Redox-Neutral Metal-Free Three-Component Carbonylative Dearomatization of Pyridine Derivatives with CO2

Article abstract of DOI:10.1002/chem.201904359

The TBD (1,3,5-triazabicyclodec-5-ene) assisted three-component carbonylation of pyridine-2-methanamines is documented by means of CO₂ as a benign CO surrogate. The redox-neutral methodology enables the realization of densely functionalized imi

Full text of DOI:10.1002/chem.201904359

A Journal of
Accepted Article
Title: Redox-neutral Metal-free Three-component Carbonylative
Dearomatization of Pyridine Derivatives with CO2
Authors: Marco Bandini, Alessandro Cerveri, Stefano Pace, Magda
Monari, and Marco Lombardo
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201904359
Link to VoR: http://dx.doi.org/10.1002/chem.201904359
Supported by

10.1002/chem.201904359
Chemistry - A European Journal
COMMUNICATION
Redox-neutral Metal-free Three-component Carbonylative
Dearomatization of Pyridine Derivatives with CO2
Alessandro Cerveri,[a] Stefano Pace,[a] Magda Monari,[a] Marco Lombardo*[a] and Marco Bandini*[a]
Abstract: The TBD (1,3,5-triazabicyclodec-5-ene) assisted three-
component carbonylation of pyridine-2-methanamines is documented
by means of CO2 as a benign CO surrogate. The redox-neutral
methodology enables the realization of densely functionalized
imidazo-pyridinones in high yields (up to 93%) and excellent
chemoselectivity. Combined computational and experimental
investigations revealed an unprecedented RCOCl/TBD concerted
electrophilic activation of carbon dioxide.
Final target of the protocol would deal with the realization of a
direct synthetic access to an important class of pharmacologically
active bicyclic-fused arenes: namely imidazo-pyridinones
A
(Figure 1).[13] As such, a simple deconvolution of the acylated
pyridinone scaffold prompted us to verify the potential double role
of acyl chlorides (i.e. acylating agents and electrophilic co-
activators of CO2) in a three component dearomative process
involving pyridine-2-methanamines as the pyridyl reagent.[14]
In this communication, our initial findings in the redox-neutral
TBD-assisted three-components one-pot synthesis of imidazo-
pyridinone scaffolds, via pyridine dearomatization, is presented.
A full mechanistic interpretation is also documented by means of
a dedicated and combined experimental, spectroscopic and
computational analysis.
The carbonylation reaction of organic compounds is counted
among the most useful synthetic methodology in organic as well
as organometallic chemistry.[1] In this scenario, the ongoing seek
for replacing highly toxic carbon monoxide with more
environmentally benign and easy handling chemical entities is
noteworthy.
The use of CO2 as a carbonylative surrogate is becoming a
popular synthetic tool being a highly desirable, abundant,
nontoxic one-carbon synthon.[2,3] On the other hand, the
combined requirements of stoichiometric reducing agents and
noble metal catalysis could represent an obstacle to apply this
straightforward approach to large scale productions.[4]
Alternatively, the so called “redox-neutral” carbonylation reaction
based on CO2 can be conveniently adopted for the direct
carbonylation of bifunctional compounds, also via C-H activation
events, in absence of external reductants.[5]
Ar
N
O
R
O
FC-type acylation
R
O
X
NH
one-pot
NHR’
X
NR’
Cl
R
N
A
N
O
CO2
negative
inotropic
agent
O
amino-carbonylation
dearomatization
Figure 1. Working plan for the one-pot synthesis of imidazo-pyridinones via
redox-neutral CO2 based carbonylation.
The field was pioneered by Iwasawa on ortho-alkenyl(aryl)
phenols[6a] and faced a rapid expansion to aniline[6b-e] and ketone
derivatives.[6f] However, despite the undoubted efficiency, the
requirements of 5d-TMs catalysis, strong inorganic bases (i.e.
CsF, NaOtBu, LiOtBu) or super-stoichiometric electrophilic co-
activators (i.e. MeOTf) are crucial issues that predict further
developments in the field.[7]
At the outset of the investigation, we addressed our attention to a
metal-free methodology in order to positively impact the overall
synthetic sustainability. In this direction, the superbase TBD was
targeted as an organocatalyst[15] in the condensation of pyridine
1a and benzoylchloride (2a) under CO2 atmosphere.
Chemoselectivity (i.e. formation of the N-benzoyl-pyridine
methanamide 3aa’) as well as regioselectivity (i.e. site-selective
final acylation) emerged as major obstacles to be faced in the
titled transformation. However, we were pleased to record that
upon an extensive screening of reaction conditions (see SI for a
complete list of attempts), the use of 1a:2a/TBD/TEA (1/3/0.5/2.5)
in MeCN at 140 °C (reaction time = 0.5 h) led to the pyridinyldene
adduct 3aa in 93% yield with specific acylation at the C(1)-position
(Table 1, entry 1).
Variations from optimal conditions resulted in a significant drop in
reaction performance as highlighted in the Table 1. In particular,
CO2 proved fundamental for the protocol, as a matter of fact,
when the process was run under nitrogen atmosphere the amide
3aa’ was isolated quantitatively (entry 2). Interestingly, by
comparing entries 3 and 4 emerged that the electrophilic
activation exerted by TBD towards CO2 was crucial for the
carbonylation event. In fact, by adopting pre-formed TBD-CO2
carbamate[15c] in the titled process (entry 4), 3aa was isolated in
comparable yield to entry 3 (55% vs 66%, respectively). Other
In continuation with our ongoing interests focused in the chemical
manipulation[8] and dearomatization[9] of aromatic compounds,[10]
we decided to combine the aforementioned carbonylation
strategies to tackle an ongoing “synthetic challenge” in the
dearomatization reaction realm: the pyridine.[11] It should be
emphasized that the use of “electrophilic” CO2 as a reaction
partner in dearomatization processes is almost unknown[12] and
this can be conveniently rationalized by considering that both
processes, namely CO2 activation and aromaticity loss are highly
energy demanding.
[a]
A. Cerveri, S. Pace, Prof. M. Monari, Prof. M. Lombardo, Prof. M.
Bandini
Dipartimento di Chimica “G. Ciamician”
Alma Mater Studiorum – Università di Bologna
via Selmi 2, 40126 Bologna, Italy
E-mail: marco.bandini@unibo.it, marco.lombardo@unibo.it
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/chem.201904359
Chemistry - A European Journal
COMMUNICATION
tertiary amines (i.e. DABCO) proved less efficient with respect to
TBD in the activation of the CO2 (entry 8) while TEA was selected
as acidity scavenger with respect to DIPEA and DABCO (entries
6 and 7) for the highest selectivity furnished.
electron-rich heteroarenes (i.e. thiophene) were adequately
tolerated, showing high regioselectivity towards the final C(1)-
imidazo-FC-acylation (3ga, yield = 78%). The replacement of the
benzylic groups with other C-sp3 units (i.e. n-C5H11, allyl,
propargyl and CH(C2H5)2) was also envisioned (3ha-3ka) and
good to excellent yields (up to 88%) were achieved in all cases.
On the contrary, the primary pyridine-2-methanamine 1l proved
unsuitable for the titled transformation, delivering the amide 3la’
as the exclusive product.[17] Modifications on the pyridine ring
were also assessed by employing the quinoline analogous 1m
and the 6-Br derivative 1n. In these reactions, moderate to good
yields (35-54%) were obtained. Finally, the protocol was not
exclusively restricted to nitrogen-based species, but also pyridyl
alcohols 1p,q reacted smoothly under optimal conditions
delivering the corresponding 3H-oxazolo[3,4-a]pyridin-3-ones
3pa and 3qa in 65% and 52% yield, respectively.
Table 1. Variations from the optimal conditions in the three-component
synthesis of imidazo-pyridinones 3.
O
CO2
1 atm (closed)
Ph
N
NHBn
NBn
3aa
PhCOCl
(0.6 mmol)
O
N
TBD (0.5 eq)
TEA (2.5 eq)
MeCN, 140 °C, 30 min
NBn
Ph
1a
N
(0.2 mmol)
N
O
O
NBn
3a’
3aa’
Run[a]
Deviations from optimal
Yield (%)
3aa[b]
Yield
3aa’[b]
(%)
X
O
CO2
1 atm (closed)
1
--
93
--
traces
95
28
40
58
15
9
X
Ph
NHR
N
O
N
TBD, 2a, TEA
MeCN, 140 °C, 30 min
NR
2
NO CO2
1
3
3
TBD (3 eq) and no TEA
Preformed TBD-CO2 (3 eq)
DBU (3 eq) instead of TBD
DIPEA (2.5 eq) instead of TEA
66
55
31
71
86
68
42
53
COPh
4[c]
5
N
O
COPh
Ar
X
N
N
N
O
3ba (X = 4-Me), Y = 85%
3ca (X = 4-OMe), Y = 67%
3da (X = 4-NO2), Y = 59%
3ea (X = 2-Cl), Y = 81%
3fa (Ar = 2-naphth), Y = 71%
3ga (Ar = 2-thienyl), Y = 78%
6
3ca
7
DABCO (2.5 eq) instead of TEA
DABCO (0.5 eq) instead of TBD
No TBD and TEA (3.0 eq)
COPh
3ha (R = C5H11), Y = 66%
3ia (R = CH(C2H5)2), Y = 75%
3ja (R = propargyl), Y = 88%
3ka (R = allyl), Y = 72%
3la (R = H), NR
COPh
N
8
26
50
41
NBn
N
N
O
9[d]
10
R
O
3ma, Y = 35%
TBD (0.2 eq)/TEA (2.8 eq)
COPh
COPh
NBn
COPh
N
CO2Me
N
O
N
N
[a] All the reactions were carried out with anhydrous solvents, unless
otherwise specified. [b] Determined after flash chromatography. [c] Under
N2 atmosphere. [d] Reaction time = 3 h. X-ray structure of 3aa is also
represented (see SI).
X
Br
O
O
O
CO2Me
3oa, Y = 82%
3pa (X = H), Y = 65%
3qa (2-thienyl = H), Y = 52%
3na, Y = 54%
Attempts to lower further the TBD loading at 20 mol% (entry
10) caused a marked drop in 3aa formation (yield = 53%) with the
concomitant isolation of the amide 3aa’ in significant amount
(41%). Finally, the crucial role of TBD in accelerating the CO2
fixation was ascertained by running the model annulation with
TEA (3 eq) as the only basic additive. The isolation of 3aa in 42%
yield in 3 h suggested that moderate CO2 activation could also be
exerted by the methanamine 1a itself.[16] It is worthy to mention
that in some sporadic cases the formation of 3a’ in traces was
observed.
The protocol proved extremely high flexibility in terms of
functional group tolerance performing effectively for a large
variety of multi-component one-pot dearomative events.
Variations on the pyridine amine congeners were operated both
at the amine group and pyridyl core (1b-q). From the data
collected in the Scheme 1 emerged that secondary benzylamines
worked excellently in the process delivering the corresponding
three-component adduct 3 in very good yields (up to 85%)
regardless size, electronic features and substitution patterns at
the benzylic site (3ba-3fa). It is worth of mention that, also
Scheme 1. Reaction with anhydrous MeCN. 1/2a/TBD/TEA = 1/3/0.5/2.5. NR =
no reaction. X-ray structure of 3ca is also represented (see SI).
Therefore, a survey of acylating agents 2b-j was undergone and
the results collected in Scheme 2. Aromatic carboxylic acid
chlorides proved effectiveness regardless the electronic nature of
the substituents as well as pattern of functionalization. They can
easily
accommodate
both
electrondonating
and
electronwithdrawing groups delivering the corresponding ketones
3 in up to 81% yield. Aliphatic acylating agents (2h,i) were also
effectively tested in the titled reaction delivering the three-
component adduct in serviceable yields: 84% and 79%
respectively. Finally, we surmised that the installation of a
trichloroacetyl unit at the C(1)-position would open interesting
opportunities to generate carboxylic derivatives. In this regard, we
were pleased to verify that trichloroacetyl chloride 2j worked
smoothly in the three-component strategy resulting in 3aj with
69% yield.
This article is protected by copyright. All rights reserved.

10.1002/chem.201904359
Chemistry - A European Journal
COMMUNICATION
O
CO2
O
1 atm (closed)
R
N
O
1a +
Cl
R
TBD, TEA
MeCN, 140 °C, 30 min
NBn
2
3
3ab (R = 4-OMe-C6H4), Y = 53%
3ac (R = 4-I-C6H4), Y = 61%
3ad (R = 4-CF3-C6H4), Y = 73%
3ae (R = 3,5-(CF3)2-C6H3), Y = 76%
3af (R = C6F5), Y = 81%
3ag (R = 2-Br-C6H4), Y = 78%
3ah (R = tBu), Y = 84%
O
R
N
O
NBn
3ai (R = nC4H9), Y = 79%
Figure 2. Experiments of a) trans-carbonylation between TBD and 1a; b)
proving the poisoning effect of CO2 towards TBD during the reaction course (1a-
CO2/TBD/TEA/2a: 1/1/2/3.
3aj (R = CCl3), Y = 69%
3af
Scheme 2. Reaction with anhydrous MeCN. 1a/2/TBD/TEA = 1/3/0.5/2.5. X-ray
structure of 3af is also represented (see SI).
These intriguing mechanistic insights prompted us to further
explore the real role of TBD as a catalyst and the possible
multiple-role played by the acid chloride. Therefore, a detailed
DFT computational investigation of the reaction course relative to
the formation of 3a’ was carried out at the ωB97X-D/6-31G(d)
level of theory in CH3CN. From this analysis (see Si for details)
the catalytic cycle depicted in the Figure 3 is proposed.
We then turned our attention to shed some light on the reaction
profile by means of a series of dedicated experimental,
spectroscopic and computational investigations.
The carbonylative events involving TBD and benzylamine 1a was
firstly studied. Interestingly, by monitoring the reaction of
[15b]
preformed TBD-CO2
and 1a in CD3CN under nitrogen, (1H-
NMR and FT-IR), we discovered that a quantitative CO2 transfer
from TBD-carbamate to 1a-CO2 analogous occurred both at rt and
140 °C in 30 min (Figure 2a and vide infra for mechanistic
-
hypotheses).[18] Therefore, 1a-CO2 /TBDH+ mixture (1 eq) was
allowed to react with TEA (2 eq) and 2a (3 eq) under two different
environmental regimes at rt: CO2 and N2. Here, while the
cyclization under CO2 performed poorly, providing a 3aa/3a’/3aa’
1
mixture only in 30% overall yield (4/3/1 ratio by H-NMR crude),
the presence of nitrogen conditions enabled the formation of a
3aa/3a’ mixture in 82% overall yield at rt (2.2/1 ratio, Figure 2b).
These results clearly prove that i) free TBD is essential during the
whole reaction course and specifically in the initial carbonation of
1a and during the dearomatization event of the pyridine (vide infra
for computational rationale) and ii) 3a’ is an intermediate of the
reaction pathway that could undergo subsequent acylation
reaction with the excess of chloride 2 to leave compound 3.[19]
The structural determinations of three compounds, namely 3aa,
3ca and 3af by SC-XRD studies were carried out. Loss of the
aromaticity involving the pyridine unit has been detected in all
cases since an alternation of double and single C-C bonds was
observed in the pyridine rings (see Table S3).
Additionally, the reaction proved competence also at rt, however
higher temperatures enable both better performance and the one-
pot addition of all the reaction partners can be operable,
concomitantly.[20]
Figure 3. Proposed catalytic cycle for the CO2-based synthesis of imidazo-
pyridinone scaffolds.
Interestingly, no direct transfer between TBD-CO2 adduct and 1a
was located. Indeed, free TBD acts as a bifunctional activator first
templating the approach of 1a and CO2 then quickly deprotonating
the intermediate I1 and finally strongly stabilizing the final adduct
P1 through a hydrogen-bonding network with the carbamate
moiety.[21]
TBD plays also a crucial role in the subsequent PhCOCl-
promoted cyclization of intermediate P1 to give the annulated
zwitterionic intermediate P2. It should be emphasized also the
This article is protected by copyright. All rights reserved.

10.1002/chem.201904359
Chemistry - A European Journal
COMMUNICATION
pillar activating role played by the acyl chloride that was found in
forming the highly electrophilic mixed anhydride of the carbamic
acid I2, responsible for the final dearomatization event.
Keywords: CO2 • Carbonylation • Metal-free • Pyridine •
Dearomatization reaction
In this process, transition states (TS3 and TS4, see SI) are
characterized by a SN2-like concerted mechanism, where no
tetrahedral intermediate is located.[22] Here the role of TBD as a
Brønsted acid is again pivotal in making the benzoate unit a much
better leaving group, allowing the nucleophilic attack by the pyridyl
nitrogen and leading to the formation of the zwitterionic product
P2. The final deprotonation step of P2a to the neutral intermediate
3a’ was modelled using both TEA and TDB as the base (see SI
for details) leading to very favourable exergonic reaction paths.
Furthermore, the three-component adduct 3 could be easily
obtained via Friedel-Crafts type acylation.[23]
Finally, the synthetic manipulation described in Scheme 3 clearly
underlined the chemical modulability of the final compounds 3. In
particular, the trichloro derivative 3aj was effectively subjected to
methanolysis in the presence of NaH/MeOH to give the
corresponding methyl ester 4aj in 98% yield (Scheme 3a).
Additionally, the partially dearomatized pyridine ring provides an
expedient platform that can be conveniently (88% yield) and
selectively reduced to a piperidinyl core (i.e. 5ai) by means of mild
reducing conditions (Pd(OH)2/H2/MeOH, Scheme 3b).
[1]
a) L. Kollar, in Modern Carbonylation Methods, Wiley-VCH, 2008; b) M.
Beller, X.-F. Wu, Transition Metal Catalyzed Carbonylation Reactions
Carbonylative Activation of C-X Bonds, Springer, 2013; c) S. Zhao, N.P.
Mankad, Catal. Sci. Technol. 2019, 9, 3603-3613.
[2]
[3]
a) K. Dong, X.-F. Wu, Angew. Chem. Int. Ed. 2017, 56, 5399-5401; b) L.
Wang, W. Sun, C. Liu, Chin. J. Chem. 2018, 36, 353-362.
For a selection of general reviews on the use of CO2 as C1-synthon in
organic synthesis see: a) Q. L, L. Wu, R. Jackstell, M. Beller, Nat.
Commun. 2014, 5, 1-15; b) D. Yu, S. P. Teong, Y. Zhang, Coord. Chem.
Rev. 2015, 293-294, 279-291; c) A. Tlili, E. Blondiaux, X. Frogneux, T.
Cantat, Green Chem. 2015, 17, 157-168; d) J. Klankermayer; S.
Wesselbaum, K. Beydoun, W. Leitner, Angew. Chem. Int. Ed. 2016, 55,
7296-7343; e) X.-F. Wu, M. Beller, Top. Curr. Chem. 2017, 376; f) S.
Dabral, T. Schaub, Adv. Synth. Catal. 2019, 361, 223-246; g) R. R.
Shaikh, S. Pornpraprom, V. D’Elia, ACS Catal. 2018, 8, 419-450; h) C.S.
Yeung, Angew. Chem. Int. Ed. 2019, 58, 2-13; i) J. R. Cabrero-Antonino,
R. Adam, M. Beller, Angew. Chem. Int. Ed. 2019, early view.
[4]
For recent examples on the use of CO2 as reductive C(1) source see: G.
Xiang, Y. Bo, Y. Zhenzhen, Z. Yanfei, Z. Hongye, H. Leiduan, H. Buxing,
ACS Catal. 2015, 5, 6648-6652; b) Z. Zhang, Q. Sun, C. Xia, W. Sun,
Org. Lett. 2016, 18, 6316-6319; c) X.-D. Lang, L.-N. He, ChemSusChem
2018, 11, 2062-2067; d) K. Yan, J. Jin, Y. Kong, B. Li, B. Wang, Adv.
Synth. Catal. 2019, 361, 3080-3085.
[5]
[6]
a) Z. Zhang, T. Ju, J.-H. Ye, D.-G. Yu, Synlett, 2017, 28, 741-750; b) H.
Wang, Z. Xin, Y. Li, Top. Curr. Chem. 2017, 375, 49.
a) K. Sasano, J. Takaya, N. Iwasawa, J. Am. Chem. Soc. 2013, 135,
10954-10957; b) Z. Zhang, L.-L. Liao, S.-S. Yan, L. Wang, Y.-Q. He, J.-
H. Ye, J. Li, Y.-G. Zhi, D.-G. Yu, Angew. Chem. Int. Ed. 2016, 55, 7068-
7072; c) S. Sun, W.-M. Hu, N. Gu, J. Cheng, Chem. Eur. J. 2016, 22,
18729-18732; d) S. Wang, P. Shao, G. Du, C. Xi, J. Org. Chem. 2016,
81, 6672-6676; e) L. Song, G.-M. Cao, W.-J. Zhou, J.-H. Ye, Z. Zhang,
X.-Y. Tian, J. Li, D.-G. Yu, Org. Chem. Front. 2018, 5, 2086-2090; f) W.-
Z. Zhang, M.-W. Yang, X.-B. Lu, Green Chem. 2016, 18, 4181-4184.
The possibility to generate in situ CO from CO2 and perform
carbonylative processes in two-chamber reactor was also documented:
a) M. T. Jensen, M. H. Rønne, A. K. Ravn, R. W. Juhl, D. U. Nielsen, X.-
M. Hu, S. U. Pedersen, K. Daasbjerg, T. Skrydstrup, Nat. Commun.
2017, 8, 1-8; b) N. Barsu, D. Kalsi, B. Sundararaju, Catal. Sci. Technol.
2018, 8, 5963-5969.
a) M. Bandini, A. Bottoni, M. Chiarucci, G. Cera, G. Miscione, J. Am.
Chem. Soc. 2012, 134, 20690-20700; b) G. Cera, S. Piscitelli, M.
Chiarucci, G. Fabrizi, A. Goggiamani, R. S. Ramón, S. P. Nolan, M.
Bandini, Angew. Chem. In. Ed. 2012, 51, 9891-9895; c) M. Chiarucci, R.
Mocci, L.-D. Syntrivanis, G. Cera, A. Mazzanti, M. Bandini, Angew.
Chem. Int. Ed. 2013, 52, 10850-10853; d) M. Chiarucci, E. Matteucci, G.
Cera, G. Fabrizi, M. Bandini, Chem. Asian J. 2013, 8, 1776-1779; e) P.
Giacinto, G. Cera, A. Bottoni, M. Bandini, G. P. Miscione, ChemCatChem
2015, 7, 2480-2484; f) Q.-Q. Yang, M. Marchini, W.-J. Xiao, P. Ceroni,
M. Bandini, Chem. Eur. J. 2015, 21, 18052-18056; g) A. De Nisi, S.
Sierra, M. Ferrara, M. Monari, M. Bandini, Org. Chem. Front. 2017, 4,
1849-1853; h) C. Sauer, Y. Liu, A. De Nisi, S. Protti, M. Fagnoni, M.
Bandini, ChemCatChem. 2017,9, 4456-4459; i) L. Favaretto, J. An, M.
[7]
[8]
Scheme 3. Examples of synthetic manipulation of the 3.
In conclusion,
a redox-neutral metal-free dearomative
carbonylation of pyridine derivatives with CO2 is documented. The
three-component one-pot methodology enables the realization of
a large library of densely functionalized and synthetically flexible
imidazo- and oxazolo-pyridinones in excellent yield and chemo-
/regioselective manner. The intriguing role of TBD as a promoter
and RCOCl as an electrophilic CO2 coactivator and acylating
agent are proposed and disclosed by means of combined
experimental, spectroscopic and computational investigations.
Attempts to extend the present CO2 activation mode to the
synthesis of other densely functionalized heterocyclic scaffolds is
currently under way in our laboratories.
Sambo, A. De Nisi, C. Bettini, M. Melucci, A. Kovtun, A. Liscio, V.
Palermo, A. Bottoni, F. Zerbetto, M. Calvaresi, M. Bandini, Org. Lett.
2018, 20, 3705-3709.
[9]
a) G. Cera, M. Chiarucci, A. Mazzanti, M. Mancinelli, M. Bandini, Org.
Lett. 2012, 14, 1350-1353; b) M. Jia, G. Cera, D. Perrotta, M. Bandini,
Chem. Eur. J. 2014, 20, 9875-9878; c) C. Romano, M. Jia, M. Monari, E.
Manoni, M. Bandini, Angew. Chem. Int. Ed. 2014, 53, 13854-13857; d)
M. Jia, M. Monari, Q.-Q. Yang, M. Bandini, Chem. Commun. 2015, 51,
2320-2322; e) L. Rocchigiani, M. Jia, M. Bandini, A. Macchioni, ACS
Catal. 2015, 5, 3911-3915; f) R. Ocello, A. De Nisi, M. Jia, Q.-Q. Yang,
P. Giacinto, A. Bottoni, G.P. Miscione, M. Bandini, Chem. Eur. J. 2015,
21, 18445-18453; g) J. An, A. Parodi, M. Monari, M. Castiñeira Reis, C.
Acknowledgements
MB, ML and MM are grateful to the University of Bologna for
financial support.
This article is protected by copyright. All rights reserved.

10.1002/chem.201904359
Chemistry - A European Journal
COMMUNICATION
Silva Lopez, M. Bandini, Chem. Eur. J. 2017, 23, 2442-2449; h) P.
Giacinto, A. Bottoni, A. Garelli, G.P. Miscione, M. Bandini,
Chem.Cat.Chem. 2018, 10, 2442-2449; i) J. An, L. Lombardi, S. Grilli, M.
Bandini, Org. Lett. 2018, 20, 7380-7383; l) A. Cerveri, O. Nieto Faza, C.
Silva Lopez, S. Grilli, M. Monari, M. Bandini, J. Org. Chem. 2019, 84,
6347-6355.
[14] D. Davey, P.W. Erhardt, W.C. Lumma, Jr., J. Wiggins, M. Sullivan, D.
Pang, E. Cantor, J. Med. Chem. 1987, 30, 1337-1342.
[15] For a representative examples of TBD-prompted CO2 activation in
organic transformations, see: a) Z. Xin, C. Lescot, S. D. Friis, K.
Daasbjerg, T. Skrydstrup, Angew. Chem. Int. Ed. 2015, 54, 6862-6866;
b) A. Boyaval, R. Méreau, B. Grignard, C. Detrembleur, C. Jerome, T.
Tassaing, ChemSusChem 2019, 10, 1241-1248. See also: Superbases
for Organic Chemistry, (Ed. T. Ishikawa), John Wiley and Sons:
Chichester, 2009.
[10] a) S.P. Roche, J.A. Porco, Angew. Chem. Int. Ed. 2011, 50, 4068-4093;
b) C.-X. Zhuo, W. Zhang, S.-L. You, Angew. Chem. Int. Ed. 2012, 51,
12662-12686; c) C.-X. Zhuo, C. Zheng, S.-L. You, Acc. Chem. Soc.
2014, 47, 2558-2573; d) C. Zheng, S.-L. You, Chem. 2016, 1, 830-857;
e) Asymmetric Dearomatization Reactions (Ed. You, S.-L.), Wiley-VCH,
2016; f) W.-T. Wu, L. Zhang, S.L. You, Chem. Soc. Rev. 2016, 45, 1570-
1580; g) X.-W. Liang, C. Zheng, S.-L. You, Chem. Eur. J. 2016, 22,
11918-11933; h) S. Park, S. Chang, Angew. Chem. Int. Ed. 2017, 56,
7720-7738; i) J. An, M. Bandini, CHIMIA 2018, 72, 610-613; j) V.
Pirovano, Eur. J. Org. Chem. 2018, 1925-1945; (i) J. Bariwal, L.G.
Voskressensky, E.V. Van der Eycken, Chem. Soc. Rev. 2018, 47, 3831-
3848.
[15] a) F. Stuani Pereira, E. Ribeiro deAzevedo, E. F. da Silva, T. J.
Bonagamba, D. L. da Silva Agostíni, A. Magalhães, A. E. Job, E. R.
Pérez González, Tetrahedron 2008, 64, 10097-10106; b) C. Villiers, J.-
P. Dognon, R. Pollet, P. Thuéry, M. Ephritikhine, Angew. Chem. Int. Ed.
2010, 49, 3465-3468; c) R. Nicholls, S. Kaufhold, B. N. Nguyen, Catal.
Sci. Technol., 2014, 4, 3458-3462.
[16] Very modest CO2·TEA complexations were experimentally proved in
solution: J. C. Meredith, K. P. Johnston, J. M. Seminario, S. G. Kazarian
and C. A. Eckert, J. Phys. Chem., 1996, 100, 10837-10848. See also ref.
15c.
[11] For selected recent examples, see: a) D.V. Gutsulyak, A. van der Est,
G.I. Nikonov, Angew. Chem., Int. Ed. 2011, 50, 1384-1387; b) M.
Arrowsmith, M.S.; Hill, T. Hadlington, G. Kociok-Kꢀhn, C. Weetman,
Organometallics 2011, 30, 5556-5562; c) M. Zurro, S. Asmus, S.
Beckendorf, C. Mꢁck-Lichtenfeld, O.G. Mancheꢂo, J. Am. Chem. Soc.
2014, 136, 13999-14002; d) Z.-P. Yang; C. Zheng, L. Huang, C. Qian,
S.-L. You, Angew. Chem. Int. Ed. 2017, 56, 1530-1534; e) S. Park, S.
Chang, Angew. Chem. Int. Ed. 2017, 56, 7720-7738 f) Z.-P. Yang, R.
Jiang, C. Zheng, S.-L. You, J. Am. Chem. Soc. 2018, 140, 3114-3119; g)
H.-J. Zhang, Z.-P. Yang, Q. Gu, S.-L. You, Org. Lett. 2019, 21, 3314-
3318.
[17] N-Boc and N-Ts methanamines resulted inert under the present reaction
conditions.
[18] On the contrary, no carbonation of 1a occurs in absence of TBD.
[19] 3aa can be obtained (35% yield) by treating 3a’ with TBD and 2a both at
rt and 140 °C.
[20] Among other possible aspects, high T could also favor the partial TBD-
CO2 dissociation during the reaction course even in the presence of a
carbon-dioxide regime.
[21] a) C. Zhang, Y. Lu, R. Zhao, W. Menberu, J. Guo, Z.-X. Wang, Chem.
Commun. 2018, 54, 10870-10873; b) A. Boyaval, R. Méreau, B.
Grignard, C. Detrembleur, C. Jerome, T. Tassaing, ChemSusChem
2017, 10, 1241-1248.
[12] J.H. Ye, L. Zhu, S.-S. Yan, M. Miao, X.-C. Zhang, W.-J. Zhou, J. Li, Y.
Lan, D.-G. Yu, ACS Catal. 2017, 7, 8324-9330
[13] For recent papers on two-component dearomatizations of pyridines with
CO2 under strong basic conditions or with sacrificial reductants see: a)
M. Xia, W. Hu, S. Sun, J.-T. Yu, J. Cheng, Org. Biomol. Chem. 2017, 15,
4064-4067; b) X. Wu, S. Sun, B. Wang, J. Cheng, Adv. Synth. Catal.
2017, 359, 3855-3859.
[22] F. Ruff, Ö. Farkas, J. Phys. Org. Chem. 2011, 24, 480-491.
[23] Subjecting 3a’ to optimal conditions (in absence of 1a) led to acylated
3aa in 35% yields.
This article is protected by copyright. All rights reserved.

10.1002/chem.201904359
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
A. Cerveri, S. Pace, M. Monari, M.
Lombardo and M. Bandini
X
Y
BA-catalysis
ClCOR1
TBD (0.5 eq.)
X
O
O
O
N
O
H
H
N
N
YR
N
N
CO2 1 atm
(closed)
R1
N
YR
R1
Page No. – Page No.
O
metal-free
redox-neutral
three-component
yield up to 93%
25 examples!!
CO2
coactivation
Redox-neutral Metal-free Three-
component Carbonylative
Dearomatization of Pyridine
Derivatives with CO2
Three is better than two. A three-component metal-free carbonylative
dearomatization of pyridine derivatives is documented with CO2 as CO surrogate. A
range of imidazo-pyridinones is obtained in high yield (up to 93%) via an
unprecedented RCOCl/TBD concerted electrophilic activation of carbon dioxide
(see Scheme).
This article is protected by copyright. All rights reserved.