Ligand-Controlled Synthesis of Azoles via Ir-Catalyzed Reactions of Sulfoxonium Ylides with 2-Amino Heterocycles

Article abstract of DOI:10.1021/acs.joc.6b00497

An iridium-catalyzed method was developed for the synthesis of imidazo-fused pyrrolopyrazines. The presence or absence of a nitrogenated ligand controlled the outcome of the reaction, leading to simple β-keto amine products in the absence of added ligand and the cyclized 7- and 8-substituted-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine products in the presence of ligand. This catalyst control was conserved across a variety of ylide and amine coupling partners. The substrate was shown to act as a ligand for the iridium catalyst in the absence of other ligands via NMR spectroscopy. Kinetic studies indicated that formation of the Ir-carbene was reversible and the slow step of the reaction. These mechanistic investigations suggest that the β-keto amine products form via an intramolecular carbene N-H insertion, and the imidazopyrrolopyrazines form via an intermolecular carbene N-H insertion.

Full text of DOI:10.1021/acs.joc.6b00497

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Article
Ligand-Controlled Synthesis of Azoles via Ir-Catalyzed
Reactions of Sulfoxonium Ylides with 2-Amino Heterocycles
Alicia M Phelps, Vincent S. Chan, José G Napolitano, Scott
W. Krabbe, Jennifer M Schomaker, and Shashank Shekhar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00497 • Publication Date (Web): 22 Apr 2016
Downloaded from http://pubs.acs.org on April 24, 2016
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Ligand-Controlled Synthesis of Azoles via Ir-Catalyzed Reactions of
Sulfoxonium Ylides with 2-Amino Heterocycles
Alicia M. Phelps,† Vincent S. Chan,‡ José G. Napolitano,§ Scott W. Krabbe,‡ Jennifer M. Schomaker, †,* and
Shashank Shekhar‡,*
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†Department of Chemistry, University of WisconsinꢀMadison, 1101 University Avenue, Madison, WI
53706, USA
‡ AbbVie Inc., Process Research and Development, 1 North Waukegan Road, North Chicago, IL 60064,
USA
§ AbbVie Inc., Discovery Chemistry and Technology, 1 North Waukegan Road, North Chicago, IL
60064, USA
Email Address: Shashank.shekhar@abbvie.com and schomakerj@chem.wisc.edu
Abstract
An iridiumꢀcatalyzed method was developed for the synthesis of imidazoꢀfused
pyrrolopyrazines. The presence or absence of a nitrogenated ligand controlled the outcome of
the reaction, leading to simple βꢀketo amine products in the absence of added ligand, and the
cyclized 7ꢀ and 8ꢀsubstitutedꢀimidazo[1,2-a]pyrrolo[2,3-e]pyrazine products in the presence of
ligand. This catalyst control was conserved across a variety of ylide and amine coupling
partners. The substrate was shown to act as a ligand for the iridium catalyst in the absence of
other ligands via NMR spectroscopy. Kinetic studies indicated that formation of the Irꢀcarbene
was reversible and the slow step of the reaction. These mechanistic investigations suggest that
the βꢀketo amine products form via an intramolecular carbene NꢀH insertion, and the
imidazopyrrolopyrazines form via an intermolecular carbene NꢀH insertion.
Introduction
βꢀKeto sulfoxonium ylides are crystalline, benchꢀstable compounds that function as
precursors to metalꢀcarbene complexes.1ꢀ3,4,5ꢀ9 These metal carbene intermediates are known to
insert into XꢀH bonds (X = N, O, S) to generate molecules of synthetic interest; however, only a
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limited number of examples have been reported.1,2,10ꢀ13,14 In contrast, the insertion of metal
carbenes generated from diazo compounds into XꢀH bonds has been wellꢀdocumented.15ꢀ18 In
many cases, the use of diazo compounds on large scales is challenging, due to safety issues
resulting from rapid exotherm upon reaction and the generation of stoichiometric nitrogen gas as
a byꢀproduct.19,20,21,22,23 Sulfoxonium ylides are a more practical alternative to diazo compounds,
as they are safer to synthesize and generate only nonꢀvolatile dimethylsulfoxide (DMSO) as the
byꢀproduct of metalꢀcarbenoid formation.3 In fact, sulfoxonium ylides have been employed on a
manufacturing scale in the synthesis of the CRTH2 antagonist MKꢀ7246.12 We are interested in
further exploring the chemistry of metalꢀcarbenoids generated from sulfoxonium ylides for the
syntheses of pharmaceutically relevant molecules.
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Imidazoꢀfused pyrrolopyrazines act as kinase inhibitors and have been shown to be
effective for treatment of oncological and immunological diseases.24,25 In a previous report, our
research group described the synthesis of azole 3 via reactions of 1 with a series of αꢀbromo
ketones 2, followed by Bocꢀdeprotection and intramolecular cyclization under acidic conditions
(equation 1).26 Although 3 was obtained in good yields, many of the αꢀbromo ketones utilized
were lachrymatory oils that were both challenging to purify and unstable under ambient
conditions.27,28ꢀ30
An alternative approach to access 3 from readily available, crystalline starting materials
can be envisaged through insertion of a metalꢀcarbenoid generated from βꢀketo sulfoxonium
ylide 5 into the NꢀH bond of 5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀamine 4 (equation 2).
Indeed, the NꢀH insertion product 6 was obtained in moderate yields (40ꢀ50%) under
conditions similar to that reported by Mangion and coꢀworkers for reactions of aromatic amines
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with sulfoxonium ylides (equation 3).2,10 In addition to the expected acyclic NꢀH insertion
product 6, the cyclized azole 7 (a regioisomer of 3) was observed as a minor product in the Irꢀ
catalyzed reaction.
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Intrigued by the facile cyclization to 7 in the absence of a dehydrating agent, we
wondered if the selectivity of the Irꢀcatalyzed reaction could be inverted to favor formation of 7
directly from 4 and 5. We describe herein a general method for the regioselective synthesis of 7ꢀ
and 8ꢀsubstitutedꢀimidazo[1,2-a]pyrrolo[2,3-e]pyrazines from Irꢀcatalyzed reactions of 5ꢀtosylꢀ
5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀamine and βꢀketo sulfoxonium ylides. The nature of the ligand on
Ir was found to significantly impact the selectivity of the reaction. In addition to imidazoꢀfused
pyrrolopyrazines, a variety of azoles derived from other aryl amidines could also be easily
accessed in high yields and selectivity.
Results and Discussions
Amine 4 reacted with sulfoxonium ylide 8 in the presence of catalytic [Ir(COD)Cl]2
(COD = 1,5ꢀcyclooctadiene) to form 9b in 42% yield along with 10% of 9a (Table 1, entry 1).2
Significant amounts of the unreacted starting materials 4 and 8 remained after 24 h at 80 °C; no
further conversion was observed by allowing the reaction to proceed for a longer time. A
slightly improved yield of 9b was observed upon addition of 4 Å molecular sieves to the reaction
mixture (entry 2). A cationic Irꢀcomplex generated in situ by addition of sodium tetrakis[3,5ꢀ
bis(trifluoromethyl)phenyl]borate (NaBArF24) formed an inferior catalyst and afforded 9b in
only 17% yield (entry 3). We speculated that the moderate yield of 9b was due to the inhibition
of the Irꢀcatalyst by the reaction byꢀproduct, DMSO.31 In addition, 4, 9a and 9b could bind to Ir
and inhibit reaction.2
Table 1: Evaluation of reaction parameters for Irꢀcatalyzed NꢀH insertion reaction to favor
formation of azole 9a
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Entry
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L
none
none
none
I
I
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II
III
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Solvent
DCE
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DCE
DCE
DCE
DCE
Additivea
none
4 Å MS
4 Å MS, NaBArF24
none
9a (%)
10
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9b (%)
9a/9b
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0.16
0.29
0.69
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NaBArF24
4 Å MS, NaBArF24
4 Å MS, NaBArF24
4 Å MS, NaBArF24
4 Å MS, NaOTf
4 Å MS, NaOTf
9
10b
5
16
I
All experiments were conducted with 4 (1.5 equiv), 8 (1 equiv), [Ir(COD)Cl]2 (2.5 mol%), L (5 mol%), 4 Å MS (240 wt% with respect to ylide) in DCE
(0.25 M) at 80 °C unless stated otherwise. The yield and ratio of 9a and 9b were determined by HPLC analysis of the reaction mixture at 210 nm.. (a) 5
mol%. (b) 4 (1.0 equiv) and 8 (1.5 equiv) were used.
Our approach to improving the yield of 9b was to overcome the suspected catalytic
inhibition by introducing a ligand onto Ir that would form a more robust catalyst. The use of
1,10ꢀphenanthroline (I) formed 9b in a disappointing yield; however, 9a was formed in a
noticeably higher ratio (compare entries 1 and 4). To our surprise, the addition of subꢀ
stoichiometric amounts of NaBArF24 to a mixture of [Ir(COD)Cl]2 and I formed a catalyst
system that inverted the selectivity of the reaction and favored formation of the cyclized product
9a over 9b in 14:1 ratio (entry 5) providing 9a in a synthetically useful yield. The beneficial
effect of the tetraꢀarylborate counteranion on the overall yield of the reaction is in contrast to the
much lower yield observed when NaBArF24 was used with [Ir(COD)Cl]2 in the absence of added
ligand. As observed earlier, addition of molecular sieves to the reaction led to a slightly
improved yield (entry 6). 4,7ꢀDimethoxyꢀ1,10ꢀphenanthroline (II) and 4,4’ꢀtertꢀbutylpyridine
(III) also favored 9a as the major product but were inferior to I (entries 7 and 8). Other nitrogen
containing ligands and triphenylphosphine formed 9b as the major product,32 clearly indicating
that the nature of ligand on Ir impacts both the selectivity and yield of the reaction. Of the nonꢀ
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coordinating counteranion additives explored the highest yield of 9a was observed in the
presence of NaOTf (entry 9), and further improvement in the yield was observed by using 1.5
equivalents of the sulfoxonium ylide 8 (entry 10).33 No product formation was observed in the
absence of [Ir(COD)Cl]2.
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Having established optimal reaction conditions to selectively form 9a, the scope of the
sulfoxonium ylide was explored. Reactions of ylides containing either alkyl (Table 2, entries 1
and 2) or electronꢀpoor aryl groups (Table 2, entries 3 and 4) connected to the carbonyl formed
azoles in higher selectivity than reactions of sulfoxonium ylides containing electronꢀrich aryl
groups (entries 8 and 9) connected to the carbonyl. Bromo, ester, nitro, N,Nꢀdimethylamino,
ether and thiophene functionalities were all wellꢀtolerated under the reaction conditions
providing azoles in synthetically useful yields. Moderate to good selectivity for the formation of
9-19a over 9-19b was observed utilizing a wide range of sterically and electronically varied βꢀ
keto sulfoxonium ylides. The selectivity could be reversed to favor βꢀketo amine products by
conducting the Irꢀcatalyzed NꢀH insertion reaction in the absence of I and NaOTf (Condition B).
Under these conditions, βꢀketo amines 9b, 12b, 14b and 18b were prepared with high selectivity
over the corresponding cyclic products 9a, 12a, 14a, and 18a.
Table 2: Substrate scope of Irꢀcatalyzed reaction of 2ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀamine
(4) with βꢀketo sulfoxonium ylides
R
O
O
H
N
N
N
R
N
R
N
N
A
B
or
+
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+
N
S
DCE, 4 Å MS,
80 °C, 24 h
Ts
N
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Ts
9b-19b
9a-19a
: [Ir(COD)Cl]2 (2.5 mol%), (5 mol%), NaOTf (5 mol%)
A
I
B: [Ir(COD)Cl]2 (2.5 mol%)
entry
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R =
Condition
yielda
ratio of productsb
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9a/9b = 16:1
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B
= 1:4
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10a/10b = 16:1
11a/11b = NAc
12a/12b = NAc
A
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A
B
= 1:19
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13a/13b = 5:1
A
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31
14a/14b = 7:1
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= 1:31
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15a/15b = 5:1
16a/16b = 3:1
17a/17b = 4:1
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18a/18b = 4:1
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19a/19b = 4:1
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All experiments were run with 4 (1 equiv) and ylide (1.5 equiv). (a) Isolated yield. (b) Ratio was determined by 1H NMR spectroscopy. (c) The βꢀ
keto amine was not detected in the 1H NMR spectra of the crude reaction mixture.
The scope of other aryl amidines (21-24) that could engage with ylide 20 was also
explored (Table 3). Good to excellent selectivity for 25a-28a over 25b-28b was observed
providing rapid access to pharmaceutically relevant heterocyclic compounds in high yields. The
selectivity for the formation of azole over βꢀketo amine depended on the nature of the aryl
amidine. While azoles 26a and 28a were the only products observed in the reactions of quinolinꢀ
2ꢀamine and pyrimidinꢀ2ꢀamine (entries 2 and 4), 25a and 27a were favored over 25b and 27b in
24:1 and 11:1 ratios respectively (entries 1 and 3).
Table 3: Substrate scope of Irꢀcatalyzed reaction of 20 with aryl amidines
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entry
amidine
desired product yielda ratio of productsb
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26a/26b = NAc
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28a/28b = NAc
All reactions were run with [Ir(COD)Cl]2 (2.5 mol%), I (5 mol%), NaOTf (5 mol%), 4 Å MS (240 wt%), amidine (1 equiv), 20 (1 equiv), in 1,2ꢀ
dichloroethane at 80 °C for 24 h. (a) Isolated yield. (b) Ratio was determined by 1H NMR spectroscopy. (c) The acyclic product (βꢀketo amine)
was not detected in the 1H NMR spectra of the crude reaction mixture
.
The underlying reasons for the influence of ligand and counteranion on the selectivity of
Irꢀcatalyzed reactions of βꢀketo sulfoxonium ylides with 4 is not immediately obvious. As
discussed above, while βꢀketo amines are the preferred product in the presence of [(COD)IrCl]2,
azoles are the preferred product in the presence of [(COD)IrCl]2, I, and NaOTf. No conversion of
the βꢀketo amines 9b to azoles 9a was observed when isolated 9b was heated for 24 h at 80 °C in
the presence of [(COD)IrCl]2, I, and NaOTf, suggesting that 9b and 9a were formed via
divergent pathways.
The mechanism of generation of Irꢀcarbene intermediates from
sulfoxonium ylides and the subsequent reaction of the carbene intermediate with amines have not
been studied in detail.34,35 We propose that 4 acts as a supporting ligand for Ir in the absence of
added ligand to form the fourꢀcoordinate intermediate A (Figure 1, left). The Irꢀamine complex
A reacts with sulfoxonium ylide to form the Irꢀcarbene intermediate B, and intramolecular
reaction of amine with Irꢀcarbenoid forms C. Protonation of Irꢀenolate forms Ir complex D,
which undergoes ligand exchange to release the product and reform complex A. In contrast,
when 1,10ꢀphenanthroline is introduced as a ligand in the presence of NaOTf, formation of the
fourꢀcoordinate Irꢀcomplex E from the reaction of [(COD)IrCl]2 with 1,10ꢀphenanthroline and
NaOTf likely occurs before coordination of the amine substrate 4 to the metal (Figure 1, right).
Complex E reacts with sulfoxonium ylide to form the Irꢀcarbene intermediate F. Intermolecular
reaction of 4 with F generates intermediate G, which tautomerizes to form intermediate H.
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Protonation of Irꢀenolate reforms complex E and generates imine J that cyclizes to form azole
9a.
7
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Figure 1. Proposed mechanisms for the formation of βꢀketo amine (left) or azole (right)
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The hypothesis proposed in Figure 1 was supported by following the interaction of
1
[(COD)IrCl]2 with 4 and 1,10ꢀphenanthroline by Hꢀ15N HMBC NMR spectroscopy (Figure 2).
Consistent with literature reports,36 15N signals for b and c were observed at ꢀ86 and ꢀ119.8 ppm,
while d was observed at ꢀ207.9 ppm. The 15N signal for a is expected between ꢀ300 to ꢀ330 ppm
but was not observed. The broad 1H signal observed for the –NH2 protons most likely causes the
15
absence of N signal for a in the 1Hꢀ15N HMBC NMR spectrum. When 4 and 0.5 equivalent of
[(COD)IrCl]2 were mixed in CD2Cl2, the 15N signal for b shifted to ꢀ176.6 ppm from ꢀ119.8 ppm.
A clear signal for a was now observed at ꢀ308.0 ppm, and minimal change in the signals for c
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and d was observed. The significant chemical shift in the N NMR peak for b is strong, albeit
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indirect, evidence for interaction of 4 with [(COD)IrCl]2. In a similar experiment, the N NMR
signal for the nitrogen atoms in 1,10ꢀphenanthroline (e) shifted from ꢀ72.9 ppm in the absence of
[(COD)IrCl]2 to ꢀ134.9 ppm in the presence of 0.5 equivalent of [(COD)IrCl]2 in CD2Cl2 (Figure
3b). When 1 equivalent each of 4 and 1,10ꢀphenathroline and 0.5 equivalent of [(COD)IrCl]2
were mixed together in CD2Cl2, the 15N NMR signal for e was observed at ꢀ134.9 ppm, whereas
the N NMR signal for b was similar to that observed in the absence of [(COD)IrCl]2.37 These
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set of 1Hꢀ15N HMBC NMR data suggest that 1,10ꢀphenanthroline is a better ligand for Ir than 4.
This observation is consistent with our proposal of formation of the Irꢀcomplex E in the presence
of 1,10ꢀphenanthroline before 4 interacts with the metal (Figure 1). As proposed inFigure 1, the
point of interaction of 4 with Ir determines the nature of the product formed in the reaction.
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Figure 2
15N HMBC spectroscopy.
.
Interaction of [(COD)IrCl]2 with amine (4) and 1,10ꢀphenanthroline as studied by 1Hꢀ
Further insight into the reaction mechanism was obtained by following the reactions by
mass and 1H NMR spectroscopy. Although no direct evidence for the generation of Irꢀcarbene
intermediate B was obtained by 1H NMR spectroscopy, formation of DMSO was observed in the
reaction of 4 with 8 catalyzed by [(COD)IrCl]2.38 The insertion of Ir into 4 was determined to be
reversible based on mass spectral studies with DMSOꢀ13C2 (Table S2). When stoichiometric
amounts of 4, 8, and [(COD)IrCl]2 were reacted in DCEꢀd4 at 40 °C, the rate of DMSO formation
matched the rate of formation of 9b (Figure 3). This suggests that the formation of Irꢀcarbene
intermediate B is the slow step of the reaction (Figure 1, left).39 Fast, intramolecular reaction of
the amine with Irꢀcarbene followed by protodemetalation likely generates the βꢀketo amine 9b.
Figure 3. Formation of DMSO and 9b in a stoichiometric reaction of 4, and 8 with [Ir(COD)Cl]2
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No evidence for the generation of Irꢀcarbene intermediate
F was obtained by H
NMR spectroscopy during the reaction of
phenanthroline and NaOTf. The rate of formation of DMSO was found to be similar to
the rate of formation of azole 9a when a reaction of (1 equiv), (10 equiv),
4 with 8 catalyzed by [(COD)IrCl]2, 1,10ꢀ
4
8
[(COD)IrCl]2 (0.5 equiv), 1,10ꢀphenanthroline (1 equivalent) and NaOTf (1 equiv) in
1
DCEꢀd4 was monitored by H NMR spectroscopy at 80°C (Figure 4), suggesting that the
generation of Irꢀcarbene intermediate
F is the rateꢀlimiting step for azole formation. The
reaction of with [(COD)IrCl]2 in the presence of 1,10ꢀphenathroline was also found to
4
be reversible (Table S2).
Figure 4. Formation of DMSO and 9a in a stoichiometric reaction of 4 and 8 with [Ir(COD)Cl]2,
1,10ꢀphenathroline and NaOTf
DMSO (kobs = 0.33 h-1)
4 (kobs = 0.33 h-1)
9a (kobs = 0.35 h-1)
Although formation of both βꢀketo amine 9b and azole 9a proceed via reversible, rateꢀ
limiting generation of putative Irꢀcarbene intermediates, the preference for formation of 9a or 9b
from Irꢀcatalyzed reactions of 4 with 8 is controlled by the nature of ligand. Insertion of the
reaction byꢀproduct, DMSO, into the Irꢀcarbene intermediate likely inhibits the reaction. Our
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future efforts will focus on studying the reactivity of sulfoxonium ylides containing leaving
groups other than DMSO (such as diaryl sulfoxide) that will be capable of irreversibly generating
the metalꢀcarbene intermediate. We expect that identification of appropriate sulfoxonium ylide
will further expand the efficiency and utility of the reported methodology.
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Conclusions
In summary, a novel method for the synthesis of a variety of azoles from Irꢀ
catalyzed reactions of
This method uses bench stable sulfoxonium ylide precursors in place of diazo
compounds, making preparation more practical and scalable. Two distinct products,
keto amines or azoles can form from the Irꢀcatalyzed reactions of ꢀketosulfoxonium
ylides with aryl amidines. Azole is formed in preference to ꢀketo amine when 1,10ꢀ
phenanthroline is used as the ligand for [Ir(COD)Cl]2 in conjunction with a nonꢀ
coordinating anion, such as triflate. ꢀKeto amine is the preferred product in the absence
βꢀketosulfoxonium ylides with aryl amidines has been developed.
β
ꢀ
β
β
β
of any additional ligand or counteranion for [Ir(COD)Cl]2. Mechanistic insight was
provided based on NMR and mass spectral studies.
Experimental
General Information
All glassware was either ovenꢀdried overnight at 130 °C or flameꢀdried under a stream of
dry nitrogen prior to use. Unless otherwise specified, reagents were used as obtained from the
vendor without further purification. Tetrahydrofuran and diethyl ether were freshly distilled from
purple Na/benzophenone ketyl. Dichloromethane, acetonitrile and toluene were dried over CaH2
and freshly distilled prior to use. All other solvents were purified in accordance with
“Purification of Laboratory Chemicals”.40 Airꢀ and moistureꢀ sensitive reactions were performed
using standard Schlenk techniques under an atmosphere of nitrogen. Analytical thin layer
chromatography (TLC) was performed utilizing preꢀcoated silica gel 60 F254 plates containing a
fluorescent indicator, while preparative chromatography was performed using SilicaFlash P60
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silica gel (230ꢀ400 mesh) via Still’s method.41 Unless otherwise stated, the mobile phases for
column chromatography were mixtures of dichloromethane/ethyl acetate. Columns were
typically run using a gradient method, beginning with 100% dichloromethane and gradually
increasing the polarity using ethyl acetate. Various stains were used to visualize reaction
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products,
including
p-anisaldehyde, KMnO4, ceric ammonium molybdate (CAM stain) and iodine powder.
Routine NMR experiments were recorded in CDCl3 at room temperature. Chemical shifts are
1
reported in partsꢀperꢀmillion (ppm) relative to TMS (δ 0.00 ppm) for H, and to the solvent
13
signal (δ 77.0 ppm) for C. Scalar coupling constants are reported in hertz (Hz). Conventional
2D NMR experiments (COSY, HSQC, and HMBC) were recorded using standard pulse
programs. In those cases where severe resonance overlap occurred, proton assignments were
obtained by means of computerꢀassisted H iterative full spin analysis (HiFSA).42 Highꢀpressure
1
liquid chromatography (HPLC) analyses were performed at 210 nm. Accurate mass
measurements were acquired using electrospray ionization, timeꢀofꢀflight analyzer or electron
impact methods.
General procedure for synthesis of sulfoxonium ylides:
A 250 mL roundꢀbottom flask equipped with a magnetic stir bar and reflux condenser was
charged with 9.9 g (45 mmol) trimethylsulfoxonium iodide and 150 mL THF under nitrogen.
NaOtBu (4.5 g, 47.25 mmol) was added, heated to reflux and allowed to stir for 2 h. After 2 h,
the reaction mixture was cooled to the room temperature, followed by dropwise addition of ester
or acid chloride (15 mmol). The reaction mixture was stirred for 18 h, then quenched with 250
mL water. The layers were separate and the aqueous layer was extracted with 3 x 150 mL
EtOAc, washed with 150 mL saturated NaCl solution, stirred over Na2SO4, filtered, then filtrate
concentrated in vacuo. The resulting solid was charged to a 50 mL roundꢀbottom flask, 16 mL
EtOAc was added. Reaction was heated to 50 °C for 1 h, then allowed to cool to room
temperature with constant stirring. The resulting slurry was filtered through Buchner funnel
under vacuum, the solid was washed with iceꢀcold EtOAc to yield pure product, which was dried
under vacuum for 12 h to remove residual solvents.
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1-(Dimethyl(oxo)-λ6-sulfanylidene)-3-phenoxypropan-2-one
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Following the general procedure methyl phenoxyacetate (2.53 g, 15 mmol) was converted to the
1ꢀ(Dimethyl(oxo)ꢀλ6ꢀsulfanylidene)ꢀ3ꢀphenoxypropanꢀ2ꢀone (1.86 g, 55%). The product was
isolated as crystalline, white solid.
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1H NMR (700 MHz, CDCl3), δ (mult., J, nH): 7.29 (m, 2H), 6.97 (m, 1H), 6.92 (m, 2H), 4.91 (s,
1H,), 4.41 (s, 2H), 3.44 (s, 6H). 13C NMR (176 MHz, CDCl3), δ: 185.7, 158.2, 129.5, 121.2,
114.6, 71.2, 68.9, 42.2. HRMS (ESI) m/z calculated for C11H14O3S [M + H]+ 227.0737, found
227.0737. mp 118ꢀ120 °C.
1-(Dimethyl(oxo)-λ6-sulfanylidene)-3-methylbutan-2-one
Following the general procedure isobutyryl chloride (1.60 g, 15 mmol) was converted to1ꢀ
(Dimethyl(oxo)ꢀλ6ꢀsulfanylidene)ꢀ3ꢀmethylbutanꢀ2ꢀone (290 mg, 12%). The product was
1
isolated as acrystalline white solid. H NMR (700 MHz, CDCl3), δ (mult., J, nH): 4.36 (s, 1H),
3.39 (s, 6H), 2.35 (hept, J = 6.9 Hz, 1H), 1.09 (d, J = 7.0 Hz, 6H). 13C NMR (176 MHz, CDCl3),
δ: 195.6, 67.0, 42.3, 38.8, 19.9. HRMS (ESI) m/z calculated for C7H14O2S [M + H]+ 163.0788,
found 163.0789. mp 135ꢀ137 °C.
2-(Dimethyl(oxo)-λ6-sulfanylidene)-1-(4-nitrophenyl)ethan-1-one
Following the general procedure 4ꢀnitrobenzoyl chloride (2.78 g, 15 mmol) was converted to 2ꢀ
(dimethyl(oxo)ꢀλ6ꢀsulfanylidene)ꢀ1ꢀ(4ꢀnitrophenyl)ethanꢀ1ꢀone (1.95 g, 54%). The product was
isolated as a crystalline yellow solid.1H NMR (700 MHz, CDCl3), δ (mult., J, nH): 8.24 (m, 2H),
13
7.93 (m, 2H), 5.03 (s, 1H), 3.55 (s, 6H). C NMR (176 MHz, CDCl3), δ: 179.3, 149.1, 144.5,
127.5, 123.5, 70.2, 42.3. HRMS (ESI) m/z calculated for C10H11NO4S [M + H]+ 242.0482, found
242.0477. mp 175ꢀ178 °C
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Methyl-4-(2-dimethyl(oxo)- λ6-sulfanylidene)-acetyl)benzoate
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Following the general procedure, methyl 4ꢀ(chlorocarbonyl)benzoate (2.98 g, 15 mmol) was
converted to methylꢀ4ꢀ(2ꢀdimethyl(oxo)ꢀ λ6ꢀsulfanylidene)ꢀacetyl)benzoate (1.03 g, 27%). The
product was isolated as a crystalline yellow solid.1H NMR (700 MHz, CDCl3), δ (mult., J, nH):
8.06 (m, 2H), 7.85 (m, 2H), 5.02 (s, 1H), 3.93 (s, 3H), 3.53 (s, 6H). 13C NMR (176 MHz,
CDCl3),
: 181.0, 166.7, 142.8, 131.8, 129.5, 126.5, 69.3, 52.2, 42.4. HRMS (ESI) m/z calculated for
C12H14O4S [M + H]+ 255.0686, found 255.0685. mp 158ꢀ160 °C.
1-(4-Bromophenyl)-2-(2-dimethyl(oxo)- λ6-sulfanylidene)ethan-1-one
Following the general procedure, 4ꢀbromobenzoyl chloride (3.29 g, 15 mmol) was converted to
1ꢀ(4ꢀBromophenyl)ꢀ2ꢀ(2ꢀdimethyl(oxo)ꢀ λ6ꢀsulfanylidene)ethanꢀ1ꢀone (3.75 g, 86%). The
product was isolated as a crystalline yellow solid.
1H NMR (700 MHz, CDCl3), δ (mult., J, nH): 7.66 (m, 2H), 7.52 (m, 2H), 4.94 (s, 1H), 3.51 (s,
6H). 13C NMR (176 MHz, CDCl3), δ: 180.9, 137.7, 131.3, 128.2, 125.2, 68.4, 42.5. HRMS (ESI)
m/z calculated for C10H11BrO2S [M + H]+ 274.9736, found 274.9735. mp 149ꢀ150 °C.
2-(Dimethyl(oxo)- λ6-sulfanylidene)-1-phenylethan-1-one
Following the general procedure, benzoyl chloride (2.11 g, 15 mmol) was converted to 2ꢀ
(Dimethyl(oxo)ꢀ λ6ꢀsulfanylidene)ꢀ1ꢀphenylethanꢀ1ꢀone (1.32 g, 34%). The product was isolated
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as a crystalline white solid.1H NMR (700 MHz, CDCl3), δ (mult., J, nH): 7.80 (m, 2H), 7.43 (m,
1H), 7.39 (m, 2H), 4.98 (s, 1H), 3.52 (s, 6H). 13C NMR (176 MHz, CDCl3), δ: 182.3, 138.8,
130.7, 128.1, 126.5, 68.1, 42.5. HRMS (ESI) m/z calculated for C10H12O2S [M + H]+ 197.0631,
found 197.0626. mp 114ꢀ116 °C.
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1-(4-(tert-butyl)phenyl)-2-(dimethyl(oxo)- λ6-sulfanylidene)ethan-1-one
Following the general procedure, 4ꢀtert-butylbenzoyl chloride (2.95 g, 15 mmol) was converted
to 1ꢀ(4ꢀ(tertꢀbutyl)phenyl)ꢀ2ꢀ(dimethyl(oxo)ꢀ λ6ꢀsulfanylidene)ethanꢀ1ꢀone (2.81 g, 74%). The
product was isolated as a crystalline tan solid.1H NMR (700 MHz, CDCl3), δ (mult., J, nH): 7.74
(m, 2H), 7.41 (m, 2H), 4.95 (s, 1H), 3.51 (s, 6H), 1.33 (s, 9H). 13C NMR (176 MHz, CDCl3), δ:
182.2, 154.1, 136.1, 126.3, 125.1, 67.6, 42.6, 34.8, 31.2. HRMS (ESI) m/z calculated for
C14H20O2S [M + H]+ 253.1257, found 253.1259. mp 168ꢀ170 °C.
1-(3,4-Dimethoxyphenyl)-2-(dimethyl(oxo)- λ6-sulfanylidene)ethan-1-one
Following the general procedure, methyl 3,4ꢀdimethoxybenzoate (2.94 g, 15 mmol) was
converted to 1ꢀ(3,4ꢀDimethoxyphenyl)ꢀ2ꢀ(dimethyl(oxo)ꢀ λ6ꢀsulfanylidene)ethanꢀ1ꢀone (696 mg,
18%). The product was isolated as a crystalline light yellow solid.1H NMR (700 MHz, CDCl3), δ
(mult.,
J,
nH):
7.44
(d,
J
=
2.0
Hz),
7.36
(dd,
J = 8.3, 2.0 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 4.92 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.51 (s,
6H). 13C NMR (176 MHz, CDCl3) δ: 181.7, 151.2, 148.6, 131.8, 119.8, 110.1, 109.3, 67.2, 55.9,
55.9, 42.7. HRMS (ESI) m/z calculated for C12H16O4S [M + H]+ 257.0843, found 257.0844. mp
131ꢀ133 °C.
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2-(Dimethyl(oxo)- λ6-sulfanylidene)-1-(4-(dimethylamino)phenyl)ethan-1-one
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Following the general procedure, 4ꢀ(dimethylamino)benzoyl chloride (2.75 g, 15 mmol) was
converted to 2ꢀ(Dimethyl(oxo)ꢀ λ6ꢀsulfanylidene)ꢀ1ꢀ(4ꢀ(dimethylamino)phenyl)ethanꢀ1ꢀone (1.52
g, 42%). The product was isolated as a crystalline yellow solid.1H NMR (700 MHz, CDCl3), δ
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(mult., J, nH): 7.77 (m, 2H), 6.72 (m, 2H), 4.91 (s, 1H), 3.56 (s, 6H), 3.07 (s, 6H). C NMR
(176 MHz, CDCl3) δ: 182.3, 152.2, 128.0, 126.5, 110.9, 65.7, 42.9, 40.2. HRMS (ESI) m/z
calculated for C12H17NO2S [M + H]+ 240.1053, found 240.1051. mp 166ꢀ168 °C.
2-(Dimethyl(oxo)- λ6-sulfanylidene)-1-(o-tolyl)ethan-1-one
Following the general procedure, oꢀtoluoyl chloride (2.30 g, 15 mmol) was converted to 2ꢀ
(Dimethyl(oxo)ꢀ λ6ꢀsulfanylidene)ꢀ1ꢀ(oꢀtolyl)ethanꢀ1ꢀone (1.08 g, 34%). The product was
isolated as a crystalline white solid.
1H NMR (700 MHz, CDCl3), δ (mult., J, nH): 7.41 (m, 1H), 7.24 (m, 1H), 7.18 (m, 1H), 7.15 (m,
1H), 4.64 (s, 1H), 3.52 (s, 6H) 2.47 (s, 3H). 13C NMR (176 MHz, CDCl3), δ: 186.8, 140.9, 135.5,
130.8, 128.9, 127.2, 125.3, 71.0, 42.3, 20.1. HRMS (ESI) m/z calculated for C11H14O2S [M + H]+
211.0788, found 211.0787. mp 104ꢀ106 °C.
2-(Dimethyl(oxo)- λ6-sulfanylidene)-1-(thiophen-2-yl)ethan-1-one
Following the general procedure, methyl 2ꢀthiophene carboxylate (2.13 g, 15 mmol) was
converted to 2ꢀ(Dimethyl(oxo)ꢀ λ6ꢀsulfanylidene)ꢀ1ꢀ(thiophenꢀ2ꢀyl)ethanꢀ1ꢀone (1.64 g, 54%).
The product was isolated as a crystalline tan solid.
1H NMR (700 MHz, CDCl3), δ (mult., J, nH): 7.44 (dd, J = 3.7, 1.2 Hz, 1H), 7.41 (dd, J = 5.0,
1.2 Hz, 1H), 7.04 (dd, J = 5.0, 3.7 Hz, 1H), 4.88 (s, 1H), 3.51 (s, 6H). 13C NMR (176 MHz,
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CDCl3) δ: 175.6, 145.6, 129.0, 127.5, 127.0, 67.0, 42.8. HRMS (ESI) m/z calculated for
C8H10O2S2 [M + H]+ 203.0195, found 203.0191. mp 165ꢀ167 °C.
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General procedure for Ir-catalyzed N-H insertion reaction
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To a thickꢀwalled pressure tube in an inert atmosphere glove box was added ylide (1.72 mmol,
1.5 equiv) and amine (1.15 mmol, 1 equiv), followed by [Ir(COD)Cl]2 (0.029 mmol, 0.025
equiv), 1,10ꢀphenanthroline (0.058 mmol, 0.05 equiv), NaOTf (0.058 mmol, 0.05 equiv), and
powdered 4 Å molecular sieves (1.15 g). 1,2ꢀDichloroethane (4.6 mL) was added, rinsing down
the sides of the pressure tube, and reaction was capped and removed from the glove box. The
reaction was heated to 80 °C for 24 h, then cooled to room temperature, vacuum filtered through
medium fritted funnel, washed with CH2Cl2, and concentrated under reduced pressure. The
resulting mixture was purified via column chromatography using CH2Cl2/EtOAc gradient unless
otherwise specified.
7ꢀ(Phenoxymethyl)ꢀ3ꢀtosylꢀ3Hꢀimidazo[1,2-a]pyrrolo[2,3-e]pyrazine (9a):
Following the general procedure, 5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀamine (72 mg, 0.25
mmol) was converted to 7ꢀ(Phenoxymethyl)ꢀ3ꢀtosylꢀ3Hꢀimidazo[1,2-a]pyrrolo[2,3-e]pyrazine
(72 mg, 68%). The resulting crystalline yellow solid was isolated after column chromatography
using a 5 to 40% gradient of EtOAc in CH2Cl2.
1H NMR (700 MHz, CDCl3), δ (mult., J, nH): 8.81 (s, 1H), 8.08 (m, 2H), 7.86 (s, 1H), 7.73 (d, J
= 4.0 Hz, 1H), 7.30 (m, 2H), 7.29 (m, 1H), 7.28 (m, 1H), 7.02 (m, 2H), 6.97 (m, 1H), 6.72 (d, J =
4.0 Hz, 1H), 5.35 (s, 2H), 2.38 (s, 3H). 13C NMR (176 MHz, CDCl3), δ 158.3, 145.8, 145.6,
139.4, 136.6, 134.9, 132.9, 129.9, 129.5, 128.2, 123.8, 121.3, 118.4, 114.7, 109.8 , 98.4, 64.9,
21.7. HRMS (ESI) m/z calculated for C22H18N4O3S [M + H]+ 419.1173, found 419.1165. mp
153ꢀ155 °C.
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1ꢀPhenoxyꢀ3ꢀ((5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀyl)amino)propanꢀ2ꢀone (9b):
Following the general procedure, 5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀamine (72 mg, 0.25mmol)
was converted to 1ꢀPhenoxyꢀ3ꢀ((5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀyl)amino)propanꢀ2ꢀone
(11 mg, 10%). The resulting amorphous orange solid was isolated after column chromatography
using a 5→40% gradient of EtOAc in CH2Cl2.
1H NMR (700 MHz, CDCl3), δ (mult., J, nH): 7.98 (m, 2H), 7.80 (s, 1H), 7.75 (d, J = 4.0 Hz,
1H), 7.33 (m, 2H), 7.25 (m, 2H), 7.02 (m, 1H), 6.94 (m, 2H), 6.54 (d, J = 4.0 Hz, 1H), 5.29 (t, J
= 4.9 Hz, 1H), 4.73 (s, 2H), 4.55 (d, J = 4.9 Hz, 2H), 2.37 (s, 3H). 13C NMR (176 MHz, CDCl3),
δ: 204.1, 157.5, 151.8, 145.3, 138.6, 135.3, 135.0, 129.8, 128.7, 128.2, 127.7, 122.0, 114.5,
105.8, 72.0, 49.1, 21.6. HRMS (ESI) m/z calculated for C22H20N4O4S [M + H]+ 437.1279, found
437.1277.
7ꢀIsopropylꢀ3ꢀtosylꢀ3Hꢀimidazo[1,2-a]pyrrolo[2,3-e]pyrazine (10a):
Following the general procedure 5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀamine (332 mg, 1.15
mmol) was converted to 7ꢀIsopropylꢀ3ꢀtosylꢀ3Hꢀimidazo[1,2-a]pyrrolo[2,3-e]pyrazine (270 mg,
66%). The resulting crystalline white solid was isolated after column chromatography using a
5→40% gradient of EtOAc in CH2Cl2.
1H NMR (700 MHz, CDCl3), δ (mult., J, nH): 8.77 (s, 1H), 8.06 (m, 2H), 7.70 (d, J = 4.0 Hz,
1H), 7.57 (s, 1H), 7.28 (m, 2H), 6.71 (d, J = 4.0 Hz, 1H), 3.18 (hept, J = 6.9 Hz, 1H), 2.37 (s,
3H), 1.39 (d, J = 7.0 Hz, 6H). 13C NMR (176 MHz, CDCl3), δ 156.5, 145.9, 139.3, 136.2, 134.9,
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132.9, 129.8, 128.0, 123.5, 118.3, 107.2, 98.4, 28.7, 22.5, 21.6. HRMS (ESI) m/z calculated for
C18H18N4O2S [M + H]+ 355.1224, found 355.1224. mp 197ꢀ199 °C.
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3ꢀMethylꢀ1ꢀ((5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀyl)amino)butanꢀ2ꢀone (10b):
Following the general procedure, 5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀamine (332 mg, 1.15
mmol) was converted to 3ꢀMethylꢀ1ꢀ((5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀyl)amino)butanꢀ2ꢀ
one (24 mg, 6%). The resulting crystalline white solid was isolated after column chromatography
using a 5→40% gradient of EtOAc in CH2Cl2.
1H NMR (700 MHz, CDCl3), δ (mult., J, nH): 7.97 (m, 2H), 7.78 (s, 1H), 7.74 (d, J = 4.0 Hz,
1H), 7.26 (m, 2H), 6.54 (d, J = 4.0 Hz, 1H), 5.40 (t, J = 4.3 Hz, 1H), 4.32 (d, J = 4.2 Hz, 2H),
2.74 (hept, J = 6.9 Hz, 1H), 2.37 (s, 3H), 1.19 (d, J = 6.9 Hz, 7H). 13C NMR (176 MHz, CDCl3),
δ: 210.0, 151.9, 145.2, 138.6, 135.3, 134.8, 129.7, 128.5, 128.4, 127.7, 105.8, 49.3, 39.0, 21.6,
18.3. HRMS (ESI) m/z calculated for C18H20N4O3S [M + H]+ 373.1251, found 373.1255. mp
134ꢀ137 °C.
7ꢀ(4ꢀNitrophenyl)ꢀ3ꢀtosylꢀ3Hꢀimidazo[1,2-a]pyrrolo[2,3-e]pyrazine (11a):
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mmol) was converted to 7ꢀ(4ꢀNitrophenyl)ꢀ3ꢀtosylꢀ3Hꢀimidazo[1,2-a]pyrrolo[2,3-e]pyrazine
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(148 mg, 34%). The resulting crystalline orange solid was isolated after column chromatography
using a 5→40% gradient of EtOAc in CH2Cl2.
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1H NMR (700 MHz, CDCl3), δ (mult., J, nH): 8.87 (s, 1H), 8.33 (m, 2H), 8.19 (s, 1H), 8.16 (m,
2H), 8.11 (m, 2H), 7.78 (d, J = 4.0 Hz, 1H), 7.33 (m, 2H), 6.79 (d, J = 3.9 Hz, 1H), 2.39 (s, 3H).
13C NMR (176 MHz, CDCl3), δ: 147.7, 146.0, 145.2, 140.2, 139.2, 137.0, 134.8, 133.1, 129.9,
128.3, 126.8, 124.3, 124.1, 118.2, 108.8, 98.2, 21.7. HRMS (ESI) m/z calculated for
C21H15N5O4S [M + H]+ 434.0918, found 434.0919. mp 250 °C (decomp).
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1ꢀ(4ꢀNitrophenyl)ꢀ2ꢀ((5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀyl)amino)ethanꢀ1ꢀone (11b):
Following the general procedure 5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀamine (332 mg, 1.15
mmol)
was
converted
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1ꢀ(4ꢀNitrophenyl)ꢀ2ꢀ((5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀ
yl)amino)ethanꢀ1ꢀone (126 mg, 28%). The resulting crystalline yellow solid was isolated inafter
column chromatography using a 2→10% gradient of EtOAc in CH2Cl2.
1H NMR (700 MHz, CDCl3), δ (mult., J, nH): 8.37 (m, 2H), 8.23 (m, 2H), 7.99 (m, 2H), 7.88 (s,
1H), 7.77 (d, J = 3.9 Hz, 1H), 7.28 (d, m, 2H), 6.56 (d, J = 4.0 Hz, 1H), 5.60 (t, J = 4.3 Hz, 1H),
4.95(d, J = 4.3 Hz, 2H), 2.38 (s, 3H). 13C NMR (176 MHz, CDCl3), δ: 194.0, 151.6, 150.8(,
145.3, 139.1, 138.5, 135.3, 135.0, 129.8, 129.1, 128.7, 128.4, 127.8, 124.1, 105.7, 48.8, 21.6.
HRMS (ESI) m/z calculated for C21H17N5O5S [M + H]+ 452.1024, found 452.1026. mp 195ꢀ197
°C.
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Methyl 4ꢀ(3ꢀtosylꢀ3Hꢀimidazo[1,2-a]pyrrolo[2,3-e]pyrazineꢀ7ꢀyl)benzoate (12a):
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Following the general procedure, 5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀamine (332 mg, 1.15
mmol) was converted to Methyl 4ꢀ(3ꢀtosylꢀ3Hꢀimidazo[1,2-a]pyrrolo[2,3-e]pyrazineꢀ7ꢀ
yl)benzoate (250 mg, 48%). The resulting crystalline orange solid was isolated after column
chromatography using a 5→40% gradient of EtOAc in CH2Cl2.
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1H NMR (700 MHz, CDCl3), δ (mult., J, nH): 8.86 (s, 1H), 8.15 (s, 1H), 8.13 (m, 2H), 8.10 (m,
2H), 8.06 (m, 2H), 7.76 (d, J = 4.0 Hz, 1H), 7.32 (m, 2H), 6.78 (d, J = 4.0 Hz, 1H), 3.94 (s, 3H),
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2.39 (s, 3H). C NMR (176 MHz, CDCl3), δ: 166.7, 146.5, 145.9, 140.1, 137.2, 136.8, 134.8,
133.0, 130.2, 129.9, 129.9, 128.2, 126.1, 123.9, 118.2, 108.3, 98.4, 52.2, 21.7. HRMS (ESI) m/z
calculated for C23H18N4O4S [M + H]+ 447.1122, found 447.1123. mp 263 °C (decomp).
Methyl 4ꢀ((5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazinꢀ2ꢀyl)glycyl)benzoate (12b):
Following the general procedure, 5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀamine (332 mg, 1.15
mmol) was converted to Methyl 4ꢀ((5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazinꢀ2ꢀyl)glycyl)benzoate(59
mg, 11%). The resulting crystalline yellow solid was isolated after column chromatography
using a 5→40% gradient of EtOAc in CH2Cl2.
1H NMR (700 MHz, CDCl3), δ (mult., J, nH): 8.17 (m, 2H), 8.11 (m, 2H), 7.98 (m, 2H), 7.87 (s,
1H), 7.75 (d, J = 4.0 Hz, 1H), 7.27 (m, 2H), 6.56 (d, J = 4.0 Hz, 1H), 5.68 (t, J = 4.4 Hz, 1H),
4.92 (d, J = 4.3 Hz, 2H), 3.97 (s, 3H), 2.37 (s, 3H). 13C NMR (176 MHz, CDCl3), δ: 194.8,
166.0, 151.8, 145.3, 138.6, 137.8, 135.3, 134.9, 134.7, 130.0, 129.7, 128.6, 128.5, 127.9, 127.76,
105.8, 52.6, 48.6, 21.6. HRMS (ESI) m/z calculated for C23H20N4O5S [M + H]+ 465.1228, found
465.1227. mp 200ꢀ203 °C.
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7ꢀ(4ꢀBromophenyl)ꢀ3ꢀtosylꢀ3Hꢀimidazo[1,2-a]pyrrolo[2,3-e]pyrazine (13a):
Following the general procedure 5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀamine (72 mg, 0.25mmol)
was converted to 7ꢀ(4ꢀBromophenyl)ꢀ3ꢀtosylꢀ3Hꢀimidazo[1,2-a]pyrrolo[2,3-e]pyrazine (74 mg,
64%). The resulting crystalline orange solid was isolated after column chromatography using a
2→10% gradient of EtOAc in CH2Cl2.
1H NMR (700 MHz, CDCl3), δ (mult., J, nH): 8.83 (s, 1H), 8.09 (m, 2H), 8.06 (s, 1H), 7.85 (m,
2H), 7.75 (d, J = 4.1 Hz, 1H), 7.59 (m, 2H), 7.33 (m, 2H), 6.77 (d, J = 4.1 Hz, 1H), 2.39 (s, 3H).
13C NMR (176 MHz, CDCl3), δ 146.7, 145.9, 140.0, 136.6, 134.9, 133.1, 132.0, 131.9, 129.9,
128.2, 127.8, 123.9, 122.7, 118.2, 107.5, 98.4, 21.7. HRMS (ESI) m/z calculated for
C21H15N4O2SBr [M + H]+ 467.0172, found 467.0170. mp 245 °C (decomp).
1ꢀ(4ꢀBromophenyl)ꢀ2ꢀ((5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀyl)amino)ethanꢀ1ꢀone (13b):
Following the general procedure, 5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀamine (72 mg, 0.25
mmol) was converted to 1ꢀ(4ꢀBromophenyl)ꢀ2ꢀ((5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀ
yl)amino)ethanꢀ1ꢀone (14 mg, 13%). The resulting crystalline yellow solid was isolatedafter
column chromatography using a 2→10% gradient of EtOAc in CH2Cl2.
1H NMR (700 MHz, CDCl3), δ (mult., J, nH): 7.98 (m, 2H), 7.92 (m, 2H), 7.86 (s, 1H), 7.75 (d,
J = 4.0 Hz, 1H), 7.66 (m, 2H), 7.27 (m, 2H), 6.56 (d, J = 4.0 Hz, 1H), 5.66 (t, J = 4.3 Hz, 1H),
4.86 (d, J = 4.4 Hz, 2H), 2.37 (s, 3H). 13C NMR (176 MHz, CDCl3): 194.2, 151.9, 145.3, 138.6,
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135.3, 134.9, 133.3, 132.3, 129.8, 129.4, 129.3, 128.6, 128.5, 127.8, 105.8, 48.2, 21.6. HRMS
(ESI) m/z calculated for C21H17N4O3SBr [M + H]+ 485.0278, found 485.0276. mp 212ꢀ214 °C.
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7ꢀPhenylꢀ3ꢀtosylꢀ3Hꢀimidazo[1,2-a]pyrrolo[2,3-e]pyrazine (14a):
Following the general procedure, 5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀamine (72 mg, 0.25
mmol) was converted to 7ꢀPhenylꢀ3ꢀtosylꢀ3Hꢀimidazo[1,2-a]pyrrolo[2,3-e]pyrazine (58 mg,
60%). The resulting crystalline offꢀwhite solid was isolated after column chromatography using a
1→10% gradient of EtOAc in CH2Cl2.
1H NMR (700 MHz, CDCl3), δ (mult., J, nH): 8.84 (s, 1H), 8.09 (m, 2H), 8.07 (s, 1H), 7.98 (m,
2H), 7.73 (d, J = 4.0, 1H), 7.45 (m, 2H), 7.37 (m, 1H), 7.31 (m, 2H), 6.77 (d, J = 4.0 Hz, 1H),
2.38 (s, 3H). 13C NMR (176 MHz, CDCl3): 147.9, 145.8, 139.9, 136.6, 134.9, 133.0, 132.9,
129.9, 128.9, 128.7, 128.1, 126.3, 123.7, 118.2, 107.4, 98.4, 21.7. HRMS (ESI) m/z calculated
for C21H16N4O2S [M + H]+ 389.1067, found 389.1069. mp 233ꢀ235 °C
1ꢀPhenylꢀ2ꢀ((5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀyl)amino)ethanꢀ1ꢀone (14b):
Following the general procedure, 5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀamine (72 mg, 0.25
mmol) was converted to 1ꢀPhenylꢀ2ꢀ((5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀyl)amino)ethanꢀ1ꢀ
one (9 mg, 9%). The resulting amorphous orange solid was isolated column chromatography
using a 2→10% gradient of EtOAc in CH2Cl2.
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1H NMR (700 MHz, CDCl3), δ (mult., J, nH): 8.05 (m, 2H), 7.98 (m, 2H), 7.85 (s, 1H, H3), 7.74
(d, J = 4.0 Hz, 1H), 7.63 (m, 1H), 7.51 (m, 2H), 7.26 (m, 2H), 6.56 (d, J = 4.0 Hz, 1H), 5.73 (t, J
= 4.4 Hz, 1H), 4.89 (d, J = 4.4 Hz, 2H), 2.37 (s, 3H). 13C NMR (176 MHz, CDCl3): 195.0,
152.0, 145.2, 138.6, 135.3, 134.8, 134.6, 134.0, 129.7, 128.9, 128.6, 128.4, 127.9, 127.7, 105.8,
48.2, 21.6. HRMS (ESI) m/z calculated for C21H18N4O3S [M + H]+ 407.1173, found 407.1175.
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7ꢀ(4ꢀ(tertꢀButyl)phenyl)ꢀ3ꢀtosylꢀ3Hꢀimidazo[1,2-a]pyrrolo[2,3-e]pyrazine (15a):
Following the general procedure, 5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀamine (72 mg, 0.25
mmol) was converted to 7ꢀ(4ꢀ(tertꢀButyl)phenyl)ꢀ3ꢀtosylꢀ3Hꢀimidazo[1,2-a]pyrrolo[2,3-
e]pyrazine (67 mg, 60%).The resulting crystalline orange solid was isolated after column
chromatography using a 5→40% gradient of EtOAc in CH2Cl2.
1H NMR (700 MHz, CDCl3), δ (mult., J, nH): 8.84 (s, 1H), 8.09 (m, 2H), 8.05 (s, 1H), 7.91 (m,
2H), 7.73 (d, J = 4.0 Hz, 1H), 7.49 (m, 2H), 7.30 (m, 2H), 6.77 (d, J = 4.0 Hz, 1H), 2.38 (s, 3H),
1.36 (s, 9H). 13C NMR (176 MHz, CDCl3), δ 151.9, 148.0, 145.8, 139.9, 136.5, 134.9, 133.0,
130.1, 129.9, 128.1, 126.0, 125.8, 123.6, 118.2, 107.2, 98.5, 34.7, 31.3, 21.6. HRMS (ESI) m/z
calculated for C25H24N4O2S [M + H]+ 445.1693, found 445.1692. mp 235 °C (decomp).
1ꢀ(4ꢀ(tertꢀButyl)phenyl)ꢀ2ꢀ((5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀyl)amino)ethanꢀ1ꢀone (15b):
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Following the general procedure, 5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀamine (72 mg, 0.25
mmol) was converted to 1ꢀ(4ꢀ(tertꢀButyl)phenyl)ꢀ2ꢀ((5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀ
yl)amino)ethanꢀ1ꢀone (14 mg, 12%). The resulting crystalline brown solid was isolated after
column chromatography using a 5→40% gradient of EtOAc in CH2Cl2.
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1H NMR (700 MHz, CDCl3), δ (mult., J): 8.06 (m, 2H), 8.04 (m, 2H), 7.92 (s, 1H), 7.81 (d, J =
4.0 Hz, 1H), 7.59 (m, 2H), 7.33 (m, 2H), 6.64 (d, J = 4.0 Hz, 1H), 5.80 (t, J = 4.3 Hz, 1H), 4.93
(d, J = 4.3 Hz, 2H), 2.43 (s, 3H), 1.42 (s, 9H). 13C NMR (176 MHz, CDCl3), δ 194.6, 158.1,
152.2, 145.3, 138.7, 135.4, 134.8, 132.1, 129.8, 128.7, 128.5, 128.0, 127.8, 125.9, 105.9, 48.4,
35.5, 31.3, 21.9. HRMS (ESI) m/z calculated for C25H26N4O3S [M + H]+ 463.1799, found
463.1797. mp 157ꢀ159 °C.
7ꢀ(3,4ꢀDimethoxyphenyl)ꢀ3ꢀtosylꢀ3Hꢀimidazo[1,2-a]pyrrolo[2,3-e]pyrazine (16a):
Following the general procedure, 5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀamine (332 mg, 1.15
mmol) was converted to 7ꢀ(3,4ꢀDimethoxyphenyl)ꢀ3ꢀtosylꢀ3Hꢀimidazo[1,2-a]pyrrolo[2,3-
e]pyrazine (196 mg, 38%). The resulting crystalline orange solid was isolated after column
chromatography using a 5→40% gradient of EtOAc in CH2Cl2.
1H NMR (700 MHz, CDCl3), δ (mult., J, nH): 8.83 (s, 1H), 8.10 (m, 2H), 8.01 (s, 1H), 7.74 (d, J
= 3.9 Hz, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.49 (dd, J = 8.3, 2.0 Hz, 1H), 7.34 – 7.29 (m, 2H), 6.95
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(d, J = 8.4 Hz, 1H), 6.77 (d, J = 3.9 Hz, 1H), 4.01 (s, 3H), 3.94 (s, 3H), 2.39 (s, 3H). C NMR
(176 MHz, CDCl3), δ 149.6, 149.4, 148.0, 145.8, 139.9, 136.3, 134.9, 133.1, 129.9, 128.2, 126.0,
123.7, 118.9, 118.2, 111.3, 109.4, 106.8, 98.4, 56.1, 56.0, 21.68. HRMS (ESI) m/z calculated for
C23H20N4O4S [M + H]+ 449.1279, found 449.1277. mp 173ꢀ175 °C.
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1ꢀ(3,4ꢀDimethoxyphenyl)ꢀ2ꢀ((5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀyl)amino)ethanꢀ1ꢀone (16b):
Following the general procedure, 5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀamine (332 mg, 1.15
mmol) was converted to 1ꢀ(3,4ꢀDimethoxyphenyl)ꢀ2ꢀ((5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀ
yl)amino)ethanꢀ1ꢀone (102 mg, 19%). The resulting amorphous yellow solid was isolatedafter
column chromatography using a 5→40% gradient of EtOAc in CH2Cl2.
1H NMR (700 MHz, CDCl3), δ (mult., J, nH): 7.98 (m, 2H), 7.86 (s, 1H), 7.75 (d, J = 4.0 Hz,
1H), 7.71 (dd, J = 8.4, 2.0 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.27 (m, 2H), 6.93 (d, J = 8.4 Hz,
1H), 6.57 (d, J = 4.0 Hz, 1H), 5.75 (t, J = 4.2 Hz, 1H), 4.85 (d, J = 4.2 Hz, 2H), 3.97 (s, 3H),
3.96 (s, 3H), 2.37 (s, 3H). 13C NMR (176 MHz, CDCl3) δ: 193.5, 154.0, 152.1, 149.3, 145.2,
138.6, 135.3, 134.8, 129.7, 128.7, 128.4, 127.8, 127.7, 122.6, 110.2, 110.0, 105.8, 56.1, 56.1,
47.7, 21.6. HRMS (ESI) m/z calculated for C23H22N4O5S [M + H]+ 467.1384, found 467.1387.
N,NꢀDimethylꢀ4ꢀ(3ꢀtosylꢀ3Hꢀimidazo[1,2-a]pyrrolo[2,3-e]pyrazineꢀ7ꢀyl)aniline (17a):
Following the general procedure, 5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀamine (332 mg, 1.15
mmol) was converted to N,NꢀDimethylꢀ4ꢀ(3ꢀtosylꢀ3Hꢀimidazo[1,2-a]pyrrolo[2,3-e]pyrazineꢀ7ꢀ
yl)aniline (287 mg, 58%).The resulting crystalline yellow solid was isolated after column
chromatography using a 5→30% gradient of EtOAc in CH2Cl2.
1H NMR (700 MHz, CDCl3), δ (mult., J, nH): 8.80 (s, 1H), 8.08 (m, 2H), 7.94 (s, 1H), 7.86 (m,
2H), 7.71 (d, J = 4.0 Hz, 1H), 7.30 (m, 2H), 6.79 (m, 2H), 6.75 (d, J = 4.0 Hz, 1H), 3.02 (s, 6H),
2.38 (s, 3H). 13C NMR (176 MHz, CDCl3), δ 150.8, 148.7, 145.7, 139.9, 136.0, 135.0, 133.1,
129.8, 128.1, 127.3, 123.5, 120.9, 118.1, 112.3, 106.0, 98.5, 40.4, 21.7. HRMS (ESI) m/z
calculated for C23H21N5O2S [M + H]+ 432.1489, found 432.1489. mp 229ꢀ231 °C.
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1ꢀ(4ꢀ(Dimethylamino)phenyl)ꢀ2ꢀ((5ꢀtosyl)ꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀyl)amino)ethanꢀ1ꢀone
(17b):
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Following the general procedure, 5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀamine (332 mg, 1.15
mmol) was converted to 1ꢀ(4ꢀ(Dimethylamino)phenyl)ꢀ2ꢀ((5ꢀtosyl)ꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ
2ꢀyl)amino)ethanꢀ1ꢀone (16 mg, 3%).The resulting crystalline orange solid was isolatedafter
column chromatography using a 5→30% gradient of EtOAc in CH2Cl2.
1H NMR (700 MHz, CDCl3), δ (mult., J, nH): 7.97 (m, 2H), 7.95 (m, 1H), 7.84 (s, 1H), 7.73 (d,
J = 3.9 Hz, 2H), 7.26 (d, m, 2H), 6.68 (m, 2H), 6.57 (d, J = 4.0 Hz, 1H), 5.87 (t, J = 4.1 Hz, 1H),
4.77 (d, J = 4.1 Hz, 2H), 3.08 (s, 6H), 2.37 (s, 3H). 13C NMR (176 MHz, CDCl3), δ 192.3, 153.9,
152.3, 145.2, 138.7, 135.4, 134.6, 130.1, 129.7, 128.8, 128.2, 127.7, 122.3, 110.7, 105.9, 47.3,
40.0, 21.6. HRMS (ESI) m/z calculated for C23H23N5O3S [M + H]+ 450.1595, found 450.1604.
mp 222 °C (decomp).
7ꢀ(oꢀTolyl)ꢀ3ꢀtosylꢀ3Hꢀimidazo[1,2-a]pyrrolo[2,3-e]pyrazine (18a):
Following the general procedure, 5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀamine (332 mg, 1.15
mmol) was converted to 7ꢀ(oꢀTolyl)ꢀ3ꢀtosylꢀ3Hꢀimidazo[1,2-a]pyrrolo[2,3-e]pyrazine (282 mg,
61%). The resulting crystalline white solid was isolated after column chromatography using a
5→30% gradient of EtOAc in CH2Cl2.
1H NMR (700 MHz, CDCl3), δ (mult., J, nH,): 8.86 (s, 1H), 8.09 (m, 2H), 7.91 (s, 1H), 7.81 (m,
1H), 7.74 (d, J = 4.0 Hz, 1H), 7.31 (m, 2H), 7.297* (m, 1H), 7.293* (m, 1H), 7.292* (m, 1H),
6.78 (d, J = 4.0 Hz, 1H), 2.56 (s, 3H), 2.38 (s, 3H). *Indicates proton assignments obtained by 1H
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iterative full spin analysis. 13C NMR (176 MHz, CDCl3) δ: 147.7, 145.8, 139.1, 136.7, 135.9,
134.9, 132.9, 132.5, 131.0, 129.8, 129.8, 128.4, 128.1, 126.1, 123.6, 118.2, 109.9, 98.5, 21.7,
21.4. HRMS (ESI) m/z calculated for C22H18N4O2S [M + H]+ 403.1224, found 403.1232. mp
194ꢀ196 °C.
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1ꢀ(oꢀTolyl)ꢀ2ꢀ((5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀyl)amino)ethanꢀ1ꢀone (18b):
Following the general procedure, 5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀamine (332 mg, 1.15
mmol) was converted to 1ꢀ(oꢀTolyl)ꢀ2ꢀ((5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀyl)amino)ethanꢀ1ꢀ
one (58 mg, 12%). The resulting amorphous white solid was isolated after column
chromatography using a 5→30% gradient of EtOAc in CH2Cl2.
1H NMR (700 MHz, CDCl3), δ (mult., J, nH): 7.98 (m, 2H), 7.85 (s, 1H), 7.83 (dd, J = 7.8, 1.3
Hz, 1H), 7.74 (d, J = 4.0 Hz, 1H), 7.45 (td, J = 7.5, 1.3 Hz, 1H), 7.32 (td, J = 7.8, 1.3 Hz, 1H),
7.30 (dd, J = 7.5, 1.3 Hz, 1H), 7.27 (m, 2H), 6.55 (d, J = 4.0 Hz, 1H), 5.69 (t, J = 4.5 Hz, 1H),
4.78 (d, J = 4.5 Hz, 2H), 2.56 (s, 3H), 2.37 (s, 3H). 13C NMR (176 MHz, CDCl3), δ: 198.1,
152.0, 145.2, 139.3, 138.6, 135.3, 134.8, 134.6, 132.4, 132.3, 129.7, 128.6, 128.6, 128.4, 127.7,
125.9, 105.8, 49.8, 21.6, 21.6. HRMS (ESI) m/z calculated for C22H20N4O3S [M + H]+ 421.1329,
found 421.1332.
7ꢀ(Thiophenꢀ2ꢀyl)ꢀ3ꢀtosylꢀ3Hꢀimidazo[1,2-a]pyrrolo[2,3-e]pyrazine (19a):
Following the general procedure, 5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀamine (72 mg, 0.25
mmol) was converted to 7ꢀ(Thiophenꢀ2ꢀyl)ꢀ3ꢀtosylꢀ3Hꢀimidazo[1,2-a]pyrrolo[2,3-e]pyrazine (40
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mg, 41%). The resulting crystalline orange solid was isolated after column chromatography
using a 2→10% gradient of EtOAc in CH2Cl2.
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1.1 Hz, 1H), 7.31 (m, 2H), 7.11 (dd, J = 5.0, 3.6 Hz, 1H), 6.75 (d, J = 3.9 Hz, 1H), 2.38 (s, 3H).
13C NMR (176 MHz, CDCl3), δ: 145.9, 142.8, 139.6, 136.5, 136.3, 134.8, 133.1, 129.9, 128.2,
127.9, 126.0, 124.7, 123.8, 118.1, 106.8, 98.4, 21.7. HRMS (ESI) m/z calculated for
C19H14N4O2S2 [M + H]+ 395.0631, found 395.0628. mp 205ꢀ207 °C.
1ꢀ(Thiophenꢀ2ꢀyl)ꢀ2ꢀ((5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀyl)amino)ethanꢀ1ꢀone (19b):
Following the general procedure, 5ꢀtosylꢀ5Hꢀpyrrolo[2,3-b]pyrazineꢀ2ꢀamine (72 mg, 0.25
mmol) was
converted
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yl)amino)ethanꢀ1ꢀone (10 mg, 10%).The resulting crystalline white solid was isolated after
column chromatography using a 5→40% gradient of EtOAc in CH2Cl2.
1H NMR (700 MHz, CDCl3), δ (mult., J, nH): 7.98 (m, 2H), 7.90 (dd, J = 3.8,
1.1 Hz, 1H), 7.84 (s, 1H), 7.75 (d, J = 4.0 Hz, 1H), 7.72 (dd, J = 4.9, 1.1 Hz), 7.27 (m, 2H), 7.19
(dd, J = 4.9, 3.8 Hz, 1H), 6.56 (d, J = 4.0 Hz, 1H), 5.57 (t, J = 4.5 Hz, 1H), 4.83 (d, J = 4.5 Hz,
2H), 2.37 (s, 3H). 13C NMR (176 MHz, CDCl3) δ: 188.2, 151.9, 145.3, 141.1, 138.6, 135.3,
134.9, 134.4, 132.3, 129.7, 128.5, 128.5, 128.4, 127.7, 105.8, 48.3, 21.6. HRMS (ESI) m/z
calculated for C19H16N4O3S2 [M + H]+ 413.0737, found 413.0737. mp 200 °C (decomp).
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