Complete stereoretention in the rhodium-catalyzed 1,2-addition of chiral secondary and tertiary alkyl potassium trifluoroborate salts to aldehydes

Full text of DOI:10.1002/anie.200901900

Angewandte
Chemie
DOI: 10.1002/anie.200901900
Homogeneous Catalysis
Complete Stereoretention in the Rhodium-Catalyzed 1,2-Addition of
Chiral Secondary and Tertiary Alkyl Potassium Trifluoroborate Salts to
Aldehydes**
Abel Ros and Varinder K. Aggarwal*
The Rh-catalyzed 1,4-addition[1] and 1,2-addition[2] of boronic
acids to Michael acceptors and aldehydes, first reported by
Miyaura and co-workers just over a decade ago, has spawned
a major area of research.[3] The 1,4-addition reaction, in
particular, has rapidly moved from methodological studies to
applications in synthesis.[4] Although less well developed, the
1,2-addition reaction has also enjoyed significant develop-
ment. For example, it has been found that alternative metals
Scheme 1. Synthesis of secondary potassium trifluoroborate salts.
Cb=N,N-diisopropylcarbamoyl, coev=co-evaporation.
to Rh[5] can be used (Pd, Ni, Cu, Ru),[6] and that the more-
stable potassium organotrifluoroborates can be employed in
place of boronic acids.[7] However, all of these reactions are
limited to the use of sp2-carbon boron derivatives (aryl- or
alkenylboronic acids, esters, or organotrifluoroborate salts).[8]
Presumably, alkyl boron derivatives suffer from a slower rate
of transmetalation and the potential for rapid b-hydride
elimination from the sp3 metalloalkyl intermediate.[9] These
two effects would conspire to render such substrates unsuit-
able in this type of coupling reaction,[10] although Crudden
and co-workers recently reported a breakthrough in the
Suzuki coupling of secondary benzylic boronic esters.[11,12]
Nevertheless, we recognized the significant potential that
would ensue if we could induce alkyl boron derivatives to
couple to electrophiles. Herein we describe our success in
achieving this goal and furthermore demonstrate complete
stereoretention in reactions involving not only secondary but
also tertiary chiral alkyl derivatives.
Scheme 2. Reaction of boronic ester 2a or trifluoroborate salt 3a with
4-nitrobenzaldehyde. cod=cycloocta-1,5-diene.
We elected to study the reactions of secondary benzylic
boron derivatives because they were expected to undergo
more rapid transmetalation. They were easily prepared in
high enantioregioselectivity by the reaction of Hoppeꢀs
lithiated carbamates with aryl/alkyl boronic esters by using
methodology that we recently reported (Scheme 1).[13] We
also converted the boronic esters into the corresponding
trifluoroborate salts to test both classes of substrates. How-
ever, reactions of boronic ester 2a with p-NO2C6H4CHO
either showed limited reactivity in the presence of [{RhCl-
(cod)}2] or direct reaction was observed with CsF accompa-
nied by substantial racemization in both cases (Scheme 2).
We therefore turned our attention to the trifluoroborate
salts, particularly as Batey et al. had reported that they show
greater reactivity than boronic acids because they undergo
more rapid transmetalation.[7a] With this switch we were
immediately rewarded with success. Using the commercially
available catalyst [{RhCl(cod)}2] (2.5 mol%) at 808C in 1,4-
dioxane/H2O (6:1), the reaction of 3a with p-NO2C6H4CHO
gave the adduct in 82% yield and with complete stereo-
retention (Scheme 2). The reaction was applied to a range of
aldehydes, and different temperatures were tested to max-
imize the enantioregioselectivity and minimize proto-deboro-
nation. Strongly activated aldehydes were found to react
efficiently at 60–1008C (Table 1, entries 1–3) and so we chose
808C to determine the scope of the reaction (Table 1, entries 2
and 4–6). However, less-activated aldehydes suffered low
yields at this temperature, because of competing protonation
(Table 1, entry 6) and so reactions were conducted at 608C
instead (Table 1, entry 7). At this temperature, non-activated
[*] Dr. A. Ros, Prof. V. K. Aggarwal
School of Chemistry, University of Bristol
Cantock’s Close, Bristol BS81TS (UK)
Fax: (+44)117-929-8611
E-mail: v.aggarwal@bristol.ac.uk
Homepage: http://www.chm.bris.ac.uk/org/aggarwal/about.html
[**] A.R. thanks the European Union for a Marie Curie Intra-European
Postdoctoral Fellowship 7th European Community Framework
Programme. V.K.A. thanks the EPSRC for a Senior Research
Fellowship, Merck, and Frontier Scientific for research support. We
thank Prof. Guy Lloyd-Jones for insightful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200901900.
Angew. Chem. Int. Ed. 2009, 48, 6289 –6292
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6289

Communications
Table 1: 1,2-Addition of the potassium trifluoroborate salts (R)-3a–c to
aldehydes.[a]
Scheme 3. TEMPO-mediated oxidation of the alcohols 6a, 4c, and 5c.
TEMPO=2,2,6,6-tetramethyl-1-piperidinoxyl (free radical).
Entry
R
R1
T
t
Product
Stereoret.
[8C] [h]
yield(%)[b] [%][c]
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
p-NO2C6H4 60
p-NO2C6H4 80
p-NO2C6H4 100
6
4
4
6
4a, 78
4a, 82
4a, 86
5a, 93
6a, 86
7a, 33
>99
>99
>99
>99
>99[d]
>99
>99
>99
97
>99
>99
>99
>99[g]
>99[g]
Having successfully demonstrated that chiral secondary
alkyl trifluoroborate salts could couple with aldehydes,[14] we
considered extending the methodology to the even more
challenging tertiary substrates. These were easily prepared, in
high enantioregioselectivity through a related lithiation–
borylation reaction, again by using methodology that we
recently reported (Scheme 4).[18]
p-CNC6H4
p-CF3C6H4
p-ClC6H4
p-ClC6H4
Ph
80
80
80
60
60
80
6
8[e]
15[e] 7a, 49
15[e] 8a, 28
9
CO2Et
4[f]
4
6
6
8
9a, 61
4b, 96
5b, 72
6b, 61
4c, 66
5c, 61
10
11
12
13
14
p-NO2C6H4 80
Et
Et
p-CNC6H4
p-CF3C6H4
80
80
(CH2)2Ph p-NO2C6H4 100
(CH2)2Ph p-CNC6H4 100
8
[a] A mixture of aldehyde (0.3 mmol), RBF3K (0.45 mmol), and [{RhCl-
(cod)}2] (2.5% mol) in deoxygenated 1,4-dioxane/H2O (6:1; 1.65 mL)
was stirred at 60–1008C. [b] Yield of isolated product. [c] Stereochemical
retention is meant to imply the degree of retention relative to the starting
material rather than retention versus inversion. Determined by HPLC on
a chiral stationary column (see the Supporting Information). [d] The
absolute configuration was assigned by comparison of the correspond-
ing ketone 10 (Scheme 3) with literature data: see Ref. [17]. All others are
assigned by analogy. [e] Starting aldehyde remained after 8 h, but all the
trifluoroborate salt was consumed and the product of proto-deborona-
tion was observed. At higher temperature (80–1008C), a lower yield was
obtained, but without loss of enantioregioselectivity [f] Four equivalents
of aldehyde were used with respect to (R)-3a. [g] The e.r. value was
determined on the corresponding ketone after oxidation using TEMPO
(Scheme 3).
Scheme 4. Synthesis of chiral tertiary potassium trifluoroborate salts.
Pin=pinacol.
Remarkably, the enantioenriched diarylalkyl trifluorobo-
rate salts 3d–f were able to couple with aldehydes in the
presence of the same rhodium catalyst without interference
from b-hydride elimination and without erosion in the
enantioregioselectivity of this exceptionally fragile stereo-
genic center. This process was general for a range of
trifluoroborate salts, although as before was limited to
relatively reactive aldehydes (Table 2, entries 1–6). Perhaps,
even more surprising was the success in coupling the
dialkylaryl trifluoroborate salt 3g with aldehydes (Table 2,
entries 7–10) since it would be expected to undergo slower
transmetalation and more rapid b-hydride elimination than
the secondary arylalkyl trifluoroborate salt. Furthermore,
these processes generate quaternary stereogenic centers with
essentially perfect enantioselectivity. The reaction of such
hindered boron derivatives, the complete transfer of chirality
of especially fragile stereocenters, and the lack of b-hydride
elimination are all noteworthy features of the novel chemis-
try.
aldehydes only gave low yields (Table 1, entry 8). Glyoxylates
were suitable aldehyde partners giving the 1,2,-adduct in
moderate yield (Table 1, entry 9). The more-hindered salts 3b
and 3c could also be employed with the activated aldehydes,
thus demonstrating the scope in the trifluoroborate salt
partner (Table 1, entries 10–14).[14] In all cases, and with all of
the aldehydes examined, essentially complete retention of
configuration was obtained at the fragile benzylic center.
Chiral benzylic organometallic reagents are notoriously
unstable towards racemization, but we have shown that the
benzylic organorhodium (or organoboron, see below) inter-
mediate is configurationally stable even at 1008C.[15]
As expected, no control of the carbinol center was
observed and a 1:1 mixture of diastereoisomers was isolated.
Nevertheless, the alcohols could be oxidized to the corre-
sponding ketones 10–12 without any detectable racemization
using TEMPO (Scheme 3).[16] Furthermore, by correlation of
the chiral ketone 10 with the literature we were able to
confirm that the addition of the secondary trifluoroborate salt
occurred with retention of configuration.[17]
The mechanism of the reaction is intriguing. By analogy
with 1,4- and 1,2-addition of boronic acids to electrophiles,[1c,2]
one would expect initial transmetalation to rhodium followed
by 1,2-addition (Scheme 5). An alternative mechanism is that
the hydroxy–rhodium complex coordinates to the boron
À
derivative and aldehyde followed by direct formation of a C
C bond. The latter mechanism would account for the
complete stereoretention and the lack of b-hydride elimina-
6290 www.angewandte.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 6289 –6292

Angewandte
Chemie
Received: April 8, 2009
Published online: July 7, 2009
Table 2: 1,2-Addition of the tertiary chiral potassium trifluoroborate salts
(R)-3d–g to aldehydes.[a]
Keywords: 1,2-addition · alkyl trifluoroborate salts · chirality ·
.
homogeneous catalysis · rhodium
[1] a) M. Sakai, H. Hayashi, N. Miyaura, Organometallics 1997, 16,
4229 – 4231; b) Y. Takaya, M. Ogasawara, T. Hayashi, M. Sakai,
N. Miyaura, J. Am. Chem. Soc. 1998, 120, 5579 – 5580; c) T.
Hayashi, M. Takahashi, Y. Takaya, M. Ogasawara, J. Am. Chem.
Soc. 2002, 124, 5052 – 5058.
Entry Trifluoroborate salt
X
T
t
Yield
[%][b]
Stereoret.
[%][c]
(3d–g)
[8C] [h]
Ar
R
[2] M. Sakai, M. Ueda, N. Miyaura, Angew. Chem. 1998, 110, 3475 –
3477; Angew. Chem. Int. Ed. 1998, 37, 3279 – 3281.
1
2
3
4
5
6
7
8
9
Ph
Ph
p-ClC6H4 NO2 60
p-ClC6H4 NO2 80
6
2
6
6
20
24
2
4d, 84 >99
4d, 68 >99
4e, 82 >99
5e, 76 >99
4 f, 89 >99
5 f, 71 >99
4g, 87 >99
5g, 90 >99
[3] a) K. Fagnou, M. Lautens, Chem. Rev. 2003, 103, 169 – 196; b) T.
Hayashi, K. Yamasaki, Chem. Rev. 2003, 103, 2829 – 2844.
[4] a) G. Lalic, E. J. Corey, Org. Lett. 2007, 9, 4921 – 4923; b) T.
Nishikata, S. Kiyomura, Y. Yamamoto, N. Miyaura, Synlett 2008,
2487 – 2490; c) C. S. Burgey, D. V. Paone, A. W. Shaw, J. Z. Deng,
D. N. Nguyen, C. M. Potteiger, S. L. Graham, J. P. Vacca, T. M.
Williams, Org. Lett. 2008, 10, 3235 – 3238.
p-MeOC6H4 Ph
p-MeOC6H4 Ph
NO2 60
CN 60
p-MeOC6H4 p-ClC6H4 NO2 60
p-MeOC6H4 p-ClC6H4 CN 60
NO2 80
Ph
Ph
Ph
Ph
Et
Et
Et
Et
CN
Cl
H
80
60
60
2
15[d] 7g, 44 >99
15[d] 8g, 35 >99[e]
[5] a) M. Ueda, N. Miyaura, J. Org. Chem. 2000, 65, 4450 – 4452;
b) A. Fꢁrstner, H. Krause, Adv. Synth. Catal. 2001, 343, 343 –
350; c) C. Moreau, C. Hague, A. S. Weller, C. G. Frost, Tetrahe-
dron Lett. 2001, 42, 6957 – 6960; d) N. Imlinger, M. Mayr, D.
Wang, K. Wurst, M. R. Buchmeiser, Adv. Synth. Catal. 2004, 346,
1836 – 1843; e) T. Fuchen, J. Rudolph, C. Bolm, Synthesis 2005,
429 – 436; f) H.-F. Duan, J.-H. Xie, W.-J. Shi, Q. Zhang, Q.-L.
Zhou, Org. Lett. 2006, 8, 1479 – 1481; g) A. F. Trindade, P. M. P.
Gois, L. F. Veiros, V. Andrꢂ, M. T. Duarte, C. A. M. Afonso, S.
Caddick, F. G. N. Cloke, J. Org. Chem. 2008, 73, 4076 – 4086.
[6] For Pd-catalyzed reactions see: a) T. Yamamoto, T. Ohta, Y. Ito,
Org. Lett. 2005, 7, 4153 – 4155; b) K. Suzuki, T. Arao, S. Ishii, Y.
Maeda, K. Kondo, T. Aoyama, Tetrahedron Lett. 2006, 47, 5789 –
5792; c) C. Qin, H. Wu, J. Cheng, X. Chen, M. Liu, W. Zhang, W.
Su, J. Ding, J. Org. Chem. 2007, 72, 4102 – 4107; d) S. Lin, X. Lu,
J. Org. Chem. 2007, 72, 9757 – 9760; e) Y.-L. Liao, C.-H. Xing, P.
He, Q.-S. Hu, Org. Lett. 2008, 10, 2509 – 2512; f) M. Kuriyama, R.
Shimazawa, R. Shirai, J. Org. Chem. 2008, 73, 1597 – 1600; for
Ni-catalyzed reactions see: g) G. Takahashi, E. Shirakawa, T.
Tsuchimoto, Y. Kawakami, Chem. Commun. 2005, 1459 – 1461;
h) K. Hirano, H. Yorimitsu, K. Oshima, Org. Lett. 2005, 7, 4689 –
4691; i) K. Yamamoto, K. Tsurumi, F. Sakurai, K. Kondo, T.
Aoyama, Synthesis 2008, 3585 – 3590; for Cu-catalyzed reactions
see: j) D. Tomita, M. Kanai, M. Shibasaki, Chem. Asian J. 2006,
1, 161 – 166; for Ru-catalyzed reactions see: k) Y. Yamamoto, K.
Kurihara, N. Miyaura, Angew. Chem. 2009, 121, 4478; Angew.
Chem. Int. Ed. 2009, 48, 4414.
10
[a] A mixture of aldehyde (0.3 mmol), RBF3K (0.45 mmol), and [{RhCl-
(cod)}2] (2.5 mol%) in deoxygenated 1,4-dioxane/H2O (6:1; 1.65 mL)
was stirred at 60–1008C. [b] Yield of isolated product. [c] Stereochemical
retention is meant to imply the degree of retention relative to the starting
material rather than retention versus inversion. Determined by HPLC on
a chiral stationary phase (see the Supporting Information). [d] Starting
aldehyde remained after 15 h, but all the trifluoroborate salt was
consumed and proto-deboronation was the main side reaction. [e] The
e.r. value was determined on the corresponding ketone. The absolute
configuration of 8g (entry 10) was assigned by comparison with
literature data: see Ref. [19]. All others are assigned by analogy.
[7] a) R. A. Batey, A. N. Thadani, D. V. Smil, Org. Lett. 1999, 1,
1683 – 1686; b) M. Pucheault, S. Darses, J.-P. Genet, Chem.
Commun. 2005, 4714 – 4716.
Scheme 5. Possible mechanisms for 1,2-addition.
[8] There is one example of a Ni-catalyzed 1,2-addition of Et3B or
Bu3B to aldehydes: see Ref. [6h].
[9] a) N. Miyaura, T. Ishiyama, H. Sasaki, M. Ishikawa, M. Satoh, A.
Suzuki, J. Am. Chem. Soc. 1989, 111, 314 – 321; b) G. Zou, J. R.
Falck, Tetrahedron Lett. 2001, 42, 5817 – 5819.
tion observed, which present unusual features had initial
transmetalation to rhodium taken place.[20]
In conclusion, we have shown that secondary and tertiary
alkyl trifluoroborate salts couple with aldehydes in the
presence of [{RhCl(cod)}2] in good yield and with complete
retention of stereochemistry of the initial chiral trifluorobo-
rate salt. In fact, the complete retention of stereochemical
information during the transformation of a chiral organome-
tallic compound is rather rare in organic chemistry. The lack
of b-hydride elimination is also especially noteworthy and
bodes well for future application to other classes of reactions.
Studies in this area are currently in progress.
[10] For examples of Ni-catalyzed coupling reactions of secondary
alkyl halides which can similarly undergo b-hydride elimination
see the following reviews: a) F. Glorius, Angew. Chem. 2008, 120,
8474 – 8476; Angew. Chem. Int. Ed. 2008, 47, 8347 – 8349; b) A.
Rudolph, M. Lautens, Angew. Chem. 2009, 121, 2694 – 2708;
Angew. Chem. Int. Ed. 2009, 48, 2656 – 2670; see also c) J. Zhou,
G. C. Fu, J. Am. Chem. Soc. 2003, 125, 14726 – 14727; d) J. S.
Zhou, G. C. Fu, J. Am. Chem. Soc. 2004, 126, 1340 – 1341; e) F. O.
Arp, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 10482 – 10483; f) S.
Son, G. C. Fu, J. Am. Chem. Soc. 2008, 130, 2756 – 2757; g) B.
Saito, G. C. Fu, J. Am. Chem. Soc. 2008, 130, 6694 – 6695; for
Angew. Chem. Int. Ed. 2009, 48, 6289 –6292
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
6291

Communications
examples of Pd-catalyzed coupling reactions of secondary alkyl
[14] Non-benzylic trifluoroborate salts (for example, PhCH2CH2CH-
(BF3K)C2H5) failed to couple under these conditions and gave a
mixture of starting material and the proto-deboronated product.
[15] For the racemization of secondary benzylic lithium and magne-
sium species see: a) G. M. Whitesides, J. D. Roberts, J. Am.
Chem. Soc. 1965, 87, 4878 – 4888; b) K. V. Baker, J. M. Brown, N.
Hughes, A. J. Skarnulis, A. Sexton, J. Org. Chem. 1991, 56, 698 –
703; c) R. W. Hoffmann, T. Riihl, F. Chemla, T. Zahneisen,
Liebigs Ann. Chem. 1992, 719 – 724; d) H. Lange, K. Bergander,
R. Frꢃhlich, S. Kehr, S. Nakamura, N. Shibata, T. Toru, D.
Hoppe, Chem. Asian J. 2008, 3, 88 – 101.
[16] L. De Luca, G. Giacomelli, A. Porcheddu, Org. Lett. 2001, 3,
3041 – 3043.
[17] P. M. Lundin, J. Esquivias, G. C. Fu, Angew. Chem. 2009, 121,
160 – 162; Angew. Chem. Int. Ed. 2009, 48, 154 – 156.
[18] J. L. Stymiest, V. Bagutski, R. M. French, V. K. Aggarwal, Nature
2008, 456, 778 – 782.
potassium trifluoroborate salts or boronic esters see: h) S. D.
Dreher, P. G. Dormer, D. L. Sandrock, G. A. Molander, J. Am.
Chem. Soc. 2008, 130, 9257 – 9259; i) A. Van den Hoogenband,
J. H. M. Lange, J. W. Terpstra, M. Koch, G. M. Visser, M. Visser,
T. J. Korstanje, J. T. B. H. Jastrzebski, Tetrahedron Lett. 2008, 49,
4122 – 4124; undesired b-hydride elimination and proto-deboro-
nation have been observed in the Pd-catalyzed Suzuki coupling
of secondary alkyl boron derivatives; see: j) G. A. Molander, T.
Ito, Org. Lett. 2001, 3, 393 – 396; k) N. Kataoka, Q. Shelby, J. P.
Stambuli, J. F. Hartwig, J. Org. Chem. 2002, 67, 5553 – 5566.
[11] a) D. Imao, B. W. Glasspoole, V. S. Laberge, C. M. Crudden, J.
Am. Chem. Soc. 2009, 131, 5024 – 5025; b) for cross-coupling
reactions of secondary benzylic trifluorosilanes see: Y. Hata-
naka, T. Hiyama, J. Am. Chem. Soc. 1990, 112, 7793 – 7794.
[12] For Kumada coupling reactions of secondary and tertiary
Grignard reagents with alkyl halides see: a) J. Terao, H.
Watanabe, A. Ikumi, H. Kuniyasu, N. Kambe, J. Am. Chem.
Soc. 2002, 124, 4222 – 4223; b) J. Terao, A. Ikumi, H. Kuniyasu,
N. Kambe, J. Am. Chem. Soc. 2003, 125, 5646 – 5647.
[19] K. R. Kopecky, T. W. Mojelsky, T. Gillan, J. A. Barry, J. A. Lopez
Sastre, Can. J. Chem. 1977, 55, 1001 – 1014.
[20] Benzylic organorhodium complexes may be stabilized by form-
ing h3 complexes: T. J. Kwok, D. J. Wink, Organometallics 1993,
12, 1954 – 1959, and references therein. However, such inter-
mediates are known to still undergo b-hydride elimination: J. M.
Brown, G. C. Lloyd-Jones, J. Am. Chem. Soc. 1994, 116, 866 –
878.
[13] a) J. L. Stymiest, G. Dutheuil, A. Mahmood, V. K. Aggarwal,
Angew. Chem. 2007, 119, 7635 – 7638; Angew. Chem. Int. Ed.
2007, 46, 7491 – 7494; b) P. OꢀBrien, J. L. Bilke, Angew. Chem.
2008, 120, 2774 – 2776; Angew. Chem. Int. Ed. 2008, 47, 2734 –
2736.
6292 www.angewandte.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 6289 –6292