Stereoselective [2,3]-sigmatropic rearrangements of unstabilized nitrogen ylides

Article abstract of DOI:10.1021/ol071188v

The steric course of the [2,3]-rearrangement of several unstabilized nitrogen ylides has been investigated. The reactions proceed cleanly through an anti transition state, affording modest to good yields of a single diastereomer of the product. In two exa

Full text of DOI:10.1021/ol071188v

ORGANIC
LETTERS
2007
Vol. 9, No. 16
3093-3096
Stereoselective [2,3]-Sigmatropic
Rearrangements of Unstabilized
Nitrogen Ylides†
Robert E. Gawley* and Kwangyul Moon
Department of Chemistry and Biochemistry, UniVersity of Arkansas,
FayetteVille, Arkansas 72701
bgawley@uark.edu
Received May 21, 2007
ABSTRACT
The steric course of the [2,3]-rearrangement of several unstabilized nitrogen ylides has been investigated. The reactions proceed cleanly
through an anti transition state, affording modest to good yields of a single diastereomer of the product. In two examples containing an
N-cinnamyl group, a competing [1,2]-rearrangement affords a minor product.
Electrophilic substitution reactions of R-alkoxy- and R-ami-
noorganolithium compounds (eq 1) have been extensively
studied and constitute an important class of synthetic
generated by tin-lithium exchange,5 which was later shown
to be invertive at the lithium-bearing carbon (eq 2).6-8
methods, with hundreds of applications reported so far.1,2
A
second class of carbon-carbon bond-forming reactions
utilizing these reactive intermediates is sigmatropic rear-
rangements.3,4 In 1978, Still and Mitra reported the first
example of a [2,3]-rearrangement of an organolithium
† Warmly dedicated to Professor Miguel Yus on the occasion of his 60th
birthday.
(1) Hoppe, D.; Marr, F.; Bru¨ggemann, M. Top. Organomet. Chem. 2003,
5, 61-138.
(2) Beak, P.; Johnson, T. A.; Kim, D. D.; Lim, S. H. Top. Organomet.
Chem. 2003, 5, 139-176.
The nitrogen (aza) analogue of the Still-Wittig [2,3]-
rearrangement (eq 3) is less facile, due primarily to the lower
stability of the lithium amide compared to the lithium
alkoxide product of the oxygen version.3,4,9,10 Once generated,
(3) Marko´, I. In ComprehensiVe Organic Synthesis. SelectiVity, Strategy
and Efficiency in Modern Organic Chemistry; Trost, B. M., Fleming, I.,
Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 913-974.
(4) Tomooka, K. In The chemistry of organolithium compounds; Rap-
poport, Z., Marek, I., Eds.; John Wiley & Sons, Ltd.: Chichester, 2004, p
749-828.
(6) Verner, E. J.; Cohen, T. J. Am. Chem. Soc. 1992, 114, 375-377.
(7) Hoffmann, R.; Bru¨ckner, R. Angew. Chem., Int. Ed. Engl. 1992, 31,
647-649.
(8) Tomooka, K.; Igarashi, T.; Watanabe, M.; Nakai, T. Tetrahedron
Lett. 1992, 33, 5795-5798.
(5) Still, W. C.; Mitra, A. J. Am. Chem. Soc. 1978, 100, 1927-1928.
10.1021/ol071188v CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/12/2007

the N-allyl R-aminoorganolithium often follows competing
[1,2]- and [2,3]-rearrangement pathways (eq 3).11-13 Quat-
ernization of the nitrogen (eq 4) with a trimethylsilyl group,14
boron trifluoride,15 or an alkyl group13,16 accelerates the
concerted [2,3]-rearrangement over the radical-mediated
[1,2]-rearrangement of the ylides. The steric course of the
anionic and ylide aza-[2,3]-rearrangements is invertive if the
metal bearing carbon is stereogenic (eqs 3 and 5),13 but the
stereoselectivity at the migration terminus of nitrogen ylides
has only been explored in stabilized ylides such as the enolate
shown in eq 4. In most cases, the diastereoselectivity is
modest,16-18 with only a few examples of high selectivity in
auxiliary mediated processes.19,20 We now report the results
of our studies on the diastereoselectivity at the migration
terminus of the [2,3]-rearrangement of several unstabilized,
lithio-nitrogen ylides (eq 5), in which we find that the
rearrangement is highly stereoselective. Note: Strictly speak-
ing, the ylide is the zwitterion having a positive nitrogen
and a negative carbon. Since the anionic carbon is stereo-
genic, we draw the carbon-lithium ion pair as a bond.
butyllithium in THF at -78 °C for 1 h, quenching with
methanol, and silica gel chromatography afforded a 69%
yield of tetrabutyltin, indicating that transmetalation to the
ylide is facile in this system. Quaternization of racemic 1
with E-crotyl bromide, and E- and Z-cinnamyl bromide
affords ammonium salts 2a-c, as shown in Scheme 1. For
Scheme 1
some compounds, anion exchange from halide to hexafluo-
rophosphate facilitated handling, provided a salt that was less
hygroscopic, and increased solubility in organic solvents (see
the Supporting Information).
Scheme 2
Stannane 1 is a challenging test of the methodology for
two reasons. First, stannane 1 fails to undergo tin-lithium
exchange, so it was of interest to determine whether
quaternization of the nitrogen would facilitate the exchange.
Second, we wanted to evaluate the diastereoselectivity of
the [2,3]-rearrangement in the context of acyclic stereose-
lection. To test the first point, 1 was simply quaternized with
methyl iodide. Treatment of the methiodide salt with
(9) Nakai, T.; Tomooka, K. Pure Appl. Chem. 1997, 69, 595-600.
(10) Gawley, R. E.; Coldham, I. In The Chemistry of Organolithium
Compounds (Patai Series); Rappoport, Z., Marek, I., Eds.; Wiley: Chich-
ester, 2004; pp 997-1053.
(11) Heard, G. L.; Yates, B. F. J. Org. Chem. 1996, 61, 7276-7284.
(12) Coldham, I. J. Chem. Soc., Perkin Trans. 1 1993, 1275-1276.
(13) Gawley, R. E.; Zhang, Q.; Campagna, S. J. Am. Chem. Soc. 1995,
117, 11817-11818.
(14) Murata, Y.; Nakai, T. Chem. Lett. 1990, 2069-2072.
(15) Kessar, S. V.; Singh, P.; Singh, K. N.; Kaul, V. K.; Kumar, G.
Tetrahedron Lett. 1995, 36, 8481-8484.
(16) Coldham, I.; Middleton, M. L.; Taylor, P. L. J. Chem. Soc., Perkin
Trans. 1 1998, 2817-2821.
(17) Roberts, E.; Sanc¸on, J. P.; Sweeney, J. B.; Workman, J. A. Org.
Lett. 2003, 5, 4775-4777.
(18) Zhou, C.-Y.; Yu, W.-Y.; Chan, P. W. H.; Che, C.-M. J. Org. Chem.
2004, 69, 7072-7082.
(19) Aggarwal, V. K.; Fang, G. y.; Charmant, J. P. H.; Meek, G. Org.
Lett. 2003, 5, 1757-1760.
(20) Workman, J. A.; Garrido, N. P.; Sanc¸on, J.; Roberts, E.; Wessel,
H. P.; Sweeney, J. B. J. Am. Chem. Soc. 2005, 127, 1066-1067.
As illustrated in Scheme 2, stannylammonium ions 2a-c
were treated with butyllithium in THF at -60 °C to effect
transmetalation and stirred at that temperature for 20-24 h.
3094
Org. Lett., Vol. 9, No. 16, 2007

After workup and column chromatography, amines 5a-c
were obtained in the yields shown in Table 1, entries 1-3.
Again, exchange of the halide anion for PF6- often facilitated
handling of the salt, increased its solubility in organic
solvents and made it less hygroscopic.
Transmetalation of 9a-c afforded ylides 10a-c, and
ultimately their rearrangement products, as summarized in
Table 1, entries 4-6, and illustrated in Scheme 4. The
Table 1. Rearrangements of Ylides (Stannane + BuLi, -60
°C, unless Otherwise Noted)
entry ylide
R1
R2
X-
product(s)
yield (%)
1
2
3
4
5a
6a
2a
2b
2c
10a
10b
10c
Me
Ph
H
Me
Ph
H
H
H
I-
PF6
5a
5b
5c
57
54
29
60
55
35
Scheme 4
-
-
-
Ph PF6
H
H
PF6
Br-
12a
12b + 14b (4:1)
12c + 14c (9:1)
Ph Br-
a T ) -83 °C; MeLi instead of BuLi for transmetalation.
Of interest in these rearrangements is the possibility of
two transition-state conformers, syn and anti 4a-c, which
would afford diasteromeric products 5 or 6, and possibly
[1,2]-rearrangement product 7. In all cases, only one dias-
tereomer was isolated. Independent synthesis of 5b and 5c
established the relative configurations (see the Supporting
Information). It appears that the [2,3]-rearrangement prefers
the transition structure anti-4, independent of alkene geom-
etry, even though anti 4c having a Z double bond appears
somewhat more congested. The lower yield from the
Z-cinnamyl intermediate 3c may indicate that steric crowding
in the anti transition state slows the rearrangement, allowing
pathways toward nonproductive decomposition to become
more competitive; in this case, there were numerous uni-
dentified polar byproducts. It is noteworthy that under these
conditions, none of the [1,2]-products 7a-c were detected.
If R2 and R3 in eq 5 are different, then the nitrogen is a
stereocenter and the stereoselectivity of the rearrangement
will rely on the stereoselective quaternization of the nitrogen.
To probe the diastereoselectivity of the rearrangement in
cyclic systems, we chose racemic N-methyl-2-(tributylstan-
nyl)piperidine, 8. Based on precedent from a single example
in an earlier report,13 we anticipated that alkylation of 8
would occur trans to the tin.
E-crotyl ylide 10a rearranged to a mixture of isomers, of
which piperidine 12a was the major (92%) component. The
isomers were not obtained in sufficient quantity to identify;
one may be the [1,2]-product 14a, while others are diaster-
eomers that could have arisen from transition structure syn-
11 or from minor contaminants of cis alkene ylide (10, R2
) Me, R1 ) H). trans-Cinnamyl ylide 10b afforded a 3.6:
1mixture of [2,3]-product 12b and [1,2]-product 14b, while
cis-cinnamyl ylide 10c afforded a 6.9:1 mixture of [2,3]-
product 12c and [1,2]-product 14c. None of the diastereo-
meric products 13b,c were detected by GC-MS, and the
structure of 12b was confirmed by independent synthesis
(see the Supporting Information). To further confirm these
assignments, stannane 8 was transmetalated with BuLi at
-78 °C in THF and alkylated with trans-cinnamyl bromide
according to our established procedure.21 Analysis of the
products revealed a 35:65 mixture of SN2 product 14b, and
SN2′ product 12b. In the rearrangement of 10b,c, the extra
stabilization afforded by the phenyl group probably facilitates
In the event, alkylation of 8 with E-crotyl bromide and
with E- and Z-cinnamyl bromide afforded ammonium ions
9a-c, with 90-94% diastereoselectivity, as indicated by
integration of the N-methyl peaks in the NMR (Scheme 3).
Scheme 3
(21) Gawley, R. E.; Zhang, Q. J. Org. Chem. 1995, 60, 5763-5769.
Org. Lett., Vol. 9, No. 16, 2007
3095

homolytic cleavage of the allylic C-N bond to produce [1,2]-
products 14b,c after radical recombination. In summary,
nitrogen ylides 3a-c and 10a-c rearrange preferentially
through transition structures anti-4 and anti-11, creating two
adjacent stereocenters with a high degree of stereoselectivity.
Further applications of the [2,3]-rearrangement of unstabi-
lized nitrogen ylides are under active investigation and will
be reported in due course.
NIH for partial support (GM 56271). Core facilities were
funded by the NIH (P20 R15569) and the Arkansas Bio-
sciences Institute. We are grateful to Dr. Donna Iula for
exploratory experiments.
Supporting Information Available: Full experimental
details, independent syntheses of 5b, 5c, and 12b, charac-
terization data, and NMR spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment is made to the donors of the Petroleum
Research Fund, administered by the American Chemical
Society, for partial support of this work. We also thank the
OL071188V
3096
Org. Lett., Vol. 9, No. 16, 2007