The combination of anionic and radical reactions to oxidative tandem processes exemplified by the synthesis of functionalized pyrrolidines [2]

Full text of DOI:10.1021/ja000565v

5212
J. Am. Chem. Soc. 2000, 122, 5212-5213
Scheme 1. Tandem Lithium Amide Conjugate Addition/
Radical 5-exo Cyclization to Pyrrolidines 9, Mediated by 5/6
The Combination of Anionic and Radical Reactions
to Oxidative Tandem Processes Exemplified by the
Synthesis of Functionalized Pyrrolidines
Ullrich Jahn,* Markus Mu¨ller, and Susanne Aussieker
Institut fu¨r Organische Chemie
Technische UniVersita¨t Braunschweig
Hagenring 30, D-38106 Braunschweig, Germany
ReceiVed February 16, 2000
The design of domino or tandem processes is one of the most
attractive areas of organic research.1 So far, most of the sequential
strategies involve intermediates of the same oxidation state.
Naturally, this leads to limitations due to the inherent reactivity
patterns of these intermediates. The most appealing way to
overcome this problem and to open new reaction channels are
strategies that allow the selective change of the oxidation state
of intermediates during reaction sequences by electron transfer.2
3
For reductive tandem processes, SmI2 has proven a valuable
reagent. On the other hand, oxidative reaction sequences incor-
porating anionic and radical reaction steps are hardly explored.4
We report the combination of anionic and radical reactions to
oxidative tandem processes, exemplified by lithium amide
conjugate addition/SET/radical 5-exo cyclization/radical trapping.
Since neither alternative intermolecular aminyl radical additions
to R,â-unsaturated carbonyl compounds nor alkali enolate addi-
tions to alkenes are feasible reaction types, the results presented
here provide a unique solution to reactivity limitations of different
intermediate types.
Table 1. Tandem Lithium Amide Conjugate Addition/Radical
5-exo Cyclizations to Pyrrolidines 9
entry
1
2
9 (%, 3,4-cis/trans) 10 (%) 4 (%) other (%)
1
2
3
4
5
6
7
8
a
a
a
a
a
a
a
b
b
b
b
a
aa (67, 1.2:1)
aa (85, 1.3:1)
ab (47, 4.9:1)
ab (63, 7.2:1)
ab (68, 5.8:1)
ac (76, 1:1.1)
ac (69, 1:1)
ba (51, 1:2.4)
ba (25, 1:1.5)
ba (53, 1:1.6)
bb (56, 4.5:1)
4
11aa (8)
11aa (4)
aa
b
12
11
12
13
11
5
20
5
10
8
bb
ba
c
ca
a
11
A brief initial study of the conjugate addition of lithium
N-allylamides 2a-c to tert-butyl enoates 1a,b5 showed that
N-allyl-â-amino esters 4aa-4bb were formed via 3 at -78 °C
in THF in good yields (Scheme 1).
12 (3)
12 (54)
12 (6)
12 (5)
9
10
11
aa
ac
b
4
18
9
a Reaction sequence in 11 mL of THF/2.5 mL of HMPA. b DME as
The tandem lithium amide conjugate addition/radical 5-exo
cyclization reactions were performed with ferrocenium hexafluo-
rophosphate 5 as SET oxidant6 for the â-amino enolate 3 (Scheme
1). For the termination of the reaction sequence, free radical
TEMPO 6 was added since it reacts more slowly with R-carbonyl
radicals 7 than with alkyl radicals 8 and oxygenated products are
obtained, which provide ample opportunities for further trans-
formations.
The reaction sequences of enoates 1a,b and lithium N-
allylamides 2a-c in THF gave only two of the four possible
pyrrolidine diastereomers 9aa-bb with complete 2,3-trans-
selectivity in good to high yield (Table 1). tert-Butyl cinnamate
1a provided a higher yield of 9aa or 9ab in the presence of HMPA
without influencing the cyclization diastereoselectivity (entries
2,5 vs 1,3). DME as the solvent yielded the cyclized product 9ab
in comparable yield (entry 4). With lithium amides 2a,c, es-
sentially no cyclization diastereoselectivity to 9aa,ac was observed
solvent. c Temperature for oxidative cyclization -45 °C.
(entries 1,2,6,7). On the other hand, the more biased lithium amide
2b gave a >4.9:1 3,4-cis-selectivity in 9ab (entries 3-5).
tert-Butyl crotonate 1b gave the pyrrolidine derivatives 9ba
and 9bb in acceptable yields (entries 8-11).7 HMPA had a
detrimental effect on the yield of 9ba, since γ-deprotonation
leading finally to 12 competes with conjugate addition (entry 9).
The stereochemical outcome depended on the lithium amide. The
reaction sequence of 1b/2a gave the 3,4-trans-pyrrolidine 9ba
preferentially at -78 °C (entry 8), but the selectivity decreased
if the temperature was raised to -45 °C (entry 10). With 2b, the
3,4-cis-pyrrolidine 9bb was formed with a 4.5:1 selectivity (entry
11). From the reactions, small amounts of the conjugate addition
products 4, acyclic TEMPO trapping products 10, and pyrrolidi-
necarboxamides 11 were isolated. To minimize the formation of
10, a mixture of 5 and 6 was added in all reactions except for the
synthesis of 9ac where TEMPO 6 was added before 5 to avoid
oxidation of the cyclized tertiary radical 8ac to a carbenium ion.
The configuration of 9 was assigned on the basis of NOE
experiments and chemical transformations (vide infra).
(1) (a) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32,
131. (b) Chem. ReV. 1996, 96, 6, issue 1.
(2) Review on electron transfer-induced reactions: Dalko, P. I. Tetrahedron
1995, 51, 7579.
(3) Review: Molander, G. A.; Harris, C. R. Tetrahedron 1998, 54, 3321.
(4) (a) Cohen, T.; McNamara, K.; Kuzemko, M. A.; Ramig, K.; Landi, J.
J., Jr.; Dong, Y. Tetrahedron 1993, 49, 7931. (b) Durand, A.-C.; Dumez, E.;
Rodriguez, J.; Dulcere, J.-P. Chem. Commun. 1999, 2437. For a review on
oxidative radical reactions of carbonyl compounds using Mn(OAc)3, see: (c)
Melikyan, G. G. Org. React. 1997, 49, 427.
(5) For amide conjugate additions, see: (a) Juaristi, E. EnantioselectiVe
Synthesis of â-Amino Acids; Wiley-VCH: Weinheim, 1997. For more recent
results, see: (b) Sewald, N.; Hiller, K. D.; Ko¨rner, M.; Findeisen, M. J. Org.
Chem. 1998, 63, 7263 and references therein.
(6) For the use of 5,6, see: (a) Jahn, U.; Hartmann, P. Chem. Commun.
1998, 209. (b) Jahn, U. J. Org. Chem. 1998, 63, 7130 and references therein.
The efficiency of the tandem process was compared to a
stepwise procedure. Deprotonation of â-amino esters 4aa or 4ba
with LDA and oxidative cyclization by 5 in the presence of
TEMPO 6 gave pyrrolidines 9aa or 9ba in 66 and 64% yield
(Scheme 2). While the overall yield of the two-step methodology
was only slightly lower than that of the tandem reactions (59 vs
(7) Although the overall yields are only in the 50% range for 1b, the average
yield of each sequence step from 2 is at least 88%.
10.1021/ja000565v CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/13/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 21, 2000 5213
Scheme 3. Rationalization of the Cyclization
Scheme 2. Cyclizations of â-Amino Esters 4 and the
Development of a cis-Selective Tandem Addition/Cyclization
Diastereoselectivity
67% for 9aa, 46 vs 51% for 9ba), the cyclization diastereose-
lectivity changed dramatically, now providing the 3,4-cis isomer
in a >10:1 ratio!
Scheme 4. Configuration Assignment of Pyrrolidines 7 by
Deprotection(/Lactonization)
This control element can be incorporated favorably into the
tandem reactions described above by inserting a protonation/
deprotonation step after conjugate addition. Thus, pyrrolidines
9aa and 9ba can now be obtained with preferred 3,4-cis-
stereoselectivity from 1a,b/2a (Scheme 2).
Enolate geometry most likely determines the contrasting radical
cyclization diastereoselectivities. Therefore, enolates 3ba derived
from conjugate addition of 2a to 1b and from deprotonation of
4ba with LDA were trapped as silyl ketene acetals (Supporting
Information). The conjugate addition derived enolate 3ba pos-
sesses (Z)-configuration, while deprotonation of â-amino ester
4ba gives (E)-enolate 3ba with a selectivity of 14:1 as determined
by NOE experiments.8
As a working hypothesis, enolate (Z)-3ba most likely exists
as a chelate that is not broken immediately after oxidation to
radical 7A or 7B (Scheme 3).9 For 3,4-trans-9ba, the cyclizing
N-allyl group is preferentially oriented toward the less demanding
C2-substituent as in 7A. Increasing steric requirements in the 1-,
2-, and 4-positions offer a more favorable orientation of the
cyclizing N-allyl group toward the ester group in transition state
7B leading to the 3,4-cis isomer (entries 8 vs 1,3,6,11). On the
other hand, enolates (E)-3aa,ba cannot chelate and the derived
radicals 7C cyclize according to a Beckwith-Houk open transi-
tion state10 with the enolate geometry of 3aa, 3ba probably
preserved in the R-ester radical 7C due to its notable rotational
barrier.11
N-protecting groups with Zn/AcOH6 to alcohols 13aa-ba in good
yields (Scheme 4). Addition of catalytic KOtBu to 3,4-cis-13aa-
ba induced lactonization to 14 in almost quantitative yield while
3,4-trans-13aa-ba remained unaffected.
In summary, we have shown that oxidative anion/radical
reaction sequences, exemplified by lithium amide conjugate
addition/SET oxidation/radical 5-exo cyclization, are an attractive
strategy to obtain highly functionalized pyrrolidines in a single
operation from very simple precursors. The study shows clearly,
that the stereochemical information of enolates can be translated
into the radical cyclizations. Further detailed investigations are
necessary to generalize this new control element for radical
chemistry. The tandem reaction results indicate that this strategy
should be general as other anionic 1,4-additions may form the
basis for similar reaction cascades.
To aid configuration assignment, the tetramethylpiperidinyl
group was cleaved in the presence of the tert-butyl ester and the
Acknowledgment. We thank the DFG and the Fonds der Chemischen
Industrie for funding. Professor H. Hopf’s support and interest in this
project is gratefully acknowledged.
(8) Similar results were reported in related investigations: Asao, N.;
Uyehara, T.; Yamamoto, Y. Tetrahedron 1990, 46, 4563.
(9) For a review on chelation in radical reactions, see: Renaud, P.; Gerster,
M. Angew. Chem., Int. Ed. 1998, 37, 2562.
(10) a) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41, 3925.
(b) Spellmeyer, D. C.; Houk, K. N. J. Org. Chem. 1987, 52, 959.
(11) Lung-min, W.; Fischer, H. HelV. Chim. Acta 1983, 66, 138.
Supporting Information Available: Experimental procedures and
characterization of compounds 4, 9-14 (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JA000565V