“This document is the Accepted Manuscript version of a Published Work that appeared in final form in Organic Letter, copyright © Amer-

ican Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see
https://pubs.acs.org/doi/10.1021/acs.orglett.9b00906 .”

Diastereodivergent Enantioselective [8+2] Annulation of Tropones and Enals Catalyzed by N-Heterocyclic Carbenes
Shoulei Wang,† Carles Rodríguez-Escrich,† Mauro Fianchini,† Feliu Maseras,*,†,‡ and Miquel A.
Pericàs*,†,§
†

Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Av. Països Catalans 16, 43007 Tarragona, Spain
‡
Departament de Química, Universitat Autonoma de Barcelona, 08193 Bellaterra, Spain
§
Departament de Química Inorgànica i Orgànica, Universitat de Barcelona, 08080 Barcelona, Spain
Supporting Information Placeholder

O

N

R1

O

+

R2

N
N Ar

[8+2]

[8+2]+epimerization

R2

R2

BF4

base

O

or
O

O

O

R1

R1

Diastereodivergent, periselective and enantioselective!

ABSTRACT: N-Heterocyclic carbene (NHC) catalysts are used for the first time to mediate asymmetric [8+2] cycloadditions of
enals with tropones. The kinetic [8+2] cis-cycloadducts can be epimerized to their trans analogues by simply using increased amounts
of base and longer reaction times. Substituted tropones are also tolerated, and the cycloaddition products can be derivatized by hydrogenation or methanolysis. The main stereochemical features of the process have been rationalized by microkinetic modeling based
on the results of DFT calculations.

Chiral catalyst development has given rise to an ever growing
toolkit that allows to cover a wide range of chemical space
through myriad transformations. However, the stress is usually
placed in selectivity rather than versatility.1 In other words, synthesis of a different isomer, where possible, usually requires
changing the catalyst or the reaction. However, in some particular cases subtle changes in the reaction conditions can give rise
to either the kinetic or the thermodynamic product. If this approach is successful, it significantly expands the chemical space
covered by a given catalyst, thus increasing its versatility.2
However, reaching good levels of selectivity for both isomers
is generally challenging, so the number of such methodologies
is relatively scarce.
Enantioselective higher order cycloadditions3-4 (HOCs) are
inherently difficult transformations due to the fact that control
of periselectivity represents another challenge that adds up to
diastereo- and enantioselectivity. However, a few authors have
shown that it is indeed a feasible approach, which gives rise to
very interesting compounds bearing unusual scaffolds.5-17
Within the realm of HOCs, several examples on [8+n] annulation reactions have been reported,18-32 albeit the asymmetric variant has been limited to heptafulvenes,33 and azaheptafulvenes34-35 (Scheme 1a). Indeed, enantioselective [6+n]5-11, 33 and
[4+2]12, 36 processes involving tropones have been described,
but this substrate remained essentially unexplored as an 8p
component for catalytic enantioselective transformations37
(Scheme 1b) until this year, when Feng and co-workers published the [8+3] annulation of tropones and azaheptafulvenes

with meso-aziridines.38 In this work, we report the first examples of NHC-catalyzed asymmetric [8+2] processes between
tropone derivatives and enals (Scheme 1c).
Scheme 1. Catalytic enantioselective [8+n] cycloadditions.
(a) Catalytic asymmetric [8+n] annulation reactions
Established
underdeveloped
R
R
R
N
O
CHO

(b) Catalytic asymmetric transformations of tropone
O

O

O

R

[6+n]

[8+3]
Feng, 2018
[8+2]
This work

[4+2]

(c) This work: NHC-catalyzed [8+2] annulation of tropones
O

O
R1

R2

NHC
Et3N

R2
O

O

R1
[8+2] via enolate

1

1a

CH2Cl2

20

1:2

–

2

1b

CH2Cl2

<10

–

–

3

1c

CH2Cl2

37

2:1

97

4

1d

CH2Cl2

<10

–

–

5

1e

CH2Cl2

48

2:1

76

6

1f

CH2Cl2

trace

–

–

7

1g

CH2Cl2

<10

1:1

93

8

1h

CH2Cl2

62

4:1

98

9

1i

CH2Cl2

35

5:1

98

10

1j

CH2Cl2

trace

–

–

11

1k

CH2Cl2

<10

–

–

R
N

12

1l

CH2Cl2

<10

–

–

N X
Nuc R
enolate

13

1h

DCE

64

5:1

98

14

1h

CHCl3

48

4:1

98

15

1h

Tol

<10

2:1

97

16

1h

THF

41

3:1

97

17

1h

CH3CN

39

2:1

95

18d

1h

DCE

73

4:1

98

We have recently reported that isothiourea catalysts are able to
mediate highly stereo- and periselective [8+2] annulations of
azaheptafulvenes, leading to [5.3.0] bicyclic products.35 However,
some limitations remained, such as the fact that tropones proved
unreactive and only arylacetic acid derivatives were tolerated as the
2p component. Thus, we started investigating whether NHC catalysts might also be able to promote these HOCs and whether this
might expand the substrate scope. NHC catalysts39-43 are known to
provide chiral azolium enolate species upon reaction with ketenes,
a-functionalized aldehydes and a,b-unsaturated aldehydes.44-46 We
reasoned that the latter, given their wide availability and stability,
would be more interesting as substrates for an annulation process.47
In this case, the Breslow intermediate undergoes proton transfer to
render an azolium enolate, which plays the role of the 2p component, in a redox neutral process (Scheme 2).

Scheme 2. Generation of an enolate equivalent by reaction
of an NHC catalyst and an a,b-unsaturated aldehyde
Breslow
intermediate
OH R

R N

X
N R

CHO

R

N

R
R

N X

H+
transfer

Nuc
OH
R

H

O

R

R
N

N X
R
homoenolate
equivalent

To assess the viability of the strategy, we selected tropone 2a
and enal 3a as the benchmark substrates (Table 1). To our delight, achiral NHC precursor 1a was able to furnish the annulated product 4a (entry 1). Despite the low yield and dr, this
result served as a proof of concept, which encouraged us to
screen the behavior of a battery of chiral NHC precursors 1b-1l
(entries 2-12). As a general trend, mesityl-containing NHC precursors performed better than analogues with less bulky groups,
which is in agreement with the rationalization made by Bode et
al.48 The most promising of these experiments, which entailed
the use of triazolium salt 1h, furnished the bicyclic product 4a
in good yield and dr and with excellent enantioselectivity
(98%). Subsequent solvent screening (entries 13-17) and optimization of the reaction time led us to conclude that the use of
DCE and 48 h reaction time were optimal for this particular example. These observations contrast with the previous report by
Nair et al. in which similar starting materials and an achiral
NHC catalyst give rise to the corresponding [8+3] product, presumably via homoenolate. 49
Table 1. Optimization of the reaction conditions for the [8+2] annulation of tropone derivatives with enals.a
O

NHC 1 (10 mol %) Ph
Et3N (50 mol %)

O
+
2a

entry

H

Ph

solvent
rt, 24 h

O

O
4a

3a

NHC
precursor

solvent

conv.
[%]b

drb

ee
[%]c

Ph
Mes

N

N

Mes

Cl

N

Ar

N

Ph

1a

N
N

Ph

1b

O
N
Bn

BF4
1d: Ar = Ph
1e: Ar = Mes

N
Ar N

Mes

N
Mes N

O

BF4
1c

BF4

Ph

N
Ph

O
N

BF4
1f: Ar = C6F5
1g: Ar = Ph
1h: Ar = Mes
1i: Ar = 2,6-Et2C6H3

Ar

N
N

BF4

N

Ph
RO Ph

1j: Ar = Ph, R = TBS
1k: Ar = Mes, R = TBS
1l: Ar = Mes, R = H

Reactions performed on a 0.1 mmol scale. b Determined by 1H
NMR spectroscopy. c Determined by chiral HPLC. d reaction time
was 48 h.
a

Identifying the optimal reaction conditions allowed us to
study the scope of this [8+2] annulation, as shown in Scheme 3.
Pristine tropone reacted with several a,b-unsaturated aldehydes
giving the corresponding products (4a-4d) in decent yields,
moderate to good dr’s and excellent enantioselectivities, a general trend in most of the examples to be discussed. 2-Phenyltropone also proved to be a good substrate for this transformation,
leading to bicyclic products 4e-4g, bearing aromatic and

heteroaromatic substituents. Even crotonaldehyde, a usually
challenging substrate, could react with 2-phenyltropone furnishing 4h in rather low yield (40%) but excellent stereoselectivity (12:1 dr, 99% ee). As for the 2-aryltropone, it could be
modified with electron-donating and electron-withdrawing substituents without affecting its behavior (4i-4j). The absolute
configuration of cycloadducts 4 was based on the X-ray diffraction of 4e.50 During the optimization of reaction conditions we
found that a selectivity switch was taking place if stoichiometric
amounts of base and extended reaction times were applied,
providing 5 (the trans-diastereomer) as the major compound.
The substrate scope for reactions leading to 5 is summarized in
Scheme 4. For instance, 2-chlorotropone reacted with a variety
of para-substituted cinnamaldehydes (5a-5e), furnishing the cycloadducts in good yields, excellent dr’s and good ee’s (8890%). The absolute configuration of 5b50 was established by Xray diffraction, the rest being assigned by analogy. o-Methoxycinnamaldehyde provided the desired product 5f, whereas introduction of a 2-furyl substituent rendered 5g in similarly good
results. The brominated analog 5h could also be produced from
2-bromotropone in very good yield, dr and ee. As a token of the
versatility of this approach, when crotonaldehyde and heptenal
were reacted at 0 °C for 48 h the cis-isomers (4r and 4t) were
obtained as the main product. However, simply warming up to
rt and extending the reaction times for a further 72 h gave the
trans cycloadducts (5i and 5j). Such a selectivity switch, from
the kinetic to the thermodynamic product, allows to cover a
wider chemical space with practically the same reaction conditions. The epimerization observed could also be carried out with
an isolated substrate, as shown by treating 4e with 2 equivalents
of Et3N, which provided 5k in moderate diastereo- but excellent
enantioselectivity (Scheme 5a). Derivatization of the cycloadducts was also proved feasible. For instance, hydrogenation of
5a gave rise to 6 in very good yield and chemoselectivity
(Scheme 5b). On the other hand, treatment with methanol effected a ring opening-elimination sequence to yield 7, with only
marginal erosion of the enantiomeric excess.
Scheme 3. Scope of the [8+2] annulation reaction under optimized conditions.
O
R1
+

O
R2

O

O
4

R1

O

4a: R2 = Ph, 58%, 4:1 dr, 98% ee
4b: R2 = 4-ClC6H4, 60%, 3:1 dr, 98% ee
4c: R2 = 4-OMeC6H4, 58%, 4:1 dr, 98% ee
4d: R2 = 2-OMeC6H4, 50%, 5:1 dr, 98% ee

O

4e: R2 = 4-BrC6H4, 62%, 4:1 dr, 99% ee
4f:a R2 = 4-MeC6H4, 61%, 6:1 dr, 99% ee
4g: R2 = 2-Furan, 52%, 7:1 dr, 99% ee

R2

R2
O

Et3N (0.5 equiv)
DCE, rt

3

2

O

NHC 1h (10 mol %)

H

R2

Ph

Ph

Me
O

O

O
Ph

4h:b

a

40%, 12:1 dr,
99% ee

O

R1

R1

4i:
= 4-MeC6H4, 60%, 5:1 dr, 99% ee
4j: R1 = 3-NO2C6H4, 65%, 4:1 dr, 99% ee

1.0 equiv of Et3N. b 3.0 equiv of enal and 1.0 equiv of Et3N.

Scheme 4. Scope of the [8+2] annulation-epimerization reaction
O
R1
+

O
R2

H

O

O
Cl

OMe

O

5f: 83%
>20:1 dr
90% ee

O

O

O
Cl

Me

a At

3

O

O

5h: 80%
>20:1 dr
90% ee

5g: 86%
>20:1 dr
91% ee

Me

Ph

Br

R1

90% ee
88% ee
88% ee
90% ee
90% ee

>20:1 dr
>20:1 dr
>20:1 dr
>20:1 dr
>20:1 dr

O

Cl

O

O

5

78%
82%
71%
72%
68%

5a: X = H
5b: X = Br
5c: X = Cl
5d: X = OMe
5e: X = Me

X

O

Et3N (1.0 equiv)
DCE, 0 ºC→rt

3

2

R2

NHC 1h (10 mol %)

O

O

O
Cl
42%, 99% ee
4:1 dr (cis)
5j:b 40%, 77% ee
13:1 dr (trans)

Cl
55%, 99% ee
5:1 dr (cis)
5i:b 63%, 77% ee
10:1 dr (trans)

4k:a

4l:a

0 ºC for 48 h. b At 0 ºC for 48 h; then, at rt for 72 h.

Scheme 5. Derivatization of the [8+2] adducts
(a)
Br

Et3N (2.0 equiv) Br
O

O
Ph

DCE (0.1 M)
24 h, rt

4e

(b)
Ph
O

H2 Ph
Pd/C

O

Cl

EtOAc O
3 h, RT

6: 93%, >20:1 dr, 91% ee

O
O
Ph
5k: 71%, 4:1 dr, 97% ee
K2CO3

O
5a

MeOH
Cl 3 h, −20 ºC

O

Ph
CO2Me

7: 91%, 86% ee

In order to explain the origin of the selectivity in the reaction, we
decided to study the system with DFT methodology,51 which has
proved to afford reliable results for organocatalytic processes.56-57
Besides gaining a general view on the factors that determine the
sense of stereoinduction, we aimed at understanding the effect of
the nature of the b-substituent of the reacting aldehyde on the diastereoselectivity (compare 4a and 4h), rationalizing the effect of a
2-chloro substituent in tropone on the observed diastereoselectivity
under kinetic control [from 4:1 for R1 = H (4a in Scheme 3) to 1:1,5
for R1 = Cl (see Table S5)], and understanding the course of the
base-mediated epimerization. To this end, we selected the combinations of reactants leading to 5a, 4a, 4e and 4h, with 1h as catalyst
precursor. The calculated reaction profile is in all cases qualitatively the same, and fits with the catalytic cycle represented in Figure 1 for the reaction leading to 5a. The triazolium salt (1h) is
deprotonated by NEt3, and the so-formed NHC catalytic species
then attacks the carbonyl of cinnamaldehyde through transition
state T1, evolving through intermediates I1, I2 (which is the Breslow intermediate58-60) and I3.46-47 This intermediate then undergoes
a rapid and irreversible 1,8-addition to the tropone derivative61
through transition state T4 (Figure 2, top), which determines both
the enantio- and the diastereoselectivity of the process. The resulting intermediate I4 further evolves, ultimately releasing the product and regenerating the NHC catalyst. In a relevant step outside

the catalytic cycle, also shown in Figure 1, the cycloaddition product can experience NEt3 catalyzed epimerization leading to the
more thermodinamically stable trans diastereomer.
O

R1

N

N
N Ar

T1

T6
O

Cl

R1
N

O

N N
Ph

I5

H

Ph

Ph

O

Ar

O

Ar

Cl
kinetic (4)

N N

R1
N

OO

Ph

OH

O

N N
Ar
I4

I1

T2

T5
Cl

R1
N

O H

Ph

Ph

O

Cl
thermodynamic (5)

Ph

Ar

R1
N

N N

I2
O

T4

O

Cl

Ph

I3

Ar

R1
N

T3

N N

azolium enolate

Figure 1. Relevant intermediates (I) and transition states (T) in the
calculated reaction profile NHC catalyzed [8+2] cycloaddition of
tropones with enals. The sequence leading to 5a is shown, and the
base has been omitted for clarity

stereoselectivity at T4 towards the production of (3R,3aS) furanone
as the major kinetic product. This is likely because of the easier
sterical accommodation of the oxygen of the tropone against the
mesityl group of the catalytic pocket in the TS leading to that configuration. According to the studied cycloaddition step, the four
systems should have a similar behavior, leading to 4a, 4e, 4h and
5a with only minor differences in the diastereomeric composition
(see Table S19). However, while this is true in the first three cases,
the prediction is completely wrong for 5a where the trans diastereomer predominates. A possible explanation for this behaviour can
be found taking into consideration the experimentally observed
base catalyzed epimerization, that could transform the (3R,3aS) cis
diastereomer into the (3S,3aS) trans one. Interestingly, the calculated barrier to epimerization is lower for 5a (22.5 kcal.mol-1) than
for 4h, 4a and 4e, (25.0, 26.9 and 23.2 kcal.mol-1, respectively).
The reason of the enhanced epimerization rate of 5a is likely related
to the presence of the chlorine substituent that stabilizes the approach of the base through H…Cl interactions (Figure 2, bottom).
In any case, it is not obvious that this subtle difference in the epimerization barrier can account in a quantitative manner for the differential course of the reaction leading to 5a. To overcome this limitation, we decided to run microkinetic modeling calculations,62
which translate activation barriers and initial concentrations into
concentrations after a given reaction time, thus providing the most
accurate insight into real reacting systems. Full details of these calculations are provided in the SI, and the finals results have been
summarized in Table 2. As it can be seen, not only the major stereoisomer formed in the reaction is correctly predicted when the full
reaction possibilities are considered, but also an almost perfect
agreement with the experimental results in the four studied cases.

Table 2. Comparison of experimental and calculated (microkinetic modeling) stereoselectivities for all investigated systems
at 298 K in DCE
Abs.
config.

Exp.
dr

Calcd.
dr

Exp.
ee [%]

Calcd.
ee [%]

4ha

(3R,3aS)

92:8

100:0

99

100

4aa

(3R,3aS)

80:20

90:10

98

98

4ea

(3R,3aS)

80:20

83:17

99

100

5ab

(3S,3aS)

94:6

98:2

87

81

a

Under optimized conditions (Scheme 3). b Under the conditions
of entry 5 in Table S6 (DCE, 1 eq Et3N, 24h, rt).
In summary, we have been able to exploit the particular reactivity of enals vs. tropones with NHC catalysts to carry out higher order cycloadditions leading to cyclohepta[b]furan-2-ones in high enantiomeric purity. Interestingly, the reaction can be directed to different diastereomers of the [8+2] adducts through small modification of reaction conditions leading to a shift from kinetic to thermodynamic control. DFT computational kinetic modeling strongly
corroborates the experimental findings in terms of periselectivity
and stereoselectivity.

ASSOCIATED CONTENT
Figure 2. Relevant steps in the mechanistic pathway leading to 5a
Since only the Z configuration of the enolate in intermediate I3
is energetically available, the cycloaddition can only lead to the
products with (3R,3aS) and (3R,3aR) configurations, depending on
the face (Re or Si, respectively) of the tropone reactant involved in
the process. For the four studied cases, catalyst 1h always biases

Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.orglett.xxxxxxxx.

General information, screening conditions, general procedures,
compound characterizations, epimerization studies, HPLC
chromatograms, and 1H and 13C NMR spectra. Computational
remarks on free energy hypersurfaces for selected cycloaddition examples, non-corrected and corrected absolute and relative thermochemical parameters for all stationary points, kinetic models, cartesian coordinates and vibrations for all the
stationary points (PDF).

Accession Codes
CCDC 1870414 and 1870415 contain the supplementary crystallographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.

AUTHOR INFORMATION
Corresponding Author
*E-mail: mapericas@iciq.es (Miquel
fmaseras@iciq.es (Feliu Maseras).

A.

Pericàs)

and

ORCID
Shoulei Wang: 0000-0002-2269-8847
Carles Rodríguez-Escrich: 0000-0001-8159-416X
Mauro Fianchini: 0000-0003-2619-7932
Feliu Maseras: 0000-0003-0195-8846
Miquel A. Pericàs: 0000-0003-0195-8846

Notes
The authors declare no competing financial interest

ACKNOWLEDGMENT
Financial support from CERCA Programme/Generalitat de Catalunya, MINECO (CTQ2015-69136-R, CTQ2017-87792-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. Our special thanks to Dr. Patricia Llanes for performing the mmol scale preparative experiment.

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