Zn-Mediated Hydrodeoxygenation of Tertiary Alkyl Oxalates

Article abstract of DOI:10.1055/a-1328-0352

Herein we describe a general, mild, and scalable method for hydrodeoxygenation of readily accessible tertiary alkyl oxalates by Zn/silane under Ni-catalyzed conditions. The reduction method is suitable for an array of structural motifs derived from tertiary alcohols that bear diverse functional groups, including the synthesis of a key intermediate en route to estrone.

Full text of DOI:10.1055/a-1328-0352

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 31, A–D
cluster
A
Modern Nickel-Catalyzed Reactions
Y. Ye et al.
Cluster
Synlett
Zn-Mediated Hydrodeoxygenation of Tertiary Alkyl Oxalates
Yang Yea
O
Guobin Mab
Ken Yaoa,b
Hegui Gong*a,b
R2
R2
O
Ni (cat.)
R1
R1
OMe
H
O
H
Zn/silane
0
0
0
0
-
0
0
0
1
-
6
5
3
4
-
5
5
6
9
MeO
O
R3
R3
60% yield, key intermediate
to estrone
a School of Materials Science and Engineering, Shanghai University,
99 Shang-Da Road, Shanghai 200444, P. R. of China
b Center for Supramolecular Chemistry and Catalysis, Department
of Chemistry, Shanghai University, 99 Shang-Da Road, Shanghai
200444, P. R. of China
hegui_gong@shu.edu.cn
Published as part of the Cluster
Modern Nickel-Catalyzed Reactions
Corresponding Author
Received: 29.10.2020
Accepted after revision: 02.12.2020
Published online: 02.12.2020
catalyzed cross-electrophile coupling of dialkyl oxalates
with aryl/vinyl halides or activated alkenes to afford all car-
bon quaternary stereogenic centers (Scheme 1).9–12
DOI: 10.1055/a-1328-0352; Art ID: st-2020-k0570-c
Tertiary alkyl radical coupling with electrophiles:
Abstract Herein we describe a general, mild, and scalable method for
hydrodeoxygenation of readily accessible tertiary alkyl oxalates by
Zn/silane under Ni-catalyzed conditions. The reduction method is suit-
able for an array of structural motifs derived from tertiary alcohols that
bear diverse functional groups, including the synthesis of a key inter-
mediate en route to estrone.
R3
R2
R1
CO2Bn
R3
CO2Bn
Ar-Cl
R2
R1
Ar
Ar
R3
R3
O
R2
R1
R2
R1
.
OCOOMe
X
Zn/MgCl2
Ni/Fe (cat.)
Key words Zn, silane, hydrodeoxygenation, C–O bonds, oxalates
OMe
Ar
O
O
Ph
The abundance of alcohols and their derivatives in na-
ture constitutes an important part of our chemical feed-
stocks. Thus, direct manipulation of C(sp3)–O bond trans-
formations is sustainably desirable.1–3 In this context,
Barton alkyl C–O bond radical fragmentation has recently
experienced rejuvenation. The traditional Barton homolytic
scission of C(sp3)–O bonds oftentimes requires forcing con-
ditions such as UV irradiation and/or toxic radical inducing
reagents, e.g., Bu3SnH as radical initiators that add to thi-
onyl- and carbonyl-modified alcohols.4,5 This conventional
strategy has been widely used in the total synthesis of bio-
active natural occurring compounds, e.g., (–)-rhodomolla-
nol A,6 (–)-conidiogenone B,7 (–)-sculponin R, and (–)-isod-
ocarpin.8 Recently, a visible-light-induced Barton C–O
bond-scission protocol has been developed that allows alkyl
(primary, secondary, and tertiary) oxalate salts and tertiary
alkyl N-phthalimidoyl (NP) oxalyl esters to generate alkyl
radicals under Ir-catalyzed oxidative and Ru-catalyzed re-
ductive conditions, respectively.5 We, on the other hand,
disclosed a Zn/MgCl2-mediated and Ni-promoted C–O
bond-fragmentation strategy that permits readily accessi-
ble dialkyl oxalates to generate alkyl radical intermediates.9
Such a process enabled us to develop effective Ni- and Fe-
Ph2SiH2
R3
R2
R1
R3
R2
R1
(this work)
Ph
H
Scheme 1 Zn/MgCl2-mediated C(sp3)–O fragmentation of tertiary al-
kyl oxalates9a,11,14
Given the importance of hydrodeoxygenative Barton re-
action in the synthesis of valuable compounds, we quest
whether the Zn/MgCl2-mediated C–O bond radical scission
process can be extended to deoxylative C–H bond-forming
reactions when silanes are used as hydrogen donors to ter-
minate the radical reactions.13
Herein, we depict an efficient Zn-mediated and Ni-pro-
moted reductive hydrodeoxygenation of unactivated tertia-
ry alkyl oxalates with diphenylsilane as the hydrogen
source (Scheme 1), which avoids use of toxic tin hydride.
The utility of this strategy was showcased in the formal to-
tal synthesis of estrone.15a
We first examined the hydrodeoxygenation of a tertiary
alkyl methyl oxalate 1a in the presence of diphenylsilane as
hydrogen donor. The previous conditions9a,11a of Ni- and Fe-
catalyzed cross-coupling of dialkyl oxalates with electro-
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Y. Ye et al.
Cluster
Synlett
philes in N,N-dimethylacetamide (DMA) gave 1 in low yields
(Table 1, entries 7 and 8). An extensive survey of the reac-
tion conditions led us to identify that a combination of
NiCl2 (5 mol%), 2-(pyridin-2-yl)-1H-benzo[d]imidazole (PBI,
1 equiv) with Zn and MgCl2 in DMA at mild temperature
provided the hydrodeoxygenated product 1 in an optimal
82% yield (entry 1). The control experiments indicated the
necessity of Zn and MgCl2 (entries 2 and 3). However, with-
out PBI, a reasonably good yield was detected (entry 5),
which was consistent with our previous reports.9a With
DMA as the solvent, the use of Co salts to replace Ni as the
promoter also generated 1 in 37% yield (entry 9), wherein
the reaction efficiency is not high.16 By contrast, copper
salts were incompetent (entry 10).17 Replacement of PBI
with other pyridine-containing additives did not improve
the results (entries 11–13). While other independent hy-
drogen sources such as H2, BH3, and H2O, were not suitable
(entries 14–16 and Supporting Information, Table S2).
However, in the absence of Ph2SiH2, 1 was detected in 32%
yield (entry 6). Using 10 L of H2O instead of Ph2SiH2, the
yield of 1 was up to 38%, while more H2O almost killed the
reaction (entries 16 and 17). Taken together, these results
suggest that the existence of small amount of water did not
affect the reaction (Supporting Information, Table S1, en-
tries 14 and 15). Finally, the reaction run on a gram scale
gave 1 in 78% yield (entry 18).
This hydrodeoxygenation method displayed excellent
compatibility for a broad range of unactivated tertiary alkyl
oxalates when treated with diphenylsilane (Scheme 2). The
tertiary alkyl oxalates containing geminal dimethyl groups
delivered 2–15 in good to excellent yields. Comparing to 7
and 8, the free hydroxyl substrate allowed the formation of
6 in 40% yield, indicated that the relatively acidic proton
may not affect the hydrodeoxygenation efficiency to an ap-
preciable extent. The N-containing heterocycle compound
15 could give 58% yield. Excellent yield was obtained for
sclareol-derived 16. The reaction also exhibited moderate
to excellent results for tertiary alkyl substrates within
closed rings, as evident in 18 and 19 including 3- and 6-
membered ones. The bicyclic cyclotryptamine product 20
was obtained in 64% yield. Interestingly, this reaction has
high hydrodeoxygenation efficiency for oxalates derived
from -hydroxyl carbonyl compounds as exemplified by 21
and 22. To our delight, the quantitative conversion was ob-
tained for citric acid derived 23. In addition, the simultane-
ous hydrodeoxygenation of the dioxalates successfully gen-
erated 24. The more sterically demanding tertiary alkyl ox-
alates contained ethyl and propyl groups proved to be
compatible, as evident in the products of 25 and 26. The
more complex steroid-tethered tertiary alcohol can be con-
verted into 27 and 28 in good yields. Finally, moderate to
excellent yields were obtained for cholesterol and cholic
acid derived 29–32, these examples showcased the utility
of this work in the preparation of sophisticated structures.
A wide range of functional groups were tolerated, and the
Table 1 Optimization of Hydrodeoxygenation of 1a with Diphenylsilane
Ph2SiH2 (2 equiv)
NiCl2 (5 mol%)
MgCl2 (2 equiv)
O
Me
Me
O
Me
Me
H
OMe
BzO
BzO
PBI (1 equiv)
Zn (2.5 equiv)
DMA (2.5 mL), 40 °C
O
1a (1 equiv)
1, 82% yield
H
N
O
O
N
N
N
N
N
N
N
N
pyridine
bipy
PBI
iPr-Pybox
i-Pr
i-Pr
Entry
Variation from the standard conditions
Yield (%)a
1
2
none
82b
without MgCl2
no reaction
3
without Zn
no reaction
4
without NiCl2
38
5
without PBI
42
6
without Ph2SiH2
NiCl2(py)4
32
7
30
8
Fe(acac)3
19
9
Co(acac)2
37
10
11
12
13
14
15
16
17
18
CuI
26
pyridine instead of PBI
bipy instead of PBI
i-Pr-Pybox instead of PBI
H2 instead of Ph2SiH2
BH3 instead of Ph2SiH2
H2O (10 μL) instead of Ph2SiH2
H2O (0.5 mL) instead of Ph2SiH2
5.0 mmol of 1a
35
30
no reaction
12
18
38
5
78b
a NMR yield using 2,5-dimethyl furan as the internal standard from a mix-
ture containing other impurities after a quick flash column chromatogra-
phy.
b Isolated yield (average of 2 independent runs).
notable ones include ester, silyl ether, aryl polycyclic and
heterocyclic, and acidic amide proton.
To illustrate the practical utility of our method, a Torgov
cyclization and the concise synthesis of estrone were real-
ized (Scheme 3).18 Accordingly, diketone 2s (obtained in
two steps from commercially available 6-methoxy-1-te-
tralone) was subjected to slightly modified asymmetric
Torgov cyclization conditions (see the Supporting Informa-
tion) to furnish 23% yield of the tertiary alcohol 3s,19
whereas tertiary alkyl oxalate 4s was prepared according to
a general procedure. It is worth noting that our method was
highly effective for hydrodeoxygenation of the oxalate 4s
with diphenylsilane, furnished product 5s in 60% yield as a
1:1 cis/trans mixture. Product 5s is a key intermediate en
route to estrone through two-step transformations.15 This
result further indicated that dialkyl oxalates derived from
tertiary alcohols undergo Barton-type homolytic scission of
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

C
Y. Ye et al.
Cluster
Synlett
from tertiary alcohol 3s but failed to obtain the thiocarbon-
ate; only 3s was recovered (Scheme 4), showing the advan-
tage of activation of tertiary alkyl alcohols with oxalates.4
"standard conditions"
O
Me
NiCl2 (5 mol%)
MgCl2 (2 equiv)
Me
O
Me
Me
H
R
OMe
Ph2SiH2
(2 equiv)
Me
R
+
PBI (1 equiv)
O
0.15 mmol
(1 equiv)
Zn (2.5 equiv)
DMA 2.5 mL, 40 °C
2–33
Me
O
HO
O
O
Me
Me
O
BrMg
Me
Me
R
H
Ph
H
H
O
THF, 40 °C
82%
Triton B
xylene/t-BuOH
MeO
MeO
2, R = CbzNH: 53%
3, R = Ac: 40%
1s
4, 74%
5, 68%
Me
73%
O
Me
Me
O
Me
H
Me
H
O
P
Me
HO
Ti(iPrO)2Cl2, 4 Å MS
H
Ph
O
TBDPSO
Ph
toluene, –20 °C
23%
6, 40%
O
8, 45%
7, 49%
OH
MeO
Cl
MeO
Me
H
Me
Me
Ph
F
3s
Me
2s
Me
Me
O
H
O
H
R
OMe
9, R = H: 52%
"standard conditions"
11, 48%
O
O
O
10, R = OMe: 72%
O
DMAP, Et3N
DCM, 0 °C
60% (1:1)
12, 60%
MeO
MeO
OMe
Me
Me
Me
H
Me
O
Me
4s
63%
Me
H
N
O
O
H
Me
14, 84%
13, 44%
15, 58%
ref. 15
H
OBz
Me
Me
H
H
H
Ph
2 steps
H
Me
H
HO
MeO
O
H
estrone
5s
H
Scheme 3 Total synthesis of estrone in seven steps
18, 41%
COOMe
19, 82%
17, 40%
16, 80% (1:1)
H
H
Me
Ph
Me
O
S
H
N
Cbz
N
Cl
O
(1.5 equiv)
O
3s
(recovered)
COOMe
OH
22, 50%
DMAP, Et3N
DCM, 0 °C
21, 72%
20, 64%
MeO
O
O
3s
H
Me
Me
H
EtOOC
COOEt
Scheme 4 The synthesis of thiocarbonate from tertiary alcohols.
Me
COOEt
H
Me
23, 99%
24, 40%
According to our previous studies on the Zn/MgCl2-me-
diated and Ni-promoted radical C–O bond scission of tertia-
ry alkyl oxalates,9a we proposed that this C–O bond hydro-
genation process undergoes a similar reaction mechanism,
wherein activation of oxalate with MgCl2 is key. Upon sin-
gle-electron reduction by Zn or low-valent Ni, the resulting
radical anion species decomposes to give a tertiary alkyl
radical which can abstract hydride from silanes (Scheme 5).
Me
Me
O
H
Me
Me
Me
Ph
H
H
H
O
O
H
25, 72%
27, 76%
O
Me
Me
Ph
H
Me
H
O
H
H
H
28, 83%
26, 68%
Me
Me
H
Me
H
H
Mg2+
O
H
Mg2+
O
Ph2SiH2
H
.
Zn
Znn+
R
O
O
H
H
O
O
R
H
H
MeO
29, 69%
30, 63% (1.6:1)
OMe
R
OMe
R
CO2Me
OOC
MeO
Ac
H
Me
H
Scheme 5 A mechanistic proposal of this hydroreduction work
H
H
H
H
H
H
31, 60% (1.4:1)
32, 86%
In summary, an efficient hydrodeoxygenation protocol
for the reductive cleavage of C–O bonds followed by C–H
bond formation has been developed. The method involves
generation of tertiary alkyl radical intermediates that are
invoked by single-electron reduction by Zn, wherein MgCl2
serves as the indispensable additive and Ni as the promoter.
The reaction displays excellent functional group tolerance
O
O
Scheme 2 Scope of hydrodeoxygenation of tertiary alkyl oxalates
C(sp3)–O bonds to afford tertiary alkyl radicals when treat-
ed with Zn and MgCl2 in the presence of Ni catalysts. By
comparison, we tried to obtain the thioacyl derivatives
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

D
Y. Ye et al.
Cluster
Synlett
and broad substrate scope. The methodology has been suc-
cessfully applied to the concise synthesis of a key interme-
diate en route to estrone. It thus may find useful applica-
tions in the synthesis of natural products and pharmaceuti-
cals.
(7) Xu, B.; Xun, W.; Su, S.; Zhai, H. Angew. Chem. Int. Ed. 2020, 59,
16475.
(8) Pan, S.; Chen, S.; Dong, G. Angew. Chem. Int. Ed. 2018, 57, 6333.
(9) (a) Ye, Y.; Chen, H.; Sessler, J. L.; Gong, H. J. Am. Chem. Soc. 2019,
141, 820. (b) Gao, M.; Sun, D.; Gong, H. Org. Lett. 2019, 21, 1645.
(c) Pan, Y.; Gong, Y.; Song, Y.; Tong, W.; Gong, H. Org. Biomol.
Chem. 2019, 17, 4230.
(10) (a) Álvarez-Bercedo, P.; Martin, R. J. Am. Chem. Soc. 2010, 132,
17352. (b) Tobisu, M.; Yamakawa, K.; Shimasaki, T.; Chatani, N.
Chem. Commun. 2011, 47, 2946. (c) Speckmeier, E.; Padié, C.;
Zeitler, K. Org. Lett. 2015, 17, 4818. (d) Qin, T.; Malins, L. R.;
Edwards, J. T.; Merchant, R. R.; Novak, A. J. E.; Zhong, J. Z.; Mille,
R. B.; Yan, M.; Yuan, C.; Eastgate, M. D.; Baran, P. S. Angew. Chem.
Int. Ed. 2017, 56, 260. (e) Sergeev, A. G.; Hartwig, J. F. Science
2011, 332, 439.
Funding Information
This work was supported by the National Natural Science Foundation
of China (grants 21871173 and 21572140).Natio
n
alNatural
S
cienceFo
u
n
d
ati
o
n
o
f
C
h
ina(2
1
8
7
1
1
7
3)Natio
n
alNatural
S
cienceFo
u
n
dati
o
n
o
f
C
h
ina(2
1
5
7
2
1
4
0)
Supporting Information
(11) (a) Ye, Y.; Chen, H.; Yao, K.; Gong, H. Org. Lett. 2020, 22, 2070.
(b) Chen, H.; Ye, Y.; Tong, W.; Fang, J.; Gong, H. Chem. Commun.
2020, 56, 454.
Supporting information for this article is available online at
https://doi.org/10.1055/a-1328-0352.
S
u
p
p
ortingI
n
formati
o
nS
u
p
p
ortingInformati
o
n
(12) For more examples on reductive formation of all-carbon quater-
nary centers, see: (a) Wang, X.; Ma, G.; Peng, Y.; Pitsch, C. E.;
Moll, B. J.; Ly, T. D.; Wang, X.; Gong, H. J. Am. Chem. Soc. 2018,
140, 14490. (b) Chen, H.; Jia, X.; Yu, Y.; Qian, Q.; Gong, H. Angew.
Chem. Int. Ed. 2017, 56, 13103. (c) Wang, X.; Wang, S.; Xue, W.;
Gong, H. J. Am. Chem. Soc. 2015, 137, 11562. (d) Zhao, C.; Jia, X.;
Wang, X.; Gong, H. J. Am. Chem. Soc. 2014, 136, 17645.
(e) Primer, D. N.; Molander, G. A. J. Am. Chem. Soc. 2017, 139,
9847. (f) Green, S. A.; Vásquez-Céspedes, S.; Shenvi, R. A. J. Am.
Chem. Soc. 2018, 140, 11317. (g) Green, S. A.; Huffman, T. R.;
McCourt, R. O.; Puyl, V.; Shenvi, R. A. J. Am. Chem. Soc. 2019, 141,
7709. (h) García-Domínguez, A.; Li, Z.; Nevado, C. J. Am. Chem.
Soc. 2017, 139, 6835. (i) Lu, X.; Wang, Y.; Zhang, B.; Pi, J.-J.;
Wang, X.-X.; Gong, T.-J.; Xiao, B.; Fu, Y. J. Am. Chem. Soc. 2017,
139, 12632.
(13) (a) Breitenfeld, J.; Scopelliti, R.; Hu, X. Organometallics 2012, 31,
2128. (b) Cornella, J.; Gómez-Bengoa, E.; Martin, R. J. Am. Chem.
Soc. 2013, 135, 1997.
(14) For reviews on cross-electrophile couplings, see: (a) Knappke, C.
E. I.; Grupe, S.; Gärtner, D.; Corpet, M.; Gosmini, C.; Wangelin, A.
J. Chem. Eur. J. 2014, 20, 6828. (b) Moragas, T.; Correa, A.;
Martin, R. Chem. Eur. J. 2014, 20, 8242. (c) Weix, D. J. Acc. Chem.
Res. 2015, 48, 1767. (d) Gu, J.; Wang, X.; Xue, W.; Gong, H. Org.
Chem. Front. 2015, 3, 1411.
References and Notes
(1) (a) Cornella, J.; Zarate, C.; Martin, R. Chem. Soc. Rev. 2014, 43,
8081. (b) Su, B.; Cao, Z.-C.; Shi, Z.-J. Acc. Chem. Res. 2015, 48,
886. (c) Pound, S. M.; Watson, M. P. Chem. Commun. 2018, 54,
12286. (d) Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang,
N.; Resmerita, A. M.; Garg, N. K.; Percec, V. Chem. Rev. 2011, 111,
1346. (e) Tollefson, E. J.; Hanna, L. E.; Jarvo, E. R. Acc. Chem. Res.
2015, 48, 2344.
(2) (a) Bisz, E.; Szostak, M. ChemSusChem 2017, 10, 3964.
(b) Sundararaju, B.; Achard, M.; Bruneau, C. Chem. Soc. Rev.
2012, 41, 4467. (c) Liu, J.; Ye, Y.; Sessler, J. L.; Gong, H. Acc. Chem.
Res. 2020, 53, 1833. (d) Lu, X.; Zhang, Z.-Q.; Lu, Y.; Zhang, B.;
Wang, B.; Gong, T.-J.; Tian, C.-L.; Xiao, B.; Fu, Y. Chin. J. Chem.
2019, 37, 11.
(3) For reviews on aryl–O couplings, see: (a) Tobisu, M.; Chatani, N.
Acc. Chem. Res. 2015, 48, 1717. (b) Zeng, H.; Qiu, Z.; Domínguez-
Huerta, A.; Hearne, Z.; Chen, Z.; Li, C.-J. ACS Catal. 2017, 7, 510.
(4) (a) Crich, D.; Quintero, L. Chem. Rev. 1989, 89, 1413.
(b) McCombie, S. W.; Motherwell, W. B.; Tozer, M. J. Org. React.
2012, 77, 161. (c) Dolan, S. C.; MacMillan, J. J. Chem. Soc., Chem.
Commun. 1985, 1588.
(5) (a) Jamison, C. R.; Overman, L. E. Acc. Chem. Res. 2016, 49, 1578.
(b) Nawrat, C. C.; Jamison, C. R.; Slutskyy, Y.; MacMillan, D. W.
C.; Overman, L. E. J. Am. Chem. Soc. 2015, 137, 11270.
(c) Lackner, G. L.; Quasdorf, K. W.; Overman, L. E. J. Am. Chem.
Soc. 2013, 135, 15342. (d) Gao, C.; Li, J.; Yu, J.; Yang, H.; Fu, H.
Chem. Commun. 2016, 52, 7292. (e) Zhang, X.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2016, 138, 13862. (f) Rackl, D.; Kais, V.;
Lutsker, E.; Reiser, O. Eur. J. Org. Chem. 2017, 2130.
(15) (a) Prévost, S.; Dupré, N.; Leutzsch, M.; Wang, Q.; Wakchaure,
V.; List, B. Angew. Chem. Int. Ed. 2014, 53, 8770. (b) Gong, Q.;
Wen, J.; Zhang, X. Chem. Sci. 2019, 10, 6350.
(16) Reddy, B. R. P.; Chowdhury, S.; Auffrant, A.; Gosmini, C. Adv.
Synth. Catal. 2018, 360, 3026.
(17) Zhang, J.; Li, Z.; Zhuo, J.; Cui, Y.; Han, T.; Li, C. J. Am. Chem. Soc.
2019, 141, 8372.
(6) Gao, J.; Rao, P.; Xu, K.; Wang, S.; Wu, Y.; He, C.; Ding, H. J. Am.
Chem. Soc. 2020, 142, 4592.
(18) See the Supporting Information for details.
(19) Enev, V. S.; Harre, J. M.; Nickisch, K. Tetrahedron: Asymmetry
1998, 9, 2693.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D