A practical nickel-catalyzed reductive alkylation of amidophenyl bromides

Article abstract of DOI:10.1016/j.tet.2014.10.061

A modified Weix's reductive coupling for alkylation of amidoaryl bromides based on Ni(COD)₂ precatalyst and 2,2′-dipyridyl ligand was developed. This reaction is reliable for amidophenyl bromides and gives yields up to 87%, and is potentially useful in the synthesis of amidophenyl-containing molecules.

Full text of DOI:10.1016/j.tet.2014.10.061

Tetrahedron 70 (2014) 9522e9529
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A practical nickel-catalyzed reductive alkylation of amidophenyl
bromides
Xuge Liu, Zhilin Yang, Ya-Min Li, Fan Yang, Liang Feng, Nengzhong Wang, Debiao Ma,
*
Kwen-Jen Chang, Yuehai Shen
Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan 650500, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 May 2014
Received in revised form 20 October 2014
Accepted 27 October 2014
Available online 30 October 2014
A modified Weix’s reductive coupling for alkylation of amidoaryl bromides based on Ni(COD)2 pre-
catalyst and 2,20-dipyridyl ligand was developed. This reaction is reliable for amidophenyl bromides and
gives yields up to 87%, and is potentially useful in the synthesis of amidophenyl-containing molecules.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Reductive coupling
Nickel
Amidophenyl bromide
1. Introduction
not require the use of organometallic reagents, which need to be
prepared sometimes under harsh conditions. Pioneer studies from
Benzenoid ansamycins (BAs), a family of macrolactam polyke-
tide antibiotics produced by soil actinobacteria, structurally com-
prise a benzoquinone or non-benzoquinone benzene nucleus
bridged by a densely functionalized aliphatic chain at non-adjacent
positions (Fig. 1).1 Although research works on these natural
products could trace back to the discovery of geldanamycin in 1970,
an upsurge has been witnessed over the past two decades after the
discovery of their potential as anticancer agents. These natural
products have also attracted significant attention in the synthetic
chemistry community. To date, 15 total syntheses and formal total
syntheses of BA natural products have been reported.1,2
Current approaches to constructing the arylealkyl linkage in BA
framework mainly rely on connecting the C14eC15 aliphatic bond
by aldol or crotylation reactions, or connecting the C15eC16 ben-
zylic bond by aryllithium chemistry. In our ongoing efforts to de-
velop new synthetic methods for total synthesis of autolytimycin,3
we envisioned that the C15eC16 bond could be built by an aryl
halide reductive alkylation (Fig. 2). The reductive cross-coupling
reactions between aryl and alkyl halides have been intensively
studied very recently.4e9 Unlike traditional palladium-catalyzed
cross-coupling reactions, reductive coupling reactions are consid-
ered step-economic and user-friendly owing to the fact that they do
several academic groups have identified cobalt,4 iron,5 palladium,6
and nickel7e9 to be able to effectively catalyze aryl halide reductive
alkylation. It is particularly attractive that nickel-catalyzed re-
ductive couplings can tolerate even acidic functional groups such as
phenols and sulfonamides. Herein, we report our work on de-
veloping a practical nickel-catalyzed reaction system for amido-
phenyl bromide substrates.
2. Results and discussion
As Weix’s group has established protocols for the reductive
coupling between aryl bromide and primary alkyl bromide,7c
we initiated a model study to test if their standard conditions are
applicable. N-(3-Bromophenyl)acetamide (1a) was reacted with
1-bromooctane in the presence of nickel(II) iodide hydrate
(NiI2$xH2O) and 4,40-dimethoxy-2,20-dipyridyl (3a) in 1,3-dimethyl-
3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) with pyridine and
sodium iodide additives (Fig. 2). However, very sluggish reactions
were observed (entry 1, Table 1). These undesired results prompted
us to look for better conditions. Several commercially available 2,20-
dipyridyl ligands were added to the screening. Alkyl-bearing
dipyridyl ligands 3b and 3c also delivered low yields (entries 2 and
3). Interestingly, there is a noticeable trend showing that yield in-
creases as ligand becomesless electron-rich (entries 1e3). Following
this clue, a reaction using 2,20-dipyridyl (3d), which contains no
electron-donating groups, provided a significantly improved 61%
* Corresponding author. Tel.: þ86 871 65920747; e-mail address: yuehaishen@
gmail.com (Y. Shen).
http://dx.doi.org/10.1016/j.tet.2014.10.061
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

X. Liu et al. / Tetrahedron 70 (2014) 9522e9529
9523
O
O
O
OH
MeO
MeO
R
O
O
O
MeO
N
H
N
N
H
H
O
MeO
MeO
OH
OH
OMe
MeO
MeO
O
O
O
O
O
O
NH2
NH2
NH2
Geldanamycin
Macbecin
Autolytimycin, R = H
Reblastatin, R = OMe
Fig. 1. Representative benzoquinone and non-benzoquinone benzenoid ansamycins.
OH
For the runs delivering the coupling product, the reactions ini-
tiated with color change from brown to black. The reactions could
proceed without nitrogen protection, which is practically attractive.
However, the reactions with nitrogen protection initiated signifi-
cantly faster, suggesting that the oxygen in the system has to be
fully consumed by reaction with zinc dust before the initiation. The
reactions typically reach completion in 48 h after initiation. For the
ease of operation, the reaction vessels were purged with nitrogen
before sealed with septa, and a 4-day reaction time was adopted.
We used a moisture-containing precatalyst NiI2$xH2O at first.
Since the percentage of its combined water could change over time,
and previous studies revealed that the amount of water in the re-
action system has profound impacts on the outcomes,7a,9 it is de-
sirable to find a precatalyst containing fixed amount of or no water.
As the active nickel(0) species in the reactions can be generated
from 2- or 0-valent nickel,7 we conducted a screening of some
commercially available precatalysts (Table 2). Three 2-valent pre-
catalysts, NiCl2$6H2O, Ni(acac)2, and Ni(OTf)2, gave lower yields
(entries 2e4). Phosphine-bound Ni(PPh3)2Cl2 and Ni(PCy3)2Cl2
afforded similar results as NiI2$xH2O did (entries 5 and 6). On the
other hand, Ni(0) precatalyst Ni(COD)2 was found to deliver
a slightly better yield (65%, entry 7). It is worth mentioning that the
reactions took place smoothly in commercially available DMPU, but
were severely hampered in anhydrous DMPU (Table 3), which are
consistent with observations made by Weix’s and Gong’s groups.7,9
The molar ratios were then surveyed to further improve the yield
of this transformation and make it synthetically useful (Table 3).
Only slight improvement was observed with increased amount
of aromatic substrate 1a (entry 2). On the other hand, use of
1.2 equiv of 1-bromooctane gave an impressive 78% yield (entry 3),
O
Reductive
coupling
1
N
H
15
+
C8H17 Br
[N]
Br
MeO
OH
MeO
1
O
9
O
NH2
Fig. 2. Design of the model system of reductive coupling.
yield (entry 4). Phosphine ligands and 1,10-phenanthroline failed to
provide meaningful results. Reactions in DMF gave lower yields than
those in DMPU, and non-amide-type solvents (THF and acetonitrile)
completely inhibited the reaction. To assess the effect of the pro-
tective group, substrates with different masks of the amino group
werealsopreparedand tested. Sulfonamide 1b and pyrrole1c10 gave
yields less than 30% (entries 6 and 7). Boc-protected 1d and nitro-
benzene 1e were not reactive (entries 8 and 9). Therefore, acetamide
1a was chosen for further investigation.
The observed side reactions are homo-coupling of both aromatic
and aliphatic substrates, as well as reduction of aryl bromide. Trials
to suppress the side reactions by changing the amount of pyr-
idine7a,9 or sodium iodide7b were unsuccessful. Any pyridine
amount other than 10% or sodium iodide amount other than 25%
gave diminished yields. Replacing pyridine with electron-richer
DMAP or bulkier 2,6-lutidine resulted in yields less than 5%.
Table 1
Screening of amino protective groups, ligands, and solventsa
Entry
[N]
Product
Ligand
Yield (%)b
1
2
3
4
5
6
7
8
9
eNHAc (1a)
1a
1a
1a
2a
2a
2a
2a
2a
2b
2c
2d
2e
3a
3b
3c
3d
3d
3d
3d
3d
3d
Trace
14
34
61
58
1a
eNHTs (1b)
1-(2,5-Dimethylpyrrolyl) (1c)
eNHBoc (1d)
24
25
n.d.c
n.d.c
eNO2 (1e)
a
Reactions were carried out at 0.5 mmol scales in 2.0 ml of DMPU for 4 days.
Isolated yields.
Not detected.
b
c

9524
X. Liu et al. / Tetrahedron 70 (2014) 9522e9529
Table 2
span from electron-rich to electron-deficient, delivered no cross-
Screening of nickel precatalystsa,b
coupling product but instead homo-coupling byproducts. Ethyl
3-bromobenzoate (1o) gave alkylated product in a moderate 45%
yield, but the reductive alkylation could not take place for 4-
bromobenzoate 1p. Notably, for more complex benzyloxy-
bearing N-aryl amides 1qet, the C16e21 aromatic fragment of
autolytimycin and its regioisomers, desired products could be ob-
tained in 38e62% yields. Overall, this reaction performed reliably
for amidophenyl bromide substrates, but gave unpredictable out-
comes for non-amide aromatic substrates. Since some of these
non-amide substrates performed well under Weix’s condition,7 the
substrate scope of our work appears complementary to their work.
Finally, structurally more complex alkyl bromide substrates
were examined. The cross-couplings between aryl bromide 1q and
alkyl bromide 6 or 10 were chosen to mimic the synthesis of the
C15eC16 benzylic bond of autolytimycin. From intermediate 5
prepared previously in our lab from (5S)-dihydro-5-(hydrox-
ymethyl)-2(3H)-furanone (4),3 6, and 10 were obtained in three and
six steps, respectively (Scheme 1). To our satisfaction, these two
alkyl bromides reacted with aryl bromide 1q smoothly and de-
livered reductive coupling products 7 and 11 in usable 60% and 55%
yields after reacted for 2 days. Both the terminal olefin, which is
prone to radical additions, and the chelating alkylated 1,2-diol are
well tolerated under this condition.
Entry
Precatalyst
Yield (%)c
Yield (%)d
1
2
3
4
5
6
7
NiI2$xH2O
NiCl2$6H2O
Ni(acac)2
61
39
26
54
61
61
65
6
Trace
n.d.
Trace
18
Trace
6
Ni(OTf)2
Ni(PPh3)2Cl2
Ni(PCy3)2Cl2
Ni(COD)2
a
Reaction condition: 1-bromooctane (1.0 equiv), Ni(COD)2 (10%), 3d (10%), zinc
dust (2.0 equiv), NaI (0.25 equiv), pyridine (0.10 equiv), DMPU, 60 ꢁC.
b
Reactions were carried out at 0.5 mmol scales in 2.0 ml of DMPU for 4 days.
Isolated yields for reactions carried out in DMPU purchased from TCI.
Isolated yields for reactions carried out in ultra-dry DMPU (dried over activated
c
d
ꢀ
4 A molecular sieves for three times).
Table 3
Optimization of Ni(COD)2/3d catalyzed reductive coupling of 1a and 1-
bromooctanea
Entry
1a/n-OctBr
Ni(COD)2/3d (%)
Zn (equiv)
Yield (%)c
1
2
3
4
5
6
7
1:1
1.5:1
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
10
10
10
20
30
30
20
20
20
20
20
20
2
2
2
2
2
3
3
2
2
2
2
2
65
68
78
85
50
15
61
77
28
70
30
87
3. Conclusion
In summary, we developed a modified Weix’s reductive cou-
pling for alkylation of aryl bromides based on Ni(COD)2 precatalyst
and 2,20-dipyridyl ligand. Specifically, this reaction is reliable for
amidophenyl bromide substrates and gives yields up to 87%. The
alkylated 1,2-diol and terminal olefin, two typical structural fea-
tures of advanced intermediates in natural product synthesis, are
well tolerated.
8b
9d
10e
11d,e
12f
a
Reactions were carried out at 0.5 mmol scales with 10% pyridine and 25% NaI in
2.0 ml of DMPU at 60 ꢁC for 4 days.
4. Experimental section
4.1. General information
b
4.0 ml of DMPU was used.
Isolated yields.
1.0 equiv of MgCl2 was added.
1.0 equiv of TBAB was added.
Ni(COD)2 and 3d were stirred in DMPU at 60 ꢁC for 2 h before adding substrates
c
d
e
1H and 13C NMR spectra were obtained on a Bruker AM-
400 MHz spectrometer. Mass spectra were performed by the Mass
Spectrometry Facilities of Kunming Institute of Botany, Chinese
Academy of Sciences, and Yunnan University. Values of optical ro-
tation were recorded on a WZZ-2S spectropolarimeter. Anhydrous
solvents were prepared by standard methods. Chemicals were
purchased from J&K Scientific, Adamas Reagent, SigmaeAldrich,
Alfa Aesar, and TCI, and were used as received.
f
and other reagents.
indicating that the formation of the cross-coupling product was
limited mainly by side reactions of the alkyl bromide partner.7e9
Increasing the precatalyst and ligand loading to 20% further en-
hanced the yield to 85% (entry 4), but 30% loading produced inferior
yields (entry 5). Adding more zinc dust or solvent resulted in lower
yields (entries 6e8). In contrast to the results of Gong’s11 and Peng’s
groups,12 the addition of magnesium chloride or tetrabutylammo-
nium bromide (TBAB) seemed detrimental to the reaction (entries
9e11). Excitingly, premixing Ni(COD)2 and ligand 3d before reaction
setup was found capable of offering more reproducible results
(entry 12).8,12
With the optimized conditions in hand, more aryl bromides
were selected for assessing the substrate scope of this reaction
(Table 4). The para-amide 1f afforded 87% yield as well, but the
reaction of ortho-substituted 1g was less effective. Sulfonamide 1b
and Boc-protected amine 1d, two problematic substrates in our
initial screening with 10% of precatalyst and ligand, gave accept-
able 50% and 65% yields, respectively, indicating the impact of
catalyst loading in this system. N,N-Dimethyl-4-bromoaniline (1h)
also worked well (77% yield). In contrast, 4-bromoanisole (1i), 3-
bromoanisole (1j), 3-(tert-butyldimethylsilyloxy)bromobenzene
(1k), bromobenzene (1m), and 3-bromobenzonitrile (1n), which
4.2. Preparation of activated zinc dust
Commercial zinc dust (2.00 g) was treated with diluted hydro-
chloric acid (0.5 M, 20 ml) for 1 min, then washed with deionized
water (10 mlꢀ4), anhydrous ethanol (10 mlꢀ4), and diethyl ether
(10 mlꢀ4), and dried under vacuum. The obtained activated zinc
dust was stored under nitrogen.
4.3. General methods for nickel-catalyzed aryl halide re-
ductive alkylation
4.3.1. General method 1. An oven-dried Schlenk tube was charged
with aryl bromide (0.5 mmol), activated zinc dust (1.0 mmol), so-
dium iodide (0.125 mmol), 2,20-bipyridyl (0.05 mmol), and a nickel
catalyst (0.05 mmol) under nitrogen and capped with a rubber
septum. DMPU (GC grade, 2.0 ml), alkyl bromide (0.5 mmol), and

X. Liu et al. / Tetrahedron 70 (2014) 9522e9529
9525
Table 4
Substrate scopea,b,c
pyridine (0.05 mmol) were injected into the tube, respectively. The
mixture was stirred at 60 ꢁC for 4 days before work-up.
dust (1.0 mmol), sodium iodide (0.125 mmol), alkyl bromide
(0.5 mmol), pyridine (0.05 mmol), and additives (if applicable)
were added. The reaction mixture was stirred at 60 ꢁC for 2e4 days
before work-up.
4.3.2. General method 2 (premixing Ni(COD)2 and 2,20-bipyridyl). An
oven-dried Schlenk tube was charged with 2,20-bipyridyl
(0.05 mmol), Ni(COD)2 (0.05 mmol), and DMPU (2.0 ml) under ni-
trogen and capped with a rubber septum. The mixture was stirred
at 60 ꢁC for 2 h, and then aryl bromide (0.5 mmol), activated zinc
4.3.3. General work-up procedure. The reaction mixture was cooled
to room temperature, diluted by addition of ethyl acetate (60 ml),
and filtered. The filtrate was washed with aqueous solution of
O
OMe
ref. [5]
OMe
CHO
c, d
a, b
OMe
11 OBn
TBSO
O
TBSO
TBSO 15
4 steps
9
OMOM
4
5
8
OH
e, f
e, f
OMe
OMe
15
11
Br 15
9
Br
OBn
6
10
OMOM
g
g
OBn
OBn
OMe
OMe
15
OBn
15
9
11
AcHN
AcHN
7
11
OMOM
Scheme 1. Synthesis of 14-desmethyl C9e21 and C11e21 fragments of autolytimycin via reductive coupling. Reagents and conditions: (a) H2, Pd/C, MeOH, 95%; (b) Swern oxi-
dation, 91%; (c) (Z)-Roush crotylation, 93%, d.r. 5.5:1; (d) MOMCl, pyridine, DCM, 94%; (e) TBAF, THF, 97% for 6, 96% for 10; (f) PPh3, CBr4, 87% for 6, 95% for 10; (g) 1q, 20% Ni(COD)2,
20% 3d, 2.0 equiv Zn, 25% NaI, 10% pyridine, DMPU, 60 ꢁC, 2 days, 55% for 7, 60% for 11.

9526
X. Liu et al. / Tetrahedron 70 (2014) 9522e9529
sodium hydrogen sulfate (0.2 M, 50 ml) and water, and the com-
bined aqueous phases were extracted with ethyl acetate (10 ml).
The combined organic phases were dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash column chromatography to afford the targeted compound.
2H), 1.31e1.23 (m, 10H), 0.88 (t, J¼6.9 Hz, 3H). 13C NMR (101 MHz,
CDCl3)
d 168.5, 159.3, 145.1, 139.0, 137.0, 128.5, 127.9, 127.6, 112.4,
111.3, 103.7, 70.0, 36.1, 31.9, 31.2, 29.5, 29.3, 29.3, 24.6, 22.7, 14.1.
HRMS (ESI) calcd for C23H31NNaOþ2 [MþNa]þ, 376.2247; found
376.2259.
4.4. Characterization of reductive alkylation products
4.4.10. N-(2-Benzyloxy-3-octylphenyl)acetamide
(400 MHz, CDCl3)
(2r). 1H NMR
8.02 (d, J¼7.9 Hz, 1H), 7.42 (s, 1H), 7.38e7.25 (m,
d
4.4.1. N-(3-Octylphenyl)acetamide (2a). 1H NMR (400 MHz, CDCl3)
5H), 6.97 (t, J¼7.9 Hz, 1H), 6.86 (d, J¼7.5 Hz, 1H), 4.76 (d, J¼10.4 Hz,
2H), 2.65e2.54 (m, 2H), 1.78 (d, J¼10.5 Hz, 3H), 1.63e1.48 (m, 2H),
1.34e1.10 (m,10H), 0.80 (t, J¼6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d
8.18 (s, 1H), 7.32e7.22 (m, 2H), 7.09 (t, J¼7.7 Hz, 1H), 6.82 (d,
J¼7.6 Hz, 1H), 2.50e2.40 (m, 2H), 2.04 (s, 3H), 1.46 (dd, J¼14.7,
7.2 Hz, 2H), 1.17 (d, J¼5.3 Hz, 11H), 0.79 (t, J¼6.9 Hz, 3H). 13C NMR
d
168.1, 146.31, 137.2, 135.4, 131.7, 129.0, 128.7, 128.1, 124.9, 124.7,
(101 MHz, CDCl3)
d
168.0, 142.8, 137.0, 127.6, 123.3, 119.1, 116.4, 34.9,
118.3, 76.3, 31.9, 30.6, 30.0, 29.7, 29.5, 29.3, 24.5, 22.7, 14.1. HRMS
30.9, 30.4, 28.6, 28.3, 28.2, 23.4, 21.7, 13.1. HRMS (ESI) calcd for
(ESI) calcd for C23H31NNaO2þ [MþNa]þ, 376.2247; found 376.2246.
C
16H25NONaþ [MþNa]þ, 270.1834; found 270.1828.
4.4.11. N-(4-Benzyloxy-5-octylphenyl)acetamide
(2s). 1H
NMR
4.4.2. 4-Methyl-N-(3-octylphenyl) benzenesulfonamide (2b).13 1H
NMR (400 MHz, CDCl3)
(400 MHz, CDCl3)
d
7.40e7.09 (m, 7H), 6.75 (d, J¼8.7 Hz,1H), 4.97 (s,
d
7.64 (d, J¼8.3 Hz, 2H), 7.21 (d, J¼8.0 Hz,
2H), 2.55 (t, 2H), 2.06 (s, 3H), 1.58e1.45 (m, 2H), 1.30e1.10 (m, 10H),
2H), 7.15e7.09 (m, 1H), 6.92 (d, J¼7.8 Hz, 1H), 6.86 (d, J¼7.2 Hz, 2H),
6.61 (s, 1H), 2.50 (t, 2H), 2.37 (s, 3H), 1.55e1.46 (m, 2H), 1.29e1.20
(m, 10H), 0.88 (t, J¼6.9 Hz, 3H).
0.80 (t, J¼6.5 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d 168.2, 153.5,
137.5, 132.5, 130.9, 128.5, 127.7, 127.0, 122.4, 118.9, 112.1, 70.2, 31.9,
30.3, 29.9, 29.6, 29.5, 29.3, 24.4, 22.7, 14.1. HRMS (ESI) calcd for
C
23H31NNaOþ2 [MþNa]þ, 376.2247; found 376.2243.
4.4.3. 2,5-Dimethyl-1-(3-octylphenyl)pyrrole
(2c). 1H
NMR
(400 MHz, CDCl3) 7.41e7.37 (m, 1H), 7.16e7.13 (m, 1H), 6.96e6.94
d
4.4.12. N-(2-Benzyloxy-5-octylphenyl)acetamide
(2t). 1H
NMR
(m, 1H), 5.83 (d, J¼3.9 Hz, 2H), 2.57 (t, J¼7.6 Hz, 2H), 1.96 (s, 3H),
(400 MHz, CDCl3) 8.15 (s, 1H), 7.66 (s, 1H), 7.36e7.24 (m, 5H), 6.74
d
1.59e1.51 (m, 2H), 1.26e1.14 (m, 10H), 0.80 (t, J¼6.8 Hz, 3H). 13C
(q, J¼8.4 Hz, 2H), 4.99 (s, 2H), 2.50e2.42 (m, 2H), 2.05 (s, 3H), 1.49
NMR (101 MHz, CDCl3)
d
140.0, 139.2, 137.5, 129.3, 127.6, 126.9,
(dd, J¼14.6, 7.1 Hz, 2H),1.24e1.13 (m,10H), 0.79 (t, J¼6.7 Hz, 3H). 13
C
126.0, 105.8, 35.9, 31.6, 31.3, 29.5, 29.3, 29.2, 22.3, 14.0, 13.4. HRMS
NMR (101 MHz, CDCl3) d 167.1, 144.0, 135.7, 135.4,127.7, 127.3, 126.9,
(ESI) calcd for C20H29NNaþ [MþNa]þ, 306.2198; found 306.2205.
126.6, 122.2, 119.0, 110.6, 70.2, 34.6, 30.9, 30.7, 28.5, 28.4, 28.3, 23.9,
21.7, 13.1. HRMS (ESI) calcd for C23H31NNaOþ2 [MþNa]þ, 376.2247;
found 376.2254.
4.4.4. tert-Butyl N-(3-octylphenyl)aminoformate (2d). 1H NMR
(400 MHz, CDCl3)
d
7.16 (d, J¼8.2 Hz, 1H), 7.12e7.02 (m, 2H), 6.77 (d,
J¼7.2 Hz, 1H), 6.43 (s, 1H), 2.53e2.44 (m, 2H), 1.50 (dd, J¼14.6,
4.5. Preparation of benzyloxy-bearing (3-bromophenyl)
acetamides
7.2 Hz, 2H), 1.44 (s, 9H), 1.20 (d, J¼11.5 Hz, 11H), 0.80 (t, J¼6.7 Hz,
3H). 13C NMR (101 MHz, CDCl3)
d 152.8, 144.0, 138.3, 128.7, 123.2,
118.5, 115.9, 80.3, 36.1, 31.9, 31.5, 29.5, 29.4, 29.3, 28.4, 22.7, 14.1.
HRMS (ESI) calcd for C19H31NNaOþ2 [MþNa]þ, 328.2247; found
328.2247.
4.5.1. N-(3-Benzyloxy-5-bromophenyl)acetamide (1q)
4.5.1.1. 3-Benzyloxy-5-bromoaniline.18 1-Benzyloxy-3-bromo-5-
nitrobenzene (0.70 g, 2.27 mmol) was dissolved in ethyl acetate
(50 ml), and stirred with tin (II) chloride dihydrate (5.10 g,
22.7 mmol) at room temperature. Once the complete conversion
was detected, the mixture was neutralized by adding sodium hy-
droxide solution (5 N) and sodium carbonate, and filtered. The fil-
tration was concentrated under reduced pressure, and the residue
was purified by flash column chromatography (petroleum ether/
ethyl acetate) to give the title compound as a light yellow solid
(0.50 g, 79%).
4.4.5. N-(4-Octylphenyl)acetamide (2f).14 1H NMR (400 MHz,
CDCl3)
d
7.32 (d, J¼8.2 Hz, 2H), 7.02 (d, J¼8.2 Hz, 2H), 2.47 (t,
J¼7.7 Hz, 2H), 2.05 (s, 3H), 1.55e1.44 (m, 2H), 1.29e1.11 (m, 10H),
0.80 (t, J¼6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d 167.6, 138.0,
134.6, 127.8, 119.1, 34.4, 30.9, 30.5, 28.5, 28.3, 23.4, 21.6, 13.1. HRMS
(ESI) calcd for C16H25NNaOþ [MþNa]þ, 270.1828; found 270.1839.
4.4.6. N-(2-Octylphenyl)acetamide (2g).15 1H NMR (400 MHz,
CDCl3)
d 7.17e7.00 (m, 4H), 6.93 (s, 1H), 2.48 (t, 2H), 2.13 (s, 3H),
4.5.1.2. N-(3-Benzyloxy-5-bromo)phenylacetamide
(1q). 3-
1.55e1.45 (m, 2H), 1.33e1.14 (m, 10H), 0.81 (t, J¼6.8 Hz, 3H). HRMS
(ESI) calcd for C16H25NNaOþ [MþNa]þ, 270.1828; found 270.1834.
Benzyloxy-5-bromoaniline (0.50 g, 1.8 mmol) was dissolved in
dichloromethane (20 ml), and stirred with acetic anhydride (0.37 g,
3.6 mmol) and pyridine (0.43 g, 5.4 mmol) at room temperature.
Once the complete conversion was detected, the mixture was
washed with water, diluted hydrochloric acid and brine, and con-
centrated under reduced pressure. The residue was purified by
flash column chromatography (petroleum ether/acetone) to give
the title compound as a light yellow solid (0.56 g, 97%). 1H NMR
4.4.7. N,N-Dimethyl-4-octylbenzenamine (2h).16 1H NMR (400 MHz,
CDCl3)
d
7.07 (d, J¼8.7 Hz, 2H), 6.71 (d, J¼8.7 Hz, 2H), 2.91 (s, 6H),
2.51 (t, 2H), 1.62e1.53 (m, 2H), 1.33e1.24 (m, 10H), 0.88 (t, J¼6.9 Hz,
3H).
4.4.8. Ethyl 3-octylbenzoate (2o).17 1H NMR (400 MHz, CDCl3)
d 7.86
(400 MHz, CDCl3)
d
7.83 (s, 1H), 7.35e7.20 (m, 5H), 7.16 (s, 2H), 6.77
167.4,
(d, J¼6.3 Hz, 2H), 7.40e7.26 (m, 2H), 4.37 (q, J¼7.1 Hz, 2H), 2.64 (t,
J¼7.8 Hz, 2H), 1.61 (dd, J¼14.3, 6.9 Hz, 2H), 1.39 (t, J¼7.1 Hz, 3H), 1.28
(d, J¼14.9 Hz,10H), 0.88 (t, J¼6.5 Hz, 3H). 13C NMR (101 MHz, CDCl3)
(s, 1H), 4.87 (s, 2H), 2.05 (s, 3H). 13C NMR (101 MHz, CDCl3)
d
158.8,138.9,135.2, 127.6, 127.2,126.5,121.71,114.2,113.1, 104.3, 69.3,
23.7. HRMS (ESI) calcd for C15H15BrNOþ2 [MþH]þ, 320.0281; found
320.0274.
d
166.8, 143.1, 132.9, 130.4, 129.4, 128.1, 126.8, 60.8, 35.7, 31.8, 31.4,
29.4, 29.2, 29.2, 22.6, 14.3, 14.0.
(2q). 1H
NMR
4.5.2. N-(2-Benzyloxy-3-bromophenyl)acetamide (1r)
4.4.9. N-(3-Benzyloxy-5-octylphenyl)acetamide
(400 MHz, CDCl3)
d
7.46e7.27 (m, 6H), 7.20 (s, 1H), 6.82 (s, 1H), 6.57
4.5.2.1. 1-Benzyloxy-2-bromo-6-nitrobenzene.19 2-Bromo-6-
(s, 1H), 5.03 (s, 2H), 2.58e2.48 (m, 2H), 2.15 (s, 3H), 1.63e1.51 (m,
nitrophenol (2.00 g, 9.2 mmol), anhydrous potassium carbonate

X. Liu et al. / Tetrahedron 70 (2014) 9522e9529
9527
(3.80 g, 27.5 mmol), and benzyl bromide (1.90 g, 11.1 mmol) were
2.05 (s, 3H). 13C NMR (101 MHz, CDCl3)
d
167.5, 150.9, 135.4, 131.1,
stirred in acetone (60 ml) under reflux. Once the complete con-
version was detected, the mixture was filtered, and the filtrate was
concentrated under reduced pressure. The residue was purified by
flash column chromatography (petroleum ether/ethyl acetate) to
give the title compound as a light yellow solid (2.59 g, 93%).
127.6, 126.9, 126.0, 124.6, 119.5, 113.1, 111.4, 70.2, 23.3.
4.5.4. N-(2-Benzyloxy-5-bromophenyl)acetamide (1t)
4.5.4.1. 4-Bromo-2-nitrophenol.22 4-Bromophenol
(10.6
g,
60 mmol), sodium nitrite (6.21 g, 90 mmol), and sodium hydrogen
sulfate monohydrate (16.6 g, 120 mmol) was stirred in acetonitrile
(100 ml) at 50 ꢁC. Once the complete conversion was detected, the
mixture was filtered, and the filtrate was concentrated under re-
duced pressure. The residue was purified by flash column chro-
matography (petroleum ether/ethyl acetate) to give the title
compound as a light yellow solid (8.50 g, 65%).
4.5.2.2. N-(2-Benzyloxy-3-bromo)phenylacetamide
(1r). 1-
Benzyloxy-2-bromo-6-nitrobenzene (2.60 g, 8.4 mmol) was dis-
solved in ethyl acetate (100 ml), and stirred with tin (II) chloride
dihydrate (19.0 g, 84 mmol) at room temperature overnight. The
mixture was neutralized by adding sodium hydroxide solution
(5 N) and sodium carbonate, and filtered. The filtration was con-
centrated under reduced pressure to give a light yellow solid. The
above-obtained crude 2-benzyloxy-3-bromoaniline was dissolved
in dichloromethane (100 ml), and stirred with acetic anhydride
(2.80 g, 27.4 mmol) and pyridine (3.30 g, 41.7 mmol) at room
temperature. Once the complete conversion was detected, the
mixture was washed with water, diluted hydrochloric acid and
brine, and concentrated under reduced pressure. The residue was
purified by flash column chromatography (petroleum ether/ace-
tone) to give the title compound as a white solid (2.52 g, 93%). 1H
4.5.4.2. 1-Benzyloxy-4-bromo-2-nitrobenzene.23 4-Bromo-2-
nitrophenol (7.0 g, 32 mmol), anhydrous potassium carbonate
(13.3 g, 96 mmol), and benzyl bromide (5.7 ml, 8.21 g, 48 mmol)
were stirred in acetone (100 ml) under reflux. Once the complete
conversion was detected, the mixture was filtered, and the filtrate
was concentrated under reduced pressure. The residue was purified
by flash column chromatography (petroleum ether/ethyl acetate)
to give the title compound as a light yellow solid (8.10 g, 82%).
4.5.4.3. 2-Benzyloxy-5-bromoaniline.24 1-Benzyloxy-4-bromo-
2-nitrobenzene (4.00 g, 13 mmol) was dissolved in ethyl acetate
(100 ml), and stirred with tin (II) chloride dihydrate (29.3 g,
130 mmol) at room temperature. Once the complete conversion
was detected, the mixture was neutralized by adding sodium hy-
droxide solution (5 N) and sodium carbonate, and filtered. The fil-
tration was concentrated under reduced pressure, and the residue
was purified by flash column chromatography (petroleum ether/
ethyl acetate) to give the title compound as a light yellow solid
(3.00 g, 83%).
NMR (400 MHz, CDCl3)
d
8.25 (d, J¼7.6 Hz, 1H), 7.50e7.39 (m, 6H),
7.32e7.25 (m, 1H), 6.99 (t, J¼8.2 Hz,1H), 5.03 (s, 2H),1.85 (s, 3H). 13
C
NMR (101 MHz, CDCl3) d 167.1, 143.9, 135.5, 132.6, 128.1, 128.0, 127.7,
126.8, 124.9, 118.4, 115.2, 75.3, 23.5. HRMS (ESI) calcd for
C
15H15BrNOþ2 [MþH]þ, 320.0281; found 320.0282.
4.5.3. N-(4-Benzyloxy-3-bromophenyl)acetamide (1s)
4.5.3.1. 1-Benzyloxy-2-bromo-4-nitrobenzene.20 4-Nitrophenol
(5.00 g, 35.9 mmol) was dissolved in concentrated sulfuric acid
(40 ml) at room temperature. The solution was cooled to 0 ꢁC, and
N-bromosuccinimide (6.40 g, 36.0 mmol) was added portionally.
Once the complete conversion was detected, the mixture was
poured onto ice. The resulted precipitates were collected by filtra-
tion, washed with water, and dried. The above-obtained crude 2-
bromo-4-nitrophenol was dissolved in acetone (100 ml), and stir-
red with potassium carbonate (12.5 g, 90.4 mmol) and benzyl
bromide (6.20 g, 36.2 mmol) under reflux for 5 h. The mixture was
filtered, and the filtrate was concentrated under reduced pressure.
The residue was purified by flash column chromatography (petro-
leum ether/ethyl acetate 20:1e9:1) to give the title compound as
a light yellow solid (8.38 g, 76% for two steps).
4.5.4.4. N-(2-Benzyloxy-5-bromo)phenylacetamide
(1t). 2-
Benzyloxy-5-bromoaniline (600 mg, 2.16 mmol) was dissolved in
dichloromethane (10 ml), and stirred with acetic anhydride (0.70 g,
6.6 mmol) and pyridine (0.70 g, 9.0 mmol) at room temperature.
Once the complete conversion was detected, the mixture was
washed with water, diluted hydrochloric acid and brine, and con-
centrated under reduced pressure. The residue was purified by
flash column chromatography (petroleum ether/acetone) to give
the title compound as a white solid (601 mg, 87%). 1H NMR
(400 MHz, CDCl3)
5H), 7.02 (dd, J¼8.6, 2.2 Hz, 1H), 6.71 (d, J¼8.7 Hz, 1H), 5.02 (s, 2H),
2.07 (s, 3H). 13C NMR (101 MHz, CDCl3)
167.1, 144.8, 134.9, 128.2,
d
8.51 (d, J¼2.1 Hz, 1H), 7.65 (s, 1H), 7.37e7.28 (m,
4.5.3.2. 4-Benzyloxy-3-bromoaniline.21 1-Benzyloxy-2-bromo-
4-nitrobenzene (4.00 g, 13 mmol) was dissolved in ethyl acetate
(100 ml), and stirred with tin (II) chloride dihydrate (35.2 g,
156 mmol) at room temperature. Once the complete conversion
was detected, the mixture was neutralized by adding sodium hy-
droxide solution (5 N) and sodium carbonate, and filtered. The fil-
tration was concentrated under reduced pressure, and the residue
was purified by flash column chromatography (petroleum ether/
ethyl acetate 3:1) to give the title compound as colorless oil (2.51 g,
69%).
d
127.8, 127.5, 126.6, 125.1, 121.5, 112.9, 112.0, 70.3, 23.9. HRMS (ESI)
calcd for C15H15BrNOþ2 [MþH]þ, 320.0281; found 320.0280.
4.6. N-[3-Benzyloxy-5-((4S)-5-benzyloxy-4-methoxypentan-
1-yl)phenyl]acetamide (7)
4.6.1. (4S)-5-Benzyloxy-4-methoxypentan-1-ol.3 (2S)-1-Benzyloxy-
5-tert-butyldimethylsiloxy-2-methoxypentane3
(5,
1.20
g,
3.54 mmol) was dissolved in a solution of tetrabutylammonium
fluoride (0.5 M in THF, 10.4 ml, 5.2 mmol) at room temperature.
Once the full conversion was detected, the mixture was concen-
trated under reduced pressure. The residue was purified by flash
column chromatography (petroleum ether/ethyl acetate) to give
the title compound as colorless oil (0.77 g, 97%).
4.5.3.3. N-(3-Bromo-4-benzyloxy)phenylacetamide
(1s).21 4-
Benzyloxy-3-bromoaniline (2.50 g, 9.0 mmol) was dissolved in
dichloromethane (10 ml), and stirred with acetic anhydride (2.20 g,
21.5 mmol) and pyridine (3.10 g, 39.2 mmol) at room temperature.
Once the complete conversion was detected, the mixture was
washed with water, diluted hydrochloric acid and brine, and con-
centrated under reduced pressure. The residue was purified by
flash column chromatography (petroleum ether/acetone 3:1) to
give the title compound as a white solid (2.40 g, 83%). 1H NMR
4.6.2. (2S)-1-Benzyloxy-5-bromo-2-methoxypentane (6).3 (4S)-5-
Benzyloxy-4-methoxypentan-1-ol (0.50 g, 2.23 mmol), triphenyl-
phosphine (1.75 g, 6.67 mmol), and carbon tetrabromide (1.11 g,
3.35 mmol) were dissolved in dichloromethane (80 ml) at room
temperature for 10 min. The mixture was washed with saturated
(400 MHz, CDCl3)
J¼6.9 Hz, 2H), 7.33e7.22 (m, 4H), 6.76 (d, J¼8.9 Hz, 1H), 5.02 (s, 2H),
d
7.62 (d, J¼2.6 Hz, 1H), 7.53 (s, 1H), 7.37 (d,

9528
X. Liu et al. / Tetrahedron 70 (2014) 9522e9529
sodium bicarbonate solution, and concentrated under reduced
pressure. The residue was purified by flash column chromatogra-
phy (petroleum ether/ethyl acetate) to give the title compound as
light yellow oil (0.56 g, 87%).
sodium hydroxide solution (1 M, 50 ml). After stirring at room
temperature for 1 h, the mixture was filtered. The separated
aqueous phase was extracted with ethyl acetate. The combined
organic layers were dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash column
chromatography over silica gel (petroleum ether/ethyl acetate
40:1) to provide the title compound as colorless oil (4.01 g, 93%).
4.6.3. N-[3-Benzyloxy-5-((4S)-5-benzyloxy-4-methoxypentan-1-yl)
phenyl]acetamide (7). (2S)-1-Benzyloxy-5-bromo-2-methoxypentane
(6, 172 mg, 0.60 mmol) was reacted with N-(3-benzyloxy-5-
bromophenyl)acetamide (1q, 160 mg, 0.50 mmol) for 2 days using
General method 2 to give the title compound as colorless oil (123 mg,
½
a 2D0
ꢂ
ꢃ11.2 (c 1.18, CHCl3). 1H NMR (400 MHz, CDCl3)
d 5.68 (ddd,
J¼17.3, 10.3, 8.2 Hz, 1H), 5.09e4.98 (m, 2H), 3.67e3.54 (m, 3H), 3.35
(s, 3H), 3.19e3.13 (m, 1H), 2.38e2.26 (m, 1H), 1.70e1.47 (m, 4H), 1.11
(d, J¼6.7 Hz, 3H), 0.88 (s, 9H), 0.03 (s, 6H). 13C NMR (101 MHz,
55%). ½a 1D7
ꢂ
ꢃ17.0 (c 2.0, CHCl3). 1H NMR (400 MHz, CDCl3)
d 7.48
(s, 1H), 7.37e7.10 (m, 11H), 6.73 (s, 1H), 6.47 (s, 1H), 4.92 (s, 2H), 4.45
(s, 2H), 3.38 (d, J¼4.8 Hz, 2H), 3.31 (s, 3H), 3.18e3.11 (m, 1H), 2.84
(s, 1H), 2.45 (t, J¼7.3 Hz, 2H), 2.04 (s, 3H), 1.66e1.38 (m, 4H). 13C NMR
CDCl3) d 140.5, 115.0, 82.0, 73.7, 63.3, 57.1, 40.1, 28.8, 26.0, 24.0, 18.3,
16.4, ꢃ5.3. HRMS (ESI) calcd for C16H34NaO3Siþ [MþNa]þ, 325.2175;
found 325.2192.
(101 MHz, CDCl3) d 167.5, 158.2, 143.4, 138.0, 137.3, 135.9, 127.5, 127.3,
126.9, 126.6, 126.6, 126.5, 111.3, 110.2, 102.8, 79.0, 72.3, 71.0, 68.9, 56.6,
35.0, 30.1, 25.9, 23.6. HRMS (ESI) calcd for C28H33NOþ4 [M]þ, 447.2410;
found 447.2415.
4.7.4. (3S,4R,5S)-8-tert-Butyldimethylsiloxy-5-methoxy-4-(methoxy)
methoxy-3-methylpent-1-ene
(9). (3S,4R,5S)-8-tert-Butyldime-
thylsiloxy-5-methoxy-3-methylpent-1-en-4-ol (3.1 g, 10.2 mmol)
was dissolved in dichloromethane (50 ml), and stirred with methyl
chloromethyl ether (5.5 ml, 72 mmol), diisopropylethylamine
(17 ml,102 mmol), and 4-dimethylaminopyridine (0.12 g, 1.0 mmol)
at room temperature overnight. The mixture was washed with
water, diluted hydrochloric acid and brine, and concentrated under
reduced pressure. The residue was purified by flash column chro-
matography (petroleum ether/ethyl acetate) to give the title com-
4.7. N-[3-Benzyloxy-5-((4S,5R,6S)-4-methoxy-5-(methoxy)
methoxy-6-methyloct-7-en-1-yl)phenyl]acetamide (11)
4.7.1. (2S)-5-tert-Butyldimethylsiloxy-2-methoxypentan-1-ol. To
a
solution of (2S)-1-benzyloxy-5-tert-butyldimethylsiloxy-2-
methoxypentane (5, 13.0 g, 38.4 mmol) in methanol (250 ml) was
added Pd/C (10% w/w, 2.0 g). The mixture was stirred under hy-
drogen till full conversion was detected, and filtered through Celite.
The filtrate was concentrated under reduced pressure. The residue
was purified by flash column chromatography (petroleum ether/
acetone) to give the title compound as colorless oil (9.08 g, 95%).
pound as colorless oil (3.38 g, 94%). ½a D22
ꢂ
þ7.56 (c 0.86, CHCl3). 1H
NMR (300 MHz, CDCl3)
d
5.70 (ddd, J¼18.1, 10.1, 8.4 Hz, 1H), 4.97 (t,
J¼13.0 Hz, 2H), 4.74 (t, J¼7.2 Hz, 1H), 4.59 (d, J¼6.6 Hz, 1H),
3.67e3.49 (m, 3H), 3.36 (s, 3H), 3.29 (s, 3H), 3.21e3.13 (m, 1H), 2.32
(dt, J¼14.2, 7.1 Hz, 1H), 1.70e1.57 (m, 2H), 1.54e1.45 (m, 2H), 1.06 (d,
J¼6.7 Hz, 3H), 0.85 (s, 9H), 0.00 (s, 6H). 13C NMR (75 MHz, CDCl3)
½
a 2D5
ꢂ
þ14.9 (c 3.2, CHCl3). 1H NMR (400 MHz, CDCl3)
d 3.71e3.57 (m,
3H), 3.54e3.44 (m, 1H), 3.41e3.37 (m, 3H), 3.32e3.24 (m, 1H),
d 141.4, 114.5, 97.4, 82.4, 80.0, 77.5, 77.2, 63.3, 40.1, 29.2, 25.9, 25.5,
1.65e1.44 (m, 4H), 0.88 (s, 9H), 0.03 (s, 6H). 13C NMR (101 MHz,
16.6, ꢃ5.3. HRMS (ESI) calcd for
C
18H38NaO4Siþ [MþNa]þ,
CDCl3)
d
81.5, 63.7, 63.0, 57.0, 28.4, 26.5, 25.9, 18.3, ꢃ5.4. HRMS (ESI)
369.2437; found 369.2435.
calcd for C12H28NaO3Siþ [MþNa]þ, 271.1705; found 271.1713.
4.7.5. (4S,5R,6S)-4-Methoxy-5-(methoxy)methoxy-6-methylpent-7-
en-1-ol. (3S,4R,5S)-8-tert-Butyldimethylsiloxy-5-methoxy-4-
(methoxy)methoxy-3-methylpent-1-ene (9) (100 mg, 0.29 mmol)
was dissolved in a solution of tetrabutylammonium fluoride (0.5 M
in THF, 2.0 ml, 1.0 mmol) at room temperature. Once the full con-
version was detected, the mixture was concentrated under reduced
pressure. The residue was purified by flash column chromatogra-
phy (petroleum ether/ethyl acetate) to give the title compound as
4.7.2. (2S)-5-tert-Butyldimethylsiloxy-2-methoxypentan-1-al (8). To
a solution of oxalyl chloride (12.3 ml, 140 mmol) in methylene
chloride (140 ml) at ꢃ80 ꢁC was added dimethyl sulfoxide (20 ml,
280 mmol). After stirring for 20 min, a solution of (2S)-5-tert-
butyldimethylsiloxy-2-methoxypentan-1-ol (8.7 g, 35 mmol) in
methylene chloride (30 ml) was added dropwise. The mixture was
stirred for 20 min. Triethylamine (74.7 ml, 525 mmol) was added,
and the reaction was allowed to warm up to room temperature.
Water (200 ml) was added, and the separated aqueous phase was
extracted with dichloromethane (30 mlꢀ3). The combined organic
layers were dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash column chro-
matography over silica gel (petroleum ether/ethyl acetate 40:1) to
colorless oil (64 mg, 96%). ½a D26
ꢂ
þ3.87 (c 2.12, CHCl3). 1H NMR
(400 MHz, CDCl3)
d
5.69 (ddd, J¼17.3, 10.3, 8.3 Hz, 1H), 5.06e4.92
(m, 2H), 4.75 (d, J¼6.7 Hz, 1H), 4.60 (d, J¼6.7 Hz, 1H), 3.63e3.55 (m,
3H), 3.38e3.33 (m, 4H), 3.30 (s, 3H), 3.20 (ddd, J¼11.1, 6.7, 4.3 Hz,
1H), 2.38e2.27 (m, 1H), 1.65e1.56 (m, 4H), 1.07 (d, J¼6.7 Hz, 3H). 13
C
NMR (101 MHz, CDCl3)
d 140.2, 113.8, 96.4, 81.8, 78.6, 61.8, 56.0,
provide the title compound as colorless oil (7.82 g, 91%). ½a D25
ꢂ
ꢃ34.2
55.0, 39.3, 28.2, 24.5, 15.8. HRMS (ESI) calcd for C12H25Oþ4 [MþH]þ,
(c 3.4, CHCl3). 1H NMR (400 MHz, CDCl3)
d
9.63 (d, J¼2.0 Hz, 1H),
233.1747; found 233.1741.
3.63e3.57 (m, 3H), 3.43 (s, 3H), 1.80e1.53 (m, 4H), 0.87 (s, 9H), 0.03
(s, 6H). 13C NMR (101 MHz, CDCl3)
d
203.4, 85.3, 62.4, 57.9, 27.6,
4.7.6. (3S,4R,5S)-8-Bromo-5-methoxy-4-(methoxy)methoxy-3-
26.0, 25.8, 18.1, ꢃ5.5. HRMS (ESI) calcd for C12H26NaO3Siþ [MþNa]þ,
methylpent-1-ene
(10). (4S,5R,6S)-4-Methoxy-5-(methoxy)
269.1549; found 269.1538.
methoxy-6-methylpent-7-en-1-ol (100 mg, 0.43 mmol), triphe-
nylphosphine (0.34 g, 1.29 mmol), and carbon tetrabromide (0.21 g,
0.63 mmol) were dissolved in dichloromethane (10 ml) at room
temperature for 10 min. The mixture was washed with saturated
sodium bicarbonate solution, and concentrated under reduced
pressure. The residue was purified by flash column chromatogra-
phy (petroleum ether/ethyl acetate) to give the title compound as
4.7.3. (3S,4R,5S)-8-tert-Butyldimethylsiloxy-5-methoxy-3-
methyloct-1-en-4-ol. To a freshly prepared solution of (Z)-Roush
crotylation reagent (0.5 M in toluene, 94 ml, 47 mmol) was added
ꢀ
activated 4 A molecular sieves (30 g). The mixture was stirred under
nitrogen at room temperature for 30 min, and then cooled to
ꢃ80 ꢁC. (2S)-5-tert-Butyldimethylsiloxy-2-methoxypentan-1-al (8)
(3.50 g, 14.2 mmol) was dissolved in toluene (10 ml), and slowly
transferred into the reaction vessel via cannula. The reaction mix-
ture was stirred at the same temperature overnight, and then
allowed to warm to room temperature, and quenched by adding
light yellow oil (120 mg, 95%). ½a D23
ꢂ
þ2.32 (c 2.5, CHCl3). 1H NMR
(400 MHz, CDCl3)
d
5.72 (ddd, J¼17.2, 10.3, 8.4 Hz, 1H), 5.10e4.97
(m, 2H), 4.78 (d, J¼6.7 Hz,1H), 4.63 (d, J¼6.7 Hz,1H), 3.58 (dd, J¼7.9,
2.9 Hz, 1H), 3.42e3.38 (m, 5H), 3.32 (s, 3H), 3.21 (dt, J¼8.8, 3.0 Hz,
1H), 2.41e2.29 (m, 1H), 2.13e2.00 (m, 1H), 1.92e1.79 (m, 1H),

X. Liu et al. / Tetrahedron 70 (2014) 9522e9529
9529
1.71e1.61 (m, 2H), 1.10 (d, J¼6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3)
3. Yang, F.; Feng, L.; Wang, N. Z.; Liu, X. G.; Li, J.; Shen, Y. H. Tetrahedron 2013, 69,
9463e9468.
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d
141.1, 114.9, 97.4, 82.0, 79.5, 57.1, 56.1, 40.4, 34.1, 29.3, 27.7, 17.0.
HRMS (ESI) calcd for C12H23BrNaOþ3 [MþNa]þ, 317.0728; found
317.0721.
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4.7.7. N-[3-Benzyloxy-5-((4S,5R,6S)-4-methoxy-5-(methoxy)me-
thoxy-6-methyloct-7-en-1-yl)phenyl]acetamide
(11). N-(3-
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Benzyloxy-5-bromophenyl)acetamide (1q) (160 mg, 0.50 mmol)
was reacted with (3S,4R,5S)-8-Bromo-5-methoxy-4-(methoxy)
methoxy-3-methylpent-1-ene (10) (177 mg, 0.60 mmol) for 2 days
using General method 2 to give the title compound as colorless oil
(137 mg, 60%). ½a D17
ꢂ
þ5.44 (c 2.5, CHCl3). 1H NMR (400 MHz, CDCl3)
d
7.38e7.22 (m, 6H), 6.74 (s, 1H), 6.52 (s, 1H), 5.64 (ddd, J¼17.2, 10.3,
8.3 Hz, 1H), 4.96 (s, 2H), 4.95e4.89 (m, 2H), 4.72 (d, J¼6.6 Hz, 1H),
4.56 (dd, J¼6.6, 3.3 Hz, 1H), 3.50 (dd, J¼7.6, 3.0 Hz, 1H), 3.32 (d,
J¼3.4 Hz, 3H), 3.25 (s, 3H), 3.16e3.10 (m, 1H), 2.48 (t, J¼7.1 Hz, 2H),
2.27 (dd, J¼14.5, 7.3 Hz, 1H), 2.08 (s, 3H), 1.54e1.45 (m, 4H), 1.03 (d,
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472e474.
13. Foss, F. W.; Snyder, A. H.; Davis, M. D.; Rouse, M.; Okusa, M. D.; Lynch, K. R.;
J¼6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d 167.5, 158.2, 143.6, 140.3,
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138.0, 136.0, 127.5, 126.9, 126.5, 113.7, 111.3, 110.2, 102.7, 96.4, 81.7,
78.9, 68.9, 56.3, 55.1, 39.2, 35.1, 27.9, 26.6, 23.6, 15.8. HRMS (ESI)
calcd for C27H37NNaOþ5 [MþNa]þ, 478.2569; found 478.2563.
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ꢁ
17. Soule, J.-F.; Miyamura, H.; Kobayashi, S. J. Am. Chem. Soc. 2013, 135,
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Acknowledgements
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Financial support for this research is obtained from Kunming
University of Science and Technology (14078134) and National
Natural Science Foundation of China (81260351). Helps from Prof.
Chengfeng Xia at Kunming Institute of Botany, Chinese Academy of
Sciences on spectrometric analyses are appreciated.
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References and notes
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