Enantioselective ortho-C H Cross-Coupling of Diarylmethylamines with Organoborons

Article abstract of DOI:10.1002/anie.201505204

The commonly used para-nitrobenzenesulfonyl (nosyl) protecting group is employed to direct the C H activation of amines for the first time. An enantioselective ortho-C H cross-coupling between nosyl-protected diarylmethylamines and arylboronic acid pinaco

Full text of DOI:10.1002/anie.201505204

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201505204
German Edition: DOI: 10.1002/ange.201505204
CÀH Activation
À
Enantioselective ortho-C H Cross-Coupling of Diarylmethylamines
with Organoborons
Brian N. Laforteza, Kelvin S. L. Chan, and Jin-Quan Yu*
Abstract: The commonly used para-nitrobenzenesulfonyl
arylmethylamines with arylboronic acid pinacol esters, adding
a valuable example to the intensively pursued development of
(
nosyl) protecting group is employed to direct the CÀH
[
7,8]
activation of amines for the first time. An enantioselective
enantioselective CÀH activation reactions.
The newly
ortho-CÀH cross-coupling between nosyl-protected diarylme-
established reactivity of nosylamides also paves the way for
thylamines and arylboronic acid pinacol esters has been
achieved utilizing chiral mono-N-protected amino acid
the further development of practical CÀH activation trans-
formations of amines.
(
MPAA) ligands as a promoter.
As illustrated in Scheme 1, we initiated our studies by
attempting the nosylamide-directed Csp
2
ÀH arylation of
D
espite extensive efforts to develop CÀH activation reac-
[1]
tions of broadly useful substrates using weak coordination,
design of practical directing groups for amines has been met
with limited success. While triflyl-protected amines have
demonstrated a relatively broad scope of both substrates
(
benzylamines, phenylethylamines, and propyl amines) and
transformations (iodination, olefination, fluorination, and
[
2]
amination), the use of expensive and corrosive triflic
anhydride for installation of the triflyl moiety, as well as the
[2a,c]
Scheme 1. Nosyl-directed Csp2ÀH activation.
relatively harsh procedures required for removal,
limits its
appeal as a synthetically useful directing group. Alternative
two-step deprotection conditions have been developed, but
have proven incompatible with compounds bearing acidic a-
hydrogens due to the potential for deprotonation, which
simple benzyl- and phenethylamines. From these preliminary
experiments, we were delighted to find that nosyl-protected
amines indeed proved to be viable directing groups for CÀH
[2e–g]
could lead to a variety of decomposition pathways.
The
[2g]
recent success in the development of enantioselective iodi-
nations of triflyl-protected amines by desymmetrization and
activation. Similar to the triflamide-directed CÀH coupling,
the use of NaHCO is required to deprotonate the sulfon-
3
[
2e,f]
kinetic resolution
has provided us incentive to seek
amide for coordination. Ag CO acts both as oxidant for the
2
3
0
a practical directing group for amine substrates to allow for
reoxidation of Pd and as promoter for the coupling step.
DMSO prevents Pd species from aggregation. Since chiral
[
3]
0
a rapid synthesis of valuable chiral amine scaffolds.
II
Although there have been a few reports of Pd -catalyzed
diarylmethylamines are known to be medicinally important
scaffolds, with ortho-substituted diarylamines in particular
[4]
CÀH arylation reactions directed by free and tertiary
[
5]
amines, the scope of these transformations is limited due
having been known to display a range of bioactivity including
[4a,b]
[9,10]
to the strongly acidic conditions required,
and the use of
g-secretase modulation and HPV inhibition (Figure 1),
we
[5]
directing groups that cannot be easily removed. The
development of CÀH activation reactions of amines employ-
ing commonly used synthetic protecting groups is a prereq-
uisite for broad applications of CÀH activation in amine
synthesis. To the best of our knowledge there are no known
protocols for the directed CÀH functionalization of the
commonly employed nosyl-protected amine (nosyl = para-
nitrobenzenesulfonyl), due to a lack of reactivity of the
nosylamide under a variety of previously developed CÀH
[
6]
activation conditions. Herein, we report a ligand-promoted
Figure 1. Bioactive ortho-aryl diarylmethylamines.
enantioselective ortho-CÀH coupling of nosyl-protected di-
redirected our focus toward the enantioselective cross-
coupling of prochiral diarylmethylamine 1 with para-me-
thoxycarbonylphenylboronic acid pinacol ester.
[
*] Dr. B. N. Laforteza, K. S. L. Chan, Prof. Dr. J.-Q. Yu
Department of Chemistry, The Scripps Research Institute
1
0550 N. Torrey Pines Road, La Jolla, CA 92037 (USA)
E-mail: yu200@scripps.edu
We were pleased to find that inclusion of the MPAA
ligand Ac-Ala-OH afforded the desired arylated product 2 in
62% yield and 76% ee. After an extensive survey of readily
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201505204.
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[
a]
Table 1: Ligand evaluation.
[
b]
[c]
Entry
Ligand
T [8C]
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
9
Ac-l-Val-OH
100
100
100
100
100
100
100
80
62
66
65
43
71
67
63
63
83
90
76
84
89
88
90
87
89
91
96
96
Boc-l-Val-OH
Fmoc-l-Val-OH
Troc-l-Val-OH
Boc-l-Leu-OH
Boc-l-Phe-OH
Fmoc-l-Ala-OH
Fmoc-l-Val-OH
Fmoc-l-Val-NHOMe
Fmoc-l-Leu-NHOMe
80
80
[
d]
1
0
[
a] Reaction conditions: 0.1 mmol of substrate, 2 equiv ArBPin, 0.1 equiv
Pd(OAc) , 0.2 equiv ligand, 2.5 equiv Ag CO , 6 equiv NaHCO , 0.5 equiv
2
2
3
3
1
,4-benzoquinone, 10 mL H O, 2.8 mL DMSO, 1 mL t-amylOH. [b] Yield
2
1
determined by H NMR analysis using 1,3-benzodioxole as an internal
standard. [c] Enantioselectivity determined by HPLC analysis on a chiral
stationary phase. [d] 0.15 equiv ligand.
available MPAA ligands (see the Supporting Information),
we quickly narrowed down our options to carbamate-
protected, aliphatic amino acids. As shown in Table 1,
Fmoc-Val-OH provided 2 in 65% yield and 89% ee
(
entry 3). Lower temperatures (808C) could also be employed
without sacrificing reaction efficiency (entry 8, 63% yield,
1% ee). In addition, by substituting the acid moiety of the
9
ligand with an N-methoxyamide, a noticeable boost in both
yield and enantioselectivity was observed (entry 9, 83% yield,
9
6% ee). It was quickly found that Fmoc-Leu-NHOMe
proved to be the optimal ligand for this enantioselective cross-
coupling protocol (entry 10, 90% yield, 96% ee).
The absolute configuration of arylated product 2 was
determined by X-ray crystallography (Figure 2). The
Scheme 2. Arylboronic acid pinacol ester scope. [a] Reaction condi-
tions: 0.1 mmol of substrate, 2 equiv ArBPin, 0.1 equiv Pd(OAc)2,
0
.15 equiv ligand, 2.5 equiv Ag CO , 6 equiv NaHCO , 0.5 equiv 1,4-
2 3 3
2
benzoquinone, 10 mL H O, 2.8 mL DMSO, 1 mL t-amylOH. [b] Yield of
isolated product. [c] Enantioselectivity determined by HPLC analysis on
a chiral stationary phase.
Figure 2. X-ray crystal structure of (R)-2a.
observed enantioselectivity is rationalized with a stereochem-
ical model analogous to one previously proposed,
and nitrile-substituted arylboron compounds afforded the
desired products in good yield (2c–f; 68–73% yield, 95–96%
ee), and both esters and ketones proved stable under the
reaction conditions (2a, 2b, 2g; 64–90% yield, 93–96% ee).
Furthermore, halogen substitution was also well tolerated, as
evidenced by arylated products 2h–j bearing chlorine and
fluorine atoms (65–84% yield, 96–97% ee). Electron-rich
arylboronic acid pinacol esters also performed well in this
reaction (2m, 2n; both 88% yield, 97% ee), as did disub-
stituted electron-deficient arylboron reagents (2b, 2k, 2l).
[2e,11]
wherein the deprotonated anionic sulfonamide coordinates
to the palladium(II) center through the imine moiety,
facilitating selective CÀH cleavage.
After elucidation of the optimized reaction conditions, we
next investigated the scope of the arylboronic acid coupling
partner. As demonstrated in Scheme 2, a variety of arylboron
reagents coupled smoothly to provide arylated products with
excellent levels of enantioselectivity. Trifluoromethyl-, nitro-,
1
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para-nitrobenzenesulfonamide as a directing group. Further
development of CÀH functionalizations directed by nosyl-
protected amines and other widely used protecting groups is
currently underway in our laboratory.
Experimental Section
General procedure for the enantioselective arylation of nosyl-
protected diarylmethylamines: nosylamide substrate (0.1 mmol),
aryl boronic acid pinacol ester (2 equiv), Pd(OAc)2 (0.1 equiv),
amino acid ligand (0.15 equiv), NaHCO (6 equiv), Ag CO (2 equiv),
3
2
3
and 1,4-benzoquinone (0.5 equiv) were added to a sealable Schlenk
tube, and a solution of H O (10 mL) and DMSO (2.8 mL) in t-AmOH
2
(
(
1 mL), and the reaction vessel was evacuated and backfilled with N2
3 ”). The Schlenk tube was sealed, and the mixture was stirred
vigorously at 808C. After 18 h, the reaction was cooled to room
temperature, EtOAc was added (5 mL), and the reaction was filtered
through a pad of Celite over a plug of silica gel, and eluted with
EtOAc (30 mL). The crude solution was concentrated in vacuo, and
the residue purified by preparative thin layer chromatography to
produce the corresponding chiral amines as white or pale yellow
solids.
Scheme 3. Diarylmethylamine substrate scope. [a] Reaction conditions:
.1 mmol of substrate, 2 equiv ArBPin, 0.1 equiv Pd(OAc) , 0.15 equiv
0
2
Fmoc-l-Leu-NHOMe, 2.5 equiv Ag CO , 6 equiv NaHCO , 0.5 equiv
2
3
3
Acknowledgements
1
,4-benzoquinone, 10 mL H O, 2.8 mL DMSO, 1 mL t-amylOH. [b] Yield
2
of isolated product. [c] Enantioselectivity determined by HPLC analysis
on a chiral stationary phase.
We gratefully acknowledge The Scripps Research Institute
and the NIH (NIGMS, 2R01GM084019) for financial sup-
port. K.S.L.C. thanks the Agency for Science, Technology and
Research (A*STAR), Singapore, for a predoctoral fellowship.
We also examined the scope of the diarylmethylamines
(
Scheme 3). Substitution on the diarylmethylamine was well
tolerated, allowing for both electron-rich and electron-
deficient substrates to readily undergo cross-coupling with
high levels of enantioselectivity. Halogenated diarylmethyl-
amines also underwent coupling smoothly (entries 4d–4 f, 60–
Keywords: amino acid ligands · CÀH activation · CÀH coupling ·
enantioselective catalysis · palladium
How to cite: Angew. Chem. Int. Ed. 2015, 54, 11143–11146
Angew. Chem. 2015, 127, 11295–11298
9
0% yield, 93–97% ee). Both ortho- and meta-substituted
substrates provided monoarylated products; however, unsub-
stituted or para-substituted substrates led predominantly to
diarylation (entries 4g–4i, 47–84% yield of diarylated prod-
ucts).
[
1] K. M. Engle, T.-S. Mei, M. Wasa, J.-Q. Yu, Acc. Chem. Res. 2012,
5, 788 – 802.
4
[
2] a) J.-J. Li, T.-S. Mei, J.-Q. Yu, Angew. Chem. Int. Ed. 2008, 47,
6452 – 6455; Angew. Chem. 2008, 120, 6552 – 6555; b) X. Wang,
T.-S. Mei, J.-Q. Yu, J. Am. Chem. Soc. 2009, 131, 7520 – 7521;
c) T.-S. Mei, X, Wang, J.-Q. Yu, J. Am. Chem. Soc. 2009, 131,
10806 – 10807; d) C. J. Vickers, T.-S. Mei, J.-Q. Yu, Org. Lett.
To demonstrate the synthetic utility of the para-nitro-
benzenesulfonamide directing group, we next sought to
remove the nosyl moiety from the arylated product under
[12]
mildly basic conditions with gentle heating. As illustrated in
Scheme 4, deprotection proceeded smoothly in the presence
of para-methoxythiophenol and potassium carbonate at 408C
to afford the corresponding free amine 5 in 84% yield.
2
010, 12, 2511 – 2513; e) L. Chu, X.-C. Wang, C. E. Moore, A. L.
Rheingold, J.-Q. Yu, J. Am. Chem. Soc. 2013, 135, 16344 – 16347;
f) L. Chu, K.-J. Xiao, J.-Q. Yu, Science 2014, 346, 451 – 455;
g) K. S. L. Chan, M. Wasa, L. Chu, B. N. Laforteza, M. Miura, J.-
Q. Yu, Nat. Chem. 2014, 6, 146 – 150; h) K. S. L. Chan, H. Fu, J.-
Q. Yu, J. Am. Chem. Soc. 2015, 137, 2042 – 2046.
[
3] a) For a review on synthesis of chiral diarylmethylamines, see: F.
Schmidt, R. T. Stemmler, J. Rudolph, C. Bolm, Chem. Soc. Rev.
2
006, 35, 454 – 470; b) For a review on the use of tert-butane-
sulfinamide as a chiral auxiliary for asymmetric additions into
imines, see: M. T. Robak, M. A. Herbage, J. A. Ellman, Chem.
Rev. 2010, 110, 3600 – 3740; c) For a review on the synthesis of
chiral amines by addition into imines, see: S. Kobayashi, Y. Mori,
J. S. Fossey, M. M. Salter, Chem. Rev. 2011, 111, 2626 – 2704; For
applications of tert-butanesulfinamide in the synthesis of diaryl-
methylamines, see: d) D. A. Pflum, D. Krishnamurthy, Z. Han,
S. A. Wald, C. H. Senanayake, Tetrahedron Lett. 2002, 43, 923 –
Scheme 4. Deprotection of nitrobenzenesulfonyl protecting group.
In conclusion, we have developed an enantioselective
cross-coupling of diarylmethylamine Csp
2
ÀH bonds and aryl-
boronic acid pinacol esters, using chiral amino acids and N-
methoxyamides to induce asymmetry. Notably, this protocol
exploits the synthetically practical and easily deprotected
9
3
26; e) N. Plobeck, D. Powell, Tetrahedron: Asymmetry 2002, 13,
03 – 310; f) D. J. Weix, Y. Shi, J. A. Ellman, J. Am. Chem. Soc.
2005, 127, 1092 – 1093; g) Y. Bolshan, R. A. Batey, Org. Lett.
Angew. Chem. Int. Ed. 2015, 54, 11143 –11146
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 11145

.
Angewandte
Communications
2
2
005, 7, 1481 – 1484; h) T. A. Boebel, J. F. Hartwig, Tetrahedron
Baudoin, Chem. Eur. J. 2012, 18, 4480 – 4484; e) R. Shintani, H.
Otomo, K. Ota, T. Hayashi, J. Am. Chem. Soc. 2012, 134, 7305 –
7308.
008, 64, 6824 – 6830.
II
[
4] For examples of Pd -catalyzed CÀH arylations directed by free
amines (RNH ), see: a) A. Lazareva, O. Daugulis, Org. Lett.
[8] For atropselective CÀH activation with moderate enantioselec-
2
2
006, 8, 5211 – 5213; b) Z. Liang, R. Feng, H. Yin, Y. Zhang, Org.
tivities: a) F. Kakiuchi, P. Le Gendre, A. Yamada, H. Ohtaki, S.
Murai, Tetrahedron: Asymmetry 2000, 11, 2647 – 2651; b) K.
Yamaguchi, J. Yamaguchi, A. Studer, K. Itami, Chem. Sci. 2012,
3, 2165 – 2169.
Lett. 2013, 15, 4544 – 4547; c) Z. Liang, J. Yao, K. Wang, H. Li, Y.
Zhang, Chem. Eur. J. 2013, 19, 16825 – 16831; d) M. Miura, C.-G.
Feng, S. Ma, J.-Q. Yu, Org. Lett. 2013, 15, 5258 – 5261.
II
[
5] Pd -catalyzed CÀH functionalizations directed by tertiary
[9] For examples of medicinally relevant compounds bearing chiral
diarylmethylamines, see: a) C. M. Spencer, D. Foulds, D. H.
Peters, Drugs 1993, 46, 1055 – 1080; b) M. J. Bishop, R. W.
McNutt, Bioorg. Med. Chem. Lett. 1995, 5, 1311 – 1314; c) E. J.
Bilsky, S. N. Calderon, N. Silvia, T. Wang, R. N. Bernstein, P.
Davis, V. J. Hruby, R. W. McNutt, R. B. Rothman, K. C. Rice, F.
Porreca, J. Pharmacol. Exp. Ther. 1995, 273, 359 – 366; d) S.
Sakurai, N. Ogawa, T. Suzuki, K. Kato, T. Ohashi, S. Yasuda, H.
Kato, Y. Ito, Chem. Pharm. Bull. 1996, 44, 765 – 777; e) N.
Plobeck, D. Delorme, Z.-Y. Wei, H. Yang, F. Zhou, P. Schwarz,
L. Gawell, H. Gagnon, B. Pelcman, R. Schmidt, S. Y. Yue, C.
Walpole, W. Brown, E. Zhou, M. Labarre, K. Payza, S. Stçnge,
A. Kamassah, P. -E. Morin, D. Projean, J. Ducharme, E. Roberts,
J. Med. Chem. 2000, 43, 3878 – 3894.
amines (R N), see: a) G. Cai, Y. Fu, Y. Li, X. Wan, Z. Shi, J.
3
Am. Chem. Soc. 2007, 129, 7666 – 7673; b) D.-W. Gao, Y.-C. Shi,
Q. Gu, Z.-L. Zhao, S.-L. You, J. Am. Chem. Soc. 2013, 135, 86 –
8
9; c) R. Feng, J. Yao, Z. Liang, Z. Liu, Y. Zhang, J. Org. Chem.
013, 78, 3688 – 3696; d) P. W. Tan, M. Haughey, D. J. Dixon,
2
Chem. Commun. 2015, 51, 4406 – 4409.
II
[
6] For selected examples of Pd -catalyzed arylations directed by
specific directing groups, see: a) O. Daugulis, V. G. Zaitsev,
Angew. Chem. Int. Ed. 2005, 44, 4046 – 4048; Angew. Chem.
2
Daugulis, J. Am. Chem. Soc. 2005, 127, 13154 – 13155; c) S.
Yang, B. Li, X. Wan, Z. Shi, J. Am. Chem. Soc. 2007, 129, 6066 –
6
005, 117, 4114 – 4116; b) V. G. Zaitsev, D. Shabashov, O.
067; d) B. Haffemayer, M. Gulias, M. J. Gaunt, Chem. Sci. 2011,
2
, 312 – 315; e) E. T. Nadres, G. I, F. Santos, D. Shabashov, O.
[10] a) Y. S. Tsantrizos, A.-M. Faucher, J. Rancourt, P. White,
WO2004108673, 2004; b) S. Sato, T. Nakamura, F. Nara, K.
Yonesu, JP2005120047, 2005; c) H. Peng, J. Cuervo, A. Ish-
chenko, G. Kumaravel, W.-C. Lee, A. Lugovskoy, T. Talreja, A.
Taveras, Z. Xin, WO2010138901, 2010.
Daugulis, J. Org. Chem. 2013, 78, 9689 – 9714; f) N. Rodríguez,
J. A. Romero-Revilla, M. . Fernµndez-IbµÇez, J. C. Carretero,
Chem. Sci. 2013, 4, 175 – 179; g) J. Han, P. Liu, C. Wang, Q.
Wang, J. Zhang, Y. Zhao, D. Shi, Z. Huang, Y. Zhao, Org. Lett.
2
014, 16, 5682 – 5685.
[11] G.-J. Cheng, Y.-F. Yang, P. Liu, P. Chen, T.-Y. Sun, G. Li, X.
Zhang, K. N. Houk, J.-Q. Yu, Y.-D. Wu, J. Am. Chem. Soc. 2014,
136, 894.
0
[
7] For Pd -catalyzed enantioselective intramolecular CÀH aryla-
tion: a) M. R. Albicker, N. Cramer, Angew. Chem. Int. Ed. 2009,
4
8, 9139 – 9142; Angew. Chem. 2009, 121, 9303 – 9306; b) M.
[12] D. C. Cranfill, M. A. Lipton, Org. Lett. 2007, 9, 3511 – 3513.
Nakanishi, D. Katayev, C. Besnard, E. P. Kündig, Angew. Chem.
Int. Ed. 2011, 50, 7438 – 7441; Angew. Chem. 2011, 123, 7576 –
7
4
579; c) S. Anas, A. Cordi, H. B. Kagan, Chem. Commun. 2011,
7, 11483 – 11485; d) N. Martin, C. Pierre, M. Davi, R. Jazzar, O.
Received: June 8, 2015
Published online: August 4, 2015
1
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