Reactions of HDDA-Derived Benzynes with Sulfides: Mechanism, Modes, and Three-Component Reactions

Article abstract of DOI:10.1021/jacs.6b01025

We report here reactions of alkyl sulfides with benzynes thermally generated by the hexadehydro-Diels-Alder (HDDA) cycloisomerization. The initially produced 1,3-betaine (o-sulfonium/aryl carbanion) undergoes intramolecular proton transfer to generate a more stable S-aryl sulfur ylide. This can react in various manners, including engaging weak acids (HA) in the reaction medium. This can produce transient ion pairs ArSR₂⁺A^- that proceed to the products ArSR + RA. When cyclic sulfides are used, A^- opens the ring and is incorporated into the product, an outcome that constitutes a versatile, three-component coupling process.

Full text of DOI:10.1021/jacs.6b01025

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Communication
Reactions of HDDA-derived Benzynes with Sulfides:
Mechanism, Modes, and Three-component Reactions
Junhua Chen, Vignesh Palani, and Thomas R. Hoye
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b01025 • Publication Date (Web): 24 Mar 2016
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Reactions of HDDA-derived Benzynes with Sulfides: Mechanism,
Modes, and Three-component Reactions
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Junhua Chen, Vignesh Palani, and Thomas R. Hoye*
Department of Chemistry, 207 Pleasant St. SE, University of Minnesota, Minneapolis, MN 55455
Supporting Information Placeholder
byproducts that necessarily accompany all other meth-
ABSTRACT: We report here reactions of alkyl sulfides
ods8 of benzyne generation. This permits interrogation
with benzynes thermally generated by the hexadehydro-
of inherent benzyne reactivity at a more fundamental
Diels–Alder (HDDA) cycloisomerization. The initially
level than is often otherwise possible.9 In addition, new
produced 1,3-betaine (o-sulfonium/aryl carbanion) un-
modes of benzyne trapping reactions10,11,12 can be un-
dergoes intramolecular proton transfer to generate a
covered that would be otherwise incompatible with most
more stable S-aryl sulfur ylide. This can react in various
if not all of the more traditional methods of benzyne
manners, including engaging weak acids (HA) in the
generation. We describe here results of our investiga-
reaction medium. This can produce transient ion pairs
tions of the reactivity between HDDA-generated ben-
+
ArSR2 A– that proceed to the products ArSR + RA.
zyne derivatives and various sulfides. These studies pro-
When cyclic sulfides are used, A– opens the ring and is
vide both mechanistic insight as well as novel trapping
incorporated into the product, an outcome that consti-
processes, including new three component reactions.8f,13
tutes a versatile, three-component coupling process.
To probe details of ylide formation, we first explored
reactions between the benzyne 8 and thioanisole (Figure
2). Heating tetrayne 4 with PhSCH3 in the presence of p-
chlorobenzaldehyde in d6-benzene produced the diaryl
o-Benzyne (1) is the parent member of one of the
most versatile of all reactive intermediates in organic
sulfide 5-h and epoxide 6 [>60% yield (NMR, see SI)].
chemistry, largely because of its adaptability as an elec-
Replacing the aldehyde with acetic acid as the additive
trophilic agent capable of capture by many different
efficiently produced 5-h (79% yield following isolation).
Both results suggest the intermediacy of ylide 10; the
types of external nucleophiles. Its reaction with sulfide
trapping agents, largely by way of ylide intermediates
(Figure 1), was studied in a number of laboratories in the
epoxide would result from a Corey-Chaykovsky-like
process4 and the outcome with AcOH would arise by
protonation of 10-h3 to give 11-h3 (not shown) and sub-
sequent methylation5b (ca. one equivalent of MeOAc
was observed by NMR spectroscopy).
period 19621-19892 but has lain fallow until the recent
report of Xu and coworkers. As they pointed out, "nu-
cleophilic attack of alkyl thioether on benzyne followed
by an intramolecular 1,4-proton shift has been almost
totally neglected since its debut3."4 The majority of those
early studies were described in a series of reports from
the Nakayama laboratory.5a All of this previous work
used simple benzyne derivatives, the vast majority of
studies being explored with o-benzyne (1) itself.
We used labeling studies to probe for the intermedia-
cy of a zwitterion like 9. Tetrayne 4 was heated in C6D6
R
R
Me Me
PhSCH3
PhSCD3
AcOH
Me
Me
p-ClPhCHO
O
O
4
SPh
SPh
C6D6
75 °C
C6D6
75 °C
H
D
5-h
5-d
R1
S
R1
S
R1
S
O
O
R2
R2
R2
MeCO2CHD2
6
7
p-ClPh
!, HDDA
H
H
H
Me
1
2
3
R
Me
Me
Me
Ph
S
Figure 1. Trapping of o-benzyne (1) with an alkyl sulfide
produces ylide 3, presumably via the zwitterionic betaine 2.
Me
Ph
Ph
S
S
D
CHD2
AcO
O
H
CH2
CH3
6
7
The generation of benzyne intermediates by the
thermal cycloisomerization reaction of tethered triynes6
via the hexadehydro-Diels–Alder (HDDA) reaction7
(e.g., 4 to 8, Figure 2) produces this important class of
reactive species in environments free of the reagents and
10-h3
9-h3
8
9-d3
11-d3
Figure 2. Trapping of HDDA-generated benzyne 8 by thi-
oanisole: epoxidation of p-ClPhCHO by ylide 10-h3 and
alkylation within the sulfonium acetate ion pair 11-d3.
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Journal of the American Chemical Society
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Table 1. Various modes of trapping of HDDA-generated
benzynes by sulfidesa
with PhSCD3 and AcOH. This gave, nearly exclusively,
1
2
3
4
5
6
7
8
the mono-deuterated sulfide 5-d and dideuterated methyl
acetate (7, NMR, see SI). Protonation by AcOH could
have occurred at the stage of either the initially formed
1,3-zwitterion 9-d3 or ylide 10-d3. The deuterium label-
ing pattern of the products 5-d and 7 clearly indicates
the involvement of 11-d3 and, importantly, establishes
the viability of intramolecular proton transfer within 9
(cf. 2 to 3). Finally, heating 4, AcOH, and an equimolar
mixture of PhSCH3 and PhSCD3 gave nearly equal
amounts of 5-h and 5-d (as well as AcOCH3 and
AcOCHD2), suggesting that reversal of formation of
adduct 9 is slower than the proton transfer that converts
9 to 10. This result also argues against a concerted event
for conversion of 8 directly to ylide 10 (cf., 1 to 3).
entry reactants
key intermediate/event
product, isolated yield
Rb
Me
Me
O
6
S
7
S
1
4
4
S
H
15-int
52% (17%)c
15
9
Rb
10
11
12
13
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Me
Me
O
S
S
X
S
X
2
X
•
X = C!CH
X = CO2Me
39% (10%) X = C!
CHc
63% (12%) X = CO2Mec
16-int
16a
16b
We next explored HDDA-benzyne trapping with a
variety of different types of sulfides (Table 1). These
studies demonstrated various modes of trapping process-
es, some precedented and some not. Consistent with our
intent, these results establish the viability of each reac-
tion mode in the context of HDDA-generated benzynes.
In each case, benzyne 8 from the symmetrical, ether-
linked tetrayne 4 (entries 1-3 and Figure 2) gives a mix-
ture of isomeric products arising from competitive trap-
ping at C6 (major, shown) and C7. Details about the
structure assignment of these constitutional isomers and
DFT calculations showing the extent of ring distortion of
the intermediate benzyne14 are provided in the SI.
Rb
Me
S
Me
Ph
O
Ph
S
3
4
S
Ph
Ph
Ph
Ph
17-int
25% (5%)c
17
Me Me
Rb
Me
S
S
Ar
Me
S
or
S
4
N
Ts
S
12
18-int
18'-int
18 90% (via 18-int)
40% (via 18'-int)
NTs
Me Me
Rb
Me
Me
Diallyl sulfide trapped the benzyne 8 to provide the
desymmetrized diene 15 (Table 1, entry 1), presumably
via 15-int. This is consistent with the outcome of the
reaction of 1 with digeranyl3 or diprenyl5c sulfide. The
rearrangement of 15-int to 15 could, in principle, occur
either by a [2,3]-sigmatropic process3,15 (green arrows)
or by a Stevens rearrangement.16 We therefore carried
out analogous reactions with a propargyl sulfide (entry
2) or dibenzyl sulfide5d (entry 3). The former cleanly
gave an allene (16a or 16b), showing that [2,3]-Wittig
processes (16-int) are viable. The latter gave adduct 17,
the product of a Stevens rearrangement (17-int).
S
5
MsN
S
S
13
40%
19-int
19
N
Ms
Rb
Me Me
Me
S
Me
R'N
S
NMe
N
R'
6
S
NHMe
N
Me
R' = Boc
AcO
14
N
Boc
NBoc
35%
20
20-int
a
Reaction conditions: Substrate tetrayne in PhH (0.1 M)
containing the indicated sulfide (1.5-2 equiv) was heated in
a sealed culture tube (see SI for reaction temperatures and
times). For entry 5, five equiv of o-NO2PhCH2CO2Me was
present. For entry 6, five equiv of AcOH was present. b R =
Given the considerable generality of the HDDA cas-
cade, we were unsurprised to see that sulfide trapping is
not unique to benzyne 8. Those derived from the
tetraynes 12–14 participate as well (entries 4–6). In
those instances, we happened to use various cyclic sul-
fides as the trapping agents. Either thiirane or tetrahy-
drothiophene gave rise to the same product, the vinyl
sulfide 18 (entry 4), likely via the fragmentations shown
in 18-int and 18'-int, respectively. Similar modes of
ring-cleavage have been reported.2,5e-f,17 In contrast, use
of thietane (entry 5) gave rise to the ring-contracted cy-
clopropane 19—an apparently unprecedented mode of
reaction. Finally, N-methylbenzothiazoline (in the pres-
ence of acetic acid) gave the aminophenyl sulfide 20
(entry 6), again a new type of trapping reaction.
c
1-propynyl. Benzyne 8 (from 4) is trapped by sulfides
competitively at C6 and C7 to give separable major and
minor (yield in parentheses) isomers, respectively.
goal of expanding this chemistry into a three-component
process.13 We are aware of one report in which such a
reaction has been described: namely, generation of o-
benzyne in the presence of (three) cyclic sulfides and
aqueous hydrochloric acid produced chloroalkyl sulfides
(e.g., 4-chlorobutyl phenyl sulfide from tetrahydrothio-
phene).5c The HDDA version, via the ion pair 22, is por-
trayed generically in the graphic at the top of Table 2. In
the products 23, the tetrayne-derived fragment and nu-
cleophile are linked in a fashion dictated by the structure
We then explored the use of cyclic sulfides in the
presence of various protic nucleophiles (H–Nu) with the
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Page 3 of 5
Journal of the American Chemical Society
gen- and oxygen-centered nucleophiles, including N-
of the sulfide used. This structural motif is relevant to
the field of drug discovery.18
heterocycles (entries 7 and 9), will all participate; (ii)
hindered (entry 5) or relatively weakly acidic H–Nu spe-
cies (Brønsted acids) are functional; (iii) the unsymmet-
rical sulfonium ion intermediate in entry 6 opens selec-
tively at the allylic center; (iv) additional functionality
can be tolerated within the cyclic thioether (entries 6 and
8); (v) a number of these nucleophiles are capable of
trapping HDDA benzyne directly—the presence of the
polarizable sulfide nucleophile outpaces those processes.
One limitation is that thiirane has not been an effective
participant in the 3-component reaction to date—
1
2
3
4
5
6
7
8
The reaction is general with respect to the type of
benzyne used (see 21a–g). Two (21d and 21e) represent
a previously unreported type of HDDA substrate. It is
notable that HDDA cycloisomerization leading to 21e
occurred faster (ca. 5x) than an analog lacking the gemi-
nal methyl substituents, presumably a reflection of the
bond angle compression that brings the proximal termini
of the diyne and diynophile closer to one another.12c
Results of three-component coupling reactions are
listed in Table 2. Some highlights are: (i) carbon-, nitro-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. Three-component reactions of HDDA benzynes (21, green), cyclic sulfides (blue), and H–nucleophiles (red)
[ benzyne
cyclic sulfide
product, isolated yield of
S
entry
intermediate ]
+ H–Nu major (minor) constitutional isomer
( )n
H
( )n
n = 1, 2, 3
23
S
S
Nu
Ra
Ra
( )n
S
H
H
O
Me
Me
S
HNu
21
22
Nu
BocN
BocN
7
N
N
N
maleimide
OCH3
( )3
Boc
Boc
O
[ benzyne
cyclic sulfide
product, isolated yield of
54%
21d
(from14)
30
entry
intermediate ]
+ H–Nu major (minor) constitutional isomer
Ra
TMS
O
TMS
O
Me
S
OCH3
S
Me
Me
21d
BocN
8
9
N
HOAc
S
OAc
1
CO2Me
Boc
CH2CN
CO2Me
S
80%
31
CN
67% (10%)
24
21a
21a
Ra
S
Me
TMS
Me
21d
O
BocN
CHO
S
H
N
N
Me
S
N
( )2
S
O
Boc
2
Me
Me
Me
OH
50%
32
acac-H
CHO
25 60% (6%)
TMS
TMS
O
O
S
I
TMS
Me
Me
Me
O
S
10
HN
Me
HN
Me
TFA-N
Boc
BocNHOBoc
3
4
21a
S
N
OBoc
Me
Me
NH(p-IPh)
S
COCF3
26 48%
21e
33 100%
NO2
CO2Me
Ra
Ra
TMS
Me
S
S
O
Me
Me
O
11
21e
HN
Me
p-HOPh-
CO2Me
N
Ts
N
Ts
NO2
S
( )3
S
CN
NC
Me
O
65%
21b
(from12)
27
69%
34
Ra
CHO
S
Me
S
TMS
TMS
O
COMe
S
21b
5
Me
COMe
CO2Et
Me
CO2Et
N
Ts
( )3
PhN
PhN
12
13
O
( )3
p-HOPhCHO
28 55%
S
43% (16%)
21f
35
36
Ra
Ra
Ra
Ra
S
S
Cl
E E
Me
Me
S
Me
Me
6
Cl
MsN
MsN
OAc
N
Ms
N
Ms
S
AcOH
E
(E = CO2Me)
E
55%
21c
29
21g (from13)
53% (21%)
a R = 1-propynyl.
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Journal of the American Chemical Society
Page 4 of 5
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In conclusion, we have (i) presented evidence sup-
porting the involvement of initial 1,3-zwitterions in reac-
tions of aliphatic sulfides with benzynes (Figure 2), (ii)
demonstrated the viability of several new modes of trap-
ping reaction (Table 1), (iii) presented two new types of
HDDA-benzynes (21d and 21e, Table 2), and (iv) shown
that three-component reactions that engage HDDA-
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considerable generality.
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ASSOCIATED CONTENT
Supporting Information. The Supporting Information is
available free of charge on the ACS Publications website.
Experimental details for the preparation of new compounds; spec-
1
troscopic data for their characterization, including copies of H
and 13C NMR spectra; and computed (DFT) geometries of ben-
zyne intermediates and transition state for ylide formation (PDF).
AUTHOR INFORMATION
Corresponding Author
* hoye@umn.edu
Notes
The authors declare to have no competing financial interests.
ACKNOWLEDGMENT
Support for this research was provided by the National Institutes
of Health (GM65597). V.P. was supported by a Gleysteen-Heisig
fellowship for undergraduate students. NMR spectra were record-
ed using instrumentation purchased with funds provided by the
NIH Shared Instrumentation Grant program (S10OD011952). We
thank Sean Ross and Juntian Zhang for providing samples of and
procedures for preparing tetraynes 13 and precursor to 21c.
(12) (a) Niu, D.; Hoye, T. R. Nature Chem. 2014, 6, 34–40. (b)
Chen, J.; Baire, B.; Hoye, T. R. Heterocycles 2014, 88, 1191–1200.
(c) Woods, B. P.; Baire, B.; Hoye, T. R. Org. Lett. 2014, 16, 4578–
4581. (d) Woods, B. P.; Hoye, T. R. Org. Lett. 2014, 16, 6370–6373.
(e) Pogula, V. D.; Wang, T.; Hoye, T. R. Org. Lett. 2015, 17, 856–
859. (f) Luu Nguyen, Q.; Baire, B.; Hoye, T. R. Tetrahedron Lett.
2015, 56, 3265–3267.
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F15845
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