Optimizing the Mizoroki–Heck reaction of cyclic allyl amines: Gram-scale synthesis of preclamol without protecting groups

Article abstract of DOI:10.1016/j.jcat.2018.01.007

Though a widely used metal-catalyzed cross-coupling process, the Mizoroki–Heck (MH) reaction can be a capricious transformation. This is particularly true for oxidation-prone alkene substrates containing ligating heteroatoms, as in the case of N-alkyl tetrahydropyridines, whose MH reactions have been underexplored due to the many side reactions that hamper the process. Since the products of tetrahydropyridine Heck reactions are direct precursors to potent pharmacophores, and therefore of commercial value, this is a significant drawback. We report here the results of our study designed to deliver an optimized, scalable MH procedure for N-alkyltetrahydropyridines and its exemplification in a gram-scale synthesis of the drug substance preclamol.

Full text of DOI:10.1016/j.jcat.2018.01.007

Journal of Catalysis 360 (2018) 97–101
Contents lists available at ScienceDirect
Journal of Catalysis
journal homepage: www.elsevier.com/locate/jcat
Optimizing the Mizoroki–Heck reaction of cyclic allyl amines:
Gram-scale synthesis of preclamol without protecting groups
b
b
b
Joseph B. Sweeney a, , Kirsty Adams , Julien Doulcet , Bimod Thapa ,
⇑
Fanny Tran c, Robert Crook d
a Department of Chemistry, Lancaster University, Lancaster LA1 4YB, UK
b Department of Chemical Sciences, University of Huddersfield, Huddersfield HD1 3DH, UK
c Department of Chemistry, University of Reading, Reading RG6 6AP, UK
d Pfizer Ltd, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Though a widely used metal-catalyzed cross-coupling process, the Mizoroki–Heck (MH) reaction can be a
capricious transformation. This is particularly true for oxidation-prone alkene substrates containing ligat-
ing heteroatoms, as in the case of N-alkyl tetrahydropyridines, whose MH reactions have been underex-
plored due to the many side reactions that hamper the process. Since the products of tetrahydropyridine
Heck reactions are direct precursors to potent pharmacophores, and therefore of commercial value, this is
a significant drawback. We report here the results of our study designed to deliver an optimized, scalable
MH procedure for N-alkyltetrahydropyridines and its exemplification in a gram-scale synthesis of the
drug substance preclamol.
Received 9 November 2017
Revised 2 January 2018
Accepted 9 January 2018
Keywords:
Catalysis
Tetrahydropyridines
Mizoroki–Heck reaction
Aryl piperidines
CNS drugs
Ó 2018 Elsevier Inc. All rights reserved.
1. Introduction
[5]), which react efficiently only if the lone pair of electrons on
nitrogen is delocalized into an electron-withdrawing protecting
Among the many catalytic processes available to the modern
synthetic chemist, the Mizoroki–Heck (MH) reaction [1] is of spe-
cial significance as the first reported method [2] that enabled
direct, substoichiometric catalytic modification of simple alkenes:
The overall transformation is effectively a CH activation process,
in which an aryl unit is inserted into an sp2 CH bond. The reaction
has been intensely studied and optimized, and a wide range of cou-
pling partners (aryl halides, triflates, sulfonates, diazonium salts,
iodonium salts), alkenes, and catalysts have been used produc-
tively in the process, with many successful applications to the pro-
duction of complex natural and synthetic targets [3].
Notwithstanding the proven synthetic power of the transforma-
tion, there are several known limitations on the process; thus,
the reactions are often heterogeneous (precluding detailed kinetic
and mechanistic analysis), and some alkene classes are unreliable
and capricious substrates. Unsaturated amines fall into this cate-
gory, often undergoing inefficient transformations that require
high substrate or catalyst loading; this is especially the case for
cyclic allylamines (such as tetrahydropyridines [4] and pyrrolines
group. This limitation is a particular drawback, since the method
in theory allows direct synthesis of N-alkyl piperidines and pyrro-
lidines, a class of heterocycles with privileged pharmacological sta-
tus, particularly in CNS-active compounds such as the marketed
drugs paroxetine [6] and niraparib [7] (Fig. 1); however, to date,
the limitations of MH reaction of tetrahydropyridines (lack of
regioselectivity, overreaction, multiple isomerization pathways,
and low yields) have severely restricted the use of this potentially
impactful catalytic process.
3-Arylpiperidines are a class of heterocycles with particular
biological potency, and preclamol (1) [8] occupies a preeminent
position as a first-in-class antipsychotic drug substance. The com-
pound is a dopamine autoreceptor agonist, and it has been used in
human beings for the treatment of schizophrenia [9]. To produce
this compound and other related biologically active compounds,
a range of heterocycles can function as chemical feedstocks for
catalytic processing (Fig. 2).
Thus, several catalytic methods using pyridines as feedstocks
have been used to produce the preclamol core (Fig. 2a), includ-
ing nickel-catalyzed Kumada [10] and Suzuki–Miyaura coupling
[11,12] of 3-bromopyridine and pyridine CAH activation [13].
In these reactions, further nontrivial steps (alkylation, reduction,
⇑
Corresponding author.
E-mail address: j.sweeney1@lancaster.ac.uk (J.B. Sweeney).
https://doi.org/10.1016/j.jcat.2018.01.007
0021-9517/Ó 2018 Elsevier Inc. All rights reserved.

98
J.B. Sweeney et al. / Journal of Catalysis 360 (2018) 97–101
Fig. 1. Arylpiperidines: privileged biological motifs accessible from tetrahydropyridines.
Fig. 2. Catalytic strategies for the synthesis of preclamol.
etc.) are needed to access the biologically active products. Cross
coupling of nonaromatic amines has been less widely used to
access the 3-arylpiperidine core, with the Co(II)-catalyzed cou-
pling of 3-iodo-N-Boc-piperidine with Grignard reagents a nota-
ble example of such a strategy (Fig. 2b) [14]. In theory, the use
of tetrahydropyridines (available in bulk from commercial
sources) in an MH reaction would allow highly efficient access
to 3-aryl piperidines, and the method has been used by Hall-
berg et al. to produce preclamol (Fig. 2c) [4a]. However, the
method reported by these authors delivered the target 3-
arylpiperidine inefficiently and required high ligand loading
and stoichiometric Ag(I) as an additive [15]. Since this pioneer-
ing report, there have been no reports of MH reactions of alkyl
tetrahydropyridines, which is likely a reflection of the poor
yields obtained in these transformations, presumably due to
the tendency of N-alkyltetrahydropyridines to undergo
palladium-catalyzed side reactions (such as aromatization, giv-
ing pyridiniums) under the heterogeneous reaction conditions.
Though in theory N-alkyl-3-arylpiperidines 2 (Fig. 3) are avail-
able via MH reaction of N-acyl tetrahydropyridines, in practice
this is difficult, as shown by the work of Correia et al. [5b], due
to the tendency for these reactions to deliver mixtures of
enamines (isolated as hydrated products
limits the utility of the reactions.
3 and 4), which
Given the ready commercial availability of N-alkyl tetrahy-
dropyridines and the great utility of 3-arylpiperidines, we under-
took a study of the factors affecting these complex MH reactions,
and we report an improved and simplified synthesis of preclamol
using our new method.
2. Materials and methods
Full experimental details and key spectra for products can be
found in the Supplementary Material.
Fig. 3. Regiochemical divergence in MH reactions of tetrahydropyridines.

J.B. Sweeney et al. / Journal of Catalysis 360 (2018) 97–101
99
to optimize the yield of the target product, 7, and quickly identify
and quantitatively estimate the side-product profile of the reaction,
thus giving valuable insights into the reaction mechanism and facil-
itating optimization. A summary of the salient data obtained from
the initial optimization phase is given in Table 1. It thus became
clear that silver(I) is not an essential additive (entries 7–12) and
that use of an amine base was important for improving conversion
of the substrate (entries 5–12).
The next phase of optimization was focused on improving the
efficiency of the transformation by reducing the loadings of cata-
lyst and substrate, and on the reaction temperature (Table 2).
Satisfyingly, the use of 1 mol.% PdCl2 was effective without
reducing the yield of 7 (Table 2, entry 3), though a 0.5% catalyst
loading was less efficient (Table 2, entry 2). Variation in the stoi-
chiometry of tetrahydropyridine had a less pronounced effect on
the reaction, with a 50% decrease in loading having little negative
impact on the yield of 7 (Table 2, entry 5). Finally, lowering the
temperature to 70 °C proved to have a positive effect on the yield
(Table 2, entries 7 and 8).
3. Results and discussion
Our project had three key aims: first, to reduce the catalyst
loading for the MH reaction to ꢀ1 mol.%; second, to avoid the
use of a silver additive; third, to develop a method involving no
protecting groups. In particular, the last goal was a demanding
one, due to the known challenges in using phenols in palladium-
catalyzed reactions [16], but was one that offered significant mass
balance advantages if successful.
Preliminary studies of the N-alkyl THPy MH reaction confirmed
the limitations of the reaction: the heterogeneous process delivered
a multitude of products in addition to the desired arylated target,
predominantly pyridinium species (and derived compounds) aris-
ing from metal-catalyzed oxidation. We therefore embarked upon
a detailed analysis of the parameters of this reaction (Pd catalyst,
ligand, base, solvent, additive, temperature). To simplify the analy-
sis of this complex reaction, we chose (3-iodo)-benzotrifluoride, 5,
as a model substrate, using 19F NMR spectroscopy to study its reac-
tion with N-propyltetrahydropyridine, 6. In this manner, we hoped
Table 1
Initial optimization of the MH reaction of tetrahydropyridine.
I
CF3
5
F3C
CF3
+
+
CF3
H
CF3
PdCl2 (5 mol%), P(o-Tol)3
Base, additive (100 mol%)
100 ˚C, 17 h, CH3CN
N
N
Pr
Pr
6
7
8
9
(4 eq.)
Entry
P(o-Tol)3/mol.%
Base
Additive
Conversion/%
Yield/%
7
8
9
1
2
3
4
5
6
7
8
20
40
10
5
5
5
5
7.5
5
7.5
7.5
7.5
–
–
–
–
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgOTf
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
100
100
100
100
92
100
100
100
100
98
18a
10
27
35
39
49
55
59
58
58
52
61
16
9
10
11
3
7
3
3
2
62
78
49
42
16
19
6
11
8
12
28
10
DMPip (5 eq.)b
DMPip (1 eq.)
DMPip (5 eq.)
DMPip (1 eq.)
DMPip (1 eq.)
DMPip (1 eq.)
DMPip (1 eq.)
DMPip (5 eq.)
9
10
11
12
(CuOTf)2ꢁPhCH3
4
2
2
Zn(OTf)2
100
100
Zn(OTf)2
a
Yields estimated from 19F NMR spectra.
N,N-dimethylpiperazine.
b
Table 2
Optimization of MH reaction of 6: influence of temperature, catalyst loading and stoichiometry.
I
CF3
5
F3C
CF3
+
+
CF3
H
CF3
PdCl2 (x mol%)
P(o-Tol)3 (1.5x mol),
DMPip (5 eq.)
Zn(OTf)2 (100 mol%)
CH3CN
N
N
Pr
Pr
6
7
8
9
Entry
PdCl2/mol%
5/eq.
Temperature (°C)
Time (h)
Conversion
Yield/%
7
8
9
1
2
3
4
5
6
7
8
9
5
0.5
1
5
5
5
1
1
1
4
4
4
3
2
1.5
3
2
1.5
100
100
100
100
100
100
70
17
17
17
17
17
17
120
120
120
100
95
61a
56
60
63
59
2
2
1
2
3
4
1
2
1
10
10
9
9
8
8
6
6
5
100
100
100
100
100
100
89
56
67
70
70
62 (55)b
57
a
Estimated from 19F NMR spectra.
Isolated yield (5 mmol scale reaction).
b

100
J.B. Sweeney et al. / Journal of Catalysis 360 (2018) 97–101
Table 3
Optimized MH reaction of 6.
I
OR
10a, R = Bn
10b, R = H
OR
RO
OR
+
PdCl2 (1 mol%)
N
N
N
Pr
P(o-Tol)3 (1.5 mol%),
DMPip (5 eq.)
Pr
Pr
6
11a, R = Bn
12a, R = Bn
Zn(OTf)2 (100 mol%)
CH3CN
11b, R = H
12b, R = H
Entry
6 (eq)
R
Yield 11/%
Yield 12/%
1
2
3
4
4
2
4
2
Bn
Bn
H
11a, 55a
11a 49
12a, 5b
12a, 13
12b, 6
11b, 55c
11b, 49
H
12b, 10
a
b
c
Isolated yield, 5 mmol scale.
Estimated from 1H NMR.
12.5 mmol scale.
Scheme 1. Improved synthesis of Preclamol 1.
mol in good overall yield. Developing an in-depth understanding of
the detailed mechanistic features of this complex heterogeneous
catalytic reaction is a focus of our current research.
Acknowledgment
We thank the University of Huddersfield and EPSRC (grant EP/
G040247/1) for funding this research program.
Fig. 4. Saturated amine 13.
Armed with an optimized procedure, we turned to the synthesis
Appendix A. Supplementary material
of preclamol, and observed that using either benzyl ether, 10a, or
free phenol, 10b, MH reactions were significantly improved com-
pared with the previously reported procedure.: in particular, 11b
was obtained in 55% yield, compared with 28% reported by Hall-
berg et al. (Table 3, entry 3). In addition to the desired products,
11a and 11b, on the larger scale of these reactions, we now also
detected the presence of novel diarylated alkenes, 12a and 12b.
When performed on a 12.5 mmol scale (Scheme 1), the extent of
side reactions involved in MH reactions of N-alkyl tetrahydropy-
ridines becomes apparent, with side products derived from other
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.jcat.2018.01.007.
References
[1] S. Braese, A. de Meijere, in: A. De Meijere, S. Brase, M. Oestreich (Eds.), Metal-
Catalyzed Cross-Coupling Reactions and More, vol. 2, 2014, p. 533; M.
Oestreich (Ed.), The Mizoroki-Heck Reaction, Wiley, Chichester, 2009.
[2] (a) T. Mizoroki, K. Mori, A. Ozaki, Bull. Chem. Soc. Jpn. 44 (1971) 581;
(b) R.F. Heck, J.P. Nolley, J. Org. Chem. 37 (1972) 2320.
[3] For a recent use of a Heck reaction of a cyclic olefin in the synthesis of a natural
product see: J. Nugent, M.G. Banwell, B.D. Schwartz Org. Lett. 18 (2016) 3798.
[4] (a) K. Nilsson, A. Hallberg, J. Org. Chem. 57 (1992) 4015;
(b) J.C. Pastre, C.R.D. Correia, Org. Lett. 8 (2006) 1657.
possible palladium
r -intermediates. Thus, in addition to 11b
and diarylated amine 12b, preclamol (1) itself and saturated amine
13 (Fig. 4) were observed in small amounts, the latter products pre-
sumably formed via reductive MH processes [17]. Hydrogenation
of either 11a or 11b gave preclamol in 49–55% overall yield.
[5] (a) C. Sonesson, M. Larhed, C. Nyqvist, A. Hallberg, J. Org. Chem. 61 (1996)
4756;
(b) M.J.S. Carpes, C.R.D. Correia, Tetrahedron Lett. 43 (2002) 741;
(c) A.C.B. Montes de Oca, C.R.D. Correia, ARKIVOC (2003) 390;
(d) A.L.L. Garcia, M.J.S. Carpes, A.C.B.M. de Oca, M.A.G. dos Santos, C.C. Santana,
C.R.D. Correia, J. Org. Chem. 70 (2005) 1050;
4. Conclusions
(e) K. Peixoto da Silva, M. Narciso Godoi, C.R.D. Correia, J. Org. Chem. 9 (2007)
2815;
(f) F.G. Finelli, M.N. Godoi, C.R.D. Correia, J. Braz. Chem. Soc. 26 (2015) 910.
[6] For a recent synthesis of Paroxetine, see: Y. Zhang, Y. Liao, X. Liu, Q. Yao, Y.
Zhou, L. Lin, X. Feng Chem. Eur. J. 22 (2016) 15119.
In summary, we have designed and implemented an improved
method for the MH reaction of N-propyltetrahydropyridine, which
is more cost-effective, milder, and more functional-group-tolerant,
and which efficiently provides access to gram quantities of precla-

J.B. Sweeney et al. / Journal of Catalysis 360 (2018) 97–101
101
[7] (a) C.K. Chung, P.G. Bulger, B. Kosjek, K.M. Belyk, N. Rivera, M.E. Scott, G.R.
Humphrey, J. Limanto, D.C. Bachert, K.M. Emerson, Org. Process Res. Dev. 18
(2014) 215;
[14] (a) L. Gonnard, A. Guérinot, J. Cossy, Chem. Eur. J. 21 (2015) 12797;
(b) , See also:A. De Filippis, D.G. Pardo, J. Cossy Lett. Org. Chem. 2 (2005) 136.
[15] (a) For the first examples of Heck reactions with silver additives, see: K.
Karabelas, C. Westerlund, A. Hallberg J. Org. Chem. 50 (1985) 3896;
(b) K. Karabelas, A. Hallberg, J. Org. Chem. 51 (1986) 5286;
(c) , For the suppression of isomerization by silver additives, see:M.M.
Abelman, T. Oh, L.E. Overman J. Org. Chem. 52 (1987) 4130;
(d) M.M. Abelman, L.E. Overman, J. Am. Chem. Soc. 110 (1988) 2328;
(e) R.C. Larock, H. Song, B.E. Baker, W.H. Gong, Tetrahedron Lett. 29 (1988)
2919;
(b) D.J. Wallace, Carl A. Baxter, K.J.M. Brands, N. Bremeyer, S.E. Brewer, R.
Desmond, K.M. Emerson, J. Foley, P. Fernandez, W. Hu, S.P. Keen, P. Mullens, D.
Muzzio, P. Sajonz, L. Tan, R.D. Wilson, G. Zhou, G. Zhou, Org. Process Res. Dev.
15 (2011) 831.
[8] (a) S. Hjorth, A. Carlsson, H. Wikström, P. Lindberg, D. Sanchez, U. Hacksell, L.-
E. Arvidsson, U. Svensson, J.L.G. Nilsson, Life Sci. 28 (1981) 1225;
(b) J. Amt, K.P. Bøgesø, A.V. Christensen, J. Hyttel, J.-J. Larsen, O. Svendsen,
Psychopharmacology 81 (1983) 199;
(f) R.C. Larock, W.H. Gong, J. Org. Chem. 54 (1989) 2047;
(c) H. Wikström, D. Sanchez, P. Lindberg, U. Hacksell, L.-E. Arvidsson, A.M.
Johansson, S.-O. Thorberg, J.L.G. Nilsson, K. Svensson, S. Hjorth, David Clark, A.
Carlssone, J. Med. Chem. 27 (1984) 1030.
(g) R.C. Larock, W.H. Gong, B.E. Baker, Tetrahedron Lett. 30 (1989) 2603;
(h) T. Jeffery, Tetrahedron Lett. 32 (1991) 2121.
[16] B. Schmidt, F. Hölter, A. Kelling, U. Schilde See, for instance, J. Org. Chem. 76
(2011) 3357, and references therein;
(a) For alternative approaches to phenols using Mizoroki–Heck reaction, see:
Y. Izawa, D. Pun, S.S. Stahl Science 333 (2011) 209;
(b) Y. Izawa, C. Zheng, S.S. Stahl, Angew. Chem., Int. Ed. 52 (2013) 3672.
[17] It has been reported that amines can be effective hydride sources for reductive
Heck reactions: S. Raoufmoghaddam, S. Mannathan, A.J. Minnaard, J.G. de
Vries, J.N. Reek Chem. Eur. J. 21 (2015) 18811.
[9] C.A. Tamminga, N.G. Cascella, R.A. Lahti, M. Lindberg, A. Carlsson, J. Neural
Transm. Genet. Sect. 88 (1992) 165.
[10] S.O. Thorberg, L. Gawell, I. Csöeregh, J.L.G. Nilsson, Tetrahedron 41 (1985) 129.
[11] J.L. Nallasivam, R.A. Fernandes, Eur. J. Org. Chem. (2015) 3558.
[12] Suzuki-Miyuara coupling of allylic substrates has also been used in
enantioselective syntheses of preclamol: P. Schafer, T. Palacin, M. Sidera, S.P.
Fletcher Nat. Commun. 8 (2017) 15762.
[13] M. Ye, G.-L. Gao, A.J.F. Edmunds, P.A. Worthington, J.A. Morris, J.-Q. Yu, J. Am.
Chem. Soc. 133 (2011) 19090.