-Cycloaddition Reactions Using Immobilized Alkynes. A Proof of Concept for an Integral Use of the Outcoming Products in Solid-Phase Synthetic Methodologies

Article abstract of DOI:10.1021/acs.joc.8b01378

The transition-metal-catalyzed [2 + 2 + 2]-cycloaddition of alkynes has become a powerful atom-economical strategy for aromatic ring construction. Unfortunately, the control of the stereo-, regio-, and chemoselectivity of these processes is usually challenging, and these reactions can potentially lead to complex unuseful mixtures. While solid-phase chemistry has proven to be a successful tool for decreasing the number of cycloadducts formed and for facilitating the purification step, an integral use of the outcoming products in this complex reaction is described herein. By using an immobilized monoalkyne, the transition-metal-catalyzed [2 + 2 + 2]-cycloaddition with soluble 1,6-diyne-esters led to the simultaneous preparation of soluble and solid-supported phthalides, showing a new way to benefit from solid-phase synthetic methodologies.

Full text of DOI:10.1021/acs.joc.8b01378

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Article
[2+2+2]-Cycloaddition reactions using immobilized
alkynes. A proof of concept for an integral use of the
outcoming products in solid-phase synthetic methodologies
Martin Jorge Riveira, Cintia M. Diez, Mirta P. Mischne, and Ernesto G. Mata
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01378 • Publication Date (Web): 29 Jun 2018
Downloaded from http://pubs.acs.org on June 30, 2018
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[
2+2+2]-Cycloaddition reactions using immobilized alkynes. A proof of concept for an
integral use of the outcoming products in solid-phase synthetic methodologies
†
†
*
*
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1
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Martín J. Riveira , Cintia M. Diez , Mirta P. Mischne and Ernesto G. Mata
Instituto de Química Rosario, Facultad de Ciencias Bioquímicas y Farmacéuticas,
Universidad Nacional de Rosario-CONICET, Suipacha 531, S2002LRK, Rosario,
Argentina.
mischne@iquirꢀconicet.gov.ar, mata@iquirꢀconicet.gov.ar
TABLE OF CONTENTS/ABSTRACT GRAPHIC
Ts
Ph
O
TFA
NH
O
O
O
Ph
7
0%
Ph
Ts
5
equiv
N
O
Rh(I)
Ph
O
O
O
6
5%
ABSTRACT
The transitionꢀmetalꢀcatalyzed [2+2+2]ꢀcycloaddition of alkynes has become a
powerful atomꢀeconomical strategy for aromatic ring construction. Unfortunately, the
control of the stereoꢀ, regioꢀ and chemoselectivity of these processes is usually challenging
and these reactions can potentially lead to complex unuseful mixtures. While solidꢀphase
chemistry has proven to be a successful tool for decreasing the number of cycloadducts
formed and for facilitating the purification step, an integral use of the outcoming products
in this complex reaction is described herein. By using an immobilized monoalkyne, the
transitionꢀmetalꢀcatalyzed [2+2+2]ꢀcycloaddition with soluble 1,6ꢀdiyneꢀesters led to the
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1
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1
1
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2
2
2
2
2
2
2
2
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3
3
3
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3
3
3
4
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4
4
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5
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6
simultaneous preparation of soluble and solidꢀsupported phthalides, showing a new way to
benefit from solidꢀphase synthetic methodologies.
0
1
2
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4
5
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8
9
0
1
2
3
4
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7
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0
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0
1
2
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5
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8
9
0
1
2
3
4
5
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7
8
9
0
INTRODUCTION
The preparation of highlyꢀsubstituted aromatic systems has received considerable
attention in organic synthesis as these structural motifs dressꢀup countless essential
pharmaceutical ingredients, natural products and important materials. The construction of
accurately decorated molecules of this type has mostly relied on performing substitution
and coupling reactions on simpler, more rudimentary aromatic precursors. In the last
decades, however, great interest has been devoted to the transitionꢀmetalꢀmediated
1
construction of aromatic rings and, in particular, on the [2+2+2]ꢀcycloaddition. This
attractive transitionꢀmetal catalyzed transformation cleanly merges three alkyne moieties
into an aromatic ring. Depending on the combinations of triple bonds, mono, bi, tri and
tetracyclic benzene ringꢀcontaining scaffolds can be obtained through inter or
intramolecular cycloadditions (Scheme 1).
Intermolecular
Intramolecular
A
C
[M]
[M]
B
D
[M]
[M]
[M] = [Rh], [Ru], [Pd],....
Scheme 1. [2+2+2]ꢀCycloaddition of alkynes
The continuous development of the field led to the successful application of the
2
3
process to the total synthesis of natural products, macrocycle construction, the preparation
4
of molecules for materials science such as dendrimers or polyaromatic hydrocarbons, and
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the asymmetric synthesis of axially chiral compounds, just to name a few.
Notwithstanding these advances, it is unarguable that the control of the chemoꢀ and
regioselectivity of these processes is a critical issue. Even if side reactions are excluded
7
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
3
3
3
3
3
4
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5
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5
6
0
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2
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4
5
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8
9
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
e.g. linear diꢀ and trimerizations), 38 possible products can be generated from the
combination of three different nonꢀsymmetrical alkynes! In this context, several strategies
have been developed to control and ultimately simplify the outcome of these apparently
unwieldy cycloadditions. Within this context, the group of Takeuchi reported highly
selective and controllable Irꢀcatalyzed [2+2+2]ꢀcycloadditions in which changing the
8
phosphine ligand completely switches the product outcome (Scheme 2A, 2:1 vs. 1:2). On
the other hand, Yamamoto’s group reported the formal cyclotrimerization between
alkynylboronates, propargyl alcohols and terminal alkynes in which the boron group acts as
a tether that controls initial boraruthenacycle construction eventually leading to a single
boraphthalide regioisomer that, in turn, can be transformed into diverse attractive aromatic
9
products (Scheme 2B). In a related approach, siliconꢀbased tetheredꢀ[2+2+2]ꢀ
cycloadditions have been reported as well. For improving chemoꢀ and regioselectivity, silyl
ethers temporary connect isolated alkyne units in order to transform an intermolecular
1
0
reaction into an intramolecular one.
The use of immobilized substrates in transitionꢀmetal catalyzed processes has been
1
1
beneficial to overcome selectivity problems. In particular, the usefulness of [2+2+2]ꢀ
cycloadditions on solidꢀsupports has been independently demonstrated by the groups of
12
13
14
Sun, Deiters and Martinez (Scheme 2C). By using solidꢀsupported diynes, these
authors got rid of sideꢀproducts such as those arising from diꢀ or trimerizations of the diyne
components. As in any typical solidꢀphase strategy, these reactions were driven to
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5
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completion by using an excess of the soluble component, so any non immobilized sideꢀ
products and unused reagents is removed by a simple filtration during workꢀup procedures.
Addressing the solidꢀphase synthesis from a different viewpoint, we envisaged a
new approach to improve the outcome of the process. We sought to devise a dualꢀpurpose
strategy for fully harnessing the solidꢀphase methodology. We reasoned that, by using an
immobilized alkyne in lieu of a diyne, synthetic and biologically relevant products could be
formed both in solution and on resin; a process in which no phase is wasted (Scheme 2D).
Herein we report the application of this conceptually new approach to the
generation of isolated, soluble and immobilized, substituted phthalides by means of a
“convergent” process integrating solution and solidꢀphase synthesis.
0
1
2
3
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5
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8
9
0
1
2
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9
0
1
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
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8
9
0
Scheme 2. Facilitated or controlled [2+2+2]ꢀcycloadditions of alkynes
RESULTS AND DISCUSSION
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Solution-phase [2+2+2]-Cycloaddition for the Synthesis of Phthalides. In order
to establish the basis of the process and to explore the scope of the cycloaddition, our first
set of experiments were performed in solution based on a procedure reported by Witulski
1
5
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
and Zimmermann which involves the use of Wilkinson's catalyst. As shown in Table 1,
esterꢀtype diynes were used as substrate since the cycloadditions would then lead to
phthalideꢀtype products which are attractive structures since these benzolactones are
frequently found in naturally occurring substances that exhibit a broad spectrum of
16ꢀ18
biological activities.
The other substrate, NꢀbenzylꢀNꢀpropargylꢀpꢀtoluenesulfonamide
(1a), was chosen as the monoyne component for three reasons: the benzyl amine group
would be easily translated to solidꢀphase either through alkylation or substitution
1
9
strategies, the behaviour of propargylamines has not been extensively explored in
cyclotrimerization reactions and, finally, because there has been recent interest in the
2
0
biological properties of secondary and tertiary sulfonamides.
Table 1. Solutionꢀphase [2+2+2]ꢀcycloaddition for the synthesis of phthalides
a,b
Entry
1
Diyne 2
Conv.
1a
T
t
Products
O
Ph
O
O
Bn
Ts Ph
Ph
O
O
O
N
Ph
O
45%
40 °C
80 °C
66 h
4 h
O
2
a
3aa, 38% (2.8:1) 4a, 28% (2.4:1)
3aa, 45% (2.1:1) 4a, 28% (1.8:1)
2
3
2a
2a
50%
66%
reflux 1.2 h
3aa, 55% (2:1)
4a, 24% (1.5:1)
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
6
4
5
6
7
8
-
2a
2a
25%
<20%
82%
74%
82%
reflux
reflux
reflux 1.3 h
reflux 2 h
reflux 1.8 h
2 h
9 h
-
c
3aa, traces (3:1) 4a, traces (4:1)
d
3aa, 15% (2.3:1)
-
2a (2 equiv)
2a (5 equiv)
3aa, 71% (2.1:1) 4a, 50% (1.7:1)
3aa, 76% (2.2:1) 4a, 56% (1.7:1)
Ph
O
O
Bn
Ts
O
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
O
9
1
57%
99%
reflux
reflux
2 h
2 h
O
O
O
Ph
Ph
Ph
2
b (2 equiv)
3
ab, 46% (1:1) 4’b, 35% (2:1)
Ph
Ph
O
O
O
Bn
Ts Ph
Ph
Ph
O
Ph
Ph
O
O
N
O
O
0
Ph
Ph
O
O
O
Ph
O
Ph
Ph
2
c (5 equiv)
3
ac, 64% (1.2:1)
4c, 13% (2:1)
4’c, 18% (3.4:1)
Et
Ph
O
O
O
Bn
Ts Et
Et
O
Et
O
O
N
O
O
11
12
Et
97%
reflux 1.5 h
O
O
O
O
Ph
Et
Ph
Ph
Ph
Ph
2
d (5 equiv)
e
3
ad, 80% (1.1:1)
4d, 21% (5:1) 4’d, 20% (1.5:1)
O
O
Ph
Ph
55%
86%
reflux
reflux
10 h
10 h
2
e
3ae, < 40% (3:1)
O
O
f
-
1
3
2f
Unless otherwise noted, all reactions were performed with 1 equiv of substrates 2, using RhCl(PPh ) as
a
3
3
catalyst (5 mol%) in toluene (0.03 M). Yields of crossꢀproducts 3 refer to the amount of 1a used. Yields of
homodimers 4/4’ refer to the amount of substrate 2 employed. Regioisomeric ratio in brackets. Grubbs 1
b
c
st
d
gen. was used as catalyst (5 mol%). Pd (dba) /PPh was used as catalytic system (2.5/5 mol%).
2
3
3
e
f
Inseparable from trimers (5d) of substrate 2d (17% yield, see SI). No product could be identified from the
complex mixture obtained.
As shown in Table 1, the reaction of substrate 1a and a variety of unsymmetrical
diynes 2 leads to the formation of crossꢀcycloaddition products 3 and homodimers 4. In
addition, for many substrates, homotrimers arising from a secondary [2+2+2]ꢀcycloaddition
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event on phthalide products 4 could also be found in the reactions mixtures in yields
ranging from 10 to 25% (see SI). The structures of the cycloadducts were determined based
on the analyses of the 1D and 2D NMR data, including in some cases NOE experiments
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
see SI). Regiochemistry of the obtained compounds was determined by analysis of the H
NMR spectra of the crude mixtures.
In general, moderate to low regioselectivity was obtained and, although this
selectivity was shown to be slightly affected as higher temperatures were reached, this was
necessary to guarantee high conversion of substrate 1a (entries 1ꢀ3). Indeed, alkyne 1a
exhibited poor reactivity, probably due to the bulky tertiary sulfonamide group and, in the
absence of any diyne substrate 2, ca. 75% of the starting material could be recovered
unaltered after 2 h under reflux in the presence of Wilkinson cat. (entry 4). Although the
production of crossꢀcycloadducts 3, as well as the conversion of substrate 1a, could be
raised by using an excess of diyne substrates 2 (entries 3 vs 7 and 8), yields of
benzolactoneꢀtype products 3 and 4 were in general moderate. It should be noted that the
use of other solvents (e.g. EtOH, dichloromethane and chloroform), or other standard Pd
2
1,22
and Ru catalysts that have been previously used for this type of processes,
did not
provide any improvement (e.g. entries 5ꢀ6). While it can instinctively be proposed that this
outcome could be due to lack of chemoselectivity, the advantages of a solidꢀphase approach
became apparent from the very beginning. The main disadvantage of this methodology lies
in the purification of the crude mixtures thus obtained. For instance, after successive
chromatography purifications, benzolactones 3aa could not be efficiently separated from
orthoꢀhomodimer of 4a; nor orthoꢀsubstituted phthalide of 3ab could be separated from
unidentified sideꢀproducts (entry 9). In addition, whereas products 3ad were, in turn,
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
inseparable from trimers of the diyne 2d (entry 11), isochromanones 3ae obtained using
23
1
,7ꢀdiyne 2e could not be separated from unidentified sideꢀproducts (entry 12).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Side-by-side Solid- and Solution-phase Synthesis of Phthalides via [2+2+2]-
Cycloadditions. In order to face such limitations, we envisaged that, by immobilizing the
monoꢀalkyne component to a solid support, homodimers of type 4 would only form in
solutionꢀphase which can be easily separated by simple filtration. Resinꢀbound crossꢀ
cycloadducts, on the other hand, could be then selectively cleaved from the solid support by
an appropriate reagent.
To this aim, resinꢀbound propargylamine 1b was prepared in two steps from BOBA
resin (7), which was in turn obtained from readily available Merrifield resin (6) according
24,25
to the procedure reported by Kobayashi and Aoki (Scheme 3).
The loading of the resin
1
b was calculated based on the amount of Nꢀpropargylꢀp-toluenesulfonamide (8) released
upon treatment with either iron chloride or trifluoroacetic acid in dichloromethane (75%
overall yield).
Scheme 3. Preparation of resin 1b from Merrifield resin.
The use of resin 1b effectively resulted in the simultaneous generation of
benzolactones in both solution and solid phase and the results are summarized in Table 2.
Using RhCl(PPh ) as catalyst (entries 1ꢀ8), the yields and selectivities obtained were
3
3
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comparable to those observed in homogeneous media except for the fact that cycloadducts
9
and 4 are naturally easily separated. From the practical point of view, the end of the
reaction can be determined by the disappearance of the dyine in the solution phase by TLC,
an operation which is not possible in traditional solidꢀphase synthesis. The release of
immobilized products from the resins has been achieved by treatment with trifluoroacetic
acid in dichloromethane at room temperature. Thus, released products, derived from
immobilized phthalides 9ba-bj, were obtained in good overall yields (40ꢀ70%). Moderate
regioselectivity was mostly obtained under conditions used in solution phase experiments,
with a preference for the meta regioisomer when the dyine was substituted with a phenyl or
ethyl group at the electron deficient triple bond (diynes 2a, 2g, 2h and 2i, entries 1, 5, 6 and
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
), regardless of the presence or absence of an internal substituent. Regioselectivity
decreased even more when both triple bonds were substituted, such as dyines 2c, 2d and 2j
(entries 3, 4 and 8), or when the phenyl substituent was attached to the less electron
deficient triple bond (2b, entry 2). In general, this pattern of regioselectivity was repeated
in the solutionꢀphase products.
Table 2. Sideꢀbyꢀside solidꢀ and solutionꢀphase synthesis of phthalides via [2+2+2]ꢀ
cycloadditions
a
a
Entry
Diyne 2
Resin-bound products
Solution-phase products
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1
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2
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2
2
2
2
2
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5
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6
Ph
O
O
Ts Ph
O
Ph
N
O
O
O
1
2
Ph
O
O
2a
9ba, 70% (2.7:1)
4a, 65% (2.2:1)
Ph
O
Ts
O
O
O
N
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
O
O
Ph
Ph
Ph
4’b, 30% (1.3:1)
Ph
2
b
9bb, 40% (1.3:1)
Ph
O
Ph
Ph
O
Ts Ph
O
O
O
N
O
O
O
3
4
O
O
Ph
O
O
Ph
Ph
Ph
Ph
Ph
Ph
2
c
9bc, 60% (1.2:1)
4c, 9% (1.4:1) 4’c, 17% (3.5:1)
Et
Ph
O
O
Ts Et
Et
Et
O
O
O
N
O
O
O
O
O
O
O
Et
Ph
Et
Ph
Ph
Ph
Ph
2
d
9bd, 60% (1.2:1)
4d, 24% (4.6:1) 4’d, 25% (1.7:1)
Ph
O
Ts Ph
O
Ph
O
O
N
O
5
6
O
O
O
Me
Ph
Me
Me
Me
2
g
9bg, 70% (2.7:1)
4g, 52% (3.3:1)
Ts Ph
O
O
N
O
O
Me
Ph
b
-
Me
Me
Me
2
h
9bh, 60% (2.5:1)
Et
O
Ts Et
O
Et
O
O
N
O
7
8
O
O
O
Ph
Et
Ph
Ph
Ph
2
i
9bi, 55% (2.8:1)
4i, 27% (2.3:1)
O
Ts Me
Me
Ph
O
N
O
O
Me
Me
O
O
O
O
O
Me
Ph
O
O
Me
O
Ph
Ph
2
j
9bj, 63% (1.5:1)
Ph
Ph
4
j, 13% (2.4:1) 4’j, 15% (1.2:1)
Ph
O
O
Ts Ph
O
Ph
O
N
c
O
O
9
Ph
O
O
2
a
9ba, 50% (14:1)
4a, 37% (13:1)
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9
Ph
O
O
Ts Ph
O
Ph
N
O
d
O
O
10
Ph
O
O
2a
9ba, 52% (11:1)
4a, 52% (13:1)
Unless stated, all reactions were performed with 5 equiv of substrates 2, using
RhCl(PPh ) as catalyst (5 mol%) in toluene (0.03 M), at reflux for 2 hours.
Yields of crossꢀproducts 9 refer to the amount of resin 1b used. Yields of
homodimers 4/4’ refer to the amount of substrate 2 employed. Yields of crossꢀ
products 9 refer to free phthalides released from resins after TFA treatment (see
SI). Regioisomeric ratio in brackets. Only DDA products 10h1-2 could be
identified in the complex mixture obtained (see text). Reaction performed with
Cp*RuCl(cod) (20 mol%) as catalyst, 4 h at 128 °C. Conditions as entry 9, at 100
3
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
b
c
d
°
C for 6 h.
Also, under these specific experimental reaction conditions it was possible to
elucidate a secondary mode of reactivity for diynes 2c and 2h. Naphthofuranones 10c1-4
and 10h1-2 were isolated in the corresponding filtrates in yields ranging from 3.6 to 9%
26
(
Scheme 4A). A possible mechanism for the formation of such cycloisomerization
products is depicted in Scheme 4B (particularly for the case of diyne 2h) and involves a
thermal dehydroꢀDielsꢀAlder (DDA) cycloaddition as key step, a reaction that is witnessing
27
a renewed interest by the chemical community. DDA reaction on substrate 2h leads to the
initial formation of a strained cyclic allene intermediate (11). Product 10h1 is then formed
after strain release on intermediate 11 via hydrogen migration. On the other hand, the
formation of 10h2 can be explained via a retroꢀDielsꢀAlder reaction on intermediate 11.
This ringꢀopening reaction produces intermediate 12 which undergoes a E-Z isomerization
and, once again, a DDA cycloaddition. Cyclic allene 14 thus formed delivers product 10h2
after a hydrogen migration.
Scheme 4. Unexpected lactones obtained as sideꢀproducts.
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9
1
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1
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2
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2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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8
9
0
1
2
3
4
5
6
7
8
9
0
As stated above, a moderate regioselectivity in phthalides 4 and 9 was obtained with
Wilkinson's catalyst (Table 2, entries 1ꢀ8). To reach an improved regioisomeric ratio, we
decided to examine other catalysts. Best results were achieved by using Cp*RuCl(cod) [15,
5
Cp* = η ꢀC (CH ) , cod = 1,5ꢀcyclooctadiene] (Scheme 5). Thus, when the [2+2+2]ꢀ
5
3 5
cycloaddition between resin 1b and unsymmetrical diyne 2a was performed in the presence
of 20 mol% of Cp*RuCl(cod) in toluene at reflux, both soluble and immobilized phthalides
were obtained with very high regioselectivity, in favor of the metaꢀsubstituted aromatic ring
(Scheme 5 and Table 2, entries 9 and 10). The regioselectivity of the process can be
reasonably explained taking into account the accepted mechanism of the Cp*RuClꢀ
1
8c,28
catalyzed [2+2+2] cycloaddition of alkynes.
After initial ruthenabicycle A formation
between catalyst 15 and diyne substrate 2a, four modes of approach of the resin 1b can be
conceived for the ensuing [2+2]ꢀcycloaddition step, two ultimately leading to the major
product 9ba1 (metaꢀisomer) and two leading to 9ba2 (orthoꢀisomer). The regioselectivity
observed can be explained by an initial preferable access of the terminal alkyne to the Ruꢀ
C bond from the less substituted side. This approach would occur, at the same time,
α
regioselectively with the terminal alkyne pointing its terminus toward the chlorine ligand
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8
9
thus avoiding steric congestion. Ring opening on brand new B and eventual reductive
elimination would release the catalytically active species Cp*RuCl and major phthalide
derivative 9ba1. On the other hand, comparable regioselectivity and yields were obtained
when the reaction was also carried out in a oneꢀgram scale of resin 1b, proving the
reliability of the protocol.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Me
Ph
Ph
O
O
Me
Me
Me
Me
cat 15
O
O
O
Ru
1b
Ru
O
Cl
Cl
Ru
Ph
H
Cl
O
O
A
B
N
15
Ts
H
Ts
9ba1 (major
2a
N
TsN
1
b
isomer)
1
1:1 to 14:1
Scheme 5. Regioselective [2+2+2]ꢀcycloaddition of immobilized alkyne 1b
In summary, a complementary approach to simplify [2+2+2]ꢀcycloadditions was
explored involving the use of a polymerꢀsupported alkyne. Polysubstituted phthalides were
sideꢀbyꢀside assembled both in solution and on a polymer support pointing to a shift in
solidꢀphase chemistry culture in which the filtrate phase becomes waste once the reaction
ends. We believe that this proofꢀofꢀconcept approach can be extended to other reactions
2
9
such as enyneꢀalkyne and diyneꢀsulfonimine
cycloadditions and alkyneꢀalkyne
metathesis, and finds its way into diverse combinatorial strategies.
EXPERIMENTAL SECTION
Materials and methods
3
0
Unsaturated precursors 1a and 2 have been previously prepared in the
1
5,18,31
literature.
All other chemical reagents were purchased from commercial suppliers and
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9
1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
used without further purification. Solvents were analytical grade or were purified by
standard procedures prior to use. Yields were calculated for material judged homogeneous
1
by thin layer chromatography (TLC) and nuclear magnetic resonance ( H NMR). All
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
reactions were monitored by thin layer chromatography performed on silica gel 60 F254 preꢀ
coated aluminum sheets, visualized by a 254 nm UV lamp, and stained with an ethanolic
solution of 4ꢀanisaldehyde. Column flash chromatography was performed using silica gel
60 (230 – 400 mesh). Melting points (M.p.) were taken on an electrothermal melting point
apparatus and are uncorrected. Nuclear magnetic resonance spectra were acquired at 300
1
13
MHz for H and 75 MHz for C using CDCl as solvent. Chemical shifts for proton nuclear
3
magnetic resonance spectra are reported in parts per million relative to the signal of
tetramethylsilane (TMS) at 0 ppm (internal standard) and coupling constants (J) are
13
reported in hertz (Hz). Chemical shifts for carbon nuclear magnetic resonance ( C NMR)
spectra are reported in parts per million relative to the center line of the CDCl triplet at
3
7
7.0 ppm. The following abbreviations are used to indicate the multiplicities: s = singlet, d
doublet, t = triplet, q = quartet, m = multiplet, quint = quintet, h = sextet, br = broad
=
signal. IR spectra were obtained using an FTꢀIR spectrometer and only partial spectral data
are listed. High resolution mass spectra (HRMS) were obtained on a QꢀTOF mass
spectrometer and detection of the ions was performed in electrospray ionization, positive
ion mode. The structure of the products were determined by a combination of spectroscopic
methods such as IR, 1D and 2D NMR (including NOE, DEPT, COSY, HSQC and HMBC
experiments) and HRMS. NMR signals assignments were based on 2D NMR experiments
performed.
Representative procedure for the preparation of phthalides 3 and 4 in solution
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9
A mixture of
NꢀbenzylꢀNꢀpropargylꢀpꢀtoluenesulfonamide (1a, 1 mmol, 299
mg), diyne (5 mmol, 5 equiv), and Wilkinson catalyst [Rh(PPh ) Cl, 46 mg, 0.05
2
3
3
mmol] in toluene (33.0 mL, 0.03 M) was heated at reflux. After approx. 2 hours, the
solvent was evaporated under reduced pressure, and the residue was purified by flash
column chromatography on silica gel (eluent hexanes/ethyl acetate) to afford the
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
following phthalides
3 and 4.
Compounds 3aa
Obtained as a pale yellow liquid consisting of an inseparable mixture of 3aa1 and
ꢀ1
3
3
3
aa2 in an approx. ratio 2.2:1 (0.367 g, 0.76 mmol, 76% yield). IR (film) (cm ): 3084,
1
061, 3028, 2926, 1776, 1769, 1454, 1159. H NMR (CDCl , 300 MHz): Major isomer
3
aa1: δ 7.79ꢀ7.72 (m, 2H, Ts), 7.49ꢀ7.29 (m, 7H, ArꢀH, Ts), 7.20ꢀ7.11 (overlapping s and
m, 3H, ArꢀH, 4ꢀH), 7.10ꢀ7.03 (m, 2H, ArꢀH), 7.00 (s, 1H, 6ꢀH), 6.96ꢀ6.88 (s, 1H, ArꢀH),
5.15 (s, 2H, 3ꢀH), 4.41 (s, 2H, 5ꢀCH ), 4.36 (s, 2H, Bn), 2.43 (s, 3H, Ts). Minor isomer
2
3
aa2: δ 7.87 (d, J = 8.0, 1H, 5ꢀH), 7.61ꢀ7.55 (m, 2H, Ts), 7.49ꢀ6.88 (m, 11H, ArꢀH, 4ꢀH),
7
.26ꢀ7.21 (m, 2H, Ts), 5.20 (s, 2H, 3ꢀH), 4.18 (s, 2H, 6ꢀCH ), 4.12 (s, 2H, Bn), 2.41(s, 3H,
2
1
3
Ts). C NMR (CDCl , 75 MHz): Major isomer 3aa1: δ 169.3 (C, Cꢀ1), 148.1 (C, Cꢀ3a),
3
1
43.7 (C, Ts), 143.0 (C, Cꢀ5), 142.4 (C, Cꢀ7), 136.6 (C, Ts), 135.8 (C, C7ꢀPh), 135.1 (C,
Bn), 130.5 (CH, Cꢀ6), 129.8 (2 × CH, Ts), 129.3 (2 × CH, Ar), 128.6 (2 × CH, Ar), 128.3
(3 × CH, Ar), 127.9 (CH, Ar), 127.8 (2 × CH, Ar), 127.1 (2 × CH, Ts), 120.8 (C, Cꢀ7a),
1
20.4 (CH, Cꢀ4), 68.1 (CH , Cꢀ3), 52.3 (CH , Bn), 51.1 (CH , C5ꢀCH ), 21.4 (CH , Ts).
2
2
2
2
3
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Minor isomer 3aa2: δ 169.2 (C, Cꢀ1), 146.2 (C, Cꢀ3a), 143.4 (C, Ts), 140.3 (C, Cꢀ7), 136.3
(C, Ts), 136.1 (C, Cꢀ6), 135.0 (C, Bn), 134.4 (CH, Cꢀ5), 133.9 (C, Ar), 129.6 (2 × CH, Ts),
128.9 (2 × CH, Ar), 128.5 (2 × CH, Ar), 128.3 (2 × CH, Ar), 128.0 (CH, Ar), 127.8 (2 ×
CH, Ar), 127.6 (CH, Ar), 127.0 (2 × CH, Ts), 122.7 (C, Cꢀ7a), 121,0 (CH, Cꢀ4), 67.9 (CH2,
Cꢀ3), 52.4 (CH , Bn), 48.0 (CH , C6ꢀCH ), 21.4 (CH , Ts). HRMS m/z calcd. for
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
2
3
+
C H NO S [M + H] 484.1577, found 484.1573.
29
26
4
Compound 4a1
Obtained as a colourless solid (0.322 g, 0.87 mmol, 35% yield). M.p.: 128.0ꢀ129.0
ꢀ1
1
°
C. IR (film) (cm ): 3059, 3030, 2936, 2222, 1749, 1724, 1279, 1190, 1171, 1049. H
NMR (CDCl , 300 MHz): δ 7.63ꢀ7.52 (m, 4H, ArꢀH), 7.52ꢀ7.35 (m, 6H, ArꢀH), 7.51
3
(overlapping s, 1H, 4ꢀH), 7.49 (overlapping s, 1H, 6ꢀH), 5.40 (s, 2H, 1’ꢀH), 5.33 (s, 2H, 3ꢀ
1
3
H). C NMR (CDCl , 75 MHz): δ 169.1 (C, Cꢀ1), 153.4 (C, Cꢀ3’), 148.4 (C, Cꢀ3a), 143.1
3
(C, Cꢀ7), 141.3 (C, Cꢀ5), 135.8 (C, 7ꢀPh), 132.9 (2 × CH, Ar), 130.8 (CH, Ar), 130.4 (CH,
Cꢀ6), 129.4 (2 × CH, Ar), 128.52 (2 × CH, Ar), 128.49 (CH, Ar), 127.9 (2 × CH, Ar), 121.8
(
C, Cꢀ7a), 120.0 (CH, Cꢀ4), 119.1 (C, Cꢀ6’), 87.5 (C, Cꢀ5’), 79.9 (C, Cꢀ4’), 68.2 (CH , Cꢀ
2
+
3
), 66.3 (CH , Cꢀ1’). HRMS m/z calcd. for C H O [M + H] 369.1121, found 369.1129.
2
24 17
4
Compound 4a2
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1
1
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1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ꢀ1
Obtained as a colourless liquid (0.193 g, 0.52 mmol, 21% yield). IR (film) (cm ):
1
2
920, 2849, 2218, 1771, 1707, 1281, 1169. H NMR (CDCl , 300 MHz): δ 7.87 (d, J = 7.9
3
Hz, 1H, 5ꢀH), 7.61ꢀ7.55 (m, 2H, Ar), 7.52 (d, J = 7.9 Hz, 1H, 4ꢀH), 7.50ꢀ7.26 (m, 8H, Ar),
1
3
5.29 (s, 2H, 3ꢀH), 5.12 (s, 2H, 1’ꢀH). C NMR (CDCl , 75 MHz): δ 169.0 (C, Cꢀ1), 153.3
3
(C, Cꢀ3’), 147.4 (C, Cꢀ3a), 142.0 (C, Cꢀ7), 134.8 (CH, Cꢀ5), 134.6 (C, Cꢀ6), 133.6 (C, C7ꢀ
Ph), 132.9 (2 × CH, Ar), 130.7 (CH, Ar), 128.9 (2 × CH, Ar), 128.5 (2 × CH, Ar), 128.3
(CH, Ar), 128.0 (2 × CH, Ar), 123.3 (C, Cꢀ7a), 121.3 (CH, Cꢀ4), 119.2 (C, Cꢀ6’), 87.0 (C,
Cꢀ5’), 80.0 (C, Cꢀ4’), 67.9 (CH , Cꢀ3), 64.2 (CH , Cꢀ1’). HRMS m/z calcd. for C H O
4
2
2
24 17
+
[
M + H] 369.1121, found 369.1124.
Compounds 3ab
Obtained as a pale yellow liquid consisting of a difficult to separable mixture of
3ab1 and 3ab2 in an approx. ratio 1:1 (0.222 g, 0.46 mmol, 46% yield). NMR spectra
recorded corresponds to a column chromatography fraction enriched in meta isomer 3ab1.
ꢀ1
1
IR (film) (cm ): 3061, 3028, 2922, 1765, 1339, 1159. H NMR (CDCl , 300 MHz): meta
3
isomer 3ab1: δ 7.79ꢀ7.74 (m, 2H, Ts), 7.52ꢀ7.38 (m, 5H, Ar, 5ꢀH, 7ꢀH), 7.36ꢀ7.30 (m, 2H,
Ts), 7.30ꢀ7.25 (m, 2H, Ar), 7.22ꢀ7.14 (m, 3H, Ar), 7.14ꢀ7.06 (m, 2H, Ar), 5.31 (s, 2H, 3ꢀ
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H), 4.43 (s, 2H, 6ꢀCH ), 4.36 (s, 2H, Bn), 2.44 (s, 3H, Ts). ortho Isomer 3ab2: δ 7.81ꢀ7.56
2
(overlapping signal, 1H, 7ꢀH), 7.66ꢀ7.58 (overlapping signals, 3H, Ts, 6ꢀH), 7.52ꢀ7.08 (m,
8H, Ar, Ts), 6.94ꢀ6.88 (m, 4H, Ar), 4.91 (s, 2H, 3ꢀH), 4.25 (s, 2H, 5ꢀCH ), 4.19 (s, 2H, Bn),
2
0
1
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
2
.44 (s, 3H, Ts). C NMR (CDCl , 75 MHz): meta isomer 3ab1: δ 170.5 (C, Cꢀ1), 143.7
3
(C, Ts), 143.4 (C, Cꢀ3a), 138.5 (C, Cꢀ6), 137.0 (C, Cꢀ4), 136.9 (C, Ar), 136.8 (C, Ts), 135.2
(C, Ar), 133.9 (CH, Cꢀ5), 129.8 (2 × CH, Ts), 129.0 (2 × CH, Ar), 128.5 (3 × CH, Ar),
1
7
28.4 (2 × CH, Ar), 127.7 (CH, Ar), 127.5 (2 × CH, Ar), 127.1 (2 × CH, Ts), 126.3 (C, Cꢀ
a), 123.9 (CH, Cꢀ7), 69.4 (CH , Cꢀ3), 51.9 (CH , Bn), 50.7 (CH , C6ꢀCH ), 21.4 (CH ,
2
2
2
2
3
Ts). ortho Isomer 3ab2: δ 170.8 (C, Cꢀ1), 145.8 (Cꢀ3a), 143.5 (C, Ts), 140.7 (C, Cꢀ5),
36.4 (C, Ts), 135.5 (C, Cꢀ4), 134.9 (C, Ar), 134.8 (C, Ar), 129.7 (CH, Cꢀ6), 128.5 (2 ×
1
CH, Ar), 128.3 (2 × CH, Ar), 127.1 (2 × CH, Ts), 124.6 (C, Cꢀ7a), 124.5 (CH, Cꢀ7), 69.0
(CH , Cꢀ3), 52.2 (CH , Bn), 48.1 (CH , C5ꢀCH ), 21.4 (CH , Ts). Unassigned signals: δ
2
2
2
2
3
+
1
28.9, 128.2, 127.8. HRMS m/z calcd. for C H KNO S [M + K] 522.1136, found
29 25 4
5
22.1135.
Compounds 4’b
Obtained as a yellow liquid consisting of a difficult to separate mixture of 4’b1 and
ꢀ1
4’b2 in an approx. ratio 2:1 (0.322 g, 0.87 mmol, 35% yield). IR (film) (cm ): 3059, 3024,
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232, 1769, 1732, 1217. H NMR (CDCl , 300 MHz): Major isomer 4’b1: δ 8.10 (d, J =
3
7
.9 Hz, 1H, 6ꢀH), 7.98 (d, J = 7.9, 1H, 7ꢀH), 7.57ꢀ7.24 (m, 10H, ArꢀH), 5.14 (s, 2H, 3ꢀH),
4.90 (s, 2H, 3’ꢀH). Minor isomer 4’b2: δ 8.65 (d, J = 1.2 Hz, 1H, 7ꢀH), 8.46 (d, J = 1.3, 1H,
1
1
1
1
1
1
1
1
1
1
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2
2
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2
2
2
2
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3
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3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
5
ꢀH), 7.57ꢀ7.24 (m, 10H, ArꢀH), 5.46 (s, 2H, 3ꢀH), 5.22 (s, 2H, 3’ꢀH). C NMR (CDCl ,
3
7
5 MHz): Major isomer 4’b1: δ 170.0 (C, Cꢀ1), 166.0 (C, Cꢀ1’), 146.2 (C, Cꢀ3a), 137.7 (C,
Cꢀ4), 135.8 (C, Ar), 135.0 (C, Cꢀ5), 131.7 (2 × CH, Ar), 131.0 (CH, Cꢀ6), 128.74 (2 × CH,
Ar), 128.3 (C, Cꢀ7a), 128.2 (2 × CH, Ar), 127.62 (2 × CH, Ar), 124.4 (CH, Cꢀ7), 121.84 (C,
Ar), 86.7 (C, Cꢀ5’), 81.9 (C, Cꢀ4’), 69.4 (CH , Cꢀ3), 53.6 (CH , Cꢀ3’). Minor isomer 4’b2:
2
2
δ 169.8 (C, Cꢀ1), 164.4 (C, Cꢀ1’), 148.3 (C, Cꢀ3a) 137.4 (C, Cꢀ4), 136.4 (C, Ar), 134.7
CH, Cꢀ5), 131.8 (2 × CH, Ar), 127.0 (C, Cꢀ7a), 126.0 (CH, Cꢀ7), 121.79 (C, Ar), 87.0 (C,
Cꢀ5’), 82.3 (C, Cꢀ4’), 69.6 (CH , Cꢀ3), 53.9 (CH , Cꢀ3’). Unassigned signals: δ 129.6,
(
2
2
1
29.2, 128.82, 128.76, 128.65, 128.4, 127.64, 127.1. HRMS m/z calcd. for C H O [M +
24 17 4
+
H] 369.1121, found 369.1122.
Compounds 3ac
Obtained as a pale yellow solid consisting of an inseparable mixture of 3ac1 and
ac2 in an approx. ratio 1.2:1 (0.358 g, 0.64 mmol, 64% yield). M.p.: 159.6ꢀ165.7 °C. IR
3
ꢀ1
1
(
film) (cm ): 3059, 3026, 2924, 1763, 1447, 1340, 1159. H NMR (CDCl , 300 MHz):
3
Major isomer 3ac1: δ 7.63ꢀ6.93 (m, 19 H, ArꢀH, Ts), 7.34 (overlapping s, 1H, 6ꢀH), 4.88 (s,
2
H, 3ꢀH), 4.28 (s, 2H, 5ꢀCH ), 4.24 (s, 2H, Bn), 2.37 (s, 3H, Ts). Minor isomer 3ac2: δ
2
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.70 (s, 1H, 5ꢀH), 7.63ꢀ6.93 (m, 19H, ArꢀH, Ts), 5.27 (s, 2H, 3ꢀH), 4.23 (s, 2H, 6ꢀCH2),
1
3
4
.18 (s, 2H, Bn), 2.38 (s, 3H, Ts). C NMR (CDCl , 75 MHz): Major isomer 3ac1: δ 169.5
3
(C, Cꢀ3), 147.2 (C, Cꢀ3a), 140.4 (C, Cꢀ5), 134.1 (C, Cꢀ4), 130.9 (CH, Cꢀ6), 120.5 (C, Cꢀ
0
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2
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4
5
6
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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5
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0
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2
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4
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6
7
8
9
0
7
a), 67.8 (CH , Cꢀ3), 52.3 (CH , Bn), 48.0 (CH , C5ꢀCH ), 21.4 (CH , Ts). Minor isomer
2 2 2 2 3
3
ac2: δ 169.2 (C, Cꢀ3), 143.7 (C, Cꢀ3a), 139.1 (C, Cꢀ7), 137.1 (C, Ar), 136.9 (C, Cꢀ6),
135.6 (C, Cꢀ4), 133.8 (CH, Cꢀ5), 123.3 (C, Cꢀ7a), 67.9 (CH , Cꢀ3), 52.7 (CH , Bn), 48.2
2
2
(CH , C6ꢀCH ), 21.4 (CH , Ts). Unassigned signals: δ 143.5, 143.4, 143.3, 141.4, 136.5,
2
2
3
1
36.2, 135.8, 135.2, 135.0, 134.7, 129.68, 129.66, 129.4, 129.1, 128.9, 128.6, 128.5, 128.4,
128.32, 128.26, 127.9, 127.82, 127.76, 127.7, 127.6, 127.1, 126.97. HRMS m/z calcd. for
+
C H NO S [M + H] 560.1890, found 560.1898.
35
30
4
Compounds 4c and 4’c
Obtained as a pale yellow liquid consisting of an inseparable mixture of compounds
c1/4c2 and 4’c1/4’c2 in an approx. ratio 2:1:3.4:1 (0.403 g, 0.77 mmol, 31% yield). IR
4
ꢀ1
1
(film) (cm ): 3057, 3022, 2218, 1771, 1738, 1711, 1194. H NMR (CDCl , 300 MHz): δ
3
7
2
.63ꢀ7.01 (m, 80H, ArꢀH), 5.17 (s, 2H, 3ꢀH), 5.13 (s, 2H, 3ꢀH), 5.10 (s, 2H, 3ꢀH), 5.08 (s,
13
H, 3ꢀH), 4.84 (s, 2H, 1’ꢀH), 4.82 (s, 2H, 1’ꢀH), 4.45 (s, 2H, 3’ꢀH), 4.42 (s, 2H, 3’ꢀH). C
NMR (CDCl , 75 MHz): δ 169.2, 169.1, 168.90, 168.87, 166.7, 166.6, 152.7, 152.6, 148.7,
3
1
47.3, 146.8, 145.6, 145.3, 145.2, 144.1, 143.1, 141.1, 141.0, 140.8, 138.9, 138.7, 137.8,
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36.9, 136.8, 136.5, 136.44, 136.40, 136.2, 136.0, 135.7, 135.3, 135.2, 134.8, 134.7, 134.1,
33.9, 133.51, 133.46, 133.1, 132.9, 131.7, 130.7, 130.6, 130.1, 130.00, 129.96, 129.8,
29.7, 129.6, 129.1, 129.0, 128.9, 128.8, 128.7, 128.65, 128.60, 128.5, 128.4, 128.2, 128.1,
27.9, 127.7, 127.64, 127.56, 127.53, 127.48, 127.4, 127.3, 127.2, 127.1, 123.7, 123.2,
1
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2
2
2
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3
3
3
3
3
3
4
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4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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7
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0
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8
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1
22.5, 122.0, 121.95, 121.92, 119.4, 119.3, 86.4, 86.3, 82.3, 81.8, 81.6, 80.1, 79.9, 68.1,
+
6
8.0, 67.8, 67.7, 62.9, 62.7, 53.13, 53.06. HRMS m/z calcd. for C H O [M + H]
36 25 4
521.1747, found 521.1731.
Compounds 3ad
Obtained as a pale yellow liquid consisting of an inseparable mixture of 3ad1 and
ad2 in an approx. ratio 1.1:1 and trimers 5d (0.409 g, 0.80 mmol, 80% yield). IR (film)
3
ꢀ1
1
(cm ): 3061, 3028, 2970, 2934, 1759, 1730, 1342, 1159. H NMR (CDCl , 300 MHz):
3
Major isomer 3ad1: δ 7.81ꢀ7.74 (m, 2H, Ts), 7.52ꢀ6.86 (m, 13H, Ar, Ts, 5ꢀH), 5.21 (s, 2H,
3
ꢀH), 4.50 (s, 2H, 6ꢀCH ), 4.37 (s, 2H, Bn), 2.96 (q, J = 7.4 Hz, 2H, 7ꢀEt), 2.42 (s, 3H, Ts),
2
1.02 (t, J = 7.5 Hz, 3H, 7ꢀEt). Minor isomer 3ad2: δ 7.66ꢀ7.59 (m, 2H, Ts), 7.52ꢀ6.86 (m,
3H, Ar, Ts, 6ꢀH), 4.84 (s, 2H, 3ꢀH), 4.23 (s, 2H, 5ꢀCH ), 4.21 (s, 2H, Bn), 3.01 (q, J = 7.5
1
2
13
Hz, 2H, 7ꢀEt), 2.43 (s, 3H, Ts), 1.21 (t, J = 7.5 Hz, 3H, 7ꢀEt). C NMR (CDCl , 75 MHz):
3
Major isomer 3ad1: δ 170.3 (C, Cꢀ1), 144.1 (C, Cꢀ3a), 143.6 (C, Ts), 143.1 (C, Cꢀ7), 137.2
(C, Ph), 136.6 (C, Ts), 135.3 (C, Bn), 135.2 (C, Cꢀ6), 134.1 (CH, Cꢀ5), 133.8 (C, Cꢀ4),
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29.8 (2 × CH, Ts), 127.1 (2 × CH, Ts), 123.1 (C, Cꢀ7a), 68.0 (CH , Cꢀ3), 51.9 (CH , Bn),
2
2
4
7.4 (CH , C6ꢀCH ), 21.4 (CH , Ts), 19.2 (CH , C7ꢀEt), 14.8 (CH , C7ꢀEt). Minor isomer
2
2
3
2
3
3ad2: δ 170.6 (C, Cꢀ1), 146.4 (Cꢀ3a), 144.6 (C, Cꢀ7), 143.5 (C, Ts), 140.2 (C, Cꢀ5), 136.6
C, Ts), 135.02 (C, Bn), 134.98 (C, Ph), 132.9 (C, Cꢀ4), 129.7 (2 × CH, Ts), 129.2 (CH, Cꢀ
), 127.0 (2 × CH, Ts), 121.4 (C, Cꢀ7a), 68.2 (CH , Cꢀ3), 52.2 (CH , Bn), 48.1 (CH , C5ꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
6
2
2
2
CH ), 23.8 (CH , C7ꢀEt), 21.3 (CH , Ts), 14.8 (CH , 7ꢀEt). Unassigned signals: δ 128.84,
2
2
3
3
+
1
28.79, 128.3, 128.2, 127.5. HRMS m/z calcd. for C H NO S [M + H] 512.1890, found
31 30 4
5
12.1881.
Compounds 4d
Obtained as a colourless liquid consisting of an inseparable mixture of 4d1 and 4d2
ꢀ1
in an approx. ratio 5:1 (0.222 g, 0.52 mmol, 21% yield). IR (film) (cm ): 3059, 2980, 2938,
1
2235, 1759, 1713, 1244. H NMR (CDCl , 300 MHz): Major isomer 4d1: δ 7.25ꢀ7.13 (m,
3
6
2
H, ArꢀH), 7.08ꢀ7.00 (m, 2H, ArꢀH), 6.99ꢀ6.93 (m, 2H, ArꢀH), 5.043 (s, 2H, 3ꢀH), 5.039 (s,
H, 6ꢀCH ), 3.29 (q, J = 7.5 Hz, 2H, 7ꢀEt), 2.34 (q, J = 7.5 Hz, 2H, 6’ꢀH), 1.35 (t, J = 7.4
2
Hz, 7ꢀEt), 1.20 (t, J = 7.5 Hz, 7’ꢀH). Minor isomer 4d2: δ 7.50ꢀ7.39 (m, 6H, ArꢀH), 7.35ꢀ
.28 (m, 2H, ArꢀH), 7.27ꢀ7.19 (m, 2H, ArꢀH), 5.03 (s, 2H, 3ꢀH), 4.65 (s, 2H, 1’ꢀH), 2.88 (q,
7
J = 7.5 Hz, 2H, 7ꢀEt), 2.32 (q, J = 7.5 Hz, 2H, 6’ꢀH), 1.20 (t, J = 7.5 Hz, 3H, 7’ꢀH), 1.08 (t,
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3
J = 7.5 Hz, 3H, 7ꢀEt). C NMR (CDCl , 75 MHz): Major isomer 4d1: δ 170.4 (C, Cꢀ1),
3
1
53.0 (C, Cꢀ3’), 148.7 (C, Cꢀ5), 147.0 (C, Cꢀ3a), 146.1 (C, Cꢀ7), 137.4 (C, Ar), 136.3 (C,
Ar), 134.4 (C, Cꢀ4), 132.4 (C, Cꢀ6), 129.6 (2 × CH, Ar), 128.9 (2 × CH, Ar), 128.1 (2 ×
CH, Ar), 127.7 (2 × CH, Ar), 127.4 (CH, Ar), 127.3 (CH, Ar), 122.2 (C, Cꢀ7a), 91.1 (C, Cꢀ
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
’), 71.9 (C, Cꢀ5’), 68.3 (CH , Cꢀ3), 61.8 (CH , Cꢀ1’), 20.8 (CH , 7ꢀEt), 15.7 (CH , 7ꢀEt),
2 2 2 3
12.4 (CH , Cꢀ7’), 12.3 (CH , Cꢀ6’). Minor isomer 4d2: δ 170.5 (C, Cꢀ1), 152.5 (C, Cꢀ3’),
3
2
1
4
45.8 (C, Cꢀ3a), 145.0 (C, Cꢀ6), 143.9 (C, Cꢀ7), 137.0 (C, Ar), 136.4 (C, Cꢀ5), 135.8 (C, Cꢀ
), 135.4 (C, Ar), 129.4 (2 × CH, Ar), 128.8 (2 × CH, Ar), 128.5 (2 × CH, Ar), 128.4 (CH,
Ar), 128.2 (2 × CH, Ar), 127.8 (CH, Ar), 123.0 (C, Cꢀ7a), 90.7 (C, Cꢀ5’), 71.8 (C, Cꢀ4’),
6
8.3 (CH , Cꢀ3), 62.4 (CH , Cꢀ1’), 21.6 (CH , 7ꢀEt), 15.4 (CH , 7ꢀEt), 12.4 (CH , Cꢀ7’),
2 2 2 3 3
+
1
2.3 (CH , Cꢀ6’). HRMS m/z calcd. for C H O [M + H] 425.1747, found 425.1753.
2
28 25
4
Compounds 4’d
Obtained as a pale yellow liquid consisting of an inseparable mixture of 4’d1 and
ꢀ1
4’d2 in an approx. ratio 1.5:1 (0.212 g, 0.50 mmol, 20% yield). IR (film) (cm ): 2972,
1
2
7
2
936, 1761, 1738, 1198, 1028. H NMR (CDCl , 300 MHz): Major isomer 4’d1: δ 7.52ꢀ
3
.20 (m, 10H, ArꢀH), 5.21 (s, 2H, 3’ꢀH), 4.89 (s, 2H, 3ꢀH), 3.13 (q, J = 7.5 Hz, 2H, 7ꢀEt),
.61 (q, J = 7.5 Hz, 2H, 5ꢀEt), 1.33 (t, J = 7.5 Hz, 3H, 7ꢀEt), 1.02 (t, J = 7.5 Hz, 3H, 5ꢀEt).
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Minor isomer 4’d2: δ 7.52ꢀ7.20 (m, 10H, ArꢀH), 5.04 (s, 2H, 3ꢀH), 4.81 (s, 2H, 3’ꢀH), 3.23
(q, J = 7.5 Hz, 2H, 7ꢀEt), 2.81 (q, J = 7.5 Hz, 2H, 6ꢀEt), 1.27 (t, J = 7.5 Hz, 3H, 7ꢀEt), 1.26
1
3
(t, J = 7.5 Hz, 3H, 6ꢀEt). C NMR (CDCl , 75 MHz): Major isomer 4’d1: δ 170.1 (C, Cꢀ1),
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
6
7
8
9
0
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2
3
4
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7
8
9
0
1
68.2 (C, Cꢀ1’), 147.9 (C, Cꢀ3a), 145.4 (C, Cꢀ5), 142.1 (C, Cꢀ7), 135.3 (C, Ar), 134.5 (C,
Cꢀ4), 131.6 (2 × CH, Ar), 128.9 (2 × CH, Ar), 128.7 (2 × CH, Ar), 128.4 (CH, Ar), 128.2 (2
× CH, Ar), 121.8 (C, Cꢀ6’), 120.5 (C, Cꢀ7a), 87.0 (C, Cꢀ5’), 82.0 (C, Cꢀ4’), 68.3 (CH , Cꢀ
2
3
), 53.5 (CH , Cꢀ3’), 24.3 (CH , C5ꢀEt), 22.3 (CH , C7ꢀEt), 15.6 (CH , C7ꢀEt), 15.3 (CH ,
2 2 2 3 3
C5ꢀEt). Minor isomer 4’d2: δ 170.3 (C, Cꢀ1), 167.8 (C, Cꢀ1’), 143.9 (C, Cꢀ7), 143.8 (C, Cꢀ
3a), 140.6 (C, Cꢀ6), 138.4 (C, Cꢀ5), 135.3 (C, Ar), 132.0 (C, Cꢀ4), 131.7 (2 × CH, Ar),
1
28.8 (CH, Ar), 128.7 (CH, Ar), 128.5 (2 × CH, Ar), 128.25 (2 × CH, Ar), 128.20 (2 × CH,
Ar), 123.7 (C, Cꢀ7a), 121.9 (C, Cꢀ6’), 86.7 (C, Cꢀ5’), 81.8 (C, Cꢀ4’), 67.9 (CH , Cꢀ3), 53.2
2
(CH , Cꢀ3’), 23.0 (CH , C6ꢀEt), 19.9 (CH , C7ꢀEt), 15.8 (CH , C6ꢀEt), 15.5 (CH , C7ꢀEt).
2
2
2
3
3
+
HRMS m/z calcd. for C H O [M + H] 425.1747, found 425.1747.
2
8
25
4
Compounds 5d
Obtained as a pale yellow liquid consisting of an inseparable mixture of trimers 5d
ꢀ1
in an approx. ratio 2:1 (0.178 g, 0.28 mmol, 17% yield). IR (film) (cm ): 3022, 2972, 2936,
1
2
876, 1759, 1728, 1028. H NMR (CDCl , 300 MHz): Only major isomer could be
3
analysed, δ 7.53ꢀ6.85 (m, 15H, ArꢀH), 5.32 (s, 2H, 3’ꢀH), 5.04 (s, 2H, 3’’ꢀH), 4.87 (s, 2H,
3
ꢀH), 3.34 (q, J = 7.4 Hz, 2H, 7’’ꢀEt), 2.95 (q, J = 7.5 Hz, 2H, 7ꢀEt), 2.48 (q, J = 7.5 Hz,
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H, 5ꢀEt), 1.36 (t, J = 7.3 Hz, 3H, 7’’ꢀH), 1.19 (t, J = 7.4 Hz, 3H, 7’ꢀH), 0.88 (t, J = 7.6 Hz,
1
3
3
H, 5ꢀH). C NMR (CDCl , 75 MHz): Signals for phenyl groups have not been assigned, δ
3
170.3 (C, Cꢀ1’’), 170.1 (C, Cꢀ1), 168.5 (C, Cꢀ1’), 148.8 (C, Cꢀ6’’), 147.7 (C, Cꢀ3a), 147.2
C, Cꢀ3a’’), 146.0 (C, Cꢀ7’’), 145.1 (C, Cꢀ5), 141.8 (C, Cꢀ7), 135.6 (C, Cꢀ6), 134.6 (C, Cꢀ
), 134.5 (C, Cꢀ4’’), 132.1 (C, Cꢀ5’’), 122.3 (C, Cꢀ7a’’), 120.5 (C, Cꢀ7a), 68.3 (2 × CH , Cꢀ
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
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4
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7
8
9
0
1
2
3
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6
7
8
9
0
(
4
2
3, Cꢀ3’’), 61.9 (CH , Cꢀ3’), 24.6 (CH , C5ꢀEt), 22.6 (CH , C7ꢀEt), 20.9 (CH , C7’’ꢀEt),
2
2
2
2
1
5.9 (CH , C7’’ꢀEt), 15.6 (CH , C7ꢀEt), 15.5 (CH , C5ꢀEt). HRMS m/z calcd. for C H O
3 3 3 42 37 6
+
[
M + H] 637.2585, found 637.2574.
Compounds 3ae
Obtained as a pale yellow liquid consisting of an inseparable mixture of 3ae1 and
3
ae2 in an approx. ratio 3:1 (0.199 g, 0.40 mmol, <40% yield, contaminated with
ꢀ1
inseparable unidentified sideꢀproducts). IR (film) (cm ): 3028, 2920, 2903, 1728, 1339,
1
1
159, 1094. H NMR (CDCl , 300 MHz): Major isomer 3ae1: δ 7.78ꢀ7.71 (m, 2H, Ts),
3
7
.46ꢀ7.02 (m, 12H, ArꢀH, Ts), 6.96 (s, 1H, 5ꢀH), 6.83 (s, 1H, 7ꢀH), 4.44 (t, J = 5.8, 2H, 3ꢀ
H), 4.34 (s, 2H, Bn), 4.33 (s, 2H, 6ꢀCH ), 2.90 (t, J = 5.7, 2H, 4ꢀH), 2.43 (s, 3H, Ts). Minor
2
isomer 3ae2: δ 7.69 (d, J = 8.1 Hz, 1H, 6ꢀH), 7.59ꢀ7.52 (m, 2H, Ts), 7.46ꢀ6.78 (m, 13H,
ArꢀH, Ts, 5ꢀH), 4.41 (t, J = 5.7, 2H, 3ꢀH), 4.11 (s, 2H, Bn), 4.03 (s, 2H, 7ꢀCH ), 3.01 (t, J =
2
1
3
5
.7, 2H, 4ꢀH), 2.40 (s, 3H, Ts). RMN de C (CDCl , 300 MHz): Major isomer 3ae1: δ
3
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63.1 (C, Cꢀ1), 145.7 (C, Cꢀ8), 143.5 (C, Ts), 141.1 (C, Cꢀ4a), 140.7 (C, Cꢀ6), 140.6 (C,
Ar), 136.8 (C, Ts), 135.3 (C, Bn), 130.3 (CH, Cꢀ7), 129.7 (2 × CH, Ar), 128.6 (2 × CH,
Ar), 128.2 (2 × CH, Ar), 128.1 (2 × CH, Ar), 127.8 (2 × CH, Ar), 127.0 (2 × CH, Ar),
0
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2
3
4
5
6
7
8
9
0
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3
4
5
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8
9
0
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7
8
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0
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1
26.0 (CH, Cꢀ5), 122.5 (C, Cꢀ8a), 66.5 (CH , Cꢀ3), 52.0 (CH , Bn), 50.8 (CH , 6ꢀCH ),
2 2 2 2
2
9.0 (CH , Cꢀ4), 21.4 (CH , Ts). Minor isomer 3ae2: δ 162.9 (C, Cꢀ1), 143.32 (C, Ts),
2
3
143.28 (C, Cꢀ8), 139.5 (C, Cꢀ4a), 138.4 (C, Ar), 136.5 (C, Ar), 135.3 (C, Cꢀ7) 135.1 (C,
Bn), 132.9 (2 × CH, Ts), 132.7 (CH, Cꢀ6), 129.5 (2 × CH, Ar), 128.5 (2 × CH, Ar), 128.1
(2 × CH, Ar), 127.9 (2 × CH, Ar), 127.6 (CH, Ar), 127.0 (2 × CH, Ts), 126.5 (CH, Cꢀ5),
1
23.9 (C, Cꢀ8a), 66.5 (CH , Cꢀ3), 52.2 (CH , Bn), 48.7 (CH , C7ꢀCH ), 28.9 (CH , Cꢀ4),
2
2
2
2
2
+
21.4 (CH , Ts). HRMS m/z calcd. for C H NO S [M + H] 498.1734, found 498.1731.
3
30 28
4
Preparation of resin 1b
To 1.0 g of BOBA resin prepared according to Kobayashi and Aoki (7, approximate
loading: 1.00 mmol/g) suspended in dichloromethane (9 mL) was added pꢀtoluenesulfonyl
chloride (0.593 g, 3.10 mmol) and triethylamine (0.65 mL, 1.57 mmol). The reaction
mixture was stirred at room temperature for 18 hours and then filtered. The remaining resin
was then washed with dichloromethane (7 × 10 mL) and dried under reduced pressure. To
this resin in DMF (18 mL) was added cesium carbonate (1.77 g, 5.4 mmol) and propargyl
bromide (80% in toluene, 1.2 mL, 10.8 mmol). The reaction mixture was stirred at room
temperature for 24 hours and then filtered. The remaining solid was washed with DMF (2 ×
10 mL), DMF:H O (2 × 10 mL), H O (2 × 10 mL), DMF (3 × 10 mL), DCM and MeOH
2
2
(alternated 5 × 10 mL each) and DCM (3 × 10 mL). The final resin was dried under
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reduced pressure to afford resin 1b (approx. 1.18 g). The loading of resin 1b was calculated
based on the amount of compound 8 released upon treatment with TFA in DCM (1 mL
TFA/3 mL DCM for 100 mg of resin 1b, 18 h, room temperature). The crude mixture thus
obtained was purified by flash column chromatography on silica gel (eluent
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
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3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
hexanes/ethyl acetate) to afford known compound
mmol/g; theoretical loading 1b: 0.88 mmol/g, isolated amount
mmol, calculated loading 1b: 0.66 mmol/g, 75% yield after five steps from resin
8
(initial loading resin
: 13.8 mg, 0.066
).
6: 1.16
8
6
3
2
Compound 8
1
Colourless solid. M.p.: 74.0ꢀ75.0 ºC. H NMR (CDCl , 300 MHz): δ 7.83ꢀ7.73 (m, 2H),
3
7
3
7
.36ꢀ7.28 (m, 2H), 4.76 (t, J = 5.5 Hz, 1H), 3.83 (dd, J = 6.0 Hz, J = 2.5 Hz, 2H), 2.43 (s,
1
3
H), 2.10 (t, J = 2.5 Hz, 1H). C NMR (CDCl , 75 MHz): δ 143.7, 136.4, 129.6, 127.3,
3
7.8, 72.9, 32.7, 21.4.
Representative procedure for the solid-phase synthesis of phthalides 9 and 4
A mixture of resin 1b (200 mg, 0.66 mmol/g, 0.13 mmol), diyne
2 (0.66
mmol, 5 equiv), and Wilkinson catalyst [Rh(PPh ) Cl, 6 mg, 0.0065 mmol] in
3
3
toluene (4.5 mL, 0.03 M) was heated at reflux. After approx. 2 hours, the reaction
was filtered and the filtrate was evaporated under reduced pressure. This residue was
purified by flash column chromatography on silica gel (eluent hexanes/ethyl acetate)
to afford the following phthalides 4. The remaining resin was treated overnight with
TFA in DCM (1 mL TFA/3 mL DCM for 100 mg of resin, room temperature). After
that time, the solvent was evaporated and the residue purified by flash column
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5
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6
chromatography on silica gel (eluent hexanes/ethyl acetate or DCM/methanol) to
afford the following phthalides 9.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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0
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0
Compounds 9ba
Obtained as a pale yellow liquid consisting of an inseparable mixture of 9ba1 and
ꢀ1
9
ba2 in an approx. ratio 2.7:1 (0.036 g, 0.09 mmol, 70% yield). IR (film) (cm ): 3059,
1
3
026, 2924, 1755, 1327, 1159. H NMR (CDCl , 300 MHz): Major isomer 9ba1: δ 7.76ꢀ
3
7.70 (m, 2H, Ts), 7.48ꢀ7.38 (m, 5H, ArꢀH), 7.35 (s, 1H, 4ꢀH), 7.30ꢀ7.25 (m, 2H, Ts), 7.23
s, 1H, 6ꢀH), 5.37 (t, J = 6.5 Hz, 1H, NꢀH), 5.19 (s, 2H, 3ꢀH), 4.27 (d, J = 6.5 Hz, 2H, 5ꢀ
(
CH ), 2.41 (s, 3H, Ts). Minor isomer 9ba2: δ 7.80 (d, J = 7.9 Hz, 1H, 5ꢀH), 7.57ꢀ7.51 (m,
2
2H, Ts), 7.47ꢀ7.36 (m, 3H, Ar, 4ꢀH), 7.29ꢀ7.17 (m, 3H, ArꢀH), 7.14ꢀ7.09 (m, 2H, Ts), 5.24
(
s, 2H, 3ꢀH), 4.71 (t, J = 6.3 Hz, 1H, NꢀH), 4.00 (d, J = 6.3 Hz, 2H, 6ꢀCH ), 2.41 (s, 3H,
2
1
3
Ts). C NMR (CDCl , 75 MHz): Major isomer 9ba1: δ 169.3 (C, Cꢀ1), 148.5 (C, Cꢀ3a),
3
143.7 (C, Ts), 143.2 (C, Cꢀ5), 142.7 (C, Cꢀ7), 136.7 (C, Ts), 135.7 (C, Ar), 130.1 (CH, Cꢀ
6
), 129.6 (2 × CH, Ts), 129.3 (2 × CH, Ar), 128.4 (CH, Ar), 127.8 (2 × CH, Ar), 126.9 (2 ×
CH, Ts), 121.0 (C, Cꢀ7a), 119.8 (CH, Cꢀ4), 68.1 (CH , Cꢀ3), 46.6 (CH , C5ꢀCH ), 21.4
2
2
2
(CH , Ts). Minor isomer 9ba2: δ 169.1 (C, Cꢀ1), 146.8 (C, Cꢀ3a), 143.4 (C, Ts), 141.1 (C,
3
Cꢀ7), 136.2 (C, Ts), 136.1 (C, Cꢀ6), 135.0 (CH, Cꢀ5), 133.8 (C, Ar), 129.5 (2 × CH, Ts),
1
28.6 (2 × CH, Ar), 128.2 (2 × CH, Ar), 128.1 (CH, Ar), 126.8 (2 × CH, Ts), 123.2 (C, Cꢀ
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a), 121.4 (CH, Cꢀ4), 68.0 (CH , Cꢀ3), 43.9 (CH , C6ꢀCH ), 21.4 (CH , Ts). HRMS m/z
2
2
2
3
+
calcd. for C H NO S [M + H] 394.1108, found 394.1092.
2
2
20
4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Compounds 9bb
Obtained as a pale yellow liquid consisting of an inseparable mixture of 9bb1 and
ꢀ1
9bb2 in an approx. ratio 1.3:1 (0.020 g, 0.052 mmol, 40% yield). IR (film) (cm ): 3026,
1
2
2
922, 1751, 1327, 1159. H NMR (CDCl , 300 MHz): Major isomer 9bb1: δ 7.79ꢀ7.72 (m,
3
H, Ts), 7.66 (s, 1H, 7ꢀH), 7.64 (s, 1H, 5ꢀH), 7.53ꢀ7.40 (m, 3H, ArꢀH), 7.40ꢀ7.34 (m, 2H,
ArꢀH), 7.33ꢀ7.27 (m, 2H, Ts), 5.36 (s, 2H, 3ꢀH), 4.97 (t, J = 6.5 Hz, 1H, NꢀH), 4.30 (d, J =
.3 Hz, 2H, 6ꢀCH ), 2.42 (s, 3H, Ts). Minor isomer 9bb2: δ 7.84 (d, J = 8.1 Hz, 1H, 7ꢀH),
6
2
7.60 (d, J = 8.0 Hz, 1H, 6ꢀH), 7.60ꢀ7.55 (m, 2H, Ts), 7.53ꢀ7.28 (m, 3H, ArꢀH), 7.24ꢀ7.18
(m, 2H, Ts), 7.17ꢀ7.11 (m, 2H, ArꢀH), 4.99 (s, 2H, 3ꢀH), 4.60 (t, J = 6.2 Hz, 1H, NꢀH), 4.10
13
(d, J = 6.3 Hz, 2H, 5ꢀCH ), 2.42 (s, 3H, Ts). C NMR (CDCl , 75 MHz): Major isomer
2
3
9bb1: δ 170.5 (C, Cꢀ1), 143.8 (C, Ts), 143.7 (C, Cꢀ3a), 138.9 (C, Cꢀ6), 137.4 (C, Cꢀ4),
1
1
36.9 (C, Ar), 136.7 (C, Ts), 133.4 (CH, Cꢀ5), 129.7 (2 × CH, Ts), 129.1 (2 × CH, Ar),
28.6 (CH, Ar), 127.5 (2 × CH, Ar), 127.0 (2 × CH, Ts), 126.8 (C, Cꢀ7a), 123.4 (CH, Cꢀ7),
69.5 (CH , Cꢀ3), 46.6 (CH , C6ꢀCH ), 21.4 (CH , Ts). Minor isomer 9bb2: δ 170.6 (C, Cꢀ
2
2
2
3
1
), 146.1 (C, Cꢀ3a), 143.6 (C, Ts), 140.4 (C, Cꢀ5), 136.4 (C, Ts), 136.2 (C, Cꢀ4), 134.8 (C,
Ar), 130.3 (CH, Cꢀ6), 129.6 (2 × CH, Ts), 129.2 (2 × CH, Ar), 128.6 (CH, Ar), 128.1 (2 ×
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