Combining Copper-Catalyzed Hydroboration with Palladium-Catalyzed Suzuki Coupling for the One-pot Synthesis of Arylallylamines under Micellar Conditions

Article abstract of DOI:10.1002/adsc.201700094

Herein we report the one-pot dual-metal catalytic synthesis of arylallylamines, by combination of a Cu-catalyzed hydroboration with a Pd-catalyzed Suzuki arylation, using a broad range of aryl halides. Importantly, the reaction sequence was entirely performed in water, in the presence of small amounts of SPGS-550M, without the need of solvent switch or addition of organic co-solvents, rendering it operationally simple and environmentally benign. The usefulness of this methodology was highlighted in a short synthesis of the pharmaceutically important compound naftifine. (Figure presented.).

Full text of DOI:10.1002/adsc.201700094

Title: Combining Cu-Catalyzed Hydroboration with Pd-Catalyzed
Suzuki Coupling for the One-pot Synthesis of Arylallylamines
under Micellar Conditions
Authors: Pedro Horn, Roger Braun, Victória Isoppo, Jessie da Costa,
Diogo Lüdtke, and Angélica Moro
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700094
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10.1002/adsc.201700094
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Combining Copper-Catalyzed Hydroboration with Palladium-
Catalyzed Suzuki Coupling for the One-pot Synthesis of
Arylallylamines under Micellar Conditions
Pedro A. Horn,a,§ Roger K. Braun,a,§ Victória G. Isoppo,a Jessie S. da Costa,a Diogo S.
Lüdtke,a and Angélica V. Moroa,*
a
Institute of Chemistry, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves 9500, 91501-970, Porto
Alegre, RS, Brazil.
Phone: +55 51 33089637; Fax: +55 51 3308 6259
E-mail: angelica.venturini@ufrgs.br
These authors contributed equally
§
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201
Abstract. Herein we report the one-pot dual-metal catalytic
synthesis of arylallylamines, by combination of a Cu-
catalyzed hydroboration with
a Pd-catalyzed Suzuki
arylation, using a broad range of aryl halides. Importantly,
the reaction sequence was entirely performed in water, in
the presence of small amounts of SPGS-550M, without the
need of solvent switch or addition of organic co-solvents,
rendering it operationally simple and environmentally
benign. The usefulness of this methodology was
highlighted in a short synthesis of the pharmaceutically
important compound naftifine.
Keywords: naftifine; tandem reactions; dual-metal
catalysis; catalysis in water; one-pot synthesis
Figure 1. Structures of biologically active arylallylamines.
Arylallylamines have been prepared by different
strategies including Petasis reaction using
vinylboronic acids,[6] one-pot oxidation of a primary
alcohol, followed by reductive amination,[7] Cu-
catalyzed hydroamination of allenes,[8] Fe-catalyzed
cross-coupling of Grignard reagents with vinyl
chlorides,[9] Lewis acid-catalyzed N-allylation of
electron deficient amides with aldehydes and non-
activated alkenes,[10] Pd-catalyzed amination of
allylic alcohols in surfactant/water,[11] and Pd-
catalyzed arylation of zincated N-Boc-allylamines.[12]
Another interesting approach to these molecules uses
the Pd-catalyzed Heck[13] and Heck-Matsuda
arylation of allylamines.[5],[14] Using this method,
branched or linear arylated compounds can be
obtained, but typically the use of one or even two
strongly electron-withdrawing N-protecting groups,
that attenuate the basicity and coordinating ability of
the nitrogen, is necessary for the reaction to occur
and to achieve good levels of regioselectivity.
Interestingly, the Pd-catalyzed Suzuki, which is a
powerful tool for the synthesis of biologically active
Introduction
The γ-arylallylamine is a structural motif present in a
number of biologically relevant molecules that
display a broad spectrum of bioactivities (Figure 1).
For example, naftifine (1) is a commercially available
antifungal agent whose mechanism of action involves
blocking of sterol biosynthesis by inhibiting the
enzyme squalene epoxidase.[1] Moreover, it has been
recently discovered that naftifine attenuated the
virulence of a variety of clinical Staphylococcus
aureus isolates, including methicillin-resistant S.
aureus (MRSA).[2] Additional examples include
abamine SG 2, which is a inhibitor of 9-cis-
epoxycarotenoid dioxygenase, an enzyme involved in
the biosynthesis of abscisic acid,[3] cinnarizine (3) and
flunarizine (4) that are calcium channel blockers and
have been prescribed as drugs for the treatment of
nausea, migraine, and vascular diseases.[4] Recently,
the arylated allylamine 5 was found to be a adenylyl
cyclase inhibitor potentially useful for treatment of
neuropathic and inflammatory pain.[5]
1
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10.1002/adsc.201700094
Advanced Synthesis & Catalysis
and pharmaceutical compounds,[15] has been scarcely
used[16] for the synthesis of this class of compounds.
Recently we have reported the regioselective Cu-
catalyzed hydroboration of propargyl-functionalized
alkynes under aqueous micellar conditions (Scheme
1A).[17],[18] Typically, the reaction was performed
using either a NHC-Cu complex as the catalyst to
afford the -arylated product or a Cu(OAc)2/dppe
catalytic system to obtain preferentially the -
Given the importance of arylated allylamines and
encouraged by our successful preliminary results on
the combination of the Cu-catalyzed hydroboration of
propargylamines with
a
Pd-catalyzed Suzuki
arylation[20],[21] using water as the solvent, we
hypothesized that broadening of the scope of the aryl
halide used in the Suzuki coupling might result in a
general, straightforward and environmentally friendly
synthesis of a series of these valuable compounds
(Scheme 1C).[22] Herein, we report our results of our
study, using a variety of aryl halides as coupling
partners. Among the advantages of our protocol are
the operationally simplicity of the reaction setup,
without the need of inert atmosphere or anhydrous
conditions and importantly, the development of a
tandem process without isolation of intermediate
compounds that obviates even more the use of
organic solvents, maximizing the efficiency and
minimizing the waste generated. In addition, we have
applied our method in a short three-step, one-pot, and
borylated
product.
Interestingly,
NMeBn-
propargylamine and NHBoc-propargylamine resulted
in different selectivities using the NHC-Cu catalyst.
The potential usefulness of the developed method in
two sequential metal-catalyzed reactions was briefly
examined, and two examples of an one-pot
hydroboration/Suzuki reaction have been reported
(Scheme 1A). Key to the success of our protocol was
the use of SPGS-550M (Scheme 1B),[19] a surfactant
that enabled the desired transformation to occur
without using organic solvents despite using water-
insoluble reagents.
environmentally
benign
synthesis
of
the
pharmaceutically relevant compound naftifine (1),
starting from commercially available amine 6.
Results and Discussion
We started our studies investigating the Cu-
catalyzed
hydroboration
of
a
range
of
propargylamines (Table 1). We performed the
hydroboration under our previously developed
conditions,[17] using 5 mol% of [Cu(Cl)(IMes)], 1.1
equiv of B2pin2 as the boron source, 5 mol% of
NaOH as the base and SPGS-550M/water as the
solvent.[23] From our previous work we have already
observed that propargylamine and N,N-dimethyl-
propargylamine are not suitable substrates for the
hydroboration, since in both cases only small
amounts of the borylated product were observed in
the crude mixture, probably due to
a
fast
protodeborylation reaction. Moreover, as already
observed by Hoveyda, the instability of the product
prevented its isolation.[24] Much improved results
were found by N,N-methylbenzyl-propargylamine
and gratifyingly the desired product 7 was observed
in 71% isolated yield after 2 h, and with an excellent
regioselectivity of 95:05 in favor of the -borylated
product (entry 1). The presence of the benzyl group
decreases the rate of the protodeborylation reaction.
However, performing the reaction in longer times
resulted in a decrease in the isolated yield, due to
protodeborylation of the product 7 (entry 2). The
introduction of a second Bn group at the nitrogen
resulted in a slightly better yield but with a decrease
in the selectivity (entry 3). A longer linear alkyl
chain at the nitrogen is well tolerated and product 9
was obtained as the -vinylboronate in high
selectivity (entry 4). When electron-withdrawing
Scheme 1. A) Previous work from our group. B) Structure
of surfactant SPGS-550M. C) This work.
groups
were
present
at
the
nitrogen,
protodeborylation did not occur and an inversion of
the regioselectivity was observed in all cases studied
(entries 5-11). In most of the examples moderate -
2
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10.1002/adsc.201700094
Advanced Synthesis & Catalysis
selectivity was observed and the best result was
achieved with N-Boc-propargylamine with the
product 10 obtained in 85% yield after 20 h and an
 ratio of 82:18 (entry 6). Since the presence of one
Boc group led to the best -selectivity, a second Boc
group was attached (entry 7). Unfortunately, this led
to a significant decrease in the selectivity of the
reaction.
different palladium catalysts have been tested, and
only yields below 20% of the desired product 16 have
been obtained (entries 10-13).
Table
2.
Optimization
of
the
sequential
Hydroboration/Suzuki reaction.
Table 1. Optimization of the reaction conditions.[a]
entry
Pd cat (mol%)
T (oC)
yield (%)[a]
1[b]
PdCl2(PPh3)2 (5)
PdCl2(PPh3)2 (5)
PdCl2(PPh3)2 (5)
PdCl2(PPh3)2 (3)
PdCl2(PPh3)2 (5)
PdCl2(PPh3)2 (5)
Pd(PPh3)4 (5)
PdCl2 (5)/PPh3 (10)
Pd(OAc)2 (5)/PPh3 (10)
Pd(OAc)2 (5)/dppe (5)
PdCl2(PhCN)2 (5)
Pd2dba3 (5)/PPh3 (10)
POPd (5)
80
25
25
80
80
80
80
80
80
80
80
80
80
65
nr
<15
43
49
33
53
52
54
20
2
3[c]
4
entry
NR2
time
(h)
product,
yield(%)
α : β[b]
5[d]
6[e]
7
1[c],[d]
2[c],[d]
3[d]
NMeBn
NMeBn
NBn2
2
20
2
2
2
7, 71
7, 38
8, 78
9, 60
10, 74
10, 85
11, nd
12, 85
13, 42
14, 60
15, 54
05 : 95
05 : 95
20 : 80
05 : 95
82 : 18
82 : 18
65 : 35
80 : 20
65 : 35
70 : 30
65 : 35
8
9
4[d]
N(nBu)Bn
5[c],[d],[e] NHBoc
6[c],[d],[e] NHBoc
10
11
12
13
20
20
<15
<15
20
7
NBoc2
N(COCF3)Bn 20
NHBz
NHTs
NPhth
8[d]
9[f]
10[f]
11[f]
20
20
20
[a]Isolated yields. [b]Previously reported in Ref [17].
[c]Reaction perfomed in 12 h. [d]1 equiv of K2CO3. [e]2
equiv NaOH instead of K2CO3.
[a]Reactions were performed using propargylamine (1.0
equiv), 1.1 equiv of B2pin2, 5 mol% NaOH 1 M, 5 mol%
of [Cu(Cl)(IMes)] in 0.5 mL of 2 wt% SPGS-550M/H2O.
With the optimized conditions in hand we
examined the scope of the reaction regarding the aryl
halide reaction partner (Scheme 2). Replacing the
halide from PhBr to PhI resulted in an increase of the
yield to 77%. Further studies to expand the scope in
respect to aryl halide coupling partner have been
carried out. A number of different aryl halides
bearing substituents with different steric and
electronic effects have been examined as coupling
partners in this reaction (Scheme 2).
The weakly electron-donating Me group did not
affect the reaction outcome when it was present at
para and meta position of the ArBr. However, when
the ortho derivative was used a decrease in the yield
was observed and product 19 was obtained in 35%
yield for the two steps, indicating that steric effects
play a role in the reaction. This was further observed
when performing the reaction using the more
hindered mesitylene derivative as the coupling
partner and product 20 was isolated in 35% yield.
The stronger electron-donating groups OMe, OH and
NH2 were tested. Good yields were obtained with the
4-OMe group (product 21, X = I, 60%; X = Br, 58%),
while aryl halides bearing 4-OH, 4-NH2 and 2-NH2
groups resulted in low yields. The presence of weak
electron-withdrawing groups such as F and Cl did not
have any significant influence on the Suzuki reaction,
regardless of their position in the aromatic ring
(compare compounds 26-28).
[b]Determined by H NMR. [c]Previously reported in Ref
1
[17]. [d]Isolated yield. [e]15 mol% NaOH 3 M. [f]NMR yield.
Having
identified
N,N-methylbenzyl-
propargylamine as the best substrate for the
hydroboration reaction, it was used for the sequential
hydroboration-Suzuki
reaction.
Thus,
the
hydroboration was performed under the optimized
conditions and after 2 h, 5 mol% of PdCl2(PPh3)2, 2.0
equiv of K2CO3 and 1.0 equiv of PhBr were added
and the reaction mixture heated at 80oC for 2 h[17]
.
Gratifyingly, the desired arylallylamine product 16
was obtained in 65% isolated yield, for the two steps
(Table 2, entry 1). Attempts to perform the Suzuki
reaction at room temperature resulted in decreased
yields, even in longer reactions times (entries 2-3).
Reducing the Pd-catalyst loading to 3 mol% resulted
in 43% yield (entry 4). In the reaction performed at
room temperature for 12 h or using lower amounts of
the Pd-catalyst, the desired product 16 is formed
alongside
significant
amounts
of
the
protodeborylation product. These results clearly
indicate that when the Suzuki reaction is not efficient
enough, the background protodeborylation reaction
becomes relevant. When Pd(PPh3)4 was used, the
desired product was obtained in 53% yield (entry 7).
Attempts to generate the palladium catalyst from
PdCl2 or Pd(OAc)2 and PPh3 (entries 8-9) led to the
formation of the desired product, albeit in lower
yields, when compared to PdCl2(PPh3)2. Finally,
Pd(OAc)2 together the bidentate phosphine dppe, and
3
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10.1002/adsc.201700094
Advanced Synthesis & Catalysis
Scheme 2. Scope of the one-pot dual-metal catalytic synthesis of arylallylamines.
The hydroboration reaction followed by Suzuki
coupling in micellar conditions allows for the
presence a range of functional groups at the aryl
halide such as aldehyde 29, nitrile 30-31,
trifluoromethyl 32-33, nitro 34-35. Notably, the
electron-deficient aryl halides resulted in very good
yields of the corresponding products 29-33. In
addition, - and -naphthyl derivatives have also
been efficiently used as coupling partners, delivering
the corresponding products 36 and 37 in 64% and
72%, respectively. Finally, when 4-bromopyridine
was used as the coupling partner, the corresponding
product 38 was obtained in an excellent yield of 70%
(two steps). Unfortunately, when 2-bromopyridine
was used a complex mixture resulted, and the desired
product 39 was not isolated.
protection/deprotection or non-strategic redox
manipulations.
Another interesting observation regarding the
overall yield of our one-pot, two-step reaction has
been made. When the hydroboration of N-MeBn-
propargylamine was performed, vinylboronate 7 was
isolated in 71%, after purification (Table 1, entry 3).
In several cases, however, when the sequential
hydroboration-Suzuki protocol was used, higher
yields of the final product have been achieved (e.g.
29, 78% yield; 30, 82% yield, 33, 83% yield). We
attribute this increased yield to some loss of 7 in the
purification and also to the fact that in the
hydroboration conditions part of the pinacolboronate
product might have been hydrolyzed to the
vinylboronic acid derivative. Albeit the isolation and
purification of this compound is somewhat difficult,
presumably being responsible for a decrease in the
isolated yield of 7, it is a competent coupling partner
in the Suzuki reaction. Therefore, combining both
reactions in a one-pot protocol has another advantage
besides its operational simplicity.
Worth to mention is that this dual-metal catalysis
was performed entirely in water as the solvent and
neither solvent switch nor addition of organic co-
solvent was needed to obtain the desired product.
This is in contrast with other metal-catalyzed
methods for the synthesis of these molecules, in
which anhydrous organic solvents are used.[7-10,12-13]
Additional advantage of our method relies on the fact
that the linear arylated product can be obtained using
substrates in which two alkyl groups are attached to
In addition, our protocol was also successfully
employed using N-Boc-propargylamine as the
substrate (Scheme 3). In this case, however, the
opposite regiochemistry was observed, since the
major product in the hydroboration step is the -
vinylboronate 10. Combining the Cu-catalyzed
the
nitrogen
atom,
therefore
minimizing
4
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10.1002/adsc.201700094
Advanced Synthesis & Catalysis
hydroboration with the Suzuki coupling efficiently
delivered the desired products 40-44 typically in good
overall yields, ranging from 57-79% yield. Exception
was found for compound 41, with the electron-rich
methoxy group at the aryl halide, with the product
being formed in only 20% yield.
vinylboronate, which enters the second catalytic cycle,
after activation by base (E). Transmetallation with
species F, followed by reductive elimination of G,
delivers the final product and regenerates the active
Pd catalyst.
We applied our method in a short synthesis of the
potent antifungal agent naftifine (1). First, N-methyl-
-naphthylamine (6) was reacted with propargyl
bromide to afford the propargylamine 45 (Scheme 5).
Typical conditions employ DMF as the solvent[14] and
the product 45 was obtained in 70% yield.
Considering that DMF is not a green solvent, we
briefly examined whether we could replace it by a
more environmentally friendly solvent. When EtOH
was used, the desired product was formed in 95%
yield, after 4 h. Gratifyingly we found that
performing the reaction under micellar conditions, 45
was also obtained in excellent yield. This result
opened the possibility of performing the synthesis of
naftifine in a single vessel, starting from 6, involving
three different reaction, using water as the solvent.
Scheme 3. Scope of the reaction using N-Boc
propargylamine.
The one-pot synthesis of the arylallylamines starts
with the Cu-catalyzed hydroboration of the alkyne
(Scheme 4).[25] The proposed catalytic cycle involves
the initial formation of a nucleophilic species of
boron C, generated by the reaction of diboron
bispinacolate with copper species B (formed in situ).
Species C then reacts with the alkyne via a syn-
borocupration reaction yielding the vinylcopper
intermediate D. Depending on the nature of the
substituents at the amine a difference on the
regioselectivity is observed. Finally, protonation of
intermediate D leads to the formation of the
Scheme 5. Optimization of the synthesis of 45
Scheme 4. Proposed catalytic cycles
5
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10.1002/adsc.201700094
Advanced Synthesis & Catalysis
Experimental Section
Reducing our plan to practice, amine 6 was
reacted with propargyl bromide in the presence of
K2CO3 as base, and using SPGS-550M/water as the
solvent (Scheme 6). After 4 h at room temperature,
the NHC-Cu(I) catalyst, B2pin2 and NaOH were
added to the reaction to promote the hydroboration of
the propargylamine 45 which was generated in situ.
Representative Experimental Procedure for the one-pot
Hydroboration-Suzuki Coupling. A 5 mL vial equipped
with a magnetic stir bar was charged with [Cu(Cl)(IMes)]
(5 mol%, 0.025 mmol, 10.1 mg), B2pin2 (1.1 equiv., 0.55
mmol, 139.7 mg), propargylamine (1.0 equiv., 0.50 mmol),
SPGS-550M (2%, w/w, 0.50 mL) and NaOH 1 molL-1 (25
µL). The resulting mixture was vigorously strirred at room
temperature for the time indicated. After this period,
[Pd(Cl)2(PPh3)2] (5 mol%, 0.025 mmol, 17.5 mg), K2CO3
(2.0 equiv., 1.00 mmol, 138.2 mg), and aryl halide (1.0
equiv., 0.50 mmol) were added. The resulting mixture was
After additional
2 h, the hydroboration was
completed and the Pd-catalyst, PhI, and K2CO3 have
been added to the reaction mixture, without isolation
of the vinylboronate intermediate 46. After further
o
reaction for 2 h at 80 C, naftifine was isolated in
42% yield (three steps) in a short, efficient and
environmentally benign synthesis of this valuable
pharmaceutical compound. In order to compare, we
have also carried out the synthesis using isolated,
pure 45. In this case, naftifine (1) was obtained in
52% yield, after the hydroboration/Suzuki sequence.
o
strirred at 80 C for 2 h. Then, the reaction was allowed to
reach room temperature and anhydrous Na2SO4 was added.
The solid mixture was washed with ethyl acetate (2 x 1
mL) and the organic layer was transferred to a round-
bottomed flask. The solvent was removed under reduced
pressure and the crude product was purified by column
chromatography using hexane:EtOAc as an eluent to afford
the desired product. In a few cases small contamination of
the product with pinacol could be removed azeotropically
with water on a rotary evaporator.[26]
Acknowledgements
This work was supported by CNPq, CAPES, and INCT-Catálise.
We are also grateful to Prof. Luiz C. Dias (IQ-Unicamp) for the
gift of chemicals.
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Scheme 6. Synthesis of naftifine (1)
Conclusions
In summary, we have developed an efficient
method for the one-pot dual-metal catalytic synthesis
of arylallylamines, through the combination of a Cu-
catalyzed hydroboration of
a
propargylamine
followed by a Pd-catalyzed Suzuki arylation. The
developed protocol is tolerant to a range of functional
groups in the arylation step, including aldehyde,
nitrile, nitro, trifluoromethyl, and halide. Importantly,
the reaction sequence was entirely performed in water
as the solvent, in the presence of small amounts of
SPGS-550M surfactant, without the need of solvent
switch or addition of organic co-solvents, rendering it
operationally simple and environmentally benign.
The usefulness of this methodology was highlighted
in a straightforward synthesis of the pharmaceutically
important compound naftifine.
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Advanced Synthesis & Catalysis
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This article is protected by copyright. All rights reserved.

10.1002/adsc.201700094
Advanced Synthesis & Catalysis
UPDATE
Combining Copper-Catalyzed
Hydroboration with Palladium-Catalyzed
Suzuki Coupling for the One-pot Synthesis of
Arylallylamines under Micellar Conditions
Adv. Synth. Catal. Year, Volume, Page – Page
Pedro A. Horn,a,§ Roger K. Braun,a,§ Victória G.
Isoppo,a Jessie S. da Costa,a Diogo S. Lüdtke,a
and Angélica V. Moroa,*
8
This article is protected by copyright. All rights reserved.