A Smooth and Practicable Azido-Iodination Reaction of Alkenes Based on IPy2BF4 and Me3SiN3

Article abstract of DOI:10.1002/1615-4169(20010430)343:4<335::AID-ADSC335>3.0.CO;2-V

The reaction of alkenes with IPy₂BF₄ and Me₃SiN₃ under the influence of BF₃ · OEt₂ provides a mild an efficient entry to vicinal azidoiodoalkanes. Besides the simplicity of the experimental protocol and the convenience found in the handling of the reagents, the use of stoichiometric amounts of the azide source is remarkable, and overrides the known and always troublesome dependence on large excesses of azide to accomplish this synthetically valuable transformation.

Full text of DOI:10.1002/1615-4169(20010430)343:4<335::AID-ADSC335>3.0.CO;2-V

COMMUNICATIONS
A Smooth and Practicable Azido-Iodination Reaction of
Alkenes Based on IPy2BF4 and Me3SiN3
Â
Jose Barluenga,* MoÂnica Alvarez-PeÂrez, Francisco J. FanÄ anaÂs, Jose M. GonzaÂlez
Instituto Universitario de QuõÂmica OrganometaÂlica ªEnrique Molesº, Unidad Asociada al CSIC, Universidad de Oviedo,
Julian ClaverõÂa 8, 33071 Oviedo, Spain
Tel. and Fax: (+34) 98-510-3450, e-mail: barluenga@sauron.quimica.uniovi.es
Received March 2, 2001; Accepted March 30, 2001
Abstract: The reaction of alkenes with IPy2BF4 and agents, the use of stoichiometric amounts of the
Me3SiN3 under the influence of BF3 ´OEt2 provides a azide source is remarkable, and overrides the
mild an efficient entry to vicinal azidoiodoalkanes. known and always troublesome dependence on
Besides the simplicity of the experimental protocol large excesses of azide to accomplish this syntheti-
and the convenience found in the handling of the re- cally valuable transformation.
Addition reactions to
alkenes promoted by
simple conversion of al-
kenes into b-iodoalkyl
azides using trimethylsi-
lyl azide[11] 2 (TMSN3) as
an appropriate supplier
Keywords: alkenes; azides; azido-iodination; elec-
trophilic additions; synthetic methods
electrophiles
straightforward entry to
saturated derivatives
offer
a
bearing vicinal functionality[1] and, to this purpose, of the required azide nucleophile.
halogenation reactions are central processes.[2] Semi-
Initial studies conducted using cycloalkenes 3 as
nal work from Hassner[3] showed that b-iodoalkyl starting materials provided evidence of the merit of
azides can be readily prepared from alkenes by addi- this approach. Thus, a CH2Cl2 solution of 1 (1.5 equiv)
tion of iodine(I) azide, providing simple access to in- was treated with 2 (1.2 equiv) and boron trifluoride
troduce nitrogen functionality into organic com- diethyl etherate (1.5 equiv) at 0 °C, followed by rapid
pounds.[4] However, the explosive character of the addition of indene 3b. Upon stirring the mixture for
iodine azide[5] has been considered a major disadvan- 3 hours keeping the temperature constant, simple hy-
tage of this process, constraining its synthetic useful- drolysis and isolation steps[12] led to the exclusive for-
ness.[6] Recently, new solution[6] and polymer- mation of trans-1-azido-2-iodoindane 4b[13] in 95%
bound[7] protocols have been introduced to override yield, as depicted in Scheme 1.
these limitations. These processes rely on the cap-
ability of iodine(III) reagents to create haloazide-like
species from iodide via oxidation and ligand transfer
steps. Moreover, the combination of reagents NaN3/
NaI/CAN led to complementary azido-iodides, ac-
cording to an anti-Markovnikov addition mode.[8]
This renewed interest prompted us to investigate
the convenience of bispyridineiodonium(I) tetra-
fluoroborate 1 (IPy2BF4)[9] to promote azido-iodina-
tion reactions of alkenes, on the basis of its already es-
tablished power to behave as a fine source of
electrophilic iodonium ions.[10] Interestingly, we have
found that it gives rise to an efficient, selective, and
Scheme 1. Representative azido-iodination of indene.
The cis-diastereoisomer was not observed in the
crude reaction mixture on the basis of 1H NMR analy-
sis (400 MHz). Furthermore, formation of the vicinal
diazide[14] was not detected. These facts are relevant
features of the herein reported procedure.[15] In the
same way, cyclohexene gave 4a in high yield, as a sin-
gle trans-stereoisomer. Although the reactions were
carried out on a 4 mmol scale as a routine basis, 5.4 g
of 4a were easily prepared in one batch from the reac-
tion of 25 mmol of 3a (see Table 1).[16] Thus the meth-
Supporting information for this article is available on the
WWW under http://www.wiley-vch.de/home/asc/ or from
the author.
Adv. Synth. Catal. 2001, 343, No. 4
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335

asc.wiley-vch.de
[a]
Table 1. Iodoazidation of alkenes using IPy2BF4
probably as a consequence of the polarity that could
be developed upon activation of 3 by attack of electro-
philic iodine. In the case of 3,4-dihydro-2H-pyran (en-
try 4) the product with trans-stereochemistry is al-
most exclusively obtained, reflecting again an anti-
addition of iodine and the azide across the alkene.
The regioselectivity in addition reactions to neutral
mono-substituted alkenes was investigated and found
to depend on the nature of the substitution on the al-
kene. The phenyl group behaves as a strong director
giving only 4e, arising from incorporation of N3 at the
benzylic position; this is again in agreement with the
expected outcome for an ionic process. However, un-
der related conditions 3f led to addition products as a
mixture of regioisomers, the Markovnikov isomer 4f
being the major component (80% combined yield,
2:1 molar ratio for 4f to 4'f). This ratio can be nicely
modulated simply by adjusting the reaction tempera-
ture (entry 7); at ±40 °C a slower (72 h) but still effi-
cient (90% yield) reaction was noticed, resulting in
higher amount of the Markovnikov component (5:1
molar ratio for 4f to 4'f). Not only electronic but steric
hindrance also plays a role as evidenced in addition
reactions to 3,3-dimethyl-1-butene 3g; the corre-
sponding anti-Markovnikov addition isomer 4g was
formed as the sole reaction product in fairly good
yield.[18] The azido-iodination of trans-1,2-diphe-
nylethene required a low reaction temperature to
give a clean transformation. Although obtained only
in moderate yield, 4h[3a] was diastereoselectively
formed according to an anti-addition mode. Trisubsti-
tuted alkenes can be equally azido-iodinated using
this reaction, as demonstrated by the regio- and dia-
stereoselective synthesis of 4i. The fact that a,b-unsa-
turated esters undergo azido-iodination by IPy2BF4/
TMSN3 significantly expands the scope of the process,
adding interest for the synthesis of modified b-amino
acids. They reacted under related conditions to those
previously described for more reactive alkenes,[19]
and furnished the regioisomer with the azide moiety
attached to the b-carbon (entries 11±13). Moreover,
only one diastereoisomer was formed in the azido-io-
dination of methyl (E)-cinnamate 3k, corresponding
to an anti-addition of N3 and I.[20] The push-pull sub-
stituted alkene (E)-3-methoxy-2-propenoate 3l yields
4l (entry 13)[21] as the major component (22 : 1 mix-
ture of stereoisomers).
[a] All the reactions have been carried out on a 4 mmol scale.
[b] Isolated yield after flash column chromatography.
[c] In brackets yield corresponding to 25 mmol scale.
[d] 20 : 1 mixture of diastereoisomers.
[e] 2 : 1 mixture of regioisomers.
[f] 5 : 1 mixture of regioisomers.
[g] Triflic acid has been used instead of boron trifluoride.
[h] IPy2OTf was used.
[i] 22 : 1 mixture of diastereoisomers.
od is also of interest to prepare moderate amounts of
azido-iodinated derivatives in a practicable manner.
It nicely compares to the more demanding polymer-
bound hypervalent iodine(III) process that relies on
larger excesses of the azide source,[17] and requires
longer reaction times to produce the desired addition
compounds; these facts could possibly allow competi-
tive side reactions to take place.[15]
On this ground, we have explored the scope of the
IPy2BF4/TMSN3-based method. The results are sum-
marized in Table 1 and reveal a general process with
respect to the electronic demand of the substituents
in 3, enabling neutral, electron-rich, and electron-de-
ficient alkenes 3 to undergo the azido-iodination re-
action in good to excellent yields. Full control over
the regioselectivity was realized in addition reactions
to enol ethers (entries 3 and 4). Adducts bearing N3 on
the carbon next to oxygen were exclusively obtained,
Although no mechanistic work has been underta-
ken, the results described are fully compatible with
an electrophilic addition process. An initial formation
of a cyclic iodonium ion, followed by its subsequent
capture by azide would lead to the formation of the
adducts with the noted regio- and stereochemistry.
The already established ability of the reaction med-
ium to liberate fluoride might be responsible for the
N-Si bond activation.[22]
In summary, a new approach to synthesize valuable
336
Adv. Synth. Catal. 2001, 343, 335±337

COMMUNICATIONS
[5] (a) K. Dehnicke, Angew. Chem. 1976, 88, 612±613; An-
gew. Chem. Int. Ed. Engl. 1976, 15, 553±554; (b) P. Bu-
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[6] A. Kirschning, A. Hashem, H. Monenschein, L. Rose,
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[7] A. Kirschning, H. Monenschein, C. Schmeck, Angew.
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[8] V. Nair, T. G. George, V. Sheeba, A. Augustine, L. Bala-
gopal, L. G. Nair, Synlett 2000, 1597±1598.
[9] IPy2BF4 is a commercial reagent from either Novabio-
chem or Aldrich.
[10] (a) For a brief overall view on early applications, see:
J. Barluenga, Pure Appl. Chem. 1999, 71, 431±436;
(b) For a recent publication: G. EspunÄ a, G. Arsequell,
G. Valencia, J. Barluenga, M. PeÂrez, J. M. GonzaÂlez,
Chem. Commun. 2000, 1307±1308.
[11] For the use of TMSN3 in related azidobromination of
alkenes, see: G. A. Olah, Q. Wang, X.-Y. Li, G. K. S.
Prakash, Synlett 1990, 487±489.
azido-iodinated derivatives from the known addition
path is established. It allows an efficient, easy, and
clean introduction of nitrogen and iodine into organic
compounds from commercial reagents. The solid and
air-stable IPy2BF4 reagent emerges as a powerful and
easy to manipulate iodonium source for this purpose,
overcoming many previously noticed limitations. It is
noteworthy that it requires lower amounts of the
azide source than other established alternatives,
overriding side reactions and minimizing the risk as-
sociated to handling the resulting reaction mixtures.
On this basis, this new reaction represents the alter-
native of choice to prepare moderate amounts of azi-
do-iodinated compounds.
Experimental Section
Typical Procedure (Compound 4b)
[12] Though we have not had any explosion while prepar-
ing these azidoiodides, care should be taken since
azides are potentially explosive compounds.
A solution of IPy2BF4 (2.23 g, 6 mmol) in CH2Cl2 (20 mL) was
treated at 0 °C with TMSN3 (0.56 g, 0.64 mL, 4.8 mmol) un-
der a nitrogen atmosphere. To the resulting yellow solution
BF3 ´ OEt2 (0.85 g, 0.76 mL, 6 mmol) was added dropwise
whereupon the color changed to dark red. Then indene
(0.46 g, 0.46 mL, 4 mmol) was added at once. The mixture
was stirred for 3 h at the same temperature. The reaction
mixture was quenched with a 5% solution of sodium thiosul-
fate pentahydrate (20 mL) and extracted with dichloro-
methane (2 ´ 10 mL). The combined organic layers were
washed with water (2 ´ 10 mL) and dried over anhydrous so-
dium sulfate. Solvents were removed under vacuum and the
residue was purified by flash column chromatography (SiO2,
hexane/ethyl acetate, 20 : 1) to yield 4b (1.08 g, 95%) as a
white solid (mp: 54±56 °C).
[13] All compounds 4 were fully characterized by IR, MS, 1H
and 13C NMR, elemental analysis and/or HRMS data.
See supporting information for representative data.
[14] For a synthesis of vicinal diazides from alkenes using
hypervalent iodine reagents, see: R. M. Moriarty, J. S.
Khosrowshahi, Tetrahedron Lett. 1986, 27, 2809±2812.
[15] In the literature, the polymer-bound approach clearly
appears as a powerful synthetic alternative to pre-
viously established procedures. However, our ap-
proach offers higher control over the selectivity as
competitive side-reactions were suppressed.
[16] The experimental protocol was slightly modified to
avoid fluoroiodination reaction as a side process. In
this case, a 200 mL solution containing the iodinating
reagent in CH2Cl2 was added over a period of 4 h to a
mixture of the rest of the components in 90 mL of the
same solvent. Once the addition was completed, the
reaction mixture was stirred for 2 h, and then stan-
dard work-up afforded 4a in 86% yield.
Acknowledgements
This work was supported by DGICYT (Grant PB97±1271). M.
A. thanks the Spanish M.E.C. for a fellowship.
[17] The polymer-bound reagent is well suited for auto-
mated high throughput synthesis where use and ac-
cess of reagents does not represent a constraint and
convenience of work-up is relevant.
[18] For a similar behavior, see ref. [3a] and related refer-
ences cited therein.
References and Notes
[19] More difficult reactions have been noticed in related
IPy2BF4-promoted additions to alkenes for electron-with-
drawing groups such as in fluoro-iodination reactions,
see: J. Barluenga, P. J. Campos, J. M. GonzaÂlez, J. L. SuaÂr-
ez, G. Asensio, J. Org. Chem. 1991, 56, 2234±2237.
[20] Compound 4k matches data previously described for
this structure. For a discussion of several reaction
paths in the azidoiodination of a,b-unsaturated sys-
tems, see: R. C. Cambie, J. L. Jurlina, P. S. Rutledge,
B. E. Swedlund, P. D. Woodgate, J. Chem. Soc., Perkin
Trans. 1 1982, 327±333.
[21] The stereochemistry was tentatively assigned on the
basis of that established for 4k.
[22] (a) J. Barluenga, I. Llorente, L. J. Alvarez-GarcõÂa, JoseÂ
M. GonzaÂlez, P. J. Campos, M. R. DõÂaz, S. GarcõÂa-
Granda J. Am. Chem. Soc. 1997, 119, 6933±6934;
(b) See also ref. [20]
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I. Fleming), Pergamon, Oxford, 1991, pp. 329±362.
[2] (a) Review: J. Rodriguez, J.-P. DulceÁre, Synthesis 1993,
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[3] (a) F. W. Fowler, A. Hassner, L. A. Levy, J. Am. Chem.
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[4] For a recent review on the synthesis of b-haloazides,
see: D. Savoia, Methoden Org. Chem. (Houben-Weyl,)
4th edn., 1996, Vol. E21/9, Thieme, Stuttgart, pp.
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