Metal-free transfer hydrogenation catalysis by B(C6F 5)3

Article abstract of DOI:10.1021/om2005832

The activation of amines by B(C₆F₅)₃ is shown to effect the catalytic racemization of a chiral amine. Extending this strategy to a bimolecular process, catalytic transfer hydrogenation of imines, enamines, and N-heterocycles is demonstrated using iPr₂NH as the source of hydrogen and a catalytic amount of the Lewis acid B(C ₆F₅)₃.

Full text of DOI:10.1021/om2005832

COMMUNICATION
pubs.acs.org/Organometallics
Metal-Free Transfer Hydrogenation Catalysis by B(C F )
6
5 3
Jeffrey M. Farrell, Zachariah M. Heiden, and Douglas W. Stephan*
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada, M5S 3H6
S Supporting Information
b
ABSTRACT: The activation of amines by B(C F ) is shown to effect the catalytic racemization
6
5 3
of a chiral amine. Extending this strategy to a bimolecular process, catalytic transfer hydrogena-
tion of imines, enamines, and N-heterocycles is demonstrated using iPr NH as the source of
2
hydrogen and a catalytic amount of the Lewis acid B(C F ) .
6
5 3
he advent of organocatalysis offers new and insightful
strategies for a variety of chemical transformations.
1
À10
T
Such strategies offer access to creative molecular syntheses and
control of stereochemistry. In addition, there are logistical and
cost advantages associated with processes that avoid removal of
trace metal residues from transition-metal catalysts. A comple-
mentary metal-free strategy to catalysis involves the use of main
group species. Indeed, in an overview of organocatalysis, Jacob-
5
sen and McMillan noted that “Lewis acid-catalyzed processes...
will likely be among the important future advances.” Interest-
ingly, this view was foreshadowed with the 1925 finding of the
1
1,12
MeerweinÀPondorf reduction,
in which aluminum alkox-
ides effect the transfer of hydrogen from isopropanol to un-
saturated ketones. Subsequently, Corey and Helal demonstrated
enantioselective transfer hydrogenations of ketones employing
Figure 1. Proton NMR spectra of (a) R-CH and (b) CH signals from
3
catalytic racemization of (R,R)-1 (1 mol % B(C F ) , C D Br, 25 °C).
6 5 3 6 5
13
BH as the reductant. More recently, the first reports of
3
enantioselective organocatalytic reductions of R,β-unsaturated
the reaction of Et
2
NH and B(C
workers reported an analogous equilibrium involving iPr
and B(C . These observations stand in contrast to the 1966
report of Massey and Park in which classical amine adducts of
6
F
5
)
3
, whereas Rieger and co-
1
4,15
23
aldehydes
have led to a plethora of chiral Brønsted acid-
NH
2
catalyzed transfer hydrogenations employing Hantzsch esters as
F )
6 5 3
3,16
the hydrogen source.
31
Following the report of the heterolytic cleavage of H by
B(C F ) were reported. The reversibility of these hydride abstrac-
6 5 3
2
17,18
“
frustrated Lewis pairs” (FLPs),
we described the use of
tions suggested two ramifications to us. Herein, we show that
the analogous abstraction of hydride from chiral amines provides
a strategy for facile and catalytic amine racemization. Moreover,
activation of an amine in this manner provides a source of hydride
and proton that can be exploited for metal-free, Lewis acid-catalyzed
transfer hydrogenations.
Lewis acids for the catalytic hydrogenation of imines, aziridines,
1
9,20
and protected nitriles.
Erker,
Subsequently, the research groups of
24
2
1,22
23
Rieger, and Soos extended and broadened the
range of applications of FLP-based catalysts to include enamines,
silyl enol ethers, and enones. Recently, Klankermayer has
25,26
elegantly extended such systems for asymmetric catalysis.
The reaction of bis((R)-1-phenylethyl)amine, (R,R-1), in the
presence of 1 mol % B(C
While these efforts have focused on H as the reductant,
F ) was found to result in conversion
6 5 3
2
alternative sources of reducing equivalents have received recent
of the optically pure amine to an equilibrium mixture of
27,28
32
1
attention. Berke and co-workers
the reduction of imines and polar olefins employing BH NH as
have clearly demonstrated
diastereomers. This was evident by H NMR spectroscopy
with the appearance of an additional doublet at 1.25 ppm
attributable to the methyl groups and a quartet at 3.7 ppm
resulting from the benzylic protons over the course of 96 h
corresponding to the meso compound (R,S-1) (Figure 1). The
resulting diastereomeric ratio of meso/dl was found to be ca. 1:2.
The racemization of the chiral amine was accelerated with
3
3
the source of H2.
In seeking alternative sources of H for transfer hydroge-
2
29
nations, we noted that Basset and co-workers had reported that
the stoichiometric reaction of B(C F ) and Et NPh did not
6
5 3
2
afford an adduct. Instead, these authors confirmed that an
equilibrium was established between free borane, amine, the salt
[
(
Et NHPh][HB(C F ) ], and the zwitterion [EtPhNdCHCH B-
Received: July 3, 2011
Published: August 02, 2011
2
6 5 3
2
30
C F ) ]. Resconi and co-workers made similar observations for
6
5 3
r 2011 American Chemical Society
4497
dx.doi.org/10.1021/om2005832
|Organometallics 2011, 30, 4497–4500

Organometallics
COMMUNICATION
a,b
Scheme 1. Catalytic Racemization of a Chiral Amine
Table 1. B(C F ) -Catalyzed Transfer Hydrogenations
6
5 3
increasing concentration of borane and increasing temperature.
For example, warming the reaction to 80 °C led to complete
racemization in minutes, whereas use of 10 mol % B(C F ) at
6
5 3
2
5 °C also gave complete racemization in 4 h. Racemization of
both chiral centers was confirmed by X-ray crystallography as
addition of HCl to the reaction afforded crystals of racemic (R,R/S,S)
33
[(Ph(Me)CH) NH ][Cl] 2. In a similar fashion, 10 mol % of
2 2
the cationic boranes [Cy PC F B(C F ) ][B(C F ) ] and
3
6
4
6
5 2
6 5 4
3
4,35
[
tBu (H)PC F B(C F ) ][B(C F ) ]
were found to race-
2
6
4
6
5 2
6 5 4
mize (S,S)-1. In contrast, 10 mol % of the chiral borane derived
26
from 2-phenyl-2-bornene, C H B(C F ) , effected racemiza-
16
20
6 5 2
tion of (S,S)-1 to a much lesser extent, affording a 7:1 diaster-
eomeric ratio after 24 h at 80 °C. This observation is consistent
with the ability ofthis boraneto effect the enantioselective catalytic
26
reduction of a series of imines under H and milder conditions.
2
The reduced capacity of this borane to effect racemization may be
attributed to a combination of reduced Lewis acidity and increased
steric crowding precluding hydride abstraction.
Probing this process in more detail, the stoichiometric reac-
tion of (S,S-1) and B(C F ) was observed to give a mixture of
6
5 3
the salt [(Ph(Me)CH) NH ][HB(C F ) ] 3 and the zwitter-
2
2
6 5 3
36
ion (Ph(Me)CH)NHdC(Ph)CH B(C F ) 4 (Scheme 1).
2
6 5 3
This observation is consistent with hydride abstraction and
deprotonation of amine 1, affording 3 and a transient ketimine
3
6
that reacts with B(C F ) to give 4. By analogy to the work of
a
1
6
5 3
Twenty-four hours at 100 °C. Yields determined by H NMR
2
9
30
23
Basset, Resconi, and Rieger, 4 is thought to exist in
b
spectroscopy. Mixture of diastereomers.
equilibrium with ketimine and B(C F ) (Scheme 1). Proton
6
5 3
NMR data for 3 are consistent with the racemization of the chiral
centers, inferring that the formation of 3 and 4 are in equilibrium
with 1 and B(C F ) . Addition of H to the reaction mixture of 3
As the above racemization proceeds via hydride abstraction,
followed by readdition, we reasoned that abstraction of hydride
from an amine and delivery to another substrate, with concurrent
proton transfer, would offer a strategy to catalytic transfer
hydrogenation. To probe this possibility, the imine substrate
6
5 3
2
and 4 afforded a 1:2 mixture of two diastereomers of 3, as
1
evidenced by the H NMR spectrum. The presence of the borate
anion was confirmed by a 1:1:1:1 quartet at 3.20 ppm that
11
PhCHdNtBu was combined with 1 mol % B(C
6
F
5
)
3
in neat
iPr NH. The approximate 100-fold excess of amine is pre-
2
collapsed to a broad singlet at 3.27 ppm upon B decoupling
45
11
and a doublet at À24.3 ppm in the B NMR spectrum. X-ray
sumed to be a driving force in the transfer hydrogenation. Upon
crystallography showed the centrosymmetric space group of the
heating to 100 °C for 24 h, NMR data revealed the formation of
isolatedcrystals to beP2 /c, consistent withthe cocrystallization of
1
PhCH NHtBu in 70% yield (see Table 1). Increasing the catalyst
2
racemic isomers (R,R/S,S) of [(Ph(Me)CH) NH ][HB(C F ) ]
2
2
6 5 3
loading to 5 mol % resulted in >98% yield of the target amine
3
demonstrating that isomerization of both of the chiral centers can
PhCH NHtBu over 24 h at 100 °C. The resulting amines are
2
occur. In this case, a close approach of the boron-bound hydride and
an NH proton was found to be 1.955(3) Å, analogous to that seen in
related phosphonium salts. While transition metal-based homoge-
neous and heterogeneous catalysts as well as enzymatic approaches
readily separated from the catalyst by chromatography through
silica. Similarly, less basic imines of the form PhCHdNAr (Ar =
Ph, C H Me ) were hydrogenated to greater than 98% yield in
6
2
3
neat iPr NH, although it was necessary to employ 20 mol % of
2
37À44
to racemization of chiral amines have been reported,
this is the
the B(C F ) catalyst. Although the ketimine PhC(Me)dNPh
6
5 3
first to utilize highly electrophilic boranes to effect this isomerization.
Clearly, this must be an important consideration in the design of
FLP systems for asymmetric hydrogenations.
was hydrogenated in only 37% yield, application of these transfer
hydrogenation conditions to the imine precursor of the com-
mercialized antidepressant sertraline resulted in a 90% yield of
4
498
dx.doi.org/10.1021/om2005832 |Organometallics 2011, 30, 4497–4500

Organometallics
COMMUNICATION
the diastereomeric mixture of the product. The enamines 1-(1-
cyclohexen-1-yl)-piperidine and 2-methylene-1,3,3-trimethylin-
doline were also quantitatively reduced by this transfer hydro-
genation protocol. Application of this transfer hydrogenation
protocol to N-heterocyclic substrates resulted in lower yields. For
example, 8-methylquinoline was reduced to 8-methyl-1,2,3,
(8) Ueda, M.; Kano, T.; Maruoka, K. Org. Biomol. Chem. 2009,
7, 2005.
(9) Enders, D.; Wang, C.; Liebich, J. X. Chem.—Eur. J. 2009, 15,
1
1058.
(10) Buckley, B. R. Annu. Rep. Prog. Chem., Sect. B: Org. Chem. 2009,
1
05, 113.
(11) Meerwein, H.; Schmidt, R. Justus Liebigs Ann. Chem. 1925, 444, 221.
4
-tetrahydroquinoline in 56% yield, whereas the aziridine
(12) Ponndorf, W. Angew. Chem. 1926, 39, 138.
cis-(PhCH) NPh was reduced to give PhN(CH Ph) in 27%
2
2
2
(13) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986.
14) Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. C. J. Am. Chem.
yield. In both cases, the residual starting material was the only
other product. The formation of PhN(CH Ph) is presumably
(
2
2
Soc. 2004, 127, 32.
derived from the thermally induced CÀC bond cleavage of the
(15) Yang, J. W.; Hechavarria Fonseca, M. T.; List, B. Angew. Chem.,
Int. Ed. 2004, 43, 6660.
4
6
47,48
aziridine, affording an azomethine ylide
that then under-
(
16) Ouellet, S. G.; Walji, A. M.; Macmillan, D. W. C. Acc. Chem. Res.
007, 40, 1327.
17) Welch, G. C.; Juan, R. R. S.; Masuda, J. D.; Stephan, D. W.
Science 2006, 314, 1124.
goes reaction via proton and hydride transfer. This stands in
2
contrast to the B(C F ) -catalyzed hydrogenation of cis-1,2,
6
5 3
(
3
-triphenylaziridine that proceeds via the protonation of aziridine
from hydrogen splitting, followed by NÀC bond scission, to give
(18) Welch, G. C.; Stephan, D. W. J. Am. Chem. Soc. 2007, 129, 1880.
19
PhCH CH(Ph)NHPh.
2
(19) Chase, P. A.; Welch, G. C.; Jurca, T.; Stephan, D. W. Angew.
In conclusion, we have demonstrated that the activation of
amines by B(C F ) via hydride abstraction is evident from the
Chem., Int. Ed. 2007, 46, 8050.
6
5 3
(20) Chase, P. A.; Jurca, T.; Stephan, D. W. Chem. Commun. 2008, 1701.
(21) Spies, P.; Schwendemann, S.; Lange, S.; Kehr, G.; Fr €o hlich, R.;
Erker, G. Angew. Chem., Int. Ed. 2008, 47, 7543.
catalytic racemization of a chiral amine. Moreover, this abstrac-
tion can be exploited for catalytic transfer hydrogenation of
imines, enamines, and N-heterocycles. This chemistry represents
a rare example of metal-free transfer hydrogenation. While other
reports have employed the pyridine derivative Hantzsch’s ester as
(22) Wang, H. D.; Fr €o hlich, R.; Kehr, G.; Erker, G. Chem. Commun.
2
008, 5966.
23) Sumerin, V.; Schulz, F.; Nieger, M.; Leskela, M.; Repo, T.;
Rieger, B. Angew. Chem., Int. Ed. 2008, 47, 6001.
24) Eros, G.; Mehdi, H.; Papai, I.; Rokob, T. A.; Kiraly, P.; Tarkanyi,
G.; Soos, T. Angew. Chem., Int. Ed. 2010, 49, 6559.
(
3
,16
the source of H2, this approach employs the readily accessible
(
iPr NH. Further studies of these and other main group-based
2
metal-free catalysts in a variety of catalytic processes is the subject
of ongoing study.
(25) Chen, D. J.; Klankermayer, J. Chem. Commun. 2008, 2130.
(26) Chen, D. J.; Wang, Y. T.; Klankermayer, J. Angew. Chem., Int. Ed.
2
010, 49, 9475.
’
ASSOCIATED CONTENT
(27) Yang, X. H.; Zhao, L. L.; Fox, T.; Wang, Z. X.; Berke, H. Angew.
Chem., Int. Ed. 2010, 49, 2058.
(28) Yang, X. H.; Fox, T.; Berke, H. Chem. Commun. 2011, 47, 2053.
S
Supporting Information. Synthetic, experimental, and
b
(
29) Millot, N.; Santini, C. C.; Fenet, B.; Basset, J. M. Eur. J. Inorg.
Chem. 2002, 3328.
30) Focante, F.; Mercandelli, P.; Sironi, A.; Resconi, L. Coord.
Chem. Rev. 2006, 250, 170.
crystallographic details. This material is available free of charge
via the Internet at http://pubs.acs.org.
(
’
AUTHOR INFORMATION
(
(
31) Massey, A. G.; Park, A. J. J. Organomet. Chem. 1964, 2, 245.
32) (R,R)-bis(Phenylethyl)amine (0.273 g, 1.21 mmol) was trans-
Corresponding Author
6 5 3 6 5
ferred with 1 mol % B(C F ) (6.2 mg, 0.0121 mmol) in 1 mL of C D Br
to a J-Young NMR tube. The tube was sealed and immersed in an oil
*E-mail: dstephan@chem.utoronto.ca.
bath at 80 °C. Conversion to a mixture of diastereomers was observed by
1
H NMR spectroscopy.
’
ACKNOWLEDGMENT
(
33) Crystallographicdatafor2: C16
H20ClN, MW = 261.78, T= 150 K,
The financial support of LANXESS Inc., NSERC of Canada,
space group = monoclinic, P2 /n, a = 7.5592(6) Å, b = 18.2567(14) Å,
c = 10.8792(8) Å, β= 92.180(4) , V = 1500.3(2) Å , Z =4, μ= 0.238mm ,
measured reflections = 13779, independent reflections = 4571, para-
meters = 165, Rint = 0.0531, R = 0.0511, Rw = 0.1417, GOF = 0.905. 3:
1
o
3
À1
and the Ontario Centres of Excellence is gratefully acknowl-
edged. D.W.S. is grateful for the award of a Killam Research
Fellowship 2009-2011 and a Canada Research Chair. Z.M.H. is
grateful for the award of an Ontario Postdoctoral Fellowship. We
would like to dedicate this work to Professor Christian Bruneau
on the occasion of his 60th birthday.
C
34
H
21BF15N, MW = 739.33, T = 150 K, space group = monoclinic,
P2 /c, a = 10.5576(6) Å, b = 11.9278(6) Å, c = 24.2325(13) Å,
1
o
3
À1
β = 98.135(2) , V = 4674.4(4) Å , Z = 4, μ = 0.159 mm , measured
reflections = 21558, independent reflections = 6876, parameters = 482,
Rint = 0.0630, R = 0.0523, Rw = 0.1221, GOF = 0.967.
’
REFERENCES
(34) Welch, G. C.; Prieto, R.; Dureen, M. A.; Lough, A. J.; Labeodan,
(
1) Weiner, B.; Szymanski, W.; Janssen, D. B.; Minnaard, A. J.;
O. A.; Holtrichter-Rossmann, T.; Stephan, D. W. Dalton Trans. 2009,
1559.
Feringa, B. L. Chem. Soc. Rev. 2010, 39, 1656.
(
(
(
2) Vicario, J. L.; Badia, D. ChemCatChem 2010, 2, 375.
3) Rueping, M.; Sugiono, E.; Schoepke, F. R. Synlett 2010, 852.
4) Nielsen, M.; Jacobsen, C. B.; Holub, N.; Paixao, M. W.; Joergensen,
(35) Welch, G. C.; Cabrera, L.; Chase, P. A.; Hollink, E.; Masuda,
J. D.; Wei, P. R.; Stephan, D. W. Dalton Trans. 2007, 3407.
(36) Heiden, Z. M.; Stephan, D. W. Chem. Commun. 2011, 47, 5729.
(37) Ahn, Y.; Ko, S.-B.; Kim, M.-J.; Park, J. Coord. Chem. Rev. 2008,
252, 647.
(38) Blacker, A. J.; Stirling, M. J.; Page, M. I. Org. Process Res. Dev.
2007, 11, 642.
(39) Jerphagnon, T.; Gayet, A. J. A.; Berthiol, F.; Ritleng, V.; Mrsic,
N.; Meetsma, A.; Pfeffer, M.; Minnaard, A. J.; Feringa, B. L.; de Vries,
J. G. Chem.—Eur. J. 2009, 15, 12780.
K. A. Angew. Chem., Int. Ed. 2010, 49, 2668.
5) Jacobsen, E. N.; MacMillan, D. W. C. Proc. Natl. Acad. Sci. U.S.A.
010, 107, 20618.
6) Buckley, B. R.; Neary, S. P. Annu. Rep. Prog. Chem., Sect. B: Org.
Chem. 2010, 106, 120.
7) Alba, A.-N. R.; Companyo, X.; Rios, R. Chem. Soc. Rev. 2010,
9, 2018.
(
2
(
(
3
4
499
dx.doi.org/10.1021/om2005832 |Organometallics 2011, 30, 4497–4500

Organometallics
COMMUNICATION
(40) Paetzold, J.; B €a ckvall, J. E. J. Am. Chem. Soc. 2005, 127, 17620.
(41) Pamies, O.; B €a ckvall, J.-E. Chem. Rev. 2003, 103, 3247.
(42) Pamies, O.; Ell, A. H.; Samec, J. S. M.; Hermanns, N.; Backvall,
J.-E. Tetrahedron Lett. 2002, 43, 4699.
43) Thalen, L. K.; Zhao, D.; Sortais, J.-B.; Paetzold, J.; Hoben, C.;
B €a ckvall, J.-E. Chem.—Eur. J. 2009, 15, 3403.
44) Samec, J. S. M.; B €a ckvall, J.-E.; Andersson, P. G.; Brandt, P.
Chem. Soc. Rev. 2006, 35, 237.
45) Typical experimental conditions: In a glovebox, B(C
mg, 0.0355 mmol, 20 mol %) was dissolved in dry iPr NH (2.5 mL, 1.8 g,
7 mmol), and the solution was added to tBuNdCHPh (28.7 mg,
.177 mmol). The resulting solution was transferred to a 25 mL bomb
(
(
(
6 5 3
F ) (18.2
2
1
0
with a sealable Teflon tap and magnetic stir bar. The reaction vessel was
sealed, removed from the glovebox, and stirred at 100 °C for 24 h, after
which it was cooled to room temperature and quenched by the addition
of silica. Subsequently, the mixture was eluted through a short silica
1
column, the filtrate concentrated, and the conversion determined by H
NMR in CDCl3.
(
(
46) Heine, H. W.; Peavy, R. Tetrahedron Lett. 1965, 35, 3123.
47) Huisgen, R.; Scheer, W.; Szeimies, G.; Huber, H. Tetrahedron
Lett. 1966, 7, 397.
48) Heine, H. W.; Peavy, R.; Durbetaki, A. J. Org. Chem. 1966,
1, 3924.
(
3
4
500
dx.doi.org/10.1021/om2005832 |Organometallics 2011, 30, 4497–4500