This is the peer reviewed version of the following article: Angewandte Chem. Int. Edition 2015, 56, 15068–15072, which has been
published in final form at http://onlinelibrary.wiley.com/doi/10.1002/anie.201707341/full . This article may be used for non-commercial
purposes in accordance with http://olabout.wiley.com/WileyCDA/Section/id-820227.html

Catalytic Asymmetric [8+2] Annulation Reactions Promoted by a
Recyclable Immobilized Isothiourea
Shoulei Wang,[a] Carles Rodríguez-Escrich,[a] and Miquel A. Pericàs*[a],[b]
Abstract: Higher order cycloadditions constitute an efficient approach
towards the construction of medium to large ring systems. However,
enantioselective versions of these transformations remain scarce,
which hampers their deployment in medicinal chemistry, or any other
discipline where homochirality is deemed crucial. Herein, we report a
novel methodology for the production of enantioenriched
cycloheptatrienes fused to a pyrrolidone ring, based on an
isothiourea-catalyzed periselective [8+2] cycloaddition between chiral
ammonium enolates (generated in situ from carboxylic acids) and
azaheptafulvenes. The resulting bicyclic compounds can be
hydrogenated but, most remarkably, they can also undergo a
completely regioselective [4+2] cycloaddition with active dienophiles
to give rise to architecturally complex polycyclic compounds in a
straightforward manner.

possible reaction pathways that can be attained with heptafulvene
derivatives, the [8+2] cycloaddition provides a direct approach to
highly functionalized bicyclic [5.3.0] rings, which are core
scaffolds in numerous natural products.[14] Since the first [8+2]
cycloaddition introduced by Wiley et al. in 1960,[15] various
methodologies to carry out this process have been described,[16]
but enantioselective versions remain scarce: to the best of our
knowledge, a metal-mediated cycloaddition reported by the Feng
group[17] (Scheme 1a) and an organocatalytic cycloaddition
described by the Jørgensen group[18] (Scheme 1b) are the only
catalytic enantioselective [8+2] reactions found in the literature.
Therefore, the development of a general and efficient approach
for the peri-, regio- and stereoselective [8+2] cycloaddition
reaction remains a highly attractive and challenging target.

Cyclic structures are ubiquitous in natural products and
pharmaceutical compounds. Among the myriad strategies
devised to construct such architectures,[1] cycloadditions
constitute one of the most efficient approaches in terms of atom
economy and overall reaction selectivity.[2] Indeed, the synthesis
of rings having up to 6 members by either thermal or
photochemical [2+2],[3] [3+2][4] and [4+2][5] processes is well
established. On the other hand, the synthesis of medium and
large rings through reactions involving more than six p electrons
(the so called higher order cycloadditions[6]) represents an
interesting approach to build complex polycyclic compounds and
bridge-containing
carbocyclic
products.
However,
this
alternative[7] is often hampered by lack of periselectivity and other
competing side reactions[8] which, along with the extra challenge
of transferring chiral information across a number of bonds, can
explain the lack of general methods to produce enantioenriched
compounds via higher order cycloadditions.[9]

We envisioned that chiral ammonium enolates[19] (derived from
activated carboxylic acids and isothioureas) could be suitable
reaction partners to undergo catalytic [8+2] cycloadditions with
azaheptafulvenes, which would play the role of 8p dipolarophiles.
Herein, we present the implementation of this strategy, which
leads to enantioenriched 7,5-fused heterocyclic compounds
(Scheme 1c). The cycloheptatrienes generated can be either
hydrogenated or derivatized in a Diels-Alder reaction that affords
bridged polycyclic products in a highly regioselective manner.

[10]

[11]

(a)

N

Ar
EWG
+ R

(b)

C(EWG)2

metal
catalysis

EWG
EWG

O

*

R

EWG

H H

organocatalysis

+

Feng et al.

*

N
Ar

*
*

O

Jørgensen et al.

*

H
EWG EWG

Heptafulvenes
and their heteroanalogues (tropone,
tropothione[12] and the azaheptafulvenes[13]), a subclass of the
“non-benzenoid aromatic compounds” family, have been
recognized as important synthons for higher order cycloadditions
due to their conjugated cyclic polyolefin systems. Among all the

(c)

[a]

Scheme 1. Enantioselective versions of [8+2] cycloaddition.

[b]

Mr. Shoulei Wang, Dr. Carles Rodríguez-Escrich, Prof. Dr. Miquel A.
Pericàs
Institute of Chemical Research of Catalonia (ICIQ), The Barcelona
Institute of Science and Technology
Av. Països Catalans 16, 43007 Tarragona, Spain
E-mail: mapericas@iciq.es
Prof. Dr. Miquel A. Pericàs
Departament de Química Inorgànica i Orgànica
Universitat de Barcelona
08080 Barcelona, Spain
Supporting information for this article is given via a link at the end of
the document.

N

R2

R1
O
+ R1

[8+2]

* *

O

BTM
BTM

N
R2

recyclable catalyst

This work:

▪︎ No isomerization
▪︎ Regioselective
▪︎ Enantioselective
▪︎ Diastereoselective
▪︎ Regio- and stereoselective derivatization

Based on our previous works on formal hetero-[4+2]
cycloadditions promoted by an immobilized isothiourea of the
benzotetramisole (BTM) type,[19e,19g] a model reaction of the
azaheptafulvene 2a with phenylacetic acid 3a catalyzed by
polystyrene-supported BTM was investigated (Table 1). After a
preliminary study, we established a standard protocol based on

the use of immobilized isothiourea 1b, PivCl and DBU in CH2Cl2
at 0 ºC. Under these conditions, azaheptafulvene 2a was fully
consumed and the desired [8+2] product 4a could be obtained in
high stereoselectivity (96:4 dr, 91% ee, entry 1). Previously
reported possible side products,[17] such as those derived from
isomerization of the cycloheptatriene unit, were not detected. For
the sake of comparison, we also tested the homogeneous
isothiourea catalyst 1a, but only moderate diastereoselectivity
was observed (entry 2). This suggested that the additional
stereocenter present in 1b was critical, which was confirmed by
the results obtained with the homogeneous analog 1c (entry 3).
Likewise, other bases like i-Pr2NEt and Et3N resulted in lower
enantioselectivities, albeit conversions and diastereoselectivities
remained the same (entries 4 and 5). Substitution of the activating
reagent (pivaloyl chloride) for BnCOCl and TsCl (entries 6 and 7)
did not improve the results either, whereas other solvents
screened had a negative impact on both reactivity and
stereoselectivity (entries 8-10). In addition, decreasing the
catalyst loading to 5 mol% resulted in lower reactivity and
stereoselectivity (entry 11).
Table 1. Optimization of reaction conditions.

N

OH
+

O

PivCl, DBU
CH2Cl2, 0 ºC

3a

2a

Cat. 1b
(10 mol%)

Tol = 4-MeC6H4

N

Ph

1a

Entry

S

Modification of the
standard conditions

N

R1

Tol

Cat. 1b
(10 mol%)

O
+ R1

O

O

Conv. [%]

4

4b

X = H (4a): 75%, >20:1 dr, 91% ee
X = Br (4b): 73%, >20:1 dr, 90% ee
X = Cl (4c): 70%, >20:1 dr, 94% ee
X = F (4d): 68%, >20:1 dr, 95% ee
X = OMe (4e): 65%, >20:1 dr, 95% ee
X = Ph (4f): 71%, >20:1 dr, 94% ee

N
Tol

X = Cl (4g): 80%
>20:1 dr, 94% ee
X = Me (4h): 73%
>20:1 dr, 97% ee

N
Tol

S

O

4j: 83%
12:1 dr
93% ee

4a

N
N N

Ph

Ph

N
S

N
Tol

4i: 81%
>20:1 dr
90% ee

N
Tol

Ph

N
Tol
O

1b

O

OH PivCl, DBU
CH2Cl2, 0 ºC
3

2a
X

O

Ph

N

N

S

Ph

N
N N

O

N

X

[a]

Tol

derivative (4j, 83% yield, 93% ee); albeit the dr decreased, the
result was still more than satisfactory (12:1). The system also
worked with unsaturated carboxylic acids, providing 4k in good
yield and dr (13:1) but moderate enantioselectivity; however,
using purely aliphatic acids resulted in no conversion. The
absolute configuration of 4b could be ascertained by X-ray
diffraction analysis,[20] that of 4a,c-k being assigned by analogy.

N

dr

[b]

O

N
Tol

O

Scheme 2. Scope of substituted arylacetic acids.

4k: 70%
13:1 dr
47% ee

N
Tol

[a]

1c
[c]

ee [%]

1

None

>95

96:4

91

2

1a as the catalyst

>95

75:25

91

3

1c as the catalyst

>95

96:4

90

4

i-Pr2NEt as the base

>95

96:4

87

5

Et3N as the base

>95

96:4

70

6

TsCl instead of PivCl

65

97:3

90

Next, we set our sights on the evaluation of various N-aryl
substituted 8-azaheptafulvenes in this cycloaddition. In general,
the [8+2] annulation reactions were insensitive to electronic
changes on the aromatic N-substituent on azaheptafulvenes (R2).
A series of cycloheptatriene-fused pyrrolidone derivatives (4l-4r,
Scheme 3) could be accessed in good yields (70-85%), and high
stereoselectivities (90-98% ee, dr >20:1 in all cases).

7

BnCOCl instead of PivCl

55

96:4

91

8

THF instead of CH2Cl2

88

98:2

N

R2

20

9

Et2O instead of CH2Cl2

20

76:24

–

10

CHCl3 instead of CH2Cl2

>95

97:3

5 mol% catalyst

78

97:3

84

2

OH
3a

Ph
O

PivCl, DBU
CH2Cl2, 0 ºC

N

R2

4

88

11

+ Ph

Cat. 1b
(10 mol%)

O

1

[a] Reactions performed on a 0.1 mmol scale. [b] Determined by H NMR
spectroscopy. [c] Determined by chiral HPLC.

After the preliminary optimized reaction conditions passed the
stress tests summarized in Table 1, we turned our attention to
validating the generality of this [8+2] annulation reaction. As
illustrated in Scheme 2, a broad range of substituted phenylacetic
acids bearing electron-withdrawing and electron-donating
substituents are tolerated, giving rise to the cycloadducts 4a-4h
in good yields (65-80%) and high enantioselectivities (90-97%)
and diastereoselectivities (>20:1). The bulkier 2-naphthylacetic
acid also proved to be a good substrate, delivering the desired
product 4i with comparable yield and stereoselectivity (>20:1 dr,
90% ee). A heteroaromatic moiety could also be accommodated
in 3, as shown by the synthesis of the corresponding 2-thienyl

Br
4l
73% yield
>20:1 dr, 97% ee

Cl
4m
72% yield
>20:1 dr, 98% ee

OMe
OCF3
4n
4o
83% yield
70% yield
>20:1 dr, 90% ee >20:1 dr, 92% ee
O

t-Bu
4p
85% yield
>20:1 dr, 91% ee

CO2Me
4q
70% yield
>20:1 dr, 94% ee

N
CF3
4r H
71% yield
>20:1 dr, 90% ee

NHPh
4s
37% yield
>20:1 dr, rac.

Scheme 3. Reactions performed on a 0.1 mmol scale (see Supporting Info).

[a]

Further attempts to explore the scope using tropone
phenylhydrazone as substrate gave the expected product (4s) in
low yield and ee, but high diastereoselectivity. Disappointingly,

no [8+2] product was observed with a tropolone derivative,
bearing a methoxy substituent on C2 of the 8-azaheptafulvene.
From a practical perspective, the possibility of recycling the
immobilized isothiourea catalyst 1b is appealing due to the
inherent reduction of costs and increase of overall efficiency. To
this end, the reaction between 2a and 3a was carried out in a
series of experiments where catalyst 1b was recovered by simple
filtration and reused by adding fresh reactants after each run. No
significant decrease of stereoselectivity was observed and only
marginal erosion in the yield took place over the first four runs
(Scheme 4). The accumulated TON for these recycling
experiments was 44.7, which shows the advantage of this
strategy over the usual approach, where a maximum TON of 10
can be achieved with 10 mol% catalyst loading.

stereoselective manner via a [8+2]/[4+2] reaction sequence. The
structure and absolute configuration of 6 were confirmed by X-ray
diffraction analysis of 6b.[20] To further prove the versatility of
these cycloadducts, we demonstrated that cycloheptatriene-fused
pyrrolidone 4a can be hydrogenated in the presence of catalytic
amounts of Pd/C, providing compound 7 in good yield while
retaining the stereochemical information of 4a (Scheme 5).
Ph

Ph
Pd/C, H2

O

N
Tol

O

EtOAc

94% yield
92% ee
>20:1 dr

N
Tol

4a

7

Scheme 5. Catalytic hydrogenation of 4a.

Tol

N

Ph
OH

+

Cat. 1b (10 mol%)

O
2a

O

PivCl, DBU
CH2Cl2, 0 ºC, 3 h

3a

N
Tol

4a

100
80
60
40

yield
ee

20
0
1

2

3

4

5

6

7

Scheme 4. Recyclability tests.

To demonstrate the synthetic potential of this metodology, we
decided to test the behaviour of the [8+2] cycloadducts 4 as 4p
components in a Diels-Alder reaction. Thus, cycloheptatrienefused pyrrolidone 4a was treated with N-phenyl triazolinedione 5a
in CHCl3 at room temperature. To our delight, the [4+2] product
6a was obtained as a single regioisomer in good yield and high
stereoselectivity (>20:1 dr, 87% ee). The general applicability of
the Diels-Alder reaction between the cycloadducts 4 and Nsubstituted triazolinediones 5 was subsequently investigated.

The catalytic cycle proposed for this transformation, based on
previous reports of isothiourea-mediated cyclizations,[21] is
depicted in Scheme 6. The events start upon in situ formation of
the mixed anhydride A from 3 and pivaloyl chloride. This
intermediate reacts with the isothiourea 1b to form the
corresponding acyl ammonium species B, which is deprotonated
by the pivalate to generate the corresponding enolate (C; DBU
acts as a shuttle base to deprotonate the pivalic acid
generated[22]). Subsequently, 1,8-conjugate addition of the
azaheptafulvene 2 onto C gives rise to D, which readily cyclizes
to generate the desired cycloadduct 4 with concomitant release of
the catalyst that can then engage in the next cycle. It is worth
noting that at present we cannot rule out a concerted mechanism,
but literature precedents suggest[16d] that a stepwise mechanism
is operative with highly polarized substrates.

R1

O

O

N
R2

4

of

4

with

different

substituted

D

N N
+

O

O

N
Tol
4

N
X

CHCl3
O

RT, 3 h

H
R1

5

N

dr

O
O

R2

BTM

O

R1

N

O

BTM

C
2

OH
(neutralized
by DBU)
tBu

O
Scheme 6. Proposed catalytic pathway.

6
1

3 + PivCl

O

R1
B

N O
N NX
Tol O

DBU
tBu

tBu

R1

O

R2

R1

A

1b

N
reactions

O

BTM

BTM

Table 2. Diels-Alder
[a]
triazolinediones.

O

R1

Entry

X

R

1

Ph (6a)

Ph

>20:1

Yield [%]

2

Ph (6b)

4-BrC6H4

>20:1

80

3

Et (6c)

Ph

>20:1

70

4

n-Bu (6d)

Ph

>20:1

77

75

[b]

[a] Reactions performed on a 0.1 mmol scale (see Supporting Information).
[b] 87% ee determined by chiral HPLC.

As shown in Table 2, structurally unique bridged-polycyclic
products 6 containing one quaternary and three tertiary
stereocenters could be efficiently prepared in a highly regio- and

In conclusion, we have developed the first asymmetric
organocatalytic
[8+2]
annulation
reaction
between
azaheptafulvenes and in situ activated arylacetic acids for the
direct synthesis of enantioenriched cycloheptatriene-fused
pyrrolidone derivatives. The transformation is promoted by a
supported isothiourea catalyst that can be recycled at least 7
times by simple filtration. Moreover, we have studied the
derivatization of the resulting [8+2] cycloadducts by means of a
[4+2] cycloaddition to give bridged-polycyclic products in a
regioselective manner. The [8+2]/[4+2] cycloaddition sequence
reported herein represents an efficient stereoselective synthetic

approach to polycyclic compounds. Further synthetic application
of this methodology is currently underway.

Acknowledgements
Financial support from CERCA Programme/Generalitat de
Catalunya, MINECO (CTQ2015-69136-R, AEI/MINECO/FEDER,
UE and Severo Ochoa Excellence Accreditation 2014–2018,
SEV-2013-0319) and DEC Generalitat de Catalunya (Grant
2014SGR827) is acknowledged. The CELLEX Foundation is
acknowledged for financing the High Throughput Experimentation
(HTE) laboratory.
Keywords: higher order cycloadditions • [8+2] cycloaddition •
isothioureas • enantioselective catalysis • immobilized catalysts
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Entry for the Table of Contents

COMMUNICATION
An isothiourea-catalyzed peri- and
enantioselective [8+2] cycloaddition
between chiral ammonium enolates
and azaheptafulvenes is presented.
Enantioenriched cycloheptatrienes
fused to a pyrrolidone ring can be
produced with this novel methodology.
Derivatization of these cycloadducts
via regio- and diastereoselective
Diels–Alder reaction allows the
production of architecturally complex
polycyclic compounds in a
straightforward manner.

Shoulei Wang, Carles RodríguezEscrich and Miquel A. Pericàs*
Page No. – Page No.
Catalytic Asymmetric [8+2]
Annulation Reactions Promoted by a
Recyclable Immobilized Isothiourea