Synthesis of Electron-Deficient Heteroaromatic 1,3-Substituted Cyclobutyls via Zinc Insertion/Negishi Coupling Sequence under Batch and Automated Flow Conditions

Article abstract of DOI:10.1021/acs.orglett.8b03588

Synthesis of 1,3-substituted cyclobutyls enabled by zinc insertion into functionalized iodocyclobutyl derivatives followed by Negishi coupling with halo-heteroaromatics is reported. Two distinct sets of conditions were developed; the first involved a two-step batch protocol using activated Rieke zinc, and the second involved a multistep continuous flow process. Both methods showed complementarity and allowed for rapid access to these medicinally relevant motifs, the possibility of scaling up, and automation for library synthesis.

Full text of DOI:10.1021/acs.orglett.8b03588

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Electron-Deficient Heteroaromatic 1,3-Substituted
Cyclobutyls via Zinc Insertion/Negishi Coupling Sequence under
Batch and Automated Flow Conditions
Matthieu Tissot,*,† Nathalie Body,§ Sylvain Petit,‡ Jehan Claessens,† Christophe Genicot,†
and Patrick Pasau†
†Global Chemistry, UCB New Medicines, UCB Biopharma SPRL, Avenue de l’industrie, 1420 Braine l’Alleud, Belgium
‡Chemical Process Research and Development, UCB Biopharma SPRL, Avenue de l’industrie, 1420 Braine l’Alleud, Belgium
§
́
Department Chimie Organique, Universite catholique de Louvain-la-Neuve, Place Louis Pasteur, 1, 1348 Louvain-la-Neuve,
Belgium
S
* Supporting Information
ABSTRACT: Synthesis of 1,3-substituted cyclobutyls enabled by zinc insertion into functionalized iodocyclobutyl derivatives
followed by Negishi coupling with halo-heteroaromatics is reported. Two distinct sets of conditions were developed; the first
involved a two-step batch protocol using activated Rieke zinc, and the second involved a multistep continuous flow process.
Both methods showed complementarity and allowed for rapid access to these medicinally relevant motifs, the possibility of
scaling up, and automation for library synthesis.
ubstituted cyclobutanes have generated significant interest
Swithin drug discovery and are frequently incorporated into
many and varied drug candidates (Figure 1).1 Due to the unique
steric properties of the core structure, this small ring system has
been extensively used to explore the chemical space.
Figure 1. Medicinally relevant compounds containing 1,3-substituted
cyclobutanes.
Over the past 30 years, Pd-catalyzed Negishi cross- coupling
has been a versatile tool to create C−C bonds, notably in the
presence of sensible functionalities.2 Among a myriad of useful
Figure 2. Negishi cross-couplings with functionalized cycloalkyls.
methodologies to couple Csp3−Csp2 under Negishi conditions,3
Knochel reported a highly diastereoselective Pd-catalyzed cross-
coupling reaction between functionalized cyclohexylzinc
Received: November 12, 2018
reagent and aryl iodide (Figure 2, eq 1).4 In this two-step
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03588
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
process, the organozinc is preformed via the insertion of
preactivated zinc metal5 and then engaged in the cross-coupling.
This sequence has also been applied successfully to introduce
the cyclopropyl moiety, taking advantage of the high reactivity of
the corresponding Reformatski reagent (Figure 2, eq 2).6
Inspired by these two methodologies and considering the
potential for the emergence of flow chemistry to generate
organometallic reagents,7 we identified an opportunity to
develop a general method to synthesize 1,3-disubstituted
heteroaryl cyclobutanes (Figure 2, eq 3). Indeed, rapid access
to this attractive motif is scarce and limited to α-arylation of
cyclobutyl carbonyl derivatives8 and direct addition of organo-
lithium or organomagnesium reagents to cyclobutanone
derivatives.9 Isolated examples of cross-coupling reactions
between cyclobutyl iodides and arylboronic acids have also
been achieved.10 Herein, we report a batch and a flow cross-
coupling procedure between halo-heteroaromatics and various
functionalized cyclobutylzinc. We were also able to achieve
automation of a multistep flow process.
°C for 6 min, and low conversion toward the organozinc reagent
2a was observed (entry 7). Full conversion was obtained at 120
°C under 8 bar of pressure (entry 8). A concentration of 0.4 M
(0.5 M expected) of the freshly prepared organozinc was
observed using the Knochel procedure.14 However, poor
stability of the organozinc was observed over time (50%
degradation after 1 h). Interestingly, 1a′ displayed almost no
conversion under the same conditions (entry 9).
With two available procedures for the formation of organozinc
reagents, we first evaluated the sequence under batch conditions.
Freshly prepared (3-cyanocyclobutyl)iodozinc 2a (1.1 equiv)
was added to a mixture of the iodobromopyrimidine, Pd(dppf)-
Cl2 (5 mol %), and THF. The reaction mixture was stirred for 1
h at 60 °C. We observed the exclusive formation of the C2
monoalkylated product 3a in 67% yield as a mixture of cis and
trans isomers in a ratio of 6/4 easily separated by
chromatography.
Encouraged by our preliminary results, we evaluated the scope
of this transformation with various 1,3-substituted cyclo-
butylzinc reagents, generated using the batch zinc insertion
procedure (Scheme 1). 1,3-Substituted cyclobutane 3b was
obtained in 50% yield. In this case, the cis isomer was determined
to be the major isomer in a ratio of dr = 6:4. The O-benzyl-
substituted cyclobutyl product 3c was obtained in 42% yield,
and no diastereoselectivity was detected. Iodocyclobutyls 1d
and 1e with nitrogen-containing functional groups were also
We started our investigation with the insertion of magnesium
to 3-iodo- and 3-bromocyclobutane carbonitrile 1a and 1a′.
Interestingly, no metal insertion was observed even after
chemical activation of the magnesium turnings by TMSCl and
dibromoethane11 (Table 1, entries 1 and 2). Next, using 3 equiv
Table 1. Optimized Metal Insertion
Scheme 1. Scope of Pd-Catalyzed Cross-Coupling of
Substituted Cyclobutyl Zinc with Aryl Halides in Batch
a e
,
Mode
temp (°C)/time
conv
a
entry method
X
metal
Mg
activation
(min)
(%)
1
batch
Br
TMSCl,
Br2C2H6
60/60
0
2
batch
I
Mg
TMSCl,
Br2C2H6
60/60
0
b
3
4
5
6
7
8
9
batch
batch
batch
batch
flow
Br
I
Br
I
I
I
Zn
Zn
HCl
HCl
Rieke
25/60
25/60
25/60
25/20
80/6
62
85
56
100
10
100
5
b
c
Zn
Zn
Zn
Zn
Zn
c
Rieke
HCl
HCl
HCl
flow
flow
120/6
120/6
Br
a
Conversion determined by capillary GC-MS analysis after protic
b
workup. Zn powder dried for 5 min at 400 °C under high vacuum.
c
Rieke zinc was purchased from Rieke Metals.
of zinc metal, preactivated under Knochel’s conditions (zinc
washed with 1 M HCl),12 we observed incomplete conversion
with bromo and iodo derivatives (entries 3 and 4). Therefore, we
performed the insertion using commercially available Rieke
zinc.13 Although the conversion was incomplete with 1a′ (entry
5), the 1a analogue displayed full conversion after 20 min (entry
6). No preactivation of the zinc source was needed with this
commercially available highly activated zinc. Alternatively, we
decided to investigate the zinc insertion flowing the
iodocyclobutyl derivative toward a column containing metallic
zinc, previously described by Alcazar.17 After preactivation of
the zinc powder with HCl (1 M), iodo-3-cyclobutane carbon-
itrile 1a (0.5 M in THF) was passed through the column at 80
a
Diastereoselectivity (trans/cis) determined by 1H NMR or by
b
capillary GC-MS analysis. Complete conversion of iodocyclobutyl
monitored by GC-MS analysis. Major isomer displayed. cBuZnBr
purchased from Aldrich. For compounds 3a, 3b, and 3g, side
products arising from the Blaise reaction were observed as minor
impurities.
c
d
e
B
DOI: 10.1021/acs.orglett.8b03588
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
submitted to the sequence, leading to Boc-protected spirocy-
clobutyl derivatives 3d and 3e in 40 and 63% yields, respectively.
Cyclobutyl iodide 1e was also probed toward zinc insertion
under flow conditions (120 °C, 6 min); however, Boc
deprotection occurred, highlighting the advantage of a mild
batch protocol when using thermosensitive compounds.15 The
reaction can be performed on gram scale using commercially
available cyclobutylzinc bromide 2f and the iodo(3-methox-
ycarbonyl-3-methylcyclobutyl)zinc 2g and delivered the desired
compounds 3f and 3g in good yields (85 and 64%, respectively).
Surprisingly, using iodo(3-methoxycarbonylcyclobutyl)zinc 2h,
we observed bisalkylation, leading to a complex mixture of
isomers 3h. In contrast, a high level of regioselectivity3d was
observed when 2-bromo-5-chloro-3-fluoropyridine was reacted
with (3-cyano-3-methylcyclobutyl)iodozinc, despite a low
conversion (20% yield, 3i). Finally, the methodology was
successfully applied to more complex bromo- and iodoheter-
oaryls to obtain 3j (78%) and 3k (80%), respectively. These last
examples demonstrate the tolerance of organozinc with
functional groups and the utility of this methodology to
functionalize druglike molecules.
Scheme 3. Pd-Catalyzed Cross-Coupling of Substituted
Cyclobutyl Zinc in Flow Using an Automated Platform
a
Having recognized the potential of this methodology to
introduce complex cyclobutyls to heteroaromatics, we inves-
tigated the possibility of performing a flow multistep process16
to react organozincs when they are produced and avoid handling
this sensitive organometallic reagent.17 Therefore, we combined
our initial zinc insertion flow protocol (Table 1, entry 8) with a
Negishi protocol in flow using a column containing 1 g of
SiliaCat DPP-Pd (Scheme 2).18 After optimization, 1.4 equiv of
1a reagents relative to the iodobromopyrimidine is required to
allow full conversion at 60 °C in THF over <3 min (Scheme 2).
Scheme 2. Pd-Catalyzed Cross-Coupling of Substituted
Cyclobutyl Zinc with Iodobromopyrimidine in Flow
a
dr (trans/cis) determined by 1H NMR [b] cBuZnBr purchased from
Aldrich.
transformation and offered an additional derivatization of the
heteroaromatic ring. 5-Bromo-2-iodopyridines 3p−3r displayed
exclusive iodo-selectivity in moderate yields ranging between 47
and 69%. With these heteroaromatics, the diastereoselectivity
appears to be low, with the best ratio of 7:3 obtained in both
cases with 2g. Interestingly, 2-methoxypyridine affords only 16%
conversion toward CN-cyclobutylpyridine 3s, whereas the esters
analogues display full conversion and yield products 3t and 3u in
53 and 44% yield.
2-Chloro-4-iodopyrimidine, 5-bromo-8-fluoroquinoline, and
protected 3,6-difluoro-5-iodopyridin-2-amine displayed incom-
plete conversion toward 3k and 3v−3x under standard
conditions within the 3 min residence time. Those results
highlight the lower reactivity of those starting materials;20
however, extending the residence time should improve the
conversions, as demonstrated by the complete conversion
toward 3k in batch mode (Scheme 1). Finally, our druglike
molecule displayed incomplete conversion under standard
conditions and gave moderate 13 and 29% yields. Products 3y
and 3z further demonstrate the utility of this method for the
rapid and late-stage introduction of substituted cyclobutyls.
In summary, we have described the development of a Pd-
catalyzed heteroarylation of functionalized cyclobutyls. A batch
mode protocol using Rieke zinc for the organozinc generation
The flow reaction was performed on 20 mmol scale, affording
3.3 g of coupling product 3a in 69% yield, demonstrating the
stability and robustness of the process over time. To establish
the scope of this flow methodology and also prepare a small
library of compounds for the exploration of the new chemical
space offered by this array of heteroaromatic substituted
cyclobutyls (Het-Cbs), we investigated automation of the
process. Integration of an autosampler to our flow system
enabled us to automatically load reagents and collect products.
Therefore, we submitted several iodocyclobutyls (Cb-I) and
haloheteroaryls (Het-X) to the zinc insertion/Negishi coupling
sequence under our optimized conditions (Scheme 3). This
automated platform allowed the preparative synthesis of one
coupling product (0.3 mmol scale) per hour and show efficiency
over 6 h using the same column.19 Cyclobutylbromopyrimidines
3a, 3b, and 3g were obtained, affording similar yields and
diastereoselectivities than in batch mode. 5-Cyano-2-iodopyr-
idines were converted to products 3l−3o in good yields (68−
80%); the nitrile functionality was not affected in the
C
DOI: 10.1021/acs.orglett.8b03588
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
11509. (j) Zhang, K.-F.; Christoffel, F.; Baudoin, O. Angew. Chem., Int.
Ed. 2018, 57, 1982.
(4) Moriya, K.; Knochel, P. Org. Lett. 2014, 16, 924.
(5) Knochel, P.; Millot, N.; Rodriguez, A. L.; Tucker, C. E. Org. React.
2001, 58, 417.
followed by heteroarylation allowed for the introduction of a
variety of substituted cyclobutyl-bearing orthogonal function-
alities. To make this sequence more attractive for library
synthesis and structure−activity relationships, we developed an
automated flow process avoiding handling of the organometallic
reagents. In addition, we discovered that organozincs could be
generated efficiently at 120 °C. The functional group tolerance
and the selectivity of the organozinc reagents under cross-
coupling conditions were demonstrated and allowed for
subsequent transformation of our products. Finally, comple-
mentarity of the two methods has been established, with the
operationally simple batch process, offering better yield when
long reaction times are required, whereas the flow process offers
the possibility of automatic generation, leading to diversity
without the need for handling the organozinc reagent.
(6) (a) Greszler, S. N.; Halvorsen, G. T.; Voight, E. A. Org. Lett. 2017,
19, 2490. (b) Reformatsky, S. Ber. Dtsch. Chem. Ges. 1887, 20, 1210.
(7) For recent advances in organometallic flow chemistry and reviews,
see: (a) Kim, H.; Nagaki, A.; Yoshida, J.-i. Nat. Commun. 2011, 2, 264.
(b) Noel, T.; Buchwald, S. L. Chem. Soc. Rev. 2011, 40, 5010.
(c) Brodmann, T.; Koos, P.; Metzger, A.; Knochel, P.; Ley, S. V. Org.
Process Res. Dev. 2012, 16, 1102. (d) Hartwig, J.; Metternich, J. B.;
Nikbin, N.; Kirschning, A.; Ley, S. V. Org. Biomol. Chem. 2014, 12,
3611. (e) Nagaki, A.; Imai, K.; Ishiuchi, S.; Yoshida, J.-I. Angew. Chem.,
Int. Ed. 2015, 54, 1914. (f) Movsisyan, M.; Delbeke, E. I. P.; Berton, J.
K. E. T.; Battilocchio, C.; Ley, S. V.; Stevens, C. V. Chem. Soc. Rev. 2016,
45, 4892. For selected examples of organozinc reagent synthesis in flow,
see: (g) Becker, M. R.; Knochel, P. Angew. Chem., Int. Ed. 2015, 54,
12501. (h) Becker, M. R.; Ganiek, M. A.; Knochel, P. Chem. Sci. 2015, 6,
6649. (i) Becker, M. R.; Knochel, P. Org. Lett. 2016, 18, 1462.
(j) Berton, M.; Huck, L.; Alcazar, J. Nat. Protoc. 2018, 13, 324.
(8) (a) McCabe Dunn, J. M.; Kuethe, J. T.; Orr, R. K.; Tudge, M.;
Campeau, L.-C. Org. Lett. 2014, 16, 6314. (b) Dalziel, M. E.; Chen, P.;
Carrera, D. E.; Zhang, H.; Gosselin, F. Org. Lett. 2017, 19, 3446.
(9) (a) Caputo, J. A.; Fuchs, R. J. Org. Chem. 1968, 33, 1959.
(b) Chernykh, A. V.; Radchenko, D. S.; Chernykh, A. V.; Kondratov, I.
S.; Tolmachova, N. A.; Datsenko, O. P.; Kurkunov, M. A.; Zozulya, S.;
Kheylik, Yu. P.; Bartels, K.; Daniliuc, C. G.; Haufe, G. Eur. J. Org. Chem.
2015, 2015, 6466.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b03588.
Experimental procedure, characterization (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: matthieu.tissot@ucb.com.
ORCID
(10) Guillemont, J. E. G.; Raboisson, P. J.-M. B.; Tahri, A.
Heterocyclic compounds as antibacterials. Patent Appl. 2017216283,
2017.
(11) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390.
Matthieu Tissot: 0000-0003-1164-6598
Patrick Pasau: 0000-0002-1777-7911
Notes
(12) Knochel, P. Organic Syntheses 1990, 70.
The authors declare no competing financial interest.
(13) (a) Rieke, R. D.; Li, P. T.; Burns, T. P.; Uhm, S. T. J. Org. Chem.
1981, 46, 4323. (b) Rieke, R. D.; Hanson, M. V.; Brown, J. D.; Niu, Q. J.
J. Org. Chem. 1996, 61, 2726.
(14) Krasovskiy, A.; Knochel, P. Synthesis 2006, 2006, 0890.
(15) Billotte, S. Synlett 1998, 1998, 379.
(16) (a) Webb, D.; Jamison, T. F. Chem. Sci. 2010, 1, 675. (b) Webb,
D.; Jamison, T. F. Org. Lett. 2012, 14, 568. (c) Ghislieri, D.; Gilmore,
K.; Seeberger, P. H. Angew. Chem., Int. Ed. 2015, 54, 678. (d) Britton, J.;
Raston, C. L. Chem. Soc. Rev. 2017, 46, 1250.
(17) (a) Alonso, N.; Miller, L. Z.; De M. Munoz, M.; Alcazar, J.;
McQuade, D. T. Adv. Synth. Catal. 2014, 356, 3737. (b) Price, G. A.;
Bogdan, A. R.; Aguirre, A. L.; Iwai, T.; Djuric, S. W.; Organ, M. G. Catal.
Sci. Technol. 2016, 6, 4733. (c) Abdiaj, I.; Fontana, A.; Gomez, M. V.; de
la Hoz, A.; Alcazar, J. Angew. Chem., Int. Ed. 2018, 57, 8473.
(18) For further information about SiliaCat catalyst, visit http://www.
silicycle.com (accessed September 18, 2018).
ACKNOWLEDGMENTS
■
We acknowledge Dr. Teresa de Haro (UCB Biopharma,
NewMedicines) for helpful discussions during the early stage
of this work.
DEDICATION
■
This work is dedicated to Prof. Alexandre Alexakis on the
occasion of his 70th birthday.
REFERENCES
■
(1) (a) Castelhano, A. L.; Cutting, G. A.; Locke, A. J.; Mao, Y.;
Mulvihill, K. M.; Norrie, R.; O’Brien, A. J.; Park, S. R.; Rechka, J. A.;
Stevens, A. M.; Thomas, C. I. Patent Appl. US 2011/045807, 2011.
(b) Fidanze, S. D.; et al. Bioorg. Med. Chem. Lett. 2010, 20, 2452.
(c) Voight, E. A.; Daanen, J. F.; Schmidt, R. G.; Gomtsyan, A.; Dart, M.
J.; Kym, P. R. J. Org. Chem. 2016, 81, 12060.
(19) Columns of reagents and catalysts displayed a decrease of
efficiency after 6−8 h and required replacement.
(20) Electron-rich heteroaromatic substrates displayed no or very low
reactivity under standard reaction conditions.
(2) (a) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117. (b) Haas,
D.; Hammann, J. M.; Greiner, R.; Knochel, P. ACS Catal. 2016, 6, 1540.
(3) (a) Thaler, T.; Haag, B.; Gavryushin, A.; Schober, K.; Hartmann,
E.; Gschwind, R. M.; Zipse, H.; Mayer, P.; Knochel, P. Nat. Chem. 2010,
2, 125. (b) Çalimsiz, S.; Organ, M. G. Chem. Commun. 2011, 47, 5181.
(c) Melzig, L.; Dennenwaldt, T.; Gavryushin, A.; Knochel, P. J. J. Org.
Chem. 2011, 76, 8891. (d) Pompeo, M.; Froese, R. D. J.; Hadei, N.;
Organ, M. G. Angew. Chem., Int. Ed. 2012, 51, 11354. (e) Atwater, B.;
Chandrasoma, N.; Mitchell, D.; Rodriguez, M. J.; Pompeo, M.; Froese,
R. D. J.; Organ, M. G. Angew. Chem., Int. Ed. 2015, 54, 9502. (f) Aikawa,
K.; Serizawa, H.; Ishii, K.; Mikami, K. Org. Lett. 2016, 18, 3690.
(g) Kalvet, I.; Sperger, T.; Scattolin, T.; Magnin, G.; Schoenebeck, F.
Angew. Chem., Int. Ed. 2017, 56, 7078. (h) Zhang, K.-F.; Christoffel, F.;
Baudoin, O. Angew. Chem., Int. Ed. 2018, 57, 1982. (i) Cao, Q.;
Howard, J. L.; Wheatley, E.; Browne, D. L. Angew. Chem. 2018, 130,
D
DOI: 10.1021/acs.orglett.8b03588
Org. Lett. XXXX, XXX, XXX−XXX