Direct Metal-Free Entry to Aminocyclobutenes or Aminocyclobutenols from Ynamides: Synthetic Applications

Article abstract of DOI:10.1002/chem.201601044

The [2+2] cycloaddition of ynamides with the highly polarized reagent Tf₂C=CH₂has been developed to regioselectively afford bis(triflyl)aminocyclobutenes in the absence of catalyst under mild conditions. Incidentally, with the ynamides bearing electron-rich aromatic rings at the C-terminal, an interesting reactivity switch was observed; a cyclization/hydroxylation sequence yielded 2-amino-3-(triflyl)cyclobut-2-enols. Aminocyclobutene construction with addition of alcohols resulted in the formation of aminocyclobutenyl ethers through a cyclization/hydroalkoxylation process. Moreover, the utility of functionalized aminocyclobutenes as precursors for further elaboration was demonstrated with the preparation of α-amino-β,γ-unsaturated ketones and 3-(triflyl)buta-1,3-dien-2-amines through 4 π-electrocyclic ring opening.

Full text of DOI:10.1002/chem.201601044

DOI: 10.1002/chem.201601044
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Synthetic Methods |Hot Paper|
Direct Metal-Free Entry to Aminocyclobutenes or
Aminocyclobutenols from Ynamides: Synthetic Applications
Benito Alcaide,*[a] Pedro Almendros,*[b] and Carlos Lµzaro-Milla[a]
Abstract: The [2+2] cycloaddition of ynamides with the
highly polarized reagent Tf2C=CH2 has been developed to
regioselectively afford bis(triflyl)aminocyclobutenes in the
absence of catalyst under mild conditions. Incidentally, with
the ynamides bearing electron-rich aromatic rings at the C-
terminal, an interesting reactivity switch was observed; a cyc-
lization/hydroxylation sequence yielded 2-amino-3-(triflyl)cy-
clobut-2-enols. Aminocyclobutene construction with addi-
tion of alcohols resulted in the formation of aminocyclobu-
tenyl ethers through a cyclization/hydroalkoxylation process.
Moreover, the utility of functionalized aminocyclobutenes as
precursors for further elaboration was demonstrated with
the preparation of a-amino-b,g-unsaturated ketones and 3-
(triflyl)buta-1,3-dien-2-amines through 4p-electrocyclic ring
opening.
Introduction
Functionalized cyclobutenes are important scaffolds present in
several bioactive compounds, which have also been used as
synthetic intermediates for the preparation of functionalized
organic molecules.[1] Of particular interest is the aminocyclobu-
tene structural motif.[2] A traditional method for aminocyclobu-
tene preparation in a single step is the Ficini reaction, a [2+2]
cycloaddition of ynamines with cyclic electron-deficient al-
kenes (Scheme 1a).[3] However, the Ficini reaction presents a se-
rious drawback, owing to the difficulty of preparing and han-
dling reactive ynamines. More recently, ynamides,[4] which bear
increased stability, has been proved as convenient substrates
for the Ficini reaction (Scheme 1b).[5] Unfortunately, their wide-
spread use in aminocyclobutene synthesis is precluded by the
narrow substrate scope of the alkene partner, which is normal-
ly a cyclic a,b-unsaturated carbonyl compound. An additional
drawback is the use of environmentally unfriendly or expensive
metallic salts, which are required for the activation of yna-
mides. Consequently, efficient metal-free synthesis of function-
Scheme 1. [2+2] cycloadditions of ynamides with alkenes.
alized aminocyclobutenes with high chemo- and regioselectivi-
ty remains a challenge.
We contemplated a possible mild, metal-free synthesis of
aminocyclobutenes through the reaction of the highly polar-
ized reagent 1,1-bis(trifluoromethylsulfonyl)ethene (1)[6] with
ynamides (Scheme 1c). Of practical interest, 2-(2-fluoropyridini-
um-1-yl)-1,1-bis[(trifluoromethyl)sulfonyl]ethan-1-ide
2
was
[a] Prof. Dr. B. Alcaide, C. Lµzaro-Milla
Grupo de Lactamas y Heterociclos Bioactivos
Departamento de Química Orgµnica I
Unidad Asociada al CSIC, Facultad de Química
Universidad Complutense de Madrid, 28040 Madrid (Spain)
Fax: (+34)91-3944103
identified as a stable precursor of 1 with the transference of
the Tf2CCH2 group to phenols, alkynes, 1,3-dienes, and
azides.[7] Herein we describe the discovery and development of
the uncatalyzed [2+2] cycloaddition of ynamides with Tf2C=
CH2 1 under mild conditions. Incidentally, with ynamides bear-
ing electron-rich aromatic rings at the C-terminal, we observed
an interesting reactivity switch.
E-mail: alcaideb@quim.ucm.es
[b] Prof. Dr. P. Almendros
Instituto de Química Orgµnica General
Consejo Superior de Investigaciones Científicas, IQOG-CSIC
Juan de la Cierva 3, 28006 Madrid (Spain)
Fax: (+34)91-5644853
Results and Discussion
E-mail: palmendros@iqog.csic.es
Figure 1 and Figure 2 show the structures of starting ynamides
Supporting information for this article and ORCIDs for the authors can be
found under http://dx.doi.org/10.1002/chem.201601044.
3a–j and 3k–z’, respectively. Initially we treated the oxazolidi-
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Figure 1. Structures of starting ynamides 3a–j.
Scheme 2. Uncatalyzed reaction of ynamides 3 with zwitterion 2. Controlled
synthesis of 4,4-bis(trifluoromethylsulfonyl)cyclobut-1-enamides 4.
were pleased to find that the desired four-membered carbocy-
clic products 4b–d were smoothly obtained (Scheme 2). We
then turned to examine a series of ynamides by varying substi-
tution on the C-terminal. Thus, dimethoxyphenyl, nitrophenyl,
and bromophenyl ynamides 3e–h afforded adducts 4e–h in
57%-quantitative yields (Scheme 2). The process was not limit-
ed to aromatic ynamides; alkyl-substituted ynamide 3i also
performed well to produce the expected product 4i. Likewise,
the silyl-protected acetylene 3j survived the reaction very well
to form 4j in quantitative yield (Scheme 2). Ynamides that con-
tained substituents with different electronic features were
well-tolerated; with the present method becoming a facile
route to aminocyclobutene scaffolds. Notably, ynamides 3a–j
instantaneously reacted to selectively give the corresponding
aminocyclobutenes 4a–j.[8]
Figure 2. Structures of starting ynamides 3k–z’.
Next, the general scope of the reaction with ynamides that
contained electron-donating methoxy groups at the ortho or
para positions of the benzene ring was examined. When elec-
tron-rich ynamides 3k–v were subjected to the above condi-
tions used for ynamides 3a–j, a remarkable effect of the elec-
tronic properties of the starting alkyne on the product forma-
tion was observed. There was no evidence of the presence of
type 4 products, with compounds 4k–v probably undergoing
further reaction. To our delight, acetylene derivatives 3k–y un-
derwent an appealing cyclization/hydroxylation sequence,
yielding novel 2-amino-3-(trifluoromethylsulfonyl)cyclobut-2-
enols 5a–j (Scheme 3). A gram-scale synthesis of 5 f demon-
strated the robustness of this methodology. Complete conver-
sion was observed by thin-layer chromatography (TLC) and
1H NMR spectroscopy of the crude reaction mixtures in all
cases. However, side reactions were detected on highly activat-
ed ynamides 3s and 3t, which may be responsible for the
none-based phenyl ynamide 3a with zwitterion 2 in acetoni-
trile at room temperature (the optimal conditions identified
earlier in our laboratory for the reaction of pyridinium salt
2).[7c,d] The nitrogenated functionality of ynamides can either
become part of a possible five-membered azaheterocycle or
be introduced as an amino substituent onto the required cy-
clobutene. Happily, the desired 4,4-bis(trifluoromethylsulfonyl)-
cyclobut-1-enamide 4a was cleanly formed with total regiose-
lectivity and isolated in an excellent 94% yield (Scheme 2). It is
important to note that excess of pyridinium salt 2 was not re-
quired and the use of equimolecular amounts of zwitterion
was enough, thus not generating additional waste. Next, we
decide to evaluate the generality of the reaction with respect
to nitrogen functionalization. Azetidin-2-one-, pyrrolidin-2-one-
, and imidazolidin-2-one-based phenyl ynamides 3b–d were
selected as the substrates to test our cyclization reaction. We
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should start from cyclobutenones, our protocol could open
new horizons for the generation of cyclobutenols in a comple-
mentary selective manner by another mechanistically different
strategy.
With a number of aromatic-substituted ynamides found to
be compatible with the optimized reaction conditions, hetero-
aromatic rings were investigated to further expand the scope
of the reaction (Scheme 4). Ynamides bearing at the C-terminal
Scheme 3. Uncatalyzed reaction of ynamides 3 with zwitterion 2. Controlled
synthesis of 1-aryl-2-amino-3-(trifluoromethylsulfonyl)cyclobut-2-enols 5.
[a] Major isomer is shown (d.r.=80:20).
Scheme 4. Uncatalyzed reaction of ynamides 3 with zwitterion 2. Controlled
synthesis of 1-hetaryl-2-amino-3-(trifluoromethylsulfonyl)cyclobut-2-enols 5.
moderate yields of isolated adducts 5i and 5j. To test the im-
portance of the steric effects, enantiopure chiral ynamides 3u
and 3v were prepared and tested. Despite the steric hindrance
from the oxazolidinone substituents, aminocyclobutenols 5k
and 5l were obtained in reasonable yields (Scheme 3). Adduct
5k was obtained as single enantiomer, whereas adduct 5l was
obtained as an 80:20 diastereomeric mixture. For conclusive
assessment of the structure of compounds 5, an X-ray crystal-
lographic analysis of adduct 5a was undertaken (Figure 3).[9]
On the basis of the structure of aminocyclobutenol 5a, it must
be assumed the participation of adventitious water. The addi-
tion of external water was not required, but the inclusion of
1.5 equivalents of H2O accelerated the process. In view of the
fact that all reported methods for accessing cyclobutenols
several heterocycles including furan, thiophene, and indole did
not reduce reactivity of the alkyne. Thus, ynamides 3w–z’ re-
acted with zwitterion 2 in acetonitrile at room temperature to
give aminocyclobutenols 5m–q. Again, it seems that moder-
ately electron-rich rings have a better performance than highly
activated ones (adduct 5m). Substrate 3z’, with a large group
flanking the ynamide, smoothly underwent the desired trans-
formation. Electronic but not steric variation of the ynamide
derivatives played a role in determining the reactivity of al-
kynes 3. The absence of hydroxylated products formed from
ynamides 3a–j points to a strong activating effect of electron-
donating substituents in ynamides 3k–z’.
Since the ratio products 4 and 5 may be considered an ap-
proximate measure of the relative reactivity of the aminocyclo-
butene ring towards oxygenated nucleophiles, we decided to
perform the reaction of ynamide 3m with alcohols under oth-
erwise identical conditions. The studies of aminocyclobutene
formation with addition of methanol, prop-2-en-1-ol, prop-2-
yn-1-ol, and propa-1,2-dien-1-ol demonstrated that the pres-
ence of the alcohol moiety exlusively gives aminocyclobutenyl
ethers 6a–d, with the hydroxy group acting as a nucleophile
(Scheme 5). Considering the versatility of alkenes, alkynes, and
allenes in chemical transformations, cyclobutenes 6b–d are po-
tentially interesting building blocks for further manipulation.
Despite the poor nucleophilicity of phenols, they exhibit ambi-
dent reactivity because phenols bear two reaction sites,
namely O and C.[10] With regards to selectivity, a major chal-
lenge with the use of phenols is to obtain exclusively aryloxyla-
Figure 3. ORTEP representation of 2-amino-3-(trifluoromethylsulfonyl)cyclo-
but-2-enol (5a). Thermal ellipsoids are shown at 50% probability.
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Scheme 5. Uncatalyzed reaction of ynamide 3m with zwitterion 2 in pres-
ence of alcohols. Controlled synthesis of 4-alkoxy-4-aryl-2-(trifluoromethylsul-
fonyl)cyclobut-1-enyl pyrrolidin-2-ones 6.
Scheme 7. Mechanistic explanation for the synthesis of aminocyclobutenes
5 and 6.
tion or hydroarylation products. Interestingly, the use of
phenol and mequinol resulted in the sole formation of the cor-
responding phenoxy derivatives 6e and 6 f (Scheme 5). How-
ever, the formation in 10% yield of cyclobutenol 5c together
with adduct 6e revealed that water addition is a competitive
reaction in the case of phenol but not for mequinol. It should
be noted that aminocyclobutenyl ethers 6a–f could be isolat-
ed and characterized, but they are not as stable as related ami-
nocyclobutenols 5a–l. The higher stability of cyclobutenols
may be ascribed to hydrogen bonding, as indicated by an in-
tramolecular O10···H19 contact in the X-ray diffraction analysis
of compound 5a.
Proposed mechanisms for the formation of aminocyclobu-
tenes 4–6 from 2-(2-fluoropyridinium-1-yl)-1,1-bis(trifluorome-
thylsulfonyl)ethan-1-ide 2 and ynamides 3 are shown in
Schemes 6 and 7. It may initially involve the formation of
alkene 1, which may be considered as a resonance hybrid be-
tween dipolar and uncharged species, from zwitterion 2. Next,
the stepwise [2+2] cycloaddition reaction between ynamides 3
and the in situ-generated bis(trifluoromethylsulfonyl)ethene
1 should take place, initially leading to the zwitterionic species
7. The addition product 7 initiates a ring-closing reaction to
afford 4,4-bis(trifluoromethylsulfonyl)cyclobut-1-enamides 4.
The observed exquisite regiocontrol may arise from the stabili-
zation imparted by the amide group in intermediate 7, which
overrides the effect of the other substituent. For activated yna-
mides 3k–z’, the presence of water or alcohols in the reaction
media could trigger a rapid nucleophilic attack with concomi-
tant trifluoro(hydrosulfonyl)methane (TfH) elimination, thus
leading to the final 1-aryl-2-amino-3-(trifluoromethylsulfonyl)-
cyclobut-2-enols
5 or 4-alkoxy-4-aryl-2-(trifluoromethylsulfo-
nyl)cyclobut-1-enyl pyrrolidin-2-ones 6. The conversion of ami-
nocyclobutenes of type 4 into adducts 5 and 6 could be cata-
lyzed by protons (Scheme 7a, top side). A possible pathway
for the formation of adducts 5 and 6 may initially involve the
formation of carbocations 8 through addition of the proton to
the enamine double bond in transient 4,4-bis(trifluoromethyl-
sulfonyl)cyclobut-1-enamide intermediates 4k–z’. The driving
force of this process may be related to the stabilization of the
positive charge in intermediates 8 by electron-rich substitu-
ents. Next, intermolecular nucleophilic attack of the oxygen at
the benzylic position of cationic species 8 would form an oxo-
nium cation of type 9. Subsequent loss of TfH-generated spe-
cies 10 followed by proton release afforded aminocyclobute-
nol derivatives 5 and 6 with concurrent regeneration of the
catalyst.
The treatment of cyclobut-1-enamide 4c with water under
acidic catalysis (HCl, H2SO4 or TfOH) did result in complex reac-
tion mixtures. This experimental result, combined with the un-
usual protonation of enamides at the a-carbon, led us to pro-
pose an alternative mechanism for the formation of cyclobute-
nol derivatives 5 and 6 (Scheme 7b, bottom side). In this way,
the direct nucleophilic attack of water or alcohols into the ben-
Scheme 6. Mechanistic explanation for the synthesis of aminocyclobutenes
4 from ynamides 3 and zwitterion 2.
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zylic position should produce intermediate 10 with concomi-
tant TfÀ release.
Having developed a direct approach to aminocyclobutenol
derivatives 5a–q and 6a–f as single isomers from ynamides,
we were then interested in using the inherent ring strain[11] of
these highly functionalized four-membered carbocycles to per-
form a selective carbon–carbon bond fragmentation as a new
entry to aminoalkenes. Attempts to generate a ring-opened
structure from 5c in refluxing benzene failed. Ring opening of
substrate 5c was successfully accomplished in a microwave re-
actor by heating a solution of aminocyclobutenol 5c in tolu-
ene at 110 8C (Scheme 8). In this way, a-amino-b,g-unsaturated
Scheme 9. Ring opening of alkoxycyclobutenamines 6. Synthesis of function-
alized buta-1,3-dien-2-amines 12 and 13.
good yield. Similarly, the use of compounds 6b–f as starting
materials also efficiently promoted the fragmentation. In each
case, (Z)-1,3-dienes 12a–f were formed with total stereoselec-
tivity.[12] The crude reaction mixtures are extremely clean for
aminocyclobutenes 6b and 6d, giving dienes 12b and 12d as
the only products detected. Remarkably, the mild conditions of
the rearrangement allow the selective formation of diene 12d
without harming the sensitive allene functionality (Scheme 9).
Surprisingly, 3-(trifluoromethylsulfonyl)buta-1,3-dien-2-amines
12 can undergo a further reaction in benzene solution through
a spontaneous uncatalyzed migration process at room temper-
ature to give (1Z,3E)-1-alkoxy-1-aryl-4-(trifluoromethylsulfonyl)-
buta-1,3-dien-2-amines 13c–f (Scheme 9). To explain the con-
version of 12 into 13, we must invoke the versatility of sul-
fone-type groups, which can act as both leaving groups and as
nucleophiles.[13] Thus, the critical step in the formal triflyl mi-
gration of dienes 12 is the elimination of a trifluoromethanesul-
finate anion to afford the allenamide intermediate 14
(Scheme 10). Next, nucleophilic addition of the trifluorometha-
nesulfinate anion to the terminal allene carbon of 14 generates
zwitterionic species 15, which, after a final rearrangement, pro-
duces triflones 13 (Scheme 10).
Scheme 8. Ring opening of aminocyclobutenols 5. Synthesis of 2-amino-3-
(trifluoromethylsulfonyl)but-3-en-1-ones 11.
ketone 11 c was cleanly obtained in quantitative yield. Remark-
ably, this rearrangement was the only operative reaction
mode. Accordingly, we carried out the thermally promoted
ring opening of several adducts 5 and we smoothly obtained
the corresponding 2-amino-3-(trifluoromethylsulfonyl)but-3-en-
1-ones 11 e, 11 f, 11 h, 11 k, 11 o, and 11 q in quantitative
yields. Enantioenriched oxazolidinone 11 k was formed as dia-
steromeric mixture (d.r.=65:35) at the newly generated stereo-
genic center. In all these cases, we once again observed the
sole formation of the b,g-unsaturated ketone (Scheme 8). It
should be noted that traditional strategies for the preparation
of functionalized b,g-unsaturated ketones are problematic
owing to the possible isomerisation to the a,b-unsaturated
ketone.
Scheme 10. Mechanistic explanation for the formal triflyl migration in dienes
12.
Conclusions
In conclusion, the [2+2] cycloaddition of ynamides with the
highly polarized reagent Tf2C=CH2 regioselectively afforded
bis(triflyl)aminocyclobutenes in the absence of catalyst under
mild conditions. Incidentally, with ynamides bearing electron-
rich aromatic rings at the C-terminal, an interesting reactivity
switch was observed. In such cases, a cyclization/hydroxylation
sequence yielded 2-amino-3-(triflyl)cyclobut-2-enols. The study
of aminocyclobutene formation with addition of alcohols re-
sulted in the formation of aminocyclobutenyl ethers through
a cyclization/hydroalkoxylation process. Moreover, the utility of
The utility of 4-alkoxy-4-aryl-2-(trifluoromethylsulfonyl)cyclo-
but-1-enyl pyrrolidin-2-ones as precursors for further elabora-
tion is demonstrated in Scheme 9. When adduct 6a was dis-
solved in benzene at room temperature, the 4p-electrocyclic
ring opening to placeto give the (Z)-1-methoxy-1-aryl-3-(tri-
fluoromethylsulfonyl)buta-1,3-dien-2-amine derivative 12a in
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analytically pure compounds. Spectroscopic and analytical data for
aminocyclobutenols 5 follow.
functionalized aminocyclobutenes as precursors for further
elaboration was demonstrated with the preparation of a-
amino-b,g-unsaturated ketones and 3-(triflyl)buta-1,3-dien-2-
amines through 4p-electrocyclic ring opening.
1-Aryl-2-amino-3-(trifluoromethylsulfonyl)cyclobut-2-enol
5a:
From ynamide 3k (50 mg, 0.23 mmol), flash chromatography of
the residue using hexanes/ethyl acetate (97:3) as eluent gave com-
pound 5a (60 mg, 64%) as a colorless solid. M.p. 116–1188C;
1H NMR (300 MHz, CDCl3, 258C): d=7.32 (m, 2H, 2CHAr), 6.91 (m,
2H, 2CHAr), 4.58 (m, 3H, CH2, OH), 4.36 (m, 1H, CHH), 4.22 (m, 1H,
CHH), 3.82 (s, 3H, OCH3), 3.19 (d, 1H, J=10.4 Hz, CHH-cyclobutene),
2.88 ppm (d, 1H, J=10.4 Hz, CHH-cyclobutene); 13C NMR (75 MHz,
CDCl3, 258C): d=159.4 (CAr–qÀOCH3), 155.3 (C=O), 154.2 (C=C-N),
132.1 (CAr–q), 125.0 (2CHAr), 119.9 (q, J(C,F)=325.6 Hz, CF3), 114.2
(2CHAr), 101.1 (C=C-N), 77.8 (Cq-OH), 64.4 (CH2), 55.2 (OCH3), 45.4
(CH2), 44.8 ppm (CH2); 19F NMR (282 MHz, CDCl3, 258C): d=
À78.34 ppm (s, 3F, CF3); IR (CHCl3): n˜ =3483 (OH), 1770 (C=O), 1620
(C=C), 1398, 1127 (O=S=O), 1198 cmÀ1 (CÀF); HRMS (ES): calcd for
C15H14NO6SF3 [M]+: 393.0494; found: 393.0478. X-ray data of 5a:
crystallized from ethyl acetate/n-hexane at 208C; C15H14F3NO6S
(Mr =393.33); orthorhombic; space group=Pbca; a=8.8736(6), b=
19.2477(14), c=39.638(3) Š; a=90, b=90, g=908; V=
6770.1(8) Š3; Z=16; cd=1.544 mgmÀ3; m=0.256 mmÀ1; F(000)=
3232. 5974 (Rint =0.0939) independent reflections were collected
on a Bruker Smart CCD difractomer using graphite-monochromat-
ed MoKa radiation (l=0.71073 Š) operating at 50 kV and 35 mA.
The structure was solved by direct methods and was refined by
full-matrix least-squares procedures on F2 (SHELXL-97). All non-hy-
drogen atoms were refined anisotropically. All hydrogen atoms
were included in calculated positions and refined riding on the re-
spective carbon atoms. Final R indices [I>2s(I)] values were R1
(reflns obsd)=0.0513 (2529), wR2 (all data)=0.1533.[9]
Experimental Section
1
General methods: H NMR and 13C NMR spectra were recorded on
a Bruker Avance AVIII-700 with cryoprobe, Bruker AMX-500, Bruker
Avance-300, or Varian VRX-300S. NMR spectra were recorded in
CDCl3 solutions, except otherwise stated. Chemical shifts are given
in ppm relative to TMS (1H:, d=0.0 ppm), or CDCl3 (1H: d=
7.27 ppm; 13C: d=76.9 ppm), or [D6]acetone (1H: d=2.0 ppm; 13C:
d=206.3 ppm), or C6D6 (1H: d=7.16 ppm; 13C: d=128.0 ppm), or
CD3CN (1H: d=2.0 ppm; 13C: d=118.2 ppm). Low- and high-resolu-
tion mass spectra were taken on an AGILENT 6520 Accurate-Mass
QTOF LC/MS spectrometer using the electronic impact (EI) or elec-
trospray modes (ES) unless otherwise stated. IR spectra were re-
corded on a Bruker Tensor 27 spectrometer. X-Ray crystallographic
data were collected on a Bruker Smart CCD difractomer using
graphite-monochromated MoKa radiation (l=0.71073 Š) operating
at 50 Kv and 35 mA with an exposure of 30.18 s in w. Specific rota-
tion [a]D is given in 10À1 degcm2 gÀ1 at 208C, and the concentra-
tion (c) is expressed in g per 100 mL. All commercially available
compounds were used without further purification.
Synthetic procedures
General procedure for 4-alkoxy-4-aryl-2-(trifluoromethylsulfo-
nyl)cyclobut-1-enyl pyrrolidin-2-ones 6a–f: 2-(2-Fluoropyridin-1-
ium-1-yl)-1,1-bis[(trifluoromethyl)sulfonyl]ethan-1-ide 2 (0.1 mmol)
and the corresponding alcohol or phenol (0.15 mmol) were se-
quentially added at room temperature to a solution of ynamide
3m (0.1 mmol) in acetonitrile (1 mL). The reaction was stirred at
room temperature until the starting material had disappeared
(TLC), and then the mixture was concentrated under reduced pres-
sure. Chromatography of the residue on silica gel eluting with hex-
anes/ethyl acetate mixtures gave analytically pure compounds.
Spectroscopic and analytical data for aminocyclobutenyl ethers 6
follow.
General procedure for 4,4-bis(trifluoromethylsulfonyl)cyclobut-
1-enamides 4a–j: 2-(2-Fluoropyridin-1-ium-1-yl)-1,1-bis[(trifluoro-
methyl)sulfonyl]ethan-1-ide 2 (1.0 mmol) was added at room tem-
perature to a solution of the appropriate ynamide 3a–j (1.0 mmol)
in acetonitrile (10 mL). The reaction was stirred at room tempera-
ture until the starting material had disappeared (instantaneous re-
action), and then the mixture was concentrated under reduced
pressure. Chromatography of the residue on silica gel eluting with
hexanes/ethyl acetate mixtures gave analytically pure compounds.
Spectroscopic and analytical data for aminocyclobutenes
follow.[14]
4
4,4-Bis(trifluoromethylsulfonyl)cyclobut-1-enamide 4a: From
ynamide 3a (30 mg, 0.16 mmol), flash chromatography of the resi-
due using hexanes/ethyl acetate (9:1) as eluent gave compound
4a (72 mg, 94%) as a colorless solid. M.p. 112–1148C; 1H NMR
(300 MHz, CDCl3, 258C): d=7.45 (m, 5H, CHAr), 4.52 (dd, 2H, J=8.7,
7.1 Hz, CH2), 4.07 (dd, 2H, J=8.9, 6.9 Hz, CH2), 3.53 ppm (s, 2H,
CH2-cyclobutene); 13C NMR (75 MHz, CDCl3, 258C): d=154.0 (C=O),
147.8 (C=C-N), 131.9 (CHAr), 129.1 (C=C-N), 128.9 (2CHAr), 128.4
(2CHAr), 119.8 (q, J(C,F)=331.3 Hz, 2CF3), 117.9 (CAr–q), 88.4 (CTf2),
63.1 (CH2), 44.8 (CH2), 31.8 ppm (CH2); 19F NMR (282 MHz, CDCl3,
258C): d=À69.87 ppm (s, 6F, 2CF3); IR (CHCl3): n˜ =1771 (C=O),
1669 (C=C), 1380, 1104 (O=S=O), 1201 cmÀ1 (CÀF); HRMS (ES):
calcd for C15H11NO6S2F6 [M]+: 478.9932; found: 478.9928.
4-Alkoxy-4-aryl-2-(trifluoromethylsulfonyl)cyclobut-1-enyl pyrro-
lidin-2-one 6d: From ynamide 3m (30 mg, 0.139 mmol), flash
chromatography of the residue using hexanes/ethyl acetate
(95:5!9:1) as eluent gave compound 6d (42 mg, 68%) as a color-
1
less oil. H NMR (300 MHz, C6D6, 258C): d=7.61 (m, 2H, 2CHAr), 6.79
(m, 2H, 2CHAr), 5.34 (m, 1H, CH=·=CH2), 4.65 (m, 2H, CH=·=
CH2), 4.11 (m, 1H, OCHH), 3.97 (m, 1H, OCHH), 3.38 (m, 2H, CH2),
3.28 (m, 4H, OCH3, CHH-cyclobutene), 2.95 (d, 1H, J=11.2 Hz, CHH-
cyclobutene), 1.38 (m, 2H, CH2), 0.87 ppm (m, 2H, CH2); 13C NMR
(75 MHz, C6D6, 258C): d=209.2 (C=C=C), 172.3 (C=O), 159.8 (CAr–q
À
OCH3), 156.1 (C=C-N), 130.6 (CAr–q), 126.8 (2CHAr), 120.9 (q, J(C,F)=
326.9 Hz, CF3), 114.1 (2CHAr), 100.5 (C=C-N), 88.6 (CH=C=CH2), 83.4
(CCq-OCH2CH=C=CH2), 76.3 (CH=C=CH2), 63.5 (OCH2), 54.8 (OCH3),
48.0 (CH2), 42.2 (CH2), 29.6 (CH2), 18.0 ppm (CH2); 19F NMR
(282 MHz, C6D6, 258C): d=À77.64 ppm (s, 3F, CF3); IR (CH2Cl2): n˜ =
1958 (C=C=C), 1761 (C=O), 1596 (C=C), 1365, 1112 (O=S=O),
1208 (CÀO), 1185 cmÀ1 (CÀF); HRMS (ES): calcd for C20H20NO5SF3
[M]+: 443.1014; found: 443.1016.
General procedure for 1-substituted-2-amino-3-(trifluoromethyl-
sulfonyl)cyclobut-2-enols 5a–q: 2-(2-Fluoropyridin-1-ium-1-yl)-1,1-
bis[(trifluoromethyl)sulfonyl]ethan-1-ide 2 (1.0 mmol) and water
(1.5 mmol) were sequentially added at room temperature to a solu-
tion of the appropriate ynamide 3k–z’ (1.0 mmol) in acetonitrile
(10 mL). The reaction was stirred at room temperature until the
starting material had disappeared (TLC), and then the mixture was
concentrated under reduced pressure. Chromatography of the resi-
due on silica gel eluting with hexanes/ethyl acetate mixtures gave
General procedure for 2-amino-3-(trifluoromethylsulfonyl)but-3-
en-1-ones 11: A stirred solution of the appropriate aminocyclobu-
tenol 5 (0.1 mmol) in toluene (2.0 mL) was heated at 110 8C under
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Full Paper
microwave irradiation until the starting material had disappeared
(TLC). The reaction was allowed to cool to room temperature and
concentrated under vacuum. Further purification was not necessa-
ry. Spectroscopic and analytical data for pure forms of compound
11 c follow.
O), 1580 (C=C), 1358, 1117 (O=S=O), 1205 cmÀ1 (CÀF); HRMS (ES):
calcd for C22H20NO5SF3 [M]+: 467.1014; found: 467.1019.
Acknowledgements
2-Amino-3-(trifluoromethylsulfonyl)but-3-en-1-one 11 c: From
aminocyclobutenol 5c (36 mg, 0.09 mmol), compound 11 c (36 mg,
quantitative yield) was obtained as a green pale oil. 1H NMR
(300 MHz, CDCl3, 258C): d=7.99 (m, 2H, 2CHAr), 6.97 (m, 2H,
2CHAr), 6.95 (d, 1H, J=1.9 Hz=CHH), 6.75 (s, 1H, CH-N), 6.55 (s, 1H,
=CHH), 3.89 (s, 3H, OCH3), 3.60 (m, 1H, CHH), 3.35 (m, 1H, CHH),
2.45 (m, 2H, CH2), 2.07 ppm (m, 2H, CH2); 13C NMR (75 MHz, CDCl3,
258C): d=191.1 (C=O), 175.9 (NC=O), 164.7 (CAr–qÀOCH3), 140.1 (=
CH2), 139.2 (=C-Tf), 131.3 (2CHAr), 126.5 (CAr–q), 119.6 (q, J(C,F)=
327.1 Hz, CF3), 114.4 (2CHAr), 55.6 (OCH3), 53.7 (CH-N), 44.8 (CH2),
30.5 (CH2), 18.4 ppm (CH2); 19F NMR (282 MHz, CDCl3, 258C): d=
À77.41 ppm (s, 3F, CF3); IR (CH2Cl2): n˜ =1690 (NC=O, C=O), 1601
(C=C), 1366, 1104 (O=S=O), 1213 cmÀ1 (CÀF); HRMS (ES): calcd
for C16H16NO5SF3 [M]+: 391.0701; found: 391.0698.
Financial support from the MINECO and FEDER (Projects
CTQ2012-33664-C02-01, CTQ2012-33664-C02-02, CTQ2015-
65060-C2-1-P, and CTQ2015-65060-C2-2-P) is gratefully ac-
knowledged. We thank Prof. H. Yanai for the kind donation of
bis(trifluoromethylsulfonyl)methane. We are grateful to Dr.
M. R. Torres for X-ray analysis.
Keywords: alkynes · amides · cyclization · fluorine · small ring
systems
[1] For selected references and reviews, see: a) M. J. Ralph, D. C. Harrowv-
en, S. Gaulier, S. Ng, K. I. Booker-Milburn, Angew. Chem. Int. Ed. 2015, 54,
1527; Angew. Chem. 2015, 127, 1547; b) S. Yang, W. Yuan, Q. Xu, M. Shi,
Chem. Eur. J. 2015, 21, 15964; c) J. Hartung, R. H. Grubbs, Angew. Chem.
Int. Ed. 2014, 53, 3885; Angew. Chem. 2014, 126, 3966; d) Y. Wang, M. E.
Muratore, Z. Rong, A. M. Echavarren, Angew. Chem. Int. Ed. 2014, 53,
14022; Angew. Chem. 2014, 126, 14246; e) K.-i. Takao, R. Nanamiya, Y.
Fukushima, A. Namba, K. Yoshida, K.-i. Tadano, Org. Lett. 2013, 15, 5582;
f) C. Souris, M. Luparia, F. FrØbault, D. Audisio, C. Far›s, R. Goddard, N.
Maulide, Chem. Eur. J. 2013, 19, 6566; g) W. R. Gutekunst, R. Gianatassio,
P. S. Baran, Angew. Chem. Int. Ed. 2012, 51, 7507; Angew. Chem. 2012,
124, 7625; h) R. Liu, M. Zhang, T. P. Wyche, G. N. Winston-McPherson,
T. S. Bugni, W. Tang, Angew. Chem. Int. Ed. 2012, 51, 7503; Angew. Chem.
2012, 124, 7621; i) A. Masarwa, A. Fürstner, I. Marek, Chem. Commun.
2009, 5760; j) M. Shi, L.-P. Liu, J. Tang, J. Am. Chem. Soc. 2006, 128,
7430; k) V. M. Dembitsky, J. Nat. Med. 2008, 62, 1; l) J. C. Namyslo, D. E.
Kaufmann, Chem. Rev. 2003, 103, 1485; m) E. Lee-Ruff, G. Mladenova,
Chem. Rev. 2003, 103, 1449.
[2] a) X.-N. Wang, E. H. Krenske, R. C. Johnston, K. N. Houk, R. P. Hsung, J.
Am. Chem. Soc. 2014, 136, 9802; b) X.-N. Wang, E. H. Krenske, R. C. John-
ston, K. N. Houk, R. P. Hsung, J. Am. Chem. Soc. 2015, 137, 5596; c) X.
Xin, D. Wang, F. Wu, C. Wang, H. Wang, X. Li, aB. Wan, Org. Lett. 2013,
15, 4512.
[3] a) J. Ficini, A. Krief, Tetrahedron Lett. 1969, 10, 1431; b) J. Ficini, J. Pouli-
que, Tetrahedron Lett. 1972, 13, 1135; c) J. Ficini, A. M. Touzin, Tetrahe-
dron Lett. 1974, 15, 1447; d) J. Ficini, A. Krief, A. Guingant, D. Desmaele,
Tetrahedron Lett. 1981, 22, 725; e) J. Ficini, A. Guingant, J. Dangelo, G.
Stork, Tetrahedron Lett. 1983, 24, 907.
General procedure for the synthesis of buta-1,3-dien-2-amines
12:
A solution of the appropriate alkoxycyclobutenamine 6
(0.1 mmol) in benzene (0.1 mL) was stirred at room temperature
until the starting material had disappeared (TLC). Then, the mixture
was concentrated under reduced pressure. Chromatography of the
residue on silica gel eluting with hexanes/ethyl acetate mixtures
gave analytically pure compounds. Spectroscopic and analytical
data for buta-1,3-dien-2-amines 12 follow.
Buta-1,3-dien-2-amine 12a: From aminocyclobutenyl ether 6a
(20 mg, 0.049 mmol), flash chromatography of the residue using
hexanes/ethyl acetate (8:2) as eluent gave compound 12a (15 mg,
1
75%) as a bright yellow oil. H NMR (500 MHz, C6D6, 258C): d=7.08
(m, 2H, 2CHAr), 6.56 (m, 2H, 2CHAr), 6.27 (s, 1H, =CHH), 6.08 (s, 1H,
=CHH), 3.59 (t, 2H, J=7.1 Hz, CH2), 3.14 (s, 3H, OCH3), 3.07 (s, 3H,
OCH3), 2.08 (t, 2H, J=8.1 Hz, CH2), 1.56 ppm (m, 2H, CH2); 13C NMR
(125 MHz, C6D6, 258C): d=175.0 (C=O), 161.0 (CAr–qÀOCH3), 159.1
(C=C-N), 142.0 (=CH2), 140.7 (C=C-N), 131.5 (2CHAr), 123.3 (CAr–q),
120.5 (q, J(C,F)=327.8 Hz, CF3), 114.3 (2CHAr), 112.0 (=C-Tf), 56.8
(OCH3), 54.7 (OCH3), 48.0 (CH2), 30.6 (CH2), 19.0 ppm (CH2); 19F NMR
(282 MHz, C6D6, 258C): d=À78.15 ppm (s, 3F, CF3); IR (CH2Cl2): n˜ =
1698 (C=O), 1606 (C=C), 1360, 1115 (O=S=O), 1209 cmÀ1 (CÀF);
HRMS (ES): calcd for C17H18NO5SF3 [M]+: 405.0858; found: 405.0868.
General procedure for the synthesis of buta-1,3-dien-2-amines
13:
A solution of the appropriate buta-1,3-dien-2-amine 12
(0.1 mmol) in benzene (0.1 mL) was stirred at room temperature
until the starting material had disappeared (TLC). Then, the mixture
was concentrated under reduced pressure. Chromatography of the
residue on silica gel eluting with hexanes/ethyl acetate mixtures
gave analytically pure compounds. Spectroscopic and analytical
data for buta-1,3-dien-2-amines 13 follow.
[4] For selected recent reviews, see: a) A. M. Cook, C. Wolf, Tetrahedron Lett.
2015, 56, 2377; b) G. Evano, C. Theunisen, M. Lecomte, Aldrichimica
Acta 2015, 48, 59; c) X.-N. Wang, S.-Z. He, L. Fang, H.-S. Yeom, B. L. Ke-
drowski, R. P. Hsung, Acc. Chem. Res. 2014, 47, 560; d) G. Evano, A.
Coste, K. Jouvin, Angew. Chem. Int. Ed. 2010, 49, 2840; Angew. Chem.
2010, 122, 2902; e) K. A. DeKorver, H. Li, A. G. Lohse, R. Hayashi, Z. Lu, Y.
Zhang, R. P. Hsung, Chem. Rev. 2010, 110, 5064.
Buta-1,3-dien-2-amine 13e: From buta-1,3-dien-2-amine 12e
(14 mg, 0.029 mmol), flash chromatography of the residue using
hexanes/ethyl acetate (8:2!7:3) as eluent gave compound 13e
(9.4 mg, 67%) as a bright yellow oil; 1H NMR (300 MHz, C6D6,
258C): d=7.91 (d, 1H, J=14.7 Hz, TfÀCH=CH), 7.13 (m, 2H, 2CHAr),
6.96 (m, 2H, 2CHAr), 6.87 (m, 2H, 2CHAr), 6.65 (m, 1H, CHAr), 6.42 (m,
2H, 2CHAr), 6.32 (d, 1H, J=14.7 Hz, TfÀCH=CH), 2.95 (s, 5H, OCH3,
CH2), 1.85 (t, 2H, J=8.0 Hz, CH2), 1.20 ppm (m, 2H, CH2); 13C NMR
[5] a) K. Villeneuve, N. Riddell, W. Tam, Tetrahedron 2006, 62, 3823; b) H. Y.
Li, R. P. Hsung, K. A. DeKorver, Y. G. Wei, Org. Lett. 2010, 12, 3780; c) C.
Schotes, A. Mezzetti, Angew. Chem. Int. Ed. 2011, 50, 3072; Angew.
Chem. 2011, 123, 3128; d) C. Schotes, M. Althaus, R. Aardoom, A. Mez-
zetti, J. Am. Chem. Soc. 2012, 134, 1331; e) C. Schotes, R. Bigler, A. Mez-
zetti, Synthesis 2012, 44, 513; f) D. L. Smith, S. R. Chidipudi, W. R. Goun-
dry, H. W. Lam, Org. Lett. 2012, 14, 4934; g) P. R. Walker, C. D. Campbell,
A. Suleman, G. Carr, E. A. Anderson, Angew. Chem. Int. Ed. 2013, 52,
9139; Angew. Chem. 2013, 125, 9309; h) K. Enomoto, H. Oyama, M.
Nakada, Chem. Eur. J. 2015, 21, 2798.
[6] H. Yanai, T. Yoshino, M. Fujita, H. Fukaya, A. Kotani, F. Kusu, T. Taguchi,
Angew. Chem. Int. Ed. 2013, 52, 1560; Angew. Chem. 2013, 125, 1600.
[7] a) H. Yanai, M. Fujita, T. Taguchi, Chem. Commun. 2011, 47, 7245; b) H.
Yanai, Y. Takahashi, H. Fukaya, Y. Dobashi, T. Matsumoto, Chem.
Commun. 2013, 49, 10091; c) B. Alcaide, P. Almendros, I. Fernµndez, C.
(75 MHz, C6D6, 258C): d=174.0 (C=O), 165.0 (C=C-N) 162.4 (CAr–q
À
OCH3), 156.3 (CAr–qÀO-C=), 150.0 (TfÀCH=CH), 132.9 (2CHAr), 129.7
(2CHAr), 124.3 (CHAr), 123.2 (CAr–q), 120.8 (q, J(C,F)=324.7 Hz, CF3),
119.6 (2CHAr), 119.2 (C=C-N), 114.4 (2CHAr), 113.5 (TfÀCH=CH), 54.7
(OCH3), 46.8 (CH2), 30.1 (CH2), 18.9 ppm (CH2); 19F NMR (282 MHz,
C6D6, 258C): d=À78.12 ppm (s, 3F, CF3); IR (CH2Cl2): n˜ =1705 (C=
Chem. Eur. J. 2016, 22, 8998 – 9005
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Lµzaro-Milla, Chem. Commun. 2015, 51, 3395; d) B. Alcaide, P. Almen-
dros, C. Lµzaro-Milla, Chem. Commun. 2015, 51, 6992.
Okamoto, T. Shimbayashi, E. Tamura, K. Ohe, Org. Lett. 2015, 17, 5843;
d) C. Souris, A. Misale, Y. Chen, M. Luparia, N. Maulide, Org. Lett. 2015,
17, 4486; e) T. Matsuda, N. Miura, Org. Biomol. Chem. 2013, 11, 3424;
f) M. Murakami, Y. Miyamoto, Y. Ito, J. Am. Chem. Soc. 2001, 123, 6441.
[12] The stereochemistry of dienes 12 was unambiguously determined by
the NOE analysis of compounds 12a–f.
[13] C. S. Hampton, M. Harmata, J. Org. Chem. 2015, 80, 12151.
[14] Experimental procedures, as well as full spectroscopic and analytical
data, for compounds not included in this Experimental Section are de-
scribed in the Supporting Information. It contains compound character-
ization data, experimental procedures, and copies of NMR spectra for
all new compounds.
[8] Aminocyclobutenes 4 bear the SO2CF3 group, a fluorinated functionality
that is able to transform the chemical properties of organic compounds
without altering the molecular complexity; see: a) Z. Huang, C. Wang, E.
Tokunaga, Y. Sumii, N. Shibata, Org. Lett. 2015, 17, 5610; b) H. Kawai, Y.
Sugita, E. Tokunaga, H. Sato, M. Shiro, N. Shibata, ChemistryOpen 2014,
3, 14 and references therein.
[9] CCDC 1023371 (5a) contains the supplementary crystallographic data
for this paper. These data are provided free of charge by The Cam-
bridge Crystallographic Data Centre.
[10] a) B. Alcaide, P. Almendros, M. T. Quirós, R. López, M. I. MenØndez, A. So-
´
chacka-Cwikła, J. Am. Chem. Soc. 2013, 135, 898; b) K. Seth, S. R. Roy,
B. V. Pipaliya, A. K. Chakraborti, Chem. Commun. 2013, 49, 5886.
[11] For the ring opening of cyclobutenes, see: a) C. Zhao, L.-C. Liu, J. Wang,
C. Jiang, Q.-W. Zhang, W. He, Org. Lett. 2016, 18, 328; b) N. Arichi, K.
Yamada, Y. Yamaoka, K. Takasu, J. Am. Chem. Soc. 2015, 137, 9579; c) K.
Received: March 4, 2016
Published online on May 27, 2016
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim