Mechanistic Insight into the Dehydro-Diels-Alder Reaction of Styrene-Ynes

Article abstract of DOI:10.1021/acs.joc.5b00200

The Diels-Alder reaction represents one of the most thoroughly studied and well-understood synthetic transformations for the assembly of six-membered rings. Although intramolecular dehydro-Diels-Alder (IMDDA) reactions have previously been employed for th

Full text of DOI:10.1021/acs.joc.5b00200

Subscriber access provided by NEW YORK UNIV
Article
Mechanistic Insight into the Dehydro-Diels-Alder Reaction of Styrene-ynes
Laura Susan Kocsis, Husain Noman Kagalwala, Sharlene Mutto, Bhaskar
Godugu, Stefan Bernhard, Dean J Tantillo, and Kay M Brummond
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00200 • Publication Date (Web): 11 Feb 2015
Downloaded from http://pubs.acs.org on February 18, 2015
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Mechanistic Insight into the Dehydro-Diels-Alder Reaction of
Styrene-ynes.
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
Laura S. Kocsis,1 Husain N. Kagalwala,2 Sharlene Mutto,3 Bhaskar Godugu,1 Stefan Bernhard,2
Dean J. Tantillo,3* and Kay M. Brummond1*
1Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15206.
2Department of Chemistry, Carnegie Mellon University, Pittsburgh, PA 15213.
3Department of Chemistry, University of California—Davis, Davis, CA 95616
KEYWORDS (Word Style “BG_Keywords”). If you are submitting your paper to a journal that requires keywords,
provide significant keywords to aid the reader in literature retrieval.
The Diels-Alder reaction represents one of the most thoroughly studied and well-understood synthetic
transformations for the assembly of six-membered rings. Although intramolecular dehydro-Diels-Alder
(IMDDA) reactions have previously been employed for the preparation of naphthalene and
dihydronaphthalene substrates, low yields and product mixtures have reduced the impact and scope of this
reaction. Through the mechanistic studies described within, we have confirmed that the thermal IMDDA
reaction of styrene-ynes produces a naphthalene product via loss of hydrogen gas from the initially
formed cycloadduct, a tetraenyl intermediate. Alternatively, the dihydronaphthalene product is afforded
from the same tetraenyl intermediate via a radical isomerization process. Moreover, we have identified
conditions that can be used to achieve efficient, high yielding, and selective IMDDA reactions of styrene-
ynes to form either naphthalene or dihydronaphthalene products. The operational simplicity and
retrosynthetic orthogonality of this method for the preparation of naphthalenes and dihydronaphthalenes
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 31
1
2
3
4
5
6
makes this transformation appealing for the preparation of medicinal and material targets. Moreover, the
mechanistic studies within may impact the development of other thermal transformations.
7
8
9
Introduction
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
Functionalized naphthalenes and their derivatives are valuable building blocks that serve as key structural
components for various material, chemical, and biological applications. Naphthalenes are used as organic
semiconductors in organic light emitting diodes (OLEDs)1 and liquid crystalline displays (LCDs).2 They
are also commonly incorporated into pharmaceuticals3 and chiral reagents.4 A classic example showcasing
the importance of this motif is naproxen (2) and its derivatives. These COX-2 selective anti-inflammatory
agents are obtained via an asymmetric hydrogenation of methoxynaphthenyl acrylic acid (1) in which
high enantioselectivities were achieved by employing the chiral biaryl ligand (R)-BINAP (3), as depicted
in Scheme 1.5 Naphthalenes are present in a number of naturally occurring compounds,6 one example
being michellamine B (4), a compound that captured the attention of the research community because of
its activity against HIV, as well as its unusual C-2 symmetric naphthylisoquinoline structure.7
Naphthalenes possessing electron donor and acceptor groups also play an important role in bioimaging
applications.8 For example, dansyl, the structure represented in the box of the guanidinium-rich molecular
transporter (MoTr) 5, was used as a fluorescent probe to measure the cellular uptake efficiency of MoTr
analogs.9 Additionally, certain bacterial genetic codes have been expanded to include the nonnatural
naphthalene and benzofused heterocycle base pair d5SICS-dNaM (6).10 By incorporating these nonnatural
base pairs into bacterial DNA, nonnatural amino acids were created in vitro using the cellular machinery.
These and other applications have revealed functionalized naphthalenes as desirable synthetic targets, but
methods to access this valuable class of aromatic compounds have not kept up with the demand for new,
diverse, and structurally complex naphthalene substrates.
2
ACS Paragon Plus Environment

Page 3 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
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
Scheme 1. Biologically relevant naphthalene-containing compounds
Because naphthalene represents the most abundant component of coal tar,11 it has been exploited in the
industrial scale production of dyes, plastics, and insecticides, to name a few. Moreover, the methods by
which naphthalene-containing compounds have conventionally been obtained are directed largely by an
abundance of this feedstock. As an example, electrophilic aromatic substitution (EAS) reactions of
naphthalene, such as Friedel–Crafts acylations and alkylations, halogenations, and nitrations, are
commonly used protocols to prepare functionalized naphthalene-containing compounds.12 While these
methods have their place in the synthetic chemist’s toolbox, alternative strategies that provide more
complex naphthalene substructures not readily available using EAS and other classical reactions are
needed. Others have recognized the limitations imposed by these more classical approaches and have
responded with new methods for naphthalene synthesis,13 including transition metal-catalyzed cross-
coupling14 and transition metal-mediated reactions,15 Diels–Alder reactions of benzyne16 or ortho-
quinodimethane derivatives,17 phthalide annulations,18 ring closing metathesis,19 and [2 + 2 + 2]
cycloaddition reactions.20 Also gaining widespread use, is an acid-catalyzed benzannulation via [4 + 2]
cycloaddition reaction of o-alkynyl(oxo)benzenes with alkynes discovered by Yamamoto.21
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 31
1
2
3
4
5
6
7
8
9
Intramolecular dehydro-Diels–Alder (IMDDA) reactions have previously been used for the construction
of naphthalenes and other polycyclic aromatic hydrocarbons.22 When aromatic products are preferred,
IMDDA reactions are typically conducted with substrates containing two reactive triple bonds and one
double bond. However, examples exist where aromatic products have been obtained from IMDDA
precursors having one triple bond and two double bonds, a reaction that should afford the dihydroaromatic
product. The formation of this product has in some cases been justified by the propensity of 1,4-
cyclohexadiene derivatives to aromatize under oxidative conditions. Along similar lines, a potentially
valuable IMDDA reaction for the preparation of aromatic hydrocarbons involves the reaction of styrene
and an alkyne to afford a cycloadduct that aromatizes to give naphthalene derivatives. Despite the
tendency for styrene polymerization, the feasibility of this reaction has been demonstrated, albeit with
mixtures of products and/or low yields.23
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
Klemm was the first to report an IMDDA reaction where styrenyl alkynoate 7 was refluxed in acetic
anhydride to provide dihydronaphthyl lactone 9 in 48% yield (Scheme 2).24 When using a similar
IMDDA precursor 10 containing a terminal alkyne, only the naphthyl lactone 11 was obtained, but in
13% yield.25 Cycloaddition of amide 13 gave naphthalene lactam 14 in 51% yield.26 More recently,
Chackalamannil effected an IMDDA reaction of alkynoate 16 to afford dihydronaphthofuranone 18 in
57% yield, along with naphthyl lactone 17; the unusual position of the double bond in 18 was discussed.27
Ruijter has reported an IMDDA reaction of styrene-functionalized -carboline 19 that generated
compounds 20 and 21 in a 1.5:1 ratio and 90% yield.28 Interestingly, attempts to oxidize the product
mixture to 20 using DDQ led to decomposition. Terashima reported the IMDDA reaction of alkynone 22,
which provided only 23 in quantitative yield.29 Finally, Matsubara has reported an IMDDA reaction of
silyl acetylene 24 that produced only the naphthalene product 25 in 80% yield; ten additional examples
were reported.30 While this nearly exhaustive listing of research in the area of IMDDA reactions of
styrene-ynes provides precedent for this reaction,31 its potential has not been realized due to harsh
reaction conditions, long reaction times, mixtures of naphthalene and dihydronaphthalene compounds,
and the inability to predict which product will be obtained
4
ACS Paragon Plus Environment

Page 5 of 31
The Journal of Organic Chemistry
1
2
3
4
5
R2
R2
R2
R2
R2
X
X
X
+
R2
O
O
O
R1
R1
R1
6
7
8
9
R1 = (3,4,5-OMe)-C6H2
R2 = OCH2O, X = O, 7
R1 = H
X = O, R2 = OCH2O, 10
R1 = Ph
Ac2O, reflux1
6 h
Ac2O, reflux1
12 - 72 h
xylene, 150 °C
5 h
8, 0%
11, 13%
9, 48%
12, 0%
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
X = NH, R2 = H, 13
14, 51%,
15, 0%
O
O
O
O
xylene
195 °C
O
O
+
24 h
C
C
BnO2
BnO2
BnO2C
16
17, 12%
18, 57%
O
N
O
N
O
N
toluene
MWI
170 °C
Ph
Ph
+
N
15 min
Ph
H
H
H
Ph
19
20, 54%
21, 36%
OMe
OMe
OMe
OMe
O
o-DCB
170 °C
O
2 h
OMe
OMe TMS
TMS
22
23, quant
xylene, Ar
160 °C
NTs
NTs
48 h
TMS
TMS
24
25, 80%
Scheme 2. Previously reported IMDDA reactions of styrene-ynes
Results and Discussion
Recently, an unexpected IMDDA reaction between the styrene and alkyne of 26 was observed during our
studies directed towards capturing a diradical intermediate of a thermal intramolecular [2 + 2]
cycloaddition reaction.32 When comparing the IMDDA reaction of styrene-yne 26 to previously reported
examples, we were intrigued by: 1) the short reaction time, 2) high yield, 3) operational simplicity of the
‘thermal only’ reaction conditions, and 4) complete selectivity for the formation of the aromatic product.
Investigation into the scope and limitations of the IMDDA reaction of styrene-ynes began by making
variations to the alkyne terminus, and ultimately showed selective formation of a number of naphthalene
products in high yield.33 Further studies involving the addition of heteroatoms to the styrene-yne tether
resulted in very different product mixtures. For example, replacing the all carbon tether of 26 with
heteroatom-containing tethers 28 (X=O) and 30 (X=NTs), and subjecting these styrene-ynes to our
standard microwave irradiation (MWI) reaction conditions, afforded naphthalenes 29a and 31a in low
yield. Additionally, dihydronaphthalenes 29b and 31b were obtained in 15% and 56% yields, respectively
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 31
1
2
3
4
5
6
(entries 2 and 3, Table 1). Notably, for styrene-yne 30 containing a tosylamide tether, the
dihydronaphthalene product 31b was formed as the major product.
7
8
9
Concentration, temperature and atmosphere studies. To further explore this result, styrene-yne 30 was
subjected to reaction conditions that involved changing the temperature, concentration, and atmosphere.
Amongst the various experiments that were performed, four key results have emerged to alter our
thoughts regarding this reaction. Prolonging microwave irradiation of 30 for 60 min at 180 °C in DCE
afforded less dihydronaphthalene 31b when compared to an example that was irradiated for 10 min
(compare entries 3 and 4, 8% vs 56%); however, the increase in naphthalene 31a was not proportionate
(38% vs 30%). This data confirms that under extended reaction times, dihydronaphthalene 31b is not
transforming to naphthalene 31a. Lowering the temperature of the reaction from 180 to 120 °C afforded a
higher ratio of 31b to 31a of 7.6:1 vs 1.9:1 (compare entries 3 and 5); the mass balance for entry 5 was
recovered starting material (34%). Increasing the reaction temperature to 225 °C resulted in a reversal of
selectivity, giving a 1:1.5 ratio of 31b:31a (entry 6). Thus, lower temperatures favor formation of
dihydronaphthalene 31b, and higher reaction temperatures produce more naphthalene 31a. Increasing the
reaction concentration from 0.06 to 0.50 M resulted in a 3.8:1 mixture of the dihydronaphthalene 31b and
naphthalene 31a products. As discussed in further detail below, this data combined with the temperature
studies suggests the possibility that two different reaction mechanisms are operating to produce the two
products. Irradiating styrene-yne 30 at 180 °C in DCE either under air or after degassing the reaction
mixture with argon both generated a 1.9:1 mixture of dihydronaphthalene 31b to naphthalene 31a in as
little as 2 min (see Table S1 for a complete listing of experimental conditions employed). While these
conditions did not ensure rigorous exclusion of oxygen, this experiment suggests that performing the
reaction in the presence or absence of oxygen has no effect on the product selectivity or the rate of
reaction for the time scale that was measured. This data strongly suggests that molecular oxygen is not
functioning as an adventitious oxidant of dihydronaphthalene 31b to naphthalene 31a. These thought-
provoking results support the need for a more thorough understanding of the mechanism of product
formation in this reaction prior to embarking on further scope and limitation studies. A discussion of the
results from these mechanistic investigations is provided herein.
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
6
ACS Paragon Plus Environment

Page 7 of 31
The Journal of Organic Chemistry
1
2
3
4
Table 1. IMDDA reaction of styrene-ynes with heteroatom tethers
5
6
7
8
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
entry
1
styrene-yne
conditions
N (%)
D (%)
26, X = CH2
DCE, 180 °C, 0.06 M, 30 min
100
0
2
3
4
5
6
7
28, X = O
DCE, 180 °C, 0.06 M, 30 min
DCE, 180 °C, 0.06 M, 10 min
DCE, 180 °C, 0.06 M, 60 min
o-DCB, 120 °C, 0.06 M, 15min
o-DCB, 225 °C, 0.06 M, 1 min
o-DCB, 180 °C, 0.50 M, 1 min
28
30
38
7
15
56
8
30, X = NTs
30
30
30
30
53
33
60
48
16
Solvent Studies. The IMDDA reaction of 30 was carried out at a constant temperature of 180 °C in
solvents of increasing dielectric constant ranging from o-DCB (ɛ = 9.93) to water (ɛ = 80.1). Regardless
of the solvent employed, each reaction was complete within 1 min. While there are some outlying results,
the dielectric constant of the solvent appears to correlate well with the selectivity of the reaction, with
product ratios of 31a:31b ranging from 1:1.2 to 1:10 as the dielectric constant of the solvent increases
(entries 1-4 and 8, Table 2).34 A control experiment was performed where 30 was irradiated in DMF-d7
and still afforded the same ratio of 31a:31b, but with no deuterium incorporation (see Supporting
Information). One outlier in the solvent data was nitrobenzene (PhNO2), which afforded exclusively
naphthalene 31a in 84% yield. We attribute this result to PhNO2 functioning as a dehydrogenating
agent,35 and this is supported by the fact that as little as 8 equiv of PhNO2 resulted in selective
naphthalene formation (see Table S2). Thus, solvent does play a significant role in the selectivity afforded
by the IMDDA reaction for the formation of naphthalene or dihydronaphthalene products.
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 31
1
2
3
4
Table 2. Effect of solvent on product selectivity
5
6
7
8
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
entrya
solvent
dielectric 31a:31bb
constant
tan 
1
2
3
4
5
6
7
8
9
o-DCB
DCE
0.28
0.127
0.079
0.799
-
9.93
1:1.2
1:1.8
1:2.6
1:4.4
1:1
10.36
18.50
20.18
28.06
32.20
34.82
36.71
80.10
MEK
iPrOH
EtNO2
NMP
PhNO2
DMF
H2O
0.275
0.589
0.161
0.123
1:3
1:0
1:10
1:2
aIrradiated reaction mixture (0.06 M) at 180 °C for 1 min;
bratio of products determined by 1H NMR spectroscopy.
Isotopic Labeling Experiments. Next, experiments involving the IMDDA reaction of isotopically labeled
DA precursors were performed to elucidate the mechanism(s) by which the naphthalene 31a and the
dihydronaphthalene 31b products are formed. Three IMDDA precursors were prepared, one with
deuterium in the double bond of the diene, and the other two with deuteriums at all remaining positions of
the aryl ring of the diene.
Synthetic Protocols. The monodeuterated alkynone 37 was prepared as follows. Reduction of 3-phenyl-2-
propyn-1-ol (32) using lithium aluminum deuteride afforded monodeuterated cinnamyl alcohol 33 in
1
quantitative yield; the E-configuration was inferred from H NMR spectroscopy (Scheme 3). Subjecting
33 to the Mitsunobu reaction conditions of triphenylphosphine, diisopropyl azodicarboxylate and 4-
methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (34) gave styrene-yne 35 in 85% yield.36 N-methoxy-N-
methylacetamide (36) was then employed to acylate the lithium acetylide of 35, providing 46% yield of
alkynone 37.37
8
ACS Paragon Plus Environment

Page 9 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
The pentadeuterated substrates 42 and 43 were prepared in a similar manner as 37; however, the synthesis
began by a Sonogashira cross-coupling reaction of bromobenzene-d5 (38) with propargyl alcohol (39) in
the presence of tetrakis(triphenylphosphine)palladium(0), copper(I) iodide, and pyrrolidine to generate
50% yield of 3-(phenyl-d5)prop-2-yn-1-ol (Scheme 3). Subsequent reduction of the alkyne using lithium
aluminum hydride produced cinnamyl alcohol 40 in 56% yield. Mitsunobu reaction conditions were
utilized for the conversion of 40 to styrene-yne 41 in 86% yield. Finally, to the lithium acetylide of 41
was added either N-methoxy-N-methylacetamide (36) or methyl chloroformate, producing alkynone 42
and alkynoate 43 in 80 or 55% yield, respectively.
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
Scheme 3. Synthesis of isotopically labeled styrene-ynes
IMDDA Reactions with Deuterated Substrates. Deuterated styrene-ynes were also subjected to thermal
conditions to further our understanding of the mechanism of the IMDDA reaction. First, heating styrene-
yne-d1 37 at 180 °C for 1 min in o-DCB-d4 generated naphthalene 31a and dihydronaphthalene-d1 44 in
1
81% yield and in a 1:5.2 ratio, as determined by H NMR spectroscopy (Scheme 4). This represents a
significant change in the product ratio when compared to heating of the non-deuterated precursor 30, and
is interpreted as a large primary kinetic isotope effect. In an additional experiment, heating of styrene-
yne-d5 42 for 1 min at 180 °C in o-DCB-d4 resulted in a 1:1 mixture of naphthalene 45 and
dihydronaphthalene 46 in 68% yield. Naphthalene 45 was separated from 46 by HPLC, and
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 31
1
2
3
4
5
6
7
8
9
characterization of 46 by 1H NMR and COSY spectroscopy showed the presence of two diastereomers in
a 1.5:1 ratio resulting from deuterium incorporation at the 4-position of the dihydronaphthalene, which
was indicative of deuterium atom transfer from the aryl ring. Incorporation of a deuterium atom at the 4-
1
position of the dihydronaphthalene altered the H NMR spectrum of 46, allowing for the diastereomeric
ratio to be distinguished. For example, the doublet of doublets and apparent triplet found at δ 2.82 and
2.51, representative of the two protons at the 4-position of 31b (Figure 1A), each changed upon deuterium
incorporation in 46 and became two doublets (Hd and He) integrating for 0.69 and 0.47 protons,
respectively. The coupling constants of Hd and He were reflective of coupling only to the neighboring
proton (Hc) and not germinal coupling (Figure 1B). Additional smaller resonances at δ 2.89, 2.86, 2.81,
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
1
2.80, and 2.54 were also noted in the H NMR spectrum of 46, which were similar to the resonances
observed for 31b.
As expected, heating 42 in DMF under the same reaction conditions resulted in a 70% combined yield of
45 and 46 in a 1:7 ratio; however, dihydronaphthalene 46 was now generated with a much greater
diastereoselectivity of 14:1 for the opposite diastereomer (Scheme 4). This change in diastereoselectivity
1
was also obvious from the H NMR spectrum of 46, in which the doublet at δ 2.50 (He) was now much
more prominent in comparison to the doublet at δ 2.80 (Hd), with integrations of 0.95 and 0.07,
respectively (Figure 1C).
Scheme 4. Deuterium labeling studies
10
ACS Paragon Plus Environment

Page 11 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
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
Figure 1. 1H NMR analysis of deuterium atom transfer in dihydronaphthalene 46
Crossover experiment. Incorporation of a deuterium atom at the 4-position of dihydronaphthalene 46
could arise via either an inter- or intramolecular transfer mechanism. To determine which mechanism was
operative, a crossover experiment was performed employing alkynone 30 and alkynoate 43, containing
deuterated and non-deuterated aryl groups, respectively, to test for intermolecular hydrogen/deuterium
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 31
1
2
3
4
5
6
7
8
9
atom transfer. If crossover were to occur, six total products would be expected (Scheme 5). Heating of a
1:1 mixture of 30 and 43 for 3 min at 180 °C in o-DCB afforded a mixture of six compounds that were
separated as four peaks by HPLC. Characterization by ESI-MS revealed two of the isolated
chromatogram peaks as naphthalenes 31a and 47, while analysis of the remaining two chromatogram
peaks showed a mixture of dihydronaphthalenes 31b and 46 in one peak, in addition to a mixture of 48
and 49 in the other peak. The (M+H)+ ions of the deuterated products 46 and 48 were observed with
relative intensities of greater than 55%, thus differentiating these peaks from those that result from the
natural abundance of carbon-13 for 31b and 49 (see Supporting Information). The observation of all
possible crossover products indicated that transfer of hydrogen or deuterium to the 4-position of the
dihydronaphthalene was taking place via an intermolecular process.
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
Scheme 5. Crossover experiment
Mechanism for the formation of dihydronaphthalene. As a result of our mechanistic studies, we postulate
that dihydronaphthalene formation occurs via an initial [4 + 2] cycloaddition reaction of 30 to produce the
tetraene 50 (Scheme 6A). In turn, the tris-allylic hydrogen atom is abstracted to afford a carbon-centered
radical, depicted as the two resonance structures 51 and 52. Next, 52 abstracts a hydrogen atom from
another equivalent of 50 to give dihydronaphthalene 31b, along with an additional radical 52 which will
propagate the reaction. The intermolecular hydrogen atom abstraction proposed is supported by both the
crossover experiment (Scheme 5), as well as the concentration studies, which demonstrated that
increasing the concentration of the IMDDA reaction provided larger amounts of the dihydronaphthalene
12
ACS Paragon Plus Environment

Page 13 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
substrate compared to naphthalene (entries 3 and 7, Table 1). Additionally, the diastereoselectivity that is
observed for reaction of the deuterated substrate in DMF also supports the intermolecular hydrogen atom
transfer mechanism (Scheme 5B).38
7
8
9
In order to initiate the radical process proposed for the formation of dihydronaphthalene 31b, hydrogen
atom abstraction must occur. It is unlikely that the tris-allylic C-H bond of 50 is spontaneously broken at
the temperatures that we perform the reaction (120-180 °C) because the bond dissociation energy of the
C-H bond of 1,4-cyclohexadiene, a related system, was measured as 71-78 kcal/mol.39 Instead, we
propose that triplet oxygen initiates the radical reaction by abstraction of the tris-allylic hydrogen atom
from 50 (Scheme 6C). This hypothesis is supported by the work of Hendry et al., who used kinetic data
and quantitative water analysis to reveal that only substoichiometric amounts of oxygen were required for
the thermal dehydrogenation of 1,4-cyclohexadiene to benzene (Scheme 6D).40 When we performed the
IMDDA reaction in the presence or absence of oxygen, the same product selectivity for naphthalene 31a
and dihydronaphthalene 31b was observed; this data is supported by Hendry’s results, which indicated
that stoichiometric quantities of oxygen are not necessary to achieve oxidation.
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
Scheme 6. Proposed mechanism for dihydronaphthalene formation. (A) Intramolecular deuterium atom
abstraction to produce dihydronaphthalene; (B) proposed mechanism to explain the diastereoselectivity
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 31
1
2
3
4
5
6
observed when the IMDDA reaction of 42 is performed in DMF; (C) initiation of the radical reaction by
triplet oxygen; (D) Hendry’s mechanism for dehydrogenation of 1,4-cyclohexadiene by triplet oxygen.
7
8
9
Attempts were also made to trap the postulated radical intermediates. Utilization of standard IMDDA
reaction conditions, along with 1,4-cyclohexadiene (10 equiv), afforded a similar yield and 1:1.2 ratio of
31a and 31b when compared to reaction mixtures in which 1,4-cyclohexadiene was not present (Scheme
7). No byproducts resulting from trapping of radical or biradical intermediates were observed. Increasing
the concentration of 1,4-cyclohexadiene (88 equiv) led to problems reaching the reaction’s target
temperature. Alternatively, heating of 30 in DCE at 180 °C for 2 min in the presence of excess (2,2,6,6-
tetramethylpiperidin-1-yl)oxyl (TEMPO, 1.5 equiv) resulted in a 52% yield of 31a; 31b and the TEMPO-
trapped product was not detected. The increase in yield of 31a from 30% in the absence of TEMPO to
52% in the presence of TEMPO may be explained by TEMPO acting as an oxidant during the reaction.41
The overall lower yield of the reaction and the lack of dihydronaphthalene product observed is attributed
to decomposition of dihydronaphthalene under the reaction conditions, and is evidenced by tosyl and
unresolved aliphatic impurities observed in the 1H NMR spectrum of the crude reaction mixture.
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
Scheme 7. IMDDA reactions in the presence of radical trapping agents
Mechanism for the formation of naphthalene. The data above presents compelling support for the
mechanism of formation of dihydronaphthalene; however, this data does not provide a satisfying
explanation for how the naphthalene product is generated, aside from evidence strongly suggesting that
the naphthalene is not produced directly from dihydronaphthalene (entries 3 and 4, Table 1). The lack of
evidence for oxidation of dihydronaphthalene to naphthalene, along with the large primary kinetic isotope
effect observed (Scheme 4), implies that the naphthalene and dihydronaphthalene products are being
formed by diverging mechanistic pathways. One possible pathway by which the naphthalene could be
formed is a concerted elimination of hydrogen gas via the same tetraene intermediate 50, a process that
was originally proposed by Matsubara (Scheme 8).30
14
ACS Paragon Plus Environment

Page 15 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
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
Scheme 8. Proposed mechanism for generation of naphthalene via concerted loss of H2
Woodward–Hoffmann state that atom transfers via a concerted unimolecular process are allowed when m
= 4q + 2, where m is the number of π electrons and q is an integer.42 Several reactions demonstrating
unimolecular elimination of H2 have been reported that have established a similar mechanism to what we
suggest for the formation of the naphthalene 31a. One such example was published by Wellington and
Walters, where thermal decomposition of 2,5-dihydrofuran showed production of both furan and H2 in
equal amounts (eq 1, Scheme 9).43 Similar reports that were published independently by Ellis and Frey or
Benson and Shaw demonstrated a related unimolecular elimination of H2 for 1,4-cyclohexadiene in the
generation of benzene (eq 2).44 Recently, a triphosphabenzene was reduced under 4 atm of hydrogen
pressure via a reversible 1,4-H2 addition (eq 3).45
Scheme 9. Unimolecular elimination reactions
To test the hypothesis that the tetraene intermediate 50 would undergo a concerted unimolecular
elimination of H2 to generate naphthalene 31a, we performed several IMDDA reactions with the goal of
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 31
1
2
3
4
5
6
detecting H2. We previously established that conventional heating and microwave irradiation conditions
provided nearly identical results for the IMDDA reaction, and we envisioned that H2 could potentially be
1
observed by H NMR spectroscopy if the IMDDA reaction was conducted in a sealed NMR tube using
7
conventional heating. After heating styrene-yne 30 in o-DCB-d4 at 180 °C for 2 min, a 1H NMR spectrum
of the reaction mixture was acquired which showed the presence of a new singlet at δ 4.73 that was not
attributed to the products 31a or 31b; this resonance was assumed to correspond to H2 that was formed
during the reaction (Figure 2). To confirm that this resonance was H2, additional H2 was bubbled through
the reaction mixture and an increase in the integration value for the resonance at δ 4.73 from 0.05 to 0.09
was observed, indicating that this resonance was correctly identified as H2. Argon was also bubbled
8
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
1
through the reaction mixture which resulted in the disappearance of this resonance from the H NMR
spectrum. This information supports our hypothesis that H2 was being produced during the reaction;
however, only the quantity of H2 in solution could be determined using this approach.
Figure 2. Detection of hydrogen gas by 1H NMR spectroscopy
In order to quantify the amount of H2 gas that was produced during the IMDDA reaction, gas
chromatography (GC) was utilized to examine the headspace of the reaction. For the GC experiments,
styrene-yne 30 was irradiated for 1 min at 180 °C in o-DCB (see Supporting Information). Based upon
the average 80% yield and 1:1.2 ratio of naphthalene 31a and dihydronaphthalene 31b products typically
generated for these IMDDA reactions, the theoretical yield of H2 was calculated (see Supporting
Information). Overall, a 39-48% yield of H2 was determined by GC for these experiments. These results
indicate that a substantial amount of H2 is produced during the IMDDA reaction, and that the original
hypothesis in which the naphthalene product is formed via intramolecular concerted elimination of H2
from tetraene intermediate 50 is supported (Scheme 8).
16
ACS Paragon Plus Environment

Page 17 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
With experimental evidence in hand supporting diverging reaction mechanisms for the formation of
naphthalene and dihydronaphthalene products, further mechanistic insight was gained through
calculations. Transition state calculations46 were performed for the direct expulsion of H2 or hydrogen
abstraction by triplet oxygen from tetraene intermediate 50, affording the naphthalene and
dihydronaphthalene products, respectively. The results from these calculations predict the hydrogen atom
abstraction process to be more favorable by 9.8 kcal/mol (Figure 3). This data correlates well with the
two-fold preference for formation of the dihydronaphthalene over the naphthalene product at 180 °C
(entry 3, Table 1). Likewise at lower temperatures an eight-fold preference for the dihydronaphthalene
was observed (120 °C, entry 5, Table 1); whereas at higher temperatures the opposite product selectivity
was afforded (225 °C, entry 6, Table 1).
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
3
Figure 3. Direct H2 expulsion and hydrogen abstraction by O2, modeled with SMD(DCE)-UM06-2X/6-
31+G(d,p) at 180 °C. Relative free energies are shown in kcal/mol and selected distances are shown in Å.
A mesyl group was used in place of a tosyl group to simplify the calculations.
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 31
1
2
3
4
5
6
7
8
9
Predicting selectivity for the formation of the dihydronaphthalene or naphthalene product may also be
possible from the calculated through-space distance between the flagpole hydrogens of the corresponding
tetraene intermediates. For example, for the tetraene intermediate with the all-carbon tether, 53, the Ha-Hb
distance was calculated to be 3.05 Å. By comparison, this distance for tetraene 50, containing a
tosylamide tether, was 3.63 Å, representing a difference of nearly 0.6 Å. These calculated distances
correlate well with our experimental observations for product selectivity, where a shorter calculated
distance between the hydrogen atoms affords the naphthalene product selectively, and a longer distance
favors dihydronaphthalene formation. For example, an IMDDA reaction of the all-carbon tether precursor
afforded the naphthalene product in quantitative yield, whereas reaction of the tosylamide tether-
containing substrate produced the dihydronaphthalene in 56% yield and the naphthalene in 30% yield
when reacted under identical conditions (entries 1 and 3, Table 1). It is interesting to note that for the
latter case, we can alter this product ratio to further favor dihydronaphthalene formation by lowering the
reaction temperature (entry 5, Table 1). For the ether tether 54, the Ha-Hb calculated distance is 3.58 Å
and the dihydronaphthalene was afforded in 15% yield and the naphthalene in 28% yield (entry 2, Table
1). To help explain this anomalous 1:2 ratio, we suspect that decomposition of the dihydronaphthalene
29b during the longer reaction time may be skewing this data, as suggested by the low yields.
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
Conclusions
In summary, the naphthalene and dihydronaphthalene product distribution afforded from the IMDDA
reaction of styrenes-ynes is attributed to mechanistic divergence. Compelling evidence, such as the
isotopic labeling and hydrogen gas detection experiments provided herein supports the premise that both
products are obtained from a common intermediate. An understanding of the mechanisms of formation of
each of these products can potentially allow for better control of product selectivity during the IMDDA
reaction through tuning of the reaction substrates and conditions. While previous examples of thermal
IMDDA reactions have been reported with variable results, this represents the first systematic study of the
mechanism of the IMDDA reaction of styrene-ynes for the production of both naphthalene and
dihydronaphthalene products. Furthermore, we expect that these mechanistic studies, along with the
operational simplicity and synthetic orthogonality of this approach, will transform the IMDDA reaction
into a synthetically useful alternative for the preparation of naphthalene and dihydronaphthalenes, as well
18
ACS Paragon Plus Environment

Page 19 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
as other previously inaccessible aromatic compounds. Finally, the removal of hydrogen gas from IMDDA
adducts to form aromatic compounds offers an environmentally benign alternative to typical oxidation
protocols.47
7
8
9
Experimental Section
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
General Experimental Methods. Dichloromethane (DCM) and tetrahydrofuran (THF) were dried by
passing through alumina, and triethylamine was freshly distilled from CaH2 prior to use. 1H and 13C NMR
1
spectra were referenced to residual chloroform (7.26 ppm for H NMR spectroscopy, 77.16 ppm, 13C),
1,2-dichlorobenzene (7.14 ppm for 1H NMR spectroscopy), or N,N-dimethylformamide (8.38 ppm for 1H
NMR spectroscopy). Chemical shifts are reported in ppm, multiplicities are indicated by s (singlet), b s
(broad singlet), d (doublet), t (triplet), q (quartet), p (pentet), and m (multiplet). In experiments where
yields were determined by 1H NMR spectroscopy, p-dimethoxybenzene was used as an internal standard.
A standard solution of p-dimethoxybenzene (20 mg) in o-DCB-d4 (0.5 mL) was prepared so that
quantities of p-dimethoxybenzene could be accurately added to the reaction mixtures. All microwave-
mediated reactions were conducted in either a Biotage Initiator Exp microwave synthesizer or in an
Anton-Paar Monowave 300 microwave synthesizer. The temperature of reactions in the Monowave 300
was monitored internally by a ruby sensor probe, unless otherwise specified. The microwave parameters
were set to variable power, constant temperature, stirring on, and a fixed hold time. Styrene-yne 30,
naphthalene 31a, and dihydronaphthalene 31b were prepared and characterized according to procedures
previously reported by our laboratory.14i See the Supporting Information for additional general methods
and details.
General Microwave Irradiation Procedure. To a microwave irradiation vial was added styrene-yne
and the reaction solvent (0.06 M). The solution was irradiated at 180 °C for 1 min, followed by
concentration of the reaction mixture under high vacuum. The crude material was purified by silica gel
column chromatography to yield the naphthalene and/or dihydronaphthalene as a solid. Mixtures of
naphthalene and dihydronaphthalene products were separated for characterization by HPLC. Experiments
conducted under argon involved initial degassing of the starting solution by bubbling with argon through
the septum of the microwave irradiation vial for 30 min prior to irradiation.
1-(2-Tosyl-2,3-dihydro-1H-benzo[f]isoindol-4-yl)ethan-1-one (31a). 31a was prepared from 30
according to the general microwave procedure. Characterization data is consistent with previously
reported literature data.14i 1H NMR (400 MHz, CDCl3): δ 7.85-7.79 (m, 4H), 7.70 (s, 1H), 7.54-7.47 (m,
2H), 7.32 (d, J = 8.2 Hz, 2H), 4.73 (s, 2H), 4.70 (s, 2H), 2.66 (s, 3H), 2.39 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 204.1, 144.1, 134.9, 133.8, 133.6, 133.3, 133.0, 130.1 (2C), 129.1, 128.7, 127.9 (2C), 127.4,
126.6, 124.8, 123.8, 53.0, 52.9, 32.1, 21.7.
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 31
1
2
3
4
5
6
7
8
9
1-(2-Tosyl-2,3,9,9a-tetrahydro-1H-benzo[f]isoindol-4-yl)ethan-1-one (31b). 31b was prepared from
30 according to the general microwave procedure. Characterization data is consistent with previously
reported literature data.14i 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.2 Hz,
2H), 7.24-7.16 (m, 3H), 7.09 (d, J = 6.9 Hz, 1H), 4.53 (dd, J = 18.0, 1.6 Hz, 1H), 3.95 (dd, J = 9.4, 8.2
Hz, 1H), 3.90 (dd, J = 18.0, 2.8 Hz, 1H), 3.02-2.93 (m, 1H), 2.86 (app t, J = 9.2 Hz, 1H), 2.82 (dd, J =
14.8, 6.4 Hz, 1H), 2.51 (app t, J = 14.8 Hz, 1H), 2.44 (s, 3H), 2.34 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ 200.9, 148.1, 144.0, 134.7, 133.1, 132.1 (2C), 130.0 (2C), 128.2, 128.1, 128.0 (2C), 127.3, 125.8, 53.1,
51.8, 40.2, 32.4, 30.2, 21.7.
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
Irradiation of 30 in DMF-d7. To a G4 Anton-Paar microwave irradiation vial was added styrene-yne
30 (0.020 g, 0.054 mmol) and DMF-d7 (0.91 mL). The solution was irradiated at 180 °C for 1 min, turning
the reaction mixture orange in color. The reaction mixture was then concentrated under high vacuum and
the crude material purified by silica gel flash column chromatography (1.5 cm, 20% ethyl
acetate/hexanes) to yield the title compounds as a white solid and as a 1:10 mixture of 31a and 31b (0.015
g, 75%). These products were separated for characterization by HPLC, utilizing 10% ethyl
acetate/hexanes as the eluent and a flow rate of 4 mL/min. The HPLC retention time of naphthalene 31a
1
was 34.2 min and the retention time of dihydronaphthalene 31b was 38.2 min. A H NMR spectrum of
the dihydronaphthalene product 31b showed no deuterium incorporation (pp. S25-26 and Figure S1).
Irradiation of 30 in the Presence of 1,4-Cyclohexadiene. To a NMR tube was added styrene-yne 30
(0.013 g, 0.036 mmol), o-DCB-d4 (0.55 mL), and a solution of p-dimethoxybenzene in o-DCB-d4 (50 μL,
1
0.002 g) as an internal standard. A H NMR spectrum of the solution was obtained, followed by transfer
of the solution to a G4 Anton-Paar microwave irradiation vial and addition of 1,4-cyclohexadiene (34 μL,
0.36 mmol). The solution was then irradiated at 180 °C for 1 min, turning the reaction mixture light
1
brown in color. The reaction mixture was then transferred to a NMR tube, and a H NMR spectrum was
obtained showing conversion of the starting material 30 to products 31a and 31b as a 1:1.2 mixture in
81% combined yield (pp. S27-28).
Irradiation of 30 in the Presence of TEMPO. To a 0.5-2 mL Biotage microwave irradiation vial was
added styrene-yne 30 (0.022 g, 0.060 mmol), DCE (1.0 mL), and (2,2,6,6-tetramethylpiperidin-1-yl)oxy
(0.014 g, 0.090 mmol). The solution was then irradiated at 180 °C for 1 min, turning the reaction mixture
dark brown in color. The reaction mixture was concentrated under reduced pressure and the crude
material purified by silica gel flash column chromatography (10% ethyl acetate hexanes) to yield 31a as a
light yellow solid (0.011 g, 52%).
1
Conventional Heating and Hydrogen Detection by H NMR Spectroscopy. To a screw-cap NMR
tube was added styrene-yne 30 (0.013 g, 0.036 mmol), o-DCB-d4 (0.55 mL), and a solution of p-
dimethoxybenzene in o-DCB-d4 (50 μL, 0.002 g) as an internal standard via pipette. The cap was screwed
20
ACS Paragon Plus Environment

Page 21 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
onto the NMR tube, and a 1H NMR spectrum of the starting solution was obtained. The solution was then
1
heated at 180 °C for 2 min in an oil bath, turning the reaction mixture brown in color. A H NMR
spectrum of the reaction mixture was obtained showing conversion of the starting material 30 to the
products 31a and 31b as a 1:1.2 mixture in 86% combined yield (pp. S29-30).
The 1H NMR spectrum of the products also showed the presence of hydrogen gas (H2) in solution as a
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
singlet integrating for 0.06H at 4.73 ppm (pg. S30), which indicated a 11:1 ratio of 31a:H2. To confirm
1
that this resonance corresponded to H2, H2 was bubbled through the reaction mixture and another H
NMR spectrum was obtained which showed an increase in the integration value from 0.06 to 0.10H,
representing a 6:1 ratio of 31a:H2 (pg. S31). Argon was then bubbled through the reaction mixture and the
resonance corresponding to H2 disappeared (see Figure 2 manuscript).
(E)-3-Phenylprop-2-en-2-d-1-ol (33). To a flame-dried two-neck 100 mL round-bottomed flask
equipped with a condenser and a septum under an atmosphere of argon was added lithium aluminum
deuteride (0.877 g, 20.9 mmol). The round-bottomed flask was evacuated and refilled with argon (3x),
and THF (35 mL) was added via syringe with stirring. 3-Phenyl-2-propyn-1-ol 32 (2.0 mL, 16 mmol) in
THF (5 mL) was then added slowly dropwise via syringe, and bubbling occurred along with a color
change from dark to light grey. The reaction mixture was heated to reflux in an oil bath for 5 h, turning
the reaction mixture brown, followed by cooling to rt then 0 °C in an ice bath. To quench the reaction,
water was added slowly dropwise and vigorous bubbling occurred. Once bubbling had ceased and the
reaction mixture had become white in color, diethyl ether was added and the aqueous layer was separated.
The aqueous layer was then extracted with diethyl ether (2x), and the combined organic layers were
washed with brine, dried over magnesium sulfate, gravity filtered, and concentrated under reduced
pressure to yield the title compound as a clear oil (2.23 g, quant). The crude material was carried on
1
without purification. Analytical TLC on silica gel, Rf = 0.4 (40% ethyl acetate/hexanes). H NMR (500
MHz, CDCl3): δ 7.39 (d, J = 7.5 Hz, 2H), 7.32 (t, J = 7.5 Hz, 2H), 7.26 (t, J = 7.5 Hz, 1H), 6.61 (s, 1H),
4.32 (s, 2H).13C NMR (100 MHz, CDCl3): δ 136.8, 131.2, 128.7 (2C), 128.3 (t, J = 24.0 Hz, 1C), 127.8
(2C), 126.6, 63.8. IR (film): 3338, 3080, 3059, 2919, 2863, 1600, 1493, 1449 cm-1. HRMS (ESI) m/z
calcd for C9H8DO [M - H]+ 134.0722, found 134.0711.
4-Methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (34). Synthesized according to the procedure
reported by Gilbertson.48
(E)-4-Methyl-N-(3-phenylallyl-2-d)-N-(prop-2-yn-1-yl)benzenesulfonamide (35). To a flame-dried
two-neck 100 mL round-bottomed flask equipped with an argon inlet adapter and a septum was added
(E)-3-phenylprop-2-en-2-d-1-ol
(33)
(1.00
g,
7.40
mmol),
4-methyl-N-(prop-2-yn-1-
yl)benzenesulfonamide (34) (1.55 g, 7.40 mmol), and triphenylphosphine (1.94 g, 7.40 mmol). The
round-bottomed flask was evacuated and refilled with argon (3x), and THF (69 mL) was added via
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 31
1
2
3
4
5
6
7
8
9
syringe with stirring. Diisopropyl azodicarboxylate (1.46 mL, 7.40 mmol) was added dropwise via
syringe, and the reaction mixture turned bright yellow in color. The reaction mixture was stirred at rt for
20 h, and was then concentrated under reduced pressure. The crude material was purified by silica gel
flash column chromatography (5 cm column, 5-15% ethyl acetate/hexanes) to yield the title compound as
a white solid (2.04 g, 85%). Analytical TLC on silica gel, Rf = 0.5 (25% ethyl acetate/hexanes). MP: 74-
75 °C. 1H NMR (300 MHz, CDCl3): δ 7.77 (d, J = 8.1 Hz, 2H), 7.35-7.26 (m, 7H), 6.56 (s, 1H), 4.13 (d, J
= 2.4 Hz, 2H), 3.99 (s, 2H), 2.44 (s, 3H), 2.04 (t, J = 2.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 143.7,
136.2 (2C), 134.9, 129.6 (2C), 128.7 (2C), 128.2, 127.9 (2C), 126.7 (2C), 122.7 (t, J = 24.0 Hz, 1C), 76.8,
74.0, 48.6, 36.0, 21.7. IR (film): 3026, 2921, 2119, 1598, 1495, 1348, 1162 cm-1. HRMS (ESI) m/z calcd
for C19H19DO2NS [M + H]+ 327.1278, found 327.1269.
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
(E)-4-Methyl-N-(4-oxopent-2-yn-1-yl)-N-(3-phenylallyl-2-d)benzenesulfonamide (37). To a flame-
dried two-neck 15 mL round-bottomed flask equipped with an argon inlet adapter and a septum was
added styrene-yne 35 (0.112 g, 0.34 mmol) in THF (7.8 mL). The solution was cooled to -78 °C in a dry
ice-acetone bath, and then lithium diisopropylamide (0.17 mL of a 2.0 M solution in
THF/heptane/ethylbenzene, 0.34 mmol) was added slowly dropwise via syringe, turning the reaction
mixture dark purple. The reaction mixture was stirred at -78 °C for 1 h and became green in color. N-
Methoxy-N-methylacetamide (36) (33 μL, 0.31 mmol) was subsequently added via syringe and the
reaction mixture turned light purple. The reaction mixture was stirred at -78 °C for 15 min and at rt for
1.5 h. Over time, the color became a dark brown. The reaction mixture was poured into brine, and sat’d aq
ammonium chloride was added. The aqueous layer was separated and extracted with ethyl acetate (2x),
and the combined organic layers were washed with brine, dried over magnesium sulfate, gravity filtered,
and concentrated under reduced pressure. The crude material was purified by silica gel flash column
chromatography (2.5 cm column, 15% ethyl acetate/hexanes) to yield the title compound as a light yellow
solid (0.052 g, 46%). Analytical TLC on silica gel, Rf = 0.3 (25% ethyl acetate/hexanes). MP: 93-94 °C.
1H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 8.0 Hz, 2H), 7.35-7.24 (m, 7H), 6.55 (s, 1H), 4.27 (s, 2H),
3.99 (s, 2H), 2.43 (s, 3H), 2.10 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 183.3, 144.2, 135.9, 135.7, 135.4,
129.9 (2C), 128.8 (2C), 128.4, 127.9 (2C), 126.7 (2C), 122.2 (t, J = 24.0 Hz, 1C), 84.9, 84.4, 49.3, 36.2,
32.4, 21.6. IR (film): 3026, 2921, 2210, 1679, 1597, 1495, 1350, 1163 cm-1. HRMS (ESI) m/z calcd for
C21H21DO3NS [M + H]+ 369.1374, found 369.1383.
(E)-3-(Phenyl-d5)prop-2-en-1-ol (40). To a flame-dried two-neck 50 mL round-bottomed flask
equipped with an argon inlet adapter and a septum was added bromobenzene-d5 (38) (1.30 mL, 12.3
mmol) and water (62 mL). Propargyl alcohol (39) (1.1 mL, 19 mmol), pyrrolidine (1.52 mL, 18.5 mmol),
tetrakis(triphenylphosphine)palladium(0) (0.071 g, 0.062 mmol), and copper(I) iodide (0.023 g, 0.12
mmol) were added sequentially. The reaction mixture was stirred at 70 °C for 1 h, turning the reaction
22
ACS Paragon Plus Environment

Page 23 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
mixture from yellow to light green. The reaction mixture was then cooled to rt and diethyl ether was
added. The aqueous layer was separated and extracted with diethyl ether (2x), and the combined organic
layers were washed with water and brine, dried over magnesium sulfate, gravity filtered, and concentrated
under reduced pressure. The crude material was filtered through a pad of silica gel with diethyl ether
washings, and then was placed under high vacuum to yield 3-(phenyl-d5)prop-2-yn-1-ol as a yellow oil
(0.844 g, 50%). Characterization data is consistent with previously reported literature data.49 Analytical
TLC on silica gel, Rf = 0.3 (20% ethyl acetate/hexanes). 1H NMR (300 MHz, CDCl3): δ 4.51 (s, 2H), 1.64
(b s, 1H).
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
To a flame-dried two-neck 15 mL round-bottomed flask equipped with a condenser and a septum
under an atmosphere of argon was added lithium aluminum hydride (0.164 g, 4.33 mmol). The round-
bottomed flask was evacuated and refilled with argon (3x), and THF (7.2 mL) was added via syringe with
stirring. 3-(Phenyl-d5)prop-2-yn-1-ol (0.457 g, 3.33 mmol) in THF (1.1 mL) was then added slowly
dropwise via syringe, and bubbling occurred. The reaction mixture was heated to reflux in an oil bath for
1 h, turning the reaction mixture from light grey to light brown, followed by cooling to rt then 0 °C in an
ice bath. To quench the reaction, water was added slowly dropwise and vigorous bubbling occurred. Once
bubbling had ceased and the reaction mixture had become white in color, diethyl ether was added and the
aqueous layer was separated. The aqueous layer was then extracted with diethyl ether (4x), and the
combined organic layers were washed with brine, dried over magnesium sulfate, gravity filtered, and
concentrated under reduced pressure to yield the title compound as an amber oil (0.257 g, 56%). The
crude material was carried on without purification. Analytical TLC on silica gel, Rf = 0.2 (20% ethyl
1
acetate/hexanes). H NMR (300 MHz, CDCl3): δ 6.63 (d, J = 15.9 Hz, 1H), 6.37 (dt, J = 15.9, 5.4 Hz,
1H), 4.33 (d, J = 5.4 Hz, 2H), 1.55 (b s, 1H).
(E)-4-Methyl-N-(3-(phenyl-d5)allyl)-N-(prop-2-yn-1-yl)benzenesulfonamide (41). To a flame-dried
two-neck 25 mL round-bottomed flask equipped with an argon inlet adapter and a septum was added (E)-
3-(phenyl-d5)prop-2-en-1-ol (40) (0.253 g, 1.82 mmol), 4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide
(34) (0.381 g, 1.82 mmol), and triphenylphosphine (0.478 g, 1.82 mmol). The round-bottomed flask was
evacuated and refilled with argon (3x), and THF (17 mL) was added via syringe with stirring. Diisopropyl
azodicarboxylate (0.36 mL, 1.8 mmol) was added dropwise via syringe, and the reaction mixture turned
bright yellow in color. The reaction mixture was stirred at rt for 16 h, and was then concentrated under
reduced pressure. The crude material was purified by silica gel flash column chromatography (2.5 cm
column, 15% ethyl acetate/hexanes) to yield the title compound as an off-white solid (0.517 g, 86%).
1
Analytical TLC on silica gel, Rf = 0.5 (25% ethyl acetate/hexanes). MP: 69-71 °C. H NMR (300 MHz,
CDCl3): δ 7.77 (dd, J = 8.4, 1.8 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 6.58 (td, J = 15.9, 1.2 Hz, 1H), 6.08
(dt, J = 15.9, 6.9 Hz, 1H), 4.13 (d, J = 2.4 Hz, 2H), 3.99 (dd, J = 6.9, 1.2 Hz, 2H), 2.44 (s, 3H), 2.04 (t, J
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 31
1
2
3
4
5
6
7
8
9
13
= 1.2 Hz, 1H). C NMR (100 MHz, CDCl3): δ 143.7, 136.2, 136.1, 135.0, 129.6 (2C), 128.5-127.5 (m,
5C), 126.2 (t, J = 24.0 Hz, 2C), 123.0, 76.7, 73.9, 48.7, 36.0, 21.7. IR (film): 3289, 3034, 2923, 2276,
2118, 1598, 1494, 1346, 1161 cm-1. HRMS (ESIMSMS) m/z calcd for C19H15D5O2NS [M + H]+ 331.1518,
found 331.1529.
(E)-4-Methyl-N-(4-oxopent-2-yn-1-yl)-N-(3-(phenyl-d5)allyl)benzenesulfonamide (42). To
a
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
flame-dried two-neck 25 mL round-bottomed flask equipped with an argon inlet adapter and a septum
was added styrene-yne 41 (0.200 g, 0.61 mmol) in THF (14 mL). The solution was cooled to -78 °C in a
dry ice-acetone bath, and then lithium diisopropylamide (0.30 mL of a 2.0 M solution in
THF/heptane/ethylbenzene, 0.61 mmol) was added slowly dropwise via syringe, turning the reaction
mixture dark purple. The reaction mixture was stirred at -78 °C for 80 min and became light yellow. N-
Methoxy-N-methylacetamide (36) (58 μL, 0.55 mmol) was subsequently added dropwise via syringe and
the reaction mixture was stirred at -78 °C for 15 min and at rt for 1 h. Over time, the reaction mixture
turned reddish in color. Sat’d aq ammonium chloride was added, and the aqueous layer was separated and
extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over
magnesium sulfate, gravity filtered, and concentrated under reduced pressure. The crude material was
purified by silica gel flash column chromatography (2.5 cm column, 15% ethyl acetate/hexanes) to yield
the title compound as a white solid (0.163 g, 80%). Analytical TLC on silica gel, Rf = 0.3 (25% ethyl
acetate/hexanes). MP: 84-86 °C. 1H NMR (300 MHz, CDCl3): δ 7.77 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.2
Hz, 2H), 6.57 (d, J = 15.9 Hz, 1H), 6.08 (dt, J = 15.9, 6.9 Hz, 1H), 4.27 (s, 2H), 4.00 (dd, J = 6.9, 0.9 Hz,
2H), 2.44 (s, 3H), 2.10 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 183.3, 144.2, 135.8 (2C), 135.4, 129.9
(2C), 128.5-127.6 (m, 5C), 126.3 (t, J = 24.0 Hz, 2C), 122.5, 84.9, 84.4, 49.4, 36.2, 32.4, 21.6. IR (film):
3031, 2922, 2246, 2209, 1670, 1597, 1494, 1349, 1163 cm-1. HRMS (ESIMSMS) m/z calcd for
C21H17D5O3NS [M + H]+ 373.1622, found 373.1634.
Methyl (E)-4-((4-methyl-N-(3-(phenyl-d5)allyl)phenyl)sulfonamido)but-2-ynoate (43). To a flame-
dried two-neck 5 mL round-bottomed flask equipped with an argon inlet adapter and a septum was added
styrene-yne 41 (0.10 g, 0.30 mmol) in THF (1.5 mL). The solution was cooled to -78 °C in a dry ice-
acetone bath, and then n-butyllithium (0.21 mL of a 1.6 M solution in hexanes, 0.33 mmol) was added
slowly dropwise via syringe, turning the reaction mixture dark purple. The reaction mixture was stirred at
-78 °C for 45 min and became light brown. Methyl chloroformate (30 μL, 0.39 mmol) was subsequently
added dropwise via syringe and the reaction mixture was stirred at -78 °C for 1 h, becoming darker brown
over time. The reaction mixture was allowed to warm slowly to -10 °C and sat’d aq ammonium chloride
was added. The aqueous layer was separated and extracted with ethyl acetate (2x), and the combined
organic layers were washed with brine, dried over magnesium sulfate, gravity filtered, and concentrated
under reduced pressure. The crude material was purified by silica gel flash column chromatography (2.5
24
ACS Paragon Plus Environment

Page 25 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
cm column, 10% ethyl acetate/hexanes) to yield the title compound as a clear oil (0.065 g, 55%).
1
Analytical TLC on silica gel, Rf = 0.3 (25% ethyl acetate/hexanes). H NMR (400 MHz, CDCl3): δ 7.76
(d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 6.58 (td, J = 16.0, 1.2 Hz, 1H), 6.07 (dt, J = 16.0, 6.8 Hz,
1H), 4.24 (s, 2H), 3.98 (dd, J = 6.8, 0.8 Hz, 2H), 3.71 (s, 3H), 2.44 (s, 3H). 13C NMR (125 MHz, CDCl3):
δ 153.2, 144.2, 135.9, 135.6 (2C), 129.9 (2C), 128.5-127.8 (m, 5C), 126.3 (t, J = 24.0 Hz, 2C), 122.6,
80.8 (2C), 52.9, 49.4, 36.1, 21.7. IR (film): 2954, 2240, 1717, 1597, 1435, 1258, 1162 cm-1. HRMS (ESI)
m/z calcd for C21H17D5O4NS [M + H]+ 389.1556, found 389.1583.
7
8
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
1-(2-Tosyl-2,3,9,9a-tetrahydro-1H-benzo[f]isoindol-4-yl-9a-d)ethan-1-one (44). To a NMR tube
was added the styrene-yne 37 (0.013 g, 0.036 mmol), o-DCB-d4 (0.60 mL), and a solution of p-
1
dimethoxybenzene in o-DCB-d4 (50 μL, 0.002 g) as an internal standard. A H NMR spectrum of the
solution was obtained, followed by transfer of the solution to a G4 Anton-Paar microwave irradiation vial
which was irradiated at 180 °C for 1 min, turning the reaction mixture brown in color. The reaction
1
mixture was then transferred to a NMR tube, and a H NMR spectrum was obtained showing conversion
of the starting material 37 to the products 31a and 44 as a 1:5.2 mixture in 81% combined 1H NMR yield
(pp. S46-49). The reaction mixture was then concentrated under high vacuum and a portion of the mixture
was separated by HPLC for characterization, utilizing 10% ethyl acetate/hexanes as the eluent and a flow
rate of 4 mL/min. The HPLC retention time of naphthalene 31a was 33.9 min and the retention time of
dihydronaphthalene 44 was 38.2 min. 1-(2-Tosyl-2,3,9,9a-tetrahydro-1H-benzo[f]isoindol-4-yl-9a-
d)ethan-1-one (44): analytical TLC on silica gel, Rf = 0.5 (35% ethyl acetate/hexanes). MP: 154-156 °C.
1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.26-7.18 (m, 3H), 7.09
(dd, J = 6.8, 2.0 Hz, 1H), 4.52 (d, J = 18.0 Hz, 1H), 3.94 (d, J = 9.6 Hz, 1H), 3.90 (d, J = 18.0 Hz, 1H),
2.86 (d, J = 9.6 Hz, 1H), 2.81 (d, J = 14.6 Hz, 1H), 2.51 (d, J = 14.6 Hz, 1H), 2.43 (s, 3H), 2.34 (s, 3H).
13C NMR (125 MHz, CDCl3): δ 200.9, 147.9, 144.0, 134.7, 133.2 (2C), 132.2, 130.0 (2C), 128.3, 128.1,
128.0 (2C), 127.3, 125.8, 53.0, 51.8, 39.8 (t, J = 20 Hz, 1C), 32.4, 30.2, 21.7. IR (film): 3059, 2925, 2255,
1682, 1622, 1598, 1347, 1163 cm-1. HRMS (ESI) m/z calcd for C21H21DO3NS [M + H]+ 369.1383, found
369.1370.
1-(2-Tosyl-2,3-dihydro-1H-benzo[f]isoindol-4-yl-5,6,7,8-d4)ethan-1-one (45) and 1-(2-tosyl-
2,3,9,9a-tetrahydro-1H-benzo[f]isoindol-4-yl-5,6,7,8,9-d5)ethan-1-one (46). To a NMR tube was
added styrene-yne 42 (0.013 g, 0.036 mmol), o-DCB-d4 (0.60 mL), and a solution of p-dimethoxybenzene
1
in o-DCB-d4 (50 μL, 0.002 g) as an internal standard. A H NMR spectrum of the solution was obtained,
followed by transfer of the solution to a G4 Anton-Paar microwave irradiation vial which was irradiated
1
at 180 °C for 1 min. The reaction mixture was then transferred to a NMR tube, and a H NMR spectrum
was obtained showing conversion of the starting material 42 to the products 45 and 46 as a 1:1 mixture in
1
70% combined H NMR yield (pp. S50-57). The reaction mixture was then concentrated under high
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 31
1
2
3
4
5
6
7
8
9
vacuum and a portion of the mixture was separated by HPLC for characterization, utilizing 10% ethyl
acetate/hexanes as the eluent and a flow rate of 4 mL/min. The HPLC retention time of naphthalene 45
was 35.0 min and the retention time of dihydronaphthalene 46 was 38.8 min. Dihydronaphthalene 46 was
1
formed as a 1.5:1 ratio of diastereomers, as evidenced by H NMR spectroscopy after chromatography
(major diastereomer shown). The diastereomers were not separable by HPLC. 1-(2-Tosyl-2,3-dihydro-
1H-benzo[f]isoindol-4-yl-5,6,7,8-d4)ethan-1-one (45): analytical TLC on silica gel, Rf = 0.5 (35% ethyl
acetate/hexanes). MP: 134-136 °C. 1H NMR (300 MHz, CDCl3): δ 7.81 (d, J = 8.1 Hz, 2H), 7.72 (s, 1H),
7.33 (d, J = 8.1 Hz, 2H), 4.74 (s, 2H), 4.72 (s, 2H), 2.67 (s, 3H), 2.40 (s, 3H). 13C NMR (125 MHz,
CDCl3): δ 204.0, 144.1, 134.9, 133.7, 133.5, 133.3, 133.0, 130.1, 129.0 (2C), 128.3 (t, J = 24.3 Hz, 1C),
127.9 (2C), 126.9 (t, J = 24.3 Hz, 1C), 126.1 (t, J = 24.3 Hz, 1C), 124.3 (t, J = 24.3 Hz, 1C), 123.8, 53.0,
52.9, 32.1, 21.7. IR (film): 2926, 2258, 1685, 1597, 1461, 1346, 1163 cm-1. HRMS (ESI) m/z calcd for
C21H16D4O3NS [M + H]+ 370.1415, found 370.1404. 1-(2-Tosyl-2,3,9,9a-tetrahydro-1H-benzo[f]isoindol-
4-yl-5,6,7,8,9-d5)ethan-1-one (46): analytical TLC on silica gel, Rf = 0.5 (35% ethyl acetate/hexanes).
MP: 159-160 °C. 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 4.53
(dd, J = 18.0, 1.6 Hz, 1H), 3.95 (dd, J = 9.6, 8.4 Hz, 1H), 3.90 (dd, J = 18.0, 2.8 Hz, 1H), 3.01-2.93 (m,
1H), 2.85 (app t, J = 9.6 Hz, 1H), 2.80 (d, J = 6.4, 0.69H), 2.49 (d, J = 14.8 Hz, 0.47H), 2.43 (s, 3H), 2.34
(s, 3H).50 13C NMR (175 MHz, CDCl3): δ 200.9, 148.1, 144.0, 134.5, 133.1 (2C), 132.0, 130.0 (2C), 128.0
(2C), 127.8-127.4 (m, 2C), 126.7 (t, J = 24.0 Hz, 1C), 125.4 (t, J = 24.0 Hz, 1C), 53.1, 51.8, 40.2, 32.0 (t,
J = 19.3 Hz, 1C), 30.2, 21.7. IR (film): 2925, 2255, 1682, 1598, 1494, 1346, 1162 cm-1. HRMS (ESI) m/z
calcd for C21H17D5O3NS [M + H]+ 373.1634, found 373.1621.
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
Irradiation of 42 in DMF. To a G4 Anton-Paar microwave irradiation vial was added styrene-yne 42
(0.015 g, 0.040 mmol) and DMF (0.67 mL). The solution was irradiated at 180 °C for 1 min and became
orange in color. The temperature of the reaction was monitored by IR sensor (no ruby sensor probe). The
1
reaction mixture was then concentrated under high vacuum, and a H NMR spectrum of the crude
material was obtained which showed a 1:7 mixture of 45 and 46. Purification by silica gel flash column
chromatography (10% ethyl acetate/hexanes) yielded the mixture as a white solid (0.013 g, 86%). The
mixture was then separated by HPLC for characterization, utilizing 10% ethyl acetate/hexanes as the
eluent and a flow rate of 4 mL/min. Dihydronaphthalene 46 was formed as a 14:1 ratio of diastereomers
1
(major diastereomer shown), as evidenced by H NMR spectroscopy after chromatography (pp. S58-59).
The diastereomers were not separable by HPLC. 1-(2-Tosyl-2,3,9,9a-tetrahydro-1H-benzo[f]isoindol-4-
yl-5,6,7,8,9-d5)ethan-1-one (46): 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.2
Hz, 2H), 4.53 (dd, J = 18.0, 1.6 Hz, 1H), 3.95 (dd, J = 9.6, 8.8 Hz, 1H), 3.90 (dd, J = 18.0, 2.8 Hz, 1H),
3.00-2.90 (m, 1H), 2.85 (app t, J = 9.6 Hz, 1H), 2.80 (d, J = 6.4 Hz, 0.07H), 2.49 (d, J = 15.2 Hz, 0.95H),
2.43 (s, 3H), 2.34 (s, 3H).51
26
ACS Paragon Plus Environment

Page 27 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Methyl 2-tosyl-2,3-dihydro-1H-benzo[f]isoindole-4-carboxylate-5,6,7,8-d4 (47) and methyl 2-
tosyl-2,3,9,9a-tetrahydro-1H-benzo[f]isoindole-4-carboxylate-5,6,7,8,9-d5 (48). To a G4 Anton-Paar
microwave irradiation vial was added styrene-yne 43 (0.022 g, 0.057 mmol) and o-DCB (0.95 mL). The
solution was irradiated at 180 °C for 4 min and became orange/brown in color. The temperature in this
experiment was monitored by IR sensor (no ruby sensor probe). The reaction mixture was then
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
1
concentrated under high vacuum, and a H NMR spectrum of the crude material was obtained which
showed a 1:1.1 mixture of 47 and 48 (pp. S60-65). Purification by silica gel flash column chromatography
(1.5 cm column, 10-15% ethyl acetate/hexanes) yielded the mixture as a white solid (0.013 g, 59%). The
mixture was then separated by HPLC for characterization utilizing 10% ethyl acetate/hexanes as the
eluent and a flow rate of 4 mL/min. Dihydronaphthalene 48 was formed as a 2.6:1 ratio of diastereomers,
1
2
as evidenced by H and H NMR spectroscopy after chromatography. The diastereomers were not
separable by HPLC. Methyl 2-tosyl-2,3-dihydro-1H-benzo[f]isoindole-4-carboxylate-5,6,7,8-d4 (47):
analytical TLC on silica gel, Rf = 0.2 (15% ethyl acetate/hexanes). HPLC retention time: 27.3 min. MP:
1
193-195 °C. H NMR (300 MHz, CDCl3): δ 7.80 (d, J = 8.1 Hz, 2H), 7.76 (s, 1H), 7.32 (d, J = 8.1 Hz,
2H), 4.92 (s, 2H), 4.74 (d, J = 0.9 Hz, 2H), 4.03 (s, 3H), 2.39 (s, 3H). 13C NMR (175 MHz, CDCl3): δ
167.4, 144.0, 138.3, 134.6, 133.6, 133.4, 130.1, 128.1-127.8 (m, 3C), 127.3 (t, J = 22.2 Hz, 1C), 126.1 (t,
J = 22.2 Hz, 1C), 125.7 (2C), 125.4 (t, J = 22.2 Hz, 1C), 54.8, 52.9, 52.5, 21.7. IR (film): 2919, 1713,
1462, 1162 cm-1. HRMS (ESI) m/z calcd for C21H16D4O4NS [M + H]+ 386.1359, found 386.1379. Methyl
2-tosyl-2,3,9,9a-tetrahydro-1H-benzo[f]isoindole-4-carboxylate-5,6,7,8,9-d5 (48): analytical TLC on
1
silica gel, Rf = 0.2 (15% ethyl acetate/hexanes). HPLC retention time: 28.7 min. MP: 148-150 °C. H
NMR (300 MHz, CDCl3): δ 7.76 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 4.68 (dd, J = 18.6, 1.5 Hz,
1H), 4.07 (dd, J = 18.6, 3.0 Hz, 1H), 3.99 (dd, J = 9.3, 9.3 Hz, 1H), 3.86 (s, 3H), 3.07-2.94 (m, 1H), 2.83-
13
2.75 (m, 1.9H), 2.52-2.42 (m, 3.4H). C NMR (175 MHz, CDCl3): δ 166.2, 152.8, 144.1, 134.1, 132.8,
130.0 (2C), 128.0 (2C), 127.5-127.2 (m, 2C), 126.8-126.2 (m, 2C), 123.4, 53.4, 52.8, 52.0, 40.7, 31.6 (t, J
= 19.0 Hz, 1C), 21.7. IR (film): 2925, 2854, 1712, 1598, 1494, 664, 595 cm-1. HRMS (ESI) m/z calcd for
C21H17D5O4NS [M + H]+ 389.1578, found 389.1574.
Crossover Study. To a G4 Anton-Parr microwave irradiation vial was added styrene-ynes 30 (6.6 mg
mg, 0.018 g) and 43 (7.0 mg, 0.018 mmol) in o-DCB (0.3 mL). The solution was irradiated at 180 °C.
After 1 min, the reaction of 30 was complete by TLC, but a significant amount of 43 remained. The
reaction was irradiated for an additional 2 min until complete by TLC. After irradiation, the reaction
mixture was orange/brown in color. The reaction mixture was then concentrated under high vacuum, and
the crude brown oil was subjected to HPLC, utilizing 10% ethyl acetate/hexanes as the eluent and a flow
rate of 4 mL/min. The HPLC chromatogram showed four major peaks with retention times of 27.284,
28.707, 34.210, and 38.200 min, which were collected and characterized by ESI-MS (Figure S2).
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 31
1
2
3
4
5
6
Characterization showed that all six potential compounds of the crossover experiment were present within
the four HPLC peaks isolated. The data pertaining to which HPLC peaks contained which products, as
well as comparison of found masses to calculated masses, are listed in Table S3.
7
8
9
Associated Content
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
Supporting Information
X-ray crystallography data, computational methods, and spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
Author Information
Corresponding Author
* E-mail: kbrummon@pitt.edu, djtantillo@ucdavis.edu
Notes
The authors declare no competing financial interest.
Acknowledgements
Kay Brummond and Laura Kocsis gratefully acknowledge the National Institutes of Health (NIGMS
P50GM067082), University of Pittsburgh, and Andrew Mellon Predoctoral Fellowship for financial
support. Dean Tantillo acknowledges the XSEDE program for computational resources. We would also
like to thank Dennis Curran for suggesting the crossover substrates, Damodaran Krishnan and
Viswanathan Elumalai for performing 2H NMR spectroscopy, Steve Geib for acquiring the X-ray crystal
structure, and David Lamal for discussions regarding the Woodward–Hoffmann rules.
References
1 (a) Lin, S.-H.; Wu, F.-I.; Liu, R.-S. Chem. Commun. 2009, 6961. (b) Sommer, M. J. Mat. Chem. C 2014,
2, 3088.
2
(a) Lietzau, L.; Bremer, M.; Klassen-Memmer, M.; Heckmeier H. Cyclopenta[b]naphthalene
derivatives. U.S. Patent 7,291,366, Nov 6, 2007. (b) Lietzau, L.; Bremer, M.; Klassen-Memmer, M.;
Heckmeier H. Cyclopenta[b]naphthalene derivatives. U.S. Patent 7,612,243, Nov 3, 2009. (c) Leight, K.
R.; Esarey, B. E.; Murray, A. E.; Reczek, J. J. Chem. Mater. 2012, 24, 3318.
3 (a) Petranyi, G.; Ryder, N.; Stutz, A. Science 1984, 224, 1239. (b) Ryder, N. S.; Frank, I.; Dupont, M. C.
Antimicrob. Agents Chemother. 1986, 29, 858. (c) Tan, A. K.; Fink, A. L. Biochem. J. 1992, 281, 191. (d)
28
ACS Paragon Plus Environment

Page 29 of 31
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Duggan, K. C.; Walters, M. J.; Musee, J.; Harp, J. M.; Kiefer, J. R.; Oates, J. A.; Marnett, L. J. J. Biol.
Chem. 2010, 285, 34950.
4 (a) Pu, L. Chem. Rev. 1998, 98, 2405. (b) Noyori, R.; Ohkuma, T. Angew. Chem. Int. Ed. 2001, 40, 40.
(c) Kumobayashi, H.; Miura, T.; Sayo, N.; Saito, T.; Zhang, X. Synlett 2001, 2001, 1055. (d) Shibasaki,
M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187.
5 Ohta, T.; Takaya, H.; Kitamura, M.; Nagai, K.; Noyori, R. J. Org. Chem. 1987, 52, 3174.
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
6
(a) Lester, W. Annu. Rev. Microbiol. 1972, 26, 85. (b) Dorsett, P. H.; Kerstine, E. E.; Powers, L. J. J.
Pharm. Sci. 1975, 64, 1073. (c) Radloff, R. J.; Deck, L. M.; Royer, R. E.; Vander Jagt, D. L. Pharmacol.
Res. Commun. 1986, 18, 1063. (d) Joseph, A. E.; Matlin, S. A.; Knox, P. Br. J. Cancer 1986, 54, 511. (e)
Lin, T. S.; Schinazi, R.; Griffith, B. P.; August, E. M.; Eriksson, B. F.; Zheng, D. K.; Huang, L. A.;
Prusoff, W. H. Antimicrob. Agents Chemother. 1989, 33, 2149. (f) Boyd, M. R.; Hallock, Y. F.;
Cardellina, J. H.; Manfredi, K. P.; Blunt, J. W.; McMahon, J. B.; Buckheit, R. W.; Bringmann, G.;
Schaeffer, M. J. Med. Chem. 1994, 37, 1740.
7 Xu, G.; Fu, W.; Liu, G.; Senanayake, C.H.; Tang, W. J. Am. Chem. Soc. 2014, 136, 570.
8
The Molecular Probes Handbook, A Guide to Fluorescent Probes and Labeling Technologies; 11 ed.;
Life Technologies Corporation: Grand Island, NY, 2010.
9 Cooley, C. B.; Trantow, B. M.; Nederberg, F.; Kiesewetter, M. K.; Hedrick, J. L.; Waymouth, R. M.;
Wender, P. A. J. Am. Chem. Soc. 2009, 131, 16401.
10 Malyshev, D.A.; Dhami, K.; Lavergne, T.; Chen, T.; Dai, N.; Foster, J.M.; Correa, I.R.; Romesberg,
F.E. Nature, 2014, 509, 385.
11 Kidd, J. Phil. Trans. R. Soc. Lond. 1821, 111, 209.
12
(a) Pearson, D. E.; Buehler, C. A. Synthesis 1972, 1972, 533. (b) Taylor, R. Electrophilic Aromatic
Substitution; John Wiley & Sons: New York, 1990. (c) Katritzky, A. R.; Li, J.; Xie, L. Tetrahedron 1999,
55, 8263.
13
(a) Bradsher, C. K. Chem. Rev. 1987, 87, 1277. (b) Katritzky, A. R.; Rachwal, S.; Rachwal, B.
Tetrahedron 1996, 52, 15031. (c) de Koning, C. B.; Rousseau, A. L.; van Otterlo, W. A. L. Tetrahedron
2003, 59, 7.
14 (a) Stará, I. G.; Starý, I.; Kollárovič, A.; Teplý, F.; Šaman, D.; Fiedler, P. Tetrahedron 1998, 54, 11209.
(b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147. (c) Jeffery, T.; Ferber, B. t. Tetrahedron Lett. 2003,
44, 193. (d) Ohta, K.; Goto, T.; Endo, Y. Inorg. Chem. 2005, 44, 8569. (e) Mei, X.; Liu, S.; Wolf, C. Org.
Lett. 2007, 9, 2729. (f) Bhosale, S. V.; Kalyankar, M. B.; Bhosale, S. V.; Langford, S. J.; Reid, E. F.;
Hogan, C. F. New J. Chem. 2009, 33, 2409. (g) Meng, H.; Sun, F. U.S. Patent 20090166590, July 2, 2009.
(h) Maiti, D.; Fors, B. P.; Henderson, J. L.; Nakamura, Y.; Buchwald, S. L. Chem. Sci. 2011, 2, 57. (i)
Benedetti, E.; Kocsis, L. S.; Brummond, K. M. J. Am. Chem. Soc. 2012, 134, 12418.
15 (a) Snider, B. B.; Zhang, Q. J. Org. Chem. 1993, 58, 3185. (b) H. Dotz, K.; Tomuschat, P. Chem. Soc.
Rev. 1999, 28, 187. (c) Kang, D.; Kim, J.; Oh, S.; Lee, P. H. Org. Lett. 2012, 14, 5636.
16
(a) Giles, R. G. F.; Hughes, A. B.; Sargent, M. V. J. Chem. Soc., Perkin Trans. 1 1991, 1581. (b)
Yudin, A. K.; Martyn, L. J. P.; Pandiaraju, S.; Zheng, J.; Lough, A. Org. Lett. 1999, 2, 41. (c) Hayes, M.
E.; Shinokubo, H.; Danheiser, R. L. Org. Lett. 2005, 7, 3917. (d) Procko, K. J.; Li, H.; Martin, S. F. Org.
Lett. 2010, 12, 5632.
17
(a) Andersen, N. G.; Maddaford, S. P.; Keay, B. A. J. Org. Chem. 1996, 61, 2885. (b) Ukita, T.;
Nakamura, Y.; Kubo, A.; Yamamoto, Y.; Takahashi, M.; Kotera, J.; Ikeo, T. J. Med. Chem. 1999, 42,
1293. (c) Allen, J. G.; Danishefsky, S. J. J. Am. Chem. Soc. 2000, 123, 351.
18
(a) Hauser, F. M.; Rhee, R. P. J. Org. Chem. 1978, 43, 178. (b) Kraus, G. A.; Sugimoto, H.
Tetrahedron Lett. 1978, 19, 2263. (c) Cox, C.; Danishefsky, S. J. Org. Lett. 2000, 2, 3493. (d) Kita, Y.;
Higuchi, K.; Yoshida, Y.; Iio, K.; Kitagaki, S.; Ueda, K.; Akai, S.; Fujioka, H. J. Am. Chem. Soc. 2001,
123, 3214. (e) Mal, D.; De, S. R. Org. Lett. 2009, 11, 4398.
19 (a) Huang, K.-S.; Wang, E.-C. Tetrahedron Lett. 2001, 42, 6155. (b) van Otterlo, W. A. L.; de Koning,
C. B. Chem. Rev. 2009, 109, 3743.
29
ACS Paragon Plus Environment