Aminomethylations via cross-coupling of potassium organotrifluoroborates with aryl bromides

Article abstract of DOI:10.1021/ol070543e

Equation presented The Suzuki-Miyaura cross-coupling reaction of N,N-dialkylaminomethyltrifluoroborates with aryl halides allows the construction of an aminomethyl aryl linkage through a disconnection based on dissonant reactivity patterns. A variety of t

Full text of DOI:10.1021/ol070543e

ORGANIC
LETTERS
2007
Vol. 9, No. 8
1597-1600
Aminomethylations via Cross-Coupling
of Potassium Organotrifluoroborates
with Aryl Bromides
Gary A. Molander* and Deidre L. Sandrock
Roy and Diana A. Vagelos Laboratories, Department of Chemistry, UniVersity of
PennsylVania, Philadelphia, PennsylVania 19104-6323
gmolandr@sas.upenn.edu
Received March 3, 2007
ABSTRACT
The Suzuki−Miyaura cross-coupling reaction of N,N-dialkylaminomethyltrifluoroborates with aryl halides allows the construction of an aminomethyl
aryl linkage through a disconnection based on dissonant reactivity patterns. A variety of these aminomethyltrifluoroborate substrates were
prepared in good to excellent yields and then shown to cross-couple with equal facility to both electron-rich and electron-poor aryl halides
as well as to a variety of heteroaromatic bromides.
Alkaloid natural products and nitrogen-containing pharma-
ceuticals are highly prominent synthetic targets.1 This is a
direct result not only of the structural complexity that many
of these molecules possess but also of their marked biological
activity. The properties associated with the nitrogen atom
itself, however, often make alkaloid synthesis a more
painstaking endeavor than the synthesis of polyketide- or
terpene-derived structures. Thus, new, facile methods of
nitrogen incorporation are in high demand.
different aminomethyl disconnection would provide a comple-
mentary (dissonant) C-C bond construction (eq 3). Con-
sideration of dissonant disconnects logically leads to a class
of carbanions that are generally difficult to access, somewhat
unstable, and consequently only employed to a limited extent
in this context.
Many bioactive molecules possess an aminomethyl alkenyl
or aryl linkage (Figure 1). There is ample precedent for the
installation of this aminomethyl moiety by nucleophilic
displacement,2 alkylation of iminium ions, or reductive
amination.3 These more classical strategies possess consonant
reactivity patterns in line with the polarities of the functional
groups involved (eqs 1-2).
Figure 1. Dissonant disconnects for the construction of nitrogen-
containing compounds.
Although these tactics have been employed extensively
and effectively, a new strategy employing a fundamentally
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© 2007 American Chemical Society
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Fortunately, cross-coupling reactions and the organome-
tallics used therein possess the potential to circumvent these
limitations. To date, however, a single cross-coupling has
been reported that takes advantage of this type of transfor-
mation (eq 4).
respectively. 2a could be produced in 83% yield under these
conditions (Table 1, entry 1).
Table 1. Cross-Coupling of Potassium
N-(Trifluoroboratomethyl)piperidine with Various Aryl Halidesa
This procedure partnered a highly specialized amino-
methylstannane and an enol triflate.4 Because of the com-
plexity of this reagent, the inherent toxicity associated with
organotin reagents, as well as difficulties associated with
purification of the resulting cross-coupled product, the Stille
reaction is a less than ideal aminomethylating platform. The
possibility of applying nontoxic, air- and moisture-stable
potassium N,N-dialkylaminomethyltrifluoroborates makes
Suzuki-Miyaura cross-couplings with organic halides an
attractive alternative.5 Herein, preliminary studies toward that
end are disclosed.
Initial analysis focused on the use of potassium N-
(trifluoroboratomethyl)piperidine, which is easily prepared
according to a previously published procedure.6 Optimization
was conducted utilizing 4-bromobenzonitrile (1a) as the
electrophile. After investigating several catalyst and ligand
systems, the combination of 3 mol % of Pd(OAc)2 and 6
mol % of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbi-
phenyl (XPhos)7 was determined to be the most effective
catalyst system. Cs2CO3 (3 equiv) and a 10:1 THF/H2O
mixture proved to be a satisfactory base and solvent,
a Conditions: all used Pd(OAc)2 (3 mol %), XPhos (6 mol %), Cs2CO3
(3.0 equiv), and 0.25 M solvent system; A, 10:1 THF/H2O, 80 °C, 22-24
h; B, 10:1 CPME/H2O, 95 °C, 12-18 h.
To investigate the method further, both electron-poor
(Table 1, entries 1-5) and electron-rich (Table 1, entries
6-10) aryl halides were examined. Both were found to cross-
couple with equal facility, providing the aminomethylated
products in good to excellent yields. A variety of functional
groups including nitriles, esters, ketones, aldehydes, amides,
and amines were successfully incorporated within the elec-
trophiles. The effects of steric hindrance were probed using
mesityl bromide as the electrophile. Thus, despite the
presence of two ortho substituents, 1h was found to couple
effectively, yielding 2h in 69% isolated yield (Table 1, entry
8).
(1) Kibayashi, C. Chem. Pharm. Bull. 2005, 53, 1375.
(2) Zhao, P.; Yin, Y. W. J. Heterocycl. Chem. 2004, 41, 157.
(3) (a) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C.
A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849. (b) Abdel-Magid, A. F.;
Mehrman, S. J. Org. Process Res. DeV. 2006, 10, 971.
(4) Jensen, M. S.; Yang, C.; Hsiao, Y. Rivera, N.; Wells, K. M.; Chung,
J. Y. L.; Yasuda, N.; Hughes, D. L.; Reider, P. J. Org. Lett. 2000, 2, 1081.
(5) (a) Suzuki, A.; Brown, H. C. Organic Syntheses Via Boranes: Suzuki
Coupling; Aldrich Chemical Co.: Milwaukee, 2003; Vol. 3. (b) Miyaura,
N. Top. Curr. Chem. 2002, 219, 11. (c) Miyaura, N.; Suzuki, A. Chem.
ReV. 1995, 95, 2457. (d) Molander, G. A.; Figueroa, R. Aldrichimica Acta
2005, 38, 49. (e) Molander, G. A.; Ellis, N. Acc. Chem. Res., published
online Jan. 26, 2007 http://dx.doi.org/10.1021/ar050199q. (f) Stefani, H.
A.; Cella, R.; Vieira, A. S. Tetrahedron, in press.
To improve the yields in some of the transformations, an
alternative solvent system consisting of cyclopentyl methyl
ether (CPME) and water was investigated. In all cases, use
of the CPME/H2O solvent system (10:1) increased the yield
(6) Molander, G. A.; Ham, J. Org. Lett. 2006, 8, 2031.
(7) (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.
1598
Org. Lett., Vol. 9, No. 8, 2007

and decreased the reaction time, presumably because it
allowed a higher reaction temperature (Table 1, entries 3-5,
8, and 10). This solvent system offers greatly improved yields
for the coupling of 2-bromomesitylene and 4-bromo-N,N-
dimethylaniline (1j) to yield 2h (77%) and 2j (82%),
respectively.
Table 3. Preparation of Various Potassium N,N-Dialkyl
Aminomethyltrifluoroboratesa
To expand the array of electrophiles that can be utilized,
we coupled the potassium N-(trifluoroboratomethyl)piperi-
dine with a variety of heteroaromatic bromides (Table 2).
Table 2. Cross-Coupling of Potassium
N-(Trifluoroboratomethyl)piperidine with Various
Heteroaromatic Bromidesa
a Conditions: A, alkylamine (solvent), 80 °C; B, alkylamine (solvent),
45 °C; C, alkylamine (1.05 equiv), THF, 80 °C.
stoichiometric reaction conditions, which yield tertiary amine
products in good yields.
Both cyclic and acyclic aminomethyltrifluoroborates were
found to be effective coupling partners using the conditions
presented here (Table 4). Of special interest are the successes
in coupling the benzyl-protected N-methylaminomethyl- (5c)
and the protected piperazinomethyltrifluoroborate (5d) de-
rivatives to yield the respective products, both of which offer
a Conditions: all used Pd(OAc)2 (3 mol %), XPhos (6 mol %), Cs2CO3
(3.0 equiv), and 10:1 THF/H2O (0.25 M), 80 °C, 18-24 h.
Table 4. Cross-Coupling of N,N-Dialkyl
Aminomethyltrifluoroborates with 4-Bromoanisolea
We found that the highest yields of these substrates could
be obtained by using the original THF/H2O solvent system
conditions. An assortment of these substrates were examined
including furan, thiophene, pyrimidine, isoquinoline, and
pyridine derivatives. The resulting aminomethylated het-
eroaromatics were obtained in modest to good yields.
5-Bromo-2-furaldehyde (3a) and 5-bromopyrimidine (3d)
coupled with the greatest facility to afford coupled products
4a and 4d, respectively.
To demonstrate the scope of this method further, we
prepared a variety of potassium N,N-dialkylaminomethyl-
trifluoroborates (Table 3) to use as coupling substrates. We
have previously disclosed a method of aminomethyltri-
fluoroborate preparation that necessitated the use of super-
stoichiometric quantities of the amine,6 which, though
functional, cannot be applied on a synthetically useful scale
with valuable amines. Table 3 (entries 3-5) illustrates
a Conditions: all used Pd(OAc)2 (3 mol %), XPhos (6 mol %), Cs2CO3
(3.0 equiv), and 10:1 THF/H2O (0.25 M), 80 °C, 18-24 h.
Org. Lett., Vol. 9, No. 8, 2007
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the potential for further functionalization of the amines
following deprotection.
elaboration of this method, as well as applications to complex
molecule synthesis, are currently underway.
Though the proline methyl ester and diallylamine nucleo-
philes were acceptable substrates for the preparation of their
trifluoroborate derivatives (Table 3, entries 5 and 6), initial
studies have shown that they were ineffective substrates with
the optimized coupling conditions in both THF/H2O and
CPME/H2O solvent systems.
In conclusion, we have synthesized a variety of potassium
dialkylaminomethyltrifluoroborates and demonstrated their
suitability as coupling partners in Suzuki-Miyaura cross-
coupling reactions with both electron-rich and electron-poor
aryl bromides. The ease with which these potassium orga-
notrifluoroborates can be prepared through a synthetically
useful one-step process from bromomethyltrifluoroborate6
provides a new means for accessing structurally significant
nitrogen-containing molecules. Efforts toward the further
Acknowledgment. The authors thank the NIH (GM
35249), Amgen, Johnson & Johnson, and Merck Research
Laboratories for their generous support of our program. We
acknowledge Johnson Matthey for their donation of pal-
ladium catalysts, Zeon for their donation of CPME, and
Professor Stephen L. Buchwald (MIT) for a donation of
phosphine ligands. Dr. Rakesh Kohli (University of Penn-
sylvania) is acknowledged for obtaining HRMS data.
Supporting Information Available: Experimental pro-
cedures, compound characterization data, and NMR spectra
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL070543E
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Org. Lett., Vol. 9, No. 8, 2007