Org. Synth. 2014, 91, 221-232
DOI: 10.15227/orgsyn.091.0221
Synthesis of 1,3-Dimethyl-3-(p-tolyl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one by Cu(II)-Mediated Direct Oxidative Coupling
Submitted by Chandan Dey and E. Peter Kündig
*1
Checked by Yen-Ku Wu and Viresh H. Rawal
1. Procedure
Caution! Thionyl chloride reacts violently with water and releases dangerous gases.
A. N-Methyl-N-(pyridin-4-yl)-2-(p-tolyl)propanamide (2). A 50-mL two-necked, round-bottomed flask equipped with a 12 mm x 2.5 mm octagonal
Teflon-coated magnetic stir bar, a reflux condenser fitted with a gas inlet with a positive pressure of N2, and a glass stopper (Note 1) is
charged with 2-(p-tolyl)propionic acid 1 (Note 2) (5.70 g, 34.7 mmol, 1.0 equiv) and thionyl chloride (Note 3) (5.1 mL, 69.4 mmol, 2.0
equiv). The reaction mixture is heated to reflux for 3 h (Note 4). After cooling to room temperature, excess thionyl chloride is removed under vacuum to
give the crude acid chloride (Note 5). Separately, a dry, 250-mL two-necked, round-bottomed flask (Note 1) equipped with a 4.0 cm long, oval-shaped
Teflon-coated magnetic stir bar, a nitrogen inlet having a positive pressure of N2, and a rubber septum is charged with 4-(methylamino)pyridine
(Note 6) (3.75 g, 34.7 mmol, 1.0 equiv), followed by dry dichloromethane (40 mL) (Note 7), which is added by syringe. The resulting solution is cooled to 0
°C (ice bath, external temperature) and treated with dry triethylamine (Note 8) (9.7 mL, 69.4 mmol, 2.0 equiv), which is added by syringe. The acid
chloride formed earlier is diluted with 30 mL dichloromethane (Note 7) and the resulting solution is withdrawn by syringe and added dropwise (Note 9) to
the flask containing 4-(methylamino)pyridine and triethylamine at 0 °C. The 50-mL round-bottomed flask is rinsed with 10 mL dichloromethane (Note 7),
and the rinsate is added to the 250-mL flask. The ice bath is removed and the reaction mixture is stirred at 25 °C for 15 h and then transferred to a
250-mL separatory funnel. The 250-mL flask is rinsed with 20 mL dichloromethane and the solution is added to the separatory funnel. The organic layer is
washed with water (50 mL) and the separated aqueous phase is back-extracted with dichloromethane (2 x 50 mL). The combined organic layers are dried over
anhydrous MgSO4 (10 g), filtered through a 150-mL medium porosity fritted glass funnel, and concentrated with a rotary evaporator (20 mmHg, 25
°C). The crude brown oil is dissolved in 10 mL EtOAc and is charged on a column (inner diameter = 6 cm, l = 15 cm) of 160 g of silica gel (Note 10)
and subjected to flash chromatography (Note 11) using EtOAc as eluent. A first 170 mL fraction is collected in a conical flask, and subsequent fractions
are collected in test tubes (Note 12). Product 2 is identified by TLC (EtOAc, Rf = 0.24, UV and KMnO4 active) (Note 13)
in test tubes 10-32. Fractions containing the product are concentrated by rotary evaporator (20 mmHg, 25 °C), and the resulting product is placed
under high vacuum (1.0 mmHg, 25 °C, 2 h) to give 2 (7.77 g, 88% yield) as a white solid that is indefinitely stable at room temperature (Notes 14 and 15).
B. 1,3-Dimethyl-3-(p-tolyl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (3). A 500-mL two-necked, round-bottomed flask equipped with an
oval-shaped 4.0 cm Teflon-coated magnetic stir bar, a nitrogen inlet with a positive pressure of N2, and a rubber septum (Note 1) is charged
with amide 2 (6.36 g, 25.0 mmol, 1.0 equiv). The flask is placed under vacuum (1.0 mmHg) for 5 min and then back-filled with nitrogen. This sequence
of vacuum and back-filling is repeated two times. Anhydrous CuCl2 (Note 16) (7.4 g, 55.0 mmol, 2.2 equiv) and NaOtBu (Note 17) (12.0 g,
125.0 mmol, 5.0 equiv) are sequentially added to the flask containing amide 2 (Note 18). Dry toluene (250 mL) (Note 19) is added by syringe under
nitrogen atmosphere while stirring (Note 20), then the rubber septum is replaced with a dry reflux condenser. The nitrogen inlet in the second neck of the
flask is transferred to the top of the reflux condenser and the flask opening is sealed with a glass stopper. The reaction mixture is heated to a gentle
reflux for 12 h (Note 21), after which no starting material is evident (Note 22). After cooling to room temperature, the reaction mixture is diluted with
150 mL EtOAc and passed through a pad of Celite (Note 23). The flask is rinsed several times with EtOAc (6 x 150 mL) and the washings are also passed
through the Celite pad (Note 24). The combined filtrate (ca. 1300 mL) is divided into two equal parts. The first half of the filtrate (ca. 650 mL) is
transferred to a 1-L separatory funnel, to which brine (200 mL) and EtOAc (100 mL) are added. After extraction, the organic layer is collected and the
aqueous layer is back-extracted with EtOAc (3 x 200 mL). The organic layers are combined. This sequence of extraction is repeated with the second half of
the filtrate. The combined organic layers are concentrated with a rotary evaporator (20 mmHg, 25 °C) to afford a brown oil. The crude product is
dissolved in 10 mL of EtOAc and charged on a column (inner diameter = 6 cm, l = 16.5 cm) of 170 g of silica gel (Note 10) and subjected to flash
chromatography (Note 11) using EtOAc as the eluent. The first 180 mL of eluent is collected in a conical flask. Subsequent fractions are collected in test
tubes (Note 12). Product 3 is found in test tubes 25-86 (Note 13). Fractions containing the product are concentrated by rotary evaporation (20 mmHg,
25 °C), and the resulting product placed under high vacuum (1.0 mmHg, 25 °C, 3 h) to afford 3 (4.67 g, 74% yield) as a pale yellow solid
that is indefinitely stable at room temperature (Notes 25, 26 and 27).
2. Notes
1. All reaction vessels were dried under vacuum (1.0 mmHg) with the aid of a heat-gun for 3-4 min and maintained under nitrogen atmosphere during the
course of the reaction.
2.
2-(p-Tolyl)propionic acid (97%) was purchased from Sigma-Aldrich and was used as received.
3.
Thionyl chloride (>99%) was purchased from Sigma-Aldrich and was used as received.
4. The temperature of the oil bath was kept at 84 °C.
5. Initially, the vacuum (1.0 mmHg) was applied slowly to the stirred, crude mixture at 0 °C for 5-10 min to avoid bumping and then the flask
was kept at room temperature for 1.5 h under vacuum (1.0 mmHg).
6.
4-(Methylamino)pyridine (99%) was purchased from Alfa Aesar and was used as received.
7.
Methylene chloride (Optima grade) was purchased from Fisher Scientific and was dried using an alumina column-based system (Innovative Technologies
PureSolv).
8.
Triethylamine (Sigma-Aldrich, >99%) was distilled over
KOH prior to use.
9. If the acid chloride solution was added too fast, strong fuming occurred. Normally, 0.5 mL/min was a reasonable rate of addition.
10. SiliCycle Silia
Flash® P60 silica gel, 40-63 mm (230-400 mesh).
11. Flash chromatography was performed using 1.3-1.4 bar air pressure. Caution: a thick walled column and protective shield should be used.
12. Fractions were collected in 150 x 20 mm test tubes, allowing the collection of 28-30 mL in each test tube.
13. TLC was performed on TLC Silica gel 60 F
254 plates.
14. Analytical data for
2:
1H NMR
pdf(500 MHz, CDCl
3) δ: 1.40 (d,
J = 7.0 Hz, 3 H), 2.30 (s, 3 H), 3.25 (s, 3 H), 3.71 (q,
J = 6.5 Hz, 1 H), 6.95 (d,
J
= 7.5 Hz, 2 H), 7.00 (br d,
J = 5.4 Hz, 2 H), 7.05 (d,
J = 8.0 Hz, 2 H),
8.57-8.58 (m, 2 H);
13C NMR
pdf(125 MHz, CDCl
3) δ: 20.4, 20.8, 36.9, 43.1, 121.5, 126.9, 129.2, 136.3, 138.0, 150.9, 151.0, 173.3;
IR (cast, cm
-1): 2975, 2930, 1668, 1587, 1513, 1496, 1375, 1274, 1126, 1063, 1024, 826; HRMS (ESI): calcd. for C
16H
19N
2O ([M+H]
+): 255.1492, found: 255.1488; mp 91-92 °C; Anal. calcd. for C
16H
18N
2O: C,
75.56; H, 7.13; N, 11.01, found: C, 75.47; H, 7.21; N, 11.
15. On half scale, the checkers obtained
2 in 87% yield. The submitters reported 83% yield for the full-scale reaction.
16. Anhydrous
CuCl2 (98%) was purchased from Strem Chemicals and used as received. It was stored in a desiccator between uses. The color of
anhydrous
CuCl2 is dark brown. The submitters note that if the reagent becomes hydrated due to exposure to moisture and the color turns
greenish, it can be dehydrated again by heating at 80 °C under vacuum (0.07 mmHg) for 12 h.
17. The checkers purchased
sodium tert-butoxide (99.9%) from Sigma Aldrich and used as received; it was stored in a desiccator between uses. The
submitter purchased
sodium tert-butoxide (98%) from Acros Organics, sublimed it at 190 °C under vacuum (0.007 mmHg), and stored in a glove box
(N
2 atmosphere) for use in this step.
18. The checkers carried out this step without a glove box.
CuCl2 and
NaOtBu were weighed under air atmosphere and quickly added to the
round-bottomed flask under a positive flow of nitrogen. The submitters carried out this step as follows: The round-bottomed flask was transferred to a
glove box (N
2 atmosphere). After adding
CuCl2 and
NaOtBu (sublimed), the round-bottomed flask was taken from the glove box and
was connected to the Schlenk line.
19.
Toluene (Optima grade) was purchased from Fisher Scientific and was dried by using an alumina column-based system (Innovative Technologies PureSolv).
20. The pale brown reaction mixture was stirred for 10 min at rt before heating was started.
21. After stirring at room temperature, the round-bottomed flask was placed in an oil bath and the temperature was set to 118 °C. It took 20-25
min for the oil to reach the preset temperature.
22. Consumption of the starting material can be checked by either TLC or
1H NMR. In case of TLC, both the starting material and reaction mixture
was spotted on a TLC plate and developed two times with
EtOAc to get separation (TLC:
EtOAc, R
fSM = 0.24, R
fproduct =
0.16, both UV and
KMnO4 active). For NMR analysis, a 0.2 mL aliquot of the reaction mixture was withdrawn under a positive flow of nitrogen and
was passed through a small pad of Celite, followed by removal of solvent under vacuum (1.0 mmHg).
1H NMR showed the disappearance of the
resonance (quartet) at 3.71 ppm. This indicated complete consumption of the starting material. The color of the reaction mixture was deep brown. The
submitters found the reaction is complete in 7 h.
23. Celite (inner diameter = 6.2 cm, l = 3 cm) was tightly packed on a glass frit (P3). The reaction mixture was added slowly to the Celite pad. Due to the
presence of large amounts of inorganic salts, the upper layer of Celite needed gentle scratching for smooth filtration.
24. The Celite was washed until the filtrate became colorless and TLC showed no further product to be present.
25. Analytical data for
3:
1H NMR
pdf(500 MHz, CDCl
3) δ: 1.80 (s, 3 H), 2.29 (s, 3 H), 3.21 (s, 3 H), 6.88 (d,
J =
5.5 Hz, 1 H), 7.12 (d,
J = 8.0 Hz, 2 H), 7.21-7.19 (m, 2 H), 8.35 (s, 1 H), 8.52 (d,
J = 5.0 Hz, 1 H);
13C NMR
pdf(125 MHz, CDCl
3) δ: 20.7, 23.7, 26.2, 50.3, 103.8,
126.1, 129.2, 130.1, 136.4, 137.2, 144.3, 149.7, 150.2, 179.0; IR (cast, cm
-1): 3028, 2972, 2931, 1728, 1603, 1512, 1496, 1373, 1338, 1110,
1018, 818; HRMS (ESI): calcd. for C
16H
17N
2O ([M+H]
+): 253.1335, found: 253.1333; mp 103-104 °C;
Anal. calcd. for C
16H
16N
2O: C, 76.16; H, 6.39; N, 11.10, found: C, 76.09; H, 6.39; N, 11.11.
26. On half scale, the checkers obtained
3 in 75% yield.
27. The submitters, who had stored the reagents in a glove box and set up the reaction there (
Note 18), reported 87% yield for the full-scale reaction.
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should
be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National
Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines
for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee
the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in
any way to the procedures herein.
3. Discussion
In 2009, this group reported a novel, efficient, and high atom economic protocol for the synthesis of 3,3-disubstituted oxindoles, which relied on the
direct oxidative coupling of an aromatic Csp
2-H and a Csp
3-H centers.
2 The reactions were carried out with
readily synthesized anilides in the presence of
CuCl2 as the oxidant and
NaOtBu as a base in
DMF at 110 °C. Shortly following this
report, Taylor and coworkers published a similar protocol leading to oxindoles with ester, nitrile and phosphonate functions in the 3-position.
3
A likely mechanism of this reaction is shown in Scheme 1. The amidyl radical formed by one electron oxidation of the amide enolate cyclizes onto the
aromatic ring. The resulting cyclohexadienyl radical is oxidized to form a σ-complex which readily aromatizes to the oxindole product.
2,3
Secondary isotope effect measurements indicates that Csp
2-H bond breaking is not involved in the rate-determining step and a radical
pathway is also indicated by the finding that a cyclopropyl-substituted substrate furnished a conjugated diene as the only product.
2,3a An
intramolecular radical cyclization reaction is the key step of this transformation. The base/oxidant procedure captivates by its simplicity.
The
CuCl2-mediated protocol was extended to the synthesis of 3,3-disubstituted aza-oxindoles.
4 Compounds containing the aza-oxindole
structural motif exhibit biological activities such as oral anti-inflammatory activity, and potent TrkA kinase and JAK 3 kinase inhibition.
5
Unlike the synthesis of oxindole, there are fewer protocols available in the literature for this class of compounds. Examples include the oxidation of
azaindoles,
6a,b radical cyclization reactions,
6c Pauson-Khand type [2+2+1] cycloadditions,
6d Pd-catalyzed intramolecular
α-pyridination of amides,
6e photo cyclizations,
6f,g and cyclization of aminopyridineacetic acids.
6h All the
aforementioned methods require a specifically functionalized precursor; for instance the presence of an
ortho-pyridyl halogen, an α-xanthate
group or an α-hydroxy group, or a preexisting bicyclic ring system. The
CuCl2-mediated oxidative radical coupling protocol
4 for
aza-oxindole synthesis does not entail such structural specificity. The reactions with the pyridyl amides were carried out in the presence of CuCl
2 and
NaOtBu in
toluene at 110 °C.
4 The key step of this transformation is a Minisci reaction, an intramolecular radical
cyclization on the pyridine ring. Substrates with varying the position of nitrogen in the pyridine ring afforded aza-oxindoles in fair to excellent yields
(Entry 1-11, Table 1). In general, yields with
para-pyridyl substrates were considerably higher than with
ortho-pyridyl substrates (Entry 1-3
vs 4-7, Table 1). The oxidative coupling reaction of
meta-pyridyl amide substrate afforded two regioisomeric products (Entry 8-11, Table 1).
The regioisomer resulting from the addition at
ortho to the pyridyl N is largely favored (Entry 8, Table 1) or is the exclusive product (Entry 9-11,
Table 1).
4 In the synthetic protocol for aza-oxindole detailed here, the concentration of the reaction was raised by a factor of two compared to
the small scale preparation previously reported (0.1M
vs 0.05M).
4
In the course of these studies, a new route to aza-oxindoles, proceeding
via a base promoted Truce-Smiles rearrangement, was found.
Appendix
Chemical Abstracts Nomenclature (Registry Number)
2-(p-Tolyl)propionic acid;
(1) (938-94-3)
Thionyl chloride,
(7719-09-7)
4-(Methylamino)pyridine;
(1121-58-0)
N-Methyl-N-(pyridin-4-yl)-2-(p-tolyl)propanamide;
(2) (1364651-81-9)
Copper (II) chloride;
(7447-39-4)
Sodium tert-butoxide;
(865-48-5)
1,3-Dimethyl-3-(p-tolyl)-1H-pyrrolo[3,2-c]pyridin-2(3H)-one;
(3) (1364652-24-3)
|
Peter Kündig graduated from the Federal Institute of Technology (ETH) in Zurich and then moved to the University of Toronto where he
obtained his Ph.D. (G.A.S. Ozin). Following a postdoctoral stay at the University of Bristol (P. Timms), he started his own research at the
University of Geneva, focusing on synthetic and mechanistic organometallic chemistry and on metal mediated and catalyzed reactions in
organic synthesis. He held from 1990-2012 a Chair in Organic Chemistry. His awards include the Werner Prize of the Swiss Chemical Society
(1986) and the EUCHEMS award (2007). Kündig was chair of the ChemComm Editorial Board (2007-11) and presently is President of the
Swiss Chemical Society.
|
|
Chandan Dey was born in Midnapore, West Bengal, India in 1984. He obtained a B.Sc. (Hons.) degree in Chemistry from Midnapore college,
India in 2006. In 2008, he received a M.Sc. degree from Indian Institute of Technology-Bombay, India. He joined the group of Prof. E. Peter
Kündig at University of Geneva, Switzerland where he completed his doctoral study in 2012.
|
|
Yen-Ku Wu was born in Taipei, Taiwan. He received his B.Sc. in chemistry in 2004 and M.Sc. with Professor Hsing-Jang Liu in 2006 from
National Tsing Hua University. In 2008, he started his Ph.D. studies working on non-conventional Nazarov chemistry under the supervision of
Professor F. G. West at the University of Alberta. After obtaining his Ph.D. in 2013, he moved to the University of Chicago, where he is
currently a postdoctoral scholar in the laboratories of Professor Viresh H. Rawal.
|
Copyright © 1921-
, Organic Syntheses, Inc. All Rights Reserved