P(i-PrNCH2CH2)3N as a Lewis base catalyst for the synthesis of β-hydroxynitriles using TMSAN

Article abstract of DOI:10.1021/jo900814t

(Equation Presented) Proazaphosphatrane 1a was found to be an efficient catalyst for synthesis of β-hydroxynitriles via the reaction of trimethylsilylacetonitrile (TMSAN) with aldehydes under mild reaction conditions and typically low catalyst loading (ca. 2 mol %). A variety of functional groups were tolerated, and good to excellent product yields were obtained.

Full text of DOI:10.1021/jo900814t

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(for example, (CH3)2CHMgBr, BuLi, or alkali amides) to
P(i-PrNCH2CH2)3N as a Lewis Base Catalyst for the
Synthesis of β-Hydroxynitriles Using TMSAN
deprotonate the R proton of acetonitrile or benzyl nitrile
to generate a nucleophile that attacks the carbonyl group.6
Low yields commonly encountered with these methods6 have
been attributed7 to reversibility of the reaction or facile
product dehydration to give R,β-unsaturated nitriles.
Kuldeep Wadhwa and John G. Verkade*
Department of Chemistry, Gilman Hall, Iowa State
University, Ames, Iowa 50011
More recently, several other methods aimed at improving
the yields of β-hydroxynitrile syntheses have appeared in the
literature.8 Using an equivalent amount of n-BuLi, addi-
tional TMSCl was added to trap the alkoxide, resulting in a
favorable shift of the equilibrium.8a Other reported methods
include the use of toxic metal catalysts such as Mn/PbCl2/
TMSCl,8d Hg(ONC)2,3 and PbCl2/Ga.8k A two-step synth-
esis of β-hydroxynitriles has been reported involving the
prior generation of an aryl anion using aryl halide in an
electrochemical cell,8e which then deprotonates acetonitrile
for subsequent addition of the resulting anion to ketones,
aldehydes, alkyl halides, and esters. However, this method
is cumbersome, providing only poor to moderate product
yields (52-74%). Another commonly utilized approach is
the use of 1,2-epoxides in the presence of a nitrile or LiClO4/
KCN to promote nucleophilic ring-opening of the epoxide.
However, this method generally favors the use of aliphatic
epoxides, and yields vary from 35 to 98%.8f-8j Additional
reported methods for the synthesis of β-hydroxynitriles
involve multistep approaches.8l,8m
TMSAN has been utilized for prior formation of the
O-silyl ether in several attempts to overcome the reaction
reversibility problem. In one such reaction, β-hydroxyni-
triles were produced in 70-73% yield via acid hydrolysis of
the O-silyl adduct formed via the use of toxic potassium
cyanide as the catalyst.9a The use of KF as a catalyst resulted
in quantitative conversion of the O-silyl ether to product, but
25 mol % of KF was required, and only benzaldehyde was
explored as a substrate.9b KF (50 mol %) loaded on alumina
jverkade@iastate.edu
Received April 20, 2009
Proazaphosphatrane 1a was found to be an efficient
catalyst for synthesis of β-hydroxynitriles via the reaction
of trimethylsilylacetonitrile (TMSAN) with aldehydes
under mild reaction conditions and typically low catalyst
loading (ca. 2 mol %). A variety of functional groups were
tolerated, and good to excellent product yields were
obtained.
Carbon-carbon bond-forming reactions are extensively
utilized in modern organic synthesis,1 and one of the most
common approaches to this process is via nucleophilic
addition to carbonyl compounds.1 β-Hydroxynitriles are
important building blocks in many natural product synth-
eses2 owing to the stability of nitriles to handling3 and the
versatility of the nitrile group to conversion to a variety of
other functionalities such as amines,4a amides,4b aldehydes,4c
esters,4d alcohols,4e or carboxylic acids.5
(6) (a) Kaiser, E. W.; Hauser, C. R. J. Am. Chem. Soc. 1967, 89, 4566–
4567. (b) Kaiser, E. W.; Hauser, C. R. J. Org. Chem. 1968, 33, 3402–3404. (c)
Li, N.-S.; Yu, S.; Kabalka, G. W. J. Org. Chem. 1995, 60, 5973–5974.
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Chem. 1999, 64, 3090–3094. (c) Kumagai, N.; Matsunaga, S.; Shibasaki, M.
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Generally, β-hydroxynitriles have been synthesized with
the aid of an equivalent amount of strong alkali metal base
*Corresponding author. Tel: þ1-515-294-5023. Fax: þ1-515-294-0105.
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Oxford, 1991; Vol. 2, pp 1-502.
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DOI: 10.1021/jo900814t
r
Published on Web 06/25/2009
J. Org. Chem. 2009, 74, 5683–5686 5683
2009 American Chemical Society

Wadhwa and Verkade
JOCNote
TABLE 1. Survey of Proazaphosphatranes as Catalysts for the Synth-
esis of β-Hydroxynitrilesa
entry
catalyst
mol %
yield of 3b (%)
1c
2
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
10
10
10
5
4
2
1
2
2
2
30
46
45
56
FIGURE 1. Proazaphosphatranes.
3d
4
with prior catalyst activation at 673 K using benzaldehyde as
the sole substrate gave a low yield of product plus 15% of
R,β-unsaturated nitrile.9d Utilizing 10 mol % of tris(di-
methylamino)sulfonium difluorotrimethylsiliconate (TASF)
at -15 °C resulted in product yields of 20-93% for a variety
of aldehydes and ketones.9c Using 2.5 mol % of [Cu(PPh3)3]-
[(EtO)3SiF2] as a catalyst in the presence of 1.2 equiv of
(EtO)3SiF as an additive for the cyanomethylation of alde-
hydes using TMSAN5 gave good product yields (75-100%),
but no scope of functional groups was reported. The use
of LiOAc and CsOAc as Lewis base catalysts has been
described,7 and although the yields are good, a high catalyst
loading (10 mol %) as well as a relatively inconvenient
solvent (DMF) is required. Piperidine (24 mol %) functioned
as a catalyst under microwave conditions in the absence of
solvent, but product yields were low to moderate (ca. 38-
73%), and reactions were typically conducted at elevated
temperature (85 °C).9e Recently, Kitazaki et al. reported the
use of tris(2,4,6-trimethoxyphenyl)phosphine (10 mol %) for
TMSAN addition to aldehydes and ketones with product
yields of 56-99% and to imines with 0-85% product yields
in DMF and DMPU.9f
5
6
7
8
9
10
74
91e
86
87e
90e
90e
aReaction conditions: (a) aldehyde (2 mmol), TMSAN (2.4 mmol),
THF (2 mL), 0 °C, 24 h, 1 N HCI (3 mL). bIsolated yield after silica gel
column chromatography. cReaction was carried out at rt. dReaction was
carried out at -15 °C. eAverage of three runs.
β-hydroxynitriles from aldehydes with TMSAN as shown
in the Abstract graphic.
To optimize the reaction conditions, we chose the reaction
of p-tolualdehyde with TMSAN (Table 1) as a model. We
selected proazaphosphatrane 1a as the screening catalyst
owing to its efficiency in this reaction and its commercial
availability.13 Using 10 mol % of 1a at room temperature,
dehydration to the corresponding R,β-unsaturated nitrile
dominated β-hydroxynitrile formation (Table 1, entry 1).
Lowering the temperature to 0 °C under the same conditions
increased the yield of the desired product to 46% (entry 2),
but lowering the temperature to -15 °C revealed essentially
no change in product yield (entry 3).
Since higher loading of a basic catalyst can lead to unde-
sired formation of R,β-unsaturated nitrile via a Peterson
olefination pathway,14 we reduced the catalyst loading to
5 mol % and found that the yield of β-hydroxynitrile was
substantially enhanced (Table 1, entry 4). Further lowering of
the catalyst loading increased the yield of β-hydroxynitrile to 74
and 91% (entries 5 and 6, respectively). However, lowering the
catalyst loading below 2% inhibited completion of the reaction,
resulting in only a good product yield (86%, entry 7). Thus, we
decided to proceed with 2 mol % catalyst at 0 °C to screen
proazaphosphatranes 1b-d, and those results are also summar-
ized in Table 1 (entries 8-10). We found that changing the R
group on the PN3 nitrogens gave comparable yields of the
desired product, although 1a was slightly better than the others.
We do not have a reasonable explanation for this observation.
Given the higher activity of 1a as a catalyst and its
commercial availability, we proceeded with 1a under the
conditions optimized in Table 1, entry 6, to extend the scope
of our protocol for the synthesis of β-hydroxynitriles. Thus, a
variety of aromatic and aliphatic aldehydes were employed
under the optimized conditions in Table 1, entry 6. The
product yields shown in Table 2 are comparable in most
We previously found10 that proazaphosphatranes (1)bearing
various organic groups on the PN3 nitrogens (Figure 1) are
strongly basic with pKa values of the their P-protonated
NbasalfP transannulated conjugate acids in the range 32-34
in MeCN.11 To the extent that NbasalfP transannulation may
be occurring during reactions catalyzed by 1, the nucleophilicity
of the phosphorus may be enhanced.10b We previously reported
reactions in which proazaphosphatranes can activate silicon
functionalities as, for example, in the silylation of alcohols using
silyl chloride,12a,12b synthesis of cyanohydrins from the addition
of trimethylsilyl nitrile to carbonyl compounds,12c,12d desilyla-
tion of TBDMS ethers,12e nucleophilic aromatic substitution of
aryl fluorides with aryl silyl ethers,12f,12g allylation of aromatic
aldehydes,12h and reduction of aldehydes and ketones using
poly(methylhydrosiloxane).12i
In the present work, we report the use of proazapho-
sphatrane 1a as an efficient catalyst for the synthesis of
(10) For reviews on proazaphosphatrane chemistry, see: (a) Verkade, J.
G. New Aspects of Phosphorus Chemistry II. In Top. Curr. Chem. Majoral, J.
P., Ed. 2002, 233, 1-44. (b) Verkade, J. G.; Kisanga, P. B. Tetrahedron 2003, 59,
7819–7858. (c) Verkade, J. G.; Kisanga, P. B. Aldrichim. Acta 2004, 37, 3–14.
(d) Urgaonkar, S.; Verkade, J. G. Specialty Chem. 2006, 26, 36–39.
(11) Kisanga, P. B.; Verkade, J. G.; Schwesinger, R. J. Org. Chem. 2000,
65, 5431–5432.
(12) (a) D’Sa, B. A.; Verkade, J. G. J. Am. Chem. Soc. 1996, 118, 12832–
12833. (b) D’Sa, B. A.; McLeod, D.; Verkade, J. G. J. Org. Chem. 1997, 62,
5057–5061. (c) Wang, Z.; Fetterly, B. M.; Verkade, J. G. J. Organomet.
Chem. 2002, 646, 161–166. (d) Fetterly, B. M.; Verkade, J. G. Tetrahedron
Lett. 2005, 46, 8061–8066. (e) Yu, Z.; Verkade, J. G. J. Org. Chem. 2000, 65,
2065–2068. (f) Urgaonkar, S.; Verkade, J. G. Org. Lett. 2005, 7, 3319–3322.
(g) Raders, S. M.; Verkade, J. G. Tetrahedron Lett. 2008, 49, 3507–3511. (h)
Wang, Z.; Kisanga, P.; Verkade, J. G. J. Org. Chem. 1999, 64, 6459–6461. (i)
Wang, Z.; Wroblewski, A. E.; Verkade, J. G. J. Org. Chem. 1999, 64, 8021–
8023.
(13) Proazaphosphatranes 1a, 1c, and 1d are commercially available.
(14) (a) Kojima, S.; Fukuzaki, T.; Yamakawa, A.; Murai, Y. Org. Lett.
2004, 6, 3917–3920. (b) Palomo, C.; Aizpurua, J. M.; Aurrekoetxea, N.
Tetrahedron Lett. 1990, 31, 2209–2210. (c) Birkofer, L.; Ritter, A.; Wieden,
H. Chem. Ber. 1962, 95, 971–976. (d) Matsuda, I.; Murata, S.; Ishii, Y. J.
Chem. Soc., Perkin Trans. 1 1979, 26–30. (e) Yamakado, Y.; Ishiguro, M.;
Ikeda, N.; Yamamoto, H. J. Am. Chem. Soc. 1981, 103, 5568–5570.
5684 J. Org. Chem. Vol. 74, No. 15, 2009

Wadhwa and Verkade
JOCNote
TABLE 2. Scope of the Reaction of Aldehydes with TMSAN Catalyzed
by 1aa
TABLE 3. Scope of the Reaction of Heterocyclic Aldehydes with
TMSAN Catalyzed by 1aa
aReaction conditions: (a) aldehyde (2 mmol), TMSAN (2.4 mmol), 1a
(2 mol %), THF (2 mL), 0 °C, 24 h, 1 N HCl (3 mL). bIsolated yield after
column chromatography. cSee ref 7. dSee ref 9f.
aReaction conditions: (a) aldehyde (2 mmol), TMSAN (2.4 mmol), 1a
(2 mol %), THF (2 mL), 0 °C, 24 h, 1 N HCl (3 mL). bIsolated yield after
column chromatography. cSee ref 9a. dSee ref 9b. eSee ref 9c. fSee ref 5.
gSee ref 7. hSee ref 9e. iSee ref 9f.
SCHEME 1. Proposed Mechanism of TMSAN Addition to
Aldehydes
cases to those reported in the literature. Both electron-
donating and -withdrawing groups afforded excellent iso-
lated yields, with only a trace of or no dehydrated product
detectable by 1H NMR spectroscopy. Electron-donating
groups such as methyl (Table 1, entry 6), methoxy at both
para and ortho positions (Table 2, entries 2 and 3), and
halogen (Table 2, entry 4) were tolerated under our condi-
tions, giving excellent isolated product yields. Electron-with-
drawing groups such as p-nitro (entry 6), m-cyano (entry 7),
and p-ester (entry 8) were also well tolerated, affording the
desired respective products in excellent isolated yields. trans-
Cinnamaldehyde gave the desired product in good isolated
yield (entry 9) with no observable evidence from NMR
spectroscopy of the corresponding Michael addition pro-
duct. Aliphatic enolizable aldehydes also gave good iso-
lated product yields (Table 2, entries 10 and 11). Unfortu-
nately, our methodology was ineffective for the ketones
tested (acetophenone, 4-chloroacetophenone, and benzo-
phenone).
excellent to good yields, respectively; N-containing 2-formyl-1-
methylindole gave an excellent isolated product yield (entry 6);
the S,N-heterocycle in entry 7 facilitated an excellent yield of
product; and the benzofuran, coumarin, and furan carboxal-
dehydes in entries 8, 9, and 10 permitted a modest, moderate,
and good yield of products, respectively. The moderate product
yield in entry 9 was pleasantly surprising in view of the
sensitivity of lactones to acid and base.
With a range of 5- and 6-membered ring heterocycle-bearing
aldehydes possessing representation of O-, N- and S-hetero-
cycle types, good to excellent yields of the desired product were
obtained (Table 3). Thus, the thiophenic aldehydes in entries
1 and 2 gave very good and excellent product yields, respec-
tively; the pyridinyl aldehydes in entries 3 and 4 and quinolyl
aldehyde in entry 5 afforded the corresponding products in
J. Org. Chem. Vol. 74, No. 15, 2009 5685

Wadhwa and Verkade
JOCNote
SCHEME 2. Alternative Proposed Mechanism of TMSAN
Addition to Aldehydes
the basis of their increased steric hindrance in the formation
of intermediates C and D.
In summary, commercially available 1a is an excellent
catalyst for the synthesis of β-hydroxynitriles via the reaction
of TMSAN with aldehydes. Our reaction conditions are
mild, and our catalyst loadings are the lowest we were able
to find in the literature for this transformation. In the case of
aryl aldehydes, both electron-withdrawing and -donating
groups are well tolerated, both heterocyclic and aliphatic
aldehydes function well, and both acid- and base-sensitive
functionalities favor the reaction. Comparing our yields to
the maximum yields for seven different methods in the
literature using seven different catalyst systems, our yields
were lower in two cases, comparable ((5%) in four cases,
and higher in one case. For the two literature yields that were
larger than ours, one literature preparation involved the use
of LiOAc in DMF and in the other 2.5 mol % of [Cu(PPh3)3]-
[(EtO)3SiF2] and 120 mol % of (EtO)3SiF as an additive
were present. In Table 3 our yields for two substrates
when compared to the maximum yields in the literature
were comparable in one case ((5%) and lower in the other;
the literature method for these two cases involved the use
of 10 mol % of LiOAc in DMF. From an environ-
mental standpoint, it is worth noting that our catalyst is
metal-free.
A proposed mechanistic pathway for the addition of
TMSAN to aldehydes is shown in Scheme 1. To obtain some
insight into this pathway, we carried out 29Si NMR experi-
ments at -40 °C in which a THF solution of TMSAN (δ29Si
5.02 ppm in THF) was treated with an equimolar amount of
1a. A new peak, which then appeared at δ29Si 9.16, was
attributed to the tetracoordinate silicon species B in which
the anionic CH2CN- has been displaced. This chemical shift
is in the same region as a peak we reported previously for a
1:1 mixture of TMSCN and 1d in C6D6 (δ29Si 7.5) in which
CN- had been displaced. If the anion had not been displaced
in both cases, an upfield rather than a downfield shift from
the parent TMSX molecule would have been observed since
the silicon would have become 5-coordinate.12c We used
similar reasoning to account for the formation of both
R- and γ-addition products in the reaction of crotyltri-
methylsilane with aldehydes in the presence of 1a.12h After
transient A forms B in Scheme 1, an aldehyde molecule reacts
with CH2CN- to form the alkoxide shown, which after
trimethylsilylation is acid-hydrolyzed to give the corre-
sponding β-hydroxynitrile as the final product, plus the
regenerated catalyst 1a. Although we have 29Si NMR evi-
dence consistent with the formation of B, we have no
convincing 31PþNMR evidence for this species. 31P chemical
shifts for PR4 cations are generally in the range of 90-
140 ppm.15 The chemical shift for B is 119 ppm at -40 °C in
THF, which is virtually unchanged from the value of 1a
under the same conditions. This result perhaps suggests a
minimal perturbation of the phosphorus shielding environ-
ment as a result of a weak Si-P interaction.
Experimental Section
General Reaction Procedure. A round-bottom flask was
charged with the required amount of proazaphosphatrane (1)
(2 mol %) in a nitrogen-filled glovebox. Anhydrous THF
(2.0 mL) was added to the flask via syringe, followed by addition
of TMSAN (2.40 mmol) at 0 °C via syringe under an argon
atmosphere. The reaction mixture was stirred at 0 °C for 15 min,
and then aldehyde (2.0 mmol) was added over a period of 5-10
min. The reaction mixture was stirred for 24 h at 0 °C, and then it
was quenched with 3 mL of aqueous HCl (1 N). The reaction
mixture was stirred at 0 °C for 1 h, and then it was neutralized
with saturated aq NaHCO3 and extracted with CH2Cl2 (3 ꢀ
30 mL). The crude product was purified by column chromato-
graphy on silica gel using 10% EtOAc/hexanes, except for
heterocyclic substrates, in which case 20-25% EtOAc/hexanes
was used as the eluent.
Acknowledgment. We are grateful to the Aldrich Chemical
Co. for their generous gift of 1a. The National Science
Foundation is gratefully acknowledged for financial support
of this research through Grant No. 0750463. We also thank Dr.
Ch. Venkat Reddy for helpful discussions.
Since six-coordinate silicon species are also well-known,
A in Scheme 1 may undergo nucleophilic attack by the
carbonyl oxygen of the aldehyde to give rise to the six-
coordinate intermediate C shown in Scheme 2. This inter-
mediate may then decompose to product and regenerated
catalyst 1a via the 4-center intermediate depicted in D. The
unreactivity of ketones in our protocol can be rationalized on
Supporting Information Available: Complete experimental
1
details, references to the known compounds, copies of H and
13C NMR spectra for all products, and HRMS spectral reports
for new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(15) Handbook of Phosphorus Nuclear Magnetic Resonance Data; Tebby,
J. C., Ed.; CRC Press Inc.: Boca Raton, 1991.
5686 J. Org. Chem. Vol. 74, No. 15, 2009