Synthesis of Differentially Protected Azatryptophan Analogs via Pd2(dba)3/XPhos Catalyzed Negishi Coupling of N-Ts Azaindole Halides with Zinc Derivative from Fmoc-Protected tert-Butyl (R)-2-Amino-3-iodopropanoate

Article abstract of DOI:10.1021/acs.joc.0c00973

Unnatural amino acids play an important role in peptide based drug discovery. Herein, we report a class of differentially protected azatryptophan derivatives synthesized from N-tosyl-3-haloazaindoles 1 and Fmoc-protected tert-butyl iodoalanine 2 via a Neg

Full text of DOI:10.1021/acs.joc.0c00973

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Note
Synthesis of Differentially Protected Azatryptophan Analogs via Pd2(dba)3/
XPhos Catalyzed Negishi Coupling of N-Ts Azaindole Halides with Zinc
Derivative from Fmoc-protected tert-Butyl (R)-2-amino-3-iodopropanoate
Roshan Y Nimje, Devaiah Vytla, Prakasam Kuppusamy, Rajeswari Velayuthaperumal, Lokesh
Babu Jarugu, China Anki Reddy, Nanjundaswamy Kanikahalli Chikkananjaiah, Richard A.
Rampulla, Cullen L. Cavallaro, Jianqing Li, Arvind Mathur, Anuradha Gupta, and Amrita Roy
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00973 • Publication Date (Web): 10 Aug 2020
Downloaded from pubs.acs.org on August 10, 2020
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Synthesis of Differentially Protected Azatryptophan Analogs via
Pd2(dba)3/XPhos Catalyzed Negishi Coupling of N-Ts Azaindole
Halides with Zinc Derivative from Fmoc-protected tert-Butyl (R)-2-
amino-3-iodopropanoate
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Roshan Y Nimje,† Devaiah Vytla,† Prakasam Kuppusamy,† Rajeswari Velayuthaperumal,†
Lokesh Babu Jarugu,† China Anki Reddy,† Nanjundaswamy Kanikahalli Chikkananjaiah,†
Richard A. Rampulla,‡ Cullen L. Cavallaro,‡ Jianqing Li,⸹ Arvind Mathur,‡ Anuradha
Gupta*† and Amrita Roy*†
†Department of Discovery Synthesis, Biocon Bristol-Myers Squibb R&D Center,
Syngene International Ltd., Biocon Park, Plot No. 2 & 3, Bommasandra-Jigani Road,
Bangalore-560 100, India
‡ Small Molecule Drug Discovery, Bristol-Myers Squibb Research and Development,
P.O. Box 5400, Princeton, New Jersey 08543-4000, United States
⸹ Small Molecule Drug Discovery, Bristol-Myers Squibb Research and Development, 100
Binney St., Cambridge, MA 02142, United States
ABSTRACT: Unnatural amino acids play an important role in peptide based drug discovery.
Herein, we report a class of differentially protected azatryptophan derivatives synthesized
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from N-tosyl-3-haloazaindoles 1 and Fmoc-protected t-butyl iodoalanine 2 via a Negishi
coupling. Through ligand screening, Pd2(dba)3/XPhos was found to be a superior catalyst for
the coupling of 1 with the zinc derivative of 2 to give tert-butyl (S)-2-((((9H-fluoren-9-
yl)methoxy)carbonyl)amino)-3-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)propanoate
derivatives 3 in 69-91% isolated yields. In addition, we have demonstrated that the protecting
groups, namely, Ts, Fmoc and tBu, can be easily removed selectively.
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O
H
O
OtBu
N
Fmoc
OtBu
Fmoc
R
N
X
I
H
Mild conditions
2
Broad substrate scope
High Yield
Selective deprotection
1. Zn dust, I2, DMF
R
N
N
N
Ts
N
Ts
2. Pd2(dba)3 (5 mol%),
XPhos (10 mol%),
DMF, 55 oC, 3 h
1c, 1i-z, and 1aa
X = Br or I
3c, 3i-3z and 3aa
20 examples
69-91% Yield
4-Aza, 5-Aza, 6-Aza
When 7-Aza, R = F, Cl, CN, CF3, NO2,
COMe, CO2Me, Me, OMe
Unnatural amino acids are important tools for modern drug discovery research.1,2 They
are widely used as chiral building blocks due to their structural diversity, functional
versatility and play a significant role in expanding the potential application of peptide-based
drugs.3 Therefore, the synthesis of unnatural amino acids has attracted much attention in
recent years and several methodologies1,4 have been developed to synthesize these novel
building blocks.
Nickel- and palladium-catalyzed Negishi cross coupling5 is a versatile method for
carbon-carbon bond formation. In the past few decades, extensive development6 in this area
has led to the widespread applications of the Negishi reaction in the synthesis of complex
natural products,7-9 including the synthesis of unnatural amino acids.10,11
Heteroaromatic unnatural amino acids are especially attractive as structural motifs for
the construction of biologically active compounds.12 In particular, 7-azatryptophan possesses
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interesting spectral properties and its incorporation can be of broad applicability in the study
of protein folding and protein-protein interactions.13, 14 In this regard, Gobel and co-workers
demonstrated that a few heteroaromatic unnatural amino acid derivatives can be synthesized
using a Nickel catalyzed Negishi cross-coupling approach.15 Similarly, a wide range of novel
heteroaryl amino acids containing pyridine, indole, furyl, and thiophene have been
successfully prepared using Palladium catalyzed Negishi coupling.16-18 Yokoyama and co-
workers have also reported the synthesis of chiral tryptophan derivatives using Negishi cross-
coupling.19 It must be mentioned that Jackson and co-workers20-22 performed pioneering work
on the synthesis of novel alkyl, aryl and heteroaryl amino acid derivatives using Negishi
coupling of the zinc reagent derived from iodoalanine with aryl halides and elaborated
additional improvements.23 However, it is important to realize that, despite the availability of
a large number of synthetic procedures, no single method can be universally applied to all
substrates and reaction protocols have to be modified as per the needs of the synthesis of the
corresponding amino acid scaffolds. For an internal peptide-based drug discovery program,
we were interested in an efficient and general synthesis of azatryptophan derivatives bearing
both N-Fmoc and t-butyl ester, which was not reported in the literature. Herein, we describe
the development of a methodology for the synthesis of this class of the differentially
protected 7-azatryptophans 3 via a Negishi coupling of the zinc derivative of the iodoalanine
2 with N-tosyl-3-haloazaindoles 1 catalyzed by Pd2(dba)3/XPhos. These products are of
importance as the three orthogonal protecting groups can be removed independently. This
allows flexibility in carrying out selective transformation from the corresponding Negishi
product for the incorporation into a C- or N-terminal peptide following one deprotection
reaction.
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As aforementioned our objective was to use an Fmoc/t-Bu protecting strategy to
synthesize azatryptophans (Scheme 1) that would be compatible with Fmoc solid-phase
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peptide synthesis (SPPS). It should be noted that there are only a few examples of novel
amino acids being prepared via the Negishi coupling of orthogonally protected iodoalanines
in which Fmoc has been employed as the protecting group.21,24 Initially, following the
Negishi conditions developed by Jackson,23 the orthogonally protected organozinc reagent21
obtained from iodoalanine 2 and N-Boc protected 3-bromo azaindole 1b were coupled using
Pd2(dba)3 and SPhos as the catalyst at room temperature. Unfortunately, during the reaction,
substantial Boc deprotection of starting material was observed without any desired product
formation. However, when the reaction temperature was increased to 55 ºC it resulted in an
extremely low conversion (14%) of 3b (Table 1, entry 2) along with unreacted deprotected
starting material. Based on this observation, we decided to investigate suitable N-protecting
groups for 3-bromo azaindole that would offer compatibility with the Negishi conditions, as
summarized in Table 1. A set of seven reactions were screened using the unprotected
azaindole and the azaindoles protected with SEM, PMB, Cbz, t-BuSO, Ts and Ns. As
anticipated, there was no reaction with the unprotected azaindole 1a (Table 1, entry 1). The
reactions of the azaindoles 1d-g protected with SEM, PMB, Cbz and tBuSO groups,
respectively, were sluggish, with very poor conversions (Table1, entries 47). Both the Ts
and Ns protected azaindoles 1c and 1h (Table 1, entries 3 and 8) showed moderate
conversion (37% and 31%, respectively, by HPLC), without the formation of side products.
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Scheme 1. Synthetic Approach to the Preparation of Fmoc/t-Bu Protected Azatryptophans
O
OtBu
Fmoc
N
Br
H
O
I
1. Zn dust, I2, DMF
H
N
Fmoc
OtBu
2. Pd2(dba)3 (5 mol%)
SPhos (10 mol%)
DMF, 55 oC,3 h
+
N
N
N
N
PG
1a-h
PG
3a-h
2
Reaction Conditions: i) Zn-dust (3.0 eq.), I2 (0.3 eq.), DMF, rt, 30 min
o
1
2
ii) (1.0 eq.), (1.5 eq.), Pd2(dba)3 (0.05 eq.), SPhos (0.1 eq.), 55 C, 3 h
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Table 1. Effect of Protecting Groups (PG) on the Yields of 3a-h
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Entry 3-Bromoazaindole
% of unreacted 1b Product 3
% of 3b
derivative 1
1
2
3
4
5
6
7
8
1a, PG = H
nda
nda
10
3a
3b
3c
3d
3e
3f
nda
14
1b, PG = Boc
1c, PG = Ts
37
1d, PG = SEM
1e, PG = PMB
1f, PG = Cbz
1g, PG = tBuSO
1h, PG = Ns
29
10.3
10.6
10
36
nda
nda
7
3g
3h
12
31
a Not detected. b HPLC conversion
With consideration for the ease of selective deprotection, the Ts-protected azaindole
1c was selected for further optimization by screening various catalyst ligands. A high
throughput screening experiment was designed using selected commercially-available
phosphine ligands and the reactions were conducted in a glovebox (Figure 1). Pd2(dba)3 was
chosen as the precatalyst since it is well documented in the literature23 that the use of
Pd2(dba)3 as a palladium source with bulky phosphine ligands in a 1:2 molar ratio is highly
efficient for the Negishi cross-coupling of aryl and heteroaryl halides with an organozinc
reagent derived from the iodoalanine intermediate 2. As shown in Figure 1, with bidentate
phosphine ligands such as BIHEP, DPPB and Mor-Dalphos, the reaction did not proceed at
all. A moderate conversion was observed with S-Phos, Ad-BippyPhos, CPhos, Ph-DavePhos,
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and CX-POMeCy. With XPhos the reaction was clean and gave the best conversion (55%
product by HPLC) with 10% unreacted N-tosyl-3-bromoazaindole (1c).
7
8
9
It would be pertinent to mention a report of a similar Negishi reaction on 4- and 7-
azaindoles in the supplementary data of a literature reference,17 where SPhos was used as the
ligand to afford the corresponding products in good yields from 3-iodo azaindoles at the
temperature of 35 oC. However, in our hands we found that the reaction of Ts-protected 3-
bromo-7-azaindole 1c was sluggish with < 60% conversion after 12 h at 35 ºC.
Figure 1. High Throughput Catalyst Screening of N-Tosyl-3-bromoazaindole (1c) with
Zinc derivative of iodoalanine 2
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High Throughput Ligand Screening
70%
60%
50%
40%
30%
20%
10%
0%
Phosphine Ligands
SM-1
Product
Reaction Conditions: i) Zn-dust (3.0 eq), I2 (0.3 eq.), DMF, rt, 30 min; ii) 1 (1.0 eq.), 2 (1.5
eq.), Pd2(dba)3 (0.05 eq.), ligand (0.1 eq.), 55 oC, 3 h
Having found the best catalyst/ligand combination for conducting Negishi coupling of
1c, the next task was to explore the scalability and reproducibility of the reaction outside of a
glove box. Under standard laboratory reaction conditions, using Pd2(dba)3/XPhos at a
molarity of 0.1 M in DMF, the reaction did not go to completion. Further experiments
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revealed that the reaction concentration played a critical role. At a concentration of 0.05 M,
the reaction was complete in 3 h and provided N-Ts-7-azatryptophan 3c in 89% isolated yield
and the same was successfully scaled-up to 3g (76 %). Notably, racemization was not
observed under these reaction conditions and the enantiomeric excess (ee) of 3c was
determined to be 99.9% by chiral HPLC analysis.
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To further explore the scope of the reaction, various positional isomers of N-Ts-
azaindole halides and substituted N-Ts-azaindole halides were reacted under the optimized
conditions using Pd2(dba)3/XPhos with the zinc derivative of iodoalanine 2. The results are
summarized in Table 2.
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Table 2. Negishi Cross-Coupling of 2 with Ts-azaindoles 1c, 1i-z and 1aa
5
6
7
8
O
H
N
O
OtBu
Fmoc
OtBu
Fmoc
R
N
H
X
I
2
9
1. Zn dust, I2, DMF
R
N
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N
N
N
2. Pd2(dba)3 (5 mol%),
XPhos (10 mol%),
DMF, 55 oC, 3 h
Ts
Ts
1c, 1i-1z and 1aa
3c, 3i-3z and 3aa
t
t
t
CO2 Bu
t
t
CO2 Bu
CO2 Bu
CO2 Bu
CO2 Bu
FmocHN
FmocHN
FmocHN
FmocHN
N
FmocHN
N
N
N
N
N
N
N
N
Ts
N
Ts
Ts
Ts
Ts
3lb
(86%)a
a
a
a
a
3k
(81%)
3j
(82%)
3c
3i
(89%, 99.9 % ee)
(84%)
t
t
t
CO2 Bu
CO2 Bu
CO2 Bu
NHFmoc
t
FmocHN
CO2 Bu
FmocHN
FmocHN
Cl
FmocHN
Cl
N
t
CO2 Bu
F
N
N
N
N
N
N
N
N
N
N
Ts
Ts
Ts
Ts
Ts
(91%)a
3mb
a
a
a
3n
3o
3pc
3q
(84%)
(76%)
(79%)
(0%) +3c (15%)
NHFmoc
t
CO2 Bu
NHFmoc
NHFmoc
NHFmoc
FmocHN
F3C
F
OMe
N
t
t
t
t
CO2 Bu
CO2 Bu
CO2 Bu
CO2 Bu
MeO
N
N
N
N
N
N
N
N
N
Ts
Ts
Ts
Ts
Ts
a
a
a
a
a
3v
(85%)
3t
(81%)
3u
(87%)
3s
(76%)
3r
(83%)
t
CO2 Bu
NHFmoc
NHFmoc
NHFmoc
NHFmoc
FmocHN
CN
N
O
NO2
t
t
t
t
CO2 Bu
CO2 Bu
CO2 Bu
CO2 Bu
MeO2C
NC
N
N
N
N
N
N
N
N
N
Ts
Ts
Ts
Ts
Ts
a
a
a
a
a
3w
(79%)
3x
(81%)
3z
(81%)
3aa
(69%)
3y
(71%)
a
1
2
,
Isolated yield. All reactions were carried out using 0.569 mmol of N-Ts-azaindole (1 eq.) in DMF (12 mL), compound (1.5 eq.) Zn
(3.0 eq.), Iodine (0.3 eq.), Pd2(dba)3 (5 mol%) and XPhos (10 mol%).
b
c
4
1p
3c
gave only des chlorinated product .
Product derived from and 5-bromo azaindole respectively. Compound
Negishi cross-coupling with all four positional isomers of N-Ts protected 3-bromo
azaindoles (4-, 5-6- and 7-azaindoles) furnished 3c, 3i, 3j, and 3k, respectively, in excellent
yields. Moreover, 4-bromo and 5-bromo N-Ts-azaindole participated in this process to afford
3l and 3m in 86% and 91% yield, respectively. In the case of N-Ts protected 5-bromo-7-
deazapurine, the reaction proceeded cleanly in 76% isolated yield (Table 2, entry 3n).
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Although substrates bearing chloro and fluoro substituents on the ring were well-tolerated
and generated the corresponding products in excellent yields (Table 2, entry 3o, 3q-3r), in the
case of 4-chloro-3-bromo N-Ts-azaindole 1p no desired product 3p was formed and 15% of
the des-chloro product 3c was observed by LCMS. Notably, the sterical hindrance associated
with a 2-methyl substituent did not interfere, providing the desired product in good yield
(Table 2, entry 3s). Substrates bearing electronically rich substituents such as the 4- and 5-
OMe moieties (Table 2, entry 3u and 3v) and electron-deficient substituents such as 4- and 5-
CN, 5-COMe, 5-CO2Me, and 4-NO2 were successfully transformed to the corresponding
products in good yields (Table 2, entry 3w-3aa).
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Having successfully demonstrated the Negishi coupling on a wide range of substituted
azaindoles, we explored the selectivity of deprotection and for this purpose, 7-azatryptophan
3c was selected as the prototype.
Scheme 2. Selective Deprotection of Differentially Protected 7-Azatryptophan 3c
O
O
O
O
O
O
Fmoc
Fmoc
N
H2N
N
Ts Cleavage
H
Fmoc Cleavage
H
SmI2, Pyrrolidine,
THF, rt, 0.5 h, 78%
Piperdine, DCM,
rt, 8 h, 91%
N
Ts
N
Ts
N
N
N
N
H
4
3c
5
t-Butyl Cleavage
TFA, DCM, rt,
0.5 h, 92%
O
OH
Fmoc
N
H
N
N
Ts
6
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The primary objective of this phase of the study was to find specific reaction conditions
that allow selective removal of the Fmoc, tBu and N-Ts moieties while preserving the other
two groups. The selective Fmoc deprotection of 7-azatryptophan 3c was achieved using
piperidine in CH2Cl2 to afford compound 5 in 91% isolated yield. The selective deprotection
of the t-butyl group was accomplished using CF3CO2H in CH2Cl2 affording 6 in 92% isolated
yield. While it was relatively straightforward to identify deprotection conditions to selectively
remove the Fmoc and tBu moieties, identifying the right conditions for selective N-Ts
deprotection proved to be considerably more challenging. The majority of the known
reaction conditions 25-27 for N-Ts deprotection led to deprotection of either the Fmoc or tBu
under basic or acidic conditions, respectively.28,29 After numerous attempts, selective
deprotection of N-Ts group on the 7-azatryptophan 3c was achieved by using a 0.1 M
solution of SmI230 in THF in the presence of pyrrolidine which furnished 4 in 78% isolated
yield. The applications of the selectively deprotected Negishi products were further
demonstrated in the synthesis of dipeptides at both C- and N-terminals. 7-Azatryptophans 5
and 6 were successfully coupled with Boc-L-valine 7 and L-valine methyl ester 9 to obtain
dipeptides 8 and 10 in good yields (Scheme 3).
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Scheme 3. Synthesis of Dipeptides 8 and 10
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N
O
OtBu
O
H
N
N
Ts
Boc
OH
H2N
N
O
H
7
N
OtBu
Boc
N
H
T3P,Et3N, EtOAc, 0 oC,
0.5 h, 79%
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O
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Fmoc
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H2N
O
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Fmoc
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H
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T3P,Et3N,EtOAc,0 oC,
0.5 h, 78%
N
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10
In summary, we have developed an efficient method to synthesize differentially
protected azatryptophan analogs 3 via a Negishi cross-coupling reaction using
Pd2(dba)3/XPhos as the catalyst. A variety of functional groups are tolerated under the
reaction conditions and the protective groups can be selectively removed to allow further
synthetic manipulation of the products as demonstrated by the synthesis of dipeptides. The
versatility of these unnatural amino acids make them a valuable tool for the synthesis of
novel therapeutic peptides.
EXPERIMENTAL SECTION
A) General Information: Commercially available reagents were used without additional
purification, unless otherwise stated. The heating reactions were conducted in an oil bath with
IKA magnetic stirrer. Thin layer chromatography was carried out using plates coated with
Kieselgel 60F254. For column chromatography, Teledyne Isco CombiFlash system and Redi-
Sep Silica columns were used. NMR characterization of the isolated products was carried out
in CDCl3 or DMSO-d6 at 25 °C. 1H and 13C{1H} NMR spectra were recorded on a Bruker
Avance III-400 MHz and Varian 500 MHz spectrometers. Coupling constants (J) are reported
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in hertz (Hz). High resolution mass spectra were obtained on an Agilent 6540 UHD Q-TOF
with ESI source. SOR was measured on RUDOLPH Autopol® V automatic polarimeter.
Compound purities were determined by analytical reverse phase HPLC in Agilent 1200 series
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instrument. Chiral purity was determined by SFC-HPLC-Hybrid-Analytical Agilent 1260
Infinity II. Melting points were recorded in BUCHI M-560 instrument.
B) Experimental procedure for the synthesis of 1b, 1d-1h
Tert-butyl 3-bromo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (1b): Following the
literature procedure31a, to a solution of 3-bromo-1H-pyrrolo[2,3-b]pyridine (0.2 g, 1.02 mmol)
in THF (4.0 mL) under nitrogen atmosphere was added DMAP (0.012 g, 0.11 mmol). The
0
resulting reaction mixture was cooled to -20 C followed by addition of di-tert-butyl
pyrocarbonate (0.259 mL, 1.12 mmol). The reaction mixture was allowed to warm to room
temperature and stirred for 2 h. Reaction progress was monitored by LC-MS. The reaction was
diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layer
was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude
was purified by flash column chromatography (5% EtOAc in petroleum ether) to obtain 1b as
colorless liquid (0.17 g, 56%); 1H NMR (CDCl3, 400 MHz) δ 8.61 - 8.55 (m, 1H), 7.89 - 7.72
(m, 2H), 7.32 - 7.27 (m, 1H), 1.69 (s, 9H); 13C{1H} NMR (CDCl3, 101 MHz) δ 146.2, 128.0,
125.4, 122.4, 94.9, 84.7, 28.0.
3-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine(1d):
To a solution of 3-bromo-1H-pyrrolo[2,3-b]pyridine (0.5 g, 2.5 mmol) in THF (15 mL) under
nitrogen atmosphere was added NaH (0.163 g, 4 mmol) at 0 °C and the reaction was stirred
for 1 h. To this was added (2-Chloromethoxyethyl) trimethylsilane (0.55 g, 3.3 mmol) and the
reaction mixture was allowed to warm to room temperature and stirred overnight. Reaction
progress was monitored by LC-MS. The reaction was quenched with water (10 mL),
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extracted with EtOAc (10 mL), washed with brine solution (10 mL) and dried over anhydrous
Na2SO4. The organic layer was evaporated to obtain the crude compound. The crude
compound was purified by flash column chromatography (5% EtOAc in petroleum ether) to
afford the title compound 1d as a colorless liquid (0.6 g, 93%); 1H NMR (CDCl3, 400 MHz)
δ 8.38 (dd, J = 1.5, 4.5 Hz, 1H), 7.87 (dd, J = 1.5, 8.0 Hz, 1H), 7.40 (s, 1H), 7.23 - 7.14 (m,
1H), 3.60 - 3.53 (m, 2H), 0.95 – 0.91 (m, 2H), 0.05 (s, 9H); 13C{1H} NMR (CDCl3,101 MHz)
δ 147.2, 144.4, 127.6, 126.8, 120.0, 117.0, 90.1, 72.8, 66.4, 17.8, 1.44 (3C); HRMS (ESI)
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m/z: [M + H] + Calcd for C13H20BrN2OSi 327.0450; Found 327.0525.
3-Bromo-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine (1e): To a solution of 3-bromo-
1H-pyrrolo[2,3-b]pyridine (2 g, 10.5 mmol) in THF (40 mL) under nitrogen atmosphere was
added NaH (0.365 g, 15.23 mmol) at 0 °C. The reaction was stirred at 0 °C for 1 h. To this 1-
(bromomethyl)-4-methoxybenzene (2.40 g, 12.18 mmol) was added and the reaction mixture
was allowed to warm to room temperature and stirred for 2 h. Reaction progress was
monitored by LC-MS. The reaction was quenched with water (30 mL), extracted with EtOAc
(30 mL), washed with brine solution (30 mL) and dried over anhydrous Na2SO4. The organic
solvents were evaporated to obtain the crude compound. The crude compound was purified
by flash column chromatography (5% EtOAc in petroleum ether) to afford title compound 1e
as colorless liquid (2.12 g, 66%); 1H NMR (CDCl3, 400 MHz) δ 8.42 (dd, J = 1.0, 5.0 Hz,
1H), 7.90 (dd, J = 1.3, 7.8 Hz, 1H), 7.23 - 7.15 (m, 4H), 6.88 (d, J = 8.5 Hz, 2H), 5.45 (s,
2H), 3.80 (s, 3H); 13C{1H} NMR (CDCl3, 101 MHz) δ 159.3, 143.7, 129.2 (3C), 128.9,
127.9, 126.7, 120.2, 116.4, 114.2 (2C), 88.6, 55.2, 47.6; HRMS (ESI) m/z: [M + H] + Calcd
for C15H14BrN2O 317.0211; Found 317.0297.
Benzyl 3-bromo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (1f): To a solution of 3-bromo-
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1H-pyrrolo[2,3-b]pyridine (0.4 g, 2.0 mmol) in DCM (4.0 mL) under nitrogen atmosphere
was added Et3N (0.7 mL, 5.08 mmol) at 0 oC. To this resulting reaction mixture was added
benzyl chloroformate (0.44 mL, 5.05 mmol). The reaction mixture was allowed to warm up
to room temperature and stirred for 2 h. Reaction progress was monitored by LC-MS. The
reaction mixture was quenched with sat. sodium bicarbonate (25 mL) and extracted with
DCM (2 x 15 mL). The combined organic layer was washed with brine solution (15 mL),
dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Title
compound 1f was purified by flash column chromatography (10% EtOAc in petroleum ether)
to obtain as off-white solid (0.7 g, 94%); mp: 69-71 oC; 1H NMR (CDCl3, 400 MHz) δ 8.59
(dd, J = 1.3, 4.8 Hz, 1H), 7.94 - 7.79 (m, 2H), 7.55 (d, J = 6.5 Hz, 2H), 7.45 – 7.39 (m, 3H),
7.34 – 7.29 (m, 1H), 5.53 (s, 2H); 13C{1H} NMR (CDCl3, 101 MHz) δ 146.8, 146.4, 134.7,
128.7, 128.7, 128.6 (3C), 128.2, 125.2, 122.6, 119.4, 95.9, 69.2; HRMS (ESI) m/z: [M + H]+
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Calcd for C15H12BrN2O2 330.0004; Found 330.0083.
3-Bromo-1-(tert-butyl)-1H-pyrrolo[2,3-b]pyridine compound with sulfurmonoxide (1g):
To a solution of 3-bromo-1H-pyrrolo[2,3-b]pyridine (0.5 g, 2.5 mmol), in THF (10 mL),
under nitrogen atmosphere was added NaH (0.365 g, 15.23 mmol) at 0 °C. The reaction was
stirred at 0 °C for 1 h. To this was added, tert-butylsulfinyl chloride (0.48 g, 3.1 mmol) and
stirred. The reaction mixture was allowed to warm to room temperature and stirred for 2 h.
Reaction progress was monitored by LC-MS. The reaction was quenched with water (30
mL), extracted with EtOAc (30 mL), washed with brine solution (30 mL) and dried over
anhydrous Na2SO4. The organic layer was evaporated to obtain a crude compound which was
purified by flash column chromatography (20% EtOAc in petroleum ether) to afford title
compound 1g as white solid (0.53 g, 69%) mp: 131-133 oC; 1H NMR (CDCl3, 400 MHz) δ
8.40 (dd, J = 1.5, 5.0 Hz, 1H), 7.91 (dd, J = 1.5, 8.0 Hz, 1H), 7.62 (s, 1H), 7.28 - 7.24 (m,
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1H), 1.36 (s, 9H); 13C{1H} NMR (CDCl3, 101 MHz) δ 148.9, 145.1, 128.3, 122.0, 121.4,
118.3, 93.9, 61.1, 22.2 (3C); HRMS (ESI) m/z: [M + H] + Calcd for C11H13BrN2OS 300.9932;
Found 301.0044.
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3-Bromo-1-((4-nitrophenyl)sulfonyl)-1H-pyrrolo[2,3-b]pyridine (1h): To a solution of 3-
bromo-1H-pyrrolo[2,3-b]pyridine (0.5 g, 2.5 mmol) in THF (25 mL) under nitrogen
atmosphere were added pyridine (1.03 mL, 12.69 mmol) and p-toluenesulfonyl chloride
(0.675 g, 3.05 mmol) and refluxed for 36 h. Reaction progress was monitored by LC-MS.
The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL).
The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated.
The title compound 1h was purified by flash column chromatography (20% EtOAc in
petroleum ether) to obtain as off-white solid (0.235 g, 24%); mp: 197-199 oC; 1H NMR
(CDCl3, 400 MHz) δ 8.62 - 8.39 (m, 3H), 8.38 - 8.25 (m, 2H), 7.91 - 7.82 (m, 1H), 7.81 -
7.76 (m, 1H), 7.36 - 7.28 (m, 1H); 13C{1H} NMR (CDCl3, 101 MHz) δ 146.3, 145.9, 143.1,
129.7 (3C), 128.9, 124.4, 124.3 (2C), 122.6, 120.0, 96.8; (ESI) m/z: [M + H]+ Calcd for
C13H18BrN3O4S 381.9419; Found 381.9497.
C) General experimental procedure for Tosylazindole intermediates (1c, 1i-1aa): To a
solution of azaindole (1.0 eq.) in THF (15 mL), cooled to 0 °C, NaH (1.5 to 3.0 eq. 60 %
dispersion in mineral oil) was added and the reaction stirred for 1 h. To the reaction mixture
p-toluenesulfonyl chloride (1.3 eq.), was added and the reaction mixture was allowed to
warm to room temperature and stirred overnight. Reaction progress was monitored by LC-
MS. The reaction was quenched with water (10 mL), extracted with EtOAc (10 mL), washed
with brine solution (10 mL) and dried over anhydrous Na2SO4. The organic layer was
evaporated to obtain the crude compound which was purified by flash column
chromatography (5-40% EtOAc in petroleum ether) to afford the pure compound.
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3-Bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (1c): Following the literature procedure 31c
,
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using 3-bromo-1H-pyrrolo[2,3-b]pyridine (5 g, 25.4 mmol), NaH (0.913 g, 38.1 mmol) and p-
toluenesulfonyl chloride (7.26 g, 38.1 mmol), 1c was obtained by flash column
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chromatography (40% EtOAc in petroleum ether) as off-white solid (7 g, 79%); H NMR
(DMSO-d6, 400 MHz) δ 8.45 (dd, J = 1.5, 5.0 Hz, 1H), 8.20 (s, 1H), 8.01 (d, J = 8.0 Hz, 2H),
7.93 (dd, J = 1.5, 8.0 Hz, 1H), 7.44 - 7.38 (m, 3H), 2.32 (s, 3H); C{1H} NMR (DMSO-d6,
13
101 MHz) 145.9, 145.8, 145.3, 134.1, 130.0, 128.5 (2C), 127.6 (2C), 125.6, 121.6, 120.0, 94.9,
21.0.
3-Bromo-1-tosyl-1H-pyrrolo[3,2-b]pyridine (1i): Following the general procedure, using
3-bromo-1H-pyrrolo[3,2-b]pyridine (1.0 g, 5.08 mmol), NaH (0.365 g , 15.23 mmol) and p-
Toluenesulfonyl chloride (1.064 g, 5.58 mmol), 1i was obtained by flash column
chromatography (30% EtOAc in petroleum ether) as off-white solid (0.9 g, 50%); mp: 197-199
oC; 1H NMR (DMSO-d6, 400 MHz) δ 8.59 = 8.58 (dd, J = 1.2, 4.6 Hz, 1H), 8.46 (s, 1H), 8.37
(dd, J = 1.1, 8.4 Hz, 1H), 7.94 (d, J = 8.3 Hz, 2H), 7.46 (dd, J = 4.6, 8.3 Hz, 1H), 7.37 (d, J =
8.1 Hz, 2H), 2.37 - 2.26 (m, 3H); 13C{1H} NMR (DMSO-d6,101 MHz) δ 147.4, 146.7, 145.1,
133.9, 130.9 (2C), 129.3, 127.7, 127.4 (2C), 121.7, 121.1, 100.4, 21.5; HRMS (ESI) m/z: [M
+ H]+ C14H11BrN2O2S 350.9797; Found 350.9783.
3-Bromo-1-tosyl-1H-pyrrolo[3,2-c]pyridine (1j): Following the general procedure, using
3-bromo-1H-pyrrolo[3,2-c]pyridine (1.0 g, 5.08 mmol), NaH (0.365 g , 15.23 mmol) and p-
toluenesulfonyl chloride (1.064 g, 5.58 mmol), 1j was obtained by flash column
chromatography (10% EtOAc in petroleum ether) as off-white solid (0.9 g, 88%); mp: 198 oC;
mp: 163-165 oC; 1H NMR (DMSO-d6, 400 MHz) δ 8.78 (s, 1H), 8.56 (d, J = 5.9 Hz, 1H), 8.26
(s, 1H), 8.04 - 7.93 (m, 3H), 7.44 (d, J = 8.1 Hz, 2H), 2.38 (s, 3H); 13C{1H} NMR (DMSO-d6,
101 MHz) δ 146.4, 145.2, 142.4, 138.0, 133.3, 130.5 (2C), 127.0 (2C), 126.4, 125.0, 107.9,
96.4, 21.0; HRMS (ESI) m/z: [M + H]+ Calcd for C14H11BrN2O2S 350.9797; Found 350.9804.
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3-Bromo-1-tosyl-1H-pyrrolo[2,3-c]pyridine (1k): Following the literature procedure31b,
using 3-bromo-1H-pyrrolo[2,3-c]pyridine (1.0 g, 5.25 mmol), NaH (0.19 g, 7.87 mmol) and p-
toluenesulfonyl chloride (1.24 g, 6.82 mmol), 1k was obtained by flash column
chromatography (10% EtOAc in petroleum ether) as off-white solid (1.08 g, 60%); 1H NMR
(DMSO-d6, 400 MHz) δ 9.27 (s, 1H), 8.51 (d, J = 5.1 Hz, 1H), 8.43 (s, 1H), 8.04 (d, J = 8.3
Hz, 2H), 7.54 (dd, J = 1.0, 5.4 Hz, 1H), 7.44 (d, J = 8.6 Hz, 2H), 2.35 (s, 3H); 13C{1H} NMR
(DMSO-d6, 101 MHz) δ 146.3, 143.1, 135.2, 134.6, 133.3, 130.5 (2C), 130.4, 129.1, 127.1
(2C), 113.9, 97.3, 21.0.
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4-Bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (1l): Following the literature procedure31c,
using 4-bromo-1H-pyrrolo[2,3-b]pyridine (1.0 g, 5.25 mmol), NaH (0.19 g, 7.87 mmol) and p-
toluenesulfonyl chloride (1.24 g, 6.82 mmol), 1l was obtained by flash column chromatography
(10% EtOAc in petroleum ether) as off-white solid (1.48 g, 82%); 1H NMR (CDCl3, 400 MHz)
δ 8.24 (d, J = 5.3 Hz, 1H), 8.08 (d, J = 8.5 Hz, 2H), 7.80 (d, J = 4.0 Hz, 1H), 7.37 (d, J = 5.3
Hz, 1H), 7.32 - 7.30 (m, 2H), 6.65 (d, J = 4.0 Hz, 1H), 2.39 (s, 3H); 13C{1H} NMR (CDCl3,
101 MHz) δ 146.7, 145.4, 144.9, 135.0, 129.6 (2C), 128.1 (2C), 126.9, 125.6, 124.3, 122.0,
104.8, 21.6.
5-Bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (1m): Following the literature procedure31c,
using 5-bromo-1H-pyrrolo[2,3-b]pyridine (1.0 g, 5.12 mmol), NaH (0.365 g, 15.23 mmol)
and p-toluenesulfonyl chloride (1.06 g, 5.58 mmol), 1m was obtained by flash column
chromatography (30% EtOAc in petroleum ether) as off-white solid (1.1 g, 62%); 1H NMR
(DMSO-d6, 400 MHz) δ 8.46 (d, J = 2.0 Hz, 1H), 8.32 (d, J = 2.5 Hz, 1H), 7.99 - 7.94 (m,
3H), 7.42 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 4.0 Hz, 1H), 2.34 (s, 3H).
5-Bromo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (1n): Following the literature procedure 31b
,
using 5-bromo-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 5.25 mmol), NaH (0.19 g, 7.87 mmol) and
p-toluenesulfonyl chloride (1.24 g, 6.82 mmol), 1n was obtained by flash column
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chromatography (petroleum ether/EtOAc, 9:1) as off-white solid (0.99 g, 55%); H NMR
(DMSO-d6, 400 MHz) δ 9.04 (s, 1H), 9.01 (s, 1H), 8.30 (s, 1H), 8.05 (d, J = 8.6 Hz, 2H), 7.45
(d, J = 7.8 Hz, 2H), 2.34 (s, 3H); 13C{1H} NMR (DMSO-d6, 101 MHz) δ 153.7, 149.8, 149.4,
146.4, 133.6, 130.2 (2C), 127.7 (2C), 126.5, 93.1, 21.0.
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3-Bromo-5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (1o): Following the literature
procedure 31d, using 3-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine (1.0 g, 5.25 mmol), NaH
(0.19 g, 7.87 mmol) and p-toluenesulfonyl chloride (1.24 g, 6.82 mmol), 1o was obtained by
flash column chromatography (10% EtOAc in petroleum ether) as off-white solid (0.81 g, 45
%); 1H NMR (DMSO-d6, 400 MHz) δ 8.41 (d, J = 2.3 Hz, 1H), 8.07 (d, J = 8.5 Hz, 2H), 7.83
(s, 1H), 7.80 (s, 1H), 7.33 (s, 1H), 7.31 - 7.28 (m, 1H), 2.41 (s, 3H); 13C{1H} NMR (DMSO-
d6, 101 MHz) δ 146.0, 143.0, 135.9, 135.2, 134.3, 131.0, 130.2 (3C), 127.8, 127.0, 114.0,
97.9, 21.5.
3-Bromo-4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1p): Following the general
procedure, using 3-bromo-1H-pyrrolo[2,3-b]pyridine (1.2 g, 5.18 mmol), NaH (0.373 g,
15.55 mmol) and p-toluenesulfonyl chloride (1.087 g, 5.7 mmol), 1p was obtained by flash
column chromatography (30% EtOAc in petroleum ether) as off-white solid (0.25 g, 12%);
mp: 159-161 oC; 1H NMR (DMSO-d6, 400 MHz) δ 8.37 (d, J = 5.0 Hz, 1H), 8.30 (s, 1H),
8.02 (d, J = 8.5 Hz, 2H), 7.50 - 7.42 (m, 3H), 2.35 (s, 3H); 13C{1H} NMR (DMSO-d6, 101
MHz) δ 146.9, 146.8, 146.3, 136.5, 134.4, 130.7 (2C), 128.4 (3C), 127.9, 121.5, 92.6, 21.7;
HRMS (ESI) m/z: [M + H]+ Calcd for C14H10BrClN2O2S 384.9408; Found 384.9417.
3-Bromo-5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (1q): Following the literature
procedure31d, using 3-bromo-5-fluoro-1H-pyrrolo[2,3-b]pyridine (1.2 g, 5.58 mmol), NaH
(0.402 g, 16.74 mmol) and p-toluenesulfonyl chloride (1.17 g, 6.14 mmol), 1q was obtained
by flash column chromatography (30% EtOAc in petroleum ether) as off-white solid (1.4 g,
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66 %); 1H NMR (DMSO-d6, 400 MHz) δ 8.50 - 8.46 (m, 1H), 8.31 (s, 1H), 8.00 (d, J = 7.8
Hz, 2H), 7.95 - 7.90 (m, 1H), 7.44 (d, J = 8.0 Hz, 2H), 2.35 (s, 3H).
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3-Bromo-4-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (1r): Following the general
procedure, using 3-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine (0.5 g, 2.33 mmol), NaH
(0.167 g, 6.98 mmol) and p-toluenesulfonyl chloride (0.488 g, 2.56 mmol), 1r was obtained
by flash column chromatography (30% EtOAc in petroleum ether) as off-white solid (0.28 g,
33%); mp: 211-213 oC; 1H NMR (DMSO-d6, 400 MHz) δ 8.45 (dd, J = 5.8, 7.5 Hz, 1H), 8.22
(s, 1H), 8.03 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 7.32 (br d, J = 5.5 Hz, 1H), 2.35 (s,
3H); 13C{1H} NMR (DMSO-d6, 101 MHz) δ 164.9, 146.5, 146.2, 133.8, 131.5 (d, J = 71.9
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Hz), 130.2, 127.2, 124.5, 122.1, 64.4, 52.5, 21.1; HRMS (ESI) m/z: [M + H]+ Calcd for
C14H10BrFN2O2S 368.9703; Found 368.9703.
3-Bromo-2-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine (1s): Following the literature
procedure31d, using 3-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine (1.0 g, 4.74 mmol), NaH
(0.34 g, 14.21 mmol) and p-toluenesulfonyl chloride (0.994 g, 5.21 mmol), 1s was obtained by
flash column chromatography (30% EtOAc in petroleum ether) as off-white solid (1 g, 57 %);
1H NMR (DMSO-d6, 400 MHz) δ 8.38 (d, J = 4.6 Hz, 1H), 8.00 (d, J = 8.1 Hz, 2H), 7.81 (d, J
= 7.8 Hz, 1H), 7.46 - 7.29 (m, 3H), 2.74 (s, 3H), 2.28 (s, 3H).
3-Iodo-1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (1t): Following the literature
procedure31d, using 3-iodo-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (1 g, 3.20 mmol),
NaH (0.23 g, 9.61 mmol) and p-toluenesulfonyl chloride (0.672 g, 3.53 mmol), 1t was obtained
by flash column chromatography (30% EtOAc in petroleum ether) as off-white solid (1.1 g,
71%); 1H NMR (DMSO-d6, 400 MHz) δ 8.80 (s, 1H), 8.37 (s, 1H), 8.18 - 8.09 (m, 1H), 8.04
(d, J = 7.8 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 2.35 (s, 3H).
3-Bromo-4-methoxy-1-tosyl-1H-pyrrolo[2,3-b]pyridine (1u): Following the general
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procedure, using 3-bromo-4-methoxy-1H-pyrrolo[2,3-b]pyridine (1.0 g, 4.40 mmol), NaH
(0.32 g, 13.21 mmol) and p-toluenesulfonyl chloride (0.92 g, 4.84 mmol), 1u was obtained
by flash column chromatography (30% EtOAc in petroleum ether) as off-white solid (1.4 g,
83%); mp: 179-181 oC; 1H NMR (DMSO-d6, 400 MHz) δ 8.29 (d, J = 5.5 Hz, 1H), 8.04 -
7.96 (m, 2H), 7.94 (s, 1H), 7.46 - 7.35 (m, 2H), 6.95 (d, J = 6.0 Hz, 1H), 3.93 (s, 3H), 2.35 (s,
3H); 13C{1H} NMR (DMSO-d6,101 MHz) δ 160.5, 148.4, 147.4, 146.2, 134.6, 130.4 (2C),
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128.2 (2C), 124.1, 110.6, 102.8, 92.2, 56.6, 21.5; HRMS (ESI) m/z: [M + H]+ Calcd for
C15H13BrN2O3S 380.9903; Found 380.9887.
3-Bromo-5-methoxy-1-tosyl-1H-pyrrolo[2,3-b]pyridine (1v): Following the literature
procedure31d, using 3-bromo-5-methoxy-1H-pyrrolo[2,3-b]pyridine (0.5 g, 2.20 mmol), NaH
(0.16 g, 6.61 mmol), and p-toluenesulfonyl chloride (0.462 g, 2.42 mmol), 1v was obtained by
flash column chromatography (30% EtOAc in petroleum ether) as off-white solid (0.5 g, 60
%); 1H NMR (DMSO-d6, 400 MHz) δ 8.19 - 8.12 (m, 2H), 7.97 (d, J = 8.5 Hz, 2H), 7.46 - 7.35
(m, 3H), 3.86 (s, 3H), 2.33 (s, 3H); 13C{1H} NMR (DMSO-d6, 101 MHz) δ 153.6, 145.7, 139.8,
136.2, 134.1, 130.0 (3C), 127.4 (2C), 126.4, 110.4, 56.1, 21.0.
3-Iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (1w): Following the general
procedure, using 3-iodo-1H-pyrrolo[2,3-b]pyridine-4-(1 g, 3.72 mmol), NaH (0.27 g, 11.15
mmol) and p-toluenesulfonyl chloride (0.78 g, 4.09 mmol), 1w was obtained by flash column
chromatography (30% EtOAc in petroleum ether) as off-white solid (1.0 g, 64%); mp: 161-
163 oC; 1H NMR (DMSO-d6, 400 MHz) δ 8.57 (d, J = 5.1 Hz, 1H), 8.42 (s, 1H), 8.03 (d, J =
8.3 Hz, 2H), 7.84 (d, J = 4.9 Hz, 1H), 7.42 (d, J = 8.1 Hz, 2H), 2.33 (s, 3H); 13C{1H} NMR
(DMSO-d6, 101 MHz) δ 146.2, 145.5, 145.3, 133.9, 133.6 (2C), 130.1, 127.8, 123.7, 121.1,
113.9, 112.6, 60.3, 21.0; HRMS (ESI) m/z: [M + H]+ Calcd for C15H10IN3O2S 423.9611;
Found 423.9582.
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3-Bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (1x): Following the general
procedure, using 3-bromo-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (1 g, 4.50 mmol), NaH
(0.324 g, 13.51 mmol) and p-toluenesulfonyl chloride (0.94 g, 4.95 mmol), 1x was obtained
by flash column chromatography (30% EtOAc in petroleum ether) as off-white solid (1.1 g,
60%); mp: 173-175 oC; 1H NMR (DMSO-d6, 400 MHz) δ 8.87 (d, J = 1.8 Hz, 1H), 8.58 (d, J
= 1.8 Hz, 1H), 8.43 (s, 1H), 8.04 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 2.35 (s, 3H);
13C{1H} NMR (DMSO-d6, 101 MHz) δ 148.5, 146.4, 145.9, 133.7, 133.3, 130.2 (2C), 128.1,
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127.8 (2C), 121.3, 116.9, 105.0, 94.7, 21.1; HRMS (ESI) m/z: [M + H]+ Calcd for
C15H10BrN3O2S 375.9750; Found: 375.9735.
1-(3-Iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)ethan-1-one (1y): Following the general
procedure, using 1-(3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)ethan-1-one (1.2 g, 4.19 mmol),
NaH (0.30 g, 12.58 mmol) and p-toluenesulfonyl chloride (0.880 g, 4.61 mmol), 1y was
obtained by flash column chromatography (30% EtOAc in petroleum ether) as off-white
solid (1.10 g, 60%); mp: 173-175 oC; 1H NMR (DMSO-d6, 400 MHz) δ 8.97 (d, J = 2.0 Hz,
1H), 8.29 (s, 1H), 8.19 (d, J = 2.0 Hz, 1H), 8.07 - 8.03 (m, 2H), 7.48 - 7.42 (m, 2H), 2.68 (s,
3H), 2.35 (s, 3H); 13C{1H} NMR (DMSO-d6, 101 MHz) δ 196.6, 147.6, 146.6, 146.3, 134.1,
131.9, 130.3, 130.2 (2C), 129.1, 127.9 (2C), 124.6, 27.3, 21.2; HRMS (ESI) m/z: [M + H]+
Calcd for C16H13IN2O3S 440.9764; Found: 440.9745.
Methyl 3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1z): Following the
general procedure, using methyl 3-iodo-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.5 g, 1.66
mmol), NaH (0.12 g, 4.97 mmol) and p-toluenesulfonyl chloride (0.35 g, 1.82 mmol), 1z was
obtained by flash column chromatography (30% EtOAc in petroleum ether) as off-white
solid (0.35 g, 46%); mp: 164-166 oC; 1H NMR (DMSO-d6, 400 MHz) δ 8.91 (d, J = 2.0 Hz,
1H), 8.29 (s, 1H), 8.16 (d, J = 2.0 Hz, 1H), 8.05 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H),
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3.90 (s, 3H), 2.34 (s, 3H); 13C{1H} NMR (DMSO-d6, 101 MHz) δ 165.4, 148.1, 147.0, 146.7,
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134.4, 132.3, 131.6, 130.6 (2C), 128.3 (2C), 125.9, 124.9, 122.6, 64.9, 53.0, 21.6; HRMS
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(ESI) m/z: [M + H]+ Calcd for C16H13IN2O4S 456.9713; found 456.9699.
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3-Iodo-4-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1aa): Following the general procedure,
using methyl 3-iodo-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1 g, 3.46 mmol), NaH (0.25 g,
10.38 mmol) and p-toluenesulfonyl chloride (0.73 g, 3.81 mmol), 1aa was obtained by flash
column chromatography (30% EtOAc in petroleum ether) as yellow solid (0.8 g, 51%); mp:
197-199 oC; 1H NMR (DMSO-d6, 400 MHz) δ 8.66 (d, J = 5.1 Hz, 1H), 8.45 (s, 1H), 8.10 -
8.01 (m, J = 8.3 Hz, 2H), 7.89 (d, J = 5.1 Hz, 1H), 7.48 - 7.40 (m, J = 8.3 Hz, 2H), 2.34 (s,
3H); 13C{1H} NMR (DMSO-d6, 101 MHz) δ 148.7, 147.2, 146.4, 146.3, 135.1, 133.5 (2C),
130.1 (2C), 127.9, 112.7, 112.7, 57.2, 21.0; HRMS (ESI) m/z: [M + H]+ Calcd for
C14H10IN3O4S 443.9509; Found 443.9500.
D) General experimental procedure for the synthesis of 3c-3aa: To a stirred suspension of
zinc dust (112 mg, 1.71 mmol) in DMF (5.0 mL) was added 0.5 mL of a solution of iodine
(43.4 mg, 0.17 mmol) in DMF (1.0 mL). After observing colour change, tert-butyl (R)-2-
((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodopropanoate 2 (421 mg, 0.85 mmol) was
added in one potion followed by addition of the remaining 0.5 mL of the iodine solution. The
solution was stirred at room temperature for 35 min; the supernatant liquid was transferred to
a mixture of N-Ts-3-haloazaindoles (1 eq., 0.57 mmol), Pd2(dba)3 (26.1 mg, 0.03 mmol),
and XPhos (27.1 mg, 0.06 mmol) in DMF (6 mL) via a syringe. The reaction mixture was
stirred at 55 oC in oil bath for 3 h. The completion of reaction was monitored by LCMS. The
reaction mixture was concentrated to remove DMF, then diluted with EtOAc (50 mL) and
passed through a celite pad. The organic layer was washed with water (20 mL), brine (20
mL), dried over anhydrous Na2SO4 and concentrated under vacuum to give the crude product
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which was purified by silica gel column chromatography (eluted with 30-40 % EtOAc in
petroleum ether) followed by recrystallization using MTBE/Heptane to afford the pure
product.
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For the large-scale synthesis, the general procedure was adapted: To a stirred
suspension of zinc dust (1.68 g, 25.65 mmol) in DMF (75.0 mL) was added 7.5 mL of a
solution of iodine (0.65 g, 2.55 mmol) in DMF (15.0 mL). After observing colour change,
tert-butyl (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodopropanoate 2 (6.32 g,
12.81 mmol) was added in one potion followed by addition of the remaining 7.5 mL of the
iodine solution. The solution was stirred at room temperature for 35 min; the supernatant
liquid was transferred to a mixture of 3-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine 1c (3.0
g, 8.54 mmol), Pd2(dba)3 (0.39 g, 0.45 mmol), and XPhos (0.41 g, 0.9 mmol) in DMF (90
mL) via a syringe. The reaction mixture was stirred at 55 oC in oil bath for 3 h. The reaction
mixture was concentrated to remove DMF, then diluted with EtOAc (750 mL) and passed
through a celite pad. The organic layer was washed with water (300 mL), brine (300 mL),
dried over anhydrous Na2SO4 and concentrated under vacuum to give the crude product
which was purified by silica gel column chromatography (eluted with 30-40 % EtOAc in
petroleum ether) followed by recrystallization using MTBE/Heptane to afford tert-Butyl (S)-
2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-
yl)propanoate (3c) in 76% yield (4.2 g).
Spectroscopic and analytical data for isolated compounds are given below:
tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-tosyl-1H-
pyrrolo[2,3-b]pyridin-3-yl)propanoate (3c): The title compound was purified by flash silica-
gel column chromatography (30% EtOAc in petroleum ether) to obtain off-white solid (323
mg, 89%, >99% ee); mp: 137-139 oC; [α]25D = +14.8 (c = 1.0, CHCl3); 1H NMR (500 MHz,
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DMSO-d6) δ 8.36 (d, J = 4.4 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.91 (br dd, J = 8.1, 14.4 Hz,
5H), 7.77 (s, 1H), 7.66 (dd, J = 4.4, 6.8 Hz, 2H), 7.46 - 7.37 (m, 2H), 7.35 - 7.24 (m, 5H),
4.35 - 4.09 (m, 4H), 3.18 - 3.08 (m, 1H), 3.06 - 2.96 (m, 1H), 2.27 (s, 3H), 1.27 (s, 9H);
13C{1H} NMR (126 MHz, DMSO-d6) δ 171.1, 156.3, 147.0, 145.8, 145.0, 144.2, 144.1,
140.1, 141.1, 135.1, 130.3 (2C), 129.1 (2C), 128.1 (2C),127.8 (2C), 127.5 (2C), 125.7, 124.9,
123.1, 120.6 (2C), 119.5, 115.6, 81.2, 66.7, 54.8, 47.0, 27.9 (3C), 26.9, 21.4; HRMS (ESI)
m/z: [M + H]+ Calcd for C36H35N3O6S 638.2319; Found 638.2294.
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tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-tosyl-1H-
pyrrolo[3,2b]pyridin-3-yl)propanoate (3i): The title compound was purified by flash silica-
gel column chromatography (30% EtOAc in petroleum ether) to obtain off-white solid (305
mg, 84%); mp: 69-71 oC; [α]25D = +1.4 (c = 2.0, CHCl3); 1H NMR (400 MHz, DMSO-d6) δ
8.52 (d, J = 4.9 Hz, 1H), 8.31 (br d, J = 8.3 Hz, 1H), 8.04 (br d, J = 7.3 Hz, 1H), 8.00 (s, 1H),
7.88 (dd, J = 8.1, 18.3 Hz, 4H),7.67 (t, J = 7.1 Hz, 2H), 7.47 - 7.36 (m, 3H), 7.35 - 7.23 (m,
4H), 4.48 - 4.40 (m, 1H), 4.32 - 4.26 (m, 1H), 4.23 - 4.11 (m, 2H), 3.23 - 3.12 (m, 1H), 3.06
(br dd, J = 8.8, 14.7 Hz, 1H), 2.26 (s, 3H), 1.19 (s, 9H); 13C{1H} NMR (126 MHz, DMSO-
d6) δ 171.1, 156.3, 147.9, 146.2, 146.1, 144.2, 144.1 (2C), 134.3, 130.8 (2C), 128.6 (2C),
128.2, 128.1, 128.0, 127.5 (2C), 127.2 (2C), 125.7, 125.6, 121.2, 120.6 (2C), 120.0, 119.1,
80.9, 66.1, 54.1, 47.0, 27.8 (3C), 26.3, 21.4; HRMS (ESI) m/z: [M + H]+ Calcd for
C36H35N3O6S 638.2319; Found 638.2305.
tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-tosyl-1H-
pyrrolo[3,2-c]pyridin-3-yl)propanoate (3j): The title compound was purified by flash silica-
gel column chromatography (30% EtOAc in petroleum ether) to obtain off-white solid (298
mg, 82%); mp: 85-87 oC; [α]25D = +12.6 (c = 2.0, CHCl3); 1H NMR (400 MHz, DMSO-d6) δ
8.95 (s, 1H), 8.45 (br d, J = 6.0 Hz, 1H), 7.94 - 7.82 (m, 6H), 7.75 (s, 1H), 7.64 (br dd, J =
2.0, 7.5 Hz, 2H), 7.46 - 7.37 (m, 2H), 7.35 - 7.21 (m, 4H), 4.34 - 4.08 (m, 4H), 3.21 - 3.00
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(m, 2H), 2.25 (s, 3H), 1.23 (s, 9H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 171.0, 156.3,
146.3, 144.6, 144.2, 144.1 (2C), 143.4, 141.1 (2C), 139.0, 134.3, 130.9 (2C), 130.8, 128.1
(2C), 127.5, 127.4, 127.3, 126.9, 125.7 (2C), 120.6 (2C), 117.9, 108.4, 81.2, 66.2, 54.9, 47.0,
27.8 (3C), 26.6, 21.4; HRMS (ESI) m/z: [M + H]+ Calcd for C36H35N3O6S 638.2319; Found
638.2306.
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tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-tosyl-1H-
pyrrolo[2,3-c]pyridin-3-yl)propanoate (3k): The title compound was purified by flash silica-
gel column chromatography (30% EtOAc in petroleum ether) to obtain off-white solid (294
mg, 81%); mp: 90-92 oC; [α]25D = +11.1 (c = 2.0, CHCl3); 1H NMR (400 MHz, DMSO-d6) δ
9.16 (s, 1H), 8.37 (d, J = 5.5 Hz, 1H), 7.95 - 7.81 (m, 6H), 7.72 - 7.57 (m, 3H), 7.40 (br dd, J
= 1.8, 7.3 Hz, 2H), 7.34 - 7.21 (m, 4H), 4.34 - 4.12 (m, 4H), 3.16 - 3.07 (m, 1H), 3.06 - 2.96
(m, 1H), 2.24 (s, 3H), 1.25 (s, 9H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 171.0, 156.3,
146.3, 144.2, 144.1, 142.8, 141.1, 136.5, 135.4, 134.2, 131.6, 130.8 (2C), 128.6 (2C), 128.1
(2C), 127.5 (2C), 127.3 (2C), 125.7, 125.6, 120.6 (2C), 118.3, 115.1, 81.2, 66.2, 54.7, 47.0,
27.9 (3C), 27.3, 21.4; HRMS (ESI) m/z: [M + H]+ Calcd for C36H35N3O6S 638.2319; Found
638.2302.
tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-tosyl-1H-
pyrrolo[2,3-b]pyridin-4-yl)propanoate (3l): The title compound was purified by flash silica-
gel column chromatography (30% EtOAc in petroleum ether) to obtain off-white solid (312
mg, 86%); mp: 90-92 oC; [α]25D = +5.1 (c = 2.0, CHCl3); 1H NMR (400 MHz, DMSO-d6) δ
8.25 (d, J = 5.0 Hz, 1H), 7.90 (dd, J = 8.3, 11.3 Hz, 4H), 7.85 - 7.81 (m, 2H), 7.62 (d, J = 7.5
Hz, 2H), 7.44 - 7.38 (m, 2H), 7.34 - 7.31 (m, 4H), 7.17 (d, J = 5.0 Hz, 1H), 6.91 (d, J = 4.0
Hz, 1H), 4.30 - 4.18 (m, 2H), 4.16 - 4.08 (m, 2H), 3.25 - 3.10 (m, 2H), 2.27 (s, 3H), 1.20 (s,
9H); 13C{1H} NMR (126 MHz, DMSO-d6) δ 170.8, 156.2, 147.0, 145.9, 144.9, 144.2, 144.1,
141.2, 141.1, 135.0, 130.3 (2C), 128.1 (2C), 128.0 (2C), 127.5 (2C), 126.8 (2C), 125.7,
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125.6, 122.9, 120.6 (2C), 120.2, 104.8, 81.3, 66.0, 55.1, 47.0, 27.8 (3C), 27.3, 21.5; HRMS
(ESI) m/z: [M + H]+ Calcd for C36H35N3O6S 638.2319; Found 638. 2296.
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tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-tosyl-1H-
pyrrolo[2,3-b]pyridin-5-yl)propanoate (3m): The title compound was purified by flash silica-
gel column chromatography (30% EtOAc in petroleum ether) to obtain off-white solid (330
mg, 91%); mp: 190-192 oC; [α]25D = +2.0 (c = 2.0, CHCl3); 1H NMR (400 MHz, DMSO-d6) δ
8.25 (s, 1H), 7.97 - 7.91 (m, 3H), 7.90 - 7.80 (m, 4H), 7.62 (br t, J = 8.8 Hz, 2H), 7.42 - 7.29
(m, 5H), 7.23 (br t, J = 7.3 Hz, 1H), 6.75 (br d, J = 4.0 Hz, 1H), 4.25 - 4.11 (m, 4H), 3.13 -
3.02 (m, 1H), 3.02 - 2.90 (m, 1H), 2.27 (s, 3H), 1.22 (s, 9H); 13C{1H} NMR (126 MHz,
DMSO-d6) δ 171.2, 156.3, 146.1 (2C), 145.9, 144.1 (2C), 141.1 (2C), 135.0, 130.8, 130.4
(2C), 129.1, 128.1 (2C), 127.9 (2C), 127.5 (2C), 127.4 (2C), 125.6, 122.6, 120.6 (2C), 106.2,
81.1, 66.1, 56.5, 47.0, 27.9 (3C), 27.3, 21.5; HRMS (ESI) m/z: [M + H]+ Calcd for
C36H35N3O6S 638.2319; Found 638. 2300.
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tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(7-tosyl-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)propanoate (3n): The title compound was purified by flash
silica-gel column chromatography (40% EtOAc in petroleum ether) to obtain off-white solid
(276 mg, 76%); mp: 90-92 oC; [α]25D = +17.6 (c = 2.0, CHCl3); 1H NMR (400 MHz, DMSO-
d6) δ 9.19 (s, 1H), 8.96 (s, 1H), 7.97 (d, J = 8.5 Hz, 2H), 7.93 - 7.82 (m, 4H), 7.62 (dd, J =
2.0, 7.5 Hz, 2H), 7.43 - 7.35 (m, 4H), 7.28 (d, J = 7.0 Hz, 2H), 4.38 - 4.28 (m, 1H), 4.27 -
4.11 (m, 3H), 3.22 - 3.14 (m, 1H), 3.13 - 3.04 (m, 1H), 2.29 (s, 3H), 1.25 (s, 9H); 13C{1H}
NMR (126 MHz, DMSO-d6) δ 170.9, 156.3, 153.3, 150.7 (2C), 146.5, 144.1 (2C), 141.1
(2C), 134.5, 130.6 (2C), 128.1 (2C), 128.0 (3C),127.5 (2C), 125.6 (2C), 121.1, 120.6 (2C),
114.9, 81.2, 66.2, 54.9, 47.0, 27.9 (3C), 26.8, 21.5; HRMS (ESI) m/z: [M + H]+ Calcd for
C35H34N4O6S 639.2272; Found 639.2254.
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tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-chloro-1-tosyl-
1H-pyrrolo[2,3-b]pyridin-3-yl)propanoate (3o): The title compound was purified by flash
silica-gel column chromatography (30% EtOAc in petroleum ether) to obtain off-white solid
(302 mg, 79%); mp: 145-147 oC; [α]25D = +16.6 (c = 2.0, CHCl3); 1H NMR (400 MHz,
DMSO-d6) δ 8.39 (d, J = 2.0 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 7.95 - 7.83 (m, 6H), 7.62 (dd,
J = 3.0, 7.0 Hz, 2H), 7.43 - 7.38 (m, 2H), 7.33 (br d, J = 8.0 Hz, 2H), 7.30 - 7.22 (m, 2H),
4.32 - 4.12 (m, 4H), 3.18 - 3.07 (m, 1H), 3.06 - 2.95 (m, 1H), 2.27 (s, 3H), 1.27 (s, 9H);
13C{1H} NMR (126 MHz, DMSO-d6) δ 171.0, 156.3, 146.1, 145.2, 144.2, 144.1, 143.2,
141.1 (2C), 134.8, 130.4 (2C), 128.9, 128.1 (2C), 127.8 (2C), 127.5 (2C), 127.0, 126.8, 125.6
(2C), 124.4, 120.6 (2C), 115.4, 81.2, 66.2, 54.8, 47.0, 27.9 (3C), 27.8, 21.5; HRMS (ESI)
m/z: [M + H]+ Calcd for C36H34ClN3O6S 672.1930; Found 672.1901.
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tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-fluoro-1-tosyl-1H-
pyrrolo[2,3-b]pyridin-3-yl)propanoate (3q): The title compound was purified by flash silica-
gel column chromatography (30% EtOAc in petroleum ether) to obtain off-white solid (313
mg, 84%); mp: 80-82 oC; [α]25D = +16.9 (c = 2.0, CHCl3); 1H NMR (400 MHz, DMSO-d6) δ
8.40 - 8.31 (m, 1H), 8.09 (dd, J = 2.5, 9.0 Hz, 1H), 7.94 - 7.81 (m, 6H), 7.63 (br d, J = 7.5
Hz, 2H), 7.40 (br t, J = 7.3 Hz, 2H), 7.35 - 7.30 (m, 2H), 7.29 - 7.19 (m, 2H), 4.32 - 4.10 (m,
4H), 3.17 - 3.07 (m, 1H), 3.05 - 2.93 (m, 1H), 2.27 (s, 3H), 1.28 (s, 9H); 19F NMR (377 MHz,
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DMSO-d6) δ -134.48 (s, 1F); C{1H} NMR (126 MHz, DMSO-d6) δ 171.0, 157.1 (d, J =
246.9 Hz), 156.3, 146.0, 144.2, 144.1, 143.4, 141.1, 134.9, 133.3 (d, J = 30.2 Hz) 130.4
(2C), 128.1 (2C), 127.8 (2C), 127.5 (2C), 127.4 (2C), 125.6 (2C), 124.2 (d, J = 6.3 Hz), 120.6
(2C), 115.8, 115.7 (d, J = 26.5 Hz), 81.2, 66.7, 54.8, 47.0, 27.9 (3C), 26.8, 21.5; HRMS (ESI)
m/z: [M + H]+ Calcd for C36H34FN3O6S 656.2225; Found 656.2205.
tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-fluoro-1-tosyl-1H-
pyrrolo[2,3-b]pyridin-3-yl)propanoate (3r): The title compound was purified by flash silica-
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gel column chromatography (30% EtOAc in petroleum ether) to obtain off-white solid (310
mg, 83%); mp: 81-83 oC; [α]25D = +7.3 (c = 2.0, CHCl3); 1H NMR (400 MHz, DMSO-d6) δ
8.38 (dd, J = 5.8, 7.8 Hz, 1H), 8.02 - 7.81 (m, 5H), 7.77 (s, 1H), 7.66 (t, J = 7.5 Hz, 2H), 7.45
- 7.36 (m, 2H), 7.35 - 7.12 (m, 5H), 4.31 - 4.13 (m, 4H), 3.16 (br d, J = 6.0 Hz, 1H), 3.08 -
2.97 (m, 1H), 2.27 (s, 3H), 1.24 (s, 9H); 19F NMR (377MHz, DMSO-d6) δ -111.13 (s, 1F);
13C{1H} NMR (101 MHz, DMSO-d6) δ 171.0, 162.4 (d, J = 263.7 Hz), 156.4, 149.7 (br d, J
= 10.0 Hz), 147.6, 147.5, 146.2, 144.2, 144.1, 141.2, 134.7, 130.4 (2C), 128.1 (2C), 128.0
(2C), 127.5 (2C), 125.7 (2C), 125.4, 120.6 (2C), 113.2, 111.6 (br d, J = 16.6 Hz), 106.7, 81.2,
66.2, 55.0, 47.1, 28.3, 27.9 (3C), 21.5; HRMS (ESI) m/z: [M + H]+ Calcd for C36H34FN3O6S
656.2225; Found 656.2236.
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tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-methyl-1-tosyl-
1H-pyrrolo[2,3-b]pyridin-3-yl)propanoate (3s): The title compound was purified by flash
silica-gel column chromatography (30% EtOAc in petroleum ether) to obtain off-white solid
(282 mg, 76%); mp: 90-92 oC; [α]25D = +4.2 (c = 2.0, CHCl3); 1H NMR (400 MHz, DMSO-
d6) δ 8.27 (dd, J = 1.3, 4.8 Hz, 1H), 7.95 (dd, J = 1.3, 7.8 Hz, 1H), 7.92 - 7.74 (m, 5H), 7.64
(dd, J = 4.5, 7.5 Hz, 2H), 7.44 - 7.39 (m, 2H), 7.36 - 7.10 (m, 5H), 4.26 - 4.00 (m, 4H), 3.11 -
3.02 (m, 1H), 3.02 - 2.88 (m, 1H), 2.61 (s, 3H), 2.23 (s, 3H), 1.19 (s, 9H); 13C{1H} NMR
(126 MHz, DMSO-d6) δ 171.1, 156.2, 148.1, 145.4, 144.2, 144.1, 143.9, 143.8, 141.1, 136.2,
135.3, 130.2 (2C), 128.1, 128.0, 127.7, 127.6 (2C), 127.5 (2C), 125.7, 125.6, 122.4, 120.6
(2C), 119.5, 113.3, 81.0, 66.1, 54.9, 46.9, 27.8 (3C), 27.3, 21.4, 13.3; HRMS (ESI) m/z: [M +
H]+ Calcd for C37H37N3O6S 652.2476; Found 652.2457.
tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-tosyl-5-
(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)propanoate (3t): The title compound was
purified by flash silica-gel column chromatography (30% EtOAc in petroleum ether) to
obtain off-white solid (325 mg, 81%); mp: 114-116 oC; [α]25D = +19.7 (c = 2.0, CHCl3); 1H
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NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.61 (s, 1H), 8.02 - 7.93 (m, 3H), 7.88 (br dd, J =
3.3, 7.8 Hz, 3H), 7.61 (br t, J = 6.5 Hz, 2H), 7.43 - 7.32 (m, 4H), 7.29 - 7.18 (m, 2H), 4.39 -
4.08 (m, 4H), 3.22 - 3.05 (m, 2H), 2.28 (s, 3H), 1.25 (s, 9H); 19F NMR (377 MHz, DMSO-d6)
δ -59.05 (s, 3F); 13C{1H} NMR (101 MHz, DMSO-d6) δ 171.0, 156.4, 148.3, 146.3, 144.2,
144.1, 141.8 (2C), 141.2, 141.1, 134.8, 130.5 (2C), 128.1 (2C), 128.0 (2C), 127.5 (2C),
127.4, 125.6 (2C), 124.8 (q, J = 273.4 Hz), 122.8, 121.2 (q, J = 31.4 Hz), 120.6 (2C), 116.1,
81.2, 66.2, 54.9, 47.0, 27.9 (3C), 26.7, 21.5; HRMS (ESI) m/z: [M + H]+ Calcd for
C37H34F3N3O6S 706.2193; Found 706.2173.
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tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-methoxy-1-tosyl-
1H-pyrrolo[2,3-b]pyridin-3-yl)propanoate (3u): The title compound was purified by flash
silica-gel column chromatography (40% EtOAc in petroleum ether) to obtain off-white solid
(330 mg, 87%); mp: 118-120 oC; [α]25D = +12.8 (c = 2.0, CHCl3); 1H NMR (400 MHz,
DMSO-d6) δ 8.22 (d, J = 5.5 Hz, 1H), 7.93 - 7.84 (m, 4H), 7.79 (d, J = 8.0 Hz, 1H), 7.67 (dd,
J = 7.3, 12.3 Hz, 2H), 7.56 (s, 1H), 7.43-7.41 (m, 3H), 7.32 (s, 1H), 7.27 (d, J = 8.0 Hz, 2H),
6.89 (d, J = 5.5 Hz, 1H), 4.32 - 4.22 (m, 2H), 4.20 - 4.10 (m, 2H), 3.92 (s, 3H), 3.21 (dd, J =
5.3, 14.3 Hz, 1H), 2.93 (dd, J = 9.5, 14.1 Hz, 1H), 2.24 (s, 3H), 1.31 (s, 9H); 13C{1H} NMR
(126 MHz, DMSO-d6) δ 171.5, 160.9, 156.3, 148.7, 147.4, 145.7, 144.2, 144.1, 141.2, 141.1,
135.1, 130.3, 130.2 (2C), 128.1 (2C), 127.9 (2C), 127.5, 125.7 (2C), 123.1, 120.6 (2C),
115.0, 112.0, 102.4, 80.9, 66.1, 56.5, 55.3, 47.0, 28.0 (3C), 27.3, 21.4; HRMS (ESI) m/z: [M
+ H]+ Calcd for C37H37N3O7S 668.2425; Found 668.2411.
tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-methoxy-1-tosyl-
1H-pyrrolo[2,3-b]pyridin-3-yl)propanoate (3v): The title compound was purified by flash
silica-gel column chromatography (40% EtOAc in petroleum ether) to obtain off-white solid
(323 mg, 85%); mp: 99-101 oC; [α]25D = +9.4 (c = 2.0, CHCl3); 1H NMR (400 MHz, DMSO-
d6) δ 8.08 (d, J = 3.0 Hz, 1H), 7.87 (t, J = 8.0 Hz, 5H), 7.71 (s, 1H), 7.68 (d, J = 2.5 Hz, 1H),
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