Direct synthesis of organic azides from primary amines with 2-azido-1,3-dimethylimidazolinium hexafluorophosphate

Article abstract of DOI:10.1002/ejoc.201001509

Organic azides were prepared from primary amines in high yields by metal-free diazo transfer with 2-azido-1,3-dimethylimidazolinium hexafluorophosphate, which is a stable, crystalline solid that is easy to handle. Organic azides were prepared from primary

Full text of DOI:10.1002/ejoc.201001509

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201001509
Direct Synthesis of Organic Azides from Primary Amines with 2-Azido-1,3-
dimethylimidazolinium Hexafluorophosphate
Mitsuru Kitamura,*[a] Masakazu Yano,[a] Norifumi Tashiro,[a] Satoshi Miyagawa,[a]
Mitsuyoshi Sando,[a] and Tatsuo Okauchi[a]
Keywords: Amines / Azides / Diazo compounds / Heterocycles
Organic azides were prepared from primary amines in high
yields by metal-free diazo transfer with 2-azido-1,3-dimeth-
ylimidazolinium hexafluorophosphate, which is a stable,
crystalline solid that is easy to handle.
Introduction
Organic azides are useful intermediates for the synthesis
of nitrogen-containing compounds.[1] The azide group is
small and stable under various conditions, but under special
conditions it shows characteristic reactivity. For example,
organic azides are used as equivalents of primary amines
and are employed in the Staudinger reaction.[2,3] Photoin-
duced nitrene formation of organic azides is widely used for
photoaffinity labeling to investigate the identification of the
ligand–target receptor and the structure of its binding
site.[4,5] Recently, a 1,3-dipole reaction of organic azides and
Figure 1. Synthesis of organic azides.
Diazo transfer to primary amines by using trifluoro-
terminal alkynes (Huisgen reaction)[6] revisited center stage methanesulfonyl azide (TfN3) by the aid of a CuII catalyst
in the field of synthetic organic chemistry, as the CuI-cata- is an alternative method for the synthesis of organic
lyzed reaction was found to be very reliable[7] and was azides.[10] The process occurs under mild reaction condi-
widely used for click chemistry.[8]
tions, high yields are obtained for nucleophilic amines, and
Various synthetic methods for organic azides have been the transformation requires only one step from the corre-
developed.[1] Among them, the nucleophilic substitution of sponding amines. TfN3, however, has an explosive nature
organic compounds having a leaving group with an azide and requires very careful treatment. Lately, imidazole-1-sul-
ion is a common method (Figure 1). Various alkyl azides fonyl azide hydrochloride has been reported as a diazo
are prepared by the reaction of sodium azide and alkyl ha- transfer reagent; it is crystalline, stable under 80 °C (decom-
lides/sulfonates, which are derived from the corresponding position temperature), and has almost the same reactivity
alkanols, whereas the synthesis of tert-alkyl azides are often as TfN3.[11]
not successful because of steric hindrance.[9] Aryl azides are
Recently, we reported that 2-azido-1,3-dimethylimid-
also prepared by substitution, but the generality of the reac- azolinium chloride (ADMC, 2) is an efficient diazo-transfer
tion is narrow compared to that of alkyl azides. Aryl halides reagent for 1,3-dicarbonyl compounds (Scheme 1).[12] In
and aryl diazonium salts are used as electrophiles; the for- this reaction, the diazotized products were easily isolated
mer require a strong electron-withdrawing group at the para because the only detectable byproduct, 1,3-dimethyl-2-imid-
or ortho position to the leaving group, and the latter are azolidinone (DMI, 4), was highly soluble in water and was
limited as substrates because aryl diazonium salts are highly separated from the desired diazo compounds by washing
reactive intermediates.
the organic extracts of the reaction mixture with water. Di-
azo-transfer reagent 2 was prepared from commercially
available chloroimidazolinium chloride 1 and sodium azide.
Imidazolinium 1 was sensitive to moisture and relatively
difficult to handle. Therefore, we expected that if the 2-
azido-1,3-dimethylimidazolinium salt was isolated as a
stable compound, the reaction using the salt would be per-
formed more conveniently.
[a] Department of Applied Chemistry, Kyushu Institute of
Technology
1-1 Sensuicho, Tobata, Kitakyushu, 804-8550 Japan
Fax: +81-93-884-3304
E-mail: kita@che.kyutech.ac.jp
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001509.
458
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Direct Synthesis of Organic Azides from Primary Amines
decomposition was observed from approximately 200 °C.
These results suggest that 6 could be used under its decom-
position temperature, preferably under 100 °C with suf-
ficient margin.
By using 6, diazo-transfer reactions to primary amines
were examined. First the reaction of 4-methoxy aniline with
6 was examined by using Et3N as a base (Table 1, Run 1).
The reaction proceeded smoothly at room temperature to
yield para-methoxyphenyl azide quantitatively. In this reac-
tion, a detectable byproduct was DMI (4), similar to the
diazotization of 1,3-dicarbony compounds shown
Scheme 2. Compound 4 was easily separated from the de-
sired azide, because their polarities were sufficiently dif-
ferent.
Scheme 1. Diazo transfer of ADMC (2) to 1,3-dicarbonyl com-
pound.
However, 2 could not be isolated because of its hygro-
scopic properties. In contrast, the corresponding hexafluo-
rophosphate salt was isolated as a stable crystalline solid
and showed the ability to undergo diazo transfer to primary
amines. In this communication, we describe the outcome of
this investigation.
Table 1. Optimization of the diazo transfer of ADMP (6) to ani-
lines 7a and 7b.
Run
R
7
Base
T
[°C]
t
[h]
8
Yield
[%][a]
Results and Discussion
2-Azido-1,3-dimethylimidazolinium
hexafluorophos-
1
2
3
4
5
6
7
8
MeO
Ac
Ac
Ac
Ac
Ac
Ac
Ac
7a
7b
7b
7b
7b
7b
7b
7b
7a
7b
Et3N
Et3N
DBU
r.t.
50
50
50
50
50
50
50
r.t.
50
0.17
7
7
7
7.5
6
8
5
0.25
7
8a
8b
8b
8b
8b
8b
8b
8b
8a
8b
quant.[b]
8
10
69
48
phate (ADMP, 6) was prepared from 1 as shown in
Scheme 2. Following a modified version of Kiso’s pro-
cedure,[13] anion exchange of 1 was accomplished by treat-
ment of KPF6 in acetonitrile to afford chloroimidazolinium
hexafluorophosphate 5. The reaction of 5 and sodium azide
in acetonitrile and successive reprecipitation by using ether
afforded 6 quantitatively. Salt 6 could be stored in a freezer
(–10 °C) for at least two months.
pyridine
2,6-lutidine
quinoline
isoquinoline
DMAP
Et3N
25
64
83
9[c] MeO
quant.[b]
75
10[c]
Ac
DMAP
[a] Isolated yield. [b] Determined by 1H NMR spectroscopy
(1,1,2,2-tetrachloroethane was used as an internal standard).
[c] The reaction was carried out in the presence of CuSO4·5H2O
(5 mol-%).
Next, para-acetylaniline, which is an unsuitable substrate
for diazo transfer with TfN3,[10d] was examined. When Et3N
was used as the base, desired azide 8b was obtained in only
8%, even though the reaction was carried out at 50 °C for
7 h (Table 1, Run 2). Then the effect of base on this reaction
was examined (Table 1, Runs 3–8). Although a strong or-
ganic base such as 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) was unsuitable for this reaction (Table 1, Run 3),
pyridine-type bases were found to be appropriate (Table 1,
Runs 4–8). By using N,N-dimethyl-4-aminopyridine
(DMAP), azide 8b was obtained in 83% yield (Table 1,
Run 8). Addition of CuSO4 did not show remarkable effect
(Table 1, Runs 9 and 10).
Scheme 2. Preparation of 2-azido-1,3-dimethylimidazolinium hexa-
fluorophosphate (ADMP, 6).
Both impact sensitivity test[14] and friction sensitivity
test[15] showed that salt 6 was negative to explosion in the
range of the tests. Figure 2 shows the results of a differential
scanning calorimetry (DSC) experiment on 6. Exothermic
We also examined the reaction of anilines 7a and 7b with
imidazolinium
2
prepared by the previous report[12]
(Table 2). In both cases, the yields of azides 8 were low com-
pared to the results using 6, and guanidine 9 was also
formed. These results suggested that the use of 6 is more
efficient for this diazo transfer than the use of an in situ
prepared azide imidazolinium salt. The low yield of azide
Figure 2. DSC measurement of ADMP (6; heating rate: 10 K/min,
sample size 3.36 mg, argon atmosphere, open Al pan).
Eur. J. Org. Chem. 2011, 458–462
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459

M. Kitamura et al.
SHORT COMMUNICATION
formation may also be attributed to the effect of ines 7 were transformed into azides in high yields (Table 3,
counteranions, because the yields of 8 using 6 were lower Runs 5 and 6). Even though low nucleophilic anilines sub-
in the presence of Cl–.[16]
stituted with strong electron-withdrawing groups such as
acetyl, cyano, and nitro groups were employed, the diazo-
transfer reaction proceeded with the use of an excess
amount of 6 and DMAP (Table 3, Runs 7–9).
Table 2. Diazo transfer of ADMC (2) to anilines 7a and 7b.[a]
In the case of ortho-disubstituted anilines, the effect of
substituent is remarkable. Aniline 7j having dimethyl groups
gave the corresponding azide 8j in good yield, regardless of
the steric hindrance, whereas dichloroaniline gave the azide
in only 22%, probably due to the low nucleophilicity
(Table 3, Runs 10 and 11). 1-Naphthylamines also reacted
similarly to the corresponding anilines (Table 3, Runs 12
and 13).
Next, the reaction of ADMP (6) with primary alk-
ylamines was examined. In the reaction of 2-phenylethylam-
ine using DMAP, azide 8n was obtained in only 21% ac-
companied by the formation of guanidine 9 in 79%
(Table 3, Run 14). The yield of azide 8n increased to 74%
when Et3N was used as the base (Table 3, Run 15). Simi-
larly, Et3N was better than DMAP as a base in the case of
diazotization of cyclohexylamine (Table 3, Runs 16 and 17).
The bulkier secondary alkylamines and the tertiary alk-
ylamines were transformed into the corresponding azides in
high yields by using DMAP as the base (Table 3, Runs 18–
20).
Run
7
Base
Conditions
Yield [%][b]
8
9
1[c]
2[d]
7a
7b
Et3N
DMAP
0 °C, 20 min
0 °CǞreflux, 3.5 h
48
34
52
35[d]
[a] To a solution of 2 (prepared by the reaction of 1 and an equi-
molar amount of NaN3 in CH3CN at 0 °C for 30 min.) was added
7 and base. [b] Determined by 1H NMR spectroscopy for Run 1
(1,1,2,2-tetrachloroethane was used as an internal standard). Iso-
lated yield for Run 2. [c] Ratio 2/base/7a = 1.2:1.2:1. [d] Ratio 2/
base/7b = 3:3:1.
To explore the scope of this reaction, various primary
amines were subjected to the diazo-transfer reaction with 6
in the presence of DMAP (Table 3). In Runs 1–13, the re-
sults of aromatic amines are shown. Nonsubstituted aniline
and anilines having electron-donating groups reacted with
6 smoothly at room temperature to give the corresponding
In the diazo-transfer reaction, DMAP showed efficiency
azides in high yields (Table 3, Runs 1–4). By using a slight as a base, in general, whereas a more nucleophilic base was
excess amount of 6 at 50 °C, monohalogen-substituted anil- found to be suitable for highly nucleophilic primary amines.
Table 3. Synthesis of various organic azides 8 from primary amines 7 by using ADMP (6).
Run
R
7
ADMP (6)
[equiv.]
DMAP
[equiv.]
T
[°C]
t
[h]
8
Yield
[%][a,b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Ph
4-MeOC6H4
4-MeC6H4
4-(nBu)C6H4
4-ClC6H4
7c
7a
7d
7e
7f
7g
7b
7h
7i
1.15
1.15
1.15
1.15
1.3
1.5
2
2
2
1.5
2
1.3
2.0
1.15
1.15
1.15
1.15
1.15
1.15
1.15
1.1
1.1
1.1
1.1
1.1
1.1
3
3
3
1.1
3
1.1
3
1.1
5[d]
1.1
5[d]
1.1
1.1
1.1
r.t.
r.t.
r.t.
r.t.
50
50
50
50
50
50
50
50
50
r.t.
r.t.
r.t.
r.t.
r.t.
50
r.t.
2.5
0.5
1.5
1.5
3
5
5
4
4
3.5
4
1.5
6
0.25
0.25
0.25
0.25
1
6
0.33
8c
8a
8d
8e
8f
8g
8b
8h
8i
87
87 (90)
94
86 (93)
95
84 (85)
83 (15)
63 (7)
61
73
22
92
43
4-BrC6H4
4-AcC6H4
4-cyano-C6H4
4-O2NC6H4
2,6-Me2C6H3
2,6-Cl2C6H3
1-naphthyl
4-nitro-1-naphthyl
PhCH2CH2
PhCH2CH2
cHex
7j
7k
7l
8j
8k
8l
7m
7n
7n
7o
7o
7p
7q
7r
8m
8n
8n
8o
8o
8p
8q
8r
21[c]
74[e]
31[f,g]
85[f,h]
73, 94[f]
99
cHex
Ph(CH3)CH
Ph3C
1-adamantyl
71
[a] For the comparable reaction with TfN3, see ref.[10d] Yield in parentheses is that from ref.[10d] [b] Isolated yield. [c] Guanidine 9 was
obtained in 79% yield. [d] Et3N was used instead of DMAP. [e] Guanidine 9 was obtained in 24% yield. [f] Determined by 1H NMR
spectroscopy (1,1,2,2-tetrachloroethane was used as an internal standard). [g] Guanidine 9 was obtained in 49% yield. [h] Guanidine 9
was obtained in 10% yield.
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Direct Synthesis of Organic Azides from Primary Amines
1.0 mmol) and N,N-dimethyl-4-aminopyridine (DMAP; 367 mg,
3.0 mmol) in CH2Cl2 (2 mL) at room temperature. The mixture was
stirred for 5 h at 50 °C. The reaction was quenched with
aq.NaHCO3 (20 mL), and the organic materials were extracted
with CH2Cl2 (3ϫ15 mL). The combined extracts were washed with
water (30 mL) and brine (30 mL) and then dried with anhydrous
sodium sulfate. The solvent was removed in vacuo to afford the
crude compound, which was purified by flash column chromatog-
raphy (silica gel, hexane/ethyl acetate = 9:1) to give 8b (134 mg,
83% yield; Table 1, Run 8).
Bases have two roles: the neutralization of the formed acid
and the activation of ADMP. On the basis of this consider-
ation, a possible reaction mechanism is depicted in
Scheme 3. In the case where the base is more nucleophilic
than the primary amine, the base first reacts with 6 to form
intermediate I, which is substituted with a primary amine
to form intermediate II, the salt of HPF6, and base. Intra-
molecular proton abstraction in II occurs to afford corre-
sponding azide 8. In the case where the primary amine is
more nucleophilic than the base, the primary amine attacks
at both the a and b positions in 6 to give guanidine 9 and
azide 8, respectively.
Supporting Information (see footnote on the first page of this arti-
cle): General methods, experimental procedure for the synthesis of
5, and physical data of 5 and 8.
Acknowledgments
This work was partially supported by Nagase Science Technology
Foundation and a Grant-in-Aid from the Ministry of Education,
Culture, Sports, Science, and Technology of Japan.
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3116.
Scheme 3. Plausible reaction mechanism.
Conclusions
We have synthesized 2-azido-1,3-dimethylimidazolinium
hexafluorophosphate (ADMP, 6), which was isolated as a
stable crystalline solid. ADMP shows efficient diazo-trans-
fer ability to primary amines even without the aid of a
metal salt such as CuII. Using this diazotization approach,
various alkyl/aryl azides were obtained directly from the
corresponding primary amines in high yields and were eas-
ily isolated.
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Experimental Section
2-Azido-1,3-dimethylimidazolinium Hexafluorophosphate (ADMP,
6): To a solution of chloroimidazolinium hexafluorophosphate (5;
2.35 g, 7.8 mmol) in CH3CN (8 mL) was added sodium azide
(717 mg, 11 mmol) at 0 °C, and the mixture was stirred for 30 min.
The mixture was filtered through a Celite pad, and the filtrate was
concentrated in vacuo. The residue was dissolved in a small amount
of CH3CN (ca 2 mL), and the solution was poured into ether to
form a precipitate, which was collected by suction filtration to af-
ford 6 (2.27 g) quantitatively. M.p. 203–205 °C (decomp.). 1H
NMR (400 MHz, CD3CN): δ = 3.74 (s, 4 H) 3.01 (s, 6 H) ppm.
13C NMR (100 MHz, CD CN): δ = 55.0, 33.8 ppm. IR (nujol): ν
˜
3
= 2360, 2173, 1647, 1578 cm–1. C5H10F6N5P (285.13): calcd. C
21.06, H 3.54, N 24.56; found C 21.07, H 3.42, N 24.27.
Typical Procedure for the Diazo Transfer of ADMP (6) to Primary
Amines: ADMP (6; 573 mg, 1.15 mmol) in CH2Cl2 (2 mL) was
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a solution of 4-aminoacetophenone (7b; 136 mg,
3800.
Eur. J. Org. Chem. 2011, 458–462
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461

M. Kitamura et al.
SHORT COMMUNICATION
[12]
[16] In the presence of LiCl, the reaction mixture gradually became
complex, as monitored by TLC, and the yields of diazotized
products 8 were low. For example, the yield of 8a became 68%
in the presence of LiCl under nearly identical conditions to
those outlined in Table 1, Run 1 (Et3N as the base). In the case
of diazo transfer to 7b with ADMP in the presence of LiCl
under nearly identical conditions to those outlined in Table 1,
Run 8 (DMAP as the base), the yield of 8b was 52% after heat-
ing at reflux for 5 h.
M. Kitamura, N. Tashiro, T. Okauchi, Synlett 2009, 2943–
2944.
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[14] Impact sensitivity was Ͼ25 Nm by German Federal Institute
for Materials Research and Testing (BAM) procedure.
[15] Friction sensitivity was Ͼ360 N by German Federal Institute
for Materials Research and Testing (BAM) procedure.
Received: November 10, 2010
Published Online: December 14, 2010
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Eur. J. Org. Chem. 2011, 458–462