Metal-free diastereoselective catalytic hydrogenations of imines using B(C6F5)3

Article abstract of DOI:10.1039/c1cc10438a

Reductions of chiral ketimines effected under H₂ by catalytic amounts of B(C₆F₅)₃ result in moderate to excellent diastereoselectivities. In the case of camphor and menthone derived imines, the reductions procee

Full text of DOI:10.1039/c1cc10438a

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COMMUNICATION
Metal-free diastereoselective catalytic hydrogenations of imines using
B(C6F5)3w
Zachariah M. Heiden and Douglas W. Stephan*
Received 22nd January 2011, Accepted 31st March 2011
DOI: 10.1039/c1cc10438a
Reductions of chiral ketimines effected under H2 by catalytic
amounts of B(C6F5)3 result in moderate to excellent diastereo-
selectivities. In the case of camphor and menthone derived
imines, the reductions proceeded with greater than 95%
diastereoselectivity.
foreshadowed in the work of Brown and Corey31,32 who
developed stoichiometric chiral borohydride reagents some
years ago. A preliminary effort to effect an enantioselective
FLP hydrogenation was described by Chen and Klankermayer.33
In that case a chiral borane was used to reduce a ketimine,
resulting in ee of 13%. In a very recent paper,34 this group has
extended this strategy, developing chiral borane catalysts for
the enantioselective imine reduction with ee’s as high as 84%.
In this report, we demonstrate catalytic hydrogenation of
chiral ketimines using B(C6F5)3 as a catalyst. In the case
of camphor and menthonimine derivatives, these reductions
proceed with high diastereoselectivity.
About 70% of all new chemicals produced today incorporate
a chiral center. In the pharmaceutical industry the most
favorable process for the introduction of a chiral center into
a chemical is through asymmetric hydrogenation. Currently
most imines reductions involve the use of stoichiometric
reagents such as NaBH4 or NaBH3CN.1–3 Although these
reagents work well, their use on industrial scales does generate
waste disposal issues. While metal-based catalysts have been
shown to reduce imines to amines,4–7 new guidelines of
United States Pharmacopeia dramatically have lowered the
allowable metal impurities such as Ru, Ir, Rh, and Os in
pharmaceuticals.8,9 This has prompted new interest in metal-
free hydrogenation processes. While stoichiometric reductions
of organic species utilizing Hantzsch’s ester as a source of H2
have garnered some attention,10–13 it has only been with the
recent discovery of ‘‘frustrated Lewis pairs (FLPs)’’,14–18 that
the possibility of metal-free hydrogenation catalysts has been
demonstrated. In our initial report of such catalysis we showed
that the species R2PHC6F4BH(C6F5)2 (R = tBu, C6H2Me3)
effectively catalyzes the hydrogenation of primarily aldimines
in excellent isolated yields.19 Subsequently, we showed that
analogous hydrogenations of imines, aziridines, and protected
nitriles are effected by catalytic amounts of the Lewis acid
B(C6F5)3.20 Subsequently, other researchers have extended
FLP reductions to include the hydrogenation of imines,
enamines and silylenol ethers.21–30
A series of ten ketimines with chiral substituents derived
from a-phenethylimine, camphor-imine and methonimine,
1–10 were prepared (Fig. 1). Hydrogenations of a series of
chiral imines using B(C6F5)3 as the catalyst were studied.
Heating toluene solutions of (S)-tBuCH(Me)NQC(Me)Ph 1
(Fig. 1) with 10 or 20 mol% of B(C6F5)3 at 80 1C under 5 atm
H2 for 48 h resulted in the complete reduction of the imine 1 to
the corresponding amine. However, in this case, there was no
diastereoselectivity. Analogous catalytic hydrogenations of imines:
(S)-CyCH(Me)NQC(Me)Ph 2, (S)-PhCH(Me)NQC(Me)Ph 3,
(S)-PhCH(Me)NQC(Et)Ph 4, (S)-PhCH(Me)NQC(iPr)Ph 5,
The potential of this finding for applications in asymmetric
synthesis is a logical and highly desirable extension. Indeed,
given that FLP reductions can be viewed as a catalytic version
of borohydride reductions, this prospect has been
Department of Chemistry, University of Toronto,
80 St. George Street, Toronto, Ontario, Canada M5S 3H6.
E-mail: dstephan@chem.utoronto.ca
w Electronic supplementary information (ESI) available: Experimental
procedures, sample calculations of borohydride cone angles, and 3D
coordinates of borohydrides. CCDC 809425–809427. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c1cc10438a
Fig. 1 Chiral imines.
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and (S)-PhCH(Et)NQC(Et)Ph 6 led to the quantitative
reduction to the corresponding amine. NMR data of the
product amines revealed that reduction afforded a mixture
of diastereomers with increasing diastereoselectivity ranging
from 11 to 65% (Table 1). Both the yield and diastereo-
selectivity were improved by using higher pressure of H2 at
lower temperature. Thus at 25 1C and 115 atm H2, 10 mol% of
B(C6F5)3 effected the quantitative catalytic hydrogenation of 3
to the corresponding amine with an improved diastereomeric
ratio of 62%. Identical results were obtained for the hydro-
genation of 3 using the less Lewis acidic borane, B(C6F4H)3.35
More forcing conditions were required for the catalytic
reduction of the following imines: N-benzyl-D-camphorimine
7, N-phenyl-D-camphorimine 8, N-benzyl-menthonimine 9,
and N-phenyl menthonimine 10 (Fig. 1). Heating these
reaction mixtures for 5 days and at 115 1C under 5 atm of
H2 gave complete reduction using 10 or 20 mol% of B(C6F5)3.
In all of these cases, high diastereoselectivities ranging
from 95–99% were obtained. The stereochemistry of the
preferred diastereomer was unambiguously established
in the case of 7. Stoichiometric reaction of the imine 7 with
B(C6F5)3 under H2 afforded R,R,R-N-benzyl-camphorammonium
tris-pentafluorophenyl-hydridoborate salt, [R,R,R-C6H9(Me)-
(CMe2)(NH2CH2Ph)][HB(C6F5)3] 11 which was crystallo-
graphically characterized (Scheme 1 and Fig. 2), confirming
the stereochemistries about C(1), C(2) and C(5).
Fig. 2 POV-ray depiction of the cation of 11. Carbon = black,
hydrogen = white, and nitrogen = green.
Table 1 Catalytic hydrogenation of chiral imines with B(C6F5)3
B(C6F5)3/ PH
/
Major
Conv. (%) de isomer
2
Imine mol%
atm
T/1C t/h
1
1
2
2
3
3
4
4
5
5
6
6
7
7
8
8
9
20
10
20
10
10
10
20
10
20
10
20
10
20
10
20
10
20
10
20
10
5
5
5
5
5
115
5
5
5
5
5
5
5
5
5
5
5
5
80
80
80
80
80
25
80
80
80
80
80
80
115
115
115
115
115
115
115
115
48 100
0
0
—
—
48 100
48 100
48 100
21 S,R
11 S,R
36 S,S
62 S,S
39 S,S
39 S,S
45 S,R
45 S,R
48
72
23 100
48 100
48 100
48 100
48 100
24 100
24 100
120 100
120 100
120 100
68 S,S
65 S,S
99 R,R,R
99 R,R,R
95 R,R,R
98 R,R,R
99 R,S,R
99 R,S,R
99 R,S,S
96 R,S,S
In the case of the imines 1–6, the hydride transfer is less
discriminating presumably as a result of the free rotation of
the chiral substituent about the C–N bond. This postulate is
also consistent with the increased diastereoselectivities with
increasing steric congestion about the imine fragment. To
further garner insight into the reactions of imine reduction,
stoichiometric reactions of imines with B(C6F5)3 in the
presence and absence of H2 were undertaken. For example,
upon stoichiometric reaction of imines 1 or 4 with B(C6F5)3
results in ready addition to the enamine-tautomers affording
the products (S)-tBuCH(Me)NHC(CH2B(C6F5)3)Ph 12 and
(S)-PhCH(Me)NHC(CH(Me)B(C6F5)3)Ph 13 (Scheme 1,
Fig. 3 and ESIw). The formation of these species was
confirmed spectroscopically and crystallographically. The
research groups of Piers36 and Basset37 have previously
observed similar additions of B(C6F5)3 to enamine tautomers.
While these species (from imines 1–6) are formed in
120
92
120 100
120 100
120 100
9
10
10
5
5
120
66
equilibrium, under H2 the reduction of the free-imine results
in the ultimate consumption of the imine and enamine. None-
theless, the accessibility of the enamine in these cases,
generates the possibility of a mutarotation, thus diminishes
facial preference generated by the chiral substituent.
Mechanistically these reductions are thought to proceed via
the previously proposed FLP hydrogenation mechanism. The
imine acts as the base partner together with B(C6F5)3 to
heterolytically cleave H2. The resulting anion [HB(C6F5)3]À
then transfers the hydride to the carbon-atom of the iminium
cation affording the amine and regenerating the B(C6F5)3
which is then available for further reduction. It is clear that
in the case of the camphorimines and menthonimines 7–10, the
transfer of the hydride from [HB(C6F5)3]À to the corresponding
iminium cations proceeds almost exclusively via approach of
the anion toward one of the two diastereotopic faces of the
iminium cations. While this explanation offers some insight
into the selectivity, the formation of differing diastereomers
from 9 and 10 remains unexplained.
For comparative purposes the precursors imines were also
reduced stoichiometrically using the reducing agents NaBH3CN
and NaBH(OAc)3 (Table 2). While the product amines were
obtained in quantitative yields under mild conditions, the
diastereoselectivities for these reagents were markedly
different from those obtained from the catalytic hydro-
genations. NaBH3CN gave rise to reduction products with
Scheme 1 Proposed mechanism for hydrogenation and formation of
11–13.
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NaBH3CN NaHB(OAc)3
NaBH3CN NaHB(OAc)3
Imine
Imine
1
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Reactions with NaBH3CN and NaBH(OAc)3 employed acetic acid as
the proton source.
diastereoselectivities ranging between 1–35% while those from
NaBH(OAc)3 gave rise to diastereoselectivities from 31 to 85%.
Collectively it appears that proximity of the chiral center to
the unsaturated-carbon center of the imine rather than the
nitrogen atom facilitates higher diastereoselectivities. In addition,
these reduction data suggest that the steric bulk around the
borohydride anion is key to diastereoselectivity. The catalytic
reductions of the camphor– and menthone–imines result in the
near quantitative diastereoselectivities. This is attributed to the
significantly larger [HB(C6F5)3]À anion in comparison to
[BH3CN]À and [BH(OAc)3]À anions used in stoichiometric
reductions. This view is supported by computed cone angles
of 1861, 1631 and 921 for the borohydrides, [HB(C6F5)3]À,
[HB(OAc)3]À and [BH3CN]À, respectively (ESIw).
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excellent diastereoselectivities when the chiral center is near the
unsaturated carbon center. This is attributed to the larger effect
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bulky [HB(C6F5)3]À. The presence of the chiral center near the
unsaturated nitrogen center had a less impact on the diastereo-
selectivity of the hydrogenation. Further mechanistic studies and
the application of FLP-based hydrogenation catalysts continue
to be a subject of intense efforts in our laboratories.
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The authors thank NSERC of Canada for financial support.
D. W. S. is grateful for the award of a Canada Research Chair
and a Killam Research Fellowship. Z. M. H. is grateful for the
award of an Ontario Postdoctoral Fellowship.
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Chem. Commun., 2011, 47, 5729–5731 5731