Phosphine-catalyzed [4+2] annulations of 2-alkylallenoates and olefins: Synthesis of multisubstituted cyclohexenes

Article abstract of DOI:10.1002/asia.201100190

From our investigations on phosphine-catalyzed [4+2] annulations between α-alkyl allenoates and activated olefins for the synthesis of cyclohexenes, we discovered a hexamethylphosphorous triamide (HMPT)-catalyzed [4+2] reaction between α-alkyl allenoates

Full text of DOI:10.1002/asia.201100190

DOI: 10.1002/asia.201100190
Phosphine-Catalyzed [4+2] Annulations of 2-Alkylallenoates and Olefins:
Synthesis of Multisubstituted Cyclohexenes
Yang S. Tran, Tioga J. Martin, and Ohyun Kwon*[a]
Dedicated to Professor Eun Lee on the occasion of his retirement and 65th birthday
Abstract: From our investigations on
phosphine-catalyzed [4+2] annulations
between a-alkyl allenoates and activat-
ed olefins for the synthesis of cyclohex-
enes, we discovered a hexamethylphos-
phorous triamide (HMPT)-catalyzed
[4+2] reaction between a-alkyl alle-
noates 1 and arylidene malonates or ar-
ylidene cyanoacetates 2 that provides
highly functionalized cyclohexenes 3
and 4 in synthetically useful yields (30–
89%), with moderate to exclusive re-
gioselectivity, and reasonable diaste-
reoselectivity. Interestingly, the [4+2]
annulations between the a-alkyl alle-
noates 1 and the olefins 2 manifested a
polarity inversion of the 1,4-dipole syn-
thon 1, depending on the structure of
the olefin, thus providing cyclohexenes
3 exclusively when using arylidene cya-
noacetates. The polarity inversion of a-
alkyl allenoates from a 1,4-dipole A to
B under phosphine catalysis can be ex-
plained by an equilibrium between the
phosphonium dienolate
C and the
Keywords: alkenes
· allenoates ·
phosphorous ylide D.
annulation · phosphine catalysis ·
regioselectivity
Introduction
phosphine catalyst, react with a long list of activated electro-
philes to form various carbocycles and heterocycles.[6] In this
area, we have disclosed our findings on the use of ethyl 2-
alkyl allenoates as a 1,4-dipole synthon and their reactions
with activated imines to generate tetrahydropyridines under
phosphine catalysis.[7] Subsequent investigations have led to
the construction of cyclohexenes when ethyl 2-alkyl alle-
noates are treated with arylidene malononitriles.[8] Intrigu-
ingly, we observed the highly regioselective formation of
ethyl 5,5-dicyano-4-arylcyclohex-1-enecarboxylate and ethyl
4,4-dicyano-5-arylcyclohex-1-enecarboxylate, depending on
the catalyst employed. In this process, the ethyl 2-alkyl alle-
noates 1 serve as a 1,4-dipole synthon A in the presence of
catalytic hexamethylphosphorous triamide (HMPT), but as
a polarity-reversed 1,4-dipole B in the presence of electron-
deficient triarylphosphines (Scheme 1). This polarity inver-
The prevalence of six-membered carbocycles in pharmaceut-
ical agents and natural products renders this ring system
among the most important chemical structural motifs.[1] Not
surprisingly, therefore, a considerable amount of effort has
been directed toward the development of new technologies
to access these systems. The Diels–Alder reaction is proba-
bly the most efficient and widely used method for the rapid
construction of these carbocycles.[2] Remarkably, relatively
few other chemical methods are available for the prepara-
tion of cyclohexenes through intramolecular processes[3]
and, even less commonly, intermolecular annulations.[4]
Nucleophilic phosphine catalysis has recently played an
important role in the development of new reactions, thus
providing access to a variety of molecular frameworks.[5] In
particular, allenoates, in the presence of a suitable tertiary
[a] Y. S. Tran, T. J. Martin, Prof. O. Kwon
Department of Chemistry and Biochemistry
University of California, Los Angeles
607 Charles E. Young Drive East
Los Angeles, CA 90095-1569 (USA)
Fax : (+1)310-206-3722
E-mail: ohyun@chem.ucla.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100190.
Scheme 1. Ethyl 2-methylallenoate functioning as 1,4-dipoles.
Chem. Asian J. 2011, 6, 2101 – 2106
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FULL PAPERS
sion from the 1,4-dipole A to the 1,4-dipole B appears to
arise from a change in the equilibrium between the phos-
phonium dienolate C and the vinylogous ylide D. The result-
ing [4+2] adducts are valuable intermediates for further
transformations, both in natural product synthesis[9] and di-
versity-oriented synthesis.[10] Herein, we provide a full ac-
count of our investigation into this [4+2] reaction using vari-
ous classes of olefinic electrophiles.
nulation was due, in part, to inefficient isomerization of the
zwitterion E to the intermediate F (Scheme 2), thus inhibit-
ing the final cyclization step.[13] To assist this isomerization
process, we envisioned that a longer-living zwitterion E
might be required to facilitate the formation of the inter-
mediate F. Therefore, we chose to employ benzylidene mal-
onate and benzylidene cyanoacetate as the coupling electro-
philes.
Promisingly, the expected cyclohexene 3a was formed
when diethyl benzylidene malonate (2a, 1.0 mmol) was
treated with ethyl 2-methyl allenoate (1a, 2.0 mmol) and tri-
phenylphosphine (20 mol%) in benzene under reflux
(Table 1, entry 1). Although product formation was apparent
Results and Discussion
Based on our previous investigations into tetrahydropyridine
syntheses,[7] we initially hypothesized that ethyl 2-methyl al-
lenoate could potentially react with alkenes to form cyclo-
hexenes under the influence of an appropriate phosphine
catalyst. Mechanistically, the first step involves the genera-
tion of a phosphonium dienolate C through conjugate addi-
tion of the phosphine to ethyl 2-methylallenoate 1a
(Scheme 2). Michael addition of the dienolate C to an acti-
vated olefin 2 facilitates the formation of the zwitterionic in-
termediate E. Subsequent proton-transfer steps facilitate
tautomerization of the vinylphosphonium zwitterion E to an
allylphosphonium zwitterion F. The intermediate F under-
goes an intramolecular 6-endo cyclization and b-elimination
of the phosphine to furnish the cyclohexene 3.
Table 1. Survey of phosphine catalysts for [4+2] annulation of the alle-
noate 1a and the alkene 2a.[a]
Entry
Phosphine
Reaction Time [h]
Yield [%][b]
3a:4a[c]
1
2
3
4
5
6
7
8
PPh3
(4-Me2NC6H4)3P
(4-MeOC6H4)3P
ACHTUGNRTNE(NUNG 4-FC6H4)3P
PBu3
PEt2Ph
PEtPh2
ACHTUNGTRENNUNG
96
24
24
24
48
48
48
48
48
48
48
48
24
32
>95:5
NA[e]
NA[e]
NA[e]
NA[e]
NA[e]
NA[e]
NA[e]
NA[e]
NA[e]
ND[f]
22:78
28:72
NR[d]
NR[d]
NR[d]
NR[d]
NR[d]
NR[d]
NR[d]
NR[d]
NR[d]
2
9
ACHTUNGTRENNUNG
10
11
12
13
G
CHTUNGTRENNUNG
G
ACHTUNGTRENNUNG
A
10
63
[a] Reaction conditions: 1a (1.4–2.0 mmol), 2a (1 mmol), and the phos-
phine (20 mol%) were heated under reflux in benzene (10 mL). [b] Yield
of isolated product. [c] Regioisomeric ratio 3a:4a was determined
1
through analysis of the H NMR spectrum of the crude reaction mixture.
[d] No reaction. [e] Not applicable. [f] Not determined.
through 1H NMR spectroscopic analysis, the reaction pro-
ceeded at a slow rate and reached completion only after
96 hours, thereby providing a moderate isolated yield of 3a
(32%). Triarylphosphines featuring benzene rings substitut-
ed with electron-rich or electron-poor groups did not yield
any product after performing the reaction for one day
(Table 1, entries 2–4). Electron-rich tertiary phosphines con-
taining alkyl, aryl, alkoxy, or diethylamino substituents were
ineffective at mediating cyclohexene formation (Table 1, en-
tries 5–11). These catalysts led to oligomerization of the alle-
noate 1a instead of incorporation of the benzylidene malo-
nate (Table 1, entries 2–11). Further examination of catalysts
revealed that bis(diethylamino)phenylphosphine could
induce cyclohexene formation with a moderate isolated
yield (10%, Table 1, entry 12). This observation led us to ex-
plore HMPT as the catalyst. To our delight, we achieved an
appreciable increased reaction efficiency, thus leading to
higher mass recovery of the [4+2] adduct, with an isolated
Scheme 2. Proposed Mechanism for phosphine-catalyzed cyclohexene for-
mation.
With this mechanism in mind, we set out to examine the
effects of a range of activated alkenes, catalysts with varying
degrees of nucleophilicity,[11] and solvents of various polari-
ty[12] on the formation of cyclohexenes through the [4+2] an-
nulations of 2-alkyl allenoates. Our initial attempts were
made using ethyl 2-methyl allenoate and commercially avail-
able electrophiles, including ethyl and methyl acrylates,
acrylonitrile, cyclohexenone, dimethyl maleate, dimethyl fu-
marate, ethyl maleimide, and ethyl cinnamate. Our prelimi-
nary results were disappointing: we could not detect any cy-
clohexene products under phosphine catalysis conditions
when using triphenylphosphine or tributylphosphine as the
catalyst in benzene or dichloromethane. We hypothesized
that the incompatibility of these electrophiles for [4+2] an-
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Phosphine-Catalyzed [4+2] Annulations
yield of 63%, albeit as a 28:72 mixture of 3a and 4a
(Table 1, entry 13). Our assignments of the structures of
compounds 3a and 4a are based on comparison with those
of their dicyano counterparts derived from the benzylidene
malononitrile.[8]
Having found the optimal catalyst, we further optimized
the reaction parameters to improve the reaction yields and
regioselectivities (Table 2). There appeared to be a trend
of the allenoate, improved the reaction yield dramatically
(89%) with retention of regioselectivity (Table 2, entry 13).
Use of a stoichiometric amount of HMPT provided a similar
result (Table 2, entry 14). Although there are reports of nu-
cleophilic phosphine catalyzed reactions of allenes being fa-
cilitated by water,[15–17] we found that the presence of water
had a detrimental effect on cyclohexene formation.
With the optimized conditions for cyclohexene formation
in hand, we performed experiments to probe the scope of
this [4+2] annulation, and found out that a wide range of ar-
ylidene malonates was tolerated (Table 3). For example, ary-
Table 2. Survey of solvents for [4+2] annulation of the allenoate 1a and
the alkene 2a.[a]
Table 3. Survey of arylidenemalonates for [4+2] annulations with the al-
lenoate 1a.[a]
Entry Solvent
Reaction
Temp. [8C]
Reaction
Time [h]
Yield [%][b] 3a:4a[c]
1
2
3
4
5
6
7
benzene
toluene
xylene
mesitylene
hexanes
pentane
CH2Cl2/pen-
tane (1:1)
CH2Cl2
Et2O
THF
dioxane
MeCN
benzene
benzene
80
24
24
48
48
24
14
24
63
65
72
trace
48
28:72
33:67
23:77
ND[d]
28:72
>5:95
55:45
Entry
Ar
R
Yield [%][b]
3a/4a[c]
111
140
165
69
36
36
1
2
3
4
5
6
7
8
Ph (2a)
Et
89
69
75
84
86
82
23
84[d]
81
83
81
72
71
87
28:72
23:77
24:76
21:79
30:70
26:74
22:78
22:78
50:50
39:61
33:66
16:84
29:71
20:80
4-O2NC6H4 (2b)
4-NCC6H4 (2c)
4-BrC6H4 (2d)
4-ClC6H4 (2e)
4-FC6H4 (2 f)
4-MeC6H4 (2g)
4-MeC6H4 (2g)
3-MeC6H4 (2h)
3-BrC6H4 (2i)
3-MeOC6H4 (2j)
2-furyl (2k)
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
72
trace
8
9
39
33
66
101
81
80
80
48
24
24
48
15
24
24
NR[e]
15
64
NA[f]
20:80
55:45
53:47
60:40
28:72
28:72
10
11
12
13
14
9
12
10
11
12
13
14
22
89[g]
90[h]
2-thienyl (2l)
N-Boc-2-indolyl (2m)
[a] Reaction conditions: 1a (1.4–2.0 mmol), 2a (1 mmol), and the phos-
phine (20 mol%) were heated under reflux in the designated solvent
(10 mL). [b] Yield of isolated product. [c] Regioisomeric ratio 3a:4a was
[a] Reaction conditions: A solution of the allenoate 1a (1.4–3.0 mmol) in
benzene (10 mL) was added to a solution of the malonate 2 (1 mmol)
and HMPT (20 mol%) in benzene (5 mL) under reflux over 4 h and then
the mixture was further heated under reflux in benzene until the disap-
pearance (TLC) of the malonate. [b] Yield of isolated product. [c] Regioi-
someric ratio 3a/4a was determined through analysis of the 1H NMR
spectrum of the crude reaction mixture. [d] The allenoate 1a was added
over 12 h.
1
determined through analysis of the H NMR spectrum of the crude reac-
tion mixture. [d] Not determined. [e] No reaction. [f] Not applicable.
[g] All starting reagents were freshly distilled. [h] 1 or 2 equivalents of
HMPT was used.
toward better mass recovery and regioselectivity when less-
polar solvents were used. For instance, aromatic solvents
were optimal, with very little difference in yield or regiose-
lectivity when using benzene, toluene, or xylene, with the
notable exception of the poor performance in high boiling
mesitylene (Table 2, entries 1–4).[14] While hexanes provided
regioselectivity similar to those of the aromatic solvents
(Table 2, entry 5), pentane exhibited excellent selectivity for
4a in good yield (Table 2, entry 6). Although pentane would
have been an ideal solvent for the formation of cyclohex-
enes 4, the arylidene malonates other than diethyl benzyli-
dene malonate did not dissolve in pentane and their reac-
tions did not proceed. Speculating that the high regioselec-
tivity might be due to the low reaction temperature, we em-
ployed dichloromethane and a series of dichloromethane/
pentane mixtures, but without success (Table 2, entries 7 and
8). Polar aprotic solvents provided modest results (Table 2,
entries 9–12). The use of freshly distilled diethyl benzyliden
emalonate (2a) and HMPT, with slow addition (over 4 h) of
ethyl 2-methyl allenoate (1a) to minimize oligomerization
lidene malonates containing benzene rings with electron-
withdrawing groups (e.g., nitro, cyano, halogen) at the para-
position produced cyclohexenes in good yields with reasona-
ble regioselectivity (favoring the cyclohexene 4; Table 3, en-
tries 2–6). The formation of the cyclohexenes was much
slower when the electron-rich para-methyl benzylidene mal-
onate 2g was used, thus leading to lower mass recovery as a
result of the competing oligomerization of the allenoate
(Table 3, entry 7). Allene oligomerization was circumvented
when the allenoate 1a was added over 12 hours to a mixture
of dimethyl 4-methylbenzylidene malonate (2g) and HMPT
(20 mol%) in benzene under reflux; here, the reaction yield
improved to 84% (Table 3, entry 8). The reaction worked
well with meta-methyl, bromo, and methoxy-substituted ben-
zylidene malonates, albeit with poorer regioselectivities
(Table 3, entries 9–11). Furthermore, the reaction was com-
patible with hetereoarylidene malonates: dimethyl 2-furyli-
Chem. Asian J. 2011, 6, 2101 – 2106
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O. Kwon et al.
FULL PAPERS
dene malonate (2k), dimethyl 2-thienylidene malonate (2l),
and dimethyl N-Boc-2-indolylidene malonate (2m) were
viable substrates that furnished cyclohexene products with
good yields and regioselectivities (Table 3, entries 12–14).
Next, we examined (Table 4) the use of arylidene cyanoa-
cetates as activated olefin partners for the [4+2] annulations
of ethyl 2-methyl allenoate (1a). Unlike the situation with
effects of various a-alkyl allenoates (Table 5). This reaction
tolerated a range of allenylic b’-substituents on the allenoate
1, including aryl, substituted aryl, and carboxylic ester moi-
Table 5. Survey of allenoates 1 for [4+2] annulations with benzylidene-
cyanoacetate 2n.[a]
Table 4. Survey of Arylidenecyanoacetates for [4 + 2] Annulations with
the Allenoate 1a.[a]
Entry
R
Product
Yield [%][b]
cis/trans[c]
1
2
3
Ph (1b)
4-ClC6H4 (1c)
CO2Et (1d)
3w
3x
3y
81
74
78
88:12
89:11
77:23
Entry
Ar
Product
Yield [%][b]
[a] Reaction conditions: A solution of the allenoate 1 (1.4–3.0 mmol) in
benzene (10 mL) was added to a solution of the olefin 2n (1 mmol) and
HMPT (20 mol%) in benzene (5 mL) under reflux over 4 h and then the
mixture was further heated under reflux. [b] Yield of isolated product.
[c] Determined through analysis of the 1H NMR spectrum of the crude
reaction mixture and by comparison with the spectrum of cis-ethyl 5,5-di-
cyano-4,6-diphenylcyclohex-1-enecarboxylate (for which a single-crystal
X-ray structure was obtained). See Ref. [8].
1
2
3
4
5
6
7
8
9
Ph (2n)
3n
3o
3p
3q
3r
3s
3t
75
75
76
68
65
63
30
60
63
4-ClC6H4 (2o)
4-BrC6H4 (2p)
4-MeC6H4 (2q)
4-MeOC6H4 (2r)
3-MeOC6H4 (2s)
2-MeOC6H4 (2t)
2-ClC6H4 (2u)
3-BrC6H4 (2v)
3u
3v
[a] Reaction conditions: A solution of the allenoate 1a (1.4–3.0 mmol) in
benzene (10 mL) was added to a solution of the cyanoacetate 2 (1 mmol)
and HMPT (20 mol%) in benzene (5 mL) under reflux over 4 h and then
the mixture was further heated under reflux. [b] Yield of isolated prod-
uct.
eties, thus providing cyclohexenes 3 in good isolated yields
with reasonable diastereoselectivities (Table 5, entries 1–3).
For these b’-substituted allenoates 1, only the cyclohexenes
3 were formed, in accordance with previous observations.[8]
Notably, dimethyl benzylidene malonate (2a) and ethyl 2-
benzylallenoate (1b) did not furnish any of their corre-
sponding cyclohexenes 3, presumably because of steric hin-
drance and the diminished reactivities of these olefins.
arylidene malonates, here we isolated only one cyclohexene
regioisomer 3 when arylidene cyanoacetates were employed
under otherwise identical conditions. Slightly higher yields
resulted from electron-deficient arylidenes (Table 4, en-
tries 1–3 and 8) compared with those from electron-rich ary-
lidenes (Table 4, entries 4, 5, and 7). Product yields of the
desired cyclohexenes 3 diminished when 2-substituted aryli-
denes were used, presumably because of steric hindrance
and subsequent decreased reactivity at the b-carbon atom
(Table 4, entries 7 and 8).[18] For a given substituent (e.g.,
chloro, bromo), the para-substituted arylidene provided a
better reaction yield than its ortho or meta counterpart
(Table 4, entries 2/8 and 3/9).
The overall mass recoveries for the [4+2] annulations
with the arylidene cyanoacetates were lower than those of
the corresponding arylidene malonates. 1H NMR spectro-
scopic analysis of the crude reaction mixtures revealed the
presence of trace amounts (typically <15%) of the other
isomer 4. All attempts to isolate and characterize these
minor products 4 were unsuccessful. Further examination of
the crude reaction mixture obtained from ortho-methoxy-
benzylidene cyanoacetate (2t) allowed the isolation of a
new minor product in 15%
Mechanistic Considerations
Based on these observations, we rationalize that the forma-
tion of 3 and 4 arises through the g- or b’-addition of the
phosphonium intermediate (CÐD) to the activated olefin 2.
With more reactive arylidene cyanoacetates and/or sterically
congested 2-alkylallenoates with a-alkyl groups larger than
methyl, the addition occurs at the g-carbon atom of the
phosphonium enolate C; the formation of regioisomer 3
ensues (Scheme 2). With less-reactive arylidene malonates,
however, the phosphonium dienolate C isomerizes into the
vinylogous ylide D, which adds to the olefin 2 and produces
intermediate G. Consecutive proton transfers provide the
deconjugated enoate H, which undergoes 6-endo cyclization
to generate the cyclic ylide I. Finally, 1,2-proton transfer and
b-elimination of the phosphine catalyst furnish the cyclohex-
ene 4 (Scheme 3).
Synthetic Application of Functionalized Cyclohexenes
yield; its structure was assigned
as that of the [2+2] adduct 5.
To further explore the sub-
strate scope for the phosphine-
catalyzed [4+2] cyclohexene
Scheme 4 illustrates the synthetic utility of the gem-cyanoa-
cetate adduct. Alkaline hydrolysis of the nitrile 3o using
aqueous potassium carbonate and hydrogen peroxide fur-
nished the carboxamide 6 in 84% yield without saponifica-
tion of the ethyl carboxylic ester groups.
formation, we investigated the
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Phosphine-Catalyzed [4+2] Annulations
verted dipole B by virtue of the steric environment around
the allenoate or the reactivity of the activated alkene. Fur-
ther manipulation of the cyclohexene adducts demonstrates
the utility of the phosphine-catalyzed [4+2] annulations of
allenoates with olefins.
Experimental Section
Materials and Methods
All reactions were performed under an atmosphere of argon with dry sol-
vents and anhydrous conditions, unless otherwise noted. Benzene, tolu-
ene, and CH2Cl2 were freshly distilled from CaH2. All other reagents
were used as received from commercial sources. All ethyl 2-substituted
methylallenoates 1 were synthesized according to procedures reported
previously. Arylidenene malonate and arylidene cyanoacetate 2 were syn-
thesized through phosphine-catalyzed Knoevenagel condensation of the
pertinent aldehyde and cyanoacetate, according to the procedure report-
ed by Yadav,[21] or through piperidine-catalyzed condensation of the cor-
responding aldehyde and malonate. HMPT was distilled under vacuum in
three fractions; only the middle fraction was used. The distilled HMPT
was then stored under an atmosphere of argon in a dry glove box. Reac-
tions were monitored through thin layer chromatography (TLC) on
0.25 mm Silicycle silica gel plates (TLG-R10011B-323), visualizing with
UV light or staining with permanganate or anisaldehyde. Flash column
chromatography was performed using Silicycle Silia-P gel (50 mm particle
size, R12030B) and compressed air. Preparative HPLC was performed by
Scheme 3. Mechanistic rationale for the formation of cyclohexenes 4.
using (R,R)-1,2-diaminocyclohexaneACHTNUTRGENNUG(DACH)-3,5-dinitrobenzoylACHTUNGTRENNUNG(DNB)-
modified silica gel. IR spectra were recorded using a Perkin–Elmer Para-
gon 1000 FTIR spectrometer. NMR spectra were obtained using Bruker
Avance-500, ARX-500, or Avance-300 instruments and calibrated using
CHCl3/CDCl3 as the internal reference (7.26 and 77.0 ppm for 1H and
13C NMR spectra, respectively). Data for 1H NMR spectra are reported
as follows: chemical shift (d ppm), multiplicity, coupling constant (Hz),
and integration. Data for 13C NMR spectra are reported in terms of
chemical shift and multiplicities, with coupling constants (Hz) in the case
of JCF coupling. The following abbreviations are used to explain the mul-
tiplicities: s, singlet; d, doublet; t, triplet; q, quartet; sept, septet; m, mul-
tiplet; br, broad; app, apparent. High-resolution electron ionization (EI)
mass spectra were recorded after rapid thermal vaporization of samples
deposited on a desorption ionization filament inserted directly into an EI
(70 eV, 2008C) source of a triple-sector high-resolution instrument (VG/
Micromass Autospec) tuned to 8000 static resolution (M/DM, 10%
valley) using perfluorinated kerosene (formula weight 705, Lancaster
Synthesis, Windham, NH) as the internal calibrant. High-resolution elec-
trospray ionization (HRESI) mass spectra were recorded after flow injec-
tion of CHCl3 solutions into an ESI source attached to a 7.5-T FTMS
(Ion Spec Ultima, Irvine, CA) instrument. Data were analyzed using the
instrument-supplied software. Melting points (m.p.) are uncorrected; they
were recorded using an electrothermal capillary melting point apparatus.
Scheme 4. Hydrolysis of the nitrile 3o to the carboxamide 6. DMSO=di-
methyl sulfoxide.
Scheme 5 further demonstrates the potential utility of this
[4+2] annulation for the synthesis of biologically active nat-
ural products. We achieved rapid entry into the tetracyclic
framework 7[19] of isoborreverine[20] through N-Boc depro-
tection of the cyclohexene triester 4m by using trifluoroace-
tic acid followed by the lactamization with the tert-butyl-
magnesium chloride.
Conclusions
We have further established that the novel phosphine-cata-
lyzed [4+2] annulation between allenoates and activated al-
kenes is a valuable strategy for cyclohexene synthesis. Ethyl
2-alkyl allenoates can serve as either a 1,4-dipole A or an in-
General Procedure for the Synthesis of Cyclohexenes 3 and 4
A solution of arylidene malonate or arylidene cyanoacetate (1.0 mmol)
and HMPT (0.2 or 1.0 mmol) in benzene (5 mL) was heated under reflux
in a 50 mL flame-dried round-bottom
flask under an atmosphere of argon.
The allenoate (3.0 mmol) in benzene
(10 mL) was added dropwise over a
period of at least 4 h. An orange-red
solution was obtained; the mixture
was stirred under reflux until TLC
analysis revealed consumption of the
olefin 2. The reaction mixture was
concentrated and the residue purified
through flash column chromatography
(gradient eluent: 520% EtOAc in hex-
Scheme 5. Pyrroloindolinone formation from the cyclohexene gem-diester 4m. TFA=trifluoroacetic acid.
anes), followed by preparative HPLC
Chem. Asian J. 2011, 6, 2101 – 2106
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2105

O. Kwon et al.
FULL PAPERS
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P41M081282) for financial support.
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Received: February 25, 2011
Published online: July 7, 2011
2106
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Chem. Asian J. 2011, 6, 2101 – 2106