Hexyl triazabutadiene as a potent alkylating agent

Article abstract of DOI:10.1016/j.tetlet.2017.05.056

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 side-product inhibition of the reaction, we show that the triazabutadiene can be pre-activated with tosyl isocyanate.

Full text of DOI:10.1016/j.tetlet.2017.05.056

Accepted Manuscript
Hexyl triazabutadiene as a potent alkylating agent
Diana C. Knyazeva, Flora W. Kimani, Jean-Laurent Blanche, John C. Jewett
PII:
S0040-4039(17)30637-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.05.056
TETL 48949
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Accepted Date:
12 May 2017
15 May 2017
Please cite this article as: Knyazeva, D.C., Kimani, F.W., Blanche, J-L., Jewett, J.C., Hexyl triazabutadiene as a
potent alkylating agent, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.05.056
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Hexyl triazabutadiene as a potent alkylating agent
Diana C. Knyazeva, Flora W. Kimani, Jean-Laurent Blanche, John C. Jewett*
a University of Arizona, Chemistry and Biochemistry, 1306 E. University Blvd., Tucson, AZ
85721 USA.
* indicates the corresponding author. email: jjewett@email.arizona.edu
Abstract Graphic:
Abstract:
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 side-product
inhibition of the reaction, we show that the triazabutadiene can be pre-activated with tosyl
isocyanate.
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
Page 1 of 9

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.
substitution
a.
reagent
N2
N3
elimination
R
R
rearrangement
ref. 2
b.
Et
Et
N
N
E
N
N
N2
N
N
N N
E
R
R
Et
Et
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.
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
Page 2 of 9

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
triazabutadienes 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 to 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 (Figure 1), leaving intact a portion of 1. Later, after more acids were
screened with a greater range of pKa values (2.2 to 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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Et
Et
N
O
N
RCO2H
N
N
R
O
N
N N
N
H
5
CH2Cl2
rt
Et
Et
1
5
2
RCO2H
pKa
(pKa2)
Ratio
(1 : acid)
1:1
Yield of ester
(based on 1)
35%
BzOH
BzOH
BzOH
4.2
1:2
1:3
54%
59%
2-nitrobenzoic
4-hydroxybenzoic
2.2
4.5
1:2
1:2
64%
51%
(9.3)
4.8
5.0
(24%)*
46%
39%
AcOH
PivOH
1:2
1:2
Table 1. Esterification of carboxylic acids with 1.
*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
Et
N2
H
N
N
H
Nu
R
Nu
R
N
Nu
N
N
N2
R
N
N
N
Et
Et
H
Nu
2
critical problem
Figure 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
Page 4 of 9

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
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 solid-
supported 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.
Et
Et
2.0 equiv.
N
N
O O
S
RSO3H
N
N
R
O
N
N N
N
H
CH2Cl2
rt
Et
Et
1
5
RSO3H
pKa
Method
Yield of sulfonate
(based on 1)
54%
CSA
(1.2)
-2.6
-2.6
-2.8
-14
A
A
B
A
A
MsOH
MsOH
TsOH
TfOH
74%
74%
62%
38%
Table 2. Alkylation of sulfonic acids with 1.
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.
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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 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).
Page 6 of 9

Et
Et
O
N
Ts
N3
N
N
N
N
N1
TsNCO
CH2Cl2
N
N
N
N
N
N
Et
Et
2 min.
(thermodynamic)
1
3
5
5
O
silica gel
HO
O
Et
O
N
Ts
NH
N
O
5
3
N
64% (based on BzOH)
+ 1-hexanol
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.
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
high-value 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.
Supporting Information
Supporting information is available online.
Page 7 of 9

References and Notes
1) a) Winberg, H. E.; Coffman, D. D. 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, J. U.; Hentschel, H.; Gußmann, F.; Alzyadi, H.; Ortmann, W. J. Prakt. Chem. 1992,
334, 241-247.
2) Khramov, D. M.; Bielawski, C. W. Chem. Commun. 2005, 39, 4958-60.
3) Patil, S.; Bugarin, A. Eur. J. Org. Chem. 2016, 5, 860-870.
4) Kimani, F. W. Triazabutadiene Chemistry in Organic Synthesis and Chemical Biology. PhD
Dissertation, University of Arizona, Tucson, AZ, 2016.
5) Myers, E. L.; Raines, R. T. Angew. Chem. Int. Ed. Engl. 2009, 48, 2359-63.
6) a) He, J.; Kimani, F. W.; Jewett, J. C. J. Am. Chem. Soc. 2015, 137, 9764-7; b) Kimani, F.
W.; Jewett, J. C. Angew. Chem. Int. Ed. 2015, 54, 4051-4; c) Cornali, B. M.; Kimani, F. W.;
Jewett, J. C. Org. Lett. 2016, 18, 4948-50; d) Guzman, L. E.; Kimani, F. W.; Jewett, J. C.
ChemBioChem 2016, 17, 2220-22; e) Jensen, S. M.; Kimani, F. W.; Jewett, J. C.
ChemBioChem 2016, 17, 2216-19.
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, 3249-55.
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 minutes, 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
Page 8 of 9

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%). 1H NMR of the white precipitate (4) (400 MHz, DMSO-d6) δ 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.
Page 9 of 9