Copper catalysed alkynylation of tertiary amines with CaC2: Via sp3 C-H activation

Article abstract of DOI:10.1039/c6gc00872k

A mild and easy-to-handle protocol to produce propargylamines with a terminal alkyne through catalytic cross-coupling of tertiary amines and calcium carbide has been developed. The reaction proceeds via sp³ C-H bond activation and C-C coupling. Good to excellent yields were obtained for the corresponding propargylamines with both alkyl and aryl substitutions. The development of these functionalized propargylamines with a terminal alkyne group will offer a wider application for the synthesis of natural or pharmaceutical products due to their unique sp C-H reactivity.

Full text of DOI:10.1039/c6gc00872k

View Article Online
View Journal
Green
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: S. P. Teong, D. Yu,
Y. N. Sum and Y. Zhang, Green Chem., 2016, DOI: 10.1039/C6GC00872K.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/greenchem

Please do not adjust margins
Page 1 of 5
Green Chemistry
View Article Online
DOI: 10.1039/C6GC00872K
Journal Name
ARTICLE
Copper catalysed alkynylation of tertiary amines with CaC2 via sp3
C-H activation
Siew Ping Teong, Dingyi Yu, Yin Ngai Sum and Yugen Zhang*
Received 00th January 20xx,
Accepted 00th January 20xx
A mild and easy-to-handle protocol to produce propargylamines with terminal alkyne through catalytic cross-coupling of
tertiary amines and calcium carbide has been developed. The reaction preceeds via sp3 C-H bond activation and C-C
coupling. Good to excellent yields were obtained for the corresponding propargylamines with both alkyl and aryl
substitutions. The development for these functionalized propargylamines with a terminal alkyne group will offer a wider
application for the synthesis of natural or pharmaceutical products due to its unique sp C-H reactivity.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Propargylamines and their derivatives are versatile key formation via sp3 C-H bond activation methodology has gained
13, 14
building blocks for the preparation of many biologically active increasing attention in recent years
and it eliminates the
compounds with wide applications in pharmaceutical and need to prepare functional groups, making it a direct, quick
synthetic chemistry.1 Various reported methods using and efficient method for C-C bond formations. Herein, we
stoichiometric nucleophilic alkynylation2 and transition metal- report a simple and mild catalytic protocol for the synthesis of
catalyzed three-component coupling of aldehydes/halides, tert-propargylamines via sp3 C-H bond activation and C-C
alkynes, and amines3,4 are indeed effective methods; however, coupling with the sustainable calcium carbide. It represents
these methods require the presence of a suitable leaving the first example of direct C-C coupling of calcium carbide with
group or pre-functionalized substrates. Hence, direct C-C bond a C-H bond.
formation of terminal alkynes with tertiary amines via sp3 C-H
activation is a more practical approach. Notably, Li and co-
workers reported an efficient copper-catalyzed alkynylation of
aryl- or benzyl- substituted tertiary amines in the presence of
t-BuOOH.5 Catalytic coupling of aliphatic tertiary amines with
terminal alkynes was also demonstrated.6,7 In all cases, the
substrates used in these methods are limited to substituted
terminal alkynes and hence produce propargylamines with
internal alkynes (Scheme 1). Though important, the internal Scheme 1. Propargylamine with (a) internal and (b) terminal
structure may hinder further synthetic applications. alkyne.
Propargylamines with terminal alkynes, on the other hand may
offer wider applications due to the unique reactivity of the sp
C-H bond which is susceptible to nucleophilic, electrophilic, Dimethylcyclohexylamine was used as the model substrate for
radical and cycloaddition reactions.8
optimization. Various copper catalysts and oxidants were
To begin our study, an aliphatic amine; N,N-
To date, the preparation of propargylamines with investigated (Table 1 and S1). Both Cu(I) and Cu(II) salts showed
terminal alkynes via catalytic cross-coupling of tertiary amines comparable activities (Table 1, entries 3 – 8) with CuBr found to be
has not been reported. In recent years, calcium carbide has the most effective catalyst. The choice of oxidants was of great
been used increasingly by our group8,9 and others10,11 as a importance.
Besides
diethylazodicarboxylate
(DEAD),
sustainable,12 easy-to-handle, and cheap feedstock in organic hydroperoxide oxidants worked moderately well (Table S1, entries
synthesis. Hence, it would be highly desirable to prepare the 1 – 6). Di-t-butyl peroxide and H2O2 however only gave trace
useful tert-propargylamines via one-step catalytic cross- amount of product. Other oxidants like KMnO4, NBS and I2 does not
coupling of tertiary amines with calcium carbide. The C-C bond work in this system.
With these in hand, the reaction conditions were further
optimized (Table 1). The reaction of this substrate in CH3CN with
S. P. Teong, Dr. D. Yu, Y. N. Sum, Dr. Y.G. Zhang.
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos,
DEAD (1.5 equiv.) was carried out at 80 °C for 16 h (Entry 1). Under
Singapore 138669, Singapore. E-mail: ygzhang@ibn.a-star.edu.sg
calcium carbide (2.5 equiv.) in the presence of CuBr (10 mol%) and
this dry condition, only trace amount of product was formed due to
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
the poor solubility of calcium carbide in organic solvents.11,15 Recent
This journal is © The Royal Society of Chemistry 20xx
J. Name, 2016, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 2 of 5
ARTICLE
Journal Name
studies have shown that adding a controlled amount of water can
resolve this issue by breaking down the polymeric structure of
calcium carbide.8,9,16 Hence, trace amount of water was added into
the system, thereby affording 96% yield, as determined from 1H
NMR spectroscopy (Entry 3). The reaction proceeded efficiently in a
wide range of solvents, including the less polar 1,4-dioxane and
polar protic isopropanol (Entries 14 – 17)
View Article Online
DOI: 10.1039/C6GC00872K
Table 1. Direct alkynylation of tertiary amines with CaC2:
optimization of reaction conditions. a
Catalyst
(mol%)
DEAD
(eq.)
H2O
Yield
Entry
Solvent
(vol%) [%]b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
CuBr (10)
CuBr (10)
CuBr (10)
CuCl (10)
CuI (10)
CuCN (10)
Cu(OAc)2 (10)
CuBr2 (10)
--
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
--
1.5
1.5
1.0
1.5
1.5
1.5
1.5
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
-
Trace
80
96
93
95
84
90
87
NR
NR
88
91
78
80
54
88
63
1
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
Scheme 2. Substrate scope of aliphatic tertiary amines with CaC2.
NMR yield. Isolated yield is in parentheses. Reaction conditions:
Amine (0.5 mmol), CaC2 (2.5 mmol), CuBr (0.1 mmol), DEAD (1.5
mmol), CH3CN + H2O (5 mL), 80 °C, 16 h a 1 mmol amine; b 2 mmol
DEAD; c 4 h; d 90 °C, 2 mmol DEAD.
CuBr (10)
CuBr (5)
CuBr (15)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
THF
dioxane
IPA
a
Reaction conditions: Amine (1 mmol), CaC2 (2.5 mmol), solvent +
b
H2O (5 mL), 80 °C, 16 h.
NMR yield. DMF = N,N-
dimethylformamide; THF = tetrahydrofuran; IPA = iso-propanol.
Subsequently, various aliphatic tertiary amines were
screened for this reaction system. Good to excellent yields
were obtained for most of the aliphatic substrates including
the bulky amine, straight or branched chain amines (Scheme 2,
3a – 3e), reactive benzylamine (3f) and amines with additional
functional groups, such as -CN, -COOEt, -OH and halide (3g, 3j,
3k, 3l). We were delighted to find that this system also worked
well for N-methyl-1,2,3,4-tetrahydro-isoquinoline and N-
methyl-piperidine as they are important structural features for
pharmaceutical synthesis (Scheme 2, 3h – 3l). The benzylic
position of benzyldimethylamine is usually more susceptible to
reactions. However, alkynylation at the methyl position was
observed in this system (3f). This phenomenon is similar to the
anodic methoxylation of the amine.17 In contrast, alkynylation
of tetrahydroisoquinoline (3h) took place exclusively at the
benzyl position instead of the methyl position, as confirmed by
COSY NMR (Figure S1). No desired product was obtained when
N,N-dimethylbenzamide (Scheme 2, 3n).
Scheme 3. Substrate scope of aromatic tertiary amines with
CaC2. NMR yield. Isolated yield is in parentheses. Reaction
conditions: Amine (0.5 mmol), CaC2 (2.5 mmol), CuBr (0.1
mmol), t-BuOOH (2 mmol), CH3CN (5 mL), 90 °C, 16 h
2 | J. Name., 2016, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 5
Green Chemistry
Please do not adjust margins
Journal Name
ARTICLE
View Article Online
DOI: 10.1039/C6GC00872K
We next screened aromatic amines as substrates under
the above reaction condition. We noted that the adduct of
DEAD with N,N-dimethylaniline was observed from GCMS
which is similar to the reaction of N,N-dimethylaniline with Scheme 5. Proposed mechanism for the catalytic alkynylation of
phenylacetylene in the presence of DEAD.6 When a different tertiary amine with CaC2.
oxidant, t-BuOOH was used, trace amount of product was
observed with secondary amine N-methylaniline as a major
side product. Attempts to optimize the reaction condition for
N,N-dimethylaniline (Table S2) led us to improve the yield to
79% by not adding water into the system. Here the reaction
could be self-accelerated as water is produced during the
Scheme 6. Sonogashira coupling of propargylamine 3a with
reaction.5 Under this set of optimized conditions, moderate to
iodobenzene.
good yields were generally obtained for aromatic amines
substituted with bulky groups and halides (Scheme 3, 5a – 5f).
While the reaction for the aromatic amines with electron-
withdrawing substituents gave low yields (Scheme 3, 5g – 5j).
Herein, the application of the synthesized propargylamine 3a
was successfully demonstrated via the Sonogashira coupling with
iodobenzene, forming N-methyl-N-(3-phenylprop-2-yn-1-
It is noted that only one methyl group of tertiary amines yl)cyclohexanamine in 83% yield.
undergoes alkynylation with CaC2 in all these reactions.5,7 When
In conclusion, we have developed a mild and easy-to-handle
protocol for affording propargylamines with terminal alkyne
through catalytic cross-coupling of tertiary amines with the
inexpensive and renewable calcium carbide. Good to excellent
yields were obtained for the corresponding propargylamines, with
the aliphatic ones working particularly well. The development for
these functionalized propargylamines with a terminal alkyne group
will offer a wider application for the synthesis of natural or
pharmaceutical products due to its unique sp C-H reactivity. The
synthetic application of this work is under investigation.
using 3a as the substrate, further alkynylation on another methyl
group did not proceed with excess calcium carbide remaining.
When diamine 6 was used as the substrate, the reaction proceeded
to give a mixture of mono- and di- product (Scheme 4). The reaction
was not selective despite the use of harsher conditions (Table S3).
Acknowledgements
Scheme 4. Alkynylation of diamine with CaC2.
This work was supported by the Institute of Bioengineering and
Nanotechnology (Biomedical Research Council, Agency for Science,
Technology and Research (A*STAR), Singapore).
It is proposed that the current reaction has a similar pathway as
reported reactions with terminal alkynes (Scheme 5).6,18 The
oxidant DEAD undergoes nucleophilic addition reaction with tertiary
amine forming an adduct. The adduct then cleaves to form the
imine cation A and DEAD anion B. Thereafter, coupling of the in-situ
generated copper acetylide C and the imine cation A results in the
desired product 3 and regenerates the copper catalyst. It is also
possible that copper catalyzes the formation of the imine
intermediate through sp3 C-H activation.5
Notes and references
1. (a) A. A. Boulton, B. A. Davis, D. A. Durden, L. E. Dyck, A. V.
Juorio, X. M. Li, I. A. Paterson, P. H. Yu, Drug Dev. Res., 1997,
42, 150; (b) M. A. Huffman, N. Yasuda, A. E. DeCamp, E. J. J.
Grabowski, J. Org. Chem., 1995, 60, 1590; (c) M. Konishi, H.
Ohkuma, T. Tsuno, T. Oki, G. D. VanDuyne, J. Clardy, J. Am.
Chem. Soc., 1990, 112, 3715; (d) B. Nilsson, H. M. Vargas, B.
Ringdahl, U. Hacksell, J. Med. Chem. Soc., 1992, 35, 285; (e)
H. Nakamura, T. Kamakura, M. Ishikura, J. F. Biellmann, J.
Am. Chem. Soc., 2004, 126, 5958; (f) P. Sienkiewich, K.
Bielawski, A. Bielawska, J. Palka, EnViron. Toxicol. Pharmacol.
2005, 20, 118; (g) J. V. Greenhill, P. Lue, Prog. Med. Chem.
1993, 30, 203.
2. (a) T. Murai, Y. Mutoh, Y. Ohta, M. Murakami, J. Am. Chem.
Soc. 2004, 126, 5968; (b) J. H. Ahn, M. J. Joung, N. M. Yoon,
D. C. Oniciu, A. R. Katritzky, J. Org. Chem. 1999, 64, 488 and
references therein.
3. (a) C. M. Wei, C. J. Li, Green Chem. 2002,
4, 39; (b) C. Wei,
C.-J. Li, Lett. Org. Chem. 2005, , 410; (c) L. Zhao, C.-J Li,
2
Chem. Asian J. 2006, 1-2, 203; (d) C. M. Wei, C. J. Li, J. Am.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 4 of 5
ARTICLE
Journal Name
Chem. Soc. 2002, 124, 5638; (e) R. Fassler, D. E. Frantz, J.
Oetiker, E. M. Carreira, Angew. Chem., Int. Ed. 2002, 41
View Article Online
DOI: 10.1039/C6GC00872K
,
3054; (f) N. Gommermann, P. Knochel, Chem. Eur. J. 2006,
12, 4380; (g) N. Gommermann, C. Koradin, K. Polborn, P.
Knochel, Angew. Chem., Int. Ed. 2003, 42, 5763; (h) C. M.
Wei, J. T. Mague, C. J. Li, Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5749; (i) T. F. Knoepfel, P. Aschwanden, T. Ichikawa, T.
Watanabe, E. M. Carreira, Angew. Chem., Int. Ed. 2004, 43
5971; (j) M. Kidwai, V. Bansal, A. Kumarb, S. Mozumdar,
Green Chem. 2007, , 742; (k) X. Zhang, A. Corma, Angew.
,
9
Chem. Int. Ed. 2008, 47, 4358.
4. (a) D. Y. Yu and Y. Zhang, Adv. Synth. Catal., 2011, 353, 163;
(b) Z. Lin, D. Yu, Y. Zhang, Tetrahedron Lett., 2011, 52, 4967;
(c) D. Aguilar, M. Contel, E. P. Urriolabeitia, Chem. Eur. J.
2010, 16, 9287.
5. (a) Z. Li, C.-J. Li, J. Am. Chem. Soc. 2004, 126, 11810; (b) Z. Li,
C.-J. Li, Org. Lett. 2004, 6, 4997
6. X. Xu, X. Li, Org. Lett., 2009, 11, 1027 and references therein
7. M. Niu, Z. Yin, H. Fu, Y. Jiang, Y. Zhao, J. Org. Chem. 2008, 73
3961.
,
8. Z. Lin, D. Yu, Y. N. Sum, Y. Zhang, ChemSusChem, 2012, 5,
625.
9. (a) Y. N. Sum, D. Yu, Y. Zhang, Green Chem., 2013, 15, 2718;
(b) D. Yu, Y. N. Sum, A. C. C. Chng, M. P. Chin, Y. Zhang,
Angew. Chem. Int. Ed., 2013, 52, 5125.
10. For a recent review paper: K. S. Rodygin, G. Werner, F. A.
Kucherov, V. P. Ananikov, Chem. Asian J., 2016,
doi:10.1002/asia.201501323.
11. (a) W. Zhang, H. Wu, Z. Liu, P. Zhong, L. Zhang, X. Huang and
J. Cheng, Chem. Commun., 2006, 4826; (b) Y. Jiang, C. Kuang
and Q. Yang, Synlett, 2009, 3163; (c) Z. Gonda, K. Lörincz
and Z. Novák, Tetrahedron Lett., 2010, 51, 6275; (d) Q. Yang,
Y. Jiang and C. Kuang, Helv. Chim. Acta, 2012, 95, 448; (e) A.
Hosseini, D. Seidel, A. Miska and P. R. Schreiner, Org. Lett.,
2015, 17, 2808; (f) K. S. Rodygin and V. P. Ananikov, Green
Chem., 2016, 18, 482; (g) R. Matake, Y. Niwa and H.
Matsubara, Org. Lett., 2015, 17, 2354; (h) R. Matake, Y.
Adachi and H. Matsubara, Green Chem., 2016, DOI:10.1039/
c5gc02977e.
12. (a) G. Li, Q. Liu, Z. Liu, Z. C. Zhang, C. Li, W. Wu, Angew.
Chem. Int. Ed. 2010, 49, 8480; (b) J. Lehmann, Nature 2007,
447, 143.
13. E. J. Corey, X. M. Cheng, The Logic of Chemical Synthesis,
John Wiley & Sons: New York, 1989, 1.
14. C.-J. Li, Acc. Chem. Res., 2009, 42, 335 and references
therein
15. (a) H. Föppl, Angew. Chem., 1958, 70, 401; (b) M.
Hamberger, S. Liebig, U. Friedrich, N. Korber, U. Ruschewitz,
Angew. Chem., Int. Ed., 2012, 51, 13006.
16. P. Chuentragool, K. Vongnam, P. Rashatasakhon, M.
Sukwattanasinitt, S. Wacharasindhu, Tetrahedron, 2011, 67
8177.
,
17. N. L. Weinberg, E. A. Brown, J. Org. Chem. 1966, 31, 4058.
18. X. Xu, X. Li, L. Ma, N. Ye, B. Weng, J. Am. Chem. Soc. 2008,
130, 14048.
4 | J. Name., 2016, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
Green Chemistry
Please do not adjust margins
Journal Name
ARTICLE
View Article Online
DOI: 10.1039/C6GC00872K
TOC
A mild and easy-to-handle protocol to produce propargylamines
with terminal alkyne through sp3 C-H bond activation and C-C
coupling of tertiary amines and calcium carbide.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins