Trans-stereoselectivity in the reaction between homophthalic anhydride and imines

Article abstract of DOI:10.1021/ol801757r

(Equation Presented) The reaction between homophthalic anhydride and imines in the presence of TiCl₄ and diisopropyl ethyl amine is frans-selective. Under these conditions, the reaction using homochiral imines can be highly diastereoselective,

Full text of DOI:10.1021/ol801757r

ORGANIC
LETTERS
2008
Vol. 10, No. 21
4759-4762
Trans-Stereoselectivity in the Reaction
between Homophthalic Anhydride and
Imines
Yosu Vara,†,‡ Tamara Bello,‡ Eneko Aldaba,† Ana Arrieta,‡ Jose´ L. Pizarro,§ Mar´ıa
I. Arriortua,§ Xabier Lopez,‡ and Fernando P. Coss´ıo*,‡
IkerChem Ltd., Tolosa Etorbidea 72, 20018 San Sebastia´n-Donostia, Spain, Kimika
Fakultatea, UniVersidad del Pais Vasco-Euskal Herriko Unibertsitatea, Manuel de
Lardizabal Etorbidea 3, 20018 San Sebastia´n - Donostia, Spain, and Zientzia eta
Teknologia Fakultatea, Mineralogia eta Petrologia Saila, UniVersidad del Pa´ıs
Vasco-Euskal Herriko Unibertsitatea, P. K. 644, Bilbao, Spain
fp.cossio@ehu.es
Received July 30, 2008
ABSTRACT
The reaction between homophthalic anhydride and imines in the presence of TiCl4 and diisopropyl ethyl amine is trans-selective. Under these
conditions, the reaction using homochiral imines can be highly diastereoselective, thus allowing the synthesis of enantiopure 1,2,3,4-tetrahydro-
1-oxoquinoline-4-carboxylic acids.
The reaction between cyclic anhydrides and imines1 to yield
lactams bearing a carboxylate functionality (Scheme 1)
constitutes a convergent route to highly valuable compounds
such as natural products2 or topoisomerase I3 and HOXA13
inhibitors.4
The mechanism of this reaction has been controversial,
and both concerted and stepwise mechanisms have been
proposed.1b Kaneti et al.5 have reported DFT and MO
calculations on the reaction between succinic anhydride and
imines. These authors concluded that the thermal reaction
takes place via a concerted mechanism (Scheme 1, pathway
A) involving the enolic form of the anhydride. Under these
conditions, the cis-isomer is the major product when (E)-
aldimines and homophthalic anhydride are used.6
† IkerChem Ltd.
‡ Kimika Fakultatea.
§ Zientzia eta Teknologia Fakultatea.
(1) (a) Castagnoli, N., Jr. J. Org. Chem. 1969, 34, 3187. (b) Cushman,
M.; Madas, E. J. J. Org. Chem. 1987, 52, 907.
(2) (a) Xu, X.-Y.; Quin, G.-W.; Xu, R.-S.; Zhu, X.-Z. Tetrahedron 1998,
54, 14179. (b) Cushman, M.; Chen, J.-K. J. Org. Chem. 1987, 52, 1517.
(3) (a) Morrell, A.; Anthony, S.; Kohlhagen, G.; Pommier, Y.; Cushman,
M. J. Med. Chem. 2006, 49, 7740. (b) Nagarajan, M.; Morrell, A.; Fort,
B.; Meckley, M. R.; Anthony, S.; Kohlhagen, G.; Pommier, Y.; Cushman,
M. M. J. Med. Chem. 2004, 47, 5651.
(5) Kaneti, J.; Bakalova, S. M.; Pojarlieff, I. G. J. Org. Chem. 2003,
68, 6824.
(6) See for example: (a) Xiao, X.; Anthony, S.; Kohlhagen, G.; Pommier,
Y.; Cushman, M. J. Org. Chem. 2004, 69, 7495. (b) Cushman, M.;
Jayaraman, M.; Vroman, J. A.; Fukunaga, A. K.; Fox, B. M.; Kohlhagen,
G.; Strumberg, D.; Pommier, Y. J. Med. Chem. 2000, 43, 3688. (c) Yadav,
J. S.; Reddy, B. V. S.; Reddy, A. R.; Narsaiah, A. V. S´ıntesis 2007, 3191.
(4) Ng, P. Y.; Tang, Y.; Knosp, W. M.; Stadler, H. S.; Shaw, J. T.
Angew. Chem., Int. Ed. 2007, 46, 5352.
10.1021/ol801757r CCC: $40.75
Published on Web 09/25/2008
2008 American Chemical Society

Scheme 1
.
Possible Routes for the Reaction between Enolizable
Anhydrides and Imines
Scheme 2
.
Reaction between Homophthalic Anhydride 1 and
Aldimines 2a-e
AEnol-based concerted pathway. BEnolate-based stepwise mechanism.
3-5) takes place with high cis-stereocontrol. The reaction
between 1 and (E)-benzylidenemethanamine 2e is trans-
selective (Table 1, entry 5). In contrast, the titanium assisted
version of the reaction takes place with higher stereocontrol,
the trans-derivative being the major one in all the cases
studied. This stereocontrol did not vary significantly when
the reaction between 1a and 2a was conducted at -20 and
-80 °C. The structures of compounds cis-3a and trans-3e
were confirmed by X-ray diffraction analysis (see the
Supporting Information). The structures of the remaining
products were established by comparison with these com-
pounds and with other analogues reported in the literature.1-3
1H NMR analysis of acids 3a-f showed coupling constants
between the vicinal methine protons of ca. 5-6 and 1-2
Hz for the cis and trans stereoisomers, respectively.
In view of these precedents, we decided to explore a
hypothetical Perkin-Mannich route (Scheme 1, pathway B)
in which an enolate derived from the enolizable anhydride
would react with the imine to yield an intermediate contain-
ing the stereochemical information of the new C-C bond.
Subsequent intramolecular cyclization would yield the cor-
responding cyclic amide, probably with a stereocontrol
different to that obtained via pathway A.
To test this hypothesis, we carried out the reaction between
homophthalic anhydride 1 and aldimines 2a-f to yield
racemic 1,2,3,4-tetrahydroisoquinidine carboxylic acids 3a-f
(Scheme 2) in the presence7 of TiCl4 and diisopropyl ethyl
amine (DIPEA) as metal source and base, respectively.8 The
results obtained, together with those observed for the direct
reaction in the absence of the TiCl4/DIPEA pair, are gathered
in Table 1.
To shed some light on the origins of the good stereocontrol
observed in the Perkin-Mannich version of this reaction, we
Our results indicate that the direct reaction between 1 and
imines 2a,b is not stereoselective (Table 1, entries 1 and 2),
whereas the reaction with aldimines 2c,d (Table 1, entries
Table 1. Formation of Compounds (()-3a-f by Reaction
between Homophthalic Anhydride 1 and Aldimines 2a-e
(7) (a) Harrison, C. R. Tetrahedron Lett. 1987, 28, 4135. (b) Evans,
D. A.; Rieger, D. L.; Bilodeau, M. T.; Urp´ı, F. J. Am. Chem. Soc. 1991,
113, 1047. (c) Adrian, J. C., Jr.; Barkin, J. L.; Fox, R. J.; Chick, J. E.;
Hunter, A. D.; Nicklow, R. A. J. Org. Chem. 2000, 65, 6264. (d) Periasamy,
M.; Zurres, S.; Ganesan, S. S. Tetrahedron: Asymmetry 2006, 17, 1323.
(e) Periasamy, M. ARKIVOC 2002, Vii, 151.
method Aa
method Ba
entry
reaction
cis:transb yield (%)c cis:transb yield (%)c
1
2
3
4
5
6
1 + 2a f 3a
1 + 2b f 3b
1 + 2c f 3c
1 + 2d f 3d
1 + 2e f 3e
1 + 2f f 3f
50:50
50:50
94:6
82:18
20:80
27:73
31d, 31e
31d, 31e
91d, 5e
7:93
17:83
3:97
>2:98
>2:98
11:89
60e
76e
80e
63e
65e
45e
(8) Typical experimental procedure: To a stirred solution of homo-
phthalic anhydride 1 (1 mmol, 0.162 g) in 2 mL of dichloromethane was
added 1 M TiCl4 in dichloromethane (1 mL) at 0 °C under argon atmosphere.
After 5 min at 0 °C, DIPEA (1 mmol, 0.17 mL) was added at the same
temperature. After stirring for 20 min, a solution of 1 mmol of the
corresponding imine 2 in 2 mL of dichloromethane was added dropwise.
The reaction mixture was stirred at room temperature for 3 h. The resulting
mixture was washed three times with saturated solution of NH4Cl (3 × 5
mL), dried with Na2SO4, evaporated, and purified by flash chromatography
(Silicagel 60 230-400 mesh, ethyl acetate/hexane 1:1 and then 5:1) to yield
the corresponding product trans-3.
47d, 11e
7d, 63e
23d, 62e
a See Scheme 2 for details. b Determined by 1H NMR on the crude
reaction mixture. c Isolated yields of pure products. d Isolated yield of the
cis-isomer. e Isolated yield of the trans-isomer.
4760
Org. Lett., Vol. 10, No. 21, 2008

carried out DFT9,10 calculations on the process indicated in
Figure 1. This transformation corresponds to the C-C bond
thetical biradical character. Our results indicated that the
electronic structure of INT1 is closed shell in nature. For
instance, the natural occupancies of the four active MOs of
the CASSCF(8,10) calculation were 1.945, 1.964, 1.969, and
1.944. In addition, the triplet state was found to be 32.1 kcal/
mol higher in energy than the singlet. These results indicate
that the more basic nitrogen atom of the iminic moiety in
INT1 does not favor the stabilization of biradicals.
We also located and characterized two different saddle
points associated with the transformation depicted in Figure
1. For this model system TS2, which has a boat conforma-
tion, is more stable than the sofa transition structure TS1.
CASSCF(8,10) single point calculations on both transition
structures also resulted in closed shell electronic structures.
The intermediate product of this C-C bond forming step is
INT2, whose intramolecular cyclization must yield the
correponding cyclic amide, as is shown in Scheme 1.
Figure 1. Transition structures TS1 and TS2 associated with the
C-C bond forming step of the reaction of complex INT1. Energies
include zero-point vibrational energy (ZPVE) corrections and have
been calculated at the B3LYP/6-31G*&LANL2DZ level. Numbers
in parentheses correspond to the relative energy differences.
forming step in the reaction between glutaconic anhydride
and methanimine.
Many mechanistic studies dealing with the TiCl4/amine
system assume that the active enolates are neutral
(CdC-OTiCl3) species11 and/or anionic (CdC-OTiCl4 )
-
complexes.12 A recent paper13 has reported the presence of
-
anionic titanium enolate complexes (CdC-OTiCl4 ) in
which the most stable form has significant biradical character.
The corresponding triplet species was characterized by
electron paramagnetic resonance. We carried out single point
calculations on the optimized structure of INT1 at the
CASSCF(4,4) and CASSCF(8,10) levels to assess its hypo-
Figure 2. Transition structures TS1a and TS2a associated with
the C-C bond forming step leading to cis- and trans-3e from 1
and imine 2e. See the caption of Figure 1 for additional details.
(9) Density-functional theory (DFT) calculations were carried out using
the B3LYP hybrid functional. See: (a) Becke, A. D. J. Chem. Phys. 1993,
98, 5648. (b) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1998, 37, 785.
(c) Vosko, S. H.; Wilk, L.; Nusair, M. Can. J. Phys. 1980, 58, 1200. The
6-31G* basis set was used for all atoms except for titanium, which was
computed using the LANL2DZ effective core potential and basis set. See:
The anionic routes shown in Figure 2 were also explored.
This second reaction corresponds to the first step in the
reaction between 1 and (E)-2e. In this case, saddle point TS3,
which has a sofa conformation and leads to trans-3e, was
found to be more stable than TS4, because of the larger steric
demand between one chlorine atom of the octahedral
environment of the titanium and the phenyl group of the
imine. Because TS4 leads to the formation of cis-3e, the
trans- stereochemical control in this Perkin-Mannich route
stems from the lower energy of transition structures similar
to TS3.
(d) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 299
.
(10) All the calculations reported in this work were carried out using
the Gaussian03 (Rev. D.02) suite of programs: Frisch, M. J. Gaussian03,
revision D.02; Gaussian, Inc.: Wallingford, CT, 2004 (full reference is given
in the Supporting Information)
.
(11) (a) Barraga´n, E.; Olivo, H. F.; Romero-Ortega, M.; Sarduy, S. J.
Org. Chem. 2005, 70, 4214. (b) Itoh, Y.; Yamanaka, M.; Mikami, K. J. Am.
Chem. Soc. 2004, 126, 13174. (c) Ambhaikar, N. B.; Snyder, J. P.; Hotta,
D. C. J. Am. Chem. Soc. 2003, 125, 3699. (d) Pinheiro, S.; Greco, S. J.;
Veiga, L. S.; de Farias, F. M. C.; Costa, P. R. R. Tetrahedron: Asymmetry
2002, 13, 1157.
Org. Lett., Vol. 10, No. 21, 2008
4761

was determined by X-ray diffraction analysis (see the
Supporting Information). This stereocontrol was observed
to be lower when the reaction was carried out between 1
and imines 2h,i (Scheme 3). In these cases, compounds 3 h′
and 3i′ were also obtained, although the trans-stereoselec-
tivity was kept. The stereochemistry of 3i′ was also confirmed
by X-Ray diffraction analysis (see the Supporting Informa-
tion).
Scheme 3
.
Reaction between Homophthalic Anhydride 1 and
Enantiopure Imines 2g-ia
In summary, we have shown that trans-stereoselectivity
can be obtained in the reaction between homophthalic
anhydride and imines. This stereocontrol is achieved by
means of the TiCl4/DIPEA pair. If enantiopure imines are
used, the corresponding homochiral derivatives can be
obtained, especially when the N-substituent is the source of
chirality.
Acknowledgment. Financial support from the UPV/EHU-
GV/EJ (Grant IT-324-07) and the Spanish MEC (Grants
CTQ2007-67528 and INGENIO-CONSOLIDER CSD
2007-00006) is gratefully acknowledged. T.B. and Y.V.
thank their respective MEC fellowships. We also thank
Sergio Villafruela for technical assistance. SGIker technical
support (MEC, GV/EJ, European Social Fund) is gratefully
acknowledged.
Supporting Information Available: Full characterization
of all novel compounds. Energies, zero-point vibrational
energies (ZPVE), imaginary frequencies, and Cartesian
coordinates of the transition structures reported in Figures 1
and 2. This material is available free of charge via the Internet
at http://pubs.acs.org.
aNumbers in parenthesis correspond to yields of isolated pure products.
The diastereomeric excess (de, in brackets) was determined by 1H NMR
on the crude reaction mixture.
OL801757R
Our next step in this preliminary study was to extend the
trans-stereocontrol observed in the titanium route to homo-
chiral imines. We observed that enantiopure imine 2g in the
presence of the TiCl4/DIPEA system at room temperature
yielded a single diastereomer 3g (Scheme 3), whose structure
(12) (a) Yan, T. H.; Lee, H. C.; Tan, C. W. Tetrahedron Lett. 1993, 34,
3559. (b) Yan, T. H.; Tan, C. W.; Lee, H. C.; Lo, H. C.; Huang, T. Y.
J. Am. Chem. Soc. 1993, 115, 2613. (c) Guz, N. R.; Phillips, A. J. Org.
Lett. 2002, 4, 2253.
(13) Moreira, I. de P. R.; Bofill, J. M.; Anglada, J. M.; Solsona, J. G.;
Nebot, J.; Romea, P.; Urp´ı, F. J. Am. Chem. Soc. 2008, 130, 3242.
4762
Org. Lett., Vol. 10, No. 21, 2008