Remarkable salt effect on in-mediated allylation of N-tert-butanesulfinyl imines in aqueous media: Highly practical asymmetric synthesis of chiral homoallylic amines and isoindolinones

Article abstract of DOI:10.1021/ol8001514

A highly practical and efficient asymmetric synthesis of chiral homoallylic amines by In-mediated allylation of chiral N-tert-butanesulfinyl imines in aqueous media at room temperature was developed. With 2-formylbenzoate imine substrates, the method allows the highly enantioselective achievement of a variety of pharmacologically important 3-allyl isoindolinone compounds.

Full text of DOI:10.1021/ol8001514

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1259-1262
Remarkable Salt Effect on In-Mediated
Allylation of N-tert-Butanesulfinyl Imines
in Aqueous Media: Highly Practical
Asymmetric Synthesis of Chiral
Homoallylic Amines and Isoindolinones
Xing-Wen Sun,† Min Liu,† Ming-Hua Xu,*,†,‡ and Guo-Qiang Lin*,†
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin
Road, Shanghai 200032, China, and Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
xumh@mail.sioc.ac.cn
Received January 22, 2008
ABSTRACT
A highly practical and efficient asymmetric synthesis of chiral homoallylic amines by In-mediated allylation of chiral N-tert-butanesulfinyl
imines in aqueous media at room temperature was developed. With 2-formylbenzoate imine substrates, the method allows the highly
enantioselective achievement of a variety of pharmacologically important 3-allyl isoindolinone compounds.
In recent years, organic reactions that can be performed in
aqueous media without using organic cosolvent have attracted
great interest because of significant environmental and
economical advantages over conventional reactions in organic
solvents.1 Among them, the indium-mediated reactions under
aqueous conditions have been an important subject.2 Since
the first report of allylindium addition to aldehydes in water
in 1991,3a considerable progress has been made in the
allylation of carbonyl compounds in aqueous media.3 How-
ever, the corresponding addition of the allylindium reagents
to imine compounds to give homoallylic amines in aqueous
media has been little explored.4 One major and severe
problem is that imines are often easily hydrolyzed in aqueous
media and are less electrophilic. Thus far, only a few
examples of using imine analogues such as sulfonimines,5
hydrazones,6 oxime ethers,7 and glyoxylate imines8 have
shown some success in aqueous indium-mediated allylation.
To the best of our knowledge, there has been no report on
(3) (a) Li, C.-J.; Chan, T.-H. Tetrahedron Lett. 1991, 32, 7017. (b)
Paquette, L. A.; Mitzel, T. M. J. Am. Chem. Soc. 1996, 118, 1931. (c)
Paquette, L. A.; Lobben, P. C. J. Org. Chem. 1998, 63, 5604. (d) Shin, J.
A.; Cha, J. H.; Pae, A. N.; Choi, K. I.; Koh, H. Y.; Kang, H.-Y.; Cho, Y.
S. Tetrahedron Lett. 2001, 42, 5489. (e) Kargbo, R. B.; Cook, G. R. Curr.
Org. Chem. 2007, 11, 1287.
(4) For recent reviews on allylation, see: (a) Nair, V.; Ros, S.; Jayan,
C. N.; Pillai, B. S. Tetrahedron 2004, 60, 1959. (b) Ding, H.; Friestad, G.
K. Synthesis 2005, 2815. (c) Merino, P.; Tejero, T.; Delso, J. I.; Mannucci,
V. Curr. Org. Synth. 2005, 2, 479. (d) Tao, C.-Z.; Zhang, W.; Liu, L.;
Guo, Q.-X. Chin. J. Org. Chem. 2007, 27, 45.
(5) (a) Lu, W.; Chan, T. H. J. Org. Chem. 2000, 65, 8589. (b) Lu, W.;
Chan, T. H. J. Org. Chem. 2001, 66, 3467.
(6) (a) Kumar, H. M. S.; Anjaneyulu, S.; Reddy, E. J.; Yadav, J. S.
Tetrahedron Lett. 2000, 41, 9311. (b) Miyabe, H.; Yamaoka, Y.; Naito, T.;
Takemoto, Y. J. Org. Chem. 2004, 69, 1415.
† Shanghai Institute of Organic Chemistry.
‡ Shanghai Institute of Materia Medica.
(1) (a) Li, C.-J.; Chan, T. H. Organic Reactions in Aqueous Media;
Wiley: New York, 1997. (b) Grieco, P. A. Organic Synthesis in Water;
Blackie: London, 1998. (c) Joo´, F. Aqueous Organometallic Catalysis;
Kluwer: Dordrecht, 2001. (d) Lindstro¨m, U. M. Chem. ReV. 2002, 102,
2751. (e) Li, C.-J. Chem. ReV. 2005, 105, 3095. (f) Li, C.-J.; Chen, L. Chem.
Soc. ReV. 2006, 35, 68. (g) Herrerias, C. I.; Yao, X.; Li, Z.; Li, C.-J. Chem.
ReV. 2007, 107, 2546.
(2) (a) Li, C.-J. Chem. ReV. 1993, 93, 2023. (b) Li, C.-J.; Chan, T.-H.
Tetrahedron 1999, 55, 11149. (c) Podlech, J.; Maier, T. C. Synthesis 2003,
633. (d) Shen, Z.-L.; Loh, T.-P. Org. Lett. 2007, 9, 5413 and references
cited therein.
10.1021/ol8001514 CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/15/2008

the asymmetric synthesis of optically active homoallylic
amines in aqueous media by indium-mediated allylations.
In this paper, we present our studies regarding a solution to
this issue and disclose a highly practical, efficient, and
stereospecific approach for the synthesis of chiral homoallylic
amines and isoindolinones under environmentally friendly
reaction conditions.
We previously documented the successful use of chiral
N-tert-butanesulfinyl imines for room-temperature highly
diastereoselective allylation in both THF and HMPA systems
mediated by zinc.9 Encouraged by these results, we consid-
ered the possibility of developing an aqueous chemical
strategy toward a more practical synthesis of chiral homo-
allylic amines. In our effort to develop such a process, we
discovered that the reaction of N-tert-butanesulfinyl imines
with indium and allyl bromide in saturated aqueous NaBr10
could proceed smoothly to give the desired allylation
products in excellent dr’s and yields at ambient temperature.
By using (R)-N-sulfinyl imine 1a as a substrate, we first
examined the potential of allylation mediated by zinc and
indium in water (Table 1, entries 1-2). To our delight, the
vents.12 To achieve better results, the reaction conditions were
carefully screened, and a series of saturated aqueous salt
solutions were employed as the reaction media. The results
were promising, as revealed in entries 3-12. An increase
of the reaction yield was observed in all cases in electrolyte-
rich aqueous solutions. When saturated aqueous NH4Br was
used as the solvent, the reaction produced a very good yield
of 90%, along with a high diastereomeric ratio of 94:6
(1S:1R) (entry 5). With saturated aqueous NaBr, a significant
improvement in diastereoselectivity (97:3 dr) was obtained
(entry 6). Notably, the use of 4 equiv of In was found
essential to achieve a higher yield (92%) than when 2 or 3
equiv was used (entry 6 vs entries 11 and 12). According to
the observations, it appears that the reaction stereoselectivity
is sensitive to the cation and anion in the solution. However,
the exact reasons for this salt effect are not clear at this time.
After identifying the optimal reaction conditions, we set
out to explore the substrate generality. A wide variety of
N-sulfinyl imines were investigated, and the results are
summarized in Table 2. Gratifyingly, aromatic, heteroaro-
Table 2. Scope of Diastereoselective Allylation in Aqueous
Media
Table 1. Effect of Salt and Optimization of the Reaction
Conditions
yield
(%)b
entrya
1
R
2
drc
time
(h)
yieldb
(%)
drc
(1S:1R)
entrya
M
solvent
H2O
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
1b
1c
1d
1e
1f
1g
1h
1i
4-ClC6H4
2b
2c
2d
2e
2f
2g
2h
2i
99
97
99
85
93
98
95
94
92
99
95
84
81
99
98
98
90
73
74
84
82
87
92
97:3
98:2
97:3
98:2
99:1
4-MeC6H4
4-CF3C6H4
4-MeOC6H4
4-PhC6H4
1
2
3
4
5
6
7
8
9
Zn
In
In
In
In
In
In
In
In
In
In
In
24
12
12
12
12
12
12
12
12
12
12
12
trace
20
76
67
90
92
88
86
92
92
83
75
-
H2O
92:8
88:12
93:7
94:6
97:3
90:10
89:11
94:6
94:6
97:3
97:3
sat. aq NH4Cl
sat. aq NH4I
sat. aq NH4Br
sat. aq NaBr
sat. aq NaI
sat. aq NaCl
sat. aq KBr
sat. aq LiBr
sat. aq NaBr
sat. aq NaBr
3-ClC6H4
98:2
98:2
3-MeOC6H4
2-MeOC6H4
2-FC6H4
>99:1
>99:1
>99:1
>99:1
>99:1
98:2
98:2
98:2
94:6
95:5
95:5
>99:1
92:8
96:4
96:4
1j
1k
1l
2j
2k
2l
2-BrC6H4
2,4-Cl2C6H3
2,4-(MeO)2C6H3
3,4-(MeO)2C6H3
R-naphthyl
â-naphthyl
2-thiophenyl
3-furanyl
2-pyridyl
ferrocenyl
propyl
10
11d
12e
1m
1n
1o
1p
1q
1r
1s
1t
1u
1v
1w
1x
2m
2n
2o
2p
2q
2r
2s
2t
2u
2v
2w
2x
a
Reaction was performed with 0.25 mmol of imine 1a in 5 mL of solvent
at rt. b Isolated yield. c Determined by 1H NMR of the crude materials. d
3
e
equiv of In. 2 equiv of In.
reaction with indium took place at room temperature and
gave the desired homoallylic amine 2a in 20% yield and
92:8 (1S:1R)11 dr after 12 h. Although the yield was not ideal,
we realized that the diastereoselectivity of the reaction re-
mained as high under aqueous conditions as in organic sol-
isopropyl
cyclohexyl
phenethenyl
95:5
a
Reactions were carried out with 0.25 mmol of imine 1, 1 mmol of
In/allyl bromide in 5 mL of sat. aq NaBr at rt. b Isolated yield. c Determined
1
by H NMR of the crude materials.
(7) (a) Miyabe, H.; Nishimura, A.; Ueda, M.; Naito, T. Chem. Commun.
2002, 1454. (b) Bernardi, L.; Cere`, V.; Femoni, C.; Pollicino, S.; Ricci, A.
J. Org. Chem. 2003, 68, 3348.
(8) Piao, X.; Jung, J.-K.; Kang, H.-Y. Bull. Korean Chem. Soc. 2007,
28, 139.
(9) Sun, X.-W.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2006, 8, 4979.
matic, aliphatic, and olefinic imines were all found to be
suitable substrates and produced the corresponding homo-
1260
Org. Lett., Vol. 10, No. 6, 2008

allylic amines in good to excellent yields as well as very
high diastereoselectivities.13 In the cases of aryl imines
1b-1n, electron-donating or -withdrawing substituents did
not seem to affect the reaction diastereoselectivity. Remark-
ably, substrates having an ortho substituent on the benzene
ring afforded extremely high diastereoselectivities (99%) in
all cases (entries 8-12), indicating an evident steric effect
of R. With ferrocenyl imine, an equally high stereoselec-
tion (>99:1 dr) was observed (entry 19). For alkyl imines,
it is similar that more bulky isopropyl and cyclohexyl gave
better selectivity (entries 20-22). Further extension to a less
reactive ketimine substrate was also studied. With the
N-sulfinyl imine of 4′-bromoacetophenone, a diastereomeric
ratio of 94:6 was observed, but the yield was low (30%).
Assuming an analogous reaction mechanism, the absolute
configurations of the amine products were considered as S.14
A demonstration of the synthetic utility of this aqueous
allylation is presented in Scheme 1. N-Sulfinyl imino ester
aqueous NaBr. The reactions proceeded smoothly at room
temperature and gave desired products 4a-g with excellent
diastereoselectivities (>99:1 dr)13 (Scheme 2). The stereo-
Scheme 2. Synthesis of Chiral 3-Substituted Isoindolinones
chemistry of the newly formed carbon center was further
confirmed as S by X-ray crystallography of homoallylic
amine 4g (Figure 1).17 It is noteworthy that the reaction
Scheme 1. Synthesis of D-Allylglycine
1y was subjected to the allylindium addition in saturated
aqueous NaBr at room temperature on a gram scale, and
N-sulfinyl-R-amino ester product 2y was obtained in 95%
yield with 96% de. Removal of the sulfinyl and ethyl groups
using 6 N HCl followed by neutralization with propylene
oxide yielded unnatural amino acid D-allylglycine.15 To our
knowledge, this approach represents one of the most
convenient asymmetric syntheses of allylglycine reported to
date.16
Inspired by the above findings that sterically encumbered
ortho-substituted arylimines are fantastic reactants, we next
turned our attention to more challenging 2-formylbenzoate
imine substrates. Under similar reaction conditions, (R)-3a-g
were treated with indium and allyl bromide in saturated
Figure 1. X-ray crystal structure of the allylation product 4g.
stereoselectivity is not influenced by the aromatic substitu-
tion. For imine 3c that contains two ortho substituents, a
relatively low yield was observed due to the understandable
addition difficulty. Furthermore, N-sulfinyl cleavage of the
obtained allyl adducts 4a-g with HCl in MeOH resulted in
the subsequent lactamization to a series of highly enantio-
merically enriched 3-allyl-isoindolinones 5a-g in excellent
yields (88-99%). The optical purity of 5a was proved to be
(10) For a report of In-mediated addition of allyl bromide to N-tert-
butanesulfinyl imines in THF, see: Foubelo, F.; Yus, M. Tetrahedron:
Asymmetry 2004, 15, 3823.
(11) The configuration was assigned by comparison with the results in
ref 9.
(12) A 90:10 dr was observed in Zn-mediated allylation in THF. See ref
9.
1
(13) The dr’s were determined by H NMR of the crude materials. For
comparsion, the minor diastereomers were assigned independently by our
previously reported Zn-mediated approach in the HMPA system. See ref 9
for reaction details.
(14) The allylation with 2-pyridyl imine (1s) may exhibit reversal of
stereoselectivity to give the (R)-product. See: Kuduk, S. D.; DiPardo, R.
M.; Chang, R. K.; Ng, C.; Bock, M. G. Tetrahedron Lett. 2004, 45, 6641.
(15) 95% ee by HPLC. The opposite stereochemical outcome in this case
may be rationalized by considering the transition state change because of
the chelation of the indium atom with the ester carbonyl.
(16) (a) Workman, J. A.; Garrido, N. P.; Sancon, J.; Roberts, E.; Wessel,
H. P.; Sweeney, J. B. J. Am. Chem. Soc. 2005, 127, 1066. (b) Douat, C.;
Heitz, A.; Martinez, J.; Fehrentz, J.-A. Tetrahedron Lett. 2001, 42, 3319,
and references cited therein. (c) Myers, A. G.; Gleason, J. L. Org. Synth.
1999, 76, 57.
(17) Crystallographic data for 4g (C17H24BrNO3S): T ) 293 (2) K;
wavelength: 0.71073 Å; crystal system: orthorhombic; space group:
P212121; unit cell dimensions: a ) 8.9648(10) Å, b ) 9.3633(11) Å, c )
24.021(3) Å, R ) 90o, â ) 90o, γ ) 90o; V ) 2016.3(4) Å3; Z ) 4; Fcalcd
) 1.325 Mg/m3; F(000) ) 832; final R indices [I > 2σ(I)]: R1 ) 0.0600,
wR2 ) 0.1180; R indices (all data), R1 ) 0.1008, wR2 ) 0.1370; 11004
reflections measured, 3953 were unique (R(int) ) 0.1437);. CCDC 671400
contains 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.
Org. Lett., Vol. 10, No. 6, 2008
1261

>99% ee by chiral HPLC analysis on a Chiralpak OJ-H
column.18 Chiral 3-substituted isoindolinones are valuable
pharmacological compounds and important synthetic building
blocks; however, methods for their stereoselective synthe-
sis remain few.19 Notably, our current strategy of chiral
3-allyl-isoindolinone synthesis provides alternative access to
a broad range of 3-alkyl-isoindolinones20 as the 3-allyl
function group offers a particularly useful reaction site for
further elaborations.
ease in aqueous media without any organic cosolvents at
room temperature. This practical method not only allows
access to a wide range of enantiomerically enriched homo-
allylic amines but also enables the further synthesis of a
variety of chiral 3-allyl-isoindolinone derivatives in good
yields.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (20672126, 20721003),
the Chinese Academy of Sciences, and the Major State
Basic Research Development Program (2006CB806106) is
acknowledged.
In summary, we have developed a simple, mild system
for highly diastereoselective indium-mediated allylation of
N-sulfinyl imines. The reactions can be accomplished with
(18) See Supporting Information for details.
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(19) (a) Comins, D. L.; Hiebel, A.-C. Tetrahedron Lett. 2005, 46, 5639,
and references cited therein. (b) Deniau, E.; Enders, D.; Couture, A.;
Grandclaudon, P. Tetrahedron: Asymmetry 2005, 16, 875. For a review,
see: Stajer, G.; Csende, F. Curr. Org. Chem. 2005, 9, 1277.
(20) For a catalytic asymmetric strategy to 3-aryl-isoindolinones by us:
Wang, Z.-Q.; Feng, C.-G.; Xu, M.-H.; Lin, G.-Q. J. Am. Chem. Soc. 2007,
129, 5336.
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