Atypical Mode of [3 + 2]-Cycloaddition: Pseudo-1,3-dipole Behavior in Reactions of Electron-Deficient Thioamides with Benzynes

Article abstract of DOI:10.1021/acs.orglett.8b02133

Thioamides bearing electron-withdrawing groups on the thiocarbonyl carbon atom react with benzynes [generated by the hexadehydro-Diels-Alder cycloisomerization] in an unprecedented fashion. Namely, the dihydrobenzothiazole products are consistent with a pathway involving initial formation of a stabilized ammonium ylide by a rare type of [3 + 2]-cycloaddition reaction. The fate of this species depends upon the nature of the R group(s) attached to the ylide nitrogen atom. The demonstration of new modes of reactivity represents the major advance arising from this study.

Full text of DOI:10.1021/acs.orglett.8b02133

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Atypical Mode of [3 + 2]-Cycloaddition: Pseudo-1,3-dipole Behavior
in Reactions of Electron-Deficient Thioamides with Benzynes
Juntian Zhang,† Annika C. S. Page,† Vignesh Palani, Junhua Chen, and Thomas R. Hoye*
Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States
S
* Supporting Information
ABSTRACT: Thioamides bearing electron-withdrawing groups on the
thiocarbonyl carbon atom react with benzynes [generated by the
hexadehydro-Diels−Alder cycloisomerization] in an unprecedented
fashion. Namely, the dihydrobenzothiazole products are consistent with
a pathway involving initial formation of a stabilized ammonium ylide by a
rare type of [3 + 2]-cycloaddition reaction. The fate of this species
depends upon the nature of the R group(s) attached to the ylide nitrogen
atom. The demonstration of new modes of reactivity represents the major
advance arising from this study.
e recently reported reactions between benzynes such as
II (thermally generated from I) and aromatic
of N,N-diethyltrifluorothioacetamide (3a) to o-benzyne (6) is
shown in Figure 2. The computed exergonicity for the
formation of the ammonium ylide 7 as well as for its further
conversion to 8 and ethylene (ca. 20 and 50 kcal·mol−1,
respectively) are notable. We identified a transition structure
(TS1) corresponding to a low barrier process for a concerted
cycloaddition of 3a to 6. The geometry of that TS suggests that
the addition proceeds with the nucleophilic portion of the
thioamide leading the way; that is, the carbon−sulfur bond
formation is more advanced than that of the carbon−nitrogen
W
thioamides such as III to produce dihydrobenzothiazines
such as V (Figure 1a, structures designated by I−V refer to
species that appeared in our previous report).1 We rationalized
this process as proceeding through the series of intermediates
IVa−IVc. With this in mind, we have been surprised to now
see an alternative type of product (and mode of reaction) to
arise upon heating 1a in the presence of electron-deficient
thioamides such as 3a. This produced, instead, the
dihydrobenzothiazole 5aa.2 We propose that this trans-
formation proceeds by a rare type of net [3 + 2]-cycloaddition
(yellow highlight) to produce the ammonium ylide3,4 4aa,
followed by ethylene elimination. We are unaware of any
similar reactions between a thioamide and a 2π (alkene or
alkyne) component, although related transformations of
trithiocarbonate and dithiocarbamate5 functional groups have
been reported.6
Although the reaction between 2a and 3a may evoke the
notion of a 1,3-dipolar cycloaddition,7 it differs in important
ways. More specifically, each of the nonsacrificial resonance
contributors of classical 1,3-dipoles has the same overall bond
order, regardless of whether it is of the allyl or propargyl type
(Figure 1b). Each is a zwitterionic species with a formal
positive charge on the central atom and negative charge on one
of its terminal atoms.8 The [3 + 2]-cycloaddition products that
arise from engagement of a 1,3-dipole with the π-bond of a
dipolarophile are, formally, uncharged at all atoms in the
principal resonance contributor of the newly created five-
membered ring. The nature of 3a as well as its conversion to
the ylide 4aa are just the opposite; that is, 3a does not meet
the definition of a 1,3-dipole, and now, the resulting adduct
4aa is zwitterionic.
̀
(cf. indicated bond lengths in TS1 vis-a-vis those in 7). The
1,2-zwitterion character in 7 sets up a facile intramolecular
elimination reaction via TS2 to produce 8, the simplified
analogue of 5aa, and ethylene. The low activation barrier for
this step (ca. 15 kcal·mol−1) is also notable.9
To gain direct experimental evidence for the ejection of an
alkene from an ylide such as 4aa (or 7), we studied the
reaction of triyne 1a and N,N-dioctyltrifluorothioacetamide
(3b, Figure 3). A 2.2:1 ratio of the isomeric N-octylbenzo-
thiazolines 5ab and 5ab′ was formed.10 In addition, a very
nearly equimolar ratio of 1-octene was observed in the crude
reaction mixture (1H NMR and GC−MS). This result is
consistent with the eliminative fragmentation shown in species
4ab.
Another example of this new type of cycloaddition (Figure
4) was revealed when the N-allyltrifluorothioacetamide 3c (3
equiv) was heated (85 °C) with triyne 1a (Figure 1a). The
dihydrobenzothiazole 5ac10b results from a [3,2]-sigmatropic
migration of the allyl group, which again implicates the
intermediacy of the ammonium ylide 4ac, formed through
capture of 2a by the polarized thioamide 3c.
We then explored a series of reactions (Table 1) to probe
additional aspects of the reaction. First, would other electron-
We turned to DFT calculations to help further assess this
novel type of [3 + 2]-cycloaddition (Figure 2). The computed
reaction profile (with minima represented by 6−8 and
transition structures by TS1 and TS2) for the model addition
Received: July 7, 2018
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.8b02133
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 3. Use of the N,N-dioctylthioamide 3b allowed identification
of 1-octene, the elimination product from 4ab, and led to the
structural assignment of the major and minor products 5ab and 5ab′,
respectively, by the indicated NOEs.
Figure 1. Background. (a) Previous and current work reporting
divergent (left vs right, respectively) behavior in the trapping
reactions of benzynes with thioamides. (b) Classical 1,3-dipolar
cycloaddition reactions. See ref 2 for a description of the two-letter
structure designations.
a
Figure 4. Product 5ac from [3,2]-sigmatropic rearrangement also
supports the intermediacy of ylide 4ac.
withdrawing groups in the thioamide also promote this new
type of cycloaddition reaction? The reactions using thioamides
3d−f, containing −CF3, −CN, and −CO2Me groups,
respectively, all gave rise to products (5ad,10b 5ae,10b and
5af,10b respectively) that demonstrate just that. Second, is the
reaction unique to benzyne 2a? No, as evidenced by the
conversions of 1b and 1c to products 5bb10b and 5cc,10b
respectively, via eliminative or [3,2]-sigmatropic processes
within the ammonium ylides 4bb or 4cc, respectively.
Trapping with the pyrrolidine-containing thioamide 3g
revealed an additional new mode of reaction (Figure 5)
beyond the products of Stevens rearrangement (5ag) and
elimination (5ag′).11 Here, we also isolated the novel
dihydrobenzo-1,4-thiazine derivative 5ag′′.10b,12 We suggest
that this formally ring-expanded compound arises from a C−H
insertion event within the intermediate, isomeric carbene 9,
arising from dissociation of the nitrogen atom from the
ammonium ylide carbon. This overall process reveals yet
another facet of the reactivity of the ammonium ylides
encountered in this study. The reverse reaction, generation
of an ammonium ylide from a carbene, is known.13
Figure 2. DFT [SMD(benzene)//M06-2X/6-311+G(d,p)] calcula-
tions for the [3 + 2]-cycloaddition and subsequent ethylene
elimination for the hypothetical reaction between o-benzyne (6)
and the N,N-diethylthioamide 3a.
A comment about the observed regioselectivities leading to
the major constitutional isomer in these reactions is warranted.
B
DOI: 10.1021/acs.orglett.8b02133
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Table 1. Products 5 Arising from Several Different Electron-
Deficient Thioamides 3 and Several Different Benzyne
Precursors 1 via the Mechanistic Events Suggested in the
Intermediates Ammonium Ylides 4
Figure 5. Pyrrolidino thioamide 3g gave rise to three distinct types of
products.
In conclusion, this study of reactions of thioamides bearing
an electron-withdrawing substituent on the thiocarbonyl
carbon (cf. 3) with benzynes generated by the HDDA reaction
of tri- and tetrayne precursors (cf. 2) has led to the
identification of a new type of [3 + 2]-cycloaddition reaction.
The sulfur and nitrogen atoms of the thioamide engage the
benzyne sp-carbon atoms to produce an intermediate
ammonium ylide structure (cf. 4). This species shows a variety
of different paths for reaction, including several heretofore
unseen, as deduced from the products that are produced. This
adds to the overall body of understanding of these relatively
rarely encountered species. Overall, this work represents
another instance14 in which the HDDA cycloisomerization
reaction has allowed a fundamentally new type of trans-
formation to be discovered.
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.8b02133.
Experimental details for the preparation of new
compounds; spectroscopic data for their character-
1
ization, including copies of H and 13C NMR spectra;
and computed (DFT) geometries and energies of
benzyne intermediates and transition states (PDF)
AUTHOR INFORMATION
■
In most cases, the major product is consistent with the well-
established preference for benzyne 2a to add nucleophilic
species14 at the sp-hybridized carbon with the larger internal
bond angle15,16 (see red triangle in 2a in Figure 1a). In
contrast, the benzynes derived from 1b and 1c generally show
a lower degree of regioselectivity for the addition of
nucleophiles.14 The rr for the product 5cc and its isomer is
only 1.5:1. However, 5bb was formed as the sole
dihydrobenzothiazole. This substrate (and intermediate
benzyne), uniquely among all studied here, contains a bulky
aryl substituent adjacent to one of the benzyne carbons and
thus sterically guides the nucleophilic sulfur atom to add to the
distal benzyne carbon. This demonstrates that steric differ-
ences encountered during benzyne trapping reactions can
override (at least small) inherent electronic preferences.17
Corresponding Author
*E-mail: hoye@umn.edu.
ORCID
Thomas R. Hoye: 0000-0001-9318-1477
Author Contributions
†J.Z. and A.C.S.P. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support for this research was provided by the National
Institutes of General Medical Sciences of the U.S. Department
of Health and Human Services (R01 GM65597, then R35
C
DOI: 10.1021/acs.orglett.8b02133
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Organic Letters
Letter
(9) We also computed the reaction energy for the transformation of
the analogue of 3a in which the CF3 substituent was replaced with a
CH3 group to give the CH3 analogue of 7. That step is less exergonic
(5 kcal·mol−1, see the Supporting Information) than that of 3a to 7.
Whereas it was a trivial matter to locate TS1, we have been unable to
identify a bound TS for the case of the methyl analogue. The presence
of the electron-withdrawing substituent in the model thioamide 3a
appears to play an important role.
(10) (a) In many of the reactions reported here, two constitutional
isomers were formed, arising from competitive modes of addition of
the thioamide to the various unsymmetrical benzynes. The assign-
ment of constitution to the major and minor isomers 5ab and 5ab′
rests on the NOEs shown in blue in Figure 3. (b) For many of the
additional isomeric pairs (ratios indicated as rr), only the major
isomer is shown in the manuscript [see the Supporting Information
for additional details]. The constitution of the major product is
assigned on the basis of the very high field chemical shift of the
aromatic H10 proton for the N-arylated products (5ac, 5ad, and 5cc),
an NOE analogous to that for 5ab for the N-alkylated products (5aa,
5ae, 5af, 5ag′′, and 5bb), and an abnormally high-field resonance for
the N-CH2 because of shielding by the nearby p-carbomethoxyphenyl
group in 5bb.
GM127097). A.C.S.P. and V.P. appreciate the support of a
Gleysteen−Heisig fellowship for undergraduate students. Some
of the NMR data were obtained with an instrument acquired
with funds from the NIH Shared Instrumentation Grant
program (S10OD011952).
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DOI: 10.1021/acs.orglett.8b02133
Org. Lett. XXXX, XXX, XXX−XXX