Synthesis of polycyclic aminocyclobutane systems by the rearrangement of N-(ortho-Vinylphenyl) 2-Azabicyclo[3.1.0]hexane derivatives

Article abstract of DOI:10.1002/chem.201300871

The acid-catalysed thermal rearrangements of a family of N-aryl 2-azabicyclo[3.1.0]hexanes is described. These substrates, designed in such a way that the aromatic system is conjugated with an alkene group located at the ortho position relative to the nitrogen atom, have been prepared by using an intramolecular Kulinkovich-de Meijere reaction. The rearrangements can then be conducted either under standard thermal conditions or with microwave activation. Depending on the conditions applied and the substitution pattern, dihydroquinoline or polycyclic aminocyclobutane derivatives can be obtained. A mechanistic discussion is provided, with the proposition of the initial protonation of the aminocyclopropane moiety to give an iminium intermediate. By analogy with related intermolecular reactions, the involvement of electrocyclic reactions among the series of elementary steps that follow is put forward. Small rings: The acid-catalysed rearrangement of bicyclic N-aryl aminocyclopropanes with an alkene group located at the ortho position, either under standard thermal conditions or with microwave activation, is described (see scheme). The method provides access to dihydroquinoline and polycyclic aminocyclobutane derivatives. By analogy with related intermolecular reactions, the involvement of an electrocyclic reaction is proposed. Copyright

Full text of DOI:10.1002/chem.201300871

FULL PAPER
Small rings: The acid-catalysed rear-
rangement of bicyclic N-aryl aminocy-
clopropanes with an alkene group
located at the ortho position, either
under standard thermal conditions or
with microwave activation, is described
(see scheme). The method provides
access to dihydroquinoline and polycy-
clic aminocyclobutane derivatives. By
analogy with related intermolecular
reactions, the involvement of electro-
cyclic reactions is proposed.
Electrocyclic Reactions
´
A. Wasilewska, B. A. Wozniak,
G. Doridot, K. Piotrowska,
N. Witkowska, P. Retailleau,
Y. Six* .......................... &&&& — &&&&
Synthesis of Polycyclic Aminocyclobu-
tane Systems by the Rearrangement of
N-(ortho-Vinylphenyl) 2-Azabicyclo-
AHCTUNGTERG[NNUN 3.1.0]hexane Derivatives
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
1
&
ÞÞ
These are not the final page numbers!

DOI: 10.1002/chem.201300871
Synthesis of Polycyclic Aminocyclobutane Systems by the Rearrangement of
N-(ortho-Vinylphenyl) 2-AzabicycloACHTUNTRGNEUNG[3.1.0]hexane Derivatives
Agnieszka Wasilewska,[a, b] Bartosz A. Wozniak,[a, b] Gabriel Doridot,[c]
´
Kamila Piotrowska,[a, d] Natalia Witkowska,[a, d] Pascal Retailleau,[c] and Yvan Six*[a]
Dedicated to Professor William B. Motherwell on the occasion of his retirement
Abstract: The acid-catalysed thermal
rearrangements of a family of N-aryl 2-
azabicycloACHTUNGTRENNUNG[3.1.0]hexanes is described.
ard thermal conditions or with micro-
wave activation. Depending on the
conditions applied and the substitution
pattern, dihydroquinoline or polycyclic
aminocyclobutane derivatives can be
obtained. A mechanistic discussion is
provided, with the proposition of the
initial protonation of the aminocyclo-
propane moiety to give an iminium in-
termediate. By analogy with related in-
termolecular reactions, the involvement
of electrocyclic reactions among the
series of elementary steps that follow is
put forward.
These substrates, designed in such a
way that the aromatic system is conju-
gated with an alkene group located at
the ortho position relative to the nitro-
gen atom, have been prepared by using
an intramolecular Kulinkovich–de Mei-
jere reaction. The rearrangements can
then be conducted either under stand-
Keywords: electrocyclic reactions ·
iminium compounds · microwave
chemistry · small ring systems · tita-
nium
Introduction
trogen-containing polycyclic systems.[6,7] A few years ago, we
reported the acid-catalysed thermal cyclisation of suitably
substituted substrates 1.[7b] These transformations proceed
by initial protonation of the cyclopropane. The iminium ion
A thus generated can participate in an intramolecular aro-
matic electrophilic substitution reaction (Scheme 1, top). In
The invention of the de Meijere variation of the Kulinkovich
reaction, in the middle of the 1990s, has opened a new and
simple route to aminocyclopropanes.[1,2,3] Work conducted in
this area has established the broad applicability of this tita-
nium-promoted transformation of carboxylic amides,
making it one of the methods of choice for the preparation
of cyclopropylamine derivatives.[4] In particular, it performs
well in the synthesis of bicyclic aminocyclopropanes.[5] These
molecules are not only interesting by themselves; they can
also be used as precursors for the construction of various ni-
´
[a] A. Wasilewska, B. A. Wozniak, K. Piotrowska, N. Witkowska,
Dr. Y. Six
Laboratoire de Synthꢁse Organique DCSO
UMR 7652 CNRS/Ecole Polytechnique
91128 Palaiseau Cedex (France)
Fax : (+33)1-6933-5972
Scheme 1. Reported reaction of 1 and anticipated rearrangement of sub-
strates 2.
E-mail: six@dcso.polytechnique.fr
´
[b] A. Wasilewska, B. A. Wozniak
Faculty of Chemistry, Nicolaus Copernicus University
´
Gagarina 7, 87-100 Torun (Poland)
the present contribution, we wanted to investigate whether
this scheme could be transposed to aminocyclopropanes of
type 2, bearing an alkenyl substituent at the ortho position.
After protonation, we anticipated that the corresponding
[c] Dr. G. Doridot, Dr. P. Retailleau
Centre de recherche de Gif
Institut de Chimie des Substances Naturelles
CNRS, avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex (France)
[d] K. Piotrowska, N. Witkowska
iminium species
B could undergo electrocyclisation to
Department of Chemistry, Faculty of Organic Stereochemistry
Adam Mickiewicz University
cation C. This intermediate would eventually lose a proton
and produce dihydroquinoline derivatives 3 (Scheme 1,
bottom). Molecules possessing this type of skeleton have
been reported to exhibit biological properties such as inhibi-
´
Umultowska 89B, 61-614 Poznan (Poland)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300871.
&
2
&
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Synthesis of Polycyclic Aminocyclobutanes
FULL PAPER
tion of recombinant human methionine aminopeptidase 2
(MetAP2),[8] antimicrobial activity against E. coli,[9] or
human androgen receptor (hAR) antagonist activity.[10]
Results and Discussion
Synthesis of the aminocyclopropane rearrangement precur-
sors: To test our hypothesis, we prepared three compounds
of type 2, derived from the aromatic amines 4a–c. These
were acetylated and then alkylated following an adaptation
of the protocol reported by Gajda and Zwierzak.[11] The N-
alkenylamides 5, thus obtained, were submitted to a Kulin-
kovich–de Meijere (KdM) reaction with ligand exchange,[4,12]
which afforded the corresponding bicyclic aminocyclopro-
panes as expected (Table 1).
Scheme 2. Syntheses of 2a and 2c by the functionalisation of 6a and 6c.
Starting from 5a, we noticed that the aminocyclopropane
6a was accompanied by a minor amount of the debrominat-
ed N-phenyl analogue 7a. Because this by-product could
stem from an ortho-metalated N-arylaminocyclopropane, in-
itially generated by bromine-magnesium exchange from 6a,
we tried to make use of this process to functionalise the aro-
Scheme 3. One-pot preparation of 8c from N-alkenylamide 5c.
dependent on the quality of the reagent, and com-
plete conversion proved difficult to achieve. Inter-
estingly, 2c was also obtained, albeit in low yield
(25%), when Swern oxidation of alcohol 8c was
attempted (Scheme 2, bottom). This unexpected
reaction outcome is rare but not unprecedented.[14]
In our case, an E1 mechanism, as depicted in
Scheme 4, can be invoked. An intramolecular E2
mechanism involving a six-membered transition
state could also be envisaged, with the nitrogen
atom of the substrate playing the role of the base.
Table 1. Construction of the 2-azabicycloACTHNUTRGNE[NUG 3.1.0]hexane framework.
Amine 4
Yield of
ArNHAc [%] [%]
Yield of 5
Yield of bicyclic amino
[%]
ACHUTGTNRENcNUG ycloHCATUNGTRENNpUGN ropane
78
86
75
5a 63–99[a,b]
74–88[a]
Thermal rearrangements: When 2a was heated to
reflux in chlorobenzene in the presence of one
equivalent of 10-camphorsulfonic acid (CSA), the
benzoindolizidine compound 3a we had anticipat-
ed was not observed. Instead, cyclobuta[b]pyrrolo-
5b 87
5c 58
77
78
AHCTUNGTREGUN[NN 1,2a]indole 9a was produced, with 65:35 diaster-
[a] The reaction was performed several times. [b] The reaction was carried out either
under standard heating conditions or by using a microwave device.
eoselectivity (Scheme 5, top). To the best of our
knowledge, no other compound with this tetracy-
clic skeleton has been reported. Starting from iso-
matic ortho position. However, even when 5–6 equivalents
of Grignard reagent were employed, 6a remained the main
product. Moreover, the minor ortho-metalated intermediate
failed to react with acetaldehyde to produce alcohol 8a,[13]
although it could be trapped with D2O. In contrast, bro-
mine–lithium exchange using two equivalents of tert-butyl-
lithium was successful, starting from either 6a or 6c
(Scheme 2). Alternatively, tert-butyllithium could be engag-
ed in a one-pot process, as illustrated in Scheme 3, in which
8c is accessed in 56% yield directly from 5c. Dehydration
of benzyl alcohols 8a and 8c with phosphorus pentoxide fur-
nished the corresponding olefin targets 2a and 2c in varia-
ble yields: the success of this transformation appeared to be
propenyl homologue 2b, a faster reaction occurred that pro-
ceeded as initially planned. Benzoindolizidine 3b, produced
as a nearly 50:50 mixture of diastereoisomers, was isolated
in 63% yield (Scheme 5, middle). In contrast, cyclobutane
Scheme 4. Proposed mechanism for the elimination of alcohol 8c under
the conditions of the Swern reaction.
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
3
&
ÞÞ
These are not the final page numbers!

Y. Six et al.
Scheme 7. Direct transformation of 8c into the pentacycle 9c.
Mechanistic aspects: Our results present a distinct analogy
with findings reported by Walter et al. in the 1990s,[15,16] in-
volving the condensation of 2-vinylaniline derivatives with
ketones (Scheme 8). These authors proposed that the initial-
Scheme 5. Thermal rearrangements of 2a and 2b under acidic conditions.
derivative 9b was obtained when
a substoichiometric
amount of acid was employed (Scheme 5, bottom).
The rearrangements of 2a and 2b could also be conducted
under microwave activation, in PhCl or in DMF, with no
qualitative change except for much shorter reaction times
(Scheme 6). Under such conditions, naphthalene derivative
Scheme 8. Reported examples of condensations of 2-isopropenylaniline
4b with ketones.[15b,16a]
ly formed imine can follow two alternative reaction path-
ways: either a six-electron electrocyclisation, eventually
leading to the formation of a 1,2-dihydroquinoline deriva-
tive, or tautomerisation to an enamine that cyclises into a
cyclobuta[b]indole compound via an azomethine ylide inter-
mediate.
Because the acid-catalysed cyclopropane ring openings of
bicyclic aminocyclopropanes are known to generate cyclic
iminium species or enamine intermediates,[7,17] a reasonable
explanation for the rearrangements observed can be put for-
ward by adapting Walterꢂs mechanism (Scheme 9).
Thus, at sufficiently high temperature, substrate 2 can un-
dergo irreversible protonation at the cyclopropane ring.[18]
An equilibrium between the resulting iminium B and the
two possible corresponding enamines D and E can then
take place by the means of proton loss/reprotonation. It is
expected that, whereas the use of a stoichiometric amount
of acid shifts this equilibrium towards B, catalytic quantities
of acid favour D and E. Indeed, in the latter case, nearly
stoichiometric amounts of free amines are present, in the
form of the substrate or the products, and can act as a base.
A six-electron electrocyclisation of B to the stabilised cation
C, followed by proton loss, can account for the formation of
Scheme 6. Rearrangements of 2a–c under acidic conditions with micro-
wave activation.
2c behaved like its lower homologue 2a: the formation of
3c was not observed and the 14-azasteroid-like compound
9c was produced with 56:44 diastereoselectivity and isolated
in 53% yield. As one might have expected, rather than em-
ploying relatively sophisticated acid mediators such as CSA
and para-toluenesulfonic acid (p-TSA), the hydrochloride
salts of the substrates, prepared using HCl aqueous solution,
could be engaged just as well.
Considering our problems with the synthesis of 2c and be-
cause elimination of the alcohol function of 8c could, in
principle, operate under the same conditions as the subse-
quent rearrangement, its direct transformation was attempt-
ed and met substantial success (Scheme 7).
&
4
&
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Synthesis of Polycyclic Aminocyclobutanes
FULL PAPER
cascade of events leading to the final products. Indeed, start-
ing from 2a or 2b, the reaction could be stopped at this
stage under a variety of conditions, and the corresponding
aminoketones 10a and 10b, presumably in equilibrium with
the corresponding hemiaminals 11a and 11b, were obtained
after a basic aqueous work-up, as illustrated in Scheme 10
Scheme 9. Proposed mechanistic pathways for the observed rearrange-
ments of aminocyclopropanes 2.
Scheme 10. Stepwise transformation of aminocyclopropane 2b; cyclopro-
pane ring-opening followed by cyclisation events.
3. The production of 9 can be explained by an eight-electron
electrocyclisation of the most kinetically and thermodynami-
cally favoured enamine D, to generate the seven-membered
ring dipolar intermediate F, followed by a six-electron elec-
trocyclisation of this species.[19]
(top). Interestingly, when a mixture containing mainly 10b
was simply heated under microwave activation, hydroxylat-
ed compound 12b was isolated in 19% yield, along with the
“normal” cyclobutane 9b [Scheme 10 (bottom)]. This result
can be rationalised by the thermal dehydration of 11b,
which should give the two possible enamines D and E.
Under these strictly nonacidic conditions, it can be inferred
that interconversion of these enamines via B operates
poorly. Whereas D can evolve to 9b as before, the lifetime
of the less favoured enamine E is long enough to allow it to
react with molecular oxygen and give the dioxacyclobutane
intermediate G (Scheme 9),[20, 21] which is a reasonable pre-
cursor of 12b.[22] Closely related unexpected processes are
documented in the literature.[7b,23] It is also worth noting
that in this run, the minor amount of aminocyclopropane 2b
present, along with the starting material 10b, survived the
reaction conditions. This supports the requirement for pro-
tonation to open the cyclopropane ring.
To gain finer insight into the elementary steps involved,
additional experiments were carried out.[13] Several purified
rearranged products 3 or 9 were submitted back to the reac-
tion conditions. These experiments neatly demonstrated that
the two diastereoisomers of 9b and 9c can interconvert,
even in the absence of acid. It was also evidenced that the
major diastereoisomers of 9b and 9c are thermodynamically
favoured, with ratios at equilibrium evaluated at about
80:20 (1408C) and 86:14 (808C) for 9b and around 58:42
(1208C) for 9c. Importantly, the dihydroquinoline products
3 were never observed in experiments conducted with cyclo-
butane derivatives 9. Whereas the electrocyclisation of F to
9 is reversible under such conditions, the electrocyclisation
of D to F thus does not appear to be reversible. Similarly, in
experiments conducted with diastereoisomeric mixtures of
3b, the formation of 9b was never observed, which shows
that the process leading to 3b from B is not reversible
under the conditions applied.[13]
It can also be deduced from our results that the electro-
cyclisation of D is generally a more facile process than the
electrocyclisation of B. Indeed, starting from 2a and 2c, it
prevails even in the presence of a stoichiometric amount of
acid. The formation of 3 takes place only with the additional
requirement that Rꢂ is a methyl group rather than a hydro-
gen atom, which can be explained by additional stabilisation
of intermediate C.
Relative configurations of the chiral centres of the products:
The relative configurations of the chiral centres of the rear-
ranged products were assigned on the basis of 2D NOESY
1
NMR experiments, as well as by comparison of key H and
13C NMR data with those of the major diastereoisomer of
9b and of the minor diastereoisomer of 9c, the structures of
which were firmly established by X-ray diffraction of single
crystals (Figure 1 and Figure 2).[24] The 1H and 13C NMR
chemical shifts of the common methyl group of the struc-
tures appear to be reliable indicators of the relative configu-
ration, with higher values for the exo than for the endo con-
1
Other experiments demonstrated that the initial cyclopro-
pane ring-opening is a faster process than the consecutive
figuration.[25] The H NMR chemical shift of the CH attach-
ed to this methyl group is also helpful, with consistently
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
5
&
ÞÞ
These are not the final page numbers!

Y. Six et al.
NMR spectra performed on both diastereoisomers. The em-
pirical chemical shift rules mentioned above are also appli-
cable in this case. The relative configuration of the (slightly)
major diastereoisomer of 3b was tentatively assigned as
endo on the sole basis of the correlations observed on a
NOESY spectrum of this compound.
Finally, it may seem peculiar that whereas the relative
configurations of the major diastereoisomers produced are
endo in the cases of 9a and 9c, it is exo in the case of 9b.
Having noted that the reactions are essentially under ther-
modynamic control, this can be readily explained by a desta-
bilisation of (endo)-9b caused by steric repulsion between
the two methyl groups of this molecule. Crude calculations
(molecular mechanics conducted with the MMFF94,
MMFF94s, Ghemical and UFF force fields) all agreed with
a lower energy of (exo)-9b than of (endo)-9b.[13,26] Only the
Ghemical force field predicted correctly that the most stable
diastereoisomers of 9a and 9c are endo, with a higher
energy difference between the two diastereoisomers of 9b
than between the two diastereoisomers of 9a or 9c, which is
fully consistent with the higher diastereoselectivity observed
in the formation of 9b.
Figure 1. Crystallographic structure of 9b (major). Ellipsoids are drawn
at the 50% probability level.
Conclusion
The transformations of N-aryl 2-azabicycloACTHUNRTGNEUNG[3.1.0]hexanes
Figure 2. Crystallographic structure of 9c (minor). Ellipsoids are drawn
have been extended to the formation of novel polycyclic sys-
tems containing an aminocyclobutane moiety, starting from
substrates that are substituted with a conjugated alkenyl
group at the ortho position of the aromatic system. This
acid-promoted rearrangement operates by regioselective iso-
merisation of the aminocyclopropane into an enamine, fol-
lowed by a sequence of electrocyclisations. The ratio of the
two diastereoisomers formed is under thermodynamic con-
trol. Moreover, when the ortho substituent is an isopropenyl
group, the reaction outcome can be altered to give access to
dihydroquinoline compounds. Our results also demonstrate
that under suitable conditions, simple ring-opening can be
achieved, without rearrangement, to afford g-aminoketones.
Finally, this work constitutes an extension to the previously
reported condensation of 2-vinylaniline derivatives with ke-
tones;[15,16] to the best of our knowledge, all the examples re-
ported involve primary anilines, and no intramolecular con-
densations of this type, with aminoketones, have been de-
scribed so far.
at the 50% probability level.
higher values for the endo configuration (Table 2). The endo
configuration of the hydroxyl group of the major diaster-
eoisomer of 12b was assigned with the help of NOESY
Table 2. Chemical shifts of selected nuclei measured with the diaster-
eoisomers of 9a–c and 12b. For each given data, the highest value is dis-
played in bold.
Compound
Highlighted methyl group
Configuration[a] 13C d
[ppm]
CHCH3
1H d
ACHTUNGTNER[NUNG ppm]
1H d
[ppm]
G
E
endo (major)
exo (minor)
14.6
14.8
1.01
1.14
2.10
1.79
endo (minor)
exo (major)[b]
14.2
16.0
0.74
1.14
2.11
1.90
endo (major)
exo (minor)[b]
14.6
15.0
1.20
1.22
2.21
2.00
Experimental Section
General information: Titanium(IV) isopropoxide (VERTECꢃ TIPT) was
purchased from Alfa Aesar, distilled under reduced pressure and stored
under nitrogen for several months. Other commercial reagents were used
as received, without purification. Cyclopentylmagnesium chloride was
purchased from Sigma–Aldrich or Acros and titrated once a month ac-
cording to a method described in the literature.[27] tert-Butyllithium was
purchased from Acros and titrated with diphenylacetic acid.[28] Tetrahy-
drofuran, diethyl ether, dichloromethane, toluene and methanol were pu-
endo (minor)
exo (major)
22.1
23.4
1.13
1.46
–
–
[a] Configuration relative to the pyrrolizidine subunit. [b] Structure estab-
lished by crystallography.
&
6
&
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Synthesis of Polycyclic Aminocyclobutanes
FULL PAPER
rified with a MB SPS-800 solvent purification system (MBRAUN). Mi-
crowave-promoted experiments were performed with a CEM Discover
Microwave Synthesis System with the temperature and time parameters
indicated; the reaction vessels were not flushed with an inert gas. All
other reactions were carried out under nitrogen. The temperatures men-
tioned are the temperatures of the cold baths or the oil baths used. Flash
column chromatography was performed on Merck silica gel 60 (40–
63 mm). Concentration under reduced pressure was carried out with
rotary evaporators operated at 408C. NMR spectra were recorded with
AM 400 and AVANCE 400 Bruker spectrometers (1H at 400 MHz, 13C at
100.6 MHz). Chemical shifts d are given in ppm, referenced to the peak
of tetramethylsilane, defined at d=0.00 ppm (1H NMR), or the solvent
peak of CDCl3, defined at d=77.0 ppm (13C NMR). Multiplicities are ab-
breviated as: s=singlet, d=doublet, t=triplet, q=quartet, quint=
quintuplet, sext=sextuplet, sept=septuplet, m=multiplet, br=broad.
Coupling constants J are given in Hz. Infrared (IR) spectra were record-
ed with a Perkin–Elmer 2000 FTIR spectrometer. Melting points were
determined with a Bꢄchi 535 apparatus and were not corrected. Low-res-
olution mass spectra were recorded with a Hewlett–Packard Quad GC-
MS engine spectrometer with direct injection. High-resolution mass spec-
trometry was performed with a JEOL GC-mate II spectrometer.
duced with 80:20 diastereoselectivity. Purification by flash column chro-
matography on silica gel (EtOAc/heptane, 5 to 100%, with a few drops
of 20% NH3 aqueous solution) gave pure 5-methyl-4-(2-naphthyl)-4-
azabicyclo
ACHTUNGTRENNUNG
methyl-4-azabicyclo
AHCTUNGTRENNUNG
diastereoisomers, 1.36 g, 5.09 mol, 56%). Note: some chromatography
fractions contained pure samples of each diastereoisomer of 8c as a vis-
cous brown oil.
Major diastereoisomer of 8c: Rf =0.2 (UV-active, EtOAc/petroleum
ether 20%, PMA); 1H NMR (400 MHz, CDCl3): d=0.64 (dd, J=8.5,
6.0 Hz, 1H), 1.33 (ddd, J=8.5, 4.5, 4.0 Hz, 1H), 1.33 (s, 3H), 1.47 (dd,
J=6.0, 4.0 Hz, 1H), 1.68 (d, J=7.0 Hz, 3H), 1.95 (dd, J=12.5, 7.0 Hz,
1H), 2.21 (dddd, J=12.5, 11.0, 8.5, 4.5 Hz, 1H), 2.59 (ddd, J=11.0, 10.0,
7.0 Hz, 1H), 3.40 (dd, J=10.0, 8.5 Hz, 1H), 5.83 (qd, J=7.0, 6.0 Hz, 1H),
7.43 (ddd, J=8.0, 7.0, 1.0 Hz, 1H), 7.49 (ddd, J=8.5, 7.0, 1.5 Hz, 1H),
7.76 (AB system, dA =7.73, dB =7.79 ppm, JAB =9.0 Hz, 2H), 7.79 (dd, J=
8.0, 1.5 Hz, 1H), 7.93 (brd, J=8.5 Hz, 1H), 9.45 ppm (d, J=6.0 Hz, 1H;
OH); 13C NMR (100.6 MHz, CDCl3): d=12.2, 19.0, 19.9, 26.2, 27.0, 45.9,
52.6, 68.5, 122.1, 123.1, 125.2, 126.3, 128.6, 128.6, 131.0, 131.8, 136.0,
142.5 ppm; IR (neat): n˜ =3378 (br, OH), 3064, 2969, 2953, 2928, 2866,
2851, 1622, 1597, 1506, 1496, 1488, 1464, 1455, 1446, 1434, 1362, 1332,
1267, 1258, 1246, 1209, 1184, 1114, 1069, 1019, 1001, 820, 810, 748 cmÀ1
;
Intramolecular Kulinkovich–de Meijere reaction: typical procedure for
2b (Table 1): Cyclopentylmagnesium chloride (1.74m in Et2O, 4.00 equiv,
33.8 mmol, 19.4 mL) was added dropwise, over 20 min at 08C, to a stirred
MS (+ve CI, NH3): m/z: 250 [MÀOH]+, 268 [MH]+, 269, 270; MS (EI):
m/z: 164, 168, 180, 196, 234, 252, 266, 267 [M]+, 268; HRMS (EI): m/z
calcd for C18H21NO: 267.1623 [M]+; found: 267.1618.
solution
of
N-but-3-enyl-N-(2-isopropenylphenyl)acetamide
(5b;
1.00 equiv 8.46 mmol, 1.94 g) and titanium(IV) isopropoxide (1.50 equiv,
12.7 mmol, 3.76 mL) in THF (0.17 L). The cold bath was removed and
the dark solution was stirred at 208C for 1 h. 20% NH3 aqueous solution
(4.0 mL) was added and stirring was maintained for 30 min. The grey re-
action mixture was filtered through a short pad of sand, Na2SO4, Celite
and sand (from bottom to top), which was then rinsed thoroughly with
Et2O (0.34 L). The resulting clear solution was concentrated under re-
duced pressure to give a yellow oil (2.21 g). Purification by flash column
chromatography on silica gel (EtOAc/heptane, 0 to 5%, with a few drops
of 20% NH3 aqueous solution) gave pure 4-(2-isopropenylphenyl)-5-
Minor diastereoisomer of 8c: Rf =0.25 (UV-active, EtOAc/petroleum
ether 20%, PMA); 1H NMR (400 MHz, CDCl3): d=0.59 (dd, J=8.0,
6.0 Hz, 1H), 1.30–1.40 (m, 1H), 1.35 (s, 3H), 1.45 (m, 1H), 1.71 (d, J=
6.5 Hz, 3H), 1.94 (dd, J=12.5, 7.0 Hz, 1H), 2.16 (dddd, J=12.5, 11.0, 8.5,
4.5 Hz, 1H), 2.69 (ddd, J=11.0, 10.0, 7.0 Hz, 1H), 3.29 (dd, J=10.0,
8.5 Hz, 1H), 5.88 (q, J=6.5 Hz, 1H), 7.45 (ddd, J=8.0, 7.0, 1.0 Hz, 1H),
7.50 (ddd, J=8.5, 7.0, 1.5 Hz, 1H), 7.70 (AB system, dA =7.66, dB =
7.73 ppm, JAB =9.0 Hz, 2H), 7.80 (dd, J=8.0, 1.5 Hz, 1H), 8.06 ppm (brd,
J=8.5 Hz, 1H); 13C NMR (100.6 MHz, CDCl3): d=12.4, 19.8, 20.2 (br),
26.8, 26.8, 47.0, 53.1, 68.5, 122.8 (br), 123.9, 125.4, 126.2, 128.5, 128.6,
130.9, 132.2, 136.8, 143.1 ppm (br); IR (neat): n˜ =3360 (br, OH), 3059,
2969, 2955, 2931, 2867, 1621, 1597, 1507, 1463, 1432, 1390, 1367, 1334,
1249, 1205, 1182, 1113, 1072, 1059, 1018, 819, 809, 747 cmÀ1; MS (+ve CI,
NH3): m/z: 121, 184, 250 [MÀOH]+, 266, 268 [MH]+; MS (EI): m/z: 127,
156, 168, 234, 252, 266, 267 [M]+, 268; HRMS (EI): m/z calcd for
C18H21NO: 267.1623 [M]+; found: 267.1626.
methyl-4-azabicycloACHTUNGTRENNUNG[3.1.0]hexane (2b; 1.39 g, 6.53 mmol, 77%) as a pale-
yellow oil. Rf =0.65 (UV-active; AcOEt/petroleum ether 10%, PMA);
1H NMR (400 MHz, CDCl3): d=0.64 (dd, J=8.5, 5.5 Hz, 1H), 1.01 (dd,
J=5.5, 4.5 Hz, 1H), 1.22 (ddd, J=8.5, 5.0, 4.5 Hz, 1H), 1.41 (s, 3H), 1.82
(dd, J=12.0, 7.5 Hz, 1H), 2.10 (dddd, J=12.0, 10.5, 8.5, 5.0 Hz, 1H), 2.13
(dd, J=1.5, 1.0 Hz, 3H), 2.25 (ddd, J=10.5, 10.0, 7.5 Hz, 1H), 3.74 (dd,
J=10.0, 8.5 Hz, 1H), 5.02 (brs, 2H), 6.92 (ddd, J=7.5, 7.0, 1.0 Hz, 1H),
7.13 (dd, J=7.0, 1.5 Hz, 1H), 7.20 (ddd, J=8.0, 7.5, 1.5 Hz, 1H),
7.29 ppm (dd, J=8.0, 1.0 Hz, 1H); 13C NMR (100.6 MHz, CDCl3): d=
13.4, 19.3, 21.3, 21.8, 26.6, 43.2, 50.3, 113.9, 119.7, 121.2, 127.4, 130.1,
138.1, 147.1, 148.2 ppm; IR (neat): n˜ =3061, 3026, 2990, 2949, 2866, 2843,
1630, 1592, 1483, 1445, 1389, 1367, 1343, 1307, 1286, 1264, 1250, 1187,
1112, 1076, 1047, 1008, 891, 869, 755 cmÀ1; MS (+ve CI, NH3): m/z: 198,
214 [MH]+, 215; HRMS (EI): m/z calcd for C15H19N: 213.1517 [M]+;
found: 213.1512.
Acid-promoted rearrangements under standard thermal conditions; typi-
cal procedure for 3b (Scheme 5): Camphorsulfonic acid (1.00 equiv,
3.84 mmol, 893 mg) was added to a solution of 4-(2-isopropenylphenyl)-
5-methyl-4-azabicycloACTHNUTRGENUG[N 3.1.0]hexane (2b; 1.00 equiv, 3.84 mmol, 820 mg)
in PhCl (0.10 L), then the mixture was heated to reflux for 6 h. After
cooling, the solvent was removed under reduced pressure and the residue
was dissolved in CH2Cl2 (50 mL). Saturated aqueous NaHCO3 (50 mL)
was added, the organic layer was separated and the aqueous phase was
extracted with CH2Cl2 (2ꢅ50 mL). The combined organic layers were
dried over Na2SO4, filtered and concentrated under reduced pressure to
give a brown oil (902 mg). Analysis by 1H NMR spectroscopy revealed
Direct synthesis of aminocyclopropane 8c by a one-pot sequence of in-
tramolecular Kulinkovich–de Meijere reaction, bromine–lithium ex-
change and alkylation (Scheme 3): Cyclopentylmagnesium chloride
(1.74m in Et2O, 4.00 equiv, 36.4 mmol, 20.9 mL) was added dropwise,
over 10 min at 08C, to a stirred solution of N-(1-bromo-2-naphthyl)-N-
but-3-enyl-acetamide (5c; 1.00 equiv 9.10 mmol, 2.90 g) and titanium(IV)
isopropoxide (1.50 equiv, 13.6 mmol, 4.04 mL) in THF (0.18 L). The cold
bath was removed and the solution was stirred at 208C for 1 h, then
cooled to À708C. tert-Butyllithium (1.43m in pentane, 2.00 equiv,
18.2 mmol, 12.7 mL) was added dropwise, over 5 min at À708C. After
15 min, acetaldehyde (2.00 equiv, 18.2 mmol, 1.02 mL) was then added
dropwise. After 30 min of further stirring at À708C, the cold bath was re-
moved and the reaction mixture was allowed to warm to 208C. 20% NH3
aqueous solution (4.5 mL) was added and stirring was maintained for
30 min. The grey reaction mixture was filtered through a short pad of
sand, Na2SO4, Celite and sand (from bottom to top), which was then
rinsed thoroughly with Et2O (0.40 L). The resulting clear solution was
concentrated under reduced pressure to give a yellow oil (3.09 g). Analy-
the presence of 3,3a,5-trimethyl-2,3-dihydro-1H-pyrroloACTHNUTRGNE[NUG 1,2-a]quinoline
(3b; d.r. about 50:50). Only traces of 2,6-dimethyl-9-azatetracy-
clo[8.4.0.02,5.05,9]tetradeca-1(10),11,13-triene (9b) were detected. Purifica-
tion by flash column chromatography on silica gel (EtOAc/heptane, 0 to
10%, with one drop of 20% NH3 aqueous solution) gave pure major dia-
stereoisomer of 3,3a,5-trimethyl-2,3-dihydro-1H-pyrroloACTHNUTRGNE[NUG 1,2-a]quinoline
(3b; 102 mg, 478 mmol, 12%) as a pale-brown oil, a mixture of both dia-
stereoisomers (275 mg, 1.29 mmol, 34%) and the pure minor diaster-
eoisomer (140 mg, 656 mmol, 17%) as a pale-brown oil.
Compound 3b (mixture of diastereoisomers): IR (neat): n˜ =3032, 2964,
2880, 1645, 1598, 1495, 1481, 1456, 1384, 1370, 1302, 1199, 1144, 1043,
739 cmÀ1; MS (EI): m/z: 171, 182, 196, 198, 199, 213 [M]+; HRMS (EI):
m/z calcd for C15H19N: 213.1517 [M]+; found: 213.1516.
Compound 3b (major diastereoisomer): Rf =0.5 [UV-active, petroleum
ether, PMA]; 1H NMR (500 MHz, CDCl3): d=0.94 (d, J=7.0 Hz, 3H),
1.06 (s, 3H), 1.58 (ddd, J=11.5, 9.0, 3.0 Hz, 1H), 2.01 (d, J=1.5 Hz, 3H),
1
sis by H NMR spectroscopy revealed that the expected alcohol was pro-
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
7
&
ÞÞ
These are not the final page numbers!

Y. Six et al.
2.05 (dq, J=8.5, 7.0 Hz, 1H), 2.29 (dddd, J=11.5, 9.5, 8.5, 7.0 Hz, 1H),
3.29 (ddd, J=10.0, 9.0, 7.0 Hz, 1H), 3.37 (ddd, J=10.0, 9.5, 3.0 Hz, 1H),
5.35 (q, J=1.5 Hz, 1H), 6.35 (dd, J=8.0, 1.0 Hz, 1H), 6.56 (td, J=7.5,
1.0 Hz, 1H), 7.08 (brddd, J=8.0, 7.5, 1.0 Hz, 1H), 7.09 ppm (brd, J=
7.5 Hz, 1H); 13C NMR (125.8 MHz, CDCl3): d=18.5, 19.1, 26.4, 29.3,
41.4, 43.9, 64.4, 110.5, 114.8, 122.1, 123.6, 124.4, 128.6, 128.8, 143.3 ppm;
IR (neat): n˜ =3061, 3034, 2961, 2921, 2881, 2869, 2856, 1647, 1598, 1495,
was extracted with EtOAc (2ꢅ20 mL). The combined organic layers
were dried over Na2SO4, filtered and concentrated under reduced pres-
sure to give a brown oil (263 mg). Analysis by 1H NMR spectroscopy re-
vealed that the pentacyclic adduct 9c was produced with 62:38 diastereo-
selectivity, with an estimated yield of 42%. Purification by flash column
chromatography on silica gel (EtOAc/heptane, 0 to 10%, with a few
drops of 20% NH3 aqueous solution) gave the two diastereoisomers of 6-
methyl-azapentacyclo[8.8.0.02,5.05,9.013,18]octadeca-1(10),11,13(18),14,16-
pentaene (9c) in pure form as light-brown crystals and a viscous brown
oil, respectively (34.3 mg and 65.4 mg respectively, 400 mmol, 38%).
1481, 1456, 1383, 1370, 1303, 1200, 1159, 1144, 1106, 1044, 740 cmÀ1
.
Compound 3b (minor diastereoisomer): Rf =0.4 [UV-active, petroleum
ether, PMA (reveals at 208C)]; 1H NMR (400 MHz, CDCl3): d=0.88 (s,
3H), 1.02 (d, J=7.0 Hz, 3H), 1.63 (dddd, J=13.0, 11.5, 10.5, 8.0 Hz, 1H),
2.01 (d, J=1.5 Hz, 3H), 2.10 (dddd, J=13.0, 8.5, 7.5, 2.5 Hz, 1H), 2.28
(dqd, J=11.5, 7.5, 7.0 Hz, 1H), 3.24 (ddd, J=9.5, 8.5, 8.0 Hz, 1H), 3.40
(ddd, J=10.5, 9.5, 2.5 Hz, 1H), 5.45 (q, J=1.5 Hz, 1H), 6.34 (dd, J=8.0,
1.0 Hz, 1H), 6.58 (td, J=7.5, 1.0 Hz, 1H), 7.08 (dd, J=8.0, 7.5 Hz, 1H),
7.09 ppm (d, J=7.5 Hz, 1H); 13C NMR (125.8 MHz, CDCl3): d=13.5,
18.7, 19.0, 28.8, 42.6, 44.2, 62.4, 110.5, 115.1, 122.5, 123.7, 124.8, 128.6,
128.6, 143.3 ppm.
Compound 9c (major diastereoisomer): Rf =0.2 [UV-active, EtOAc/pe-
troleum ether 10%, PMA]; 1H NMR (400 MHz, CDCl3): d=1.20 (d, J=
7.0 Hz, 3H), 1.35 (dtd, J=12.0, 10.0, 7.0 Hz, 1H), 1.87 (dddd, J=12.0,
6.0, 5.5, 3.0 Hz, 1H), 2.02 (m, 1H), 2.21 (dqd, J=10.0, 7.0, 5.5 Hz, 1H),
2.35–2.55 (m, 3H), 3.18 (ddd, J=10.5, 7.0, 3.0 Hz, 1H), 3.43 (ddd, J=
10.5, 10.0, 6.0 Hz, 1H), 4.33 (m, 1H), 7.25 (ddd, J=8.0, 7.0, 1.0 Hz, 1H),
7.39 (AB system, dA =7.09, dB =7.69 ppm, JAB =8.5 Hz, 2H), 7.40 (ddd,
J=8.5, 7.0, 1.0 Hz, 1H), 7.53 (dd, J=8.5, 1.0 Hz, 1H), 7.77 ppm (brd, J=
8.0 Hz, 1H); 13C NMR (100.6 MHz, CDCl3): d=14.6, 25.1, 33.5, 34.0,
40.8, 42.8, 53.5, 81.0, 115.8, 122.5, 123.1, 126.3, 128.6, 128.6, 128.5, 129.6,
130.2, 153.2 ppm; IR (neat): n˜ =3407 (br), 3052, 2957, 2931, 2872, 1622,
1588, 1516, 1462, 1444, 1371, 1349, 1318, 1277, 1212, 1143, 1126, 810,
745 cmÀ1; MS (EI): m/z: 204, 206, 207, 221, 222, 249 [M]+; HRMS (EI):
m/z calcd for C18H19N: 249.1517 [M]+; found: 249.1516.
Acid-promoted rearrangements using microwave activation; typical pro-
cedure for 9b (Scheme 6): Camphorsulfonic acid (5.00% equiv,
26.9 mmol, 6.2 mg) was added to a solution of 2b (1.00 equiv, 539 mmol,
115 mg) in PhCl (1.0 mL), then the mixture was heated with a CEM Dis-
cover microwave apparatus (power: 300 W, temperature: 1408C, ramp
time: 2 min, hold time: 10 min, max. pressure: 4 bar). After cooling, the
solvent was removed under reduced pressure and the residue was dis-
solved in CH2Cl2 (10 mL). Saturated aqueous NaHCO3 (10 mL) was
added, the organic layer was separated and the aqueous phase was ex-
tracted with CH2Cl2 (2ꢅ10 mL). The combined organic layers were dried
over Na2SO4, filtered and concentrated under reduced pressure to give
the crude product (115 mg). Analysis by 1H and 13C NMR spectroscopy
Compound 9c (minor diastereoisomer): Rf =0.3 [UV-active, EtOAc/pe-
troleum ether 10%, PMA]; m.p. 100.1–101.18C (tBuOMe); 1H NMR
(400 MHz, CDCl3): d=1.22 (d, J=6.5 Hz, 3H), 1.63 (dddd, J=11.5, 9.5,
9.0, 7.0 Hz, 1H), 1.95 (dddd, J=11.5, 6.5, 6.0, 3.0 Hz, 1H), 2.00 (dquint,
J=9.5, 6.5 Hz, 1H), 2.05 (ddt, J=10.5, 5.0, 4.5 Hz, 1H), 2.15 (m, 1H),
2.53 (dddd, J=11.5, 10.5, 8.5, 6.0 Hz, 1H), 2.61 (m, 1H), 2.93 (ddd, J=
9.5, 9.0, 6.0 Hz, 1H), 3.64 (ddd, J=9.0, 7.0, 3.0 Hz, 1H), 4.20 (distorted
dd, J=8.5, 5.0 Hz, 1H), 7.23 (ddd, J=8.0, 7.0, 1.0 Hz, 1H), 7.37 (AB
system, dA =7.06, dB =7.68 ppm, JAB =8.5 Hz, 1H), 7.39 (ddd, J=8.0, 7.0,
1.0 Hz, 1H), 7.50 (brd, J=8.0 Hz, 1H), 7.76 ppm (brd, J=8.0 Hz, 1H);
13C NMR (100.6 MHz, CDCl3): d=15.0, 25.6, 29.4, 33.9, 38.8, 45.9, 52.0,
81.0, 114.8, 122.3, 122.8, 126.3, 128.6, 128.6, 127.8, 129.4, 130.4,
153.3 ppm; IR (neat): n˜ =3488 (br), 3051, 2982, 2960, 2947, 2923, 2900,
2865, 2845, 1622, 1588, 1515, 1466, 1442, 1369, 1348, 1329, 1308, 1157,
1142, 813, 753 cmÀ1; MS (EI): m/z: 151, 162, 182, 206, 212, 217, 221, 222,
232, 236, 248, 249 [M]+; HRMS (EI): m/z calcd for C18H19N: 249.1517
[M]+; found: 249.1517.
revealed
clo[8.4.0.02,5.05,9]tetradeca-1(10),11,13-triene (9b; 68% estimated yield,
d.r. 80:20). Only traces of 3,3a,5-trimethyl-2,3-dihydro-1H-pyrrolo[1,2-
that
it
contained
mainly
2,6-dimethyl-9-azatetracy-
AHCTUNGTRENNUNG
a]quinoline (3b) were detected (d.r. about 50:50). In other experiments,
9b was obtained in pure form as a pale-brown oil by purification by flash
column chromatography on silica gel (EtOAc/heptane, 0 to 5%, with one
drop of 20% NH3 aqueous solution). However, the two diastereoisomers
proved difficult to separate.
Compound 9b (mixture of diastereoisomers): d.r. 89:11; IR (neat): n˜ =
3020, 2959, 2927, 2854, 1738, 1603, 1474, 1459, 1377, 1344, 1296, 1260,
1152, 1127, 1096, 1021, 800, 743 cmÀ1; MS (EI): m/z: 132, 150, 151, 162,
170, 175, 182, 185, 186, 194, 201, 212, 213 [M]+; HRMS (EI): m/z calcd
for C15H19N: 213.1517 [M]+; found: 213.1528.
Structure analysis by X-ray crystallography: X-ray data collection was
carried out at ambient temperature with an Enraf–Nonius Kappa-CCD
diffractometer using graphite-monochromated Mo-Ka (l=0.71070 ꢆ) ra-
diation. A total of 220 images for (121) with 28 rotation per image and 30
(75) second exposure per degree of oscillation and a crystal-to-detector
distance of 31 mm were measured according to a f+w scan profile data
strategy derived by the COLLECT software package.[29] Intensities were
reduced and merged after semiempirical absorption correction using
HKL-2000 software.[30] The structure was solved by direct methods
Compound 9b (major diastereoisomer): Colourless needles; Rf =0.23
[UV-active, petroleum ether, PMA]; m.p. 43–458C; 1H NMR (400 MHz,
CDCl3): d=1.14 (d, J=6.5 Hz, 3H), 1.43 (s, 3H), 1.63 (m, 1H), 1.90 (m,
1H), 1.93 (m, 1H), 1.94 (m, 1H), 1.97 (m, 1H), 2.11 (very distorted ddd,
J=12.5, 10.0, 7.5 Hz, 1H), 2.53 (very distorted ddd, J=12.5, 10.0, 7.5 Hz,
1H), 2.86 (distorted td, J=9.5, 6.5 Hz, 1H), 3.56 (distorted ddd, J=9.5,
7.5, 2.0 Hz, 1H), 6.61 (brd, J=8.0 Hz, 1H), 6.76 (ddd, J=7.5, 7.0, 1.0 Hz,
1H), 6.95 (dd, J=7.0, 1.0 Hz, 1H), 7.10 ppm (ddd, J=8.0, 7.5, 1.0 Hz,
1H); 13C NMR (75.5 MHz, CDCl3): d=16.0, 20.0, 27.3, 33.3, 34.4, 34.8,
50.6, 51.1, 82.1, 110.7, 119.1, 121.9, 127.5, 139.6, 155.1 ppm.
2
(SHELXS-97)[31] and refined on F by means of full-matrix least-squares
methods (SHELXL-97).[31] All non-hydrogen atoms were refined aniso-
tropically, whereas hydrogen atoms, located from difference Fourier
maps, were refined by using a riding model with Uiso =1.2Ueq of the
carbon parent atom (1.5 for the methyl hydrogen atoms). ORTEP draw-
ings were made by using ORTEP3[32] as implemented within PLATON.[33]
Compound 9b (minor diastereoisomer): Rf =0.27 [UV-active, petroleum
1
ether, PMA]; H NMR (400 MHz, CDCl3; characteristic signals): d=0.74
(d, J=7.0 Hz, 3H), 1.61 (s, 3H), 2.11 (m, 1H), 3.05 (ddd, J=9.5, 9.0,
7.0 Hz, 1H), 3.50 (distorted ddd, J=9.5, 7.5, 3.0 Hz, 1H), 6.53 (brd, J=
8.0 Hz, 1H), 6.70 (td, J=7.5, 1.0 Hz, 1H), 6.89 (dd, J=7.5, 1.0 Hz, 1H),
7.06 ppm (ddd, J=8.0, 7.5, 1.0 Hz, 1H); 13C NMR (75.5 MHz, CDCl3):
d=14.2, 20.8, 33.4, 33.6, 33.7, 39.9, 49.2, 50.9, 84.0, 108.2, 118.1, 120.8,
127.2, 139.8, 155.5 ppm.
X-ray data for compound 9b (major):[24] C15H19N; Mr =213.31; colourless
prism; 0.35ꢅ0.30ꢅ0.12 mm; monoclinic; space group P 21/c (no. 14); a=
13.295 (5) ꢆ, b=7.626 (6) ꢆ, c=12.509 (1) ꢆ, b=105.359 (11)8; V=
1223.0 (8) ꢆ3; Z=4; 1calcd =1.159 gcmÀ3; 2qmax =50.68; 15925 measured
reflections, 2229 independent, À16ꢀhꢀ15, À9ꢀkꢀ9, À14ꢀlꢀ14, R-
AHCTUNGTRENNUNG
(int)=0.022, m=0.067 mmÀ1, multi-scan absorption correction, Tmin =0.92
Direct synthesis of 9c by the microwave-induced cyclisation of the hydro-
and Tmax =0.99, 148 parameters were refined against all 2229 reflections,
R1=0.069, wR2=0.131 based on all observed values, R1=0.044,
chloride salt of 8c (Scheme 7):
A
solution of 1-[2-(5-methyl-4-
chloride 8c·HCl
F
azoniabicyclo[3.1.0]hexan-4-yl)-1-naphthyl]ethanol
ACHTUNGTRENNUNG
wR2=0.115 [1553 reflections with I>2s(I)], D1min and 1max =À0.125 and
(1.00 equiv, assumed 1.05 mmol, 332 mg) in DMF (5.0 mL) was heated
with a CEM Discover microwave apparatus (power: 250 W, temperature:
1008C, ramp time: 2 min, hold time: 15 min, max. pressure: 4 bar). After
cooling, 1m NaOH aqueous solution (20 mL) was added and the mixture
0.145 eꢆÀ3, extinction coefficient 0.029(6), GOF=1.036 based on F2.
X-ray data for compound 9c (minor):[24] C18H19N; Mr =249.34; brown
prism; 0.40ꢅ0.39ꢅ0.22 mm; monoclinic; space group C 2/c (no. 15); a=
&
8
&
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Synthesis of Polycyclic Aminocyclobutanes
FULL PAPER
19.589(2) ꢆ, b=9.240(1) ꢆ, c=15.434(6) ꢆ, b=95.055(5)8; V=
2782.7(12) ꢆ3; Z=8; 1calcd =1.190 gcmÀ3; 2qmax =50.48; 8851 measured re-
flections, 2455 independent, À23ꢀhꢀ23, À11ꢀkꢀ9, À18ꢀlꢀ18, R-
[8] S. M. Cramp, H. J. Dyke, T. D. Pallin, R. Zahler (Zafgen corpora-
tion), WO2012/154678A1, 2012.
[9] A. S. Wagman, H. E. Moser, G. A. McEnroe, J. B. Aggen, M. S. Lin-
sell, A. A. Goldblum, R. D. Gaston, J. H. Griffin (Achaogen, Inc.),
WO2011/031744A1, 2011.
[10] L. G. Hamann, R. I. Higuchi, L. Zhi, J. P. Edwards, X.-N. Wang,
K. B. Marschke, J. W. Kong, L. J. Farmer, T. K. Jones, J. Med. Chem.
1998, 41, 623–639.
ACHTUNGTRENNUNG
(int)=0.044, m=0.069 mmÀ1, multi-scan absorption correction, Tmin =0.90
and Tmax =0.98, 174 parameters were refined against all (2453) reflec-
tions, R1=0.074, wR2=0.156 based on all observed F values, R1=0.053,
wR2=0.139 [1820 reflections with I>2s(I)], D1min and 1max =À0.148 and
0.15 eꢆÀ3, extinction coefficient 0.023(3), GOF=1.051 based on F2.
[11] T. Gajda, A. Zwierzak, Synthesis 1981, 1005–1008.
[12] Primary reference: J. Lee, J. K. Cha, J. Org. Chem. 1997, 62, 1584–
1585.
[13] See the Supporting Information for additional details.
[14] See for instance: M. Gordaliza, M. ꢊ. Castro, J. M. Miguel del Cor-
ral, M. L. Lꢈpez-Vꢋzquez, P. A. Garcꢌa, A. San Feliciano, M. D.
Garcꢌa-Grꢋvalos, H. Broughton, Tetrahedron Lett. 1997, 38, 15473–
15760.
[15] a) H. Walter, H. Sauter, T. Winkler, Helv. Chim. Acta 1992, 75,
1274–1280; b) H. Walter, H. Sauter, J. Schneider, Helv. Chim. Acta
1993, 76, 1469–1475; c) H. Walter, Helv. Chim. Acta 1994, 77, 608–
614; d) H. Walter, J. Schneider, Heterocycles 1995, 41, 1251–1259;
e) H. Walter, C. Sundermann, Heterocycles 1998, 48, 1581–1591;
f) H. Walter, J. Prakt. Chem. 1998, 340, 309–314.
[16] See also: a) J. P. Edwards, J. D. Ringgenberg, T. K. Jones, Tetrahe-
dron Lett. 1998, 39, 5139–5142; b) S. E. Denmark, S. Venkatraman,
J. Org. Chem. 2006, 71, 1668–1676.
[17] For early examples of thermal aminocyclopropane ring-opening in
protic solvents, see: a) C. Kaiser, A. Burger, L. Zirngibl, C. S. Davis,
C. L. Zirkle, J. Org. Chem. 1962, 27, 768–773; b) M. E. Kuehne,
J. C. King, J. Org. Chem. 1973, 38, 304–311; c) I. G. Bolesov, L. S.
Surmina, G. M. Abramova, B. Avezov, Y. A. Ustynyuk, R. Y.
Levina, Zh. Org. Khim. 1974, 10, 2107–2113; Russ. J. Org. Chem.
1974, 10, 2122–2128.
Acknowledgements
We are grateful to Michel Levart for the MS and HRMS analyses of our
compounds. We warmly thank the European Commission for grants
given to A.W., B.A.W., K.P. and N.W. in the frame of the Erasmus pro-
gramme. We also acknowledge the Institut de Chimie des Substances Na-
turelles (ICSN) for the grant provided to G.D. This work was financially
supported by the ꢇcole Polytechnique and the Centre National de la Re-
cherche Scientifique (CNRS). Finally, Y.S. and G.D. wish to thank Prof.
´
Jan Epsztajn, Dr Aleksandra Szczesniak and Dr Zbyszek Malinowski of
´
the University of Łꢈdz, Poland, for useful and friendly discussions.
[1] V. Chaplinski, A. de Meijere, Angew. Chem. 1996, 108, 491–492;
Angew. Chem. Int. Ed. Engl. 1996, 35, 413–414.
[2] For the importance of aminocyclopropane derivatives, see: A. de
Meijere, V. Chaplinski, H. Winsel, M. Kordes, B. Stecker, V. Gazizo-
va, A. I. Savchenko, R. Boese, F. Schill (nꢉe Brackmann), Chem.
Eur. J. 2010, 16, 13862–13875.
[3] For the first reports on the Kulinkovich reaction, see: a) O. G. Kulin-
kovich, S. V. Sviridov, D. A. Vasilevskii, T. S. Prityskaya, Zh. Org.
Khim. 1989, 25, 2244–2245; Russ. J. Org. Chem. 1989, 25, 2027–
2028; b) O. G. Kulinkovich, S. V. Sviridov, D. A. Vasilevski, Synthesis
1991, 234.
À
[18] The cyclopropane C C bond that is broken is the only one that is
more or less aligned with the lone pair of the nitrogen atom, which
accounts for the regioselectivity of the ring cleavage.
[19] O. AnaÅ, F. S¸. Gꢄngçr, Tetrahedron 2010, 66, 5931–5953.
[20] Whereas the rearrangements carried out under standard thermal
conditions were performed under a flow of nitrogen, the vessels
used for the microwave reactions were not flushed with an inert gas
for practical reasons.
[21] G. Pitacco, E. Valentin in The Chemistry of Functional Groups, Sup-
plement F: The Chemistry of Amino, Nitroso and Nitro Compounds
and their Derivatives, Part 1 (Ed.: S. Patai), Wiley, Chichester, 1982,
pp. 639–640.
[4] For recent reviews, see: a) J. K. Cha, O. G. Kulinkovich in Organic
Reactions, Vol. 77 (Ed.: S. E. Denmark), Wiley, New York, 2012,
Chapter 1; b) A. Wolan, Y. Six, Tetrahedron 2010, 66, 15–61. See
also ref. [2]
[5] For selected recent examples of alternative methods, see: a) S.
Couty, C. Meyer, J. Cossy, Tetrahedron 2009, 65, 1809–1832; b) S.
Ouizem, F. Chemla, F. Ferreira, A. Pꢉrez-Luna, Synlett 2012, 1374–
1378; c) D. Declerck, S. Josse, A. Nguyen Van Nhien, J. Szymoniak,
P. Bertus, D. Postel, Tetrahedron 2012, 68, 1145–1152; d) D. Astash-
ko, H. G. Lee, D. N. Bobrov, J. K. Cha, J. Org. Chem. 2009, 74,
5528–5532; e) A. H. Stoll, S. B. Blakey, J. Am. Chem. Soc. 2010,
132, 2108–2109; f) H. Li, J. E. Antoline, J.-H. Yang, Z. F. Al-Rashid,
R. P. Hsung, New J. Chem. 2010, 34, 1309–1316; g) P. K. Mykhailiuk,
S. Afonin, G. V. Palamarchuk, O. V. Shishkin, A. S. Ulrich, I. V. Ko-
marov, Angew. Chem. 2008, 120, 5849–5851; Angew. Chem. Int. Ed.
2008, 47, 5765–5767; h) E. G. Occhiato, A. Casini, A. Guarna, D.
Scarpi, Eur. J. Org. Chem. 2011, 6544–6552; i) H. Sajiki, Y. Iida, K.
Ikawa, Y. Sawama, Y. Monguchi, Y. Kitade, Y. Maki, H. Inoue, K.
Hirota, Molecules 2012, 17, 6519–6546.
[6] For selected examples, see: a) P. A. Grieco, M. D. Kaufman, J. Org.
Chem. 1999, 64, 7586–7593; b) H. B. Lee, M. J. Sung, S. C. Black-
stock, J. K. Cha, J. Am. Chem. Soc. 2001, 123, 11322–11324; c) T.
Voigt, H. Winsel, A. de Meijere, Synlett 2002, 1362–1364; d) F. De
Simone, J. Gertsch, J. Waser, Angew. Chem. 2010, 122, 5903–5906;
Angew. Chem. Int. Ed. 2010, 49, 5767–5770; e) F. de Nanteuil, J.
Waser, Angew. Chem. 2011, 123, 12281–12285; Angew. Chem. Int.
Ed. 2011, 50, 12075–12079; f) S. Maity, M. Zhu, R. S. Shinabery, N.
Zheng, Angew. Chem. 2012, 124, 226–230; Angew. Chem. Int. Ed.
2012, 51, 222–226.
[22] When triphenylphosphane was added to an NMR tube containing a
1
solution of the major diastereoisomer of 12b in CDCl3, the H NMR
signals of this compound were unaffected, which supports the pres-
ence of an alcohol rather than a hydroperoxide group. This is also
consistent with the MS spectra of both diastereoisomers.
[23] G. Massiot, F. Sousa Oliveira, J. Lꢉvy, Tetrahedron Lett. 1982, 23,
177–180.
[24] CCDC 926693 [9b (major)] and 926694 [9c (minor)] contain the
supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif
[25] The exo and the endo configurations are named as such according to
the relative configuration of the methyl group with respect to the bi-
cyclic pyrrolizidine subunit.
[26] Calculations were performed with the software Avogadro 1.1.0:
M. D. Hanwell, D. E. Curtis, D. C. Lonie, T. Vandermeersch, E.
Zurek, G. R. Hutchison, J. Cheminf. 2012, 4, 17; references for the
force fields: MMFF94: T. A. Halgren, J. Comput. Chem. 1996, 17,
490–519; MMFF94s: T. A. Halgren, J. Comput. Chem. 1999, 20,
720–729; UFF: A. K. Rappe, C. J. Casewit, K. S. Colwell, W. A.
Goddard III, W. M. Skiff, J. Am. Chem. Soc. 1992, 114, 10024–
10035.
[7] For contributions from our group, see: a) L. Larquetoux, J. A. Ko-
walska, Y. Six, Eur. J. Org. Chem. 2004, 3517–3525; b) L. Larque-
toux, N. Ouhamou, A. Chiaroni, Y. Six, Eur. J. Org. Chem. 2005,
4654–4662; c) C. Madelaine, N. Ouhamou, A. Chiaroni, E. Vedr-
enne, L. Grimaud, Y. Six, Tetrahedron 2008, 64, 8878–8898.
[27] H.-S. Lin, L. A. Paquette, Synth. Commun. 1994, 24, 2503–2506.
[28] W. G. Kofron, L. M. Baclawski, J. Org. Chem. 1976, 41, 1879–1880.
[29] Nonius, COLLECT, Nonius BV, Delft, The Netherlands, 1999.
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
9
&
ÞÞ
These are not the final page numbers!

Y. Six et al.
[30] Z. Otwinowski, W. Minor in Methods in Enzymology, Vol. 276
(Eds.: C. W. Carter, Jr., R. M. Sweet), Academic Press, New York,
1997, pp. 307–326.
[32] M. N. Burnett, C. K. Johnson, ORTEP-III: Oak Ridge Thermal El-
lipsoid Plot Program for Crystal Structure Illustrations, Oak Ridge
National Laboratory Report ORNL-6895, 1996.
[33] A. L. Spek, J. Appl. Crystallogr. 2003, 36, 7–13.
[31] a) G. M. Sheldrick, Acta Crystallogr. Sect. A 2008, 64, 112–122;
b) R. Welter, Acta Crystallogr. Sect. A 2006, 62, s252.
Received: March 6, 2013
Published online: && &&, 0000
&
10
&
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!