Continuous flow as an enabling technology: a fast and versatile entry to functionalized glyoxal derivatives

Article abstract of DOI:10.1039/d1ob00288k

We herein report two complementary strategies employing organolithium chemistry for the synthesis of glyoxal derivatives. Micro-mixer technology allows for the generation of unstable organometallic intermediates and their instantaneous in-line quenching with esters as electrophiles. Selective mono-addition was observedviaputative stabilized tetrahedral intermediates. Advantages offered by flow chemistry technologies facilitate direct and efficient access to masked 1,2-dicarbonyl compounds while mitigating undesired by-product formation. These two approaches enable the production of advanced and valuable synthetic building blocks for heterocyclic chemistry with throughputs of grams per minute.

Full text of DOI:10.1039/d1ob00288k

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
COMMUNICATION
Continuous flow as an enabling technology:
a fast and versatile entry to functionalized
glyoxal derivatives†
Cite this: Org. Biomol. Chem., 2021,
19, 2420
Received 16th February 2021,
Accepted 25th February 2021
Fabio Lima,
Joerg Sedelmeier
*
a,b Mark Meisenbach,b Berthold Schenkelb and
b,c
DOI: 10.1039/d1ob00288k
*
rsc.li/obc
We herein report two complementary strategies employing orga- atom-efficient entry to dicarbonyls (3 and 5) while mitigating
nolithium chemistry for the synthesis of glyoxal derivatives. Micro- the formation of the undesired tertiary alcohol by-product,
mixer technology allows for the generation of unstable organo- amongst others.7–10 The selective mono-addition of an organo-
metallic intermediates and their instantaneous in-line quenching metallic species to a carboxylic acid derivative is a well-estab-
with esters as electrophiles. Selective mono-addition was observed lished method for the synthesis of ketone derivatives.11
via putative stabilized tetrahedral intermediates. Advantages However, pre-functionalization (e.g. as amides12) is required to
offered by flow chemistry technologies facilitate direct and
efficient access to masked 1,2-dicarbonyl compounds while miti-
gating undesired by-product formation. These two approaches
enable the production of advanced and valuable synthetic building
blocks for heterocyclic chemistry with throughputs of grams per
minute.
Functionalized glyoxal derivatives are important precursors for
the synthesis of a plethora of heteroaromatic compounds such
as pyrazines, quinazolines, 1,2,4-triazines, oxazoles, thiazoles,
imidazoles and derivatives thereof.1,2 These 5- and 6-mem-
bered heterocycles are commonly encountered pharmaco-
phores3–5 and therefore are of high importance in the pharma-
ceutical small-molecules landscape as exemplified in the
recurrence of these motifs in recently discovered kinase inhibi-
tors (Scheme 1).6
Scheme 1 Highlight of the possible use of glyoxal derivatives in the
synthesis of a selection of kinase inhibitors.6
Previously, we reported on the formation of dichloromethyl
lithium (DCM-Li) in continuous flow mode and its electrophi-
lic quench onto aldehydes to afford α,α′-bis-chloro carbinols
(1) as outlined in Scheme 2.46
Inspired by this developmental work we envisaged to
expanded on this concept and targeted the synthesis of glyoxal
derivatives (3 and 5) in a single step approach. The challenge
with the described chemistry is to identify a high yielding and
aGlobal Discovery Chemistry, Novartis Institutes for Biomedical Research, Novartis
Pharma AG, Basel, Switzerland. E-mail: fabio.lima@novartis.com
bChemical and Analytical Development, Novartis Pharma AG, Basel, Switzerland.
E-mail: joerg.sedelmeier.js1@roche.com
cCurrent affiliation: F. Hoffmann-La Roche Ltd, Small Molecules Technical
Development, Basel, Switzerland
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1ob00288k
Scheme 2 Flow methods to access glyoxal derivatives.
2420 | Org. Biomol. Chem., 2021, 19, 2420–2424
This journal is © The Royal Society of Chemistry 2021

View Article Online
Organic & Biomolecular Chemistry
Communication
Table 1 Approach A: access to α,α’-bis-chloroketonesa,b
perform chemoselective transformations to ketones.12–20
Despite their broad chemical availability, esters are rarely used
as electrophiles to access ketones, reasons being the greater
instability of the transient tetrahedral intermediate leading to
unavoidable, consecutive over-addition products.21,22 Some
pioneering studies made use of stabilization of the corres-
ponding tetrahedral intermediates via chelation23–25 or induc-
tive effects25–29 under cryogenic conditions to enable selective
ketone formation from esters. We therefore postulated that the
quenching of selected flow generated organolitium species
(DCM-Li and Ar-Li) with esters could allow the access of both
α,α′-bis-chloro ketones (3) and the keto-acetals (5) from chelate
stabilized intermediates (Scheme 2). Finally, both synthetic
approaches A and B pose fundamental issues when conducted
in traditional batch mode; firstly due to the involvement of
unstable organolithium moieties and secondly because of the
inherent formation of the tertiary alcohol as a dominant by-
product by consecutive over-addition. Inspired by the advan-
tages of continuous flow methodologies30–37 and to comp-
lement existing methodologies for the synthesis of ketones in
continuous flow,38–42 we envisioned to develop a flash chem-
istry (chemical synthesis on a timescale of <1 second) platform
that would facilitate the outlined strategy.
We started our investigation with the reaction of dichloro-
methyl lithium (DCM-Li) and compound 2a following
Approach A to form 3a (Table 1).
Based on our previous work in the field of organometallic
reactions, we reverted to our established continuous flow setup
which is a reliable working horse in our process development
labs.43 The automated flow platform dedicated to organo-
lithium chemistry consists of simple PTFE T-pieces (ID =
0.5 mm) as mixing elements and PFA tubing (ID = 0.8 mm) as
tubular reactors. Minimum total flow rates of ∼20 mL min−1
a Reactions were performed on 8.5 mmol scale (2.0 min run, 255 mmol
h−1 throughput). b Isolated yield without column chromatography.
c Obtained after column chromatography of the crude mixture.
For the Br/Li exchange reaction we reverted to our pre-
per mixing element are essential to ensure highly efficient viously established continuous flow protocol.43,44 Fluorine-
mixing and short mixing times (≤500 ms).43 Pleasingly, we containing aromatics were well tolerated in this reaction and
observed excellent results without the necessity to adjust or provided scaffolds 5a and 5b in excellent yields (88 and 95%
optimize any process parameter compared to our previously respectively).
reported protocol and α,α′-bis-chloroketone 3a was obtained in
excellent yield and purity. With a particular focus on medicin- relative to aryl bromide allows for a selective single Br/Li
ally relevant heterocyclic examples, our methodology was suc- exchange of
dibrominated aromatic compound (5d).
The precise control of flow rates and stoichiometry of nBuLi
a
cessfully applied to pyridines (3a to 3c), pyrazine (3d), oxazole Electron-rich aromatic systems could also be successfully
(3e) and a N-Boc-protected piperidine (3f). Also, an alkynyl engaged in selective mono-additions with 4 resulting in a
ester and ortho-nitro benzoyl reacted smoothly affording α,α′- range of benzo keto acetals 5e–g. Finally, we were pleased to
bis-chloroketones 3g and 3h. It should be noted that most α,α′- observe that all positions around the pyridine core were well
bis-chloro ketones were synthesized in high purity following a tolerated giving rise to highly functionalized heterocycles
simple extractive work-up without the need for column chrom- (5h–j). 5-Bromoquinoline could also be engaged, albeit less
atography or crystallization.
selectively in our method, further demonstrating the possi-
The limited number of commercially available functiona- bility to extend the range of compatible heterocyclic com-
lized esters encouraged us to seek for more available sub- pounds. The structural motif of aryl keto acetals (5) is barely
strates. In an effort to extend the scope of this chemistry we reported in the literature and the two outlined approaches now
next turned our attention to Approach B (Scheme 2). Aryl- and open doors to new ways to install biaryl heterocycles by classi-
heteroaryl bromides are readily available and pose a rich and cal condensation reactions.
valuable source of starting materials for our investigation. A
In an effort to confirm the origin of selectivity in this
series of commercially available aryl bromides were engaged in mono-addition to esters, we reacted 3-bromochlorobenzene
the mono-addition to ethyl diethoxy acetate 4 using our opti- with a selection of ester derivatives (Table 3). The ester screen-
mized flash chemistry protocol (Table 2).
ing revealed the importance of the presence of heteroatoms on
This journal is © The Royal Society of Chemistry 2021
Org. Biomol. Chem., 2021, 19, 2420–2424 | 2421

View Article Online
Communication
Organic & Biomolecular Chemistry
Table 2 Approach B: access to ketoacetalsa,b
Table 3 Approach B: extension and limits of electrophile scopea,b
a Reactions were performed on 1.7 mmol scale (20 s, 306 mmol h−1
throughput). b Isolated yield after column chromatography is given.
c From the corresponding methyl ester.
a Reactions were performed on 10.2 mmol scale (2.0 min run,
306 mmol h−1 throughput). b Isolated yield after column chromato-
graphy is given.
excellent scaffolds in this transformation, giving rise to unsym-
metrical diaryl ketones 6f and 6g,45 while 3- and 4-positions of
pyridine (4j and 4k) both exclusively resulted in over-addition.
These observations emphasize the complementarity of the
two approaches and allow to design the synthesis of a desired
glyoxal derivative accordingly. We believe that in approach B a
5-membered chelate stabilization of the tetravalent adduct was
responsible for the high selectivity.23–25 The tetrahedral adduct
from Approach A could also benefit from a similar stabiliz-
ation effect in addition from an inductive stabilization orig-
inating from the dichloromethyl moiety.25–29
the ester moiety for coordination and stabilization of reaction
intermediates. Indeed, alkyl esters bearing α-heteroatom were
successfully transformed into their respective ketones 6a–c in
74 to 82% yield. While in the absence of a heteroatom (and
therefore no coordination), using esters 4h to 4k exclusively
formed the corresponding tertiary alcohols (over-addition pro-
ducts). These observations are in line with the hypothesis that
a lithium chelate stabilization of the tetrahedral adduct is
necessary in order to observe selective ketone formation.
These observations were backed with literature precedence
with similar systems.25 Based on this rational, we identified
ethyl 5-oxazole carboxylate (see 6d) and 2-anisole carboxylate
(see 6e) to be suitable reaction partners while the 4-anisole
Conclusions
substrate (4i) was transformed into its corresponding tertiary In conclusion, we expanded on an established and reliable
alcohol. Finally, 2-pyridyl carboxylates were also identified as continuous flow protocol to synthesize aryl glyoxal building
2422 | Org. Biomol. Chem., 2021, 19, 2420–2424
This journal is © The Royal Society of Chemistry 2021

View Article Online
Organic & Biomolecular Chemistry
Communication
blocks, which serve as valuable intermediates for the formation 11 B. Figadère and X. Franck, Sci. Synth., 2005, 26, 243.
of medicinally relevant heterocyclic motifs. Two complementary 12 V. Pace, W. Holzer and B. Olofsson, Increasing the reactivity
routes are presented leading to a wide range of α,α′-bis-chloro
ketones (3) and aryl keto acetals (5) with high throughputs. We
of amides towards organometallic reagents: An overview, 2014,
vol. 356.
added two synthetically valuable transformations to the “flow 13 W. S. Bechara, G. Pelletier and A. B. Charette, Nat. Chem.,
toolbox” using the identical flow reactor setup as previously
2012, 4, 228–234.
reported for lithiation/borylation43 or/sulfination44 and 14 R. K. Dieter, Tetrahedron, 1999, 55, 4177–4236.
Matteson chemistry.46 This strongly emphasizes the usefulness 15 X. J. Wang, L. Zhang, X. Sun, Y. Xu, D. Krishnamurthy and
and scope of this flow platform and showcases the synthetic
utility of organolithium chemistry. The reported flow setup is 16 M. McLaughlin, K. M. Belyk, G. Qian, R. A. Reamer and
equally suitable for the delivery of small quantities for medic- C. Y. Chen, J. Org. Chem., 2012, 77, 5144–5148.
inal chemistry purposes or for larger quantities for early devel- 17 E. A. Chung, C. W. Cho and K. H. Ahn, J. Org. Chem., 1998,
opment phases. The straightforward concept boosts the syn- 63, 7590–7591.
thetic utility of organolithium chemistry, reduces development 18 M. Masubuchi, K. Kawasaki, H. Ebiike, Y. Ikeda, S. Tsujii,
C. H. Senanayake, Org. Lett., 2005, 7, 5593–5595.
times and appeals attractive to the scientific community.
S. Sogabe, T. Fujii, K. Sakata, Y. Shiratori, Y. Aoki,
T. Ohtsuka and N. Shimma, Bioorg. Med. Chem. Lett., 2001,
11, 1833–1837.
Conflicts of interest
19 C. Liu, M. Achtenhagen and M. Szostak, Org. Lett., 2016,
18, 2375–2378.
20 F. G. J. Odille, A. Stenemyr and F. Pontén, Org. Process Res.
Dev., 2014, 18, 1545–1549.
There are no conflicts to declare.
21 J. Mulzer, A. Mantoulidis and O. Elisabeth, J. Org. Chem.,
2000, 65, 7456–7467.
Acknowledgements
22 O. Delgado, G. Heckmann, H. M. Mu and T. Bach, J. Org.
Chem., 2006, 71, 4599–4608.
23 P. G. Lima, C. Sequeira and P. R. R. Costa, Tetrahedron
Lett., 2001, 42, 3525–3527.
24 A. Avenoza, H. Busto and J. M. Peregrina, Tetrahedron,
2002, 58, 10167–10171.
25 X. Creary, J. Org. Chem., 1987, 52, 5026–5030.
26 J. Barluenga, L. Llavona, M. Yus and J. M. Concellon,
Tetrahedron, 1991, 47, 7875–7886.
27 J. Barluenga, L. Llavona, M. Yus and J. M. Concellon,
Synthesis, 1990, 1003–1005.
28 L. Llavona, J. M. Concellon and M. Yus, J. Chem. Soc.,
Perkin Trans. 1, 1991, 8, 297–300.
The authors are very thankful for the support of the Novartis
Continuous Manufacturing Unit. We would like to thank
Stephane Schmitt for analytical support. The authors would
like to dedicate this article to the living memory of Dr Mark
Meisenbach (1966–2020), an admirable chemist, manager and
person. You are dearly missed in Novartis.
Notes and references
1 B. Eftekhari-Sis, M. Zirak and A. Akbari, Chem. Rev., 2013,
113, 2958–3043.
2 B. Eftekhari-Sis and M. Zirak, Chem. Rev., 2015, 115, 151–264.
3 A. Ayati, S. Emami, A. Asadipour, A. Shafiee and 29 J. B. L. Llavona, J. M. Concellon and M. Yus, J. Chem. Soc.,
A. Foroumadi, Eur. J. Med. Chem., 2015, 97, 699–718. Perkin Trans. 1, 1990, 7, 417.
4 A. R. Katritzky, Comprehensive Heterocyclic Chemistry III, 30 J.-I. Yoshida, Flash Chemistry: Fast Organic Synthesis in
2008, vol. 6. Microsystems, John Wiley and Sons, Chichester (UK), 2008.
5 E. Vitaku, D. T. Smith and J. T. Njardarson, J. Med. Chem., 31 A. Nagaki, H. Kim, Y. Moriwaki, C. Matsuo and
2014, 57, 10257–10274. J.-I. Yoshida, Chem. – Eur. J., 2010, 16, 11167–11177.
6 H. L. Lightfoot, F. W. Goldberg and J. Sedelmeier, ACS Med. 32 H. Kim, A. Nagaki and J.-I. Yoshida, Nat. Commun., 2011, 2,
Chem. Lett., 2019, 10, 153–160. 264–266.
7 F. Ayala-Mata, C. Barrera-Mendoza, H. A. Jiménez-Vázquez, 33 A. Nagaki, K. Imai, S. Ishiuchi and J.-I. Yoshida, Angew.
E. Vargas-Díaz and L. G. Zepeda, Molecules, 2012, 17,
13864–13878.
8 C. Sibbersen, J. Palmfeldt, J. Hansen, N. Gregersen,
Chem., Int. Ed., 2015, 54, 1914–1918.
34 A. Nagaki, Y. Tsuchihashi, S. Haraki and J.-I. Yoshida, Org.
Biomol. Chem., 2015, 13, 7140–7145.
K. A. Jørgensen and M. Johannsen, Chem. Commun., 2013, 35 A. Nagaki, S. Ishiuchi, K. Imai, K. Sasatsuki, Y. Nakahara
49, 4012–4014. and J.-I. Yoshida, React. Chem. Eng., 2017, 2, 862–870.
9 E. Cleator, J. P. Scott, P. Avalle, M. M. Bio, S. E. Brewer, 36 J.-I. Yoshida, H. Kim and A. Nagaki, J. Flow Chem., 2017, 7,
A. J. Davies, A. D. Gibb, F. J. Sheen, G. W. Stewart, 1–5.
D. J. Wallace and R. D. Wilson, Org. Process Res. Dev., 2013, 37 A. Nagaki, H. Yamashita, Y. Takahashi, S. Ishiuchi, K. Imai
17, 1561–1567. and J.-I. Yoshida, Chem. Lett., 2018, 47, 71–73.
10 M. Adamczyk, D. D. Johnson, P. G. Mattingly, Y. Pan and 38 S. Y. Moon, S. H. Jung, U. Bin Kim and W. S. Kim, RSC
R. E. Reddy, Synth. Commun., 2002, 32, 3199–3205.
Adv., 2015, 5, 79385–79390.
This journal is © The Royal Society of Chemistry 2021
Org. Biomol. Chem., 2021, 19, 2420–2424 | 2423

View Article Online
Communication
Organic & Biomolecular Chemistry
39 J. Wu, X. Yang, Z. He, X. Mao, T. A. Hatton and 43 A. Hafner, M. Meisenbach and J. Sedelmeier, Org. Lett.,
T. F. Jamison, Angew. Chem., Int. Ed., 2014, 53, 8416–8420. 2016, 18, 3630–3633.
40 A. Nagaki, D. Ichinari and J.-I. Yoshida, Chem. Commun., 44 F. Lima, J. André, A. Marziale, A. Greb, S. Glowienke,
2013, 49, 3242–3244.
M. Meisenbach, B. Schenkel, B. Martin and J. Sedelmeier,
41 B. Heinz, D. Djukanovic, M. A. Ganiek, B. Martin,
Org. Lett., 2020, 22, 6082–6085.
B. Schenkel and P. Knochel, Org. Lett., 2020, 22, 493– 45 H. Wang, W. Xu, Z. Wang, L. Yu and K. Xu, J. Org. Chem.,
496. 2015, 80, 2431–2435.
42 J. Hartwig, J. B. Metternich, N. Nikbin, A. Kirschning and 46 A. Hafner, V. Mancino, M. Meisenbach, B. Schenkel and
S. V. Ley, Org. Biomol. Chem., 2014, 12, 3611–3615. J. Sedelmeier, Org. Lett., 2017, 19, 786–789.
2424 | Org. Biomol. Chem., 2021, 19, 2420–2424
This journal is © The Royal Society of Chemistry 2021