Unified strategy for Iodine(III)-Mediated Halogenation and azidation of 1,3-Dicarbonyl compounds

Article abstract of DOI:10.1021/ol403504z

A mild and rapid (diacetoxyiodo)benzene-mediated formal electrophilic a-azidation of 1,3-dicarbonyl compounds using commercially available Bu ₄NN₃ as the azide source is reported. The reaction conditions employed are based on optimization studies conducted on the analogous halogenations with Et₄NX (X = Cl, Br, I).

Full text of DOI:10.1021/ol403504z

Letter
pubs.acs.org/OrgLett
Unified Strategy for Iodine(III)-Mediated Halogenation and Azidation
of 1,3-Dicarbonyl Compounds
Marc J. Galligan, Ramulu Akula, and Hasim Ibrahim*
Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin
4, Ireland
S
* Supporting Information
ABSTRACT: A mild and rapid (diacetoxyiodo)benzene-mediated
formal electrophilic α-azidation of 1,3-dicarbonyl compounds using
commercially available Bu4NN3 as the azide source is reported. The
reaction conditions employed are based on optimization studies
conducted on the analogous halogenations with Et4NX (X = Cl, Br, I).
α-Halo and α-azido 1,3-dicarbonyl compounds are fundamen-
tally important synthetic intermediates with wide ranging
applications.1 Often the former is a synthetic precursor to the
latter by nucleophilic substitution with NaN3.2 Many electro-
philic methods exist to access α-halo 1,3-dicarbonyl compounds
of which the most used involve the reaction of enolate
nucleophiles with electrophilic halogenating agents as sources
of X+.3 An attractive alternative is the use of in situ generated
X+ equivalents by oxidation or Umpolung of halide salts.4
Hypervalent iodine(III) reagents5 in particular have proven to
be suitable for such Umpolung strategies.6,7
to develop a system for α-halogenation that could be adopted
for α-azidation. The method described herein requires no
+
catalyst, additive, substrate modification, or the synthesis of N3
reagents.15
Ammonium salts are mildly acidic and can be easily modified
to solubilize counterions in organic solvents. The use of
ammonium halides (R4NX) as sources for X− in hypervalent
iodine-mediated α-halogenation is rare.16 Thus, and with the
above goal in mind, we attempted the α-chlorination of our test
substrate 1a with NH4Cl as the Cl− source. Initially, we added 2
equiv of (diacetoxyiodo)benzene (DIB) to an equimolar
mixture of 1a and NH4Cl in MeCN, which resulted in a
heterogeneous reaction mixture that gave the α-chloro product
2a in 60% conversion after 24 h (Table 1, entry 1).17 In an
In contrast, direct electrophilic methods to access α-azido
1,3-dicarbonyl compounds are relatively rare. Such methods
rely mostly on the use of arylsulfonyl azides as N3+ equivalents;
however, there is competition between the α-azido and α-diazo
products with the former obtained in mostly moderate yields.8
a
Table 1. Optimization of the DIB-Mediated α-Chlorination
9
+
The other sources of N3 are ArI(N3)2. These reagents are
generated in situ from 1 equiv of an aryl-λ3-iodane and 2 equiv
of TMSN39,10a or NaN310b and consist of an Umpolung of one
of the added azide equivalents. However, scope is limited to
simple non-α-substituted 1,3-dicarbonyl compounds.
b
entry R4NCl (equiv)
n
solvent
MeCN
t
conv (%)
Iodine(III)-mediated formal electrophilic α-azidation of
carbonyl compounds has also been reported. In these one-pot
procedures, an in situ installed α-leaving group, such as the α-
1
2
3
H4NCl (1.1)
H4NCl (1.1)
H4NCl (1.1)
Et4NCl (0.1)
Et4NCl (1.1)
Et4NCl (1.1)
Et4NCl (1.1)
2.0
2.0
2.0
24 h
24 h
6 h
60
60
70
MeCN/H2O (9:1)
MeCN/H2O (9:1)
11
−
tosyloxy group with Koser’s reagent, is substituted by N3 .
Once again, substrate scope is limited.
4
5
6
2.0
2.0
1.2
MeCN
1 h
≥98 (90)
≥98 (91)
≥98 (92)
The α-azidation of enolizable substrates has very recently
attracted much attention. Kirsch reported an iodine(V)-
mediated α-azidation method comprising the NaN3/IBX-
SO3K tandem and substoichiometric amounts of NaI as an
additive.12 Subsequently, Gade13 and Waser14 published Lewis
acid catalyzed α-azidation procedures utilizing cyclic azido-
iodinanes, with the former reporting the first high enantio-
selectivites with chiral iron(II)-based catalysts. These reports
prompted us to disclose our own investigation into the α-
azidation of 1,3-dicarbonyls, which was initiated with the goal
MeCN/H2O (9:1)
MeCN/H2O (9:1)
5 min
5 min
a
Reaction conditions: substrate (1.0 mmol), solvent (3 mL).
Determined by H NMR spectroscopy of the crude material; yield
b
1
of isolated product after column chromatography is given in
parentheses.
Received: December 4, 2013
© XXXX American Chemical Society
A
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Organic Letters
Letter
attempt to improve conversion by increasing the solubility of
NH4Cl, we carried out the reaction in MeCN/H2O (9:1) but
observed no improvement (entry 2). A marked acceleration of
the reaction was observed when we added 10 mol % of Et4NCl
as phase-transfer catalyst. The reaction mixture became
homogeneous with 70% conversion reached after 6 h. This
experiment prompted us to examine Et4NCl as the sole Cl−
source in MeCN. Gratifyingly, this gave a complete conversion
to the product in 1 h, with 2a isolated in 90% yield after
chromatography (Table 1, entry 4). Moreover, when using a
MeCN/H2O mixture as the solvent, the reaction time could be
shortened to just 5 min (entry 5). Further optimization
revealed that 1.2 equiv of DIB was equally effective (entry 6).
With the optimized conditions from Table 1, entry 6, in
hand, we examined the substrate scope of this reaction and
were pleased to find that β-keto esters 1b and 1d, lactone 1e, as
well as 1,3-diketones 1f−h were α-chlorinated in high yields
(Table 2). α-Allyl-substituted substrate 1c gave poor results in
Having established that the Et4NX/DIB tandem is an
efficient system for α-halogenation, we proceeded to test
commercially available Bu4NN3 as a N3− source for α-azidation.
Initial experiments with 1a under the same conditions for
halogenation, that is, adding DIB to a mixture of 1a/Bu4NN3 or
adding Bu4NN3 to a mixture of 1a/DIB, were either
irreproducible or gave product mixtures.17,18 However, when
combining Bu4NN3 and DIB in MeCN/H2O first, followed by
the immediate addition of the substrate in one portion, we were
able to detect a rapid consumption of the starting material in a
slightly exothermic reaction. To our delight, workup confirmed
complete conversion to the α-azido product 3a which was
isolated in 84% yield (Table 3, entry 1). In contrast, all other
Table 3. Optimization of the DIB-Mediated α-Azidation of
a
1a
Table 2. α-Halogenation of 1,3-Dicarbonyl Compounds with
a
the Et4NX/DIB System (X = Cl, Br, I)
b
c
entry
N3 source
solvent
conv (%)
yield (%)
d
1
2
3
4
5
6
7
8
Bu4NN3
Bu4NN3
Bu4NN3
Bu4NN3
Bu4NN3
Bu4NN3
TMSN3
NaN3
MeCN/H2O (9:1)
MeCN
≥98
85
84
70
69
64
71
46
CH2Cl2
82
toluene
79
Et2O
74
THF
67
MeCN
MeCN/H2O (9:1)
trace
a
b
c
Reaction conditions: substrate (1.0 mmol), solvent (3 mL).
Determined by 1H NMR spectroscopy of the crude material.
d
Isolated yield after column chromatography. Reaction time: 5 min.
solvents tested were inferior to the MeCN/H2O solvent system
(Table 3, entries 2−6), confirming our findings with Et4NX.
−
Other N3 sources were also tested, with no reaction observed
with TMSN3 (entry 7)19 and only traces of 3a detected with
NaN3 (entry 8).10b,20 These experiments clearly demonstrate
−
the unique properties of Bu4NN3 as a source of N3 in our α-
azidation reaction.
The α-azidation conditions from Table 3, entry 1, were
amenable to a variety of cyclic and acyclic β-keto esters (Table
4, entries 1−9) and a 1,3-diketone (entry 10), with the majority
of the corresponding α-azido compounds obtained in fair-to-
good yields. Ketones were unreactive under these conditions.
In contrast to α-halo transfer to carbonyl compounds from
hypervalent I−X reagents,6b,21 there is only very limited
understanding of α-N3 transfer to carbonyl compounds from
hypervalent I−N3 reagents. Azidation studies on other
substrates have suggested the involvement of azido radicals
a
Reaction conditions: substrate (1.0 mmol), Et4NX (1.1 mmol), DIB
19c
(N3 ) or free radical chain mechanisms.19a,22 In an attempt
•
b
(1.2 mmol), MeCN/H2O (9:1, 3 mL). Isolated yield after column
chromatography. MeCN/AcOH (9:1, 3 mL) was used as solvent.
c
to probe a radical pathway, we first subjected β-keto ester 1m
with a α-cyclopropyl radical clock to our standard reaction
conditions.23 After 1 h, no α-azido product 3m was detected
with the starting material recovered unchanged, presumably
due to steric arguments. Moreover, products 4 and/or 5
originating from a cyclopropylcarbinyl to 3-butenyl radical
rearrangement and subsequent hydrogen atom abstraction and/
MeCN/H2O. However, carrying out the reaction in MeCN/
AcOH (9:1) gave 2c in an acceptable 61% yield, presumably
due to the higher enol content of 1c in AcOH.
The use of Et4NX was general with respect to the other
halides. Using Et4NBr as the Br− source, α-bromination
occurred in good yields with substrates 1a, 1e, and 1g (entries
9−11). Similarly, α-iodination of 1g proceeded within 5 min in
72% yield with Et4NI as the I− source.
or N3 trapping were also not observed (Scheme 1a).19c,24
•
In a second experiment, we conducted the azidation of 1a in
the presence of the radical trap N-tert-butyl-α-phenylnitrone
(6).19a This reaction was not significantly inhibited by the
B
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Letter
Table 4. α-Azidation of 1,3-Dicarbonyl Compounds with the
Bu4NN3/DIB System
Scheme 2. Proposed Mechanism for α-Azidation
a
stabilizing cyclic benziodoxolone structure.22 Subsequent C−I
bond forming attack by the substrate enol tautomer onto 7 can
occur by two pathways. The first, resulting from ligand
exchange with AcO−, generates intermediate 8a which upon
reductive elimination of iodobenzene gives the α-azido product
10 (pathway A). Alternatively, ligand exchange can occur with
the N3 ligand to give intermediate 8b (pathway B). This can be
rationalized by the fact that the I−N bond in 7 is likely to be
longer and more polarized than the I−OAc bond.22,26
Subseqent SN2 substitution of the hypernucleofuge in 8b by
N3− furnishes 10.2,27 Support for pathway B can also be drawn
from the fact that competing formation of the α-OAc product is
−
observed when an excess of AcOH or AcO− over N3 ion is
present in the reaction mixture.18,28
In conclusion, we have developed a novel, mild and rapid
hypervalent iodine-mediated α-azidation of 1,3-dicarbonyl
compounds by employing commercially available Bu4NN3 as
a
Reaction conditions: substrate (1.0 equiv), Bu4NN3 (1.1 equiv), DIB
b
(1.2 equiv), MeCN/H2O (9:1, 3 mL). Isolated yield after column
chromatography. Bu4NN3 (2.1 equiv), DIB (2.1 equiv).
−
c
the N3 source. The success of this procedure depended on
studies conducted with the analogous α-halogenations with
Et4NX that led to crucial choices with respect to solvent and
the type of ammonium salt used. This study reports, to the best
of our knowledge, the first conditions for the use of the putative
azidoiodinane 7 at room temperature and could set precedent
for the use of ammonium salts as sources of nucleophiles in
hypervalent iodine chemistry.
Scheme 1. Probing the Involvement of a Radical Pathway
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and analytical data of all α-azido
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
presence of 6, with 3a formed in 80% conversion under our
standard reaction conditions (Scheme 1b).
*E-mail: hasim.ibrahim@ucd.ie.
Notes
These experiments support an ionic pathway for the α-
azidation reaction. On the basis of the stoichiometry used, we
propose that the initial mixing of equimolar amounts of
Bu4NN3 and PhI(OAc)2 generates azidoiodinane 7 (Scheme
2).25 Such mixed-ligand azido λ3-iodanes are predicted to be
highly reactive due to the unfavorable combination of trans
influences of the OAc/N3 ligand set26 and the absence of a
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by SFI and UCD’s School of
Chemistry and Chemical Biology.
C
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Organic Letters
Letter
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