Palladium-catalyzed direct functionalization of 2-aminobutanoic acid derivatives: Application of a convenient and versatile auxiliary

Article abstract of DOI:10.1002/anie.201306583

New group on the block: 2-Methoxyiminoacetyl is a readily available auxiliary for promoting palladium-catalyzed γarylation of C(sp ³)-H bonds. This auxiliary can be easily removed by either treatment with 1n KOH at room temperature, or converted into a glycine moiety for peptide synthesis. Copyright

Full text of DOI:10.1002/anie.201306583

Angewandte
Chemie
DOI: 10.1002/anie.201306583
À
C H Activation
Palladium-Catalyzed Direct Functionalization of 2-Aminobutanoic
Acid Derivatives: Application of a Convenient and Versatile
Auxiliary**
Mengyang Fan and Dawei Ma*
The last decade has witnessed great progress on transition-
[1,2]
À
metal-catalyzed C H bond functionalization.
Although
many synthetically useful methods for regioselective func-
2
À
tionalization of the C(sp ) H bond of arenes and heteroar-
enes have been discovered,[3] direct functionalization of
3
[4]
À
C(sp ) H bonds in common alkyl groups is still challenging.
3
À
This challenge arises from the inert nature of most C(sp ) H
bonds and the difficulty in controlling regioselectivity. A
promising approach is to use directing groups which can bind
to metal centers and selectively deliver the catalyst to
À
a proximal C H bond. For this strategy to be synthetically
useful, an ideal directing group should be readily available,
easily introduced and removed under mild reaction condi-
tions, and even applicable for further chemical manipulations
to afford desired functional groups. To date, a considerable
number of auxiliaries derived from carboxylic acids have been
demonstrated to have the directing ability to promote metal-
3
À
Figure 1. Auxiliary-directed g arylation of C(sp ) H bond. Boc=tert-
butoxycarbonyl, TBS=tert-butyldimethylsilyl.
3
À
catalyzed C(sp ) H bond activation, and include amides
derived from 8-aminoquinoline,[5] O-methyl hydroxyamine,[6]
2-methylthioaniline,[5c,d,7] 2,3,4,5,6-pentafluoro-aniline,[8a–c] or
4-trifluoromethyl-2,3,5,6-tetrafluoro-aniline,[8d,e] oxazoline,[9]
esters,[10] and even carboxylic acid[11] itself. However, only
three structurally similar directing groups derived from
amines have been discovered (Figure 1).[5a,12,13] In 2005,
Daugulis and co-workers reported that palladium-catalyzed
g arylation of amine derivatives could be achieved by employ-
ing a picolinamide auxiliary as the directing group.[5a] The
difficulty in removing this amide auxiliary prompted Chen,
He and co-workers to employ 3-[(tert-butyldimethylsilyloxy)-
methyl]picolinamide as a modified directing group, which can
be removed through intramolecular acyl transfer under acidic
conditions, although it is not conveniently available.[12]
Recently, Carretero and co-workers described that N-(2-
pyridyl)sulfamide could serve as the directing group for
palladium-catalyzed g arylation of amino acid derivatives.[13]
The auxiliary could be easily removed in this case by
treatment with zinc/NH4Cl. However, their arylation step
needed relatively high reaction temperatures (ca. 1508C) to
ensure satisfactory conversion, and led to the desired
arylation product being isolated in a low yield (44%) when
a 2-aminobutanoic acid derivative was used as the substrate.
Herein, we wish to report 2-methoxyiminoacetyl (MIA)
as a powerful auxiliary for promoting palladium-catalyzed
3
À
functionalization of the C(sp ) H bonds of amines. The
corresponding amides, derived from substituted aminobuta-
noic acids, can couple with aryl iodides in the presence of
Pd(OAc)2 at 60–1008C to afford the g-arylation products 2 in
good yields. The amides 2 can be hydrolyzed at room
temperature and hydrogenated to deliver the substituted
homophenylalanines 3 and homophenylalanine-embodied
peptides 4, respectively. Noteworthy is that substituted
homophenylalanines have been frequently used in developing
peptidomimetics which possess important biological activi-
ties.[14] This effort has led to the discovery of several marketed
drugs such as the antihypertensives enalapril and quinapril,[15]
and the antitumor agent carfilzomib[16] (Figure 2). Thus,
synthetic methods for quick assembly of substituted homo-
phenylalanines are highly desirable so as to fully explore the
structure–activity relationship of homophenylalanine-embod-
ied peptidomimetics.
[*] M. Fan, Prof. Dr. D. Ma
State Key Laboratory of Bioorganic & Natural Products Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Fenglin Lu, Shanghai 200032 (China)
E-mail: madw@mail.sioc.ac.cn
[**] We are grateful to the National Basic Research Program of China
(973 Program, grant 2010CB833200), Chinese Academy of Sciences,
and the National Natural Science Foundation of China (grant
21132008 & 20921091) for financial support.
As indicated in Table 1, we started our exploration by
conducting the direct arylation of 1a, which was derived from
methyl (2S)-aminobutanate and 2-methoxyiminoacetic acid
by condensation. To our delight, reaction of 1a with 4-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201306583.
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Table 2: Direct arylation of 1a with aryl iodides.[a]
Entry
Ar
Product
Yield [%][b]
1
2
3
4
5
6
7
8
3-MeOC6H4
4-CF3OC6H4
4-PhC6H4
2-naphthyl
4-ClC6H4
4-FC6H4
3,4-F2C6H3
4-BrC6H4
2b
2c
2d
2e
2 f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
68
69
69
54
71
63
69
75
64
64
70
74
74
87
69
70
88
80[c]
67
74
Figure 2. Drugs containing the homophenylalanine moiety.
Table 1: Reaction conditions for the arylation of 1a.[a]
9
3-BrC6H4
10
11
12
13
14
15
16
17
18
19
20
4-CF3C6H4
3-CF3C6H4
4-MeO2CC6H4
3-MeO2CC6H4
2-MeO2CC6H4
4-O2NC6H4
3-O2NC6H4
2-O2NC6H4
2-O2NC6H4
4-MeOCC6H4
3-MeOCC6H4
Entry
Additives (equiv)
Solvent
Yield [%][b]
1
AgOAc (1.0)
neat
15
2
AgOAc (2.0)
neat
15
3
4
5
6
AgOAc (1.5)
AgOAc (1.5)
AgOAc (1.5)
AgOAc (1.5)
toluene
tAmylOH
tBuOH
HFIP
11
26
23
58
2r
2s
2t
7
Ag2CO3 (1.5)
HFIP
6
8
AgOAc/PivOH (1.5:1.0)
AgOAc/PivOH (1.5:1.0)
HFIP
HFIP
62
[a] Reaction was carried out on a 0.5 mmol scale. [b] Yields of isolated
products. [c] Reaction was conducted on a 5 mmol scale, at 1108C for
36 h.
9[c]
74 (67)[d]
[a] All of the screening reactions were carried out in a 5 mL Teflon cap-
sealed tube on a 0.5 mmol scale ([1a]=0.5m) unless otherwise
specified. [b] The yields were determined by 1H NMR analysis of the
crude reaction mixture using CH2Br2 as the internal standard. [c] A
diluted reaction system was applied ([1a]=0.1m) and was carried out in
a 15 mL Teflon cap-sealed tube. [d] Yield of isolated product; 99% ee.
Piv=pivaloyl, HFIP=hexafluoroisopropanol.
and 2j were obtained in good yields. Particularly interesting
was that ortho-substituted aryl iodides provided better yields
than the corresponding para- and meta-substituted aryl
iodides (compare 2m–o, and 2p–r), presumably because of
the additional binding to palladium complexes provided by
ester and nitro groups. This advantage allows assembly of
conformationally rigid cyclic homophenylalanine analogues.
Although a detailed mechanistic investigation of the
present arylation awaits further experimentation, tentative
proposals are outlined in Scheme 1. Based on the studies by
Daugulis and co-workers,[5a–d] we believed that an MIA-
generated amide might react with Pd(OAc)2 to form the
iodoanisole in the presence of 10 mol% Pd(OAc)2 and
AgOAc[5a] provided the desired arylation product 2a success-
fully at 1008C, however the yield (15%) was poor because of
a low conversion (entry 1). Increasing the loading of AgOAc
and using toluene as the solvent failed to give any improve-
ment (entries 2 and 3). However, increased yields were
observed when reaction was carried out in tBuOH and
tAmylOH (entries 4 and 5). Further improvement could be
achieved by using hexafluoroisopropanol (HFIP)[7,13] as the
solvent (entry 6) and employing pivalic acid (PivOH) as
another additive (entry 8).[17] The best result (67% yield) was
obtained when the reaction was run as a dilute solution
(entry 9). More importantly, the high enantiopurity of 2a
(99% ee) indicated that no racemization occurred during the
reaction course. It is notable that changing the silver salt to
Ag2CO3 led to a poor conversion (entry 7).
À
palladium amidate 5 and therefore facilitate a subsequent C
H insertion to give the double five-membered palladium
chelate 6. After oxidative addition of 6 to aryl iodide, the
resultant complex 7 would undergo reductive elimination to
deliver 2 through the intermediate 8.
We next moved our attention to other substituted 2-
aminobutanoic acid derivatives. As shown in Scheme 2, direct
With the optimal reaction conditions in hand, we next
examined the reaction scope by varying aryl iodides and the
results are summarized in Table 2. Gratifyingly, a wide range
of aryl iodides bearing either electron-donating or electron-
withdrawing groups worked well, thus giving the correspond-
ing arylation products in 54–88% yield upon isolation. The
reaction chemoselectivity between aryl iodides and aryl
bromides was achieved, as is evident from the fact that 2i
Scheme 1. Possible reaction mechanism.
2
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enantiopurity. Noteworthy is that 3a–d have been used in the
preparation of anthranil amino acid derivatives possessing
anticholecystokinin activity,[18] novel a-amino-g-lactams as b-
secretase inhibitors,[19] propionamide derivatives as endopep-
tidase inhibitors,[20] and small peptides for controlling Wnt
activity.[21] Compound 3e was easily converted into the lactam
11, a promising intermediate for preparing antihypertensive
drug benazepril.[22]
Additionally, we found that the MIA auxiliary could be
conveniently transformed into a glycine moiety which could
be used in peptide synthesis, and is illustrated by formation of
the dipeptides 4a and 4b from the corresponding arylation
products 2c and 2m by hydrogenation and subsequent
protection (Scheme 4). Interestingly, selective hydrolysis of
the ester moiety in 2 could be achieved by treatment of 2 with
1.5 equivalents of LiOH in dioxane, and the resultant acids
were condensed with another protected amino acid or peptide
to synthesize oligopeptides, as indicated by formation of the
tripeptide 12 and tetrapeptide 13.
Scheme 2. Reagents and conditions: a) 10 mol% Pd(OAc)2, 4-iodoani-
sole (2–3 equiv), AgOAc (1.5 equiv), HFIP, 60–808C, 24 h. b) 10 mol%
Pd(OAc)2, PhI(OAc)2 (2.0 equiv), toluene, 908C, 10 h. Ar=4-methoxy-
phenyl, MIA=2-methoxyiminoacetyl.
arylation of the l-valine derivative 1b afforded the g-
monoarylated product 2u and g,g’-biarylated product 2v in
a combined yield of 77% under very mild reaction conditions
(608C). Notably, 2u was isolated as a single diastereoisomer,
thus indicating that the arylation occurred exclusively at the
pro-S methyl of 1b. The l-threonine derivative 1c gave 2w in
only 40% yield, probably because of its steric hindrance. The
d-allo-isoleucine derivative 1d provided the desired 2x in
70% yield. Additionally, the a-quaternary amino acid deriv-
ative 1e is compatible with these conditions, thus leading to
formation of 2y in 72% yield. Besides g-arylation, acetox-
ylation at the same position was also found to be feasible
using PhI(OAc)2 as the oxidant. Accordingly, oxidation of 1c
and 1e afforded the g-acetoxylated products 9 (55%) and 10
(87%), respectively.
Scheme 4. Reagents and conditions: a) Pd/C, H2, (Boc)2O. b) aq
LiOH, 1,4-dioxane. c) ClCO2iBu, N-ethylmorpholine; then H-Val-
OMe·HCl. d) ClCO2iBu, N-ethylmorpholine; then H-Ala-Leu-OMe·TFA.
TFA=trifluoroacetic acid.
To demonstrate the synthetic utility of the present direct
arylation reaction, we conducted further transformations of
the arylation products. As depicted in Scheme 3, we were
pleased to find that the MIA auxiliary could be simply
removed by hydrolysis of 2 with 1n KOH in dioxane at room
temperature, and the resultant amino acids were protected
with (Boc)2O to afford 3a–e with good yields and excellent
Additional investigations demonstrated that the amino
ester moiety is necessary for this arylation, as evidenced from
the generation of 15 in 38% yield from the MIA-protected 2-
butylamine 14 under our typical reaction conditions
(Scheme 5). However, N-methyl 2-butylamine, methyl 2-
aminopentanoate, and methyl 2-amino-4-methylpentanoate-
derived substrates 16–18 did not give any arylation products
even at 1208C, thus indicating that secondary amides are not
suitable substrates and g arylation of the methylene unit and
d arylation of the terminal CH3 group cannot occur under the
Scheme 3. Reagents and conditions: a) 1m KOH, 1,4-dioxane, RT;
then (Boc)2O. b) Pd/C, H2. c) EDCI, HOAt, DIPEA. DIPEA=diisopro-
pylethylamine, EDCI=1-ethyl-3-(3’-dimethylaminopropyl)carbodiimide.
Scheme 5. Functionalization with other substrates.
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In summary, we have developed an effective protocol for
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3
À
amine auxiliary for palladium-catalyzed C(sp ) H bond
functionalization. Application of this auxiliary for other
coupling reactions involving C(sp ) H bond activation is
being actively pursued in our group and the results will be
disclosed in due course.
3
À
Received: July 28, 2013
Published online: && &&, &&&&
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À
Keywords: amino acids · C H activation ·
homogeneous catalysis · palladium · peptides
.
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4
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À
C H Activation
M. Fan, D. Ma*
&&&& — &&&&
Palladium-Catalyzed Direct
Functionalization of 2-Aminobutanoic
Acid Derivatives: Application of
New group on the block: 2-Methoxy-
can be easily removed by either treatment
a Convenient and Versatile Auxiliary
iminoacetyl is a readily available auxiliary
with 1 n KOH at room temperature, or
converted into a glycine moiety for pep-
tide synthesis.
for promoting palladium-catalyzed g ary-
3
À
lation of C(sp ) H bonds. This auxiliary
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