Room temperature N-arylation of amino acids and peptides using copper(i) and β-diketone

Article abstract of DOI:10.1039/c5ob00288e

A mild and efficient method for the N-arylation of zwitterionic amino acids, amino acid esters and peptides is described. The procedure provides the first room temperature synthesis of N-arylated amino acids and peptides using CuI as a catalyst, diketone as a ligand, and aryl iodides as coupling partners. The method is equally applicable for using relatively inexpensive aryl bromides as coupling partners at 80 °C. Using this procedure, electronically and sterically diverse aryl halides, containing reactive functional groups were efficiently coupled in good to excellent yields.

Full text of DOI:10.1039/c5ob00288e

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Room Temperature NꢀArylation of Amino Acids and
Peptides Using Copper(I) and βꢀDiketone
Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 20xx,
Accepted 00th January 20xx
Krishna K. Sharma, Swagat Sharma, Anurag Kudwal, and Rahul Jain*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
mild and efficient method for the Nꢀarylation of
diamines,7bꢀd ethylene glycol,7e diethylsalicylamide,7f oximeꢀtype
and Schiff base ligands,7gꢀh thiopheneꢀ2ꢀcarboxylate,7i amino acids
and their derivatives,7jꢀk βꢀdiketones and BINOL.7lꢀm
zwitterionic amino acids, amino acid esters and peptides is
described. The procedure provides the first room
temperature synthesis of
Nꢀarylated amino acids and peptides
using CuI as a catalyst, diketone as a ligand, and aryl iodides
as coupling partners. The method is equally applicable with
relatively inexpensive aryl bromides as coupling partner at 80
oC. Using this procedure, electronically and sterically diverse
aryl halides, containing reactive functional groups were
efficiently coupled in good to excellent yields.
Recent progress in the copperꢀcatalyzed Nꢀaryl bond formation
reaction makes it as one of the most important methods in drug
discovery.8ꢀ9 It is amply documented that modified amino acids have
great potential in synthetic organic chemistry, and drug discovery.9
A large number of literature reports on the modifications of amino
acids and synthesis of Nꢀarylated amino acids, and their
incorporations into bioactive peptides or peptidomimetics are
available.10 However, it is well documented that the generalized
protocols on Nꢀarylation of amines or heterocycles are generally not
applicable for the zwitterionic amino acids and peptides due to the
concern of racemization.7ꢀ8
Copperꢀmediated CꢀN bond formation reactions have completed
more than a century since its first report by Fritz Ullmann in 1903.1
The longꢀknown limitations of this pioneering reaction include, high
temperature, use of stoichiometric amount of metal, and long
reaction time, leading to limited functional group applicability and
usual generation of undesired waste.1ꢀ2 Therefore, this traditional
method has limited application for the Nꢀarylation transformation
reactions involving enantiomerically pure substrates, because using
high temperature and strong basic conditions are known to result in
the racemization of the product.3 To circumvent these drawbacks,
palladiumꢀcatalyzed CꢀN bond formation reactions with aryl halides
have been developed using sterically hindered phosphine ligand and
Nꢀheterocyclic carbenes, under relatively milder conditions.4,5
However, airꢀ and moistureꢀsensitivity, and higher cost of palladium
catalysts and ligands limits their applications.6
A number of palladiumꢀcatalyzed Nꢀarylation reactions of amino
acids with aryl halides are known, which mainly suffer due to
relatively harsh reaction conditions.11 More recently, a few protocols
on copperꢀcatalyzed Nꢀarylation of amino acids using aryl halides as
coupling partners are reported, which preclude some of the
previously known limitations.12 Despite these efforts, copperꢀ
catalyzed Nꢀarylation of amino acids still encounters some
limitations, i.e. high temperature, long reaction times, and lack of
electronically and sterically diverse aryl substrates scope.Therefore,
an efficient and facile approach for facilitating Nꢀarylation of
zwitterionic amino acids with relatively inexpensive aryl halides
under relatively milder conditions is desirable. We report that aryl
halides efficiently react with amino acids and peptides at room
temperature to 80 oC, with reduced reaction time. To the best of our
knowledge, this is the first report on the Nꢀarylation of amino acids
at room temperature using aryl iodides.
During the past decade, Ullmannꢀtype coupling reactions have
perceived great progress, which mainly relied on utilization of
bidentate ligands, such as 1,10ꢀphenanthrolines,7a aliphatic
Department of Medicinal Chemistry, National Institute of Pharmaceutical
Education and Research, Sector 67, S. A. S. Nagar, Punjab, 160 062, India.
Corresponding Author * E-mail: rahuljain@niper.ac.in
After a careful examination of earlier reports,7,12ꢀ13 our investigations
were started by reacting Lꢀalanine (1.2 equiv.) with iodobenzene (1
equiv.) in the presence of easily available and inexpensive
acetylacetone (L1, 20 mol%), CuI (5 mol%) and cesium carbonate (2
equiv.) in DMF (3 mL) as solvent for 8 h. To our delight, reaction
Electronic Supplementary Information (ESI) available: Experimental
procedures, product characterization, copies of 1H and 13C and chiral
purity studies. See DOI: 10.1039/c000000x/
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DOI: 10.1039/C5OB00288E
afforded 41% yield of the desired product (table 1, entry 1), opening We also screened various solvents for the reaction (table 1, entries
the feasibility of Nꢀarylated amino acids at room temperature. 12ꢀ15); however, none offered advantage over the use of DMF as the
Various βꢀdiketoneꢀtype ligands were investigated to see their effect reaction solvent medium. In the case of toluene much lower yield
on the reaction (table 1, entries 2ꢀ5). We observed that using 2ꢀ was observed probably due to the poor solubility of amino acid.
isobutyrylcyclohexanone as ligand (L4, 20 mol%) and keeping the Reducing the amount of CuI to 2 mol% and L4 to 8 mol% afforded
reactants and reaction conditions indicated above intact, gave 87% 2a in 72% yield (table 1, entry 20), with the recovery of some
yield of 2a (Table 1, entry 4), thereby offering the best Nꢀarylation unreacted starting material even after 24 h. After several attempts
reaction condition. While, the use of 2,2,6,6ꢀtetramethylꢀ3,5ꢀ (table 1, entries 17ꢀ19), it was concluded that reaction also proceed
heptanedione (L2) and 2ꢀacetylcyclohexanone(L3) afforded 2a in smoothly at 80 ˚C for 12 h to afford 2a in 81% yield (table 1, entry
71% and 80% yield, respectively (table 1, entries 2ꢀ3). Interestingly, 18), when PhBr is used as a coupling partner instead of PhI.
the first documented use of 1,3ꢀcyclohexanedione (L5) as a diketone
ligand for the Nꢀarylation reaction resulted in formation of 2a in 18%
yield (table 1, entry 5), presumably due to the rigid structural
framework of the ligand, resulting in the weaker transition metalꢀ
ligand coordination. The attempts to identify alternate copper
catalyst failed (table 1, entries 9ꢀ11), and CuI was found to be the
best transition metal catalyst. The use of alternate bases, such as
K2CO3, NaOtBu, and K3PO4 (table 1, entries 6ꢀ8) did not improve
yield. An attempt to conduct Nꢀarylation reaction in the absence of
ligand produced a trace amount of desired product (table 1, entry
16).
The scope of newly developed intermolecular Nꢀarylation protocol
was investigated with a panel of substituted aryl coupling partners
(table 2). Aryl partners with electronꢀwithdrawing groups were wellꢀ
tolerated and afforded excellent yield (table 2, entries 2cꢀe, 2gꢀh, 2lꢀ
n). At the same time, challenging substrates and electronꢀdonating
group containing electrophilic aryl partners were also successfully
coupled in high yields (table 2, entries 2b, 2f, and 2iꢀk).
Table 2. Substrate scope of aryl halides with 1a,b,c
Table 1.
N
ꢀarylation of
L
ꢀalanine (1)a
Entry [Cu]
(5 mol%)
CuI
Ligand
(mol%)
Base
Solven
t
2a (%
Yield)b
1
2
3
4
5
6
7
L1
L2
L3
L4
L5
L4
L4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
41
71
80
87
18
74
78
CuI
CuI
CuI
CuI
CuI
CuI
NaOtBu
8
9
CuI
L4
L4
K3PO4
Cs2CO3
DMF
DMF
DMF
DMF
NMP
Toluene
Dioxane
DMA
DMF
DMF
DMF
81
82
72
65
78
35
65
62
CuBr
CuCl
CuOAc
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
10
11
12
13
14
15
16
17
18
19
20
L4
L4
L4
L4
L4
L4
ꢀ
L4
L4
L4
L4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Trace
Tracec
81d
DMF
DMF
78e
72f
aAll reactions were performed with
Lꢀalanine (1.2 equiv.), ArI (1
equiv., 2 mmol), base (2 equiv.), solvent (3 mL), rt; bArBr (1 equiv.,
2 mmol), base (2 equiv.), solvent (3 mL), 80 ˚C; isolated yields;
reaction time in parentheses.
aAll reactions were performed with
equiv., 2 mmol), base (2 equiv.), solvent (3 mL), CuI (5 mol%),
Lꢀalanine (1.2 equiv.), PhI (1
c
b
c
ligand (20 mol%); isolated yield; PhBr (1 equiv., 2 mmol) used
d
instead of PhI at room temp.; PhBr (1 equiv., 2 mmol) used at 80
Electronically and sterically diverse ortho-, meta-, and paraꢀ
substituted aryl halides and bulky aryl partners were coupled
efficiently (table 2). Due to the mild nature of protocol, demanding
substrates, such as reactive halo group containing aryl iodides were
e
f
˚C; PhBr (1 equiv., 2 mmol) used at 100 ˚C; CuI (2 mol%), L4 (8
mol%) percentage were used.
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coupled chemoselectively at room temperature (table 2, entries 2lꢀn). Based upon the above results and the literature reports,14 a plausible
Further, 1ꢀbromoꢀ4ꢀchlorobenzene was coupled with complete cascade mechanism of this copper(I)ꢀcatalyzed transformation is
chemoselectivity at 80 ˚C in 81% yield (table 2, entry 2mb). provided in scheme 1. It is proposed that, copper(I) first forms a
However as observed, iodobenzenes are superior as coupling complex with L4, followed by nucleophile coordination, resulting in
partners and gave high yields of the products compared to the transition state (TSꢀ1). Next, deprotonation by the base results in
bromobenzenes as aryl coupling partners.
the complex TSꢀ2, and subsequent electrophile partner coordination
The applicability of developed protocol to various natural and gave TSꢀ3. The oxidative addition results in the Cu(III)ꢀcentered
unnatural amino acids and their esters was investigated, and results complex (TSꢀ4), with the expulsion of Iꢀ anion. This complex (TSꢀ4)
are summarized in table 3. Various αꢀamino acids and esters were Nꢀ rearranges to give desired product via reductive elimination, and
arylated in high yields irrespective of the nature of alkyl group on regeneration of βꢀdiketoneꢀCu complex in the reaction medium.
the αꢀposition (table 3).
Scheme 1. Plausible reaction mechanism
Table 3. Substrate scope of amino acidsa,b
CulI
o
o
base
o
o
LH
L
CulI
L =
L CulI =
L CulI
- I
OH
O
H2N
L Cul
OH
HN
O
reductive
elimination
nucleophile
coordination
OH
O
Ph
H2N
L CuIII
HN
TS-4
L Cul
TS-1
OH
O
B
oxidative
addition
deprotonation
I
BH+
Ph
OH
O
I
L Cul -
L Cul -
HN
H2N
TS-2
electrophile
coordination
O
OH
TS-3
PhI
Table 4. NꢀArylation of peptidesa
aAll reactions were performed with amino acid or their esters (1.2 (i) Amino acid esters (1 equiv.), BocꢀAAꢀOH (1.2 equiv.), DIC (1.2
equiv.), PhI (1 equiv., 2 mmol), Cs2CO3 (2 equiv.), DMF (3 mL); equiv.), HONB (1.2 equiv.), 50 ˚C MW, 30 min; (ii) 7N HCl in
bisolated yield; reaction time in parentheses.
CH3OH, 30 min; (iii) 5aꢀd (1.2 equiv.), PhI (1 equiv., 2 mmol),
Cs2CO3 (2 equiv.), CuI (5 mol%), L4 (20 mol%), DMF (3 mL), 8h,
rt; aisolated yield.
The protocol was also applicable to selectively Nꢀarylate sideꢀchain
reactive group containing serine with iodobenzene (table 3, entry 4l).
By using this reaction, unnatural αꢀ βꢀ and γꢀamino acids and their To analyze the chiral purity of the Nꢀarylated amino acids, chiral
esters were Nꢀarylated in high yields (table 3, entries 4gꢀi). For HPLC using ChiralPakꢀWH column was performed. The mobile
reasons unknown, Nꢀarylation of amino acid esters gave slightly phase was 0.5 mM copper(II) sulfate in water and 2ꢀpropanol in 95ꢀ
lower yields of the products as compared with their zwitterionic
amino acid counterparts.
5% for 180 min. The column temperature was kept at 50 ˚C, and the
flow rate of the mobile phase was 1 mL/min. The chiral integrity of
the synthesized NꢀphenylꢀLꢀPhe (4c) and NꢀphenylꢀDꢀPhe (4j) using
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bromobenzene as the coupling partner, under the optimized
conditions (table 1, entry 18) remained intact during this
transformation (see SI for the chiral HPLC chromatograms).
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4
,
The newly developed protocol was next applied for the direct Nꢀ
arylation of peptides (5aꢀd). The peptides (5aꢀd) were synthesized
using earlier developed microwave (MW)ꢀassisted peptide synthesis
protocol.15 The reaction were performed at room temperature in the
presence of PhI as the aryl coupling partner in DMF for 8 h. High
yield of the desired Nꢀarylated peptides was obtained (table 4, entries
6aꢀd) without any apparent racemization (see SI for the HPLC
chromatogram).
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5
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In conclusion, we have developed a mild, efficient and high yielding
generalized method for the Nꢀarylation of zwitterionic amino acids,
amino acid esters and peptides using aryl iodides and catalyzed by
CuI and Cs2CO3in the presence of 2ꢀisobutyrylcycloꢀhexanone as a
βꢀdiketoneꢀtype ligand at room temperature. The protocol is also
applicable to the coupling of relatively inexpensive aryl bromides
efficiently at 80 ˚C in high yields. A wide range of natural and
unnatural amino acids and their derivatives were efficiently Nꢀ
arylated. The chiral integrity of the synthesized amino acids
remained intact during this mild catalytic transformation. The
method was also extended to include Nꢀarylation of peptides. To best
of our knowledge, this is the first ever report on the direct Nꢀ
arylation of peptides. The other highlight of the reaction is the
racemizationꢀfree Nꢀarylation. The application of this protocol in the
Nꢀarylation of bioactive peptides and peptidomimetics is currently
pursued.
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