Lewis Acid Mediated [2,3]-Sigmatropic Rearrangement of Allylic α-Amino Amides

Article abstract of DOI:10.1021/jo035618g

Boron trifluoride and BBr₃ mediated [2,3]-sigmatropic rearrangements of allylic α-amino amides have been developed affording secondary amines in good yields. (E)-Crotyl and (E)-cinnamyl α-amino amides 2b and 2c exhibit excellent syn-diastereoselectivity upon rearrangement with either Lewis acid. The allylic amine 2a forms upon treatment with BF ₃ or BBr₃ a five-membered heterocylic complex in which a single halide anion has been displaced by the carbonyl oxygen atom. The structures of the Lewis acid-amine complexes were elucidated using NMR spectroscopy. A plausible reaction mechanism, based on DFT calculations, is presented. Thus, BF₃- or BBr₃-complexed allylic amines 2 are shown to preferentially proceed, after deprotonation, via an endo transition state.

Full text of DOI:10.1021/jo035618g

Lew is Acid Med ia ted [2,3]-Sigm a tr op ic Rea r r a n gem en t of Allylic
r-Am in o Am id es
J an Blid,† Peter Brandt,‡ and Peter Somfai*,†
Organic Chemistry, KTH Chemistry, Royal Institute of Technology, SE-100 44 Stockholm, Sweden, and
Department of Structural Chemistry, Biovitrum AB, SE-112 76 Stockholm, Sweden
somfai@kth.se
Received November 4, 2003
Boron trifluoride and BBr3 mediated [2,3]-sigmatropic rearrangements of allylic R-amino amides
have been developed affording secondary amines in good yields. (E)-Crotyl and (E)-cinnamyl R-amino
amides 2b and 2c exhibit excellent syn-diastereoselectivity upon rearrangement with either Lewis
acid. The allylic amine 2a forms upon treatment with BF3 or BBr3 a five-membered heterocylic
complex in which a single halide anion has been displaced by the carbonyl oxygen atom. The
structures of the Lewis acid-amine complexes were elucidated using NMR spectroscopy. A plausible
reaction mechanism, based on DFT calculations, is presented. Thus, BF3- or BBr3-complexed allylic
amines 2 are shown to preferentially proceed, after deprotonation, via an endo transition state.
SCHEME 1. [2,3]-Sigm a tr op ic Rea r r a n gem en t of
Ylid esa
In tr od u ction
Carbon-carbon bond-forming reactions are of central
importance in organic chemistry. Consequently, much
effort has been expended in this area, and of particular
interest are transformations that introduce the new bond
in high regio- and stereoselectivity. Although a plethora
of these reactions have been successfully developed, the
pursuit of stereocontrolled C-C bond-forming reactions
is still a challenging goal. In this respect, ylidic [2,3]-
sigmatropic rearrangement reactions are useful tools for
forming new C-C bonds (Scheme 1).1 Several ylidic
precursors such as amines,2 sulfides,3 ethers,4 selenides,5
and halogens6 have been investigated, establishing this
rearrangement as a powerful and diverse transformation.
a
Key: R, R′ ) alkyl, Ar; X ) OR′′, SR′′, NR2′′, SeR′′; G ) Ar,
CO2Me, CN, CCTMS.
* Corresponding author. Phone: (+46)-8-790 6960. Fax: (+46)-8-
791 2333.
† Royal Institute of Technology.
The rearrangement is believed to proceed via a concerted
five-membered cyclic transition state.7,8 The stereochem-
ical outcome is dependent on steric and electronic inter-
actions between the migrating allyl moiety and the anion-
stabilizing group (G, Scheme 1) in the exo and endo
transition states.1 An attractive feature of the [2,3]-
sigmatropic rearrangement is that it creates a new C-C
bond adjacent to both the heteroatom and the anion-
stabilizing group. Also, the olefin moiety provides pos-
sibilities for further functionalization, and the efficacy
of the reaction has been demonstrated by application in
a number of natural product syntheses.9 One drawback
inherent in the [2,3]-sigmatropic rearrangement of ylides
‡ Department of Structural Chemistry, Biovitrum AB.
(1) Marko´, I. E. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 913-974.
(2) Some recent examples: (a) Glaeske, K. W.; West, F. G. Org. Lett.
1999, 1, 31-33. (b) Arbore´, A. P. A.; Cane-Honeysett, D. J .; Coldham,
I.; Middleton, M. L. Synlett 2000, 236-238. (c) Smith, R. S.; Bentley,
P. D. Tetrahedron Lett. 2002, 43, 899-902. (d) Sweeney, J . B.;
Tavassoli, A.; Carter, N. B.; Hayes, J . F. Tetrahedron 2002, 58, 10113-
10126.
(3) Selected references: (a) Blackburn, G. M.; Ollis, W. D.; Plackett,
J . D.; Smith, C.; Sutherland, I. O. J . Chem. Soc., Chem. Commun. 1968,
186-188. (b) Baldwin, J . E.; Hackler, R. E.; Kelly, D. P. J . Chem. Soc.,
Chem. Commun. 1968, 537-538. (c) Chappie, T. A.; Weekley, R. M.;
McMills, M. C. Tetrahedron Lett. 1996, 37, 6523-6526. (d) Gulea, M.;
Marchand, P.; Masson, G.; Saquet, M.; Collignon, N. Synthesis 1999,
1635-1639. (e) Aggarwal, V. K.; Ferrara, M.; Hainz, R.; Spey, S. E.
Tetrahedron Lett. 1999, 40, 8923-8927.
(4) (a) Doyle, M. P.; Griffin, J . H.; Chinn, M. S.; van Leusen, D. J .
Org. Chem. 1984, 49, 1917-1925. (b) Pirrung, M. C.; Werner, J . A. J .
Am. Chem. Soc. 1986, 108, 6060-6062. (c) Roskamp, E. J .; J ohnson,
C. R. J . Am. Chem. Soc. 1986, 108, 6062-6063. (d) Hodgson, D. M.;
Pierard, F. Y. T. M.; Stupple, P. A. Chem. Soc. Rev. 2001, 30, 50-61.
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47, 954-959. (b) Nishibayashi, Y.; Ohe, K.; Uemura, S. J . Chem. Soc.,
Chem. Commun. 1995, 1245-1264. (c) Kurose, N.; Takahashi, T.;
Koizumi, T. J . Org. Chem. 1997, 62, 4562-4563.
(6) (a) Doyle, M. P.; Tamblyn, W. H.; Bagheri, V. J . Org. Chem. 1981,
46, 5094-5102. (b) Simonneaux, G.; Galardon, E.; Paul-Roth, C.; Gulea,
M.; Masson, S. J . Organomet. Chem. 2001, 617-618, 360-363.
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nonth, Y. J . Chem. Soc., Chem. Commun. 1971, 1494-1495. (b)
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10.1021/jo035618g CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/27/2004
J . Org. Chem. 2004, 69, 3043-3049
3043

Blid et al.
SCHEME 2. Lew is Acid Med ia ted
[2,3]-Sigm a tr op ic Rea r r a n gem en t of 2a
is that the heteroatom moiety in the resultant product
is fully substituted rendering further derivatization of
this functionality problematic.
We have recently demonstrated that activation of
tertiary allylic amino amides with BBr3 followed by
deprotonation with a strong base promote the [2,3]-
sigmatropic rearrangement.10 The resultant secondary
amines are formed in good yields and with high diaster-
eoselectivity, establishing the reaction as an efficient
approach to R-amino acid derivatives.11 Herein is de-
scribed the full details of that investigation. In addition,
computational and NMR spectroscopic investigations of
the rearrangement have been performed, the details of
which will be presented.
TABLE 1. BF 3-Assisted Rea r r a n gem en t of 2a a
entry BF3‚OEt2 (equiv) base/(equiv) T (°C)/t (h) 3a b (%)
1
2
1.1
3.0
1.2
1.2
LDA/3.0
rt/16
-20/23
NRc
4 (42)
12 (63)
KHMDS/3.0
3
KHMDS/1.2d -20/20
4e
i-Pr2NEt/1.2
reflux/13 h 57 (15)
a
Reaction conditions: to 2a in THF were added BF3‚OEt2 and
b
base. Yields determined by HPLC. Yield of recovered starting
material in parentheses. c NR ) no reaction. 1.2 equiv of 18-
d
Com p u ta tion a l Meth od s
crown-6 was added. e PhMe used as solvent.
Mod el System . The N-benzyl group of 2a was replaced by
a methyl group to avoid the requirement of conformational
sampling and the pyrrolidine in the amide moiety was replaced
by a dimethylamine affording model compound 1.
Treating 2a with BF3‚OEt2 followed by addition of
various bases either provided 3a in low yields or did not
effect the desired rearrangement (Table 1, entries 1-3).
The best yield was achieved when using equimolar
amounts of BF3‚OEt2 and KHMDS in the presence of 18-
crown-6, affording a mere 12% of 3a (entry 3). Attempts
to improve the outcome by varying the reaction temper-
ature and amount of reagents met with no success.
Interestingly, when employing the weaker base i-Pr2NEt
a smooth rearrangement took place at elevated temper-
atures, affording 3a in 57% yield (entry 4). Encouraged
by this result, it was decided to investigate whether
stronger neutral bases could promote the rearrangement
at lower temperatures. Hence, the Schwesinger phos-
phazene bases 4-6 were chosen, due to their commercial
availability and ease of handling (Figure 1).18
The complex formed by mixing 2a and BF3‚OEt2 was
treated with phosphazene bases 4-6. From the results
a clear trend could be discerned: using stronger bases
increased the yield of 3a (Table 2). Phosphazene bases 4
and 5 gave at -20 °C similar yields of 3a as KHMDS
(entries 1 and 3 vs Table 1, entry 3), while higher yields
were obtained at room temperature (entries 2 and 4). The
stronger phosphazene base 6 gave a substantial increased
yield of 3a : 36% at -20 °C and 42% at room temperature
(entries 5 and 6). Although these results did not produce
as high yields as with using i-Pr2NEt, the rearrangement
could be run at lower temperatures.
Den sity F u n ction a l Th eor y Ca lcu la tion s. All geometric
optimizations together with final gas-phase energy determina-
tions were performed using the B3LYP hybrid density func-
tional.12 Geometric optimizations and vibrational analyses
were performed with the J aguar program using the LACVP
basis set keyword.13 LACVP refers to the use of the double-ú
quality LANL2DZ basis set for Br and the 6-31G basis set for
other atoms.14 LANL2DZ implies the use of effective core
potentials for 28 electrons of bromine and the use of a (3s,3p)
primitive basis contracted to [3s,2p]. Transition state searches
were performed using the quadratic synchronous transit (QST)
method. Final energies were calculated in J aguar using the
6-311+G** basis set.
Solvation free energies were calculated with the polarized
continuum model (PCM/HF/6-31+G*)15 in the Gaussian 98
program package.16
Resu lts a n d Discu ssion
Scr een in g of Br øn sted Ba ses. Previous investiga-
tions have shown that Lewis acid mediated [2,3]-sigma-
tropic rearrangements of R-amino esters proceed with low
conversion.17 Since enolates derived from amides tend to
be more reactive then ester enolates, compound 2a was
selected as model substrate together with BF3‚OEt2 as a
Lewis acid for initial screening experiments (Scheme 2).
(16) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J . R.; Zakrzewski, V. G.; Montgomery, J . A.;
Stratmann, R. E., J r.; Burant, J . C.; Dapprich, S.; Millam, J . M.;
Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J .;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo,
C.; Clifford, S.; Ochterski, J .; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J . B.; Cioslowski, J .; Ortiz, J . V.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J .; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; J ohnson, B.; Chen, W.;
Wong, M. W.; Andres, J . L.; Gonzalez, C.; Head-Gordon, M.; Replogle,
E. S.; Pople, J . A. Gaussian 98, revision A.3; Gaussian, Inc.: Pittsburgh,
PA, 1998.
(17) (a) Coldham, I.; Middleton, M. L.; Taylor, P. L. J . Chem. Soc.,
Perkin Trans. 1 1998, 2817-2821. (b) Murata, Y.; Nakai, K. Chem.
Lett. 1990, 2069-2072.
(18) Schwesinger, R.; Schlemper, H.; Hasenfratz, C.; Willaredt, J .;
Dambacher, T.; Breuer, T.; Ottaway, C.; Fletschinger, M.; Boele, J .;
Fritz, H.; Putzas, D.; Rotter, H. W.; Bordwell, F. G.; Satish, A. V.; J i,
G. Z.; Peters, E. M.; Peters, K.; von Schnering, H. G.; Walz, L. Liebigs
Ann./ Recueil 1996, 1055-1081.
(9) (a) Blackburn, G. M.; Ollis, W. D.; Sutherland, I. O. J . Chem.
Soc., Chem. Commun. 1969, 99. (b) Kaiser, G. V.; Ashbrook, C. W.;
Baldwin, J . E. J . Am. Chem. Soc. 1971, 93, 2342-2344. (c) Trost, B.
M.; Conway, P.; Stanton, J . J . Chem. Soc., Chem. Commun. 1971,
1639-1640. (d) Bu¨chi, G.; Wu¨est, H. J . Am. Chem. Soc. 1974, 96,
7573-7574. (e) Evans, D. A.; Sims, C. L.; Andrews, G. C. J . Am. Chem.
Soc. 1977, 99, 5453-5461. (f) Vedejs, E.; Reid, J . G.; Rodgers, J . D.;
Wittenberger, S. J . J . Am. Chem. Soc. 1990, 112, 4351-4357.
(10) Blid, J .; Somfai, P. Tetrahedron Lett. 2003, 44, 3159-3162.
(11) Williams, R. M. Synthesis of Optically Active R-Amino Acids;
Pergamon Press: Oxford, 1989.
(12) (a) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785.
(b) Becke, A. D. J . Chem. Phys. 1993, 98, 5648.
(13) J aguar 4.0, Schro¨dinger, Inc., Portland, OR, 1991-2000.
(14) (a) Hay, P. J .; Wadt, W. R. J . Chem. Phys. 1985, 82, 285. (b)
Hay, P. J .; Wadt, W. R. J . Chem. Phys. 1985, 82, 299.
(15) Cossi, M.; Barone, V.; Cammi, R.; Tomasi, J . Chem. Phys. Lett.
1996, 255, 327.
3044 J . Org. Chem., Vol. 69, No. 9, 2004

[2,3]-Sigmatropic Rearrangement of Allylic R-Amino Amides
TABLE 4. Rea r r a n gem en ts of Am in es 2b-ea
entry amine
R1
R2
Lewis acid
3b (%)
syn/antic
1
2
3
4
5
2b
2c
2d
2e
2b
Me
Ph
H
H
H
BBr3
BBr3
b 71 (20)
c 62 (32)
d 56 (33)
e 60 (31)
b 14 (48)
>20:1
11:1
6:5
Me BBr3
Me Me BBr3
Me BF3‚OEt2
H
>20:1
a
Reaction conditions: to the amine (1.0 equiv) in PhMe at -78
°C were added Lewis acid (1.1 equiv) and 6 (1.0 equiv), and the
resultant mixture was stirred overnight (18-20 h) at -20 °C.
b
Yield of recovered starting material in parentheses. c Ratio
determined by 1H NMR.
F IGURE 1. Schwesinger phosphazene bases 4-6.
in the absence of a Lewis acid did not furnish the
rearrangement (entry 7). It was also noted that when the
complex formed by mixing BBr3 and 2a was reacted with
weaker nonionic bases, such as 4, 5, or Et3N, compound
3a was formed in yields comparable that obtained when
using phosphazene 6. On the other hand, LDA did not
promote the BBr3-mediated rearrangement as efficiently
and afforded 3a in only 31% yield (53% recovered starting
material).
TABLE 2. Rea r r a n gem en t of 2a To Give 3a Med ia ted by
BF 3‚OEt2 a n d P h osp h a zen e Ba ses 4-6a
entry
base
T (°C)
3a b (%)
1
2
3
4
5
6
4
4
5
5
6
6
-20
rt
-20
rt
-20
rt
11 (62)
24 (61)
12 (78)
31 (68)
36 (64)
42 (50)
Scop e a n d Ster eoselectivity. To investigate the
scope and stereoselectivity of the rearrangement amines
2b-e were prepared. Gratifyingly, di- and trisubstituted
olefins 2b-e showed similar reactivity as the allyl
derivative 2a (Table 4). E-Olefins 2b and 2c rearranged
with high diastereoselectivity, affording syn-3b in 71%
yield and >20:1 ds, and syn-3c in 62% yield and 11:1 ds,
respectively (entries 1 and 2). However, Z-olefin 2d
afforded 3d with poor syn:anti selectivity (entry 3). Boron
trifluoride also furnished syn-3b with high diastereose-
lectivity, albeit in low yield (entry 5).
The anion-stabilizing group can influence the stereo-
chemical outcome of [2,3]-sigmatropic rearrangements.8,21
To investigate if this was also the case for the title
reaction and hopefully improve diastereoselectivity in the
rearrangements of Z-olefins corresponding to 2d , ester
and propargyl substrates 7 and 8 were prepared. When
subjected to BBr3 and base 6 neither of the two substrates
provided the corresponding products. Ester 7 was prob-
ably transformed to the corresponding acid under the
reaction conditions since only a small amount of 7 could
be recovered, while starting material was retrieved
exclusively when amine 8 was subjected to identical
conditions.
a
Reaction conditions: to 2a (1.0 equiv) in PhMe at -78 °C were
added BF3‚OEt2 (1.2 equiv) and base (1.2 equiv), and the resultant
b
mixture was stirred overnight (18-20 h). Yield of recovered
starting material in parentheses.
TABLE 3. Rea r r a n gem en t of 2a To Give 3a Med ia ted by
Va r iou s Lew is Acid s a n d 6a
entry
LA/(equiv)
T (°C)
3a b (%)
1
2
3
4
5
6
7
BF3/1.2
-20
-20
-20
rt
rt
rt
36 (64)
46 (40)
66 (22)
0 (93)
14 (63)
23 (68)
0 (91)
BCl3/1.2
BBr3/1.2
Bu2BOTf/1.2
InCl3/1.1
ZnCl2/1.0
No LA
rt
a
Reaction conditions: to 2a (1.0 equiv) in PhMe at -78 °C were
added Lewis acid and 6 (1.2 equiv). Stirred overnight (16-20 h)
b
at -20 °C or rt. Yield of recovered starting material in paren-
theses.
Scr een in g of Lew is Acid s. With useful conditions for
the rearrangement at hand, a survey of various Lewis
acids was planned, and initial focus was directed toward
those containing boron. When applying BCl3 or BBr3,
which are both considered to be stronger Lewis acids than
BF3,19,20 3a was obtained in 46% and 66% yield, respec-
tively (Table 3, entries 2 and 3); however, when Bu2BOTf
was used to promote the rearrangement, 2a was recov-
ered unaffected (entry 4). It was also found that InCl3
and ZnCl2 promoted the rearrangement but afforded 3a
in only low yields (entries 5 and 6), while other Lewis
acids, e.g., CuCl, CuCl2, TiCl4, Yb(OTf)3, FeCl3, ZrCl2Cp2,
and ScCl3 failed to promote the process. A control
experiment was also conducted. Treatment of 2a with 6
Den sity F u n ction a l Ca lcu la tion s. Understanding
the reaction mechanism could provide information re-
garding some of the experimental observations discussed
above.22 Of particular interest is the diastereoselectivity
of the reaction and the role of the Lewis acid. Under-
standing this could facilitate the design of chiral auxil-
(19) No¨th, H.; Wrackmeyer, B. Nuclear Magnetic Resonance Spec-
troscopy of Boron Compounds; Springer-Verlag: New York, 1978.
(20) Ishihara, K. In Lewis Acids in Organic Synthesis; Yamamoto,
H., Ed.; Wiley-VCH: Weinheim, 2000; Vol. 1, pp 89-133.
(21) J emison, R. W.; Laird, T.; Ollis, W. D.; Sutherland, I. O. J .
Chem. Soc., Perkin Trans. 1 1980, 1436-1449.
J . Org. Chem, Vol. 69, No. 9, 2004 3045

Blid et al.
SCHEME 3. An ion ic Rea ction P a th s for th e Lew is
Acid Med ia ted [2,3]-Sigm a tr op ic Rea r r a n gem en t of
E-1 (X ) F or Br )
F IGURE 2. Diastereomeric transition states for the neutral
BF2+-mediated [2,3]-sigmatropic rearrangement of E-1.
TABLE 6. Activa tion F r ee En er gies (k ca l m ol-1) for th e
Neu tr a l Mech a n ism (F igu r e 2)a
TABLE 5. Activa tion F r ee En er gies (k ca l m ol-1) for th e
An ion ic Mech a n ism a
LA
substrate
TS
∆Gq ∆∆Gq b ∆∆Gq (exp)c
+
BF2
E-1
E-1
E-1
E-1
Z-1
Z-1
exo-TS3
22.3
LA
TS
∆Gq
∆∆Gq b
endo-TS3 21.0
exo-TS3 17.4
endo-TS3 15.8
exo-TS3 17.2
endo-TS3 17.4
-1.3
-1.6
0.2
<-1.7
<-1.5
≈-0.1
+
+
BF3
exo-TS1
endo-TS1
exo-TS2
endo-TS2
exo-TS1
endo-TS1
18.7
19.9
19.6
19.4
25.5
27.8
BBr2
BBr2
1.2
-0.2
2.3
BBr3
a
b
Solvation effect included in the free energy. Calculated
diastereoselectivity, ∆∆Gq ) ∆Gq(endo) - ∆Gq(exo). c Calculated
from the experimentally determined diastereomeric ratio.
a
b
Solvation effect included in the free energy. Calculated
diastereoselectivity, ∆∆Gq ) ∆Gq(endo) - ∆Gq(exo).
easily be characterized from their 11B and 19F NMR
through the 11B-19F splitting pattern and chemical shifts
(vide infra).19,24 It was assumed that similar complexes
would be formed between BF3 or BBr3 and substrate 2a .
Initially, we investigated the energetics of the reaction
wherein one halide is displaced by the bidentate sub-
strate. Starting with BF3, the calculations suggest that
the displacement is endergonic by 12.4 kcal mol-1. In the
case of BBr3, the reaction is conversely favorable by -13.7
kcal mol-1 of free energy. The unfavorable BF3 mediated
reaction could be promoted via addition of an additional
1 equiv of the Lewis acid to account for the liberated
fluoride ion. Theoretically, this makes the reaction ex-
ergonic by -14.9 kcal mol-1. The analogous reaction with
an additional equivalent of BBr3 predicted a favorable
reaction with a free energy of -32.6 kcal mol-1. Thus,
the reactions seem likely to exhibit differing chemistry.
Whereas the BF3-mediated process could not enter this
rearrangement pathway without consuming an addi-
tional equivalent of the Lewis acid, the BBr3 reaction is
likely to be less dependent on an additional equivalent.
Figure 2 shows the two diastereomeric transition states
possible for the BF2+-mediated [2,3]-sigmatropic rear-
rangement of E-1. No apparent structural cause for the
selectivity is revealed by these structures. However, this
type of transition state generates both acceptable rates
of the reaction and a correct estimation of the diastereo-
selectivity as shown in Table 6.
iaries and also help identify new substrates suitable for
the reaction. As part of an initial hypothesis, we inves-
tigated the chemistry surrounding the deprotonated, BF3-
or BBr3-coordinated R-amino amide 1. Two different
coordination modes were investigated as illustrated in
Scheme 3, and an inactivated state characterized by a
single BX3 binding to the amide oxygen was also taken
into account.
The results given in Table 5 exhibit concordant theo-
retical activation energies for the BF3-promoted reaction
but the calculated diastereoselectivities are not in ac-
cordance with the experimental result. In the case of the
BBr3-promoted reaction, the calculated activation ener-
gies are well above the limits suggested by the time of
the experimental reaction. Again, the predicted diaster-
eoselectivity is erroneous. The high activation energy in
case of BBr3 appears to be due to a very strong coordina-
tion of this Lewis acid to the amide oxygen.
At this point, alternative reaction mechanisms had to
be explored. One possible alternative would be a mech-
anism where the carbonyl oxygen atom displaces one of
the halides from the Lewis acid. It has previously been
established that boron Lewis acids, such as ArBF2 and
BF3, form cyclic complexes with N,N-dialkylamino acids
by displacing a fluoride anion.23 These complexes can
(22) DFT-calculations on related [2,3]-sigmatropic rearrange-
ments: (a) Wu, Y.-D.; Houk, K. N.; Marshall, J . A. J . Org. Chem. 1990,
55, 1421-1423. (b) Mikami, K.; Uchida, T.; Hirano, T.; Wu, Y.-D.;
Houk, K. N. Tetrahedron 1994, 50, 5917-5926. (c) J ursic, B. S.
THEOCHEM 1995, 339, 161-168.
(23) (a) Halstrøm, J .; Nebelin, E.; Pedersen, E. J . J . Chem. Res. 1978,
80-81. (b) Vedejs, E.; Fields, S. C.; Lin, S.; Schrimpf, M. R. J . Org.
Chem. 1995, 60, 3028-3034.
NMR Sp ectr oscop ic In vestiga tion of Com p lexes
9a ,b. To determine the structure of the complexes formed
(24) Harris, R. K.; Mann, B. E. NMR and the Periodic Table;
Academic Press: London, 1978.
3046 J . Org. Chem., Vol. 69, No. 9, 2004

[2,3]-Sigmatropic Rearrangement of Allylic R-Amino Amides
TABLE 7. NOE En h a n cem en t Mea su r em en ts of 9b a
by mixing the Lewis acid with the substrate 2a and to
find additional support for the computationally deter-
mined reaction pathway, an NMR spectroscopic investi-
gation was undertaken. Consequently, adding 1 equiv of
BF3‚OEt2 to 2a afforded, according to 1H NMR, ap-
proximately a 3:2 mixture of 2a and the 2a -BF2 complex
9a , and addition of a second equivalent of BF3‚OEt2
transformed the remaining 2a into 9a .
entry
NOE interaction
NOE enhancement (%)
1
2
3
4
5
6
7
H1 f H3
H1 f H4
H5 f H2
H6 f H2
H6 f H1
H7 f H1
H7 f H2
6
5
6
4
<1
5
<1
a
Mixing time: 800 ms (T1 ) 1.2 s).
Examining the 11B NMR spectrum of 9a revealed one
triplet at δ 4.9 ppm (1J B,F ) 15 Hz) and one singlet at δ
-0.7 ppm.25 The triplet signal was indicative of a boron
atom with two fluorine substituents, and the observed
11B chemical shift was in good agreement with those
observed with related compounds.23 It can be suggested
that 1 equiv of BF3‚OEt2 was required for the complex-
ation to 2a while the second reacted with the liberated
TABLE 8. BF 3- a n d BBr 3-Med ia ted [2,3]-Sigm a tr op ic
Rea r r a n gem en ts of Am in es 2b-d a
entry
amine
Lewis acid/(equiv)
syn/antib
3c (%)
1
2
3
4
5
6
7
8
9
(E)-Me, 2b
(E)-Me, 2b
(E)-Ph, 2c
(Z)-Me, 2d
(Z)-Me, 2d
(E)-Me, 2b
(E)-Me, 2b
(Z)-Me, 2d
(Z)-Me, 2d
BF3‚OEt2/1.1
BF3‚OEt2/2.0
BF3‚OEt2/2.0
BF3‚OEt2/1.1
BF3‚OEt2/2.0
BBr3/1.1
BBr3/2.0
BBr3/1.1
BBr3/2.0
>30:1
>30:1
>30:1d
3:1
14 (48)
55 (22)
52 (35)
2 (56)
F
- forming BF4-, which corresponds to the 11B signal at
2:1
3 (72)
δ -0.7 ppm (1J B,F ) ∼1 Hz gives apparent singlet).19 In
the 19F NMR spectrum of 9a , two multiplet signals at δ
-85.7 and -88.5 ppm were observed corresponding to
>20:1
>20:1
6:5
71 (20)
78 (10)
56 (33)
49 (22)
4:3
the diastereotopic fluorine atoms26 and a singlet at -88.6
a
- 24,27
Reaction conditions: to 2 (1.0 equiv) in PhMe at -78 °C were
added Lewis acid and 6 (1.0 equiv), and the resultant mixture was
ppm arising from BF4
.
When BBr3 and 2a were mixed in equimolar amounts,
1H NMR spectroscopy revealed that two distinct com-
plexes were formed in a 5:2 ratio. Increasing the relative
amount of BBr3 to 2 and 3 equiv increased the ratio
between the two complexes to 5:1 and 8:1, respectively.
The appearance of the two complexes on 1H NMR
changed on going from 1 to 2 equiv of BBr3 but was
unchanged with a further increase to 3 equiv.
b
stirred overnight (18-20 h) at -20 °C. Ratio determined by 1H
d
NMR. c Yield of recovered starting material in parentheses. Only
one diastereomer visible on crude 1H NMR.
of BF3‚OEt2, and the results are collected in Table 8. For
2b, these conditions resulted in an increased yield of 3b
without compromising diastereoselectivity (entries 1 and
2). Using identical reaction conditions, 2c gave a similar
yield of 52% and an excellent diastereoselectivity of >30:1
(entry 3). Surprisingly, the (Z)-olefin 2d was unreactive
providing a very low yield and diastereoselectivity re-
gardless of the amount of BF3‚OEt2 employed (entries 4
and 5). Subjecting 2b and 2d to 2 equiv of BBr3 did not
significantly influence the yield or diastereoselectivity
(entries 6-9).
Deter m in a tion of Rela tive Ster eoch em istr y of
syn -3b, a n ti-3b, a n d syn -3c. syn-3b, anti-3b and syn-
3c were converted into pyrrolidines 10a , 10b, and a
mixture of 10c and 11, respectively, by Hg2+-mediated
cyclization followed by reductive demercuration (Scheme
4). The relative stereochemistry of 10a ,b and 11 could
then be determined by NOE experiments (Figure 3).
Examining the 11B NMR spectra revealed one major
peak at δ 5.7. At 1 equiv of BBr3 an additional minor
signal at δ -24.3 was observed. At 2-3 equiv of BBr3,
the signal at δ -24.3 disappeared and instead a minor
peak at δ -11.8 was revealed. Although the 11B chemical
1
shift of 5.7 ppm and the matching appearance of the H
NMR with that of complex 9a suggested a similar
chelating complex, the structure of 9b could not be
confirmed by 1H and 11B NMR alone. However, the
problem was resolved by 2D NOESY spectroscopy (Table
7). NOE enhancement measurements showed that H1
exhibited NOE interactions with H3 and H4 (entries 1 and
2), while negligible interactions (<1%) were observed
between H1 and H5. The opposite was the case for H2
(entry 3). The two methylene protons, H6 and H7 on the
pyrrolidine ring, exhibited opposite NOE interactions
toward H1 and H2 further supporting the assignment of
complex 9b (entries 4-7). Similar NOE interactions could
be found when examining complex 9a .
Con clu sion s
The structures of complexes 9a and 9b have been
confirmed by NMR spectroscopy. While the complex 9b
was readily formed by mixing 2a with 1 equiv of BBr3,
an additional 1 equiv of BF3 was needed to account for
the displaced fluoride anion upon forming the complex
9a allowing the reaction to proceed. It has been shown
that reaction of amines 2a -e with BBr3 followed by
deprotonation results in a [2,3]-sigmatropic rearrange-
Having established the structures of complexes 9a ,b,
the rearrangement of 2b-d was repeated with 2 equiv
(25) Relative to BF3‚OEt2 as external standard.
(26) Relative to CF3C6H5 as external standard.
(27) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf,
M. R. J . Org. Chem. 1995, 60, 3020-3027.
J . Org. Chem, Vol. 69, No. 9, 2004 3047

Blid et al.
F IGURE 3. NOE enhancement measurements of amines 10a ,b and 11. Mixing times were 700 (T1 ) 1.1 s), 600 (T1 ) 0.9 s), and
1250 ms (T1 ) 1.9 s) for 10a ,b and 11. G ) CON(CH2CH2)2.
SCHEME 4. Hg2+-Med ia ted Cycliza tion of th e
1-(2-Ben zyla m in o-1-oxo-4-p en ten yl)p yr r olid in e (3a ):
1H NMR (CDCl3, 400 MHz) δH 7.34-7.22 (m, 5H), 5.82 (ddt,
Secon d a r y Am in es syn -3b, a n ti-3b, a n d syn -3c
1H, J ) 17.1, 10.1, 7.1 Hz), 5.10 (d, 1H, J ) 17.1 Hz), 5.04 (d,
1H, J ) 10.1 Hz), 3.83 (d, 1H, J ) 13.1 Hz), 3.59 (d, 1H, J )
13.1 Hz), 3.54 (dt, 1H, J ) 12.2, 6.7 Hz), 3.45 (dt, 1H, J )
12.2, 6.9 Hz), 3.36 (t, 1H, J ) 6.8 Hz), 3.30 (dt, 1H, J ) 9.9,
6.7 Hz), 3.21 (dt, 1H, J ) 9.9, 6.6 Hz), 2.40-2.28 (m, 2H), 2.21
(bs, 1H), 1.92-1.80 (m, 4H); 13C NMR (CDCl3, 100 MHz) δC
172.7, 140.0, 134.4, 128.28, 128.26, 126.9, 117.3, 58.6, 51.8,
46.1 45.7, 37.9, 26.0, 24.1; IR (neat) 3316, 2973, 2876, 1637
cm-1; HRMS (EI+) calcd for C16H22N2O [M]+ 258.1732, found
258.1732.
(2R*,3R*)-1-(2-Ben zylam in o-3-m eth yl-1-oxo-4-pen ten yl)-
1
p yr r olid in e (a n ti-3b): H NMR (CDCl3, 500 MHz) δH 7.31
(m, 4H), 7.22 (m, 1H), 5.89 (ddd, 1H, J ) 17.6, 10.1, 7.2 Hz),
5.07 (d, 1H, J ) 17.6 Hz), 5.07 (d, 1H, J ) 10.1 Hz), 3.86 (d,
1H, J ) 13.6 Hz), 3.57 (d, 1H, J ) 13.6 Hz), 3.55 (m, 1H), 3.45
(m, 1H), 3.31 (m, 1H), 3.15 (d, 1H, J ) 7.2 Hz), 3.12 (m, 1H),
2.46 (sextet, 1H, J ) 7.2 Hz), 2.18 (bs, 1H), 1.89-1.78 (m, 4H),
1.02 (d, 3H, J ) 7.2 Hz); 13C NMR (CDCl3, 125 MHz) δC 172.6,
140.7, 140.3, 128.21, 128.17, 126.9, 114.9, 63.0, 51.9, 46.2, 45.6,
ment affording secondary amines 3 in good yields. (E)-
Crotyl- and (E)-cinnamylamine 2b and 2c displayed
excellent syn-diastereoselectivities in the rearrangement.
40.9, 26.1, 24.1, 16.7; IR (neat) 3327, 2971, 2875, 1632 cm-1
;
HRMS (CI+) calcd for C17H25N2O [M + H]+ 273.1967, found
273.1965.
DFT calculations on the deprotonated BF2+-1 and
BBr2+-1 complexes were in agreement with the experi-
mentally obtained diastereoselectivities, thereby provid-
ing a plausible reaction pathway for the BF3- and BBr3-
mediated [2,3]-sigmatropic rearrangement of allylic
R-amino amides.
(2R*,3S*)-1-(2-Ben zylam in o-3-ph en yl-1-oxo-4-pen ten yl)-
p yr r olid in e (syn -3c): H NMR (CDCl3, 400 MHz) δH 7.38-
1
7.17 (m, 10H), 6.17 (ddd, 1H, J ) 16.5, 9.7, 7.9 Hz), 5.12 (d,
1H, J ) 16.5 Hz), 5.09 (d, 1H, J ) 9.7 Hz), 3.81 (d, 1H, J )
13.4 Hz), 3.67 (t, 1H, J ) 7.9 Hz), 3.57 (d, 1H, J ) 13.4 Hz),
3.57 (d, 1H, J ) 7.9 Hz), 3.49 (m, 1H), 3.38 (m, 1H), 2.90 (m,
1H), 2.63 (m, 1H), 2.04 (bs, 1H), 1.72 (m, 3H), 1.59 (m, 1H);
13C NMR (CDCl3, 100 MHz) δC 171.4, 141,0, 139.8, 136.9,
128.4, 128.3, 128.2, 128.2, 126.9, 126.7, 117.4, 62.2, 54.0, 51.3,
46.0, 45.5., 25.9, 24.0; IR (neat) 3325, 3060, 3028, 2974, 2951,
1633 cm-1; HRMS (CI+) calcd for C22H27N2O [M + H]+
335.2123, found 335.2120.
Exp er im en ta l Section
Typ ica l P r oced u r e for th e Lew is Acid [2,3]-Sigm a tr o-
p ic Rea r r a n gem en t of Allylic Am in es 2. (2R*,3S*)-1-(2-
Ben zylam in o-3-m eth yl-1-oxo-4-pen ten yl)pyr r olidin e (syn -
3b). To a stirred solution of 2b (35 mg, 0.13 mmol) in toluene
(1.5 mL) at -78 °C was added BBr3 (1.0 m in hexanes; 0.15
mL, 0.15 mmol). To the resultant solution was added 6 (0.13
mmol), and the mixture was allowed to reach -20 °C. After
the mixture was stirred for 19 h at -20 °C, the reaction was
quenched by addition of H2O (1 mL) and allowed to stir for 1
h at rt. The solution was made alkaline with 2 M NaOH (1.5
mL) and the resultant mixture filtered through a prepacked
extraction tube, which was eluted with CH2Cl2 (15 mL). The
concentrated residue was chromatographed (MeCN/Et2O 0:1f1:
0) to provide syn-3b as a pale yellow oil (25 mg, 71%, ds >20:
1): 1H NMR (CDCl3, 500 MHz) δH 7.34 (d, 2H, J ) 7.1 Hz),
7.30 (t, 2H, J ) 7.1 Hz), 7.22 (t, 1H, J ) 7.1 Hz), 5.79 (ddd,
1H, J ) 17.2, 10.3, 7.3 Hz), 5.05 (d, 1H, J ) 17.2 Hz), 4.96 (d,
1H, J ) 10.3 Hz), 3.85 (d, 1H, J ) 13.4 Hz), 3.54 (d, 1H, J )
13.4 Hz), 3.54 (m, 1H,), 3.42 (dt, 1H, J ) 12.0, 6.6 Hz), 3.27
(m, 1H), 3.12 (m, 1H), 3.11 (d, 1H, J ) 7.3 Hz), 2.38 (sextet,
1H, J ) 7.3 Hz), 2.20 (bs, 1H), 1.88-1.77 (m, 4H), 1.12 (d, 3H,
J ) 7.3 Hz); 13C NMR (CDCl3, 125 MHz) δC 172.8, 140.7, 140.3,
128.22, 128.18, 126.8, 114.7, 63.1, 52.1, 46.2, 45.5, 41.4, 26.0,
24.2, 15.9; IR (neat) 3318, 2972, 2875, 1632 cm-1; HRMS (CI+)
calcd for C17H25N2O [M + H]+ 273.1967, found 273.1964.
(2R*,3R*)-1-(2-Ben zylam in o-3-ph en yl-1-oxo-4-pen ten yl)-
p yr r olid in e (a n ti-3c): 1H NMR (CDCl3, 500 MHz) δH 7.31
(m, 4H), 7.22 (m, 5H), 7.16 (m, 1H), 6.28 (ddd, 1H, J ) 17.2,
10.3, 8.3 Hz), 5.23 (d, 1H, J ) 17.2 Hz), 5.13 (d, 1H, J ) 10.3
Hz), 3.90 (d, 1H, J ) 13.6 Hz), 3.58 (d, 1H, J ) 13.6 Hz), 3.55
(t, 1H, J ) 8.3 Hz), 3.44 (d, 1H, J ) 9.5 Hz), 3.33 (m, 1H),
3.09 (m, 1H), 2.78 (m, 1H), 2.42 (m, 1H), 1.58 (m, 2H), 1.43
(m, 1H), 1.32 (m, 1H); 13C NMR (CDCl3, 125 MHz) δC 172.0,
141.2, 140.0, 138.4, 128.4, 128.24, 128.20, 128.1, 126.9, 126.7,
117.0, 63.4, 53.2, 51.8, 45.7, 45.2, 25.7, 23.8; IR (neat) 3311,
3049, 3029, 2970, 2873, 1633 cm-1; HRMS (CI+) calcd for
C
22H27N2O [M + H]+ 335.2123, found 335.2120.
1-(2-Ben zyla m in o-3,3-d im eth yl-1-oxo-4-p en ten yl)p yr -
r olid in e (3e): 1H NMR (CDCl3, 400 MHz) δH 7.30 (m, 4H),
7.22 (m, 1H), 5.95 (dd, 1H, J ) 17.5, 10.7 Hz), 5.01 (d, 1H, J
) 17.5 Hz), 4.99 (d, 1H, J ) 10.7 Hz), 3.85 (d, 1H, J ) 13.7
Hz), 3.54 (m, 1H), 3.52 (d, 1H, J ) 13.7 Hz), 3.40 (m, 1H),
3.25 (m, 1H), 3.01 (s, 1H), 2.99 (m, 1H), 2.09 (bs, 1H), 1.79 (m,
4H), 1.10 (s, 3H), 1.09 (s, 3H,); 13C NMR (CDCl3, 100 MHz) δC
172.5, 145.1, 140.4, 128.16, 128.15, 126.9, 112.2, 65.2, 52.1,
46.8, 45.4, 40.5, 26.1, 24.4, 24.2, 23.1; IR (neat) 3330, 3084,
3062, 2964, 2875, 1633 cm-1; HRMS (EI+) calcd for C18H27N2O
[M + H]+ 287.2123, found 287.2125.
3048 J . Org. Chem., Vol. 69, No. 9, 2004

[2,3]-Sigmatropic Rearrangement of Allylic R-Amino Amides
Com p lex 9a : 1H NMR (CD3CN, 500 MHz) δH 7.55 (dd, 2H,
J ) 8.1, 1.7 Hz), 7.52-7.45 (m, 3H), 5.97 (ddt, 1H, J ) 17.1,
10.1, 7.3 Hz), 5.63 (d, 1H, J ) 17.1 Hz), 5.59 (d, 1H, J ) 10.1
Hz), 4.43 (d, 1H, J ) 17.3 Hz), 4.40 (d, 1H, J ) 12.7 Hz), 4.25
(d, 1H, J ) 12.7 Hz), 4.22 (d, 1H, J ) 17.3 Hz), 3.78 (dd, 1H,
J ) 13.0, 7.3 Hz), 3.70 (dd, 1H, J ) 13.0, 7.3 Hz), 3.50 (m,
2H), 3.40 (m, 1H), 3.29 (m, 1H), 2.00-1.79 (m, 4H); 11B NMR
(CD3CN, 160 MHz) δB 4.9 (t, 1J BF ) 15 Hz), -0.7 (s); 19F NMR
(CD3CN, 470 MHz) δF -85.7 (m), -88.5 (m), -88.6 (s).
Com p lex 9b: 1H NMR (CD2Cl2, 500 MHz) δH 7.82 (dd, 2H,
J ) 7.6, 1.3 Hz), 7.60-7.52 (m, 3H), 6.22 (ddt, 1H, J ) 17.2,
10.0, 7.3 Hz), 5.83 (d, 1H, J ) 17.2 Hz), 5.68 (d, 1H, J ) 10.0
Hz), 5.10 (d, 1H, J ) 13.0 Hz), 4.85 (d, 1H, J ) 16.7 Hz), 4.68
(d, 1H, J ) 13.0 Hz), 4.66 (d, 1H, J ) 16.7 Hz), 4.34 (m, 1H),
4.20 (m, 1H), 3.89 (m, 1H), 3.72 (m, 2H), 3.50 (m, 1H), 2.20-
1.94 (m, 4H); 11B NMR (CD2Cl2, 160 MHz) δB 5.7 (s).
P yr r olid in e 10a . To a stirred solution of syn-3b (9 mg,
0.033 mmol) in THF (0.5 mL) was added Hg(CF3CO2)2 (25 mg,
0.058 mmol) in THF (1 mL) and the resultant solution heated
at reflux for 1.5 h. The reaction mixture was cooled to 0 °C,
0.5 M NaBH4/2 M NaOH (1.5 mL) was added, and the mixture
was stirred at rt for 2.5 h. The mixture was diluted with Et2O
and centrifuged. The dried (K2CO3) organic phase was con-
centrated and chromatographed (pentane/EtOH 18:1 f 9:1 +
1% NH3) to provide 10a (5.4 mg, 60%): 1H NMR (CDCl3, 500
MHz) δH 7.32-7.20 (m, 5H), 3.89 (d, 1H, J ) 12.9), 3.66 (d,
1H, J ) 12.9), 3.47 (m, 2H), 3.38 (d, 1H, J ) 8.5), 3.17 (m,
2H), 2.88 (m, 1H), 2.67 (dt, 1H, J ) 8.5, 7.3), 2.45 (m, 1H),
1.98 (m, 1H), 1.77 (m, 5H), 0.93 (d, 3H, J ) 7.3); 13C NMR
(CDCl3, 100 MHz) δC 170.4, 138.7, 129.3, 128.0, 126.9, 66.5,
57.5, 52.8, 46.1, 45.4, 35.3, 32.3, 26.3, 24.0, 16.3; IR (neat) 3025,
2965, 1623 cm-1; HRMS (FAB+) calcd for C17H25N2O [M +
H]+ 273.1967, found 273.1971.
P yr r olid in e 10b: 1H NMR (CDCl3, 500 MHz) δH 7.31-7.20
(m, 5H), 3.83 (d, 1H, J ) 12.9 Hz), 3.59 (d, 1H, J ) 12.9 Hz),
3.54 (m, 1H), 3.40 (m, 2H), 3.14 (m, 2H), 3.00 (d, 1H, J ) 6.7
Hz), 2.55 (m, 1H), 2.41 (m, 1H), 2.15 (m, 1H), 1.76 (m, 4H),
1.42 (m, 1H), 1.10 (d, 3H, J ) 6.8 Hz); 13C NMR (CDCl3, 125
MHz) δC 171.8, 138.9, 129.0, 128.0, 126.9, 73.3, 58.3, 52.9, 46.2,
46.1, 37.9, 32.2, 26.3, 23.8, 20.1; IR (neat) 3052, 2959, 1631
cm-1; HRMS (FAB+) calcd for C17H25N2O [M + H]+ 273.1967,
found 273.1968.
1
P yr r olid in e 11: H NMR (CDCl3, 500 MHz) δH 7.35-7.19
(m, 10H), 5.01 (m, 1H), 3.94 (d, 1H, J ) 12.7 Hz), 3.88 (d, 1H,
J ) 8.2 Hz), 3.75 (d, 1H, J ) 12.7 Hz), 3.74 (m, 1H), 3.50 (t,
1H, J ) 8.2 Hz), 3.27 (m, 1H), 3.00 (m, 1H), 2.97 (dd, 1H, J )
9.2, 4.9 Hz), 2.50 (m, 1H), 2.32 (m, 1H), 1.74 (d, 1H, J ) 5.0
Hz), 1.49 (m, 2H), 1.32 (m, 1H), 1.15 (m, 1H); 13C NMR (CDCl3,
125 MHz) δC 169.4, 137.3(×2), 129.2, 128.8, 128.2, 128.1, 127.3,
127.0, 76.2, 67.3, 60.2, 56.9, 56.2, 45.5, 45.1, 25.7, 23.7; IR
(neat) 3381, 2950, 1631, 1451, 1081 cm-1; HRMS (FAB+) calcd
for C22H27N2O2 [M + H]+ 351.2073, found 351.2078.
Ack n ow led gm en t. This work was supported finan-
cially by the Swedish Research Council. We also grate-
fully acknowledge Dr. Colin Ray from AstraZeneca,
So¨derta¨lje, for his careful proof reading of the manu-
script.
Su p p or tin g In for m a tion Ava ila ble: Synthesis and char-
acterization of 2. 1H and 13C NMR spectra for 2, 3, 7, 8, 10a ,b,
11, 12, 14b-e, 15b-e, and 16b-e; 1H, 11B, and 19F NMR
spectra for 9a ; 1H and 11B NMR spectra for 9b. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O035618G
J . Org. Chem, Vol. 69, No. 9, 2004 3049