Convergent synthesis of a 5HT7/5HT2 dual antagonist

Article abstract of DOI:10.1021/op2001194

The development of an efficient and convergent route to 3-(4-fluorophenyl)-2-isopropyl-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine (1), a potent 5HT₇/5HT₂ dual antagonist, is described. Significant features of this route are: (a) a r

Full text of DOI:10.1021/op2001194

ARTICLE
pubs.acs.org/OPRD
Convergent Synthesis of a 5HT7/5HT2 Dual Antagonist
Jimmy T. Liang,* Xiaohu Deng, and Neelakandha S. Mani
Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, California 92121, United States
S Supporting Information
b
ABSTRACT: The development of an efficient and convergent route to 3-(4-fluorophenyl)-2-isopropyl-2,4,5,6,7,8-hexahydropyrazolo-
[3,4-d]azepine (1), a potent 5HT7/5HT2 dual antagonist, is described. Significant features of this route are: (a) a regioselective
construction of a tetra-substituted pyrazole 6a by reacting an N-monosubstituted hydrazone 4a with an elaborated nitroolefin 5b
and (b) a unique Pd-catalyzed hydrogenation method that carries out the four-step, ring-closing reductive amination sequence in a
notable one-pot operation to provide 1 in excellent overall yields.
’ INTRODUCTION
with isopropyl hydrazine followed by triflate formation with
phenyl-bis-trifluoromethanesulfonamide, a palladium-catalyzed
SuzukiꢀMiyaura reaction8 with (4-fluorophenyl)boronic acid
and then Boc-deprotection afforded compound 1. Despite the
efficiency of this route, there were potential drawbacks when
considering large-scale process development. The major concerns
were the following: (1) the use of hazardous ethyl diazoacetate9
in the ring-expansion step; (2) the use of a homogeneous pal-
ladium catalyst in the SuzukiꢀMiyaura coupling reaction, as the
need for removal of Pd in the final step may be necessary and
expensive; and (3) use of chromatographic purifications in steps
one and four. To circumvent all of the above concerns, we report
a new convergent route based on a novel regioselective pyrazole
synthesis that was designed and carried out in our lab on 200-g
scale. Our synthetic approach demonstrates a regioselective
reaction of hydrazone 4a with nitroolefin 5b to obtain pyrazole
6a. Further development of the last stage led to a four-step, one-pot
intramolecular ring closure of the azepane ring of product 1.
Overall, this route is high-yielding, inexpensive, chromatography-
free, and adaptable for large-scale production.
Serotonin (5-hydroxytryptamine, 5-HT), a biochemically derived
monoamine neurotransmitter, is mostly produced and found in
the intestine with the remainder in the central nervous system.1
Serotonin regulates sleep, memory and learning, mood, behavior,
muscle contraction, appetite, temperature, and function of the
cardiovascular and endocrine system via activation of serotonin
receptors (5-hydroxytryptamine receptors, 5-HT receptors).2
These receptors are classified into seven distinct families termed
5HT1 through 5HT7 and all are G protein-coupled receptors
with the exception of the 5-HT3 receptor, which is a ligand-gated
ion channel.3 Within these general classes of serotonin receptors,
at least 14 distinct subtype receptors have been identified by
molecular cloning studies. The identification of several subtype
5-HT receptors has provided scientists with opportunities to
characterize therapeutic agents believed to act via the serotonergic
system.
Our interest to target serotonin receptors was directly related
to one of our drug discovery programs. Recent efforts from our
neuroscience group led to the discovery of a novel class of
pyrazole compounds showing potent 5HT7 and/or 5HT2 an-
tagonist activity.4 Compound 1 was recognized as an important
lead candidate for the potential treatment of depression, psy-
chosis, anxiety, and sleep disorders (Figure 1).5 The notable
feature of 1 is the fused pyrazolo[3,4-d]azepane core structure.
Several pharmacological compounds are also known to contain
this core for potential indications of Alzheimer’s, obesity, sub-
stance abuse, and other diseases.6 The challenge associated with
these molecules primarily consists of constructing the pyrazolo-
[3,4-d]azepane core with its synthesis proceeding through one of
two general linear strategies: (1) from commercially available
4-azepanone followed by protection, pyrazole formation, deriva-
tizations then deprotection or (2) from a preassembled pyrazole
followed by derivatizations then cyclization to the azepane ring.
Unfortunately, both strategies suffer from lengthy routes and
require expensive starting materials.
’ RESULTS AND DISCUSSION
In our search for alternative ways to synthesize pyrazoles, we
found sporadic examples in the literature describing the reaction
of N-monosubstituted hydrazones and substituted nitroolefins
affording pyrazole and/or pyrazolidine products.10 Most recently,
Deng and Mani11 have demonstrated excellent regioselectivity in
the reaction of N-monosubstituted hydrazones with various
substituted nitroolefins in a variety of solvents and at various
reaction temperatures under air atmosphere. The results of these
studies prompted us to speculate that this particular pathway
could be employed to regioselectively build the requisite pyrazole.
By analyzing compound 1 retrosynthetically (Scheme 2), we
chose to first disconnect the azepane ring at the CꢀN posi-
tion where the linkages on both ends could be protected as in
compound 6. With intermediate 6 in hand, one could potentially
conceive the synthesis of the azepane ring via deprotection on
both ends followed by intramolecular reductive amination to give
Early on, the medicinal chemistry team employed a sequence
based on late-stage introduction of the fused pyrazole beginning
with commercially available Boc-piperidone (Scheme 1). Ring
expansion by treatment with ethyl diazoacetate7 furnished the
azepanone ester. A subsequentpyrazole synthesis7 by condensation
Received: April 27, 2011
Published: May 31, 2011
r
2011 American Chemical Society
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Figure 1. Structure of pyrazolo[3,4]azepanes of clinical interest.
Scheme 1. Original synthesis of 1
Scheme 2. Retrosynthetic analysis of compound 1
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the final compound 1. As for the formation of 6, we envisaged the
disconnection of the pyrazole at the CꢀN and CꢀC bonds. The
synthesis of 6 would then derive from the key reaction of
hydrazone 4 and nitroolefin 5 presumably through a stepwise
cycloaddition pathway.11a Keep in mind, one of the challenges in
the synthesis of both 4 and 5 was finding suitable protecting
groups, which offered stability during the pyrazole synthesis
and then facile deprotection during the cyclization step. We
envisioned the synthesis of 5 utilizing the Knoevenagel conden-
sation conditions or by Henry reaction of 4-fluoro-benzaldehyde
with a protected nitro-propane acetal. For the synthesis of 4, we
anticipated utilizing commercially available isopropyl hydrazine
reacting with an N-protected 3-amino propionaldehyde.
In the preparation of hydrazone 4, we primarily selected benzyl
N-(3-oxopropyl)carbamate as our starting material (Scheme 3).
We reasoned that the use of Cbz protection would provide adequate
stability during pyrazole formation and at the same time would be
reasonably labile to removal prior to or possibly following the
cyclization to the seven-membered ring. Our initial attempt using
standard hydrazone formation conditions provided the requisite
4a in 98% yield. The light-yellow oil was used directly without
further purification.
For the protection of the nitroolefin 5, we initially examined
the diethyl acetal group (Scheme 4). Following literature
procedures,12 1,1-diethoxy-3-nitropropane was prepared without
difficulty but unfortunately, the subsequent Henry reaction-
elimination step provided the desired olefin 5a only in very
low yield after silica gel chromatographic purification. Several
other base-catalyzed reactions at varying temperatures were also
evaluated without success, as most of the reactions afforded
mixtures of starting material and nitro aldol compound. In
addition, when the reaction was heated up to 80 °C, we observed
slow decomposition of the starting material. It thus became
apparent that 1,1-diethoxy-3-nitropropane was not a suitable
material for our use. The problem was solved by the selection of
2-(2-nitroethyl)-1,3-dioxolane with the expectation that the
ethylene acetal protecting group could endure elevated tempera-
ture conditions. By applying classic condensation conditions to
2-(2-nitroethyl)-1,3-dioxolane and 4-fluoro-benazldehyde, we
successfully synthesized nitroolefin 5b in quantitative crude
yield.13 The viscous brown oil was isolated in high purity and
used directly in the next step.
Scheme 3. Preparation of hydrazone
With two major building blocks 4a and 5b at hand, we directed
our efforts to the important pyrazole synthesis. By combining 4a
and 5b in THF at 60 °C, the reaction undergoes a slow oxidation
step under open air for several days, followed by a fast elimination
of HNO2 to furnish pyrazole 6a in quantitative crude yield.
However, in order to drive the reaction to completion, several
equivalents of 4a were necessary. Presumably, the elimination of
HNO2 in the reaction gradually caused decomposition of 4a.11
We rationalized that the addition of a base to capture the nitrous
acid could be helpful in preventing this decomposition. We were
pleased to find that using triethylamine as the solvent indeed
eliminated this undesirable decomposition and the reaction went
to completion with 1.2 equiv of 4a. After stirring for 2 days at
room temperature in open air, the reaction afforded pyrazole 6a
in >80% yield (Scheme 5). Upon further optimization, we found
that trituration from Et2O/hexanes effectively increased the
purity of the solid product to >95%. This reaction was success-
fully performed on 200-g scale.
Scheme 4. Synthesis of nitroolefin
With the completion of the pyrazole synthesis, we initially
envisaged a stepwise cyclization of 6a to azepane 1. By employ-
ing 6 N HCl14 to remove the Cbz and the acetal protecting
group, our analysis of the reaction mixture by mass spectro-
metry indicated several possible compounds (Scheme 6). After
workup of the crude intermediates, we proceeded with the
reductive amination step utilizing Na(OAc)3BH to afford the
final compound 1 in 80% crude yield. Although a valid route to
Scheme 5. Pyrazole formation
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Scheme 6. Two-step sequence to compound 1
Scheme 7. One-step cyclization of compound 1
the complete synthesis of 1 was now established, the cyclization
step still needed improvement. While examining the removal of
the Cbz group by mild hydrogenolysis, we realized that we
could perhaps achieve both Cbz and acetal deprotection, as well
as reductive cyclization by hydrogenation in a mild aqueous
HCl/alcohol mixture. The acidic medium should induce cycliza-
tion and subsequent elimination to form imine or enamine
intermediates followed by hydrogenation again to provide com-
pound 1, all in a one-pot process (Scheme 7). Indeed, after some
optimization on small scale, we eventually obtained >90% yield
of 1 using a 3 N HCl/EtOH mixture with 10% Pd/C, hydro-
genating at 40 psi and 45 °C. Interestingly, when the reaction was
repeated on a 30-g scale, to our surprise, we only isolated 84%
yield of crude product. Close examination of reaction products
revealed 22% of dimer 1a. Upon further investigation, we realized
several factors contributed to dimer formation (Table 1). First,
there was the concentration effect. A range of concentration
levels in the reaction was screened to analyze the HPLC ratio of
1/1a. We noticed that, when the concentration of 6a in IPA was
decreased from 0.3 to 0.2 M or 0.1 M with 10% by weight of
catalysts (entries 4ꢀ6), greater intramolecular formation of 1
was observed. Second, there was the solvent effect. We examined
several solvents such as EtOH, IPA, AcOH, EtOAc, and tert-amyl
alcohol. Interestingly, we found that secondary and tertiary
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Table 1. Contributing factors to the formation of compound 1
entry
concentration (M)
solvents
EtOH
weight 10% Pd/C (wt %)
HPLC ratio 1/1a
1
0.2
0.2
0.2
0.3
0.2
0.1
0.2
0.2
0.2
0.2
10
10
10
10
10
10
5
85/15
60/40
85/15
65/35
90/10
99/1
2
AcOH
3
EtOAc
4
IPA
5
IPA
6
IPA
7
tert-amyl OH
tert-amyl OH
tert-amyl OH
tert-amyl OH
87/13
93/7
8
10
20
25
9
95/5
10
99/1
alcohols such as IPA or tert-amyl alcohol decreased dimer for-
mation while enhancing intramolecular cyclization to product 1,
whereas AcOH did not offer any significant advantage. As for
EtOH and EtOAc, both solvents did facilitate the formation of 1
but less than IPA and tert-amyl alcohol. Last, there was an effect
of catalyst loading (entries 7ꢀ10). We conducted several reac-
tions with various quantities of 10% Pd/C and found that 20%
and 25% by weight of catalysts increased the intramolecular
formation of 1. In comparison, 5% and 10% by weight of catalysts
afforded the least amount of 1. With all the factors taken into
consideration, the synthesis of the azepane ring was finally
optimized utilizing 3 equiv of 3 N HCl and 25% by weight of
10% Pd/C in 0.2 M of tert-amyl alcohol. The reaction was
hydrogenated at 40 psi for 18 h at 45 °C to afford product 1 in
89% crude yield with <2% of impurity 1a present. Purification
was accomplished by recrystallization of 1 in MeOH/EtOAc as
its citrate salt, followed by base liberation to provide the final
compound 1 in 71% yield.
It should be noted that all of our operations described were
performed in a research laboratory setting not in a process plant.
Additional fine-tuning of the process work is necessary if further
up-scaling is required. Due to time constraints, optimization of
the synthesis route was not thoroughly investigated during the
production campaign. In this case, the use of unsuitable solvents
(hexane and MTBE) in the trituration step can be substituted
with more process friendly solvents such as heptanes and MTBE.
Additionally, the repeated stripping to dryness operations can
also be circumvented by simple solvent exchange.
olefin; (2) a direct four-step process of deprotection, intramole-
cular cyclization, elimination, and reduction all in a one-pot
operation to obtain the final drug substance 1. With several
pharmacological compounds containing a similar pyrazolo-fused
azepane core, we anticipate the utility of this sequence to be
applicable to the syntheses of many other biologically active
compounds.
’ EXPERIMENTAL SECTION
Benzyl 3-(2-Isopropylhydrazono)propylcarbamate (4a). A
solution of isopropyl hydrazine hydrochloride (92.4 g, 0.84 mol)
and benzyl (3-oxopropyl)carbamate (173 g, 0.84 mol) in iso-
propyl alcohol (1.7 L) was treated with Et3N (140 mL, 1.0 mol)
over 20 min. White solids precipitated to form a thick reaction
mixture. The slurry mixture was heated to reflux temperature for
3 h then cooled down to room temperature. The solvent was
concentrated under reduced pressure (30 Torr, 40 °C) and the
recovered residue was diluted in EtOAc (700 mL). The organic
layer was washed with water (3 ꢁ 500 mL), brine (300 mL) and
dried over MgSO4. After filtration and evaporation under reduced
pressure, the title compound 4a was isolated as a light-yellow oil
(216 g, 0.82 mol, 98%). The crude product was used in the next
reaction without further purification. The hydrazone 4a is stable at
room temperature for weeks. However, it is recommended to use
it right away. 1H NMR (400 MHz, CDCl3) δ: 7.38ꢀ7.26 (m, 5H),
7.01 (t, J = 4.5 Hz, 1H), 5.11 (br s, 1H), 5.08 (s, 2H), 3.46ꢀ3.32
(m, 3H), 2.42ꢀ2.32 (m, 2H), 1.11 (d, J = 6.4 Hz, 6H); 13C NMR
(125.7 MHz, CDCl3) δ: 156.5, 139.4, 136.6, 128.7, 128.2, 66.7,
50.1, 38.4, 32.7, 22.0; HRMS-ESI (m/z) calcd for C14H21N3O2
[M þ H]þ 264.1707, undetectable.
’ CONCLUSIONS
In summary, we have demonstrated a compelling route for the
complete synthesis of compound 1 (Scheme 8). The convergent
synthesis proceeds through a significantly less expensive, very
efficient, and chromatography-free route that is adaptable
to large-scale manufacture. The accomplishments include the
following: (1) a regioselective pyrazole synthesis involving an
N-monosubstituted hydrazone reacting with a disubstituted nitro
2-(3-(4-Fluorophenyl)-2-nitroallyl)-1,3-dioxolane (5b). A
solution of 2-(2-nitroethyl)-1,3-dioxolane (162.5 g, 1.10 mol),
fluorobenzaldehyde (124 g, 1.0 mol), and piperidine (15 mL,
0.15 mol) in toluene (1.2 L) was heated to reflux under N2 for
18 h using a DeanꢀStark trap, then cooled to room temperature.
Approximately, 15 mL of water was collected. The reaction mixture
was washed with water (2 ꢁ 300 mL) and brine (2 ꢁ 300 mL). The
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Scheme 8. Convergent synthesis of compound 1
extracted organic layer was dried over MgSO4 and filtered.
Activated powder charcoal (80.0 g) was added to the organic
solution, and the suspension was stirred for 1 h. After filtration,
the solvent was evaporated under reduced pressure to obtain the
title compound 5b as a brown, viscous oil (264 g, 1.04 mol,
quantitative crude yield). The crude product was used in the next
reaction without further purification. 1H NMR (500 MHz, CDCl3)
δ: 8.15 (s, 1H), 7.69ꢀ7.67 (m, 2H), 7.16ꢀ7.12 (m, 2H), 5.23
(t, J = 4.5 Hz, 1H), 4.02ꢀ3.98 (m, 2H), 3.94ꢀ3.89 (m, 2H), 3.26
(d, J = 4.5 Hz, 2H); 13C NMR (125.7 MHz, CDCl3) δ: 165.0,
163.0, 146.8, 135.7, 132.3, (128.3, 128.3), (116.4, 116.3), 102.0,
65.3, 32.3; HRMS-ESI (m/z) calcd for C12H12FNO4 [M þ H]þ
254.0823, found 254.0816.
2H), 2.85 (t, J = 6.0 Hz, 2H), 2.59 (d, J = 4.8 Hz, 2H), 1.35 (d, J =
6.6 Hz, 6H); 13C NMR (125.7 MHz, CDCl3) δ: 163.8, 161.8,
156.5, 148.4, 140.5, 137.0, (131.91, 131.85), 128.4, (127.96,
127.88), 126.78, 126.75, (115.81, 115.64), 111.2, 104.2, 66.3, 64.8,
49.9, 40.3, 28.4, 26.6, 22.8; HRMS-ESI (m/z) calcd for
C26H31FN3O4 [M þ H]þ 468.2295, found 468.2292; IR (film)
3305.90 1716.90, 1690.20, 1546.39, 1508.40, 1265.50 cmꢀ1; mp
99ꢀ100 °C.
3-(4-Fluorophenyl)-2-isopropyl-2,4,5,6,7,8-hexahydropy-
razolo[3,4-d]azepine, (1). A 2.25-L, glass hydrogenation bottle
was charged with pyrazole 6a (90.0 g, 0.19 mol) in tert-amyl
alcohol (910 mL) and 3 N HCl (190 mL, 0.57 mol). With
compound6a in solution and the bottle under N2, 10%Pd/C (22.2
g) was added into the mixture. The reaction mixture was
hydrogenated to 40 psi for 18 h at 45 °C and then filtered
through acid-treated low-metal filter paper. The filtrate was
concentrated under reduced pressure (30 Torr, 50 °C) to an
oil and then diluted with H2O (500 mL). The aqueous solution
was washed with EtOAc (3 ꢁ 250 mL) and then adjusted to pH
13ꢀ14 by adding KOH pellets under cold ice bath. The aqueous
layer was washed with EtOAc (3 ꢁ 250 mL), and the extracted
organic phase was filtered through acid-treated low-metal filter
paper to remove any remaining solids. The filtrate was dried over
Na2SO4, filtered, and concentrated under reduced pressure to
recover 46.2 g of crude 1 as a tan solid. The crude material was
dissolved in MeOH (200 mL) and then treated with warm citric
acid (35.4 g, 0.18 mol) in MeOH (120 mL). When additional
EtOAc (250 mL) was added to the mixture, precipitation of
citrate salt 1 began to develop. The slurry mixture was stirred for
18 h and then filtered to recover 63.8 g of the citrate salt of 1. The
solids thus obtained were stirred in EtOAc (400 mL) and 1 N
NaOH (350 mL). After the solids dissolved, the aqueous phase
was removed, and the organic layer was dried over Na2SO4,
filtered, and concentrated under reduced pressure to recover 1 as
an off-white solid (36.9 g, 0.13 mol, 71% yield). Pd analysis of the
final drug substance was less than 1 ppm. 1H NMR (400 MHz,
CDCl3 δ: 7.20ꢀ7.25 (m, 2H), 7.13ꢀ7.18 (t, J = 8.6 Hz, 2H),
4.21ꢀ4.28 (sept, J = 6.6 Hz, 1H), 3.01ꢀ3.04 (m, 2H), 2.88ꢀ2.94
(m, 4H), 2.46 (t, J = 5.2 Hz, 2H), 1.40 (d, J = 6.6 Hz, 6H); 13C
NMR (125.7 MHz, CDCl3 δ: 161.9, 151.9, 139.3, 132.0, 131.9,
Benzyl2-(4-((1,3-Dioxolan-2-yl)methyl)-5-(4-fluorophenyl)-
1-isopropyl-1H-pyrazol-3-yl)ethylcarbamate (6a). A solution of
compound 4a (216 g, 0.82 mol) in Et3N (1 L) was treated with
compound 5b (173 g, 0.68 mol) over 20 min. The reaction was
stirred open to air at room temperature for 2 days. Caution!
Although air is needed for the reaction, care should be taken when
stirring in open air due to potential safety hazard. Et3N was
evaporated by rotary evaporation (50 Torr, 40 °C), and the
remaining residue was dissolved in EtOAc (1.2 L). Any remaining
insoluble material was filtered off through filter paper. The organic
solution was washed with water (3 ꢁ 500 mL) and brine (500 mL),
dried over MgSO4, andthen filtered througha short pad of silica gel
(∼200 g). Evaporation of solvent under reduced pressure afforded
the title compound 6a as an orange, viscous oil (330 g, 100%). After
2 days under house vacuum (15 Torr), the crude oil 6a solidified to
form an orange solid. The solid was slurried in Et2O (350 mL) and
hexanes (600 mL) for 3 h at room temperature and then was
collected by filtration. The solids were dried under house vacuum
oven (15 Torr) at 40 °C overnight to obtain compound 6a as an
orange fine powder (260 g, 0.56 mol, 81%). To recover additional
6a, the mother liquor was concentrated under reduced pressure,
and the same trituration procedure was repeated. Sometimes the
recovered material from the mother liquor did not solidify and
1
required chromatography to isolate 6a. H NMR (500 MHz,
CDCl3) δ: 7.40ꢀ7.24 (m, 7H), 7.17ꢀ7.10 (m, 2H), 5.82 (br s,
1H), 5.10 (s, 2H), 4.75 (t, J = 4.8 Hz, 1H), 4.18 (sept, J = 6.6 Hz,
1H), 3.90ꢀ3.68 (m, 2H), 3.68ꢀ3.65 (m, 2H), 3.58 (q, J = 6.0 Hz,
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127.1, 118.3, 116.0, 115.8, 50.8, 49.9, 49.3, 33.8, 28.4, 23.0; HRMS-
ESI (m/z) calcd for C16H20FN3 [M þ H]þ 274.1714, found
274.1701; mp 145 ꢀ147 °C.
13167–13180. (e) Padwa, A., Pearson, W. H., Eds. Synthetic Applications of
1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products;
John Wiley & Sons: New York, 2002.
(11) (a) Deng, X.; Mani, N. S. J. Org. Chem. 2008, 73, 2412–2415.
(b) Deng, X.; Mani, N. S. Org. Lett. 2006, 8, 3505–3508. (c) Deng, X.;
Mani, N. S. Org. Lett. 2008, 10, 1307–1310.
(12) (a) Ohrlein, R.; Schwab, W.; Ehrler, R.; Jager, V. Synthesis
1986, 535–537. (b) Griesser, H.; Ohrlein, R.; Schwab, W.; Ehrler, R.;
Jager, V. Org. Synth. 2000, 77, 236–242.
(13) Abdallah-El Ayoubi, S.; Texier-Boullet, F.; Hamelin, J. Synthesis
1994, 258–260.
2-(5-(4-Fluorophenyl)-4-(2-(3-(4-fluorophenyl)-2-isopropyl-
2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepin-4-yl)ethyl)-1-
1
isopropyl-1H-pyrazol-3-yl)ethanamine, (1a). H NMR (400
MHz, CDCl3 δ: 7.10ꢀ7.05 (m, 8H), 4.21ꢀ4.05 (m, 2H),
3.26ꢀ3.20 (m, 1H), 3.03ꢀ3.00 (dd, J = 3.7, 13.5 Hz, 1H),
2.95ꢀ2.88 (m, 3H), 2.72ꢀ2.62 (m, 5H), 2.22ꢀ2.17 (m, 1H),
2.03ꢀ1.92 (m, 2H), 1.76ꢀ1.58 (m, 1H), 1.52ꢀ1.44 (m, 1H),
1.38ꢀ1.32 (m, 12H); 13C NMR (125.7 MHz, CDCl3) δ: 163.4,
161.8, 150.4, 147.6, 139.2, 139.1, 131.7, 131.4, 127.2, 127.0,
121.5, 117.1, 115.8, 115.7, 115.6, 115.6, 53.0, 49.6, 49.1, 41.9,
36.0, 34.6, 33.2, 31.0, 22.8, 22.7, 21.1; HRMS-ESI (m/z) calcd for
C32H40F2N6 [M þ H]þ 547.3355, found 547.3355.
(14) Chelucci, G.; Falorni, M.; Giacomelli, G. Synthesis 1990, 1121–
1122.
’ ASSOCIATED CONTENT
Supporting Information. 1H NMR and 13C NMR spec-
S
b
tra for all compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*jliang4@its.jnj.com.
’ ACKNOWLEDGMENT
We thank Prof. Scott E. Denmark for helpful discussions and
Dr. Jiejun Wu and Ms. Heather McAllister for analytical support.
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