Facile and efficient synthesis of 1-haloalkynes via DBU-mediated reaction of terminal alkynes and N-haloimides under mild conditions

Article abstract of DOI:10.1039/c4ra04736b

Directly from terminal alkynes and with N-halosuccinimides (halo = Br and I) or N-cholorophthalimide as the halogen sources, DBU as the activator, 1-haloalkynes were prepared in good to excellent yields at room temperature. Bis(bromoalkyne) and bis(iodoal

Full text of DOI:10.1039/c4ra04736b

RSC Advances
View Article Online
View Journal | View Issue
COMMUNICATION
Facile and efficient synthesis of 1-haloalkynes via
DBU-mediated reaction of terminal alkynes and
N-haloimides under mild conditions†
Cite this: RSC Adv., 2014, 4, 30046
a
a
a
a
b
Received 20th May 2014
Accepted 30th June 2014
*
*
Mengru Li, Yueju Li, Baozhong Zhao, Fushun Liang and Long-Yi Jin
DOI: 10.1039/c4ra04736b
www.rsc.org/advances
Directly from terminal alkynes and with N-halosuccinimides (halo ¼ Br NBP (N-bromophthalimide) activated by DBU via a halogen
and I) or N-cholorophthalimide as the halogen sources, DBU as the bond interaction can be used as an efficient aminating
activator, 1-haloalkynes were prepared in good to excellent yields at reagent7a–c or bromoamination reagent.7d Herein, we would like
room temperature. Bis(bromoalkyne) and bis(iodoalkyne) were also to communicate that DBU-activated NXS (X ¼ Br or I) or NCP
synthesized in excellent yields with the NBS(NIS)/DBU combination. can be used as a straightforward and efficient halogenating
The reaction features inexpensive and readily available reagents, mild reagent in the conversion of terminal alkynes into 1-haloalkynes
conditions, simple execution, extremely short reaction time, broad under very mild conditions (Scheme 2).
halogen scope, high efficiency and is metal-free. Compared to the
Our initial experiment was carried out with 1-chloro-4-ethynyl-
literature reported methods, our synthetic strategy provided a greener benzene (1a), NBS (1.1 equiv.), and DBU (1.1 equiv.) in MeCN
approach towards 1-haloalkynes.
(2.0 mL) at room temperature (Table 1). The reaction proceeded
rapidly and aer 1 min (monitored by TLC), 1-(bromoethynyl)-4-
chlorobenzene (2a) was produced in 99% isolated yield (Table 1,
entry 1). Other solvents tested include DCM, DMF, toluene and
THF (Table 1, entry 2–5). DCM and DMF gave similar to or
slightly lower yield, but the yield of 2a in toluene and THF was
much lower than that in MeCN. Similar to DBU, DBN can also
be used to produce 2a in 95% yield (Table 1, entry 6). Other
bases like NEt3 and DABCO proved to be less efficient (Table 1,
entries 7 and 8). Upon replacing NBS by NBP, the reaction
proceeded well, furnishing product 2a in a comparable yield
(Table 1, entry 9). Catalytic amount of DBU (0.2 equiv.) was also
tried and product 2a could be obtained in 93% yield, with
Haloalkynes are both versatile intermediates in organic
synthesis1 and important building blocks in material and
polymer sciences.2 Classical approaches for the synthesis of 1-
haloalkynes up to now include halogenation of metal acetylides
(path a, Scheme 1),3 halogenations of propiolic acid/trialkylsilyl
acetylenes/alkynyltriuoroborates (path b, Scheme 1),4 oxidative
halogenation of terminal alkynes (path c, Scheme 1),5 and
dehydrohalogenation of 1,1-dihaloalkenes (path d, Scheme 1).6
Among all the methods described above, path c, i.e., the prep-
aration of 1-haloalkynes directly from terminal alkyne
substrates are highly desirable. In this regard, the utilization of
AuPtBu3/NBS,5a AgF/NBS,5b AgNO3/NBS,5c,d n-BuLi/X2,5e–g n-BuLi/
NCS or NBS,5h,I DBU/CCl3Br,5j PPh3/CBr4,5k and KOH/CBr4
(ref. 5l) have been reported. However, some of these methods
may suffer from hazardous reagents, harsh reaction conditions,
or generation of wastes that bring about environmental prob-
lems. Although considerable progress has been made, the
development of new and efficient and environmentally benign
protocols is still required.
In our research on halogen-mediated organic trans-
formations,7 we discovered that NBS (N-bromosuccinimide) or
aDepartment of Chemistry, Northeast Normal University, Changchun 130024, China.
E-mail: liangfs112@nenu.edu.cn; Fax: +86-431-85090759; Tel: +86-431-85099759
bFaculty of Chemistry, Yanbian University, Yanji 133002, China
† Electronic supplementary Information (ESI) available: Experimental details and
characterization for all new compounds. See DOI: 10.1039/c4ra04736b
Scheme 1 Approaches toward 1-haloalkynes.
30046 | RSC Adv., 2014, 4, 30046–30049
This journal is © The Royal Society of Chemistry 2014

View Article Online
Communication
RSC Advances
Table 2 Synthesis of 1-bromoalkynes: scope of terminal alkynesa,b
Scheme 2 This work.
Table 1 Optimization of the reaction conditionsa
Entry NBS(P) Activator (equiv.) Solvent Time (min) Yieldb (%)
1
2
3
4
5
6
7
8
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBP
NBS
NBS
DBU (1.1)
DBU (1.1)
DBU (1.1)
DBU (1.1)
DBU (1.1)
DBN (1.1)
DABCO (1.1)
NEt3 (1.1)
DBU (1.1)
DBU (0.2)
—
MeCN
DCM
DMF
Toluene
THF
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
1
5
5
99
98
94
60
51
95
Trace
20
10
10
15
30
30
25
240
30
9
10
11
96
93c
n.r.
a
Reactions were carried out with 1a (1.0 mmol), NBS(P) (1.1 equiv.) and
the activator in 2.0 mL solvent at rt. b Isolated yield. c Performed at 0 ꢀC.
a
Reactions were carried out with 1a (1.0 mmol), NBS (1.1 equiv.), DBU
b
(1.1 equiv.) in 2.0 mL MeCN at rt. Isolated yield.
prolonged reaction time (240 min) (Table 1, entry 10). By
contrast, in the absence of DBU, the reaction could not occur at
all, with starting material 1a quantitatively recoverable (Table 1,
entry 11).
With the optimized conditions in hand (Table 1, entry 1), we
explored the scope of terminal alkynes in the bromination
reaction (Table 2). A variety of 1-bromoalkynes were prepared in
good to excellent yields. The substituents on the alkyne
substrates may be aryls including either electron-withdrawing
groups (2a–c) or electron-donating substituents (2e–h), hetero-
aryls such as 2-thienyl (2i), and alkysl groups (2j–k). For
conjugated enyne substrate, the ethynylic bond is more reactive
than the C–C double bond, giving rise to product 2l in 92%
yield.
Next, we wish to synthesize 1-haloalkynes containing other
halogen atoms like chlorine and iodine. Thus, the reactions of
alkynes with N-halosuccinimides were conducted (Scheme 3).
Reactions of terminal alkynes with N-iodosuccinimide (NIS)
proceeded smoothly, giving the desired products 3a–c in high to
excellent yields. However, treatment of 1a with N-chlor-
osuccinimide (NCS) under otherwise identical conditions gave
no reaction. When N-chlorophthalimide (NCP) was employed,
the reactions could proceed efficiently, and corresponding 1-
Scheme 3 Synthesis of 1-iodo(chloro)alkynes.
Considering that bis(haloalkyne)s are quite important
chloroalkynes 4a–c were isolated in 81–86% yields. We can not building block, we tried to synthesize such type of compounds
elucidate the different reactivity exhibited by NCS and NCP in using the strategy developed herein. To our delight, under the
the explored chlorination reactions at the current stage.
conditions of NBS or NIS (3.2 equiv.)/DBU (3.2 equiv.), 1,4-
bis(bromoethynyl)benzene (5) and 1,4-bis(iodoethynyl)benzene
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 30046–30049 | 30047

View Article Online
RSC Advances
Communication
halosuccinimide(phthalimide) by DBU to be a highly electro-
philic bromine, and subsequent deprotonative halogenation of
terminal alkynes. The reaction has distinct advantages of inex-
pensive and readily available reagents, mild conditions, simple
execution, short reaction time, broad halogen scope, high effi-
ciency and metal-free. Compared to literature reported
methods, our synthetic strategy provided a greener approach
towards 1-haloalkynes. Further work on halogen-mediated
organic reactions is ongoing in our laboratory.
Scheme 4 Synthesis of bis(haloalkyne)s.
Acknowledgements
Financial support from the National Natural Science Founda-
tion of China (21172034 and 21372039), Program for New
Century Excellent Talents in University (NCET-11-0611), and
Open Project of State Key Laboratory of Supramolecular Struc-
ture and Materials (sklssm201406), is gratefully acknowledged.
Notes and references
1 (a) Z. Chen, H. Jiang, Y. Li and C. Qi, Chem. Commun., 2010,
46, 8049; (b) A. Tromov, N. Chernyak and V. Gevorgyan, J.
Am. Chem. Soc., 2008, 130, 13538; (c) K. Okamoto,
M. Watanabe, N. Sakata, M. Murai and K. Ohe, Org. Lett.,
2013, 15, 5810; (d) G. Pelletier, S. Lie, J. J. Mousseau and
A. B. Charette, Org. Lett., 2012, 14, 5464.
Scheme 5 Possible mechanism.
2 (a) L. Luo, C. Wilhelm, A. Sun, C. P. Grey, J. W. Lauher and
N. S. Goroff, J. Am. Chem. Soc., 2008, 130, 7702; (b) A. Sun,
J. W. Lauher and N. S. Goroff, Science, 2006, 312, 1030; (c)
M. D. Shair, T. Yoon and J. S. Danishefsky, J. Org. Chem.,
1994, 59, 3755.
Scheme 6 Multigram scale preparation of 1-bromophenylacetylene
(2a).
3 (a) Z. Wang, S. Campagna, K. Yang, G. Xu, M. E. Pierce,
J. M. Fortunak and P. N. Confalone, J. Org. Chem., 2000, 65,
1889; (b) I. J. Blackmore, A. N. Boa, E. J. Murray, M. Dennis
and S. Woodward, Tetrahedron Lett., 1999, 40, 6671; (c)
G. J. Hollingworth, A. M. E. Richecoeur and J. Sweeney, J.
Chem. Soc., Perkin Trans. 1, 1996, 2833.
4 (a) D. Naskar and S. Roy, J. Org. Chem., 1999, 64, 6896; (b)
J. Das and S. Roy, J. Org. Chem., 2002, 67, 7861; (c)
T. Nishikawa, S. Shibuya, S. Hosokawa and M. Isobe,
Synlett, 1994, 485; (d) T. Lee, H. Kang, S. Kim and S. Kim,
Tetrahedron, 2006, 62, 4081; (e) G. W. Kabalka and
A. R. Mereddy, Tetrahedron Lett., 2004, 45, 1417; (f)
K. W. Kabalka and A. R. Mereddy, Organometallics, 2004, 23,
4519.
(6) were successfully prepared in excellent yields of 93% and
95% yields, respectively (Scheme 4).
On the basis of the results described above, along with
previous study by others5a,b and us7a–d, a possible mechanism for
the halogenation of the terminal alkynes was proposed in
Scheme 5. Initially, a highly electrophilic bromine species I is
supposed to generate from the 1 : 1 NBS/DBU halogen bond
adduct.8 Then, the bromine species I reacts with alkyne 1 to
form a p-coordinated complex II. Finally, alkynyl halides would
be produced via deprotonation of terminal alkynes by DBU,
along with succinimide or phthalimide side-product.9
To demonstrate the practicality of this halogenation reaction
of alkynes, we carried out the reaction on a gram scale
(Scheme 6). Reaction of 1.3658 g (10 mmol) of 1-chloro-4-ethy-
nylbenzene (1a) with NBS (1.1 equiv.)/DBU (1.1 equiv.) in
acetonitrile at room temperature gave 2a (2.01 g) in 94% iso-
lated yield.
´
´
5 (a) A. Leyva-Perez, P. Rubio-Marques, S. S. Al-Deyab, S. I. Al-
Resayes and A. Corma, ACS Catal., 2011, 1, 601; (b) Y. Li,
X. Liu, D. Ma, B. Liu and H. Jiang, Adv. Synth. Catal., 2012,
354, 2683; (c) M. S. Reddy, Y. K. Kumar and N. Thirupathi,
Org. Lett., 2012, 14, 824; (d) K. Villeneuve, N. Riddell,
R. W. Jordan, G. Tsui and W. Tam, Angew. Chem., Int. Ed.,
2004, 43, 610; (e) E. Kloster-Jensen, Tetrahedron, 1966, 22,
965; (f) T. Mandai, T. Matsumoto, M. Kawada and J. Tsuji, J.
Org. Chem., 1992, 57, 6090; (g) J. A. Luithle and
J. Pietruszka, Eur. J. Org. Chem., 2000, 2557; (h) E. J. Corey
and T. Ravindranathan, J. Am. Chem. Soc., 1972, 94, 4013; (i)
W. Werboom, H. Westmijze, L. J. Notten, P. Vermeer and
Conclusions
In summary, a simple, novel and efficient halogenation of
terminal alkynes has been developed by using DBU-activated N-
halosuccinimide(phthalimide) as the halogen sources. The
reaction mechanism involves the activation of N-
30048 | RSC Adv., 2014, 4, 30046–30049
This journal is © The Royal Society of Chemistry 2014

View Article Online
Communication
RSC Advances
H. J. T. Bos, Synthesis, 1979, 296; (j) Y. Hori, Y. Nagano,
H. Uchiyama, Y. Hamada and H. Taniguchi, Chem. Lett.,
1978, 73; (k) E. Abele, K. Rubina, R. Abele, A. Gaukhman
and E. Lukevics, J. Chem. Res., 1998, 618; (l) A. Wagner,
M. P. Heitz and C. Mioskowski, Tetrahedron Lett., 1990, 31,
3141; (m) T. Mandai, T. Matsumoto, M. Kawada and
5186; (d) M. Li, H. Yuan, B. Zhao, F. Liang and J. Zhang,
Chem. Commun., 2014, 50, 2360; (e) Y. Wei, S. Lin, J. Zhang,
Z. Niu, Q. Fu and F. Liang, Chem. Commun., 2011, 47,
12394; (f) Y. Wei, S. Lin, H. Xue, F. Liang and B. Zhao, Org.
Lett., 2012, 14, 712; (g) H. Xue, H. Tan, D. Wei, Y. Wei,
S. Lin, F. Liang and B. Zhao, RSC Adv., 2013, 3, 5382.
J. Tsuji, J. Org. Chem., 1992, 57, 6090; (n) J. Yan, J. Li and 8 Examples for the formation of halogen bond complexes: (a)
´
I. Castellote, M. Moron, C. Burgos, J. Alvarez-Builla,
D. Cheng, Synlett, 2007, 2442; (o) K. R. Reddy,
M. Venkateshwar, C. U. Maheswari and P. S. Kumar,
Tetrahedron Lett., 2010, 51, 2170; (p) I. Nishiguchi,
O. Kanbe, K. Itoh and H. Maekawa, Synlett, 2000, 89.
6 (a) P. Michel, D. Gennet and A. Rassat, Tetrahedron Lett., 1999,
40, 8575; (b) M. Okutani and Y. Mori, J. Org. Chem., 2009, 74,
442; (c) E. J. Corey and P. L. Fuchs, Tetrahedron Lett., 1972, 36,
´
A. Martin, P. Gomez-Sal and J. J. Vaquero, Chem. Commun.,
2007, 1281; (b) E. H. Crowston, A. M. Lobo, S. Prabhakar,
H. S. Rzepa and D. J. Williams, Chem. Commun., 1984, 276;
(c) K. Raatikainen and K. Rissanen, Chem. Sci., 2012, 3,
1235; (d) Y.-M. Wang, J. Wu, C. Hoong, V. Rauniyar and
F. D. Toste, J. Am. Chem. Soc., 2012, 134, 12928.
3769; (d) V. Ratovelomanana, Y. Rollin, C. Gebehenne, 9 Upon activation by cationic bromine, we think the
C. Gosmini and J. Perichon, Tetrahedron Lett., 1994, 35, 4777.
7 (a) Y. Wei, S. Lin and F. Liang, Org. Lett., 2012, 14, 4202; (b)
Y. Wei, S. Lin, F. Liang and J. Zhang, Org. Lett., 2013, 15,
852; (c) Y. Wei, F. Liang and X. Zhang, Org. Lett., 2013, 15,
deprotonation of terminal alkynes (the pKa of terminal
alkynes is around 29) by DBU (pKa of DBU ¼ 12) may be
feasible. See: F. G. Bordwell, Acc. Chem. Res., 1988, 21, 456.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 30046–30049 | 30049