Functionalization of organotrifluoroborates: Reductive amination

Article abstract of DOI:10.1021/jo800383e

(Chemical Equation Presented) Herein we report the conversion of aldehyde-containing potassium and tetrabutylammonium organotrifluoroborates to the corresponding amines through reductive amination protocols. Potassium formate facilitated by catalytic pall

Full text of DOI:10.1021/jo800383e

Functionalization of Organotrifluoroborates: Reductive Amination
Gary A. Molander* and David J. Cooper
Roy and Diana Vagelos Laboratories, Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104-6323
gmolandr@sas.upenn.edu
ReceiVed February 21, 2008
Herein we report the conversion of aldehyde-containing potassium and tetrabutylammonium organotri-
fluoroborates to the corresponding amines through reductive amination protocols. Potassium formate
facilitated by catalytic palladium acetate, sodium triacetoxyborohydride, and pyridine borane have all
served as effective hydride donors, reducing the initially formed imines or iminium ions to provide the
corresponding amines.
Introduction
reactions can be performed in the presence of the organotrif-
luoroborate unit, creating a novel entry to unique and potentially
valuable organic synthons.2 Herein we describe the reductive
amination3 of aldehyde-containing potassium and tetrabutylam-
monium organotrifluoroborates, which not only demonstrates
the resistance of the carbon-boron bond to a variety of
aggressive reaction conditions but also provides a unique access
to amine-substituted organotrifluoroborates.
Owing to the existence of an empty p orbital on boron,
boronic acids and, to a lesser extent, boronate esters exhibit
sensitivity to several classes of useful reagents commonly
employed during the course of organic synthesis. Their reactivity
toward oxidants, bases, nucleophiles, and organic acids limits
the conditions to which these organoboron species can be
exposed, and to a great extent this dictates at which point the
boron must be introduced during a synthesis campaign. Orga-
notrifluoroborates, which lack an empty p orbital and therefore
are mechanistically inhibited from reacting through modes
normally observed for tricoordinate organoboron compounds,
fulfill all of the criteria needed for a protected boronic acid with
little cost and substantial benefits.1 Thus, the tetracoordinate
nature of these species, fortified with exceptionally strong
boron-fluorine bonds, provides extraordinary opportunities for
manipulation of ancillary functional groups with retention of
the trifluoroborate, allowing one to make or purchase a very
simple organoboron compound and build molecular complexity
into the molecule from the ground up. The full development of
organotrifluoroborates has the potential to liberate strategic
planning in the construction of complex molecules as well as
the design of scaffolds for diversity-oriented synthesis. As
previously reported, we have demonstrated that alkene ozo-
nolysis, Wittig reactions, dihydroxylations, and epoxidation
Results and Discussion
During our investigation of methods to access tetrabutylam-
monium 3-(trifluoroborato)propanal (1) by an ozonolysis pro-
tocol, it was discovered that the remarkably stable secondary
ozonide 2, formed by treatment of tetrabutylammonium 3-bute-
nyltrifluoroborate (3) with ozone, could be treated with an amine
base to generate the desired aldehyde product 1 (eq 1).2e,4
Interestingly, while the desired product was obtained in pure
form when pyridine was used as the base, it was also observed
(1) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275–286.
(2) (a) Molander, G. A.; Ribagorda, M. J. Am. Chem. Soc. 2003, 125, 11148–
11149. (b) Molander, G. A.; Ellis, N. M. J. Org. Chem. 2006, 71, 7491–7493.
(c) Molander, G. A.; Figueroa, R. Org. Lett. 2006, 8, 75–78. (d) Molander, G. A.;
Figueroa, R. J. Org. Chem. 2006, 71, 6135–6149. (e) Molander, G. A.; Cooper,
D. J. J. Org. Chem. 2007, 72, 3558–3560.
(3) (a) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.
J. Org. Chem. 1996, 61, 3849–3862. (b) Abdel-Magid, A. F.; Mehrman, S. J.
Org. Process ReV. DeV. 2006, 10, 971–1031. (c) Quan, M. L.; Han, Q.; Fevig,
J. M.; Lam, P. Y. S.; Bai, S.; Knabb, R. M.; Luettgen, J. M.; Wong, P. C.;
Wexler, R. R. Bioorg. Med. Chem. Lett. 2006, 16, 1795–1798. (d) Baxter, E. W.;
Reitz, A. B. Organic Reactions; Wiley: New York, 2002; Vol. 59.
10.1021/jo800383e CCC: $40.75
Published on Web 04/16/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 3885–3891 3885

Molander and Cooper
that if a secondary amine was used instead of pyridine, the
corresponding tertiary amine 4 was obtained in addition to the
desired aldehyde (Scheme 1). We rationalized that a process
closely resembling the Leuckart reaction occurred, whereby
ammonium formate was liberated during the course of the
reaction and served as a reducing agent for a reductive amination
process.5 Although this reaction gave an inseparable mixture
of the aldehyde and the amine as products, it foretold that
conditions could be developed to access valuable amine-
containing organoboron coupling partners in pure form.
There is precedent for the reductive amination of aldehyde-
containing boronic acids and, in particular, (2-formylaryl)boronic
several different mechanistic pathways have been proposed for
these transformations,9a,b,f,g,11 including the traditional Petasis
boronic acid Mannich mechanism through an intermediate
hemiaminal or aminal (eqs 2 and 3)8,9b,11 and direct intramo-
lecular addition via an imine-complexed RBF2 species (eq 4).9c
SCHEME 1
acids and derivatives.6 However, to our knowledge unless this
boronic acid or structurally related ortho-substituted arylboronic
acids are used, there exist few examples where the amine
component is something other than an aniline derivative.7 To
fill this perceived void, a more general method for the reductive
amination of aldehyde-containing organoborons was sought to
provide access to nucleophilic cross-coupling partners incor-
porating various amine functional groups.
There was initially some concern that one of several different
processes could result in unproductive side reactions resulting
from reaction of the aldehyde-containing organotrifluoroborate
with the amine. It was hoped that the tetracoordinate organo-
trifluoroborates, in contrast to their tricoordinate boronic acid
counterparts, would prevent coordination of the boron with the
oxygen atom of the intermediate hemiaminal, a necessary initial
step for subsequent bond formation in the Petasis boronic acid
Mannich reaction (eq 2).8 Although this and related types of
transformations have been reported using organotrifluoroborates
(eqs 3 and 4),9 it has only occurred in the presence of strong
fluorophiles that generate difluoroboranes in situ.10 Depending
on the nature of the organotrifluoroborate and electrophile,
More relevant to the current work, during the course of our
studies MacMillan et al. demonstrated that potassium aryl- and
heteroaryltrifluoroborates12 participate as nucleophiles in amine-
catalyzed 1,4-additions to enals without Lewis acid activation
(although in the presence of 1 equiv of HF) through a
mechanism involving direct addition of the organotrifluoroborate
to the intermediate conjugated iminium ions. This raised the
possibility that related 1,2-additions might occur between
organotrifluoroborates and iminium ions generated via Mannich-
type reactions from the corresponding aldehydes (Scheme 2).
As it transpired, none of these potentially deleterious issues
were validated in our studies, as under the conditions developed
there was no evidence of these alternative reaction pathways.
Instead, when tetrabutylammonium (4-formylfuran-2-yl)trifluo-
roborate (5) was treated with piperidine and formic acid in the
presence of 4 Å molecular sieves, a near-quantitative yield of
the corresponding iminium ion was isolated (eq 5).
(4) Schwartz, C.; Raible, J.; Mott, K.; Dussault, P. H. Org. Lett. 2006, 8,
3199–3201.
(5) Leuckart, R. J. Prakt. Chem. 1890, 41, 33.
(6) (a) Gray, C. W.; Walker, B. T.; Brian, T.; Foley, R. A.; Houston, T. A.
Tetrahedron Lett. 2003, 44, 3309–3312. (b) Johnson, L. L.; Houston, T. A.
Tetrahedron Lett. 2002, 43, 8905–8908. (c) Luvino, D. Tetrahedron Lett. 2006,
47, 9253–9256.
(7) (a) Hall, D. G.; Gravel, M.; Thompson, M. Z.; Berube, C. J. Org. Chem.
2002, 67, 3–15. (b) Martin, B.; Posse´me´, F.; Barbier, C.; Carreaux, F.; Carboni,
B.; Seiler, N.; Moulinoux, J.-P.; Delcros, J.-G. J. Med. Chem. 2001, 44, 3653.
(c) Asano, T.; Nakamura, H.; Uehara, Y. Yamamoto, Y. ChemBioChem 2004,
5, 483–490. (d) Prullano, L.; Rohovec, J.; Aime, S.; Maschmeyer, T.; Prata,
M. I.; Lima, J.; Geraldes, C.; Peters, J. Chem. Eur. J. 2004, 10, 5205–5217.
(8) (a) Petasis, N. A.; Akritopoulou, L. Tetrahedron Lett. 1993, 34, 583–
586. (b) Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997, 53,
16463–16470. (c) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119,
445–446.
On the basis of these initial observations, an in situ reductive
amination was developed to provide the amine product 6 using
potassium formate facilitated by a palladium catalyst (eq 6).13
(9) (a) Billard, T.; Langlois, B. R. J. Org. Chem. 2002, 67, 997–1000. (b)
Tremblay-Morin, J.-P.; Raeppel, S.; Gaudette, R. Tetrahedron Lett. 2004, 45,
3471–3474. (c) Tehrani, K. A.; Stas, S. Tetrahedron 2007, 63, 8921–8931. (d)
Li, S.-W.; Batey, R. A. Chem. Commun. 2004, 1382–1383. (e) Schlienger, N.;
Bryce, M. R.; Hansen, T. K. Tetrahedron Lett. 2000, 41, 1303–1305. (f) Morgan,
I. R.; Yazici, A.; Pyne, S. G. Tetrahedron 2008, 64, 1409–1419. (g) Vieira,
A. S.; Ferreira, F. P.; Fiorante, P. F.; Guadagnin, R. C.; Stefani, H. A. Tetrahedron
2008, 64, 3306–3314.
(11) Petasis, N. A. Method for the Synthesis of Amines and Amino Acids
with Organoboron Derivatives. WO 98/00398, January 8, 1998.
(12) MacMillan, D. W. C.; Lee, S. J. Am. Chem. Soc. 2007, 129, 15438–
15439.
(10) Exception: Kabalka, G. W.; Venkataiah, B.; Dong, G. Tetrahedron Lett.
2004, 45, 729–731.
(13) Basu, B.; Jha, S.; Mosharef, H.; Das, P. Synlett 2003, 4, 555–557.
3886 J. Org. Chem. Vol. 73, No. 10, 2008

Functionalization of Organotrifluoroborates
TABLE 1. Organotrifluoroborate Substrates Subjected to
Palladium-Catalyzed Reductive Amination Using Various Amines
SCHEME 2
This method was optimized for 5 and applied to a variety of
aldehyde-containing trifluoroborates to give the corresponding
piperidinyl methylamines (Table 1). To determine the scope of
the method, aldehyde 7 was then transformed using two different
secondary amines, providing the corresponding tertiary amines
in excellent yields (Table 1, entries 5 and 6).
Unfortunately, this first reductive amination protocol suffered
in several respects. Although it proved effective for access to
pure amine-containing trifluoroborates in high yields when
applied to the furanyl substrates 5 (83%) and (5-formylfuran-
2-yl)trifluoroborate (7) (86%), the substrate scope was limited.
When the protocol was extended to a variety of activated and
nonactivated benzaldehydes, it gave either an inseparable
impurity that appeared to derive from a side reaction with DMF
or a mixture of the aldehyde starting material, the corresponding
imine, and the amino product. This method was also determined
to be effective almost exclusively for tetrabutylammonium
trifluoroborate substrates, with only one of the potassium
trifluoroborates surveyed, (4-formylfuran-2-yl)trifluoroborate
(11) (74%), giving the desired product (Table 1, entry 4).
Furthermore, following the survey of a variety of primary amines
including aniline, benzylamine, n-butylamine, tert-butylamine,
and cyclohexylamine, the method was determined to be inef-
fective in the installation of secondary amines into the trifluo-
roborate substrates examined. Thus, in an effort to expand this
chemistry to include a range of potassium organotrifluoroborates
and primary amines as effective partners, other protocols for
the reductive amination were considered.
a Greater than 5% impurity from DMF.
Sodium triacetoxyborohydride (STAB) seemed an obvious
choice as a selective reducing agent. In addition to its high level
of selectivity, reactions utilizing STAB with acetonitrile as a
solvent have also been well-developed.14 This was encouraging
to us, as we expected many of the iminium ion intermediates
to be soluble in acetonitrile. With this in mind, a variety of
conditions for the reductive amination of aldehyde 15 and
cyclohexylamine using STAB were explored.
J. Org. Chem. Vol. 73, No. 10, 2008 3887

Molander and Cooper
TABLE 2. Organotrifluoroborate Substrates Subjected to
Reductive Amination Using Pyridine-Borane and Various Amines
There was some anxiety concerning a single-step protocol,
wherein the reduction took place on an imine or iminium ion
derived in situ, because it could result in the formation of a
mixture of amine and alcohol products.12 Because such a
mixture could prove difficult to separate, a two-step, one-pot
reductive amination process was utilized whereby addition of
the reducing agent was delayed until complete conversion to
the imine or iminium ion had occurred. Thus, the overall
conversion from aldehyde to amine was considered in two
stages, examining first the conversion of the aldehyde to the
corresponding imine. When 15 and cyclohexylamine were
stirred with anhydrous methanol as a solvent, conversion to the
imine was realized in 20 min without the use of acetic acid (eq
7). The second stage, reduction of the imine using STAB, was
conducted in acetonitrile and proceeded smoothly using 1.4
equiv of STAB and 1.1 equiv of acetic acid at ambient
temperature to give the desired methylaminofuran 16. Although
this new method did allow the reductive amination of the
potassium salt 15, the method demonstrated significant substrate
dependence, and obtaining reasonable yields of pure material
with other substrates proved difficult.
Other selective reducing agents were examined to solve this
problem. Because borane-amine complexes allow the use of
methanol, a solvent that had proven very effective in the
conversion of formyltrifluoroborates to the corresponding imi-
nes, and because these reducing agents demonstrate a high
degree of selectivity for reduction of the iminium ion over the
aldehyde,15 use of these reagents would allow the entire
sequence to be run in methanol.11 After several boranes were
screened, including tert-butylamine-borane, picoline-borane,
and triethylamine-borane, pyridine-borane (pyr ·BH3) was
found to reduce the iminium ion generated from aldehyde 17
and cyclohexylamine most efficaciously. Furthermore, while
acetic acid can be used in conjunction with these boranes to
protonate the imine, giving the reactive iminium ion,16 inex-
pensive KHF2 was used instead. This served double duty. Acting
as an acid, the KHF2 activated the imine. Additionally, the KHF2
appeared to serve as a fluoride source, allowing removal of
borane byproducts that otherwise contaminated the desired
organotrifluoroborates.
A variety of amines were then used with 17 to determine the
scope of this protocol (Table 2). We were delighted to discover
that good to excellent yields could be achieved for a wide range
of amines. Although application of this method to benzaldehyde
17 and n-butylamine gave a mixture of the aminomethyl product
18 and the corresponding internal ammonium salt, other primary
amines, including cyclopropylamine and cyclohexylamine, gave
a Product exists as greater than 5% internal ammonium salt.
the desired products in pure form (entries 5 and 7). Furthermore,
the method was successfully applied to a variety of amine-
containing heterocycles to give the corresponding tertiary amine
products. Pyrrolidine, piperidine, morpholine, and even Boc-
protected piperazine could be used to give the corresponding
boron-containing amines in good yield and in high purity (Table
2, entries 2-4 and 6).
(14) Abdel-Magid, A. F.; Maryanoff, C. A. Org. Process Res. DeV. 2006,
10, 971–1031.
(15) Domannn, M. D.; Guch, I. C.; DiMare, M. J. Org. Chem. 1995, 60,
5995–5996.
Cyclohexylamine and piperidine were then used to show that
the method could be applied to a variety of aryl and heteroaryl
(16) Pelter, A.; Rosser, R. M.; Mills, S. J. Chem. Soc., Perkin Trans. 1 1984,
4, 717–720.
3888 J. Org. Chem. Vol. 73, No. 10, 2008

Functionalization of Organotrifluoroborates
TABLE 3. Organotrifluoroborate Substrates Subjected to
Reductive Amination Using Pyridine-Borane
easily purified by precipitation from acetone using diethyl ether,
those derived from substrates with an ortho relationship between
the aldehyde and trifluoroborate functional groups (16, 26, and
35) had to be further dried by azeotropically removing the water
with toluene and placing the resulting powders under vacuum
(0.01 Torr).
Amino alcohols can be utilized as substrates in the reductive
amination. Thus, it was shown that the method could be
employed using the chiral cis-aminoindanols in reactions with
aldehydes 15 and 31 (entries 8 and 9). Optimal experimental
conditions in these two cases required that 1 equiv of cis-
aminoindanol and no acid be used in the reaction mixture to
obtain pure product. Thus, good yields of the chiral products
36 and 37 were obtained by the method, which remained one-
pot but which was conducted in two steps to ensure that the
aldehyde was completely converted to the corresponding imine
prior to introduction of pyridine-borane.
Finally, we demonstrated that the amine-substituted organ-
otrifluoroborates formed in these reductive aminations could be
coupled in high yields to aryl halide partners. In an adaptation
of conditions developed by our group, the coupled product was
realized by employing 3 mol % Pd(OAc)2 under ligandless
conditions (eq 8).17 In this variation, K2CO3 (3.0 equiv) was
utilized as the base and the reaction was performed in MeOH
at 75 °C for 3 h. Under these conditions, no column chroma-
tography was required and the coupled product was isolated in
82% yield.
In summary, protocols for the reductive amination of alde-
hyde-containing organotrifluoroborates using potassium formate
facilitated by catalytic palladium acetate (Table 1), sodium
triacetoxyborohydride (eq 2), and pyridine-borane (Tables 2
and 3) have been developed. These methods offer access to
valuable amine-containing organoborons and provide another
example of the complementarity between organotrifluoroborates
(which allow functionalization of ancillary carbonyls) and
boronic acids. Use of organotrifluoroborates provides access to
both trifluoroborato-substituted imines and iminium ions, where
under similar reaction conditions boronic acids might be
expected to undergo the Petasis boronic acid Mannich or related
reactions. Reduction of the imine and iminium ion substituted
organotrifluoroborates generated in situ affords the correspond-
ing trifluoroborato-functionalized amines in a one-pot process.
The amino-substituted organotrifluoroborates thus generated can
be cross-coupled under ligandless conditions, affording high
yields of a biaryl product wherein no chromatography is utilized
at any point in the multistep process.
Experimental Section
a Gram scale reaction. b Product exists as greater than 5% internal
ammonium salt. c Performed in two stages with no KHF2.
General Procedure for Preparation of Tetrabutylammo-
nium (Formylaryl)trifluoroborates. Tetrabutylammonium (4-
aldehydes (Table 3, entries 1-7). Although the majority of the
aminomethyl-substituted organotrifluoroborates synthesized were
(17) Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302–4314.
J. Org. Chem. Vol. 73, No. 10, 2008 3889

Molander and Cooper
Formylfuran-2-yl)trifluoroborate (5). To a slurry of potassium
(4-formylfuran-2-yl)trifluoroborate (101 mg, 0.50 mmol) in H2O
(1 mL) and CH2Cl2 (5 mL) was added an aqueous solution of (n-
Bu)4NOH (0.32 mL, 0.50 mmol, 1.6 M in water) with stirring. The
biphasic solution was stirred for 0.5 h. The layers were separated.
The aqueous layer was extracted with CH2Cl2 (3 × 5 mL), after
which the combined organic layers were washed with H2O, dried
(MgSO4), and concentrated under high vacuum to give the product
and the white solid was rinsed with MeOH (3 × 5 mL). To the
filtrate was added an aqueous solution of KHF2 (1 mL, 4.4 M)
with stirring, which was continued for 1 h. The solution was then
concentrated under vacuum. The resulting yellow solid was
extracted with 10% MeOH in acetone (3 × 5 mL). This was
concentrated and precipitated with Et2O (10 mL) to give the title
compound as a yellow solid (190 mg, 74%). Mp: >200 °C. IR:
1
2933, 1669 cm-1. H NMR (500 MHz, acetone-d6): δ 1.38-1.44
1
as a colorless oil (154 mg, 76%). IR: 1673 cm-1. H NMR (500
(m, 2H), 1.52-1.60 (m, 4H), 2.10-2.16 (m, 4H), 3.44 (s, 2H),
6.21 (s, 1H), 7.30 (s, 1H). 13C NMR (125.8 MHz, acetone-d6): δ
23.7, 25.1, 53.1, 53.1, 113.1, 140.8. 19F NMR (471 MHz, acetone-
d6): δ -142.1. 11B NMR (128 MHz, acetone-d6): δ 0.662. HRMS
(ESI): m/z calcd for C10H14BF3NO (M - K) 232.1121, found
232.1129.
MHz, CDCl3): δ 0.89 (t, J ) 8 Hz, 12H), 1.25-1.36 (m, 8H),
1.45-1.55 (m, 8H), 3.08 (t, J ) 9 Hz, 8H), 6.56 (s, 1H), 8.0 (s,
1H), 9.82 (s, 1H). 13C NMR (125.8 MHz, CDCl3): δ 13.5, 19.5,
23.7, 58.5, 107.5, 129.1, 152.8, 185.5. 19F NMR (471 MHz, CDCl3):
δ -142.5. 11B NMR (128 MHz, CDCl3): δ -0.42. HRMS (ESI):
m/z calcd for C5H3BF3O2 [M - C16H36N]- 163.0178, found
163.0222.
Potassium (3-((Cyclohexylamino)methyl)furan-2-yl)trifluo-
roborate (16). To a sealed test tube containing potassium (3-
formylfuran-2-yl)trifluoroborate (110 mg, 0.54 mmol) in MeOH
(4 mL) was added cyclohexylamine (198 mg, 2.0 mmol) with
stirring. Stirring was continued for 1 h, and then the solvent was
removed to give a yellow solid. This was taken up into acetonitrile
(4 mL). Acetic acid (40 mg, 0.67 mmol) and sodium triacetoxy-
borohydride (150 mg, 0.71 mmol) were added, and the test tube
was resealed. This mixture was stirred for 16 h at room temperature.
KOH (168 mg, 1.5 mmol) was then added, followed by H2O (2
mL). This mixture was stirred for 20 min, KHF2 (421 mg, 5.4
mmol) was then added, and this solution was stirred for an
additional 30 min. The solution was then concentrated under
vacuum. The resulting yellow solid was extracted with 10% MeOH
in acetone (3 × 5 mL). This was concentrated and precipitated
with Et2O (5 mL) to give the product as a yellow solid (135 mg,
General Procedure A for the Reductive Amination of Tet-
rabutylammonium (Formylaryl)trifluoroborates using Palladium-
Catalyzed Formate. Tetrabutylammonium (4-((Piperidin-1-
yl)methyl)furan-2-yl)trifluoroborate (6). A test tube containing
activated 4 Å molecular sieves and tetrabutylammonium (4-
formylfuran-2-yl)trifluoroborate (5) was evacuated under vacuum
(0.01 Torr) for 15 min. DMF (1 mL), piperidine (60 mg, 0.71
mmol), and formic acid (28 mg, 0.61 mmol) were then added with
stirring. The solution was heated under nitrogen for 5 h at 70 °C,
after which potassium formate (100 mg, 1.19 mmol) and palladium
acetate (5 mg, 0.02 mmol, 6 mol %) were added, and stirring was
continued for an additional 4 h. Heat was removed, and the reaction
mixture was cooled to room temperature. Aqueous KHF2 (1 mL,
4.5 M) was then added, and the solution was stirred for 20 min.
The mixture was filtered, and the white solid was rinsed with
CH2Cl2 (2 × 5 mL). The filtrate was washed with H2O, 3 M NaOH,
and brine, and dried (MgSO4), and the solvent was removed to
give the product as a deep yellow oil (130 mg, 83%). IR: 2933,
1
87%). Mp: >200 °C. IR (KBr): 2939 cm-1. H NMR (500 MHz,
acetone-d6): δ 1.06-1.31 (m, 5H), 1.60 (d, J ) 12 Hz, 1H), 1.74
(dd, J ) 9, 4 Hz, 2H), 1.99-2.19 (m, 3H), 2.83-2.87 (m, 1H),
3.95 (s, 2H), 6.28 (d, J ) 1 Hz, 1H), 7.31 (d, J ) 1 Hz, 1H). 13C
NMR (125.8 MHz, acetone-d6): δ 24.4, 25.4, 30.6, 40.9, 55.6, 110.3,
141.4. 19F NMR (471 MHz, acetone-d6): δ -139.7. 11B NMR (128
MHz, acetone-d6): δ 1.61. HRMS (ESI): m/z calcd for C11H16-
BF3NO (M - K) 246.1277, found 246.1281.
1
1669 cm-1. H NMR (500 MHz, CDCl3): δ 0.81 (t, J ) 8 Hz,
12H), 1.17-1.26 (m, 10H), 1.35-1.44 (m, 12H), 2.23 (s, 4H), 2.98
(t, J ) 9 Hz, 8H), 3.32 (s, 2H), 6.11 (s, 1H), 7.09 (s, 1H). 13C
NMR (125.8 MHz, CDCl3): δ 13.6, 19.5, 23.7, 24.2, 26.1, 53.9,
56.0, 58.3, 107.8, 111.7, 151.0. 19F NMR (471 MHz, CDCl3): δ
-141.2. 11B NMR (128 MHz, CDCl3): δ 0.164. HRMS (ESI): m/z
calcd for C10H14BF3NO (M - C16H36N) 232.1121, found 232.1131.
General Procedure for Preparation of Potassium (Formyl-
aryl)trifluoroborates. Potassium (4-Formylfuran-2-yl)trifluo-
roborate (11). To (4-formylfuran-2-yl)boronic acid (5.0 g, 3.57
mmol) in MeOH (20 mL) was added dropwise a solution of KHF2
(13.65 g, 0.175 mol) in H2O (40 mL) using an addition funnel.
The mixture was stirred for 2 h and then concentrated under high
vacuum. The residual solids were extracted with 20% MeOH in
acetone (4 × 10 mL). The combined extracts were concentrated
close to the saturation point. Et2O (20 mL) was then added until
no more precipitation was observed. The solids were collected,
washed with Et2O (2 × 10 mL), and dried under high vacuum to
afford the product as a white crystalline solid (4.78 g, 66%). Mp:
>200 °C. IR (KBr): 1687 cm-1. 1H NMR (500 MHz, DMSO-d6):
δ 6.29 (d, J ) 20 Hz, 1H), 8.34 (s, 1H), 9.81 (s, 1H); 13C NMR
(125.8 MHz, DMSO-d6): δ 106.8, 128.9, 154.3, 186.3. 19F NMR
(471 MHz, DMSO-d6): δ -140.5. 11B NMR (128 MHz, DMSO-
d6): δ -0.225. HRMS (ESI): m/z calcd for C5H3BF3O2 (M - K)
163.0178, found 163.0176.
General Procedure B for the Reductive Amination of Potas-
sium (Formylaryl)trifluoroborates using Pyridine-Borane. Po-
tassium (3-((Pyrrolidin-1-yl)methyl)phenyl)trifluoroborate (20).
To a test tube containing potassium (3-formylphenyl)trifluoroborate
(106 mg, 0.50 mmol) and KHF2 (156 mg, 2.00 mmol) in MeOH
(2 mL) was added pyrrolidine (53 mg, 0.75 mmol). This was stirred
for 2 h at room temperature. Pyridine-borane (46 mg, 0.5 mmol)
was then added, and stirring was continued for 16 h. The solvent
was then removed, and the resulting white solid was rinsed with
Et2O (2 × 5 mL). The resulting solid was then extracted with 10%
MeOH/acetone (3 × 5 mL), after which the combined extracts were
concentrated and precipitated with Et2O (10 mL) to give potassium
3-((pyrrolidin-1-yl)methyl)phenyltrifluoroborate (102 mg, 76%).
(For some substrates it proved necessary to add solid KHCO3 (50
mg, 0.5 mmol) to the MeOH/acetone extracts to neutralize the
product.) Mp: >200 °C. IR (KBr): 2975 cm-1. 1H NMR (500 MHz,
acetone-d6): δ 1.66-1.77 (m, 4H), 2.52 (s, 4H), 3.63 (s, 2H), 7.05
(d, J ) 5 Hz, 2H), 7.37 (t, J ) 4 Hz, 1H), 7.47 (s, 1H). 13C NMR
(125.8 MHz, acetone-d6): δ 23.2, 53.7, 60.5, 126.3, 126.4, 130.7,
132.4, 135.7. 19F NMR (471 MHz, acetone-d6): δ -142.4. 11B NMR
(128 MHz, acetone-d6): δ 3.95. HRMS (ESI): m/z calcd for
C11H14BF3N (M - K) 228.1171, found 228.1173.
N-((4′-Methoxybiphenyl-4-yl)methyl)cyclohexanamine (38)
Using Ligandless Conditions. A sealed microwave vial containing
potassium (4-((cyclohexylamino)methyl)phenyl)trifluoroborate (34;
89 mg, 0.30 mmol), p-bromoanisole (58 mg, 0.31 mmol), Pd(OAc)2
(2 mg, 3 mol %), and K2CO3 (124 mg, 0.90 mmol) was placed
under vacuum (0.01 Torr) for 30 min, after which MeOH (1 mL)
was added with stirring. The reaction mixture was heated at 75 °C
for 3 h and then cooled to room temperature. Water (1 mL) was
added, resulting in the formation of a white precipitate. This was
Potassium (4-((Piperidin-1-yl)methyl)furan-2-yl)trifluorobo-
rate (12). A test tube containing activated 4 Å molecular sieves
(400 mg) and potassium (4-formylfuran-2-yl)trifluoroborate (192
mg, 0.95 mmol) was evacuated under vacuum (0.01 Torr) for 15
min. DMF (1 mL), piperidine (212 mg, 2.49 mmol), and formic
acid (69 mg, 1.5 mmol) were added with stirring, and the solution
was then heated under nitrogen for 5 h at 70 °C. Palladium acetate
(22 mg, 0.10 mmol, 10 mol %) and potassium formate (195 mg,
2.32 mmol) were then added, and stirring was continued for an
additional 4 h. Heat was removed, the reaction mixture was filtered,
3890 J. Org. Chem. Vol. 73, No. 10, 2008

Functionalization of Organotrifluoroborates
filtered, and the white solid was then rinsed with water (2 × 1
mL). The white solid was taken up in EtOAc (5 mL), and the
organic phase was washed with H2O (3 × 3 mL) and brine (1 mL),
dried (MgSO4), and filtered to give title compound 38 (73 mg, 82%)
as a solid following solvent removal. Mp: 65-70 °C. IR (KBr):
2918, 2845 cm-1. 1H NMR (500 MHz, methanol-d4): δ 1.12-1.26
(m, 6H), 1.57 (d, J ) 12 Hz, 1H), 1.73 (d, J ) 9 Hz, 2H), 1.96 (d,
J ) 10 Hz, 2H), 2.42-2.47 (m, 1H), 3.77 (s, 2H), 3.80 (s, 3H),
6.95 (d, J ) 8 Hz, 2H), 7.36 (d, J ) 8 Hz, 2H), 7.51 (dd, J ) 11,
2 Hz, 4 H). 13C NMR (125.8 MHz, methanol-d4): δ 24.7, 25.8,
32.3, 49.5, 54.3, 55.7, 113.9, 126.2, 127.5, 128.5, 133.3, 137.8,
139.6, 159.4. HRMS (ESI): calcd for C20H26NO (M + H) 296.2014,
found 296.2014.
Acknowledgment. Financial support was derived from the
NIH (No. R01 GM35249), and unrestricted funds from Merck
Research Laboratories and Amgen are gratefully acknowledged.
We thank Frontier Scientific and Johnson Matthey for donations
of materials used in this research.
Supporting Information Available: Text and figures giving
full experimental details and copies of all pertinent NMR
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO800383E
J. Org. Chem. Vol. 73, No. 10, 2008 3891