Amino acid-promoted C-H alkylation with alkylboronic acids using a removable directing group

Article abstract of DOI:10.1039/c6ob00674d

Palladium-catalyzed C-H alkylation reaction with alkylboronic acids has successfully been developed using a removable pyridyldiisopropylsilyl directing group. The amino acid played a crucial role as a ligand in the reaction. The alkylation protocol is also applicable to the coupling of C(sp³)-H bonds with alkylboronic acids.

Full text of DOI:10.1039/c6ob00674d

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Organic & Biomolecular Chemistry
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Amino Acid-Promoted C–H Alkylation with Alkylboronic Acids
Using a Removable Directing Group
Received 00th January 20xx,
Accepted 00th January 20xx
Yu Zhang, Hang Jiang, Dushen Chen, Yanghui Zhang*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Palladium-catalyzed C–H alkylation reaction with alkylboronic
acids has successfully been developed using removable
pyridyldiisopropylsilyl directing group. The amino acid played a
crucial role as a ligand in the reaction. The alkylation protocol is
also applicable to the coupling of C(sp3)–H bonds with alkylboronic
acids.
In the past few decades, C–H functionalization has attracted
considerable interest and is emerging as a novel and valuable
strategy in organic synthesis.1 While the ubiquility of C–H
bonds in organic molecules provides great opportunities for
the application of C–H functionalization reactions, it also poses
regioselectivity problems for this type of reaction. To develop
synthetically applicable C–H functionalization reactions, it is
critical to activate desirable C–H bonds selectively. However,
C–H bonds often have very similar reactivities, so it is usually
challenging to achieve high site-selectivity. Currently, the most
common strategy to address this issue relies on the use of
directing groups.2 The directing groups can coordinate to
transition-metal catalysts, and as a consequence, only C-H
bonds at the appropriate positions can be cleaved through the
formation of a cyclic pre-transition state. Although this
strategy is efficient and reliable in achieving high selectivity,
the directing groups are not needed in products for the
majority of the reactions and should be removed. However,
many of the directing groups are not easily removable, so it
limits the reactions to particular types of substrates bearing
directing groups.
Recently, a removable directing group strategy is arousing
great attention. For this strategy, the directing groups can be
removed after C–H functionalization, so it overcomes the
drawbacks of the common directing group strategy. Currently,
a variety of removable directing groups have been developed.3
Figure 1. Pyridyldiisopropylsilyl-directed C–H functionalization.
Excellent examples are pyridyldiisopropylsilyl-directed C–H
halogenation and acyloxylation reactions developed by the
Gevorgyan group (Figure 1).4 Furthermore, the Gevorgyan5
and Ge group6 reported silinol-assisted C–H functionaliztion
respectively. Although additional synthetic steps are needed to
install the directing group, the synthesis of arylsilanes
containing the pyridyldiisopropylsilyl directing group is
straightforward.4a
Although transition-metal-catalyzed alkylation reactions are
usually challenging, owing to its great advantages, C–H
alkylation has still been extensively studied. While a number of
C–H alkylation reactions using alkyl halides have been
reported,7 the reactions with alkylmetallic reagents remains
comparatively underexploited.8 Attracted by the great
advantages of the removable directing group strategy, we set
out to investigate its feasibility in C–H alkylation with
alkylmetallic reagents. Considering the favorable properties of
Department of Chemistry, and Shanghai Key Lab of Chemical Assessment and
Sustainability, Tongji University, 1239 Siping Road, Shanghai, 200092, P. R. China.
E-mail: zhangyanghui@tongji.edu.cn.
†Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Table 1. Condition Survey for PyrDipSi-Directed C–H Alkylation with Alkylboronic Acid
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DOI: 10.1039/C6OB00674D
entry BQ
(equiv) (equiv)
Ag2CO3 (1.0)
oxidant
solvent
additive
yield
(%)b
40
37
39
28
57
72
60
trace
55
30
trace
0
50
1
0.5
0.5
0.5
0.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
t-Amyl-OH
t-Amyl-OH
t-Amyl-OH
t-Amyl-OH
t-Amyl-OH
THF
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
AgOAc (1.0)
Ag2O(1.0)
Cu(OAc)2 (1.0)
Ag2CO3 (1.0)
Ag2CO3 (1.0)
Ag2CO3 (1.0)
Ag2CO3 (1.0)
Ag2CO3 (1.0)
Ag2CO3 (1.0)
Ag2CO3 (1.0)
Ag2CO3 (1.0)
Ag2CO3 (1.0)
Ag2CO3 (1.0)
Ag2CO3 (1.0)
Ag2CO3 (2.0)
Ag2CO3 (2.0)
Ag2CO3 (2.0)
Ag2CO3 (2.0)
Ag2CO3 (2.0)
Ag2CO3 (2.0)
Ag2CO3 (2.0)
Et2O
MeCN
t-BuOH
dioxane
DCE
toluene
DMF
DMSO
THF
THF
THF
THF
THF
THF
0
78
83
49
Na2CO3
NaHCO3
KHCO3
NaHCO3
NaHCO3
NaHCO3
89 (85c)
43
21d
36e
60f
THF
THF
a Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol. 3.0 equiv), Pd(OAc)2 (0.02
mmol, 10 mol%), Ac-Gly-OH (0.04 mmol, 20 mol%), BQ, oxidant, additive (0.2
mmol, 1.0 equiv), solvent (1.0 mL), 60 ºC, 48 h. b The yields were determined by
1H NMR analysis of the crude reaction mixtures using CHCl2CHCl2 as an internal
Scheme 1. Substrate Scope with the Respect to 2-(Diisopropyl(phenyl)silyl)pyridi-
d
e
f
standard.c Isolated yield. No Ac-Gly-OH. Pd(OAc)2 (2.5 mol%). Pd(OAc)2 (5.0
ne. a Isolated yield.
mol%)
amyl alcohol (Table 1, entry 1). Oxidant survey showed that
other silver(I) salt could also promote the reaction (entries 2
and 3) and Cu(OAc)2 was an effective oxidants as well, albeit in
a lower yield (entry 4). The yield was improved to 57% when
1.0 equiv Ag2CO3 was used in the presence of 1.0 equiv BQ,
and was further enhanced to 72% by carrying out the reaction
in THF (entry 6). THF proved to be the optimal solvent, since
the use of other solvents led to lower yields or even failed to
form the alkylated product (entries 7-14). Fine tuning reaction
condition enhanced the yield to 83% using 1.2 equiv BQ and
2.0 equiv Ag2CO3 (entry 16). To obtain an optimal yield, we
examined the impact of inorganic bases on the alkylation
reaction. While the reaction gave a lower yield in the presence
of Na2CO3 or KHCO3 (entries 17 and 19), the yield was
optimized to 89% when 1.0 equiv NaHCO3 was added (entry
18). Finally, the absence of N-acetylglycine led to a much lower
yield, indicating that the amino acid played a critical role in
promoting the alkylation reaction (entry 20). To gain some
insights into the impact of amino acids on the reaction, a range
of other N-protected amino acids were examined (See
Supporting Information). All the surveyed amino acids gave
organoboron reagents, we chose alkylboronic acids as the
coupling partner. It is noted that some pioneering C–H
alkylation reactions with organoboron reagents have been
disclosed.9 However, most of the reactions are limited to me-
thylation, and competing difunctionalizaiton can occur.
Ligands can provide transition-metal-catalysts with novel
reactivities and allow for otherwise unfeasible reactions to be
realized.10 In this context, amino acids proved to be extremely
versatile and powerful in Pd-catalyzed C–H functionalization,
and have enabled a range of reactions to be developed.9c,11
Amino acids have advantageous properties such as low cost,
ready availability, and facile modification, making them
desirable ligands. Herein, we report 2-pyridyldiisopropylsilyl
(PyrDipSi)-directed C–H alkylation with alkylboronic acids with
the aid of an amino acid ligand.
We initiated this research project by investigating the C–H
alkylation of 2-(diisopropyl(phenyl)silyl)pyridine (1a) with n-
butylboronic acid (2a).After extensive reaction screening, the
reaction formed the desired alkylated product (3aa) in 40%
yield in the presence of 10 mol% Pd(OAc)2, 20 mol% N-acetyl-
glycine, 0.5 equiv benzoquinone, and 1.0 equiv Ag2CO3 in tert-
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C6OB00674D
was alkylated in a yield similar to 1a (3ba)， the presence of a
methoxy group at the para- or meta-position resulted in much
lower yields (3ca and 3da). As a comparison, the substrates
with electron-withdrawing trifluoromethyl groups were
butylated in medium yields (3ea and 3fa). Notably, the halo
groups, including F, Cl, and Br, were well-tolerated in the
reaction (3ga
functional groups, such as phenyl, ester, and amide groups
underwent the alkylation reaction in satisfying yield (3ka 3ma).
-3ja). The substrates containing other common
-
Finally, the disubstituted benzene rings were successfully
alkylated under the reaction conditions (3na-3pa).
Subsequently, we investigated the substrate scope with
respect to the alkylboronic acid coupling partner. As shown in
Scheme 2, linear primary alkylboronic acid containing a variety
of functional groups effectively underwent the alkylation
reaction under the standard conditions to form the
corresponding alkylated products. The phenyl, ether, carbonyl,
and cyano groups were tolerated in the reaction (3ac-3af and
Scheme 2. Substrate Scope with the Respect to Alkylboronic Acids. a Isolated yield.
3ai). The boronic acid bearing furan or isoindoline-1,3-dione
moiety at the terminal positions were reactive, albeit in low
yields (3ag and 3ah). Notably, a coumarin and estrone
derivative could be installed onto the benzene ring of 1a via
the C–H alkylation reaction (3aj and 3ak).
much lower yields. Furthermore, replacing the amino acid with
pivalic acid led to 22% yield, which is close to that of the
reaction in the absence of an amino acid ligand. Finally, in the
presence of 5 or 2.5 mol% Pd(OAc)2, the reaction formed the
desired product in 60% and 36% respectively.
With the optimal conditions in hand, we next investigated
the substrate scope of this C–H alkylation reaction. We first
examined performance of 2-(diisopropyl(phenyl)silyl)pyridine
derivatives bearing a variety of substituents on the phenyl
group under the optimized conditions. Thus, as shown in
Scheme 1, while the substrate containing a para-methyl group
The compatibility of other directing groups was also
examined (scheme 3). Although both the diethyl(pyridyl)silyl
and isobutyl(methyl)(pyridyl)silyl groups could enable the C–H
alkylation to occur, the yields were much lower, primarily due
to the decomposition of the directing groups.
Transition-metal-catalyzed C(sp3)–C(sp3) coupling is one of
the most challenging reactions in organometallic chemistry.
Although the coupling of C(sp3)–H bonds with with C(sp3)
Scheme 3. Substrate Scope with the Respect to Directing Groups. a Isolated yield.
Scheme 4. Removal of the pyridyldiisopropylsilyl directing group.
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boron reagents has been achieved by the Yu group,9a,12 almost
no other reactions involving the coupling of C(sp3)–H bonds
and C(sp3) organometallic reagents have been reported ever
since. Inspired by the success of the alkylation of C(sp2)-H
bonds, we examined the applicability of this protocol for
C(sp3)–H bonds.13 Therefore, 2-(butyldimethylsilyl)pyridine was
subjected to the standard reaction conditions. Gratefully, the
methyl group was butylated selectively in 36% (eq. 1).
Synthesis , eds. Y.-H. Zhang, G.-F. Shi and J.-Q. Yu, Elsevier,
View Article Online
Oxford, 2nd edn, 2014.
DOI: 10.1039/C6OB00674D
2
Reviews on directed C–H activation: (a) T. W. Lyons and M. S.
Sanford, Chem. Rev., 2010, 110, 1147; (b) K. M. Engle, T.-S.
Mei, M. Wasa and J.-Q. Yu, Acc. Chem. Res., 2012, 45, 788; (c)
D. A. Colby, A. S. Tsai, R. G. Bergman and J. A. Ellman, Acc.
Chem. Res., 2012, 45, 814; (d) G. Rouquet and N. Chatani,
Angew. Chem., Int. Ed., 2013, 52, 11726; (e) Z. Chen, B. Wang,
J. Zhang, W. Yu, Z. Liu and Y. Zhang, Org. Chem. Front., 2015,
2
, 1107.
Interestingly,
2-(dimethyl(phenyl)germyl)pyridine
also
3
4
Review on removable directing groups: F. Zhang and D. R.
Spring, Chem. Soc. Rev., 2014, 43, 6906.
underwent the alkylation reaction with butylboronic acid and
the phenyl group was butylated in 26% yield (eq.2).
The pyridyldiisopropylsilyl directing group can be
quantitatively removed using AgF (Scheme 4),4a demonstrating
the practical utility of this alkylation reaction.
In conclusion, we have successfully developed
pyridyldiisopropylsilyl-directed C–H alkylation reaction with
alkylboronic acids. The amino acid, Ac-Gly-OH, played a crucial
role in the reaction. The pyridyldiisopropylsilyl directing group
can be removed or transformed into other functional groups,
so the reaction provides an efficient method for the alkylation
of arenes. The protocol is also applicable to the coupling of
C(sp3)–H bonds with alkylboronic acid.
(a) N. Chernyak, A. S. Dudnik, C. Huang and V. Gevorgyan, J.
Am. Chem. Soc., 2010, 132, 8270; (b) A. S. Dudnik, N.
Chernyak, C. Huang and V. Gevorgyan, Angew. Chem., Int.
Ed., 2010, 49, 8729; (c) C. Huang, N. Chernyak, A. S. Dudnik
and V. Gevorgyan, Adv. Synth. Catal., 2011, 353, 1285; (d) A.
V. Gulevich, F. S. Melkonyan, D. Sarkar and V. Gevorgyan, J.
Am. Chem. Soc., 2012, 134, 5528; (e) D. Sarkar, A. V. Gulevich,
F. S. Melkonyan and V. Gevorgyan, ACS Catal., 2015, 5, 6792.
5
(a) C. Huang, N. Ghavtadze, B. Chattopadhyay and V.
Gevorgyan, J. Am. Chem. Soc., 2011, 133, 17630; (b) C.
Huang, B. Chattopadhyay and V. Gevorgyan, J. Am. Chem.
Soc., 2011, 133, 12406; (c) C. Huang, N. Ghavtadze, B. Godoi
and V. Gevorgyan, Chem. Eur. J., 2012, 18, 9789.
6
7
C. Wang and H. Ge, Chem. Eur. J., 2011, 17, 14371.
Review on C–H alkylation with alkyl haldies: L. Ackermann,
Chem. Commun., 2010, 46, 4866.
Reviews on reaction of C–H bonds with organometallic
reagents: (a) C.-L. Sun, B.-J. Li and Z.-J. Shi, Chem. Commun.,
2010, 46, 677; (b) R. Giri, S. Thapa and A. Kafle, Adv. Synth.
Catal., 2014, 356, 1395.
8
Acknowledgements
The work was supported by the National Natural Science
Foundation of China (No. 21372176), Tongji University 985
Phase III funds, the Program for Professor of Special
Appointment (Eastern Scholar) at Shanghai Institutions of
Higher Learning, and Shanghai Science and Technology
Commission (14DZ2261100).
9
(a) X. Chen, C. E. Goodhue and J.-Q. Yu, J. Am. Chem. Soc.,
2006, 128, 12634; (b) R. Giri, N. Maugel, J. J. Li, D.-H. Wang, S.
P. Breazzano, L. B. Saunders and J.-Q. Yu, J. Am. Chem. Soc.,
2007, 129, 3510; (c) B.-F. Shi, N. Maugel, Y.-H. Zhang and J.-Q.
Yu, Angew. Chem., Int. Ed., 2008, 47, 4882; (d) J. A. Romero-
Revilla, A. Garcia-Rubia, R. Gomez Arrayas, M. A. Fernandez-
Ibanez and J. C. Carretero, J. Org. Chem., 2011, 76, 9525; (e)
S. R. Neufeldt, C. K. Seigerman and M. S. Sanford, Org. Lett.,
2013, 15, 2302; (f) P. S. Thuy-Boun, G. Villa, D. Dang, P.
Notes and references
Richardson, S. Su and J.-Q. Yu, J. Am. Chem. Soc., 2013, 135
,
1
Reviews on transition-metal-catalyzed C–H activation: (a) A.
A. Kulkarni and O. Daugulis, Synthesi, 2009, 24, 4087; (b) X.
Chen, K. M. Engle, D.-H. Wang and J.-Q. Yu, Angew. Chem.,
Int. Ed., 2009, 48, 5094; (c) C–H Activation. In Topics in
Current Chemistry, eds. J.-Q. Yu and Z. Shi, Springer-Verlag:
Berlin Heidelberg, Germany, 2010; (d) I. A. I. Mkhalid, J. H.
Barnard, T. B. Marder, J. M. Murphy and J. F. Hartwig, Chem.
Rev., 2010, 110, 890; (e) C. Liu, H. Zhang, W. Shi and A. Lei,
Chem. Rev., 2011, 111, 1780; (f) C. S. Yeung and V. M. Dong,
Chem. Rev., 2011, 111, 1215; (g) L. Ackermann, Chem. Rev.,
17508; (g) H. Wang, S. Yu, Z. Qi and X.-W. Li, Org. Lett., 2015,
17, 2812; (h) J. Wippich, I. Schnapperelle and T. Bach, Chem.
Commun., 2015, 51, 3166.
10 K. M. Engle and J.-Q. Yu, J. Org. Chem., 2013, 78, 8927.
11 (a) K. M. Engle, D.-H. Wang and J.-Q. Yu, Angew, Chem., Int.
Ed., 2010, 49, 6169; (b) D.-H. Wang, K. M. Engle, B.-F. Shi and
J.-Q. Yu, Science, 2010, 327, 315; (c) K. M. Engle, P. S. Thuy-
Boun, M. Dang and J.-Q. Yu, J. Am. Chem. Soc., 2011, 133
,
18183; (d) D.-W. Gao, Y.-C. Shi, Q. Gu, Z.-L. Zhao and S.-L.
You, J. Am. Chem. Soc., 2013, 135, 86; (e) G. Li, D. Leow, L.
Wan and J.-Q. Yu, Angew. Chem., Int. Ed., 2013, 52, 1245; (f)
K. J. Xiao, D. W. Lin, M. Miura, R. Y. Zhu, W. Gong, M. Wasa,
M and J.-Q. Yu, J. Am. Chem. Soc., 2014, 136, 8138; (g) R. Y.
Tang and J.-Q. Yu, Nature, 2014, 507, 215; (h) K. S. L. Chan, H.
Y. Fu and J.-Q. Yu, J. Am. Chem. Soc., 2015, 137, 2042; (i) Y.
Deng and J.-Q. Yu, Angew. Chem., Int. Ed., 2015, 54, 888; (j) B.
N. Laforteza, K. L. Chan and J.-Q. Yu, Angew. Chem., Int. Ed.,
2015, 54, 11143; (k) J. Li, S. Warratz, D. Zell, S. D. Sarkar, E. E.
2011, 111, 1315; (h) O. Baudoin, Chem. Soc. Rev., 2011, 40
,
4902; (i) S. H. Cho, J. Y. Kim, J. Kwak and S. Chang, Chem. Soc.
Rev., 2011, 40, 5068; (j) H. M. L. Davies and D. Morton, Chem.
Soc. Rev., 2011, 40, 1857; (k) L. McMurray, F. O'Hara and M. J.
Gaunt, Chem. Soc. Rev., 2011, 40, 1885; (l) T. C. Boorman and
I. Larrosa, Chem. Soc. Rev., 2011, 40, 1910; (m) J. L. Bras and
J. Muzart, Chem. Rev., 2011, 111, 1170; (n) C.-L. Sun, B.-J. Li
and Z.-J. Shi, Chem. Rev., 2011, 111, 1293; (o) J. Yamaguchi, A.
D. Yamaguchi and K. Itami, Angew. Chem., Int. Ed., 2012, 51
,
Ishikawa and L. Ackermann, J. Am. Chem. Soc., 2015, 137
,
8960; (p) N. Kuhl, M, N. Hopkinson, J. Wencel-Delord and F.
Glorius, Angew. Chem., Int. Ed., 2012, 51, 10236; (q) S. R.
Neufeldt and M. S. Sanford, Acc. Chem. Res., 2012, 45, 936;
13894. (l) X.-F. Cheng, Y. Li, Y.i-M. Su, F. Yin, J.-Y. Wang, J.
Sheng, H. U. Vora, X.-S. Wang and J.-Q. Yu, J. Am. Chem. Soc.,
2013, 135, 1236. (m) Y. Li, Y.-J. Ding, J.-Y. Wang, Y.-M. Su and
X.-S. Wang, Org. Lett., 2013, 15, 2574.
(r) G. Song, F. Wang and X. Li, Chem. Soc. Rev., 2012, 41
,
3651; (s) P. B. Arockiam, C. Bruneau and P. H. Dixneuf, Chem.
Rev., 2012, 112, 5879; (t) Carbon–Carbon σ-Bond Formation
via C–H Bond Functionalization in Comprehensive Organic
12 D.-H. Wang, M. Wasa, R. Giri and J.-Q. Yu, J. Am. Chem. Soc.,
2008, 130, 7190.
13 C. Wang, H. B. Ge, Synthesis, 2011, 16, 259.
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