Enantioselective organocatalytic synthesis of arylglycines via friedel-crafts alkylation of arenes with a glyoxylate imine

Article abstract of DOI:10.1002/adsc.201000143

The enantioselective organocatalytic synthesis of arylglycines has been developed employing 1 mol% of an enantiopure N-triflyl phosphoramide Bronsted acid as organocatalyst. Various differently substituted phenylglycine derivatives can be synthesized in good to excellent yields and enantiomeric excesses based on a Friedel-Crafts alkylation of electron-rich arenes with a glyoxylate imine. A novel protocol for the deprotection of the N-tert-butylsulfonyl (Bus) group has also been developed.

Full text of DOI:10.1002/adsc.201000143

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DOI: 10.1002/adsc.201000143
Enantioselective Organocatalytic Synthesis of Arylglycines via
Friedel–Crafts Alkylation of Arenes with a Glyoxylate Imine
Dieter Enders,a,* Matthias Seppelt,a and Tobias Beckb
a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax : (+49)-241-809-2127; e-mail: enders@rwth-aachen.de
Department of Structural Chemistry, Georg-August University Gçttingen, Tammannstr. 4, 37077 Gçttingen, Germany
b
Received: February 23, 2010; Published online: May 28, 2010
Dedicated to Professor Henri Kagan on the occasion of his 80th birthday.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000143.
Abstract: The enantioselective organocatalytic syn-
thesis of arylglycines has been developed employing
1 mol% of an enantiopure N-triflyl phosphoramide
Brønsted acid as organocatalyst. Various differently
substituted phenylglycine derivatives can be synthe-
sized in good to excellent yields and enantiomeric
excesses based on a Friedel–Crafts alkylation of
electron-rich arenes with a glyoxylate imine. A
novel protocol for the deprotection of the N-tert-bu-
tylsulfonyl (Bus) group has also been developed.
many protocols have been developed offering power-
ful methods to synthesize various enantiopure aro-
matic compounds, employing both metal-based cata-
lysts and organocatalysts.[12] Although significant
progress has been made in the field of enantioselec-
tive organocatalytic Friedel–Crafts-type alkylations
there remain limitations in the substrate scope. In
most cases heteroaromatic compounds have been
used due to their higher reactivity. For example, sev-
eral additions of indoles to aromatic imines promoted
by chiral phosphoric acids[13] as well as thiourea-Cin-
chona alkaloids[14] have been described. Other exam-
ples of Friedel–Crafts alkylations of heteroaromatic
compounds include the chiral phosphoric acid-cata-
lyzed addition of furans[15] and pyrroles[16] to electron-
poor aromatic aldimines. However, there are relative-
ly few protocols for the enantioselective organocata-
Keywords: amino acids; Brønsted acids; Friedel–
Crafts reaction; organocatalysis; phosphoric acids
The enantioselective synthesis of a-amino acids is the lytic Friedel–Crafts-type alkylations of simple ben-
focus of intensive current research due to their central zene derivatives. Phenols can be added to trifluoro-
role in organic synthesis.[1] a-Amino acids are com- pyruvate[17] and b,g-unsaturated a-keto esters[18] while
monly used as enantiopure substrates for auxiliaries, naphthols are known to undergo an alkylation–cas-
ligands, catalysts and chiral building blocks in total cade reaction with nitroolefins[19] and alkylation/cycli-
synthesis.[2] A further important field is in the synthe- zation reactions with a,b-unsaturated aldehydes.[20]
A
sis of non-natural proteins and peptides.[3] Further- protocol for the enantioselective organocatalytic addi-
more, arylglycines are characteristic structural motifs tion of heteroaromatic compounds to an a-imino
in biologically active compounds like glycopeptide an- ester was developed recently by You and co-work-
tibiotics[4] and b-lactam antibiotics.[5] Glyoxylate ers.[10l] Several indoles can be added to a glyoxylate-
imines are highly electrophilic substrates for the syn- derived PMP-protected imine using this methodology.
thesis of non-proteinogenic amino acids and have
As an extension of our contributions in the field of
been used in ene reactions,[6] cycloadditions,[7] radical the asymmetric synthesis of amino acids[21] and the
additions,[8] nucleophilic additions[9] and Friedel– application of Friedel–Crafts reactions in asymmetric
Crafts-type reactions.[10]
synthesis[22] we investigated an enantioselective orga-
The Friedel–Crafts reaction, discovered in 1877, is nocatalytic Friedel–Crafts alkylation of arenes with an
an important methodology to form carbon-carbon a-imino ester. To the best of our knowledge an enan-
bonds.[11] In particular, the alkylation of arenes by un- tioselective organocatalytic Friedel–Crafts alkylation
saturated compounds constitutes an atom-economic of simple arenes with imines has not been described
reaction with a broad range of applications. To date in the literature. We decided to use a highly activated
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Table 1. Evaluation of the chiral Brønsted acids 4 in the
Friedel–Crafts-type reaction of 1,3-dimethoxybenzene (2a)
with glyoxylate imine 1 to form 3a.[a]
Scheme 1. Enantioselective organocatalytic synthesis of pro-
tected phenylglycine derivatives 3.
a-imino ester bearing an electron-withdrawing Bus-
protecting group as electrophile.[23,24] The use of
glyoxylate imine 1 in Friedel–Crafts-type alkylation
reactions would provide access to a wide range of
non-proteinogenic a-amino acids 3 (Scheme 1).
Initial tests showed that the imine 1 was sufficiently
reactive to undergo a Friedel–Crafts-type electrophilic
substitution with dimethoxybenzene. For further stud-
ies a test system with glyoxylate imine 1, dimethoxy-
benzene 2a and 5 mol% of a chiral Brønsted acid was
investigated (Table 1). First results with the N-triflyl
phosphoramides 4a and 4b and 2.0 equivalents of nu-
cleophile 2a revealed that the alkylation product 3a is
obtained in good yields but low enantioselectivity
(Table 1, entries 1 and 2). In the case of phosphoric
acid 4c as catalyst only little product could be detect-
ed (Table 1, entry 3). This might be explained by the
higher pKa value of catalyst 4c, which may not be suf-
ficient to protonate the a-imino ester 1. Further
screening of catalysts showed that the TRIP-catalyst
4f furnished 3a with 82% ee (Table 1, entry 7)[25] al-
though, remarkably, only after a much longer reaction
time. The more acidic thiophosphorus derivative 4g
provided the product with only 24% ee (Table 1,
entry 8), while the sterically demanding catalyst 4h
gave the opposite enantiomer of 3a with low selectivi-
ty (Table 1, entry 9). To evaluate the background re-
action, the a-imino ester 1 was mixed with 1.1 equiva-
lents of dimethoxybenzene 2a without catalyst. After
three days a yield of 23% was obtained (Table 1,
entry 10).
Entry
Catalyst
Time [d]
Yield [%][b]
ee [%][c]
1[d]
2[d]
3
5
6
4a
4b
4c
4d
4e
4f
4g
4h
–
3
3
9
1
1
7
6
6
3
83
87
30
79
78
76
77
80
23
0
11
0
15
0
82
24
À21
–
7
8[e]
9[e]
10
[a]
Unless otherwise specified, the reactions were performed
on a 0.5 mmol scale of glyoxylate imine 1 using 1.1 equiv.
of dimethoxybenzene (2a) and 5 mol% catalyst 4 at
room temperature in 1.0 mL dichloromethane.
Yield of isolated 3a.
Determined by chiral stationary phase HPLC analysis.
Carried out with 2.0 equiv. of dimethoxybenzene (2a).
Catalyst loading was 1 mol%.
[b]
[c]
[d]
[e]
Having identified N-triflyl phosphoramide 4f as a
suitable catalyst, the optimal catalyst loading was in-
vestigated. Increasing the amount of catalyst to
10 mol% improved the yield slightly without affecting
the enantioselectivity (Table 2, entry 1). Notably, the
catalyst loading could be reduced to only 1 mol%
without a significant change in either yield or stereo-
selectivity (Table 2, entry 4). Reducing the catalyst
loading further to 0.01 mol% led to a considerable
drop in the enantiomeric excess to 26% ee (Table 2,
entry 6). Therefore a catalyst loading of 1 mol% was
used in all further experiments.
Table 2. Optimization of the catalyst loading.
Entry
4f [mol%]
Time [d]
Yield [%]
ee [%]
1
2
3
4
5
6
10
5
2
1
0.1
0.01
5
7
7
7
9
13
88
76
73
76
81
64
82
82
82
83
77
26
We next examined the effect of the solvent on the directed catalysis, the selectivity of this reaction drop-
reaction. Both deuterated chloroform and dichloro- ped to 14% ee. Interestingly, diethyl ether served as
ethane showed similar results as compared to di- an adequate solvent (Table 3, entry 5), despite being
chloromethane (Table 3, entry 1–3). Although aceto- expected to coordinate to and destabilize the inter-
nitrile is used occasionally in asymmetric counterion- mediate ion-pair. Benzene and toluene proved to be
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Enantioselective Organocatalytic Synthesis of Arylglycines via Friedel–Crafts Alkylation
Table 3. Influence of the solvent on the Friedel–Crafts-type
Table 4. Substrate scope for the enantioselective organocata-
lytic Friedel–Crafts-type alkylation.[a]
reaction.[a]
Entry Product Ar
Yield [%][b] ee [%][c]
1
2
3
3a
3b
3c
76
87
62
93
82
91
Entry
Solvent
Time [d]
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
CH2Cl2
CDCl3
ACHTUNGTRENNUNG(ClCH2)2
CH3CN
Et2O
benzene
toluene
toluene
toluene
toluene
toluene
7
6
6
6
6
6
6
5
2
9
12
76
73
75
70
64
72
79
88
85
75
76
83
85
81
14
85
87
87
83
85
92
93
8[d]
9[d,e]
10[f]
11[g]
4
3d
3e
74
89
96
87
[a]
Unless otherwise specified, reactions were performed on
a 0.5 mmol scale of glyoxylate imine 1 using 1.1 equiv. of
dimethoxybenzene (2a) and 1 mol% catalyst 4f at room
temperature in 1.0 mL solvent.
Yield of isolated 3a.
Determined by chiral stationary phase HPLC analysis.
5 ꢁ molecular sieve was added.
Carried out with 2.0 equiv. nucleophile.
Reaction was performed at 08C.
Reaction was performed at À228C.
5
6
[b]
[c]
[d]
[e]
[f]
3f
3g
86
68
95
81
[g]
7
the best solvents (Table 3, entries 6 and 7). Due to its
lower toxicity toluene was chosen as the solvent for
this Friedel–Crafts-type alkylation. You and co-work-
ers described an improvement of the enantioselectivi-
ty by the addition of molecular sieves.[10l] This led to
an increase in yield, although in our case no better se-
lectivity was observed. Using 2.0 equivalents of nucle-
ophile improved the reaction time but resulted in a
slightly lower ee. Lowering the temperature to À228C
provided an increase in the enantioselectivity to 93%
Table 3, entry 11).
Once the reaction conditions had been optimized,
we investigated the substrate scope of this Friedel–
Crafts alkylation. Several electron-rich benzene deriv-
atives reacted with imine 1 in good yields and good to
excellent enantioselectivities (Table 4). Less activated
8[d]
3h
3i
60
68
70
68
9[e]
[a]
Unless otherwise specified, reactions were performed on
a 0.5 mmol scale of glyoxylate imine 1 using 1.1 equiv. of
arene 2 and 1 mol% catalyst 4 at À228C for 12 days in
1.0 mL toluene.
[b]
[c]
[d]
[e]
Yield of isolated 3.
Determined by chiral stationary phase HPLC analysis.
Carried out in 0.5 mL thioanisole at room temperature.
Carried out at room temperature for 7 days.
arenes like anisole and 1-methoxynaphthalene are (Figure 1). To broaden the substrate scope thioanisole
suitable substrates in this reaction as well as a chlori- and 1,3-bis(methylthio)benzene[27] were tested in the
nated benzene derivative (Table 4, entries 3–6). The reaction, although a slight reduction in both yield and
absolute configuration of 3f has been determined by enantioselectivity was observed. Less activated nucle-
X-ray diffraction analysis of a crystalline sample (see ophiles could not be used in combination with catalyst
also Supporting Information).[26] The analysis revealed 4f. For example, although mesitylene does react with
that the stereocenter has the (S)-configuration imine 1 using p-toluenesulfonic acid as catalyst, no
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Dieter Enders et al.
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Scheme 2. Removal of the protecting group.
Scheme 3. Hydrolysis of amino acid ethyl ester 4a.
and a catalytic amount of a chiral Brønsted acid. The
corresponding phenylglycine derivatives were isolated
in good to excellent yields (60–89%) and enantiose-
lectivities (68–96% ee). The Friedel–Crafts products
Figure 1. The molecular structure of (S)-3f as determined by
X-ray crystallography.
addition was observed with catalyst 4f. Even though have been successfully converted into the correspond-
catalyst 4f showed to be ineffective, the metal free ing free amines 5 by removal of the Bus-protecting
Friedel–Crafts alkylation of mesitylene is remarkable. group. Furthermore, it was demonstrated in the case
In comparison, Kim and co-workers have reported a of 6a that the free amino acid hydrochlorides can be
Friedel–Crafts-type reaction of heteroarenes and acti- obtained without racemization.
vated arenes with a-amido sulfones,[28] though this re-
action is limited to 1,2,4-trimethoxybenzene and less
activated arenes could not be used.
Experimental Section
To demonstrate the synthetic relevance of the de-
veloped Friedel–Crafts-type reaction, we tried to General Procedure for the Friedel–Crafts-Type
remove the Bus-protecting group and then hydrolyze Alkylation
the ethyl ester of the corresponding amino acid. With
this in mind, we initially attempted to remove the
In a dry, argon-flushed Schlenk tube glyoxylate imine 1
(111 mg, 0.5 mmol) and chiral phosphoric acid amide 4f
protecting group with trifluoroacetic acid or trifluoro-
methanesulfonic acid under admixture of anisole as
described by Weinreb and co-workers.[23] Unfortu-
nately the removal of the protecting group was not
successful under these conditions. A screening of
other Brønsted and Lewis acids revealed that the de-
protection occurs with aluminium chloride. However,
a side-product identified as the amino acid ester bear-
ing a tert-butyl group at the aromatic moiety was pro-
duced. We assumed that a tert-butyl carbocation is
formed during deprotection which then reacts with
the aromatic residue. To prevent this side reaction
2.0 equivalents of anisole were added. The deprotec-
tion with aluminium chloride under these conditions
proceeded smoothly and furnished the desired free
amine 5 in excellent yield without affecting the ste-
reogenic center (Scheme 2). The amino acid ester 5a
could then be hydrolyzed in hydrochloric acid (4.0M)
which led to the free amino acid 6a (Scheme 3).
(4.4 mg, 0.005 mmol, 1 mol%) were dissolved in dry toluene
(1.0 mL). The solution was cooled to À228C and the ben-
zene derivative 2 (0.55 mmol, 1.1 equiv.) was added. After
12 days stirring at the same temperature the reaction mix-
ture was directly transferred onto a column and purified via
flash chromatography over silica gel (diethyl ether/n-pen-
tane=1:10 to 1:2) to yield the corresponding phenylglycine
derivative as a colourless oil or solid. Racemic samples were
prepared using p-toluenesulfonic acid as catalyst in dry di-
chloromethane at room temperature.
General Procedure for the Cleavage of the Bus-
Protecting Group
In a one-necked flask equipped with a drying tube the Frie-
del–Crafts product (1.0 mmol) was dissolved in dry dichloro-
methane (25 mL). Anisole (214 mL, 2.0 mmol) and alumini-
um chloride (467 mg, 3.5 mmol) were added successively in
one portion to the reaction mixture. After being stirred for
40 min at room temperature the yellow solution was diluted
with diethyl ether (80 mL) and an aqueous solution of
sodium hydroxide (70 mL, 0.1M). The precipitated alumini-
In summary, we have developed a Friedel–Crafts-
type alkylation of several substituted electron-rich
arenes using the glyoxylate imine 1 as electrophile um hydroxide was dissolved by addition of a solution of
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Enantioselective Organocatalytic Synthesis of Arylglycines via Friedel–Crafts Alkylation
sodium hydroxide (1.0M) until a clear solution was ob-
tained. The phases were separated and the aqueous phase
was extracted with diethyl ether (3ꢂ80 mL). The combined
organic layers were dried over sodium sulfate, filtered and
concentrated under vacuum. Column chromatography over
silica gel (dichloromethane/methanol=100:1) afforded the
pure product as a yellow oil.
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Acknowledgements
This work was supported by the Deutsche Forschungsgemein-
schaft (priority program Organocatalysis) and the Fonds der
Chemischen Industrie. We thank the former Degussa AG and
BASF AG for the donation of chemicals and Regine Herbst-
Irmer (University of Gçttingen) for advice regarding the crys-
tal structure analysis.
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