Chromium-Catalyzed Linear-Selective Alkylation of Aldehydes with Alkenes

Article abstract of DOI:10.1021/acs.orglett.0c03180

We developed a chromium-catalyzed, photochemical, and linear-selective alkylation of aldehydes with alkylzirconium species generated in situ from a wide range of alkenes and Schwartz's reagent. Photochemical homolysis of the C-Zr bond afforded alkyl radicals, which were then trapped by a chromium complex catalyst to generate the alkylchromium(III) species for polar addition to aldehydes. The reaction proceeded with high functional group tolerance at ambient temperature under visible-light irradiation.

Full text of DOI:10.1021/acs.orglett.0c03180

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Letter
Chromium-Catalyzed Linear-Selective Alkylation of Aldehydes with
Alkenes
Yuki Hirao, Yuri Katayama, Harunobu Mitsunuma,* and Motomu Kanai*
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ABSTRACT: We developed a chromium-catalyzed, photochemical,
and linear-selective alkylation of aldehydes with alkylzirconium species
generated in situ from a wide range of alkenes and Schwartz’s reagent.
Photochemical homolysis of the C−Zr bond afforded alkyl radicals,
which were then trapped by a chromium complex catalyst to generate
the alkylchromium(III) species for polar addition to aldehydes. The
reaction proceeded with high functional group tolerance at ambient
temperature under visible-light irradiation.
ucleophilic alkylation of carbonyl compounds with
Norganometallics is a fundamental process in organic
synthesis. Despite the high utility of organolithium and
-magnesium reagents, their excessive reactivity and basicity
often make them incompatible with functionalized substrates.
Therefore, improving the chemoselectivity and utility of
nucleophilic organometallic reagents is a very important
research topic.1 Among nucleophilic and chemoselective
organometallics for the alkylation of aldehydes,
alkylchromium(III) reagents are versatile for the synthesis of
multifunctional molecules.2 Alkyl halides (in most cases, alkyl
iodides) are traditionally used as precursors of alkylchromium-
(III) reagents (Figure 1a).3 Recently, Shenvi4 and Baran5
developed elegant methods for accessing alkylchromium(III)
reagents that allowed for chemoselective alkylation of
aldehydes with feedstock starting materials such as alkenes or
activated carboxylic acids (Figure 1a). Specifically, in Shenvi’s
reaction, branched addition products were obtained due to the
regioselectivity of Co-catalyzed hydrosilylation followed by
Co/Cr exchange through a secondary alkyl radical. Yahata
reported the nucleophilic addition of hydrocarbon alkanes to
aldehydes by combined use of a chromium salt and photoredox
catalyst, which also produced branched products (Figure 1a).6
Those methods significantly expanded the scope of Cr-
mediated carbonyl alkylation, but stoichiometric amounts of
Cr salts are required. Although catalytic processes for
generating alkylchromium species have been reported, the
substrate scope remains to be improved.7,8 Here, we developed
Cr-catalyzed, linear-selective alkylation of aldehydes by
alkylzirconium species generated in situ from alkenes and
Schwartz’s reagent (Figure 1b). Due to the mild reaction
conditions, various multifunctional substrates are compatible.
Our working hypothesis for Cr-catalyzed alkylation of
aldehydes is shown in Figure 2. Alkylzirconium 2 is
Figure 1. Precursors (R−X) of alkylchromium(III) species in
alkylation of aldehydes. (a) For previously reported Cr-mediated
reactions. (b) This work: alkylzirconium species as a precursor for
alkylchromium(III) species.
regioselectively prepared from alkene 1 and Schwartz’s reagent
under mild conditions.9 Photoactivation of 2 by visible-light
Received: September 22, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03180
© XXXX American Chemical Society
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A

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a
Scheme 1. Substrate Scope of Alkenes
Figure 2. Proposed catalytic cycle.
irradiation produces reduced Zr(III) species 3 and alkyl radical
4 through homolysis of the C−Zr bond,10 the latter of which is
oxidatively intercepted by Cr(II) complex 5 to afford
alkylchromium(III) 6.4−8,11 Then, 6 reacts with aldehydes 7
to produce Cr(III) alkoxide 8. Ligand exchange between 8 and
Zr(IV) species affords Zr(IV) alkoxide 9 and Cr(III) salt 10.7a
Finally, single-electron reduction of 10 by Zr(III) species 3
regenerates 5 and closes the catalytic cycle.12 We envisioned
catalytic turnover in Cr and linear selectivity due to the high
oxophilicity of Zr(IV) salts (8 to 9) and the regioselectivity in
hydrozirconation (1 to 2).
According to this hypothesis, we optimized the reaction
conditions using benzaldehyde (7a) and 1-hexene (1a).
Hexylzirconocene was prepared in situ by mixing alkene 1a
and Schwartz’s reagent in THF for 30 min. Alkylation product
11a was obtained in 70% yield in the presence of 20 mol % of
CrCl2 under visible-light irradiation. A linear product was
predominantly observed. Control experiments revealed that
CrCl2 and light irradiation were both essential for efficient
reaction progress.13
We next studied the substrate scope under the optimized
conditions. First, the scope of alkenes was investigated
(Scheme 1a). The reaction with terminal alkenes afforded
linear alkylated products in up to 70% yield (11a−11e).14
A
silyl group, alkyl halides, and alkyl tosylate were all tolerated
(11f−11i). Ether-containing alkenes gave the target product in
an acceptable yield (11j, 11k). Free alcohol did not interfere
with the reaction (11l). The reactivity of the present
chromium catalysis using 5-hexen-1-ol as an alkene substrate
was compared with the previously reported catalytic alkylation
of aldehydes, silver perchlolate-15a or zinc bromide-cataly-
zed15b reactions. A higher yield was obtained when using the
chromium catalysis, demonstrating the utility of the present
conditions.13 Alkenes containing a protected amine afforded an
amino alcohol derivative (11m). Hydrozirconation proceeded
chemoselectively at a CC double bond in the presence of a
CC triple bond, and the alkylation reaction proceeded at the
alkene moiety of the substrate (11n).16 Increasing the reaction
scale to 1.0 mmol did not affect the results (68%, 11a). When
1,5-hexadiene was used, 11c was obtained as a major product
(28%), suggesting the presence of a radical intermediate. This
result was consistent with the proposed reaction mechanism
shown in Figure 2.13
a
General reaction conditions: 1 (0.44 mmol) and ZrCp2HCl (0.4
mmol) were reacted in THF (0.5 mL) at room temperature. After 30
min, the resulting solution was added to a solution of 7a (0.2 mmol)
and CrCl2 (0.04 mmol) in THF (1.5 mL). The mixture was stirred at
room temperature under blue LED irradiation for 20 h. Yield was
b
c
isolated yield. 1.0 mmol scale. Methylenecyclopentane was used as
the alkene substrate. 1 (0.4 mmol) and ZrCp2HCl (0.8 mmol) were
used. General reaction conditions: 1 (0.44 mmol) and ZrCp2HCl
(0.4 mmol) were reacted in THF (0.5 mL) at 50 °C. After 5 h, the
resulting solution was added to a solution of 7a (0.2 mmol) and CrCl2
(0.04 mmol). The mixture was stirred at room temperature under
blue LED irradiation for 20 h. Yield was isolated yield.
d
e
alkylated product 11a with bond formation at the terminal
carbon in 68% yield. trans-Anethole gave 11o in 61% yield.
We next investigated the scope of aldehydes (Scheme 2). A
series of aromatic aldehydes bearing halogens (11p−11r),
electron-withdrawing groups (11s, 11t), an electron-donating
group (11u), and pinacol boron ester (11v) reacted with 1-
hexene (1a), affording the corresponding products. The
reaction chemoselectively proceeded with the aldehyde moiety
in the presence of an ester or amide group (11w−11y). The
When internal alkenes were used, terminal alkylzirconocenes
were generated under thermodynamic conditions.17 Based on
this chain walking strategy,18 we tested internal alkenes as an
alkyl group source (Scheme 1b). 2-Hexene afforded linear
B
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a
a
Scheme 2. Substrate Scope of Aldehydes
Scheme 3. Application to Functionalized Substrate
a
General reaction conditions: 1 (0.44 mmol) and ZrCp2HCl (0.4
mmol) were reacted in THF (0.5 mL) at room temperature. After 30
min, the resulting solution was added to a solution of 7 (0.2 mmol)
and CrCl2 (0.04 mmol) in THF (1.5 mL). The mixture was stirred at
room temperature under blue LED irradiation for 20 h. Yield was
a
General reaction conditions: 1a (0.44 mmol) and ZrCp2HCl (0.4
mmol) were reacted in THF (0.5 mL) at room temperature. After 30
min, the resulting solution was added to a solution of 7 (0.2 mmol)
and CrCl2 (0.04 mmol) in THF (1.5 mL). The mixture was stirred at
room temperature under blue LED irradiation for 20 h. Yield was
b
isolated yield. 1 (0.4 mmol) and ZrCp2HCl (0.8 mmol) were used.
c
CrCl2 (0.06 mmol) was used.
Finally, we demonstrated the applicability of this method to
an enantioselective variant (Scheme 4). When the carbazole-
based bisoxazoline ligand7b,19 was evaluated for the reaction
between 7a and 1a, product 11a was obtained in 71% ee.13
This preliminary result demonstrated, at least in principle, the
b
c
isolated yield. CrCl2 (0.06 mmol) was used. NMR yield.
introduction of a methyl substituent at a meta- or para-position
did not affect the results (11z, 11aa). The reaction of aliphatic
aldehydes also proceeded in the presence of 30 mol % of CrCl2
(11ab, 11ac). The reaction conditions were applicable to a
ketone substrate (11ad), although the yield was low.
Scheme 4. Preliminary Result of Asymmetric Reaction
We then studied functionalized substrates to assess the
functional group tolerance (Scheme 3). Alkenes from natural
products, eugenol, linalool, estrone, and quinine were
competent substrates (11ae−11ah). The reaction proceeded
in the presence of phenol, tertiary alcohol, tertiary amine, and
pyridine moieties. Hydrozirconation selectively proceeded at a
terminal CC double bond in the presence of a sterically
hindered trisubstituted CC double bond (11af). Citronellal
reacted with allylbenzene to afford the product 11ai in 45%
yield. Drug-conjugated aldehydes provided the corresponding
products in 67% and 50% yield (11aj, 11ak), respectively.
These results demonstrated the high functional group
compatibility and chemoselectivity of this method.
C
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(2) For selected reviews on reactivity of organochromium(III)
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In conclusion, we developed a linear-selective alkylation of
aldehydes using a chromium catalyst and alkylzirconium
reagents generated in situ through the hydrozirconation of
alkenes. The reaction proceeded under mild conditions at
ambient temperature and visible-light irradiation. Linear-
alkylated products were selectively obtained from both
terminal and internal alkenes. The high chemoselectivity of
this reaction makes it applicable to functionalized substrates,
including nonprotected hydroxy groups.
́
Alvarez, M. Role of the Nozaki−Hiyama−Takai−Kishi Reaction in
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03180.
■
sı
Experimental procedures, characterization data for all
new compounds, results of optimization and mechanistic
studies, and NMR spectra for all compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Harunobu Mitsunuma − Graduate School of Pharmaceutical
Sciences, The University of Tokyo, Tokyo 113-0033, Japan;
orcid.org/0000-0001-7609-905X; Email: h-mitsunuma@
mol.f.u-tokyo.ac.jp
Motomu Kanai − Graduate School of Pharmaceutical Sciences,
The University of Tokyo, Tokyo 113-0033, Japan;
orcid.org/0000-0003-1977-7648; Email: kanai@mol.f.u-
tokyo.ac.jp
(6) Yahata, K.; Sakurai, S.; Hori, S.; Yoshioka, S.; Kaneko, Y.;
Hasegawa, K.; Akai, S. Coupling Reaction between Aldehydes and
Non-Activated Hydrocarbons via the Reductive Radical-Polar Cross-
over Pathway. Org. Lett. 2020, 22, 1199−1203.
Authors
Yuki Hirao − Graduate School of Pharmaceutical Sciences, The
University of Tokyo, Tokyo 113-0033, Japan
(7) Kishi achieved the first chromium-catalyzed alkylation reactions
using alkyl iodides. (a) Namba, K.; Kishi, Y. New Catalytic Cycle for
Couplings of Aldehydes with Organochromium Reagents. Org. Lett.
2004, 6, 5031−5033. (b) Guo, H.; Dong, C.-G.; Kim, D.-S.; Urabe,
D.; Wang, J.; Kim, J. T.; Liu, X.; Sasaki, T.; Kishi, Y. Toolbox
Approach to the Search for Effective Ligands for Catalytic
Asymmetric Cr-Mediated Coupling Reactions. J. Am. Chem. Soc.
2009, 131, 15387−15393. (c) Kim, D.-S.; Dong, C.-G.; Kim, J. T.;
Guo, H.; Huang, J.; Tiseni, P. S.; Kishi, Y. New Syntheses of E7389
C14-C35 and Halichondrin C14-C38 Building Blocks: Double-
Inversion Approach. J. Am. Chem. Soc. 2009, 131, 15636−15641.
(8) Glorius recently developed a photocatalytic protocol to generate
α-aminoalkylchromium reagents from α-silyl amine: Schwarz, J. L.;
Kleinmans, R.; Paulisch, T. O.; Glorius, F. 1,2-Amino Alcohols via
Cr/Photoredox Dual-Catalyzed Addition of α-Amino Carbanion
Equivalents to Carbonyls. J. Am. Chem. Soc. 2020, 142, 2168−2174.
(9) Song, Z.; Takahashi, T. Hydrozirconation of Alkenes and
Alkynes. In Comprehensive Organic Synthesis; Elsevier, 2014; pp 838−
876.
(10) (a) Gao, Y.; Yang, C.; Bai, S.; Liu, X.; Wu, Q.; Wang, J.; Jiang,
C.; Qi, X. Visible-Light-Induced Nickel-Catalyzed Cross-Coupling
with Alkylzirconocenes from Unactivated Alkenes. Chem. 2020, 6,
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Chemoselective Cross-Coupling of gem-Borazirconocene Alkanes
with Aryl Halides. J. Am. Chem. Soc. 2020, 142, 11506−11513.
(11) For oxidative trap of allyl radicals by Cr complexes to generate
allylchromium(III) species in radical−polar crossover reactions, see:
(a) Takai, K.; Matsukawa, N.; Takahashi, A.; Fujii, T. Three-
Component Coupling Reactions of Alkyl Iodides, 1,3-Dienes, and
Carbonyl Compounds by Sequential Generation of Radical and
Yuri Katayama − Graduate School of Pharmaceutical Sciences,
The University of Tokyo, Tokyo 113-0033, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03180
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by JSPS KAKENHI Grant
Numbers JP17H06442 (M.K.) (Hybrid Catalysis) and
18H05969 (H.M.).
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