Fast dye salts provide fast access to azidoarene synthons in multi-step one-pot tandem click transformations

Article abstract of DOI:10.1016/j.tetlet.2011.08.069

This study examined whether commercially available diazonium salts could be used as efficient aromatic azide precursors in one-pot multi-step click transformations. Seven different diazonium salts, including Fast Red RC, Fast Blue B, Fast Corinth V and Va

Full text of DOI:10.1016/j.tetlet.2011.08.069

Tetrahedron Letters 52 (2011) 5512–5515
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Fast dye salts provide fast access to azidoarene synthons in multi-step
one-pot tandem click transformations
⇑
James T. Fletcher , Jacqueline E. Reilly
Department of Chemistry, Creighton University, 2500 California Plaza, Omaha, NE 68178, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
This study examined whether commercially available diazonium salts could be used as efficient aromatic
azide precursors in one-pot multi-step click transformations. Seven different diazonium salts, including
Fast Red RC, Fast Blue B, Fast Corinth V and Variamine Blue B were surveyed under aqueous click reaction
conditions of CuSO4/Na ascorbate catalyst with 1:1 t-BuOH/H2O solvent. Two-step tandem reactions with
terminal alkyne and diyne co-reactants led to 1,2,3-triazole products in 66–88% yields, while three-step
tandem reactions with trimethylsilyl-protected alkyne and diyne co-reactants led to 1,2,3-triazole
products in 61–78% yields.
Received 28 July 2011
Accepted 11 August 2011
Available online 19 August 2011
Keywords:
Tandem reaction
Cycloaddition
Diazonium salts
Alkynes
Ó 2011 Elsevier Ltd. All rights reserved.
The high chemospecificity of the copper-catalyzed Huisgen 1,3-
dipolar cycloaddition, commonly termed the Sharpless–Meldal
‘click’ reaction,1–4 has proven amenable to the development of tan-
dem click reactions involving multiple reaction steps within a sin-
gle reaction pot. Due to the potential danger in isolating small
organic azides,1,5 such reactions often involve the in situ formation
of azide intermediates that are subsequently converted into 1,2,3-
triazole products. Established organic azide precursors for multi-
step one-pot click transformations include alkyl, benzylic,6–8
Diazonium salts are known to undergo reactions such as diazo
coupling with electron-rich partners, a commonly used approach
to prepare pH indicators as well as colorfast fabric dyes (hence
the ‘fast dye salt’ moniker).24 They can also undergo a variety of
nucleophilic substitution reactions, including hydrolysis.25,26
Although substitution by the azide nucleophile used in these reac-
tions was predicted to be rapid, the potential for competitive del-
eterious side reactions was
a concern. Hence, an important
component of this investigation was to determine whether
allylic8 and
a
-carbonyl halides,9 as well as amines,10–12 boronic
acids,13 epoxides14,15 and alcohols.16
While a variety of precursors able to generate aliphatic azides
have been reported recently in the literature, examples of synthons
able to efficiently generate aromatic azides in the context of tan-
dem click reactions are limited in comparison.17–19 Hence, the goal
of this investigation was to identify a new class of synthons able to
serve as aromatic azide precursors for such processes. Because a
variety of aromatic diazonium salts are commercially available
and represent an interesting diversity of chemical functionality,
this study aimed to determine whether such compounds could
be used directly as efficient aromatic azide precursors in one-pot
tandem click reactions. In this study both two-step and three-step
one-pot click transformations were evaluated: a two-step process
(Scheme 1) involving the in situ formation of organic azide fol-
lowed by copper-catalyzed Huisgen 1,3-dipolar cycloaddition,
and a three-step process (Scheme 2) that additionally incorporates
a base-catalyzed trimethylsilylalkyne deprotection step.20–23
NaN3
CuSO4
N
R
Na ascorbate
N
N
+
R
N2+X-
R'
t-BuOH:H2O
room temperature
24 h
R'
Scheme 1. Two-step tandem click transformation.
NaN3
K2CO3
CuSO4
N
R
Na ascorbate
N
N
+
R
N2+X-
TMS
R'
t-BuOH:H2O
room temperature
24 h
R'
⇑
Corresponding author. Tel.: +1 402 280 2273; fax: +1 402 280 5737.
E-mail address: jamesfletcher@creighton.edu (J.T. Fletcher).
Scheme 2. Three-step tandem click transformation.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.069

J. T. Fletcher, J. E. Reilly / Tetrahedron Letters 52 (2011) 5512–5515
5513
Because the reactions were run at room temperature, there was
some concern that electron rich arene reactants might lead to dia-
zonium coupling side reactions competing with the desired Cu-cat-
alyzed cycloaddition. These concerns were found to be
unwarranted, in that no major differences in yield or product pur-
ity were observed between the aliphatic alkyne 1 and the aromatic
alkyne 2. For reactions with trimethylsilyl-protected 3, simple
addition of potassium carbonate to the reaction mixtures pro-
moted the third tandem step of alkyne deprotection. In comparing
the results of the two-step and three-step transformations it was
concluded that the addition of a third step in the tandem process
did not negatively impact overall product yield or purity. As sum-
marized in Table 1, an appreciable diversity of arene units can be
directly incorporated into 1,2,3-triazole products using commer-
cially available diazonium salts 1-6. Reactions of the diazido salt
7 gave bis-functionalized products in yields largely analogous to
the monofunctionalized derivatives, even though the formation
of such products required twice the overall number of chemical
transformations. Identity of the diazonium salt counterion did
not impact reaction efficiency.
Cl
H
N
O
O
N
N
O
NO2
-X+N2
-X+N2
-X+N2
O
O
1
2
3
H
O
N
-X+N2
N
O
-X+N2
5
4
H
N
O
O
-X+N2
N2+X-
-X+N2
O
7
No differences in product purity were observed by 1H NMR be-
tween one-pot procedures where all reagents were introduced at
once versus an analogous time-delayed procedure where diazo-
nium salts and sodium azide were allowed to react for 10 min in
water before the remaining reactants were introduced. This high-
lights the orthogonality of each step of these tandem two- and
three-step reactions. In addition, withholding either catalyst or al-
kyne co-reactant from each reaction resulted in the isolation of
only aromatic azide intermediate products as observed by 1H
NMR. It is noteworthy that the yields of isolated azide intermedi-
ates prepared in control studies ranged from 81% to 91% (Table
2), largely reflecting the commercial purity of these reactants. No
attempts were made to purify the commercially available diazo-
nium salts before use. Hence, the efficiency of azide formation from
such precursors does significantly impact triazole product yields in
the tandem reactions.
Because aromatic azides are commonly prepared from aromatic
amines via diazotization reactions in acidic media, attempts were
made to utilize such crude diazonium salt solutions or suspensions
directly in tandem click reactions. Such attempts were unsuccess-
ful, likely due to the acidic environment required of the diazotiza-
tion reaction. No attempts were made to isolate any of the
diazotization reaction intermediates from their acidic media. In
spite of the observed purity issues for several of the commercially
available dyes utilized, the ability to introduce diazonium reac-
tants directly as solids in tandem click reactions proved to be a
practical and efficient method for preparing a variety of aromatic
azides in situ.
In summary, commercially-available diazonium salts have been
identified as useful organic azide precursors in tandem click trans-
formations. A series of mono- and difunctionalized fast dye salts
produced 1,2,3-triazole products in good yields under both two-
step one-pot tandem reactions with terminal alkyne reactants
and three-step one-pot tandem reactions with trimethylsilyl-
protected alkyne reactants. These findings establish diazonium
salts as new and practical additions to a recently evolving class
of synthons able to generate organic azide intermediates in situ
for participation in common click reactions that avoid the need
for isolating potentially shock-sensitive intermediate azido and
diazido intermediate reactants. Utilizing such synthons in tandem
click reactions serve as an efficient means by which to prepare 1,4-
disubstituted-1,2,3-triazole compounds with medicinally relevant
subunits, due to the diversity of structural functionality repre-
sented in commercially available diazonium salts.
6
Figure 1. Diazonium salts surveyed in this investigation. For 1, 2, 3, 4, and 7
XÀ = 0.5 ZnCl42À; for 5 XÀ = HSO4À; for 6 XÀ = ClÀ.
N
Si
A
B
C
Figure 2. Alkynes surveyed in this investigation.
diazonium salts utilized as aromatic azide precursors in multi-step
one-pot click reactions would successfully undergo substitution
with azide followed by Cu(I)-catalyzed Huisgen 1,3-dipolar cyclo-
addition while avoiding both hydrolysis and diazo coupling side
reactions under the room-temperature aqueous conditions
employed.
As illustrated in Figure 1, the diazonium salt synthons surveyed
in this study include Fast Red RC (1), Fast Blue BB (2), Fast Corinth
V (3), 2-methoxy-4-morpholinobenzene diazonium chloride (4),
Variamine Blue RT (5), Variamine Blue B (6) and the bifunctional
analog Fast Blue B (7). The alkyne reactants examined in this study
are shown in Figure 2. The aliphatic terminal alkyne 1-hexyne (A)
and the aromatic terminal alkyne phenylacetylene (B) were used to
survey two-step one-pot tandem reaction conditions.27 Three-step
one-pot tandem reaction conditions were examined using 2-trim-
ethylsilylethynylpyridine (C), a synthon previously reported to
efficiently participate in tandem click reactions involving trimeth-
ylsilyl deprotection.22,23
Table 1 summarizes the utility of the diazonium salts 1-7 as the
azide sources in two-step and three-step one-pot tandem click
reactions with terminal and trimethylsilyl-protected alkyne
reactants A, B and C. These reaction setups involved the simple
addition of diazonium and alkyne reactants to 1:1 solutions of
tert-butanol/water containing 20 mol % CuSO4 and 40 mol %
sodium ascorbate. Only upon addition of the final reagent, sodium
azide, did vigorous evolution of gas occur, signifying the rapid
completion (within minutes) of the first step of the tandem reac-
tion. Each reaction was stirred for 24 h, and the products isolated
via simple extraction procedures.28

5514
J. T. Fletcher, J. E. Reilly / Tetrahedron Letters 52 (2011) 5512–5515
Table 1
Summary of tandem reactions surveyed
Entry
Diazonium salt
Alkyne
Condition
ID
Structure
Yield (%)
88
O
O
1
a
1A
N
N
Cl
-X+N2
O
Cl
Cl
Cl
N
O
2
3
a
b
1B
1C
71
78
N
N
Cl
-X+N2
O
N
N
O
Si
N
N
N
Cl
-X+N2
N
H
H
O
N
O
N
4
5
6
a
a
a
2A
2B
3A
83
68
86
O
O
O
O
N
N
-X+N2
O
N
H
N
H
O
O
N
O
O
N
N
-X+N2
O
N
O
N
O
N
N
N
NO2
NO2
N
N
-X+N2
N
O
-X+N2
O
O
7
8
a
a
4A
4B
74
66
N
N
O
O
N
N
O
N
N
N
O
-X+N2
N
N
O
N
H
N
H
N
9
10
11
a
a
a
5A
5B
6B
82
70
67
-X+N2
-X+N2
-X+N2
-X+N2
N
N
N
H
N
H
N
N
N
N
N
H
N
H
N
O
O
O
N
N
N
H
N
H
N
Si
12
13
b
c
6C
7B
63
66
N
O
N
N
N
N
O
O
O
O
-X+N2
N2+X-
N
N
N
N
N

J. T. Fletcher, J. E. Reilly / Tetrahedron Letters 52 (2011) 5512–5515
5515
Table 1 (continued)
Entry
Diazonium salt
Alkyne
Condition
ID
Structure
Yield (%)
N
O
O
N
N
O
O
Si
-X+N2
N2+X-
14
d
7C
61
N
N
N
N
N
N
Reaction conditions: (a) 1.0 mmol diazonium salt, 1.2 mmol sodium azide, 1.2 mmol alkyne, 0.2 mmol CuSO4, 0.4 mmol sodium ascorbate, 5 mL t-BuOH, 5 mL H2O, 24 h, room
temperature; (b) identical to a with addition of 1.2 mmol K2CO3; (c) identical to a except with 0.5 mmol diazonium salt; (d) identical to b except with 0.5 mmol dizonium salt.
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Isolated yields of azide reactants prepared from diazonium salts
5188–5240.
NaN3
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(1-7)
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(1-7)D
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81
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Acknowledgments
This publication was made possible by Grant No. P20 RR16469
from the National Center for Research Resources (NCRR), a compo-
nent of the National Institutes of Health (NIH) and its contents are
the sole responsibility of the authors and do not necessarily repre-
sent the official views of NCRR or NIH.
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Supplementary data
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26. Wu, Z. Y.; Glaser, R. J. Am. Chem. Soc. 2004, 126, 10632–10639.
27. Fletcher, J. T.; Keeney, M. E.; Walz, S. E. Synthesis 2010, 3339–3345.
28. General procedure: To a 20 mL scintillation vial was added (in order) CuSO4,
sodium ascorbate, diazonium salt, water, tert-butanol, and alkyne reactant
(amounts as noted in Table 1). Lastly, sodium azide was added with stirring,
resulting in a rapid evolution of gas from the vial over approximately 10 min.
After the majority of gas evolution had subsided, the vial was loosely sealed
with a screw cap and continued to stir rapidly at room temperature. After 24 h
the reaction was extracted between methylene chloride and 5% aqueous
ammonium hydroxide solution, and the aqueous layer was washed a second
time with methylene chloride. The combined organic layers were dried over
magnesium sulfate and the solution isolated via gravity filtration through
fluted filter paper into a round bottom flask. Volatiles were removed via rotary
evaporation to give the final 1,2,3-triazole product.
Experimental procedures and characterization including copies
of 1H NMR and MS spectra for all reported azide and triazole prod-
ucts are available. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2011.08.069.
References and notes
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