Ruthenium-Catalyzed [2+2+2] Cycloaddition of 1,6-Enynes and Unactivated Alkynes: Access to Ring-Fused Cyclohexadienes

Article abstract of DOI:10.1002/asia.201700642

The [2+2+2] intermolecular carbocyclization reactions between 1,6-enynes and alkynes catalyzed by [RuCl(cod)(Cp*)] (cod=1,5-cyclooctadiene, Cp=pentamethylcyclopentadienyl) are reported to provide bicyclohexa-1,3-dienes. The presented reaction conditions are compatible with internal and terminal alkynes and the chemo- and regioselectivity issues are controlled by the presence of substituents at the propargyl carbon center of the alkyne(s) partner(s).

Full text of DOI:10.1002/asia.201700642

CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: Ruthenium-Catalyzed [2 + 2 + 2] Cycloaddition of 1,6-Enynes and
Unactivated Alkynes: Access to Ring-fused Cyclohexadienes
Authors: Alphonse Tenaglia, Rui Liu, and Laurent Giordano
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Ruthenium-Catalyzed [2 + 2 + 2] Cycloaddition of 1,6-Enynes and
Unactivated Alkynes: Access to Ring-fused Cyclohexadienes
Rui Liu,[a] Laurent Giordano[a], Alphonse Tenaglia*,[a]
Abstract: The [2 + 2 + 2] intermolecular carbocyclization reactions
between 1,6-enynes and alkynes catalyzed by Cp*Ru(cod)Cl are
reported to provide bicyclohexa-1,3-dienes. The presented reaction
conditions are compatible with internal and terminal alkynes and the
chemo- and regioselectivity issues are controlled by the presence of
substituents at the propargyl carbon center of the alkyne(s)
partner(s).
leading to aromatic compounds was observed when the alkyne
functions are unsubstituted at the terminal position. This
approach offered opportunities for the enantioselective
construction of quaternary carbon stereocenters,[10] and DFT
calculations,[11] kinetic studies as well as characterization of a
rhoda(III)cyclopentadiene intermediate[12] supported similar
reaction paths for the Co, Rh and Ru-catalyzed reactions.
The alternative strategy, consisting on the combination of 1,6-
enynes and alkynes (Scheme 1, b), was scarcely investigated
over the past decades and presented major challenges.[13] First,
the competitive self-carbocyclization of enynes has long
hampered the success of such an event.[6,14] To circumvent this
issue, a large excess amounts of alkynes (up to 10 equiv) is
often required. Second, specific structural requirements such as
internal, terminal, electron-poor or unactivated alkynes and
enynes featuring internal alkyne framework are often mandatory
depending on the nature of the catalyst. To date, a general
sketch of this simple assembly of reactants remains to establish.
Recent developments accomplished by the groups of Shibata
and Evans based on the use of cationic rhodium catalysts were
dedicated to the enantioselective synthesis of chiral
bicyclohexadienes containing one quaternary stereocenter
generated at the ring-fused position.[15] Despite the ability of
ruthenium complexes to catalyze a myriad of [2 + 2 + 2]
cycloadditions of 1,6-diynes with alkynes[16] or electron-deficient
carbon-heteroatom multiple bond compounds,[17] to the best of
our knowledge, the intermolecular cross-carbocyclization of
enynes with alkynes leading to Type II compounds has not yet
been described. Herein, we have achieved the intermolecular
carbocyclization of enynes with unactivated alkynes using a
Introduction
The development of synthetic strategies and methodologies
based on transition-metal catalyzed transformations to construct
complex molecular structures from readily available starting
materials is an intensive area of research.[1] The generation of
ring systems through cycloaddition reactions is representative of
multiple bond- and/or stereocenters- forming synthetic methods
preserving atom economy.[2] Thus, the [2 + 2 + 2] intermolecular
carbocyclization reactions between two alkynes and one alkene
conceptually represents a straightforward route to cyclohexa-
1,3-dienes.[3] To this end, two main options have been devised to
form Types I and II bicyclic cyclohexa-1,3-dienes from: (a)
reactions between diynes and alkenes and (b) reactions
between enynes and alkynes, respectively (Scheme 1). Early
examples illustrating routes (a)[4] and (b)[5] were reported by
Vollhardt and co-workers making use of stoichiometric cobalt-
(a)
(b)
+
+
Type I
neutral ruthenium catalyst providing
a ready access to
cyclohexa-1,3-diene frameworks. Importantly, selectivities and
regioselectivities issues can be controlled by a suitable choice of
substituents at the propargyl carbon atom of one or both
alkyne(s) partner(s).
Type II
Scheme 1. Substrate topology for cyclohexadiene synthesis through crossed
intermolecular [2 + 2 + 2] carbocyclization
Results and Discussion
mediated processes. Rhodium-,[6] cobalt-[7] and ruthenium-
based[8] complexes proved to be catalysts of choice among
other transition-metal complexes[9] for reactions giving rise to
Type I products. These reactions were however restricted to
electron-deficient[6a,7b,8,9c-d] or strained[7a,7c] alkenes and, despite
their use in large excess, substancial alkyne trimerization
We recently disclosed the ruthenium-catalyzed hydroalkynylative
cyclizations of enynes.[18] These transformations generate five-
membered cyclic compounds featuring a 1,5-enyne subunit
through the formation of C(sp2)-H and C(sp3)-C(sp) bonds.
During these studies, we observed few cases of self-coupling of
enynes as a result of [2 + 2 + 2] cycloaddition, suggesting that
the cross-cycloaddition between enynes and alkynes would be
possible. Based on these observations, initial examination of the
carbocyclization of enynes with alkynes was performed by using
nitrogen tethered enynes 1a/1b and but-2-yne-1,4-diyl diacetate
(2a) in the presence of 5 mol% of Cp*Ru(cod)Cl in THF at 60°C.
To our delight, the targeted bicyclodiene 3aa was isolated from
[a]
R. Liu, Dr. L. Giordano, Dr. A. Tenaglia
Aix Marseille Univ, CNRS, Centrale Marseille, iSm2, Marseille,
France
E-mail: alphonse.tenaglia@univ-amu.fr
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1a in 44% yield along with the cyclodimer 4a[18] (47%) as a 4.8/1
mixture of regioisomers (the major isomer is depicted in Scheme
2). The reaction involving the enyne 1b bearing methyl
substituents at the propargyl carbon atom exclusively led to 3ba
in almost quantitative yield. At this stage, it seemed obvious that
the competitive insertion of two different alkynes in the putative
ruthenacyclopentene generated by the oxidative coupling of the
enyne 1 could be oriented towards the cross-coupling product 3
by minimizing the non-bonded interactions between the metal
ligands and the substituents at the propargyl position of alkynes.
generate the neutral complex Cp*Ru(CH3CN)2Cl[19]
which
restored the performance level at 91% yield (entry 7). Owing to
the more labile bidentate cod ligand compared to the
triphenylphosphine, Cp*Ru(cod)Cl gave the best result (entries 2
and 5). The Cp*Ru(cod)Cl catalyst loading can be lowered to 2.5
mol % to give 89% yield of 3ba, however the reaction requires
24 h (instead of 3 h) for complete conversion (entry 6). The
examination of the solvent effect of carbocyclization reaction
using Cp*Ru(cod)Cl as the catalyst revealed that the polarity of
solvent had no major influence on the catalyst efficiency. For
instance, ethyl acetate (92%), acetone (90%), DCE (88%) or
toluene (86%) can be used albeit slightly decreased yields of
3ba were observed if compared to the reaction performed in
THF (97%). However, when protic solvents such as MeOH were
used, the yield of 3ba dramatically dropped (61%). In these
conditions, an in situ generated cationic ruthenium complex is
likely to be formed and the yield of 3ba matched with the one
observed with a cationic catalyst (see entry 4). Interestingly,
water as co-solvent along with THF (1/1 v/v) was not detrimental
to the reaction since 3ba was isolated in 95% yield. We found
that 1b/2a ratio of 1/3 was convenient to obtain 3ba in high
yields and to suppress the homo-hydroalkynylative cyclization of
1,6-enyne. [18] Indeed, carrying out the reaction with a 1/1 molar
ratio 1b/2a resulted in the formation of 3ba with lower yield
(52%). Most of the excess of 2a is recovered unchanged and
isolated by chromatography for recycling. Cyclotrimer was not
detected in the crude reaction mixture by 1H NMR.
OAc
R
R
Cp*Ru(cod)Cl
(5 mol %)
R
R
OAc
OAc
+
+
TsN
TsN
TsN
THF, 60 °C, 3 h
NTs
OAc
1a R = H
2a
3aa (44%)
3ba (97%)
4a (47%) (dr 4.8/1)
1b R = Me
"
(3 equiv)
Scheme 2. Initial studies
Having identified 1b as the ideal enyne, the [2 + 2 + 2]
cycloaddition involving 2a was studied with series of
a
structurally close ruthenium complexes as catalysts. The
screening results are summarized in Table 1.
Table 1. Screening of ruthenium catalysts[a]
OAc
Having the optimal conditions in hand, the scope of enyne
substrates was then investigated. As shown in Scheme 3, a
variety of bicyclodienes 3 was easily prepared in good to
excellent yields with this simple protocol. Interestingly, the
homodimerization of enynes (< 5%) was observed in few cases
as judged by 1H NMR analysis of the crude reaction mixture.
First, variation of the substituent of double bond of enyne (R2)
showed that an electrophilic (1d) or nucleophilic (1e) functional
group was well tolerated for the [2 + 2 + 2] cycloaddition
providing the azabicycles 3da (98%) and 3ea (73%) respectively.
Interestingly the sterically demanding phenyl group, compared to
the methyl group, can be introduced at the ring junction of the
bicycle 3ca although the yield dramatically dropped to 62%.
Enynes 1f-g lacking substituent R1 were also good candidates,
furnishing adducts such as 3fa (92%) and 3ga (87%). Variation
of substitution at the propargyl carbon center of enyne (3g-h, 3k),
and groups in the nitrogen atom (3h-i) did not impact
significantly the formation of the corresponding adducts. Oxygen
and carbon containing tethered enynes could be employed as
Ru catalyst
(5 mol %)
OAc
+
TsN
TsN
THF, 60 °C, 3 h
OAc
OAc
1b
2a
3ba
Entry
Ru catalyst
Yield [%][b]
1
2
3
4
5
6
7
CpRu(PPh3)2Cl
15[c]
Cp*Ru(PPh3)2Cl
85
CpRu(CH3CN)3]PF6
[Cp*Ru(CH3CN)3]PF6
Cp*Ru(cod)Cl
Cp*Ru(cod)Cl[e]
[Cp*Ru(CH3CN)3]PF6/nBu4NCl[g]
9[d]
61
97
89[f]
91
[a] Reaction conditions: [Ru] cat. (5 mol %), 1b (1 equiv), 2a (3 equiv),
60 °C, 3 h, c = 0.1 M. [b] Isolated yields. [c] 70% of 1b was recovered. [d]
62% of 1b was recovered. [e] 2.5 mol %. [f] reaction time: 24 h. [g] 10 mol %
of nBu4NCl.
well
thus
providing
oxabicycle
3ka
(85%)
and
bicylo[4.3.0]nonadiene 3la (88%) respectively.
These results showed that the [2 + 2 + 2] cycloaddition was best
performed using electron-rich ruthenium complexes containing a
pentamethylcyclopentadienyl (Cp*) ligand rather than the
cyclopentadienyl (Cp) one (compare entries 1/2 and 3/4). The
cationic complex such as [Cp*Ru(CH3CN)3]PF6 (entry 4)
appeared less effective than the neutral ones (entries 2 and 5).
This result was supported by the reaction carried out with a
catalyst combining [Cp*Ru(CH3CN)3]PF6 with nBu4NCl to
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R1
R1
Cp*Ru(cod)Cl
(5 mol%)
R1
R1
R
R
Cp*Ru(cod)Cl
(5 mol %)
OAc
OAc
R
R
+
TsN
TsN
+
X
X
THF, 60 °C, 3 h
THF, 60 °C, 3 h
AcO
OAc
R2
R2
1b
2b-m
3
1b-l
2a
3
b X = NTs, R1 = R2 = Me
c X = NTs, R1 = Me, R2 = Ph
d X = NTs, R1= Me, R2 = CH2Cl
e X = NTs, R1 = Me, R2 = CH2TMS
f X = NTs, R1 = Me, R2 = H
g X = NTs, R1,R1= (CH2)5, R2 = H
h X = NTs, R1,R1= (CH2)5, R2 = Me
b
R = CH2OCO2Me
R = CH2OMe
R = CH2OBn
R = CH2OBoc
R = CH2OCbz
R = CH2OCOC6H4pNO2
R = CH2OCOC6H4pOMe
R = CH2OH
R = CH2Cl
R = Et
R = Ph
3bb 95%
3bc 94%
3bd 92%
3be 89%
3bf 81%
3bg 83%
3bh 93%
3bi 86%
3bj 86%
3bk 98%
3bl 21%
3bm 0%
c
d
e
f
g
h
i
j
k
l
i
X = NMs, R1 = R2 = Me
j X = NBz, R1 = R2 = Me
k X = O, R1,R1= (CH2)5, R2 = Me
l
X = C(CO2Et)2, R1 = R2 = Me
m R = TMS
OAc
OAc
OAc
OAc
OAc
TsN
TsN
Cl
TsN
OAc
Ph
3ca (62%)
TsN
NTs
3da (98%)
3ga (87%)
3ja (91%)
3ba (97%)
5
OAc
OAc
OAc
OAc
OAc
OAc
TsN
TMS
TsN
TsN
Scheme 4. Ruthenium-catalyzed [2
symmetrical alkynes 2b-m
+ 2 + 2] cycloaddition of 1b and
3ea (73%)
3fa (92%)
Interestingly, not only internal alkynes took part to the [2 + 2 + 2]
co-cyclization reaction but also terminal alkynes participated as
well under similar reaction conditions provided that a twofold
catalyst charge (10 mol %) was used (Scheme 5).
OAc
OAc
OAc
OAc
OAc
OAc
BzN
TsN
MsN
3ha (93%)
3ia (93%)
Cp*Ru(cod)Cl (10 mol %)
EtO2C
EtO2C
+
R
OAc
OAc
OAc
OAc
TsN
TsN
TsN
O
THF, 60 °C, 24 h
R
7
1b
6a-f
(3 equiv)
3ka (85%)
3la (88%)
Scheme 3. Ruthenium-catalyzed [2 + 2 + 2] cycloaddition of 1,6-enynes 1b-l
and alkyne 2a
TsN
TsN
TsN
OH
OH
HO
Ph
7bc (85%) (dr: 1/1)
7ba (86%)
7bb (70%)
To expand the scope of the intermolecular carbocyclization, the
reaction of 1b with various functionalized internal alkynes 2 was
performed under the optimized conditions (Scheme 4). Bicyclic
dienes 3bb-bk were obtained in very good to excellent yields
and protecting groups of hydroxyl group such as esters, mixed
carbonates or ethers are well compatible with our conditions.
Even functional groups such as free alcohol and chloride are
satisfactory tolerated and unactivated alkyne such as hex-3-yne
(2k) afforded 3bk in an almost quantitative yield. Interestingly,
diphenylacetylene 2l allowed the formation of 3bl, albeit in
modest yield (21%), which contrasts with similar rhodium-
catalyzed carbocyclization reactions.[13h] In this case, the major
product (61%) was the alkynylative cyclized adduct 5.[18]
Similarly, bistrimethylsilylethyne 2m, which is an excellent
partner in cobalt-catalyzed cycloadditions,[20] did not provide the
expected adduct, instead dienyne 5 was formed as the sole
product in 86% yield instead.
TsN
TsN
OH
NHTs
TMS
Ph Ph
7bd (91%)
7be (64%)
7bf (83%)
Scheme 5. Regioselective ruthenium-catalyzed [2 + 2 + 2] cycloaddition of 1b
and terminal alkynes 6a-f
On the basis of our previous observations,18 we thought that
increasing the steric bulk at the propargyl carbon atom of 6
could impact the regioselectivity even though the selectivity of
the reaction (self-coupling vs cross-coupling) might be eroded.
Gratifyingly, tertiary propargyl alcohols 6a-d afforded adducts
7ba-bd as single regioisomers although the reactions required
24 hours for complete conversion. This trend was also observed
with the tertiary propargyl sulfonamide 6e[21] and alkyne 6f
featuring the bulky trimethylsilyl group which afforded 7be (64%)
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and
dienylsilane 7bf[18]
(83%). We wondered on the
regioselectivity observed in these reactions specially for cases
involving tertiary propargyl alcohols insofar as the coordination
of free hydroxyl group to ruthenium was invoked in a number of
catalytic reactions involving this class of substrates.[22] Indeed,
performing the reaction of 3-methoxy-3-methylbut-1-yne (6g)[23]
with 1b resulted in loss of both regio- and chemoselectivity thus
leading to bicyclic dienes 7bg/7bg’ (63%, 0.83/1 ratio of
TsN
TsN
TsN
Scheme 9. Non-suitable enynes for ruthenium-catalyzed [2
+ 2 + 2]
cycloaddition
A mechanism rationale involving ruthenacycles as intermediates
is depicted in Scheme 10. The catalytic cycle I starts with the
dissociation of the weakly coordinated cod ligand from the
ruthenium allowing intramolecular coordination of both triple and
double bonds of enyne. Oxidative cyclization gave the bicyclic
ruthenacyclopentene intermediate A which upon coordination of
alkyne 2 to the ruthenium centre (B), followed by its insertion
generated the ruthenacycloheptadiene C. Finally, reductive
elimination released the bicyclic product and regenerated the
active metal species. An alternative mechanism (II) leading to
intermediate C might involve first intermolecular coordination of
the alkyne reactants (D) to form ruthenacyclopentadiene E and
subsequent insertion of the pendant olefin. At this point, it
cannot be obvious to privilege one of the two pathways.
However, on the basis of the hydroalkynylative cyclization of
enyne 1b,[18] achieved in the absence of 2a, we are inclined to
favor mechanism path I.
regioisomers) and 1,5-enyne
8
(34%) arising from the
alkynylative coupling reaction[18] (Scheme 6). The structure of
regioisomer 7bg’ was confirmed by single crystal X-ray
diffraction analysis.[24]
TsN
+
Cp*Ru(cod)Cl
(10 mol %)
OMe
OMe
TsN
+
OMe
TsN
+
TsN
1b
6g
THF, 60 °C, 3 h
7bg
7bg'
7bg/7bg' (63%, 0.83/1)
OMe
8 (34%)
Scheme 6. Ru-catalyzed coupling of 1b and 6g
Further scope of the reaction was examined with variation of
substitution either on the enyne or alkyne. Loss of
regioselectivity was observed in coupling reactions involving
phenylethyne 6h and primary propargyl alcohols 6i and 9
(Scheme 7). The pair of regioisomers 7bi/7bi’ and 10/10’ were
separated by chromatography and fully characterized by
spectroscopic means. Enyne 11[25] with monosubstitution at
propargyl carbon participate equally in the coupling reaction with
TsN
1b + 2
1b
R
TsN
[Ru]
R
[Ru]
R
TsN
A
R
2a
and
yielded
bicyclohexadiene
12
with
poor
D
2
diastereoselectivity (Scheme 8). Examination of enynes
featuring internal alkyne or 1,2-disubstituted alkene as well as
1,7-enyne failed to give cycloadducts with 2a. Representative
examples of such substrates are given in Scheme 9.
Cp*Ru(cod)Cl
Cp*RuCl
II
R
R
cod
TsN
TsN
I
[Ru]
R
[Ru]
TsN
R
R
B
R
TsN
E
R
R
Ph
Ph
6h
[Ru]
+
TsN
TsN
C
Ph
Conditions:
1b/alkyne 1/3
Cp*Ru(cod)Cl
(5 mol %)
7bh
7bh'
TsN
7bh/7bh' (85%, 3/1)
Scheme 10. Mechanism of the [2+2+2] intermolecular carbocyclization
THF, 60 °C, 3 h
R
OH
1b
+
TsN
TsN
OH
R
R
OH
The origin of the regioselectivity observed with tertiary
propargylic alcohols (Scheme 5) can be ascribed to the notion of
interligand interactions through hydrogen bonding of the
hydroxyl proton to a chloride ligand of the RuCl fragment,
recently introduced by Fürstner[26] (Scheme 11). This allowed to
control the orientation of alkynol insertion within the ruthenacycle
(B → C, Scheme 10). According to the mechanisms depicted in
Scheme 10, intermediates F-H can be considered from the initial
couplings of of enyne 1b and 6a but only F and G might lead to
the formation of the cycloadduct 7ba (Scheme 11). As the less
congested ruthenacyclopentadiene H, compared to G, is
catalytically inoperative, again we are inclined to favor the
mechanism through ruthenacyclopentene. In analogy with
intermediate F, the interaction between the chloride of [Ru]Cl
6i R = H
9
7bi (49%)
10 (49%)
7bi' (48%)
10' (38%)
R = Ph
Scheme 7. Ruthenium-catalyzed [2 + 2 + 2] cycloaddition of 1b with terminal
arylalkyne 6h or primary propargyl alcohols 6i and 9
OAc
Cp*Ru(cod)Cl
(5 mol %)
OAc
OAc
+
TsN
TsN
THF, 60 °C, 3 h
OAc
12
66% (dr 1.5/1)
11
2a
Scheme 8. Ruthenium-catalyzed [2 + 2 + 2] cycloaddition of 11 with 2a
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fragment with the TMS group of alkyne 6f[26] might explain the
formation of 7bf.
functional groups. The chemo- and regioselectivity of the
reaction is controlled by a suitable choice of substituents at the
propargyl carbon(s) atom(s) of the reactants. The latent
functions within these bicylic building blocks provide
opportunities for chemical transformations into more complex
and/or functionalized polycyclic molecules in a limited number of
steps as illustrated with the generation of the tetracyclic
structure 13 and aldehyde 14.
Ts
N
6a
6f
Ru
O
TsN
TsN
TsN
[Ru]
Cl
[Ru]
SiMe3
Cl
O
H
Cl
Ru
Cl
H
O
H
F
G
H
I
7bf
7ba
Scheme 11. Possible intermediates for the regioselectivity control
Experimental Section
To get insights on initial intermediates formed in the coupling
reactions, we attempted the stoichiometric reaction of 1b with 6b
and one molar equivalent of Cp*Ru(cod)Cl. Unfortunately, no
metalacycle intermediate was detected and we observed the
fast formation of 7bb just after data aquisition by NMR.
All reactions, unless otherwise stated, were carried out under argon
atmosphere using oven-dried (120 °C) glassware. Reaction solvents
were purified according to the standard procedures[27] and degased
before use. All ruthenium complexes were purchased and used as
received. 1H NMR spectra were measured with 300 and 400 MHz
spectrometers as solutions in deuterochloroform (CDCl3), unless
otherwise indicated. Chemicals shifts are given in parts per million (δ
units) downfield from tetramethylsilane using the residual solvent signal
(CHCl3 7.26) as internal standard. 1H NMR information is given in the
following format: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; qui,
quintet; sept, septet; m, multiplet), coupling constant(s) (J) in Hertz (Hz),
number of protons. The prefix app is occasionally applied when the true
signal multiplicity was unresolved and br indicates the signal in question
broadened. 13C NMR spectra are reported in ppm (δ) relative to residual
CHCl3 (77.4) unless otherwise noted. Ruthenium complexes and alkynes
2c, 2i-m were supplies from commercial sources. High-resolution mass
spectra (HRMS) were performed at the “Spectropôle” of Aix-Marseille
Université.
Chemical transformations into more complex ring-fused
polycycles were briefly examined (Scheme 12). Thus, the
treatment of adduct 7bd in toluene solution with camphorsulfonic
acid (CSA) at 60 °C provided the tetracyclic structure 13 in 74%
isolated yield through the dehydrative cyclization of
a
pentadienyl-like cation intermediate. Additionally, conversion of
diol 3bi to the conjugated aldehyde 14 (48%) occurred smoothly
at room temperature in the presence of CSA. The location of the
formyl group was ascertained by Noesy experiments.
Interestingly, the formation of 14 as a single regioisomer could
be rationalized on the basis of the preferred generation of a
pentadienyl cation intermediate and subsequent release of a
proton.
But-2-yne-1,4-diyl dimethyl bis(carbonate) (2b).[28] Methyl chloformate
(2.27 g, 24 mmol) was added dropwise to a solution of 2-butyne-1,4-diol
(861 mg, 10 mmol), 4-dimethylaminopyridine (122 mg, 1 mmol) and
triethylamine (4 g, 40 mmol) in dry dichloromethane (50 mL) at 0 °C. The
mixture was stirred at room temperature overnight, then was washed with
10% HCl solution (50 mL), brine (30 mL), dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by flash chromatography
on silica gel to afford 1.8 g (91%) of the title compound as a white
semisolid. Rf (PE/Et2O 4/6) 0.35. 1H NMR (400 MHz, CDCl3) δ 4.77 (m,
4H), 3.81 (m, 6H). 13C NMR (101 MHz, CDCl3) δ 155.1 (C), 80.9 (C), 55.2
(CH3), 55.1 (CH2).
CSA (1 equiv)
TsN
TsN
OH
Ph Ph
toluene, 60 °C, 5 h
Ph
13 (74%)
7bd
CHO
CSA (1 equiv)
toluene, rt, 2 d
OH
OH
TsN
TsN
[29]
1,4-Bis(benzyloxy)but-2-yne (2d).
2-Butyne-1,4-diol (861 mg, 10
mmol) was added dropwise to a suspension of NaH (880 mg, 22 mmol,
60 % dispersion in mineral oil) in dry THF (50 mL) at 0 °C. The mixture
was stirred for 1 h, and then benzyl bromide (4.1 g, 24 mmol) was added
dropwide. The mixture was warmed to rt and stirred until completion
(TLC monitoring), diluted with a saturated aqueous NH4Cl (30 mL),
extracted with diethyl ether (3 x 15 mL). The combined extracts were
washed with brine (30 mL), dried over Na2SO4, and concentrated in
vacuo. The residue was purified by flash chromatography on silica gel to
afford 1.7 g (65%) of the title compound as a colorless oil. Rf (PE/Et2O
4/1) 0.45. 1H NMR (300 MHz, CDCl3) δ 7.47–7.28 (m, 10H), 4.64 (s, 4H),
4.27 (s, 4H). 13C NMR (75 MHz, CDCl3) δ 137.6 (C), 128.6 (CH), 128.2
(CH), 128.0 (CH), 82.8 (C), 71.8 (CH2), 57.6 (CH2).
14 (48%)
3bi
+ H+
- H+
OH
+
TsN
- H2O
Scheme 12. Synthetic transformations of cycloadducts 3bi and 7bd
Conclusions
In summary, the crossed intermolecular ruthenium-catalyzed [2
+ 2 + 2] carbocyclization reactions between 1,6-enynes with
alkynes has been developed. This catalytic reaction provides a
facile access to bicyclohexadienes containing a quaternary
center at the ring junction and tolerates a wide range of
But-2-yne-1,4-diyl di-tert-butyl bis(carbonate) (2e). [30] A solution of di-
tert-butyl dicarbonate (5.24 g, 24 mmol) in dichloromethane (25 mL) was
added to
a solution of 2-butyne-1,4-diol (861 mg, 10 mmol), 4-
dimethylaminopyridine (122 mg, 1 mmol) and triethylamine (4 g, 40
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mmol) in dichloromethane (50 mL). The mixture was stirred overnight,
then washed with 10% HCl solution (50 mL), brine (30 mL), dried over
Na2SO4, filtered and concentrated in vacuo. The residue was purified by
flash chromatography on silica gel to afford 2.1 g (73%) of the title
compound as a colorless oil. Rf (PE/Et2O 1/1) 0.35. 1H NMR (300 MHz,
CDCl3) δ 4.68 (s, 4H), 1.47 (s, 18H). 13C NMR (101 MHz, CDCl3) δ 152.9
(C), 83.0 (C), 81.1 (C), 54.6 (CH2), 27.8 (CH3).
4.70 (d, J = 12.4 Hz, 1H), 4.62 (d, J = 12.4 Hz, 1H), 4.54 (d, J = 12.5 Hz,
1H), 4.20 (dd, J = 15.6, 2.1 Hz, 1H), 3.75 (d, J = 15.6 Hz, 1H), 3.54 (d, J
= 9.0 Hz, 1H), 2.78 (d, J = 9.0 Hz, 1H), 2.43 (s, 3H), 2.20 (s, 2H), 2.03 (s,
3H), 2.02 (s, 3H), 0.99 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 171.1 (C),
144.1 (C), 144.0 (C), 133.2 (C), 130.1 (CH), 129.2 (C), 128.7 (C), 128.0
(CH), 116.9 (CH), 63.4 (CH2), 62.1 (CH2), 62.0 (CH2), 50.2 (CH2), 41.5
(C), 37.6 (CH2), 21.9 (CH3), 21.6 (CH3), 21.2 (CH3), 21.1 (CH3). HRMS
(ESI-MS) calcd. for C22H28NO6S+ ([M+H]+): 434.1632, found 434.1627.
Dibenzyl but-2-yne-1,4-diyl bis(carbonate) (2f). Benzyl chloroformate
(4.09 g, 24 mmol) was added to a solution of 2-butyne-1,4-diol (861 mg,
10 mmol), 4-dimethylaminopyridine (122 mg, 1 mmol) and triethylamine
(4 g, 40 mmol) in dichloromethane (50 mL) at 0 °C. The resulting mixture
was stirred overnight at room temperature, washed with 10% HCl
solution (50 mL), brine (30 mL), dried over Na2SO4, filtered and
concentrated in vacuo. The residue was purified by flash chromatography
on silica gel to afford 2.4 g (69%) of the title compound as a white solid,
mp 74–75 °C. Rf (PE/Et2O 3/2) 0.45. IR (neat) ν 3034, 2955, 1744, 1497,
1389, 1223, 1153, 932, 910, 751, 694, 576 cm-1. 1H NMR (300 MHz,
CDCl3) δ 7.40–7.31 (m, 10H), 5.19 (s, 4H), 4.78 (s, 4H). 13C NMR (75
MHz, CDCl3) δ 154.8 (C), 135.2 (C), 128.9 (CH), 128.9 (CH), 128.6 (CH),
(1,1,3a-Trimethyl-2-tosyl-2,3,3a,4-tetrahydro-1H-isoindole-5,6-
diyl)bis(methylene) diacetate (3ba). General Procedure B afforded
89.5 mg (97%) of the title compound as a colorless oil. Rf (PE/Et2O 4/6)
0.35. IR (neat) ν 3055, 2979, 2254, 1733, 1353, 1264, 1091, 907, 727
1
cm-1. H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.3 Hz, 2H), 7.27 (d, J =
8.9 Hz, 2H), 5.65 (s, 1H), 4.80 (d, J = 12.5 Hz, 1H), 4.74 (d, J = 12.4 Hz,
1H), 4.66 (d, J = 12.4 Hz, 1H), 4.57 (d, J = 12.5 Hz, 1H), 3.40 (d, J = 9.2
Hz, 1H), 3.01 (d, J = 9.2 Hz, 1H), 2.41 (s, 3H), 2.20–2.14 (m, 2H), 2.04 (s,
3H), 2.03 (s, 3H), 1.69 (s, 3H), 1.46 (s, 3H), 0.96 (s, 3H). 13C NMR (75
MHz, CDCl3) δ 171.0 (C), 156.6 (C), 143.2 (C), 138.2 (C), 129.6 (CH),
129.4 (C), 128.7 (C), 127.7 (CH), 115.3 (CH), 67.3 (C), 63.3 (CH2), 62.1
(CH2), 60.8 (CH2), 39.5 (C), 38.4 (CH2), 31.1 (CH3), 28.4 (CH3), 21.9
(CH3), 21.7 (CH3), 21.1 (CH3), 20.9 (CH3). HRMS (ESI-MS) calcd. for
C24H32NO6S+ ([M+H]+): 462.1945, found 462.1947.
+
81.3 (C), 70.4 (CH2), 55.7 (CH2). HRMS (ESI-MS) calcd. for C20H22NO6
([M+NH4]+): 372.1442, found 372.1442.
General Procedure for Acylation of 2-butyne-1,4-diol (A). Acyl
chloride (24 mmol) was added dropwise to a solution of 2-butyne-1,4-diol
(861 mg, 10 mmol), 4-dimethylaminopyridine (122 mg, 1 mmol) and
triethylamine (4 g, 40 mmol) in dry dichloromethane (50 mL) at 0 °C. The
resulting mixture was stirred overnight at room temperature, washed with
10% HCl solution (50 mL), brine (30 mL), dried over Na2SO4, filtered and
concentrated in vacuo. The residue was purified by flash chromatography
on silica gel.
(1,1-Dimethyl-3a-phenyl-2-tosyl-2,3,3a,4-tetrahydro-1H-isoindole-5,6-
diyl)bis(methylene) diacetate (3ca). General Procedure B afforded 64.9
mg (62%) of the title compound as a colorless oil. Rf (PE/Et2O 4/6) 0.43.
IR (neat) ν 2932, 2868, 2252, 1734, 1218, 1090, 1023, 728, 581 cm-1. 1H
NMR (400 MHz, CDCl3) δ 7.28 (d, J = 8.3 Hz, 2H), 7.19–7.11 (m, 5H),
6.99 (d, J = 8.0 Hz, 2H), 6.11 (s, 1H), 4.79 (d, J = 12.4 Hz, 1H), 4.69 (d, J
= 12.4 Hz, 1H), 4.56 (d, J = 12.5 Hz, 1H), 4.31 (d, J = 12.5 Hz, 1H), 4.16
(d, J = 10.0 Hz, 1H), 3.49 (d, J = 10.0 Hz, 1H), 2.57 (d, J = 16.1 Hz, 1H),
2.52 (d, J = 16.1 Hz, 1H), 2.32 (s, 3H), 2.05 (s, 3H), 1.64 (s, 3H), 1.62 (s,
3H), 1.53 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 170.9 (C), 170.5 (C),
152.7 (C), 142.8 (C), 140.7 (C), 138.6 (C), 130.6 (C), 129.3 (CH), 129.1
(C), 128.3 (CH), 127.1 (CH), 127.1 (CH), 127.0 (CH), 119.4 (CH), 66.8
(C), 62.6 (CH2), 61.9 (CH2), 61.4 (CH2), 48.0 (C), 40.4 (CH2), 29.1 (CH3),
29.0 (CH3), 21.6 (CH3), 21.1 (CH3), 20.7 (CH3). HRMS (ESI-MS) calcd.
for C29H34NO6S+ ([M+H]+): 524.2101, found 524.2101.
But-2-yne-1,4-diyl bis(4-nitrobenzoate) (2g). The above procedure
afforded 2.8 g (72%) of the title compound as a white solid, mp 148–
149 °C. Rf (Et2O) 0.40. IR (neat) ν 3113, 2913, 1729, 1522, 1344, 1262,
1094, 944, 878, 718 cm-1. 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 8.9
Hz, 4H), 8.25 (d, J = 9.0 Hz, 4H), 5.05 (s, 4H). 13C NMR (75 MHz, CDCl3)
δ 164.2 (C), 151.1 (C), 135.0 (C), 131.3 (CH), 123.9 (CH), 81.3 (C), 53.6
+
(CH2). HRMS (ESI-MS) calcd. for C18H16N3O8 ([M+NH4]+): 402.0932,
found 402.0928.
But-2-yne-1,4-diyl bis(4-methoxybenzoate) (2h). The above procedure
afforded 2.9 g (82%) of the title compound as a white solid, mp 117–
118 °C. Rf (PE/AcOEt 4/1) 0.35. IR (neat) ν 2933, 2846, 1701, 1606,
1512, 1444, 1310, 1269, 1260, 1161, 1101, 842, 765, 693, 615 cm-1. 1H
NMR (300 MHz, CDCl3) δ 8.02 (d, J = 8.4 Hz, 4H), 6.92 (d, J = 8.4 Hz,
4H), 4.96 (s, 4H), 3.86 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 164.9 (C),
163.0 (C), 131.3 (CH), 121.2 (C), 113.1 (CH), 80.4 (C), 54.8 (CH3), 51.7
(3a-(Chloromethyl)-1,1-dimethyl-2-tosyl-2,3,3a,4-tetrahydro-1H-
isoindole-5,6-diyl)bis(methylene) diacetate (3da). General Procedure
B afforded 97.2 mg (98%) of the title compound as a colorless oil. Rf
(PE/Et2O 4/6) 0.35. IR (neat) ν 2975, 2871, 1735, 1364, 1220, 1150,
1112, 1089, 991, 728, 576 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J =
8.3 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 5.81 (s, 1H), 4.83 (d, J = 12.7 Hz,
1H), 4.76 (dd, J = 12.5, 1.7 Hz, 1H), 4.67 (d, J = 12.5 Hz, 1H), 4.51 (d, J
= 12.7 Hz, 1H), 3.91 (d, J = 10.2 Hz, 1H), 3.22 (dd, J = 10.9, 1.6 Hz, 1H),
3.17 (d, J = 10.9 Hz, 1H), 2.97 (dd, J = 10.2, 1.6 Hz, 1H), 2.78 (d, J =
17.0 Hz, 1H), 2.41 (s, 3H), 2.05 (s, 3H), 2.03 (s, 3H), 2.01 (br s, 1H), 1.61
(s, 3H), 1.49 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 171.0 (C), 170.9 (C),
152.3 (C), 143.5 (C), 138.4 (C), 129.8 (CH), 129.6 (C), 129.5 (C), 127.4
(CH), 118.8 (CH), 66.9 (C), 62.6 (CH2), 61.9 (CH2), 56.0 (CH2), 44.7 (C),
44.2 (CH2), 32.4 (CH2), 30.3 (CH3), 28.9 (CH3), 21.7 (CH3), 21.2 (CH3),
21.1 (CH3). HRMS (ESI-MS) calcd. for C24H31ClNO6S+ ([M+H]+):
496.1555, found 496.1553.
+
(CH2). HRMS (ESI-MS) calcd. for C20H19O6 ([M+H]+): 355.1176, found
355.1172.
General Procedure of the Ru(II)-catalyzed Coupling Reaction of
Enynes and Alkynes (B). A solution of 1, 6-enyne (0.2 mmol) and
alkyne (0.6 mmol) in THF (0.5 mL) was added to
a solution of
Cp*Ru(cod)Cl (3.80 mg, 0.01 mmol) in THF (0.5 mL). The mixture was
stirred at 60 °C until completion of the reaction (TLC monitoring), cooled
to room temperature, filtered over celite, and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel.
(1,1-Dimethyl-2-tosyl-3a-((trimethylsilyl)methyl)-2,3,3a,4-tetrahydro-
(3a-methyl-2-tosyl-2,3,3a,4-tetrahydro-1H-isoindole-5,6-
1H-isoindole-5,6-diyl)bis(methylene)
diacetate
(3ea).
General
diyl)bis(methylene)diacetate (3aa). General Procedure B afforded 38.1
mg (44%) of the title compound as colorless oil. Rf (PE/Et2O 1/1) 0.30. IR
(neat) ν 2960, 2862, 1734, 1376, 1221, 1161, 1092, 1021, 817, 711, 664,
Procedure B afforded 77.9 mg (73%) of the title compound as a colorless
oil. Rf (PE/Et2O 4/6) 0.38. IR (neat) ν 2976, 2869, 2257, 1733, 1364,
1221, 1141, 1023, 959, 729 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J
= 8.3 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 5.59 (s, 1H), 4.71–4.69 (m, 4H),
3.45 (d, J = 9.3 Hz, 1H), 2.94 (dd, J = 9.3, 2.0 Hz, 1H), 2.40 (s, 3H), 2.32
1
601, 549 cm-1. H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.2 Hz, 2H), 7.33
(d, J = 7.9 Hz, 2H), 5.70 (t, J = 2.1 Hz, 1H), 4.77 (d, J = 12.5 Hz, 1H),
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(d, J = 16.9 Hz, 1H), 2.20 (d, J = 16.9 Hz, 1H), 2.04 (s, 3H), 2.03 (s, 3H),
1.76 (s, 3H), 1.47 (s, 3H), 0.88 (dd, J = 14.9, 2.0 Hz, 1H), 0.72 (dd, J =
14.9, 1.3 Hz, 1H), -0.12 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 171.0 (C),
171.0 (C), 158.5 (C), 143.4 (C), 138.1 (C), 130.1 (C), 129.7 (CH), 128.4
(C), 127.9 (CH), 114.3 (CH), 67.0 (C), 63.7 (CH2), 62.3 (CH2), 59.8 (CH2),
41.9 (C), 38.1 (CH2), 31.4 (CH3), 28.7 (CH3), 23.1 (CH2), 21.7 (CH3), 21.1
(CH3). 0.7 (CH3). HRMS (ESI-MS) calcd. for C27H40NO6SSi+ ([M+H]+):
534.2340, found 534.2339.
2.05 (s, 3H), 2.05 (s, 3H), 1.64 (s, 3H), 1.52 (s, 3H), 1.12 (s, 3H). 13C
NMR (75 MHz, CDCl3) δ 171.0 (C), 156.2 (C), 129.4 (C), 128.8 (C), 115.7
(CH), 66.6 (C), 63.3 (CH2), 62.1 (CH2), 61.1 (CH2), 40.3 (CH3), 39.4 (C),
38.4 (CH2), 30.9 (CH3), 28.2 (CH3), 22.2 (CH3), 21.1 (CH3), 21.0 (CH3).
HRMS (ESI-MS) calcd. for C18H31N2O6S+ ([M+NH4]+): 403.1897, found
403.1897.
(2-Benzoyl-1,1,3a-trimethyl-2,3,3a,4-tetrahydro-1H-isoindole-5,6-
diyl)bis(methylene) diacetate (3ja). General Procedure B afforded 74.9
mg (91%) of the title compound as a colorless oil. Rf (PE/Et2O 1/1) 0.36.
(1,1-Dimethyl-2-tosyl-2,3,3a,4-tetrahydro-1H-isoindole-5,6-
diyl)bis(methylene) diacetate (3fa). General Procedure B afforded 82.3
mg (92%) of the title compound as a colorless oil. Rf (PE/Et2O 2/3) 0.37.
IR (neat) ν 2995, 2938, 1717, 1410, 1229, 1159, 1086, 723, 589 cm-1. 1H
NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.0 Hz,
2H), 5.69 (d, J = 2.7 Hz, 1H), 4.79 (d, J = 12.6 Hz, 1H), 4.72 (dd, J = 12.4,
1.4 Hz, 1H), 4.65 (d, J = 12.4 Hz, 1H), 4.57 (d, J = 12.6 Hz, 1H), 3.82 (t, J
= 7.8 Hz, 1H), 3.01–2.88 (m, 2H), 2.41 (s, 4H), 2.04 (s, 6H), 2.02 – 1.99
(m, 1H), 1.59 (s, 3H), 1.53 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 171.0 (C),
171.0 (C), 151.8 (C), 143.3 (C), 138.3 (C), 130.4 (C), 129.7 (CH), 129.6
(C), 127.6 (CH), 115.8 (CH), 67.3 (C), 63.2 (CH2), 62.2 (CH2), 54.0 (CH2),
36.0 (CH), 30.6 (CH2), 30.5 (CH3), 27.3 (CH3), 21.7 (CH3), 21.1 (CH3).
HRMS (ESI-MS) calcd. for C23H29NO6SNa+ ([M+Na]+): 470.1608, found
470.1607.
IR (neat) ν 2974, 2891, 2252, 1734, 1628, 1445, 1225, 904, 723, 647 cm-
1
.
1H NMR (400 MHz, CDCl3) δ 7.37 (s, 5H), 5.76 (s, 1H), 4.81 (d, J =
12.5 Hz, 1H), 4.78 (d, J = 12.4 Hz, 1H), 4.69 (d, J = 12.4 Hz, 1H), 4.58 (d,
J = 12.5 Hz, 1H), 3.49–3.44 (m, 1H), 3.20 (d, J = 10.7 Hz, 1H), 2.23 (d, J
= 16.4 Hz, 1H), 2.13 (d, J = 16.4 Hz, 1H), 2.06 (s, 3H), 2.02 (s, 3H), 1.83
(s, 3H), 1.64 (s, 3H), 1.09 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 170.9 (C),
170.9 (C), 170.2 (C), 157.1 (C), 138.9 (C), 129.4 (C), 129.3 (CH), 128.6
(CH), 128.2 (C), 126.3 (CH), 115.1 (CH), 64.6 (C), 63.3 (CH2), 62.9 (CH2),
62.1 (CH2), 39.7 (C), 38.4 (CH2), 29.2 (CH3), 26.1 (CH3), 22.1 (CH3), 21.0
+
(CH3), 20.8 (CH3). HRMS (ESI-MS) calcd. for C24H30NO5 ([M+H]+):
412.2118, found 412.2118.
(3a'-Methyl-3a',4'-dihydro-3'H-spiro[cyclohexane-1,1'-
isobenzofuran]-5',6'-diyl)bis(methylene) diacetate (3ka). General
Procedure B afforded 59.2 mg (85%) of the title compound as a colorless
oil. Rf (PE/Et2O 4/1) 0.45. IR (neat) ν 2932, 2855, 2255, 1734, 1375,
1221, 1021, 959, 727 cm-1. 1H NMR (400 MHz, CDCl3) δ 5.64 (s, 1H),
4.83 (d, J = 12.4 Hz, 1H), 4.79 (dd, J = 12.3, 1.3 Hz, 1H), 4.70 (d, J =
12.3 Hz, 1H), 4.61 (d, J = 12.4 Hz, 1H), 3.83 (d, J = 8.3 Hz, 1H), 3.51 (d,
J = 8.3 Hz, 1H), 2.25 (d, J = 16.4 Hz, 1H), 2.16 (d, J = 16.4 Hz, 1H), 2.07
(s, 3H), 2.06 (s, 3H), 1.80–1.51 (m, 8H), 1.30–1.21 (m, 2H), 1.06 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 170.7 (C), 170.7 (C), 157.3 (C), 129.5 (C),
128.1 (C), 113.6 (CH), 82.3 (C), 77.8 (CH2), 63.2 (CH2), 62.0 (CH2), 42.1
(C), 38.4 (CH2), 37.1 (CH2), 35.5 (CH2), 25.2 (CH2), 22.4 (CH2), 22.1
(CH2), 21.2 (CH3), 20.8 (CH3), 20.7 (CH3). HRMS (ESI-MS) calcd. for
C20H32NO5+ ([M+NH4]+): 366.2275, found 366.2275.
(2'-Tosyl-2',3',3a',4'-tetrahydrospiro[cyclohexane-1,1'-isoindole]-
5',6'-diyl)bis(methylene) diacetate (3ga). General Procedure B afforded
84.8 mg (87%) of the title compound as a colorless oil. Rf (PE/Et2O 4/6)
0.33. IR (neat) ν 2925, 2869, 1736, 1376, 1221, 1155, 1044, 663, 588
1
cm-1. H NMR (300 MHz, CDCl3) δ 7.65 (d, J = 8.0 Hz, 2H), 7.19 (d, J =
7.9 Hz, 2H), 6.07 (s, 1H), 4.74–4.49 (m, 4H), 3.70 (t, J = 8.1 Hz, 1H),
2.95–2.77 (m, 2H), 2.55–2.45 (td, J = 12.5, 4.6 Hz, 2H), 2.34 (s, 3H),
2.30–2.25 (m, 1H), 1.98 (s, 3H), 1.97 (s, 3H), 1.80–1.75 (m, 1H), 1.67–
1.41 (m, 7H), 1.35–1.19 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 171.1 (C ),
149.6 (C), 143.1 (C), 139.2 (C), 130.6 (C), 129.7 (CH), 129.5 (C), 127.5
(CH), 118.5 (CH), 70.9 (C), 63.2 (CH2), 62.5 (CH2), 53.8 (CH2), 36.7 (CH),
36.1 (CH2), 35.2 (CH2), 30.7 (CH2), 24.7 (CH2), 22.9 (CH2), 21.8 (CH3),
21.2 (CH3), 21.2 (CH3). HRMS (ESI-MS) calcd. for C26H37N2O6S+
([M+NH4]+): 505.2367, found 505.2368.
Diethyl 5,6-bis(acetoxymethyl)-1,1,3a-trimethyl-1,3,3a,4-tetrahydro-
2H-indene-2, 2-dicarboxylate (3la). General Procedure B afforded 79.3
mg (88%) of the title compound as a colorless oil. Rf (PE/Et2O 3/1) 0.40.
IR (neat) ν 2913, 2900, 1796, 1431, 1185,1025, 997, 835, 775, 564 cm-1.
1H NMR (400 MHz, CDCl3) δ 5.61 (s, 1H), 4.81 (d, J = 12.5 Hz, 1H),
4.75–4.68 (m, 2H), 4.50 (d, J = 12.5 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H),
4.10 (qd, J = 7.2, 1.5 Hz, 2H), 2.60–2.54 (m, 2H), 2.05 (s, 3H), 2.04 (s,
3H), 2.03 (d, J = 16.4 Hz, 1H), 1.98 (d, J = 16.4 Hz, 1H), 1.38 (s, 3H),
1.29 (t, J = 7.1 Hz, 3H), 1.22–1.13 (m, 9H). 13C NMR (75 MHz, CDCl3) δ
171.8 (C), 171.19 (C), 171.15 (C), 170.7 (C), 158.5 (C), 129.8 (C), 129.6
(C), 114.8 (CH), 68.0 (C), 63.5 (CH2), 62.4 (CH2), 61.3 (CH2), 61.2 (CH2),
48.3 (C), 44.3 (CH2), 41.6 (CH2), 38.8 (C), 26.5 (CH3), 25.9 (CH3), 23.2
(CH3), 21.3 (CH3), 21.1 (CH3), 14.4 (CH3), 14.2 (CH3). HRMS (ESI-MS)
calcd. for C24H38NO8+ ([M+NH4]+): 468.2592, found 468.2593.
(3a'-Methyl-2'-tosyl-2',3',3a',4'-tetrahydrospiro[cyclohexane-1,1'-
isoindole]-5',6'-diyl)bis(methylene)
diacetate
(3ha).
General
Procedure B afforded 93.3 mg (93%) of the title compound as a colorless
oil. Rf (PE/Et2O 2/3) 0.33. IR (neat) ν 2931, 2872, 2255, 1733, 1225,
1154, 905, 724, 603 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.3
Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 6.10 (s, 1H), 4.79 (d, J = 12.5 Hz, 1H),
4.74 (d, J = 12.4 Hz, 1H), 4.69 (d, J = 12.4 Hz, 1H), 4.56 (d, J = 12.5 Hz,
1H), 3.26 (d, J = 9.3 Hz, 1H), 3.10 (d, J = 9.3 Hz, 1H), 2.87–2.79 (m, 1H),
2.47–2.42 (m, 1H), 2.40 (s, 3H), 2.22 (d, J = 16.3 Hz, 1H), 2.10 (d, J =
16.3 Hz, 1H), 2.03 (s, 3H), 2.02 (s, 3H), 1.85 (d, J = 13.0 Hz, 1H), 1.74–
1.59 (m, 6H), 1.42–1.33 (m, 1H), 0.86 (s, 3H). 13C NMR (75 MHz, CDCl3)
δ 171.0 (C), 170.9 (C), 154.4 (C), 143.1 (C), 138.8 (C), 129.6 (C), 129.6
(CH), 128.6 (C), 127.5 (CH), 117.9 (CH), 70.8 (C), 63.2 (CH2), 62.4 (CH2),
60.3 (CH2), 40.2 (C), 38.3 (CH2), 36.3 (CH2), 36.1 (CH2), 24.5 (CH2), 22.7
(CH2), 22.2 (CH2), 22.1 (CH3), 21.7 (CH3), 21.1 (CH3), 20.9 (CH3). HRMS
(ESI-MS) calcd. for C27H36NO6S+ ([M+H]+): 502.2258, found 502.2258.
Dimethyl ((1,1,3a-trimethyl-2-tosyl-2,3,3a,4-tetrahydro-1H-isoindole-
5,6-diyl) bis(methylene)) bis(carbonate) (3bb). General Procedure B
afforded 93.8 mg (95%) of the title compound as a colorless oil. Rf
(PE/Et2O 1/1) 0.30. IR (neat) ν 2998, 2890, 1710, 1495, 1220, 1106, 895,
698 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz, 2H), 7.27 (d, J
= 8.1 Hz, 2H), 5.69 (s, 1H), 4.88 (d, J = 12.5 Hz, 1H), 4.85 (d, J = 12.3 Hz,
1H), 4.73 (d, J = 12.3 Hz, 1H), 4.63 (d, J = 12.5 Hz, 1H), 3.76 (s, 3H),
3.75 (s, 3H), 3.40 (d, J = 9.2 Hz, 1H), 3.00 (d, J = 9.2 Hz, 1H), 2.40 (s,
3H), 2.23 (s, 2H), 1.68 (s, 3H), 1.45 (s, 3H), 0.96 (s, 3H). 13C NMR (75
MHz, CDCl3) δ 157.2 (C), 155.9 (C), 155.8 (C), 143.3 (C), 138.2 (C),
129.7 (CH), 129.5 (C), 128.7 (C), 127.7 (CH), 115.0 (CH), 67.4 (C), 66.6
(CH2), 65.4 (CH2), 60.7 (CH2), 55.2 (CH3), 39.4 (C), 38.2 (CH2), 31.0
(1,1,3a-Trimethyl-2-(methylsulfonyl)-2,3,3a,4-tetrahydro-1H-
isoindole-5,6-diyl)bis(methylene) diacetate (3ia). General Procedure B
afforded 71.7 mg (93%) of the title compound as a colorless oil. Rf
(PE/Et2O 3/7) 0.35. IR (neat) ν 2998, 2819, 2254, 1761, 1395, 1210,
1159, 1034, 719, 537 cm-1. 1H NMR (400 MHz, CDCl3) δ 5.70 (s, 1H),
4.83 (d, J = 12.5 Hz, 1H), 4.78 (d, J = 12.4 Hz, 1H), 4.69 (d, J = 12.4 Hz,
1H), 4.60 (d, J = 12.5 Hz, 1H), 3.53 (d, J = 9.2 Hz, 1H), 3.10 (d, J = 9.2
Hz, 1H), 2.91 (s, 3H), 2.29 (d, J = 16.4 Hz, 1H), 2.24 (d, J = 16.4 Hz, 1H),
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(CH3), 28.4 (CH3), 21.9 (CH3), 21.7 (CH3). HRMS (ESI-MS) calcd. for
C24H32NO8S+ ([M+H]+): 494.1843, found 494.1842.
HRMS (ESI-MS) calcd. for C36H43N2O8S+ ([M+NH4]+): 663.2735, found
663.2734.
5,6-Bis(methoxymethyl)-1,1,3a-trimethyl-2-tosyl-2,3,3a,4-tetrahydro-
1H-isoindole (3bc). General Procedure B afforded 76.2 mg (94%) of the
title compound as a colorless oil. Rf (PE/Et2O 4/6) 0.37. IR (neat) ν 3441,
2926, 2819, 1726, 1598, 1379, 1156, 1089, 663, 549 cm-1. 1H NMR (400
MHz, CDCl3) δ 7.74 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 5.71 (s,
1H), 4.05 (d, J = 12.0 Hz, 1H), 4.04 (dd, J = 11.6, 1.7 Hz, 1H), 3.98 (d, J
= 11.6 Hz, 1H), 3.92 (d, J = 12.0 Hz, 1H), 3.40 (d, J = 9.1 Hz, 1H), 3.27 (s,
3H), 3.26 (s, 3H), 3.01 (d, J = 9.1 Hz, 1H), 2.41 (s, 3H), 2.27 (d, J = 16.4
Hz, 1H), 2.24 (d, J = 16.4 Hz, 1H), 1.70 (s, 3H), 1.46 (s, 3H), 1.00 (s, 3H).
13C NMR (75 MHz, CDCl3) δ 155.3 (C), 143.2 (C), 138.4 (C), 130.0 (C),
129.9 (C), 129.7 (CH), 127.7 (CH), 115.7 (CH), 71.1 (CH2), 70.1 (CH2),
67.5 (C), 61.1 (CH2), 58.1 (CH2), 39.5 (C), 38.3 (CH2), 31.1 (CH3), 28.6
(CH3), 22.4 (CH3), 21.7 (CH3). HRMS (ESI-MS) calcd. for C22H32NO4S+
([M+H]+): 406.2047, found 406.2047.
(1,1,3a-Trimethyl-2-tosyl-2,3,3a,4-tetrahydro-1H-isoindole-5,6-
diyl)bis(methylene) bis(4-nitrobenzoate) (3bg). General Procedure B
afforded 112 mg (83%) of the title compound as a white solid. Mp 156-
158 °C, Rf (PE/Et2O 4/6) 0.50. IR (neat) ν 3639, 3020, 2257, 1755, 1558,
1298, 1178, 1091, 862, 731, 647 cm-1. 1H NMR (300 MHz, CDCl3) δ 8.26
(d, J = 8.7 Hz, 4H), 8.14 (d, J = 8.7 Hz, 4H), 7.74 (d, J = 8.1 Hz, 2H), 7.28
(d, J = 7.2 Hz, 2H), 5.78 (s, 1H), 5.22 (d, J = 12.5 Hz, 1H), 5.14 (d, J =
12.5 Hz, 1H), 5.07 (d, J = 12.5 Hz, 1H), 4.94 (d, J = 12.5 Hz, 1H), 3.42 (d,
J = 9.2 Hz, 1H), 3.06 (d, J = 9.2 Hz, 1H), 2.41 (s, 3H), 2.35 (d, J = 6.4 Hz,
2H), 1.70 (s, 3H), 1.51 (s, 3H), 0.99 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
164.8 (C), 164.7 (C), 157.9 (C), 151.0 (C), 151.0 (C), 143.5 (C), 138.2
(C), 135.5 (C), 135.5 (C), 131.0 (CH), 131.0 (CH), 129.98 (C), 129.8 (CH),
128.8 (C), 127.7 (CH), 124.0 (CH), 123.9 (CH), 115.2 (CH), 67.4 (C),
64.8 (CH2), 63.6 (CH2), 60.7 (CH2), 39.7 (C), 38.6 (CH2), 31.2 (CH3), 28.5
(CH3), 22.1 (CH3), 21.8 (CH3). HRMS (ESI-MS) calcd. for C34H34N3O10S+
([M+H]+): 676.1959, found 676.1959.
5,6-Bis((benzyloxy)methyl)-1,1,3a-trimethyl-2-tosyl-2,3,3a,4-
tetrahydro-1H-isoindole (3bd). General Procedure B afforded 103 mg
(92%) of the title compound as a colorless oil. Rf (PE/Et2O 6/4) 0.45. IR
(neat) ν 2919, 2893, 2230, 1317, 1153, 1094, 1039, 721, 544 cm-1. 1H
NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.3 Hz, 2H), 7.36 – 7.26 (m, 12H),
5.76 (s, 1H), 4.43 (dd, J = 11.8, 5.0 Hz, 2H), 4.37 (dd, J = 11.8, 2.7 Hz,
2H), 4.11 (d, J = 11.8 Hz, 1H), 4.09 (dd, J = 11.5, 1.5 Hz, 1H), 4.03 (d, J
= 11.5 Hz, 1H), 3.98 (d, J = 11.8 Hz, 1H), 3.42 (d, J = 9.1 Hz, 1H), 3.03
(d, J = 9.1 Hz, 1H), 2.42 (s, 3H), 2.34 (d, J = 16.5 Hz, 1H), 2.20 (d, J =
16.5 Hz, 1H), 1.72 (s, 3H), 1.47 (s, 3H), 1.04 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ 155.3 (C), 143.2 (C), 138.6 (C), 138.4 (C), 138.4 (C), 130.2 (C),
130.0 (C), 129.7 (CH), 128.7 (CH), 128.7 (CH), 128.2 (CH), 128.0 (CH),
127.9 (CH), 127.9 (CH), 127.7 (CH), 115.9 (CH), 72.2 (CH2), 72.1 (CH2),
68.7 (CH2), 67.5 (CH2), 67.5 (C), 61.1 (CH2), 39.6 (C), 38.5 (CH2), 31.2
(CH3), 28.6 (CH3), 22.5 (CH3), 21.8 (CH3). HRMS (ESI-MS) calcd. for
C34H43N2O4S+ ([M+NH4]+): 575.2938, found 575.2938.
(1,1,3a-Trimethyl-2-tosyl-2,3,3a,4-tetrahydro-1H-isoindole-5,6-
diyl)bis(methylene)
bis(4-methoxybenzoate)
(3bh).
General
Procedure B afforded 120 mg (93%) of the title compound as a colorless
oil. Rf (PE/Et2O 4/6) 0.32. IR (neat) ν 2967, 2865, 1701, 1604, 1510,
1249, 1164, 1087, 815, 608, 549 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.93
(d, J = 9.0 Hz, 4H), 7.73 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 6.88
(d, J = 1.7 Hz, 2H), 6.86 (d, J = 1.7 Hz, 2H), 5.77 (s, 1H), 5.10 (d, J =
12.5 Hz, 1H), 5.03 (d, J = 12.4 Hz, 1H), 4.97 (d, J = 12.4 Hz, 1H), 4.85 (d,
J = 12.5 Hz, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.40 (d, J = 9.2 Hz, 1H), 3.03
(d, J = 9.2 Hz, 1H), 2.40 (s, 3H), 2.31 (s, 2H), 1.69 (s, 3H), 1.48 (s, 3H),
1.00 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 166.3 (C2), 163.8 (C), 163.7
(C), 156.6 (C), 143.2 (C), 138.2 (C), 131.9 (CH), 131.9 (CH), 129.9 (C),
129.7 (CH), 129.2 (C), 127.7 (CH), 122.7 (C), 122.6 (C), 115.6 (CH),
114.0 (CH), 113.9 (CH), 67.4 (C), 63.7 (CH2), 62.6 (CH2), 60.8 (CH2),
55.7 (CH3), 39.6 (C), 38.6 (CH2), 31.2 (CH3), 28.5 (CH3), 22.0 (CH3), 21.7
(CH3). HRMS (ESI-MS) calcd. for C36H43N2O8S+ ([M+NH4]+): 663.2735,
found 663.2739.
Di-tert-butyl
((1,1,3a-trimethyl-2-tosyl-2,3,3a,4-tetrahydro-1H-
isoindole-5,6-diyl) bis(methylene)) bis(carbonate) (3be). General
Procedure B afforded 103 mg (89%) of the title compound as a colorless
oil. Rf (PE/Et2O 7/3) 0.48. IR (neat) ν 2980, 2259, 1737, 1270, 1149, 906,
725 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz, 2H), 7.27 (d, J
= 8.0 Hz, 2H), 5.68 (s, 1H), 4.81 (d, J = 12.5 Hz, 1H), 4.77 (d, J = 12.3 Hz,
1H), 4.65 (d, J = 12.3 Hz, 1H), 4.53 (d, J = 12.5 Hz, 1H), 3.38 (d, J = 9.2
Hz, 1H), 2.99 (d, J = 9.2 Hz, 1H), 2.41 (s, 3H), 2.24 (d, J = 16.7 Hz, 1H),
2.19 (d, J = 16.7 Hz, 1H), 1.68 (s, 3H), 1.46 (s, 9H), 1.44 (s, 12H), 0.96 (s,
3H). 13C NMR (75 MHz, CDCl3) δ 156.7 (C), 153.7 (C), 153.7 (C), 143.3
(C), 138.3 (C), 129.7 (CH), 129.5 (C), 128.8 (C), 127.7 (CH), 115.3 (CH),
82.6 (C), 82.5 (C), 67.5 (C), 65.7 (CH2), 64.5 (CH2), 60.8 (CH2), 39.5 (C),
38.2 (CH2), 31.1 (CH3), 28.5 (CH3), 28.1 (CH3), 21.9 (CH3), 21.8 (CH3).
HRMS (ESI-MS) calcd. for C30H47N2O8S+ ([M+NH4]+): 595.3048, found
595.3052.
(1,1,3a-Trimethyl-2-tosyl-2,3,3a,4-tetrahydro-1H-isoindole-5,6-
diyl)dimethanol (3bi). General Procedure B afforded 64.9 mg (86%) of
the title compound as a colorless oil. Rf (AcOEt) 0.36. IR (neat) ν 3516,
3086, 2965, 1680, 1236, 1185, 1055, 980, 796, 663, 544 cm-1. 1H NMR
(400 MHz, CDCl3) δ 7.74 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H),
5.69 (s, 1H), 4.26–4.08 (m, 4H), 3.38 (d, J = 9.1 Hz, 1H), 3.00 (d, J = 9.1
Hz, 1H), 2.41 (br s, 5H, CH3 + 2OH), 2.26 (d, J = 16.6 Hz, 1H), 2.20 (d, J
= 16.6 Hz, 1H), 1.68 (s, 3H), 1.45 (s, 3H), 0.98 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ 155.6 (C), 143.4 (C), 138.3 (C), 131.8 (C), 129.8 (CH), 127.7
(CH), 116.3 (CH), 67.5 (C), 62.4 (CH2), 61.3 (CH2), 61.1 (CH2), 39.6 (C),
39.1 (CH2), 31.2 (CH3), 28.6 (CH3), 22.1 (CH3), 21.8 (CH3). HRMS (ESI-
MS) calcd. for C20H27NO4SNa+ ([M+Na]+): 400.1553, found 400.1553.
Dibenzyl ((1,1,3a-trimethyl-2-tosyl-2,3,3a,4-tetrahydro-1H-isoindole-
5,6-diyl)bis (methylene)) bis(carbonate) (3bf). General Procedure B
afforded 112 mg (87%) of the title compound as a white waxy oil. Rf
(PE/Et2O 1/1) 0.53. IR (neat) ν 3086, 2916, 2230, 1711, 1236, 1244, 945,
726, 684 cm-1. 1H NMR (300 MHz, CDCl3) δ 7.76 (d, J = 7.3 Hz, 2H),
7.45–7.26 (m, 12H), 5.69 (s, 1H), 5.15 (s, 4H), 4.91 (d, J = 12.4 Hz, 1H),
4.87 (d, J = 12.2 Hz, 1H), 4.77 (d, J = 12.2 Hz, 1H), 4.66 (d, J = 12.4 Hz,
1H), 3.40 (d, J = 8.7 Hz, 1H), 3.01 (d, J = 8.7 Hz, 1H), 2.44 (s, 3H), 2.22
(s, 2H), 1.68 (s, 3H), 1.46 (s, 3H), 0.92 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ 157.2 (C), 155.3 (C), 155.2 (C), 143.2 (C), 138.2 (C), 135.4 (C),
129.7 (CH), 129.5 (C), 128.9 (CH), 128.6 (C), 128.6 (CH), 127.7 (CH),
115.0 (CH), 70.0 (CH2), 67.4 (C), 66.7 (CH2), 65.5 (CH2), 60.7 (CH2),
39.4 (C), 38.1 (CH2), 31.0 (CH3), 28.4 (CH3), 21.8 (CH3), 21.7 (CH3).
5,6-Bis(chloromethyl)-1,1,3a-trimethyl-2-tosyl-2,3,3a,4-tetrahydro-
1H-isoindole (3bj). General Procedure B afforded 73.7 mg (89%) of the
title compound as a colorless oil. Rf (PE/Et2O 7/3) 0.38. IR (neat) ν 2931,
2878, 2255, 1733, 1375, 1225, 1154, 905, 724, 588 cm-1. 1H NMR (300
MHz, CDCl3) δ 7.75 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 5.68 (s,
1H), 4.30 (d, J = 11.5 Hz, 1H), 4.19 (d, J = 11.6 Hz, 1H), 4.11 (d, J = 11.6
Hz, 1H), 4.06 (d, J = 11.5 Hz, 1H), 3.43 (d, J = 9.2 Hz, 1H), 3.04 (d, J =
9.2 Hz, 1H), 2.41 (s, 3H), 2.33 (d, J = 16.4 Hz, 1H), 2.23 (d, J = 16.4 Hz,
1H), 1.71 (s, 3H), 1.49 (s, 3H), 1.02 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
157.8 (C), 143.4 (C), 138.2 (C), 130.8 (C), 129.7 (CH), 129.4 (C), 127.7
(CH), 115.3 (CH2), 67.4 (C), 60.7 (CH2), 43.9 (CH2), 41.6 (CH2), 39.8 (C),
38.9 (CH2), 31.1 (CH3), 28.5 (CH3), 22.4 (CH3), 21.8 (CH3). HRMS (ESI-
MS) calcd. for C20H26NO2SCl2+ ([M+H]+): 414.1056, found 414.1056.
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5,6-Diethyl-1,1,3a-trimethyl-2-tosyl-2,3,3a,4-tetrahydro-1H-isoindole
2H), 7.34–7.27 (m, 2H), 7.25–7.20 (m, 3H), 6.17 (dd, J = 5.5, 2.9 Hz,
0.5H), 6.11 (dd, J = 5.5, 2.9 Hz, 0.5H), 5.67 (dd, J = 5.4, 2.4 Hz, 1H),
3.28 (d, J = 9.0 Hz, 0.5H), 3.25 (d, J = 9.1 Hz, 0.5H), 2.91 (d, J = 9.2 Hz,
0.5H), 2.88 (d, J = 9.1 Hz, 0.5H), 2.39 (s, 3H), 1.97–1.80 (m, 2H), 1.78 (s,
0.5H), 1.76 (s, 0.5 H), 1.71–1.66 (m, 6H), 1.44 (s, 1.5H), 1.43 (s, 1.5H),
0.82 (s, 1.5H), 0.73 (s, 1.5H). 13C NMR (75 MHz, CDCl3) δ 154.3 (C x
0.5), 154.1 (C x 0.5), 145.6 (C x 0.5), 145.4 (C x 0.5), 143.1 (C), 141.0 (C
x 0.5), 140.8 (C x 0.5), 138.3 (C x 0.5), 138.2 (C x 0.5), 129.6 (CH x 2),
128.4 (CH x 2), 127.7 (CH x 2 x 0.5), 127.7 (CH x 2 x 0.5), 127.3 (CH x
0.5), 127.2 (CH x 0.5), 125.81(CH x 2 x 0.5), 125.7 (CH x 2 x 0.5), 117.5
(CH2 x 0.5), 117.2 (CH2 x 0.5), 113.6 (CH2 x 0.5), 113.59 (CH2 x 0.5),
(3bk). General Procedure
B afforded 73.2 mg (98%) of the title
compound as a colorless oil. Rf (PE/Et2O 8/2) 0.55. IR (neat) ν 2963,
2867, 1598, 1362, 1288 1148, 1014, 926, 799, 709, 548cm-1. 1H NMR
(400 MHz, CDCl3) δ 7.68 (d, J = 8.3 Hz, 2H), 7.20 (d, J = 7.2 Hz, 2H),
5.41 (s, 1H), 3.31 (d, J = 9.0 Hz, 1H), 2.91 (d, J = 9.0 Hz, 1H), 2.34 (s,
3H), 2.15 – 2.03 (m, 3H), 1.99 – 1.81 (m, 3H), 1.60 (s, 3H), 1.38 (s, 3H),
0.90 – 0.84 (m, 9H). 13C NMR (75 MHz, CDCl3) δ 152.5 (C), 143.1 (C),
138.6 (C), 129.9 (C), 129.7 (C), 129.6 (CH), 127.8 (CH), 117.7 (CH), 67.5
(C), 61.3 (CH2), 40.2 (CH2), 39.9 (C), 31.4 (CH3), 28.7 (CH3), 25.9 (CH2),
24.4 (CH2), 22.0 (CH3), 21.8 (CH3), 14.3 (CH3), 13.0 (CH3). HRMS (ESI-
MS) calcd. for C22H32NO2S+ ([M+H]+): 374.2148, found 374.2146.
76.6 (C x 0.5), 76.2 (C x 0.5), 67.3 (C), 61.0 (CH2 x 0.5), 60.95 (CH2
x
0.5), 40.0 (C x 0.5), 39.9 (C x 0.5), 35.8 (CH2 x 0.5), 35.7 (CH2 x 0.5),
31.4 (CH3 x 0.5), 31.2 (CH3 x 0.5), 28.6 (CH3), 28.5 (CH3 x 0.5), 28.1
(CH3 x 0.5), 22.2 (CH3 x 0.5), 21.8 (CH3 x 0.5), 21.7 (CH3). HRMS (ESI-
MS) calcd. for C26H32NO3S+ ([M+H]+): 438.2097, found 438.2096.
1,1,3a-trimethyl-5,6-diphenyl-2-tosyl-2,3,3a,4-tetrahydro-1H-
isoindole (3bl). General Procedure B afforded 19.7 mg (21%) of the title
compound as a colorless oil. Rf (PE/Et2O 8/2) 0.45. IR (neat) ν 2965,
2918, 1612, 1497, 1381, 1153, 1036, 930, 723, 706, 528 cm-1. 1H NMR
(300 MHz, CDCl3) δ 7.79 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H),
7.16–7.08 (m, 6H), 7.01–6.96 (m, 4H), 5.88 (s, 1H), 3.49 (d, J = 9.1 Hz,
1H), 3.14 (d, J = 9.1 Hz, 1H), 2.76 (d, J = 16.1 Hz, 1H), 2.48 (d, J = 16.1
Hz, 1H), 2.43 (s, 3H), 1.76 (s, 3H), 1.56 (s, 3H), 1.21 (s, 3H). 13C NMR
(75 MHz, CDCl3) δ 155.0 (C), 143.3 (C), 142.5 (C), 141.2 (C), 138.4 (C),
132.9 (C), 131.2 (C), 129.8 (CH), 129.4 (CH), 129.1 (CH), 128.3 (CH),
128.3 (CH), 127.8 (CH), 126.8 (CH), 126.7 (CH), 119.1 (CH), 67.67 (C),
61.1 (CH2), 43.2 (CH2), 40.1 (CH3), 31.4 (CH3), 28.7 (CH3), 22.1 (CH3),
21.8 (CH3). HRMS (ESI-MS) calcd. for C30H32NO2S+ ([M+H]+): 470.2148,
found 470.2146.
Diphenyl(1,1,3a-trimethyl-2-tosyl-2,3,3a,4-tetrahydro-1H-isoindol-5-
yl)methanol (7bd). General Procedure
B using 10 mol % of
Cp*Ru(cod)Cl afforded 90.9 mg (91 %) of the title compound as a white
solid. Mp 112-113 °C. Rf (PE/Et2O 1/1) 0.60. IR (neat) ν 3018, 2947,
1610, 1508, 1485, 1112, 1023, 742, 712 cm-1. 1H NMR (400 MHz, CDCl3)
δ 7.63 (d, J = 8.3 Hz, 2H), 7.28–7.23 (m, 8H), 7.23–7.19 (m, 2H), 7.19–
7.17 (m, 2H), 5.58 (dd, J = 5.5, 2.7 Hz, 1H), 5.52 (d, J = 5.5 Hz, 1H), 3.24
(d, J = 9.1 Hz, 1H), 2.86 (d, J = 9.1 Hz, 1H), 2.33 (s, 3H), 2.30 (s, 1H),
2.08 (d, J = 16.3 Hz, 1H), 1.98 (dd, J = 16.3, 2.7 Hz, 1H), 1.59 (s, 3H),
1.37 (s, 3H), 0.84 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 154.7 (C), 144.6
(C), 144.6 (C), 143.2 (C), 140.3 (C), 138.3 (C), 129.7 (CH), 128.3 (CH),
128.25 (CH), 128.0 (CH), 127.9 (CH), 127.7 (CH), 127.7 (CH), 122.2
(CH), 113.6 (CH), 82.6 (C), 67.3 (C), 61.1 (CH2), 40.3 (C), 36.5 (CH2),
31.3 (CH3), 28.5 (CH3), 22.5 (CH3), 21.8 (CH3). HRMS (ESI-MS) calcd.
for C31H34NO3S+ ([M+H]+): 500.2254, found 500.2256.
2-(1,1,3a-Trimethyl-2-tosyl-2,3,3a,4-tetrahydro-1H-isoindol-5-
yl)propan-2-ol (7ba). General Procedure
B using 10 mol % of
Cp*Ru(cod)Cl afforded 64.6 mg (86%) of the title compound as a
colorless oil. Rf (PE/Et2O 1/1) 0.23. IR (neat) ν 3510, 3054, 2304, 1670,
1421, 1264, 1158, 730, 702 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J
= 8.3 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 5.95 (dd, J = 5.5, 2.9 Hz, 1H),
5.63 (d, J = 5.5 Hz, 1H), 3.41 (d, J = 9.1 Hz, 1H), 3.03 (d, J = 9.1 Hz, 1H),
2.41 (s, 3H), 2.19 (d, J = 16.1 Hz, 1H), 2.09 (dd, J = 16.1, 2.9 Hz, 1H),
1.67 (s, 3H), 1.45 (s, 3H), 1.37 (s, 1H), 1.33 (s, 3H), 1.31 (s, 3H), 0.98 (s,
3H). 13C NMR (75 MHz, CDCl3) δ 153.8 (C), 143.2 (C), 142.3 (C), 138.3
(C), 129.7 (CH), 127.7 (CH), 115.7 (CH), 113.8 (CH), 72.6 (C), 67.4 (C),
61.1 (CH2), 40.0 (C), 35.8 (CH2), 31.2 (CH3), 28.6 (CH3), 28.6 (CH3), 28.4
(CH3), 21.8 (CH3), 21.6 (CH3). HRMS (ESI-MS) calcd. for C21H30NO3S+
([M+H]+): 376.1941, found 376.1938.
4-methyl-N-(2-(1,1,3a-trimethyl-2-tosyl-2,3,3a,4-tetrahydro-1H-
isoindol-5-yl)propan-2-yl)benzenesulfonamide
(7be).
General
Procedure B afforded 67.6 mg (64%) of the title compound as a pale
yellow solid, mp 58-59 oC. Rf (PE/Et2O 4/6) 0.33. IR (neat) ν 3276, 2977,
1598, 1450, 1382, 1146, 1090, 909, 661, 548 cm-1. 1H NMR (400 MHz,
CDCl3) δ 7.74 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 8.2 Hz, 2H), 7.29 (d, J =
8.2 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 5.88 (dd, J = 5.5, 2.8 Hz, 1H), 5.58
(d, J = 5.5 Hz, 1H), 4.43 (s, 1H), 3.38 (d, J = 9.1 Hz, 1H), 2.89 (d, J = 9.1
Hz, 1H), 2.42 (s, 3H), 2.37 (s, 3H), 2.07 (d, J = 16.1 Hz, 1H), 1.79 (dd, J
= 16.1, 2.8 Hz, 1H), 1.66 (s, 3H), 1.42 (s, 3H), 1.36 (s, 3H), 1.28 (s, 3H),
0.96 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 153.6 (C), 142.3 (C), 142.2 (C),
139.3 (C), 138.8 (C), 137.3 (C), 128.8 (CH), 128.7 (CH ), 126.8 (CH),
126.4 (CH), 117.1 (CH), 112.6 (CH), 66.3 (C), 60.1 (CH2), 58.1 (C), 39.1
(C), 34.4 (CH2), 30.3 (CH3), 27.5 (CH3), 27.0 (CH3), 25.3 (CH3), 20.8
1-(1,1,3a-Trimethyl-2-tosyl-2,3,3a,4-tetrahydro-1H-isoindol-5-
yl)cyclohexan-1-ol (7bb). General Procedure B using 10 mol % of
Cp*Ru(cod)Cl afforded 58.2 mg (70%) of the title compound as a white
solid. Mp 71-73 °C. Rf (PE/Et2O 1/1) 0.41. IR (neat) ν 2918, 2877, 2271,
1310, 1125, 1076, 959, 749, 544 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.75
(d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 5.96 (dd, J = 5.5, 2.9 Hz, 1H),
5.63 (d, J = 5.5 Hz, 1H), 3.41 (d, J = 9.1 Hz, 1H), 3.03 (d, J = 9.1 Hz, 1H),
2.41 (s, 3H), 2.24 (d, J = 16.0 Hz, 1H), 2.06 (dd, J = 16.0, 2.9 Hz, 1H),
1.67 (s, 3H), 1.65–1.51 (m, 9H), 1.45 (s, 3H), 1.26–1.13 (s, 2H), 0.98 (s,
3H). 13C NMR (75 MHz, CDCl3) δ 153.9 (C), 143.2 (C), 142.5 (C), 138.4
(C), 129.7 (CH), 127.8 (CH), 116.5 (CH), 113.9 (CH), 73.3 (C), 67.4 (C),
61.2 (CH2), 40.0 (C), 35.7 (CH2), 35.6 (CH2), 35.5 (CH2), 31.2 (CH3), 28.6
(CH3), 25.9 (CH2), 22.2 (CH2), 22.1 (CH2), 21.8 (CH3), 21.5 (CH3). HRMS
(ESI-MS) calcd. for C24H34NO3S+ ([M+H]+): 416.2254, found 416.2254.
+
(CH3), 20.7 (CH3). HRMS (ESI-MS) calcd. for C28H37N2O4S2 ([M+H]+):
529.2189, found 529.2188.
5-(2-methoxypropan-2-yl)-1,1,3a-trimethyl-2-tosyl-2,3,3a,4-
tetrahydro-1H-isoindole (7bg). General Procedure B afforded 22.3 mg
(29%) of the title compound as a colorless oil. Rf (PE/Et2O 3/1) 0.44. IR
(neat) ν 3018, 2932, 1698, 1454, 1214, 1156, 1090, 940, 751, 667, 570
1
cm-1. H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.3 Hz, 2H), 7.28 (d, J =
8.4 Hz, 2H), 5.86 (dd, J = 5.5, 3.0 Hz, 1H), 5.62 (d, J = 5.5 Hz, 1H), 3.42
(d, J = 9.0 Hz, 1H), 3.05 (s, 3H), 3.02 (d, J = 9.0 Hz, 1H), 2.41 (s, 3H),
2.28 (d, J = 16.3 Hz, 1H), 1.95 (dd, J = 16.3, 2.9 Hz, 1H), 1.69 (s, 3H),
1.46 (s, 3H), 1.28 (s, 3H), 1.27 (s, 3H), 1.00 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 154.5 (C), 143.2 (C), 139.9 (C), 138.3 (C), 129.7 (CH), 127.8
(CH), 119.2 (CH), 113.6 (CH), 76.8 (C), 67.4 (C), 61.3 (CH2), 50.8 (CH3),
40.1 (C), 35.0 (CH2), 31.3 (CH3), 28.6 (CH3), 25.4 (CH3), 25.1 (CH3), 22.4
(CH3), 21.8 (CH3). HRMS (ESI-MS) calcd. for C22H32NO3S ([M+H]+):
390.2097, found 390.2097.
Phenyl-1-(1,1,3a-trimethyl-2-tosyl-2,3,3a,4-tetrahydro-1H-isoindol-5-
yl)ethan-1-ol (7bc). General Procedure
B using 10 mol % of
Cp*Ru(cod)Cl afforded 74.4 mg (85%) of the title compound as a white
solid in a 1:1 mixture of diastereomers. Mp 75–76 °C. Rf (PE/Et2O 1/1)
0.54. IR (neat) ν 2997, 2868, 2253, 1373, 1150, 1121, 904, 701, 593, 549
cm-1. 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.2 Hz, 2H), 7.39–7.36 (m,
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(3,3,7a-trimethyl-6-phenyl-2-tosyl-2,3,7,7a-tetrahydro-1H-isoindol-5-
yl)methanol (10). General Procedure B afforded 41.5 mg (49%) of the
title compound as a white solid, mp 61-62°C. Rf (PE/Et2O 1/1) 0.42. IR
(neat) ν 3520, 2974, 2929, 1598, 136, 1149, 1090, 1028, 703, 572, 549
cm-1. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.2 Hz, 2H), 7.36 – 7.26
(m, 5H), 7.15 (d, J = 7.2 Hz, 2H), 5.93 (s, 1H), 4.16 (d, J = 5.5 Hz, 2H),
3.43 (d, J = 9.2 Hz, 1H), 3.06 (d, J = 9.2 Hz, 1H), 2.60 (d, J = 16.2 Hz,
1H), 2.42 (s, 3H), 2.34 (d, J = 16.2 Hz, 1H), 1.75 (s, 3H), 1.54 (s, 3H),
1.24 (t, J = 5.4 Hz, 1H), 1.13 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 155.1
(C), 143.2 (C), 141.3 (C), 138.3 (C), 132.8 (C), 130.6 (C), 129.7 (CH),
128.6 (CH), 128.2 (CH), 127.7 (CH), 127.5 (CH ), 115.9 (CH ), 67.6 (C),
62.0 (CH2), 61.0 (CH2), 42.8 (CH2), 39.9 (C), 31.3 (CH3), 28.7 (CH3), 22.1
6-(2-methoxypropan-2-yl)-1,1,3a-trimethyl-2-tosyl-2,3,3a,4-
tetrahydro-1H-isoindole (7bg’). General Procedure B afforded 26.8 mg
(34%) of the title compound as a white solid. Slow evaporation technique
from a petroleum ether solution of 7bg’ yielded good single crystals for
X-ray analysis. Crystal data: C22H31NO3S, FW = 389.54, monoclinic, P 1
21 1, a = 6.4533(5) Å, b = 8.1500(5) Å, c = 20.626(2) Å, β = 93.939(8)°, V
= 1082.25(16) Å3, Z = 2, Dcalcd = 1.195 g cm−3, R = 0.0684 (Rw = 0.1905)
for 3537 reflections with I > 2.00σ(I) and 251 variable parameters. CCDC
1535396 (7bg’) contains supplementary crystallographic data for this
compound. These data can be obtained free of charge from The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif. Mp 56–57 °C. Rf (PE/Et2O 1/1)
0.60. IR (neat) ν 2975, 2821, 1599, 1451, 1271, 1223, 1074, 951, 903,
784, 598 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.3 Hz, 2H), 7.22
(d, J = 8.2 Hz, 2H), 5.82 (s, 1H), 5.50 (t, J = 4.5 Hz, 1H), 3.41 (d, J = 9.1
Hz, 1H), 3.01 (d, J = 9.1 Hz, 1H), 2.99 (s, 3H), 2.41 (s, 3H), 2.14 (d, J =
4.5 Hz, 2H), 1.70 (s, 3H), 1.48 (s, 3H), 1.27 (s, 3H), 1.26 (s, 3H), 1.00 (s,
3H). 13C NMR (101 MHz, CDCl3) δ 155.7 (C), 143.2 (C), 140.3 (C), 138.4
(C), 129.7 (CH), 127.8 (CH), 1178.0 (CH), 113.4 (CH), 76.1 (C), 67.6 (C),
61.2 (CH2), 50.7 (CH3), 39.3 (C), 35.6 (CH2), 31.4 (CH3), 28.7 (CH3), 25.9
(CH3), 25.5 (CH3), 22.1 (CH3), 21.8 (CH3). HRMS (ESI-MS) calcd. for
C22H32NO3S ([M+H]+): 390.2097, found 390.2097.
(CH3), 21.8 (CH3).
HRMS (ESI-MS) calcd. for C25H29NO3SNa+
([M+Na]+): 446.1760, found 446.1759.
(1,1,3a-trimethyl-6-phenyl-2-tosyl-2,3,3a,4-tetrahydro-1H-isoindol-5-
yl)methanol (10’). General Procedure B afforded 32.2 mg (38%) of the
title compound as a white solid, mp 68-69 oC. Rf (PE/Et2O 1/1) 0.40. IR
(neat) ν 3515 2972, 2927, 1598, 1363, 1224, 1147, 973, 780, 701, 581
cm-1. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.2 Hz, 2H), 7.37 – 7.26
(m, 5H), 7.14 (d, J = 7.0 Hz, 2H), 5.72 (s, 1H), 4.19 (d, J = 11.7 Hz, 1H),
4.04 (d, J = 11.7 Hz, 1H), 3.47 (d, J = 9.2 Hz, 1H), 3.11 (d, J = 9.2 Hz,
1H), 2.44 (d, J = 16.3 Hz, 1H), 2.43 (s, 3H), 2.34 (d, J = 16.3 Hz, 1H),
1.70 (s, 3H), 1.50 (s, 3H), 1.22 (dt, J = 6.9, 4.3 Hz, 1H), 1.11 (s, 3H). 13
C
(3,3,7a-Trimethyl-2-tosyl-2,3,7,7a-tetrahydro-1H-isoindol-5-
NMR (75 MHz, CDCl3) δ 155.3 (C), 143.3 (C), 140.1 (C), 138.4 (C), 134.1
(C), 129.8 (C), 129.7 (CH), 128.6 (CH), 128.5 (CH), 127.8 (CH), 127.5
(CH), 118.0 (CH), 67.6 (C), 63.2 (CH2), 61.1 (CH2), 39.7 (C), 38.0 (CH2),
31.2 (CH3), 28.7 (CH3), 22.2 (CH3), 21.8 (CH3). HRMS (ESI-MS) calcd.
for C25H29NO3SNa+ ([M+Na]+): 446.1760, found 446.1757.
yl)methanol (7bi). General Procedure B afforded 34.1 mg (49%) of the
title compound as a colorless oil. Rf (PE/Et2O 4/6) 0.30. IR (neat) ν 3490,
2929, 2899, 1738, 1318, 1209, 953, 749, 559 cm-1. 1H NMR (400 MHz,
CDCl3) δ 7.74 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 5.57-5.54 (m,
1H), 5.66 (s, 1H), 4.14–4.07 (m, 2H), 3.37 (d, J = 9.1 Hz, 1H), 3.00 (d, J
= 9.1 Hz, 1H), 2.41 (s, 3H), 2.14 (d, J = 4.4 Hz, 2H), 1.69 (s, 3H), 1.47 (s,
3H), 1.42 (br s, 1H), 1.01 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 156.2 (C),
143.3 (C), 138.3 (C), 135.8 (C), 129.7 (CH), 127.8 (CH), 119.1 (CH),
113.9 (CH), 67.4 (C), 65.5 (CH2), 61.1 (CH2), 39.6 (C), 35.3 (CH2), 31.2
(CH3), 28.7 (CH3), 22.3 (CH3), 21.8 (CH3). HRMS (ESI-MS) calcd. for
C19H26NO3S+ ([M+H]+): 348.1628, found 348.1630.
(1,3a-dimethyl-2-tosyl-2,3,3a,4-tetrahydro-1H-isoindole-5,6-
diyl)bis(methylene) diacetate (12); General Procedure B afforded 59.1
mg (66%, 15:1 md) of the title compound as a colorless oil. Rf (PE/Et2O
6/4) 0.35. IR (neat) ν 2972, 2869, 1736, 1376, 1223, 1162, 1048, 915,
712, 549 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.1 Hz, 0.8H),
7.69 (d, J = 8.1 Hz, 1.2H), 7.33 (d, J = 8.0 Hz, 1.2H), 7.30 (d, J = 8.0 Hz,
0.8H), 5.66 – 5.64 (m, 1H), 4.79 – 4.51 (m, 4H), 4.44 (q, J = 6.6 Hz,
0.4H), 3.89 (q, J = 6.6 Hz, 0.6H), 3.59 (d, J = 8.6 Hz, 0.6H), 3.56 (d, J =
10.8 Hz, 0.4H), 3.20 (d, J = 10.8 Hz, 0.4H), 2.65 (d, J = 8.6 Hz, 0.6H),
2.44 (s, 1.8H), 2.41 (s, 1.2H), 2.27 – 2.08 (m, 2H), 2.04– 2.02 (m, 6H),
1.60 (d, J = 6.6 Hz, 1.8H), 1.45 (d, J = 6.6 Hz, 1.2H), 1.15 (s, 1.8H), 0.51
(s, 1.2H). 13C NMR (75 MHz, CDCl3) δ 171.0 (C), 150.9 (C), 150.7 (C),
144.1 (C), 143.7 (C), 136.8 (C), 132.6 (C), 130.0 (CH), 129.9 (CH), 129.2
(C), 129.1 (C), 128.9 (C), 128.8 (C), 128.4 (CH), 127.6 (CH), 116.7 (CH),
116.4 (CH), 63.4 (CH2), 63.3 (CH2), 62.2 (CH2), 62.1 (CH2), 61.0 (CH2),
58.8 (CH), 57.4 (CH), 41.4 (C), 39.5 (C), 38.3 (CH2), 38.1 (CH2), 24.8
(CH3), 22.6 (CH3), 21.8 (CH3), 21.7 (CH3), 21.6 (CH3), 21.2 (CH3),
(1,1,3a-Trimethyl-2-tosyl-2,3,3a,4-tetrahydro-1H-isoindol-5-
yl)methanol (7bi’). General Procedure B afforded 33.4 mg (48%) of the
title compound as a colorless oil. Rf (PE/Et2O 4/6) 0.28. IR (neat) ν 3501,
2917, 2900, 1696, 1299, 1152, 949, 687, 660, 593 cm-1. 1H NMR (400
MHz, CDCl3) δ 7.75 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 5.92–
5.89 (m, 1H), 5.62 (d, J = 5.4 Hz, 1H), 4.13–4.05 (m, 2H), 3.39 (d, J = 9.1
Hz, 1H), 3.03 (d, J = 9.1 Hz, 1H), 2.41 (s, 3H), 2.19 – 2.11 (m, 1H), 2.06
(d, J = 16.4 Hz, 1H), 1.68 (s, 3H), 1.45 (s, 3H), 1.41 (br s, 1H), 1.00 (s,
3H). 13C NMR (101 MHz, CDCl3) δ 154.6 (C), 143.3 (C), 138.3 (C), 135.4
(C), 129.7 (CH), 127.8 (CH), 119.2 (CH), 113.5 (CH), 67.4 (C), 66.4
(CH2), 61.0 (CH2), 39.9 (C), 36.6 (CH2), 31.2 (CH3), 28.7 (CH3), 22.2
(CH3), 21.8 (CH3). HRMS (ESI-MS) calcd. for C19H26NO3S+ ([M+H]+):
348.1628, found 348.1631.
21.1(CH3)
, 21.0 (CH3), 20.9 (CH3). HRMS (ESI-MS) calcd. for
C23H30NO6S + ([M+H]+): 448.1788, found 448.1786.
3,3,10a-Trimethyl-9-phenyl-2-tosyl-1,2,3,4a,10,10a-
4-(4-methoxy-4-methylpent-2-yn-1-yl)-2,2,4-trimethyl-3-methylene-1-
tosylpyrrolidine (8). General Procedure B afforded 26.5 mg (34%) of
the title compound as a colorless oil. Rf (PE/Et2O 7/3) 0.35. IR (neat) ν
3019, 2911, 1599, 1447, 1214, 1156, 1091, 930, 744, 667, 566, 550 cm-1.
1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.4 Hz,
2H), 4.89 (s, 1H), 4.87 (s, 1H), 3.37 (d, J = 9.7 Hz, 1H), 3.25 (s, 3H), 3.10
(d, J = 9.7 Hz, 1H), 2.41 (s, 3H), 2.30 (d, J = 16.7 Hz, 1H), 2.19 (d, J =
16.7 Hz, 1H), 1.55 (s, 3H), 1.53 (s, 3H), 1.35 (s, 6H), 1.17 (s, 3H). 13C
NMR (75 MHz, CDCl3) δ 162.6 (C), 142.3 (C), 137.4 (C), 128.7 (CH),
126.8 (CH), 104.3 (CH2), 83.5 (C), 80.4 (C), 69.8 (C), 67.7 (C), 56.3
(CH2), 50.8 (CH3), 43.1 (C), 29.1 (CH2), 28.6 (CH3), 28.5 (CH3), 27.9
(CH3), 27.8 (CH3), 23.7 (CH3), 20.8 (CH3). HRMS (ESI-MS) calcd. for
C22H32NO3S ([M+H]+): 390.2097, found 390.2097.
hexahydroindeno[1,2-f]isoindole (13). Camphorsulfonic acid (55.7 mg,
0.24 mmol) was added to a solution of dienol 7bd (99.9 mg, 0.2 mmol) in
toluene (10 mL). The mixture was stirred for 5 h at 60 °C, and then
concentrated in vacuo. The crude residue was purified by flash
chromatography on silica gel to give 69.4 mg (74%) of the title compound
as a white solid. Mp 113–114 °C. Rf (PE/Et2O 2/3) 0.28. IR (neat) ν 3025,
2930, 1598, 1363, 1156, 1038, 1015, 939, 702, 658, 546 cm-1. 1H NMR
(300 MHz, CDCl3) δ 7.73 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 7.0 Hz, 1H),
7.48–7.34 (m, 5H), 7.30–7.22 (m, 5H), 5.92 (d, J = 3.8 Hz, 1H), 4.07 (d, J
= 3.8 Hz, 1H), 3.20 (d, J = 9.1 Hz, 1H), 3.07 (d, J = 9.1 Hz, 1H), 2.79 (d, J
= 12.2 Hz, 1H), 2.47 (d, J = 12.2 Hz, 1H), 2.40 (s, 3H), 1.62 (s, 3H), 1.59
(s, 3H), 0.71 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 154.1 (C), 145.1 (C),
144.6 (C), 143.9 (C), 143.2 (C), 139.1 (C), 138.4 (C), 134.8 (C), 129.7
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(CH), 129.4 (CH), 128.9 (CH), 127.7 (CH), 127.2 (CH), 125.0 (CH), 123.0
(CH), 120.5 (CH), 115.9 (CH), 67.0 (C), 59.1 (CH2), 50.9 (CH), 46.2 (C),
35.8 (CH2), 30.7 (CH3), 29.0 (CH3), 26.7 (CH3), 21.8 (CH3). HRMS (ESI-
MS) calcd. for C31H32NO2S+ ([M+H]+): 482.2148, found 482.2148.
Chem. 1986, 51, 5496-5498; d) Boese, R.; Knolker, H.-J.; Vollhardt, K.
P. C. Angew. Chem., lnt. Ed. Engl. 1987, 26, 1035-1037; e) Halterman,
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3,3,6,7a-tetramethyl-2-tosyl-2,3,7,7a-tetrahydro-1H-isoindole-5-
carbaldehyde (14). Camphorsulfonic acid (46.4 mg, 0.2 mmol) was
added to a solution of diol 3bi (75.5 mg, 0.2 mmol) in toluene (10 mL).
The mixture was stirred for 2 days at room temperature, and then
concentrated in vacuo. The crude residue was purified by flash
chromatography to give 34.5 mg (48 %) of the title compound as a yellow
solid. Mp 144–145 °C, Rf (PE/Et2O 1/1) 0.37. IR (neat) ν 3019, 2975,
2866, 1668, 1449, 1214, 1150, 1121, 1033, 747, 667, 540 cm-1. 1H NMR
(400 MHz, CDCl3) δ 10.08 (s, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.28 (d, J =
8.0 Hz, 2H), 6.18 (s, 1H), 3.42 (d, J = 9.2 Hz, 1H), 3.02 (d, J = 9.2 Hz,
1H), 2.43 (d, J = 17.3 Hz, 1H), 2.41 (s, 3H), 2.24 (d, J = 1.4 Hz, 3H), 2.14
(d, J = 17.3 Hz, 1H), 1.70 (s, 3H), 1.47 (s, 3H), 0.98 (s, 3H). 13C NMR (75
MHz, CDCl3) δ 187.9 (CH), 154.3 (C), 152.3 (C), 143.3 (C), 138.2 (C),
130.9 (C), 129.7 (CH), 127.7 (CH), 109.8 (CH), 67.5 (C), 60.7 (CH2), 44.8
(CH2), 39.1 (C), 31.0 (CH3), 28.5 (CH3), 22.7 (CH3), 21.8 (CH3), 19.1
(CH3). HRMS (ESI-MS) calcd. for C20H26NO3S+ ([M+H]+): 360.1628,
found 360.1628.
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We thank the Cente National de la Recherche Scientifique
(CNRS) and the Ministère de l’Enseignement Supérieur et de la
Recherche (MESR) for financial support. R.L. is grateful for a
Ph.D. fellowship from the China Scholarship Council (CSC). We
thank Dr. I. DeRiggi (ECM) for help with the NMR spectra
analysis, Dr. M. Giorgi (Aix-Marseille Université) for the X-ray
structural analysis, Dr H. Clavier for help with the x-ray data and
Dr V. Monnier (Aix-Marseille Université) for HRMS assistance.
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R1
R1
Rui Liu,[a] Laurent Giordano[a], Alphonse
Tenaglia*,[a]
R1
Z
R1
Cp*Ru(cod)Cl (5 or 10 mol %)
THF, 60 °C
+
Z
R2
R2
Z = NTs, O, C(CO2Et)2
Page No. – Page No.
29 examples
62-98%
Ruthenium-Catalyzed [2 + 2 + 2]
Cycloaddition of 1,6-Enynes and
Unactivated Alkynes: Access to Ring-
fused Cyclohexadienes
The [2 + 2 + 2] intermolecular carbocyclization reactions between 1,6-enynes and
alkynes catalyzed by Cp*Ru(cod)Cl are reported to provide bicyclohexa-1,3-dienes.
The chemo- and regioselectivity issues are controlled by the presence of
substituents at the propargyl carbon center of the alkyne(s) partner(s).
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