The hetero Diels-Alder reactions of masked o-benzoquinones with nitroso compounds

Article abstract of DOI:10.1039/b103649c

The first examples of hetero Diels-Alder reaction of masked o-benzoquinones with nitroso dienophiles leading to novel and highly functionalized heterocycles, which are potential intermediates for nitrogenous natural products are reported.

Full text of DOI:10.1039/b103649c

The hetero Diels–Alder reactions of masked o-benzoquinones with
nitroso compounds
Ken-Ching Lin and Chun-Chen Liao*
Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan 300.
E-mail: ccliao@mx.nthu.edu.tw; Fax: +886-3-5728123
Received (in Cambridge, UK) 24th April 2001, Accepted 2nd July 2001
First published as an Advance Article on the web 9th August 2001
The first examples of hetero Diels–Alder reaction of masked
o-benzoquinones with nitroso dienophiles leading to novel
and highly functionalized heterocycles, which are potential
intermediates for nitrogenous natural products are re-
ported.
conditions increased the yield to 90%. This overwhelming
result prompted us to extend this reaction to other 2-methoxy-
phenols. Thus, a variety of phenols 2b–j in the reaction with 4a
were examined as summarized in Scheme 2 and Table 1.† The
MOBs 1b–g reacted very smoothly with nitroso compound 3a
at 0 °C resulting in the formation of adducts 5b–g in good to
excellent yields (entries 1, 3, 5, 7, 9, 11 and 13). However, the
reactions of phenols 2h–j bearing electron-releasing sub-
stituents at C-4 did not proceed at 0 °C. A workable solution was
found by the slow addition of hydroxamic acid 4a to a mixture
of phenol 2h and oxidants in MeOH–CH2Cl2 at 50 °C and
continuing the reaction at the same temperature. Under these
The hetero Diels–Alder reaction represents a powerful strategy
for the stereoselective construction of highly functionalized
heterocyclic systems.1 A nitroso function that is directly linked
with an electron-withdrawing group acts as an efficient
dienophile as a result of extremely low LUMO energy and weak
p-bond.2 Acyl nitroso compounds have been used as dieno-
philes in both intermolecular and intramolecular versions of
hetero Diels–Alder reactions to produce highly functionalized
cycloadducts that provide valuable synthetic intermediates to a
variety of biologically interesting molecules.1,3
Masked o-benzoquinones (MOBs),4 a highly reactive class of
2,4-cyclohexadienones with extensive utility can be generated
by the oxidation of easily available 2-methoxyphenols using
hypervalent iodine reagents such as diacetoxyiodobenzene
(DAIB) and phenyliodonium(III) bis(trifluoroacetate) (PIFA) in
MeOH. In the course of our investigations on MOB chemistry,
we have developed methods for their in situ generation and
studied their inter-5 and intramolecular6 carbo-Diels–Alder
reactions. The synthetic potential of this methodology has been
demonstrated in the total/formal syntheses of several natural
products by us7 and others.8 Very recently, MOBs were shown
to drive heteroaromatics such as furans,9 pyrroles10 and
indoles11 as 2p-components in the carbo-Diels–Alder reaction.
In continuation of our efforts to broaden the versatility of
MOBs, we contemplated their hetero Diels–Alder reaction with
nitroso dienophiles to generate functionalized bicyclo[2.2.2]oc-
tenone derivatives that are possible intermediates for several
biologically active natural products such as aminocyclitols,12
pancratistatin13 and tetrodotoxin14 (Scheme 1).
Owing to their highly reactive nature, both MOB (diene) and
nitroso dienophile were transiently generated in the reaction
medium. Thus, at the outset of our study, we examined the
reaction of MOB 1a, obtained from the parent 2-methoxyphenol
i.e. guaiacol (2a), with nitroso compound 3a. The oxidation of
2a with DAIB in MeOH produced MOB 1a and the periodate
oxidation of tert-butyl N-hydroxycarbamate (4a) produced 3a.
When the reaction was performed with an equimolar ratio of 2a
and 4a, the two transient intermediates reacted very efficiently
at 0 °C to furnish the Diels–Alder adduct 5a in 80% yield.
However, use of two equivalents of 4a under the same
Scheme 2
Table 1 Hetero Diels–Alder reaction of masked o-benzoquinones 1a–j with
BocNO (3a) and CbzNO (3b)
MOB
R1 R2
Adduct
Nitroso Temp.a/ Timeb/ (Yield
compd °C
Entry
R2
H
H
H
H
H
h
(%))c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
1a H
H
3a
3b
3a
3b
3a
3b
3a
3b
3a
3b
0
0
0
0
0
0
0
0
0
0
0
0
0
1
1
1
1
1
1
1
1
1
1
1
1
1
1
3
3
5a (90)
6a (96)
5b (71)
6b (81)
5c (93)
6c (95)
5d (92)
6d (96)
5e (69)
6e (81)
5f (70)
6f (74)
5g (57)
6g (52)
5h (84)
6h (90)
5i (71)
6i (92)
5j (91)
6j (90)
1b H CO2Me
1c H Me
1d H
1e Me H
1f
H
H
H
H
H
H
CO2Me 3a
3b
1g H
1h H
COMe
Me
3a
3b
3a
3b
3a
3b
3a
3b
0
50
50
50
50
50
50
1i
1j
H
H
12
12
12
12
Br
a Reaction temperature. b Reaction time after the addition of RNHOH.
c Yields of pure and isolated adducts.
Scheme 1
1624
Chem. Commun., 2001, 1624–1625
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b103649c

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Notes and references
† General procedure for phenols 2a–g and N-hydroxycarbamates 4a,b: to
a stirred mixture of DAIB (1.1 mmol) and Bu4NIO4 (2 mmol) in MeOH (5
mL) at 0 °C, was added phenol 2 (1 mmol) in CH2Cl2 (5 mL) at once. After
10 min of stirring at 0 °C, was added carbamate 4 (2 mmol) in a 1+1 mixture
of MeOH–CH2Cl2 (5 mL) at once and the reaction was continued for 1 h at
the same temperature. Then the solvent and other volatiles were removed
under reduced pressure and the residue was subjected to silica gel column
chromatography (ethyl acetate–hexanes) to obtain pure cycloadducts 5a–g
and 6a–g.
General procedure for phenols 2h–j and N-hydroxycarbamates 4a,b: To
a stirred mixture of DAIB (1.1 mmol) and Bu4NIO4 (2 mmol) in MeOH (5
mL) at 0 °C, was added phenol 2 (1 mmol) in CH2Cl2 (5 mL) at once. After
10 min of stirring at 0 °C, the reaction flask was moved to a preheated oil
bath (50 °C ), and carbamate 4 (2 mmol) in a 1+1 mixture of MeOH–CH2Cl2
(5 mL) was added dropwise using a syringe pump (addition time: 1 h for
entries 15 and 16, 4 h for entries 17 and 18, and 8 h for entries 19 and 20)
and the reaction was continued [for 3 h (entries 15 and 16) or 12 h (entries
17–20)] at the same temperature. Thus formed adducts 5h–j and 6h–j were
isolated as described in the above procedure.
‡ Crystal data for 5a: C13H19NO6, M = 285.29, triclinic, a = 12.035(2), b
= 6.288(2), c = 19.541(2) Å, a = 90, b = 100.71(2), g = 90°, V =
1453.0(6) Å3, T = 295(2)K, space group P21, Z = 4, m(Mo-Ka) = 0.103
mm21, 3344 reflections collected, independent reflections (Rint = 0.0000),
final R indices [I > 2s(I)], R1 = 0.0418, wR2 = 0.1249. CCDC 161113. See
http://www.rsc.org/suppdata/cc/b1/b103649c/ for crystallographic data in
CIF or other electronic format.
Fig. 1 ORTEP plot of the crystal structure of cycloadduct 5a (numbering is
arbitrary).
conditions, phenols 2h–j afforded the cycloadducts 5h–j in high
to excellent yields (entries 15, 17 and 19).
In an effort to ascertain whether the N-substitution of nitroso
compound has influenced the reaction, we have evaluated the
Diels–Alder reaction of MOBs 1a–j with (N-carbobenzyl-
oxy)nitroso compound 3b (Scheme 2). These cycloadditions
were found to be quite efficient and the adducts 6a–j were
obtained in very good to excellent yields. These results are
summarized in Table 1.
1 (a) D. L. Boger and S. M. Weinreb, Hetero-Diels–Alder Methodology in
Organic Synthesis, Academic Press, San Diego, 1987; (b) D. L. Boger,
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Fleming, Pergamon, New York, 1991, pp. 451–551; (c) H. Waldmann,
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The structures of all the cycloadducts were based on the IR,
1H (400 MHz) and 13C (100 MHz) NMR, DEPT, low-, and
high-resolution mass spectral analyses. The regiochemistry of
the adduct 5a was confirmed by its single crystal X-ray structure
(Fig. 1)‡ and that of the adducts 5b–j and 6a–j is derived by
1
comparing the chemical shifts of their H NMR spectra with
that of 5a.
The excellent regioselectivity of this Diels–Alder reaction is
in full agreement with our earlier studies on Diels–Alder
reactions of MOBs.5,9–11 The moderately stable MOBs such as
1i,j require higher temperature and prolonged reaction times for
the reaction as reflected by the reaction conditions employed for
phenols 2i,j (entries 17–20), which is in accordance with our
earlier findings.15
In conclusion, bicyclo[2.2.2]octenone derivatives embedded
with heteroatoms—types of substrate that are useful in the total
syntheses of natural products possessing an aminopolyhydroxy-
cyclohexane or cyclohexene moiety—are accessed in a highly
regioselective manner from simple 2-methoxyphenols. The
simplicity of the experimental procedure and the ready
accessibility of masked o-benzoquinones and nitroso dieno-
philes thus renders this an experimentally attractive method for
the preparation of nitrogenous heterocycles. Currently, we are
actively pursuing the transformation of such cycloadducts to
pertinent targets including conduramines and natural products
such as pancratistatin and tetrodotoxin.
9 (a) C.-H. Chen, P. D. Rao and C.-C. Liao, J. Am. Chem. Soc., 1998, 120,
13 254; (b) P. D. Rao, C.-H. Chen and C.-C. Liao, Chem. Commun.,
1999, 713.
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press.
11 M.-F. Hsieh, P. D. Rao and C.-C. Liao, Chem. Commun., 1999, 1441.
12 M. Balci, Y. Sütbeyaz and H. Seçen, Tetrahedron, 1990 46, 3715.
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14 Y. Kishi, T. Fukuyama, M. Aratani, F. Nakatsubo, T. Goto, S. Inoue, H.
Tanino, S. Sugiura and H. Kakoi, J. Am. Chem. Soc., 1972, 94, 9219.
15 C.-F. Yen, R. K. Peddinti and C.-C. Liao, Org. Lett., 2000, 2, 2909.
We gratefully acknowledge financial support from the
National Science Council of the Republic of China. We thank
Mr G.-H. Lee of the Department of Chemistry, National Taiwan
University for X-ray diffraction studies and Dr R. K. Peddinti
for helpful discussions.
Chem. Commun., 2001, 1624–1625
1625