Hexyl triazabutadiene as a potent alkylating agent

Tetrahedron Letters 58 (2017) 2700–2702

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Hexyl triazabutadiene as a potent alkylating agent Diana C. Knyazeva, Flora W. Kimani, Jean-Laurent Blanche, John C. Jewett ⇑ University of Arizona, Chemistry and Biochemistry, 1306 E. University Blvd., Tucson, AZ 85721, USA

a r t i c l e

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Article history: Received 12 May 2017 Accepted 15 May 2017 Available online 26 May 2017 Keywords: Alkyl diazonium ion Alkylating reagent Brønsted-Lowry acid

a b s t r a c t Alkyl diazonium ions are among the most reactive alkylating agents in the synthetic chemists’ arsenal. That said, there are precious few methods by which one can selectively and safely utilize this chemistry. Herein, we show the use of a bench stable hexyl triazabutadiene as a source of reactive diazonium ions that undergo substitution chemistry with weak nucleophiles, such as carboxylates and even sulfonates. In the absence of a nucleophile, elimination was observed to occur. To overcome issues stemming from sideproduct inhibition of the reaction, we show that the triazabutadiene can be pre-activated with tosyl isocyanate. Ó 2017 Elsevier Ltd. All rights reserved.

Triazabutadienes are a class of molecules that have remained largely outside of the focus of research in organic chemistry. These molecules were first characterized in 1965, but it wasn’t until the efforts of Fanghänel spanning the mid-1970s to the mid-1990s that the reactivity of this unique functionality was better understood.1 More recently, Bielawski revitalized the presence of this functionality in the chemical literature.2,3 Our work in the area of triazabutadienes started back in 2012, with a general interest in using the scaffold to gain insight into a potential catalytic conversion of alkyl azides to alkyl diazonium ions (Scheme 1).4 We proposed that ready, mild, access to alkyl diazonium ions would open many new avenues within synthetic organic chemistry. Inspired by a similar transformation from Raines whereby Staudinger intermediates could be re-routed,5 and insights into azide reactivity from Bielawski2 we set about to revive the study and explore the scope of new reactions that triazabutadienes could provide (Scheme 1b). We have previously reported our efforts with the use of triazabutadienes as protection for aryl diazonium ions,6 but prompted by a recent study by Bugarin,7 we discuss herein our complementary understanding of alkyl triazabutadienes and the reactions that they undergo. At the outset of this project we sought a generalizable way to provide synthetically useful alkyl diazonium ions under mild reaction conditions. While starting with benzylic substrates, similar to those shown by Bugarin,7 we moved away from these species due to the stability and unique reactivity of benzylic cations. For the sake of broad generalizability, we sought to understand the reactivity of simple long-chain alkyl groups. The synthesis of our triaz⇑ Corresponding author. E-mail address: [email protected] (J.C. Jewett). http://dx.doi.org/10.1016/j.tetlet.2017.05.056 0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.

abutadienes followed protocols established by Bielawski,2 and we elected to use diethyl imidazolium precursors for reasons of reagent handling, and to increase the molecular weight out of a general concern that these compounds may decompose via a highly energetic side pathway. One of the first modes of reactivity explored was the reaction of alkyl triazabutadienes with various carboxylic acids. It was expected that these would react analogously to diazomethane where protonation of the reagent would afford a diazonium ion that would readily alkylate the conjugate base of the acid substrate, forming the corresponding ester. While in situ generated diazomethane8 and commercially available trimethylsilyl diazomethane9 are commonly used organic reagents, there are no analogous reagents for longer, more complex alkyl chains. We synthesized hexyl triazabutadiene 1 and examined the reaction with a small panel of carboxylic acids that contained varied pKa (4.2–5.1), alkyl versus aryl substituent, and steric concerns (from the small acetic acid to the bulky pivalic acid). During this initial screening, it was noted that an excess of acid was required to achieve a yield (based on 1) of greater than 50% (Table 1). It was surmised that the guanidine byproduct 2 was more basic than 1, and was consuming the acid to form a guanidinium salt (Fig. 1), leaving intact a portion of 1. Later, after more acids were screened with a greater range of pKa values (2.2–9.3), it was noted that there was no diminution of yield with stronger acids, in fact the reactions appeared to perform better with these poorly nucleophilic conjugate bases. Interestingly, when p-hydroxybenzoic acid was tested, a mixture of the ester with free phenol, and ester with alkylated phenol was observed. Given that the reaction was performed with excess acid and the relative pKa values, this implies that the alkylating agent was able to alkylate a protonated phenol.

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a.

substitution reagent

N3

N2

elimination

R

R

Table 2 Alkylation of sulfonic acids with 1.

Et N

rearrangement

N

ref. 2

b.

Et N N Et

N Et

Et N

E

N N N

N N Et

R

N2

E

R

Scheme 1. a) The transformation for alkyl azides to alkyl diazonium ions was desired. This was proposed to be possible through conversion to a triazabutadiene and, b) treatment with an electrophile.

N N 1

RCO2H

R

CH 2Cl 2 rt

5

Et N

O

RCO 2H

N N Et

O

N N Et

5

H 2

pKa (pKa2)

Ratio (1: acid)

Yield of ester (based on 1)

4.2

1:1 1:2 1:3 1:2 1:2 1:2 1:2

35% 54% 59% 64% 51% (24%)* 46% 39%

BzOH BzOH BzOH 2-Nitrobenzoic 4-Hydroxybenzoic AcOH PivOH

2.2 4.5 (9.3) 4.8 5.0

* 4-Hydroxybenzoic acid produced a mixture of mono- and bisalkylated products in a 5:1 ratio. The 24% yield is based on the stoichiometry of 2 additions of the hexyl coming from 1.

Et N N Et

H N

Nu

Et N

R

N Et

N N 2

N N 1

5

RSO3H

pKa

CSA MsOH MsOH TsOH TfOH

(1.2) 2.6 2.6 2.8 14

O O S O R

CH 2Cl 2 rt

Et N N N Et

5

H

Method

Yield of sulfonate (based on 1)

A A B A A

54% 74% 74% 62% 38%

Method A: A solution of 1 was added to a solution of the sulfonic acid dropwise. Method B: A solution of the acid was added to a solution of 1 dropwise. Although there was no difference in yield for MsOH, this method produced an inseparable mixture of products for TfOH and was therefore discontinued.

Table 1 Esterification of carboxylic acids with 1.

Et N

2.0 equiv. RSO 3H

H N Nu

Nu N2 H

N2 Nu R

conditions (Table 2). This alkylation of sulfonates appears to follow the observation from above where poorly nucleophilic conjugate bases provide reasonable yields. In the case with trifluoromethanesulfonic acid, the product is unstable and it is difficult to obtain a high yield. There is little precedent for such a reaction with minimally competent nucleophiles like sulfonate anions, but upon scouring the literature, we found that Bräse had reported a solidsupported triazene accomplishing a similar remarkable alkylation.10 Indeed, Bräse’s work accomplished a second long-term goal of ours wherein alkyl amines were directly converted into potent leaving groups in one synthetic transformation. To the best of our knowledge, this reactivity has been underutilized in the area of synthetic organic chemistry. To move this chemistry beyond synthetic trumpery, we sought a means by which a carboxylic acid could be treated as precious and not used in excess. With an understanding that alkyl diazonium species are likely being formed concurrent with a basic guanidine byproduct, we returned to the idea of using a sacrificial electrophile to activate the triazabutadiene. From previous work, we knew that triazabutadienes preferentially react at the N1 nitrogen,11 so we sought an electrophile that would have reversibility. We found a solution in the form tosyl isocyanate. If formed, the N1 addition product is reversible and equilibrates to the thermodynamically more stable N3 addition product, 3. We have invoked an

R

critical problem Fig. 1. Mechanism for the alkylation of acids with a triazabutadiene. A problem arises because the side product of diazonium release is significantly more basic than the starting triazabutadiene.

We sought to overcome this competitive deprotonation by adding a stoichiometric amount of a sacrificial strong acid. Camphor sulfonic acid (CSA) was initially chosen as it provided ease of handling, organic solvent solubility, and a conjugate base that would serve as a non-nucleophilic counter ion. Surprisingly, our yields of the ester did not improve significantly; in fact, a mixture of products was observed. To probe the cause of the poor yield, an attempt was made to assess the degradation products of the reaction of 1 with the sacrificial acid alone. Remarkably, it was determined that 1 alkylated the sulfonic acid! Wondering if this was somehow unique to CSA, we went on to show that p-toluenesulfonic acid, methanesulfonic acid and even trifluoromethanesulfonic acid (with a pKa of 14!) were alkylated under these

Et N N Et

N3 N1

TsNCO

5

CH2Cl2 2 min. (thermodynamic)

N N N 1

Et O Ts N N N N N N Et 3 5

O silica gel

HO O

3

+ 1-hexan ol

5

O

64% (based on BzOH)

Ts Et O NH N N N 4 Et

Scheme 2. Triazabutadiene 1 reacts with tosyl isocyanate to form 3, which goes on to release diazonium ions upon protonation. The resulting diazonium ion can go on to do substitution or elimination chemistry depending upon conditions.

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electrostatic, dipole minimization argument to understand the relative stability of this inner salt. While the thermodynamic product, this species is highly prone to degradation in protic environments, even exposure to trace amounts of water in the organic solvent results in its release to a hexyl diazonium ion and 4. The by-product, 4, is not basic compared with guanidine 2, and as such does not consume extra equivalents of the species that protonated it. True to expectations, when treated with one equivalent benzoic acid we observed immediate bubbling and obtained a 64% yield of the resulting ester based on the acid.12 To further probe this type of reactivity and to determine the outcome when a diazonium is formed without a nucleophile present, silica gel was added to a solution of 3. Violent bubbling was observed and 1-hexene was obtained, as well as 1-hexanol due to advantageous water acting as a nucleophile (Scheme 2). In conclusion, we have reported on the reactivity of alkyl triazabutadienes as sources for liberating alkyl diazonium ions under mild conditions. These reactions could prove useful with highvalue acids that are sensitive to conditions traditionally used for esterification reactions. To this end we developed a protocol to pre-activate the triazabutadiene to improve yields. Viewed together with the recent work of Bugarin, this report exposits the diversity of reactivity that can be garnered from this scaffold.

Funding information The authors thank the following sources of funding for support: an NSF GRFP to DCK (DGE-1143953); an ACS PRF to JCJ. We also thank the NSF for a departmental instrumentation grant for the NMR facility (CHE-0840336).

Acknowledgment The authors would like to thank the NMR and MS facilities at the University of Arizona.

A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2017.05. 056. References 1. (a) Winberg HE, Coffman DD. J Am Chem Soc. 1965;87:2776; (b) Fanghänel E, Hänsel R, Ortmann W, Hohlfeld J. J Prakt Chem. 1975;317:631–640; (c) Fanghänel E, Bauroth JU, Hentschel H, Gußmann F, Alzyadi H, Ortmann W. J Prakt Chem. 1992;334:241–247. 2. Khramov DM, Bielawski CW. Chem Commun. 2005;39:4958–4960. 3. Patil S, Bugarin A. Eur J Org Chem. 2016;5:860–870. 4. Kimani FW. Triazabutadiene Chemistry in Organic Synthesis and Chemical Biology (PhD Dissertation). Tucson, AZ: University of Arizona; 2016. 5. Myers EL, Raines RT. Angew Chem Int Ed Engl. 2009;48:2359–2363. 6. (a) He J, Kimani FW, Jewett JC. J Am Chem Soc. 2015;137:9764–9767; (b) Kimani FW, Jewett JC. Angew Chem Int Ed. 2015;54:4051–4054; (c) Cornali BM, Kimani FW, Jewett JC. Org Lett. 2016;18:4948–4950; (d) Guzman LE, Kimani FW, Jewett JC. ChemBioChem. 2016;17:2220–2222; (e) Jensen SM, Kimani FW, Jewett JC. ChemBioChem. 2016;17:2216–2219. 7. Barragan E, Bugarin A. J Org Chem. 2017;82:1499–1506. 8. Hopps H. Aldrichemica Acta. 1970;3:33. 9. Aoyama T, Shioiri T. Chem Pharm Bull. 1981;29:3249–3255. 10. Vignola N, Dahmen S, Enders D, Brase S. Tetrahedron Lett. 2001;42:7833–7836. 11. Fanghänel E, Poleschner H, Radeglia R, Hänsel R. J Prakt Chem. 1977;319:813–826. 12. Experimental for Use of Tosyl Isocyanate with 1. To a solution of tosyl isocyanate (0.028 g, 0.14 mmol) in methylene chloride (1.0 mL) was added 1 (0.036 g, 0.14 mmol) in methylene chloride (0.25 mL). The reaction mixture was stirred at room temperature for 5 min, after which a solution of benzoic acid (0.012 g, 0.096 mmol) in methylene chloride (0.25 mL) was added. This mixture was stirred under argon for 4 hours at room temperature, after which a white precipitate was observed. The mixture was filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in ether and washed with saturated sodium bicarbonate, water, and brine, dried over sodium sulfate, and concentrated under reduced pressure. Column chromatography (9:1 hexanes/ether) yielded hexyl benzoate (0.013 g, 64%). 1 H NMR of the white precipitate (4) (400 MHz, DMSO-d6) d 9.33 (br s, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.43 (s, 2H), 7.23 (d, J = 8.1 Hz, 2H), 3.78 (q, J = 6.8 Hz, 4H), 2.33 (s, 3H), 1.19 (t, J = 7.1 Hz, 6H). 13C NMR (DMSO-d6, 125 MHz) 128.28, 126.68, 41.59, 20.88, 14.17. HRMS calculated for C15H20N4O3S [M+H+]: 337.13289 measured 337.13295.