Aminals as substrates for sulfur ylides: A synthesis of functionalized aziridines and N-heterocycles

Article abstract of DOI:10.1021/ol070507f

Sulfur ylides stabilized by Ar, vinyl, or amide groups react with five-membered-ring tert-butylsulfinyl aminals to give functionalized chiral, nonracemic aziridines in high yield and with good selectivities (up to 15:1 transxis, up to >95:5 trans dr, alwa

Full text of DOI:10.1021/ol070507f

ORGANIC
LETTERS
2007
Vol. 9, No. 11
2099-2102
Aminals as Substrates for Sulfur
Ylides: A Synthesis of Functionalized
Aziridines and N-Heterocycles
Christoforos G. Kokotos and Varinder K. Aggarwal*
School of Chemistry, UniVersity of Bristol, Bristol BS8 1TS, United Kingdom
V.aggarwal@bristol.ac.uk
Received February 28, 2007
ABSTRACT
Sulfur ylides stabilized by Ar, vinyl, or amide groups react with five-membered-ring tert-butylsulfinyl aminals to give functionalized chiral,
nonracemic aziridines in high yield and with good selectivities (up to 15:1 trans:cis, up to >95:5 trans dr, always >95:5 cis dr). The intermediate
aziridines can be converted into pyrrolidines or piperidines depending on the reaction conditions.
Lactols and related hemiaminals, readily available synthetic
intermediates, are masked electrophiles but nevertheless react
readily with a range of nucleophiles including phosphorus
ylides1 and stabilized2 and semistabilized3 sulfur ylides. These
reactions occur via the ring-opened aldehyde, which is only
present in very low concentrations. Even so, despite the
propensity for semistabilized sulfur ylides to undergo
competing rearrangement reactions when the desired reaction
with the electrophile is slow (because in this case it was in
low concentration), we were able to achieve a highly
enantioselective synthesis of functionalized pyrrolidines and
piperidines (Scheme 1).3 These reactions occur via the
intermediate epoxides which can be isolated, or ring opened
to give the corresponding 1,2-amino alcohols.3
In considering the extension of this process to the synthesis
of 1,2-diamines, we required reactions of sulfur ylides with
Scheme 1. Reactions of Sulfur Ylides with N,O-Hemiacetals:
Synthesis of Functionalized Pyrrolidines and Piperidines
* Address correspondence to this author. Fax: +44 (0) 117-929-8611.
Phone: +44 (0) 117-954-6315.
(1) (a) Kawada, K.; Tsushima, T. Heterocycles 1989, 28, 573. (b) Seno,
K.; Hagishita, S. Chem. Pharm. Bull. 1989, 37, 948. (c) Kamata, S.; Haga,
N.; Tsuri, T.; Uchida, K.; Kakushi, H.; Arita, H.; Hanasaki, K. J. Med.
Chem. 1990, 33, 229. (d) Ohtani, M.; Narisada, M. J. Med. Chem. 1990,
33, 1027. (e) Holmes, A. B.; Smith, A. L.; Williams, S. F. J. Org. Chem.
1991, 56, 1393.
(2) (a) Valpuesta, M.; Durante, P.; Lopez-Herrera, F. J. Tetrahedron 1993,
49, 9547. (b) Heras-Lopez, A.; Pino-Gonzalez, M. S.; Sarabia-Garcia, F.;
Lopez-Herrera, F. J. J. Org. Chem. 1998, 63, 9630 and references cited
therein.
(3) Kokotos, C. G.; Aggarwal, V. K. Chem. Commun. 2006, 2156.
10.1021/ol070507f CCC: $37.00
© 2007 American Chemical Society
Published on Web 04/28/2007

aminals. However, a search of the literature revealed that
while nucleophilic additions of Grignard reagents to N,O-
acetals had been described,4 there were no reported reactions
with aminals (Scheme 2). Furthermore, there were no reports
Table 1. Reaction of Aminal 4 with Sulfur Ylide 5
Scheme 2. Aminals as Substrates for Nucleophilic Additions
overall
6 + 7 trans
cis
dr
entry
1
conditions
trans:cisa (%)
dr
8
LiHMDS, 18 h,
R1 ) Ts
NaHMDS, 18 h,
R1 ) Ts
KHMDS, 18 h,
R1 ) Ts
P2 base, 3.5 h,
R1 ) Ts
trace
of reactions of more complex nucleophiles such as ylides
with either N,O-acetals or aminals. Nevertheless, we recog-
nized a potential opportunity to effect such reactions and
also to render them asymmetric. In particular, following
amine deprotonation of aminal 1, if R2 is less anion-
stabilizing than R1 the ring-opened, active electrophile 3 will
be favored over aminal 2, thus promoting the reaction with
a sulfur ylide (Scheme 3). For these reasons and to introduce
2
3
4
5
trace
6:1
13:1
12:1
11
>95:5
>95:5
77b
70:30 >95:5
P2 base, 5 h,
reflux 15 h,
R1 ) Ts
46c
6
P2 base, 3.5 h,
R1 ) Boc
15:1
39
>95:5
>95:5
Scheme 3. Proposed Reaction of Aminals with Sulfur Ylides
a Overall trans/cis ratios determined by calculation from isolated yields.
b Major trans-aziridine was isolated pure in 50%. c Pyrrolidine 8 was isolated
as a single diastereomer. Piperidine 16 was also isolated in 12% yield.
reaction following aziridination led to ring closure to give
pure pyrrolidine 8 in 46% isolated yield as a single
diastereoisomer (entry 5). The less electron-withdrawing Boc
group at R1 could also be employed and although the
aziridine was obtained with good diastereoselectivity in this
case, the yield was rather low (entry 6). Presumably, there
is a lower concentration of the active imine due to the lower
pKa of the amide (pKa of t-BuOCONH2 ) 25; pKa of TsNH2
) 16)8 and so side-reactions involving the semistabilized
ylide now effectively compete with the desired reaction
resulting in reduced yields.
asymmetry, substrate 45 with R1 ) Ts and R2 ) S(O)t-Bu6
was selected for a study employing the phenyl-stabilized
ylide derived from 5.
Exploration of the reaction conditions revealed that the
choice of base was critical to the success of the reaction
(Table 1). While standard Li-, Na-, and K-hexamethyldi-
silazide bases gave very little product (entries 1-3), the use
of the P2-phosphazene base7 was much more successful
furnishing the desired aziridines in 77% yield (entry 4).
Although high trans selectivity was observed (6:7, 13:1),
diastereocontrol imparted from the tert-butylsulfinyl group
was rather low (trans dr, 70:30). Subsequent heating of the
Aminal 4 was subsequently reacted with a much broader
range of sulfur ylides (Table 2). The electron-rich aryl
sulfonium salt 9 gave broadly similar selectivity to the benzyl
sulfonium salt 5 in relation to the sulfinyl auxiliary (entry
1), whereas the electron-deficient salt 10 gave improved
diastereoselectivity (entry 2). Allyl- and amide-stabilized
sulfonium ylides (11 and 12) also worked well furnishing
aziridines in good yields (entries 3 and 4). In these two cases
the auxiliary imparted essentially perfect stereocontrol
although a mixture of cis- and trans-aziridines was obtained.
In the case of the amide-stabilized ylide concomitant ring
opening of the trans-aziridine occurred during the course of
the reaction. Simply leaving the reaction mixture for longer
(4) For selected references see: (a) Carcano, M.; Nicotra, F.; Pauza, L.;
Russo, G. J. Chem. Soc., Chem. Commun. 1989, 297. (b) Behr, J. B.; Erard,
A.; Guillerm, G. Eur. J. Org. Chem. 2002, 1256. (c) Liautard, V.;
Desvergnes, V.; Martin, D. R. Org. Lett. 2006, 7, 1299.
(5) Unthank, M. G.; Husain, N.; Aggawal, V. K. Angew. Chem., Int.
Ed. 2006, 45, 7066.
(6) (a) Cogan, D. A.; Liu, G.; Ellman, J. A. Tetrahedron 1999, 55, 8883.
(b) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org.
Chem. 1999, 64, 1278. (c) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am.
Chem. Soc. 2003, 125, 11276.
(7) P2 base is N,N,N′,N′-tetraethyl-N′-[tris(dimethylamino)phosphor-
anylidene)phosphoric triamide ethylamine.
(8) pKa values (DMSO) obtained from the following: http://
www.chem.wisc.edu/areas/reich/pkatable/index.htm.
2100
Org. Lett., Vol. 9, No. 11, 2007

it is assumed that the same situation applies to the intermedi-
ate sulfinylimines. If this is the case, the addition transition
states are responsible for the stereochemical outcome of the
reaction. During betaine formation there is a preference for
the sulfonium group to be gauche to the imine nitrogen to
enable a positive Coulombic interaction to occur. In the case
of the formation of the trans-aziridine, this will place the
small hydrogen adjacent to the bulky sulfinyl group, but in
the case of the cis-aziridine it places the bulky Ph group
close to the sulfinyl group and so is less favored. However,
steric factors may outweigh electronic factors as Robiette
has suggested in related reactions of N-Ts imines11 and so
formation of the cis isomer may occur via TS-I instead,
which again should be less favored as stabilizing Coulombic
interactions are now absent. This should lead to high levels
of trans selectivity. However, with allyl- or amide-stabilized
ylides the cis/trans ratio was very low. In the former case
this could be because the vinyl substituent is small and both
anti and syn TS’s are equally tolerated, and in the latter case
it could be because the reaction is now reversible. Addition
of amide-stabilized ylides to N-Ts imines has been shown
to be reversible9 and in such cases cis isomers are favored
as the two carbon substituents prefer to be anti to the bulky
tosyl group. The tert-butylsulfinyl group is likely to be of
intermediate size and so may not control the stereochemistry
as well, accounting for the low cis/trans selectivity observed.
The good to excellent diastereoselectivity imparted from
the auxiliary can be rationalized by the established model
for the preferred conformation of the sulfinylimine (Figure
2),12 which has been reinforced by DFT calculations.13 The
Table 2. Reaction of Aminal 4 with Various Sulfur Ylides
overall
trans
dr
cis
dr
entry
R
trans:cisa 13 + 14 (%)
15
1
4-MeO-Ph (9)
4-Cl-Ph (10)
CHdCH2 (11)
CONHPh (12)
CONHPh (12)
4.5:1
11.5:1
1.3:1
43
65:35 >95:5
85:15 >95:5
2
66b
73
3
>95:5
>95:5
>95:5
4
1.1:1
63c
45
>95:5 29
>95:5 47
5d
1.1:1
a Overall trans/cis ratios determined by calculation from isolated yields.
b trans-Aziridine 13 was isolated in 50% as a single diastereomer.
c Aziridines were isolated as a mixture of trans:cis 1:4. d Reaction time was
48 h.
reaction time resulted in complete conversion of the trans-
aziridine into pyrrolidine 15, leaving the cis-aziridine behind
(entry 5).
As has been observed with aldehydes,9 ester-stabilized
ylides did not react with aminal 4. Presumably, the higher
barrier to the ring closure of the betaine (relative to aryl
stabilized ylides), coupled with higher stability of the ylide
promotes reversion of the betaine back to starting materials
rather than ring closure.9b
The high cis/trans selectivity observed with aryl-stabilized
ylides can be rationalized by analysis of the likely transition
states involved in betaine formation (Figure 1). It has been
Figure 2. Proposed model for addition of ylide to the imine.
origin of this preference has been attributed to the follow-
ing: (i) the repulsions between the lone pairs of electrons
present on the N, S, and O atoms, (ii) the nN f σ*SO negative
hyperconjugation, and (iii) the intramolecular C-H‚‚‚O
electrostatic interaction (this H-bond is analogous to metal-
oxo complexes with aldehydes as reported by Corey14). In
the absence of metal counterions (which might otherwise
chelate to the sulfinyl group or the nucleophile) this
conformation is also likely to be the reactive conformation
Figure 1. Proposed transition states leading to betaine intermedi-
ates.
established that betaine formation is nonreversible in the case
of addition of phenyl-stabilized ylides to N-Ts imines,10 and
(11) Robiette, R. J. Org. Chem. 2006, 71, 2726.
(12) (a) Plobeck, N.; Powell, D. Tetrahedron: Asymmetry 2002, 13, 303.
(b) Morton, D.; Pearson, D.; Field, R. A.; Stockman, R. A. Chem. Commun.
2006, 1833. (c) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res.
2002, 35, 985.
(13) Bharatam, P. V.; Punam Uppal, A.; Kaur, D. J. Chem. Soc., Perkin
Trans. 2 2000, 43.
(9) (a) Payne, G. B. J. Org. Chem. 1968, 33, 3517. (b) Aggarwal, V.
K.; Charmant, J. P. H.; Fuentes, D.; Harvey, J. N.; Hynd, G.; Ohara, D.;
Picoul, W.; Robiette, R.; Smith, C.; Vasse, J. L.; Winn, C. L. J. Am. Chem.
Soc. 2006, 128, 2105.
(10) Yang, X. F.; Zhang, M. J.; Hou, M. X.; Dai, L. X. J. Org. Chem.
2002, 67, 8097.
Org. Lett., Vol. 9, No. 11, 2007
2101

of the sulfinylimine. In this conformation the t-Bu group
makes one face of the imine (the Si face) much more
hindered than the other. On the basis of this established
model, the stereochemistry of the major products has been
assigned. Although the aziridine could be ring-opened under
the reaction conditions to give pyrrolidine, we were interested
in exploring if the regioselectivity could be diverted to give
piperidine instead. For this reason, we explored a range of
Lewis acids, and were pleased to find that Yb(OTf)3 provided
the piperidine cleanly and in high yield (Scheme 4). To fully
Scheme 5. Cleavage of the tert-Butylsulfinyl Group
Scheme 4. Ring-Opening of Aziridine 6 to Afford Piperidine
16
astereocontrol (from the auxiliary) was achieved with aryl-,
allyl-, and amide-stabilized ylides although cis/trans selectiv-
ity was more variable. The aziridines could be made to
undergo ring closure under the reaction conditions to give
pyrrolidines, while treatment with Yb(OTf)3 led to pip-
eridines instead.
Acknowledgment. We thank Avecia/NPil Pharma (Robin
Fieldhouse/John Blacker), Johnson Matthey (Mark Hooper),
Syngenta (David Ritchie), and the DTI for support of this
work through an MMI grant.
realize the potential of this methodology, the tert-butylsul-
finyl group was removed efficiently by using ethanolic HCl
in dioxane from both the aziridine and piperidine (Scheme
5).15 Piperidines with this general structure have emerged
as highly potent antagonists of the NK-1 receptor, which
has implications in the pathogenesis of a diverse range of
diseases.16
In conclusion, we have described the first reaction of
aminals with sulfur ylides which lead to aziridines. By using
the Ellman tert-butylsulfinyl group, good to perfect di-
Supporting Information Available: Procedures and full
characterization of new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL070507F
(16) Desai, M. C.; Lekowitz, S. L.; Thadeio, P. F.; Longo, K. P.; Suider,
R. M. J. Med. Chem. 1992, 35, 4911. There are over 300 references in
SciFinder to the piperidine (+)-CP 99,994.
(14) Corey, E. J.; Lee, T. W. Chem. Commun. 2001, 1321.
(15) Morton, D.; Pearson, D.; Field, R. A.; Stockman, R. A. Org. Lett.
2004, 14, 2377.
2102
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