Catalytic chemoselective addition of acetonitrile to enolizable aldehydes with cationic Ru complex/DBU combination

Article abstract of DOI:10.1039/b504519c

The cooperative catalysis of CpRu(PPh₃)₂(CH ₃CN)PF₆ (1b) and DBU enables chemoselective nucleophilic activation of acetonitrile in the presence of base-sensitive aldehydes 2 to afford corresponding β-hydroxynitr

Full text of DOI:10.1039/b504519c

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Catalytic chemoselective addition of acetonitrile to enolizable aldehydes
with cationic Ru complex/DBU combination{
Naoya Kumagai, Shigeki Matsunaga and Masakatsu Shibasaki*
Received (in Cambridge, UK) 31st March 2005, Accepted 9th May 2005
First published as an Advance Article on the web 9th June 2005
DOI: 10.1039/b504519c
The cooperative catalysis of CpRu(PPh3)2(CH3CN)PF6 (1b)
and DBU enables chemoselective nucleophilic activation of
acetonitrile in the presence of base-sensitive aldehydes 2 to
afford corresponding b-hydroxynitriles 3 in good yield.
The control of chemoselectivity is ongoing challenge in synthetic
organic chemistry. For decades, reagent-controlled chemoselec-
tivity has been realized using more than stoichiometric amounts of
additional reagents. For example, a separate preparation process
of metal-enolate or enol silyl ether enables various cross-aldol
reactions,1 while a simple base-promoted cross-aldol protocol
often results in complicated product mixtures, including self-aldol
products of aldehydes. Recently, attention in aldol-type reaction
development has shifted to a catalyst controlled chemoselective
process;2 that is, in situ catalytic generation of active nucleophiles
and subsequent integration into a C–C bond forming process.
Although a-cyano carbanions are widely utilized in organic
synthesis as useful carbon nucleophiles, the catalytic process for
generating a-cyano carbanions is limited to reactive nitriles such as
b-cyanocarbonyl (pKa y13 in DMSO) and a-arylnitrile (pKa 21.9
in DMSO) compounds.3,4 Simple alkylnitriles are among the least
acidic carbon pro-nucleophiles (pKa 31.3 in DMSO, 28.9 in H2O)5
and preparation of a-cyano carbanions from alkylnitriles usually
requires more than stoichiometric amounts of a strong base in a
separate process.3 Recently, a few methods for catalytic generation
of a-cyano carbanions from alkylnitriles were reported;6 however,
the conditions were still highly basic, severely limiting the substrate
scope of the electrophile due to the chemoselectivity issue. The
catalytic aldol-type addition of a-cyano carbanions generated
from non-activated alkylnitriles has been mostly limited to non-
enolizable aldehydes,6 because enolizable, a,a-nonsubstituted
aldehydes (pKa 15.7–16.9 in H2O)7 tend to undergo considerable
self-condensation under basic conditions. Therefore, it is a
formidable task to compensate for the large pKa gap between
alkylnitriles and a,a-nonsubstituted aldehydes to chemoselectively
promote the reaction through catalyst control. Herein we report
chemoselective in situ nucleophilic activation of acetonitrile in the
presence of more acidic a,a-nonsubstituted aldehydes using a
diphosphine Ru complex and DBU to afford b-hydroxynitriles in
good yield (63–90%) (Scheme 1).
Scheme 1
Recently, we reported catalytic generation of a-cyano carbanion
of acetonitrile and subsequent addition to non-enolizable alde-
hydes with a soft Lewis acid–amine base combination.8 In this
system, CpRu(PPh3)(CH3CN)2PF6 (1a)9 (Fig. 1) chemoselectively
activates nitrile functionality to lower the pKa of acetonitrile to be
deprotonated by DBU.10 Considering that DBU itself promoted
neither self-condensation of heptanal (2a) nor the desired reaction
(Table 1, entry 1), we anticipated that chemoselective deprotona-
tion of acetonitrile over more acidic enolizable aldehyde would be
possible by combination with an Ru catalyst. With 10 mol% of 1a
and 50 mol% of DBU, chemoselective activation of the acetonitrile
occurred at 50 uC to give 3a with little formation of a self-
condensation product, although the chemical yield was unsatisfac-
tory (Table 1, entry 2, 54%) likely due to decomposition of the
catalyst caused by the formation of an unstable Ru-DBU complex
6a in the catalytic cycle (Fig. 2).11 In the previous report for non-
enolizable aldehyde,8 10 mol% of NaPF6 was added to prevent the
formation of the unfavorable Ru-DBU complex 6a through cation
exchange from in situ-formed Ru-alkoxide 5a into Na-alkoxide
and 1a, enhancing the catalytic efficiency. With enolizable
aldehyde 2a, however, self-condensation of 2a proceeded exten-
sively in the presence of 10 mol% of NaPF6 and the desired
b-hydroxynitrile 3a was obtained in only 38% yield (Table 1, entry
3). We ascribed the inferior effect of the Na salt to the strong
Brønsted basicity of the Na-alkoxide generated in situ. Thus, an
alternative strategy to accelerate the catalyst regeneration step (6 to
1 in Fig. 2) without NaPF6 was required to minimize the
concentration of the unstable Ru-DBU complex 6. To address this
issue, we chose a Ru-diphosphine complex 1b (Fig. 1) as a catalyst.
ESI-MS analysis of 1a and 1b with DBU indicated that 1b was
{ Electronic supplementary information (ESI) available: Spectroscopic
data of 3 and ESI-MS data of Ru complex-DBU mixture. See http://
www.rsc.org/suppdata/cc/b5/b504519c/
Graduate School of Pharmaceutical Sciences, The University of Tokyo,
Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. E-mail: mshibasa@mol.f.
u-tokyo.ac.jp; Fax: +81-3-5684-5206; Tel: +81-3-5841-4830
*mshibasa@mol.f.u-tokyo.ac.jp
Fig. 1 Structure of Ru complexes 1a and 1b.
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Table 1 Optimization of direct addition of acetonitrile to heptanal (2a) with cationic Ru complex and DBUa
Entry
Ru catalyst
x 5
y 5
NaPF6 (mol%)
Time (h)
Yield (%)
1
2
3
4
none
0
10
10
10
10
10
50
50
50
50
50
25
0
0
10
0
0
0
24
24
24
10
10
10
0
54
38
64
82
76
CpRu(PPh3)(CH3CN)2PF6 (1a)
CpRu(PPh3)(CH3CN)2PF6 (1a)
CpRu(PPh3)2(CH3CN)PF6 (1b)
CpRu(PPh3)2(CH3CN)PF6 (1b)
CpRu(PPh3)2(CH3CN)PF6 (1b)
b
5b
6b
a
0.3 mmol scale. 2a was added slowly over 7 h.
Table 2 Addition of acetonitrile to various enolizable aldehydes 2
with diphosphine Ru complex 1b and DBUa,b
Entry
RCH2CHO
Time (h)
Yield (%)
1
2a
2a
10
10
76
82
2c
3c
2b
10
77
4
2c
2d
10
16
86
85
5d
Fig. 2 Proposed catalytic cycle.
6
7
2e
2f
24
14
63
90
much less likely to form the Ru-DBU complex 6b than the
monophosphine complex 1a, owing to the large steric constraint
around the Ru center.12,13 Thus, the equilibrium between 1b and
6b in the catalytic cycle would strongly favor 1b, accelerating the
catalyst regeneration step (6b to 1b). With 10 mol% of 1b in the
absence of NaPF6, the reaction time was reduced to 10 h and
the chemical yield was improved to 64% (Table 1, entry 4). The
slow addition of 2a further improved the yield of 3a to 82%
(Table 1, entry 5).14 The amount of DBU was successfully
reduced to 25 mol% and 3a{was obtained in 76% yield (Table 1,
entry 6).
8
9
2g
2h
10
14
74
82
10e
11
2i
2j
12
10
87
75
Having determined the suitable reaction conditions for chemo-
selective deprotonation of acetonitrile, the reaction was performed
with a series of a,a-nonsubstituted aldehydes 2 (Table 2).15,16 In
entries 1–5, deprotonation of acetonitrile proceeded chemoselec-
tively and the subsequent addition to acyclic enolizable aldehydes
2a–d afforded the desired product in good yield. The reaction with
2e resulted in moderate yield, probably due to an undesired
reaction at the unsaturated bond (entry 6). Carbamate and ester
functionality were tolerated without any side reactions (entries 8
and 9). The reaction proceeded smoothly with aldehyde 2i bearing
a
b
0.3 mmol scale. Aldehyde was added slowly over 7 h. 50 mol%
c
d
of DBU was used. Aldehyde was added slowly over 12 h.
Aldehyde was added as HMPA solution.
e
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A. Bøgevig, N. Kumaragurubaran and K. A. Jørgensen, Chem.
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a free OH group (87%, entry 10), which is not compatible with
reaction conditions using metalated nitriles. 2j was successfully
converted into the corresponding b-hydroxynitrile in 75% yield
and the methylketone moiety of 2j served as neither an electrophile
nor a pro-nucleophile under the standard conditions, highlighting
the highly chemoselective nature of the present catalysis. When 2c
or 2j was treated with 10 mol% of KOtBu at 0 uC, the reaction
mixture became complicated and b-hydroxynitrile 3 was obtained
in less than 5% yield.
In summary, we developed suitable reaction conditions for
chemoselective nucleophilic activation of acetonitrile in the
presence of enolizable aldehydes. The use of a stable diphosphine
Ru complex gave b-hydroxynitrile 3 in good yield (63–90%). The
chemoselective deprotonation despite the large pKa gap is
noteworthy. Further studies to develop an enantioselective variant
are in progress.
5 In DMSO, see: (a) F. G. Bordwell, Acc. Chem. Res., 1988, 21, 456; in
H2O, see: (b) J. P. Richard, G. Williams and J. Gao, J. Am. Chem. Soc.,
1999, 121, 715.
6 (a) J. G. Verkade and P. Kisanga, Aldrichimica Acta, 2004, 37, 3; (b)
Y. Suto, N. Kumagai, S. Matsunaga, M. Kanai and M. Shibasaki, Org.
Lett., 2003, 5, 3147; (c) T. Bunlaksananusorn, A. L. Rodriguez and
P. Knochel, Chem. Commun., 2001, 745 for an example of Ir catalyzed
C–H activation of simple alkylnitrile for C–C bond cleavage, see: (d)
H. Terai, H. Takaya and S.-I. Murahashi, Synlett, 2004, 2185.
7 J. P. Guthrie and J. Cossar, Can. J. Chem., 1986, 64, 2470.
8 N. Kumagai, S. Matsunaga and M. Shibasaki, J. Am. Chem. Soc., 2004,
126, 13632. In ref. 8, a-mono substituted aldehdye (cyclohexanecarbox-
aldehyde) was also used as an electrophile. a-Mono substituted
aldehdyes are, however, much more robust against self-aldol reaction
than a,a-nonsubstituted, linear, aldehdyes due to steric factors.
9 Reviews for general use of cationic CpRu complex, see: (a) B. M. Trost,
F. D. Toste and A. B. Pinkerton, Chem. Rev., 2001, 101, 2067; (b)
C. Slugovc, E. Ru¨ba, R. Schmid, K. Kirchner and K. Mereiter,
Monatsh. Chem., 2000, 131, 1241. An excellent example of Ru catalyzed
in-situ activation of malonate as nucleophile, see: (c) M. Watanabe,
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10 NMR chemical shift (CDCl3) of Ru(1a)-bounded CH3CN was
downfielded (1H: d 2.12 ppm, 13C: d 3.8 ppm) in comparison with
that of free CH3CN (1H: d 1.93 ppm. 13C: d 1.97 ppm); For an example
of Lewis acid–amine (more than stoichiometric amount) cooperative
deprotonation of acetonitrile: T. Sugasawa and T. Toyoda, Synth.
Commun., 1979, 9, 553.
We thank financial support by Grant-in-Aid for
Encouragements for Young Scientists (B) and for Specially
Promoted Research from JSPS and MEXT. NK thanks JSPS
Research Fellowship for Young Scientists. We thank Dr. M.
Kanai and Mr. Y. Suto for useful discussion.
Notes and references
{ Representative procedure: A test tube was charged with magnetic stirrer
bar and MS 4A (240 mg) under Ar. MS 4A was flame-dried under reduced
pressure (ca. 0.7 kPa) for 5 minutes. After cooling, to the flask were added
CpRu(PPh3)2(CH3CN)PF6 (1b) (500 mL, 0.03 mmol, 0.06 M/CH3CN), dry
CH3CN (100 mL) and HMPA (200 mL) successively under Ar and stirred at
room temperature. To the mixture was added DBU (11.2 mL, 0.075 mmol)
at room temperature, and resulting mixture was degassed. After warming
up to 50 uC, heptanal (2a) (42.3 mL, 0.3 mmol) was added over 7 h via
syringe drive. After stirring for 24 h at 50 uC, the mixture was quenched
with 1 M HCl and extracted with diethyl ether. The combined organic
layers were washed with sat. NaHCO3 aq. and brine, then dried over
Na2SO4. The organic solvent was evaporated and resulting crude mixture
was purified by flash column chromatography (SiO2, eluent: hexane/ethyl
acetate 4/1) to give 3a (35.3 mg, 0.227 mmol, 76% yield) as a colorless oil.
11 Ru-DBU complex was unstable and gradually decomposed to give
PPh3LO and Ru black. Furthermore, considering the spatial arrange-
ment of ligands in CpRu-DBU complex, ligated DBU is positioned too
far away to deprotonate acetonitrile intramolecularly.
1 (a) R. Mahrwald, Ed. Modern Aldol Reactions, Wiley-VCH, Weinheim,
2004; (b) B. M. Trost and I. Fleming, Eds. Comprehensive Organic
Synthesis, vol 2, Pergamon, Oxford, 1991.
12 See Electronic Supplementary Information (ESI) for details.
13 In the present studies, only CpRu complexes were examined, because
bulkier Cp*Ru complexes showed lower reactivity than CpRu
complexes in the initial screening using benzaldehyde as an electrophile.
14 Slow addition of 2a in the presence of NaPF6 resulted in a worse result.
15 Further condensation of product 3 with aldehyde was negligible. Only
trace, if any, dehydrated adducts were observed. Sterically less crowded
acetonitrile would coordinate more easily to the Ru center than product
3. In addition, the excess amount of acetonitrile exists in the reaction
mixture. Thus, nucleophilic activation of product 3 would effectively be
prevented.
16 At the moment, 10 mol% of the Ru complex and 25–50 mol% of DBU
are required to obtain products in good yield. Substrate generality of
nitriles also remained unsolved. Only acetonitrile was used in the present
studies. Further trials to reduce catalyst loading and broaden substrate
generality are in progress.
2 Selected leading references in direct aldol reactions, reviews: (a)
B. Alcaide and P. Almendros, Eur. J. Org. Chem., 2002, 1595; (b)
B. List, Tetrahedron, 2002, 58, 5573 metal catalyzed direct aldol
reactions, see: (c) Y. M. A. Yamada, N. Yoshikawa, H. Sasai and
M. Shibasaki, Angew. Chem. Int. Ed., 1997, 36, 1871; (d) N. Yoshikawa,
Y. M. A. Yamada, J. Das, H. Sasai and M. Shibasaki, J. Am. Chem.
Soc., 1999, 121, 4168; (e) B. M. Trost and H. Ito, J. Am. Chem. Soc.,
2000, 122, 12003; (f) R. Mahrwald and B. Ziemer, Tetrahedron Lett.,
2002, 43, 4459; (g) D. A. Evans, C. W. Downey and J. L. Hubbs, J. Am.
Chem. Soc., 2003, 125, 8706; (h) G. Lalic, A. D. Aloise and M. D. Shair,
J. Am. Chem. Soc., 2003, 125, 2852 and references cited therein; direct
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C. F. Barbas, III, J. Am. Chem. Soc., 2000, 122, 2395; (j) W. Notz and
B. List, J. Am. Chem. Soc., 2000, 122, 7386; (k) K. Sakthivel, W. Notz,
T. Bui and C. F. Barbas, III, J. Am. Chem. Soc., 2001, 123, 5260; (l)
S. Saito, M. Nakadai and H. Yamamoto, Synlett, 2001, 1245; (m)
3602 | Chem. Commun., 2005, 3600–3602
This journal is ß The Royal Society of Chemistry 2005