Novel ene-like cycloisomerization reaction of nitrile oxides with a tethered allyltrimethylsilyl group

Article abstract of DOI:10.1002/1521-3773(20020503)41:9<1586::AID-ANIE1586>3.0.CO;2-M

"I took the road less traveled by and that has made all the difference." Not only fans of the poet Robert Frost recognize the attraction of the less common reaction path. Rather than the expected [3+2] cycloaddition, a novel ene-like cycloisomerization oc

Full text of DOI:10.1002/1521-3773(20020503)41:9<1586::AID-ANIE1586>3.0.CO;2-M

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[5] a) Review: P. Grieco, Synthesis 1975, 67 82. Recent synthesis: b) R.
Ballini, G. Bosica, D. Livi, Synlett 2001, 1519 1522; c) B. Leroy, R.
Dumeunier, I. E. Marko, Tetrahedron Lett. 2000, 41, 10215 10218;
d) P. K. Chouahury, F. Foubelo, M. Yus, Tetrahedron 1999, 55, 107 7 9
10788; e) Y.-L. Lin, M.-H. Cheng, W.-C. Chen, S.-M. Peng, S.-L. Wang,
H. Kuo, R.-S. Liu, J. Org. Chem. 2001, 66, 1781 1786.
[6] For recently reports of ruthenium-catalyzed cyclocarbonylation of
allenic alcohols and b-allenic sulfonamides, respectively, see: a) E.
Yoneda, T. Kaneko, S.-W. Zhang, K. Onitsuka, S. Takahashi, Org. Lett.
2000, 2, 441 443; b) S.-K. Kang, K.-J. Kim, C.-M. Yu, J.-W. Hwang, Y.-
K. Do, Org. Lett. 2001, 3, 2851 2853.
fused a-methylene-g-butyrolactam, we explored the cyclo-
carbonylation of d-allenyl imine 3 and examined the stereo-
chemistry of the resulting products (Scheme 4). We observed
only the cis-fused a-methylene-g-butyrolactam 4 as the sole
product, which supports a [2 ‡ 2 ‡ 1] cycloaddition. The cis
stereochemistry of 4 was clearly determined by NOE
interactions in NOESY experiments (see Supporting Infor-
mation).
[7] The a-methylene-g-butyrolatones were synthesized from acetylenic
alcohols by PdII-catalyzed cyclocarbonylation; see: a) T. F. Murray,
E. G. Samsel, V. Varma, J. R. Norton, J. Am. Chem. Soc. 1981, 103,
7520 7528; b) T. F. Murray, J. R. Norton, J. Am. Chem. Soc. 1979, 101,
4107 4119; c) T. F. Murray, V. Varma, J. R. Norton, J. Org. Chem. 1978,
43, 353 355.
[8] For a recent synthesis of a-methylene-g-butyrolatones, see: a) V. J.
Bryan, T.-H. Chan, Tetrahedron Lett. 1996, 37, 5341 5342; b) C.-C.
Chen, J.-S. Fan, S.-J. Shieh, G.-H. Lee, S.-M. Peng, S.-L. Wang, R.-S. Liu,
J. Am. Chem. Soc. 1996, 118, 9279 9287; c) P. K. Choudhury, F.
Foubdo, M. Yus, Tetrahedron 1999, 55, 10779 10788 and references
therein; d) B. Leroy, R. Dumeunier, I. E. Marko, Tetrahedron Lett.
2000, 41, 10215 10218; e) R. Grigg, V. Savic, Chem. Commun. 2000,
2381 2382; f) R. Ballini, G. Bosica, D. Livi, Synlett 2001, 1519 1522.
[9] Preparation of allenyl aldehyde 1a: a) propargyl p-tosylamide,
BrCH2CH2(OMe)2, K2CO3, DMF, 1008C, 10 h, 85%; b) Crabbe
reaction: HCHO, CuBr, iPr2NH, dioxane, reflux, 68% (see: F. Crabbe,
B. Nassim, M-T. Robert-Lopes, Org. Synth. Coll. Vol. 7 (Ed.: J. P.
Freeman), 1990, pp 276 277); c) trifluoroacetic acid/CHCl3/H2O
(1:2:1), 08C, 1.5 h, 78% (see Supporting Information).
Scheme 4. The cyclocarbonylation of d-allenyl imine 3 gave cis-fused a-
methylene-g-butyrolactam 4 as the sole product.
In summary, the results presented above show that ruthe-
nium-catalyzed cycloaddition reactions of allenyl aldehydes
and ketones with carbon monoxide efficiently afford a-
methylene-g-butyrolactone products. This methodology
should find wide applications in the synthesis of natural
products that contain the exo-methylene-g-butyrolactone
functionality, and further investigations are underway in our
laboratory.
Experimental Section
Typical procedure: A stainless-steel autoclave was charged with the allenyl
aldehyde 1a (80 mg, 0.30 mmol), 1,4-dioxane (4 mL), and [Ru3(CO)12]
(2 mg, 1 mol%). The system was flushed three times with CO (20 atm). The
autoclave was then pressurized to 20 atm, and the mixture was stirred at
1208C for 12 h. The solution was then cooled and concentrated in vacuo to
give a residue, which was subjected to silica-gel column chromatography
(EtOAc/hexane 1:2) to yield the cyclized product 2a (66 mg, 75%) as a
white solid. M.p. 1158C; Rf ˆ 0.48 (EtOAc/hexanes 1:1); 1H NMR
(500 MHz, CDCl3): d ˆ 2.45 (s, 3H), 3.07(dd, 1H, J ˆ 5.3, 11.7Hz), 3.22
(dd, 1H, J ˆ 10.0, 7.6 Hz), 3.37 (dd, 1H,J ˆ 10.0, 2.9 Hz), 3.55 (m, 1H), 3.63
Novel Ene-Like Cycloisomerization Reaction
of Nitrile Oxides with a Tethered
Allyltrimethylsilyl Group**
Teruhiko Ishikawa,* Jin Urano, Shushiro Ikeda,
Yasuhiro Kobayashi, and Seiki Saito*
(dd, 1H, J ˆ 0.6, 11.7Hz), 4.97(m, 1H), 5.77(d, 1H,
J ˆ 2.4 Hz), 6.35 (d,
1H, J ˆ 2.4 Hz), 7.36 (d, 2H,J ˆ 8.2 Hz), 7.68 (d, 2H,J ˆ 8.2 Hz); 13C NMR
(125 MHz, CDCl3): d ˆ 169.6, 145.2, 137.4, 132.1, 130.6, 128.7, 125.8, 79.7,
The nitrile oxide functional group is a well-known 1,3-
dipole and highly useful owing to its high reactivity toward
55.2, 54.7, 42.6, 22.3; HR-MS: calcd for C H15NO4S: 293.0776, found:
14
293.0705.
[1]
À
unsaturated C C bonds to furnish [3‡2] cycloadducts. In
Typical experimental procedures for the preparation of 1a, 1c j, 2a, and 3,
as well as spectroscopic and analytical data for 1a j, 2a, 2c f, 2i j, and 4
can be found in the Supporting Information.
addition to such a traditional role, we have found that it also
functions as an enophile[2] in an intramolecular reaction with
an allyltrimethylsilyl group.[3] 5-Methylene-6-(trimethylsilyl)-
hexanal oxime (1a) was treated with sodium hypochlorite[4] in
dichloromethane at 08C for 2 h to give the product of an ene-
like reaction (2a) in 82% yield as a single diastereomer; no
Received: January 10, 2002 [Z18509]
[1] a) N. M. Kablaoui, S. L. Buchwald, J. Am. Chem. Soc. 1995, 117, 6785
6786; b) N. M. Kablaoui, S. L. Buchwald, J. Am. Chem. Soc. 1996, 118,
3182 3191; c) N. M. Kablaoui, F. A. Hicks, S. L. Buchwald, J. Am.
Chem. Soc. 1996, 118, 5818 5819; d) N. M. Kablaoui, F. A. Hicks, S. L.
Buchwald, J. Am. Chem. Soc. 1997, 119, 4424 4431.
[2] a) W. E. Crowe, A. T. Vu, J. Am. Chem. Soc. 1996, 118, 1557 1558;
b) W. G. Crowe, M. Rachita, J. Am. Chem. Soc. 1995, 117, 6787 6789.
[3] N. Chatani, T. Morimoto, Y. Fukumoto, S. Murai, J. Am. Chem. Soc.
1998, 120, 5335 5336.
[4] a) H. M. R. Hoffmann, J. Rabe, Angew. Chem. 1985, 97, 96 112;
Angew. Chem. Int. Ed. Engl. 1985, 24, 94 110; b) The Total Synthesis
of Natural Products, Vol. 5 (Ed. J. Apsimon), Wiley, New York, 1983,
pp 93 107; c) H. Matsuda, H. Shimoda, T. Uemura, M. Yoshikawa,
Bioorg. Med. Chem. Lett. 1999, 9, 2647 2652; d) G. Fardella, P.
Barbetti, G. Grandolini, I. Chiappini, V. Ambrogi, V. Scarcia, A. F.
Candiani, Eur. J. Med. Chem. 1999, 34, 515 523.
[*] Dr. T. Ishikawa, Prof. S. Saito, J. Urano, S. Ikeda, Y. Kobayashi
Department of Bioscience and Biotechnology
Faculty of Engineering, Okayama University
Tsushima, Okayama, 700-8530 (Japan)
Fax : (‡81)86-251-8209
E-mail: seisaito@biotech.okayama-u.ac.jp
[**] This work was supported by a Grant-in-Aid for Scientific research on
Priority Areas (A) ™Exploitation of Multi-Element Cyclic Molecules∫
from the Japanese Ministry of Education, Culture, Sports, Science, and
Technology.
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
1586
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4109-1586 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 9

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[3‡2] cycloadducts, fused or bridged, were detected
(Scheme 1). In NMR experiments a distinct nuclear Over-
hauser enhancement (NOE) observed between the exocyclic
olefinic proton and C(4) protons indicates their close prox-
imity.
‡
H
TMS
H
TMS
δ+
TMS
H
1
δ–
O–
O
N+
OH
N
TS
N
2
Ha
O
δ+
NOE 9.3%
TMS
Ha
δ–
Hb
δ+
O–
H
O
H
H
N
N
N+
R'
δ–
N
O
Hb
R
a )
TMS
TMS
'R
H
N
OH
TS1 for 1a
TS2: unfavorable
N
nitrile oxide dimer
(furoxane)
OH
1a: R = TMS
1a': R = H
2a: 82%
from 1a'
2a
TMS
H
R
R
H
a )
2a'
TMS
TMS
(not formed)
N
O
N
OH
OH
N
Scheme 2. Possible reaction mechanism of the novel cycloisomerization
reaction.
3a: R = H
3b: R = Me
4a: 72%
4b: 62%
TMS
C8H17
OH
TMS
for the ene-like reaction, and a simple allylic substrate 1a'
lacking the TMS group gave the nitrile oxide dimer (Scheme 1).
C8H17
N
a )
N
O
5
6: 91%
À
For this new C C bond-forming process to be accepted as a
Scheme 1. Cycloisomerization reactions of 1 and [3‡2] cycloaddition
reactions of 3 and 5. Conditions: a) NaOCl, CH2Cl2, 08C, 2 h. TMS ˆ tri-
methylsilyl.
general protocol in organic synthesis, simple and versatile
methods for preparing 1 must be available. We have
developed methods leading to key intermediate alcohols
7a e and esters 7 f h,[9] which are direct precursors for
oximes 1a h, through oxidation and reduction, respectively,
followed by condensation with hydroxylamine. These oximes
underwent cycloisomerization under standard conditions to
give the expected products 2a h (Scheme 3).
To our surprise, this novel reaction did not occur with
substrates of similar structure such as 1a', 3a, and 3b, which
instead underwent dimerization of nitrile oxide and expected
[3‡2] cycloaddition to give furoxane and isoxazolines (4a and
4b), respectively (Scheme 1). Furthermore, no ene-like proc-
ess was effected at all for the intermolecular version: the
reaction of nonanal oxime 5 and allyltrimethylsilane afforded
cycloadduct 6 almost quantitatively (Scheme 1).[5]
This ene-like reaction is unprecedented[6, 7] and highly
profitable because it features very mild reaction conditions
(08C, 2 h), the formation of C C bonds through a cyclo-
isomerization process, and the retention of oxime and vinyl-
trimethylsilyl functions in the products, which would be
suitable for further manipulations.
The selection of reaction pathways–the ene-like reaction
or [3‡2] cycloaddition–depends on whether the allyltrimeth-
ylsilyl unit is tethered to the oxime at the b-position (1a) or g-
position (3a, 3b). Closely inspecting molecular models led us
to speculate that 1a is much more flexible than 3a (or 3b),
which after deprotonation would lead to effective overlap of
the p orbitals of the allyl sp2 carbon atom and the nitrile oxide
sp carbon atom. If this orbital overlap progresses at the
transition state (Scheme 2, TS1 for 1a), proton delivery from
the allylic position (Ha) to the negatively charged oxygen
atom would be enhanced in a concerted manner and give rise
to the cyclic oxime 2a as a single isomer. The transition state
leading to 2a' (TS2) is unfavorable because of inevitable steric
interactions.
In every case a single geometrical isomer was obtained in
moderate to high yields.[10] NOE experiments revealed their
geometries, which were additionally supported by the regio-
specific Beckmann rearrangements of 2a and 2b to 8 and 9,
respectively (Scheme 4).[11] Competitive ene-like reactions
and intramolecular [3‡2] cycloaddition reactions were ob-
served for the aza versions 1g and 1h to give a mixture of
cyclic oximes 2g and 2h, respectively, and isoxazolines
(Scheme 3). Heptanal oxime 1i proved to be amenable to
the ene-like reaction to give cycloheptanone oxime 2i in 40%
yield as a mixture of exo and endo isomers (bottom in
Scheme 3).[12]
Although further studies are needed to completely under-
stand the mechanism shown in Scheme 2, the potential
intermediates 10 and 11 can be ruled out. Bredt×s rule[13] does
not support the formation of the bridged [3‡2] cycloadduct
10. In addition, 10 and the cationic intermediate 11, if
produced, should afford possible geometrical isomer 2a' and
3-(methylene)cyclohexanone oxime (12), which, in fact, were
not detected at all (Scheme 5).
À
Experimental Section
General procedure for ene-like cyclizations: To a solution of oxime 1a
(70 mg, 0.36 mmol) in CH2Cl2 (7mL) was slowly added an aqueous
solution of NaOCl (available chlorine 5%, 1.0 mL) at 08C over 1 h. The
mixture was stirred vigorously and allowed to warm to room temperature
for 1 h. The reaction mixture was diluted with water and extracted with
several portions of EtOAc. The combined extracts were dried over Na2SO4
Although positive charge develops on the carbon b to the
TMS group as the orbital overlap progresses at the transition
state, it can be stabilized by the b-effect of the silicon atom.[8]
This is the reason why the allyltrimethylsilyl group is required
Angew. Chem. Int. Ed. 2002, 41, No. 9
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4109-1587 $ 20.00+.50/0
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TMS
a ) or b )
TMS
TMS
X
TMS
2a
+
R
[3+2]
c )
X
A
X
H
O
R
R
N
2a'
OH
N
OR
NOH
aq. NaOCl
CH2Cl2
0 °C, 2 h
+
10
7a–e (A = H2; R = H)
7f–h (A = O; R = Et or Me)
1a–h
2a–h
1a
TMS
Si'
Si'
OR
Si'
Si'
AcO
N
allylation
OH
N
O–
12
11
Scheme 5. Hypothetical products via intermediates 10 and 11.
OH
OH
OH
OH
7b
7a
7c
7d
Si'
Si'
Si'
Si'
Z
Z
O
O
N
N
À
[1] For reviews of intramolecular [3‡2] cycloadditions between C C
double bonds and nitrile oxides, see: a) P. A. Wade in Comprehensive
Organic Synthesis, Vol. 4 (Eds.: B. M. Trost, I. Fleming, M. F.
Semmelhack), Pergamon, Oxford, 1991, pp. 1111 1168; b) W. Car-
ruthers, Cycloaddition Reactions in Organic Synthesis, Pergamon
Press, Oxford, 1990, pp. 269 331.
CO2Et
CO2Me
CO2Me
OH
7e
7f
7g[a]
7h[a]
OMOM
AcO
Si'
Si'
Si'
[2] Takahashi et al. reported that a formal ene-type product was isolated
as a minor product of an intramolecular [3‡2] cycloaddition reaction
À
Si'
between
a nitrile oxide and C C double bond; however, they
N
N
N
OH
OH
OH
N
postulated that this product resulted from a [3‡2] cycloaddition
leading to a regioisomer followed by isomerization: T. Takahashi, Y.
Hirose, H. Iwamoto, T. Doi, J. Org. Chem. 1998, 63, 5742 5743.
[3] For an intramolecular ene reaction of allenyltrimethylsilyl imine
system, see: J. Jin, D. T. Smith, S. M. Weinreb, J. Org. Chem. 1995, 60,
5366 5367.
OH
2b: 82%[b]
2a: 82%
2c: 78%
2d: 55%
Z
Z
N
Si'
N
Si'
O
Si'
O
Si'
N
N
[4] G. A. Lee, Synthesis 1982, 508 509.
N
N
OH
OH
OH
OH
[5] For intermolecular [3‡2] cycloaddition reactions between a nitrile
oxide and an allyltrimethylsilyl group, see: a) D. P. Curran, B. H. Kim,
Synthesis 1986, 312 315; b) D. P. Curran, S. A. Gothe, Tetrahedron
1988, 44, 3945 3952.
[6] For the [4‡4] ene reactions with dienes as enophiles, see: J. M. Takacs,
L. G. Anderson, G. V. B. Madhavan, F. L. Seely, Angew. Chem. 1987,
99, 1073; Angew. Chem. Int. Ed. Engl. 1987, 26, 1013 1015, and
references therein.
2e: 41%
2f: 75%[b]
2g: 33%[a]
([3+2] 48%)[d] ([3+2] 43%)[d]
2h: 40%[a]
(Si' = TMS; Z = CO2CH3)
Si'
Si'
Si'
N
N
HO
2i: 40%[c]
(exo/endo=2.2/1)
OH
OH
7i
1i
[7] For reviews of the carbonyl ene reactions, see: a) B. B. Snider in
Comprehensive Organic Synthesis, Vol. 2 (Eds.: B. M. Trost, I. Flem-
ing, C. H. Heathcock), Pergamon, Oxford, 1991, pp. 527 561; b) B. B.
Snider in Comprehensive Organic Synthesis, Vol. 5 (Eds.: B. M. Trost,
I. Fleming, L. A. Paquette), Pergamon, Oxford, 1991, pp. 1 27 .
[8] The silicon atom has been attributed a similar effect in the intra-
molecular ene reaction of an allenyltrimethylsilyl imine system, see
ref. [3].
[9] See the Supporting Information for the syntheses of 7a h.
[10] Two sets of NMR signals (1H and 13C, at 238C) were observed for 2h.
Variable-temperature 1H NMR experiments showed that the signal
intensity for each set changed at 408C and the two signals for each set
fused and became broad at 508C; upon cooling, the original spectrum
was restored. An isopropyl substituent in 2h would probably raise the
barrier for inversion at the nitrogen atom at room temperature for
steric reasons. In marked contrast this inversion seems to be quite
facile in the corresponding methyl version 2g (see Supporting
Information pp. S21 S23). Thus, 2h would exist as a mixture of
conformers probably due to inversion at the nitrogen atom.
[11] We do not yet know why the initial product of the Beckmann
Scheme 3. Cycloisomerization reactions of various allylsilyl oximes. Yields
are for products isolated by SiO2 column chromatography in step c.
Conditions: a) 1. SO3 ¥ pyridine, Et3N/DMSO, 2. NH2OH, Et3N/EtOH; b) 1.
DIBALH, THF, À788C, 1 h, 2. NH2OH, Et3N/EtOH; c) NaOCl/CH2Cl2,
08C ! RT, 2 h. [a] Racemic product was obtained under the given
conditions (see Supporting Information) though optically active amino
acid esters were employed. [b] Optical purity, not determined. [c] Com-
bined yield of exo and endo isomers, which could be separated by SiO2
column chromatography. [d] For structures, see Supporting Information.
DIBALH ˆ diisobutylaluminum hydride, MOM ˆ methoxymethyl.
TMS
TMS
a)
a)
2a
2b
N
N
O
O
H
H
8: 48%
9: 98%[a]
rearrangement product of 2b, a g-trimethylsilyl-b,g-unsaturated
lactam, efficiently isomerized to 9. Achiral 2a simply rearranged to
8 (48% yield) without subsequent isomerization.
[12] Other compounds such as 4-methylene-5-(trimethylsilyl)pentanal
oxime gave furoxanes as the only isolable product.
[13] K. J. Shea, Tetrahedron 1980, 36, 1683 1715. The construction of
bicyclo[4.2.1] framework has been reported for intramolecular nitrone
[3‡2] cycloaddition process: S. Majumdar, A. Bhattacharjya, A. Patra,
Tetrahedron Lett. 1997, 38, 8581 8584.
Scheme 4. Synthesis of functionalized seven-membered lactams by the
regiospecific Beckmann rearrangement. Conditions: a) MsCl, pyridine/
CH2Cl2, 08C, 2 h. [a] Optical purity, not determined. Ms ˆ methane
sulfonyl.
and concentrated to give an oil, which was purified by column chromatog-
raphy on silica gel to afford the cyclic oxime 2a (58 mg, 82%).
Received: September 21, 2001
Revised: February 4, 2002 [Z17943]
1588
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4109-1588 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 9