Spiroazetidine-piperidine bromoindane as a key modular template to access a variety of compounds via C-C and C-N bond-forming reactions

Article abstract of DOI:10.1016/j.tetlet.2012.09.047

In the context of our ghrelin inverse agonist program, a functionalized bromoindane 3 provided a versatile intermediate for structure-activity relationship studies. After developing operationally simple cross-coupling reactions, a broad spectrum of chemical space was successfully explored. Optimization of a one-pot borylation/Suzuki sequence provided the desired products in high yield with low loading of the palladium catalyst. High yields of N-linked heterocyclic analogues were obtained through palladium catalyzed C-N bond formation. In addition, carboxylation of the bromoindane provided an indane carboxylic acid for further diversification.

Full text of DOI:10.1016/j.tetlet.2012.09.047

Tetrahedron Letters 53 (2012) 6351–6354
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Spiroazetidine–piperidine bromoindane as a key modular template to access
a variety of compounds via C–C and C–N bond-forming reactions
Dilinie P. Fernando, Wenhua Jiao, Jana Polivkova, Jun Xiao, Steven B. Coffey, Colin Rose, Allyn Londregan,
James Saenz, Ramsay Beveridge, Yingxin Zhang, Gregory E. Storer, Derek Vrieze, Noe Erasga, Ryan Jones,
⇑
Vishal Khot, Kimberly O. Cameron, Kim F. McClure, Samit K. Bhattacharya, Suvi T. M. Orr
Pfizer Worldwide Research and Development, Eastern Point Rd, Groton, CT 06340, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
In the context of our ghrelin inverse agonist program, a functionalized bromoindane 3 provided a
versatile intermediate for structure–activity relationship studies. After developing operationally simple
cross-coupling reactions, a broad spectrum of chemical space was successfully explored. Optimization
of a one-pot borylation/Suzuki sequence provided the desired products in high yield with low loading
of the palladium catalyst. High yields of N-linked heterocyclic analogues were obtained through palla-
dium catalyzed C–N bond formation. In addition, carboxylation of the bromoindane provided an indane
carboxylic acid for further diversification.
Received 23 August 2012
Revised 4 September 2012
Accepted 5 September 2012
Available online 24 September 2012
Keywords:
Cross-coupling
Suzuki
Ó 2012 Elsevier Ltd. All rights reserved.
Bromoindane
Spiroazetidine–piperidine
Heterocycle
Modular intermediates are key components of any drug discov-
ery program. They can provide efficient access to analogues and al-
low for rapid structure–activity relationship (SAR) exploration.
Points of diversity within an intermediate combined with a robust
synthesis allow the discovery team to make rational decisions on
the structures they wish to pursue for their program. Our team
was interested in the structural diversity of spiroazetidine–piperi-
dines 1 and 2 (Fig. 1) as ghrelin1 inverse agonists and their use as
therapeutic agents to treat type 2 diabetes.2 We recently disclosed
the SAR work around scaffold 1,3 the synthesis of the chiral spiro-
azetidine–piperidines,4 and now wish to report the synthetic
enablement of the heteroaromatic region of scaffold 2.
The bromoindane 3 was prepared as described previously from
a chirally pure bromoindane amine and N-Boc-piperidine chloroal-
dehyde under reductive amination/cyclization conditions.4
Reaction of 3 with a variety of boronic acids was demonstrated;
however, the limited availability of heteroaryl boronic acid mono-
mers impacted the diversity of chemical space that could be
explored.5 In comparison, a diverse pool of heteroaryl halides are
available and we therefore reasoned that conversion of 3 to the
intermediate boronate 4 followed by Suzuki coupling with a vari-
ety of aryl halides would allow us to probe broader chemical space.
To access various structural analogues of 2, synthetic
enablement was required to effectively vary the heteroaryl group
off the indane ring. It was envisioned that intermediate 3 could
be a modular starting point conducive to chemical space expansion
and SAR exploration. The N-Boc protected piperidine ring would al-
low for orthogonal piperidine amide SAR development, while the
aryl halide would allow for exploration of a variety of aryl groups
at C5 (Scheme 1).
Ar
5
Ar
SAR exploration
Cl
R
N
N
N
N
R
O
O
1
2
⇑
Corresponding author. Tel.: +1 860 686 4192.
E-mail address: suvi.orr@pfizer.com (S.T.M. Orr).
Figure 1. Core structures of ghrelin inverse agonists for SAR exploration.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.047

6352
D. P. Fernando et al. / Tetrahedron Letters 53 (2012) 6351–6354
Et
O
B
N
Br
5
O
N
5
Et
N
(pinB)2
Pd(dppf)Cl2
5e
Cl
N
N
N
Boc
3
N
N
Pd(dppf)Cl2
K2CO3 (aq)
dioxane
KOAc
dioxane
N
Boc
N
Boc
6e
4
Scheme 1. One-pot borylation/Suzuki reaction of bromoindane 3.
The intermediate 4 was isolated in 64% yield and was subjected to
the Suzuki coupling, but the overall yield over the two-steps was
low (ꢀ50%) and 4 was not stable for storage (prone to hydrolysis
and further decomposition). Thus, the one-pot approach seemed
more appealing. Initial conditions for the one-pot two-step Suzuki
sequence involved heating 3 with 5 mol % of 1,10-bis(diphenyl-
phosphino)ferrocene)dichloro palladium (Pd(dppf)Cl2), bis(pinaco-
lato)diboron ((pinB)2) (1.1 equiv), and potassium acetate (4 equiv)
in 1,4-dioxane at 80–110 °C for 4–6 h, followed by addition of the
heteroaryl chloride such as 5e, additional 5 mol % of Pd(dppf)Cl2,
and aqueous potassium carbonate (7 equiv) and heating the mix-
ture in 1,4-dioxane at 110 °C for 18 h to give 68% yield of 6e after
silica gel chromatography. Several analogues were made following
this protocol (Table 1, conditions A) and they tended to have dark
color even after several chromatographic purifications. The
relatively large amount of palladium used over the two-steps
was considered to be the cause of the discoloration.
To avoid additional chromatography and to increase purity, the
two-step one-pot Suzuki process was optimized using 2-chloro-5-
ethylpyrimidine as the coupling partner. Each step was studied
separately by following the course of the reaction by HPLC. First,
the temperature and time of the borylation reaction were studied.
With 5 mol % of the Pd-catalyst the reaction did not proceed at all
at room temperature. Increasing the temperature to 110 °C for 1 h
with the same catalyst loading showed full conversion to the inter-
mediate boronate 4. The catalyst loading was reduced to 3 mol %
and finally to 1 mol % at 110 °C resulting in full conversion to 4 in
1 h. To this reaction mixture was added 2-chloro-5-ethylpyrimidine
(5e), potassium carbonate (7 equiv), various amounts of catalyst
(1–5 mol %) and the reactions were monitored by HPLC. After 3 h
at 110 °C, the reactions with 2–5 mol % catalyst had reached com-
pletion, whereas the reaction with just 1 mol % was 90% complete.
This reaction did not proceed further even after heating for 18 h.
However, the total catalyst loading was reduced from 10 to
3 mol % and the reaction time was reduced from 24 to 4 h. In
addition, the purity increased to 98% (HPLC) to produce 6e as an
off-white solid.6
The primary amide containing halide 5n also gave the desired
product under conditions A (entry 14); however, the reaction did
not go to completion (21% conversion by HPLC), even after pro-
longed heating and isolation of 6n was unsuccessful. Compound
6w was made from the boronic acid 5w (entry 23) in quantitative
yield under direct Suzuki coupling of 3 with 5 mol % of Pd(OAc)2
and trisodium triphenylphosphine-3,30,300-trisulfonate (TPPTS)
ligand (20 mol %). Five-membered heteroaryl analogues were
obtained from the bromides 5o–5t under conditions A to give
6o–6t between 32–96% yields (entries 15–20). The yield of 6u from
2-iodooxazole7 (5u) (entry 21) was rather low due to the instability
of 2-iodooxazole under aqueous conditions.
Upon scale-up of 6f and 6g, the one-pot Suzuki procedure was
further optimized using only one portion of 2.5 mol % of Pd
(PPh3)2Cl2 to give the desired products in high purity without chro-
matographic purification. The solvent was exchanged to toluene to
avoid potential peroxide generating 1,4-dioxane on larger scale.
Using NaOH in place of K2CO3 also improved the reaction, presum-
ably by effecting a more efficient in-situ boronate ester hydrolysis
reaction. An aqueous acid–base work up followed by treatment
with IsoluteÒ Ultra pure thiol silica gel gave >99% pure material.8
Both 6f and 6g were scaled up (>100 g) via this method in almost
quantitative yields.
In addition to one-pot borylation/Suzuki couplings and direct
Suzuki couplings, the bromoindane
3 can be subjected to
Buchwald-type couplings with NH-containing heterocycles 7a–7b
(entries 24 and 25).9 Using 4 mol % of tris(dibenzylideneace-
tone)dipalladium (Pd2(dba)3) catalyst and 8 mol % of 5-(di-tert-
butylphosphino)-103050-triphenyl-10H-[1,4]bipyrazole (BippyPhos)
ligand10 products 8a and 8b were isolated in great yields and
purity. Carboxylation of bromoindane 3 provided an additional
handle for structural diversity and was achieved with Mo(CO)6
and 5 mol % of Herrmann’s catalyst11 (trans-bis(acetate)bis[o-(di-
o-tolylphosphine)benzyl]dipalladium(II)) in the presence of aque-
ous sodium carbonate to give carboxylic acid 8c in moderate yield.
Removal of the N-Boc-group of compounds 6a–w and 8a–c using
standard acidic conditions (TFA or HCl) followed by amide coupling
with a variety of carboxylic acids provided a number of potent
ghrelin inverse agonists. A description of these compounds along
with key data will be provided in a separate communication.
In conclusion we have discovered smooth and operationally
simple methods for efficient delivery of a number of heteroaryl
analogues 2 from a key intermediate 3. These include a one-pot
two-step Suzuki protocol, a Buchwald-type coupling reaction,
and a carboxylation reaction. Optimization of the Suzuki reaction
for lower catalyst loading provided final products in high yield
and purity on small as well as on large scale. The synthetic meth-
ods identified enabled rapid SAR exploration of the indane scaffold
3 in the context of the drug discovery program.
Several other heteroaryl halides were tested in this reaction and
the results are shown in Table 1. In general, the reaction works well
with six-membered heteroaryl chlorides 5a–5i (yields between
63% and 94%, entries 1–9). When a hydrolytically labile group
(i.e., nitrile or ester) is present, the yield drops due to partial
hydrolysis of the final product under the reaction conditions (en-
tries 10–12). A similar result was observed for compound 6v which
was obtained in 24% yield from the boronic acid 5v under standard
Suzuki conditions with 5 mol % of Pd(PPh3)4 (entry 22). In contrast,
compound 6m (entry 13) and the starting material 5m seemed to
be stable toward hydrolysis and the product was isolated in
quantitative yield.

D. P. Fernando et al. / Tetrahedron Letters 53 (2012) 6351–6354
6353
Table 1
Examples of compounds accessible from bromoindane 3
Br
R
5a-u
One-pot borylation/
Suzuki conditions
A-C (via 4)
N
N
5v-w direct Suzuki
conditions D-E
7a-b C-N coupling
conditions F
7c carboxylation
conditions G
N
Boc
N
Boc
6a-w
8a-c
3
Entry
1
Reactant
Conditionsa
B
Product (yield)b (%)
Entry
Reactant
Conditionsa
A
Product (yield)b (%)
H2NOC
5a
5n
N
6a (99)
14
6n (21)c
6o (80)
6p (60)
N
Br
N
N
Cl
Cl
N
S
5b
5c
5o
5p
N
2
3
A
B
6b (63)
6c (94)
15
16
A
A
N
Cl
Me
N
Br
Br
Me
N
Cl
S
N
Me
5d
5e
5q
5r
N
4
A
6d (81)
17
A
6q (32)
S
N
Me
Me
N
Cl
Et
N
N
N
Br
5
6
B
C
6e (>99)
6f (84)
18
19
A
A
6r (47)
6s (78)
O
N
Cl
Cl
5s
5t
5f
N
N
Me
N
Me
Me
N
N
Br
5g
N
Br
N
7
8
C
A
6g (86)
6h (88)
20
21
A
A
6t (96)
6u (20)
S
Me
Cl
N
5u
5h
5i
N
Et
N
I
O
Cl
Me
N
5v MeO2C
N
N
9
A
A
6i (82)
6j (19)
22
23
D
E
6v (24)
Me
NC
Cl
B(OH)2
B(OH)2
5j
H2NOC
5w
N
N
Br
10
6w (>99)
5k NC
7a
NH
N
11
12
13
A
A
B
6k (54)
6l (20)
24
25
26
F
8a (82)
8b (79)
8c (51)
N
N
Cl
7b
5l
Me
NC
N
NH
F
N
Cl
5m NC
6m (>99)
7c Mo(CO)6
G
N
Br
a
Conditions: (A) (i) Pd(dppf)Cl2 (5 mol %), (pinB)2 (1.1 equiv), KOAc (4 equiv), dioxane, 110 °C, 4–6 h; (ii) Ar-X (1.2 equiv), Pd(dppf)Cl2 (5 mol %), K2CO3 (7 equiv), dioxane,
110 °C, 18 h. (B) (i) Pd(dppf)Cl2 (1.6 mol %), (pinB)2 (1.1 equiv), KOAc (4 equiv), dioxane, 110 °C, 1 h; (ii) Ar-X (1.2 equiv), Pd(dppf)Cl2 (2.5 mol %), K2CO3 (7 equiv), dioxane,
110 °C, 3 h. (C) (i) Pd(PPh3)2Cl2 (2.5 mol %), (pinB)2 (1.1 equiv), KOAc (4 equiv), toluene, 100 °C, 1.5 h; (ii) Ar-X (1.2 equiv), NaOH (5 equiv), toluene, 90 °C, 5 h; (iii) HCl,
isoluteÒ ultra pure thiol silica gel. (D) Pd(PPh3)4 (5 mol %), K2CO3 (2 equiv), dioxane, 95 °C, 18 h. (E) Pd(OAc)2 (5 mol %), TPPTS (20 mol %), iPrNH (2.4 equiv), H2O/MeCN, 90 °C,
2 h. (F) Pd2dba3 (4 mol %), BiPPyPhos (8 mol %), Cs2CO3 (1.5 equiv), dioxane, 100 °C, 18 h. (G) Herrmann’s catalyst (5 mol %), Na2CO3 (3 equiv), 155 °C,
lwave, 20 min.
b
Yield refers to isolated product and is reported as an average of minimum of two experiments.
c
HPLC conversion, not isolated.

6354
D. P. Fernando et al. / Tetrahedron Letters 53 (2012) 6351–6354
30.0, 29.3, 27.5; HRMS (CI): m/z 421.2587 (Calculated 421.2598 for
25H32N4O2+H).
Supplementary data
C
7. Bayh, O.; Awad, H.; Mongin, F.; Hoarau, C.; Bischoff, L.; Trécourt, F.; Quéguiner,
G.; Marsais, F.; Blanco, F.; Abarga, B.; Ballesteros, R. J. Org. Chem. 2005, 70,
5190–5196.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.09.
047. These data include MOL files and InChiKeys of the most
important compounds described in this article.
8. Exemplary procedure for conditions C: To a 50 mL flask containing tert-butyl
2-[(R)-5-bromo-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane-7-carb
oxylate 3 (4.0 g, 9.49 mmol) were added bis(triphenylphosphine)palla dium(II)
chloride (0.17 g, 0.24 mmol), potassium acetate (3.73 g, 37.97 mmol), and
bis(pinacolato)diboron (2.65 g, 10.44 mmol) followed by degassing via vacuum
then backfilling with nitrogen five times. De-oxygenated (N2 stream for
30 min) toluene (40 mL) was added to the mixture and the reaction was heated
at 100 °C for 1.5 h. The reaction was monitored for completion by HPLC. Upon
formation of the boronic ester intermediate, the reaction was cooled to 40 °C
and charged with a degassed solution of 4 M sodium hydroxide (11.87 mL,
47.46 mmol) followed by the addition of 4-chloro-6-methylpyrimidine 5g
(1.53 g, 11.87 mmol). The resulting mixture was then heated to 90 °C for 5 h
under nitrogen. The reaction was cooled to room temperature and charged
with water (25 mL). After stirring for 20 min, the mixture was filtered to
remove black solids. The organic layer was extracted to an aqueous solution
containing HCl (40 mL). The organic layer was removed and the resulting
solution was treated with (4 g) ISOLUTEÒ Ultra Pure Si-Thiol silica gel for 1.5 h
and filtered. The pH of the aqueous solution was then adjusted with 4 N NaOH
to pH 7.8 and extracted to toluene (40 mL). The toluene layer was concentrated
to approximately 15 mL under reduced pressure at 45 °C and heptane (75 mL)
was added slowly with stirring at 20 °C for 1 h. The product was then filtered
and dried under vacuum at 45 °C for 8 h to afford 6g (3.56 g, 86%) as a white
solid. 1H NMR (500 MHz, Cd3Od): d 9.00 (s, 1 H), 8.03 (s, 1 H), 7.98 (d, J = 5.0 Hz,
1 H), 7.86 (s, 1 H), 7.49 (d, J = 10.0 Hz, 1 H), 4.07–4.04 (m, 1 H), 3.36 (s, 4 H),
3.32–3.29 (m, 2 H), 3.26 (d, J = 5.0 Hz, 2 H), 3.16–3.10 (m, 1 H), 2.93–2.87 (m, 1
H), 2,57 (s, 3 H), 2.29–2.23 (m, 1 H), 1.96–1.90 (m, 1 H), 1.72–1.67 (m, 4 H), 1.45
(s, 9 H); 13C NMR (125 MHz, Cd3Od): d 167.9, 164.4, 157.9, 155.3, 146.2, 145.7,
136.4, 125.6, 125.0, 123.7, 116.9, 79.8, 71.6, 62.3, 48.0, 35.6, 33.9, 30.1, 29.3,
27.5, 22.7; HRMS (CI): m/z 435.2753 (Calculated 435.2755 for C26H34N4O2 + H).
Spectral data for compound 6f: 1H NMR (500 MHz, DMSO-d6): d 8.70 (d,
J = 5.4 Hz, 1 H), 8.04 (s, 1 H), 7.96 (dd, J = 7.9, 1.6 Hz, 1 H), 7.82 (d, J = 5.4 Hz, 1
H), 7.40 (d, J = 7.8 Hz, 1 H), 3.87 (dd, J = 6.5, 3.5 Hz, 1 H), 3.30–3.20 (m, 4 H),
3.08 (d, J = 6.6 Hz, 2 H), 3.03–2.93 (m, 3 H), 2.81 (ddd, J = 15.9, 8.7, 4.4 Hz, 1 H),
2.66 (s, 3 H), 2.11–2.01 (m, 1 H), 1.85 (ddt, J = 12.5, 8.4, 4.1 Hz, 1 H), 1.60–1.53
(m, 4 H), 1.37 (s, 9 H); 13C NMR (125 MHz, DMSO-d6): d 167.3, 162.8, 157.9,
153.9, 146.5, 144.9, 135.6, 125.0, 124.9, 123.2, 113.9, 99.3, 78.5, 70.2, 61.5, 35.3,
33.8, 30.0, 28.9, 28.1, 25.9; HRMS (CI): m/z 435.2759 (Calculated 435.2755 for
References and notes
1. For ghrelin background, see: (a) Kojima, M.; Hosoda, H.; Date, Y.; Nakazato, M.;
Matsuo, H.; Kangawa, K. Nature 1999, 656–660; (b) Leite-Moreira, A. F.; Soares,
J.-B. Drug Discovery Today 2007, 12, 276–288; (c) Dezaki, K.; Sone, H.; Yada, T. J.
Biochem. 2008, 118, 239–249; (d) Sato, T.; Nakamura, Y.; Shiimura, Y.; Ohgusu,
H.; Kangawa, K.; Kojima, M. J. Biochem. 2012, 151, 119–128.
2. Bhattacharya, S. K.; Cameron, K. O.; Fernando, D. P.; Kung, D.W.; Londregan, A.
T.; McClure, K. F.; Simila, S. T. M. PCT Int. Appl. WO2011114271, 2011; PCT/
1B2011/051035; Chem. Abstr. 2011, 155, 483976.
3. Kung, D. W.; Coffey, S. B.; Jones, R. M.; Cabral, S.; Jiao, W.; Fichtner, M.; Carpino,
P. A.; Rose, C. R.; Hank, R. F.; Lopaze, M. G.; Swartz, R.; Chen, H.; Hendsch, Z.;
Posner, B.; Wielis, C. F.; Manning, B.; Dubins, J.; Stock, I. A.; Varma, S.; Campbell,
M.; DeBartola, D.; Kosa-Maines, R.; Steyn, S. J.; McClure, K. F. Bioorg. Med. Chem.
Lett. 2012, 22, 4281–4287.
4. Orr, S. T. M.; Cabral, S.; Fernando, D. P.; Makowski, T. Tetrahedron Lett. 2011, 52,
3618–3620.
5. Based on search and comparison of commercially available heteroaryl boronic
acids and heteroaryl halides by SciFinderÒ
.
6. General procedure for conditions B: To a vial with septa containing tert-butyl
2-[(R)-5-bromo-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane-7-
carboxylate 3 (2.42 mmol) were added bis(pinacolato)diboron (2.61 mmol),
potassium acetate (12.12 mmol), and Pd(dppf)Cl2 (0.039 mmol). The vial was
purged with a stream of nitrogen, and anhydrous 1,4-dioxane (12 mL) was
added. The resulting mixture was purged with nitrogen for three times, and the
mixture was heated at 95 °C for 1 h. The aryl halide 5 (2.61 mmol), Pd(dppf)Cl2
(0.062 mmol), and 9 ml of 2 M aqueous potassium carbonate solution
(de-oxygenated by bubbling through N2 for 15 min) were added. The mixture
was purged with N2 three times and heated at 95 °C for 17 h. The mixture was
cooled to room temperature and the organic layer was separated from the
aqueous layer. The organic layer was filtered through a thin plug of silica gel,
and rinsed with 5 mL of isopropyl alcohol followed by 5 mL of MeOH. The
filtrate and the washings were concentrated under reduced pressure to give the
crude product that was purified by silica gel chromatography eluting with a
gradient of 0–10% MeOH in CH2Cl2 to give the desired product. Spectral data for
compound 6a: 1H NMR (500 MHz, Cd3Od): d 8.83 (d, J = 5.0 Hz, 2 H), 8.29 (s, 1
H), 8.24 (d, J = 10.0 Hz, 1 H), 7.48 (d, J = 10.0 Hz, 1 H), 7.34 (t, J = 5.0 Hz, 1 H),
4.10–4.08 (m, 1 H), 3.37 (s, 4 H), 3.32–3.30 (m, 2 H), 3.29–3.28 (m, 2 H), 3.17–
3.11 (m, 1 H), 2.94–2.88 (m, 1 H), 2.31–2.24 (m, 1 H), 1.97–1.91 (m, 1 H), 1.74–
1.72 (m, 4 H), 1.45 (s, 9 H); 13C NMR (125 MHz, Cd3Od): d 164.7, 157.5, 155.3,
145.6, 145.2, 137.6, 126.4, 124.5, 119.5, 99.9, 79.8, 71.7, 62.3, 51.0, 35.6, 33.9,
C
26H34N4O2+H).
9. Yin, J.; Buchwald, S. J. Am. Chem. Soc. 2002, 124, 6043–6048.
10. (a) Singer, R. A.; Withbroe, G. J.; Sieser, J. E. Org. Process Res. Dev. 2008, 12,
480–489; (b) Singer, R. A.; Doré, M.; Sieser, J. E.; Berliner, M. A. Tetrahedron Lett.
2006, 47, 3727–3731; (c) Singer, R. A.; Tom, N. J.; Frost, H. N.; Simon, W. M.
Tetrahedron Lett. 2004, 45, 4715–4718.
11. Wu, X.; Larhed, M. Org. Lett. 2005, 7, 3327–3329.