The silicon-assisted aza-[2,3]-wittig sigmatropic rearrangement

Full text of DOI:10.1021/jo960329w

4820
J . Org. Chem. 1996, 61, 4820-4823
Sch em e 1
Th e Silicon -Assisted Aza -[2,3]-Wittig
Sigm a tr op ic Rea r r a n gem en t†
J ames C. Anderson,*,‡ D. Craig Siddons,‡
Stephen C. Smith,*,§ and Martin E. Swarbrick‡
Department of Chemistry, University of Sheffield,
Sheffield, S3 7HF UK and Zeneca Agrochemicals,
J ealott’s Hill Research Station,
Bracknell, Berkshire, RG42 6ET, UK
Received February 16, 1996
We have independently reported the first example of
an acyclic aza-[2,3]-Wittig sigmatropic rearrangement (eq
1).1 There are only two prior reports of true examples of
this transformation, although they involved the use of
cyclic precursors 1-benzyl-4-vinyl-2-azetidinone2 and vi-
nyl aziridines.3 The ease with which these particular
rearrangements occurred is undoubtedly due to relief of
ring strain in the four- and three-membered ring sub-
strates, respectively. There have been unsuccessful
attempts to perform the acyclic variant which do not
invoke this driving force.4,5 Recently, Gawley has re-
ported acyclic examples involving R-lithio pyrrolidines,
but the desired products of the anionic rearrangements
were contaminated with [1,2] products.6 Higher yields
and enantioselectivities were obtained via the corre-
sponding ylide rearrangements.
Sch em e 2
1). We anticipated that increasing the steric bulk of R
would favor 5 with respect to 4 so as to avoid a
destabilizing 1,2 interaction. Preparation of the desired
allylic amines 9a -c was accomplished in four steps from
the allylic alcohols 6a -c via the established procedure
for stereoselective conversion of secondary allylic alcohols
to E allyl amides 7a -c (Scheme 2).9 Isolation of the free
amine from the basic hydrolysis of the trichloroaceta-
mides 7a -c was low yielding, presumably due to the
volatility of the amines involved. A more satisfactory
procedure was to Boc protect the crude amide in situ and
then remove the trichloroacetyl group by addition of 6 N
NaOH with warming to 50 °C overnight. Standard
N-benzylation of the purified Boc protected allylic amines
8a -c gave the diastereomerically pure rearrangement
precursors 9a -c in 54-58% overall yield from 6a -c.
Rearrangement under standard conditions1 led to the
Boc protected homoallylic amines 10 and 11 (eq 2, Table
1).
The rearrangement of Li-1 occurred at -40 °C over-
night and gave a 3:2 ratio of diastereoisomers. In accord
with the calculated transition state structure of Houk7
for the oxy-[2,3]-Wittig rearrangement8 we attribute the
poor diastereoselectivity in our rearrangement to the
presumably small difference in transition state energies
of 4 versus 5 (Scheme 1).
We now report details of how we have achieved reliably
high yielding, diastereoselective rearrangements by judi-
cious placement of a trimethylsilyl group in the precursor.
This modification should now allow the aza-[2,3]-Wittig
rearrangement wider scope in synthesis.
Our initial plans to enhance diastereoselection were
to survey the effect of changing the bulk of R in 4 (Scheme
† Dedicated to Clayton H. Heathcock on the occasion of his 60th
birthday.
‡ University of Sheffield.
§ Zeneca Agrochemicals.
(1) Anderson, J . C.; Siddons, D. C.; Smith, S. C.; Swarbrick, M. E.
J . Chem. Soc., Chem. Commun. 1995, 1835.
(2) Durst, T.; Elzen, R. V. D.; Le Belle, M. J . J . Am. Chem. Soc.
1972, 94, 9261.
(3) (a) Ahman, J .; Somfai, P. J . Am. Chem. Soc. 1994, 116, 9781.
(b) Coldham, I.; Collis, A. J .; Mould, R. J .; Rathmell, R. E. J . Chem.
Soc., Perkin Trans. 1 1995, 2739.
(4) (a) Broka, C. A.; Shen, T. J . Am. Chem. Soc. 1989, 111, 2981.
(b) Murata, Y.; Nakai, T. Chem. Lett. 1990, 2069. (c) Coldham, I. J .
Chem. Soc., Perkin Trans 1 1993, 1275.
The sense of diastereoselection for the rearrangement
of 9b was assigned by comparison of its H NMR spectra
1
with that of the two diastereoisomers from eq 1. We
noted that the Me group of major diastereoisomer 2
appeared at δ 0.96, upfield with respect to the Me group
of minor diastereoisomer 3 δ 0.71. In both 2 and 3 the
protons R to nitrogen appeared as doublets with the
identical coupling constants (9.0 Hz). As the relative
(5) The rearrangement in ref 4a has been shown to proceed by a
[1,2] mechanism.4b
(6) Gawley, R. E.; Zhang, Q.; Campagna, S. J . Am. Chem. Soc. 1995,
117, 11817.
(7) Wu, Y.-D.; Houk, K. N.; Marshall, J . A. J . Org. Chem. 1990, 55,
1421. See also Mikami, K.; Uchida, T.; Hirano, T.; Wu, Y.-D.; Houk,
K. N. Tetrahedron 1994 50, 5917.
(8) For a recent review see Nakai, T.; Mikami, K. Org. React. 1994,
46, 105.
(9) Overman, L. E. J . Am. Chem. Soc. 1976, 98, 2901.
S0022-3263(96)00329-5 CCC: $12.00 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 14, 1996 4821
Ta ble 1. Aza -[2,3]-Wittig Rea r r a n gem en ts of 9a -c, X ) H
Ta ble 3. Aza -[2,3]-Wittig Rea r r a n gem en ts of 9d -f, X )
SiMe3
diastereo-
selectivityb
diastereo-
R
yielda (%)
10:11
yielda
(%)
selectivityb
R
10:11
1
Me
Et
i-Pr
t-Bu
82
69
54
-
3:2
1:1
4:3
-
9a
9b
9cc
9d
9e
9f
Me
Et
i-Pr
88
92
94
<1:20
1:18
1:11
a
b
a
b
Isolated yields of purified 10 and 11 together. Ratios of
Isolated yields of purified 10 and 11 together. Ratios of
unpurified products determined by 250-MHz NMR. c Low yield of
impure material that could not be conclusively characterised.
unpurified products determined by 250-MHz NMR.
change the direction of diastereoselection as anticipated
based upon the transition state model (Scheme 1).
In an attempt to circumvent these inherent problems
to our system we expected that stabilizing the transition
state in some way would allow milder reaction conditions
and possibly enhanced diastereoselectivity. Taking note
of the computed transition state structure for the oxy-
[2,3]-Wittig rearrangement7 (Scheme 1) there was pre-
dicted to be a small build up of negative charge at the
central vinyl carbon during the rearrangement. Assum-
ing a similar transition state structure for the aza
variant, substitution at this carbon atom with an anion-
stabilizing group should stabilize this transition state
structure and promote the rearrangement. Additionally
a bulky substituent at this position may increase dia-
stereoselectivity by favoring structure 5 over 4 so as to
avoid a destabilizing 1,3 interaction.
The trimethylsilylstabilizing group was selected due
to the known propensity of silicon to stabilize an adjacent
negative charge.11,12 The steric bulk of the group should
also maximize steric interactions.13 Substrates 9d -f
were prepared (Scheme 2) in an analogous fashion to
9a -c starting from the addition product of (1-lithiovinyl)-
trimethylsilane with the requisite aldehyde14 in compa-
rable overall yields of 33-48%. The efficiency of prepar-
ing the N-(trichloroacetyl)-2-(trimethylsilyl)allylamines
7d -f (60-78%) was compromised when exchange of
protecting group on nitrogen was performed to give the
N-Boc-2-(trimethylsilyl)allylamines. Unfortunately the
precursor 9 where X ) SiMe3 and R ) t-Bu could not be
prepared by this route, failing at the formation of the
trichloroacetimidate.
We were gratified to find that treatment of 9d with
n-BuLi at -78 °C in a mixture of Et2O and HMPA
consumed all starting material after 10 min. The product
was formed as a major diastereoisomer (>15:1) in an
isolated yield of 67%. We have subsequently found that
by conducting the experiment in THF for 20 h there is
no need for any HMPA, and that an 88% yield of
rearranged material was obtained with a diastereoselec-
tivity of >20:1 in favor of 11d . Treatment of 9e,f with
n-BuLi led to mainly one rearranged product 11e,f in
high yields (Table 3). These rearrangements both pro-
ceeded at -78 °C, but the incorporation of HMPA as
cosolvent was required to push the reaction to completion.
F igu r e 1.
Ta ble 2. Selected NMR Da ta for 10 a n d 11
diastereo-
selectivitya
10:11
δ
R(Me groups)
J
X
R
10:11b
C1H-C2H
H
H
Me
i-Pr
3:2
4:3
<1:20
1:18
1:11
0.96; 0.71
9.0 (10 & 11)
0.85, 0.81; 0.78, 0.75 10.1 (10); 9.3 (11)
SiMe3 Me
SiMe3 Et
SiMe3 i-Pr
1.02; 0.66c
10.4 (11)d
10.2 (11)d
9.8 (11)d
0.73; 0.57c
0.84, 0.79; 0.71
a
Ratios of unpurified products determined by 250-MHz NMR.
DMSO-d6. c Minor diastereoisomer visible from less selective
b
d
reactions run at 0 °C. J for 10 not visible.
stereochemistry of 2 and 3 have been proven by manipu-
lation to known compounds,1 these characteristics in the
NMR spectrum of 2 and 3 can be rationalized by
conformational analysis. By examining the Newmann
projections of the energetically most favorable conforma-
tions of 2 and 3 (10 and 11, X ) H, R ) Me; Figure 1) it
is only the anti diastereoisomer 11 in which the R group
can feel the shielding effect of the proximal aromatic ring
and thus account for the lower chemical shift of this
substituent. The equivalence of the coupling constant
between C1H-C2H (Figure 1) for both diastereoisomers
and its magnitude indicates a trans diaxial arrange-
ment10 in each case and supports the conformations
drawn. Products 10b and 11b have different chemical
shifts for their isopropyl methyl groups. As the C1H-
C2H coupling constant for this set of diastereoisomers is
of the same magnitude as that for diastereoisomers 2 and
3 we assign the syn diastereoisomer 10b to the major
component that exhibits the lowest field signals for R
(Figure 1 and Table 2).
(11) Schleyer, P. v R.; Clark, T.; Kos, A. J .; Spitznagel, G. W.; Rohde,
C.; Arad, D.; Houk, K. N.; Rondan, N. G. J . Am. Chem. Soc. 1984, 106,
6467.
(12) We have also investigated substitution by phenyl and thiophen-
yl, both of which promote the rearrangement, the results of which will
be reported in due course.
Increasing the steric bulk of R (Me, Et, i-Pr) when X
) H had little effect on the diastereoselection. Extremely
bulky groups, such as t-Bu, are not compatible with this
rearrangement. Increasing the steric bulk of R does not
(13) Trialkylsilyl groups have been used specifically to alter the
stereochemical outcome of the resultant alkenes in oxy-[2,3]-Wittig
rearrangements, but we have found no references to their use in control
of diastereoselectivity in such rearrangements. Crawley, J . E.; Kaye,
A. D.; Pattenden, G.; Roberts, S. M. J . Chem. Soc., Perkin Trans 1
1993, 2001.
(10) These coupling constants may be slightly smaller than one
would expect for
a trans diaxial coupling, but it is known that
electronegative substituents reduce coupling constants. J ackman, L.
M.; Sternhell, S. Applications of Nuclear Magnetic Resonance Spec-
troscopy in Organic Chemistry; Pergamon: New York, 1969, p 238 and
references therein.
(14) Chan, T. H.; Mychajlowskij, W.; Ong, B. S.; Harpp, D. N. J .
Org. Chem. 1978, 43, 1526.

4822 J . Org. Chem., Vol. 61, No. 14, 1996
Notes
tracted with CH2Cl2, the combined organics were dried over
MgSO4 and filtered, and the solvent was removed in vacuo.
Purification by flash-column chromatography eluting with EtOAc/
light petroleum furnished the diastereomerically pure N-Boc-
(E)-allylic amines 8 as mobile, colorless oils.
The major diastereoisomer for these silicon-assisted
rearrangements has been assigned as 11 on the basis of
the difference in chemical shift of the R substituents Me
groups for the two diastereoisomers as before (Figure 1,
Table 2). Unambiguous proof of this assignment, by
conversion of mixture 10/11d to a mixture of 2/3, was
thwarted by the reluctance of the vinyl silane to undergo
protodesilylation under reported conditions.15
It would seem that increasing the steric bulk of the R
group in precursors 9d -f (R ) Me, Et or i-Pr) slightly
erodes the diastereoselectivity of this process, but has no
effect on the yield or the sense of diastereoselection. It
is clear that in our systems the trialkylsilyl group is not
only acting as a steric control element in a direction
consistent with the transition state model (Scheme 1),
but also increasing the rate of the reaction as planned.
In view of the high diastereoselectivites observed we are
confident that these rearrangements proceed by a con-
certed [2,3] sigmatropic mechanism.
We have shown that the aza-[2,3]-Wittig rearrange-
ment is applicable to a variety of substrates containing
a trans arrangement of alkyl groups on the alkene. The
reaction can be accelerated by the judicious placement
of an anion-stabilizing trimethylsilyl group, which greatly
enhances the diastereoselectivity of these rearrange-
ments. These results support the transition state model
in Scheme 1 and indirectly, Houk’s calculations on the
transition state of related rearrangements.7 We are
currently extending this methodology to diastereo- and
enantioselective variants and pursuing the synthesis of
unnatural amino acids, which will all be reported in due
course.
N-Boc-P en t-2(E)-en yla m in e (8a ): 71% from 6a . IR (thin
film) 3347, 1694, 1521 cm-1 1H NMR δ 0.98 (3H, t, J ) 7.6),
;
1.45 (9H, s), 2.03 (2H, quin q, J ) 7.3, 1.2), 3.70 (2H, t, J ) 5.5),
4.53 (1H, s, NH, by D2O exchange), 5.41 (1H, dtt, J ) 15.3, 6.1,
1.2), 5.63 (1H, dtt, J ) 15.3, 6.1, 1.2); 13C NMR δ 13.4, 25.2,
28.4, 42.5, 79.1, 125.3, 134.5, 155.7; MS (EI+) m/z 185 (M+). Anal.
Calcd for C10H19NO2: C, 64.82; H, 10.34; N, 7.56. Found: C,
64.69; H, 10.06; N, 7.67%.
N-Boc-4-Meth ylp en t-2(E)-en yla m in e (8b): 69% from 6b.
1
IR (thin film) 3347, 1699, 1522 cm-1; H NMR δ 0.96 (6H, d, J
) 6.7), 1.45 (9H, s), 2.28 (1H, oct, J ) 6.7), 3.66 (2H, t, J ) 5.8),
4.50 (1H, s, NH, by D2O exchange), 5.37 (1H, dtd, J ) 15.3, 6.1,
0.9), 5.55 (1H, ddt, J ) 15.3, 6.4, 1.2); 13C NMR δ 22.2, 28.4,
30.7, 42.6, 79.2, 123.3, 140.0, 156.0; MS (EI+) m/z 199 (M+). Anal.
Calcd for C11H21NO2: C, 66.28; H, 10.63; N, 7.03. Found: C,
66.37; H, 10.59; N, 6.80%.
N-Boc-4,4-Dim eth ylp en t-2(E)-en yla m in e (8c): 68% from
1
6c. IR (thin film) 3346, 1694, 1522 cm-1; H NMR δ 0.98 (9H,
s), 1.43 (9H, s), 3.67 (2H, t, J ) 5.5), 4.48 (1H, s, NH, by D2O
exchange), 5.32 (1H, dt, J ) 15.6, 6.1), 5.58 (1H, dt, J ) 15.6,
1.2); 13C NMR δ 28.4, 29.5, 32.8, 42.8, 79.1, 121.1, 143.9, 155.7;
MS (EI+) m/z 213(M+). Anal. Calcd for C12H23NO2: C, 67.55;
H, 10.87; N, 6.57. Found: C, 67.27; H, 10.77; N, 6.62%.
N-Boc-2-(Tr im eth ylsilyl)bu t-2(Z)-en yla m in e (8d ): 52%
1
from 6d . IR (thin film) 3353, 1705 cm-1; H NMR δ 0.15 (9H,
s), 1.40 (9H, s), 1.76 (3H, dt, J ) 7.0, 1.2), 3.71 (2H, d, J ) 4.6),
4.33 (1H, br s, NH, by D2O exchange), 6.17 (1H, qt, J ) 7.0,
1.3); 13C NMR δ -0.2, 17.4, 28.4, 47.6, 79.0, 136.6, 138.7, 157.6;
MS (EI+) 243 (M+). Anal. Calcd for C12H25NO2Si: C, 59.21; H,
10.35; N, 5.75. Found: C, 59.16; H, 10.25; N, 5.60%.
N-Boc-2-(Tr im eth ylsilyl)p en t-2(Z)-en yla m in e (8e): 34%
1
from 6e. IR (thin film) 3353, 1705 cm-1; H NMR δ 0.14 (9H,
s), 0.96 (3H, t, J ) 7.3), 1.43 (9H, s), 2.13 (2H, pen, J ) 7.5),
3.71 (2H, d, J ) 5.2), 4.32 (1H, br.s, NH, by D2O exchange), 6.04
(1H, tt, J ) 7.6, 1.2); 13C NMR δ 0.01, 14.3, 25.0, 28.4, 47.6,
79.1, 135.0, 146.4, 154.5; MS (EI+) 258 (M+); HRMS C13H27NO2-
Si calcd 257.1811, found 257.1817.
Exp er im en ta l Section
Gen er a l Meth od s. All nonaqueous reactions were per-
formed under an oxygen-free atmosphere of nitrogen with
rigorous exclusion of moisture from reagents and glassware.
Thin layer chromatography was carried out using Merck 5554
60F silica gel coated aluminum plates and visualization was
effected using ultraviolet light or by development using iodine,
potassium iodoplatinate solution, potassium permanganate solu-
tion, or ceric ammonium molybdate solution. Flash chromatog-
raphy16 was performed using the indicated solvent system on
BDH silica gel for flash chromatography (40-63 µm). 1H and
13C NMR spectra were recorded at 250 and 63 MHz, respectively,
in CDCl3 unless otherwise stated. Elemental analyses were
obtained in the Department of Chemistry at the University of
Sheffield.
Reagents and solvents were purified prior to use when
necessary according to established procedures.17 THF was
distilled from K/benzophenone ketyl, Et2O was distilled from Na/
benzophenone ketyl, and CH2Cl2 and Et3N were distilled from
CaH. Allylic alcohols 6a -f were obtained from the addition of
either vinylmagnesium bromide or (1-lithiovinyl)trimethylsilane
to the requisite aldehyde followed by distillation.
N-Boc-2-(Tr im eth ylsilyl)-4-m eth ylp en t-2(Z)-en yla m in e
(8f): 38% from 6f as a white amorphous solid; mp 91-3 °C; IR
(thin film) 3327,1683 cm-1; 1H NMR δ 0.13 (9H, s), 0.93 (6H, d,
J ) 6.7), 1.42 (9H, s), 2.53 (1H, d sept, J ) 10.4, 6.4), 3.69 (2H,
d, J )5.2), 4.29 (1H, br s, NH, by D2O exchange), 5.82 (1H, dt,
J ) 9.2, 1.2); 13C NMR δ 0.14, 22.9, 28.4, 30.8, 47.6, 79.0, 132.6,
152.1, 154.5; MS (EI+) 271 (M+). Anal. Calcd for C14H29NO2Si:
C, 61.94; H, 10.77; N, 5.16. Found: C, 61.87; H, 10.92; N, 5.14%.
Gen er a l P r oced u r e for P r ep a r a tion of N-Boc-N-Ben zyl
Allylic Am in es 9a -f. A solution of the N-Boc-allylic amine (1
equiv) in THF (2 mL/mmol) was added dropwise via cannula to
a stirred suspension of KH (1.2 equiv of a 35% dispersion in
mineral oil, washed twice with hexane) in an equal volume of
THF at 0 °C. After stirring for 1 h at 0 °C, a solution of BnBr
(1.2 equiv) in THF (total concentration 5 mL/mmol) was added
and the reaction stirred for 1 h at 0 °C followed by 14 h at rt.
Saturated aqueous NaHCO3 was added, and the THF was
removed in vacuo. The residue was partitioned between satu-
rated aqueous NaHCO3 and Et2O and the aqueous further
extracted with Et2O. The combined organics were dried over
MgSO4 and filtered, and the solvent was removed in vacuo to
give crude products which were purified by flash-column chro-
matography eluting with EtOAc/light petroleum to furnish the
N-Boc-N-benzyl allylic amines 9a -f as colorless oils.
Gen er a l P r oced u r e for th e P r ep a r a tion of N-Boc-(E)-
Allylic Am in es 8. A solution of the crude N-trichloroacetyl-
(E)-allylamine18 7 (1 equiv), (Boc)2O (1.5 equiv), and DMAP (0.1
equiv) in MeCN (4 mL/mmol) was stirred at 50 °C. After 1-4
h, NaOH (6 N, 12 equiv) was added and stirring continued for
14 h at 50 °C. The mixture was allowed to cool, the MeCN
removed in vacuo, and the residue partitioned between H2O and
CH2Cl2. Upon separation the aqueous layer was further ex-
N-Boc-N-[P en t-2(E)-en yl]ben zyla m in e (9a ): 97%. IR (thin
film) 1695 cm-1 1H NMR δ 0.98 (3H, t, J ) 7.6), 1.50 (9H, s),
;
2.06 (2H, quin q, J ) 7.3, 1.2), 3.74 (2H, m), 4.40 (2H, s), 5.40
(1H, m), 5.53 (1H, m), 7.10-7.40 (5H, m); 13C NMR δ 13.5, 25.2,
28.4, 47.9, 48.9, 79.5, 124.0, 126.9, 127.3, 128.3, 135.5; MS (EI+)
m/z 275 (M+). Anal. Calcd for C17H25NO2: C, 74.14; H, 9.15;
N, 5.09. Found: C, 73.95; H, 8.93; N, 5.14%.
(15) Fleming, I.; Dunodue`s, J .; Smithers, R. Org. React. 1989, 37,
57. Protodesilylation of a terminal vinylsilane where the silyl group is
on C2 is known to be difficult, presumably because the accepted
mechanism would require the formation of an incipient primary
carbocation.
(16) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
(17) Perrin, D. D., Armarego, W. L. F., Eds. Purification of Labora-
tory Chemicals; Pergamon Press: New York.
N-Boc-N-(4-Meth ylpen t-2(E)-en yl)ben zylam in e (9b): 98%
1
IR (thin film) 1695 cm-1; H NMR δ 0.96 (6H, d, J ) 6.7), 1.48
(9H, s), 2.26 (1H, oct, J ) 6.7), 3.75 (2H, m), 4.42 (2H, br s),
(18) Prepared according to the procedure outlined in ref 9.
5.33 (1H, m), 5.47 (1H, m), 7.15-7.45 (5H, m); 13C NMR δ 22.3,

Notes
J . Org. Chem., Vol. 61, No. 14, 1996 4823
28.5 30.8, 48.0, 49.0, 79.6, 122.1, 127.0, 127.8, 128.4, 140.6; MS
(EI+) m/z 289 (M+); HRMS C18H27NO2 calcd 289.2042, found
289.2043.
N-Boc-N-(4,4-Dim eth ylp en t-2(E)-en yl)ben zyla m in e (9c):
98%. IR (thin film) 1695 cm-1; 1H NMR δ 0.95 (9H, s), 1.48 (9H,
s), 3.75 (2H, m), 4.39 (2H, s), 5.26 (1H, m), 5.49 (1H, m), 7.15-
7.40 (5H, m); 13C NMR δ 28.5, 29.5, 32.9, 48.2, 49.0, 79.6, 119.8,
127.0, 127.8, 128.3, 138.6, 144.4; MS (EI+) m/z 303 (M+). Anal.
Calcd for C19H29NO2: C, 75.21; H, 9.63; N, 4.62. Found: C,
75.05; H, 9.38; N, 4.65%.
yla m in e (11b): 54% of 10b:11b, in an inseparable ratio of 4:3,
as a white amorphous solid; mp 94-6 °C; IR (thin film) 3348,
1702, 1495 cm-1; 1H NMR (DMSO-d6) for 10b δ 0.81 (3H, d, J )
7.0), 0.85 (3H, d, J ) 7.0), 1.31 (9H, s), 1.92-2.06 (1H, m), 2.22
(1H, br td, J ) 11.5, 3.7), 4.48 (1H, t, J ) 10.1), 4.55 (1H, dd, J
) 17.1, 2.1), 4.77 (1H, dd, J ) 10.4, 2.4), 5.38 (1H, dt, J ) 17.1,
10.1), 7.09-7.31 (6H, m); 1H NMR (DMSO-d6) for 11b δ 0.75
(3H, d, J ) 7.0), 0.78 (3H, d, J ) 6.7), 1.20-1.35 (10H, br s),
2.11-2.25 (1H, m), 4.58 (1H, t, J ) 9.3), 4.92 (1H, dd, J ) 16.8,
2.1), 5.07 (1H, dd, J ) 10.1, 2.1), 5.67 (1H, dt, J ) 16.8, 10.1),
7.09-7.31 (5H, m), 7.40 (1H, d, J ) 9.3); 13C NMR (100 MHz)
for 10b δ 17.2, 21.5, 21.7, 28.3, 54.7, 56.8, 79.2, 118.2, 126.8,
127.5, 128.0, 136.6, 140.7, 154.9; 13C NMR (100 MHz) for 11b δ
19.6, 27.3, 27.6, 28.3, 54.7, 56.6, 79.2, 118.9, 126.9, 127.5, 128.3,
N-Boc-N-[2-(Tr im et h ylsilyl)bu t -2(Z)-en yl]b en zyla m in e
(9d ): 90%. IR (thin film) 1695 cm-1 1H NMR δ 0.14 (9H, s),
;
1.46 (9H, s), 1.81 (3H, dt, J ) 7, 1.5), 3.88 (2H, br s), 4.34 (2H,
br s), 5.99 (1H, q, J ) 7.0), 7.15-7.37 (5H, m); 13C NMR δ -0.23,
17.3, 28.4, 48.3, 51.9, 79.6, 126.9, 127.5, 128.34, 138.5; MS (EI+)
333 (M+). Anal. Calcd for C19H31NO2Si: C, 68.42; H, 9.37; N,
4.20. Found: C, 68.26; H, 9.28; N, 4.08%.
135.6, 142.5, 155.2; MS (EI+) 289 (M+). Anal. Calcd for C18H27
-
NO2: C, 74.70; H, 9.40; N, 4.84. Found: C, 74.55; H, 9.42; N,
4.66%.
N -B o c -N -[2-(T r im e t h y ls ily l)p e n t -2(E )-e n y l]b e n zy l-
(1S*,2R*)-N-Boc-2-Met h yl-1-p h en yl-3-(t r im et h ylsilyl)-
bu t-3-en yla m in e (11d ). n-BuLi (1.47 mL of 2.5M in hexanes,
3.67 mmol, 1.2 equiv) was added slowly to a stirred solution of
9d (1.02 g, 3.06 mmol) in THF (20 mL) at -78 °C. After stirring
for 20 h the reaction was quenched, worked up, and purified as
for 10/11a -c above to give 11d (0.89 g, 88%) (ds 20:1), as a clear
a m in e (9e): 96%. IR (thin film) 1696 cm-1 1H NMR δ 0.12
;
(9H, s), 0.98 (3H, t, J ) 7.6), 1.45 (9H, s), 2.16 (2H, pent, J )
7.5), 3.85 (2H, br s), 4.36 (2H, br s), 5.83 (1H, t, J ) 7.3), 7.13-
7.38 (5H, m); 13C NMR δ -0.01, 14.6, 25.0, 28.5, 48.3, 51.9, 79.6,
127.0, 127.6, 128.5, 138.5; MS (EI+) 347 (M+); HRMS C20H33
NO2Si calcd 347.2281, found 347.2275.
-
1
oil; IR (thin film) 3273, 1703, 1495, cm-1; H NMR (DMSO-d6)
N-Boc-N-[2-(Tr im eth ylsilyl)-4-m eth ylpen t-2(E)-en yl]ben -
zyla m in e (9f): 100%. IR (thin film) 1696 cm-1; 1H NMR δ 0.11
(9H, s), 0.95 (6H, d, J ) 6.4), 1.47 (9H, s), 2.60 (1H, d sept, J )
10.5, 6.5), 3.84 (2H, br s), 4.35 (2H, br s), 5.61 (1H, d, J ) 10.4),
7.12-7.42 (5H, m); 13C NMR δ 0.01, 23.0, 28.4, 30.7, 48.3, 51.7,
79.5, 126.9, 127.6, 128.3, 138.3; MS (EI+) 361 (M+); HRMS
δ 0.17 (9H, s), 0.66 (3H, d, J ) 7.0), 1.37 (9H, s), 2.60 (1H, dq,
J ) 10.4, 7.3), 4.46 (1H, t, J ) 9.8), 5.43 (1H, d, J ) 2.4), 5.73
(1H, d, J ) 2.4), 7.08 (1H, d, J ) 9.5), 7.20-7.40 (5H, m); 13C
NMR δ 0.4, 19.4, 28.7, 47.182, 58.8, 77.9, 126.6, 127.2, 127.9,
128.4, 143.3, 154.8, 155.1; MS (EI+) 333 (M+). Anal. Calcd for
C19H31NO2Si: C, 68.42; H, 9.37; N, 4.20. Found: C, 68.30; H,
9.36; N, 4.21%.
C
21H35NO2Si calcd 361.2437, found 361.2444
Gen er a l Exp er im en ta l for th e Aza -[2,3]-Wittig Sigm a -
Gen er a l Exp er im en ta l for th e Aza -[2,3]-Wittig Sigm a -
tr op ic Rea r r a n gem en t of 9e,f. n-BuLi (2.5 M in hexanes, 1.2
equiv) was added slowly to a stirred solution of the silyl-
substituted N-Boc-N-allylbenzylamine 9e,f (1 equiv) in THF/
HMPA (4:1, 5 mL/mmol) at -78 °C. After stirring for 30 m the
reaction was quenched, worked up, and purified as for 10/11a -
c.
tr op ic Rea r r a n gem en t of 1 a n d 9a -c. n-BuLi (2.5 M in
hexanes, 1.2 equiv) was added slowly to a stirred solution of the
N-Boc-N-allylbenzylamine 1 or 9a -c (1 equiv) in Et2O/HMPA
(4:1, 5 mL/mmol) at -78 °C. After 1 h the reaction mixture was
warmed to -40 °C and stirred for 14 h before being quenched
by the addition of MeOH and partitioned between saturated
aqueous NaHCO3 and Et2O. The aqueous was further extracted
with Et2O, and the combined organics were dried over MgSO4,
filtered, and concentrated in vacuo. The resulting crude prod-
ucts were purified by flash-column chromatography (EtOAc/light
petroleum or Et2O/light petroleum) to furnish the rearranged
products 2, 3, and 10a -c, 11a -c.
(1S*,2R*)-N-Boc-2-Eth yl-1-p h en yl-3-(tr im eth ylsilyl)bu t-
3-en yla m in e (11e): 92% (ds 18;1), as a clear oil; IR (thin film)
3352, 1702, 1496 cm-1; 1H NMR (DMSO-d6) δ 0.15 (9H, s), 0.57
(3H, t, J ) 7.3), 0.91-1.15 (2H, m), 1.31 (9H, s), 2.37 (1H, td, J
) 10.4, 4.0), 4.42 (1H, t, J ) 10.1), 5.54 (1H, d, J ) 2.7), 5.70
(1H, d, J ) 2.7), 7.02 (1H, d, J ) 9.2), 7.18-7.32 (5H, m); 13C
NMR (100 MHz) δ -0.22, 12.2, 24.2, 28.3, 56.1, 58.3, 79.0, 126.9,
127.2, 128.1, 128.8, 143.0, 152.5, 154.8; MS (EI+) 347 (M+). Anal.
Calcd for C20H33NO2Si: C, 69.11; H, 9.57; N, 4.03. Found: C,
69.03; H, 9.66; N, 3.96%.
(1R*,2S*)-N-Boc-2-Meth yl-1-p h en ylbu t-3-en yla m in e (2)
an d (1S*,2S*)-N-Boc-2-Meth yl-1-ph en ylbu t-3-en ylam in e (3):
82% of 2:3, in an inseparable ratio of 3:2, as a white amorphous
solid; mp 95-7 °C; IR (thin film) 3374, 1681, 1527 cm-1; 1H NMR
(DMSO-d6) for 2 δ 0.96 (3H, d, J ) 6.3), 1.34 (9H, s), 2.49-2.44
(2H, m), 4.35 (1H, t, J ) 8.8), 4.79 (2H, d, J ) 13.2), 5.57 (1H,
(1S*,2R*)-N-Boc-2-Isop r op yl-1-p h en yl-3-(tr im eth ylsilyl)-
bu t-3-en yla m in e (11f): 94% (ds 11;1), as a clear oil; IR (thin
1
dt, J ) 17.1, 8.6), 7.17-7.28 (5H, m), 7.35 (2H, d, J ) 9.1); H
NMR (DMSO-d6) for 3 δ 0.71 (3H, d, J ) 6.6), 1.33 (9H, s), 2.49-
2.44 (2H, m), 4.29 (1H, t, J ) 9.1), 4.95 (1H, d, J ) 10.8), 5.00
(1H, d, J ) 18.5), 5.77 (1H, dt, J ) 17.8, 8.8), 7.17-7.28 (5H,
m), 7.35 (2H, d, J ) 9.1); 13C NMR (100 MHz) for 2 δ 16.1, 28.3,
43.7, 58.5, 79.4, 115.8, 126.7, 127.2, 128.2, 139.6, 155.4; 13C NMR
(100 MHz) for 3 δ 17.0, 28.3, 43.1, 59.1, 79.4, 116.1, 126.9, 127.0,
127.2, 128.1, 139.8, 155.2; MS (CI, NH3) 279 (MNH4+), 262
(MH+). Anal. Calcd for C16H23NO2: C, 73.53; H, 8.87; N, 5.36.
Found: C, 73.39; H, 9.07; N, 5.20%.
1
film) 3445, 1722, 1701, 1494 cm-1; H NMR (DMSO-d6) δ 0.03
(9H, s), 0.71 (6H, d, J ) 6.7), 1.31 (9H, s), 1.21-1.41 (1H, m),
2.55 (1H, dd, J ) 10.7, 5.5), 4.71 (1H, t, J ) 9.8), 5.64 (1H, br d,
J ) 1.5), 5.79 (1H, d, J ) 2.1), 6.81 (1H, d, J ) 9.5), 7.18-7.39
(5H, m); 13C NMR δ -1.0, 20.6, 21.8, 28.3, 29.3, 54.4, 56.3, 79.1,
126.76, 126.81, 128.1, 128.2, 143.3, 152.5, 155.0; MS (EI+) 361
(M+). Anal. Calcd for C21H35NO2Si: C, 69.75; H, 9.76; N, 3.87.
Found: C, 69.60; H, 9.66; N, 3.80%.
(1R*,2S*)-N-Boc-2-Eth yl-1-p h en ylbu t-3-en yla m in e (10a )
an d (1S*,2S*)-N-Boc-2-Eth yl-1-ph en ylbu t-3-en ylam in e (11a):
69% of 10a :11a , in an inseparable ratio of 1:1, as a white
amorphous solid; mp 132-43 °C; IR (thin film) 3386, 1683, 1520
cm-1; 1H NMR (DMSO-d6) δ 0.68 (3H, t, J ) 7.3), 0.77 (3H, t, J
) 7.3), 1.03-1.20 (2H, m), 1.31 (9H, s), 1.53-1.57 (2H, m), 2.16-
2.22 (1H, m), 4.35 (1H, t, J ) 9.2), 4.37 (1H, t, J ) 9.2), 4.70
(1H, dd, J ) 16.8, 1.5), 4.80 (1H, dd, J ) 10.4, 2.1), 4.97 (1H, d,
J ) 16.8), 5.02 (1H, d, J ) 10.4), 5.35 (1H, dt, J ) 17.1, 10.1),
5.54 (1H, dt, J ) 16.8, 10.1), 7.15-7.29 (6H, m); 13C NMR δ 11.6,
11.8, 23.8, 24.1, 28.3, 51.4, 51.8, 57.5, 79.3, 117.6, 117.9, 126.8,
126.9, 127.4, 127.9, 128.2, 138.0, 138.3, 142.3, 155.0, 155.3; MS
(EI+) 275 (M+). Anal. Calcd for C17H25NO2: C, 74.14; H, 9.15;
N, 5.09. Found: C, 73.96; H, 9.14; N, 4.99%.
Ack n ow led gm en t. We thank Zeneca Agrochemicals
for a studentship (M.E.S.), the EPSRC for an earmarked
studentship (D.C.S.), the Royal Society for support, Ms
F. Gill for recording mass spectra, and Mr A. J ones and
Ms J . Stanbra for measuring microanalytical data.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra for compounds 8e, 9b,e, f (4 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
(1R*,2S*)-N-Boc-2-Isop r op yl-1-p h en ylb u t -3-en yla m in e
(10b) a n d (1S*,2S*)-N-Boc-2-Isop r op yl-1-p h en ylbu t-3-en -
J O960329W