Catalytic Multisite-Selective Acetoxylation Reactions at sp2 vs sp3 C-H Bonds in Cyclic Olefins

Article abstract of DOI:10.1021/acs.orglett.6b02458

The first Pd-catalyzed multisite-selective acetoxylation reactions are disclosed at an unactivated alkene sp² C-H bond versus secondary allylic sp³ C-H bond in cyclic olefins via the modulation of directing groups. The different directing groups overcome the key challenge in differentiating C-H bonds and provide a new controlling approach for site-specific C-H activation. A wide variety of substrates are readily acetoxylated under operationally simple conditions. Mechanistic studies suggest that different Pd (IV) intermediates were involved in the multisite-selective acetoxylation reactions.

Full text of DOI:10.1021/acs.orglett.6b02458

Letter
pubs.acs.org/OrgLett
Catalytic Multisite-Selective Acetoxylation Reactions at sp2 vs sp3
C−H Bonds in Cyclic Olefins
Zhong-Lin Zang,† Sheng Zhao,† Shuklachary Karnakanti, Cheng-Lin Liu, Pan-Lin Shao,* and Yun He*
School of Pharmaceutical Sciences and Innovative Drug Research Centre, Chongqing University, 55 Daxuecheng South Road,
Shapingba, Chongqing 401331, P.R. China
S
* Supporting Information
ABSTRACT: The first Pd-catalyzed multisite-selective acetox-
ylation reactions are disclosed at an unactivated alkene sp2 C−H
bond versus secondary allylic sp3 C−H bond in cyclic olefins via
the modulation of directing groups. The different directing
groups overcome the key challenge in differentiating C−H
bonds and provide a new controlling approach for site-specific
C−H activation. A wide variety of substrates are readily
acetoxylated under operationally simple conditions. Mechanistic
studies suggest that different Pd (IV) intermediates were
involved in the multisite-selective acetoxylation reactions.
ue to the ubiquitous nature of C−H bonds in organic
pathways afforded different and complementary site-selectivities
in the same cyclic olefins.
D
molecules, it is challenging to achieve selective function-
alizations among different kinds of C−H bonds.1−3 The
introduction of oxygen functionalities to C−H bonds with site
selectivity4−9 is critically important, and the principles and tactics
for achieving vinyl sp2 C−H10 and allylic sp3 C−H
acetoxylation,11−17 respectively, have been established.18 How-
ever, multisite-selective acetoxylation using similar catalytic
systems has been scarcely reported in the literature.1c One
obvious challenge is the formation of intractable mixture of
regioisomers due to the similar reactivities. Herein, we disclose
the first Pd-catalyzed multisite-selective acetoxylation reactions
at the unactivated alkene sp2 C−H bond versus the secondary
allylic sp3 C−H bond in cyclic olefins via the modulation of
directing groups (DGs).9
Our initial studies focused on the acetoxylation of sp2 C−H
bond in cyclic olefins. 2-(Cyclohex-1-en-1-yl)ethanamines with
different protecting groups were examined (Table 1). Gratify-
ingly, when PA was used as the directing group, the vinyl
acetoxylation product (2, entry 1) was obtained in 70% isolated
yield with excellent site-selectivity. When Ts was employed
(entry 2), the allylic acetoxylation products (C3:6 = 5:1) along
with double acetoxylation product (Di-4) were observed, while
no vinyl acetoxylation product was generated. Moreover,
excellent site-selectivity (C3:C6 = 33:1) was realized with 4-
(trifluoromethyl)benzenesulfonyl (TFTs) as the directing group
(entry 4). Similar site-selectivity was observed when 4-nitro-
benzenesulfonyl (4-Ns) or 2-nitrobenzenesulfonyl (2-Ns) was
introduced (entries 5 and 6). These results suggest that the
selectivity could be enhanced by the electron-withdrawing
benzenesulfonyl groups. However, the ratio of the products of
allylic acetoxylation (C3:C6) was about 1:1 when the amine was
protected by a weaker coordinating group (Boc, Cbz, and Ac)
(entries 7−9). It is noteworthy that the substrate underwent
acetoxylation with high site selectivity (C6:C3 > 30:1, entry 10)
at the proximal sp3 C−H bond (6-position) when the amine was
protected by Ts and Me groups. No acetoxylation occurred if the
Ts group was replaced by a Bn group (entry 12). Notably, by
employing White’s conditions,13g the acetoxylation occurred at
the 6-position mainly with low yield, as the majority of starting
materials remained (entry 3 and 11).
As shown in Scheme 1, our multisite-selective acetoxylation
strategy relies on the choice of appropriate directing groups. The
Scheme 1. Approaches for Multisite-Selective Acetoxylation
The substrate scope of vinyl sp2 C−H acetoxylation was
explored, and the results are summarized in Scheme 2 (see the
Supporting Information for optimization details). The substrates
chemoselectivity of the vinyl sp2 C−H bond versus allylic sp3 C−
H bond (2- vs 3- or 6-position) could be achieved in cyclic olefins
by using picolinamide (PA)19 and p-toluenesulfonyl (Ts) groups
as DGs.20 Furthermore, by introducing a methyl group on the N-
Ts group, regioselective acetoxylation was also obtained between
the two allylic sp3 C−H bonds (3- vs 6-position). These three
Received: August 18, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02458
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
possessing five-, six-, seven-, and eight-membered rings afforded
the desired products 2a−d in moderate to good yields. In
particular, optically pure amino acid derivatives also produced
the target products in moderate to high yields without erosion of
enantiopurities (2e−i). The derivatives with an α-methyl group
or one carbon shorter chain proceeded smoothly with
satisfactory yields (2j,k). The cyclohexene with bulky 6,6-
dimethyl groups provided the desired product in moderate yield
(2l). Moreover, the electron-withdrawing group on PA had no
effect on this transformation (2m). Surprisingly, a spirocyclic
product (2n) via an Friedel−Crafts alkylation and double
acetoxylation was isolated in moderate yield when an α-phenyl
group was introduced into the substrate. Furthermore,
introduction of a methyl group to the N-PA group completely
inhibited this transformation (2o), suggesting that N−H as the
coordination group plays a key role in these reactions.
Table 1. Optimization of Acetoxylation Reactions with
Different DGs −
a c
yield (%)
entry
R1/R2
2
4
6
Di-4
1
2
PA/H
70
<2
<2
<2
<2
<2
<2
<2
<2
<2
<2
<2
<2
50
3
<2
10
17
2
<2
15
<2
13
18
15
<2
<2
<2
<2
<2
<2
Ts/H
d
3
Ts/H
4
TFTs/H
4-Ns/H
2-Ns/H
Boc/H
Cbz/H
Ac/H
66
50
60
17
19
18
<2
<2
<2
To gain an understanding of the site-selectivity in the vinyl sp2
C−H acetoxylation reaction, d3-1a (52% deuterium) was
prepared to distinguish acetoxylations at the 2- and 6-positions
(eq 1, Scheme 3). Under the optimized reaction conditions, d3-
5
3
6
8
7
16
18
17
34
12
<2
8
9
Scheme 3. Deuterium-Labeling Experiments of sp2 C−H
Acetoxylation
10
Ts/Me
Ts/Me
Bn/Me
d
11
12
a
Reactions conditions: substrate (0.3 mmol), PhI(OAc)2 (0.75
mmol), Pd(OAc)2 (0.03 mmol, 10 mol %), Ac2O (1.5 mmol),
b
AcOH (1.5 mmol), toluene (4 mL), N2, 2 h. Yield is that of the
c
isolated product. The site selectivity is determined by 1H NMR (400
d
MHz) of the crude reaction mixture. Reactions conditions: substrate
(0.3 mmol), 1,4-benzoquinone (0.60 mmol), Pd(OAc)2 (0.03 mmol,
10 mol %), (vinylsulfinyl)benzene (0.03 mmol, 10 mol %), AcOH (1.2
mmol), dioxane (1 mL), 30 h.
a,b
Scheme 2. Substrate Scope of sp2 C−H Acetoxylation
2a was obtained in 57% yield at C2 of the cyclohexene, and no C6
acetoxylation product was generated. Comparison of the initial
acetoxylation rates of 1a versus its deuterated analogue d3-1a
provided a KH/KD of 2.10 in toluene. These data suggest that the
sp2 C−H(D) bond breaking to form the cyclopalladium is rate
limiting in the system. Significant deuteration occurred at the C2
position and acetoxylation product 2c was formed when the
reaction was carried out with excess D2O (2.0 equiv) under the
standard conditions (eq 2, Scheme 3). This result suggests that
acetoxylation occurs through an sp2 C−H activation process via
the postulated intermediate (Int-1, Scheme 2)21,22 at the 2-
position of the cyclohexene. The exchange of deuterium between
the alkene and D2O was observed. The H/D exchange also
implied that the process occurred through the cyclopalladated
intermediate.
To date, there are only a few examples of Pd-catalyzed C−H
functionalization at secondary sp3 C−H bonds.13f,14 Therefore,
we turned our attention to the development of acetoxylation of
secondary allylic sp3 C−H bonds and achieved C3-selectivity
when proper sulfonyl groups were employed as the directing
groups (Scheme 4; see the Supporting Information for
optimization details). For the cyclohexene derivative with a Ts
group, the ratio of the products of C3 and C6 acetoxylation (4a
and 4a′) was improved with PdCl2(PhCN)2 instead of
Pd(OAc)2. The substrate with an Ns group led to the C3-
selective product (4b) and double-acetoxylation product (Di-
4b) in 53% and 18% yields, respectively, while no C6-
acetoxylation occurred. The structure of 4b was confirmed by
X-ray diffraction of its hydrolysate (4b-OH).23 Furthermore,
when TFTs was used as the directing group, better yield and
a
Reactions conditions: 1 (0.3 mmol), Pd(OAc)2 (0.03 mmol),
PhI(OAc)2 (0.75 mmol), 2-Chloro-4-cyanopyridine (0.12 mmol),
toluene (5 mL), N2, 2 h. Yield is that of the isolated product. Yield is
based on the recovered starting material.
b
c
B
DOI: 10.1021/acs.orglett.6b02458
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 4. Substrate Scope of sp3 C−H Acetoxylation 1
Moreover, introduction of a methyl group into the substrates
of the C3-acetoxylation led to C6-acetoxylation. A series of
sulfonamides 5 were surveyed (Scheme 6). The model C6-
a,b
Scheme 6. Substrate Scope of sp3 C−H Acetoxylation 2
a
Reactions conditions: 3 (0.3 mmol), PdCl2(PhCN)2 (0.015 mmol),
PhI(OAc)2 (0.75 mmol), Ac2O (1.5 mmol), AcOH (1.5 mmol), DCE
b
(4 mL), N2, 2 h. C6-acetoxylation products 4a′ and Di4a were found.
c
X-ray structure of 4b-OH. For simplicity, one of the two
d
configurations has been omitted. Yield is based on the recovered
starting material. At 80 °C. The dr value is about 1:1.
a
e
f
Reactions conditions: 5 (0.3 mmol), PdCl2(PhCN)2 (0.03 mmol),
PhI(OAc)2 (0.75 mmol), Ac2O (1.5 mmol), AcOH (1.5 mmol), DCE
b
c
d
(4 mL), N2, 2 h. Yield is that of the isolated product. At 80 °C. C3-
e
side product 6i′. The dr value is about 1:1.
selectivity were achieved. In addition, a five-membered ring
substrate with TFTs gave a mixture of C3- and C6-acetoxylation
products (4d and 4d′) with a ratio of 3:1. The substrates with
seven- and eight-membered rings also worked, providing only
the C3 acetoxylation products 4e and 4f with lower yields,
respectively. Interestingly, the substrates of chiral amino acid
ester proceeded smoothly (4g−k). The substrates with α-methyl
or phenyl group also performed well (4l,m). When two methyl
groups were introduced into the six-membered ring, the
corresponding acetoxylation product was still obtained in good
yield (4n). The steric hindrance on the ring had negligible impact
on the cyclohexene C3-selectivity acetoxylation.
acetoxylation product (6a) was formed in 70% yield. The
substrates with one less or more carbon on the side chain
compared with 5a afforded the corresponding products (6b23
and 6c). The ester group in 6d was well tolerated. Additional
protecting groups were also screened (6e−g), and the TFTs
group provided the highest yield. The substrates with five- and
seven-membered rings generated the products in moderate
yields with good site selectivities (6h,i). The amines with
different α-substituents (ester, methyl, phenyl) also furnished the
C6-acetoxylation (6j−n) with satisfactory yields.
2-Deuterated (cyclohex-1-en-1-yl)ethanamine (d1-5a, 97%
deuterium) was synthesized to examine the possibility of the
double-bond migration (Scheme 7). Under the optimized
reaction conditions, d1-6a and d1-6a′ were obtained in 34%
yield with a ratio of 1:1 (eq 3). The possible palladium(II)
2-Deuterated (cyclohex-1-en-1-yl)ethanamine (d1-3a, 97%
deuterium) was prepared to determine if this sp3 C−H bond
acetoxylation occurred at the 3- or 6-position as shown in
Scheme 5. Under the optimized reaction conditions, d1-4a was
obtained in 54% yield at the 3-position, and the acetoxylation
product at the 6-position was formed in 6% yield. This result
indicates that acetoxylation occurs through the postulated π-
(1,2,3)-allylpalladium species (Int-2, Scheme 4).14
Scheme 7. Deuterium-Labeling and Palladium(II)
Intermediate Experiments
Scheme 5. Deuterium-Labeling Experiments of sp3 C−H
Acetoxylation
C
DOI: 10.1021/acs.orglett.6b02458
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
complex 723 was prepared from the alkene 5a and Pd(TFA)2 (eq
4),24 and the isolated complex could be converted into the
desired product 6a when heated to 60 °C with PhI(OAc)2. These
results suggest that acetoxylation occurs through the postulated
π-(6,1,2)-allylpalladium species (Int-3, Scheme 6).14,21
In summary, a straightforward strategy for the multisite-
selective acetoxylation of vinyl sp2 versus secondary allylic sp3
C−H bonds in cyclic olefins has been developed using a Pd(II/
IV) catalysis system via the modulation of directing groups.
Mechanistic studies and deuteration experiments suggest that
different Pd(IV) intermediates were involved in the acetox-
ylations. Efforts toward to the development of asymmetric allylic
acetoxylation as well as applications of the methodologies in the
synthesis of natural and designed products of biological
importance are currently ongoing in our laboratory.
Chem. Soc. 2007, 129, 12072. (c) Grimster, N. P.; Gauntlett, C.;
Godfrey, C. R. A.; Gaunt, M. J. Angew. Chem., Int. Ed. 2005, 44, 3125.
(6) Disite-selective sp2 or sp3 C−H activation: (a) Zhang, J.; Sha, S.-C.;
Bellomo, A.; Trongsiriwat, N.; Gao, F.; Tomson, N. C.; Walsh, P. J. J.
Am. Chem. Soc. 2016, 138, 4260. (b) Santhoshkumar, R.; Mannathan, S.;
Cheng, C.-H. J. Am. Chem. Soc. 2015, 137, 16116. (c) Bisht, R.;
Chattopadhyay, B. J. Am. Chem. Soc. 2016, 138, 84. (d) Alderson, J. M.;
Phelps, A. M.; Scamp, R. J.; Dolan, N. S.; Schomaker, J. M. J. Am. Chem.
Soc. 2014, 136, 16720.
(7) Disite-selective sp2 vs sp3 C−H activation: (a) Schipper, D. J.;
Campeau, L.-C.; Fagnou, K. Tetrahedron 2009, 65, 3155. (b) Larsen, M.
A.; Wilson, C. V.; Hartwig, J. F. J. Am. Chem. Soc. 2015, 137, 8633.
(c) Wang, Z.; Kuninobu, Y.; Kanai, M. Org. Lett. 2014, 16, 4790.
(d) Davies, H. M. L.; Ren, P.; Jin, Q. Org. Lett. 2001, 3, 3587.
(8) Kim, H. J.; Ajitha, M. J.; Lee, Y.; Ryu, J.; Kim, J.; Lee, Y.; Jung, Y.;
Chang, S. J. Am. Chem. Soc. 2014, 136, 1132.
(9) (a) Li, S.; Ji, H.; Cai, L.; Li, G. Chem. Sci. 2015, 6, 5595. (b) Kang,
D.; Hong, S. Org. Lett. 2015, 17, 1938.
(10) Yu, W.; Chen, J.; Gao, K.; Liu, Z.; Zhang, Y. Org. Lett. 2014, 16,
ASSOCIATED CONTENT
■
4870.
S
* Supporting Information
(11) (a) Baeckvall, J.-E.; Hopkins, R. B.; Grennberg, H.; Mader, M.;
Awasthi, A. K. J. Am. Chem. Soc. 1990, 112, 5160. (c) Baeckvall, J. E.;
Nystroem, J. E.; Nordberg, R. E. J. Am. Chem. Soc. 1985, 107, 3676.
(12) (a) Campbell, A. N.; Stahl, S. S. Acc. Chem. Res. 2012, 45, 851.
(b) McDonald, R. I.; Liu, G.; Stahl, S. S. Chem. Rev. 2011, 111, 2981.
(13) For selected recent examples of palladium-catalyzed allylic C−H
acyloxylation, see: (a) Mitsudome, T.; Umetani, T.; Nosaka, N.; Mori,
K.; Mizugaki, T.; Ebitani, K.; Kaneda, K. Angew. Chem., Int. Ed. 2006, 45,
481. (b) Xing, X.; O’Connor, N. R.; Stoltz, B. M. Angew. Chem., Int. Ed.
2015, 54, 11186. (c) Thiery, E.; Aouf, C.; Belloy, J.; Harakat, D.; Le Bras,
J.; Muzart, J. J. Org. Chem. 2010, 75, 1771. (d) Check, C. T.; Henderson,
W. H.; Wray, B. C.; Vanden Eynden, M. J.; Stambuli, J. P. J. Am. Chem.
Soc. 2011, 133, 18503. (e) Chen, M. S.; White, M. C. J. Am. Chem. Soc.
2004, 126, 1346. (f) Gormisky, P. E.; White, M. C. J. Am. Chem. Soc.
2011, 133, 12584. (g) Chen, M. S.; Prabagaran, N.; Labenz, N. A.;
White, M. C. J. Am. Chem. Soc. 2005, 127, 6970.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02458.
Experimental procedures, characterization of the products,
X-ray analysis, and NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: shaopl@cqu.edu.cn.
*E-mail: yun.he@cqu.edu.cn.
Author Contributions
†Z.-L.Z. and S.Z. contributed equally.
Notes
(14) (a) Alam, R.; Pilarski, L. T.; Pershagen, E.; Szabo,
Chem. Soc. 2012, 134, 8778. (b) Pilarski, L. T.; Selander, N.; Bose, D.;
Szabo, K. J. Org. Lett. 2009, 11, 5518.
́
́
K. J. J. Am.
The authors declare no competing financial interest.
̈
ACKNOWLEDGMENTS
(15) (a) Yu, J.-Q.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 3232.
(b) Catino, A. J.; Forslund, R. E.; Doyle, M. P. J. Am. Chem. Soc. 2004,
126, 13622. (c) Horn, E. J.; Rosen, B. R.; Chen, Y.; Tang, J.; Chen, K.;
Eastgate, M. D.; Baran, P. S. Nature 2016, 533, 77.
■
We are grateful to the National Natural Science Foundation of
China (Nos. 21572027, 21372267, and 21402150) for financial
support. We sincerely thank Prof. Dr. Yu Lan (Chongqing
University) for insightful discussions. We also thank Dr. Yong-
Liang Shao (Lanzhou University) for the X-ray crystallographic
analysis.
(16) (a) Eames, J.; Watkinson, M. Angew. Chem., Int. Ed. 2001, 40,
3567. (b) Andrus, M. B.; Zhou, Z. J. Am. Chem. Soc. 2002, 124, 8806.
(17) (a) Huang, D.; Wang, H.; Guan, H.; Huang, H.; Shi, Y. Org. Lett.
2011, 13, 1548. (b) Huang, D.; Wang, H.; Xue, F.; Shi, Y. J. Org. Chem.
2011, 76, 7269.
(18) Kondo, H.; Yu, F.; Yamaguchi, J.; Liu, G.; Itami, K. Org. Lett. 2014,
16, 4212.
(19) Zhang, S.-Y.; He, G.; Zhao, Y.; Wright, K.; Nack, W. A.; Chen, G. J.
Am. Chem. Soc. 2012, 134, 7313.
(20) (a) García-Rubia, A.; Laga, E.; Cativiela, C.; Urriolabeitia, E. P.;
Gomez-Arrayas, R.; Carretero, J. C. J. Org. Chem. 2015, 80, 3321.
́ ́
(b) Laforteza, B. N.; Chan, K. S. L.; Yu, J.-Q. Angew. Chem., Int. Ed. 2015,
54, 11143.
REFERENCES
■
(1) (a) Godula, K.; Sames, D. Science 2006, 312, 67. (b) Labinger, J. A.;
Bercaw, J. E. Nature 2002, 417, 507. (c) Hartwig, J. F. J. Am. Chem. Soc.
2016, 138, 2.
(2) (a) Davies, H. M. L.; Morton, D. Chem. Soc. Rev. 2011, 40, 1857.
(b) Newhouse, T.; Baran, P. S. Angew. Chem., Int. Ed. 2011, 50, 3362.
(c) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936. (d) Giri,
R.; Shi, B.-F.; Engle, K. M.; Maugel, N.; Yu, J.-Q. Chem. Soc. Rev. 2009,
38, 3242.
(3) (a) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
(b) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173.
(c) Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O.
Chem. - Eur. J. 2010, 16, 2654. (d) Liu, C.; Zhang, H.; Shi, W.; Lei, A.
Chem. Rev. 2011, 111, 1780.
(4) Monosite selective C−H oxidations: (a) Calleja, J.; Pla, D.;
Gorman, T. W.; Domingo, V.; Haffemayer, B.; Gaunt, M. J. Nat. Chem.
2015, 7, 1009. (b) Ren, Z.; Mo, F.; Dong, G. J. Am. Chem. Soc. 2012, 134,
16991. (c) Simmons, E. M.; Hartwig, J. F. Nature 2012, 483, 70.
(5) Disite-selective sp2 C−H activation: (a) Potavathri, S.; Pereira, K.
C.; Gorelsky, S. I.; Pike, A.; LeBris, A. P.; DeBoef, B. J. Am. Chem. Soc.
2010, 132, 14676. (b) Stuart, D. R.; Villemure, E.; Fagnou, K. J. Am.
(21) (a) Muniz, K. Angew. Chem., Int. Ed. 2009, 48, 9412. (b) Xu, L.-M.;
̃
Li, B.-J.; Yang, Z.; Shi, Z.-J. Chem. Soc. Rev. 2010, 39, 712. (c) Hickman,
A. J.; Sanford, M. S. Nature 2012, 484, 177. (d) Topczewski, J. J.;
Sanford, M. S. Chem. Sci. 2015, 6, 70.
(22) (a) Sibbald, P. A.; Rosewall, C. F.; Swartz, R. D.; Michael, F. E. J.
Am. Chem. Soc. 2009, 131, 15945. (b) Peng, H.; Yuan, Z.; Wang, H.-Y.;
Guo, Y.-L.; Liu, G. Chem. Sci. 2013, 4, 3172.
(23) CCDC 1489306 (4b-OH), CCDC 1488818 (6b), and CCDC
1488820 (7) contain the crystallographic data for this paper. These data
can be obtained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Selected data
are also included in the Supporting Information.
(24) Trost, B. M.; Metzner, P. J. J. Am. Chem. Soc. 1980, 102, 3572.
D
DOI: 10.1021/acs.orglett.6b02458
Org. Lett. XXXX, XXX, XXX−XXX