Copper/titanium catalysis forms fully substituted carbon centers from the direct coupling of acyclic ketones, amines, and alkynes

Article abstract of DOI:10.1002/anie.201206674

Three-component coupling, with a pair: The combination of Cu^II and Ti^IV catalyzes the first three-component coupling of unactivated ketones with a diverse range of amines and terminal alkynes. Tetrasubstituted propargylamines are for

Full text of DOI:10.1002/anie.201206674

Angewandte
Chemie
DOI: 10.1002/anie.201206674
Tetrasubstituted Carbon Centers
Copper/Titanium Catalysis Forms Fully Substituted Carbon Centers
from the Direct Coupling of Acyclic Ketones, Amines, and Alkynes**
Conor J. Pierce, Mary Nguyen, and Catharine H. Larsen*
A wide range of natural products and bioactive compounds
contain fully substituted carbon centers.[1] To circumvent the
each of 2-pentanone and phenylacetylene, this AuIII system
produces what they term a quaternary propargylamine in
54% yield.
À
difficulty of creating these hindered C N bonds in one step,
compounds are commonly synthesized and rearrangement
induced.[2] A catalytic system capable of overcoming the
barrier to the condensation of a ketone and an amine to
a ketimine, while leaving a nucleophile able to attack would
lead to the direct formation of tetrasubstituted carbon atoms
bearing amines.[3] In contrast to the wide array of three-
component couplings (3CC) of aldehydes by the in situ
formation of aldimines, reactions of ketones as electrophiles
require an extra step that costs time, energy, and chemicals to
produce and purify the ketimine starting material.[4] Dozens
of enantioselective additions to ketimines have appeared
without examples of the corresponding 3CC in either
asymmetric or racemic form.[1] This situation suggests that
the direct 3CC of ketones is more difficult to achieve than the
asymmetric addition of nucleophiles to preformed ketimines.
The nucleophilic attack on imines by terminal alkynes has
been widely studied owing to the intrinsic biological activity
and utility of the resulting propargylamines as synthetic
building blocks.[5] Aldehyde–amine–alkyne couplings (A3)
abound,[6–8] but as ketones are 750-times less-active than
aldehydes as electrophiles,[9] the corresponding KA2 proce-
dure for unactivated ketones has not been reported. The three
catalytic methods developed for cyclohexanones[10–12] rely on
the fact that they undergo nucleophilic attack 300-times faster
than acyclic ketones.[13] Cyclohexanone is a special case of
near aldehyde-like reactivity,[14] and its corresponding keti-
mines[15] readily react to release torsional strain.[16]
We recently disclosed a green[18] copper(II)-catalyzed
solvent-free KA2 of cyclohexanone that uses 1:1:1 stoichiom-
etry of the three coupling partners, such that the sole by-
product is one equivalent of water.[12] Heating cyclohexanone
(1), benzylamine (2), and 1-octyne (3) in with 5 mol% CuCl2
produces the N-benzyl propargylamine 4 in 91% yield
(Scheme 1). However, when cyclohexanone is replaced with
Scheme 1. Catalysts reported for cyclohexanone KA2 cannot convert
simple 2-butanone under the same conditions.
2-butanone (1a), neither ketimine intermediate nor the
desired propargylamine product is observed under identical
conditions (Scheme 1). Elevated temperatures, microwave
conditions, and standard drying agents do not improve the
reaction.[19] The conditions reported by Van der Eycken and
Ji also fail. Thus, the KA2 of acyclic ketones pose a serious
synthetic challenge.
The catalytic cycle proposed for these types of reactions
involves condensation of amine and carbonyl with subsequent
attack of the resultant imine by the metal acetylide formed
from the terminal alkyne.[6,7] We hypothesized that a more-
active Lewis acid additive could overcome both the barrier to
in situ ketimine formation and activate these less-reactive
ketimines for subsequent attack. Ellman and co-workers and
Davis et al. have demonstrated that the formation of aldi-
mines can be facilitated by a range of Lewis acidic dehydrat-
ing agents.[20] However, their result showed that titanium (IV)
ethoxide was unique in its ability to form ketimines without
competitive aldol reactions. Ti(OEt)4 is inexpensive and
filtration removes the benign TiO2 by-products.[20]
Until Van der Eycken and co-workers described their
solvent-free KA2 methodology,[10] the catalytic incorporation
of any ketone was an isolated, low-yielding event.[17] By
applying microwave conditions in the presence of 20 mol%
CuI, cyclohexanones and benzylamines couple with phenyl-
acetylenes in 31–82% yield.[10] Employing 4 mol% AuBr3, Ji
and co-workers focused on cyclic amines and phenylacety-
lenes.[11] With 1 equivalent morpholine and 1.5 equivalents
[*] C. J. Pierce, M. Nguyen, Prof. C. H. Larsen
Department of Chemistry, University of California
Riverside, CA 92521 (USA)
E-mail: catharine.larsen@ucr.edu
[**] Acknowledgement is made to the Donors of the American Chemical
Society Petroleum Research Fund for partial support of this
research. Additional support was provided by the University of
California, Riverside, and M.N. was awarded a Dean’s Summer
Undergraduate Research Fellowship. We thank Mr. Daniel Reza for
assistance.
Exploration of Lewis acid additives began with the
combination of 2-butanone (1a), benzylamine (2), and 1-
octyne (3) which is unreactive under all known conditions
(Scheme 1). Table 1 shows a range of Lewis acids tested in
conjunction with 5 mol% CuCl2. When added in a fraction of
the 2 or 5 equivalents previously reported,[20] 50 mol% of
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206674.
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À
Table 1: Lewis acids tested for the conversion into propargylamine.
Table 2: Acyclic ketones form fully substituted C N bonds.
Entry
Lewis acid
GC yield [%][a]
Entry
1
Ketone 1
t [d]
Product 5
Yield [%][a]
1
2
3
4
5
6
Ti(OEt)4
Ti(OiPr)4
AlCl3
FeCl3
AuCl3
92
34
0
0
0
2
84[b]
AuBr3
0
[a] Reaction conditions: neat with 1.0 mmol each of ketone, amine, and
alkyne, CuCl2 (0.05 mmol), and Lewis acid (0.5 mmol) under Ar; best
result highlighted in bold.
2
3
3
2
71
75
Ti(OEt)4 or Ti(OiPr)4 provide propargylamine 5 in 92% or
34% GC yield, respectively. Lewis acidic aluminum, iron, and
gold sources tested induce no conversion from starting
materials despite their utility in imine alkynylation.[7,11]
Under an atmosphere of either air or N2, propargylamine 5
forms cleanly but conversion halts at two-thirds that of the
same reaction under Ar. Thus, heating ketone, amine, and
alkyne with 5 mol% CuCl2 and 50 mol% Ti(OEt)4 produces
the N-benzyl propargylamine 5 in 74% yield. The cooperative
effect of both metals is required. In the absence of Ti(OEt)4,
the starting materials do not react. If copper is removed,
ketimine forms in the presence of titanium but is not
alkynylated.
The simple method of heating equimolar amounts of
ketone, amine, and alkyne with CuII/TiIV is successful for
a variety of nonsymmetric ketones (Table 2). With 5 mol%
CuCl2 and 25 mol% Ti(OEt)4, 2-butanone (1a) combines
with morpholine and 1-octyne to give 5a in 84% yield
(entry 1). For most substrates, 25 mol% Ti(OEt)4 is sufficient
for conversion to product but 50 mol% provides higher
yields.[19] Hindered pinacolone (1d) forms propargylamine 5d
4
2
82
5
6
3
3
64[c]
82
[a] Yield of isolated product under standard conditions: neat with 1:1:1
stoichiometry of ketone, amine, and alkyne (1.0 mmol each), CuCl2
(0.05 mmol), and Ti(OEt)4 (0.5 mmol) under Ar. [b] 0.25 mmol Ti(OEt)4.
[c] 1.0 mmol Ti(OEt)4.
À
where the new C N bond bridges a tertiary amine and
tetrasubstituted carbon with a vicinal quaternary carbon.
However, aromatic ketones remain unreactive.[11]
Titanium appears to work cooperatively with copper to
accelerate in situ imine formation and alkynylation. The rate
of alkynylation of purified ketimine heated in the presence of
5 mol% CuCl2 is half the rate of the direct KA2 with 5 mol%
CuCl2 and 50 mol% Ti(OEt)4.[19] As nonsymmetric ketones
are utilized, all the products described herein are chiral. The
first catalytic diastereoselective KA2 was achieved using this
new method (Scheme 2): 1R-(+)-camphor (1g), benzylamine
(2), and 1-octyne (3) produce 5g in 61% yield with over 95:5
diastereoselectivity as determined by 1H NMR spectrosco-
py.[21]
As shown in Table 3, terminal alkynes bearing aryl, alkyl,
chlorinated, and cyano groups couple efficiently (71–91%
yield). This contrasts with previous cyclohexanone KA2
conditions in which utilizing alkyl alkynes reduces the product
yield by half.[10,11] In addition to the synthetic utility of
propargylamines,[5] the nitrile group of 6d and the chloro
group of 6e (entries 4 and 5) can be readily converted into
a variety of other functional groups. Note that these yields are
Scheme 2. Highly diastereoselective KA2 reaction with camphor.
achieved using equimolar amounts of the three coupling
partners.
Table 4 displays the scope of the amine component of
these KA2 reactions. Propargylamines 6 f and 6g from
piperidine and morpholine provide 90% and 91% yields of
tertiary amines attached to a fully substituted carbon center
(Table 4, entries 1 and 2). While primary amines are consid-
ered to be difficult substrates compared to secondary
amines,[10] aminomethyl naphthalene provides 6h, with
À
a free N H moiety for derivatization. Bearing additional
pharmacophores, N-propyl cyclopropylmethyl (6i) and N-
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Table 3: A range of alkyl and aryl terminal alkynes react efficiently.
dary and tertiary N-propargylamines at tetrasubstituted
carbon centers. Compared to current syntheses reliant on
stoichiometric metal acetylide addition to ketimines,[5d] our
approach provides a faster route to compounds with both
therapeutic activity and utility in natural-product synthesis.[5]
A highly diastereoselective example with camphor inspires
our current efforts to make this KA2 reaction enantioselec-
tive.
The cooperative effects of inexpensive titanium(IV)
ethoxide and copper(II) chloride[24] catalyze in situ ketimine
formation and activates the ketimine for alkynylation.
Nucleophiles successful in 3CCs with aldehydes and amines
lack the corresponding 3CC with ketones.[3–5] This unique
CuII/TiIV system for the activation of ketone electrophiles may
enable expansion to nucleophiles other than alkynes for
direct access to a wide range of fully substituted carbon
centers bearing amines.
Entry
Propargylamine 6
t [h]
Yield [%][a]
1
2
3
4
5
6
6a: R=n-Hex
6b: R=Ph
6c: R=(CH2)3Ph
6d: R=(CH2)3CN
6e: R=(CH2)3Cl
6 f: R=tBu
48
22
72
48
21
23
85
70
71
76
91
90
[a] Yield of isolated product under standard conditions: neat with 1:1:1
stoichiometry of ketone, amine, and alkyne (1.0 mmol each), CuCl2
(0.05 mmol), and Ti(OEt)4 (0.5 mmol) under Ar.
Table 4: Primary and secondary, cyclic and acyclic amines in KA2.
Experimental Section
To an oven-dried test tube equipped with magnetic stir bar and
Teflon-seal screw cap was added CuCl2 (5 mol%) and Ti(OEt)4
(50 mol%). The tube was purged with argon for 5 min. Ketone
(1.0 mmol), alkyne (1.0 mmol), and amine (1.0 mmol) were added,
and the reaction was stirred at 1108C for the indicated time. Upon
reaction completion, as judged by GC, the mixture was cooled to
room temperature and directly loaded onto a silica gel column and
eluted with ethyl acetate in hexanes to afford the desired product.
Entry
1
Amine
t [h]
Product
Yield [%][a]
23
90
Received: August 18, 2012
Published online: October 26, 2012
2
3
4
23
22
48
91
73
73
Keywords: alkynes · amines · cooperative effects · ketones ·
multicomponent reactions
.
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