Iron-catalyzed chemoselective azidation of benzylic silyl ethers

Article abstract of DOI:10.1002/chem.201202984

Azidation: Siloxy groups derived from secondary and tertiary benzyl alcohols can be transformed into azide groups at room temperature using TMSN₃ in the presence of an iron catalyst (see scheme; TMS=trimethylsilyl). Secondary and tertiary benzy

Full text of DOI:10.1002/chem.201202984

DOI: 10.1002/chem.201202984
Iron-Catalyzed Chemoselective Azidation of Benzylic Silyl Ethers
Yoshinari Sawama,* Saori Nagata, Yuki Yabe, Kosuke Morita, Yasunari Monguchi, and
Hironao Sajiki*[a]
Silyl ethers are traditionally used for the protection of al-
cohols and are stable in the presence of most nucleophiles,
owing to the low leaving-group ability of the siloxy groups.[1]
Carbon nucleophiles, such as allylsilanes[2] and enol ace-
tates,[3] can react with silyl ethers in the presence of suitable
Lewis acids. Furthermore, the bromination, thiocyanation,
and isothiocyantion of silyl ethers in an ionic liquid were
also developed.[4] Although azides are important because,
for example, they can be transformed into triazoles by the
Huisgen reaction[5] and into amines by reduction,[6] there are
only a few methods for the azidation of silyl ethers; this
transformation can be accomplished by the use of nBu4NN3
as an azido source in the presence of PPh3 and either 2,3-di-
(Table 1, entry 1). FeCl3 and FeBr3, which are cheaper and
more common Lewis acids, were found to be suitable cata-
lysts (Table 1, entries 2 and 3), whereas the reaction using
Table 1. Azidation of benzylic sec-TBS ether (1a).
Entry Azido source Lewis acid Solvent
Yield of 1a/2a/3a [%][a]
1
2
3
4
5
6
7
8
9
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
NaN3
AuCl3
FeCl3
FeBr3
TMSOTf
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
chloro-5,6-dicyanobenzoquinone[7] or 2,4,6-trichloro
ACHTUNGTRENNUNG
azine.[8] In these reports, nonprotected (free) alcohols[9] are
ACHTUNGTRENUN[NG 1,3,5]tri-
CH2Cl2
CHCl3
toluene
46/46/0
20/68/0
62/19/0
more reactive than silyl ethers toward nucleophilic attack of
the azide anion and primary alcohols are preferentially con-
verted into the corresponding primary azido products in the
presence of secondary and tertiary alcohols. We now demon-
strate a novel iron-catalyzed azidation of silyl ethers, the re-
action conditions allowing chemoselective transformation of
secondary and tertiary benzylic silyl ethers in the presence
of primary benzylic silyl ethers. Moreover, secondary and
tertiary benzylic silyl ethers undergo azidation more effi-
ciently relative to that of the corresponding free benzylic al-
cohols, and many reactive functional groups, such as alkyl
chlorides,[10] a,b-unsaturated esters,[11] and aldehydes,[12] were
stable under the azidation conditions.
Our research group has been focusing on the develop-
ment of an efficient method for preparing pharmaceutically
useful azido derivatives[13] and we wondered whether the
direct azidation of silyl ethers, which are normally stable
under nucleophilic-substitution conditions, was possible. For-
tunately, AuCl3 (5 mol%) facilitated the desirable azidation
of 1-phenylethanol TBS ether (1a) in the presence of
4 equivalents of TMSN3 in (CH2Cl)2 at room temperature
AHCTUNGTRENNUNG
DPPA
ACHTUNGTRENNUNG
[a] Yield was determined by 1H NMR spectroscopy. DPPA=diphenyl-
phosphoryl azide, Tf=trifluoromethanesulfonyl, TMS=trimethylsilyl.
either FeCl2, FeACTHUNTRGNE(GNU OAc)2, InCl3, AuCl3, TMSOTf, or TFA as a
catalyst gave no reaction or inefficient transformations.[14]
Chlorinated solvents, such as CH2Cl2, CHCl3, and (CH2Cl)2,
were more effective than either toluene or THF.[14] The azi-
dation reaction was most efficient when conducted in
(CH2Cl)2 (Table 1, entries 2, and 5–7). Furthermore, TMSN3
was a more effective azide source than either NaN3 or
DPPA (Table 1, entries 8 and 9).
The substrate scope was next examined (Table 2).[15]
Whereas the azidation of TBS, TES, and TIPS ethers de-
rived from 1-phenylethanol (1a–c) required a large excess
(4 equivalents) of TMSN3 and long reaction times (3–
6 hours) to complete the reaction (Table 1 and Table 2; en-
tries 1 and 2), the azidation of the corresponding TMS ether
(1d), which is less sterically hindered, was complete within
30 minutes when 1d was treated with 5 mol% of FeCl3 and
only 1.1 equivalents of TMSN3, thus affording 2a in good
yield (Table 2, entry 3). Notably, when the nonprotected al-
cohol (3a) was treated under the same reaction conditions
(Table 2, entry 3), a longer reaction time was necessary and
2a was obtained in a very low yield (28%) together with
the generation of dimeric compound 4 as the main product
[Eq. (1)]. This result suggests that the present azidation
does not proceed by the deprotection of 1a to give 3a. 1e
[a] Dr. Y. Sawama, S. Nagata, Y. Yabe, K. Morita, Dr. Y. Monguchi,
Prof. Dr. H. Sajiki
Laboratory of Organic Chemistry, Gifu Pharmaceutical University
1-25-4 Daigakunishi, Gifu 501-1196 (Japan)
Fax : (+81)58-230-8109
E-mail: sawama@gifu-pu.ac.jp
sajiki@gifu-pu.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202984.
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Chem. Eur. J. 2012, 18, 16608 – 16611

COMMUNICATION
Table 2. Scope and limitations.[a]
and propargyl alcohols (1j–l) could also be used as sub-
strates to afford the corresponding allylic and propargyl
azides (2j–l), in which the double bond is in the more ther-
modynamically stable position, that is, in conjugation with
the phenyl group (Table 2, entries 9–11). The reaction was
also applicable to the TMS ether derived from tertiary ben-
zylalcohol 1m (Table 2, entry 12), whereas primary benzyl
TMS ether 1n and nonbenzylic secondary alkyl alcohol
TMS ether 1o were inactive toward the azidation probably
because of the lower stability of the corresponding benzyl
cations that are formed upon elimination of the siloxy
group. Encouraged by these results, the chemoselectivity of
the transformation was investigated by using a substrate
containing both a primary and a secondary silyl ether
(Table 3; entries 1 and 3).
Entry
Substrate
Product
X
t
Yield
[%]
AHCTUNGTERG[NNUN min]
1[b]
2[b]
3
1b: R3 =H
2a: R3 =H
2a: R3 =H
2a: R3 =H
2e: R3 =MeO
2 f: R3 =Cl
Br
Br
Cl
Cl
Br
180
360
30
48
71
71
88
79
Si(R2)3 =TES
1c: R3 =H
Si(R2)3 =TIPS
1d: R3 =H
Si(R2)3 =TMS
1e: R3 =MeO
Si(R2)3 =TMS
1 f: R3 =Cl
4
15
When 1p, which contains both a primary and a secondary
silyl ether, was subjected to the reaction conditions (5 mi-
5
60
Si(R2)3 =TMS
Table 3. Chemoselective azidation.[a]
6
Cl
10
96
7
8
Cl
Cl
15
10
>99
Entry
1[b]
Substrate
Product
X
t
Yield
[%]
AHCTUNGTERG[NNUN min]
96
Br
5
90
9
Cl
45
99
74
2[b]
Cl
120
53
82
10
Br
120
11[c]
Br
240
69
3[c]
Br
Br
30
5
12
13
Cl
360
180
99
4
77
66
Br
trace
14
Br
180
trace
5[d]
Cl
60
[a] Reactions were performed using FeCl3 or FeBr3 as the catalyst. Since
similar yields were obtained using both catalysts, the better results are de-
scribed in Table 2. [b] 4 equiv of TMSN3 was used. [c] 35 mol% of FeBr3
and 2 equiv of TMSN3 were used.
27
68
6[e]
Br
20
[a] Reactions were performed using either FeCl3 or FeBr3 as the catalyst.
Because the use of these catalysts led to similar yields, the better results
are described. [b] The product was isolated after acetylation of the result-
ing primary benzyl alcohol moiety resulting from the deprotection of the
primary benzylic TMS ether during the reaction. [c] 20 mol% of FeBr3
and 2 equiv of TMSN3 were used at 08C; because there was partial desil-
and 1 f bearing electron-donating and electron-withdrawing
groups, respectively, on the aromatic ring and TMS ethers
derived from 1-naphthylethanol, diphenylmethanol, and 1-
indanol (1g–i) efficiently underwent the azidation with high
yields (Table 2, entries 4–8). TMS ethers derived from allyl
ACHUTNGRENUyNG lACTHUNGTRENNUaG tion of the primary TMS ether during the reaction, the reaction was
quenched by the addition of TBAF so as to ensure complete conversion
into the alcohol product (2q). [d] The reaction was carried out using
7 mol% of FeCl3 and 1.5 equiv of TMSN3. [e] The reaction was carried
out using 10 mol% of FeCl3 and 2 equiv of TMSN3 at 08C.
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Y. Sawama, H. Sajiki et al.
nutes, room temperature), only the secondary benzylic TMS
ether moiety was transformed into the azido group, thus
giving 2p in good yield.[16] However, the azidation of nonsi-
lylated substrate 5 resulted in a lower yield of product and
required a longer reaction time (2 hours) for the total con-
sumption of 5 (Table 3, entries 1 and 2). Additionally, 1q
was also chemoselectively converted into the secondary
azido product (2q) in a modest yield (Table 3, entry 3). Al-
kylhalides, a,b-unsaturated esters, and aldehydes are easily
converted into the corresponding alkylazides, b-azido esters,
and nitriles, respectively, when treated with azide
anion.[6,10–12] However, substrate 1r, which bears an alkyl-
chloride moiety, chemoselectively underwent the azidation
at the secondary benzylic TMS ether moiety to give the cor-
responding benzylic azide (2r) (Table 3, entry 4). Moreover,
1s, which contains both an allylalcohol TMS ether and an
a,b-unsaturated ester substructure, was transformed into a
mixture of a- and g-azidated esters (2sa and 2sb) as an iso-
meric mixture resulting from the chemoselective azidation
associated with the elimination of the siloxy moiety
(Table 3, entry 5). Although 2sa and 2sb were separated by
silica-gel column chromatography, each isolated product
(2sa and 2sb) underwent smooth isomerization into the
other isomer by the rapid rearrangement of the allylic azide
group. The conversion of the aromatic aldehyde moiety of
1t into a nitrile could be prevented by conducting the azida-
tion reaction at 08C and the azidated product (2t) was ob-
tained in a good yield (Table 3, entry 6).
ly).[18,19] The corresponding carbocation species (C), which is
generated upon elimination of TMSOTMS, reacts with azide
anion to give the benzylic azido product.[20]
In conclusion, we have shown that benzylic silyl ethers un-
dergo efficient azidation using TMSN3 in the presence of
FeCl3 as a general, cheap, and safe Lewis acid. The present
azidation occurs smoothly under mild reaction conditions
and in short reaction times to give the azido products in
high yield. Moreover, the reaction is chemoselective, in that
secondary and tertiary benzyl silyl ethers are transformed
selectively in the presence of primary benzyl silyl ethers,
and alkyl chloride, a,b-unsaturated ester, and aldehyde moi-
eties are stable under the reaction conditions.
Experimental Section
Typical procedure for the azidation: To
a solution of silylether
(0.2 mmol) in (CH2Cl)2 (0.2m: 1 mL) was added trimethylsilylazide
(0.22 mmol) and either FeCl3 or FeBr3 (0.01 mmol: 5 mol% with respect
to the substrate) at room temperature under argon. After stirring the re-
action mixture until the substrate was completely consumed, as deter-
mined by TLC analysis, water was added to the reaction mixture and the
resulting mixture was extracted with CH2Cl2. The combined organic layer
was dried with Na2SO4, and concentrated in vacuo. The residue was puri-
fied by silica-gel column chromatography using cyclohexane/EtOAc
(10:1) as the eluent.
When a solution of 1e in CDCl3 in the presence of
5 mol% of FeCl3 and 1 equivalent of TMSN3 at room tem-
perature, as aged for a period of 15 minutes, was analyzed
using 29Si NMR spectroscopy, it was shown that hexamethyl-
disiloxane (TMSOTMS, 7.33 ppm) was formed as the reac-
tion progressed.[17] When an enantiomerically pure sample
of a benzylic TMS ether was subjected to the azidation con-
ditions, the resulting benzylic azide was obtained in racemic
form [Eq. (2)], thus revealing that the azidation proceeds
via a carbocation intermediate (Scheme 1, C). The proposed
mechanism is shown in Scheme 1. The oxygen atom of the
silyl ether could be either activated by coordination to both
Lewis acids or by coordination to a complex of the Lewis
acids, TMSN3 and FeCl3 (intermediates B and A, respective-
Acknowledgements
This work was partially supported by Grant-in-Aid for Young Scientists
(B) from the Japan Society for the Promotion of Science (JSPS).
Keywords: azides · chemoselectivity · ethers · homogeneous
catalysis · iron
[1] P. G. M. Wuts and T. W. Greene, Greeneꢀs Protective Groups in Or-
ganic Synthesis, 4th Edition, Wiley, Hoboken, 2007.
[2] a) M. Kira, T. Hino, H. Sakurai, Chem. Lett. 1992, 21, 555–558;
b) T. Yokozawa, K. Furuhashi, H. Natsume, Tetrahedron Lett. 1995,
36, 5243–5246; c) M. Braun, W. Kotter, Angew. Chem. 2004, 116,
520–523; Angew. Chem. Int. Ed. 2004, 43, 514–517; d) T. Saito, Y.
Nishimoto, M. Yasuda, A. Baba, J. Org. Chem. 2007, 72, 8588–8590.
[3] Y. Onishi, Y. Nishimoto, M. Yasuda, A. Baba, Org. Lett. 2011, 13,
2762–2765.
[4] N. Iranpoor, H. Firouzabadi, R. Azadi, Tetrahedron Lett. 2006, 47,
5531–5534.
[5] Representative reports are cited. See; a) R. Huisgen, Angew. Chem.
1963, 75, 604–637; Angew. Chem. Int. Ed. Engl. 1963, 2, 565–598;
b) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless,
Angew. Chem. 2002, 114, 2708–2711; Angew. Chem. Int. Ed. 2002,
41, 2596–2599.
[6] E. F. V. Scriven, Chem. Rev. 1988, 88, 297–368.
[7] N. Iranpoor, H. Firouzabadi, B. Akhlaghinia, N. Nowrouzi, Tetrahe-
dron Lett. 2004, 45, 3291–3294.
[8] B. Akhlaghinia, S. Samiei, J. Braz. Chem. Soc. 2007, 18, 1311–1315.
[9] For selected recent reports for the direct azidation of free alcohols,
see: a) M. Mizuno, T. Shioiri, Chem. Commun. 1997, 2165–2166;
b) C. Yu, B. Liu, L. Hu, Org. Lett. 2000, 2, 1959–1961; c) M. N. Sol-
tani Rad, S. Behrouz, A. Khalafi-Nezhad, Tetrahedron Lett. 2007,
Scheme 1. Proposed mechanism.
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Azidation of Benzylic Ethers
COMMUNICATION
48, 3445–3449; d) A. R. Hajipour, A. Rajaei, A. E. Ruoho, Tetrahe-
dron Lett. 2009, 50, 708–711.
[10] a) K. Nishiyama, H. Karigomi, Chem. Lett. 1982, 11, 1477–1478;
b) M. Ito, K. Koyakumaru, T. Ohta, H. Takaya, Synthesis 1995, 376–
378.
the reaction mixture, which contained indeterminable side products.
Therefore, 2p was isolated as an acetate through acetylation.
[17] An 29Si NMR spectrum of a solution of 1e in the presence of
5 mol% of FeCl3 and 1 equiv of TMSN3 at RT, as aged for a period
of 15 minutes, is shown in the Supporting Information.
[11] a) P. Lakshmipathi, A. V. R. Rao, Tetrahedron Lett. 1997, 38, 2551–
2552; b) D. J. Guerin, T. E. Horstmann, S. J. Miller, Org. Lett. 1999,
1, 1107–1109.
[12] K. Nishiyama, A. Watanabe, Chem. Lett. 1984, 13, 773–774.
[13] We recently established the gold-catalyzed azidation associated with
the ring-opening of thermodynamically stable dihydrofuran deriva-
tives using trimethylsilyl azide (TMSN3) as an azido source, see: Y.
Sawama, Y. Sawama, N. Krause, Org. Lett. 2009, 11, 5034–5037.
[14] Details of the optimization of reaction conditions using other acids
and solvents are shown in the Supporting Information.
[18] The formation of the combined Lewis acid derived from TMSCl and
InCl3 was suggested in Ref. [3].
[19] Double activation by two different Lewis acids is also possible; see:
G-L. Chua and T.-P. Loh in Acid Catalysis in Modern Organic Syn-
thesis, Vol. 1, Chapter 8 (Eds: H. Yamamoto and K. Ishihara),
Wiley-VCH, Weinheim, 2008, pp. 389.
[20] The possibility that the azidation may be proceeding through a radi-
cal pathway cannot be ruled out. For an example of a radical-medi-
ated nitrogen transfer involving azides, see; T. Bach, C. Kçrber, J.
Org. Chem. 2000, 65, 2358–2367.
[15] FeCl3 and FeBr3 exhibited similar levels of activity for the azidation;
therefore, only the better results are described in Tables 2 and 3; see
the Supporting Information for further details.
[16] The silylated primary alcohol was deprotected during the aqueous
work-up and the obtained free alcohol could not be isolated from
Received: August 22, 2012
Revised: October 22, 2012
Published online: November 30, 2012
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www.chemeurj.org
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