Catalyst-free activation of methylene chloride and alkynes by amines in a three-component coupling reaction to synthesize propargylamines

Article abstract of DOI:10.1039/c4ob00986j

Propargylamines are synthesized via metal-free activation of the C-halogen bond of dihalomethanes and the C-H bond of terminal alkynes in a three-component coupling without catalyst or additional base and under mild reaction conditions. The dihalomethanes

Full text of DOI:10.1039/c4ob00986j

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
Catalyst-free activation of methylene chloride and
alkynes by amines in a three-component coupling
reaction to synthesize propargylamines†
Cite this: Org. Biomol. Chem., 2014,
12, 6725
Vikas S. Rawat, Thulasiram Bathini, S. Govardan and Bojja Sreedhar*
Propargylamines are synthesized via metal-free activation of the C–halogen bond of dihalomethanes and
the C–H bond of terminal alkynes in a three-component coupling without catalyst or additional base and
under mild reaction conditions. The dihalomethanes are used both as solvents as well as precursors for
the methylene fragment (C1) in the final product. The scope of the reaction and the influence of various
reaction variables has been investigated. A plausible reaction mechanism is proposed and the involvement
of various intermediates that can be generated in situ in the process is discussed. The metal-free con-
ditions also make this protocol environmentally benign and atom economical.
Received 13th May 2014,
Accepted 26th June 2014
DOI: 10.1039/c4ob00986j
www.rsc.org/obc
Although these are effective methods, they require the pres-
ence of a leaving group or the formation of an imine from an
Introduction
Over the decades, propargylamine derivatives have attracted aldehyde and an amine (preformed or in situ), or an aryl/benzyl-
great attention in organic synthesis, which can mainly be substituted tertiary amine having at least one methyl group.
attributed to their wide application in medicinal and synthetic
Direct C–H activation is one of the most atom economical
chemistry.1 The various protocols that have been developed for and green reactions for C–C bond formation in modern syn-
the synthesis of propargylamines (Scheme 1) include the thetic chemistry.5 Recently, an alternative transition metal-
addition of stoichiometric alkynyl nucleophiles to imines catalyzed activation of the C–H bond of alkynes and the C–X
(Path A),2 transition metal-catalyzed addition of alkynes to bond of dihalomethanes for reaction with amines in a three-
imines (Paths B and C),3 and transition metal-catalyzed oxi- component coupling to synthesize propargylamines has also
dative functionalization of tertiary amines (Path D).4
been reported (Path E).6 The following catalytic systems have
been used for this purpose: CuCl/DBU,6a CoBr2/DBU,6b nano
In2O3/DABCO,6c FeCl3/TMG6d and K[AuCl4]6e (Scheme 2). The
advantages of these methods over others are simple operation,
mild conditions, and good to excellent yields.
The proposed mechanism for this protocol is depicted in
Scheme 3.6a There are two plausible pathways for this three-
component coupling: one proceeds via the intermediacy of a
propargylhalide that forms due to the interaction of the dihalo-
methane with the metal-alkynyl complex; this propargylhalide
further reacts with amines to give propargylamines (Path F).
The other pathway involves the formation of an iminium ion
Scheme 1 Various procedures for the synthesis of propargylamines.
Inorganic & Physical Chemistry Division, Indian Institute of Chemical Technology
(Council of Scientific & Industrial Research), Hyderabad-500607, India.
E-mail: sreedharb@iict.res.in; Fax: (+)91-40-27160921
†Electronic supplementary information (ESI) available: FTIR, 1H NMR,
13C NMR, LRMS and HRMS data, and 1H and 13C NMR spectra. See DOI:
10.1039/c4ob00986j
Scheme 2 Transition metal-catalyzed synthesis of propargylamines via
activation of the C–H bond of alkynes and the C–X bond of
dihalomethanes.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 6725–6729 | 6725

View Article Online
Paper
Organic & Biomolecular Chemistry
also isolated chloromethyl-triethylammonium chloride from
the reaction of triethylamine with dichloromethane
(Menschutkin reaction) and confirmed its identity by proton
NMR.8c Further, it was established that the reaction of methylene
chloride with a secondary amine results in the corresponding
chloromethylamine, iminium ion and methylene-bisamine
(aminal) in an equilibrium (Scheme 4).10
Aminals react as electrophiles with a variety of nucleo-
philes, such as ketones (Mannich addition),11a aldehydes,11b
phenols,11c esters,9b indoles12a and 2,6-diethyl-4,4-difluoro-
1,3,5,7,8-pentamethyl-4-bora-3a,4a-diaza-s-indacene (BODIPY),12b
and are also used in the synthesis of natural products.12c,d
A similar reaction with copper acetylide resulted in the
formation of propargylamines (Scheme 4).13
Initially, to optimize the reaction conditions, phenyl-
acetylene, dichloromethane and piperidine were used as
model substrates, and the influence of various reaction vari-
ables such as the base, solvent and temperature on the reac-
tion was investigated (Table 1). It was observed that the best
results were obtained by using dichloromethane as solvent at
70 °C, with an isolated yield of 72% of 4a (Table 1, entry 28).
Both the addition of bases and the use of other solvents
were completely ineffective for this transformation, so either
no 4a or a very low yield (Table 1, entries 1–24) was obtained.
The inhibitory effect of various solvents on this reaction can
be explained on the basis of solvation of the amine, which is
quite facile especially in the case of protic solvents, and results
in the formation of hydrogen bonds between the amine and
the solvent,14 consequently weakening the nucleophilic charac-
ter of the amine and leading to a slower reaction rate.8a,14
Moreover, it was observed that this reaction was susceptible
to temperature changes. At room temperature the yield of 4a
was 15% (Table 1, entry 25), which increased to 72% at 70 °C
(Table 1, entry 28). This may be attributed to the fact that the
reaction between amines and dichloromethane is slower at low
temperature, however an increase in temperature generates a
high pressure inside the pressure vial (as reported by Songstad
et al.), resulting in a higher reaction rate under high pres-
sure.8a However, any further increase in temperature above
70 °C does not affect the reaction outcome.
Scheme 3 The proposed mechanism for the three-component coup-
ling to give propargylamines.
intermediate via interaction of the dihalomethane with the
amine; the reaction of this iminium ion with the metal-alkynyl
complex results in propargylamines (Path G).
By using various experimental and spectroscopic methods,
it has been proved that Path G is operative in the copper-cata-
lyzed reaction,6a and Path F is operative in the iron-6d and
gold6e-catalyzed reactions. From these studies, it is evident
that the presence of a catalyst is essential for initial C–H acti-
vation of alkynes and for the reaction to proceed further.
However, during our studies on the application of magnetic
nanoparticles to similar processes, we surprisingly found that
a catalyst is not needed for this transformation and thus,
herein we would like to report a novel metal-free synthesis of
propargylamines via a three-component coupling (AHA).
Notably, there was no appreciable difference in the yield
with any of the three commercially available dihalomethanes
Results and discussion
Among commercially available dihalomethanes, methylene used (Table 1, entries 28, 30, 31). Finally, the reaction mixture
chloride has been chosen as a model substrate for these was analyzed via inductively coupled plasma atomic emission
studies. Methylene chloride is a relatively inert volatile organic
liquid that has been used extensively as a solvent in synthesis
and extraction processes.7 Despite its vast utilization as a
solvent, there are few published reports on its role as a reac-
tant.8 In particular, the reaction of methylene chloride with
amines has been studied from a kinetic and mechanistic point
of view,8 and it has been established that certain secondary
and tertiary amines react with dichloromethane resulting in
hydrochloride salts, aminals and/or quaternary salts. However,
the reaction rates are very sluggish with half-lives of many
weeks to several months.8 Later, the reaction rate was acceler-
Scheme 4 The proposed mechanism for copper-catalyzed three-
ated by using high temperature or pressure,9 and Wulff et al. component coupling to propargylamines.
6726 | Org. Biomol. Chem., 2014, 12, 6725–6729
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
Table 1 Optimization of reaction conditions for the three-component
coupling to give propargylaminesa
Table 2 Scope of the synthesis of propargylaminesa
Entry
R1
Amine
Yieldb (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Piperidine
Pyrrolidine
72
68
70
65
62
0
Entry
Solvent
Base
Temp. (°C)
Yieldb (%)
Dimethylamine
Diethylamine
Dibutylamine
Diisopropylamine
Aniline
Butan-1-amine
Piperidine
1
2
3
4
5
6
7
8
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DMF
Et3N
DBU
DABCO
K2CO3
Na2CO3
NaHCO3
NaOMe
t-BuOK
K3PO4
NaOH
KOH
—
—
—
—
—
—
—
—
—
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
25
50
60
70
80
70
70
15
20
27
30
15
0
0
0
0
0
0
35
0
0
0
0
0
0
0
0
0
0
0
10
15
42
55
72
72
75c
78d
0
0
9
4-Methylphenyl
4-Methylphenyl
4-Methylphenyl
4-Methylphenyl
4-Methylphenyl
4-(tert-Butyl)phenyl
4-(tert-Butyl)phenyl
2-(6-Methoxynaphthyl)
4-Bromophenyl
3-Fluorophenyl
3-Fluorophenyl
3-Fluorophenyl
3-Ethynylphenyl
Hexyl
78
72
68
66
62
83
70
72
65
57
54
50
50
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Pyrrolidine
Dimethylamine
Diethylamine
Dibutylamine
Piperidine
Dibutylamine
Diethylamine
Piperidine
Dimethylamine
Diethylamine
Dibutylamine
Dibutylamine
Piperidine
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
DMSO
CH3CN
MeOH
THF
H2O
Dioxane
Toluene
EtNO2
Hexane
EtOAc
DCE
DCM
DCM
DCM
DCM
DCM
DBM
DIM
Pentyl
Piperidine
0
—
—
—
—
—
—
—
—
a Reaction conditions: alkyne (1 mmol) and amine (3.2 mmol) in 5 mL
dichloromethane at 70 °C for 12 h. b Isolated yield.
easy accessibility of the lone pair of electrons on the nitrogen
of such amines. Hence, these amines showed an excellent con-
version rate to the corresponding propargylamines.
Among the acyclic amines, the reaction rate is found to
depend on the steric influence of the attached alkyl groups in
the order dimethylamine > diethylamine > dibutylamine. Con-
sequently, diisopropylamine reacts very slowly under the opti-
mized reaction conditions, and no product was obtained
(Table 2, entry 6).6d,8a,d,e
—
—
—
a Reaction conditions: phenyl acetylene (1.0 mmol), piperidine
(3.2 mmol), base (2.2 mmol) and dichloromethane (2.0 mmol) in 2 mL
solvent for 12 h. b Isolated yield. c Reaction with dibromomethane.
d Reaction with diiodomethane.
Due to the low basicity of primary (aromatic and aliphatic)
amines, the reaction rate with dichloromethane was much
slower when compared to secondary amines, and no product
was formed in these cases (Table 2, entries 7–8).6d,8a,d,e Unfor-
tunately, the reaction with aliphatic terminal alkynes did not
yield any product (Table 2, entries 22–23).6d
spectroscopy (ICP-AES) for a broad range of transition metals
including cobalt, copper, platinum, etc. However, none of
these metals were present in concentrations above a level of
0.1 ppm, which confirms that this reaction is not metal-
catalyzed.
After establishing the optimized reaction conditions
(Table 1, entry 28), we further explored the generality and func-
tional group compatibility of this protocol using various struc-
turally diverse alkynes and amines, and the results are shown
in Table 2.
The reaction proceeds smoothly with various aryl acetylenes
and amines to afford the corresponding propargylamines in
good to excellent yields. However, the output of the reaction
favors alkynes with electron-donating substituents. Generally,
amines with alkyl substituents that are conformationally
restricted such as dimethylamine, piperidine and pyrroli-
dine8d,e,15 are more reactive, which can be attributed to the
Based on the following observations and control
experiments,
a
plausible mechanism is shown in
Scheme 5.8a,d,13,9b,10a,b,16 In one of our first observations
during optimization of the reaction conditions, we noticed
the formation of a white solid in the reaction, which was iso-
lated from the reaction mixture via filtration, and on spectro-
scopic analysis it was found to be piperidinium chloride.
Hence, we can conclude that the formation of intermediate
I is the initial step of the reaction. Thus, there are three plausi-
ble pathways for the metal-free three-component coupling to
occur. The first proceeds via nucleophilic substitution of the
halide by an alkyne (Path H); the second via nucleophilic
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 6725–6729 | 6727

View Article Online
Paper
Organic & Biomolecular Chemistry
ling of various dihalomethanes, alkynes, and secondary
amines, affording moderate to good yields of the desired pro-
ducts. Metal-free conditions make the process highly economi-
cal and hence suitable for large-scale synthesis. The notable
advantages of this methodology over the existing procedures
are simplicity of operation, mild conditions, and high func-
tional group tolerance.
Acknowledgements
VSR and TB thank the University Grant Commission (UGC),
New Delhi for the award of a Research Fellowship.
Notes and references
1 (a) P. Sienkiewicz, K. Bielawski, A. Bielawska and J. Pałka,
Environ.
Toxicol.
Pharmacol.,
2005,
20,
118;
Scheme 5 The plausible mechanism for the three-component coup-
(b) J. V. Greenhill and P. Lue, Prog. Med. Chem., 1993, 30,
203; (c) H. Nakamura, T. Kamakura, M. Ishikura and
J.-F. Biellmann, J. Am. Chem. Soc., 2004, 126, 5958;
(d) A. Farwick and G. Helmchen, Org. Lett., 2010, 12, 1108;
(e) B. Jiang and M. Xu, Angew. Chem., Int. Ed., 2004, 43,
2543; (f) T. Yoon, M. D. Shair, S. J. Danishefsky and
G. K. Shulte, J. Org. Chem., 1994, 59, 3752; (g) R. L. Giles,
R. A. Nkansah and R. E. Looper, J. Org. Chem., 2010, 75,
261; (h) S. Samai, G. C. Nandi and M. S. Singh, Tetrahedron
Lett., 2010, 51, 5555; (i) E. J. Trybulski, J. Zhang,
R. H. Kramss and R. M. Mangano, J. Med. Chem., 1993, 36,
3533; ( j) M. A. Huffman, N. Yasuda, A. E. DeCamp and
E. J. J. Grabowski, J. Org. Chem., 1995, 60, 1590;
(k) M. Konishi, H. Ohkuma, T. Tsuno, T. Oki,
G. D. VanDuyne and J. Clardy, J. Am. Chem. Soc., 1990, 112,
3715; (l) M. Miura, M. Enna, K. Okuro and M. Nomura,
J. Org. Chem., 1995, 60, 4999; (m) A. Jenmalm, W. Berts,
Y.-L. Li, K. Luthman, I. Csoeregh and U. Hacksell, J. Org.
Chem., 1994, 59, 1139; (n) G. Dyker, Angew. Chem., Int. Ed.,
1999, 38, 1698; (o) T. Naota, H. Takaya and S.-I. Murahashi,
Chem. Rev., 1998, 98, 2599.
2 (a) T. Murai, Y. Mutoh, Y. Ohta and M. Murakami, J. Am.
Chem. Soc., 2004, 126, 5968; (b) J. H. Ahn, M. J. Joung,
N. M. Yoon, D. C. Oniciu and A. R. Katritzky, J. Org. Chem.,
1999, 64, 488 and references cited therein.
3 (a) L. Zani and C. Bolm, Chem. Commun., 2006, 4263;
(b) R. Fässler, D. E. Frantz, J. Oetiker and E. M. Carreira,
Angew. Chem., Int. Ed., 2002, 41, 3054; (c) C. Koradin,
K. Polborn and P. Knochel, Angew. Chem., Int. Ed., 2002, 41,
2535; (d) V. A. Peshkov, O. P. Pereshivko and E. V. Van der
Eycken, Chem. Soc. Rev., 2012, 41, 3790 and references
cited therein.
ling to give propargylamines.
addition of an alkyne to an iminium ion (Path I); and the third
via nucleophilic substitution of a methylene-bisamine by an
alkyne (Path J). As it is well known that the reaction of a second-
ary amine with a dihalomethane affords either an electrophilic
iminium ion II under acidic conditions or a bis-aminomethane
intermediate III under basic conditions,15 under the present
acidic conditions the reactive species formed is probably either
the iminium ion II or the halo-methyleneamine I, and not the
bis-aminomethane III; therefore, the possibility of Path J is
ruled out. Further, to confirm this we carried out a separate
reaction with bis(dimethylamino)methane17 and piperidine,
and found that the dimethylamine-derived propargylamine was
not formed in the reaction at all.
On the other hand, the possibility of Path I is also ruled out
based on the observations of Vogel et al. that only a trace
amount of propargylamine is formed via the reaction of an
iminium ion II with alkynes under catalyst-free conditions.4e
We confirmed this by the fact that no imine-derived propargyl-
amine was formed in the presence of benzaldehyde under the
optimized reaction conditions. As a result, the only plausible
mechanism that could occur in the present protocol is Path H,
i.e. the nucleophilic substitution of the halide by an alkyne; an
example of such a nucleophilic substitution of a halogen atom
with an adjacent substituent by PMe3 was recently reported by
Macgregor et al.18 The formed carbocation IV on deprotonation
affords the desired propargylamines. However, the mechanism
presented here is preliminary and needs further investigation,
which will be part of our research in the future.
4 (a) M. Niu, Z. Yin, H. Fu, Y. Jiang and Y. Zhao, J. Org.
Chem., 2008, 73, 3961; (b) Z. Li and C.-J. Li, J. Am. Chem.
Soc., 2004, 126, 11810; (c) S. Murata, K. Teramoto, M. Miura
and M. Nomura, J. Chem. Res., Miniprint, 1993, 2827;
(d) X. Xu and X. Li, Org. Lett., 2009, 11, 1027;
Conclusions
In conclusion, we have developed a metal-free protocol for the
synthesis of propargylamines via the three-component coup-
6728 | Org. Biomol. Chem., 2014, 12, 6725–6729
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
(e) C. M. R. Volla and P. Vogel, Org. Lett., 2009, 11, 1701; 10 (a) J. E. Mills, C. A. Maryanoff, D. F. McComsey,
(f) Z. Xu, X. Yu, X. Feng and M. Bao, J. Org. Chem., 2011,
76, 6901.
5 (a) G. Dyker, in Handbook of C-H Transformations, Wiley-
R. C. Stanzione and L. Scott, J. Org. Chem., 1987, 52, 1857;
(b) H. J. Federsel, E. Koenberg, L. Lilljequist and
B. M. Swahn, J. Org. Chem., 1990, 55, 2254.
VCH, Weinheim, 2005; (b) L. Ackermann, A. Althammer 11 (a) K. Matsumoto, Angew. Chem., Int. Ed. Engl., 1982, 21,
and R. Born, Angew. Chem., Int. Ed., 2006, 45, 2619;
(c) A. Company, L. Gómez, M. Güell, X. Ribas, J. M. Luis,
L. Que Jr. and M. Costas, J. Am. Chem. Soc., 2007, 129,
922; (b) Y.-S. Hon, Y.-W. Liu and C.-H. Hsieh, Tetrahedron,
2004, 60, 4837; (c) Y.-S. Hon, Y.-Y. Chou and I.-C. Wu,
Synth. Commun., 2004, 34, 2253.
15766; (d) K. R. Campos, Chem. Soc. Rev., 2007, 36, 1069; 12 (a) K. Matsumoto, T. Uchida, S. Hashimoto, Y. Yonezawa,
(e) J. C. Lewis, R. G. Bergman and J. A. Ellman, Acc. Chem.
Res., 2008, 41, 1013; (f) B.-J. Li, S.-D. Yang and Z.-J. Shi,
Synlett, 2008, 949; (g) Y. J. Park, J.-W. Park and C.-H. Jun,
Acc. Chem. Res., 2008, 41, 222.
H. Iida, A. Kakehi and S. Otani, Heterocycles, 1993, 36,
2215; (b) L. Yang and H. Yan, Synlett, 2012, 1526;
(c) Y.-S. Hon, C.-H. Hsieh and Y.-W. Liu, Tetrahedron, 2005,
61, 2713; (d) Y.-S. Hon, C.-H. Hsieh and H.-F. Chen, Synth.
Commun., 2007, 37, 1635.
6 (a) D. Yu and Y. Zhang, Adv. Synth. Catal., 2011, 353, 163;
(b) Y. Tang, T. Xiao and L. Zhou, Tetrahedron Lett., 2012, 53, 13 B. R. Buckley, A. N. Khan and H. Heaney, Chem. – Eur. J.,
6199; (c) M. Rahman, A. Kr. Bagdi, A. Majee and A. Hajra, 2012, 18, 3855.
Tetrahedron Lett., 2011, 52, 4437; (d) J. Gao, Q.-W. Song, 14 M. Auriel and E. de Hoffmann, J. Am. Chem. Soc., 1975, 97,
L.-N. He, Z.-Z. Yang and X.-Y. Dou, Chem. Commun., 2012, 7433.
48, 2024; (e) D. Aguilar, M. Contel and E. P. Urriolabeitia, 15 (a) W. C. Hunt and E. C. Wagner, J. Org. Chem., 1951, 16,
Chem. – Eur. J., 2010, 16, 9287.
1792; (b) E. C. Wagner, J. Org. Chem., 1954, 19, 1862;
(c) M. Tramontini and L. Angiolini, Tetrahedron, 1990, 46,
1791; (d) M. Tramontini, L. Angiolini and N. Ghedini,
Polymer, 1988, 29, 771; (e) M. Tramontini, Synthesis, 1973,
703; (f) B. B. Thompson, J. Pharm. Sci., 1968, 57, 715;
(g) F. F. Blicke, Org. React., 1942, 1, 303.
7 (a) S. Bekkevoll, I. Svorstøl, H. Høiland and J. Songstad,
Acta Chem. Scand. Ser. B, 1983, 37, 935; (b) D. Kost and
K. Aviram, J. Am. Chem. Soc., 1986, 108, 2006.
8 (a) G. O. Nevstad and J. Songstad, Acta Chem. Scand. Ser. B,
1984, 38, 469; (b) B. Almarzoqi, A. V. George and
N. S. Isaacs, Tetrahedron, 1986, 42, 601; (c) D. A. Wright and 16 (a) A. Mohammadi, M. Amini, M. P. Hamedani,
C. A. Wulff, J. Org. Chem., 1970, 35, 4252; (d) J. E. Mills,
C. A. Maryanoff, R. M. Cosgrove, L. Scott and
D. F. McComsey, Org. Prep. Proced. Int., 1984, 16, 97;
(e) H. K. Hall Jr., J. Org. Chem., 1964, 29, 3539.
H. H. Torkabadi and R. B. Walker, Asian J. Chem., 2008, 20,
5573; (b) J.-J. Lee, K. J. Stanger, B. C. Noll, C. Gonzalez,
M. Marquez and B. D. Smith, J. Am. Chem. Soc., 2005, 127,
4184.
9 (a) K. Matsumoto, Angew. Chem., Int. Ed. Engl., 1982, 94, 17 M. Gaudry, Y. Jasor and T. B. Khac, Org. Synth., 1979, 59, 153.
937; (b) K. Matsumoto, S. Hashimoto, Y. Ikemi and 18 A. G. Algarra, P. Braunstein and S. A. Macgregor, Dalton
S. Otani, Heterocycles, 1984, 22, 1417.
Trans., 2013, 42, 4208.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 6725–6729 | 6729