A consecutive process for C-C and C-N bond formation with high enantio-and diastereo-control: Direct reductive amination of chiral ketones using hydrogenation catalysts

Article abstract of DOI:10.1039/c9cc00923j

High diastereoselectivity was observed in the Rh-catalysed reductive amination of 3-arylcyclohexanones to form tertiary amines. This was incorporated into a one-pot enantioselective conjugate addition and diastereoselective reductive amination, including an example of assisted tandem catalysis.

Full text of DOI:10.1039/c9cc00923j

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
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Received 00th January 20xx,
A consecutive process for C-C and C-N bond formation with high
enantio-and diastereo-control: Direct Reductive Amination of
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
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chiral ketones using hydrogenation catalysts.
Sophie H Gilbert,a Virginie Viseura and Matthew L. Clarke a
High diastereoselectivity was observed in the Rh-catalysed
reductive amination of 3-arylcyclohexanones to form tertiary
amines. This was incorporated into a one-pot enantioselective
conjugate addition and diastereoselective reductive amination,
including an example of assisted tandem catalysis.
electron rich alkenes of low reactivity. Iminium ions are
readily reduced, but there is a challenge in controlling
chemoselectivity when made in situ, and stereochemistry in
an outer-sphere reaction. Rh catalysts derived from a
combination of a Rh source and weakly donating phosphine
were recently found to be very active achiral enamine
hydrogenation catalysts.6e Here we show that simple Rh
catalysts can promote direct reductive amination using H2
gas on a range of chiral ketone substrates. Apart from
furthering this challenging topic in the hydrogenation field,
this provides a solution for reactions that are actually
problematic using any classical procedure using reducing
agents. Finally a rare example of assisted tandem catalysis is
The synthesis of enantiomerically pure amines is of special
significance in Organic Synthesis: it is estimated that chiral
amines are present in around 40% of pharmaceuticals.1
Direct reductive amination is a particularly appealing method
to prepare amines since it avoids the generation of waste
salts inherent in alkylation methods, or the alternative of
isolation of imine or enamine intermediates. Direct reductive
amination is also potentially quite general in being applicable
to many combinations of carbonyl compounds and primary
or secondary amines as substrates. Some useful
enantioselective and diastereoselective direct reductive
amination processes have been reported.2 The most
industrially important method to make any chiral
compounds with chemo-catalysts is catalytic hydrogenation,
due to economic and environmental considerations.
Hydrogenations that are also direct reductive aminations are
at the cutting edge of what is possible to do with current
hydrogenation catalysts and need further research.3,4
Reductive aminations that produce tertiary amines are the
presented:7 catalyst speciation is altered during
consecutive process that needs two different catalysts.
a
Table 1 Ligand effects on catalytic reductive aminationa
Entry
1
Ligand
Yield b (%)
64
dr c (%)
96
least well developed of all, and particularly need
a
breakthough to become useful procedures.5,6 Tertiary
amines appear in many bio-active compounds and launched
drugs,5 so a hydrogenation-based method for their synthesis
could have broad application.
(TFP)
2
3
4
5
6
7
8
9
Ph3P
(4-FC6H4)3P
(3,4,5-C6F3H4)3P
(C6F5)3P
(4-ClC6H4)3P
(PhO)3P
Trace
21
56
58
49
70
Trace
0
90
92
96
75
91
82
82
-
Direct reductive amination of secondary amines with
ketones would likely involve a common reduction step,
whether that be an enamine or iminium ion hydrogenation.
Either of these are very challenging hydrogenations, as is
clear from the literature.6 Effective alkene hydrogenations
generally make use of alkenes with a coordinating groups
such as enamides. This restricts rotation and enhances
association. Without this the substrates are hindered
(rac)-BINAP
10
dppf
TFP
0
57
-
93
11d
a General catalytic conditions: 3-(4-fluoro-phenyl)-cyclohexanone
(0.5 mmol), pyrrolidine (0.75 mmol), [Rh(COD)Cl]2 (0.4 mol%),
ligand (1.6 mol%), in toluene (1 mL) under 60 bar H2 at 65°C for 22
aSchool of Chemistry, University of St Andrews, EaStCHEM, St Andrews, Fife, UK.
E-mail: mc28@st-andrews.ac.uk; Fax: +(44) 1334 463808; Tel: +(44) 1334 463850
Electronic Supplementary Information (ESI) available: Full experimental procedures,
analytical data, NMR and HPLC spectra. See DOI: 10.1039/x0xx00000x
hours. b Isolated yields. c dr values were determined by 19F{1H} NMR.
d1 atm of H2.
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A range of ligands in combination with [RhCl(COD)]2 deliver order that the process could produce enantiomerically and
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DOI: 10.1039/C9CC00923J
catalysts for directive reductive amination of racemic ketone diastereomerically pure isomers of the desired amines, we
2a (Table 1). The selectivity always favours the trans relative also investigated conditions to produce the chiral ketones in
stereochemistry shown, as determined by 1H NMR enantiomerically rich form. Adapting a known protocol12 for
spectroscopy (see ESI for stereochemical assignment) The reactions with the aryl boronic acids shown delivers the
weakly donating ligands such as those described in entry 1, 3 desired enantiomerically enriched ketones in varying yields,
and
4
give
increased
amine
formation
and but generally high ee (Scheme 1). Heteroaryl boronic acids
diastereoselectivity. It has already been noted that weakly nucleophiles are more challenging, as they are more prone
donating phosphines are associated with increased catalyst to protodeborylation.13 For example, 2f has only been
activity in enamine hydrogenations.8 The (C6F5)3P ligand is synthesised in a couple of publications using aryl-boron
associated with a decrease in diastereoselectivty when reagents, and these gave poor yields.14 These procedures
compared to the other substituted triarylphosphines, even needed to use alternative boronates such as Ar-Β(MIDA) and
though it is the weakest electron donor of all the phosphine Ar-Βpin. These ketone substrates (2a-i) could all be applied
examples. This may have to do with unfavourable sterics – to the reductive amination procotol and form the
(C6F5)3P has a tolman angle of 184°, whereas the other corresponding amines with high diastereoselectivity and
ligands in entries 1-4 and 6 have angles of 145°.9 One of the good yield (Table 2).
preferred ligands is weakly donating and commercially
available tri(2-furyl)phosphine (TFP), as it displays both high
Table 2 Catalytic reductive amination of several ketone substrates
activity and selectivity. Various bidentate ligands were tested
(entries 8-10) but none of these showed any activity. It was
also found that the protocol is tolerant of a wide range of
conditions; the experiment described in entry 11 shows that
this reaction works at atmospheric pressures. This reaction
tolerates a range of solvents including EtOAc and MeTHF.
Full details are provided in the supporting information.
Entry
Ketone
2a
Yield b (%)
dr c (%)
93
1
2
3
4
5
6
7
8
9
89
88
89
86
82
89
99
72
79
2b
2c
94
97
2d
2e
96
89
2f
2g
63
99
2h
Ar = Ph 2i
94
87
a General catalytic conditions: ketone (0.5 mmol), pyrrolidine (0.75
mmol), [Rh(COD)Cl]2 (0.4 mol%), TFP (1.6 mol%), in dioxane (1 mL)
under 40 bar H2 at 80°C for 22 hours. b Isolated yields. c dr values
were determined by NMR.
The 2-furyl substituted ketone gives the lowest selectivity;
perhaps unsurprising given it is the smallest aryl substituent
tested. Fig. 1 shows a comparison on the dr obtained in this
atom-efficient approach relative to the dr of the classical
process using NaBH(OAc)3. Thus not only is this reaction
more atom efficient, but it benefits from significantly higher
selectivity.
Scheme 1 Enantioselective synthesis of 3-substituted
cyclohexanones and piperidonesa. Yields quoted are isolated yields.
ee values were determined by HPLC. a Uses 1.5 eq of boronic acid.
Different amines were explored in this catalytic system.
Pyrrolidine is a sterically unhindered nucleophilic amine, so is
especially good at forming enamines in situ. The other
amines studied do not so readily undergo enamine formation
so molecular sieves and trifluoroacetic acid was required as
additives to allow workable yields. We note the unsuccessful
tert-butyl methyl amine did not undergo reductive amination
using reducing agents or hydrogenation catalysts. Pleasingly
even an aniline derivative does undergo the reaction
Rh catalysed conjugate additions are a powerful method to
produce ketones of this type.10 Expanding a known protocol
for the conjugate addition to cyclohexenone using an achiral
catalyst enabled us to prepare further racemic chiral ketones
2a-i (see ESI for details).11 Racemic ketones were used for the
majority of the hydrogenation studies (d.r. is excepted to be
the same for racemic or single enantiomer compounds). In
2 | J. Name., 2012, 00, 1-3
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(Scheme 3). Preliminary studies using a cyclopentyl ketone
and a 4-piperidinone type substrate show that the
procedures could extend to other quite different substrates
(see ESI).
amination step (Table 1, Entry 8). To get around this issue,
TFP was added after the conjugate addition had gone to
completion, prior to putting the reaction mixture under
hydrogenation conditions. (Scheme 4)
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DOI: 10.1039/C9CC00923J
This process effectively contains 3 steps within the same pot.
From simple starting materials, a complex product with
multiple chiral centers is formed with good yields, high
diastereoselectivity and enantioselectivity. This is an
example of assisted tandem catalysis.7,15 Once the initial
reaction step is complete, the original catalyst is converted
into a new catalytic species, with the latter converting the
new intermediate into the desired final product. Ligand
exchange is perhaps an underutilised method to achieve
assisted tandem catalysis, and hence increase the value
delivered by a precious metal precatalyst.
100
99
90
80
70
60
50
40
30
20
10
0
97
96
94
94
93
89 89
87
77
72
71
71
71
70
65
63
61
2a 2b
2c
2d 2e
2f
2g 2h
2i
Ketone Substrate
Hydrogenation
NaBH(OAc) 3
Figure 1 A comparison of diastereoselectivity between the catalytic
hydrogenation and the classical reductive amination using
stochiometric NaBH(OAc)3. dr values were determined by NMR.
Scheme 4 The one-pot reaction of sequential enantioselective
conjugate addition followed by diastereoselective reductive
amination a Isolated yield from cyclohexenone. b ee was determined
using 19F{1H} NMR analysis on the chiral salts made in situ from (R)-
α-methoxyphenylacetic. c dr was determined by 19F NMR.
The active catalyst in Scheme 4, step II was formed by
addition of the TFP. This active hydrogenation catalyst could
contain just TFP phosphorus containing ligands, similar to the
active catalyst of Table 2, or this particular active catalyst
may also include a BINAP ligand. 31P NMR experiments (see
ESI) are suggestive of both Rh-TFP complexes and Rh-TFP-
BINAP complexes within the reaction mixture in step II. As
this was inconclusive, a further experiment was done
replicating the conditions for step II with (S)- 2a to see if any
difference in performance between the catalyst enantiomers
could be seen (Table 3). While a Rh-BINAP complex shows a
matched/mismatched interaction and expected low yields
(entry 1 and 2), the active catalyst formed in step II does not
show any significant effects (entry 3 and 4). While these
results are far from entirely conclusive, it may suggest the
chiral catalyst is an achiral Rh-TFP complex, as the
enantiomer of BINAP used has no effect on the dr.
Scheme 3 Catalytic reductive amination for less nucleophilic
secondary amine substrates. Yields quoted are isolated yields, and
dr values were determined by 19F{1H} NMR.
Both this conjugate addition and reductive amination use
similar rhodium sources. It seemed feasible that these two
steps could be done consecutively to allow the rhodium to
be recycled in the second step. This could be achieved by
carrying out the conjugate addition under inert conditions,
then adding pyrrolidine and charging the system with
hydrogen. While BINAP was a great ligand for the conjugate
addition, this proved to be almost inactive for the reductive
The reaction mechanism could potentially proceed through
the catalyst hydrogenating either the enamine or iminium
ion intermediate. Deuterium labelling experiments were
carried out using deuterium gas. If there was no exchange
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3
4
For enantioselective examples see (a) H. Huang, X. Liu, L.
View Article Online
and a clean C=C reduction took place, d labelling would
confirm this. However, unfortunately fast exchange occured
between the protons alpha to the C-N bond, resulting in
mixed labeling at 5 different protons, a scenario that is
possible with either enamine or iminium ion intermediate
(see ESI).
Zhou, M. Chang and X. Zhang, Angew.DCOhIe:m10..1I0n3t9. /ECd9.C, 2C0010962,3J
55, 5309-5312 (b) C. Li, B. Villa-Marcos and J. Xiao, J. Am.
Chem. Soc., 2009, 131, 6967-6969. For diastereoselective
examples see (c) R. P. Tripathi, S. S. Verma, J. Pandey and V.
K. Tiwari, Curr. Org. Chem., 2008, 12, 1093-1115; (d) T. C.
Nugent, A. K. Ghosh, V. N. Wakchaure and R. R. Mohanty,
Adv. Synth. Catal., 2006., 348, 1289-1299
(a) D. Steinhuebel, Y. Sun, K. Matsumura, N. Sayo, and T.
Saito, J. Am. Chem. Soc. 2009, 131, 11316-11317 (b) T.
Senthamarai, K. Murugesan, J. Schneidewind, N. V. Kalevaru,
W. Baumann, H. Neumann, P. C. J. Kamer, M. Beller, R. V.
Jagadeesh., Nature Comm. 2018, 9, 4123 (c) J. Gallardo-
Donaire, M. Hermsen, J. Wysocki, M. Ernst, F. Rominger, O.
Trapp, A. S. K. Hashmi, A. Schäfer, P. Comba, and T. Schaub,
J. Am. Chem. Soc. 2018, 140, 355-361 (d) X. Tan, S. Gao, W.
Zeng, S. Xin, Q. Yin, and Xumu Zhang, J. Am. Chem. Soc.
2018, 140 , 2024-2027 (e) Zhang-Pei Chen, Shu-Bo Hu, Ji
Zhou, and Y-G Zhou, ACS Catalysis 2015, 5, 6086-6089 (f) F.
Christie, A. Zanotti-Gerosa,
Table 3 Enantiomer ligand effects on diastereoselctive reductive
amination of enantiomer X
Entry
BINAP
eq. of TFP
Yield b (%)
dr c (%)
D.Grainger, ChemCatChem 2018, 10, 1012-1018 (g) Transfer
hydrogenation is a competing technology, again more
focussed towards primary and seconday amine synthesis,
see D. Talwar, N. P. Salguero, C. M. Robertson and J. Xiao,
Chem. Eur. J. 2014, 20, 245-252 and ref’s therein
T. C. Nugent, M. El-Shazly, Adv. Synth. Catal., 2010, 352, 753-
819, (b) B. Villa-Marcos, C. Li, K. R. Mulholland, P. J. Hogan
and J. Xiao, Molecules, 2010, 15, 2453-2472, (c) J. Margalef,
O. Pàmies and M. Diéguez, Chem. Eur. J., 2017, 23, 813-822
For selected examples, see: (a) G. Hou, J. Xie, P. Yan and Q.
Zhou, J. Am. Chem. Soc., 2009, 131, 1366-1367 (b) S. Tin, T.
Fanjul and M. L. Clarke, Catal. Sci. Technol., 2016, 6, 677-680
(c) V. I. Tararov, R. Kadyrov, T. H. Riermeirer, J. Holz and A.
Börner, Tet. Lett., 2000, 41, 2351-2355 (d) N. E. Lee, S. L.
Buchwald, J. Am. Chem. Soc., 1994, 116, 5985-5986 (e) S. Tin,
T. Fanjul and M. L. Clarke, Beilstein J. Org. Chem., 2015, 11,
622-627
D. E. Fogg and E. N. dos Santos, Coord. Chem. Rev., 2004,
248, 2365-2379
J. A. Fuentes, P. Wawrzyniak, G. J. Roff, M. Bühl and M. L.
Clarke, Catal. Sci. Tech., 2011, 1, 431-436
M. L. Clarke, D. Ellis, K. L. Mason, A. G. Orpen, P. G. Pringle,
R. L. Wingad, D. A. Zaher and R. T. Baker, Dalton Trans.,
2005, 1294-1300
(mol%)
1
2
3
4
(S)-BINAP
(R)-BINAP
(S)-BINAP
(R)-BINAP
0
0
3
3
15
13
51
53
83
93
90
91
5
6
a see experimental in ESI for reaction details. b Isolated yields. c dr
values were determined by 19F{1H} NMR.
In conclusion, an atom-efficient way of synthesising tertiary
chiral amines has been developed. We have demonstrated
some of the potential of this reaction; adapting it to both a
consecutive process and a range of substrates. Further
developments of reactions such as this will lead to a broader
range of scaleable tertiary amine syntheses than are
currently avalible.
7
8
9
Conflicts of interest
There are no conflicts to declare
Notes and references
10 (a) Y. Takaya, M. Ogasawara and T. Hayashi, J. Am. Chem.
Soc., 1998, 120, 5579-5580 (b) T. Hayashi, M. Takahashi, Y.
Takaya and M. Ogasawara, J. Am. Chem. Soc., 2002, 124,
5052-5058 (c) K. Fagnou and M. Lautens, Chem. Rev., 2003,
103, 169-196
11 R. Itooka, Y. Iguchi and N. Miyaura, J. Org. Chem., 2003, 68,
6000-6004
12 K. Lukin, Q. Zhang and M. R. Leanna, J. Org. Chem., 2009, 74,
929-931
13 (a) E. Tyrell and P. Brookes, Synthesis, 2003, 4, 469-483. (b)
H. G. Kuivila, J. F. Reuwer and J. A. Mangravite, Can. J. Chem.,
1963, 41, 3081-3090.
14 (a) F. Albrecht, O. Sowada, M. Fistikci and M. M. K. Boysen,
Org. Lett., 2014, 16, 5212-5215; (b) X. Yu, T. Shirai, Y.
Yamamoto and N. Miyaura, Chem. Asian J., 2011, 6, 932-937
15 For selected examples, see: (a) J. G de Vries, Can. J. Chem.,
2001, 79, 1086-1092, (b) M. Renom-Carrasco, P. Gajewski, L.
Pignataro, J G. de Vries, U. Piarulli, C. Gennari and L. Lefort,
Adv. Synth. Catal., 2015, 357, 2223-2228 (c) A. N. Thadani
and V. H. Rawal, Org. Lett., 2002, 4, 4317-4320 (d) B.
Schmidt, S. Krehl and S. Hauke, J. Org. Chem. 2013, 78, 5427-
5435
§ We would like to thank the University of St Andrews, and
the EPSRC Centre for Doctoral Training in Critical Resource
Catalysis (CRITICAT) for financial support [Ph.D. studentship
to SG; Grant code: EP/L016419/1]. The research data
supporting this publication can be accessed
at https://doi.org/10.17630/9835792a-fd68-4622-b273-
3868b664b500
1
2
D. Ghislieri and N. J. Turner, Top. Catal., 2014, 57, 284-300
For selected examples, see: (a) H. Blaser, H. Buser, H. Jalett,
B. Pugin and F. Spindler, Synlett, 1999, 867-868; (b) J. Zhou,
B. List, J. Am. Chem. Soc., 2007, 129, 7498-7499; (c) A. F.
Abdel-Magid and S. J. Mehrman, Org. Process. Res. Dev.,
2006, 10, 971-1031; (d) . N. Wakchaure, J. Zhou, S. Hoffman,
B. List, Angew Chem. Int. Ed. 2010, 49, 4612-4614; (e) J.
Zhou, B. List, Synlett, 2007, 13, 2037-2040; (f) F. Leipold, S.
Hussain, D. Ghislieri, N. J. Turner, ChemCatChem 2013, 5,
3505-3508; (g) S. Hussain, F. Leipold, H. Man, E. Wells, S. P.
France, K. R. Mulholland, G. Grogan, N. J. Turner,
ChemCatChem, 2015, 7, 579-583; C. J. Dunsmore, R. Carr, T.
Fleming, N. J. Turner, J. Am. Chem. Soc., 2006, 128, 2224-
2225.
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A consecutive process for C-C and C-N bond formation with
high enantio-and diastereo-control: Direct Reductive
Amination of chiral ketones using hydrogenation catalysts
Sophie H Gilbert, Virginie Viseur and Matthew L. Clarke*
A Rh catalyst derived from tri-(2-furyl)phosphine enables the direct reductive
amination of 1,3-substituted ketones to occur in high yield and
diastereoselectivity