Enantioselective A3 Reactions of Secondary Amines with a Cu(I)/Acid-Thiourea Catalyst Combination

Article abstract of DOI:10.1021/jacs.5b02071

Pyrrolidine and related amines undergo asymmetric A³ reactions in the presence of copper iodide and an easily accessible cocatalyst possessing both a carboxylic acid and a thiourea moiety. Propargylamines are obtained with up to 96% ee, and catalyst loadings can be as low as 1 mol %. Pyrrolidine-derived propargylamines, in the absence of directing groups, can be transformed to the corresponding allenes without loss of enantiopurity.

Full text of DOI:10.1021/jacs.5b02071

Communication
pubs.acs.org/JACS
Enantioselective A3 Reactions of Secondary Amines with a Cu(I)/
Acid−Thiourea Catalyst Combination
Chenfei Zhao and Daniel Seidel*
Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United
States
S
* Supporting Information
Scheme 1. Synthesis of Enantioenriched Propargylamines
ABSTRACT: Pyrrolidine and related amines undergo
asymmetric A3 reactions in the presence of copper iodide
and an easily accessible cocatalyst possessing both a
carboxylic acid and a thiourea moiety. Propargylamines are
obtained with up to 96% ee, and catalyst loadings can be as
low as 1 mol %. Pyrrolidine-derived propargylamines, in
the absence of directing groups, can be transformed to the
corresponding allenes without loss of enantiopurity.
ropargylamines are compounds of substantial synthetic
Pvalue and are most readily accessed by addition of terminal
alkynes to imines or iminium ions (Scheme 1).1 When the
imine or iminium ion is prepared in situ from an aldehyde and
an amine, these transformations are referred to as A3 coupling
reactions.1 The catalytic enantioselective synthesis of propargyl-
amines derived from primary amines is a well-developed
process, most commonly utilizing copper(I) catalysis and
ligands such as pybox.2 Copper and silver salts have also been
used in combination with different organocatalysts.3 When
secondary rather than primary amines are employed, the nature
of the reaction changes dramatically as do the requirements for
asymmetric catalysis. Rather than involving imines as
intermediates (e.g., 1), secondary amines by necessity require
the intermediacy of iminium ions such as 4. These species lack
an available lone pair on nitrogen and thus are not readily
amenable to activation/enantiocontrol via hydrogen bonding,
protonation, or metal coordination. Presumably because of this
added difficulty, relatively few reports have addressed the
challenge of performing catalytic enantioselective A3 reactions
with secondary amines.4−7 Without exception, these processes
require the use of phosphine-based ligands. Trimethylsilylace-
tylene is used predominantly and is often required to achieve
high enantioselectivities. Here we report the application of
readily available carboxylic acid−thiourea compounds (e.g., 5)
as efficient cocatalysts in copper(I)-catalyzed asymmetric A3
reactions with pyrrolidine and related amines.
The first catalytic enantioselective A3 reaction with secondary
amines was reported by Knochel and co-workers who
Figure 1. Cocatalysts evaluated in this study.
employed copper(I) bromide in combination with QUINAP.4
Carreira et al. later introduced tunable PINAP ligands which
were applied to asymmetric A3 coupling reactions with
a new type of chiral Brønsted acid catalyst containing both a
carboxylic acid and a thiourea subunit (Figure 1).8−11 These
dibenzylamine and 4-piperidinone.5 Recently, the Aponick
group developed an imidazole-based P,N ligand (L1) for
enantioselective A3 reactions.6,7 As part of our ongoing efforts
to develop new organocatalytic processes, we recently reported
Received: February 25, 2015
Published: April 2, 2015
© 2015 American Chemical Society
4650
DOI: 10.1021/jacs.5b02071
J. Am. Chem. Soc. 2015, 137, 4650−4653

Journal of the American Chemical Society
Communication
catalysts were designed with the notion that the thiourea
moiety would function as an anion receptor, serving to stabilize
the catalyst’s conjugate base and thus increasing its Brønsted
acidity. Compound 5a emerged as an effective catalyst for
asymmetric Povarov reactions with secondary amines.8a As
these reactions likely proceed via intermediates related to 4
(with X− representing the conjugate base of 5a), we reasoned
that carboxylic acid−thioureas 5 might serve as effective chiral
cocatalysts in Cu(I)-catalyzed A3 reactions.12
Further optimizations were conducted with catalyst 5j.13
Replacement of 4 Å with 5 Å molecular sieves provided a slight
boost in enantioselectivity (74% vs 82% ee).15 Reactions
performed in the absence of molecular sieves or with other
dehydrating agents (3 Å MS, Drierite, Na2SO4, MgSO4) gave
inferior results (not shown).13 Evaluation of various ratios of
CuI and cocatalyst 5j led to the observation that higher
selectivities are obtained when CuI is used in slight excess.16
Furthermore, the catalyst loading could be reduced and optimal
results were obtained with 4 mol % of CuI and 3 mol % of 5j.
Finally, product 3a was obtained with 92% ee in a reaction
conducted at 0 °C (entry 18).
Benzaldehyde, pyrrolidine, and phenylacetylene were se-
lected as model substrates to evaluate the title reaction (Table
1). Catalyst 5a, when used in combination with CuI, facilitated
The scope of the catalytic enantioselective A3 reaction with
pyrrolidine was found to be relatively broad (Scheme 2).
Aromatic aldehydes and terminal arylalkynes with diverse
substituents in different ring positions were well tolerated.
More challenging terminal alkynes with alkyl and alkenyl
substituents were also viable substrates. Lower selectivities were
obtained with aliphatic aldehydes. Whereas azepane performed
Table 1. Optimization of Reaction Conditions
entry
cocatalyst
solvent
time [h]
yield (%)
ee (%)
1
5a
5b
5b
5b
5b
5c
5d
5e
5f
PhCH3
PhCH3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
3
6
78
91
90
92
82
92
89
92
92
94
96
94
91
92
70
92
91
92
20
60
73
64
25
0
2
3
4
5
6
7
8
9
Scheme 2. Substrate Scope
2
a
b
2
3
3
4
14
64
73
70
42
−5
74
0
2
2
10
11
12
13
14
15
16
17
18
5g
5h
5i
2
4
4
5j
3
5k
5l
3
24
3
8
c
5j
82
88
92
cd
,
5j
3
cde
, ,
5j
CH2Cl2
12
a
b
c
d
With CuBr. With CuCl. With 5 Å MS. Reaction was run at a 1
e
mmol scale with 4 mol % CuI and 3 mol % cocatalyst. Reaction was
run at 0 °C.
the formation of product 3a in good yield albeit with only 20%
ee (entry 1). Surprisingly, acid−thiourea 5b, a poor catalyst for
Povarov and Pictet−Spengler reactions,8 provided a marked
increase in enantioselectivity (entry 2). Subsequent evaluation
of various solvents led to further improvements with dichloro-
methane providing the best results (entry 3).13 Replacement of
CuI for either CuBr or CuCl led to inferior results (entries 4
and 5). Remarkably, and in stark contrast to our previous
studies, urea catalyst 5c was equally active as thiourea 5a.
However, product 3a was obtained in racemic form (entry 6).
Removal of the two trifluoromethyl groups on the catalyst’s
thiourea moiety was also detrimental (entry 7). Other
modifications targeting the carboxylic acid moiety were
tolerated to varying degrees but failed to provide any
improvements (entries 8−12). A slightly more selective
catalyst, compound 5j, was obtained through introduction of
a bromine substituent between the two flanking trifluoromethyl
groups (entry 13). The poor results obtained with catalyst 5k
and the Nagasawa catalyst14 (5l) clearly demonstrate that a
carboxylic acid substituent is essential for effective catalysis
(entries 14 and 15).
a
b
Run at −30 °C for 48 h. The ee was determined after
c
d
demethylation. Run at rt for 24 h. CuBr was used instead of CuI.
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DOI: 10.1021/jacs.5b02071
J. Am. Chem. Soc. 2015, 137, 4650−4653

Journal of the American Chemical Society
Communication
similarly to pyrrolidine with regard to selectivity and reactivity,
piperidine proved to be less reactive and provided product with
reduced selectivity. Interestingly, 1,2,3,4-tetrahydroisoquinoline
(THIQ) afforded mixtures of the expected product 3x and the
corresponding redox-A3 product (not shown).17,18 The use of
CuBr in place of CuI allowed for the exclusive formation of 3x,
albeit with moderate enantioselectivity. To illustrate the utility
of this process, a reaction was performed on a 10 mmol scale
with only 1 mol % of 5j (Scheme 3). A high level of efficiency
was maintained, and product 3a was obtained in 94% yield and
90% ee.
Scheme 3. Scale-up Reaction at Lower Catalyst Loading
Figure 2. Nonlinear effects study.
the enantiodetermining step remains unclear at present.
Carboxylate could conceivably interact with copper to form a
cuprate complex or serve as the counterion to an intermediate
iminium species. Either of these roles could alternatively be
fulfilled by iodide which also appears to be involved in the
enantiodetermining step.
In summary, we have developed an efficient method for the
synthesis of enantioenriched propargylamines, using CuI in
combination with a readily available Brønsted acid cocatalyst.
Pyrrolidine-based propargylamines lacking directing groups can
be transformed to allenes without loss of enantiopurity. The
present approach features the lowest catalyst loadings reported
to date for catalytic enantioselective A3 reactions with
secondary amines.
Nonracemic propargylamines derived from cyclic amines
have been used extensively as starting materials for
enantioenriched allenes.19,20 These reactions proceed via
activation of the alkyne by a metal ion, triggering a 1,5-hydride
transfer and subsequent elimination of an imine byproduct. In
all cases known to us, the presence of a stereogenic center on
the amine moiety or a directing group on the amine or alkyne is
required for an efficient transfer of point-to-axial chirality. In
preliminary experiments, we have accomplished an efficient
transfer of chirality in the absence of such control elements
(Scheme 4).
Scheme 4. Transformation of A3 Products to
Enantioenriched Allenes
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization data, including
an X-ray crystal structure of product 3o (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*seidel@rutchem.rutgers.edu
■
Notes
The authors declare no competing financial interest.
To obtain insights into potential catalyst aggregation
phenomena that might affect the catalytic process, we evaluated
A3 reactions catalyzed by 5b possessing varying levels of
enantiopurity (Figure 2). However, no nonlinear effects were
observed. The available data seem to suggest that cocatalyst 5j
acts as a ligand for copper(I),21 forming a highly reactive
copper acetylide complex that serves to attack a transient
iminium ion. Supporting this notion is the complete lack of
selectivity observed for the corresponding urea catalyst 5c,
making it highly likely that coordination of copper to the
thiourea sulfur atom is crucial for efficient catalysis.22 Also, the
strong dependence on the counteranion of the copper salt
speaks against one alternative scenario, namely that a neutral
copper acetylide reacts with an ion pair such as 4 where X−
represents the conjugate base of 5j. While the carboxylic acid
moiety of 5j is undoubtedly involved in the formation of the
active iminium ion, the role of the corresponding carboxylate in
ACKNOWLEDGMENTS
■
This material is based upon work supported by the National
Science Foundation under Grant No. CHE-1300382. We thank
Dr. Tom Emge (Rutgers University) for crystallographic
analysis.
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Communication
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