2-Azadienes as Reagents for Preparing Chiral Amines: Synthesis of 1,2-Amino Tertiary Alcohols by Cu-Catalyzed Enantioselective Reductive Couplings with Ketones

Article abstract of DOI:10.1021/jacs.7b12213

We introduce a new strategy for synthesis of chiral amines: couplings of α-aminoalkyl nucleophiles generated by enantioselective migratory insertion of 2-azadienes to a Cu-H. In this report, we demonstrate its application in catalytic reductive coupling of 2-azadienes and ketones to furnish 1,2-amino tertiary alcohols with vicinal stereogenic centers.

Full text of DOI:10.1021/jacs.7b12213

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Communication
2-Azadienes as Reagents for Preparing Chiral Amines:
Synthesis of 1,2-Amino Tertiary Alcohols by Cu-Catalyzed
Enantioselective Reductive Couplings with Ketones
Kangnan Li, Xinxin Shao, Luke Tseng, and Steven J. Malcolmson
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b12213 • Publication Date (Web): 22 Dec 2017
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2-Azadienes as Reagents for Preparing Chiral Amines: Synthesis of
1,2-Amino Tertiary Alcohols by Cu-Catalyzed Enantioselective Re-
ductive Couplings with Ketones
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Kangnan Li,‡ Xinxin Shao,‡ Luke Tseng, and Steven J. Malcolmson*
Department of Chemistry, Duke University, Durham, NC 27708, United States
Supporting Information Placeholder
forming an -aminoalkyl transition metal for the enantiose-
lective synthesis of amines. 2-Azadienes, which have rarely
been used in synthesis,15 undergo migratory insertion at their
least-hindered -bond with a Cu–H to generate a 2-azaallyl-
Cu intermediate, which may participate in stereoselective ad-
dition to a carbon electrophile. This reaction modality thus
constitutes umpolung reactivity of an enamine. We demon-
strate the feasibility of this approach in reductive coupling16–19
with ketones to furnish 1,2-amino tertiary alcohols in up to
87% yield, >20:1 dr, and >99:1 er.20–23
ABSTRACT: We introduce a new strategy for synthesis of chi-
ral amines: couplings of -aminoalkyl nucleophiles generated
by enantioselective migratory insertion of 2-azadienes to a
Cu–H. In this report, we demonstrate its application in cata-
lytic reductive coupling of 2-azadienes and ketones to furnish
1,2-amino tertiary alcohols with vicinal stereogenic centers.
New methods for the stereoselective synthesis of chiral
amines are highly valuable as these units are found within nu-
merous natural products, pharmaceuticals, ligands for metals,
and fine chemicals. Classic C–C bond-forming approaches to
chiral amines rely on nucleophilic addition to imines.1 Yet sev-
eral classes of chiral amines, including 1,2-amino alcohols,2 are
challenging to prepare by this normal polarity paradigm. A
traditional reverse polarity strategy that addresses this issue
utilizes nitroalkanes as a means of accessing N-substituted
carbanions;3 however, this tactic requires subsequent nitro
group reduction to form the amine, adversely affecting
step/redox economy.4 A streamlined approach would enanti-
oselectively assemble the desired amine building block via C–
C bond formation with all atoms in the correct oxidation state.
Scheme 1. Methods and Uses for Catalytically-Gener-
ated -Aminoalkyl-Substituted Transition Metals
-Amino Anions, -Amino Zincs, & -Amino Borates
G
G
G
[Pd] or [Ni]
• aryl cross-coupling
• alkyl cross-coupling
N
N
N
or
R
R
Zn/BXn
R
[M]
-C H Functionalizations
R1
R1
R
[Pd], [Ru],
• aryl cross-coupling
• allylic substitution
• olefin addition
[Ta], or [Nb]
N
N
R
H
[M]
-Radical Generation
• aryl/alkyl cross-coupling
• acyl cross-coupling
• borylation
R1 R2
R1 R2
R1 R2
Direct enantioselective -lithiation of alkylamines for addi-
tion to electrophiles provides one path, but these methods rely
on strong alkyllithium bases and often stoichiometric quanti-
ties of sparteine or its analogues.5 Catalytic formation of an -
aminoalkyl transition metal reagent (Scheme 1) is a powerful
means of generating chiral amines with several established ap-
proaches. Deprotonation to form a 2-azaallyl anion and addi-
tion to a Pd catalyst6 or alternatively transmetallation of an -
amino zinc7 or -amino borate8 to Ni or Pd has enabled aryl
and alkyl cross-coupling reactions. Metal-catalyzed C–H
functionalization at the N--position has also permitted aryl
cross-coupling,9 allylic substitution reactions,10 or addition to
olefins.11 Finally, catalytic formation of an -amino radical,
followed by recombination with a Ni or Fe catalyst, has al-
lowed a variety of aryl, alkyl, or acyl cross-couplings,12 boryla-
tions,13 or conjugate additions to take place.14 In each ap-
proach, enantioselective reactions are uncommon.6b,7,10b,11b–c,12d
[Ni] or [Fe]
N
N
N
R
G
R
R
[M]
• conjugate addition
This Work: Migratory Insertion of 2-Azadienes
Ph
Ph
O
N
Ph
N
NH2
Ph
[Cu]
R1 R2
[Cu]
H
R2
R1
R
R
HO
H
R
H
then aq acid
catalytic enantioselective additions to ketones
1,2-Amino tertiary alcohols are important building blocks
for synthesis, but enantioselective construction of this func-
tionality is all but unknown. Enantioselective Henry reactions
with ketone electrophiles are few.24 The direct catalytic en-
antioselective synthesis of amino tertiary alcohols is lim-
ited.25,26 Furthermore, there are few examples where this
functionality bears vicinal stereogenic centers. Typically this
moiety is prepared by stepwise stereoselective addition of or-
ganometallics to -amino acid derivatives.27
In this work, we introduce a new strategy for catalytically
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We envisioned that enantioselective Cu-catalyzed reductive
Page 2 of 5
somer is isolated in 45–87% yield. Ketones containing aro-
matic heterocycles deliver amino alcohols 6l–n in good dia-
stereoselectivity and excellent enantioselectivity (5–9:1 dr and
95:5 to >99:1 er, entries 11–13). Longer alkyl chains within the
ketone (20–p) generate amino alcohols with improved dia-
stereoselectivity (8–10:1 dr, entries 14–15) and with high enan-
tioselectivity. Diaryl ketones undergo efficient azadiene cou-
pling but with poor diastereoselectivity. For example, feno-
fibrate adduct 6q is formed in only 1:1 dr. The isomers may be
separately isolated; each is generated in 99:1 er (entry 16). 2-
Indanone undergoes reductive coupling to form 6r in 73%
yield, 8:1 dr, and 97:3 er. Azadiene addition to the fragrance
celestolide delivers 6s as a single stereoisomer in 72% yield.
coupling of 2-azadienes and ketones,16a,d followed by hydro-
lytic workup, would directly form a 1,2-amino tertiary alcohol
(Scheme 1). We therefore began by examining the reaction of
terminal azadiene 1a, acetophenone 2a, and a silane reducing
agent (Table 1) and quickly identified Ph-BPE (L1) as uniquely
effective at delivering desired product 3a (entry 1).16d Other
ligands (entries 2–6) afford <2% 3a while generating signifi-
cant amounts of ketone reduction product 4a and/or imino-
pyrrolidine 5, formed by reductive dimerization of 1a.28 In
contrast, L1 gives >98% conv to 3a within 1.5 h (entry 7), which
is formed in 4:1 dr as the major product (<10% ketone hydros-
ilylation). After imine reduction and ether desilylation (for
ease of handling/assay purposes), the major diastereomer 6a
is solely isolated in 73% yield and 99:1 er.29,30
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Table 2. Ketone Variation for Cu-Catalyzed Enantiose-
lective Reductive Couplings with Azadiene 1aa
Table 1. Ligand Identification for Reductive Coupling
of Acetophenone and 2-Azadiene 1aa
NHCHPh2
R
5 mol % Cu(OAc)2
NCPh2
O
6 mol % L1
+
Me
Ar
R
Ar
HO
3 equiv Me(OMe)2SiH
THF, 0 to 22 °C, 1.5 h;
then NaBH4, MeOH;
then NH4F, MeOH
(1.5 equiv)
2b s
6b s
isolated in
>20:1 dr
1a
yield (%)c
er of 6d
entry
product, Ar, R
dr of 3b
3.5:1
4.0:1
4.0:1
3.5:1
4.5:1
7.5:1
>20:1
13.0:1
3.5:1
5.5:1
5.0:1
9.0:1
5.5:1
10.0:1
8.0:1
1.0:1
1e
2
6b, 4-MeOC6H4, Me
6c, 4-F3CC6H4, Me
6d, 4-N-pyrazolylC6H4, Me
6e, 3-BrC6H4, Me
6f, 3-ClC6H4, Me
60
50
96.5:3.5
>99:1
>99:1
>99:1
>99:1
>99:1
99:1
3
62
4e
5e
6
45
57
6g, 3-HOC6H4, Me
6h, 2-BrC6H4, Me
6i, 2-MeOC6H4, Me
6j, 2-napthyl, Me
62
7e
77
8
87
97:3
9
65
99:1
10
11
12
13
14
15
16
6k, 3,4-dioxolatoC6H3, Me
6l, 2-furyl, Me
61
98.5:1.5
>99:1
99:1
55
6m, 3-thiophenyl, Me
6n, 3-pyrrolyl(NTs), Me
6o, Ph, Et
83
58
95:5
67
99:1
6p, Ph, CH2CH2Ph
6q, 4-ClC6H4,
63
98:2
99:1, 99:1g
39, 37f
4-(i-PrO2CCMe2O)C6H4
NHCHPh2
Me
NHCHPh2
Me
Me
Me
Me
HO
HO
6r
6s
b
aReaction under N2 with 0.1 mmol ketone 2a for 1 h. Determined
73% yield, 97:3 er
72% yield, >99:1 er
>20:1 dr of 3s
by 400 MHz 1H NMR spectroscopy according to remaining 2a in com-
t-Bu
8.0:1 dr of 3r
c
1
parison to an internal standard. Determined by 400 MHz H NMR
spectroscopy of the unpurified mixture. dDetermined by HPLC analy-
sis of purified 6a. eIsolated yield of amino alcohol 6a (>20:1 dr). fReac-
tion with 0.2 mmol ketone 2a for 1.5 h. [Si] = Si(OMe)2Me.
aReaction with 0.2 mmol ketone 2. Diastereomeric ratio of 3 deter-
b
1
mined by 400 MHz H NMR spectroscopy of the unpurified mixture
c
d
prior to workup. Isolated yield of purified 6 (>20:1 dr). Enantiomeric
e
Several aryl/alkyl ketones undergo efficient reductive cou-
pling with azadiene 1a under the optimized conditions (Table
2); the major diastereomer may be selectively isolated after the
reductive/desilylative workup and chromatographic purifica-
tion.29 A variety of substituents on the aromatic ring are tol-
erated (6b–k),31 including N-heterocycles (6d) and free hy-
droxyl (6g) functionality (entries 1–10). For aromatic rings
bearing ortho groups (6h–i), diastereoselectivity is signifi-
cantly higher. For example, 6h is formed as a single stereoi-
somer and 6i generated in 13:1 dr. Enantioselectivity is high in
all cases (96.5:3.5 to >99:1 er) and the major product stereoi-
f
ratio determined by HPLC analysis of 6. Cu(OAc)2∙H2O used. Iso-
lated yield of each diastereomer. gEnantiomeric ratio of each isomer.
A number of 4-alkyl-substituted 2-azadienes efficiently re-
act with ketone 2i to afford -alkyl chiral amines 7a–j as a sin-
gle diastereomer in 43–59% yield (Table 3). The added steric
hindrance imposed by the alkyl group necessitates a 12 h reac-
tion time and leads to competitive ketone reduction, a path-
way which is exacerbated with less-hindered ketones (e.g.,
acetophenone leads to >90% ketone reduction). A variety of
functional groups are tolerated, such as thioether (entry 4),
ether (entries 6–8), ester (entry 9), and halogen (entry 10).
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Although we have been able in most cases to separate the
Table 3. Substituted 2-Azadienes for Enantioselective
Additions to Ketonesa
1
2
3
4
5
6
7
8
two product diastereomers, we have not successfully isolated
the minor stereoisomer of aryl/alkyl ketone addition in order
to secure its stereochemical assignment. Experiments with
symmetrical ketones (Scheme 3), however, suggest that the
minor isomer differs in its stereochemistry at the hydroxyl-
containing center. Both benzophenone and acetone32 undergo
coupling with 1a with significantly higher enantioselectivity
(6t–u formed in 95:5 to 97.5:2.5 er) than the diastereoselectiv-
ity observed in most other reactions (Tables 1–2). Addition-
ally, unlike for 6q, where each diastereomer is formed in equal
enantiopurity, in the case of 6v (Scheme 3), the major (2S,3R)-
diastereomer is formed in >99:1 er but the minor, likely
(2R,3R)-isomer, is furnished in only 95.5:4.5 er.
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Based on the available data, a working model that accounts
for the stereochemical outcome of the azadiene/ketone cou-
plings is proposed in Scheme 3. Coordination of azadienes to
[(S,S)-Ph-BPE]Cu–H occurs to place the benzophenone imine
portion in the least hindered quadrant, leading to insertion
into the Re-face, consistent with previous models.16d–e Stere-
orententive addition of the alkyl–Cu to the ketone’s Re-face
delivers the major stereoisomer. The minor isomer arises
from addition to the ketone’s Si-face, and all other stereoiso-
mers are generated by stereoinvertive alkyl–Cu addition.
aReaction of (E)-azadiene 1 unless otherwise noted. bDetermined by
1
400 MHz H NMR spectroscopy of the unpurified mixture prior to
c
workup. Isolated yield of purified 7. dEnantiomeric ratio determined
by HPLC analysis of 7. e(E)- and (Z)-azadienes 1c deliver identical re-
sults. fFrom (Z)-1e.
Scheme 3. Implications for Stereochemistry of the Mi-
nor Diastereomer and Stereochemical Model
Symmetrical Ketones Lead to High Enantioselectivity
Carbamates 8–9 (Scheme 2) may be obtained by the sequen-
tial reductive coupling of azadiene 1a and ketones 2h–i with
desilylative workup, imine hydrolysis under mildly acidic con-
ditions,27 and Boc protection of the resulting primary amine
(40–60% overall yield for the three-step sequence). The ste-
reochemistry of the major isomer of 9 has been assigned as (R)
at the amino center and (S) at the hydroxyl center. The free
amine (10) may also be utilized for C–N cross-coupling reac-
tions such as the Ullman coupling to generate aniline 11. The
amine and hydroxyl group can instead both be engaged to
form heterocycles such as oxazoline 12.
NHCHPh2
NHCHPh2
NCPh2
O
rxn conditions
Ph
Me
+
Me
Me
R
R
& standard
workup
Ph
Me
HO
HO
1a
2t u
6ta
6ub
58% yield
45% yield
95:5 er
97.5:2.5 er
Each Diastereomer Formed with High Enantiopurity
standard
rxn
conditions
NCPh2
1a
major isomer
(2S,3R)
NHCHPh2
3
2
Me
Me
+
>99:1 er
O
HO
& workup
Scheme 2. Derivatization of Coupled Products
minor isomer
(2R,3R)
6va
Me
N
95.5:4.5 er
2v
57% yield, 4.5:1 dr
N
Proposed Stereochemical Model for Major Isomer Formation
Ph
Ph
Ph
Ph
O
O
H
Me
P
P
P
P
Ph
Me
NCPh2
Me
Ph
Cu
Cu
Ph
H
Ph
Me
Ph
Ph
Ph
Me
[Si]O
insertion to
azadiene Re face
N
N
stereoretentive addn
to ketone Re face
Ph
Ph
Ph
Ph
b
aStandard catalysis conditions; see Table 2. 3.0 equiv acetone, 5.0
equiv silane, 5 mol % Cu(OAc)2, 6 mol % L1, THF, 22 C, 1 h.
2-Azadienes are a promising class of reagents for prepara-
tion of chiral amines. Here, through reductive coupling with
ketones, they have enabled catalytic enantioselective con-
struction of 1,2-amino tertiary alcohols that have previously
been inaccessible. Application of 2-azadienes for preparing
other challenging amine scaffolds is underway.
ASSOCIATED CONTENT
Supporting Information
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Corresponding Author
*steven.malcolmson@duke.edu
Author Contributions
‡These authors contributed equally.
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Shen, X.; Riedel, R.; Harms, K.; Meggers, E. Angew. Chem., Int. Ed.
2016, 55, 685.
(26) For non-enantioselective allenamide/aldehyde reductive cou-
pling to generate 1,2-amino secondary alcohols, see: Skucas, E.; Zbieg,
J. R.; Krische, M. J. J. Am. Chem. Soc. 2009, 131, 5054.
(27) Ooi, T.; Takeuchi, M.; Kato, D.; Uematsu, Y.; Tayama, E.; Sakai,
D.; Maruoka, K. J. Am. Chem. Soc. 2005, 127, 5073.
(28) For additional ligand and other screening results, see the Sup-
porting Information.
(29) The minor diastereomer is removed by chromatography and
its fate is unclear at this time.
(30) t-BuOH addition increases the quantity of 4a relative to 3a.
(31) Ketones 2c and 2e undergo a more competitive reduction com-
pared to C–C bond formation, which adversely affects yield.
(32) >90% ketone reduction is observed with other dialkyl ketones.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the NIH (GM124286), ACS Petroleum Research
Fund (56575-DNI1), and Duke University for financial support.
K.L. is grateful to the Duke Chemistry Department for a Bur-
roughs-Welcome Fellowship. We thank Dr. Roger Sommer
(NC State) for X-ray crystallographic analysis.
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