Palladium-catalyzed regio- and stereoselective β-arylation of tertiary allylic amines: Identification of potent adenylyl cyclase inhibitors

Article abstract of DOI:10.1021/ol503748t

Substituted allylic amines and their derivatives are key structural motifs of many drug molecules and natural products. A general, mild, and practical palladium-catalyzed β-arylation of tertiary allylic amines, one of the most challenging Heck arylation substrates, has been developed. The β-arylation products were obtained in excellent regio- and stereoselectivity. Moreover, novel and potent adenylyl cyclase inhibitors with the potential for treating neuropathic and inflammatory pain have been identified from the β-arylation products.

Full text of DOI:10.1021/ol503748t

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Regio- and Stereoselective γ‑Arylation of
Tertiary Allylic Amines: Identification of Potent Adenylyl Cyclase
Inhibitors
Zhishi Ye,† Tarsis F. Brust,‡ Val J. Watts,*,‡ and Mingji Dai*,†
‡
†Department of Chemistry and Center for Cancer Research and Department of Medicinal Chemistry & Molecular Pharmacology,
Purdue University, West Lafayette, Indiana 47907, United States
S
* Supporting Information
ABSTRACT: Substituted allylic amines and their derivatives
are key structural motifs of many drug molecules and natural
products. A general, mild, and practical palladium-catalyzed γ-
arylation of tertiary allylic amines, one of the most challenging
Heck arylation substrates, has been developed. The γ-arylation
products were obtained in excellent regio- and stereo-
selectivity. Moreover, novel and potent adenylyl cyclase
inhibitors with the potential for treating neuropathic and inflammatory pain have been identified from the γ-arylation products.
γ-Arylated N,N-dialkylallylamines are ubiquitous structural
motifs and have been widely found in biologically active
natural products, life-saving drugs, and other molecules of
important functions.1 For example, naftifine (1, Figure 1A) is
an allylamine antifungal drug and selectively blocks sterol
biosynthesis via inhibition of the squalene 2,3-expoxidase
enzyme.2 Cinnarizine (2) and flunarizine (3) are effective
calcium channel blockers and are characterized as antihist-
amines. They have been widely used for various conditions
such as nausea, vertigo, migraine, and vascular diseases.3
Abamine SG (4) is an abscisic acid biosynthesis inhibitor to
target 9-cis-epoxycarotenoid dioxygenase.4 Various strategies
have been developed for the construction of γ-arylated N,N-
dialkylallylamine derivatives.5 One of the most desirable and
straightforward ways would be a Heck arylation of N,N-
dialkylallylamines at the terminal olefinic carbon (γ-position).
In general, Heck arylations work well with activated and biased
olefins such as acrylates and styrenes.6 Recently, significant
progress in the Heck arylation of electronically nonbiased
olefins have been made by the groups of Sigman (cf. eq 1,
Figure 1B), Zhou, Jamison, Stahl, and others.7 Because of these
elegant studies, regio- and stereoselective arylations of simple
terminal olefins such as allylic alcohols, homoallylic alcohols,
and other unactivated olefins have become important and
powerful synthetic tools in preparing complex and functional
molecules.
predominantly due to the intrinsic directing ability of the
nitrogen atom (eq 2, Figure 1B).8 (II) Oxidative addition of
palladium(0) catalyst with allylamines to form π-allyl palladium
species competes with the Heck arylation, which renders
allylamines as allyl group donors (eq 3, Figure 1B) or amine
sources.8a Zhang and Tan have independently reported elegant
examples of using allylamines as allyl donors.9 (III) Selective β-
hydride elimination (Ha vs Hb, eq 5, Figure 1B) to form the
desired product remains as an issue as well. In order to get
around these intrinsic competing factors and obtain desired γ-
arylated products, protecting and directing group strategies
have been employed (eq 4, Figure 1B).10 The basic nitrogen
atoms are masked as amides, carbamates, etc. The protecting
groups also serve as directing groups to ensure the arylation
takes place at the γ-position. Still, in some of these cases poor
regioselectivity or β-arylation were obtained.11 In addition to
the installation of the required protecting and directing groups,
extra steps are required to remove them or convert them to the
desired alkyl groups. Our recent need of diverse γ-arylated N,N-
dialkylallylamines with potential CNS activity12 (cf. 7aa, Table
1) prompted us to develop a straightforward synthesis of them
(eq 5, Figure 1B). Herein, we report a mild palladium-catalyzed
regio- and stereoselective γ-arylation of N,N-dialkylallylamines
and the identification of potent adenylyl cyclase inhibitors with
therapeutic potential for treating neuropathic and inflammatory
pain from the arylation products.
Since aryl diazonium salts have been used frequently in Heck
arylation of nonactivated olefins,7d our investigation started
with phenyl diazonium tetrafluoroborate (6a) and a relatively
complex and challenging allylic amine substrate, 5a. In order to
override the intrinsic coordination of the tertiary nitrogen with
palladium center to control the regioselectivity, 2,2′-bipyridine
Despite these significant advancements, stereoselective γ-
arylation of N,N-dialkylallylamines persists as a great synthetic
challenge due to the following difficulties presented by N,N-
dialkylallylamine substrates. (I) The strong basicity and
coordinating capability of these tertiary amines make most of
the Heck arylation conditions invalid for γ-arylation. For
example, Hallberg and Wu have independently reported
palladium-catalyzed Heck arylation of N,N-dialkylallylamines,
and in both cases, β-arylated products were obtained
Received: December 29, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ol503748t
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Condition Optimization
b
yield
entry
Pd cat.
x
y
solvent ligand
base
(%)
1
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(OAc)2
PdCl2
1.5
1.5
1.5
1.5
1.5
2.0
2.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
5
DMF
DMA
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
54
33
2
5
5
c
3
49
4
5
Et3N
0
5
5
K2CO3
0
6
5
73
71
80
85
81
54
90
54
55
trace
trace
7
5
8
8
9
10
10
10
10
10
10
10
10
10
11
12
13
14
15
16
L4
L4
L4
Pd(PPh3)4
Figure 1. Selected allylic amine drugs, Heck arylation of nonbiased
olefins, current status of arylation of allylic amine derivatives, and our
method.
a
General reaction conditions unless otherwise noted: A mixture of
palladium catalyst and ligand in DMF was stirred at rt for 20 min
under argon before 5a and 6a were added. The reaction mixture was
b
stirred at rt and monitored by thin-layer chromatography. Isolated
reaction yield. 60 °C.
c
ligand L1 was selected. When 5a (1 equiv) and 6a (1.5 equiv)
were subjected to the conditions of Pd(dba)2 with L1 (Pd:L =
1:1.2) at room temperature in DMF, the desired product 7aa
was obtained in 54% yield. Other solvents such as THF,
CH3CN, DMSO, and DMA are inferior to DMF or completely
inhibit the reaction (see the Supporting Information). Slightly
reduced yield was obtained when the reaction was conducted at
an elevated temperature (entry 3). Bases such as triethylamine
and K2CO3 shut down the reaction (entries 4 and 5). A further
increase in the amount of 6a or the catalyst−ligand loading has
beneficial effects. We also found that among the four nitrogen-
containing bidentate ligands tested, L4 gave the best result
(entry 12). The reaction yield dropped significantly when
several bidentate phosphine ligands were used (see the
Supporting Information). Other palladium catalysts including
PdCl2, Pd(PPh3)4, and Pd(OAc)2 were less effective than
Pd(dba)2. Overall, under the optimized conditions (entry 12),
the desired product could be produced in 90% yield with
excellent regio- and stereoselectivity.
We then evaluated the substrate scope. As summarized in
Figure 2, this reaction is very general and compatible with many
functional groups including halogens (I, Br, Cl, and F), ester
groups, amides, nitro groups, and indoles. Diazonium salts with
both electron-withdrawing and electron-donating groups are
effective coupling partners. A variety of γ-arylated N,N-
dialkylallylamines were produced in good to excellent yield,
including those derived from azepanes, diazepanes, and
piperazines. Notably, we were able produce naftifine (1) in
90% yield. When the reaction was conducted on a gram scale,
naftifine (1) was obtained in 72% yield. Cinnarizine (2) and
flunarizine (3) were synthesized smoothly as well, while the
corresponding substrates present several challenging factors
including two basic nitrogen atoms, potential debenzylation,
and deallylation reactions.
Additionally, these γ-arylated products could be converted to
other useful products as well (Scheme 1). For example, amine
oxidation followed by [2,3]-sigmatropic rearrangement con-
verted 1 to 11.13 Dihydroxylation or hydrogenation converted
1 to 12 or 13, respectively, in good yields. A one-pot, double-
bond isomerization followed by Picktet−Spengler reaction
coverted 7aa to tetrahydro-β-carboline 14.14 The latter
represents the core structure of many bioactive natural products
and pharmaceutical molecules.15
We then evaluated these γ-arylated N,N-dialkylallylamine
products for their ability to inhibit adenylyl cyclase activity.
Adenylyl cyclases are enzymes that catalyze the production of
cAMP from ATP. These enzymes are very important mediators
of signaling through G protein-coupled receptors.16 There are
nine different isoforms of membrane-bound adenylyl cyclases,
each of which displays unique regulatory properties and
expression patterns. Adenylyl cyclase type I (AC1) belongs to
a family of adenylyl cyclases that are stimulated by calcium in a
calmodulin-dependent manner.17 Notably, AC1 has been
associated with chronic pain responses in several regions of
the central nervous system.18 It has been previously shown that
administration of NB001, a small molecule inhibitor of AC1
(IC50 = 10 μM in cell models) leads to analgesic effects in both
inflammatory and neuropathic pain rodent models.19
To determine whether these γ-arylated products have an
inhibitory effect on AC1 activity, HEK (human embryonic
kidney) cells stably expressing AC1 (HEK-AC1) were
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Letter
dependently inhibited this cAMP response (Table 2). These
compounds displayed IC50 values in the low micromolar range,
with the most potent being 7ag, with an IC50 value of 6.91
( 0.50) μM.
Table 2. AC1 Inhibition
compd
7ag
7aa
7c
7je
IC50 (μM) 6.91 ( 0.50) 9.92 ( 2.28) 8.95 ( 1.55) 9.10 ( 0.82)
In summary, we have developed a general and practical
palladium-catalyzed γ-arylation of tertiary allylic amines. The
arylated products were obtained in high regio- and stereo-
selectivity. We have applied it to prepare several drug molecules
including naftifine, cinarizine, flunarizine, and their analogues.
Moreover, we have identified potent adenylyl cyclase type I
inhibitors from the γ-arylation products. These novel AC1
inhibitors are of great potential for treating neuropathic and
inflammatory pain. The new synthetic capability developed
here will also facilitate the optimization of these lead
compounds in terms of potency, isoform selectivity, and
pharmacological properties.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization for new com-
pounds are provided. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: wattsv@purdue.edu.
*E-mail: mjdai@purdue.edu.
Notes
Figure 2. Substrate scope.
The authors declare no competing financial interest.
Scheme 1. Diversification of the γ-Arylation Products
ACKNOWLEDGMENTS
■
We thank Professor Yu Xia and her group at Purdue University
for mass spectrometric assistance. M.D. acknowledges startup
support from the Purdue Chemistry Department and Center
for Cancer Research. We thank the NIH (P30CA023168) for
supporting shared NMR resources at the Purdue Center for
Cancer Research.
REFERENCES
■
(1) For a review, see: Johannsen, M.; Jørgensen, K. A. Chem. Rev.
1998, 98, 1689−1708.
(2) Stutz, A.; Georgopoulos, A.; Granitzer, W.; Petranyi, G.; Berney,
̈
D. J. Med. Chem. 1986, 29, 112−125.
́
(3) St-Onge, M.; Dube, P.-A.; Gosselin, S.; Guimont, C.; Godwin, J.;
Archambault, P. M.; Chauny, J.-M.; Frenette, A. J.; Darveau, M.; Le
Sage, N.; Poitras, J.; Provencher, J.; Juurlink, D. N.; Blais, R. Clin.
Toxicol. 2014, 52, 926−944.
(4) Kitahata, N.; Han, S.-Y.; Noji, N.; Saito, T.; Kobayashi, M.;
Nakano, T.; Kuchitsu, K.; Shinozaki, K.; Yoshida, S.; Matsumoto, S.;
Tsujimoto, M.; Asami, T. Bioorg. Med. Chem. 2006, 14, 5555−5561.
(5) For leading references, see: (a) Xie, Y.; Hu, J.; Wang, Y.; Xia, C.;
Huang, H. J. Am. Chem. Soc. 2012, 134, 20613−20616. (b) Banerjee,
D.; Junge, K.; Beller, M. Angew. Chem., Int. Ed. 2014, 53, 1630−1635.
For selected reviews, see: (c) Overman, L. E.; Carpenter, N. E. Org.
React. 2005, 66, 1. (d) Hartwig, J. F.; Stanley, L. M. Acc. Chem. Res.
2010, 43, 1461−1475. (e) Ramirez, T. A.; Zhao, B.; Shi, Y. Chem. Soc.
Rev. 2012, 41, 931−942.
employed, and inhibition of Ca2+-stimulated cAMP accumu-
lation was determined. A23187 is a Ca2+ ionophore that
promotes Ca2+ binding to calmodulin in the cells and
subsequent stimulation of AC1. As expected, treatment of
HEK-AC1 cells with A23187 led to a robust increase in cAMP
accumulation consistent with Ca2+/calmodulin activation of
AC1 (data not shown). Several of the γ-arylated N,N-
dialkylallylamine products from the 7a−c and 7j series dose-
C
DOI: 10.1021/ol503748t
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(6) For a review, see: Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev.
2000, 100, 3009−3066.
(7) For a review, see: (a) Oestreich, M. Angew. Chem., Int. Ed. 2014,
53, 2282−2285. For examples, see: (b) Olofsson, K.; Larhed, M.;
Hallberg, A. J. Org. Chem. 1998, 63, 5076−5079. (c) Werner, E. W.;
Mei, T.-S.; Burckle, A. J.; Sigman, M. S. Science 2012, 338, 1455−1458.
(d) Werner, E. W.; Sigman, M. S. J. Am. Chem. Soc. 2011, 133, 9692−
9695. (e) Werner, E. W.; Sigman, M. S. J. Am. Chem. Soc. 2010, 132,
13981−13983. (f) Hu, J.; Hirao, H.; Li, Y.; Zhou, J. Angew. Chem., Int.
Ed. 2013, 52, 8676−8680. (g) Wu, C.; Zhou, J. J. Am. Chem. Soc. 2014,
136, 650−652. (h) Qin, L.; Ren, X.; Lu, Y.; Li, Y.; Zhou, J. Angew.
Chem., Int. Ed. 2012, 51, 5915−5919. (i) Zheng, C.; Wang, D.; Stahl,
S. S. J. Am. Chem. Soc. 2012, 134, 16496−16499. (j) Tasker, S. Z.;
Gutierrez, A. C.; Jamison, T. F. Angew. Chem., Int. Ed. 2014, 53, 1858−
1861.
(8) (a) Olofsson, K.; Larhed, M.; Hallberg, A. J. Org. Chem. 2000, 65,
7235−7239. (b) Wu, J.; Marcoux, J.-F.; Davies, I. W.; Reider, P. J.
Tetrahedron Lett. 2001, 42, 159−162.
(9) (a) Zhao, X.; Liu, D.; Guo, H.; Liu, Y.; Zhang, W. J. Am. Chem.
Soc. 2011, 133, 19354−19357. (b) Li, M.-B.; Wang, Y.; Tan, S.-K.
Angew. Chem., Int. Ed. 2012, 51, 2968−2971. (c) Wu, X.-S.; Chen, Y.;
Li, M.-B.; Zhou, M.-G.; Tian, S.-K. J. Am. Chem. Soc. 2012, 134,
14694−14697.
́
(10) For examples, see: (a) Prediger, P.; Barbosa, L. F.; Genisson, Y.;
Correia, C. R. D. J. Org. Chem. 2011, 76, 7737−7749. (b) Ripin, D. H.
B.; Bourassa, D. E.; Brandt, T.; Castaldi, M. J.; Frost, H. N.; Hawkins,
J.; Johnson, P. J.; Massett, S. S.; Neumann, K.; Phillips, J.; Raggon, J.
W.; Rose, P. R.; Rutherford, J. L.; Sitter, B.; Stewart, A. M., III;
Vetelino, M. G.; Wei, L. Org. Process Res. Dev. 2005, 9, 440−450.
(c) Alvisi, D.; Blart, E.; Bonini, B. F.; Mazzanti, G.; Ricci, A.; Zanti, P.
J. Org. Chem. 1996, 61, 7139−7146. (d) Dong, Y.; Busacca, C. A. J.
Org. Chem. 1997, 62, 6464−6465. (e) Reddington, M. V.;
Cunninghan-Bryant, D. Tetrahedron Lett. 2011, 52, 181−183.
(f) Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Sferrazza, A. Org. Biomol.
Chem. 2011, 9, 1727−1730. (g) Millet, A.; Baudoin, O. Org. Lett.
2014, 16, 3998−4000.
(11) Olofsson, K.; Sahlin, H.; Larhed, M.; Hallberg, A. J. Org. Chem.
2001, 66, 544−549.
(12) Ajay; Bemis, G. W.; Murcko, M. A. J. Med. Chem. 1999, 42,
4942−4951.
(13) (a) Bao, H.; Qi, X.; Tambar, U. K. J. Am. Chem. Soc. 2011, 133,
1206−1208. (b) Bao, H.; Qi, X.; Tambar, U. K. Synlett 2011, 1789−
1792.
(14) (a) Ascic, E.; Jensen, J. F.; Nielsen, T. E. Angew. Chem., Int. Ed.
2011, 50, 5188−5191. (b) Ascic, E.; Hansen, C. L.; Le Quement, S. T.;
Nielsen, T. E. Chem. Commun. 2012, 48, 3345−3347. (c) Hansen, C.
L.; Clausen, J. W.; Ohm, R. G.; Ascic, E.; Le Quement, S. T.; Tanner,
D.; Nielsen, T. E. J. Org. Chem. 2013, 78, 12545−12565. (d) Cai, Q.;
Liang, X.-W.; Wang, S.-G.; Zhang, J.-W.; Zhang, X.; You, S.-L. Org.
Lett. 2012, 14, 5022−5025. (e) Cai, Q.; Liang, X.-W.; Wang, S.-G.;
You, S.-L. Org. Biomol. Chem. 2013, 11, 1602−1605.
(15) (a) Stockigt, J.; Antonchick, A. P.; Wu, F.; Waldmann, H.
̈
Angew. Chem., Int. Ed. 2011, 50, 8538−8564. (b) Cao, R.; Peng, W.;
Wang, Z.; Xu, A. Curr. Med. Chem. 2007, 14, 479−500.
(16) Cooper, D. M.; Crossthwait, A. J. Trends Pharmacol. Sci. 2006,
27, 426−431.
(17) Sadana, R.; Dessauer, C. W. Neurosignals 2009, 17, 5−22.
(18) Zhou, M. Drug Discovery Today 2012, 17, 573−582.
(19) Wang, H.; Xu, H.; Wu, L.-J.; Kim, S. S.; Chen, T.; Koga, K.;
Descalzi, G.; Gong, B.; Vadakkan, K. I.; Zhang, X.; Kaang, B.-K.; Zhuo,
M. Sci. Transl. Med. 2011, 3, 65ra3.
D
DOI: 10.1021/ol503748t
Org. Lett. XXXX, XXX, XXX−XXX