Ni-Catalyzed Regioselective Dicarbofunctionalization of Unactivated Olefins by Tandem Cyclization/Cross-Coupling and Application to the Concise Synthesis of Lignan Natural Products

Article abstract of DOI:10.1021/acs.joc.8b00184

We disclose a (terpy)NiBr₂-catalyzed reaction protocol that regioselectively difunctionalizes unactivated olefins with tethered alkyl halides and arylzinc reagents. The reaction shows an excellent functional group tolerance (such as ketones, es

Full text of DOI:10.1021/acs.joc.8b00184

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Article
Ni-Catalyzed Regioselective Dicarbofunctionalization of
Unactivated Olefins by Tandem Cyclization/Cross-Coupling and
Application to the Concise Synthesis of Lignan Natural Products
Shekhar KC, Prakash Basnet, Surendra Thapa, Bijay Shrestha, and Ramesh Giri
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00184 • Publication Date (Web): 15 Feb 2018
Downloaded from http://pubs.acs.org on February 16, 2018
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The Journal of Organic Chemistry
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Ni-Catalyzed Regioselective Dicarbofunctionalization of Unactivated
Olefins by Tandem Cyclization/Cross-Coupling and Application to the
Concise Synthesis of Lignan Natural Products
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Shekhar KC, Prakash Basnet, Surendra Thapa, Bijay Shrestha, and Ramesh Giri*
Department of Chemistry & Chemical Biology, The University of New Mexico, Albuquerque, NM 87131, USA.
ABSTRACT: We disclose a (terpy)NiBr2-catalyzed reaction protocol that regioselectively difunctionalizes unactivated olefins with
tethered alkyl halides and arylzinc reagents. The reaction shows excellent functional group tolerance (such as ketones, esters, nitriles
and halides) and moderate to good level of diastereoselectivity. The current cyclization/cross-coupling also tolerates molecules con-
taining base-sensitive racemizable stereocenters, which are preserved without racemization during reaction. This cyclization/cross-
coupling provides rapid access to (arylmethyl)carbo- and heterocyclic scaffolds, which occur widely as structural cores in various
natural products and bioactive molecules. In order to show synthetic utility and generality, we have applied this new method in gram-
scale quantities to the concise synthesis of six lignan natural products containing three different structural frameworks. We further
conducted mechanistic investigations with radical probes and selectivity studies, which indicated that the current reaction proceeds
via a single electron transfer (SET) process.
INTRODUCTION
Transition metal (TM)-catalyzed dicarbofunctionalization of
unactivated olefins via cross-coupling could afford a straight-
forward synthetic route to complex molecular structures, natu-
ral products and pharmaceuticals. Especially, the functionaliza-
tion of olefins with tethered organohalides and organometallic
reagents via a cyclization/cross-coupling process could furnish
complex (carbomethyl)carbo- and heterocyclic scaffolds, such
as benzylbutyrolactone, benzylbutyrolactol and benzylfuran,
rapidly from simple and readily available chemical feedstock in
one synthetic step. Such cyclic frameworks are profusely im-
bedded as structural cores in a variety of natural products and
biologically active molecules such as lignans (Scheme 1).1 Mol-
ecules containing these structural scaffolds generally display a
wide range of biological activities including antiviral, antitumor
and anti-HIV.1
Scheme 2. Pathways for olefin dicarbofunctionalization and
major side reactions
Scheme 3. Literature precedents and the current work
Despite tremendous synthetic potentials, the regioselective di-
carbofunctionalization of unactivated olefins2 via cross-cou-
pling (Scheme 2, Path A) remains a formidable challenge due
to the need to overcome two well-established transformations
Scheme 1. Lignan natural products and bioactive molecules
containing (arylmethyl)heterocyclic cores
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that act as side reactions – a) direct cross-coupling of organo- or Ni(PPh3)4 (entry 11). While the reaction did not proceed in
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halides with organometallic reagents prior to olefin insertion
(Scheme 2, Path B), and b) Heck reaction after -hydride (-H)
elimination from a C(sp3)-[M] intermediate generated in situ af-
ter olefin insertion (Scheme 2, Path C).3 Therefore, the early
examples of olefin 1,2-dicarbofunctionalization reactions4 with
organohalides and organometallic reagents generally required
substrates without -H’s5 or utilized conjugated dienes/styrenes
to stabilize C(sp3)-[M] intermediates as -allyl-[M]/-benzyl-
[M] complexes.6
CH2Cl2 and toluene, the product 13 was generated in moderate
yields in THF, dioxane, DMF or DMSO (entries 12-14).
Table 1. Optimization of reaction conditionsa
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While no general solution has emerged yet,7 a limited number
of reactions have demonstrated that the use of base metal cata-
lysts enables the cyclization/cross-coupling, a reaction that pro-
ceeds by a radical process8 thus expediting olefin insertion and
avoiding complications by -H elimination.9 In this respect,
Oshima et al. disclosed in 2001 a (dppe)CoCl2-catalyzed radical
cyclization/cross-coupling of olefin-tethered alkyl halides with
aryl Grignard reagents (Scheme 3).10 In 2007, a similar catalytic
system was developed by Cárdenas et al.11 with pybox/NiCl2
combination for cyclization/cross-coupling of olefin-tethered
alkyl iodides with excess alkylzinc reagents.12 While these
early examples represent some progress in this area, the scope
and synthetic utility of the cyclization/cross-coupling reactions
is still limited especially for their application to the synthesis of
natural products.
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RESULTS AND DISCUSSION
Recently, we reported a Cu-catalyzed cyclization/cross-cou-
pling of alkylzinc reagents derived from olefin-tethered alkyl
halides with aryl iodides that furnished (arylmethyl)heterocy-
clic cores.13 While the functional group tolerance remained ex-
cellent, the reaction was limited to the use of electron-deficient
and heteroaryl iodides owing to low reactivity of Cu-catalysts
with electron-rich aryl halides. This limitation precluded the ap-
plication of cyclization/cross-coupling to the synthesis of natu-
ral products, such as lignans (Scheme 1), that contain benzyl-
butyrolactone frameworks with electron-rich polyphenol deriv-
atives. In order to expand the scope of cyclization/cross-cou-
pling to the synthesis of natural products and bioactive mole-
cules, we envisioned to utilize a combination of terpydine
(terpy) and NiX2 that is known to generate (terpy)NiR catalyst
in the presence of RZnX and efficiently produce alkyl radicals
from alkyl halides during Negishi coupling.14
aYields were determined by 1H NMR using pyrene as an internal
standard. Value in parenthesis is the isolated yield from a 0.5 mmol
scale reaction.
In our efforts to examine the efficacy of (terpy)NiX2 as a cata-
lyst, we conducted the reaction of olefin-tethered alkyl bromide
12-Br with (4-cyanophenyl)zinc iodide. We were pleased to
find that reaction proceeded with 3 mol% NiBr2 and 4 mol%
terpy in NMP at 50 °C affording the cyclization/cross-coupling
product 13 in 87% yield (Table 1, entry 1).15 We further exam-
ined tBu, Me and MeO-substituted terpy derivatives 2-4, of
which only the tBu-substituted terpy 2 furnished the expected
product in comparable yield (entries 2-3). A similar tridentate
ligand, pybox 5, afforded the product only in 12% yield (entry
4). Nitrogen- and phosphorus-based bidentate ligands such as
phen 6, bipy 7, bis-amines 8-9, dppbz 10 and xantphos 11 also
furnished the product in low to moderate yields (entries 5-6).
The current reaction is strongly ligand-controlled as only a trace
amount of the product 13 was formed in the absence of terpy
(entry 7). The reaction also did not proceed in the absence of
NiBr2 (entry 8). The product 13 was formed in lower yields in
shorter reaction time and at room temperature (entries 9-10),
and in moderate yields when NiBr2 was replaced with Ni(cod)2
Scope of the Cyclization/Cross-Coupling. With the optimized
conditions in hand, we studied the scope of the current cycliza-
tion/cross-coupling reaction with respect to both the olefin-teth-
ered alkyl halides and arylzinc reagents (Table 2). A variety of
olefin-tethered alkyl halides can be cyclized to furnish carbocy-
cles (14-17), and N- (18-20) and O-heterocycles (21-25) in good
yields.16,17 The reaction proceeds well with both electron-rich
and deficient arylzinc reagents, which affords products in good
to excellent yields. Synthetically important functional groups
such as nitriles (17 and 23), esters (18), ketones (24) and halides
(Br, Cl, F) (20, 21 and 25) are also tolerated on arylzinc rea-
gents.
We further examined the scope of the reaction with respect to
olefin-tethered alkyl halides containing pre-existing stereocen-
ters in order to determine diastereoselectivity of the reaction
(Table 3). Olefin-tethered alkyl iodides such as trans-2-(al-
lyloxy)-3-iodotetrahydrofuran, trans-1-(allyloxy)-2-iodocyclo-
hexane, trans-2-(allyloxy)-3-iodotetrahydro-2H-pyran, and 1-
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(1-(allyloxy)-2-iodoethoxy)butane could be cyclized and cross-
coupled with arylzinc reagents bearing electron-donating
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groups (Me, OMe) (26-31), electron-withdrawing and highly
sensitive groups (CF3, CN, COMe, Br, Cl) (33-38 and 42-45),
and ortho-substituents (27, 28, 31) to furnish bicyclic heterocy-
cles in good to excellent yields. The reaction also tolerates ke-
tones and esters in olefin-tethered alkyl halides, which could be
coupled after cyclization with arylzinc reagents containing
other sensitive functional groups such as nitrile (45). This ex-
ample demonstrates the tolerance of multiple, highly sensitive
and synthetically important functional groups, such as CN,
COMe and CO2Me, together in one molecule. These products
were formed in moderate to good levels of diastereoselectivity
with the major diastereoisomers containing three contiguous
stereocenters in all-cis configuration. Olefin-tethered alkyl io-
dides could also be cyclized and cross-coupled with heteroaryl-
zinc reagents, such as (2-chloropyridin-4-yl)zinc iodide, thio-
phen-2-ylzinc iodide and di(furan-2-yl)zinc (38-41), which af-
forded the products in good to excellent yields with moderate
to good degrees of diastereoselectivities.
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Table 2. Cyclization/cross-coupling of olefin-tethered alkyl
halidesa
aValues are isolated yields from 0.5 mmol scale reactions. dr was
determined by H NMR and GC. 1 equiv di(furan-2-yl)zinc was
used. 10 h.
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our standard reaction of olefin-tethered alkyl bromide 12-Br
with (4-cyanophenyl)zinc iodide (Table 4). After the reaction
was complete, the additives were isolated by column chroma-
tography. Determination of enantiomeric ratios (er’s) of the iso-
lated compounds 46 and 47 by chiral high performance liquid
chromatography (HPLC) indicated that their er’s remained un-
changed compared to their er’s prior to addition to the reaction.
These results confirmed that our cyclization/cross-coupling re-
action condition tolerates base sensitive and racemizable stere-
ocenters. These results also clearly demonstrate the importance
of our current reaction for the construction or manipulation of
synthetically challenging molecules containing base sensitive,
enantioenriched chiral centers.
aValues are isolated yields from 0.5 mmol scale reactions.
bRoom temperature, 12 h. cValue in parenthesis is the yield when 1
equiv Ph2Zn was used instead of PhZnI. d8 h.
We further examined the tolerance of molecules containing rac-
emizable stereocenters under our reaction conditions. In this
process, we utilized two commercially available, enantiomeri-
cally enriched compounds containing one chiral center – N-
Boc-D-proline methyl ester (46, R-enantiomer) and (R)-dime-
thylmethylsuccinate (47) – as stoichiometric additives in
Table 3. Diastereoselective cyclization/cross-couplinga
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3,4-dimethoxybenzyl bromide to afford (±)-kusunokinin (51)
and (±)-dimethylmatairecinol (52), respectively, in high yields
and diastereoselectivities (Scheme 4).
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Table 4. Tolerance of base-sensitive and racemizable stereo-
centersa
We also constructed the intermediate lactone 53 in a gram-scale
quantity (11 mmol, 60% yield, 1.453 g), which was subse-
quently converted to (±)-bursehernin (54) and (±)-yatein (55) in
high yields and diastereoselectivities after benzylation with 3,4-
dimethoxybenzyl bromide and 3,4,5-trimethoxybenzyl bro-
mide, respectively (Scheme 5).
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We also utilized the current cyclization/cross-coupling method
to synthesize (±)-collinusin in two-pot three steps from readily
available starting materials via carbonylbutyrolactone 57
(Scheme 6). The latest known synthesis of a similar lignan nat-
ural product required seven linear synthetic sequence to con-
struct the dihydronaphthofuranone core.26 In our synthesis, we
utilized the highly functionalized (2-aryoylaryl)zinc iodide 56
as the coupling partner to construct the carbonylbutyrolactone
core 57 in one-pot two steps in 70% yield (2.5 mmol scale,
0.672 g). The corresponding aryl iodide for the arylzinc 56 is
readily prepared in one step by the Friedel-Crafts reaction of
1,3-benzodioxole with the commercially available 6-iodovera-
tric acid (See SI for details). The carbonylbutyrolactone 57 was
then treated with lithium diisopropylamide (LDA) followed by
SOCl2 to furnish (±)-collinusin (58) in 65% yield. We note that
the concise synthesis of (±)-collinusin (58) by this new method
became feasible due to the ability to readily access the arylzinc
reagent 56 containing a carbonyl group.
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aReactions were run in 0.4 mmol scale in 2.0 mL NMP with 1.0
equiv of chiral additives. The additives were isolated by column
chromatography and their er’s were determined by chiral HPLC.
Application to the Synthesis of Natural Products. We also
applied the current method to the concise synthesis of six lignan
natural products – (±)-dimethylretrodendrin, (±)-kusunokinin,
(±)-dimethylmatairesinol, (±)-bursehernin, (±)-yatein and (±)-
collinusin – with three different structural frameworks that con-
tain benzylbutyrolactone backbones (Scheme 4-6). These types
of lignan natural products containing dibenzylbutyrolactone
and aryltetralin scaffolds display a wide range of biological
properties such as antibiotic, fungicidal, antiviral, antitumor and
anti-HIV.18 Both (±)-dimethylretrodendrin and (±)-collinusin
belong to the class of aryltetralin lignans, which show antitumor
activities by functioning as potent inhibitors of human DNA
topoisomerase II.19 Collinusin was isolated from the leaves of
Cleistanthus collinus (Roxb.) that has insecticidal and piscicidal
activities.20 Kusunokinin shows antitrypanosomal and insecti-
cidal activities.21 Bursehernin shows potent cytotoxic activities
in colon, prostate and breast cancer cell lines among others.22
Recent studies have shown that yatein exhibits antiproliferative
activity23 and suppresses herpes simplex virus type 1 replication
in HeLa cells.24
Mechanistic Studies. We have further conducted mechanistic
investigations of the current reaction, and proposed a catalytic
cycle (Scheme 7) based on our results and prior reports on the
Ni/terpy-catalyzed Negishi cross-coupling of alkyl halides with
organozinc reagents.27 Negishi cross-coupling catalyzed by a
combination of NiX2 and terpyridine has been shown by both
experiments and density functional theory (DFT) calculations
to proceed with the generation of a (terpy)NiX catalyst (59) that
undergoes transmetalation with organozinc reagents to form a
(terpy)NiR species.14 The alkyl halides are then reduced by a
single electron transfer (SET) from (terpy)NiR species followed
by recombination of the resultant alkyl radicals with
(terpy)Ni(X)(R) and reductive elimination to generate desired
products. Under our reaction conditions where olefin-tethered
alkyl halides are used, the alkyl radicals generated by electron
transfer from a (terpy)NiAr species (60) would undergo cycliza-
tion onto the tethered olefin to generate a cyclized primary alkyl
radical prior to recombination with the (terpy)Ni(X)(Ar) spe-
cies (62) to generate (terpy)Ni(R)(Ar) species (63). Reductive
elimination from this species 63 then furnishes the desired prod-
uct with the regeneration of the active (terpy)NiX catalyst (59).
Prior synthesis of these lignan natural products generally re-
quired a multi-step process to construct the benzylbutyrolactone
skeleton.25 Our new method allowed us to synthesize the ben-
zylbutyrolactone structure in one-pot two steps in gram-scale
quantities. For example, the intermediate lactone 49 was con-
structed from the cyclization/cross-coupling of 1-(1-(allyloxy)-
2-iodoethoxy)butane (48) with (3,4-dimethoxyphenyl)zinc io-
dide followed by oxidation of the crude product with the Jones
reagent (Scheme 4). The reaction was conducted in 10 mmol
scale, which afforded the lactone 49 in 62% isolated yield
(1.464 g). The lactone 49 could then be treated with 3,4-di-
methoxybenzaldehyde after deprotonation with lithium diiso-
proylamide (LDA) at -78 °C followed by Friedel-Crafts alkyla-
tion in presence of trifluoroacetic acid to furnish (±)-dimethyl-
retrodendrin (50) as a 19:1 diastereomeric mixture in 73% iso-
lated yield (Scheme 4). The intermediate lactone 49 could also
be benzylated with (3,4-methylenedioxy)benzyl bromide and
In order to determine the mechanistic similarity of our reaction
with the Ni/terpy-catalyzed direct cross-coupling of alkyl hal-
ides with organozinc reagents, we conducted selectivity studies
by reacting separately n-octyl iodide and the olefin-tethered pri-
mary alkyl iodide 12-I with the excess of two electronically bi-
ased arylzinc reagents (Schemes 8 and 9). The premise of the
experiment is that two separate reactions proceeding via analo-
gous reaction intermediates under otherwise identical reaction
conditions would generate similar ratios of products in comp-
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Scheme 4. Concise synthesis of (±)-dimethylretrodendrin, (±)-kusunokinin and (±)-dimethylmatairesinol
Scheme 5. Concise synthesis of (±)-bursehernin and (±)-yatein
Scheme 6. Concise synthesis of (±)-collinusin
Scheme 7. Proposed catalytic cycle
etition experiments. In one experiment, we allowed n-octyl io-
dide to freely compete for reaction with the
(trifluoromethyl)phenyl)zinc iodide and
phenyl)zinc iodide under our standard reaction condition
(Scheme 8). This reaction, which is known to proceed via the
generation of primary alkyl radical/Ni(II) and primary alkyl-
Ni(III) species (66 and 67),14 furnished 4-n-octylbenzotrifluo-
ride (64) and 4-n-octylanisole (65) in an 18:10 ratio (combined
yield, 54%). In another experiment, a similar olefin-tethered
primary alkyl iodide 12-I was allowed to freely compete for re-
action with the excess of (4-(trifluoromethyl)phenyl)zinc iodide
and (4-methoxyphenyl)zinc iodide under our standard reaction
condition (Scheme 9). This reaction also furnished the corre-
sponding benzotrifloride and anisole products 68 and 16 in
excess of (4-
(4-methoxy-
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17:10 (combined yield, 65%), a ratio that is similar to the one product 72 in 63% and 74% yields, respectively, with the same
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observed for the competition reaction of n-octyl iodide. The re-
sults of these competition experiments indicate that the
terpy/NiBr2-catalyzed direct cross-coupling of alkyl halides
with arylzinc reagents and the cyclization/cross-coupling of
olefin-tethered alkyl halides with arylzinc reagents proceed via
similar reaction intermediates 66-67 and 69-70 as indicated in
Schemes 8 and 9.
degree of diastereoselectivity (1.3:1). These results indicate that
the reactions of both cis- and trans-isomers proceed via the for-
mation of the same radical intermediate 73 with the loss of ste-
reochemistry at the C-Br chiral center.
In order to further confirm the formation of alkyl radical inter-
mediates, we also performed an experiment with a racemic, chi-
ral olefin-tethered alkyl bromide 74 under our reaction condi-
tion and compared its diastereoselectivity with that of the reac-
tion involving the same alkyl bromide 74 under a condition that
is known to generate alkyl radicals as intermediates (Scheme
11). Herein, we reacted the racemic, chiral alkyl bromide 74
with Bu3SnH in the presence of 10 mol % 2,2′-Azobis(2-
methylpropionitrile) (AIBN) as a radical initiator28 under UV
light (300 nm). This reaction, which is known to proceed with
the formation of uncyclized and cyclized alkyl radicals 77 and
78,28 furnished the trans-isomer of the cyclization/H-atom ab-
straction product 75 as a single diastereomer in 70% yield. In a
separate experiment, the racemic, chiral alkyl bromide 74 was
subjected to our standard cyclization/cross-coupling reaction
condition using PhZnI as a coupling partner. This latter reaction
also furnished the trans-isomer of the cyclization/cross-cou-
pling product 76 as a single diastereomer in 58% yield. The re-
sults of these experiments indicate that the current cycliza-
tion/cross-coupling proceeds via the same diastereoselectivity-
determining cyclization step as the known AIBN-catalyzed rad-
ical cyclization reaction via the formation of the same alkyl rad-
ical intermediates 77 and 78 prior to the formation of the cy-
clization/cross-coupling product 76.
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Scheme 8. Selectivity in Negishi cross-coupling of primary al-
kyl iodide with electronically biased arylzinc reagents
Scheme 10. Diastereoselectivity studies with cis- and trans-1-
(allyloxy)-2-bromocyclohexane (71)
Scheme 9. Selectivity in cyclization/cross-coupling with elec-
tronically biased arylzinc reagents
Next, we conducted experiments to determine if the reaction in-
volved alkyl radical intermediates. Our first experiment in-
volved the determination of stereochemical outcomes of a reac-
tion involving the cis- and trans-isomers of 1-(allyloxy)-2-bro-
mocyclohexane (71) (Scheme 10). In this process, we reacted
cis- and trans-1-(allyloxy)-2-bromocyclohexane (71) sepa-
rately with PhZnI under the standard reaction condition. Both
cis- and trans-isomers generated the cyclization/cross-coupling
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NMR, and 19F NMR at 7.26, 77.16 ppm, −164.9 ppm respec-
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tively. The chemical shifts of NMR and the coupling constants
(J) for 1H, 13C, and 19F NMR are reported in δ parts per millions
(ppm) and in Hertz, respectively. The following conventions are
used for multiplicities: s, singlet; d, doublet; t, triplet; q, quartet;
m, multiplet; dd, doublet of doublet; br, broad. High resolution
mass spectra for new compounds were recorded at the Mass
Spectrometry, Department of Chemistry and Chemical Biology,
University of New Mexico (UNM), University of Texas Austin
and University of California, Riverside. All NMR spectra were
collected at Department of Chemistry and Chemical Biology,
University of New Mexico (UNM). The HPLC used was Wa-
ters e2695 separations module and Waters 2489 UV/Vis detec-
tor. Infrared (IR) spectra were recorded on Bruker Alpha-P
ATR-IR at UNM and νmax is reported in cm-1. The starting ma-
terials diethyl-2-allyl-2-(2-bromoethyl)malonate29(12-Br), 3-
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(2-iodoethoxy)prop-1-ene10c
methylbenzenesulfonamide30,
,
N-allyl-N-(2-bromoethyl)-4-
N-allyl-N-(2-bromoethyl)ani-
line31, trans-2-(allyloxy)-3-iodotetrahydrofuran and trans-2-
(allyloxy)-3-iodotetrahydro-pyran8g,32, trans-1-(allyloxy)-2-io-
docyclohexane33, (1-(allyloxy)-2-iodoethyl)benzene34, 1-(1-(al-
lyloxy)-2-iodoeth-oxy)butane8g, 1-(allyloxy)-1-ethoxy-2-iodo-
butane8g, 3-(2-bromoethoxy)oct-1-ene8c, trans-1-(Allyloxy)-2-
bromocyclohexane33, cis-1-(allyloxy)-2-bromocyclohexane35
and 3-(2-bromoethoxy)oct-1-ene8c were prepared according to
the given literature procedure.
Scheme 11. Diastereoselectivity in the known radical cycliza-
tion and the current cyclization/cross-coupling reactions
21
22
23
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27
28
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30
31
32
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45
46
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50
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53
54
55
56
57
58
59
60
CONCLUSION
General procedure for the preparation of arylzinc reagent
In summary, we have developed an efficient (terpy)NiBr2 cata-
lytic system for cyclization/cross-coupling of olefin-tethered al-
kyl halides with arylzinc reagents. The reaction tolerates a wide
range of synthetically important functional groups and base-
sensitive racemizable stereocenters. This method affords (aryl-
methyl)carbo- and heterocyclic structures that widely occur as
structural motifs in a wide range of lignan natural products and
bioactive molecules. The use of this method for the concise syn-
thesis of six lignan natural products with three different struc-
tural frameworks in gram-scale quantities clearly demonstrates
the practical application of the olefin dicarbofunctionalization
reaction to the construction of complex natural products, bioac-
tive molecules and pharmaceuticals in short synthetic routes via
unprecedented retrosynthetic disconnections. In addition, we
have also conducted mechanistic studies with radical probes
and competition experiments, which indicate that the current
cyclization/cross-coupling reaction proceeds via a SET process.
Procedure A.36 To a Schlenk flask in a glovebox, anhydrous
LiCl (210 mg, 5 mmol) and zinc powder (492 mg, 7.5 mmol)
was added and the mixture was dried under high vacuum at 150
°C to 170 °C for 2 h outside the glovebox. After 2 h, it was
cooled down to room temperature and the reaction flask was
flushed with nitrogen. Then it was again taken to a glovebox
and anhydrous THF (5mL) was added with stirring the solution
at room temperature. Later, zinc was activated with the addition
of 5 mol% of BrCH2CH2Br and 3 mol% of TMSCl to the
zinc/THF suspension and the mixture was stirred for 5 minutes
at room temperature. To this stirred solution was added corre-
sponding aryl iodides (5 mmol) (neat) dropwise (liquid) or por-
tion-wise (solid) and the reaction mixture was either heated at
50 °C for heteroaryl iodides for 6 h or refluxed for electron-
deficient and electron rich aryl iodides for 12-96 h. The final
concentration of the arylzinc reagent was determined by titra-
tion with molecular iodine in THF.37
EXPERIMENTAL SECTION
Procedure B.38 Under nitrogen atmosphere, naphthalene (563.9
mg, 4.4 mmol) was dissolved in anhydrous THF (4 ml) in 15
mL pressure vessel, potassium (156.4 mg, 4 mmol) was added
to the solution and stirred overnight at room temperature. The
solution turned dark green immediately indicating the genera-
tion of potassium naphthalenide. Anhydrous ZnCl2 (272.6 mg,
2.0 mmol) was then suspended in dry THF (4 mL) in a separate
vial, which was then added dropwise to the potassium naph-
talenide solution. The resultant solution was then stirred for 12
h at room temperature. Aryl iodide (1.0 mmol, neat) was added
to the stirred solution and stirred again overnight at room tem-
perature. Thus formed organozinc was filtered through Celite
upon completion of the reaction (monitored by GC for the re-
maining starting aryl iodides as well as the protonation product
by quenching the organozinc reagents with acetic acid). The fi-
nal concentration was determined by titration with molecular
iodine in THF.37
General Information. All the reactions were set up inside a
nitrogen-filled glovebox and all the chemicals were handled un-
der nitrogen atmosphere unless stated otherwise. All the glass-
ware including the 4-dram and 1-dram borosilicate (Kimble-
Chase) vials, and pressure vessels were properly dried in an
oven before use. Bulk solvents were obtained from EMD and
anhydrous solvents (DMF, DMA, DMSO, NMP, dioxane, tolu-
ene) were obtained from Sigma-Aldrich, and were used directly
without further purification. Deuterated solvents were pur-
chased from Sigma-Aldrich. NiBr2 was purchased from Alfa-
Aesar. Aryl halides were purchased from Acros, Sigma-Al-
drich, Oakwood, TCI-America, Matrix and Alfa-Aesar. ZnCl2
(99.95%) was obtained from Alfa-Aesar was used as received.
1H, 13C, and 19F NMR spectra were recorded on a Bruker instru-
ment (300, 75, and 282 MHz respectively) and internally refer-
1
enced to the residual solvent signals of CDCl3 for H and 13C
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Procedure C.39 Under nitrogen atmosphere, LiCl (63 mg, 0.3
Characterization data for new compounds
Page 8 of 20
1
2
3
4
5
6
7
8
mmol), InCl3 (30mg, 0.03 mmol) and Zn powder (983 mg, 15
mmol) were weigh out in a dry schlenk-tube equipped with a
stir bar. The mixture was heated at 170°C under high vaccum
for 3 h. After cooling down to room temperature, the tube was
flushed with nitrogen and freshly distilled THF (5mL) and
DMPU (5ml) was added and stirred at room temperature. Later
TMSCl (3 mol%) and aryl iodide (5 mmol) was added to the
suspension. The mixture was further stirred at room tempera-
ture for 1 h. The completion of reaction was monitored by GC-
analysis of acetic acid-quenched aliquots. The excess zinc dust
was allowed to settle down and filtered through celite pad. Fi-
nally, the concentration of resulting organozinc was determined
by titration with molecular iodine in THF.37
Ethyl 2-acetyl-2-(2-bromoethyl)pent-4-enoate. The title com-
pound was prepared according to the modified procedure de-
scribed in the given literature40. To a dry flask, NaH (864 mg,
36 mmol) was weigh out and dry THF (30 mL) was added. The
flask was stirred and cooled to 0 °C. To the stirring suspension,
ethyl acetoacetate (30 mmol) was added dropwise for 5
minutes. The resulting mixture was stirred at room temperature
for an hour. Later, the reaction mixture was again cooled down
to 0 °C and allylbromide (2.83 mL, 33 mmol) was added drop-
wise in the mixture. After the complete addition of allylbro-
mide, the reaction mixture was stirred at room temperature for
12 h. It was diluted with EtOAc (30 mL) and washed with H2O
(15 mL). The ethyl acetate fraction was dried over Na2SO4 and
the solvent was removed in a rotary evaporator. The product
was purified by silica gel column chromatography using ethyl
acetate/hexane as eluent and colorless oil of ethyl 2-acetyl-2-(2-
bromoethyl)pent-4-enoate was obtained in 90% yield.
9
10
11
12
13
14
15
16
17
18
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20
21
22
23
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General procedure for screening reaction conditions
In a glovebox, THF solution of (4-cyanophenyl)zinc iodide
(0.150 mmol) was taken in a 1-dram vial and the solvent was
removed under vacuum. To the ArZnI residue was added NiBr2
(0.65 mg, 0.003 mmol), terpyridine (0.9 mg, 0.004 mmol), and
diethyl-2-allyl-2-(2-bromoethyl)malonate (30.6 mg, 0.10
mmol). The mixture was then dissolved in 0.5 mL of NMP. The
vial was tightly capped and removed from the glovebox. It was
placed in a hotplate preheated to 50 °C with vigorous stirring.
After 6 h, the reaction mixture was cooled to room temperature
and 50 µL of pyrene (0.010 mmol, 0.2 M stock solution) as an
internal standard was added, diluted with EtOAc (2 mL) and
filtered through a short pad of silica gel in a pipette. The filtrate
was then analyzed by GC, GC-MS and 1H NMR.
To a dry flask, NaH (720 mg, 30 mmol) was weigh out and dry
DMF (20 mL) was added. The flask was stirred and cooled to
0 °C. To the stirring suspension, ethyl 2-acetylpent-4-enoate (20
mmol) was added dropwise for 5 minutes. The resulting
mixture was stirred at room temperature for an hour. Later, the
reaction mixture was again cooled down to 0 °C and
dibromoethane ( 3.5 ml, 40 mmol) was added dropwise in the
mixture. After the complete addition of dibromoethane, the
reaction mixture was stirred at room temperature for 12 h. It
was then diluted with EtOAc (20 mL) and washed with H2O (10
mL). The ethyl acetate fraction was dried over Na2SO4 and the
solvent was removed in a rotary evaporator. The title compound
was obtained as a colorless oil (3.03 ml, 55% yield) after
purification by silica gel column chromatography (Hex : Et2O
= 8:1). 1H NMR (300 MHz, CDCl3):  1.28 (t, J = 7.5 Hz, 3H),
2.16 (s, 3H), 2.30-2.40 (m, 1H), 2.45-2.56 (m, 1H), 2.64 (d, J =
9.0 Hz, 2H), 3.20-3.34 (m, 2H), 4.23 (q, J = 7.0 Hz, 2H), 5.07-
5.17 (m, 2H), 5.51-5.64 (m, 1H); 13C NMR (75 MHz, CDCl3):
 14.1, 26.9 27.0, 35.3, 36.6, 61.9, 63.4, 119.8, 131.6, 171.0,
203.4.
General procedure for large scale reaction
In a glovebox, arylzinc stock solution in THF (0.750 mmol) was
taken in a 15mL sealed tube and the solvent was removed under
vacuum. To the residue of ArZnI was added NiBr2 (3.3 mg,
0.015 mmol), terpyridine (4.7 mg, 0.020 mmol), and olefin-
tethered alkyl halides (0.5 mmol). The mixture was then dis-
solved in NMP (2.5 mL). The sealed tube was tightly capped
and removed from the glovebox. It was then placed in an oil-
bath preheated to 50 °C with vigorous stirring. After 6 h, the
reaction mixture was cooled to room temperature, diluted with
EtOAc (10 mL) and washed with H2O (5 mL × 3). The aqueous
fraction was extracted back with ethyl acetate (5 mL × 3) and
combined with the first ethyl acetate fraction. The combined
ethyl acetate fraction was dried over Na2SO4 and the solvent
was removed in a rotary evaporator. The product was purified
by silica gel column chromatography using ethyl acetate/hex-
ane as eluent.
Diethyl
3-(4-cyanobenzyl)cyclopentane-1,1-dicarboxylate
(13):13a This reaction was performed by using organozinc pre-
pared according to procedure A in our standard condition. The
title compound 13 was obtained as a yellow oil (133.2 mg, 81%
yield) after purification by silica gel column chromatography
(Hex: EtOAc = 19:1). 1H NMR (300 MHz, CDCl3):  1.22 (q,
J = 7.9 Hz, 6H), 1.31-1.41 (m, 1H), 1.76-1.84 (m, 2H), 2.11-
2.39 (m, 4H), 2.64-2.76 (m, 2H), 4.11-4.21 (m, 4H), 7.25 (d, J
= 9.0 Hz, 2H), 7.55 (d, J = 9.0 Hz, 2H); 13C NMR (75 MHz,
CDCl3):  14.1, 32.0, 33.7, 40.2, 41.2, 41.4, 59.9, 61.5, 109.9,
119.1, 129.5, 132.2, 146.9, 172.5, 172.6; IR (neat): 2980, 2937,
2227, 1723, 1607,1249, 1156, 1024; HRMS (ESI-TOF) m/z:
(M+H)+ Calcd for C19H24NO4 330.1705; found 330.1694.
Determination of diastereoselectivity and identification of
major diastereoisomers. The diastereoselectivity was deter-
1
mined based on crude H NMR and crude GC trace. The cor-
responding GC traces are provided in the respective places. The
dr’s in the reported 1H NMR spectra of analytically pure com-
pounds do not reflect the actual dr’s of the reaction. The dia-
stereomer either contained the other diastereomer in analyti-
cally pure samples, or a small fraction of the separated minor
diastereomer was contaminated with some other impurities,
which are not included in the reported yields. Therefore, the re-
ported 1H NMR show different dr’s than those that are actually
formed in the reaction. The structures of major diastereomers
Diethyl 3-benzylcyclopentane-1,1-dicarboxylate (14):41 This
reaction was performed by using organozinc prepared accord-
ing to procedure A in our standard condition. The title com-
pound 14 was obtained as a colorless oil (127.6 mg, 84% yield)
after purification by silica gel column chromatography (Hex:
EtOAc = 19:1). 1H NMR (300 MHz, CDCl3):  1.23 (q, J = 7.9
Hz, 6H), 1.34-1.44 (m, 1H), 1.80-1.87 (m, 2H), 2.04-2.44 (m,
4H), 2.58-2.72 (m, 2H), 4.12-4.22 (m, 4H), 7.14-7.29 (m, 5H);
13C NMR (75 MHz, CDCl3):  14.1, 32.0, 33.8, 40.4, 41.3,
1
were determined by comparing H NMR spectra and the cou-
pling constants with the same or similar compounds in the liter-
ature.8g,10a,11,13a
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The Journal of Organic Chemistry
1
41.6, 60.0, 61.3, 61.4, 125.9, 128.3, 128.8, 141.3, 172.7, 172.8;
by silica gel column chromatography (Hex: EtOAc = 9:1). H
NMR (300 MHz, CDCl3):  1.40-1.55 (m, 1H), 1.82-1.92 (m,
1H), 2.32 (app. septet, J = 7.5 Hz, 1H), 2.25-2.40 (m, 1H), 2.44
(s, 3H), 2.54 (d, J = 9 Hz, 2H), 2.92 (t, J = 9 Hz, 1H), 3.19 (q, J
= 7.9 Hz 1H), 3.31-3.42 (m, 2H), 7.05 (d, J = 6 Hz, 2H), ), 7.16-
7.33 (m, 5H), 7.69 (d, J = 9 Hz, 2H) ; 13C NMR (75 MHz,
CDCl3):  21.6, 31.1, 39.1, 40.4, 47.4, 52.8, 126.3, 127.5,
128.5, 128.6, 129.7, 133.9, 139.8, 143.4; IR (neat): 2949, 1733,
1339, 1157, 1027, 1014; HRMS (ESI-TOF) m/z: (M+H)+
Calcd for C18H22NO2S 316.1371; found 316.1363.
1
2
3
4
5
6
7
8
IR (neat): 2980, 1725, 1453, 1247, 1155, 1096 ; HRMS (ESI-
TOF) m/z: (M+H)+ Calcd for C18H25O4 305.1753; found
305.1737.
Diethyl
3-(4-methylbenzyl)cyclopentane-1,1-dicarboxylate
(15). The organozinc prepared for this reaction was according
to procedure A. The title compound 15 was obtained as a color-
less oil (119.2 mg, 75% yield) after purification by silica gel
1
column chromatography (Hex: EtOAc = 19:1) H NMR (300
9
MHz, CDCl3):  1.23 (q, J = 6.9 Hz, 6H), 1.29-1.43 (m, 1H),
1.76-1.86 (m, 2H), 2.08-2.43 (m, 4H), 2.31 (s, 3H), 2.54-2.68
(m, 2H), 4.12-4.22 (m, 4H), 7.03-7.12 (m, 4H); 13C NMR (75
MHz, CDCl3):  14.1, 21.1, 32.0, 33.8, 40.4, 40.9, 41.7, 60.0,
61.3, 128.7, 129.0, 135.3, 138.2, 172.7, 172.8; IR (neat): 2980,
1725, 1445, 1366, 1247, 1096; HRMS (ESI-TOF) m/z:
(M+H)+ Calcd for C19H27O4 319.1909; found 319.1910.
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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
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56
57
58
59
60
3-(4-Fluorobenzyl)-1-tosylpyrrolidine (20). The organozinc
prepared for this reaction was according to procedure A. This
reaction was completed in 8 h using our standard condition. The
title compound 20 was obtained as a colorless oil (104.8 mg,
63% yield) after purification by silica gel column chromatog-
1
raphy (Hex: EtOAc = 9:1). H NMR (300 MHz, CDCl3): 
1.40-1.53 (m, 1H), 1.80-1.91 (m, 1H), 2.28 (app. septet, J = 6.9
Hz, 1H), 2.43 (s, 3H), 2.52 (d, J = 9 Hz, 2H), 2.89 (q, J = 6 Hz,
1H), 3.14-3.22 (m, 1H), 3.28-3.42 (m, 2H), 6.90-7.03 (m, 4H),
), 7.32 (d, J = 9 Hz, 2H), 7.68 (d, J = 9 Hz, 2H); 13C NMR (75
MHz, CDCl3):  21.6, 31.0, 38.3, 40.5, 47.4, 52.7, 115.3 (d,
JCF = 21.0 Hz), 127.6, 129.7, 130.0 (d, JCF = 8.2 Hz), 133.9,
135.4 (d, JCF = 3.0 Hz), 143.4, 161.4 (d, JCF = 243 Hz); 19F
NMR (282 MHz, CDCl3)  -115.2 IR (neat): 1598, 1508,
1448, 1155, 1090, 1014 ; HRMS (CI) m/z: (M+H)+ Calcd for
C18H21FNO2S 334.1277; found 334.1284.
Diethyl 3-(4-methoxybenzyl)cyclopentane-1,1-dicarboxylate
(16). The organozinc prepared for this reaction was according
to procedure A. The title compound 16 was obtained as a color-
less oil (116.9 mg, 70% yield) after purification by silica gel
1
column chromatography (Hex: EtOAc = 19:1). H NMR (300
MHz, CDCl3):  1.23 (q, J = 6.9 Hz, 6H), 1.28-1.45 (m, 1H),
1.77-1.84 (m, 2H), 2.08-2.42 (m, 4H), 2.52-2.65 (m, 2H), 3.78
(s, 3H), 4.12-4.21 (m, 4H), 6.81 (d, J = 9.0 Hz, 2H), 7.08 (d, J
= 9.0 Hz, 2H); 13C NMR (75 MHz, CDCl3):  14.1, 31.9, 33.7,
40.3, 41.8, 55.2, 60.0, 61.3, 113.7, 129.6, 133.3, 157.8, 172.7,
172.8; IR (neat): 2980, 1724, 1611, 1443, 1242, 1095; HRMS
(ESI-TOF) m/z: (M+H)+ Calcd for C19H27O5 335.1858; found
335.1858.
3-(3,4-Dichlorobenzyl)tetrahydrofuran (21). The organozinc
prepared for this reaction was according to procedure A. The
title compound 21 was obtained as a colorless oil (85.1 mg, 74%
yield) after purification by silica gel column chromatography
(Hex: EtOAc = 9:1). 1H NMR (300 MHz, CDCl3):  1.51-1.63
(m, 1H), 1.93-2.04 (m, 1H), 2.46 (app. septet, J = 7.5 Hz, 1H),
2.57-2.70 (m, 2H), 3.42 (t, J = 7.5 Hz, 1H), 3.71-3.93 (m, 3H),
4-(cyclopentylmethyl)benzonitrile (17).13a The organozinc pre-
pared for this reaction was according to procedure A. The title
compound 17 was obtained as a colorless oil (47 mg, 51% yield)
after purification by silica gel column chromatography (Hex:
6.99 (d, J = 6 Hz, 1H), 7.26 (s, 1H), 7.34 (d, J = 6 Hz, 1H); 13
C
1
EtOAc = 19:1). H NMR (300 MHz, CDCl3:  1.11-1.27 (m,
NMR (75 MHz, CDCl3):  32.0, 38.5, 40.7, 67.9, 72.8, 128.2,
130.1, 130.4, 130.6, 132.4, 141.1; IR (neat): 2966, 2856, 1470,
1372, 1240, 1130, 1044, 1029; HRMS (CI) m/z: (M)+ Calcd
for C11H12Cl2O 230.0265; found 230.0273.
2H), 1.49-1.72 (m, 6H), 2.07 (app. septet, J = 7.5 Hz, 1H), 2.65
(d, J = 9.0 Hz, 2H), 7.26 (d, J = 9.0 Hz, 2H), 7.55 (d, J = 9.0
Hz, 2H); 13C NMR (75 MHz, CDCl3):  25.0, 32.5, 41.7, 42.3,
109.6, 119.3, 129.6, 132.1, 148.1 ; IR (neat): 2948, 2865, 2226,
1606, 1506.
3-(3,5-Bis(trifluoromethyl)benzyl)tetrahydrofuran (22). The or-
ganozinc prepared for this reaction was according to procedure
A. The title compound 22 was obtained as a colorless oil (105.7
mg, 71% yield) after purification by silica gel column chroma-
tography (Hex: EtOAc = 9:1). 1H NMR (300 MHz, CDCl3): 
1.56-1.67 (m, 1H), 1.97-2.08 (m, 1H), 2.55 (app. septet, J = 7.5
Hz, 1H), 2.76-2.90 (m, 2H), 3.47 (t, J = 7.5 Hz, 1H), 3.74-3.97
(m, 3H), 7.63 (s, 2H), ), 7.73 (s, 1H); 13C NMR (75 MHz,
Methyl 4-((1-phenylpyrrolidin-3-yl)methyl)benzoate (18). The
organozinc prepared for this reaction was according to proce-
dure A. The reaction was done at room temperature for 12 h
using standard condition. The title compound 18 was obtained
as a white solid (79.6 mg, 54% yield) after purification by silica
1
gel column chromatography (Hex: EtOAc = 19:1). H NMR
(300 MHz, CDCl3):  1.69-1.82 (m, 1H), 2.06-2.16 (m, 1H),
2.62 (app. septet, J = 7.5 Hz, 1H), 2.82 (d, J = 9 Hz, 2H), 3.02
(t, J = 9 Hz, 1H), 3.26-3.45 (m, 3H), 3.93 (s, 3H), 6.54 (d, J = 9
Hz, 2H), 6.68 (t, J = 9.0 Hz, 1H), 7.21-7.31 (m, 4H), 8.01 (d, J
= 9.0 Hz, 2H); 13C NMR (75 MHz, CDCl3):  31.4, 40.0, 40.2,
47.2, 52.1, 53.0, 111.5, 115.6, 128.3, 128.8, 129.2, 129.9, 146.2,
147.8, 167.1; IR (neat): 2959, 2822, 1713, 1599, 1505, 1308,
1276, 1107; HRMS (ESI-TOF) m/z: (M+H)+ Calcd for
C19H22NO2 296.1651; found 296.1648.
CDCl3):  32.0, 39.0, 40.6, 67.9, 72.7, 120.4, 123.4 (q, JCF
=
270.9 Hz), 128.9, 131.9 (q, JCF = 32.7 Hz), 143.3 ; 19F NMR
(282 MHz, CDCl3)  -61.5 IR (neat): 2936, 2864, 1622, 1456,
1378, 1274, 1166, 1002; HRMS (CI) m/z: (M+H)+ Calcd for
C13H13F6O 299.0871; found 299.0864.
4-((Tetrahydrofuran-3-yl)methyl)benzonitrile (23). The or-
ganozinc prepared for this reaction was according to procedure
A. The title compound 23 was obtained as a colorless oil (60.7
mg, 65% yield) after purification by silica gel column chroma-
tography (Hex: EtOAc = 9:1). 1H NMR (300 MHz, CDCl3): 
1.53-1.65 (m, 1H), 1.94-2.05 (m, 1H), 2.51 (app. septet, J = 7.5
Hz, 1H), 2.68-2.81 (m, 2H), 3.44 (t, J = 7.5 Hz, 1H), 3.72-3.94
3-Benzyl-1-tosylpyrrolidine (19). The reaction was conducted
using one equiv diphenylzinc (115.5 mg, 67% yield) instead of
PhZnI (88.2mg, 56%) in our standard condition for 8 h. The title
compound 19 was obtained as a colorless oil after purification
(m, 3H), 7.28 (d, J = 6.0 Hz, 2H), 7.58 (d, J = 6 Hz, 2H); 13
C
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The Journal of Organic Chemistry
Page 10 of 20
1043; HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C16H23O2
247.1698; found 247.1691. The actual dr (1.7:1) was calculated
using GC. See SI for GC trace.
NMR (75 MHz, CDCl3):  32.0, 39.4, 40.5, 67.8, 72.7, 110.1,
119.0, 129.5, 132.3, 146.4 ; IR (neat): 2965, 2856, 2226, 1606,
1506, 1415, 1177, 1042; HRMS (ESI-TOF) m/z: (M+H)+
Calcd for C12H14NO 188.1075; found 188.1081.
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4
5
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7
8
(±)-(3R,3aS,6aR)-3-(2-Methylbenzyl)hexahydrofuro[2,3-b]fu-
ran (28). The organozinc prepared for this reaction was accord-
ing to procedure A. The title compound 28 was obtained as a
colorless oil (65.4 mg, 60% yield; 5:1 dr) after purification by
1-(4-((tetrahydrofuran-3-yl)methyl)phenyl)ethan-1-one (24).
The organozinc prepared for this reaction was according to pro-
cedure C. The title compound 24 was obtained as a colorless oil
(67.3mg, 66% yield) after purification by silica gel column
1
silica gel column chromatography (Hex: EtOAc = 9:1;). H
1
chromatography (Hex: EtOAc = 4:1). H NMR (300 MHz,
NMR (300 MHz, CDCl3):  1.87-2.08 (m, 2H), 2.32 (s, 3H),
2.62-2.86 (m, 4H), 3.56-3.64 (m, 1H), 3.83-4.00 (m, 3H), 5.73
(d, J = 6 Hz, 1H), 7.10-7-16 (m, 4H); 13C NMR (75 MHz,
CDCl3):  19.5, 25.3, 31.0, 42.3, 45.8, 69.2, 72.2, 109.8, 126.1,
126.4, 128.6, 130.5, 135.8, 138.2 ; IR (neat): 2949, 2867, 1603,
1490, 1371, 1180, 1071; HRMS (ESI-TOF) m/z: (M+H)+
Calcd for C14H19O2 219.1385; found 219.1377. The actual dr
(5:1) of this compound was calculated using crude 1H NMR by
integrating peaks at  5.73 ppm (major isomer) and  5.74 ppm
(minor isomer). The characterization data given above corre-
spond to the major isomer isolated by column chromatography.
9
CDCl3):  1.55-1.67 (m, 1H), 1.94-2.05 (m, 1H), 2.48-2.69 (m,
4H), 2.68-2.75 (d, J = 6.0 Hz, 2H), 3.45 (t, J = 7.5 Hz, 1H),
3.74-3.94 (m, 3H), 7.26 (d, J = 6.0 Hz, 2H), 7.89 (d, J = 6 Hz,
2H); 13C NMR (75 MHz, CDCl3):  26.6, 32.2, 39.4, 40.7,
67.9, 72.9,128.7, 129.0, 135.4, 146.6, 197.8 ; IR (neat): 2855,
1677, 1605, 1413, 1265, 956; HRMS (APCI) m/z: (M+H)+
Calcd for C13H17O2 205.1229; found 205.1217.
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-(4-bromobenzyl)tetrahydrofuran (25). The organozinc pre-
pared for this reaction was according to procedure A. The title
compound 25 was obtained as a colorless oil (84.0 mg, 70%
yield) after purification by silica gel column chromatography
(±)-(3R,3aS,7aR)-3-(4-Methylbenzyl)hexahydro-4H-furo[2,3-
b]pyran (29). The organozinc prepared for this reaction was ac-
cording to procedure A. The title compound 29 was obtained as
colorless oil (71.9 mg, 62% yield; 5:1 dr) after purification by
1
(Hex: EtOAc = 19:1). H NMR (300 MHz, CDCl3):  1.53-
1.65 (m, 1H), 1.92-2.04 (m, 1H), 2.47 (app. septet, J = 7.0 Hz,
1H), 2.61-2.70 (m, 2H), 3.43 (t, J = 7.5 Hz, 1H), 3.71-3.93 (m,
3H), 7.04 (d, J = 9.0 Hz, 2H), 7.41 (d, J = 9.0 Hz, 2H); 13C
NMR (75 MHz, CDCl3):  32.1, 38.8, 40.9, 67.9, 72.9, 119.9,
130.5, 131.6, 139.8 ; IR (neat): 2965, 2856, 2226, 1606, 1506,
1415, 1177, 1042; HRMS (CI) m/z: (M)+ Calcd for C11H13BrO
240.0150; found 240.0152.
1
silica gel column chromatography (Hex: EtOAc = 9:1). H
NMR (300 MHz, CDCl3):  1.49-1.63 (m, 3H), 1.72-1.79 (m,
1H), 1.91-1.99 (m, 1H), 2.32(s, 3H), 2.53-2.74 (m, 3H), 3.63-
3.67 (m, 1H), 3.74-3.79 (m, 2H), 3.88 (t, J = 7.5 Hz, 1H), 5.27
(d, J = 3.0 Hz, 1H), 7.04-7.11 (m, 4H); 13C NMR (75 MHz,
CDCl3):  19.5, 21.0, 23.2, 32.9, 36.5, 42.6, 61.0, 69.9, 102.0,
128.2, 129.2, 135.6, 137.0; IR (neat): 2939, 1736, 1515, 1144,
1109, 1018; HRMS (ESI-TOF) m/z: (M+H)+ Calcd for
C15H21O2 233.1542; found 233.1537. The actual dr (5:1) of this
(±)-(3R,3aS,6aR)-3-(4-Methoxybenzyl)hexahydrofuro[2,3-
b]furan (26).42 The organozinc prepared for this reaction was
according to procedure A. The title compound 26 was obtained
as a colorless oil (90.0 mg, 77% yield; 8:1 dr) after purification
1
compound was calculated using crude H NMR by integrating
1
by silica gel column chromatography (Hex: EtOAc = 9:1). H
peaks at  5.27 ppm (major isomer) and  5.01 ppm (minor iso-
mer). The characterization data given above correspond to the
major isomer isolated by column chromatography.
NMR (300 MHz, CDCl3):  1.77-2.03 (m, 2H), 2.55-2.79 (m,
4H), 3.52 (t, J = 10.5 Hz, 1H), 3.76 (s, 3H), 3.81-3.97 (m, 3H),
5.69 (d, J = 6 Hz, 1H), 6.81 (d, J=9.0 Hz, 1H), 7.07 (d, J=6.0
Hz, 1H); 13C NMR (75 MHz, CDCl3):  25.0, 32.8, 43.9, 45.4,
55.2, 69.0, 72.1, 109.8, 113.9, 129.1, 131.9, 158.0; IR (neat):
2952, 1735, 1611, 1511, 1372, 1242, 1178; HRMS (ESI-TOF)
m/z: (M+H)+ Calcd for C14H19O3 235.1334; found 235.1330.
The actual dr (8:1) of this compound was calculated using crude
1H NMR by integrating peaks at  5.69 ppm (major isomer) and
 5.72 ppm (minor isomer). The characterization data given
above correspond to the major isomer isolated by column chro-
matography.
(±)-(3R,3aS,7aS)-3-(4-Methylbenzyl)octahydrobenzofuran
(30). The organozinc prepared for this reaction was according
to procedure A. The title compound 30 was obtained as a color-
less oil (79.3 mg, 69% yield; 1.7:1 dr) after purification by silica
1
gel column chromatography (Hex: EtOAc = 19:1). H NMR
(300 MHz, CDCl3):  1.18-1.42 (m, 3H), 1.47-1.65 (m, 4H),
1.73-1.89 (m, 2H), 1.98-2.02 (m, 1x0.37H), 2.24-2.31 (m,
1x0.63H), 2.34 (s, 3H), 2.54-2.63 (m, 1H), 2.67-2.79 (m, 1H),
3.54 (dd, J = 9.0, 6.0 Hz, 1x0.63H), 3.67 (t, J = 7.5 Hz,
1x0.37H), 3.89-4.12 (m, 2H), 7.06-7.13 (m, 4H); 13C NMR (75
MHz, CDCl3):  20.5, 21.0, 21.2, 22.2, 23.7, 24.5, 27.5, 28.4,
28.6, 33.1, 39.4, 40.0, 43.0, 45.6, 45.8, 70.9, 72.0, 76.2, 78.4,
128.2, 128.6, 129.1, 135.4, 137.5, 137.9; IR (neat): 2926,
2853, 1514, 1446, 1061, 1022; HRMS (CI) m/z: (M)+ Calcd
for C16H22O 230.1671; found 230.1669. The actual dr (1.7:1)
was calculated using GC. See SI for GC trace.
(±)-(3R,3aS,7aS)-3-(2-Methoxybenzyl)octahydrobenzofuran
(27). The organozinc prepared for this reaction was according
to procedure A. The title compound 27 was obtained as a color-
less oil (78.7 mg, 64% yield; 1.7:1 dr) after purification by silica
1
gel column chromatography (Hex: EtOAc = 19:1). H NMR
(300 MHz, CDCl3):  1.14-1.40 (m, 3H), 1.44-1.64 (m, 4H),
1.71-1.89 (m, 2H), 1.96-2.00 (m, 1x0.37H), 2.26-2.33 (m,
1x0.63H), 2.53-2.62 (m, 1H), 2.67-2.78 (m, 1H), 3.52 (dd, J =
9.0, 6.0 Hz, 1x0.63H), 3.64 (t, J = 7.5 Hz, 1x0.37H), 3.80 (s,
3H), 3.88-4.11 (m, 2H), 6.73-6.79 (m, 3H), 7.17-7.23 (m, 1H);
13C NMR (75 MHz, CDCl3):  20.5, 21.2, 22.2, 23.7, 24.6,
27.5, 28.4, 28.7, 33.7, 39.9, 40.1, 43.1, 45.4, 45.7, 55.2, 70.9,
72.0, 76.2, 78.4, 111.1, 111.2, 114.4, 114.7, 120.9, 121.2, 129.4,
142.3, 142.7, 159.7; IR (neat): 2930, 1737, 1584, 1239, 1152,
(±)-(2S,4R)-2-Butoxy-4-(2,4-dimethoxybenzyl)tetrahydrofuran
(31). The organozinc prepared for this reaction was according
to procedure A. The title compound 31 was obtained as a color-
less oil (98.4 mg, 67% yield; 1.4:1 dr) after purification by silica
1
gel column chromatography (Hex: EtOAc = 19:1). H NMR
(300 MHz, CDCl3):  0.88-0.96 (m, 3H), 1.30-1.46 (m, 2H),
1.50-1.65 (m, 3H), 1.92-1.98 (m, 1x0.42H), 2.10-2.20 (m,
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The Journal of Organic Chemistry
1065, 997; HRMS (ESI-TOF): (M+H)+ Calcd for C14H16F3O2
1x0.58H), 2.45-2.55 (m, 1x0.58H), 2.59 (d, J = 6.0 Hz,
1
2
3
4
5
6
7
8
1x0.42H), 2.69 (d, J = 9.0 Hz, 2H), 3.34-3.42 (m, 1H), 3.54-
3.73 (m, 2H), 3.79 (s, 6H), 3.83-3.96 (m, 1H), 5.08-5.12 (m,
1H), 6.38-6.43 (m, 2H), 7.00 (d, J = 9.0 Hz, 1H); 13C NMR (75
MHz, CDCl3):  14.0, 19.5, 32.0, 33.2, 33.7, 37.5, 38.6, 38.9,
39.2, 55.2, 55.4, 67.2, 67.5, 72.0, 98.5, 103.7, 104.3, 104.7,
121.7, 130.5, 158.4, 159.4; IR (neat): 2934, 1738, 1612, 1506,
1456, 1286, 1207, 1155, 1063; HRMS (CI) m/z: (M)+ Calcd
for C17H26O4 294.1831 found 294.1832. The actual dr (1.4:1)
was calculated using GC. See SI for GC trace.
273.1102; found 273.1093. The actual dr (10:1) of this com-
pound was calculated using crude 1H NMR by integrating peaks
at 5.70 ppm (major isomer) and  5.74 ppm (minor isomer).
The characterization data given above correspond to the major
isomer isolated by column chromatography.
(±)-4-(((3R,3aS,7aR)-Hexahydro-4H-furo[2,3-b]pyran-3-
yl)methyl)benzonitrile (35). The organozinc prepared for this
reaction was according to procedure A. The title compound 35
was obtained as colorless oil (93.5 mg, 77% yield; 10:1 dr) after
purification by silica gel column chromatography (Hex: EtOAc
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
(±)-(2S,4R)-4-Benzyl-2-phenyltetrahydrofuran (32). The or-
ganozinc prepared for this reaction was according to procedure
A. The title compound 32 was obtained as a colorless oil (94.0
mg, 79% yield; 6.5:1 dr) after purification by silica gel column
chromatography (Hex: EtOAc = 19:1).1H NMR (300 MHz,
CDCl3):  1.97-2.07 (m, 1H), 2.11-2.20 (m, 1H), 2.45 (app.
septet, J = 7.1 Hz, 1x0.13H), 2.71 (app. septet, J = 7.5 Hz,
1x0.87H), 2.79 (d, J = 9.0 Hz, 2H), 3.70 (t, J = 7.5 Hz,
1x0.87H), 3.82 (t, J = 7.5 Hz, 1x0.13H), 4.09 (t, J = 7.5 Hz,
1x0.13H), 4.20 (t, J = 7.5 Hz, 1x0.87H), 4.93 (t, J = 7.5 Hz,
1x0.13H), 5.12 (t, J = 7.5 Hz, 1x0.87H), 7.20-7.39 (m, 10H);
13C NMR (75 MHz, CDCl3):  39.2, 39.5, 40.6, 40.7, 41.9,
42.3, 73.7, 73.8, 80.1, 81.4, 125.5, 125.6, 126.2, 127.1, 128.3,
128.4, 128.5, 128.7, 140.6, 143.8; IR (neat): 3061, 2933, 1602,
1494, 1067, 1028; HRMS (CI) m/z: (M)+ Calcd for C17H18O
238.1358; found 238.1357. The actual dr (6.5:1) was calculated
using GC. See SI for GC trace.
1
= 9:1). H NMR (300 MHz, CDCl3):  1.48-1.64 (m, 3H),
1.67-1.73 (m, 1x0.90H), 1.81-1.85 (m, 1x0.10H), 1.90-1.98 (m,
1H), 2.62-2.82 (m, 3x0.90H), 2.82-2.85 (m, 3x0.10H), 3.37-
3.45 (m, 1x0.10H), 3.60-3.66 (m, 1x0.90H), 3.71-3.79 (m, 2H),
3.85 (t, J = 7.5 Hz, 1x0.90H), 4.13 (t, J = 7.5 Hz, 1x0.10H), 5.01
(d, J = 3.0 Hz, 1x0.10H), 5.25 (d, J = 3.0 Hz, 1x0.90H), 7.27
(d, J = 6.0 Hz, 2H), 7.57 (d, J = 6.0 Hz, 2H); 13C NMR (75
MHz, CDCl3):  19.6, 23.0, 33.7, 36.5, 42.0, 61.0, 69.6, 101.8,
110.2, 118.8, 129.2, 132.4, 145.8; IR (neat): 2940, 2869, 2226,
1716, 1606, 1252, 1177, 1049; HRMS (ESI-TOF): (M+H)+
Calcd for C15H18NO2 244.1338; found 244.1320. The actual dr
1
(10:1) of this compound was calculated using crude H NMR
by integrating peaks at  5.27 ppm (major isomer) and  5.03
ppm (minor isomer). The characterization data given above cor-
respond to the major isomer isolated by column chromatog-
raphy.
(±)-(2S,4R)-2-Phenyl-4-(4-(trifluoromethyl)benzyl)tetrahydro-
furan (33). The organozinc prepared for this reaction was ac-
cording to procedure A. The title compound 33 was obtained as
colorless oil (114.7 mg, 75% yield; 10:1 dr) after purification
by silica gel column chromatography (Hex: EtOAc = 19:1). 1H
NMR (300 MHz, CDCl3):  1.95-2.05 (m, 1H), 2.08-2.16 (m,
1H), 2.42 (app. septet, J = 6.75 Hz, 1x0.10H), 2.66 (app. septet,
J = 6.90 Hz, 1x0.90H), 2.83 (d, J = 9.0 Hz, 2H), 3.65 (t, J = 7.5
Hz, 1x0.90H), 3.79 (t, J = 7.5 Hz, 1x0.10H), 4.06 (t, J = 7.5 Hz,
1x0.10 H), 4.18 (t, J = 7.5 Hz, 1x0.90H), 4.92 (t, J = 7.5 Hz,
1x0.10H), 5.10 (t, J = 7.5 Hz, 1x0.90H), 7.24-7.36 (m, 7H),
7.55 (d, J = 9.0 Hz, 2H),; 13C NMR (75 MHz, CDCl3):  39.0,
39.4, 40.5, 40.6, 41.7, 42.0, 73.5, 73.6, 80.1, 81.4, 124.4 (q, JCF
= 159.0 Hz), 125.5 (q, , JCF = 12.6 Hz ), 127.3, 127.4, 128.4 (q,
JCF = 5.3 Hz ), 128.9, 129.1, 143.0, 143.6, 144.7; 19F NMR (282
MHz, CDCl3):  -61.1; IR (neat): 2973, 2867, 1614, 1321,
1151, 1108, 1062; HRMS (CI) m/z: (M-H)+ Calcd for
C18H16F3O 305.1153; found 305.1145. The actual dr (10:1) of
this compound was calculated using crude 1H NMR by integrat-
ing peaks at  5.10 ppm (major isomer) and  4.92 ppm (minor
isomer).
(±)-(2S,4R)-2-Butoxy-4-(3-chlorobenzyl)tetrahydrofuran (36).
The organozinc prepared for this reaction was according to pro-
cedure A. The title compound 36 was obtained as a colorless oil
(101.8 mg, 76% yield; 4.1:1 dr) after purification by silica gel
1
column chromatography (Hex: EtOAc = 19:1). H NMR (300
MHz, CDCl3):  0.88-0.96 (m, 3H), 1.30-1.43 (m, 2H), 1.50-
1.69 (m, 3H), 1.95-2.02 (m, 1x0.20H), 2.11-2.20 (m, 1x0.80H),
2.46 (app.septet, J = 7.9 Hz, 1x0.80H), 2.62-2.65 (m, 1x0.20H),
2.75 (d, J = 9.0 Hz, 2H), 3.31-3.42 (m, 1H), 3.51-3.73 (m, 2H),
3.88-4.00 (m, 1H), 5.09-5.13 (m, 1H), 7.03-7.06 (m, 1H), 7.15-
7.26 (m, 3H); 13C NMR (75 MHz, CDCl3):  14.0, 19.5, 32.0,
38.5, 39.2, 39.7, 67.5, 71.6, 104.5, 126.3, 126.9, 128.8, 129.7,
134.2, 143.0; IR (neat): 2956, 2931, 2869, 1598, 1474, 1430,
1080, 1011; HRMS (CI) m/z: (M)+ Calcd for C15H21ClO2
268.1230; found 268.1221. The actual dr (4.1:1) was calculated
using GC. See SI for GC trace.
(±)-4-(3,4-Dichlorobenzyl)-2-ethoxy-3-ethyltetrahydrofuran
(37). The organozinc prepared for this reaction was according
to procedure A. The. title compound 37 was obtained as a col-
orless oil (104.2 mg, 69% yield; 6: 4.5: 3.4: 1 dr) after purifica-
tion by silica gel column chromatography (Hex: EtOAc = 9:1).
1H NMR (300 MHz, CDCl3):  0.85-0.90 (m, 1H), 0.93-1.02
(m, 2H), 1.16-1.23 (m, 3H), 1.32-1.73 (m, 2H), 1.99-2.11 (m,
1H), 2.36-2.86 (m, 3H), 3.39-3.56 (m, 1H), 3.59-3.90 (m, 3H),
4.78 (d, J = 2.1 Hz, 1x0.40H), 4.85 (d, J = 2.6 Hz, 1x0.23H),
4.95 (d, J = 4.8 Hz, 1x0.30H), 4.98 (d, J = 4.5 Hz, 1x0.07H),
6.98 (d, J = 9.0 Hz, 1H), 7.23-7.34 (m, 2H); 13C NMR (75
MHz, CDCl3):  12.2, 12.8, 13.0, 15.3, 15.4, 15.5, 18.0, 19.3,
20.8, 25.5, 32.8, 35.1, 38.5, 40.4, 41.9, 45.8, 48.8, 50.0, 52.9,
63.0, 63.3, 70.6, 71.6, 71.7, 104.1, 107.9, 109.1, 128.1, 128.4,
129.8, 130.1, 130.3, 130.4, 130.6, 130.8, 132.3, 132.4, 140.9,
141.1, 141.2, 142.2; IR (neat): 2965, 2874, 1472, 1131, 1044,
1028, 999; HRMS (CI) m/z: (M)+ C15H20Cl2O2 302.0840;
(±)-(3R,3aS,6aR)-3-(4-(Trifluoromethyl)benzyl)hexahydro-
furo[2,3-b]furan (34). The organozinc prepared for this reac-
tion was according to procedure A. The title compound 34 was
obtained as a colorless oil (93.8 mg, 69% yield; 10:1 dr) after
purification by silica gel column chromatography (Hex: EtOAc
1
= 9:1). H NMR (300 MHz, CDCl3):  1.79-2.03 (m, 2H),
2.60-2.84 (m, 4H), 3.55 (t, J = 9.0 Hz, 1H), 3.82-3.99 (m, 3H),
5.70 (d, J = 6.0 Hz, 1H), 7.28 (d, J = 6.0 Hz, 2H), 7.54 (d, J =
6.0 Hz, 2H); 13C NMR (75 MHz, CDCl3):  25.1, 33.6, 43.5,
45.4, 69.0, 71.9, 109.7, 124.2 (q, JCF= 270.4 Hz), 125.5(q, JCF=
3.9 Hz), 128.0, 128.6 (q, JCF= 10.9 Hz), 144.1; 19F NMR (282
MHz, CDCl3)  -60.8 IR (neat):2951, 2871, 1321, 1160, 1108,
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The Journal of Organic Chemistry
Page 12 of 20
NMR (300 MHz, CDCl3):  1.82-2.04 (m, 2H), 2.64-3.01 (m,
found 302.0840. The actual dr (6: 4.5: 3.4: 1) was calculated
using GC. See SI for GC trace.
1
2
3
4
5
6
7
8
4H), 3.54 (t, J = 10.5 Hz, 1H), 3.84-3.99 (m, 3H), 5.74 (d, J =
3.0 Hz, 1H), 6.80 (d, J = 3.0 Hz, 1H), 6.93 (t, J = 4.5 Hz, 1H),
7.14 (d, J = 6.0 Hz, 1H); 13C NMR (75 MHz, CDCl3):  25.2,
28.0, 44.1, 45.4, 69.2, 72.2, 109.9, 123.6, 124.8, 126.9, 142.5;
IR (neat): 2948, 1438, 1252, 1107, 997, 921; HRMS (ESI-
TOF): (M+H)+ Calcd for C11H15O2S 211.0793; found
211.0792. The actual dr (10:1) of this compound was calculated
using crude 1H NMR by integrating peaks at  5.70 ppm (major
isomer) and  5.80 ppm (minor isomer). The characterization
data given above correspond to the major isomer isolated by
column chromatography.
(±)-(2S,4R)-4-((5-Butoxytetrahydrofuran-3-yl)methyl)-2-chlo-
ropyridine (38). The organozinc prepared for this reaction was
according to procedure A. The title compound 38 was obtained
as a colorless oil (108.9 mg, 81% yield; 2.2:1 dr) by silica gel
1
column chromatography (Hex: EtOAc = 9:1). H NMR (300
MHz, CDCl3):  0.87-0.96 (m, 3H), 1.30-1.44 (m, 2H), 1.47-
1.64 (m, 3H), 1.97-2.04 (m, 1x0.31H), 2.10-2.19 (m, 1x0.69H),
2.48 (app.septet, J = 6.9 Hz, 1x0.69H), 2.64-2.67 (m, 1x0.31H),
2.79 (d, J = 9.0 Hz, 2H), 3.33-3.41 (m, 1H), 3.54-3.72 (m, 2H),
3.91-4.01 (m, 1H), 5.09-5.12 (m, 1H), 7.03 (t, J = 6.0 Hz, 1H),
7.15 (s, 1H), 8.28 (d, J = 6.0 Hz, 1H); 13C NMR (75 MHz,
CDCl3):  13.9, 19.4, 19.5, 31.8, 31.9, 37.8, 38.3, 38.6, 38.7,
39.0, 67.2, 67.5, 71.3, 71.5, 103.9, 104.3, 122.9, 123.0, 124.5,
149.7, 151.8, 152.9, 153.3; IR (neat): 2955, 2869, 1592, 1465,
1385, 1085, 1013; HRMS (ESI-TOF): (M+H)+ Calcd for
C14H21ClNO2 270.1261; found 270.1247. The actual dr (2.2:1)
was calculated using GC. See SI for GC trace.
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-(4-(((3R,3aS,7aR)-hexahydro-4H-furo[2,3-b]pyran-3-yl)me-
thyl)phenyl)ethan-1-one (42). This reaction was performed by
using organozinc prepared according to procedure C in our
standard condition. The title compound 42 was obtained as
white solid (101.4 mg, 78% yield; 10:1 dr) after purification by
1
flash column chromatography (Hex: EtOAc = 2:1). H NMR
(300 MHz, CDCl3):  1.51-1.61 (m, 3H), 1.72-1.76 (m, 1H),
1.92-1.98 (m, 1H), 2.58 (s, 3H), 2.64-2.82 (m, 3H), 3.64 (t, J =
7.5 Hz, 1H), 3.74-3.81 (m, 2H), 3.87 (t, J = 7.5 Hz, 1H), 5.27
(d, J = 6.0 Hz, 1H), 7.26 (d, J = 8.1 Hz, 2H), 7.88 (d, J = 8.1
Hz, 2H); 13C NMR (75 MHz, CDCl3):  19.6, 23.1, 26.6, 33.6,
36.6, 42.2, 61.0, 69.7, 101.9, 128.6, 128.7, 135.5, 145.9, 197.7;
IR (neat): 2932, 1676, 1355, 1138, 1014, 866; HRMS (APCI):
(M+H)+ Calcd for C16H21O3 261.1491; found 261.1481 The ac-
(±)-(3R,3aS,7aR)-3-(Furan-2-ylmethyl)hexahydro-4H-
furo[2,3-b]pyran (39). This reaction was performed by using
di(furan-2-yl)zinc (1 eqvt.) in our standard condition. The title
compound 39 was obtained as colorless oil (84.2 mg, 81%
yield; 8:1 dr) after purification by silica gel column chromatog-
raphy (Hex: EtOAc = 9:1). 1H NMR (300 MHz, CDCl3): 
1.45-1.64 (m, 3H), 1.72-1.80 (m, 1H), 1.96-2.05 (m, 1H), 2.58-
2.79 (m, 3H), 3.60-3.67 (m, 1H), 3.72-3.82 (m, 2H), 3.97 (t, J
= 7.5 Hz, 1H), 5.28 (d, J = 3.0 Hz, 1H), 5.99 (d, J = 3.0 Hz, 1H),
6.27 (t, J = 3.0 Hz, 1H), 7.29 (d, J = 3.0 Hz, 1H); 13C NMR (75
MHz, CDCl3):  19.5, 23.2, 26.1, 36.7, 39.9, 61.2, 69.9, 102.0,
105.5, 110.2, 141.3, 154.1; IR (neat): 2936, 2871, 1769, 1436,
1143, 1047, 1015; HRMS (ESI-TOF): (M+H)+ Calcd for
C12H17O3 209.1178; found 209.1174. The actual dr (8:1) of this
1
tual dr (10:1) of this compound was calculated using crude H
NMR by integrating peaks at  5.25 ppm (major isomer) and 
5.03 ppm (minor isomer). The characterization data given
above correspond to the major isomer isolated by column chro-
matography.
1-(4-(((3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl)me-
thyl)phenyl)ethan-1-one (43). This reaction was performed by
using organozinc prepared according to procedure C in our
standard condition. The title compound 43 was obtained as a
white solid (86.1 mg, 70% yield; 10:1 dr) after purification by
1
compound was calculated using crude H NMR by integrating
peaks at  5.30 ppm (major isomer) and 5.01 ppm (minor iso-
mer). The characterization data given above correspond to the
major isomer isolated by column chromatography.
1
flash column chromatography (Hex: EtOAc = 2:1). H NMR
(300 MHz, CDCl3):  1.78-2.02 (m, 2H), 2.57 (s, 3H), 2.62-
2.84 (m, 4H), 3.54 (t, J = 10.5 Hz, 1H), 3.81-3.98 (m, 3H), 5.69
(d, J = 6 Hz, 1H), 7.25 (d, J = 9 Hz, 2H), ), 7.87 (d, J = 9 Hz,
2H); 13C NMR (75 MHz, CDCl3):  25.2, 26.6, 33.9, 43.5,
45.4, 69.1, 72.0, 109.8, 128.6, 128.8, 135.5, 145.7, 197.6; IR
(neat): 1669, 1415, 1267, 1107, 1003, 921; HRMS (APCI):
(M+H)+ Calcd for C15H19O3 247.1334; found 247.1323. The ac-
(±)-(3R,3aS,6aR)-3-(Furan-2-ylmethyl)hexahydrofuro[2,3-
b]furan (40). This reaction was performed by using di(furan-2-
yl)zinc (1 eqvt.) in our standard condition. The title compound
40 was obtained as colorless oil (63.0 mg, 65% yield; 9.3:1 dr)
after purification by silica gel column chromatography (Hex:
1
EtOAc = 9:1). H NMR (300 MHz, CDCl3):  1.82-2.01 (m,
1
2H), 2.65-2.89 (m, 4H), 3.54 (t, J = 9.0 Hz, 1H), 3.84-3.99 (m,
3H), 5.74 (d, J = 6.0 Hz, 1H), 6.01 (d, J = 3.0 Hz, 1H), 6.28 (t,
J = 1.5 Hz, 1H), 7.31 (d, J = 0.72 Hz, 1H); 13C NMR (75 MHz,
CDCl3):  25.2, 26.3, 41.1, 45.6, 69.2, 72.2, 105.6, 109.8,
110.3, 141.3, 153.8; IR (neat): 2949, 2873, 1716, 1254, 1106,
1072, 996; HRMS (ESI-TOF): (M+H)+ Calcd for C11H15O3
195.1021; found 195.1015. The actual dr (9.3:1) of this com-
pound was calculated using crude 1H NMR by integrating peaks
at  5.70 ppm (major isomer) and  5.81 ppm (minor isomer).
The characterization data given above correspond to the major
isomer isolated by column chromatography.
tual dr (10:1) of this compound was calculated using crude H
NMR by integrating peaks at  5.70 ppm (major isomer) and 
5.80 ppm (minor isomer). The characterization data given
above correspond to the major isomer isolated by column chro-
matography.
(2S,4R)-4-(4-bromobenzyl)-2-phenyltetrahydrofuran (44). This
reaction was performed by using organozinc prepared accord-
ing to procedure A in our standard condition. The title com-
pound 44 was obtained as colorless oil (98.0mg, 62% yield;
10:1 dr) after purification by silica gel column chromatography
1
(Hex: EtOAc = 19:1). H NMR (300 MHz, CDCl3):  1.93-
(±)-(3R,3aS,6aR)-3-(Thiophen-2-ylmethyl)hexahydrofuro[2,3-
b]furan (41). The organozinc prepared for this reaction was ac-
cording to procedure A. The title compound 41 was obtained as
a colorless oil (76.6 mg, 73% yield; 10:1 dr) after purification
2.02 (m, 1H), 2.05-2.14 (m, 1H), 2.41 (app. septet, J = 6.0 Hz,
1x0.10H), 2.63 (app. septet, J = 6.75 Hz, 1x0.90H), 2.72 (d, J =
9.0 Hz, 2H), 3.63 (t, J = 7.5 Hz, 1x0.90H), 3.76 (t, J = 7.5 Hz,
1x0.10H), 4.04 (t, J = 7.5 Hz, 1x0.10H), 4.16 (t, J = 7.5 Hz,
1x0.90H), 4.90 (t, J = 7.5 Hz, 1x0.10H), 5.07 (t, J = 7.5 Hz,
1
by silica gel column chromatography (Hex: EtOAc = 9:1). H
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Page 13 of 20
The Journal of Organic Chemistry
(ESI-TOF): (M+H)+ Calcd for C13H17O4 237.1127; found
1x0.90H), 7.05 (d, J = 8.1 Hz, 2H), 7.25-7.35 (m, 5H), 7.41 (d,
J = 8.1 Hz, 2H),; 13C NMR (75 MHz, CDCl3):  38.6, 38.9,
40.5, 41.7, 42.1, 73.5, 73.6, 80.0, 81.3, 120.0, 125.5, 125.6,
127.2, 127.4, 128.4 (br, s), 131.6 (br, s), 139.5, 143.6; IR
(neat): 1558, 1161, 1008, 760, 701, 528; HRMS (CI): (M)+
Calcd for : C17H17BrO 316.0463; found 316.0461. The actual
dr (10:1) of this compound was calculated using crude 1H NMR
by integrating peaks at 5.07 ppm (major isomer) and  4.90
ppm (minor isomer).
1
2
3
4
5
6
7
8
237.1116.
(3aR,9S,9aR)-9-(3,4-dimethoxyphenyl)-6,7-dimethoxy-
3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1(3H)-one (50).25d
Compound 49 (94.4 mg, 0.4 mmol) was dissolved in dry THF
(2.5 mL) then the solution was cooled to -78 °C. To the cooled
solution, LDA (0.8 mmol, 1.6 ml of 0.5M solution in THF) was
added dropwise for 5 minutes. The solution was stirred for 1h
at -78 °C which turns the solution to yellow. To the reaction
mixture, solution 3,4-dimethoxybenzaldehyde (99.6 mg, 0.6
mmol) in 1.5 mL THF was added dropwise at -50 °C and and
stirred at room temperature for 6 h. Then solvent was removed
and the reaction crude was dissolved in 1 mL CH2Cl2. To the
stirring reaction mixture at room temperature, Trifluoroacetic
acid (309 µl, 4 mmol) was added dropwise. It was stirred over-
night at room temperature and quenched with saturated Na-
HCO3 (2.0 ml). The reaction mixture was extracted with CH2Cl2
(8 mL). The organic layer was dried with Na2SO4 and the sol-
vent was removed. The title compound 50 was obtained as a
white solid (112.1 mg, 73% yield; 19:1 dr) after purification by
9
ethyl (1R)-1-acetyl-3-(4-cyanobenzyl)cyclopentane-1-carbox-
ylate (45). The organozinc prepared for this reaction was ac-
cording to procedure A. The title compound 45 was obtained as
a colorless oil (89.7 mg, 60 % yield; 3:2 dr) after purification
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
by silica gel column chromatography (Hex: Et2O = 8:1). H
NMR (500 MHz, CDCl3):  1.21-1.23 (m, 3H), 1.30-1.40 (m,
1H), 1.99-2.13 (m, 4H), 2.22-2.34 (m, 3H), 2.65-2.74 (m, 2H),
4.14-4.21 (m, 2H), 7.26 (d, J =7.5 Hz, 2H), 7.55 (d, J = 7.5 Hz,
2H); 13C NMR (125 MHz, CDCl3):  14.1, 26.2, 26.5, 32.0,
32.1, 32.2, 32.3, 38.5, 38.7, 41.2, 41.3, 41.4, 61.6, 66.3, 66.5,
109.9, 119.1, 129.5, 132.2, 146.8, 146.9, 173.3, 173.4, 203.4;
HRMS (CI): (M+H)+ Calcd for for C18H22NO3 300.1600;
found 300.1590. The actual dr (3:2) of this compound was cal-
culated using crude 1H NMR by integrating peaks at  2.10 ppm
(major isomer) and  2.08 ppm (minor isomer).
1
flash column chromatography (Hex: EtOAc = 2:1). H NMR
(500 MHz, CDCl3):  2.50 (dd, J = 13.8, 10.8 Hz, 1H), 2.58-
2.68 (m, 1H), 2.93 (t, J = 13.2 Hz, 1H), 3.00 (dd, J = 15.0, 4.5
Hz, 1H), 3.60 (s, 3H), 3.82 (s, 3H), 3.87 (s, 6H), 3.99 (dd, J =
10.0, 9.5 Hz, 1H), 4.11 (d, J = 11.0 Hz, 1H), 4.52 (dd, J = 8.0,
7.5 Hz, 1H), 6.33 (s, 1H), 6.61 (s, 1H), 6.70 (s, 1H), 6.80 (d, J
= 8.0 Hz, 1H), 6.83 (d, J = 8.5 Hz, 1H); 13C NMR (75 MHz,
CDCl3):  32.6, 40.1, 45.8, 48.9, 55.8, 55.9, 56.0, 71.0, 111.0,
111.4, 112.4, 112.9, 121.9, 126.9, 131.4, 135.6, 147.7, 147.8,
147.9, 148.8, 175.6, ; IR (neat): 1759, 1652, 1514, 1246, 1217,
1102, 981 ; HRMS (ESI-TOF): (M+H)+ Calcd for C22H25O6
385.1651; found 385.1653. The stereochemistry of the com-
pound was assigned by comparing the spectral data and the J-
coupling values with the known compound in the literature.25d
The actual dr (19:1) was calculated using GC and observation
of single isomer in crude 1H NMR. See SI for GC trace.
(±)-4-(3,4-Dimethoxybenzyl)dihydrofuran-2(3H)-one (49). The
dicarbofunctionalization reaction was conducted in 10.0 mmol
scale in 50 mL NMP in 8 h using the standard procedure. Or-
ganozinc ((3,4-dimethoxyphenyl)zinc iodide) for this reaction
was prepared according to above procedure B. Under nitrogen
atmosphere, (3,4-dimethoxyphenyl)zinc iodide stock solution
in THF (15 mmol) was taken in a 150 mL sealed tube and the
solvent was removed under vacuum. To the residue of ArZnI
was added NiBr2 (30 mg, 0.3 mmol), terpyridine (45 mg, 0.4
mmol), and 1-(1-(allyloxy)-2-iodoethoxy)butane (48) (10
mmol). The mixture was then dissolved in NMP (50 mL). The
sealed tube was tightly capped, and placed in an oil-bath pre-
heated to 50 °C with vigorous stirring. The resultant cyclized
cross coupled product was oxidized without further purification
as follow: The crude reaction mixture (brown color) was diluted
with ethyl acetate (30 mL) and washed three times with 10 mL
water. The combined EtOAc layer was dried with Na2SO4 and
solvent was removed. For oxidation, the crude reaction mixture
was taken in a reaction flask and 200 mL acetone was added to
the flask. 30 mL of Jones reagent (prepared by dissolving 1 gm
CrO3 in 1 mL conc. H2SO4 and 3 mL H2O) was added dropwise
to the reaction mixture at 0 °C. The reaction was stirred for 1 h
at 0 °C. Then the reaction was quenched with isopropyl alcohol
(30 mL) and stirred for a while and filtered. The filtrate was
neutralized with saturated NaHCO3 solution (10 mL) and ex-
tracted with EtOAc (30 mL). The combined EtOAc layer was
dried with Na2SO4 and the solvent was pumped off. The title
compound 49 was obtained as a colorless oil (1463.2 mg, 62%
yield) after purification by silica gel column chromatography
(Hex: EtOAc = 4:1). 1H NMR (300 MHz, CDCl3):  2.21 (dd,
J = 18.0, 6.0 Hz 1H), 2.52 (dd, J = 18.0, 9.0 Hz 1H), 2.63-2.84
(m, 3H), 3.78 (d, J = 3.0 Hz, 6H), 3.95 (dd, J = 9.0, 6.0 Hz, 1H),
4.25 (dd, J = 9.0, 6.0 Hz, 1H), 6.62-6.65 (m, 2H), 6.75 (d, J =
9.0 Hz, 1H); 13C NMR (75 MHz, CDCl3):  34.0, 37.1, 38.3,
55.7, 72.5, 111.2, 111.7, 120.5, 130.7, 147.6, 148.9, 176.8; IR
(neat): 2935, 2835, 1767, 1512, 1261, 1138, 1011; HRMS
(±)-(3R,4R)-3-(Benzo[d][1,3]dioxol-5-ylmethyl)-4-(3,4-di-
methoxybenzyl)dihydrofuran-2(3H)-one (51).43 In a 4 dram
vial, compound 49 (94.4 mg, 0.4 mmol) was dissolved in dry
THF (4 mL) . The solution was cooled to -78 °C. To the cooled
solution, LDA (0.48 mmol, 0.96 ml of 0.5M) solution was
added dropwise for 5 minutes. The solution was stirred for 1 h
at -78 °C which turns the solution to yellow. To the reaction
mixture, solution 5-(bromomethyl)benzo[d][1,3]dioxole44
(127.8 mg, 0.6 mmol) in 1.5 mL THF was added dropwise at -
50 °C followed by addition of HMPA ( 72 µl, 0.4 mmol) and
stirred at room temperature 6 h. The reaction mixture was
quenched with NH4Cl (1 mL) and extracted with EtOAc (10
mL). The organic layer was dried with Na2SO4 and the solvent
was removed. The title compound 51 was obtained as a color-
less viscous oil (127.2 mg, 86% yield; 40:1 dr) after purification
1
by silica gel column chromatography (Hex: EtOAc = 3:1). H
NMR (300 MHz, CDCl3):  2.46-2.62 (m, 4H), 2.84 (dd, J =
15.0, 9.0 Hz, 1H), 2.96 (dd, J = 15.0, 6.0 Hz, 1H), 3.82 (s, 3H),
3.85 (s, 3H), ), 3.87-3.90 (m, 1H), 4.14 (dd, J = 9.0, 6.8 Hz, 1H),
5.92 (dd, J = 3.2, 1.4 Hz, 1H), 6.47 (d, J = 3.0 Hz, 1H), 6.55-
6.59 (m, 3H), 6.73 (dd, J = 15.0, 9.0 Hz, 2H); 13C NMR (75
MHz, CDCl3):  34.8, 38.3, 41.3, 46.5, 55.8, 56.0, 71.3, 101.1,
108.2, 109.5, 111.4, 111.8, 120.7, 122.3, 130.5, 131.4, 146.5,
147.9, 149.1, 178.5; IR (neat): 1767, 1732, 1514, 1442, 1236,
1155, 1027; HRMS (ESI-TOF): (M+H)+ Calcd for C21H23O6
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The Journal of Organic Chemistry
Page 14 of 20
371.1495, found 371.1490. The actual dr (40:1) was calculated 37.0, 38.3, 72.3, 100.8, 108.2, 108.7, 121.4, 131.9, 146.1, 147.7,
1
2
3
4
5
6
7
8
using GC. See SI for GC trace.
176.7; IR (neat): 2906, 1769, 1488, 1238, 1166, 1011; HRMS
(ESI-TOF): (M+H)+ Calcd for C12H13O4 221.0814; found
221.0806.
(±)-(3R,4R)-3,4-Bis(3,4-dimethoxybenzyl)dihydrofuran-2(3H)-
one (52).43 In a 4 dram vial, compound 49 (94.4 mg, 0.4 mmol)
was dissolved in dry THF (4 mL) . The solution was cooled to
-78 °C. To the solution, LDA (0.48 mmol, 0.96 ml of 0.5M)
solution was added dropwise for 5 minutes. The solution was
stirred for 1 h at -78 °C which turns the solution to yellow. To
the reaction mixture, solution of 4-(bromomethyl)-1,2-di-
methoxybenzene45 (, 138 mg, 0.6 mmol) in 1.5 mL THF was
added dropwise at -50 °C followed by addition of HMPA (72
µl, 0.4 mmol) and stirred at room temperature 6 h. The reaction
mixture was quenched with NH4Cl (1 mL) and extracted with
EtOAc 10 (mL). The organic layer was dried with Na2SO4 and
the solvent was removed. The title compound 52 was obtained
as a white solid (109.6 mg, 71% yield; 33:1 dr) after purification
(±)-(3R,4R)-4-(Benzo[d][1,3]dioxol-5-ylmethyl)-3-(3,4-di-
methoxybenzyl)dihydrofuran-2(3H)-one (54).25g In a 4 dram
vial, compound 53 (88.0 mg, 0.4 mmol) was dissolved in dry
THF (4 mL) . The solution was cooled to -78 °C. To the solu-
tion, LDA (0.48 mmol, 0.96 ml of 0.5M) solution was added
dropwise for 5 minutes. The solution was stirred for 1 h at -78
°C which turns the solution to yellow. To the reaction mixture,
solution of 4-(bromomethyl)-1,2-dimethoxybenzene45 ( 138
mg, 0.6 mmol) in 1.5 mL THF was added dropwise at -50 °C
followed by addition of HMPA ( 72 µl, 0.4 mmol) and stirred
at room temperature 6 h. The reaction mixture was quenched
with NH4Cl (1 mL) and extracted with EtOAc (10 mL). The
organic layer was dried with Na2SO4 and the solvent was re-
moved. The title compound 54 was obtained as a colorless vis-
cous oil (113.9 mg, 77% yield; 23:1 dr) after purification by
silica gel column chromatography (Hex: EtOAc = 3:1). The ac-
tual dr ratio is calculated using GC trace. See SI for GC trace.
1H NMR (300 MHz, CDCl3):  2.42-2.60 (m, 4H), 2.88 (dd, J
= 15.0, 9.0 Hz, 1H), 2.96 (dd, J = 15.0, 6.0 Hz, 1H), 3.83 (s,
3H), 3.86 (s, 3H), 3.86-3.88 (m, 1H), 4.11 (dd, J = 9.0, 6.0 Hz,
1H), 5.92 (dd, J = 3.3, 1.5 Hz, 1H), 6.42-6.47 (m, 2H), 6.66-
6.70 (m, 3H), 6.79 (d, J = 9.0 Hz, 1H); 13C NMR (75 MHz,
CDCl3):  34.7, 38.4, 41.1, 46.6, 55.9, 71.2, 101.1, 108.3,
108.8, 111.2, 112.2, 121.4, 121.6, 130.2, 131.7, 146.4, 148.0,
149.1, 178.7; IR (neat): 1766, 1514, 1464, 1236, 1140, 1025;
HRMS (ESI-TOF): Calcd for (M+H)+ C21H23O6 371.1495;
found 371.1529. The actual dr (23:1) was calculated using GC.
See SI for GC trace.
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
by silica gel column chromatography (Hex: EtOAc = 3:1). H
NMR (300 MHz, CDCl3);  2.47-2.65 (m, 4H), 2.88-3.00 (m,
2H), 3.81-3.89 (m, 13H), 4.12 (dd, J = 9.0, 6.0 Hz, 1H), 6.48 (s,
1H), 6.54 (d, J = 9.0 Hz, 1H), 6.63-6.67 (m, 2H), 6.75 (dd, J =
9.0, 6.0 Hz, 2H); 13C NMR (75 MHz, CDCl3):  34.6, 38.3,
41.1, 46.6, 55.9, 71.3, 111.1, 111.4, 111.9, 112.4, 120.6, 121.4,
130.3, 130.5, 147.9, 148.0, 149.1, 178.8; IR (neat): 2935, 1765,
1512, 1452, 1234, 1155, 1014; IR (neat): 1765, 1512, 1452,
1234, 1081, 974; HRMS (ESI-TOF): (M+H)+ Calcd for
C22H27O6 387.1808; found 387.1818. The actual dr (33:1) was
calculated using GC. See SI for GC trace.
(±)-4-(Benzo[d][1,3]dioxol-5-ylmethyl)dihydrofuran-2(3H)-
one (53). The dicarbofunctionaliz-ation reaction was conducted
in 10.0 mmol scale in 50 mL NMP in 8 h using the standard
procedure. Organozinc (benzo[d][1,3]dioxol-5-ylzinc iodide)
for this reaction was prepared according to procedure B. Under
nitrogen atmosphere, benzo[d][1,3]dioxol-5-ylzinc iodide stock
solution in THF (15 mmol) was taken in a 150 mL sealed tube
and the solvent was removed under vacuum. To the residue of
ArZnI was added NiBr2 (30 mg, 0.3 mmol), terpyridine (45 mg,
0.4 mmol), and 1-(1-(allyloxy)-2-iodoethoxy)butane (48) (10
mmol). The mixture was then dissolved in NMP (50 mL). The
sealed tube was tightly capped, and placed in an oil-bath pre-
heated to 50 °C with vigorous stirring. The resultant cyclized
cross coupled product was oxidized without further purification
as follow: The crude reaction mixture (brown color) was diluted
with ethyl acetate (30 mL) and washed three times with 10 mL
of water. The combined EtOAc layer was dried with Na2SO4
and solvent was removed. For oxidation, the crude reaction
mixture was taken in a reaction flask and 220 mL acetone was
added to the flask. 33 mL of Jones reagent (prepared by dissolv-
ing 1 gm CrO3 in 1 mL conc. H2SO4 and 3 mL H2O) was added
dropwise to the reaction mixture at 0°C. The reaction was
stirred for 1 h at 0°C. Then the reaction was quenched with
isopropyl alcohol (33 ml) and stirred for a while and filtered.
The filtrate was neutralized with saturated NaHCO3 solution (10
mL) and extracted with EtOAc (30 mL). The combined EtOAc
layer was dried with Na2SO4 and the solvent was pumped off.
The title compound 53 was obtained as a colorless oil (1452 mg,
60% yield) after purification by silica gel column chromatog-
raphy (Hex: EtOAc = 4:1). 1H NMR (300 MHz, CDCl3):  2.19
(dd, J = 18.0, 9.0 Hz 1H), 2.52 (dd, J = 18.0, 9.0 Hz 1H), 2.60-
2.78 (m, 3H), 3.93 (dd, J = 9.0, 6.0 Hz, 1H), 4.25 (dd, J = 12.0,
9.0 Hz, 1H), 5.86 (s, 2H), 6.54 (d, J = 6.0 Hz, 1H), 6.58 (s, 1H),
6.68 (d, J = 6.0 Hz, 1H); 13C NMR (75 MHz, CDCl3):  33.8,
(±)-(3R,4R)-4-(Benzo[d][1,3]dioxol-5-ylmethyl)-3-(3,4,5-tri-
methoxybenzyl)dihydrofuran-2(3H)-one (55).25a In a 4 dram
vial, compound 52 (88 mg, 0.4 mmol) was dissolved in dry THF
(4 mL) . The solution was cooled to -78 °C. To the solution,
LDA (0.48 mmol, 0.96 mL of 0.5M) solution was added drop-
wise for 5 minutes. The solution was stirred for 1 h at -78 °C
which turns the solution to yellow. To the reaction mixture, so-
lution of 5-(bromomethyl)-1,2,3-trimethoxybenzene46 (165.6
mg, 0.6 mmol,) in 1.5 mL THF was added dropwise at -50 °C
followed by addition of HMPA (72 µl, 0.4 mmol) and stirred at
room temperature 6 hrs. The reaction mixture was quenched
with NH4Cl (1 mL) and extracted with EtOAc (10 mL). The
organic layer was dried with Na2SO4 and the solvent was re-
moved. The title compound 55 was obtained as a colorless oil
(128.0 mg, 80% yield; 40:1 dr) after purification by silica gel
1
column chromatography (Hex: EtOAc = 3:1). H NMR (300
MHz, CDCl3):  2.44-2.65 (m, 4H), 2.84-2.96 (m, 2H), 3.82
(s, 9H), 3.84-3.90 (m, 1H), 4.17 (dd, J = 9.0, 6.0 Hz, 1H), 5.93
(dd, J = 2.8, 1.3 Hz, 1H), 6.35 (s, 2H), 6.45-6.48 (m, 2H), 6.69
(d, J = 9.0 Hz, 1H); 13C NMR (75 MHz, CDCl3):  35.3, 38.4,
41.1, 46.5, 56.1, 60.9, 71.2, 101.1, 106.2, 108.3, 108.8, 121.6,
131.6, 133.4, 136.9, 146.4, 147.9, 153.3, 178.5; IR (neat):
1766, 1589, 1489, 1237, 1123, 1010; HRMS (ESI-TOF):
(M+H)+ Calcd for C22H25O7 401.1600; found 401.1594. The ac-
tual dr (40:1) was calculated using GC. See SI for GC trace.
Benzo[d][1,3]dioxol-5-yl(2-iodo-4,5-dimethoxyphenyl)meth-
anone . The compound was prepared by Friedel-Crafts acyla-
tion of 1,3-benzodioxole with 6-iodoveratric acid according to
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The Journal of Organic Chemistry
dried with Na2SO4 and the solvent was removed. The title com-
the literature procedure.47 The title compound benzo[d][1,3]di-
1
2
3
4
5
6
7
8
oxol-5-yl(2-iodo-4,5-dimethoxyphenyl)methan-one was ob-
pound 58 was obtained as a white solid (59.4 mg, 65% yield)
after purification by silica gel column chromatography (Hex:
EtOAc = 1:1). 1H NMR (300 MHz, CDCl3):  2.79 (t, J = 9.9
Hz, 1H), 2.93 (dd, J = 15.0, 6.0 Hz, 1H), 3.33-3.46 (m, 1H),
3.67 (s, 3H), 3.92 (s, 3H), 4.00 (t, J = 9.0 Hz, 1H), 4.69 (t, J =
9.0 Hz, 1H), 6.02 (d, J = 3.0 Hz, 2H), 6.54 (s, 1H), 6.78 (br.s,
3H), 6.86 (d, J = 9.0 Hz, 1H); 13C NMR (75 MHz, CDCl3): 
33.0, 35.8, 56.1, 71.05, 101.3, 107.9, 110.6, 111.2, 112.5, 119.6,
123.9, 127.9, 128.6, 129.3, 147.1, 147.2, 147.7, 147.9, 150.3,
168.4; IR (neat): 2915, 2849, 1745, 1683, 1540, 1378, 1063 ;
HRMS (ESI): (M+H)+ Calcd for C21H19O6 367.1182; found
367.1190.
tained as a white solid (94% yield) after purification by silica
1
gel column chromatography (Hex : EtOAc = 9:1). H NMR
(300 MHz, CDCl3):  3.80 (s, 3H), 3.88 (s, 3H), 6.03 (s, 2H),
6.78 (d, J = 6.0 Hz, 2H), 7.24-7.26 (m, 2H), 7.33 (s, 1H); 13C
NMR (75 MHz, CDCl3):  56.1, 56.3, 81.5, 102.0, 107.9,
109.4, 111.7, 121.8, 127.9, 130.6, 136.8, 148.3, 148.9, 150.4,
152.3, 195.2; IR (neat): 2900, 1635, 1499, 1323, 1179, 1033;
HRMS (ESI-TOF): (M+H)+ Calcd for C16H14IO5 412.9886,
found 412.9879. The title compound was used directly for the
preparation of organozinc 56 using the standard procedure A.
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
(±)-4-(2-(Benzo[d][1,3]dioxole-5-carbonyl)-4,5-dimethox-
ybenzyl)dihydrofuran-2(3H)-one (57). The dicarbofunctionali-
zation reaction was conducted in 2.50 mmol scale in 12.5 mL
NMP using the standard procedure for 8 h. For this reaction, the
organozinc (56) (2-(benzo[d][1,3]dioxole-5-carbonyl)-4,5-di-
methoxyphenyl)zinc iodide was prepared according to the
standard procedure A. The resultant product was oxidized with-
out further purification as follows: The crude reaction mixture
(brown color) was diluted with ethyl acetate (15 mL) and
washed three times with 5 mL water. The aqueous layer was
extracted back with EtOAc (10 mL) and all the EtOAc layer
were combined and dried with Na2SO4 and solvent was re-
moved. For oxidation, the crude reaction mixture was taken in
a reaction flask and acetone (70 mL) was added to the flask. 7.5
mL of Jones reagent (prepared by dissolving 1 gm CrO3 in 1 mL
conc. H2SO4 and 3 mL H2O) was added dropwise to the reaction
mixture at 0 °C. The reaction was stirred for 1 h at 0 °C. Then
the reaction was quenched with isopropyl alcohol (6 mL) and
stirred for a while and filtered. The filtrate was neutralized with
NaHCO3 (2 mL) and extracted with EtOAc (15 mL). The com-
bined EtOAc layer was dried with Na2SO4 and the solvent was
pumped off. The title compound 57 was obtained as a white
solid (672.0 mg, 70% yield) after purification by silica gel col-
umn chromatography (Hex: EtOAc = 3:1). 1H NMR (300 MHz,
CDCl3):  2.14 (dd, J = 18.0, 6.0 Hz 1H), 2.37 (dd, J = 18.0,
9.0 Hz 1H), 2.66-2.80 (m, 3H), 3.67 (s, 3H), 3.80 (s, 3H), 3.86
(dd, J = 9.0, 6.0 Hz, 1H), 4.13 (dd, J = 9.0, 6.0 Hz, 1H), 5.91 (s,
2H), 6.64-6.69 (m, 2H), 6.73 (s, 1H), 7.13 (d, J = 6.0 Hz, 1H),
7.17 (s, 1H); 13C NMR (75 MHz, CDCl3):  33.8, 35.3, 37.1,
55.7, 72.3, 101.8, 107.4, 108.9, 112.4, 112.9, 126.8, 130.2,
131.1, 132.2, 146.3, 147.9, 150.2, 151.7, 176.7, 195.3; IR
(neat): 2935, 1771, 1646, 1436, 1225, 1032; HRMS (ESI-
TOF): (M+H)+ Calcd for C21H21O7 385.1287; found 385.1276.
1-octyl-4-(trifluoromethyl)benzene (64).49 The organozinc pre-
pared for this reaction was according to procedure A. Under ni-
trogen atmosphere, in a sealed tube, (4-(trifluoromethyl)phe-
nyl)zinc iodide stock solution in THF (0.750 mmol) was taken
and the solvent was removed under vacuum. To the residue of
ArZnI, NiBr2 (3.3 mg, 0.015 mmol), terpyridine (4.7 mg, 0.02
mmol), and iodooctane (0.5 mmol) were added successively.
Then the mixture was dissolved in NMP (2.5 mL). Later, sealed
tube was tightly capped, and placed in an oil-bath preheated to
50 °C with vigorous stirring. After 6 h, the reaction mixture was
cooled to room temperature, diluted with EtOAc (10 mL) and
washed with H2O (5 mL × 3). The aqueous fraction was ex-
tracted back with ethyl acetate (5 mL × 3) and combined with
the first ethyl acetate fraction. The combined ethyl acetate frac-
tion was dried over Na2SO4 and the solvent was removed in a
rotary evaporator. The title compound 64 was obtained as a col-
orless oil (78.1 mg, 88% yield) after purification by silica gel
column chromatography in hexane. 1H NMR (300 MHz,
CDCl3):  0.87 (t, J = 6.0 Hz, 3H), 1.25-1.33 (m, 10H), 1.56-
1.63 (m, 2H), 2.64 (t, J = 7.8 Hz, 2H), 7.26 (d, J = 6.0 Hz, 2H),
7.45 (d, J = 7.8 Hz, 2H); 13C NMR (75 MHz, CDCl3):  14.2,
22.8, 29.4, 29.5, 31.3, 32.0, 35.98, 123.5 (q, J = 72.0 Hz), 125.3
(q, J = 4.1 Hz), 126.8 (q, J = 63.7 Hz), 128.8, 147.1; 19F NMR
(282 MHz, CDCl3)  -62.3. The NMR data are consistent with
the reported values.
1-methoxy-4-octylbenzene (65).49 The organozinc prepared for
this reaction was according to procedure A. Under nitrogen at-
mosphere, in a sealed tube, (4-((4-methoxyphenyl)zinc iodide
stock solution in THF (0.750 mmol) was taken and the solvent
was removed under vacuum. To the residue of ArZnI, NiBr2
(3.3 mg, 0.015 mmol), terpyridine (4.7 mg, 0.020 mmol), and
iodooctane (0.5 mmol) were added successively. Then the mix-
ture was dissolved in NMP (2.5 mL). Later, sealed tube was
tightly capped and placed in an oil-bath preheated to 50 °C with
vigorous stirring. After 6 h, the reaction mixture was cooled to
room temperature, diluted with EtOAc (10 mL) and washed
with H2O (5 mL × 3). The aqueous fraction was extracted back
with ethyl acetate (5 mL × 3) and combined with the first ethyl
acetate fraction. The combined ethyl acetate fraction was dried
over Na2SO4 and the solvent was removed in a rotary evapora-
tor. The title compound 65 was obtained as a colorless oil (46.5
mg, 69% yield) after purification by silica gel column chroma-
tography (Hex: EtOAc = 32:1). 1H NMR (300 MHz, CDCl3):
 0.90 (t, J = 6.3 Hz, 3H), 1.28-1.35 (m, 10H), 1.54-1.64 (m,
2H), 2.56 (t, J = 7.8 Hz, 2H), 3.80 (s, 3H), 6.82 (d, J = 9.0 Hz,
2H), 7.10 (d, J = 9.0 Hz, 2H); 13C NMR (75 MHz, CDCl3): 
14.2, 22.8, 29.4, 29.6, 31.9, 32.0, 35.2, 55.3, 113.7, 129.3,
(±)9-(Benzo[d][1,3]dioxol-5-yl)-6,7-dimethoxy-3a,4-dihy-
dronaphtho[2,3-c]furan-1(3H)-one (58).48 Compound 57 (76.8
mg, 0.25 mmol) was dissolved in dry THF (2.5 mL) and the
solution was cooled to -78 °C. To the cooled solution, LDA (0.5
mmol, 1.0 mL of 0.5M solution in THF) was added dropwise
for 5 minutes. The solution was stirred for 1 h at -78 °C which
turns the solution to yellow. To the same reaction mixture,
HMPA (45 µl, 0.25 mmol) was added dropwise and stirred at
room temperature for additional 3 h. Then the solvent was re-
moved and the crude reaction was dissolved in 2.4 mL pyridine
solution. The reaction mixture was cooled back to 0 °C and
SOCl2 (182 µl, 2.5 mmol,) was added dropwise. It was stirred
for 1 h at 0 °C and was diluted with CH2Cl2 (10 mL) and
quenched with 1M HCl (2.5 ml). The reaction mixture was ex-
tracted with additional 10 mL CH2Cl2. The organic layer was
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The Journal of Organic Chemistry
Page 16 of 20
135.2, 157.7. The NMR data are consistent with the reported
values.
For complete picture of both enantiomer, their % area and re-
tention time see SI.
1
2
3
4
5
6
7
8
9
Test for the tolerance of base-sensitive racemizable stereo-
center in (R)-Dimethylmethylsuccinate (47) To a sealed tube,
(4-cyanophenyl)zinc iodide stock solution in THF (0.6 mmol)
was taken and the solvent was removed under vacuum. To the
residue of ArZnI, NiBr2 (2.5 mg, 0.012 mmol), terpyridine (3.6
mg, 0.016 mmol), and diethyl-2-allyl-2-(2-bromoethyl)malo-
nate (12-Br) (0.4 mmol) were added respectively. The chiral
additives (R)-dimethylmethylsuccinate (0.5 mmol) was then
added in the mixture. Then the mixture was dissolved in NMP
(2.0 mL). Later, the tube was sealed and placed in an oil-bath
preheated to 50 °C with vigorous stirring. After 6 h, the reaction
mixture was cooled to room temperature, diluted with EtOAc
(10 mL) and washed with H2O (5 mL × 3). The aqueous fraction
was extracted back with ethyl acetate (5 mL × 3) and combined
with the first ethyl acetate fraction. The combined ethyl acetate
fraction was dried over Na2SO4 and the solvent was removed in
a rotary evaporator. The product was purified by column chro-
matography using 15% EtOAc in hexane. The compound di-
ethyl 3-(4-cyanobenzyl)cyclopentane-1,1-dicarboxylate (13)
was obtained in 78% yield with the recovery of chiral additives
(R)-dimethylmethylsuccinate in 89% yield. After this reaction,
the epimerization of chiral additives was checked using chiral
HPLC. At first, racemic mixture of (R,S)-dimethylmethylsuc-
cinate were separated in HPLC by using Chiral-Pak-IB in 5%
IPA in hexane with the flow of 0.5ml/min at 210 nm wave-
length. The two peaks of (R)- and (S)- configuration were ob-
served at 10.9 and 13.9 min. Then pure (R)-dimethylmethylsuc-
cinate appeared as a peak at 10.9 and minor at 13.9 min with
90.5:9.5 er. Later, (R)-dimethylmethylsuccinate which is recov-
ered from our reaction was analyzed through chiral HPLC. It
shows two peaks at 10.9 and 13.9 min with 90.5:9.5 er which is
exactly same with the value of (R)-dimethylmethylsuccinate be-
fore reaction. For complete picture of both enantiomer, their %
area and retention time see SI.
diethyl 3-(4-(trifluoromethyl)benzyl)cyclopentane-1,1-dicar-
boxylate (68).13a The organozinc prepared for this reaction was
according to procedure A. Under nitrogen atmosphere, in a
sealed tube, (4-(trifluoromethyl)phenyl)zinc iodide stock solu-
tion in THF (0.750 mmol) was taken and the solvent was re-
moved under vacuum. To the residue of ArZnI, NiBr2 (3.3 mg,
0.015 mmol), terpyridine (4.7 mg, 0.02 mmol), and diethyl-2-
allyl-2-(2-Iodoethyl)malonate (12-I) (0.5 mmol) were added
successively. Then the mixture was dissolved in NMP (2.5 mL).
Later, sealed tube was tightly capped, and placed in an oil-bath
preheated to 50 °C with vigorous stirring. After 6 h, the reaction
mixture was cooled to room temperature, diluted with EtOAc
(10 mL) and washed with H2O (5 mL × 3). The aqueous fraction
was extracted back with ethyl acetate (5 mL × 3) and combined
with the first ethyl acetate fraction. The combined ethyl acetate
fraction was dried over Na2SO4 and the solvent was removed in
a rotary evaporator. The title compound 68 was obtained as a
colorless oil (148.8 mg, 80% yield) after purification by silica
gel column chromatography (Hex: EtOAc = 9:1).1H NMR (300
MHz, CDCl3):  1.17-1.25 (m, 6H), 1.28-1.41 (m, 1H), 1.76-
1.84 (m, 2H), 2.07-2.40 (m, 4H), 2.62-2.75 (m, 2H), 4.10-4.20
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
(m, 4H), 7.26 (d, J = 6.0 Hz, 2H), 7.51 (d, J = 6.0 Hz, 2H); 13
C
NMR (75 MHz, CDCl3):  14.1, 32.1, 33.7, 40.3, 41.1, 41.4,
60.0, 61.5, 122.6, 125.4(q, JCF= 3.8 Hz), 126.0 (q, JCF= 31.5
Hz), 128.4 (q, JCF= 34.1 Hz), 129.1, 145.4, 172.6, 172.7; 19F
NMR (282 MHz, CDCl3)  -60.8; IR (neat): 2981, 2944, 2855,
1725, 1617.
Test for the tolerance of base-sensitive racemizable stereo-
center in N-Boc D-proline methyl ester (46) In a sealed tube,
(4-cyanophenyl)zinc iodide stock solution in THF (0.60 mmol)
was taken and the solvent was removed under vacuum. To the
residue of ArZnI was added NiBr2 (2.5 mg, 0.012), terpyridine
(3.6 mg, 0.016 mmol), and diethyl-2-allyl-2-(2-bromoethyl)ma-
lonate (12-Br) (0.4 mmol) respectively. The chiral additives N-
Boc D-Proline methyl ester (0.4 mmol) was then added in the
mixture. Then the mixture was dissolved in NMP (2.0 mL). The
sealed tube was tightly capped, and placed in an oil-bath pre-
heated to 50 °C with vigorous stirring. After 6 h, the reaction
mixture was cooled to room temperature, diluted with EtOAc
(10 mL) and washed with H2O (5 mL × 3). The aqueous fraction
was extracted back with ethyl acetate (5 mL × 3) and combined
with the first ethyl acetate fraction. The combined ethyl acetate
fraction was dried over Na2SO4 and the solvent was removed in
a rotary evaporator. The product was purified by column chro-
matography using 20% EtOAc in hexane. The compound di-
ethyl 3-(4-cyanobenzyl)cyclopentane-1,1-dicarboxylate (13)
was obtained in 76% yield with the recovery of chiral additives
N-Boc D-proline methyl ester in 93% yield. After the reaction,
the racemization was checked using chiral HPLC. At first, the
racemic mixture of N-Boc proline methyl ester in chiral HPLC
were separated by chiral pak IA-3 in 1% IPA in hexane with the
flow of 1.0 mL/min with detection by UV detector at 210 nm.
The two peaks of (S)- and (R)-compounds were observed at 11.1
min and 12.8 min. Then pure N-Boc D-proline methyl ester
{(R)-enantiomer)} appeared as a single peak at 12.8 min with
100:0 enantiomeric ratio (er). Later, N-Boc D-proline methyl
ester recovered from our reaction was analyzed with the chiral
HPLC which showed a single peak at 12.8 min with 100:0 er.
Selectivity study in Negishi cross-coupling reaction: To a dry
1dram vial, arylzinc stock solution in THF, (4-(trifluoromethyl)
phenyl)zinc iodide (0.6 mmol) and (4-methoxyphenyl)zinc io-
dide (0.6 mmol) was taken and the solvent was removed under
vacuum. To the residue of mixture of ArZnI, NiBr2 (1.3 mg,
0.006 mmol), terpyridine (1.8 mg, 0.008 mmol), and iodooctane
(0.2 mmol) were added respectively. Then the mixture was dis-
solved in NMP (1.0 mL). The sealed tube was tightly capped,
and placed in a hot plate preheated to 50 °C with vigorous stir-
ring. After 6 h, the reaction mixture was cooled to room tem-
perature, diluted with EtOAc (6 mL) and filtered through silica
pad. The peaks of cross coupling product of 4-(trifluorome-
thyl)phenyl)zinc iodide with iodooctane and (4-methoxy-
phenyl)zinc iodide with iodooctane were analyzed using GC
and GC/MS using pyrene as an internal standard. The ratio of
64:65 was found as 18: 10 which was calculated after calibra-
tion from the factor using pyrene as an internal standard.
Selectivity study in the cyclization/cross-coupling reaction:
To a dry 1 dram vial, arylzinc stock solution in THF, (4-(trifluo-
romethyl)phenyl)zinc iodide (0.6 mmol) and (4-methoxy-
phenyl)zinc iodide (0.6 mmol) was taken and the solvent was
removed under vacuum. To the residue, NiBr2 (1.3 mg, 0.006
mmol), terpyridine (1.8 mg, 0.008 mmol), and Diethyl-2-allyl-
2-(2-iodoethyl)malonate (12-I) (0.2 mmol) were added respec-
tively. The mixture was dissolved in NMP (1.0 mL) as a solvent
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The Journal of Organic Chemistry
Bu3SnH (175 mg, 0.6 mmol) and 3-(2-bromoethoxy)oct-1-ene
then sealed tube was tightly capped and placed in a hot plate
1
2
3
4
5
6
7
8
preheated to 50 °C with vigorous stirring. After 6 h, the reaction
mixture was cooled to room temperature, diluted with EtOAc
(10 mL) and filtered through silica pad. The clear solution was
run in GC using pyrene as an internal standard. The product
peak of cyclization cross coupled product of 4-(trifluorome-
thyl)phenyl)zinc iodide with 12-I and (4-methoxyphenyl)zinc
iodide with 12-I were analyzed by GC and GC/MS using pyrene
as an internal standard. The ratio of 68:16 was found as 17: 10
which was calculated after calibration of their value from the
factor using pyrene as an internal standard.
(74) (105 µL, 0.4 mmol) were added respectively. The mixture
was dissolved in benzene (1.0 mL). Then the quartz tube was
tightly capped, and placed in UV light of 300 nm at 37 °C with
vigorous stirring. After 12 h, the reaction mixture was cooled to
room temperature and the solvent was pumped off. The dia-
stereoselectivity of the reaction was analyzed through GC and
1H NMR where the trans-isomer of the cyclization/H-atom ab-
straction product 75 was formed as a single diastereomer. The
title compound 75 was obtained as a colorless oil (54.6 mg, 70%
yield) after purification by silica gel column chromatography in
Hexane. 1H NMR (300 MHz, CDCl3):  0.88 (t, J = 6.6 Hz,
3H), 1.11 (d, J = 6.0 Hz, 3H), 1.28-1.56 (m, 9H), 1.70-1.84 (m,
1H), 2.00-2.51 (m, 1H), 3.23-3.30 (m, 1H), 3.73-3.85 (m, 2H);
13C NMR (75 MHz, CDCl3):  14.1, 17.4, 22.7, 26.3, 32.2,
34.5, 34.9, 39.1, 66.7, 86.1; IR (neat): 2925, 1655, 1457, 1300,
1076, 661; HRMS (CI): (M+H)+ Calcd for C10H21O 157.1592;
found 157.1590.
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
Diastereoselectivity study of trans-1-(allyloxy)-2-bromocy-
clohexane: The organozinc prepared for this reaction was ac-
cording to procedure A. In a sealed tube, phenylzinc iodide
stock solution in THF (0.750 mmol) was taken and the solvent
was removed under vacuum. To the residue of PhZnI was added
NiBr2 (3.3 mg, 0.015 mmol), terpyridine (4.7 mg, 0.020 mmol),
and trans-1-(allyloxy)-2-bromocyclohexane (71) (0.5 mmol)
respectively. Then the mixture was dissolved in NMP (2.5 mL).
The sealed tube was tightly capped, and placed in an oil-bath
preheated to 50 °C with vigorous stirring. After 6 h, the reaction
mixture was cooled to room temperature, diluted with EtOAc
(10 mL) extracted with ethyl acetate. The combined ethyl ace-
tate fraction was dried over Na2SO4 and the solvent was re-
moved in a rotary evaporator. The crude reaction solution was
analyzed in GC and GC/MS and their diastereomeric ratio was
calculated. The diastereomeric ratio of the product from this re-
action was found to be 1.3:1. The product (3R,3aS,7aS)-3-ben-
zyloctahydrobenzofuran (72) was purified by column chroma-
Diastereoselectivity study in cyclization/cross-coupling re-
action: The organozinc prepared for this reaction was accord-
ing to procedure A. To a sealed tube, phenylzinc iodide stock
solution in THF (0.750 mmol) was taken and the solvent was
removed under vacuum. To the residue of PhZnI, NiBr2 (3.3 mg,
0.015 mmol), terpyridine (4.7 mg, 0.02 mmol), and 3-(2-bro-
moethoxy)oct-1-ene (74) (0.5 mmol) were added respectively.
Then the mixture was dissolved in NMP (2.5 mL). The sealed
tube was tightly capped, and placed in an oil-bath preheated to
50 °C with vigorous stirring. After 6 h, the reaction mixture was
cooled to room temperature and extracted with ethyl acetate (15
mL) and H2O (10 mL). The combined ethyl acetate fraction was
dried over Na2SO4 and the solvent was removed in a rotary
1
tography in 63% yield using 5% EtOAc in hexane. H NMR
(300 MHz, CDCl3):  1.06-1.39 (m, 3H), 1.44-1.62 (m, 4H),
1.71-1.87 (m, 2H), 1.95-2.05 (m, 1x0.43H), 2.23-2.34 (m,
1x0.57H), 2.55-2.63 (m, 1H), 2.69-2.80 (m, 1H), 3.52 (dd, J =
6.0, 3.0 Hz, 1x0.57H), 3.65 (t, J = 8.5 Hz, 1x0.43H), 3.86-4.10
(m, 2H), 7.14-7.30 (m, 5H); 13C NMR (75 MHz, CDCl3): 
20.5, 21.2, 22.3, 23.7, 24.6, 27.6, 28.5, 28.7, 33.7, 39.9, 40.1,
43.1, 45.6, 45.8, 71.2, 72.0, 76.3, 78.4, 126.0, 126.1, 128.5,
128.8, 140.7, 141.0; IR (neat): 2926, 1452, 1022, 749, 698;
HRMS (CI): (M)+ Calcd for C15H20O 216.1514; found
216.1503.
1
evaporator. The diastereomer was analyzed through H NMR
and GC. The diastereoselectivity of the reaction was analyzed
through GC and 1H NMR where the trans-isomer of the cycliza-
tion/cross-coupling product 76 was formed as a single diastere-
omer. The title compound 76 was obtained as a colorless oil
(67.2 mg, 58% yield) after purification by silica gel column
1
chromatography (Hex: EtOAc = 19:1). H NMR (300 MHz,
CDCl3):  0.87 (t, J = 7.5 Hz, 3H), 1.25-1.44 (m, 8H), 1.57-
1.68 (m, 1H), 1.89-2.11 (m, 2H), 2.54 (dd, J = 12.0, 9.0 Hz,
1H), 2.77 (dd, J = 12.0 Hz, J = 9.0 Hz, 1H), 3.49-3.55 (m, 1H),
3.80 (t, J = 6.0 Hz, 2H), 7.15-7.31 (m, 5H); 13C NMR (75 MHz,
CDCl3):  14.1, 22.7, 26.1, 32.0, 32.6, 34.8, 39.5, 46.32, 66.8,
84.3, 126.1, 128.4, 128.9, 140.8; IR (neat): 2926, 1453, 1079,
754, 689; HRMS (ESI-TOF): Calcd for C16H24ONa (M+Na)+
255.1725; found 255.1720.
Diastereoselectivity study of cis-1-(allyloxy)-2-bromocyclo-
hexane: In a sealed tube, phenylzinc iodide stock solution in
THF (0.750 mmol) was taken and the solvent was removed un-
der vacuum. To the residue of PhZnI was added NiBr2 (3.3 mg,
0.015 mmol), terpyridine (4.7 mg, 0.020 mmol), and cis-1-(al-
lyloxy)-2-bromocyclohexane (71) (0.5 mmol) respectively.
Then the mixture was dissolved in NMP (2.5 mL). The sealed
tube was tightly capped, and placed in an oil-bath preheated to
50 °C with vigorous stirring. After 6 h, the reaction mixture was
cooled to room temperature, diluted with EtOAc (10 mL) ex-
tracted with ethyl acetate. The combined ethyl acetate fraction
was dried over Na2SO4 and the solvent was removed in a rotary
evaporator. The clear solution was analyzed in GCand GC/MS
and their diastereomeric ratio was calculated. The diastereo-
meric ratio of the product from this reaction was found to be
1.3:1. The product (3R,3aS,7aS)-3-benzyloctahydrobenzofuran
(72) was purified by column chromatography in 74% yield us-
ing 5% EtOAc in hexane.
ASSOCIATED CONTENT
Supporting Information
NMR spectra of new compounds, and GC and HPLC traces.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
rgiri@unm.edu
Notes
Diastereoselectivity study in radical cyclization.28 Under ni-
trogen, in a quartz glass tube, AIBN (6.4 mg, 0.04 mmol),
The authors declare no competing financial interests.
ACKNOWLEDGMENT
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Tetrahedron Lett. 1987, 28, 4533 For olefin dicarbofunctionalization
We thank the University of New Mexico (UNM) and the National
Science Foundation (NSF CHE-1554299) for financial support,
and upgrades to the NMR (NSF grants CHE08-40523 and CHE09-
46690) and MS Facilities. We also thank Prof. Abhaya K. Datye at
the Department of Chemical & Biological Engineering (UNM), and
Prof. Wei Wang at the Department of Chemistry & Chemical Biol-
ogy (UNM) for providing us generous access to their chiral
HPLC’s.
assisted by a heteroatom coordination with Ni-catalysts, see: (e)
Shrestha, B.; Basnet, P.; Dhungana, R. K.; Kc, S.; Thapa, S.; Sears, J.
M.; Giri, R. J. Am. Chem. Soc. 2017, 139, 10653; (f) Thapa, S.;
Dhungana, R. K.; Magar, R. T.; Shrestha, B.; Kc, S.; Giri, R. Chem.
Sci. 2018,9, 904; (g) Li, W.; Boon, J. K.; Zhao, Y. Chem. Sci. 2018, 9,
600; (h) Derosa, J.; Tran, V. T.; Boulous, M. N.; Chen, J. S.; Engle, K.
M. J. Am. Chem. Soc. 2017, 139, 10657.
(10) (a) Wakabayashi, K.; Yorimitsu, H.; Oshima, K. J. Am. Chem.
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methylallyl)oxy)ethoxy)butane
internal
olefins
such
and
as
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(E)-(3-(1-butoxy-2-
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