Directed Lithiation of Protected 4-Chloropyrrolopyrimidine: Addition to Aldehydes and Ketones Aided by Bis(2-dimethylaminoethyl)ether

Abstract

Pyrrolopyrimidines are important scaffolds for the preparation of bioactive molecules. Therefore, developing efficient and flexible ways for selective functionalization of the pyrrolopyrimidine skeleton is of interest. We have investigated lithiation-addition at C-6 of protected 4-chloro-7H-pyrrolo [2,3-d]pyrimidine as a route to new building blocks for medicinal chemistry. It was found that bis(2-dimethylaminoethyl) ether as an additive increased the yield in the additional reaction with benzaldehyde. Deuterium oxide quench experiments showed that this additive offered both a higher degree of lithiation and increased stability of the lithiated intermediate. The substrate scope of the protocol was investigated with 16 aldehydes and ketones, revealing the method to be excellently suited for reaction with aldehydes, cyclohexanone derivatives and 2,2,2-trifluoroacetophenone, while being less efficient for acetophenones. Yields in the range of 46–93% were obtained.

1. Introduction

Due to their bioisosteric relationship with purines, pyrrolopyrimidines are attractive pharmacophores in medicinal chemistry [1,2], with a wide range of applications, including antiviral, antimicrobial, inflammatory, and cancer indications. The chemistry pertaining to a variety of advanced pyrrolopyrimidines has been reviewed [3,4]. To prepare new pyrrolopyrimidines of interest, having access to advanced building blocks with accessible and selective reactive handles is of major importance. One key starting material for pyrrolopyrimidine synthesis is 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (Scheme 1). The C-4 position is reactive in both nucleophilic aromatic substitutions (S_NAr) and cross-couplings, while N-7 can be alkylated, arylated, or glycosylated. Additional reactive handles for cross-coupling chemistry can be inserted by electrophilic aromatic substitution at C-5, resulting in structure I [5,6], and the N-7 benzyl analogue of II has been borylated using iridium-catalysis to provide III [7]. Further, introducing a coordinating protection group at N-7 allows for directed lithiation at C-6, providing us with the reactive intermediate IV. Quenching of IV with iodine provides the building block V [8,9], and the use of CO₂ gives the carboxylic acid VI [10]. Another possibility is to react the lithiated intermediate IV with aldehydes and ketones to result in structures like VII. Sakomoto et al. used n-butyllithium (n-BuLi) to functionalize a benzenesulfonyl protected 2,4-dimethoxy-pyrrolo[2,3-d]pyrimidine [11].

Zhao et al. [12] employed the same protection group and reacted IV with cyclic ketones, resulting in yields in the range of 55–77%. In ongoing projects to prepare bioactive pyrrolopyrimidines, we wanted to functionalize the C-6 position with a sp²-sp³ carbon linker, such as that exemplified in structure VII. We realized that directed lithiation, followed by quenching with ketones and aldehydes, could be a viable approach. Although we have previously found the benzenesulfonyl group useful in directing lithiation at C-6, its lability under amination conditions at C-4 is highly inconvenient [9]. Thus, the 2-(trimethylsilyl)ethoxymethyl (SEM) protection group was seen as an interesting alternative. Herein, we report our study on the directed lithiation of SEM-protected pyrrolopyrimidines and addition to aldehydes and ketones for the preparation of advanced intermediates for medicinal chemistry. We found that the lithiation process could be improved by utilizing bis(2-dimethylaminoethyl) ether as an additive, resulting in higher overall yields. Furthermore, the substrate scope has been explored by reaction with 16 different ketones and aldehydes of varying acidity and coordinating groups.

2. Results and Discussion

2.1. Study of the Lithiation Process

We have previously used SEM-protected pyrrolopyrimidine 1 in lithiation-iodination at C-6 [8], and knew that the directing properties of the SEM group was suitable. As a starting point, we treated 1 with LDA at −78 °C in THF, followed by quenching with benzaldehyde (2a) to give the product 3a, see Scheme 2. This resulted in an isolated yield of 68%. Higher consumption of the starting material was observed when the reaction mixture was allowed to reach room temperature, but with no increase in product formation. Instead, the by-products 4 and 6 were formed (Scheme 2), resulting from the nucleophilic attack by diisopropylamine at C-4. The use of lithium bis(trimethylsilyl)amide resulted in no conversion and appears too weak to deprotonate this scaffold, while n-BuLi produced a complex mixture with reaction also at C-4. To establish a foundation to improve the process, we first decided to evaluate the lithiation step in more detail. To monitor conversion of 1 to the lithiated intermediate IV, samples of the reaction mixture after lithiation were quenched in D₂O giving the C-6 deuterium analogue 5. The ratio between the D-6 and H-6 analogues could be estimated by ¹H NMR analysis. This ratio was used to estimate the degree of lithiation (% Li). Initially, the reproducibility of the measured conversion seemed low, and did not correspond with yields obtained in iodination. Challenges with this type of quench have previously been noted [13,14]. Seebach concluded that the lithiated intermediate likely forms an aggregate with diisopropylamine, which, due to its proximity, efficiently competes with added D₂O in the quench [14]. Tuning of the sample preparation by introducing a sonication step with D₂O gave an average conversion of 83 ± 2% (n = 5) in the lithiation process at −78 °C. The accuracy of this measurement is dependent on the quality of the integration by ¹H NMR spectroscopy.

A key question was the stability of the lithiated intermediate IV under operating conditions. It has been reported that deprotonations of this type can be reversible in nature, especially at non-cryogenic temperatures [15,16]. Therefore, we conducted experiments at three different temperatures (−78 °C, −40 °C and −10 °C) and monitored the degree of lithiation as a function of time (Figure 1). At −10 °C, the degree of lithiation was low, even after 1 h, and at both −10 °C and −40 °C the degree of lithiation decreased rapidly as a function of time, whereas this process was considerably slower at −78 °C. Additionally, elevated levels of the by-product 4 were noted at higher temperatures. To further improve upon the reaction, we evaluated the effects of LDA amount, solvent composition, and additives on the conversion to the lithiated intermediate IV. The reaction was quenched with D₂O after 1 h reaction time. The results of these experiments are displayed in

Table 1. Effect amount of LDA, toluene and additives on the lithiation process.

Entry	Solvent	Additive (Equiv.)	LDA Equiv	%Li 1
1	THF	-	1.1	64
2	THF	-	1.6	83 2
3	THF	-	2.0	85
4	Toluene	-	1.6	17
5	Toluene/THF 1:1	-	1.6	26
6	Toluene/THF 1:2	-	1.6	50
7	Toluene/THF 1:3	-	1.6	67
8	THF	LiCl (0.1)	1.6	89
9	THF	LiCl (0.5)	1.6	89
10	THF	LiCl (1.0)	1.6	81
11	THF	TMEDA (1.5)	1.6	84
12	THF	BDMAE 3 (1.5)	1.6	96 2

¹ Degree of conversion (% Li) after 1 h reaction time was measured by ¹H NMR following quench with D₂O for 1 h at 22 °C under sonification. ² Average of 5 experiments; ³ Bis[2-(N,N-dimethylamino)ethyl] ether (see structure above the table).

. Using 1.1 equivalents (equiv.) of LDA resulted in lower conversion (Table 1, entry 1) than seen when using the initial conditions 1.6 equiv. (entry 2). Employing 2 equiv. of LDA (entry 3) had a slight positive effect. To evaluate the effect of solvent polarity on the lithiation, reactions were also conducted in toluene and mixtures of toluene and THF. Lowering the polarity of the reaction medium had a detrimental effect on lithiation (entries 4–7), highlighting the need for a polar coordinating solvent. Lithium chloride is known to increase the speed of the lithiation step [15,17]. In our case, we noticed a marginal positive effect using 0.1 and 0.5 equiv. of added LiCl (entries 8–9), and no effect when using 1 equiv. (entry 10). However, LiCl is highly hygroscopic, and its use requires careful handling. Another group of additives used to improve directed metalation are chelating agents; although their role in lithiations can be quite complex [18], they are often claimed to prevent aggregation of LDA and the lithiated intermediates. The most commonly used chelator, N,N,N′,N′-tetramethylethylenediamine (TMEDA), had no clear effect on the lithiation (entry 11), while an obvious positive effect was seen when employing bis[2-(N,N-dimethylamino)ethyl] ether (BDMAE), where the degree of lithiation increased to an average of 96% (entry 12). BDMAE appears to be somewhat overlooked as an additive in lithiations, but it has previously been investigated in combination with LDA in dehydrobromination of a bromoalkene [19], in Grignard reactions [20], and in lithiation of N-tosyl indols [21].

With these initial positive results, we went on to evaluate the stability of the lithium complex at −78 °C as a function of time in the presence of BDMAE. Importantly, the stability was found to be higher than that seen in lithiation without the additive (see Figure 1). Furthermore, this naturally improved conversion in the addition step and, in a preparative experiment with benzaldehyde, increased the isolated yield from 68 to 93%.

2.2. Substrate Scope

With these promising results, we went on to evaluate the substrate scope of the lithiation-addition protocol using BDMAE as an additive, see Scheme 3. Different classes of aldehydes and ketones were included, having a difference in reactivity and acidity. The results from these reactions are displayed in

Table 2. Evaluation of the substrate scope in lithiation addition reaction using 16 different aldehydes and ketones. The reactions were run using ca 500 mg of 1 with BDMAE as an additive in THF at −78 °C.

Entry	R1	R2	%Li 1	Conv. (%) 2	Yield (%) 3	Comp.
1	H	Ph	95	97	93	3a
2	H	C6H4-p-OMe	95	98	83	3b
3	H	C6H4-o-F	95	96	78	3c
4	H	2-thienyl	96	99	70	3d
5	H	2-pyridyl	96	97	75	3e
6	H	C6H11	97	99	75	3f
7	CH3	C6H4-p-OMe	96	63	46	3g
8	CH3	C6H4-p-OBn	97	56	32	3h
9	CH3	Ph	97	77	61	3i
10	CH3	C6H4-p-CF3	95	71	46	3j
11	CH3	C6H4-p-NO2	94	77	49	3k
12	CF3	Ph	98	99	73	3l
13			97	96	91	3m
14			97	93	79	3n
15			94	87	72	3o
16			98	72	51	3p

¹ Degree of conversion (% Li) was estimated by ¹H NMR following a 1 h. quench with D₂O at 22 °C under sonification. ² Conversion measured by ¹H NMR of the crude reaction mixture prior to purification. ³ Isolated yield after purification by silica-gel chromatography.

.

After lithiation, the success of the process was monitored by ¹H NMR (Li %), and the efficiency of the addition step was checked by a ¹H NMR measurement of levels of 1 and product 3. The lithiation process proceeded well in all cases, with >94% measured lithiation. Careful development of isolation protocols for each derivative was not performed; thus, several of the compounds had to be purified twice. Surprisingly, the removal of the starting material was challenging in several cases. First, the lithiation-addition reactions with 6 aldehydes were tested (entries 1–6). The conversion in the addition step was excellent in all cases, and the reaction with the enolizable aldehyde 2f (entry 6) also proceeded well. Majewski reported that when benzaldehydes were treated with LDA, generated from n-BuLi and diisopropylamine, reduction to the corresponding benzyl alcohols occurred [22]. These by-products were not seen in our experiments. The acetophenones were a more challenging substrate class. The more electron-rich ketones (entries 7–8) with higher pKa [23], appeared to be more sluggish in the addition reaction than the other acetophenones (entries 9–11). One hypothesis that can explain the mediocre conversion in this series is that the acetophenones equilibrate with lithiated IV and are trapped as enolates. Aldol condensations could also be envisioned. The complete formation of the enolate of acetophenone by LDA deprotonation (THF, −78 °C) has previously been observed in trapping experiments with trimethylsilyl chloride by Silva et al. [24]. However, in self-condensation experiments between this enolate and acetophenone, only 11% of the aldol product was formed. We did not detect aldol condensation products in our experiments. Moreover, we also found no aldol products when p-methoxyacetophenone (2g) was deprotonated by LDA followed by quenching with 2g. Wu et al. [21] also observed mediocre conversion between 2-lithioindols and acetophenone and proposed that the lithium enolate of acetophenone was stabilized by the chelating agent, rendering it unreactive at low temperatures. Having no acidic protons and a highly electrophilic carbonyl carbon [25], 2,2,2-trifluoroacetophenone (2l) was a less complicated substrate. Full conversion was seen for this substrate (entry 12). Finally, we evaluated four cyclic ketones in the lithiation-addition protocol. Only minor differences in conversion were noted for the 6-membered ring ketones (entries 13–15); however, the protocol seems excellently suited for this substrate class overall. Surprisingly, the reaction with cyclopentanone only resulted in 72% conversion; ¹H NMR of the crude material, in addition to 3p, mostly contained 1 and cyclopentanone. There were no indications of aldol products being formed. The altered reactivity going from six- to five-membered rings might be due to internal strain differences as observed in other addition reactions [26,27].

The directed lithiation-addition protocol reported here is complementary to cross-coupling methodology, as sp²-sp³ C-C bonds are formed. In other cases, directed lithiation-addition can be an alternative to cross-coupling, which is most obvious for the cyclic ketones. For instance, the product 3m, obtained in 91% of yields, is a simple dehydration away from the Suzuki–Miyaura product 8, obtained in 83% of yields from 7, see Scheme 4. The dehydration can be affected under acidic conditions typically used to deprotect the SEM group, or by mesylation of the alcohol and treatment with a sterically-hindered base, as reported by Chaitanya et al.[28]). Since very few alkenyl boronic acids are commercially available, and at high prices, this addition protocol can be highly useful in these settings.

All of these transformations can be further tuned both in terms of details in the addition protocol and the purification method. As pointed out by Collum [18], the role of additives such as TMEDA is not necessarily as a lithium chelating agent. Thus, it can be that certain substates perform best with other additives. The use of BDMAE in combination with LDA seems excellently suited for the addition of lithiated pyrrolopyrimidines to aldehydes, trifluoroketones and cyclohexanone derivatives.

3. Materials and Methods

3.1. Chemicals and Analysis

All solvents and reagents used in the project were purchased from VWR and Merck. 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine was obtained from 1 Click Chem, while compound 7 was prepared as previously described [8]. Silica gel chromatography was performed using silica gel 60A, purchased from VWR with a pore size of 40–63 µm. Solvents were dried on a Braun MB SPS-800 Solvent Purification System (MBRAUN, Garching, Germany) and stored over molecular sieves (4 Å) for 24 h prior to use. ¹H- and ¹³C-NMR spectra were recorded using a Bruker Advance III HD NMR spectrometer (Bruker, Billerica, MA, US) with a Smartprobe 5 mm probe head, operating at 400 MHz or 600 MHz, and carbon spectra at 100 MHz or 150 MHz, respectively. Samples were mainly analyzed in DMSO-d₆ or chloroform-d where specified. ¹H and ¹³C NMR chemical shifts are in ppm relative to the DMSO solvent peak at 2.50 ppm and 39.5 ppm, respectively. The NMR spectra are included in the Supporting information file (See Supplementary Materials). High-resolution mass spectroscopy (HRMS) was performed using a WaterTM’s Synapt G2-S Q-TOF instrument (Waters, Milford, MA, USA). Samples were ionized by Electrospray Ionization (ESI/70eV) and analyzed using an Atmospheric Solids Analysis Probe (ASAP). Calculated exact mass and spectra processing was performed by WatersTM Software (Masslynx V4.1 SCN871).

3.2. Degree of Lithiation (Li %)

A sample (ca 0.1 mL) was removed from the reaction mixture with a dry glass Hamiltonian syringe. The sample was directly added to a vial containing D₂O (0.5 mL). The vial was capped and sonicated at 22 °C for 30 min. The vial was removed from the sonication bath and vigorously stirred for 1 min. The vial was left at 22 °C for an additional 30 min before being extracted with CH₂Cl₂ (1mL). The solvent was then removed under pressure, and the sample was added DMSO-d₆ (0.5 mL) for ¹H NMR analysis. Present lithiation (%Li) was estimated by employing the integrals of the H-6 and H-2 protons. The substitution of H-6 for deuterium does not result in a large enough shift difference at H-2 to differentiate the H-6 and D-6 analogs. However, the shift belonging to H-6 at 7.22, resulting from the residual non-lithiated substrate, can be used. The integral belonging to H-6 is compared to the signal arising from H-2, originating from both the H-6 and D-6 compounds. This allows for quick and easy estimation of % lithiation using the formula: Li % = 100 × [∫(H-2)–∫(H-6)]/∫(H-2). Here, ∫(H-2) is the total integral of the H-2 protons (both analogues), and ∫(H-6) is the integral of the doublet at 7.87 originating from the H-6 analogue.

3.3. Synthesis

3.3.1. General Procedure A: Directed Lithiation without Additives

Under an N₂ atmosphere 4-chloro-7-((2-(trimethylsilyl) ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 1.83 mmol) was dissolved in dry THF (4 mL) and cooled down to −78 °C. Then, LDA (2 M in THF/n-hexane/ethylbenzene, 1.47 mL, 2.93 mmol, 1.6 equiv) was added dropwise over 30 min by cannulation. This was followed by the dropwise addition of the ketone/aldehyde (2.19 mmol, 1.2 equiv.) dissolved in THF (2 mL). After another 60 min, the reaction mixture was quenched with saturated NH₄Cl solution (0.5 mL) and stirred until ambient temperature was reached. The mixture was concentrated and CH₂Cl₂ (25 mL) and water (30 mL) were added. After phase separation, the water phase was extracted with more CH₂Cl₂ (2 × 20 mL) and washed with brine (20 mL). The combined organic phase was dried over Na₂SO₄ and the solvent was removed under reduced pressure. The crude product was purified by silica gel flash chromatography, as specified.

3.3.2. General Procedure B: Directed Lithiation Using Bis(N,N′-dimethylaminoethyl) ether as Additive

Under an N₂ atmosphere 4-chloro-7-((2-(trimethylsilyl) ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 1.83 mmol) was dissolved in dry THF (4 mL) and cooled down to −78 °C. Bis(N,N’-dimethylaminoethyl) ether (2.75 mmol, 1.5 equiv) was added through the septum, followed by the addition of LDA (2 M in THF/n-hexane/ethylbenzene) (1.47 mL, 2.93 mmol, 1.6 equiv) dropwise over 30 min by cannulation. This was followed by the dropwise addition of the ketone/aldehyde (2.19 mmol, 1.2 equiv.) dissolved in THF (2 mL). After another 60 min, the reaction mixture was quenched with saturated NH₄Cl solution (0.5 mL) and stirred until the ambient temperature was reached. The mixture was concentrated and CH₂Cl₂ (25 mL) and water (30 mL) were added. After phase separation, the water phase was extracted with more CH₂Cl₂ (2 × 20 mL) and washed with brine (20 mL). The combined organic phase was dried over Na₂SO₄ and the solvent was removed under reduced pressure. The crude product was purified by silica gel flash chromatography, as specified.

3.3.3. 4-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1)

Dry DMF (50 mL) was cooled to 0 °C and added to NaH (60% dispersion in oil) (2.7 g, 80.4 mmol). Next, 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (10.2 g, 67.1 mmol) was dissolved in dry DMF (20 mL) and added portion-wise to the chilled suspension over 15 min. The reaction mixture was left stirring at 0 °C for 20 min. Then, SEM-Cl (14.2 mL, 80.4 mmol) was added. The mixture was left stirring for 1 h, while cooling, before quenching with sat. aq. NH₄Cl (2 mL). The mixture was transferred to a round-bottom flask and concentrated in a vacuum. The concentrated residue was partitioned between CH₂Cl₂ (40 mL) and water (50 mL). The layers were separated, and the water-phase was extracted with more CH₂Cl₂ (3 × 50 mL). The combined organic layers were washed with water (4 × 50 mL) and brine (50 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (n-pentane/EtOAc 10:1, R_f = 0.24) yielding 14.3 g (50.3 mmol, 76%) of a clear oil. ¹H NMR (400 MHz, DMSO-d₆) 8.68 (s, 1H), 7.87 (d, J = 3.6 Hz, 1H), 6.71 (d, J = 3.6 Hz, 1H), 5.65 (s, 2H), 3.52 (t, J = 8.0 Hz, 2H), 0.82 (t, J = 8.0 Hz, 2H), −0.10 (s, 9H). ¹³C NMR (100 MHz, DMSO-d₆) δ: 151.3, 150.8, 150.7, 131.5, 116.9, 99.3, 72.9, 65.8, 17.1, −1.5 (3C); IR (neat, cm⁻¹): 3120 (br,w), 3088 (w), 2950 (m), 2896 (w), 1587 (s), 1542 (s), 1348 (s), 1033 (s), 833 (s), 744 (s); HRMS (ES+, m/z): found 284.099, calcd. C₁₂H₁₉N₃OSiCl [M + H]⁺, 284.0986.

3.3.4. (4-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)(phenyl)methanol (3a)

Compound 1 (650 mg, 2.28 mmol) and benzaldehyde (0.291 mL, 2.74 mmol) were reacted as described in general procedure B. The reaction time was 1 h. Purification by silica gel chromatography (gradient from n-pentane/acetone/MeOH, 90:10:2 to 85:15:2, TLC: n-pentane/acetone/MeOH, 90:10:2, R_f = 0.21), produced 835 mg (2.14 mmol, 93%) of a thick, oil. ¹H NMR (600 MHz, DMSO-d₆) δ 8.66 (s, 1H), 7.43–7.34 (m, 5H), 6.39 (d, J = 5.5 Hz, 1H), 6.27 (d, J = 0.9 Hz, 1H), 6.05 (d, J = 5.5 Hz, 1H), for N-CH₂-O an AB-system: δ_A= 5.77, δ_B = 5.56, J_AB =11.0 Hz, 3.50–3.37 (m, 2H), 0.83–0.70 (m, 2H), −0.11 (s, 9H); ¹³C NMR (151 MHz, DMSO-d₆) δ 152.5, 150.7, 150.3, 146.4, 141.5, 128.3 (2C), 127.9, 126.9 (2C), 115.9, 98.1, 70.7, 67.6, 65.5, 17.0, −1.47 (3C). IR (neat, cm⁻¹): 3483 (br, w), 3057 (w), 2950 (m), 2896 (w), 1557 (s), 1455 (s), 1252 (s), 1163 (s), 834 (s), 763 (s); HRMS (ES+, m/z): found 390.1407, calcd for C₁₉H₂₅ClN₃O₂Si, [M + H]⁺, 390.1404.

3.3.5. (4-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)(4-methoxyphenyl)methanol (3b)

Compound 1 (456 mg, 1.61 mmol) and 4-methoxybenzaldehyde (0.231 mL, 1.92 mmol) were reacted as described in general procedure B. The reaction time was 1 h. Purification by silica gel chromatography (gradient from n-pentane/EtOAc, 9:1 to 8:2, TLC: n-pentane/EtOAc, 10:1, R_f = 0.42), produced 546 mg (1.34 mmol, 83%) of a clear oil. ¹H NMR (600 MHz, DMSO-d₆) δ 8.66 (s, 1H), 7.35–7.30 (m, 2H), 6.98–6.93 (m, 2H), 6.31 (s, 1H), 6.28 (d, J = 5.4 Hz, 1H), 5.99 (d, J = 5.3 Hz, 1H), for N-CH₂-O an AB-system: δ_A= 5.76, δ_B = 5.50, J_AB =10.8 Hz, 3.76 (s, 3H), 3.49–3.36 (m, 2H), 0.83–0.72 (m, 2H), -0.10 (s, 9H); ¹³C NMR (151 MHz, DMSO-d₆) δ 158.9, 152.6, 150.7, 150.2, 146.8, 133.5, 128.3 (2C), 115.9, 113.7 (2C), 97.9, 70.7, 67.3, 65.5, 55.1, 17.03, −1.46 (3C). IR (neat, cm⁻¹): 3308 (br, w), 2955 (m), 1587 (s), 1510 (s), 1352 (s), 1243 (s), 1078 (s), 917 (s), 815 (s); HRMS (ES+, m/z): found 420.1512, calcd for C₂₀H₂₇ClN₃O₃Si, [M + H]⁺, 420.1510.

3.3.6. (4-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)(2-fluorophenyl)methanol (3c)

Compound 1 (531 mg, 1.87 mmol) and 2-fluorobenzaldehyde (0.238 mL, 2.24 mmol) were reacted as described in general procedure B. The reaction time was 1 h. Purification by silica gel chromatography (n-pentane/acetone/MeOH, 90:10:2, R_f = 0.27) produced 588 mg (1.44 mmol, 78%) of a light red oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (s, 1H), 7.56 (td, J = 7.6, 1.9 Hz, 1H), 7.47–7.36 (m, 1H), 7.31–7.20 (m, 2H), 6.50 (d, J = 5.9 Hz, 1H), 6.35 (d, J = 5.9 Hz, 1H), 6.18 (d, J = 0.9 Hz, 1H), for N-CH₂-O an AB-system: δ_A= 5.79, δ_B = 5.65, J_AB =11.0 Hz, 3.51–3.34 (m, 2H), 0.89–0.62 (m, 2H). −0.16 (s, 9H); ¹³C NMR (101 MHz, DMSO-d₆) δ 159.4 (d, J_CF = 245 Hz), 152.6, 150.9, 150.4, 145.1, 130.1 (d, J_CF = 8.2 Hz), 128.6 (d, J_CF = 3.4 Hz), 128.4 (d, J_CF = 13.7 Hz), 124.6 (d, J_CF = 3.4 Hz), 115.8, 115.3 (d, J_CF = 21.6 Hz), 98.1, 70.8, 65.5, 61.1,17.0, −1.51 (3C); ¹⁹F NMR (565 MHz, DMSO-d₆, C₆F₆) d: −121.1; IR (neat, cm⁻¹): 3342 (br, w), 2951 (m), 1589 (s), 1455 (s), 1347 (s), 1246 (s), 1197 (s), 1077 (s), 831 (s), 748 (s); HRMS (ES+, m/z): found 408.1312, calcd for C₁₉H₂₄ClFN₃O₂Si, [M + H]⁺, 408.1310.

3.3.7. (4-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)(thiophen-2-yl)methanol (3d)

Compound 1 (491 mg, 1.73 mmol) and thiophene-2-carbaldehyde (0.193 mL, 2.07 mmol) were reacted as described in general procedure B. The reaction time was 1 h. Purification by silica gel chromatography twice (first: gradient from n-pentane/EtOAc, 90:10 to 85:15, TLC: n-pentane/EtOAc, 10:1, R_f = 0.40, then n-pentane/acetone/(MeOH 85:5:2, TLC: n-pentane/acetone/MeOH, 85:5:2, Rf = 0.36) produced 468 mg (1.18 mmol, 70%) of a yellow wax. ¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (s, 1H), 7.54 (dd, J = 5.0, 1.3 Hz, 1H), 7.08–6.99 (m, 2H), 6.73 (d, J = 5.5 Hz, 1H), 6.49 (d, J = 0.8 Hz, 1H), 6.32 (d, J = 5.5 Hz, 1H), for N-CH₂-O an AB-system: δ_A= 5.75, δ_B = 5.56, J_AB =11.0 Hz, 3.52–3.36 (m, 2H), 0.84–0.72 (m, 2H), −0.11 (s, 9H);¹³C NMR (101 MHz, DMSO-d₆) δ 152.5, 150.9, 150.5, 145.8, 145.6, 126.8, 126.0, 125.4, 115.9, 97.7, 70.7, 65.6, 63.62, 17.0, −1.47 (3C); IR (neat, cm⁻¹): 3427 (br, w), 2953 (m), 1587 (s), 1538 (s), 1348 (s), 1246 (s), 1064 (s), 830 (s), 695 (s); HRMS (ES+, m/z): found 396.0971, calcd for C₁₇H₂₃ClN₃O₂SSi, [M + H]⁺, 396.0968.

3.3.8. (4-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)(pyridin-2-yl)methanol (3e)

Compound 1 (463 mg, 1.63 mmol) and picolinaldehyde (0.187 mL, 1.95 mmol) were reacted as described in general procedure B. The reaction time was 1 h. Purification by silica gel chromatography twice (first gradient from n-pentane/EtOAc/MeOH, 86:13:1 to 82:17:1, TLC: n-pentane/EtOAc/MeOH, 82:17:1, R_f = 0.40, then n-pentane/acetone 95:5 to 90:10, TLC: n-pentane/acetone/, 85:5, Rf = 0.24), produced 476 mg (1.22 mmol, 75%) of a yellow oil. ¹H NMR (600 MHz, DMSO-d₆) δ 8.65 (s, 1H), 8.50 (dd, J = 4.9, 1.8, 1H), 7.87 (td, J = 7.7, 1.8 Hz, 1H), 7.66 (dd, J = 7.9, 1.2 Hz, 1H), 7.34 (dd, J = 7.6, 4.8 Hz, 1H), 6.62 (d, J = 5.6 Hz, 1H), 6.33 (d, J = 0.8 Hz, 1H), 6.12 (d, J = 5.6 Hz, 1H), 5.79 (s, 2H), 3.43 (t, J = 8.1 Hz, 2H), 0.85–0.72 (m, 2H), −0.10 (s, 9H);¹³C NMR (151 MHz, DMSO-d₆) δ 160.9, 152.4, 150.7, 150.3, 148.5, 145.8, 137.1, 123,0, 121.0, 116.0, 97.9, 70.8, 69.1, 65.5, 17.0, −1.47 (3C); IR (neat, cm⁻¹): 3361 (br, w), 2921(m), 1587 (m), 1073 (s), 832 (s); HRMS (ES+, m/z): found 391.1360, calcd for C₁₈H₂₄ClN₄O₂Si, [M + H]⁺, 391.1357.

3.3.9. (4-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)(cyclohexyl)methanol (3f)

Compound 1 (510 mg, 1.81 mmol) and cyclohexanecarbaldehyde (0.27 mL, 2.2 mmol) were reacted as described in general procedure B. The reaction time was 1 h. Purification by silica gel chromatography (gradient from n-pentane/EtOAc, 9:1 to 8:2, TLC: n-pentane/EtOAc, 7:1, R_f = 0.37), produced 537 mg (1.35 mmol, 75%) of a clear oil. ¹H NMR (600 MHz, DMSO-d₆) δ 8.64 (s, 1H), 6.57 (s, 1H), for N-CH₂-O an AB-system: δ_A= 5.75, δ_B = 5.71, J_AB =11.0 Hz, 5.54 (d, J = 5.5 Hz, 1H), 4.59 (dd, J = 7.6, 5.5 Hz, 1H), 3.50 (t, J = 8.1 Hz, 2H), 1.97–1.85 (m, 2H), 1.75–1.58 (m, 4H), 1.38–1.31 (m, 1H), 1.26–0.99 (m, 4H), 0.89–0.77 (m, 2H), −0.09 (s, 9H); ¹³C NMR (151 MHz, DMSO-d₆) δ 152.4, 150.2, 149.8, 146.4, 116.1, 97.4, 70.4, 70.20, 65.6, 42.1, 29.5, 28.2, 26.0, 25.5 (2C), 17.2, −1.5 (3C); IR (neat, cm⁻¹): 3344 (br, w), 2920 (s), 2950 (m), 2850 (w), 1587 (s), 1449 (s), 1351(s), 1248 (s), 1200 (s), 1075 (s), 833 (s), 741 (s); HRMS (ES+, m/z): found 396.1878, calcd for C₁₉H₃₁ClN₃O₂Si, [M + H]⁺, 396.1874.

3.3.10. 1-(4-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1-(4-methoxyphenyl)ethan-1-ol (3g)

Compound 1 (340 mg, 1.19 mmol) and 4-methoxyacetophenone (215 mg, 1.43 mmol) were reacted as described in general procedure B. The reaction time was 1 h. Purification by silica gel chromatography was performed twice (first gradient from n-pentane/acetone 95:5 to 90:10, then n-pentane/acetone/MeOH, 85:15:2, TLC: n-pentane/acetone, 15:1, R_f = 0.30), producing 241 mg (0.555 mmol, 46%) of a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.63 (s, 1H), 7.31–7.22 (m, 2H), 6.90–6.81 (m, 2H), 6.72 (s, 1H), 6.20 (s, 1H), 5.47 (s, 2H), 3.72 (s, 3H), 3.26–3.10 (m, 2H), 1.90 (s, 3H), 0.57–0.50 (m, 2H), −0.13 (s, 9H); ¹³C NMR (101 MHz, DMSO-d₆) δ 158.1, 153.1, 150.7, 150.2, 148.8, 138.1, 126.2 (2C), 115.8, 113.3 (2C), 97.7, 71.9, 71.4, 65.2, 54.9, 31.8, 17.2, −1.54 (3C); IR (neat, cm⁻¹): 3337 (br, w), 2947 (m), 1675 (m), 1588 (s),1511 (s), 1352 (s),1244 (s), 1081 (s), 833 (s); HRMS (ES+, m/z): found 434.1671, calcd for C₂₁H₂₉ClN₃O₃Si, [M + H]⁺, 434.1666.

3.3.11. 1-(4-(Benzyloxy)phenyl)-1-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)ethan-1-ol (3h)

Compound 1 (313 mg, 1.10 mmol) and 1-(4-(benzyloxy)phenyl)ethan-1-one (298 mg, 1.32 mmol) were reacted as described in general procedure B. The reaction time was 1 h. Purification by silica gel chromatography was performed twice (first gradient from n-pentane/acetone 95:5 to 90:10, then n-pentane/acetone/MeOH, 90:10:2, (TLC: 90:10:2, R_f = 0.40) produced 181 mg (0.36 mmol, 32%) of a white wax. ¹H NMR (400 MHz, DMSO-d₆) δ 8.63 (s, 1H), 7.44–7.34 (m, 5H), 7.29–7.24 (m, 2H), 6.98–6.91 (m, 2H), 6.72 (s, 1H), 6.21 (s, 1H), 5.48 (s, 2H), 5.05 (s, 2H), 3.27–3.12 (m, 2H), 1.90 (s, 3H), 0.59–0.52 (m, 2H), −0.13 (s, 9H). ¹³C NMR (101 MHz, DMSO d₆) δ 157.3, 153.1, 150.8, 150.3, 148.8, 138.4, 137.1, 128.4 (2C), 127.80, 127.6 (2C), 126.3 (2C), 115.8, 114.2 (2C), 97.7, 71.9, 71.4, 69.2, 65.2, 31.8, 17.2, −1.50 (3C); IR (neat, cm⁻¹): 3419 (br, w), 2952 (m), 2902 (m), 1674 (s), 1588 (s), 1506 (s), 1245 (s), 1169 (s), 827 (s), 748 (s), 707 (s); HRMS (ES+, m/z): found 510.1981, calcd for C₂₇H₃₃ClN₃O₃Si, [M + H]⁺, 510.1979.

3.3.12. 1-(4-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1-phenylethan-1-ol (3i)

Compound 1 (520 mg, 1.83 mmol) and acetophenone (0.256 mL, 2.19 mmol) were reacted as described in general procedure B. The reaction time was 1 h. Purification by silica gel chromatography (n-pentane/acetone, 10:1, R_f = 0.32) produced 455 mg (1.17 mmol, 61%) of a pale, thick oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.64 (s, 1H), 7.41–7.31 (m, 2H), 7.32–7.26 (m, 2H), 7.26–7.18 (m, 1H), 6.77 (s, 1H), 6.29 (s, 1H), for N-CH₂-O an AB-system: δ_A= 5.49, δ_B = 5.44, J_AB =11.0 Hz, 3.22–3.07 (m, 2H), 1.92 (s, 3H), 0.57–0.46 (m, 2H), −0.12 (s, 9H); ¹³C NMR (101 MHz, DMSO-d₆) δ 153.1, 150.8, 150.3, 148.5, 146.17, 128.0 (2C), 126.8, 124.9 (2C), 115.8, 97.9, 72.2, 71.4, 65.1, 31.9, 17.1, −1.48 (3C); IR (neat, cm⁻¹): 3413 (br, w), 2951 (m), 2885 (m), 1587 (s), 1347 (s), 1248 (s), 1248 (s), 1068(s), 833 (s), 741 (s), 696 (s); HRMS (ES+, m/z): found 404.1568, calcd for C₂₀H₂₇ClN₃O₂Si, [M + H]⁺, 404.1561.

3.3.13. 1-(4-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1-(4-(trifluoromethyl)phenyl)ethan-1-ol (3j)

Compound 1 (510 mg, 1.70 mmol) and 1-(4-(trifluoromethyl)phenyl)ethan-1-one (402 mg, 2.14 mmol) were reacted as described in general procedure B. The reaction time was 1 h. Purification by silica gel chromatography twice (first: gradient n-pentane/acetone, 95:5 to 90:10, then n-pentane/acetone/CH₂Cl₂, 85:15:2, TLC: n-pentane/acetone, 20:1, R_f = 0.28), produced 391 mg (0.83 mmol, 46%) of a clear oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.65 (s, 1H), 7.64 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 6.92 (s, 1H), 6.59 (s, 1H), 5.58 (d, J = 9.9 Hz, 1H), 5.52 (d, J = 9.9 Hz, 1H), 3.07–2.92 (m, 2H), 1.94 (s, 3H), 0.35–0.18 (m, 2H), −1.70 (9H); ¹³C NMR (101 MHz, DMSO-d₆) δ 153.1, 151.0 (2C), 150.5, 147.4, 127.3 (q, J_CF = 32 Hz), 125.7 (2C), 125.3 (q, J_CF = 190 Hz), 124.9 (q, J_CF = 3.8 Hz, 2C), 115.7, 98.3, 72.2, 71.3, 64.7, 32.0, 16.8, −1.7 (3C); ¹⁹F NMR (565 MHz, DMSO-d₆, C₆F₆) d: −63.0; IR (neat, cm⁻¹): 3357 (br, w), 2953 (m), 1590 (m), 1322 (s), 1159 (s), 1120 (s), 1092 (s), 832 (s); HRMS (ES+, m/z): found 472.1437, calcd for C₂₁H₂₆ClF₃N₃O₂Si, [M + H]⁺, 472.1434.

3.3.14. 1-(4-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1-(4-nitrophenyl)ethan-1-ol (3k)

Compound 1 (490 mg, 1.72 mmol) and 4-nitroacetophenone (340 mg, 2.06 mmol) were reacted as described in general procedure B. The reaction time was 1 h. Purification by silica-gel chromatography (gradient n-pentane/acetone, 95:5 to 90:10, TLC: n-pentane/acetone, 10:1, R_f = 0.31), produced 373 mg (0.83 mmol, 49%) of a white wax. ¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (s, 1H), 8.18–8.14 (m, 2H), 7.67–7.59 (m, 2H), 6.95 (s, 1H), 6.72 (s, 1H), for N-CH₂-O an AB-system: δ_A= 5.55, δ_B = 5.52, J_AB =10.0 Hz, 3.00 (dd, J = 9.2, 7.5 Hz, 2H), 1.96 (s, 3H), 0.25 (td, J = 7.8, 1.7 Hz, 2H), −0.20 (s, 9H); ¹³C NMR (101 MHz, DMSO-d₆) δ 154.0, 153.1, 151.1, 150.7, 146.9, 146.3, 126.4 (2C), 123.2 (2C), 115.7, 98.5, 72.2, 71.2, 64.72, 31.8, 16.9, −1.7 (3C); IR (neat, cm⁻¹): 3312 (br, w), 2951 (m), 1518 (s), 1344 (s), 1075 (s), 836 (s), 1696 (s); HRMS (ES+, m/z): found 449.1412, calcd for C₂₀H₂₆ClN₄O₄Si, [M + H]⁺, 449.1411.

3.3.15. 1-(4-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2,2,2-trifluoro-1-phenylethan-1-ol (3l)

Compound 1 (341 mg, 1.20 mmol) and 2,2,2-trifluoro-1-phenylethan-1-one (0.132 mL, 1.44 mmol) were reacted as described in general procedure B. The reaction time was 1 h. Purification by silica gel chromatography (gradient n-pentane/EtOAc, 10:1 to 5:1, TLC: n-pentane/EtOAc, 10:1, R_f = 0.31) produced 381 mg (0.87 mmol, 73%) of a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.74 (s, 1H), 8.08 (s, 1H), 7.46–7.33 (m, 5H), 6.90–6.85 (m, 1H), 5.48–5.37 (m, 2H), 3.06–2.89 (m, 2H), 0.39–0.37 (m, 2H), −0.15 (s, 9H); ¹³C NMR (101 MHz, DMSO-d₆) δ 152.8, 151.8, 151.4, 138.2, 135.8, 128.9, 128.1 (2C), 127.7 (q, J_CF = 280 Hz), 127.1 (2C), 115.4, 99.8, 75.9 (q, J_CF= 29 Hz), 71.5, 65.1, 16.9, −1.52 (3C); ¹⁹F NMR (565 MHz, DMSO-d₆, C₆F₆) d: −77.6; IR (neat, cm⁻¹): 3484 (br, w), 3057 (w), 1557 (m), 1359 (m), 1163 (s), 1069 (s), 1252 (s), 994 (s), 864 (s); HRMS (ES+, m/z): found 458.1287, calcd for C₂₀H₂₄ClF₃N₃O₂Si, [M + H]⁺, 458.1278.

3.3.16. 1-(4-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)cyclohexan-1-ol (3m)

Compound 1 (346 mg, 1.21 mmol) and cyclohexanone (0.151 mL, 1.46 mmol) were reacted as described in general procedure B. The reaction time was 1 h. Purification by silica gel chromatography (n-pentane/EtOAc, 10:1, R_f = 0.44) produced 423 mg (1.11 mmol, 91%) of white wax. ¹H NMR (600 MHz, DMSO-d₆) δ: 8.64 (s, 1H), 6.54 (s, 1H), 5.99 (s, 2H), 5.28 (s, 1H), 3.64 (t, J = 8.0 Hz, 2H), 2.11–2.17 (m, 2H), 1.79–1.86 (m, 2H), 1.70–1.79 (m, 2H), 1.59–1.64 (m, 1H), 1.48–1.54 (m, 2H), 1.22–1.31 (m, 1H), 0.83 (t, J = 8.0 Hz, 2H), −0.09 (s, 9H); ¹³C NMR (150 MHz, DMSO-d₆) δ: 153.2, 150.7, 150.5, 150.0, 115.8, 96.1, 71.6, 69.5, 66.1, 36.9 (2C), 25.1, 21.3 (2C), 17.4, −1.5 (3C); IR (neat, cm⁻¹): 3364 (br, w), 3152 (w), 2938 (m), 2847 (w), 1586 (m), 1547 (m); HRMS (ES+, m/z): found 382.1721 calcd for C₁₈H₂₉N₃O₂SiCl, [M + H]⁺, 382.1718.

3.3.17. 1-(4-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-4-methylcyclohexan-1-ol (3n)

Compound 1 (546 mg, 1.92 mmol) and 4-methylcyclohexan-1-one (0.283 mL, 2.31 mmol) were reacted as described in general procedure B. The reaction time was 1 h. Purification by silica gel chromatography (n-pentane/EtOAc, 7:1, R_f = 0.63) produced 594 mg (1.50 mmol, 79%) of a slightly yellow wax. ¹H NMR (400 MHz, DMSO-d₆) δ 8.66 (s, 1H), 6.62 (s, 1H), 5.94 (s, 2H), 5.40 (s, 1H), 3.71–3.59 (m, 2H), 2.47–2.33 (m, 2H), 1.82–1.74 (m, 4H), 1.64–1.60 (1, 2H), 1.18–1.05 (m, 2H), 0.89 (d, J = 6.7 Hz, 3H), 0.85–0.81 (m, 2H), −0.08 (s, 9H); ¹³C NMR (101 MHz, DMSO-d₆) δ 153.2, 150.6, 150.0, 148.3, 115.7, 98.0, 71.4, 70.0, 66.1, 36.0 (2C), 30.5 (2C), 29.8, 20.3, 17.41, −1.44 (3C); IR (neat, cm⁻¹): 3444 (br, w), 2946 (m), 1715 (m), 1245 (m), 1092 (s), 831 (s), 747 (s); HRMS (ES+, m/z): found 396.1881, calcd for C₁₉H₃₁ClN₃O₂Si, [M + H]⁺, 396.1874.

3.3.18. 4-(4-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)tetrahydro-2H-pyran-4-ol (3o)

Compound 1 (542 mg, 1.91 mmol) and tetrahydro-4H-pyran-4-one (0.283 mL, 2.29 mmol) were reacted as described in general procedure B. The reaction time was 1 h. Purification by silica gel chromatography (n-pentane/EtOAc, 2:1, R_f = 0.40) yielding 524 mg (1.37 mmol, 72%) of a clear yellow oil.¹H NMR (600 MHz, DMSO-d₆) δ 8.67 (s, 1H), 6.61 (s, 1H), 5.99 (s, 2H), 5.63 (s, 1H), 3.84–3.77 (m, 2H), 3.75–3.68 (m, 2H), 3.65–3.58 (m, 2H), 2.12–2.05 (m, 4H), 0.86–0.81 (m, 2H), -0.09 (s, 9H); ¹³C NMR (151 MHz, DMSO-d₆) δ 153.3, 150.7, 150.3, 149.3, 115.7, 96.5, 71.4, 67.2, 66.0, 62.5 (2C), 37.2 (2C), 17.4, −1.5 (3C); ¹³C NMR (151 MHz, DMSO) δ 153.3, 150.7, 150.3, 149.3, 115.7, 96.5, 71.4, 67.2, 66.0, 62.5 (2C), 37.2 (2C), 17.4, −1.47 (3C); IR (neat, cm⁻¹): 3482 (br, w), 3380 (m), 3057 (m), 1558 (m), 1360 (s), 1162 (s), 1069 (s), 967(s), 835 (s); HRMS (ES+, m/z): found 384.1514, calcd for C₁₇H₂₇ClN₃O₃Si, [M + H]+, 384.1510.

3.3.19. 1-(4-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)cyclopentan-1-ol (3p)

Compound 1 (463 mg, 1.63 mmol) and cyclopentanone (0.174 mL, 1.95 mmol) were reacted as described in general procedure B. The reaction time was 1 h. Purification by silica gel chromatography (n-pentane/EtOAc, 7:1, R_f = 0.51) produced 301 mg (0.81 mmol, 51%) of a clear oil. ¹H NMR (600 MHz, DMSO-d₆) δ 8.65 (s, 1H), 6.58 (s, 1H), 5.91 (s, 2H), 5.35 (s, 1H), 3.64–3.58 (m, 2H), 2.11–2.04 (m, J = 5.6, 3.2 Hz, 5H), 1.90–1.80 (m, 1H), 1.75–1.65 (m, 2H), 0.87–0.79 (m, 2H), −0.09 (s, 9H); ¹³C NMR (151 MHz, DMSO-d₆) δ 153.3, 150.5, 150.1, 148.7, 115.8, 95.9, 78.0, 71.3, 65.9, 40.1 (2C), 23.00 (2C), 17.4, −1.46 (3C); IR (neat, cm⁻¹): 3431 (br, w), 2955 (m), 1587 (m), 1549 (w), 1354 (m), 1063 (s), 830 (s), 771 (s); HRMS (ES+, m/z): found 368.1566, calcd for C₁₇H₂₇ClN₃O₂Si, [M + H]⁺, 368.1561.

3.3.20. N,N-Diisopropyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (4)

Compound 4 was isolated after a reaction of 1 using general procedure A, allowing the temperature to react after the addition of LDA, followed by 15 h of reaction time. Purification by silica gel column chromatography (n-pentane/EtOAc, 7:1, R_f = 0.41) produced 152 mg (0.436 mmol, 25%) of compound 4. ¹H NMR (600 MHz, DMSO-d₆) δ: 8.21 (s, 1H), 6.62 (d, J = 3.4 Hz, 1H), 6.19 (d, J = 3.4 Hz, 1H), 5.15 (s, 2H), 4.56 (hept, J = 6.7 Hz, 1H), 3.73 (hept, J = 6.7 Hz, 1H), 3.49–3.41 (m, 2H), 1.24–1.21 (m, 12H), 0.84–0.78 (m, 2H), −0.07 (s, 9H); ¹³C NMR (101 MHz, DMSO-d₆) δ 152.1, 150.5, 119.1, 117.4, 108.6, 74.0, 72.9, 65.2, 46.6, 45.6, 23.4 (2C), 19.4 (2C), 17.2, −1.5 (3C). HRMS (ES+, m/z): found 349.2426, calcd for C₁₈H₃₃N₄OSi, [M + H]+, 349.2423.

3.3.21. 4-Chloro-6-deutero-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (5)

Under an N₂ atmosphere 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (64 mg, 0.226 mmol) was dissolved in dry THF (2 mL) and cooled down to −78 °C. Bis(N,N’-dimethylaminoethyl) ether (0.064 mL 0.338 mmol, 1.5 equiv) was added through the septum, followed by the addition of LDA (2 M in THF/n-hexane/ethylbenzene) (0.180 mL, 0.36 mmol, 1.6 equiv) dropwise over 30 min by cannulation. This was followed by the dropwise addition of deuterium oxide (1.2 mL) and THF (1 mL). The reaction mixture was allowed to warm to room temperature and stirred for 30 min before being sonicated for an additional 30 min at room temperature. The reaction mixture was quenched with saturated NH₄Cl solution (0.5 mL). Before being concentrated and added CH₂Cl₂ (25 mL) and water (30 mL). After the phase separation, the water phase was extracted with more CH₂Cl₂ (2 × 20 mL) and washed with brine (20 mL). The combined organic phase was dried over Na₂SO_4, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (n-pentane/EtOAc, 10:1, R_f = 0.24) yielding 54 mg (0.189 mmol, 84%) of a clear oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (s, 1H), 6.71 (s, 1H), 5.65 (s, 2H), 3.54–3.51 (m, 2H), 0.86–0.83 (m,2H), −0.10 (s, 9H); ¹³C NMR (100 MHz, DMSO-d6) δ 151.3, 150.8, 150.7, 131.3 (t, J = 30.0 Hz), 116.9, 99.2, 72.9, 65.8, 59 17.1, −1.5 (3C); HRMS (ES+, m/z): found 285.1049, calcd. C₁₂H₁₈DClN₃OSi [M + H]₊, 285.1047.

3.3.22. (4-(Diisopropylamino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)(phenyl)methanol (6)

Compound 6 was isolated after the reaction of 1, using general procedure A and allowing the temperature to react after the addition of LDA, followed by 15 h of reaction time. Purification by silica gel column chromatography (n-pentane/EtOAc, 7:1, R_f = 0.21) produced 74 mg (0.163 mmol, 9%), ¹H NMR (400 MHz, DMSO–d₆) δ 8.18 (s, 1H), 7.37–7.25 (m, 5H), 5.78 (d, J = 5.4 Hz, 1H), 5.71 (d, J = 5.4 Hz, 1H), 5.55 (s, 1H), for N-CH₂-O an AB-system: δ_A= 5.40, δ_B = 5.22, J_AB =10.6 Hz, 4.56 (hept, J = 6.7 Hz, 1H), 3.73 (hept, J = 6.7 Hz, 1H), 3.47–3.43 (m, 2H), 1.31–1.25 (m, 12H), 0.85–0.76 (m, 2H), −0.05 (s, 9H); ¹³C NMR (151 MHz, DMSO–d₆) δ 152.2, 151.6, 142.7, 132.2, 127.9 (2C), 127.2, 126.6 (2C), 119.0, 107.9, 72.8, 70.4, 67.1, 65.1, 46.8, 45.8, 23.4 (2C), 19.4 (2C), 17.3, −1.4 (3C); HRMS (ES+, m/z): found 455.2838, calcd for C₂₅H₃₉N₄O2Si, [M + H]+, 455.28.

3.3.23. 4-Chloro-6-(cyclohex-1-en-1-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (8)

4-Chloro-6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (569 mg, 1.38 mmol), cyclohex-1-en-1-ylboronic acid (238 mg, 1.89 mmol), K₂CO₃ (574 mg, 4.16 mmol) and Pd(dppf)Cl₂ (51.2 mg, 69.7 μmol) were added to a Schlenk tube in an N₂ atmosphere. Degassed H₂O (5 mL) and 1,4-dioxane (10 mL) were added, and the reaction was stirred at 80 °C for 60 min. The vessel was then cooled to room temperature before the addition of H₂O (20 mL) and CH₂Cl₂ (20 mL). After phase separation, the aqueous phase was extracted with more CH₂Cl₂ (3 × 20 mL) and the combined organic layers were washed with brine (20 mL) before being dried over Na₂SO₄, filtered and concentrated in vacuo. Purification by silica gel chromatography (n-pentane/EtOAc, 10:1, R_f = 0.32) produced 419 mg (1.15 mmol, 83%) of a clear oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.64 (s, 1H), 6.61 (s, 1H), 6.43 (td, J = 3.9, 1.9 Hz, 1H), 5.60 (s, 2H), 3.63–3.61 (m, 2H), 2.44–2.36 (m, 2H), 2.28–2.19 (m, 2H), 1.79–1.69 (m, 2H), 1.73–1.59 (m, 2H), 0.90–0.80 (m, 2H), −0.09 (s, 9H); ¹³C NMR (101 MHz, DMSO-d₆) δ 152.9, 150.4, 149.8, 144.9, 131.8, 127.5, 116.6, 96.9, 71.2, 66.1, 27.9, 25.2, 22.2, 21.2, 17.2, −1.5 (3C); HRMS (ES+, m/z): found 364.1612, calcd for C₁₈H₂₇ClN₃OSi, [M + H]+, 364.1611.

4. Conclusions

A route to new pyrrolopyrimidine building blocks using lithiation-addition reactions has been investigated. The lithiation was directed to the C-6 position by installing a 2-trimethylsilyl)ethoxymethyl group at N-7 of the pyrrolpyrimidine. Key to improving the process was a robust analysis of the lithiation step, in which ultrasonic treatment during D₂O quench, followed by ¹H NMR analysis, proved useful. A study of the lithiation process showed that increased lithiation could be achieved by including BDMAE as an additive, while LiCl had only minor effects. The role of BDMAE in the reaction is not clear, however, its presence improved conversion, storage stability and yield in the following reaction with benzaldehyde. A substrate scope study revealed that the protocol was excellently suited for lithiation-addition to aldehydes, trifluoroketones, and cyclohexanone derivatives, while more mediocre conversions and yields were obtained for acetophenones and cyclopentanone. The lithiation-addition approach for pyrrolopyrimidines complements and is also, in certain cases, an alternative to cross-coupling methodology.