Indirect C-H azidation of heterocycles via copper-catalyzed regioselective fragmentation of unsymmetrical λ3-iodanes

Article abstract of DOI:10.1021/ja305574k

A C-H bond of electron-rich heterocycles is transformed into a C-N bond in a reaction sequence comprising the formation of heteroaryl(phenyl)iodonium azides and their in situ regioselective fragmentation to heteroaryl azides. A Cu(I) catalyst ensures complete regiocontrol in the fragmentation step and catalyzes the subsequent 1,3-dipolar cycloaddition of the formed azido heterocycles with acetylenes. The heteroaryl azides can also be conveniently reduced to heteroarylamines by aqueous ammonium sulfide. The overall C-H to C-N transformation is a mild and operationally simple one-pot sequential multistep process.

Full text of DOI:10.1021/ja305574k

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Article
Indirect C–H Azidation of Heterocycles via Copper-Catalyzed
Regioselective Fragmentation of Unsymmetrical lambda3-Iodanes
Dmitrijs Lubriks, Igors Sokolovs, and Edgars Suna
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja305574k • Publication Date (Web): 22 Aug 2012
Downloaded from http://pubs.acs.org on August 23, 2012
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Indirect C–H Azidation of Heterocycles via Copper-Catalyzed Regioselective
Fragmentation of Unsymmetrical λ3-Iodanes
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Dmitrijs Lubriks, Igors Sokolovs and Edgars Suna*
Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006, Riga, Latvia
edgars@osi.lv
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Abstract. C–H Bond of electron-rich heterocycles is transformed into a C–N bond in
a reaction sequence comprising the formation of heteroaryl(phenyl)iodonium azides
and their in situ regioselective fragmentation to heteroaryl azides. Cu(I) Catalyst
ensures complete regiocontrol in the fragmentation step and catalyzes the subsequent
1,3-dipolar cycloaddition of the formed azido-heterocycles with acetylenes. The
heteroaryl azides can also be conveniently reduced to heteroaryl amines by aqueous
ammonium sulfide. The overall C–H to C–N transformation is mild and operationally
simple one-pot sequential multi-step process.
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Introduction.
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Symmetrical diaryliodonium salts have found numerous applications as
electrophilic arylating reagents both in the transition metal-catalyzed and metal-free
reactions with carbon and heteroatom nucleophiles.1 Unsymmetrical diaryliodonium
salts, however, are less frequently employed, because the presence of two different
aromatic moieties in λ3-iodanes can potentially lead to the formation of products
mixtures in the reactions with nucleophiles. Nevertheless, the regiocontrol can be
achieved by differentiation of electronic and steric properties of aromatic moieties.
Thus, nucleophile would preferentially react with the more electron-deficient and/or
sterically hindered ortho-substituted aromatic ring of unsymmetrical diaryliodonium
salts (Figure 1).2 In the meantime, regioselective reaction of nucleophiles with
electron-rich aromatic or heteroaromatic moieties of unsymmetrical diaryl-λ3-iodanes
is a challenging task. We envisioned, however, that the desired regioselectivity of
nucleophile attack can be ensured by transition metal catalyst, because in the catalytic
cross-coupling reactions electron-rich3 and/or less sterically hindered4 aryl moieties
are selectively transferred from unsymmetrical iodonium salts to the transition metal
(Figure 1).
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Figure 1. Regioselectivity in the reactions of non-symmetrical iodonium salts.
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We have recently demonstrated that the regioselectivity of acetoxylation of
heteroaryl(phenyl)iodonium acetates can be directed to the more electron rich
heteroaryl moiety by Pd(II) catalyst.5 We reasoned that use of other counter ions
instead of acetate would provide a straightforward access to differently substituted
heterocycles by the transition metal catalyzed regioselective fragmentation of
unsymmetrical heteroaryliodonium species. Herein we report a one-pot sequential
procedure for C–H to C–N transformation in electron-rich heterocycles (pyrroles,
pyrrolo-pyridines, thieno-pyrroles, pyrrolo-pyrimidines and uracil) comprising in situ
preparation of heteroaryl(phenyl)iodonium azides and their Cu–catalyzed conversion
to heteroarylazides. The formed azides are not sufficiently stable to be isolated,
however they can be in situ reduced to heteroaromatic amines. The developed one-pot
four step C–H to C–N transformation sequence is a mild and convenient alternative to
the transition metal–catalyzed direct C–H amination of arenes6 and heteroarenes,7,8
which usually requires elevated temperatures to proceed. The in-situ formed
heteroarylazides can also undergo Cu–catalyzed azide-alkyne cycloaddition to furnish
1,2,3-triazoles,9 thus allowing for the direct ligation of heterocycles to biomolecular
frameworks via triazole linker, an approach that is widely used in bioconjugate
chemistry10 for labeling and modification of oligonucleotides11 and
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peptidomimetics.12 The developed C–H azidation/1,3-dipolar cycloaddition sequence
is suitable also for the use in discovery of lead compounds by target–directed
synthesis13 as well as in the design of novel peptidomimetics.14 Furthermore, 1,2,3-
triazoles can be employed for synthesis of other heterocyclic systems.15
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Results and Discussion.
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At the outset of the investigation we examined the regioselectivity of
fragmentation of indolyl(phenyl)iodonium azide 3a. The iodonium salt 3a was
synthesized by the reaction of indole 1a with a mixture of PhI(OAc)2 and TsOH,16
followed by exchange of tosylate anion for azide in the intermediate 2a. The formed
iodonium azide 3a was unstable and in the crystalline form it slowly decomposed to
iodo-indole 5a even at –18 oC. Nevertheless, the indolyl azide 3a as well as its pyrrole
analogue 3h could be characterized and their structure was confirmed by X-ray
crystallographic analysis (Table 1).17 In the crystal lattice azides 3a,h exist in a
characteristic slightly distorted T-shaped geometry with heterocycle in the equatorial
position and Ph moiety and azide anion in axial positions (for selected
crystallographic parameters see Table 1). Notably, I–N bonds in the azides 3a,h are
considerably longer than hypervalent I–N bonds in structurally related
azidobenziodoxole18 (2.182 Å) and polymeric iodine azide (2.26-2.30 Å).19
Furthermore, the distance between hypervalent iodine in 3h and azide anion (2.837 Å,
Table 1) is much longer than that between the iodine of the phenyl(pyrrolyl)iodonium
moiety of 3h and acetate anion (2.592 Å).5 Apparently, the long hypervalent I–N bond
possesses partial ionic character,20 which accounts for the low stability of iodonium
azides 3a,h.
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Table 1. Selected crystallographic parameters for iodonium azides 3a,h.
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λ3-iodane
N3–I–C(Het) angle
174.1
I–N3 (Å) I–C(Ph) (Å) I-C(Het) (Å)
2.813
2.837
2.112
2.129
2.083
2.064
3a
3h
177.3
In MeCN and CH2Cl2 solutions at room temperature the iodonium azide 3a
spontaneously decomposed to 3-iodoindole 5a and phenylazide (see Table 2, entries
1,2). Importantly, the desired indolylazide 4a was not formed in MeCN and CH2Cl2.
The regioselectivity of the non-catalyzed fragmentation of iodonium salt 3a
apparently is controlled by electronic factors, as evidenced by the delivery of the
azide nucleophile to the relatively more electron-deficient phenyl ring rather than to
the electron-rich indole moiety of 3a.21 Notably, λ3-iodane 3a was stable in DMSO
(entry 3) at room temperature. The addition of Pd(OAc)2 (5 mol%) did not alter the
course of the reaction (entries 4,5), whereas Cu salts completely reversed the
fragmentation regioselectivity, and the iodonium azide 3a was smoothly converted to
the desired indolylazide 4a (entries 6–15).
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Table 2. Fragmentation of indolyliodonium azide 3a.
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entry catalyst (mol%)
solvent
MeCN
time
60 h
conversion, %a,b 4a:5a ratiob
1
none
35c
70
<5
32
35
60
1:99
1:99
-
2
none
CH2Cl2 3 h
3
none
DMSO
MeCN
3 h
4
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Cu(OTf)2 (10)
CuOTf •PhH (10)
CuOTf •PhH (10)
CuOTf •PhH (10)
CuOTf •PhH (10)
CuOTf •PhH (10)
CuCl (10)
24 h
1:5
5
CH2Cl2 3 h
CH2Cl2 3 h
1:99
9:1
6
7
CH2Cl2 30min 100
9:1
8
MeCN
toluene
THF
30 min 87
30 min 85
30 min 60
30 min 45
9:1
9
4:1
10
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12
13
14
15
5:1
DMSO
9:1
CH2Cl2 5 min 100
9:1
CuCl (10)
MeCN
DMSO
5 min 100
30 min 78
12:1
12:1
10:1
CuCl (10)
CuCl (10)
MeCN- 15 min 85
DMSO
1:1
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19
TfOH (200)
CH2Cl2 3 h
CH2Cl2 3 h
CH2Cl2 3 h
CH2Cl2 3 h
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27
20
45
1:99
1:99
1:99
1:99
Zn(OTf)2 (10)
Sc(OTf)3 (10)
(Ph3P)AuCl (10)
a Reactions at room temperature. b Determined by LC-MS assay. c 100% Conversion
(4a:5a=1:99) after 30 min at 80 oC
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Copper catalysts decreased considerably the reaction time with CuCl and
CuOTf in CH2Cl2 being the most efficient (entries 7,12). Interestingly, both Cu(I) and
Cu(II) salts can be used, however the Cu(I) species ensured faster reaction (entry 7 vs.
6). Other solvents either retarded the reaction (entries 10,11,14) or deteriorated the
regioselectivity (entries 9,10). It should be noted that the conversion of 3a was faster
in CH2Cl2 compared to MeCN (entries 2 vs. 1 and 7 vs. 8). Lewis acids such as
(Ph3P)AuCl, Zn(OTf)2 and Sc(OTf)3 as well as TfOH were completely inefficient as
catalysts (entries 16–19). Consequently, CuCl (10 mol%) was chosen for all
subsequent experiments.
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The observed high regioselectivity of the Cu(I)-catalyzed fragmentation of
iodonium salt 3a to azide 4a (4a:5a=9:1) in CH2Cl2 is slightly lower than the
regioselectivity of the alternative non-catalyzed formation of 5a from 3a
(4a:5a=1:99). The determined initial rates of the non-catalyzed fragmentation of 3a to
iodide 5a in CH2Cl2 (rate coefficient k=9•10-5 s-1, CH2Cl2–d2, 23 oC and reaction half-
life t1/2=128 min) evidences that spontaneous fragmentation of iodonium azide 3a
delivers ca. 10% of 5a within the first 10 minutes. By this time, the CuOTf-catalyzed
conversion of 3a to azide 4a in CH2Cl2 is almost 90%.22 Consequently, the
regioselectivity of the Cu-catalyzed conversion of 3a to 4a is compromised by the
competing non-catalyzed fragmentation to 5a, and this observation renders CH2Cl2
inferior as a solvent compared to alternatives such as MeCN and DMSO (entry 2 vs.
1,3, Table 2). The non-catalyzed fragmentation of 3a in MeCN is considerably less
pronounced, and azide 3a is virtually stable in DMSO. Therefore, MeCN and DMSO
are solvents of choice for CuCl catalyzed fragmentation of iodonium azides (entries
13–15, Table 2).
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The formed indolylazide 4a decomposed during attempted purification,
however it can be employed in further transformations without the isolation. Thus,
addition of substituted acetylene directly to the azide 4a and CuCl in the presence of
DIPEA and AcOH23 resulted in the clean formation of 1,4-disubstituted 1,2,3-triazole
6a as a sole regioisomer.24 Hence, CuCl catalyzed both the in situ formation of
indolylazide 4a and its subsequent 1,3-dipolar cycloaddition with 3-
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chlorophenylacetylene (Table 3).9
A series of heterocycles was subsequently subjected to azidation-cycloaddition
sequence to show the scope of the developed methodology. All heterocycles that can
form iodonium salts in the reaction with a mixture of PhI(OAc)2 and TsOH are
suitable substrates,25 including indoles26 1a–g, pyrroles27 1h–n, thieno[3,2-b]pyrroles
1o, pyrrolo[2,3-b]pyridines 1p,r, pyrrolo[3,2-b]pyridines 1s, pyrrolo[2,3-d]pyrimidine
1t and uracil28 1u (Table 3). In general, the regioselectivity of heteroaryliodonium salt
formation is consistent with that of SEAr reactions. Thus, λ3-iodanes are formed at the
β-position of indoles 1a–g and fused pyrroles 1o–t, at the α-position of pyrroles 1i,j,n
and at 5th position of uracil 1u (Table 3). In 2,5-disubstituted pyrroles 1h,k–m,
however, iodonium salts were formed at β-position. Importantly, the reaction
conditions are compatible with the presence of iodine, bromine and chlorine, thus
rendering feasible their further functionalization. N-Alkyl, N-aryl, N-benzoyl, N-
benzyl substituents as well as N-SEM protecting groups are tolerated (Table 3).
The formed heteroaryl azides 4a–u could also be converted to the
corresponding heteroaromatic amines 7a–u by the in situ reduction with aqueous
(NH4)2S at room temperature within 30 min (see
Table 4). Other reducing agents
such as Ph3P are equally efficient, however, the use of (NH4)2S in the reduction
generates less waste, requiring simple extractive workup to obtain crude product 7a–
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u. In general, the one-pot three-step azidation/reduction sequence allows for
amination of heteroaryl C–H bonds under mild conditions and in high overall yields.
Additional experiments have been carried out to determine the oxidation state
of copper species responsible for the catalytic azidation of heterocycles. The
considerably faster formation of 4a in the presence of Cu(I) ions compared to Cu(II)
counterparts (entry 7 vs. 6, Table 2) suggests that Cu(I) salts are catalytically active
species. This assumption was supported by the observed inhibition of 4a formation by
neocuproin (2 equiv. with respect to CuOTf; see Figure 2). Neocuproin, a highly
specific chelating agent for Cu(I) ions, forms a stable bright orange–colored complex
of formula Cu(I)(neocuproin)2,29 thus acting as an inhibitor of Cu(I)-catalyzed
reactions.30
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Kinetic studies demonstrated that the CuOTf-catalyzed conversion of 3a to 4a
in DMSO–d6 is the first order in CuOTf in the range of 0.25–5 mol % at 25 oC (Figure
3). This indicates that Cu(I) salts are involved in the rate limiting step of the catalytic
cycle. The decomposition of 3a to 4a was found to be zeroth-order with respect to N3
anion (Figure 4) suggesting that the formation of azide 4a presumably is an
intramolecular process. Finally, a radical inhibition test was also performed to verify
the possibility of 3a fragmentation via radical chain pathway. Accordingly, the
addition of radical scavengers such as 1,1-diphenylethylene31 and 2,6-di-tert-butyl-4-
methylphenol6a (both 200 mol% with respect to Cu(I)) did not affect the rate of
CuOTf–catalyzed 3a to 4a conversion in CH2Cl2-d2. Furthermore, we did not observe
indole 1a, which could form by a proton abstraction from solvent by indolyl radical
during the decomposition of 3a. All these data points against the involvement of free-
radical intermediates.32
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Figure 2. Inhibition of the CuOTf–catalyzed 3a to 4a conversion by neocuproin.
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35.00
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CuOTf (1 mol%) in DCM
30.00
CuOTf (1 mol%) + neocuproine (2 mol%) in DCM
25.00
20.00
15.00
10.00
5.00
0.00
0
200
400
600
800
1000
1200
Time (s)
Figure 3. Plot of initial rates vs. concentration of CuOTf in DMSO-d6.
-2
-2.5
-3
y = 1.7719x + 2.877
R2 = 0.9898
-3.5
-4
-4.5
-5
-5.5
-6
-6.5
-5.5
-5
-4.5
-4
-3.5
-3
ln[CuOTf]
Figure 4. Plot of initial rates vs. concentration of azide ion in DMSO-d6.
-4
-4.2
-4.4
-4.6
-4.8
-5
y = 0.0465x - 4.6504
R2 = 0.9164
-5.2
-5.4
-5.6
-4
-3.5
-3
-2.5
-2
ln[N3]
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Table 3. Sequential one-pot synthesis of heteroaryl azides 4a–u and triazoles 6a–u.
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entry
1
product
time
yield (%)c
90
entry
11
product
time yield (%)c
30
min
10
65
min
6a
6k
30
65
2
18 h
71
12
min
6b
6l
30
73
3
4
5 min
3 h
65
71
13
14
min
6m
6c
5 min
59
75
6n
6d
30
min
5
6
3 h
75
73
15
16
6o
6e
30
min
3 h
62
6pa
6f
7
8
18 h
72
64
17
18
5 min
72 h b
70
42
6r
6g
10
min
6s
6h
10
min
9
5 min
5 min
53
55
19
20
47
65
6i
6t
10
18 h
6u
6j
a DAGlc (Diacetone-D-Glucose). b 2.2 equiv. of TsOH-H2O; c Yields were calculated
based on the starting heterocycle 1a–u
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Table 4. Sequential azidation-reduction sequence for one-pot synthesis of heteroaryl
5
6
amines 7a–u.
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8
9
10
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12
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a
entry
1
product
yield (%)
84
7a
2
3
80
82
7b
7d
4
5
6
84
79
65
7f
7g
7h
7
8
60
62
7j
7k
9
72
53
66
7m
7n
10
11
7o
7p
12
13
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a Yields were calculated based on the starting heterocycle 1a–u
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A working mechanism for the Cu–catalyzed formation of heteroaryl azides is
outlined in Scheme 1. Oxidative addition of iodonium azide I to Cu(I) salts would
generate Cu(III) species II.33 The complex II can directly collapse into azide III via
the highly regioselective coupling of heterocycle with azide, and the regioselectivity
of azide attack presumably is ensured by the formation of transient π–complex
between the highly electrophilic Cu(III) species and electron-rich heterocycle.34
Alternatively, complex II can undergo regioselective transformation to PhI and
heteroaryl–Cu(III) IV species,35 followed by reductive elimination of III and
regeneration of Cu(I) species.
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Scheme 1. Working mechanism for azidation of heterocycles.
To verify the role of putative π-Cu(III) complex II in the control of
regioselectivity of the azide formation, we envisioned the in situ preparation of a π-
complex between a suitable π-acidic transition metal and electron-rich heterocycle
moiety of unsymmetrical λ3-iodane 3a. Among various transitions metals, Os(II)
species are known to form well–defined and stable η2–complexes with pyrroles.36 We
examined the fragmentation of iodonium azide 3a in the presence of 10 mol% of
Os[NH3]5(OTf)3 in CH2Cl2. Notably, the indolylazide 4a was formed regioselectively
(4a:5a=7:3) within 30 min as a major product (30% conversion). This result is in
sharp contrast to the opposite regioselectivity in the non-catalyzed decomposition of
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3a to 5a in the presence of representative Lewis acids (entries 4,5,17–19, Table 2).
Possibly, π-complexation of pyrrole ring to the Os(III) facilitates the substitution of
iodonium group by azide nucleophile in transient complex V (Scheme 1), however,
additional experiments are needed to support such a scenario.37,38 The involvement of
Cu(I) complex V (M=Cu(I)) to activate heterocycle towards azide attack seems less
likely because of insufficient electrophilicity of Cu(I) species. Finally, Lewis acid
activation of hypervalent iodonium species by Cu(I) or Cu(III) salts was shown to be
kinetically insensitive to concentration of copper species,6a an observation that
contradicts our results.
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Conclusions.
In summary, a rapid and versatile approach to heteroaryl azides via C–H to C–
N bond transformation has been developed. The one-pot sequential procedure
comprises formation of heteroaryl(phenyl)iodonium azides, followed by Cu(I)–
catalyzed fragmentation to heteroaryl azides. The regioselectivity of the fragmentation
is controlled by Cu(I) salts. The formed heteroaryl azides can be in situ reduced to
heteroaryl amines. Alternatively, the heteroaryl azides can undergo Cu–catalyzed
click–chemistry with a range of acetylenes to furnish 1,2,3-triazoles. The developed
procedure is suitable for a variety of electron-rich heterocycles such as pyrroles,
indoles, thieno-pyrroles, pyrrolo–pyridines, pyrrolo–pyrimidines and uracil. Further
studies to expand the scope of nucleophiles in the Cu–catalyzed regioselective
fragmentation of heteroaryl(phenyl)iodonium salts are ongoing in our laboratory.
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Experiment Section
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Preparation of Iodonium Azides 3a and 3h.
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Hazard Warning: Azides 3a,h are thermally unstable and possess high thermal
hazard potential.39 Therefore, care must be taken during handling of azides 3a,h and
small scale is strongly encouraged.
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Ethyl 3-[(azido)(phenyl)-λ3-iodanyl]-1,5-dimethyl-1H-indole-2-carboxylate (3a).
To a solution of PhI(OAc)2 (509 mg, 1.58 mmol, 1.05 equiv) in CH2Cl2 (10 mL) was
added TsOH●H2O (342 mg, 1.80 mmol, 1.2 equiv) and the resulting suspension was
stirred for 5 min at room temperature. Then, a solution of indole 1a (423 mg, 1.50
mmol, 1 equiv) in CH2Cl2 (5 mL) was added rapidly to the stirred suspension. The
progress of the reaction was monitored by TLC, and within 30 min complete
conversion of the starting 1a was observed. The reaction was then poured into the
solution of NaN3 (146 mg, 2.25 mmol, 1.5 equiv) in water (50 mL) and extracted with
CH2Cl2 (3x30 mL). Organic layers were combined, dried over Na2SO4, filtered and
concentrated. The solid residue was washed with diethyl ether to afford 3a as a white
powder (727 mg, 92% yield); analytical TLC on silica gel, 20:80:5
MeOH/CH2Cl2/AcOH, Rf=0.56. Pure material was obtained by crystallization from
CH2Cl2/diethylether: mp 102-103 oC (dec). IR (film, cm-1) 1999 (N=N=N), 1716
(C=O); 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.13-8.07 (3H, m), 7.73 (1H, d, J=9.0
Hz), 7.60 (1H, dd, J=9.0, 1.6 Hz), 7.55-7.50 (1H, m), 7.45-7.40 (2H, m), 4.51 (2H, q,
J=7.1 Hz), 4.07 (3H, s), 1.43 (3H, t, J=7.1 Hz). 13C NMR (100.6 MHz, DMSO-d6,
pmm) δ 159.1, 137.0, 133.9, 131.3, 131.2, 131.0, 129.1, 128.6, 123.5, 115.9, 114.6,
62.4, 33.5, 14.0. HRMS-ESI (m/z) calcd for C18H16NO2BrI [M-N3]+ 483.9409, found
483.9419.
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Methyl 4-[(azido)(phenyl)-λ3-iodanyl]-1-(2-bromobenzyl)-2,5-dimethyl-1H-
pyrrole-3-carboxylate (3h). The same procedure was used as for 3a. Accordingly, 3-
[1-(2-bromobenzyl)-4-(methoxycarbonyl)-2,5-dimethyl-1H-pyrrole 1h (482 mg, 1.50
mmol) was converted to iodonium azide 3h. Purification of the crude 3h by washing
with diethylether afforded product as a white powder (723 mg, 85% yield); analytical
TLC on silica gel, 20:80:5 MeOH/CH2Cl2/AcOH, Rf=0.54. Pure material was
obtained by crystallization from CH2Cl2/diethylether: mp 96-97 oC (dec). IR (film,
cm-1) 2002 (N=N=N), 1696 (C=O); 1H NMR (400 MHz, DMSO-d6, ppm) δ 7.95-7.91
(2H, m), 7.73-7.68 (1H, m), 7.61-7.55 (1H, m), 7.50-7.45 (2H, m), 7.29-7.24 (2H, m),
6.19-6.14 (1H, m), 5.30 (2H, s), 3.80 (3H, s), 2.43 (3H, s), 2.37 (3H, s). 13C NMR
(100.6 MHz, DMSO-d6, pmm) δ 162.3, 138.2, 137.5, 134.9, 133.5, 133.0, 131.2,
131.0, 129.7, 128.4, 126.1, 121.1, 110.4, 109.6, 51.3, 48.5, 12.6, 11.8.. HRMS-ESI
(m/z) calcd for C21H20NO2BrI [M-N3]+ 523.9722, found 523.9734.
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Experimental Procedures for Substituted 1,2,3-Triazoles 6a–u.
To a solution of PhI(OAc)2 (0.53 mmol, 1.05 equiv) in MeCN (1.5 mL) was added
TsOH●H2O (0.60 mmol, 1.2 equiv) and the resulting suspension was stirred for 5 min
at room temperature. Then, a solution of heterocycle 1a-u (0.50 mmol, 1 equiv) in
MeCN (1 mL) was added to the stirred suspension and the progress of the reaction
was monitored by TLC (disappearance of the starting material spot; mobile phase
petroleum ether/EtOAc=3:1; the formed heteroaryliodonium salt does not migrate
from the application point). Immediately upon full conversion of the starting 1a–u
(see Table 3 for appropriate time), a solution of NaN3 (0.75 mmol, 1.5 equiv) in water
(500 ꢀL) was added (decomposition of the formed iodonium salt begins if the addition
of NaN3 is delayed), followed with DMSO (2.5 mL), and solid CuCl (5 mg, 10 mol%;
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CuCl must be added immediately after NaN3 in order to avoid the non-catalyzed
decomposition of iodonium azide) whereupon the color of reaction changed to brown.
After stirring for 30 min at room temperature, acetylene (0.75 mmol, 1.5 equiv),
DIPEA (1.00 mmol, 2 equiv) and AcOH (1.00 mmol, 2 equiv) were added and stirring
was continued for 3 h at room temperature. Reaction mixture was poured into 50 mL
of water and 25 mL of saturated NaHCO3, extracted with DCM (3x30 mL). Organic
extracts were combined, dried over Na2SO4, filtered and evaporated. The residue was
purified by column chromatography on silica gel.
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Experimental Procedures for Heteroarylamines 7a–u.
To a solution of PhI(OAc)2 (0.53 mmol, 1.05 equiv) in MeCN (4 mL) was added
TsOH●H2O (0.60 mmol, 1.2 equiv) and the resulting suspension was stirred for 5 min
at room temperature. Then, a solution of heterocycle 1a-u (0.50 mmol, 1 equiv) in
MeCN (1 mL) was added to the stirred suspension and the progress of the reaction
was monitored by TLC (disappearance of the starting material spot; mobile phase
petroleum ether/EtOAc=3:1; the formed heteroaryliodonium salt does not migrate
from the application point). Immediately upon full conversion of the starting 1a–u
(see Table 3 for appropriate time), a solution of NaN3 (0.75 mmol, 1.5 equiv) in water
(500 ꢀL) was added (decomposition of the formed iodonium salt begins if the addition
of NaN3 is delayed), followed with solid CuCl (5 mg, 10 mol%; CuCl must be added
immediately after NaN3 in order to avoid the non-catalyzed decomposition of
iodonium azide) whereupon the color of reaction changed to brown. After stirring for
30 min at room temperature, aqueous (NH4)2S (40-48 wt% solution in water, Aldrich,
1.25 mmol, 200 ꢀL, 2.5 equiv) was added. After stirring for another 30 min at room
temperature the reaction was poured into a mixture of water (50 mL) and saturated
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aqueous NaHCO3 (25 mL) and extracted with CH2Cl2 (3x30 mL). Organic extracts
were combined, dried over Na2SO4, filtered and evaporated. The residue was purified
by column chromatography on silica gel.
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Associated Content
Supporting Information.
Experimental procedures, products characterization data, copies of 1H and 13C NMR
spectra, X-ray crystallographic data for iodonium azides 3a and 3h (CIF files) and
details of kinetic experiments. This material is available free of charge via the Internet
at http://pubs.acs.org.
Author Information
Corresponding Author
edgars@osi.lv
Notes
The authors declare no competing financial interest.
Acknowledgments
This work was supported by the European Regional Development Fund (No.
2DP/2.1.1.1.0/10/APIA/VIAA/066). We thank Dr. S. Belyakov for X-ray
crystallographic analysis and Dr. J. Zicans for DSC analysis. We also thank Prof. S.
Cornaja for helpful discussions.
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References.
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Chem. Soc. 1959, 81, 336–342. (b) Lockhart, T. P. J. Am. Chem. Soc. 1983, 105,
1940.
(31) Barton, D. H. R.; Finet, J.-P.; Giannotti, C.; Halley, F. J. Chem. Soc., Perkin
Trans. 1 1987, 241.
(32) Radical pathway has been proposed for α-azidation of silyl enol ethers with
hypervalent iodonium azides: (a) Magnus, P.; Lacour, J.; Evans, P. A.; Roe, M.
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B.; Hulme, C. J. Am. Chem. Soc. 1996, 118, 3406. (b) Magnus, P.; Roe, M. B.;
Hulme, C. J. Chem. Soc., Chem. Commun. 1995, 263.
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(33) Related Cu(III) complexes have been proposed: (a) Ochiai, M. In Hypervalent
Iodine Chemistry; Wirth, T., Ed.; Springer Berlin Heidelberg: Berlin,
Heidelberg, 2003; Vol. 224, pp. 5–68. (b) Lee, J. M.; Park, E. J.; Cho, S. H.;
Chang, S. J. Am. Chem. Soc. 2008, 130, 7824.(c) Beringer, F. M.; Bodlaender, P.
J. Org. Chem. 1969, 34, 1981.
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(34) Related π-CuIII complex has been recently suggested in the copper-catalyzed
arylation of indoles with diaryl-λ3-iodanes: Zhu, S.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2012, 134, 10815. π-CuIII complex has also been proposed in α-
arylation and α-vinylation of aldehydes: Allen, A. E.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2011, 133, 4260. Skucas, E.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2012, 134, 9090. See also: Seayad, J.; Seayad, A. M.; Chai, C. L. L. Org.
Lett. 2010, 12, 1412.
(35) Formation of aryl-Cu(III) species form Cu(I) salts and diaryl-λ3-iodanes has
been proposed: (a) Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc.
2008, 130, 8172. (b) Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593. (c)
Phipps, R. J.; McMurray, L.; Ritter, S.; Duong, H. A.; Gaunt, M. J. J. Am. Chem.
Soc. 2012, 134, 10773. (d) Harvey, J. S.; Simonovich, S. P.; Jamison, C. R.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2011, 133, 13782. (e) ref. 30b. For
studies of the mechanism of Cu–catalyzed aryl halide activation, see: Strieter, E.
R.; Bhayana, B.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 78 and
references cited therein. For a well-defined aryl-Cu(III) species, see King, A. E.;
Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am. Chem.
Soc. 2010, 132, 12068.
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(36) (a) Cordone, R.; Harman, W. D.; Taube, H. J. Am. Chem. Soc. 1989, 111, 5969.
(b) Hodges, L. M.; Gonzalez, J.; Koontz, J. I.; Myers, W. H.; Harman, W. D. J.
Org. Chem. 1995, 60, 2125. (c) Myers, W. H.; Sabat, M.; Harman, W. D. J. Am.
Chem. Soc. 1991, 113, 6682. (d) Valahovic, M. T.; Myers, W. H.; Harman, W.
D. Organometallics 2002, 21, 4581.
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(37) Formation of Cu(I)-acetylene π-complex was proposed to rationalize the
regioselective attack of nucleophiles on acetylene moiety of
alkynyl(phenyl)iodonium salts: (a) Stang, P. J.; Surber, B. W. J. Am. Chem. Soc.
1985, 107, 1452. (b) Stang, P. J.; Surber, B. W.; Chen, Z. C.; Roberts, K. A.;
Anderson, A. G. J. Am. Chem. Soc. 1987, 109, 228. For the related Au(I)-
acetylene π-complexes, see: c) Brand, J. P.; Chevalley, C.; Scopelliti, R.; Waser,
J. Chem.–Eur. J. 2012, 18, 5655. d) Brand, J. P.; Charpentier, J.; Waser, J.
Angew. Chem. Int. Ed. 2009, 48, 9346.
(38) Control experiments supported the importance of electronic effects in the
regiocontrol of the Cu–catalyzed fragmentation of iodonium azide 3a. Thus,
replacement of Ph group in 3a with electron-poor 4-NO2-C6H4 moiety altered
the regioselectivity of azide attack and favored the formation of arylazide 4-
NO2-C6H4-N3 (4a:5a=1:1 in MeCN and 4a:5a=1:3 in DCM). In the meantime,
substitution of Ph ring for more electron-rich mesityl moiety in 3a did not
change the fragmentation regioselectivity (4a:5a=9:1 in MeCN). Likewise,
CuOTf–catalyzed decomposition of 3a possessing 4-MeO-C6H4 moiety instead
of Ph ring afforded 4a, albeit with diminished regioselectivity (4a:5a=4:1 in
DCM).
(39) The decomposition of indolyl azide 3a was investigated by differential scanning
calorimetry (DSC) and thermogravimetry (TG) methods. The DSC analysis of
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3a (heating rate 5 K/min) showed two exotherms: from 100 oC to 120 oC with a
heat release of 122.0 J/g and from 212 oC to 263 oC with a heat release of 1842.7
J/g. The total decomposition enthalpy of 1964.7 J/g points toward high thermal
hazard potential for iodonium azide 3a.
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