis of 11 and 12,
however, supported the experimental results showing
that these two chiral boronates were the most efficient
ones at providing steric discrimination between the two
faces of the dienophile component, with diastereomeric
excesses that were notably higher than those obtained
with boronates 9 and 10. The qualitative models of
boronates 11 and 12 show that the chiral auxiliaries are
significantly closer to the acrylamide unit than the
pinanediol moiety in boronates 9 and 10 (Fig. 4).
However, as with the other two chiral boronates, the
auxiliaries are still too far removed from the reaction
centre to induce high levels of selectivity.
Boron NMR spectra are referenced to external BF3×
/
1
OEt2. H-NMR data are presented as follows: chemical
shift in ppm downfield from Me4Si (multiplicity, cou-
pling constant, integration). The following abbrevia-
tions are used in reporting NMR data: s, singlet; br s,
broad singlet; d, doublet; t, triplet; ap t, apparent triplet;
dd, doublet of doublets; dt, doublet of triplets; AB, AB
quartet; m, multiplet. High resolution mass spectra were
recorded by the University of Alberta Mass Spectro-
metry Services Laboratory using either electron impact
(EI) ionization techniques. Infrared spectra were re-
corded by University of Alberta Spectral Services and
combustion analyses were performed by the University
of Alberta Micro-Analytical Lab.

J.W.J. Kennedy, D.G. Hall / Journal of Organometallic Chemistry 680 (2003) 263Á
/
270
267
Fig. 4. Molecular models of acrylanilides 9Á12 with atom numbering as per Fig. 3 [16].
/
4.2. Preparation of aminoarylboronic acids
tography (20% EtOAcÁ
product as a white solid (76%).
1H-NMR (400 MHz, CDCl3): d 7.68 (dd, Jꢂ
/
toluene, 160 g SiO2) to give the
/
7.4, 1.4
8.2 Hz,
4.2.1. 2-Aminophenylboronic acid, pinacol ester (3)
A solution of 2-aminoboronic acid 2 (1.68 g, 12.3
mmol) and pinacol (1.50 g, 12.6 mmol) in THF (120 ml)
was stirred under N2 overnight. The solvent was
removed and the residue was purified by flash chroma-
Hz, 1H), 7.26 (m, 1H), 6.72 (m, 1H), 6.63 (d, Jꢂ
/
1H), 4.76 (br s, 2H), 1.39 (s, 12H); 13C-NMR (100 MHz,
CDCl3): d 153.3, 136.3, 132.6, 116.5, 114.6, 110.2
(broad), 83.3, 24.6; IR (microscope): 3488, 3384, 2977,

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J.W.J. Kennedy, D.G. Hall / Journal of Organometallic Chemistry 680 (2003) 263Á270
/
1606, 1354 cmꢁ1
;
C12H BNO2 219.14307, found 219.14317.
HRMS (EI, m/z): Calc. for
(EI, m/z): Calc. for C36/
555.23687.
H1314
BNO4 555.25812, found
/
11
18
4.2.5. 2-Nitro-6-methylphenylboronic acid,
neopentylglycol ester (15)
4.2.2. 2-Aminophenylboronic acid, (ꢀ
As per 3, with 2-aminoboronic acid 2 (585 mg, 4.27
mmol) and (ꢀ)-pinanediol (811 mg, 4.76 mmol) in THF
(50 ml). Flash chromatography (20% EtOAcÁtoluene,
/
)-pinanediol ester
A slurry of bis(neopentyl glycolato)diboron (677 mg,
3.00 mmol), PdCl2(dppf)2, (56 mg, 0.069 mmol), dppf
(39 mg, 0.071 mmol) and KOAc (758 mg, 7.72 mmol) in
anhydrous dioxane (15 ml) under Ar was treated with 3-
nitro-2-bromotoluene 14 (553 mg, 2.56 mmol) and
heated at 80 8C for 2 days. The resulting dark mixture
was then diluted with toluene (50 ml), washed with brine
(50 ml), dried (Na2SO4) and evaporated to give the
crude product. Krugelrhro distillation (250 8C, 0.1 torr)
gave the product as a brown oil that solidified over time
(385 mg, 1.54 mmol, 60%).
/
/
40 g silica) gave the product as a white solid (1.03 g, 3.81
mmol, 89%).
1H-NMR (300 MHz, CDCl3): d 7.63 (d, Jꢂ
/
7.4 Hz,
7.3, 1H), 6.60
8.1 Hz, 1H), 4.69 (br s, 2H), 4.44 (dd, Jꢂ8.6, 1.1
1H), 7.22 (t, Jꢂ
/
8.2 Hz, 1H), 6.68 (t, Jꢂ
/
(d, Jꢂ
/
/
Hz, 1H), 2.40 (m, 1H), 2.22 (m, 1H), 2.14 (m, 1H), 1.99
(m, 1H), 1.94 (m, 1H), 1.48 (s, 3H), 1.31 (s, 3H), 0.89 (s,
3H); 13C-NMR (75 MHz, CDCl3): d 153.5, 136.7, 132.5,
116.7, 114.6, 110.4, 85.8, 77.7, 51.3, 39.4, 38.0, 35.5,
28.7, 27.0, 26.4, 23.9; IR (CH2Cl2 cast): 3487, 3388, 1605
1H-NMR (500 MHz, CDCl3): d 7.96 (dd, Jꢂ
8.3, 0.5
/
cmꢁ1; HRMS (EI, m/z): Calc. for C16
/
H1212
BNO2
/
Hz, 1H), 7.43 (m, 1H), 7.33 (m, 1H), 3.81 (s, 4H), 2.49 (s,
3H), 1.13 (s, 6H); 13C-NMR (125 MHz, acetone-d6): d
151.7, 142.8, 136.1, 130.0, 120.7, 73.0, 32.3, 22.5,
21.5;11B-NMR (64 MHz, acetone-d6): d 28.1; IR
271.17435, found 271.17466.
(CH2Cl2 cast): 2941, 1519, 1352, 1282 cmꢁ1; HRMS
4.2.3. 2-Aminophenylboronic acid, (ꢁ)-1,2-
/
11
H16BNO4 249.11723, found
dicyclohexyl-1,2-ethanediol ester
(EI, m/z): Calc. for C
249.11772.
/
12
/
As per 3, with 2-aminoboronic acid 2 (152 mg, 1.11
mmol), (ꢁ)-1,2-dicyclohexyl-1,2-ethanediol (282 mg,
1.25 mmol) and THF (10 ml). Flash chromatography
(10% Et2OÁhexane, 27 g silica, pre-absorption) gave the
product as a colourless oil (340 mg, 1.04 mmol, 93%).
1H-NMR (300 MHz, CDCl3): d 7.65 (dd, Jꢂ
7.5, 1.6
Hz, 1H), 7.23 (m, 1H), 6.88 (dt, Jꢂ7.2, 0.8 Hz, 1H),
6.61 (d, Jꢂ8.2 Hz, 1H), 4.65 (br s, 2H), 4.00 (d, Jꢂ5.3
0.8 (m,
/
4.2.6. 2-Nitro-6-methylphenylboronic acid, (ꢀ
pinanediol ester (16)
A solution of boronate 15 (48 mg, 0.19 mmol) and
(ꢀ)-pinanediol (44 mg, 0.26 mmol) in THF (2.5 ml) and
/
)-
/
/
/
/
water (1 ml) was stirred at room temperature (r.t.) under
Ar for 48 h. The mixture was then concentrated, diluted
with water (5 ml) and extracted with ether (3ꢃ5 ml).
The combined ether layers were washed with brine (5
ml), dried (Na2SO4) and evaporated to give the crude
product as an oil (106 mg). Flash chromatography (25%
/
/
Hz, 2H), 2.0Á
/
1.6 (m, 9H), 1.42 (m, 2H), 1.3Á
/
/
11H); 13C-NMR (75 MHz, CDCl3): d 153.6, 136.9,
132.7, 116.9, 114.8, 83.6, 43.0, 28.5, 27.5, 26.4, 26.0,
25.8; IR (CH2Cl2 cast): 3488, 3389, 1609, 754 cmꢁ1
;
H30BNO2 327.23697,
11
HRMS (EI, m/z): Calc. for C
found 327.23704.
/
20
/
EtOAcÁ
crystals (23 mg, 0.072 mmol, 38%) that were contami-
nated with Â2% of the initial boronate.
1H-NMR (400 MHz, CDCl3): d 7.99 (m, 1H), 7.45
(m, 1H), 7.37 (m, 1H), 4.56 (dd, Jꢂ8.9, 2.6 Hz, 1H),
2.50 (s, 3H), 2.45 (m, 1H), 2.28 (m, 1H), 2.14 (m, 1H),
11.4, 1H), 1.55 (s, 3H), 1.32 (s,
/hexanes, 5.6 g SiO2) gave the product as brown
/
4.2.4. 2-Aminophenylboronic acid, (2R,3R)-1,4-
dimethoxy-1,1,4,4-tetraphenyl-2,3-butanediol ester
/
2-Aminoboronic acid 2 (133 mg, 0.970 mmol) and
(2R,3R)-1,4-dimethoxy-1,1,4,4-tetraphenyl-2,3-butane-
diol (438 mg, 0.964 mmol) were refluxed in THF (5 ml)
˚
in the presence of 4 A molecular sieves under Ar for 2
days. The mixture was then filtered through silica and
concentrated to give the crude product. Flash chroma-
1.98 (m, 2H), 1.70 (d, Jꢂ
/
3H), 0.90 (s, 3H); 13C-NMR (125 MHz, CDCl3): d
151.3, 143.0, 135.2, 129.6, 120.4, 86.8, 78.4, 51.4, 39.7,
38.6, 35.4, 28.3, 27.1, 26.4, 24.3, 22.0;11B-NMR (64
MHz, acetone-d6): d 29.7; IR (CH2Cl2 cast): 2928, 1617,
tography (10% acetoneÁ
product as a colourless oil (408 mg, 0.735 mmol, 76%).
1H-NMR (500 MHz, CDCl3): d 7.40Á
7.20 (m, 21H),
7.07 (dt, Jꢂ8.2, 1.5 Hz, 1H), 6.47 (t, Jꢂ7.2 Hz, 1H),
6.39 (d, Jꢂ8.1 Hz, 1H), 5.45 (s, 2H), 4.15 (br s, 2H),
/
hexanes, 25 g SiO2) gave the
1349 cmꢁ1; HRMS (EI, m/z): Calc. for C17
315.16418, found 315.16508.
/
H1212
BNO4
/
/
/
/
4.3. Preparation of N-acryloylaminoarylboronic esters
/
2.98 (s, 6H); 13C-NMR (125 MHz, CDCl3): d 152.8,
141.5, 141.1, 136.6, 132.3, 129.5, 128.3, 127.8, 127.5,
127.4, 127.2, 116.5, 114.4, 83.5, 78.0, 52.0;11B-NMR (64
MHz, CDCl3): d 30.6; IR (CH2Cl2 cast): 3490, 3392,
3056, 2832, 1617, 1605, 1353, 757, 701 cmꢁ1; HRMS
4.3.1. N-Acryloylaniline 6
This compound was prepared as per the literature
1
procedure [9]. H-NMR (CDCl3, 300 MHz): d 7.58 (m,
2H), 7.31 (m, 2H), 7.18 (br s, 1H), 7.10 (m, 1H), 6.43 (d,
Jꢂ
/
17 Hz, 1H), 6.25 (dd, Jꢂ17, 10.2 Hz, 1H), 5.78 (d,
/

J.W.J. Kennedy, D.G. Hall / Journal of Organometallic Chemistry 680 (2003) 263Á
/
270
269
Jꢂ
/
10 Hz, 1H); 13C (CDC13, 75 MHz): d 164.0, 140.2,
132.8, 129.5, 126.9, 124.4, 120.3.
1667, 1635, 1593, 1361, 860 cmꢁ1; HRMS (EI): Calc.
11
H20BNO3 273.15363, found 273.15381.
for C /
15
/
4.3.2. 2-N-Acryloylaminophenylboronic acid, pinacol
ester (4)
4.3.4. 2-N-Acryloylaminophenylboronic acid, (ꢀ
pinanediol ester (9)
/
)-
A solution of aniline 3 (296 mg, 1.35 mmol), pyridine
(0.22 ml, 2.7 mmol) and DMAP (42 mg, 0.34 mmol) in
THF (5 ml) at 0 8C was treated dropwise with a solution
of acryloyl chloride (152 mg, 1.68 mmol) in THF (2.5
ml). After 1 h the mixture was warmed to r.t. and left to
stir for 4 h. The thick white slurry was then partitioned
between brine (20 ml) and THF (20 ml). The layers were
separated and the aqueous layer was extracted with
As per 4, with the aniline (613 mg, 226 mmol),
pyridine (0.37 ml, 4.5 mmol), and DMAP (29 mg, 0.24
mmol) in THF (25 ml), and acryloyl chloride (243 mg,
2.69 mmol) in THF (5 ml). Once the reaction was
complete, the mixture was diluted with brine (25 ml) and
the layers were separated. The aqueous layer was then
extracted with THF (3ꢃ
layers were then washed with 0.1 M H2SO4Á
ml), saturated NaHCO3, (2ꢃ20 ml) and brine (20 ml),
/25 ml). The combined THF
/
brine (10
THF (3ꢃ
/
10 ml). The combined organic layers were
/
dried (Na2SO4) and evaporated to give a light brown
solid which was dried under vacuum overnight to give
the product (181.3 mg, 49%).
dried (Na2SO4) and evaporated to give the crude
product as a white solid (619 mg, 1.90 mmol, 84%).
1H-NMR (300 MHz, C6D6): 9.73 (br s, 1H), 9.16 (d,
1H-NMR (acetone-d6, 400 MHz): d 10.34 (br s, 1H),
Jꢂ
Jꢂ
Jꢂ
5.29 (dd, Jꢂ
/
8.4 Hz, 1H), 8.06 (dd, Jꢂ
8.8, 1.5 Hz, 1H), 6.93 (t, Jꢂ
17.0, 1.0 Hz, 1H), 6.17 (dd, Jꢂ
10.4, 1.1 Hz, 1H), 4.09 (dd, Jꢂ
/
7.4, 1.2 Hz, 1H), 7.29 (dd,
7.4 Hz, 1H), 6.40 (dd,
17.0, 10.3 Hz, 1H),
8.5, 1.6 Hz,
8.06 (m, 1H), 7.67 (d, Jꢂ
/
8 Hz, 1H), 7.37 (m, 1H), 7.10
7,
/
/
(apparent t, Jꢂ 8 Hz, 1H), 6.38 (m, 2H), 5.82 (dd, Jꢂ
/
/
/
/
5 Hz, 1H), 1.38 (s, 12H);13C-NMR (acetone-d6, 100
MHz): d 164.1, 143.6, 136.0, 135.9, 132.2, 131.8, 131.7,
127.9, 127.8, 124.6, 124.5, 119.0, 84.1, 84.0, 25,6, 25.5;
13C-NMR (benzene-d6, 100 MHz): d 163.2, 145.3, 136.4,
133.1, 132.8, 125.8, 123.4, 119.6, 83.9, 24.8. A very slight
peak duplication effect, ca. 0.05 ppm, was observed for
arene carbons in acetone. This duplication may be due
to a slow competing effect from this coordinating
solvent; 11B-NMR (benzene-d6, 64 MHz): d 30.1; IR
/
/
1H), 2.04 (m, 1H), 2.00 (m, 1H), 1.94 (m, 1H), 1.79 (m,
1H), 1.57 (m, 1H), 1.19 (s, 3H), 1.14 (m, 1H), 1.03 (s,
3H), 0.49 (s, 3H); 13C-NMR (125 MHz, C6D6): d 163.2,
145.4, 136.6, 133.4, 132.9, 125.9, 123.4, 119.8, 86.6, 78.2,
51.6, 39.7, 38.0, 35.5, 28.6, 26.9, 26.6, 23.8; 11B-NMR
(64 MHz, C6D6): d 30.4; IR (CH2Cl2 cast): 3362, 3054,
2924, 1644, 1628, 1050, 735 cmꢁ1; HRMS (EI, m/z):
11
H24BNO3 325.18494, found 325.18508.
Calc. for C
/
19
/
(CH2Cl2 cast): 3316, 3058, 2970, 1646, 731 cmꢁ1
;
20BNO3 273.15363, found
11
HRMS (EI): Calc. for C
273.15376.
/H
15
/
4.3.5. 2-N-Acryloylamino-6-methylphenylboronic acid,
(ꢀ)-pinanediol ester (10)
/
Nitro compound 16 (36 mg, 0.11 mmol) was hydro-
genated in a Parr bottle over 10% Pd/C (4 mg) in EtOH
(2 ml) at r.t. under 45 psi H2 for 4 h. The mixture was
filtered through Celite† and the pad was washed with
4.3.3. 4-N-Acryloylaminophenylboronic acid, pinacol
ester (8)
A slurry of 4-aminophenylboronic acid hydrochloride
pinacol ester (524 mg, 2.05 mmol), Et3N (0.85 ml, 6.1
mmol) and DMAP (45 mg, 0.37 mmol) in THF (7.5 ml)
at 0 8C was treated dropwise with a solution of acryloyl
chloride (1.9 ml, 2.3 mmol) in THF (2.5 ml). The
resulting mixture was stirred at 0 8C for 2 h and then
at r.t. overnight. The thick mixture was then diluted
with brine (25 ml) and water was added to make the
mixture homogenous. The layers were separated and the
EtOH (5ꢃ1 ml). The combined alcohol filtrates were
/
evaporated to give the crude aniline (31 mg, 94%) as a
yellow oil. This oil was dissolved in THF (0.8 ml),
cooled to 0 8C and treated successively with DMAP (8
mg, 0.07 mmol), pyridine (25 ml, 0.30 mmol) and
acryloyl chloride (16 ml, 0.20 mmol). The thick mixture
was then stirred at. r.t. for 90 min. It was then diluted
with brine (2 ml) and extracted with THF (4ꢃ2 ml).
/
aqueous phase was extracted with THF (3ꢃ
combined organic extracts were washed with brine (25
ml), dried (MgSO4,) and evaporate. Flash chromato-
/
25 ml). The
The combined organic extracts were washed with brine
(2 ml), dried (Na2SO4) and evaporated to give the crude
product (35 mg). Flash chromatography (5% EtOAcÁ
/
graphy (20% EtOAcÁ
product as a white solid (0.38 g, 1.4 mmol, 68%).
1H-NMR (acetone-d6, 300 MHz): d 7.75 (AB, Jꢂ
Hz, 2H), 7.68 (AB, Jꢂ9 Hz, 2H), 6.46 (dd, Jꢂ17, 10
Hz, 1H), 6.34 (dd, Jꢂ16, 3 Hz, 1H), 5.70 (dd, Jꢂ10, 3
/
toluene, 51 g SiO2) gave the pure
toluene, 16 g SiO2) and Krugelrhro distillation (250 8C,
0.1 torr) gave the pure product (15 mg, 0.045 mmol,
40%).
/
9
/
/
1H-NMR (500 MHz, acetone-d6): d 9.88 (br s, 1H),
/
/
7.81 (m, 1H), 7.24 (ap t, Jꢂ
Hz, 1H), 6.34 (m, 2H), 5.78 (dd, Jꢂ
4.53 (dd, Jꢂ8.7, 1.9 Hz, 1H), 2.52 (s, 3H), 2.46 (m, 1H),
2.22 (m, 1H), 2.12 (m, 1H), 2.1Á1.9 (m, 2H), 1.52 (s,
3H), 1.44 (m, 1H), 1.31 (s, 3H), 1.30 (m, 1H), 0.93 (s,
/
7.7 Hz, 1H), 6.94 (d, Jꢂ
/7.5
Hz, 1H), 1,31 (s, 12H); 13C-NMR (acetone-d6, 100
MHz): d 164.1, 142.8, 136.3, 136.2 (broad), 132.7,
127.4, 119.2, 84.3, 25.2; 11B-NMR (benzene-d6, 64
MHz): d 30.8; IR (CH2Cl2 cast): 3303, 3102, 2978,
/
8.4, 3.4 Hz, 1H),
/
/

270
J.W.J. Kennedy, D.G. Hall / Journal of Organometallic Chemistry 680 (2003) 263Á270
/
3H); 13C-NMR (100 MHz, CDCl3): d 163.5, 146.2,
144.6, 132.6, 131.6, 126.2, 126.0, 117.6, 86.3, 77.6, 51.4,
39.6, 38.2, 35.5, 28.7, 27.0, 26.5, 24.0, 23.4; 11B (64 MHz,
acetone-d6): d 30.0; IR (CH2Cl2 cast): 2915, 1640, 1627
J.K. thanks NSERC and the Alberta Heritage Founda-
tion for Medical Research (AHFMR) for graduate
scholarships. The authors thank Mr. Juan Venegas for
the preparation of some acrylamide substrates, Mr.
Glen Bigam for help in NMR studies, and Dr. Bob
McDonald for X-ray crystallographic analysis.
cmꢁ1; HRMS (EI, m/z): Calc. for C20
/
H1216
BNO3
/
339.20056, found 339.20054.
4.3.6. 2-N-Acryloylaminophenylboronic acid, (ꢁ
/
)-1,2-
dicyclohexyl-1,2-ethanediol ester(11)
As per 4, with the aniline (211 mg, 0.646 mmol),
pyridine (0.10 ml, 1.2 mmol), and DMAP (catalytic
amount) in THF (6 ml), and acryloyl chloride (73 mg,
0.80 mmol) in THF (1 ml). Work-up gave the product as
an off white solid (188 mg, 0.510 mmol, 79%).
References
[1] For recent examples, see: (a) K. Krohn, J. Michcel, M. Zukowski,
Tetrahedron 56 (2000) 4753Á
(b) D.S. Larsen, M.D. O’Shea, J. Chem. Soc. Perkin Trans.1
(1995) 1019Á1028. For an example involving a chiral borate ester;
(c) T.R. Kelly, A. Whiting, N.S. Chandrakumar, J. Am. Chem.
Soc. 108 (1986) 3510Á3512.
[2] K. Mikami, M. Shimizu, H.-C. Zhang, B.E. Maryanoff, Tetra-
hedron 57 (2001) 2917Á2951.
/4758;
1H-NMR (300 MHz, CDCl3,): d 9.56 (br s, 1H), 8.56
/
(d, Jꢂ
Jꢂ7.7 Hz, 1H), 7.10 (ap t, Jꢂ
16.5 Hz, 1H), 6.20 (dd, Jꢂ16.8, 9.9 Hz, 1H), 5.72 (d,
Jꢂ10.4 Hz, 1H), 4.08 (d, Jꢂ4.2 Hz, 2H), 2.0Á1.0 (m,
22Hꢀ
Hydrocarbon impurities); 13C-NMR (75 MHz,
/
7.8 Hz, 1H), 7.79 (d, Jꢂ/7.6 Hz, 1H), 7.45 (ap t,
/
/
/
7.5 Hz, 1H), 6.40 (d, Jꢂ
/
/
/
/
/
/
[3] For selected examples of remote asymmetric induction using
/
chiral boronates, see: (a) H.E. Sailes, J.P. Watts, A. Whiting, J.
CD2Cl2): d 163.6, 135.7, 131.6, 131.0, 128.0, 124.5,
118.9, 84.4, 75.4, 43.5, 40.8, 30.1, 29.6, 28.6, 28.2, 26.9,
26.7, 26.5, 26.4; 11B-NMR (64 MHz, C6D6): d 29.6; IR
Chem. Soc. Perkin Trans. 1 (2000) 3362Á
(b) G.A. Molander, K.L. Bobbitt, J. Am. Chem. Soc. 115 (1993)
7517Á7518;
/
3374;
/
(Microscope) 3278, 1647, 1575 cmꢁ1; HRMS (EI, m/z):
For a receptor-system based on internal activation by a boronic
11
H32BNO3 381.24753, found 381.24790.
ester, see: (c): M.P. Hughes, B.D. Smith, J. Org. Chem. 62 (1997)
Calc. for C
/
23
/
4492Á/4499.
[4] D.S. Matteson, P.G. Allies, J. Organomet. Chem. 54 (1973) 35Á
/
4.3.7. 2-N-Acryloylaminophenylboronic acid, (2R,3R)-
1,4-dimethoxy-1,1,4,4-tetraphenyl-2,3-butanediol ester
(12)
A solution of the aniline (346 mg, 0.624 mmol),
pyridine (100 ml, 1.24 mmol), and DMAP (l5 mg, 0.12
mmol) in THF (3 ml) at 0 8C was treated slowly with
acryloyl chloride (55 ml, 0.68 mmol). The resulting
mixture was stirred as 0 8C for 1 h then at r.t. for 4 h
before being worked-up as per 4. Flash chromatography
50.
[5] Diaryloxy or acyloxy boronic ester catalysts are more acidic and
have been used in several catalysts for asymmetric synthesis. For a
noticeable example on a dialkoxyboronic ester catalyst based on a
tartrate substituent, see: T.-P. Loh, R.-B. Wang, K.-Y. Sim,
Tetrahedron Lett. 37 (1996) 2989Á2992. Tartrate boronic esters,
/
however, are considered moderately activated by the electron-
withdrawing ester groups.
[6] J.W.J. Kennedy, D.G. Hall, Synlett (2002) 477Á
[7] W. Scaman, J.R. Johnson, J. Am. Chem. Soc. 53 (1931) 711Á
[8] M.P. Groziak, A.D. Ganguly, P.D. Robinson, J. Am. Chem. Soc.
116 (1994) 7597Á7605.
[9] L.S. Hegedus, G.F. Allen, D.J. Olsen, J. Am. Chem. Soc. 102
(1980) 3583Á3587.
[10] D.S. Matteson, H.-W. Man, J. Org. Chem. 58 (1993) 6545Á
[11] J.E.A. Luithle, J. Pietruszka, J. Org. Chem. 64 (1999) 8287Á
/479.
/
723.
(20 g SiO2, 5% EtOAcÁ
colourless glass (209 mg, 0.343 mmol, 55%).
1H-NMR (500 MHz, C6D6): d 9.06 (d, Jꢂ
1H), 8.70 (br s, 1H), 7.48 (m, 9H), 7.2Á6.9 (m, 13H),
6.68 (dt, Jꢂ7.4, 1.0 Hz, 1H), 6.31 (dd, Jꢂ16.8, 1.6 Hz,
1H), 5.78 (s, 2H), 5.46 (dd, Jꢂ16.8, 10.2 Hz, 1H), 5.17
(dd, Jꢂ
10.3, 1.7 Hz, 1H), 2.96 (s, 6H); 13C-NMR (100
/toluene) gave the product as a
/
/8.3 Hz,
/
/
/
6547.
8297.
/
/
/
[12] T. Herold, U. Schrott, R.W. Hoffmann, G. Schnelle, W. Ladner,
K. Steinbach, Chem. Ber. 114 (1981) 359Á374.
[13] (a) T. Ishiyama, M. Murata, N. Miyaura, J. Org. Chem. 60 (1995)
7508Á7510;
(b) T. Ishiyama, Y. Itoh, T. Kitano, N. Miyaura, Tetrahedron
Lett. 38 (1997) 3447Á3450.
/
/
/
MHz, CDCl3): d 163.3, 143.6, 140.6, 140.2, 135.8, 132.5,
131.8, 129.6, 128.3, 128.0, 127.8, 127.6, 127.5, 126.5,
122.8, 119.1, 83.4, 78.5, 51.9; 11B-NMR (64 MHz,
CDCl3): d 30.5; IR (CH2Cl2 cast): 3377, 3057, 2938,
/
/
[14] X-ray crystallographic data have been deposited to the Cam-
bridge Crystallographic Data Centre (file number: CCDC
166880).
1693, 1611, 1348, 760, 701 cmꢁ1; HRMS (EI, m/z):
11
H36BNO5 609.26868, found 609.26921.
Calc. for C
/
39
/
[15] D.S. Matteson, T.J. Michnick, R.D. Willett, C.D. Patterson,
Organometallics 8 (1989) 726Á729.
/
[16] Starting structures used in the molecular modeling calculations
were drawn in ChemDraw Ultra (version 7.0.1) using the X-ray
structure of compound 9 as a guide. The structures were then
imported into Chem3D Pro (version 5) and minimized using the
MM2 force field.
Acknowledgements
This work was funded by the Natural Sciences and
Engineering Research Council (NSERC) of Canada.