Disulfonimide-Catalyzed Asymmetric Reduction of N-Alkyl Imines

Article abstract of DOI:10.1002/anie.201504052

A chiral disulfonimide (DSI)-catalyzed asymmetric reduction of N-alkyl imines with Hantzsch esters as a hydrogen source in the presence of Boc₂O has been developed. The reaction delivers Boc-protected N-alkyl amines with excellent yields and enantioselectivity. The method tolerates a large variety of alkyl amines, thus illustrating potential for a general reductive cross-coupling of ketones with diverse amines, and it was applied in the synthesis of the pharmaceuticals (S)-Rivastigmine, NPS R-568 Hydrochloride, and (R)-Fendiline. A chiral disulfonimide (DSI)-catalyzed asymmetric reduction of N-alkyl imines with Hantzsch esters as a hydrogen source in the presence of Boc₂O was developed. The reaction delivers Boc-protected N-alkyl amines with excellent yields and enantioselectivity. The method was successfully applied to the synthesis of the pharmaceuticals (S)-Rivastigmine, NPS R-568 Hydrochloride, and (R)-Fendiline.

Full text of DOI:10.1002/anie.201504052

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International Edition: DOI: 10.1002/anie.201504052
German Edition: DOI: 10.1002/ange.201504052
Organocatalysis
Disulfonimide-Catalyzed Asymmetric Reduction of N-Alkyl Imines
Vijay N. Wakchaure, Philip S. J. Kaib, Markus Leutzsch, and Benjamin List*
Abstract: A chiral disulfonimide (DSI)-catalyzed asymmetric
reduction of N-alkyl imines with Hantzsch esters as a hydrogen
source in the presence of Boc2O has been developed. The
reaction delivers Boc-protected N-alkyl amines with excellent
yields and enantioselectivity. The method tolerates a large
variety of alkyl amines, thus illustrating potential for a general
reductive cross-coupling of ketones with diverse amines, and it
was applied in the synthesis of the pharmaceuticals (S)-
Rivastigmine, NPS R-568 Hydrochloride, and (R)-Fendiline.
N-Alkyl imines are highly attractive substrates for asym-
metric reductions since they would directly furnish the N-
alkyl amine pharmacophore. Chiral phosphoric acids typically
fail in the corresponding Hantzsch ester mediated imine
reductions and alternative approaches have only rarely been
investigated and remain a major challenge.[3b,6,9,10] At the
onset of our work, we hypothesized that owing to the high
basicity of the desired N-alkyl amine products, a stronger
Brønsted acid catalyst may be required for Hantzsch ester
reductions to achieve high turnover and enantioselectivity.
Indeed, we found that both phosphoric acids (2a–c) and N-
triflyl phosphoramide 2d promoted the reduction of N-
methyl imine 1a with Hantzsch ester 3b to give amine 4 with
only disappointing conversion and enantioselectivity
(Table 1, entries 1–4). Recently, we introduced chiral disul-
fonimides (DSIs) as effective precatalysts in silicon-based
E
nantiomerically pure amines, in particular a-chiral N-alkyl
amines, represent a privileged pharmacophore that can be
found in a vast number of pharmaceutical and agrochemical
substances, including (S)-Rivastigmine (Alzheimerꢀs and
Parkinsonꢀs diseases), NPS R-568 (hyperparathyroidism),
and (R)-Fendiline (angina pectoris; Figure 1).[1]
Table 1: Reaction development.[a]
Figure 1. a-Chiral N-alkyl amine pharmaceuticals.
Entry Cat. Hantzsch ester additive t [h] Conv.[%][b]
e.r.[c]
Catalytic asymmetric imine reductions and reductive
aminations of carbonyl compounds represent efficient
approaches for the construction of optically pure amines.[2]
Recently, we developed a Brønsted acid catalyzed asymmet-
ric imine reduction and reductive amination of ketones using
Hantzsch esters as hydrogen source,[3] and independent
variations and applications have appeared.[4–8] Despite these
advances, however, such reductions have been limited to N-
aryl imines. We now report a highly enantioselective chiral
disulfonimide (DSI)-catalyzed Hantzsch ester mediated
reduction of N-alkyl imines.
1
2a
2b
2c
2d
2e
2 f
2g
2h
2i
3b
3b
3b
3b
3b
3b
3b
3b
3b
3a
3c
3d
3d
3d
3d
3d
–
72
72
72
72
48
72
72
48
48
48
48
24
48
48
48
48
18
6
51.5:48.5
63:37
51.5:48.5
51:49
77:23
70:30
76:24
85:15
88:12
2
–
3
4
5
6
7
8
9
10
11
12
13[d]
–
–
–
–
–
–
–
–
–
–
–
–
25
50
84
86
80
83
83
40
81
99
88
60
99
80
2i
2i
2i
2i
89.5:10.5
88.5:11.5
88:12
93:7
14[d,e] 2i
15[d–f] 2i
16[d–f] 2b
95.5:4.5
95.5:4.5
62:38
Boc2O
Boc2O
[*] Dr. V. N. Wakchaure, P. S. J. Kaib, M. Leutzsch, Prof. Dr. B. List
Max-Planck-Institut für Kohlenforschung
Kaiser -Wilhelm-Platz 1, 45470 Mülheim an der Ruhr (Germany)
E-mail: list@kofo.mpg.de
[a] Reactions were run on a 0.1 mmol scale. [b] Determined by GC–MS.
[c] Determined by GC or HPLC with a chiral stationary phase.
[d] Reactions were run at 108C. [e] Mesitylene was used as a solvent.
[f] Obtained product 5a.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201504052.
11852
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Lewis acid catalysis[11] and also as strong Brønsted acid
catalysts.[12] Indeed, our chiral DSIs (2e–i) catalyzed the
transformation more rapidly than the alternative phosphoric
acid based catalysts and also afforded amine 4 with higher
enantioselectivity (entries 5–9). After careful investigation,
we identified reaction conditions in which the reduction of
imine 1a is performed using 5 mol% of catalyst (R)-DSI-2i,
Hantzsch ester 3d (1.4 equiv), and 5 Š molecular sieves in
mesitylene at 108C for 2 days. Amine 4 was obtained with
a high enantiomeric ratio (e.r.) of 95.5:4.5, however the
reaction was still rather sluggish and the product was isolated
in only 41% yield [Eq. (1)]. We speculated that the poor yield
of isolated product was still due to catalyst deactivation
through salt formation with the highly basic amine 4. It has
previously been reported that related product inhibition
pathways can be eliminated by in situ protection.[10c,d,13]
Encouraged by these reports, we investigated the effect of
running the reaction in the presence of di-tert-butyl dicar-
bonate (Boc2O). Remarkably, we found that full conversion
into the desired N-Boc-protected product 5a in 97% yield
with an identical e.r. of 95.5:4.5 was observed under these
conditions [Eq. (2)].
Table 2: Substrate scope of the asymmetric reduction of N-methyl
imines.[a]
Entry
1
Products
Yield [%]
97
e.r.[b]
5a
5b
5c
5d
5e
5 f
5g
5h
5i
95.5:4.5
2
88
91
93
94
96
95
96
95
90
92
94
67
95
95:5
98.5:1.5
96:4
3
4[c]
5
95:5
6
95.5:4.5
96:4
7
8
97:3
9[c]
10
11[d,e]
12
13[c]
14[c]
95:5
5j
95:5
5k
5l
94:6
95:5
5m
5n
67.5:33.5
97:3
Other reagents, such as acetic anhydride and dibenzyl
dicarbonate (Cbz2O), could also be used and afforded the
corresponding N-Ac product in 90% yield with an e.r. of
94.5:5.5 and the N-Cbz product in 92% yield with an e.r. of
95:5, respectively (see the Supporting Information). Encour-
aged by this result, the scope of the enantioselective reduction
of N-methyl imines was next investigated (Table 2). A variety
of N-methyl imines were efficiently reduced in the presence
of (R)-DSI-2i (5.0 mol%) to afford the corresponding Boc-
protected N-methyl amines with high yields and enantiose-
lectivity. Electron-donating para substituents are well toler-
ated (entries 1–4). For example, tert-butyl-substituted imine
1c provided amine 5c in 91% yield with an e.r. of 98.5:1.5
(entry 3). A p-methoxy group in imine 1d decreased the
reactivity and required 5days to achieve high yield and 96:4
e.r. (entry 4). Electron-withdrawing para substituents such as
fluorine, chlorine, bromine, or trifluoromethyl groups have no
significant influence on enantioselectivity or reactivity
(entries 5–8). However, the p-cyano group in imine 1i
decreased the reactivity and also required a longer reaction
time to achieve full conversion with an e.r. of 95:5 (entry 9).
Substitutions at the meta position are equally well tolerated
and both electron-donating and electron-withdrawing groups
15
16
5o
5p
92
89
95.5:4.5
90.5:9.5
17[d]
18[c]
19
5q
5r
74
63
90
52.5: 47.5
53.5:46.5
71:29
5s
[a] Reactions were run on a 0.25 mmol scale. [b] Determined by HPLC
with a chiral stationary phase. The absolute configuration was deter-
mined by preparing an authentic sample of 5a and by comparing various
known optical rotation values (see the Supporting Information).
[c] Reaction time 5 d. [d] Reaction time 3 d. [e] The S-enantiomer of
disulfonimide 2i was used.
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provided the corresponding amines in high yields and
enantioselectivity (entries 10–12). ortho Substitution proved
detrimental to both reactivity and selectivity, while meta,para
disubstitution led to good results with an e.r. of 97:3
(entries 13 and 14). Interestingly, N-methyl imine 1o, which
is derived from a-tetralone, was reduced in high yield with an
e.r. of 95.5:4.5 (entry 15). N-Methyl imine 1p, which is derived
from 1-indanone, gave less satisfactory results (entry 16). An
aliphatic imine can also be employed but gave poor enantio-
selectivity (entries 17 and 18). Propiophenone-derived imine
1s was reduced in 90% yield with an e.r. of 71:29 (entry 19).
An additional strength of our method is revealed upon
exploring longer and substituted N-alkyl groups. Gratifyingly,
the reduction of N-ethyl imine 6a proceeded in 83% yield
and with an e.r. of 97:3 (Table 3, entry 2). Remarkably, even
Table 3: Scope of the asymmetric reduction of N-alkyl imines.[a]
Scheme 1. Synthesis of (S)-Rivastigmine, NPS R-568 Hydrochloride,
and (R)-Fendiline.
Entry
1
Products
Yield [%]
97
e.r./d.r.[b]
95.5:4.5
5a
7a
7b
7c
7d
7e
7 f
To illustrate the synthetic utility of our method, several
marketed pharmaceuticals were prepared (Scheme 1). For
example, a short synthesis of (S)-Rivastigmine, which is
currently used for treating Alzheimerꢀs disease, was real-
ized.[14] Boc-protected N-methyl amine 5k (Table 2, entry 11)
was converted into N,N-dimethyl amine 8 in 93% yield upon
LiAlH4 reduction. This transformation illustrates an addi-
tional benefit of the Boc moiety, which not only enables
turnover in the asymmetric reduction but also introduces
a useful N-methyl precursor. Next, cleavage of the O-methyl
group using aqueous HBr provided (S)-3-(1-dimethylaminoe-
thyl)phenol 9 in 95% yield. A single recrystallization from
CH2Cl2/pentane gave product 9 in 76% yield with an e.r. of
99.6:0.4. Finally, carbamoylation of alcohol (S)-9 with com-
mercially available N-ethyl-N-methylcarbamoyl chloride 10
in the presence of sodium hydride furnished (S)-Rivastigmine
in 98% yield with an e.r. of 99.6:0.4.
Furthermore, the calcimimetic compound NPS R-568
hydrochloride, which has been shown to be effective against
both primary and secondary hyperparathyroidism, was syn-
thesized.[15] In this case, imine generation from commercially
available ketone 11 and amine 12, asymmetric reduction, and
Boc deprotection, were all performed in one pot, thereby
providing NPS R-568 in 82% yield with an e.r. of 97:3. A
single recrystallization of the corresponding HCl salt from
CH2Cl2/MTBE gave NPS R-568 hydrochloride in 82% yield
with an e.r. of 99.7:0.3.
2
83
90
82
77
94
83
94
97:3
3
97.5:2.5
97.5:2.5
95.5:4.5
97:3
4
5
6
7[c]
8
95.5:4.5
97.5:2.5
7g
9[c]
7h
75
79
93:7
10[c,d]
ent-7h
97.5:2.5
[a] Reactions were run on a 0.25 mmol scale. [b] Determined by HPLC
with a chiral stationary phase. [c] Reaction time 3 d. [d] The S-enantiomer
of disulfonimide 2i was used.
the N-n-propyl, N-n-butyl, N-allyl, N-2-phenylethyl, N-2-(3,4-
dimethoxy)-phenylethyl, and N-3-phenylpropyl imine sub-
strates (6b–6g) are well tolerated and reacted with excellent
enantioselectivity (entries 3–8). Interestingly, the reduction of
imine 6h, which is derived from methyl (tert-butoxycar-
bonyl)-l-lysinate, with (R)-DSI-2i resulted in a d.r. of 93:7,
while (S)-DSI-2i gave a d.r. of 97.5:2.5, which is indicative of
a matched combination (entries 9 and 10).
In a similar manner, an enantioselective synthesis of (R)-
Fendiline, an effective antianginal drug for the treatment of
coronary heart diseases, was achieved in 78% yield with an
e.r. of 97.5:2.5.[16]
In summary, we have developed a highly enantioselective
Brønsted acid catalyzed reduction of N-alkyl imines. The
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Acknowledgements
Generous support by the Max-Planck-Society and the Euro-
pean Research Council (Advanced Grant “High Performance
Lewis Acid Organocatalysis, HIPOCAT”) is gratefully
acknowledged.
Keywords: Brønsted acids · disulfonimide · N-alkyl amines ·
organocatalysis · reduction
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Received: May 4, 2015
Published online: August 14, 2015
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