Synthesis of conformationally restricted glutamate and glutamine derivatives from carbonylation of orthopalladated phenylglycine derivatives

Article abstract of DOI:10.3762/bjoc.8.179

A new method for the regioselective synthesis of 2-alkoxycarbonyl- and 2-(aminocarbonyl)phenylglycinate methyl esters has been developed. The reaction of the orthopalladated complex [Pd(μ-Cl)(C₆H ₄(CH(CO₂Me)NMe₂)-2)]₂ (1) with nucleophiles HNu under a CO atmosphere results in the selective incorporation of the C(O)Nu moiety to the phenyl ring and formation of the carbonyl species ortho-C₆H₄(C(O)Nu)(CH(CO₂Me)NMe₂) (2a-j) (Nu = OR, NHR, NR₂). Compounds 2a-j are conformationally restricted analogues of glutamic acid and glutamine and are interesting due to their biological and pharmacological properties. The reaction of [Pd(μ-Cl)(C₆H₄(CH(CO₂Me)NHTf)-2)] ₂ (3) with nucleophiles in a CO atmosphere results, however, in the formation of the cyclic isoindolinone or the open 2-carboxyphenylglycine methyl esters, with the reaction outcome being driven by the choice of the solvent.

Full text of DOI:10.3762/bjoc.8.179

Synthesis of conformationally restricted glutamate
and glutamine derivatives from carbonylation of
orthopalladated phenylglycine derivatives
Esteban P. Urriolabeitia*, Eduardo Laga and Carlos Cativiela
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1569–1575.
Instituto de Síntesis Química y Catálisis Homogénea, CSIC -
Universidad de Zaragoza, Pedro Cerbuna 12, 50009 Zaragoza, Spain
doi:10.3762/bjoc.8.179
Received: 25 June 2012
Email:
Accepted: 16 August 2012
Published: 18 September 2012
Esteban P. Urriolabeitia* - esteban@unizar.es
* Corresponding author
This article is part of the Thematic Series: "C–H Functionalization".
Guest Editor: H. M. L. Davies
Keywords:
C–H functionalization; carbonylation; glutamic acid; glutamide;
palladium; phenylglycine
© 2012 Urriolabeitia et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A new method for the regioselective synthesis of 2-alkoxycarbonyl- and 2-(aminocarbonyl)phenylglycinate methyl esters has been
developed. The reaction of the orthopalladated complex [Pd(μ-Cl)(C6H4(CH(CO2Me)NMe2)-2)]2 (1) with nucleophiles HNu under
a CO atmosphere results in the selective incorporation of the C(O)Nu moiety to the phenyl ring and formation of the carbonyl
species ortho-C6H4(C(O)Nu)(CH(CO2Me)NMe2) (2a–j) (Nu = OR, NHR, NR2). Compounds 2a–j are conformationally restricted
analogues of glutamic acid and glutamine and are interesting due to their biological and pharmacological properties. The reaction of
[Pd(μ-Cl)(C6H4(CH(CO2Me)NHTf)-2)]2 (3) with nucleophiles in a CO atmosphere results, however, in the formation of the cyclic
isoindolinone or the open 2-carboxyphenylglycine methyl esters, with the reaction outcome being driven by the choice of the
solvent.
Introduction
The selective functionalization of organic molecules is, at the position [4], therefore affording highly selective processes and
present time, one of the most developed areas of organic and avoiding the obtainment of unwanted isomers.
organometallic chemistry. Several factors have contributed to
this spectacular growth. The main one is the use of transition Probably the aspect of this method of synthesis with the greatest
metals, such as Rh, Ru, Pd, Pt or Au, with the capability of acti- impact is the oxidative coupling of two C–H bonds to give a
vating and breaking C–H bonds and, thus, transforming the new C–C bond, because it avoids the use of prefunctionalized
inert C–H unit into the reactive C–M group (M = transition substrates, minimizes the amount of waste generated during the
metal) [1-3]. In addition, the introduction of the concept of a reaction and, in general, allows for the reactions to occur under
"directing group" enables the attack of the metal on a unique mild conditions and tolerates a variety of functional groups
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Beilstein J. Org. Chem. 2012, 8, 1569–1575.
[5-10]. This is advantageous when reactive or sensitive frag- aminoacids is based on the fact that their incorporation into
ments are present in the molecular scaffold.
peptides constitutes a very useful strategy to reduce their flexi-
bility and retard enzymatic degradation. Moreover, these
We are interested in the regioselective functionalization of restricted amino acids can stabilize particular conformational
α-amino acids [11-13], due to the extraordinary interest in these features, which may lead to improvements in the biological
delicate molecules as building blocks of peptides and proteins, potency if the bioactive conformation is tethered [14-16].
and because of their relevant biological activity. In this context,
Results and Discussion
we have recently reported C–H bond activation processes on a
variety of arylglycines substituted at the phenyl ring, and the Synthesis of new orthopalladated derivatives
corresponding synthesis of a new family of orthopalladated Two phenylglycinate derivatives have been used as starting ma-
complexes [12]. The carbonylation of these compounds allows terials, one of them containing a sterically hindered
for a general synthesis of methyl (1H)-isoindolin-1-one-3- N atom, protected by two methyl groups, namely
carboxylates under very mild reaction conditions, regardless of [C6H5C(H)(CO2Me)NMe2] [17,18], and the other one
whether the substituents at the aryl ring Rn are electron-with- containing a less hindered, but strongly electron-withdrawing,
drawing or electron-releasing. This method, shown in triflate (Tf) group [C6H5C(H)(CO2Me)NHTf] [19]. The
Scheme 1, represents a real synthetic alternative to other clas- orthopalladation of [C6H5C(H)(CO2Me)NMe2] has been
sical preparative pathways [12].
reported previously by Ryabov and Beck [17,18], and
affords complex 1 by heating of Pd(OAc)2 and
[C6H5C(H)(CO2Me)NMe2] in acetic acid (55–60 °C over
15–20 min), followed by stirring at room temperature for 2–3
days. In this way, complex 1 is obtained in 50% yield. We did
not use this method, and we present here an optimized syn-
thesis of complex 1, which is achieved by heating a solution of
Pd(OAc)2 with [C6H5C(H)(CO2Me)NMe2] (1:1 molar ratio) in
acetone under reflux for 24 h, followed by the typical
metathesis of acetate by chloride bridging ligands in MeOH.
Our improved procedure takes place in a shorter reaction time
(1 versus 3 days) and affords analytically pure complex 1 in
yields typically higher than 65%. The characterization of 1 was
performed by comparison of its spectral data with those previ-
ously reported [18]. On the other hand, the reaction of
[C6H5C(H)(CO2Me)NHTf] with Pd(OAc)2 (1:1 molar ratio)
affords the orthometallated [Pd(µ-Cl)(C6H4CH(CO2Me)NHTf-
Scheme 1: Synthesis of methyl (1H)-isoindolin-1-one-3-carboxylates
by carbonylation of phenylglycine derivatives [12].
With the aim of expanding the scope of application of this 2)]2 (3), after metathesis of acetate by chloride bridging ligands,
method, we report in this paper the results obtained when other as shown in Scheme 2. In this case the reaction also takes place
functional groups on the same starting material (methyl phenyl- in acetone under reflux, but 48 h of heating is necessary to
glycinate) are changed. In particular, we have detected that the achieve completion. Complex 3 was characterized following the
presence of different types of substituents at the nitrogen atom usual techniques. Both microanalytical and mass spectral data
has a critical effect on the final outcome of the reaction and that, are in good agreement with the proposed dinuclear stoichiom-
instead of the expected (1H)-isoindolin-1-ones, conformation- etry for 3. The 1H NMR spectrum of 3 shows broad signals,
ally restricted glutamines and glutamates can be obtained. The probably due to different equilibrium processes. These could
undoubted importance of conformationally constrained involve the interconversion between the two possible diastereo-
Scheme 2: Synthesis and NMR characterization of orthometallated complex 3.
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Beilstein J. Org. Chem. 2012, 8, 1569–1575.
isomers (RR/SS and RS/SR) through cleavage of the chloride very simple, since the evaporation of the solvent affords 2a–j as
bridges, as well as the potential formation of cisoid and tran- analytically pure yellow oils. Compounds 2a–f can be consid-
soid geometric isomers. The breakage of the chloride bridging ered as glutamic acid derivatives, while 2g–j are analogues of
system by NC5D5 and "in situ" formation of the corresponding glutamine, in which the β- and γ-positions belong to an aryl ring
mononuclear derivative (3-py, see Scheme 2), which is static on and display, therefore, a severe conformational restriction.
the NMR time scale, simplifies notably the NMR spectra. The
1H NMR spectrum shows then the presence of four well-spread The present method appears to be quite general, since it is valid
signals, one of them (H6) strongly shifted upfield due to the for a wide range of alcohols and amines. In the case of alcohols,
anisotropic shielding of the cis-pyridine ring. This observation, primary (2a, 2b, 2d, 2e) and secondary (2c) aliphatic alcohols,
together with the presence of six different peaks in the and even arylic substrates (2f) have been incorporated into the
13C NMR spectrum, one of them clearly deshielded (C1, phenylglycine scaffold. Very good yields are obtained with
151.41 ppm), points to the presence of the PdC6H4 unit. All the acidic alcohols, such as methanol (2a), ethanol (2b) or even 1,2-
other features of the NMR data are in keeping with the struc- ethanediol (2d). These values drop when 2-propanol (2c) or
ture depicted in Scheme 2.
phenol (2f) are used, and moderate yields are obtained (≈40%),
whereas no reaction at all is observed for bulky tertiary alco-
hols, for example when Me3COH is used.
Synthesis of conformationally restricted gluta-
mates and glutamines
Complex 1 reacts with CO in the presence of alcohols or amines In alkoxycarbonylation reactions the nucleophile finally incor-
(even aminoesters) affording the corresponding alkoxycarbony- porated into the carbonyl group (an alkoxide) usually comes
lated (2a–f) or aminocarbonylated species (2g–j), as shown in from the reaction solvent (an alcohol). This fact guarantees the
Scheme 3 and Figure 1, under very mild reaction conditions full displacement of the reaction, but sometimes hampers the
(CH2Cl2, 1 atm CO, 25 °C).
purification of the target products, mainly when alcohols of
high boiling point and/or viscosity are involved. However, in
The clear formation of black palladium indicates the progress of our method, CH2Cl2 is used as the solvent and stoichiometric
the reaction, which is completed typically in 16 h in all studied amounts of the nucleophiles are used instead, without any
cases. After removal of the Pd0 the workup of the reaction is problem in the purification step.
Interestingly, there is a clear difference in the reactivity of 1
with CO, depending on the presence or lack of nucleophiles.
The reaction of 1 with CO in CH2Cl2 has been reported previ-
ously by Beck [18], and this process affords the γ-lactam
displayed in Scheme 4. Assuming the mechanism shown in
Scheme 1, it seems that, in the absence of any other nucle-
ophile, the intramolecular C–N coupling takes place with
Scheme 3: Carbonylation of 1 to afford glutamate and glutamine
derivatives 2a–j.
concomitant formation of a N,N-dimethylisoindolinonium salt,
which undergoes further elimination of a methyl group by
Figure 1: Scope of the carbonylation reaction.
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Beilstein J. Org. Chem. 2012, 8, 1569–1575.
arylglycine fragment, as stated above. Then, the reaction of 1
with CO, in CH2Cl2, and in the presence of stoichiometric
amounts of benzylamine, aniline, methyl (R)-phenylglycinate or
di-n-butylamine, occurs with smooth insertion of CO into the
Pd-Caryl bond and further incorporation of the C(O)NHCH2Ph
(2g), C(O)NHPh (2h), C(O)NHCH(CO2Me)Ph (2i) or
C(O)NBu2 (2j) moieties into the ortho-position of the
C6H4C(H)(CO2Me)NMe2 ligand. This results in the synthesis
Scheme 4: Reaction of 1 and CO in CH2Cl2 [18].
1,2-shift of the Me unit from the N atom to the Pd centre, as of the corresponding conformationally restricted glutamines
previously reported by Heck et al. [20].
2g–j in moderate to good yields, as shown in Figure 1. This
means that the process can be efficiently performed not only
As we have shown previously in Scheme 3, in the presence of with a variety of O-nucleophiles, but also with different types of
nucleophiles the process results in the formation of conforma- N-nucleophiles.
tionally restricted glutamate derivatives. This is mainly due to
the fact that the demethylation of the NMe2 unit shown in In comparison with other aminocarbonylations found in the
Scheme 4 is not a very favourable process, and the reaction can recent literature [21-24], our method is remarkable since it
take a different outcome, especially if alternative pathways are occurs under very mild reaction conditions (1 atm CO, 25 °C)
accessible. Taking into account these facts, we can propose a and, mainly, because it occurs through C–H bond activation
sensible explanation for the different reactivity. Therefore, the processes without the need to use prefunctionalized substrates.
attack of the oxygen of an O-bonded alcohol on the electro- Typical aminocarbonylations catalysed by Pd usually start from
philic acyl carbon in our complexes seems to be favoured, since the corresponding iodides or bromides, and require high CO
no demethylation is involved, and the C–O coupling occurs pressures and high reaction temperatures. Obviously, further
selectively instead of the intramolecular C–N bond formation. It efforts in our systems have to be directed to the transformation
seems that the reaction is driven by the pathway that tends to of the stoichiometric process into a catalytic one, a challenge
avoid the demethylation, while the comparison of the different that is still not accomplished in the case of the aminocarbonyla-
nucleophilic abilities of the species coordinated to the metal tion, even though several catalytic examples are known of the
(O-bonded alcohols versus N-bonded amines) plays in this case related alkoxycarbonylation reaction [25-30].
only a minor role.
Once we had determined the reactivity of complex 1, having a
Using the same arguments we can explain the different reactiv- N,N-dimethyl-phenylglycine ligand, we focused our attention
ity found for 1, and shown in Scheme 3, when compared to on complex 3, possessing a triflate as a N-protecting group, in
related Pd complexes previously reported by us [12], resumed order to study the influence of the substituents at the N atom in
in Scheme 1. Therefore, the synthesis of the methyl (1H)-isoin- the carbonylation further. The reaction of 3 with CO (1 atm) in
dolin-1-one-3-carboxylates by carbonylation of [Pd(μ- CH2Cl2 at room temperature, that is, in the absence of nucle-
Cl)(C6H4CH(CO2Me)NH2-2)]2 occurs by C–N coupling, irre- ophiles, occurs with C–N coupling and formation of the methyl
spective of the presence of additional nucleophiles, since the 3-oxo-2-((trifluoromethyl)sulfonyl)isoindoline-1-carboxylate
cyclization generates an isoindolinonium salt, from which it is (4) in good yields, as shown in Scheme 5 (right).
relatively easy to promote a simple deprotonation.
This means that the N atom is still nucleophilic enough to
Very interestingly, the reactivity of 1 is not limited to the add- promote the cyclization, in spite of the presence of the highly
ition of alcohols, and primary amines, secondary amines, and electron-withdrawing triflate group. It is also clear that, after
even α-aminoesters can also be coupled to the N,N-dimethyl- C–N coupling, the resulting ammonium salt eliminates easily
Scheme 5: Reactivity of 3 with CO in the presence (left) and absence (right) of nucleophiles.
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Synthesis of methyl N,N-dimethyl-α-(2-
HCl (formally) affording the neutral amine, in close similarity
to the process shown in Scheme 1. However, when the reaction methoxycarbonylphenyl)glycinate (2a)
of 3 with CO (1 atm) is performed in MeOH, a mixture of the Methanol (13 μL, 0.300 mmol) was added to a solution of 1
compounds derived from intramolecular cyclization (4) and (100.0 mg, 0.150 mmol) in CH2Cl2 (10 mL), and the resulting
alkoxycarbonylation (5) is obtained (molar ratio 4/5 2.4:1). This mixture was stirred under a CO atmosphere for 16 h. Decompo-
mixture can be separated by column chromatography, and pure sition to black metallic palladium was observed. The mixture
isolated compound 5 has been characterized as containing the was filtered through a plug of Celite. The light yellow solution
NHTf group and two different CO2Me moieties, as represented was washed with water (3 × 20 mL), dried over MgSO4, filtered
in Scheme 5 (left). This result can be interpreted as a competing and evaporated to give compound 2a as a yellow oil. Yield:
reaction between the nucleophilic abilities of the N atom of the 72.9 mg, 0.290 mmol, 97%.
glycine moiety and the oxygen atom of the methanol, which in
this case is the reaction solvent. It is clear that the introduction 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J = 7.7 Hz, 1H, C6H4),
of the triflate group decreases the electron density of the N 7.68 (d, J = 7.7 Hz, 1H, C6H4), 7.50 (t, J = 7.7 Hz, 1H, C6H4),
atom, which is now less nucleophilic in comparison, for 7.35 (t, J = 7.7 Hz, 1H, C6H4), 5.12 (s, 1H, CH), 3.89 (s, 3H,
example, with the complex containing the NH2 unit, shown in OMe), 3.69 (s, 3H, OMe), 2.31 (s, 6H, NMe2); 13C NMR
Scheme 1. In that case the N was quite nucleophilic, and (75 MHz, CDCl3) δ 172.08 (s, CO), 168.36 (s, CO), 137.60 (s,
cyclization occurred regardless of the solvent used for the reac- C), 131.96 (s, CH), 130.99 (s, C), 130.32 (s, CH), 129.03 (s,
tion [12]. In the present case the N is less nucleophilic and CH), 127.88 (s, CH), 68.42 (s, CH), 52.34 (s, OCH3), 51.88 (s,
competes with other nucleophiles, giving mixtures 4 and 5 in OCH3), 42.97 (s, NMe2); IR (ν, cm−1) 1724 (C=O), 1257
the presence of methanol. Obviously, in absence of additional (C-O); ESIMS (positive mode) (m/z): 251.9 [M + H]+; anal.
nucleophiles, 4 is obtained selectively. We attempted several calcd for C13H17NO4 (251.12): C, 62.14; H, 6.82; N, 5.57;
reaction conditions in order to prepare selectively compound 5, found: C, 62.35; H, 6.91; N, 5.36.
but it seems to be difficult to quench the intramolecular cycliza-
Synthesis of [Pd(μ-
tion, and in all studied cases the 4/5 mixture is obtained. Due to
this fact, we have not studied other alcohols.
Cl)(C6H4CH(CO2Me)NHTf-2)]2 (3)
To a solution of Pd(OAc)2 (421.1 mg, 1.836 mmol) in acetone
Conclusion
(30 mL), PhCH(CO2Me)NHTf [19] (545.8 mg, 1.836 mmol)
The reactivity of the orthopalladated dimers [Pd(µ- was added, and the resulting mixture was heated under reflux
Cl){C6H4(CH(CO2Me)NR2)-2}]2 (NR2 = NMe2, NHTf) for 48 h. After the reaction time, the solution was evaporated to
towards CO in the presence of alcohols or amines as nucle- dryness, the residue was treated with CH2Cl2 (40 mL), and the
ophiles allows for the synthesis of conformationally restricted resulting suspension was filtered over a Celite pad. The
glutamates or glutamines, respectively, through alkoxycarbony- resulting clear solution was again evaporated to dryness, and the
lation or aminocarbonylation intermolecular processes. In spite residue was dissolved in MeOH and allowed to react with NaCl
of the presence of an intramolecular nucleophile (the N atom of (243.6 mg, 4.167 mmol) at room temperature for 4 h. The pale
the NR2 group), the formation of the cyclic isoindolinone yellow solution was evaporated to dryness, the dry residue
derivatives has been observed only in one case. This means that extracted with CH2Cl2 (30 mL), and the resulting suspension
the nitrogen atoms of the NMe2 or the NHTf groups behave as filtered to eliminate the excess of NaCl. Evaporation of this
weaker nucleophiles than the oxygen or nitrogen atoms of the clear solution and treatment of the residue with pentane
external nucleophiles involved (alcohols, amines). In addition, afforded 3 as a yellow–brownish solid. Yield: 452.6 mg,
the results also show that the nucleophilic abilities 0.516 mmol, 56.2% yield.
of the N atom in the starting materials [Pd(µ-
Cl)(C6H4CH(CO2Me)NR2)]2 (NR2 = NMe2, NHTf) are weaker 1H NMR (300 MHz, CDCl3 + py-d5) δ 7.21 (dd, J = 7.6,
than those observed in [Pd(µ-Cl)(C6H4CH(CO2Me)NH2)]2, for 1.5 Hz, 1H, C6H4), 6.94 (td, J = 7.4, 1.2 Hz, 1H, C6H4), 6.71
which a systematic intramolecular aminocarbonylation was (td, J = 7.5, 1.5 Hz, 1H, C6H4), 5.91 (dd, J = 7.7, 1.2 Hz, 1H,
observed.
C6H4), 5.38 (s, 1H, CH), 3.78 (s, 3H, OCH3), 2.24 (s, 1H, NH);
13C NMR (75 MHz, CDCl3+py-d5) δ 173.94 (s, CO), 151.41 (s,
C, C6H4), 149.54 (m, CD, py), 146.10 (s, C, C6H4), 135.55 (m,
Experimental
General Methods. The general methods are reported in the CD, py), 132.49 (s, CH, C6H4), 125.57 (s, CH, C6H4), 124.46
Supporting Information File 1. The complex [Pd(μ- (s, CH, C6H4), 123.29 (m, CD, py), 122.69 (s, CH, C6H4),
Cl)(C6H4CH(CO2Me)NMe2-2)]2 (1) has been prepared 120.82 (q, J = 324.6 Hz, CF3), 72.37 (s, CH), 52.30 (s, OCH3);
following previously reported procedures [17,18].
19F NMR (282 MHz, CDCl3 + py-d5) δ −76.71 (s, CF3); IR (ν,
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Beilstein J. Org. Chem. 2012, 8, 1569–1575.
cm−1): 3375 (br, N-H), 1742 (νCOO); ESIMS (positive mode) ESIMS (positive mode) (m/z): 324.2 [M − OMe]+, 356.0 [M +
(m/z): 439 [M/2 + H]+; anal. calcd for C20H18Cl2F6N2O8Pd2S2 H]+; anal. calcd for C12H12F3NO6S (355.03): C, 40.57; H, 3.40;
(876.23): C, 27.41; H, 2.07; N, 3.20; S, 7.32; found: C, 26.93; N, 3.94; S, 9.03; found: C, 40.42; H, 3.24; N, 3.82; S, 8.93.
H, 2.02; N, 3.45; S, 6.98.
Supporting Information
Synthesis of methyl 3-oxo-2-
((trifluoromethyl)sulfonyl)isoindoline-1-
carboxylate (4)
Supporting Information File 1
General methods and experimental and analytical data of
compounds 2b–j.
A solution of 3 (50.0 mg, 0.057 mmol) in dichloromethane was
stirred under a CO atmosphere for 16 h. Decomposition to black
palladium was observed. The mixture was filtered through a
plug of Celite, and the yellow solution was washed with water
(3 × 20 mL), dried over MgSO4, filtered and evaporated to give
4 as a yellow oil. Yield: 26.7 mg, 0.083 mmol, 72%.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-179-S1.pdf]
Acknowledgements
Financial support from the Spanish Ministerio de
Economía y Competitividad (projects CTQ2011-22589 and
CTQ2010-17436) and Gobierno de Aragón (Spain, research
groups E97 and E40) is gratefully acknowledged. E. L. thanks
Gobierno de Aragón (Spain) for a PhD grant (reference
B008/10).
1H NMR (300 MHz, CDCl3) δ 7.98 (dt, J = 7.7, 1.0 Hz, 1H,
C6H4), 7.79 (td, J = 7.6, 1.2 Hz, 1H, C6H4), 7.68 (dd, J = 7.8,
0.9 Hz, 1H, C6H4), 7.65 (td, J = 7.5, 0.7 Hz, 1H, C6H4), 5.72 (s,
1H, CH), 3.85 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3) δ
166.65 (s, CO), 164.37 (s, CO), 139.43 (s, C), 135.84 (s, CH),
130.87 (s, CH), 127.63 (s, C), 126.49 (s, CH), 123.54 (s, CH),
119.59 (q, J = 323.5 Hz, CF3), 63.20 (s, CH), 53.94 (s, OCH3);
19F NMR (282 MHz, CDCl3) δ −74.04 (s, CF3); IR (ν, cm−1):
1758 (COO). ESIMS (positive mode) (m/z): 324.0 [M + H]+;
anal. calcd for C11H8F3NO5S (323.01): C, 40.87; H, 2.49; N,
4.33; S, 9.92; found: C, 40.94; H, 2.53; N, 4.41; S, 10.05.
References
1. Yu, J.-Q.; Shi, Z., Eds. Top. Curr. Chem.; 2010; Vol. 292, pp 1–379.
doi:10.1007/978-3-642-12356-6
2. Davies, H. M. L.; Du Bois, J.; Yu, J.-Q. Chem. Soc. Rev. 2011, 40,
1845–2039. doi:10.1039/c1cs90010b
3. Simmons, E. M.; Hartwig, J. F. Nature 2012, 483, 70–73.
doi:10.1038/nature10785
Synthesis of methyl N-trifluoromethylsulfon-
amido-α-(2-methoxycarbonylphenyl)glyci-
4. Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147–1169.
doi:10.1021/cr900184e
5. Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215–1292.
doi:10.1021/cr100280d
nate (5)
A solution of 3 (100.0 mg, 0.114 mmol) in methanol was stirred
under a CO atmosphere for 16 h. During the reaction, the for-
mation of Pd0 was evident. The black material was eliminated
by filtration through a plug of Celite, and the resulting light
yellow solution was washed with water (3 × 20 mL), dried over
MgSO4, filtered and evaporated to give an oily residue charac-
terized as the mixture of compounds 4 and 5. This mixture was
separated by column chromatography (silica, hexane/CH2Cl2:
3/7), yielding pure 5 as a colourless oil. Yield: 14.2 mg,
0.040 mmol, 18%.
6. Le Bras, J.; Muzart, J. Chem. Rev. 2011, 111, 1170–1214.
doi:10.1021/cr100209d
7. You, S.-L.; Xia, J.-B. Top. Curr. Chem. 2010, 292, 165–194.
doi:10.1007/128_2009_18
8. Yoo, W.-J.; Li, C.-J. Top. Curr. Chem. 2010, 292, 281–302.
doi:10.1007/128_2009_17
9. Newhouse, T.; Baran, P. S. Angew. Chem., Int. Ed. 2011, 50,
3362–3374. doi:10.1002/anie.201006368
10.Aguilar, D.; Cuesta, L.; Nieto, S.; Serrano, E.; Urriolabeitia, E. P.
Curr. Org. Chem. 2011, 15, 3441–3464.
doi:10.2174/138527211797247923
11.Nieto, S.; Arnau, P.; Serrano, E.; Navarro, R.; Soler, T.; Cativiela, C.;
Urriolabeitia, E. P. Inorg. Chem. 2009, 48, 11963–11975.
doi:10.1021/ic901941s
1H NMR (300 MHz, CDCl3) δ 8.10 (dd, J = 7.8, 1.5 Hz, 1H,
C6H4), 7.61 (td, J = 7.5, 1.5 Hz, 1H, C6H4), 7.50 (td, J = 7.6,
1.4 Hz, 1H, C6H4), 7.41 (dd, J = 7.6, 1.5 Hz, 1H, C6H4), 7.00
(d, J = 9.4 Hz, 1H, NH), 5.42 (d, J = 9.3 Hz, 1H, CH), 3.92 (s,
3H, OCH3), 3.75 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3) δ
168.89 (s, CO), 168.43 (s, CO), 137.53 (s, C), 133.86 (s, C),
132.59 (s, CH), 132.01 (s, CH), 129.68 (s, CH), 127.30 (s, CH),
119.53 (q, J = 320.7 Hz, CF3), 61.35 (s, CH), 53.42 (s, OCH3),
53.03 (s, OCH3); 19F NMR (282 MHz, CDCl3) δ −77.53 (s,
CF3); IR (ν, cm−1): 3282 (br, N-H), 1747 (COO), 1711 (COO);
12.Nieto, S.; Sayago, F. J.; Laborda, P.; Soler, T.; Cativiela, C.;
Urriolabeitia, E. P. Tetrahedron 2011, 67, 4185–4191.
doi:10.1016/j.tet.2011.04.064
13.Nieto, S.; Cativiela, C.; Urriolabeitia, E. P. New J. Chem. 2012, 36,
566–569. doi:10.1039/c2nj20909h
14.Cowell, S. M.; Lee, Y. S.; Cain, J. P.; Hruby, V. J. Curr. Med. Chem.
2004, 11, 2785–2798. doi:10.2174/0929867043364270
15.Toniolo, C.; Crisma, M.; Formaggio, F.; Peggion, C. Biopolymers 2001,
60, 396–419.
doi:10.1002/1097-0282(2001)60:6<396::AID-BIP10184>3.0.CO;2-7
1574

Beilstein J. Org. Chem. 2012, 8, 1569–1575.
16.Sagan, S.; Karoyan, P.; Lequin, O.; Chassaing, G.; Lavielle, S.
Curr. Med. Chem. 2004, 11, 2799–2822.
doi:10.2174/0929867043364108
17.Ryabov, A. D.; Polyakov, V. A.; Yatsimirski, A. K. Inorg. Chim. Acta
1984, 91, 59–65. doi:10.1016/S0020-1693(00)84220-6
18.Böhm, A.; Polborn, K.; Sünkel, K.; Beck, W. Z. Naturforsch. 1998, 53b,
448–458.
19.Hendrickson, J. B.; Bergeron, R.; Sternbach, D. D. Tetrahedron 1975,
31, 2517–2521. doi:10.1016/0040-4020(75)80263-8
20.Thompson, J. M.; Heck, R. F. J. Org. Chem. 1975, 40, 2667–2674.
doi:10.1021/jo00906a021
21.Wu, X.-F.; Schranck, J.; Neumann, H.; Beller, M. ChemCatChem 2012,
4, 69–71. doi:10.1002/cctc.201100268
22.Wu, X.-F.; Neumann, H.; Beller, M. Chem.–Eur. J. 2010, 16,
9750–9753. doi:10.1002/chem.201000090
23.Dang, T. T.; Zhu, Y.; Ghosh, S. C.; Chen, A.; Chai, C. L. L.;
Seayad, A. M. Chem. Commun. 2012, 48, 1805–1807.
doi:10.1039/c2cc16808a
24.Sawant, D. N.; Wagh, Y. S.; Bhatte, K. D.; Bhanage, B. M.
J. Org. Chem. 2011, 76, 5489–5494. doi:10.1021/jo200754v
25.Houlden, C. E.; Hutchby, M.; Bailey, C. D.; Gair Ford, J.;
Tyler, S. N. G.; Gagné, M. R.; Lloyd-Jones, G. C.; Booker-Milburn, K. I.
Angew. Chem., Int. Ed. 2009, 48, 1830–1833.
doi:10.1002/anie.200805842
26.Yoo, E. J.; Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132,
17378–17380. doi:10.1021/ja108754f
27.Giri, R.; Lam, J. K.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 686–693.
doi:10.1021/ja9077705
28.Wu, X.-F.; Anbarasan, P.; Neumann, H.; Beller, M.
Angew. Chem., Int. Ed. 2010, 49, 7316–7319.
doi:10.1002/anie.201003895
29.Yu, W.-Y.; Sit, W. N.; Lai, K.-M.; Zhou, Z.; Chan, A. S. C.
J. Am. Chem. Soc. 2008, 130, 3304–3306. doi:10.1021/ja710555g
30.Xie, P.; Xie, Y.; Qian, B.; Zhou, H.; Xia, C.; Huang, H.
J. Am. Chem. Soc. 2012, 134, 9902–9905. doi:10.1021/ja3036459
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