Alkylation of 1-alkynes in THF

Article abstract of DOI:10.1016/S0040-4039(01)01131-5

Alkynes may be easily alkylated by sequential treatment with n-BuLi followed by an alkyl halide in THF. Primary iodides give excellent yields (75-99%) as do bromides in the presence of catalytic amounts of Bu₄NI or NaI; in the absence of an iodide source, bromides react poorly. This method offers advantages over existing methods which use HMPA or NH₃ as co-solvents.

Full text of DOI:10.1016/S0040-4039(01)01131-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5825–5827
Alkylation of 1-alkynes in THF
Matthew Buck and J. Michael Chong*
Department of Chemistry, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1
Received 22 May 2001; accepted 18 June 2001
Abstract—Alkynes may be easily alkylated by sequential treatment with n-BuLi followed by an alkyl halide in THF. Primary
iodides give excellent yields (75–99%) as do bromides in the presence of catalytic amounts of Bu4NI or NaI; in the absence of an
iodide source, bromides react poorly. This method offers advantages over existing methods which use HMPA or NH3 as
co-solvents. © 2001 Elsevier Science Ltd. All rights reserved.
A classic method for the formation of carbonꢀcarbon
bonds is the alkylation of metal acetylides with alkyl
halides.1 Traditionally, this reaction was carried out in
the literature that the range of conditions employed for
alkynylations is related principally to reactivity: with
very reactive carbonyl compounds, reactions occur in
THF at −78°C; with reactive halides, reactions take
place in THF at rt or below. An obvious extension
(which seems not to have been explored) is then to use
THF at elevated temperatures with ‘regular’ alkyl
halides rather than introducing a more polar solvent to
promote the SN2 reaction. Part of the reluctance to use
THF as a solvent with ‘regular’ alkyl halides is likely
due to the observation that alkynyllithiums ‘react slug-
gishly in Et2O or THF with most alkyl halides’.13
Moreover, it has been reported that refluxing dioxane
(which is similar to THF) is a mediocre medium for
these reactions, especially with volatile alkyl halides.4,14
However, with the limitations of the other methods
currently used and the ready availability of dry THF,
we felt that it was worthwhile to re-examine this solvent
for alkynylations.
2
liquid NH3 but problems with acetylide solubility and
variable yields led to the development of alternative
reaction conditions. Particularly noteworthy was the
introduction of hexamethylphosphoramide (HMPA) as
a dipolar aprotic solvent for promoting such SN2 reac-
tions in 1973.3 Since that time, HMPA has been shown
to be a potential health hazard as a carcinogen. Thus,
N,N%-dimethylpropyleneurea (DMPU) was examined as
a safer and comparably efficacious alternative in 1988.4
Such alkylations have also been carried out in
dimethylsulfoxide (DMSO) but, unfortunately, the
acidity of DMSO limits the reaction to relatively acidic
alkynes (e.g. PhCꢁCH, THPOCH2CꢁCH).5 Based on
safety and/or convenience concerns, one might expect
that HMPA and NH3 would not be particularly popu-
lar solvent choices, but a survey of the recent literature
revealed that the vast majority of alkyne alkylations are
carried out using HMPA as a co-solvent6 with NH3
also used regularly7 and DMPU8 used only rarely. We
now report that, under the appropriate conditions, the
ubiquitous solvent THF may be used and virtually any
1-alkyne may be alkylated with excellent results.
Initial studies were carried out using 1-hexyne, which
was readily converted (n-BuLi) to the lithium acetylide.
As expected, alkylations of 1-hexynyllithium (Table 1,
entries 1–7) were very slow at ambient temperatures.
However, simply warming the reaction mixture to
reflux temperatures allowed for complete reaction
within 8 h for primary iodides (entries 1 and 4). Bro-
mides were much slower and gave incomplete reactions,
even after extended periods (entry 2). However, it was
gratifying to discover that the addition of a catalytic
amount of n-Bu4NI (TBAI) or NaI to these reactions
had a dramatic effect: reactions now proceeded to
completion with reaction times only slightly longer than
when iodides are used (entries 3 and 6). The use of an
iodide source (presumably to form small amounts of
more reactive alkyl iodides via Finkelstein reactions) to
In examining the conditions reported for the alkylation
of alkynyllithiums, it became apparent that the use of a
dipolar aprotic solvent or NH3 is not necessary if the
alkyl halide is particularly reactive (e.g. MeI,9 allylic,10
or ROCH2X11). Similarly, alkynyllithiums add to car-
bonyl compounds readily in THF (at low tempera-
tures).12 Thus, it was clear from the results presented in
* Corresponding author. Tel.: 519 888 4567 ext 6643; fax: 519 746
0435; e-mail: jmchong@uwaterloo.ca
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01131-5

5826
M. Buck, J. M. Chong / Tetrahedron Letters 42 (2001) 5825–5827
promote SN2 reactions is well-known, particularly in
ether synthesis.15 However, with a primary chloride
(entry 5), even TBAI did not enhance reactivity suffi-
ciently to provide a good yield of alkylation product.
previously when elevated temperatures (boiling diox-
ane, 100°C) were used with low boiling alkyl halides.4
The successful use of ethyl bromide (bp 40°C) was
unexpected but suggests that alkylations of alkynes in
THF are not limited to high-boiling alkyl halides. In
fact, given that MeI reacts at or below room tempera-
ture, one should be able to introduce essentially any
length of alkyl group using this procedure.
A number of other alkynes were alkylated with bro-
mides and iodides in THF at reflux temperatures (Table
1). In all cases, reactions were very clean with no
detectable (GC–MS and TLC) side products and excel-
lent isolated yields were obtained. Both TBAI and NaI
were equally effective in promoting alkylations with
bromides (entries 12 and 13), an unexpected result
given the limited solubility of NaI in THF. With TBAI,
traces of Bu3N were sometimes detected in crude reac-
tion mixtures (by GC–MS) but did not interfere with
product isolation (since it would be lost during the
aqueous work-up). It is noteworthy that THP ethers,
protecting groups very commonly used in syntheses of
long chain unsaturated pheromones, are tolerated in
both the alkyne and alkyl halide (entry 7, 14–21). A
THP-protected propargyl alcohol (entries 14 and 15)
showed lower reaction rates, likely due to stabilization
of the alkynyllithium by the neighbouring THPO.5
Other THP-protected alkynyl alcohols showed reactivi-
ties comparable to hydrocarbon 1-alkynes.
There are some limitations to this chemistry. For exam-
ple, it seems to be limited to primary halides: no
reaction was observed when 1-hexynyllithium was
treated with 2-iodooctane in refluxing THF for 24 h.
With a homoallylic halide (Table 1, entry 22), consider-
able amounts of starting alkyne were isolated, likely
due to a competing E2 pathway. Nonetheless, the
desired alkylation product 15 was produced in reason-
able yield; this compares very favourably to a compara-
ble reaction using the same halide in HMPA that
afforded a 19% yield of product as a mixture of iso-
mers.3 The only other limitation observed was when the
silyl-protected propargyl alcohol 16 was used (Eq. (1)):
a mixture of products was formed including alkynylsi-
lane 17,16 suggesting that TBS groups are incompatible.
1. n-BuLi, THF
TBSOCH2
16
H
TBSOCH2
TBS
2. R’-X, ∆
Successful alkylations using ethyl iodide (bp 69–73°C,
entries 17 and 19) are significant (but not too surprising
since THF boils at 66°C) given the poor results noted
17
(1)
Table 1. Alkylation of 1-alkynes in THFa
1. n-BuLi, THF
2. R’-X, ∆
R
H
R
R’
Entry
R
R%-X
Additiveb
Time (h)
Product
Yield (%)c
1
2
3
4
5
6
7
8
n-C4H9
n-C4H9
n-C4H9
n-C4H9
n-C4H9
n-C4H9
n-C4H9
t-C4H9
t-C4H9
t-C4H9
Ph
Ph
n-C10H21
n-C10H21Br
n-C10H21Br
I
–
–
8
18
12
9
60
15
16
7
1
1
1
2
3
3
4
5
5
6
7
8
8
9
9
10
11
12
13
13
14
15
75
50d
95
88
52
90
85
86
85
84
99
90
86
89
83
94
91
89
93
92
94
55
TBAI
–
TBAI
NaI
NaI
–
NaI
–
–
TBAI
NaI
–
NaI
–
n-C5H11
I
n-C7H15Cl
n-C7H15Br
THPO(CH2)9Br
n-C10H21
n-C10H21Br
n-C7H15
n-C10H21
I
9
11
7
10
11
12
13
14
15
16
17
18
19
20
21
22
I
I
12
16
16
33
40
11
2
11
2
8
n-C5H11Br
n-C5H11Br
n-C10H21
n-C10H21Br
n-C10H21
EtI
n-C10H21
EtI
EtBr
n-C3H7I
CH2ꢂCHCH2CH2Br
Ph
THPOCH2
THPOCH2
THPO(CH2)2
THPO(CH2)2
THPO(CH2)4
THPO(CH2)4
THPO(CH2)4
THPO(CH2)4
THPO(CH2)4
I
I
I
–
–
–
NaI
–
3
16
NaI
a See text for details.
b 10 mol% TBAI or NaI added.
c Isolated yields of purified products.
d GC yield.

M. Buck, J. M. Chong / Tetrahedron Letters 42 (2001) 5825–5827
5827
Overall, while not universally applicable, this procedure
is operationally very simple, uses common reagents and
solvents, and is very effective. It should be adopted as
the method of choice for many alkyne alkylations.
7. For use of NH3 as solvent/co-solvent, see: (a) Emde, U.;
Koert, U. Eur. J. Org. Chem. 2000, 1889–1904; (b)
Charoenying, P.; Davies, D. H.; Mckerrecher, D.; Taylor,
R. J. K. Tetrahedron Lett. 1996, 37, 1913–1916.
8. DMPU as co-solvent: Morishita, K.; Kamezawa, M.;
Ohtani, T.; Tachibana, H.; Kawase, M.; Kishimoto, M.;
Naoshima, Y. J. Chem. Soc., Perkin Trans. 1 1999,
513–518.
9. Dotz, K. H.; Gerhardt, A. J. Organomet. Chem. 1999,
578, 223–228.
10. Hayashi, N.; Noguchi, H.; Tsuboi, S. Tetrahedron 2000,
56, 7123–7137.
A typical experimental procedure follows: To a cold
(−78°C), stirred solution of 1-alkyne (12 mmol) in THF
(50 mL) was added n-BuLi (1.6 M in hexanes, 11
mmol).17 The solution was allowed to warm to room
temperature before adding alkyl halide (10 mmol along
with 1 mmol of NaI or TBAI for bromides). The
reaction mixture was heated to gentle reflux and stirred
until all of the alkyl halide was consumed (GC or TLC,
8–40 h). The mixture was cooled to 0°C and quenched
with satd NH4Cl. Standard aqueous work-up (ether,
satd NH4Cl) provided crude material, which was >90%
pure (GC) in most cases. Purification was effected by
Kugelrohr distillation or flash chromatography.18
11. Banfi, L.; Guanti, G.; Basso, A. Eur. J. Org. Chem. 2000,
939–946.
12. (a) Lactones: Chabala, J. C.; Vincent, J. E. Tetrahedron
Lett. 1978, 937–940; (b) Lithium acetylide: Midland, M.
J. Org. Chem. 1975, 40, 2250–2252; (c) Propynyllithium:
Suffert, J.; Toussaint, D. J. Org. Chem. 1995, 60, 3550–
3553.
13. Reference 1, p. 39.
14. Warthen, D.; Jacobson, M. J. Med. Chem. 1968, 11,
373–374.
Acknowledgements
15. Czernecki, S.; Georgoulis, C.; Prevelenghiou, C. Tetra-
hedron Lett. 1976, 3535–3536.
16. Bishop, B. C.; Cottrell, I. F.; Hands, D. Synthesis 1997,
1315–1320.
We thank the Natural Sciences and Engineering
Research Council of Canada (NSERC) for financial
support of this research.
17. A slight excess of alkyne was used when it was deemed to
be easily separated from products (e.g. Table 1, entries
1–16); with low-boiling halides (which could be easily
removed by rotoevaporation, e.g. entries 19–22), an
excess (1.5 equiv.) of alkyl halide was used to facilitate
complete consumption of alkyne.
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