Solid-phase synthesis of 4-biaryl-piperidine-4-carboxamides

Article abstract of DOI:10.1016/j.tetlet.2006.06.070

A novel solid-phase synthesis of 4-biaryl-piperidine-4-carboxamides has been developed using FDMP resin with a carboxamide as the anchor point. With this approach, three points of diversity were incorporated into a GPCR-directed scaffold. Final products w

Full text of DOI:10.1016/j.tetlet.2006.06.070

Tetrahedron Letters 47 (2006) 7267–7270
Solid-phase synthesis of 4-biaryl-piperidine-4-carboxamides
Jin Zhu,* Richard S. Pottorf and Mark R. Player
Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 8 Clarke Drive, Cranbury, NJ 08512, United States
Received 16 December 2005; revised 11 June 2006; accepted 12 June 2006
Abstract—A novel solid-phase synthesis of 4-biaryl-piperidine-4-carboxamides has been developed using FDMP resin with a carb-
oxamide as the anchor point. With this approach, three points of diversity were incorporated into a GPCR-directed scaffold. Final
products were obtained in good purity and yield.
ꢀ 2006 Published by Elsevier Ltd.
Two common structural motifs that are found in G-pro-
tein coupled receptor (GPCR) ligands contain either
biaryl or piperidinyl groups, which are considered to
be privileged structures for GPCR ligands.1 Examples
of these include compound 1, an SQS inhibitor,2a and
compound 2, an MCH antagonist (Fig. 1).2b The fact
that these moieties frequently appear in different GPCR
ligands is attributed to their binding to conserved
regions of target proteins. In efforts to discover potent
ligands for GPCR targets based on the structural motifs
of the biaryl and piperidinyl groups, compound 3, fea-
turing three points of diversity, was designed (Fig. 2).
Compound 3 could be derived from scaffold 4, which
would allow for a structurally diverse set of compounds
through solid-phase chemistry. As the first point of
diversity, a variety of amines (for R1 in 3) would serve
as an anchor point to immobilize scaffold 4 onto a solid
H
N
R1
N
OH
O
O
NH
R3
Br
R2
4
3
Figure 2. Design of compound 3 with three points of diversity.
Cl
Cl
CN
NaH,
N
CN
Boc
Br
N
DMF, 80 o
65%
C
Boc
Br
6
5
FmocCl
Na2CO3
COOH
NH
H2SO4/ H2O
Cl
Cl
100 oC
84%
DCM
98%
Br
O
NH
OH
7
N
N
COCl
COOH
(COCl)2
N
DCM
95%
N
N
Fmoc
Fmoc
Br
Br
CN
1
2
8
9
Figure 1. Biologically important molecules featuring biaryl or piperi-
Scheme 1. Synthesis of scaffold material.
dino moieties.
support. The piperidinyl end of the scaffold could allow
for reductive amination, acylation, or N-arylation3 to
introduce the second diversity point. Finally, the third
Keywords: Solid-phase; Suzuki coupling; Biaryl-piperidine.
*
Corresponding author. Tel.: +1 609 655 6927; fax: +1 609 655
6930; e-mail: jzhu14@prdus.jnj.com
0040-4039/$ - see front matter ꢀ 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.06.070

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J. Zhu et al. / Tetrahedron Letters 47 (2006) 7267–7270
diversity point could be incorporated through a Suzuki
coupling reaction on the aromatic ring.
N R1
NH2R1
9
O
CHO
HN R1
DIEA
DCM
Na(OAc)3BH
DCE
The synthesis of scaffold 8 commenced with dialkylation
of 5 yielding Boc protected piperidine 6 (Scheme 1),4
which upon hydrolysis,5 provided the free amine 7. Sub-
sequent protection with FmocCl provided acid 8.
N
Fmoc
Br
12
10
11
FDMP resin (loading 1.5 mmol/g), known for its versa-
tility in solid-phase chemistry,6 was employed in the
chemistry development process. Amines were first
attached to this solid support through a reductive amina-
tion reaction7 with NaBH(OAc)3 in 1,2-dichloroethane
(Scheme 2). Direct coupling of acid 8 to the solid bound
amine 11 via coupling reagents was problematic, pre-
sumably due to the steric hindrance involved. However,
conversion of the acid to the corresponding acid chlo-
ride 9 allowed for smooth acylation with 11 in the pres-
ence of Hunig’s base. Deprotection of 12 was effected
with 25% piperidine in DMF, followed by a second
round of reductive amination leading to 13.
R3B(OH)2
N
R1
N
Pd(PPh3)4
1. 25% piperidine
O
aq. Na2CO3
2. R2CHO
dioxane, 75 ºC
Na(OAc)3BH
Br
R2
13
H
N
N R1
O
R1
N
O
10% TFA
N
R3
R3
R2
R2
Finally, the third diversity point was introduced through
a Suzuki coupling of 13. The coupling reaction did
not go to completion upon a catalytic amount of
PdCl2(PPh3)2. However, when Pd(PPh3)4 was used, the
reaction went to completion in both high yields and
14
15
Scheme 2. Solid-phase synthesis of biaryl-piperidines.
Table 1. Solid-phase synthesis of biaryl-piperidines
Entry
1
Amine R1NH2
Aldehyde R2CHO
Boronic acid R3B(OH)2
Purity of 15a (%)
Yieldb (%)
45
S
O
O
B(OH)2
H2N
N
94
CHO
B(OH)2
O
H2N
N
CHO
2
3
93
96
42
NC
NH2
O
O
B(OH)2
N
CHO
66
61c
OMe
NH2
H
N
F
MeO
B(OH)2
B(OH)2
4
5
90
99
62
N
OMe
CHO
NH2
N
S
CHO
70
64c
O
OMe
NH2
N
B(OH)2
B(OH)2
6
7
95
42
NC
NC
CHO
H2N
N
O
CHO
100
72
66c

J. Zhu et al. / Tetrahedron Letters 47 (2006) 7267–7270
7269
Table 1 (continued)
Entry
Amine R1NH2
Aldehyde R2CHO
Boronic acid R3B(OH)2
Purity of 15a (%)
Yieldb (%)
86
H2N
H2N
N
B(OH)2
CHO
S
8
100
HO
B(OH)2
N
N
N
CHO
CHO
9
96
85
80c
MeO
HO
N
H2N
H2N
N
N
B(OH)2
B(OH)2
10
11
96
91
67
66
CHO
MeO
N
NC
a Determined by LC–MS with both UV and ELSD detectors; further confirmed with 1H NMR analysis.
b Determined by weight of the crude products based on the loading of the resins.
c Isolated yield.
Shapiro, S.; McBriar, M. D.; Clader, J. W.; Greenlee, W. J.;
Spar, B.; Kowalski, T. J.; Farley, C.; Cook, J.; Heek, M. V.;
Weig, B.; O’Neil, K.; Graziano, M.; Hawes, B. J. Med.
Chem. 2005, 48, 4746.
purity. In addition, the purity of the final products
appeared to be better when dioxane was used as the
solvent rather than with DMF or THF. Cleavage with
10% TFA in DCM afforded the desired product 15.
3. Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999,
576, 125.
As shown in Table 1, a variety of amines were examined.
Some amines led to a low yield of the final products,
though the purity was found to be satisfactory (entries
1 and 2).8 Heterocyclic aldehydes were incorporated to
further increase structural diversity. Examples include
thiophenyl, furanyl, and pyridinyl groups (entries 1, 2,
and 3). Both electron-donating groups and electron-
withdrawing groups on the aryl moiety of boronic acids
led to the expected products in good purity. Functional
groups such as alcohols, phenols, cyano, and carbonyl
groups are tolerated in the final coupling reaction
(entries 2, 5, 9, and 11).
4. Yang, L.; Morriello, G.; Prendergast, K.; Cheng, K.; Jacks,
T.; Chan, W. W.; Schleim, K. D.; Smith, R. G.; Patchett, A.
A. Bioorg. Med. Chem. Lett. 1998, 8, 107.
5. Burkholder, T. P.; Kudlaca, E. M.; Maynard, G. D.; Liu,
X.; Le, T.; Webster, M. E.; Horgan, S. W.; Wenstrup, D.
L.; Freund, D. W.; Boyer, F.; Bratton, L.; Gross, R. S.;
Knippenberg, R. W.; Logan, D. E.; Jones, B. J.; Chen, T.;
Geary, J. L.; Correll, M. A.; Poole, J. C.; Mandagere, A.
K.; Thompson, T. N.; Hwang, K. Bioorg. Med. Chem. Lett.
1997, 7, 2531.
6. (a) Bork, J. T.; Lee, J. W.; Khersonsky, S. M.; Moon, H.;
Chang, Y. Org. Lett. 2003, 5, 117; (b) Ashley-Fenwick, A.
E.; Garnier, B.; Gribble, A. D.; Ife, R. J.; Rawlings, A. D.;
Witherington, J. Bioorg. Med. Chem. Lett. 2001, 11, 195.
7. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.;
Maryanoff, C. A.; Shah, R. J. Org. Chem. 1996, 61, 3849.
8. Analytical data for selected compounds. Compound 15-1:
1H NMR (400 MHz, CDCl3): d 7.60–6.88 (m, 10H), 4.28 (s,
2H), 4.26 (s, 2H), 4.21 (s, 1H), 3.61–3.44 (m, 4H), 3.15–2.82
(m, 4H), 2.68 (s, 3H), 2.58 (s, 3H), 2.40–2.16 (m, 6H); MS
(ELS): 506.2 (M+H+). Compound 15-2: 1H NMR
(400 MHz, CDCl3): d 7.79–7.38 (m, 9H), 6.02–5.98 (m,
1H), 4.12 (s, 1H), 3.80–3.62 (m, 4H), 3.18–2.80 (m, 2H),
2.76 (s, 3H), 2.58 (s, 3H), 2.24 (s, 3H), 2.25–1.90 (m, 8H);
MS (ELS): 471.6 (M+H+). Compound 15-3: 1H NMR
(400 MHz, CDCl3): d 7.78–6.75 (m, 14H), 4.92 (bs, 1H),
4.32 (s, 4H), 4.28 (s, 2H), 3.78 (s, 3H), 3.42 (br s, 2H), 2.59
(s, 3H), 2.58–2.42 (m, 8H); MS (ELS): 564.7 (M+H+).
9. Typical procedures. Attachment of amines to solid support:
To a suspension of FDMP (2-(3,5-dimethoxy-4-formyl-
phenoxy)ethoxymethyl) resin (1.5 mmol/g) in 2% acetic
acid in DCE was added the amine (6 equiv, 0.4 M). The
reaction mixture was shaken for 2 h, followed with the
addition of NaBH(OAc)3 (10 equiv). The mixture was
shaken overnight at room temperature. After quenching the
excess of NaBH(OAc)3 with methanol, the resin was
washed with MeOH, DCM, then DMF (2·), MeOH, and
DCM successively, and then dried in vacuo overnight.
In conclusion, an efficient solid-phase synthesis of bi-
aryl-piperidines has been developed.9 The immobilized
bromo-aryl scaffold could allow not only for manipula-
tion of the nitrogen, but also incorporation of various
groups on the aryl moiety.
Acknowledgments
The authors would like to thank Mr. George Elgar for
providing analytical support.
References and notes
1. (a) Bondensgaard, K.; Ankerson, M.; Thogersen, H.;
Hansen, B. S.; Wulff, B. S.; Bywater, R. P. J. Med. Chem.
2004, 47, 888–899; (b) Bemis, G. W.; Murcko, M. A. J.
Med. Chem. 1996, 39, 2887.
2. (a) Brown, G. R.; Clarke, D. S.; Foubister, A. J.; Freeman,
S.; Harrison, P. J.; Johnson, M. C.; Mallion, K. B.;
McCormick, J.; McTaggart, F.; Reid, A. C.; Smith, G. J.;
Taylor, M. J. J. Med. Chem. 1996, 39, 2971; (b) Palani, A.;

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J. Zhu et al. / Tetrahedron Letters 47 (2006) 7267–7270
Acylation of solid bound amines and deprotection: To a
successively, and then dried in vacuo overnight. Suzuki
coupling: To a suspension of resin 13 in dioxane was added
Pd(PPh4)3 (5 mol %), aqueous Na2CO3 (2 M, 20 equiv),
and boronic acid (10 equiv). The mixture was flushed with
argon, and the reaction vessel was then sealed. The reaction
vessel was heated at 75 ꢁC for 20 h. The resin was washed
with water, DMF, MeOH, DCM, and MeOH, and then
dried in vacuo overnight. Cleavage of product from the
resin: The resin was treated with 10% TFA in DCM for
30 min. After the solvent was evaporated, the compounds
were analyzed with proton NMR and LC–MS. The LC–
MS instrument was equipped with an analytical HPLC
column and a UV detector in determining the purity of the
products. NMR data was also collected on the crude
products. To further confirm on the yield and purity of the
products, a small set of compounds (out of those in Table 1)
were purified. The yields of the purified compounds
were consistent with the reported yields of the crude
products.
suspension of resin 10 in DCM was added DIEA (5 equiv),
followed with acid chloride 9 (2 equiv). The mixture was
shaken at room temperature for 5 h. The resin was washed
with DCM, MeOH, DMF, and MeOH successively. A
solution of 20% piperidine in DMF was added to the resin.
The mixture was shaken for 30 min. After draining the
solvent, a fresh solution of piperidine in DMF was added to
the resin, and the mixture was shaken for another 30 min.
The solvent was then drained. The resin was washed
successively with DMF, MeOH, and DCM, and then dried
in vacuo overnight. Reductive amination: To a suspension
of the resin (1.5 mmol/g) in 2% acetic acid in DCE was
added the aldehyde (6 equiv, 0.4 M). The reaction mixture
was shaken for 2 h, followed with the addition of
NaBH(OAc)3 (10 equiv). The mixture was shaken over-
night at room temperature. After quenching the excess of
NaBH(OAc)3 with methanol, the resin was washed with
MeOH, DCM, then twice with DMF, MeOH, and DCM