Accessing the Rare Diazacyclobutene Motif

Article abstract of DOI:10.1021/acs.orglett.8b03590

A formal [2 + 2] cycloaddition of 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) with electron-rich alkynyl sulfides and selenides is described. These investigations provide a convenient method to access diazacyclobutenes in good yield while tolerating a rela

Full text of DOI:10.1021/acs.orglett.8b03590

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Accessing the Rare Diazacyclobutene Motif
Chandima J. Narangoda,† Timothy R. Lex,† Madelyn A. Moore,† Colin D. McMillen,†
Alex Kitaygorodskiy,† James E. Jackson,‡ and Daniel C. Whitehead*,†,§
†Department of Chemistry, Clemson University, Clemson, South Carolina 29634, United States
‡Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States
§Eukaryotic Pathogens Innovation Center, Clemson University, Clemson, South Carolina 29634, United States
S
* Supporting Information
ABSTRACT: A formal [2 + 2] cycloaddition of 4-phenyl-
1,2,4-triazoline-3,5-dione (PTAD) with electron-rich alkynyl
sulfides and selenides is described. These investigations
provide a convenient method to access diazacyclobutenes in
good yield while tolerating a relatively broad substrate scope
of thio-acetylenes. This method provides ready access to a
unique and hitherto rarely accessible class of heterocycles. A
combination of dynamic NMR, X-ray crystallography, and
computation sheds light on the potential aromaticity of the
scaffold.
moiety that formally follows the Huckel (4n+2) rule of
̈
he triazolinediones, such as 4-phenyl- and 4-methyl-1,2,4-
Ttriazoline-3,5-dione (PTAD and MTAD, respectively)
have proven to be versatile synthetic tools to effect a number of
useful transformations.1 We present here the results of a study
that evaluated the reactivity of these species with electron-rich
alkynyl sulfides and selenides for the preparation of a rarely
accessible molecular architecture, the diazacyclobutenes.2 The
diazacyclobutenes (1−4, 6) are a unique class of four
membered heterocycles consisting of a carbon−carbon double
bond and two adjacent nitrogen atoms (Scheme 1).
Historically, these heterocycles gained attention in the
literature owing to the electronic framework resident in the
aromaticity.3,4 Thus, these molecules, their potential aroma-
ticity, and their putative reactivity have been the subject of
several computational5−9 and comparatively fewer synthetic
studies.5,10−13 Despite the first report on the preparation of a
small set of stable diazacyclobutenes appearing over half a
century ago,10 less than 10 examples of this scaffold are known
(1−4), and typically have been accessed in rather poor
yields.5,10−13
With an interest in accessing this interesting and relatively
unexplored scaffold, we set out to develop a convenient
method to synthesize diazacyclobutenes. Initial grounding
experiments focused on combining PTAD and unmodified
alkynes (i.e., similar to the work of Greene)12 under a variety
of conditions, efforts that ultimately failed to bear any
productive fruit. We next hypothesized that more electron-
rich alkynes might fare better in the desired transformation.
Thus, we settled on the preparation of a series of alkynyl
sulfides, which provided enhanced electron density on the
alkyne substrate coupled with relative ease of synthesis
(Scheme 2). Briefly, the alkynyl sulfides, 5, were accessible
by direct deprotonation of terminal alkynes followed by either
interception with elemental sulfur followed by quenching the
incipient sulfide anion with an alkyl halide (Condition A), or
direct reaction of the lithium acetylide intermediate with an
appropriate dialkyl disulfide (Condition B) (see Supporting
Information (SI) for more details).14−16 Two alkynyl selenides
were also prepared using analogous conditions to those
depicted in Scheme 2.17,18
Scheme 1. Historical Examples of Diazacyclobutenes and a
New Synthetic Route
Received: November 9, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03590
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Letter
continued optimization of these substrate classes remains an
area of active study in our laboratory.
Scheme 2. Synthesis of Alkynyl Sulfides
We next explored the substrate scope of the transformation
(Scheme 3). First, we evaluated varying the length of the alkyl
Scheme 3. Substrate Scope (1 mmol Scale)
Next, we investigated the potential cycloaddition between
PTAD and methyl phenylethynyl sulfide (i.e., 5a) to provide
the corresponding diazacyclobutene 6a (Table 1). We first
Table 1. Optimization of Diazacyclobutene synthesis
a
entry
solvent
5a (equiv)
time [h]
yield [%]
1
2
3
4
5
6
7
8
9
CHCl3
DCM
THF
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.0
1.1
1.2
1.3
24
24
24
24
24
6
12
24
24
24
82
78
68
67
89
80
83
71
69
72
75
toluene
ACN
ACN
ACN
ACN
ACN
ACN
ACN
10
11
b
24
a
b
Isolated yields after column chromatography. Reaction conducted
at 0.2 M. DCM = dichloromethane, THF = tetrahydrofuran, ACN =
acetonitrile.
examined the yield of the reaction when PTAD (1 equiv) and
5a (1.3 equiv) were heated under reflux conditions for 24 h in
a series of common solvents (entries 1−5). Acetonitrile was
found to afford the highest yield (i.e 89% yield, entry 5) of
diazacyclobutene 6a, although the transformation tolerates a
range of solvents reasonably well. Chloroform and dichloro-
methane gave slightly lower yields of 82% and 78%,
respectively, whereas tetrahydrofuran and toluene provided
even lower yields of 68% and 67% (entries 1−4). Reaction
conditions were further tuned by conducting a time study:
refluxing in acetonitrile for 6 h (80%) and 12 h (83%) returned
6a in good but slightly lower yields compared to the
corresponding 24 h reaction (entries 6−7). Furthermore,
decreasing the equivalence of alkynyl sulfide 5a resulted in
lower isolated yields of product 6a (i.e., 71%, 69%, and 72%
yield for 1.0, 1.1, and 1.2 equiv 5a, respectively (entries 8−
10)). Finally, when the concentration of the reaction was
doubled (i.e., to 0.2 M in PTAD), the yield was also
diminished to 75% of 6a (entry 11). Thus, on the basis of
these observations we selected the conditions in entry 5
(highlighted in bold) as the optimal conditions. The
cyclization of related N-methyl-N-tosyl ynamines and silyl
ynol ethers proceeded rather poorly under the present reaction
conditions (i.e., 30−40% yield for ynamines in the presence of
a Lewis acid catalyst, and not at all with silyl ynol ethers). The
chain resident on the sulfur atom (i.e., R2) of the alkynyl
sulfide component (6a−6f). Products bearing shorter n-alkyl
chains at R2 such as methyl, ethyl, n-propyl, and n-butyl were
successfully converted into their corresponding diazacyclobu-
tene derivatives 6a−d in 77−89% yields. The diazacyclobutene
derivatives 6e and 6f bearing n-pentyl and n-octyl groups at
B
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Letter
sulfur were generated in 78% and 81% yields, respectively.
Incorporating a benzyl group at R2 returned 6g in moderate
yield (62%), while the R2 = Ph analogue (6h) was prepared in
85% isolated yield at 1 mmol scale.
tional studies have explored the potential for aromaticity in this
system.5−7,9 However, all of the compounds that we have
analyzed by X-ray crystallography show a puckered structure
with the five-membered ring canted out-of-plane with respect
to the core diazacyclobutene moiety. On average, the angle of
intersection of the four-membered and five-membered ring
planes is θ = 125.0 1.8°, see Figure 1A and Table S4).
The puckered geometry of the 4/5 bicyclic ring system
results in the appearance of two distinct enantiomers (Figure
1B) in the unit cell for every compound we have probed by X-
ray analysis. These two enantiomers appear to rapidly
equilibrate at room temperature. Thus, we analyzed the double
We then examined the reactivity of alkyl phenylacetylene
sulfides bearing para-substituted electron donating and with-
drawing substituents on the phenyl group situated at R1.
Substrates with arenes bearing electron donating groups such
as p-methyl (i.e., 6i and 6j, 92 and 77% yields, respectively)
and p-methoxy (i.e., 6k, 74% yield) proceeded in good yield.
Substrates with arenes bearing electron withdrawing sub-
stituents such as p-chloro and p-trifluoromethyl (6l−m, 85 and
83%, respectively) also generated the corresponding diazacy-
clobutene derivatives in good yields. We also probed the
transformation with thio-acetylenes bearing an alkyl chain (i.e.
n-butyl) at R1 in lieu of an arene. Thus, diazacyclobutenes 6n
(R2 = methyl) and 6o (R2 = n-butyl) were prepared in
moderate yields of 61% and 56%, respectively. Additionally,
diazacyclobutene 6p, for which R1 = cyclopropyl, was prepared
in 94% yield. Finally, modulating the chalcogen in the system
to selenium provided two examples, 6q and 6r, in 80 and 93%
yield, respectively. The reaction also scales reasonably well.
The synthesis of 6h was carried out on a 6 mmol scale,
returning the diazacyclobutene in 81% isolated yield (1.87 g).
The compounds presented in Scheme 3 are almost
universally crystalline. Thus, we have obtained single crystal
X-ray structures of 11 of them (see Figure 1 for 6k; see SI for
1
nitrogen inversion barrier by means of dynamic H NMR
analysis19 under cryogenic conditions. Specifically, the S-benzyl
methylene protons in diazacyclobutene 6g appear as a clean
singlet (4.21 ppm, 300 MHz) at room temperature, but
gradual cooling of the sample to −25 °C revealed a clear
coalescence point followed by resolution into a clean AB
quartet (4.22 ppm, 4.15 ppm, J = 12.8 Hz), indicative of
diastereotopicity at lower temperatures (see Figure 2A for
experimental spectra). Dynamic NMR simulations and line
shape analyses were performed using Bruker Topspin version
3.5 software, and the exchange rate constant, Kex, was
extracted. An Eyring plot (Figure 2B) was used to calculate
the ΔH⧧ and ΔS⧧ terms: 14.4 0.7 kcal/mol and 3.2 2.7
cal/mol·K, respectively. From these data, the activation energy,
(ΔG⧧), for the inversion was determined to be 13.4
0.7
kcal/mol at 298 K (25 °C). A similar analysis was conducted
for the S-ethyl methylene protons in 6b (see SI), revealing an
inversion barrier, ΔG⧧, of 13.6 0.5 kcal/mol at 298 K (25
°C).
Finally, we evaluated the inversion barrier computationally
for 6a at 25 °C in the gas phase and in simulated chloroform
solvent, using the wB97X-D/6-311+G(2df,2pd) DFT meth-
od20 and the SMD solvation model of Cramer et al.21 as
implemented in the Gaussian 16 program suite.22 The results,
ΔH⧧ = 12.6 and 11.3 kcal/mol respectively, show solvation
lowering the enthalpy barrier to inversion. This finding
surprised us, but accords with the larger dipole moment
(2.62 vs 2.25 D) calculated for the near-planar transition
structure (TS) for inversion than for the strongly bent ground
state (GS) minima. To further explore this issue, we reanalyzed
the above TS and GS structures using the wave function-based
T1 method of Hehre et al.,23 with solvation computed at the
B3LYP/6-31+G*/SM8 level, as implemented in the Spartan
quantum chemistry code (Figure 3).24 The resulting gas- and
CHCl3 solvated barriers were 14.9 and 14.2 kcal/mol,
respectively, in good agreement with experiment. Inclusion
of entropy terms to compute free energy barriers did not
change them from the above values, consistent with the small
ΔS⧧ values obtained experimentally.
Figure 1. (A) Single crystal X-ray structure of diazacyclobutene 6k,
highlighting the 4/5 ring plane intersection angle, θ. (B) Enantiomers
evident in the X-ray structure.
The increase and orientation of the dipole in the flat
inversion TS suggest that charge may be shifting from the
vicinal nitrogen centers into the carbonyl groups of the urazole
ring, and perhaps gaining some delocalization and potentially
aromatic stabilization for these two formally 4n+2 π electron
rings. To probe this question, we performed NICS(1)zz
(Nucleus Independent Chemical Shift) calculations on all four
rings of the GS and TS structures. NICS(1)zz extracts the out-
of-plane (zz) tensor component of the isotropic NICS, thus
minimizing σ-orbital contributions.25 Positive values of
ΔNICS(1)zz upon ring flattening would indicate increased
paratropic (i.e., antiaromatic) ring current, suggesting destabi-
more details and data for 6a−c, 6h, 6i, 6l, 6m, 6p, 6q, and 6r;
CCDC 1871105−1871115 contain the supplementary crys-
tallographic data for this manuscript). Leveraging this data and
our ability to access a large number of diazacyclobutene
derivatives for the first time, we were in a position to evaluate
the potential aromaticity of this class of molecules by exploring
the X-ray structures of the diazacyclobutene core in a suite of
electronically distinct compounds (see section VI in SI).
Indeed, the core diazacyclobutene scaffold formally obeys the
Huckel 4n+2 rule for aromaticity, and a number of computa-
̈
C
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Letter
overlap and potential for delocalization, aromaticity is not an
element in stabilizing the inversion TS.
On the basis of the puckered nature of the scaffold that is
evident in every example that we have analyzed by X-ray
crystallography, and on the basis of the experimental
observation of the racemizing inversion by dynamic 1H
NMR, and our computational results, it appears that the
diazacyclobutanes arising from our study are not aromatic,
even in the TS that is traversed during the inversion process.
Our observations provide experimental evidence that corrob-
orates the conclusions drawn earlier computationally by
others.5−7,9. For a broader historical perspective on the
potential aromaticity of diazacyclobutenes, see section VI in
the SI.
In conclusion, we have developed a straightforward
approach for the synthesis of rare diazacyclobutanes by
means of a formal [2 + 2] cycloaddition between alkynyl
sulfides or selenides and PTAD. This effort provides ready
access to a molecular scaffold that was hitherto inaccessible
over the last half-century, with the exception of a handful of
examples. Experimental and computational evidence suggests
that the compounds are not aromatic, despite formally obeying
the Huckel 4n+2 rule for aromaticity. Efforts are underway
̈
currently to expand the substrate scope of this transformation
by exploring new triazoline diones and electron-rich alkynes, to
probe the mechanism of the transformation, and to explore the
further synthetic manipulation and biological activity of this
unique molecular scaffold. More broadly, this study contributes
to the challenging research area devoted to the preparation of
four-membered and other strained heterocycles.26,27
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03590.
Experimental details, further discussion on the potential
aromaticity of diazacyclobutenes, X-ray crystallography
data, and full characterization data for all synthetic
compounds (PDF)
Figure 2. Dynamic NMR analysis (300 MHz) of the inversion barrier
of 6g. (A) Experimental spectra at variable temperature. (B) Eyring
plot originating from simulated spectra. Box: Thermodynamic
parameters for the inversion barrier extracted from the Eyring plot.
Accession Codes
CCDC 1871105−1871115 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*dwhiteh@clemson.edu
ORCID
Figure 3. Calculated minima (A and C) and transition state (B) for
the double nitrogen inversion of 6a calculated at the wB97X-D/6-
311+G(2df,2pd) level.
Daniel C. Whitehead: 0000-0001-6881-2628
Notes
The authors declare no competing financial interest.
lization of the TS, and vice versa. The ΔNICS(1)zz values
observed for both the four- and five-membered rings show
substantial paratropic shifts at −3.2 and −4.8 ppm for probe
sites positioned 1 Å above the center of the respective rings
(exo face, for GS). The implication is that despite improved π
ACKNOWLEDGMENTS
■
We thank Xinliang Ding (Michigan State University) for
HRMS analyses.
D
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Letter
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