Ethyl 2,2-bis(4-methylphenylsulfonamido)acetate to aromatic α-amino acids: Stable substrates for catalytic arylation reactions

Article abstract of DOI:10.1016/j.tet.2013.09.053

This paper reports the development of a novel methodology for the catalytic synthesis of aromatic α-amino acids, which involves the addition of aryl-organoboron reagents to α,α-ditosylamino esters derived from ethyl glyoxylate, using transition metal catalysts, like Rh and Pd. A library of α-amino esters (12 with Pd and 8 with Rh), was synthesized with moderate to excellent yields. A highest enantioselectivity of 30% ee was obtained using Hayashi's ligand. This method was applied to the synthesis of phenylglycine.

Full text of DOI:10.1016/j.tet.2013.09.053

Tetrahedron 69 (2013) 10091e10097
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Tetrahedron
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Ethyl 2,2-bis(4-methylphenylsulfonamido)acetate to aromatic
a-amino acids: stable substrates for catalytic arylation reactions
,
,b,
Carolina S. Marques a b, Anthony J. Burke a
*
a
ꢀ
ꢀ
ꢀ
~
Department of Chemistry and Centro de Química de Evora, Universidade de Evora, Rua Romao Ramalho, 59, 7000 Evora, Portugal
Chiratecnics Lda, Colegio Pedro de Fonseca, Universidade de Evora, Rua da Barba Rala, 1, Parque Industrial e Tecnologico e PITE, Evora, 7006-802
b
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Evora, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 June 2013
Received in revised form 12 September 2013
Accepted 17 September 2013
Available online 24 September 2013
This paper reports the development of a novel methodology for the catalytic synthesis of aromatic a-
amino acids, which involves the addition of aryl-organoboron reagents to
rived from ethyl glyoxylate, using transition metal catalysts, like Rh and Pd. A library of
a
,
a
-ditosylamino esters de-
-amino esters
a
(12 with Pd and 8 with Rh), was synthesized with moderate to excellent yields. A highest enantiose-
lectivity of 30% ee was obtained using Hayashi’s ligand. This method was applied to the synthesis of
phenylglycine.
Keywords:
Arylation
Ó 2013 Elsevier Ltd. All rights reserved.
Catalysis
Arylboronic acids
Amino acids
a,a-Ditosylamino esters
1. Introduction
literature,4 amongst these, there is the Strecker synthesis, which
relies on the stereoselective addition of carboxylate synthons
Unnatural or non-proteinogenic
a
-amino acids,1 are ubiquitous
across C]N bonds,4,7 the Knowles Monsanto asymmetric hydro-
in all living organisms on earth and perhaps the most important
family of carbonyl compounds in biological systems. Due to both
their structural diversity and functional versatility, their scope of
application is huge, covering the field of organic and medicinal
chemistry, biology and agrochemical science.2 For instance, nu-
merous therapeutically relevant compounds,3 such as Amoxicillin
(an antibacterial agent) or Enalapril (an antihypertensive agent)
consist of this functionality (see Fig. 1). They can be used as well as
building blocks, in natural product synthesis, or as chiral auxiliaries,
catalysts or ligands.4
genation of a di-dehydro amino acid8 (an efficient industrial pro-
cess to synthesize
that involves asymmetric addition of hydride to a ketone precursor.
L
-Dopa (see Fig. 1), and the Corey-Link reaction,9
Although enzymatic synthesis and chiral resolutions are viable
methods for the production of naturally occurring chiral
a-amino
acids,5 they are often not useful for synthesizing non-natural
D-
amino acids or amino acids with non-natural side chains. The for-
mation of diastereomeric salts of optically impure amino acid
mixtures,6 followed by chiral resolution is time consuming and
therefore expensive, and thus a need to invest in alternative syn-
thetic routes was deployed. Due to their importance, a variety of
general methods for the synthesis have been described in the
Fig. 1. Examples of important compounds containing the
a-amino acid scaffold; L-
Dopa: anti-Parkinson therapeutic agent; Enalapril: antihypertensive therapeutic agent;
L-Canavanive: anti-predatory agent in plants; (S)-Azetidine-2-carboxylic acid: an ana-
logue of proline; Ampicillin and Amoxicillin: antibacterial therapeutic agents; D-Peni-
cillamine: anti-rheumatic therapeutic agent.
* Corresponding author. Tel.: þ351 266 745 310; fax: þ351 266 745 303; e-mail
addresses: ajb@chiratecnics.com, ajb@dquim.uevora.pt (A.J. Burke).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.09.053

10092
C.S. Marques, A.J. Burke / Tetrahedron 69 (2013) 10091e10097
There are, of course, many other routes to chiral
such as the addition of organic nucleophiles to -imino esters or
enolates, a methodology that has emerged as one of the most
promising routes to optically enriched - and -amino acid de-
rivatives, including
-lactams.10 Sodeoka and co-workers reported
the first example of an asymmetric addition of enol silyl ethers to
a
-amino acids,
acid and Pd(OAc)2/bpy (Table 1). Despite the moderate yield, we
were encouraged by the result and proceeded with screening
a plethora of other boronic acids, using the catalytic system de-
scribed above. The advantage of using these arylating agents is that
they are commercially available from a number of suppliers, easy to
handle and have a low toxicity profile.23 The results can be seen in
Table 1. The principle advantage of this method appears to be the
avoidance of imine substrates that undergo facile hydrolysis under
the reaction conditions of their arylation.16c
a
a
b
b
a
-
imino esters employing a hydrated Pd(II)-based chiral Lewis acid
system.11 This so called Mannich-type reaction led to optically ac-
tive g-oxo-a-amino esters with modest to high enantioselectivities
(45e95% yield and 53e90% ee). Later on, Kobayashi’s group12 re-
ported an improvement of this methodology using N-acylimine
esters with enol silanes and Cu(II) catalysts to produce N-acylated
amino acids with high yields and high enantioselectivities (77e97%
yield and 90e97% ee) under smooth reaction conditions. Transition
metalephosphane complexes were applied as catalysts by Lectka
Table 1
Screening of arylboronic acid derivatives to afford the
with Pd catalysts, using the di-tosylamine ester (2) as substrate
a-amino ester derivatives (3)
group13 for the catalytic asymmetric alkylation of
a-imino esters
and N,O-acetals with enol silanes, ketene acetals, alkenes and
allylsilanes. Jorgensen and co-workers14 and Johannsen,15 in-
dependently applied the combination of CuPF6 and (R)-tol-BINAP in
the enantioselective addition of imines to electron-rich aromatic
compounds, affording protected optically active
a-aryl a-amino
Entrya
a
-Amino ester (3)
Yield/%b
esters in good to high yields and with high regioselectivity and
enantioselectivity (up to 98% ee). The limitation with this approach
is the restriction to electron-rich aromatic compounds, although
the avoidance of often troublesome enol silyl ethers or silyl ketene
acetals, is the main advantage of this methodology.
Our group is currently engaged in the development of catalytic
reactions for carbonecarbon bond formation using imine sub-
strates and aldehydes, organoboron reagents and transition metal
catalysts.16 We have now developed a new process that affords aryl
1
2
3
4
5
6
7
8
C6H5
2-Naph
a
38
28
58
35
56
61
79
45
30
31
37
39
b
c
d
e
f
g
h
i
2-CH3OC6H4
4-ClC6H4
3-CH3OC6H4
3-AcC6H4
1-Naph
4-FC6H4
9
3-PhCH2OC6H4
3-HOC6H4
3-NH2C6H4
4-CH3OC6H4
10
11
12
j
k
l
a
-amino acids via arylation of di-a,a-tosylamino esters with aryl-
boronic acids and transition metal catalysts.
a
Reaction conditions: Pd(OAc)2 (5 mol %), bpy (10 mol %), di-
a
,a
-tosylamine ester
(2) (0.3 mmol), ArB(OH)2 (1.0 mmol) and dioxane (2 ml) was used.
b
2. Results and discussion
Isolated yields after liquid chromatography.
Using the same methodology applied previously in the synthesis
of imine derivatives,16c the 2,2-bis(4-methylphenylsulfonamido)
acetate ester (2) was synthesized from commercially available ethyl
glyoxylate (1), through the addition of p-toluenesulfonamide, in
toluene, with a catalytic quantity of the Lewis acid BF3$Et2O, by
The yields were moderate to good, showing good tolerance for
the presence of both electron-donating and electron-withdrawing
substituents in the phenyl ring of organoboron reagent. The best
yield was obtained with 1-naphthylboronic acid (Table 1, entry 7).
No significant difference was observed using an electron-donating
or an electron-withdrawing group in the organoboron reagent, but
apparently the reaction yield improveddas confirmed from liter-
ature precedent16c,24dwhen an electron-withdrawing group was
present (see Table 1, entries 6 and 8). No very significant differences
in the yield were noted when either electron-donating or electron-
withdrawing substituents were present in the ortho, meta or para
positions of the aromatic ring (see Table 1), thus showing good
tolerance for both electronic and steric effects. However in the case
of Rh catalysis (vide infra) this is not the case, and is discussed
below. We were also curious to check the scope of this reaction with
aliphatic boronic acids.25 So, we decided to test three of these
specific reagents: methylboronic acid, ethylboronic acid and 1-
dodecylboronic acid. Unfortunately the reactions didn’t work,
since only the aminal substrate (2) was recovered. The problem
with these reactions in the context of Pd catalysis was that probably
unnecessary side-reactions, such as homocoupling26 and base-
catalyzed proto-deboration,27 ensued, with the inevitable con-
sumption of the arylboronic acid derivatives. We tried to promote
an asymmetric version of this reaction, using (R,R)-Me-DuPhos
(Fig. 2) as chiral phosphane ligand, and other chiral ligands, such as
oxazoline type and NHC type, applying the conditions previously
developed by us16a but, this was unsuccessful and the yields were
very poor, and thus further investigation was abandoned. At this
point we decided to explore the use of Rh catalysts, for two reasons:
i) to try and improve the yields, and ii) to develop chiral catalysts
refluxing in a DeaneStark trap (Scheme 1). The di-a,a-tosylamino
ester (2) has already been prepared by Lectka’s group17 and was
obtained in 20% yield, using equimolar amounts of ethyl glyoxylate
(1) and p-toluenesulfonamide.
Scheme 1. Synthesis of N,N-di-p-toluenesulfonylglycine ester (2) using ethyl glyox-
ylate (1) and p-toluenesulfonamide (NH2Ts).
Great advances have been made in the field of a-arylation of
carbonyl compounds catalyzed by transition metal catalysts.18 The
nucleophilic aromatic substitution of enolates with aryl halides19
and the transition-metal-catalyzed
a-arylation of carbonyl com-
pounds20 are the two main methods for efficient construction of
quaternary centres with good enantioselectivity.21 As far as we
know, the arylation of di-a,a-tosylamino estersdwhich are acti-
vated aminal compoundsdhas never been reported in the litera-
ture, so we decided to develop the catalytic arylation of di-
tosylamino ester (2).22 Gratifyingly we observed that the di-
tosylamine ester (2) could be converted to the desired N-tosyl-
amine ester (3a) in 38% yield, when treated with phenylboronic

C.S. Marques, A.J. Burke / Tetrahedron 69 (2013) 10091e10097
10093
PPh
R
As the enantioselectivities were lower than what we expected,
we decided to establish if there was any racemization taking place.
On performing the reactions with D2O in the reaction medium, it
was established by 1H NMR that there was no incorporation of
Ph P
P
P
O
O
R
N
NH
HN
Ph
R
PPh
P
R
deuterium in the a-position. The reaction was also monitored over
(R,R) DuPhos (6a) R= i-Propyl
(R,R)-Naph Trost (5)
(6b) R = Methyl
(R)-DeguPhos (4a)
(S)-Deguphos (4b)
a 24 h period, and no deterioration in the reaction enantiose-
lectivity was observed from the 1st to the 24th hour. These ex-
periments show that racemization was not the cause of the low
enantioselectivities. Based on our previous experience,16d it ap-
pears that during the catalytic cycle there is a likely possibility of
exchange of the chiral ligand with the imine substrate, thus elim-
inating or diminishing greatly the asymmetric induction.
HPLC analysis has shown the presence of the imine precursor to
(2) in some of the chromatograms. This seems to support the
conjecture that (2) undergoes elimination of p-tosylsulfonamine
during the catalytic reaction.
O
MeO
O
PPh
PPh
PPh
O
O
Ph
Ph
P
P
MeO
O
PPh
O
(R)-DioxPhos (8a)
(S)-DioxPhos (8b)
(R)-BINAP (7)
(R)-SegPhos (9)
(1S,4S)-2,5-Diphenylbicyclo
[2,2,2]octa-2,5-diene (10)
Fig. 2. Some of the chiral ligands that were screened in this study. Note: (6a), (6b), (7),
(8a) and (8b) gave very low enantioselectivities (<5% ee).
We decided on the basis of the good yields achieved with (R,R)-
DeguPhos (4a) and [Rh(COD)OH]2 in this initial screening study
(99% yield, Table 2, entry 8) to access the reaction scope using
a variety of arylboronic acids (Table 3).
that would lead to a successful asymmetric version of this reaction.
Thus for this purpose PPh3 and a variety of chiral phosphane li-
gands, were investigated (Fig. 2). Only the best results are high-
lighted in Table 2. We decided to use [Rh(COD)OH]2, as one of the
catalyst precursors, because of its many interesting applications in
the literature.28 Ru was also investigatedd[RuCl2( 6-p-cymene)]2
h
Table 3
Transformation of di-tosylamino ester (2) to arylamino esters (3) using Rh catalysis
with (R,R)-Me-DuPhos (6a) and Trost’s ligand (5)dbut the yield
was very poor and the % ee was not determined. In fact, this Rh(I)
catalyst along with (R,R)-DeguPhos (4a) was already applied suc-
cessfully by Ellman’s group in the enantioselective addition of
arylboronic acids to diphenylphosphinoyl imines.28f We also
screened the commercial chiral diene of Hayashi (10) (Fig. 2).29 As
of yet we haven’t established the configuration of the major
enantiomer.
Entrya
a
-Amino ester (3)
Yield/%b
1
C6H5
C6H5
C6H5
C6H5
a
a
a
a
b
c
d
e
f
g
h
i
j
k
l
99
13
74
34
74
83
61
0
0
99
0
25
0
17
61
2c
3d
4e
5
Table 2
Transformation of di-tosylamino ester (2) to arylamino ester (3a) using Rh catalysis
O
NHTs
Rh catalyst (3 mol%),
2-Naph
TsHN
PhB(OH)2
+
Ligand (3.3 mol%),
55-100oC
O
O
Ph
(3a)
6
7
8
9
10
11
12
13
14
15
2-CH3OC6H4
4-ClC6H4
3-CH3OC6H4
3-AcC6H4
1-Naph
NHTs
O
(2)
Entry Rh catalyst
Ligand Additive/solvent/temp Time
eeb
(h)/yield (%)a (%)
(ꢀC)
4-FC6H4
1
[Rh(COD)OH]2 PPh3
[Rh(COD)OH]2 PPh3
[Rh(COD)OH]2 None
K3PO4/dioxane/70
NEt3/toluene/70
18(14)
18(22)
24(13)
23(22)
16(52)
17(96)
21(18)
24(99)
24(94)
24(58)
24(30)
n.a.
n.a.
n.a.
n.a.
15
15
18
<5
<5
13
3-PhCH2OC6H4
3-HOC6H4
3-NH2C6H4
4-CH3OC6H4
2
3c
4
KHF2/dioxane/100
MgSO4/dioxane/80
MeOH/dioxane/100
KHF2/dioxane/80
KHF2/toluene/55
KHF2/dioxane/100
KHF2/dioxane/100
KHF2/dioxane/100
KHF2/dioxane/100
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)OH]2 (5)
[Rh(COD)OH]2 (7)
[Rh(COD)OH]2 (9)
[Rh(COD)OH]2 (10)
None
(4a)
(4a)
(4a)
5
a
6c
7
Reaction conditions: [Rh(COD)OH]2 (1.5 mol %), (R)-DeguPhos (3.3 mol %), di-
tosylamine ester (2) (0.12 mmol), ArB(OH)2 (0.4 mmol), KHF2 (0.8 mmol) and di-
oxane (2 ml) was used.
8d
9d
10d
11d
b
Isolated yields after liquid chromatography. All the products were obtained in
racemic form, as determined by HPLC with a chiral column.
c
Reaction made without (R,R)-DeguPhos.
Reaction run with KHF2 3 M (aq solution). Note: the ee values have not been
12
d
n.a. not applicable.
included due to being too low.
a
Isolated yields after liquid chromatography.
As determined by HPLC with a chiral column.
Reaction run with KHF2 3 M (aq solution).
0.8 mmol KHF2 was used.
e
Reaction runs without additive.
b
c
d
Starting with the simple phenylboronic acid, the reaction gave
the expected a-amine ester product (3a) with full conversion (99%
The results were very interesting. What was immediately ob-
yield, Table 3, entry 1). To test the reaction conditions we decided to
run the same reaction without ligand, in H2O and without additive
(Table 3, entries 2, 3 and 4, respectively). The importance of the
diphosphane ligand on the activity of the active catalyst was clearly
shown (compare entries 1 and 2, Table 3), as well as the importance
of an inorganic additive (KHF2), already used with success in this
reaction type30 (compare entries 1 and 4, Table 3). Since KHF2
under aqueous conditions can react with the organoboronic acids
to generate the more reactive potassium organotrifluoroborates30c
we investigated the direct use of this type of reagent on the
served was that better yields than those achieved with Pd were
obtained (e.g., 99%, Table 2, entry 8). We found that generally the
chiral ligands gave better yields than PPh3 (Table 2, entries 1 and 2)
and in fact, when no ligand was present, a yield comparable to that
obtained with PPh3 was obtained (Table 2, entries 3 and 4). The
highest enantioselectivity obtained was 30% ee using Hayashi’s li-
gand (10) and the best with phosphanes was 16% ee recorded with
(4b), but, unfortunately the yields were very low. Although, it
seems that the use of KHF2 as base gave the best yields.

10094
C.S. Marques, A.J. Burke / Tetrahedron 69 (2013) 10091e10097
outcome of the reaction (Table 3, entry 3). The yield decreased from
99% to 34% (Table 3, compare entries 1 and 3). This was un-
doubtedly due to hydrolysis of the activated imine.16a,c
3. Conclusions
We have reported herein an alternative innovative method for
Motivated by the excellent result obtained with this optimized
method (Table 3, entry 1), in order to establish the scope of this
method, we conducted a screening of a range of arylboronic acids.
The yield increased in particular when a naphthylboronic acid was
used (Table 3, entries 5 and 10). Almost all of the organoboron
reagents containing an electron-withdrawing group in the phenyl
ring were inactive (Table 3, entries 8, 9, 11 and 13).
In the case of Rh catalysis, it seems that the catalyst is sensitive
to electronic effects in the aromatic ring of the organoboron re-
agent, as the use of electron-donating substituents in the ortho and
para positions gave good yields, (see Table 3, entries 5, 6, 10 and 15).
But, there was no reaction when strong inductively electron-
withdrawing groups were present in the meta position of the
arylboronic acid (Table 3, entries 8,9 and 13) and when a p-fluoro
group was present (Table 3, entry 11).
No products were obtained when aliphatic boronic acids were
used (methylboronic acid, ethylboronic acid and 1-dodecylboronic
acid). It seems that an aromatic system needs to be present.
Upon finding the optimal conditions for HPLC analysis, we were
very disappointed to find very low enantioselectivities of the order
<5e10% ee for all the compounds synthesized. We then screened
a plethora of commercial diphosphane chiral ligands, to try and
improve the reaction enantioselectivity. Well known ligands,16a,c
such as BINAP (7), DuPhos (6) or Trost-diphosphane (5) (see
Fig. 2) were all screened, but no outstanding improvements were
achieved (a maximum of 15% ee was the best obtained using the
commercial ligand (R,R)-naphthyl Trost-diphosphane (5), Fig. 2).
the synthesis of a-amino acid derivatives using stable 2,2-bis(4-
methylphenylsulfonamido)acetate ester (2). This new methodol-
ogy utilizing arylboronic acids with transition metal catalysts, al-
though not suitable yetddespite promising indicationsdfor the
synthesis of enantioenriched
a-aryl amino acids, afforded a diverse
library of -amine ester products. On-going studies on the mech-
a
anism are currently underway, as well as studies at optimizing and
improving the reaction enantioselectivity.
4. Experimental section
4.1. General remarks
All the reagents were obtained from Aldrich, Fluka and Acros. The
commercial diphosphane ligands were obtained from either Strem
Chemicals, or Aldrich, with the exception of the (R,R)-DeguPhos, (R)
and (S)-DioxPhos, which were obtained from ChiraTecnics Lda
(Portugal). The solvents used were dried under current laboratory
techniques.33 1,4-Dioxane was distilled from Na and benzophenone.
All the reagents applied in this work were used as received. All re-
actions with transition metals (Pd, Rh) were conducted under a ni-
trogen atmosphere. The di-tosylamino ester (2) was synthesized
according to literature procedures.16 Column chromatography was
carried out on silica gel (SDS, 70e200 mm). Thin layer chromatogra-
phy (TLC) was carried out on aluminium backed Kieselgel 60 F254
plates (Merck). Plates were visualized either by UV light or with
phosphomolybdic acid in ethanol. The NMR analyses were recorded
on a Bruker Avance instrument (400 MHz) using CDCl3 as solvent and
the signal from the residual CHCl3 used as an internal standard. High
performance liquid chromatographic (HPLC) analysis was performed
on an Agilent 1100 series instrument. The conditions used were:
pmax¼50 bar; flux¼1 ml/min; detector¼wavelength light
In order to establish an efficient route to obtaining the free a-
amino acids, the amine activating group needs to be removed. In
fact, this has previously proved to be particularly troublesome with
these systems.31 We thus developed a simple reaction process to
phenylglycine (11) (Scheme 2)dan important motif in the antibi-
otic Ampicillin (see Fig. 1), using an aqueous solution of NaOH in
THF (Scheme 2).32 Obviously, this method of deprotection will
probably lead to the racemic amino acid product when the sub-
strate is optically pure, however, for the purpose of at least
accessing the amino acid product, we successfully demonstrated
the applicability of this method (Scheme 2).
(
l
¼230 nm); eluent¼hexane/isopropanol; column¼Chiralcel OD-H
(0.46 cmꢁ25 cm), fitted with a guard column composed of the
same stationary phase. Mass spectra were recorded on either a Wa-
ters-Micromass MaldiTOF or MicroTOF Focus (Bruker Daltonics) by
using the TOF (time-of-light) technique.
4.2.
a,a-Ditosylamine ester synthesis
4.2.1. Synthesis of ethyl 2-(tosylimino)acetate substrate (2).17 By
using a DeaneStark trap to facilitate water removal, BF3$Et2O
(1.6ꢁ10ꢂ3 mol) was added (through a syringe) to a refluxing solu-
tion of ethyl glyoxylate (1) (50% in toluene, 0.1 mol) and p-tolue-
nesulfonamide (0.1 mol) in toluene (200 ml). The mixture was kept
under reflux until the theoretical amount of water (0.1 mol) was
collected. The solution was then cooled to room temperature and
a white solid precipitated. The mixture was filtrated and the white
solid washed with toluene. After drying under reduced pressure,
we obtained the desired product in 32% yield. Mp: 178e189 ꢀC (mp
lit.: 178e180 ꢀC); FTIR (cmꢂ1): 1200,1344,1597, 1728, 3257. 1H NMR
Scheme 2. Conversion to the racemic unnatural
(rac)- -phenylglycine.
a-amino acid derivatives. Synthesis of
a
We also discovered that by adding K2CO3 to the reaction me-
dium during the arylation of the di-tosylamino ester (2), the tosyl
group was removed after presumably the formation of the arylated
ester product affording the amine ester product (12), in 72% yield
(Scheme 3). We are currently further investigating the scope of this
procedure.
(400 MHz, CDCl3þDMSO-d6)
d: 1.00 (t, CH3, 3H), 2.35 (s, CH3Ts, 3H),
3.84e3.89 (q, CH2, 2H), 6.97e6.99 (d, NH, 2H), 7.17e7.19 (d, Ar, 2H),
7.62e7.64 (d, HC]N, 1H) ppm. 13C NMR (100 MHz, CDCl3þDMSO-
d6)
d: 13.64, 21.53, 62.51, 63.39, 127.08, 129.41, 137.92, 143.35,
167.43 ppm. MS (ESI-TOF) m/z: 256.07 (Mþ1). HPLC analysis
[Chiralcel OD-H, hexane/2-propanol (95:5), flow rate¼1.0 ml/min,
l¼230 nm]: tR¼11.3 min.
4.3. Catalytic reactions
4.3.1. General procedure for the catalytic addition of boronic acids to
Scheme 3. One-pot arylationeamine deprotection protocol.
ethyl 2,2-bis(4-methylphenylsulfonamido)acetate (2) using
a Pd

C.S. Marques, A.J. Burke / Tetrahedron 69 (2013) 10091e10097
10095
catalyst22 (Table 1). 1,4-Dioxane (2.0 ml) was added to a round-
bottom flask containing Pd(OAc)2 (5 mol %), bpy ligand
(10 mol %), the organoboron reagent (1.0 mmol) and the 2,2-bis(4-
methylphenylsulfonamido)acetate (2) (0.3 mmol) under nitrogen.
The mixture was stirred at 100 ꢀC for 2 days. The crude mixture was
filtered over Celite using a sintered glass filter and washed with
CH2Cl2. The organic phase was washed with saturated NH4Cl (aq),
dried with anhydrous MgSO4, filtered and concentrated under re-
duced pressure. Purification by column chromatography (SiO2 gel,
1.10 (dd, CH3, 3H), 2.38 (s, CH3Ts, 3H), 3.72 (s, OCH3, 3H), 3.93e4.11
(m, CH2, 2H), 5.02 (d, CH, 1H), 5.72e5.74 (d, NH, 1H), 6.72 (Ar, 1H),
6.77e6.83 (Ar, 2H), 7.14e7.20 (Ar, 3H), 7.61e7.64 (Ar, 2H). 13C NMR
(100 MHz, CDCl3) d: 13.97, 21.60, 55.32, 59.44, 62.38, 112.54, 114.41,
119.56, 127.24, 128.48, 129.42, 129.58, 129.92, 136.83, 137.12, 143.62,
159.90, 170.10. MS (ESI-TOF) m/z: 364.14 (Mþ1). HPLC analysis not
carried out.
4.3.8. Ethyl 2-(3-acetylphenyl)-2-(4-methylphenylsulfonamido)ace-
hex/AcOEt (5:1)) provided the final
a-amine ester product (3).
tate (3f). White solid (61% yield). 1H NMR (400 MHz,
CDCl3þDMSO-d6)
d: 0.97 (m, CH3, 3H), 2.40 (s, CH3, 3H), 2.49 (s,
4.3.2. General procedure for the catalytic addition of boronic acid and
derivatives to 2,2-bis(4-methylphenylsulfonamido)acetate (2) using
a Rh catalyst34 (Tables 2 and 3). 1,4-Dioxane (2.0 ml) was added to
a round-bottom flask containing [Rh(COD)OH]2 (1.5 mol %), (R,R)-
DeguPhos (3.3 mol %), 2,2-bis(4-methylphenylsulfonamido)acetate
(2) (0.12 mmol), organoboron reagent (0.4 mmol) and KHF2
(0.8 mmol) under nitrogen. The mixture was stirred at 100 ꢀC for 1
day. The solvent was evaporated under reduced pressure and the
crude mixture purified by column chromatography (SiO2 gel, hex/
CH3Ts, 3H), 3.81e3.86 (m, CH2, 2H), 5.15e5.20 (s, CH, 1H),
5.90e6.05 (d, NH, 1H), 7.05e7.07 (Ar, 2H), 7.19e7.22 (Ar, 2H),
7.33e7.38 (Ar, 1H), 7.44e7.45 (Ar, 2H), 7.71e7.73 (Ar, 1H). 13C NMR
(100 MHz, CDCl3þDMSO-d6)
d: 13.64, 21.32, 29.59, 62.22, 63.36,
126.17, 126.84, 127.01, 128.54, 129.22, 129.26, 129.33, 129.41, 129.78,
132.96, 137.92, 143.24, 167.47, 197.89. MS (ESI-TOF) m/z: 376.12
(Mþ1). HPLC analysis not carried out.
4.3.9. Ethyl 2-(4-methylphenylsulfonamido)-2-(naphthalen-1-yl)ac-
AcOEt (5:1)) providing the final
a-amine ester product (3).
etate (3g). Yellow solid (79% yield). 1H NMR (400 MHz,
CDCl3þDMSO-d6)
d: 1.15 (m, CH3, 3H), 2.31 (s, CH3Ts, 3H),
3.98e4.25 (m, CH2, 2H), 5.74 (s, CH, 1H), 5.81 (s, NH, 1H), 7.48e7.53
(Ar, 2H), 7.57e7.61 (Ar, 4H), 7.91e7.98 (Ar, 2H), 8.11e8.18 (Ar, 2H),
4.3.3. Ethyl 2-(4-methylphenylsulfonamido)-2-phenylacetate
(3a).35 White solid (38% yield). Mp: 88.6e90.4 ꢀC. 1H NMR
(400 MHz, CDCl3)
3.92e4.08 (m, CH2, 2H), 5.02e5.04 (d, CH, 1H), 5.69e5.71 (m, NH,
1H), 7.18e7.20 (Ar, 2H), 7.22e7.26 (Ar, 5H), 7.62e7.64 (Ar, 2H). 13
NMR (100 MHz, CDCl3) : 13.96, 21.61, 59.48, 62.35, 127.10, 127.21,
d: 1.09 (dd, CH3, 3H), 2.38 (s, CH3Ts, 3H),
8.35e8.41 (Ar, 1H). 13C NMR (100 MHz, CDCl3þDMSO-d6)
d: 14.13,
21.67, 57.25, 62.63, 125.16, 125.30, 125.95, 126.60, 127.01, 127.28,
128.05, 128.96, 129.85, 130.96, 132.55, 133.55, 137.76,139.20,143.75,
149.27, 157.94. MS (ESI-TOF) m/z: 384.14 (Mþ1). HPLC analysis not
carried out.
C
d
127.34, 128.63, 128.89, 129.55, 129.58, 129.61, 135.63, 137.09, 138.63,
143.64, 170.19. MS (ESI-TOF) m/z: 334.12 (Mþ1). HPLC [Chiralcel
OD-H column, hexane/2-propanol (95:5), flow rate¼1.0 ml/min,
4.3.10. Ethyl 2-(4-fluorophenyl)-2-(4-methylphenylsulfonamido)ace-
tate (3h).35 White solid (45% yield). 1H NMR (400 MHz,
l¼230 nm]: tR¼20.1 and 21.9 min.
CDCl3þDMSO-d6)
d: 0.92e0.97 (m, CH3, 3H), 2.31 (s, CH3Ts, 3H),
4.3.4. Ethyl 2-(4-methylphenylsulfonamido)-2-(naphthalen-2-yl)ac-
3.77e3.93 (m, CH2, 2H), 5.12e5.17 (d, CH, 1H), 6.03 (s, NH, 1H),
7.13e7.19 (Ar, 4H), 7.39e7.53 (Ar, 1H), 7.57e7.59 (Ar, 2H), 7.69e7.72
etate (3b).35a,36 Yellow solid (28% yield). Mp: 115.0e116.7 ꢀC. 1H
NMR (400 MHz, CDCl3)
d
: 1.11 (dd, CH3, 3H), 2.26 (s, CH3Ts, 3H),
(Ar, 1H). 13C NMR (100 MHz, CDCl3þDMSO-d6)
d: 13.60, 21.33,
4.16e4.31 (m, CH2, 2H), 5.22e5.23 (d, CH, 1H), 5.86e5.88 (d, NH,
1H), 7.14e7.15 (Ar, 2H), 7.29e7.34 (Ar, 2H), 7.40e7.44 (Ar, 1H),
7.48e7.49 (Ar, 1H), 7.73e7.77 (Ar, 3H), 7.84e7.86 (Ar, 2H). 13C NMR
63.00, 66.81, 115.26, 115.42, 125.71, 126.92, 128.20, 128.72, 129.09,
137.08, 137.86, 138.08, 140.34, 142.94, 167.23. MS (ESI-TOF) m/z:
352.11 (Mþ1). HPLC analysis not carried out.
(100 MHz, CDCl3)
d: 14.08, 22.97, 59.64, 62.34, 109.60, 117.93,
123.67,124.26, 126.04,126.46, 126.60,127.88,128.57, 129.02, 129.49,
129.92, 133.43, 134.73, 135.85, 153.60, 173.79. MS (ESI-TOF) m/z:
384.13 (Mþ1). HPLC analysis not carried out.
4.3.11. Ethyl 2-(3-(benzyloxy)phenyl)-2-(4-methylphenylsulfona
mido)acetate (3i). Colourless oil (30% yield). 1H NMR (400 MHz,
CDCl3) d: 1.10 (dd, CH3, 3H), 2.36 (s, CH3Ts, 3H), 3.94e4.07 (m, CH2,
2H), 4.95e4.96 (d, CH2, 1H), 5.07 (d, CH2, 1H), 5.12e5.14 (d, CH, 1H),
5.74e5.76 (d, NH, 1H), 6.83e6.88 (Ar, 2H), 7.18e7.20 (Ar, 2H),
4.3.5. Ethyl 2-(2-methoxyphenyl)-2-(4-methylphenylsulfonamido)
acetate (3c). White solid (58% yield). 1H NMR (400 MHz, CDCl3)
d:
7.33e7.45 (Ar, 7H), 7.62e7.64 (Ar, 2H). 13C NMR (100 MHz, CDCl3)
d:
1.09 (dd, CH3, 3H), 2.36 (s, CH3Ts, 3H), 3.92 (s, OCH3, 3H), 4.02e4.24
(m, CH2, 2H), 5.27e5.29 (d, CH, 1H), 5.93e5.95 (d, NH, 1H),
6.91e6.93 (Ar, 2H), 7.02e7.06 (Ar, 2H), 7.44e7.47 (Ar, 2H), 7.85e7.87
14.06, 22.66, 59.33, 62.36, 69.43, 113.02, 113.30, 115.07, 115.25,
119.34, 119.86, 127.34, 127.60, 128.64, 128.19, 128.73, 129.58, 136.64,
137.15, 140.12, 143.61, 159.11, 173.70. MS (ESI-TOF) m/z: 440.17
(Mþ1). HPLC analysis not carried out.
(Ar, 2H). 13C NMR (100 MHz, CDCl3)
d: 14.06, 21.26, 55.62, 61.72,
70.60, 110.10, 111.23, 120.97, 121.39, 127.20, 127.49, 129.41, 130.01,
130.27, 132.70, 133.11, 136.98, 164.64. MS (ESI-TOF) m/z: 364.13
(Mþ1). HPLC analysis not carried out.
4.3.12. Ethyl 2-(3-hydroxyphenyl)-2-(4-methylphenylsulfonamido)
acetate (3j). White solid (31% yield). 1H NMR (400 MHz,
CDCl3þDMSO-d6)
OH, 1H), 3.81e3.93 (m, CH2, 2H), 5.17e5.19 (d, CH, 1H), 5.87 (s, NH,
1H), 6.77e6.79 (Ar, 2H), 7.10e7.21 (Ar, 4H), 7.60e7.63 (Ar, 2H). 13
: 13.62, 21.07, 63.37, 66.55,
d: 0.97 (dd, CH3, 3H), 2.33 (s, CH3Ts, 3H), 3.63 (s,
4.3.6. Ethyl 2-(4-chlorophenyl)-2-(4-methylphenylsulfonamido)ace-
tate (3d).35a,36 Yellow oil (35% yield). Mp: 86.8e89.0 ꢀC. 1H NMR
C
(400 MHz, CDCl3)
d
: 1.10 (m, CH3, 3H), 2.39 (s, CH3Ts, 3H), 3.97e4.10
NMR (100 MHz, CDCl3þDMSO-d6)
d
(m, CH2, 2H), 4.99e5.01 (d, CH, 1H), 5.77e5.79 (d, NH, 1H),
6.75e6.77 (Ar, 2H), 7.14e7.22 (Ar, 2H), 7.32e7.38 (Ar, 2H), 7.59e7.61
115.45, 119.39, 126.16, 127.00, 128.36, 129.33, 129.35, 129.44, 137.86,
140.20, 143.29, 156.94, 167.34. MS (ESI-TOF) m/z: 350.11 (Mþ1).
HPLC analysis not carried out.
(Ar, 2H). 13C NMR (100 MHz, CDCl3)
d: 14.07, 21.76, 58.73, 62.86,
116.80, 127.20, 127.92, 128.53, 128.98, 129.50, 129,59, 133.94, 134.64,
136.86, 143.92, 154.42, 169.75. MS (ESI-TOF) m/z: 368.08 (Mþ1).
HPLC analysis not carried out.
4.3.13. Ethyl 2-(3-aminophenyl)-2-(4-methylphenylsulfonamido)ac-
etate (3k). Orange solid (37% yield). 1H NMR (400 MHz, CDCl3)
d:
0.88 (m, CH3, 3H), 2.43 (s, CH3Ts, 3H), 4.09e4.25 (m, CH2þNH2, 4H),
4.89e4.91 (d, CH, 1H), 6.17 (s, Ar, 1H), 6.21e6.27 (d, NH, 1H),
6.96e7.01 (Ar, 2H), 7.29e7.36 (Ar, 2H), 7.79e7.83 (Ar, 2H). 13C NMR
4.3.7. Ethyl 2-(3-methoxyphenyl)-2-(4-methylphenylsulfonamido)
acetate (3e). Yellow oil (56% yield). 1H NMR (400 MHz, CDCl3)
d:

10096
C.S. Marques, A.J. Burke / Tetrahedron 69 (2013) 10091e10097
(100 MHz, CDCl3)
d
: 14.26, 21.65, 61.02, 62.03, 114.09, 114.39, 117.88,
References and notes
126.59, 129.69, 130.33, 137.45, 137.25, 139.25, 143.75, 145.56, 172.15.
MS (ESI-TOF) m/z: 287.15. HPLC analysis not carried out.
1. (a) Barrett, G. C.; Telmore, D. Amino Acids and Peptides; Cambridge University,
2004; (b) Hughes, A. B.; Amino Acids, Peptides and Proteins in Organic Chemistry,
1st ed.; Wiley-VCH, 2009, Vol. 1; (c) Loscha, K. V.; Herlt, A. J.; Qi, R.; Huber, T.;
Ozawa, K.; Otting, G. Angew. Chem., Int. Ed. 2012, 51, 2243e2246; (d) Shen, B.;
Xiang, Z.; Miller, B.; Louie, G.; Wang, W.; Noel, J. P.; Gage, F. H.; Wang, L. Stem
Cells 2011, 29, 1231e1240; (e) Unnatural Amino Acids: Methods and Protocols,
Methods in Molecular Biology; Pollegioni, L., Servi, S., Eds.; Humana: 2012; Vol.
794; (f) Chin, J. W. Science 2012, 336, 428e429.
4.3.14. Ethyl 2-(4-methoxyphenyl)-2-(4-methylphenylsulfonamido)
acetate (3l). White solid (39% yield). 1H NMR (400 MHz, CDCl3)
d:
1.09 (t, CH3, 3H), 2.38 (s, CH3Ts, 3H), 3.76 (s, OCH3, 3H), 3.89e4.05
(m, CH2, 2H), 4.97e4.99 (d, CH, 1H), 5.71e5.73 (d, NH, 1H),
6.75e6.78 (Ar, 2H), 6.88e6.90 (Ar, 1H), 7.12e7.21 (Ar, 3H), 7.32 (Ar,
2. See, for instance: (a) Huang, T.; Jander, G.; de Vos, M. Phytochemistry 2011, 72,
1531e1537; (b) Williams, R. M. Synthesis of Optically Active R-Amino Acids In
The Organic Chemistry Series; Baldwin, J. E., Ed.; Pergamon: Oxford, UK, 1989; (c)
1H), 7.62e7.64 (Ar, 1H). 13C NMR (100 MHz, CDCl3)
d: 14.38, 22.98,
55.45, 58.73, 62.04, 114.11, 114.25, 114.90, 126.58, 127.34, 127.61,
127.96, 128.48, 129.58, 130.77, 143.66, 159.62, 170.54. MS (ESI-TOF)
m/z: 386.11 (Mþ1þNa). HPLC analysis was not carried out.
ꢀ
Williams, R. M.; Hendrix, J. A. Chem. Rev. 1992, 92, 889e917; (d) Cordova, A.;
Notz, W.; Zhong, G.; Betancort, J. M.; Barbas, C. F. J. Am. Chem. Soc. 2002, 124,
1842e1843.
3. (a) Ma, J. S. Chem. Today 2003, 21, 65e68; (b) El-Gamel, N. E. A. J. Coord. Chem.
2010, 63, 534e543; (c) Theodoridis, G.; Konsta, G.; Bagia, C. J. Chromatogr., B
2004, 804, 43e51.
4.4. Synthesis of (rac)-a-phenylglycine (11)
4. (a) Martens, J. Topics in Current Chemistry; Springer: Heidelberg, Germany, 1984,
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Vol. 125, pp 167e246; (b) Najera, C.; Sansano, J. M. Chem. Rev. 2007, 107,
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Michaux, J.; Niel, G.; Campagne, J. M. Chem. Soc. Rev. 2009, 38, 2093e2116; (f)
Ethyl 2-(4-methylphenylsulfonamido)-2-phenylacetate (3a)
(92.3 mg, 0.3 mmol) in THF (5 ml) was stirred with an aqueous
solution of NaOH (2 M) (1.0 ml, 1.5 mmol) at 50 ꢀC and monitored
by TLC. THF was evaporated under reduced pressure and the mix-
ture extracted with CH2Cl2 (5ꢁ10 ml). The aqueous phase was
€
Perdih, A.; Dolenc, M. S. Curr. Org. Chem. 2007, 11, 801e832; (g) Muller, R.;
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L.-W.; Lu, Y. Org. Biomol. Chem. 2008, 6, 2047e2053; (i) Jarvo, E.; Miller, S. J.
Tetrahedron 2002, 58, 2481e2495; (j) Qu, Z.-R.; Zhao, H.; Wang, X.-S.; Li, Y.-H.;
Song, Y.-M.; Liu, Y.-J.; Ye, Q.; Xiong, R.-G.; Abrahams, B. F.; Xue, Z.-L.; You, X.-Z.
Inorg. Chem. 2003, 42, 7710e7712.
5. Schoemaker, H. E.; Boesten, W. H. J.; Kaptein, B.; Hermes, H. F. M.; Sonke, T.;
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6. (a) Tolman, V.; Simek, P. J. Fluorine Chem. 2000, 107, 4584e4671; (b) Kesslin, G.;
Kelly, K. W. In Resolution of Racemic Mandelic Acid, Key Fries, US4322548, USA,
1982.
7. For some recent examples, see: (a) Saravanan, S.; Sadhukhan, A.; Khan, N. H.;
Kureshy, R. I.; Abdi, S. H. R.; Bajaj, H. C. J. Org. Chem. 2012, 77, 4375e4384; (b)
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evaporated under reduced pressure and the desired
a-phenyl-
glycine (11) was obtained as a white solid (>90% yield). Mp:
>300 ꢀC. 1H NMR (400 MHz, D2O)
d
: 4.47 (s, CH, 1H), 7.18e7.19 (m,
Ar, 5H). 13C NMR (100 MHz, D2O)
d: 65.63, 126.35, 126.58, 127.50,
128.17, 128.96, 140.86, 181.51. MS (ESI-TOF) m/z: 158.97 (Mþ).
4.5. General procedure for the one-pot arylationeamine de-
protection to afford a-amino ester (12)
1,4-Dioxane (1.0 ml) was added to a round-bottom flask con-
taining [Rh(COD)OH]2 (5 mol %) and (R,R)-DeguPhos (5.5 mol %)
and left stirring at room temperature 30 min. 2,2-Bis(4-
methylphenylsulfonamido)acetate (2) (0.19 mmol), phenylboronic
8. Knowles, W. S. Adv. Synth. Catal. 2003, 345, 3e13.
9. Corey, E. J.; Link, J. O. J. Am. Chem. Soc. 1992, 114, 1906e1908.
10. Taggi, A. E.; Hafez, A. M.; Lectka, T. Acc. Chem. Res. 2003, 36, 10e19.
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A. E.; Lectka, T. J. Am. Chem. Soc. 2002, 124, 67e77.
14. (a) Saaby, S.; Fang, X.; Gathergood, N.; Jorgensen, K. A. Angew. Chem., Int. Ed.
2000, 39, 4114e4116; (b) Saaby, S.; Bayon, P.; Aburel, P. S.; Jorgensen, K. A. J. Org.
Chem. 2001, 67, 4352e4361.
ꢁ
acid (0.38 mmol), 3 A MS (200 mg) and 1,4-dioxane (3 ml) were
added to the reaction vessel sequentially, followed by NEt3
(0.29 mmol) and K2CO3 (1.14 mmol). The reaction was left stirring at
70 ꢀC for 2 days. After cooling to room temperature, the crude
mixture was filtered over Celite in a sintered glass filter and washed
with AcOEt. The solvent was evaporated under reduced pressure
and the crude product purified by column chromatography (SiO2
gel, hex/AcOEt (5:1)) providing the deprotected amine product (12)
15. Johannsen, M. Chem. Commun. 1999, 2233e2234.
16. (a) Marques, C. S.; Burke, A. J. Eur. J. Org. Chem. 2010, 1639e1643; (b) Marques,
C. S.; Burke, A. J. ChemCatChem 2011, 3, 635e645; (c) Marques, C. S.; Burke, A. J.
Eur. J. Org. Chem. 2012, 4232e4239; (d) Marques, C. S.; Burke, A. J. Tetrahedron
2012, 68, 7211e7216; (e) Marques, C. S.; Burke, A. J. Tetrahedron: Asymmetry
2013, 24, 628e632.
17. Ferraris, D.; Young, B.; Dudding, T.; Drury, W. J., III; Lectka, T. Tetrahedron 1999,
55, 8869e8882.
18. Johansson, C. C. C.; Colacot, T. J. Angew. Chem., Int. Ed. 2010, 49, 676e707.
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vakumar, N.; Reddy, B. Y.; Kumar, G.-S.; Iqbal, J. Tetrahedron Lett. 2001, 42,
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as a yellow oil (72% yield). 1H NMR (400 MHz, CDCl3)
d: 1.22 (t,
J¼8 Hz, CH3, 3H), 1.26 (s, NH2, 1H), 2.42 (s, NH2, 1H), 4.12e4.28 (m,
CH2, 2H), 5.16 (s, CH, 1H), 7.28e7.38 (m, Ar, 2H), 7.41e7.43 (m, Ar,
2H), 7.79e7.81 (d, Ar, 1H). 13C NMR (100 MHz, CDCl3)
d: 14.13, 62.37,
73.01, 126.55, 128.53, 128.69, 129.81, 138.51, 143.65, 173.81. MS (ESI-
20. Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234e245.
21. (a) Zhou, J. S. Synlett 2012, 1e5; (b) Arya, P.; Qin, H. Tetrahedron 2009, 56,
917e947.
TOF) m/z: 203.07 (Mþ1). HPLC analysis not carried out.
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Acknowledgements
We are grateful for the award of a PhD grant to C.S.M. (SFRH/BD/
25. For catalytic imine alkylations with aliphatic boronic acids see: (a) Yu, X.;
~
^
ꢀ
45132/2008) from the Fundac¸ ao para a Ciencia e a Tecnologia (FCT)
2010. We acknowledge LabRMN at FCT-UNL for the acquisition of
the NMR spectra; the NMR spectrometers are part of the National
NMR Network and were purchased within the framework of the
National Programme for Scientific Re-equipment (contract REDE/
1517/RMN/2005), with funds from POCI 2010 (FEDER) and FCT. The
University of Vigo (Spain) is gratefully acknowledgement for MS
analysis.
Liebeskind, L. S. J. Org. Chem. 2004, 69, 3554e3557; (b) Cyranski, M. K.; Jez-
_
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ierska, A.; Klimentowska, P.; Panek, J. J.; Zukowska, G. Z.; Sporzynski, A. J. Chem.
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ꢀ
26. (a) Moreno-Manas, M.; Perez, M.; Pleixats, R. J. Org. Chem. 1996, 61, 2346e2351;
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27. Kuivila, H. G.; Reuwer, J. F., Jr.; Mangravite, J. A. Can. J. Chem. 1963, 41,
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Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.09.053.
29. Shintani, R.; Takeda, M.; Tsuji, T.; Hayashi, T. J. Am. Chem. Soc. 2010, 132,
13168e13169.

C.S. Marques, A.J. Burke / Tetrahedron 69 (2013) 10091e10097
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