Diastereoselective tin-free tandem radical additions to 3-formylchromones

Article abstract of DOI:10.1021/jo201350w

A tin-free tandem radical addition methodology onto 3-formylchromones is presented. This radical process yields functionalized chromone structures via two carbon-carbon bond-forming steps. These products contain up to three contiguous stereocenters with good to excellent dr's and yields.

Full text of DOI:10.1021/jo201350w

NOTE
pubs.acs.org/joc
Diastereoselective Tin-Free Tandem Radical Additions to
3-Formylchromones
Jake R. Zimmerman,* Madhuri Manpadi, Russell Spatney, and Aaron Baker
Department of Chemistry and Biochemistry, Ohio Northern University, Ada, Ohio 45810, United States
S Supporting Information
b
ABSTRACT:
A tin-free tandem radical addition methodology onto 3-formylchromones is presented. This radical process yields functionalized
chromone structures via two carbonÀcarbon bond-forming steps. These products contain up to three contiguous stereocenters with
good to excellent dr’s and yields.
rguably, one of the most intensely studied areas within
synthetic organic chemistry is the development of new
Scheme 1. Radical Addition to 3-Formylchromone
A
stereoselective methods for the synthesis of biologically signifi-
cant molecules.1 Stereoselective free-radical reactions have been
studied over the past several decades; however, there are still
several obstacles to be overcome.2 One major problem that plagues
free-radical processes is the use of organotin reagents.3 These
reagents are toxic, and the byproducts can be very difficult to remove
from reaction mixtures. A variety of alternatives for organotin
reagents have been presented in the literature,3 yet this is still a
developing field of research. Some research groups have also
reported tin-free radical additions using Et3B4 and Et2Zn5 as
initiators and chain-transfer reagents.
Another drawback to stereoselective free-radical reactions is
the lack of functional group complexity in the products syn-
thesized via these methods.2 Therefore, we set out to identify
substrates that would produce useful, small molecule scaffolds
utilizing tin-free radical processes. We ultimately focused on
3-formylchromone (1) as our radical acceptor (Scheme 1). This
compound (and a variety of related structures) is commer-
cially available6 or easily prepared from simple procedures.7 This
substrate has been studied extensively in conjugate addition
reactions with cuprates wherein products similar to enol 2 can be
prepared,8 and more recently, they have been studied in annula-
tion reactions.9 A variety of natural products contain modified
chromone frameworks that are related to the structures produced
in this new method (Figure 1).10 Herein we demonstrate a highly
diastereoselective tin-free tandem radical addition to 3-formyl-
chromones yielding functionalized products with up to three
contiguous stereocenters.
Figure 1. Natural products containing substituted chromone frameworks.
hydrogen atom sources for this free radical process. Although the
desired products were produced under silane conditions, the
crude reaction mixtures were difficult to purify, and as a result,
product yields were low (data not shown). We ultimately dis-
covered that a hydrogen atom source was not required in this
process as triethylborane was acting as both an initiator and chain-
transferagent. Interestingly, a mixture of thesingle(4) and tandem
Our experiments began with the evaluation of tert-butyl radical
additions onto 3-formylchromone. Simple silanes such as tri-
ethylsilane and PMHS (polymethylhydrosiloxane) were initially
screened as possible alternatives to toxic alkyltin hydride as
Received: July 2, 2011
Published: August 12, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo201350w J. Org. Chem. 2011, 76, 8076–8081
|

The Journal of Organic Chemistry
NOTE
Table 1. Optimization of Radical Additions onto
3-Formylchromone
Table 2. Radical Precusor Scope for Single Additions to
3-Formylchromone
entry
product
R
yielda (%)
entry
Lewis acid
time (min)
Et3B equiv
product
yielda (%)
1
4a
4b
4c
4d
4e
tert-butyl
isopropyl
c-hexyl
c-pentyl
ethyl
92
85
88
81
83
4:5b
4:5c
4
4:5d
4e
NRe,f
4e
76
87
77
83
92
0
2
1
2
3
4
5
6
7
8
9
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
15
5
2
2
1
2
1
1
1
5
5
3
4
5
5
5
a Isolated yields.
5
5
5
77
85
93
Yb(OTf)3
180
5
180
5
a Isolated yields. b A 3:1 mixture of 4:5 was observed. A 15:1 mixture
of 4:5 was observed. d A 17:1 mixture of 4:5 for entry 4. e Reaction carried
outatroomtemperature. f One equiv of TEMPO was added to the reaction.
c
and, in the case of R = t-Bu (5), can even be chromatographed.
We made several attempts to trap boron enolate 5 with benzal-
dehyde (aldol reaction); however, only recovered starting ma-
terial was observed.15 Therefore, in order to access the desired
aldol-like products (6), oxidative conditions were required to
remove boron and give products 6aÀi. These results were very
exciting as two carbonÀcarbon bonds and three contiguous
stereocenters are formed in a single transformation with good
stereoselectivity. Again, primary, secondary, and tertiary radicals
all added efficiently to give compounds 6aÀi in good yields and
dr’s. Ethyl radical adds significantly slower to the enol intermediate
so longer reaction times were necessary (6 h for ethyl and 3 h for
theothers). Thistandemradical addition methodis alsotolerantof
substituents on the aromatic ring. Of particular interest are the
bromo and chloro derivatives (Table 3, entries 6 and 7) which
contain synthetic handles for further transformations.
We were able to determine the relative stereochemistry for the
major diastereomer in this reaction by obtaining an X-ray structure
for compound 6i (see Figure 2). This structure clearly shows the
trans relationship between the two substituents on the pyrone ring.
The stereochemistry suggests that the two radicals add from
opposite faces of the substrate (see 6j) followed by protonation
to yield the thermodynamically favored trans compound.
(5) addition adducts was isolated in the presence excess of
triethylborane (Table 1).
Intrigued by this result, we set out to develop reaction
conditions that would give either pure single or tandem addition
products. After extensive experimentation, it was discovered that
product distribution was dependent on reaction time and
equivalents of radical initiator (Et3B). Using 1.0À2.0 equiv of
triethylborane and short reaction times (5 min or less), excellent
yields of 4 were observed (Table 1, entries 1À5). With excess
triethylborane and long reaction times (3 h), the tandem addi-
tion adduct 5 was produced as a single diastereomer in excel-
lent yields (entries 8 and 9). A variety of Lewis acids were
screened including Yb(OTf)3, Cu(OTf)2, Sc(OTf)3, PdCl2,
and Zn(OTf)2 (not all data shown). Ultimately, we found that
Zn(OTf)2 afforded the most reproducible and highest yielding
reactions. Lewis acid additives seemed to give higher yields for
the single addition products but were found to have little impact
under the double addition reaction conditions. Addition of 1 equiv
of radical inhibitor TEMPO resulted in no observed product,
thereby suggesting a radical pathway (entry 6). Attempts to use
diethylzinc as an initiator and chain-transfer agent were unsuccess-
ful in this methodology.11
Next, we investigated the scope of our single radical addition
method (Table 2). Using 0.5 equiv of Zn(OTf)2, 1 equiv of Et3B,
with a reaction time of 3À5 min at room temperature,12 com-
pounds 4aÀe were prepared in excellent yields. Primary, sec-
ondary, and tertiary radicals all added very efficiently. We also
studied chromones 1b and 1c under these reaction conditions.
Chromone (1b) gave the radical adduct 4f in nearly quantitative
yields. 3-Cyanochromone also proved to be an excellent sub-
strate for this tin-free radical method.13 Again, the single addition
product 4g was isolated with excellent yields as a 1:1 mixture of
diastereomers.
Next, we wanted to investigate the sequential addition of two
different radical precursors in order to increase the com-
plexity of the products formed in this method (see Table 4). Initially,
a single-pot procedure was envisioned for this process; however, we
found that it was best to quench the single addition reaction on silica
and then, to the crude product, add the second radical followed by
oxidative (30% H2O2, 1 M NaOH) workup conditions to remove
the boron. A variety of alkyl radicals were successfully added with
good dr’s and yields to give the desired compounds 7aÀd. This
method allows for rapid substitution of the chromone core
giving functionalized building blocks for more complex benzo-
pyran targets.
While conditions for the single addition reaction using 3-
formylchromone were being optimized, it was discovered that
triethylborane was incorporated into the tandem addition
product 5.14 This boron enolate compound is remarkably stable
A proposed mechanism is shown in Scheme 2.16 The first step
in this reaction is generation of an ethyl radical via the reaction of
O2 with triethylborane. Atom abstraction from the excess alkyl
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NOTE
Table 3. Tandem Radical Additions to 3-Formylchromonesa
Table 4. Sequential Radical Additions to
3-Formylchromonea
entry
product
R
X
drb
yieldc (%)
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6e
6f
tert-butyl
isopropyl
c-hexyl
H
H
H
H
H
10:1
7:1
82
86
84
71
70d
83
81
77
86
4:1
c-pentyl
ethyl
7:1
8:1
tert-butyl
tert-butyl
tert-butyl
tert-butyl
chloro
bromo
fluoro
ethyl
10:1
10:1
7:1
6g
6h
6i
10:1
a Reaction conditions: (a) R-I (10 equiv), Et3B, CH2Cl2, À60 °C, 3À6
h; (b) 30% H2O2, 1 M NaOH, 0 °C, 2 h. b Determined by 200
a Reaction conditions: (a) R1-I (10 equiv), Zn(OTf)2, Et3B, CH2Cl2/
THF, RT, 3À5 min b) R2-I (10 equiv), Et3B, CH2Cl2, À60 °C, 3 h. c)
30% H2O2, 1 M NaOH, 0 °C, 2 h. b Diastereomeric ratios determined by
200 MHz NMR. c Isolated yields.
c
MHz NMR. Isolated yields. d Reaction without Et-I gave 10À15% of
unreacted starting material. Under identical reaction conditions, no
unreacted starting material was observed when 10 equiv of Et-I was used.
Scheme 2. Proposed Mechanism
biological acitivities. Experiments focusing on the enantioselec-
tive variant of this method are currently underway.
Figure 2. Crystal structure of 6i.
’ EXPERIMENTAL SECTION
iodide reagent produces the desired alkyl radical. Next, addition
to the alkene acceptor gives a resonance-stabilized radical 8,
which undergoes a reaction with triethylborane to yield inter-
mediate 9. A second alkyl radical addition to conjugated enolate 9
yields free radical 10 that ultimately cyclizes to give boron enolate
11. Due to the stability of 11, oxidative conditions are required in
order to isolate the final alcohol product 12. The enolate formed
after the single addition is more labile as the free enol is isolated
after workup and purification via chromatography, whereas the
cyclic enolate (11) is quite stable and can be chromatographed
with little hydrolysis observed.17
In conclusion, we have developed an efficient tin-free radical
methodology for single, tandem, and sequential additions to
3-formylchromones. In this process, up to two carbonÀcarbon
bonds andthree contiguous stereocenterscan be formed in a single
step. These functionalized chromone products contain structural
features of natural products and derivatives that have significant
General Experimental Methods. Spectroscopic data were re-
corded as follows: 1H NMR and 13C NMR spectra were run at 200 and
50 MHz, respectively. Infrared spectra were recorded using NaCl pellets.
Absorptions are given in wavenumbers (cmÀ1).
General Procedure for Single Addition (4aÀg). To chromone
(0.2 mmol) and Zn(OTf)2 (0.1 mmol) in a 15 mL vial were added
CH2Cl2 (1.5 mL) and THF (0.5 mL), and the mixture was stirred at
room temperature. Alkyl iodide (2 mmol) was added, and the reaction
was initiated using 1.0 M Et3B in hexanes (0.2 mmol). The reaction
mixture turned yellow immediately after the addition of Et3B. The
reaction was stirred for 3 min for tertiary and secondary radicals. For
primary radicals the reaction was stirred for 5 min to get complete
conversion of the single addition product. Immediate quenching on
silica after 3À5 min for 3-formylchromone is crucial to get pure single
addition product. Extended reaction times lead to a mixture of single and
double addition products. The reaction mixture was quenched on a bed
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NOTE
of silica gel and filtered using CH2Cl2. The solvent was concentrated
under reduced pressure, adsorbed on silica, and purified using column
chromatography(5À30%EtOAcinhexanes) togive pure products4aÀg.
(Z)-2-tert-Butyl-3-(hydroxymethylene)chroman-4-one (4a): 94%
dr’s were determined on crude reaction mixtures. The compound was
further adsorbed on silica gel and purified using column chromatography
(5À30% EtOAc in hexanes) to give products 6aÀi.
4,5-Di-tert-butyl-2-ethyl-4,5-dihydro-1,3,2-dioxaborinino[5,4-c]-
chromene (5): 93% yield; IR (cmÀ1) 2957, 2872, 1666, 1607, 1489,
1396, 1363; 1H NMR (CDCl3, 200 MHz) δ 7.71 (dd, J = 1.7, 7.6 Hz,
1H), 7.08 (td, J = 1.7, 7.6 Hz, 1H), 6.83À6.63 (m, 2H), 4.47 (s, 1H),
4.12 (s, 1H), 1.15À0.95 (m, 5H, B-CH2CH3), 0.93 (s, 9H), 0.86
(s, 9H); 13C NMR (CDCl3, 50 MHz) δ155.9, 141.9, 130.2, 121.7,
120.5, 119.4, 115.1, 104.6, 83.9, 80.2, 40.9, 39.8, 26.6, 25.9, 7.8; 11B NMR
was recorded on a 400 MHz instrument using BF3 as the external
standard; 11B signal was observed at 32.1 ppm; (CI/MS) m/z calcd for
C20H30BO3 [M + H] 329.2, found 329.2.
1
yield; IR (cmÀ1) 3201, 2961, 2870, 1607, 1465; H NMR (CDCl3,
200 MHz) δ 14.38 (bs, 1H), 8.05 (s, 1H), 7.80 (d, J = 8.2 Hz, 1H),
7.47À7.36 (m, 1H), 7.00À6.85 (m, 2H), 4.68 (s, 1H), 0.88 (s, 9H); 13C
NMR (CDCl3, 50 MHz) δ 178.6, 176.7, 159.7, 136.0, 126.0, 121.1,
119.1, 116.9, 104.8, 83.7, 39.2, 25.5; (CI/MS) m/z calcd for C14H17O3
[M + H] 233.2, found 233.2.
(Z)-3-(Hydroxymethylene)-2-isopropylchroman-4-one (4b): 85%
yield;IR(cmÀ1) 3084, 2966, 2934, 1686, 1607, 1465; 1HNMR(CDCl3, 200
MHz) δ 14.36 (bs, 1H), 7.92 (s, 1H), 7.82 (dd, J = 1.5, 7.8 Hz, 1H),
7.47À7.34 (m, 1H), 7.06À6.88 (m, 2H), 4.53 (d, J = 8.2 Hz, 1H), 1.87 (m,
1H), 1.12(d,J= 6.6 Hz, 3H), 0.89 (d, J= 6.6 Hz, 3H); 13CNMR(CDCl3, 50
MHz) δ 180.1, 173.2, 158.5, 135.9, 126.4, 126.7, 120.1, 117.9, 107.9, 81.7,
32.9, 18.5; (CI/MS) m/z calcd for C13H13O3 [M À H] 217.1, found 217.1.
(Z)-2-Cyclohexyl-3-(hydroxymethylene)chroman-4-one (4c): 88%
2-tert-Butyl-3-(1-hydroxy-2,2-dimethylpropyl)chroman-4-one (6a):
1
82% yield; IR (cmÀ1) 3483, 2958, 2872, 1674, 1607, 1464; H NMR
(CDCl3, 200 MHz) δ 7.74 (dd, J = 1.9, 8.2 Hz, 1H), 7.52À7.38 (m, 1H),
6.97À6.85 (m, 2H), 4.70 (s, 1H), 3.49 (t. J = 4.8 Hz, 1H), 3.01 (d, J = 4.6
Hz, 1H), 2.11 (d, J = 5.2 Hz, 1H), 0.97 (s, 9H), 0.95 (s, 9H); 13C NMR
(CDCl3, 50 MHz) δ 195.3, 160.9, 136.5, 126.8, 120.8, 120.6, 117.4, 85.4,
80.0, 48, 37.5, 37.2, 27.2, 26.4; HRMS exact mass calcd for C18H26O3Na
[M + Na]+ 313.1780, found 313.1765.
1
yield; IR (cmÀ1) 2969, 2783, 1640, 1604, 1485; H NMR (CDCl3, 200
MHz) δ 14.36 (bs, 1H), 7.82 (s, 1H), 7.76 (dd, J = 1.6, 7.8 Hz, 1H),
7.43À7.39 (m, 1H), 7.00À6.78 (m, 2H), 4.50 (d, J= 8.2 Hz, 1H), 2.30À2.11
(m, 5H), 1.76À0.98 (m, 6H); 13C NMR (CDCl3, 50 MHz) δ 179.6, 172.9,
158.2, 135.7, 126.2, 121.4, 119.8, 117.8, 107.2, 80.5, 41.8, 28.7, 28.3, 26.1, 25.7,
25.5; (CI/MS) m/z calcd for C17H21O2 [M + H] 257.1, found 257.2.
(Z)-2-Cyclopentyl-3-(hydroxymethylene)chroman-4-one (4d): 81%
3-(1-Hydroxy-2-methylpropyl)-2-isopropylchroman-4-one (6b):
1
86% yield; IR (cmÀ1) 3466, 2963, 2875, 1678, 1606, 1463, 1323; H
NMR (CDCl3, 200 MHz) δ 7.76À7.69 (m, 1H), 7.45À7.35 (m, 1H),
6.94À6.84 (m, 2H), 4.38 (dd, J = 2.3, 9.6 Hz, 1H), 3.76 (d, J = 7.9 Hz,
1H), 2.75 (dd, J = 2.4, 8.6 Hz, 1H), 2.07 (bs, 1H), 2.00À1.83 (m, 1H),
1.68À1.52 (m, 1H), 0.93 (d, J = 6.4 Hz, 3H), 0.90 (d, J = 6.4 Hz, 3H),
0.86 (d, J = 6.8 Hz, 6H); 13C NMR (CDCl3, 50 MHz) δ 194.2, 159.5,
136.5, 126.9, 121.5, 121.1, 118.3, 83.9, 74.0, 52.4, 31.0, 28.7, 20.5, 19.5,
18.8, 15.2; HRMS exact mass calcd for C16H22O3Na [M + Na]+
285.1467, found 285.1463.
1
yield; IR (cmÀ1) 2968, 2862, 1642, 1603, 1487 ; H NMR (CDCl3, 200
MHz) δ 14.37 (bs, 1H), 7.82 (s, 1H), 7.76 (dd, J = 1.5, 7.8 Hz, 1H),
7.43À7.31 (m, 1H), 6.99À6.80 (m, 2H), 4.54 (d, J= 9.0 Hz, 1H), 2.30À2.11
(m, 1H), 1.76À0.98 (m, 8H); 13C NMR (CDCl3, 50 MHz) δ 180.9, 171.6,
158.6, 135.9, 126.4, 121.7, 120.3, 118.1, 109.2, 80.6, 44.3, 29.4, 29.0, 25.6, 25.4;
(CI/MS) m/z calcd for C15H15O3 [M À H] 243.1, found 243.2.
(Z)-2-Ethyl-3-(hydroxymethylene)chroman-4-one (4e): 83% yield;
IR (cmÀ1) 2967, 2933, 2876, 2360, 1645, 1608, 1465; 1H NMR (CDCl3,
200 MHz) δ 14.38 (bs, 1H), 7.85 (m, 2H), 7.49À7.39 (m, 1H), 7.06À6.88
(m, 2H), 4.87 (dd, J = 5.6, 7.9 Hz, 1H), 2.01À1.79 (m, 1H), 1.77À1.58
(m, 1H), 1.00 (t, J = 7.3 Hz, 3H); 13C NMR (CDCl3, 50 MHz) δ 181.4,
170.9, 158.8, 135.9, 126.6, 121.8, 120.2, 118.2, 109.3, 77.6, 28.5, 9.8;
(CI/MS) m/z calcd for C12H13O3 [M + H] 205.1, found 205.2.
2-Cyclohexyl-3-(cyclohexyl(hydroxy)methyl)chroman-4-one (6c):
1
84% yield; IR (cmÀ1) 3467, 2925, 2852, 1682, 1606, 1463, 1319; H
NMR (CDCl3, 200 MHz) δ 7.79 (dd, J = 1.8, 7.8 Hz, 1H), 7.51À7.41
(m, 1H), 7.01À6.88 (m, 2H), 4.51 (dd, J = 2.2, 9.1 Hz, 1H), 3.78 (d, J =
8.1 Hz, 1H), 2.87 (dd, J = 2.3, 9.3 Hz, 1H), 2.00À1.48 (m, 11H),
1.38À0.97 (m, 11H); 13C NMR (CDCl3, 50 MHz) δ 194.4, 159.6,
136.5, 126.9, 121.5, 121.1, 118.3, 82.9, 74.1, 51.1, 40.9, 38.0, 30.7,
29.5, 28.9, 26.5, 26.3, 26.1, 25.9, 25.7; HRMS exact mass calcd for
C22H30O3Na [M + Na]+ 365.2093, found 365.2094.
2-tert-Butylchroman-4-one (4f). This compound is reported in the
literature, and the corresponding 1H NMR, 13C NMR, and HRMS are
consistent with literature data.18
2-Cyclopentyl-3-(cyclopentyl(hydroxy)methyl)chroman-4-one (6d):
71% yield; IR (cmÀ1) 3452, 2953, 2867, 1675, 1606, 1462, 1322; 1H NMR
(CDCl3, 200 MHz) δ 7.86 (dd, J = 1.7, 7.7 Hz, 1H), 7.49À7.40 (m, 1H),
6.99À6.88 (m, 2H), 4.57 (dd, J = 1.9, 10.3 Hz, 1H), 3.93 (dd,
J = 5.2, 7.5 Hz, 1H), 2.62 (dd, J = 1.9, 7.5 Hz, 1H), 2.07À1.06 (m, 18H);
13CNMR(CDCl3,50MHz) δ194.4, 159.5, 136.5, 126.8, 121.7, 121.1, 118.3,
82.8, 73.2, 55.2, 43.6, 40.7, 30.2, 29.6, 28.9, 26.9, 26.0, 25.9, 25.5, 25.4; HRMS
exact mass calcd for C20H26O3Na [M + Na]+ 337.1780, found 337.1764.
2-Ethyl-3-(1-hydroxypropyl)chroman-4-one (6e): 70% yield; IR
(cmÀ1) 3410, 2967, 2936, 1681, 1606, 1463, 1325; 1H NMR (CDCl3,
200 MHz) δ 7.87À7.79 (m, 1H), 7.52À7.42 (m, 1H), 7.03À6.92 (m,
2H), 4.64À4.52 (m, 1H), 3.92À3.74 (m, 1H), 2.75 (t, J = 6.1 Hz, 1H),
1.97À1.69 (m, 2H), 1.51 (m, 2H), 1.05 (t, J = 7.5 Hz, 3H), 1.00 (t, J =
7.5 Hz, 3H); 13C NMR (CDCl3, 50 MHz) δ 195.5, 160.4, 136.7, 127.1,
121.3, 121.1, 118.3, 79.9, 71.8, 55.5, 26.9, 25.1, 10.4, 9.8; HRMS exact
mass calcd for C14H18O3Na [M + Na]+ 257.1154, found 257.1146.
2-tert-Butyl-6-chloro-3-(1-hydroxy-2,2-dimethylpropyl)chroman-4-
one (6f): 70% yield; IR (cmÀ1) 3447, 2961, 2873, 1676, 1604, 1471,
1426, 1367; 1H NMR (CDCl3, 200 MHz) δ 7.70 (d, J = 2.7 Hz, 1H),
7.37 (dd, J = 2.7, 8.9 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 4.71 (s, 1H), 3.47
(d, J = 4.3 Hz, 1H), 3.01 (d, J = 4.6 Hz, 1H), 2.05 (bs, 1H), 0.97 (s, 9H),
0.93 (s, 9H); 13C NMR (CDCl3, 50 MHz) δ 194.3, 159.5, 136.3, 126.1,
125.9, 121.5, 119.2, 85.7, 79.9, 47.8, 37.5, 37.2, 27.1, 26.4; HRMS exact
mass calcd for C18H25ClO3Na [M + Na]+ 347.1390, found 347.1375.
2-tert-Butyl-4-oxochroman-3-carbonitrile (4g): 87% yield; 1:1 in-
separable mixture of diastereomers; 1H NMR (CDCl3, 200 MHz) δ 7.29
(d, J = 7.4 Hz, 2H), 7.63À7.49 (m, 2H), 7.12À6.95 (m, 4H), 4.26 (dd,
J = 1.0, 10.5 Hz, 1H), 3.97 (dd, J = 1.0, 2.0 Hz, 1H), 3.87 (dd, J = 1.0, 10.5
Hz, 1H), 3.63 (dd, J = 1.0, 2.0 Hz, 1H), 1.23 (s, 9H), 1.21 (s, 9H); 13C
NMR (CDCl3, 50 MHz) δ 183.7, 183.3, 162.0, 161.3, 137.6, 137.5,
128.6, 127.9, 122.7, 118.8, 118.5, 118.4, 118.2, 114.9, 114.2, 85.7, 85.1,
45.8, 39.1, 36.1, 35.4, 26.4, 26.3, 25.6; HRMS exact mass calcd for
C14H15NO2Na [M + Na]+ 252.1000, found 252.0993.
General Procedure for Tandem Double Addition 6aÀi. Chromone
(0.2 mmol), CH2Cl2 (1.5 mL), and THF (0.5 mL) were added to a
15 mL vial, and the mixture was cooled to À60 °C while stirring. Alkyl
iodide (2 mmol) was added, and the reaction was initiated using 1.0 M
Et3B in hexanes (1 mmol). The reaction mixture as stirred at À60 °C for
3 h. The reaction was quenched on a bed of silica, washed with ether, and
concentrated to afford the boron enolate. The boron compound was
then dissolved in 5 mL of THF and cooled to 0 °C. A mixture of 1 M
NaOH (5 mL) and 30% H2O2 (5 mL) was added to the reaction flask
and stirred for 2 h at 0 °C, during which time the reaction was usually
completed. The reaction was ultimately deemed complete by monitor-
ing via TLC (30% EtOAc in hexanes). The reaction mixture was
transferred to a separatory funnel, extracted with EtOAc (2 Â 15 mL),
washed with brine, dried, and concentrated under reduced pressure. All
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The Journal of Organic Chemistry
NOTE
6-Bromo-2-tert-butyl-3-(1-hydroxy-2,2-dimethylpropyl)chroman-4-
one (6g): 81% yield; IR (cmÀ1) 3494, 2960, 2872, 1677, 1600, 1469,
1421, 1277; 1H NMR (CDCl3, 200 MHz) δ 7.84 (d, J = 2.6 Hz, 1H),
7.53À7.46 (m, 1H), 6.83 (d, J = 8.8 Hz, 1H), 4.71 (s, 1H), 3.46 (d, J = 4.5
Hz, 1H), 2.99 (d, J = 4.6 Hz, 1H), 0.95 (s, 9H), 0.92 (s, 9H); 13C NMR
(CDCl3, 50 MHz) δ 194.2, 160.0, 139.1, 129.2, 121.9, 119.5, 113.0, 85.7,
79.9, 47.8, 37.5, 37.2, 27.1, 26.3; HRMS exact mass calcd for
C18H25BrO3Na [M + Na]+ 391.0885, found 391.0872.
2-tert-Butyl-6-fluoro-3-(1-hydroxy-2,2-dimethylpropyl)chroman-4-
one (6h): 77% yield; IR (cmÀ1) 3494, 2961, 2871, 1676, 1486, 1439,
1278; 1H NMR (CDCl3, 200 MHz) δ 7.40 (dd, J = 3.2, 8.2 Hz, 1H),
7.23À7.11 (m, 1H), 6.90 (dd, J = 4.3, 9.1 Hz, 1H), 4.70 (s, 1H), 3.49 (d,
J = 4.6 Hz, 1H), 3.00 (d, J = 4.6 Hz, 1H), 2.07 (bs, 1H), 0.97 (s, 9H),
0.93 (s, 9H); 13C NMR (CDCl3, 50 MHz) δ 194.8, 157.2, 156.5
(d, J = 241.0 Hz), 124.1 (d, J = 24.4 Hz), 120.9 (d, J = 6.2 Hz), 119.0
(d, J = 7.2 Hz), 111.7 (d, J = 23.1 Hz), 85.6, 79.9, 47.8, 37.5, 37.2, 27.1,
26.3; HRMS exact mass calcd for C18H25FO3Na [M + Na]+ 331.1685,
found 331.1680.
3-(1-Hydroxy-2,2-dimethylpropyl)-2-isopropylchroman-4-one (7c):
1
73% yield; IR (cmÀ1) 3447, 2962, 2873, 1680, 1607, 1463, 1322; H
NMR (CDCl3, 200 MHz) δ 7.82À7.73 (m, 1H), 7.53À7.42 (m, 1H),
6.99À6.82 (m, 2H), 4.56 (d, J = 10.5 Hz, 1H), 3.71À3.59 (m, 1H), 2.85
(d, J = 7.1 Hz, 1H), 2.19 (d, J = 5.3 Hz, 1H), 2.02À1.94 (m, 1H), 0.99 (d,
J = 6.5 Hz, 3H), 0.93 (s, 9H), 0.99À0.89 (m, 3H); 13C NMR (CDCl3, 50
MHz) δ 194.5, 159.2, 136.7, 127.1, 121.8, 118.1, 85.7, 84.8, 77.8, 50.4,
36.3, 28.2, 26.4, 19.7, 18.2; HRMS exact mass calcd for C17H24O3Na
[M + Na]+ 299.1623, found 299.1625.
2-Ethyl-3-(1-hydroxy-2,2-dimethylpropyl)chroman-4-one (7d):
71% yield; 3477, 2963, 2875, 1680, 1606, 1463, 1320; 1H NMR (CDCl3,
200 MHz) δ 7.68 (dd, J = 1.7, 7.7 Hz, 1H), 7.45À7.36 (m, 1H),
6.95À6.85 (m, 2H), 4.86 (dd, J = 5.1, 9.7 Hz, 1H), 3.67À3.55 (m, 1H),
2.57 (d, J = 7.1 Hz, 1H), 2.09 (d, J = 4.9 Hz, 1H), 1.79À1.70 (m, 1H),
1.54À1.44 (m, 1H), 0.92 (t, J = 7.2 Hz, 3H), 0.86 (s, 9H); 13C NMR
(CDCl3, 50 MHz) δ 195.5, 158.6, 136.3, 127.2, 121.4, 121.2, 118.2, 80.6,
53.2, 36.6, 30.9, 26.2, 24.7, 10.6; HRMS exact mass calcd for
C16H22O3Na [M + Na]+ 285.1467, found 285.1458.
2-tert-Butyl-6-ethyl-3-(1-hydroxy-2,2-dimethylpropyl)chroman-4-
one (6i): 86% yield; IR (cmÀ1) 3483, 2962, 2873, 1675, 1618, 1491; 1H
NMR (CDCl3, 200 MHz) δ 7.55 (d, J = 2.4 Hz, 1H), 7.28 (dd, J = 1.8,
8.5 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 4.65 (s, 1H), 3.48 (d, J = 4.3 Hz,
1H), 2.98 (d, J = 4.3 Hz, 1H), 2.56 (q, J = 7.6 Hz, 2H), 1.19 (t, J = 7.5 Hz,
3H), 0.96 (s, 9H), 0.93 (s, 9H); 13C NMR (CDCl3, 50 MHz) δ 195.6,
159.2, 136.6, 136.4, 125.2, 120.4, 117.3, 85.2, 80.1, 47.9, 37.5, 37.2, 27.2,
26.4, 15.6; HRMS exact mass calcd for C20H30O3Na [M + Na]+
341.2093, found 341.2096.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra for
S
b
new compounds 4aÀe,g, 6aÀi, and 7aÀd. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
General Procedure for Sequential Double Addition (7aÀd). The
first radical addition togivethesingleaddition productwas done following
the general procedure for single addition (see above). The crude com-
pound was quenched on silica, concentrated, and used for the second
radical addition without further purification. The crude material was
dissolved in CH2Cl2 (1.5 mL) and THF (0.5 mL) and cooled
to À60 °C. Alkyl iodide (2 mmol) was added, and the reaction was
initiated using 1.0 M Et3B in hexanes (1 mmol). The reaction mixture as
stirred at À60 °C for 3 h. The reaction was quenched on a bed of silica,
washed with ether, and concentrated to afford the boron enolate. The
boron compound was then dissolved in THF (5 mL) and cooled to 0 °C.
A mixture of 1 M NaOH (5 mL) and 30% H2O2 (5 mL) was added to the
reaction flask and stirred for 2 h at 0 °C during which time the reaction
was usually completed. The reaction was ultimately deemed complete by
monitoring via TLC (30% EtOAc in hexanes). The reaction mixture was
transferred to a separatory funnel, extracted with EtOAc (2 Â 15 mL),
washed with brine, dried, and concentrated under reduced pressure. The
compound was further adsorbed on silica gel and purified using column
chromatography (5À30% EtOAc in hexanes) to give products 7aÀd.
2-tert-Butyl-3-(1-hydroxy-2-methylpropyl)chroman-4-one (7a):
Corresponding Author
*E-mail: j-zimmerman.3@onu.edu.
’ ACKNOWLEDGMENT
We thank the donors of the American Chemical Society
Petroleum Research Fund for support of this research (ACS
PRF 49489-UNI). J.R.Z., M.M., and R.S. thank the ONU
Chemistry and Biochemistry Signature Program for funding.
J.R.Z. thanks Dr. Mukund Sibi. J.R.Z. thanks Dr. Brian Myers for
many discussions regarding this work. J.R.Z. thanks Dr. Richard
Staples for obtaining data for the X-ray crystal structure and
Dr. D. Y. Chen for acquiring 11B NMR data.
’ REFERENCES
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1
86% yield; IR (cmÀ1) 3461, 2962, 2873, 1673, 1607, 1464, 1322; H
NMR (CDCl3, 200 MHz) δ 7.74 (dd, J = 2.0, 8.3 Hz, 1H), 7.45 (m, 1H),
6.97À6.88 (m, 2H), 4.62 (s, 1H), 3.71 (dd, J = 3.8, 7.8 Hz, 1H), 2.85
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1
78% yield; IR (cmÀ1) 3461, 2962, 2873, 1673, 1607, 1464, 1322; H
NMR (CDCl3, 200 MHz) δ 7.81À7.73 (m, 1H), 7.49À7.35 (m, 1H),
6.85À6.75 (m, 2H), 4.59 (s, 1H), 3.74À3.65 (m, 1H), 2.89 (d, J = 7.5
Hz, 1H), 1.27À1.15 (m, 6H), 1.17À1.05 (m, 5H), 0.92 (s, 9H); 13C
NMR (CDCl3, 50 MHz) δ 194.4, 161.1, 136.6, 126.5, 121.1, 120.5,
117.5, 85.3, 75.9, 49.5, 40.5, 37.1, 30.7, 27.0, 26.5, 26.4, 26.0, 25.9;
HRMS exact mass calcd for C20H28O3Na [M + Na]+ 339.1936, found
339.1923.
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NOTE
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