Base-promoted c→n acyl rearrangement: An unconventional approach to α-amino acid derivatives

Article abstract of DOI:10.1002/chem.201402514

We have discovered that N-alkyl aminomalonates undergo a fast and selective intramolecular C→N acyl rearrangement reaction in the presence of a strong base, leading to N-protected glycinates in excellent yield. Moreover, the fact that the reaction proceeds through a nucleophilic enolate intermediate has been used for implementing a tandem rearrangement/alkylation sequence that has been applied to the preparation of synthetically relevant nonproteinogenic tertiary and quaternary N-alkyl α-amino acids in a very simple and reliable way.

Full text of DOI:10.1002/chem.201402514

DOI: 10.1002/chem.201402514
Communication
&
Rearrangement Reactions
Base-Promoted C!N Acyl Rearrangement: An Unconventional
Approach to a-Amino Acid Derivatives
Iratxe Ugarriza, Uxue Uria, Luisa Carrillo,* Jose L. Vicario,* and Efraim Reyes[a]
unprecedented base-promoted intramolecular C!N rearrange-
Abstract: We have discovered that N-alkyl aminomalo-
ment which, moreover, proceeds through the formation of an
nates undergo a fast and selective intramolecular C!N
intermediate glycine enolate species that has the potential to
acyl rearrangement reaction in the presence of a strong
be alkylated with a variety of electrophiles, ending in the for-
base, leading to N-protected glycinates in excellent yield.
mation of a-alkyl-a-amino acids (Scheme 1). Notably, this un-
Moreover, the fact that the reaction proceeds through
precedented reaction shows up as a very effective procedure
a nucleophilic enolate intermediate has been used for im-
for the easy and modular preparation of unusual nonproteino-
plementing a tandem rearrangement/alkylation sequence
genic a-amino acids using an alternative synthetic approach to
that has been applied to the preparation of synthetically
the classical methods reported in the literature that typically
relevant nonproteinogenic tertiary and quaternary N-alkyl
involve the alkylation of protected glycine derivatives through
a-amino acids in a very simple and reliable way.
the corresponding enolate.[6] These approaches typically re-
quire complex synthetic maneuvers because of the inherent in-
stability and difficulties associated with the generation and
manipulation of glycine enolates.[7]
Rearrangement reactions involving carbon–carbon or carbon–
heteroatom translocation of functional groups have been very
often considered as exotic or rather limited transformations.
However, after comprehensive mechanistic understanding, re-
arrangement processes have become the basis of several well-
established, powerful CꢀC and CꢀX bond-forming methodolo-
gies, which in many cases allow the construction of molecular
architectures that are not easily accessible by other conven-
tional approaches.[1] Rearrangements involving the transfer-
ence of acyl groups within the molecular framework represent
a particular class of transformations, typically consisting of in-
tramolecular transfer of acyl groups between heteroatoms.[2]
Scheme 1. Access to a-amino acid derivatives through base-promoted intra-
molecular C!N acyl rearrangement.
Several very limited cases detailing the transference of acyl
groups from a heteroatom to a carbon atom have been report-
ed in the literature;[3] however, as far as we are aware, the op-
We started our work with the identification of the optimal
posite process consisting of the transference of an acyl group
reaction conditions for the C!N acyl transfer reaction by
from a carbon atom to a heteroatom has only been limited to
intramolecular C!N acyl transfer processes in indazoles or pyr-
azoles through a [1,5]-sigmatropic rearrangement[4] and to the
cyanide-mediated C!O acyl transfer observed in benzils.[5] The
fact that this type of rearrangement implies a CꢀC bond cleav-
age event, which is a thermodynamically difficult process,
might explain this situation.
using N-benzyl diethylaminomalonate as a model substrate,
which was synthesized by standard N-alkylation of the corre-
sponding bromomalonate (Scheme 2). Using these conditions,
a variety of other differently substituted N-alkylaminomalo-
nates were also synthesized in good to moderate yields.
We next proceeded to study the rearrangement of 1a, ini-
tially surveying the use of different bases. As it can be seen in
Table 1, one equivalent of nBuLi was found to promote the re-
action within 2 h, leading to a moderate yield of the rearrange-
ment product, 2a, after aqueous work-up (entry 1); however,
the use of weaker bases ended up in the full recovery of start-
In this context, we have found in our laboratories that ami-
nomalonates can be converted into glycines through a novel
[a] I. Ugarriza, Dr. U. Uria, Prof. L. Carrillo, Prof. J. L. Vicario, Prof. E. Reyes
Departamento de Quꢀmica Orgꢁnica II
Facultad de Ciencia y Tecnologꢀa
Universidad del Paꢀs Vasco/Euskal Herriko Unibertsitatea UPV/EHU
P.O. Box 644, 48080 Bilbao (Spain)
E-mail: marisa.carrillo@ehu.es
joseluis.vicario@ehu.es
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402514.
Scheme 2. Synthesis of the starting N-alkylaminomalonates 1a–q.
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Table 1. Screening for the best experimental conditions by using 1a as
model substrate.[a]
Table 2. Scope of the reaction.
Entry
Product R1
R2
R3
Yield
[%][a]
Entry
Base
Solvent
T
[8C]
t
Yield
[%][b]
[min]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
2a
2b
2c
2d
2e
2 f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
Et
Et
Et
Et
Et
Et
Et
Et
Me
iPr
tBu
crotyl
Et
Et
Et
Et
Et
Et
Et
Et
Me
iPr
tBu
crotyl
PhCH2
91
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
nBuLi
LDA
LiH
LiOH
DABCO
DBU
Et3N
tBuLi
MeLi
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
Et2O
toluene
THF
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ30
0
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
120
300
300
300
300
300
300
120
45
45
45
45
10
40
(4-MeOC6H4)CH2
(4-FC6H4)CH2
nPr
nBu
iPr
cyclohexyl
CH2=CHCH2
PhCH2
PhCH2
PhCH2
68
70
58
81
75
73
73
68
89
80
68
89
69
81
n.r.[c]
n.r.[c]
n.r.[c]
n.r.[c]
n.r.[c]
n.r.[c]
31
79
55
40
75
88
42
80
91
MeLi
MeLi
PhCH2
MeLi/TMEDA[d]
MeLi/LiCl[e]
MeLi/LiCl[e]
MeLi/LiCl[e]
MeLi/LiCl[e,f]
PhCH2 PhCH2 PhCH2
Et
Et
Et
Et
Et
tBu
Et
Et
Et
Et
PhCH2
(2-thienyl)CH2
(benzo[b]thiophen-2-yl)CH2 80
(2-furyl)CH2
H
45
10
10
77
17
[a] Reaction conditions: 1.0 mmol of 1a and 1.0 mmol of base were
stirred in the corresponding solvent at the specified temperature and,
after the indicated reaction time, water was added and the reaction was
allowed to reach RT. [b] Yield of pure product after flash column chroma-
tography. [c] n.r. indicates that no reaction was observed, recovering
starting material. [d] 1:1 TMEDA/MeLi ratio. [e] 4:1 LiCl/1a ratio. [f] 1a·HCl
was employed together with 2.0 equiv of MeLi and the reaction was
quenched with 1m HCl. DABCO=1,4-diazabicyclo[2.2.2]octane, DBU=
1,8-diazabicyclo[5.4.0]undec-7-ene, LDA=lithium diisopropylamide.
[a] Yield of pure isolated product after flash column chromatography.
reaction and its performance for the preparation of a variety of
substituted N-protected glycinates. As it can be seen in
Table 2, the reaction proceeded well by using diethyl amino-
malonates with different substituents at the nitrogen atom, in-
cluding benzyl groups that contain both electron-donating
and electron-withdrawing substituents (compounds 1a–c), and
linear and branched alkyl chains (compounds 1d—g); also, N-
allyl substituted malonate 1h reacted efficiently providing the
corresponding N-protected glycinate in high yield. The sub-
stituent at the carboxylate moiety of the malonate reagent
could also be changed without negatively affecting the reac-
tion outcome (compounds 1i–m). This also includes the use of
dibenzyl aminomalonate derivative 1m, which leads to prod-
uct 2m that formally incorporates two benzyl protecting
groups at the carboxylate and the amino moiety that can be
simultaneously deprotected if necessary. Remarkably, the use
of aminomalonate 1n in which two different carboxylate
groups are incorporated took place cleanly with complete che-
moselectivity, observing the exclusive formation of one single
product arising from the transfer of the bulkier tert-butoxycar-
bonyl group. N-Heteroarylmethyl-substituted aminomalonates
also performed well in the reaction (compounds 1o–q). Finally,
when we tested N-unsubstituted diethylaminomalonate 1r as
substrate, the rearrangement reaction took place very slug-
gishly and a very low yield of N-monoprotected glycinate 2r
was obtained (Table 2, entry 18).
ing material (entries 2–7). When tBuLi was tested (entry 8), the
reaction behaved similar to the reaction with nBuLi, probably
due to the high basicity of this reagent; however, changing to
MeLi cleanly led to 2a after 45 min (entry 9). The temperature
of the reaction was found to be an important parameter, as
using higher temperatures (entries 10 and 11) led to poorer re-
sults. We next studied the incorporation of other additives,
which are known to modify the basicity and reactivity of orga-
nolithium reagents. In this sense, the use of N,N,N’,N’-tetra-
methylethylenediamine (TMEDA) did not have any remarkable
influence but when LiCl was added (4 equiv)[8] the yield of the
reaction increased to an excellent 88% (entry 13), the reaction
being complete within 10 min. We continued our study, sur-
veying other solvents, and observed that although the reaction
proceeded well in toluene (entry 15), a significant decrease in
the yield was observed when Et2O was used (entry 14). Impor-
tantly, we also carried out the reaction by using the starting
material as the corresponding hydrochloride salt, which is
a much more easily handled compound,[9] observing that the
reaction proceeded well when two equivalents of base were
used (entry 16).
An interesting result was observed when the reaction of
substrate 1a was quenched with D2O: the reaction led to the
incorporation of deuterium at the a-position of glycinate 3
(Scheme 3). This result indicates that the reaction proceeds
through the formation of a glycinate enolate intermediate,
which is stable enough under the conditions employed for the
Having established a robust experimental protocol for the
acyl transfer reaction, we next proceeded to extend the reac-
tion, exploring other N-alkyl aminomalonates with different
substitution patterns in order to determine the scope of the
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Scheme 3. Quenching experiments.
Scheme 4. C!N acyl transfer reaction with cyclic aminomalonates.
rearrangement for undergoing a subsequent reaction with the
proton (deuterium) source. We therefore surveyed the possibil-
ity of carrying out the tandem C!N acyl transfer reaction/al-
kylation by treating this enolate intermediate with an alkyl-
ating agent. To our delight, when MeI was added to the reac-
tion mixture after the acyl transfer process, a clean reaction oc-
curred, ethyl N-ethoxycarbonylalanine 4a being isolated in an
excellent 78% yield.
ing to ethyl N-ethoxycarbonyl prolinate (6a) directly from 5a.
The reaction was also successful with piperidine-2,2-dicarboxyl-
ate 5b leading to the formation of pipecolic acid derivative 6b
in an excellent 85% yield. We also tested the tandem C!N
acyl transfer/alkylation process with substrate 5a, a reaction
that also proceeds with excellent results by using MeI and the
more challenging ethyl iodide as the alkylating agent, thus
showing that this reaction is a very appropriate methodology
for accessing quaternary proline derivatives, which are key
structural motifs for modifying the secondary structure of pep-
tides and proteins.[11]
In view of these results, we explored the scope of this novel
approach to the a-amino acid scaffold, by testing different al-
kylating agents. As can be noted in Table 3, the reaction pro-
Finally, we also decided to check the feasibility of the remov-
al of the alkoxycarbonyl moiety in the obtained products in
order to demonstrate that this approach can be of practical
applicability for the preparation of a wide variety of a-amino
acid derivatives (Scheme 5). For the N-Boc protected deriva-
Table 3. Tandem C!N acyl rearrangement/alkylation.
Entry
Product
R1
R2
R3
Yield
[%][a]
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4 f
4g
4h
4i
Et
Et
Et
Et
Et
Et
Et
Me
tBu
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
iPr
Me
Et
nBu
PhCH2
CH2=CHCH2
CH2=CH(CH3)CH2
EtO2CCH2
CH2=CHCH2
Me
78
78
44
68
71
69
81
72
81
PhCH2
[a] Yield of pure isolated product after flash column chromatography.
Scheme 5. Removal of the protecting group.
ceeded with high yield when highly reactive alkylating agents,
such as allyl, methallyl, or benzyl iodides (compounds 4d–f
and 4h), were used; good results were also obtained when
using the less reactive ethyl and butyl iodides (compounds 4b
and 4c) or a functionalized reagent such as ethyl iodoacetate
(compound 4g). Similarly, substrates with other alkoxide or N-
alkyl substituents also reacted efficiently (compounds 4h and
4i).
In addition to these acyclic aminomalonates, we also turned
our attention to the use of pyrrolidine-2,2-dicarboxylates[10] as
suitable substrates to undergo this C!N acyl transfer reaction
that would eventually lead to the formation of the proline skel-
eton. As it is shown in Scheme 4, this type of substrates was
also found to be reactive under the optimized conditions and
the acyl transfer reaction took place in an excellent yield, lead-
tives, this was easily carried out under standard reaction with
trifluoroacetic acid (TFA). For the removal of the ethoxycarbon-
yl and methoxycarbonyl groups, an alternative methodology
had to be found; ultimately, the deprotection was achieved by
O-silylation of the carbamate moiety by reaction with TMSI fol-
lowed by in situ methanolysis. Under these conditions, a set of
representative adducts was subjected to deprotection afford-
ing the expected protecting group free a-amino ester deriva-
tives in good yields.
We propose the following mechanism for the base-promot-
ed C!N acyl transfer reaction (Scheme 6). Initially, deprotona-
tion of the starting material can occur at the nitrogen atom,
this process being favored over CꢀH deprotonation of the
acidic malonate moiety because of the kinetic conditions used.
Next, the formed amide anion is proposed to undergo intra-
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Communication
which the lateral a-substituent is chosen by the selection of
the alkylating agent and also provides the final products as
the N-alkoxycarbonyl-protected form, thus being an advantage
for future synthetic applications.[13] Moreover, this C!N acyl
transfer reaction can also be applied to pyrrolidine- and piperi-
dine-2,2-dicarboxylates, leading to the formation of quaternary
prolines and pipecolinic acid derivatives in a single step.
Scheme 6. Proposed mechanism for the C!N acyl rearrangement.
Experimental Section
molecular addition to one of the two carboxylate groups, lead-
ing to the formation of a key 2-alkoxyaziridine-2-olate inter-
mediate.[12] This strained intermediate would next undergo
a fast and irreversible ring-opening process, generating the in-
termediate enolate species, which is finally quenched by the
addition of a proton source or an alkylating agent. The impor-
tance of kinetic control in the deprotonation of the substrate
is also evidenced by the fact that the use of weak bases, that
would very likely favor an aminomalonate enolate intermedi-
ate, do not provide any rearrangement product. When two dif-
ferent carboxylate groups are incorporated in the starting ma-
terial (for example, 1n), the formation of an equilibrating mix-
ture of both possible aziridine intermediates is proposed, in
which the most strained one should have a more pronounced
tendency to undergo the subsequent irreversible ring-opening
process in order to exclusively form the product 2n.
We have tried to detect or identify these proposed inter-
mediates through NMR experiments though with no success.
However, when the reaction was quenched with trimethylsilyl
triflate (TMSOTf), 2,2-dialkoxyaziridine 10 could be isolated and
fully characterized in a moderate yield (Scheme 7). Importantly,
this compound led to the formation of 2o after reacting with
tetra-n-butylammonium fluoride (TBAF), thus providing addi-
tional support for this mechanistic proposal.
General procedure for the C!N acyl rearrangement:
synthesis of 2a–r
MeLi (2.00 mmol) was added to a solution of the corresponding
amine hydrochloride 1a–r·HCl (1.00 mmol) and LiCl (4.00 mmol) in
THF at ꢀ788C under inert atmosphere and vigorous stirring. The
reaction mixture was stirred at ꢀ788C for 10 min. Then, HCl aq.
(1m) and brine (10 mL) were added and, after separating the
phases, the aqueous layer was extracted with EtOAc (3ꢁ15.0 mL).
The combined organic layers were dried over Na2SO4 and the sol-
vent was removed under reduced pressure. The residue was puri-
fied by flash column chromatography (hexanes/EtOAc 8:2) to
afford pure N-alkoxycarbonyl-a-amino esters 2a–r.
General procedure for the C!N acyl rearrangement/
alkylation: synthesis of 4a-i
MeLi (2.00 mmol) was added to a solution mixture of the corre-
sponding hydrochloride 1a–r·HCl (1.00 mmol) and LiCl (4.00 mmol)
in THF at ꢀ788C under inert atmosphere and vigorous stirring. The
reaction mixture was stirred at ꢀ788C for 10 min, then the corre-
sponding alkylating agent (4.00 mmol) was added and the reaction
mixture was stirred overnight at room temperature. Once the reac-
tion was finished, HCl (1m, 2 mL) and brine (10 mL) were added
and the phases were separated. The aqueous layer was extracted
with EtOAc (3ꢁ15.0 mL), the combined organic layers were dried
over Na2SO4 and the solvent was removed under reduced pressure.
The residue was purified by flash column chromatography (hex-
anes/EtOAc 8:2) to afford pure N-alkoxycarbonyl-a-amino esters
4a–i.
Acknowledgements
The authors thank the Spanish MINECO (CTQ2011–22790 and
Juan de la Cierva contract to U. U.), the Basque Government
(Grupos IT328–10), and UPV/EHU (EHUA12/09, UFI QOSYC 11/
22, and fellowship to I. U.) for financial support. We also ac-
knowledge Petronor S.A. (Muskiz, Bizkaia) for the generous gift
of solvents. Membership in the COST Action CM0905 is also ac-
knowledged.
Scheme 7. Isolation of key intermediate 10.
In conclusion, we have developed a novel unprecedented
C!N acyl rearrangement reaction promoted by a strong base,
a reaction that constitutes a useful approach for the synthesis
of a-amino acid derivatives starting from aminomalonates. De-
spite the presence of abundant references regarding intramo-
lecular acyl transfer processes between heteroatoms, this is the
first case of an anionic rearrangement in which an acyl group
is transferred from a carbon atom to a heteroatom, the process
requiring a CꢀC bond cleavage event. Moreover, the fact that
an enolate intermediate is generated after the acyl transfer
process, allows the formation of an additional CꢀC bond if
a carbon electrophile is subsequently added in a typical
tandem sequence. In this sense, the reaction is a highly effi-
cient and modular approach to a-amino acid derivatives in
Keywords: acyl transfer
·
alkylation
·
amino acids
·
rearrangements · tandem reactions
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Communication
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Rammeloo, Tetrahedron 2005, 61, 6749 and ref. 3a.
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[13] We have made several attempts to render the reaction enantioselective.
In particular, we tried to alkylate the enolate intermediate generated
after the rearrangement process with allyl acetate under Pd catalysis in
the presence of a variety of chiral phosphine ligands. However, we ob-
tained very poor levels of enantioselectivity (ee<10% in all cases
tested).
[5] a) A. W. Burgstahler, D. E. Walker, J. P. Kuebrich, R. L. Schowen, J. Org.
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3803.
Received: March 7, 2014
Published online on July 30, 2014
Chem. Eur. J. 2014, 20, 11650 – 11654
www.chemeurj.org
11654
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