Synthesis of aminocyclobutanes by iron-catalyzed [2+2] cycloaddition

Article abstract of DOI:10.1002/anie.201303803

Fab Four: An iron-catalyzed [2+2] cycloaddition furnishes aminocyclobutanes with a broad range of substituents in excellent yields and diastereoselectivities. The products can be obtained on a gram scale and can be further converted to β-peptide derivatives in a few steps. Furthermore, a [4+2] cycloaddition between an aminocyclobutane and an olefin leads to the corresponding cyclohexylamines. Copyright

Full text of DOI:10.1002/anie.201303803

Angewandte
Chemie
Communications
Cycloaddition
F. de Nanteuil, J. Waser*
&&&& — &&&&
Synthesis of Aminocyclobutanes by Iron-
Catalyzed [2+2] Cycloaddition
Fab Four: An iron-catalyzed [2+2] cyclo-
addition furnishes aminocyclobutanes
with a broad range of substituents in
excellent yields and diastereoselectivities.
The products can be obtained on a gram
scale and can be further converted to b-
peptide derivatives in a few steps. Fur-
thermore, a [4+2] cycloaddition between
an aminocyclobutane and an olefin leads
to the corresponding cyclohexylamines.
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DOI: 10.1002/anie.201303803
Cycloaddition
Synthesis of Aminocyclobutanes by Iron-Catalyzed [2+2]
Cycloaddition**
Florian de Nanteuil and Jꢀrꢁme Waser*
Locking the spatial orientation of the substituents of a mol-
ecule is essential in order to induce desirable properties such
as bioactivity or supramolecular organization. Nitrogen-
substituted cyclobutanes in particular combine a small and
rigid carbocyclic skeleton with amine-based functional
groups, which are omnipresent in bioactive compounds.[1] In
fact, this scaffold can be found in natural or synthetic
biologically active compounds such as lannotinidine F (1),
cyclobut-G (2), or rhodopeptine analogue 3 (Figure 1).[2] The
most often applied to the synthesis of cyclobutanes.[6–8]
However, the scope of these transformations was limited,
and harsh conditions or specialized equipment was often
required. An alternative strategy based on organocatalysis
was recently reported, but it remains limited to nitrocyclobu-
tanes.[9] Methods involving Lewis acid catalysts were success-
ful for diverse donor–acceptor-substituted cyclobutanes.[10,11]
In the specific case of aminocyclobutanes however, there is
only a single report by Avenoza and co-workers, who made
use of a superstoichiometric amount of an aluminum-based
Lewis acid for the synthesis of a-amino acid derivatives
(Scheme 1a).[12] There is consequently a great need for milder
catalytic methods to access differently substituted amino-
cyclobutanes.
Figure 1. Examples of aminocyclobutanes in natural products and
synthetic bioactive compounds.
use of aminocyclobutanes as constrained amino acids has also
been studied, as their introduction into peptides results in
foldamers with interesting properties ranging from cell-
penetrating agents to low-molecular-weight gelators.[3]
In addition to their exceptional structural properties,
cyclobutanes are also versatile synthetic precursors.[4] Never-
theless, the use of donor–acceptor-substituted cyclobutanes to
access formal 1,4-dipoles is far less exploited than the use of
cyclopropanes to access formal 1,3-dipoles.[5] The first exam-
ple of such a process was reported by Saigo and co-workers in
1991, who described a formal [4+2] cycloaddition between
aminocyclobutanes and carbonyl compounds.[5a] However,
the nitrogen atom was lost during the process. In subsequent
related studies, carbo- and alkoxy-substituted four-membered
rings were employed.[5b–f]
Scheme 1. Lewis acid catalyzed [2+2] cycloaddition for the synthesis of
aminocyclobutanes. MAO=methylaluminoxane, MABR=methylalumi-
num bis(4-bromo-2,6-di-tert-butyl phenoxide).
Herein, we report the first Lewis acid catalyzed [2+2]
cycloaddition between enimides and alkylidene malonates to
access b-amino acid cyclobutane derivatives (Scheme 1b).
The reaction involves the use of cheap and non-toxic iron
trichloride as catalyst and tolerates a wide range of substitu-
ents. The method can be used to prepare the aminocyclobu-
tanes in gram quantities. The synthetic potential of the
obtained products was demonstrated by the transformation of
one of them into a b-peptide derivative, and by the first
catalytic [4+2] cycloaddition of aminocyclobutane proceed-
ing without loss of the precious nitrogen atom.
The structural and synthetic versatility of aminocyclobu-
tanes makes the development of new synthetic methods
toward these compounds particularly attractive. In the past,
photochemical and thermal [2+2] cycloadditions have been
[*] F. de Nanteuil, Prof. Dr. J. Waser
Laboratory of Catalysis and Organic Synthesis
Ecole Polytechnique Fꢀdꢀrale de Lausanne
EPFL SB ISIC LCSO, BCH 4306, 1015 Lausanne (Switzerland)
E-mail: jerome.waser@epfl.ch
We recently reported that di(alkoxycarbonyl)-substituted
cyclopropanes were stable, yet still reactive as formal dipoles
when substituted by a phthalimide.[13] We wondered if
similarly substituted aminocyclobutanes would display the
same reactivity. Consequently, commercially available N-
Homepage: http://lcso.epfl.ch/
[**] EPFL, F. Hoffmann-La Roche Ltd and SNF (grant number
200021_129874) are acknowledged for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303803.
2
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Table 1: Optimization of the [2+2] cycloaddition.
Entry
Catalyst (mol%)
t
[h]
Malonate
T
[8C]
Ratio of
6/4[a]
1
2
3
4
5
6
7
8
ZnBr2 (100)[b]
1
0.75
0.75
0.75
0.5
12
12
12
5a
5a
5a
5a
5a
5b
5b
5b
À78
À78
À78
À30
0
RT
RT
RT
0:1
0:1
tr. of 6
1:2
1:0
0:1
1.5:1
1:0
Yb(OTf)3 (10)[b]
Sc(OTf)3 (10)[b]
Sc(OTf)3 (10)[b]
Sc(OTf)3 (10)[b]
Sc(OTf)3 (20)[c]
In(OTf)3 (20)[c]
FeCl3·Al2O3 (20)[c]
[a] Monitored by 1H NMR spectroscopy. [b] Known procedures were
followed.[5] [c] Lewis acid (0.2 equiv), dimethyl 2-ethylidenemalonate (5b,
1 equiv) and 2-vinylisoindoline-1,3-dione (4a, 1.2 equiv) added drop-
wise, CH2Cl2, 0.1 mm. Phth=phthaloyl, tr.=traces
vinyl phthalimide (4a) and methylidene malonate 5a were
chosen as reaction partners to attempt the synthesis of
aminocyclobutane 6aa (Table 1). The use of the conditions
reported for the synthesis of carbo- or alkoxy-substituted
cyclobutanes[5] did not give the desired product (entries 1–3).
Nevertheless, when scandium triflate was used as catalyst,
traces of the product could be detected by 1H NMR spectro-
scopic analysis of the crude product (entry 3) and by
increasing the reaction temperature, a complete conversion
could be observed (entries 4 and 5). In this case, the major
product was the desired cyclobutane 6aa. At a higher
temperature than 08C, degradation of starting material 4a
as well as product 6aa was observed. In order to test this
system with less reactive substrates, commercially available
ethylidene malonate 5b was reacted with 4a in the presence
of scandium triflate at room temperature (entry 6). As no
conversion was achieved in this case, other Lewis acids were
examined for the [2+2] cycloaddition. Indium triflate and iron
trichloride supported on alumina[14] were able to catalyze the
reaction, even if full conversion was not achieved with the
former Lewis acid (entries 7 and 8).[15] Based on these
preliminary results, the iron catalyst was selected to study
the scope of the reaction.
On preparative scale, iron trichloride on alumina was also
a good catalyst (10 mol%) for the reaction between 4a and
unsubstituted methylidene malonate 5a (Scheme 2). Varia-
tion of the nitrogen substituent was first examined.[16]
Succinimide as well as maleimide were tolerated, giving the
cyclobutanes 6ba and 6ca in 91% and 48% yield, respec-
tively. The reaction also allowed the formation of Boc-
protected thymine cyclobutane 6da in 76% yield. The use of
an N-vinyl oxazolidinone failed to deliver product 6ea as
a result of decomposition of the starting material. Cyclo-
addition of keto ester substrates was possible, affording
cyclobutane 6ac in 62% yield.
Scheme 2. Scope of the [2+2] cycloaddition with methylidene dicar-
bonyl compounds. Reaction conditions: enimide (0.20 mmol, 1 equiv),
alkylidene malonate (0.40 mmol, 2 equiv), Fe catalyst (1 mmolgÀ1
20 mg, 0.020 mmol, 0.1 equiv) in CH2Cl2 (1 mL) for 0.2–5 h. [a] 4 equiv
of methylidene malonate were used. [b] b.r.s.m., 50% yield of isolated
product. [c] b.r.s.m., 38% yield of isolated product. b.r.s.m.=based on
recovered starting material, Boc=tert-butoxycarbonyl, E=CO2Me,
Succ=succinyl.
,
enimides[17] was examined first. Enimides substituted with
a methyl, hexyl, or cyclopropyl group afforded the corre-
sponding cyclobutanes 6 fa, 6ga, and 6ha in 74–85% yield. An
aliphatic chloro substituent was also compatible with the
reaction conditions (product 6ia). Succinimide-substituted
cyclobutanes 6ja and 6ka could also be obtained in 81 and
83% yield, respectively. Importantly, in all the experiments
that involve the use of (E)-substituted enimides (except for
the formation of cyclobutane 6ka), only one cyclobutane
diastereoisomer could be detected in the crude mixture of the
reaction. Aromatic substitution of the enimide was next
investigated. The reaction delivered a single diastereoisomer
of cyclobutane 6la bearing a phenyl substituent in 90% yield.
A para-bromo substituent on the benzene ring slowed down
the reaction and full conversion to cyclobutane 6ma was not
observed. However, decreasing the conjugation of the ben-
zene ring with the enimide by moving the bromine atom to
the ortho position[18] restored the reactivity, and product 6na
At this point, we turned to the synthesis of aminocyclo-
butanes with multiple substituents. The use of (E)-substituted
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could be obtained in 93% yield. Finally, the reaction was
slower in the presence of a trifluoromethyl group, but
cyclobutane 6oa could still be obtained in 38% yield (45%
based on recovered starting material).
When we switched to electron-rich aromatic rings as
substituents, we observed
a
different regioselectivity
(Scheme 3). When tolyl-substituted enimide 4p was used,
a 2.5:1 mixture of “normal” and “inverted” products 6pa and
6pa’ was obtained (Scheme 3a). p-Methoxybenzene-substi-
Scheme 4. Scope of the [2+2] cycloaddition with alkylidene malonates.
Reaction conditions: Enimide (0.20 mmol, 1 equiv), alkylidene malo-
nate (0.40 mmol, 2 equiv), Fe catalyst (1 mmolgÀ1, 20 mg,
0.020 mmol, 0.1 equiv) in CH2Cl2 (1 mL). Cy=cyclohexyl.
Scheme 3. [2+2] Cycloaddition with enamides substituted with elec-
tron-rich benzene rings. Tol=tolyl.
tuted substrate 4q gave only the “inverted” product 6qa’
(Scheme 3b). This switch in regioselectivity is interesting as it
gives access to equally important g-amino acid cyclobutane
derivatives.[19] Additionally, it allowed the assignment of the
relative donating ability of the phthaloyl group compared to
electron-rich aromatic groups in the [2+2] cycloaddition,
which may also be useful in future for the design of other
transformations.
Less reactive substituted alkylidene malonates[20] also
afforded cyclobutanes 6ab, 6ad, and 6ae in 59–71% yields,
but usually without diastereoselectivity (Scheme 4).[21] The
use of benzyl-substituted alkylidene malonates 5 f allowed the
formation of product 6af in a better diastereomeric ratio of
3:1 and 62% yield. In the case of trifluoromethyl-substituted
aminocyclobutane 6ag, only the trans diastereoisomer was
obtained in 76% yield. This is an important result, as methods
for the synthesis of trifluoromethyl-substituted aminocyclo-
butanes are rare, require numerous steps, and usually lack
diastereoselectivity.[6b,22]
Methylidene malonates such as 5a are very reactive
compounds and start to decompose after a few days, even
when stored under argon at À208C. The access to these
building blocks involves a complex Knoevenagel/Diels–
Alder/recrystallization/cracking sequence followed by
a base-sensitive distillation in paraffin.[23] This difficult
access to methylidene malonates was a serious limitation for
the preparative use of our [2+2] cycloaddition methodology.
We found that the method developed by Connell and co-
workers for the methenylation of dicarbonyl compounds[20b]
could be adapted to the synthesis of the sensitive methylidene
malonates (Scheme 5). When the reaction was completed, the
crude mixture could be used directly in the cycloaddition
reaction. The efficacy of this method was demonstrated by
Scheme 5. Gram-scale synthesis of aminocyclobutanes.
accessing cyclobutanes 6aa, 6ah, 6ai, and 6 fa within a few
hours from commercially available starting materials on
a gram scale using a catalyst loading of 5 mol%.
In order to better understand the reaction mechanism, it
would be important to know whether the reaction is
stereospecific in relation to the geometry of the enamide, or
whether the observed high trans diastereoselectivity is due
only to thermodynamic control. When (Z)-substituted eni-
mides were used, no conversion was detected, even after
prolonged reaction times. The lack of reactivity in the case of
the (Z)-substituted isomer could be tentatively attributed to
the loss of conjugation between the p orbital of the nitrogen
atom and the p system of the olefin as a result of steric
interactions, thus leading to lower nucleophilicity. To answer
the question of stereospecificity, deuterated enimide 4r was
synthesized[24] and submitted to the reaction conditions
(Scheme 6). Only a slight loss of stereoinformation was
observed during the reaction. This result supported a stepwise
mechanism via a zwitterionic intermediate A, but also
indicated a fast ring closure, which could compete with
single-bond rotation.
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Scheme 6. Reaction with deuterated enamide 4r and speculative
zwitterionic intermediate A.
Finally, we selected two key transformations to highlight
the potential of aminocyclobutanes both as synthetic pre-
cursors and as structural units (Scheme 7). The reaction of
aminocyclobutane 6aa with enol silane 9 catalyzed by tin
tetrachloride afforded one diastereoisomer of aminocyclo-
hexane 10 in 95% yield (Scheme 7a). To the best of our
knowledge, this is the first report of such a formal [4+2]
cycloaddition[25] between an aminocyclobutane and an olefin.
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Scheme 7. Formal [4+2] cycloaddition and synthesis of dipeptide 11.
The conversion of cyclobutane 6ai to glycine–dipeptide 11
was achieved in three steps with an overall yield of 78%
(Scheme 7b).[26]
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In conclusion, we have developed the first Lewis acid
catalyzed [2+2] cycloaddition for the synthesis of b-amino
acid cyclobutane derivatives. The reaction gave access to
cyclobutanes with multiple substituents, including important
derivatives for medicinal chemistry, such as nucleoside
analogues or trifluoromethylated compounds. A simplified
access to highly sensitive methylidene malonates was also
developed, allowing the gram-scale synthesis of aminocyclo-
butanes. The synthetic potential of the obtained aminocyclo-
butanes was demonstrated by the transformation of one of
them to a b-peptide derivative and by a catalytic [4+2]
annulation reaction for the synthesis of cyclohexylamines.
Received: May 3, 2013
Published online: && &&, &&&&
Keywords: aminocyclobutanes · cycloaddition · cyclobutanes ·
.
iron
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[14] Iron trichloride on alumina was used, as it is more stable and
easier to handle than the free Lewis acid.
[15] A control experiment confirmed that basic alumina does not
catalyze the reaction in the absence of iron.
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known tedious three-step method.[20c] See the Supporting
Information for more details.
[21] No reaction was observed when both the enimide and the
alkylidene malonate were b-substituted.
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[24] 4r was synthesized by reduction of the deuterated ynimide with
Lindlar catalyst. See the Supporting Information for further
details.
[25] As the reaction between cyclobutane 6aa and silyl enol ether 9
À
involves a C C bond cleavage, the reaction is best described as
a “formal cycloaddition”, in contrast to the [2+2] cycloaddition.
See also the discussion in reference [13c].
[26] Cleavage of the phthaloyl group from product 10 occurred
smoothly in 87% yield using diaminoethane as reagent. In
contrast, cleavage of the phthaloyl group from cyclobutane 11
was not possible in a good yield. Alternative synthetic routes to
generate the free cyclobutylamines are currently under inves-
tigation.
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