Allyl transfer to aldehydes and ketones by Bronsted acid activation of allyl and crotyl 1,3,2-dioxazaborolidines

Article abstract of DOI:10.1021/ol1020515

Alkyl dioxazaborolidines are air-stable and often crystalline organoboranes. A variety of Bronsted acids activate allyl dioxazaborolidines to generate reactive allyl-transfer reagents in situ. These reagents add to aldehydes and ketones to generate the corresponding alcohols in good yields under mild conditions. The E- and Z-crotyl reagents react diastereoselectively with aldehydes and ketones to produce anti and syn adducts, respectively, a result consistent with a cyclic transition state (type I mechanism).

Full text of DOI:10.1021/ol1020515

ORGANIC
LETTERS
2010
Vol. 12, No. 21
4892-4895
Allyl Transfer to Aldehydes and Ketones
by Brønsted Acid Activation of Allyl and
Crotyl 1,3,2-Dioxazaborolidines
Maureen K. Reilly and Scott D. Rychnovsky*
Department of Chemistry, 1102 Natural Sciences II, UniVersity of CaliforniasIrVine,
IrVine, California 92697, United States
srychnoV@uci.edu
Received August 29, 2010
ABSTRACT
Alkyl dioxazaborolidines are air-stable and often crystalline organoboranes. A variety of Brønsted acids activate allyl dioxazaborolidines to
generate reactive allyl-transfer reagents in situ. These reagents add to aldehydes and ketones to generate the corresponding alcohols in good
yields under mild conditions. The E- and Z-crotyl reagents react diastereoselectively with aldehydes and ketones to produce anti and syn
adducts, respectively, a result consistent with a cyclic transition state (type I mechanism).
The allylation of aldehydes and ketones to afford synthetically
versatile homoallylic alcohols constitutes an important class of
carbon-carbon bond forming reactions.1 Many allyl transfer
reagents have been reported, including allylstannanes,2 allyl-
silanes,3 and allylboranes,4-6 among others.1 Recent catalytic
methods are particularly exciting.7 Despite the variety of allyl
transfer methods, many of them require stoichiometric
amounts of toxic metal,2,8 expensive chiral reagents3,9,10 or
catalysts,4f,7,9 or preparation of reagents from expensive
starting materials.3 Therefore, we sought to design an
inexpensive allyl transfer reagent with a practical balance
of stability and reactivity.
This project was inspired by research exploring the activation
of organoborane reagents. Studies conducted by Hall5 demon-
strated that the addition of 2-alkoxycarbonyl allylboronates to
carbonyl compounds could be promoted by Lewis or Brønsted
acid activation to provide the cyclized R-exo-methylene γ-lac-
tones. In a related strategy, Corey demonstrated that chiral
oxazaborolidines could be protonated with very strong acids
to produce exceptionally reactive Lewis acids that were highly
effective catalysts for Diels-Alder reactions.11 By adding triflic
acid at low temperatures, they were able to observe the
(1) (a) Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763–2794. (b)
Hatano, M.; Ishihara, K. Synthesis 2008, 11, 1647–1675. (c) Lachance, H.;
Hall, D. G. Org. React. 2008, 73, 1–554.
(2) (a) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc.
1993, 115, 8467–8468. (b) Teo, Y.-C.; Goh, J.-D.; Loh, T.-P. Org. Lett.
2005, 7, 2743–2745.
(3) (a) Kinnaird, J. W.; Ng, P. Y.; Kubota, K.; Wang, X.; Leighton,
J. L. J. Am. Chem. Soc. 2002, 124, 7920–7921. (b) Kubota, K.; Leighton,
J. L. Angew. Chem., Int. Ed. 2003, 42, 946–948. (c) Hackman, B. M.;
Lombardi, P. J.; Leighton, J. L. Org. Lett. 2004, 6, 4375–4377.
(4) (a) Roush, W. R.; Walts, A. E.; Hoong, L. K. J. Am. Chem. Soc.
1985, 107, 8186–8190. (b) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc.
1983, 105, 2092–2093. (c) Corey, E. J.; Yu, C. M.; Kim, S. S. J. Am. Chem.
Soc. 1989, 111, 5495–5496. (d) Burgos, C. H.; Canales, E.; Matos, K.;
Soderquist, J. A. J. Am. Chem. Soc. 2005, 127, 8044–8049. (e) Canales,
E.; Prasad, K. G.; Soderquist, J. A. J. Am. Chem. Soc. 2005, 127, 11572–
11573. (f) Kanai, M.; Wada, R.; Shibuguchi, T.; Shibasaki, M. Pure Appl.
Chem. 2008, 80, 1055–1062. (g) Lou, S.; Moquist, P. N.; Schaus, S. E.
J. Am. Chem. Soc. 2006, 128, 12660–12661. (h) Barnett, D. S.; Moquist,
(6) (a) Nowrouzi, F.; Thadani, A. N.; Batey, R. A. Org. Lett. 2009, 11,
2631–2634. (b) Matsuoka, H.; Kondo, K. Tetrahedron Lett. 2009, 50, 2320–
2321. (c) Batey, R. A.; Thadani, A. N.; Smil, D. V.; Lough, A. J. Synthesis
2000, 990–998. (d) Batey, R. A.; Thadani, A. N.; Smil, D. V. Tetrahedron
Lett. 1999, 40, 4289–4292
(7) (a) Kim, I. S.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc. 2008,
130, 6340–6341. (b) Kim, I. S.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem.
.
P. N.; Schaus, S. E. Angew. Chem., Int. Ed. 2009, 48, 8679–8682
.
(5) (a) Kennedy, J. W. J.; Hall, D. G. J. Am. Chem. Soc. 2002, 124,
11586–11587. (b) Yu, S. H.; Ferguson, M. J.; McDonald, R.; Hall, D. G.
J. Am. Chem. Soc. 2005, 127, 12808–12809. (c) Rauniyar, V.; Hall, D. G.
J. Am. Chem. Soc. 2004, 126, 4518–2519. (d) Hall, D. G. Pure Appl. Chem.
2008, 80, 913–927. (e) Rauniyar, V.; Zhai, H.; Hall, D. G. J. Am. Chem.
Soc. 2008, 130, 14891–14899
.
(8) Li, C. J.; Chan, T. H. Tetrahedron Lett. 1991, 32, 7017–7020
.
(9) Miller, J. J.; Sigman, M. S. J. Am. Chem. Soc. 2007, 129, 2752–
2753
.
(10) Tietze, L. F.; Kinzel, T.; Brazel, C. C. Acc. Chem. Res. 2009, 42,
367–378.
Soc. 2008, 130, 8481–8490
.
10.1021/ol1020515  2010 American Chemical Society
Published on Web 10/13/2010

N-protonated species by NMR spectroscopy.11a We sought to
apply the activation modes developed by Hall and Corey to
enhance the reactivity of allyloxazaborolidines.5,12 Batey and
Kondo have used a similar strategy to activate allyltrifluo-
roborates.6 With an eye toward developing bench-stable
reagents, we investigated allyldioxazaborolidines, which were
first reported by Roush.13 Allyldioxazaborolidine 1 is a white,
crystalline solid that can be stored in the freezer for months
with no noticeable decomposition14 and appeared to be a
promising precursor for an allyl transfer reagent.
Kinetic studies were conducted to determine the influence
of acid on the rate of allylation by monitoring reaction progress
using 1H NMR spectroscopy. The formation of 4 was observed
under pseudofirst-order conditions to provide reaction rates as
a function of TFA concentration (Figure 1). A plot of these
Although at room temperature dioxazaborolidine 1 does not
react with ketones, a variety of protic acids were found to activate
this complex (Table 1). Triflic acid primarily led to the decomposi-
Table 1. Acid-Promoted Allyl Transfer with Allyl
Dioxazaborolidine 1
Figure 1. Relationship between rate of allylation and concentration of
acid.
rates against the concentration of TFA demonstrates that the
reaction rate is first-order in TFA. The first-order dependence
on TFA concentration is consistent with a simple protonation
to activate dioxazaborolidine 1.
The activated reagent was first investigated with aldehydes.
Allyl reagent 1, when activated with TFA, affected the allylation
of aldehydes to provide the corresponding secondary alcohols
5-9 in excellent yields (Table 2). The most efficient conditions
required equal amounts of 1 and TFA.15 The reaction with
b
acida e
TfOH
pKa
yield of 2 (%)c yield of 3 (%)c
,
entry
1
2
3
4
5
6
7
-15
0
88
95
68
70
85
50
0
0
CH3SO3H
CF3CO2H
BINPA
ClCH2CO2H
CH3CO2H
PhOH
-5.0
-0.25
1.3
2.9
4.8
98
40d
38
28
0
10
a Standard conditions: reaction scale, 1.0 mmol ketone. Concentration
of 1 in CH2Cl2 was 0.5 M. Unreacted ketone was detected for low yielding
reactions. Reactions were conducted at room temperature and were worked
up after 6 h. Either 1.3 or 1.7 equiv of the acid and 1 were used for the
reactions to form 2 and 3, respectively. b Reported pKa values were in water.
c Isolated yield. d No enantioselectivity was observed. e TfOH ) triflic acid.
BINPA ) (S)-(-)-1,1′binaphthyl-2,2′diyl hydrogenphosphate.
Table 2. Allyl Transfer Reactions with Aldehydes
tion of reagent 1 (entry 1). Methanesulfonic acid aided the allylation
of cyclohexanone but not acetophenone, possibly because ac-
etophenone is less reactive toward allylation and the rate of
allylation is slower than that of decomposition of 1. Trifluoroacetic
acid (TFA) provided both homoallylic alcohols 2 and 3 in excellent
yields (entry 3). Weaker acids such as phenol and acetic acid also
promoted the allylation of cyclohexanone, but with lower efficiency
(entries 7 and 6). TFA was the most active promoter and was used
for subsequent allylation reactions.
(11) (a) Corey, E. J.; Shibata, T.; Lee, T. W. J. Am. Chem. Soc. 2002,
124, 3808–3809. (b) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2003,
125, 6388–6390. (c) Shibatomi, K.; Futatsugi, K.; Kobayashi, F.; Iwasa,
S.; Yamamoto, H. J. Am. Chem. Soc. 2010, 132, 5625–5627.
(12) Brown, H. C.; Racherla, U. S.; Pellechia, P. J. J. Org. Chem. 1990,
55, 1868–1874.
(13) (a) Roush, W. R.; Grover, P. T. J. Org. Chem. 1995, 60, 3806–
3813. (b) Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A. D.;
Halterman, R. L. J. Am. Chem. Soc. 1990, 112, 6339–6348.
(14) Reagent 1 is stable for months in a -5 °C freezer. It can be weighed
in air, but it will decompose into a yellow liquid if left open to the air for
several days.
a Standard conditions: reaction scale, 1.0 mmol aldehyde. Concentration of 1
in CH2Cl2 was 0.5 M, and the ratio of TFA to 1 was 1:1. Reactions were conducted
at room temperature and completed in 1-18 h. b Isolated yield.
Org. Lett., Vol. 12, No. 21, 2010
4893

p-anisaldehyde (entry 3) was slower than with m-anisaldehyde
(entry 2); this rate order disfavors a carbonyl protonation step
in the reaction. Conveniently, all of the side products are water
soluble, and a simple aqueous workup led to products with
minimal impurities.
none and benzophenone (entries 1 and 3) were less reactive
in this system and required excess 1 and TFA to provide
high yields of 3 and 11. In general, aliphatic ketones required
fewer equivalents of reagents (1.1-1.5 equiv). Allyl transfer
to an R-keto ester (entry 7) provided 13 in excellent yield.
Only 1,2-addition products were observed with R,ꢀ-unsatur-
ated ketones (entry 8).16 The acidic nature of the reaction
conditions allowed for allyl transfer to enolizable ketones
to provide products 15a/15b and 16 (entries 9 and 10) that
are not accessible using basic allylating agents. Although
acidic, the reaction conditions were tolerant to silyl ether
protecting groups (entries 11-13), and no deprotection was
observed. The activated reagent is a highly effective allyl
transfer reagent with a variety of aldehydes and ketones.
Allyl transfer to a variety of ketones using reagent 1
proceeded in good to excellent yields (Table 3). Acetophe-
Table 3. Allyl Transfer Reactions with Ketones
The activation strategy is also effective with substituted
allyldioxazaborolidines. Crotyl reagents 20 and 21 were
obtained in gram quantities following a literature pro-
cedure.13b The Z- and E-crotylations provided the R-meth-
ylhomoallylic alcohols in good yields and diastereoselec-
tivities (Table 4). Z-Crotyl reagent 20 provided the syn
Table 4. Crotyl Tranfer to Aldehydes and Ketones Using Crotyl
Dioxazaborolidine Reagents (Z)-20 and (E)-21
a Standard conditions: reaction scale, 1.0 mmol ketone. Concentration
of 20 and 21 in CH2Cl2 was 0.5 M. The ratio of 20 or 21 and TFA was 1:1.
Reactions were conducted at room temperature and completed in 16 h.
b Isolated yield. c Diastereomeric ratios were determined by proton NMR
of the crude reaction mixture.
diastereomers as the major products, while E-crotyl reagent
21 led to anti diastereoselectivity. These diastereoselectivities
are consistent with a type I mechanism, where the crotyl
group transfer occurs through a closed, six-membered
transition state.1
a Standard conditions: reaction scale, 1.0 mmol ketone. Concentration
of 1 in CH2Cl2 was 0.5 M, and the ratio of TFA to 1 was 1:1. Reactions
were conducted at room temperature and completed in 12-18 h. b Isolated
yield. c The dr of 15a:15b was 1:1. d The diastereomers of 19 were formed
in a 1:1 ratio.
4894
Org. Lett., Vol. 12, No. 21, 2010

The combination of the bench-stable allyl dioxazaboroli-
dine 1 and TFA leads to a highly reactive allyl transfer
reagent. The actual intermediate in the reaction has not been
identified. The diastereoselective crotylations suggest a boron
allyl transfer reagent with an open coordination site on the
boron, and the reaction apparently proceeds through an
organized six-membered ring transtion state. Figure 2 shows
and 26 reacting with acetaldehyde were calculated using
B3LYP/6-311G(d,p).17 Computationally, oxazaborolidine 25
is predicted to be more reactive than dioxaborolane 26 by
ca. 5.0 kcal/mol (Figure 3).18 We will continue to evaluate
the mechanism of the reaction.
Figure 2. Possible allyl transfer reagent generated under the reaction
conditions.
Figure 3. Calculated transitions states 1,3,2-oxazaborolidine from
25 (left) and 1,3,2,6-dioxazaborocane from 26 (right).18
several possible trivalent boron reagents that might be
responsible for the allyl transfer reaction. The first two
reagents, 25 and 26, would arise from protonation and
decomplexation of an oxygen or a nitrogen from the boron
center. The third class of reagent (27) would arise from
decomplexation of the diethanolamine. Roush used the
dioxazaborolidines to generate other boronate esters by
exchange,13 so this mode of activation is possible and perhaps
likely with the less acidic promoters in Table 1 such as
phenol. Allylboronic acid is a quite active allyl transfer
reagent,12 but it is unlikely to be responsible for most of the
reactivity because the allylation reactions proceed equally
well in the presence of 4 Å MS. Complexes 25, 26, and 27
are all plausible intermediates in the reaction.
This research has demonstrated the utility of allyldiox-
azaborolidine 1 as a stable, crystalline allyl transfer reagent
for aldehydes and ketones. A variety of homoallylic alcohols
were accessed in high yield with simple in situ activation
by TFA. Crotylation reagents 20 and 21 provided the
requisite R-methylhomoallylic alcohols in good yields and
diastereoselectivities. Ongoing research is directed to devel-
oping enantioselective variants of this transformation.
Acknowledgment. This work was supported by the S. T.
Li foundation and the Schering-Plough Research Institute.
Supporting Information Available: Characterization data
and experimental procedures for all compounds described
are included. Geometries for calculated TS are included. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Experiments to elucidate the mechanism of this system
have been conducted, including monitoring reaction progress
by 1H, 11B, and 13C NMR spectroscopy. Unfortunately, only
starting materials and products could be observed spectro-
scopically. The transition states for activated complexes 25
OL1020515
(17) Sakata, K.; Fujimoto, H. J. Am. Chem. Soc. 2008, 130, 12519–
12526.
(15) An excess of either allyl reagent 1 or TFA did not drive allylations
to completion; an excess of both reagents was required to complete the
reaction.
(16) Isomerization of the homoallylic alcohol to the more substituted
olefin was observed in acid-sensitive products.
(18) Calculated reaction profiles using the B3LYP/6-311G(d,p) level (ref
17) with ∆G (298 K) and unscaled ZPE. The 1,3,2-oxazaborolidine TS
from 25 is about 5.0 kcal/mol lower in energy than the 1,3,6,2-dioxazabo-
rocane TS from 26.
Org. Lett., Vol. 12, No. 21, 2010
4895