Generation and Cross-Coupling of Organozinc Reagents in Flow

Article abstract of DOI:10.1021/acs.orglett.8b03156

A versatile flow synthesis method for in situ formation of organozinc reagents and subsequent cross-coupling with aryl halides and activated carboxylic acids is reported. Formation of organozinc reagents is achieved by pumping organic halides, in the presence of ZnCl₂ and LiCl, through an activated Mg-packed column under flow conditions. This method provides efficient in situ formation of aryl, primary, secondary, and tertiary alkyl organozinc reagents, which are subsequently telescoped downstream to a Negishi or decarboxylative Negishi cross-coupling reaction. The described method offers access to a variety of C-C bond formations with organozinc reagents that are otherwise commercially unavailable or difficult to prepare under traditional batch reaction conditions.

Full text of DOI:10.1021/acs.orglett.8b03156

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Generation and Cross-Coupling of Organozinc Reagents in Flow
Ananda Herath, Valentina Molteni, Shifeng Pan, and Jon Loren*
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
S
* Supporting Information
ABSTRACT: A versatile flow synthesis method for in situ formation of organozinc reagents and subsequent cross-coupling
with aryl halides and activated carboxylic acids is reported. Formation of organozinc reagents is achieved by pumping organic
halides, in the presence of ZnCl2 and LiCl, through an activated Mg-packed column under flow conditions. This method
provides efficient in situ formation of aryl, primary, secondary, and tertiary alkyl organozinc reagents, which are subsequently
telescoped downstream to a Negishi or decarboxylative Negishi cross-coupling reaction. The described method offers access to
a variety of C−C bond formations with organozinc reagents that are otherwise commercially unavailable or difficult to prepare
under traditional batch reaction conditions.
column was recently reported. These reagents were used in
ransition-metal-mediated C−C bond-forming reactions
Twith organometallic reagents are widely used in organic subsequent cross-coupling with aryl bromides.9 This method
synthesis.1 Organoboranes are frequently employed cross-
provides direct in situ access to organozincs reagents; however,
it is limited to benzyl bromides and secondary alkyl iodides,
warranting further investigation to expand substrate scope.
To satisfy our medicinal chemistry needs, we sought to
identify a generalized flow protocol with broader substrate scope
for the organozinc reagents that would enable telescoping in-line
by cross-coupling with aryl halides and activated carboxylic
acids.
Work by Knochel demonstrated an efficient batch method for
the synthesis of organozinc reagents using Mg in the presence of
LiCl and ZnCl2.10 As Mg is a stronger reducing agent than zinc,
halogen/metal exchange11 with Mg proceeds faster with higher
substrate scope in generating organozincs.2b,12 Importantly, this
method allows for the formation of sterically hindered
organozincs such as adamantylzinc reagents. Based on this
work, we investigated Mg-packed columns to form transient
Grignard intermediates as precursors to organozinc reagents
under flow conditions. Few groups have reported the synthesis
of Grignard reagents using a Mg column in flow,13 yet direct
transmetalation to the organozinc reagent is largely unexplored.
Our initial efforts focused on selecting the optimal Mg particle
size and activation conditions for the Mg column by studying the
conversion of 1-bromoadamantane (1) to its corresponding
adamantylzinc reagent (2) (Table 1). The concentration of
adamantylzinc was determined by quenching with iodine.14
coupling partners in drug development due to their stability
and abundant availability. In contrast, organozinc reagents are
less commonly used due to their limited commercial availability
and methods of preparation yet can provide a reactivity scope
superior to that of oganoboranes.2 Organozinc reagents strike a
balance in reactivity between organoboroanes and Grignard or
organolithium reagents. Negishi3 (sp3−sp2 and sp2−sp2) and
decarboxylative Negishi4 (sp2−sp3 and sp3−sp3) cross-cou-
plings are two attractive applications of organozic reagents in
medicinal chemistry settings. Formation of bench-stable
organozinc reagents can be technically challenging due to their
strong nucleophilic and basic character.5 Standard flask or batch
synthesis of organozinc reagents is often complicated by inert
and anhydrous atmosphere conditions and irregular Mg
activation, factors that are easily remedied under flow chemistry
conditions.
Flow chemistry technology is ideally suited for in situ
synthesis of reactive intermediates with subsequent in-line
trapping or reaction telescoping.6 Moreover, the potential to run
moisture-sensitive reactions in a single, uninterrupted micro-
reactor sequence is beneficial for rapid and efficient generation
of large numbers of compounds with high purity and minimal
byproducts.7 Modern flow chemistry instrumentation enables
telescoping of multiple synthetic steps in one continuous flow
and even allows for in-line aqueous workups and purification.6b,8
Generation of organozinc reagents using flow chemistry by
simply passing alkyl halides through an activated zinc packed
Received: October 3, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03156
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Magnesium Activation and Particle Size
Optimization with 1-Bromoadamantane (1) in Flow
Table 2. Negishi Coupling and Catalyst Optimization with
Adamantylzinc Reagent
a
b
c
entry
Mg0 particle size
temp (°C)
rt (min)
conversion (%)
1
2
3
4
turnings
turnings
turnings
25
50
100
25
5
5
10
10
<5
10
75
75
d
e
−50 mesh
a
Reaction condition: 1 (0.3 M in THF), ZnCl2 (1.1 equiv), LiCl (1.1
a
b
entry
catalyst
conversion (%)
equiv). Residence time (rt) as measured in an Omnifit 150 mm × 6.6
c
1
2
3
Pd(OAc)2/Sphos
Pd(I) dimer
Pd-PEPPSI-IPr
55
65
20
mm column. Conversion was determined by quenching with
iodine.14 As supplied by Aldrich, catalog# 253987. Omnifit 150
d
e
mm × 15 mm column.
a
Reaction mixtures were stirred for 5 min at rt. Conversions were
determined by LCMS analysis.
Reactions were first carried out using Mg turnings which were
activated with TMSCl (2 M in THF) and 1,2-dibromoethane.
Under these conditions, precipitation of Mg salts was observed
at the end of the column and the exit tubing, which led to system
clogging. Further optimization suggested that lowering the
concentration of 1,2-dibromoethane (0.3 M in THF) was
necessary to avoid precipitation of Mg salts during activation.
Once the Mg column was activated, a combined solution of
organohalide, LiCl, and commercially available ZnCl2 in THF
flowed through the column reactor at rt to generate the
corresponding organozinc reagents. Even though Mg turning
activation was successful (Table 1, entry 3), it required increased
temperatures and longer residence times to achieve high
transmetalation conversion to adamantylzinc reagent. After
screening several conditions and Mg sources, we found Mg with
a particle size of −50 mesh at rt was optimal for reaction
telescoping (Table 1, entry 4).13 One intriguing observation was
that an activated Mg column could be stored under solvent
(THF) for several weeks and reused for organozinc reagent
formation without reactivating the column.
Scheme 1. Negishi (sp3−sp2 and sp2−sp2) Cross-Coupling
with In Situ Generated Organozinc Reagents
†
Generation of organozinc reagents was further simplified by
pumping separate stock solutions of LiCl and ZnCl2 with a
solution of organohalide in flow via a T-mixer before passing
through the Mg column with a residence time of 5 min (Table 2
flow scheme). This protocol allows rapid exchange of the
organohalide and, when combined with an injection loop, can be
used to generate organozinc reagents in a library format. An
additional advantage of this flow protocol is the ability to simply
inject organohalides to prepare the organozinc reagents on
demand without reactivating the Mg column between each
substrate. We next investigated a telescoping protocol where in
situ generated organozinc reagents were subjected to Negishi
cross-coupling reaction conditions with the goal of identifying
an effective catalyst (Table 2). The in situ generated
adamantylzinc reagent exiting the reactor was collected into a
stirring THF solution of 3-bromo-4-methylpyridine while
varying the Pd catalysts. Notable reactivity was observed with
Pd(I) dimer15 and Pd(OAc)2/Sphos.10 Reactions with both
catalysts showed good conversion at rt within 5 min (Table 2,
entries 1 and 2).
†
Reaction conditions: RX (3.3 equiv), LiCl (3.6 equiv), ZnCl2 (3.6
a
equiv), ArBr (1.0 equiv), PdCat (0.01 equiv). Palladium(I) dimer.
b
Pd(OAc)2/SPhos.
reagents were mixed downstream with a THF solution of aryl
bromide and either Pd(I) dimer or Pd(OAc)2/Sphos catalyst in
a glass chip reactor at rt (Scheme 1) with a residence time of 1
min. A variety of substrates were amenable to organozinc
formation with good conversion to the corresponding cross-
coupling products with yields of 40−91%. Reactions with
heterocycles bearing electron-donating groups (3, 5, and 7) or
an electron-withdrawing group (6) proceeded efficiently with
similarly good yields. A variety of functional groups on the aryl
halide coupling partner, such as ketones, amines, aldehydes,
With the optimized set of flow and catalyst conditions in hand,
we explored the substrate scope for Negishi cross-coupling
reactions (Scheme 1).16 The in situ generated organozinc
B
DOI: 10.1021/acs.orglett.8b03156
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Decarboxylative Negishi (sp2−sp3 and sp3−sp3)
acids, and esters were well tolerated (4, 8, 10, 14, and 6,
respectively) without hindrance of product formation. Fur-
thermore, good chemoselectivty (Br vs Cl) was observed when
using Pd(I) dimer (9, 10, and 11).15 A noteworthy feature of
this flow protocol is its compatibility with both sp3−sp2 and sp2−
sp2 carbon bond formation, which enabled formation of primary,
secondary, and tertiary alkyl aryl cross-coupling products (5, 7,
and 3, respectively). Additionally, sterically congested biaryl
cross-coupling products (12, 13, and 14) form in modest to
good yield.
Cross-Coupling with In Situ Generated Organozinc
†
Reagents
We expanded the downstream protocols to include
decarboxylative Negishi cross-coupling, reminiscent of recent
work by the McMillan and Baran groups. McMillan demon-
strated this transformation by directly combining carboxylic
acids and organohalides under photoredox conditions.17
Although this method is attractive, implementation of this
procedure requires specialized photoreactors and expensive Ir
catalysts. Baran showed that organozinc reagents can be used in
a nickel-mediated decarboxylative Negishi coupling with redox-
active esters, that is, carboxylic acids activated with standard
amide couplings reagents.4a,b,d,18 This transformation offers
tremendous utility with access to C−C bond formations
between sp2−sp3 and sp3−sp3 carbon centers from readily
available carboxylic acids yet still requires inert and anhydrous
atmosphere conditions to generate moisture-sensitive organo-
zinc reagents, which can often be tedious in batch. This,
combined with the stepwise synthesis of the redox-active esters,
could limit its usage in an industrial medicinal chemistry setting.
Adapting our standardized in situ organozinc formation to
decarboxylative Negishi coupling in flow required its own
optimization. This work was initially focused on the sp2−sp3
coupling of phenylzinc halide with 1-(tert-butoxycarbonyl)-3-
piperidinecarboxylic acid to form compound 15 (Scheme 2) to
probe other flow reaction parameters (i.e., nickel catalyst
solubility and solvent compatibility). 15 was activated using
HATU and triethylamine and then treated with different nickel
catalysts in DMF and acetonitrile (see Supporting Information
(SI)). Screening solvents and catalysts suggested that Ni-
(acac)2/4,4′-dimethyl-2,2′-bipyridine in MeCN worked best in
terms of solubility and conversion, while providing a
productivity rate of approximately 5 mmol/h. Although other
conditions (i.e., NiCl2 in DMF) provided similar conversion, the
catalyst was not practical to employ in flow due to poor
solubility. Reactions in DMF also provided similar conversions;
however, the solvent was not ideal due to formation of dimethyl
amine amide byproducts and substrate precipitation in the
reactor (see SI).
Under the optimized conditions, activation of the carboxylic
acid in flow was performed by addition of HATU and
triethylamine in acetonitrile. The resulting activated carboxylic
acids were combined downstream with in situ generated
organozinc reagents and catalyst and then passed through a
glass reactor at rt with a residence time of 1 min. The scope of
this flow protocol was explored and found to be remarkably
broad (Scheme 2).16 Both electron-rich para methoxy and
electron-poor para fluoro aromatic organozinc reagents were
well tolerated, affording the corresponding arylated derivatives
in respectable yields (17 and 18, respectively). Synthetically
demanding biphenyl bioisosteres for medicinal chemistry were
quickly generated by coupling readily available [2.2.2] and
[1.1.1] bicyclo tertiary carboxylic acids, providing 16/19 and 21
in modest yields, respectively. Decarboxylative alkenylation18a
coupling was also achieved, rendering 20 in 40% yield.
†
Reaction conditions: RX (3.3 equiv), LiCl (3.6 equiv), ZnCl2 (3.6
equiv), R’-CO2H (1.0 equiv), HATU (1.0 equiv), TEA (1.0 equiv),
Ni(acac)2/L (0.1 equiv, 1:1.5). L = 4,4′-dimethyl-2,2′-bipyridine.
Decarboxylative Negishi cross-coupling in flow is applicable
to both sp2−sp3 and sp3−sp3 couplings, requiring only a simple
organohalide substrate change (Scheme 2). This further
increases the value and utility of this method by enabling C−
C bond formation between primary, secondary, and tertiary alkyl
groups under flow conditions. For example, in situ generated
alkyl organozinc reagents containing functional groups such as
ester and methoxy undergo coupling with carboxylic acids to
generate novel compounds 25 and 27, respectively. Addition-
ally, sterically demanding amino acids can be modified efficiently
using this protocol to form 28, suggesting the potential for late-
stage modification or manufacturing of custom peptidomimetic
derivatives. In all cases, coupling occurred smoothly and without
interruption in the presence of protecting group functionality,
i.e. esters and protected amines, which provides products
suitable for further structural elaboration applicable to medicinal
chemistry.
In summary, we have developed a versatile flow synthesis
method for in situ formation of a wide variety of organozinc
reagents prepared directly from readily available organohalides
using a Mg column with direct transmetalation using ZnCl2.
Telescoping of the resulting organozinc reagents to Negishi
(sp3−sp2 and sp2−sp2) and decarboxylative Negishi (sp2−sp3
and sp3−sp3) cross-coupling reactions avoids the need to isolate
or transfer moisture-sensitive organozinc reagents. Modern flow
C
DOI: 10.1021/acs.orglett.8b03156
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(5) Hammann, J. M.; Lutter, F. H.; Haas, D.; Knochel, P. Angew.
Chem., Int. Ed. 2017, 56, 1082.
chemistry instrumentation features allow compatibility of this
protocol to proceed in a single flow setup, in either one-off or
library format. We anticipate that these advances will facilitate
quick access to organozinc chemistry and cross-coupling
adducts for medicinal chemists. Further exploration of the
reactivity scope beyond this methodology and applications to
the synthesis of complex molecules in drug discovery is in
progress.
(6) (a) Usutani, H.; Tomida, Y.; Nagaki, A.; Okamoto, H.; Nokami,
T.; Yoshida, J.-i. J. Am. Chem. Soc. 2007, 129, 3046. (b) Watts, P.;
Haswell, S. J. Drug Discovery Today 2003, 8, 586. (c) Hafner, A.; Ley, S.
V. Synlett 2015, 26, 1470. (d) Fukuyama, T.; Chiba, H.; Kuroda, H.;
Takigawa, T.; Kayano, A.; Tagami, K. Org. Process Res. Dev. 2016, 20,
503. (e) Becker, M. R.; Knochel, P. Org. Lett. 2016, 18, 1462. (f) Becker,
M. R.; Ganiek, M. A.; Knochel, P. Chem. Sci. 2015, 6, 6649. (g) Becker,
M. R.; Knochel, P. Angew. Chem., Int. Ed. 2015, 54, 12501.
(h) Mastronardi, F.; Gutmann, B.; Kappe, C. O. Org. Lett. 2013, 15,
5590. (i) Pinho, V. D.; Gutmann, B.; Miranda, L. S. M.; de Souza, R. O.
M. A.; Kappe, C. O. J. Org. Chem. 2014, 79, 1555.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b03156.
(7) (a) Newby, J. A.; Blaylock, D. W.; Witt, P. M.; Pastre, J. C.;
Zacharova, M. K.; Ley, S. V.; Browne, D. L. Org. Process Res. Dev. 2014,
18, 1211. (b) Gutmann, B.; Cantillo, D.; Kappe, C. O. Angew. Chem.,
Int. Ed. 2015, 54, 6688.
(8) (a) Wiles, C.; Watts, P. Eur. J. Org. Chem. 2008, 2008, 1655.
(b) Illg, T.; Loeb, P.; Hessel, V. Bioorg. Med. Chem. 2010, 18, 3707.
(c) Hamlin, T. A.; Lazarus, G. M. L.; Kelly, C. B.; Leadbeater, N. E. Org.
Process Res. Dev. 2014, 18, 1253. (d) Porta, R.; Benaglia, M.; Puglisi, A.
Org. Process Res. Dev. 2016, 20, 2.
Experimental procedures, characterization data, and
copies of NMR spectra for all products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jloren@gnf.org.
ORCID
(9) (a) Alonso, N.; Miller, L. Z.; de M. Munoz, J.; Alcazar, J.;
McQuade, D. T. Adv. Synth. Catal. 2014, 356, 3737. (b) Berton, M.;
́
Huck, L.; Alcazar, J. Nat. Protoc. 2018, 13, 324.
(10) Samann, C.; Dhayalan, V.; Schreiner, P. R.; Knochel, P. Org. Lett.
2014, 16, 2418.
Jon Loren: 0000-0002-5646-5937
Notes
(11) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 3333.
(12) Piller, F. M.; Appukkuttan, P.; Gavryushin, A.; Helm, M.;
Knochel, P. Angew. Chem., Int. Ed. 2008, 47, 6802.
The authors declare no competing financial interest.
(13) Huck, L.; de la Hoz, A.; Diaz-Ortiz, A.; Alcazar, J. Org. Lett. 2017,
19, 3747.
(14) Krasovskiy, A.; Knochel, P. Synthesis 2006, 2006, 0890.
(15) (a) Kalvet, I.; Magnin, G.; Schoenebeck, F. Angew. Chem., Int. Ed.
2017, 56, 1581. (b) Keaveney, S. T.; Kundu, G.; Schoenebeck, F.
Angew. Chem., Int. Ed. 2018, 57, 12573.
ACKNOWLEDGMENTS
■
We thank Ashley Chong of the Genomics Institute of the
Novartis Research Foundation for HRMS measurement and
analytical support.
(16) A single Omnifit 150 mm × 15 mm −50 mesh column was used
to perform all reactions described in Schemes 1 and 2, without requiring
Mg repacking or recharging. Isolated yields are comparable to literature
precedence.10,15,18
(17) (a) Johnston, C. P.; Smith, R. T.; Allmendinger, S.; MacMillan,
D. W. C. Nature 2016, 536, 322. (b) Prier, C. K.; Rankic, D. A.;
MacMillan, D. W. C. Chem. Rev. 2013, 113, 5322.
(18) (a) Edwards, J. T.; Merchant, R. R.; McClymont, K. S.; Knouse,
K. W.; Qin, T.; Malins, L. R.; Vokits, B.; Shaw, S. A.; Bao, D. H.; Wei, F.
L.; Zhou, T.; Eastgate, M. D.; Baran, P. S. Nature 2017, 545, 213.
(b) Chen, T. G.; Barton, L. M.; Lin, Y.; Tsien, J.; Kossler, D.; Bastida, I.;
Asai, S.; Bi, C.; Chen, J. S.; Shan, M.; Fang, H.; Fang, F. G.; Choi, H.-w.;
Hawkins, L.; Qin, T.; Baran, P. S. Nature 2018, 560, 350.
REFERENCES
■
(1) (a) Knappke, C. E. I.; Jacobi von Wangelin, A. Chem. Soc. Rev.
2011, 40, 4948. (b) Tamao, K.; Kiso, Y.; Sumitani, K.; Kumada, M. J.
Am. Chem. Soc. 1972, 94, 9268. (c) Li, L.; Wang, C.-Y.; Huang, R.;
Biscoe, M. R. Nat. Chem. 2013, 5, 607. (d) Littke, A. F.; Fu, G. C. Angew.
Chem., Int. Ed. 1999, 38, 2411. (e) Kirchhoff, J. H.; Netherton, M. R.;
Hills, I. D.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 13662. (f) de Meijere,
A. D.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions; Wiley-
VCH: Weinheim, 2004, 2nd ed. (g) Jana, R.; Pathak, T. P.; Sigman, M.
S. Chem. Rev. 2011, 111, 1417. (h) Miyaura, N.; Ishiyama, T.; Sasaki,
H.; Ishikawa, M.; Sato, M.; Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314.
(i) Dreher, S. D.; Dormer, P. G.; Sandrock, D. L.; Molander, G. A. J. Am.
Chem. Soc. 2008, 130, 9257.
(2) (a) Lennox, A. J. J.; Lloyd-Jones, G. C. J. Am. Chem. Soc. 2012, 134,
7431. (b) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P.
Angew. Chem., Int. Ed. 2006, 45, 6040. (c) Ohmura, T.; Awano, T.;
Suginome, M. J. Am. Chem. Soc. 2010, 132, 13191.
(3) (a) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117.
(b) Knochel, P.; Schade, M. A.; Bernhardt, S.; Manolikakes, G.;
Metzger, A.; Piller, F. M.; Rohbogner, C. J.; Mosrin, M. Beilstein J. Org.
Chem. 2011, 7, 1261. (c) King, A. O.; Okukado, N.; Negishi, E.-i. J.
Chem. Soc., Chem. Commun. 1977, 683. (d) Haas, D.; Hammann, J. M.;
Greiner, R.; Knochel, P. ACS Catal. 2016, 6, 1540.
(4) (a) Qin, T.; Cornella, J.; Li, C.; Malins, L. R.; Edwards, J. T.;
Kawamura, S.; Maxwell, B. D.; Eastgate, M. D.; Baran, P. S. Science
2016, 352, 801. (b) Cornella, J.; Edwards, J. T.; Qin, T.; Kawamura, S.;
Wang, J.; Pan, C. M.; Gianatassio, R.; Schmidt, M.; Eastgate, M. D.;
Baran, P. S. J. Am. Chem. Soc. 2016, 138, 2174. (c) Huihui, K. M. M.;
Caputo, J. A.; Melchor, Z.; Olivares, A. M.; Spiewak, A. M.; Johnson, K.
A.; DiBenedetto, T. A.; Kim, S.; Ackerman, L. K. G.; Weix, D. J. J. Am.
Chem. Soc. 2016, 138, 5016. (d) Toriyama, F.; Cornella, J.; Wimmer, L.;
Chen, T. G.; Dixon, D. D.; Creech, G.; Baran, P. S. J. Am. Chem. Soc.
2016, 138, 11132.
D
DOI: 10.1021/acs.orglett.8b03156
Org. Lett. XXXX, XXX, XXX−XXX