Synthesis of Allene Substituted Nipecotic Acids by Allenylation of Terminal Alkynes

Article abstract of DOI:10.1021/acs.joc.7b00630

The relative reactivities of several secondary amines serving as hydride donors in propargylic amines undergoing a [1,5]-hydride transfer reaction to yield the respective terminal and 1,3-disubstituted allenes were studied. For this study, a two-step procedure was employed. At first, the synthesis of propargylic amines via the Cu^I-catalyzed aldehyde-alkyne-amine reactions (A³ coupling) was accomplished. The obtained propargylic amines were subsequently transformed to the desired allenes under CdI₂ or ZnI₂ catalysis. As a result, among the various secondary amines employed, differing in steric bulk, electronic nature, and conformational properties, allyl(tert-butyl)amine was found to be the best hydride donor for the synthesis of terminal allenes. For the synthesis of 1,3-disubstituted allenes, the propyne derivatives containing either a allyl(tert-butyl)amine or a 1,2,3,6-tetrahydropyridine unit in propargylic position performed best. Finally, with the developed procedure, nipecotic acid derivatives containing an N-allenyl substituent were synthesized with good yields using either ZnI₂ as catalyst for the preparation of 1-substituted or CdI₂ for the synthesis of 1,3-disubstitued allenes.

Full text of DOI:10.1021/acs.joc.7b00630

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Article
Synthesis of Allene Substituted Nipecotic
Acids by Allenylation of Terminal Alkynes
Maren Schaarschmidt, and Klaus T. Wanner
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00630 • Publication Date (Web): 12 Jul 2017
Downloaded from http://pubs.acs.org on July 12, 2017
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Synthesis of Allene Substituted Nipecotic Acids by
Allenylation of Terminal Alkynes
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Maren Schaarschmidt and Klaus T. Wanner*
Department of Pharmacy ꢀ Center for Drug Research, LudwigꢀMaximiliansꢀUniversität
München,
Butenandtstr.
5ꢀ13,
Dꢀ81377
Munich,
Germany,
Eꢀmail:
klaus.wanner@cup.uniꢀmuenchen.de
th
Dedicated to Prof. Dr. Herbert Mayr with warmest wishes on the occasion of his 70
birthday.
Abstract
The relative reactivities of several secondary amines serving as hydride donors in
propargylic amines undergoing a [1,5]ꢀhydride transfer reaction to yield the respective
terminal and 1,3ꢀdisubstituted allenes were studied. For this study, a twoꢀstep
I
procedure was employed. At first the synthesis of propargylic amines via the Cu ꢀ
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catalyzed aldehydeꢀalkyneꢀamine reactions (A coupling) was accomplished. The
obtained propargylic amines were subsequently transformed to the desired allenes
2 2
under CdI or ZnI catalysis. As a result, among the various secondary amines
employed, differing in steric bulk, electronic nature and conformational properties,
allyl(tertꢀbutyl)amine was found to be the best hydride donor for the synthesis of
terminal allenes. For the synthesis of 1,3ꢀdisubstituted allenes, the propyne
derivatives containing either a allyl(tertꢀbutyl)amine or a 1,2,3,6ꢀtetrahydropyridine
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(
THP) unit in propargylic position performed best. Finally, with the developed
procedure, nipecotic acid derivatives containing an Nꢀallenyl substituent could be
synthesized with good yields using either ZnI as catalyst for the preparation of 1ꢀ
for the synthesis of 1,3ꢀdisubstitued allenes.
2
substituted or CdI
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Introduction
Allenes are important and useful building blocks in organic synthesis. Many natural
products, molecular materials and pharmaceuticals with an allene moiety are
1,2,3,4
known.
For example, allenic derivatives of γꢀaminobutyric acid (GABA) 1 and 2
have been synthesized as potential inhibitors of the pyridoxalphosphateꢀdependent
5,6
enzyme GABAꢀaminotransferase (Scheme 1).
Scheme 1. Allenic derivatives of γꢀaminobutyric acid
With GABA being the major inhibitory neurotransmitter in the mammalian central
nervous system, a malfunction of its neurotransmission is involved in several
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diseases like epilepsy, Alzheimer`s disease, neuropathic pain, and depression.
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mGAT1 is considered to be the most important GABA transporter subtype for the
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regulation of neurotransmitter levels in the synaptic cleft. Lipophilic derivatives of
the nipecotic acid are known to inhibit the uptake of mGAT1. One example of such a
®
nipecotic acid based drug is Tiagabine (Gabitril ) (3), which is used as addꢀon
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therapy for epilepsy (Scheme 2, structure 3). It is known that nipecotic acid
derivatives with a diaryl moiety attached via a spacer to the cyclic amino acid exhibit
good inhibitory activities at mGAT1. Hence it appears promising to synthesize similar
nipecotic acid derivatives, for example by implementation of an allene moiety in the
spacer (Scheme 2, structure 4), as new potential mGAT1 inhibitors. To be able to
compare the inhibitory activity of nipecotic acid derivatives such as 4 with the
nipecotic acid derivative containing solely an allenyl spacer, the parent compound 5
is of interest, too, as this would allow to analyze the contribution of the different
subunits to the overall potencies of the final inhibitors.
Scheme 2. Tiagabine (3), new nipecotic acid
derivatives with allenyl spacer (4,5)
Efficient synthetic methods for the preparation of terminal and 1,3ꢀdisubstituted
allenes are of high interest in organic chemistry. Until now, many synthetic methods
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have been developed to access allenes.
One of these methods is the so called
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ATA reaction, the allenylation of terminal alkynes by their reaction with aldehydes or
ketones and secondary amines in the presence of metal promoters like CuBr, CdI2
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and ZnI
2
.
This method is based on the pioneering Crabbé homologation
(Scheme 3), the generation of monosubstituted allenes 9 by a threeꢀcomponent
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reaction of terminal alkynes 6, paraformaldehyde (7), and diisopropylamine (8) in the
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presence of substoichiometric amounts of CuBr. Until now, several modifications of
this reaction have been reported. For example, Ma and coworkers reported a oneꢀpot
synthesis of 1,3ꢀdisubstituted allenes 13 from terminal alkynes 10, aldehydes 11, and
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morpholine (12) in the presence of ZnI
2
at elevated temperature (Scheme 3). Later
on, several groups developed asymmetric versions of this kind of reaction by using
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either chiral ligands in combination with Lewis acids or chiral secondary amines
20,21,22,27ꢀ33
(20, 23)
for the synthesis of chiral propargylic amines as intermediates.
Che and coworkers for instance described a twoꢀstep procedure for the synthesis of
axially chiral allenes 22, including first a gold(III)salen complex catalyzed synthesis of
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+
+
chiral propargylic amines 21 from chiral amine 20 followed by a Au or Ag mediated
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rearrangement providing chiral allenes 22 in high enantioselectivity (Scheme 3).
A oneꢀstep procedure to axially chiral 1,3ꢀdisubstituted allenes has been reported by
21,22
20,27ꢀ33
Periasamy and coworkers
as well as by Ma and coworkers
(Scheme 3).
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Crabbé homologation
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Ma and coworkers
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Yu and coworkers / Ma and coworkers
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Scheme 3. Previous works
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According to the reaction mechanism proposed by Ma et al. in the ATA reaction at
first propargylic amines are formed which upon [1,5]ꢀhydride transfer and subsequent
elimination of the thus formed iminium subunit yield the final allenes (Scheme 4).
Since it is reported that the generation of propargylic amines from terminal alkynes,
3
4,35
aldehydes, and secondary amines can be performed at room temperature,
it is
15
reasonable to assume that the [1,5]ꢀhydride transfer process described by Ma is the
3
4
rateꢀdetermining step in the allene synthesis. Accordingly, this is the step which
requires elevated temperature to proceed (Scheme 4). To accelerate the [1,5]ꢀ
3
4
hydride transfer reaction, Yu and coworkers selected their amine on the criterion of
the best hydride donating ability (Scheme 3), but despite their good results with
tetrahydroisoquinoline (THIQ, 17) as hydride donor for the synthesis of 1,3ꢀ
disubstituted allenes 13, they were not able to perform the formation of terminal
allenes 9 with paraformaldehyde and THIQ in noticeable yields. Based on this
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observation, we assumed that besides the known electronic influence of the hydride
donor, there might be some additional factors that could have an important impact on
the allene formation. Hence, we were interested in studying of how the nature of the
hydride donor influences the formation of terminal and 1,3ꢀdisubstituted allenes. To
this end, the ATA reaction should be performed in two steps, i.e. the synthesis of the
propargylic amines and the rearrangement of the latter to the corresponding allene
derivatives.
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Scheme 4. Postulated mechanism for the ATA reaction by Ma and coworkers
For the intended synthesis of allene substituted nipecotic acid derivatives such as 5
and related compounds by a [1,5]ꢀhydride transfer process, alkyne derivatives such
as 25 had to serve as starting materials. However, with two amino groups in
propargylic position in 25 the [1,5]ꢀhydride transfer process may deliver either the
allenyl substituted amine 26 or the desired nipecotic acid derivative 24 depending on
the propensity of the amino function NR
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serve as hydride donor (Scheme 5). This study ought to identify amines with distinctly
better capabilities in mediating the allene formation than a nipecotic acid residue to
exclude the latter to participate in the [1,5]ꢀhydride transfer process. With amino
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residues NR suitable for this purpose nipecotic acid derivatives 24 (Scheme 5) and
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53aꢀe (Table 5) containing an allene moiety in the spacer should be synthesized.
Scheme 5. Intramolecular competition reaction
Results and Discussion
Synthesis of propargylic amines
In order to be able to study the [1,5]ꢀhydride transfer process separately from the
formation of the propargylic amines, a twoꢀstep procedure was followed, i.e. at first
the propargylic amines were synthesized and subsequently subjected to a
rearrangement reaction to give the corresponding allenes. The propargylic amines
3
2
9aꢀo and 31aꢀo required for this study were synthesized by A coupling from
terminal alkynes 27a, 27b, and 30, and a set of different secondary amines and
aldehydes (Scheme 6, Table S1, for the use of ketones in this reaction see chapter 1
of SI).The propargylic amines 29aꢀo derived from 4,4ꢀdiphenylbutꢀ1ꢀyne (27a,b) were
intended to serve as test systems to study the [1,5]ꢀhydride transfer process in the
absence of a nipecotic acid residue. The substituents on the amino nitrogen were
varied with respect to sterical demand, utilizing methyl, ally, iPr and tꢀBu residues,
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and with respect to electronic properties, introducing residues like methyl, allyl and
iPr as the hydride donating part of the amine.
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Scheme 6: Synthetic route to employed propargylic amines
Studies on the effect of hydride donors on the formation of terminal allene 32
For the conversion of propargylic amines 29aꢀk derived from formaldehyde as
carbonyl component to terminal allene 32, reaction conditions similar to a protocol
1
5
established by Ma and coworkers were employed. However, to improve the
solubility of the reactants, chlorobenzene instead of toluene was used as solvent in
the present experiments. Initial allene formation reactions were carried out with the
propargylic amine 29a, derived from the known hydride donor morpholine, also
17
frequently used by Ma and coworkers (Table 1, entry 1). This reaction and all other
reactions listed in Table 1 were conducted by heating the respective propargylic
2
amine (29aꢀk) with 0.8 equiv of CdI in chlorobenzene at 130 °C, conditions under
which all compounds were found to undergo a transformation reaction. In each case,
the reaction was run until all starting material had been consumed or in the case of
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the less reactive hydride donors until no further transformation could be observed by
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Table 1. Influence of different hydride donors on the
a
formation of terminal allene 32
1
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entry starting material
NR R
t [h]
yield [%]
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29c
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29k
1.25
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a
The reaction was conducted using propargylic amine (0.5 mmol) and
CdI2 (0.8 equiv) at 130 °C in 4.0 mL of anhyd chlorobenzene. The
reaction was stopped when all starting material was consumed (detection
by TLC). The reaction was stopped when no further transformation could
b
c
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be observed (detection by TLC).
Electronic properties of hydride donors
In case of 29a the yield of 32 was surprisingly low (2%, Table 1, entry 1). Utilizing
piperidine as hydride donor afforded a similar low yield of allene 32 (3%, Table 1,
entry 2), whereas the 1,2,3,6ꢀtetrahydropyridine (THP) mediated allene conversion
resulted in a significantly higher yield of 29% (Table 1, entry 3). Similar to THIQ,
34
which according to Yu et al. is especially well suited as hydride donor because of its
electronic properties, also THP can be assumed to possess improved hydride donor
capabilities. In addition to the ring structure, THP possesses two hydrogens in allylic
position, adjacent to the amino group that should exhibit an increased propensity for
the hydride shift reaction. This explains well the increased yield of allene 32 when
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utilizing the THP derivative 29c.
Steric properties of hydride donors
With the electronic properties having clearly a positive effect on the [1,5]ꢀhydrogen
transfer reaction, next allene formation reactions were studied, employing acyclic
amines with an allyl group as hydride donating moiety for which the second amine
substituent was varied with respect to the steric demand. With increasing steric
demand of the second amine substituent, i.e. in the row from methyl to allyl to iPr and
tꢀBu the yields for allene 32 increased from 18 to 88% (Table 1, entry 5ꢀ8). As
indicated in Scheme 7 depicting the reaction mechanism for the formation of the
allenes, the Lewis acid, CdI
2
, will promote the [1,5]ꢀhydride transfer reaction by
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complexation of the alkyne moiety (34). This will initiate the hydride transfer to give
the corresponding iminium ion 35, which undergoes an elimination to give allene 13
as final product. Instead of complexing the triple bond, the Lewis acid may also
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spectra that have been obtained from mixtures of propargylic amine 29g and ZnI
chlorobenzeneꢀd5 are in support of this assumption. In the presence of ZnI signals
arising from protons closest to the amino nitrogen experience a clear line
2
in
2
37
1
broadening and downfield shift as compared to those in the H NMR spectrum of
the pure amine 29g (Figure S1). This may be best rationalized by the assumed
complexation of the amino nitrogen of the propargylic amines by the Lewis acids (for
more information see SI). Due to the electron withdrawing effect of the Lewis acid,
when attached to the amino group, this species will not be able to undergo a [1,5]ꢀ
hydride transfer reaction even if an additional molecule of Lewis acid was present at
the triple bond. These three forms, the free starting material (33), the starting material
complexing the CdI
2
via the triple bond (34) and the starting material complexing the
CdI via the amino function (36) will exist in an equilibrium (Scheme 7). The position
2
of this equilibrium will depend on the steric demand of the amino subunit. With
increasing steric demand the amino function will be less capable of complexing the
2
Lewis acid CdI . Accordingly, the equilibrium will shift towards the reactive species
with the triple bond attached to the Lewis acid, resulting in an increased reaction rate
for the desired rearrangement reaction. In line with this hypothetic model, the yields
of the final product steadily increase with the steric demand of the ”second” residue
of the amino function in 29hꢀ29e.
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24
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32
33
34
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 7. Proposed mechanism for the allene formation
Conformational properties of hydride donors
The data listed for the rearrangement reaction of 29e, 29i, and 29j also allow a
comparison of the influence the nature of the hydride donating residue has on the
outcome of the reaction. All of these compounds contain the same inert tꢀBu group
but vary with regard to the hydride donating Nꢀsubstituent which is an allyl (29e), iPr
(
29i), or methyl substituent (29j). Whereas the yield of the product decreases from
88% (Table 1, entry 5) to only 21% (Table 1, entry 9) when the allyl moiety is
replaced by an iPr residue, it raises to 66% (Table 1, entry 10) when a methyl group
is present. With this trend not being in line with the electron donating ability of the
varied residues (allyl, iPr, methyl), the rearrangement must be governed by additional
factors. For the [1,5]ꢀhydride shift to occur the hydride donating residue must place
the migrating hydride in a syn orientation to the alkyne acceptor. In case of the
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
isopropyl(tertꢀbutyl)amino substituent in 29i, the two major conformations given in
Scheme 8 should exist in which the migrating hydride is either oriented syn (37) or
anti (38) to the alkyne acceptor. Because of severe steric interactions between the
methyl groups of the iPr residue with the bulky tꢀBu group, the syn orientation of the
hydride should be strongly disfavored and as consequence thereof also the [1,5]ꢀ
hydride shift reaction which nicely explains the low yield observed in this case.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 8. Isopropyl(tertꢀbutyl)amine as hydride donor
Best performing hydride donor – a comparison
According to the results of the above described experiments the allyl group appears
to possess the highest propensity to act as hydride donor, whereas the tꢀBu residue
is best suited as “second” Nꢀsubstituent, that due to its steric demand hinders the
formation of a complex between the amino function and the Lewis acid, that would
hamper the desired rearrangement reaction. For comparison of the above described
results with those of Crabbé and coworkers utilizing diisopropylamine as hydride
18
donor (Scheme 3), in addition transformation of the propargylic amine 29k into
allene 32 was studied (Table 1, entry 11). With the diisopropylamine residue in 29k
as hydride donor, terminal allene 32 could be obtained in a good yield of 82%. This is
in line with the reasoning outlined above. For electronic reasons, the iPr residues
should exhibit favorable hydride donating abilities, whereas the steric demand of the
two iPr residues will lower the tendency of the amino nitrogen to form a complex with
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the Lewis acid that would negatively affect the transfer reaction. Obviously, there is
also a subtle control of the reactive conformation. Whereas a tꢀBu residue as
“
second” substituent in combination with an iPr as hydride donating moiety appears
to disfavor the reactive conformation required for the hydride transfer reaction
Scheme 8), an iPr instead of an tꢀBu residue is obviously compatible with it. Besides,
also the influence of the amount of CdI on the formation of terminal allene 32 was
studied employing propargylic amine 29e that had led to the highest yield of the
rearrangement product 32 (Table 1, entry 5). Applying 0.4, 0.8 and 1.2 equiv of CdI
10
11
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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
(
2
2
under the same reaction conditions as for the reactions listed in Table 1, neither a
trend nor a significant variation of the yield of allene 32 could be observed (Table S2,
entry 1ꢀ3, 88ꢀ93% yield).
The scope of terminal alkynes
To demonstrate the applicability of the developed method for the synthesis of
terminal allenes applying allyl(tertꢀbutyl)amine as hydride donor, additionally alkynes
39ꢀ42 exhibiting different residues were included in this study (Table 2). All
substrates (39ꢀ42) exhibiting either a pure alkyl residue, or a halogen, nitrile or ether
function underwent transformation to the corresponding allene in excellent yields (83ꢀ
97%, Table 2, entry 1ꢀ4).
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 2. The scope of terminal alkynes
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
entry
R
t [h]
3.00
3.00
3.00
2.75
yield [%]
94
1
2
3
CH
Cl(CH
NC(CH
PhCH OCH
3 2 7
(CH )
2
)
3
83
97
95
2
)
3
4
2
2
a
The reaction was conducted using propargylic
amine (0.5 mmol) and CdI (0.8 equiv) at 130 °C in
2
4.0 mL of anhyd chlorobenzene. The reaction was
stopped when all starting material was consumed
(
detection by TLC).
Studies on the effect of hydride donors on the formation of 1,3-disubstituted
allene 47
In additional experiments, the suitability of some of the above mentioned amino
residues in [1,5]ꢀhydride transfer reactions should be studied in which the substrate
carries an additional substituent, i.e. a phenyl residue next to the amino group. For
these experiments THP, allyl(methyl)amine, allyl(tertꢀbutyl)amine, and diallylamine
with different steric and electronic properties were selected as hydride donors. In
contrast to the less substituted starting materials 29c, 29g, and 29h exhibiting the
same, sterically less demanding amino residues, i.e. THP, diallylamine and
allyl(methyl)amine, that due to this feature had given low yields of the rearrangement
product 32 (18ꢀ29%), the corresponding phenyl derivatives performed significantly
better. In case of the THP derivative 29l, the yield rose from 29% (for 29c ꢀ 32) to
8
9% (for 29l ꢀ 47). Thereby a temperature of only 100 °C (instead of 130 °C for 29c)
was sufficient to effect the desired transformation. For the diallylamine and
allyl(methyl)amine derivatives, 29n and 29o, the yields for the rearrangement product
4
7 were likewise substantially higher, 75% for the transformation of 29n to 47 (Table
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3, entry 4) and 43% for the transformation of 29o in 47 (Table 3, entry 6), compared
to those of the less substituted propargylic amines (Table 1, entry 7, 29g ꢀ 32, 24%;
Table 1, entry 8, 29h ꢀ 32, 18%). However, for this transformations again a reaction
temperature of 130 °C was required, the yields at a temperature of 100 °C being in
both cases with 10% of 47 much lower (Table 3, entry 3, 5). As with the formation of
terminal allene 32 allyl(tertꢀbutyl)amine performed well as hydride donor in the
synthesis of 1,3ꢀdisubstituted allene 47 (29m, Table 3, entry 2) providing it in 76%
yield, whereby the [1,5]ꢀhydride transfer occurs already at a lower temperature of 100
10
11
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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
°C. Diisopropylamine as well should be studied as a hydride donor in the formation of
1,3ꢀdisubsituted allene 47. However, all attempts to synthesize the required
propargylic amine, from the corresponding alkyne 27a, benzaldehyde (28), and
diisopropylamine failed, indicating that this amine is not suitable for this purpose
which is most likely due to its high steric demand. Overall the transformations of the
propargylic amines 29lꢀ29o to 1,3ꢀdisubstituted allene 47 appears to be less sensitive
1
2
to the steric demand of R and R attached to the amino residue. This supports the
assumption that complexation of the amino nitrogen by the Lewis acid, in competition
with the complexation of the triple bond required for the induction of the
rearrangement reaction, negatively affects the hydride donating ability of the
respective alkyl amino subunit. With a phenyl residue in the direct neighborhood to
the amino nitrogen contributing to the steric shielding of the latter, the steric
1
2
encumbrance of the amino function provided by R and R becomes obviously less
important for the reduction of the complexation of the amino nitrogen by the Lewis
acid.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 3. Influence of different hydride donors on the formation of
a
1,3ꢀdisubstituted allene 47
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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8
9
0
1
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
entry starting material
NR R
temp [°C]
100
t [h] yield [%]
b
1
29l
3.25
89
b
2
29m
4.25
76
100
c
100
130
3
29n
29n
6.00
4.50
10
75
b
4
c
c
5
29o
29o
5.00
4.00
10
43
1
00
30
6
1
a
The reaction was conducted using propargylic amine (0.5 mmol) and CdI2
b
(0.8 equiv) at 100/130 °C in 4.0 mL of anhyd chlorobenzene. The reaction
c
was stopped when all starting material was consumed (detection by TLC).
The reaction was stopped when no further transformation could be observed
(detection by TLC).
Synthesis of allene substituted nipecotic acid ester 24
Based on the above described results, the formation of the nipecotic acid derived
allene 24 was undertaken with the propargylic amine 31a exhibiting an allyl(tertꢀ
butyl)amino residue as hydride donor, which had performed well in the [1,5]ꢀhydride
transfer reaction independent of the substitution in propargylic position adjacent to
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the hydride donor. Using the same conditions as given in Table 1 for the preparation
of 32, i.e. treating 31a in chlorobenzene with 0.8 equiv of CdI at 130 °C for 2 h, no
2
terminal allene 24, but only side products 51 and 52 (Scheme 9) could be obtained
(Table 4, entry 1). It appeared likely that the desired allene 24 might have had
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15
16
17
18
19
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21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
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56
57
58
59
60
formed, but underwent subsequent transformation reactions to give the two side
products 51 and 52. This assumption was supported by literature data, according to
which butaꢀ2,3ꢀdienyl amines are prone to rearrangement reactions giving rise to 2,5ꢀ
dihydropyrroles, which may further easily undergo an oxidation reaction to give the
38,39
corresponding pyrroles.
A reasonable reaction pathway for the formation of the
pyrrole derivatives 51 and 52 from allene 24 is given in Scheme 9. As indicated in the
first step the Lewis acid causes the aminobutadiene subunit to form the
dihydropyrrole ring 48 as part of a spirocyclic ring system. The latter undergoes a
retro Michael reaction to give the Nꢀmonoꢀsubstituted dihydropyrrole derivative 49
which after exchange of the metal substituent by a proton and either a subsequent
oxidation or disproportionation yields pyrrole derivatives 51 and 52.
Scheme 9: Proposed mechanism for the formation of side products 51 and 52 from
allene 24.
Optimization of the reaction conditions
This led us to vary the reaction conditions to possibly be able to isolate 24 under
milder reaction conditions. Indeed, when the reaction temperature was lowered to
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
100 °C after 2 h minute amounts (< 4%) of allene 24 together with 5% of the side
products 51 and 52 could be isolated (Table 4, entry 2). Lowering the temperature to
90 °C led to a slightly improved yield of 7% for 24 after 2 h (Table 4, entry 3) together
with neglectable amounts of 51 and 52 (1%). However, when the reaction time was
extended to 3.75 h, the desired product 24 was not detectable any longer, whereas
the yield of the side products 51 and 52 had increased to 10% (Table 4, entry 4).
Lowering the reaction temperature to 70 °C neither met any success leading only to
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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1
2
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0
1
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
51 and 52 (11%), after an extended reaction time of 3 d required for a detectable
conversion of small amounts of the starting material 31a (Table 4, entry 5). With the
subsequent reaction of allene 24 leading to the side products 51 and 52, being quite
fast as compared to the formation of 24, further attempts to optimize the reaction with
CdI as catalyst were considered futile. Interestingly, with 0.8 equiv of ZnI instead of
2
2
2
CdI
at 90 °C after 7.75 h, 25% of allene 24 could be isolated whereas only 1% of the
side products 51 and 52 had formed (Table 4, entry 8). The yield of 24 could be
further increased to 37%, when the reaction was conducted at 100 °C, with no side
products 51 and 52 being detectable (Table 4, entry 7). In this case the reaction had
been stopped after 4.75 h, when still some starting material was left, but no further
conversion could be observed by TLC. However, increasing the temperature to 130
°C was detrimental for the formation of the desired product: only the side products 51
and 52 (36%), but no allene 24 could be isolated (Table 4, entry 6). To support the
assumption according to which the side products 51 and 52 are formed via allene 24,
additional experiments have been performed. When allene 24 was treated either with
0.8 equiv of ZnI
from 80ꢀ100 °C, TLC analysis of the reaction mixture revealed, that with CdI
catalyst the formation of side products 51 and 52 started already at 80 °C, whereas
2
or 0.8 equiv of CdI
2
(in chlorobenzene) at a reaction temperature
2
as
with ZnI
2
side product formation started at a distinctly higher temperature, i.e. 100 °C.
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Furthermore, up to 150 °C barely any of the side product 51 and 52 formed when
neither of the catalyst was present. Obviously, CdI2 appears to affect the
transformation of 24 into the side products 51 and 52 already at lower temperature as
compared to ZnI
2
, whereas the [1,5]ꢀhydride transfer reaction seems to be faster
catalysis. Hence, ZnI is the more appropriate Lewis
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23
24
25
26
27
28
29
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37
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42
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
under ZnI as compared to CdI
2
2
2
acid for the synthesis of allene 24 from propargylic amine 31a.
Table 4. Optimization of reaction conditions for the synthesis
a
of allene 24
temp
°C]
yield side products
entry catalyst equiv
t
[
[%]
51/52 [%]
1
2
CdI
2
2
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.8
1.6
0.4
130
100
90
2.00 h
2.00 h
2.00 h
3.75 h
3.00 d
4.75 h
4.75 h
7.75 h
4.00 h
4.50 h
ꢀ
47
CdI
<4
7
5
1
b
3
CdI2
CdI2
CdI2
4
90
ꢀ
10
11
36
ꢀ
c
5
70
ꢀ
6
7
ZnI
ZnI
2
2
130
100
90
ꢀ
37
25
50
29
d
8
ZnI2
ZnI
ZnI
1
9
2
100
100
-
10
2
ꢀ
a
The reaction was conducted using propargylic amine (0.5 mmol) and
b
catalyst in 4.0 mL of anhyd chlorobenzene. About 15% of starting
material could be covered. Small amount of 24 could be observed after
c
6
.50 h, after 3 d, all of 24 was transformed into 51/52 and starting
d
material was still present. About 20% of starting material could be
covered.
Effect of different hydride donors on the formation of allene 24
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2
2
2
2
2
2
2
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3
3
3
3
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3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
The yields for converting propargylic amines 31cꢀf (Table S3, entries 5ꢀ8), bearing
different hydride donors, under optimized reaction conditions applying 0.8 equiv of
ZnI
2
follow the same trends as in the test system (Table 1). Whereas
diisopropylamine (Table S3, entry 3, 31b) as well as allyl(tertꢀbutyl)amine (Table S3,
entry 1, 31a) as hydride donors had afforded allene 24 in good yields, the starting
materials with amino residues which are less hindered (Table S3, entry 5ꢀ7, THP
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
1c, diallylamine 31d, allyl(methyl)amine 31e) or adopt a conformation less favorable
for the [1,5]ꢀhydride transfer reaction (Table S3, entry 8, isopropyl(tertꢀbutyl)amine
1f) afforded much lower yields of allene 24. The generally lower yields compared to
3
the test system 29 (Table 1) might be due to additional coordination of the catalyst to
the nitrogen of the nipecotic acid subunit. But most notably, in none of the above
described transformations of 31aꢀf, an alternative allene product resulting from the
nipecotic acid residue serving as a hydride donor could be detected. This agrees with
former results according to which the nipecotic acid residue appeared to be among
the least suited hydride donors tested (Table 1, entry 4, 29d ꢀ 32, 6%).
Effect of amount of Lewis acid
Next, it was investigated how the amount of Lewis acid effects the outcome of the
rearrangement reaction (Table 4). In contrast to the test system, where the yields of
allene 32 were not influenced by the catalyst loading (Table S2), the use of 1.6 equiv
2
instead of 0.8 equiv of ZnI increased the yield for the transformation of 31a into
allene 24 from 37% (Table 4, entry 7) to 50% (Table 4, entry 9). In line with this result
the yield of 24 decreased to 29% when only 0.4 equiv ZnI were used (Table 4, entry
2
10). Alike the allyl(tertꢀbutyl)amino derivative 31a also 31b (Table S3) containing the
sterically demanding diisopropylamino residue gave upon treatment with 0.8 equiv of
ZnI
2
a high yield of 24 (42%, Table S3, entry 3), which in contrast to the
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transformation of 31a in 24, however, lowered to 12% when the amount of ZnI was
doubled (Table S3, entry 4). Hence, in case of the nipecotic acid derived propargylic
amines, it depends on the hydride donor what influence the catalyst loading has on
the yield of allene 24.
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16
17
18
19
20
21
22
23
24
25
26
27
28
29
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32
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36
37
38
39
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Synthesis of nipecotic acid ethyl esters with 1,3-disubstituted allene residues
Finally, the twoꢀstep procedure comprising preparation of the respective propargylic
amine and subsequent rearrangement to an allene was also used for the preparation
a a
of the nipecotic acid derivatives racꢀ(R ,R)ꢀ53aꢀe and racꢀ(R ,S)ꢀ53aꢀe exhibiting an
Nꢀallene substituent with a terminal aryl or alkyl residue (Table 5) employing the
propargylic amines 31gꢀo as starting materials (mixture of racemic diastereomers,
~
1:1; preparation see Scheme 6 and Table S1). Propargylic amines 31g exhibiting an
allyl(tertꢀbutyl)amino residue and 31h equipped with a THP moiety gave good yields
of the allene derivative mixture racꢀ(R ,R)ꢀ53a/racꢀ(R ,S)ꢀ53a (82% and 74%,
a
a
respectively, Table 5, entry 1,2). This is in good line with the results obtained so far,
the sterically demanding allyl(tertꢀbutyl)amino moiety leading to good results
independent of whether an additional residue in propargylic position adjacent to the
amino function is present or not and the THP hydride donor only when, as in this
case, a residue increasing the steric encumbrance of the amino nitrogen, like a
phenyl group, is nearby. An attempt to improve the yield for the transformation of 31h
a a
into racꢀ(R ,R)ꢀ53a/racꢀ(R ,S)ꢀ53a by increasing the reaction temperature from 100
°C to 130 °C, led to the opposite, the yield being lower (Table 5, entry 3). This is
likely to be assigned to an instability inferred by the nipecotic acid moiety.
To explore the scope of aldehydes applicable in this method, furthermore propargylic
amines 31iꢀo derived from different aromatic (2ꢀnaphthaldehyde, biphenylꢀ2ꢀ
carboxaldehyde) and aliphatic (butyraldehyde, isobutyraldehyde) aldehydes,
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
allyl(tertꢀbutyl)amine and THP were employed as starting materials in this
rearrangement reaction (Table 5, entry 4ꢀ11). Applying compounds with aryl
residues, both hydride donors, allyl(tertꢀbutyl)amine and THP, performed well,
providing allenes 53b and 53c in yields of 63ꢀ86% (Table 5, entry 4ꢀ7). In case of the
propargylic amines 31m and 31n with an alkyl residue present, i.e. an nꢀpropyl
substituent, the THP mediated allene formation (Table 5, entry 9) performed distinctly
better than the allene formation based on propargylic amine 31m, containing
allyl(tertꢀbutyl)amine as hydride donor (Table 5, entry 8). Compared to the THPꢀ
mediated allene formation, the allene formation mediated by allyl(tertꢀbutyl)amine
required longer reaction times. In a control experiment, the reaction time of THP
containing propargylic amine 31n has been extended from 1.5 h to 2.5 h. This led to
a decrease in yield from 90% to 76% (Table 5, entry 9,10), which is likely to be due to
product instability. Therefore, the longer reaction time required for the complete
consumption of 31m might explain the lower yield with allyl(tertꢀbutyl)amine as
hydride donor as compared to the excellent yield of the faster THPꢀmediated allene
formation. The synthesis of allene 53e exhibiting an isopropyl residue could only be
performed with propargylic amine 31o exhibiting THP as hydride donor (Table 5,
entry 11), as attempts to synthesize the analogous propargylic amine based on
isobutyraldehyde and allyl(tertꢀbutyl)amine failed which is likely to be attributed to the
high steric demand of these two components. Nonetheless, as indicated by these
results THP and allyl(tertꢀbutyl)amine are well suited hydride donors in [1,5]ꢀhydride
transfer reactions allowing a broad range of substituents in propargylic position next
to the aforementioned amino groups.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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a
Table 5. Synthesis of 1,3ꢀdisubstituted allenes 53aꢀe
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
b
1
2
3
yield
[%]
entry starting material
NR R
R
product
temp [°C] t [h]
racꢀ(R,S)ꢀ31g
racꢀ(R,R)ꢀ31g
racꢀ(R
racꢀ(R
a
,S)ꢀ53a
a
,R)ꢀ53a
1
phenyl
100
3.75
82
racꢀ(R,S)ꢀ31h
racꢀ(R,R)ꢀ31h
racꢀ(R
racꢀ(R
a
,S)ꢀ53a
a
,R)ꢀ53a
2
phenyl
phenyl
100
130
3.00
1.25
74
51
racꢀ(R,S)ꢀ31h
racꢀ(R,R)ꢀ31h
racꢀ(R ,S)ꢀ53a
a
3
racꢀ(R
a
,R)ꢀ53a
racꢀ(R,S)ꢀ31i
racꢀ(R,R)ꢀ31i
racꢀ(R
a
,S)ꢀ53b
,R)ꢀ53b
4
2ꢀnaphthyl
2ꢀnaphthyl
2ꢀbiphenyl
2ꢀbiphenyl
nꢀpropyl
100
100
100
100
100
2.75
1.50
4.00
1.75
2.50
76
75
63
86
51
racꢀ(R
a
racꢀ(R,S)ꢀ31j
racꢀ(R,R)ꢀ31j
racꢀ(R ,S)ꢀ53b
a
racꢀ(R ,R)ꢀ53b
a
5
racꢀ(R,S)ꢀ31k
racꢀ(R,R)ꢀ31k
racꢀ(R
racꢀ(R
a
,S)ꢀ53c
a
,R)ꢀ53c
6
racꢀ(R,S)ꢀ31l
racꢀ(R,R)ꢀ31l
racꢀ(R ,S)ꢀ53c
a
7
racꢀ(R
a
,R)ꢀ53c
racꢀ(R,S)ꢀ31m
racꢀ(R,R)ꢀ31m
racꢀ(R
a
,S)ꢀ53d
,R)ꢀ53d
8
racꢀ(R
a
racꢀ(R,S)ꢀ31n
racꢀ(R,R)ꢀ31n
racꢀ(R
racꢀ(R
a
,S)ꢀ53d
a
,R)ꢀ53d
9
nꢀpropyl
nꢀpropyl
100
100
1.50
2.50
90
76
25
racꢀ(R,S)ꢀ31n
racꢀ(R,R)ꢀ31n
racꢀ(R
racꢀ(R
a
,S)ꢀ53d
a
,R)ꢀ53d
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
racꢀ(R,S)ꢀ31o
racꢀ(R,R)ꢀ31o
racꢀ(R
racꢀ(R
a
,S)ꢀ53e
,R)ꢀ53e
11
isopropyl
100
1.50
84
a
a
The reaction was conducted using propargylic amine (0.5 mmol) and CdI
2
(0.8 equiv) at 100 °C/130 °C
in 4.0 mL of anhyd chlorobenzene. The reaction was stopped when all starting material was consumed
b
(
detection by TLC). ≈ 1:1 mixture of both racemic diastereomers.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Conclusion
Studying the synthesis of terminal and 1,3ꢀdisubstituted allenes from propargylic
2 2
amines via [1,5]ꢀhydride transfer reactions under CdI or ZnI catalysis gave insight of
how the electronic, steric and conformational properties of different secondary
amines serving as hydride donors influence this reaction. Besides the known
influence of the electronic properties of the amines, steric demand was found to play
an important role regarding the synthesis of terminal allenes. By applying sterically
demanding hydride donors like allyl(tertꢀbutyl)amine, the reactivity limiting
complexation of the hydride donor nitrogen by the Lewis acid is suppressed and the
[
1,5]ꢀhydride transfer reaction can occur in significantly higher yields. With allyl(tertꢀ
butyl)amine an amine was found, which due to its electronic and steric characteristics
is well suited for both, the synthesis of terminal and of 1,3ꢀdisubstituted allenes. With
this herein reported method also terminal and 1,3ꢀdisubstituted allenes attached to a
nipecotic acid building block were accessible in good yields.
Experimental
Unless otherwise noted, all reactions were performed in oven dried glassware under
moistureꢀfree conditions and argonꢀ or nitrogen atmosphere. All commercial available
reagents were used without further purification. Chlorobenzene was dried over CaCl2,
distilled under nitrogen atmosphere and stored over molecular sieves (4 Å) under
nitrogen atmosphere prior to use. For chromatographic purposes only distilled
solvents were used (EtOAc, PE 42ꢀ62 °C, DCM, MeOH). Flash column
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chromatography was performed using silica gel (grading 0.035 ꢀ 0.070 mm). Thin
layer chromatography (TLC) was carried out on precoated silica gel F254 glass plates.
1
13
NMR spectra were measured at 298.1 K on 400 MHz ( H NMR: 400 MHz, C NMR:
1
13
1
01 MHz) and 500 MHz ( H NMR: 500 MHz, C NMR: 126 MHz) spectrometers.
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
These NMR spectrometers were also used for DEPT, HMQC, HMBC and COSY
experiments. The coupling constants were stated with an accuracy of 0.5 Hz.
MestreNova was used for further analysis of the NMR data (s = broad singlet, hept
br
13
=
septet, Nip = nipecotic acid residue, dia = diastereomeric racemate, C signals
separated by a slash are illustrating the slightly different ppm values of the
diastereomeric racemates). IR spectra were recorded with a FTꢀIR spectrometer and
Spectrum v2.00 software was used for analysis. Highꢀresolution mass spectrometry
was performed with sector field mass spectrometer or LTQ FT Ultra mass
spectrometer.
Synthesis of Alkynes:
(4,4ꢀDiphenylbutꢀ1ꢀynꢀ1ꢀyl)trimethylsilane (27b). To a Schlenk flask was added
diphenylmethane (1.00 g, 5.94 mmol) in anhyd THF (20 mL). After cooling to 0 °C in
an ice bath, a 1.6 M solution of nꢀBuLi in hexane (3.71 mL, 5.94 mmol) was added
dropwise. The reaction mixture was stirred at 0 °C for 2 h. Then 3ꢀbromoꢀ1ꢀ
(trimethylsilyl)ꢀ1ꢀpropine (1.09 mL, 6.54 mmol) was added dropwise and the reaction
was stirred at room temperature for 20 h. The completion of the reaction was
monitored by TLC (PE/DCM = 9:1). The reaction mixture was quenched with 40 mL
of phosphate buffer (pH 7) and extracted 6 times with Et O. The combined organic
2
4
phases were then dried over MgSO and concentrated under vacuum. The crude
product was purified by column chromatography (PE/DCM = 9:1) to afford 27b (1.59
1
g, 96%) as colorless viscous oil: TLC: R
f
= 0.33 (PE/DCM = 9:1); H NMR (500 MHz,
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1
1
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
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5
5
5
5
5
6
CDCl
3 3 3 2
) δ 0.04 (s, 9 H, Si(CH ) ), 2.91 (d, J = 7.6 Hz, 2 H, CHCH ), 4.21 (t, J = 7.6 Hz,
13
1
H, CHCH ), 7.16–7.25 (m, 2 H, ArH), 7.21–7.33 (m, 8 H, ArH); C NMR (126 MHz,
2
3
CDCl ) δ ꢀ0.1, 26.9, 50.0, 86.9, 105.6, 126.4, 128.0, 128.3, 143.4; IR (neat) 3374,
3086, 3062, 3028, 2958, 2361, 2176, 1600, 1494, 1450, 1249, 1043, 842, 757, 697
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ꢀ1
cm ; HRMS (ESI) m/z calcd for C19
H22Si 278.1491, found 278.1471.
40
4,4ꢀDiphenylbutꢀ1ꢀyne (27a). This compound is literature known. Because of
41
already synthesized compound 27b, a simple deprotection reaction instead of the
procedure described in literature was performed. Analytical data obtained agreed
with published data. To a solution of TMS protected alkyne 27b (3.31 g, 11.9 mmol)
in THF (55 ml) was added 1 M TBAF solution in THF (1.50 eq, 5.17 mL, 17.9 mmol)
and the mixture was stirred at rt overnight. After evaporation, the residue was filtered
through a pad of silica gel (PE/DCM = 9:1) to afford 27a as pale yellow crystals (1.80
g, 73%): mp = 72.1 °C (lit. 73.0ꢀ73.5 °C); TLC: R = 0.29 (PE/DCM = 9:1).
f
Ethyl 1ꢀ(propꢀ2ꢀynꢀ1ꢀyl)piperidineꢀ3ꢀcarboxylate (30). Compound 30 was synthesized
42
employing a synthesis route similar to a procedure described in literature. Propargyl
bromide solution (80 wt% in xylene, 1.00 equiv, 1.08 mL, 10.0 mmol) and ethyl
nipecotate (1.20 equiv, 1.87 mL, 12.0 mmol) were dissolved in acetone (20 mL) and
2 3
Na CO (2.50 equiv, 2.65 g, 25.0 mmol) and NaI (0.50 equiv, 749 mg, 5.00 mmol)
were added. The reaction mixture was refluxed for 72 h and the reaction was
monitored by TLC. For quenching, DCM (50 mL) and water (50 mL) were added and
the product was extracted five times with DCM. The combined organic phases were
then dried over Na SO and concentrated under vacuum. The crude product was
2
4
purified by column chromatography (PE/EtOAc = 8:2) to afford 30 as pale yellow oil
1
(1.85 g, 95%): TLC: R
f
= 0.60 (PE/EtOAc = 1:1); H NMR (400 MHz, CDCl
3
) δ 1.26 (t,
J = 7.1 Hz, 3 H, OCH
2
CH
3
), 1.44 (qd, J = 11.7/3.9 Hz, 1 H, NCH
2
CHCHax
H
eq), 1.60
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2 2 2 2
(m, 1 H, NCH CHaxHeqCH CH), 1.71–1.83 (m, 1 H, NCH CHaxHeqCH CH), 1.89–2.00
(
m, 1 H, NCH CHCH H ), 2.22 (td, J = 11.0/3.1 Hz, 1 H, NCH H CH CH CH),
2
ax eq
ax eq
2
2
2
.26 (t, J = 2.4 Hz, 1 H, NCH
2
CCH), 2.38 (t, J = 10.4 Hz, 1 H, NCHax
CHaxCH
CH), 2.96–3.05 (m, 1 H, NCHax eqCHCH
AB, J = 17.2 Hz, 2 H, NCH CCH), 4.14 (q, J = 7.1 Hz, 2 H, OCH
MHz, CDCl ) δ 14.2, 24.5, 26.5, 41.9, 47.3, 52.2, 54.2, 60.4, 73.3, 78.7, 173.9; IR
H
eqCHCH
2
), 2.59
(ddt, J = 11.0/10.4/3.9 Hz, 1 H, NCH
2
2
), 2.72–2.82 (m, 1 H,
), 3.32 (d, J = 2.4 Hz, or
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
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NCHax
H
eqCH
2
CH
2
H
2
13
2
2 3
CH ); C NMR (101
3
(neat) 3291, 2942, 2864, 2807, 1730, 1468, 1450, 1368, 1311, 1223, 1183, 1153,
ꢀ
1
1
133, 1095, 1031, 1002, 900, 864, 791, 654 cm ; HRMS (ESI) m/z calcd for
+
C
11
H
18NO
2
[M+H] 196.1338, found 196.1332.
Synthesis of Propargylic Amines:
General Procedure 1: To a Schlenk flask was added CuCl (1.5 equiv). Dioxane
anhyd (12.0 mL/mmol) was then added, followed by TMSꢀprotected alkyne (1.0
3 2
equiv), paraformaldehyde (1.2 equiv), amine (1.2 equiv) and BF —OEt (1.0 equiv).
The reaction mixture was stirred at rt for 10 minutes and at 50 °C overnight. The
completion of the reaction was monitored by TLC. After cooling to rt the reaction
mixture was added to a 1:1 solution of saturated potassium sodium tartrate solution
and saturated sodium hydrogen carbonate solution (44.0 mL/mmol) and extracted 5
times with EtOAc. The combined organic phases were then filtrated, dried over
4
MgSO and concentrated under vacuum. The crude product was purified by column
chromatography to afford the corresponding propargylic amine.
General Procedure 2: To a Schlenk flask was added CuBr (0.15 equiv) and
molecular sieve (4Å). Toluene anhyd (5.00 mL/mmol) was then added, followed by
the addition of the corresponding aldehyde (1.80 equiv), amine (1.40 equiv) and
alkyne (1.00 equiv). The reaction mixture was stirred at rt overnight. The completion
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