β-aminoethyltrifluoroborates: Efficient aminoethylations via Suzuki-Miyaura cross-coupling

Article abstract of DOI:10.1021/ol062610v

(Chemical Equation Presented) A set of phenethylamines has been successfully prepared via Suzuki-Miyaura cross-coupling of diverse potassium β-aminoethyltrifluoroborates with aryl halides. The potassium β-aminoethyltrifluoroborates were easily prepared vi

Full text of DOI:10.1021/ol062610v

ORGANIC
LETTERS
2007
Vol. 9, No. 2
203-206
â
-Aminoethyltrifluoroborates: Efficient
Aminoethylations via Suzuki
Cross-Coupling
−Miyaura
Gary A. Molander* and Fabricio Vargas
Roy and Diana Vagelos Laboratories, Department of Chemistry, UniVersity of
PennsylVania, Philadelphia, PennsylVania 19104-6323
gmolandr@sas.upenn.edu
Received October 23, 2006
ABSTRACT
A set of phenethylamines has been successfully prepared via Suzuki−Miyaura cross-coupling of diverse potassium
â-aminoethyltrifluoroborates
with aryl halides. The potassium
â
-aminoethyltrifluoroborates were easily prepared via hydroboration of enamine and enamide precursors.
Phenethylamines and their structural analogues comprise
important substructures of a variety of biologically important
compounds including dopamine, tyrosine, amphetamine, and
adrenaline. These privileged scaffolds are also widely found
as components of alkaloid natural products1 and often serve
as key building blocks in the synthesis of numerous nitrogen-
containing complex molecules. Previous methods to intro-
duce an aminoethyl group into an arene have employed the
Friedel-Crafts acylation of activated arenes with N-protected
amino acid chlorides,2 Heck arylation of N-vinyloxazolone
followed by hydrogenation,3 and cross-coupling reactions
involving â-amino organozinc reagents, which are somewhat
unstable to â-elimination.4 Earlier investigations to access
these important units also include the direct coupling of
â-aminoethyl organolithiums with aryl and alkenyl halides.5
A more broadly applicable Suzuki cross-coupling6 approach
to this interesting class of compounds has been developed
by Overman.7 However, although there are distinct advan-
tages of this one-pot â-aminoethylation procedure in cross-
coupling reactions and total synthesis (e.g., the reactions can
be performed at room temperature),8 there are some limita-
tions as well. In particular, the organoborane reagents
prepared in situ via hydroboration of benzyl vinyl carbamate
cannot be easily isolated and stored but must be prepared
and utilized on a reaction-by-reaction basis.
By contrast, potassium organotrifluoroborates have been
shown to overcome this particular limitation. These salts are
unique organoboron compounds, notable for their stability
to moisture and air.9 They are powders or crystalline solids
that are easy to access and handle, and these properties have
(6) For a review of the Suzuki reaction, see: (a) Miyaura, N.; Suzuki,
A. Chem. ReV. 1995, 95, 2457. (b) Kotha, S.; Lahiri, K.; Dhurke, K.
Tetrahedron 2002, 58, 9633.
(1) (a) Bentley, K. W. Nat. Prod. Rep. 1999, 16, 367. (b) Lednicer,
Mitscher, L. A. The Organic Chemistry of Drug Synthesis; Wiley: New
York, 1997; Vol. 7.
(2) Nordlander, J. E.; Payne, M. J.; Njoroge, F. G.; Balk, M. A.; Laikos,
G. D.; Vishwanath, V. M. J. Org. Chem. 1984, 49, 4107.
(3) Busacca, C. A.; Johnson, R. E.; Swestock, J. J. Org. Chem. 1993,
58, 3299.
(4) (a) Duddu, R.; Eckhardt, M.; Furlong, M.; Knoess, H. P.; Berger,
S.; Knochel, P. Tetrahedron 1994, 50, 2415. (b) Hunter, C.; Jackson, R. F.
W.; Rami, H. K. J. Chem. Soc., Perkin Trans. 1 2000, 219. (c) Rilatt, I.;
Caggiano, L.; Jackson, R. F. W. Synlett 2005, 2701.
(5) Barluenga, J.; Montserrat, J. M.; Florez, J. J. Org. Chem. 1993, 58,
5976.
(7) Kamatani, A.; Overman, L. E. J. Org. Chem. 1999, 64, 8743.
(8) (a) Kamatani, A.; Overman, L. E. Org. Lett. 2001, 3, 1229. (b)
Dounay, A. B.; Overman, L. E.; Wrobleski, A. D. J. Am. Chem. Soc. 2005,
127, 10186. (c) Fuchs, J. R.; Funk, R. L. Org. Lett. 2005, 7, 677.
(9) For the synthesis of organotrifluoroborates, see: (a) Vedejs, E.;
Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf, M. R. J. Org. Chem.
1995, 60, 3020. (b) Vedejs, E.; Fields, S. C.; Hayashi, R.; Hitchcock, S.
R.; Powell, D. R.; Schrimpf, M. R. J. Am. Chem. Soc. 1999, 121, 2460.
For reviews of organotrifluoroborate salts, see: (c) Molander, G. A.;
Figueroa, R. Aldrichimica Acta 2005, 38, 49. (d) Darses, S.; Geneˆt, J.-P.
Eur. J. Org. Chem. 2003, 4313. (e) Molander, G. A.; Ellis, N. Acc. Chem.
Res. 2007, 40, in press.
10.1021/ol062610v CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/21/2006

made them attractive synthetic intermediates. Herein, we
describe our initial efforts to develop a convenient and
practical access to phenethylamines via Suzuki cross-
coupling of potassium â-aminoethyltrifluoroborates with aryl
electrophiles.
Table 2. Optimization of a Cross-Coupling Reaction for the
Synthesis of 2a
To initiate studies on the aminoethylation reactions, a
hydroboration protocol was employed that mimicked pro-
cedures reported by Overman.7,8 Thus, the respective N-vinyl
substrates10 were hydroborated using Snieckus’ di(isopro-
pylprenyl)borane (i-PP2BH),11 and the resulting organoborane
intermediates were treated with an aqueous solution of KHF2
to afford the desired â-aminoethyltrifluoroborates 1a-e as
depicted in Table 1.
entry
catalyst/ligand (mol %)
basea
% isolated yield
1
2
3
4
5
6
7
8
9
PdCl2(dppf)‚CH2Cl2 (10)
PdCl2(dppf)‚CH2Cl2 (5)
PdCl2(dppf)‚CH2Cl2 (2)
Pd(OAc)2/2PPh3 (5)
PdCl2/2PPh3 (5)
PdCl2(PPh3)2 (5)
Pd(PPh3)4 (5)
PdCl2(dppf)‚CH2Cl2 (5)
PdCl2(dppf)‚CH2Cl2 (5)
PdCl2(dppf)‚CH2Cl2 (5)
PdCl2(dppf)‚CH2Cl2 (5)
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
Et3N
84
90
68
78
56
72
51
69
77
73
75b
Table 1. Preparation of Potassium
â-Aminoethyltrifluoroborates
10
11
Cs2CO3
a 3 equiv. A mixture of THF/H2O (10:1) was used as the solvent.
b
roborates and aryl bromides,12 we first conducted the reaction
in the presence of different loadings of PdCl2(dppf)‚CH2Cl2
using Cs2CO3 (3 equiv) as base, in a mixture of toluene/
H2O (3:1) as solvent (Table 2, entries 1-3). It was observed
that, using 5 mol % of the catalyst, the desired phenethy-
lamine 2a was obtained in 90% yield (Table 2, entry 2).
Subsequently, systems were tested using 5 mol % of different
palladium sources and ligands (Table 2, entries 4-7), but
the desired product was formed in lower yields. The
efficiency of PdCl2(dppf)‚CH2Cl2 was also evaluated in the
presence of different inorganic bases and Et3N, as well as
in a different solvent [THF/H2O (10:1)]. However, in all
cases, no improvement could be observed (Table 2, entries
8-11).
The optimized conditions were subsequently applied to
cross-coupling reactions with electron-poor electrophiles, as
depicted in Table 3. The reaction proceeds with comparable
yields when different leaving groups attached to p-AcPhX
(X ) Br, I, OTf) were tested in the cross-coupling reaction
(Table 3, entry 2). All of the desired phenethylamines were
obtained with good to excellent yields (73-90%) in the
presence of a wide variety of functional groups including
nitriles, ketones, esters, aldehydes, halides, and nitro groups
in the para position. The cross-coupling reaction also tolerates
bromides with substituents in the ortho and meta positions,
as the corresponding products were afforded in uniform
yields (Table 3, entries 9 and 10).
Although organotrifluoroborate 1a has been obtained in
excellent yield (Table 1, entry 1), the organotrifluoroborates
containing a seven-membered and a five-membered lactam
1b and 1c (Table 1, entries 2 and 3) were obtained in lower
yields. The Snieckus hydroboration protocol also tolerates
nitrogen-protecting groups such as Boc and Cbz. However,
the desired salts 1d and 1e were obtained in moderate yields
(Table 1, entries 4-5). All of the new potassium â-amino-
ethyltrifluoroborates were obtained as powders or crystalline
white solids that were stored on the benchtop without
detectable degradation.
Initially, we focused on optimization of the reaction
conditions for the Suzuki cross-coupling of â-aminoethyl-
trifluoroborates and aryl electrophiles (Table 2). Thus, 1a
and 4-bromobenzonitrile were chosen as representative
coupling partners. On the basis of the optimized cross-
coupling reaction conditions reported between alkyltrifluo-
The introduction of an ethylamine moiety was also
evaluated under the same reaction conditions using electron-
rich bromides, as shown in Table 4. The coupling products
were synthesized in moderate to good yields in the presence
(10) 9-Vinylcarbazole, N-vinylcaprolactam, and N-vinyl-2-pyrrolidone
are commercially available. N-Boc vinyl carbamate and N-Cbz vinyl
carbamate were prepared according to the procedures described in the
literature (see Supporting Information).
(11) Kalinin, A. V.; Scherer, S.; Snieckus, V. Angew. Chem., Int. Ed.
2003, 42, 3399.
(12) (a) Molander, G. A.; Ito, T. Org. Lett. 2001, 3, 393. (b) Molander,
G. A.; Yun, C.-S.; Ribagorda, M.; Biolatto, B. J. Org. Chem. 2003, 68,
5534.
204
Org. Lett., Vol. 9, No. 2, 2007

Table 3. Cross-Coupling of Potassium
â-Aminoethyltrifluoroborate 1a with Electron-Poor Aryl
Bromides
Table 4. Cross-Coupling of Potassium
â-Aminoethyltrifluoroborate 1a with Electron-Rich Bromides
After investigating several conditions, 2 mol % of Pd-
(OAc)2 and 4 mol % of RuPhos (Table 5, entry 4) showed
the best catalytic performance, affording the product in 71%
yield.
Having demonstrated the efficiency of organotrifluorobo-
rate 1a as a convenient aminoethylating agent for aryl- and
heteroaryl bromides, we investigated the scope of the method
using the â-aminoethyltrifluoroborates 1b and 1c. We
initially conducted the reaction using 5 mol % of PdCl2-
of functionalized bromides. Interestingly, comparable yields
for the corresponding phenethylamines were obtained when
a nonsubstituted bromide and a sterically hindered bromide
were used as coupling partners (Table 4, compare entries 1
and 2). As observed with the electron-poor bromides, sub-
stituents located at different positions about the aromatic ring
do not seem to show a strong influence in terms of yield for
the respective phenethylamines (Table 4, entries 6 and 7).
Next, the scope of the cross-coupling reaction was
explored using heteroaryl bromides as coupling partners, as
outlined in Table 5. The optimized conditions are quite
general, as the present reaction provides the desired products
in acceptable yields (Table 5, entries 1-3) and also tolerates
different functional groups attached to furan, pyridine, and
indole moieties. However, when a thiophene derivative was
used, no coupling was observed. This unsatisfactory result
prompted us to screen different coupling conditions as well
as alternative ligands such as SPhos, XPhos, and RuPhos
(Figure 1).13
Table 5. Cross-Coupling of Potassium
â-Aminoethyltrifluoroborate 1a with Heteroaryl Bromides
a Pd(OAc)2 (2 mol %) and RuPhos (4 mol %) were used in the catalytic
system.
(13) (a) Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126,
13028. (b) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2005, 127, 4685.
Org. Lett., Vol. 9, No. 2, 2007
205

particularly relevant because it provides an easy and efficient
alternative to prepare phenethylamines containing free amino
groups after appropriate deprotection of the respective Boc
and Cbz protecting groups.
In summary, we have described an efficient and convenient
synthesis of an important class of compounds through the
Suzuki-Miyaura cross-coupling reaction. The potassium
â-aminoethyltrifluoroborates, readily obtained as stable
crystalline solids in moderate to excellent yields via Snieckus
hydroboration with i-PP2BH, have successfully proven their
utility and versatility as useful aminoethylating reagents in
the synthesis of a series of phenethylamines. The â-amino-
ethylation procedure tolerates diverse functional groups in
the organotrifluoroborates as well as in the respective aryl
and heteroaryl electrophiles, affording the desired products
in good to excellent yields. The stability of the â-amino-
ethyltrifluoroborates recommends them to diversity oriented
synthesis, as a variety of these reagents can be prepared and
stored indefinitely, awaiting coupling to diverse electrophiles.
In this regard, studies directed toward a general method to
prepare a wider range of potassium â-aminoethyltrifluorobo-
rates are underway.
Figure 1. Buchwald ligands.
(dppf)‚CH2Cl2, but the desired products were not obtained.
On the basis of the successful procedure with the thiophene
derivative, we used the RuPhos catalytic system, and in this
case, the phenethylamines 3a and 3b were obtained in 78%
and 71% yields, respectively, as displayed in eq 1.
Acknowledgment. This work was supported by the CNPq
(Conselho Nacional de Desenvolvimento Cient´ıfico e Tec-
nolo´gico) (SWE 201094/2005-3). We thank the National
Institutes of Health (GM 35249), Amgen, Merck Research
Laboratories, and Johnson Matthey for their generous sup-
port.
The organotrifluoroborates 1d and 1e were also employed
as coupling partners in the cross-coupling reaction. The
previously optimized conditions were used to couple the
corresponding â-aminoethyltrifluoroborates with 4-bromoben-
zonitrile, affording the corresponding phenethylamines 4a
and 4b in good yields as outlined in eq 2. This coupling is
Supporting Information Available: Experimental pro-
cedures, spectral characterization, and copies of 1H, 13C, 11B,
and 19 F spectra for all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL062610V
206
Org. Lett., Vol. 9, No. 2, 2007