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Synthesis 2009(11): 1935-1940  
DOI: 10.1055/s-0029-1216795
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© Georg Thieme Verlag Stuttgart ˙ New York

One-Pot Curtius Rearrangement Processes from Carboxylic Acids

Olivier Leogane, Hélène Lebel*
Département de chimie, Université de Montréal, Montréal H3C 3J7, Québec, Canada
Fax: +1(514)3437586; e-Mail: helene.lebel@umontreal.ca;

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Publication History

Received 8 January 2009
Publication Date:
12 May 2009 (online)

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Abstract

An efficient and practical synthesis of amine derivatives from carboxylic acids is described using new one-pot Curtius rearrangement processes. The preparation of carbamate-protected amines and anilines, as well as ureas was achieved in good to excellent yields on a multigram scale.

Key words

Curtius rearrangement - acyl azides - carbamates - protected amino acids - anilines - ureas

Scheme 1

Introduction

Carbon-nitrogen bond formation is of high interest in organic chemistry as numerous nitrogen-containing molecules are found in natural and/or biologically active products. As a result, a variety of synthetic strategies have been developed to address the preparation of such molecules. Among them, the Curtius rearrangement, [¹] which involves the concerted degradation of an acyl azide into an isocyanate (Scheme  [²] ), has been used quite extensively. [²] The synthesis of a variety of carbamates and ureas using such a strategy is possible by trapping the isocyanate intermediate with an alcohol or an amine. The one-pot transformation of carboxylic acids into carbamates is most commonly achieved using diphenylphosphorazidate (DPPA­), which not only provides a soluble source of azide, but also activates the carboxylic acid to form the corresponding acyl azide in situ. [³] This reagent has been widely used for the preparation of pharmacologically active compounds. [4] However, the requirement of high temperatures and the potential difficulties associated with the isolation of the desired product from the phosphorus residues remain as serious drawbacks. We have recently reported a mild and efficient one-pot Curtius rearrangement to convert aliphatic carboxylic acid into Boc-protected amines and amino acids (Scheme  [¹] , Procedures 1 and 2). [5] The process is based on the in situ formation of acyl azides from carboxylic acids by treating with di-tert-butyl dicarbonate and sodium azide. These aliphatic acyl azides spontaneously rearrange at 40 ˚C to produce the corresponding isocyanates. No additional alcohol reagent is required to form the carbamate as the degradation of Boc anhydride results in the formation of sodium tert-butoxide as a by-product. The latter alkoxide then reacts with the isocyanate, albeit slowly at 40 ˚C. Conversely, the use of a catalytic amount of tetrabutylammonium bromide and zinc triflate promoted the formation of the desired Boc-protected amine (presumably through the formation of a zinc carbamoyl bromide species). [6] α,α-Disubstituted protected amino acids are also available using such a procedure. Despite the lack of reactivity of aromatic carboxylic acids under these conditions (as a result of the inherent stability of aromatic acyl azides at 40 ˚C) the desired rearrangement occurred at 75 ˚C. Therefore, a variety of Alloc­, CBz, and Troc-protected anilines were produced from aromatic carboxylic acids using the corresponding chloroformate reagent in the presence of sodium azide and a catalytic amount of sodium tert-butoxide (Scheme  [¹] , Procedure 3). [7] Moreover, when phenyl chloroformate is used, the addition of an external nucleophile, such as an amine, to the isocyanate intermediate led to the corresponding aromatic urea (Scheme  [¹] , Procedure 4), as the phenoxide by-product resulting from the degradation of the chloroformate is not nucleophilic enough. In this report, we wish to disclose convenient procedures (30 mmol scale) for one-pot Curtius rearrangement processes with aliphatic and aromatic carboxylic acids.

Scheme 2

Scope and Limitations

The catalytic Curtius rearrangement provided a variety of Boc-protected aliphatic amines from carboxylic acids in good to excellent yields. A large variety of substrates were tested under the optimal reaction conditions using 1.1 equivalents of di-tert-butyl dicarbonate, 3.5 equivalents of sodium azide, 15 mol% of tetrabutylammonium bromide, and 3.3 mol% of zinc triflate in THF at 40 ˚C. [8] [9] The reaction proceeds easily with tertiary, secondary, and primary carboxylic acids to give access to protected amines in good yields (Table  [¹] ).

Table 1 Zinc-Catalyzed Curtius Rearrangement Using Procedures 1 and 2
Entry Product
 Yield (%)
1  9

94
2 10

80
3 11

68
4 12

72
5 13

58
6 14

49a(98% ee)
7 15

65b
a Starting material was 99% ee; 0.5 equiv of t-BuOH was added.
b Temp: 50 ˚C.

Unprotected ketones, alcohols, or silyl ether groups are compatible with the reaction conditions. The scope was extended to the synthesis of racemic α,α-disubstituted protected amino acids by increasing the temperature to 50 ˚C. All reagents are commercially available, easy to handle and are introduced simultaneously. The desired pure products are typically obtained after a simple flash chromatography. The only by-product observed is the corresponding tert-butyl ester, which affects the yield of some substrates (entries 5 and 6). The formation of this by-product might result from the addition of the tert-butoxy­ moiety onto the corresponding ketene, generated from the acyl azide by formal elimination of hydrazoic acid. Although the Curtius rearrangement is known to proceed with retention of configuration, carbamate 14 was recovered with a slight erosion of the enantiomeric excess (91% ee) under standard reaction conditions. To decrease the basicity of the reaction mixture, 0.5 equivalent of tert-butyl alcohol was added. Under these new reaction conditions, the Curtius rearrangement of enantioenriched α-chiral carboxylic acids led to the isolation of the carbamate with complete stereospecificity. The versatility of this procedure was further evaluated on a multigram scale. The one-pot procedure was scaled up to 30 mmol and the Boc-carbamate 2 was obtained in 87% yield under standard reaction conditions (Table  [²] , entry 1). Similar conversion was observed by decreasing the loading of zinc triflate and tetrabutylammonium bromide to 2 and 9 mol%, respectively (entry 2). In addition, the stoichiometry of sodium azide could be decreased to 2 equivalents and carbamate 2 could be consistently isolated in 85% yield (entry 3). To ensure the safety of the protocol, the reaction was quenched with a 10% aqueous solution of sodium nitrite to eliminate the azide residues. [¹0] This new set of reaction conditions provides a safe and efficient multigram scale procedure for the Curtius rearrangement. Furthermore, this protocol can also be used for the synthesis of protected unnatural amino acids (Procedure 2).

Table 2 Optimization of the Reaction Conditions for the Synthesis of Carbamate 2 a
Entry NaN3
(equiv) 		Zn(OTf)2 (mol%) Bu4NBr (mol%) Conversion (%)a
1 3.5 3.3 15 87b
2 3.5 2  9 90
3 2 2  9 85b
a Procedure 1 (30 mmol scale). a Conversion measured by GC-MS.
b Isolated yield.

Aromatic carboxylic acids did not undergo rearrangement under the previously developed catalytic Curtius procedure, as higher temperatures are required to promote the rearrangement of the corresponding acyl azide intermediate. The synthesis of Boc-aniline derivatives was shown to occur in DME at 75 ˚C (with 1.1 equiv of Boc2O and 1.5 equiv of NaN3), but with a poor functional group tolerance possibly due to the generation of a stoichiometric amount of sodium tert-butoxide as a by-product. [¹¹] Conversely, the use of chloroformates as acid activating agents (generating sodium chloride as a by-product) in the presence of 1.7 equivalents of sodium azide and 15 mol% of sodium tert-butoxide in DME at 75 ˚C produced a wide range of carbamates in high yields. [¹²] Allyl, benzyl and trichloroethyl chloroformate were successfully used to generate Alloc-, CBz-, and Troc-protected anilines. Such protecting groups can be selectively removed under mild reaction conditions. Both electron-rich and electron-withdrawing substituted aromatic carboxylic acids are compatible with the reaction conditions (Table  [³] , entries 2-4). The use of other sp²-substituted carboxylic acids such as cinnamic acid or benzofuran carboxylic acid is also possible (entry 5). In contrast, pyridine carboxylic acid derivatives are not reactive under these conditions as the acyl azide intermediate appears not to be formed.

Table 3 Curtius Rearrangement with Benzoic Acid Derivatives Using­ Procedure 3
Entry Carbamate PG Yield (%)
1

Alloc (16)
CBz (17) 		57
64
2

Alloc (18)
CBz (6)
Troc (19) 		72
93
71a
3

Alloc (20)
CBz (21) 		78
84
4

Alloc (22)
CBz (23) 		45
62
5

Alloc (24)
CBz (25) 		69
80
a Temp: 85 ˚C.

2-Iodobenzoic acid was the chosen substrate to scale up the procedure (30 mmol scale), because of the high synthetic value of the corresponding 2-iodoaniline, which is an important intermediate for indole derivatives synthesis through palladium-catalyzed heteroannulation. [¹³] [¹4] The reaction was run at 0.3 M and the catalyst loading of sodium tert-butoxide was decreased to 8 mol% to produce the desired protected aniline in 92% yield (Table  [4] ). Unfortunately, it was not possible to decrease the amount of sodium azide, as lower yield was observed with 1.2 equivalents instead of 1.5.

Table 4 Optimization of the Reaction Conditions for the Synthesis of Carbamate 6 a
Entry t-BuONa (mol%) NaN3 (equiv) Yield (%)
1 15 1.5 88
2  8 1.5 92
3  8 1.2 82
a Procedure 3 (30 mmol scale).

So far, the final product resulted from the addition of a nucleophilic alkoxide (arising from the degradation of the corresponding chloroformate) to the isocyanate. Addition of an external nucleophile would further expand the scope of such a procedure. For instance, the synthesis of ureas should be possible by trapping the isocyanate with a nucleophilic amine. To achieve this task, the carboxylic acid was treated with sodium azide and phenyl chloroformate to form the corresponding acyl azide. The reaction was then heated at 75 ˚C to promote the rearrangement, followed by the addition of an amine derivative to produce the desired urea (Table  [5] ).

Table 5 Synthesis of Aromatic Ureas using Procedure 4
Entry Carbamate
 Yield (%)
1 26

74
2 27

54
3 28

63

According to this protocol a variety of aromatic ureas were efficiently prepared via addition of substituted anilines, aliphatic amines and N-hydroxylamine. A gram scale procedure was developed for the synthesis of diphenylurea 8. A mixture of benzoic acid, sodium azide, phenyl chloroformate, and sodium tert-butoxide was heated at 75 ˚C, then the aniline was added and stirred at 75 ˚C for 12 hours (Procedure 4). After precipitation in hexanes and trituration with diethyl ether, the desired urea 8 was isolated in 70% yield (Scheme  [¹] ).

In conclusion, we have developed very efficient one-pot processes for the Curtius rearrangement, which allows the direct conversion of carboxylic acids into amine derivatives. The new zinc-catalyzed Curtius rearrangement gives access to aliphatic Boc-protected amines at low temperature. An extension of the methodology using chloroformate reagent and a catalytic amount of sodium tert-butoxide leads to the formation of a wide range of protected anilines. Interestingly, these new conditions were also compatible with the synthesis of urea derivatives.

Procedures

Herein, we describe four typical synthetic procedures for the direct conversion of carboxylic acids into various amine derivatives through one-pot Curtius reaction. First, the zinc-catalyzed Curtius rearrangement can be performed on aliphatic carboxylic acids using THF as a solvent at 40 ˚C. This procedure was run on a 30 mmol scale using only 2 mol% of zinc triflate and 2 equiv of NaN3 (Procedure 1). Carbamate 2 was isolated in 85% yield after recrystallization. Monoester of malonic acid was also compatible with this protocol at 50 ˚C. We also report the synthesis of carboxylic acid 3 from diethyl methylmalonate. The commercially available diethyl methylmalonate was alkylated with phenethyl bromide in quantitative yield in the presence of NaH in DMF at 25 ˚C. The monosaponification of the resulting disubstituted malonate with KOH in a H2O-EtOH mixture at 50 ˚C affords the acid 3 in 62% yield. The racemic disubstituted protected amino acid 4 was isolated in 74% yield (Procedure 2). The large scale optimization was extended to aromatic carboxylic acids. The reaction was achieved on a 30 mmol scale and the best conditions required DME as solvent at 75 ˚C with 8 mol% of t-BuONa. This procedure enabled us to isolate the CBz-protected aniline 6 in 96% yield (Procedure 3). The same conditions have been used for the synthesis of aromatic urea 8 (Procedure 4). The poor solubility of the benzoate anion prompted us to modify the standard procedure reported for the urea synthesis. Indeed, the mixture was heated prior to the addition of aniline, and the diphenyl urea 8 was obtained in 70% yield.

Υνλεσσ οτηερωισε νοτεδ, αλλ νον−αθυεουσ ρεαχτιονσ ωερε περϕορµεδ υνδερ αν οξψγεν−ϕρεε ατµοσπηερε οϕ αργον ωιτη ριγιδ εξχλυσιον οϕ µοιστυρε ϕροµ ρεαγεντσ ανδ γλασσωαρε. Τηε σολϖεντσ ωερε δριεδ υσινγ στανδαρδ µετηοδσ πριορ το υσε. ΝαΝ3 ανδ σοδιυµ tert−βυτοξιδε αρε χοµµερχιαλλψ αϖαιλαβλε ανδ ωερε πυρχηασεδ ϕροµ Αλδριχη. Σοδιυµ tert−βυτοξιδε ωασ ηανδλεδ υνδερ ινερτ ατµοσπηερε. Χαρβοξψλιχ αχιδσ αρε χοµµερχιαλλψ αϖαιλαβλε ανδ ωερε πυριϕιεδ υσινγ στανδαρδ µετηοδσ πριορ το υσε. Αναλψτιχαλ τηιν λαψερ χηροµατογραπηψ (ΤΛΧ) ωασ περϕορµεδ υσινγ ΕΜ Ρεαγεντ 0.25 µµ σιλιχα γελ 60−Φ πλατεσ. ςισυαλιζατιον οϕ τηε δεϖελοπεδ χηροµατογραµ ωασ περϕορµεδ βψ Υς αβσορβανχε, αθυεουσ χεριυµ µολψβδατε, ετηανολιχ πηοσπηοµολψβδιχ αχιδ, ορ αθυεουσ ποτασσιυµ περµανγανατε. Φλαση χηροµατογραπηψ ωασ περϕορµεδ υσινγ ΕΜ Σιλιχα Γελ 60 (230∠400 µεση) ωιτη τηε ινδιχατεδ σολϖεντ σψστεµ. Οπτιχαλ ροτατιονσ ωερε µεασυρεδ ον α Περκιν−Ελµερ 341 διγιταλ πολαριµετερ ατ 589 νµ. Δατα αρε ρεπορτεδ ασ ϕολλοωσ: [α]Δτεµπ., χονχεντρατιον (χ γ/100 µΛ), ανδ σολϖεντ. ¹Η ΝΜΡ σπεχτρα ωερε ρεχορδεδ ιν ΧΔΧλ3, υνλεσσ οτηερωισε νοτεδ, ον Βρυκερ Ας−400, Βρυκερ ΑΡΞ−400, Βρυκερ ΑΜΞ−300 ορ Βρυκερ Ας−300 σπεχτροµετερσ (400, 400, 300 ανδ 300 ΜΗζ, ρεσπεχτιϖελψ), ρεσπεχτιϖελψ. Χηεµιχαλ σηιϕτσ αρε ρεπορτεδ ιν ππµ ον τηε δ σχαλε ϕροµ αν ιντερναλ στανδαρδ οϕ ρεσιδυαλ χηλοροϕορµ (7.27 ππµ). Δατα αρε ρεπορτεδ ασ ϕολλοωσ: χηεµιχαλ σηιϕτ, µυλτιπλιχιτψ (σ = σινγλετ, δ = δουβλετ, τ = τριπλετ, θ = θυαρτετ, θν = θυιντετ, µ = µυλτιπλετ ανδ βρ = βροαδ), χουπλινγ χονσταντ ιν Ηζ, ιντεγρατιον. ¹³Χ ΝΜΡ σπεχτρα ωερε ρεχορδεδ ιν ΧΔΧλ3, υνλεσσ οτηερωισε νοτεδ, ον Βρυκερ Ας−400, Βρυκερ ΑΡΞ−400, Βρυκερ ΑΜΞ−300 ορ Βρυκερ Ας−300 σπεχτροµετερσ (100, 100, 75 ανδ 75 ΜΗζ, ρεσπεχτιϖελψ), ρεσπεχτιϖελψ, ωιτη χοµπλετε προτον δεχουπλινγ. Χηεµιχαλ σηιϕτσ αρε ρεπορτεδ ιν ππµ ϕροµ τηε χεντραλ πεακ οϕ ΧΔΧλ3 (77.0 ππµ) ον τηε δ σχαλε. Μασσ σπεχτρα ωερε οβταινεδ ον α ΛΧ−ΜΣΔ ΤΟΦ (ΕΣΙ) Αγιλεντ Τεχηνολογιεσ ηιγη ρεσολυτιον ϕροµ τηε Χεντρε ρéγιοναλ δε σπεχτροµéτριε δε µασσε δε λ∏Υνιϖερσιτé δε Μοντρéαλ. Αναλψτιχαλ γασ χηροµατογραπηψ ωιτη α µασσ σπεχτροσχοπψ (ΓΧ−ΜΣ) ωασ χαρριεδ ουτ ον α Ηεωλεττ Παχκαρδ 6890 σεριεσ γασ χηροµατογραπη εθυιππεδ ωιτη α σπλιτ µοδε χαπιλλαρψ ινϑεχτορ ανδ ελεχτρον ιµπαχτ µασσ δετεχτορ. Υνλεσσ οτηερωισε νοτεδ, ινϑεχτορ ανδ δετεχτορ τεµπερατυρεσ ωερε 250 ˚Χ ανδ τηε χαρριερ γασ ωασ ηψδρογεν (2 µΛ/µιν) ωιτη α ΗΠ−5ΜΣ χολυµν. Δατα αρε ρεπορτεδ ασ ϕολλοωσ: χολυµν τψπε, οϖεν τεµπερατυρε, ανδ ρετεντιον τιµε (t R).

N - tert -Butyl Adamantan-1-yl-carbamate (2); Procedure 1

To a solution of 1-adamantanecarboxylic acid (1; 5.40 g, 30.0 mmol), NaN3 (3.90 g, 60.0 mmol), TBAB (870 mg, 2.70 mmol), and zinc triflate (220 mg, 0.600 mmol) in THF (150 mL) was added warm di-tert-butyl dicarbonate (7.60 mL, 33.0 mmol) via a syringe over 10 sec. The resulting reaction mixture was then stirred with a mechanical stirrer under argon at 40 ˚C for 64 h. The mixture was cooled to r.t. and quenched with aq 10% NaNO2 (50 mL). The biphasic mixture was stirred for 30 min at r.t. The two layers were separated, and the organic layer was washed successively with sat. aq NH4Cl (75 mL), brine (75 mL), and then dried (Na2SO4). The organic solution was filtered and concentrated at 40 ˚C by rotary evaporation to afford a white solid. The solid residue was dissolved in a boiling mixture of hexanes (90 mL) and EtOAc (2 mL). The complete dissolution of the solid led to the formation of a viscous orange oil. The clear solution was separated from this residue and then concentrated at 40 ˚C by rotary evaporation to afford a white solid, which was recrystallized from a mixture of hexanes (70 mL) and CHCl3 (2 mL). The resulting crystalline product was filtered through a fritted funnel and dried under vacuum to yield 5.5 g of the product. The mother liquor was concentrated at 40 ˚C by rotary evaporation, and the resulting white solid recrystallized from hexanes (30 mL) to yield 0.85 g of additional product after filtration through a fritted funnel and drying as mentioned above. The solids were combined to provide 6.41 g (85%) of the desired carbamate 2 as a crystalline white solid; mp 101 ˚C; R f = 0.46 (10% EtOAc-hexanes).

IR (neat): 3266, 3130, 2907, 2851, 1685, 1359, 1164, 1151, 1026, 778, 628 cm-¹.

¹H NMR (400 MHz, C6D6, 70 ˚C): δ = 4.37 (br s, 1 H), 2.05 (br s, 3 H), 1.91 (s, 6 H), 1.64 (m, 6 H), 1.42 (s, 9 H).

¹³C NMR (100 MHz, CDCl3): δ = 154.0 (br), 78.4 (br), 50.3, 41.8, 36.3, 29.3, 28.4.

HMRS (ESI): m/z calcd for C15H25NO2 + Na [M + Na]+: 274.1777; found: 274.1778.

Anal. Calcd for C15H25NO2: C, 71.67; H, 10.02; N, 5.57; O, 12.73. Found: C, 71.41; H, 9.81; N, 5.66.

Diethyl 2-Methyl-2-phenethylmalonate

To a solution of NaH (60% dispersion in mineral oil, 4.00 g, 100 mmol) in DMF (140 mL) at 0 ˚C was added dropwise a solution of diethyl methylmalonate (17.2 mL, 100 mmol) in DMF (30 mL). The colorless mixture was stirred for 45 min under argon at 0 ˚C. A solution of 2-bromoethylbenzene (13.7 mL, 100 mmol) in DMF (30 mL) was then added dropwise over 20 min. The resulting mixture was stirred under argon at r.t. for 4.5 h. The mixture was then poured into cold H2O (400 mL) and stirred for 15 min. The two layers were separated and the aqueous layer was extracted with EtOAc (2 × 350 mL). The combined organic layers were washed with brine (350 mL), dried (Na2SO4), filtered, and concentrated at 40 ˚C by rotary evaporation. The resulting oil was placed on a high vacuum pump for 24 h to remove the residual solvent traces affording the crude title product as a clear pale yellow oil, which was used in the next step without further purification; R f = 0.38 (10% EtOAc-hexanes).

IR (neat): 2981, 1729, 1455, 1258, 1182, 1105, 1027, 700 cm-¹.

¹H NMR (400 MHz, CDCl3): δ = 7.30-7.27 (m, 2 H), 7.20-7.18 (m, 3 H), 4.19 (q, J = 7 Hz, 4 H), 2.60-2.56 (m, 2 H), 2.19-2.15 (m, 2 H), 1.50 (s, 3 H), 1.26 (t, J = 7 Hz, 6 H).

¹³C NMR (100 MHz, CDCl3): δ = 172.2, 141.5, 128.37, 128.34, 125.9, 61.2, 53.6, 37.5, 30.8, 20.0, 14.1.

HMRS (ESI): m/z calcd for C16H23NO4 [M + H]+: 279.1591; found: 279.1588.

Anal. Calcd for C16H22NO4: C, 69.04; H, 7.97; O, 22.99. Found: C, 69.03; H, 8.26; O, 22.48.

2-(Ethoxycarbonyl)-2-methyl-4-phenylbutanoic Acid (3)

To a solution of diethyl 2-methyl-2-phenethylmalonate (16.7 g, 60.0 mmol) in EtOH (150 mL) at 50 ˚C was added dropwise over 15 min a solution of KOH (3.40 g, 60.6 mmol) in a H2O (15 mL)-EtOH (25 mL) mixture. The colorless homogeneous solution was then allowed to stir under argon at 50 ˚C for 64 h. The reaction mixture was then cooled to r.t., and concentrated at 50 ˚C by rotary evaporation. The resulting white solid was dissolved in H2O (250 mL), and the resulting aqueous layer was washed with EtOAc (350 mL). The aqueous solution was then acidified with concd HCl (8 mL), and extracted with EtOAc (2 × 350 mL). The combined organic layers were washed with brine (250 mL), dried (Na2SO4), and concentrated at 40 ˚C by rotary evaporation. The resulting colorless oil was dried under vacuum, which smoothly crystallized at r.t. to afford 9.3 g (62%) of the monoester of malonic acid 3 as a white crystalline solid; mp 80 ˚C; R f = 0.49 (10% MeOH-CH2Cl2).

IR (neat): 2966, 2941, 1744, 1701, 1453, 1280, 1179, 1066, 933, 751, 696 cm-¹.

¹H NMR (400 MHz, CDCl3): δ = 7.30-7.27 (m, 2 H), 7.21-7.18 (m, 3 H), 4.23 (q, J = 7 Hz, 2 H), 2.63-2.59 (m, 2 H), 2.27-2.14 (m, 2 H), 1.55 (s, 3 H), 1.29 (t, J = 7 Hz, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 177.9, 172.2, 141.1, 128.4, 128.3, 126.1, 61.8, 53.6, 37.7, 30.9, 20.3, 14.6.

HMRS (ESI): m/z calcd for C14H18O4 + Na [M + Na]+: 273.1097; found: 273.1094.

Anal. Calcd for C14H18O4: C, 67.18; H, 7.25. Found: C, 67.18; H, 7.25.

N - tert -Butyl 2-(Ethoxycarbonyl)-4-phenylbutan-2-ylcarbamate (4); Procedure 2

To a solution of 2-(ethoxycarbonyl)-2-methyl-4-phenylbutanoic acid (3; 7.51 g, 30.0 mmol), NaN3 (3.90 g, 60.0 mmol), TBAB (0.870 g, 2.70 mmol), and zinc triflate (220 mg, 0.600 mmol) in THF (150 mL) was added warm di-tert-butyl dicarbonate (7.60 mL, 33.0 mmol) via a syringe over 10 sec. The reaction mixture was stirred with a mechanical stirrer under argon at 50 ˚C for 50 h. The mixture was cooled to r.t. and quenched with aq 10% NaNO2 (50 mL). The biphasic mixture was stirred for 30 min at r.t. and the two layers were separated, and the organic layer was washed successively with sat. aq NH4Cl (75 mL), brine (75 mL), and dried (Na2SO4, 50 g). The organic layer was filtered and concentrated at 40 ˚C by rotary evaporation to afford an orange oil. Purification by column chromatography (2% EtOAc-hexanes, then 5% EtOAc-hexanes) afforded 6.75 g (70%) of the pure protected amino acid 4 as a colorless oil; R f = 0.28 (10% EtOAc-hexanes).

IR (neat): 3425, 3265, 2978, 2932, 1704, 1495, 1365, 1252, 1163, 1055, 1028, 698 cm-¹.

¹H NMR (400 MHz, C6D6, 70 ˚C): δ = 7.11-6.99 (m, 11 H), 5.32 (br s, 1 H), 3.86 (q, J = 7 Hz, 2 H), 2.63-2.47 (m, 2 H), 2.44-2.37 (m, 1 H), 2.10-2.03 (m, 1 H), 1.52 (s, 3 H), 1.40 (s, 9 H), 0.89 (t, J = 7 Hz, 3 H).

¹³C NMR (100 MHz, CDCl3): δ = 174.3, 154.1, 141.3, 128.3, 128.2, 125.9, 79.3, 61.5, 59.4, 38.4, 30.6, 28.3, 23.6, 14.1.

HMRS (ESI): m/z calcd for C18H27NO4 + Na [M + Na]+: 344.1832; found: 344.1817.

Anal. Calcd for C18H27NO4: C, 67.26; H, 8.47; N, 4.36; O, 19.91. Found: C, 67.24; H, 8.44; N, 4.46; O, 19.88.

Benzyl 2-Iodophenylcarbamate (6); Procedure 3

To a solution of 2-iodobenzoic acid (5; 7.44 g, 30.0 mmol), NaN3 (2.92 g, 45.0 mmol), t-BuONa (231 mg, 2.40 mmol) in DME (100 mL) was added dropwise benzyl chloroformate [¹²] (4.71 mL, 33.0 mmol) over 15 min at 25 ˚C. The resulting reaction mixture was then stirred at 75 ˚C for 16 h. The mixture was cooled to r.t. and quenched with aq 10% NaNO2 (50 mL). The biphasic mixture was stirred 30 min at r.t.. The two layers were separated, and the organic layer was washed successively with sat. aq NH4Cl (75 mL), brine (75 mL), and dried ( Na2SO4). The organic solution was filtered and concentrated at 40 ˚C by rotary evaporation to afford an orange oil. The solvent was removed under reduced pressure. The desired anilide 6 (9.74 g, 92%) was obtained as a white solid after flash chromatography (3% EtOAc-hexanes); mp 49 ˚C; R f = 0.57 (20% EtOAc-hexanes).

IR (neat): 3383, 3031, 2953, 1732, 1586, 1514, 1432, 1201, 1036, 741 cm-¹.

¹H NMR (400 MHz, CDCl3): δ = 8.10 (d, J = 8 Hz, 1 H), 7.77 (d, J = 8 Hz, 1 H), 7.46-7.33 (m, 6 H), 7.05 (br s, 1 H), 6.81 (t, J = 8 Hz, 1 H), 5.24 (s, 2 H).

¹³C NMR (100 MHz, CDCl3): δ = 153.2, 151.4, 138.8, 138.2, 135.7, 129.2, 128.6, 128.3, 125.1, 120.3, 88.8, 67.2.

HMRS (ESI): m/z calcd for C14H12INO2 [M + H]+: 353.9985; found: 353.9982.

1,3-Diphenylurea (8); Procedure 4

To a solution of benzoic acid (7, 3.66 g, 30.0 mmol), NaN3 (2.92 g, 45.0 mmol), t-BuONa (231 mg, 2.40 mmol) in DME (100 mL) was added phenyl chloroformate [¹5] (4.14 mL, 33.0 mmol) over 15 min at 25 ˚C. The resulting reaction mixture was then stirred at 75 ˚C during 8 h, then aniline (4.10 mL, 45.0 mmol) was added and the mixture was stirred at 75 ˚C for 16 h. The mixture was cooled to r.t. and diluted with hexanes (70 mL). The solution was then cooled to 0 ˚C (ice bath) with continuous stirring; H2O (10 mL) was added and the stirring maintained for 25 min at 0 ˚C. The solid was filtered and triturated with Et2O (40 mL). The desired urea 8 (4.45 g, 70%) was obtained as a white solid; R f = 0.51 (40% EtOAc-hexanes); mp 219 ˚C.

IR (neat): 3281, 3036, 1646, 1592, 1538, 1496, 1439, 1230, 893, 751 cm-¹.

¹H NMR (400 MHz, CDCl3): δ = 8.24 (br s, 2 H), 7.45 (d, J = 8 Hz, 4 H), 7.27 (t, J = 8 Hz, 4 H), 6.96 (t, J = 7 Hz, 2 H).

¹³C NMR (100 MHz, CDCl3): δ = 152.4, 139.6, 128.7, 121.7, 118.1.

HMRS (ESI): m/z calcd for C13H12N2O + Na [M + Na]+: 235.0842; found: 235.0843.

Acknowledgment

This research was supported by NSERC (Canada), F.C.A.R (Québec), the Canadian Foundation for Innovation, the Research Corporation, Boehringer Ingelheim (Canada) Ltée, Merck Frosst Canada, and the Université de Montréal. O.L. would like to thank ‘Conseil Général de la Guadeloupe’ for a graduate fellowship.

8

When the reaction was run at 66 ˚C, the yields for compounds 9 and 13 decreased to 48% and 40%, respectively. The remaining product was the corresponding tert-butyl ester.

9

Lower yields (15-40%) were obtained with other solvents, such as Et2O, dioxane, DMSO, and CH2Cl2. This process is not compatible with protic solvents.

11

79% of unsubstituted Boc-aniline was obtained under these reaction conditions. However, functional groups such as methyl ether, thiomethyl ether, nitro, and halides were not tolerated, and the corresponding anilines were isolated in less than 25% yield.

12

A control experiment was run with chloroformate, NaN3, and carboxylic acid at r.t., which showed the formation of acyl azide, suggesting that the base is not essential for the formation of this intermediate. The base is probably involved in the formation of the carbamate from the isocyanate, by trapping the proton of the nucleophile.

15

The chloroformate reagent must be stored in a refrigerator prior to use.

8

When the reaction was run at 66 ˚C, the yields for compounds 9 and 13 decreased to 48% and 40%, respectively. The remaining product was the corresponding tert-butyl ester.

9

Lower yields (15-40%) were obtained with other solvents, such as Et2O, dioxane, DMSO, and CH2Cl2. This process is not compatible with protic solvents.

11

79% of unsubstituted Boc-aniline was obtained under these reaction conditions. However, functional groups such as methyl ether, thiomethyl ether, nitro, and halides were not tolerated, and the corresponding anilines were isolated in less than 25% yield.

12

A control experiment was run with chloroformate, NaN3, and carboxylic acid at r.t., which showed the formation of acyl azide, suggesting that the base is not essential for the formation of this intermediate. The base is probably involved in the formation of the carbamate from the isocyanate, by trapping the proton of the nucleophile.

15

The chloroformate reagent must be stored in a refrigerator prior to use.

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Scheme 1

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