Chemoselective Homologation-Deoxygenation Strategy Enabling the Direct Conversion of Carbonyls into (n+1)-Halomethyl-Alkanes

Article abstract of DOI:10.1021/acs.orglett.0c02831

The sequential installation of a carbenoid and a hydride into a carbonyl, furnishing halomethyl alkyl derivatives, is reported. Despite the employment of carbenoids as nucleophiles in reactions with carbon-centered electrophiles, sp3-type alkyl halides remain elusive materials for selective one-carbon homologations. Our tactic levers on using carbonyls as starting materials and enables uniformly high yields and chemocontrol. The tactic is flexible and is not limited to carbenoids. Also, diverse carbanion-like species can act as nucleophiles, thus making it of general applicability.

Full text of DOI:10.1021/acs.orglett.0c02831

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Letter
Chemoselective Homologation−Deoxygenation Strategy Enabling
the Direct Conversion of Carbonyls into (n+1)‑Halomethyl-Alkanes
Margherita Miele,⊥ Andrea Citarella,⊥ Thierry Langer, Ernst Urban, Martin Zehl, Wolfgang Holzer,
Laura Ielo, and Vittorio Pace*
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ABSTRACT: The sequential installation of a carbenoid and a hydride into a carbonyl, furnishing halomethyl alkyl derivatives, is
reported. Despite the employment of carbenoids as nucleophiles in reactions with carbon-centered electrophiles, sp3-type alkyl
halides remain elusive materials for selective one-carbon homologations. Our tactic levers on using carbonyls as starting materials
and enables uniformly high yields and chemocontrol. The tactic is flexible and is not limited to carbenoids. Also, diverse carbanion-
like species can act as nucleophiles, thus making it of general applicability.
Scheme 1. General Context of the Presented Work
mbodying a halogen-containing functionality within a
Ecarbon skeleton profoundly influences the physicochem-
ical features, thus properly modulating the reactivity profile of
the array.1 Accordingly, solid synthetic methodologies levered
on different logics (e.g., radical, electrophilic, and nucleophilic)
have been designed and thoroughly applied.2 In this sense, the
introduction of metalated α-halogenated carbon species
(MCR1R2Hal, i.e., the so-called carbenoid reagents) reacting
under a nucleophilic or electrophilic regime (Scheme 1, path
a), depending on the nature of the metal, has emerged as a
valuable tool for delivering synthons featuring the exact degree
of functionalization requested (i.e., halogen loading).3 As a
result, common downsides associated with the use of
conceptually different approaches, such as polyhalogenations,
can be conveniently skipped. The initial installation of the
CR1R2Hal unit, that is, a homologative event, is later exploited
en route to the construction of more complex molecular
architectures accessible through a single synthetic operation,
as, for example, illustrated in the versatile Matteson
homologation of sp3-hybridized boron electrophiles, elegantly
adapted by Aggarwal to the assembly line concept.4
Regrettably, carbon-based platforms suitable for homologa-
tions with halocarbenoids are restricted to sp2-type systems:
For example, our group demonstrated that homologations of
carbonyl-type derivatives conduct, through a single operation,
to more sophisticated architectures (quaternary aldehydes5 and
aziridines).6 Also, olefins are amenable substrates for C1
insertions into cyclopropanes.7 In this scenario, the endeavored
homologations of (primary) sp3-carbon platforms resulted in
uncontrollable multi-insertion phenomena (up to four
consecutive homologations) of questionable synthetic value,
Received: August 24, 2020
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© XXXX American Chemical Society
A

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a
Table 1. Model Reaction: Optimization
a
entry
LiCH2I (equiv)/time (h)
deoxygenation reductant/solvent
Lewis acid
yield of 2 (%)
b
1
1.4/0.5
1.4/0.5
1.4/0.5
1.4/0.5
1.4/0.5
1.4/0.5
1.4/0.5
1.4/0.5
1.4/0.5
BMC
Oestreich
11
46
52
66
68
77
84
89
60
c
2
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
InCl3
d
3
Et3SiH/DCM
Et3SiH/DCM
Ph2SiH2/DCM
Et2SiH2/DCM
PhSiH3/DCM
hexSiH3/DCM
e
4
5
6
7
8
9
hexSiH3/DCM
a
b
Isolated yield after the homologation/deoxygenation sequence. BMC, Barton−McCombie (R1 = PhCS, Bu3SnH, AIBN, toluene, reflux).
c
d
e
Oestreich (R1 = Ts, Et3SiH, B(C6F5)3, DCM). Upon quenching with H2O, DCM was added, and the two phases were separated. Sat. NaCl (aq)
and DCM were added prior to phase separation. Unless otherwise stated, B(C6F5)3 (0.1 equiv) was used.
first noticed in the seminal works by Huisgen8 and later
observed by Hahn9 (Scheme 1, path b). An initial solution to
the polymethylene homologation problem is offered by the
Knochel’s mixed copper−zinc mono-iodocarbenoids intro-
duced in 1989, which, to the best of our knowledge, represent
unique C1-halogenated units able to selectively control the
process (Scheme 1, path c). Unfortunately, the attainable
chemical space is narrowed by specific structural characteristics
demanded of reactions partners, an allylic bromide as the
recipient electrophile and an iodo-methyl-Cu-ZnI2 as the
nucleophile, with the final result being the preparation of
exclusively homoallylic iodides. This significant aspect is in
contrast with the wide applications described for diverse halo
methyl zinc carbenoids developed and thoroughly applied, for
example, by Marek11 or different (non)-halomethyl Cu/Zn
mixed carbenoids of Knochel.10a−−d
We reasoned that realizing the carbenoid installation on a
carbonyl sp2-carbon followed by the deoxygenation12 of the
intermediate carbinol would represent a general and modular
synthesis of homologous alkyl halides not dependent on the
specific layout of reagents. Collectively, the strategy can be
regarded as the employment of sp2-carbonyl systems as naked
sp3-C-LG systems (LG = leaving group), which, after the
envisaged sequence, would release the targeted motifs. We
anticipate that this tactic will offer a robust and highly flexible
solution for streamlining homologous (n+1)-haloalkyls that are
tunable by selecting, at the operator’s discretion, both reaction
partners: the electrophilic carbonyls and the nucleophilic
carbenoids.
deduced by H NMR and GC-MS analyses, thus yielding the
tetrahedral intermediate 1a. Leaving the reaction mixture for a
longer time or increasing the temperature to −50 °C resulted
in significant epoxidation. (For full details, see the SI.) Direct
treatment under Barton−McCombie conditions14 gave
iodoalkane 2 in low yield after a long time and at a high
temperature (entry 1). We next applied the extremely versatile
and convenient Oestreich’s formal reduction of alcohols,15
upon their conversion to tosylates, followed by B(C6F5)3-
catalyzed dehydroxylation16 with Et3SiH and obtained a good
46% yield (entry 2). Further refinement was secured by simply
quenching the homologation reaction crude product with
water, thus making a formal iodohydrin that was directly
suitable for deoxygenation after a trivial separation of the
organic phases. Although the reduction took place in moderate
yield (52%), we hypothesized that the THF (used for the
homologation) still present in the reaction mixture, upon
dilution with DCM, could interfere with the C−O breaking
event (entry 3). Indeed, the prior complete removal of THF
(washing of the homologation crude product with sat. NaCl
(aq)) benefited the dehydroxylation, giving a 66% yield (entry
4). Less hindered silanes such as Ph2SiH2, Et2SiH2, PhSiH3,
and hexSiH3 were also effective: Excellent selectivity (i.e., no
side reduction was noticed) was observed, suggesting the latter
as the ideal agent (entries 5−8). Replacing B(C6F5)3 with a
different Lewis acid such as InCl317 had a negative effect on the
process (entry 9).
1
Once the reaction conditions were set, we studied the scope
of the sequential process (Scheme 2). The chemocontrol was
superb, as illustrated in the case of sensitive substrates such as a
cyclic enone (3) and an α,β-unsaturated ester (4): No over-
reduction of the olefinic and ester carbonyl motifs was noticed.
The protocol was highly flexible, as deduced when using a
different carbenoid homologating agent. The chloromethyla-
tion−deoxygenation methodology was effective in the case of
benzaldehyde derivatives decorated with several functionalities
of diverse electronic behavior, including alkyl (5), amino (9),
and polyaromatics (10), among others. Notably, the acetal-
containing bromo derivative (11) did not interfere in either
We selected benzaldehyde (1) as the model substrate for the
homologative deoxygenation with LiCH2I to gain insights into
both separate moments of the process (Table 1). In principle,
installing an iodo-containing motif would be critical because,
on one hand, it could trigger an internal nucleophilic
displacement, giving an epoxide5 (1b, homologation side
reduction), whereas, on the other hand, it could suffer from
over-reduction to C−H (1c, deoxygenation side reduction).13
The optimized homologation step proceeded quantitatively
within 0.5 h at −78 °C in THF using 1.4 equiv of LiCH2I, as
B
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14), as is increasing the sterical hindrance close to the carbonyl
(e.g., 2,6-disubstituted systems, 15 and 16). Aliphatic
aldehydes could be subjected to the reaction conditions,
giving ω-chloro phenylalkanes (17 and 18) in high yields.
Remarkably, a propargylic aldehyde smoothly gave the
homologated analogue (19), preserving the chemical integrity
of the alkyne. The protocol could be extended to ketones as
starting substrates. Aliphatic derivatives reacted well, giving α-
chloro tertiary centers in the case of both cyclic (20) and
acyclic (21) derivatives. Analogously, indanone and tetralone
derivatives (22 and 23) underwent the transformation;
remarkably, scaling up to 15 mmol validated the method
(22, 87% yield). During the reduction step, concomitant bis-
demethoxylation was observed, thus affording the interesting
biologically relevant dihydroxyphenyl (catechol-like) scaffold
23.
Scheme 2. Scope of the Sequential LiCH2X Homologation/
Deoxygenation
Acetophenone derivatives were excellent materials, further
documenting the high degree of chemocontrol associated with
the reductive homologation. The presence of sensitive groups
is fully tolerated, as illustrated by sensitive halogen iodo (24),
bromo (25), chloro (26 and 27), fluoro (28 and 29), and
trifluoromethyl substituents (30). Substituents on the aromatic
ring of the opposite electronic effect maintain an unaltered
efficiency: ethyl (31), tert-butyl (32), methoxy (33), and acetal
(34). The progressive enlargement of the aliphatic terminus of
the acetophenone core (35−38) was not detrimental. The
genuine homologative conditions were further deduced by the
precise nucleophilic attack, reduction on the carbonyl of ω-
chloro-propiophenone, without noticing any collateral effect
(e.g., side homologation) on the constitutive CH2Cl appendix
(39). Analogously, chloromethyl derivatives of 1,2-diphenyl-
ethane (40), cyclohexyl-toluene (41), and alkylpyrazol (42)
could also be synthesized in high yield with high selectivity.
Again, a propargyl fragment did not touch its integrity under
the reaction conditions, giving 43. Diaryl ketones proved to be
highly effective substrates for the transformation, as indicated
by a series of (mono)-substituted alkyls (44−47), including an
adamantyl derivative (48) and aryl (49) benzophenone
functionalities. Alkoxy (50), alkylthio (51), and arylseleno
(52) groups could be opportunely incorporated on the
benzophenone core, highlighting the fact that no simultaneous
Se−Li exchange occurred during the carbenoid genesis. As a
further confirmation of the chemoselectivity, potentially
exchangeable halogens, such as iodine (53), bromine (54),
chloro (55), and fluoro (56 and 57), or modifications thereof
(trifluoromethyl (58)) were unambiguously endured. It is
noteworthy that an azido substituent did not undergo a
concomitant reduction and was intact at the end of the
transformation (59), thus remarking on the chemoselectivity
profile. Disubstituted symmetric (60 and 61) and asymmetric
(62 and 63) benzophenones could react in high yields
regardless of the electronic orientation of the substituents,
including cases of heteroaromatic systems such as benzofuran
(64) and dithienyl (65). The versatility of the method was also
gathered by modifying the nature of nucleophilic carbenoids:
When LiCH2Br4g was conducted to the bromomethyl
analogues (66 and 67), also on a higher scale (20 mmol,
66), while using the highly unstable LiCH2F,18 an efficient
synthesis of the fluoro derivative (68) could be performed.
Notably, tricyclic-type ketones of xanthene (69) and
thioxanthene (70−72) types also reacted under similar chloro-
or bromo-methylation/deoxygenation conditions.
the homologation or the reduction steps. Positioning differ-
ently constituted halogen substituents is permitted (6−8, 12−
C
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The successful outcome inferred by reacting monohalocar-
benoids as the first nucleophiles spurred us to widen the
method to dihalomethyl analogues, notoriously challenging
entities for which unified, general, and reliable strategies are
still underdeveloped.19 Benefiting from the tunable intrinsic
versatility of carbenoid precursors, the simple switching from a
halogen−lithium exchange (shown above) to a hydrogen−
lithium exchange (i.e., deprotonation with lithium tetrame-
thylpiperidide (LTMP)) resulted in the formation of diverse
dihalomethyl fragments that expeditiously reacted with ketones
and aldehydes prior to deoxygenation, thus giving dibromo (73
and 74, further suitable for scaling in the case of the former)
and dichloro (75 and 76) derivatives. When a halo-halo′-
methane (XCH2Y) was selected as the pro-carbenoid, the
treatment with the same LTMP afforded the corresponding
mixed carbenoids (LiCHXY)20 deliverable to carbonyls with
comparable efficiency and chemoselectivity: After the deoxy-
genation, chlorobromo (77 and 78), chloroiodo (79), and
bromoiodo (80) analogues were prepared in high yield with
high control (Scheme 3). As an additional proof of the
Scheme 4. General Nucleophilic Addition/Deoxygenation
Protocol with Various Carbanion-like Reagents
(C6F5)2 catalysis, enables access to a plethora of halomethyl−
alkyl derivatives. The conditions established for both phases of
the sequence feature very high chemocontrol, thus guarantee-
ing safe and reliable transformations in the presence of several
sensitive functionalities, such as halogens, olefins, alkynes,
esters, and so on. The robustness of the logic proposed,
assessed across ca. 90 presented cases, entails adding not only a
wide range of monohalo- and dihalomethyl carbenoids but also
fluorinated, silylated, mercapto, and, more generally, simple
alkyl and aryl organolithiums.
Scheme 3. Dihalomethyl Homologation/Deoxygenation
Sequence
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02831.
Experimental procedures, NMR spectra, and analytical
data for all of the compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Vittorio Pace − Department of Pharmaceutical Chemistry,
University of Vienna, 1090 Vienna, Austria; Department of
Chemistry, University of Turin, 10125 Turin, Italy;
orcid.org/0000-0003-3037-5930; Email: vittorio.pace@
univie.ac.at, vittorio.pace@unito.it
modularity of the concept, we were pleased to prepare
difluoromethyl (81) and trifluoromethyl (82) derivatives.
The well-known reluctance of using polyfluoromethyl-
lithiums21 was circumvented with silylated suitable precursors
22
(TMSCHF2 and TMSCF323), which, upon adequate
Authors
activation, furnished the corresponding formal carbanions.
This conceptually intuitive carbonyl nucleophilic addition−
deoxygenation sequence represents a formidable tool for
forging C−C bonds, as documented by the perfect extensibility
to nonhalogenated carbanions (Scheme 4). Hence, by adding
an α-silyl methyl carbanion (TMSCH2Li), terminal silanes
were produced from both an aldehyde (83) and a ketone (84),
whereas terminal thioethers were prepared through the
reaction of carbonyls with an α-thio methyllithium reagent
(85−87).24 More generally, two unfunctionalized organo-
lithiums, MeLi and PhLi (selected as model representatives for
alkyl and aryl species), were amenable to reaching the
corresponding trisubstituted methanes (88 and 89).
In summary, we have documented the high-yielding addition
of two nucleophiles, a halo-carbenoid and a hydride, to the
carbonyl carbon of aldehydes and ketones, thus increasing their
(already) high potential and versatility in synthesis.25 The
overall operation consisting of two distinct processes, namely,
homologation and silane-mediated deoxygenation under B-
Margherita Miele − Department of Pharmaceutical Chemistry,
University of Vienna, 1090 Vienna, Austria
Andrea Citarella − Department of Pharmaceutical Chemistry,
University of Vienna, 1090 Vienna, Austria; Department of
Chemical, Biological, Pharmaceutical and Environmental
Sciences, University of Messina, 98166 Messina, Italy
Thierry Langer − Department of Pharmaceutical Chemistry,
University of Vienna, 1090 Vienna, Austria; orcid.org/
0000-0002-5242-1240
Ernst Urban − Department of Pharmaceutical Chemistry,
University of Vienna, 1090 Vienna, Austria
Martin Zehl − Faculty of Chemistry − Department of Analytical
Chemistry, University of Vienna, 1090 Vienna, Austria;
orcid.org/0000-0001-9685-0373
Wolfgang Holzer − Department of Pharmaceutical Chemistry,
University of Vienna, 1090 Vienna, Austria
Laura Ielo − Department of Pharmaceutical Chemistry,
University of Vienna, 1090 Vienna, Austria
D
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(11) For authoritative recent works with Zn carbenoids, see:
(a) Roy, S. R.; Didier, D.; Kleiner, A.; Marek, I. Chem. Sci. 2016, 7,
5989−5994. (b) Marek, I.; Minko, Y.; Pasco, M.; Mejuch, T.; Gilboa,
N.; Chechik, H.; Das, J. P. J. Am. Chem. Soc. 2014, 136, 2682−2694.
(c) Das, J. P.; Marek, I. Chem. Commun. 2011, 47, 4593−4623.
(d) Marek, I. Chem. Rev. 2000, 100, 2887−2900. (e) Eppe, G.; Didier,
D.; Marek, I. Chem. Rev. 2015, 115, 9175−9206. (f) Pasco, M.;
Gilboa, N.; Mejuch, T.; Marek, I. Organometallics 2013, 32, 942−950.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02831
Author Contributions
⊥N.N. and A.C. contributed equally.
Notes
The authors declare no competing financial interest.
̈
(12) For excellent reviews, see: (a) Herrmann, J. M.; Konig, B. Eur.
J. Org. Chem. 2013, 2013, 7017−7027. (b) Chenneberg, L.; Goddard,
J. P.; Fensterbank, L. Reduction of Saturated Alcohols and Amines to
Alkanes. In Comprehensive Organic Synthesis II, 2nd ed.; Knochel, P.,
Ed.; Elsevier: Amsterdam, 2014; pp 1011−1030. (c) Dai, X.-J.; Li, C.-
J. J. Am. Chem. Soc. 2016, 138, 5433−5440. (d) Yang, S.; Tang, W.;
Yang, Z.; Xu, J. ACS Catal. 2018, 8, 9320−9326. (e) Isomura, M.;
Petrone, D. A.; Carreira, E. M. J. Am. Chem. Soc. 2019, 141, 4738−
4748. (f) Zheng, J.; Jongcharoenkamol, J.; Peters, B. B. C.; Guhl, J.;
Ponra, S.; Ahlquist, M. S. G.; Andersson, P. G. Nat. Catal. 2019, 2,
1093−1100. (g) Bauer, J. O.; Chakraborty, S.; Milstein, D. ACS Catal.
2017, 7, 4462−4466.
ACKNOWLEDGMENTS
■
We thank the University of Vienna and Fondazione Ri.Med
(Palermo, Italy) for financial support and abcr Germany for the
generous supply of fluoroiodomethane. M.M. and A.C. thank
the OeAD for a Blau grant and the University of Messina for
predoctoral grants.
REFERENCES
■
(1) For reviews, see: (a) Vetter, W.; Janussen, D. Environ. Sci.
Technol. 2005, 39, 3889−3895. (b) Chung, W.-j.; Vanderwal, C. D.
Angew. Chem., Int. Ed. 2016, 55, 4396−4434.
(2) For overviews of halogenation methods, see: (a) Yoel, S.
Formation of Carbon−Halogen Bonds (Cl, Br, I). In PATAI’S
Chemistry of Functional Groups; Rappoport, Z., Ed.; Wiley-VCH:
Weinheim, Germany, 1995. (b) Petrone, D. A.; Ye, J.; Lautens, M.
Chem. Rev. 2016, 116, 8003−8104.
(3) For reviews on carbenoids chemistry, see: (a) Braun, M. Lithium
Carbenoids. In The Chemistry of Organolithium Compounds;
Rappoport, Z., Marek, I., Eds.; John Wiley and Sons: Chichester,
U.K., 2004; Vol. 1; pp 829−900. (b) Castoldi, L.; Monticelli, S.;
Senatore, R.; Ielo, L.; Pace, V. Chem. Commun. 2018, 54, 6692−6704.
(c) Gessner, V. H. Chem. Commun. 2016, 52, 12011−12023.
(d) Boche, G.; Lohrenz, J. C. W. Chem. Rev. 2001, 101, 697−756.
(e) Capriati, V.; Florio, S. Chem. - Eur. J. 2010, 16, 4152−4162.
(f) Capriati, V. Modern Lithium Carbenoid Chemistry. In
Contemporary Carbene Chemistry; John Wiley & Sons, Inc: 2013; pp
325−362.
(13) Dang, H.; Cox, N.; Lalic, G. Angew. Chem., Int. Ed. 2014, 53,
752−756.
(14) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1, 1574−1585.
(15) Chatterjee, I.; Porwal, D.; Oestreich, M. Angew. Chem., Int. Ed.
2017, 56, 3389−3391 The excellent versatility of the Oestreich
procedure is evidenced by the perfect adaptation to primary and
secondary alkyl halides that can be reduced to alkanes..
(16) For authoritative reviews, see: (a) Oestreich, M.; Hermeke, J.;
́
Mohr, J. Chem. Soc. Rev. 2015, 44, 2202−2220. (b) Weber, D.; Gagne,
M. R. Si−H Bond Activation by Main-Group Lewis Acids. In
Organosilicon Chemistry; Hiyama, T., Oestreich, M., Eds.; Wiley-VCH:
Weinheim, Germany, 2020; pp 33−85. For key contributions in the
area, see: (c) Parks, D. J.; Blackwell, J. M.; Piers, W. E. J. Org. Chem.
2000, 65, 3090−3098. (d) Houghton, A. Y.; Hurmalainen, J.;
̈
Mansikkamaki, A.; Piers, W. E.; Tuononen, H. M. Nat. Chem. 2014, 6,
́
983−988. (e) Adduci, L. L.; Bender, T. A.; Dabrowski, J. A.; Gagne,
M. R. Nat. Chem. 2015, 7, 576−581. (f) Bender, T. A.; Payne, P. R.;
́
Gagne, M. R. Nat. Chem. 2018, 10, 85−90. (g) Bender, T. A.;
(4) For key works in the field, see: (a) Matteson, D. S.; Majumdar,
D. J. Am. Chem. Soc. 1980, 102, 7588−7590. (b) Balieu, S.; Hallett, G.
E.; Burns, M.; Bootwicha, T.; Studley, J.; Aggarwal, V. K. J. Am. Chem.
Soc. 2015, 137, 4398−4403. (c) Burns, M.; Essafi, S.; Bame, J. R.;
Bull, S. P.; Webster, M. P.; Balieu, S.; Dale, J. W.; Butts, C. P.; Harvey,
J. N.; Aggarwal, V. K. Nature 2014, 513, 183−188. (d) Fawcett, A.;
Murtaza, A.; Gregson, C. H. U.; Aggarwal, V. K. J. J. Am. Chem. Soc.
2019, 141, 4573−4578. (e) Advances in Organoboron Chemistry
́
Dabrowski, J. A.; Gagne, M. R. ACS Catal. 2016, 6, 8399−8403.
(h) Adduci, L. L.; McLaughlin, M. P.; Bender, T. A.; Becker, J. J.;
́
Gagne, M. R. Angew. Chem., Int. Ed. 2014, 53, 1646−1649. (i) Drosos,
N.; Morandi, B. Angew. Chem., Int. Ed. 2015, 54, 8814−8818.
(j) Drosos, N.; Cheng, G.-J.; Ozkal, E.; Cacherat, B.; Thiel, W.;
Morandi, B. Angew. Chem., Int. Ed. 2017, 56, 13377−13381.
(k) Hazra, C. K.; Gandhamsetty, N.; Park, S.; Chang, S. Nat.
Commun. 2016, 7, 13431. (l) Zhang, J.; Park, S.; Chang, S. Angew.
Chem., Int. Ed. 2017, 56, 13757−13761.
́
towards Organic Synthesis; Fernandez, E., Ed.; Georg Thieme Verlag:
Stuttgart, Germany, 2020. (f) Blakemore, P. R.; Burge, M. S. J. Am.
Chem. Soc. 2007, 129, 3068−3069. For the homologation of sp3-
heteroatom electrophiles, see: (g) Pace, V.; Pelosi, A.; Antermite, D.;
Rosati, O.; Curini, M.; Holzer, W. Chem. Commun. 2016, 52, 2639−
2642.
(17) Yasuda, M.; Onishi, Y.; Ueba, M.; Miyai, T.; Baba, A. J. Org.
Chem. 2001, 66, 7741−7744.
(18) Parisi, G.; Colella, M.; Monticelli, S.; Romanazzi, G.; Holzer,
W.; Langer, T.; Degennaro, L.; Pace, V.; Luisi, R. J. Am. Chem. Soc.
2017, 139, 13648−13651.
(5) Pace, V.; Castoldi, L.; Mazzeo, E.; Rui, M.; Langer, T.; Holzer,
W. Angew. Chem., Int. Ed. 2017, 56, 12677−12682.
(6) Ielo, L.; Touqeer, S.; Roller, A.; Langer, T.; Holzer, W.; Pace, V.
Angew. Chem., Int. Ed. 2019, 58, 2479−2484.
(19) (a) Jiang, X.; Kulbitski, K.; Nisnevich, G.; Gandelman, M.
Chem. Sci. 2016, 7, 2762−2767. (b) Jiang, X.; Sakthivel, S.; Kulbitski,
K.; Nisnevich, G.; Gandelman, M. J. Am. Chem. Soc. 2014, 136,
9548−9551. (c) Jiang, X.; Gandelman, M. J. Am. Chem. Soc. 2015,
137, 2542−2547.
(20) (a) Pace, V.; Castoldi, L.; Mamuye, A. D.; Langer, T.; Holzer,
W. Adv. Synth. Catal. 2016, 358, 172−177. (b) Pace, V.; Castoldi, L.;
Mamuye, A. D.; Holzer, W. Synthesis 2014, 46, 2897−2909.
(c) Castoldi, L.; Holzer, W.; Langer, T.; Pace, V. Chem. Commun.
2017, 53, 9498−9501. (d) Pace, V.; Holzer, W.; De Kimpe, N. Chem.
Rec. 2016, 16, 2061−2076. (e) Musci, P.; Colella, M.; Sivo, A.;
Romanazzi, G.; Luisi, R.; Degennaro, L. Org. Lett. 2020, 22, 3623−
3627.
(7) (a) Beaulieu, L.-P. B.; Schneider, J. F.; Charette, A. B. J. Am.
Chem. Soc. 2013, 135, 7819−7822. (b) Colella, M.; Tota, A.;
Großjohann, A.; Carlucci, C.; Aramini, A.; Sheikh, N. S.; Degennaro,
L.; Luisi, R. Chem. Commun. 2019, 55, 8430−8433.
(8) Huisgen, R.; Burger, U. Tetrahedron Lett. 1970, 11, 3053−3056.
(9) Hahn, R. C.; Tompkins, J. Tetrahedron Lett. 1990, 31, 937−940.
(10) (a) Knochel, P.; Chou, T. S.; Chen, H. G.; Yeh, M. C. P.;
Rozema, M. J. J. Org. Chem. 1989, 54, 5202−5204. (b) Knochel, P.;
Jeong, N.; Rozema, M. J.; Yeh, M. C. P. J. Am. Chem. Soc. 1989, 111,
6474−6476. (c) Sidduri, A.; Rozema, M. J.; Knochel, P. J. Org. Chem.
1993, 58, 2694−2713. (d) Sidduri, A.; Knochel, P. J. Am. Chem. Soc.
1992, 114, 7579−7581. For an excellent review, see: (e) Marek, I.
Tetrahedron 2002, 58, 9463−9475.
(21) Monticelli, S.; Colella, M.; Pillari, V.; Tota, A.; Langer, T.;
Holzer, W.; Degennaro, L.; Luisi, R.; Pace, V. Org. Lett. 2019, 21,
584−588.
E
https://dx.doi.org/10.1021/acs.orglett.0c02831
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(22) Miele, M.; Citarella, A.; Micale, N.; Holzer, W.; Pace, V. Org.
Lett. 2019, 21, 8261−8265.
(23) Liu, X.; Xu, C.; Wang, M.; Liu, Q. Chem. Rev. 2015, 115, 683−
730.
(24) Senatore, R.; Ielo, L.; Urban, E.; Holzer, W.; Pace, V. Eur. J.
Org. Chem. 2018, 2018, 2466−2470.
(25) For illuminating perspectives on using carbonyls in syntheses,
see: (a) Seebach, D. Angew. Chem., Int. Ed. 2011, 50, 96−101.
(b) Deng, L.; Dong, G. Trends Chem. 2020, 2, 183−198.
F
https://dx.doi.org/10.1021/acs.orglett.0c02831
Org. Lett. XXXX, XXX, XXX−XXX