Development of a two-step route to 3-PBC and βcCt, two agents active against alcohol self-administration in rodent and primate models

Article abstract of DOI:10.1021/jo200425m

To gain access to 3-propoxy-β-carboline hydrochloride (3-PBC·HCl) (1·HCl) and β-carboline-3-carboxylate-tert-butyl ester (βCCt) (2), potential clinical agents active against alcohol self-administration, a two-step route was developed. This process involve

Full text of DOI:10.1021/jo200425m

NOTE
pubs.acs.org/joc
Development of a Two-Step Route to 3-PBC and βCCt,
Two Agents Active against Alcohol Self-Administration
in Rodent and Primate Models
Ojas A. Namjoshi,† Angelica Gryboski,† German O. Fonseca,† Michael L. Van Linn,† Zhi-jian Wang,†
Jeffrey R. Deschamps,‡ and James M. Cook†,*
†Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211, United States
‡Center for Biomolecular Science and Engineering, Code 6930, Naval Research Laboratory, 4555 Overlook Avenue SW, Washington,
DC 20375, United States
S Supporting Information
b
ABSTRACT: To gain access to 3-propoxy-β-carboline hydro-
chloride (3-PBC HCl) (1 HCl) and β-carboline-3-carboxy-
3
3
late-tert-butyl ester (βCCt) (2), potential clinical agents active
against alcohol self-administration, a two-step route was devel-
oped. This process involves a palladium-catalyzed Buch-
waldꢀHartwig coupling and an intramolecular Heck reaction.
This two-step route provides rapid access to multigram quantities of 3-PBC (1) and βCCt (2), as well as analogues for studies of
alcohol self-administration. The overall yield of 3-PBC (1) was improved from 8% to 50% by this route.
he GABAA receptor is the major inhibitory neurotransmitter
T
receptor of the central nervous system (CNS) and the site of
action of a variety of pharmacologically and clinically important
drugs, such as benzodiazepines, barbiturates, neuroactive ster-
oids, anesthetics, and convulsants.1 There are several disease
states thought to be associated with the improper functioning of
this system, including anxiety, epilepsy, insomnia, depression,
bipolar disorder, and schizophrenia, as well as mild cognitive
impairment and Alzheimer’s disease.2
Figure 1. Structures of 3-PBC (1) and βCCt (2).
Alcohol addiction and dependence remain significant public
health concerns, impacting physical and mental well-being, family
structure, and occupational stability. The design of clinically safe
and effective drugs that reduce alcohol addiction and depen-
dence remains a high priority.3,4 While the precise neuromechan-
isms regulating alcohol-seeking behaviors remain unknown,
there is now compelling evidence that the GABAA receptors
within the striatopallidal and extended amygdala system are
involved in the “acute” reinforcing actions of alcohol.5ꢀ9
The synthesis of both 1 and 2 have been accomplished
previously.14ꢀ17 The overall yield of 1 (via 6 steps) as reported
previously was 8%, and that of 2 (5 steps) was 35% from DL-
tryptophan. The syntheses involved a number of steps, some of
which occurred in low yields.
In 2005 Weerts et al. reported that 3-PBC HCl significantly
3
reduced alcohol self-administration in baboons.18 More impor-
tantly, it reduced craving in the subjects as well.18 This important
finding led to the interest in a short and concise synthesis of
3-PBC (1), capable of scale-up to multigram levels, as well as a
similar route to βCCt (2). Retrosynthetically, both of these
compounds can be envisioned to arise from a substituted aniline
A and a substituted pyridine derivative B (Scheme 1).
The β-carbolines 3-propoxy-β-carboline hydrochloride 1 HCl
3
(3-PBC HCl) and β-carboline-3-carboxylate-tert-butyl ester 2
3
(βCCt) are mixed benzodiazepine agonist-antagonist ligands with
binding selectivity at R1 receptors (see Figure 1).10ꢀ12 In studies
that involve the R1 subtype, the orally active 1 HCl and 2 were
3
observed to selectively reduce alcohol-motivated behaviors in a
As shown in Scheme 2, bromopyridine 319 was reacted with
aniline 4a in toluene at 100 °C in the presence of 5 mol %
Pd(OAc)2 and 7.5 mol % X-Phos to obtain diarylamine 5a in 93%
yield. Various conditions were screened to effect a coupling
reaction between 3 and aniline 4a in high yield.20ꢀ23 Other
variety of experiments.10,13 Moreover, both 1 HCl and 2 dis-
3
played mixed weak agonist-antagonist profiles in vivo in alcohol P
and HAD rats and may be capable of reducing alcohol intake while
eliminating or greatly reducing the anxiety associated with habitual
alcohol, abstinence, or detoxification.10,13 These types of ligands,
subsequently, may be ideal clinical agents for the treatment of
alcohol-dependent individuals.
Received: March 3, 2011
Published: April 15, 2011
r
2011 American Chemical Society
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|

The Journal of Organic Chemistry
NOTE
Scheme 1. Retrosynthetic Analysis of 1 and 2
refluxing toluene or in acetic acid.29 Interestingly, when the
reaction was carried out at 120 °C in acetic acid as a solvent with
an oxygen atmosphere, 5a appeared to react, and the β-carboline
1 was obtained as an equimolar mixture with its regiosiomer, a δ-
carboline, 6. However, the reaction did not go to completion in
15 h, and only a 30% combined yield was obtained. Further
modifications of these conditions with 5a (longer duration,
increased catalytic loading) did not result in any improvement
in the yield or the ratio of 1 to 6.
At this point it was decided to explore a Heck-type cyclization
of model compound 5b utilizing Pd(0) as a catalyst. Initial
attempts, which included previously reported Buchwaldꢀ
Hartwig amination conditions [Pd(OAc)2, X-Phos, Cs2CO3 or
NaOt-Bu, toluene, 100 °C] did not provide β-carboline 1 even
after heating for 24 h (Table 1, entries 1 and 2). Use of polar
solvents such as DMF or DMA led to dechlorination of the
starting material (entries 3 and 4). Air-stable monodentate ligand
Scheme 2. Synthesis of Intermediates 5a and 5b
(t-Bu)3P HBF4 had been used previously for similar types of
3
transformations in a different system.30 Interestingly, Pd(OAc)2
with (t-Bu)3P HBF4 as a catalyst in the presence of NaOt-Bu in
3
DMA gave 32% yield of the mixture of regioisomers 1 and 6. A
large amount of decomposition products were observed on TLC
(entry 5). When K2CO3 was employed as the base, the reaction
went smoothly within 16 h at 120 °C and afforded a readily
separable mixture of regioisomers 1 and 6 in a ratio of 1.75:1
combinations of conditions (lower temperature, different li-
gands, different bases, copper-based methods) resulted either
in inferior yields and/or debromination of 3. In a similar fashion,
5b was obtained from 3 and 2-chloroaniline 4b in 91% yield.
Once diarylamines 5a and 5b were in hand as potential
precursors to 1, various methods to carry out the required
intramolecular cyclization were attempted. A Heck-type cou-
pling reaction and CH activation/oxidative couplingꢀcyclization
reaction were more appealing because of atom economy.23,24 In
recent years, such direct arylation reactions have been developed
extensively.25ꢀ30 One advantage is that the preactivated, func-
tionalized arenes can be replaced with a simple arene, conse-
quently reducing the number of steps and overall cost of the
process.25
Various approaches for the construction of substituted carba-
zoles via coupling processes have been described in the
literature.29ꢀ33 Bedford et al. have carried out a microwave-
mediated one-pot synthesis of carbazoles from 2-chloroanilines
via consecutive amination and CH activation.30 Budꢀen et al. have
used photostimulated reactions of chloro diarylamines for the
synthesis of substituted carbazoles.31 However, the issue of
regioselectivity was not addressed in those reports since the
authors dealt with reactions leading to a symmetrical product or
one of the possible positions for cyclization was blocked. Hostyn
and co-workers have described palladium-catalyzed regioselec-
tive synthesis of R-carbolines by using 2,3-dichloropyridines and
substituted anilines.32 Recently Sridharan et al. have reported a
Pd(OAc)2-promoted cyclodehydrogenation of diphenylamines
to carbazole using Cu(OAc)2 as an oxidant.33 In addition Ohno
et al. have carried out the synthesis of substituted carbazoles by
intramolecular oxidative direct arylation in an aerobic
atmosphere.29 Interestingly the extension of these methods for
the synthesis of β-carbolines had not been demonstrated to these
authors knowledge.
(entries 6 and 7). Substitution of (t-Bu)3P HBF4 with ligand
3
Cy3P HBF4 afforded comparable results (entry 8). The desired
3
β-carboline 1 and its regioisomer 6 (δ-carboline) can be differ-
entiated from each other by examination of their correspon-
1
ding H NMR spectra. In addition, X-ray crystal structures
(Supporting Information) of both regioisomers 1 and 6 were
obtained to further confirm the structures.
Since many 3-substituted β-carbolines exhibit subtype selec-
tivity at R1β2/3γ2 BZR/GABAergic receptors, it was decided to
apply these conditions for the synthesis of various substituted β-
carbolines previously reported.14,15,17,34ꢀ36 In addition, it was
important to evaluate the effect of different substitutions located
ortho to the pyridyl nitrogen atom on the regioselectivity of the
process (Scheme 3). The required bromopyridine ether deriva-
tives 7aꢀg are commercially available and can be synthesized via
known literature procedures.19 BuchwaldꢀHartwig aminations
of 7aꢀg with 2-chloroaniline led to the chloro diarylamines
8aꢀg smoothly in 81ꢀ92% yields. Heck-type cyclization of
8aꢀg afforded the regioisomers β-carbolines 9aꢀg and δ-
carbolines 10aꢀg in good yields (Table 2). The substituents
ortho to the pyridyl nitrogen atom appeared to have some effect
on the regioselectivity. The smaller substituents (Me, Et) tended
to provide equimolar amounts of the regioisomers 9 and 10
(Table 2, entries 1 and 2), while the bulkier substituents (i-Pr, t-
Bu) afforded the β-carbolines as the major product (entries 3 and
6). The best ratio of 9 to 10 for a β-carboline was obtained for the
5-bromo-2-t-butoxypyridine (1.9:1; entry 6).
Large-Scale Synthesis of 3-PBC (1) and βCCT (2). Because
3-PBC HCl (1 HCl) reduced alcohol self-administration in
3
3
primates18 while both 3-PBC HCl (1 HCl) and βCCt (2)
3
3
had been shown to reduce alcohol self-administration in both
alcohol preferring (P) and high alcohol drinking (HAD) rats
when given orally and systemically, a large-scale synthesis of
3-PBC (1) and βCCt (2) via this short route was required. This
synthesis of 3-PBC (1) and βCCt (2) is illustrated in Scheme 4.
In regard to the synthesis of 3-PBC (1), the BuchwaldꢀHartwig
amination step was scaled up to the 50 g level (87% yield), while
With this history in mind, initial attempts were made to cyclize
5a using catalytic Pd(II)-mediated oxidative coupling. Diaryla-
mine 5a failed to cyclize using Pd(OAc)2 as a Pd(II) source and
Cu(OAc)2 as the co-oxidant for palladium, even after heating in
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NOTE
Table 1. Optimization of Conditions for the Cyclization of 5b to 1a
entry
ligand
X-Phos
base
solvent
temp (time)
results (yield)b
no reaction
1
2
3
4
5
Cs2CO3
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
toluene
toluene
DMF
100 °C (24 h)
100 °C (24 h)
120 °C (24 h)
120 °C (24 h)
120 °C (24 h)
X-Phos
X-Phos
X-Phos
no reaction
dechlorination
dechlorination
DMA
(t-Bu)3P HBF4
DMA
32% yield (mixture of 1 and 6)
þ decomposed material
52% 1 þ 30% 6
56% 1 þ 32% 6
55% 1 þ 30% 6
3
6
7
8
(t-Bu)3P HBF4
K2CO3
K2CO3
K2CO3
DMA
DMA
DMA
120 °C (24 h)
120 °C (16 h)
120 °C (16 h)
3
(t-Bu)3P HBF4
3
Cy3P HBF4
3
a The reactions were carried out using 5b (0.1 mmol), Pd(OAc)2 (0.01 mmol), ligand (0.02 mmol), and base (0.2 mmol) in solvent (1.0 mL)
under argon. b Isolated yield.
Scheme 3. Synthesis of Substituted Carboline Analogues
the Heck-type cyclization reaction was performed on a 20 g scale.
The overall conversion of N-(2-chlorophenyl)-6-propoxypyri-
din-3-amine (5b) into 3-PBC (1) via this two-step route was
50%, as compared to 8% previously obtained.14,15 The large-scale
synthesis of βCCt (2) via this process is shown in Scheme 4. The
BuchwaldꢀHartwig amination of tert-butyl 5-bromopicolinate
1137 with 2-chloroaniline afforded the coupled diarylamine 12 in
94% yield on 50 g scale. Heck-type cyclization of 12 was carried
out on 10 g scale and afforded a mixture of βCCT (2) and its
regioisomer 13 in 83% yield. (Ratio of 2:13 = 2:1). The overall
yield of βCCT (2) from 11 on 10 g scale was 52%, as compared
to the previous yield of 35%.16
Table 2. Ratios of β (9) and δ (10) Carbolines
entry
R
yielda (9:10)
1
2
3
4
5
6
7
Me
Et
81% (1.2:1)
85% (1.25:1)
90% (1.8:1)
87% (1.35:1)
93% (1.4:1)
85% (1.9:1)
87% (1.5:1)
i-Pr
n-Bu
i-Bu
t-Bu
Bn
In summary, a two-step route to the two anti-alcohol agents of
biological interest, 3-PBC (1) and βCCT (2), has been devel-
oped in much improved yields as compared to their earlier
reported syntheses. This two-step synthesis of 3-PBC (1) and
a Combined isolated yield.
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NOTE
Scheme 4. Large-Scale Synthesis of 3-PBC (1) and βCCt (2) Using the New Route
1
βCCT (2) is capable of scale-up, which cuts down the number of
steps in the reported routes from 6 and 5, respectively, to 2. The
yield of 3-PBC (1) via this two-step route was 50%, as compared
to the previously reported 8%, and that for βCCT (2) was 52%,
as compared to the previous yield of 35%. In addition, to extend
the SAR in vivo, different β-carboline analogues 9aꢀg were
synthesized in superior yields. It is easy to separate the β-
carboline and δ-carboline regioisomers from each other by flash
chromatography. Further studies are underway to render this
transformation regiospecific.
(20% EtOAc/hexanes) Rf = 0.33; mp 60.6ꢀ61.9 °C; H NMR (300
MHz, CDCl3) δ 8.01 (d, J = 2.7 Hz, 1H), 7.47 (dd, J1 = 8.7 Hz, J2 = 3.0
Hz, 1H), 7.25 (m, 2H), 7.87 (m, 3H), 6.74 (d, J = 8.7 Hz, 1H), 5.46 (br,
1H), 4.25 (t, J = 6.6 Hz, 2H), 1.82 (m, 2H), 1.06 (t, J = 7.5 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 160.3, 145.0, 139.9, 133.3, 132.6, 129.4,
119.9, 115.3, 111.1, 67.7, 22.4, 10.5. Anal. Calcd for C14H16N2O: C,
73.66; H, 7.06; N, 12.27. Found: C, 73.75; H, 7.08; N, 12.10.
N-(2-Chlorophenyl)-6-methoxypyridin-3-amine (8a). Following the
general procedure, 5-bromo-2-methoxypyridine 7a19 (0.5 g, 2.66 mmol)
with 4b (0.36, 2.8 mmol), Pd(OAc)2 (29.9 mg, 0.13 mmol), X-Phos
(89.1 mg, 0.20 mmol), and Cs2CO3 (1.04 g, 3.2 mmol) after flash
chromatography (silica gel, 20:1 hexanes/ethyl acetate) afforded 8a
1
(0.56 g, 89%): yellow oil; TLC (20% EtOAc/hexanes) Rf = 0.62; H
NMR (300 MHz, CDCl3) δ 8.08 (d, J = 2.7 Hz, 1H), 7.50 (dd, J1 = 8.7
Hz; J2 = 2.7 Hz, 1H), 7.35 (dd, J1 = 7.9 Hz; J2 = 1.3 Hz, 1H), 7.09 (t, J =
7.6 Hz, 1H), 6.87 (dd, J1 = 8.2 Hz; J2 = 1.3 Hz, 1H), 6.75 (m, 2H), 5.92
(br, 1H), 3.97 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.1, 142.0,
141.8, 135.1, 131.2, 129.5, 127.5, 120.1, 119.5, 113.5, 111.2, 55.5;
HRMSꢀESI (m/z) calcd for C12H12ClN2O [M þ H]þ: 235.0638,
found 235.0628.
’ EXPERIMENTAL SECTION
General Methods. All reactions were performed in oven-dried
round-bottomed flasks or in resealable screw-cap test tubes or heavy-wall
pressure vessels. Stainless steel syringes or cannulae were used to
transfer air-sensitive liquids. Chemical shifts are reported in δ (ppm)
relative to TMS in CDCl3 as internal standard (1H NMR) or the residual
CHCl3 signal (13C NMR).
General Procedure for the Synthesis of Diarylamines: Representa-
tive Procedure for the Synthesis of N-(2-Chlorophenyl)-6-propoxypyr-
idin-3-amine (5b). 5-Bromo-2-propoxypyridine 319 (0.65 g, 3 mmol),
Pd(OAc)2 (33.7 mg, 0.15 mmol), Cs2CO3 (1.17 g, 3.6 mmol), and
X-Phos (107 mg, 0.225 mmol) were added to a screw-cap vial. The vial
was fitted with a rubber septum, evacuated, and backfilled with argon.
2-Chloroaniline 4b (0.4 g, 3.15 mmol) was injected into the vial with a
syringe under a positive pressure of argon. Toluene (10 mL) was added
via a syringe. The rubber septum was replaced with a screw-cap, and the
sealed vial was introduced into a preheated oil bath at 100 °C. After 15 h
the reaction mixture was filtered through a short pad of Celite, washed
with water and brine, dried (Na2SO4), and concentrated under
reduced pressure. The crude product was purified by flash chroma-
tography (silica gel; 20:1 hexanes/ethyl acetate) to afford 5b (0.73 g,
93%) as a pale yellow oil: TLC (20% EtOAc/hexanes) Rf 0.73; 1H NMR
(300 MHz, CDCl3) δ 8.06 (d, J = 2.7 Hz, 1H), 7.49 (dd, J1 = 8.7 Hz; J2 =
2.7 Hz, 1H), 7.34 (dd, J1 = 8.1 Hz; J2 = 1.5 Hz, 1H), 7.09 (dd, J1 =
8.4 Hz; J2 = 1.2 Hz, 1H), 6.86 (dd, J1 = 8.4 Hz; J2 = 1.5 Hz, 1H), 6.76 (m,
2H), 5.90 (br, 1H), 4.27 (t, J = 6.9 Hz, 2H), 1.84 (m, 2H), 1.06 (t, J = 7.5
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 161.2, 142.3, 142.0, 135.3,
131.0, 129.6, 127.6, 120.1, 119.5, 113.5, 111.4, 67.8, 22.4, 10.6;
HRMSꢀESI (m/z) calcd for C14H16ClN2O [M þ H]þ: 263.0951,
found 263.0961.
N-(2-Chlorophenyl)-6-ethoxypyridin-3-amine (8b). Following the
general procedure, 5-bromo-2-ethoxypyridine 7b19 (0.303 g, 1.5 mmol)
with 4b (0.2 g, 1.575 mmol), Pd(OAc)2 (16.8 mg, 0.075 mmol), X-Phos
(26.7 mg, 0.112 mmol), and Cs2CO3 (0.85 g, 1.8 mmol) after flash
chromatography (silica gel, 20:1 hexanes/ethyl acetate) afforded 8b
(0.35 g, 94%): light brown solid; TLC (20% EtOAc/hexanes) Rf = 0.68;
mp 49.5ꢀ51.0 °C; 1H NMR (300 MHz, CDCl3) δ 8.06 (d, J = 2.7 Hz,
1H), 7.49 (dd, J1 = 8.7 Hz; J2 = 2.8 Hz, 1H), 7.35 (dd, J1 = 7.9 Hz; J2 = 1.4
Hz, 1H), 7.09 (t, J = 7.9 Hz, 1H), 6.86 (dd, J1 = 8.4 Hz; J2 = 1.5 Hz, 1H),
6.77 (m, 2H), 5.90 (br, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 160.9, 142.2, 141.8, 135.1, 130.9,
129.5, 127.5, 120.0, 119.4, 113.4, 111.3, 61.8, 14.6; HRMSꢀESI (m/z)
calcd for C13H14ClN2O [M þ H]þ: 249.0795, found 249.0799.
N-(2-Chlorophenyl)-6-isopropoxypyridin-3-amine (8c). Following
the general procedure, 5-bromo-2-isoprpoxypyridine 7c19 (0.22 g, 1.0
mmol) with 4b (0.134 g, 1.05 mmol), Pd(OAc)2 (11.2 mg, 0.05 mmol),
X-Phos (35.7 mg, 0.075 mmol), and Cs2CO3 (0.39 g, 1.2 mmol) after
flash chromatography (silica gel, 20:1 hexanes/ethyl acetate) afforded 8c
(0.247 g, 94%): pale yellow oil; TLC (20% EtOAc/hexanes) Rf = 0.65; 1H
NMR (300 MHz, CDCl3) δ 8.06 (d, J = 2.7 Hz, 1H), 7.47 (dd, J1 = 8.7
Hz; J2 = 2.8 Hz, 1H), 7.34 (dd, J1 = 7.9 Hz; J2 = 1.4 Hz, 1H), 7.09 (t, J =
7.6 Hz, 1H), 6.87 (dd, J1 = 8.2 Hz; J2 = 1.4 Hz, 1H), 6.61 (m, 2H), 5.89
(br, 1H), 5.20 (m, 1H), 1.38 (d, J = 6.0 Hz, 6H); 13C NMR (75 MHz,
CDCl3) δ 160.5, 142.2, 141.9, 135.2, 130.6, 129.5, 127.5, 120.0, 119.3,
113.4, 111.8, 68.1, 22.0; HRMSꢀESI (m/z) calcd for C14H16ClN2O
[M þ H]þ: 263.0951, found 263.0963.
N-Phenyl-6-propoxypyridin-3-amine (5a). Following the general
procedure, 319 (0.43 g, 2 mmol) with aniline 4a (0.2 g, 2.10 mmol),
Pd(OAc)2 (22.5 mg, 0.10 mmol), X-Phos (71.4 mg, 0.15 mmol), and
Cs2CO3 (0.78 g, 2.4 mmol) after flash chromatography (silica gel, 20:1
hexanes/ethyl acetate) afforded 5a (0.43 g, 93%): off-white solid; TLC
6-Butoxy-N-(2-chlorophenyl)pyridin-3-amine (8d). Following the
general procedure, 5-bromo-2-butoxypyridine 7d19 (0.23 g, 1.0 mmol)
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NOTE
with 4b (0.134 g, 1.05 mmol), Pd(OAc)2 (11.2 mg, 0.05 mmol), X-Phos
(35.7 mg, 0.075 mmol), and Cs2CO3 (0.39 g, 1.2 mmol) after flash
chromatography (silica gel, 20:1 hexanes/ethyl acetate) afforded 8d
(0.25 g, 91%): colorless oil; TLC (20% EtOAc/hexanes) Rf = 0.71; 1H
NMR (300 MHz, CDCl3) δ 8.06 (d, J = 2.8 Hz, 1H), 7.48 (dd, J1 = 8.8
Hz; J2 = 2.8 Hz, 1H), 7.34 (dd, J1 = 7.9 Hz; J2 = 1.4 Hz, 1H), 7.09 (t, J =
8.4 Hz, 1H), 6.86 (dd, J1 = 8.2 Hz; J2 = 1.4 Hz, 1H), 6.77 (m, 2H), 5.90
(br, 1H), 4.31 (t, J = 6.7 Hz, 2H), 1.79 (m, 2H), 1.52 (m, 2H), 1.01 (t, J =
7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 161.1, 142.2, 141.9, 135.2,
130.9, 129.5, 127.5, 120.0, 119.4, 113.4, 111.3, 65.9, 31.1, 19.2, 13.8;
HRMSꢀESI (m/z) calcd for C15H18ClN2O [M þ H]þ: 277.1108,
found 277.1102.
N-(2-Chlorophenyl)-6-isobutoxypyridin-3-amine (8e). Following
the general procedure, 5-bromo-2-isoprpoxypyridine 7e19 (0.23 g, 1.0
mmol) with 4b (0.134 g, 1.05 mmol), Pd(OAc)2 (11.2 mg, 0.05 mmol),
X-Phos (35.7 mg, 0.075 mmol), and Cs2CO3 (0.39 g, 1.2 mmol), after
flash chromatography (silica gel, 20:1 hexanes/ethyl acetate) afforded 8e
(0.257 g, 93%): light green oil; TLC (20% EtOAc/hexanes) Rf = 0.69;
1H NMR (300 MHz, CDCl3) δ 8.06 (d, J = 2.2 Hz, 1H), 7.49 (dd, J1 =
8.7 Hz; J2 = 2.6 Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H),
6.86 (d, J = 8.2 Hz, 1H), 6.77 (m, 2H), 5.90 (br, 1H), 4.08 (d, J = 6.7 Hz,
2H), 2.12 (m, 1H), 1.05 (d, J = 6.7 Hz, 6H); 13C NMR (75 MHz,
CDCl3) δ 161.2, 142.2, 141.9, 135.2, 130.9, 129.5, 127.5, 120.0, 119.4, 113.4,
111.3, 72.5, 30.7, 19.2; HRMSꢀESI (m/z) calcd for C15H18ClN2O
[M þ H]þ: 277.1108, found 277.1099.
General Procedure for Heck Cyclization: Representative Procedure
for the Synthesis of 3-Propoxy-9H-pyrido[3,4-b]indole (3-PBC; 1) and
2-Propoxy-5H-pyrido[3,2-b]indole (6). Pd(OAc)2 (22.4 mg, 0.1 mmol),
(t-Bu)3P HBF4 (58 mg, 0.2 mmol), 5b (263 mg, 1.0 mmol), and
3
K2CO3 (276 mg, 2.0 mmol) were added to a screw-cap vial. The vial was
fitted with a rubber septum, evacuated, and backfilled with argon.
Degassed DMA (4.0 mL) was added via a syringe. The rubber septum
was replaced with a screw cap, and this sealed tube was introduced in a
preheated oil bath at 120 °C. After stirring for 16 h, the reaction mixture
was allowed to cool to rt. The reaction mixture was passed through a
short pad of Celite, which was further washed with ethyl acetate until no
product (TLC; silica gel) was detected in the eluent. The combined
filtrates were washed with water and brine, dried (Na2SO4),
and concentrated under reduced pressure. The crude product was
purified by flash chromatography (silica gel; 5:1 hexanes/ethyl acetate)
to afford 3-PBC (1) and 6. Data for 1 (127 mg): colorless crystals; mp
119.3ꢀ120.5 °C. Anal. Calcd for C14H14N2O 0.33 H2O: C, 72.43; H,
3
6.36; N, 12.07. Found: C, 72.48; H, 6.49; N, 11.78. A hydrochloride salt
of 1 was prepared by the reported method to obtain 3-PBC HCl
3
(1 HCl): yellow solid; mp 194.7ꢀ195.6 °C (lit.15 mp 194.0ꢀ
mp) with that reported in the literature.15
3
195.0 °C). The data for this compound matched in all aspects (1H NMR,
Data for 6 (72 mg): white solid; TLC (50% EtOAc/hexanes) Rf =
0.63; mp 123.2ꢀ124.3 °C; 1H NMR (300 MHz, CDCl3) δ 8.27 (d, J =
7.8 Hz, 1H), 7.99 (br, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.46 (m, 2H), 7.27
(m, J1 = 7.1 Hz, J2 = 1.8 Hz, 1H), 6.84 (d, J = 8.7 Hz, 1H), 4.45 (t, J = 6.6
Hz, 2H), 1.91 (m, 2H), 1.11 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 159.7, 140.2, 138.4, 128.3, 126.8, 122.6, 121.5, 120.6, 119.8,
111.3, 108.8, 67.8, 22.7, 10.8. Anal. Calcd for C14H14N2O: C, 74.31; H,
6.24; N, 12.38. Found: C, 74.17; H, 6.30; N, 12.30. [Combined yield =
199 mg, 88%]
6-(tert-Butoxy)-N-(2-chlorophenyl)pyridin-3-amine (8f). Following
the general procedure, 2-(benzyloxy)-5-bromopyridine 7f19 (0.229 g,
1.0 mmol) with 4b (0.134 g, 1.05 mmol), Pd(OAc)2 (11.2 mg, 0.05
mmol), X-Phos (35.7 mg, 0.075 mmol), and Cs2CO3 (0.39 g, 1.2 mmol)
after flash chromatography (silica gel, 20:1 hexanes/ethyl acetate)
afforded 8f (0.252 g, 91%): colorless oil; TLC (20% EtOAc/hexanes)
Rf = 0.81; 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J = 2.8 Hz, 1H), 7.44
(dd, J1 = 8.7 Hz; J2 = 2.7 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.10 (t, J = 8.7
Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 6.77 (t, J = 7.2 Hz, 1H), 6.70 (d, J = 8.7
Hz, 1H), 5.89 (br, 1H), 1.60 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
160.6, 141.7, 141.6, 134.2, 130.9, 129.5, 127.5, 120.1, 119.4, 113.9, 113.6,
79.5, 28.6; HRMSꢀESI (m/z) calcd for C15H18ClN2O [M þ H]þ:
277.1108, found 277.1116.
3-Methoxy-9H-pyrido[3,4-b]indole (9a) and 2-Methoxy-5H-pyrido-
[3,2-b]indole (10a). Following the general procedure, 8a (130 mg, 0.55
mmol), Pd(OAc)2 (12.4 mg, 0.055 mmol), (t-Bu)3P HBF4 (31.9 mg,
3
0.11 mmol) and K2CO3 (152 mg, 1.11 mmol) after flash chromatog-
raphy (silica gel, 5:1 hexanes/ethyl acetate) afforded 9a and 10a. Data
for 9a (48 mg): off-white solid; HRMSꢀESI (m/z) calcd for C12H11-
N2O [M þ H]þ: 199.0871, found 199.0877. Hydrochloride salt of 9a:
light brown solid; mp 214.8ꢀ216.0 °C (lit.15 mp 215.0ꢀ217.0 °C). The
data for this compound matched in all aspects (1HNMR, mp) with that
reported in the literature.15
6-(Benzyloxy)-N-(2-chlorophenyl)pyridin-3-amine (8g). Following
the general procedure, 2-(benzyloxy)-5-bromopyridine 7g19 (0.263 g,
1.0 mmol) with 4b (0.134 g, 1.05 mmol), Pd(OAc)2 (11.2 mg, 0.05
mmol), X-Phos (35.7 mg, 0.075 mmol), and Cs2CO3 (0.39 g, 1.2 mmol)
afterflashchromatography(silicagel, 20:1 hexanes/ethylacetate) afforded
8g (0.28 g, 90%): off-white solid; TLC (10% EtOAc/hexanes) Rf = 0.63;
Data for 10a (40 mg): light brown solid; TLC (50% EtOAc/hexanes)
Rf = 0.72; mp 94.5ꢀ97.0 °C; 1H NMR (300 MHz, CDCl3) δ 8.28 (d, J =
7.9 Hz, 1H), 8.01 (br, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.46 (m, 2H), 7.29
(m, J1 = 6.7 Hz, J2 = 2.1 Hz, 1H), 6.85 (d, J = 8.7 Hz, 1H), 4.12 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 159.6, 140.0, 138.1, 129.3, 128.2, 126.7,
121.3, 120.4, 119.9, 111.1, 108.5, 53.5; HRMSꢀESI (m/z) calcd for
C12H11N2O [M þ H]þ: 199.0871, found 199.0876. [Combined yield =
88 mg, 81%]
1
mp 101.2ꢀ102.3 °C; H NMR (300 MHz, CDCl3) δ 8.09 (d, J =
2.7Hz, 1H), 7.51 (m, 3H), 7.39(m, 4H), 7.10 (t, J=8.4Hz, 1H), 6.90 (dd,
J1 = 8.1 Hz, J2 = 1.2 Hz, 1H), 6.86 (d, J = 8.7 Hz, 1H), 6.78 (m, J1 = 7.5 Hz,
J2 = 1.5 Hz, 1H), 5.92(br, 1H), 5.40(s, 2H);13C NMR(75MHz, CDCl3)
δ 159.9, 141.2, 140.3, 136.8, 135.3, 131.9, 129.6, 128.8, 128.4, 127.9, 127.6,
120.6, 120.0, 114.1, 111.8, 68.4. Anal. Calcd for C18H15ClN2O 0.05CH3-
3-Ethoxy-9H-pyrido[3,4-b]indole (9b) and 2-Ethoxy-5H-pyrido[3,2-
b]indole (10b). Following the general procedure, 8b (75 mg, 0.3 mmol),
3
(CH2)4CH3: C, 69.76; H, 5.02;N, 8.89. Found:C, 69.98; H, 4.86; N, 9.01.
tert-Butyl 5-[(2-Chlorophenyl)amino]picolinate (12). Following the
general procedure, tert-butyl 5-bromopicolinate 1137 (50 g, 194 mmol)
with 4b (26 g, 203 mmol), Pd(OAc)2 (2.18 g, 9.7 mmol), X-Phos (6.9 g,
14.55 mmol), and Cs2CO3 (75.9 g, 233 mmol) after flash chromatog-
raphy (silica gel, 5:1 hexanes/ethyl acetate) afforded 12 (55.6 g, 94%):
lustrous off-white solid; TLC (50% EtOAc/hexanes) Rf = 0.46; mp
147.8ꢀ149.4 °C; 1H NMR (300 MHz, CDCl3) δ 8.51 (d, J = 2.7 Hz,
1H), 7.99 (d, J = 8.7 Hz, 1H), 7.44 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 7.8 Hz,
1H), 7.24 (t, J = 7.2 Hz, 1H), 7.01 (t, J = 8.1 Hz, 1H), 6.34 (br, 1H), 1.63
(s, 9H); 13C NMR (75 MHz, CDCl3) δ 164.1, 141.8, 141.3, 139.6,
137.4, 130.3, 127.7, 125.8, 124.4, 123.5, 122.5, 118.5, 81.7, 28.2. Anal.
Calcd for C16H17ClN2O2: C, 63.05; H, 5.62; N, 9.19. Found: C, 62.67;
H, 5.65; N, 8.95.
Pd(OAc)2 (6.7 mg, 0.03 mmol), (t-Bu)3P HBF4 (17.4 mg, 0.06 mmol)
3
and K2CO3 (83 mg, 0.6 mmol) after flash chromatography (silica gel, 5:1
hexanes/ethyl acetate) afforded 9b and 10b. Data for 9b (30 mg):
yellow-brown solid; HRMSꢀESI (m/z) calcd for C13H13N2O [M þ
H]þ: 213.1028, found 213.1018. Hydrochloride salt of 9b was a yellow
solid; mp 222.0ꢀ223.3 °C (lit.15 mp 221.0ꢀ223.0 °C). The data for this
compound matched in all aspects (1HNMR, mp) with that reported in
the literature.15
Data for 10b (24 mg): off-white crystals; TLC (20% EtOAc/hexanes)
1
Rf = 0.35; mp 130.4ꢀ131.1 °C; H NMR (300 MHz, CDCl3) δ 8.26
(d, J = 7.8 Hz, 1H), 7.91 (br, 1H), 7.68 (d, J = 8.7 Hz, 1H), 7.45 (m, 2H),
7.27 (m, 2H), 6.83 (d, J = 8.7 Hz, 1H), 4.56 (q, J = 6.9 Hz, 2H), 1.49 (t,
J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 159.3, 140.2, 128.3,
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NOTE
126.9, 122.4, 121.6, 120.7, 119.8, 111.2, 108.6, 61.9, 14.9; HRMSꢀESI
(m/z) calcd for C13H13N2O [M þ H]þ: 213.1028, found 213.1019.
[Combined yield = 54 mg, 85%]
3-Isopropoxy-9H-pyrido[3,4-b]indole (9c) and 2-Isopropoxy-5H-
pyrido[3,2-b]indole (10c). Following the general procedure, 8c (263 mg,
9f (48 mg): colorless crystals; TLC (50% EtOAc/hexanes) Rf = 0.30; mp
207.9ꢀ209.8 °C (lit.36 208.0ꢀ212.0 °C); HRMSꢀESI (m/z) calcd for
C15H17N2O [M þ H]þ: 241.1341, found 241.1339. The data for this
compound matched in all aspects (1HNMR, mp) with that reported in
the literature.36
1.0 mmol), Pd(OAc)2 (22.5 mg, 0.1 mmol), (t-Bu)3P HBF4 (58 mg,
Data for 10f (25 mg): light brown solid; TLC (50% EtOAc/hexanes)
Rf = 0.59; mp 110.5ꢀ112.2 °C; 1H NMR (300 MHz, CDCl3) δ 8.26 (d,
J = 7.8 Hz, 1H), 7.94 (br, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.45 (m, 2H),
7.27 (t, J = 6.3 Hz, 1H), 6.80 (d, J = 8.7 Hz, 1H), 1.69 (s, 9H); 13C NMR
(75 MHz, CDCl3) δ 158.7, 140.1, 138.3, 128.2, 126.6, 122.7, 120.7,
120.4, 119.6, 111.8, 111.0, 79.3, 29.8; HRMSꢀESI (m/z) calcd for
C15H17N2O [M þ H]þ: 241.1341, found 241.1349. [Combined
yield =73.0 mg, 85%].
3
0.2 mmol) and K2CO3 (276 mg, 2.0 mmol) after flash chromatography
(silica gel, 5:1 hexanes/ethyl acetate) afforded 9c and 10c. Data for 9c
(131 mg): off-white solid; HRMSꢀESI (m/z) calcd for C14H15N2O
[M þ H]þ: 227.1184, found 227.1176. Hydrochloride salt of 9c: brown
solid; mp 169.5ꢀ171.3 °C (lit.34 mp 168.0ꢀ172.0 °C). The data for this
compound matched in all aspects (1H NMR, mp) with that reported in
the literature.34
Data for 10c (72 mg): off-white solid; TLC (20% EtOAc/hexanes)
Rf = 0.38; mp 105.6ꢀ107.7 °C; 1H NMR (300 MHz, CDCl3) δ 8.28 (d,
J = 7.8 Hz, 1H), 8.04 (br, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.44 (m, 2H),
7.27 (t, J = 7.4 Hz, 1H), 6.79 (d, J = 8.7 Hz, 1H), 5.56 (m, J = 6.3 Hz, 1H),
1.46 (d, J = 6.3 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 158.7, 140.1,
138.2, 128.1, 126.6, 122.4, 121.3, 120.4, 119.6, 111.1, 109.2, 68.0, 22.1;
HRMSꢀESI (m/z) calcd for C14H15N2O [M þ H]þ: 227.1184, found
227.1173. [Combined yield =203 mg, 90%]
3-Benzyloxy)-9H-pyrido[3,4-b]indole (9g) and 2-(Benzyloxy)-5H-
pyrido[3,2-b]indole (10g). Following the general procedure, 8g (65
mg, 0.21 mmol), Pd(OAc)2 (4.7 mg, 0.021 mmol), (t-Bu)3P HBF4
3
(12.2 mg, 0.042 mmol) and K2CO3 (58 mg, 0.42 mmol) after flash
chromatography (silica gel, 5:1 hexanes/ethyl acetate) afforded 9g and
10g. Data for 9g (30 mg): off-white solid; HRMSꢀESI (m/z) calcd for
C18H15N2O [M þ H]þ: 275.1184, found 275.1194. Hydrochloride salt
of 9g: yellow solid; mp 197.8ꢀ199.2 °C (lit.35 mp 198.0ꢀ199.0 °C).
The data for this compound matched in all aspects (1HNMR, mp) with
that reported in the literature.35
3-Butoxy-9H-pyrido[3,4-b]indole (9d) and 2-Butoxy-5H-pyrido[3,2-b]-
indole (10d). Following the general procedure, 8d (125 mg, 0.45
mmol), Pd(OAc)2 (10.1 mg, 0.045 mmol), (t-Bu)3P HBF4 (26.1 mg,
Data for 10g (20 mg): white solid; TLC (20% EtOAc/hexanes) Rf =
0.23; mp 137.5ꢀ139.5 °C; 1H NMR (300 MHz, CDCl3) δ 8.30 (d, J =
8.1 Hz, 1H), 7.96 (br, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.60 (d, J = 7.2 Hz,
2H), 7.40 (m, 6H), 6.91 (d, J = 8.7 Hz, 1H), 5.60 (s, 2H); 13C NMR (75
MHz, CDCl3) δ 159.0, 140.1, 138.1, 137.9, 128.4, 128.3, 127.7, 126.8,
122.4, 121.4, 120.5, 119.8, 111.2, 108.9, 67.7; HRMSꢀESI (m/z) calcd
for C18H15N2O [M þ H]þ: 275.1184, found 275.1196. [Combined
yield = 50 mg, 87%]
3
0.09 mmol) and K2CO3 (125 mg, 0.9 mmol) after flash chromatography
(silica gel, 5:1 hexanes/ethyl acetate) afforded 9d and 10d. Data for 9d
(48.2 mg): buff colored solid; HRMSꢀESI (m/z) calcd for C15H17N2O
[M þ H]þ: 241.1341, found 241.1346. Hydrochloride salt of 9d: light
yellow solid; mp 178.0ꢀ180.0 °C (lit.34 mp 178.0ꢀ181.0 °C). The data
for this compound matched in all aspects (1HNMR, mp) with that
reported in the literature.34
Large-Scale Synthesis of 3-PBC (1) and βCCt (2). Step 1. General
Procedure: Representative Procedure for the Synthesis of N-(2-
Chlorophenyl)-6-propoxypyridin-3-amine (5b). Pd(OAc)2 (2.6 g,
11.6 mmol), 3 (50 g, 231.4 mmol), Cs2CO3 (90.5 g, 277.7 mmol),
and X-Phos (8.3 g, 17.3 mmol) were added to a three-neck flask with a
reflux condenser. The flask was evacuated and backfilled with argon.
Compound 4b (31 g, 25.6 mL, 243 mmol) was injected into the flask
with a syringe. Toluene (500 mL) was added via a cannula, and the flask
was introduced into a preheated oil bath at 100 °C. After 15 h at 100 °C
the reaction mixture was cooled to rt and filtered through a short pad of
Celite, and the pad was washed with ethyl acetate. The combined
organic eluents were washed with water and brine, dried (Na2SO4), and
concentrated under reduced pressure. The crude product was purified
by flash chromatography on silica gel (20:1 hexanes/ethyl acetate) to
afford 5b (52.9 g, 87%).
Large-Scale Synthesis of tert-Butyl-5-[(2-chlorophenyl)amino]-
picolinate (12). Following the general procedure, the tert-butyl 5-bro-
mopicolinate 1137 (50 g, 194 mmol) was reacted with 4b (26 g, 25.6 mL,
203 mmol), Pd(OAc)2 (2.18 g, 9.7 mmol), Cs2CO3 (75.9 g, 233 mmol),
and X-Phos (6.9 g, 14.55 mmol). Purification by flash chromatography
(silica gel, 5:1 hexanes/ethyl acetate) afforded 12 (55.6 g, 94%).
Step 2. General Procedure: Representative Procedure for Large-
Scale Synthesis of 3-Propoxy-9H-pyrido[3,4-b]indole (3-PBC; 1).
Compound 5b (20 g, 76.1 mmol), Pd(OAc)2 (1.71 g, 7.61 mmol), (t-
Data for 10d (35.8 mg): off-white solid; TLC (20% EtOAc/hexanes)
Rf = 0.35; mp 113.3ꢀ115.5 °C; 1H NMR (300 MHz, CDCl3) δ 8.28 (d,
J = 7.8 Hz, 1H), 7.05 (br, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.43 (m, 2H),
7.27 (m, J1 = 7.8 Hz, J2 = 1.5 Hz, 1H), 6.83 (d, J = 8.7 Hz, 1H), 4.50 (t, J =
6.6 Hz, 2H), 1.87 (m, 2H), 1.57 (m, 2H), 1.04 (t, J = 7.5 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 159.5, 140.0, 138.2, 128.2, 126.6, 122.3,
121.3, 120.4, 119.6, 111.1, 108.6, 65.8, 31.3, 19.3, 13.9; HRMSꢀESI (m/z)
calcd for C15H17N2O [M þ H]þ: 241.1341, found 241.1347. [Combined
yield = 84 mg, 87%]
3-Isobutoxy-9H-pyrido[3,4-b]indole (9e) and 2-Isobutoxy-5H-pyrido-
[3,2-b]indole (10e). Following the general procedure, 8e (139 mg, 0.50
mmol), Pd(OAc)2 (11.3 mg, 0.05 mmol), (t-Bu)3P HBF4 (29 mg, 0.10
3
mmol) and K2CO3 (138 mg, 1.0 mmol) after flash chromatography
(silica gel, 5:1 hexanes/ethyl acetate) afforded 9e and 10e. Data for 9e
(63 mg:) off-white crystalline solid; HRMSꢀESI (m/z) calcd for
C15H17N2O [M þ H]þ: 241.1341, found 241.1337. Hydrochloride salt
of 9e: light yellow solid; mp 221.5ꢀ223.0 °C (lit.35 mp 222.0ꢀ
223.0 °C). The data for this compound matched in all aspects (1HNMR,
mp) with that reported in the literature.35
Data for 10e (45 mg): off-white solid; TLC (20% EtOAc/hexanes)
Rf = 0.31; mp 120.5ꢀ121.4 °C; 1H NMR (300 MHz, CDCl3) δ 8.28 (d,
J = 7.8 Hz, 1H), 7.04 (br, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.45 (m, 2H),
7.27 (m, J1 = 7.9 Hz, J2 = 1.5 Hz, 1H), 6.84 (d, J = 8.7 Hz, 1H), 4.27 (d,
J = 6.7 Hz, 2H), 2.20 (m, 2H), 1.10 (d, J = 6.7 Hz, 6H); 13C NMR (75
MHz, CDCl3) δ 159.6, 140.0, 138.1, 128.2, 126.6, 122.3, 121.3, 120.4,
119.6, 111.1, 108.6, 72.4, 28.1, 19.4; HRMSꢀESI (m/z) calcd for C15H17-
N2O [M þ H]þ: 241.1341, found 241.1335. [Combined yield = 108 mg,
93%]
Bu)3P HBF4 (4.41 g, 15.22 mmol), and K2CO3 (21 g, 152.2 mmol)
3
were added to a heavy-walled pressure vessel (350 mL). The vessel was
fitted with a rubber septum, evacuated, and backfilled with argon.
Degassed DMA (250 mL) was added to this vial via a cannula. The
rubber septum was replaced with a Teflon screw cap, and this sealed
vessel was introduced in a preheated oil bath at 120 °C. After stirring at
this temperature for 16 h, the reaction mixture was allowed to cool to rt
and was passed through a short pad of Celite, which was further washed
with ethyl acetate until no product (TLC; silica gel) was detected in the
3-tert-Butoxy)-9H-pyrido[3,4-b]indole (9f) and 2-(tert-Butoxy)-5H-
pyrido[3,2-b]indole (10f). Following the general procedure, 8f (100 mg,
0.36 mmol), Pd(OAc)2 (8.0 mg, 0.036 mmol), (t-Bu)3P HBF4 (21 mg,
3
0.072 mmol) and K2CO3 (100 mg, 0.72 mmol) after flash chromatog-
raphy (silica gel, 5:1 hexanes/ethyl acetate) afforded 9f and 10f. Data for
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The Journal of Organic Chemistry
NOTE
eluent. The combined filtrate was washed with water and brine, dried
(Na2SO4), and concentrated under reduced pressure. The crude solid
was purified by flash chromatography (5:1; hexanes/ethyl acetate) to
afford 3-PBC (1) (10 g, 58%).
Large-Scale Synthesis of tert-Butyl 9H-Pyrido[3,4-b]indole-3-car-
boxylate (βCCt; 2). Following the general procedure, 12 (10 g, 32.8
(12) Cox, E. D.; Hagen, T. J.; Mckernan, R. M.; Cook, J. M. Med.
Chem. Res. 1995, 5, 710–718.
(13) Rowlett, J. K.; Spealman, R. D.; Lelas, S.; Cook, J. M.; Yin, W. Y.
Psychopharmacology 2003, 165, 209–215.
(14) Hagen, T. J.; Guzman, F.; Schultz, C.; Cook, J. M.; Skolnick, P.;
Shannon, H. E. Heterocycles 1986, 24, 2845–2855.
(15) Allen, M. S.; Hagen, T. J.; Trudell, M. L.; Codding, P. W.;
Skolnick, P.; Cook, J. M. J. Med. Chem. 1988, 31, 1854–1861.
(16) Yin, W.; Sarma, P. V. V. S.; Ma, J.; Han, D.; Chen, J. L.; Cook,
J. M. Tetrahedron Lett. 2005, 46, 6363–6368.
mmol), Pd(OAc)2 (735 mg, 3.28 mmol), (t-Bu)3P HBF4 (1.9 g, 6.56
3
mmol), and K2CO3 (9.06 g, 65.6 mmol) after flash chromatography
(silica gel, 1:1 hexanes/ethyl acetate) afforded βCCt (2) (4.87 g,
55.6%): white solid; mp 302.5ꢀ303.4 °C (lit.17 mp 301ꢀ303 °C).
The spectral data for this compound matched in all aspects (1H NMR)
with that reported in the literature.17
(17) Yin, W.; Majumder, S.; Clayton, T.; Petrou, S.; Van Linn, M. L.;
Namjoshi, O. A.; Ma, C.; Cromer, B. A.; Roth, B. L.; Platt, D. M.; Cook,
J. M. Bioorg. Med. Chem. 2010, 18, 7548–7564.
The regioisomer tert-butyl 5H-pyrido[3,2-b]indole-2-carboxylate
(13): fluffy white solid (2.43 g, 27.4%); TLC (2:1 EtOAc/hexanes) Rf =
0.53; mp 218ꢀ219.2 °C; 1H NMR (300 MHz, CDCl3) δ 8.89 (br, 1H),
8.45 (d, J = 7.8 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H),
7.52 (m, 2H), 7.31 (t, J = 7.2 Hz, 1H), 1.69 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 165.1, 142.8, 141.6, 141.2, 134.6, 128.6, 122.5, 122.4, 122.0,
(18) Weerts, E.; Kaminski, B.; Yin, W.; Sarma, P. V. V. S.; Cook, J. M.
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’ ASSOCIATED CONTENT
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Supporting Information. Copies of spectra and crystal-
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lographic information files in CIF format. This material is
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Corresponding Author
*E-mail: capncook@uwm.edu.
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’ ACKNOWLEDGMENT
We thank the NIMH (MH 046851) (J.M.C.) and NIAAA
(AA016179) as well as the Lynde and Harry Bradley Foundation
for generous financial support. The crystallographic analysis was
carried out at the Naval Research Laboratory.
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