Continuous Flow Preparation of (Hetero)benzylic Lithiums via Iodine-Lithium Exchange Reaction under Barbier Conditions

Article abstract of DOI:10.1021/acs.orglett.0c01991

Herein we report the generation of benzylic lithiums via an iodine-lithium exchange reaction on benzylic iodides performed in continuous flow using tBuLi as the exchange reagent. The resulting benzylic lithium species are trapped in situ by carbonyl electrophiles under Barbier conditions, resulting in benzylic secondary and tertiary alcohols. This flow procedure further allows the generation of highly reactive heterobenzylic lithium compounds, which are difficult to generate under batch conditions. A general scale-up was possible without further optimization.

Full text of DOI:10.1021/acs.orglett.0c01991

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Letter
Continuous Flow Preparation of (Hetero)benzylic Lithiums via
Iodine−Lithium Exchange Reaction under Barbier Conditions
Niels Weidmann,† Johannes H. Harenberg,† and Paul Knochel*
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ABSTRACT: Herein we report the generation of benzylic
lithiums via an iodine−lithium exchange reaction on benzylic
iodides performed in continuous flow using tBuLi as the exchange
reagent. The resulting benzylic lithium species are trapped in situ
by carbonyl electrophiles under Barbier conditions, resulting in
benzylic secondary and tertiary alcohols. This flow procedure
further allows the generation of highly reactive heterobenzylic
lithium compounds, which are difficult to generate under batch
conditions. A general scale-up was possible without further
optimization.
rganolithiums are widely used in organic syntheses.1
nBuLi as the exchange reagent for a halogen−lithium exchange
OBecause of the high polarity of the carbon−lithium reaction in the presence of MgCl2·LiCl, resulting in the more
bond, they react readily with various electrophiles.2 Generation
stable organomagnesium species, which were subsequently
quenched with various electrophiles.6
of lithium intermediates and control of their reactivity and
selectivity are ongoing tasks.3 A great improvement has been
Although substituted benzylic lithiums were previously
prepared by halogen−lithium exchange or insertion reactions
from the corresponding benzylic halides, their synthesis is
often accompanied by side reactions such as Wurtz
homocouplings.7 Furthermore, iodine−lithium exchange on
alkyl iodides is virtually instantaneous, outcompeting even the
deprotonation of MeOH.8 On the basis of those facts, we
envisioned that the need for an ultrafast in-line quench or in
situ trapping with metal salts could be overcome by adding an
electrophile to the starting material solution (Barbier
conditions).
Herein we report an iodine−lithium exchange reaction on
benzylic iodides of type 1 in the presence of carbonyl
electrophiles of type 2 in a microflow reactor setup.9 The
resulting benzylic lithium species of type 3 were instanta-
neously trapped in a Barbier-type reaction by electrophiles of
type 2 already present in the reaction solution, affording the
desired secondary and tertiary alcohols of type 4 (Scheme 1b).
We first examined the generation of benzyllithium (3a)
under Barbier-type conditions from benzyl iodide (1a) (65 mg,
0.20 mmol, 1.0 equiv) using nBuLi (0.25 mmol, 1.25 equiv) as
the exchange reagent in the presence of benzaldehyde (2a) (32
achieved by performing these organometallic reactions in
continuous flow.4 Yoshida and co-workers successfully
generated highly reactive lithium species via exchange
reactions, direct metalation, or insertion, which were quenched
within milliseconds by various electrophiles using custom-
made microreactors allowing ultrafast mixing and very short
residence times (Scheme 1a).5 We recently reported an
efficient method of in situ trapping transmetalation using
Scheme 1. (a) Lithium Insertion into Benzylic Halides
Using Ultrafast in-Line Electrophile Quench;5e (b) Iodine−
Lithium Exchange on (Hetero)benzylic Iodides under
Barbier Conditions
Received: June 15, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01991
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Table 1. Optimization of the Reaction Conditions for Iodine−Lithium Exchange of Benzyl Iodide (1a) with Lithium Bases and
In Situ Barbier-Type Reaction with Benzaldehyde (2a) Enabled by Continuous Flow
a
entry
base (equiv)
t [s]
V
[mL]
flow rate [mL/min]
T [°C]
conv. [%]
GC yield [%]
1
2
3
4
5
6
7
8
9
nBuLi (1.25)
nBuLi (1.25)
tBuLi (2.5)
tBuLi (2.5)
tBuLi (2.5)
tBuLi (2.5)
tBuLi (2.5)
tBuLi (2.5)
150
30
30
2.5
30
6
5
1
1
0.02
1
1
1
0.02
0.02
0.02
0.02
2
2
2
2
2
10
10
10
10
10
10
0
0
0
−78
−78
−20
−78
-78
−78
−78
67
64
89
90
90
95
95
94
100
100
79
50
48
74
84
83
72
80
87
13
10
68
6
bc
,
0.1
0.1
0.1
0.1
d
tBuLi (2.5)
tBuLi (2.5)
e
10
11
nBuLi (1.25)
−78
a
b
c
Volume of the reactor. Isolated yield of the analytically pure product on a 0.20 mmol scale: 79%. Isolated yield on a 4.00 mmol scale: 78%.
TMEDA (2.5 equiv) was added. PMDTA (2.5 equiv) was added.
d
e
Scheme 2. General Setup for the Iodine−Lithium Exchange
of Benzylic Iodides with tBuLi and In Situ Barbier Trapping
with Carbonyl-Containing Electrophiles under Continuous
Flow Conditions
Table 2. In Situ Exchange Reaction and Subsequent
Barbier-Type Reaction of (Sterically Demanding) Benzylic
Iodides of Type 1 Leading via Reactive Benzylic Lithium
Species of Type 3 to Functionalized Alcohols of Type 4
a
b
Isolated yield of the reaction on a 4.00 mmol scale. The reaction
was performed under Barbier conditions (−40 °C, 30 min) in batch
(for detailed information, see p SI-31 in the Supporting Information)
mg, 0.30 mmol, 1.5 equiv) at 0 °C using a combined flow rate
of 2.0 mL/min, resulting in a 50% GC yield with a significant
amount of nBuLi addition product to benzaldehyde and
Wurtz-type homocoupling (Table 1, entry 1).10 Decreasing the
reactor volume had no impact on the conversion and GC yield
(entry 2). Investigation of various lithium bases (e.g., sBuLi,
tBuLi, nHexLi, neopentyllithium)10 revealed a significant
increase in the GC yield when tBuLi was used (74%; entry
3). We further optimized the reaction conditions by increasing
the flow rate and lowering the temperature, resulting in an 87%
GC yield (−78 °C, 10 mL/min combined flow rate, 0.02 mL
reactor volume, 0.1 s; entry 8). Entries 1−8 demonstrate the
strong mixing dependence of the iodine−lithium exchange
using benzylic iodides. In accordance with the literature,11
higher flow rates and smaller reactor diameters resulted in
more efficient mixing, favoring the exchange reaction.
Coordinating additives such as N,N,N′,N′-tetramethylethyle-
nediamine (TMEDA) and N,N,N′,N″,N′′-pentamethyldiethy-
lenetriamine (PMDTA) afforded secondary alcohol 4a in only
10−13% GC yield (entries 9 and 10) with the Wurtz-type
coupling as a major side reaction.12 Using nBuLi as the
exchange reagent under the optimized conditions led to
decreased conversion and GC yield (entry 11).
a
b
c
Yields of analytically pure isolated products. T = −78 °C. T = −20
d
°C. T = 25 °C.
resulting in a 78% isolated yield. Interestingly, performing the
reaction under batch conditions led to a significantly decreased
yield of 15%.13
Having these optimized conditions in hand, we investigated
the scope of various carbonyl derivatives and substituted
benzylic iodides (Table 2).14 Benzyllithium (3a) was generated
in the presence of m-anisaldehyde (2b), resulting in a 63%
isolated yield of secondary alcohol 4b (entry 2). However,
Under the optimized reaction conditions (Table 1, entry 8
and Scheme 2), the desired alcohol 4a was obtained in 79%
isolated yield. A scale-up was possible without further
optimization of the reaction conditions by increasing the run
time from 12 s (0.20 mmol scale) to 240 s (4.00 mmol scale),
B
https://dx.doi.org/10.1021/acs.orglett.0c01991
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Table 3. In Situ Exchange Reaction and Subsequent
Table 4. In Situ Exchange Reaction and Subsequent
Barbier-Type Reaction of Electron-Rich Benzylic Iodides of
Type 5 Leading via Reactive Benzylic Lithium Species of
Type 6 to Functionalized Alcohols of Type 7
Barbier-Type Reaction of Electron-Poor Benzylic Iodides of
Type 8 Leading via Reactive Lithium Species of Type 9 to
Functionalized Alcohols of Type 10
a
b
c
Yields of analytically pure isolated products. T = −78 °C. T = 0
°C.
Scheme 3. In Situ Exchange Reaction and Subsequent
Barbier-Type Reaction of Heterobenzylic Iodides of Type
11 Leading via Highly Reactive Lithium Species of Type 12
to Functionalized Alcohols of Type 13
a
b
c
Yields of analytically pure isolated products. T = −40 °C. T = −78
d
e
f
°C. T = −30 °C. T = −20 °C. The reaction was performed under
Barbier conditions (−20 °C, 30 min) in batch (for detailed
information, see p SI-37).
using aliphatic aldehydes such as 2-ethylbutanal or noncyclic
ketones such as 2-hexanone under Barbier-type reaction
conditions afforded the desired aliphatic alcohols in lower
GC yields, possibly as a result of enolization of the aldehydes
or ketones. Alkyl-substituted substrates such as 4-tert-
butylbenzyl iodide (1b) and 4-isopropylbenzyl iodide (1c)
afforded the desired benzylic alcohols 4c−f after in situ
quenching with aromatic and aliphatic aldehydes in 56−76%
isolated yield (entries 3−6). Remarkably, addition to ketones,
which is typically slower than addition to aldehydes,5e was also
possible without a significant loss of yield using 1c and
acetophenone (2e), affording tertiary alcohol 4g in 68%
isolated yield (entry 7).
a
No product was detected under various batch conditions.13
benzylic iodide 5a was lithiated at −40 °C within 0.1 s,
providing secondary alcohol 7a in 50% isolated yield after an in
situ quench with 2a (entry 1). Alternatively, benzylic
organolithium 6a reacted with cyclohexyl carboxaldehyde
(2d), leading to aliphatic alcohol 7b in 62% isolated yield
(entry 2). Flow lithiation of thioether-substituted benzylic
iodide 5b and in situ trapping with 2e led to the desired
carbinol 7c in 68% isolated yield (entry 3). m- and p-methoxy-
substituted benzylic organolithiums (6c and 6d) were prepared
from the corresponding iodides (5c and 5d) and afforded
We then subjected electron-rich benzylic iodides bearing a
TBS-substituted alcohol, thioether, or methoxy substituent to
the optimized flow conditions (Table 3). 3-OTBS-substituted
C
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secondary benzylic alcohols 7d and 7e in 53−67% isolated
yield (entries 4 and 5). Furthermore, Barbier-type reactions
with sterically demanding ketones such as norcamphor (2g)
and adamantanone (2h) were possible without further
optimization of the flow conditions, affording tertiary alcohols
7f−h in 59−85% isolated yield (entries 6−8). Using Barbier
conditions in batch led to 7g in only 40% isolated yield,13
which is significantly lower than the 85% yield obtained under
continuous flow conditions.
orcid.org/0000-0001-7913-4332; Email: paul.knochel@
cup.uni-muenchen.de
Authors
Niels Weidmann − Department Chemie, Ludwig-Maximilians-
̈
̈
̈
Universitat Munchen, 81377 Munchen, Germany
Johannes H. Harenberg − Department Chemie, Ludwig-
̈
̈
̈
Maximilians-Universitat Munchen, 81377 Munchen, Germany
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01991
To further extend the scope of the lithiation protocol, we
applied this method to electron-deficient benzylic substrates
(Table 4). 2-Fluoro- and 2-chloro-substituted benzylic iodides
(8a and 8b) were converted to the corresponding lithiated
species 9a and 9b within 0.1 s. Trapping the intermediates of
type 9 with aldehyde 2a or 2c or ketone 2h gave the desired
alcohols 10a−d in 44−80% yield (entries 1−4). The presence
of a trifluoromethyl group at the meta position was also
tolerated, affording the secondary alcohol 10e in 64% isolated
yield after reaction with 2a using Barbier conditions (entry 5).
Having in mind that functionalization of heteroaromatics is
an important synthetic goal13 and that heterocycles are among
the most important structural motifs in current research
because of their wide range of bioactive properties and
frequent use in agrochemical and pharmaceutical chemistry,15
we turned our attention to heterobenzylic iodides (Scheme
3).16 We found that readily prepared 2-chloro-5-(iodomethyl)-
pyridine (11a)17 reacted instantaneously with tBuLi (2.5
equiv) to give the corresponding pyridylmethyllithium 12a. In
the presence of 2a, benzylic alcohol 13a was obtained in 92%
isolated yield, whereas no product was detected by GC−MS
under various batch conditions.13 6-Chloro-2-fluoro-3-
(iodomethyl)pyridine (11b) was lithiated at −78 °C within
0.1 s, affording the desired secondary alcohol 13b in 61% yield
via Barbier trapping with 2,6-dichlorobenzaldehyde (2i).
Furthermore, flow lithiation of 6-chloro-3-(iodomethyl)-2-
(methylthio)pyridine (11c) led to the corresponding pyr-
idylmethyllithium 12c, which was instantaneously quenched in
situ by various aromatic aldehydes to afford secondary alcohols
13c−e in 48−55% yield.18
Author Contributions
†N.W. and J.H.H. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
N.W. thanks the German Academic Scholarship Foundation
for a fellowship. We also thank the DFG and LMU for financial
support and Albemarle (Frankfurt) and BASF AG (Ludwig-
shafen) for generous gifts of chemicals.
REFERENCES
■
(1) (a) Clayden, J. Organolithiums: Selectivity for Synthesis; Baldwin,
J. E., Williams, R. M., Eds.; Pergamon Press: Oxford, U.K., 2002.
(b) Science of Synthesis, Volumes 8a,b; Snieckus, V., Majewski, M.,
Eds.; Georg Thieme Verlag: Stuttgart, Germany, 2005. (c) Whisler,
M. C.; Mac-Neil, S.; Snieckus, V.; Beak, P. Angew. Chem., Int. Ed.
2004, 43, 2206.
(2) (a) Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel, P. Angew.
Chem., Int. Ed. 2000, 39, 4414. (b) Goldfuss, B. Synthesis 2005, 14,
2271.
(3) (a) Nagaki, A.; Yamashita, H.; Hirose, K.; Tsuchihashi, Y.;
Yoshida, J.-I. Angew. Chem., Int. Ed. 2019, 58, 4027. (b) Pulis, A. P.;
Varela, A.; Citti, C.; Songara, P.; Leonori, D.; Aggarwal, V. K. Angew.
Chem., Int. Ed. 2017, 56, 10835. (c) Lutter, F. H.; Hofmayer, M. S.;
Hammann, J. M.; Malakhov, V.; Knochel, P. Generation and Trapping
of Functionalized Aryl- and Heteroarylmagnesium and -Zinc
Compounds. In Organic Reactions; Denmark, S. E., Ed.; John Wiley
& Sons: Hoboken, NJ, 2019; Vol. 100. (d) Skotnitzki, J.; Kremsmair,
A.; Keefer, D.; Gong, Y.; de Vivie-Riedle, R.; Knochel, P. Angew.
Chem., Int. Ed. 2020, 59, 320. (e) Skotnitzki, J.; Kremsmair, A.;
Knochel, P. Synthesis 2020, 52, 189. (f) Morozova, V.; Skotnitzki, J.;
Moriya, K.; Karaghiosoff, K.; Knochel, P. Angew. Chem., Int. Ed. 2018,
57, 5516. (g) Degennaro, L.; Nagaki, A.; Moriwaki, Y.; Romanazzi,
In summary, we have reported a convenient method for the
generation and efficient quenching of (hetero)benzylic lithium
species via an iodine−lithium exchange reaction on readily
available benzylic iodides using tBuLi as the exchange reagent.
The highly reactive (hetero)benzyl lithiums were trapped in
situ by carbonyl-containing electrophiles using Barbier
conditions in a commercially available continuous flow setup.
A general scale-up was possible by increasing the run time
without further optimization.
́
G.; DellAnna, M. M.; Yoshida, J.-i.; Luisi, R. Open Chem. 2016, 14,
377. (h) Dilauro, G.; Quivelli, A. F.; Vitale, P.; Capriati, V.; Perna, F.
M. Angew. Chem., Int. Ed. 2019, 58, 1799. (i) Ghinato, S.; Dilauro, G.;
Perna, F. M.; Capriati, V.; Blangetti, M.; Prandi, C. Chem. Commun.
2019, 55, 7741. (j) Dell’Aera, M.; Perna, F. M.; Vitale, P.; Altomare,
A.; Palmieri, A.; Maddock, L. C. H.; Bole, L. J.; Kennedy, A. R.; Hevia,
E.; Capriati, V. Chem. - Eur. J. 2020, DOI: 10.1002/chem.202001294.
(4) (a) Comer, E.; Organ, M. G. J. Am. Chem. Soc. 2005, 127, 8160.
(b) Price, G. A.; Hassan, A.; Chandrasoma, N.; Bogdan, A. R.; Djuric,
S. W.; Organ, M. G. Angew. Chem., Int. Ed. 2017, 56, 13347.
(c) Comer, E.; Organ, M. G. Chem. - Eur. J. 2005, 11, 7223.
(d) Brodmann, T.; Koos, P.; Metzger, A.; Knochel, P.; Ley, S. V. Org.
Process Res. Dev. 2012, 16, 1102.
(5) (a) Nagaki, A.; Sasatsuki, K.; Ishiuchi, S.; Miuchi, N.; Takumi,
M.; Yoshida, J.-I. Chem. - Eur. J. 2019, 25, 4946. (b) Lee, H.-j.; Kim,
H.; Yoshida, J.-I.; Kim, D.-P. Chem. Commun. 2018, 54, 547. (c) Kim,
H.; Yonekura, Y.; Yoshida, J.-I. Angew. Chem., Int. Ed. 2018, 57, 4063.
(d) Kim, H.; Min, K.-I.; Inoue, K.; Im, D. J.; Kim, D.-P.; Yoshida, J.-I.
Science 2016, 352, 691. (e) Nagaki, A.; Tsuchihashi, Y.; Haraki, S.;
Yoshida, J.-I. Org. Biomol. Chem. 2015, 13, 7140.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01991.
General experimental procedures, detailed synthetic
procedures, and analytical data for all compounds
mentioned (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Paul Knochel − Department Chemie, Ludwig-Maximilians-
̈
̈
̈
Universitat Munchen, 81377 Munchen, Germany;
D
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(6) (a) Ketels, M.; Ganiek, M. A.; Weidmann, N.; Knochel, P.
Angew. Chem., Int. Ed. 2017, 56, 12770. (b) Ketels, M.; Ziegler, D. S.;
Knochel, P. Synlett 2017, 28, 2817.
(7) (a) Parham, W. E.; Jones, L. D.; Sayed, Y. A. J. Org. Chem. 1976,
41, 1184. (b) Warren, S.; Wyatt, P.; McPartlin, M.; Woodroffe, T.
Tetrahedron Lett. 1996, 37, 5609. (c) Kupracz, L.; Kirschning, A. Adv.
Synth. Catal. 2013, 355, 3375. (d) Gilman, H.; McNinch, H. A.;
Wittenberg, D. J. Org. Chem. 1958, 23, 2044.
(8) (a) Bailey, W. F.; Patricia, J. J.; Nurmi, T. T.; Wang, W.
Tetrahedron Lett. 1986, 27, 1861. (b) Stein, C. A.; Morton, T. H.
Tetrahedron Lett. 1973, 14, 4933.
(9) For applications of benzyllithiums in flow, see: (a) Nagaki, A.;
Tsuchihashi, Y.; Haraki, S.; Yoshida, J.-I. Org. Biomol. Chem. 2015, 13,
7140. For usage of benzyllithiums under Barbier conditions, see:
́
(b) Gomez, C.; Huerta, F. F.; Yus, M. Tetrahedron 1997, 53, 13897.
́
(c) Gomez, C.; Huerta, F. F.; Yus, M. Tetrahedron 1998, 54, 1853.
(10) For detailed flow screening conditions, including the major side
products, see pp SI-5−SI-7.
(11) (a) Soleymani, A.; Yousefi, H.; Turunen, I. Chem. Eng. Sci.
2008, 63, 5291. (b) Plutschack, M. B.; Pieber, B.; Gilmore, K.;
Seeberger, P. H. Chem. Rev. 2017, 117, 11796.
(12) For detailed screening of coordinating ligands, see pp SI-6−SI-
9.
(13) For detailed batch screening conditions, see pp SI-35−SI-38.
(14) A temperature screening was conducted separately for each
reaction.
(15) (a) Beak, P.; Snieckus, V. Acc. Chem. Res. 1982, 15, 306.
(b) Schlosser, M. Angew. Chem., Int. Ed. 2005, 44, 376. (c) Chinchilla,
́
R.; Najera, C.; Yus, M. Chem. Rev. 2004, 104, 2667. (d) Snieckus, V.
Chem. Rev. 1990, 90, 879. (e) Foubelo, F.; Yus, M. Chem. Soc. Rev.
2008, 37, 2620.
(16) (a) Astruc, D. In Modern Arene Chemistry; Wiley-VCH:
Weinheim, Germany, 2002. (b) Penning, T. D.; Talley, J. J.;
Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.; Docter, S.; Graneto,
M. J.; Lee, L. F.; Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.;
Rogier, D. J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J.
N.; Gregory, S. A.; Koboldt, C. M.; Perkins, W. E.; Seibert, K.;
Veenhuizen, A. W.; Zhang, Y. Y.; Isakson, P. C. J. Med. Chem. 1997,
40, 1347. (c) Bhat, G. A.; Montero, J. L.-G.; Panzica, R. P.; Wotring,
L. L.; Townsend, L. B. J. J. Med. Chem. 1981, 24, 1165. (d) Vicentini,
C. B.; Mares, D.; Tartari, A.; Manfrini, M.; Forlani, G. J. Agric. Food
Chem. 2004, 52, 1898. (e) Ziegler, D. S.; Klier, L.; Mueller, N.;
Karaghiosoff, K.; Knochel, P. Synthesis 2018, 50, 4383. (f) Heinz, B.;
Balkenhohl, M.; Knochel, P. Synthesis 2019, 51, 4452.
(17) (a) Barl, N. M.; Sansiaume-Dagousset, E.; Monzon, G.;
Wagner, A. J.; Knochel, P. Org. Lett. 2014, 16, 2422. (b) Metzger, A.;
Piller, F. M.; Knochel, P. Chem. Commun. 2008, 44, 5824.
(18) For the preparation of heterobenzylic iodides, see pp SI-47−SI-
51. The reaction of various other heterobenzylic iodides, such as
quinolines and pyrimidines, were investigated. However, the GC yield
of the Barbier-type flow exchange reaction dropped significantly.
E
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