. Author manuscript; available in PMC: 2013 May 4.

Published in final edited form as: J Org Chem. 2012 Apr 18;77(9):4425–4431. doi: 10.1021/jo300162c

Friedel-Crafts Amidoalkylation via Thermolysis and Oxidative Photocatalysis

Chunhui Dai ¹, Francesco Meschini ¹, Jagan M R Narayanam ¹, Corey R J Stephenson ^1,^*

PMCID: PMC3360956 NIHMSID: NIHMS368213 PMID: 22458307

Abstract

Friedel-Crafts amidoalkylation was achieved by oxidation of dialkylamides using persulfate (S₂O₈²⁻) in the presence of the visible light catalyst, Ru(bpy)₃Cl₂, at room temperature, via a reactive N-acyliminium intermediate. Alternatively, mild heating of the dialkylamides and persulfate afforded a metal and Lewis acid-free Friedel-Crafts amidoalkylation. Alcohols and electron–rich arenes served as effective nucleophiles, forming new C–O or C–C bonds. In general, photocatalysis provided higher yields and better selectivities.

Photoredox catalysis has emerged as a powerful tool for organic synthesis.¹ Extensive studies demonstrated that photocatalysts, such as Ru(bpy)₃Cl₂ (1), can initiate single electron transfer (SET) processes under visible light irradiation, providing a new means to selectively activate molecules and promote chemical transformations.² For instance, by harnessing the reductive quenching cycle of Ru(bpy)₃Cl₂, we have recently demonstrated the oxidative functionalization of N-arylamines. ^3,4 Key to this process was the mild and efficient visible light promoted generation of iminium ion intermediates, using Ru(bpy)₃Cl₂ and BrCCl₃ as the terminal oxidant. The amino radical cation was generated through oxidation of N-aryltetrahydroisoquinoline by Ru²⁺* (E_red = +0.84 V vs SCE). A subsequent H-atom abstraction, or deprotonation followed by oxidation, provided the electrophilic iminium ion intermediate (Scheme 1, top).

Scheme 1 — α-C–H Functionalization of Amines and Amides via Visible Light-Mediated Photocatalysis

In line with our investigative pursuit into α-amine functionalization via visible light mediated photoredox catalysis, we decided to explore the formation of N-acyliminium ions. N-Acyliminium ions are known to be more reactive than the simple N-alkyliminium or N-aryliminium ions, and thus, open to a broader range of functionalization.⁵ The importance of N-acyliminium ions in organic synthesis has been well documented, especially in the synthesis of alkaloid natural products.⁶ In general, these highly reactive N-acyliminium ions historically are generated in situ from α-oxyalkylated amides by Lewis acid- or Brønsted acid-promoted elimination, ⁷ or through direct anodic oxidation of amides.⁸ However, amides have a significantly more positive reduction potential (2.0 V for primary amides, 1.8 V for secondary amides and 1.2–1.5 V (vs. SCE) for tertiary amides)⁹ than the corresponding amines, making them far less susceptible to direct oxidation, including photocatalyst-mediated oxidation.

However, this difficulty in oxidation can be circumvented by reordering the steps, that is C–H abstraction followed by oxidation. The α-amine C–H bond has been shown to be prone to H-atom abstraction under a number of reaction conditions, normally requiring a combination of metal complex catalyst/peroxide and sometimes elevated temperatures are needed. ^10,11 The α-amino radical thus generated is strongly reducing, potentially allowing for the generation of N-acyliminium ions by a photocatalyzed oxidation (Scheme 1, bottom). Meanwhile, one of the hallmarks of visible light photocatalysis is the mild reaction condition and outstanding functional group tolerance which would provide some advantages over the current methods. It is well precedented that persulfate (S₂O₈²⁻) is an effective oxidative quencher of Ru(bpy)₃²⁺*,¹² and the generated sulfate radical anion (SO₄˙⁻) is a reactive intermediate known to abstract activated hydrogen atoms and also be a strong oxidant.¹³ Herein, we report a visible light enabled Friedel-Crafts amidoalkylation using persulfate at room temperature via the oxidative quenching cycle of Ru(bpy)₃Cl₂. In addition, a metal free thermal decomposition of persulfate was observed upon heating of the reaction to 55 °C, leading to the same amide oxidation products albeit with attenuated yields and selectivities.

When 3-phenyl-1-propanol (2a) or 3-(4-methoxyphenyl)-1-propanol (2b) was treated with Ru(bpy)₃Cl₂ (1.0 mol %), Na₂S₂O₈ (5.0 equiv) and 2,6-lutidine (2.0 equiv) in DMF, upon visible light irradiation for 12 h at room temperature, formation of the N,O-aminal product (3a or 3b), presumably resulting for DMF oxidation followed by nucleophilic trapping was observed (Scheme 2).¹⁴ Despite complete consumption of the starting material, the isolated yields were relatively low (30–66%) due to the lability of the N,O-aminals during the aqueous workup and chromatographic purification. However, these results demonstrated that N-acyliminium ions could be generated via the visible light-mediated reduction of persulfate at room temperature.

We next explored the use of electron-rich aromatics as nucleophiles to form more stable C–C bonds via a Friedel-Crafts reaction. At the onset, 1,3,5-trimethoxybenzene (4a) was chosen as the nucleophile in DMF. Full consumption of 4a was observed when treated with Ru(bpy)₃Cl₂ and 5.0 equivalents of persulfate after 12 h of visible light irradiation at room temperature (Table 1, entry 1). Little or no conversion was observed in the absence of catalyst or light (entries 2–4) and rigorous degassing was required to achieve optimal results, presumably a consequence of undesired, and unproductive, excited state energy transfer with oxygen. Persulfate was found to be essential for the transformation, requiring 5.0 equivalents for optimal results (entries 5–6). Interestingly, we discovered that reactivity was observed in the absence of photocatalyst (entry 7), however, the reaction required elevated temperature (55 °C). This result verified that Friedel-Crafts amidoalkylation can be achieved in a metal and Lewis acid-free condition via the thermolysis of persulfate.

Table 1.

Optimization and Control Experiments



entry	conditions^a	conversion^b
1	catalyst, persulfate (5.0 equiv), 25 °C	99%
2	no catalyst, persulfate (5.0 equiv), 25 °C	<5%
3	catalyst, persulfate (5.0 equiv), 25 °C, no blue LEDs	0
4	catalyst, persulfate (5.0 equiv), 25 °C, no degassing	59 %
5	catalyst, no persulfate, 25 °C	0
6	catalyst, persulfate (4.0 equiv), 25 °C	86%
7^c	no catalyst, persulfate (5.0 equiv), 55 °C	99%

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Except for entries 4 and 7, the reactions were rigorously degassed.

Determined by crude ¹H NMR.

Reaction was complete in 2 h.

With the optimized conditions in hand, we then examined various electron-rich aromatic and heteroaromatic substrates with dialkylamides in the presence of ammonium persulfate, under both photocatalytic and thermolytic conditions (Table 2). Treatment of 1,3,5-trimethoxybenzene (4a) with Ru(bpy)₃Cl₂ in DMF (5a) at room temperature under photocatalytic conditions afforded mono-substituted product 6aa exclusively, in contrast to thermolytic conditions, which gave both mono-substituted (6aa) and disubstituted products (7aa, entry 1). Switching to DMA (5b), both photocatalysis and thermolysis provided mono-substituted (6ab) and di-substituted products (7ab, entry 2) in a 3.9:1 ratio, but better yields were observed under photocatalytic reaction conditions. A differentiated dialkylamide, such as 1-methyl-2-pyrrolidinone (5c), afforded a mixture of regioisomeric, mono-substituted products 6ac and 6ac’ (entry 3) under both reaction conditions, but higher selectivities were observed with photocatalysis. Surprisingly, when 1,2,3-trimethoxybenzene (4b) was treated with the same conditions in the presence of 5a or 5b, the reaction failed to provide either of the desired products. Prolonged reaction time or higher temperature did not improve the conversion (entry 4). Less nucleophilic substrates, such as 4c and 4d, needed higher temperature and longer reaction times under photocatalytic conditions, although under thermolytic conditions, higher temperatures did not show obvious improvement (entries 5–8). Substrates that have multiple nucleophilic sites, such as 4d, generated mixtures of regioisomers. Furthermore, 1,4-dimethoxybenzene (4e) failed to provide the desired products (entry 9). Highly reactive substrates, such as indole (4f, entry 10) and N-methylindole (4g, entry 11), performed poorly for this oxidative coupling reaction. We speculate that the low yield was due to the oxidative decomposition of the highly electron-rich substrate itself, or the loss of the product 4fa and 4ga by oxidation at the methylene carbon adjacent to the amide nitrogen.¹⁵ When switching to indoles known to be less prone to oxidation, such as N-phenyl indole (4h, entry 12) and N-benzyl indole (4i, entry 13), the reactions gave moderate yields of the desired products. In all cases, substitution at the C-2 position of the indoles was not observed. As a general observation, photocatalysis provided higher yields and better selectivities than thermolysis.

Table 2.

Oxidation of Dialkylamides and Coupling with Electron–rich Aromatics



entry	substrate	alkylamide	product	photocatalysis^a (A)			thermolysis^b (B)
entry	substrate	alkylamide	product	T (°C)	hour	yield (%)^c	T (°C)	hour	yield (%)^c
1		5a		25	12	89 only 6aa	55	12	75 6aa:7aa=12:1
2	4a	5b		25	12	72 6ab:7ab=3.9:1	55	12	64 6ab:7ab=3.9:1
3	4a	5c		25	12	85 6ac:6ac’=50:	55	12	86 6ac:6ac’=11:1
4		5a/5b	NR	25	12	NR	55–85	12	NR
5		5a		30	36	66 (82) ^e	55	36	45 (57)^e
6	4c	5b		30	36	68 (85) ^e	55	36	35 (53) ^e
7		5a		30	60	44 (67) ^e 6da:6da’=12:1	55	60	42 (66) ^e 6da:6da’=10:
8	4d	5b		30	60	40 (51) ^e 6db:6db’=9.5:1	55	60	31 (48) ^e 6db:6db’=8.1:1
9		5a/5b	NR	30	60	NR	55–85	60	NR
10		5a		25	12	10	55	12	8
11		5a		25	2	23	55	2	28
12		5a		25	12	56	55	2	45
13		5a		25	12	52	55	2	44

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The reaction was degassed (freeze-pump-thaw) and carried out under argon atmosphere using a nucleophile (4, 0.5 mmol) and ammonium persulfate (2.5 mmol) in the presence of Ru(bpy)₃Cl₂ (1.0 mol %) in dialkylamides (5, 5.0 mL).

The reaction was carried out under argon atmosphere using a nucleophile (4, 0.5 mmol) and ammonium persulfate (2.5 mmol) in dialkylamides (5, 5.0 mL).

Isolated yields.

Determined by crude ¹H NMR.

Yields are based on recovered starting material.

Proposed Reaction Mechanism

Plausible mechanisms for the oxidation of dialkylamides, using DMF as an example, are shown in Scheme 3. Under the photocatalytic conditions, persulfate¹⁶ is reduced by Ru(bpy)₃²⁺* to give sulfate and sulfate radical anion 8. Alternatively, under thermal conditions persulfate may decompose to generate two equivalents of 8. The alkyl amide (DMF in this case) can then undergo H-atom abstraction by 8 to give α-amido radical 9. Direct oxidation of 9 by Ru³⁺ (+1.27 V vs. SCE)¹⁷ or via electron-transfer of persulfate can lead to N-acyliminium ion 10 (Pathway A), which can also be achieved via a radical chain process (Pathway B) to give oxyalkylamide 11 followed by elimination of sulfate. Either way, the generated acyliminium ion 10 is susceptible to nucleophilic trapping by various electron-rich arenes to afford the desired product 6. Intermolecular H-atom abstraction was supported by an isotopic labeling experiment using 1:1 mixture of DMF/DMF-d₇ as solvent with 4a, which provided the product with a H/D ratio of 2.3:1. Surprisingly, a very small amount (7%) of deuterium incorporation on the aromatic ring of the product also occurred. This might be the result of a reversible oxidation of trimethoxybenzene during the course of the reaction (Scheme 3, eq. 1).

In conclusion, utilizing the oxidative quenching cycle of Ru(bpy)₃Cl₂ and a mechanistically distinct reaction design compared to previous studies in photoredox catalysis, we have developed a protocol for the oxidative functionalization of dialkyl amides. Persulfate was found to be an inexpensive and efficient reagent for this transformation, and is operative under either thermal or photochemical reaction conditions. Electron-rich species, such as alcohols and arenes served as suitable nucleophiles. In most cases, photocatalysis provided higher yields and better selectivities for the Friedel-Crafts reactions compared with the thermolytic reaction conditions. This method is highlighted by its operational simplicity and mild reaction conditions. Further studies on substrate expansion are now in progress.

EXPERIMENTAL SECTION

General Remarks

Glassware was dried in a 170 °C oven or flame dried under vacuum and cooled under inert atmosphere before use. Chemicals were either used as received or purified according to the procedures outlined in Purification of Common Laboratory Chemicals. All reactions were performed using common dry, inert atmosphere techniques. ¹H- and ¹³C- NMR spectra were recorded on Varian Mercury 300, Varian Unity Plus 400 or a Varian 500 spectrometers, using an internal deuterium lock.

General Procedure for the Oxidation of Alkylamides Using Ru(bpy)₃Cl₂ Catalyst (Table 2)

A flame dried 10 mL Schlenk flask with a rubber septum and magnetic stir bar was charged with tris(2,2’-bipyridyl)ruthenium(II) chloride hexahydrate (5.0 µmol), the corresponding substrate (0.5 mmol) and ammonium persulfate (2.5 mmol). Then 5.0 mL of dry dimethylformamide (DMF), dimethylacetamide (DMA), or 1-methyl-2-pyrrolidinone (DMP) was added via syringe. The mixture was degassed by the freeze-pump-thaw procedure (3x), and placed in a 250 mL beaker with blue LEDs wrapped inside. The reaction mixture was stirred at room temperature (or 30 °C using a 100 mL beaker) under argon atmosphere for the time specified in Table 2. Then the mixture was poured into a separatory funnel containing 100 mL of ethyl acetate and 50 mL of sat. NaHCO₃ solution. The layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were washed with H₂O (2 × 50 mL), brine and dried over Na₂SO₄. Solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel to afford the desired product.

General Procedure for the Oxidation of Alkylamides Under Thermolysis (Table 2)

To a solution of substrate (0.5 mmol) in 5.0 mL of dimethylformamide (DMF), dimethylacetamide (DMA), or 1-methyl-2-pyrrolidinone (DMP) in a 10 mL round bottom flask was added ammonium persulfate (2.5 mmol). The mixture was then heated to 55 °C and stirred at that temperature for the time specified in Table 2. Then the reaction mixture was poured into a separatory funnel containing 100 mL of ethyl acetate and 50 mL of sat. NaHCO₃ solution. The layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were washed with H₂O (2 × 50 mL), brine and dried over Na₂SO₄. Solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel to afford the desired product.

N-Methyl-N-((3-phenylpropoxy)methyl)formamide (3a)

A colorless oil. Observed as two rotamers of 82/18 ratio in ¹H NMR (500 MHz, CDCl₃) δ 8.15/8.15 (s, 1 H), 7.31–7.27 (m, 2 H), 7.21–7.16 (m, 2 H), 4.82/4.66 (s, 2 H), 3.34/3.45 (t, J = 6.4 Hz, 2 H), 2.98/2.93 (s, 3 H), 2.71-2.66 (m, 2 H), 1.94-1.87 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ 163.4, 162.8, 141.7, 141.3, 128.4 (two overlapping signals: 128.41, 128.37), 128.3, 126.0, 125.8, 80.3, 73.6, 67.7, 66.6, 33.0, 32.3, 32.2, 31.1, 30.9, 29.0. HRMS (ESI) m/z calcd for C₁₂H₁₈NO₂ [M + H]⁺: 208.1338; found: 208.1345.

N-((3-(4-methoxyphenyl)propoxy)methyl)-N-methylformamide (3b)

A colorless oil. Observed as two rotamers of 81/19 ratio in ¹H NMR (400 MHz, CDCl₃) δ 8.16/8.16 (s, 1 H), 7.10–7.06 (m, 2 H), 6.85–6.81 (m, 2 H), 4.82/4.65 (s, 2 H), 3.79/3.79 (s, 3 H), 3.44/3.33 (t, J = 6.4 Hz, 2 H), 2.98/2.93 (s, 3 H), 2.65–2.59 (m, 2 H), 1.90–1.83 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃) δ 163.4, 162.7, 157.8, 133.7, 133.4, 129.2, 113.8, 113.7, 80.3, 73.6, 67.7, 66.5, 55.2, 33.0, 31.3 (two overlapping signals: 31.32, 31.29), 31.2, 31.1, 28.9. HRMS (ESI) m/z calcd for C₁₃H₂₀NO₃ [M + H]⁺: 238.1443; found: 238.1453.

N-Methyl-N-(2,4,6-trimethoxybenzyl)formamide (6aa)

A colorless solid. Observed as two rotamers of 92/8 ratio in ¹H NMR (400 MHz, CDCl₃) δ 8.25/8.03 (s, 1 H), 6.11/6.11 (s, 2 H), 4.56/4.35 (s, 2 H), 3.81/3.81 (s, 3 H), 3.80/3.80 (s, 6 H), 2.72/2.66 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃) δ 163.6, 162.0, 161.3, 161.1, 160.0, 159.6, 104.4, 103.8, 90.3, 90.2, 55.6, 55.5, 55.3, 41.3, 35.3, 33.0, 28.7. HRMS (ESI) m/z calcd for C₁₂H₁₇NO₄Na [M + Na]⁺: 262.1055; found: 262.1055.

N,N'-((2,4,6-Trimethoxy-1,3-phenylene)bis(methylene))bis(N-methylformamide) (7aa)

A colorless solid. Each component was observed as a set of 2–4 peaks due to existence of three rotamers. ¹H NMR (400 MHz, CDCl₃) δ 8.25/8.06 (s, 2 H), 6.28/6.28 (s, 1 H), 4.60/4.36 (s, 4 H), 3.84/3.84 (s, 6 H), 3.72/3.71 (s, 3 H), 2.70/2.69/2.67/2.66 (s, 6 H). ¹³C NMR (100 MHz, CDCl₃) δ 163.4, 163.3, 162.3, 160.3, 160.1, 159.9, 159.8, 159.7, 109.4, 109.2, 108.9, 91.5, 91.2, 63.2, 62.8, 55.8, 55.7, 55.6, 42.2 (two overlapping signals: 42.22, 42.20), 36.0, 33.1, 28.8, 28.7. HRMS (ESI) m/z calcd for C₁₅H₂₂N₂O₅Na [M + Na]⁺: 333.1426; found: 333.1439.

N-methyl-N-(2,4,6-trimethoxybenzyl)acetamide (6ab)

A colorless solid. Observed as two rotamers of 80/20 ratio in ¹H NMR (400 MHz, CDCl₃) δ 6.12/6.12 (s, 2 H), 4.62/4.45 (s, 2 H), 3.82/3.82 (s, 3 H), 3.80/3.79 (s, 6 H), 2.71/2.71 (s, 3 H), 2.28/2.07 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃) δ 170.7, 170.0, 161.1, 160.8, 160.0, 159.6, 105.2, 104.8, 90.2, 90.1, 55.6, 55.4, 55.2 (two overlapping signals: 55.25, 55.23), 42.1, 37.9, 33.7, 31.1, 22.1, 21.4. HRMS (ESI) m/z calcd for C₁₃H₁₉NO₄Na [M + Na]⁺: 276.1212; found: 276.1208.

N,N'-((2,4,6-Trimethoxy-1,3-phenylene)bis(methylene))bis(N-methylacetamide) (7ab)

A colorless solid. Each component was observed as a set of 2–4 peaks due to existence of three rotamers. ¹H NMR (400 MHz, CDCl₃) δ 6.29/6.28 (s, 1 H), 4.67/4.65/4.47/4.46 (s, 4 H), 3.84/3.83 (s, 6 H), 3.67/3.65 (s, 3 H), 2.71/2.69 (s, 6 H), 2.28/2.08 (s, 6 H). ¹³C NMR (100 MHz, CDCl₃) δ 170.7, 170.6, 170.2, 170.1, 160.6, 160.2, 159.8, 159.7, 159.6, 159.5, 159.3, 110.3, 110.2, 109.9, 109.7, 91.4, 91.2, 63.0, 62.5, 62.1, 55.7, 55.6, 55.5, 55.4, 42.9, 38.5, 38.4, 33.7, 33.6, 31.1, 22.0 (two overlapping signals: 21.99, 21.96), 21.4. HRMS (ESI) m/z calcd for C₁₇H₂₆N₂O₅Na [M + Na]⁺: 361.1739; found: 361.1729.

1-Methyl-5-(2,4,6-trimethoxyphenyl)pyrrolidin-2-one (6ac)

A colorless solid. This product could not be isolated in a pure form, being contaminated with 6ac’ (6ac:6ac’ = 94:6). ¹H NMR (400 MHz, CDCl₃) δ 6.12 (s, 2 H), 5.23 (dd, J = 9.6, 4.6 Hz, 1 H), 3.81 (s, 3 H), 3.77 (s, 6 H), 2.63–2.53 (m, 1 H), 2.53 (s, 3 H), 2.47–2.38 (m, 1 H), 2.36–2.25 (m, 1 H), 2.06–1.97 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃) δ 175.3, 160.8, 159.8 (broad), 108.4, 90.5 (broad), 55.7, 55.2, 53.9, 31.1, 27.3, 23.6. HRMS (ESI) m/z calcd for C₁₄H₂₀NO₄ [M + H]⁺: 266.1392; found: 266.1392.

Key peaks for compound 6ac’: ¹H NMR (400 MHz, CDCl₃) δ 4.48 (s, 2 H), 3.13 (t, J = 7.0 Hz, 2 H), 1.90-1.82 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃) δ 174.1, 161.0, 159.8, 104.6, 90.2, 55.7, 55.2, 46.0, 34.4, 31.2, 17.6.

N-(2,4-Dimethoxy-5-methylbenzyl)-N-methylformamide (6ca)

A colorless oil. Observed as two rotamers of 75/25 ratio in ¹H NMR (400 MHz, CDCl₃) δ 8.26/8.11 (s, 1 H), 6.97/6.87 (s, 1 H), 6.42/6.42 (s, 1 H), 4.48/4.28 (s, 2 H), 3.84/3.84/3.83/3.82 (s, 6 H), 2.82/2.74 (s, 3 H), 2.13/2.11 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃) δ 163.2, 162.5, 158.3, 157.9, 156.8, 156.7, 131.8, 131.5, 118.3, 117.8, 115.3, 114.7, 94.8, 94.7, 55.6, 55.4, 48.4, 41.3, 34.1, 28.9, 15.1. HRMS (ESI) m/z calcd for C₁₂H₁₇NO₃Na [M + Na]⁺: 246.1106; found: 246.1104.

N-(2,4-Dimethoxy-5-methylbenzyl)-N-methylacetamide (6cb)

A colorless oil. Observed as two rotamers of 62/38 ratio in ¹H NMR (400 MHz, CDCl₃) δ 6.98/6.79 (s, 1 H), 6.43/6.41 (s, 1 H), 4.53/4.40 (s, 2 H), 3.84/3.83/3.82 (s, 6 H), 2.91/2.88 (s, 3 H), 2.16/2.13/2.12 (s, 6 H). ¹³C NMR (100 MHz, CDCl₃) δ 171.1, 170.5, 157.8, 157.6, 156.5, 156.1, 131.5, 129.4, 118.2, 117.9, 116.7, 115.4, 94.8, 94.7, 55.6, 55.4 (two overlapping signals: 55.44, 55.37), 55.3, 49.2, 44.1, 35.5, 33.1, 21.8, 21.2, 15.2, 15.1. HRMS (ESI) m/z calcd for C₁₃H₁₉NO₃Na [M + Na]⁺: 260.1263; found: 260.1251.

N-(2,4-Dimethoxybenzyl)-N-methylformamide (6da)

A colorless solid. Observed as two rotamers of 75/25 ratio in ¹H NMR (400 MHz, CDCl₃) δ 8.24/8.10 (s, 1 H), 7.13/7.03 (d, J = 8.8 Hz, 1 H), 6.46–6.43 (m, 2 H), 4.48/4.29 (s, 2 H), 3.80/3.79 (s, 6 H), 2.83/2.73 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃) δ 163.3, 162.6, 161.0, 160.4, 158.8, 158.6, 130.7, 130.4, 116.6, 116.1, 104.2, 103.8, 98.7, 98.4, 55.4, 55.3 (two overlapping signals: 55.35, 55.29), 48.6, 41.7, 34.2, 29.0. HRMS (ESI) m/z calcd for C₁₁H₁₆NO₃ [M + H]⁺: 210.1130; found: 210.1138.

N-(2,6-Dimethoxybenzyl)-N-methylformamide (6da’)

A colorless solid. This product could not be isolated in a pure form, being contaminated with 6da. The following data were obtained from a pure form by an alternative synthetic route, which resemble the spectra of the mixture. Observed as two rotamers of 91/9 ratio in ¹H NMR (400 MHz, CDCl₃) δ 8.29/8.05 (s, 1 H), 7.25 (t, J = 8.4 Hz, 1 H), 6.55/6.55 (d, J = 8.4 Hz, 2 H), 4.65/4.43 (s, 2 H), 3.82/3.81 (s, 6 H), 2.74/2.67 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃) δ 163.7, 162.1, 159.3, 158.9, 129.6, 129.3, 111.7, 111.2, 103.5, 55.7, 55.6, 41.4, 35.5, 33.1, 28.8. HRMS (ESI) m/z calcd for C₁₁H₁₅NO₃Na [M + Na]⁺: 232.0950; found: 232.0943.

N-(2,4-Dimethoxybenzyl)-N-methylacetamide (6db)

A colorless solid. Observed as two rotamers of 62/38 ratio in ¹H NMR (400 MHz, CDCl₃) δ 7.14/6.96 (d, J = 8.8 Hz, 1 H), 6.47–6.43 (m, 2 H), 4.54/4.42 (s, 2 H), 3.81/3.80/3.79 (s, 6 H), 2.93/2.89 (s, 3 H), 2.15/2.12 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃) δ 171.4, 170.8, 160.5, 160.1, 158.5, 158.2, 130.4, 128.2, 117.9, 116.8, 104.2, 103.8, 98.6, 98.3, 55.4, 55.3 (two overlapping signals: 55.33, 55.30), 55.2, 49.5, 44.7, 35.8, 33.3, 21.8, 21.2. HRMS (ESI) m/z calcd for C₁₂H₁₇NO₃Na [M + Na]⁺: 246.1106; found: 246.1113.

N-(2,6-Dimethoxybenzyl)-N-methylacetamide (6db’)

A colorless solid. This product could not be isolated in a pure form, being contaminated with 6db. The following data were obtained from a pure form by an alternative synthetic route, which resemble the spectra of the mixture. Observed as two rotamers of 80/20 ratio in ¹H NMR (400 MHz, CDCl₃) δ 7.25/7.23 (t, J = 8.0 Hz, 1 H), 6.56/6.55 (d, J = 8.0 Hz, 2 H), 4.71/4.53 (s, 2 H), 3.82/3.81 (s, 6 H), 2.73/2.73 (s, 3 H), 2.31/2.08 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃) δ 170.9, 170.1, 159.3, 158.9, 129.4, 129.0, 112.7, 112.2, 103.5 (two overlapping signals: 103.54, 103.51), 55.7, 55.5, 42.3, 38.2, 33.8, 31.2, 22.0, 21.3. HRMS (ESI) m/z calcd for C₁₂H₁₇NO₃Na [M + Na]⁺: 246.1106; found: 246.1099.

N-((1H-Indol-3-yl)methyl)-N-methylformamide (6fa)

A yellow oil. Observed as two rotamers of 54:46 ratio in ¹H NMR (400 MHz, CDCl₃) δ 8.42/8.12 (s, 1 H), 8.30–8.17 (br s, 1 H), 7.71/7.54 (d, J = 7.6 Hz, 1 H), 7.39 (t, J = 9.0 Hz, 1 H), 7.24–7.17 (m, 3 H), 4.71/4.59 (s, 2 H), 2.83/2.82 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃) δ 162.6, 162.3, 136.6, 126.6, 126.3, 124.2, 123.6, 122.5, 122.3, 120.0, 119.8, 119.1, 118.3, 111.5, 111.2, 110.5, 110.1, 45.4, 38.8, 33.9, 29.2. HRMS (ESI) m/z calcd for C₂₂H₂₅N₄O₂ [2M + H]⁺: 377.1978; found:377.1965.

N-Methyl-N-((1-methyl-1H-indol-3-yl)methyl)formamide (6ga)

A yellow oil. Observed as two rotamers of 54:46 ratio in ¹H NMR (400 MHz, CDCl₃) δ 8.41/8.10 (s, 1 H), 7.69/7.52 (d, J = 8.0 Hz, 1 H), 7.35–7.22 (m, 2 H), 7.17–7.11 (m, 1 H), 7.05/7.00 (s, 1 H), 4.68/4.57 (s, 2 H), 3.79/3.77 (s, 3 H), 2.83/2.81 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃) δ 162.3, 162.0, 137.1, 136.9, 128.6, 128.0, 127.1, 126.7, 122.0, 121.8, 119.5, 119.3, 119.2, 118.4, 109.4, 109.1 (two overlapping signals: 109.13, 109.08), 108.7, 45.1, 38.4, 33.7, 32.6, 32.5, 29.0. HRMS (ESI) m/z calcd for C₁₂H₁₄N₂ONa [M + Na]⁺: 225.1004; found: 225.1006.

N-Methyl-N-((1-phenyl-1H-indol-3-yl)methyl)formamide (6ha)

A yellow oil. Observed as two rotamers of 54:46 ratio in ¹H NMR (400 MHz, DMSO-d₆) δ 8.48/8.11 (s, 1 H), 7.73-7.53 (m, 7 H), 7.43–7.38 (m, 1 H), 7.25–7.11 (m, 2 H), 4.66/4.63 (s, 2 H), 2.84/2.70 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃) δ 162.5, 162.2, 139.4, 139.2, 136.5, 136.2, 129.7, 129.6, 128.0, 127.7, 127.6, 127.0, 126.8, 126.5, 124.3, 124.2, 123.0, 122.9, 120.7, 120.5, 119.7, 118.8, 111.9, 111.5, 110.9, 110.5, 45.2, 38.6, 33.9, 29.3. HRMS (ESI) m/z calcd for C₁₇H₁₆N₂ONa [M + Na]⁺: 287.1160; found: 287.1165.

N-((1-Benzyl-1H-indol-3-yl)methyl)-N-methylformamide (6ia)

A yellow oil. Observed as two rotamers of 55:45 ratio in ¹H NMR (400 MHz, DMSO-d₆) δ 8.42/8.07 (s, 1 H), 7.59–7.53 (m, 1 H), 7.54/7.50 (s, 1 H), 7.45–7.40 (m, 1 H), 7.30-7.17 (m, 5 H), 7.14–7.08 (m, 1 H), 7.06-6.98 (m, 1 H), 5.40/5.39 (s, 2 H), 4.60/4.57 (s, 2 H), 2.77/2.64 (s, 3 H). ¹³C NMR (100 MHz, DMSO-d₆) δ 162.4, 162.0, 138.2, 138.1, 136.3, 136.2, 128.9, 128.7, 128.5 (two overlapping signals: 128.53, 128.51), 127.3 (two overlapping signals: 127.32, 127.30), 127.0, 126.9, 121.6, 121.5, 119.2, 119.1, 119.0, 118.6, 110.4, 110.2, 109.4 (two overlapping signals: 109.41, 109.39), 49.0 (two overlapping signals: 48.98, 48.94), 43.8, 37.7, 33.1, 28.4. HRMS (ESI) m/z calcd for C₁₈H₁₈N₂ONa [M + Na]⁺: 301.1317; found: 301.1316.

Supplementary Material

1_si_001

NIHMS368213-supplement-1_si_001.pdf^{(7.7MB, pdf)}

ACKNOWLEDGMENT

Financial support for this research from the NIH-NIGMS (R01-GM096129), NSF (CHE-1056568), the Alfred P. Sloan Foundation, Amgen, Boehringer Ingelheim, and Boston University is gratefully acknowledged. C.D. thanks AstraZeneca for a graduate fellowship. J.M.R.N. thanks the Swiss National Science Foundation for a postdoctoral fellowship. NMR (CHE-0619339) and MS (CHE-0443618) facilities at BU are supported by the NSF.

Footnotes

Supporting Information. ¹H and ¹³C NMR spectra for all products. This material is available free of charge via the Internet at http://pubs.acs.org.

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