Conversion of bromoalkenes into alkynes by wet tetra-n-butylammonium fluoride

Article abstract of DOI:10.1021/jo802101a

(Chemical Equation Presented) Tetra-n-butylammonium fluoride was found to be a mild and efficient base for the elimination reaction of bromoalkenes. Treatment of 1,1-dibromoalkenes, (Z)-1-bromoalkenes, and internal bromoalkenes with 5 equiv of TBAF·3H₂O in DMF yielded terminal and internal alkynes in high yields without undue regard to the presence of water.

Full text of DOI:10.1021/jo802101a

SCHEME 1
Conversion of Bromoalkenes into Alkynes by Wet
Tetra-n-butylammonium Fluoride
Masaru Okutani and Yuji Mori*
Faculty of Pharmacy, Meijo UniVersity, 150 Yagotoyama,
presence of water provides a useful method, because the
commercially available solid TBAF contains 3 mol of water
and a THF solution of TBAF also contains approximately 5%
water. In this paper, we wish to extend the scope of the TBAF-
induced elimination reaction to 1,1-dibromoalkenes, (Z)-1-
bromoalkenes, and internal bromoalkenes as substrates.
Tempaku-ku, Nagoya 468-8503, Japan
mori@ccmfs.meijo-u.ac.jp
ReceiVed September 23, 2008
1-Bromoalkynes are key building blocks for the synthesis of
di- and polyynes5 and N-alkynyl compounds6 by metal-catalyzed
coupling reactions. They are commonly obtained by bromination
7
of terminal alkynes with NBS/AgNO3 or PPh3/CBr4.8 Dehy-
drobromination of 1,1-dibromoalkenes, which can be obtained
by the Ramirez and Corey-Fuchs procedures,9 also provides a
useful method for preparing 1-bromoalkynes. The common
bases employed for dehydrobromination are strong bases such
as DBU,10 t-BuOK,11 LiHMDS,12 and NaHMDS.13 TBAF is
Tetra-n-butylammonium fluoride was found to be a mild and
efficient base for the elimination reaction of bromoalkenes.
Treatment of 1,1-dibromoalkenes, (Z)-1-bromoalkenes, and
internal bromoalkenes with 5 equiv of TBAF ·3H2O in DMF
yielded terminal and internal alkynes in high yields without
undue regard to the presence of water.
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Fleming, I., Eds.; Pergamon Press: Oxford, UK, 1991; Vol. 3, pp 551-561. (b)
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Terminal alkynes are important functional groups, acting as
versatile building blocks and synthetic intermediates in organic
synthesis. Recent progress with transition metal-catalyzed
carbon-carbon coupling reactions such as Sonogashira coupling
reactions, Pauson-Khand reactions, and metatheses has also
proven the importance of terminal acetylenes.1 One of the
methods for the preparation of terminal alkynes is dehydroha-
logenation of haloalkenes with bases such as alkoxides, alkali
hydrides, and alkali metal amides. The disadvantage of these
methods is the need for a very strong base as well as strictly
anhydrous reaction conditions. It is therefore important to
develop a new method that can tolerate moisture or water. In
this context, we have recently reported that tetra-n-butylam-
monium fluoride trihydrate (TBAF·3H2O) induces dehydro-
bromination of 2-bromoalkenes to give the corresponding
terminal acetylenes in high yields (Scheme 1).2
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3772.
This acetylene formation is interesting in that TBAF is a weak
base and that TBAF contains water. The potential ability of a
fluoride anion to act as a base might be predicted by formation
of a strong H-F bond (569 kJ mol-1).3 Since the function of a
fluoride anion depends upon the initial formation of a hydrogen
bond to a reactant molecule, any water present in the reaction
mixture is considered to reduce its effectiveness.4 Therefore,
the elimination reaction by TBAF without undue regard to the
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Borchardt, D. B.; Norman, A. W.; Mueller, L. J. J. Org. Chem. 2002, 67, 1637–
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* Corresponding author. Phone: +81-52-839-2658. Fax: +81-52-834-8090.
(1) Tsuji, J. In Transition Metal Reagents and Catalysts; Tsuji, J., Ed.; John
Wiley & Sons Ltd.: Chichester, UK, 2000.
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1983, 48, 2112–2114. (b) Cox, D. P.; Terpinski, J.; Lawrynowicz, W. J. Org.
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2005, 127, 2050–2051.
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Peterson, A.; Wallberg, A.; Oesterlund, K.; Karis, D.; Boije, M.; Wensbo, D.
Bioorg. Med. Chem. Lett. 2006, 16, 4788–4791. (b) Wong, L. S.-M.; Sharp,
L. A.; Xavier, N. M. C.; Turner, P.; Sherburn, M. S. Org. Lett. 2002, 4, 1955–
1957. (c) Giacobbe, S. A.; Di Fabio, R.; Baraldi, D.; Cugola, A.; Donati, D.
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442 J. Org. Chem. 2009, 74, 442–444
10.1021/jo802101a CCC: $40.75 2009 American Chemical Society
Published on Web 11/13/2008

TABLE 1. Dehydrobromination of 1,1-Dibromoalkenes
TABLE 2. Dehydrobromination of (Z)-1-Bromoalkenes.
SCHEME 2
TBAF in DMF. (Z)-1-Bromoalkenes 3 were prepared by the
Pd-catalyzed stereoselective hydrogenolysis of 1,1-dibromoalk-
enes with Bu3SnH,16 and (E)-1-bromoalkenes 5 were synthe-
sized by the reaction of alkynes with DIBALH followed by
bromine.17 Treatment of (Z)-1-bromoalkenes with TBAF under
the standard reaction conditions yielded the expected products
in high yield after 2 h (Table 2).18 However, (E)-isomers 5
proved difficult to dehydrobrominate and starting materials were
recovered with more than 90% yield after 4 h (Scheme 2). This
result is in sharp contrast to the reaction with strong bases such
as n-BuLi and t-BuOK in which both (E)- and (Z)-1-bromoalk-
enes can be dehydrohalogenated.19 These results suggest that
dehydrobromination of 1,1-dibromoalkenes by TBAF proceeds
via an anti-elimination transition state (Figure 1).
also effective for this purpose, although there have been only a
few examples of its use reported in the literature.14 The reported
elimination reactions utilizing TBAF were all carried out in THF
and required prolonged reaction times, usually 4-48 h, to go
to completion. We therefore examined the TBAF-induced
dehydrobromination in DMF, which would be expected to
accelerate dehydrobromination since the basic properties of the
fluoride ion would increase in polar aprotic solvents.3
Several 1,1-dibromoalkenes were subjected to dehydrobro-
mination by TBAF. When a solution of dibromoalkene 1 and
TBAF·3H2O (5 equiv) in DMF was heated at 60 °C, dehydro-
bromination was completed within 1 h to give bromoacetylenes
2 in high yield (Table 1).15 Comparable experiments of 1a with
5 equiv of commercially available TBAF in THF (1 M solution)
required a more prolonged reaction time (entry 1). Clearly, DMF
is a better solvent in facilitating the dehydrobromination.
To investigate the mechanism of this reaction, we examined
the reactivity of (Z)- and (E)-1-bromoalkenes 3 and 5 toward
We next extended the dehydrobromination by TBAF to
internal bromoalkenes. Although strong bases have convention-
ally been used to eliminate HBr from internal bomoalkenes,20
fluoride-induced dehydobromination would be expected to serve
as a mild procedure in this case. (Z)-Trisubstituted alkenes 6
(16) Uenishi, J.; Kawahama, R.; Yonemitsu, O.; Tsuji, J. J. Org. Chem. 1998,
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(17) Posner, G. H.; Tang, P.-W. J. Org. Chem. 1978, 43, 4131–4136.
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2657. (b) Uwai, K.; Oshima, Y.; Sugihara, T.; Ohta, T. Tetrahedron 1999, 55,
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(15) Dehydrobromination of 1a with 3 equiv of TBAF · 3H2O in DMF was
not complete after 3 h at 60°C. The use of more than 4 equiv of TBAF · 3H2O
is necessary to achieve a complete conversion of 1 to 2.
J. Org. Chem. Vol. 74, No. 1, 2009 443

TABLE 3. Dehydrobromination of Trisubstituted Bromoalkenes
FIGURE 1. Anti-elimination of 1,1-dibromoalkenes.
were synthesized from (Z)-R-bromo-R,ꢀ-unsaturated alde-
hydes,20d,21 involving transformation into the corresponding
R-bromoallyl bromides followed by alkylation with tert-butyl
lithioacetate.22 When bromoalkenes 6 were heated at 60 °C in
DMF in the presence of 5 equiv of TBAF, dehydrobromination
proceeded smoothly to give the corresponding internal alkynes
in high yield (Table 3). We were initially concerned about
concomitant allene formation,20c but an allene was not detected
in any case. The allylic alcohol 6a listed in entry 1 was a special
case that required a much longer reaction time (22 h), while
elimination of HBr in other cases was completed after 2 h.
The low reactivity of 6a could be explained by participation of
the allylic hydroxy group proximate to the olefinic hydrogen to
be abstracted, which could trap the fluoride anion by forming a
hydrogen bond.23 Such a proximate effect of the hydroxy group
was not observed when the hydroxy group was protected with
benzyl and pivaloyl groups (entries 2 and 3). Bis(homoallylic)
alcohols 6e and 6i also dehydrobrominated without trouble since
the hydroxyl group is too remote to trap the fluoride ion entering
the reaction center. The marked difference in reactivity between
6a and other bromoalkenes (6b-i) is a characteristic feature of
fluoride-induced dehydrobromination. The decreased yield of
7c (entry 3) was attributable to partial hydrolysis of the pivaloyl
group of the starting material and the product by hydroxide ion,
which can be present in wet TBAF. The corresponding
bromoallylic alcohol and acetylenic alcohol were isolated in 16%
and 5% yields, respectively.
In conclusion, TBAF was found to be an efficient and mild
base in the dehydrobromination of terminal and internal
bromoalkenes to the corresponding alkynes. The elimination
reaction can be carried out with commercially available
TBAF·3H2O in DMF, and the water tolerance and the absence
of metal salts make this method attractive. This procedure
provides a reasonable alternative to other methods that require
strong bases and anhydrous conditions.
with water and brine, dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography (5% ethyl acetate in hexane) to give 7b (144
mg, 96%) as a colorless oil: IR (CHCl3), 2223, 1496, 1455, 1354,
Experimental Section
1
1070 cm-1; H NMR (400 MHz, CDCl3) δ 0.88 (3H, t, J ) 6.8
Representative Procedure for Dehydrobromination of Bro-
moalkenes. Bromoalkene (6b, 190 mg, 0.5 mmol) was dissolved
in 2.5 mL of DMF. TBAF ·3H2O (0.78 g, 2.5 mmol) was added to
the solution and the reaction mixture was heated at 60 °C for 2 h
(TLC). The reaction mixture was cooled to room temperature and
diluted with diethyl ether (50 mL). The organic phase was washed
Hz), 1.26-1.41 (16H, m), 1.53 (2H. quint, J ) 7.3 Hz), 2.24 (2H,
tt, J ) 7.3, 2.4 Hz), 4.16 (2H, t, J ) 2.4 Hz), 4.58 (2H, s),
7.28-7.37 (5H, m); 13C NMR (100 MHz, CDCl3) δ 14.1, 18.8,
22.7, 28.6, 28.9, 29.1, 29.3, 29.5, 29.6 (2 × C), 31.9, 57.7, 71.3,
75.8, 87.4, 127.7, 128.1 (2 × C), 128.4 (2 × C), 137.7; HREIMS
m/z calcd for C21H32O 300.2453, found 300.2464.
(20) Dehydrobromination of internal bromoalkenes: (a) Ma, Y.; Ramirez,
A.; Singh, K. J.; Keresztes, I.; Collum, D. B. J. Am. Chem. Soc. 2006, 128,
15399–15404. (b) Myers, A. G.; Sogi, M.; Lewis, M. A.; Arvedson, S. P. J.
Org. Chem. 2004, 69, 2516–2525. (c) Guzma´n-Dura´n, A.; Guzma´n, E.; Pannell,
K. H.; Lloyd, W. D. Synth. Commun. 2003, 33, 3271–3283. (d) Lu¨tjens, H.;
Nowotny, S.; Knochel, P. Tetrahedron: Asymmetry 1995, 6, 2675–2678. (e)
Takahashi, A.; Shibasaki, M. J. Org. Chem. 1988, 53, 1227–1231. (f) Nakamura,
T.; Namiki, M.; Ono, K. Chem. Pharm. Bull. 1987, 35, 2635–2645. (g) Schuda,
P. F.; Heimann, M. R. J. Org. Chem. 1982, 47, 2484–2487.
(21) Allen, C. F.; Edens, C. O. In Organic Synthesis; Wiley: New York,
1955; Collect. Vol. III, pp 731-733.
(22) For the preparation of 6a-i, see the Supporting Information.
(23) (a) Clark, J. H.; Miller, J. M. J. Chem. Soc., Perkin 1 1977, 1743–
1745. (b) Ogilvie, K. K.; Beaucage, S. L.; Schifman, A. L.; Theriault, N. Y.;
Sadana, K. L. Can. J. Chem. 1978, 56, 2768–2780.
Acknowledgment. This work was supported by a Grant-in-
Aid for Scientific Research (C) (No. 18590020) from the Japan
Society for the Promotion of Science.
Supporting Information Available: Characterization data
for compounds 2a-f and experimental procedures, characteriza-
tion data, and 1H NMR spectra for compounds 6a-i and 7a-i.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO802101A
444 J. Org. Chem. Vol. 74, No. 1, 2009