Arylation of azlactones using diaryliodonium bromides and silver carbonate: Facile access to α-tetrasubstituted amino acid derivatives

Article abstract of DOI:10.1002/adsc.201400035

With the combined use of silver carbonate, diaryliodonium bromides were successfully utilized as aryl source to realize the highly efficient arylation of azlactones under mild conditions. The reaction worked well with various alkyl- and aryl-substituted azlactones, providing a range of α-tetrasubstituted amino acid derivatives in moderate to high yields.

Full text of DOI:10.1002/adsc.201400035

UPDATES
DOI: 10.1002/adsc.201400035
Arylation of Azlactones using Diaryliodonium Bromides and
Silver Carbonate: Facile Access to a-Tetrasubstituted Amino
Acid Derivatives
Zhuo Chai,a,b,* Biao Wang,a Jia-Nan Chen,a and Gaosheng Yanga
a
The Key Laboratory of Functional Molecular Solids, Ministry of Education, Anhui Laboratory of Molecule-Based
Materials, College of Chemistry and Materials Science, Anhui Normal University, Wuhu, Anhui 241000, Peopleꢀs
Republic of China
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese
b
Academy of Sciences, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-0553-388-3517; e-mail: chaizhuo@mail.ahnu.edu.cn
Received: January 10, 2014; Revised: March 18, 2014; Published online: May 28, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400035.
Abstract: With the combined use of silver carbon-
ate, diaryliodonium bromides were successfully uti-
lized as aryl source to realize the highly efficient ar-
ylation of azlactones under mild conditions. The re-
action worked well with various alkyl- and aryl-sub-
stituted azlactones, providing a range of a-tetrasub-
stituted amino acid derivatives in moderate to high
yields.
diaryliodonium salts as both the oxidizer and aryl
source.[5]
The structures of diaryliodonium salts, especially
the counteranion of the cationic iodine center, have
influences on both their solubility and arylating abili-
ty. Most current successful systems rely on the use of
reactive diaryliodonium salts with weakly coordinat-
ing, non-nucleophilic anions such as OTf, BF4 and
PF6. In contrast, diaryliodonium salts bearing coordi-
nating anions like halides have been found to be gen-
erally less reactive with much fewer applications in ar-
ylation, despite their easy accessibility and stability
towards heat, oxygen and humidity.[1g] Early arylations
with these diaryliodonium salts were mainly done
with relatively reactive enolates or their equivalents,
Keywords: amino acids; arylation; azlactones; dia-
ryliodonium salts; oxazolones; silver
Diaryliodonium salts are among the most studied the preparation of which usually required strongly
iodine(III) reagents with extensive applications in or- basic conditions or special combinations of substrate-
ACHTUNGTRENNUNG
ganic synthesis.[1] Particularly, their utility as efficient s.[2e–h] An approach to enhance the reactivities of
electrophilic arylating reagents for various nucleo- these diaryliodonium salts towards arylation would be
philes has experienced significant advances recently. to make the electrophilic cationic iodine center more
Probably due to their modest arylating capacity, exposed, namely the exclusion of the coordinating,
direct electrophilic arylation of enolates and their nucleophilic halogen anions. We presumed that the
equivalents with diaryliodonium salts under metal- addition of a silver salt might serve this purpose via
free conditions is only applicable to a fairly limited the precipitation of AgX, which has been widely used
reaction scope.[2] The most extensive application of in organic synthesis for the creation of reactive cat-
these arylating reagents in organic synthesis has been ionic species.
achieved with the combined use of a metal salt as cat-
alyst. Outstanding examples include the successful ap- zolones) have recently attracted much attention
plications of Cu(I/II) salts in catalyzing the arylation mainly as nucleophiles in various reactions due to
On the other hand, azlactones (also known as oxa-
ACHTUNGTRENNUNG
of various compounds. disclosed by Gaunt and co- their versatility in the synthesis of a-tetrasubstituted
workers, which were presumed to involve a highly amino acids and peptides.[6] In contrast to the numer-
electrophilic aryl-CuACTHNUTRGNEUGN(III) species as the key inter- ous reports on the traditional reactions of azlactones
mediate;[3,4] and the arylation of arenes with diarylio- such as benzylation, allylation and Michael addition,
donium salts using Pd(II) catalysts developed by San- the introduction of an aryl group to this type of struc-
ford and co-workers, which was supposed to proceed tures has been rare. To the best of our knowledge,
through the formation of Pd(IV) intermediates with only two examples dealing with the arylation of azlac-
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UPDATES
Arylation of Azlactones using Diaryliodonium Bromides and Silver Carbonate
Table 1. Optimization of reaction conditions.[a]
tones have so far been reported. One was developed
by Hartwig and co-workers via Pd-catalyzed reaction
with aryl bromides in the presence of a bulky phos-
phine ligand at 808C or 1008C.[7a] The other one by
Gelmi utilized the SNAr reaction between 1-halo-2,4-
dinitrobenzenes/2-chloro-3,5-dinitropyridine
and
azlactones.[7b] We disclose herein a novel system for
this with the usually less reactive diaryliodonium bro-
mides as the aryl source, enabling the facile arylation
of azlactones under very mild conditions to provide
a wide range of a-tetrasubstituted amino acid deriva-
tives.
Entry Solvent
Temp. Time Yield [%][b]
1
toluene
toluene
toluene
toluene
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
458C
458C
r.t.
r.t.
458C
r.t.
458C
r.t.
r.t.
9 h
60
0
0
2[c]
3[d]
4[e]
5[f]
6
18 h
18 h
18 h
19 h
6 h
0
toluene
62
56
71
68
As expected, the reaction of azlactone 1a with di-
phenyliodonium bromide 2a proceeded smoothly in
toluene in the presence of Ag2CO3 to give the target
product 3a in modest yield (Table 1, entry 1) while no
conversion of 1a was observed when Ag2CO3 was
C6H5CF3
1,3-xylene
mesitylene
CH2Cl2
1,2-DCE
CCl4
TBME
n-hexane
CH3CN
CCl4-CH3CN (9:1)
CCl4-CH3CN (200:1) r.t.
CCl4-toluene (9:1)
CCl4-toluene (9:1)
CCl4-toluene (9:1)
7
8
9
3 h
3 h
3.5 h 58
3.5 h 51
13 h
24 h
12 h
0.5 h 50
1 h
10 h
5 h
7 h
10
11
12
13
14
15
16
17
18[g]
19[h]
absent (entry 2). The use of 10 mol% of CuACTHNUGTRENUNG(OTf)2,
77
<10
52
a common effective catalyst for electrophilic arylation
using reactive diaryliodonium salts with non-nucleo-
philic anions, hardly provided any target product but
led to the decomposition of the starting material to
give a complex mixture (entry 3). Moreover, using di-
phenyliodonium triflate 2a’ also led to no conversion
of 1a (entry 4). These results suggest that a new reac-
tive arylating species might be generated from the
combination of Ar2IBr and Ag2CO3 to effect the ary-
lation of 1a. Although raising the amount of 2a result-
ed in a negligible influence on the yield (entry 5), the
screen of several different solvents revealed a pro-
nounced solvent effect for this reaction (entries 6–14).
The reaction generally proceeded faster to give inferi-
or yields in polar solvents than in less polar ones. In
polar solvents, the reaction systems generally gave
more complex mixtures in addition to the major prod-
uct 3a, probably due to the accelerated side reactions
such dimerization and decomposition in these sol-
vents.[8] In order to improve both the yield and reac-
67
82
86
74
41
458C
458C
458C
23 h
[a]
Reaction conditions: 1a (0.15 mmol), 2a (0.165 mmol),
Ag2CO3 (0.0875 mmol) in 1.0 mL of solvent under argon.
When a co-solvent was used, volume ratios are given.
Isolated yields.
No Ag2CO3 was added.
CuACTHUNTGRENUNG(OTf)2 (10 mol%) was used instead of Ag2CO3.
2a’ was used instead of 2a.
1.5 equiv. of 2a were used.
Run in 0.5 mL of co-solvent.
AgOAc (1.1 equiv.) was used instead of Ag2CO3; 35% of
1a was recovered.
[b]
[c]
[d]
[e]
[f]
[g]
[h]
tion rate, some co-solvent systems were screened. ance of a bromide on the benzene ring in 1d is worthy
Gratifyingly, after some experimentation, a co-solvent of note in that it might not be compatible with the
of CCl4-toluene (9/1, v/v) was indentified as the best previously developed Pd-catalyzed system.[7] More-
to give the target product in 86% yield at 458C within over, when R1 and/or R2 were an alkyl group(s), the
5 h (entry 17). Notably, when the reaction was con- reaction still proceed uneventfully to give moderate
ducted at a higher concentration or AgOAc was used to high yields of the desired products. Notably, azlac-
instead of Ag2CO3, a significant decrease in the yield tone 1j bearing a bulky R2 group (i-Pr), which gave
was observed (entries 18 and 19).
only 29% yield in the Pd-catalyzed system, participat-
With the optimized conditions in hand (Table 1, ed well in the reaction to give a high yield (87%,
entry 17), the phenylation of diversely substituted entry 9). Azlactone 1k containing a thioether func-
azlactones 1 was investigated with diphenyliodonium tionality was well tolerated to give the highest yield
bromide 2a (Table 2). When the R1 was an aryl group, (91%, entry 10). In addition, azlactone 1l could under-
electron-donating substituents on the benzene ring go fast double phenylation to deliver the product 3l in
were more favored over electron-withdrawing ones in good yield. Notably, this reaction could be run on
terms of yield (entries 1–4). This phenomenon might a 1 mmol scale with no appreciable decrease in the
be ascribed to the observation that electron-withdraw- yield (entry 11).
ing substituents would render the azlactones more
Next, a series of diaryliodonium bromide 2 was ex-
prone to other side reactions such as decomposition amined for a scope study with azlactone 1a under the
and dimerization. Despite the modest yield, the toler- same optimized conditions as described above, and
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UPDATES
Zhuo Chai et al.
Table 2. Phenylation of azlactones.[a]
Table 3. Arylation of 1a using different 2.[a]
Entry 1 (R1, R2)
Time
3
Yield [%][b]
Entry
2 (Ar)
T [h]
3
Yield [%][b]
87
1
1b (3-CH3C6H4, CH3)
4 h
3b 84
3c
3d 67
3e 65
3f
3g 74
3h 81
3i
3j
1
2
3
4
5
6
7
8
2a (Ar=Ph)
10
0.7
1
1
0.7
5
3a
3m 63
3n
3o
3p
3q
3r
2
1c (4-CH3OC6H4, CH3) 4 h
87
2b (Ar=4-FC6H4)
2c (Ar=4-ClC6H4)
2d (Ar=4-BrC6H4)
2e (Ar=4-CF3C6H4)
2f (Ar=4-MeOC6H4)
2g (Ar=mesityl)
2h (Ar=2-thienyl)
3
4
5
1d (4-BrC6H4, CH3)
1e (4-CF3C6H4, CH3)
1f (Ph, Bn)
1 h
1 h
3.5 h
5 h
3.5 h
4 h
52
51
55
80
79
6
1g (Bn, Bn)
7
1h (n-Pr, Bn)
4
23
28
8
1i (Ph, n-Pr)
84
87
3s
93[c]
9
1j (Ph, i-Pr)
5 h
10
11
1k (Ph, CH2CH2SCH3)
1l (Ph, H)
5 h
1.5 h
3k 91
3l
[a]
Reaction conditions: 1a (0.3 mmol),
Ag2CO3 (0.165 mmol) in 2.0 mL of solvent under argon.
Isolated yields.
0.15 mmol scale. 2.2 equiv. of 2h were used.
2
(0.33 mmol),
74 (73)[c]
[b]
[c]
[a]
Reaction conditions:
1 (0.3 mmol), 2a (0.33 mmol),
Ag2CO3 (0.165 mmol) in 2.0 mL of solvent under argon.
[b]
[c]
Isolated yields.
2.2 equiv. of 2a were used. For product 3l, R1 =R2 =Ph
yield in the parenthesis refers to that of the reaction run
on a 1.0 mmol scale.
by-products (entry 7). Notably, the heterocyclic di(2-
thienyl)iodonium bromide 2h also performed well in
the reaction to give 2-thienylated product 3s in excel-
lent yield, although a larger amount of 2h and longer
the results are listed in Table 3. Complementary to reaction time were required (entry 8).
the Pd-catalyzed system, this reaction system general-
We then studied the reactivities of unsymmetrical
ly could proceed to completion within a shorter time diaryliodonium bromides 2j and 2k under the opti-
with a good tolerance of functionalities like halogens mized reaction conditions (Scheme 1). For 2j, the ob-
on the Ar group. For symmetric diaryliodonium salts served priority of aryl transfer in this reaction system
2a–2h, the reactions were significantly affected by the was similar to that observed in previous studies on
electronic nature of the substituents on the aromatic the arylation of enolates and heteroatoms:[2] the more
rings: the presence of electron-withdrawing substitu- electron-deficient aryl group was transferred prefera-
ents led to apparently lower yields (entries 2–5), al- bly. For 2k, the presence of a bulky mesityl group di-
though the reactions were faster than in the cases of minished the yield significantly and transfer of the
electron-donating ones. As to the steric factor, when less bulky phenyl group was favored. The products
the Ar was a sterically demanding group like the me- were isolated as mixtures that were inseparable by
sityl group in 2g, the yield of the desired product also column chromatography, and the product ratios were
1
diminished while full conversion of the azlactone was estimated by H NMR analysis. Moreover, following
still observed with the formation of other unidentified a literature method,[9] the product 3a could be con-
Scheme 1. Reaction with unsymmetrical diaryliodonium bromides and conversion of product 3a to a-tetrasubstituted amino
acid hydrogen chloride salt 6
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UPDATES
Arylation of Azlactones using Diaryliodonium Bromides and Silver Carbonate
Scheme 2. A mechanistic proposal for the arylation of azlactones and the free radical trapping experiment with BHT.
verted to the corresponding a-tetrasubstituted amino cient arylating reagents for the arylation of azlac-
acid hydrogen chloride salt 6 in excellent yield.
tones, which has rarely been realized using other
Based on previous studies and our own experimen- methods. The reaction worked well for a broad scope
tal results, a tentative mechanism for the present reac- of both diverse azlactones and diaryliodonium salts,
tion was proposed (Scheme 2).[10] The role of Ag2CO3 providing a series of a-tetrasubstituted amino acid de-
in the reaction system was dual: as a base promoting rivatives in moderate to good yields under very mild
the formation of enolate I and as an activator con- conditions. Efforts towards the elaboration of this
verting 2a to the cation II. As suggested by the recent system to other substrates as well as the development
computational study of Olofsson[2d] and previous stud- of an asymmetric version are now in progress in our
ies[2f,10] on the reaction between diaryliodonium salts laboratory.
and an enolate, the key intermediates IIIa or IIIb
(formed by I and II) might undergo non-radical re-
ductive elimination to give the final product through Experimental Section
[2,3]- and [1,2]-rearrangements, respectively. In our
case, some experimental results correlating to a radical General Procedure
process were observed, such as the isolation of the di-
merized product 4. Moreover, when three equivalents
of TEMPO (2,2,6,6-tetramethylpiperidine N-oxide,
Under argon atmosphere, azlactone 1 (0.3 mmol), diarylio-
donium salt 2 and 2.0 mL of co-solvent CCl4-toluene (v/v=
9:1) were added to an oven-dried Schlenk vessel at room
a radical scavenger) were added to the reaction under
the optimized conditions as in Table 1, entry 17, only
a 30% yield of the desired product was obtained with
other unidentifiable products. More importantly, the
addition of 1 equivalent of BHT (2,6-di-tert-butyl-4-
methylphenol) led to the formation of a 47% yield of
compound 5, which would be best explained by a radi-
cal process. Therefore, although the exact reaction
mechanism remains unclear at this stage, we presume
that the formation of intermediates IIIa or IIIb pro-
ceeds at least partly via a radical coupling between I
and II following a SET (single electron transfer) pro-
cess between the enolate and cationic iodonium
center.
temperature. The mixture was stirred for 5 min before
Ag2CO3 (46.9 mg, 0.17 mmol) was added. The resultant mix-
ture was stirred at 458C and monitored by TLC. After com-
pletion, the reaction mixture was directly purified by
column chromatography on silica gel eluting with petroleum
ether and ethyl acetate (v/v=100:1) to deliver the desired
product.
Acknowledgements
Financial supports for this work from the National Natural
Science Foundation of China (21202001, 21172002) and the
In summary, we have developed a novel method
enabling the use of diaryliodonium bromides as effi- NSF of Anhui province (11040606M36) are acknowledged.
Adv. Synth. Catal. 2014, 356, 2714 – 2718
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