Tandem nucleophilic addition-intramolecular aza-michael reaction: Facile synthesis of chiral fluorinated isoindolines

Article abstract of DOI:10.1021/ol102341n

A highly stereoselective synthesis of fluorinated 1,3-disubstituted isoindolines is described. To this end, a tandem reaction consisting of a diastereoselective addition of fluorinated nucleophiles to Ellman's N-(tert-butanesulfinyl)imines followed by an

Full text of DOI:10.1021/ol102341n

ORGANIC
LETTERS
2010
Vol. 12, No. 23
5494-5497
Tandem Nucleophilic Addition-
Intramolecular Aza-Michael Reaction:
Facile Synthesis of Chiral Fluorinated
Isoindolines
Santos Fustero,*,†,‡ Javier Moscardo´,† Mar´ıa Sa´nchez-Rosello´,† Elsa Rodr´ıguez,†
and Pablo Barrio†
Departamento de Qu´ımica Orga´nica, UniVersidad de Valencia, E-46100 Burjassot, Spain,
and Laboratorio de Mole´culas Orga´nicas, Centro de InVestigacio´n Pr´ıncipe Felipe,
E-46012 Valencia, Spain
santos.fustero@uV.es
Received October 1, 2010
ABSTRACT
A highly stereoselective synthesis of fluorinated 1,3-disubstituted isoindolines is described. To this end, a tandem reaction consisting of a
diastereoselective addition of fluorinated nucleophiles to Ellman’s N-(tert-butanesulfinyl)imines followed by an intramolecular aza-Michael
reaction has been developed. This strategy allows for the construction of isoindolines bearing several degrees of fluorination (mono-, di-, or
trifluoromethyl as well as heavier fluorinated groups). In the majority of all cases, the products are formed as single isomers.
Selective incorporation of fluorine atom(s) into organic
molecules has become a powerful strategy to modulate their
biological properties. Specifically, the replacement of one
or more hydrogen atoms by fluorine in the vicinity of an
amine function results in a lower basicity. Thus, a decrease
in acute toxicity and an increase in the metabolic stability
of the target drug are usually observed.1 On the other hand,
although isoindolines are substructures present in a variety
of natural products and pharmaceuticals,2 they still lack
general routes for their preparation in a stereoselective
manner.3 Furthermore, tandem reactions are very attractive
since they increase synthetic efficiency by decreasing the
number of laboratory operations required and the quantities
of solvents and chemicals used, reducing cost and time and
allowing for the creation of molecular complexity from
simple substrates. Moreover, the synthesis of optically active
compounds plays a pivotal role in medicinal chemistry.
(2) (a) Valencia, E.; Freyer, A. J.; Shamma, M.; Fajardo, V. Tetrahedron
Lett. 1984, 25, 599. (b) Portevin, B.; Tordjman, C.; Pastoureau, P.; Bonnet,
J.; De Nanteuil, G. J. Med. Chem. 2000, 43, 4582–4593. (c) Stuk, C. L.;
Assink, B. K.; Bates, R. C.; Erdman, B. T.; Fedij, V.; Jennings, S. M.;
Lassig, J. A.; Smith, R. J.; Smith, T. L. Org. Process Res. DeV. 2003, 7,
851.
(3) (a) Gawley, R. E.; Chemburkar, S. R.; Smith, A. L.; Anklelar, T. V.
J. Org. Chem. 1988, 53, 5381. (b) Meyers, A. I.; Santiago, B. Tetrahedron
Lett. 1995, 36, 5877. (c) Enders, D.; Braig, V.; Raabe, G. Can. J. Chem.
2001, 79, 1528. (d) Backer, R. T.; Collado Cano, I.; De Frutos-Garc´ıa,
O.;Doecke, C. W.; Fischer, M. J.; Kuklish, S. L.; Mancuso, V.; Martinelli,
M.; Mullaney, J. T.; Ornstein, P. L.; Xie, C. Eli Lilly & Co., WO 2003
1061 600, 2003. (e) Clayden, J.; Menet, C. J. Tetrahedron Lett. 2003, 44,
3059. (f) Lamblin, M.; Couture, A.; Deniau, E.; Granclaudon, P. Tetrahe-
dron: Asymmetry 2008, 19, 111.
† Universidad de Valencia.
‡ Centro de Investigacio´n Pr´ıncipe Felipe.
(1) (a) Be`gue´, J.-P.; Bonnet-Delpon, D. Bioorganic and Medicinal
Chemistry of Fluorine; Wiley: Hoboken, NJ, 2008. (b) Flourine in
Bioorganic Chemistry; Welch, J. T., Eswarakrishman, S., Eds.; Wiley: New
York, 1991.
10.1021/ol102341n  2010 American Chemical Society
Published on Web 10/29/2010

Therefore, the interest in combining asymmetric processes
with tandem reactions is obvious since multiple stereogenic
centers can be created in a single synthetic step.4 Our group’s
interest in organofluorine chemistry5 together with our
ongoing efforts in tandem reactions including an intramo-
lecular aza-Michael reaction as the last step6 has led us to
design the following cascade approach to R-fluoroalkylated
1,3-isoindolines (Scheme 1).7 The isoindoline core would
the envisioned tandem reaction. Moreover, both 2a and its
noncyclized precursor 3a were formed as single diastereoi-
somers.12 This positive preliminary result prompted us to
optimize this interesting transformation. Our initial screening
for conditions is summarized in Table 1.
Table 1. Optimization of the Tandem Reaction Using CF3TMS/
TBAT as the Fluorinated Nucleophile
Scheme 1. Cascade Design
be formed through an intramolecular aza-Michael addition
onto an R,ꢀ-unsaturated ester conveniently placed. The
isoindoline structures thus obtained would constitute a new
family of fluorinated ꢀ-amino acid derivatives.5b The required
R-fluoroalkylated amine would arise from the diastereose-
lective addition of a fluorinated nucleophile to a suitable
imine. Among the available chiral auxiliaries (CA), we chose
Ellman’s (R)-N-(tert-butanesulfinyl) imines8 as they have
been successfully used in this context.9
2a + 3ac
entry xa yb solv temp (°C) t (h) H+ yield (%) 2a:3a
1
2
3
4
5
6
7
8
1
1
2
2
2
2
2
2
1
2
1
2
2
2
2
2
THF -55
THF -55
THF -55
THF -55
THF -55 to rt
DMF -55 to rt
1
1
1
1
3
3
3
1
A
A
A
A
A
A
A
B
67
70
73
90
99
40
0
1:5
1:4
1:5
1:5
3:1
5:1
-
Tol
-55 to rt
THF -55 to rt
99
>20:1
Given its wide use and availability, the Ruppert-Prakash
reagent10 (CF3TMS) was regarded as the fluorinated nucleo-
phile of choice in a first approach. TBAT has proved to be
the appropriate activating agent for the addition of this
nucleophile onto sulfinylimines.11 When model substrate 1a
was reacted with CF3TMS in the presence of TBAT in THF
at -55 °C, we observed the formation of two products along
with unreacted starting material. We were pleased to identify
in the reaction mixture the target product 2a resulting from
a CF3TMS equiv. b TBAT equiv. c 2a and 3a were formed as single
diastereoisomers. A: NH4Cl. B: 1 N HCl (2 drops)/SiO2.
The addition of 2 equiv of both CF3TMS and TBAT proved
crucial for achieving good conversion (Table 1, entries 1-4).
By allowing the reaction to reach room temperature, most of
the product was obtained in the cyclized form 2a, but a
considerable proportion of the addition product 3a was still
observed (Table 1, entry 5).13 THF was the best solvent, while
the use of other solvents such as DMF or toluene led to
unfavorable results (Table 1, entries 5-7). Finally, the quench-
ing step was considered to obtain an optimum result. When
using HCl/SiO2 instead of NH4Cl for the hydrolysis, only the
desired tandem product was obtained (Table 1, entry 8). With
these optimized conditions in hand, we turned to study the scope
and limitations of this new transformation.14 First, we explored
the use of differently substituted arene rings (Table 2, entries
1-7). Electron-rich (Table 2, entries 2-4) as well as electron-
poor (Table 2, entries 5-7) aromatic rings are suitable substrates
for this transformation. We then turned our attention to the ester
group, thus proving the expected lack of influence of the substitu-
(4) For a recent review of asymmetric tandem reactions, see: Pellissier,
H. Tetrahedron 2006, 62, 1619.
(5) For recent reviews, see: (a) Fustero, S.; Sanz-Cervera, J. F.; Acen˜a,
J. L.; Sa´nchez-Rosello´, M. Synlett 2009, 525. (b) Acen˜a, J. L.; Simo´n-
Fuentes, A.; Fustero, S. Curr. Org. Chem. 2010, 14, 928.
(6) (a) Fustero, S.; Jime´nez, D.; Sa´nchez-Rosello´, M.; del Pozo, C. J. Am.
Chem. Soc. 2007, 129, 6700. (b) Fustero, S.; Jime´nez, D.; Moscardo´, J.;
Catala´n, S.; del Pozo, C. Org. Lett. 2007, 9, 5283. (c) Fustero, S.; Moscardo´,
J.; Jime´nez, D.; Pe´rez-Carrio´n, M. D.; Sa´nchez-Rosello´, M.; del Pozo, C.
Chem.sEur. J. 2008, 14, 9868. (d) Fustero, S.; Monteagudo, S.; Sa´nchez-
Rosello´, M.; Flores, S.; Barrio, P.; del Pozo, C. Chem.sEur. J. 2010, 16,
9835. (e) Fustero, S.; Catala´n, S.; Sa´nchez-Rosello´, M.; Simo´n-Fuentes,
A.; del Pozo, C. Org. Lett. 2010, 12, 3484.
(7) For a recent approach to nonfluorinated 1,3-disubstituted isoindolines,
see: Enders, D.; Narine, A. A.; Toulgoat, F.; Bisshops, T. Angew. Chem.,
Int. Ed. 2008, 47, 566, and references therein.
(8) The reaction was also performed with the (S)-N-(p-tolylsulfinyl)imine
derivative; however, no product was formed, and mostly starting material
was recovered from the reaction mixture.
(9) For a recent and exhaustive review about tert-butanesulfinamide and
its use in synthesis, see: Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem.
ReV. 2010, 110, 3600.
(12) Diastereoselectivities were determined by integration of character-
istic signals both in the 1H and 19F NMR on the crude NMR spectra. They
were found inaltered after column chromatography. See: Soloshonok, V.
Angew. Chem., Int. Ed. 2006, 45, 766.
(10) (a) Krishnamurti, R.; Bellew, B. R.; Prakash, G. K. S. J. Org. Chem.
1991, 56, 984. (b) Prakash, G. K. S.; Yudin, A. K. Chem. ReV. 1997, 97,
757. (c) Singh, R. P.; Shreeve, J. M. Tetrahedron 2000, 56, 7613.
(11) For the diastereoselective addition of CF3TMS to (R)-N-(tert-
butanesulfinyl)imines, see: (a) Prakash, G. K. S.; Mandal., M.; Olah, G. A.
Angew. Chem., Int. Ed. 2001, 40, 589. (b) Prakash, G. K. S.; Mandal, M.;
Olah, G. A. Synlett 2001, 77.
(13) In all cases, the intermediate product 3a-l could be isolated.
Treatment of the former with t-BuOK in THF at -40 °C gave the
corresponding cyclized product 2a-l.
(14) The required substrates (R,S)-1a-l are conveniently synthesized
from commercially available starting materials in a two-step sequence (see
Supporting Information).
Org. Lett., Vol. 12, No. 23, 2010
5495

evaporation of a solution of 2k in hexanes (Figure 1, right
side). The stereochemical outcome is in accordance with the
previous reports.10a
Table 2. Scope of the New Tandem Reaction
For one derivative of each class (bearing CF3, C2F5, or
C3F7), namely, 2a, 2j, and 2l, the tert-butanesulfinyl group
was removed with 4 M HCl in dioxane yielding the
corresponding free amines after basification (Scheme 2).16
a
entry
2
X
Y
R
RF
yield (%)b
dr
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
MeO
O-CH2-O
Me
F
CF3
NO2
H
H
H
H
H
Et
Et
Et
Et
Et
Et
Et
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
C2F5
C2F5
C3F7
94
74
77c
84
80
62
52
70
88c
45
71
37
99:1
20:1
99:1
35:1
24:1
60:1
89:1
99:1
99:1
99:1
99:1
99:1
Scheme 2. Removal of the tert-Butanesulfinyl Group
H
H
H
H
H
H
H
H
H
iPr
tBu
Et
10
11
12
2j
2k
2l
H
H
tBu
tBu
a RFTMS (2.0 equiv), TBAT (2.0 equiv). b Isolated yields after flash
column chromatography c Yields for the two-step procedure: the crude
reaction was dissolved in THF and treated with t-BuOK at -40 °C for
0.5 h.
To expand our methodology and make it synthetically
more useful, we decided to use some partially fluorinated
nucleophiles. The introduction of CF2H and CFH2 units,
along with CF3, in organic molecules is of major importance
as the degree of fluorination plays a crucial role in the
modification of their physical, chemical, and biological
properties. Thus, for instance, R-monofluoromethylamines
have been used as building blocks in the design of anticho-
linergic, antiemetic, and antispastic drugs and enzyme
inhibitors since they were first reported as selective inhibitors
of the biosynthesis of aminergic neurotransmitters more than
30 years ago.17 Therefore, we used the nucleophilic fluoro-
alkylating agents PhSO2CFXH (5, X ) H; 6, X ) F).18
tion at this position (Table 2, entries 8 and 9). Finally, we decided
to try some heavier analogues of the Ruppert-Prakash reagent.
Both CF3CF2TMS and CF3CF2CF2TMS participate in this
new tandem reaction, and the corresponding products were
obtained in moderate to good yields (Table 2, entries 10-12).
The observed syn diastereoselectivity was determined by
the cross peak observed between the CF3 and the CH2 R to
the ester group in the 2D-NMR HOESY experiment carried
out on product 2b (Figure 1, left side).15 The absolute
When using the monofluorinated reagent 5, product 7 (X
) H) was obtained as a 1.5:1 mixture of two separable
diastereoisomers, at the exocyclic stereocenter bearing the
fluorine atom, in excellent yield by treating the crude addition
product with t-BuOK in THF at -40 °C for 30 min (Scheme
3). The formation of the product 7 as a mixture of
diastereoisomers is inconsequencial as this stereocenter is
meant to be destroyed in a later step. On the other hand, the
product 8 (X ) F) arising from reagent 6 was formed in a
tandem fashion just by allowing the reaction mixture to reach
-20 °C during 3 h (Scheme 3).19 For both substrates 7 and
8 the deprotection of the isoindoline nitrogen was carried
(15) Assuming the reversibility of the aza-Michael addition (see ref 6d)
the formation of the thermodynamic product is expected. As can be inferred
from the ORTEP diagram (Figure 1, right side), the substituents at the 1
and 3 positions are oriented anti to the bulky substituent on the nitrogen
(thus syn to each other).
(16) During the deprotection step, a transesterification reaction with
MeOH was observed.
(17) Kollonitsch, J.; Perkins, L. M.; Patchett, A. A.; Doldouras, G:A:;
Marburg, S.; Duggen, D. E.; Maycock, A. L.; Aster, S. D. Nature 1978,
274, 906.
Figure 1. Determination of the relative and absolute stereochemistry
by 2D-NMR and X-ray experiments.
(18) (a) For the addition of 5 to N-(tert-butanesulfinyl)imines, see: Li,
Y.; Ni, C.; Liu, J.; Zhang, L.; Zheng, J.; Zhu, L.; Hu, J. Org. Lett. 2006, 8,
1693. (b) For the addition of 6 to N-(tert-butanesulfinyl)aldimines, see: Li,
Y.; Hu, J. Angew. Chem., Int. Ed. 2005, 44, 5882. (c) For the addition of
6 to N-(tert-butanesulfinyl)ketimines, see: Liu, J.; Hu, J. Chem.sEur. J.
2010, 16, 11443.
stereochemistry was assigned related to the known (RS)
stereochemistry of the chiral auxiliary by analysis of the
X-ray difraction pattern of a suitable crystal obtained by slow
5496
Org. Lett., Vol. 12, No. 23, 2010

Scheme 3
.
Reaction with Mono- and Difluorinated Nucleophiles
Scheme 4. Desulfonylation and Hydrolysis of 7 and 8
5 and 6a
strategy for the synthesis of other heteroaromatic motifs and
the use of other nucleophiles (fluorinated and nonfluorinated)
are currently ongoing in our laboratories and will be reported
in due course.
a Method A: t-BuOK (0.5 equiv), THF, -40 °C, 0.5 h. Method B:
-78 to -20 °C.
out prior the desulfonylation step. The latter was achieved
by treatment with Na(Hg) in MeOH (Scheme 4).20
Acknowledgment. We would like to thank the Spanish
Ministerio de Ciencia e Innovacio´n (CTQ2007-61462 and
CTQ2010-19774) and Generalitat Valenciana (PROMETEO/
2010/061) for its financial support. M.S.-R. and P.B. express
their thanks for Juan de la Cierva contracts, and J.M. thanks
the Generalitat Valenciana for a predoctoral contract.
In conclusion, a new tandem reaction consisting of the
addition of fluorinated nucleophiles to (R)-N-(tert-butane-
sulfinyl)imines followed by an intramolecular aza-Michael
addition has been described. This process has been applied
to the diastereoselective synthesis of fluorinated 1,3-disub-
stituted isoindolines. Studies on the application of this
Supporting Information Available: Experimental pro-
cedures and NMR spectra for all new compounds, as well
as crystallographical data for compound 2k. This material
is available free of charge via the Internet at http://pubs.acs.org.
(19) Moreover, 28% of the noncyclized precursor 3m was also obtained.
(20) (a) Other methods described for desulfonylation, such as Mg/MeOH,
Mg/DMF, and Raney Ni proved ineffective for these systems. (b) In the
desulfonylation step, a transesterification reaction with MeOH took place.
OL102341N
Org. Lett., Vol. 12, No. 23, 2010
5497