Petasis borono-Mannich reaction and allylation of carbonyl compounds via transient allyl boronates generated by palladium-catalyzed substitution of allyl alcohols. An efficient one-pot route to stereodefined α-amino acids and homoallyl alcohols

Article abstract of DOI:10.1021/ja074917a

An efficient one-pot procedure was designed by integration of the pincer-complex-catalyzed borylation of allyl alcohols in the Petasis borono-Mannich reaction and in allylation of aldehydes and ketones. These procedures are suitable for one-pot synthesis of α-amino acids and homoallyl alcohols from easily available allyl alcohol, amine, aldehyde, or ketone substrates. In the presented transformations, the active allylating agents are in situ generated allyl boronic acid derivatives. These transient intermediates are proved to be reasonably acid-, base-, alcohol-, water-, and air-stable species, which allows a high level of compatibility with the reaction conditions of the allylation of various aldehyde/ketone and imine electrophiles. The boronate source of the reaction is diboronic acid or in situ hydrolyzed diboronate ester ensuring that the waste product of the reaction is nontoxic boric acid. The regio- and stereoselectivity of the reaction is excellent, as almost all products form as single regio- and stereoisomers. The described procedure is suitable to create quaternary carbon centers in branched allylic products without formation of the corresponding linear allylic isomers. Furthermore, products comprising three stereocenters were formed as single products without formation of other diastereomers. Because of the highly disciplined consecutive processes, up to four-step, four-component transformations could be performed selectively as a one-pot sequence. For example, stereodefined pyroglutamic acid could be prepared from a simple allyl alcohol, a commercially available amine, and glyoxylic acid in a one-step procedure. The presented method also grants an easy access to stereodefined 1,7-dienes that are useful substrates for Grubbs ring-closing metathesis.

Full text of DOI:10.1021/ja074917a

Published on Web 10/12/2007
Petasis Borono-Mannich Reaction and Allylation of Carbonyl
Compounds via Transient Allyl Boronates Generated by
Palladium-Catalyzed Substitution of Allyl Alcohols. An
Efficient One-Pot Route to Stereodefined r-Amino Acids and
Homoallyl Alcohols
Nicklas Selander, Andreas Kipke, Sara Sebelius, and Ka´lma´n J. Szabo´*
Contribution from the Department of Organic Chemistry, Arrhenius Laboratory, Stockholm
UniVersity, SE-106 91, Stockholm, Sweden
Received July 4, 2007; E-mail: kalman@organ.su.se
Abstract: An efficient one-pot procedure was designed by integration of the pincer-complex-catalyzed
borylation of allyl alcohols in the Petasis borono-Mannich reaction and in allylation of aldehydes and ketones.
These procedures are suitable for one-pot synthesis of R-amino acids and homoallyl alcohols from easily
available allyl alcohol, amine, aldehyde, or ketone substrates. In the presented transformations, the active
allylating agents are in situ generated allyl boronic acid derivatives. These transient intermediates are proved
to be reasonably acid-, base-, alcohol-, water-, and air-stable species, which allows a high level of
compatibility with the reaction conditions of the allylation of various aldehyde/ketone and imine electrophiles.
The boronate source of the reaction is diboronic acid or in situ hydrolyzed diboronate ester ensuring that
the waste product of the reaction is nontoxic boric acid. The regio- and stereoselectivity of the reaction is
excellent, as almost all products form as single regio- and stereoisomers. The described procedure is
suitable to create quaternary carbon centers in branched allylic products without formation of the
corresponding linear allylic isomers. Furthermore, products comprising three stereocenters were formed
as single products without formation of other diastereomers. Because of the highly disciplined consecutive
processes, up to four-step, four-component transformations could be performed selectively as a one-pot
sequence. For example, stereodefined pyroglutamic acid could be prepared from a simple allyl alcohol, a
commercially available amine, and glyoxylic acid in a one-step procedure. The presented method also
grants an easy access to stereodefined 1,7-dienes that are useful substrates for Grubbs ring-closing
metathesis.
1. Introduction
As a consequence, there is a high current demand for new
efficient synthetic procedures providing functionalized allyl
boronates. However, development of these procedures raises
two important synthetic issues: (i) the synthetic procedures have
to be highly stereo- and regioselective and have to tolerate many
functionalities, and (ii) the prepared functionalized allyl bor-
onates are required to be stable under the purification and
isolation procedures, yet sufficiently reactive in the desired
allylation reactions.
Several recent procedures have been developed addressing
problem i above. The direct methods, based on addition of
reactive allylmetal reagents20,21 (such as allyl lithium and
Grignard reagents) to borate esters, are suitable for bulk
preparation of allyl boronates. However, a potential draw-back
of this approach is the poor stereo- and regiochemical stability
of the allylmetal reagents which leads to formation of isomeric
mixtures of the allyl boronates. Another problem is the poor
Synthetic application of allyl boronates have received con-
siderable recent attention because of the highly selective and
efficient carbon-carbon bond formation performed by these
reagents in allylation reactions.1-7 Allyl boronates are most
widely employed for allylation of aldehydes;1-8 however,
allylation of ketones9-12 and imines13-19 were also reported.
(1) Hall, D. G. Boronic Acids; Wiley: Weinheim, Germany, 2005.
(2) Kennedy, J. W. J.; Hall, D. G. Angew. Chem., Int. Ed. 2003, 4732.
(3) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207.
(4) Otera, J. Modern Carbonyl Chemistry; Wiley: Weinheim, Germany, 2000.
(5) Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763.
(6) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1982, 21, 555.
(7) Marshall, J. A. Chem. ReV. 2000, 100, 3163.
(8) Wu, T. R.; Chong, J. M. Org. Lett. 2004, 6, 2701.
(9) Schneider, U.; Kobayashi, S. Angew. Chem., Int. Ed. 2007, 46, 5909.
(10) Wada, R.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2004,
126, 8910.
(11) Pace, R. D.; Kabalka, G. W. J. Org. Chem. 1995, 60, 4838.
(12) Lou, S.; Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc. 2006, 128, 12660.
(13) Wada, R.; Shibuguchi, T.; Makino, S.; Oisaki, K.; Kanai, M.; Shibasaki,
M. J. Am. Chem. Soc. 2006, 128, 7687.
(18) Sebelius, S.; Wallner, O. A.; Szabo´, K. J. Org. Lett. 2003, 5, 3065.
(19) Hoffmann, R. W.; Endesfelder, A. Liebigs Ann. Chem. 1983, 2000.
(20) Roush, W. R.; Walts, A. E.; Hoong, L. K. J. Am. Chem. Soc. 1985, 107,
8186.
(21) Batey, R. A.; Thadani, A. N.; Smil, D. V.; Lough, A. J. Synthesis 2000,
990.
(14) Sugiura, M.; Hirano, K.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 7182.
(15) Kobayashi, S.; Hirano, K.; Sugiura, M. Chem. Commun. 2005, 104.
(16) Sugiura, M.; Mori, C.; Hirano, K.; Kobayashi, S. Can. J. Chem. 2005, 83,
937.
(17) Dhudshia, B.; Tiburcio, J.; Thadani, A. N. Chem. Commun. 2005, 5551.
9
10.1021/ja074917a CCC: $37.00 © 2007 American Chemical Society
J. AM. CHEM. SOC. 2007, 129, 13723-13731
13723

A R T I C L E S
Selander et al.
functional group tolerance arising from the high reactivity of
the allyl metal species. On the other hand, high selectivity and
functional group tolerance can be achieved in transition-metal-
catalyzed procedures for generation of allyl boronates,22-30
which often involves application of diboronates as a source of
the boronate functionality. In this respect, palladium-,22-26
platinum-,27,28,31 nickel-,29 and copper-catalyzed30,32 boronation
of allenes, dienes, and substituted allylic substrates represent
the most efficient procedures.
Considering the relatively low stability of the functionalized
allyl boronates, their isolation and purification often becomes
a major issue (ii, above), which may encumber the synthetic
application of allyl boronates. Allyl boronic acids are more
reactive allylating reagents17,33 than allyl boronate esters;
however, these species rapidly decompose (probably oxidized)
under solvent-free conditions.20,23,34,35 An attractive solution for
the above purification issues is the development of one-pot
procedures, in which the transient allyl boronates are not isolated
butdirectlyreactedwiththecorrespondingallylacceptors.18,23,32,34,36-38
Development of these procedures requires highly selective
formation of allyl boronates and carefully designed reaction
conditions to avoid undesired side products in the multicom-
ponent processes. We18,34,36 and others32,37,38 have shown that
transition-metal-catalyzed generation of allyl boronates followed
by subsequent allylation of aldehydes can be performed in a
one-pot sequence. In a couple of recent communications,23,24,36
we have shown that allyl boronates can be efficiently prepared
from simple allylic substrates, such as allyl alcohols, employing
palladium pincer complex39-44 catalysis. This efficient boryla-
tion procedure can be integrated in a one-pot sequence36 for
stereo- and regioselective carbon-carbon bond coupling of allyl
alcohols and aldehydes. The selective coupling reaction proceeds
via generation of transient allyl boronic acids from diboronic
acid45 as boronate source. In this paper, we give a full account
of our results with extending the allyl-alcohol-based allylation
procedures to new one-pot transformations, new reagents, and
catalysts. These new results clearly indicate that complex, highly
Figure 1. General scheme of the studied one-pot reactions for synthesis
of homoallyl alcohols and R-amino acids via catalytic generation of allyl
boronates.
functionalized, regio- and stereodefined products can easily be
prepared from allyl alcohols via catalytic generation of allyl
boronates in a one-pot sequence. Furthermore, the cost efficiency
of the transformations has been improved by application of a
new boronate source and catalyst. The new aspects of the full
paper version can be summarized as follows: (a) Extension of
the synthetic scope of the reaction to the Petasis borono-Mannich
reaction is achieved.14,16,17,46,47 Using this procedure stereo- and
regiodefined R-amino acids48-55 can be prepared from inex-
pensive allyl alcohols in a multicomponent one-pot reaction.
(b) Allylation of ketones by in situ generated allyl boronic acids
in the presence of catalytic amounts of InI takes place.9 (c) By
appropriate choice of the reaction conditions and allyl alcohol
substrates, selective carbon-carbon bond formation involving
quaternary carbons can be achieved. (d) The reactions are made
suitable for one-pot stereoselective synthesis of 1,7-dienes,
which are useful precursors for Grubbs-cyclization.56,57(e) With
a slight change of the reaction conditions, the one-pot procedures
can be performed using commercially readily available bis-
(pinacolato)diboron in place of diboronic acid. (f) A new SCS
based pincer complex catalyst was introduced as a complement
for the very efficient and easily accessible selenium based SeCSe
complex. A new straightforward procedure for synthesis of this
latter complex is included in the Supporting Information.
(22) Ishiyama, T.; Ahiko, T.-A.; Miyaura, N. Tetrahedron Lett. 1996, 37, 6889.
(23) Sebelius, S.; Olsson, V. J.; Szabo´, K. J. J. Am. Chem. Soc. 2005, 127,
10478.
(24) Olsson, V. J.; Sebelius, S.; Selander, N.; Szabo´, K. J. J. Am. Chem. Soc.
2006, 128, 4588.
(25) Suginome, M.; Ohmura, T.; Miyake, Y.; Mitani, S.; Ito, Y.; Murakami,
M. J. Am. Chem. Soc. 2003, 125, 11174.
(26) Yang, F.-Y.; Cheng, C.-H. J. Am. Chem. Soc. 2001, 123, 761.
(27) Ishiyama, T.; Yamamoto, M.; Miyaura, N. Chem. Commun. 1996, 2073.
(28) Clegg, W.; Johann, T. R. F.; Marder, T. B.; Norman, N. C.; Orpen, A. G.;
Paekman, T. M.; Quayle, M. J.; Rice, C. R.; Scott, A. J. J. Chem. Soc.,
Dalton Trans. 1998, 1431.
(29) Suginome, M.; Matsuda, T.; Yoshimoto, T.; Ito, Y. Org. Lett. 1999, 1,
1567.
(30) Ito, H.; Kawakami, C.; Sawamura, M. J. Am. Chem. Soc. 2005, 127, 16034.
(31) Suginome, M.; Nakamura, H.; Matsuda, T.; Ito, Y. J. Am. Chem. Soc. 1998,
120, 4248.
(32) Carosi, L.; Hall, D. G. Angew. Chem., Int. Ed. 2007, 46, 5913.
(33) Brown, H. C.; Racherla, U. S.; Pellechia, P. J. J. Org. Chem. 1990, 55,
1868.
2. Results and Discussion
As mentioned above, the present studies (Figure 1) are mostly
directed to one-pot synthesis of functionalized homoallyl
alcohols (9) and R-amino acids (10) from inexpensive, easily
accessible allyl alcohols (1). The reactions proceed via pincer-
(34) Sebelius, S.; Szabo´, K. J. Eur. J. Org. Chem. 2005, 2539.
(35) Sebelius, S.; Olsson, V. J.; Wallner, O. A.; Szabo´, K. J. J. Am. Chem. Soc.
2006, 128, 8150.
(46) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445.
(47) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798.
(48) Kazmaier, U.; Zumpe, F. L. Angew. Chem., Int. Ed. 1999, 38, 1468.
(49) Zumpe, F. L.; Kazmaier, U. Synlett. 1998, 1199.
(36) Selander, N.; Sebelius, S.; Estay, C.; Szabo´, K. J. Eur. J. Org. Chem. 2006,
4085.
(50) Kazmaier, U. Angew. Chem., Int. Ed. 1994, 33, 998.
(51) Kazmaier, U.; Krebs, A. Angew. Chem., Int. Ed. 1995, 34, 2012.
(52) Bakke, M.; Ochta, H.; Kazmaier, U.; Sugai, T. Synthesis 1999, 1671.
(53) Mock, M. L.; Michon, T.; Hest, J. C. M. v.; Tirrell, D. A. ChemBiochem.
2006, 7, 83.
(37) Goldberg, S. D.; Grubbs, R. H. Angew. Chem., Int. Ed. 2002, 41, 807.
(38) Kabalka, G. W.; Venkataiah, B.; Dong, G. J. Org. Chem. 2004, 69, 5807.
(39) Albrecht, M.; Koten, G. v. Angew. Chem., Int. Ed. 2001, 3750.
(40) Dupont, J.; Consorti, C. S.; Spencer, J. Chem. ReV. 2005, 105, 2527.
(41) Boom, M. E. v. d.; Milstein, D. Chem. ReV. 2003, 103, 1759.
(42) Singleton, J. T. Tetrahedron 2003, 59, 1837.
(43) Beletskaya, I. P.; Cheprakov, A. V. J. Organomet. Chem. 2004, 689, 4055.
(44) Szabo´, K. J. Synlett. 2006, 811.
(45) Baber, R. A.; Norman, N. C.; Orpen, A. G.; Rossi, J. New J. Chem. 2003,
27, 773.
(54) Ellis, T. K.; Ueki, H.; Yamada, T.; Ohfune, Y.; Soloshonok, V. A. J. Org.
Chem. 2006, 71, 8572.
(55) Soloshonok, V. A.; Cai, C.; Hruby, V. C.; Meervelt, L. V.; Yamazaki, T.
J. Org. Chem. 2000, 65, 6688.
(56) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
(57) Heo, J.-N.; Micalizio, G. C.; Roush, W. R. Org. Lett. 2003, 5, 1693.
9
13724 J. AM. CHEM. SOC. VOL. 129, NO. 44, 2007

Petasis Borono-Mannich Reaction of Carbonyl Compounds
A R T I C L E S
complex58-62 (3) catalyzed generation of allyl boronic acids (5)
using diboronates45 (2) as boronate source in the presence of
catalytic amounts of p-toluenesulfonic acid (4) followed by
coupling to the corresponding electrophiles. The presented one-
pot procedures are not moisture and air sensitive, and therefore
the reactions are conducted without employing inert gas
atmosphere or using carefully dried solvents.
Allylation of Aldehydes. Allylation of aldehydes using allyl
alcohol as allylating reagent is a highly efficient and attractive
synthetic route to functionalized homoallyl alcohols. Allyl
alcohols are one of the least expensive and most accessible
allylating agents, and therefore carbon-carbon couplings be-
tween allyl alcohols and aldehydes represent excellent examples
for value-added synthesis. However, a usual problem of these
types of reactions is the activation of the allylic carbon-oxygen
bond of the alcohol functionality. Many excellent solutions for
this problem were presented by using palladium-catalyzed
substitution3,5,7 of the in situ activated hydroxy group of allyl
alcohols. The most important strategies for activation of the
hydroxy group63,64 involve application of SnCl2,65-68 BEt3,69-71
Et2Zn,72 and various indium salts.73-75 However, by using these
activating reagents, functionalities coordinating to Lewis acids
or sensitive to reduction cannot be tolerated in the substrates.
Another problem is often the unsatisfactorily low stereoselec-
tivity of the reaction.
As we have shown in our previous communication,36 the
majority of these selectivity problems can be avoided by
conversion of the hydroxy group of the allyl alcohol to a
boronate. In these reactions the hydroxy group was activated
by diboronic acid,45 which does not affect the usual functional
groups, and therefore the reaction tolerates carbonyl, cyano,
aromatic halogenide, and nitro groups. As the allylation proceeds
via a cyclic six-membered ring transition state (TS),1,2,6 the
stereoselectivity of the coupling of the transient allyl boronate
with aldehydes proceeds with a remarkably high stereoselec-
tivity. In fact, all the presented coupling reactions of aldehydes
with in situ generated allyl boronates provided a single
diastereomer without formation of traces of the other isomer.
Considering the allylation reactions of aldehydes with allyl
alcohols, we mainly focused on extension of the synthetic scope
of the reactions, on application of commercially easily available
diboronate 2b, and on the acceleration of the sluggish reactions
by using a new catalyst. Some of the previously communicated36
reference reactions (entries 1, 2, 4, 8, 9, 13, 14, 16, 17, 18, 21,
and 23) are given in Table 1, while the rest of the processes
listed in this table are newly developed transformations.
The coupling reaction between the corresponding allyl alcohol
and aldehyde can be performed as an operationally simple one-
pot, one-step procedure. Accordingly, in a typical reaction,
reactants 1, 2, and 6 and catalysts 3a58,59 (5 mol %) and 4 (5
mol %) were dissolved in a mixture of DMSO and methanol
(1:1) at the beginning of the reaction, then after the allotted
reaction time the coupling product was isolated (Table 1). We
have previously shown that primary (1a,f,g), secondary (1b,e,h),
cyclic (1h), and acyclic (1a-g) alcohols react with an excellent
regioselectivity to give branched homoallyl products (9a-f and
9i-k).
We have now found that the high regioselectivity is main-
tained even for tertiary alcohols 1c,d. The reaction of these
alcohols with aldehydes 6a and 6d resulted in exclusively the
corresponding homoallyl alcohols (9g,h) creating a new qua-
ternary carbon center (Table 1, entries 11, 12). Formation of
the linear product with a new carbon-carbon bond to a
secondary center was not observed at all. Applying 4-pentenal
(6c) as aldehyde component with alcohols 1a, 1b, and 1f we
could perform an operationally simple one-pot formation of
stereodefined 1,7-dienes 9c, 9f, and 9k (Table 1, entries 5-7,
10, and 15). These products undergo facile Grubbs ring-closing
metathesis (RCM) to give stereodefined cyclohexenes (vide
infra).
As we have shown in recent publications,23,24 the transient
allyl boronic acids can be isolated and fully characterized.
Probably, the only exception is the dienyl boronic acid
intermediate (5e) formed by borylation of 1e (Table 1, entry
13), which resisted all attempts to isolation. However, because
of the one-pot/one-step conditions, the unstable 5e intermediate
was allowed to react directly after formation with 6a, and thus
the corresponding product (9i) could be isolated in high yield.
The previously communicated23,24,35,36 efficient borylation
procedures are based on application of diboronic acid 2a, which
is a highly efficient reagent in the pincer-complex-catalyzed
transformation of allyl alcohols and other easily accessible
substrates. Furthermore, the subsequent coupling reaction is also
highly environmentally benign, as the only byproduct is nontoxic
boric acid. Nevertheless, the difficult commercial availability
of diboronic acid 2a can be considered as a limiting factor for
the widespread use of the above processes. Therefore, we studied
the possibility to replace 2a with commercially easily available
bis(pinacolato)diboron 2b. As we reported before,23 diboronate
2b performs much less efficiently in the pincer complex
catalyzed boronation reactions, than 2a. This may be due to
destabilizing steric interactions between the pinacolato moiety
of 2b and the pincer ligand of 3a. Accordingly, it is not
surprising that using 2b in place of 2a under the standard
reaction conditions described above gives only (if at all) traces
of homoallyl product 9 and the reaction mixture contains largely
unreacted allyl alcohol 1 and aldehyde 6. We have reasoned
that the in situ hydrolysis of 2b to 2a could help to improve
the performance of the bispinacolato derivative 2b in the
coupling reactions. We have previously reported24 that addition
of water does not inhibit the robust boronation process of allyl
(58) Yao, Q.; Kinney, E. P.; Zheng, C. Org. Lett. 2004, 6, 2997.
(59) Yao, Q.; Sheets, M. J. Org. Chem. 2006, 71, 5384.
(60) Aydin, J.; Selander, N.; Szabo´, K. J. Tetrahedron Lett. 2006, 47, 8999.
(61) Dupont, J.; Beydoun, N.; Pfeffer, M. J. Chem. Soc., Dalton Trans. 1989,
1715.
(62) Bergbreiter, D. E.; Osburn, P. L.; Liu, Y.-S. J. Am. Chem. Soc. 1999, 121,
9531.
(63) Tamaru, Y. Eur. J. Org. Chem. 2005, 2647.
(64) Muzart, J. Tetrahedron 2005, 61, 4179.
(65) Takahara, J. P.; Masuyama, Y.; Kurusu, Y. J. Am. Chem. Soc. 1992, 114,
2577.
(66) Masuyama, Y.; Takahara, J. P.; Kurusu, Y. J. Am. Chem. Soc. 1998, 110,
4473.
(67) Carde, L.; Llebaria, A.; Delgado, A. Tetrahedron Lett. 2001, 42, 3299.
(68) Banerjee, M.; Roy, S. J. Mol. Catal. A 2005, 246, 231.
(69) Kimura, M.; Tomizawa, T.; Horino, Y.; Tanaka, S.; Tamaru, Y. Tetrahedron
Lett. 2000, 41, 3627.
(70) Mukai, R.; Horino, Y.; Tanaka, S.; Tamaru, Y.; Kimura, M. J. Am. Chem.
Soc. 2004, 126, 11138.
(71) Zhu, S.-F.; Yang, Y.; Liu, B.; Zhou, Q.-L. Org. Lett. 2005, 7, 2333.
(72) Kimura, M.; Shimizu, M.; Shibata, K.; Tazoe, M.; Tamaru, Y. Angew.
Chem., Int. Ed. 2003, 42, 3392.
(73) Araki, S.; Kamei, T.; Hirashita, T.; Yamamura, H.; Kawai, M. Org. Lett.
2000, 2, 847.
(74) Hirashita, T.; Kambe, S.; Tsuji, H.; Omori, H.; Araki, S. J. Org. Chem.
2004, 69, 5054.
(75) Jang, T.-S.; Keum, G.; Kang, S. B.; Chung, B. Y.; Kim, Y. Synthesis 2003,
775.
9
J. AM. CHEM. SOC. VOL. 129, NO. 44, 2007 13725

A R T I C L E S
Selander et al.
Table 1. Allylation Aldehydes via Transient Allyl Boronates
alcohols; however, the catalytic reactions are slightly slowed
down. This involves that the in situ hydrolysis of 2b to 2a have
to be solved by the addition of as small amount of water as
possible. Our optimization studies show that the best results
can be achieved by the addition of 8 equiv of water per 1 equiv
of allyl alcohol and increasing the amount of cocatalyst 4 to 20
mol %. Under these conditions, the coupling reactions with 2b
proceeds with almost as high yield as with 2a (Table 1, entries
3, 6, 7, 19, 20, and 22). Using catalyst 3a in these transforma-
tions, the required reaction times were usually longer with 2b,
than with 2a (cf. entries 1 and 3, or entries 18 and 19 in Table
1). This is probably because of the decelerating effect of the
water in the borylation process, when 2b was used as boronate
source.
Generated from Allyl Alcoholsa
In the coupling reactions we also employ catalytic amounts
of p-toluenesulfonic acid (4). As it was pointed out previ-
ously,23,36,76,77 4 has a catalytic effect for at least two important
procedures of the coupling reactions, such as the borylation
reaction23 and the allylation of aldehyde with the in situ
generated allyl boronate.36,76,77 Although the coupling reactions
can be carried out in the absence of 4 (Table 1, entry 2), the
reaction proceeds much faster when catalytic amounts of
p-toluenesulfonic acid is present in the reaction mixture (cf.
Table 1, entries 1, 2). Furthermore, p-toluenesulfonic acid (4)
probably has an important catalytic effect even in the in situ
hydrolysis of 2b to 2a. Accordingly, in the procedures when
bis-pinacolato derivative 2b is employed as borylation agent
(Table 1, entries 3, 6, 7, 19, 20, and 22), acid 4 catalyzes three
distinct processes under the applied one-pot conditions: hy-
drolysis of 2b to 2a in the presence of water, borylation of 1 to
5, and allylation of 6 with 5.
Some structural features in the allyl alcohol substrates, such
as the presence of carboxy functionality (1g,h) and the cyclic
topology of the substrate (1h), leads to a decrease of the
reactivity. As application of 2b in place of 2a leads to a further
slow down of the processes, some of the reactions required
extended reaction times (e.g., Table 1 entries 19 or 21). We
attempted to accelerate these reactions by employing other type
of catalysts. It was found that application of SCS catalyst 3b61,62
(Figure 1) instead of 3a58-60 led to much faster coupling
reactions without significant decrease of the yields. For example,
the coupling reaction of cyclic substrate 1h with benzaldehyde
(6a) using 2b as boronate source required 48 h using 3a as
catalyst (Table 1, entry 19), while the same reaction with 3b
could be completed in only 6 h (Table 1, entry 20).
Considering the above-described coupling reactions of allyl
alcohols and aldehydes, it can be concluded that the reaction
has a very broad synthetic scope, involving primary, secondary,
and tertiary alcohols with both cyclic and acyclic architecture.
The reactions are highly regio- and stereoselective and tolerate
many substituents. For example, products 9n,o with three
stereocenters forms as a single diastereomer without trace of
the other stereoisomers (Table 1, entries 18-22). Furthermore,
the obtained densely functionalized homoallyl alcohols involve
functionalities (such as 9c,f,i,k) that can be directly employed
in further catalytic processes. For example, stereodefined 1,7-
dienes (9c,f,k) can easily be cyclized (Figure 2) affording
a In a typical reaction 1, 2 (1.2 equiv) and 6 (1.2 equiv) were dissolved
in a DMSO/MeOH mixture in the presence of catalytic amounts of 3 and
4 (each 5 mol %). b When 2b was applied, also 8.0 equiv of water and 20
mol % of pTsOH were employed. c Catalyst employed. d Temperature/time,
°C/h. e Isolated yield. f pTsOH (4) was not used. g Reaction run using 3.0
equiv. of aldehyde. h Reaction run using 50 mol % of pTsOH.
(76) Yu, S. H.; Ferguson, M. J.; McDonald, R.; Hall, D. G. J. Am. Chem. Soc.
2005, 127, 12808.
(77) Elford, T. G.; Arimura, Y.; Yu, S. H.; Hall, D. G. J. Org. Chem. 2006, 72,
1276.
9
13726 J. AM. CHEM. SOC. VOL. 129, NO. 44, 2007

Petasis Borono-Mannich Reaction of Carbonyl Compounds
A R T I C L E S
R-Amino Acids from Allyl Alcohols via Petasis Borono-
Mannich Reaction. Petasis and co-workers46,47 have reported
a new powerful three component method for coupling of alkenyl
boronic acids with amines and aldehydes to obtain homoallylic
amines, including R-amino acids. This efficient coupling reaction
have found many applications,46,47,79-83 and recently, it was also
extended by Kobayashi and Thadani and their co-workers14,16,17
to coupling of allyl boronates with aldehydes and ammonia.
These reactions proceed with high regio- and stereoselectivity,
however their synthetic scope is limited by the poor availability
of functionalized allyl boronates. Therefore, we decided to
extend the three-component Petasis borono-Mannich reaction
to a four-component coupling involving in situ generation of
the allyl boronate component of the reaction (Figure 1, Table
3). As far as we know, allyl alcohols were not employed
previously as reagents to allylate imine substrates, and, further-
more, the Petasis borono-Mannich reactions were not carried
out with in situ generated organoborane substrates either. It was
found that several elements of the above-described coupling of
alcohols and aldehydes can be flexibly employed in combination
with the Petasis reaction. The most important difference was
that amines 7a-c and glyoxylic acid (8) were not added at the
beginning of the coupling reaction but after the allotted times
required for the borylation process. Addition of the amine
component at the beginning of the reaction probably leads to
coordination of the nitrogen atom to palladium deactivating
catalyst 3 and thus preventing formation of 5.
Figure 2. Synthesis of stereodefined cyclohexenes from the products of
the one-pot allylation of 6c with various allyl alcohols.
Table 2. One-Pot Allylation of Ketones Using InI as Cocatalyst
a In a typical reaction, 1 and 2 (1.2 equiv) were dissolved in a DMSO/
MeOH mixture in the presence of catalytic amounts of 3 and 4 (each 5 mol
%). After the borylation was completed, 6f/6g (1.2 equiv) and InI (20 mol
%) were added. b Catalyst employed. c Temperature/time, °C/h. d Isolated
yield. e Formation of 10% of the syn diastereomer was also observed.
stereodefined cyclohexene derivatives (12a-c) using Grubbs
RCM procedure.56,57
First we studied the substrate scope of the reactions. It was
found that primary (1a,f,g), secondary (1b,i,j) and tertiary (1c)
alcohols perform equally well in the reactions, and that
benzyloxy (1f) and carbethoxy/methoxy (1g,i,j) groups are
tolerated (Table 3). The four-component coupling reactions
proceeded very cleanly, and the crude reaction mixtures
indicated formation of a single product with a very high
selectivity. The stereo- and regioselectivity of these processes
was as high as the analogue coupling reaction of allyl alcohols
and aldehydes, as the R-amino acid derivatives (10a-k) were
formed as single regio- and stereoisomers from readily available
substrates 1a-c,f,g and 1i,j. Accordingly, the presented reactions
provide an easy access to stereo defined analogues and homo-
logues of natural amino acids, such as phenylalanine (10a,b),
isoleucine (10c-e), valine (10f), serine (10g,h), glutamic acid
(10i and 10j), and pyroglutamic acid (10k). In the coupling
reactions we have employed benzyl and aryl amines 7a-c,
which proved to be beneficial for avoiding the allylic rear-
rangement of the products. According to Kobayashi and co-
workers,16 branched homoallyl R-amino acids with unprotected
amino groups show a tendency for rearrangement to the
corresponding linear isomers via aza-Cope rearrangement. This
process is the most extensive for products formed with a
quaternary carbon center,16 such as 10f (Table 3, entry 9);
however, even in this case formation of the linear isomer could
be completely avoided. The benzhydryl and anilyl derivatives
10a-d and 10f-k could be purified by silica gel chromatog-
raphy, however, methoxy anilyl derivative 10e displayed some
Allylation of Ketones. Although allyl boronates do not react
directly with ketone substrates,5,7 these transformations can be
performed by activation of one of the reactants.9-11 In a recent
paper, Kobayashi and Schneider9 reported an operationally
simple and elegant way of activation of allyl boronates by using
InI as catalyst. We have found that application of InI catalysis
can also be employed for activation of allyl boronic acids
generated in situ from allyl alcohols (Table 2). The reaction
was conducted similarly to the allylation of aldehydes, except
that the ketone substrate (6f,g) and InI (20 mol %) was added
after completion of the borylation step. This slight modification
was necessary to avoid the deactivation of catalyst 3a by InI in
the borylation reaction. The limited number of reactions we have
carried out with alcohols 1a,b and ketones 6f,g suggest a broad
synthetic scope. The regioselectivity of the process is excellent,
as the branched allylic isomer with a new quaternary carbon
center is formed as the only product. The diastereoselectivity
of the coupling of 1a and acetophenone (6f) is still high (Table
2, entry 1), as the two diastereomers are formed in a 9:1 ratio.
As expected,5,7,78 this level of stereoselectivity is somewhat
lower than in the corresponding reaction with benzaldehyde
(Table 1, entry 1).
The high regio- and stereoselectivity and the high yield in
the presented reactions clearly shows that the one-pot allylation
reactions using alcohols as allyl sources can easily be extended
to ketone substrates as well. Although, the above results clearly
demonstrate the benefits of the operationally simple coupling
of easily available allyl alcohols and carbonyl compounds, we
wished to further extend the synthetic scope of the reaction by
integrating the multicomponent Petasis borono-Mannich reac-
tion14,16,17,46,47 as a crucial segment in our one-pot approach.
(79) Schlienger, N.; Bryce, M. R.; Hansen, T. K. Tetrahedron 2000, 56, 10023.
(80) Naskar, D.; Roy, A.; Seibel, W. L.; Portlock, D. E. Tetrahedron Lett. 2003,
44, 8865.
(81) Jourdan, H.; Gouhier, G.; Hijfte, L. V.; Angibaud, P.; Piettre, S. R.
Tetrahedron Lett. 2005, 46, 8027.
(82) Sieber, J. D.; Morken, J. P. J. Am. Chem. Soc. 2006, 128, 74.
(83) Southwood, T. J.; Curry, M. C.; Hutton, C. A. Tetrahedron 2006, 62, 236.
(78) Yashuda, M.; Hirata, K.; Nishio, M.; Yamamoto, A.; Baba, A. J. Am. Chem.
Soc. 2002, 124, 13442.
9
J. AM. CHEM. SOC. VOL. 129, NO. 44, 2007 13727

A R T I C L E S
Selander et al.
Table 3. One-pot Synthesis of R-Amino Acids from Allyl Alcohols
via Petasis Borono-Mannich Reaction of in Situ Generated Allyl
Boronates
homologue of 1g, allyl alcohol 1i, showed a somewhat different
behavior. Although, when 1i was reacted under mild, standard
conditions coupling product 10j could be isolated in good yield;
compound 10j showed a clear tendency for lactam formation
(10k) on heating. Furthermore, when the methoxy analogue 1j
was reacted in similar conditions as 1i followed by a gentle
heating of the crude reaction mixture, the cyclized product, pyro-
glutamic acid derivative 10k, could be isolated in a high yield.
Similarly to the coupling reactions of alcohols and aldehydes
(Table 1, entries 3, 6, 7, 19, 20, and 22) the four-component
coupling reactions proceeds smoothly when diboronic acid 2a
is replaced with 2b (Table 3, entries 2 and 6). As described
above, using 2b required a slight modification of the reaction
conditions, such as the addition of water (8 equiv) and an
increase in the catalyst loading of p-toluenesulfonic acid (4, 20
mol %). However, these changes led only to a slight change of
the isolated yields (cf. Table 3, entries 1 and 2, or entries 5 and
6). Use of diboronic acid 2a (either directly or in situ hydrolyzed
from 2b) to generate transient allyl boronic acids 5 is probably
an important factor in obtaining high yield and reactivity in the
described coupling reactions with amines 7 and 8. Thadani and
co-workers17 have pointed out that the analogue coupling
reactions of (isolated) allyl boronates with ammonia and
aldehydes proceed most efficiently when allyl boronic acid is
employed as a substrate instead of allyl boronic esters. This is
because allyl boronic acids are more reactive in allylation
reactions than the allyl boronic ester analogues.33 Similarly to
the aldehyde coupling reactions (Table 1, entries 7, 20, and 22)
SeCSe complex 3a can be replaced by SCS complex 3b (Table
3, entries 5 and 6). In this case, we could also observe the
acceleration effect by 3b, which was also significant for coupling
of aldehydes and alcohols.
Mechanistic Aspects. Although the in-depth mechanistic
details of the distinct chemical reactions involved in the above
one-pot procedures are not fully understood, the consecutive
processes and their connectivity can be described (Figures 3
and 4) on the basis of the above studies, our previous com-
munications,23,24,36 and literature reports on allylation reactions
with allyl boronates.1-7,16,46,47 Accordingly, the coupling reaction
of allyl alcohols and aldehydes (Figure 3) is initiated by the
activation of the hydroxy functionality of 1 with diboronic acid
2a.24 Diboronic acid 2a is either present as a reactant or it is
generated by hydrolysis of 2b. It was found that under the
reaction conditions of application of 2b (Table 1, entries 3, 6,
7, 19, 20, and 22, or Table 3, entries 2 and 6) as a boronate
source (i.e., in the presence of 8 equiv of water and 20 mol %
of 4), immediate formation of free pinacol can be observed.
Hydrolysis of 2b to 2a under these conditions is probably an
equilibrium process (Figure 3), as after extended reaction times
the ratio of the boron-bound and free pinacol (3:1) is about
constant. We have previously suggested24 that the activation of
the hydroxy group of 1 takes place by formation of boronic
ester 13. This is a very mild way of activation compared to the
analogue SnCl2-,65-68 BEt3-,69-71 Et2Zn-,72 and indium-based73-75
methods, which explains the broad synthetic scope and high
functional group tolerance of the above presented procedure.
a In a typical reaction, 1 was dissolved in a DMSO/MeOH mixture in
the presence of catalytic amounts of 3 and 4 (5 mol %). After the allotted
times (cond. A), 7 (2.0 equiv) was added followed by addition of 8 (1.5
equiv) and the reaction was continued for the reaction times and temperatures
given in column cond. B. b When 2b was applied, also 8.0 equiv of water
and 20 mol % of pTsOH were used. c Catalyst. d Conditions A: temperature/
time ) °C/h for the boronation reaction. e Conditions B: temperature/time
) °C/h for the allylation reaction. f Isolated yield. All products except 10k
were isolated as the corresponding HCl salts.
tendency for decomposition, and therefore it was purified by
recrystallization.
Carbethoxy compound 1g undergoes a carbon-carbon bond
formation reaction followed by lactonization with benzaldehyde
(Table 1, entry 17) under forced reaction condition. In contrast,
10i (also derived from 1g) did not undergo analogous lactam
formation (Table 3, entry 12). When 1g was reacted with amine
7a and 8 (Table 3, entry 12) compound 10i was remained
unchanged even under forced reaction conditions. The isomeric
The detailed mechanism of the catalytic formation of 5 from
13 is a subject of ongoing and future studies; however, we
strongly suggest that the catalytic transfer of the boronate group
from diboronic acid 2a or its derivatives (such as 13) proceeds
9
13728 J. AM. CHEM. SOC. VOL. 129, NO. 44, 2007

Petasis Borono-Mannich Reaction of Carbonyl Compounds
A R T I C L E S
Figure 3. Plausible mechanism for the allylation of aldehydes with allyl alcohols.
The next step of the process is the allylation of aldehyde 6,
which proceeds with an excellent stereo- and regioselectivity,
as the reaction takes place via a six-membered ring TS.1,5,6,86
The very high stereoselectivity is probably explained by the
fact that in the TS the carbonyl oxygen of the aldehyde (6) and
the boron atom of the allyl boronate comes to a very close
proximity.6,86 As the metal atoms (Si, Sn, Zn, etc.) in other
widely used allyl metal species are derived from higher periods
of the periodical table, such close proximity between the
reactants in the TS of the allylation cannot be realized.6
Therefore, the stereoselectivity of allylation of electrophiles is
much higher with allyl boronates than with any other allylmetal
species. Obviously, the high stereoselectivity of formation of 9
is based on the availability of regio- and stereodefined allyl
boronic acids (5), which is delivered by the efficient pincer-
complex-catalyzed borylation reaction.
Figure 4. Suggested mechanism for the one-pot four-component coupling
Using ketones as substrates, Kobayashi and Schneider9
suggested that allyl boronates are activated by InI followed by
electrophilic coupling with the carbon atom of the keto
functionality. In the presented reactions involving ketones 6f,g
(Table 2) allyl boronic acid 5 is supposed to be activated in a
similar way, and the TS geometry of the allylation is probably
similar to that of the corresponding reaction with aldehydes.
Allyl boronates are self-activating with aldehydes; however,
recent studies revealed87-90 that Lewis acids accelerate this
reaction probably via activation of the allylic component. This
activation may be particularly important for allylation of
deactivated aldehydes with sterically hindered allyl boronates,
such as in the reaction of 6a,b with transient boronate 5h
generated from 1h (Table 1, entries 18, 19, and 21). For
example, the reaction of 1h, 6a, and 2b catalyzed by 3a requires
48 h to provide product 9n (Table 1, entry 19). On the other
hand, in the replacement of 3a with catalyst 3b, in which the
counterion is loosely coordinated, the reaction is completed in
only 6 h (Table 1, entry 20). This acceleration effect can
reaction.
by a similar mechanism as the analogue stannylation process.
Previously, we have shown84,85 that hexamethylditin (dimetallic
analogue of 2a) readily reacts with pincer complexes under
stoichiometric conditions to give an η1-coordinated monostannyl
pincer complex, which is the tin analogue of 3d. Subsequent
DFT modeling studies have shown that the stannyl group is
easily transferred from palladium to the allylic position of
unsaturated carbons.84 Accordingly, we suppose that the bor-
onate group is transferred from diboronate 13 to catalyst 3c,
affording η1-boronato complex 3d. Subsequently, the boronato
group substitutes the activated hydroxy group of 14 to give allyl
boronic acid 5 and boric acid. In the absence of aldehydes or
other electrophiles, these allyl boronic acid derivatives can also
be isolated.24 Using functionalized allyl alcohols the boronation
reaction takes place with an excellent stereo- and regioselec-
tivity,23,24 which is very important for the subsequent allylation
processes.35,36 The boronation reaction shows a clear preference
for the formation of the linear allyl boronates, as both primary
(e.g., 1a) and secondary (e.g., 1b) allyl alcohols give the
corresponding terminally borylated products.24
(86) Gung, B. W.; Xue, X.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 10692.
(87) Rauniyar, V.; Hall, D. G. J. Am. Chem. Soc. 2004, 126, 4518.
(88) Lachance, H.; Lu, X.; Gravel, M.; Hall, D. G. J. Am. Chem. Soc. 2003,
125, 10160.
(89) Kennedy, J. W. J.; Hall, D. G. J. Am. Chem. Soc. 2002, 124, 11586.
(90) Ishiyama, T.; Ahiko, T.-a.; Miyaura, N. J. Am. Chem. Soc. 2002, 124, 12414.
(84) Kjellgren, J.; Sunde´n, H.; Szabo´, K. J. J. Am. Chem. Soc. 2005, 127, 1787.
(85) Kjellgren, J.; Sunde´n, H.; Szabo´, K. J. J. Am. Chem. Soc. 2004, 126, 474.
9
J. AM. CHEM. SOC. VOL. 129, NO. 44, 2007 13729

A R T I C L E S
Selander et al.
probably be ascribed to the participation of 3b in the allylation
process, as for example a Lewis-acid catalyst.87-89 Another
beneficial effect of the accessible palladium atom in 3b might
be a facile transmetallation of 3c to 3d.
in the allylation reaction. For example, products with quaternary
carbon, such as 9g,h, and 10f formed as single branched
regioisomers, although formation of the corresponding linear
form would have been favored by steric factors. Furthermore,
products 9n,o comprising three stereocenters were afforded as
single diastereomers in high yields.
While the coupling of allyl alcohols with aldehydes is based
on three stoichiometric components and involves two core
processes (Figure 3), application of allyl alcohols as input
reagents in the Petasis reaction (Figure 4) is a four-component
(1, 2a/b, 7, and 8) reaction in at least three different processes:
the borylation (1 f 5), imine formation (7 + 8 f 15), and
allylation (5 f 10). The borylation process takes place similarly
to the above-described mechanism; however, as mentioned
above, the amine component 7 and glyoxylic acid 8 cannot be
added to the reaction mixture at the beginning of the process.
Addition of 7 inhibits the boronation process probably by
coordination to the palladium atom of pincer complex 3c. This
coordination hinders the transmetallation of diboronate 13 to
form 3d, which prevents formation of 5. On the other hand,
addition of 8 alone leads to allylation of the aldehyde func-
tionality providing homoallyl alcohol as product.
The high level of compatibility of the boronation procedure
with allylation of various electrophiles forms the basis of the
above-described reactions. This compatibility relies on three
main factors: (a) the high selectivity of the employed pincer-
complex catalyst, which does not undergo further reactions with
the other components and allyl boronic acid products; (b)
application of 2a/b as boronate source allowing that the only
byproduct of the borylation reaction is unreactive (and nontoxic)
boric acid; (c) the high reactivity of the in situ formed allyl
boronic acids,33 which is accompanied with a fairly high
chemical inertness, such as their acid (4), base (7), water, and
air stability and tolerance of alcohol as cosolvent. As demon-
strated above, the presented one-pot procedures are suitable for
synthesis of densely substituted stereodefined homoallyl alcohols
and amines from commercially available inexpensive starting
materials in a benign and operationally simple one-pot proce-
dure. These products are useful drug intermediates48-55 (10a-
k) or building blocks in advanced organic synthesis (i.e.,
Figure 2).
Formation of imine 15 and its addition to organoboronates
is still a subject of mechanistic studies.1,79 Similarly to the
studies with isolated vinyl and allyl boronates, we have also
observed that addition of 7 and 8 separately gives higher yields
than addition of imine 15 formed in a separate process. This
suggests precoordination of 7 to the boron atom of 5, which is
probably important for the in situ formation of imine 15. Then,
this imine-boronate complex undergoes the allylation process
affording product 10. Coordination of 7 to 5 may also explain
the fact that in the presented reactions we could not observe
allylation of aldehyde 8, whereas the in situ formation of 15 is
an equilibrium process. Considering that the regio- and stereo-
selectivity of formation of amino acids (10) is similar to the
allylation of aldehydes, we suppose a similar type of TS structure
in both processes. When allyl alcohol 1j was employed as
reagent, the reaction is not terminated by formation of an
R-amino acid derivative (such as 10j), but the primarily formed
amino carboxylate intermediate underwent lactam formation
affording 10k. Accordingly, the reaction of 1j, 2a, 7a, and 8
triggers a spectacular four-step cascade, which can be performed
as a one-pot reaction (Table 3, entry 14).
Considering the above, the one-pot procedure described here
provides a simple, benign and cost efficient access to regio-
and stereodefined R-amino acids and homoallyl alcohols. The
reaction has a broad synthetic scope and the principal element
of the transformations, the efficient pincer-complex-catalyzed
generation of allyl boronic acids, can easily be integrated in
further one-pot allylation reactions of electrophiles.
4. Experimental Section
Further detailed experimental procedures and characterization of the
products are given in the Supporting Information.
General Procedure for Allylation of Aldehydes (Table 1). The
corresponding allyl alcohol 1 (0.15 mmol) was dissolved in a mixture
of DMSO and MeOH (0.2/0.2 mL) followed by the addition of
tetrahydroxydiboron 2a or bis(pinacolato)diboron 2b (0.18 mmol),
pincer complex 3 (0.0075 mmol, 5 mol %), p-toluenesulfonic acid 4
(0.0075 mmol, 5 mol %), and aldehyde 6 (0.18 mmol). This reaction
mixture was stirred for the allotted temperatures and times listed in
Table 1. Thereafter, the reaction mixture was quenched by water and
extracted with ether. After evaporation of the organic phase, product 9
was purified by silica gel chromatography. In the case of using 2b as
boronate source, 20 mol % of 4 (0.03 mmol) and 8.0 equiv of water
(1.20 mmol) were also employed. These reactions were performed
without using inert atmosphere or application of carefully dried solvents.
3-Phenyl-1,7-octadien-4-ol (9c). 1H NMR (CDCl3): 7.32 (m, 2H),
7.22 (m, 3H), 6.13 (ddd, J ) 9.0, 10.3, 17.0 Hz, 1H), 5.76 (dddd, J )
6.7, 6.7, 10.2, 17.0 Hz, 1H), 5.23 (d, J ) 10.3 Hz, 1H), 5.21 (d, J )
17.0 Hz, 1H), 4.99 (d, J ) 17.0 Hz, 1H), 4.93 (d, J ) 10.2 Hz, 1H),
3.82 (tt, J ) 3.3, 7.6 Hz, 1H), 3.25 (dd, J ) 7.6, 9.0 Hz, 1H), 2.23 (m,
1H) 2.11 (m, 1H), 1.83 (d, J ) 3.3 Hz, 1H), 1.43 (m, 2H). 13C NMR
(CDCl3): 141.9, 138.8, 138.6, 129.1, 128.3, 127.1, 118.3, 115.1, 73.7,
57.8, 33.9, 30.4. HRMS (ESI): calcd for [C14H18O + Na]+, m/z,
225.1250; found, 225.1248.
Considering the fact that the employed reactants, catalysts,
transient allyl boronic acids, and catalytic intermediates are
moisture and air stable species, the reactions can be performed
without using inert atmosphere, and the applied solvents do not
require careful drying. These features further increase the
operational simplicity of the presented one-pot procedures.
3. Conclusions
In this study we have demonstrated that homoallyl alcohols
and amino acids can efficiently be prepared from allyl alcohols
via transient allyl boronates in a one-pot sequence. The reactions
have a very broad synthetic scope involving cyclic and acyclic
alcohols, aromatic and aliphatic aldehydes, and various amines.
The mild conditions for activation of the allyl alcohols allow
the application of a wide range of functionalities involving
ethers, carboxylates, nitro, and other36 groups. The reaction
proceeds with an excellent regio- and stereoselectivity even for
problematic substrates, which is due to the high regio- and
stereoselectivity both in the formation of allyl boronates (5) and
Methyl 5-[hydroxy(phenyl)methyl]-3-cyclohexene-1-carboxylate
(9n). This compound was prepared according to the above general
procedure except that 0.30 mmol of 2a or 2b was used. 1H NMR
(CDCl3): 7.32 (m, 5H), 5.79 (m, 1H), 5.30 (m, 1H), 4.56 (d, J ) 7.1
Hz, 1H), 3.68 (s, 3H), 2.76 (dtd, J ) 3.7, 7.1, 10.2 Hz, 1H), 2.57, (m,
9
13730 J. AM. CHEM. SOC. VOL. 129, NO. 44, 2007

Petasis Borono-Mannich Reaction of Carbonyl Compounds
A R T I C L E S
1H), 2.26 (m, 2H), 2.14 (dt, J ) 3.7, 13.5 Hz, 1H), 2.02 (bs, 1H), 1.81
(ddd, J ) 6.0, 10.2, 13.5 Hz, 1H). 13C NMR (CDCl3): 176.4, 143.0,
128.7, 128.3, 128.0, 127.7, 126.8, 77.0, 52.0, 41.3, 36.5, 27.6, 26.1.
HRMS (ESI): calcd for [C15H18O3 - OH]+, m/z, 229.1223; found,
229.1223.
acidified by addition of a few drops of 37% aq HCl and evaporated.
The crude products were purified by silica gel column chromatography
using a mixture of dichloromethane, methanol, and 37% aq HCl (450:
50:1) as eluent. In the case of using bis(pinacolato)diboron (2b), 20
mol % of 4 (0.03 mmol), and 8.0 equiv of water (1.20 mmol) were
also added at the beginning of the reaction. As above, these reactions
were also performed without using inert atmosphere or carefully dried
solvents.
2-(Benzhydrylamino)-3-[(benzyloxy)methyl]-4-pentenoic Acid (10g)
1H NMR (CD3OD): 7.44 (m, 5H), 7.37 (m, 8H), 7.28 (m, 2H), 5.68
(ddd, J ) 8.7, 10.3, 17.1 Hz, 1H), 5.54 (s, 1H), 5.36 (d, J ) 17.1 Hz,
1H), 5.30 (d, J ) 10.3 Hz, 1H), 4.52 (m, 2H), 4.12 (d, J ) 5.6 Hz,
1H), 3.71 (m, 2H), 3.22 (m, 1H). 13C NMR (CD3OD): 169.2, 138.6,
136.6, 135.4, 132.1, 130.8, 130.5, 130.4, 129.7, 129.3, 129.0, 129.0,
121.9, 74.7, 72.5, 67.2, 62.2, 45.7. HRMS (ESI): calcd for [C26H27-
NO3 + H]+, m/z, 402.2064; found, 402.2062.
1-Benzhydryl-5-oxo-3-vinyl-2-pyrrolidine Carboxylic Acid (10k)
1H NMR (CD3OD): 7.28 (m, 10H), 7.25 (s, 1H), 6.05 (ddd, J ) 6.8,
10.6, 17.3 Hz, 1H), 5.23 (m, 2H), 4.00 (d, J ) 1.5 Hz, 1H), 2.99 (dddd,
J ) 1.5, 1.5, 6.8, 8.1 Hz, 1H), 2.89 (m, 1H), 2.38 (m, 1H). 13C NMR
(CD3OD): 177.3, 174.4, 141.0, 139.8, 139.2, 131.5, 129.4, 129.2, 128.7,
128.4, 116.7, 66.6, 62.3, 41.8, 36.4. HRMS (ESI): calcd for [C20H19-
NO3 + H]+, m/z, 322.1438; found, 322.1437.
Ring-Closing Metathesis of Dienes 9c, f, and k. Dienes 9c,f or k
(0.08 mmol) and catalyst 11 (5 mol %, 0.004 mmol) were dissolved in
freshly distilled dichloromethane (8.5 mL) under Ar atmosphere. This
reaction mixture was stirred at 40 °C for 2 h, evaporated, and purified
by column chromatography.
General Procedure for Allylation of Ketones (Table 2). The
corresponding allyl alcohol 1 (0.15 mmol) was dissolved in a mixture
of DMSO/MeOH (0.2/0.2 mL) followed by addition of 2a (0.18 mmol),
3a (0.0075 mmol, 5 mol %), and 4 (0.0075 mmol, 5 mol %). This
reaction mixture was stirred for 16 h at 50 °C. Thereafter, ketone 6
(0.165 mmol) and InI (0.03 mmol, 20 mol %) were added, and the
mixture was stirred for a further 16 h at 50 °C. Then, the reaction
mixture was quenched with water and extracted with ether. After
evaporation of the organic phase, product 9 was purified by silica gel
column chromatography. These reactions were also performed without
using inert atmosphere or application of carefully dried solvents.
2,3-Diphenyl-4-penten-2-ol (9q). This product was formed as a 9:1
mixture of two diastereomers. The obtained NMR data are identical
with the literature78 values. NMR data for the major isomer is as follows.
1H NMR (CDCl3): 7.28 (m, 10H), 6.14 (ddd, J ) 8.6, 10.3, 17.1 Hz,
1H), 5.07 (d, J ) 10.3 Hz, 1H), 4.95 (d, J ) 17.1 Hz, 1H), 3.65 (d, J
) 8.6 Hz, 1H), 2.01 (s, 1H), 1.46 (s, 3H). 13C NMR (CDCl3): 146.7,
140.5, 137.7, 130.0, 128.5, 128.1, 127.2, 126.9, 125.9, 118.4, 76.6,
62.2, 28.9. HRMS (ESI): calcd for [C17H18O + Na]+, m/z, 261.1250;
found, 261.1247.
1-(1-Pentylpropen-2-yl) cyclohexane-1-ol (9s). 1H NMR
(CDCl3): 5.60 (ddd, J ) 10.1, 10.1, 17.1 Hz, 1H), 5.14 (d, J ) 10.1
Hz, 1H), 5.03 (d, J ) 17.1 Hz, 1H), 1.89 (m, 1H), 1.40 (m, 18H), 1.32
(s, 1H), 0.87 (t, J ) 7.0 Hz, 3H). 13C NMR (CDCl3): 139.5, 118.1,
72.8, 56.0, 35.2, 35.1, 32.2, 28.2, 28.0, 26.3, 23.0, 22.2, 22.1, 14.4.
HRMS (ESI): calcd for [C14H26O + Na]+, m/z, 233.1876; found,
233.1872.
General Procedure for One-Pot Synthesis of R-Amino Acids
(Table 3). To the corresponding allyl alcohol 1 (0.15 mmol) in a mixture
of DMSO/MeOH (0.2/0.2 mL) 2 (0.18 mmol), pincer complex 3 (0.0075
mmol, 5 mol %), and 4 (0.0075 mmol, 5 mol %) were added. The
resulted solution was stirred for the allotted temperatures and times
listed in column conditions A in Table 3. Thereafter, amine 7 (0.30
mmol) was added, and the mixture was stirred for a further 10 min at
room temperature followed by the addition of glyoxylic acid 8 (0.23
mmol). Subsequently, this reaction mixture was stirred for the allotted
temperatures and times given in column conditions B in Table 3. After
filtration of the reaction mixture through a cotton plug, the solvent
was removed, and the residue was dissolved in a mixture of dichlo-
romethane, methanol, and 37% aq HCl (450:50:1). This solution was
2-[(Benzyloxy)methyl]-3-cyclohexen-1-ol (12c) 1H NMR
(CDCl3): 7.32 (m, 5H), 5.78 (m, 1H), 5.43 (m, 1H), 4.55 (s, 2H), 4.15
(m, 1H), 3.62 (m, 2H), 2.99 (d, J ) 5.0 Hz, 1H), 2.65 (m, 1H), 2.21
(m, 1H), 2.05 (m, 1H), 1.79 (m, 2H). 13C NMR (CDCl3): 138.1, 129.3,
128.8, 128.2, 128.1, 125.2, 73.8, 71.8, 68.5, 40.6, 28.3, 22.7. HRMS
(ESI): calcd for [C14H18O2 + Na]+, m/z, 241.1199; found, 241.1200.
Acknowledgment. This work was supported by the Swedish
Natural Science Research Council (VR). A.K. is grateful for
an Erasmus stipend funded by the EU.
Supporting Information Available: Detailed experimental
1
procedures; characterization and H and 13C NMR spectra of
the products. This material is available free of charge via the
Internet at http://pubs.acs.org.
JA074917A
9
J. AM. CHEM. SOC. VOL. 129, NO. 44, 2007 13731