Novel use of N-carboalkoxy α,β-unsaturated iminium ions as dienophiles in Diels-Alder reactions

Article abstract of DOI:10.1055/s-2008-1072658

Tricyclic spiro-N,O-acetals have been assembled in a single step by cycloaddition of hydroxymethyl-substituted dienes to iminium ion activated dienophiles that were generated by acidolysis of α,β-unsaturated-N- carboalkoxy-N,O-acetals or β-methoxymethyl-N

Full text of DOI:10.1055/s-2008-1072658

1036
LETTER
Novel Use of N-Carboalkoxy a,b-Unsaturated Iminium Ions as Dienophiles in
Diels–Alder Reactions
N
-Carboalkox
a
y
a
,
b
-Unsa
t
turated
r
Iminium
i
Ions
a
c
s
D
ienophi
k
r
R
D
eactions . O’Connor, Karsten Körber, Margaret A. Brimble*
Department of Chemistry, The University of Auckland, 23 Symonds Street, Auckland 1142, New Zealand
Fax +64(9)3737422; E-mail: m.brimble@auckland.ac.nz
Received 1 February 2008
O
OBn
O
OBn
Brønsted or
Lewis acid
activation
O
OBn
Abstract: Tricyclic spiro-N,O-acetals have been assembled in a
single step by cycloaddition of hydroxymethyl-substituted dienes to
iminium ion activated dienophiles that were generated by acidolysis
of a,b-unsaturated-N-carboalkoxy-N,O-acetals or b-methoxymeth-
yl-N-carboalkoxy-enamines. The cycloaddition was conducted us-
ing Sc(OTf)3 as a mild Lewis acid affording the endo adducts in
moderate yields.
H
R1O
N
R1O
N
N
R2
R2
Scheme 2 Putative N-carboalkoxy iminium ion activated Diels–
Key words: iminium ion, Diels–Alder, cycloaddition
Alder cycloaddition
carboalkoxy iminium species upon treatment with acid
(Scheme 2).3
The last decade has witnessed a significant increase in the
number of examples of iminium ion catalyzed Diels–Al-
der cycloadditions. Largely thanks to the work of the
MacMillan group, a range of imidazolidinone salts now
commercially available that can be used to achieve inter-
molecular asymmetric organocatalysis of Diels–Alder cy-
cloadditions by iminium ion activation of both enal and
more impressively, enone dienophiles.1 Despite exhibit-
ing broad scope, this method of intermolecular iminium
ion activation has not yet been reported to tolerate a-func-
tionalization of the dienophile with only limited examples
of intramolecular iminium ion activation of dienophiles
involving a-functionalized cyclic imines being disclosed
(Scheme 1).2
Ionic Diels–Alder cycloadditions have previously been
reported by Gassman et al.4 in which highly reactive oxo-
nium ion dienophiles, generated by the acidolysis of ac-
rolein derived O,O-acetals, participated in Diels–Alder
additions with a number of dienes. With these ideas in
mind, we focused our attention on the synthesis of cyclic
a,b-unsaturated N-carboalkoxy N,O-acetals as precursors
to putative iminium ion dienophiles. Towards that end, the
readily available N-Cbz-protected lactams 1 and 25 were
a-methylenated by alkylation of the amide enolates with
Eschenmoser’s salt followed by Hofmann elimination to
afford the a,b-unsaturated amides (Scheme 3). The amide
carbonyl was then reduced using DIBAL-H in the pres-
ence of TMSCl. By quenching the reaction at low temper-
ature the desired N,O-acetals 3 and 4 were obtained albeit
in low yields.
R3
R3
R2NH·HA
+
R2
R2
α
R1
R1
O
O
OBn
O
O
OBn
1. LiHMDS, THF
–78 °C, [CH2=NMe2] I
2. MeI, CH2Cl2, 24 h
intermolecular iminium ion activation
MeO
N
O
N
NH2
HA
n
3. TMSCl, DIBAL-H,
–78 °C, 1 h then
MeOH (3 equiv)
n
α
+
O
R1
R1
1 n = 1
2 n = 2
3 n = 1, 11% (3 steps)
4 n = 2, 20% (3 steps)
R2
N
R2
intramolecular iminium ion activation
Scheme 3 Synthesis of a,b-unsaturated N-carboalkoxy N,O-acetals
Scheme 1 Iminium ion activation of Diels–Alder cycloadditions
An alternative route to the required iminium dienophile
involving methylenation of hemiaminal 6 was next inves-
tigated (Scheme 4). The N-Cbz piperidine intermediate 56
was subjected to electrochemical oxidation to furnish the
hydrogen bonded hemiaminal 6.7 This less conventional
electrochemical method provided 6 in superior yield to the
alternative literature procedure based on Swern oxidation
of the open-chain Cbz-protected amino alcohol.8 Methyl-
enation of 6 using Pihko’s organocatalytic method8 af-
forded a,b-unsaturated aldehyde 7 that notably existed as
As a novel extension to recently developed Diels–Alder
organocatalytic methodology we decided to explore the
possibility of forming cyclic iminium ion dienophiles via
acidolysis of cyclic N-carboalkoxy N,O-acetals, that are
well known for their ability to generate electrophilic N-
SYNLETT 2008, No. 7, pp 1036–1038
x
x.
x
x.
2
0
0
8
Advanced online publication: 28.03.2008
DOI: 10.1055/s-2008-1072658; Art ID: D03908ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
N-Carboalkoxy a,b-Unsaturated Iminium Ions as Dienophiles in Diels–Alder Reactions
1037
the open-chain tautomer. This reaction was hampered by
the competing formation of the enecarbamate,9 and more-
over as noted by Pihko, aldehydes that exist predominant-
ly as hemiacetals are poor methylenation substrates. The
crude enal 7 was next treated with a catalytic quantity of
scandium triflate in methanol to unexpectedly afford
enamine 8 in multigram quantities. To the best of our
knowledge the resultant b-alkoxy-N-carboalkoxy enam-
ines, despite their synthetic utility,10 have not been pre-
pared by the simple alcoholysis of acyclic starting
materials. Notably, enamine 8 is formed under thermody-
namic conditions in contrast to its constitutional isomer 3,
which is formed under kinetic conditions using a low-tem-
perature DIBAL-H reduction.
O
OBn
O
OBn
3.1 Faraday/mol
MeCN–H2O (6:1)
Et4NOTs, 3 °C
H
O
N
N
(based on
92%
recovered
5
6
starting material)
pyrrolidine (0.1 equiv),
propionic acid (0.1 equiv),
formalin (1 equiv)
O
OBn
O
OBn
MeOH,
Sc(OTf)3
N
HN
O
32% (2 steps)
8
7
MeO
Scheme 4 Synthesis of a,b-unsaturated N-carboalkoxy N,O-acetals
We reasoned, however, that both compounds 3 and 8 un-
der acidic conditions would form the same a,b-unsaturat-
ed iminium ion that could then be trapped as a Diels–
Alder adduct. Iminium ion precursors 3, 4, and 8 did not
react with simple butadienes such as isoprene despite
screening a range of Lewis acids for their ability to medi-
ate this reaction. Gratifyingly, reaction of 3, 4, and 8 with
PMB-protected hydroxymethyl diene 911 in the presence
of 20 mol% BF3·OEt2 furnished the tricyclic adducts 10
and 11 (Table 1) in which in situ deprotection of the PMB
ether appeared to precede intramolecular N,O-acetal for-
mation.
In order to further probe this novel reaction we next pre-
pared adducts 12 and 13 by reaction of enamine 8 with the
unprotected hydroxy diene 14.12 The isomeric iminium
ion precursor 8 was equally amenable to the use of
Sc(OTf)3 or BF3·OEt2 to catalyze the cycloaddition.
Cycloadducts 10–13 were assigned as the thermodynami-
cally favored13 anti-methine endo adducts on the basis of
NOE evidence. Typically, cyclic exo-methylene dieno-
philes give exo cycloadducts due to a combination of ster-
ic and electronic factors14 associated with s-cis dienophile
Table 1 Novel Iminium Ion Activated Diels–Alder Cycloaddition
Dienophile
Diene
Reagents
Product
Yield (%)
78
BF3·OEt2 (20 mol%), –78 °C to r.t., 2 h
BnO
O
BnO
O
OBn
MeO
N
H
N
O
H
OPMB
BnO
9
4
10
BF3·OEt2 (10 mol%), –78 °C to r.t., 2 h
53
60
BnO
O
OBn
BnO
O
MeO
N
H
N
OPMB
O
BnO
3
9
H
11
Sc(OTf)3 (3.5 mol%), CH2Cl2, 0 °C, 2 h
O
OBn
BnO
O
O
N
H
N
OH
14
14
MeO
H
8
12
Sc(OTf)3 (5 mol%), CH2Cl2, 0 °C, 2 h
BF3·OEt2 (10 mol%), –78 °C to r.t., 2 h
41
68
MeO
O
OMe
O
N
H
N
OH
O
H
MeO
15
13
Synlett 2008, No. 7, 1036–1038 © Thieme Stuttgart · New York

1038
P. D. O’Connor et al.
LETTER
(3 × 20 mL), dried over MgSO4, and evaporated. Purification by sil-
ica gel chromatography eluting with hexane–EtOAc (6:1) afforded
12 as a colorless oil (99 mg, 60%). IR (film): 2931, 1708, 1430,
1281 cm–1. 1H NMR (300 MHz, DMSO-d6, 70 ºC): d = 7.38–7.30
(m, 5 H, HPh), 5.49 (s, 1 H, H4a), 5.27–5.23 (m, 1 H, H7), 5.16 (d,
J = 12.6 Hz, 1 H, H2¢), 5.06 (d, J = 12.6 Hz, 1 H, H2¢), 4.17 (dd,
J = 8.2, 7.4 Hz, 1 H, H6a), 3.86–3.78 (m, 1 H, H3), 3.37 (dd, J = 8.3,
3.0 Hz, 1 H, H6b), 2.99–2.89 (m, 1 H, H3), 2.43–2.36 (m, 1 H, H6a),
1.96 (q, J = 7.5 Hz, 2 H, H1¢), 1.91–1.79 (m, 3 H), 1.65–1.51 (m, 3
H), 1.43–1.31 (m, 2 H), 0.95 (t, J = 7.5 Hz, 1 H, H2¢). 13C NMR (75
MHz, DMSO-d6, 70 °C): d = 154.8 (C1¢¢), 137.7 (C8), 136.2 (CPh),
127.8 (2 CPh), 127.3 (CPh), 126.9 (2 CPh), 120.8 (C7), 83.7 (C4a), 69.4
(C6), 66.0 (C2¢¢), 38.3 (C3), 37.6 (C10¢), 31.0 (C1), 29.1 (C1¢), 25.5
(C2), 23.6 (C9), 19.3 (C10), 11.6 (C2¢). HRMS (EI): m/z calcd for
C21H27NO3 [M+]: 341.1991; found: 341.1993.
configuration. However in the present case, the formation
of the endo adduct is consistent with secondary orbital
overlap between the diene and the s-trans configured imi-
nium dienophiles.
Given that the presence of a hydroxy group on the diene
is essential for reactivity, it is reasoned that the cycloaddi-
tion proceeds through a metal-templated intermediate.
Following cycloaddition, the incipient iminium ion is
trapped by the alkoxide ion to form the tricyclic adduct.
Confirmation of this mechanistic proposal awaits a theo-
retical investigation.
In summary, we have developed a novel application of Pi-
hko’s organocatalytic methylenation that has led to a con-
cise synthesis of synthetically useful b-methoxymethyl-
N-carboalkoxy-enamines. Both the aforementioned
enamines and their isomeric N,O-acetals were shown to
undergo novel diastereoselective iminium ion activated
cycloadditions to furnish 6,6,5- and 7,6,5-spirotricyclic
N,O-acetals.
Acknowledgment
Financial support for this work is gratefully acknowledged from the
New Zealand Foundation for Research Science and Technology.
References and Notes
(1) (a) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc.
2002, 124, 2458. (b) Wilson, R. M.; Jen, W. S.; MacMillan,
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(2) (a) Johannes, J. W.; Wenglowsky, S.; Kishi, Y. Org. Lett.
2005, 7, 3997. (b) Tchabanenko, K.; Adlington, R. M.;
Cowley, A. R.; Baldwin, J. E. Org. Lett. 2005, 7, 585.
(3) Petrini, M. Chem. Rev. 2005, 105, 3949.
Procedure for the organocatalytic formation of 7
A 25 mL round-bottom flask equipped with stirrer bar was charged
with hemiaminal 6 (1.39 g, 5.91 mmol), pyrrolidine (42 mg, 590
mmol), propionic acid (44 mg, 590 mmol), formalin (0.50 mL, 6
mmol), and i-PrOH (0.5 mL) and the mixture was heated to 45 °C
for a period of 24 h. The reaction was quenched with sat. NaHCO3,
extracted with CH2Cl2 (3 × 20 mL), and dried over MgSO4. Evapo-
ration of the solvent afforded an oil that was further purified by sil-
ica gel chromatography eluting with hexane–EtOAc (3:1) to give 7
as a colorless oil (580 mg, 40%). IR (film): 2943, 1694, 1531, 1256
cm–1. 1H NMR (300 MHz, CDCl3): d = 9.56 (s, 1 H), 7.41–7.30 (m,
5 H), 7.19–6.90 (br m, 1 H), 6.39–6.37 (m, 1 H), 6.17–6.16 (m, 1
H), 5.05 (s, 2 H), 3.07–3.00 (m, 2 H), 2.24–2.17 (m, 2 H), 1.64–1.53
(m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): d = 195.5 (C), 149.6 (C),
138.0 (C), 135.4 (CH), 128.9 (CH), 128.2 (CH), 128.1 (CH), 65.8
(CH2), 28.3 (CH2), 25.2 (CH2) ppm. HRMS (EI): m/z calcd for
C14H17NO3 [M+]: 247.1208; found: 247.1203.
(4) Gassman, P. G.; Singleton, D. A.; Wilwerding, J. J.; Chavan,
S. P. J. Am. Chem. Soc. 1987, 109, 2182.
(5) Ishihara, J.; Horie, M.; Shimada, Y.; Tojo, S.; Murai, A.
Synlett 2002, 403.
(6) (a) Shono, T.; Matsumura, Y.; Tsubata, K.; Sugihara, Y.;
Yamane, S.; Kanazawa, T.; Aoki, T. J. Am. Chem. Soc.
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Procedure for the Conversion of 7 into 8
To a stirred solution of unsaturated aldehyde 7 (914 mg, 3.70 mmol)
in CH2Cl2 (30 mL) and MeOH (5 mL) at 0 °C was added Sc(OTf)3
(21 mg, 427 mmol). After stirring at 0 °C for 3 h the reaction was
quenched with sat. NaHCO3, extracted with CH2Cl2 (3 × 20 mL),
dried over MgSO4, and the solvent evaporated. Purification by silica
gel chromatography eluting with hexane–EtOAc (4:1) afforded the
title compound as a colorless oil (648 mg, 67%). IR (film): 2930,
1705, 1673, 1411 cm–1. 1H NMR (300 MHz, DMSO-d6, 70 °C): d =
7.44–7.35 (m, 5 H), 6.87 (m, 1 H), 5.21 (s, 2 H), 3.83 (s, 2 H), 3.60–
(i), 39.
(12) Kuehne, M. E.; Xu, F. J. Org. Chem. 1998, 63, 9434.
(13) The anti-methine endo adducts were identified as the lowest
energy conformers on the basis of B3LYP/6-
3.55 (m, 2 H), 3.22 (s, 3 H), 2.07–2.01 (m, 2 H), 1.87–1.77 ppm. 13
NMR (75 MHz, CDCl3): d = 153.2, 137.2, 129.0, 128.5, 128.3,
123.2, 116.4, 74.8, 67.4, 57.2, 42.5, 23.1, 21.6 ppm. HRMS (EI):
m/z calcd for C15H19NO3 [M+]: 261.1365; found: 261.1365.
C
311G(d)optimization and frequency calculations which
were performed using Chem3D®.
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68, 8991. (b) Roush, W. R.; Brown, B. B. J. Org. Chem.
1992, 57, 3380.
Procedure for Iminium Diels–Alder Cycloaddition
To a solution of enamine 8 (126 mg, 482 mmol) and diene 14 (206
mg, 1.84 mmol) in CH2Cl2 (20 mL) at 0 °C was added Sc(OTf)3
(10.5 mg, 21.3 mmol). After stirring for 2 h the mixture was
quenched with sat. NaHCO3 (10 mL), extracted with CH2Cl2
Synlett 2008, No. 7, 1036–1038 © Thieme Stuttgart · New York

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