Metal-free reductive cleavage of C-O σ-bonds in acyloin derivatives by an organic neutral super-electron-donor

Article abstract of DOI:10.1021/jo901815t

(Chemical Equation Presented) Neutral organic electron-donor 7, formally a pyridinylidene carbene dimer, effects reductive cleavage of C-O σ-bonds in acyloin derivatives Ar(CO)CRR′OX (X = OAc, OPiv, OBz, OMs) and this represents the first cleavage of C-O σ-bonds by a neutral organic electron-donor. The methodology is applicable to a large array of substrates and the reduced counterparts were isolated in good to excellent yields. For certain substrates, donor 7 behaves as a base, effecting condensation reactions with some acetate ester derivatives of acyloins, leading to butenolides. The variation in reactivity among the different substrates was rationalized. 2009 American Chemical Society.

Full text of DOI:10.1021/jo901815t

pubs.acs.org/joc
Metal-Free Reductive Cleavage of C-O σ-bonds in Acyloin Derivatives
by an Organic Neutral Super-Electron-Donor†
Sylvain P. Y. Cutulic,‡ Neil J. Findlay,‡ Sheng-Ze Zhou,‡ Ewan J. T. Chrystal,§ and
John A. Murphy*,‡
‡WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham
Building, 295 Cathedral Street, Glasgow, G1 1XL, United Kingdom, and §Syngenta, Research International
Centre, Bracknell RG42 6EY, United Kingdom
john.murphy@strath.ac.uk
Received August 24, 2009
Neutral organic electron-donor 7, formally a pyridinylidene carbene dimer, effects reductive cleavage
of C-O σ-bonds in acyloin derivatives Ar(CO)CRR0OX (X = OAc, OPiv, OBz, OMs) and this
represents the first cleavage of C-O σ-bonds by a neutral organic electron-donor. The methodology
is applicable to a large array of substrates and the reduced counterparts were isolated in good to
excellent yields. For certain substrates, donor 7 behaves as a base, effecting condensation reactions
with some acetate ester derivatives of acyloins, leading to butenolides. The variation in reactivity
among the different substrates was rationalized.
Introduction
long been efficiently synthesized from esters by the acyloin
condensation by using dissolving metals, with or without
trimethylchlorosilane.2 Spectacular recent advances have
greatly increased access to acyloins and related compounds,
using aldehydes and ketones in reactions that are mediated
by N-heterocyclic carbenes present either as enzyme cofac-
tors3 or as reagents in organic solution.4,5
The assembly of the two carbonyl components to form an
acyloin is a useful C-C bond formation, but the products
have wider use when they can be converted into simple
ketones by reductive cleavage of the R-hydroxy group.
Methodologies have been developed recently to perform this
reductive C-O bond cleavage. Yamaguchi reduced benzoin
derivatives using a complex system containing 1,3-propane-
dithiol, N-methylmorpholine, and tetrabutylammonium
fluoride hydrate. (We assume that this works through oxida-
tion of the thiolate.6) Metal-based methodologies have also
been developed: acyloin derivatives have been successfully
Benzoins are classically prepared by the cyanide-mediated
benzoin condensation of aromatic aldehydes,1 and, more
generally, acyloins (R-hydroxyketones and aldehydes) have
† This paper is dedicated to the memory of the late Dr. Ewan J. T. Chrystal.
(1) Woehler, F.; von Liebig, J. Ann. Pharm. 1832, 3, 249–282. Lapworth,
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1971, 236–253. Makosza, M.; Grela, K. Synlett 1997, 267–268. Kashimura,
S.; Murai, Y.; Ishifune, M.; Masuda, H.; Murase, H.; Shono, T. Tetrahedron
Lett. 1995, 36, 4805–4808. Bloomfield, J. J.; Owsley, D. C.; Ainsworth, C.;
Robertson, R. E. J. Org. Chem. 1975, 40, 393–402.
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34, 530–542. Muller, M.; Gocke, D.; Pohl, M. FEBS J. 2009, 276, 2894–2904.
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Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719–3726. Stetter, H.; Ramsch,
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Enders, D.; Kallfass, U. Angew. Chem., Int. Ed. 2002, 41, 1743–1745.
Dudding, T.; Houk, K. N. Proc. Nat. Acad. Sci. U.S.A. 2004, 101, 5770–
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2007, 107, 5606–5655. Rovis, T. Chem. Lett. 2008, 37, 2–7. Enders, D.;
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DOI: 10.1021/jo901815t
r
Published on Web 10/21/2009
J. Org. Chem. 2009, 74, 8713–8718 8713
2009 American Chemical Society

Cutulic et al.
JOCArticle
SCHEME 1. Reduction of Substrates by Super-Electron-Donors 1, 4, and 7
reduced into their ketone counterparts with use of zinc and
ammonium chloride in ethanol under reflux,7 titanium on
activated graphite,8 Raney nickel,9 or metallic salts, such as
titanium chloride in combination with zinc10 or samarium-
(II) diiodide.11 Alternative approaches have used phenyldi-
methylsilyllithium12 and a vanadium complex [V2Cl3-
(THF)6]2[Zn2Cl6], prepared in situ from vanadium trichlor-
ide and zinc dust.13 Hence this is a very active area of wide
interest to synthetic chemists.
Our aim was to develop a tailored organic reagent for this
reduction. Along these lines, neutral ground state “super-
electron-donor” reagents [defined as organic ground state
electron-donors that are powerful enough to dehalogenate
haloarenes] have recently been developed in our
laboratories.14-20 Reagent 1, formally a dimer of a benzimi-
dazolylidene carbene, reduced aryl and alkyl iodides to aryl
and alkyl radicals, respectively; in appropriate substrates,14
these radicals underwent cyclization reactions as shown for
iodoarene 2 in Scheme 1. Recently, two more powerful
neutral ground state electron-donors, 4 and 7, have been
developed within our laboratories.15-20 These reagents read-
ily transfer two electrons, converting aryl iodides into aryl
anions, performing reductive cleavages of sulfones and
reductively cleaving N-O bonds in Weinreb amides
(Scheme 1).19 This paper now explores the first cleavages
of C-O σ-bonds with the strong, neutral organic electron-
donor 7.
SCHEME 2. Reduction of Substrates 14 with Donor 7, Pre-
pared in Situ from Salt 13
(7) Yao, Z.; Ye, D.; Liu, H.; Chen, K.; Jiang, H. Synth. Commun. 2007,
37, 149–156.
(8) Fuerstner, A.; Jumbam, D. N. Tetrahedron 1992, 48, 5991–6010.
(9) Satoh, T.; Hayashi, Y.; Mizu, Y.; Yamakawa, K. Tetrahedron Lett.
1992, 33, 7181–7184.
(10) Fuerstner, A.; Hupperts, A.; Ptock, A.; Janssen, E. J. Org. Chem.
1994, 59, 5215–5229.
(11) Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102,
2693–2698.
Results and Discussion
(12) Fleming, I.; Roberts, R. S.; Smith, S. C. J. Chem. Soc., Perkin Trans.
1 1998, 1215–1228.
Acyloins were purchased commercially or prepared by
reaction of N-heterocyclic carbenes with the appropriate
aldehydes. The acyloin OH groups were then converted into
ether and ester derivatives.
(13) Inokuchi, T.; Kawafuchi, H.; Torii, S. Chem. Lett. 1992, 1895–1896.
(14) Murphy, J. A.; Khan, T. A.; Zhou, S.; Thomson, D. W.; Mahesh, M.
Angew. Chem., Int. Ed. 2005, 44, 1356–1360. This work emanated from
previous electron transfer studies with tetrathiafulvalene: Fletcher, R. J.;
Lampard, C.; Murphy, J. A.; Lewis, N. J. Chem. Soc., Perkin Trans. 1 1995,
623–633. Lampard, C.; Murphy, J. A.; Lewis, N. J. Chem. Soc., Chem.
Commun. 1993, 295–297.
(15) Murphy, J. A.; Zhou, S.; Thomson, D. W.; Schoenebeck, F.;
Mahesh, M.; Park, S. R.; Tuttle, T.; Berlouis, L. E. A. Angew. Chem., Int.
Ed. 2007, 46, 5178–5183.
(16) Schoenebeck, F.; Murphy, J. A.; Zhou, S.; Uenoyama, Y.; Miclo, Y.;
Tuttle, T. J. Am. Chem. Soc. 2007, 129, 13368–13369.
(17) Murphy, J. A.; Garnier, J.; Park, S. R.; Schoenebeck, F.; Zhou, Z.-S.;
Turner, A. T. Org. Lett. 2008, 10, 1227–1230.
(18) Garnier, J.; Murphy, J. A.; Zhou, S.-Z.; Turner, A. T. Synlett 2008,
2127–2131.
Different substrates were reacted as shown in Scheme 2
with electron-donor 7, prepared in situ from precursor 13.17
Results of these reactions are summarized in Table 1. Methy-
lated benzoin derivative 14a was first selected. At 20 °C, no
reaction was seen. Even when the temperature of the reaction
mixture was brought to 100 °C, very little reductive C-O
bond cleavage was observed (tentative identification was
estimated at 5% maximum from the 1H NMR spectrum of
the unpurified reaction mixture). However, when the meth-
oxy group was replaced by a more electron-withdrawing
group (substrates 14b-e) efficient reduction was achieved at
room temperature to afford desoxybenzoin 15 in excellent
(19) Cutulic, S. P. Y.; Murphy, J. A.; Farwaha, H.; Zhou, S.-Z.; Chrystal,
E. Synlett 2008, 2132–2136.
(20) Murphy, J. A.; Schoenebeck, F.; Findlay, N. J.; Thomson, D. W.;
Zhou, S.-Z.; Garnier, J. J. Am. Chem. Soc. 2009, 131, 6475–6479.
8714 J. Org. Chem. Vol. 74, No. 22, 2009

Cutulic et al.
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TABLE 1. Reduction of Substrates 14 with Donor 7
aFrom 1H NMR spec of crude reaction product.
yields (93-98%). The reaction was then successfully ex-
tended to benzoin-related compounds with either electron-
withdrawing substituents (entries 14f-k) or electron-donat-
ing substituents (14l,m) on the arene rings. In both cases,
C-O bond reductive cleavage was performed with 1.5 equiv
of donor 7 at room temperature and their reduced counter-
parts 16, 17, and 18 were isolated in excellent yields
(92-98%). The same reaction also proved successful on
benzoin-related compounds derived from either furans
(14n,o) or naphthalenes (14p,q) to afford their reduced
counterparts 19 and 20 in very good yields (88-94%).
The results can be rationalized (Scheme 3). Initial single
electron transfer (S.E.T.) from the neutral electron-donor 7
to the LUMO of the substrate 14 [computations with Spar-
tan (Hartree-Fock 6-31G**) indicate that the LUMO is
delocalized over the aroyl unit] generates the ketyl radical
SCHEME 3. Reduction of Acyloin Derivatives 14 and Oxida-
tion of Donor 7
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Cutulic et al.
JOCArticle
anion 21, leading to cleavage of the C-O bond and affording
the enolyl radical 22. The latter can then receive another
electron from 7 (or from the radical-cation 24) to generate
enolate 23, protonation of which yields ketone 15. The
electronic character of the O-X group can therefore be
important both for decreasing the energy of the LUMO of
the acyloin system and for facilitating the departure of the
leaving group as an anion.
The use of an organic reducing agent, 7, leads to inter-
mediates such as the ketyl 21 and the enolate 23 that differ
from normal ketyls and enolates in that the counterion
(24/25) is organic. Although the cations 24 and 25 derived
from 7 are potentially electrophilic, the high yields of desired
products obtained indicate that reaction with the intermedi-
ate ketyls 21 and enolates 23 is unfavorable; this is undoubt-
edly influenced by the twist undergone by the cations 24 and
25,17 giving steric protection to the unsubstituted 6-positions
of both pyridinium rings.
With the above benzoin derivatives and analogues, high
yields of reduced products were observed. Substrates 14r-w
(Table 2) then explored the replacement of the aryl group β to
the carbonyl group by aliphatic groups. In the gem-dimethyl
substrates, the mesylate 14r and pivalate 14s examples
afforded the expected product 26 cleanly. However, the
acetate derivative 14t afforded none of the desoxyacyloin
product 26, and instead afforded the butenolide 27 in high
yield (86%).
The related substrates 14u-w were then tested. Once
again, the mesylate 14u and pivalate 14v examples cleanly
afforded the desired desoxy product 28 (63% and 62%,
respectively), while the acetate derivative 14w again afforded
a butenolide, 29, in high yield (85%).
can be easily rationalized, since protonation will lead to the
pyridinium salt 30, and the gain in aromaticity will be a good
driving force for this reaction.
The interesting question that arises is why acetates 14t,w
undergo butenolide formation while the earlier examples
14c,g,j,l,n,p do not. Both the electron transfer to the sub-
strates 14 to form the corresponding radical-anions and the
deprotonation of the acetate substrates are likely to be
endothermic reactions for donor 7, associated with unfavor-
able equilibria. [The first reduction potential of 14c is seen
at Ep = -1.76 V vs. Ag/AgCl/KCl (sat), while that of 14t
occurs at Ep = -1.81 V; the redox potential of 7 is
E1/2(DMF) = -1.13 V17]. Factors that favor one pathway
within these substrates could lead to the observed prefer-
ences. For the radical-anions of the 1,2-diaryl substrates 14c,
g,j,l,n,p, departure of the acetate leaving group affords a very
conjugated π-system spanning both the aryl rings; the transi-
tion state leading to the loss of the acetate anion may
therefore be relatively encouraged. With the gem-dialkyl
substrates 14t,w (entries 3 and 6, Table 2) on the other hand,
loss of the acetate ion does not lead to such extended
conjugation. By contrast, cyclization of the ester enolates
of substrates 14t,w could be accelerated due to the gem-
dialkyl effect and the reactive rotamer effect.21 This effect
would not be present to encourage cyclizations of the ester
enolates of substrates 14c,g,j,l,n,p.
In conclusion, we disclosed a novel reactivity for neutral
electron-donors. Electron-donor 7 reductively cleaves the
C-O σ-bonds of acyloin derivatives in very good yields with
the reaction proving successful for a diverse range of sub-
strates.
Experimental Section
The formation of butenolides from substrates 14t,w merits
comment. By comparison with the pivalates 14s,v these
substrates are similarly activated for electron transfer to
occur from donor 7. However, this reaction is not observed,
and instead the donor acts as a base, transforming the
substrate to an ester enolate 32, which then attacks the
benzoyl carbonyl affording the β-hydroxylactone product
34, which undergoes easy dehydration to give the butenolide
product 35 (Scheme 4). The basic character of the donor 7
Example of the Preparation of Acyloins. 1,2-Bis(4-fluoro-
phenyl)-2-hydroxyethanone: Sodium hydride (0.8 g, 20 mmol,
0.2 equiv) was added to a suspension of 4-fluorobenzaldehyde
(12.4 g, 100 mmol, 1 equiv) and 1,3-dimethyl-1H-imidazol-3-
ium iodide (2.23 g, 10 mmol, 0.1 equiv) in anhydrous tetrahy-
drofuran (150 mL) at room temperature under argon. The
resulting mixture was then heated to reflux under argon over-
night. The reaction mixture was then concentrated under re-
duced pressure and the residue was taken in dichloromethane
(100 mL) and water (100 mL). The aqueous phase was then
washed with dichloromethane (2 ꢀ 100 mL) and the combined
organic fractions were further washed with water (3 ꢀ 100 mL)
and brine (100 mL). The resulting organic phase was eventually
dried over anhydrous sodium sulfate, filtered, and concentrated
under reduced pressure. The crude product was then adsorbed
onto silica and purified by flash chromatography on silica gel
(PE/EtOAc 75/25) to afford 1,2-bis(4-fluorophenyl)-2-hydro-
xyethanone, isolated as a fine yellow powder (9.68 g, 78%): mp.
86-88 °C (lit.22 mp 81-82 °C); νmax (film)/cm-1 3432, 3113,
3076, 2918, 1682, 1599, 1508, 1412, 1387, 1300, 1276, 1234, 1156,
1104, 1075; found [M þ Na]þ (ESþ) 271.0545, C14H10F2O2
requires [M þ Na]þ, 271.0541; δH (CDCl3, 500 MHz) 4.50 (2H,
d, J = 5.9 Hz), 5.90 (2H, d, J = 5.9 Hz), 7.01-7.05 (2H, m),
7.07-7.11 (2H, m), 7.29-7.32 (2H, m), 7.92-7.95 (2H, m); δC
(CDCl3, 125 MHz) 75.4, 116.1 (d, JC-19F = 21.3 Hz), 116.2 (d,
JC-19F = 20.4 Hz), 129.5 (d, JC-19F = 8.5 Hz), 129.7, 131.9 (d,
SCHEME 4. Donor 7 Behaves also as a Base: Formation of
Butenolides 35
(21) Jung, M. E. Synlett 1990, 186–190.
(22) Hicks, L. D.; Hyatt, J. L.; Moak, T.; Edwards, C. C.; Tsurkan, L.;
Wierdl, M.; Ferreira, A. M.; Wadkins, R. M.; Potter, P. M. Bioorg. Med.
Chem. 2007, 15, 3801–3817.
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TABLE 2. Reductive Cleavage from Substrates 14r,s,u,v and Butenolides Arising from Acetoxy-Substituted Substrates 14t,w
JC-19F = 9.3 Hz), 134.8 (d, JC-19F = 2.9 Hz), 163.4 (d, JC-19F
= 409.2 Hz), 165.4 (d, JC-19F = 417.6 Hz), 197.2; m/z (ESþ)
519 ([2M þ Na]þ, 22%), 271 ([M þ Na]þ, 100), 231 (14).
Preparation of Substrates 14. 2-Methoxy-1,2-diphenyletha-
none, 14a:. Methyl iodide (2.8 mL, 45 mmol, 6 equiv) was added
to a suspension of benzoin (1.59 g, 7.5 mmol, 1 equiv) and
silver(I) oxide (3.48 g, 15 mmol, 2 equiv) in chloroform (40 mL).
The resulting mixture was then heated to reflux for 24 h. The
reaction mixture was then cooled and 1 mL of methyl iodide was
added to the mixture. The resulting suspension was heated for
another 2 h and allowed to cool to room temperature. The
reaction mixture was then treated with decolorizing activated
charcoal (1 g) and filtered on Celite. The filtrate was then dried
over anhydrous sodium sulfate, filtered, and concentrated under
reduced pressure. The crude product was then adsorbed onto
silica and purified by flash chromatography on silica gel
(gradient petroleum ether/EtOAc from 95/5 to 90/10) to afford
2-methoxy-1,2-diphenylethanone 14a23 as a yellowish oil slowly
crystallizing into white rosettes (1.31 g, 77%): mp 50-52 °C
(lit.21 mp 49-51 °C); νmax (film)/cm-1 3063, 3030, 3004, 2934,
2827, 1692, 1597, 1581, 1493, 1449, 1316, 1275, 1260, 1224, 1194,
1178, 1106, 1020, 1001; found [M þ H]þ (ESIþ) 227.1063,
C15H14O2 requires [M þ H]þ 227.1067; δH (CDCl3, 400 MHz)
3.46 (3H, s), 5.52 (1H, s), 7.28-7.41 (5H, m), 7.45-7.43 (3H, m),
7.98-8.01 (2H, m); δC (CDCl3, 100 MHz) 57.5, 86.5, 127.6,
128.5, 128.6, 128.8, 129.1, 133.3, 136.0, 139.1, 197.1; m/z (ESIþ)
227 ([M þ H]þ, 100%).
allowed to warm to room temperature. The reaction progress
was monitored by TLC until no starting material was observed.
After being stirred for 2 h at room temperature, the reaction
mixture was successively washed with a saturated aqueous
solution of sodium bicarbonate (3 ꢀ 100 mL) and brine (3 ꢀ
100 mL). The organic extract was eventually dried over anhy-
drous sodium sulfate, filtered, and concentrated under reduced
pressure. The crude product was then adsorbed onto silica and
purified by flash chromatography on silica gel (gradient PE/
EtOAc 95/5 to 80/20) to afford 2-oxo-1,2-diphenylethylmetha-
nesulfonate 14b as a fine white powder (4.20 g, 72%) and 2-
chloro-1,2-diphenylethanone as white rosettes (0.722 g, 16%).
Data for 2-oxo-1,2-diphenylethylmethanesulfonate, 14b: mp
120-122 °C (lit.24 mp 120-121 °C); νmax (film)/cm-1 3383,
3064, 3033, 2938, 2851, 1700, 1597, 1580, 1495, 1449, 1412, 1354,
1259, 1223, 1174, 1100, 1033, 1022, 1001; found [M þ NH4]þ
(ESþ) 308.0955, C15H14O4S requires [M þ NH4]þ, 308.0951; δH
(CDCl3, 400 MHz) 3.08 (3H, s), 7.41-7.45 (5H, m), 7.46-7.48
(2H, m), 7.49-7.51 (1H, m), 7.91-7.95 (2H, m); δC (CDCl3, 125
MHz) 39.6, 82.6, 128.8, 128.9, 129.0, 129.4, 130.1, 132.5, 133.9,
134.0, 192.3; m/z (CIþ) 308 ([M þ NH4]þ, 82%), 214 (100), 197
(50), 105 (49).
Data for 2-chloro-1,2-diphenylethanone: mp 66-68 °C (lit.25
mp 68 °C); found [Mþ] (EIþ) 230.0492, C14H1135ClO requires
[Mþ], 230.0493; νmax (film)/cm-1 3374, 3063, 3031, 3006, 2926,
2853, 1904, 1810, 1783, 1697, 1596, 1580, 1496, 1448, 1319, 1277,
1208, 1175, 1075, 1000; δH (CDCl3, 400 MHz) 6.32 (1H, s),
7.31-7.42 (3H, m), 7.43-7.46 (2H, m), 7.47-7.51 (2H, m),
7.53-7.58 (1H, m), 7.95-7.99 (2H, m); δC (CDCl3, 100 MHz)
69.6, 127.6, 127.9, 128.6, 128.8, 129.2, 133.1, 136.2, 136.7, 188.8;
m/z (EIþ) 230 ([Mþ] (35Cl), 100%).
Example of the Preparation of Mesylates. 2-Oxo-1,2-diphe-
nylethylmethanesulfonate, 14b: Triethylamine (4.21 mL, 30
mmol, 1.5 equiv) was added dropwise to a solution of benzoin
(4.24 g, 20 mmol, 1 equiv) and methanesulfonyl chloride
(2.33 mL, 30 mmol, 1.5 equiv) in dichloromethane under argon
at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and
Example of Preparation of Acetates. 2-Oxo-1,2-diphenylethyl
acetate, 14c: Acetic anhydride (1.42 mL, 15 mmol, 1 equiv) was
(24) Borowitz, I. J.; Rusek, P. E.; Virkhaus, R. J. Org. Chem. 1969, 34,
1595–1600.
(25) Buck, J. S.; Ide, W. S. J. Am. Chem. Soc. 1932, 54, 4359–4365.
(23) Reddy, G. D.; Usha, G.; Ramanathan, K. V.; Ramamurthy, V.
J. Org. Chem. 1986, 51, 3085–3093.
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Cutulic et al.
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added to a solution of benzoin (2.12 g, 10 mmol, 1 equiv) in
pyridine (25 mL) at room temperature under argon. The reac-
tion mixture was then stirred at room temperature under argon
overnight. The reaction mixture was then concentrated under
reduced pressure. The residue was then dissolved in diethyl ether
(100 mL) and successively washed with aqueous hydrochloric
acid (1 N, 3 ꢀ 100 mL), a saturated aqueous solution of sodium
bicarbonate (3 ꢀ 100 mL), and brine (3 ꢀ 100 mL). The resulting
organic extract was then dried over anhydrous sodium sulfate,
filtered, and concentrated under reduced pressure. The resulting
residue was then adsorbed onto silica and purified by flash
chromatography on silica gel (PE/EtOAc 95/5) to afford 2-oxo-
1,2-diphenylethyl acetate 14c as a colorless oil, slowly crystal-
lizing as white rosettes (2.49 g, 98%): mp 80-81 °C (lit.26 mp 81
°C); νmax (film)/cm-1 3381, 3064, 3033, 1740, 1697, 1597, 1579,
1495, 1448, 1373, 1230, 1180, 1160, 1079, 1055, 1029, 1004;
found [M þ NH4]þ (ESþ) 272.1281, C16H14O3 requires [M +
NH4]+ 272.1281; δH (CDCl3, 500 MHz) 2.21 (3H, s), 6.87
(1H, s), 7.32-7.42 (5H, m), 7.45-7.49 (2H, m), 7.51-7.55
(1H, m), 7.92-7.96 (2H, m); δC (CDCl3, 100 MHz) 20.7, 78.6,
127.6, 128.4, 128.6, 129.2, 129.6, 133.0, 136.5, 136.7, 169.1,
194.2; m/z (CIþ) 272 ([M þ NH4]þ, 100%), 255 ([M þ H]þ,
22), 212 (41), 197 (18), 105 (36).
The resulting organic extract was then dried over anhydrous
sodium sulfate, filtered, and concentrated under reduced pressure.
The resulting residue was then adsorbed onto silica and purified
by flash chromatography on silica gel (PE/EtOAc 90/10) to afford
2-oxo-1,2-diphenylethyl benzoate 14e as a pale yellow oil,
which slowly crystallized into white rosettes (5.57 g, 88%): mp
124-126 °C (lit.28 mp 123.5-125 °C); νmax (film)/cm-1 3063,
3033, 1719, 1696, 1598, 1495, 1316, 1280, 1250, 1226, 1176, 1109,
1070, 1025; found [M þ H]þ (ESþ) 317.1173, C21H16O3 requires
[M þ H]þ, 317.1172]; δH (CDCl3, 500 MHz) 7.12 (1H, s),
7.38-7.47 (7H, m), 7.53-7.60 (4H, m), 8.01-8.03 (2H, m),
8.14-8.15 (2H, m); δC (CDCl3, 125 MHz) 78.0, 128.4, 128.7,
128.9, 129.2, 129.3, 129.4, 130.0, 133.4, 133.5, 133.8, 134.8, 166.1,
193.7; m/z (ESþ) 650 ([2M þ NH4]þ, 30%), 317 ([M þ H]þ, 100),
195 (48).
General Procedure for Reducing Substrates, 14. In a centrifuge
tube under argon at room temperature, DMAP-derived salt
13 (0.810 g, 1.5 mmol, 1.5 equiv) and sodium hydride (0.6 g,
15 mmol, 15 equiv) were washed three times with anhydrous
hexane. An excess of hexane was removed by a flow of argon.
Anhydrous N,N-dimethylformamide (15 mL) was then added to
the resulting fine white powder and the resulting mixture was
stirred at room temperature under argon for 3 h. The resulting
dark purple suspension was then centrifuged and the upper
liquid phase was transferred to substrate 14 (1 mmol, 1.0 equiv)
via a cannula. The resulting mixture was then stirred at room
temperature under argon overnight. The reaction mixture was
then washed with EtOAc (100 mL) and water (100 mL). The
aqueous phase was further extracted with EtOAc (2 ꢀ 50 mL).
Combined organic phases were then further washed with water
(2 ꢀ 50 mL) and brine (50 mL). The resulting organic extract was
eventually dried over anhydrous sodium sulfate, filtered, and
concentrated under reduced pressure. The crude product was
then adsorbed onto silica and purified by flash chromatography
on silica gel (PE/EtOAc 95/5) to afford product.
Example of Preparation of Pivalates. 2-Oxo-1,2-dipheny-
lethyl pivalate, 14d: Pivaloyl chloride (3.70 mL, 30 mmol, 1.5
equiv) was added dropwise to a solution of benzoin (4.24 g,
20 mmol, 1 equiv) in pyridine (25 mL). The resulting solution
was stirred at room temperature under argon overnight. The
reaction mixture was then concentrated under reduced pressure.
The residue was then dissolved in dichloromethane (100 mL)
and successively washed with aqueous hydrochloric acid (1 N,
3 ꢀ 100 mL), a saturated aqueous solution of sodium bicarbo-
nate (3 ꢀ 100 mL), and brine (3 ꢀ 100 mL). The resulting organic
extract was then dried over anhydrous sodium sulfate, filtered,
and concentrated under reduced pressure. The resulting residue
was then adsorbed onto silica and purified by flash chromatog-
raphy on silica gel (PE/EtOAc 90/10) to afford 2-oxo-1,2-
diphenylethyl pivalate27 14d as a pale yellow oil (5.39 g, 91%):
15 from 14b: 1,2-diphenylethanone 15 was isolated as a fine
white powder (0.182 g, 93%); mp 60-62 °C (lit.29 mp 59 °C);
found [Mþ] (EIþ) 196.0882, C14H12O requires [Mþ], 196.0883];
ν
1496, 1478, 1449, 1396, 1364, 1287, 1225, 1151, 1045; found [M
max (film)/cm-1 3065, 3033, 2972, 2934, 2872, 1731, 1687, 1597,
ν
max (film)/cm-1 3086, 3059, 3028, 2924, 2852, 1686, 1596, 1579,
1448, 1411, 1337, 1213, 1176, 1101, 1075; δH (CDCl3, 400 MHz)
4.30 (2H, s), 7.24-7.29 (3H, m), 7.32-7.36 (2H, m), 7.45-7.49
(2H, m), 7.55-7.59 (1H, m), 8.02-8.05 (2H, m); m/z (EIþ) 196
([Mþ], 100%), 165 (89), 157 (52).
þ H]þ (ESþ) 297.1486, C19H20O3 requires [M þ H]þ, 297.1485;
δ
H (CDCl3, 500 MHz) 1.29 (9H, s), 6.80 (1H, s), 7.31-7.43 (5H,
m), 7.46-7.54 (3H, m), 7.93-7.96 (2H, m); δC (CDCl3, 125
MHz) 27.1, 38.7, 77.3, 128.3, 128.6, 128.8, 129.0, 129.1, 133.4,
133.9, 134.9, 178.0, 194.3; m/z (ESþ) 615 ([2M þ Na]þ, 10%),
297 ([M þ H]þ, 100), 195 (56).
Acknowledgment. We thank Syngenta, WestCHEM, and
EPSRC for funding. We also thank EPSRC Mass Spectrometry
Service Centre, Swansea, for high resolution mass spectra.
Example of Preparation of Benzoates. 14e: Benzoyl chloride
(3.48 mL, 30 mmol, 1.5 equiv) was added dropwise to a solution
of benzoin (4.24 g, 20 mmol, 1 equiv) in pyridine (25 mL). The
resulting solution was stirred at room temperature under argon
overnight. The reaction mixture was then concentrated under
reduced pressure. The residue was then dissolved in dichloro-
methane (100 mL) and successively washed with aqueous
hydrochloric acid (1 N, 3 ꢀ 100 mL), a saturated aqueous solution
of sodium bicarbonate (3 ꢀ 100 mL), and brine (3 ꢀ 100 mL).
Supporting Information Available: Spectroscopic data for
the preparation of all compounds except those described in the
1
above Experimental Section, together with H and 13C NMR
spectra of compounds 14a-w, 15-20, and 26, 28, and 29. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(28) Stevens, C. L.; Weiner, M. L.; Freeman, R. C. J. Am. Chem. Soc.
1953, 75, 3977–3980.
(29) Mathey, F.; Lampin, J.-P. Tetrahedron Lett. 1972, 13, 1949–1952.
(26) Hattori, K.; Sajiki, H.; Hirota, K. Tetrahedron 2001, 57, 4817–4824.
(27) Evans, D. A.; Nagorny, P.; Xu, R. Org. Lett. 2006, 8, 5669–5671.
8718 J. Org. Chem. Vol. 74, No. 22, 2009