Regio- and diastereoselective stepwise [8 + 3]-cycloaddition reaction between tropone derivatives and donor-acceptor cyclopropanes

Article abstract of DOI:10.1021/ol4020656

A novel SnCl₄-catalyzed [8 + 3]-cycloaddition reaction between tropone derivatives and donor-acceptor aminocyclopropanes is described. The process leads to the formation of amino-substituted tetrahydrocyclohepta[b] pyrans with complete regio- and diastereoselectivity. Density functional theory calculations suggest that the cycloaddition occurs stepwise through an aromatic zwitterionic intermediate.

Full text of DOI:10.1021/ol4020656

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
Regio- and Diastereoselective Stepwise
000–000
[
8 þ 3]-Cycloaddition Reaction between
Tropone Derivatives and
DonorꢀAcceptor Cyclopropanes
ꢀ
Alexandra R. Rivero, Israel Fern ꢀa ndez,* and Miguel Angel Sierra*
Departamento de Quı´mica Org aꢀ nica I, Facultad de Ciencias Quı´micas,
Universidad Complutense de Madrid, 28040-Madrid, Spain
israel@quim.ucm.es; sierraor@quim.ucm.es
Received July 22, 2013
ABSTRACT
A novel SnCl -catalyzed [8 þ 3]-cycloaddition reaction between tropone derivatives and donorꢀacceptor aminocyclopropanes is described.
4
The process leads to the formation of amino-substituted tetrahydrocyclohepta[b]pyrans with complete regio- and diastereoselectivity. Density
functional theory calculations suggest that the cycloaddition occurs stepwise through an aromatic zwitterionic intermediate.
4
Cycloaddition reactions are highly valuable transforma-
tions in modern organic synthesis because of their ability
to increase the molecular complexity in a single synthetic
demonstrated their potential in organic synthesis. Never-
theless, the use of DACs in high-order cycloaddition reac-
5
tions has been scarcely explored.
Within the context of our ongoing work in the reaction
mechanims and synthetic applications of cycloaddition
reactions and based on previous studies, we recently re-
ported that tropone derivatives can be used as 8-component
1
2
step. In this sense, donorꢀacceptor cyclopropanes (DACs),
which can be considered as 1,3-zwitterionic synthons, have
proven to be very useful for the direct synthesis of five-
membered carbo- and heterocycles via [3 þ 2]-cycloaddition
6
7
3
reactions. Recent applications of these processes to
the synthesis of complex natural products have clearly
(
5) To the best of our knowledge, only a [4 þ 3]-cycloaddition
reaction involving DACs has been reported. See: (a) Ivanova, O. A.;
Budynina, E. M.; Grishin, Y. K.; Trushkov, I. V.; Verteletskii, P. V.
Angew. Chem., Int. Ed. 2008, 47, 1107. (b) Ivanova, O. A.; Budynina,
E. M.; Grishin, Y. K.; Trushkov, I. V.; Verteletskii, P. V. Eur. J. Org.
Chem. 2008, 5329.
(6) (a) Fern ꢀa ndez, I.; Sierra, M. A.; Cossı
71, 6178. (b) Fern ꢀa ndez, I.; Cossı
o, F. P.; Sierra, M. A. Organometallics
2007, 26, 3010. (c) Fern ꢀa ndez, I.; Sierra, M. A.; Cossı
o, F. P. J. Org.
Chem. 2008, 73, 2083. (d) Fern ꢀa ndez, I.; Cossıo, F. P.; de C oꢀ zar, A.;
Lled oꢀ s, A.; Mascare n~ as, J. L. Chem.;Eur. J. 2010, 16, 12147. (e) Saya,
L.; Bhargava, G.; Navarro, M. A.; Gulı
as, M.; L oꢀ pez, F.; Fern ꢀa ndez, I.;
Castedo, L.; Mascare n~ as, J. L. Angew. Chem., Int. Ed. 2010, 49, 9886. (f)
Andrada, D. M.; Granados, A. M.; Sol ꢀa , M.; Fern ꢀa ndez, I. Organome-
tallics 2011, 30, 466. (g) Fern ꢀa ndez, I.; Cossı
´
o, F. P.; Bickelhaupt, F. M.
J. Org. Chem. 2011, 76, 2310. (h) Fern ꢀa ndez, I.; Mascare n~ as, J. L. Org.
Biomol. Chem. 2012, 10, 699. (i) Fern ꢀa ndez, I.; Sol ꢀa , M.; Bickelhaupt,
F. M. Chem.;Eur. J. 2013, 19, 7416.
(
1) (a) Cycloaddition Reactions in Organics Synthesis; Kobayashi, S.,
Jorgensen, K. A., Eds.; Wiley-VCH: Weinheim, 2001. (b) Synthetic Appli-
cations of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and
Natural Products; Padwa, A., Pearson,W. H., Eds.; Wiley: New York, 2002.
´
o, F. P. J. Org. Chem. 2006,
(
2) For reviews on DACs, see: (a) Reissig, H. U.; Zimmer, R. Chem.
Rev. 2003, 103, 1151. (b) Yu, M.; Pagenkopf, B. L. Tetrahedron 2005, 61,
21. (c) De Simone, F.; Waser, J. Synthesis 2009, 3353.
3) Selected recent examples: (a) Parsons, A. T.; Johnson, J. S. J. Am.
´
´
3
´
(
Chem. Soc. 2009, 131, 3122. (b) Parsons, A. T.; Smith, A. G.; Neel, A. J.;
Johnson, J. S. J. Am. Chem. Soc. 2010, 132, 9688. (c) Goldberg, A. F. G.;
O’Connor, N. R.; Craig, R. A., II; Stoltz, B. M. Org. Lett. 2012, 14, 5314.
´
(
2
d) Xiong, H.; Xu, H.; Liao, S.; Xie, Z.; Tang, Y. H. J. Am. Chem. Soc.
013, 135, 7851. For a review, see: (e) Carson, C. A.; Kerr, M. A. Chem.
Soc. Rev. 2009, 38, 3051.
4) See, for instance: (a) Morales, C. L.; Pagenkopf, B. L. Org. Lett.
(
2008, 10, 157. (b) Campbell, M. J.; Johnson, J. S. J. Am. Chem. Soc. 2009,
131, 10370. (c) Karadeolian, A.; Kerr, M. A. Angew. Chem., Int. Ed.
2010, 49, 1133. (c) Zhang, H.; Curran, D. P. J. Am. Chem. Soc. 2011, 133,
10376. (e) Goldberg, A. F. G.; Stoltz, B. M. Org. Lett. 2011, 13, 4474.
(7) For a review on high-order cycloadditions involving tropone
derivatives, see: (a) Nair, V.; Abhilash, K. G. Top. Heterocycl. Chem.
´ ´
2008, 13, 173. (b) Barluenga, J.; Garcıa-Rodrı
guez, J.; Su ꢀa rez-Sobrino,
A. L.; Tom ꢀa s, M. Chem.;Eur. J. 2009, 15, 8800.
1
0.1021/ol4020656 r XXXX American Chemical Society

8
in high-order [8 þ 2]-cycloaddition reactions. These pre-
vious results prompted us to explore the reaction between
DACs and tropone derivatives, which would lead to the
formation of [8 þ 3]-cycloadducts. In addition, Density
Functional Theory (DFT) calculations were carried out to
unravel the reaction mechanism of this novel transformation.
The reaction between the parent tropone 1a and do-
norꢀacceptor aminocyclopropane 2 was explored first.
This particular DAC was chosen due to its proven ability
to produce N-containing hetero- and carbocycles as re-
Scheme 1. [8 þ 3]-Cycloaddition between Tropone 1a and 2
9
cently demostrated by Waser and co-workers. Optimiza-
tion of the reactions conditions (different Lewis acids,
temperature, solvent, and stoichiometry) indicated that
the use catalytic amounts of SnCl (5 mol %) and equi-
zwitterionic intermediate INT1. The ease of this process,
which occurs via transition state TS1, is reflected in the
very low activation barrier (ΔGa,298 = 2.8 kcal/mol) and
exergonicity (ΔGR = ꢀ3.1 kcal/mol) computed for this
transformation. From INT1, a ring closure reaction occurs
to produce the corresponding [8 þ 3]-cycloadduct INT2
viaTS2, a saddlepoint associatedwiththe formation of the
new CꢀC bond (see optimized geometries of TS2 in the
Supporting Information).
4
molar amounts of 1a and 2, in CH Cl as solvent, at room
2
2
temperature leads to the formation of cycloaduct 3a in
6
1
1% reaction yield (Scheme 1). Interestingly, no traces of
0
the corresponding [3 þ 2]-cycloadduct (the product ob-
served in the related reaction involving different ketones
9
c
and 2) were detected in the crude reaction mixtures. The
bias of tropone to experience high order cycloaddition
reactions can be ascribed to its peculiar electronic structure
7
,8
(
see below). In addition, 3a is formed exclusively as the
syn diastereoisomer as revealed by NOESY experiments.
Therefore, this novel [8 þ 3]-cycloaddition reaction invol-
1
1
ving 1a occurs with complete diastereoselectivity.
To gain more insight into the origin of the diastereos-
electivityoftheaboveprocess, a computational DFT study
1
2
was carried out. The computed reaction profile of the
process between 1a and 2 is illustrated in Figure 1, which
shows the relative free energies in CH Cl solution.
2
2
1
3,14
As proposed previously,
the process is assumed to
begin with the coordination of the Lewis acid to the DAC
to produce the intimate ion pair 4a, which is in equilibrium
withthe completelydissociatedzwitterion 4b. Nucleophilic
attack of the lone pair of the oxygen atom of 1a to the
iminium cation moiety of 4b leads to the formation of the
(
8) (a) Lage, M. L.; Fern ꢀa ndez, I.; Sierra, M. A.; Torres, M. R. Org.
Lett. 2011, 13, 2892. (b) Rivero, A. R.; Fern ꢀa ndez, I.; Sierra, M. A.
J. Org. Chem. 2012, 77, 6648.
(9) (a) de Nanteuil, F.; Waser, J. Angew. Chem., Int. Ed. 2011, 50,
1
3
4
2075. (b) Benfatti, F.; de Nanteuil, F.; Waser, J. Org. Lett. 2012, 14,
86. (c) Benfatti, F.; de Nanteuil, F.; Waser, J. Chem.;Eur. J. 2012, 18,
844.
Figure 1. Computed reaction profile of the [8 þ 3]-cycloaddition
between tropone 1a and SnCl
energies (ΔG, 298 K) and bond distances are given in kcal/mol
and angstroms, respectively. All data have been computed at the
4
ꢀDAC complex 4. Relative free
(
nitrogen inlet, tropone 1a (1 equiv) and aminocyclopropane 2 (1 equiv)
were dissolved in anhydrous dichloromethane at room temperature.
After 5 min, SnCl in dichloromethane (5 mol %) was added. The
4
10) Typical procedure: In a two-necked flask equipped with a
PCM(CH Cl )-B3LYP/def2-SVP level.
2
2
mixture was stirred under nitrogen at 16 h, and then the reaction
was quenched by the addition of triethylamine and subsequently
flushed through a short plug of silica gel, eluting with EtOAc. The
solvent was removed in vacuo to give the crude reaction mixture, which
was submitted to flash column chromatography to yield pure cycload-
duct 3a.
Two possible ring closures leading to the syn- and anti-
cycloadducts are possible. As readily seen in Figure 1, the
experimentally observed exclusive formation of the syn-
isomer takes place under kinetic control in view of the
lower activation barrier computed for the process involving
(
11) The reaction between diethyl 2-phenylcyclopropane-1,1-dicar-
boxylate and tropone 1a was also tested. Under the same reaction
conditions used for the aminocyclopropane 2 (i.e., 5 mol % SnCl , rt,
6 h), the corresponding [8 þ 3]-cycloadduct was not formed.
12) DFT calculations were carried out at the PCM(CH
4
the saddle point TS2-syn (ΔΔG (syn-anti) = 3.4 kcal/mol).
1
a
(
2
Cl
2
)-
Final decoordination of SnCl in INT2-syn produces the
4
B3LYP/def2-SVP level of theory using the Gaussian 09 suite of pro-
grams. See computational details in the Supporting Information.
observed [8 þ 3]-cycloadduct 3a thus regenerating the cata-
lyst. Therefore, similar to related high-order cycloaddition
(
13) Pohlhaus, P. D.; Sanders, S. D.; Parsons, A. T.; Li, W.; Johnson,
8
J. S. J. Am. Chem. Soc. 2008, 130, 8642.
reactions involving tropone derivatives, the present [8 þ 3]-
(
14) For a computational study on the Sn(II)-catalyzed [3 þ 2]-
cycloaddition between the parent tropone 1a and DAC 2
occurs stepwise through a zwitterionic intermediate (INT1).
cycloaddition reaction between DACs and benzaldehyde, see: Zhang,
J.; Shen, W.; Li, M. Eur. J. Org. Chem. 2007, 4855.
B
Org. Lett., Vol. XX, No. XX, XXXX

The structure of zwitterion INT1 deserves further ana-
lysis. As shown in Figure 1, INT1 can also be described by
the resonance form INT1b, where the positive charge is
delocalized within the seven-membered ring. This species,
which resembles the tropyl cation, should therefore possess
remarkable aromatic character. Indeed, the computed
Scheme 2. [8 þ 3]-Cycloaddition Reactions between 2-Substituted
Tropones 1bꢀj and 2
1
5
negative Nucleus Independent Chemical Shift (NICS)
values (NICS(0) = ꢀ3.6 and NICS(1) = ꢀ7.2 ppm) and
the corresponding out-of-plane tensor component
(
NICS(1) = ꢀ16.7 ppm) confirm the magnetic aromatic
zz
nature of this zwitterion. In addition, the optimized geo-
metry of INT1 indicates that the seven-membered ring
is highly planar (C1(O)ꢀC2ꢀC3ꢀC4 dihedral angle of
ꢀ
0.3°) with CꢀC bond distances which are intermediate
between single and double bonds (ranging from 1.382 to
1
˚
.425 A), thus satisfying the so-called geometrical criterion
a
No cycloadduct was formed. See text.
1
6
for aromaticity as well. Therefore, it can be suggested
that the gain in stability by aromaticity occurring in INT1
is in part responsible for the stepwise nature of the
transformation.
Once the reaction mechanism of the process was ana-
lyzed, the influence of substituents attached to the tropone
ring on the regioselectivity of the [8 þ 3]-cycloaddition was
explored. To this end, a series of different 2-substituted
tropones 1bꢀj having donor or acceptor groups directly
attached to the C2-carbon atom of the tropone ring were
reacted with DAC 2 in the reaction conditions used above
(
i.e., 5 mol % SnCl , room temperature, CH Cl for 16 h).
4 2 2
As shown in Scheme 2, all the reactions tested lead to the
formation of the corresponding [8 þ 3]-cycloadducts 3 in
good yields, with the exception of the reactions involving
2-alkoxytropones 1i and 1h and 2-silyloxytropone 1j,
which were recovered unaltered together with a new
product arising from the cyclopropane (see below). Strik-
ingly, inall cases the ring closureoccurredatthe C7-carbon
atom of the initial tropone, which indicates that this
Figure 2. ORTEP-diagram of compound 3e. Ellipsoids are drawn
at the 30% probability level.
[
8 þ 3]-cycloaddition reaction proceeds with complete
thermodynamically (ΔΔG (Ph7ꢀPh2) = 12.9 kcal/mol)
regioselectivity (no traces of the corresponding C2-
cycloadduct were observed in the respective reaction
crudes). In addition, and as expected, cycloadducts
R
favored over the ring closure process forming the C2-
regioisomer via TS2-Ph2. A similar result was computed
in the [8 þ 3]-cycloaddition involving 2-bromotropone
3
as confirmed by NOESY experiments. Single crystals of
bꢀg were formed exclusively as syn-diastereoisomers
1
c (ΔΔG (Br7ꢀBr2) = 6.8 kcal/mol). As the electronic
a
effects of phenyl and bromide substituents are markedly
different, and no effect of the substituents attached to the
aromatic ring was observed, this regioselectivity should
be steric in origin. It can be thus suggested that the steric
hindrance exerted by the substituent attached at the
C2-position may hamper the ring closure at this position
directing the ring closure to occur at the sterically unhin-
dered C7-position of the tropone ring.
the cycloadduct 3e (grown in hexanes/CH Cl solution)
2
2
suitable for X-ray diffraction analysis fully confirm, by
analogy, both the regio- and the relative stereochemistry
of compounds 3 (Figure 2).
We carried out DFT-calculations as well to understand
the regioselectivity, namely the exclusive formation of the
C7- over the C2-cycloadduct, of the transformation. Thus,
both regioisomeric syn-ring closure reactions arising from
the zwitterionic species INT1-Ph2 and INT1-Ph7, formed
upon the initial nucleophilic attack of the phenyltropone
As stated above, 2-alkoxytropones 1h and 1i and 2-sily-
loxytropone 1j did not undergo the [8 þ 3]-cycloaddition,
which may be attributed to the electronic effect exerted
1d to 4b, were computed. As readily seen in Figure 3, the
ring closure leading to the C7-regioisomer (via TS2-Ph7)
1
7
by the donor alkoxy or silyloxy group. Instead, a new
is kinetically (ΔΔG (Ph7ꢀPh2) = 14.4 kcal/mol) and also
a
(
17) Alternatively, coordination of the 2-alkoxytropone to the cata-
(
15) Chen, Z.; Wannere, C. S.; Corminboeuf, C.; Puchta, R.;
Schleyer, P. v. R. Chem. Rev. 2005, 105, 3842.
16) Schleyer, P. v. R.; Jiao, H. Pure Appl. Chem. 1996, 68, 209 and
lyst may be responsible for the lack of reactivity of compounds 1h and 1i.
However, this coordination seems unlikely in the presence of the bulky
TBS-substituent of compound 1j. We thank a reviewer for pointing out
this experiment.
(
references therein.
Org. Lett., Vol. XX, No. XX, XXXX
C

Figure 4. ORTEP-diagram of compound 5. Ellipsoids are drawn
at the 30% probability level.
Figure 3. Computed profile for the ring closure of the [8 þ 3]-
cycloaddition between tropone 1d and SnCl ꢀDCA complex 4.
derivatives and donorꢀacceptor aminocyclopropane 2
has been studied. The process leads to the formation of
amino-substituted tetrahydrocyclohepta[b]pyrans in good
reaction yields and with complete regio- and diastereo-
selectivities. By means of computational-DFT methods, it
was found that this transformation proceeds stepwise
through a zwitterionic intermediate, which resembles the
tropyl cation and therefore is stabilized by some degree of
π-aromaticity. From this intermediate, a ring closure step,
which controls the regio- and diastereoselectivities, occurs
to produce the observed [8 þ 3]-cycloadducts.
4
See caption for Figure 1 for additional details.
compound 5 lacking the characteristic signals of the tro-
pone in the corresponding NMR spectra was isolated in
the processes involving 1h and 1i. Single crystals of the new
compound 5 suitable for X-ray diffraction analysis were
grown in hexanes/CH Cl solution at room temperature.
2
2
As seen in Figure 4, the structure of 5 corresponds to a
dimer of the DAC 2. As tropones 1h,i were recovered
1
unaltered in the reaction conditions used, species 5 is very
8
likely formed by the self-coupling of two molecules of the
SnCl ꢀDAC complex 4. The formation of this dimer
4
Acknowledgment. We are grateful for financial support
from the Spanish MINECO (CTQ2010-20714-C02-01/
BQU and Consolider- Ingenio 2010, CSD2007-00006)
and CAM (S2009/PPQ-1634). A.R.R. acknowledges the
MEC for an FPU grant.
constitutes therefore a side reaction which occurs when
DAC 2 reacts with electron-rich substrates such as alkoxy-
tropones. We want to point out that, although the self-
9
dimerization product of 2 has not been observed so far,
1
9
related dimerization products of DACs have been described.
In summary, the novel Lewis acid catalyzed [8 þ 3]-
cycloaddition reaction between tropone and tropone
Supporting Information Available. Experimentaldetails,
NMR spectra of isolated compounds, crystallographic
data for compounds 3e and 5, computational details,
Cartesian coordinates, and freeenergiesof all the stationary
points discussed in the text. This material is available free of
charge via the Internet at http://pubs.acs.org.
(
18) Moreover, dimer 5 was formed in the reactions of tropones 1h,i
with 2 at ꢀ78 °C for prolonged reaction times. In addition, in a control
experiment, dimer 5 was also formed in the reaction of DAC 2 and SnCl
conducted in the absence of any tropone derivative.
4
(19) (a) Ivanova, O. A.; Budynina, E.a M.; Chagarovskiy, A. O.;
Trushkov, I. V.; Melnikov, M. Y. J. Org. Chem. 2011, 76, 8852. (b)
Chagarovskiy, A. O.; Ivanova, O. A.; Budynina, E. M.; Trushkov, I. V.;
Melnikov, M. Y. Tetrahedron Lett. 2011, 52, 4421.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX