The enantioselective construction of tetracyclic diterpene skeletons with Friedel-Crafts alkylation and palladium-catalyzed cycloalkenylation reactions

Article abstract of DOI:10.1039/c4ob02489c

Due to the profound extent to which natural products inspire medicinal chemists in drug discovery, there is demand for innovative syntheses of these often complex materials. This article describes the synthesis of tricarbocyclic natural product architectu

Full text of DOI:10.1039/c4ob02489c

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The Enantioselective Construction of Tetracyclic Diterpene
Skeletons with Friedel-Crafts Alkylation and Palladium-catalyzed
Cycloalkenylation Reactions
Sarah J. Burke, William P. Malachowski*, Sharan K. Mehta and Roselyn Appenteng
Department of Chemistry, Bryn Mawr College, Bryn Mawr, Pennsylvania 19010-2899 USA.
wmalacho@brynmawr.edu
ABSTRACT: Due to the profound extent to which natural products inspire medicinal chemists
in drug discovery, there is demand for innovative syntheses of these often complex materials.
This article describes the synthesis of tricarbocyclic natural product architectures through an
extension of the enantioselective Birch-Cope sequence with intramolecular Friedel-Crafts
alkylation reactions. Additionally, palladium-catalyzed enol silane cycloalkenylation of the
tricarbocyclic structures afforded the challenging bicyclo[3.2.1]octane C/D ring system found in
the gibberellins and the ent-kauranes, two natural products with diverse medicinal value. In the
case of the ent-kaurane derivative, an unprecedented alkene rearrangement converted four alkene
isomers to one final product.
1

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Introduction
Natural product structures continue to inspire synthetic chemists and drug developers alike
with their complex molecular architecture that frequently exceeds human imagination. More
importantly, these fascinating structures often possess useful and unique biological activities that
1
-5
6
7, 8
inspire new therapeutic approaches . Gibberellin and ent-kaurane derivatives
are two
9
diterpene natural products with a complex tetracyclic molecular architecture (Figure 1) featuring,
most prominently, a bicyclo[3.2.1]octane system, which has been the focus of significant recent
1
0, 11
synthetic efforts
gibberellins as plant hormones and growth regulators
therapies. In fact, recent therapeutic applications of ent-kauranes include anti-inflammation ,
. Both gibberellins and ent-kauranes have noteworthy biological activity; the
1
2-14
, and the ent-kauranes in a wide array of
1
5
1
6
17
18
19-23
anti-HIV , antibacterial , anti-tuberculosis , and anti-cancer
. Clearly these molecular
architectures have promising potential value.
Although both gibberellins and ent-kauranes have members that are commercially available,
the de novo construction of their structures can facilitate derivatization and potentially more
active analogs. Since the 1970’s, there has been considerable synthetic effort aimed at the de
novo construction of both frameworks, although there has been much less enantioselective work.
Enantioselective de novo syntheses of gibberellins include two impressive works in 1981 by
2
4, 25
26
Takano
and one by Corey in 1991 . Enantioselective de novo syntheses of the ent-kauranes
2
7, 28
29
30, 31
include two works by Corey in 1997
, Toyota in 2000 , and Reisman in 2013
.
Figure 1: Structures of ent-kaurane skeleton and a gibberellin.
2

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At the core of both the gibberellins and the ent-kauranes is a tetracarbocyclic ring system that
creates significant synthetic challenges, including an all-carbon quaternary stereocenter. We
hypothesized that the tetracyclic ring system might be accessible from a properly designed
3
2
product of our previously reported Birch-Cope sequence . We have illustrated applications of
the Birch-Cope sequence products in the enantioselective synthesis of two alkaloids, (-)-
3
3
34
lycoramine and (+)-mesembrine . An enantioselective approach to the diterpene frameworks
of gibberellins or ent-kauranes would expand the potential applications in natural product-like
molecule synthesis. To that end, we fashioned the retrosynthetic plan shown in Scheme 1, in
which the tetracarbocyclic core of these valuable compounds is generated with just two
additional steps after the Birch-Cope sequence: a Friedel-Crafts alkylation and a palladium-
catalyzed cycloalkenylation. The final product would contain the carbon skeleton of the
gibberellins or ent-kauranes depending on the length of the linker between the two diaryl rings of
the Birch-Cope sequence starting material. In the process, the strategy would create ring D and
the bicyclo[3.2.1]octane at a later stage, after rings A-C have been generated. To the best of our
knowledge, this approach has not previously been used with the palladium-catalyzed
3
5-38
39-43
cycloalkenylation
. The Friedel-Crafts alkylation would rely on precedent
and would be
the second example of an intramolecular carbon nucleophile conjugate addition to the enone
system of the Birch-Cope sequence product; along with the Rauhut-Currier reaction that we have
4
4, 45
recently communicated
. In combination, the two steps would be a relatively short
enantioselective entry to two natural product-like scaffolds.
3

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Scheme 1. Retrosynthetic Plan for the Construction of the Gibberellin and ent-Kaurane Skeletons
Results and Discussion
Construction of the Diaryl Starting Materials. The first stage of the process to generate
gibberellin or ent-kaurane carbon skeletons involved synthesizing the Birch-Cope sequence
reactants. We previously used cross-coupling chemistry in our synthesis of (-)-lycoramine and
(+)-mesembrine to make biaryl reactants, but the diaryl materials with methane or ethane linkers
required for this work would, at first glance, seem to necessitate the much less common cross-
2
3
coupling reaction of an sp carbon with an sp carbon. Therefore, we initially explored the
synthesis of the diarylmethane substrates through Grignard reagent nucleophilic additions to
benzaldehyde derivatives followed by reduction of the resulting diaryl alcohol. These efforts
were successful, but not without some complications (e.g. magnesium-Oppenhauer oxidation
4
6
side reactions ) and eventually proved less expedient than a cross-coupling approach. In
3
4
particular, Suzuki reaction of the 5-iodo-salicylate derivative 1 (Table 1) with benzyl boronic
4
7
acid derivatives in the presence of catalytic Pd (dba) rapidly afforded the diaryl substrates 2
2
3
with a methane linker, albeit with some modest yields. Benzylboronic pinacol ester is
commercially available and the four other aryl substituted derivatives were synthesized
4
8
following literature protocols in one step from the appropriately substituted benzyl bromide,
stoichiometric magnesium and pinacolborane.
4

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Table 1. Synthesis of Diarylmethane Starting Materials
Ar
Product
2a
% Yield
84
C H -
6
5
3
4
-MeO-C H -
2b
58
6
5
-MeO-C H -
2c
61
6
5
a
3
,4-(MeO) C H -
2d
56
2
6
5
3
-Me-C H -
2e
47
6
5
a
°
Coupling conditions: Pd(OAc) , SPhos, K CO , DMF, 60 C
2
2
3
2
2
To leverage the facility of sp -sp cross-coupling reactions and avoid the beta-hydride
elimination complications introduced by a phenylethane cross-coupling partner, the ethane
linked diaryl substrates were synthesized through a two-step process: Heck reaction of 1 with an
appropriate styrene analog and subsequent hydrogenation of the resulting stilbene derivative
(Table 2). Styrene worked efficiently with N,N-dimethyl-β-alanine as the ligand, but the same
alanine ligand afforded low yields with the more electron rich styrene derivative in the synthesis
of 3b. After some experimentation, the optimal Heck reaction conditions were found with the
4
9
ligandless palladium conditions of Botella . As can be seen in Table 2, both steps of the process
were quite efficient for a range of substrates.
Table 2. Synthesis of Diarylethane Starting Materials
Ar
Product % Yield Product % Yield
a
C H -
3a
3b
3c
76
95
86
4a
4b
4c
90
83
87
6
5
3
4
-MeO-C H -
6 5
-MeO-C H -
6
5
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3
,4-(MeO) C H -
3d
3e
88
88
4d
4e
88
85
2
6
5
3
-Me-C H -
6 5
a
Conditions: Pd(OAc) , K CO , N,N-dimethyl-β-alanine,
2
2
3
50
NMP
Birch-Cope sequence. Subjecting the methane- and ethane-linked diaryl substrates, 2 and 4,
to the Birch-Cope sequence began with the enantioselective Birch reduction-allylation, which
afforded products 5 and 6 in moderate to very good yields (Table 3). As has been demonstrated
3
2, 33
before
, the Birch reduction is selective for the more electron deficient aryl ring. The
enantioselectivity of the Birch reduction-alkylation has been demonstrated on many previous
3
2-34, 51, 52
occasions
and was confirmed to afford an enantiomeric ratio of 24:1 for 4d in the
current work (see Supporting Information). Note that the natural enantiomers of the gibberellins
and ent-kauranes would be generated from the use of D-prolinol as a chiral auxiliary (Xc),
however L-prolinol was used for this exploratory work to reduce costs while still illustrating the
feasibility of the process. The Birch products, 5 and 6, were purified, but they decomposed over
time so they were immediately taken through the next two steps of the Birch-Cope sequence. In
that event, hydrolysis of the enol ether and stereoselective Cope rearrangement provided 9 and
3
2, 34
1
0. Like prior analogs
conjugated enone and the reduction in steric congestion around the C-2 position of the cyclohex-
-enones 7 and 8. Although all of these substrates were new examples in the Birch-Cope
, the Cope rearrangement favors the more thermodynamically stable
3
sequence, they demonstrated similar efficiency as previously reported examples with aryl or
alkyl groups in the C-4 position.
6

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Table 3. Birch-Cope Sequence
Reactant Ar/n
Product / % Yield
2
2
2
2
2
4
4
4
4
4
a
b
c
C
6
H
5
-/1
5a/48
5b/46
7a/87
9a/59
3-MeO-C
4-MeO-C
H
H
-/1
-/1
7b/75
7c/90
7d/85
7e/62
8a/90
8b/70
8c/81
8d/89
8e/94
9b/59
9c/80
6
6
5
5c/70
5
d
e
3,4-(MeO)
2
C
6
H
5
-/1 5d/72
5e/61
9d/73
9e/69
3-Me-C
-/2
H
5
-/1
6
a
b
c
C
6
H
5
6a/97
10a/75
10b/76
10c/63
10d/72
10e/84
3-MeO-C
4-MeO-C
H
H
-/2
-/2
6b/73
6
6
5
6c/67
5
d
e
3,4-(MeO)
3-Me-C
2
C
6
H
5
-/2 6d/72
6e/78
H
5
-/2
6
Intramolecular Friedel-Crafts alkylation. Elaboration of these Birch-Cope sequence
products, 9 and 10, into the tetracarbocyclic framework of the gibberellins or the ent-kauranes
began by the construction of the central B ring through a Friedel-Crafts alkylation. A standard
selection of Lewis acids were screened including AlCl , TiCl , and SnCl , but BF ·Et O was
3
4
4
3
2
clearly the best at coaxing the conjugate addition of the aromatic nucleophile to add to the
4
0-43
cyclohexenone electrophile
. The cyclization occurred to form the cis isomers 11 and 12, but
most of the products were isolated as C-2 epimers, typically a 1:1 mixture. Subsequent cleavage
of the chiral auxiliary (vide infra) confirmed this observation by affording one enantiomerically
pure product, thus dispelling the possibility of epimers at the C-3 bridgehead position. As
anticipated, the intramolecular Friedel-Crafts alkylation reactions were most facile when a strong
electron donating group was located para to the aromatic carbon that attacks the conjugated
7

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enone system (e.g. 9b, 9d, 9e, 10b, 10d, and 10e). Substrates without this characteristic suffered
from lower conversion. For example, electron releasing groups meta to the nucleophilic aromatic
carbon (9c and 10c) exerted a stronger inductive effect and the reaction suffered accordingly.
Where regioisomeric ortho/para products could result (i.e. 9b, 9e, 10b, and 10e), complete
selectivity for the para addition product was observed. Following chiral auxiliary removal, two-
dimensional NMR experiments (see Supporting Information) confirmed both the structrure of the
Friedel-Crafts products and the formation of the expected cis isomers.
Table 4. Intramolecular Friedel-Crafts Alkylation
Reactant
n
1
1
1
1
1
2
2
2
2
2
R1
H
R2
H
Product
11a
11b
11c
% Yield
dec.
98*
dec.
97*
76*
63
9
9
a
b
OCH
H
3
3
H
9
c
OCH
OCH
H
3
3
9
d
OCH
11d
11e
9
e
CH
H
3
1
0a
0b
H
12a
12b
12c
1
OCH
H
3
3
H
88*
dec.
84*
70*
1
0c
0d
0e
OCH
OCH
H
3
3
1
OCH
12d
12e
1
CH
3
*Product was obtained as a mixture of C-2 epimers; dec=decomposed
L-Prolinol chiral auxiliary removal occurred efficiently through a previously reported
3
3, 34
procedure
involving formation of an oxime and intramolecular isoxazolidinone formation
(
Table 5). Reduction of the N-O bond in 13/14 by Mo(CO) facilitates hydrolysis and
6
8

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decarboxylation to provide 15/16. Compound 12a failed to undergo isoxazolidinone formation
and therefore the chiral auxiliary could not be removed.
Table 5: Chiral Auxiliary Removal
R2
R2
O
O
H
Xc
HO
O
NH-HCl
H
R1
R1
N
O
EtOH, reflux
R2
(
)n
( )n
1
1, n=1
13, n=1
14, n=2
1
2, n=2
H
O
R1
Mo(CO)6, ACN
H2O, reflux
N
OCH3
Xc=
(
)n
1
1
5, n=1
6, n=2
Reactant
N
R1
R2
H
Product / % Yield Product / % Yield
1
1
1b
1d
1
OCH
OCH
3
3
13b/77
13d/72
13e/60
14b/83
14d/84
14e/77
15b/86
15d/82
15e/80
16b/89
16d/82
16e/70
1
1
2
2
2
OCH
H
3
3
1
1e
CH
3
1
1
2b
2d
OCH
OCH
3
3
H
OCH
H
1
2e
CH
3
Palladium-catalyzed cycloalkenylation. A variety of approaches to form ring D and the
bicyclo[3.2.1]octane with the palladium-catalyzed cycloalkenylation were explored. Initially,
these included reactions with earlier structures, i.e. 10a, 10d, 12d, and 14b, where greater
regiocontrol could be expected in the palladium-catalyzed cycloalkenylation. Consistent with
3
6-38
literature reports on similar compounds
, cyclohexenones 10a and 10d afforded a 75 and 66%
yield of the cycloalkenylation product upon conversion to an enol silane and exposure to the
o
standard cyclization conditions (10 mol% Pd(OAc) , O , DMSO, 45 C). However, both
2
2
cycloalkenylation products failed to undergo the Friedel-Crafts alkylation. Attempted
cycloalkenylation with 12d was stymied by regioisomeric mixtures in the silylation step and with
14b, by the absence of any enol silane formation.
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With the failure of these approaches using earlier intermediates, attention turned to
compounds 15 and 16 with the hope that a cycloalkenylation could be realized despite the
rigidifying effect of the tricyclic structures and the regioselectivity challenges created by removal
of the chiral auxiliary. A variety of silylation procedures were explored with 15d and 16b, the
representative substrates chosen from the 6-5-6 and 6-6-6 tricyclic category, respectively. In
both cases, standard enol silane formation conditions (TBS-OTf, Et N) afforded a 2:1 mixture of
3
desired (17 and 19, Table 6) to undesired enol silane (18 and 20). Although trimethylsilyl (TMS)
and triethylsilyl (TES) were also tried, tert-butyldimethylsilyl (TBS) enol ethers proved the most
reproducible and stable for purification of the enol silane prior to the cycloalkenylation reaction.
In addition, there is evidence from the Toyota lab that TBS enol silanes work best in palladium-
5
3
catalyzed cycloalkenylation reactions . The use of a bulkier base (iPr NEt), kinetic conditions
2
5
4
(
LiHMDS at -78°C) or a bromomagnesium diisopropylamide failed to improve the yield or the
ratio of desired to undesired enol silane. A small improvement in the regioisomeric distribution
5
0, 55
was achieved by using a chiral lithium amide base
regioselectivity for 17 (2.5:1 versus 18) from 15d and even better results for the synthesis of 19
4:1 versus 20) from 16b. Not unexpectedly, these silyl ether regioisomers could not be separated
, which provided moderately better
(
chromatographically; therefore they were subjected to the cycloalkenylation conditions as a
mixture.
Table 6: Enol Silane Formation
1
0

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Reactant
n
R1
R2
Product
% Yield
(
regioselectivity)
1
1
5d
6b
1
2
OCH
OCH
3
3
OCH
H
3
17, 18
19, 20
91 (2.5:1)
95 (4:1)
With the TBS enol silanes in hand, we were poised to attempt the palladium-catalyzed
cycloalkenylation with the tricyclic substrates. For enol silane mixture 17/18, treatment with
o
Pd(OAc) in DMSO under an oxygen atmosphere at 45 C resulted in selective cyclization of 17
2
to the desired tetracyclic structure 21 in a modest 41% yield (Table 7). The product was slightly
contaminated by the undesired cycloalkenylation product 23 (5%) and unreacted enol silane 18
(6%). The use of different palladium catalysts (Pd(OCOCF ) , [Pd(CH CN) BF ]), or solvents
3 2 3 4 4
(
CH CN) failed to improve the outcome. A similar array of reaction conditions were also
3
surveyed for cycloalkenylation of the enol silane mixture 19/20. In the end, the best results were
obtained with the slightly more electrophilic catalyst Pd(OCOCF ) , however it afforded a
3
2
mixture of four inseparable products: the two cycloalkenylation products, 25 and 27, along with
their alkene regioisomers, 26 and 28. The overall yield of the four isomers was 60%, but the
product was a 46:31:15:8 mixture of 25:26:27:28. It should be noted that this distribution
roughly parallels the 4:1 enol silane composition with 25 and 26 arising from 19, and 27 and 28
derived from 20. Running the reaction at a lower temperature (room temp.) failed to reduce the
formation of alkene isomers. The richer mixture of products resulting from the 6-6-6 tricyclic
system versus the 6-5-6 system is likely the result of slightly greater conformational flexibility
which permits alternative reaction paths. In contrast, there was a greater proportion of the
undesired silane 18 in the 6-5-6 tricycle, but very little of the corresponding cycloalkenylation
products 23/24 actually formed. Nevertheless, the overall mixed results in the cycloalkenylation
transformation of the 6-5-6 and 6-6-6 systems highlights the challenges of conducting the
reaction on the more rigid tricyclic systems.
1
1

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Table 7: Palladium-catalyzed Cycloalkenylation
Reactant
Palladium catalyst
Pd(OAc)2
Product
21
% Yield
41
1
1
7, 18
9, 20
Pd(OCOCF3)2
25-28
60 (46:31:15:8 ratio)
In an attempt to isomerize the alkene mixture 25-28 to the most thermodynamically stable
regioisomers, presumably 26 and 28, the mixture of 25-28 was exposed to pTsOH under benzene
5
6
reflux conditions . Unexpectedly and quite fortuitously, this resulted in complete conversion of
the entire mixture to 26 in a 74% yield. We hypothesize that this rearrangement and
isomerization occurs along the path shown in Figure 2. Protonation of the alkenes to form a
tertiary carbocation and formation of the enol begins the process. Preliminary computational
modeling suggests the empty tertiary carbocation p orbital is not far from the enol pi system.
Consequently, a four-member transition state can permit 1,3-migration of the alkyl carbocation
piece to the opposite alpha position generating the isomeric tertiary carbocation and enol.
Elimination and isomerization affords the product 26. Thermodynamic calculations support
compound 26 as the most stable constitutional isomer among 25-28. A similar attempt to
isomerize the 6-5-6 tricyclic mixture of 21 and 23 noted above, failed to afford a similar
transformation despite an analogous calculated thermodynamic preference for compound 22.
1
2

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Figure 2: Possible pathway for rearrangement of 27/28 into 26
Conclusion
An enantioselective procedure for the synthesis of the tetracarbocyclic skeleton of the
gibberellins or the ent-kauranes has been illustrated. The reported results demonstrate another
extension of the Birch-Cope sequence products, which in this case affords a diterpene natural
product-like structure. An intramolecular Friedel-Crafts alkylation of the enone system
demonstrates the ability of aromatic carbon nucleophiles to be used in conjugate addition
reactions with the Birch-Cope sequence products. The tricarbocyclic products were subsequently
subjected to palladium-catalyzed cycloalkenylation to create the challenging
bicyclo[3.2.1]octane C/D ring system. The cycloalkenylation reaction was modestly successful
1
3

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and illustrated the challenges of conducting this reaction on more complex and rigid substrates.
An unprecedented isomerization of the ent-kaurane skeleton under acid conditions provided a
good yield of the final ent-kaurane-like structure from a mixture of alkene isomers. The overall
process illustrates a new enantioselective procedure towards a complex and important natural
product-like carbon skeleton.
Experimental
General Procedures. All reactants and reagents were commercially available and were used
without further purification unless otherwise indicated. Anhydrous THF was obtained by
distillation from benzophenone-sodium under nitrogen. All reactions were carried out under an
inert atmosphere of argon or nitrogen unless otherwise indicated. Concentrated refers to the
removal of solvent with a rotary evaporator at normal water aspirator pressure followed by
further evacuation with a direct-drive rotary vane vacuum pump. Yields refer to
chromatographically and spectroscopically pure (>95%) compounds, except as otherwise
indicated. All new compounds were determined to be >95% pure by NMR and/or GC as
indicated. Thin layer chromatography was performed using silica gel 60 Å precoated aluminum
backed plates (0.25 mm thickness) with fluorescent indicator, which were cut. Developed TLC
plates were visualized with UV light (254 nm), iodine, and p-anisaldehyde staining. Flash
column chromatography was conducted with the indicated solvent system using normal phase
silica gel 60 Å, 230-400 mesh. Optical rotation measurements were taken on a Perkin-Elmer 341
1
13
polarimeter. H and C NMR spectra were recorded at 400 MHz. Chemical shifts are reported in
δ values (ppm) relative to an internal reference (0.05% v/v) of tetramethylsilane (TMS) or
1
13
1
residual CHCl for H NMR and CDCl in C NMR. Peak splitting patterns in the H NMR are
3
3
1
3
reported as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. C NMR
1
4

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1
3
experiments were conducted with the attached proton test (APT) pulse sequence.
C
multiplicities are reported as δ (up) for methyl and methine, and δ (down) for methylene and
u
d
quaternary carbons. IR data was obtained with an FT-IR spectrometer. GC analyses were
performed with an EI-MS detector fitted with a 30 m x 0.25 mm column filled with cross-linked
5% PH ME siloxane (0.25 µm film thickness); gas pressure 7.63 psi He. One method for analysis
of samples involved heating from 70 to 250°C (10°C/min) and finally holding at 250°C for 7 min.
HRMS were determined by electrospray ionization (ESI) using an infusion pump on a Thermo-
Electron LTQ-FT 7T Fourier transform ion cyclotron resonance (FT-ICR) spectrometer. Samples
were dissolved in neat methanol and then diluted to a 90/10/0.01 solution of CH OH/H O/formic
3
2
acid. Alternatively, for lower molecular weight samples, determinations were by solid probe
desorption, chemical ionization (CI) at 35 eV, using methane as the ionizing gas, on a
Micromasss (now Waters) AutoSpec-Ultima M high-resolution triple sector (EBE) mass
spectrometer. Thermodynamic computational calculations were conducted with Spartan ’14 v.
1.1.8 using density functional theory with EDF2 functional, basis set 6-31G* and toluene as the
solvent.
General Procedures for Diarylmethylene Synthesis.
Benzylboronic Pinacol Ester Coupling:
Method A: Aryl iodide (1.0 eq.), Pd (dba) (8 mol%), PPh (1.0 eq.), Ag O (1.5 eq.) and
2
3
3
2
benzylboronic acid pinacol ester (1.5 eq.) were dissolved in THF and heated overnight at 70°C.
The next day the reaction mixture was passed through a plug of silica using EtOAc. The
resulting solution was washed with five times with saturated sodium bicarbonate and brine, dried
1
5

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over Na SO , filtered and concentrated under reduced pressure to yield the diaryl methylene
2
4
4
7
product. Pure product was obtained through column chromatography (EtOAc in heptanes) .
Method B: DMF (3 mL/mmol aryl halide) was added to a flask containing Pd(OAc) (3 mol%)
2
and SPhos (6 mol%). Next finely crushed K PO (3.0 eq.) was added, followed by aryl halide
3
4
(1.0 eq.) and boronic ester (2.0 eq.). This was heated to 60°C overnight. The next day the
reaction mixture was diluted with EtOAc and this was washed two times with 20% NaOH, then
brine. The organic layer was dried over Na SO , filtered, and concentrated under reduced
2
4
pressure to yield the diaryl methylene product. Pure product was obtained through column
5
7
chromatography (7:3 EtOAc in heptanes).
Diarylmethylene 2a, Method A: Use of the general procedure with aryl iodide 1 (207.4 mg,
1
0
.553 mmol) provided 130.2 mg of the diarylmethylene product, an 84% yield. H NMR (CDCl ,
3
a mixture of rotamers) δ 7.31-7.24 (m, 2H), 7.23-7.05 (m, 5H), 6.88-6.79 (m, 1H), 4.44-4.34 (m,
1H), 3.93 (s, 2H), 3.83-3.79 (2s, 3H), 3.78-3.70 (m, 1H), 3.60-3.51 (m, 1H), 3.41 (s, 2H), 3.27-
1
3
3
.14 (m, 1H), 3.00 (s, 2H), 2.07-1.98 (m, 1H), 1.97-1.86 (m, 2H), 1.82-1.69 (m, 1H). C NMR
(
CDCl , a mixture of rotamers) δ 130.5, 128.85, 128.80, 128.2, 126.1, 111.35, 111.28, 59.1,
3 u
5
8.7, 56.3, 55.8, 55.7; δ 168.0, 153.7, 141.2, 133.5, 127.7, 127.2, 73.4, 72.4, 48.4, 45.8, 40.9,
d
+
2
8.5, 27.8, 24.2, 22.2. GC t = 11.77 min. EI-MS m/z (%): 339 (M , 1), 307 (9), 294 (15), 225
R
(
100). HRMS (CI) (m/z): [M+H]+ calcd for C H NO :340.1913, found: 340.1926.
21 26 3
Diarylmethylene 2b, Method A: Use of the general procedure with aryl iodide 1 (1.53 g,
1
4
.08 mmol) provided 874 mg of the diarylmethylene product, a 58% yield. H NMR (CDCl , a
3
mixture of rotamers) δ 7.24-7.6 (m, 3H), 6.88-6.69 (m, 4H), 4.42-4.38 (m, 1H), 3.91 (s, 2H),
.84-3.80 (2s, 3H), 3.80-3.77 (2s, 3H), 3.77-3.72 (m, 1H), 3.60-3.52 (m, 1H), 3.42 (s, 2H), 3.29-
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1
3
3
.17 (m, 1H), 3.01 (s, 2H), 2.07-1.98 (m, 1H), 1.97-1.87 (m, 2H), 1.82-1.72 (m, 1H). C NMR
(
CDCl , a mixture of rotamers) δ 130.51, 130.46, 129.4, 128.1, 121.2, 121.16, 114.6, 111.37,
3
u
1
11.33, 59.0, 58.5, 57.2, 56.3, 55.67, 55.61, 55.02, 55.00 ; δ 167.9, 159.7, 153.18, 153.6, 142.69,
d
1
42.56, 133.3, 127.5, 127.2, 73.4, 72.35, 48.4, 45.7, 40.8, 28.5, 27.6, 23.96, 22.2. GC t = 13.51
R
+
min. EI-MS m/z (%): 369 (M , 1), 337 (7), 324 (10), 255 (100). HRMS (CI) (m/z): [M+1]+ calcd
for C H NO : 370.2018, found: 370.2022.
2
2
28
4
Diarylmethylene 2c, Method A: Use of the general procedure with aryl iodide 1(531.0 mg,
1
1
.42 mmol) provided 320.7 mg of the diarylmethylene product, a 61% yield based on GCMS. H
NMR (CDCl , a mixture of rotamers) δ 7.17-7.03 (m, 4H), 6.87-6.74 (m, 3H), 4.49-4.32, (m, 1H),
3
3.73 (s, 2H), 3.85-3.76 (m, 6H), 3.76-3.71 (m, 1H), 3.61-3.51 (m, 1H), 3.40 (s, 2H), 3.29-3.13 (m,
1
3
1
H), 3.10-2.95 (m, 1H), 2.08-1.84 (m, 4H), 1.81-1.69 (m, 1H). C NMR (CDCl , a mixture of
3
rotamers) δ 130.41, 130.38, 130.3, 130.2, 129.79, 129.75, 128.0, 127.7, 120.79, 120.73. 113.9,
u
1
11.3, 111.2, 111.15, 59.1, 58.7, 57.2, 56.3, 55.74, 55.67, 55.61, 55.2; δ 168.1, 157.97, 153.6,
d
133.99, 133.97, 133.26, 133.14, 127.5, 127.1, 73.4, 72.3, 48.4, 45.8, 40.0, 28.4, 28.9, 24.2, 22.2.
+
GC t = 13.91 min. EI-MS m/z (%): 369 (M , 1), 337 (7), 324 (10), 255 (100). HRMS (CI) (m/z):
R
[
M+1]+ calcd for C H NO : 370.2018, found: 370.2018.
22 28 4
Diarylmethylene 2d, Method B: Use of the general procedure with aryl iodide 1 (191.6 mg,
1
0
.511 mmol) provided 114.2 mg of the diarylmethylene product, a 56% yield. H NMR (CDCl ,
3
a mixture of rotamers) δ 7.19-7.02 (m, 2H), 6.88-6.74(m, 2H), 6.74-6.62 (m, 2H), 4.42-4.34 (m,
1
3
1
1
H), 3.86 (s, 2H), 3.86-3.84 (2s, 3H), 3.82 (s, 3H), 3.81-3.78 (2s, 3H), 3.77-3.70 (m, 1H), 3.60-
.50 (m, 1H), 3.41 (s, 2H), 3.28-3.14 (m, 1H), 3.01 (s, 2H), 2.06-1.97 (m, 1H), 1.97-1.85 (m, 2H),
1
3
.81-1.69 (m, 1H). C NMR (CDCl , a mixture of rotamers) δ 130.38, 130.35, 128.0, 120.87,
3
u
20.83, 112.17, 112.12, 111.27, 111.22, 59.1, 58.7, 57.2, 56.3, 55.9, 55.8, 55.7, 55.66; δ 168.1,
d
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153.6, 148.9, 147.4, 133.78, 133.60, 127.5, 127.1, 73.4, 72.3, 48.4, 45.7, 40.4, 28.4, 28.77, 24.2,
+
2
2.2.GC t = 15.64 min. EI-MS m/z (%): 399 (M , 1), 367 (3), 354 (17), 285 (100). HRMS (CI)
R
(
m/z): [M+1]+ calcd for C H NO :400.2124, found: 400.2113.
23 30 5
Diarylmethylene 2e, Method A: Use of the general procedure with aryl iodide 1 (2.11 g,
1
5
.62 mmol) provided 930 mg of the diarylmethylene product, a 47% yield. H NMR (CDCl , a
3
mixture of rotamers) δ 7.22-7.06 (m, 3H), 7.05-6.92 (m, 3H), 6.89-6.78 (m, 1H), 4.50-4.35, (m,
1H), 3.89 (s, 2H), 3.85-3.79 (2s, 3H), 3.79-3.71 (m, 1H), 3.62-3.52 (m, 1H), 3.42 (s, 2H), 3.29-
1
3
3
.15 (m, 1H), 3.06-2.92 (m, 1H), 2.34-2.29 (2s, 3H), 2.08-1.86 (m, 4H), 1.83-1.70 (m, 1H). C
NMR (CDCl , a mixture of rotamers) δ 130.52, 130.49, 129.66, 129.60, 128.3, 128.2, 126.8,
3
u
1
25.90, 125.84, 111.3, 59.1, 58.6, 57.2, 56.3, 55.76, 55.68, 21.4; δ 167.98, 153.7, 141.0, 140.96,
d
1
38.02, 133.6, 127.6, 127.2, 73.4, 72.4, 48.4, 45.8, 40.8, 28.5, 27.8, 24.8, 22.2. GC t = 12.28
R
+
min. EI-MS m/z (%): 353 (M , 1), 331 (7), 308 (10), 239 (10). HRMS (CI) (m/z): [M+1]+ calcd
for C H NO : 354.2069, found: 354.2070.
2
2
28
3
General Procedures for the Heck Cross-Coupling Reaction:
Method A, for electron-poor styrenes: A flame-dried flask was charged with Pd(OAc) (0.15
2
eq.), K CO (2.0 eq.), N,N-dimethyl-β-alanine (0.15 eq.), and styrene (1.5 eq.). Next aryl iodide
2
3
(1.0 eq.) dissolved in NMP was added and this was heated to 130°C overnight. The next day the
reaction was concentrated directly onto silica under reduced pressure and purified via column
5
8
chromatography (1:1 EtOAc in heptanes) .
Method B, for electron-rich styrenes: To a flask containing aryl iodide (1.0 eq.) was added
triethylamine (1.5 eq.), Pd(OAc) (0.10 eq.), and DMA. This was heated overnight at 120°C. The
2
1
8

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next day the reaction was concentrated directly onto silica under reduced pressure and purified
4
9
via column chromatography (1:1 EtOAc in heptanes) .
Stilbene 3a, Method A: Use of the general procedure with aryl iodide 1 (2.81 g, 7.48 mmol)
provided 2.02 g of the cross-coupled product in a 77% yield (as the desired product and a Heck
1
regioisomer). H NMR (CDCl a mixture of regioisomers and rotamers) δ 7.54-7.42 (m, 3H),
3,
7
4
3
.41-7.31 (t, 2H, J=7.84 Hz), 7.31-7.22 (m, 2H), 7.12-6.97 (m, 2H), 6.96-6.86 (m, 1H), 4.50-
.39 (m, 1H), 3.87 (s, 3H), 3.83-3.73 (m, 1H), 3.67-3.54 (m, 1H), 3.45 (s, 2H), 3.34-3.19 (m, 1H),
1
3
.16-3.07 (m, 1H), 2.10-1.88 (m, 4H), 1.85-1.73 (m, 1H). C NMR (CDCl a mixture of
3
,
regioisomers and rotamers) δ 128.5, 128.47, 128.41, 128.0, 127.9, 127.3, 127.28, 127.25, 127.21,
u
1
1
2
3
9
26.1, 125.4, 111.3, 58.9, 58.6, 56.2, 55.6, 55.5, 29.3, 24.4; δ 177.1, 167.45, 167.41, 154.7,
d
37.2, 137.17, 130.1, 130.0, 127.8, 127.4, 73.4, 72.2, 49.1, 48.2, 45.7, 45.6, 30.4, 28.4, 28.0,
7.7, 24.0, 22.1, 17.4. GC t = 12.347 min. (Minor Heck regioisomer, 4.38%). EI-MS m/z (%):
R
+
51 (M , 2), 306 (11), 237 (100), 178 (11), 165 (11). t = 15.29 min (Major Heck regioisomer,
R
+
4.97%). EI-MS m/z (%): 351 (M , 6), 306 (11), 237 (100), 178 (14), 165 (15). HRMS (CI)
(
m/z): [M+1]+ calcd for C H NO : 352.1913, found: 352.1910.
22 26 3
Stilbene 3b, Method B: Use of the general procedure with aryl iodide 1 (4.79 g, 12.8 mmol)
provided 4.88 g of the cross-coupled product in a 96% yield (as the desired product and a Heck
1
regioisomer). H NMR (CDCl a mixture of regioisomers and rotamers) δ 7.52-7.43 (m, 2H),
3,
7
6
3
.31-7.25 (t, 2H, J=7.68 Hz), 7.12-7.06 (t, 1H, J=7.36 Hz), 7.05-6.98 (d, 2H, J=11.28 Hz), 6.96-
.86 (m, 1H), 6.84-6.80 (m, 1H), 4.50-4.40 (m, 1H), 3.89-3.83 (m, 6H), 3.83-3.53 (m, 2H), 3.48-
1
3
.40 (m, 2H), 3.33-3.20 (m, 1H), 3.15-3.06 (m, 1H), 2.10-1.88 (m, 4H), 1.86-1.73 (m, 1H). C
NMR (CDCl a mixture of regioisomers and rotamers) δ 130.1, 130.02, 129.6, 129.2, 128.63,
3
,
u
128.60, 127.79, 127.7, 127.46, 127.4, 125.7, 120.86, 120.81, 120.79, 119.0, 113.9, 113.3, 113.13,
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1
1
7
13.09, 111.58, 111.41, 111.18, 110.9, 59.1, 58.8, 57.3, 56.3, 56.2, 55.8, 55.75, 55.2; δ 167.74,
d
67.67, 159.46, 155.0, 154.89, 148.9, 138.8, 134.1, 130.36, 130.24, 128.2, 127.55, 113.64, 73.5,
2.34, 48.5, 45.8, 28.52, 28.47, 27.8, 24.2, 22.2, 20.3. GC t = 14.30 min. (Minor Heck
R
+
regioisomer, 4.72%). EI-MS m/z (%): 381 (M , 1), 336 (8), 267 (100), 133 (8). t = 19.99 min.
R
+
(
Major Heck regioisomer, 92.79%). EI-MS m/z (%): 381 (M , 9), 336 (5), 267 (100), 133 (10).
HRMS (CI) (m/z): [M+1]+ calcd for C H NO : 382.2018, found: 382.2007.
2
3
28
4
Stilbene 3c, Method B: Use of the general procedure with aryl iodide 1 (5.016 g, 13.4 mmol)
provided 4.39 g of the cross-coupled product in an 86 % yield (as the desired product and a Heck
1
regioisomer). H NMR (CDCl a mixture of regioisomers and rotamers) δ 7.42-7.35 (m, 3H),
3,
7
9
4
1
1
1
.29-7.19 (m, 1H), 6.96-6.78 (m, 5H), 4.46-4.37 (m, 1H), 3.83-3.76 (m, 6H), 3.76-3.70 (dd, 1H,
.4 Hz) 3.61-3.47 (m, 1H), 3.40 (s, 2H), 3.31-3.15 (m, 1H), 3.14-3.01 (m, 1H), 2.05-1.82 (m,
13
H), 1.81-1.66 (m, 1H). C NMR (CDCl a mixture of regioisomers and rotamers) δ 132.8,
3
,
u
32.29, 132.26, 132.74, 132.67, 130.19, 130.14, 129.4, 128.29, 128.25, 127.5, 127.06, 125.40,
25.33, 114.12, 114.04, 113.62, 113.57, 111.38, 59.1, 58.9, 56.3, 55.8, 55.3; δ 167.91, 167.83.
d
59.19, 154.5, 127.9, 73.5, 72.36, 72.25, 48.57, 48.58, 45.8, 28.5, 27.81, 27.78, 24.2, 22.2. GC tR
+
=
14.89 min. (Minor Heck regioisomer, 5.87%). EI-MS m/z (%): 381 (M , 1), 336 (10), 267
+
(
100), 133 (8). t = 20.68 min. (Major Heck regioisomer, 92.92%). EI-MS m/z (%): 381 (M , 21),
R
336 (3), 267 (100), 133 (8). HRMS (CI) (m/z): [M+1]+ calcd for C H NO : 382.2018, found:
23 28 4
3
82.2031.
Stilbene 3d, Method B: Use of the general procedure with aryl iodide 1 (3.65 g, 9.73 mmol)
provided 3.51 g of the cross-coupled product in an 88% yield (as the desired product and a Heck
1
regioisomer). H NMR (CDCl a mixture of regioisomers and rotamers) δ 7.46-7.36 (m, 2H),
3,
7.07-6.94 (m, 2H), 6.93-6.78 (m, 4H), 4.47-4.36 (m, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.81 (m, 3H),
2
0

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3
1
1
1
1
2
4
.78-3.70 (m, 1H), 3.64-3.50 (m, 1H), 3.41 (s, 2H), 3.30-3.16 (m, 1H), 3.12-3.02 (m, 1H), 2.06-
1
3
.84 (m, 4H), 1.81-1.68 (m, 1H). C NMR (CDCl a mixture of regioisomers and rotamers) δ
u
3,
30.05, 130.04, 128.25, 127.2, 125.6, 125.3, 120.9, 119.65, 119.61, 111.48, 111.39, 111.31,
10.88, 110.82, 108.7, 59.02, 59.01, 56.3, 55.86, 55.78, 55.70, 55. 64; δ 167.7, 154.5, 149.1,
d
48.6, 134.2, 130.52, 130.49, 130.44, 127.9, 127.46, 127.43, 112.3, 73.5, 72.3, 72.27, 48.3, 45.8,
8.5, 27.8, 24.1, 22.2. GC t = 16.66 min. (Minor Heck regioisomer, 8.57%). EI-MS m/z (%):
R
+
11 (M , 4), 366 (8), 297 (100), 148 (11). t = 25.84 min. (Major Heck regioisomer, 87.67%).
R
+
EI-MS m/z (%): 411 (M , 13), 366 (1), 297 (100), 148 (13). HRMS (CI) (m/z): [M]+ calcd for
C H NO : 411.2046, found: 411.2039.
24
29
5
Stilbene 3e, Method B: Use of the general procedure with aryl iodide 1 (3.13 g, 8.57 mmol)
provided 2.78 g of the cross-coupled product in an 89% yield (as the desired product and a Heck
1
regioisomer). H NMR (CDCl a mixture of regioisomers and rotamers) δ 7.47-7.41 (m, 2H),
3,
7
3
4
1
1
1
2
3
9
.33-7.18 (m, 3H), 7.17-6.82 (m, 4H), 4.49-4.36 (m, 1H), 3.82 (s, 3H), 3.79-3.72 (dd, 1H, 9.4 Hz)
.65-3.47 (m, 1H), 3.43 (s, 2H), 3.31-3.16 (m, 1H), 3.17-3.02 (m, 1H), 2.36 (s, 3H), 2.13-1.84 (m,
1
3
H), 1.81-1.68 (m, 1H). C NMR (CDCl a mixture of regioisomers and rotamers) δ 128.95,
3,
u
28.93, 128.55, 128.52, 128.28, 128.24, 128.09, 127.60, 127.45, 127.28, 127.02, 125.56, 125.41,
25.36, 123.52, 111.4, 110.9, 59.1, 58.8, 57.4, 56.4, 55.8, 55.7, 21.4; δ 167.7, 154.97, 138.14,
d
38.12, 137.32, 137.27, 130.51, 130.4, 128.02, 113.28, 73.5, 72.40, 72.27, 48.5, 45.82, 45.76,
8.54, 27.8, 24.2, 22.2. GC t = 12.89 min. (Minor Heck regioisomer, 5.78%). EI-MS m/z (%):
R
+
65 (M , 1), 333 (10), 320 (14), 251 (100), 178 (14). t = 16.83 min. (Major Heck regioisomer,
R
+
4.21%). EI-MS m/z (%): 365 (M , 9), 333 (3), 320 (7), 251 (100), 178 (19). HRMS (CI) (m/z):
[
M+1]+ calcd for C H NO : 366.2069, found: 366.2072.
23 28 3
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General Procedure for Alkene Hydrogenation: A flask containing alkene(1.0 eq.) was
reduced under a hydrogen atmosphere in a Parr shaker hydrogenator with Pd/C (0.20 g/g alkene)
and a 1:1 mixture of EtOAc and EtOH. After 4 h the reaction mixture was filtered through celite
and concentrated under reduced pressure. The reduced product was then purified via column
chromatography (1:1 EtOAc in heptanes).
Diaryl 4a: Use of the general procedure with alkene 3a (2.32 g, 8.11 mmol) provided 2.09 g
1
of the hydrogenated product in an 90% yield. H NMR (CDCl a mixture of regioisomers and
3
,
rotamers) δ 7.30-7.21 (m, 2H), 7.22-6.99 (m, 5H), 6.83-6.78 (d, 1H, J=8.56 Hz), 4.44-4.35, (m,
1H), 3.85-3.77 (m, 3H), 3.77-3.70 (m, 1H), 3.60-3.50 (m, 1H), 3.41 (s, 2H), 3.25-3.10 (m, 1H),
13
3
.09-2.95 (m, 1H), 2.87 (s, 4H), 2.07-1.84 (m, 4H),1.80-1.68 (m, 1H). C NMR (CDCl a
3
,
mixture of regioisomers and rotamers) δ 130.06, 129.98, 128.47, 128.43, 128.30, 128. 25,
u
1
1
3
27.67, 125.89, 125.83, 111.2, 59.07, 58.71, 57.2, 56.2, 55.71, 55.62, 24.7; δ 177.3, 167.99.
d
53.5, 151.54, 151.45, 133.99, 133.90, 127.4, 127.03, 73.5, 72.4, 48.4, 45.7, 37.91, 37.88, 36.81,
6.72, 28.47, 28.17, 27.78, 24.2, 22.2. GC t = 11.98 min. (Minor Heck regioisomer, 4.66%). EI-
R
+
MS m/z (%): 353 (M , 1), 321 (8), 308 (13), 239 (100), 164 (8). t = 12.57 min. (Major Heck
R
+
regioisomer, 95.09%). EI-MS m/z (%): 353 (M , 1), 321 (7), 308 (11), 239 (100), 91 (8). HRMS
(
CI) (m/z): [M+1]+ calcd for C H NO : 354.2069, found: 354.2069.
22 28 3
Diaryl 4b: Use of the general procedure with alkene 3b (4.67 g, 12.26 mmol) provided 3.91 g
1
of the hydrogenated product in an 83% yield. H NMR (CDCl a mixture of regioisomers and
3
,
rotamers) δ 7.24-7.16 (t, 1H, J=7.36 Hz), 7.16-7.11 (dd, 1H, J=8.40, 2.20 Hz), 7.07-7.03 (d, 1H,
J=2.12 Hz), 6.87-6.80 (d, 1H, 8.44 Hz), 6.80-6.69 (m, 3H), 4.47-4.38, (m, 1H), 3.86-3.71 (m,
7H), 3.64-3.52 (m, 1H), 3.44 (s, 2H), 3.27-3.12 (m, 1H), 3.11-2.98 (m, 1H), 2.88 (s, 4H), 2.08-
1
3
1
.84 (m, 4H), 1.83-1.64 (m, 1H). C NMR (CDCl a mixture of regioisomers and rotamers) δ
u
3,
2
2

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DOI: 10.1039/C4OB02489C
1
1
1
3
30.07, 130.01, 129.29, 129.25, 127.7, 120.91, 120.85, 114.25, 114.19, 111.27, 111.22, 111.18,
11.04, 59.1, 58.7, 57.3, 56.2, 55.76, 55.65, 55.62, 55.1, 43.88, 43.82; δ 168.13, 168.06, 159.65,
d
59.60, 153.5, 143.2, 143.1, 134.0, 133.95, 127.06, 73.5, 72.4, 48.45, 48.41, 37.99, 37.95, 36.73,
6.62, 28.5, 27.8, 24.2, 22.2.GC t = 13.73 min. (Minor Heck regioisomer, 3.59%). EI-MS m/z
R
+
(
%): 383 (M , 1), 351 (5), 338 (8), 269 (100), 134 (7). t = 15.27 min. (Major Heck regioisomer,
R
+
9
5.30%). EI-MS m/z (%): 383 (M , 1), 351 (10), 338 (14), 269 (100), 134 (7). HRMS (CI) (m/z):
[
M+1]+ calcd for C H NO : 384.2175, found: 384.2191.
23 30 4
Diaryl 4c: Use of the general procedure with alkene 3c (4.44 g, 11.7 mmol) provided 3.90 g
1
of the hydrogenated product in an 87% yield. H NMR (CDCl a mixture of regioisomers and
3
,
rotamers) δ 7.16-7.00 (m, 4H), 6.85-6.78 (m, 3H), 4.46-4.37 (m, 1H), 3.80 (s, 3H), 3.78 (s, 3H),
3.76-3.73 (m, 1H), 3.59-3.51 (m, 1H), 3.42 (s, 2H), 3.24-3.11 (m, 1H), 3.10-2.98 (m, 1H), 2.83 (s,
1
3
4
H), 2.06-1.98 (m, 2H), 1.98-1.86 (m, 2H), 1.80-1.70 (m, 1H). C NMR (CDCl a mixture of
3
,
regioisomers and rotamers) δ 130.1, 130.0, 129.4, 129.36, 127.7, 113.74, 113.69, 111.15, 59.1,
u
5
8.8, 57.3, 56.26, 56.21, 55.74, 55.63, 55.23;δ 168.1, 157.8, 134.1, 134.0, 133.7 133.6, 127.4,
d
7
3.5, 72.4, 48.4, 45.8, 37.12, 37.04, 37.03, 28.5, 27.8, 24.2, 22.26, 22.22.GC t = 13.99 min.
R
+
(
Minor Heck regioisomer, 10.20%). EI-MS m/z (%): 383 (M , not shown due to loss of two
methyl groups in the GC-MS), 351 (7), 338 (10), 269 (100), 126 (10). t = 14.76 min. (Major
R
+
Heck regioisomer, 89.49%). EI-MS m/z (%): 383 (M , 1), 351 (7), 338 (12), 269 (100), 121 (15).
HRMS (CI) (m/z): [M+1]+ calcd for C H NO : 384.2175, found: 384.2162.
2
3
30
4
Diaryl 4d: Use of the general procedure with alkene 3d (3.51 g, 8.54 mmol) provided 3.12 g
1
of the hydrogenated product in an 88% yield. H NMR (CDCl a mixture of regioisomers and
3
,
rotamers) δ 7.13-7.03 (td, 2H, J=8.08, 2.48 Hz), 6.83-6.74 (m, 2H), 6.72-6.63 (m, 2H), 4.45-4.36,
m, 1H), 3.85 (s, 4H), 2.83 (s, 2H), 3.82-3.78 (m, 3H), 3.77-3.70 (m, 1H), 3.61-3.5 (m, 1H), 3.41
(
2
3

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(s, 2H), 3.27-3.11 (m, 1H), 3.10-2.96 (m, 1H), 2.83 (s, 4H), 2.06-1.85 (m, 4H), 1.82-1.67 (m,
1
3
1
1
5
1
1
H). C NMR (CDCl a mixture of regioisomers and rotamers) δ 130.12, 130.6, 127.7, 120.31,
3
,
u
20.28, 111.94, 111.87, 111.25, 111.23, 111.16, 59.1, 59.7, 58.6, 57.3, 56.26, 56.22, 55.89, 55.83,
5.80, 55.79, 55.78, 55.74, 55.63, 43.4; δ 168.1, 148.8, 147.33, 147.26, 134.23, 134.14, 134.05,
d
33.96, 127.5, 127.07, 73.5, 72.4, 48.4, 45.7, 37.5, 37.0, 36.95, 28.45, 27.8, 24.2, 22.2. GC t =
R
+
5.59 min. (Minor Heck regioisomer, 5.82%). EI-MS m/z (%): 413 (M , 2), 381 (3), 368 (7), 299
+
(
100), 149 (8). t = 16.86 min. (Major Heck regioisomer, 91.76%). EI-MS m/z (%): 413 (M , 5),
R
3
81 (3), 368 (8), 299 (100), 151 (18). HRMS (CI) (m/z): [M+1]+ calcd for C H NO : 414.2280,
23 32 5
found: 414.2279.
Diaryl 4e: Use of the general procedure with alkene 3e (3.10 g, 8.49 mmol) provided 3.12 g
1
of the hydrogenated product in an 85% yield. H NMR (CDCl a mixture of regioisomers and
3
,
rotamers) δ 7.19-7.05 (m, 2H), 7.01-6.87 (m, 4H), 6.84-6.73 (d, 1H, J=7.2 Hz), 4.46-4.32 (m,
1H), 3.80-3.64 (m, 4H), 3.60-3.47 (m, 1H), 3.41-3.35 (s, 2H), 3.22-2.93 (m, 2H), 2.88-2.76 (s,
1
3
4
H), 2.32-2.26 (s, 3H), 2.05-1.80 (m, 2H). C NMR (CDCl a mixture of regioisomers and
3
,
rotamers) δ 130.07, 130.00, 129.30, 129.26, 128.25, 127.7, 126.7, 126.6, 125.50, 125.46, 111.2,
u
5
9.1, 58.7, 57.30, 56.2, 55.78, 55.67, 43.8, 21.4; δ 168.2, 153.6, 141.5, 141.48, 137.90, 137.88,
d
1
34.27, 134.13, 73.55, 72.45, 48.4, 45.8, 37.91, 36.90, 36.81, 28.5, 27.8, 22.2. GC t = 12.42 min.
R
+
(
Minor Heck regioisomer, 5.74%). EI-MS m/z (%): 367 (M , 1), 335 (10), 322 (13), 253 (100). tR
+
=
13.14 min. (Major Heck regioisomer, 93.26%). EI-MS m/z (%): 367 (M , 2), 335 (8), 322 (10),
2
53 (100), 105 (24). HRMS (CI) (m/z): [M+1]+ calcd for C H NO : 368.2226, found:368.2215.
23 30 3
General Procedure for Birch Reduction-Allylation: To a solution of benzamide (1.0 eq.)
and tert-butyl alcohol (1.0 eq.) in THF (10 mL/mmol amide) and NH (130 mL/mmol amide) at -
3
78°C was added potassium in small pieces until blue coloration was maintained for 20 min.
2
4

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Isoprene was added dropwise to consume the excess metal, and then allyl bromide (2.5 eq.) was
added. The solution was stirred at -78°C and allowed to slowly warm to room temperature to
allow the NH to evaporate. Water was then added, and the mixture was extracted three times
3
with DCM. The combined organics were washed with brine, dried over Na SO , filtered and
2
4
concentrated under reduced pressure to yield the 2,5-cyclohexadiene product. Pure product was
obtained through column chromatography (3:7 EtOAc in heptanes). Note: Birch reduction-
allylation products were not stable enough to obtain an HRMS or optical rotations.
Cyclohexadiene 5a: Use of the general procedure with benzamide 2a (1.1710 g, 3.45 mmol)
1
provided 0.640 g of the 2,5-cyclohexadiene product in a 49% yield. H NMR (CDCl , a mixture
3
of rotamers) δ 7.28 (t, 2H, J=7.80 Hz), 7.22-7.12 (m, 3H), 5.73-5.55 (m, 1H), 5.25 (s, 1H), 5.07-
4.90 (m, 2H), 4.68 (t, 1H, J=3.44 Hz), 4.39-4.26 (m, 1H), 3.67-3.55 (m, 1H), 3.47 (s, 3H), 3.38-
1
3
3
.25 (m, 6H), 3.23-3.11 (m, 1H), 2.87-2.47 (m, 3H), 1.91-1.74 (m, 3H), 1.74-1.59 (m, 1H). C
NMR (CDCl , a mixture of rotamers) δ 135.1, 128.8, 128.3, 126.3, 122.8, 92.6, 58.9, 58.1, 54.2;
3
u
δd 170.7, 152.5, 139.3, 136.9, 116.8, 72.1, 52.8, 46.0, 43.3, 41.3, 29.3, 26.6, 24.8.
Cyclohexadiene 5b: Use of the general procedure with benzamide 2b (0.971 g, 2.63 mmol)
1
provided 0.497 g of the 2,5-cyclohexadiene product in a 46% yield. H NMR (CDCl , a mixture
3
of rotamers) δ 7.18 (t, 1H, J=7.72 Hz), 6.79-6.65 (m, 3H), 5.70-5.56 (m, 1H), 5.24 (s, 1H), 5.04-
4
2
1
1
4
.89 (m, 2H), 4.68 (t, 1H, J=3.64 Hz), 4.36-4.24 (m, 1H), 3.78 (s, 3H), 3.68-3.56 (m, 1H), 3.49 (t,
H, J=2.12 Hz), 3.46 (s, 2H), 3.37-3.26 (m, 6H), 2.91-2.28 (m, 3H), 1.93-1.76 (m, 3H), 1.74-
1
3
.54 (m, 1H). C NMR (CDCl , a mixture of rotamers) δ 135.1, 129.3, 122.9, 121.2, 114.7,
3
u
11.4, 92.6, 58.9, 58.1, 55.1, 54.23; δ 170.7, 159.7, 153.0, 140.9, 136.8, 116.8, 72.0, 52.8, 46.1,
d
3.3, 41.1, 29.4, 26.5, 24.9.
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5

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Cyclohexadiene 5c: Use of the general procedure with benzamide 2c (1.07 g, 2.89 mmol)
1
provided 0.8359 g of the 2,5-cyclohexadiene product in a 70% yield. H NMR (CDCl , a mixture
3
of rotamers) δ 7.13-7.00 (t, 2H, J=7.24 Hz), 6.87-6.76 (d, 2H, J=8.60 Hz), 5.70-5.54 (m, 1H),
5
3
1
1
1
4
.24-5.17 (d, 1H, J=7.32 Hz), 5.03-4.89 (m, 2H), 4.67 (s, 1H), 4.38-4.26, (m, 1H), 3.78 (s, 3H),
.66-3.50 (m, 2H), 3.46 (s, 3H), 3.39-3.30 (m, 4H), 3.30-3.12 (m, 3H), 2.89-2.44 (m, 4H), 1.93-
13
.73 (m, 3H), 1.74-1.59 (m, 1H). C NMR (CDCl , a mixture of rotamers) δ 135.2, 129.7, 123.1,
3
u
22.4, 113.74, 113.71, 92.76, 92.65, 58.92, 58.88, 58.04, 57.89, 55.23, 54.25, 54.21; δ 170.8,
d
70.3, 158.2, 152.9, 152.5, 137.3, 136.9, 131.4, 131.3, 116.7, 72.17, 72.07, 52.8, 52.77, 46.2,
6.0, 42.3, 41.28, 41.27, 29.31, 29.26, 26.6, 26.4, 25.0, 24.8, 22.7.
Cyclohexadiene 5d: Use of the general procedure with benzamide 2d (2.62 g, 6.34 mmol)
1
provided 2.07 g of the 2,5-cyclohexadiene product in a 72% yield. H NMR (CDCl , a mixture of
3
rotamers) δ 6.78-6.71 (d, 1H, J=8.0 Hz), 6.71-6.59 (m, 2H), 5.67-5.53 (m, 1H), 5.19 (s, 1H),
5.00-4.84 (m, 2H), 4.64 (s, 1H), 4.33-4.21, (m, 1H), 3.84-3.75 (m, 7H), 3.61-3.46 (m, 2H), 3.43
(s, 3H), 3.37-3.10 (m, 6H), 2.84-2.68 (m, 1H), 2.68-2.60 (m, 1H), 2.60-2.43 (m, 2H), 1.91-1.70
1
3
(
m, 3H), 1.69-1.54 (m, 1H). C NMR (CDCl , a mixture of rotamers) δ 135.2, 123.2, 122.5,
3
u
1
1
2
20.9, 112.0, 111.1, 92.7, 58.9, 58.1, 57.9, 55.9, 55.8, 54.3, 54.2; δ 170.3, 152.9, 148.9, 147.5,
d
37.1, 136.9, 131.9, 116.1, 72.6, 72.02, 72.0, 51.3, 47.7, 46.3, 46.0, 43.0, 41.3, 29.7, 29.3, 29.3,
6.9, 26.5, 26.4, 25.2, 25.0, 24.9.
Cyclohexadiene 5e: Use of the general procedure with benzamide 2e (0.880 g, 2.49 mmol)
1
provided 0.60 g of the 2,5-cyclohexadiene product in a 61% yield. H NMR (CDCl , a mixture of
3
rotamers) δ 7.17 (t, 1H, J=7.48 Hz), 7.08-6.91 (m, 3H), 5.73-5.53 (m, 1H), 5.27 (s, 1H), 5.09-
4.88 (m, 2H), 4.68 (t, 1H, J=3.52 Hz), 4.41-4.27, (m, 1H), 3.70-3.60 (m, 1H), 3.60-3.52 (m, 1H),
3.48 (s, 3H), 3.41-3.24 (m, 6H), 3.23-3.14 (m, 1H), 2.87-2.52 (m, 4H), 2.33 (2s, 3H), 1.75-1.57
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13
(
m, 2H). C NMR (CDCl , a mixture of rotamers) δ 135.5, 129.7, 129.66, 128.2, 127.0, 125.9,
3 u
1
23.3, 92.7, 59.0, 57.9, 54.3, 21.4; δ 170.8, 170.3, 152.9, 152.5, 139.2, 137.9, 136.9, 116.7, 72.1,
d
52.8, 46.1, 43.2, 41.3, 29.4, 26.6.
Cyclohexadiene 6a: Use of the general procedure with benzamide 4a (3.45 g, 9.77 mmol) as
2
separate Birch reductions which were combined for purification provided 3.74 g of the 2,5-
1
cyclohexadiene product in a 97% yield. H NMR (CDCl , a mixture of rotamers) δ 7.31-7.22 (t,
3
2H, J=5.28 Hz), 7.22-7.13 (d, 3H, J=6.52 Hz), 5.60-5.45 (m, 1H), 5.15 (s, 1H), 4.99-4.85, (m,
2H), 4.73-4.68 (t, 1H, 3.56 Hz), 4.31-4.24 (m, 1H), 3.62-3.57 (dd, 1H, J=9.6, 3.2 Hz), 3.47 (s,
3H), 3.33 (s, 3H), 3.31-3.15 (m, 3H), 2.89-2.63 (m, 5H), 2.53- 2.45 (m, 1H), 2.43-2.35 (t, 2H,
1
3
J=8.00 Hz), 1.87-1.56 (m, 5H). C NMR (CDCl , a mixture of rotamers) δ 135.0, 128.3, 128.2,
3
u
1
25.9, 121.6, 92.7, 58.8, 58.1, 54.2;δ 170.3, 152.99, 141.45, 136.6, 116.5, 71.9, 52.6, 45.8, 45.3,
d
37.5, 33.9, 29.9, 26.3, 24.9.
Cyclohexadiene 6b: Use of the general procedure with benzamide 4b (8.52 g, 22.2 mmol) as
3
separate Birch reductions which were combined for purification to provide 6.96 g of the 2,5-
1
cyclohexadiene product in a 73% yield. H NMR (CDCl , a mixture of rotamers) δ 7.24-7.17 (m,
3
1H), 6.83-6.70 (m, 3H), 5.63-5.47 (m, 1H), 5.17 (s, 1H), 5.00-4.88 (m, 2H), 4.73 (t, 1H, J=3.64
Hz), 4.36-4.24 (m, 1H), 3.81 (s, 3H), 3.66-3.59 (m, 1H), 3.50 (s, 3H), 3.39-3.33 (m, 3H), 3.33-
3
1
1
3
.17 (m, 2H), 3.89-2.65 (m, 5H), 2.56-2.46 (m, 1H), 2.40 (t, 2H, J=8.04 Hz), 1.90-1.70 (m, 3H),
1
3
.68-1.59 (m, 2H). C NMR (CDCl , a mixture of rotamers) δ 135.1, 129.3, 121.6, 120.7, 114.1,
3
u
11.1, 92.6, 58.9, 58.1, 55.1, 54.2; δ 170.5, 159.7, 153.0, 143.1, 136.6, 116.6, 71.9, 45.9, 41.3,
d
7.4, 34.1, 29.9, 26.3, 24.8.
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Cyclohexadiene 6c: Use of the general procedure with benzamide 4c (0.500 g, 1.30 mmol)
1
provided 0.290 g of the 2,5-cyclohexadiene product in a 52% yield. H NMR (CDCl , a mixture
3
of rotamers) δ 7.14-7.04 (d, 2H, J=8.52 Hz), 6.85-6.76 (d, 2H, J=10.7 Hz) 5.66-5.44 (m, 1H),
5
3
1
.13 (s, 1H), 5.00-4.85 (m, 2H), 4.74-4.67 (t, 1H, J=3.56 Hz), 4.36-4.22 (m, 1H), 3.75 (s, 3H),
.66-3.54 (m, 1H), 3.47 (s, 3H), 3.33 (s, 3H), 3.30-3.13 (m, 3H), 2.91-2.61 (m, 4H), 2.56-2.41 (m,
1
3
H), 2.40-2.31 (t, 2H, J=3.96 Hz), 2.02-1.53 (m, 5H). C NMR (CDCl , a mixture of rotamers)
3
δu 135.1, 129.24, 129.14, 128.23, 128.18, 121.5, 113.73, 113.69, 113.62, 92.6, 58.9, 58.0, 55.2,
5
4.2 ;δ 170.8, 157.8, 136.7, 133.5, 116.54, 72.0, 52.6, 45.9, 41.29, 41.06, 37.7, 33.1, 29.9, 26.3,
d
24.9.
Cyclohexadiene 6d: Use of the general procedure with benzamide 4d (2.62 g, 6.34 mmol)
1
provided 2.07 g of the 2,5-cyclohexadiene product in a 72% yield. H NMR (CDCl , a mixture of
3
rotamers) δ 6.80-6.67 (m, 3H), 5.64-5.46 (m, 1H), 5.19-5.12 (d, 1H, J=9.56 Hz), 4.98-4.87 (m,
2H), 4.74-4.69 (t, 1H, J=3.92 Hz), 4.36-4.23 (m, 1H), 3.89-3.86 (d, 3H, J= 2.44 Hz), 3.86-3.82
(d, 3H, J=2.28 Hz), 3.65-3.52 (m, 1H), 3.49 (s, 3H), 3.37-3.31 (d, 3H, J=4.00 Hz), 3.32-3.16 (m,
1
3
3
H), 2.60-2.29 (m, 3H), 2.90-2.62 (m, 4H), 1.89-1.57 (m, 5H). C NMR (CDCl , a mixture of
3
rotamers) δ 134.33, 134.30, 126.22, 126.19, 112.2, 110.61, 110.68, 55.4, 44.2, 38.4;δ 171.3,
u
d
164.2, 159.1, 159.07, 142.0, 136.4, 118.1, 118.06, 102.7, 45.7, 42.9, 41.1, 27.7, 18.9.
Cyclohexadiene 6e: Use of the general procedure with benzamide 4e (1.6299 g, 4.44 mmol)
1
provided 1.43 g of the 2,5-cyclohexadiene product in a 78% yield. H NMR (CDCl , a mixture of
3
rotamers) δ 7.14 (t, 1H, J=7.36 Hz), 7.02-6.91 (m, 3H), 5.66-5.46 (m, 1H), 5.15 (s, 1H), 5.00-
4
3
1
.86 (m, 2H), 4.71 (t, 1H, J=3.48 Hz), 4.35-4.21 (m, 1H), 3.61-3.57 (m, 1H), 3.33 (s, 3H), 3.27-
.13 (m, 1H), 2.90-2.62 (m, 4H), 2.56-2.44 (m, 1H), 2.35 (t, 2H, J=3.96 Hz), 2.31 (2, 3H), 1.88-
1
3
.53 (m, 4H), 1.42-1.30 (m, 1H). C NMR (CDCl , a mixture of rotamers) δ 135.1, 129.0, 128.2,
3
u
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8

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1
26.6, 125.2, 121.5, 92.6, 58.8, 58.1, 54.2, 21.4; δ 170.3, 153.0, 141.4, 137.8, 136.7, 116.5,
d
71.97, 52.6, 45.9, 41.3, 37.6, 34.1, 29.9, 26.3, 24.8.
General Procedure for Enol Ether Hydrolysis: Enol ether (1.0 eq.) was dissolved in MeOH
(6 mL/mmol enol ether), cooled to 0°C, and treated with 6 N HCl (2.5 mL/mmol enol ether).
After stirring overnight, the reaction solution was diluted with water and extracted three times
with DCM. The combined organics were washed with brine, dried over Na SO , filtered and
2
4
concentrated under reduced pressure. Column chromatography (1:1 EtOAc in heptanes) afforded
pure ketone.
Ketone 7a: Use of the general procedure with enol ether 5a (0.64 g, 1.68 mmol) provided
2
4
1
0
.5411 g of the ketone product in an 88% yield. [α]D = -16.5 (c=0.4, CH Cl ). H NMR (CDCl ,
2
2
3
a mixture of rotamers) δ 7.33-7.26 (m, 2H), 7.26-7.20 (m, 1H), 7.19-7.23 (m, 2H), 5.90-5.73 (m,
1
3
2
H), 5.49 (s, 1H), 5.09-4.99 (m, 2H), 4.34-4.21 (m, 1H), 3.66-3.59 (m, 1H), 3.42 (s, 2H), 3.39 (s,
H), 3.33 (m, 1H), 3.28-3.12 (m, 1H), 3.07-2.96 (m, 1H), 2.73-2.65 (d, 2H, J=7.36 Hz), 2.60-
1
3
.29 (m, 4H), 1.96-1.76 (m, 3H), 1.76-1.61 (m, 1H). C NMR (CDCl , a mixture of rotamers)
3
δ 134.3, 134.2, 128.73, 128.70, 128.55, 126.6, 124.9, 124.4, 59.0, 57.9; δ 208.2, 207.7, 169.0,
u
d
1
68.5, 139.3, 138.6, 118.2, 72.1, 71.9, 61.2, 46.7, 46.4, 43.7, 41.9, 41.6, 37.0, 36.9, 28.4, 28.2,
6.8, 26.7, 24.6. HRMS (CI) (m/z): [M+1]+ calcd for C H NO : 368.2226, found: 368.2235.
2
2
3
30
3
Ketone 7b: Use of the general procedure with enol ether 5b (0.497 g, 1.21 mmol) provided
2
4
1
0
.362 g of the ketone product in a 75% yield. [α]D = -14.8 (c=0.73, CH Cl ). H NMR (CDCl ,
2
2
3
a mixture of rotamers) δ 7.25-7.17 (t, 1H, J=7.80 Hz), 6.81-6.67 (m, 3H), 5.89-5.74 (m, 1H),
.48 (s, 1H), 5.10-4.98 (m, 2H), 4.34-4.21 (m, 1H), 3.78 (m, 2H), 3.67-3.58 (m, 1H), 3.43-3.29
m, 6H), 3.30-3.18 (m, 1H), 3.10-2.96 (m, 1H), 2.72-2.64 (d, 2H, J=7.32 Hz), 2.62-2.26 (m, 4H),
5
(
2
9