Mild Ullmann-type biaryl ether formation reaction by combination of ortho-substituent and ligand effects

Article abstract of DOI:10.1002/anie.200503538

(Chemical Equation Presented) An important position: A strong orthosubstituent effect caused by NHCOR groups in 2-haloacetanilides in combination with the ligand effect greatly promotes an Ullmann-type biaryl formation reaction that takes place at room te

Full text of DOI:10.1002/anie.200503538

Communications
Coupling Reactions
fall short of that needed for cyclopeptide synthesis because
the reaction temperatures are still too high. Recently, we
found that the NHCOR groups in 2-haloacetanilides could
greatly promote the Ullmann-type biaryl formation reaction,
which in combination with the known ligand effect led to this
reaction taking place at room temperature. Herein, we wish to
disclose these results.
DOI: 10.1002/anie.200503538
Mild Ullmann-Type Biaryl Ether Formation
Reaction by Combination of ortho-Substituent
and Ligand Effects**
As indicated in Table 1, the reaction of 2-bromotrifluoro-
acetanilide (1a)with l-tyrosine derivative 2 using CuI/N,N-
dimethylglycine in the presence of Cs2CO3 at room temper-
Qian Cai, Benli Zou, and Dawei Ma*
Many natural cyclopeptides bearing a biaryl ether bridge[1]
possess remarkable physiological activities. These include
antibiotics (vancomycin,[1,2] ristocetin,[3] and teicoplanin[1,4]),
antitumor agents (K-13[5,6e] and bouvardin[6a–c]), neurotensin
antagonist RP-66453,[7] and anti-HIV agents (e.g., chloropep-
tins[8]). For elaboration of these synthetically challenging
molecules, several elegant methods that feature biaryl ether
formation have been developed. Examples include oxidative
phenolic coupling,[1c] o-nitro-[1b,2e,f,7] or metal-activated[1c,5a]
nucleophilic aromatic substitution, modified Ullmann-type
coupling reactions,[1,2a,6] and boronic acid based biaryl ether
synthesis.[4,8–10] However, more practical and flexible proto-
cols are still required to improve the synthetic approaches to
these biologically important cyclopeptides.
The Ullmann-type coupling reaction of aryl halides and
phenols is a reliable method for elaborating biaryl ethers.[10,11]
Although this reaction has been employed for the assembly of
certain cyclopeptides,[1c,6] the danger of racemization of the
amino acid moieties under basic conditions and high reaction
temperatures ( ꢀ 1308C)prevents its wide application in this
area. In 1997, Nicolaou et al. found that a triazene unit ortho
to the halogen atom facilitates coupling with phenol moieties
so that the reaction proceeds at 808C.[2a] Successful applica-
tion of the method to the total synthesis of vancomycin has
been reported.[1a,2b–d] However, good conversion of the
substrates requires at least five equivalents of CuBr·SMe2.
Recently, we and other groups discovered that some special
Table 1: CuI-catalyzed reaction of aryl halides 1 with phenol 2.[a]
Entry
Y
X
Ligand[b]
t [h]
Yield [%][c]
1
2
3
4
5
6
7
8
9
COCF3
COCF3
COCF3
COCF3
COCF3
COCF3
COCH3
COPh
2-Br
2-Br
2-Br
2-Br
2-I
2-Cl
2-Br
2-Br
2-Br
3-Br
4-Br
A
B
C
–
A
A
A
A
A
A
A
2
4
2
5
5
24
15
24
24
2
88
49[d]
26[d]
0[d]
43[d]
7[d]
53[d]
14[d]
0[d]
SO2Me
COCF3
COCF3
[e]
10
11
–
–
[f]
2
[a] Reaction conditions: CuI (0.15 mmol), ligand (0.5 mmol),
1
(0.5 mmol), 2 (0.75 mmol), Cs2CO3 (1.5 mmol), 1,4-dioxane (2 mL),
RT. [b] A: N,N-dimethylglycine, B: N-methyl-l-proline, C: l-proline.
[c] Yield of the isolated products. [d] Aryl halide was recovered in 40–
90% yield. [e] Corresponding cross-coupling product was isolated in less
than 3% yield. [f] No conversion was observed. Tr=triphenylmethyl.
ature is completed in 2 h and delivers the coupling product 3a
in 88% yield (entry 1). Low yields were observed with N-
methyl-l-proline or l-proline as the ligands (entries 2 and 3),
and no coupling occurred in the absence of a ligand (entry 4).
Relative to aryl bromide 1a, aryl iodide and chloride were
poorer substrates (entries 5 and 6). In addition, a reactivity
trend for the N-substituent (Y= COCF3 > COCH3 > COPh @
SO2Me)was noted (entries 1 and 7–9). Furthermore, little or
no conversion was noticed in the case of 3-bromotrifluoroa-
cetanilide or 4-bromotrifluoroacetanilide as the substrates
(entries 10 and 11). These results clearly show the existence of
an accelerating effect caused by an ortho-amide group and
that its combination with ligand effects is essential for this
reaction to take place at room temperature.
With the optimized reaction conditions in hand, we
studied the process with a few other aryl bromides and
phenols (Table 2). Both N-Cbz- and N-Boc-l-tyrosine methyl
esters were suitable for this reaction and gave 6a and 6b in
good yields without any racemization, as determined by
chiral-column HPLC analysis. Some loss of optical purity was
observed when N-Boc-(R)-4-hydroxyphenylglycine methyl
ester was used (see 6c). Fortunately, this problem could be
obviated by changing the N-protecting group from Boc to Tr
À
ligands could promote CuI-catalyzed C(aryl) O bond for-
mation.[10,11] Unfortunately, these new reaction conditions still
[*] Q. Cai, Prof. Dr. D. Ma
State Key Laboratory of Bioorganic and Natural Products Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Fenglin Lu, Shanghai 200032 (China)
Fax: (+86)21-6416-6128
E-mail: madw@mail.sioc.ac.cn
B. Zou
Department of Chemistry
Fudan University
Shanghai 200433 (China)
[**] The authors are grateful to the Chinese Academy of Sciences,
National Natural Science Foundation of China (grants 20321202
and 20572119) and the Science and Technology Commission of
Shanghai Municipality (grants 02JC14032 and 03XD14001) for their
financial support. We also thank Professor T.-L. Ho for helpful
discussions.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 2: CuI/N,N-dimethylglycine-catalyzed coupling reaction of aryl bromides 4 with phenols 5.[a]
(3 equiv)in dilute dioxane
(0.01m), and the desired cycliza-
tion product 10 was isolated in
45–51% yields. Next, the macro-
lactam 10 was converted into K-
13 in 34% overall yield through
five routine transformations,
which included proper changes
of the protecting groups, hydrol-
ysis of the ester and trifluoro-
acetanilide groups, and diazoti-
zation of the aniline unit to a
phenol moiety.
Product
t [h] Yield [%]
Product
t [h] Yield [%]
6a[b]
5
8
82
88
6b[b] 5 h 90
6c[c]
6d[b]
8
82
We also carried out a syn-
thesis of 12 (see Scheme 2)from
6e 14 85
6 f
14 80
dipeptide
11,
which
was
obtained by coupling a liberated
acid from 4b with l-tyrosine
methyl ester. Although an initial
attempt to effect its macrocycli-
zation under our standard con-
ditions failed, when the solvent
was changed to MeCN/pyridine
(4:1), and the reaction temper-
ature was raised to 458C, we
were pleased to notice that the
desired cyclic product 12, which
might serve as an intermediate
for synthesizing RP 66453, was
isolated in 42% yield.[7] This
cyclization is comparable with
those reported by two groups
who used o-nitro-activated
nucleophilic aromatic substitu-
tion,[7] but in our case two amino
acid units could be readily
6g
6i
3
4
4
88
81
76
6h[d] 10 51
6j
4
4
82
70
6k
6m[e]
[a] Reaction conditions: CuI (0.15 mmol), N,N-dimethylglycine (0.5 mmol), 4 (0.5 mmol), 5 (0.75 mmol),
Cs2CO3 (1.5 mmol), 1,4-dioxane (2 mL), RT. [b] 99% ee, as determined by HPLC. [c] 91% ee, as
determined by HPLC. [d] 40% aryl bromide was recovered. [e] Phenol (1.5 mmol) was added. Cbz=
benzyloxycarbonyl, Boc=tert-butoxycarbonyl.
(see 6d). From a l-phenylalanine-derived bromide 4b (see
Scheme 1 for the preparation), two isodityrosine analogues
6e and 6 f were produced in good yields. These compounds
are promising synthetic intermediates for isodityrosine,[9] K-
13,[5] and related natural products. We found that electron-
deficient aryl bromides are less reactive (see 6h). The
exclusive formation of 6i from a coupling of 2,4-dibromotri-
fluoroacetanilide provided further support of an ortho-
substituent effect by an NHCOR group. An amino acid
residue in the phenol component is not necessary for the
reaction, as demonstrated by examples 6j–6m. The formation
of 6k and 6m also indicated that steric factors might not be
critical and a twofold ortho-substitution is possible, for
example, with 2,6-dibromotrifluoroacetanilides.
Encouraged by the above success, we extended our work
to intramolecular macrocyclization, with the total syntheses
of antitumor agent K-13 and a cycloisodityrosine derivative.
As shown in Scheme 1, 7 was reduced by hydrogenation,
brominated with NBS, and treated with (CF3CO)2O to afford
aryl bromide 4b. Hydrolysis of 8 with LiOH was followed by
coupling with a liberated amine from 4b. Tripeptide 9, thus
obtained, was subjected to macrocyclization in the presence
of CuI (3 equiv) N,N-dimethylglycine (3 equiv), and Cs2CO3
obtained from l-phenylalanine and l-tyrosine. This advant-
age would allow large-scale preparation.
Since the Hurtley reaction was disclosed in 1929, consid-
erable efforts have been devoted to identifying suitable ortho-
substituents that can promote Ullmann-type couplings.[2a,12]
However, only carboxylate and triazene units have been
found to have the desired accelerating effect prior to our
present work. Two mesomerism models have been proposed
for interpreting the early results,[2a,12c] but a similar model is
not suitable for rationalizing the present ortho-substituent
effect. Consequently, we propose a plausible mechanism as
follows (Scheme 3): Oxidative addition of the chelated CuI
center A to ArX produces complex B, in which the oxygen of
the NHCOR group may coordinate with the Cu center to
provide additional stabilization. It is noteworthy that similar
PdII complexes have been determined by Tremont and
Rahman in their palladium acetate catalyzed ortho-alkylation
of acetanilides.[13a] After reaction of B with cesium phen-
oxides to give C, reductive elimination occurs to afford the
biaryl ethers and regenerate the catalytic species. This model
was supported by the difference in reactivity between the
trifluoroacetanilides and acetanilides discussed above. The
higher reactivity of the aryl bromides might be explained by
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Communications
the different contributions of the bromide and iodide anions
to the stabilization of B. Besides this speculation, more work
should be performed to prove this mechanism further or other
possible mechanisms should be put forward.
In summary, we have found that the NHCOR group has a
strong ortho-substituent effect on an Ullmann-type biaryl
ether formation reaction. This ortho-substituent effect is the
third type discovered to date, which should facilitate the
development of more mild Ullmann-type coupling reac-
tions.[10] In addition, although the substrates tested so far are
limited, our new reaction is rather mild and fast relative to the
previous CuI-catalyzed coupling reactions of aryl halides with
phenols,[11] and therefore should find further applications in
organic synthesis.
Received: October 6, 2005
Revised: November 27, 2005
Published online: January 20, 2006
Keywords: biaryl ethers · coupling · ligand effects · ortho effect ·
.
peptides
Scheme 1. Synthesis of K-13. Reagents and conditions: a) Pd/C/H2,
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e) aq. LiOH, THF, MeOH; f) HATU/DIPEA, DMF; g) Cs2CO3, CuI,
N,N-dimethylglycine, 1,4-dioxane, RT; h) TFA then Ac2O/TEA; i) aq.
NaOH, MeOH; j) tBuONO/HBF4, MeCN; k) Cu(NO3)2/Cu2O.
NBS=N-bromosuccinimide, DMF=dimethylformamide, TFA=tri-
fluoroacetic acid, HATU=2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetra-
methyluronium hexafluorophosphate, DIPEA=diisopropylethylamine,
TEA=triethylamine.
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conditions: a) 1. aq. LiOH, MeOH, THF; 2. l-tyrosine methyl ester,
EDCI, HOBt, DIPEA, CH2Cl2, 90% for two steps; b) CuI (3 equiv),
Me2NCH2CO2H (4 equiv), Cs2CO3 (4 equiv), MeCN/Py (4:1), 0.01m,
458C, 42%. EDCI=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride.
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Scheme 3. Plausible mechanism for mild biaryl formation.
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