Efficient preparation of 2-aminomethylbiphenyls via suzuki-miyaura reactions

Article abstract of DOI:10.1055/s-0030-1258554

We prepared four 2-(aminomethyl)arylboronic acids and studied their reactivity in the Suzuki-Miyaura coupling reaction with different aryl halides. We observed significant increases in yields and shorter reaction times when the amine adjacent to the boron

Full text of DOI:10.1055/s-0030-1258554

LETTER
2449
Efficient Preparation of 2-Aminomethylbiphenyls via Suzuki–Miyaura
Reactions
Preparation of
i
2-Ami
e
nomethylbi
rphenylsre-Luc Boudreault, Sébastien Cardinal, Normand Voyer*
Département de Chimie and PROTEO, Université Laval, Pavillon Alexandre-Vachon, Faculté des Sciences et de Génie,
1045 Avenue de la Médecine, Québec, QC, G1V OA6, Canada
Fax +1(418)6567916; E-mail: normand.voyer@chm.ulaval.ca
Received 8 June 2010
examples of Suzuki–Miyaura cross-coupling reactions us-
ing boronic acid and ester derivatives like structures 1–4
(Figure 1) described in the literature.6,7,10–14 We now re-
port the results of our study on the efficient preparation of
Abstract: We prepared four 2-(aminomethyl)arylboronic acids and
studied their reactivity in the Suzuki–Miyaura coupling reaction
with different aryl halides. We observed significant increases in
yields and shorter reaction times when the amine adjacent to the bo-
ronic acid was protected by a tert-butyloxycarbonyl (t-Boc) group. o-aminomethylbiphenyls.
We then investigated the origin of the greater reactivity of N-t-Boc-
protected substrates with regard to the potential role of an N–B
bond.
In the study with boronic acids 1–4, we used aryl halides
with electron-withdrawing and electron-donating groups
at the para position as coupling partners. The results are
shown in Table 1.
Key words: Suzuki–Miyaura cross-coupling, biaryls, (aminometh-
yl)arylboronic acids, N–B dative bond
Table 1 Suzuki–Miyaura Coupling Reactions of 1–4
R1
There has recently been a steady stream of new develop-
ments and refinements reported about the application of
the Suzuki–Miyaura coupling reaction.
X
N
R2
R3
Pd(PPh3)4 (2 mol%), NaOH
+
During the course of our investigation on the synthesis of
natural products, we decided to use a retrosynthetic strat-
egy that employs a Suzuki–Miyaura coupling between 2-
(aminomethyl)arylboronic acids and aryl halides and
leads to 2-aminomethylbiphenyls. Aside from being
found in many types of organic compounds,1,2 the struc-
tural motifs derived from the 2-aminomethylbiphenyl
moiety are present in several natural and bioactive prod-
ucts.3–5
toluene, 100–110 °C
R3
1–4
Entry Substrate R1
R2
R3
X
Product Isolated
yield (%)
1
2
1
1
1
1
2
2
2
2
3
3
3
3
4
4
4
4
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
Br
I
5
5
25
37
75
23a
63
65
76
48
98
96
94
94
97
99
97
97
H
H
3
H
NO2
Br
6
Despite the importance of these motifs, there are only a
few examples of studies of aryl–aryl coupling leading to
2-aminomethylbiphenyl derivatives.6,7 In most cases, the
aminomethylbiphenyl unit was obtained by a multistep
synthesis, such as a C–C coupling reaction followed by
SN2 reactions,8 reductive amination,8 and/or reduction9 of
the corresponding functional group. There are also a few
4
H
OMe Br
7
5
Me
Me
Me
Me
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
H
Br
I
8
6
H
8
7
NO2
Br
9
8
OMe Br
10
11
11
12
13
14
14
15
16
Me
Me
Me
9
H
Br
I
N
N
H
10
11
12
13
14
15
16
H
H
B
OH
B
OH
OH
OH
H
NO2
Br
2
1
Boc
H
OMe Br
Boc
N
N
H
Me
Me
Me
Me
Me
H
Br
I
B
OH
B
OH
OH
OH
H
3
4
NO2
Br
Figure 1 Structures of the four boronic acids that we studied
OMe Br
a 75% purity by analytical HPLC.
SYNLETT 2010, No. 16, pp 2449–2452
x
x
.x
x
.2
0
1
0
Advanced online publication: 03.09.2010
DOI: 10.1055/s-0030-1258554; Art ID: S03210ST
© Georg Thieme Verlag Stuttgart · New York

2450
P.-L. Boudreault et al.
LETTER
When we used primary and secondary amine boronic ac-
ids 1 and 2, yields were modest and reactions proceeded
slowly (entries 1–8). It is well established that electron-
rich aromatic systems, specifically those with an electron-
donating group in the para position, are generally less sus-
ceptible to oxidative addition.15 As expected, results ob-
tained with the methoxy-substituted system (entries 4 and
8) showed an even slower reaction rate and led to lower
yields of biaryl products with boronic acids 1 and 2. GC-
MS analysis revealed that the consumption of starting ma-
terials was not complete, even after prolonged reaction
times (up to 48 h). We also observed the formation of de-
boronation byproducts, the loss of the methoxy group in
some cases, but only a small amount of homocoupling
byproduct (<2%). Using an aryl iodide instead of an aryl
bromide accelerated the reactions and led to modest in-
creases in yields (see entries 1 vs. 2 and 5 vs. 6).
Figure 2 ORTEP X-ray crystal structure of boronic acid 1, showing
50% probability ellipsoids
As expected, the N–B dative bond is not observed in the
crystal structure of boronic acid 3 (Figure 3). As shown by
the short N–C bond (1.33 Å), the lone electron pair of the
nitrogen is involved in a partial double bond within the
carbamate and is unavailable to coordinate with the boron
atom. Interestingly, compound 3 crystallized as a dimer
stabilized by hydrogen bonds between the trigonal boron-
ic acid group.
However, when N-Boc-protected boronic acid substrates
3 or 4 were used, the reactions were much faster (<1 h
compared with up to 48 h for 1 and 2). Yields were higher
than 94% in all cases. This comparison of the results ob-
tained with boronic acids 1 and 2 vs. 3 and 4 clearly illus-
trates the influence of the adjacent N atom lone pair on the
outcome of the Suzuki–Miyaura reaction. To get a better
understanding of the results, we investigated the possible
interaction between the N and B atoms.
The boronic acid functional group is frequently incorpo-
rated into synthetic receptors for recognition of diols and
secondary and tertiary amines; complexes of boronic ac-
ids have been extensively studied.5,16,17 Wulff has demon-
strated that the incorporation of an amine adjacent to the
boronic acid creates a tetrahedral sp3 boron, where the
lone pair on the nitrogen associates with the empty p or-
bital on the boron to form a dative bond.18,19 The presence
of such bonds surely affects the acidic character of the bo-
ron, and concomitantly, its electrophilicity.20 On that ba-
sis, we investigated the relationship between the reactivity
of 1–4 and the N–B coordination.
We used two methods to observe the extent of N–B dative
bond formation: X-ray crystallography and 11B NMR
spectroscopy.
To confirm the geometry of the boronic acid, we obtained
an X-ray structure of structures 1 and 3 with crystals from
CDCl3 solution. The structure of 1 shows that this com-
pound co-crystallizes with cyclotrimeric anhydride
(Figure 2). To the best of our knowledge, such a co-crys-
tallization pattern has not yet been observed for this type
of compound. However, analogous trimerized cyclic bo-
ronic anhydride is a structural motif often found for bo-
ronic acids.20–22 In the cyclic form of 1, the boron atom is
tetrahedral and coordinated with the nitrogen to form a da-
tive bond. The N–B bond length is about 1.75 Å in the bo-
ronic acid and in two of the three N–B interactions.
However, in the last N–B bond, the stronger nature of the
interaction is evident by a shorter N–B length of 1.67 Å,
which is comparable to the one observed with the dietha-
nolamine adduct of phenylboronic acid.23
Figure 3 ORTEP X-ray crystal structure of boronic acid 3, showing
50% ellipsoids
Internal hydrogen bonds were also observed between the
B–OH group and the carbamate C=O. We were unable to
obtain good quality diffraction crystals for compound 4,
but it is reasonable to believe that the boron atom of 4 is
not involved in bonding with the nitrogen lone electron
pair.
Interaction in solution between the boron and nitrogen at-
oms may be evaluated by 11B NMR chemical
shift.20,21,24,25 Toyota et al. reported the presence of N–B
coordination bond in the boronic ester derivative of 2 and
showed that the dissociation of the dative bond proceed by
Synlett 2010, No. 16, 2449–2452 © Thieme Stuttgart · New York

LETTER
Preparation of 2-Aminomethylbiphenyls
2451
a SN2-type mechanism.26 A sp2 trigonal, uncoordinated current methodology provides an efficient way to produce
boron NMR signal and a tetragonal sp3-coordinated signal useful intermediates. We are currently working to exploit
with an amine are approximately d = 30 and 15 ppm, re- this versatile synthetic method to prepare useful biphenyl
spectively.20 As shown in Table 2, the 11B NMR chemical derivatives.
shift of boronic acids 1 and 2 indicates that the boron atom
is tetracoordinated in solution. Boronic acid 1 displays a
Supporting Information for this article is available online at
signal at d = 12.3 ppm, while 2 displays a signals at d = 4.6
http://www.thieme-connect.com/ejournals/toc/synlett.
ppm.
Table 2 11B NMR Chemical Shift of Boronic Acids 1–4 in CDCl3
Acknowledgment
Compound
11B NMR (d, ppm, 128.34 MHz)
We wish to thank Professor Frederic-Georges Fontaine for his X-
ray crystallography experiments and also Mr. Pierre Audet for his
technical assistance with the NMR experiments. This work was
supported by NSERC of Canada, FQRNT of Quebec, and Universi-
té Laval. PLB and SC thank the NSERC of Canada for postgraduate
sholarships.
1
2
3
4
12.3
4.6
34.4
31.2
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thons for the preparation of functionalized 2-
aminomethylbiphenyl derivatives. The presence of a pro-
tonable N atom adjacent to the boronate was shown to de-
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Synlett 2010, No. 16, 2449–2452 © Thieme Stuttgart · New York

2452
P.-L. Boudreault et al.
LETTER
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Synlett 2010, No. 16, 2449–2452 © Thieme Stuttgart · New York