Preparation and Diels-Alder/cross coupling reactions of a 2-diethanolaminoboron-substituted 1,3-diene

Article abstract of DOI:10.3762/bjoc.5.45

A 2-diethanolamine boronyl substituted 1,3-diene has been synthesized in high yield and characterized spectroscopically as well as by X-ray crystallography. This diene has then subsequently been used in a number of fast, high yielding Diels-Alder/cross co

Full text of DOI:10.3762/bjoc.5.45

Preparation and Diels–Alder/cross coupling reactions
of a 2-diethanolaminoboron-substituted 1,3-diene
Liqiong Wang, Cynthia S. Day, Marcus W. Wright and Mark E. Welker*
Preliminary Communication
Open Access
Address:
Beilstein Journal of Organic Chemistry 2009, 5, No. 45.
Department of Chemistry, Wake Forest University, P.O. Box 7486,
Winston-Salem, NC 27109 (USA)
doi:10.3762/bjoc.5.45
Received: 02 July 2009
Email:
Accepted: 08 September 2009
Published: 21 September 2009
Mark E. Welker* - welker@wfu.edu
* Corresponding author
Associate Editor: I. Marek
Keywords:
© 2009 Wang et al; licensee Beilstein-Institut.
License and terms: see end of document.
cross coupling; Diels–Alder; organoboron
Abstract
A 2-diethanolamine boronyl substituted 1,3-diene has been synthesized in high yield and characterized spectroscopically as well as
by X-ray crystallography. This diene has then subsequently been used in a number of fast, high yielding Diels–Alder/cross coup-
ling reactions.
Introduction
Our group [1] and the Tada group [2] independently reported be separated from the desired diene [9]. To overcome these
the preparation and Diels–Alder reactions of pyridine methodology challenges we have begun to prepare diethano-
cobaloxime dienyl complexes over 15 years ago. Since that laminoboron substituted dienes and we communicate our first
time, we have reported a number of synthetic routes to these results in this area here.
and other related types of cobalt dienyl complexes as well as
their subsequent cycloaddition and demetallation chemistry Results and Discussion
[3-5], and other groups have now made use of the cycloadducts The diethanolamine boronyl substituted diene 2 was obtained as
thus prepared [6] as well as the methodology [7].
white needles on a several gram scale from a simple procedure
which involved preparing the Grignard reagent from chloro-
We have now subsequently reported the preparation of 2-BF3 prene 1, adding this reagent to trimethoxyborane followed by
substituted 1,3-butadienes and demonstrated that they can be the addition of dilute HCl and diethanolamine (Scheme 1). The
used in sequential Diels–Alder/cross coupling reactions [8,9]. boron substituted diene 2 thus obtained has C1 (δ 5.23 vs δ
These trifluoroborate substituted dienes are stable but their 5.04, 4.96 (d6-DMSO) and C3 (δ 6.31 vs. δ 6.19) hydrogen
organic solvent solubility is not ideal. Preparation of more atoms which are significantly more deshielded than the BF3
highly substituted BF3 dienes also requires a transmetallation substituted diene. In the solid state (Figure 1, see Supporting
protocol which yields a Grignard-BF3 by-product which has to Information), C(1)–C(2) and C(2)–C(3) bond lengths were
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Beilstein Journal of Organic Chemistry 2009, 5, No. 45.
Scheme 1: Synthesis of 2-diethanolaminoborate-1,3-butadiene.
virtually identical in both dienes whereas B–C(2) (1.609(5) Å Scheme 2) [8]. Qualitatively, we initially noticed that whereas
vs 1.576(13) Å) and C(3)–C(4) (1.308(6) Å vs 1.279(13) Å) the BF3 diene required 16 h of heating at 95–100 °C in a sealed
were significantly longer in the diethanolamine boronyl diene 2. tube in toluene with N-phenylmaleimide to obtain >90% yield
of cycloadduct, the diethanolamine boronyl diene 2 reacted with
this same dienophile to afford a 98% isolated yield of
cyclaooduct 4 after only 15 min at 25 °C! We tried to get more
quantitative rate constant data about this Diels–Alder reaction
via NMR spectroscopy but when we try to perform this reac-
tion under pseudo first order conditions at −10 °C, we can only
say that the t1/2 is less than 4 minutes. Attempts to get more
accurate kinetic data by NMR at −40 °C resulted instead in
diene 2 precipitation. This diene 2 is by far the most reactive
main group element substituted diene we have made in the
boron or silicon substituted series to date. What is perhaps even
more surprising to us is that this diene 2 is even more reactive
than the most reactive cobaloxime substituted diene we ever
prepared in our earlier work [10] and those cobaloxime dienes
consistently favored the s-cis conformation in the solid state.
Diene 2 is in the s-trans conformation in the solid state (Figure
1) but in this case we suspect that the preference for the s-trans
Figure 1: Molecular structure of boron substituted diene 2.
conformer is due to intermolecular hydrogen bonding between
the N–H and one of the adjacent molecule’s boronate oxygen
This diethanolamine boronyl diene 2 has proved to be signific- atoms. This hydrogen bonding would make a C(2)–C(3)
antly more reactive and more regioselective in Diels–Alder dihedral angle of 50–60° (on the order of those we observed in
reactions compared to its BF3 diene counterpart (Table 1, cobaloxime diene solid state structures) unfavorable. At 25 °C
Scheme 2: Diels–Alder reactions.
Table 1: Diels–Alder reactions of diene 2.
Product #
Dienophile
Temp (°C)
Time (h)
Yield (%)
Major:Minor
3
4
5
ethyl acrylate
reflux
25
6
0.25
8
84
98
95
16.4:1
NA
N-phenyl maleimide
2-methyl N-phenyl maleimide
reflux
4.0:1
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Beilstein Journal of Organic Chemistry 2009, 5, No. 45.
in CDCl3, we saw no evidence for the s-cis conformer by
Table 2: Results of cross coupling reactions.
NOESY.
Entry Cycloadduct
(#)
R
Yield
(%)
Isomer Product
ratio
(#)
In an effort to further understand this reactivity difference,
geometry-optimization with DFT using the B3LYP functional
and a 6-31G(d) basis set followed by population analysis was
performed using Gaussian 03 on 2-diethanolaminoboronyl-1,3-
butadiene (2) and its BF3 diene counterpart. 2-Diethano-
laminoboronyl-1,3-butadiene has a HOMO energy of −6.00 eV,
whereas its BF3 diene counterpart has a HOMO energy of
−12.58 eV. These energies are consistent with our observations
that 2-diethanolaminoboronyl-1,3-butadiene (2) is more reactive
than its BF3 diene counterpart. Furthermore, a Mulliken popula-
tion analysis indicates a build-up of electron density on carbons
1
2
3
4
5
6
7
8
9
3
3
3
4
4
4
5
5
5
H
85
97
80
64
70
60
58
70
75
17.2:1
17.9:1
18.0:1
NA
6
7
CF3
OMe
H
8
9
CF3
OMe
H
NA
10
11
12
13
14
NA
3.5:1
3.4:1
3.3:1
CF3
OMe
C1 and C4 of 0.15e and 0.14e respectively in 2-diethano- Conclusion
laminoboronyl-1,3-butadiene (2) compared to its BF3 diene In conclusion, we report a simple preparation of a 2-boronyl
counterpart, which is also consistent with our observations. In substituted 1,3 diene which has proved to be the most reactive
addition to enhanced Diels–Alder reaction rates, we also noted 2-main group element or 2-transition metal element substituted
greatly improved regioselectivities (Table 1). Whereas the BF3 diene for Diels–Alder reactions that we have prepared to date.
diene required 36 h of heating to 95–100 °C in a sealed tube in We have also demonstrated that this boron-substituted diene can
ethanol to provide a 3.3:1 mixture of regioisomers from reac- serve as a synthon for a host of organic dienes via cross coup-
tion with ethyl acrylate, the diethanolamine boronyl diene 2 ling reactions which we performed on Diels–Alder reaction
reacted with this same dienophile at reflux for 6 h to provide a cycloadducts.
16.4:1 mixture of para (1,4) to meta (1,3) isomers 3 in identical
isolated yield. Similarly, when we used a citraconamide deriv- Experimental
ative (2-methyl N-phenylmaleimide), we isolated cycloadduct 5 Preparation of 1,3-butadiene-2-diethanolamine boronate 2:
in high yield although with reduced regioselectivity (4:1). A mixture of magnesium (1.0 g, 41.1 mmol), 1,2-dibromo-
However, the BF3 diene proved unreactive with citraconic acid ethane (0.5 mL), and THF (10 mL) was refluxed under nitrogen
derived dienophiles. This diethanolamine boronyl diene 2 once for 15 min to activate the magnesium. To the mixture anhyd-
again reacted under much milder conditions and with better rous zinc chloride (0.6 g) in THF (60 mL) was added and reflux
regioselectivity than highly reactive silicon substituted dienes was continued for another 15 min. 2-Chloro-1,3-butadiene (4.9
we have also reported previously [11].
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
Lastly, in order to prove that diethanolamine boronyl diene 2 dropwise over a period of 30 min. This addition was controlled
could serve as a synthon for a host of other organic dienes, we so as to bring the mixture into a gentle reflux. The color of the
took cycloadducts 3–5 and proved that they could be cross contents changed gradually from grayish white to greenish
coupled efficiently to iodobenzene, 4-trifluoromethyl-1- black. The mixture was heated to reflux for an additional 30
iodobenzene, and 4-iodoanisole (Table 2, Scheme 3). Cross min after completion of the addition. The Grignard reagent thus
coupled cycloadducts 6–14 were all isolated in good to excel- obtained was immediately added dropwise to a solution of
lent yield and regioselectivities observed in the original trimethoxyborane (4.25 mL, 38.5 mmol) in THF (25 mL) using
Diels–Alder reactions were maintained after cross coupling. a double-ended needle. The addition was controlled in such a
Scheme 3: Cross coupling reactions.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 45.
way that the internal temperature of the mixture was main- Et2O (4 × 50 mL). The combined organic layers were dried
tained below –60 °C all the time. After completion of the addi- over MgSO4 and volatiles were removed by rotary evaporation.
tion, the solution was allowed to warm to room temperature The resulting cross-coupled cycloadduct residue was purified
quickly. The cloudy gray colored reaction mixture was stirred by flash chromatography (ethyl ether:hexane = 1:1). Optimiza-
for 1 h. To the resulting mixture at room temperature, 0.5 M t i o n
o f
c o n d i t i o n s :
2 %
P d 2 ( d b a ) 3
HCl solution (100 mL) was added. The reaction mixture was [ T r i s ( d i b e n z y l i d e n e a c e t o n e ) d i p a l l a d i u m ( 0 ) ] ,
extracted with Et2O (2 × 75 mL). The combined colorless clear acetonitrile:ethanol = 5:1, boron cycloadduct:iodoaromatic
organic layers were dried over MgSO4, and the volatiles were compounds = 1:2, K2CO3 (3 equiv) reaction time: 36 h.
removed by a rotary evaporator (30 °C, 20 Torr) to yield the
dieneboronic acid. The boronic acid was added at once to a Preparation of 6-(4-methoxyphenyl)-3a-methyl-2-phenyl-
solution of diethanolamine (0.8 equiv, 22.5 mmol, 8.411g) 3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione (14):
dissolved in THF (100 mL). Sodium sulfate (8 g) was added Following the general procedure, 4-iodoanisole (0.234 g, 1
and refluxed for 6 h. At the end of the reaction, the flask was mmol) and 5 (0.178 g, 0.5 mmol) were added along with
cooled to room temperature. Solid Na2SO4 was separated from Pd2(dba)3 (10 mg) and K2CO3 (0.207 g, 1.5 mmol) to a flask
the solution by filtration. The solution was reduced by 50 mL under N2 (30 mL acetonitrile and ethanol). The flask was heated
using a rotary evaporator. A cold bath of −30 °C was used to and refluxed for 36 h. The resulting brown oily crude product
induce crystallization. After 4 h, the solid was filtered and mixture was subjected to flash chromatography to yield the
washed with cold chloroform. The product 2 was obtained as cross-coupled product as a white solid (0.134 g, 0.39 mmol,
white needles (2.40 g, 14.4 mmol, 62.4%). 1H NMR (300 MHz, 78%). 14: 1H NMR (300 MHz, CDCl3) δ Major isomer: 7.38
CDCl3) δ 6.51 (dd, J = 17.9, 10.9 Hz, 1H-H3), 5.46–5.40 (m, (d, J = 7.5 Hz, 2H), 7.31 (d, J = 8.7 Hz, 2H), 7.26 (m, 1H), 7.13
3H), 4.98 (dd, J = 17.9, 1.9 Hz, 1H-H4), 5.18 (s, 1H-H7), 4.05 (d, J = 7.5 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 6.1 (m, 1H), 3.80
(m, 2H-H5,8), 3.89 (m, 2H-H5,8), 3.31 (m, 2H-H6,9), 2.76 (m, (s, 3H), 3.25 (dd, J = 15.4, 2.4 Hz, 1H), 2.99 (dd, J = 6.5, 2.4
2H-H6,9) 13C NMR (300, MHz, CDCl3) δ 143.6-C3, 124.3-C4, Hz, 1H), 2.86 (dd, J = 15.4, 6.5 Hz, 1H), 2.61 (ddt, J = 15.4,
114.6-C1, 63.4-C5,8, 52.1-C6,9, the signal of carbon C2 next to 6.5, 2.4 Hz, 1H), 2.16 (dd, J = 15.4, 2.4 Hz, 1H), 1.50 (s, 3H).
a tetravalent boron is generally not observed due to quadru- Minor isomer selected resonances: 3.15 (d, J = 15.4), 2.44
polar broadening [12]. Elemental anal. calcd for C8H14BNO2: (m), 2.30 (m). 13C NMR (300 MHz, CDCl3) δ 182.3, 178.5,
C, 57.53; H, 8.45. Found: 57.06, 8.44.
159.5, 139.8, 133.1, 132.4, 129.4, 128.8, 127.0, 126.8, 122.0,
114.3, 55.6, 48.4, 45.1, 36.7, 30.6, 25.9. Elemental anal. calcd
for C22H21NO3: C, 76.06; H, 6.09. Found: 76.34, 6.31.
Representative Diels–Alder procedure
Preparation of Diels–Alder product 3: Diene 2 (0.167 g, 1
mmol) and ethyl acrylate (0.700 g, 7 mmol) were dissolved in
chloroform (15 mL) in a round bottomed flask and refluxed for
6 h. The white product was precipitated with pentane (150 mL)
and obtained by vacuum filtration, (0.224 g, 0.84 mmol, 84%).
3: 1H NMR (300 MHz, CDCl3) δ 5.91 (m, 1H), 4.86 (s, 1H),
4.12 (q, J = 7.25, 2H), 3.97 (m, 2H), 2.893 (m, 2H), 3.224 (m,
2H), 2.79 (m, 2H), 2.48 (m, 1H), 2.23 (m, 2H), 2.11(m, 2H),
1.99 (m, 1H), 1.76 (s, 1H), 1.25 (t, J = 7.25, 3H). 13C NMR
(300 MHz, CDCl3) δ Major isomer: 176.7, 139.9 (=C-B),
126.9, 62.85, 62.81, 60.0, 51.2, 40.1, 39.8, 28.6, 26.4, 25.9,
14.0. Minor isomer selected resonances: 176.2, 127.6, 24.7,
24.6. Major isomer: minor isomer = 16.4:1. Elemental anal.
calcd. for C13H22BNO4: C, 58.45; H, 8.30. Found: 58.17, 8.32.
Supporting Information
Supporting Information File 1
1H and 13C NMR spectra of compounds 2–14.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-5-45-S1.doc]
Supporting Information File 2
Experimental procedures for compounds 4–13.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-5-45-S2.doc]
Acknowledgments
We thank the National Science Foundation for their support of
Representative Suzuki coupling procedure
General procedure: Boron compounds and iodoaromatic this work (CHE-0450722 and CHE-0749759) and the NMR
compounds were added to a N2 flushed flask with Pd2(dba)3 instrumentation used to characterize the compounds reported
and K2CO3 in acetonitrile and ethanol (30 mL). The mixture here. The UNC Center for Mass Spectrometry performed high
was refluxed for 36 h and cooled to room temperature. The resolution mass spectral analyses. We thank Fred Salsbury of
solution was filtered through silica gel to remove catalysts. The the Department of Physics for performing the DFT calculations
filtrate was quenched with water (50 mL) and extracted with discussed in this manuscript.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 45.
References
1. Smalley, T. L.; Wright, M. W.; Garmon, S. A.; Welker, M. E.;
Rheingold, A. L. Organometallics 1993, 12, 998–1000.
doi:10.1021/om00028a006
2. Tada, M.; Shimizu, T. Bull. Chem. Soc. Jpn. 1992, 65, 1252–1256.
doi:10.1246/bcsj.65.1252
3. Pickin, K. A.; Kindy, J. M.; Day, C. S.; Welker, M. E.
J. Organomet. Chem. 2003, 681, 120–133.
doi:10.1016/S0022-328X(03)00587-4
4. Welker, M. E. Curr. Org. Chem. 2001, 5, 785–807.
doi:10.2174/1385272013375175
5. Tucker, C. J.; Welker, M. E.; Day, C. S.; Wright, M. W. Organometallics
2004, 23, 2257–2262. doi:10.1021/om040010z
6. Miyaki, Y.; Onishi, T.; Ogoshi, S.; Kurosawa, H. J. Organomet. Chem.
2000, 616, 135–139. doi:10.1016/S0022-328X(00)00583-0
7. Chai, C. L. L.; Johnson, R. C.; Koh, J. Tetrahedron 2002, 58, 975–982.
doi:10.1016/S0040-4020(01)01160-7
8. De, S.; Welker, M. E. Org. Lett. 2005, 7, 2481–2484.
doi:10.1021/ol050794s
9. De, S.; Day, C.; Welker, M. E. Tetrahedron 2007, 63, 10939–10948.
doi:10.1016/j.tet.2007.08.063
10.Wright, M. W.; Smalley, T. L.; Welker, M. E.; Rheingold, A. L.
J. Am. Chem. Soc. 1994, 116, 6777–6791. doi:10.1021/ja00094a037
11.Pidaparthi, R. R.; Welker, M. E.; Day, C. S.; Wright, M. W. Org. Lett.
2007, 9, 1623–1626. doi:10.1021/ol070089e
12.Darses, S.; Guillaume, M.; Genet, J.-P. Eur. J. Org. Chem. 1999, 8,
1875–1883.
doi:10.1002/(SICI)1099-0690(199908)1999:8<1875::AID-EJOC1875>3
.3.CO;2-N
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