Enantioselective synthesis of 4-isoxazolines by 1,3-dipolar cycloadditions of nitrones to alkynals catalyzed by fluorodiphenylmethylpyrrolidines

Article abstract of DOI:10.1002/adsc.201200033

The first organocatalytic enantioselective 1,3-dipolar reaction between nitrones and alkynals catalyzed by (S)-2-(fluorodiphenylmethyl)pyrrolidine to give 4-isoxazolines (2,3-dihydroisoxazoles) with high enantiomeric excess, excellent yields and low catal

Full text of DOI:10.1002/adsc.201200033

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DOI: 10.1002/adsc.201200033
Enantioselective Synthesis of 4-Isoxazolines by 1,3-Dipolar
Cycloadditions of Nitrones to Alkynals Catalyzed by
Fluorodiphenylmethylpyrrolidines
Josꢀ Alemꢁn,a,* Alberto Fraile,a,* Leyre Marzo,a Josꢀ Luis Garcꢂa Ruano,a
Cristina Izquierdo,a and Sergio Dꢂaz-Tenderob
a
Departamento de Quꢂmica Orgꢁnica (Mꢃdulo 1), Universidad Autꢃnoma de Madrid, Cantoblanco, 28049 Madrid, Spain
Fax : (+34)-91-497-3966; e-mail: jose.aleman@uam.es or alberto.fraile@uam.es
Departamento de Quꢂmica (Mꢃdulo 13), Universidad Autꢃnoma de Madrid, Cantoblanco, 28049 Madrid, Spain
b
Received: January 12, 2012; Revised: March 9, 2012; Published online: June 5, 2012
Dedicated to Dr. Rosario Martꢂn Ramos on the occasion of her retirement.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200033.
Abstract: The first organocatalytic enantioselective
1,3-dipolar reaction between nitrones and alkynals
catalyzed by (S)-2-(fluorodiphenylmethyl)pyrroli-
dine to give 4-isoxazolines (2,3-dihydroisoxazoles)
with high enantiomeric excess, excellent yields and
low catalyst loading (1–5 mol%) is presented. The
catalytic loading could be reduced to 1 mol% with
only slight increases in reaction times.
Keywords: ACHTUNGTRENNUNG[3+2]cycloaddition reactions; 2,3-dihy-
droisoxazoles; iminium ions; 4-isoxazolines; orga-
nocatalysis
Scheme 1. Usefulness of 4-isoxazolines.
4-Isoxazolines or 2,3-dihydroisoxazoles[1] are com-
pounds exhibiting interesting pharmacological proper- quent cyclization of the resulting zinc intermediate
ties (anti-inflamatory action[2] and mitotic kinesin in- [Eq. (1), Scheme 2].[11] This method is not very practi-
hibition[3]), along with other biological activities.[4] cal though because of the required laborious experi-
They have also been used as synthons for preparing mentation. The second method is related to asymmet-
1,3-amino alcohols,[5] aziridines,[6] b-lactams[7] and ric 1,3-dipolar cycloadditions of nitrones and prop-
a wide variety of heterocycles (Scheme 1).[8]
ioloylpyrazoles catalyzed by copper[7a] [Eq. (2),
ACHTUNGTRENNUNG
Several approaches have been developed for the Scheme 2]. The scope of this method is limited to
synthesis of these compounds in racemic form,[9] with R3 =H, Me, CH2Cl and requires the incorporation of
the 1,3-dipolar cycloadditions of nitrones with alkynes the acylpyrazole moiety (which is later transformed
being one of the most successfully used despite prob- into other functionalities) to coordinate the metal
lems with the regioselectivity.[9a] By contrast, very few forming the rigid intermediate that is responsible of
methods concerning the asymmetric synthesis of these the activation of the triple bond as well as the stereo-
compounds have been reported (most of them start- selectivity. To the best of our knowledge, no organo-
ing from chiral pool molecules),[10] with only two of catalytic[12] version of this reaction has been reported,
them involving nitrones and being enantioselecti- despite the fact that catalysts able to interact cova-
ve.[7a,11] The first method consists of the asymmetric lently and non-covalently with different EWG-activat-
addition of alkynylzinc reagents to nitrones in the ed triple bonds are well known.[13] This fact suggests
presence of (R,R)-tartrate as ligand, and the subse- that the main difficulties in the stereoselective control
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Scheme 2. Enantioselective approaches for preparing 4-isoxazolines [Eqs. (1) and (2)] and the present work Eq. (3).
of the cycloaddition of nitrones to activated alkynes VIII, which provided a complete conversion after
will be related with finding the proper catalyst to pro- 24 h and 81:19 enantiomeric ratio (entry 9).
mote restrictions in the many possible approaches of
Next, we examined the influence of increasing the
the nitrone to the linear triple bond. In this work, we size of R (nitrone) on the stereoselectivity. Nitrones
describe our efforts toward finding such a catalyst, 2B and 2C bearing benzyl and tert-butyl groups joined
which allowed us to achieve the first highly efficient to nitrogen, respectively, were interesting for the
organocatalytic method for obtaining 4-isoxazolines larger size. Reactions of 2B (R=Bn) showed a com-
by 1,3-dipolar reaction of nitrones and alkynals under plete conversion under catalysis of VI and VII (also
aminocatalysis [Eq. (3), Scheme 2].[13a]
with VIII), indicating a higher reactivity than 2A
As the model reaction for optimization, nitrone 2A (compare entries 10 and 11 with 7 and 8). Moreover,
was exposed to alkynal 1a in the presence of different the best enantiomeric ratios in reactions of 2B with
secondary amine catalysts I–VIII (Table 1). First, we 1a were obtained using catalyst VI (compare en-
confirmed that the reaction takes place at room tem- tries 10–12). Therefore, this reaction was studied at
perature even in the absence of catalyst (entry 1, lower temperature (08C) and the er was increased to
Table 1), demonstrating that the alkynals are suffi- 88:12 (entry 13). Less important were the results ob-
ciently reactive at room temperature. This reaction tained using other temperatures and solvents (see the
gave racemic 3aA and required 5 days to proceed to Supporting Information). The use of the commercially
completion. Since this background reaction could de- available nitrone 2C (R=t-Bu) gave even better re-
crease the enantiomeric excess, we decided to stop sults (entries 14–17) with VI. The obtained stereose-
the rest of the reactions with this nitrone (2A)[14] after lectivity was higher than with 2B (compare entries 12
24 h in case that the catalyst could decrease its activi- and 14), slightly improved when the temperature was
ty. Incomplete conversion and low enantiomeric lowered (compare entries 14–16), and was maintained
ratios were found with proline (I) and prolinamide by decreasing the catalyst loading to 5% (entry 17) or
(II) (entries 2 and 3). The use of MacMillanꢅs catalyst even 1% (entry 18), although in the latter case the re-
(III) and Jørgensen–Hayashiꢅs catalysts (IV and V) action required 4 days for completion. The enantio-
provided full conversion but poor enantiomeric ratios meric ratio decreased when 0.5 mol% of VI was used
(entries 4–6). Toluene was used as solvent in all these (entry 19). We observed unaltered starting materials
reactions, but the change to THF, DCE or CH2Cl2 did with the use of an acid co-catalyst (TFA) (entry 20),
not improve these results (see the Supporting Infor- whereas the use of benzoic acid gave full conversion,
mation for details). Interestingly, when the OTMS and the obtained ee was similar to the previous one
group of the Jørgensen–Hayashi catalysts (IV and V) (compare entries 17 and 21).
was substituted by fluorine (VI) or hydrogen (VII,
The scope of this reaction was investigated using
VIII), the enantiomeric ratios were improved (en- the optimized reaction conditions in entry 17
tries 7–9), with the best results obtained using catalyst (Table 1). Results obtained for different aryl-substi-
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Enantioselective Synthesis of 4-Isoxazolines by 1,3-Dipolar Cycloadditions of Nitrones to Alkynals
Table 1. Representative screening results for the catalyzed reactions of nitrones 2A–C with the alkynal 1a.[a]
Entry
Cat (mol%)
2-R
Temp. [8C]/Time [h]
Conversion [%][b]
er[c]
1
2
3
4
5
6
7
8
–
2A-Me
2A-Me
2A-Me
2A-Me
2A-Me
2A-Me
2A-Me
2A-Me
2A-Me
2B-Bn
r.t./12
r.t./24
r.t./24
r.t./24
r.t./24
r.t./24
r.t./24
r.t./24
r.t./24
r.t./24
r.t./24
r.t./24
0/24
100
44
30
>99
>99
>99
60
-
I (20 mol%)
II (20 mol%)
III (20 mol%)
IV (20 mol%)
V (20 mol%)
VI (20 mol%)
VII (20 mol%)
VIII (20 mol%)
VI (20 mol%)
VII (20 mol%)
VIII (20 mol%)
VI (20 mol%)
VI (20 mol%)
VI (20 mol%)
VI (10 mol%)
VI (5 mol%)
VI (1 mol%)
VI (0.5 mol%)
VI (5 mol%)[d]
VI (5 mol%)[f]
55:45
52:28
64:36
55:45
55:45
75:25
70:30
81:19
85:15
70:30
70:30
88:12
90:10
95:5
70
9
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
n.r.[e]
>99
10
11
12
13
14
15
16
17
18
19
20
21
2B-Bn
2B-Bn
2B-Bn
2C-t-Bu
2C-t-Bu
2C-t-Bu
2C-t-Bu
2C-t-Bu
2C-t-Bu
2C-t-Bu
2C-t-Bu
r.t./24
ꢀ10/24
ꢀ10/24
ꢀ10/24
0/96
96:4
95:5
95:5
88:12
–
0/120
ꢀ10/24
ꢀ10/24
95:5
[a]
All reactions were performed on a 0.2-mmol scale in 0.4 mL of solvent and stopped at the indicated time
Conversion was determined by H NMR.
Enantiomeric ratio was determined by chiral HPLC.
Reaction carried out with a 5 mol% of TFA.
No reaction.
[b]
[c]
[d]
[e]
[f]
1
Reaction carried out with a 5 mol% of PhCO2H.
tuted (1a–h), alkyl-substituted (1i–l) and alkenyl-sub- 2-octynal (1i) with 2C was slower (5 days) and gave
stituted (1m) alkynals with nitrones 2C–2I (all of lower yield (58%) than that of arylalkynals (24 h and
them N-tert-butyl derivatives) are collected in Table 2. >80% yield), but the high stereoselectivity was main-
These reactions were performed on a 0.2-mmol scale, tained (entry 10). The incorporation of a secondary
except for the entry 2 which was carried out on a 2.0- alkyl group (1j) strongly decreased the reactivity
mmol scale, affording 3aC in 84% isolated yield with- (5 days, entry 11), whereas substrates with tertiary
out any significant erosion of the stereoselectivity alkyl groups (1k) did not react (entry 12), which was
(compare entries 1 and 2). Enantioselectivity and re- also the case for the TMS derivative 1l (entry 13). Re-
activity were exceptionally unaffected by the incorpo- markably, enynals (1m) evolved with good yields and
ration of electron-donating (1b–1d, entries 3–5) or excellent er (entry 14).
electron-withdrawing (1e–1h, entries 6–9) groups on
Finally, we studied the behavior of different N-tert-
the aromatic ring of the arylalkynals. The reaction of butylnitrones.[15] The introduction of electron-donat-
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Table 2. Scope of the reaction of nitrones 2C–I with alkynals 1a–m under catalysis with VI.[a]
Entry
R1/R2
Yield [%]: Product
er [%][b]
1
2
3
4
5
6
7
8
Ph-1a/Ph-2C
Ph-1a/Ph-2C
>99: 3aC
84:[c] 3aC
90: 3bC
>99: 3cC
99: 3dC
85: 3eC
96: 3fC
80: 3gC
99: 3hC
58: 3iC
56: 3jC
n.r.
95:5
96:4
95:5
95:5
95:5
90:10
95:5
94:6
92:8
90:10
92:8
–
p-MeC6H4-1b/Ph-2C
p-MeOC6H4-1c/Ph-2C
p-(t-Bu)C6H4-1d/Ph-2C
p-BrC6H4-1e/Ph-2C
p-F-C6H4-1f/Ph-2C
3,5-(CF3)2C6H3-1g/Ph-2C
3,4-(Cl)2C6H3-1h/Ph-2C
n-pentyl-1i[e]/Ph-2C
cyclohexyl-1j[e]/Ph-2C
t-Bu-1k/Ph-2C
9
10
11
12
13
14
15[d]
16[d]
17[d]
18[d]
19[d]
20[d]
TMS-1l/Ph-2C
n.r.
–
cyclohexenyl-1m/Ph-2C
Ph-1a/p-MeOC6H4-2D
Ph-1a/p-MeC6H4-2E
Ph-1a/p-ClC6H4-2F
Ph-1a/o-MeOC6H4-2G
Ph-1a/p-CNC6H4-2H
Ph-1a/PhCH=CH-2I
72: 3mC
90: 3aD
69: 3aE
80: 3aF
90: 3aG
89: 3aH
96: 3aI
97:3
94:6
94:6
93:7
88:12
83:17
87:13
[a]
All reactions were performed on a 0.2-mmol scale in 0.4 mL of solvent and stopped after 24 h.
Enantiomeric ratio was determined by chiral HPLC (see Supporting Information).
This reaction was carried out in a 2.0-mmol scale.
This reaction was carried out with 5 mol% of catalyst IV.
This reaction was stopped after 5 days.
[b]
[c]
[d]
[e]
ing (2D and 2E) and weakly electron-withdrawing [obtained by reaction of 3aC with (S)-p-tolylsulfin-
(2F) groups did not affect the reactivity and stereose- amide, Scheme 3], which after crystallization could be
lectivity (entries 15–17). However, enantiomeric unequivocally assigned by X-ray diffraction studies.[16]
ratios were not as good when the substituents occu- In order to explain the obtained results, we propose
AHCTUNGTRENNUNG
pied the ortho position (2G, entry 18) or were strongly the stereochemical course indicated in Scheme 4. The
electron-withdrawing (2H, entry 19). Alkenyl nitrone iminium intermediate resulting from reaction of alk-
2I (R2 =PhCH=CH-) also underwent the reaction
ACHTUNGTRENyNGNU nals 2 with catalyst VI could adopt E or Z configura-
tions around the C=N bond, which should be in equi-
with slightly lower stereoselectivity (entry 20).
The absolute configuration of 4-isoxazolines (3) librium in solution.[17] On the basis of the steric situa-
was deduced from that of the N-sulfinylimine 4aC tion, diastereoisomer E should be the more stable
Scheme 3. Synthesis and ORTEP diagram of compound 4aC.
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Enantioselective Synthesis of 4-Isoxazolines by 1,3-Dipolar Cycloadditions of Nitrones to Alkynals
Scheme 4. Proposal for the approach of the nitrone to the iminium ion.
one, because it lacks the interactions of the alkynyl tional theory (DFT), in particular using the B3LYP
with the CFPh2 group, but it is not easy to conclude functional[20] in combination with the 6-31+
whether the stability difference between them ex-
+G
ACHTUNGTREN(NUNG d,p) basis. We first optimized the geometry of
cludes participation of the Z isomer in the reaction.
the E and Z iminium ions formed by reaction of the
At the triple bond, only the p-bond conjugated catalyst VI with the alkynal 1a. We have considered
with the C=N is activated enough for reaction with the three starred conformations for the Z-iminium
the dipole. Thus, four approaches of the nitrone to (first file, Figure 1) and E-iminium (second file,
the E isomer (the same would be true for the Z) are Figure 1). Over the geometry obtained for these six
possible. Two of them correspond to the pseudoendo isomers, we performed single point energy calcula-
approaches to each face of the reactive p bond (syn tions with a more accurate level of theory B3LYP/6-
or anti with respect to the CFPh2 group at the cata- 311+ +GACTHNUTRGNEU(GN 3df,2p). Relative energies shown in
lyst), and the other two to the pseudoexo approaches Figure 1 include zero-point energy correction [ZPE
(Scheme 4). The pseudoendo approaches (endoIsyn and computed with the 6-31+ +G
ACTHNUTRGNE(UNG d,p)] basis set and sol-
endo
I
) should be strongly destabilized by electrostatic vent effects (toluene) using the polarizable continuum
anti
repulsion of the positively charged nitrogens. The model (PCM).[21] According to these calculations, the
exo
pseudoexo approach
I
is likely less stable than the E-iminium ion is clearly favored with respect to the Z
syn
exo
I
because of the steric interactions whenever one isomer. Also, rotamer 3, shown in Scheme 4 for pre-
anti
of the phenyl groups at the catalyst is oriented as indi- dicting the stereochemical course of the reactions, is
exo
cated in Scheme 4. The evolution of the
I
ap- the most populated. Therefore we can conclude that
anti
proach would produce compounds 3, which are the the model proposed in Scheme 4 is supported by the-
major products obtained in the reactions we have oretical calculations indicated in Figure 1. The higher
studied.[18]
stability of rotamer 3 could be attributed to electro-
This analysis, despite satisfactorily predicting the static attractions between the positively charged nitro-
experimental results, is based on two assumptions that gen and the electon-rich fluorine[22] (also stabilizing
are not entirely evident: first, the exclusion of the Z- rotamer 2) and to steric effects.
isomers as participating species in the reaction; and
In conclusion, we have presented the first organo-
second, the arrangement of one of the phenyl groups catalytic enantioselective 1,3-dipolar reaction between
at the catalyst hindering the syn approach of the ni- arylnitrones and alkynals catalyzed by (S)-2-(fluorodi-
trone. In order to clarify these two points, we decided phenylmethyl)pyrrolidine (VI) to yield 4-isoxazolines
to calculate the relative stability of the geometric iso- (2,3-dihydroisoxazoles). It takes place in 1–2 days
mers E and Z in their three possible conformations with high enantiomeric excess, excellent yields and
ꢀ
around the C C bond supporting the fluorinated sub- low catalyst loading (1–5 mol%). The reaction is effi-
stituent of the catalyst. To this end, we performed the- cient with alkenyl, aryl (regardless the electronic char-
oretical calculations using the Gaussian 09 code.[19] acter of the substituents), and primary or secondary
The simulations were carried out with density func- alkyl alkynals. Other 1,3-dipolar and Diels–Alder re-
Adv. Synth. Catal. 2012, 354, 1665 – 1671
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Josꢀ Alemꢁn et al.
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Figure 1. Different conformations of the alkynal iminium ion.
the MICINN for “Ramon y Cajal” contracts. L. M. thanks
the Ministerio de Educaciꢀn y Ciencia for a predoctoral fel-
lowship. We gratefully acknowledge computational time pro-
vided by the Centro de Computaciꢀn Cientꢁfica at the Univer-
sidad Autꢀnoma de Madrid CCC-UAM.
actions of alkynals catalyzed by VI are currently
being studied in our group.[23]
Experimental Section
General Methods
NMR spectra were acquired on a Bruker 300 spectrometer,
running at 300 and 75 MHz for 1H and 13C, respectively.
Chemical shifts (d) are reported in ppm relative to residual
solvent signals (CHCl3, 7.26 ppm for 1H NMR, CDCl3,
77.0 ppm for 13C NMR). 13C NMR spectra were acquired in
the broad-band decoupled mode. Optical rotations were
measured on a Perkin–Elmer 241 polarimeter. Flash column
chromatography was performed using silica gel Merk-60
(230–400 mesh). The ees were determined by HPLC em-
ploying a Daicel Chiralpack IC column.
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12168) and CAM (“programa AVANCAT CS2009/PPQ-
1634”) is gratefully acknowledged. J. A. and S. D. T. thank
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Adv. Synth. Catal. 2012, 354, 1665 – 1671

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[15] In these cases, the ers were slighgly better when cata-
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[16] CCDC 852722 contains the supplementary crystallo-
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[or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK;
fax:
(internat.)
+44-(1223)-336-033,
e-mail:
deposit@ccdc.cam.ac.uk].
[17] For a study iminium ions of a,b-unsaturated aldehydes,
see: C. Sparr, W. B. Schweizer, H. Martꢂn Senn, R. Gil-
mour, Angew. Chem. 2009, 121, 3111; Angew. Chem.
Int. Ed. 2009, 48, 3065.
[18] The model indicated in Scheme 4 suggests that the ste-
reochemical course of these reactions, and therefore
their enantioselectivity, is not depending on the sub-
stituent joined to the nitrogen of the nitrone, but we
have checked that reactions with N-t-Bu nitrone (2C)
are much more enantioselective than those with N-
methyl nitrone (2A). In order to clarify this question
we studied the composition of the uncatalyzed reaction
mixtures (1a+2A) and (1a+2C) at ꢀ108C after 24 h
(the usual time for the reactions in Table 2). In the first
case, the formation of racemic 3aA has taken place,
with a conversion degree around 50%, whereas in the
second one only trazes of 3aC can be detected by
NMR. This would explain the decrease of the enantio-
selectivity observed in uncatatalyzed reactions of 1a
with 2A.
[19] M. J. Frisch et al., Gaussian 09 (Revision B.01), Gaussi-
[11] W. Wei, M. Kobayashi, Y. Ukaji, K. Inomata, Heterocy-
an, Inc., Wallingford CT, 2010.
cles 2009, 78, 717.
[20] a) A. D. Becke, J. Chem. Phys. 1993, 98, 1372; b) C.
Lee, W. Yang, R. G. Parr, Phys. Rev. B 1998, 37, 785.
[21] J. Tomasi, B. Mennucci, R. Cammi, Chem. Rev. 2005,
105, 2999.
[22] A significant contribution of the gauche effect (hyper-
conjugative electron donation from the s orbital of the
[12] In constrast, the aminocatalytic 1,3-dipolar reactions of
nitrones with acroleins to obtain isoxazolidines have
been widely used and, the factors controlling the access
of the nitrones to the two prochiral faces of the imini-
um intermediates are well established, see: a) W. S. Jen,
J. J. M. Wienr, D. W. C. MacMillan, J. Am. Chem. Soc.
2000, 122, 9874; b) S. S. Chow, M. Navalainen, C. A.
Evans, C. W. Johanner, Tetrahedron Lett. 2007, 48, 277;
c) S. Karlsson, H.-E. Hçgberg, Eur. J. Org. Chem. 2003,
2782; d) M. Lemay, J. Trant. W. W. Ogilvie, Tetrahedron
2007, 63, 11644; e) for a general review in 1,3-dipolar
reactions, see: H. Pellissier, Tetrahedron 2007, 63, 3235.
[13] During the evaluation of this manuscript a related
work was published, see: a) X. Cai, C. Wang, J. Sun
Adv. Synth. Catal. 2012, 354, 359–363. For leading refer-
ences on the activation of alkynals, see: b) S. B. Jones,
B. Simmons, D. W. C. MacMillan, J. Am. Chem. Soc.
2009, 131, 13606; c) X. Zhang, S. Zhang, W. Wang,
Angew. Chem. 2010, 122, 1523; Angew. Chem. Int. Ed.
2010, 49, 1481; d) J. Alemꢁn, A. NfflÇez, L. Marzo, V.
Marcos, C. Alvarado, J. L.Garcꢂa Ruano, Chem. Eur. J.
2010, 16, 9453; e) J. Alemꢁn, C. Alvarado, V. Marcos,
A. Nunez, J. L. Garcꢂa Ruano, Synthesis 2011, 1840.
ꢀ
C H bond to the parallel, low-lying antiboding orbital
ꢀ
ꢀ
ꢀ
of the C F bond [sC H!s*C F]) cannot be disre-
garded. This interaction has been proposed by Gilmour
et al. for explaining a similar conformational behavior
of the iminium intermediates formed by VI and a,b-un-
saturated aldehydes (see ref.[17]). They found that VI is
a better organocatalyst than other non-fluorinated
amines of similar structure in some reactions of a,b-un-
saturated aldehydes (epoxidation). They attributed this
behavior to the fact that the gauche effect provides an
extra degree of torsional rigidity to the intermediate
iminium, which improves the stereoselctive control.
[23] A preliminary attempt at deprotection of the N-tert-
butyl-4-isoxazolines was not successful: treatment of
3aC with 5% HCl at room temperature and at 508C
did not give the desired product.
Adv. Synth. Catal. 2012, 354, 1665 – 1671
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1671