Tandem C-C Bond Cleavage of Cyclopropanols and Oxidative Aromatization by Manganese(IV) Oxide in a Direct C-H to C-C Functionalization of Heteroaromatics

Article abstract of DOI:10.1002/ejoc.201501405

We report a direct C-H to C-C bond functionalization of electron-deficient heteroaromatics enabled by mild C-C bond cleavage of cyclopropanols as a new route to β-aryl carbonyl-containing products. Additionally, as an alternative to using a "catalyst" tha

Full text of DOI:10.1002/ejoc.201501405

DOI: 10.1002/ejoc.201501405
Communication
C–C Bond Formation
Tandem C–C Bond Cleavage of Cyclopropanols and Oxidative
Aromatization by Manganese(IV) Oxide in a Direct C–H to C–C
Functionalization of Heteroaromatics
Desta Doro Bume,[a] Cody Ross Pitts,[a] and Thomas Lectka*[a]
Abstract: We report a direct C–H to C–C bond functionaliza- heterocycles proved competent for regioselective C–C bond for-
tion of electron-deficient heteroaromatics enabled by mild C–C
bond cleavage of cyclopropanols as a new route to β-aryl
carbonyl-containing products. Additionally, as an alternative to
using a “catalyst” that requires an excess amount of a sacrificial
oxidant for regeneration and/or oxidative aromatization, this
paper features manganese(IV) oxide as an inexpensive “dual
role” reagent – effecting both C–C bond cleavage and ultimate
rearomatization. Under the specified conditions, a variety of
mation, alongside a diverse array of cyclopropanols with broad
functional-group tolerance. We highlight applications to com-
plex-molecule synthesis and direct derivatization of biologically
active alkaloids. Furthermore, kinetic isotope effect (KIE) experi-
ments, radical scavengers, and some insight into the application
of tri- and tetravalent manganese species are invoked to shape
an initial mechanistic hypothesis.
Introduction
Notably, a common feature of modern heterocycle alkylation
methods (e.g., in many decarboxylation reactions[4]) is the cata-
lytic generation of alkyl radicals; yet, this is invariably counter-
balanced by the necessity for an excess amount of a “sacrificial
oxidant” to restore aromaticity and/or regenerate the cata-
lyst.[11] Accordingly, it may be equally if not more advantageous
to find one inexpensive reagent to play both roles efficiently by
(1) generating alkyl radicals and (2) re-establishing aromaticity
following radical addition, thus obviating the need for a sacrifi-
cial reagent. In this paper, the “dual role” reagent approach is
applied to the search for conditions whereby heterocyclic C–C
bond formation is achieved from cyclopropanol ring-opening
chemistry. Upon screening a number of potential oxidants, we
rapidly found that stoichiometric manganese(IV) oxide success-
fully balances this dual role (Scheme 1). Manganese(IV) oxide is
inexpensive, mild, abundant, and relatively nontoxic, making it
an ideal candidate.
The C–H to C–C bond functionalization of aromatic molecules
is an essential part of organic synthesis. As the prototypical
example, Friedel–Crafts chemistry has been instrumental in
alkylation, arylation, and acylation of countless aromatic sys-
tems.[1] However, these reactions are less amenable to electron-
deficient substrates, such as the nitrogen-based heterocycles
that comprise a substantial portion of biologically relevant mol-
ecules.[2] Instead, such substrates provide a better electronic
platform to construct C–C bonds by pairing, for instance, nu-
cleophilic radicals with electron-deficient sites on the aromatic
ring (thus guiding the opposite selectivity of Friedel–Crafts
chemistry).[3] This concept has received a large amount of atten-
tion in recent decades, especially regarding the addition of sp3-
carbon-centered radicals to heteroaromatics by decarboxyla-
tion,[4] dehalogenation,[5] and the decomposition of alkylboron
species[6] and metal sulfinate compounds,[7] among other
methods.[8] From another vantage point, more efficient meth-
ods and increasingly complex structures may be accessible by
applying direct C–C activation. Given our recent experience
with cyclopropane ring-opening chemistry,[9] we envisioned
that the generation of an alkyl radical by C–C bond cleavage of
a cyclopropanol in the presence of an electron-deficient aro-
matic ring could yield an interesting variety of β-aryl
carbonyl-containing products not previously reported in the lit-
erature.[10]
Scheme 1. “Dual role” reagent.
[a] Department of Chemistry, Johns Hopkins University
3400 North Charles Street, Baltimore, MD, 21218, USA
E-mail: Lectka@jhu.edu
Results and Discussion
lectka.chemistry.jhu.edu
We began screening with 2-n-hexyl-1-methylcyclopropan-1-ol
(1) and an excess of pyridinium tosylate (2) in MeCN in the
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201501405.
Eur. J. Org. Chem. 2016, 26–30
26
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
presence of the oxidants in Table 1 under N2. Although most position of pyridine with electron-withdrawing substituents
of these oxidants consumed the starting material (primarily (e.g. 5, 6, and 7), the only major product was alkylated in the
generating the corresponding enone[12]), we quickly found that 2-position.[17] No 3-alkylated products were isolated in any in-
manganese(IV) oxide was competent in eliciting the desired stance, and the presence of electron-donating substituents on
heterocycle alkylation reaction. Manganese(IV) oxide is a very the ring produced a substantial decrease in yield (i.e. 4-meth-
logical “dual role” candidate, as there is precedent for this rea- oxypyridine derivative 8 was isolated in only 22 % yield). This
gent playing both necessary roles. For instance, manganese(IV) is consistent with the concept of pairing a nucleophilic carbon
oxide has been widely utilized as a mild oxidant for allylic, radical with the most electron-deficient site(s) on the hetero-
benzylic, and propargylic alcohols, and under certain circum- cycle.
stances saturated alcohols.[13] It has also been used as an
oxidant in the rearomatization of 1,4-dihydropyridines.[14]
Table 1. Screening for “dual role” oxidants.
[a] Combined 2- and 4-isomers of alkylated pyridine. [b] Using pyridinium
tosylate or pyridine/trifluoroacetic acid.
Regarding additional reaction optimization, we found that:
(1) Pyridine (as opposed to pyridinium) is significantly less com-
petent in the reaction. This is likely due to more favorable or-
bital overlap of the pyridinium LUMO with the HOMO of the
nucleophilic carbon-centered radical.[15] (2) For ease of prepara-
Figure 1. Reaction scope: varying heterocycles. Isolated yields reported.
[a] Unless otherwise specified.
tion, the pyridinium salt can be generated in situ with equimo-
lar trifluoroacetic acid and with no sacrifice in yield. (3) Heating
of the reaction mixture to 80 °C provides no further increase in
yield. (4) Decreasing the amount of pyridinium (and also the
MnO2) is accompanied by a decrease in yield.[16] (5) Lower-
valent manganese species (Entries 4 and 5, Table 1) are less
competent. Thus, the optimal conditions require stirring of
1.0 equiv. of the cyclopropanol, 1.1 equiv. of MnO2, 5.0 equiv.
of trifluoroacetic acid, and 5.0 equiv. of pyridine at room tem-
perature in MeCN overnight.
Beyond substituted pyridines, other nitrogen-based hetero-
cycles proved equally competent in the reaction, particularly
quinoline derivatives 9–14. Quinoline behaved similarly to pyr-
idine, providing only the 2- and 4-alkylated adducts in up to
81 % yield (11 and 12). Blocking the 2- or 4-position also re-
sulted in only one product (9, 10, and 13). Additionally, 4-
bromoisoquinoline and polycyclic heterocycles, such as acridine
and phenanthridine, were regioselectively converted into one
alkylated product (14–16). Aromatic molecules that contain
Using these conditions, we surveyed the scope of the reac- multiple heteroatoms (i.e. quinoxaline and benzothiazole) also
tion for various commercially available heterocycles using 2- exhibit efficient regioselective alkylation (17 and 18). Lastly, we
benzyl-1-methylcyclopropan-1-ol and 2-n-hexyl-1-methylcyclo- demonstrate the value of these products as potential building
propan-1-ol (Figure 1). In the prototypical example, 2- and 4- blocks in complex-molecule synthesis, e.g., the dehydration of
alkylated adducts of pyridine were isolated in 80 % yield in a alkylated isoquinoline (obtained from the reaction of 19 and
2.4:1 (3a/3b) ratio using 2-benzyl-1-methylcyclopropan-1-ol 20) to obtain the extended benzopyrrocoline skeleton 21,
[similar ratio of 2:1 (4a/4b) using 1]. When obstructing the 4- present in the lamellarin natural products (Scheme 2).[18]
Eur. J. Org. Chem. 2016, 26–30
www.eurjoc.org
27
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
In addition to the synthesis of non-natural steroid 33, we
also briefly explored the application of this reaction to other
particularly complex substrates that represent drug derivatives
and/or natural products (Figure 3). Bisacodyl, a known laxative
containing a substituted pyridine,[21] was alkylated in the 2- and
4-positions in a 1:1 ratio in 44 % yield (34). Benzoylquinine, an
antimalarial derivative[22] also employed as an asymmetric cata-
lyst,[23] was selectively alkylated in the 2-position of its quinol-
ine ring in 39 % yield (35).
Scheme 2. Potential application to natural-product synthesis.
Next, we examined the substrate scope with respect to vary-
ing the cyclopropanols (Figure 2). The majority of cyclopropan-
ols in Figure 2 were easily prepared by Kulinkovich chemistry,[19]
and acridine was chosen for screening purposes due to high
regioselectivity and ease of isolation. The reaction consistently
afforded very good yields for cyclopropanols that putatively in-
volve both primary and secondary carbon-centered radical in-
termediates (22–33). To highlight a few entries: (1) The cyclo-
propanol derived from safrole produced compound 22 in 86 %
yield; this reasonably translated into a gram-scale application
of the reaction. (2) The tricyclic cyclopropanol derived from nor-
bornene produced the bicyclo[2.2.1]heptane derivative 25 in
73 % yield. (3) The presence of an amine or ether substituent
does not greatly affect the product yields (28 and 30). (4) Bi-
cyclo[3.1.0]hexan-1-ol selectively ungergoes a ring expansion to
afford β-substituted cyclohexanone 31 in good yield. (5) If the
cyclopropanol employed is a hemiacetal, the β-substituted es-
ter is equally accessible (32). (6) Finally, the reaction can also
be applied to larger molecular skeletons, such as 33 (whose
starting cyclopropanol was derived from methyl lithochol-
ate[20]). Remarkably, the secondary alcohol (in the 3-position) is
not oxidized over the course of the reaction.
Figure 3. Direct application to complex molecules.
As a final point of interest, we offer initial insight into the
reaction mechanism. The first step of our working hypothesis
involves putative coordination of manganese(IV) oxide and
one-electron oxidation of the cyclopropanol, activating the
more substituted C–C bond to produce a β-oxo carbon-cen-
tered radical intermediate (possibly in equilibrium with the cor-
responding metalloradical[24]).[25] In the presence of TEMPO
(36), a notorious radical scavenger,[26] no alkylation of the
heterocycle was observed in the 1H NMR spectrum of the crude
reaction mixture (Scheme 3). Additionally, we took the opportu-
nity to apply Selectfluor (37) as a radical trap, as it is an estab-
lished source of atomic fluorine in the presence of alkyl radicals
(Scheme 3).[27] The β-fluorinated product 38 is, in fact, observed
by 19F NMR spectroscopy, strongly supporting initial cyclo-
propanol ring-opening to produce a radical intermediate.[28]
Scheme 3. Radical scavengers.
In the subsequent step of the mechanism, the heterocycle
acts as the “radical trap”, and the C–C bond is formed. Then, a
manganese species is likely responsible for oxidative aromatiza-
tion. To investigate the C–C bond formation and C–H cleavage
steps, we designed both inter- and intramolecular kinetic iso-
tope effect (KIE) experiments with deuterated pyridine deriva-
tives (Scheme 4). Both instances reflect a small, secondary iso-
Figure 2. Reaction scope: varying cyclopropanols. Isolated yields reported.
[a] Alkylated solely in the 9-position.
Eur. J. Org. Chem. 2016, 26–30
www.eurjoc.org
28
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
tope effect (average intermolecular KIE = 1.03 for the 2- and 4-
positions, average intramolecular KIE = 1.18 for the 2-position),
allowing us to state with certainty that C–H cleavage is not
rate-determining.[29] This step is expectedly facile due to a gain
in aromaticity.[30]
Scheme 6. Working mechanistic hypothesis.
Conclusions
The “dual role” nature of manganese(IV) dioxide allows for effi-
cient (1) C–C bond cleavage of cyclopropanols and (2) rearoma-
tization following C–C bond formation in the alkylation of
heterocycles. This method is tolerant of multiple combinations
of heterocycles and cyclopropanols, containing a variety of sub-
stituents. We demonstrate that products of this reaction can be
used as building blocks for natural-product synthesis; we also
explore the direct derivatization of complex biologically rele-
vant molecules. Initial mechanistic insights suggest a radical-
based mechanism from radical scavenger experiments, that C–
H cleavage is not rate-limiting from competitive KIE experi-
ments, and that at least two different oxidation states of man-
ganese (III and IV) might play a role in both C–C bond cleavage
and rearomatization.
Scheme 4. Competitive kinetic isotope effects (averages of at least two runs).
[PH] = product of C–H bond cleavage; [PD] = product of C–D bond cleavage.
Perhaps the most complicated aspect of the mechanism in-
volves the precise nature of the reactive manganese species.
Although an in-depth mechanistic study is beyond the scope
of this article, we offer a few notes on the involvement of man-
ganese in cyclopropanol ring-opening and oxidative aromatiza-
tion. In the literature, manganese(III) reagents have been suc-
cessfully employed in cyclopropanol ring-opening chemistry.[31]
In our hands, both manganese(IV) and manganese(III) reagents
produced the desired product; however, the product yield
when using manganese(III) is virtually one-half that of the opti-
mized conditions (Table 1). The fact that a manganese(III) rea-
gent produces the desirable product at all may hint at the idea
that manganese(III) could be a key player in oxidative aromati-
zation. In fact, there is literature precedent for the rearomatiza-
tion of 1,4-dihydropyridines (i.e., Hantzsch esters 39 to 40)
using both manganese(III) and manganese(IV) reagents
(Scheme 5).[14,32] Depending on the nature of the substrate, it
is conceivable that rearomatization could occur by an electron
transfer/loss of proton or a hydrogen atom abstraction mecha-
nism.[8b,32,33] In any case, current findings suggest that both
oxidation states of manganese could play a role in the cyclo-
propanol C–C bond cleavage and rearomatization steps. One
feasible mechanistic pathway is proposed in Scheme 6.
Experimental Section
Supporting Information (see footnote on the first page of this
article): General experimental procedures and characterization data.
Acknowledgments
T. L. would like to thank the National Science Foundation (NSF)
(CHE 1152996, CHE 1465131) for support. The authors also
would like to thank James Levi Knippel for his assistance.
Keywords: Manganese · C-H functionalization ·
Heterocycles · Cyclopropanols · Dual role reagent
[1] For some reviews, see: a) N. O. Calloway, Chem. Rev. 1935, 17, 327–392;
b) P. H. Gore, Chem. Rev. 1955, 55, 229–281; c) M. Rueping, B. J. Nacht-
scheim, Beilstein J. Org. Chem. 2010, DOI: 10.3762/bjoc.6.6.
[2] See: a) J. E. Robbers, M. K. Speedie, V. E. Tyler, Pharmacognosy and Phar-
macobiotechnology, Lippincott, Williams & Wilkins, Philadelphia, 1996,
pp. 143–185; b) T. Naito, Chem. Pharm. Bull. 2008, 56, 1367–1383; c) P.
Russo, A. Frustaci, A. Del Bufalo, M. Fini, A. Cesario, Curr. Med. Chem.
2013, 20, 1686–1693; d) P. Kittakoop, C. Mahidol, S. Ruchirawat, Curr. Top.
Med. Chem. 2014, 14, 239–252; e) T. P. Cushnie, B. Cushnie, A. J. Lamb,
Int. J. Antimicrob. Agents 2014, 44, 377–386; f) S. Qiu, H. Sun, A.-H. Zhang,
Scheme 5. Precedent for the role of tri- and tetravalent manganese in the
oxidative aromatization of Hantzsch esters.
Eur. J. Org. Chem. 2016, 26–30
www.eurjoc.org
29
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
H.-Y. Xu, G.-L. Yan, Y. Han, X.-J. Wang, Chin. J. Nat. Med. 2014, 12, 401–
406.
F. O'Hara, D. G. Blackmond, P. S. Baran, J. Am. Chem. Soc. 2013, 135,
12122–12134.
[20] A. Enhsen, W. Kramer, G. Wess, Drug Discovery Today 1998, 9, 409–418.
[21] S. D. Wexner, D. E. Beck, T. H. Baron, R. D. Fanelli, N. Hyman, B. Shen, K. E.
Wasco, Gastrointest. Endosc. 2006, 63, 894–909.
[22] World Health Organization, WHO Model List of Essential Medicines, 19th
ed., WHO, 2015, http://www.who.int/medicines/publications/essenti-
almedicines/en/.
[23] For instance: a) S. France, D. J. Guerin, S. J. Miller, T. Lectka, Chem. Rev.
2003, 103, 2985–3012; b) S. France, A. Weatherwax, A. E. Taggi, T. Lectka,
Acc. Chem. Res. 2004, 37, 592–600; c) D. H. Paull, C. J. Abraham, M. T.
Scerba, T. Lectka, Acc. Chem. Res. 2008, 41, 655–663; d) D. H. Paull, A.
Weatherwax, T. Lectka, Tetrahedron 2009, 65, 6771–6803.
[3]
[4]
a) F. Minisci, R. Bernadi, F. Bertini, R. Galli, M. Perchinunno, Tetrahedron
1971, 27, 3575–3580; b) F. Minisci, E. Vismara, F. Fontana, Heterocycles
1989, 28, 489–519; c) F. Minisci, F. Fontana, E. Vismara, J. Heterocycl.
Chem. 1990, 27, 79–96; d) C. J. Cowden, Org. Lett. 2003, 5, 4497–4499;
e) P. B. Palde, B. R. McNaughton, N. T. Ross, P. C. Gareiss, C. R. Mace, R. C.
Spitale, B. L. Miller, Synthesis 2007, 15, 2287–2290.
a) F. Minisci, E. Vismara, F. Fontana, J. Org. Chem. 1989, 54, 5224–5227;
b) J. A. Murphy, M. S. Sherburn, Tetrahedron Lett. 1990, 31, 1625–1628;
c) J. A. Murphy, M. S. Sherburn, Tetrahedron Lett. 1990, 31, 3495–3496;
d) F. Minisci, F. Fontana, G. Pianese, Y. M. Yan, J. Org. Chem. 1993, 58,
4207–4211; e) M. A. J. Duncton, M. A. Estiarte, R. J. Johnson, M. Cox,
D. J. R. O'Mahony, W. T. Edwards, M. G. Kelly, J. Org. Chem. 2009, 74,
6354–6357.
a) Y. Fujiwara, V. Domingo, I. B. Seiple, R. Gianattassio, M. D. Bel, P. S.
Baran, J. Am. Chem. Soc. 2011, 133, 3292–3295; b) G. A. Molander, V.
Colombel, V. A. Braz, Org. Lett. 2011, 13, 1852–1855.
Y. Fujiwara, J. A. Dixon, F. O'Hara, E. D. Funder, D. D. Dixon, R. A. Rodri-
guez, R. D. Baxter, B. Herlé, N. Sach, M. R. Collins, Y. Ishihara, P. S. Baran,
Nature 2012, 492, 95–99.
[5]
[24] For a review on manganese(III) chemistry, see: B. B. Snider, Chem. Rev.
1996, 96, 339–363.
[25] We draw an analogy of the proposed ring-opening step to the proposed
manganese(IV) oxide oxidation of alcohols mechanism; however, in this
system, C–C cleavage occurs to relieve ring strain and produce an alkyl
radical, as opposed to H-atom abstraction. For reports on the mecha-
nism of alcohol oxidation, see: R. J. Gritter, G. D. Dupre, T. J. Wallace,
Nature 1964, 202, 179–181, and references therein.
[6]
[7]
[8]
[26] V. W. Bowry, K. U. Ingold, J. Am. Chem. Soc. 1992, 114, 4992–4996.
[27] For an in-depth mechanistic study on this topic, see: C. R. Pitts, S. Bloom,
R. Woltornist, D. J. Auvenshine, L. R. Ryzhkov, M. A. Siegler, T. Lectka, J.
Am. Chem. Soc. 2014, 136, 9780–9791. For applications, see: a) M. Rueda-
Becerril, C. C. Sazepin, J. C. T. Leung, T. Okbinoglu, P. Kennepohl, J.-F.
Paquin, G. M. Sammis, J. Am. Chem. Soc. 2012, 134, 4026–4029; b) S.
Bloom, C. R. Pitts, D. Miller, N. Haselton, M. G. Holl, E. Urheim, T. Lectka,
Angew. Chem. Int. Ed. 2012, 51, 10580–10583; Angew. Chem. 2012, 124,
10732; c) S. Bloom, C. R. Pitts, R. Woltornist, A. Griswold, M. G. Holl, T.
Lectka, Org. Lett. 2013, 15, 1722–1724; d) S. Bloom, S. A. Sharber, M. G.
Holl, J. L. Knippel, T. Lectka, J. Org. Chem. 2013, 78, 11082–11086; e) Y.
Amaoka, M. Nagamoto, M. Inoue, Org. Lett. 2013, 15, 2160–2163; f) J.-B.
Xia, C. Zhu, C. Chen, J. Am. Chem. Soc. 2013, 135, 17494–17500; g) S.
Bloom, J. L. Knippel, T. Lectka, Chem. Sci. 2014, 5, 1175–1178; h) C. R.
Pitts, B. Ling, R. Woltornist, R. Liu, T. Lectka, J. Org. Chem. 2014, 79, 8895–
8899; i) S. Bloom, M. McCann, T. Lectka, Org. Lett. 2014, 16, 6338–6341;
j) J.-B. Xia, C. Zhu, C. Chen, Chem. Commun. 2014, 50, 11701–11704; k)
J.-B. Xia, Y. Ma, C. Chen, Org. Chem. Front. 2014, 1, 468–472; l) C. W. Kee,
K. F. Chin, M. W. Wong, C.-H. Tan, Chem. Commun. 2014, 50, 8211–8214;
m) M. Rueda-Becerril, O. Mahe, M. Drouin, M. B. Majewski, J. G. West,
M. O. Wolf, G. M. Sammis, J.-F. Paquin, J. Am. Chem. Soc. 2014, 136, 2637–
2641; n) D. Cantillo, O. de Frutos, J. A. Rincon, C. Mateos, O. C. Kappe, J.
Org. Chem. 2014, 79, 8486–8490; o) S. D. Halperin, H. Fan, S. Chang, R. E.
Martin, R. Britton, Angew. Chem. Int. Ed. 2014, 53, 4690–4693; Angew.
Chem. 2014, 126, 4778.
a) D. A. DiRocco, K. Dykstra, S. Krska, P. Vachal, D. V. Conway, M. Tudge,
Angew. Chem. 2014, 126, 4902–4906; b) N. Nishida, H. Ida, Y. Kuninobu,
M. Kanai, Nat. Commun. 2014, 5, 3387; c) J. Jin, D. W. C. MacMillan,
Angew. Chem. 2015, 127, 1585–1589; d) R.-J. Tang, L. Kang, L. Yang, Adv.
Synth. Catal. 2015, 357, 2055–2060.
[9]
S. Bloom, D. D. Bume, C. R. Pitts, T. Lectka, Chem. Eur. J. 2015, 21, 8060–
8063.
[10]
Note that non-heteroaromatic β-aryl carbonyl-containing products can
be accessed using cyclopropanols and palladium chemistry; see: a) D.
Rosa, A. Orellana, Chem. Commun. 2013, 49, 5420–5422; b) D. Rosa, A.
Nikolaev, N. Nithiy, A. Orellana, Synlett 2015, 26, 441–448. Also, note that
heteroaromatic β-aryl carbonyl-containing products can be accessed us-
ing conjugate addition chemistry; see: c) A. C. Spivey, L. Shukla, J. F.
Hayler, Org. Lett. 2007, 9, 891–894; d) X.-Q. Yu, Y. Yamamoto, N. Miyaura,
Synlett 2009, 6, 994–998; e) J.-L. Shih, T. S. Nguyen, J. A. May, Angew.
Chem. Int. Ed. 2015, 54, 9931–9935.
[11] Many catalytic methods for generating alkyl radicals for heterocycle alk-
ylation in the literature require typically a three- to ten-fold excess of a
sacrificial oxidant; see ref.[4–8]
[12] a) J. Jiao, L. X. Nguyen, D. R. Patterson, R. A. Flowers II, Org. Lett. 2007,
9, 1323–1326; b) H. Tsuchida, M. Tamura, E. Hasegawa, J. Org. Chem.
2009, 74, 2467–2475.
[28] Note that the β-fluorinated product is prone to dehydrofluorination
upon isolation; see ref.[9]
[13] a) A. J. Fatiadi, Synthesis 1976, 2, 65–104; b) R. J. K. Taylor, M. Reid, J.
Foot, S. A. Raw, Acc. Chem. Res. 2005, 38, 851–869; c) G. Tojo, M. Fernán-
dez, Oxidation of Alcohols to Aldehydes and Ketones, Springer, New York,
2006, pp. 290–309.
[29] a) E. V. Anslyn, D. A. Dougherty, Modern Physical Organic Chemistry, Uni-
versity Science Books, Sausalito, CA, 2006; b) E. M. Simmons, J. F. Hart-
wig, Angew. Chem. Int. Ed. 2012, 51, 3066–3072; Angew. Chem. 2012,
124, 3120.
[14] J. J. V. Eynde, F. Delfosse, A. Mayence, Y. Van Haverbeke, Tetrahedron
1995, 51, 6511–6516.
[15] J. Tauber, D. Imbri, T. Opatz, Molecules 2014, 19, 16190–16222.
[16] With some exceptions, most direct heterocycle alkylation reactions to
date require a threefold or higher excess of either the radical source or
the heterocycle.
[17] Note that obstructing the 3-position of pyridine may result in three re-
gioisomers. As the result is a decrease in yield of each individual isomer
(detrimental to synthetic utility), starting materials with this substitution
were not explored further in this work.
[18] a) A. R. Quesada, M. D. García Grávalos, J. L. Fernández Puentes, Br. J.
Cancer 1996, 74, 677–682; b) C. Bailly, Curr. Med. Chem. Anti-Cancer
Agents 2004, 4, 363–378; c) D. Pla, F. Albericio, M. Alvarez, Anti-Cancer
Agents Med. Chem. 2008, 8, 746–760.
[30] For some examples of similar kinetic isotope effects in other Minisci-
type reactions, see: a) Z. Shi, F. Glorius, Chem. Sci. 2013, 4, 829–833; b)
R. Xia, M.-S. Xie, H.-Y. Niu, G.-R. Qu, H.-M. Guo, Org. Lett. 2014, 16, 444–
447; c) J. Kan, S. Huang, J. Lin, M. Zhang, W. Su, Angew. Chem. Int. Ed.
2015, 54, 2199–2203; Angew. Chem. 2015, 127, 2227.
[31] a) N. Iwasawa, S. Hayakawa, M. Funahashi, K. Isobe, K. Narasaka, Bull.
Chem. Soc. Jpn. 1993, 66, 819–827; b) Y.-F. Wang, S. Chiba, J. Am. Chem.
Soc. 2009, 131, 12570–12572; c) Y.-F. Wang, K. K. Toh, E. P. Ng, S. Chiba,
J. Am. Chem. Soc. 2011, 133, 6411–6421.
[32] R. S. Varma, D. Kumar, Tetrahedron Lett. 1999, 40, 21–24.
[33] a) M. Moghadam, M. Naser-Esfahani, S. Tangestaninejad, V. Mirkhani, Bio-
org. Med. Chem. Lett. 2006, 16, 2026–2030; b) A. Saini, S. Kumar, J. S.
Sandhu, J. Sci. Ind. Res. 2008, 67, 95–111, and references cited therein.
[19] a) O. G. Kulinkovich, S. V. Sviridov, D. A. Vasilevski, Synthesis 1991, 3, 234;
b) O. G. Kulinkovich, Chem. Rev. 2003, 103, 2597–2632.
Received: November 6, 2015
Published Online: November 24, 2015
Eur. J. Org. Chem. 2016, 26–30
www.eurjoc.org
30
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim