Novel Functionalized Trisubstituted Allylboronates via Hosomi-Miyaura Borylation of Functionalized Allyl Acetates

Article abstract of DOI:10.1021/ol035952z

(Equation presented) A series of novel functionalized achiral and chiral allylboronates have been synthesized via the nucleophilic addition of boronates on allyl acetates derived via vinylalumination or Baylis-Hillman reaction of aldehydes. These reagents

Full text of DOI:10.1021/ol035952z

ORGANIC
LETTERS
2004
Vol. 6, No. 4
481-484
Novel Functionalized Trisubstituted
Allylboronates via Hosomi−Miyaura
Borylation of Functionalized Allyl
Acetates
P. Veeraraghavan Ramachandran,* Debarshi Pratihar, Debanjan Biswas,
Amit Srivastava, and M. Venkat Ram Reddy
Herbert C. Brown Center for Borane Research, 560 OVal DriVe, Department of
Chemistry, Purdue UniVersity, West Lafayette, Indiana 47907-2084
chandran@purdue.edu
Received October 6, 2003
ABSTRACT
A series of novel functionalized achiral and chiral allylboronates have been synthesized via the nucleophilic addition of boronates on allyl
acetates derived via vinylalumination or Baylis−Hillman reaction of aldehydes. These reagents, upon allylboration with aldehydes, furnish
â-substituted-r-methylene-γ-butyrolactones stereoselectively.
Since the initial discovery by Mikhailov and Bubnov,1
allylboration has become one of the extremely important
C-C bond-forming reactions for the stereoselective synthesis
of homoallylic alcohols.2 Extensive work by Hoffmann3 and
Roush4 on allylboronates and by Brown5 on allylboranes has
led to the development of various organoborane reagents.
Many of these reagents have become invaluable tools in the
arsenal of organic chemists for the total synthesis of complex
natural products.6
in situ from diboronates to simple R,â-unsaturated carbonyl
compounds. Our longstanding tradition in the area of
(4) (a) Roush, W. R. In A. C. S. Sym. Ser. 1989, 386, p 242. (b) Roush,
W. R. In Houben-Weyl Methods of Organic Chemistry; Georg Thieme
Verlag: Stuttgart, Germany, 1995; Vol. E 21, p 1410. (c) Roush, W. R.
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, UK, 1991; Vol. 2, p I.
(5) Brown, H. C.; Ramachandran, P. V. J. Organomet. Chem. 1995, 500,
1.
(6) (a) Smith, A. B.; Adams, C. M.; Barbosa, S. A. L.; Degnan, A. P. J.
Am. Chem. Soc. 2003, 125, 350. (b) Hung, D. T.; Nerenberg, J. B.; Schreiber,
S. L. J. Am. Chem. Soc. 1996, 118, 11054. (c) White, J. D.; Blakemore, P.
R.; Green, N. J.; Hauser, E. B.; Holoboski, M. A.; Keown, L. E.; Kolz, C.
S. N.; Phillips, B. W. J. Org. Chem. 2002, 67, 7750. (d) Coleman, R. S.;
Li, J.; Navarro, A. Angew. Chem., Int. Ed. 2001, 40, 1736.
(7) (a) Ramachandran, P. V.; Rudd, M. T.; Burghardt, T. E.; Reddy, M.
V. R. J. Org. Chem. 2003, 68, 9310. (b) Ramachandran, P. V.; Reddy, M.
V. R.; Rudd, M. T. Chem. Commun. 1999, 1979. (c) Ramachandran, P. V.;
Krzeminski, M. P. Tetrahedron Lett. 1999, 40, 7879. (d) Ramachandran,
P. V.; Reddy, M. V. R.; Rudd, M. T. Tetrahedron Lett. 1999, 40, 627. (e)
Ramachandran, P. V.; Reddy, M. V. R.; Rudd, M. T.; de Alaniz, J. R.
Tetrahedron Lett. 1998, 39, 8791
For the past few years we have been developing the
vinylalumination (VA) reaction for the synthesis of func-
tionalized allyl alcohols.7 Similar types of products can also
be obtained via Baylis-Hillman (BH) reaction.8
Hosomi9 and Miyaura10 have independently reported the
1,4-addition of nucleophilic boryl copper species generated
(1) Mikhailov, B. M.; Bubnov, Y. N. IzV. Akad. Nauk SSSR, Ser. Khim.
1964, 1874; Chem. Abstr. 1965, 62, 11840e.
(2) (a) Yamamoto, Y. Acc. Chem. Res. 1987, 20, 243. (b) Yamamoto,
Y.; Asao, N. Chem. ReV. 1993, 93, 2207.
(3) (a) Hoffmann, R. W. Pure Appl. Chem. 1988, 60, 123. (b) Hoffmann,
R. W Angew. Chem., Int. Ed. Engl. 1987, 26, 489.
(8) (a) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. ReV. 2003,
103, 811. (b) Ciganek, E. Org. React. 1997, 51, 201. (c) Basavaiah, D.;
Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001.
(9) Ito, H.; Yamanaka, H.; Tateiwa, J.-I.; Hosomi, A. Tetrahedron Lett.
2000, 41, 6821
10.1021/ol035952z CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/16/2004

organoborane chemistry11 and current projects involving
vinylalumination7 of carbonyl compounds prompted us to
investigate the SN2′-type addition of boronates on the acetates
derived from VA or BH product alcohols. We envisaged a
novel class of functionalized allylboronates by the nucleo-
philic addition of boryl copper species to the allylic acetates
with a concomitant elimination of the acetates. The successful
synthesis of such allylboronates and the subsequent allylbo-
ration study are reported herein.
For the present study, several representative allyl acetates
3-4 were prepared via the vinylalumination of aldehydes,
followed by the esterification of the resulting alcohols with
Ac2O and pyridine (Scheme 1). We chose three commercially
Table 1. Asymmetric Allylboration of Benzaldehyde with
Allylboronates Derived via SN2′-Borylation
allylboronate
acetate
no.
(B(OR)2)2
no.
rxn
conda
no.
yield, %
E/Z
3a
3a
3b
3c
4a
4c
3d
3a
3c
4a
4a
5
5
5
5
5
5
5
6
6
6
7
M
H
8a
8a
8b
8c
9a
9c
9d
10a
10c
11a
12a
88
86
97
84
85
96
76
99
70
98
b
>95/<5
>95/<5
>95/<5
>95/<5
90/10
88/12
94/6
>95/<5
>95/<5
>95/<5
M
M
M
M
M
M
M
M
H
Scheme 1
a M ) Miyaura conditions: CuCl, LiCl, KOAc, DMF. H ) Hosomi
conditions: CuCl or (CuOTf)2‚C6H6, Bu3P, DMF. b The reagent was
generated in situ and used without further purification in the next step.
since it employs simpler reagents, such as LiCl and KOAc.
The reaction of acetate 4a with 5 provided the allylboronate
9a in 85% yield. The crude NMR analysis of the boronates
8a and 9a revealed the isomeric purity of the double bond
to be >90% (E). These boronates are quite stable and could
be readily purified by silica gel chromatography.12 The
acetates 3c and 4c contain a methyl group â to the ester
group and the reactions were slow. However, the yield of
the allylboronates 8c and 9c were high. The acetate 3d
containing menthol as a chiral auxiliary also reacted in a
facile manner and the chiral allylboronate 9d was isolated
in 76% yield. The preparation of various allylboronates is
summarized in Table 1.
available diboron compounds, viz., bispinacolatodiboron 5,
bis(pinanediolato)diboron 6, bis(diethyl-L-tartarate glycol-
lato)diboron 7, for the generation of nucleophilic boronates
(Figure 1).
We decided to incorporate tartarate-based boronates 12a
since the presence of two ester groups should make boron
more electrophilic and, consequently, more reactive. More-
over, tartarate is C2-symmetric and hence will reduce the
number of competitive diastereomeric transition states in the
allylboration reaction. However, the reaction of 7 with 4a
under Miyaura conditions did not proceed smoothly and the
Figure 1.
(12) General procedure for the preparation of allylboronates under
Miyaura conditions: A mixture of CuCl (1.4 mmol) and LiCl (1.4 mmol)
in DMF (2 mL) was stirred under N2 for 1 h at 25 °C and diboron species
5 or 6 (1.4 mmol) dissolved in DMF (2 mL) was added to it. KOAc (1.4
mmol) was added to the reaction mixture followed by the addition of allyl
acetates 3-4 (1.0 mmol) dissolved in DMF (1 mL). The reaction mixture
was further stirred for 3-5 h. (In the case of â-substituted acetates, the
reaction mixture was stirred for 3 d and all the reagents were taken in 3.5
equiv.) The reaction mixture was then quenched with water and extracted
with ether (3 × 20 mL). The combined organic layers were dried (MgSO4),
concentrated under vacuum, and purified by column chromatography (silica
gel, hexanes:ethyl acetate) to obtain 50-99% yields of 8-11. 1H NMR
(300 MHz, CDCl3) δ (ppm) 6.82 (q, J ) 7.02 Hz, 1H), 3.70 (s, 3H), 1.85
(s, 2H), 1.77 (d, J ) 7.05 Hz, 3H), 1.23 (s, 12H); 13C NMR (75 MHz,
CDCl3) δ (ppm) 168.5, 137.8, 135.7, 130.0, 83.3, 51.6, 24.6, 14.5; 11B NMR
δ (ppm) 32; EI-MS m/z 240 (M)+, 54; CI-MS m/z 241 (M + H)+; HRMS-
CI 240.1541 (actual), 240.1533 (calcd).
The reaction of 3a with 5 under Miyaura conditions10 took
place smoothly in SN2′ fashion with allylic rearrangement
and the elimination of the acetate to provide 8a in 88% yield.
The same reaction under Hosomi conditions9 employing
CuOTf and PBu3 was also very facile and 8a was obtained
in 86% yield (Table 1). We opted for Miyaura conditions
(10) (a) Takahashi, K.; Ishiyama, T.; Miyaura, N. Chem. Lett. 2000, 982.
(b) Takahashi, K.; Ishiyama, T.; Miyaura, N. J. Organomet. Chem. 2001,
625, 47.
(11) (a) Ramachandran, P. V. Aldrichim. Acta 2002, 35, 23. (b) Brown,
H. C.; Ramachandran, P. V. Acc. Chem. Res. 1992, 25, 16. (c) Brown, H.
C.; Ramachandran, P. V. Pure Appl. Chem. 1991, 62, 307.
482
Org. Lett., Vol. 6, No. 4, 2004

reagent 12a invariably decomposed under the reaction
conditions. Hence we resorted to Hosomi’s conditions and
allylboronate 12a could be readily obtained with 7 and PBu3/
CuCl. However, attempts to isolate the allylboronate by
aqueous workup led to the quenching of the reagent and
hence this reagent was generated and utilized in situ for the
next step.
To demonstrate the generality of the preparation of func-
tionalized allylboronates, the reagent bearing a ketone moiety
(14) was similarly prepared in high yield and selectivity from
the corresponding allyl acetate (13) (Scheme 2).
γ-butyrolactones.15 The reaction of 9a with benzaldehyde
in THF was very slow at room temperature and was complete
in 7 d. Removal of the solvent, followed by the addition of
a catalytic amount of pTSA and refluxing in CH2Cl2,
converted the intermediate homoallylic alcohol to R-meth-
ylene-â-methyl-γ-butyrolactone 17 in 64% yield. Analysis
of the crude reaction mixture indicated the diastereomeric
mixture to be 84:16 (cis:trans). Refluxing the reaction
mixture in THF or heating to 100 °C in toluene shortened
the reaction time to 4 d and 1 d, respectively. However, the
diastereomeric ratio was found to be essentially similar
(Table 2). Allylboration with chiral reagent 9d also proceeded
Scheme 2 a
Table 2. Asymmetric Allylboration of Benzaldehyde with
Allylboronates Derived via SN2′-Borylation
a Reagents and conditions: 5, CuCl, LiCl, KOAc, DMF, 92%.
rxn condns
temp, time, yield,
lactone 17
The allylboronate (16) incorporating a nitrile group was
prepared from the corresponding allyl acetate 15 derived
from the BH reaction of acrylonitrile with acetaldehyde,
followed by esterification with acetic anhydride. Reaction
of 15 and 5 under Miyaura conditions provided the allyl-
boronate 16. However, the stereochemistry of the double
bond was found to be in the ratio 37:63 (E:Z) (Scheme 3).
rgnt
no.
ee,a
%
solv
THF
THF,
Tol
THF
THF
Tol
DMF
°C
d
%
cis:trans
9a
9a
9a
9d
25
7
4
1
5
7
3
2
3
6
6
7
2
2
2
2
2
2
64
83
87
50
75
80
80
52
76
40b
56
75
69
64
67
74
76
84:16
85:15
87:13
87:13
79:21
83:17
94:6
95:5
96:4
94:6
98:2
98:2
98:2
98:2
98:2
98:2
98:2
70
100
25
25
100
25
0
-25
-78
-25
0
25
10
8
11a
11a
12a
12a
12a
12a
12a
12a d
12a e
12a d
12a e
12a d
12a e
26
27
25
20
21
22
19
16
22
25
12
Scheme 3 a
DMF
DMF/THF
DMF/THF
DMF/THFc
THF
THF
0
0
0
0
CH2Cl2
CH2Cl2
f
Tol
Tolf
a Reagents and conditions: (a) CH3CHO, DABCO, 78%; (b)
Ac2O, Py, 70%; (c) 5, CuCl, LiCl, KOAc, DMF, 50%.
0
a % ee was determined on a HPLC, using a Chiralcel-ODH column.
Absolute configuration was not determined. b 40% of benzaldehyde re-
mained unreacted. c In the presence of 30% BF3-Et2O. d Reagent generated
with CuCl and PBu3. e Reagent generated with (CuOTf)2‚C6H6 and PBu3.
f In the presence of 4 Å molecular sieves.
The Z preference is similar to those reported by Hoffmann
and also by Basavaiah13 with other nucleophiles.
After successfully synthesizing various chiral and achiral
allylboronate reagents,14 we applied them for the allylboration
of aldehydes in the synthesis of R-alkylidene-â-substituted-
slowly at room temperature (5 d) and the diastereomeric ratio
was similar to that obtained from 9a. Regretably, the ee of
the lactone 17 as determined on a HPLC (using a CHIRAL-
CEL-ODH column) was only 25%.
Similar results were obtained with pinanediolato-allylbo-
rane reagent 11a and the de was essentially similar to that
obtained with 9a. The ee of the lactone was only 8% at 100
°C and 10% at 25 °C. We then switched to the more reactive
(13) (a) Buchholz, R.; Hoffmann, H. M. R. HelV. Chim. Acta 1991, 74,
1213. (b) Basavaiah, D.; Sarma, P. K. S. J. Chem. Soc., Chem. Commun.
1992, 955. (c) Basavaiah, D.; Sarma, P. K. S.; Bhavani, A. K. D. J. Chem.
Soc., Chem. Commun. 1994, 1091.
(14) A similar type of boronates have been prepared recently via the
reaction of vinyl copper or vinyl aluminium on iodomethylboronate. (a)
Kennedy, J. W. J.; Hall, D. G. J. Am. Chem. Soc. 2002, 125, 898. (b)
Kennedy, J. W. J.; Hall, D. G. J. Am. Chem. Soc. 2002, 125, 11586. (c)
Chataigner, I.; Lebreton, J.; Zammatio, F.; Villie´ras, J. Tetrahedron Lett.
1997, 38, 3719. (d) For the preparation of allylboronates via cross-metathesis
reaction, see: Goldberg, S. D.; Grubbs, R. H. Angew. Chem., Int. Ed. 2002,
41, 807.
(15) For a review on R-methylene-γ-butyrolactones please see: Hoff-
mann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. Engl. 1985, 24, 110.
Org. Lett., Vol. 6, No. 4, 2004
483

tartarate reagent 12a and, as expected, the reaction was fast
and the aldehyde was consumed in less than 2 d. The dr of
the lactone was found to be 94:6. Again, the ee of the product
was only 26%. Decreasing the reaction temperature to 0,
-25, and -78 °C increased the reaction time for the
allylboration, but did not improve the ee. We suspected that
the low and similar ee’s obtained for the allylboration
products at all temperatures ranging from 25 to -78 °C could
be due to the coordination of boron atom with the solvent
DMF and the loss of the rigidity of the cylic six-membered
transition state forcing the reaction to go through an acyclic
transition state. We envisioned that changing the DMF to
noncoordinating solvents might improve the ee. The reagent
12a was generated from 4a and CuCl or CuOTf in THF,
toluene, or CH2Cl2. Upon addition of benzaldehyde at 0 °C,
lactone 17 was obtained in good yield and in excellent de
(>95% cis).16 Unfortunately the ee values obtained were
again low as in the case with DMF (Table 2). We attribute
this to the limitation of the tartarate auxiliary in this type of
allylboration or the interference by the copper salts present
in the reaction medium.
In conclusion, we have developed a novel methodology
to prepare various highly functionalized chiral and achiral
allylboronate reagents via an SN2′ reaction on acetates of
alcohols derived from VA or BH reaction of aldehydes. The
wide range of densely functionalized allyl alcohols, which
could be readily obtained via VA or BH reaction, makes
this procedure very attractive for the stereoselective construc-
tion of multifunctional molecules. The allylborane reagents
bearing an ester moiety have been applied for the synthesis
of R-alkylidene-â-substituted-γ-butyrolactones. Further work
is in progress to improve the enantioselectivity of the
lactones. We believe that these reagents will find applications
in organic synthesis.
Acknowledgment. Financial assistance from the Herbert
C. Brown Center for Borane Research17 and Aldrich Chemi-
cal Co. are gratefully acknowledged.
Supporting Information Available: Experimental and
spectral data along with 1H and 13C NMR spectra for various
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL035952Z
(16) General procedure for the preparation of tartarate-based
allylboronates followed by lactonization: A mixture of CuCl or CuOTf
(0.20 mmol) and PBu3 (0.25 mmol) in toluene (2 mL) was stirred under N2
for 15 min at 25 °C and diboron 7 (1.5 mmol) dissolved in toluene (3 mL)
was added to the solution dropwise followed by the addition of allyl acetate
4a (1.0 mmol) dissolved in toluene (1 mL). The reaction mixture was further
stirred for 4 h in the case of CuOTf and for 12 h in the case of CuCl. The
reaction mixture was cooled to 0 °C and benzaldehyde (0.5 mmol) was
added to it and stirred at 0 °C for 2 d. The reaction mixture was then
quenched with sat. NH4Cl and extracted with ether (3 × 20 mL). The
combined organic layers were dried (MgSO4) and concentrated under
vacuum. The crude product was dissolved in CH2Cl2 (2 mL) and a catalytic
amount of pTSA was added and refluxed for 5 h. The reaction mixture
was quenched with sat. NaHCO3 and extracted with CH2Cl2 and the
combined organic layers were dried (MgSO4) and concentrated under
vacuum and purified by column chromatography (silica gel, hexanes:ethyl
acetate) to obtain 74-76% yield of 17. 1H NMR (300 MHz, CDCl3) δ
(ppm) 7.37-7.29 (m, 3H), 7.16-7.13 (m, 2H), 6.30 (d, J ) 2.85 Hz, 1H),
5.60 (d, J ) 8.19 Hz, 1H), 5.56 (d, J ) 2.61 Hz, 1H), 3.42 (m, 1H), 0.77
(d, J ) 7.11 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ (ppm) 170.8, 140.1,
136.4, 128.5, 128.4, 126.0, 121.8, 82.2, 38.9, 15.4; EI-MS m/z 188 (M)+,
54 [(C4H6)+, 100%]; CI-MS m/z 189 (M + H)+; HRMS-CI 189.0913
(actual), 189.0916 (calcd).
(17) Contribution No. 32 from the Herbert C. Brown Center for Borane
Research.
484
Org. Lett., Vol. 6, No. 4, 2004