General and highly α-regioselective zinc-mediated prenylation of aldehydes and ketones

Article abstract of DOI:10.1021/jo102516a

A simple, efficient, and general R-prenylation approach for the synthesis of a variety of R-prenylated alcohols has been successfully developed. A wide range of R-prenylated alcohol derivatives could be obtained in good yields by highly R-regioselective zinc-mediated prenylation of various aldehydes and ketones with prenyl bromide at 120 °C in HMPA. By simply altering the reaciton solvent and temperature, the method allows the achievement of a highly notable opposite regiocontrol, providing the expected regiochemical product. The method provides a convenient route for the direct α-prenylation of carbonyl compounds in a highly R-regioselective manner using a cheap and convenient mediator. Two possible pathways are proposed to account for the formation of these synthetically difficult-toobtain molecules.

Full text of DOI:10.1021/jo102516a

ARTICLE
pubs.acs.org/joc
General and Highly r-Regioselective Zinc-Mediated Prenylation of
Aldehydes and Ketones
Li-Ming Zhao,* Hai-Shan Jin, Li-Jing Wan, and Li-Ming Zhang
School of Chemistry and Chemical Engineering, Xuzhou Normal University, Xuzhou 221116, Jiangsu, China
S Supporting Information
b
ABSTRACT: A simple, efficient, and general R-prenylation approach for
the synthesis of a variety of R-prenylated alcohols has been successfully
developed. A wide range of R-prenylated alcohol derivatives could be
obtained in good yields by highly R-regioselective zinc-mediated prenyla-
tion of various aldehydes and ketones with prenyl bromide at 120 °C in
HMPA. By simply altering the reaciton solvent and temperature, the
method allows the achievement of a highly notable opposite regiocontrol, providing the expected regiochemical product. The
method provides a convenient route for the direct R-prenylation of carbonyl compounds in a highly R-regioselective manner using a
cheap and convenient mediator. Two possible pathways are proposed to account for the formation of these synthetically difficult-to-
obtain molecules.
he R-prenylated alcohol structural unit is found in a large
alcohol derivatives, only one highly R-regioselective prenylation
example has been reported by Cuerva and Oltra using tita-
nocene(III) complexes as the catalyst so far in the literature.7 The
substrate generality of this reaction, however, remained limited.
In particular, the reaction with nonconjugated aldehydes and
ketones resulted only in the formation of γ-adducts because of
the weak coordination between the carbonyl and TiIII. Further-
more, this method suffered from the preparation of the
titanocene(III) complexes, bis(cyclopentadienyl)titanium(III)
chloride. These disadvantages prevented a general application
of this approach. Thus, our continued interest in the synthesis of
drug-like molecules, derived from a prenyl fragment containing
the natural products, spurred us to investigate an alternative and
practical method to directly access the R-prenylated alcohols by
addition of prenyl metal to aldehyde. We recently reported a
highly R-regioselective zinc-mediated addition of prenyl bromide
to 1,4,5,8-tetramethoxynaphthalene-2-carbaldedehyde.8 The re-
action offered a concise, high-yielding, and highly R-regioselec-
tive route from aldehyde to shikonin compared with the reported
syntheses of shikonin.4a,b9 We therefore considered whether we
might be able to exploit similar reaction to directly access R-
prenylated alcohols by addition of the prenylzinc to different
aldehydes and ketones. We report herein the successful attain-
ment of this goal. This methodology enables the efficient syn-
thesis of R-prenylated alcohol via a highly R-regioselective
prenylmetal-aldehyde addition using convenient and inexpensive
zinc as the mediator with broad substrate scope. Although zinc
has been often used for the addition of allyl metal reagents to
carbonyl compounds,5a,10 zinc as a mediator employed in pre-
nylmetal-aldehyde R-regioselectivity addition has not been well
demonstrated so far. As a related reaction, Loh’s group reported
T
number of interesting natural products such as shikonin,
inotodiol, and terpenpoids.1 The structure is also important
organic building block and versatile synthon.2 Moreover, many
natural compounds containing this fragment have been isolated
continually from natural sources in recent years.3 The synthesis
of this important structure, therefore, has been the focus of
synthetic organic chemists.4 In principle, the metal-mediated
nucleophilic prenyl addition to aldehydes is the most reliable
method to construct R-prenylated alcohols, but there is con-
siderable difficulty in controlling the R-regioselectivity of the
addition. The reason is that the metal-mediated prenylation of
carbonyl compounds with prenyl halides occurs regioselectively
at the γ-position (eq 1).5 Although considerable efforts have
been made to explore the simple and direct R-regioselectivity
addition of carbonyl compounds, less progress with this ap-
proach has been achieved because of severe difficulty in regios-
electivity control. Only a limited number of examples of R-
selective carbonyl prenylation have been reported, and they
usually require relatively expensive samarium or reactive barium
and generally give mixtures containing an amount of undesired
γ-addition product.6 In practice, R-prenylated alcohols are often
reached by alternative methods that are flawed by low synthetic
efficiency such as harsh reaction conditions, multiple-step synthe-
sis, or use of not readily available substances.4
Although the addition of a prenylmetal reagent to a carbonyl
compound represents a very straightforward route to R-prenylated
Received: December 22, 2010
Published: February 17, 2011
r
2011 American Chemical Society
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Table 1. Optimization of Reaction Conditions
Table 2. r-Prenylation of Various Aldehydes and Ketones
entry
substrate
product
yield (%)
entry
solvent
Et2O
T (°C)
t
2a (%)
3a (%)
1
2-FC6H4CHO 1b
2b
2c
2d
2e
2f
92
85
80
79
88
84
79
83
80
81
84
75
87
91
86
88
80
1
2
3
4
5
6
7
8
reflux
reflux
reflux
100
3 d
ND
trace
13
92
2
3-FC6H4CHO 1c
THF
3 d
94
3
4-FC6H4CHO 1d
THF/HMPA
HMPA
HMPA
HMPA
DMF
3 d
72
4
4-BrC6H4CHO 1e
2,6-Cl2C6H3CHO 1f
3,4-(OCH2O)C6H3CHO 1g
2-furaldehyde 1h
8 h
60
10
5
120
8 h
87
trace
ND
ND
ND
6
2g
2h
2i
130
12 h
12 h
12 h
91
7
130
31
8
2-thenaldehyde 1i
DMSO
130
20
9
isonicotinaldehyde 1j
cinnamaldehyde 1k
c-C6H11CHO 1l
2j
10
11
12
13
14
15
16
17
2k
2l
the first example of the indium-, tin-, and zinc-mediated addition
reaction of crotyl bromide with aldehydes to give R-adduct.
However, they found that when the same conditions were
extended to the R-prenylation of aldehydes, it did not work.4f
cyclohexanone 1m
C6H5COCH3 1n
2m
2n
2o
2p
2q
2r
4-ClC6H4COCH3 1o
4-OCH3C6H4COCH3 1p
2-ClC6H4COCH3 1q
4-OHC6H4COCH3 1r
’ RESULTS AND DISCUSSION
Our work started with the determination of optimal reaction
conditions using the addition of prenylzinc bromide with
2-methoxybenzaldehyde 1a as model reaction. In an initial study,
when prenylzinc bromide reacted with aldehyde 1a in diethyl
ether (Et2O), only γ-addition took place leading to γ-adduct 3a
in an isolated yield of 92% (Table 1, entry 1). Interesting, a trace
In addition, the addition reaction in refluxing Et2O for 3 d did
not lead to the desired R-adduct, only γ-addition adduct. However,
the R-adduct could be found in the reaction when the same reaction
was performed in refluxing THF. High reaction temperature
in HMPA (100 °C) led to the increased R-addition product.
R-Regioselectivity increased significantly when a higher temperature
was applied. Thus, we further reasoned that the temperature also has
an important influence on the regioselective outcome of the
addition. High reaction temperature facilitated the generation of
the R-adduct, whereas low reaction temperature favored γ-regiose-
lective addition. We then proceeded to perform the reaction at a
higher temperature. To our delight, when reacting aldehyde 1a with
prenylzinc bromide in HMPA at 120 °C, the R-adduct 2a was
obtained in 87% yield together with a trace amount of the γ-adduct
(entry 5). Further increase in the temperature and the reaction time
improved the yield of R-adduct to 91% (entry 6). These results
showed that the higher temperature used in the reaction condition
was also effective in isomerizing the initially formed γ-isomer to the
R-isomer. The results of the reaction of 1a under these conditions
with prenylzinc bromide are listed in Table 1. It was evident that this
reaction was solvent- and temperature-dependent and led predo-
minantly to the R-addition product. In order to probe the function
of HMPA and to eventually replace this carcinogen by a less toxic
solvent, we examined several other solvents that exhibit the proper-
ties similar to those of HMPA. To our disappointment, changing the
solvent from HMPA to N,N-dimethylformamide (DMF) or di-
methyl sulfoxide (DMSO) caused the yield of R-adduct to decrease
sharply and afforded some unidentified byproduct (entries 7 and 8).
This may be ascribed to the different solvation structure of the zinc
ion in these solvents13 and different metal complexation.14
1
amount of R-adduct was detected by GC-MS and H NMR
when the reaction was performed in more basic tetrahydrofuran
(THF) (entry 2). Moreover, we observed the same reaction for
which addition of HMPA to the THF solution increased the
amount of R-adduct. In THF-HMPA both γ- and R-adducts
were obtained in 72% and 13% isolated yields, respectively (entry 3).
The experiments described in entries 1-3 in Table 1 showed that
the solvent played an important role in product distribution.
Based on this observation, could the regioselectivity be con-
trolled by the use of different solvent? There are many precedents
in which the regioselectivity depends on the reaction solvent
used (Et2O or THF vs HMPA), particularly the work of Reich
and co-workers about the impact of HMPA on the organolithium
chemistry (CIP vs SSIP interactions).11 To examine this hypoth-
esis, we turned our attention on the use of HMPA as a solvent. As
expected, a dramatic increase in the yield of R-adduct was
observed by evaporation of the initial reaction solvent (THF),
addition of HMPA, and heating the reaction to 100 °C. As shown
in entry 4, the R-regioselecivity was significantly shifted toward
the formation of R-adduct 2a in HMPA, producing 3a in only a
10% yield. These results indicated that the use of polar aprotic
solvent HMPA in the addition promoted isomerization of the
γ-adduct to the corresponding R-adduct. When the reaction was
carried out in Et2O or THF, the process of isomerization was
more difficult than in HMPA. This difference can probably be
attributed to the greater basicity of HMPA.12 Because HMPA is a
stronger Lewis base than Et2O and THF, it could be expected to
complex more strongly with the zinc atom of initially formed
γ-prenylated zinc alcoholate, thereby causing the zinc-oxygen
bond to be more ionic in HMPA.
Having established the optimized conditions for R-regiose-
lective addition, we proceeded to investigate the scope of sub-
strates using a wide range of aldehydes. Gratifyingly, as shown in
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Scheme 1. Proposed Mechanism for the Reaction Regiocontrol
Table 2, all of these substrates underwent highly R-regioselective
prenylation and afforded the prenylation product in good to high
yields after purification by column chromatography on silica gel.
Prenyl bromide was readily reacted with aryl aldehydes bearing
ortho, meta, and para substitutions on the aryl ring to give the
corresponding products 2b-2d in good to high yields. For example,
2-fluorobenzaldehyde 1b gave the R-prenylation product with the
highest yield (92% yield) (entry 1), the R-prenylated alcohol from
3-fluorobenzaldehyde 1c was obtained with 85% yield (entry 2),
and 4-fluorobenzaldehyde 1d gave 80% yield (entry 3). The rea-
ctions performed smoothly with aryl aldehydes containing electron-
donating 1g (entry 6) and electron-withdrawing groups 1b-1f
(entries 1-5). Heterocyclic aldehydes containing oxygen 1h
(entry 7), sulfur 1i (entry 8), and nitrogen 1j (entry 9) were also
found to give the corresponding R-prenylation products 2h-2j
in satisfactory yields using the present conditions. A noteworthy
observation was that this prenylation was highly chemoselective,
reacting selectively with the carbonyl group without affecting the
R,β-unsaturated bond moiety of cinnamaldehyde 1k (entry 10).
Another outstanding advantage of the zinc-promoted R-prenyla-
tion method was that this reaction tolerated nonconjugated
aldehydes such as cyclohexanecarboxaldehyde 1l very well
(entry 11) and afforded functionalized R-prenylation product
2l that was difficult to prepare by other methods.7
Inspired by the results from aldehyde, we were subsequently
interested in the regioselectivity of zinc-mediated prenylation of
ketones, which were inherently subject to less electrophilic and
higher steric hindrance than aldehydes. Aliphatic and aromatic
ketones were surveyed. We treated cyclohexanone 1m, acetophe-
none 1n, and substituted acetophenones 1o-1r with prenyl bro-
mide using the same conditions with aldehydes. In this way we also
obtain desired R-adducts 2m, 2n, 2o, 2p, 2q, and 2r, respectively
(entries 12-17). The regiochemical outcomes were similar to those
using aldehydes, thus confirming the validity of this procedure.
Such satisfactory results displayed by zinc-mediated prenyla-
tion reaction prompted us to investigate the mechanism. A
plausible scenario of the R-regioselective prenylation of carbonyl
compounds is illustrated in Scheme 1. Two possible pathways are
proposed to account for the formation of these compounds. One
pathway involves the formation of the γ-prenylation product,
which originate from the nucleophilic attack of the γ-carbon of
the prenylzinc bromide, via a cyclic transition state analogous to
that reported previously.15 The initially formed zinc alcoholate A
undergoes a bond cleavage to generate the parent aldehyde or
ketone and primary prenylzinc in situ. This behavior is similar to
that observed in earlier work by Benkeser et al.16 Subsequently a
metallotropic equilibrium between primary and tertiary prenyl-
zinc occurs in the presence of HMPA.12a The resulting tertiary
prenylzinc adds again to the aldehyde with a different regios-
electivity compared to that of the reaction in THF to afford zinc
alcoholate F via a six-membered cyclic transition state (path A).
Another possible pathway also involves the formation of
γ-prenylation product at the beginning. Then HMPA would
be able to coordinate the zinc atom of initially formed zinc
alcoholate A as observed for various metal ions13a and more
particularly for lithium,11 thus activating the organozinc reagent
as a Lewis base (path B). The origin of activation by HMPA is
believed to be the enhanced Lewis acidity of zinc.17 The metal
zinc center in the resulting complex B maintains sufficient Lewis
acidity and further coordinates the aldehyde, which results in the
formation of the transition state C.18 The latter reaction involves
a [3,5]-sigmatropic shift at an elevated temperature, proceeding
via a eight-membered transition state. Though [3,5]-sigmatropic
shifts are not theoretically allowed by the Woodward-Hoffmann
rules, it seems to be possible as Birney and co-workers repor-
ted.19 We would like to classify this rearrangement as a metallo-
[3,5]-sigmatropic shift. The σ-bond migrates across the con-
jugated π-system containing the zinc counterion to form more
stable transition state D, which is sterically less hindered and
thermodynamically more stable. Subsequently, the parent alde-
hyde or ketone is regenerated from metal zinc-oxygen bond
cleavage of transition state D to reenter the reaction. Finally, the
dissociation of HMPA from the intermediate E liberates the
ligand to afford zinc alcoholate F.
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Scheme 2. Reaction of Zinc Alcoholate and
2-Methoxybenzaldehyde
Scheme 4. Crossover Reaction between 2-Chloroacetophe-
none and 4-Chloroacetophenone
Scheme 3. Crossover Reaction between 2-Methoxybenzal-
dehyde and 3-Fluorobenzaldehyde
’ CONCLUSION
In conclusion, we have developed a general and practical zinc-
mediated R-prenylation method using aldehydes and ketones for
the straightforward synthesis of R-prenylated alcohol derivatives.
This approach provides the easiest pathway for accessing this
class of valuable compounds. Although somewhat higher tem-
peratures are needed, the reaction is easy to perform and is more
convenient than the previously described carbonyl prenylation
methods,6a,7 which require metal complexes as catalysts that are
not always easy to prepare. By simply altering the reaction solvent
and temperature, a remarkable reversal of regioselectivity can be
achieved to give the desired regiochemical outcome. Moreover,
our investigations have shown that this R-regioselective zinc-
meditated prenylation is highly feasible for a wide range of
substrates including aliphatic, aromatic, conjugated, and non-
conjugated aldehydes and ketones. Two possible pathways are
proposed to account for the formation of these synthetically
difficult-to-obtain molecules. Further study to show the synthetic
utility of the highly R-regioselective zinc-mediated prenylation is
now in progress. Several attempts have been made to replace the
carcinogenic HMPA, but it is still the solvent of choice in terms of
high yields of the desired product in this highly R-regioselective
prenylation so far. Efforts are still in progress to replace HMPA
by a safer, but still efficient solvent for the zinc-mediated addition.
To test the proposed mechanism, we treated γ-adduct 3a first
with BuLi and then with zinc bromide to afford the zinc alco-
holate,20 which allowed to react with 2-methoxybenzaldehyde 1a
at 120 °C in HMPA (Scheme 2). Analysis of the reaction mix-
ture by GC-MS and 1H NMR indicated complete consumption
of 3a and the formation of 2a, which favors the proposed mech-
anism.
We next studied the crossover reaction between 2-methox-
ybenzaldehyde 1a and 3-fluorobenzaldehyde 1c. 2-Methoxy-
benzaldehyde 1a reacted with prenylzinc bromid in THF at
room temperature to afford the γ-adduct 3a after workup
procedure. Treatment of pure γ-adduct 3a first with BuLi and
then with zinc bromide, followed by reaction with 3-fluoro-
benzaldehyde 1c at 120 °C in HMPA, afforded the crossover
products 2a and 2c in 21% and 34% yields, respectively, after
column chromatography (Scheme 3). Furthermore, a crossover
reaction between 2-chloroacetophenone 1q and 4-chloroace-
tophenone 1o was also conducted under the aforementioned
conditions (Scheme 4). Similarly to the case of the reaction with
aldehydes, reaction with ketones gave products 2q and 2o in
32% and 44% yields, respectively, after chromatographic pur-
ification. By performing the crossover reaction, we thought it
was possible to distinguish between pathway A and B. However,
transition state C or D cannot be observed in the reaction.
Thus, it should be noted that the possibility of pathway A could
not be completely ruled out.
’ EXPERIMENTAL SECTION
General Procedure for the Synthesis of r-Adducts 2. Ex-
ample for the Synthesis of 2a. Prenyl bromide (0.5 mL, 4.37 mmol) was
added into a suspension of activated zinc powder21 (500 mg, 7.7 mmol)
in dry THF (15 mL); the reaction mixture was stirred for 1 h at room
temperature. The solution was filtered through a Schlenk filter and kept
under N2 for the following reaction. A solution of 2-methoxybenzalde-
hyde 1a (272 mg, 2.0 mmol) in dry THF (3 mL) was added to the
solution of prenylzinc bromide prepared above. The solution was stirred
for 1 h at room temperature. Then HMPA (1.1 mL) was added into the
reaction mixture, followed by removal of initial reaction solvent (THF).
The mixture was heated to 120 °C for 8 h. After cooling to room
temperature, the reaction was quenched with saturated NH4Cl solution.
The mixture was extracted with dichloromethane and washed with brine,
dried, and concentrated. The residue was purified by flash column
chromatography (petroleum ether/ethyl acetate, 15/1, v/v) to afford
1
the R-adduct 2a (358 mg, 87% yield) as pale yellow oil. H NMR
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(400 MHz, CDCl3): δ 7.34 (d, J = 7.2 Hz, 1H), 7.24 (t, J = 7.2 Hz, 1H),
6.96 (t, J = 7.6 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 5.22 (t, J = 7.6 Hz, 1H),
4.90 (t, J = 6.0 Hz, 1H), 3.84 (s, 3H), 2.57 (br. s, 1H), 2.53-2.43 (m,
2H), 1.72 (s, 3H), 1.60 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 156.5,
134.7, 132.2, 128.2, 126.8, 120.7, 120.5, 110.4, 70.5, 55.3, 36.2, 25.9, 17.9.
HRMS (ESI): m/z calcd for C13H18O2Na [M þ Na]þ 229.1199, found
229.1200.
Characterization of 2j. Yellow oil. 1H NMR (400 MHz, CDCl3):
δ 8.51 (d, J = 5.6 Hz, 2H), 7.29 (d, J = 5.6 Hz, 2H), 5.14 (t, J = 7.6 Hz,
1H), 4.69 (t, J = 6.4 Hz, 1H), 2.72 (br. s, 1H), 2.44 (t, J = 7.2 Hz, 2H),
1.73 (s, 3H), 1.59 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 154.1,
149.2, 149.2, 136.0, 121.1, 121.1, 119.0, 72.3, 37.9, 25.8, 17.9. HRMS
(ESI): m/z calcd for C11H16NO [M þ H]þ 178.1226, found 178.1228.
1
Characterization of 2k. Pale yellow oil. H NMR (400 MHz,
1
Characterization of 2b. Pale yellow oil. H NMR (400 MHz,
CDCl3): δ 7.38 (d, J = 7.6 Hz, 2H), 7.31 (t, J = 7.6 Hz, 2H), 7.23 (t, J =
7.2 Hz, 1H), 6.60 (d, J = 16.0 Hz, 1H), 6.25 (dd, J = 6.4 Hz, J = 16.0 Hz,
1H), 5.20 (t, J = 7.2 Hz, 1H), 4.30 (q, J = 6.4 Hz, 1H), 2.39-2.31 (m,
2H), 1.83 (s, 1H), 1.74 (s, 3H), 1.66 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 136.9, 135.6, 132.0, 130.1, 128.6, 127.6, 126.5, 126.5,
119.3, 72.5, 36.4, 26.0, 18.1. HRMS (ESI): m/z calcd for C14H18ONa
[M þ Na]þ 225.1250, found 225.1247.
CDCl3): δ 7.48 (dt, J = 7.6 Hz, J = 1.6 Hz, 1H), 7.27-7.21 (m, 1H), 7.15
(t, J = 7.6 Hz, 1H), 7.01 (t, J = 8.8 Hz, 1H), 5.19 (t, J = 7.6 Hz, 1H),
5.03-4.99 (m, 1H), 2.53-2.42 (m, 2H), 2.07 (d, J = 4.0 Hz, 1H), 1.73
(s, 3H), 1.61 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 159.8 (d, J =
243.7 Hz), 136.0, 131.2 (d, J = 13.0 Hz), 128.6 (d, J = 8.5 Hz), 127.2 (d,
J = 4.0 Hz), 124.1 (d, J = 3.3 Hz), 119.4, 115.1 (d, J = 21.0 Hz), 68.0 (d,
J = 2.2 Hz), 37.0, 25.9, 17.9. HRMS (ESI): m/z calcd for C12H15FONa
[M þ Na]þ 217.0999, found 217.1003.
1
Characterization of 2l. Pale yellow oil. H NMR (400 MHz,
CDCl3): δ 5.17 (t, J = 6.8 Hz, 1H), 3.35-3.34 (m, 1H), 2.22-2.09 (m,
1
2H), 1.87 (d, 1H), 1.74 (s, 3H), 1.64 (s, 3H), 1.78-0.97 (m, 11H); 13
C
Characterization of 2c. Pale yellow oil. H NMR (400 MHz,
CDCl3): δ 7.32-7.26 (m, 1H), 7.12-7.07 (m, 2H), 6.95 (dt, J = 8.0 Hz,
J = 2.0 Hz, 1H), 5.14 (dt, J = 6.8 Hz, J = 1.2 Hz, 1H), 4.66 (t, J = 6.8 Hz,
1H), 2.49-2.36 (m, 2H), 2.15 (s, 1H), 1.73 (s, 3H), 1.61 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 162.9 (d, J = 243.4 Hz), 147.0 (d, J =
7.4 Hz), 136.2, 129.8 (d, J = 8.7 Hz), 121.4 (d, J = 2.9 Hz), 119.3, 114.1
(d, J = 21.1 Hz), 112.7 (d, J = 22.0 Hz), 73.3 (d, J = 1.7 Hz), 38.2, 25.9,
17.9. HRMS (ESI): m/z calcd for C12H15FONa [M þ Na]þ 217.0999,
found 217.0997.
NMR (100 MHz, CDCl3): δ 135.1, 120.7, 75.8, 43.1, 32.9, 29.2, 28.2,
26.6, 26.3, 26.1, 25.9, 17.9. HRMS (ESI): m/z calcd for C12H22ONa
[M þ Na]þ 205.1563, found 205.1565.
Characterization of 2m. Yellow oil. 1H NMR (400 MHz, CDCl3):
δ 5.24 (t, J = 7.6 Hz, 1H), 2.15 (d, J = 7.6 Hz, 2H), 1.75 (s, 3H), 1.64 (s,
3H), 1.61-1.39 (m, 10H); 13C NMR (100 MHz, CDCl3): δ 134.4, 117.9,
70.9, 39.5, 36.3, 36.3, 25.1, 24.8, 21.2, 21.2, 17.0. HRMS (ESI): m/zcalcd for
C11H20ONa [M þ Na]þ 191.1406, found:.191.1410.
1
1
Characterization of 2d. Pale yellow oil. H NMR (400 MHz,
Characterization of 2n. Pale yellow oil. H NMR (400 MHz,
CDCl3): δ 7.32 (t, J = 8.2 Hz, 2H), 7.02 (t, J = 8.4 Hz, 2H), 5.14 (t, J =
6.8 Hz, 1H), 4.65 (t, J = 6.0 Hz, 1H), 2.50-2.34 (m, 2H, CH2), 2.07 (s,
1H), 1.72 (s, 3H), 1.60 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 162.1
(d, J = 243.7 Hz), 140.0 (d, J = 2.6 Hz), 135.9, 127.5, 127.4, 119.5, 115.2,
114.9, 73.4, 38.4, 25.9, 17.9. HRMS (ESI): m/z calcd for C12H15FONa
[M þ Na]þ 217.0999, found 217.0992.
CDCl3): δ 7.44 (d, J = 7.6 Hz, 2H), 7.34 (t, J = 7.6 Hz, 2H), 7.23 (t, J =
7.6 Hz, 1H), 5.00 (t, J = 8.0 Hz, 1H), 2.54 (d, J = 8.4 Hz, 2H), 2.04
(s, 1H), 1.68 (s, 3H), 1.61 (s, 3H), 1.53 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 148.1, 136.5, 128.1, 128.1, 126.5, 124.9, 124.9, 118.9,
74.5, 42.5, 29.8, 26.1, 18.1. HRMS (ESI): m/z calcd for C13H18ONa
[M þ Na]þ 213.1250, found:.213.1254
1
1
Characterization of 2e. Pale yellow oil. H NMR (400 MHz,
Characterization of 2o. Pale yellow oil. H NMR (400 MHz,
CDCl3): δ 7.46 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 5.13 (t, J =
6.8 Hz, 1H), 4.64 (t, J = 6.4 Hz, 1H), 2.48-2.35 (m, 2H), 1.73 (s, 3H),
1.60 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 143.2, 136.2, 131.4,
131.4, 127.6, 127.6, 121.1, 119.2, 73.3, 38.3, 25.9, 18.0. HRMS (ESI):
m/z calcd for C12H15BrONa [M þ Na]þ 277.0198, found 277.0199.
CDCl3): δ 7.37 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 4.97 (t, J =
7.6 Hz, 1H), 2.51 (d, J = 7.2 Hz, 2H), 2.01 (s, 1H), 1.69 (s, 3H), 1.61 (s,
3H), 1.51 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 146.7, 136.9, 132.3,
128.1, 128.1, 126.4, 126.4, 118.4, 74.2, 42.4, 29.8, 26.0, 18.0. HRMS
(ESI): m/z calcd for C13H17ClONa [M þ Na]þ 247.0860, found:.
247.0863.
1
Characterization of 2f. Pale yellow oil. H NMR (400 MHz,
1
CDCl3): δ 7.28 (d, J = 8.0 Hz, 2H), 7.12 (t, J = 8.0 Hz, 2H), 5.41 (t, 1H),
5.20 (t, J = 7.2 Hz, 1H), 2.87 (br. s, 1H), 2.83-2.58 (m, 2H), 1.70 (s,
3H), 1.58 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 137.6, 135.4, 134.4,
129.3, 129.3 128.8, 128.8, 119.2, 72.0, 34.3, 25.8, 17.8. HRMS (ESI):
m/z calcd for C12H14Cl2ONa [M þ Na]þ 267.0314, found 267.0315.
Characterization of 2p. Pale yellow oil. H NMR (400 MHz,
CDCl3): δ 7.37 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 5.02 (t, J =
8.8 Hz, 1H), 3.82 (s, 3H), 2.52 (d, J = 8.8 Hz, 2H), 1.98 (s, 1H), 1.69 (s,
3H), 1.62 (s, 3H), 1.52 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 158.2,
140.4, 136.2, 126.0, 126.0, 119.0, 113.4, 113.4, 74.2, 55.2, 42.6, 29.8, 26.0,
18.0. HRMS (ESI): m/z calcd for C14H20O2Na [M þ Na]þ 243.1356,
found:.243.1355.
1
Characterization of 2g. Pale yellow oil. H NMR (400 MHz,
CDCl3): δ 6.88 (s, 1H), 6.82-6.74 (m, 2H), 5.94 (s, 2H), 5.14 (dt, J =
6.6 Hz, J = 1.2 Hz, 1H), 4.58 (dd, J = 8.0 Hz, J = 5.2 Hz, 1H), 2.49-2.32
(m, 2H), 2.04 (br. s, 1H), 1.72 (s, 3H), 1.62 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 142.4, 141.5, 133.2, 130.4, 114.5, 114.0, 102.8, 101.2,
95.7, 68.7, 33.1, 20.7, 12.8. HRMS (ESI): m/z calcd for C13H16O3Na
[M þ Na]þ 243.0992, found 243.0994
1
Characterization of 2q. Pale yellow oil. H NMR (400 MHz,
CDCl3): δ 7.68 (dd, J = 7.8 Hz, J = 1.6 Hz, 1H), 7.34 (dd, J = 7.8 Hz, J =
1.6 Hz, 1H), 7.25 (td, J = 8.0 Hz, J = 1.6 Hz, 1H), 7.18 (td, J = 7.6 Hz, J =
2.0 Hz, 1H), 4.92 (t, J = 7.6 Hz, 1H), 3.02-2.69 (m, 2H), 2.55 (s, 1H),
1.69 (s, 3H), 1.67 (s, 3H), 1.63 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ 144.2, 136.4, 131.3, 130.9, 128.1, 128.0, 126.8, 118.8, 75.1, 39.3, 27.2,
25.9, 18.0. HRMS (ESI): m/z calcd for C13H17ClONa [M þ Na]þ
247.0860, found:.247.0861.
Characterization of 2h. Yellow oil. 1H NMR (400 MHz,
CDCl3): δ 7.38 (t, J = 0.8 Hz, 1H), 6.33 (dd, J = 1.6 Hz, J = 2.8 Hz,
1H), 6.23 (d, J = 3.2 Hz, 1H), 5.14 (t, J = 7.2 Hz, 1H), 4.69 (t, J = 6.8 Hz,
1H), 2.63-2.52 (m, 2H), 2.05 (s, 1H), 1.73 (s, 3H), 1.65 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 156.4, 141.9, 135.7, 119.0, 110.1, 105.9, 67.6,
34.5, 25.9, 17.9. HRMS (ESI): m/z calcd for C10H14O2Na [M þ Na]þ
189.0886, found 189.0888.
1
Characterization of 2r. Pale yellow oil. H NMR (400 MHz,
CDCl3): δ 7.20 (t, J = 8.0 Hz, 1H), 7.01 (t, J = 2.0 Hz, 1H), 6.94 (dddd, J =
8.0 Hz, J = 1.6 Hz, J = 1.2 Hz, J = 0.8 Hz, 1H), 6.71 (dddd, J = 8.0 Hz, J = 2.6
Hz, J = 1.2 Hz, J = 0.8 Hz, 1H), 5.42 (br.s, 1H), 5.00 (t, J = 8.0 Hz, 1H), 2.53
(d, J = 8.0 Hz, 2H), 2.17 (s, 1H), 1.68 (s, 3H), 1.62 (s, 3H), 1.52 (s, 3H);
13C NMR (100 MHz, CDCl3): δ 155.9, 150.0, 136.9, 129.4, 118.6, 117.2,
113.5, 112.2, 74.7, 42.3, 29.7, 26.0, 18.0. HRMS (ESI): m/z calcd for
C13H18O2Na [M þ Na]þ 229.1199, found:.229.1200.
Characterization of 2i. Yellow oil. 1H NMR (400 MHz, CDCl3):
δ 7.24 (dd, J = 1.6 Hz, J = 4.2 Hz, 1H), 6.98-6.96 (m, 2H), 5.18 (t, J =
6.8 Hz, 1H), 4.93 (t, J = 7.2 Hz, 1H), 2.63-2.50 (m, 2H), 2.17 (d, J = 4.0
Hz, 1H), 1.73 (s, 3H), 1.64 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
148.3, 136.0, 126.6, 124.4, 123.6, 119.3, 70.1, 38.3, 25.9, 18.1. HRMS
(ESI): m/z calcd for C10H14OS [M þ Na]þ 205.0658, found 205.0657.
General Procedure for the Synthesis of γ-Adducts 3. Ex-
ample for the synthesis of 3a. Prenyl bromide (0.5 mL, 4.37 mmol) was
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ARTICLE
added into a suspension of activated zinc powder21 (500 mg, 7.7 mmol)
in dry THF (15 mL); the reaction mixture was stirred for 1 h at room
temperature. The solution was filtered through a Schlenk filter and kept
under N2 for the following reaction. A solution of 2-methoxybenzalde-
hyde 1a (272 mg, 2.0 mmol) in dry THF (3 mL) was added to the
solution of prenylzinc bromide prepared above. The solution was stirred
for 1 h at room temperature and then quenched with saturated NH4Cl
solution. The mixture was extracted with dichloromethane and washed
with brine, dried, and concentrated. The residue was purified by flash
column chromatography (petroleum ether/ethyl acetate, 15/1, v/v) to
afford the γ-adduct 3a (386 mg, 94% yield) as pale yellow oil. 1H NMR
(400 MHz, CDCl3): δ 7.28 (d, J = 8.0 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H),
6.94 (t, J = 7.6 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 5.96 (dd, J = 10.8 Hz, J =
17.6 Hz, 1H), 5.07 (d, J = 10.8 Hz, 1H), 5.02 (d, J = 17.6 Hz, 1H), 4.84(s,
1H), 3.80 (s, 3H), 2.55 (br. s, 1H), 1.03(s, 3H), 0.98 (s, 3H).
(4) (a) Nicolaou, K. C.; Hepworth, D. Angew. Chem., Int. Ed. 1998,
37, 839–841. (b) Couladouros, E. A.; Strongilos, A. T.; Papageorgiou,
V. P.; Plyta, Z. F. Chem.—Eur. J. 2002, 8, 1795–1803. (c) Cheng, H. S.;
Loh, T. P. J. Am. Chem. Soc. 2003, 125, 4990–4991. (d) Tan, K. T.; Chng,
S. S.; Cheng, H. S.; Loh, T. P. J. Am. Chem. Soc. 2003, 125, 2958–2963.
(e) Tsubuki, M.; Matsuo, S.; Honda, T. Heterocycles 2005, 66, 535–542.
(f) Cheng, H. S.; Loh, T. P. Pure Appl. Chem. 2005, 77, 1199–1206.
(g) Sagnou, M.; Strongilos, A.; Hadjipavlou-Litina, D.; Couladouros,
E. A. Lett. Drug Des. Discovery 2009, 6, 172–177. (h) Nokami, J.;
Nomiyama, K.; Matsuda, S.; Imai, N.; Kataoka, K. Angew. Chem., Int.
Ed. 2003, 42, 1273–1276.
(5) (a) Denmark, S. E.; Fu, J. Chem. Rev. 2003, 103, 2763–2794.
(b) Loh, T. P.; Zhou, J. R.; Zheng, Y. Org. Lett. 1999, 1, 1855–1857.
(c) Moslin, R. M.; Jamison, T. F. J. Org. Chem. 2007, 72, 9736–9745.
(d) Ma, C.; Schiltz, S.; Le Goff, X. F. Chem.—Eur. J. 2008, 14, 7314–
7323. (e) Zhang, Z.; Huang, J.; Ma, B.; Kishi, Y. Org. Lett. 2008,
10, 3073–3076. (f) Fleury, L. M.; Ashfeld, B. L. Org. Lett. 2009,
11, 5670–5673. (g) Sinha, P.; Roy, S. Chem. Commun. 2001, 1798–
1799.
’ ASSOCIATED CONTENT
(6) (a) Guo, B. S.; Doubleday, W.; Cohen, T. J. Am. Chem. Soc. 1987,
109, 4710–4711. (b) Matsukawa, S.; Funabashi, Y.; Imamoto, T.
Tetrahedron Lett. 2003, 44, 1007–1010. (c) Girard, P.; Namy, J. L.;
Kagan, H. B. J. Am. Chem. Soc. 1980, 102, 2693–2698. (d) Hamann-
Gaudinet, B.; Namy, J. L.; Kagan, H. B. J. Organomet. Chem. 1998,
567, 39–47. (e) Yanagisawa, A.; Habaue, S.; Yamamoto, H. J. Am. Chem.
Soc. 1991, 113, 8955–8956. (f) Yanagisawa, A.; Habaue, S.; Yasue, K.;
Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 6130–6141.
(7) Estevez, E.; Justicia, J.; Bazdi, B.; Fuentes, N.; Paradas, M.;
Choquesillo-Lazarte, D.; Garcia-Ruiz, J. M.; Robles, R.; Gansauer, A.;
Cuerva, J. M.; Oltra, J. E. Chem.—Eur. J. 2009, 15, 2774–2791.
(8) Zhao, L. M.; Xu, D. F.; Zhou, W.; Li, S. S. Lett. Org. Chem. 2008,
5, 234–236.
S
Supporting Information. Detailed crossover experimen-
b
tal procedure and copies of H and 13C NMR spectra. This
material is available free of charge via the Internet at http://pubs.
acs.org.
1
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: lmzhao@xznu.edu.cn.
’ ACKNOWLEDGMENT
(9) (a) Terada, A.; Tanoue, Y.; Hatada, A.; Sakamoto, H. Bull. Chem.
Soc. Jpn. 1987, 60, 205–213. (b) Braun, M.; Bauer, C. Liebigs Ann. Chem.
1991, 1157–1164. (c) Torii, S.; Akiyama, K.; Yamashita, H.; Inokuchi, T.
Bull. Chem. Soc. Jpn. 1995, 68, 2917–2922. (d) Couladouros, E. A.; Plyta,
Z. F.; Strongilos, A. T.; Papageorgiou, V. P. Tetrahedron Lett. 1997,
38, 7263–7266. (e) Lu, Q.; Duan, W. H.; Cai, J. C. Chin. Chem. Lett.
2002, 13, 113–114. (f) Yang, H.; Li, Q.; Bao, J. X.; Lu, W.; Aisa, H. A.;
Cai, J. C. Chin. Chem. Lett. 2002, 13, 515–518.
(10) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207–2293.
(11) (a) Sikorski, W. H.; Reich, H. J. J. Am. Chem. Soc. 2001,
123, 6527–6535. (b) Reich, H. J.; Sikorski, W. H. J. Org. Chem. 1999,
64, 14–15. (c) Reich, H. J.; Borst, J. P.; Dykstra, R. R. Tetrahedron 1994,
50, 5869–5880. (d) Reich, H. J.; Sanders, A. W.; Fiedler, A. T.; Bevan,
M. J. J. Am. Chem. Soc. 2002, 124, 13386–13387. (e) Reich, H. J.; Borst,
J. P.; Dykstra, R. R.; Green, P. D. J. Am. Chem. Soc. 1993, 115, 8728–
8741.
(12) (a) Courtois, G.; Miginiac, L. J. Organomet. Chem. 1974, 69,
1–44. (b) Normant, H. Angew. Chem., Int. Ed. 1967, 6, 1046–1067.
(13) (a) Ozutsumi, K.; Abe, Y.; Takahashi, R.; Ishiguro, S. J. Phys.
Chem. 1994, 98, 9894–9899. (b) Abe, Y.; Ishiguro, S. J. Solution Chem.
1991, 20, 793–803.
(14) (a) Abe, Y.; Ozutsumi, K.; Ishiguro, S. J. Chem. Soc., Faraday
Trans. 1 1989, 85, 3747–3756. (b) Ishiguro, S.; Ozutsumi, K.; Ohtaki, H.
Bull. Chem. Soc. Jpn. 1987, 60, 531–538. (c) Ishiguro, S.; Ozutsumi, K.;
Ohtaki, H. J. Chem. Soc., Faraday Trans. 1 1988, 84, 2409–2419.
(d) Suzuki, H.; Ishiguro, S.; Ohtaki, H. J. Chem. Soc., Faraday Trans.
1990, 86, 2179–2185.
We are thankful for financial support from Universities
Natural Science Foundation of Jiangsu Province
(09KJD150006), Science and Technology Project of Xuzhou
(XJ09078), and Qing Lan Project (08QLT001).
’ REFERENCES
(1) (a) Thomasar, A. F.; Bessiere, Y. In The Total Synthesis of Natural
Products; ApSimon, J. W., Ed.; Wiley: New York, 1988; Vol 7, pp 275-
454. (b) Mann, J.; Davidson, R. S.; Hobbs, J. B.; Banthorpe, D. V.;
Harborne, J. B. In Natural Products: Their Chemistry and Biological
Significance; Longman Scientific & Technical: Essex, 1994; pp 289-
359. (c) Poyser, J. P.; Hirtzbac, F. D.; Ourisson, G. Tetrahedron
1974, 30, 977–986. (d) Papageorgiou, V. P.; Assimopoulou, A. N.;
Couladouros, E. A.; Hepworth, D. H.; Nicolaou, K. C. Angew. Chem., Int.
Ed. 1999, 38, 270–300. (e) Papageorgiou, V. P.; Assimopoulou, A. N.;
Samanidou, V. F.; Papadoyannis, I. N. Curr. Org. Chem. 2006, 10, 2123–
2142.
(2) (a) Koepler, O.; Laschat, S.; Baro, A.; Fischer, P.; Miehlich,
B.; Hotfilder, M.; le Viseur, C. Eur. J. Org. Chem. 2004, 17, 3611–
3622. (b) Roulland, E.; Ermolenko, M. S. Org. Lett. 2005, 7, 2225–
2228. (c) Gebauer, J.; Blechert, S. Synlett. 2005, 18, 2826–2828.
(d) Eckelbarger, J. D.; Wilmot, J. T.; Epperson, M. T.; Thakur, C. S.;
Shum, D.; Antczak, C.; Tarassishin, L.; Djaballah, H.; Gin, D. Y. Chem.—
Eur. J. 2008, 14, 4293–4306. (e) Kamata, K.; Hirano, T.; Kuzuya, S.;
Mizuno, N. J. Am. Chem. Soc. 2009, 131, 6997–7004.
(3) (a) Rodríguez Brasco, M. F.; Genzano, G. N.; Palermo, J. A.
Steroids 2007, 72, 908–913. (b) Yoshikawa, M.; Nakamura, S.; Li, X.;
Matsuda, H. Chem. Pharm. Bull. 2008, 56, 695–700. (c) Gao, X.; Zhang,
Z. X.; Jia, Z. J. Helv. Chim. Acta 2008, 91, 1934–1939. (d) Reddy, P.;
Urban, S. Phytochemistry 2009, 70, 250–255. (e) Nakamura, S.; Iwami, J.;
Matsuda, H.; Mizuno, S.; Yoshikawa, M. Tetrahedron 2009, 65, 2443–
2445. (f) Zhang, P.; Bao, B.; Dang, H. T.; Hong, J.; Lee, H. J.; Yoo, E. S.;
Bae, K. S.; Jung, J. H. J. Nat. Prod. 2009, 72, 270–275. (g) Lee, C. L.;
Chiang, L. C.; Cheng, L. H.; Liaw, C. C.; Abd El-Razek, M. H.; Chang,
F. R.; Wu, Y. C. J. Nat. Prod. 2009, 72, 1568–1572.
(15) (a) Hoffmann, R. W. Angew. Chem., Int. Ed. 1982, 21, 555–566.
(b) Isaac, M. B.; Chan, T.-H. Tetrahedron Lett. 1995, 36, 8957–8960.
(c) Kira, M.; Zhang, L. C.; Kabuto, C.; Sakurai, H. Organometallics 1996,
15, 5335–5341. (d) Hada, M.; Nakatsuji, H.; Ushio, J.; Izawa, M.;
Yokono, H. Organometallics 1993, 12, 3398–3404. (e) Yamamoto, Y.;
Maruyama, K. Heterocycles 1982, 18, 357–386. (f) Takahara, J. P.;
Masuyama, Y.; Kurusu, Y. J. Am. Chem. Soc. 1992, 114, 2577–2586.
(16) Benkeser, R. A.; Broxterman, W. E. J. Am. Chem. Soc. 1969,
91, 5162–5163.
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The Journal of Organic Chemistry
ARTICLE
(17) (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004,
43, 5138–5175.(b) Jensen, W. B. The Lewis Acid-Base Concepts; Wiley:
New York, 1980; Chapter 4, pp 136-137. (c) Denmark, S. E.; Beutner,
G. L. Angew. Chem., Int. Ed. 2008, 47, 1560–1638.
(18) (a) Jones, P.; Knochel, P. Chem. Commun. 1998, 2407–2408.
(b) Jones, P.; Knochel, P. J. Org. Chem. 1999, 64, 186–195.
(19) Birney, D. M.; Xu, X.; Ham, S. Angew. Chem., Int. Ed. 1999,
38, 189–193.
(20) Jones, P.; Millot, N.; Knochel, P. Chem. Commun. 1998, 2405–
2406.
(21) Zinc powder was activated using acetic acid in MeOH. After 20
min of stirring, the metal was filtered, washed, and dried under full
vacuum for 3 h.
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