Vitamin B12 Enables Consecutive Generation of Acyl and Alkyl Radicals from One Reagent

Article abstract of DOI:10.1002/ejoc.201901137

Co complex – Cby(OMe)₇ - enables consecutive generation of alkyl and acyl radicals from adequately designed carboxylic acids possessing a halogen atom in theirs structures. Mechanistic studies reveal that alkyl corrins forms at much higher rate than the respective acyl derivatives enabling selective reactions with activated olefins.

Full text of DOI:10.1002/ejoc.201901137

DOI: 10.1002/ejoc.201901137
Full Paper
Co-Catalysis | Very Important Paper |
Vitamin B Enables Consecutive Generation of Acyl and Alkyl
12
Radicals from One Reagent
[a]
[a]
[a]
[a]
Aleksandra Potrząsaj, Michał Ociepa, Oskar Baka, Grzegorz Spólnik, and
Dorota Gryko*[
a]
Abstract: Co complex – Cby(OMe) - enables consecutive gen- Mechanistic studies reveal that alkyl corrins forms at much
7
eration of alkyl and acyl radicals from adequately designed higher rate than the respective acyl derivatives enabling selec-
carboxylic acids possessing a halogen atom in theirs structures. tive reactions with activated olefins.
Introduction
The formation of carbon–carbon bonds via free-radical-medi-
ated reactions is a powerful tool for constructing molecules that
are inaccessible by other means or for functionalization of com-
[
1–7]
plex molecules under mild conditions.
sition metal complexes (Co, Fe, Ni, Mn) became a viable tool for
In recent years, tran-
[
8–14]
achieving selective radical reactions.
Of particular impor-
tance are Co complexes that mimic native reactivity of vitamin
[
15–18]
B12 (1, cobalamin) (Figure 1, Scheme 1).
sented by cobaloxime (2)
These are repre-
and heptamethyl cobyrinate
(CN)(H O)Cby(OMe) 3) which is a derivative of vitamin B12
[
19]
(
2
7,
that have been already successfully applied to radical-proc-
[
15,20]
esses.
Scheme 1. Catalytic modes of action of vitamin B12
.
and +2 oxidation states (Scheme 1). In particular, heptamethyl
ccobyrinate (3) can be reduced chemically (Zn/NH Cl, NaBH ,
4
4
[
21]
[22]
etc.)
–0.4 V vs. SCE) or nucleophilic Co(I) (–-0.6 V vs. SCE) species,
which when reacted respectively with radicals or electrophiles
or electrochemically
generating either radical Co(II)
(
[
15,16,23–28]
give alkyl cobalamins. The weak Co–C bond is suscep-
tible to cleavage upon thermolytic, electrolytic or photolytic
conditions providing C-centered radicals. In fact, most of the
[
29]
vitamin B -catalysed reactions proceed via a radical mecha-
1
2
nism and various chemical processes utilizing this unique cata-
[
15]
lyst have been developed up to date.
These include cou-
[
26,30,31]
[32,33]
dehalogenation,[34–41] cyclo-
pling,
isomerization,
propanation or transmethylation[43–48] etc. However, the area
of vitamin B12 catalysis has so far been mainly dominated by
only one type of species being formed during the reactions,
namely alkyl radicals. One of the latest advancements in this
[
42]
Figure 1. Vitamin B12 and heptamethyl cobyrinate structures.
Catalytic activity of these compounds is inherently con- area was the discovery regarding generation of acyl radicals
nected with the central Co(III) ion and its ability to access +1 from 2-S-pyridyl thioesters in the presence of vitamin B12 deriv-
[
49]
ative 3.
[
a] Institute of Organic Chemistry Polish Academy of Sciences,
Kasprzaka 44/52, 01-224 Warsaw, Poland
We wondered whether it would be possible to generate both
alkyl and acyl radicals at the same time from one starting mate-
rial and achieve selective reactions. High reactivity of radicals is
often associated with low selectivity due to many side reactions
that can occur including homo-coupling of free radicals. This
E-mail: dorota.gryko@icho.edu.pl
https://ww2.icho.edu.pl/gryko_group/
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901137.
Eur. J. Org. Chem. 0000, 0–0
1
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
seems even more problematic for processes when two different
radicals are formed at the same time. However alkyl and acyl
radicals are generated via different mechanisms and they differ
in their nucleophilic character, thus we assumed that these
should permit their selective reactions with electrophilic olefins.
Herein, we demonstrate that both acyl and alkyl radicals can
be generated by means of vitamin B12 catalysis from one mole-
cule and their reaction with an electrophile proceed in a selec-
tive manner.
Scheme 4. Model reaction of S-pyridin-2-yl 6-bromohexanethioate (5) with
acrylonitrile (13).
Results and Discussion
Interestingly, the structure of products 15 and 16, the lack
of halide and the presence of thioester moiety respectively,
suggests that alkyl radicals generate faster than acyl ones.
In the next step we optimized the reaction conditions (for
details see SI). The yield substantially increased when the sub-
strates (5/13) were used in 1:2.2 ratio. For vitamin B -catalysed
Our studies commenced with the design and synthesis of
specifically substituted thioesters as a source of acyl radicals
possessing halide moiety at the distant alkyl chain as a precur-
sor of alkyl radicals (Scheme 2).
1
2
reactions Zn/NH Cl system usually furnishes superior results but
4
the amount and ratio of these components is often a crucial
issue for effective catalyst reduction (Table 1).
Table 1. Optimization of the Zn/NH
4
Cl system.[a]
Cl [equiv.] Ratio Zn/NH
Scheme 2. Adequately designed precursor of alkyl and acyl radicals.
Entry
Zn [equiv.]
NH
4
4
Cl
Yield 14 [%][b]
1
2
3
4
5
6
1.5
3
3
6
3
1.5
1
3.4
1.5
4.5
6
1:1
3:1
1:1.1
4:1
1:1.5
1:2
traces
traces
51
29
64
These starting materials are synthesized from commercially
available either carboxylic acids or acid chlorides bearing halide
substituent (Scheme 3).
3
55
[
a] Conditions: (CN)(H
2
7
O)Cby(OMe) (3, 5 mol%), acrylonitrile (13, 0.55 mmol),
thioester (5, 0.45 equiv.), MeCN (2.5 mL). [b] Isolated yield.
Indeed, once the amount of NH Cl was changed from 1.5 to
4
3
.4 equiv. the yield increased to 51 % (entries 1 and 3). This
result further improved upon fine tuning of the Zn/NH Cl ratio,
4
being 64 % for 1:1.5 (entry 5). The use of other solvents as reac-
tion medium or the addition of a base, an acid, or H O had only
2
detrimental effect on the yield of product 14.
With the optimized conditions in hand, we explored the
scope of the developed transformation by subjecting to the
reaction a set of structurally different thioesters differing in the
chain length, position and a halogen as well as various olefins.
The designed 2-S-pyridyl thioesters possess primary, secondary,
tertiary, benzylic bromide and chloride in their structure
Scheme 3. Synthesis of thioesters 4–12. Conditions for: a) acids, X = OH,
b) acid chlorides, X = Cl.
In order to verify the hypothesis of the consecutive genera- (Scheme 3). Homologous bromoalkyl carboxylic acid derivatives
tion of alkyl/acyl radicals from 2-S-pyridyl thioesters we en- 4–7 and 9 reacted equally well with acrylonitrile (13) giving
gaged the Giese type reaction. The initial set of conditions for products 14, 18–20 in decent yield while for thioester (9) with
the model reaction of S-pyridin-2-yl 6-bromohexanethioate (5) secondary bromide attached product 21 formed in 35 % yield
with acrylonitrile (13) relied on our previous work on vitamin (Figure 2).
B -catalysed acylation of activated olefins – Zn/NH Cl system
Dechlorination is one of the biomimetic reactions catalysed by
1
2
4
was applied as a reductant and MeCN was used as a solvent vitamin B12 thus utilizing halogenated derivatives in B -catalyzed
12
[
49]
(
Scheme 4).
To provide sufficient solubility hydrophobic reactions is often plagued by the formation of a significant
[
34–41,50]
vitamin B12 derivative (CN)(H O)Cby(OMe) (3) was selected as amount of dehalogenated products.
In accordance, the
2
7
a catalyst. The formation of desired product 14 in only 30 % reaction with thioester 8 possessing the chlorine substituent
yield and the presence of by-products indicated a number of afforded desired product 14 in only 23 % yield in contrast to
competing reactions, including: dehalogenation (15), genera- 64 % for the respective bromide. For substrates with more reac-
tion of only alkyl radical (16), reduction (17), all common for tive benzyl substituents the competing dehalogenation pre-
B12 catalysis.
dominated under optimized conditions, for thioester S-pyridin-
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
2
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Figure 2. Scope and limitations of double functionalization of carboxylic acid
derivatives.
Scheme 5. Plausible reaction mechanism.
sence of light, the catalyst, or the reducing agent did not afford
desired product thus confirming the catalytic process (see SI for
full optimization studies, section 3). The addition of a radical
trap (TEMPO) stopped the reaction completely proving its radi-
cal character (see SI, section 4.3).
ESI MS analysis of the reaction mixture showed signals at
m/z 1244.5 and 1188.0 corresponding to alkyl and acyl-Co com-
plexes A and E respectively. Kinetic studies confirmed that
cobalt-alkyl complex A generates almost immediately and at
much faster rate as compared with cobalt-acyl species E (Fig-
ure 3). Over time, the concentration of complex A decreases
2
-yl-3-(chloromethyl)benzothioate (11) product 22 formed in
only 29 % yield, while substrate (10) with benzyl bromide moi-
ety was entirely dehalogenated affording product 23. In con-
trast, tertiary bromide remained intact allowing for selective
generation of acyl radical leading to nitrile 24. For activated
olefins, their reactivity depended on the nature of the electron-
withdrawing group. Methyl and tert-butyl acrylates gave a de-
sired product 25 and 26 in 54 % and 61 % yield, for vinyl sulf-
one the yield slightly decreased. We found that under opti-
mized conditions acryl amides, styrenes, and internal olefins are
unreactive while for vinyl ketones side reactions predominate.
Scheme 5 outlines the proposed mechanism. Based on the
literature data and our experience, we assumed that after re-
duction of the central Co(III) ion with Zn, formed supernucleo-
philic Co(I) should react with halide and thioester moieties. Tak-
ing into consideration the structure of side-products 15 and 16,
the halide moiety reacts faster with cobalamin derivative giving
alkyl-cobalt complex A (confirmed by ESI MS (m/z = 1244.5
+
[
M+H] , see SI section 4.4). Upon light irradiation it decomposes
to give alkyl radical B that is quickly trapped by an electron-
deficient olefin. After reduction intermediate D is formed as
+
detected by ESI MS (m/z = 263.0 [M+H] ). Cobalt at the first
oxidation state enters the second cycle and immediately reacts
with D to form acyl-cobalt complex E (detected by ESI MS,
+
m/z = 1188.0 [M+H] ). Upon light irradiation another homolytic
cleavage liberate nucleophilic acyl radical F which reacts with
the second molecule of the olefin while the Co(II)-catalyst is
reduced back to its Co(I)-form by Zn to maintain the catalytic
cycle.
To confirm the aforementioned mechanism several experi-
ments were performed. First, the control reaction in the ab-
Figure 3. Kinetic studies.
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
3
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
indicating the cleavage of the Co–C bond, while the concentra- from red to dark green) for 15 min. Subsequently, an olefin
(
0
0.55 mmol, 1.0 equiv.) followed by a thioester (0.25 mmol,
.45 equiv.) were added via syringe and the reaction mixture was
tion of cobalt-acyl derivative E increases.
Moreover, once radical B is formed, it has to be immediately
trapped by the olefin because we were not able to detect a
species with two molecules of the catalyst attached.
irradiated with blue LED light (λ = 460 nm) for 16 h at room temper-
ature. It was then diluted with Et O, filtered through the cotton
wool and concentrated in vacuo. A crude product was purified by
column chromatography.
2
When the reaction was performed with the addition of ND Cl
4
in CD CN, the deuterium incorporation occurred only at the
3
α positions to the electron withdrawing groups originating
from the olefin thus indicating the formation of anions at these
positions resulted from reduced radicals C and G (Scheme 6).
Acknowledgments
Financial support for this work was provided by the Foundation
for Polish Sciences (FNP TEAM POIR.04.04.00–00–4232/17–00)
and National Science Center (MO, Etiuda no. 2018/28/T/ST5/
0
0162).
Keywords: Photocatalysis · Acyl radicals · Alkyl radicals ·
Vitamin B12 · Giese reaction
[
[
1] B. König, Chemical Photocatalysis, DE GRUYTER, Berlin, Boston, 2013.
2] K. J. Romero, M. S. Galliher, D. A. Pratt, C. R. J. Stephenson, Chem. Soc.
Rev. 2018, 47, 7851–7866.
[
[
3] L. Capaldo, D. Ravelli, Eur. J. Org. Chem. 2017, 2017, 2056–2071.
4] C. Raviola, S. Protti, D. Ravelli, M. Fagnoni, Green Chem. 2019, 21, 748–
7
64.
[
[
5] I. V. Alabugin, T. Harris, Chem 2017, 2, 753–755.
6] L. Marzo, S. K. Pagire, O. Reiser, B. König, Angew. Chem. Int. Ed. 2018, 57,
1
0034–10072; Angew. Chem. 2018, 130, 10188-10228..
[
[
7] N. A. Romero, D. A. Nicewicz, Chem. Rev. 2016, 116, 10075–10166.
8] S. W. M. Crossley, C. Obradors, R. M. Martinez, R. A. Shenvi, Chem. Rev.
2
016, 116, 8912–9000.
Scheme 6. Experiment with deuterated reagent.
[
9] P. Gandeepan, T. Müller, D. Zell, G. Cera, S. Warratz, L. Ackermann, Chem.
Rev. 2019, 119, 2192–2452.
[
10] L. K. G. Ackerman, L. L. Anka-Lufford, M. Naodovic, D. J. Weix, Chem. Sci.
015, 6, 1115–1119.
2
Conclusions
[11] C. E. I. Knappke, S. Grupe, D. Gärtner, M. Corpet, C. Gosmini, A. Ja-
cobi Von Wangelin, Chem. Eur. J. 2014, 20, 6828–6842.
[12] J. A. Milligan, J. P. Phelan, S. O. Badir, G. A. Molander, Angew. Chem. Int.
Ed. 2019, 58, 6152–6163; Angew. Chem. 2019, 131, 6212-6224..
In summary, under light irradiation vitamin B -mediated reac-
12
tion of adequately substituted thioesters with electron-deficient
olefins yields products resulting from the addition of two mole-
cules of olefin to the alkyl and acyl radical respectively. Interest-
[
13] W. J. Zhou, Y. H. Zhang, Y. Y. Gui, L. Sun, D. G. Yu, Synthesis 2018, 50,
359–3378.
3
[
14] J. Twilton, C. Le, P. Zhang, M. H. Shaw, R. W. Evans, D. W. C. MacMillan,
ingly, dehalogenation, a reaction common for B -catalysis is
12
Nat. Rev. Chem. 2017, 1, 0052.
competing with the developed transformation only in the case
of alkyl chlorides and benzyl halides. Inactivity of tertiary alkyl
bromides enables selective acylation of carboxylic acid bearing
this type of substituents.
Mechanistic studies revealed that alkyl bromides react with
the Co complex instantly and at much higher rate as compared
to thioesters. Both alkyl and acyl radicals selectively react with
electron deficient olefins via the Giese-type alkylation and acyl-
ation giving access to highly functionalized molecules in just
one step.
[15] M. Giedyk, K. Goliszewska, D. Gryko, Chem. Soc. Rev. 2015, 44, 3391–
404.
16] K. Tahara, L. Pan, T. Ono, Y. Hisaeda, Beilstein J. Org. Chem. 2018, 14,
553–2567.
17] M. Giedyk, S. N. Fedosov, D. Gryko, Chem. Commun. 2014, 50, 4674–
4676.
3
[
[
[
2
18] M. Giedyk, K. Goliszewska, K. Ó Proinsias, D. Gryko, Chem. Commun.
2016, 52, 1389–1392.
[
[
19] G. Pattenden, Chem. Soc. Rev. 1988, 17, 361–182.
20] R. Banerjee, Chemistry and Biochemistry of B12, Wiley, 1999.
[21] K. L. Brown, Chem. Rev. 2005, 105, 2075–2149.
[22] R. Scheffold, S. Abrecht, R. Orlinski, H.-R. Ruf, P. Stamouli, O. Tinembart,
L. Walder, C. Weymuth, Pure Appl. Chem. 1987, 59, 363–372.
[
[
23] A. Fischli, Helv. Chim. Acta 1982, 65, 1167–1190.
24] H. V. Motwani, C. Fred, J. Haglund, B. T. Golding, M. Törnqvist, Chem. Res.
Toxicol. 2009, 22, 1509–1516.
Experimental Section
[
[
25] C. J. Gantzer, L. P. Wackett, Environ. Sci. Technol. 1991, 25, 715–722.
26] J. Shey, C. M. McGinley, K. M. McCauley, A. S. Dearth, B. T. Young, W. A.
Van der Donk, J. Org. Chem. 2002, 67, 837–846.
General Synthetic Procedure: A glass tube (inner diameter =
1
8 mm) equipped with a magnetic stirrer was charged with hep-
tamethyl cobyrinate (14 mg, 5.0 mol%), activated Zn (48 mg,
.75 mmol, 3 equiv.), and NH Cl (60 mg, 1.1 mmol, 4.5 equiv.) and
[
[
27] F. Sun, T. Darbre, Org. Biomol. Chem. 2003, 1, 3154–3159.
28] H. A. O. Hill, J. M. Pratt, M. P. O'Riordan, F. R. Williams, R. J. P. Williams, J.
Chem. Soc. A 1971, 1859–1962.
0
4
sealed with a septum. Then MeCN (2.5 mL) was added and the
reaction mixture was degassed by purging the solution with argon
with simultaneous sonication in an ultrasonic bath (solution turned
[29] G. Li, F. F. Zhang, H. Chen, H. F. Yin, H. L. Chen, S. Y. Zhang, J. Chem. Soc.,
Dalton Trans. 2002, 105–110.
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
4
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[
30] M. Giedyk, H. Shimakoshi, K. Goliszewska, D. Gryko, Y. Hisaeda, Dalton
Trans. 2016, 45, 8340–8346.
31] L. Chen, Y. Hisaeda, H. Shimakoshi, Adv. Synth. Catal. 2019, 361, 2877–
[42] Y. Chen, X. P. Zhang, J. Org. Chem. 2004, 69, 2431–2435.
[43]
L. Pan, H. Shimakoshi, T. Masuko, Y. Hisaeda, Dalton Trans. 2009, 9898–
[
9
905.
2884.
[
44] A. Schnyder, T. Darbre, R. Keese, Angew. Chem. Int. Ed. 1998, 37, 1283–
[
[
[
32] Z. Da Zhang, R. Scheffold, Helv. Chim. Acta 1993, 76, 2602–2615.
33] T. Toraya, Chem. Rev. 2003, 103, 2095–2127.
34] Y. Hisaeda, K. Tahara, H. Shimakoshi, T. Masuko, Pure Appl. Chem. 2013,
1
285; Angew. Chem. 1998, 110, 1301-1302..
[
45] D. Zheng, T. Darbre, R. Keese, J. Inorg. Biochem. 1999, 73, 273–275.
[
46] C. Wedemeyer-Exl, T. Darbre, R. Keese, Org. Biomol. Chem. 2007, 5, 2119–
8
5, 1415–1426.
2
128.
[
35] K. A. P. Payne, C. P. Quezada, K. Fisher, M. S. Dunstan, F. A. Collins, H.
Sjuts, C. Levy, S. Hay, S. E. J. Rigby, D. Leys, Nature 2015, 517, 513–516.
36] C. N. Schrauzer, R. N. Katz, Bioinorg. Chem. 1978, 9, 123–143.
37] D. R. Burris, C. A. Delcomyn, M. H. Smith, A. L. Roberts, Environ. Sci. Tech-
nol. 1996, 30, 3047–3052.
[
[
47] B. Kräutler, M. Hughes, C. Caderas, Helv. Chim. Acta 1986, 69, 1571–1575.
48] L. Pan, K. Tahara, T. Masuko, Y. Hisaeda, Inorg. Chim. Acta 2011, 368, 194–
[
[
1
99.
49] M. Ociepa, O. Baka, J. Narodowiec, D. Gryko, Adv. Synth. Catal. 2017, 359,
560–3565.
50] N. A. Isley, M. S. Hageman, B. H. Lipshutz, Green Chem. 2015, 17, 893–
97.
[
[
3
[38] J. Shey, W. A. Van der Donk, J. Am. Chem. Soc. 2000, 122, 12403–12404.
[39] H. Shimakoshi, M. Tokunaga, Y. Hisaeda, Dalton Trans. 2004, 7, 878-882..
[40] Y. Sun, W. Zhang, T.-Y. Ma, Y. Zhang, H. Shimakoshi, Y. Hisaeda, X.-M.
Song, RSC Adv. 2018, 8, 662–670.
8
[
41] H. Shimakoshi, L. Li, M. Nishi, Y. Hisaeda, Chem. Commun. 2011, 47,
10921-10923..
Received: August 1, 2019
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
5
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Co-Catalysis
A. Potrząsaj, M. Ociepa, O. Baka,
G. Spólnik, D. Gryko* ........................ 1–6
Vitamin B12 Enables Consecutive
Generation of Acyl and Alkyl Radi-
cals from One Reagent
Under light-irradiation the Co-corrin signed carboxylic acid derivatives and
complex enables generation of alkyl their reaction with activated olefins.
and acyl radicals from adequately de
DOI: 10.1002/ejoc.201901137
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
6
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim