Terminal alkynes from aldehydes via dehydrohalogenation of (Z)-1-iodo-1-alkenes with TBAF

Article abstract of DOI:10.1016/j.tetlet.2008.09.060

Terminal alkynes were prepared in near quantitative yields via dehydrohalogenation of (Z)-1-iodo-1-alkenes with tetrabutylammonium fluoride (TBAF) under mild conditions. The methodology was expanded to include a one-pot, direct synthesis of terminal alkynes from aldehydes without the necessity of isolating and purifying the intermediate iodoalkene.

Full text of DOI:10.1016/j.tetlet.2008.09.060

Tetrahedron Letters 49 (2008) 6794–6796
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Terminal alkynes from aldehydes via dehydrohalogenation
of (Z)-1-iodo-1-alkenes with TBAF
*
Mira Beshai, Bhartesh Dhudshia, Ryan Mills, Avinash N. Thadani
Department of Chemistry and Biochemistry, University of Windsor, 401 Sunset Avenue, Windsor, Ontario, Canada N9B 3P4
a r t i c l e i n f o
a b s t r a c t
Article history:
Terminal alkynes were prepared in near quantitative yields via dehydrohalogenation of (Z)-1-iodo-1-
alkenes with tetrabutylammonium fluoride (TBAF) under mild conditions. The methodology was
expanded to include a one-pot, direct synthesis of terminal alkynes from aldehydes without the necessity
of isolating and purifying the intermediate iodoalkene.
Received 2 September 2008
Accepted 10 September 2008
Available online 15 September 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Alkynes
Iodoalkenes
Dehydrohalogenation
TBAF
The carbon–carbon triple bond is an important and versatile
functional group in organic chemistry. Alkynes are present in
numerous important products that have application in biological,
medicinal, and materials chemistry.1 Consequently, a variety of
protocols have been developed to synthesize alkynes,2 including
the widely used Corey–Fuchs reaction3,4 and the Seyferth–Gilbert
homologation.5
During the course of an alkaloid synthesis program, we encoun-
tered an unanticipated side reaction during a routine deprotection
of a silyl ether using tetrabutylammonium fluoride (TBAF, 5). In
addition to the removal of the silyl protecting group, we observed
a facile dehydrohalogenation of an appended (Z)-1-iodo-1-alkene
that resulted in the formation of the corresponding terminal alkyne
(Scheme 1). The dehydrohalogenation of 1-halo-1-alkenes has
been employed as a deliberate strategy in several natural product
syntheses albeit with strong/harsh bases,6–8 and is thus ripe for
further improvement.
A search in the literature revealed that Naso and Ronzini had
previously disclosed the dehydrohalogenation of a (Z)-1-bromo-
1-alkene (Scheme 1, 4: R = p-NO2C6H4) using tetraethylammonium
fluoride.9 Recently, Okutani and Mori have also reported the dehy-
drobromination of 2-bromo-1-alkenes using TBAF.10 Inspired by
both these precedents, we aimed to explore in more detail the
dehydrohalogenation of (Z)-1-iodo-1-alkenes (3) with particular
emphasis on expanding the substrate scope and developing an
alternate direct, one-pot route to terminal alkynes from aldehydes
via 3 (Scheme 1).
We initially investigated the parameters of the methodology
using 3a as the test substrate (Table 1, vide infra). First, the (Z)-
1-iodo-1-alkenes (3) were selected as test substrates because the
corresponding (Z)-1-bromo-1-alkenes (4) could not be reliably
synthesized with high diastereoselectivities using phosphorane
2b (Scheme 1).11,12 In contrast, 3 could be readily synthesized in
good yields (90–72%, see Supplementary data) and high diastere-
oselectivities [dr = P93:7 (Z:E)] using Stork’s procedure with phos-
phorane 2a.13 The high (Z)-selectivity is essential because the
subsequent dehydrohalogenation reaction with TBAF (5) requires
the anti-relationship of the hydrogen and halogen atoms (i.e., (E)-
1-halo-1-alkene are unreactive in the presence of TBAF).9,12
With 3a in hand, we initiated optimization studies as shown in
Table 1. The reaction parameters that were varied included the
solvent, stoichiometry, and temperature, full details of which are
included in Supplementary data. Prior reports on the dehydrohalo-
genation of 1-halo-1-alkenes utilized much stronger and poten-
tially harsher bases such as nBuLi, LDA, and KOtBu.7,8 We,
Ph3P CHX
2a: X = I
nBu4N+ F— (5)
2b: X = Br
O
R
R
X
THF, 2
R
H
THF
-78 °C to rt
1
3: X = I
6
4: X = Br
Scheme 1. Formation of (Z)-1-halo-1-alkenes (3,4) and subsequent TBAF (5)-
mediated dehydrohalogenation to form terminal alkynes (6).
* Corresponding author. Tel.: +1 519 253 3000x3556; fax: +1 519 973 7098.
E-mail address: athadani@uwindsor.ca (A. N. Thadani).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.060

M. Beshai et al. / Tetrahedron Letters 49 (2008) 6794–6796
6795
Table 1
aromatic halogens (entry 4), and trifluoromethyl groups (entry
6). In addition, heteroaromatic groups such as pyridine (entries 9
and 10) did not pose a problem under the standard reaction condi-
tions. We could not, however, generate enynes in high yields from
the corresponding (Z)-1-iodo-1,2-diene due to decomposition of
the starting materials under the standard reaction conditions.
Aliphatic variants of 3 (Table 2, entries 11 and 12) did react with
TBAF (5), albeit in a sluggish manner. Consequently, the reaction
temperature had to be elevated to 80 °C, and the reaction time
had to be lengthened to 12 h in order to obtain satisfactory isolated
yields of the resulting alkynes (entries 11 and 12).15
After establishing the validity of synthesizing terminal alkynes
via TBAF-mediated dehydrohalogenation of (Z)-1-iodo-1-alkenes
(3), we next sought to investigate the possibility of developing a
one-pot variant of preparing terminal alkynes directly from alde-
hydes without the necessity of isolating 3.12 The outcome of these
studies is summarized in Table 3 (vide infra). The results show that
it is indeed not necessary to isolate the intermediate (Z)-1-iodo-1-
alkenes (3). After the initial Wittig olefination of aldehyde 1 with
phosphorane 2a, nBu4N+ FÀ (TBAF, 5, 2.5 equiv) was directly added
to the crude reaction mixture.16 The entire reaction mixture was
then heated at 60 °C for 6 h (80 °C for 12 h for aliphatic aldehydes
1s and 1t). A variety of terminal alkynes (6) were thus synthesized
in isolated yields ranging from 86% to 73% (Table 3, average of two
runs).17
The overall yield of this two-step, one-pot reaction is limited by
initial lower yielding Wittig olefination with phosphorane 2a
rather than the subsequent near quantitative yielding dehydro-
halogenation step. A comparison of this newly developed one-pot
methodology to the earlier developed procedure shows that the
overall isolated yields, from the corresponding aldehyde, are com-
parable (e.g., for 6a the overall isolated yields was 81% and 79% for
the one-pot and two-pot protocols, respectively).18 We did not
observe any difference in the two procedures in terms of substrate
scope or functional group tolerance. The advantages of the one-pot
methodology, however, are the omission of a work-up step, and
subsequent chromatographic purification with attended savings
in time and materials.
Optimization studies for the formation of terminal alkyne 6a from (Z)-1-iodo-1-
alkene 3a
nBu4N+ F— (5)
solvent, 2
MeO
MeO
I
3a
Solvent
6a
Entry
Temperature (°C)a
TBAF (equiv)
Yieldb (%)
1
2
3
4
5
6
7
8
THF
THF
THF
THF
20
60
80
60
60
60
60
60
1.5
1.5
1.5
1.0
2.0
1.5
1.5
1.5
22
96
96
82
97
94
85
19
THF
DME
DMF
PhCH3
a
Reactions were conducted in a sealed tube.
Isolated yield (average of two runs).
b
however, settled on tetrabutylammonium fluoride (TBAF, 5) as the
base of choice for the dehydrohalogenation reaction due to two
factors: (i) it is a much milder base with greater functional group
tolerance; and (ii) its tolerance to moisture and oxygen.9,10
The results in Table 1 show that the elimination reaction is pro-
moted at slightly elevated temperatures (entries 1–3), in polar,
aprotic solvents (entries 2, 6–8), and that TBAF (5) is required in
excess (entries 2, 4, and 5). The reaction conditions that were sub-
sequently employed for all subsequent reactions were as follows: 3
(1 equiv), nBu4N+ FÀ (1.5 equiv), THF, 60 °C, 6 h.14 The scope of the
reaction is then evaluated by examining other (Z)-1-iodo-1-
alkenes (3) under the reaction conditions listed above, as listed
in Table 2. It should be noted that the dehydrohalogenation
reactions were carried out under ambient atmospheric conditions
without undue regard to oxygen or moisture, which is a direct
benefit of using a mild and tolerant base such as TBAF (5).
The results in Table 2 indicate that a variety of aromatic (entries
1–8) and heteroaromatic (entries 9, 10) (Z)-1-iodo-1-alkenes (3)
successfully underwent the dehydrohalogenation reaction with
nBu4N+ FÀ to afford the corresponding terminal alkynes (6) in uni-
formly high isolated yields ranging from 98% to 81% (average of
two runs). The reaction methodology was tolerant of several
functional groups such as the nitro (entry 2), carbonyl (entry 3),
Table 3
One-pot direct synthesis of terminal alkynes from aldehydes
(i) Ph3P=CHI (2a, 1.1 equiv.)
THF, -78 °C to rt
O
R
R
H
(ii) nBu4N+ F— (5, 2.5 equiv.)
Table 2
1
6
Dehydrohalogenation of (Z)-1-iodo-1-alkenes (3) with TBAF (5)
60 °C, 6 h
nBu4N+ F— (5, 1.5 equiv.)
Entry
R
Yielda (%)
R
1
2
3
4
5
6
7
8
9
2-MeOC6H4 (1a)
2-NO2C6H4 (1b)
4-CH3C(O)C6H4 (1c)
3,5-(CF3)2C6H3 (1f)
1-Naphthyl (1g)
3-Pyridyl (1j)
4-CNC6H4 (1m)
2,4-F2C6H3 (1n)
4-MeO-2-MeC6H3 (1o)
4-PhC6H4 (1p)
81 (6a)
80 (6b)
83 (6c)
77 (6f)
80 (6g)
74 (6j)
80 (6m)
81 (6n)
77 (6o)
86 (6p)
R
I
THF, 60 °C, 6 h
3
6
Entry
R
Yielda,b (%)
1
2
3
4
5
6
7
8
9
2-MeOC6H4 (3a)
2-NO2C6H4 (3b)
4-CH3C(O)C6H4 (3c)
4-BrC6H4 (3d)
4-Me2NC6H4 (3e)
3,5-(CF3)2C6H3 (3f)
1-Naphthyl (3g)
2-Naphthyl (3h)
2-Pyridyl (3i)
96 (6a)
95 (6b)
94 (6c)
92 (6d)
98 (6e)
93 (6f)
92 (6g)
92 (6h)
88 (6i)
91 (6j)
87 (6k)c
81 (6l)c
10
11
(1q)
78 (6q)
N
N
Me
12
13
14
3-Thienyl (1r)
PhCH2CH2 (1s)
CH3CH2CH2CH2CH(OTBS) (1t)
75 (6r)
10
11
12
3-Pyridyl (3j)
Cyclohexyl (3k)
C7H15 (3l)
73 (6s)b
78 (6t)b,c
a
a
Isolated yield (average of two runs).
Reaction conducted at 80 °C for 12 h.
3.5 equiv of nBu4N+ FÀ was used.
Isolated yield (average of two runs).
Reactions were conducted in a sealed tube.
Reaction conducted at 80 °C for 12 h.
b
c
b
c

6796
M. Beshai et al. / Tetrahedron Letters 49 (2008) 6794–6796
8. For other selected applications of dehydrohalogenations of 1-halo-1-alkenes in
In conclusion, we have demonstrated that a variety of terminal
synthesis, see: (a) Pianetti, P.; Rollin, P.; Pougny, J. R. Tetrahedron Lett. 1986, 27,
5853–5856; (b) Viger, A.; Coustal, S.; Perard, S.; Marquet, A. Tetrahedron 1988,
44, 1127–1134; (c) Ekhato, I. V.; Robinson, C. H. J. Org. Chem. 1989, 54, 1327–
1331; (d) Ito, T.; Okamoto, S.; Sato, F. Tetrahedron Lett. 1989, 30, 7083–7086; (e)
Frye, L. L.; Robinson, C. H. J. Org. Chem. 1990, 55, 1579–1584; (f) Ottow, E.;
Rohde, R.; Schwede, W.; Wiechert, R. Tetrahedron Lett. 1993, 34, 5253–5256; (g)
Napolitano, E.; Fiaschi, R.; Carlson, K. E.; Katzenellenbogen, J. A. J. Med. Chem.
1995, 38, 2774–2779; (h) Tobe, Y.; Kubota, K.; Naemura, K. J. Org. Chem. 1997,
62, 3430–3431; (i) Arnold, D. P.; Hartnell, R. D. Tetrahedron 2001, 57, 1335–
1345; (j) Rodríguez, J. G.; Martín-Villamil, R.; Lafuente, A. Tetrahedron 2003, 59,
1021–1032.
alkynes can be readily synthesized in high yields via dehydrohalo-
genation of the corresponding 1-iodo-1-alkenes using a mild and
tolerant base, tetrabutylammonium fluoride. In addition, the one-
pot direct synthesis of terminal alkynes from aldehydes, without
the necessity of isolating the intermediate iodoalkene, was also
presented. The broad substrate scope and functional group toler-
ance of this reaction methodology make it an attractive addition
to the current repertoire of routes to synthesize terminal alkynes
from aldehydes.
9. Naso, F.; Ronzini, L. J. Chem. Soc., Perkin Trans. 1 1974, 340–343.
10. Okutani, M.; Mori, Y. Tetrahedron Lett. 2007, 48, 6856–6859.
11. For example, in our hands, the reaction of aldehyde 1a with phosphorane 2b
afforded a 75:25 (Z:E) mixture of the corresponding 1-bromo-1-alkene under
otherwise identical conditions.
Acknowledgments
12. For a one-pot synthesis of terminal alkynes from aldehydes using phosphorane
2b and KOtBu, see: Matsumoto, M.; Kuroda, K. Tetrahedron Lett. 1980, 21, 4021–
4024.
The National Science and Engineering Research Council (NSERC)
of Canada and Kanata Chemical Technologies Inc. are thanked for
their generous financial support.
13. Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173–2174.
14. General procedure for the dehydrohalogenation of (Z)-1-iodo-1-alkenes (3) with
TBAF (Table 2): To a solution of the (Z)-1-iodo-1-alkene (3) (0.500 mmol) in
anhydrous THF (0.75 mL) in a SwagelockÒ 50 mL stainless steel cylinder or an
AceÒ pressure tube was added a solution of TBAF (1.0 M in THF, 0.75 mL,
0.75 mmol) dropwise. The cylinder (or tube) was sealed and heated in an oil
bath at 60 °C or 80 °C (for 3k and 3l) for 6 h or 12 h (for 3k and 3l), respectively.
The cylinder (or tube) was then removed and allowed to cool to rt. The
SwagelockÒ cylinder (or pressure tube) was opened, and the contents were
transferred to a small round bottom flask. All the volatiles were removed in
vacuo and the crude product was purified by silica gel chromatography
(gradient, hexanes/EtOAc, 100:0/80:20). Note: The dehydro-halogenation
reaction of aliphatic (Z)-1-iodo-1-alkene 3k and 3l was carried on a 5 mmol
scale. The resulting aliphatic alkynes (6k and 6l) were isolated by fractional
distillation from the crude reaction mixture. See Supplementary data for full
details including complete characterization data.
Supplementary data
Supplementary data (complete experimental details, character-
ization data, and copies of NMR spectra (1H and 13C) of 3 and 6)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2008.09.060.
References and notes
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15. For a prior example on the dehydrohalogenation of a (Z)-1-chloro-1-alkene
with TBAF, see: Bowling, N. P.; Halter, R. J.; Hodges, J. A.; Seburg, R. A.; Thomas,
P. S.; Simmons, C. S.; Stanton, J. F.; McMahon, R. J. J. Am. Chem. Soc. 2006, 128,
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16. We found it necessary to increase the equivalence of nBu4N+ FÀ (TBAF) from 1.5
to 2.5 in order to obtain satisfactory isolated yields of the terminal alkynes (6).
Also note that we observed the addition of HMPA as cosolvent during the
formation of the (Z)-1-iodo-1-alkene caused a decrease in the isolated yield of
the terminal alkyne (6), and was thus omitted in the one-pot protocol.
17. General procedure for the one-pot direct synthesis of terminal alkynes from
aldehydes (Table 3): To a suspension of iodomethyltriphenylphosphonium
iodide (584 mg, 1.10 mmol) in THF (1.5 mL) was added NaHMDS (1M in THF,
1.10 mL, 1.10 mmol) dropwise. The mixture was allowed to stir at rt for
10 min. The resulting red solution that formed was cooled to À78 °C, and a
solution of the aldehyde (1.00 mmol) in THF (1.0 mL) was slowly added
dropwise. The reaction mixture was allowed to stir for 2.5 h while warming to
rt. TBAF (1.0 M in THF, 2.50 mL, 2.50 mmol) was then added dropwise. The
reaction mixture was subsequently heated to 60 °C or 80 °C for 6 h or 12 h,
respectively. After cooling to rt, all volatiles were removed in vacuo. Hexanes
(3 Â 10 mL) was then added, and the mixture was filtered through CeliteÒ. The
filtrate was concentrated in vacuo and the residue was purified by silica gel
chromatography (gradient, hexanes/EtOAc from 100:0 to 80:20) to afford
terminal alkyne 6. Note: The reaction of aldehyde 1r was carried out on a
5 mmol scale. Alkyne 6r was isolated by Kugelrohr distillation from the crude
reaction mixture after removal of the solvent under atmospheric pressure. See
Supplementary data for full details including complete characterization data.
18. (Z)-1-iodo-1-alkene 3a was prepared in 82% isolated yield (see Supplementary
data).
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