Thieme Chemistry Journal awardees - Where are they now? Intermolecular cross-acyloin reactions by fluoride-promoted additions of O-silyl thiazolium carbinols

Article abstract of DOI:10.1055/s-0028-1087555

The addition of acyl anion equivalents to aliphatic aldehydes (crossed-acyloin reaction) has been developed. Cesium fluoride with isopropanol as solvent promotes the addition of O-silyl thiazolium carbinols to various aliphatic aldehydes in moderate to go

Full text of DOI:10.1055/s-0028-1087555

LETTER
377
Thieme Chemistry Journal Awardees– Where are They Now?
Intermolecular Cross-Acyloin Reactions by Fluoride-Promoted Additions of
O-Silyl Thiazolium Carbinols
C
ross-Acyloin Re
a
l
ctions ex K. Mathies, Anita E. Mattson, Karl A. Scheidt*
Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208, USA
Fax +1(847)4672184; E-mail: scheidt@northwestern.edu
Received 3 October 2008
Abstract: The addition of acyl anion equivalents to aliphatic alde-
hydes (crossed-acyloin reaction) has been developed. Cesium fluo-
ride with isopropanol as solvent promotes the addition of O-silyl
thiazolium carbinols to various aliphatic aldehydes in moderate to
good yields. These reactions represent a general procedure for the
selective coupling of aliphatic aldehydes by an acyl anion reaction
which have been problematic until now.
Key words: acyloin reaction, carbinols, cesium fluoride, acyl an-
ions, thiazolium
Professor Karl Scheidt received his B.Sc. degree from the Universi-
The construction of carbon–carbon bonds through inverse
reactivity patterns, or Umpolung, fuels potential strategies
for the syntheses of biologically active molecules.1,2 The
benzoin3–7 and Stetter reactions8–12 are two transforma-
tions that utilize the in situ generation of acyl anion equiv-
alents for the formation of new C–C bonds. The acyloin
reaction is related to the benzoin condensation and entails
the addition of an acyl anion to an aliphatic aldehyde. This
process is another potentially useful Umpolung transfor-
mation that allows for direct formation of a-hydroxy
ketones, a useful motif in organic chemistry.
ty of Notre Dame in 1994 while working in the laboratory of Profes-
sor Marvin J. Miller. Under the direction of Professor William R.
Roush, Karl earned his Ph.D. from Indiana University in 1999. Follo-
wing his graduate research, he was a National Institutes of Health
Postdoctoral Fellow in the laboratory of Professor David Evans at
Harvard University where he developed asymmetric reactions cataly-
zed by chiral Lewis acids. In 2002, he joined the faculty of North-
western University where he is currently an Associate Professor and
holds the Irving M. Klotz Research Chair in Chemistry. Professor
Scheidt’s contributions to the areas of carbene catalysis, organosili-
con methodology, and total synthesis have been highly recognized by
awards from Abbott Laboratories, Amgen, AstraZeneca, Boehringer-
Ingelheim, 3M, GlaxoSmithKline and Novartis. He is also the recipi-
ent of a National Science Foundation CAREER award, an Alfred P.
Sloan Fellowship, an American Cancer Society Scholar Award, and
a Distinguished Teaching Award from Northwestern University.
While there are reports describing catalytic intramolecu-
lar additions of aldehydes to ketones,13,14 the literature has
very few examples of successful cross-acyloin reactions
in which both reactive components are aliphatic alde-
hydes (Scheme 1, R1, R2 = alkyl).15–19 To the best of our
knowledge, there is only one example of a selective cross-
acyloin reaction of this type reported by Johnson which
involves an acylsilane and cyanide as a catalyst.20 Alter-
natively, the deprotonation of protected cyanohydrins21,22
or dithianes23–25 with strong bases (e.g., LDA, n-BuLi) has
generated acyl anion equivalent as suitable nucleophiles
with aldehyde acceptors. While the cyanohydrin strategy
can be an effective acyl anion equivalent, the liberation of
cyanide to generate a ketone renders the use of cyano-
hydrins undesirable. Additionally, the use of cyanohy-
drins and dithianes as acyl anion equivalents requires a
further deprotection step after completion of the key
carbon–carbon bond-forming process. Lastly, a potential
liability for these two approaches is the generation of a nu-
cleophilic acyl anion equivalent under strongly basic con-
ditions. To increase the effectiveness in natural product
synthesis,26–31 an alternative is desirable to directly form
the a-hydroxyketones without the need for strong base, or
further unmasking of the carbonyl functionality.
In our investigations aimed at developing new unconven-
tional nucleophiles, we have discovered that the combina-
tion of azolium salts and acylsilanes generates unique acyl
anion equivalents for additions to electrophiles, including
a,b-unsaturated ketones (sila-Stetter reaction) and N-
diphenylphosphinoyl imines.32–34 However, use of these
N-heterocyclic carbene (NHC) catalysts for cross-acyloin
reactions has two major problems which are primarily re-
sponsible for the current dearth of solutions to accomplish
this transformation: a) rapid and undesired aldol side reac-
tions through deprotonation of the aldehyde and b) self-
acyloin reactions (dimerization of aldehyde electrophile)
in the presence of a Lewis base catalyst (Scheme 1).
While the development of catalytic acyl anion equivalents
continues to undergo a resurgence,35–40 the basic condi-
tions to generate acyl anion equivalents or catalysts in situ
SYNLETT 2009, No. 3, pp 0377–0383
x
x.
x
x.
2
0
0
9
Advanced online publication: 21.01.2009
DOI: 10.1055/s-0028-1087555; Art ID: S10308ST
© Georg Thieme Verlag Stuttgart · New York

378
A. K. Mathies et al.
LETTER
Cross-acyloin reaction
O
Lewis base
catalyst
O
R1
R,R1 = alkyl
H
O
O
R1
OH
R
R
X
R
1
2
3
acyl anion
α-hydroxy ketone
Potential problems
O
dimer
formation
O
OH
O
aldol
R2
R2
R2
R2
H
H
R2
OH
4
5
Scheme 1 Cross-acyloin reaction
OH
O
Me
Me
N+
I–
Me
N
DBU
TMS
+
Me
S
S
Cl
Cl
Me
Me
1
6
acyl anion
equivalent 7
I–
OTES
O–
Me
Me
Me
N+
N+
F–
Me
Me
S
S
Cl
Cl
Me
8a
9
Scheme 2 Azolium and fluoride-induced acyl anion equivalents
(e.g., NHC) have limited new directions that utilize sensi-
tive acceptors, such as enolizable aldehydes.
Table 1 Formation of O-Silyl Thiazolium Carbinols
Me
I–
OTES
H
R1
Our current mechanistic understanding of our NHC-cata-
lyzed Stetter reaction invokes the generation of an acyl
anion equivalent 7, commonly referred to as the ‘Breslow
intermediate’ due to the early work by Breslow on the
thiazolium-catalyzed benzoin reaction. Accessing this
acyl anion equivalent without the use of an aldehyde is ac-
complished through interaction of the deprotonated thia-
zolium salt 6 with an acyl silane (1, X = SiR3, Scheme 2).
However, an amine base (typically DBU) is necessary to
generate the requisite thiazolium zwitterion/carbene. Our
initial attempts to employ an NHC–acylsilane strategy to
solve the cross-acyloin challenge proved fruitless due to
the anticipated aldol side reaction.
N
N
O
Me
a, b, c
Me
+
R1
S
S
H
Me
Me
10
8b–i
Entry
Carbinol
R1
Yield (%)
1
2
3
4
5
6
7
8
8b
8c
8d
8e
8f
CH2CH2Ph
74
48
56
46
45
52
76
50
(CH2)4Me
(CH2)4OBn
Me
CHMe2
We have developed an alternative strategy to access acyl
anion reactivity without the use of amine bases involving
fluoride activation of O-silyl thiazolium carbinols.41,42
The desilylation of a carbinol such as 8a, followed by a
formal 1,2-proton shift would presumably generate the
acyl anion equivalent 7. We have used these O-silyl thi-
azolium carbinols in successful direct nucleophilic acyla-
tions of nitroalkenes and o-quinone methides. Key to the
success compared to previous studies is that less-basic
conditions are used to promote additions of O-silyl thia-
zolium carbinols.
8g
8h
8i
Cyclohexyl
Cyclopropyl
CH2CHMe2
a n-Butyllithium, THF, –78 °C.
b TESCl, imidazole, THF, 23 °C.
c MeI, reflux.
Formation of O-silyl thiazolium carbinols 8b–i for utiliza-
tion as acyl anion equivalents can be accomplished in
three easy steps from 4,5-dimethylthiazole (10) and vari-
ous aldehydes (Table 1). This method is compatible with
Synlett 2009, No. 3, 377–383 © Thieme Stuttgart · New York

LETTER
Cross-Acyloin Reactions
379
Table 2 Optimization of Acyl Anion Additions to Aldehydes
OTES
Me
N+
I–
O
O
F–
n-C5H11
Me
+
Ph
n-C5H11
H
S
OH
3b
8b
Me
Entry
Fluoride source
Me4NF
Me4NF
Me4NF
Me4NF
Me4NF
CsF
Aldehyde (equiv)
Solvent
Temp (°C)
0 to 23
0 to 23
0 to 23
0 to 23
23
Yield (%)
1
2
2
1
4
4
4
4
4
4
4
2
2
CH2Cl2 (0.2 M)
CH2Cl2 (0.2 M)
CH2Cl2 (0.2 M)
CH2Cl2 (0.2 M)
CH2Cl2 (0.2 M)
CH2Cl2 (0.2 M)
DMF (0.2 M)
38
27
64
58a
61
38
64
70
48
39
52
3
4
5
6
23
7
CsF
23
8
CsF
i-PrOH (0.2 M)
i-PrOH (0.2 M)
i-PrOH (1 M)
23
9
Me4NF
CsF
23
10
11
23
CsF
i-PrOH (0.4 M)
23
a Three equiv i-PrOH added.
straight chain and branched aldehydes as well as alde- solvents were examined. In our previously published
hydes bearing a benzyl ether (entry 3).43 These thiazolium NHC-catalyzed additions to chalcone, the addition of iso-
salts are crystalline, easily purified (involving one col- propanol increased the yield of the reaction, and we were
umn, a filtration, and a crystallization for the three steps), inspired to investigate this additive as the actual solvent.
and bench-top stable.
Hence, we discovered that CsF as well as the carbinol are
soluble in isopropanol. The combination of isopropanol as
solvent with the Me4NF conditions, however, had little ef-
fect on the overall yield of the reaction (entry 4). Upon
submission of the carbinol to cesium fluoride in isopro-
panol, a 70% yield was observed (entry 8). Further at-
tempts to increase concentration and vary reaction
temperatures produced inferior yields. Moreover, the use
of other alcohols (such as tert-amyl alcohol and methanol)
as well as water affords little or no desired addition prod-
ucts, and many decomposition products are observed.
Prolonged exposure of the silyl-protected carbinol to iso-
propanol also results in decomposition. Due to this degra-
dation process, the immediate addition of the cesium
fluoride showed slight increases in yield.
With a collection of O-silyl carbinols in hand, we began a
survey with the addition of the hydrocinnamaldehyde-
derived carbinol 8b to hexanal (Table 2). Use of tetrame-
thylammonium fluoride (Me4NF) at 0 °C to generate the
acyl anion equivalent resulted in addition in 38% yield
(entry 1). Altering the equivalents of aldehyde, however,
increased the yield to 64% (entry 3). The major byproduct
in these reactions was the dimerization that results from
the liberated thiazolium carbene interacting with the alde-
hyde in solution under the thiazolium-catalyzed self-
acyloin reaction.
In addition to Me4NF, several other fluoride sources were
examined. Tetrabutylammonium fluoride (TBAF) pro-
duced similar results as with Me4NF. Copper fluoride, in-
dium fluoride, and magnesium fluoride promoted only the
aldol condensation of the aldehyde, producing none of the
desired hydroxy ketone. Cesium fluoride as the desilylat-
ing reagent was successful in producing the desired prod-
uct and showed a low amount of observed dimer (4,
Scheme 1) and no aldol product 5. However, diminished
yields in dichloromethane were observed (entry 6). It was
noted that the solubility of CsF was poor in dichloro-
methane, thereby prompting a change of solvent to DMF
(entry 7). Further examination of the solvent choice was
then considered. Due to the limited solubility of the
carbinol in THF, diethyl ether, and benzene, additional
To expand the scope of this addition, several aldehyde ac-
ceptors were examined (Table 3). Initial experiments with
aldehydes lacking a-substitution resulted in good to high
yield, with the addition to the b-branched isovaleralde-
hyde producing 77% of the desired compound (entry 3).
Additions to a-branched aldehydes such as cyclohexane-
carboxaldehyde, isobutyraldehyde, and cyclopropylcarb-
oxaldehyde (entries 4–6) resulted in moderate to good
yields in 41%, 49%, and 71%, respectively. Interestingly,
additions to O-protected 4-hydroxyaldehydes afford good
yielding additions with benzyl and benzoyl protection
Synlett 2009, No. 3, 377–383 © Thieme Stuttgart · New York

380
A. K. Mathies et al.
LETTER
(entries 7 and 8), as well as selective desilylation of the
TES group over a TIPS-protected alcohol (entry 9).
Table 4 Survey of Silyl-Protected Carbinols
O
O
CsF
R1
i-PrOH
8b–i
+
R2
R1
H
Table 3 Fluoride-Promoted Additions to Aldehydes
OH
3b, 3k–m
O
O
CsF
R
+
8b
Ph
R
H
i-PrOH
Entry
1
Carbinol Product
Yield (%)
70
OH
3b–j
O
n-C5H11
Entry
R
Yield (%)
Ph
8a
OH
1
2
3
4
5
6
7
8
9
(CH2)4Me
Me
70
80
77
41
49
71
70
67
72
3b
O
Ph
CH2CHMe2
Cyclohexol
CHMe2
2
3
8c
62
49
n-C5H11
OH
3k
O
8d
8e
BnO
3l
Cyclopropyl
(CH2)3OBz
(CH2)3OBn
(CH2)3OTIPS
Ph
OH
O
Me
Ph
4
56
OH
3m
Variations of the carbinol were also explored (Table 4).
Addition of carbinol 8c to hydrocinnamaldehyde (3k)
successfully produced the regioisomer of the addition of
8b to hexanal (3b). With this result, regioselective synthe-
ses of a-hydroxyketones can be imagined. Other additions
of unbranched O-silyl carbinols 8d and 8e produced sim-
ilar results with good additions to hexanal.
spiroepoxide intermediate arising from cyclization of the
alkoxide anion onto the thiazolium ring (II). It is interest-
ing to note that the presence of the isopropanol does not
hinder the reaction of aliphatic carbinols, but produces no
product with aryl carbinols.47–50 A possible explanation is
that protic solvents further stabilize the intermediates (I
and II), thereby minimizing possible elimination of the
carbene to form the aldehyde.
Our proposed reaction pathway is shown in Scheme 3 and
begins with the desilylation promoted by cesium fluoride
(I). A formal 1,2-proton shift results in formation of the
Breslow intermediate (III), which is the reactive acyl an-
ion equivalent.44,45 Recent MP2/6-31+G(d,p) level calcu-
lations by Gronert46 explored the possibility of a
Upon formation of the acyl anion equivalent 7, addition to
the aldehyde (III), a proton shift (IV), and subsequent
elimination of the thiazolium carbene (V) completes the
OTES
O–
Me
Me
N+
Me
N+
O
N
R1
R1
R1
F–
2α
Me
Me
Me
S
S
S
Me
Me
Me
Me
II
8
I
formal 1,2-H shift
O
R1 OH
OH
OH
R1
Me
N+
Me
R2
N+
N
H
R2
R1
–
Me
Me
Me
O–
S
S
S
7
Me
Me
Me
III
Breslow Intermediate
Me
N+
O– R1
Me
N+
O
R2
–
R2
OH
+
Me
R1
Me
S
S
OH
Me
Me
IV
V
3
Scheme 3 Proposed reaction pathway
Synlett 2009, No. 3, 377–383 © Thieme Stuttgart · New York

LETTER
Cross-Acyloin Reactions
381
(s, 3 H), 2.50 (s, 3 H), 1.96–1.87 (m, 2 H), 1.51–1.50 (m, 2 H), 1.30–
1.26 (m, 4 H), 0.97 (t, J = 7.6 Hz, 9 H), 0.88 (m, 3 H), 0.72 (q,
J = 7.6 Hz, 6 H). 13C NMR (100 MHz, CDCl3): d = 177.3, 143.9,
130.2, 70.8, 41.1, 37.1, 31.4, 23.8, 22.6, 14.1, 13.8, 13.1, 6.9, 4.9.
LRMS (MALDI-TOF): m/z calcd for C18H36NOSSi [M]+: 342.2;
found: 342.7.
synthesis of the a-hydroxy ketones 3. Further reactions of
the generated thiazolium carbene (V) can occur with alde-
hyde in solution producing the self-acyloin product. Iso-
propanol as the solvent seems to reduce this side reaction.
In summary, cross-acyloin reactions have been accom-
plished employing O-silyl thiazolium carbinols and ali-
phatic aldehydes. Due to the relatively mild reaction
conditions compared to other catalytic conditions, side
reactions have been minimized. A variety of branched and
unbranched aldehydes as well as O-silyl thiazolium
carbinols have been explored, showing compatibility with
several different O-protecting groups. This process is an
important addition to the synthetic methods available for
Umpolung transformations.
2-[4-(Benzyloxy)-1-(triethylsilyloxy)butyl]-3,4,5-trimethylthia-
zol-3-ium Iodide (8d)
Isolated in 56% yield over three steps as a yellow oil. IR (film):
1
2953, 1713, 1603, 1097 cm–1. H NMR (500 MHz, CDCl3): d =
7.28–7.18 (m, 5 H), 5.58 (t, J = 5.4 Hz, 1 H), 4.38 (s, 2 H), 4.05 (s,
3 H), 3.46 (t, J = 6.3 Hz, 2 H), 2.41 (s, 3 H), 2.40 (s, 3 H), 2.07–1.99
(m, 1 H), 1.95–1.88 (m, 1 H), 1.79–1.73 (m, 1 H), 1.55–1.49 (m, 1
H), 0.86 (t, J = 7.8 Hz, 9 H), 0.62 (q, J = 7.8 Hz, 6 H). 13C NMR
(125 MHz, CDCl3): d = 176.6, 143.3, 137.8, 129.8, 128.0, 127.5,
127.3, 72.8, 70.1, 69.4, 40.2, 33.9, 23.6, 13.1, 12.5, 6.4, 4.4. LRMS
(MALDI-TOF): m/z calcd for C23H38NO2SSi [M]+: 420.2; found:
421.4.
1
The H NMR and 13C NMR spectra were obtained on a Varian
Inova 500 (operating at 500 MHz for 1H and 125 MHz for 13C), or
a Mercury 400 (operating at 400 MHz for 1H and 100 MHz for 13C).
The FT-IR spectra were obtained on a Perkin Elmer 1600 series FT-
IR. Mass spectra data were obtained on a Varian 1200 Quadrupole
Mass Spectrometer. Laser desorption mass spectra were obtained
with PE BioSystems time-of-flight MALDI mass spectrometer with
2,5-dihydroxybenzoic acid as matrix.
3,4,5-Trimethyl-2-[1-(triethylsilyloxy)ethyl])thiazol-3-ium
Iodide (8e)
Isolated in 46% yield over three steps as a pale yellow solid; mp
115–115.5 °C. IR (film): 2955, 2877, 1607, 1109, 1016, 745 cm–1.
1H NMR (500 MHz, CDCl3): d = 5.67 (d, J = 6.4 Hz, 1 H), 4.25 (s,
3 H), 2.57 (s, 3 H), 2.49 (s, 3 H), 1.72 (d, J = 6.4 Hz, 3 H), 0.99 (t,
J = 7.8 Hz, 9 H), 0.74 (q, J = 7.8 Hz, 6 H). 13C NMR (125 MHz,
CDCl3): d = 178.0, 143.7, 129.9, 67.3, 40.8, 24.4, 13.4, 12.6, 6.8,
4.8. LRMS (MALDI-TOF): m/z calcd for C14H28NOSSi [M]+:
286.2: found: 287.0.
Typical Procedure for Formation of O-Silyl Thiazolium
Carbinols (8)
To a –78 °C solution of 4,5-dimethylthiazole (1.0 mL, 9.5 mmol) in
THF (50 mL) was added a 1.4 M solution of n-BuLi (7 mL, 9.45
mmol). After 1 h, hydrocinnamaldehyde (3.7 mL, 28 mmol) was
slowly added to the reaction flask and the mixture warmed to 23 °C.
After 4 h, the reaction was quenched with H2O (50 mL) and extract-
ed with Et2O (3 × 25 mL). The organic layers were combined, dried
over anhyd Na2SO4, and then concentrated in vacuo. The residue
was purified by flash chromatography (SiO2, 5% to 30% Et2O–
hexane) to produce 2.264 g (91%) of a yellow oil. To the thiazole
product (1.057 g, 4.03 mmol) and imidazole (330 mg, 4.84 mmol)
in THF (40 mL) was added triethylchlorosilane (1.1 mL, 6.1 mmol).
After 4 h, the reaction was diluted with Et2O (50 mL) and washed
with sat. aq NaHCO3 (2 × 25 mL) and brine (25 mL). The organic
layer was dried over anhyd Na2SO4 then concentrated in vacuo. The
residue oil was dissolved in MeI (5 mL) and heated at reflux for 16
h. The reaction was cooled and the excess MeI removed in vacuo.
Diethyl ether (25 mL) was added to the unpurified oil and stirred
1 h producing a solid. Filtration afforded 1.635 g (81%) of a yellow
solid (8b).
3,4,5-Trimethyl-2-[2-methyl-1-(triethylsilyloxy)propyl]thiazol-
3-ium Iodide (8f)
Isolated in 45% yield over three steps as a white solid; mp 159–160
1
°C. IR (film): 2959, 2875, 1609, 1463, 1058, 799, 733 cm–1. H
NMR (500 MHz, CDCl3): d = 5.32 (d, J = 2.9 Hz, 1 H), 4.28 (s, 3
H), 2.63 (s, 3 H), 2.51 (s, 3 H), 2.28–2.26 (m, 1 H), 1.15 (d, J = 6.8
Hz, 3 H), 0.97 (t, J = 8.3 Hz, 9 H), 0.89 (d, J = 6.3 Hz, 3 H), 0.72 (q,
J = 7.8 Hz, 6 H). 13C NMR (125 MHz, CDCl3): d = 168.0, 144.0,
130.3, 75.2, 41.6, 34.2, 20.2, 15.8, 14.0, 13.1, 7.1, 5.1. LRMS
(MALDI-TOF): m/z calcd for C16H32NOSSi [M]+: 314.2; found:
315.3.
2-[Cyclohexyl(triethylsilyloxy)methyl]-3,4,5-trimethylthiazol-
3-ium Iodide (8g)
Isolated in 52% over three steps as a pale yellow solid; mp 158–159
°C. IR (film): 2928, 2870, 1605, 1450, 1110, 1008 cm–1. 1H NMR
(500 MHz, CDCl3): d = 5.25 (d, J = 3.7 Hz, 1 H), 4.28 (s, 3 H), 2.63
(s, 3 H), 2.50 (s, 3 H), 1.88–1.01 (m, 1 H), 0.97 (t, J = 7.9 Hz, 9 H),
0.70 (q, J = 7.9 Hz, 6 H). 13C NMR (100 MHz, CDCl3): d = 176.4,
144.1, 130.3, 75.0, 43.8, 41.5, 30.1, 26.1, 25.9, 25.7, 14.0, 13.1, 7.1,
5.0. LRMS (MALDI-TOF): m/z calcd for C19H36NOSSi [M]+:
354.2; found: 354.9.
3,4,5-Trimethyl-2-[3-phenyl-1-(triethylsilyloxy)propyl]thia-
zole-3-ium Iodide (8b)
Isolated in 74% yield over three steps as a pale yellow solid; mp
138–139.5 °C. IR (film): 2954, 2885, 1604, 1454, 1100, 734 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.28–7.14 (m, 5 H), 5.76 (dd,
J = 4.4, 4.4 Hz, 1 H), 4.09 (s, 3 H), 2.92–2.86 (m, 1 H), 2.76–2.70
(m, 1 H), 2.43 (s, 3 H), 2.41 (s, 3 H), 2.38–2.32 (m, 2 H), 1.00 (t,
J = 7.8 Hz, 9 H), 0.78 (q, J = 7.8 Hz, 6 H). 13C NMR (125 MHz,
CDCl3): d = 177.0, 143.6, 139.9, 130.0, 128.5, 128.4, 126.2, 70.0,
40.9, 38.0, 29.3, 13.2, 12.5, 6.9, 4.9. LRMS (MALDI-TOF): m/z
calcd for C21H34NOSSi [M]+: 376.2; found: 377.0.
2-[Cyclopropyl(triethylsilyloxy)methyl]-3,4,5-trimethylthiazol-
3-ium Iodide (8h)
Isolated in 78% yield over three steps as a pale yellow solid; mp
110–111 °C. IR (film): 2955, 2877, 1605, 1458, 1072, 734 cm–1. 1H
NMR (500 MHz, CDCl3): d = 5.26 (d, J = 6.8 Hz, 1 H), 4.26 (s,
3 H), 2.57 (s, 3 H), 2.51 (s, 3 H), 1.41–1.38 (m, 1 H), 0.95 (t, J = 7.8
Hz, 9 H), 0.92 (m, 1 H), 0.78 (m, 1 H), 0.71 (q, J = 7.8 Hz, 6 H),
0.62 (m, 1 H). 13C NMR (125 MHz, CDCl3): d = 176.0, 143.8,
130.2, 71.8, 41.6, 17.2, 13.7, 13.0, 7.1, 5.3, 4.7, 4.5. LRMS
(MALDI-TOF): m/z calcd for C16H30NOSSi [M]+: 312.2; found:
313.0.
3,4,5-Trimethyl-2-[1-(triethylsilyloxy)hexyl]thiazol-3-ium
Iodide (8c)
Isolated in 48% yield over three steps as a white solid; mp 106–107
°C. IR (film): 2951, 1606, 1458, 1241, 1092, 1009 cm–1. 1H NMR
(500 MHz, CDCl3): d = 5.55 (t, J = 5.5 Hz, 1 H), 4.25 (s, 3 H), 2.60
Synlett 2009, No. 3, 377–383 © Thieme Stuttgart · New York

382
A. K. Mathies et al.
LETTER
3,4,5-Trimethyl-2-[3-methyl-1-(triethylsilyloxy)butyl]thiazol-3-
ium Iodide (8i)
(d, J = 4.6 Hz, 1 H), 3.21–2.98 (m, 3 H), 2.86–2.81 (m, 1 H), 0.93–
0.89 (m, 1 H), 0.64–0.55 (m, 3 H), 0.46–0.43 (m, 1 H). 13C NMR
(100 MHz, CDCl3): d = 210.5, 140.6, 128.6, 128.3, 126.3, 78.9,
39.9, 29.5, 14.3, 2.9, 2.1. LRMS (ES): m/z calcd for C13H16O2 [2 M
+ 23]+: 431.2; found: 431.8.
Isolated in 50% yield over three steps as a pale yellow solid; mp
143–144 °C. IR (film): 2956, 2876, 1607, 1462, 1096, 1004, 748
cm–1. 1H NMR (500 MHz, CDCl3): d = 5.44 (dd, J = 6.8, 4.4 Hz, 1
H), 4.23 (s, 3 H), 2.62 (s, 3 H), 2.51 (s, 3 H), 1.87–1.76 (m, 3 H),
1.05 (d, J = 6.3 Hz, 3 H), 0.97 (t, J = 5.9 Hz, 9 H), 0.93 (d, J = 6.8
Hz, 3 H), 0.73 (q, J = 5.9 Hz, 6 H). 13C NMR (125 MHz, CDCl3):
d = 177.5, 144.2, 130.2, 69.8, 47.0, 41.0, 24.5, 23.7, 22.2, 14.0, 13.1,
7.05, 5.10. LRMS (MALDI-TOF): m/z calcd for C17H34NOSSi
[M]+: 328.2; found: 328.8.
4-Hydroxy-5-oxo-7-phenylheptyl Benzoate (3h)51
Isolated in 70% yield as a clear oil. 1H NMR (500 MHz, CDCl3):
d = 8.03 (d, J = 7.3 Hz, 1 H), 7.58 (t, J = 7.6 Hz, 1 H), 7.45 (t,
J = 7.9 Hz, 2 H), 7.38–7.06 (m, 5 H), 4.38–4.29 (m, 2 H), 4.22 (dd,
J = 7.6, 2.1 Hz, 1 H), 3.00–2.72 (m, 4 H), 2.00–1.60 (m, 4 H),
LRMS (ES): m/z calcd for C20H22O4 [2 M + Na]+: 675.3; found:
675.4.
Typical Procedure for Cesium Fluoride Activated Addition of
Silylcarbinols to Aldehydes
To a flask charged with carbinol 8b (117 mg, 0.233 mmol) was add-
ed hexanal (112 mL, 0.932 mmol) in 2-PrOH (1.1 mL). Immediate-
ly, CsF (53 mg, 0.35 mmol) was added to the reaction flask and the
mixture stirred. After 16 h, 1 mL of water was added. After 1 h,
CH2Cl2 (10 mL) was added and the layers separated. The aqueous
phase was washed with CH2Cl2 (2 × 10 mL) and the combined or-
ganic layers washed with brine (25 mL). The solution was dried and
concentrated. Flash chromatography (5% to 25% Et2O–hexane) af-
forded 38 mg (70%) of a yellow oil (3b).
7-(Benzyloxy)-4-hydroxy-1-phenylheptan-3-one (3i)
Isolated in 67% yield as a clear oil. IR (film): 3448 (br), 2925, 2857,
1712, 1450, 1093, 739, 699 cm–1. 1H NMR (500 MHz, CDCl3): d =
7.39–7.12 (m, 10 H), 4.51 (s, 2 H), 4.15 (dd, J = 7.3, 3.9 Hz, 1 H),
3.64 (brs, 1 H), 3.54–3.49 (m, 2 H), 2.98–2.93 (m, 2 H), 2.88–2.75
(m, 2 H), 2.00–1.89 (m, 1 H), 1.81–1.57 (m, 3 H). 13C NMR (125
MHz, CDCl3): d = 211.8, 140.8, 138.5, 128.8, 128.7, 128.6, 127.9,
127.9, 126.6, 76.6, 73.2, 69.9, 39.9, 30.8, 29.8, 25.4. LRMS (ES):
m/z calcd for C20H24O3 [M + Na]+: 335.2; found: 335.9.
4-Hydroxy-1-phenylnonan-3-one (3b)
4-Hydroxy-1-phenyl-7-(triisopropylsilyloxy)heptan-3-one (3j)
Isolated in 72% yield as a clear oil. IR (film): 3484 (br), 2943, 2866,
1712, 1604. 1458, 1103, 883, 682 cm–1. 1H NMR (500 MHz,
CDCl3): d = 7.31–7.19 (m, 5 H), 4.19 (dd, J = 7.3, 3.2 Hz, 1 H),
3.76–3.69 (m, 3 H), 2.98–2.77 (m, 4 H), 2.00–1.95 (m, 1 H), 1.72–
1.53 (m, 3 H), 1.09–0.88 (m, 21 H). 13C NMR (125 MHz, CDCl3):
d = 211.8, 140.6, 128.5, 128.4, 126.4, 76.5, 62.8, 39.5, 30.4, 29.5,
28.2, 18.0, 11.9. LRMS (ES): m/z calcd for C22H38O3Si [2 M + 23]+:
779.5; found: 779.8.
Isolated in 70% yield as a pale clear oil. IR (film): 3480, 2927, 2857,
1712, 1454, 1081 cm–1. 1H NMR (500 MHz, CDCl3): d = 7.31–7.18
(m, 5 H), 4.14 (dd, J = 7.0, 3.5 Hz, 1 H), 3.43 (d, J = 4.9 Hz, 1 H),
2.99–2.93 (m, 2 H), 2.86–2.74 (m, 2 H), 1.79–1.75 (m, 1 H), 1.52–
1.41 (m, 3 H), 1.29–1.22 (m, 4 H), 0.88 (t, J = 6.8 Hz, 3 H). 13C
NMR (125 MHz, CDCl3): d = 211.4, 140.5, 128.5, 128.3, 126.3,
76.5, 39.6, 33.5, 31.6, 29.5, 24.4, 22.4, 13.9. LRMS (ES): m/z calcd
for C15H22O2 [M + 23]+: 257.2; found: 257.6.
4-Hydroxy-1-phenylpentan-3-one (3c)
3-Hydroxy-1-phenylnonan-4-one (3k)
Isolated in 77% yield as a clear oil. IR (film): 3479 (br), 2955, 2927,
1711, 1080 cm–1. 1H NMR (500 MHz, CDCl3): d = 7.34–7.14 (m, 5
H), 4.15 (dd, J = 10.2, 10.2 Hz, 1 H), 3.37 (s, 1 H), 3.02–2.94 (m, 2
H), 2.92–2.72 (m, 2 H), 1.94–1.88 (m, 1 H), 1.50–1.46 (m, 1 H),
1.45–1.36 (m, 1 H), 0.97 (d, J = 6.4 Hz, 3 H), 0.94 (d, J = 6.7 Hz, 3
H). 13C NMR (125 MHz, CDCl3): d = 211.8, 140.5, 128.6, 128.8,
126.4, 75.3, 42.7, 39.6, 29.6, 24.7, 23.6, 21.2. LRMS (ES): m/z cal-
cd for C14H20O2 [2 M + Na]+: 463.3; found: 463.5.
Isolated in 62% yield as a clear oil. IR (film): 3468 (br), 2928, 2859,
1712, 1602, 1454, 1072, 700 cm–1. 1H NMR (500 MHz, CDCl3):
d = 7.33–7.20 (m, 5 H), 4.17 (dd, J = 8.3, 4.4 Hz, 1 H), 3.61 (d,
J = 4.9 Hz, 1 H), 2.84–2.72 (m, 2 H), 2.49–2.37 (m, 2 H), 2.19–2.12
(m, 1 H), 1.86–1.79 (m, 1 H), 1.64–1.58 (m, 2 H), 1.35–1.24 (m, 4
H), 0.90 (t, J = 7.3 Hz, 3 H). 13C NMR (125 MHz, CDCl3): d =
212.3, 141.1, 128.6, 128.5, 126.1, 75.6, 37.8, 35.6, 31.3, 31.2, 23.3,
22.4, 13.8. LRMS (ES): m/z calcd for C15H22O2 [2 M + Na]+: 491.3;
found: 491.9.
1-Cyclohexyl-1-hydroxy-4-phenylbutan-2-one (3e)
Isolated in 41% yield as a clear oil. IR (film): 3470 (br), 2927, 2851,
1715, 1455, 1084 cm–1. 1H NMR (400 MHz, CDCl3): d = 7.28–7.15
(m, 5 H), 3.97 (ap s, 1 H), 3.23 (ap s, 1 H), 2.95–2.90 (m, 2 H), 2.81–
2.72 (m, 2 H), 1.77–0.85 (m, 11 H). 13C NMR (100 MHz, CDCl3):
d = 211.3, 140.5, 128.6, 128.3, 126.3, 80.9, 41.2, 39.9, 30.1, 29.5,
26.5, 26.0, 25.8, 25.0. LRMS (ES): m/z calcd for C16H22O2 [2 M +
Na]+: 515.3; found: 516.0.
1-(Benzyloxy)-5-hydroxydecan-4-one (3l)
Isolated in 49% yield as a clear oil. IR (film): 3479 (br), 2929, 2858,
1
1715, 1455, 1361, 1100 cm–1. H NMR (500 MHz, CDCl3): d =
7.39–7.29 (m, 5 H), 4.49 (s, 2 H), 4.18–4.17 (m, 1 H), 3.51 (t,
J = 5.9 Hz, 2 H), 3.46 (d, J = 3.4 Hz, 1 H), 2.66–2.53 (m, 2 H),
1.99–1.94 (m, 2 H), 1.85–1.80 (m, 1 H), 1.65–1.42 (m, 3 H), 1.40–
1.21 (m, 4 H), 0.90 (t, J = 6.4 Hz, 3 H). 13C NMR (125 MHz,
CDCl3): d = 212.2, 138.2, 128.4, 127.7, 127.6, 76.5, 72.9, 67.0,
34.5, 33.7, 31.6, 24.5, 23.8, 22.5, 14.0. LRMS (ES): m/z calcd for
C17H26O3 [2 M + Na]+: 579.4; found: 579.9.
4-Hydroxy-5-methyl-1-phenylhexan-3-one (3f)
Isolated in 49% yield as a clear oil. IR (film): 3476 (br), 2962, 2924,
1709, 1455, 1026 cm–1. 1H NMR (500 MHz, CDCl3): d = 7.37–7.15
(m, 5 H), 4.05 (dd, J = 4.9, 2.4 Hz, 1 H), 3.36 (d, J = 4.9 Hz, 1 H),
3.00–2.96 (m, 2 H), 2.84–2.76 (m, 2 H), 2.19–2.21 (m, 1 H), 1.11
(d, J = 6.8 Hz, 3 H), 0.68 (d, J = 2.8 Hz, 3 H). 13C NMR (125 MHz,
CDCl3): d = 211.2, 140.4, 128.5, 128.3, 126.4, 80.8, 39.8, 31.2,
29.4, 20.0, 14.6. LRMS (ES): m/z calcd for C13H18O2 [M]+: 206.1;
found: 206.2.
Acknowledgment
We gratefully acknowledge support of this work by NIGMS
(GM73072) Abbott Laboratories, Amgen, 3M, and Boehringer-
Ingelheim. A.E.M. was supported in part by an ACS Division of
Organic Chemistry Fellowship sponsored by Eli Lilly. We thank
FMCLithium, Wakker Chemical Company, and BASF for provi-
ding reagents used in this work. Funding for the NU Analytical
Services Laboratory has been furnished in part by the NSF (CHE-
9871268). K.A.S. is a fellow of the A. P. Sloan Foundation.
1-Cyclopropyl-1-hydroxy-4-phenylbutan-2-one (3g)
Isolated in 71% yield as a clear oil. IR (film): 3475 (br), 2922, 2850,
1712, 1602, 1453, 1028, 749, 699 cm–1. 1H NMR (500 MHz,
CDCl3): d = 7.37–7.21 (m, 5 H), 3.62 (dd, J = 7.6, 4.9 Hz, 1 H), 3.50
Synlett 2009, No. 3, 377–383 © Thieme Stuttgart · New York

LETTER
Cross-Acyloin Reactions
383
(27) Deng, L. S.; Huang, X. P.; Zhao, G. J. Org. Chem. 2006, 71,
4625.
(28) Bio, M. M.; Leighton, J. L. J. Org. Chem. 2003, 68, 1693.
(29) Armstrong, A.; Barsanti, P. A.; Jones, L. H.; Ahmed, G.
J. Org. Chem. 2000, 65, 7020.
(30) Fukuda, Y.; Okamoto, Y. Tetrahedron 2002, 58, 2513.
(31) Cousson, A.; Legouadec, G.; Monneret, C.; Florent, J. C.
J. Chem. Soc., Chem. Commun. 1993, 388.
(32) Bharadwaj, A. R.; Scheidt, K. A. Org. Lett. 2004, 6, 2465.
(33) Mattson, A. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am.
Chem. Soc. 2004, 126, 2314.
References and Notes
(1) Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239.
(2) Grobel, B. T.; Seebach, D. Synthesis 1977, 357.
(3) Breslow, R. J. Am. Chem. Soc. 1958, 79, 3719.
(4) Breslow, R.; Schmuck, C. Tetrahedron Lett. 1996, 37, 8241.
(5) Chen, Y. T.; Barletta, G. L.; Haghjoo, K.; Cheng, J. T.;
Jordan, F. J. Org. Chem. 1994, 59, 7714.
(6) Hassner, A.; Lokanatha Rai, K. M. In Comprehensive
Organic Synthesis, Vol. 1; Trost, B. M.; Fleming, I., Eds.;
Pergamon Press: Oxford, 1991, 541–577.
(7) White, M. J.; Leeper, F. J. J. Org. Chem. 2001, 66, 5124.
(8) Harrington, P. E.; Tius, M. A. Org. Lett. 1999, 1, 649.
(9) Hempenius, M. A.; Langeveld-Voss, B. M. W.; van Haare,
J. A. E. H.; Janssen, R. A. J.; Sheiko, S. S.; Spatz, J. P.;
Moller, M.; Meijer, E. W. J. Am. Chem. Soc. 1998, 120,
2798.
(34) Mattson, A. E.; Bharadwaj, A. R.; Zuhl, A. M.; Scheidt,
K. A. J. Org. Chem. 2006, 71, 5715.
(35) Takemiya, A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128,
14800.
(36) Enders, D.; Niemeier, O.; Balensiefer, T. Angew. Chem. Int.
Ed. 2006, 45, 1463.
(10) Stetter, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 639.
(11) Stetter, H.; Kuhlmann, H. Synthesis 1975, 379.
(12) Stetter, H.; Kuhlmann, H. Chem. Ber. 1976, 109, 2890.
(13) Enders, D.; Niemeier, O. Synlett 2004, 2111.
(14) Takikawa, H.; Hachisu, Y.; Bode, J. W.; Suzuki, K. Angew.
Chem. Int. Ed. 2006, 45, 3492.
(37) Enders, D.; Niemeier, O.; Raabe, G. Synlett 2006, 2431.
(38) Marion, N.; Díez-González, S.; Nolan, S. P. Angew. Chem.
Int. Ed. 2007, 46, 2988.
(39) Johnson, J. S. Angew. Chem. Int. Ed. 2004, 43, 1326.
(40) Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004, 37, 534.
(41) Mattson, A. E.; Zuhl, A. M.; Reynolds, T. E.; Scheidt, K. A.
J. Am. Chem. Soc. 2006, 128, 4932.
(15) Kramme, R.; Martin, H. D.; Mayer, B.; Weimann, R. Angew.
Chem., Int. Ed. Engl. 1986, 25, 1116.
(42) Mattson, A. E.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129,
(16) Kurniadi, T. H.; Rhlid, R. B.; Juillerat, M. A.; Gefflaut, T.;
Bolte, J.; Berger, R. G. Tetrahedron 2003, 59, 6109.
(17) Kurniadi, T. H.; Rhlid, R. B.; Juillerat, M. A.; Schuler, M.;
Berger, R. G. Tetrahedron: Asymmetry 2003, 14, 363.
(18) Matsumoto, T.; Ohishi, M.; Inoue, S. J. Org. Chem. 1985,
50, 603.
(19) Stetter, H.; Dambkes, G. Synthesis 1977, 403.
(20) Linghu, X.; Bauch, C. C.; Johnson, J. S. J. Am. Chem. Soc.
2005, 1833.
(21) Albright, J. D. Tetrahedron 1983, 39, 3207.
(22) Hunig, S.; Marschner, C. Chem. Ber. 1989, 122, 1329.
(23) Seebach, D. Synthesis 1969, 17.
(24) Smith, A. B.; Adams, C. M. Acc. Chem. Res. 2004, 37, 365.
(25) Yus, M.; Najera, C.; Foubelo, F. Tetrahedron 2003, 59,
6147.
4508.
(43) The use of aldehydes with benzoyl and triisopropylsiloxy
functionalities was incompatible with this sequence.
(44) Breslow, R. J. Am. Chem. Soc. 1957, 79, 1762.
(45) Ugai, T. T. S.; Dokawa, S. J. Pharm. Chem. Jpn. 1943, 63,
269.
(46) Gronert S.; Org. Lett.; 2007, 9, 3065.
(47) Bordwell, F. G.; Satish, A. V. J. Am. Chem. Soc. 1991, 113,
985.
(48) Bordwell, F. G.; Satish, A. V.; Jordan, F.; Rios, C. B.;
Chung, A. C. J. Am. Chem. Soc. 1990, 112, 792.
(49) Jordan, F.; Kudzin, Z. H.; Rios, C. B. J. Am. Chem. Soc.
1987, 109, 4415.
(50) Barletta, G. L.; Zou, Y.; Huskey, W. P.; Jordan, F. J. Am.
Chem. Soc. 1997, 119, 2356.
(51) The 13C NMR and IR spectra were not obtained due to
decomposition of product upon purification.
(26) Smith, A. B.; Zhu, W. Y.; Shirakami, S.; Sfouggatakis, C.;
Doughty, V. A.; Bennett, C. S.; Sakamoto, Y. Org. Lett.
2003, 5, 761.
Synlett 2009, No. 3, 377–383 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.