Autocatalytic one pot orchestration for the synthesis of α-arylated, α-amino esters

Article abstract of DOI:10.1039/c3cc48884e

A novel acetyl chloride-mediated cascade transformation involving three components (benzyl carbamate, ethyl glyoxylate and arene nucleophiles) is reported. Aryl orthogonally protected α-amino acids are obtained in a one pot cascade, using a mild AcOH-AcCl system, via a critical autocatalytic dehydration-activation step ensuring an original and efficient Friedel-Crafts orchestration. The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c3cc48884e

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Autocatalytic one pot orchestration for the
synthesis of a-arylated, a-amino esters†
Cite this:DOI: 10.1039/c3cc48884e
Stephane P. Roche,* Shyam S. Samanta and Marine M. J. Gosselin
´
Received 20th November 2013,
Accepted 9th January 2014
DOI: 10.1039/c3cc48884e
www.rsc.org/chemcomm
A novel acetyl chloride-mediated cascade transformation involving arise through a pathway involving three main steps: (1) conden-
three components (benzyl carbamate, ethyl glyoxylate and arene sation, (2) activation and (3) arylation. To be successful, these
nucleophiles) is reported. Aryl orthogonally protected a-amino three steps would need to be perfectly orchestrated to direct the
acids are obtained in a one pot cascade, using a mild AcOH–AcCl desired arylation of advanced intermediates 5 or 6 with arene 7
system, via a critical autocatalytic dehydration-activation step and circumvent the direct condensation with ethyl glyoxylate 2.
ensuring an original and efficient Friedel–Crafts orchestration.
Supporting this idea, the work by Fessner established a rare
example of a one pot multicomponent Friedel–Crafts reaction
Facile and scalable synthesis of a-amino acids has attracted using acetic acid and excess of hydrochloric acid gas to form
significant attention in the past decades. Several synthetic racemic a-arylated amino acids.8j Inspired by this appreciable
methods of functionalizing a-iminoglycinates 6 to access precedent, we envisioned that the highly regioselective Friedel–
a-amino acids or esters have been reported (Strecker,1 Mannich2 Crafts reaction could be redesigned to become more effective
or Friedel–Crafts3 reactions). While these methods have proven and suitable for asymmetric catalysis applications.
to be applicable for the enantioselective synthesis of a-amino
A proposed concept, rationalizing a possible orchestration
esters, both access to the starting a-iminiumglycinates 6 (1 to between three components 1, 2 and 7 is outlined in Scheme 1.
3 steps) and late stage protecting group manipulations required A catalytic amount of acid would facilitate the condensation
several synthetic steps to produce marketable a-amino acids or between benzyl carbamate 1 and ethyl glyoxylate 2 to form
esters, leading to a lengthy overall sequence.1–3 On the other hemiaminal 3. Next, acetyl chloride would simultaneously
hand, a-hydroxy 3,4 a-alkoxy,5 a-acetoxy,6 and a-halogeno7
5
activate hemiaminal 3 to deliver chloroaminal 5 while trapping
glycinate esters, which are valuable in situ precursors of water thereof, generating acetic acid and rending the process
a-iminiumglycinates 6, have been less studied for function- autocatalytic in acid.
alizing the glycine a-stereocenter. Thus, only sparse examples
During the chlorination step, a putative onium 4 would be
of cascade reactivity (so called multicomponent reactions) to formed which would likely undergo nucleophilic displacement
synthesize a-amino esters in a single step have been reported.8
We decided to develop a suitable system for a novel and
versatile one pot synthesis of a-amino esters bearing marketable
carbamate protecting groups.9 In this communication, a reliable
synthesis of racemic arylglycine derivatives 8 is described, taking
advantage of an unprecedented autocatalytic process and the
high reactivity of chloroaminal intermediate 5 to initiate the
desired Friedel–Crafts arylation (Scheme 1). To this end, a single
pot transformation of primary carbamate 1 with ethyl glyoxylate
2 and arene nucleophiles 7 was envisioned. If the reaction would
advance in an orderly fashion, the desired a-amino esters 8 could
Department of Chemistry and Biochemistry, Florida Atlantic University,
777 Glades Road, Boca Raton, FL, 33431, USA. E-mail: sroche2@fau.edu
Scheme 1 Concept of autocatalysis in AcOH promoting simultaneously
both condensation and activation steps (steps 1/2) to chloroaminal 5.
† Electronic supplementary information (ESI) available: Experimental procedures
and characterization data. See DOI: 10.1039/c3cc48884e
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Table 1 Attempts of a one pot synthesis of a-amino esters 8a
Entry
Solvent, temperature
Time (h)
Yield (%)
1
2
CHCl3, RT
Ethyl acetate, RT
18
18
9 (57%) 10 (22%)
8a (28%) 10 (17%)a
a
Hemiaminal 3 was isolated in 13% yield.
to in situ deliver the activated chloroaminal 5. Finally, the
arylation will likely proceed via an SN1 mechanism through
iminium 6 to ultimately provide the desired a-amino ester 8.
In our initial studies for the synthesis of activated aminals
(such as chloro, bromo, or acetoxy from hemiaminal 3 (step
2)),5–7 acetyl chloride was found to be the most efficient and
milder reagent in the prospect of a tandem process. Our first
attempts at a one pot reaction between benzyl carbamate 1,
ethyl glyoxylate 2 and 1,3 dimethoxybenzene 7a, with catalytic
amounts of acetic acid and excess of acetyl chloride confirmed
the anticipated nucleophilic chemoselectivity issues leading to
multiple uncontrolled arylations (Table 1). In chloroform and
ethyl acetate (entries 1 and 2), reaction profiles differ but both
by-products 9 or 10 from direct glyoxylate 2 arylations were
isolated. To our delight, the reaction in ethyl acetate yielded the
desired a-amino ester 8a in 28% in the first attempt.
To gain more insight into the proposed concept of auto-
catalysis and the reaction mechanism, control experiments
starting from hemiaminal 3 and other plausible reaction inter-
mediates acetoxy- and chloroaminal 5 were investigated.10
Interestingly, addition of arene 7a to hemiaminal 3 (or
acetoxy-derivative) afforded the bis-arylated product 10 along
with the desired a-amino ester 8a in 35% and 16% yields
respectively.10 This result supports that hemiaminal 3 has a
high tendency to fragment (retro-condensation) before under-
going successive arylations leading to 10.11
Also, treatment of chloroaminal 5 with D2O regenerates the
deuterated-hemiaminal 3 demonstrating that water should be
entirely excluded from the reaction media to achieve full con-
version to a-chloroglycinate 5 and enable the cascade reaction.
Due to the lack of controlled reactivity in one pot (Table 1),
we then examined the condensation and activation steps in
more detail. Xu7e and others12 demonstrated that both acidity
and the amount of Brønsted acid used to catalyze the conden-
sation between carboxamides and alkyl glyoxylates are impor-
tant to efficiently produce hemiaminals. As shown by the slow
rate of the acid catalysis (10 mol%) (Fig. 1; catalysis A), the
modest conversions13 to hemiaminal 3 may result from the
reversibility of the condensation.10,11 Upon addition of acetyl
chloride, the reaction proceeded more quickly to full conver-
sion in hemiaminal 3 and further afforded the desired chloro-
aminal 5 in good yield (Fig. 1; autocatalysis B). These kinetic
experiments support that acetyl chloride displaces the reac-
tion equilibrium towards hemiaminal 3 and chloroaminal 5.10
Fig. 1 Experimental kinetic evidence showing high performance auto-
catalysis. Reactions were performed with: catalysis A: 1 (1.0 mmol), 2
(1.3 mmol), acetic acid (10 mol%) at RT, in chloroform; autocatalysis B:
similar reaction condition to A with acetyl chloride (2.5 mmol); conversions
are reported using a quantitative 1H NMR technique [ref. 13] with mesitylene
as the internal standard.
Thus, acetyl chloride was found to not only activate hemiaminal 3,
but also trap the water formed during the reaction, producing
acetic acid which autocatalyzes and accelerates the first step of the
cascade (Scheme 1).14 It is important to notice that acetic and
hydrochloric acids are the main reaction by-products and that
the reaction was not compatible with the use of molecular
sieves.10 Several solvents were also tested in the reaction
(toluene, THF, ethyl acetate, chloroform and acetonitrile), and
full conversion in chloroaminal 5 was established either in
acetonitrile or chloroform at 60 1C.10
We then examined the tandem cascade reaction in the
preselected solvents (Table 2). Experiments were conducted
with a reduced amount of ethyl glyoxylate (1.05 equiv.) to avoid
any formation of arylated by-products 9–10. In ethyl acetate, the
cascade reaction was messy (Table 2, entry 1) leading to a
difficult isolation of the desired product 8a in a modest 9%
yield. After optimization, both reactions in CHCl3 and CH3CN
effectively delivered the a-amino ester 8a at a variable tempera-
ture (Table 2, entries 2–4). The best result was obtained in
chloroform at 60 1C leading to the isolation of a-amino ester 8a
in 82% yield (Table 2, entry 3).
Having established two sets of conditions in CHCl3 and
CH3CN for Friedel–Crafts reaction, we turned our attention to
Table 2 Optimization for a one pot synthesis of racemic a-amino esters 8a
Step 1/2
Time (h)
Step 3
Entry
Solvent
Time (h)
Temp.
Yield (%)
1
2
3
4
5
CH3CO2Et
CHCl3
CHCl3
CH3CN
CH3CN
9
12
12
24
24
24
36
9
2
0.5
RT
RT
60 8C
RT
60 1C
9
65
82
74
69
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Table 3 Scope for the synthesis of racemic a-amino esters 8b–la
Neuroscience) for helpful scientific discussions and editing of
this manuscript.
Notes and references
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Method A: reaction performed in CHCl3, steps 1/2 for 12 h, method B:
reaction performed in CH3CN, step 1/2 for 24 h; both methods are
followed by the addition of arenes (step 3) for the specified time and
temperature; isolated yields are reported. Using excess arenes
(3.0 equiv.), the isolated yields for 8b and 8h are 60% and 61%
respectively. Using method B at 60 1C for 4 h, 8d was isolated in
74% yield (2 : 1 mixture of regioisomers). Nucleophile employed is the
aniline hydrochloric salt.
b
c
d
the scope of the cascade reaction with a series of challenging
arene nucleophiles (Table 3). According to the empirical
nucleophilicity scale from Mayr,15 we discovered that the most
reactive arenes (N factor > 3.0) reacted regioselectively in CHCl3
at low temperatures (Method A) while less reactive arenes
(N factor o 1.5) reacted more cleanly in CH3CN and at higher
temperatures (Method B). Several phenolic and aniline deriva-
tives 8a–e were selected to compare their innate reactivity
(electronic and steric factors) while heteroaromatic substrates
also showed a broad scope of reactivity as demonstrated by the
range of temperature utilized for the synthesis of 8f–j. Pyrrolyl
8f–g, furanyl 8h and indolyl 8i–j aminoester derivatives were
prepared in high yields as single regioisomers. Finally, anthra-
cenyl product 8k was obtained easily in 82% yield, while the
more unusual and complex chalcone a-amino ester derivative 8l
was isolated in a reasonable 39% yield.
¨
2003, 68, 5819; (d) L. E. Kaım, M. Gizolme, L. Grimaud and J. Oble,
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´
(g) I. Ibrahem, W. Zou, M. Engqvist, Y. Xu and A. Cordova,
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¨ ¨
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In summary, we reported a one pot synthesis of aryl a-amino
acid bearing orthogonal protecting groups via Friedel–Crafts
reaction employing activated iminiums generated from inexpen-
sive, commercially available starting materials. Our results
show this cascade to be autocatalytic in acetic acid and
mediated by acetyl chloride to shuttle water out of the system.
This novel one pot synthesis is efficient and versatile as high-
lighted by the synthetic scope of arylated a-amino esters 8a–l
prepared. Ongoing studies are aimed at developing an
asymmetric variant of this transformation and expanding the
scope to additional classes of nucleophiles.
´
´
´
¨
I. Szatmari, A. Mandi, T. Kurtan and F. Fu¨lop, Synlett, 2011, 1940.
9 For a discussion on protecting groups used in peptide synthesis and
a-iminoglycinate functionalization, see: Y. Nakamura, R. Matsubara,
H. Kiyohara and S. Kobayashi, Org. Lett., 2003, 5, 2481.
10 See ESI† for complete experimental details.
11 Treatment of hemiaminal 3 without nucleophile, in presence of
acids such as acetic acid, thioureas, boron trifluoride or scandium
triflate results in a quantitative fragmentation back to glyoxylate 2.
12 E. Valente, J. R. B. Gomes, R. Moreira and J. Iley, J. Org. Chem., 2004, 69, 3359.
13 T. D. W. Claridge, in High Resolution NMR Techniques in
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The authors thank Florida Atlantic University for financial
support and Professor S. Lepore (FAU) and Dr A. Kleinke (Dart
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun.