Copper-catalysed selective hydroamination reactions of alkynes

Article abstract of DOI:10.1038/nchem.2131

The development of selective reactions that utilize easily available and abundant precursors for the efficient synthesis of amines is a long-standing goal of chemical research. Despite the centrality of amines in a number of important research areas, including medicinal chemistry, total synthesis and materials science, a general, selective and step-efficient synthesis of amines is still needed. Here, we describe a set of mild catalytic conditions utilizing a single copper-based catalyst that enables the direct preparation of three distinct and important amine classes (enamines, ±-chiral branched alkylamines and linear alkylamines) from readily available alkyne starting materials with high levels of chemo-, regio-and stereoselectivity. This methodology was applied to the asymmetric synthesis of rivastigmine and the formal synthesis of several other pharmaceutical agents, including duloxetine, atomoxetine, fluoxetine and tolterodine.

Full text of DOI:10.1038/nchem.2131

ARTICLES
PUBLISHED ONLINE: 15 DECEMBER 2014 | DOI: 10.1038/NCHEM.2131
Copper-catalysed selective hydroamination
reactions of alkynes
Shi-Liang Shi and Stephen L. Buchwald
*
The development of selective reactions that utilize easily available and abundant precursors for the efficient synthesis of
amines is a long-standing goal of chemical research. Despite the centrality of amines in a number of important research
areas, including medicinal chemistry, total synthesis and materials science, a general, selective and step-efficient synthesis
of amines is still needed. Here, we describe a set of mild catalytic conditions utilizing a single copper-based catalyst that
enables the direct preparation of three distinct and important amine classes (enamines, α-chiral branched alkylamines and
linear alkylamines) from readily available alkyne starting materials with high levels of chemo-, regio- and stereoselectivity.
This methodology was applied to the asymmetric synthesis of rivastigmine and the formal synthesis of several other
pharmaceutical agents, including duloxetine, atomoxetine, fluoxetine and tolterodine.
omplex organic molecules play a crucial role in the study and developed for their synthesis by alkyne hydroamination, control of
treatment of disease. The extent to which they can be utilized the regio- and stereochemistry of enamine formation is non-trivial16.
C
in these endeavours depends on the efficient and selective
In addition to enamine synthesis, we speculated on the possi-
chemical methods for their construction1. Amines are widely bility that conditions could be developed to convert alkynes to enan-
represented in biologically active natural products and medicines2 tioenriched α-branched alkylamines and/or linear alkylamines in
(a small selection of which are shown in Fig. 1a). Consequently, one synthetic operation (Fig. 1b, B). Such cascade processes are
the selective assembly of amines from readily available precursors highly desirable in organic synthesis, because potentially difficult
is a prominent objective in chemical research3. There are a work-up and isolation steps can be avoided and the generation of
number of powerful methods that address this challenge, including chemical waste is minimized37. In particular, we envisioned a scen-
metal-catalysed cross-coupling4,5, nucleophilic addition to imines6, ario in which the starting alkyne is initially reduced to a transiently
C–H nitrogen insertion7 and enzymatic methods8,9. However, the formed alkene, which would then undergo hydroamination to
direct production of amines from simple olefins or alkynes rep- afford the alkylamine product. If successful, this approach would
resents a highly attractive alternative, given the abundance and be particularly attractive due to the ease and low cost of the
accessibility of these starting materials. For this reason, the addition Sonogashira process for the preparation of alkyne starting materials
of nitrogen and hydrogen across carbon–carbon multiple bonds relative to the cross-coupling of stereodefined vinylmetal reagents or
(hydroamination) has long been pursued as a means to access other routes used to access geometrically pure alkenes for hydroami-
amines10–12. Although much progress has been made, a generally nation. We were aware that, mechanistically, the vinyl- and alkyl-
effective strategy to achieve chemo-, regio- and enantioselective copper intermediates in the proposed process are required to react
hydroamination of simple alkenes or alkynes remains elusive.
in a highly chemoselective manner (Fig. 1c). Specifically, the vinyl-
We became interested in developing hydroamination reactions of copper species formed upon hydrocupration of the alkyne would
alkynes as a convenient and powerful means of accessing aminated need to be selectively intercepted by the proton source in the
products (Fig. 1b). Reactions that employ alkynes as starting materials presence of the aminating reagent to furnish the intermediate
are synthetically versatile, because alkynes can be prepared by a alkene, while the alkylcopper species formed upon hydrocupration
variety of strategies, including Sonogashira coupling13, nucleophilic of this alkene would need to selectively engage the electrophilic
addition of metal acetylides14 and homologation of carbonyl nitrogen source in the presence of a proton donor to ultimately
groups15. In addition, one or both π-bonds of alkynes may be utilized, furnish the desired alkylamine product. Although both steps (that
further increasing their flexibility as starting materials. For these is, alkyne semireduction38–40 and alkene hydroamination23) are
reasons, the hydrofunctionalization of alkynes has recently become well precedented, the ability to achieve the desired selectivity in
an active area of research16–22. We recently detailed23 (as have one pot via a cascade sequence has never been demonstrated41,42
.
Hirano and Miura24) catalyst systems for the asymmetric hydroami- Here, we report mild and scalable conditions for the highly
nation of styrenes that operate through the addition of a catalytic chemo-, regio- and stereoselective synthesis of enamines (‘direct
copper hydride species25–32 to a carbon–carbon double bond followed hydroamination’) and alkylamines (‘reductive hydroamination’)
by carbon–nitrogen bond formation using an electrophilic nitrogen products from alkynes, using a single copper catalyst system.
source33–36. We surmised that we could apply this approach to the
selective functionalization of alkynes wherein alkyne hydrocupration Results and discussion
would give a stereodefined vinylcopper intermediate. We anticipated Direct hydroamination: development and scope. To assess the
that, in analogy to our previous work, direct interception of this inter- feasibility of the outlined alkyne hydroamination (Fig. 1b, A), we
mediate would potentially enable the stereoselective formation of treated 1,2-diphenylacetylene (1a) with N,N-dibenzyl-O-
enamines (Fig. 1b, A). Enamines are versatile intermediates in benzoylhydroxylamine (2a, 1.2 equiv.) and an excess of
organic synthesis, and although catalytic methods have been diethoxymethylsilane (3) in the presence of 2 mol% copper
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. e-mail: sbuchwal@mit.edu
*
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2131
ARTICLES
a
c
Required selectivity for reductive hydroamination cascade
H
HO
N
Me
S
N
O
O
H
R
R
L*Cu
R1
N
MeO
N
R2N–OBz
R1
ROH
OH
Me
H
R1
R2
Undesired
amination
Desired
HO
N
R2
R2
protonation
Quinine
(malaria)
Morphine
(pain)
Duloxetine
(depression)
Vinylcopper
intermediate
Me
Me
O
OH
Me
Me
Me
Me
L*Cu (Cat.)
Me
N
N
· Regioselective
· Chemoselective
· Stereoselective
hydrosilane
O
Et
R1
R2
N
Me
Me
N
O
ROH
R2N–OBz
Me
Tolterodine
Me
H
Atomoxetine
(depression)
Rivastigmine
(dementia)
(urinary disorders)
b
This work: divergent access to enamines and alkylamines
R
R
R
R
R
R
R
R
L*Cu
R1
N
N
N
N
R1
R2N–OBz
A
B
R1
ROH
or
R1
R2
R1
R1
R2
Desired
amination
Undesired
protonation
R2
R2
R2
R2
R1
Alkylcopper
intermediate
Direct hydroamination
Alkyne
Reductive hydroamination
Figure 1 | Bioactive amines, the synthesis of amines from alkynes, and the reductive hydroamination cascade strategy. a, Representative alkaloids and
drugs demonstrating the ubiquitous nature of amines in bioactive organic molecules. b, Catalytic hydroamination of alkynes to generate three product
classes. c, Contrasting reactivities of vinyl- and alkylcopper intermediates required to achieve a reductive hydroamination cascade.
acetate and a range of phosphine ligands. A number of ligands selective protonation of the formed vinylcopper intermediate
could be used to perform the direct hydroamination reaction, (Fig. 1c). Indeed, inclusion of methanol as an additive under the
and the resulting enamine 4a was efficiently produced as a reaction conditions in Table 1 resulted in the formation of the
single geometric isomer, as determined by 1H NMR analysis desired reductive hydroamination product 5a in moderate yield,
(Table 1, entries 1–4). Although copper catalysts based on along with a significant amount of enamine 4a (18%) and stilbene
2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP, L1), (17%) as side products (Table 2, entry 1). Fortunately, an
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, evaluation of alcohol additives revealed that ethanol was a suitable
L2) or 4,4′-bi-1,3-benzodioxole-5,5′-diylbis(diphenylphosphane) proton source, which minimized the formation of these side
(SEGPHOS, L3) were effective in this context, the catalyst based on products to afford benzylamine 5a in excellent yield and high
5,5′-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4′-bi-1,3- enantioselectivity (entry 2, 92% yield, 89% e.e.). Interestingly, in
benzodioxole (DTBM-SEGPHOS, L4) was found to be the most contrast to the direct alkyne hydroamination protocol for enamine
efficient and generally applicable. We then evaluated the substrate formation, L4 was uniquely able to perform the reductive
scope of this reaction and, as shown in entries 5–9, a diverse hydroamination cascade reaction. Reaction utilizing copper
range of aryl-substituted internal alkyne substrates could be catalysts based on L1, L2 or L3 provided only enamine 4a in high
converted to the corresponding (E)-enamines 4 with complete yields, even in the presence of ethanol (entries 4–6). We attribute
stereoselectivity (4b–4e; 80–99%). Notably, sterically hindered the success of the catalyst system based on L4 to the ability of the
amines, which were problematic substrates for previously reported CuH species to hydrocuprate alkynes and alkenes more rapidly. In
hydroamination reactions of alkynes43, could be successfully contrast, the hydrocupration of alkynes occurred less efficiently
transformed using the current conditions (4b and 4d). More when L1–L3 were used, resulting in consumption of the alcohol
importantly, direct hydroamination of unsymmetrical internal additive by the CuH before alkyne hydrocupration could take
alkynes occurred with excellent regioselectivity (4c–4e; >19:1). In place. Therefore, only the enamine product was obtained in these
addition, we found that a 1,2-dialkylacetylene was left intact under cases. In addition, we found that arylacetylenes could also undergo
these conditions (4e) and pharmaceutically important heterocycles, reductive hydroamination, although in the case of these substrates,
including morpholine (4c), thiophene (4d), piperidine (4e) and isopropanol was a superior protic additive (entry 8).
pyrimidine (4e), were well-tolerated. Although the direct
Under the optimized set of reaction conditions, a range of chiral
hydroamination of terminal alkynes to construct monosubstituted benzylamine derivatives could be prepared in moderate to high yield
enamines was not successful, the current method represents a rare (61–85%) with very high levels of enantioselectivity (≥97% e.e.,
example of a highly regio- and stereoselective hydroamination of Table 3). These mild catalytic conditions tolerated a range of
internal alkynes for the construction of dialkyl enamines43.
common functional groups including ethers (5c, 5h), alcohols
(5i), aryl halides (5e, 5f), pyridines (5d), indoles (5g), acetals (5j)
Reductive hydroamination: development and scope. As and ketals (5m, 5n). Moreover, a reaction conducted on a 10 mmol
previously described, we were hopeful that the addition of a protic scale proceeded efficiently in the presence of 1 mol% catalyst, fur-
additive could divert this reaction from direct alkyne nishing the product in undiminished yield and enantioselectivity
hydroamination to the outlined reductive hydroamination by (5j). The applicability of new synthetic methods to the late-stage
2
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2131
ARTICLES
Table 1 | Optimization and scope of copper-catalysed direct hydroamination of aryl alkynes.
Cu(OAc)2 (2.0 mol%)
R2
R3
R1
N
R1
R2
R3
ligand (2.2 mol%)
N
+
Ar
Ar
OBz
HSiMe(OEt)2 (3, 3.0 equiv.)
THF, 45 °C, 18 h
Aryl alkyne 1
Electrophilic amine 2
(E)-enamine 4
Yield
Entry
1
2
Ligand
4
1
rac-L1
90%
Bn
2
L2
95%
Ph
Bn
Bn
Ph
Ph
N
PPh2
PPh2
N
Bn
3
rac-L3
rac-L4
rac-L4
87%
Ph
OBz
4
5*
99%
1a
2a
4a
99% (88%)
L1 (BINAP)
Me
Me
Ph
Me
Me
Me
Me
Ph
N
PPh2
6*
7*
8*
99% (93%)†
97%‡ (94%)
80%‡ (70%)
N
rac-L4
rac-L4
rac-L4
Ph
Me
Me
Me
4b
OBz
O
Ph
1a
1b
1c
Me
2b
PPh2
O
O
L2 (Xantphos)
Ph
Ph
N
N
nBu
nBu
OBz
O
2c
4c
O
PPh2
S
iPr
PPh2
O
iPr
iPr
N
S
iPr
N
O
NC
OBz
NC
L3 (SEGPHOS)
2d
4d
O
N
N
O
N
N
PAr2
Ph
Ph
N
PAr2
O
N
N
9*
90%‡ (85%)
rac-L4
N
nBu
BzO
O
nBu
4e
1d
2e
L4 (DTBM-SEGPHOS)
Ar = 3,5-(tBu)2-4-MeO-C6H2
Conditions: 1a (0.2 mmol), 2a (0.24 mmol), 3 (0.6 mmol), Cu(OAc)2 (2.0 mol%), ligand (2.2 mol%), THF (1 M), 45 °C, 18 h. Yields and stereoselectivities were
determined by 1H NMR analysis using 1,1,2,2-tetrachloroethane as an internal standard. In all cases only (E)-enamine products were observed.
*Conditions: 1 (1.0 mmol), 2 (1.2 mmol), 3 (3.0 mmol), Cu(OAc)2 (2.0 mol%), rac-L4 (2.2 mol%), THF (1 M), 45 °C, 18 h. Isolated yields of products after reduction
are given in parentheses (average of two runs). †Isolated yield of enamine after purification by flash column chromatography. ‡Major regioisomers are shown; in all
cases, <5% of the minor regioisomer was observed as determined by 1H NMR analysis of the crude enamine product.
modification of complex natural products is a highly desirable observed when simple alkylacetylene substrates were used, giving
feature, as analogues of bioactive molecules can be prepared rise to linear tertiary amines in high yields (71–88% yield). We
without the need for de novo synthesis. Accordingly, readily avail- note that it was crucial to use a slight excess of isopropanol
able alkynes derived from the natural products δ-tocopherol and compared to the alkylacetylene substrate in the case of terminal
oestrone were subjected to asymmetric reductive hydroamination alkyne substrates, probably due to deactivation of the catalyst
conditions to afford aminated products with good yields and excel- through formation of a copper acetylide species when the amount
lent catalyst-controlled diastereoselectivities (d.r.: 99:1, 5k−5n). It is of isopropanol was insufficient40. It is noteworthy that this
noteworthy that in all reductive hydroamination reactions employ- methodology could be applied to a substrate bearing an unprotected
ing aryl-substituted alkynes, the amination products were delivered secondary amine to provide 1,3-diamine 6a in high yield.
with exclusive Markovnikov regioselectivity, with C–N bond for- Furthermore, alkynol silyl ethers were suitable substrates for the
mation occurring adjacent to the aryl group.
current method. Upon reductive hydroamination and silyl
In addition to aryl-substituted alkynes, we found that terminal deprotection, 1,3-amino alcohol products were prepared in good
aliphatic alkynes readily participate in catalytic reductive yields (6f, 6g). An enantioenriched 1,3-amino alcohol could be
hydroamination to deliver alkylamines (Table 4). In contrast to generated from the optically active alkynol silyl ether (98% e.e.)
aryl-substituted alkynes, anti-Markovnikov regioselectivity was without erosion of enantiomeric excess (6g, 98% e.e.). The use of
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2131
ARTICLES
the current reductive hydroamination methodology, in conjunction
with well-developed methods for the asymmetric synthesis of alky-
nols14, represents an attractive approach for the synthesis of these
biologically relevant compounds.
Table 2 | Optimization of reductive hydroamination.
Cu(OAc)2 (2.0 mol%)
ligand (2.2 mol%)
Bn
Ph
Bn
Bn
Ph
Bn
Ph
N
N
Ph
2a (1.2 equiv.)
Application to drug synthesis. The functionalized amines obtained
by the cascade hydroamination developed in this study have broad
utility. To illustrate this point, 1,3-amino alcohol 6f can be readily
transformed to the antidepressant drug duloxetine following the
literature procedure44 (Fig. 2a). Moreover, 1,3-amino alcohol 6g is
a key intermediate for the synthesis of the attention deficit
hyperactivity disorder (ADHD) drug atomoxetine45, as well as the
antidepressant drug fluoxetine46 (Fig. 2b). Furthermore,
diisopropylamine 8 could be prepared by reductive hydroamination
of readily synthesized alkyne 7 (Fig. 2c). Tolterodine, a drug used
for symptomatic treatment of urinary incontinence, could be
prepared by demethylation of 847. Our method was also applied to
a new two-step synthesis of rivastigmine, a drug used to treat
dementia (Fig. 2d). Condensation of commercially available
reagents gave carbamate 9, which, upon asymmetric reductive
hydroamination, furnished the target in an enantiopure form and
good chemical yield. These syntheses exemplify the potential utility
of the current hydroamination method for the rapid and efficient
construction of medicinally relevant molecules.
+
Ph
HSiMe(OEt)2 (3, 4.0 equiv.)
alcohol (1.5 equiv.)
Ph
1a
4a
5a
THF, 40 °C, 18 h
Bn
Bn
N
Conditions above
Me
nBu
nBu
1e
5b
Entry Substrate Ligand Alcohol Yield 4a Yield 5a or 5b (e.e.)
1
2
3
4
5
6
7
8†
1a
1a
1a
1a
1a
1a
1e
1e
(R)-L4 MeOH
(R)-L4 EtOH
(R)-L4 iPrOH
(R)-L1 EtOH
18%
2%
2%
83%
95%
80%
–*
60% (89% e.e.)
92% (89% e.e.)
83% (89% e.e.)
0
0
0
L2
EtOH
(R)-L3 EtOH
(R)-L4 EtOH
(R)-L4 iPrOH
78% (99% e.e.)
83% (99% e.e.)
–*
Conditions: 1a or 1e (0.2 mmol), 2a (0.24 mmol), 3 (0.8 mmol), alcohol (0.3 mmol), Cu(OAc)2
(2.0 mol%), ligand (2.2 mol%), THF (1 M), 40 °C, 18 h. Yields were determined by gas
chromatography using dodecane as an internal standard. Enantiomeric excesses (e.e.) were
determined by HPLC analysis using chiral stationary phases. *The corresponding enamines were
Mechanistic discussion. The proposed mechanisms for the
formation of enamines and alkylamines (Fig. 3a) both commence
with syn-selective Cu–H addition to the alkyne substrate to give
vinylcopper species 11. In the absence of a proton source
not observed. †Conditions: 1e (1.1 mmol), 2a (1.0 mmol),
Cu(OAc)2 (2.0 mol%), (R)-L4 (2.2 mol%), THF (1 M), 40 °C, 18 h.
3 (4.0 mmol), i-PrOH (1.2 mmol),
Table 3 | Scope of copper-catalysed reductive hydroamination of aryl alkynes.
2.0 mol % Cu(OAc)2
R3
R1
R4
R2
Me
R2
2.2 mol % (R)-L4
N
Bn
Bn
N
EtO Si OEt
H
+
+
R1
OBz
Alcohol
THF, 40 °C, 18 h
Aryl alkyne 1
Electrophilic amine2a
Hydrosilane 3
Chiral amine 5
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
N
N
N
N
N
Ph
Cl
Me
Me
Me
Me
nBu
N
MeO
5c, 81% yield, >99% e.e.
5b, 75% yield, 99% e.e.
5d, 63% yield, 98% e.e.
5e, 71% yield, 97% e.e.
5a, 85% yield, 89% e.e.*
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
N
Bn
Bn
N
N
N
OEt
OEt
N
Me
OMe
OH
Me
N
Ts
F
5g, 80% yield, 98% e.e.
5h, 83% yield, 98% e.e.*
5i, 70% yield, 98% e.e.*
5j, 85% yield, 99% e.e.*,†
5f, 75% yield, 97% e.e.
O
O
Me
Me
O
O
Bn
Bn
N
Bn
Bn
N
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Bn
N
Bn
N
Me
Me
3
H
H
H
H
O
Me
O
Me
Bn
Bn
3
3
3
3
3
Me
Me
Me
Me
with (R)-L4: 5k, 75% yield, >99:1 d.r.
with (S)-L4: 5l, 76% yield, <1:99 d.r.
with (R)-L4: 5m, 62% yield, 99:1 d.r.
with (S)-L4: 5n, 61% yield, <1:99 d.r.
Conditions: 1 (1.1 mmol), 2 (1.0 mmol), 3 (4.0 mmol), i-PrOH (1.2 mmol), Cu(OAc)2 (2.0 mol%), (R)-L4 (2.2 mol %), THF (1 M), 40 °C, 18 h. Isolated yields are reported (average of two runs). Enantiomeric
excesses (e.e.) and diastereomeric ratios (d.r.) were determined by HPLC analysis.
*Using EtOH instead of i-PrOH. †Reaction performed on 10 mmol scale using 1 mol% of catalyst. See Supplementary Section 3 for details.
4
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2131
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15 and 16 would deliver the alkylamine 5. As previously detailed,
these amination protocols both provide products in excellent
regioselectivity; aryl-substituted internal alkynes (and alkenes)
proceed through a Markovnikov selective hydrocupration event
and terminal aliphatic alkynes (and alkenes) undergo anti-
Markovinikov hydrometallation. This regioselectivity is in accord
with results previously reported for copper-catalysed alkyne
semireduction39,40 and hydroamination23. We rationalize the
Markovnikov regioselectivity observed for aryl alkynes as arising
from the electronic stabilization of the vinyl- or alkylcopper
species by an adjacent aryl group. In contrast, we attribute the
anti-Markovnikov selectivity observed in the case of terminal
aliphatic alkynes to steric effects (that is, formation of the less
substituted vinyl- or alkylcopper species).
Table 4 | Reductive hydroamination of alkylacetylenes.
2.0 mol% Cu(OAc)2
2.2 mol% rac-L4
R3
2 (1.0 equiv.)
H
N
R1
R2
R1
iPrOH (1.2 equiv.)
HSiMe(OEt)2 (3, 4.0 equiv.)
Alkyne1
Alkyl amine6
THF, 40 °C, 18 h
Bn
N
Bn
N
N(H)Bn
OMe
Bn
N
Bn
N
Bn
Bn
Ph
tBu
Bn
Bn
5
We conducted mechanistic experiments to gain a better under-
standing of the factors that result in the high selectivities observed
in our system. Subjecting enamine 4a to the conditions developed
for either alkyne hydroamination or reductive hydroamination
resulted in no observed reaction (Fig. 3b). The inertness of the
enamine under these conditions accounts for the exclusive
formation of monoamination product in the case of alkyne hydro-
amination. In addition, these experiments suggest that alkyne
hydroamination followed by enamine reduction does not occur in
the case of reductive hydroamination. Furthermore, we subjected
cis-stilbene (18) to the hydroamination conditions in the presence
of 1.5 equiv. ethanol (Fig. 3c). Although a small amount of
1,2-diphenylethane (19, 3% yield) was formed, presumably as a
result of protonation of the alkylcopper intermediate48, hydro-
6a, 86% yield
6b, 76% yield
6c, 71% yield
6d, 88% yield
Bn
Me
Bn
Me
Ph
N
N
N
Bn
Bn
S
Me
OTBS
OH
OH
6e, 73% yield
6f, 72% yield
6g, 72% yield
(from silyl ether)
(from silyl ether)
Conditions: 1 (1.1 mmol), 2 (1.0 mmol), 3 (4.0 mmol), i-PrOH (1.2 mmol), Cu(OAc)2 (2.0 mol%),
rac-L4 (2.2 mol%), THF (1 M), 40 °C, 18 h. Isolated yields are reported (average of two runs).
See Supplementary Section 3 for details.
(alcohol), direct interception by electrophilic amine 2 (likely via amination adduct 5a was generated as the predominant product
oxidative addition/reductive elimination) would produce the (97% yield). This result suggests that amination of the alkylcopper
(E)-enamine product 4 and copper benzoate complex 13 that, species 15 occurs selectively in the presence of a proton source.
upon transmetallation with hydrosilane, would regenerate the Combined, the results of these experiments are in agreement with
active CuH species 10. On the other hand, in the presence of our original hypothesis that vinylcopper species 11 and alkylcopper
alcohol, direct protonation of the vinylcopper intermediate 11 species 15 undergo selective protonation and amination, respect-
could afford the cis disubstituted alkene 14. A hydroamination ively, thereby allowing the desired cascade reaction to proceed
similar to that we have previously reported via alkylcopper species as designed.
a
b
H
N
H
H
Me
S
N
Me
N
N
Bn
N
Me
Me
O
Ref. 44
Ref. 45
Ref. 46
O
Bn
O
S
Me
OH
6f
OH
6g
Me
CF3
(
)-Duloxetine
Atomoxetine
(ADHD drug)
Fluoxetine
(antidepressant)
(antidepressant)
c
d
Cu(OAc)2 (4.0 mol%)
Cu(OAc)2 (4.0 mol%)
(R)-L4 (4.4 mol%)
rac-L4 (4.4 mol%)
OMe
Ph
OMe
Ph
Me
N
(iPr)2N–OBz (1.0 equiv.)
i-Pr
Me2N–OBz (2.0 equiv.)
O
N
Et
Me
Me
i-Pr
3 (4.0 equiv.)
3 (4.0 equiv.)
iPrOH (1.1 equiv.)
THF, rt, 18 h
O
iPrOH (1.2 equiv.)
7, 60% yield
9, 93% yield
8, 74% yield
THF, 40 °C, 18 h
Ref. 47
Me
Me
FeCl3 (10 mol%)
4-methylanisole (2.0 equiv.)
CH3CN, 60 °C, 16 h
K2CO3 (1.4 equiv.)
Carbamic chloride (1.1 equiv.)
EtOAc, 80 °C, 8 h
Me
N
N
O
OH
Et
Me
iPr
O
N
Me
iPr
Rivastigmine
(antidementia drug)
HO
HO
Ph
)-Tolterodine (urinary incontinence drug)
(
Ph
69% yield, >99% e.e.
Figure 2 | Concise routes to drugs through cascade reductive hydroamination of alkynes. a, Hydroamination product 6f as a key synthetic precursor for
duloxetine synthesis. b, Hydroamination product 6g as a known synthetic precursor to atomoxetine and fluoxetine. c, Rapid synthesis of 8, a known
precursor to tolterodine. d, Two-step synthesis of rivastigmine.
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2131
ARTICLES
R3
R4
a
R3
R4
N
BzO
LCu N
LCu
R1
LCu
R1
OBz
R1
ROH
LCu
H
2
R2
R1
R2
R2
Amination
Protonation
R2
11
14
15
12
R3
R4
R3
R1
R4
R2
N
N
Direct hydroamination
R1
R2
Reductive hydroamination
OBz
2
R3
BzO
LCu N
(E)-enamine 4
LCu
13
LCu
10
H
OBz
LCu OBz
R4
HSiR3
R3SiOBz
R3SiOBz
HSiR3
13
R1
R2
R3
R1
R4
R2
N
16
Aryl alkynes
LCu
Aliphatic alkynes
CuL
H
H
Ar
R
R
H
Amine 5
Markovnikov selectivity
Anti-Markovnikov selectivity
c
b
Cu(OAc)2 (2.0 mo%)
Cu(OAc)2 (2.0 mol%)
(R)-L4 (2.2 mol%)
3 (4.0 equiv.)
Bn
Ph
Bn
Bn
Bn
Ph
Bn
Ph
Bn
Ph
Bn
N
Bn
Ph
Bn
Ph
Bn
Ph
N
(R)-L4 (2.2 mol%)
3 (4.0 equiv.)
N
N
Bn
N
N
Ph
Ph
Ph
Ph
Bn
+
+
+
Ph
Ph
2a (1.2 equiv.)
Ph
2a (1.2 equiv.)
EtOH (1.5 equiv.)
THF, 40 °C, 18 h
THF, 45 °C, 18 h
4a
4a
17
5a
18
5a
19
With or without
alcohol additive
99% recovered
0%
0%
3%
97%
Figure 3 | Proposed catalytic cycles and mechanistic experiments. a, Both direct hydroamination and reductive hydroamination are proposed to proceed
through vinylcopper intermediate 11. In the absence of alcohol additive, electrophilic amination occurs directly to give the enamine product (left cycle). In the
presence of alcohol additive, protonation of 11 affords alkene 14, which undergoes further hydrocupration and electrophilic amination to furnish the
alkylamine product (right cycle). Internal aryl alkynes and terminal aliphatic alkynes undergo hydrocupration with Markovnikov and anti-Markovnikov
regioselectivity, respectively. b, Enamine 4a is inert to direct hydroamination conditions (no alcohol additive), thus accounting for the lack of over-reduction
or diamination products observed under these conditions. Enamine 4a is also inert to reductive hydroamination conditions (alcohol additive present).
Enamine 4a is thus unlikely to be an intermediate in the reductive hydroamination reaction. c, In the presence of ethanol as a proton source and electrophilic
amination reagent 2a, cis-stilbene selectively undergoes hydroamination rather than reduction. Hence, the presence of alcohol does not interfere with the
hydroamination of proposed alkene intermediate 14, allowing the reductive hydroamination cascade to proceed efficiently to afford the alkylamine product.
ester 2a (381 mg, 1.2 mmol, 1.2 equiv.). The reaction tube was sealed with a screw-
cap septum, and then evacuated and backfilled with argon (this process was repeated
a total of three times). Anhydrous THF (0.5 ml) and EtOH (88 µl, 1.5 mmol,
1.5 equiv.) were added, followed by dropwise addition of the catalyst solution from
Conclusion
We have developed catalytic conditions that allow for the controlled
construction of enamines or alkylamines from alkynes and electro-
philic amine sources. The products from these complementary
systems were obtained with uniformly high levels of regio- and
stereocontrol. Both catalytic processes operate through the for-
mation of a vinylcopper intermediate, the product being determined
by the presence or absence of an alcohol additive. The development
of a protocol for the direct conversion of alkynes to alkylamines is
especially notable, given the ease of access to requisite substrates
and the demonstrable applicability of this method to the rapid syn-
thesis of a number of pharmaceutical agents. Beyond the broad
utility of this new protocol, we anticipate that this cascade strategy
will motivate the design of other cascade processes for the more
efficient synthesis of valuable targets.
the first vial to the stirred reaction mixture at RT. The reaction mixture was then
heated at 40 °C for 18 h. After cooling to RT, the reaction was quenched by addition
of EtOAc and a saturated aqueous solution of Na2CO3. The phases were separated,
the organic phase was concentrated, and product 5a was purified by flash column
chromatography. The e.e. of each product was determined by HPLC analysis using
chiral stationary phases. All new compounds were fully characterized (see
Supplementary Information).
Received 18 September 2014; accepted 6 November 2014;
published online 15 December 2014
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Author contributions
S-L.S. and S.L.B. designed the project, analysed the data and wrote the manuscript. S-L.S.
performed the experiments.
Additional information
Supplementary information and chemical compound information are available in the
online version of the paper. Reprints and permissions information is available online at
www.nature.com/reprints. Correspondence and requests for materials should be addressed
to S.L.B.
reduction as a route to novel β-azaheterocyclic acid derivatives. Proc. Natl Acad. Competing financial interests
Sci. USA 101, 5821−5823 (2004).
The authors declare no competing financial interests.
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