Simple catalytic mechanism for the direct coupling of α-carbonyls with functionalized amines: A one-step synthesis of plavix

Article abstract of DOI:10.1021/ja4096472

The direct α-amination of ketones, esters, and aldehydes has been accomplished via copper catalysis. In the presence of catalytic copper(II) bromide, a diverse range of carbonyl and amine substrates undergo fragment coupling to produce synthetically useful α-amino-substituted motifs. The transformation is proposed to proceed via a catalytically generated α-bromo carbonyl species; nucleophilic displacement of the bromide by the amine then delivers the α-amino carbonyl adduct while the catalyst is reconstituted. The practical value of this transformation is highlighted through one-step syntheses of two high-profile pharmaceutical agents, Plavix and amfepramone.

Full text of DOI:10.1021/ja4096472

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Communication
A Simple Catalytic Mechanism for the Direct Coupling of #-Carbonyls
with Functionalized Amines: A One-Step Synthesis of Plavix
Ryan W. Evans, Jason R. Zbieg, Shaolin Zhu, Wei Li, and David W. C. MacMillan
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja4096472 • Publication Date (Web): 09 Oct 2013
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Journal of the American Chemical Society
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A Simple Catalytic Mechanism for the Direct Coupling of α-Carbonyls with
Functionalized Amines: A One-Step Synthesis of Plavix
Ryan W. Evans, Jason R. Zbieg, Shaolin Zhu, Wei Li, and David W. C. MacMillan*
4
5
6
Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544
dmacmill@princeton.edu
7
RECEIVED DATE
8
9
HBr regenerates the catalyst;
water is the only by-product
O
Abstract: The direct α-amination of ketones, esters, and
aldehydes has been accomplished via copper catalysis. In the
presence of catalytic copper(II) bromide, a diverse range of
carbonyl and amine substrates undergo fragment coupling to
produce synthetically useful α-amino substituted motifs. The
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60
Me
X
2 CuIIBr2
carbonyl
2 H2O
1/2 O2 + 2 HBr
transformation is proposed to proceed via
a catalytically
generated α-bromo carbonyl species; nucleophilic displacement
of the bromide by the amine then delivers the α-amino carbonyl
adduct while the catalyst is reconstituted. The practical value of
this transformation is highlighted through one-step syntheses of
two high–profile pharmaceutical agents, Plavix and
amfepramone.
Br
Cu
Br
Copper
O
Cu
Br
2 CuIBr
Catalytic Cycle
X
Me
Carbonyls bearing α-amino substitution are widely
represented among pharmaceutically active compounds and
complex natural products1 (Figure 1). The invention of catalytic
strategies toward this high-value synthon is a longstanding goal
in organic synthesis, and a number of methods have been
developed for the installation of specifically tailored amine
substrates at the carbonyl α-position.2 For example, the catalytic
α-amination of ketones and aldehydes (via enolate derivatives)
often involve the use of 2π-electrophile aza-substrates to deliver
α-hydrazinyl or α-oxy-amino products, two structural classes
that must be chemically modified prior to natural product or
medicinal chemistry applications. Slower to develop,
α-aminocarbonyl
HBr
O
transient
O
Me
Me
electrophilic
α-bromo
X
X
H
N
N
Br
carbonyl
Catalyst Regeneration Using Oxygen and Transient HBr
2 HBr + 1/2 O2 + 2 CuBr 2 CuBr2 + H2O
Carbonyl α-amine: Common pharmacophore in medicinal agents
O
O
O
Scheme 1. Design of Cu(II)-catalyzed carbonyl–amine coupling.
Me
Me
MeO
however, have been catalytic protocols3 that allow for the merger
of carbonyl-derived enolates with a generic range of nitrogen-
containing structures or functionalities, a more direct strategy
that would bypass the requirement for post-reaction amine
modification. Conceptually, the catalytic α-coupling of amines
and enolates appears to be electronically mismatched, given that
both reaction partners are inherently nucleophilic and that
amines readily undergo 1,2-addition with electrophilic ketones,
aldehydes, esters, etc. As such, we recently questioned whether
catalysis could be employed to transiently render carbonyls
electrophilic at the α-position, thereby enabling the in situ
addition of a broad range of nitrogen coupling partners. Herein
we describe the successful conclusion of these studies and
present a simple, copper(II) bromide catalysis protocol for the
catalytic α-amination of aldehydes, ketones, esters, and imides
with an expansive structural range of functionalized amines.
N
N
F
N
Cl
Me
S
S
AcO
amfepramone
Plavix
Effient
Traditional strategy: Nucelophilic enolate with electrophilic amine
O
O
O
R
Me
steps
Me
N
N
X
X
X
N
N
R
Me
R
R
N
H
2π
2π
nucleophile electrophile
α-hydrazinyl
functionalized
Direct α-Amination: Oxidative coupling with green byproducts
Design Plan: Drawing inspiration from the powerful
Buchwald-Hartwig4 and Chan-Lam5 cross-coupling strategies, in
which secondary amines are merged with aryl halides or boronic
acids to generate aryl amine adducts, we envisioned an
analogous direct fragment coupling of carbonyls and secondary
amines en route to α-amino carbonyl synthons (Figure 1). An
ongoing area of research in our lab is the invention of reactions
that use copper catalysis to install high-value α-carbonyl
functionality. Toward this end, we have demonstrated the ability
H
N
O
O
catalyst
oxygen
Me
Me
X
H2O
X
N
benign
2π
2π
nucleophile nucleophile
byproduct
directly formed
Figure 1. Medicinal use, strategies towards α-amino carbonyls.
1
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Table 2: Scope of the Ketone Coupling Component.
Table 1: Initial Studies towards α-Amination of Carbonyls
1
O
O
O
2
3
4
5
O
O
Me
O
10 mol% [Cu]
10 mol% CuBr2
air, DMSO, rt
X
R
Me
N
O
N
O
air, DMSO, rt, 12h
X
R
N
H
N
H
6
propiophenone
morpholine
α-amino carbonyl
carbonyl
α-amino carbonyl
morpholine
7
8
entry
[Cu] catalyst
yielda
solvent
1
2
3
O
O
O
9
Me
Me
Me
1
2
CuBr2
CuCl2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
68%
2%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
N
O
N
O
F3C
MeO
3
CuBr
31%
0%
O
92% Yielde
78% Yieldb
4
Cu(TFA)2
Cu(TFA)2
CuBr2
93% Yield
5b
6c
7
50%
62%
45%
67%
71%
93%d
4
5
6
O
O
O
Me
Me
Me
O
Me
CuBr2
CHCl3/EtOAc
N
N
N
N
O
CuBr2
8
THF
DMF
O
O
CuBr2
9
85% Yield
82% Yielde
73% Yieldc
CuBr2
DMSO
10
7
8
9
O
O
O
aGC yield using Bn2O as an internal standard. bWith 30 mol% LiBr. cPerformed
over 24 hours. dIsolated Yield.
Me
Me
Me
Me
N
N
O
N
of copper(I) to catalyze the α-arylation of enol-silanes in the
presence of diaryliodonium salts.6 Additionally, the synergistic
merger of copper(I) catalysis with enamine catalysis has led to
the development of methods for the enantioselective α-
O
O
61% Yielda,g
63% Yielda,g
71% Yielda,f
10
11
12
O
O
O
arylation,7
α-vinylation,8
α-oxygenation,9
and
α-
Me
Me
Me
Me
Me
Me
Me
trifluoromethylation10 of aldehyde substrates. On this basis, the
proposed mechanism for the carbonyl amination is presented in
Scheme 1. We postulated that in the presence of catalytic
copper(II) bromide, a diverse range of carbonyl substrates would
undergo bromination at the α-position11 via a copper-bound
enolate to generate an α-bromo carbonyl along with two
molecules of copper(I) bromide and an equivalent of HBr.12,13,14
Facile nucleophilic displacement of the α-C=O bromide
functionality by a secondary amine would then deliver the α-
amino carbonyl adduct along with a second equivalent of HBr.
Oxygen-mediated reoxidation of copper(I) bromide in the
presence of HBr would reconstitute the copper(II) bromide
catalyst. Importantly, we recognized that water would be the
only molecular by-product of this proposed catalytic cycle.
Me
N
O
Me
N
O
N
O
41% Yielda,h
75% Yielda,b,g
50% Yielda,d,f,i,j
The cited yields are of material isolated by column chromatography. aConducted
under 1 atm of O2. bConducted at 60 °C. cConducted at 50 °C. dConducted at 10 °C.
eConducted at 5 °C. ZnBr2 was employed as cocatalyst. gNiBr2 was employed as
f
i
j
cocatalyst. hMgI2 was employed as cocatalyst. NaI was employed. THF was
substituted as solvent. See supporting information for experimental details.
lithium bromide led to a substantial recovery of catalytic
efficiency (entry 5, 50% yield). These findings lend support to
the existence of the crucial α-bromocarbonyl intermediate as
depicted in Scheme 1. While extended reaction times did not
lead to an improvement in overall efficiency (entry 6, 62%
yield), the choice of solvent significantly influenced the coupling
yield (entries 7–10, 45–93% yield), with DMSO proving to be
the optimal reaction medium, presumably due to solvent
stabilization of the transient copper enolate species (entry 10,
93% yield).18
With optimized conditions in hand, we next sought to define
the scope of the carbonyl coupling partner. As shown in Table 2,
electron-rich and -poor aryl ketones readily undergo fragment
coupling with morpholine (entries 2 and 3, 92% and 78% yield).
More specifically, the efficient conversion of electron deficient
ketones was achieved at sub-ambient temperatures to prevent
product decomposition, while systems that involve a π-rich aryl
ring require elevated temperatures. This disparity is attributed to
the rate differential in both the ketone enolization and amine
nucleophilic addition steps. It is important to note that electron-
rich aromatic systems do not undergo Friedel-Crafts bromination
under these catalytic conditions.19 Heteroaromatic ketones are
also productive coupling partners, delivering α-amino ketones in
Results: Our evaluation of the proposed carbonyl–amine
fragment coupling began with exposure of propiophenone and
morpholine to a series of copper catalysts (Table 1). The reaction
was performed under an ambient air atmosphere to provide the
oxygen necessary for catalyst turnover. As expected, the most
suitable catalyst was copper(II) bromide, which delivered the α-
amino carbonyl product in 68% yield (entry 1). By comparison,
copper(II) chloride and copper(I) bromide were significantly less
effective at mediating this transformation (entries 2 and 3, 2%
and 31% yield). Although we postulated the intermediacy of an
α-bromo carbonyl species, we recognized that an alternative
mechanism might involve C–N bond formation via reductive
elimination from
a
transient copper(III) species.15,16 To
distinguish these pathways, the coupling was evaluated with a
series of Cu(II) salts that did not contain halogens (e.g.
Cu(OTf)2, Cu(TFA)2), and indeed, no desired amination
products were observed in any case.17 Moreover, while the use
of catalytic copper(II) bistrifluoroacetic acid provided no
observable product (entry 4, 0% yield), addition of 30 mol%
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Table 3: Scope of the Ester and Aldehyde Component.
Table 4: Scope of the Amine Coupling Component.
1
2
3
4
5
6
O
O
H
N
O
O
Me
O
10 mol% CuBr2
10 mol% CuBr2
air, DMSO, rt
R
X
Me
N
N
O
R
X
N
H
air, DMSO, 50 °C
cyclic or acyclic
dialkyl amine
propiophenone
α-amino carbonyl
carbonyl
α-amino carbonyl
morpholine
7
8
9
3
1
2
Br
NHTs
1
O
2
O
3
O
O
O
O
Me
Me
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
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53
54
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56
57
58
59
60
MeO
MeO
MeO
N
N
S
N
N
N
O
N
O
N
Me
O
81% Yield
91% Yield
70% Yielda,b
88% Yield
87% Yieldb
75% Yield
4
5
6
6
O
4
5
O
O
O
O
O
Me
Me
Me
Me
MeO
OMe
H
Me
H
Me
5
N
N
N
N
O
N
N
O
Me
Me
Me
Me
O
71% Yield
75% Yieldc,d
67% Yieldc,d
82% Yield
90% Yield
71% Yieldc
The cited yields are of material isolated by column chromatography. aConducted
b
under 1 atm of O2. Conducted at 70 °C. Conducted at rt. MeCN was substituted
c
d
7
8
9
O
O
O
as solvent. See supporting information for experimental details.
Me
Me
Me
OMe
OMe
high yield (entries 5 and 6, 92% and 82% yield). Moreover,
steric bulk at the carbonyl β-position is well-tolerated (entry 4,
73% yield). Efficient α-amination of aliphatic ketones was
found to require the introduction of a co-catalyst – such as
NiBr2, ZnBr2 or MgI2 – to facilitate the ketone enolization
event.20 Under these modified conditions, the coupling of non-
symmetrical methyl, alkyl substituted ketones proceeds with
high efficiency and regiocontrol to introduce the morpholine
group exclusively at the internal methylene position (entry 7,
71% yield).21,22 Moreover, α-amino ketone adducts that could be
susceptible to 1,2-elimination are readily accessed without any
observable product degradation (entries 8 and 9, 61% and 63%
yield). Notably, the use of 3-pentanone leads to mono-
amination adducts exclusively (entry 10, 50% yield), while the
incorporation of sterically demanding alkyl substituents
(isopropyl, tert-butyl), on the ketone substrate leads to selective
amination at the less hindered methylene position in moderate to
good yield (entries 11 and 12, 41% and 75% yield).
We anticipated that our catalytic carbonyl–amine fragment
coupling should also be compatible with a range of non-ketonic
carbonyls. Indeed, a series of α-aryl esters bearing a diverse
array of aryl substituents readily undergo morpholine
incorporation in the presence of catalytic CuBr2 to generate α-
amino esters with good efficiency (Table 3, entries 1–4, 70–91%
yield). Notably, the reaction is compatible with an aryl bromide
motif (entry 2, 91% yield); i.e. no undesired Buchwald-Hartwig
coupling product was observed using our standard conditions. A
survey of ester substrates revealed the importance of the α-aryl
group in enabling efficient coupling under these conditions.
More specifically, the inductive effect of the aryl group
promotes rapid ester enolization, a critical step that engenders
the subsequent bromination–amine addition pathway that is not
possible at this time with α-aliphatic esters. However, aliphatic
aldehydes, which we presumed would have a propensity to
undergo non-productive enamine formation,23 serve as highly
suitable coupling partners24 in this α-carbonyl functionalization
reaction (entries 5 and 6, 75% and 67% yield).
N
N
n-Pr
N
OMe
OMe
74% Yielda,d
70% Yielda,d
74% Yielda,d
The cited yields are of material isolated by column chromatography. aConducted at
60 °C. bConducted at 50 °C. cConducted at 40 °C. dNaI was employed. See
supporting information for experimental details.
A defining attribute of this new α-amination protocol is its
potential to provide direct access to a broad array of amine
groups at the carbonyl α-position. As shown in Table 4, a wide
range of synthetically useful secondary amines is readily
employed in this transformation. For example, cyclic amines of
various ring sizes readily participate to deliver the α-cyclic
amino product in high yield (entries 1–6, 71–90% yield).
Differentially protected acyclic alkyl amines also serve as
One step synthesis of racemic amfepramone via Cu–amination (eq 1)
O
O
20 mol% CuBr2
22 mol% Phen
H
N
Me
Me
Me
DMSO, 35 °C
O2 (1 atm), 1.5 h
N
Me
Me
Me
80% Yield
both substrates commercial
One step synthesis of racemic Plavix (eq 2)
O
H
N
MeO
O
10 mol% CuBr2
N
Cl
DMSO, 50 °C
O2 (1 atm), 24 h
MeO
Cl
S
(±)-
S
Plavix
87% Yield
both substrates commercial
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efficient coupling partners when elevated reaction temperatures
are employed along with sodium iodide as an additive (entries
7–9, 61–74% yield). Addition of sodium iodide presumably
1
2
3
4
5
6
6. Harvey, J. S.; Simonovich, S. P.; Jamison, C. R.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2011, 133, 13782−13785.
7. Allen, A. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2011, 133, 4260−4263.
8. (a) Skucas, E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2012, 134, 9090−9093.
(b) Stevens, J. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135,
11756−11759.
allows the intermediate α-bromocarbonyl to undergo
a
Finkelstein substitution to generate a more electrophilic α-
iodocarbonyl, thereby accelerating the subsequent amine
displacement step.
9. Simonovich, S. P.; Van Humbeck, J. F.; MacMillan, D. W. C. Chem. Sci. 2012,
3, 58−61.
Given the operational simplicity and broad generality of this
amine coupling protocol, we sought to demonstrate the utility of
this new catalytic process for the production of high-profile
medicinal agents. As shown in equation 1, we have developed a
one-step racemic synthesis of the appetite suppressant
amfepramone in 80% yield using an analogous Phen•CuBr2
catalyst, an operation that is complete in less than two hours.25
Moreover, we have also demonstrated a one-step route to the
antiplatelet agent Plavix (eq 2).26 Formation of this blockbuster
drug was accomplished in 87% yield from inexpensive
commercial materials using our standard CuBr2 catalysis
protocol.27
Finally, to demonstrate the preparative utility of this new
amine coupling process, we performed the union of morpholine
and propiophenone on a 37 mmol scale to generate 7.1 g (87%
yield) of the desired α-amination product (cf. Table 2, entry 1,
93% yield).
In conclusion, we have developed a generic approach to the
synthesis of complex α-amino carbonyls via the direct copper-
catalyzed coupling of carbonyls and functionalized secondary
amines. This process provides a useful alternative to standard
“atom transfer” approaches to the installation of amine
functionality at the carbonyl α-position. This simple yet versatile
method, which readily tolerates a range of functionality on the
carbonyl and amine reaction components, has been applied to
rapid syntheses of two prominent pharmaceutical agents. Studies
toward a catalytic asymmetric variant of this new transformation
are ongoing.28
7
8
9
10. Allen, A. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 4986−4987.
11. King, L. C.; Ostrum, G. K. J. Org. Chem. 1964, 29, 3459-3461.
12. (a) Kochi, J. K. J. Am. Chem. Soc. 1955, 77, 5274−5278. (b) Kosower, E. M.;
Wu, G. S. J. Org. Chem. 1963, 28, 633−638. (c) Kojima, Y.; Usui, K.;
Kawaguchi, S. Bull. Chem. Soc. Jpn. 1972, 45, 3127−3130. (d) Kojima, Y.;
Kawaguchi, S. Bull. Chem. Soc. Jpn. 1972, 45, 1293−1299.
13. An alternative mechanism for the bromination of ketones involves reductive
elimination of a bromide from the copper bound enolate to form the desired α-
bromocarbonyl and Cu(0). Under these reaction conditions, we recognize that such
a mechanism could be operable. For further mechanistic information see ref. 12(a)
and 12(b).
14. A reviewer has postulated an alternative mechanism for the bromination step
which involves the intermediacy of a Copper(III)Br2 bound enolate, that could
undergo addition to another molecule of Copper(II)Br2 via a one electron pathway
to form the desired α-bromocarbonyl.
15. For examples of amination reactions following this mechanism, see: (a)
Yamamoto, H.; Maruoka, K. J. Org. Chem. 1980, 45, 2739−2740. (b) Alberti, A.;
Canè, F.; Dembech, P.; Lazzari, D.; Ricci, A.; Seconi, G. J. Org. Chem. 1996, 61,
1677−1681. (c) Canè, F.; Brancaleoni, D.; Dembech, P.; Ricci, A.; Seconi, G.
Synthesis 1997, 545−548. (d) del Amo, C. L. Dubbaka, S. R.; Krasovskiy, A.;
Knochel, P. Angew. Chem. Int. Ed. 2006, 45, 7838−7842. (e) Kienle, M.; Dubbaka,
S. R.; del Amo, V.; Knochel, P. Synthesis 2007, 1272−1278.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
16. In the absence of oxygen and amine, a trace amount of α-bromopropiophenone
was detected. The reaction of propiophenone with super-stoichiometric amounts of
copper(II) bromide, however, generated
bromopropiophenone.
a
quantitative yield of α-
17. A survey of various copper(II) salts was undertaken. These included: Cu(OTf)2,
Cu(TFA)2, Cu(BF4)2, Cu(NO3)2, Cu(ClO4)2, CuCO3, Cu(OAc)2, Cu(HCO2)2. In all
cases no detectable amount of product was formed.
18. A variant of Table 1, entry 10, was preformed under a nitrogen atmosphere.
We observed a total of 4% amination product. This result is strongly indicative
that oxygen is required for catalyst turnover.
19. For selected examples of CuBr2 brominations of aromatic rings, see: (a) Yang,
L.; Lu, Z.; Stahl, S. S. Chem. Commun. 2009, 45, 6460−6462. (b) Song, Y.-F.; van
Albada, G. A.; Tang, J.; Mutikainen, I., Turpeinen, U.; Massera, C.; Roubeau, O.;
Costa, J. S.; Gamez, P.; Reedijk, J. Inorg. Chem. 2007, 46, 4944−4950. (c) Bhatt,
S.; Nayak, S. K. Synth. Commun. 2007, 37, 1381−1388.
20. Wei, H. X.; Jasoni, R. L.; Shao, H.; Hu, J.; Pare, P. W. Tetrahedron 2004, 60,
11829−11835.
21. The chlorination of 2-butanone has been shown to occur regioselectively to
produce 3-chloro-2-butanone when using CuCl2, please see: Kosower, E. M.; Cole,
W. J.; Wu, G. -S.; Cardy, D. E.; Meisters, G. J. Org. Chem. 1963, 23, 630−633.
22. The substituted enolate derived from 2-butanone is substantially more π-
Acknowledgement. Financial support was provided by the
NIGMS (R01 GM103558-01) and kind gifts from Merck,
Amgen and Abbvie.
Supporting Information Available. Experimental procedures
and spectral data are provided. This material is available free of
charge via the Internet at http://pubs.acs.org.
nucleophilic,
a feature that likely contributes to selective bromination and
thereafter amination at the butanone 3-position. Mayr nucleophile index values for
enol silanes are consistent with this finding: Mayr, H.; Kempf, B.; Ofial, A. R.
Acc. Chem. Res. 2003, 36, 66−77.
23. Mukherjee, S.; Yang, J. W.; Hoffmann. S.; List, B. Chem. Rev. 2007, 107,
5471−5569.
24. Products isolated after an in situ Wittig olefination.
25. Silverstone, T. Drugs 1992, 43, 820−836.
26. Li, J.-J.; Johnson, D. S.; Sliskovic, D. R.; Roth, B. D. Contemporary Drug
Synthesis; Wiley, Hoboken, 2004.
27. The use of air as the terminal oxidant in this case resulted in diminished yield.
28. Preliminary efforts towards an asymmetric catalytic version of this reaction
have demonstrated feasibility but not levels of efficiency or selectivity that would
be deemed worthy of disclosure. We hope to overcome such limitations in the near
future.
References:
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Direct α−Amination: Oxidative coupling with green byproducts
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