Oxidant-dependent Cu-catalyzed alkynylation and aminomethylation: C-H versus C-C cleavage in TMEDA

Article abstract of DOI:10.1016/j.tetlet.2013.09.118

Oxidant-dependent Cu-catalyzed alkynylation and aminomethylation reactions have been achieved under facile and mild conditions. TMEDA coupled with various terminal alkynes via C-H bond cleavage in good yields using atmospheric oxygen as an oxidant. Switching from air to TBHP afforded aminomethylation products of terminal alkynes through C-C bond cleavage of TMEDA. The protocol provided a novel strategy to prepare bi/tridentate N-ligand.

Full text of DOI:10.1016/j.tetlet.2013.09.118

Tetrahedron Letters 54 (2013) 6725–6728
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Oxidant-dependent Cu-catalyzed alkynylation and
aminomethylation: C–H versus C–C cleavage in TMEDA
⇑
Qi Shen, Lei Zhang, Yu-Ren Zhou, Jian-Xin Li
Key Lab of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 July 2013
Revised 18 September 2013
Accepted 27 September 2013
Available online 3 October 2013
Oxidant-dependent Cu-catalyzed alkynylation and aminomethylation reactions have been achieved
under facile and mild conditions. TMEDA coupled with various terminal alkynes via C–H bond cleavage
in good yields using atmospheric oxygen as an oxidant. Switching from air to TBHP afforded aminome-
thylation products of terminal alkynes through C–C bond cleavage of TMEDA. The protocol provided a
novel strategy to prepare bi/tridentate N-ligand.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Alkynylation
Aminomethylation
Bond cleavage
TMEDA
Introduction
functionalization of TMEDA. Very interestingly, when TBHP was
used as oxidant in place of air, TMEDA acted as an aminemethyl
As an important strategic approach for constructing C–C bonds,
direct cross-dehydrogenative coupling (CDC) of C–H bonds has
been extensively studied.1,2 Tertiary-amine substrates, especially
those with N-aryl substituents, such as N-aryltetrahydroisoquino-
lines and N,N-dimethylanilines underwent alkylation, arylation,
alkynylation, cyanation, indolation, and phosphonation by the
CDC reactions have been achieved with remarkable success.3 How-
ever, functionalization of aliphatic tertiary amines through the CDC
reactions is always facing a low efficiency,3g,4 which attributes to
the fact that the key intermediate iminium ion cannot be stabilized
without an N-aromatic ring in aliphatic tertiary amines.2g,3o,5
Therefore, the development of efficient and practical methods for
CDC of aliphatic amines remains a big challenge.
source for the synthesis of propargyl amines. Propargyl amines or
b-aminoalkynes are versatile intermediates for the construction
of nitrogen-containing biologically active molecules and the syn-
thesis of polyfunctional amino derivatives.8
Results and discussion
In our initial study, the alkynylation of TMEDA (1a) with
N-methyl-N-propargylaniline (2a) was chosen as a model reac-
tion,9 and the screening of various reaction parameters such as cat-
alyst, additive, solvent, and temperature were performed (Table 1).
Several salts such as CuCl2, Cu(OAc)2, CuBr, FeCl3, NiCl2, Cu(OTf)2,
Cu(acac)2, CuCl, and CuI were tested as catalysts, and 10 mol %
CuCl2 gave the best result. The control experiment confirmed that
the reaction did not run in the absence of the catalyst (Table 1,
entry 1). DMSO showed to be the best solvent for alkynylation of
TMEDA, which offered 3a with high yield and excellent chemose-
lectivity (Table 1, entry 8). Notably, the temperature was crucial
in this transformation since the yield was sharply lowered at
100 °C, however, at 40 °C no alkynylation of product 3a was de-
tected even when the reaction time was prolonged to 12 h (Table 1,
entries 9 and 10).
Recently, we6 and other groups7 have been involved in the
development of a methodology using amines as an alternative
source for methylenation and acylation through metal or visible
light catalyzed C–N cleavage. As our continuous efforts on Cu
-catalyzed C–H functionalization of amines,6 herein, we wish to
report a successful CDC reaction of aliphatic tertiary amine, an
unprecedented modification of TMEDA, direct alkynylation under
copper catalyzation with air as a sustainable and efficient oxidant.
TMEDA and related aliphatic amines are often used as important
bidentate ligands for lithium alkylide mediated lithiation, metal
chelation, and metal-catalyzed couplings.8 As far as we know,
It was noted that O2 was essential in this transformation, which
was clearly exemplified as seen from the inefficient coupling by
carrying out the reaction under a nitrogen atmosphere instead of
air (Table 1, entry 11). Very meaningfully, when tert-butyl hydro-
peroxide (TBHP) was used as an oxidant at room temperature,
aminomethylation product 4a was observed as the main product
there are no successful and disclosed examples of
a direct
⇑
Corresponding author. Tel./fax: +86 25 83686419.
E-mail address: lijxnju@nju.edu.cn (J.-X. Li).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.09.118

6726
Q. Shen et al. / Tetrahedron Letters 54 (2013) 6725–6728
Table 1
Table 2
Optimization of reaction conditions for alkynylation of TMEDAa
Amines were selected for alkynylation
Entry
Cat. (mol %)
Solvent
T (°C)
t (h)
Yieldb 3a/4a (%)
1
2
3
4
5
6
7
8
None
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
MeCN
Dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
80
80
80
80
80
80
80
80
40
100
80
80
80
Reflux
80
80
80
80
80
80
80
80
80
12
2
5
5
5
5
12
5
12
2
12
5
5
5
5
5
5
5
5
5
NRc
82/12
79/10
45/trace
56/8
CuCl2 (50)
CuCl2 (10)
Cu(OAc)2 (10)
CuBr (10)
FeCl3 (10)
NiCl2 (10)
CuCl2 (10)
CuCl2 (10)
CuCl2 (10)
CuCl2 (10)
CuCl2 (10)
CuBr (10)
CuCl2 (10)
CuCl2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(acac)2 (10)
Cu(acac)2 (10)
CuCl (10)
Messy
8/0
91/trace
9
NRc
10
11d
12d,e
13e
14
15
16
17e
18
19e
20
21e
22
23e
66/trace
14/trace
<3/89
a
Substrates recovered.
Compound 4a was isolated as the main product in 74% yield.
No reaction.
21/74
b
62f/0
c
NRc
d
With some unknown compounds.
85/7
e
N,N,N0,N0-Tetramethylbenzidine11 was isolated as the main product in 56% yield.
Tracy/91
<25/trace
0/messy
71/trace
11/80
CuCl (10)
CuI (10)
CuI (10)
5
5
5
With the optimized reaction conditions in our hand, a series of
novel TMEDA derivatives (3a–u) were synthesized through Cu
-catalyzed CDC reaction in good to excellent yields (Table 3).
Screening disclosed that this alkynylation was tolerant of a wide
range of functional groups, including amines (3a–3c), sulfona-
mides (3e–3i), indole (3c), halides (3h, and 3o), ether (3r), ester
(3s), amide (3u), and thiphene (3y). It should be mentioned that es-
ter-masked propargyl alcohol and phthalimide-masked propargyl
amine can be easily released by hydrolysis and hydrazinolysis for
further functionalization. Aromatic alkynes (2n–2q, 2y and 2z)
and aliphatic alkynes both provided alkynylation products in good
yields. It was worth mentioning that the electronic nature of the
substituents on the alkyne affected this transformation, alkynes
with electron-donating groups underwent the reaction smoothly
in higher yields(2a–u), while those with electron-withdrawing
groups such as acetyl ethyne (2w) and tert-butyl propiolate (2x)
decomposed under standard conditions. Also, silylethylene (2v)
was an inefficient coupling partner for alkynylation of TMEDA un-
der optimized reaction conditions.
As described above, replacement of air with TBHP as oxidant in
the present reaction afforded aminomethylation products, thus,
diversified propargylic amine derivatives (4 series) were prepared
using TMEDA as an aminemethyl donor (Table 3). It was noted that
aromatic alkynes (2n–2q, 2y, and 2z) and those with an N/O tether
at 3-position of terminal alkynes (2a–i, 2r–t) furnished propargylic
amine in moderate to good yields. While simple aliphatic (2j–m),
acetyl ethyne (2w), tert-butyl propiolate (2x), and silylethylene
(2v) gave a complex reaction mixture, no aminemethylation prod-
ucts were isolated. The current protocol provided a facile and prac-
tical tool for the synthesis of propargyl amine derivatives.
56/trace
20/messy
a
Reaction conditions: a solution of 1a (1.5 mmol) in a solvent (5 mL) was added
as catalyst, stirred for 5 min, 2a (1.0 mmol) was added and heated to the indicated
temperature and time.
b
Isolated yield.
No reaction, only 2a recovered.
Reaction under nitrogen atmosphere.
TBHP (2.0 equiv, 70% in aqueous solution) was added as a oxidant, at room
c
d
e
temperature.
f
With some unknown compounds.
(Table 1, entry 12), which provided a new strategy for aminome-
thylation of terminal alkynes.10 The standard reaction conditions
were established to be 10 mol % of CuCl2 relative to alkyne, 1.5
equiv of TMEDA, DMSO as the solvent, at 80 °C, and under air or
TBHP.
To evaluate the potential of various amines that underwent
alkynylation, other aliphatic and aromatic amines were also
subjected to the reaction conditions optimized for 2a (Table 1,
entry 8) as shown in Table 2. Tetramethylpropanediamine
(TMPDA, 1b) afforded the corresponding alkynylation products in
31%. Trimethylpropanediamine (1d) and tetraethylpropanedi-
amine (1e) were ineffective coupling partners, which suggested
that the number of substituents and type of substituents play an
important role in this transformation. Interestingly, tetrame-
thylmethanediamine (TMMDA, 1c) under standard condition fur-
nished aminomethylation product [xx] 4a in 74% yield (Table 2).
Surprisingly, N,N-dimethylaniline 1i, which was often used as a
model substrate for alkynylation reaction conditions screening,3e,f
provided direct coupling product 4,40-dimetylaminoxenene. These
results clearly demonstrate that the selection of amines is crucial
to achieve alkynylation. It is reported that N-methylated diamines
chelate with Cu to form a five or six membered Cu(II)-TMEDA
or -TMPDA complexes which play an important role in chemical
transformation8c,e and the present study also indicated that the
chelating effect, which may stabilize the charged iminium
intermediate, is crucial for the alkynylation.
To gain an insight into the reaction pathway, we examined
hydroquinone monomethyl ether (MEHQ) as a radical inhibitor
and TBHP as an oxidant (Fig. S1, ESI). The results indicated that a
radical mechanism could be involved in the formation of 4a. On
the basis of a mass spectrometry study, Cu(I)-TMEDA complex F
was observed to serve as the key intermediate of the coupling cycle
(Fig. S2, ESI). In the light of the works on the CDC type alkynyla-
tion3f–h,5a,b and the results obtained in the current study, a

Q. Shen et al. / Tetrahedron Letters 54 (2013) 6725–6728
6727
plausible mechanism is proposed in Scheme 1. Initially, TMEDA
(1a) coordinated with CuCl2 to afford Cu(II)-TMEDA complex
A,8c,e iminium ion (B) is generated by selective oxidation of C–H
bond of TMEDA.1e,6 Following this, nucleophilic addition of copper
alkynylide affords the Mannich-type products 3 (path I). In view of
aminomethylation (path II),7c,11,12 the formation of iminium ion (E)
is resulted from C–C bond cleavage and this pathway could be pro-
moted by adding TBHP. Subsequent Mannich-type addition to E af-
fords aminomethylation product 4. Path I and II presented in the
reaction system simultaneously, which could be easily switched
by adjusting the reaction conditions.
Table 3
Substrate scope of the alkynylation of TMEDAa
Conclusions
In summary, we have described a novel and efficient method for
the synthesis of TMEDA derivatives, through Cu(II)-catalyzed CDC
reaction under mild conditions, in the presence of only atmo-
spheric oxygen as an oxidant. Meanwhile, aminomethylation of
terminal alkynes has been achieved using TMEDA as an amino-
methyl source through TBHP mediated C–C cleavage. This new pro-
tocol provides a facile and practical strategy for the preparation of
novel diamine-based ligands and polyamines. Further detailed
studies on the Cu(II)-catalyzed alkynylation of TMEDA are under-
way in our laboratory.
Acknowledgment
We gratefully acknowledge the National Natural Science Foun-
dation of China (21272114, 90913023) and the National Natural
Science Fund for Creative Research Groups of China (21121091)
for their financial support. We also would like to thank the editor
and the referees for very constructive suggestions and comment.
Supplementary data
Supplementary data (detailed experimentals for all compounds
including 1H and 13C NMR spectral assignments, and other supple-
mentary information) associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
09.118. These data include MOL files and InChiKeys of the most
important compounds described in this article.
a
Reaction conditions: for 3 reaction was run with TMEDA (1.5 mmol),
DMSO (5 mL), CuCl2 (0.1 mmol), 2a (1.0 mmol), air, 80 °C, for indicated time;
for 4 using TBHP (1.0 mmol) at room temperature.
b
With some unknown compounds.
The alkyne decomposed.
References and notes
c
1. For a recent set of reviews on CDC reactions, see: (a) Yeung, C. S.; Dong, V. M.
Chem. Rev. 2011, 111, 1215; (b) Scheuermann, C. J. Chem. Asian J. 2010, 5, 436;
(c) Li, C.-J. Acc. Chem. Res. 2008, 42, 335; (d) W.-J. Yoo and C.-J. Li, in C-H
Activation, eds. J.-Q. Yu and Z. Shi, Springer, Berlin Heidelberg, 2010, Vol. 292,
pp. 281.; (e) Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41, 3464.
2. For selected examples of different C–H bonds underwent CDC reactions,
benzylic C–H bonds see: (a) Correia, C. A.; Li, C.-J. Adv. Synth. Catal. 2010, 352,
1446; (b) Guo, C.; Song, J.; Luo, S.-W.; Gong, L.-Z. Angew. Chem., Int. Ed. 2010, 49,
5558; (c) Benfatti, F.; Capdevila, M. G.; Zoli, L.; Benedetto, E.; Cozzi, P. G. Chem.
Commun. 2009, 5919; (d) Li, Z.; Cao, L.; Li, C.-J. Angew. Chem., Int. Ed. 2007, 46,
6505; allylic C–H bonds see: (e) Paradine, S. M.; White, M. C. J. Am. Chem. Soc.
2012, 134, 2036; (f) Young, A. J.; White, M. C. J. Am. Chem. Soc. 2008, 130, 14090;
C–H bonds of tertiary amines see: (g) Xie, J.; Li, H.; Zhou, J.; Cheng, Y.; Zhu, C.
Angew. Chem., Int. Ed. 2012, 51, 1252; (h) Freeman, D. B.; Furst, L.; Condie, A. G.;
Stephenson, C. R. J. Org. Lett. 2011, 14, 94; (i) Shen, Y.; Tan, Z.; Chen, D.; Feng, X.;
Li, M.; Guo, C.-C.; Zhu, C. Tetrahedron 2009, 65, 158; (j) Li, Z.; Bohle, D. S.; Li, C.-J.
Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 8928; C–H bonds of ethers see: (k) Chen,
L.; Shi, E.; Liu, Z.; Chen, S.; Wei, W.; Li, H.; Xu, K.; Wan, X. Chem. Eur. J. 2011, 17,
4085; (l) Li, Z.; Yu, R.; Li, H. Angew. Chem., Int. Ed. 2008, 47, 7497; (m) Zhang, Y.;
Li, C.-J. Angew. Chem., Int. Ed. 1949, 2006, 45. C–H bonds of alkanes see; (n)
Ramesh, D.; Ramulu, U.; Mukkanti, K.; Venkateswarlu, Y. Tetrahedron Lett.
2012, 53, 2904; (o) Deng, G.; Li, C.-J. Org. Lett. 2009, 11, 1171; (p) Deng, G.;
Ueda, K.; Yanagisawa, S.; Itami, K.; Li, C.-J. Chem. Eur. J. 2009, 15, 333.
3. For selected examples of functionalization of N-aryl tertiary amines through
CDC reactions, for alkylation see: (a) Zhang, J.; Tiwari, B.; Xing, C.; Chen, X.;
Chi, Y. R. Angew. Chem., Int. Ed. 2012, 51, 3649; (b) Huang, L.; Zhang, X.;
Zhang, Y. Org. Lett. 2009, 11, 3730; (c) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005,
127, 3672; for arylation see: (d) Huang, L.; Niu, T.; Wu, J.; Zhang, Y. J. Org.
Scheme 1. Plausible mechanism.

6728
Q. Shen et al. / Tetrahedron Letters 54 (2013) 6725–6728
Chem. 2011, 76, 1759; (e) Baslé, O.; Li, C.-J. Org. Lett. 2008, 10, 3661; for
7. (a) Yoo, W.-J.; Tanoue, A.; Kobayashi, S. Chem. Asian J. 2012, 7, 2764; (b) Wu,
W.; Su, W. J. Am. Chem. Soc. 2011, 133, 11924; (c) Chen, J.; Liu, B.; Liu, D.; Liu, S.;
Cheng, J. Adv. Synth. Catal. 2012, 354, 2438; (d) Li, H.; He, Z.; Guo, X.; Li, W.;
Zhao, X.; Li, Z. Org. Lett. 2009, 11, 4176.
8. For TMEDA relate compounds see: (a) (a) Nichols, M. A.; Williard, P. G. J. Am.
Chem. Soc. 1993, 115, 1568; (b) Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. J. Am.
Chem. Soc. 2008, 130, 6686; (c) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2010, 1,
13; (d) Nakajima, M.; Miyoshi, I.; Kanayama, K.; Hashimoto, S.-I.; Noji, M.;
Koga, K. J. Org. Chem. 1999, 64, 2264; (e) Collman, J. P.; Zhong, M. Org. Lett. 2000,
2, 1233; For propargyl amines relate compounds see: (a) Naota, I.; Takaya, H.;
Murahashi, S. I. Chem. Rev. 1998, 98, 2599; (b) Huffman, M. A.; Yasuda, N.;
DeCamp, A. E.; Grabowski, E. J. J. J. Org. Chem. 1995, 60, 1590; (c) Nilsson, B.;
Vargas, H. M.; Ringdahl, B.; Hacksell, U. J. Med. Chem. 1992, 35, 285.
alkynylation see: (f) Rueping, M.; Koenigs, R. M.; Poscharny, K.; Fabry, D. C.;
Leonori, D.; Vila, C. Chem. Eur. J. 2012, 18, 5170; (g) Volla, C. M. R.; Vogel, P.
Org. Lett. 2009, 11, 1701; (h) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2004, 126,
11810; for cyanation see: (i) Murahashi, S.-I.; Nakae, T.; Terai, H.; Komiya, N.
J. Am. Chem. Soc. 2008, 130, 11005; (j) Murahashi, S.-I.; Komiya, N.; Terai, H.
Angew. Chem., Int. Ed. 2005, 44, 6931; (k) Murahashi, S.-I.; Komiya, N.; Terai,
H.; Nakae, T. J. Am. Chem. Soc. 2003, 125, 15312; for indolation see: (l) Yang,
F.; Li, J.; Xie, J.; Huang, Z.-Z. Org. Lett. 2010, 12, 5214; (m) Li, Z.; Li, C.-J. J. Am.
Chem. Soc. 2005, 127, 6968; for phosphonation see: (n) Alagiri, K.; Devadig,
P.; Prabhu, K. R. Tetrahedron Lett. 2012, 53, 1456; (o) Basle, O.; Li, C.-J. Chem.
Commun. 2009, 4124.
4. Alkynylation of aliphatic tertiary amine often with low to moderate yield and
other additives were needed (e.g., DEAD, NBS), recent examples see: (a)
Sugiishi, T.; Nakamura, H. J. Am. Chem. Soc. 2012, 134, 2504; (b) Ghobrial, M.;
Schnürch, M.; Mihovilovic, M. D. J. Org. Chem. 2011, 76, 8781; (c) Xu, X.; Li, X.
Org. Lett. 2009, 11, 1027; (d) Niu, M.; Yin, Z.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org.
Chem. 2008, 73, 3961.
5. (a) Boess, E.; Schmitz, C.; Klussmann, M. J. Am. Chem. Soc. 2012, 134, 5317; (b)
Boess, E.; Sureshkumar, D.; Sud, A.; Wirtz, C.; Farès, C.; Klussmann, M. J. Am.
Chem. Soc. 2011, 133, 8106; (c) Xie, J.; Huang, Z.-Z. Angew. Chem., Int. Ed. 2010,
49, 10181.
9. N-Methyl-N-propargylaniline (2a) was chosen as
a substrate to furnish
diphenylmethanes using TMEDA as a methylene donor as reported in our
previous report [6], however, alkynylation product 3a of TMEDA was isolated
as the main compound.
10. Other oxidants such as THYDRO, TBP, DDQ, and BPO were also tried, however,
none of them were better than TBHP to afford aminomethylation product.
11. N,N-Dimethylaniline react with Cu2+ to form the corresponding amine radical
cations which dimerized to form tetramethylbenzidines, see: M. Kirchgessner,
K. Sreenath and K. R. Kanayama, J. Org. Chem., 2006, 71, 9849.
12. Cai, S.; Zhao, X.; Wang, X.; Liu, Q.; Li, Z.; Wang, D. Z. Angew. Chem., Int. Ed. 2012,
51, 8050.
6. Zhang, L.; Peng, C.; Zhao, D.; Wang, Y.; Fu, H.-J.; Shen, Q.; Li, J.-X. Chem.
Commun. 2012, 5928.