Iron-Catalyzed Radical Intermolecular Addition of Unbiased Alkenes to Aldehydes

Article abstract of DOI:10.1021/acs.orglett.0c03081

The intermolecular reductive radical coupling of aldehydes with nonactivated alkenes, employing metal hydride atom transfer (MHAT) catalysis with a combination of FeII and FeIII salts, is described. This constitutes the first use of aldehydes as viable acceptor groups in MHAT reactions. The insights gained in this study led to the reexamination of the previously reported intramolecular version of the reaction, and the addition of FeII salts allowed the development of a more efficient second-generation approach.

Full text of DOI:10.1021/acs.orglett.0c03081

pubs.acs.org/OrgLett
Letter
Iron-Catalyzed Radical Intermolecular Addition of Unbiased Alkenes
to Aldehydes
Mar Saladrigas, Jordi Puig, Josep Bonjoch,* and Ben Bradshaw*
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ABSTRACT: The intermolecular reductive radical coupling of aldehydes with
nonactivated alkenes, employing metal hydride atom transfer (MHAT) catalysis
with a combination of FeII and FeIII salts, is described. This constitutes the first
use of aldehydes as viable acceptor groups in MHAT reactions. The insights
gained in this study led to the reexamination of the previously reported
intramolecular version of the reaction, and the addition of FeII salts allowed the
development of a more efficient second-generation approach.
long-standing challenge in the field of radical chemistry is
A
the use of CO bonds (aldehydes or ketones), one of
the most common functionalities in organic chemistry, as
acceptor groups. Despite the feasibility of radical addition, the
thermodynamic instability of the resulting alkoxyl radical1
rapidly leads to homolytic cleavage of the coupled product,
which reverts back to the more stable initial carbon-centered
radical via β-fragmentation.2 Indeed, the proclivity to this
reverse reaction is such that it is often used to cleave alcohols
across adjacent C−C bonds to generate carbonyl compounds3
(Figure 1A).
Various strategies to overcome this energetically unfavorable
addition have been devised, as outlined in Figure 1B. One of
the most successful approaches is to tether the carbonyl to the
radical precursor,4 which we illustrated when demonstrating
that ketones5 can serve as viable radical acceptors under metal
hydride atom transfer (MHAT)6 conditions (Figure 1Bi).7
However, our initial attempts to carry out the intermolecular
variant of this reaction were unsuccessful. Moreover, very few
examples of intermolecular radical coupling have been reported
in the literature. Glorius was able to carry out the
intermolecular radical addition to aldehydes by using visible-
light photoredox initiated hole catalysis in combination with in
situ Brønsted acid activation of the carbonyl (Figure 1 Bii).8
This resulted in a favorable thermodynamic driving force while
also kinetically improving the rate of the electron transfer step.
Finally, a third possible approach involves transmetalation of
the initially formed radical, which circumvents the formation of
the unfavorable alkoxyl radical species altogether. For example,
the Shenvi group developed a radical polar crossover strategy
using a MHAT reaction to form a putative organocobalt
species, which then was transmetalated with chromium to
allow a subsequent Nozaki−Hiyama type coupling reaction
(Figure 1Biii).9 Interestingly, as we had previously observed,
their attempts to carry out the MHAT coupling without the
transmetalation step provided only trace amounts of the
coupled product.
Figure 1. Using carbonyls as radical acceptors.
Received: September 14, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03081
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© XXXX American Chemical Society
A

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After our subsequent experience in developing a successful
MHAT intermolecular coupling of Cbz hydrazones to access
amines10 as well as tosylhydrazones11 as a general alkylation
reaction, we decided to revisit the intermolecular MHAT
coupling reaction of aldehydes. Based on both experimental
observations and mechanistic considerations,12 we proposed a
new strategy involving the addition of FeII, which could play
multiple positive roles within the catalytic cycle of the reaction
(Figure 2). It was envisaged that the addition of FeII would
Table 1. Screening of Reaction Conditions
entry
1a
2a
FeIII/FeII
solvent
time
yield
1
2
3
1
1
1
1
1
1
1
1
2
1
1
1
1
1
1
1
1
1
1
1
1
2
1
1
0.2:0
1:0
1:0
EtOH
EtOH
EtOH
EtOH
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
8 h
7%
25%
10%
32%
48%
50%
70%
35%
69%
58%
69%
59%
a
4
5
6
7
0.2:0.8
0.2:0.8
0.5:0.5
0.5:0.5
0:1
0.5:0.5
0.5:0.5
0.5:0.5
0.2:0.2
b
THF
THF
THF
THF
THF
THF
THF
b
c
d
c
8
c
9
c
10
11
12
c
c
THF
8 h
a
b
c
Heated at 60 °C. 2 equiv of MeOH as additive. 10 equiv of MeOH
d
as additive. Open to air.
1a (entry 9). Unexpectedly, however, adding more alkene 2a
proved detrimental, likely because the alkene is the least stable
component in the reaction mixture and more prone to side
reactions before the coupling takes place (entry 10). Cutting
the reaction time from 24 to 8 h produced almost identical
results (entry 11), whereas a further reduction to 3 h proved
unfeasible. Reducing the quantity of Fe to substoichiometric
amounts (0.2:0.2 of FeIII/FeII) resulted in a respectable 59%
yield (entry 12). Extending the reaction time to compensate
for the expected loss of reactivity from using less catalyst led to
a lower rather than higher yield. Once the optimum reaction
conditions were established (Table 1, entries 7 and 11), we
began to explore the scope of the reaction (Scheme 1).
Modifying the alkene component revealed that the reaction
worked with a wide range of functional groups (2a−k)
(Scheme 1), although slight modifications of the reaction time
and equivalents were required for more optimal results (see
Scheme 1 footnotes). For example, the very low yield of 3g
under the optimized conditions shown in Table 1 was greatly
improved by increasing the reaction time to 48 h. On the other
hand, the presence of a Lewis basic substituent on the alkenes,
as in the synthesis of 3c and 3e,16 generally accelerated the
reaction, which was usually completed within 8 h. As might be
expected, more substituted alkenes fared worse, the increased
stability of the carbon-centered radical favoring the reverse
process.
Compound 3k needed extensive reaction optimization to
achieve a relatively moderate 40% yield, while 3l (derived from
the tertiary radical intermediate) gave a disappointingly low
13% yield.
Variations in the acceptor showed that aromatic aldehydes
(3m−s) with both electron-donating and -withdrawing
substituents are well tolerated. The results were strikingly
improved when the benzaldehyde counterpart incorporated an
oxygenated ortho substituent (OH or OMe) that can act as a
Lewis base in the reactions leading to compounds 3r and 3s.
Aromatic heterocycles were also feasible, such as thiophenes
(3t) or pyridines (3u), as were aliphatic aldehydes (3v).
Given the important role of FeII in the intermolecular
coupling reaction, we next sought to evaluate its effects on the
Figure 2. Possible beneficial roles of FeII in the MHAT coupling
reaction of nonactivated alkenes with aldehydes.
facilitate the SET process, enabling a faster reduction and rapid
entrapment of the formed alkoxyl radical, and thus pre-empt a
reverse reaction via β-fragmentation (option A). Second, by
reacting with the initially formed carbon radical species
(option B), FeII would stabilize the radical via the persistent
radical effect (P.R.E)12b,13 and prevent its loss before the
desired reaction could take place. Finally, FeII may act as a
Lewis acid, lowering the activation energy of the reaction8 and
subsequently facilitating a direct SET process (option C). We
report here the validation of this theory and the first successful
use of aldehydes as radical acceptors in MHAT reactions.
To evaluate the reaction parameters, based on our
intermolecular MHAT couplings of alkenes with hydrazones,10
4-cyanobenzaldehyde 1a was chosen as the acceptor group and
4-phenyl-1-butene 2a as the radical precursor. As can be seen,
the use of FeIII alone in EtOH gave the coupled product 3a in
very low yields (7%) (Table 1, entry 1), which were
moderately improved using stoichiometric quantities of
Fe(acac)3 in EtOH (entry 2). As in all our previously
developed intermolecular MHAT coupling reactions,10,11
heating was found to be detrimental (entry 3). We then
began to evaluate the effect of adding FeII to the reaction,
observing a slight increase in yield to 32% when using
stoichiometric iron in a 2:8 FeIII/FeII ratio (entry 4), although
the improvement was far less than expected.
However, after changing the solvent from EtOH to THF
with MeOH as an additive (2 equiv),14 a synthetically useful
yield (48%) was obtained for the first time (entry 5). Changing
the Fe ratio to 1:1 led to a minor improvement (entry 6). In
further tests, increasing the amount of MeOH to 10 equiv
resulted in a higher yield (entry 7), but 20 equiv led to only a
slight improvement compared to 2 equiv.
The use of FeII alone, open to the air, gave a lower yield
(entry 8), probably due to competing Mukaiyama oxidation.15
Next, when evaluating the acceptor 1a/donor 2a ratio, the
yield was found to be unaffected by increasing the amounts of
B
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Scheme 1. Reaction Scope
a
b
c
d
e
3.8 mmol scale. 48 h instead of 24 h. 2 equiv of alkene used. 2 equiv of aldehyde used. 2.9 mmol scale.
intramolecular version with ketones.5 One of the drawbacks of
our previously reported method is that the reaction often
required the use of stoichiometric FeIII to be viable. Two
examples were chosen to evaluate the utility of FeII addition
(Scheme 2), and after extensive screening it was found that the
intramolecular reaction could also be greatly improved by the
addition of FeII.
Scheme 2. Intramolecular Couplings Using FeII
It was possible to carry out the reactions with catalytic
amounts of iron, although with some modifications. In contrast
with the intermolecular version, ethanol was found to be an
optimal solvent. Moreover, heating gave better outcomes, as
did the controlled addition of phenylsilane via a syringe pump,
which was key to minimizing the competing alkene reduction
reaction in 4a. For keto alkene 4b, the reaction was slower and
syringe pump addition of the silane afforded no beneficial
effect; however, the addition of FeII had a more notable impact,
significantly improving the catalytic reaction yield from 20% to
60%.
In summary, we have developed an intermolecular reductive
C−C coupling reaction of nonactivated alkenes with aldehydes
under MHAT conditions using both FeII and FeIII salts. The
use of carbonyls as intermolecular radical acceptors has long
been hampered by reaction reversibility caused by the
thermodynamically unstable alkoxyl radical intermediate. The
good results obtained here hinged on the use of FeII, which is
believed to play multiple beneficial synergistic roles in the
reaction mechanism. Its application also allowed us to improve
the conditions of our previous intramolecular version of the
reaction, which often required stoichiometric iron to be
a
PhSiH3 was added for 4 h with a syringe pump and left to react for
b
an additional 1 h. All components were reacted for 24 h.
effective. We hope that the ability to couple together two of the
most common functional groups in synthetic chemistry
(alkenes and aldehydes) in stoichiometric ratios, using cheap
nontoxic reagents under operationally straightforward con-
ditions, will prove useful for a great many applications.
Mechanistic studies to elucidate the different functions of FeII
C
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Bond Cleavage Reactions. J. Am. Chem. Soc. 2019, 141, 1457−1462
and references therein.
(4) (a) Nishida, A.; Takahashi, H.; Takeda, H.; Takada, N.;
Yonemitsu, O. Sequential Radical Cyclization, Alkoxy Radical
Fragmentation, and Recyclization Processes: A Novel Method for
the Synthesis of Fused Cycloheptanones and Cyclooctenones from
in the reaction are underway and will be reported in due
course.
ASSOCIATED CONTENT
■
sı
* Supporting Information
́
Cyclohexanones. J. Am. Chem. Soc. 1990, 112, 902−904. (b) Fernan-
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03081.
́
dez-Mateos, A.; de La Nava, E. M.; Coca, G. P.; Silvo, A. R.; Gonzalez,
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H.; Qu, J.-P.; Kang, Y.-B. Strategy for Overcoming Full Reversibility
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(5) Saladrigas, M.; Bosch, C.; Saborit, G. V.; Bonjoch, J.; Bradshaw,
B. Radical Cyclization of Alkene-Tethered Ketones Initiated by
Hydrogen-Atom Transfer. Angew. Chem., Int. Ed. 2018, 57, 182−186.
(6) For reviews on MHAT, see: (a) Crossley, S. W. M.; Martinez, R.
M.; Obradors, C.; Shenvi, R. A. Mn, Fe, and Co-Catalyzed Radical
Hydrofunctionalizations of Olefins. Chem. Rev. 2016, 116, 8912−
Experimental procedures, characterization data, and
NMR spectra (PDF)
FAIR data, including the primary NMR FID files, for
compounds 3a−3v (ZIP)
AUTHOR INFORMATION
Corresponding Authors
■
́
̀
Josep Bonjoch − Laboratori de Quımica Organica, Facultat de
̀
Farmacia, IBUB, Universitat de Barcelona, 08028 Barcelona,
Spain; orcid.org/0000-0002-5551-6720;
Email: josep.bonjoch@ub.edu
́
̀
Ben Bradshaw − Laboratori de Quımica Organica, Facultat de
̀
Farmacia, IBUB, Universitat de Barcelona, 08028 Barcelona,
Spain; orcid.org/0000-0001-9612-9199;
Email: benbradshaw@ub.edu
Authors
́
̀
Mar Saladrigas − Laboratori de Quımica Organica, Facultat de
́
9000. (b) Green, S. A.; Crossley, S. W. M.; Matos, J. L. M.; Vasquez-
̀
Farmacia, IBUB, Universitat de Barcelona, 08028 Barcelona,
́
Cespedes, S.; Shevick, S. L.; Shenvi, R. A. The High Chemofidelity of
Metal-Catalyzed Atom Transfer. Acc. Chem. Res. 2018, 51, 2628−
Spain
2640.
́
̀
Jordi Puig − Laboratori de Quımica Organica, Facultat de
(7) (a) Gualandi, A.; Mengozzi, L.; Cozzi, P. G. Iron-Promoted
Radical Reactions: Current Status and Perspectives. Asian J. Org.
̈
Chem. 2017, 6, 1160−1179. (b) Lubken, D.; Saxarra, M.; Kalesse, M.
Tris(acetylacetonato) Iron(III): Recent Developments and Synthetic
Applications. Synthesis 2019, 51, 161−177.
̀
Farmacia, IBUB, Universitat de Barcelona, 08028 Barcelona,
Spain
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03081
(8) (a) Pitzer, L.; Sandfort, F.; Strieth-Kalthoff, F.; Glorius, F.
Intermolecular Radical Addition to Carbonyls Enabled by Visible
Light Photoredox Initiated Hole Catalysis. J. Am. Chem. Soc. 2017,
139, 13652−13655. For another example using photocatalysis, see:
(b) Kawamoto, T.; Fukuyama, T.; Ryu, I. Radical Addition of Alkyl
Halides to Formaldehyde in the Presence of Cyanoborohydride as a
Radical Mediator. A New Protocol for Hydroxymethylation Reaction.
J. Am. Chem. Soc. 2012, 134, 875−877.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for this research was provided by Project
CTQ2016-75350-P (MINECO, Spain)/FEDER funds and
PID2019-104188GB-I00 (MICINN, Spain). B.B. acknowl-
edges the Serra Hunter program (Generalitat de Catalunya).
́
́
(9) (a) Matos, J. L. M.; Vasquez-Cespedes, S.; Gu, J.; Oguma, T.;
Shenvi, R. A. Branch-Selective Addition of Unactivated Olefins into
Imines and Aldehydes. J. Am. Chem. Soc. 2018, 140, 16976−16981.
For a review of this approach see: (b) Pitzer, L.; Schwarz, J. L.;
Glorius, F. Reductive radical-polar crossover: traditional electrophiles
in modern radical reactions. Chem. Sci. 2019, 10, 8285−8291. For
other related examples of this approach, see: (c) Nishikawa, K.; Ando,
T.; Maeda, K.; Morita, T.; Yoshimi, Y. Photoinduced Electron
Transfer Promoted Radical Ring Expansion and Cyclization Reactions
of α-(ω-Carboxyalkyl) β-Keto Esters. Org. Lett. 2013, 15, 636−638.
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E
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