Building Congested Ketone: Substituted Hantzsch Ester and Nitrile as Alkylation Reagents in Photoredox Catalysis

Article abstract of DOI:10.1021/jacs.6b06379

For the first time, 4-alkyl Hantzsch esters were used to construct molecules with all-carbon quaternary centers by visible light-induced photoredox catalysis via transfer alkylation. Up to a 1500 h^-1 turnover frequency was achieved in this reaction. Reactions of 4-alkyl Hantzsch nitriles as tertiary radical donors joined two contiguous all-carbon quaternary centers intermolecularly, and this chemistry was used to synthesize a common precursor of a class of hydroxysteroid dehydrogenase inhibitors.

Full text of DOI:10.1021/jacs.6b06379

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Communication
Building Congested Ketone: Substituted Hantzsch Ester
and Nitrile as Alkylation Reagents in Photoredox catalysis
Wenxin Chen, Zheng Liu, Jiaqi Tian, Jin Li, Jing Ma, Xu Cheng, and Guigen Li
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b06379 • Publication Date (Web): 13 Sep 2016
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Building Congested Ketone: Substituted Hantzsch Ester and Nitrile
as Alkylation Reagents in Photoredox Catalysis
Wenxin Chena, Zheng Liua, Jiaqi Tianb, Jin Lia, Jing Mab*, Xu Chenga*, Guigen Lia,c
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a Institute of Chemistry and Biomedical Sciences, School of Chemistry and Chemical Engineering, Nanjing Univer-
sity, Nanjing, China
b Key Laboratory of Mesoscopic Chemistry of MOE, Collaborative Innovation Center of Chemistry for Life Sciences,
School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China
c Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas, United States
Supporting Information Placeholder
centers, as well as two contiguous centers, via visible light–
induced catalytic alkyl transfer reactions (Scheme 1).
ABSTRACT: For the first time, 4-alkyl Hantzsch esters were
used to construct molecules with all-carbon quaternary cen-
ters by visible light–induced photoredox catalysis via transfer
alkylation. Up to 1500 h-1 turnover frequency was achieved in
this reaction. Reactions of 4-alkyl Hantzsch nitriles as ter-
tiary radical donors joined two contiguous all-carbon qua-
ternary centers intermolecularly, and this chemistry was
used to synthesize a common precursor of a class of hy-
droxysteroid dehydrogenase inhibitors.
Scheme 1 Hantzsch Ester in Photoredox Catalysis.
We began by optimizing the conditions for the alkyl trans-
fer reaction of -bromo-isobutyrophenone 1a and 4-
Table 1. Selected Results of Reaction Optimization
Experiments.[a]
Constructing all-carbon quaternary centers is a challeng-
ing synthetic task.[1] Intermolecular formation of bonds join-
ing two contiguous all-carbon quaternary centers is even
more difficult owing to thermodynamic disadvantages, and
the number of strategies to construct these sterically con-
gested structures is limited.[2] Visible light–induced photore-
dox catalysis has recently demonstrated potential for synthe-
sis of novel molecules via highly reactive radicals.[3] Various
congested all-carbon quaternary centers have been con-
structed via photoredox strategies.[4] However, intermolecu-
lar construction of two contiguous all-carbon quaternary
centers by visible light–induced photoredox catalysis has not
been reported.
Entry
R
Catalyst
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
Ir(ppy)2(dtbpy)PF6
Ru(byp)3Cl2
fac-Ir(ppy)3
Yield(%)[b]
44[c]
1
Me (2a)
Et (2b)
2
3
4
5
6
7
8
40
91[d]
89[d,e]
44[d,f]
87[d]
N R
t-Bu (2c)
t-Bu (2c)
t-Bu (2c)
t-Bu (2c)
t-Bu (2c)
The Hantzsch ester serves as a reductant in transfer hy-
drogenation reactions catalyzed by Brønsted and Lewis acids
and transition metals.[5] In addition, it acts as an electron and
hydrogen donor in reactions involving cleavage of C-
heteroatom bonds;[6] reduction of azide compounds;[7] and
reductive coupling of imines and ketones.[8] In the progress
other than the transferhydrogenation reaction,[9] Hantzsch
ester homologues such as 2 have been known for more than
50 years[10] but had not found any synthetic applications until
recently.[11] For the only two examples, Tang group reported
Lewis acid–catalyzed alkyl transfer reactions of alkyl
Hantzsch esters, as well as AIBN-initiated radical substitu-
tion reactions. The excellent redox chemistry with Hantzsch
ester did not give rise to any advance for its substituted ana-
logue. Herein, we report the use of alkyl Hantzsch esters for
intermolecular construction of single all-carbon quaternary
41
(2d)
[a] Conditions: 1a (0.1 mmol), 2 (0.3 mmol), Cs2CO3(0.1
mmol), CH3CN, 1 mol % catalyst, 12W white LEDs, 40 min, rt.
[b] Unless otherwise noted, yields were calculated by GC
with diphenylketone as an internal standard. NR = no reac-
tion. [c] Isobutyrophenone was obtained in 18% yield. [d]
Isolated yield. [e] 0.1 mol % catalyst loading. [f] 0.01 mol %
catalyst loading.
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benzyl Hantzsch esters 2a–2c in the presence of Cs2CO3 and
also converted to the corresponding products 3q and 3r in
1
2
3
4
5
6
7
8
photocatalysts (Table 1). To our delight, Hantzsch esters 2a
gave a moderate yield of the desired product 3a along with
an 18% yield of isobutyrophenone from transferhydrogena-
tion reaction. This selectivity was also observed in the reac-
tion of 2b. By introducing t-Bu ester, we achieved a 91% yield
with 2c with 1 mol % fac-Ir(ppy)3. With 0.1 mol % fac-
Ir(ppy)3 as the photocatalyst and Cs2CO3 as the base, the
reaction of 2c was complete in 40 min with a turnover fre-
quency up to 1500 h–1 with almost the same yield as that from
1.0 mol % catalyst loading. Further decreasing the catalyst
loading resulted in decreased yield (entry 5). When
Ir(ppy)2(dtbpy)PF6 was used instead, the reaction gave simi-
lar yield (entry 6). There was not any product detected when
ruthenium catalyst was used (entry 7). When the Hantzsch
nitrile 2d was used instead, low conversion was observed due
to the reduced reactivity of 2d (entry 8).
good yields. Compounds 3s and 3t with Me/Et and Et/Et
substituents also gave good yields. Cyclic ketone 3u and ke-
to-ester 3v were also obtained in good yields. 2-Bromo-2-
nitropropane was also compatible with this protocol and
desired product 3w was achieved in moderate yield. Com-
pound 3x with a methoxyl could be prepared in 73% yield.
Next, we used a series of 4-alkyl Hantzsch esters 2 to con-
struct products with all-carbon quaternary centers by reac-
tion with 1 (Table 3). Hantzsch esters 2e with an electron-
donating methoxy group and 2f with an electron-
withdrawing chloride atom were suitable for C–C bond for-
mation (affording products 3y–3ad). An ester 2g with a thio-
phenylmethyl substituent gave heterocyclic product 3ae in
good yield. To our delight, the Hantzsch ester 2h could even
donate a tertiary benzyl moiety to generate sterically con-
gested compounds 3af and 3ag with reactivity comparable to
the reactivities of less-hindered esters.
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Using the optimized conditions (Table 1, entry 4), we
screened various substrates 1 in reactions with Hantzsch
ester 2c as the alkyl donor (Table 2). To our delight, a broad
range of functional groups was tolerated, and we obtained
good yields of desired products 3b-3l, including ring-
containing products 3k and 3l. Substrates 1m and 1n did not
Table 3. Scope of Alkyl Transfer Reactions of
Hantzsch Esters 2.[a]
Table 2. Visible Light–Induced Alkyl Transfer Reac-
tions of Hantzsch Ester 2c with Compounds 1.[a]
[a] Conditions: 1 (0.1 mmol), 2 (0.3 mmol), fac-Ir(ppy)3 (0.1
mol %), Cs2CO3 (0.1 mmol), CH3CN (2.0 mL), 12 W white
LEDs, rt, 1 h, isolated yields.
In order to gain some insight into the reaction, we per-
formed control experiments and calculations. First, we con-
firmed that the reaction did not proceed in the absence of
either light or fac-Ir(ppy)3; the electron-donor-acceptor
complex was not observed by NMR or UV–vis spectroscopy.
A Stern–Volmer plot showed strong quenching of fac-
*III/II
Ir(ppy)3 (E1/2
= +0.31 V vs SCE) by Hantzsch ester 2c
red
(E1/2 = +1.08 V vs SCE), favoring a reductive quenching cy-
cle (Figure 1).[12]
[a] Conditions: 1 (0.1 mmol), 2c (0.3 mmol), fac-Ir(ppy)3
(0.1 mol %), Cs2CO3 (0.1 mmol), CH3CN (2.0 mL), 12 W white
LEDs, rt, 1 h, isolated yields. [b] 0.2 mol % fac-Ir(ppy)3. [c] 0.3
mol % fac-Ir(ppy)3. [d] Reaction time 2 h.
undergo any detectable radical addition reactions of the al-
kene or alkyne substituent and yielded 3m and 3n as the only
adducts. Thiophene-containing substrates 1o and 1p gave the
corresponding products (3o and 3p) in high yields. In addi-
tion to the -bromo ketones, -bromo esters 1q and 1r were
Figure 1 Fluorescence quenching of fac-Ir(ppy)3 by 2c or 1a.
Hantzsch esters 2a-2c are similar in terms of electrochem-
istry and spectroscopy, but reacted distinctly in the reaction
(Table 1, entry 1-3). So a density functional theory calculation
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on the pathways of C-C bond cleavage that provide the cou-
fore, we explored the possibility of connecting two all-carbon
1
2
3
4
5
6
7
8
pling unit was carried out at B3LYP/6-311G(d,p) level
(Scheme 2, a). The difference of free energy (ΔG) for the re-
action from the radicals A to the benzyl radical and corre-
sponding pyridine suggested the t-Bu Hantzsch ester radical
intended to expel the side benzyl group to form the less-
congested pyridine compounds. This difference might ac-
count for the predominant C-C bond formation in the case of
2c. In order to investigate the radical species in the reaction,
a standard reaction (Table 1, entry 4) was carried out in the
presence of 4.0 equiv TEMPO (Scheme 2, b). Two TEMPO
derivatives 5[13] and 6[14] could be isolated in comparable yield
above 80% and 3a was not generated.
quaternary centers by means of an intermolecular reaction.
We were unable prepare a Hantzsch ester with an all carbon
quaternary side chain, so we instead prepared a series of
Hantzsch nitriles substituted with an all-carbon quaternary
center, and subjected the nitriles to the protocol with various
substrates 1.(Table 4) To our delight, congested ketone 8a
was the major product of the reaction of 1a and 7a. To our
knowledge, this is the first report of the joining of two all-
carbon quaternary centers by means of visible light–induced
photoredox catalysis. We confirmed the structure of prod-
ucts 8 by converting 8b to corresponding 3,5-dinitrobenzoate
9 and subjecting it to X-ray diffraction analysis. In addition to
tetramethyl products 8c-8e, we could obtain 8f, which has
two methyl groups and a cyclopentyl group, after irradiation
of the corresponding substrates with 12 W white LEDs for 2 h
in the presence of 0.2 mol % fac-Ir(ppy)3. Nitriles and bro-
moketones with heterocyclic groups such as thiophene and
benzofuran were evaluated, and gave heterocycle-phenyl,
phenyl-heterocycle, and heterocycle-heterocycle product
combinations (8g–8l). The moderate yields of the reactions
with 7 might be due to its high oxidative potential relative to
that of 2, which made the electron transfer cycle involving
7[20] less effective than that involving 2. This difference led to
side reactions such as hydrolysis and elimination of 1. An
exception was that compound 8n with even more congested
carbon centers was prepared in 70% yield. Ester 8o was
achieved with the same protocol in 40 % yiel; and carboxylic
acid 8p, a common precursor for a class of hydroxysteroid
dehydrogenase inhibitors,[21] was prepared in 38% yield in
two steps.
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Scheme 2 Radical Generated from Different Ester
and Radical-Capturing Reaction.
A plausible pathway is proposed in Scheme 3. The reaction
starts with the oxidation of 2 by the excited-state fac-
Ir(ppy)3* in the presence of base, yielding radical A and IrII.
Cleavage of the C–C bond, driven by aromatization
Table 4. Joining of Two All-Carbon Quaternary Cen-
ters with Hantzsch Nitriles.[a]
Scheme 3 Plausible Reaction Mechanism
red
of A[15], affords benzyl radical B (Ar = Ph, E1/2 = –1.43 V vs
III/II
SCE) [16] and by-product pyridine C. The IrII species (E1/2
=
–2.19 V vs SCE) effects second single electron transfer (SET)
red
to compound 1 (E1/2 = –1.65 V vs SCE), giving the anionic
radical D, which undergoes mesolysis to radcdial E and bro-
mide.[17] The coupling of E and benzyl radical B generates the
product 3 (path 1). [18] Another pathway 2 of direct coupling
between anionic radical D and radical B is also possible from
the computational study (SI, part 16.2). Meanwhile, an iridi-
um species might work as catalyst in the process of C-C bond
formation. [19] Note that other pathways are also possible for
further investigation.
[a] Conditions: 1 (0.2 mmol), 7 (0.6 mmol), fac-Ir(ppy)3
(0.2 mol %), Cs2CO3 (0.2 mmol), CH3CN (4.0 mL), 12 W white
LEDs, rt, 2 h. Isolated yield after chromatography.
In summary, we report the first use of alkyl transfer reac-
tions involving 4-alkyl Hantzsch esters and their nitrile ana-
logues to construct products with a single all-carbon quater-
nary center, or with two contiguous centers, via visible light–
With the results achieved with benzyl Hantzsch ester, we
further hypothesized that strong steric hindrance could be
overcome during the formation of the new C–C bond. There-
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Supporting Information
Experimental procedures, compound characterizations,
spectra, GC traces and calculation details. This material is
available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
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*chengxu@nju.edu.cn
*majing@nju.edu.cn
Notes
The authors declare no competing financial interests.
Acknowledgements
We are grateful for grants from the National Science
Foundation of China (21572099, 21332005, 21290192, 21273102),
the Natural Science Foundation of Jiangsu Province
(BK20151379), the Ph.D. Programs Foundation of the Ministry
of Education of China (20130091120047), and SRF for ROCS,
SEM. We appreciate Wenmin Wang for the assistance on the
theoretical calculations.
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red
[20] For an comparision to 2c, the E1/2 of 2d (Talbe 1) is +1.25 V
vs SCE.
[21] Linders, J. T. M.; Willemsens, G. H. M.; Gilissen, R. A. H. J.;
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