Preparation and Diels-Alder/cross coupling reactions of new 2-boron-substituted 1,3-dienes

Article abstract of DOI:10.1021/jo3016727

Several new 2-boron substituted dienes have been prepared and characterized. Their reactivity in Diels- Alder reactions has been examined and the boron substituted cycloadducts of those cycloaddition reactions have been used in cross coupling reactions. One-pot tandem Diels-Alder/ cross coupling reactions of 2-boron substituted dienes are then also reported along with some experimental evidence that these one-pot reactions are proceeding through a Pd(II)-catalyzed Diels-Alder/cross coupling reaction pathway.

Full text of DOI:10.1021/jo3016727

Article
pubs.acs.org/joc
Preparation and Diels−Alder/Cross Coupling Reactions of New
2‑Boron-Substituted 1,3-Dienes
Liqiong Wang and Mark E. Welker*
Department of Chemistry, Wake Forest University, P.O. Box 7486, Winston-Salem, North Carolina 27109, United States
S
* Supporting Information
ABSTRACT: Several new 2-boron substituted dienes have
been prepared and characterized. Their reactivity in Diels−
Alder reactions has been examined and the boron substituted
cycloadducts of those cycloaddition reactions have been used
in cross coupling reactions. One-pot tandem Diels−Alder/
cross coupling reactions of 2-boron substituted dienes are then also reported along with some experimental evidence that these
one-pot reactions are proceeding through a Pd(II)-catalyzed Diels−Alder/cross coupling reaction pathway.
(CDCl3)) was found to have a stronger N−B bond than N-
methyl diethanolamine boronate-1,3-butadiene (4) (δ11.31,
(CD3)2SO; δ11.38, CDCl3) (these 11B NMR chemical shifts
are similar to other reported diolamine boronates in
(CD3)2SO).6 When the temperature was raised gradually to
60 °C, there was only one boron peak in the diethanolamine
boronate-1,3-butadiene (3) spectrum, but an extra small peak
appears (δ10.43, (CD3)2SO) in N-methyl diethanolamine
boronate-1,3-butadiene (4), which is consistent with some
B−N bond dissociation (accompanied most likely by residual
water coordination) at higher temperature.7 Finally, when the
similar N-donating chelator (3,3′-(methylazanediyl)-
dipropanoic acid))8 was tried, no product was detected by
NMR or GC-MS.
Following this analysis of possible N and O chelating ligands
for boron dienes, we examined a number of non amine
containing diols and triols. Initially, we tried adding diols or
triols to the transient boronic acid diene (2) followed by reflux
or the addition of acidic dehydrating reagents such as sodium
sulfate or molecular sieves, but in all cases, this resulted in diene
decomposition or dimerization.9 Attempts to prepare 7 by
other groups previously by alternative routes had also noted
this easy diene dimerization.5a,10 Alternatively, we found that
boronic acid diene (2) could be dissolved in THF and then
treated with the diol or triol of interest followed by NaH (1.5
equiv) and that from these basic conditions we were able to
isolate a series of new 2-boron substituted dienes (6−10)
(Scheme 2) without dimerization, so we now suspect that the
earlier reports of easy dimerization of 7 may have been Lewis or
Bronsted acid catalyzed dimerizations. When we prepared 6−9
under these basic conditions, we found that we could heat these
dienes for 6 h in toluene and recover them unreacted and that
we saw only a trace of dimerization when they were heated for
24 h in THF. Brown and co-workers had also previously noted
that when they treated bromo-alkenylboronic esters with
INTRODUCTION
■
We have been interested in the preparation and reaction
chemistry of metal substituted dienes for over 15 years. Initially,
we prepared a number of transition metal substituted dienes1
for these studies, but more recently, we have been interested in
the investigation of silicon and boron substituted dienes.2 In the
case of boron substituted diene chemistry, we initially reported
the preparation of 2-BF3 substituted 1,3-butadienes and
demonstrated that they could be used in sequential Diels−
Alder/cross coupling reactions.3 These trifluoroborate sub-
stituted dienes are stable, but their organic solvent solubility is
not ideal. Preparation of more highly substituted BF3 dienes
also requires a transmetalation protocol which yields a
byproduct from a side reaction of the commercially available
Grignard reagent used and which has to be separated from the
desired diene.3b To overcome these methodology challenges,
we wanted to prepare additional boron substituted 1,3-dienes,4
and we report our most recent results in this area here.5
RESULTS AND DISCUSSION
■
Preparation of New Boron Substituted 1,3-Dienes. All
the new dienes reported here were obtained as white solids on a
multigram scale via a simple procedure which involved
preparing the Grignard reagent from chloroprene (1), adding
this reagent to trimethoxyborane followed by the addition of
acid at low temperature and finally the chelating di- or triol
ligand of interest.
In 2009, we communicated this method to prepare the
diethanolamine chelated boron diene (3) and then also
reported on its subsequent Diels−Alder and cross coupling
reaction chemistry.4 Subsequent to this initial report, we have
found that N-methyl diethanolamine also works well in this
procedure to produce 4, but somewhat surprisingly, N-phenyl
diethanolamine fails to produce an isolable product (5) and
only the transiently stable boronic acid diene (2) was observed
in that case by NMR (Scheme 1).
When their 11B NMR spectra were obtained, diethanolamine
boronate-1,3-butadiene (3) (δ10.08, (CD3)2SO); δ10.46,
Received: August 6, 2012
Published: August 31, 2012
© 2012 American Chemical Society
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Scheme 1. Preparation of Boron Dienes Containing Diethanolamine Ligands
most reactive of any transition element or main group element
substituted diene that we had prepared to this point. The
enhanced Diels−Alder reactivity was consistent with a relatively
high calculated diene HOMO energy of −6.00 eV for this
boron substituted diene as compared to −12.58 eV for a 2-BF3
substituted 1,3-butadiene.4 New dienes reported here (4 and
6−10) were also examined for their reactivity in Diels−Alder
chemistry (Scheme 3). The diene obtained from the N-methyl
Scheme 2. Preparation of Boron Dienes Containing Diol
and Triol Ligands
Scheme 3. Diels−Alder Reactions of Boron Dienes
diethanolamine (4) proved to be slightly less reactive than its
diethanolamine counterpart (3), and where we thought it might
have even better organic solvent solubility than 3, we found
them to be virtually identical and both highly soluble.4 Whereas
3 had reacted completely with N-phenylmaleimide in 0.25 h at
20 °C (t1/2 < 4 min @ −10 °C), 4 required 2 h to go to
completion (Table 1, entry 1). Similarly, where 3 reacted with
ethyl acrylate and N-phenyl citraconimide after 6 h and 8 h of
reflux to provide products in 84% and 95% isolated yields with
16.4 and 4:1 regioisomeric ratios, 4 required 20 h of reflux to
provide the cycloadducts (12 and 13) in 90% and 75% yields
with reduced (3:1) regioselectivities (Table 1, entries 2 and 3).
Dienes (6−9), which all contain 3 coordinate boron in dry
solvents, failed to produce any product when reacted with N-
phenylmaleimide at 20 °C for 20 h in THF. Switching to
toluene reflux yielded just trace amounts of product when
heated with N-phenylmaleimide with the exception of diene 6
which did produce about a 50% yield of cycloadduct after 10 h
of reflux. The other diene, which contained four coordinate
boron from a triol ligand (10), reacted well with N-
phenylmaleimide at 20 °C (Table 1, entry 4) and N-
phenylcitraconimide (Table 1, entry 6) but produced a poor
yield of cycloadduct with ethyl acrylate (Table 1, entry 5).
Suzuki Cross Coupling Reactions of Boron Substi-
tuted Diels−Alder Cycloadducts and Tandem Diels−
Alder/Cross Coupling Reactions. A variety of cross coupling
reactions of the boron substituted cycloadducts of the
diethanolamine boron diene (3) were reported in our earlier
communication.4 Initially, here we just took the N-methyl
diethanolamine cycloadduct (11), as well as the triol boronate
substituted cycloadduct (14), and cross coupled them with
iodobenzene using conditions analogous to those we had used
for cycloadducts of 3 (Scheme 4) (Table 2, entries 1 and 2).
We then performed Diels−Alder reactions to produce 12 and
13, but rather than stop to purify those cycloadducts, we just
took the crude products on into the cross coupling reaction and
found that this approach also produced organic cycloadducts
(18 and 19) in good yields for the 2 steps (Table 2, entries 3
alkenyl lithium reagents under basic conditions they could also
isolate the dienes, which they subsequently proto-deboronated
or oxidized.11
Initially, we had thought we might be able to determine
whether or not the boron in one of these dienes was three or
1
four coordinate from differences in their H or 13C NMR
spectra, but they proved to all be very similar. Dienes (6−10)
show C1 and H1 resonances (d6-DMSO) from 116.9 to 119.7
and 4.82−5.09, C3 and H3 from 144.6 to 145.5 and 6.18−6.32,
and C4 and H4 from 112.4 to 113.2 and H4trans 5.36−5.50, H4cis
4.65−4.71. Dienes (6−9) exhibit interesting 11B NMR
resonances. In CDCl3 (dried over molecular sieves) where
they are sparingly soluble and we filter samples into the NMR
tubes, they have 11B NMR spectra typical of 3 coordinate boron
(δ25−30 ppm).12 When we obtain NMR spectra from those
same samples of material but in d6-DMSO, all the 11B
resonances occur at 1−6 ppm, so we believe they are all 4
coordinate in this solvent13 as a result of the basic reaction
conditions used to prepare them and traces of NaOH that may
be present or traces of water that are more prevalent in d6-
DMSO than CDCl3. Dienes (6, 8, and 9) all appear to exist as a
mixture of s-cis and s-trans conformers in solution at 25 °C,
since we see NOESY cross peaks between H3 as well as H4
protons and the H1 protons. Dienes (7 and 10), on the other
hand, only show NOESY cross peaks between H3 and the H1
protons indicating that s-cis to s-trans interconversion is not as
rapid for those 2 dienes.
Diels−Alder Reactions of Boron Substituted Dienes.
Diels−Alder reactions of diene (3) were reported in our earlier
communication.4 We noted at that time that this diene was the
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Table 1. Diels−Alder Reactions of Dienes
Scheme 4. Cross Coupling Reactions of Boron Substituted
Diels−Alder Cycloadducts
Scheme 5. Tandem Diels−Alder/Cross Coupling Reactions
of Boron Substituted Dienes
Table 2. Results of Cross Coupling Reactions
Table 3. Tandem Diels−Alder/Suzuki Cross Coupling
Reactions
*
Yield reported is cumulative for 2 steps, the Diels−Alder reaction
followed by the cross coupling reaction.
entries 3 and 4). These reactions failed for the pinacol boron
diene (7) and the two diethanolamine boron dienes (3 and 4)
resulting instead in diene decomposition.
and 4; avg yield of 82% per step for 18 and 78% per step for
19).
The success with the no purification two-step approach to
produce 18 and 19 led us to try one-pot tandem reactions
combining boron substituted diene, dienophile, and iodoben-
zene (Scheme 5). Surprisingly, these one-pot reactions worked
very well for 3 out of 4 of the boron substituted dienes (6, 8,
and 9), which had failed to react in Diels−Alder chemistry
previously (Table 3, entries 1, 2, 5, and 6) and these reactions
worked well for triol boronate substituted diene (10) (Table 3,
We thought of several possible mechanistic pathways which
could be used to explain the observation of Diels−Alder/cross
coupled products here under these conditions where we had
seen no Diels−Alder products from thermal reactions of several
of these dienes and dienophiles earlier. One possibility (labeled
path 1 below) would be that oxidative addition of iodobenzene
occurred followed by transmetalation and reductive elimination
to produce 2-phenyl-1,3-butadiene (20). Diene (20) would
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then simply undergo a thermal or Pd-catalyzed Diels−Alder
reaction with N-phenylcitraconimide to produce 19. However,
we saw no traces of 20 by H NMR, and when we treated
dienes (6, 8, 9, and 10) with these reaction conditions less the
dienophile, N-phenylcitraconimide, we isolated no diene (20)
and instead just observed boron substituted diene decom-
position.
(0) was added to diene (6) in CD3CN and no attempts were
made to exclude oxygen, we see a new set of diene peaks grow
in over 1.5 h at 50 °C. We postulated that these peaks were due
to the formation of a 2-Pd(II) substituted 1,3-diene (22).16
This postulate is further corroborated by the observation that
when diene (6) is added to Pd(CH3CN)2Cl2 or Pd(PPh3)2Cl2
in CD3CN these same diene peaks are observed in less than 1
min. However, when this diene which is formed in the presence
of Pd is treated with iodobenzene and N-phenylcitraconimide
and heated to 50 °C for 12 h in CD3CN, we observe no change
1
With respect to path 2, this pathway could have occurred for
diene (10), since it will react thermally with N-phenyl-
citraconimide and no catalyst is required (Table 1, entry 6).
However, when dienes (6, 8, and 9) were heated under these
reaction conditions with Pd(0) with N-phenylcitraconimide, we
saw no cycloadducts (21) and the dienes decomposed, so we
do not believe path 2 is being catalyzed by Pd(0) for those
dienes. However, when those dienes were heated in CH3CN
for 18 h with dienophile and a Pd(II) source (Pd-
(CH3CN)2Cl2), we did see evidence for the formation of
1
in the H NMR, no product 19, nor any new peaks which
might be attributed to a Pd substituted cycloadduct (23). To
summarize, Pd(II) appears to catalyze a Diels−Alder reaction
between boron dienes and N-phenylcitraconimide. Having a
Pd(II) complex present with a Pd−Ph bond appears critical,
since adding Ph-I to a solution containing 22 does not lead to
product, i.e., we assume the products we are seeing here are
coming from a Pd(0) to Pd(II) cycle rather than a Pd(II) to
Pd(IV) cycle.
1
boron substituted cycloadducts (21) by H NMR and MS, but
we could not isolate those boron cycloadducts like we could
some others here. A Pd(II) catalyzed Diels−Alder reaction14 to
produce 21 followed by cross coupling to produce 19 would fit
these observations as a route from dienes 6, 8, and 9 to 19.
CONCLUSION
■
We have prepared six new 2-boron substituted 1,3 dienes. We
found that preparing these dienes under basic reaction
conditions allows them to be isolated as monomers and
alleviates previous complications that were noted as facile
Diels−Alder dimerization of diene 7. We found that boron
substituted dienes where the boron was 4 coordinate
participated readily in Diels−Alder reactions, whereas the
boron dienes with 3 coordinate boron were unreactive. Where
boron substituted Diels−Alder cycloadducts were isolated, they
could be used in cross coupling reactions. Lastly, we discovered
that 3 dienes, which were unreactive in thermal Diels−Alder
chemistry, participated in tandem Diels−Alder/cross coupling
reactions which appear to be Pd(II) catalyzed.
EXPERIMENTAL SECTION
■
General. The 1H NMR were recorded on a 500 MHz spectrometer
and a 300 MHz spectrometer operating at 500.13 MHz and 300.13
MHz, respectively. 13C NMR were recorded on a 300 MHz
spectrometer and a 500 MHz spectrometer operating at 75.48 MHz
and 125.77 MHz, respectively. Chemical shifts were reported in parts
per million (δ) relative to tetramethylsilane (TMS), or the residual
proton resonances in the deuterated solvents: chloroform (CDCl3)
Finally, we investigated path 3 as a possibility via a palladium
substituted diene (22) as an intermediate.15 When palladium
Figure 1. Comparison of NMR chemical shifts of boron substituted diene (6) and palladium substituted diene (22) in CD3CN.
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and dimethyl sulfoxide (DMSO). Coupling constants (J values) were
reported in hertz (Hz).
145.5, 113.1, 112.4, 60.4, 30.0; 11B NMR (96 MHz, (CD3)2SO) δ 2.53,
CDCl3 δ 26.30; HRMS (Magnetic Sector EI) calcd for C7H11BO2:
138.0852, found 138.08522.
All reactions were carried out under an inert atmosphere unless
otherwise noted. Flash chromatography was performed using thick-
walled glass chromatography columns and ultrapure silica gel. Ether
and pentane were distilled over Na. Absolute ethanol and methanol
were used without further purification. THF was purchased in the
form of solvent kegs and purified using the centrally located solvent
dispensing system developed by J. C. Meyer. Deuterated solvents were
dried over molecular sieves. Magnesium sulfate, magnesium small
turnings, iodobenzene, 4-iodobenzotrifluoride, 2-iodoanisole, 4-
iodoanisole, ethyl acrylate, N-phenylmaleimide, and methyl N-
phenylmaleimide were used as received. 2-Chloro-1,3-butadiene,
50% in xylene (Chloroprene) was purchased from Pfaltz & Bauer,
Inc and used as received.
Preparation of 1,3-Butadiene-(2-pinacol)-borate (7). Follow
the general procedure to obtain diene boronic acid (2). The dried
diene boronic acid was added at once to a solution of pinacol (0.7
equiv, 17.5 mmol, 2.07 g) dissolved in THF (100 mL). Sodium
hydride (1.5 equiv, 37.5 mmol, 0.086 g) was added slowly to the
mixture at room temperature. The solvent was removed by rotovap
after 2 h. Dry THF (2 × 100 mL), followed by dry diethyl ether (2 ×
100 mL), was added to dissolve and wash the solid. The solid was
removed by filtration and the solvent was removed by rotary
evaporation and high vacuum to yield the white solid product (7)
1
(1.83 g, 10.15 mmol, 58%): H NMR (300 MHz, (CD3)2SO) δ 6.28
(dd, J = 17.5, 10.6 Hz, 1H), 5.40 (dd, J = 17.5, 3.4 Hz, 1H), 5.08 (d, J
= 6.3 Hz, 1H), 4.81 (d, J = 6.3, Hz, 1H), 4.71 (dd, J = 10.6, 3.4 Hz,
1H), 1.00 (s, 6H), 0.86 (s, 6H); 13C NMR (75 MHz, (CD3)2SO) δ
145.7, 116.5, 112.9, 76.5, 26.7, 25.3; 11B NMR (96 MHz, (CD3)2SO) δ
5.97, CDCl3 δ 29.88; HRMS (Magnetic Sector EI) calcd for
C10H17BO2: 180.1322, found: 180.13217.
General Procedure for Preparing Boron Substituted Dienes.
A mixture of magnesium (1.0 g, 41.1 mmol), 1,2-dibromoethane (0.5
mL,5.3 mmol), and THF (10 mL) was refluxed under nitrogen for 15
min to activate the magnesium. To the mixture, anhydrous zinc
chloride (0.6 g, 4.1 mmol) in THF (60 mL) was added and reflux was
continued for another 15 min. 2-Chloro-1,3-butadiene (4.9 mL, 25
mmol) (density 0.915 g/mL, 50% in xylene) and 1,2-dibromoethane
(0.95 g, 5 mmol) in THF (30 mL) were added dropwise over a period
of 30 min. This addition was controlled so as to bring the mixture into
a gentle reflux. The color of the contents changed gradually from
grayish-white to greenish-black. The mixture was heated to reflux for
an additional 30 min after completion of the addition. The Grignard
reagent thus obtained was immediately added dropwise to a solution
of trimethoxyborane (4.25 mL, 38.5 mmol) in THF (25 mL) using a
double-ended needle. The addition was controlled in such a way that
the internal temperature of the mixture was maintained below −60 °C
all the time. After completion of the addition, the solution was allowed
to warm to room temperature quickly. The cloudy gray-colored
reaction mixture was stirred for 1 h . To the resulting mixture at room
temperature, 0.5 M HCl (100 mL) was added. The reaction mixture
was extracted with Et2O (2 × 75 mL). The combined colorless clear
organic layers were dried over MgSO4, and the volatiles were removed
by rotovap (30 °C, 20 Torr) to yield diene boronic acid (2). We have
already reported previously on how to use diene 2 to make 3.4
Preparation of 1,3-Butadiene-2-N-methyl Diethanolamine
Borate (4). Follow the general procedure to obtain boronic acid (2),
then the boronic acid was added at once to a solution of N-methyl
diethanolamine (0.8 equiv, 22.5 mmol, 2.68 g) dissolved in THF (100
mL). Sodium sulfate (8 g) was added and refluxed for 6 h. At the end
of the reaction, the flask was cooled to room temperature. Solid
Na2SO4 was separated from the solution by filtration. The solution was
reduced by 150 mL using a rotary evaporator. Pentane (10 mL) was
added to precipitate the product, and product 4 was obtained as white
solid following filtration, washing with cold pentane, and drying under
Preparation of 1,3-Butadiene-(2-(2′,2′-dimethyl-propane-
1,3-diol))-borate (8). Follow the general procedure to obtain diene
boronic acid (2). The dried diene boronic acid was added at once to a
solution of 2,2-dimethylpropane-1,3-diol (0.7 equiv, 17.5 mmol, 1.82
g) dissolved in THF (100 mL). Sodium hydride (1.5 equiv, 37.5
mmol, 0.086 g) was added slowly to the mixture at room temperature.
The solvent was removed by rotovap after 2 h. Dry THF (2 × 100
mL) followed by dry diethyl ether (2 × 100 mL) was added to dissolve
and wash the solid. The solid was removed by filtration and the solvent
was removed by rotary evaporation to obtain the white solid product
1
(8) (1.92 g, 11.55 mmol, 66%): H NMR (300 MHz, (CD3)2SO) δ
6.30 (dd, J = 17.5, 10.6 Hz, 1H), 5.40 (dd, J = 17.5, 3.7 Hz, 1H), 5.02
(m, 2H), 4.66 (dd, 10.6, 3.8 Hz, 1H), 3.13 (s, 4H), 0.91 (s, 3H), 0.54
(s, 3H); 13C NMR (75 MHz, (CD3)2SO) δ 145.6, 119.0, 112.3, 32.1,
24.0, 22.7; 11B NMR (96 MHz, (CD3)2SO) δ 2.62, CDCl3 δ 25.98;
HRMS (Magnetic Sector EI) calcd for C9H15BO2: 166.1165, found:
166.11652.
Preparation of Sodium 2-(Buta-1,3-dien-2-yl)-6-methyl-
1,3,2-dioxaborocan-6-borate (9). Follow the general procedure
to obtain diene boronic acid (2). The dried diene boronic acid was
added at once to a solution of 3-methylpentane-1,3,5-triol (0.7 equiv,
2.34 g,17.5 mmol) dissolved in THF (100 mL). Sodium hydride (1.5
equiv, 37.5 mmol, 0.086 g) was added slowly to the mixture at room
temperature. The solvent was removed by rotovap after 2 h. Dry
acetone (2 × 100 mL) was added to dissolve and wash the solid. The
solid was removed by filtration, and the solvent was removed by rotary
evaporation and high vacuum to obtain the white solid product (9)
1
(2.15 g, 11.03 mmol, 63%): H NMR (300 MHz, (CD3)2SO) δ 6.21
(dd, J = 17.6, 10.7 Hz, 1H), 5.45 (dd, J = 17.6, 3.9 Hz, 1H), 4.97 (d, J
= 6.4 Hz, 1H), 4.82 (d, J = 6.4 Hz, 1H), 4.64 (dd, J = 10.7, 3.9 Hz,
1H), 3.70 (m, 2H), 3.39 (m, 2H), 1.38 (t, J = 5.7 Hz, 4H), 0.97 (s,
3H); 13C NMR (75 MHz, (CD3)2SO) δ 145.2, 116.5, 112.3, 64.3,
56.3, 41.4, 34.2; 11B NMR (96 MHz, (CD3)2SO) δ 4.42; CDCl3 δ
26.20; HRMS (Magnetic Sector EI) calcd for C10H16BNO3: 195.1192,
found: 195.1192.
1
vacuum. (2.70 g, 14.9 mmol, 66%): H NMR (300 MHz, CDCl3) δ
6.58 (dd, J = 17.6, 10.7 Hz,), 5.58 (m, 1H), 5.52−5.55 (m, 2H), 4.95
(dd, J = 10.9, 2.6 Hz, 1H), 4.09 (m, 2H), 3.99 (m, 2H), 3.09 (m, 2H),
2.96 (m, 2H), 2.62 (s, 3H); 13C NMR (75 MHz, (CD3)2SO) δ 143.5,
124.0, 113.6, 61.5, 59.8, 45.7; 11B NMR (96 MHz, (CD3)2SO) δ 11.31,
CDCl3 δ 11.38; HRMS (TOF ESI) [M + Na]+ calcd for
C9H16BNO2Na: 204.1172, found 204.1172.
Preparation of Sodium 1-(Buta-1,3-dien-2-yl)-4-methyl-
2,6,7-trioxa-1-borabicyclo(2,2,2) octan-1-uide (10). Follow the
general procedure to obtain diene boronic acid (2). The dried diene
boronic acid was added at once to a solution of 2-(hydroxymethyl)-2-
methylpropane-1,3-diol (0.7 equiv, 2.10 g,17.5 mmol) dissolved in
THF (100 mL). Sodium hydride (1.5 equiv, 37.5 mmol, 0.086 g) was
added slowly to the mixture at room temperature. The solvent was
removed by rotovap after 2 h. Dry acetone (3 × 100 mL) was added to
dissolve and wash the solid. The solid was removed by filtration, and
the solvent was removed by rotary evaporation and high vacuum to
Preparation of 1,3-Butadiene-(2-propane-1,3-diol)-borate
(6). Follow the general procedure to obtain diene boronic acid (2).
The dried diene boronic acid was added at once to a solution of
propane-1,3-diol (0.7 equiv, 17.5 mmol, 1.33 g) dissolved in THF
(100 mL). Sodium hydride (1.5 equiv, 37.5 mmol, 0.086 g) was added
slowly to the mixture at room temperature. The solvent was removed
by rotovap after 2 h. Dry THF (3 × 100 mL) was added to dissolve
and wash the solid. The solid was removed by filtration, and all the
solution was removed by rotary evaporation and high vacuum to
1
1
obtain the white solid product (6) (1.62 g, 11.73 mmol, 67%): H
obtain the white solid product (10) (2.68 g, 13.13 mmol, 75%): H
NMR (300 MHz, (CD3)2SO) δ 6.32 (dd, J = 17.3, 10.5 Hz, 1H), 5.50
(dd, J = 17.3,3.8 Hz, 1H), 5.16−5.02 (m, 2H), 4.70 (dd, J = 10.5, 3.8
Hz, 1H), 3.62 (m, 2H), 3.50 (td, J = 11.0, 2.6 Hz, 2H), 1.61 (m, 1H),
1.04 (dt, J = 12.2, 2.6 Hz, 1H); 13C NMR (75 MHz, (CD3)2SO) δ
NMR (300 MHz, (CD3)2SO) δ 6.18 (dd, J = 17.1, 10.5 Hz, 1H), 5.40
(dd, J = 17.1, 3.8 Hz, 1H), 4.90 (m, 2H), 4.65 (dd, J = 10.5, 3.8 Hz,
1H), 3.49 (s, 6H), 0.43 (s, 3H); 13C NMR (300, MHz, (CD3)2SO) δ
144.5, 118.0, 113.0, 73.1, 34.4, 16.3; 11B NMR (96 MHz, (CD3)2SO) δ
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Article
1.10; HRMS (TOF ESI) calcd for C9H14BNaO3 [M +H]+: 205.1012,
found: 205.1012.
raphy (ethyl ether:hexane = 1:1). Optimization of conditions: 2%
Pd2(dba)3 [Tris(dibenzylideneacetone)dipalladium (0) ], acetonitri-
le:ethanol = 5:1, boron cycloadduct:iodoaromatic compounds = 1:2,
K2CO3 (3 equiv). Reaction time: 36 h.
General Procedure for Diels−Alder Reactions. Diene and
dienophile (1:5) were dissolved in the solvent indicated in Table 1 and
were allowed to react for the indicated time at the indicated
temperature. The Diels−Alder adducts were then typically precipitated
by the addition of pentane, vacuum filtered, and dried under high
vacuum.
Preparation of Cycloadduct 11. Diene (4) (0.181 g, 1 mmol)
and dienophile N-phenylmaleimide (0.865 g, 5 mmol) were dissolved
in chloroform (15 mL) in a round-bottom flask at room temperature.
After stirring for 2 h, the product (11) was obtained by precipitation as
a white powder (0.318 g, 0.90 mmol, 90%) following addition of
pentane (50 mL), vacuum filtration, and drying under high vacuum:
1H NMR (300 MHz, CDCl3) δ 7.43 (t, J = 7.6 Hz, 2H), 7.35 (t, J =
7.4 Hz,1H), 7.23 (d, J = 7.6 Hz, 2H), 6.35 (m, 1H), 3.98 (m, 4H), 3.21
(m, 2H), 3.05 (m, 2H), 2.81 (m, 2H), 2.69 (m, 2H), 2.44 (s, 3H), 2.38
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 180.4, 179.8, 132.5, 132.2,
129.0, 128.8, 126.2, 62.0, 61.7, 60.9, 60.4, 46.4, 39.7,39.5, 26.5, 24.8;
Preparation of 2,5-Diphenyl-3a,4,7,7a-tetrahydro-1H-isoin-
dole-1,3(2H)-dione (17) from 11. Following the general procedure,
iodobenzene (0.204 g, 1 mmol) and 11 (0.177 g, 0.5 mmol) were
added along with Pd2(dba)3 (10 mg, 0.01 mmol) and K2CO3 (0.207 g,
1.5 mmol) to a flask under N2 (30 mL acetonitrile and ethanol). The
flask was heated and refluxed for 36 h and worked up as described in
the general procedure. The resulting brown oily crude product mixture
was subjected to flash chromatography to yield the cross coupled
1
product (17) as a white solid (0.139 g, 0.46 mmol, 92%). H NMR
data were identical to that previously reported.3a
Preparation of Ethyl-4-phenyl cyclohex-3-enecarboxylate
(18) from 12 without Isolation of 12. Diene (4) (0.090 g, 0.5
mmol) and dienophile ethyl acrylate (0.250 g, 2.5 mmol) were
dissolved in chloroform (5 mL) in a round-bottom flask and refluxed
for 6 h. The flask was cooled to room temperature. Iodobenzene
(0.204 g, 1 mmol) was added along with Pd2(dba)3 (10 mg, 0.01
mmol) and K2CO3 (0.207 g, 1.5 mmol) to the crude product in the
flask under N2 (30 mL acetonitrile and ethanol). The flask was heated
and refluxed for 36 h and worked up as described in the general
procedure. The resulting brown oily crude product mixture was
subjected to flash chromatography to yield the cross-coupled product
Anal. calcd for C19H23N2O4B C 64.38, H 6.54; Found: C 63.73, H
+
6.43. HRMS (Magnetic Sector 17EI) calcd for C19H23BN2O4 M
354.1751, found: 354.1751.
=
Preparation of Cycloadduct 12. Diene (4) (0.181 g, 1 mmol)
and dienophile ethyl acrylate (0.500 g, 5 mmol) were dissolved in
chloroform (10 mL) in a round-bottom flask and refluxed for 6 h. The
white product was precipitated with pentane (150 mL) and obtained
by vacuum filtration followed by drying under high vacuum (0.252 g,
0.90 mmol, 90%): 1H NMR (300 MHz, CDCl3) δ 6.05 (m, 1H), 4.07
(q, J = 7.2 Hz, 2H), 3.97 (m, 2H), 3.90 (m, 2H), 3.01 (m, 3H), 2.67
(m, 2H), 2.55 (s, 3H), 2.44 (m, 1H), 2.24 (m, 1H), 2.09 (m, 2H), 1.93
(m, 1H), 1.57 (m, 1H), 1.25 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3) Major isomer: δ 176.6, 130.2, 62.0, 60.3, 59.8, 46.3, 39.7, 28.7,
27.0, 25.9, and 14.1; Minor isomer’s peaks found: δ 177.0, 131.4, 59.9,
59.1, 59.0, 46.4, 40.1, 30.2, 25.6, and 25.2; HRMS (TOF ESI) calcd for
C14H24BNO4Na [M + Na]+: = 304.1696, found: 304.1696.
1
(18) as a light yellow oil (0.082 g, 0.34 mmol, 68%). H NMR data
were identical to that previously reported.3a Major isomer:minor
isomer = 3:1
Preparation of 3a-Methyl-2,6-diphenyl-3a,4,7,7a-tetrahy-
dro-1H-isoindole-1,3(2H)-dione (19) from 13 without isolation
of 13. Diene (4) (0.090 g, 0.5 mmol) and dienophile 2-methyl-N-
phenylmaleimide (0.250 g, 2.5 mmol) were dissolved in chloroform (5
mL) in a round-bottom flask and refluxed for 6 h. The flask was cooled
to room temperature. 4-Iodobenzene (0.204 g, 1 mmol) was added
along with Pd2(dba)3 (10 mg, 0.1 mmol) and K2CO3 (0.207 g, 1.5
mmol) to a flask under N2 (30 mL acetonitrile and ethanol). The flask
was heated and refluxed for 36 h and worked up as described in the
general procedure. The resulting brown oily crude product mixture
was subjected to flash chromatography to yield the cross-coupled
product (19) as a white solid (0.095 g, 0.3 mmol, 60%). 1H NMR data
were identical to that previously reported.3a Major isomer:minor
isomer = 1.3:1.
General Procedures for Tandem Diels−Alder/Suzuki Cross
Coupling Reactions. Diene and dienophile (1:4) were added to an
N2 flushed high-pressure resistant thick-walled tube with Pd2(dba)3
and K2CO3 in acetonitrile and ethanol (5 mL). Iodobenzene was
added. The mixture was sealed and heated for 24 h and cooled to
room temperature. The solution was filtered through silica gel with
CH3CN to remove catalysts. The filtrate was washed with water (50
mL) and the aqueous extracted with Et2O (4 × 50 mL). The
combined organic layers were dried over MgSO4 and volatiles were
removed by rotary evaporation. The final product was purified by silica
flash chromatography (ethyl acetate:hexane = 6:1).
Preparation of Cycloadduct 13. Diene (4) (0.181 g, 1 mmol)
and dienophile 2-methyl-N-phenylmaleimide (0.500 g, 5 mmol) were
dissolved in chloroform (10 mL) in a round-bottom flask and refluxed
for 6 h. The white product (13) was precipitated with pentane (150
mL) and obtained by vacuum filtration followed by drying under high
1
vacuum (0.276 g, 0.75 mmol, 75%). H NMR (300 MHz, CDCl3) δ
7.42 (t, J = 7.8 Hz, 2H), 7.36 (t, J = 7.2 Hz, 1H), 7.22 (d, J = 7.8 Hz,
2H), 6.33 (m, 1H), 3.97 (m, 4H), 3.04 (m, 2H), 2.87 (m, 2H), 2.78
(m, 3H), 2.40 (s, 3H), 2.39 (m, 1H), 2.05 (dt, J = 15.0, 7.0 Hz, 1H),
1.46 (s, 3H); 13C NMR (75 MHz, CDCl3) δ Major isomer: 182.6,
179.0, 132.6, 132.3, 129.0, 128.2, 126.1, 61.8, 60.9, 60.4, 47.3, 46.6,
44.2, 35.5, 26.3, 25.3, 25.2. HRMS (TOF ESI) calcd for C20H25BN2O4:
368.1907, found: 368.19075.
Preparation of Cycloadduct 14. Diene (10) (0.204 g, 1 mmol)
and dienophile N-phenylmaleimide (0.865 g, 5 mmol) were dissolved
in toluene (15 mL) in a round-bottom flask at room temperature.
After stirring for 2 h, the product (14) was obtained by precipitation as
a white powder (0.347 g, 0.92 mmol, 92%) by addition of pentane (50
mL), vacuum filtration, and drying under high vacuum: 1H NMR (300
MHz, (CD3)2SO) δ 7.43 (m, 2H), 7.37 (m, 1H), 7.26 (m, 2H), 5.64
(m, 1H), 3.49 (s, 6H), 3.03 (m, 1H), 2.92 (m, 1H), 2.19 (m, 4H), 0.44
(s, 3H); 13C NMR (75 MHz, (CD3)2SO) δ 179.8, 179.7, 132.8, 128.8,
128.6, 127.9, 127.2, 73.3, 72.6, 34.5, 26.4, 23.6, 16.3 (one sp3 C signal
is apparently obscured by the DMSO C resonance); HRMS (TOF
ESI) calcd for C19H21NO5B: [M-Na+H]+ = 355.1597, found 355.1591.
General Procedure for Stepwise Suzuki Cross Coupling
Reactions. Boron substituted cycloadducts and iodoaromatic
compounds were added to a N2 flushed flask with Pd2(dba)3 and
K2CO3 in acetonitrile and ethanol (30 mL). The mixture was refluxed
for 36 h and cooled to room temperature. The solution was filtered
through silica gel with CH3CN to remove catalysts. The filtrate was
washed with water (50 mL) and the aqueous extracted with Et2O (4 ×
50 mL). The combined organic layers were dried over MgSO4, and
volatiles were removed by rotary evaporation. The resulting cross-
coupled cycloadduct residue was purified by silica flash chromatog-
Tandem Diels−Alder/Suzuki Cross Coupling Reactions. Entry
1 of Table 3: Preparation of 17. Diene (6) (0.10 g, 0.72 mmol) and
N-phenylmaleimide (0.50 g, 2.88 mmol) (1:4) were used along with
iodobenzene (0.59 g, 2.88 mmol) (diene:iodobenzene = 1:4) and
catalysts as described in the general procedure. After heating, workup,
and chromatography (ethyl acetate:hexane = 4:1), 17 was obtained as
a white powder (0.16 g, 0.52 mmol, 73%). 1H NMR data were
identical to that previously reported.3a
Entry 2 of Table 3: Preparation of 19. Diene (6) (0.10 g, 0.72
mmol) and 2-methyl-N-phenylmaleimide (0.54 g, 2.88 mmol) (1:4)
were used along with iodobenzene (0.29 g, 1.44 mmol)
(diene:iodobenzene = 1:2) and catalysts as described in the general
procedure. After heating, workup, and chromatography, 19 was
1
obtained as a white powder (0.19 g, 0.60 mmol, 83%). H NMR was
identical to that previously reported.4 Major isomer:minor isomer =
2:1.
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The Journal of Organic Chemistry
Article
Entry 3 of Table 3: Preparation of 19. Diene (10) (0.10 g, 0.49
mmol) and 2-methyl-N-phenylmaleimide (0.37 g, 1.96 mmol) (1:4)
were used along with iodobenzene (0.20 g, 0.98 mmol)
(diene:iodobenzene = 1:2) and catalysts according to the general
procedure. After heating, workup, and chromatography, 19 was
(6) Abreu, A.; Jesus Alas, S.; Beltran
Organomet. Chem. 2006, 691, 337.
́
, H. I.; Santillan, R.; Farfan
́
, N. J.
̀
(7) (a) Akiba, K. Y.; Yamamoto, Y. Heteroatom Chem. 2007, 18, 161.
(b) Tomsho, J. W.; Benkovic, S. J. J. Org. Chem. 2012, 77, 2098.
(c) Collins, B. E.; Sorey, S.; Hargrove, A. E.; Shabbir, S. H.; Lynch, V.
M.; Anslyn, E. V. J. Org. Chem. 2009, 74, 4055.
(8) Knapp, D. M.; Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2009,
131, 6961.
(9) Carreaux, F.; Posseme, F.; Carboni, B.; Arrieta, A.; Lecea, B.;
Cossio, F. P. J. Org. Chem. 2002, 67, 9153.
(10) (a) Kamabuchi, A.; Miyaura, N.; Suzuki, A. Tetrahedron Lett.
1993, 34, 4827. (b) Guennouni, N.; Rassetdeloge, C.; Carboni, B.;
Vaultier, M. Synlett 1992, 581.
1
obtained as a white powder (0.12 g, 0.38 mmol, 78%). H NMR was
identical to that previously reported.4
Entry 4 of Table 3: Preparation of 18. Diene (10) (0.10 g, 0.49
mmol) and ethyl acrylate (0.098 g, 0.98 mmol) (1:2) were used along
with iodobenzene (0.20 g, 0.98 mmol) (diene:iodobenzene = 1:2) and
catalysts according to the general procedure. After heating, workup,
and chromatography (ethyl ether:hexane = 1:1), 18 was obtained as a
light yellow oil (0.071 g, 0.31 mmol, 63%). 1H NMR data was identical
to that previously reported.3a Major isomer:minor isomer = 3:1.
Entry 7 of Table 3: Preparation of 19. Diene (8) (0.10 g, 0.60
mmol) and 2-methyl-N-phenylmaleimide (0.45 g, 2.40 mmol) (1:4)
were used along with iodobenzene (0.50 g, 2.4 mmol) (diene:iodo-
benzene = 1:4) and catalysts according to the general procedure. After
heating, workup, and chromatography, 19 was obtained as a white
(11) Brown, H. C.; Bhat, N. G.; Iyer, R. R. Tetrahedron Lett. 1991, 32,
3655.
(12) (a) Meiland, M.; Heinze, T.; Guenther, W.; Liebert, T.
Tetrahedron Lett . 2009, 50, 469. (b) Odom, J. D.; Moore, T. F.;
Goetze, R.; Noth, H.; Wrackmeyer, B. J. Organomet. Chem. 1979, 173,
15.
(13) Oliveira, R. A.; Silva, R. O.; Molander, G. A.; Menezes, P. H.
Magn. Reson. Chem. 2009, 47, 873.
1
powder (0.125 g, 0.39 mmol, 65%). H NMR was identical to that
previously reported.4
Entry 8 of Table 3: Preparation of 19. Diene (9) (0.10 g, 0.46
mmol) and 2-methyl-N-phenylmaleimide (0.34 g, 1.83 mmol) (1:4)
were used along with iodobenzene (0.37 g, 1.83 mmol)
(diene:iodobenzene = 1:4) and catalysts as described in the general
procedure. After heating, workup, and chromatography, 19 was
(14) (a) Duan, Z. B.; Long, Y. H.; Yang, D. Q. Chin. J. Org. Chem.
2010, 30, 368. (b) Sole, D.; Serrano, O. Org. Biomol. Chem. 2009, 7,
3382.
(15) Gidlof, R.; Johansson, M.; Sterner, O. Org. Lett. 2010, 12, 5100.
(16) (a) Canovese, L.; Visentin, F.; Chessa, G.; Uguagliati, P.; Santo,
C.; Dolmella, A. Organometallics 2005, 24, 3297. (b) Benyunes, S. A.;
Brandt, L.; Fries, A.; Green, M.; Mahon, M. F.; Papworth, T. M. T. J.
Chem. Soc., Dalton Trans. 1993, 3785.
1
obtained as a white powder (0.10 g, 0.33 mmol, 72%). H NMR was
identical to that previously reported.4
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of all novel compounds produced.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: Mark E. Welker welker@wfu.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation for their support of
this work (CHE-0749759) and the NMR instrumentation used
to characterize the compounds reported here.
REFERENCES
■
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