On the use of 2-(trimethylsilyl)iodobenzene as a benzyne precursor

Article abstract of DOI:10.1016/j.tetlet.2010.10.052

A mild method for the generation of benzynes from 2-(trimethylsilyl) iodobenzene derivatives is reported. The employment of silver fluoride in conjunction with caesium fluoride is key for promoting useful levels of elimination and providing benzyne derived products in good yields. Moreover, the substrates are accessed by a novel alkynyl iodide cycloaddition.

Full text of DOI:10.1016/j.tetlet.2010.10.052

Tetrahedron Letters 51 (2010) 6608–6610
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Tetrahedron Letters
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On the use of 2-(trimethylsilyl)iodobenzene as a benzyne precursor
⇑
⇑
James A. Crossley, James D. Kirkham, Duncan L. Browne , Joseph P. A. Harrity
Department of Chemistry, University of Sheffield, Sheffield, S3 7HF, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild method for the generation of benzynes from 2-(trimethylsilyl)iodobenzene derivatives is reported.
The employment of silver fluoride in conjunction with caesium fluoride is key for promoting useful levels
of elimination and providing benzyne derived products in good yields. Moreover, the substrates are
accessed by a novel alkynyl iodide cycloaddition.
Received 10 September 2010
Revised 29 September 2010
Accepted 8 October 2010
Available online 16 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Kobayashi’s discovery that 2-(trimethylsilyl)phenyl trifluoro-
methanesulfonate behaves as a competent benzyne precursor in
the presence of a fluoride source has revolutionised the application
of benzynes in organic synthesis.1 This is largely attributable to the
mild conditions under which the benzyne can be unmasked, there-
by allowing substrates and reagents bearing sensitive functionality
to participate in efficient reaction processes.2 However, a poten-
tially limiting factor is associated with this useful precursor.
Although a handful of 2-(trimethylsilyl)phenyl trifluoromethane-
sulfonates are commercially available, if a more complex benzyne
precursor is required the synthesis can become rather lengthy. Typ-
ical preparative routes involve a three-step method consisting of
the treatment of a silylated phenol with a strong base followed by
O–Si bond cleavage and triflation of the resulting phenol. Several
efforts have been made to improve this strategy.3 Moreover, we re-
cently reported an alternative protocol which involves the oxida-
tion and subsequent triflation of a trimethylsilyl alkynylboronate
cycloadduct.4 Herein we report some useful and general conditions
for the in situ generation of benzyne from 2-(trimethylsilyl)iodo-
benzenes; substrates which offer the potential to be obtained in
fewer synthetic steps than their triflate congeners.
In 1973, Cunico reported that 2-(trimethylsilyl)halobenzenes
could be utilised for the generation of benzynes.5 For example, they
found that treatment of 2-(chloro)trimethylsilylbenzene with KOt-
Bu in hexamethylphosphoramide and furan afforded the corre-
sponding cycloadduct in 18% yield. However, products arising
from desilylation were also isolated along with tert-butyl phenyl
ether (18% and 4%, respectively). Similar results were also observed
when the bromo- and iodo-analogues were employed. Since this
pioneering work, these potential precursors have largely been ig-
nored. Given the advances since these investigations, specifically
within the area of mild fluoride sources for the activation of silyl
groups, we decided to reassess this timely problem.
For the purposes of these studies we chose to prepare our ben-
zyne precursors via a novel alkynyl iodide cycloaddition; our re-
sults are depicted in Eqs. 1 and 2. Pleasingly, treatment of methyl
coumalate (1) with trimethylsilyl iodoacetylene (3) afforded the
desired product in excellent yield and as a 2:1 mixture of regioi-
somers. The presence of regioisomers should prove inconsequen-
tial as they were expected to converge to a single benzyne
intermediate. The reaction could also be conducted in a microwave
reactor (200 °C, 2 h) to provide 4 in 87% yield with an identical reg-
ioisomer ratio. Pyranone 2 reacted similarly, whereas substrates 6
and 7 gave marginally improved regioselectivities [Eq. 2; only one
regioisomer was shown for clarity)].6 Notably, this synthesis repre-
sents the first reported cycloaddition of alkynyl iodides with pyra-
nones and extends the utility and potential application of such
alkynes in organic synthesis.7,8
Me3Si
I
R
SiMe3
3
O
R
1,2-C6H4Cl2
reflux, 24 h
O
I
ð1Þ
ð2Þ
R=CO2Me; 1
R=CN; 2
R=CO2Me; 4; 81% (2:1)
R=CN; 5; 68% (2:1)
Me3Si
I
R
O
R
SiMe3
I
3
1,2-C6H4Cl2
reflux, 24 h
O
Br
Br
R=CO2Me; 6
R=CN; 7
R=CO2Me; 8; 84% (7:2)
R=CN; 9; 80% (6:1)
We next turned our attention to uncovering conditions to gen-
erate the appropriate benzynes in situ. We decided to use com-
pound 4 for our optimisation studies in conjunction with furan
as a benzyne trap. For the iodide precursor to be deemed useful,
we stipulated that any such conditions should be mild in nature
and comparable to those used for the analogous 2-(trimethyl-
silyl)phenyl trifluoromethanesulfonate. Accordingly, when 4 was
treated with 2 equiv of TBAF in the presence of 5 equiv of furan
the desired adduct 10 was isolated in 32% yield along with 54%
of desilylated product 11 (Scheme 1). We considered that the
⇑
Corresponding authors.
E-mail address: j.harrity@shef.ac.uk (J.P.A. Harrity).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.052

J. A. Crossley et al. / Tetrahedron Letters 51 (2010) 6608–6610
6609
SiMe3
I
With these promising results in hand we continued our optimi-
sation studies using CsF on preparative scale, our results are sum-
marised in Scheme 2. Pleasingly, upon heating the benzyne
precursor to reflux in acetonitrile in the presence of two equiva-
lents of CsF and two equivalents of AgF, the desired product 10
was provided in 81% yield along with 15% of the desilylated
byproduct 11. Interestingly, in the absence of AgF, the propensity
for benzyne formation was markedly reduced. Conversely, in the
absence of caesium fluoride, none of the furan-benzyne adduct
10 was detected. The latter result demonstrates that silver fluoride
alone was not sufficient to unveil the benzyne intermediate.9
The generality of the CsF/AgF conditions for the generation of a
benzyne from an o-iodoaryl trimethylsilane precursor was
explored and the results are depicted in Scheme 3. We found that
the reaction conditions were applicable to a range of standard ben-
zyne cycloadditions; substituted furan substrates underwent
cycloaddition with 4 to deliver the products 13 and 14 in good
yield. Generation of benzyne in the presence of benzyl azide gave
the desired benzotriazole product 15 in 73% yield as a 1:1 mixture
of regioisomers. Moreover, tetraphenylcyclopentadienone also
MeO2C
TBAF, THF
O
MeO2C
O
+
MeO2C
11; 54% (2:1)
I
4
10; 32%
-
F
silicate
formation
O
Me3
HI addition
across alkyne
Si
F
MeO2C
elimination
MeO2C
I
12
protodesilylation
Scheme 1. TBAF promoted benzyne formation.
iodobenzene byproduct 11 could be derived from two pathways:
(1) Addition of hydrogen iodide across the benzyne intermediate.
(2) Protodesilylation, resulting in incomplete benzyne formation.
The observation that 11 was present as a 2:1 ratio of regioisomers
(analogous to the starting material 4) suggested that it was derived
from protodesilylation rather than addition of HI across the triple
bond of the benzyne. This observation in conjunction with Cunico’s
results led us to consider the employment of an additive which
could help promote the halide elimination process. Moreover, we
also considered the use of alternative fluoride sources; our results
are displayed in Table 1.
Whilst experiments showed that increasing the number of
equivalents of TBAF increased the observed ratio of 10:11 favour-
ably (entries 1–4), we were unable to achieve a ratio reflecting
preference for the desired product. The use of TBAF on silica gel of-
fered no improvement over the use of TBAF in THF (cf. entries 2
and 5), whereas the use of TBAT did appear to provide an increase
in product formation compared to TBAF (cf. entries 2 and 6). Con-
ducting the reaction in acetonitrile with caesium fluoride as the
fluoride source gave no improved ratio, although, in this case the
reaction mixture also contained starting material (entry 7). How-
ever, we were pleased to find that in the presence of silver fluoride
both caesium fluoride and TBAT delivered promising outcomes,
resulting in 5:1 and 2.5:1 ratios of 10:11, respectively (entries 8
and 9).
MeO2C
MeCN, 6 h, Δ
4
+
MeO2C
O
I
O
10
11
2 equiv CsF, 2 equiv AgF 10; 81%, 11; 15%
2 equiv CsF 10; 19%, 11; 76%
2 equiv AgF 4:11; 1.8:1.0
Scheme 2. Cycloaddition optimisation studies.
CsF (2 equiv)
AgF (2 equiv)
MeCN, 6 h, Δ
O
MeO2C
4
4
4
4
13; 81% (1:1)
O
CsF (2 equiv)
AgF (2 equiv)
MeCN, 6 h, Δ
MeO2C
O
14; 83%
O
Table 1
CsF (2 equiv)
AgF (2 equiv)
MeCN, 6 h, Δ
N
N
MeO2C
BnN3
N
MeO2C
Bn
15; 73% (1:1)
conditions
THF, rt, 2 h
O
10
11
SiMe3
I
MeO2C
CsF (2 equiv)
AgF (2 equiv)
MeCN, 6 h, Δ
Ph
MeO2C
Ph
Ph
O
4
MeO2C
I
Ph
Ph
16; 85%
Ph
Ph
Ph
Entry
Fluoride source (equiv)
Additive (equiv)
(10:11)a
O
1
2
3
4
TBAF (1)
TBAF (2)
TBAF (4)
TBAF (10)
TBAF/Si (2)
TBAT (2)
CsF (2)
—
—
—
—
—
—
—
1.0:5.2
1.0:2.8
1.0:2.2
1.0:1.1
1.0:4.2
1.0:1.6
1.0:4.0
5.0:1.0
2.5:1.0
CsF (2 equiv)
AgF (2 equiv)
MeCN, 6 h, Δ
SiMe3
I
NC
NC
O
5
5
6b
7c,d
8c,d
9
17; 65%
O
CsF (2 equiv)
AgF (2 equiv)
MeCN, 6 h, Δ
CsF (2)
TBAT (2)
AgF (2)
AgF (2)
MeO2C
SiMe3
I
MeO2C
O
a
b
c
Relative ratios calculated from GC–MS analysis.
TBAT: tetrabutyl-ammonium triphenyldifluorosilicate.
Reaction conducted in acetonitrile.
Br
O
Br
18; 16%
8 (7:2)
d
Starting material also observed by GC–MS analysis.
Scheme 3. Scope of the benzyne cycloaddition method.

6610
J. A. Crossley et al. / Tetrahedron Letters 51 (2010) 6608–6610
4. Kirkham, J. D.; Delaney, P. M.; Ellames, G. J.; Row, E. C.; Harrity, J. P. A. Chem.
Commun. 2010, 46, 5154.
5. Cunico, R. F.; Dexheimer, E. M. J. Organomet. Chem. 1973, 59, 153.
6. The regiochemical identities of the major isomers in compounds 4 and 5 were
not determined. The regiochemistry of the major isomer in 8 was identified by
participated in a benzyne cycloaddition under these conditions to
afford product 16 in 85% yield. Nitrile substituted benzyne was
successfully generated and trapped by furan to provide 17 in good
yield, unfortunately however, the more heavily substituted sub-
strate 8 was found to be less efficient and only provided 18 in
low yield, together with a significant quantity of protodesilylated
material.
In conclusion, we have developed conditions that significantly
improve the potential for the generation of benzynes from 2-(tri-
methylsilyl)iodobenzenes. Such benzyne precursors offer the po-
tential to be synthesised in relatively short order compared to
their triflate counterparts, for example, via the described alkynyl
iodide cycloaddition process.10,11
NOE NMR spectroscopy. The regiochemistry of the major isomer in
tentatively assigned by inference.
9 is
7. For the employment of alkynyl iodides for the synthesis of iodotriazoles, see:
(a) Hein, J. E.; Tripp, J. C.; Krasnova, L. B.; Sharpless, K. B.; Fokin, V. V. Angew.
Chem., Int. Ed. 2009, 48, 8018; For the synthesis of iodoisoxazoles, see: (b)
Crossley, J. A.; Browne, D. L. J. Org. Chem. 2010, 75, 5414.
8. (a) Woodward, B. T.; Posner, G. H. Adv. Cycloaddit. 1999, 5, 47; (b) Afarinkia, K.;
Vinader, V.; Nelson, T. D.; Posner, G. H. Tetrahedron 1992, 48, 9111; (c)
Afarinkia, K.; Bearpark, M. J.; Ndibwami, A. J. Org. Chem. 2005, 70, 1122; (d)
Delaney, P. M.; Moore, J. E.; Harrity, J. P. A. Chem. Commun. 2006, 3323; (e)
Delaney, P. M.; Browne, D. L.; Adams, H.; Plant, A.; Harrity, J. P. A. Tetrahedron
2008, 64, 866.
9. We also explored the use of tetrabutylammonium triphenyldifluorosilicate in
conjunction with AgF. Whilst we found that these reactions also provided 10,
the yields were slightly lower in comparison and the recovery of side product
11 was hampered by co-elution with fluorotriphenylsilane.
Acknowledgements
10. Representative experimental procedure for the cycloaddition of alkynyl
iodides with methyl coumalate: To methyl coumalate (612 mg, 3.97 mmol),
and trimethylsilyliodoacetylene (1.80 g, 8.03 mmol) was added 1,2-
dichlorobenzene (10 mL). The mixture was heated to reflux and stirred for
24 h before cooling to room temperature. The crude reaction mixture was
purified by flash column chromatography (stepwise gradient: starting with
petroleum ether, finishing with 5% EtOAc in petroleum ether) to give the
product 4 as a pale orange oil (1.08 g, 81%, 2:1 mixture of regioisomers). 1H
NMR (250 MHz, CDCl3): 8.49 (0.67H, d, J = 1.5 Hz), 8.03 (0.33H, d, J = 2.5 Hz),
7.97–7.94 (1H, m), 7.64 (0.33H, dd, J = 8.0, 2.0 Hz), 7.47 (0.67H, d, J = 8.0 Hz),
3.93 (3H, s), 0.47 (3H, s), 0.46 (6H, s); 13C NMR (62.8 MHz, CDCl3): 167.7,
166.7, 142.9, 139.7, 138.9, 133.2, 132.2, 131.2, 130.8, 130.6, 129.9, 101.9,
94.9, 53.5, 53.4. FTIR (CH2Cl2): 2952 (s), 2898 (m), 1732 (s), 1434 (s), 1253 (s),
We are grateful to the EPSRC and the University of Sheffield for
generous financial support.
References and notes
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Chandrasekhar, S.; Seenaiah, M.; Rao, C. L.; Reddy, C. R. Tetrahedron 2008, 64,
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;
1192 (m), 1097 (s), 1005 (s) cmꢀ1 HRMS (ES) m/z [MH]+ calcd for
C
11H16O2SiI: 334.9964, found: 334.9969.
11. Representative experimental procedure for the generation of benzynes: To a
microwave vial were added iodobenzene 4 (68 mg, 0.2 mmol), CsF (60 mg,
0.4 mmol), AgF (50 mg, 0.4 mmol) and MeCN (2 mL). After the addition of a
stirrer bar, the vial was sealed and furan (72 lL, 1 mmol) was injected through
the septum. The vial was then heated at reflux in an oil bath for 6 h before
purification by flash column chromatography (product eluted with 10% EtOAc
in petroleum ether) to give the desired product 10 as a colourless solid (33 mg,
81%). 1H NMR (250 MHz, CDCl3): d 7.89 (1H, s), 7.78 (1H, d, J = 7.5 Hz), 7.32 (1H,
d, J = 7.5 Hz), 7.05 (2H, m), 5.77 (2H, m), 3.91 (3H, s). 13C NMR (100.6 MHz,
CDCl3): 167.4, 154.8, 150.0, 143.8, 142.8, 128.5, 127.7, 121.1, 120.4, 82.6 (ꢁ2),
52.5.
3. For examples, see: (a) Bonner, S. M.; Garg, N. K. J. Org. Chem. 2009, 74, 8842; (b)
Atkinson, D. J.; Sperry, J.; Brimble, M. A. Synthesis 2010, 911.