Direct Azidation of Phenols

Article abstract of DOI:10.1002/ejoc.201900967

Direct azidation of phenols was developed. By treating chloroimidazolinium chloride 1b and sodium azide with phenol in the presence of a secondary amine in methoxyethanol, ortho-azidation of phenol was achieved.

Full text of DOI:10.1002/ejoc.201900967

A Journal of
Accepted Article
Title: Direct Azidation of Phenols
Authors: Mitsuru Kitamura, Kento Murakami, Tatsuya Koga, Takashi
Eto, Akihiro Ishikawa, Hirokazu Shimooka, and Tatsuo
Okauchi
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900967
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900967
Supported by

10.1002/ejoc.201900967
European Journal of Organic Chemistry
COMMUNICATION
Direct Azidation of Phenols
Mitsuru Kitamura*,[a] Kento Murakami, Tatsuya Koga, Takashi Eto, Akihiro Ishikawa, Hirokazu
Shimooka, Tatsuo Okauchi
Abstract: Direct azidation of phenols was developed. By treating
–
chloroimidazolinium chloride 1b and sodium azide with phenol in the
presence of a secondary amine in methoxyethanol, ortho-azidation of
phenol was achieved.
+
N
Cl–
N
Cl–
2-naphthol
Et3N
Cl
N
NaN3
+
NMe
MeN
NMe
MeN
1a
ADMC
Introduction
O
NH
NMe
N
H
Aryl azides have often been used in organic syntheses as
equivalents of protected aniline, and they have recently become
increasingly important in biological chemistry.1 Photoinduced
nitrene formation from aryl azides is a common method of
photoaffinity labeling to investigate the functions of enzymes and
proteins.2 1,3-Dipole reactions of aryl azides and alkynes are
indispensable for drug discovery and linking labeling groups to
biomolecules.3
N
+
O
MeN
N
+
–
N
N
MeN NMe
2
3
I
Scheme 1. Diazo-transfer of ADMC to naphthol.
Various methods of synthesizing aryl azides have been
reported.4–9 Aryl azides are often prepared from aryl amines by i)
diazotization and subsequent reaction of thus formed diazonium
salts with nitrogen nucleophiles, such as azide ions,4 or ii) diazo-
transfer.5,6 Aryl halides are also used as starting materials for
synthesizing aryl azides. For example, aryl azides are
synthesized by nucleophilic substitution (SNAr reaction) of
activated aryl halides with azide ions,7 and substitution of sulfonyl
azides with aryl magnesium or aryl lithium reagents formed from
aryl halides.8 Recently, metal-catalyzed coupling of aryl halides or
aryl boronic acids with azide anions was developed.9 Direct
substitution of aromatic hydrogen with an electrophile by
electrophilic aromatic substitution is a powerful method for
synthesizing substituted arenes, and electron-rich aryl
compounds such as phenols are efficient aryl donors in the
reaction.10 However, direct azidation of arenes has not been
reported even for phenols.
Stable N-heterocyclic carbenes (NHC) are used as ligands of
metal catalysts and organocatalysts in organic reactions.13 Five-
membered imidazole-derived NHC 7, bearing
a
bulkier
substituent R on its nitrogen, is commonly used for the reactions.
We expected that direct introduction of the azide group to phenol
could be achieved using azidoimidazolinium salt 5 when stable
NHC 7 was released from adduct II of azidoimidazolinium salt 5
and phenol 4 (Scheme 2). We then began to investigate the direct
azidation of phenol. Herein, we describe the results in detail.
–
N
R
R
+
N
O
O
base
N
+
N
N
H
N
N
H
+
–
HO
RN
NR
R
N
N
+
4
5
MeN NMe
MeN NMe
II
We have been studying the reactions of 2-azido-1,3-
dimethylimidazolinium salts, which showed efficient diazo-
transfer ability;11 2-azido-1,3-dimethylimidazolinium chloride
(ADMC), prepared from 2-chloro-1,3-dimethylimidazolinium
chloride (1a) and sodium azide, reacted with naphthols in the
presence of Et3N to give diazonaphthoquinones 2, which were
formed via intermediate I, releasing guanidine 3 (Scheme 1).12
+
RN NR
HO
R
N3
7
6
Scheme 2. Plan of direct azidation of phenol.
Results and Discussion
[a]
Prof. Dr. M. Kitamura,
Department Applied Chemistry
Kyushu Institute of Technology
1-1 Sensuicho, Tobata, Kitakyushu, 804-8550
E-mail: kita@che.kyutech.ac.jp
Homepage: http://www.che.kyutech.ac.jp/chem27/chem27.html
For the azidation, 2,4-dimethylphenol (m-xylenol, 4a) was chosen
as a model compound. First, chloroimidazolinium chloride 1 (1.2
equiv., Figure 1) and sodium azide (10 equiv.) were mixed at −30
°C in acetonitrile to prepare azide imidazolinium 5, and m-xylenol
(4a) and base were added to the reaction mixture (Method A)
(Table 1, runs 1–4). Using chloroimidazolinium chloride 1b, the
expected azidation proceeded in the presence of various
bases,14 and azidophenol 6a was obtained in the highest yield
Supporting information for this article is given via a link at the end of
the document. General methods, experimental procedure, physical
data of 1, 6, 9a-PF6, 10, and 1H and 13C NMR spectra of 1, 6, 9a-
PF6, 10.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900967
European Journal of Organic Chemistry
COMMUNICATION
(57%) when Et2NH was used (Table 1, run 1). When 1c was
employed, 6a was obtained in 38% yield (run 2). Although
azidation proceeded using saturated chloroimidazolinium chloride
1c, the yield of 6a was lower than that using unsaturated 1b (run
1 vs. run 3). ADMC, prepared from 1a, did not work for the
azidation of phenol 4a (run 4).
instead of sodium azide, azidophenol 6a was not formed at all
(run 16).
Table 1. Direct azidation of m-xylenol (4a).[a]
1) NaN3, solvent
–30 °C, 20 min.
method A
Cl–
R1
R1
2) m-Xylenol (4a), Et2NH
-30 °C to rt, 8 h
OH
Cl
Cl–
Cl
N3
+
N
R2
R2
+
NR
N
RN
1b: R1 = iPr, R2 = H
1c: R1 = R2 = CH3
1) m-Xylenol (4a), iPr2NH
solvent , 0 °C to rt, 1 h
R1
R1
1
6a
2) NaN3
0 °C to rt, 7-8 h
Cl–
iPr
method B
iPr
iPr
iPr
iPr
iPr
Cl
F
F
+
ArN
+
N
N
N
N
N
Ar
N
N
iPr
iPr
O
+
N
1f
1e
ArN
NAr
ArN
NAr
8a
Figure 1. Imidazolinium chlorides 1b–1e and related compound 1f.
Ar = 2,6-(iPr)2C6H3
9a
Run
1
Method[a]
1
solvent
CH3CN
Yield [%]
By changing the order of mixing reagents (1b, 4a, base, and
sodium azide), azidophenol 6a was also obtained. That is, phenol
4a, 1b, and base were mixed first, and then sodium azide was
added to the mixture (Method B). When phenol 4a was treated
with 1b in the presence of Et2NH in acetonitrile, phenol 4a was
gradually consumed and a new TLC spot was observed; this was
consumed on adding sodium azide to form azidophenol 6a in 46%
yield (Table 1, run 5). Although we could not confirm the structure
of the intermediate in the first step, this may be 8a, similar to the
A
A
A
A
B[b]
B
B
B
B
B
B
B
A
B
B
B
1b
1c
1d
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
57
38
13
0
2
CH3CN
3
CH3CN
4
CH3CN
5
CH3CN
46
62
69
72
71
61
87
90
85
70
49
0
i
adduct of phenol and 1f, reported by Ritter et al.15 When Pr2NH
6
CH3CN
was used, 6a was obtained in the highest yield (62%) (run 6)
among the bases we examined.14
7
CH3OH
In the reactions using methods A and B in acetonitrile, not all the
sodium azide dissolved in the solvent, and the reaction mixture
changed from colorless to reddish as the formation of 6a
progressed. For example, in the reactions using 1b (runs 1, 5, and
6 in Table 1), the reaction mixtures became red as the reaction
progressed. The red color was attributed to the formation of 9a,
8
EtOH
9
iPrOH
10
11
12
13
14[c]
15[d]
16[e]
tBuOH
HO(CH2)2OH
HO(CH2)2OCH3
HO(CH2)2OCH3
HO(CH2)2OCH3
HO(CH2)2OCH3
HO(CH2)2OCH3
1
by comparison with the H NMR spectrum of the PF6 salt of 9a
(9a-PF6). Authentic 9a-PF6 was synthesized as shown in Scheme
3. When 1b and sodium azide were mixed in acetonitrile at room
temperature, the reaction mixture became red. The red species
was isolated as the PF6 salt by treating the mixture with KPF6, and
its structure was confirmed by single crystal X-ray structure
analysis (Figure 2).16,17
Further optimization of the azidation with 1b and iPr2NH was
conducted using Method B. When protic solvents were used, the
reaction mixture formed a single phase because sodium azide
was dissolved in the solvents, and it did not change color (runs 7–
12). Using ethylene glycol and ethylene glycol monomethyl ether
increased the yield of 6a to 87% and 90%, respectively (runs 11
and 12). The efficiency of ethylene glycol monomethyl ether was
also confirmed in the reaction using Method A (run 13). The use
of excess sodium azide was important in achieving a high yield in
the azidation (runs 12, 14, 15). When trimethylsilyl azide was used
[a] Reaction conditions. Method A: i) 1 (1.2 equiv.), NaN3 (10 equiv.), in
solvent −40 °C, 10 min, ii) 4a (1 equiv.), Et2NH (2.0 equiv.), −40 °C to r.t., 8
h. Method B: i) 4a (1 equiv.), 1b (1.2 equiv.), iPr2NH (2.0 equiv.), in solvent
0 °C to r.t., 1 h, ii) NaN3 (10 equiv.), 0 °C to r.t., 7–8 h. [b] Et2NH was used
instead of iPr2NH. [c] 5 equiv. of NaN3 was used. [d] 2.5 equiv. of NaN3 was
used. [e] 10 equiv. of trimethylsilyl azide was used instead of NaN3.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900967
European Journal of Organic Chemistry
COMMUNICATION
+
ArN
2
4c (R1
CH3)
=
OCH3, R2
=
6c (65)
8
Cl–
iPr
iPr
Cl
–
1) NaN3, MeCN
r.t., 2 h
N
Ar
PF6
N
+
N
N
3
4
5
6
7
4d (R1 = CHO, R2 = CH3
4e (R1 = CH3, R2 = Cl)
4f (R1 = H, R2 = tBu)
4g (R1 = H, R2 = CH3)
6d (30)
6e(28)
6f (26)
6g (29)
6h (74)
61
35
40
52
0
N
N
2) KPF6
r.t., 1 h
iPr
iPr
1b
ArN
NAr
41%
10f (30)
10g (13)
9a-PF6 Ar = 2,6-(iPr)2C6H3
Scheme 3. Synthesis of 9a-PF6.
4h (R1
=
H, R2
=
CO2CH3)
8
4i (R1 = H, R2 = OCH3)
4j (R1 = H, R2 = Cl)
6i (30)
6j (10)
6k (13)
66
56
26
9
10
11
4k (R1 = CH3, R2 = H)
HO
O
HO
N
11 (37)
4l
0
-
[c]
12
2-naphthol
-
[a] Reaction conditions: i) substrate (phenol, 1 equiv.), 1b (1.2 equiv.), iPr2NH
(2.0 equiv.), HO(CH2)2OCH3, r.t., 1 h, ii) NaN3 (10 equiv.), r.t., 7-8 h. [b]
Recovery of substrate. [c] Complex mixture.
Figure 2. X-ray structure of 9a-PF6 omitting hydrogen atoms and PF6.
To explore the scope and limitations of the azidation, various
phenols were examined under the optimal conditions for Method
B (Table 2). In the reaction with 2,4-disubstituted phenol 4, 6-
azidophenol 6 was obtained in good yield when the substituents
were electron-donating groups (runs 1 and 2). However, the yields
of azide 6 were low when one substituent R in 4 was electron-
withdrawing (runs 3 and 4). In the reaction with 4-monosubstituted
phenol, monoazide 6 and diazide 10 were formed depending on
the substituents (runs 5–9); 4-alkylphenol gave a mixture of 6 and
10 (runs 5 and 6). Conversely, 4-methoxycarbonylphenol (4h)
gave monoazide 6h in high yield (run 7). In the reactions with 4-
methoxyphenol (4i) and 4-chlorophenol (4j), monoazides 6 were
formed selectively, but the yields were low (runs 8 and 9). In the
reaction with 2-methylphenol (4k), azide 6k was obtained in 13%
yield (run 10); 2,6-dimethylphenol (4l) did not give the
corresponding azide but afforded quinoneimine 11 (run 11). The
reaction with 2-naphthol was complex, and no compounds were
identified (run 12).
Conclusion
We have developed a new synthetic method for direct azidation
of phenols. Although azidophenols have been prepared from
phenol by several steps via aminophenols, generally, our method
offers one-step transformation of phenol to azidophenol. The
drawbacks of this reaction are the requirement for an equimolar
amount of a large leaving group and excess sodium azide, which
are under consideration for improvement.
Experimental Section
Typical procedure for Method A: To a solution of imidazolium chloride 1
(1.2 mmol) in acetonitrile (2.5 mL) at -40 °C, sodium azide (10 mmol) was
added, and the mixture was stirred at -40 °C for 10 min. Phenol 4 (1.0
mmol) and diethylamine (2.0 mmol) in acetonitrile (2.5 mL) was added to
the mixture at -40 °C. The reaction mixture was warmed to room
temperature, and was stirred for 8 h. Then, the reaction was quenched by
adding water. The organic materials ware extracted with ethyl acetate
three times. The combined extracts ware washed with brine and then dried
over anhydrous Na2SO4. The solvent was removed in vacuo to afford
crude compounds, which was purified by silica gel column
chromatography (hexane/ethyl acetate) to give pure azidophenol 6.
Table 2. Direct azidation of various phenols.[a]
Run
Substrate
Product (Yield [%])
Rec.
of
4
[%][b]
N3
N3
HO
N3
HO
R1
HO
R1
R2
R2
R2
Typical procedure for Method B: To a solution of imidazolium chloride 1
(0.80 mmol) in ethylene glycol mono methyl ether (5 mL) at room
temperature, phenol 4 (0.67 mmol) and diisopropylamine (1.3 mmol) were
added. After stirring the mixture for 1 h at room temperature, sodium azide
6
10
1
4b (R1 = tBu, R2 = CH3)
6b (71)
22
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900967
European Journal of Organic Chemistry
COMMUNICATION
(6.7 mmol) was added. The reaction mixture was stirred for 7-8 hour at this
temperature, then the reaction was quenched by adding water. The
organic materials ware extracted with ethyl acetate three times. The
combined extracts ware washed with brine and then dried over anhydrous
Na2SO4. The solvent was removed in vacuo to afford crude compounds,
which ware purified by silica gel column chromatography (hexane/ethyl
acetate) to give pure azidophenols 6 and 10.
C.-H. Liang, K. M. Koeller, C.-H. Wong, J. Am. Chem. Soc., 2002, 124,
10773; e) J. R. Suárez, B. Trastoy, M. E. Pérez-Ojeda, R. Marín-Barrios,
J. L. Chiara, Adv. Synth. Catal., 2010, 352, 2515. f) E. D. Goddard-
Borger, R. V. Stick, Org. Lett. 2007, 9, 3797; g) N. Fischer, E. D.
Goddard-Borger, R. Greiner, T. M. Klapötke, B. W. Skelton, J.
Stierstorfer, J. Org. Chem. 2012, 77, 1760. h) A. R. Katritzky, M. El Khatib,
O. Bol'shakov, L. Khelashvili, P. J. Steel, J. Org. Chem. 2010, 75, 6532.
a) M. Kitamura, M. Yano, N. Tashiro, S. Miyagawa, M. Sando, T. Okauchi,
Eur. J. Org. Chem. 2011, 458; b) M. Kitamura, S. Kato, M. Yano, N.
Tashiro, Y. Shiratake, M. Sando, T. Okauchi, Org. Biomol. Chem. 2014,
12, 4397.
[6]
[7]
Acknowledgments
a) J. F. W. Keana, S. X. Cai, J. Org. Chem. 1990, 55, 3640. b) C. K.
Lowe-Ma, R. A. Nissan, W. S. Wilson, J. Org. Chem. 1990, 55, 3755.
P. A. S. Smith, C. D. Rowe, L. B. Bruner, J. Org. Chem. 1969, 34, 3430.
a) W. Zhu, D. Ma, Chem. Commun. 2004, 888. b) J. Andersen, U.
Madsen, F. Bjorkling, X. Liang, Synlett 2005, 2209; c) K. D. Grimes, A.
Gupte, C. C. Aldrich, Synthesis 2010, 1441; d) M. Karimzadeh, K.
Niknam, N. Manouchehria, D. Tarokha, RSC Adv. 2018, 8, 25785.
This work was supported by JSPS KAKENHI Grant Number
17K19125. This work was performed under the Cooperative
Research Program of "Network Joint Research Center for
Materials and Devices.".
[8]
[9]
Keywords: azidation • azides • phenols
[10] M. B. Smith, J. March, March's Advanced Organic Chemistry, Wiley, New
Jersey, 2007, p. 657.
[11] For reviews, see: a) M. Kitamura, Yuki Gosei Kagaku Kyokaishi, 2014,
72, 14; b) M. Kitamura, Chem. Rec. 2017, 17, 653.
[1]
a) E. F. V. Scriven, K. Turnbull, Chem. Rev. 1988, 88, 297; b) S. Bräse,
C. Gil, K. Knepper, V. Zimmermann, Angew. Chem., Int. Ed. 2005, 44,
5188; c) S. Bräse, K. Banert, Organic Azides, Wiley, Wiltshire, 2010.
a) H. Bayley, Photogenerated Reagents in Biochemistry and Molecular
Biology, Elsevier, New York, 1983; b) J. V. Staros, Trends Biochem. Sci.
1980, 5, 320; c) J. S. Fedan, G. K. Hogaboom, J. P. O’Donnell, Biochem.
Pharmacol. 1984, 33, 1167; d) A. Radominska, R. Rdrake, Methods
Enzymol. 1994, 230, 330.
[12] a) M. Kitamura, N. Tashiro, R. Sakata, T. Okauchi, Synlett 2010, 2503;
b) M. Kitamura, R. Sakata, N. Tashiro, A. Ikegami, T. Okauchi, Bull.
Chem. Soc. Jpn. 2015, 88, 824.
[2]
[13] For reviews, see: a) W. A. Herrmann, Angew. Chem. Int. Ed. 2002, 41,
1290; b) D. Bourissou, O. Guerret, F. P. Gabbaï, G. Bertrand, Chem. Rev.
2000, 100, 39, c) M. N. Hopkinson, C. Richter, M. Schedler, F. Glorius,
Nature, 2014, 510, 485.
[14] Various bases were examined for the reactions, such as nBuNH2, Et2NH,
iPr2NH, iPr2NEt, Et3N, 1,8-Diazabicyclo[5.4.0]-7-undecene (DBU),
pyridine, 4-dimethylaminopyridine (DMAP), imidazole, and 1,2,4-triazole.
[15] P. Tang, W. Wang, T. Ritter, J. Am. Chem. Soc. 2011, 133, 11482.
[16] CCDC 1912420 contains the supplementary crystallographic data for
compound 9a-PF6.
[3]
[4]
a) F. Amblard, J. H. Cho, R. F. Schinazi, Chem. Rev. 2009, 109, 4207;
b) M. D. Best, Biochemistry, 2009, 48, 6571; c) P. Thirumurugan, D.
Matosiuk, K. Jozwiak, Chem. Rev. 2013, 113, 4905.
a) J. D. Wallis, J. D. Dunitz, J. Chem. Soc., Chem. Commun. 1983, 910;
b) M. F. Joucla, C. W. Rees, J. Chem. Soc., Chem. Commun. 1984, 374;
c) T. Keumi, T. Umeda, Y. Inoue, H. Kitajima, Bull. Chem. Soc. Jpn. 1989,
62, 89; d) S. M. Capitosti, T. P. Hansen, M. L. Brown, Org. Lett. 2003, 5,
2865. e) C. Cismas, T. Gimisis, Tetrahedron Lett. 2008, 49,1336. f) K. V.
Kutonova, M. E. Trusova, P. S. Postnikov, V. D. Filimonov, J. Parello,
Synthesis 2013, 45. 2706.
[17] a) S. Haslinger, G. Laus, V. Kahlenberg, K. Wurst, T. Bechtold, S.
Vergeiner,
H.
Schottenberger,
Crystals
2016,
6,
40;
doi:10.3390/cryst6040040; b) J. Back, J. Park, Y. Kim, H. Kang, Y. Kim,
M. J. Park, K. Kim, E. Lee, J. Am. Chem. Soc. 2017, 139, 15300.
[5]
a) C. J. Cavender, V. J. Shiner, Jr, J. Org. Chem. 1972, 37, 3567; b) J.
Zaloom, D. C. Roberts, J. Org. Chem. 1981, 46, 5173; c) P. B. Alper, S.-
C. Hung, C.-H. Wong, Tetrahedron Lett. 1996, 37, 6029; d) P. T. Nyffeler,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900967
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Azidation
M. Kitamura*, K. Murakami, T. Koga, T.
Eto, A. Ishikawa, H. Shimooka, T.
Okauchi
Cl–
iPr
iPr
iPr
Cl
OH
OH
1) 1b, iPr2NH
MeOCH2CH2OH
+
N
N3
N
2) NaN3
Page No. – Page No.
iPr
R
R
1b
Direct Azidation of Phenols
Direct azidation to phenol was archived by the treatment of chloroimidazolinium
cloride 1b, secondary amine, and sodium azide in methoxyethanol.
This article is protected by copyright. All rights reserved.