Remarkable [3+2] annulations of electron-rich olefins with unstabilized azomethine ylides

Article abstract of DOI:10.1055/s-0030-1258026

Herein we would like to communicate that an unstabilized azomethine ylide generated from commercial trimethylamine N-oxide will undergo a remarkable 1,3-dipolar cycloaddition in good yield with electron-rich and unpolarized olefins. A broad range of substituents on the alkenes are tolerated provided they are compatible with excess LDA. This demonstration of novel reaction scope should encourage others to try trimethylamine N-oxide as an azomethine ylide precursor in the synthesis of challenging 3,4-disubstituted pyrrolidines. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258026

2490
LETTER
Remarkable [3+2] Annulations of Electron-Rich Olefins with Unstabilized
Azomethine Ylides
[3+2]
A
nn
e
ulations of
n
Electron-Ric
n
hOlefins
w
i
i
thUnst
f
a
bilized
e
A
zomethin
r
e
Y
lides E. Davoren,* David L. Gray,* Anthony R. Harris, Deane M. Nason, Wenjian Xu
Neurosciences Chemistry, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA
Fax +1(860)6867444; E-mail: jennifer.e.davoren@pfizer.com
Received 22 July 2010
Pyrrolidines whose requisite alkenes were unreactive un-
Abstract: Herein we would like to communicate that an unstabi-
lized azomethine ylide generated from commercial trimethylamine
N-oxide will undergo a remarkable 1,3-dipolar cycloaddition in
good yield with electron-rich and unpolarized olefins. A broad
der the acid-catalyzed conditions required a different
preparation. A survey of the chemical literature unearthed
a little used, but powerful method wherein a reactive un-
range of substituents on the alkenes are tolerated provided they are stabilized azomethine ylide can be generated by treating
compatible with excess LDA. This demonstration of novel reaction
scope should encourage others to try trimethylamine N-oxide as an
azomethine ylide precursor in the synthesis of challenging 3,4-di-
tions, ylide formation is thought to proceed by deoxygen-
substituted pyrrolidines.
trimethylamine N-oxide 4 with lithium diisopropylamide
at low temperature.7 Under these strongly basic condi-
ation of the N-oxide. The resultant intermediate is
Key words: 3,4-disubstituted pyrrolidine, cycloaddition, unstabi-
lized azomethine ylide
extremely reactive and can be trapped by simple alkenes
such as hex-1-ene, cyclopentene, styrene, and stilbene.8
R2
R1
O–
N+
Substituted pyrrolidines are common structural motifs
present in a wide variety of natural products,1 chiral
ligands,2 and biologically active compounds.3 One of the
most prevalent and reliable methods for the diastereo-
selective construction of 3,4-substituted architecture is the
1,3- dipolar cycloaddition reaction of an azomethine ylide
and an appropriately substituted alkene.4
LDA, 1–2 h, 0 °C to r.t.
R1
Me
Me
N
R2
Me
4
Me
2
5
Scheme 2 Basic [3+2]-cycloaddition reaction
During the course of our research we became interested in
constructing novel 3,4-disubstituted pyrrolidine ring sys-
tems. Since we did not require substitution on the 2- and
5-positions of the pyrrolidine ring, the azomethine ylide
derived from the acid-catalyzed decomposition of com-
mercial N-methoxymethyl-N-trimethylsilyl methyl phe-
nyl methanamine (1)5 was deemed a suitable choice
(Scheme 1).
Herein we would like to report that this cycloaddition re-
action furnished targeted N-methyl pyrrolidines in yields
ranging from good to excellent in nearly all cases exam-
ined.9 A broad range of substituents on the alkenes were
tolerated in this transformation provided that functional-
ities were compatible with excess LDA. Among the suc-
cessful dipolarophiles were several examples of electron-
rich olefins including those that failed under the acid con-
ditions (specifically products 8–10, Table 1). We found
this reaction to be operationally straightforward with cy-
cloadditions generally reaching completion in less than
one hour.
R2
CF3CO2H (1–2 equiv)
R1
CH2Cl2, r.t., 24–48 h
MeO
N
TMS
Bn
R1
N
R2
1
Bn
Despite its broad substrate scope, superior yields, and fast
reaction times we presume that this reaction has gained
only a modest following10 among the synthetic communi-
ty because the corresponding N-Me group on the pyrroli-
dine is difficult to remove. In our hands, we found 1-
chloroethyl chloroformate (ACE-Cl) to be a useful re-
agent for this cleavage as its purification is operationally
simple.11 Furthermore, we found we could accelerate this
N-demethylation to reach completion in just 30 minutes
using microwave irradiation (Scheme 3).12 For substrates
like those in Table 1, the microwave ACE-Cl deprotection
proceeded in low to moderate yield (Scheme 3).
2
3
Scheme 1 Acid-catalyzed [3+2]-cycloaddition reaction
In general, with compatible substrates, we found this well-
precedented chemistry to be operationally simple and
scalable. In several cases we obtained multigram quanti-
ties of the corresponding N-benzyl pyrrolidine. A well-
documented drawback of this method is that this type of
unstabilized azomethine ylide does not readily undergo
cycloaddition with unactivated dipolarophiles.6
In summary, we have demonstrated that the 1,3-dipolar
cycloaddition between an unstabilized azomethine ylide
and an unactivated olefin is not only possible, but can be
SYNLETT 2010, No. 16, pp 2490–2492
Advanced online publication: 09.08.2010
DOI: 10.1055/s-0030-1258026; Art ID: S04010ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
0

LETTER
[3+2] Annulations of Electron-Rich Olefins with Unstabilized Azomethine Ylides
2491
to additional systems is on-going and will be reported in
due time.
Table 1 Representative Trimethylamine-N-oxide [3+2]-Cycloaddi-
tion Products
Entry
Product
Yield (%)
Acknowledgment
NHCPh3
We would like to acknowledge Jotham Coe, Audrey Corman,
Andrew Flick, Brian O’Neill, and Donn Wishka for helpful sugges-
tions and discussions.
N
1
74
S
N
Me
References and Notes
6
(1) (a) Lewis, J. R. Nat. Prod. Rep. 2001, 18, 95. (b) O’Hagan,
D. Nat. Prod. Rep. 2000, 17, 435.
(2) Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M.
Chem. Rev. 2000, 100, 2159.
F3C
2
3
4
90
92
63
(3) For select recent examples, see: (a) Fish, P. V.; Andrews,
M. D.; Fray, M. J.; Stobie, A.; Wakenhut, F.; Whitlock, G.
A. Bioorg. Med. Chem. Lett. 2009, 19, 2829. (b)Fish, P. V.;
Fray, M. J.; Stobie, A.; Wakenhut, F.; Whitlock, G. A.
Bioorg. Med. Chem. Lett. 2007, 17, 2022. (c) Kohrt, J. T.;
Bigge, C. F.; Bryant, J. W.; Casimiro-Garcia, A.; Chi, L.;
Cody, W. L.; Dahring, T.; Dudley, D. A.; Filipski, K. J.;
Haarer, S.; Heemstra, R.; Janiczek, N.; Narasimhan, L.;
McClanahan, T.; Peterson, J. T.; Sahasrabudhe, V.; Schaum,
R.; Van Huis, C. A.; Welch, K. M.; Zhang, E.; Leadley,
R. J.; Edmunds, J. J. Chem. Biol. Drug Des. 2007, 70, 100.
(4) For recent reviews, see: (a) Coldham, I.; Hufton, R. Chem.
Rev. 2005, 105, 2765. (b) Pandey, G.; Banerjee, P.; Gadre,
S. R. Chem. Rev. 2006, 106, 4484.
(5) Padwa, A.; Dent, W. J. Org. Chem. 1987, 52, 235.
(6) Lown, J. W. 1,3-Dipolar Cycloaddition Chemistry, Vol. 1;
Padwa, A., Ed.; Wiley: New York, 1984, Chap. 6.
(7) Beugelmans, R.; Negron, G.; Roussi, G. J. Chem. Soc.,
Chem. Commun. 1983, 31.
(8) (a) Beugelmans, R.; Benadjila-Iguertsira, L.; Chastanet, J.;
Negron, G.; Roussi, G. Can. J. Chem. 1985, 63, 725.
(b) Beugelmans, R.; Chastanet, J.; Roussi, G. Heterocycles
1987, 26, 3197. (c) Beugelmans, R.; Chastanet, J.; Roussi,
G. Heterocycles 1987, 26, 3197.
N
Me
7
OMe
MeO
N
Me
8
N
Me
9
OMe
MeO
5
74
(9) Representative Procedure
Commercial LDA (2.5 M in THF, 3.1 mL, 4.7 mmol, 4.5
equiv) was added to a solution of (E)-1,2-dimethoxy-4-
styrylbenzene (250 mg, 1.0 mmol, 1 equiv) and trimethyl-
amine N-oxide 4 (117 mg, 1.6 mmol, 1.5 equiv) in anhyd
THF (10 mL) at 0 °C. After 1 h, the reaction was quenched
with H2O and extracted with EtOAc. The combined organic
layers were dried (Na2SO4) and concentrated under reduced
pressure. The crude residue was purified by flash chroma-
tography eluting with CH2Cl2–MeOH (95:5) to give 285 mg
(92%) of trans-3,4-disubstituted pyrrolidine 8 as a yellow
oil: 1H NMR (400 MHz, CDCl3): d = 7.26–7.12 (m, 5 H),
6.75–6.70 (m, 2 H), 6.68 (s, 1 H), 3.81 (s, 3 H), 3.78 (s, 3 H),
3.36–3.26 (m, 2 H), 3.12–3.06 (m, 2 H), 2.87–2.80 (m, 2 H),
2.44 (s, 3 H) ppm. LC-MS: m/z = 298.1 [M + 1].
N
Me
10
OMe
OMe
MeO
MeO
ACE-Cl, MW, then MeOH, Δ
21%
N
N
H
Me
8
11
Scheme 3 Chemoselective N-methyl deprotection
(10) (a) De, B..; DeBernardis, J. F.; Prasad, R. Synth. Commun.
1988, 18, 481. (b) Negron, G.; Calderon, G.; Vazquez, F.;
Lomas, L.; Cardenas, J.; Marquez, C.; Gavino, R. Synth.
Commun. 2002, 32, 1977. (c) Kemperman, G. J.; Stuk,
T. L.; Van Der Linden, J. J. M. WO2008003460, 2008.
(11) Olofson, R. A.; Martz, J. T.; Senet, J. P.; Piteau, M.;
Malfroot, T. J. Org. Chem. 1984, 49, 2081.
high yielding. Electron-rich olefins that did not react un-
der the more traditional acidic conditions5 (Scheme 1),
rapidly underwent a [3+2] cycloaddition in good yield un-
der the basic conditions (Scheme 2) described herein. Use
of this basic [3+2] cycloaddition enabled us to synthesize
pyrrolidines whose assembly would be otherwise inacces-
sible by the acidic route. Application of this methodology
(12) Representative Procedure
A solution of N-methylpyrrolidine 8 (255 mg, 0.9 mmol) in
neat ACE-Cl (3 mL) was irradiated in a microwave reactor
at 170 °C for 30 min. MeOH (3 mL) was added to the
mixture and thermally refluxed for an additional 1 h. The
Synlett 2010, No. 16, 2490–2492 © Thieme Stuttgart · New York

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J. E. Davoren et al.
LETTER
crude reaction mixture was purified by ion exchange on a
MP-TsOH column to give 51 mg (21%) of pyrrolidine 11 as
a pale yellow oil: 1H NMR (400 MHz, CDCl3): d = 7.26–
7.20 (m, 2 H), 7.18–7.12 (m, 3 H), 6.73–6.70 (m, 1 H), 6.70–
6.66 (m, 1 H), 6.62 (d, J = 2.0 Hz, 1 H), 3.79 (s, 3 H), 3.75
(s, 3 H), 3.66–3.54 (m, 2 H), 3.35–3.25 (m, 2 H), 3.24–3.14
(m, 2 H), 2.62 (br s, 1 H) ppm. LC-MS: m/z = 284.0 [M + 1].
Synlett 2010, No. 16, 2490–2492 © Thieme Stuttgart · New York