Synthetic applications of 2-(azidomethyl)allyltrimethylsilane

Article abstract of DOI:10.1055/s-0032-1318144

Starting from commercially available 2-(chloromethyl)-allyltrimethylsilane, the corresponding 2-(azidomethyl)allyl silane was prepared through reaction with NaN₃. The product was stable upon isolation and storage and could be used for thermal c

Full text of DOI:10.1055/s-0032-1318144

LETTER
▌491
lSetyternthetic Applications of 2-(Azidomethyl)allyltrimethylsilane
Synthetic Applications of 2-(Azidomethyl)allyltrimethylsilane
Serena Ferrini, Elena Cini, Maurizio Taddei*
Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy
Fax +39(577)234333; E-mail: taddei.m@unisi.it
Received: 06.11.2012; Accepted after revision: 10.01.2013
synthesis can be readily accomplished from commercially
available 2-(chloromethyl)allyltrimethylsilane (1). In
fact, reaction of 1 in DMF in the presence of NaN3 at room
temperature gave product 2 in almost quantitative yield
Abstract: Starting from commercially available 2-(chloromethyl)-
allyltrimethylsilane, the corresponding 2-(azidomethyl)allylsilane
was prepared through reaction with NaN3. The product was stable
upon isolation and storage and could be used for thermal
cycloaddition of the azido group with alkenes to give allylsilane- (Scheme 1). Compound 2 was found to be stable at room
containing triazolines or aziridines. This reaction was not accelerat-
temperature and could be stored at 4 °C for several
ed by microwave (MW) dielectric heating, however, the azide frag-
months without decomposition.
ment undergoes MW-assisted Cu(I)-catalyzed cycloaddition with a
range of alkynes (including ynamides). Lewis acid mediated
Hosomi–Sakurai reaction of the allylsilane with aldehydes was also
possible. A one-pot transformation into different triazolo-contain-
ing homoallyl alcohols was carried out through a sequence of Cu(I)-
catalyzed azide cycloaddition under MW dielectric heating and
BCl3-mediated reaction with aromatic aldehydes.
NaN3, DMF, r.t.
96% yield
Me3Si
Me3Si
N3
Cl
1
2
Scheme 1 Preparation of azidoallylsilane 2
Key words: microwaves, click chemistry, azides, cycloaddition,
allylation
The differing reactivity of the two functional groups was
first studied independently in order to explore the poten-
tial and scope of this novel reagent. Initially, standard cy-
cloaddition with alkenes was investigated, reacting
compound 2 with a range of alkenes (Table 1). The reac-
tion of azide with alkenes is known to proceed with the
formation of triazolines or aziridines (or other products
derived from these intermediates) depending on the reac-
tion modes.14,15 Generally, [3+2] cycloaddition under
thermal conditions initially gives the sometimes unstable
triazoline that can be further transformed into an aziridi-
ne.16–21 However, under photochemical conditions, the
aziridine is the major product.22,23 To find the optimal re-
action conditions, the cycloaddition of 2 with N-phenyl-
maleimide 3 was investigated.24 Reaction did not take
place in polar solvents (THF, CH2Cl2) or under attempted
transition-metal catalysis. A poor reactivity was also ob-
served under photochemical irradiation. Using a low-
pressure Hg lamp at 254 nm in MeCN, compound 2 and
N-phenylmaleimide gave a very low yield of aziridine 9
with several by-products arising from photodegradation
of 2, with the majority of 3 being recovered. However, re-
action of 2 and 3 in toluene at 115 °C for 12 h gave triazo-
line 8 in acceptable yield (Table 1, entry 1), whereas only
aziridine 9 was isolated in 65% yield when the reaction
temperature was increased to 140° (Table 1, entry 2). Us-
ing ethyl acrylate 4 and acrylonitrile 5 as alkenes, aziridi-
nes 10 and 11 were formed at 115 °C, whilst γ-
crotolactone 6 gave aziridine 12 in good yield. On the oth-
er hand, acyclic α,β-unsaturated aldehydes and ketones
(cinnamaldehyde or cyclopentanone) did not react at all.
When an electron-rich alkene such as dihydrofuran 7 was
submitted to the thermal reaction, aziridine 13 was
obtained as the sole product.25,26
Azides have been widely applied in organic synthesis, ex-
ploiting their versatility in cycloaddition reactions.1
Azides are readily applicable to the preparation of small
molecule libraries for biological applications and for bio-
conjugation within large biomolecules,2–5 so that the term
‘click chemistry’ has been coined based on azide reactiv-
ity.6 Allylsilanes are another class of very versatile mole-
cules. They are stable, electron-rich compounds that may
react in the presence of electrophiles (generally carbonyl
compounds activated by Lewis acids)7,8 or as nucleo-
philes, triggering the silane reactivity with fluoride
through the formation of pentacoordinate silicon.9 How-
ever, allylsilanes and azides do not react together and so
can be considered as two compatible groups that can be
introduced into the same molecule for further selective
functionalization.
Following our long-term interest in allylsilane
chemisty10,11 and, more recently, in azide chemistry,12 we
were intrigued to develop a molecule in which the two
groups coexist and can be selectively and sequentially
functionalized. After a click reaction of the azide and a nu-
cleophilic reaction of the allylsilane, a double bond and an
alcohol function would still be present on the scaffold for
additional transformations. 2-(Azidomethyl)allyltrimeth-
ylsilane 2 is an ideal substrate for this strategy, providing
a methallyl scaffold linked to the two moieties in a suit-
able form for elaboration. Surprisingly, this simple mole-
cule has never been reported before,13 although its
SYNLETT 2013, 24, 0491–0495
Advanced online publication: 31.01.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318144; Art ID: ST-2012-D0957-L
© Georg Thieme Verlag Stuttgart · New York

492
S. Ferrini et al.
LETTER
Attempts to accelerate the cycloaddition by using micro- a temperature of 140 °C to be achieved, but cycloaddition
wave dielectric heating were unsuccessful. Using toluene still did not occur. The addition of a heating adjuvant to
as the solvent, it was not possible to reach the internal the toluene (a few drops of ionic liquid or a carbon fiber
temperature required for the cycloaddition; whereas heat- plug-in)28,29 allowed the temperature to increase, but start-
ing in a more polar solvent (MeOH, DMF, DCE) allowed ing materials were recovered unchanged after 2 h of MW
Table 1 Thermal Reaction of Azidoallylsilane 2 and Alkenes
Me3Si
Me3Si
N
R1
or
R1
N
Me3Si
+
N
R2
N
R2
R1
N3
R2
2
Entry
Alkene
Conditionsa
Productb
Yield (%)c
Me3Si
O
O
N
N
N
O
1
A
72
N
N
O
3
3
8
Me3Si
N
O
N
2
B
65
O
9
CO2Et
Me3Si
N
N
3
4
A
A
CO2Et
68
73
4
5
10
CN
O
Me3Si
CN
11
Me3Si
N
O
O
5
6
A
A
62
66
O
6
7
12
Me3Si
N
O
O
13
a Reacion conditions A: toluene, 115 °C, 12 h. Conditions B: toluene, 140 °C, 12 h. In both cases, the tube containing the reaction mixture was
immersed in the heating bath until it reached the required temperature.
b The regiochemistry of compounds 1019 and 1121 was assumed on the basis of previous reports. Compounds 8, 9, 12 and 13 were isolated as
single diastereomers, probably the cis-isomers.
c Yield of isolated and fully characterized products.
Synlett 2013, 24, 491–495
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthetic Applications of 2-(Azidomethyl)allyltrimethylsilane
493
heating at 150 °C. Although rare, the ineffectiveness of together with derivative 16 (Scheme 3). However, when
microwave heating to accelerate a thermal reaction has azidoalcohol 15 was submitted to cyclization with alkenes
been observed previously.27
3 or 7, the reaction did not proceed cleanly (Scheme 3).
After initial functionalization of the azide moiety, the re-
activity of the aziridine allylsilanes was explored. Howev-
er, when aziridines 9–12 were mixed with benzaldehyde
in the presence of BF3·OEt2, protodesilylation products
were formed exclusively. An analogous result was ob-
tained with other Lewis acids such as Sc(OTf)2, BCl3,
TiCl4 or ZnCl2 or in the presence of trifluoroacetic acid
(TFA), tetrabutylammonium fluoride (TBAF) or CsF. A
different reactivity was observed with aziridine 13 de-
rived from dihydrofuran. When submitted to BF3·OEt2-
mediated reaction with benzaldehyde, the hydroxymeth-
allyl amide 14 was isolated in 62% yield (Scheme 2) and
was also obtained with BF3·OEt2 alone. The formation of
this γ-hydroxymethallyl amide is proposed to occur
through initial coordination of BF3 to the ethereal oxygen
(13b), followed by fluoride-mediated desilylation. Fur-
ther abstraction of the acidic proton between the two het-
eroatoms yields intermediate enaminal 13c, which
undergoes attack by water to generate the final amide 14
through ring opening of the dihydrofuran ring (Scheme 2).
OH
3 or 7
PhMe
115–140 °C
Ph
N3
PhCHO, BF3⋅OEt2
15 25%
CH2Cl2
Me3Si
+
N3
2
N3
16 75%
Scheme 3 Attempted sequence: Hosomi–Sakuari reaction / cyclo-
addition with alkenes
Attributing this unsatisfactory behavior to the high reac-
tivity of the triazoline/aziridine rings, we decided to in-
vestigate the reaction of azidoallylsilane 2 with alkynes
(Scheme 4). In this instance, Cu-mediated cycloaddition
of 2 with phenylacetylene (DMF, CuI) occurred under
MW dielectric heating, giving compound 17 in good
yield. It is worth noting that the cycloaddition worked ex-
clusively using CuI in DMF, and no reaction was ob-
served using Cu(I) generated in situ from CuSO4 and
ascorbic acid. On isolation, 17 was submitted to the Hoso-
mi–Sakurai reaction with benzaldehyde in CH2Cl2 in the
presence of BF3·OEt2, to form the corresponding triazole
homoallyl alcohol 18 in 80% yield. However, when ho-
moallyl alcohol 15 was submitted to cycloaddition with
phenylacetylene, the reaction gave a very low yield of tri-
azole 18, with the homoallyl alcohol decomposing rapidly
(Scheme 4).
BF3⋅OEt2, CH2Cl2
Me3Si
N
NH
O
O
13
HO
14
N
Me3Si
H
+
HN
O
–B
Looking to the possibility of performing a multicompo-
nent reaction, we tried mixing compound 2, benzaldehyde
and phenylacetylene in the presence of different Lewis
acids and Cu(I) salts, or using CuOTf alone.30 However,
formation of compound 18 was never observed.31
O
F
F
F
13b
13c
H
Me3Si
O
CuI, DMF, MW
N
+
Me3Si
NH
N
86%
Ph
N
O
N3
O
N
HO
O
2
H
H
Ph
14
17
PhCHO, BF3⋅OEt2
13d
CH2Cl2
OH
Scheme 2 Proposed mechanism for the formation of γ-hydroxyam-
ide 14
Ph
OH
CuI, MeCN, DMF, MW
N
+
Ph
N
Ph
As the allylsilane functionalization appeared to be prob-
lematic, we decided to invert the sequence of events, per-
forming an initial Hosomi–Sakurai reaction on
azidoallylsilane 2 followed by [3+2] cycloaddition with
alkenes (Scheme 3). Compound 2 reacted with benzalde-
hyde at 0 °C in the presence of BF3·OEt2 to give homoal-
lyl alcohol 15, which was isolated in poor yield (ca. 25%)
N
N3
15
Ph
18
80% from 17 (35% from 15)
Scheme 4 Exploration of the sequence of events for the Cu(I)-medi-
ated cycloaddition
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 491–495

494
S. Ferrini et al.
LETTER
Subsequently, a one-pot multistep operation was attempt- on the multistep, one-pot preparation of methallyltriazole
ed.32 Allylsilane azide 2 was mixed with phenylacetylene derivatives. Some limitations in the reactivity of the azi-
in DMF with a catalytic amount of CuI and submitted to
MW-assisted cycloaddition. Then, without opening, the
microwave vial was cooled and benzaldehyde plus
BF3·OEt2 were added by using a syringe. However, exclu-
sive desilylation of the intermediate occurred with forma-
tion of the methallyl triazole 19.33 Assuming that the
cycloaddition reaction medium was not compatible with
the Lewis acid, the protocol developed for the click reac-
tion was adapted to conditions more compatible with the
second step (Scheme 5).
Table 2 One-Pot Preparation of Triazole Homoallyl Alcohols
O
OH
R2
BCl3
H
R2
CuI, MeCN
+
Me3Si
N
R1
N
N3
N
2
R1
20–37
Entry R1
R2
Product Yield (%)a
1
2
3
4
5
MeO2C
Ph-
Ph
Ph
Ph
Ph
20
21
22
23
24
66
61
68
72
64
1) CuI, MeCN, DMF
N
Me(CH2)3
4-PhC6H4
2) PhCHO, BF3⋅OEt2
N
N
Ph
19
OH
Me3Si
4-MeOC6H4
+
Ph
1) CuI, MeCN
N3
2) PhCHO, BCl3
2
Ph
S
N
N
6
7
Ph
Ph
25
26
65
70
N
HO
Ph
18 75%
Scheme 5 One-pot operation from azidoallylsilane 2 to triazole
homoallyl alcohol 20; the choice of MeCN and BCl3
Bn
N
8
9
H2NC6H4
Ph
27
28
29
30
31
32
33
34
62b
70
74
68
68
62
42c
79
After much optimization, CuI and acetonitrile were found
to be the best combination for the first step; while a 75%
yield of 18 was obtained in the second step using BCl3
(1 M in CH2Cl2). Thus, the established procedure consist-
ed of reacting the alkyne with azidoallylsilane 2 in MeCN
in the presence of CuI under MW dielectric heating, fol-
lowed by addition of the aldehyde and BCl3 (Scheme 5).34
This two-step, one-pot sequence was extended to a range
of aromatic aldehydes (Table 2) and the corresponding tri-
azolyl methallyl alcohols 20–37 were obtained in good
yields. Aromatic and aliphatic alkynes could be success-
fully employed but the use of BCl3 was incompatible with
enolizable aldehydes. The presence of carboxymethyl or
benzyl groups, alcohols or tertiary amines was compatible
with the reaction conditions (Table 2, entries 1, 6, 7, and
9), thus expanding the potential of the reaction. Boc pro-
tection on the nitrogen was removed (Table 2, entries 8
and 18), whereas benzylated phenol suffered partial de-
benzylation (entry 14); both results being attributable to
the presence of BCl3. Ynamides could also be successful-
ly employed, as in the case of N-Boc-N-phenyl amino-
acetylene,35 which gave the 4-anilino-substituted triazole
37 in 63% yield. In all cases, the products were obtained
in an acceptable purity and could be isolated in yields of
more than 60% (except Table 2, entry 14). However, col-
umn chromatography was necessary to obtain analytically
pure samples.
BnO2CCH2
Ph
10
11
12
13
14
15
Ph
Ph
Ph
Ph
Ph
Ph
4-MeOC6H4
4-BrC6H4
4-CNC6H4
2-NO2C6H4
4-BnOC6H4
Cl
16
Ph
Ph
35
60
Cl
HO
17
18
36
37
66
MeO
H
N
4-MeOC6H4
63d
a Yield of isolated and fully characterized products.
b Starting alkyne R1 = p-BocNHC6H4.
c Partial debenzylation occurred.
d Starting alkyne R1= Ph(Boc)N.
In conclusion, the synthesis and synthetic applications of
novel azidoallylsilane 2 have been described with a focus
Synlett 2013, 24, 491–495
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthetic Applications of 2-(Azidomethyl)allyltrimethylsilane
495
(24) For reaction of maleimide with azides, see: Awad, W. I.;
Omran, S. M. A. R.; Nagieb, F. Tetrahedron 1963, 1400.
(25) D’Auria, M.; Racioppi, R.; Viggiani, L.; Zanirato, P. Eur. J.
Org. Chem. 2009, 932.
doallylsilane highlight the real scope of the new scaffold,
which can be considered as a useful multi-reactive system
for application in diversity-oriented synthesis.
(26) Scheiner, P. J. Org. Chem. 1967, 32, 2022.
(27) For a previous example of failure in the use of microwaves
to accelerate a thermal reaction, see: Piras, L.; Ghiron, C.;
Minetto, G.; Taddei, M. Tetrahedron Lett. 2008, 49, 459.
(28) Leadbeater, N. E.; Torenius, H. M. J. Org. Chem. 2002, 67,
3145.
Acknowledgment
The authors thanks Sigma-tau Pharmaceuticals Inc. (Pomezia,
Rome, Italy) and MIUR (Rome, PRIN Project
2009RMW3Z5_006) for financial support.
n
R
(29) Chen, W.; Gutmann, B.; Kappe, C. O. ChemistryOpen 2012,
1, 39.
(30) Salomon, R. G.; Kochi, J. K. J. Am. Chem. Soc. 1973, 95,
3300.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SuppInigfor
m
o
ti
(31) A microwave-assisted allylation of acetals with
allyltrimethylsilane in the presence of Cu(I) salts has been
reported. However, when azidoallylsilane 2 was reacted
with benzaldehyde dimethyl acetal and phenylacetylene in
the presence of CuBr under the conditions reported in the
paper, triazole allylsilane 17 was the only product isolated.
See: Jung, M. J.; Maderna, A. J. Org. Chem. 2004, 69, 7755.
(32) For a similar one-pot reaction, see: Ishikawa, H.; Suzuki, T.;
Hayashi, Y. Angew. Chem. Int. Ed. 2009, 48, 1304.
(33) Identified as in: Wang, Z.-X.; Zao, Z.-G. J. Heterocycl.
Chem. 2007, 44, 89.
Reference and notes
(1) Chiba, S. Synlett 2012, 23, 21.
(2) Tron, G. C.; Pirali, T.; Billington, R. A.; Canonico, P. L.;
Sorba, G.; Genazzani, A. A. Med. Res. Rev. 2008, 28, 278.
(3) Agalawe, S. G.; Maujan, S. R.; Pore, V. S. Chem. Asian J.
2011, 6, 2696.
(4) Jewett, J. C.; Bertozzi, C. R. Chem. Soc. Rev. 2010, 39, 1388.
(5) Mamidyala, S. K.; Finn, M. G. Chem. Soc. Rev. 2010, 39,
1251.
(34) 1-Phenyl-3-[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]but-
3-en-1-ol (18); Typical Procedure: In a vial suitable for
MW reactions, azidoallylsilane 2 (100 mg, 0.59 mmol) was
dissolved in anhydrous MeCN (2 mL) and phenylacetylene
(60 mg, 0.6 mmol) was added, followed by CuI (10 mg, 0.05
mol). The vial was closed and inserted in a MW oven
(Discover from CEM) and heated to 120 °C for 15 min (max
power 200 W, max internal pressure 200 psi). The vial was
cooled to 0 °C and anhydrous benzaldehyde (60 mg, 0.56
mmol) dissolved in anhydrous MeCN (0.5 mL) was added
by using a syringe. BCl3 (1 M in toluene, 0.6 mL, 0.6 mmol)
was slowly added by using a syringe to the vial under
vigorous stirring. The mixture was stirred at r.t. for 6 h, and
then solid Na2CO3 (150 mg) was added followed by EtOAc
(5 mL). The mixture was stirred at r.t. for 10 min then water
(2 mL) was added. The organic layer was separated, washed
with 1 M aq Na2CO3 (3 mL), 1 M aq NH4Cl (3 mL) and brine
(3 mL). The organic layer was separated, dried over
anhydrous Na2SO4, filtered and the solvent evaporated.
Compound 18 (135 mg, 75%) was isolated as a waxy
material by flash chromatography (hexane–EtOAc, 2:1). 1H
NMR (400 MHz, CDCl3): δ = 7.80 (d, J = 8.1 Hz, 2 H), 7.72
(s, 1 H,), 7.46–7.21 (m, 8 H), 5.15 (s, 1 H), 5.08–4.90 (m,
3 H,), 4.87 (dd, J = 8.4, 4.3 Hz, 1 H), 2.67 (br s, 1 H, OH),
2.42 (dd, J = 19.5, 6.4 Hz, 2 H). 13C NMR (100 MHz,
CDCl3): δ = 147.9, 143.8, 140.6, 128.8 (2C), 128.2 (2C),
127.8 (2C), 125.7 (4C), 120.0 (2C), 117.6, 72.9, 55.3, 43.1.
HRMS (ESI): m/z [M + Na]+ calcd for C19H19N3ONa+:
328.1426; found: 328.1424.
(6) Meldal, M.; Tomøe, C. W. Chem. Rev. 2008, 108, 2952.
(7) Hosomi, A.; Endo, M.; Sakurai, H. Chem. Lett. 1976, 941.
(8) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207.
(9) Furin, G. G.; Vyazankina, O. A.; Gostevsky, B. A.;
Vyazankin, N. S. Tetrahedron 1988, 44, 2675.
(10) Schneider, M. R.; Mann, A.; Taddei, M. Tetrahedron Lett.
1996, 8493.
(11) D’Aniello, F.; Taddei, M. J. Org. Chem. 1992, 57, 5247.
(12) Balducci, E.; Bellucci, L.; Petricci, E.; Taddei, M.; Tafi, A.
J. Org. Chem. 2009, 74, 1314.
(13) Searching for the structure of 2 on SciFinder (December
2012) gave no hits. However, the product is described as an
intermediate for the synthesis of 4-amino-2-
(trimethylsilylmethyl)but-1-ene, see: Furman, B.; Dziedzic,
M. Tetrahedron Lett. 2003, 44, 8249.
(14) Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 297.
(15) Bräse, S.; Gil, C.; Knepper, K.; Zimmerman, V. Angew.
Chem. Int. Ed. 2005, 44, 5188.
(16) Huisgen, R.; Szeimies, G.; Mobius, L. Chem. Ber. 1966, 99,
475.
(17) Broeckx, W.; Overbergh, N.; Samyn, C.; Smets, G.; L‘Abbé,
G. Tetrahedron 1971, 27, 3527.
(18) Sha, C.-K.; Ouyang, S.-L.; Hsieh, D.-Y.; Chang, R.-C.;
Chang, S.-C. J. Org. Chem. 1986, 51, 1490.
(19) Mahoney, J. M.; Smith, C. R.; Johnston, J. N. J. Am. Chem.
Soc. 2005, 127, 1354.
(20) Chen, M.; Gan, Y.; Harwood, L. M. Synlett 2008, 2119.
(21) Belei, D.; Bicu, E.; Jones, P. G.; Birsa, M. L. J. Heterocycl.
Chem. 2011, 48, 129.
(35) Pizzetti, M.; Russo, A.; Petricci, E. Chem. Eur. J. 2011, 17,
4523.
(22) Dahl, R. S.; Finney, N. S. J. Am. Chem. Soc. 2004, 126,
8356.
(23) Allemann, S.; Vogel, P. Synthesis 1991, 923.
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