Synthesis of N,N-disubstituted 3-amino-1,4-diynes and 3-amino-1-ynes by addition of alkynyldimethylaluminum reagents to N,N-disubstituted formamides and N,O-acetals

Article abstract of DOI:10.1002/ejoc.201402464

A wide range of alkynyldimethylaluminum reagents, which were derived from terminal alkynes and trimethylaluminum, underwent a double addition to N,N-disubstituted formamides and their acetals to provide the corresponding N,N-disubstituted 3-amino-1,4-diynes in moderate to excellent yields. Also, these reagents smoothly underwent the addition to N,O-acetals to give the corresponding N,N-disubstituted 3-amino-1-ynes in excellent yields.

Full text of DOI:10.1002/ejoc.201402464

FULL PAPER
DOI: 10.1002/ejoc.201402464
Synthesis of N,N-Disubstituted 3-Amino-1,4-diynes and 3-Amino-1-ynes by
Addition of Alkynyldimethylaluminum Reagents to N,N-Disubstituted
Formamides and N,O-Acetals
Balaji L. Korbad[a] and Sang-Hyeup Lee*[a]
Keywords: Synthetic methods / Nucleophilic addition / Aluminum / Alkynes / Amides
A wide range of alkynyldimethylaluminum reagents, which
were derived from terminal alkynes and trimethylaluminum,
disubstituted 3-amino-1,4-diynes in moderate to excellent
yields. Also, these reagents smoothly underwent the addition
underwent a double addition to N,N-disubstituted form- to N,O-acetals to give the corresponding N,N-disubstituted
amides and their acetals to provide the corresponding N,N-
3-amino-1-ynes in excellent yields.
dimethyl acetals, imines, and thioformamides.[16] Alterna-
tive approaches involve the Cu-catalyzed coupling of ter-
minal alkynes with N,N-dialkylformamide dialkyl acetals,
but N,N-dialkylformamides cannot be directly coupled by
this method.[17] Multicomponent coupling reactions be-
tween amines, aldehydes, and terminal alkynes have also
been reported.[18] Many disadvantages are associated with
these aforementioned methods. For example, expensive met-
als and ligands are required in many of the reported cases.
With traditional methods, the employment of strong bases
(e.g., butyllithium, lithium diisopropylamide, and organom-
agnesium reagents) limits the functional group tolerance.
Although the reaction of 1-(α-aminoalkyl)benzotriazoles
with sodium dialkynyldiethylaluminates was reported by
Ahn et al.,[19] these precursors are difficult to prepare. So
far there has been no precedent for the direct use of N,N-
dialkylformamides as substrates.
As part of our ongoing program on the development of
new synthetic methods that utilize organoaluminum rea-
gents,[20] we recently reported the syntheses of α,β-alkynyl
ketones and N–H ketimines by the reactions of nitriles with
alkynyldimethylaluminum reagents that are derived from
terminal alkynes.[20a] As a continuation of our interest in
the use of these reagents, we herein report the addition of
these reagents to N,N-disubstituted formamides and N,O-
acetals to yield N,N-disubstituted 3-amino-1,4-diynes and
3-amino-1-ynes, respectively.
Introduction
Organoaluminum reagents have received considerable at-
tention because of their low cost and high selectivity, and
they are frequently used to develop new synthetic methods
in organic chemistry.[1] They presently have a wide range of
applications as reagents in transition-metal-catalyzed cou-
pling[2] and addition reactions[3] and as the catalyst in poly-
merization reactions.[4] The high Lewis acidity of organoal-
uminum reagents provides an efficient method for the hy-
dro- and carboalumination of alkynes.[5,6] Recently, Mic-
ouin et al. developed an alkynyldimethylaluminum reagent
that was formed from the reaction of terminal alkynes and
trimethylaluminum by using
a catalytic amount of
Et3N.[6b,6c] This reagent has also been utilized in a wide
range of organic transformations such as the ring-opening
alkynylation of activated epoxides[7] and oxazolidines[8] as
well as addition reactions with acid chloride and N-p-tolyl-
sulfinylimines to form α,β-alkynyl ketones and chiral pro-
pargylamines, respectively.[9] In addition, this reagent has
been employed in the synthesis of leustroducsin B,[10] alumi-
noisoxazoles, pyrazoles,[11] and 1,4,5-trisubstituted tri-
azoles.[12]
Propargylamine is a key structural unit in natural prod-
ucts[13] and pharmaceutical agents[14] and also one of the
synthons for the synthesis of nitrogen-containing heterocy-
cles such as pyrroles, pyrrolidines, oxazolidinones, and
imidazoles.[15] Several methods have been reported for the
preparation of propargylamines. They can be accessed by
the addition of a metal acetylide to N,N-dialkylformamide
Results and Discussion
Initially, we attempted the formylation of alkynyldi-
methylaluminum reagent 1a by using N,N-dimethylform-
amide (DMF, 2a, 1.2 equiv.) as the source of the formyl
group.[21] Although the reaction failed to afford the initially
desired 3-phenylpropiolaldehyde, we surprisingly found that
[a] Department of Life Chemistry, Catholic University of Daegu,
Gyeongsan-si, Gyeongbuk 712-702, Korea
E-mail: leeshh@cu.ac.kr
http://dept.cu.ac.kr/user/chem/index.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402464.
Eur. J. Org. Chem. 2014, 5089–5095
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5089

B. L. Korbad, S.-H. Lee
FULL PAPER
N,N-disubstituted 3-amino-1,4-diyne 4a was obtained as Table 1. Double addition of alkynyldimethylaluminum reagents to
N,N-disubstituted formamides and their dialkyl acetals.[a]
1
the main product (40% yield), as confirmed by H NMR
analysis and HRMS. To the best of our knowledge, this is
the first report of a double addition of an alkynyldimethyl-
aluminum reagent to a formyl group of an N,N-disubsti-
tuted formamide. Encouraged by this, DMF (2a, 1 equiv.)
was then set as the limiting reagent and treated with the
alkynyldimethylaluminum reagent 1a (2.5 equiv.) in toluene
at room temperature to give 4a in 90% yield after 16 h of
reaction time.
Entry 1 (R1)
2 (R2,R3)
Product % Yield[b]
The molar ratio of the reagents [i.e., 1a/DMF (2a)], the
reaction temperature, and the solvent were then examined.
The use of an excess amount of 1a (5.0 equiv.) did not sig-
nificantly improve the yield. To accelerate the reaction, it
was performed at a higher temperature. Indeed, in this case,
the reaction was completed within 3 h at 40–60 °C to give
4a in a comparable yield (92% yield) to that performed at
room temperature reaction (see Table 1, Entry 1). The em-
ployment of a higher temperature (Ͼ60 °C) could accelerate
the rate of reaction more significantly, however, this re-
sulted in a lowered yield and the formation of colored im-
purities. Of the solvents tested, dichloroethane gave a com-
parable good yield, whereas that with tetrahydrofuran
(THF) gave a somewhat lowered yield.
With the optimized conditions in hand (i.e., N,N-dialk-
ylformamides/alkynyldimethylaluminum reagent, 1:2.5, tol-
uene, 40 °C), the scope and limitations of this reaction were
examined by employing a wide range of terminal alkynes
and N,N-disubstituted formamides or the corresponding
acetal (see Table 1). The reactivity of the alkyne substrate
was not significantly affected by the substitution pattern of
the benzene ring in the acetylenes (see Table 1, Entries 1–
3). Alkyl and heterocyclic substituted acetylenes underwent
the reaction with 2a to give the corresponding product in
good to high yield (see Table 1, Entries 4–7). Then, we ex-
amined the scope of N,N-disubstituted formamides 2. N,N-
dialkylformamides that were derived from acyclic and cyclic
dialkylamines (i.e., 2b–2e) smoothly underwent the reaction
with various aromatic, aliphatic, and heteroaromatic alkyn-
yldimethylaluminum reagents to afford the corresponding
products in high yields (see Table 1, Entries 8–21). N-alkyl-
N-aryl and N,N-diarylformamides (i.e., 2f and 2g, respec-
1
2
3
4
5
6
7
8
1a (Ph)
2a (Me, Me)
4a
4b
4c
4d
4e
4f
4g
4h
4i
92
89
82
88
95
90
80
97
75
95
93
90
95
73
88
98
85
63
89
96
82
75
70
70
1b (4-MeC6H4) 2a
1c (4-ClC6H4) 2a
1d [CH3(CH2)4] 2a
1e [Ph(CH2)2] 2a
1f (cyclopropyl) 2a
1g (thiophenyl) 2a
1a
1a
1a
1b
1c
1d
1d
1d
1e
1f
2b [–(CH2)5–]
2c (Et, Et)
2d [–(CH2)2O(CH2)2–]
2b
2b
2b
2c
2d
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
4u
4v
4w
4x
4y
4a
4d
4f
2b
2b
2c
1f
1f
1f
2e [-(CH2)4-]
2d
2b
2f (Ph, Me)
2f
2g (Ph, Ph)
2h (H, H)
3 (Me, Me)
3
3
1g
1d
1f
1d
1a
1a
1d
1f
[c]
–
95
92
85
[a] Reagents and conditions: alkynyldimethylaluminum reagent 1/
formamide 2 (or acetal 3), 2.5:1, toluene [4 mLmmol–1 of for-
mamide 2 (or acetal 3)], 0Ǟ40 °C for 3 h (Entries 1–7), 0Ǟ60 °C
for 3 h (Entries 8–21 and 26–28), 0Ǟr.t. for 6 h (Entries 22–25).
[b] Isolated yield based on 2 or 3. [c] Complex mixture.
Next, piperazine-1,4-dicarbaldehyde (5), a substrate that
tively) also underwent the reaction with alkynyldimethyl- contains two formyl groups, was treated with an excess
aluminum reagents at room temperature for 6 h to give the amount of the alkynyldimethylaluminum reagent. This re-
corresponding products in moderate yields (see Table 1, En- action afforded the desired symmetrical product 6 in mod-
tries 22–24). The primary amide (R2 and R3 = H, see erate yield (see Table 2, Entries 1–3).
Table 1, Entry 25) and secondary amides (R2 = alkyl or
We then tried to expand the scope of this protocol by
aryl, R3 = H, data not shown here) were consumed under employing different types of substrates, and we were pleased
the reaction conditions but gave complex mixtures of prod- to find that N,O-acetals[22] 7 are also good substrates (see
ucts, which were not further analyzed. We also found that Table 3). When treated with alkynyldimethylaluminum rea-
1,1-dimethoxy-N,N-dimethylmethanamine (3), a dimeth- gents 1 (1.2 equiv.) at room temperature in toluene, the alk-
ylacetal of DMF, was a suitable substrate. Acetal 3 under- oxy group of the 7 was substituted by the alkynyl unit to
went the reaction with the alkynyldimethylaluminum rea- afford within a short period of time (Ͻ30 min) the corre-
gents at 60 °C for 3 h to afford the desired products in good sponding alkynylamines 8 in excellent yields (see Table 3,
yields (see Table 1, Entries 26–28). It should be noted that Entries 1–11).
the above results could be reproduced when the reaction
was performed at room temperature for an extended period bined with an equimolar amount of either methyl benzoate,
of time (16 h). benzonitrile, nitrobenzene, or styrene oxide and then treated
To examine the functional group tolerance, 7a was com-
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Eur. J. Org. Chem. 2014, 5089–5095

Synthesis of Propargylamines
Table 2. Synthesis of symmetrical propargylamines.[a]
of 10 to give complex 11. Iminium formation and concomi-
tant attack of the acetylide moiety followed by treatment
with H2O/tetrahydrofuran (1:1) affords product 4a.
Entry
1 (R1)
Product
% Yield[b]
1
2
3
1a (Ph)
1d [CH3(CH2)4]
1f (cyclopropyl)
6a
6b
6c
68
65
60
[a] Reagents and conditions: alkynyldimethylaluminum reagent 1/
1,4-dicarbaldehyde 5, (5:1), toluene/tetrahydrofuran (1:1,
4 mLmmol–1 of 5), 0Ǟ60 °C, 5 h. [b] Isolated yield based on 5.
Scheme 1. Plausible mechanism.
Table 3. Monoaddition of alkynyldimethylaluminum reagents to
N,O-acetals.[a]
Conclusions
In summary, we have demonstrated that alkynyldimethyl-
aluminum reagents efficiently undergo reaction with a vari-
ety of N,N-disubstituted formamides and their acetals un-
der mild reaction conditions to produce the corresponding
N,N-disubstituted 3-amino-1,4-diynes in moderate to excel-
lent yields. Moreover, when these reagents are treated with
N,O-acetals, the corresponding N,N-disubstituted 3-amino-
1-ynes are produced in excellent yields. Cyano, ester, and
nitro functional groups were tolerated under the optimized
reaction conditions. This is a simple and effective method
for the preparation of a variety of propargylamines.
Entry
1 (R1)
7 (R4)
Product % Yield[b]
1
2
3
4
5
6
7
8
1a (Ph)
7a (Ph)
8a
8b
8c
8d
8e
8f
98
94
98
90
97
92
98
97
97
95
96
1d [CH3(CH2)4] 7a
1e [Ph(CH2)2]
7a
1f (cyclopropyl) 7a
1a
7b (4-ClC6H4)
7b
1f
1a
7c (H)
7c
8g
8h
8i
1c (4-ClC6H4)
Experimental Section
9
10
11
1d
1e
1f
7c
General Methods: Unless otherwise noted, commercially available
chemicals were obtained from a commercial supplier and used
without further purification. 1-[tert-Butoxy(phenyl)methyl]piper-
idine (7a),[22a] 1-[tert-butoxy(4-chlorophenyl)methyl]piperidine
(7b),[22a] and 1-(tert-butoxymethyl)piperidine (7c)[22b] were prepared
according to their respective literature procedures. Thin layer
chromatography was carried out with Merck 60 F254 plates with
a 0.25 mm thickness. Flash chromatography was carried out with
Merck silica gel 60 (230–400 mesh), and a mixture of ethyl acetate/
hexanes was employed as the eluent. The NMR spectroscopic data
7c
8j
8k
7c
[a] Reagents and conditions: alkynyldimethylaluminum reagent 1/
N,O-acetal 7 (1.2:1), toluene (4 mLmmol–1 of 7), 0Ǟr.t., 30 min.
[b] Isolated yield based on 7.
with 1a (1.2 equiv.). We found that the ester, nitrile, and
nitro groups were stable under the reaction conditions, and
the desired product 8a was obtained in Ͼ90% yield. On the
other hand, the epoxide ring of styrene oxide was reactive,
and the reaction afforded the ring-opened product as well
as 8a in 60% yield.
On the basis of the results described above, a plausible
mechanism for the product formation is depicted in
Scheme 1 with 1a and 2a as the model substrates. Phenyl-
acetylene undergoes a reaction with trimethylaluminum to
afford alkynyldimethylaluminum reagent 1a, as evidenced
by the evolution of methane gas. Then, reagent 1a coordi-
nates to 2a to activate the carbonyl group and form Lewis
acid-base complex 9. The addition of the acetylide to the
carbonyl group through a four-membered cyclic transition
state affords aluminated N,O-acetal intermediate 10. Then,
1
were recorded with an Agilent V NMR (at 600 MHz for H and at
150 MHz for 13C) or a Varian INOVA-399 (at 400 MHz for 1H and
at 100 MHz for 13C). Chemical shifts (δ) are reported in ppm rela-
tive to tetramethylsilane as an internal reference. High resolution
mass spectrometry data were obtained from Korea Basic Science
Institute (Daegu) with a Jeol JMS 700 high resolution mass spec-
trometer. The mass spectrometer operated in the EI and FAB mode
at 70 eV, and the MS spectra were recorded in the range of mass-
to-charge ratios from 50 to 650.
General Procedure for the Double Addition of Alkynyldimethyl-
aluminum Reagents 1 to N,N-Dialkylformamides 2 [or 1,1-Dimeth-
oxy-N,N-dimethylmethanamine (3)]
Ϫ
N,N-Dimethyl-1,5-di-
phenylpenta-1,4-diyn-3-amine (4a): (see Table 1, Entry 1). A solu-
tion of alkynyldimethylaluminum 1a was prepared according to the
described procedure.[6b] The solution of alkynyldimethylaluminum
the second molecule of 1a coordinates to the oxygen atom 1a (1.4 m in toluene, 1.8 mL, 2.5 mmol) was added dropwise to a
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B. L. Korbad, S.-H. Lee
FULL PAPER
solution of N,N-dimethylformamide 2a (0.073 g, 1.0 mmol) in tolu-
ene (4 mL) under argon. The resulting mixture was stirred at 40 °C,
and the progress of the reaction was monitored by TLC. Upon
completion (3 h), the mixture was diluted with THF (5 mL). The
reaction mixture was then quenched by the dropwise addition of
THF/water (1:1, 2 mL). The resulting mixture was stirred for
20 min and then filtered through Celite®, which was rinsed with
THF (5 mL). The combined filtrates were evaporated to dryness to
provide the crude product, which was purified by chromatography
on a silica gel column (ethyl acetate/hexanes, 2:8) to provide pro-
pargylamine 4a (0.238 g, 0.92 mmol, 92%) as a light yellow oil.
4 H), 2.68 (br. s, 4 H), 4.68 (s, 1 H), 7.16–7.23 (m, 6 H), 7.34–7.43
(m, 4 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 24.1, 25.9, 50.2,
50.4, 83.9, 84.3, 122.6, 128.1, 128.2, 131.8 ppm. HRMS (EI+):
calcd. for C22H21N [M]+ 299.1674; found 299.1672.
N,N-Diethyl-1,5-diphenylpenta-1,4-diyn-3-amine (4i):[17] 1H NMR
(600 MHz, CDCl3): δ = 1.19 (t, J = 6.9 Hz, 6 H), 2.80 (q, J =
7.2 Hz, 4 H), 4.98 (s, 1 H), 7.20–7.35 (m, 6 H), 7.40–7.51 (m, 4
H) ppm. 13C NMR (150 MHz, CDCl3): δ = 13.4, 45.1, 45.8, 83.8,
84.7, 122.8, 128.16, 128.24, 131.8 ppm. HRMS (EI+): calcd. for
C21H21N [M]+ 287.1674; found 287.1671.
1-(1,5-Diphenylpenta-1,4-diyn-3-yl)morpholine (4j):[16d] 1H NMR
(600 MHz, CDCl3): δ = 2.84 (t, J = 4.8 Hz, 4 H), 3.82 (t, J =
4.8 Hz, 4 H), 4.77 (s, 1 H), 7.25–7.35 (m, 6 H), 7.40–7.52 (m, 4
H) ppm. 13C NMR (150 MHz, CDCl3): δ = 49.5, 49.8, 66.8, 83.1,
84.9, 122.3, 128.2, 128.5, 131.8 ppm. HRMS (EI+): calcd. for
C21H19NO [M]+ 301.1467; found 301.1466.
The procedures for those compounds in Table 1, Entries 2–7 were
performed under the same reaction conditions (40 °C for 3 h).
Those for Table 1, Entries 8–21 and 26–28 were carried out at 60 °C
for 3 h. Those for Table 1, Entries 22–25 were performed at room
temperature for 6 h and then purified by column chromatography
(toluene/hexanes, 2:8).
1-(1,5-Di-p-tolylpenta-1,4-diyn-3-yl)piperidine (4k): 1H NMR
(600 MHz, CDCl3): δ = 1.49 (br. s, 2 H), 1.71 (quint, J = 5.7 Hz,
4 H), 2.34 (s, 6 H), 2.78 (br. s, 4 H), 4.77 (s, 1 H), 7.11 (d, J =
8.4 Hz, 4 H), 7.40 (d, J = 7.8 Hz, 4 H) ppm. 13C NMR (150 MHz,
CDCl3): δ = 21.1, 23.9, 25.7, 50.0, 50.2, 83.1, 84.2, 119.4, 128.6,
131.5, 138.0 ppm. HRMS (EI+): calcd. for C24H25N [M]+
327.1987; found 327.1985.
N,N-Dimethyl-1,5-diphenylpenta-1,4-diyn-3-amine
(4a):[17]
1H
NMR (600 MHz, CDCl3): δ = 2.48 (s, 6 H), 4.78 (s, 1 H), 7.27–7.33
(m, 6 H), 7.46–7.53 (m, 4 H) ppm. 13C NMR (150 MHz, CDCl3): δ
= 41.3, 50.0, 83.5, 84.4, 122.5, 128.2, 128.3, 131.8 ppm. HRMS
(EI+): calcd. for C19H17N [M]+ 259.1361; found 259.1359.
N,N-Dimethyl-1,5-di-p-tolylpenta-1,4-diyn-3-amine (4b):[17] 1H
NMR (600 MHz, CDCl3): δ = 2.33 (s, 6 H), 2.47 (s, 6 H), 4.75 (s,
1 H), 7.10 (d, J = 8.4 Hz, 4 H), 7.38 (d, J = 8.4 Hz, 4 H) ppm. 13C
NMR (150 MHz, CDCl3): δ = 21.4, 41.3, 50.1, 82.9, 84.5, 119.5,
128.9, 131.7, 138.4 ppm. HRMS (EI+): calcd. for C21H21N [M]+
287.1674; found 287.1670.
1,5-Bis(4-chlorophenyl)-N,N-dimethylpenta-1,4-diyn-3-amine (4c):[17]
1H NMR (600 MHz, CDCl3): δ = 2.46 (s, 6 H), 4.75 (s, 1 H), 7.25–
7.32 (m, 4 H), 7.38–7.44 (m, 4 H) ppm. 13C NMR (150 MHz,
CDCl3): δ = 41.4, 50.0, 83.5, 84.3, 121.0, 128.6, 133.1, 134.5 ppm.
HRMS (EI+): calcd. for C19H15Cl2N [M]+ 327.0582; found
327.0579.
N,N-Dimethylpentadeca-6,9-diyn-8-amine (4d):[17] 1H NMR
(600 MHz, CDCl3); δ = 0.90 (t, J = 7.2 Hz, 6 H), 1.27–1.43 (m, 8
H), 1.53 (quint, J = 7.4 Hz, 4 H), 2.22 (dt, J = 2.2, 7.4 Hz, 4 H),
2.31 (s, 6 H), 4.28 (t, J = 2.1 Hz, 1 H) ppm. 13C NMR (150 MHz,
CDCl3): δ = 13.8, 18.5, 22.0, 28.3, 30.9, 40.9, 48.9, 74.8, 84.3 ppm.
HRMS (FAB+): calcd. for C17H28N [M – 1] 246.2216; found
246.2225.
N,N-Dimethyl-1,9-diphenylnona-3,6-diyn-5-amine (4e): 1H NMR
(600 MHz, CDCl3): δ = 2.22 (s, 6 H), 2.51 (dt, J = 2.4, 7.5 Hz, 4
H), 2.83 (t, J = 7.5 Hz, 4 H), 4.25 (t, J = 2.1 Hz, 1 H), 7.17–7.22
(m, 6 H), 7.27–7.80 (m, 4 H) ppm. 13C NMR (150 MHz, CDCl3):
δ = 20.8, 35.0, 40.9, 48.9, 75.4, 83.6, 126.1, 128.2, 128.3, 140.5 ppm.
HRMS (FAB+): calcd. for C23H24N [M – 1] 314.1903; found
314.1913.
1,5-Dicyclopropyl-N,N-dimethylpenta-1,4-diyn-3-amine (4f):[17] 1H
NMR (600 MHz, CDCl3): δ = 0.65–0.81 (m, 8 H), 1.20–1.30 (m, 2
H), 2.27 (s, 6 H), 4.21 (t, J = 1.8 Hz, 1 H) ppm. 13C NMR (CDCl3,
150 MHz): δ = 0.0, 8.7, 41.5, 49.6, 70.5, 88.1 ppm. HRMS (EI+):
calcd. for C13H17N [M]+ 187.1361; found 187.1357.
N,N-Dimethyl-1,5-di(thiophen-2-yl)penta-1,4-diyn-3-amine (4g):[17]
1H NMR (600 MHz, CDCl3): δ = 2.45 (s, 6 H), 4.79 (s, 1 H), 6.94–
6.98 (m, 2 H), 7.22–7.26 (m, 4 H) ppm. 13C NMR (150 MHz,
CDCl3): δ = 41.2, 50.2, 77.8, 86.9, 122.1, 126.6, 127.0, 132.2 ppm.
HRMS (EI+): calcd. for C15H13NS2 [M]+ 271.0489; found
271.0486.
1-[1,5-Bis(4-chlorophenyl)penta-1,4-diyn-3-yl]piperidine (4l): 1H
NMR (600 MHz, CDCl3): δ = 1.48 (br. s, 2 H), 1.69 (quint, J =
5.6 Hz, 4 H), 2.74 (br. s, 4 H), 4.75 (s, 1 H), 7.27–7.35 (m, 4 H),
7.35–7.42 (m, 4 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 24.1,
25.9, 50.2, 50.5, 83.4, 84.8, 121.1, 128.5, 133.1, 134.4 ppm. HRMS
(EI+): calcd. for C22H19Cl2N [M]+ 367.0895; found 367.0891.
1-(Pentadeca-6,9-diyn-8-yl)piperidine (4m): 1H NMR (600 MHz,
CDCl3): δ = 0.90 (t, J = 7.2 Hz, 6 H), 1.28–1.48 (m, 10 H), 1.52
(quint, J = 7.3 Hz, 4 H), 1.64 (quint, J = 5.6 Hz, 4 H), 2.21 (dt, J
= 2.2, 7.2 Hz, 4 H), 2.59 (br. s, 4 H), 4.27 (t, J = 2.0 Hz, 1 H) ppm.
13C NMR (150 MHz, CDCl3): δ = 13.8, 18.5, 22.0, 24.2, 25.8, 28.2,
30.9, 49.1, 49.9, 75.1, 84.2 ppm. HRMS (EI+): calcd. for C20H33N
[M]+ 287.2613; found 287.2610.
1
N,N-Diethylpentadeca-6,9-diyn-8-amine (4n): H NMR (600 MHz,
CDCl3): δ = 0.90 (t, J = 7.2 Hz, 6 H), 1.10 (t, J = 6.9 Hz, 6 H),
1.28–1.42 (m, 8 H), 1.52 (quint, J = 7.4 Hz, 4 H), 2.20 (dt, J = 1.8,
6.9 Hz, 4 H), 2.62 (q, J = 7.4 Hz, 4 H), 4.49 (t, J = 2.1 Hz, 1
H) ppm. 13C NMR (150 MHz, CDCl3): δ = 13.3, 13.9, 18.6, 22.1,
28.3, 31.0, 44.60, 44.64, 75.8, 83.7 ppm. HRMS (EI+): calcd. for
C19H33N [M]+ 275.2613; found 275.2610.
4-(Pentadeca-6,9-diyn-8-yl)morpholine (4o): 1H NMR (600 MHz,
CDCl3): δ = 0.90 (t, J = 7.2 Hz, 6 H), 1.27–1.42 (m, 8 H), 1.53
(quint, J = 7.2 Hz, 4 H), 2.2 (dt, J = 2.0, 7.4 Hz, 4 H), 2.67 (t, J =
4.0 Hz, 4 H), 3.77 (t, J = 4.0 Hz, 4 H), 4.28 (t, J = 2.1 Hz, 1
H) ppm. 13C NMR (150 MHz, CDCl3): δ = 13.9, 18.6, 22.1, 28.3,
31.0, 48.9, 49.2, 66.9, 74.4, 85.1 ppm. HRMS (EI+): calcd. for
C19H31NO [M]+ 289.2406; found 289.2404.
1-(1,9-Diphenylnona-3,6-diyn-5-yl)piperidine (4p): 1H NMR
(600 MHz, CDCl3): δ = 1.39 (br. s, 2 H), 1.58 (t, J = 4.5 Hz, 4 H),
2.30–2.60 (m, 8 H), 2.83 (dt, J = 2.4, 7.2 Hz, 4 H), 4.24 (q, J =
2.2 Hz, 1 H), 7.16–7.23 (m, 6 H), 7.25–7.30 (m, 4 H) ppm. 13C
NMR (150 MHz, CDCl3): δ = 20.8, 24.0, 25.8, 34.9, 49.1, 49.9,
75.8, 83.5, 126.1, 128.2, 128.4, 140.5 ppm. HRMS (EI+): calcd. for
C26H29N [M]+ 355.2300; found 355.2296.
1-(1,5-Dicyclopropylpenta-1,4-diyn-3-yl)piperidine (4q): 1H NMR
1-(1,5-Diphenylpenta-1,4-diyn-3-yl)piperidine (4h):[17] 1H NMR (600 MHz, CDCl3): δ = 0.66–0.78 (m, 8 H), 1.20–1.30 (m, 2 H),
(600 MHz, CDCl3): δ = 1.38 (br. s, 2 H), 1.60 (quint, J = 5.7 Hz, 1.43 (br. s, 2 H), 1.62 (quint, J = 5.7 Hz, 4 H), 2.53 (br. s, 4 H),
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Eur. J. Org. Chem. 2014, 5089–5095

Synthesis of Propargylamines
4.21 (t, J = 1.8 Hz, 1 H) ppm. 13C NMR (150 MHz, CDCl3): δ =
0.0, 8.6, 24.7, 26.4, 49.7, 50.5, 70.8, 87.8 ppm. HRMS (EI+): calcd.
for C16H21N [M]+ 227.1674; found 227.1671.
stirred for 20 min and then filtered through Celite®, which was
rinsed with THF (5 mL). The combined filtrates were evaporated
to dryness to provide the crude product, which purified by
chromatography on a silica gel column (ethyl acetate/hexanes, 2:8)
to give 1,4-bis(1,5-diphenylpenta-1,4-diyn-3-yl)piperazine (6a,
0.175 g, 0.34 mmol, 68%) as a white solid.
1,5-Dicyclopropyl-N,N-diethylpenta-1,4-diyn-3-amine
(4r):
1H
NMR (600 MHz, CDCl3): δ = 0.66–0.79 (m, 8 H), 1.07 (t, J =
6.9 Hz, 6 H), 1.20–1.29 (m, 2 H), 2.58 (q, J = 7.2 Hz, 4 H), 4.42
(t, J = 1.8 Hz, 1 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 0.0,
8.6, 13.8, 45.1, 45.2, 71.4, 87.2 ppm. HRMS (EI+): calcd. for
C15H21N [M]+ 215.1674; found 215.1674.
The procedures for those compounds in Table 2, Entries 2 and 3
were performed under the same reaction conditions (60 °C for 5 h).
1,4-Bis(1,5-diphenylpenta-1,4-diyn-3-yl)piperazine (6a): 1H NMR
(600 MHz, CDCl3): δ = 3.01 (br. s, 8 H), 4.85 (s, 2 H), 7.27–7.33
1-(1,5-Dicyclopropylpenta-1,4-diyn-3-yl)pyrrolidine (4s): 1H NMR
(600 MHz, CDCl3): δ = 0.62–0.78 (m, 8 H), 1.18–1.29 (m, 2 H), (m, 12 H), 7.45–7.52 (m, 8 H) ppm. 13C NMR (150 MHz, CDCl3):
1.79 (quint, J = 3.3 Hz, 4 H), 2.61–2.72 (m, 4 H), 4.40 (t, J = δ = 49.2, 49.5, 83.5, 84.9, 122.5, 128.2, 128.4, 131.9 ppm. HRMS
1.8 Hz, 1 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 0.0, 8.7, 24.1,
45.3, 49.8, 71.2, 87.4 ppm. HRMS (EI+): calcd. for C15H19N [M]+
213.1517; found 213.1516.
(EI+): calcd. for C38H30N2 [M]+ 514.2409; found 514.2409.
1,4-Di(pentadeca-6,9-diyn-8-yl)piperazine (6b):
1H
NMR
(600 MHz, CDCl3): δ = 0.89 (t, J = 6.9 Hz, 12 H), 1.26–1.40 (m,
16 H), 1.52 (quint, J = 7.2 Hz, 8 H), 2.16 (dt, J = 1.8, 6.9 Hz, 8
1-(1,5-Dicyclopropylpenta-1,4-diyn-3-yl)morpholine (4t): 1H NMR
(600 MHz, CDCl3): δ = 0.65–0.80 (m, 8 H), 1.15–1.30 (m, 2 H), H), 2.76 (br. s, 8 H), 4.32 (t, J = 1.8 Hz, 2 H) ppm. 13C NMR
2.62 (t, J = 4.8 Hz, 4 H), 3.75 (t, J = 4.8 Hz, 4 H), 4.21 (t, J =
1.8 Hz, 1 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 0.0, 8.8, 49.4,
49.7, 67.4, 70.1, 88.6 ppm. HRMS (EI+): calcd. for C15H19NO
[M]+ 229.1467; found 229.1464.
(150 MHz, CDCl3): δ = 13.9, 18.7, 22.1, 28.3, 31.1, 48.5, 48.7, 74.8,
84.8 ppm. HRMS (EI+): calcd. for C34H54N2 [M]+ 490.4287; found
490.4284.
1,4-Bis(1,5-dicyclopropylpenta-1,4-diyn-3-yl)piperazine (6c): 1H
NMR (600 MHz, CDCl3): δ = 0.65–0.79 (m, 16 H), 1.18–1.30 (m,
4 H), 2.71 (t, J = 1 Hz, 8 H), 4.26 (t, J = 1.7 Hz, 2 H) ppm. 13C
NMR (150 MHz, CDCl3): δ = –0.5, 8.2, 48.5, 48.7, 70.0, 87.8 ppm.
1-[1,5-Di(thiophen-2-yl)penta-1,4-diyn-3-yl]piperidine
(4u):
1H
NMR (600 MHz, CDCl3): δ = 1.47 (br. s, 2 H), 1.68 (quint, J =
5.7 Hz, 4 H), 2.73 (br. s, 4 H), 4.79 (s, 1 H), 6.90–6.97 (m, 2 H),
7.20–7.27 (m, 4 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 24.0, HRMS (FAB+): calcd. for C26H31N2 [M + 1] 371.2487; found
25.9, 50.5, 50.6, 77.9, 87.5, 122.5, 126.8, 127.1, 132.4 ppm. HRMS
371.2488.
(EI+): calcd. for C18H17NS2 [M]+ 311.0802; found 311.0805.
General Procedure for the Monoaddition of Alkynyldimethyl-
aluminumReagentstoN,O-AcetalsϪ1-(1,3-Diphenylprop-2-yn-1-yl)-
piperidine (8a): (see Table 3, Entry 1). A solution of alkynyldimeth-
ylaluminum 1a (1.4 m in toluene, approximately 0.86 mL,
1.2 mmol) was added dropwise to a solution of 1-[tert-butoxy-
(phenyl)methyl]piperidine (7a, 0.247 g, 1.0 mmol) in toluene (2 mL)
N-Methyl-N-(pentadeca-6,9-diyn-8-yl)aniline (4v): 1H NMR
(400 MHz, CDCl3): δ = 0.87 (t, J = 7.2 Hz, 6 H), 1.20–1.38 (m, 8
H), 1.47 (quint, J = 7.1 Hz, 4 H), 2.19 (dt, J = 2.0, 7.2 Hz, 4 H),
2.97 (s, 3 H), 5.28 (t, J = 2.0 Hz, 1 H), 6.84 (t, J = 7.4 Hz, 1 H),
6.92–7.00 (m, 2 H), 7.18–7.30 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 14.2, 18.9, 22.4, 28.5, 31.2, 34.8, 45.5, 75.8, 84.3, 116.7, at 0 °C. The resulting mixture was stirred at room temperature for
119.7, 129.1, 149.4 ppm. HRMS (EI+): calcd. for C22H31N [M]+
309.2457; found 309.2455.
30 min, and the progress of the reaction was monitored by TLC.
Then, the mixture was diluted with THF (5 mL), and the reaction
mixture was quenched by the dropwise addition of THF/water (1:1,
1 mL). The resulting mixture was stirred for 20 min and then fil-
tered through Celite®, which was rinsed with THF. The combined
filtrates were evaporated to dryness to provide the crude product,
which purified by chromatography on a silica gel column (ethyl
acetate/hexanes, 1:10) to give 1-(1,3-diphenylprop-2-yn-1-yl)piper-
idine (8a, 0.269 g, 0.98 mmol, 98%) as a colorless oil.
N-(1,5-Dicyclopropylpenta-1,4-diyn-3-yl)-N-methylaniline (4w): 1H
NMR (400 MHz, CDCl3): δ = 0.56–0.82 (m, 8 H), 1.17–1.28 (m, 2
H), 2.92 (s, 3 H), 5.20 (s, 1 H), 6.83 (t, J = 7.2 Hz, 1 H), 6.90 (d,
J = 8.0 Hz, 2 H), 7.18–7.29 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = –0.3, 8.37, 8.39, 34.7, 45.5, 70.8, 87.2, 116.6, 119.6,
129.0, 149.3 ppm. HRMS (EI+): calcd. for C18H19N [M]+
249.1517; found 249.1514.
The procedures for those compounds in Table 3, Entries 2–11 were
performed under the same reaction conditions (room temperature
for 30 min).
N-(Pentadeca-6,9-diyn-8-yl)-N-phenylaniline (4x): 1H NMR
(600 MHz, CDCl3): δ = 0.89 (t, J = 7.1 Hz, 6 H), 1.27–1.33 (m, 8
H), 1.46 (quint, J = 7.1 Hz, 4 H), 2.18 (dt, J = 2.2, 7.1 Hz, 4 H),
5.56 (t, J = 2.2 Hz, 1 H), 7.03–7.08 (m, 2 H), 7.12–7.18 (m, 4 H),
1-(1,3-Diphenylprop-2-yn-1-yl)piperidine (8a):[18a] 1H NMR
7.26–7.31 (m, 4 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 14.0, (600 MHz, CDCl3): δ = 1.38–1.48 (m, 2 H), 1.54–1.70 (m, 4 H),
18.7, 22.2, 28.1, 30.9, 44.7, 76.1, 85.0, 122.6, 123.3, 128.8,
146.9 ppm. HRMS (EI+): calcd. for C27H33N [M]+ 371.2613;
found 371.2614.
2.60 (t, J = 5.1 Hz, 4 H), 4.86 (s, 1 H), 7.28–7.42 (m, 6 H), 7.49–
7.59 (m, 2 H), 7.67 (d, J = 7.2 Hz, 2 H) ppm. 13C NMR (150 MHz,
CDCl3): δ = 24.2, 25.9, 50.4, 62.1, 85.8, 87.6, 123.1, 127.2, 127.75,
127.77, 128.0, 128.2, 131.5, 138.3 ppm. HRMS (EI+): calcd. for
C20H21N [M]+ 275.1674; found 275.1676.
General Procedure for the Synthesis of Symmetrical Prop-
argylamines 6 Ϫ 1,4-Bis(1,5-diphenylpenta-1,4-diyn-3-yl)piperazine
(6a): (see Table 2, Entry 1). A solution of alkynyldimethylaluminum
1a (1.4 m in toluene, 1.8 mL, 2.5 mmol) was added dropwise to a
solution of piperazine-1,4-dicarbaldehyde (5, 0.071 g, 0.5 mmol) in
toluene/THF (1:1, 4 mL) under argon. The resulting mixture was
stirred at 60 °C, and the progress of the reaction was monitored by
TLC. Upon completion (5 h), the mixture was diluted with THF
(5 mL). Then, the reaction mixture was quenched by the dropwise
addition of THF/water (2 mL, 1:1). The resulting mixture was
1-(1-Phenyloct-2-yn-1-yl)piperidine (8b): 1H NMR (600 MHz,
CDCl3): δ = 0.94 (t, J = 7.5 Hz, 3 H), 1.31–1.49 (m, 6 H), 1.52–
1.66 (m, 6 H), 2.33 (dt, J = 2.0, 7.4 Hz, 2 H), 2.48 (br. s, 4 H), 4.56
(s, 1 H), 7.27 (t, J = 6.6 Hz, 1 H), 7.34 (t, J = 7.5 Hz, 2 H), 7.58
(d, J = 8.4 Hz, 2 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 14.2,
19.0, 22.4, 24.7, 26.4, 28.9, 31.3, 50.7, 62.2, 76.4, 88.1, 127.3, 128.0,
128.7, 139.4 ppm. HRMS (EI+): calcd. for C19H27N [M]+
269.2143; found 269.2145.
Eur. J. Org. Chem. 2014, 5089–5095
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5093

B. L. Korbad, S.-H. Lee
FULL PAPER
1-(1,5-Diphenylpent-2-yn-1-yl)piperidine (8c): H NMR (600 MHz,
1
0.0, 8.6, 24.5, 26.4, 48.6, 53.9, 71.2, 88.6 ppm. HRMS (EI+): calcd.
CDCl3): δ = 1.40–1.49 (m, 2 H), 1.52–1.67 (m, 4 H), 2.46 (br. s, 4 for C11H17N [M]+ 163.1361; found 163.1359.
H), 2.69 (dt, J = 1.1, 7.3 Hz, 2 H), 2.95 (t, J = 7.5 Hz, 2 H), 4.57
Supporting Information (see footnote on the first page of this arti-
(s, 1 H), 7.25–7.38 (m, 8 H), 7.55 (d, J = 7.8 Hz, 2 H) ppm. 13C
NMR (150 MHz, CDCl3): δ = 20.8, 24.3, 26.1, 35.3, 50.4, 61.9,
77.1, 86.9, 126.1, 127.1, 127.8, 128.2, 128.4, 128.5, 138.9,
140.6 ppm. HRMS (EI+): calcd. for C22H25N [M]+ 303.1987;
found 303.1986.
cle): Copies of 1H and 13C NMR spectra for compounds 4a–4x,
6a–6c, and 8a–8k.
Acknowledgments
1-(3-Cyclopropyl-1-phenylprop-2-yn-1-yl)piperidine (8d): 1H NMR
(600 MHz, CDCl3): δ = 0.65–0.82 (m, 4 H), 1.29–1.36 (m, 1 H),
1.37–1.45 (m, 2 H), 1.48–1.62 (m, 4 H), 2.35–2.52 (m, 4 H), 4.48
(s, 1 H), 7.20–7.30 (m, 1 H), 7.30 (t, J = 7.2 Hz, 2 H), 7.52 (d, J =
7.2 Hz, 2 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 0.0, 8.8, 24.8,
26.5, 50.9, 62.3, 71.9, 91.4, 127.5, 128.2, 128.8, 139.5 ppm. HRMS
(EI+): calcd. for C17H21N [M]+ 239.1674; found 239.1671.
This research was supported by the Basic Science Research Pro-
gram through the National Research Foundation of Korea (grant
number 2011-0007322).
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1-[1-(4-Chlorophenyl)-3-phenylprop-2-yn-1-yl]piperidine (8e):[18e] 1H
NMR (600 MHz, CDCl3): δ = 1.38–1.47 (m, 2 H), 1.51–1.68 (m, 4
H), 2.54 (br. s, 4 H), 4.76 (s, 1 H), 7.29–7.36 (m, 5 H), 7.49–7.54
(m, 2 H), 7.58 (d, J = 7.8 Hz, 2 H) ppm. 13C NMR (150 MHz,
CDCl3): δ = 24.3, 26.1, 50.6, 61.7, 85.3, 88.2, 123.1, 128.15, 128.16,
128.3, 129.8, 131.8, 133.2, 137.3 ppm. HRMS (EI+): calcd. for
C20H20ClN [M]+ 309.1284; found 309.1288.
1-[1-(4-Chlorophenyl)-3-cyclopropylprop-2-yn-1-yl]piperidine
(8f):
1H NMR (600 MHz, CDCl3): δ = 0.69–0.75 (m, 2 H), 0.78–0.84
(m, 2 H), 1.30–1.37 (m, 1 H), 1.38–1.47 (m, 2 H), 1.48–1.63 (m, 4
H), 2.40 (br. s, 4 H), 4.46 (s, 1 H), 7.28 (d, J = 8.4 Hz, 2 H), 7.48
(d, J = 8.4 Hz, 2 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 0.0,
8.9, 24.8, 26.5, 50.9, 61.7, 71.3, 92.0, 128.4, 130.2, 133.3,
138.3 ppm. HRMS (EI+): calcd. for C17H20ClN [M]+ 273.1284;
found 273.1286.
1-(3-Phenylprop-2-yn-1-yl)piperidine (8g):[18f] 1H NMR (600 MHz,
CDCl3): δ = 1.44 (br. s, 2 H), 1.64 (quint, J = 5.7 Hz, 4 H), 2.57
(br. s, 4 H), 3.47 (s, 2 H), 7.25–7.32 (m, 3 H), 7.38–7.45 (m, 2
H) ppm. 13C NMR (150 MHz, CDCl3): δ = 23.9, 25.9, 48.4, 53.4,
84.9, 85.0, 123.2, 127.8, 128.1, 131.6 ppm. HRMS (EI+): calcd. for
C14H17N [M]+ 199.1361; found 199.1360.
1-[3-(4-Clorophenylprop-2-yn-1-yl)]piperidine (8h): 1H NMR
(600 MHz, CDCl3): δ = 1.44 (br. s, 2 H), 1.64 (quint, J = 5.6 Hz,
4 H), 2.55 (br. s, 4 H), 3.45 (s, 2 H), 7.25 (d, J = 8.5 Hz, 2 H), 7.35
(d, J = 8.5 Hz, 2 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 23.8,
25.8, 48.3, 53.4, 83.7, 86.1, 121.7, 128.4, 132.8, 133.8 ppm. HRMS
(EI+): calcd. for C14H16ClN [M]+ 233.0971; found 233.0967.
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1
1-(Oct-2-yn-1-yl)piperidine (8i): H NMR (600 MHz, CDCl3): δ =
0.90 (t, J = 7.2 Hz, 3 H), 1.28–1.46 (m, 6 H), 1.51 (quint, J =
7.4 Hz, 2 H), 1.61 (quint, J = 5.7 Hz, 4 H), 2.19 (tt, J = 2.4, 6.6 Hz,
2 H), 2.47 (br. s, 4 H), 3.21 (t, J = 2.4 Hz, 2 H) ppm. 13C NMR
(150 MHz, CDCl3): δ = 13.9, 18.6, 22.1, 24.0, 25.9, 28.5, 31.0, 48.0,
53.3, 75.2, 85.0 ppm. HRMS (EI+): calcd. for C13H23N [M]+
193.1830; found 193.1828.
1-(5-Phenylpent-2-yn-1-yl)piperidine (8j): 1H NMR (600 MHz,
CDCl3): δ = 1.40 (br. s, 2 H), 1.58 (quint, J = 6.0 Hz, 4 H), 2.41
(br. s, 4 H), 2.49 (tt, J = 3.6, 7.8 Hz, 2 H), 2.82 (t, J = 7.5 Hz, 2
H), 3.18 (t, J = 2.1 Hz, 2 H), 7.14–7.22 (m, 3 H), 7.24–7.31 (m, 2
H) ppm. 13C NMR (150 MHz, CDCl3): δ = 20.8, 23.9, 25.8, 35.2,
48.0, 53.2, 76.1, 84.1, 126.1, 128.2, 128.3, 140.7 ppm. HRMS (EI+):
calcd. for C16H21N [M]+ 227.1674; found 227.1671.
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1-(3-Cyclopropylprop-2-yn-1-yl)piperidine
(8k):
1H
NMR
(600 MHz, CDCl3): δ = 0.62–0.75 (m, 4 H), 1.20–1.28 (m, 1 H),
1.34–1.48 (m, 2 H), 1.61 (quint, J = 5.7 Hz, 4 H), 2.45 (br. s, 4 H),
3.17 (d, J = 1.8 Hz, 2 H) ppm. 13C NMR (150 MHz, CDCl3): δ =
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Received: April 22, 2014
Published Online: June 25, 2014
Eur. J. Org. Chem. 2014, 5089–5095
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5095