α-Arylation of Saturated Azacycles and N-Methylamines via Palladium(II)-Catalyzed C(sp3)-H Coupling

Article abstract of DOI:10.1021/jacs.5b06740

Pd(II)-catalyzed α-C(sp³)-H arylation of pyrrolidines, piperidines, azepanes, and N-methylamines with arylboronic acids has been developed for the first time. This transformation is applicable to wide arrays of pyrrolidines and boronic acids, including heteroaromatic boronic acids. A diastereoselective one-pot heterodiarylation of pyrrolidines has also been achieved.

Full text of DOI:10.1021/jacs.5b06740

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Communication
#-Arylation of Saturated Azacycles and N-Methylamines
via Palladium(II)-catalyzed C(sp3)–H Coupling
Jillian E. Spangler, Yoshihisa Kobayashi, Pritha Verma, Dong-Hui Wang, and Jin-Quan Yu
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 31 Aug 2015
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α-Arylation of Saturated Azacycles and N-Methylamines via Palladium(II)-catalyzed
C(sp3)–H Coupling
Jillian E. Spangler,† Yoshihisa Kobayashi,§ Pritha Verma,† Dong-Hui Wang,† Jin-Quan Yu*†
†Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037
§Medicinal Chemistry, Eisai Product Creation Systems, Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan
promoter for reductive elimination; no product formation is
observed in the absence of 1,4-BQ.
ABSTRACT: Pd(II)-catalyzed -C(sp3)–H arylation of
pyrrolidines, piperidines, azepanes and N-methyl amines
with arylboronic acids has been developed for the first time.
This transformation is applicable to both a wide array of
pyrrolidines and boronic acids, including heteroaromatic
Scheme 1. Stoichiometric -Arylation of Pyrrolidine
boronic acids.
A
diastereoselective one-pot hetero-
diarylation of pyrrolidines is also achieved.
The prevalence of cyclic saturated amines in bioactive natural
products and pharmaceutical compounds has led to significant
interest in the functionalization of sp3 C–H bonds adjacent to
nitrogen.1 Important progress has been made in the direct
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Upon further reaction development, we found that the
formation of palladacycle 2 and subsequent cross-coupling with
phenylboronic acid can be rendered catalytic by treatment of
pyrrolidine 1 with 10 mol% Pd(TFA)2 catalyst and 1,4-BQ (Table
1). We were pleased to find that arylation of the pyrrolidine is
highly mono- selective (>20:1 mono:diarylation). It is interesting
to note that no functionalization is observed at the terminal methyl
groups of the thioamide (4), despite significant precedent for the
preferential activation of primary C–H bonds over secondary C–H
bonds.15 It is also surprising that our workhorse catalyst,
Pd(OAc)2, gives negligible amount of product (Table 1, entries 1-
6). 1,4-BQ is also uniquely successful as the oxidant in this
transformation due to facile oxidation of the thioamide with the
other oxidants that we examined, including Ag(I) salts and
peroxides; the resultant amide is an unreactive byproduct in this
directed α-arylation.
arylation of cyclic amines through α-anion2 α-radical,3-5 and α-
,
cation6 pathways. Extensive efforts at Merck led to the
development of an elegant procedure for the enantioselective
arylation
of
N-Boc-pyrrolidine
via
an
asymmetric
lithiation/Negishi coupling.2d In contrast, direct α-arylation
through catalytic transition metal-catalyzed C(sp3)–H bond
activation remains under-developed.7-11 To date, all pioneering
studies on metal-catalyzed arylation employ low-valent
ruthenium(0) catalysts, although the high reaction temperatures
(120-150 °C) required for these transformations often leads to
over-arylation and poor stereocontrol. These methods also use a
heterocyclic directing group that requires multiple steps to
remove.
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Table 1. Optimization of the -arylation of aminesa,b
In 2006, our group disclosed a method for the palladium-
catalyzed C(sp3)–H oxidation of N-methylcarbamates.12 Our early
efforts in this field, in conjunction with the high value of α-aryl
cyclic amines, prompted us to pursue the development of a
method for palladium-catalyzed α-C(sp3)–H arylation of cyclic
amines. Herein we report the discovery of a method for the direct
Pd(II)-catalyzed α-C(sp3)–H cross-coupling of pyrrolidines,
piperidines and azepanes with both aryl and heteroaryl boronic
acids, a rare of example of the coupling of methylene C–H bonds
with organometallic reagents. The excellent monoselectivity of
this reaction also enables a one-pot sequential diastereoselective
di-arylation.
Although our initial efforts to achieve Pd-catalyzed α-C(sp3)–H
arylation with carbamate or heterocyclic directing groups were
generally unsuccessful, we were inspired by a 1981 report of the
cyclopalladation of N-alkylthioamides13 to explore the α-C(sp3)–
H arylation of thioamides. As such, we were pleased to find that
the palladacycle 2 can be formed as an air-stable yellow solid
upon heating of thioamide 1 with stoichiometric Pd(PhCN)2Cl2
(Scheme 1). We further discovered that palladacycle 2 readily
undergoes efficient cross-coupling with phenyl boronic acids at
80°C in tert-amyl alcohol in the presence of a mild base and
stoichiometric 1,4-benzoquinone (1,4-BQ) to provide 2-phenyl
pyrrolidine 3 in 78% yield. This reaction can be conducted
without exclusion of oxygen with no decrease in yield. Consistent
with our early discovery of Pd(II)-catalyzed cross-coupling of C-
H bonds with organotin reagents,14 1,4-BQ is essential as a
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aReaction conditions: thioamide 1 (0.2 mmol, 1.0 eq), arylboronic acid (0.4 mmol,
2.0 eq), Pd(TFA)2 (0.02 mmol, 0.1 eq), 1,4-BQ (0.22 mmol, 1.1 eq), KHCO3 (0.4
mmol, 2.0 eq), t-AmylOH (4.0 mL), 100 °C, 4 h; bThe yield was determined by 1H
NMR analysis of the crude product using mesitylene as the internal standard.
With these optimized reaction conditions in hand, we next
evaluated the scope of the arylboronic acids that can participate in
this transformation. As shown in Table 2, this C–H arylation
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substituted (8a-8e, 51-99% yield) and 2-substituted (8g-l, 54-86%
protocol is tolerant of a broad range of coupling partners,
including both electron-rich (Table 2, entries 5a-f, 51-78% yield)
and electron- poor (Table 2, entries 5g-o, 70-80% yield) boronic
acids. However, the use of electron-rich boronic acids does lead to
slight increase in the formation of the corresponding diarylated
product (4-8%). We were pleased to find that para-, meta-, and
even sterically hindered ortho-substituted boronic acids (5a, 5k,
51-70% yield) can all be effectively coupled in this
transformation. This reaction is tolerant of a range of functional
groups, including ketones (5n, 5o, 72-80% yield), amides (5f,
78% yield), ethers (5e, 5g, 75-76% yield), and aryl halides (5h-l,
70-79% yield).
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yield) pyrrolidines couple efficiently in this transformation with
moderate to high levels of diastereoselectivity. In all cases
arylation occurs selectively at the less hindered α-methylene with
preferential formation of the trans-diastereoisomer.17 An array of
heteroatom-substituted pyrrolidines are tolerated in this
Table 3. Heteroaryl Boronic Acid Scopea,b
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Table 2. -Arylation of Pyrrolidine: Boronic Acid Scopea,b
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aReaction conditions: thioamide 1 (0.2 mmol, 1.0 eq), arylboronic acid (0.4 mmol,
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2.0 eq), Pd(TFA)2 (0.02 mmol, 0.1 eq), 1,4-BQ (0.22 mmol, 1.1 eq), KHCO3 (0.4
mmol, 2.0 eq), t-AmylOH (4.0 mL), 100 °C,
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h. bYield after isolation by
chromatography. c3 eq 1,4-BQ.
transformation (8b,c,e,h, 51-87% yield).
A (3,3,0)-bicyclic
pyrrolidine is also an effective substrate in this transformation,
providing the desired product in 92% yield (8f). An array of 2,5-
diaryl pyrrolidines can be synthesized using this protocol with
extremely high levels of diastereoselectivity (8i-l, 55-86%
yield, >20:1 dr). In accordance with our previous observation that
electron-rich boronic acids lead to higher levels of diarylation,
aryl pyrrolidines 8i,j (76-86% yield) showed higher reactivity
than aryl pyrrolidines 8k,l (55-57% yield).
Table 4. Pyrrolidine Substrate Scopea,b
aReaction conditions: thioamide 1 (0.2 mmol, 1.0 eq), arylboronic acid (0.4 mmol,
2.0 eq), Pd(TFA)2 (0.02 mmol, 0.1 eq), 1,4-BQ (0.22 mmol, 1.1 eq), KHCO3 (0.4
mmol, 2.0 eq), t-AmylOH (4.0 mL), 100 °C,
4
h. bYield after isolation by
chromatography. c1.2 eq 1,4-BQ. d1.4 eq 1,4-BQ.
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The relatively efficient coordination of the thioamide directing
group with Pd(II) catalysts led us to speculate that this coupling
reaction would be compatible with heteroarylboronic acids, which
are generally challenging coupling partners in palladium-
catalyzed C(sp3)–H functionalization reactions due to their
propensity to coordinate to the palladium catalyst. As such, we
were pleased to find that a broad range of heteroarylboronic acids
react in this transformation to provide α-heteroaryl pyrrolidines
(Table 3). Electron-rich benzofuran- and indole-containing
boronic acids are particularly good coupling partners and provide
the corresponding pyrroldine products in excellent yields (6a-c,
58-82% yield). A variety of substituted pyridinylboronic acids can
be effectively coupled in good yield with complete mono-
selectivity (6d-h, 51-76% yield). However, the coupling of
unsubstituted pyridinylboronic acids was not successful under
current conditions. Presumably, the pyridyl outcompetes the
thioamide for coordinating with Pd catalyst. Similar
phenonmenon have been observed in asymmetric hydrogenation
of 2-pyridyl cyclic imines.16
aReaction conditions: thioamide 7 (0.2 mmol, 1.0 eq), arylboronic acid (0.4 mmol,
2.0 eq), Pd(TFA)2 (0.02 mmol, 0.1 eq), 1,4-BQ (0.4 mmol, 2.0 eq), KHCO3 (0.4
mmol, 2.0 eq), t-AmylOH (4.0 mL), 100 °C, 4 h. bYields after isolation by
chromatography. c0.15 eq Pd(TFA)2 (0.03 mmol). d1.4 eq 1,4-BQ (0.28 mmol), 0.15
eq Pd(TFA)2 (0.03 mmol).
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We next turned our attention to the scope of pyrrolidines that
can be used in this transformation. As shown in Table 4, 3-
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We subsequently found that this arylation can be extrapolated
In examining the reactivity of other N,N-dialkylthioamides in
our α-C(sp3)–H arylation reaction, we discovered that N-methyl
thioamides are also competent substrates in this transformation.
As shown in Table 6, a variety of N-methyl thioamides can be
arylated to provide the corresponding benzyl thioamides in good
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into a consecutive one-pot hetero-diarylation of pyrrolidines to
provide 2,5-diarylated pyrrolidine products (Table 5). All of these
reactions proceed with complete diastereoselectivity (>20:1 dr).
Notably, this one-pot procedure does not require the addition of a
second batch of palladium catalyst. We observed that the use of a
more mono-selective electron-deficient boronic acid in the first
arylation step provides higher yields of the hetero-diarylated
product with negliable formation of the undesired homo-
diarylated byproducts.
yield (11a-e, 68-94% yield). The reaction of N-methyl thioamides
with both electron-rich and electron-deficient heteroarylboronic
acids can also be achieved (11f-h, 77-99% yield). In all cases the
reaction is completely regioselective; no methylene C(sp3)–H
arylation is observed. Surprisingly, N-methyl anilines also
undergo regioselective α-C(sp3)–H arylation (11i-k, 51-75%
yield) without reacting at the ortho-positions of the aryl group.
Table 5. One-pot Hetero-diarylation of Pyrrolidinesa,b
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We also explored the application of our methodology to the
arylation of larger azacycles. As shown in Scheme 2, azepane 12
undergoes arylation in good yield under standard reaction
conditions (13, 68% yield). In contrast, the arylation of piperidine
14a proceeds in poor yield, even with addition of a large excess of
1,4-BQ (15a, 13% yield). Further studies demonstrated that, while
palladacycle formation from 14a is facile, the rate reductive
elimination is significantly slower than reductive elimination from
complex 2. As such, we hoped to optimize this transformation via
the use of a more bulky thioamide directing group in order to
promote reductive elimination.18 We were pleased to find that the
use of a the bulky 2,2-diethylbutanoic acid directing group (14b)
provides the corresponding product in excellent yield without
formation of any diarylated byproduct (15b, 92% yield).
Scheme 2. Arylation of Larger Azacycles
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aReaction conditions: thioamide 1 (0.2 mmol, 1.0 eq), arylboronic acid-1 (0.4 mmol,
2.0 eq), Pd(TFA)2 (0.02 mmol, 0.1 eq), 1,4-BQ (0.28 mmol, 1.4 eq), KHCO3 (0.4
mmol, 2.0 eq), t-AmylOH (4.0 mL), 100 °C, 4 h then arylboronic acid-2 (0.4 mmol,
2.0 eq), 1,4-BQ (0.4 mmol, 2.0 eq), 12 h. bYield after isolation by chromatography,
dr determined by 1H NMR.
Lastly, these arylated products can be readily deprotected by
cleavage of the thioamide to the corresponding amine with methyl
lithium at 0 °C in good yield after protection as the Boc-
carbamate 16 (73% yield, Scheme 3).19 Alternatively, the
thioamide 1 can be converted to amide 17 by oxidation with
silver(II)-salts in nearly quantitative yield.
Table 6. Arylation of N-Methylaminesa,b
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Scheme 3. Deprotection of Thioamide
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In conclusion, we have demonstrated the -arylation of
saturated azacycles and N-methyl amines via Pd(II)-catalyzed
C(sp3)–H coupling with boronic acids. This method allows for
highly monoselective arylation as well as sequential
diastereoselective di-arylation of pyrrolidines. The successful C–
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H
coupling of pyrrolidines with aryl boronic acids also
demonstrates the first example of Pd-catalyzed cross-coupling of
methylene C–H bonds with organometallic reagents.
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AUTHOR INFORMATION
Corresponding Author
yu200@scripps.edu
aReaction conditions: thioamide 10 (0.2 mmol, 1.0 eq), arylboronic acid (0.4 mmol,
Acknowledgements. We gratefully acknowledge The Scripps
Research Institute, EISAI Co., ltd, and the NIH (NIGMS,
2.0 eq), Pd(TFA)2 (0.02 mmol, 0.1 eq), 1,4-BQ (0.4 mmol, 2.0 eq), KHCO3 (0.4
mmol, 2.0 eq), t-AmylOH (4.0 mL), 100 °C,
4
h. bYield after isolation by
chromatography. c1.0 eq 1,4-BQ (0.2 mmol).
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into -C–H bonds of amines: c) Lu, C. C.; Peters, J. C. J. Am. Chem. Soc.
2R01GM084019) for financial support. We thank Dr. Richard
Clark from Eisai for helpful discussions.
2004, 126, 15818-15832.
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Supporting Information Available: Experimental procedures and
spectral data. This material is available free of charge via the Internet
at http://pubs.acs.org.
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Asaumi, T.; Yorimitsu, S.; Ikeda, T.; Kakiuchi, F.; Murai, S. J. Am. Chem.
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Aelvoet, K.; Diels, G.; Meerpoel, L.; Maes, B. U. W. Chem. Eur. J. 2012,
18, 10393-10398; e) Schmitt, D. C.; Lee, J.; Dechert-Schmitt, A.-M.;
Yamaguchi, E.; Krische, M. J. Chem. Commun., 2013, 49, 6096-6098; f)
Schinkel, M.; Wang, L.; Bielefeld, K.; Ackermann, L. Org. Lett. 2014, 16,
1876-1879.
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(10) For references on Ir-catalyzed alkenylation of amides see: a) Tsuchikama,
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Pan, S. Matsuo, Y.; Endo, K.; Shibata, T. Tetrahedron, 2012, 68, 9009-
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(11)For references on the Rh/Ir-catalyzed borylation of amines and amides see:
a) Kawamorita, S.; Miyazaki, T.; Iwai, T.; Ohmiya, H.; Sawamura, M. J.
Am. Chem. Soc. 2012, 134, 12924-12927; b) Li, Q.; Liskey, C. W.; Hartwig,
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E. I.; Livantsov, M. V.; Grishin, Y. K.; Kuzmina, L. G.; Churakov, A. V.
Russ. Chem. Bull., Int. Ed., 2006, 55, 2193-2211; e) For direct Pd insertion
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