Phenyloxycarbonyl (Phoc) Carbamate: Chemioselective Reactivity and Tetra-n-butylammonium Fluoride Deprotection Study

Abstract

We present the results of the chemoselective reactivity of phenylcarbamates. Phenylcarbamates of primary amines are reactive to form urea, and phenylcarbamates of secondary amines can be used as tags due to the existence of rotamers. Moreover, deprotection attempts to to recover the primary amines in use of a catalytic amount of TBAF show the possibility of obtaining the symmetrical urea from the corresponding phenylcarbamate. We have begun the study of the transformation of Phoc carbamates into the corresponding free amines by TBAF. We present here our most significant results concerning the sensitivity of this reaction in terms of the solvent and substrate.

Introduction

Carbamates¹ and phenylcarbamates are widely described in the literature, primarily para-nitrophenyl carbamates. Although they have a strong group leaving group, phenylcarbamates are very stable over time and thus, they allow the preparation of synthon on a large scale. The use of phenyloxycarbonyl (Phoc) as an amine protecting group for peptide synthesis has been studied, but Phoc was rapidly displaced by Boc and Fmoc because of intramolecular cyclization reactions in peptides.² A revival of phenyloxycarbamates occurred for the preparation of oxazolidinone, urea, and polyurea³ and more recently for the synthesis of the peptide bond via amide formation without a coupling agent.⁴ In our group, we work on peptides and/or peptidomimetics to inhibit protein–protein interactions, and this approach would be very useful in synthesis.

The use of urea in the synthesis of biologically active compounds⁵ or for the preparation of organic materials is experiencing a revival.⁶ In therapy, the urea motif is likened to an amide and it can be used as an amide bioisostere or in the case of peptide cyclization. An important development is in the formation of cyclic peptides⁷ and polyurea as a peptidomimetic,⁸ where structuring of these polyureas is perfectly defined.⁹

The para-nitrophenyloxycarbonyl group is more reactive than the simple phenyloxycarbonyl group, and the yellow color of the para-nitrophenol makes it possible to gauge the transformation of the para-nitrophenyloxycarbonyl group. However, phenylcarbamates have the advantage of being stable in an organic acid medium and in an aqueous medium (except in the presence of hydroxide ions),^10,11 allowing isolation and purification by flash chromatography. As part of our work on the synthesis of bioactive molecules containing the urea motif¹² and the special reactivity of these ureas,¹³ we scope the limitation of the Phoc strategy for preparation of valuable synthons.¹⁴

Results and Discussion

To facilitate the understanding of the nomenclature of urea formation, we have systematically assigned the name 3xy (Scheme 1). Phoc carbamate 2x from amine 1x is coupled to amine 1y to form the asymmetric 3xy urea. Due to the symmetry of the urea moiety, compound 3xy is identical to compound 3yx. The symmetrical ureas are thus systematically noted 3xx.

Scheme 1. Retrosynthesis and Nomenclature of Ureas 3.

In order to easily follow the reaction by UV spectroscopy, we used the Phoc of carbamate para-methoxy-benzylamine 2a. We chose to study this reaction in chloroform in the presence of triethylamine as a base. In the absence of triethylamine or refluxing chloroform, no urea is formed. The nucleophilicity of the amine is essential, and aniline 1d does not lead to the desired urea (Table 1, entry 4), but no degradation of carbamate 2a was observed. Non-reactivity of aromatic primary amines in our conditions is confirmed by the chemoselective reactivity of 4-aminobenzylamine: only the addition of the aliphatic primary amine on carbamate 2a is effective to afford urea 3ag; thereby, we can use aromatic amines without protection. Amino acids, as free acids or ester derivatives, react very well (Table 1, entries 8–10), and no trace of hydantoin was detected.

Table 1. Substituent Effect for Phoc Coupling with Amine for the Synthesis of Urea.

entry	R1R2NH 1a–j	R1	R2	urea	yield
1	PMB–NH21a	PMB	H	3aa	89%
2	n-pentyl–NH21b	n-pentyl	H	3ab	88%
3	tBu–NH21c	tBu	H	3ac	85%
4	Ph–NH21d	Ph	H		no reactiona
5	Bn–NH21e	Bn	H	3ae	90%
6	Bn(Et)NH 1f	Bn	Et	3af	84%
7	4-NH2–Bn–NH21g	4-NH2–Bn	H	3ag	65%
8	EtO2C–CH2CH2–NH21h	CH2CH2CO2Et	H	3ah	80%
9	tBuO2C–CH2–NH21i	CH2CO2tBu	H	3ai	85%
10	HO2C–CH2–NH21j	CH2CO2H	H	3aj	72%

^a2a was fully recovered.

Obtaining urea 3af by creating the C–N bond starting from carbamate 2f is not possible (Figure 1), even under conditions in high concentration of a base and at a higher temperature. Carbamate 2f is integrally recovered, demonstrating the stability of N,N-disubstitued phenylcarbamates under hard conditions.

Figure 1.

Urea 3af synthetic strategy from Phoc carbamate.

This chemoselective reactivity of Phoc carbamate was studied from N-ethyl-1,2-diamine (Scheme 2). Protecting both amine functions is performed in the classic conditions of the laboratory to yield bis(carbamate) 2k. Selective transformation of the NH-Phoc moiety is observed: only dissymmetric urea 3ke is formed in our reaction conditions after mixing bis(carbamate) 2k and excess of benzylamine 1e.

Scheme 2. Chemioselective Reactivity of Bis-Phoc Carbamate 1k.

An important point is the existence of rotamers for carbamates derived from secondary amines. ¹H and ¹³C NMR spectra made at different temperatures show coalescence of the signal (Figure 2). Conformers can track reactivity or stability of the phenylcarbamate from secondary amines by simple NMR analysis. For example, ¹H NMR spectra of 2k and 3ke (see the Supporting Information) indicate the existence of rotamers, confirming the presence of a Phoc derived from a secondary amine.

Figure 2.

Rotamers of 2k by ¹H NMR coalescence experimentation (CDCl₃).

The phenylcarbamate is very stable in an acidic aqueous medium and relatively stable in a dilute basic aqueous medium, so we can perform aqueous work-up using a saturated solution of NaHCO₃ or KOH (1 M). We use this Phoc group very widely in our research. However, the deprotection is carried out in a strong basic medium by the use of hydroxide anions (or a strong basic resin), so this deprotection is not compatible with a large number of chemical functions. We also investigated the reactivity of Phoc at room temperature using TBAF. We were intrigued by the results of Jacquemard concerning the deprotection of the Phoc group with TBAF.¹⁵

The mechanism of the basic hydrolysis of Phoc carbamates differs according to the number of substituents on the nitrogen atom. In particular, Phoc carbamates from primary amines react via an E1cb-type mechanism by in situ formation of an isocyanate intermediate.¹⁶ For the N,N-disubstituted carbamate phenyl esters (i.e., RR′N-Phoc), the reaction conditions are more drastic via a B_Ac2 mechanism.¹¹ In our research work, we were surprised to obtain mainly symmetrical urea 3kk (Scheme 3) and not the free amine under the reaction conditions of ref (15). Once again, only the Phoc group of the primary amine is involved in the reaction, which suggests the need for a labile hydrogen on the nitrogen atom for the Phoc group to react.

Scheme 3. Unexpected Synthesis of Symmetric Urea 3kk Mediated by TBAF.

Therefore, we have begun the study of the reactivity of Phoc carbamates with TBAF. Using carbamate 2a as a reference, we looked for the effect of the solvent (Table 2). In THF, an almost equimolar mixture of amine 1a and urea 3aa is rapidly obtained (entry 1, Table 2). Theoretically, if only amine 1a and urea 3aa could be formed by consumption of Phoc carbamate 2a, the maximum ratio should be 1a:3aa close to 33:67, which is what we get. The reaction is much slower in chloroform with an exclusive formation of urea 3aa after 72 h. The use of the more polar solvent MeCN leads to the exclusive and fast formation of urea 3aa. In DMSO (entry 4, Table 2), we note the formation of urea 3aa without amine 1a, but other signs indicate the presence of undetermined structures. Although NMR monitoring shows a modification of the chemical shifts of compound 2a (see the Supporting Information), the reaction carried out in methanol leads to no reaction and contains only reagent 2a.

Table 2. Solvent Effect on Phoc 2a Deprotection Mediated by TBAF.

no	solvent	ratio 2a:1a:3aaa (30 mn)
1	THF	0:42:58
2	CHCl3	86:0:14b
3	MeCN	0:0:100
4	DMSO	0:0:100c
5	MeOH	no reaction

^a1H NMR in the crude mixture.

^bComplete formation of 3aa in 72 h.

^cComplex mixture of polyurea.

Using THF as the reference solvent, we investigated the effect of the TBAF amount on the amine/urea ratio (Table 3). It should be noted that the reaction is effective with less than 1 equiv (relative to Phoc carbamate 2a). However, lowering the amount of TBAF promotes the formation of urea 3aa, which is consistent with the formation reaction of urea 3kk (Scheme 3). Unfortunately, an increase in the amount of TBAF does not make it possible to increase the proportion of amine 1a but makes the reaction medium complex, likely by the formation of novel polyurea molecules.

Table 3. TBAF Equivalent Effect on Phoc 2a Deprotection^a.

no	TBAF (equiv)	time	ratio 1a:3aab
1	0.3	20 h	0:100c
2	0.6	2 h	17:83
3	1.2	30 min	42:58
4	2.4	10 min	19:81d
5	5.0	5 min	n.d.e

^aReaction performed in THF.

^b1H NMR in the crude mixture.

^c88% yield of purified 3aa.

^d1a and 3aa are minor products.

^eComplex mixture of 3aa and polyurea (see the Supporting Information).

By fixing the optimum amount of TBAF for obtaining the amine from Phoc 2a, we studied the effect of the N-substituted phenylcarbamate with aliphatic, aromatic, and hindered groups (Table 4). The Phoc compounds and symmetric ureas are prepared according to the usual laboratory method (Scheme 3); 3dd urea was purchased.

Table 4. Substituent Effect on Phoc Deprotection Mediated by TBAF.

entry	Phoc carbamate	R	ratio amine/ureaa
1	2a	PMB	1a:3aa 42:58
2	2b	n-pentyl	1b:3bb 0:100b
3	2c	tBu	1c:3cc 94:4
4	2d	Ph	1d:3dd 100:0

^a1H NMR in the crude mixture.

^b89% yield of purified 3bb.

From carbamate 2d, only aniline 1d is formed. Hydrolysis of the aromatic amine Phoc by TBAF would selectively yield the corresponding amine.¹⁷ Since the aromatic amine is very little nucleophilic, the hydrolysis of the isocyanate is then faster than the addition of the amine to give the urea (Scheme 4). For the aliphatic amines, the size of the substituent modulates the proportion of the corresponding amine and urea. The very bulky, tert-butyl group favors the formation of tert-butylamine 1c from carbamate 2c. Conversely, 1,3-bis(pentylurea) 3bb is selectively obtained from Phoc carbamate 2b.

Scheme 4. Proposed Mechanism of Phoc Carbamate Hydrolysis Mediated by TBAF.

The intermediate steric size of the PMB group gives an almost equimolar mixture of amine 1a and the corresponding urea 3aa. For the aliphatic amines, the size of the substituent modulates the proportion of the corresponding amine and urea. Interestingly, carbamate 2f (Scheme 1) does not react under these conditions to afford free amine or the corresponding urea, supporting the idea that the presence of a labile proton is obligatory to initiate the reaction.

With all the data in hand, we can propose a mechanism for the reaction of TBAF with phenylcarbamate. This reactivity is consistent with the mechanisms proposed in the literature for the basic hydrolysis via passage through an isocyanate intermediate resulting from the deprotonation of the ionizable NH-Phoc (step 1, Scheme 4).¹⁶ The isocyanate intermediate is hydrolyzed to amine by the water molecules present in TBAF (step 2, Scheme 4). Depending on the nature of the amine formed, this amine can trap the isocyanate intermediate to yield the corresponding urea (step 3, Scheme 4), which is corroborated by the results in Table 5. Moreover, by using a catalytic amount of TBAF, the hydrolysis of the Phoc group is relatively slowed down, allowing the amine to trap the isocyanate formed in situ, even if this amine is not very nucleophilic for steric reasons (i.e., tert-butylamine).

Table 5. Amine Trapping Effect on Phoc Carbamate 2a Deprotection Mediated by TBAF.

entry	amine	R′	Y (equiv)	X (equiv)	urea ratioa
1	1c	tBu	20	1.2	3ac:3aa 100:0b
2	1c	tBu	1.0	1.2	3ac:3aa 60:40
3	1c	tBu	1.0	0.25	3ac:3aa 86:14
4	1b	n-pentyl	1.0	1.2	3ab:3aa 100:0c
5	1a	PMB	1.0	1.2	3aa 100d

^a1H NMR in the crude mixture.

^b93% yield of purified product 3ac.

^c85% yield of purified product 3ab.

^d92% yield of purified product 3aa.

It is unclear whether TBAF is reformed or whether the phenolate anion serves as the basis for step 1. We have already described the activation of ureas by TBAF,^13a and in this case, no other base is present. Unfortunately, ¹⁹F NMR reaction monitoring was inconclusive.

This mechanistic hypothesis is supported by trapping experiments of the isocyanate intermediate (Table 5). In the presence of a large excess of tert-butylamine 1a, dissymmetric urea 3ac is quantitatively formed (entry 2, Table 5). With a single equivalent, a majority of dissymmetric urea 3ac is formed with respect to symmetrical urea 3aa (entry 2, Table 5). By comparison, dissymmetric urea 3ab is the only product obtained under the same reaction conditions using n-pentylamine, a less sterically hindered amine (entry 4, Table 5). The proportion of dissymetric urea 3ac can be increased with a single equivalent of tert-butylamine 1c using a catalytic amount of TBAF (entry 1, Table 5): in this case, the formation of amine 1a is slowed, allowing time for the tert-butylamine to react despite a nucleophilic character diminished by steric hindrance. The use of a catalytic amount of TBAF (entry 3, Table 5) allows a relative increase in dissymmetrical urea 3ac. One justification is the presence of a lower quantity of amine 1a resulting from the hydrolysis of Phoc carbamate 2a: in the first catalytic round, a maximum of 0.25 equiv of amine 1a would be formed in the presence of 1.0 equiv of amine 1c. Even if amine 1c is less nucleophilic than 1a, its presence in a major proportion allows the attack of the isocyanate resulting from 2a before competing with amine 1a. With 1.2 equiv of TBAF, the proportion of amine 1a increases more rapidly; hence, there is a higher final proportion of dissymmetrical urea 3aa (entry 2, Table 5). By reversing the place of the substituents (Scheme 5), only 3ac urea is obtained with 1.2 equiv of TBAF.

Scheme 5. Amine Trapping Effect on Phoc Carbamte 2c Deprotection Mediated by TBAF.

The steric factor is evidenced by the exclusive formation of the dissymmetric urea 3ac from Phoc carbamate 2c in the presence of an equivalent of p-methoxybenzylamine 1a and 1.2 equiv of TBAF (Scheme 5). Under these conditions, the symmetric urea 3cc is not detected. Since p-methoxybenzylamine is less sterically bulky, the addition is much more effective with carbamate 2c than that of tert-butylamine with 1a (entry 2, Table 4).

Conclusions

In summary, we showed that the phenylcarbamate serves as both a protective group for amines and a chemoselective group to discriminate phenyl carbamates of primary or secondary amines. Dissymmetric ureas were obtained with very good yields, with total selectivity for aliphatic versus aromatic amines. We can perform the formation of symmetrical urea under mild conditions using a catalytic amount of TBAF. This kind of tool could have a major role in peptidic and pseudopeptide chemistry. We continue our research in this direction for the preparation of dissymmetric ureas.

Experimental Section

General Information and Materials

General Consideration

All reagents were purchased from commercial sources and were used without any further purification unless mentioned otherwise. Melting points were uncorrected. Thin-layer chromatograms were run on glass plates coated with silica gel G for thin-layer chromatography (TLC) using the solvent system EtOAc/cyclohexane. Compounds were purified by column chromatography using silica gel (40–63 mesh) with EtOAc/cyclohexane (of a specific proportion as required) as an eluent. ¹H NMR (300 and 400 MHz) and ¹³C NMR (75 and 100 MHz) were recorded using CDCl₃, DMSO-d₆, or MeOD as a solvent. Chemical shifts (δ) are reported in parts per million (ppm), with the internal reference (0.05 to 1%) tetramethylsilane. Coupling constants (J) are reported in Hz: singlet (s), doublet (d), triplet (t), doublet of doublet (dd), multiplet (m), or broad (br). High-resolution mass spectrometry (HRMS) was performed on a Q-TOF Waters spectrometer and an electrospray ionization (ESI) ion source. IR spectra were recorded on a Jasco FT-IR spectrometer. Data for previously reported compounds (cited) matched well with our observed data.

Preparation of Phenyl Carbamate (General Procedure)

For starting materials listed in Table 1, the following protocol was used: phenyl chloroformate (5.5 mmol, 1.1 equiv) in one portion was added to a magnetically stirred solution of amine (5.0 mmol, 1.0 equiv) in dry THF (20.0 mL) at room temperature under an Ar atmosphere. The reaction mixture was stirred at room temperature until complete consumption of starting materials monitored by TLC and then diluted with 1 N NaOH aqueous solution. The resulting mixture was extracted twice with dichloromethane, and the combined organic extracts were washed with brine and dried with MgSO₄. Then, it was evaporated to dryness, and the residue was purified by flash column chromatography to give phenyl carbamate.

Phenyl 4-Methoxybenzylcarbamate (2a)

Yield: 1.2 g (94%). White solid. R_f. 0.32 (15% EtOAc in cyclohexane); mp: 88 °C; FTIR (neat) 3292, 3077, 1699, 15432, 1515, 1483, 1248 cm^–1. ¹H NMR (400 MHz, CDCl₃) δ: 7.38 (m, 2H), 7.30 (m, 2H), 7.24–7.15 (m, 3H), 6.92 (d, J = 8.1 Hz, 2H), 5.33 (br.s, 1H), 4.41 (d, J = 5.8 Hz, 2H), 3.83 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 159.2, 154.6, 151.1, 130.1, 129.3 (× 2), 129.1, 125.3, 121.6, 114.2, 55.3, 44.8. HRMS (ESI): calcd for C₁₅H₁₅NO₃Na [M + Na]⁺, 280.0950; found, 280.0960.

Phenyl n-Pentylcarbamate (2b)

Yield: 890 mg (86%). White solid. R_f. 0.38 (15% EtOAc in cyclohexane). ¹H NMR (300 MHz, DMSO-d₆) δ: 7.70 (t, J = 5.1 Hz, 1H), 7.37 (m, 2H), 7.19 (m, 1H), 7.09 (m, 2H), 3.05 (td, J = 6.5, 5.1 Hz, 2H), 1.48 (m, 2H), 1.38–1.22 (m, 4H), 0.89 (t, J = 6.4 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆) δ: 154.8, 151.6, 129.6, 125.2, 122.2, 40.9, 29.3, 28.9, 22.3, 14.3. Chemical and spectroscopic data are identical to those from a previous report.¹⁸

Phenyl tert-Butylcarbamate (2c)

Yield: 820 mg (85%). White solid. R_f. 0.32 (15% EtOAc in cyclohexane). ¹H NMR (300 MHz, DMSO-d₆) δ: 7.53 (brs, 1H), 7.37 (t, J = 7.6 Hz, 2H), 7.19 (dd, J = 8.4,7.2 Hz, 1H), 7.07 (d, J = 8.4 Hz, 2H), 1.29 (s, 9H). ¹³C NMR (75 MHz, DMSO-d₆) δ: 153.7, 151.5, 129.6, 125.1, 122.3, 50.2, 29.9. Chemical and spectroscopic data are identical to those from a previous report.¹⁹

Phenyl Phenylcarbamate (2d)

Yield: 930 mg (87%). White solid. R_f. 0.3 (10% EtOAc in cyclohexane). ¹H NMR (400 MHz, DMSO-d₆) δ: 10.22 (bs, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.44 (t, J = 8.2 Hz, 2H), 7.36–7.20 (m, 5H), 7.05 (t, J = 7.4 Hz, 1H). ¹³C NMR (100 MHz, DMSO-d₆) δ: 152.2, 151.0, 139.1, 129.9, 129.3, 125.9, 123.4, 122.4, 118.9. Chemical and spectroscopic data are identical to those from a previous report.²⁰

Phenyl Benzyl(ethyl)carbamate (2f)

Yield: 1.21 g (94%). Yellow oil. R_f. 0.40 (10% EtOAc in cyclohexanes). FTIR (neat) 3028, 2977, 2942, 1715, 1495, 1468, 1455, 1416, 1249, 1200 cm^–1. ¹H NMR (400 MHz, CDCl₃) δ: 7.4–7.2 (m, 7H), 7.2–7.0 (m, 3H), 4.56 and 4.49 (s, 2H), 3.33 (q, J = 7.2 Hz, 2H), 1.11 and 1.10 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 155.2, 154.4, 129.4, 128.8, 128.2, 127.6, 127.4, 125.3, 121.9, 50.6, 50.5, 42.5, 41.9, 13.7, 13.0. HRMS (ESI): calcd for C₁₆H₁₇NO₂Na [M + Na]⁺, 278.1157; found, 278.1152.

Phenyl Ethyl(2-((phenoxycarbonyl)amino)ethyl)carbamate (2k)

Yield: 1.51 g (93%). Yellowish solid. R_f = 0.32 (30% EtOAc in cyclohexane). mp: 74–75 °C. FTIR (neat) 3316, 2965, 2941, 1741, 1694, 1538, 1493, 1474, 1424, 1280, 1250, 1210 cm^–1. ¹H NMR (400 MHz, CDCl₃) δ: 7.5–7.3 (m, 4H), 7.3–7.0 (m, 2H), 5.72 and 5.48 (brs, 1H), 3.4–3.7 (m, 6H), 1.4–1.2 (m, 3H). ¹³C NMR (150 MHz, CDCl₃) δ: 155.4, 155.1, 155.0, 154.4, 151.4, 151.1, 151.0, 129.3, 125.3, 125.2, 121.8, 121.7, 121.6, 46.8, 46.2, 43.1, 43.0, 40.0, 39.9, 14.0, 13.1. HRMS (ESI): calcd for C₁₈H₂₀N₂NaO₄ [M + Na]⁺, 351.1321; found, 351.1335.

Preparation of Urea (Table 1)

For experiments listed in Table 4, the following protocol was used: A mixture of phenyl carbamate (1.0 mmol, 1.0 equiv), NEt₃ (3.0 mmol), and selected amine (1.2 mmol, 1.2 equiv) in chloroform (10 mL) was refluxed for 48 h. The cooled reaction mixture was diluted with dichloromethane and extracted with 1 N NaOH aqueous solution. The combined organic phase was washed with 2 N HCl aqueous solution, dried, and evaporated to dryness. The residue was purified by flash column chromatography to afford pure urea.

1,3-Bis-(4-methoxybenzyl)urea (3aa)

Yield: 270 mg (89%). White powder. mp: 177.7–178.4 °C. ¹H NMR (400 MHz, DMSO-d₆) δ: 7.17 (d, J = 8.2 Hz, 4H), 6.87 (d, J = 8.1 Hz, 4H), 6.28 (t, J = 5.7 Hz, 2H), 4.15 (d, J = 5.7 Hz, 4H), 3.73 (s, 6H). ¹³C NMR (100 MHz, DMSO-d₆) δ: 158.5, 158.4, 133.3, 128.8, 114.1, 55.5, 42.9. Chemical and spectroscopic data are identical to those from a previous report.²¹

1-(4-Methoxybenzyl)-3-pentylurea (3ab)

Yield: 220 mg (88%). White powder. mp: 112–114 °C. FTIR (neat) 3350, 3324, 3100, 2952, 2923, 1618, 1579, 1513, 1253, 1241, 1172, 1109, 1031, 811 cm^–1. ¹H NMR (400 MHz, DMSO-d₆) δ: 7.16 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 6.14 (t, J = 5.8 Hz, 1H), 5.83 (t, J = 5.5 Hz, 1H), 4.11 (d, J = 5.8, 2H), 3.73 (s, 3H), 2.99 (q, J = 6.7 Hz, 2H), 1.42–1.15 (m, 6H), 0.87 (t, J = 7.5 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆) δ: 158.4, 133.4, 128.8, 114.1, 55.5, 42.8, 39.7, 30.2, 22.3, 14.4. HRMS (ESI): calcd for C₁₄H₂₂N₂O₂Na [M + Na]⁺, 273.1570; found, 273.1579.

1-(tert-Butyl)-3-(3-methoxybenzyl)urea (3ac)

Yield: 200 mg (85%). White powder. mp: 100–102 °C. FTIR (neat) 3356, 3318, 3100, 2961, 2917, 1631, 1564, 1512, 1260, 1250, 1173, 1037, 1031 cm^–1. ¹H NMR (300 MHz, DMSO-d₆) δ: 7.15 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 5.97 (t, J = 5.8 Hz, 1H), 5.67 (s, 1H), 4.08 (d, J = 5.8, 2H), 3.73 (s, 3H), 1.23 (s, 9H). ¹³C NMR (100 MHz, DMSO-d₆) δ: 158.5, 157.8, 133.3, 128.7, 114.1, 55.5, 49.5, 42.5, 29.8. HRMS (ESI): calcd for C₁₃H₂₀N₂O₂Na [M + Na]⁺, 259.1413; found, 259.1422.

1-Benzyl-3-(4-methoxybenzyl)urea (3ae)

Yield: 245 mg (90%). White solid. R_f. 0.38 (50% EtOAc in cyclohexane). mp: 126 °C. FTIR (neat) 3349, 3316, 2954, 1624, 1575, 1512, 1250 cm^–1. ¹H NMR (400 MHz, CDCl₃) δ 7.14–7.28 (m, 5H), 7.11 (d, J = 8.6 Hz, 2H), 6.77 (d, J = 8.6 Hz, 2H), 4.29 (s, 2H), 4.23 (s, 2H), 3.72 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 159.0, 158.0, 138.9, 130.9, 128.8, 128.7, 127.4, 127.3, 114.1, 55.3, 44.6, 44.2. Chemical and spectroscopic data are identical to those from a previous report.²²

1-Benzyl-1-ethyl-3-(4-methoxybenzyl)urea (3af)

Yield: 250 mg (84%). Yellow oil. R_f. 0.2 (30% EtOAc in cyclohexane). FTIR (neat) 3352, 3031, 2965, 2928, 1627, 1532, 1510, 1453, 1404, 1361, 1243 cm^–1. ¹H NMR (400 MHz, CDCl₃) δ: 7.4–7.3 (m, 5H), 7.18 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 4.78 (t, J = 5.4 Hz, 1H), 4.52 (s, 2H), 4.39 (d, J = 5.4 Hz, 2H), 3.81 (s, 3H), 3.36 (q, J = 7.1 Hz, 2H), 1.17 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 158.7, 157.9, 138.2, 131.8, 128.8, 128.7, 127.3, 127.1, 113.9, 55.3, 49.9, 44.4, 41.9, 13.4. HRMS ESI(−): calcd for C₁₈H₂₂N₂O₂ [M – H] 297.1603; found, 297.1609.

1-(4-Aminobenzyl)-3-(4-methoxybenzyl)urea (3ag)

Yield: 186 mg (65%). Yellow solid. R_f. 0.6 (100% EtOAc). mp: 184 °C. FTIR (neat) 3462, 3336, 2957, 2877, 1609, 1597, 1585, 1564, 1514, 1472, 1303, 1285, 1247 cm^–1. ¹H NMR (400 MHz, MeOD) δ: 7.20 (d, J = 8.2 Hz, 2H), 7.04 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 6.70 (d, J = 8.2 Hz, 2H), 4.20 (s, 2H), 4.26 (s, 2H), 3.78 (s, 3H). ¹³C NMR (100 MHz, MeOD) δ: 159.6, 158.8, 146.2, 131.8, 129.2, 128.1, 127.9, 115.2, 113.5, 54.3, 43.2, 42.9. HRMS (ESI): calcd for C₁₆H₁₉N₃O₂Na [M + Na]⁺, 308.1375; found, 308.1381.

Ethyl 3-(3-(4-Methoxybenzyl)ureido)propanoate (3ah)

Yield: 225 mg (80%). Brown solid. R_f. 0.12 (50% EtOAc in cyclohexanes). mp: 97–98 °C. FTIR (neat) 3325, 2924, 1724, 1714, 1611, 1577, 1512, 1439, 1334, 1301, 1250 cm^–1. ¹H NMR (400 MHz, CDCl₃) δ 7.23 (d, J = 8.1 Hz, 2H), 6.88 (d, J = 8.1 Hz, 2H), 4.30 (s, 2H), 4.14 (q, J = 7.1 Hz, 2H, 3.81 (s, 3H), 3.79 (t, J = 4.6 Hz, 2H), 2.54 (t, J = 4.6 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ: 173.0, 158.9, 158.0, 131.0, 128.8, 114.0, 60.7, 55.3, 44.1, 35.9, 34.8, 14.2. HRMS (ESI): calcd for C₁₄H₂₀N₂O₄Na [M + Na]⁺, 303.1321; found, 303.1324.

tert-Butyl 2-(3-(4-Methoxybenzyl)ureido)acetate (3ai)

Yield: 250 mg (85%). White solid. R_f. 0.31 (50% EtOAc in cyclohexanes). mp: 95–96 °C. FTIR (neat) 3315, 3047, 2985, 2968, 1733, 1617, 1558, 1174, 821 cm^–1. ¹H NMR (400 MHz, CDCl₃) δ: 7.21 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 8.0 Hz, 2H), 4.65 (br, 2H), 4.28 (s, 2H), 3.87 (s, 2H), 3.79 (s, 3H), 1.45 (s, 9H). ¹³C NMR (100 MHz, CDCl₃) δ: 170.3, 158.9, 158.0, 131.0, 128.8, 114.0, 82.0, 55.3, 44.0, 42.9, 28.0. HRMS (ESI): calcd for C₁₅H₂₂N₂O₂Na [M + Na]⁺, 317.1477; found, 317.1479.

2-(3-(4-Methoxybenzyl)ureido)acetic Acid (3aj)

Yield: 172 mg (72%). White solid. R_f. 0.11 (100% AcOEt). mp: 180–182 °C. FTIR (neat) 3379, 3314, 2951, 1695, 1624, 1592, 1582, 1513, 1411, 1282, 1231 cm^–1. ¹H NMR (300 MHz, DMSO-d₆) δ: 12.42 (brs, 1H), 7.17 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 6.55 (t, J = 5.8 Hz, 1H), 6.14 (t, J = 5.8 Hz, 1H), 4.13 (d, J = 5.8 Hz, 2H), 3.72 (s, 3H), 3.71 (d, J = 5.8 Hz, 2H). ¹³C NMR (75 MHz, DMSO-d₆) δ: 173.0, 158.5, 158.4, 133.1, 128.8, 114.0, 55.5, 42.8, 42.0. HRMS (ESI): calcd for C₁₁H₁₄N₂O₄Na [M + Na]⁺, 261.0851; found, 261.0853.

Phenyl (2-(3-Benzylureido)ethyl)(ethyl)carbamate (3ke)

Yield: 318 mg (93%). Yellow oil. R_f. 0.30 (65% EtOAc in cyclohexanes). FTIR (neat) 3361, 3020, 2934, 1717, 1633, 1560, 1471, 1417, 1253, 1201, 1145 cm^–1. ¹H NMR (400 MHz, MeOD) δ: 7.2–7.4 (m, 7H), 7.12 (m, 2H), 4.31 (d, J = 11.8 Hz, 2H), 3.60–3.35 (m, 6H, CH₂), 1.27 and 1.19 (t, J = 6.9 Hz, 3H). ¹³C NMR (100 MHz, MeOD) δ: 159.6, 155.4, 154.0, 139.9, 139.8, 128.9, 128.1, 126.9, 126.6, 125.0, 121.6, 121.5, 47.1, 46.8, 43.4, 42.8, 42.7, 38.3, 38.0, 12.8, 11.9. HRMS (ESI): calcd for C₁₉H₂₃N₃O₃Na [M + Na]⁺, 364.1637; found, 364.1624.

1,3-Dibutylurea (3cc)

Yield: 155 mg (90%). Colorless solid. R_f. 0.35 (50% EtOAc in cyclohexane). ¹H NMR (300 MHz, DMSO-d₆) δ: 5.44 (s, 2H), 1.19 (s, 18H). ¹³C NMR (300 MHz, DMSO-d₆) δ: 157.5, 49.2, 29.8. Chemical and spectroscopic data are identical to those from a previous report.²³

Diphenyl ((Carbonylbis(azanediyl))bis(ethane-2,1-diyl))bis(ethylcarbamate) (3kk)

A solution of carbamate 1k (328 mg, 1.0 mmol) in dry THF (10 mL) was stirred at room temperature under argon. A freshly prepared 1 M solution of TBAF in THF (0.3 equiv) was added and stirred at room temperature until complete consumption of starting materials monitored by TLC; then water (20 mL) was added, and the aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over MgSO₄, filtered, dried, and evaporated to dryness. The residue was purified by flash column chromatography to afford pure urea 3kk. Yield: 305 mg (69%). Brownish solid. R_f. 0.24 (50% EtOAc in cyclohexanes). mp: 122–123 °C. FTIR (neat): 3340, 3008, 2928, 1716, 1574, 1472, 1421, 1264, 1200, 1145, 1038, 955 cm^–1. ¹H NMR (400 MHz, MeOD) δ: 7.39 (m, 4H), 7.23 (m, 2H), 7.13 (m, 4H), 3.60–3.32 (m, 12H), 1.35–1.10 (m, 6H). ¹³C NMR (100 MHz, MeOD) δ: 159.6, 155.3, 154.9, 152.4, 128.9, 125.1, 121.5, 121.4, 46.7, 42.8, 42.7, 38.3, 38.0, 12.8, 11.9. HRMS (ESI): calcd for C₂₃H₃₀N₄O₅Na [M + Na]⁺, 465.2114; found, 465.2127.

Solvent Screening Conditions with TBAF-Mediated Phoc Deprotection (Table 2)

The following general procedure was used to determine the solvent effect unless otherwise stated: a solution of carbamate 2a (0.5 mmol, 1.0 equiv) in dry THF (5 mL) was stirred at room temperature under argon. A freshly prepared 1 M solution of TBAF (1.2 equiv) in THF was added. After 1 h, water (10 mL) was added and the aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over MgSO₄, filtered, dried, and evaporated to dryness. The conversion and ratio were determined by comparison of the ¹H NMR spectra of starting material 2a and the pure sample of amine 1a and the corresponding symmetric urea 3aa.

TBAF Equivalent Screening Conditions with TBAF-Mediated Phoc Deprotection (Table 3)

The following general procedure was used unless otherwise stated: a solution of carbamate 2a (0.5 mmol, 1.0 equiv) in dry THF (5 mL) was stirred at room temperature under argon. A freshly prepared 1 M solution of TBAF (X equiv) in THF was added, and the reaction mixture was stirred at room temperature until complete consumption of starting materials monitored by TLC. Then water (10 mL) was added, and the aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over MgSO₄, filtered, dried, and evaporated to dryness. The conversion and ratio were determined by comparison of the ¹H NMR spectra of starting material 2a and the pure sample of amine 1a and the corresponding symmetric urea 3aa.

Substrate Screening for TBAF-Mediated Phoc Deprotection (Table 4)

The following general procedure was used unless otherwise stated: a solution of carbamate (0.5 mmol, 1.0 equiv) in dry THF (5 mL) was stirred at room temperature under argon. A freshly prepared 1 M solution of TBAF (1.2 equiv) in THF was added. After 1 h of stirring, water (10 mL) was added and the aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over MgSO₄, filtered, dried, and evaporated to dryness. Purification was performed using silica column flash chromatography for 3bb.

1,3-Dipentylurea (3bb)

Yield: 45 mg (89%). ¹H NMR (400 MHz, DMSO-d₆) δ: 5.71 (t, J = 5.0 Hz, 2H), 2.95 (q, J = 6.6 Hz, 4H), 1.40–1.17 (m, 12 H), 0.87 (t, J = 7.0 Hz). ¹³C NMR (100 MHz, DMSO-d₆): d = 158.5, 39.6, 30.2, 29.1, 22.4, 14.4. Chemical and spectroscopic data are identical to those from a previous report.²¹

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.2c04979.

• ¹H NMR and ¹³C NMR spectra of the solvent effect and TBAF equivalent effect and ¹H NMR and ¹³C NMR spectra of Phoc and urea compounds including ¹H NMR and ¹³C NMR coalescence spectra (PDF)

The authors declare no competing financial interest.