Synthesis of polysubstituted cyclopentenones via [4+1] reactions of TIPS-vinylketenes

Article abstract of DOI:10.1021/jo702109e

(Chemical Equation Presented) An efficient method for preparing a series of polysubstituted cyclopentenones from TIPS-vinylketenes and Koebrich reagent has been developed in this paper. Additionally, highly substituted cyclopentenones can be prepared via

Full text of DOI:10.1021/jo702109e

group suppresses the dimerization process typical of ketenes.8
With Ko¨brich reagent as a 1,1-dipole equivalent, we decided
to use silyl vinylketene as the activated diene part to carry out
research on the [4+1] reaction as people have done before.7a,d
Since Ko¨brich reagents are highly unstable and have to be
generated from alkyl dihalides by RLi in the presence of
substrates at low temperature, the difficult subject is that the
ketene group will suffer from direct nucleophilc attack of RLi
because of its known electrophilic property.8b
Synthesis of Polysubstituted Cyclopentenones via
[4+1] Reactions of TIPS-Vinylketenes
Zhi Li,† William H. Moser,‡ Ruixue Deng,† and
Liangdong Sun*,†
Department of Chemistry, School of Science, Tianjin UniVersity,
Tianjin, 300072, People’s Republic of China, Department of
Chemistry, Indiana UniVersity-Purdue UniVersity Indianapolis,
Indianapolis, Indiana 46202
Bearing a formally divalent carbon, isocyanides are highly
reactive toward cations, anions, and radicals. But most of the
reactions reported thus far require a promoter to proceed
efficiently. In this paper, we found isocyanide could serve as a
1,1-dipole equivalent to undergo [4+1] reaction9a with silyl
vinylketenes without any promoter. To date, however, all
reported reactions between ketenes and isocyanides only af-
forded imino lactone-type products9b or l-imino-2,4-
cyclopentanediones.9c
ldsun@tju.edu.cn
ReceiVed September 27, 2007
The classical synthetic route to silyl vinylketenes contained
two steps, the silylation of R-diazo ketones and the photochemi-
cal Wolff rearrangement of R-silyl-R-diazo ketones. Recently,
Moser has discovered an efficient method for preparing C4
oxygenated triisopropylsilyl (TIPS) vinylketenes 1A from the
thermal reaction of Fischer carbene complexes with TIPS-
substituted acetylenes.10 It was found that the aromatic ring of
R2 on TIPS-vinylketenes 1B was usually complexed with Cr-
(CO)3 even if R1 was a phenyl group (eq 1). [4+1] reaction of
An efficient method for preparing a series of polysubstituted
cyclopentenones from TIPS-vinylketenes and Ko¨brich re-
agent has been developed in this paper. Additionally, highly
substituted cyclopentenones can be prepared via [4+1]
reaction of TIPS-vinylketenes with tert-butyl isocyanide and
there is a remarkable preference for formation of products
with an exocyclic (Z)-imine moiety.
Cyclopentenones are common structural units in bioactive
natural products and useful building blocks.1 While various
approaches such as the Nazarov,2 Pauson-Khand,3 [3+2],4
Rautenstrauch rearrangement,5 and Intramolecular Hydroacy-
lation reaction6 have been developed for construction of this
important ring system, only a few [4+1] reactions to these five-
membered carbocycles have been reported to date.7
such ketenes with diazoalkanes and sulfur ylides10b by Dan-
heiser’s protocol7a afforded cyclopentenones bearing an oxygen-
ated quaternary center on C4, an important structural moiety
found in many bioactive natural products.11 The Cr(CO)3 moiety
in the [4+1] products10b could provide a handle for further
synthetic manipulations based on the significant ways in which
the Cr(CO)3 fragment alters reactivity on the arene ring itself,
Silyl vinylketenes have recently been used as versatile “1,4-
dipole” equivalents7a,b,d and the stabilizing influence of the silyl
† Tianjin University.
‡ Indiana University-Purdue University Indianapolis.
(8) (a) Pommier, A.; Kocienski, P.; Pons, J. J. Chem. Soc., Perkin Trans.
1 1998, 14, 2105. For a review, see: (b) Tidwell, T. T. Ketenes; Wiley:
New York, 1995. (c) George, D. M.; Danheiser, R. L. Science of Synthesis;
Danheiser, R. L., Ed.; Thieme: New York, 2006; Vol. 23, Chapter 2,
Houben-Weyl.
(9) (a) Rigby’s pioneering work revealed that isocynides could undergo
[4+1] reaction with vinyl isocyanates to form nitrogen heterocycles. See:
Rigby, J. H.; Qabar, M. J. Am. Chem. Soc. 1991, 113, 8975. (b) Ugi, I.;
Rosendahl, K. Chem. Ber. 1961, 94, 2233. (c) Moore, H. W.; Yu, C.-C. J.
Org. Chem. 1981, 46, 4935.
(10) (a) Moser, W. H.; Sun, L.; Huffman, J. C. Org. Lett. 2001, 3, 3389.
(b) Moser, W. H.; Feltes, L. A.; Sun, L.; Giese, M. W.; Farrell, R. W. J.
Org. Chem. 2006, 71, 6542.
(11) (a) Iwashima, M.; Terada, I.; Okamoto, K.; Iguchi, K. J. Org. Chem.
2002, 67, 2977. (b) Duh, C.; El-Gamal, A. A. H.; Chu, C.; Wang, S.; Dai,
C. J. Nat. Prod. 2002, 65, 1535. (c) Wu, C.; Liou, C.; Ean, U. J. Chin.
Chem. Soc. (Taipei) 2001, 48, 1197. (d) Shikishima, Y.; Takaishi, Y.; Honda,
G.; Ito, M.; Takeda, Y.; Tori, M.; Takaoka, S.; Kodzhimatov, O. K.;
Ashurmetov, O. J. Nat. Prod. 2002, 65, 1897.
(1) For reviews, see: (a) Roberts, S. M.; Santoro, M. G., Sickle, E. S. J.
Chem. Soc., Perkin Trans. 1 2002, 1735. (b) Proksch, P.; Edrada, R.; Ebel,
R.; Bohnenstengel, F. I.; Nugroho, B. W. Curr. Org. Chem. 2001, 5, 923.
(2) For reviews, see: (a) Tius, M. A. Eur. J. Org. Chem. 2005, 2193.
(b) Frontier, A. J.; Collison, C. Tetrahedron 2005, 61, 7577. (c) Pellissier,
H. Tetrahedron 2005, 61, 6479.
(3) For a recent review, see: Geis, O.; Schmalz, H.-G. Angew. Chem.,
Int. Ed. 1998, 37, 911.
(4) (a) Hayakawa, Y.; Yokoyama, K.; Noyori, R. J. Am. Chem. Soc.
1978, 100, 1799. (b) Stokes, H. L.; Ni, L.; Belot, J. A.; Welker, M. E. J.
Organomet. Chem. 1995, 487, 95.
(5) (a) Shi, X.; Gorin, D. J.; Toste, F. D. J. Am. Chem. Soc. 2005, 127,
5802. (b) Rautenstrauch, V. J. Org. Chem. 1984, 49, 950.
(6) Tanaka, K.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 11492.
(7) (a) Loebach, J. L.; Bennett, D. M.; Danheiser, R. L. J. Am. Chem.
Soc. 1998, 120, 9690. (b) Rigby, J. H.; Wang, Z. Org. Lett. 2003, 5, 263.
(c) Gagnier, S. V.; Larock, R. C. J. Am. Chem. Soc. 2003, 125, 4804. (d)
Davie, C. P.; Danheiser, R. L. Angew. Chem., Int. Ed. 2005, 44, 5867.
10.1021/jo702109e CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/16/2007
10254
J. Org. Chem. 2007, 72, 10254-10257

TABLE 1. Reactions of TIPS-Vinylketene 1a with Carbenoid
Reagents
TABLE 2. Reactions with Ko1brich Reagentsa
yield of
entry
carbenoid reagent
solvent
3aa [%]
1
2
3
4
5
6
7
8
9
CH2I2/Zn-Cu
CH2I2/i-PrMgCl
CH2Cl2/n-BuLi
CH2Br2/n-BuLi
CH2I2/n-BuLi
CH2I2/n-BuLi
CH2I2/n-BuLi
CH2I2/n-BuLi
CH2I2/n-BuLi
CH2I2/n-BuLi
Et2O
THF
THF
THF
0
0
27
60
62
20
5
10
12
93
THF
DME
Toluene
Hexane
cyclohexane/Et2O ) 1:1
Et2O
10
a Isolated yield.
as well as on the vicinal functionality.12 All silyl vinylketenes
in this paper were prepared by this protocol (see the Supporting
Information).13
As shown in Table 1, TIPS-vinylketene 1a was selected as a
model substrate and a variety of reaction conditions were
screened. Attempts by the employment of carbenoids prepared
from CH2I2/Zn-Cu, CH2I2/i-PrMgCl, and CH2I2/Et2Zn were
unsuccessful; in each case no significant reaction occurred and
1a was recovered. We assumed that these carbenoids were not
active to fulfill this transformation.14a We were pleased to find
that Li/Cl carbenoid generated from CH2Cl2 by n-BuLi in THF
did afford the desired cyclopentenone 3a, however, in only 27%
yield. Switching to the Li/I carbenoid significantly improved
the yield. Examination of the effect of solvent revealed that
Et2O produced the desired adduct with a marked improvement
in yield. The reaction was easily performed by slow addition
of n-BuLi to an ether solvent of 1a and CH2I2 at -78 °C and
no byproduct formed by addition of n-BuLi to the ketene group
of 1a was observed. All attempts to employ carbenoids
generated from dibromoalkenes14b with n-BuLi were unsuc-
cessful.
With optimized reaction conditions in hand, we set out to
synthesize polysubstituted cyclopentenones via this [4+1]
reaction. The reaction is tolerant of substituents at the C3
position of TIPS-vinylketenes. Specifically, C3 chromium
complexed aryl- (entries 1, 2, 4, 7, 8, and 9, Table 2), alkyl-
(entries 5, 6, and 10, Table 2), and alken- (entry 3, Table 2)
substituted TIPS-vinylketenes participated in the [4+1] reaction.
The [4+1] reaction also proceeded smoothly with substrates
such as C4 aryl- (entries 3 and 9, Table 2) and alkyl-substituted
a All products in this table are racemic. b The removal of chromium
fragment could be achieved quantitatively by the exposure of the crude
product to air with the aid of silica gel. c The chromium fragment was
decomposed in the reaction. d Ko¨brich reagent was generated from Br2CHCH3
instead of CH2I2.
(12) (a) Schmalz, H. G.; Siegel, S.; Bats, J. W. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2383. (b) Lin, H.; Yang, L.; Li, C. Organometallics 2002,
21, 3848. (c) Merlic, C. A.; Miller, M. M.; Hietbrink, B. N.; Houk, K. N.
J. Am. Chem. Soc. 2001, 123, 4904. (d) Lin, C.; Chen, Q.; Cao, L.; Yang,
L.; Wu, Y.-D.; Li, C. J. Org. Chem. 2006, 71, 3328.
(13) In the preparation of 1k, product with Cr(CO)3 complexed C3
naphthyl ring was not found probably because Cr(CO)3 was easily
decomposed in refluxing benzene. In the case of 1l, the TIPS-vinylketene
with Cr(CO)3 complexed C3 naphthyl ring was found to be very unstable
as expected, so 1l was formed by photolysis of crude product.
(14) (a) Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem. Soc. 2003,
125, 2341. (b) For a review, see: Braun, M. Angew. Chem., Int. Ed. 1998,
37, 430.
TIPS-vinylketenes. Methoxy substituents on the C3 chromium
complexed phenyl ring have little effect on product yield (entries
4 and 7-9, Table 2). The Cr(CO)3 in annulation products could
be removed quantitatively by exposure of the crude product to
air with the aid of silica gel (entries 4-6, Table 2).
Interestingly, two diastereoisomers 3ka and 3kb were isolated
in 61% yield with a 3 to 5 ratio in entry 11. Diastereoisomers
J. Org. Chem, Vol. 72, No. 26, 2007 10255

TABLE 3. [4+1] Reactions of TIPS-Vinylketenes with tert-Butyl
3ka and 3kb were formed by a rotation-restricted 1-naphthyl
group on the C3 of the cyclopentenone ring. In entry 12, the
C4 substituent of TIPS-vinylketene 1l was shifted to isopro-
poxyl, the reverse diastereoselectivity of 1l in the [4+1] reaction
was observed, and 3la and 3lb were separated in 40% yield
with a ratio of 4 to 3.
Isocyanidea
We were also pleased to find that Ko¨brich reagents generated
from 1,1-dibromoethane serve as suitable reagents in [4 + 1]
annulations with the silyl vinylketenes (entries 13 and 14, Table
2). Notably, the cyclopentenone products 3a′ and 3j′ contain
two contiguous stereogenic centers, and in both cases only a
single diastereomer could be observed by 1H NMR spectroscopy
of the crude reaction mixtures. NOE experiment of cyclopen-
tenone 3a′ established the cis relationship between the two
methyl substituents on the cyclopentenone ring.
In entries 15 and 16, the ring expansion reaction of cy-
clobutenones 1m and 1n with Li/I carbenoid proceeded smoothly
to afford 3m and 3n, respectively. The mechanism of this
reaction may be similar to the reaction of cyclobutanone with
diazomethane.15 Despite a number of reports on one-carbon
insertion to cyclobutanones, only a few16 on cyclobutenone have
been reported. Since this one-carbon insertion preferentially
takes place between C1 and C4 of cyclobutenones, it could avoid
regiochemical difficulties found in the reaction of cyclobu-
tanones with carbene reagents.15,17
More recently, aminocyclopentitols have been recognized as
important bioactive compounds in their role as glycosidase
inhibitors.18 Several groups19 have reported that isocyanides
could be used in place of CO in the intramolecular Pauson-
Khand-type transformation of enynes to iminocyclopentenes or
cyclopentenones, but the use of a transition metal promoter was
necessary. Successful [4+1] reaction of TIPS-vinylketenes with
isocyanide will lead to cyclopentenone products with C5 imine
groups, which could serve as precursors for the synthesis of
aminocyclopentitols. As indicated in Table 3, reactions of TIPS-
vinylketenes (entries 1, 2) with tert-butyl isocyanide in THF at
room temperature afforded cyclopentenone products with C5
imine groups in excellent yield without any promoter. In entries
3-6, elevated temperature was required to complete cyclizations
and desired products could also be separated in good yield. A
notable feature of these [4+1] annulations is that exocyclic C5
imine groups in all products are Z configuration.
a All products in this table are racemic. b Stirred at room temperature
for 48 h. c Refluxed in THF for 4 h. d The chromium fragment was
decomposed in the reaction.
same plane as that containing the ketene substituent.8b,20a Thus
Li/Br carbenoid will attack the ketene group from the side of
the vinyl substitute of the ketene group of 1j to avoid steric
hindrance with the bulky TIPS group, and the Z-bromo enolate
5 is formed stereoselectively. The following SN1 loss of
bromide20b from the bromo enolate 5 leads to the oxidopenta-
dienylic cation 6 containing a C1 external methyl group.
Obviously, 6 is more stable than its stereoisomer with a C1
internal methyl group that will suffer steric hindrance with the
C5 internal methyl.20c A similar SN1 loss of bromide from the
bromo enolate is proposed in the mechanism of formation of
cyclopropanone from R,R′-dibromoketone with PPN+Cr(CO)4
NO-.20b Since oxidopentadienylic cation could be regarded as
a vinyl-stabilized oxyallyl,21 the SN1 loss of bromide from 5
should be more favorable than that from simple bromo
enolate.20b The oxidopentadienylic cation 6 undergoes conro-
tatory 4π-electrocyclic closure to afford the cyclopentenone
product 3j′ with two cis methyl groups. Since the C3 or C5
electron of the dienolate system in 5 is not suitably situated for
direct backside SN2 displacement of bromide because of its
planar structure, formation of cyclopentenone product 3j′ or a
vinyl cyclopropanone from 5 by intramolecular SN2 reaction
should be difficult. Sorensen’s recent work20b may support that
oxidopentadienylic cations are involved in the reaction pathway
of the [4+1] reaction of TIPS-vinylketenes with Ko¨brich
reagents. In his research, an oxyallyl structure is proposed as
A mechanistic hypothesis that accounts for the [4+1] reaction
of TIPS-vinylketenes with Ko¨brich reagents or isocyanide is
shown in Scheme 1 (1j was selected as the model). Because of
the allenic bonding in a ketene, the nucleophile is required to
approach the π-orbital of the carbonyl group in ketenes in the
(15) For reviews, see: (a) Bellus, D.; Ernst, B. Angew. Chem., Int. Ed.
Engl. 1987, 27, 797. (b) Lee-Ruff, E. New Synthetic Pathways from
Cyclobutanones. In AdVances in Strain in Organic Chemistry; Halton, B.,
Ed.; JAI Press: Greenwich, CT, 1991; Vol. 1, pp 167-213. (c) Namyslo,
J. C.; Kaufmann, D. E. Chem. ReV. 2003, 103, 1485.
(16) Yamamoto, Y.; Noda, M.; Ohno, M.; Eguchi, S. J. Org. Chem. 1997,
62, 1292.
(17) (a) Mahuteau-Betzer, F.; Ghosez, L. Tetrahedron Lett. 1999, 40,
5183. (b) Kanazawa, A.; Delair, P.; Pourashraf, M.; Greene, A. E. J. Chem.
Soc., Perkin Trans. 1 1997, 13, 1911.
(18) For reviews, see: (a) Bereubar, A.; Grandjean, C.; Siriwardena, A.
Chem. ReV. 1999, 99, 779. (b) Acar, E. A.; Glarner, F.; Burger, U. HelV.
Chim. Acta 1998, 81, 1095.
(19) (a) Tamao, K.; Kobayashi, K.; Ito, Y. J. Am. Chem. Soc. 1988, 110,
1286. (b) Berk, S. C.; Grossman, R. B.; Buchwald, S. L. J. Am. Chem.
Soc. 1994, 116, 8593.
(20) (a) Sorensen, T. S.; Sun, F. J. Am. Chem. Soc. 1997, 119, 11327.
(b) Sorensen, T. S.; Sun, F. J. Am. Chem. Soc. 1995, 117, 5592. (c) Frontier,
A. J.; Collison, C. Tetrahedron 2005, 61, 7577.
(21) Hess, B. A. J. Am. Chem. Soc. 2002, 124, 5592.
10256 J. Org. Chem., Vol. 72, No. 26, 2007

SCHEME 1. Proposed Mechanism for [4+1] of 1j
dried over anhydrous Na2SO4. After filtration, the solvent was
removed under reduced pressure and the residue was purified via
flash chromatography (SiO2) to afford the cyclopentenone com-
pound.
the key intermediate in the reaction of ketenes with diazoalkanes
to form cyclopropanones.22
The formation of 4j with exocyclic (Z)-imine moiety involves
the initial formation of zwitterion 723 by the attack of isocyanide
to the ketene group as Moore suggested.9c The oxidopentadi-
enylic cation 8 is another resonance form of the zwitterion 7.
The following step is conrotatory 4π-electrocyclic closure of 8
to 4j. Although conrotation in both the clockwise and the
counterclockwise sense of 8 is allowed, for steric reasons, 8
will preferentially undergo counterclockwise conrotation. In this
way, the bulky tert-butyl group moves away from the methyl
group on C5. The proposed transition 8 resembles the interme-
diate in the cyclization of oxyallenones, which lead to cyclo-
pentenones with an exocyclic (Z)-double bond.24
In summary, we have developed an efficient method for
preparing polysubstituted cyclopentenones from TIPS-vi-
nylketenes and Ko¨brich reagents. Additionally, highly substi-
tuted cyclopentenones can be prepared via [4+1] reaction of
TIPS-vinylketenes with tert-butyl isocyanide without any
promoter. Ongoing studies on the application of the [4+1]
reaction in the synthesis of natural products will be reported in
due course.
Cyclopentenone 3c: mp 106-107 °C. IR (neat) υ 2944, 2863,
1968, 1900, 1692, 1610, 1186, 1076, 1020 cm-1. 500 MHz 1H NMR
(CDCl3) δ 7.37-7.30 (m, 4H), 7.25-7.21 (m, 1H), 7.01 (d, J )
16.0 Hz, 1H), 6.70 (d, J ) 16.0 Hz, 1H), 5.32-5.23 (m, 5H), 3.29
(s, 3H), 3.01 (d, J ) 19.0 Hz, 1H), 2.55 (d, J ) 19.0 Hz, 1H),
1.68-1.62 (m, 3H), 1.17-1.02 (m, 18H). 13C NMR (125 MHz,
CDCl3) δ 232.1, 209.3, 175.6, 145.9, 145.0, 137.9, 128.8, 127.3,
124.5, 123.3, 101.9, 93.1, 92.5, 91.6, 91.5, 91.1, 87.0, 50.6, 49.7,
19.2, 19.1, 12.4. HRMS (FAB) m/z calcd for C32H38CrO5Si
582.1894, found 582.1890.
General Procedure for the [4+1] Annulation of Silyl Vi-
nylketenes with Isocyanide in THF. A solution of the silyl
vinylketene (0.33 mmol, 1.0 equiv) and tert-butyl isocyanide (42
mg, 0.50 mmol, 1.5 equiv) in 10 mL of THF was stirred at room
temperature or 66 °C until the TLC analysis revealed that the
reaction was complete. The solvent was removed under reduced
pressure and the residue was purified via flash chromatography
(SiO2) to afford the cyclopentenone compound.
Cyclopentenone 4a: mp 146-147 °C. IR (neat) υ 3085, 2946,
2866, 1975, 1885, 1700, 1552, 1454, 1388, 1361, 1228, 1117, 1068,
1
1018 cm-1. H NMR (500 MHz, CDCl3) δ 5.90 (d, J ) 6.5 Hz,
1H), 5.63 (t, J ) 6.0 Hz, 1H), 5.57 (d, J ) 6.0 Hz, 1H), 5.13 (t, J
) 6.0 Hz, 1H), 5.08 (t, J ) 6.5 Hz, 1H), 3.24 (s, 3H), 1.71 (s, 3H),
1.44 (s, 9H), 1.26 (sept, J ) 7.0 Hz, 3H), 1.00 (d, J ) 7.0 Hz,
9H), 0.97 (d, J ) 7.0 Hz, 9H). 13C NMR (125 MHz, CDCl3) δ
231.6, 191.3, 175.3, 161.2, 153.1, 102.2, 97.5, 96.3, 95.6, 86.0,
85.2, 80.7, 57.9, 51.5, 29.8, 24.1, 19.3, 19.2, 11.9. HRMS (FAB)
m/z calcd for [C29H41CrNO5Si + H]+ 564.2232, found 564.2229.
Experimental Section
General Procedure for the [4+1] Annulation of Silyl Vi-
nylketenes with Ko1brich Reagents in Et2O. A solution of the
silyl vinylketene (0.5 mmol, 1.0 equiv) and CH2I2 or Br2CHCH3
(0.75 mmol, 1.5 equiv) in 5 mL of Et2O was cooled to -78 °C.
n-BuLi (2.2 M, 0.36 mL, 0.75 mmol, 1.5 equiv) was added within
10 min by syringe. After stirring at -78 °C for 1 h, the solution
was allowed to warm to room temperature and stirred overnight.
The resulting solution was diluted with 30 mL of Et2O and extracted
with saturated NaCl (3 × 10 mL). The aqueous layer was back-
extracted with Et2O (3 × 10 mL). The combined organic layer was
Acknowledgment. This work was supported by NNSFC
(20402010) and SKLEOC of Nankai University.
Note Added after ASAP Publication. There was an error
in Scheme 1 in the version published ASAP on November 16,
2007; the corrected version was published November 19, 2007.
(22) Zaitseva, G. S.; Lutsenko, I. F.; Kisin, A. V.; Baukov, Y. I.; Lorberth,
J. J. Organomet. Chem. 1988, 345, 253.
(23) The formation of 7 is proposed to involve rehybridization and a
geometry change at nitrogen to sp2, with the plus charge on carbon. An sp
geometry may also be reasonable, as this would maintain conjugation of
all the electrons on nitrogen, with plus charge on N.
Supporting Information Available: Detailed experimental
procedures and characterization data for all cyclopentenone products
and new silyl vinylketenes. This material is available free of charge
via the Internet at http://pubs.acs.org.
(24) Tius, M. A. Acc. Chem. Res. 2003, 36, 284.
JO702109E
J. Org. Chem, Vol. 72, No. 26, 2007 10257