Controlling, Understanding, and Redirecting the Thermal Rearrangement of 3,3-Dicyano-1,5-enynes

Article abstract of DOI:10.1021/jacs.8b08553

The thermal [3,3] rearrangement of 3,3-dicyano-1,5-enynes to γ-allenyl alkylidenemalononitriles (the "enyne Cope rearrangement") has largely eluded synthetic value as the desired products, too, are thermally reactive and ultimately yield 6π electrocycliza

Full text of DOI:10.1021/jacs.8b08553

Subscriber access provided by The University of Texas at El Paso (UTEP)
Article
Controlling, understanding, and redirecting the
thermal rearrangement of 3,3-dicyano-1,5-enynes
Sarah K. Scott, Jacob N. Sanders, Katherine E White,
Roland A. Yu, Kendall N. Houk, and Alexander J. Grenning
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b08553 • Publication Date (Web): 31 Oct 2018
Downloaded from http://pubs.acs.org on October 31, 2018
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 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 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.
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 7
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Controlling, understanding, and redirecting the thermal rearrange-
ment of 3,3-dicyano-1,5-enynes
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
Sarah K. Scott,1 Jacob N. Sanders,2 Katherine E. White,3 Roland A. Yu,2 K. N. Houk2*, and Alexander
J. Grenning1*
1 University of Florida, Department of Chemistry, P.O. Box 117200, Gainesville, Florida 32611, United States
2 Department of Chemistry and Biochemistry, University of California – Los Angeles, 607 Charles E. Young Drive East, Box
951569, Los Angeles, CA 90095ꢀ1569, USA
Supporting Information Placeholder
and its reduced counterpart “H2-2” are attractive
bifunctional building blocks.
ABSTRACT: The thermal [3,3] rearrangement of 3,3ꢀ
dicyanoꢀ1,5ꢀenynes to γꢀallenyl alkylidenemalononitriles
(the “enyne Cope rearrangement”) has largely eluded
synthetic value as the desired products, too, are thermalꢀ
ly reactive and ultimately yield 6π electrocyclization
products. Herein, we describe experimental and compuꢀ
tation studies related to the thermal rearrangement of
1,5ꢀenynes, structural features to halt the thermal rearꢀ
rangement at the alleneꢀstage, and a reductive variant for
preparing bifunctional allenyl malononitriles. We also
describe various ways that the bifunctional building
blocks can be manipulated and converted to cyclic and
acyclic architectures.
INTRODUCTION
Thermal rearrangement of 3,3ꢀdicyanoꢀ1,5ꢀenynes can
yield a suite of products (Scheme 1A).1 In cascade fashꢀ
ion, they undergo [3,3] sigmatropic rearrangement to γꢀ
allenyl alkylidenemalononitrile 2, “proton transfer” to
the triene, 6πꢀelectrocyclization to 3, and [1,5]CN shift
to 4. This thermal sequence was originally reported by
Roger Brown and coꢀworkers with little exploration of
optimization or scope.1 Although many of the products 2
– 4 likely have synthetic value, we are interested in the
allenyl intermediate 2, which bears a reactive alkyliꢀ
denemalononitrile and allene. Generally speaking, the
enyne Cope rearrangement, also known in the literature
as the acetylenic Cope rearrangement or the propargyl
Cope rearrangement, has only a few reports including
physical organic studies,2 a retroꢀvariant,3 and theoretiꢀ
cal studies.4 Notably, the [3,3] rearrangement of proparꢀ
gyl enol ethers (the “propargyl Claisen rearrangement”)
has seen considerable application in modern synthesis.5
We are interested in applying the enyne Cope rearꢀ
rangement of 3,3ꢀdicyanoꢀ1,5ꢀenynes 1 to complex molꢀ
ecule synthesis.6 Enynes 1 are readily constructed from
Scheme 1. A: Thermal rearrangement of 3,3-dicyano-
1,5-enynes. B and C: The allenyl intermediate “2”
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 7
ketones, malononitrile, and propargyl bromides, which
Scheme 2. Thermal cascade reaction of 3,3-dicyano-
1,5-enynes.
1
2
3
4
5
6
7
8
allows for significant substrate diversity. If the products
2 are rendered highly accessible by the Cope rearrangeꢀ
ment of enynes 1, a vast array of chemical space can be
easily accessed by standard chemistry (Scheme 1B). For
example, alkylidenemalononitriles undergo mild reducꢀ
tion (e.g. to H2ꢀ2)7 or can be alkylated by deconjugative
alkylation (e.g. to I).6 Attractively, 2 are bifunctional in
that they can undergo mild deconjugative alkylation then
cyclization with propargyl bromides or furfurylꢀderived
alkyl halides to yield hydroazulenes II8 or decalins III9,
respectively, in two steps. The reduced counterparts H2ꢀ2
also have some unique and noteworthy reactivity
(Scheme 2C). Monoꢀalkylmalononitriles undergo oxidaꢀ
tive decyanation to yield esters or amides IV.10 It has
also been found that these building blocks undergo a
mildꢀbase catalyzed cycloisomerization to cyclopentenes
V.11 Additionally, deconjugative alkylation/cyclization,
similar to as described for 2, can yield common natural
product frameworks (VI – VII). The major limitation is
accessing these versatile building blocks via the enyne
Cope rearrangement because, as described above, the
thermal reaction results in various products (2 – 4,
Scheme 1A). This is the primary contributor to the modꢀ
est yields of γꢀallenylalkylidenemalononitriles. Considꢀ
ering the potential value of the enyne Cope rearrangeꢀ
ment of 3,3ꢀdicyanoꢀ1,5ꢀenynes to synthesis, we wished
to better understand the transformation and improve its
scope, efficiency, and applicability, which is described
herein.
NC
NC
NC
NC
CN
NC
CN NC
CN
NC
( )n
( )n
( )n
( )n
( )n
n = 1; 1a
n = 0; 1b
2a
2b
3a
3b
4a
4b
5a
5b
[3,3]
[1,3]H/6π
[1,5]CN
[O]
entry n (1a/b)
Solvent
Temp (°C) Time (h) % conv.
2
3
4
5
9
1 (1a
1 (1a
0 (1b
0 (1b
0 (1b
)
)
)
)
)
1
2
3
4
5
tol
tol
tol
tol
130
130
130
130
130
6
24
6
24
6
59
95
90
95 <5 <5 <5
36 25 39 <5
42 32 26 <5
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
>95 <5 64 36 <5
72 <5 42 58 <5
tol:TFE (5:1)
NC
NC
temperature variable:
150 °C: <05% conv.
180 °C: ~50% conv.a
200 °C; ~95% conv.b
reaction conditions:
toluene, 0.1M, 2h
R
1c R = Me
1d R = CH2OAc
results: a complex mixtures observed, trace allene signals in crude NMRs
b complex mixtures observed, no allene signals in crude NMRs
COMPUTATIONAL ANALYSIS OF THE [3,3]
REARRANGEMENT OF MODEL 3,3-DICYANO-1,5-
ENYNES
We next turned to computation and performed stateꢀ
ofꢀtheꢀart density functional theory computations to betꢀ
ter understand the sigmatropic rearrangement step (Figꢀ
ure 1). Our main finding was that the enyne Cope rearꢀ
rangement is sensitive to whether the starting alkyne is
terminal or internal. In particular, we computed a free
energy barrier of 31.5 kcal/mol for the parent terminal
alkyne 1a, but larger barriers of 33.6 kcal/mol and 33.5
kcal/mol respectively for the related internal alkynes 1c
and 1d. The breaking and forming bonds in the internal
alkyne transition states were approximately 0.1 Å longer
than in the terminal alkyne transition state, suggesting
that the higher barrier comes from steric hindrance that
prevents the enyne termini from approaching each other
as closely. This computational result is consistent with
the experimental finding that internal alkynes require
higher temperatures for the Cope rearrangement, making
them more prone to rearrangement through the pathway
shown in Scheme 1A.
THERMAL TRANSFORMATION OF SIMPLE, MODEL
3,3-DICYANO-1,5-ENYNES
As noted in previous work from Brown,1 our own
studies,6 and further explored herein, the thermal rearꢀ
rangement of 1a begins to occur at temperatures above
~110 °C. We first evaluated the effect of time on the
product distribution (Scheme 2, entries 1 and 2). The
allene is favored at shorter reaction times (entry 1);
however, as the heating time is increased, the reaction
proceeds to favor the electrocyclization products (entry
2). We saw similar results with the fiveꢀmembered ring
variant (1b, entries 3 – 5). In trace amounts, we also obꢀ
served products of autoꢀoxidation to the benzodinitriles
5 in these studies. Brown and coꢀworkers noted signifiꢀ
cantly more benzenoid formation under their conditions
(200 °C). Furthermore, we found that the acidic additive
trifluoroethanol (TFE) helped promote the proton transꢀ
fer step as well as the [1,5]CN shift. In a similar fashion,
we also examined the 1,5ꢀenyne 1c and 1d bearing an
internal alkyne. Under analogous conditions (150 °C,
toluene), no reaction occurred, indicating a high barrier
to [3,3] rearrangement. When increasing the temperaꢀ
ture, conversion began to occur, but in no cases were
allenes observed. This is likely because the additional
energy necessary for the [3,3] also facilities the addiꢀ
tional isomerizations.
We found a similar trend with bicyclic scaffolds (Figꢀ
ure 1), with internal alkynes 1f and 1g having free enerꢀ
gy barriers that were 1ꢀ2 kcal/mol higher and bond
lengths that were ~0.1 Å longer than terminal alkyne 1e.
However, as compared to the monocyclic scaffolds, the
bicyclic scaffolds exhibit a lower free energy barrier, and
computations reveal that this is due to a raised ground
state that possesses significant torsional strain. As
shown in Figure 2, the bicyclic scaffold 1e requires the
starting material to adopt a nearꢀeclipsed conformation
with an illustrated HCCH dihedral angle of 19.6 degrees.
This highꢀenergy dihedral angle is subsequently relaxed
to 39.7 degrees in the transition state (and 61.8 degrees
in the product). In contrast, monocyclic starting material
1a has a corresponding dihedral angle of 44.2 degrees,
ACS Paragon Plus Environment

Page 3 of 7
Journal of the American Chemical Society
so it is not significantly destabilized and consequently
has a higher free energy barrier for the enyne Cope rearꢀ
rangement.
1
2
3
4
+2.8 kcal/mol
Transition State and
Free Energy Barrier
Transition State and
Free Energy Barrier
Substrate
Substrate
5
6
7
8
allylic strain
CN
NC
CN
NC
chair-ax
chair-eq
H
H
Figure 3. The axial conformation of allene 2a is more
stable than the equatorial conformation by 2.8
kcal/mol.
9
1a
31.5 kcal/mol
1e
30.1 kcal/mol
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
Based on the above experimental and computational
data, we have come to the following conclusions:
CN
NC
CN
NC
CH3
CH3
(1) The transformation is sensitive to steric effects at
the enyne termini. Experimentally, internal alkynes
require higher temperature and therefore decompose
unless structural features are present which prevent
access to the reactive conformer. This is supported
by the computational studies showing a ~2 kcal/mol
difference in transition state energy between termiꢀ
nal alkyne 1a and internal alkynes 1c and 1d.
1c
33.6 kcal/mol
1f
31.3 kcal/mol
CN
NC
CN
NC
OAc
OAc
(2) The bicyclic scaffolds examined have a lower actiꢀ
vation energy as a result of a destabilized ground
state.
1d
33.5 kcal/mol
1g
31.8 kcal/mol
Figure 1. Free energy barriers for the enyne Cope
rearrangement of terminal and internal alkynes.
(3) The allene prefers to be axial, which minimizes alꢀ
lylic strain between the alkylidenemalononitrile and
the allene.
CN
CN
(4) Restricting conformations post [3,3] rearrangement
can preclude the protonꢀtransfer step (and therefore
downstream rearrangements) resulting in higher
yields of the targeted allenes. This is because the γꢀ
C–H bond is more readily deprotonated when it is
aligned with the alkylidenemalononitrile π system.
H
H
39.7o
61.8o
H
19.6o
1e
Figure 2. In bicyclic scaffold 1e, the illustrated
HCCH dihedral angle increases from 19.6 degrees in
the starting material to 39.7 degrees in the transition
state and 61.8 degrees in the product.
Scheme 3. Detailed mechanism for thermal rear-
rangement
Because some allene products undergo further reaction
(Scheme 2), we performed a conformational study of
product allene 2a formed from terminal alkyne 1a. As
shown in Figure 3, the axial conformation of the allene
formed directly in the Cope rearrangement is more staꢀ
ble than the equatorial conformation by 2.8 kcal/mol.
The equatorial conformation suffers from allylic strain
between the allene and alkylidenemalononitrile moieties,
which is alleviated by having the allene eclipse the axial
γꢀC–H bond. Nevertheless, the equatorial conformation
of the allene is readily accessible via a chairꢀchair interꢀ
conversion under the reaction conditions. We hypotheꢀ
size that this conformation is critical to decomposition
because the axial γꢀC–H bond is aligned with the π sysꢀ
tem of the alkylidenemalononitrile for deprotonation
and, therefore, further reaction. In contrast, in the bicyꢀ
clic systems 1e, 1f, and 1g, the allene is locked in the
axial conformation and the γꢀC–H bond is orthogonal to
the π system of the alkylidenemalononitrile, so no furꢀ
ther reaction can occur.
This computational data supports the following mechꢀ
anism for thermal cascade rearrangement (Scheme 3):
[3,3] rearrangement occurs to yield the chair conformer
having the allene axial (chairꢀax). This conformer must
undergo a chairꢀchair interconversion to the equatorial
allene conformer (chairꢀeq), the acidic conformer, to
allow for proton transfer to the triene, followed by elecꢀ
trocyclization and 1,5[CN] shift.
The above computational discoveries set the stage for
new hypotheses aimed at improving the scope of allene
synthesis by [3,3] rearrangement. Specifically, we
ACS Paragon Plus Environment

Journal of the American Chemical Society
wished to identify substrate classes that would stop
thermally rearranging prior to allene isomerization as
well as devise a protocol to prepare allenes by this
method that is not tied to substrate structure. These are
the subjects of the following two sections, respectively.
Page 4 of 7
other (locked or biased substrates). Although pleased to
better understand the Cope rearrangement and yield
structurally unique allenes, this approach is somewhat
limiting, as it requires specific biasing elements. A
method not tied to a structural architecture would yield a
wider scope. We hypothesized that the Cope rearrangeꢀ
ment in the presence of a reductant that could chemoseꢀ
lectively react with the in situ generated alkyliꢀ
denemalononitrileꢀmoiety would divert the transforꢀ
mation before the γꢀallenylalkylidenemalononitrile can
further isomerize (Scheme 5). If achieved, this would
yield bifunctional allenyl malononitriles H2ꢀ2, useful
building blocks for synthesis.
1
2
3
4
5
6
7
8
PREVENTING THE THERMAL CASCADE THROUGH
SUBSTRATE STRUCTURE BIAS
We suspected that certain substructures could be inꢀ
corporated onto the 1,5ꢀenyne to prevent the proton
transfer step, thus preventing thermal cascade and yieldꢀ
ing the targeted bifunctional γꢀallenyl alkylidenemaloꢀ
nonitriles. Considering that the allene is delivered axialꢀ
ly and that the axial allene is preferred over the equatoꢀ
rial allene, we reasoned that biasing one chair conforꢀ
mation over another could halt the thermal cascade folꢀ
lowing allene formation.
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 5. The Reductive Enyne Cope Rearrange-
ment
Scheme 4. Preventing thermal cascade by substruc-
ture bias
Table 1. Development of the reductive Cope rear-
rangement
entry Reductant (2 equiv.)
Solvent
(h)
% conv.
6b
2b 3b 4b
We prepared substrates 1e, 1h – 1i, which would lock
the allene in a nonꢀacidic conformation, and substrates
1j – 1m, which would bias the allene in a nonꢀacidic
conformation (Scheme 4). The locked substrates underꢀ
went smooth transformation and gave high yields of the
desired allenes 2e, 2h, and 2i. Notably, this transforꢀ
mation was tolerant to alkyne substitution, which was
not possible in the simple system (e.g. 1c). A large tbutyl
group also gave a high yield of the desired allene 2j
when the starting enyne was terminal. The analogous
internal enyne 1k (R = Me) also yielded the desired alꢀ
lene 2k. Although modest yield and conversion was obꢀ
served, this is a substantial improvement, as 1c, lacking
the biasing group, shows no allene product. Similarly,
the menthone derived enynes successfully yielded alꢀ
lenes 2i and 2m. In this case, smaller alkyl groups on the
cyclohexyl ring, when compounded, are effective at biꢀ
asing chair conformations.
1
2
3
4
5
6
7
Hantzsch Ester
Hantzsch Ester
Hantzsch Ester
Hantzsch Ester
Hantzsch Ester
Hantzch Amide
NaCNBH3
tol
tol
2
7
2
2
2
2
2
40
1
0
0
0
0
0
0
0
0
0
0
0
0
1
1
0
0
0
0
1
0
1
>95 1 (70%)
propanol
tol:PrOH (5:1)
tol:TFE (5:1)
tol
35
52
64
39
40
1
1
3
0
0
tol
To test the hypothesis, we prepared the 3,3ꢀdicyanoꢀ
1,5ꢀenyne 1b derived from cyclopentanone, malonoꢀ
nitrile, and propargyl bromide and began examining the
reductive enyne Cope rearrangement (Table 1). After
some experimentation, it was found that adding
Hantzsch ester (HE) to the reaction results in product 6b
exclusively in good yield as a mixture of diastereomers
(entry 1).8 Other solvents and mixtures of solvents proꢀ
vided the desired product with varying efficiency. We
also explored a few other reductants that were unsucꢀ
cessful.
With optimized conditions in hand, we found that
many allenyl malononitriles could be prepared (Scheme
6). The scope was broad, in part, due to the ready availꢀ
ability of the 1,5ꢀenynes examined. For example, prodꢀ
ucts 6a – 6h were prepared from malononitrile, proparꢀ
gyl bromide and a variable cycloalkanone: cyclohexaꢀ
THE REDUCTIVE ENYNE COPE REARRANGEMENT
In the above section, we described that the thermal
cascade can be halted at the allene stage when utilizing
substrates that prefer one chair conformation over the
ACS Paragon Plus Environment

Page 5 of 7
Journal of the American Chemical Society
In final examples related to the scope of the reductive
none (6a), cyclopentanone (6b), protected 1,4ꢀ
cycloalkandione (6c), NꢀBoc piperidinone (6d), αꢀ
tetralone (6e), βꢀtetralone (6f), 4ꢀmethylcyclohexanone
(6g), and 2ꢀmethylcyclohexanone (6h). We also examꢀ
ined acyclic ketones (6i – 6m) and aldehydes (6n – 6p).
The reaction is generally tolerant to functional groups
such as ketals (6c), acetals (6l), Bocꢀprotected amines
(6d), esters (6j), and cyclopropanes (6m). Regarding
diastereoselectivity, the reduction step is poorly selecꢀ
tive, generally speaking. However, the Cope rearrangeꢀ
mentꢀstep is diastereoselective (6g and 6h). In both these
cases, the reduction step still yields a diastereomeric
mixture. Products 6a, 6e, 6l, 6m, and 6n were prepared
on the > gram scale. Generally speaking, the standard
scale (50 – 100 mgs) and the scale up procedures (2 – 5
grams) gave similar results.
1
2
3
4
5
6
7
8
enyne Cope rearrangement, methyl and allyl cyanoaceꢀ
tate derived substrates were examined (Scheme 6). Altꢀ
hough they required a higher temperature to react (180
°C in lieu of 140 – 150 °C), they still yielded the desired
allenes 6q and 6r in good yield with the expected modꢀ
est diastereoselectivity.
In a few cases, we found that the reductive Cope
product was inseparable from the Hantzsch ester. We
found that “telescoping” the reaction by malononitrile
alkylation with 7a would allow for isolation of target
building blocks, in this case the furanꢀallene building
block 8a (Scheme 6).
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 7. Utility of allenyl malononitrile building
blocks
Scheme 6. Scope of the reductive Cope rearrange-
ment.
We next examined the utility of the alꢀ
lene/malononitrile building blocks (Scheme 7). Funcꢀ
tionally dense methylcyclopentenes 9 can be prepared
by a baseꢀcatalyzed cycloisomerization.11 Decalin ring
systems 10 are accessible by an alkylation (with
7a)/thermal [4+2] strategy.9 Hydroazulenes 11 are preꢀ
pared by allenicꢀPausonꢀKhand reaction (PKR) under
the conditions reported by Brummond.8
As final experiments, we explored how the malonoꢀ
nitrile moiety can be manipulated (Scheme 8). Monoalꢀ
kylmalononitriles can be thought of as carboxylate
equivalents: Using magnesium monoperoxyphthalate
(MMPP) as an oxidant in methanol, allene/carboxylic
esters 12 are prepared.10 In the cases of disubstituted
malononitriles, formal decyanation can mildly be
achieved by Pinner reaction with allyl alcohol to the
allyl cyanoacetates 13 followed by Pdꢀcatalyzed decarꢀ
boxylative protonation yielding monoꢀnitriles 14.12
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 7
In conclusion, we have explored various aspects of the
REFERENCES
1
2
3
4
5
6
7
8
rearrangement of 3,3ꢀdicyanoꢀ1,5ꢀenynes. Through exꢀ
perimental and computational studies, we have a better
understanding of how to control and halt the rearrangeꢀ
ment at the prior to allene isomerization, as well as a
method to divert from the thermal pathway by chemoseꢀ
lective reduction. The bifunctional allenyl alkyliꢀ
denemalononitriles and allenyl malononitriles are also
well suited for manipulation into a variety of cyclic or
acyclic building blocks. Future directions include comꢀ
plex molecule synthesis, scope expansion, improving the
diastereoselectivity, and identifying enantioselective
variants.
(1) Brown, R. F. C.; McAllan, C. G. Aust. J. Chem. 1977, 30,
1747–1755.
(2) (a) Black, D. K.; Landor, S. R. Allenes. X. J. Chem. Soc. 1965,
6784–6788. (b) Huntsman, W. D.; De Boer, J. A.; Woosley, M. H. J.
Am. Chem. Soc. 1966, 88, 5846–5850. (c) Owens, K. A.; Berson, J. A.
J. Am. Chem. Soc. 1990, 112, 5973–5985.
(3) Miura, T.; Kiyota, K.; Kusama, H.; Iwasawa, N. Org. Lett.
2005, 7, 1445–1447.
(4) (a) Bozkaya, U.; Özkan, I. J. Org. Chem. 2012, 77, 2337–2344.
(b) Xia, Y.; Zhou, F.; Li, Y.; Li, W. J. Mol. Struct. THEOCHEM
2009, 904, 69–73. (c) NavarroꢀVázquez, A.; Prall, M.; Schreiner, P.
R. Org. Lett. 2004, 6, 2981–2984. (d) Black, K. A.; Wilsey, S.; Houk,
K. N. J. Am. Chem. Soc. 1998, 120, 5622–5627.
(5) Tejedor, D.; MendezꢀAbt, G.; Cotos, L.; GarciaꢀTellado, F.
Chem. Soc. Rev. 2013, 42, 458–471.
(6) Scott, S. K.; Grenning, A. J. Angew. Chem. Int. Ed. 2017, 56,
8125–8129.
(7) (a) Garden, S. J.; Guimarães, C. R. W.; Corréa, M. B.; Oliveira,
C. A. F. de; Pinto, A. da C.; Bicca de Alencastro, R. J. Org. Chem.
2003, 68, 8815. (b) Zhu, X.ꢀQ.; Liu, Y.ꢀC.; Cheng, J.ꢀP. J. Org.
Chem. 1999, 64, 8980. (c) Zhu, X.ꢀQ.; Zou, H.ꢀL.; Yuan, P.ꢀW.; Liu,
Y.; Cao, L.; Cheng, J.ꢀP. J. Chem. Soc. Perkin Trans. 2 2000, 1857.
(8) (a) Alcaide, B.; Almendros, P. E. J. Org. Chem. 2004, 3377–
3383. (b) BlancoꢀUrgoiti, J.; Anorbe, L.; PerezꢀSerrano, L.;
Dominguez, G.; PerezꢀCastells, J. Chem. Soc. Rev. 2004, 33, 32–
42. (c) Brummond, K. M.; Chen, D.; Davis, M. M. J. Org. Chem.
2008, 73, 5064–5068. (d) Brummond, K. M.; Chen, H.; Fisher, K. D.;
Kerekes, A. D.; Rickards, B.; Sill, P. C.; Geib, S. J. Org. Lett. 2002, 4,
1931–1934. (e) Grillet, F.; Huang, C.; Brummond, K. M. Org. Lett.
2011, 13, 6304–6307.
(9) (a) Juhl, M.; Tanner, D. Chem. Soc. Rev. 2009, 38, 2983–2992.
(b) Takao, K.; Munakata, R.; Tadano, K. Chem. Rev. 2005, 105,
4779–4807.
(10) (a) Förster, S.; Tverskoy, O.; Helmchen, G. Synlett 2008,
2803. (b) Yang, K. S.; Nibbs, A. E.; Türkmen, Y. E.; Rawal, V. H. J.
Am. Chem. Soc. 2013, 135, 16050. (c) Kagawa, N.; Nibbs, A. E.;
Rawal, V. H. Org. Lett. 2016, 18, 2363. (d) Hethcox, J. C.; Shockley,
S. E.; Stoltz, B. M. Org. Lett. 2017, 19, 1527.
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. Malononitrile functional group intercon-
versions.
ASSOCIATED CONTENT
Supporting Information
• The Supporting Information is available free of charge
on the ACS Publications website.
• Experimental procedures
• Compound characterization (1H NMR, 13C NMR, and
HRMS)
(11) Kitagawa, O.; Suzuki, T.; Fujiwara, H.; Fujita, M.; Taguchi, T.
Tetrahedron Lett. 1999, 40, 4585.
(12) Roger, R.; Neilson, D. G. Chem. Rev. 1961, 61, 179–211.
1
• H and 13C NMR reprints
AUTHOR INFORMATION
Corresponding Authors
* grenning@ufl.edu
* houk@chem.ucla.edu
ACKNOWLEDGMENT
We thank the College of Liberal Arts and Sciences and the
Department of Chemistry at the University of Florida for
startꢀup funds. We thank the Mass Spectrometry Research
and Education Center and their funding source: NIH S10
OD021758ꢀ01A1.” J.N.S. acknowledges the support of the
National Institute of General Medical Sciences of the Naꢀ
tional Institutes of Health under Award Number
F32GM122218. Computational resources were provided by
the UCLA Institute for Digital Research and Education
(IDRE).
ACS Paragon Plus Environment

Page 7 of 7
Journal of the American Chemical Society
Graphical Abstract Figure:
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
7
ACS Paragon Plus Environment