Scope of the Suzuki-Miyaura aminoethylation reaction using organotrifluoroborates

Article abstract of DOI:10.1021/jo7015955

(Chemical Equation Presented) Potassium β-aminoethyltrifluoroborates were prepared in good yields via hydroboration of the corresponding enecarbamates using the Snieckus hydroborating reagent. A wide variety of phenethylamines containing a potentially fre

Full text of DOI:10.1021/jo7015955

Scope of the Suzuki-Miyaura Aminoethylation Reaction Using
Organotrifluoroborates
Gary A. Molander* and Ludivine Jean-Ge´rard
Roy and Diana Vagelos Laboratories, Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104-6323
gmolandr@sas.upenn.edu
ReceiVed July 21, 2007
Potassium â-aminoethyltrifluoroborates were prepared in good yields via hydroboration of the corre-
sponding enecarbamates using the Snieckus hydroborating reagent. A wide variety of phenethylamines
containing a potentially free primary amine after appropriate deprotection have been successfully prepared
in good yield using these organotrifluoroborates as partners in Suzuki-Miyaura coupling with aryl
bromides, iodides, and triflates.
Introduction
Aminoethyl groups, and particularly phenethylamines, are of
great interest because they are incorporated within a number of
natural and synthetic compounds that exhibit important biologi-
cal activities, and they are also important synthetic intermediates
for the construction of these types of molecules. Examples
include the erythrina and indole classes of alkaloids (Figure 1).
Prior to the development of transition-metal-catalyzed pro-
cesses, the phenethylamine unit was normally installed by
multistep sequences involving, for example, Friedel-Crafts
acylation of activated arenes with N-protected amino acid
chlorides followed by reduction of the ketone carbonyl group1
or a sequence of three steps involving a chloromethylation of
the aryl core followed by conversion to a nitrile group and
subsequent reduction.2 In certain cases, â-aminoethyl organo-
lithiums could be directly coupled with aryl halides.3 With the
advent of metal-catalyzed coupling reactions, new avenues for
preparing â-aminoethyl aromatics became available. For in-
stance, aminoethylating strategies such as the Heck arylation
of N-vinyloxazolone followed by hydrogenation4 were reported.
Additionally, nucleophilic aminoethylating reagents were de-
veloped such as â-amino organozinc reagents utilized in Negishi
cross-coupling reactions.5
FIGURE 1. Nitrogen heterocycles containing aminoethyl groups.
The use of the Suzuki-Miyaura cross-coupling reaction
for â-aminoethylation was first reported by Overman6 and
has been utilized in the synthesis of a variety of complex organic
molecules.7 This method possesses several distinct advan-
tages. In addition to being performed at room temperature, the
reaction is reported to have a wide substrate scope and
(5) (a) Duddu, R.; Eckhardt, M.; Furlong, M.; Knoess, H. P.; Berger,
S.; Knochel, P. Tetrahedron 1994, 50, 2415-2432. (b) Hunter, C.; Jackson,
R. F. W.; Rami, H. K. J. Chem. Soc., Perkin Trans. 1 2000, 2, 219-223.
(c) Rilatt, I.; Caggiano, L.; Jackson, R. F. Synlett 2005, 2701-2719.
(6) Kamatani, A.; Overman, L. E. J. Org. Chem. 1999, 64, 8743-8744.
(7) (a) Kamatani, A.; Overman, L. E. Org. Lett. 2001, 3, 1229-1232.
(b) Dounay, A. B.; Overman, L. E.; Wrobleski, A. D. J. Am. Chem. Soc.
2005, 127, 10186-10187. (c) Fuchs, J. R.; Funk, R. L. Org. Lett. 2005, 7,
677-680.
(1) Nordlander, J. E.; Payne, M. J.; Njoroge, F. B.; Balk, M. A.; Laikos,
G. D.; Vishwanath, V. M. J. Org. Chem. 1984, 49, 4107-4111.
(2) Ladd, D. L.; Weinstock, J.; Wise, M.; Gessner, G. W.; Sawyer, J.
L.; Flaim, K. E. J. Med. Chem. 1986, 29, 1904-1912.
(3) Barluenga, J.; Montserrat, J. M.; Florez, J. J. Org. Chem. 1993, 58,
5976-5980.
(4) Busacca, C. A.; Johnson, R. E.; Swestock, J. J. Org. Chem. 1993,
58, 3299-3303.
10.1021/jo7015955 CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/04/2007
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J. Org. Chem. 2007, 72, 8422-8426

Scope of the Suzuki-Miyaura Aminoethylation Reaction
moreover can be executed in a one-pot fashion. However,
it has some limitations as well. The procedure works well
with aryl and alkenyl iodides, but the corresponding bromides
generally require 1.5 equiv of the organoborane reagent. In
addition, the aminoethylating reagent prepared in situ by
hydroboration of the corresponding vinyl carbamate is
air-sensitive and cannot be conveniently isolated and stored.
While highly desirable within the context of a total synthesis,
this in situ strategy is perhaps not ideal for reaction optimization
on novel substrates and is not readily applicable to diversity-
oriented synthesis or efforts in parallel synthesis.
The development of a new Suzuki-Miyaura approach that
makes use of the more stable organotrifluoroborates would be
a good complement to the strategy pioneered and developed
by Overman. The nature of these boron reagents also makes
them an attractive alternative to the classical boronic acids or
boronate esters. The organotrifluoroborates are crystalline
compounds that are indefinitely stable to moisture and air.8 Their
monomeric form, coupled with their lower tendency to pro-
todeboronate as compared to boronic acids,9 permits the use of
stoichiometric amounts of these nucleophiles. We recently
reported an efficient and convenient synthesis of an important
class of tertiary phenethylamines through the Suzuki-Miyaura
cross-coupling reaction using â-aminoethyltrifluoroborates.10 To
expand the scope of this procedure, it appeared desirable to be
able to prepare phenethylamines containing the equivalent of a
primary amine. Herein, we disclose the results obtained from
the preparation of several potassium â-aminoethyltrifluorobo-
rates and their coupling with a wide variety of aryl halides and
triflates.
can be envisioned because many vinylcarbamates containing
various protecting groups are available.12
With these compounds in hand, Suzuki cross-coupling
reactions with a variety of aryl electrophiles were attempted.
The first halide partner studied was the electron-poor 4-bro-
mobenzonitrile 2a. On the basis of the optimized conditions
reported for the cross-coupling of the 9-vinylcarbazole-derived
potassium aminoethyltrifluoroborate and aryl bromides,10 we
first conducted the reaction in the presence of PdCl2(dppf)‚CH2-
Cl2 (5 mol %) using Cs2CO3 as a base and a mixture of toluene/
H2O as the solvent system. Under these conditions, a hetero-
geneous mixture was formed that, over time, eventually gave
rise to two homogeneous phases. These conditions allowed the
formation of the cross-coupled product 3a in a yield of 75%.
This promising result led us to test the generality of the method
by attempting the reaction on various electron-poor aryl
bromides containing diverse functional groups. The results
obtained are summarized in Table 1.
All electron-poor aryl electrophiles gave rise to the corre-
sponding cross-coupled products in good to excellent yields.
The use of the aryl bromides, iodides, or triflates (entry 7) did
not affect the efficiency of the reaction. As expected, the
coupling reaction tolerates a wide variety of functional groups
such as nitrile, halide, aldehyde, ketone, and ester and also
permits the use of nitro-containing derivatives. This last result
underscores an advantage of organotrifluoroborates over clas-
sical organoboron reagents such as alkyl 9-BBNs, where some
reduction of the nitro group can be observed during the cross-
coupling process.13 Reaction of the Cbz-protected organotri-
fluoroborate with electron-poor aryl electrophiles was proven
efficient even when only a slight excess of the organoboron
substrate is used (entry 7). The reaction also scaled up efficiently
to 3.5 mmol of potassium â-aminoethyltrifluoroborate, providing
nearly identical yields.
Results and Discussion
The current study began with the preparation of potassium
â-aminoethyltrifluoroborates using an adaptation of Overman’s
procedure.6,7 Thus, the desired N-vinyl carbamates6 were
hydroborated using the Snieckus hydroborating reagent (i-PP2-
BH),11 and the resulting organoborane intermediates were treated
with an aqueous solution of KHF2 (eq 1). The potassium
â-aminoethyltrifluoroborates produced in this way were isolated
in good yields and can be stored on the benchtop indefinitely
without any detectable degradation.
We next expanded the scope of this method using the Cbz-
protected trifluoroborate with various electron-rich aryl bro-
mides. Initial experiments (Table 2, entries 1 and 2) showed
that the conditions previously developed failed to give the
desired coupled compounds in satisfactory yields. These results
prompted us to choose another protocol. On the basis of a
successful procedure utilizing the Buchwald ligands,10,14 the
combination of 5 mol % of Pd(OAc)2 and 10 mol % of RuPhos
(Figure 2) was chosen as the catalytic system, and this offered
greatly improved yields for the coupling of 1-bromo-2,4-
dimethoxybenzene 4a (entry 1). These reactions generally
proceeded more efficiently if they were conducted at 95 °C.
Several electron-rich aryl electrophiles were coupled in good
yields using this procedure, and even the use of sterically
hindered electrophiles such as 2-bromomesitylene 4h did not
affect the efficiency of the reaction. However, when an aryl
bromide containing an amino group was used, only a moderate
yield (46%) was obtained (entry 7). Under the standard
conditions utilized, the reaction was incomplete, and several
byproducts were formed as well.
After optimization, the reaction could reliably be used to
prepare at least 5 g of the organotrifluoroborate without
compromising the yield of the reaction. The preparation of a
broader variety of these potassium â-aminoethyltrifluoroborates
To investigate the method further, the array of electrophiles
was expanded to heteroaromatic bromides (Table 3).
(8) For reviews of organotrifluoroborate salts, see: (a) Molander, G. A.;
Figueroa, R. Aldrichimica Acta 2005, 38, 49-56. (b) Darses, S.; Geneˆt,
J.-P. Eur. J. Org. Chem. 2003, 4313-4327. (c) Molander, G. A.; Ellis, N.
Acc. Chem. Res. 2007, 40, 275-286. (d) Stefani, H. A.; Cella, R.; Vieira,
A. S. Tetrahedron 2007, 63, 3623-3658.
(9) Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302-4314.
(10) Molander, G. A.; Vargas, F. Org. Lett. 2007, 9, 203-206.
(11) Definition: i-PP2BH ) di(isopropylprenyl)borane. Kalini, A. V.;
Scherer, S.; Snieckus, V. Angew. Chem., Int. Ed. 2003, 42, 3399-
3404.
(12) (a) Carpino, L. A.; Tsao, J.-H. J. Chem. Soc., Chem. Commun. 1978,
358-359. (b) Hart, R. Bull. Soc. Chim. Belg. 1957, 66, 229-242.
(13) Oh-e, T.; Miyaura, N.; Suzuki, A. Synlett 1990, 4, 221-223.
(14) (a) Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126,
13028-13209. (b) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald,
S. L. J. Am. Chem. Soc. 2005, 127, 4685-4696.
J. Org. Chem, Vol. 72, No. 22, 2007 8423

Molander and Jean-Ge´rard
TABLE 1. Cross-Coupling of the Cbz-Protected Potassium
â-Aminoethyltrifluoroborate 1a with Various Electron-Poor Aryl
Electrophilesa
TABLE 2. Cross-Coupling of the Cbz-Protected Potassium
â-Aminoethyltrifluoroborate 1a with Various Electron-Rich Aryl
Electrophilesa
a
All reactions were carried out using 0.24 mmol of aryl bromide
b
and 0.26 mmol of potassium â-aminoethyltrifluoroborate. Conditions:
method A, PdCl2(dppf)‚CH2Cl2 (5 mol %), Cs2CO3 (3 equiv), toluene/H2O
(3:1), 80 °C, 12 h. c Conditions: method B, Pd(OAc)2 (5 mol %), RuPhos
a
Regarding the previously described conditions, all reactions, unless
d
(10 mol %), Cs2CO3 (3 equiv), toluene/H2O (3:1), 95 °C, 12 h. This
indicated, were carried out using 1.1 equiv of potassium â-aminoethyltri-
fluoroborate (0.26 mmol). During the course of this study, we observed
that only 1.01 equiv was necessary. b This reaction was performed on a 3.5
mmol scale using only 1.01 equiv of potassium â-aminoethyltrifluoroborate.
reaction was performed using 1.01 equiv of potassium â-aminoethyltri-
fluoroborate.
tions [Pd(OAc)2 (5 mol %), RuPhos (10 mol %), Cs2CO3 (3.0
equiv) in toluene/H2O at 95 °C] to give rise to the desired
compounds in very good yields. Interestingly, the isoquinoline
(6a) and indole (6e) derivatives underwent coupling with the
greatest efficiency to afford the aminoethylated products in
excellent yields.
c
This reaction was performed using only 1.01 equiv of potassium
â-aminoethyltrifluoroborate.
Different heteroaryl bromides, such as thiophene, pyrimidine,
isoquinoline, and indole derivatives, were successfully coupled
to the trifluoroborate 1a under our previously described condi-
8424 J. Org. Chem., Vol. 72, No. 22, 2007

Scope of the Suzuki-Miyaura Aminoethylation Reaction
TABLE 4. Cross-Coupling of the Boc-Protected Potassium
â-Aminoethyltrifluoroborate 1b with Various Aryl Electrophilesa
FIGURE 2. RuPhos ligand.
TABLE 3. Cross-Coupling of the Cbz-Protected Potassium
â-Aminoethyltrifluoroborate 1a with Various Heteroaryl Bromidesa
a
All reactions were carried out using 0.24 mmol of aryl bromide and
b
0.242 mmol of potassium â-aminoethyltrifluoroborate (1.01 equiv).
Conditions: method A, PdCl2(dppf)‚CH2Cl2 (5 mol %), Cs2CO3 (3 equiv),
toluene/H2O (3:1), 80 °C, 12 h. c Conditions: method B, Pd(OAc)2 (5 mol
%), RuPhos (10 mol %), Cs2CO3 (3 equiv), toluene/H2O (3:1), 95 °C,
12 h.
rimidine 8e were also successfully reacted to afford the title
compound in a yield of 83%.
Conclusion
We have extended the method of â-aminoethylation previ-
ously developed toward the preparation of phenethylamines that
would possess free primary amines after appropriate deprotection
of the respective Boc or Cbz protecting groups. The strategy
consists of a Suzuki-Miyaura cross-coupling reaction of aryl
electrophiles with potassium â-aminoethyltrifluoroborates pre-
pared via Snieckus hydroboration. A number of electron-poor,
electron-rich, and heteroaryl electrophiles containing various
functional groups (carbonyl, nitro, ester, etc.) and various
substitution patterns were evaluated, demonstrating the ef-
ficiency of this strategy. These results should permit easy access
to other nitrogen-containing materials incorporating the phen-
ethylamine group. Efforts toward the extension of this strategy
to the cross-coupling with alkenyl bromides are currently
underway.
a
All reactions were carried out using 0.24 mmol of aryl bromide and
b
0.26 mmol of potassium â-aminoethyltrifluoroborate. Using 5 mol % of
PdCl2(dppf)‚CH2Cl2 as the catalyst.
We next examined the efficiency of potassium 2-(tert-
butoxycarbonylamino)ethyltrifluoroborate 1b using our previ-
ously developed conditions (Table 4). Expanding the reaction
to this organotrifluoroborate is particularly relevant, as it enables
the introduction of either the Boc- or the Cbz-functionalized
amino moiety, depending on the nature of the protection scheme
desired within the target molecule.
Experimental Section
Under the conditions previously developed, the Boc-protected
trifluoroborate coupled as efficiently as the Cbz-protected
organoboron with electron-poor or electron-rich aryl electro-
philes (entries 1-4). Heteroaryl bromides such as 5-bromopy-
METHOD A. Preparation of Benzyl 4-Acetylphenethylcar-
bamate (3g). To a mixture of potassium â-aminoethyltrifluoroborate
(1a) (1.0 g, 3.5 mmol), 4-bromoacetophenone (691.5 mg, 3.47
J. Org. Chem, Vol. 72, No. 22, 2007 8425

Molander and Jean-Ge´rard
mmol), Cs2CO3 (3.39 g, 10.41 mmol), and PdCl2(dppf)‚CH2Cl2
(141.7 mg, 0.17 mmol) under nitrogen was added toluene/H2O (3:
1, 22 mL). The reaction was heated at 80 °C with stirring under a
nitrogen atmosphere in a sealed tube for 12 h and then cooled to
rt. A saturated aqueous solution of NH4Cl (10 mL) was added, and
the resulting mixture was extracted with CH2Cl2 (3 × 20 mL). The
organic layer was dried (MgSO4) and then filtered. The solvent
was removed in vacuo, and the crude product was purified by silica
gel chromatography (elution with EtOAc/hexane 3:7) to afford the
product as a white solid (mp 84-85 °C, lit. 85-87 °C6) in 85%
organic layer was dried (MgSO4) and then filtered. The solvent
was removed in vacuo, and the crude product was purified by silica
gel chromatography (elution with EtOAc/hexane 3:7) to afford the
product as a white solid in 79% yield (59.5 mg, 0.19 mmol). mp
) 91-92 °C; 1H NMR (500 MHz, CDCl3) δ 7.35-7.27 (m, 5H),
6.99 (d, 1H, J ) 8.1 Hz), 6.42-6.39 (m, 2H), 5.07 (s, 2H), 4.88
(br s, 1H), 3.77 (s, 6H), 3.40-3.36 (m, 2H), 2.75 (app t, 2H, J )
6.7 Hz); 13C NMR (125.8 MHz, CDCl3) δ 159.8, 158.5, 156.5,
136.9, 130.9, 128.5, 128.11, 128.07, 119.6, 104.1, 98.7, 66.5, 55.4,
55.3, 41.4, 30.1; IR (KBr) 3341, 1697, 1546, 1465, 1260, 1133
cm-1; HRMS (ES+) m/z calcd for C18H21NO4Na+ (M+Na+)
338.1368, found 338.1369.
1
yield (876 mg, 2.95 mmol). H NMR (500 MHz, CDCl3) δ 7.88
(d, 2H, J ) 8.0 Hz), 7.36-7.26 (m, 7H), 5.09 (s, 2H), 4.82 (br s,
1H), 3.50-3.46 (m, 2H), 2.88 (app t, 2H, J ) 6.6 Hz), 2.57 (s,
3H); 13C NMR (125.8 MHz, CDCl3) δ 197.8, 156.3, 144.6, 136.5,
135.6, 129.1, 128.7, 128.6, 128.2, 128.1, 66.7, 41.9, 36.2, 26.6.
The spectroscopic data correspond to those reported in the
literature.6
METHOD B. Preparation of Benzyl 2,4-Dimethoxypheneth-
ylcarbamate (5a). To a mixture of potassium â-aminoethyltrif-
luoroborate (1a) (69.1 mg, 0.242 mmol), 1-bromo-2,4-dimethox-
ybenzene (46.0 mg, 0.24 mmol), Cs2CO3 (234.6 mg, 0.72 mmol),
Pd(OAc)2 (2.7 mg, 0.012 mmol), and RuPhos (11.2 mg, 0.024
mmol) under nitrogen was added toluene/H2O (3:1, 1.5 mL). The
reaction was heated at 95 °C with stirring under a nitrogen
atmosphere in a sealed tube for 12 h and then cooled to rt. A
saturated aqueous solution of NH4Cl (4 mL) was added, and the
resulting mixture was extracted with CH2Cl2 (3 × 5 mL). The
Acknowledgment. This work was generously supported by
the National Institutes of Health (GM035249), Amgen, and
Merck Research Laboratories. We also acknowledge Frontier
Scientific and Johnson Matthey for a donation of palladium
catalysts and Professor Stephen L. Buchwald (MIT) for a sample
of phosphine ligands.
Supporting Information Available: Experimental procedures,
spectral characterization, and copies of 1H, 13C, 11B, and 19F spectra
for all compounds prepared by the method described. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO7015955
8426 J. Org. Chem., Vol. 72, No. 22, 2007