Zn(OTf)2-Mediated Expeditious and Solvent-Free Synthesis of Propargylamines via C-H Activation of Phenylacetylene

Article abstract of DOI:10.1055/s-0035-1562114

Zn(OTf)₂-mediated expeditious and solvent-free synthesis of propargylamines via A³ coupling of aldehydes, amines, and phenylacetylene has been described. The described protocol proceeds effectively with variety of substituted benzaldehydes, enolizable aldehyde, and formaldehyde. Recyclability of the catalyst, low catalyst loading, and use of inexpensive catalyst are the key features of the present protocol.

Full text of DOI:10.1055/s-0035-1562114

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
©
Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
A
letter
Synlett
P. B. Sarode et al.
Letter
Zn(OTf) -Mediated Expeditious and Solvent-Free Synthesis of
2
Propargylamines via C–H Activation of Phenylacetylene
Prashant B Sarode
Sandeep P Bahekar
Hemant S Chandak*
X
X
N
N
H
R1
Department of Chemistry, G. S. Science, Arts and
Commerce College, Khamgaon 444303, India
chemants@gmail.com
solvent-free
100 °C
R2
Zn(OTf)2
20 examples
75–96% yield
CHO
R1
R2
X = CH , O, -
2
1
R
R
= aryl, alkyl, H
= Ph, SiMe3
2
Received: 23.02.2016
Accepted after revision: 10.04.2016
Published online: 10.05.2016
and graphene oxide as supports have also been exemplified
recently. Zinc-catalyzed reactions have emerged as a sus-
12
DOI: 10.1055/s-0035-1562114; Art ID: st-2016-d0127-l
tainable alternative to use of more expensive or toxic tran-
sition metals.13
Abstract Zn(OTf) -mediated expeditious and solvent-free synthesis of
2
Propargylamines are the useful building blocks for the
construction of fused N- and O-heterocycles and β-lac-
3
propargylamines via A coupling of aldehydes, amines, and phenylacet-
ylene has been described. The described protocol proceeds effectively
with variety of substituted benzaldehydes, enolizable aldehyde, and
formaldehyde. Recyclability of the catalyst, low catalyst loading, and
use of inexpensive catalyst are the key features of the present protocol.
tams.14 In addition, they are important skeletal motifs of bi-
ologically active compounds and natural products.1
4b,15
Zinc
catalyst mediated synthesis of propargylamines via three-
3
component coupling of aldehydes, alkynes, and amines (A
Key words Zn(OTf) , solvent-free synthesis, C–H activation, A3 cou-
2
16
coupling) is documented in the literature. Zn(OTf) finds a
2
pling, propargylamine
myriad catalytic applications due to high thermal stability,
low toxicity, ease of availability, and low cost. Zn(OTf) has
2
Increasing environmental concerns demand the devel-
opment of environmentally benign, efficient, economical,
and green synthesis. Multicomponent reactions (MCR)
been used for in situ generation of reactive acetylides and
17
18
their subsequent addition to carbonyl groups, nitrones,
1
19
and enones to construct propargyl derivatives. Herein, we
report a simple and efficient protocol for the addition of re-
active acetylides to iminium ions to afford propargyl-
have emerged as a powerful tool to construct complex mo-
lecular architecture in a single reaction step with high atom
2
3
efficiency, and MCR under solvent-free conditions offers
amines. Thus, we have achieved A coupling using inexpen-
eco-friendly alternatives and unfolds possibilities for con-
ducting rapid organic synthesis in an efficient manner. De-
sive and reusable Zn(OTf)2 under solvent-free conditions
(Scheme 1).
3
velopments of reactions that afford C–C or C–heteroatom
bonds via C–H activation of alkynes using transition-metal
catalyst continue to be a key area of research in organic syn-
thesis. Various catalytic systems using late-transition-metal
X
Zn(OTf)2
X
N
R1 CHO
R2
+
+
solvent-free
R1
4
5
catalysts such as silver(I) salts, gold(I)/(III) salts, gold(III)–
N
H
R2
salen complexes, indium(III), iron(III), copper(II),9 and
6
7
8
10
copper(I) have been used to increase structural as well as
skeletal diversity from simple and readily available alkynes,
aldehydes, and amines. However, the loss of an expensive
metal catalyst (silver, gold, etc.) at the end of a reaction is a
serious concern of such processes. A few processes involv-
ing the recycling of these expensive catalysts have also been
1
2
3
4
3
Scheme 1 Zn(OTf) -catalyzed A coupling
2
In our initial attempts, several zinc salts were screened
for effective A coupling of benzaldehyde, piperidine, and
phenylacetylene (Table 1). To our satisfaction, three-com-
ponent coupling proceeded smoothly in the presence of 10
mol% of Zn(OTf)2 in toluene to afford propargylamine in
3
11
developed. Striving for recyclability, heterogeneous cata-
lysts employing inexpensive metals like copper and iron us-
ing metal-organic frameworks, resins, oyster-shell waste,
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
Synlett
P. B. Sarode et al.
Letter
Table 1 Screening of Zinc Catalysts for the Synthesis of 4aa
ployed acetonitrile, ethanol, or THF as the solvents, product
4
a was generated in slightly lower yields (Table 1, entries
Entry Catalyst (mol%)
Solvent
Temp
Time (h) Yield (%)b
8–10). Interestingly, the solvent-free reaction at 100 °C pro-
ceeded rapidly in excellent yields (Table 1, entries 11–12).
Lowering the catalyst loading to 5 mol% did not affect the
outcome. However, yields were decreased when the reac-
tion temperature and catalyst loading were further lowered
(Table 1, entries 13–15).
1
2
3
4
5
6
7
8
9
ZnCl
ZnBr
ZnSO
2
(10)
(10)
toluene
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
100 °C
100 °C
90 °C
80 °C
100 °C
6
20
17
trace
69
38
40
80
55
45
50
96
96
84
78
48
2
toluene
6
4
(10)
toluene
6
ZnO (10)
toluene
6
We speculate that Zn(OTf) facilitates the generation of
Zn dust (10)
triflic acid (10)
toluene
6
2
a reactive acetylide from alkynes and its subsequent nucleo-
philic addition to the in situ generated iminium ion to af-
ford the A -coupled product. The complexation of alkynes
with zinc(II) yields a π-complex that further activates the
terminal C–H. With this expeditious and efficient protocol
in hand, its scope and generality were examined (Scheme
toluene
6
Zn(OTf)
Zn(OTf)
Zn(OTf)
Zn(OTf)
Zn(OTf)
Zn(OTf)
Zn(OTf)
Zn(OTf)
Zn(OTf)
2
2
2
2
2
2
2
2
2
(10)
(10)
(10)
(10)
(10)
(5)
toluene
8
3
MeCN
6
EtOH
8
1
0
1
2
3
4
5
THF
8
20
2). A variety of substituted aldehydes was investigated,
1
1
1
1
solvent-free
solvent-free
solvent-free
solvent-free
Solvent-free
0.5
0.5
1
and we found this protocol to be very general for substitut-
ed benzaldehydes. Benzaldehydes with electron-rich or
electron-poor groups reacted smoothly and furnished the
desired propargylamines in excellent yields. Enolizable al-
dehydes and formaldehyde also reacted smoothly giving
propargylamines in excellent yields (Scheme 2, 4p, 4q, and
(5)
(5)
1.5
3
1
(3)
a
Reaction conditions: 1.0 mmol benzaldehyde, 1.2 mmol piperidine and
1
.5 mmol phenylacetylene.
Isolated yields.
4s). We also observed that aldehydes with electron-with-
b
drawing groups reacted rapidly, while those with electron-
rich groups required longer reaction times. However, het-
eroaromatic aldehydes such as furfuraldehyde and pyri-
dine-2-carbaldehyde did not furnish the desired product.
good yield (Table 1, entry 7). We next studied the effect of
solvents on the outcome of the reaction. When we em-
X
X
Zn(OTf)2 (5 mol%)
solvent-free, 100 °C
N
R1 CHO
R2
+
+
N
H
R1
R2
1a–k
2a–c
3a,b
4a–t
N
Cl
N
N
Br
N
N
N
N
Br
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Cl
Br
4a, 30 min, 96%
4b, 30 min, 95%
4c, 30 min, 89%
4e, 35 min, 85%
4f, 30 min, 82%
4g, 50 min, 75%
4d, 30 min, 92%
O
O
O
O
O
O
O
N
N
N
Br
N
N
N
N
Cl
Br
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Cl
Br
4h, 30 min, 88%
4i, 30 min, 84%
4j, 30 min, 85%
4k, 30 min, 85%
4l, 30 min, 90%
4m, 30 min, 85%
4n, 50 min, 85%
O
O
N
N
N
N
OEt
N
N
H
H
nBu
SiMe3
Ph
Ph
Ph
Ph
Ph
MeO
4
o, 50 min, 82%
4p, 30 min, 92%
4q, 30 min, 91%
4r, 30 min, 85%
4s, 50 min, 81%
4t, 30 min, 92%
Scheme 2 Zn(OTf) -catalyzed synthesis of propargylamines; a isolated yields
2
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

C
Synlett
P. B. Sarode et al.
Letter
Five- and six-membered cyclic secondary amines reacted
smoothly, affording the desired products. Trimethylsilyl-
acetylene also underwent the reaction smoothly.
The ease of product isolation prompted us to consider
the recyclability of the catalyst (see Supporting Information
for details of recyclability). The catalytic efficacy of
(4) (a) Li, Z.; Wei, C.; Chen, L.; Varma, R. S.; Li, C.-J. Tetrahedron Lett.
2004, 45, 2443. (b) Wei, C.; Li, Z.; Li, C.-J. Org. Lett. 2003, 5, 4473.
(c) Yan, W.; Wang, R.; Xu, Z.; Xu, J.; Lin, L.; Shen, Z.; Zhou, Y.
J. Mol. Catal. A: Chem. 2006, 255, 81. (d) Zhang, Y.; Santos, A.
M.; Herdtweck, E.; Mink, J.; Kühn, F. E. New J. Chem. 2005, 29,
366.
(5) (a) Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2003, 125, 9584. (b) Wei, C.;
Zn(OTf) was tested in up to five runs for the synthesis of 4a
Li, Z.; Li, C.-J. Synlett 2004, 1472.
2
(
Figure 1), and it was found that there was no appreciable
(6) Lo, V. K.-Y.; Liu, Y.; Wong, M.-K.; Che, C.-M. Org. Lett. 2006, 8,
529.
1
loss of catalytic activity of the catalyst.
(7) Zhang, Y.; Li, P.; Wang, M.; Wang, L. J. Org. Chem. 2009, 74, 4364.
8) (a) Li, P.; Zhang, Y.; Wang, L. Chem. Eur. J. 2009, 15, 2045.
(
(b) Chen, W.-W.; Nguyen, R. V.; Li, C.-J. Tetrahedron Lett. 2009,
50, 2895.
(
9) (a) Choudary, B. M.; Sridhar, C.; Kantam, M. L.; Sreedhar, B. Tet-
rahedron Lett. 2004, 45, 7319. (b) Fodor, A.; Kiss, Á.; Debreczeni,
N.; Hell, Z.; Gresits, I. Org. Biomol. Chem. 2010, 8, 4575.
(
c) Aliaga, M. J.; Ramón, D. J.; Yus, M. Org. Biomol. Chem. 2010, 8,
3.
10) (a) Wang, M.; Li, P.; Wang, L. Eur. J. Org. Chem. 2008, 2255.
b) Patil, M. K.; Keller, M.; Reddy, B. M.; Pale, P.; Sommer, J. Eur.
J. Org. Chem. 2008, 4440. (c) Li, P.; Wang, L. Tetrahedron 2007,
3, 5455.
11) (a) Jeganathan, M.; Dhakshinamoorthy, A.; Pitchumani, K. ACS
Sustainable Chem. Eng. 2014, 2, 781. (b) Mallampati, R.;
Valiyaveettil, S. ACS Sustainable Chem. Eng. 2014, 2, 855.
4
(
(
6
Figure 1 Reuse of Zn(OTf) in the synthesis of 4a
2
(
In conclusion, we have developed a Zn(OTf) -catalyzed
three-component coupling of aldehydes, terminal alkynes,
and amines via C–H activation. Use of economical and read-
2
(
2
c) Karimi, B.; Gholinejad, M.; Khorasani, M. Chem. Commun.
012, 48, 8961. (d) Salam, N.; Sinha, A.; Roy, A. S.; Mondal, P.;
Jana, N. R.; Islam, S. M. RSC Adv. 2014, 4, 10001.
ily available Zn(OTf) offers a sustainable alternative to oth-
2
(12) (a) Yang, J.; Li, P.; Wang, L. Catal. Commun. 2012, 27, 58. (b) Li,
P.; Regati, S.; Huang, H.-C.; Arman, H. D.; Chen, B.-L.; Zhao, J. C.
G. Chin. Chem. Lett. 2015, 26, 6. (c) Borah, B. J.; Borah, S. J.;
Saikia, L.; Dutta, D. K. Catal. Sci. Tech. 2014, 4, 1047. (d) Bhuyan,
D.; Saikia, M.; Saikia, L. Catal. Commun. 2015, 58, 158. (e) Bosica,
G.; Gabarretta, J. RSC Adv. 2015, 5, 46074. (f) Xiong, X.; Chen, H.;
Zhu, R. Chin. J. Catal. 2014, 35, 2006. (g) Xiong, X.; Chen, H.; Zhu,
R. Catal. Commun. 2014, 54, 94. (h) Dulle, J.; Thirunavukkarasu,
K.; Mittelmeijer-Hazeleger, M. C.; Andreeva, D. V.; Shiju, N. R.;
Rothenberg, G. Green Chem. 2013, 15, 1238.
er expensive metal catalysts. Recyclability of the catalyst,
low catalyst loading, solvent-free conditions, and easy
workup are attributes of this protocol. The catalytic genera-
tion of zinc acetylides under solvent-free and sustainable
conditions provides avenues for further development of ef-
ficient C–C bond formation in this area.
Acknowledgment
(
13) González, M. J.; Lopez, L. A.; Vicente, R. Tetrahedron Lett. 2015,
6, 1600.
14) (a) Kende, A. S.; Liebeskind, L. S. J. Am. Chem. Soc. 1976, 98, 267.
b) Wongsa, N.; Sommart, U.; Ritthiwigrom, T.; Yazici, A.;
5
The authors are grateful to UGC New Delhi, India (F. No. 41-335 /2012
SR) dt.13.07.2012) for the financial support and SIF, VIT University,
Vellore for NMR analysis.
(
(
(
Kanokmedhakul, S.; Kanokmedhakul, K.; Willis, A. C.; Pyne, S.
G. J. Org. Chem. 2013, 78, 1138. (c) Binda, C.; Hubálek, F.; Li, M.;
Herzig, Y.; Sterling, J.; Edmondson, D. E.; Mattevi, A. J. Med.
Chem. 2004, 47, 1767.
Supporting Information
(
15) Park, K.; Heo, Y.; Lee, S. Org. Lett. 2013, 15, 3322.
Supporting information for this article is available online at
(
16) (a) Kantam, M. L.; Balasubrahmanyam, V.; Kumar, K. S.;
Venkanna, G. Tetrahedron Lett. 2007, 48, 7332. (b) Ramu, E.;
Varala, R.; Sreelatha, N.; Adapa, S. R. Tetrahedron Lett. 2007, 48,
7184. (c) Mukhopadhyay, C.; Rana, S. Catal. Commun. 2009, 11,
http://dx.doi.org/10.1055/s-0035-1562114.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
References and Notes
285. (d) Eagalapati, N. P.; Rajack, A.; Murthy, Y. L. N. J. Mol. Catal.
(1) (a) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and
A: Chem. 2014, 381, 126.
Practice; Oxford University Press: New York, 2000. (b) Jiménez-
González, C.; Constable, D. J.; Ponder, C. S. Chem. Soc. Rev. 2012,
(17) (a) Corey, E. J.; Shimoji, K. Tetrahedron Lett. 1983, 24, 169.
(b) Afraj, S. N.; Chen, C.; Lee, G.-H. RSC Adv. 2014, 4, 26301.
(c) Borah, B. J.; Borah, S. J.; Saikia, K.; Dutta, D. K. Catal. Sci. Tech-
nol. 2014, 4, 4001.
(18) (a) Zhang, X.; Corma, A. Angew. Chem. 2008, 120, 4430. (b) Shi,
L.; Tu, Y.; Wang, M.; Zhang, F.; Fan, C. Org. Lett. 2004, 6, 1001.
(c) Ren, G.; Zhang, J.; Duan, Z.; Cui, M.; Wu, Y. Aust. J. Chem.
2009, 62, 75.
41, 1485. (c) Sheldon, R. A. Chem. Soc. Rev. 2012, 41, 1437.
(
(
2) Choudhury, L. H.; Parvin, T. Tetrahedron 2011, 67, 8213.
3) (a) Nasir Baig, R. B.; Varma, R. S. Solvent-Free Synthesis, In An
Introduction to Green Chemistry Methods; Future Science:
London, 2013, 18–38. (b) Singh, M. S.; Chowdhury, S. RSC Adv.
2012, 2, 4547.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

D
Synlett
P. B. Sarode et al.
Letter
(
19) Tajbaksh, M.; Farhang, M.; Mardani, H. R.; Hosseinzadeh, R.;
centration of the combined organic layers afforded the crude
product, which was further purified by column chromatogra-
phy on 100–200 silica gel (hexane–EtOAc, 20:1) to afford prop-
Sarrafi, Y. Chin. J. Catal. 2013, 34, 2217.
20) Typical Experimental Procedure: Preparation of 1-(1,3-
Diphenylprop-2-yn-1-yl)piperidine (4a)
(
argylamine 4a as a pale yellow oil; yield 0.284g, 96%; R = 0.8
f
1
To a 25 mL flask were added aldehyde 1a (0.110 mL, 1.0 mmol),
amine 2a (0.130 mL, 1.2 mmol), alkyne 3a (0.165 mL, 1.5
(5% EtOAc–hexane). H NMR (500 MHz, CDCl ): δ = 7.65–7.63
3
(m, 2 H), 7.55–7.51 (m, 2 H), 7.38–7.29 (m, 6 H), 4.81 (s, 1 H),
2.62–2.55 (m, 4 H), 1.63–1.57 (m, 4 H), 1.47–1.45 (m, 2 H). The
catalyst was recovered from the aqueous layer via evaporation
under reduced pressure and dried at 120 °C for 2 h to obtain
mmol), and Zn(OTf) (0.02 g, 0.05 mmol). The reaction mixture
2
was stirred at 100 °C until complete consumption of starting
aldehyde (TLC monitoring). The reaction mixture was cooled to
room temperature, diluted with EtOAc, and then washed with
pure Zn(OTf) . The recovered catalyst was reused for the next
2
cold H O (2 × 5 mL). The organic phase was separated, and the
reaction in the same way.
2
aqueous layer was extracted further with EtOAc (2 × 5 mL). Con-
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D