Palladium(II)-Catalyzed C(sp2)-H Carbonylation of Sterically Hindered Amines with Carbon Monoxide

Article abstract of DOI:10.1021/acs.orglett.8b02856

A palladium-catalyzed, amine-directed C(sp²)-H carbonylation of α,α-disubstituted benzylamine under 1 atm of CO for the facile synthesis of sterically hindered benzolactam has been developed. The key to success is the use of 2,2,6,6-tetramethyl-1-piperidinyloxy as the crucial sole oxidant. The synthetic utility of this transformation has been demonstrated by the first concise synthesis of the natural product spiropachysin-20-one.

Full text of DOI:10.1021/acs.orglett.8b02856

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium(II)-Catalyzed C(sp2)−H Carbonylation of Sterically
Hindered Amines with Carbon Monoxide
Xiu-Fen Cheng,†,‡,§ Tao Wang,†,§ Yan Li,*,† Yun Wu,† Jie Sheng,† Rui Wang,† Chao Li,† Kang-Jie Bian,†
and Xi-Sheng Wang*,†
†Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, Center for Excellence in
Molecular Synthesis of CAS, University of Science and Technology of China, 96 Jinzhai Road, Hefei 230026, China
‡College of Chemistry, Chemical Engineering and Material Science, Collaborative Innovation Center of Functionalized Probes for
Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Institute of
Molecular and Nano Science, Shandong Normal University, Jinan 250014, China
S
* Supporting Information
ABSTRACT: A palladium-catalyzed, amine-directed C(sp2)−H carbonylation of α,α-
disubstituted benzylamine under 1 atm of CO for the facile synthesis of sterically hindered
benzolactam has been developed. The key to success is the use of 2,2,6,6-tetramethyl-1-
piperidinyloxy as the crucial sole oxidant. The synthetic utility of this transformation has
been demonstrated by the first concise synthesis of the natural product spiropachysin-20-
one.
Scheme 1. Steric Effect of Pd-Catalyzed C(sp2)−H
Carbonylation of Amines with CO
s the most essential and easily available C1 feedstock, the
Ause of carbon monoxide (CO) as a carbonylation reagent
has long caused extensive concern from both academia and
industry.1 Along with the rapid development of C−H
activation reactions in the past decade, transition-metal-
catalyzed direct insertion of carbon monoxide into inert C−
H bonds has emerged as a powerful strategy to introduce a
transformable carbonyl group into organic molecules.2 Since
the pioneering work of Fujiwara’s group in 1980,3 palladium-
catalyzed C(sp2)−H carbonylation with CO has been
developed as a facile approach for direct C−H functionaliza-
tion4 and been used as a potential disconnecting tactic for the
total synthesis of complex biologically active molecules. For
example, amine-directed C−H activation/CO insertion has
been used as an efficient approach to construct (benzo)-
lactams, which widely exist in a variety of natural products as
key skeletons.
The first example of Pd-catalyzed, amine-directed ortho-
selective C(sp2)−H carbonylation of benzylic amines with CO
was reported by Orito and co-workers in 2004.5 However, this
low reactivity of such sterically hindered amines comes from
the lower coordination capacity of the nitrogen atom and
higher cyclization capacity due to the steric hindrance and
Thorpe−Ingold effect caused by α,α-disubstituents. To address
this issue, herein, we reported a novel Pd-catalyzed C(sp2)−H
carbonylation of α,α-disubstituted benzylamines under 1 atm
of CO for facile synthesis of 3,3-disubstituted isoindolin-1-
ones. The key to success is the use of 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) as the crucial sole oxidant. The
synthetic utility of this transformation has also been
demonstrated by the first concise synthesis of the natural
product spiropachysin-20-one.
reaction occurred only for α,α-unsubstituted benzylamines,
rather than the sterically constrained α-substituted benzyl-
amines (Scheme 1, eq 1).6 Meanwhile, the Granell and Garcia
group reported that while the stoichiometric palladium-
mediated carbonylation of quaternary α-amino α-benzyl ester
with CO gave five-membered benzolactam, the catalytic
reaction furnished only six-membered isoquinolin-1-one
(Scheme 1, eq 2).7 These results clearly indicate that the
steric circumstance around the C−H bond of arene was the
pivotal factor of the benzylamines’ reactivity. In 2011, Gaunt
and co-workers described a Pd(II)-catalyzed C−H carbon-
ylation of α-monosubstituted benzylamines with CO in 2011,8
but more sterically hindered α,α-disubstituted amines still
remained challenging in this system. It was speculated that the
Received: September 7, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02856
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Our study commenced with examining the C(sp2)−H
carbonylation with N-methyl-2,2-diphenylethylamine 1a used
as the pilot substrate in the presence of a catalytic amount of
Pd(OAc)2 (10 mol %) under 1 atm of CO in toluene at 120
°C for 24 h. Not surprisingly, only a trace amount of lactam 2a
was obtained when 0.5 equiv of Cu(OAc)2 under air was used
as the oxidant (entry 1, Table 1), as shown in Orito’s
12, Table 1), a series of solvents have also been carefully
examined. To our delight, chlorobenzene was found to be the
optimal choice to give a slightly higher yield of 2a (entry 17,
Table 1). It should be noted that good repeatability has also
been demonstrated for this reaction when chlorobenzene was
used as the solvent instead of toluene. Notably, the
benzolactam product was afforded in excellent yield in the
presence of 10 mol % of Pd(OAc)2 in chlorobenzene at 130 °C
for 48 h (98%, entry 20, Table 1). Finally, the control
experiment showed that only a trace amount of 2a was
detected without Pd(OAc)2 catalyst.
Table 1. Palladium-Catalyzed C(sp2)−H Carbonylation of
a
Sterically Hindered Amines: Optimization of Conditions
With the optimized conditions in hand, we next investigated
the scope of sterically hindered benzylic amines. As shown in
Scheme 2, the electron-donating and -neutral groups on the
phenyl ring were well tolerated in this carbonylation reaction.
Not surprisingly, the subjection of electron-donating methoxy
group substituted aryl amine (1c, 1k, and 1l) to the standard
b
entry
oxidant (equiv)
solvent
yield (%)
1
2
3
4
5
6
7
8
Cu(OAc)2 (0.5) /air (1 atm)
Cu(OAc)2 (0.5) /O2 (1 atm)
Cu(OAc)2 (4.0)
O2 (1 atm)
BQ (2.0)
PhI(OAc)2 (2.0)
K2S2O8 (2.0)
Ag2CO3 (2.0)
TEMPO (4.0)
AgOAc (4.0)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
MeCN
DCE
trace
7
17
39
20
Scheme 2. Palladium-Catalyzed C(sp2)−H Carbonylation of
a,b
Sterically Hindered Amines: Substrate Scope
NR
trace
26
76−87
10
9
10
11
CuCl2 (4.0)
26
c
12
TEMPO (4.0)
TEMPO (4.0)
TEMPO (4.0)
TEMPO (4.0)
TEMPO (4.0)
TEMPO (4.0)
TEMPO (4.0)
TEMPO (4.0)
TEMPO (4.0)
TEMPO (4.0)
52−76
28
c
13
c
14
27
c
15
16
trace
63
c
mesitylene
xylene
PhCl
PhCl
PhCl
c
17
64
84
86
98
c
18
19
d
20
e
21
PhCl
trace
a
Unless otherwise noted, the reaction conditions were as follows: 1a
(0.2 mmol), Pd(OAc)2 (0.02 mmol, 10 mol %), oxidant, toluene (0.1
b
c
mol/L), CO (1 atm), 120 °C, 24 h. Isolated yield. Pd(OAc)2 (5
d
e
mol %), 48 h. 130 °C, 48 h. No Pd(OAc)2.
reports.5,6 It was speculated that the squeeze of the sterically
hindered amine on the nitrogen atom causes its reduction of
coordination capacity and, thus slowing the reoxidation of
Pd(0) to Pd(II) catalyst might cause the agglomeration of the
Pd(0) species. As a corresponding tactic to speed up the
reoxidation, oxygen was used to replace air in the presence of a
catalytic amount of Cu(OAc)2, which afforded a slightly higher
yield of 2a (7%, entry 2, Table 1). To our delight, using
stoichiometric Cu(OAc)2 or O2 directly as the sole oxidant
could afford the desired product 2a in 16% or 39% yields,
respectively (entries 3 and 4, Table 1). These results clearly
indicate the key role of oxidants to accelerate this trans-
formation. As a result, a careful examination of oxidants was
next carried out, which showed that most of the commonly
used oxidants, such as BQ, copper salts, silver salts, PhI(OAc)2,
and K2S2O8, proved to be less effective. However, to our
excitement, 2a could be furnished in almost 80% yield when
TEMPO was used as the oxidant (entry 9, Table 1).9
Unfortunately, the yield of 2a in the reaction using toluene
as the solvent afforded a poor repeatability. While decreasing
the catalyst loading to 5 mol % resulted in a lower yield (entry
a
Unless otherwise noted, the reaction conditions were as follows: 1
(0.2 mmol), Pd(OAc)2 (0.02 mmol, 10 mol %), TEMPO (0.8 mmol,
4.0 equiv), chlorobenzene (2 mL), CO (1 atm), 130 °C, 48 h.
b
c
d
e
Isolated yield. 120 °C. Pd(OAc)2 (15 mol %), 24 h. Pd(OAc)2 (5
f
mol %). Toluene was used as the solvent.
B
DOI: 10.1021/acs.orglett.8b02856
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
conditions furnished a relatively lower yield along with some
byproducts, probably due to the decomposition of the
corresponding electron-rich arenes under the oxidation
conditions. To improve the yield of these electron-rich
substrates, increasing the catalyst loading and reducing
reaction time (2c) or decreasing the reaction temperature
(2k and 2l) has been demonstrated as effective approaches to
afford good yields of the corresponding benzolactams.
Moreover, meta-substituted benzylamines gave mixtures of
two regioisomers, and the carbonylation occurred slightly
preferentially at the less hindered C−H bond. The substituent
effects on the α-position of the nitrogen atom were next
examined in this transformation. To our satisfaction, a variety
of α-substituents, including ethyl, ethoxymethyl, isopropyl, and
isobutyl, as well as spiro-cyclohexyl and spiro-cyclopentyl, on
the benzylic amines were compatible with this novel method
(2e−g, 2m−o). In addition, polycyclic arenes, such as
naphthalene (1p), and heterocyclic arenes, such as thiophene
(1q) derivatives, were also well tolerated in this reaction, with
both giving the corresponding benzolactams in 85% yield.
Finally, the investigation of the N-protecting groups revealed
that ethyl-protected amine (1r) gave almost the same excellent
yield as the methyl group, while the phenyl-protecting group
(1s) reduced the yield to only moderate.
skeleton could be efficiently made using our catalytic reaction.
As shown in Scheme 4, pregnane-3,20-dione, cyclic 20-(1,2-
Scheme 4. Concise Synthesis of Spiropachysin-20-one
To demonstrate the different regioselectivity of our method
to known reports from the groups of Orito6 and Granell and
Garcia,7 tertiary amines 1t and 1u have been synthesized and
tested in our reaction. As displayed in Scheme 3, when amine
ethanediyl acetal) 4 was synthesized from the commercially
available pregnenolone via a known approach.12 The carbonyl
group was transformed to imine via condensation of
methylamine, followed by attack of phenyllithium to afford
steroid-derived benzylamine 1v.13 With our newly developed
palladium-catalyzed C−H carbonylation reaction as the key
step, the precursor 1v was transferred to lactam 2v in 23%
yield. After removing the ketal protecting group under the
acidic conditions, the natural product spiropachysin-20-one
was finally obtained in 68% yield. Although the key step in this
total synthesis afforded only relatively low yield, the first easily
handled chemical synthesis of this natural product would
promote its biological study.
Scheme 3. Intramolecular Competitive Experiments
In summary, a Pd-catalyzed C(sp2)−H carbonylation of
sterically hindered α,α-disubstituted benzylamines under 1 atm
of CO for the facile synthesis of 3,3-disubstituted isoindolin-1-
one has been developed in which TEMPO was used as the
crucial sole oxidant. The synthetic utility of this transformation
has been demonstrated by the concise total synthesis of natural
product spiropachysin-20-one. Further studies using this
strategy to construct other heterocyclic ring systems and to
obtain the total synthesis of more biologically active complex
molecules are currently underway in our laboratory.
1t was subjected to the standard conditions, the carbonylation
occurred preferentially at the more steric ally hindered aryl C−
H bond to afford isoindolin-1-one 2t as the major product in
49% yield, while the six-membered isoquinolin-1-one 3t was
obtained in only 29% yield (eq 1, Scheme 3). Moreover, when
the side chain was prolonged to reduce the reactivity, the more
sterically hindered C−H bond on the phenyl ring of 1u was
carbonylated with excellent regioselectivity, furnishing iso-
indolin-1-one 2u as the sole product at 90% yield (eq 2).
Different from the report of Garcia and Granell,7 these results
clearly indicate that the more sterically hindered reaction site
was preferred in our catalytic system.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02856.
To demonstrate the synthetic application and prospects of
this transformation, we next attempted to use it as the key step
for the first total synthesis of the natural alkaloid
spiropachysin-20-one, which was isolated from Pachysandra
terminalis.10 While the only known method to make
spiropachysin-20-one was derivation from spiropachysine,11 it
was speculated that the construction of the spiro-lactam
skeleton was the possible problem. We envisioned that this
Experimental materials and procedures and NMR
spectra of new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: liyan08@ustc.edu.cn.
*E-mail: xswang77@ustc.edu.cn.
C
DOI: 10.1021/acs.orglett.8b02856
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
(t) Rajeshkumar, V.; Lee, T.-H.; Chuang, S.-C. Org. Lett. 2013, 15,
1468. (u) Chen, M.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-H. J. Org.
Chem. 2015, 80, 1258. (v) Li, W.; Duan, Z.; Jiang, R.; Lei, A. Org. Lett.
2015, 17, 1397. (w) Feng, M.; Tang, B.; Xu, H.-X.; Jiang, X. Org. Lett.
2016, 18, 4352. (x) Shi, R.; Lu, L.; Xie, H.; Yan, J.; Xu, T.; Zhang, H.;
Qi, X.; Lan, Y.; Lei, A. Chem. Commun. 2016, 52, 13307. (y) Shi, R.;
Niu, H.; Lu, L.; Lei, A. Chem. Commun. 2017, 53, 1908.
(5) Orito, K.; Horibata, A.; Nakamura, T.; Ushito, H.; Nagasaki, H.;
Yuguchi, M.; Yamashita, S.; Tokuda, M. J. Am. Chem. Soc. 2004, 126,
14342.
(6) Orito, K.; Miyazawa, M.; Nakamura, T.; Horibata, A.; Ushito,
H.; Nagasaki, H.; Yuguchi, M.; Yamashita, S.; Yamazaki, T.; Tokuda,
M. J. Org. Chem. 2006, 71, 5951.
(7) (a) Lopez, B.; Rodriguez, A.; Santos, D.; Albert, J.; Ariza, X.;
Garcia, J.; Granell, J. Chem. Commun. 2011, 47, 1054. (b) Albert, J.;
Xi-Sheng Wang: 0000-0003-2398-5669
Author Contributions
§X.-F.C. and T.W. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Strategic Priority Research
Program of the Chinese Academy of Sciences (Grant No.
XDB20000000), the National Basic Research Program of
China (973 Program 2015CB856600), the National Science
Foundation of China (21602213, 21522208, 21372209), and
the China Postdoctoral Science Foundation (2017M622255)
for financial support.
́
Ariza, X.; Calvet, T.; Font-Bardia, M.; Garcia, J.; Granell, J.; Lamela,
A.; Lopez, B.; Martinez, M.; Ortega, L.; Rodriguez, A.; Santos, D.
Organometallics 2013, 32, 649. (c) Taneda, H.; Inamoto, K.; Kondo,
Y. Org. Lett. 2016, 18, 2712.
́
(8) Haffemayer, B.; Gulias, M.; Gaunt, M. J. Chem. Sci. 2011, 2, 312.
(9) Wang, P.-L.; Li, Y.; Wu, Y.; Li, C.; Lan, Q.; Wang, X.-S. Org. Lett.
2015, 17, 3698.
(10) Zhai, H.-Y.; Zhao, C.; Zhang, N.; Jin, M.-N.; Tang, S.-A.; Qin,
N.; Kong, D.-X.; Duan, H.-Q. J. Nat. Prod. 2012, 75, 1305.
(11) Kikuchi, T.; Nishinaga, T.; Inagaki, M.; Niwa, M.; Kuriyama, K.
Chem. Pharm. Bull. 1975, 23, 416.
(12) (a) Hitchin, J. R.; Hamilton, N. M.; Jordan, A. M.; Lyons, A. J.;
Ogilvie, D. J. Tetrahedron Lett. 2012, 53, 2868. (b) Hamilton, N. M.;
Dawson, M.; Fairweather, E. E.; Hamilton, N. S.; Hitchin, J. R.; James,
D. I.; Jones, S. D.; Jordan, A. M.; Lyons, A. J.; Small, H. F.; Thomson,
G. J.; Waddell, I. D.; Ogilvie, D. J. J. Med. Chem. 2012, 55, 4431.
(13) The NMR spectrum of 2w was in agreement with that of ref 11.
To further infer the stereochemistry of the newly constructed
quaternary carbon, benzylamine 1v can also be gained via Ellman’s
protocol: McMahon, J. P.; Ellman, J. A. Org. Lett. 2004, 6, 1645. For
details, see the Supporting Information.
REFERENCES
■
(1) (a) Brown, H. C. Acc. Chem. Res. 1969, 2, 65. (b) Murai, S.;
Sonoda, N. Angew. Chem., Int. Ed. Engl. 1979, 18, 837. (c) Milstein, D.
Acc. Chem. Res. 1988, 21, 428. (d) Brunet, J.-J.; Chauvin, R. Chem.
Soc. Rev. 1995, 24, 89. (e) Ryu, I.; Sonoda, N.; Curran, D. P. Chem.
Rev. 1996, 96, 177. (f) Khumtaveeporn, K.; Alper, H. Acc. Chem. Res.
1995, 28, 414. (g) Drent, E.; Budzelaar, P. H. M. Chem. Rev. 1996, 96,
663. (h) Chatani, N.; Murai, S. Synlett 1996, 1996, 414. (i) Ryu, I.;
Sonoda, N. Angew. Chem., Int. Ed. Engl. 1996, 35, 1050. (j) Ryu, I.
Chem. Soc. Rev. 2001, 30, 16. (k) Kiss, G. Chem. Rev. 2001, 101, 3435.
(l) Church, T. L.; Getzler, Y. D. Y. L.; Byrne, C. M.; Coates, G. W.
Chem. Commun. 2007, 657. (m) Barnard, C. F. Organometallics 2008,
27, 5402. (n) Brennfu
Int. Ed. 2009, 48, 4114. (o) Lee, H.-W.; Kwong, F.-Y. Eur. J. Org.
̃
̈
Chem. 2010, 2010, 789. (p) Romao, C. C.; Blattler, W. A.; Seixas, J.
̈
hrer, A.; Neumann, H.; Beller, M. Angew. Chem.,
D.; Bernardes, G. J. L. Chem. Soc. Rev. 2012, 41, 3571. (q) Wu, X.-F.;
Fang, X.; Wu, L.; Jackstell, R.; Neumann, H.; Beller, M. Acc. Chem.
Res. 2014, 47, 1041. (r) Wang, Y.; Yu, Z.-X. Acc. Chem. Res. 2015, 48,
2288. (s) Ambrosi, A.; Denmark, S. E. Angew. Chem., Int. Ed. 2016,
55, 12164. (t) Li, Y.; Hu, Y.; Wu, X.-F. Chem. Soc. Rev. 2018, 47, 172.
(u) Peng, J.-B.; Wu, X.-F. Angew. Chem., Int. Ed. 2018, 57, 1152.
(2) (a) Liu, Q.; Zhang, H.; Lei, A. Angew. Chem., Int. Ed. 2011, 50,
10788. (b) Liu, B.; Hu, F.; Shi, B.-F. ACS Catal. 2015, 5, 1863.
(3) Fujiwara, Y.; Kawauchi, T.; Taniguchi, H. J. Chem. Soc., Chem.
Commun. 1980, 220.
(4) (a) Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14082.
(b) Houlden, C. E.; Hutchby, M.; Bailey, C. D.; Ford, J. G.; Tyler, S.
́
N. G.; Gagne, M. R.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. Angew.
Chem., Int. Ed. 2009, 48, 1830. (c) Lu, Y.; Leow, D.; Wang, X.; Engle,
K. M.; Yu, J.-Q. Chem. Sci. 2011, 2, 967. (d) Wrigglesworth, J. W.;
Cox, B.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. Org. Lett. 2011, 13,
5326. (e) Ma, B.; Wang, Y.; Peng, J.; Zhu, Q. J. Org. Chem. 2011, 76,
6362. (f) Lee, T.-H.; Jayakumar, J.; Cheng, C.-H.; Chuang, S.-C.
Chem. Commun. 2013, 49, 11797. (g) Luo, S.; Luo, F.-X.; Zhang, X.-
S.; Shi, Z.-J. Angew. Chem., Int. Ed. 2013, 52, 10598. (h) Liang, D.;
He, Y.; Zhu, Q. Org. Lett. 2014, 16, 2748. (i) Shin, S.; Jeong, Y.; Jeon,
W. H.; Lee, P. H. Org. Lett. 2014, 16, 2930. (j) Liu, B.; Jiang, H.-Z.;
Shi, B.-F. Org. Biomol. Chem. 2014, 12, 2538. (k) Ji, F.; Li, X.; Wu, W.;
Jiang, H. J. Org. Chem. 2014, 79, 11246. (l) Li, W.; Duan, Z.; Zhang,
X.; Zhang, H.; Wang, M.; Jiang, R.; Zeng, H.; Liu, C.; Lei, A. Angew.
Chem., Int. Ed. 2015, 54, 1893. (m) Wang, Y.; Gevorgyan, V. Angew.
Chem., Int. Ed. 2015, 54, 2255. (n) Xu, Y.; Hu, W.; Tang, X.; Zhao, J.;
Wu, W.; Jiang, H. Chem. Commun. 2015, 51, 6843. (o) Wang, P.-L.;
Li, Y.; Ma, L.; Luo, C.-G.; Wang, Z.-Y.; Lan, Q.; Wang, X.-S. Adv.
Synth. Catal. 2016, 358, 1048. (p) Zhang, L.; Wang, C.; Han, J.;
Huang, Z.-B.; Zhao, Y. J. Org. Chem. 2016, 81, 5256. (q) Wang, Y.;
Gevorgyan, V. Angew. Chem., Int. Ed. 2017, 56, 3191. For amine-
directed C(sp2)−H carbonylation, see: (r) Guan, Z.-H.; Chen, M.;
Ren, Z.-H. J. Am. Chem. Soc. 2012, 134, 17490. (s) Liang, D.; Hu, Z.;
Peng, J.; Huang, J.; Zhu, Q. Chem. Commun. 2013, 49, 173.
D
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