Development of oxidative formylation and ketonylation reactions

Article abstract of DOI:10.1055/S-0029-1218663

The first oxidative formylation and oxidative ketonylation of alkenylamines and alkenyl alcohols is demonstrated. A range of substrates that participate in this process are provided. Oxidative formylation was found to proceed optimally with the use of triphenylsilane as the hydride source. Oxidative ketonylation was feasible with a number of organometallic partners, especially dialkylzinc or organostannanes. An interesting finding regarding the fate of various acylpalladium intermediates is discussed. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/S-0029-1218663

870
FEATURE ARTICLE
Development of Oxidative Formylation and Ketonylation Reactions
O
xidative For
m
i
ylation
s
and Keto
anylation M. Ambrosini, Tim A. Cernak, Tristan H. Lambert*
Department of Chemistry, Columbia University, New York, NY 10027, USA
Fax +1(212)9321289; E-mail: tl2240@columbia.edu
Received 2 November 2009; revised 4 November 2009
oxidative
O
O
Abstract: The first oxidative formylation and oxidative ketonyla-
tion of alkenylamines and alkenyl alcohols is demonstrated. A
formylation
R
R
X
X
H
R
R
R
XH
XH
range of substrates that participate in this process are provided. Ox-
idative formylation was found to proceed optimally with the use of
triphenylsilane as the hydride source. Oxidative ketonylation was
feasible with a number of organometallic partners, especially di-
alkylzinc or organostannanes. An interesting finding regarding the
fate of various acylpalladium intermediates is discussed.
oxidative
ketonylation
Key words: oxidative carbonylation, palladium, multicomponent
· valuable functional groups
reaction, formylation, ketonylation
· amenable to in situ
transformations
· oxidative formylation and
oxidative ketonylation
unknown reactions
One-pot, multi-transformation processes offer significant
advantages in terms of synthetic efficiency, yield, time,
and waste reduction. Our research group is interested in
exploring such strategies to advance the capacity to rapid-
ly generate valuable molecular architectures.1 A major
strategy in this regard is to invent new methodologies that
produce reactive functionalities amenable to facile in situ
derivatization, which may then serve as linchpin transfor-
mations for highly productive multicatalytic2 or
telescopic3 processes.
Scheme 1 Oxidative formylation and ketonylation reactions
ketones (oxidative ketonylation) have been disclosed.
This report describes our invention of such processes.
In contemplating the development of palladium(II)-medi-
ated oxidative formylation and ketonylation reactions, we
noted that these proposed transformations should be
mechanistically identical to traditional oxidative carbony-
lations except in the fate of the acylpalladium species
(Scheme 2). Thus, instead of termination of acylpalladi-
um intermediate 2 with an equivalent of alcohol to pro-
duce an ester product 3 as in the traditional Semmelhack-
type carbonylation, generation of an aldehyde or ketone
product 4 would require transmetalation with a suitable
organometallic reagent followed by reductive elimina-
tion.
As a platform for the development of linchpin methods,
we have been attracted to the palladium(II)-catalyzed in-
tramolecular oxidative carbonylation chemistry devel-
oped by Semmelhack4 and Hegedus.5 Intramolecular
oxidative carbonylation reactions produce substantial in-
creases in molecular complexity and accordingly have
found impressive application in natural product synthe-
sis.6 We believe the utility of these reactions would be fur-
ther increased if alternative, more reactive carbonyl
functionalities could be generated from this process in ad-
dition to the traditional ester or amide linkages.7 In this
context, we recently reported an oxidative aminochloro-
carbonylation reaction that generates acid chlorides,
which we employed in tandem with Friedel–Crafts acyla-
tion to produce complex a-pyrrolidinyl aryl ketones.1a
Of course, cross-coupling reactions of acylpalladium spe-
cies are well known in Pd(0)–Pd(II) catalytic cycles.
However, the feasibility of achieving this type of reaction
under oxidative carbonylation conditions was not clear,
especially given that during the generation of acylpalladi-
um intermediates 2 an equivalent of strong acid is pro-
duced. Given the substantial potential benefit of achieving
reactions of the type engendered by 1 → 4, we decided to
investigate whether this type of reaction was feasible.
As a result of the broad synthetic versatility of aldehydes
and ketones, we viewed the development of intramolecu-
lar oxidative carbonylation reactions that would generate
these functionalities as an especially attractive goal
(Scheme 1). To the best of our knowledge, no examples of
oxidative carbonylation of alkenyl alcohols or alkenyl-
amines to generate aldehydes (oxidative formylation) or
To begin, we decided to examine quenching of an acylpal-
ladium intermediate with a hydride source to generate al-
dehyde products. In these reactions, the substrate 5 and
one equivalent of PdCl2(PhCN)2 were stirred in a,a,a-tri-
fluorotoluene under an atmosphere of carbon monoxide
for one hour, after which time a hydride source was added
(Table 1). Using this protocol, tributyltin hydride (1
equiv) resulted in the production of aldehyde 6 in 21%
yield, but also induced rapid palladium black formation
SYNTHESIS 2010, No. 5, pp 0870–0881
x
x
.
x
x
.2
0
1
0
Advanced online publication: 05.02.2010
DOI: 10.1055/s-0029-1218663; Art ID: Z23109SS
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Oxidative Formylation and Ketonylation
871
O
ROH
known
R
R
OR
X
O
PdII
CO
3
esters→low
reactivity
R
Pd(II)
R
X
XH
O
2
1
H–M
or
R–M
H(R)
X
4
aldehydes or
ketones→
unknown
(this work)
high reactivity
Scheme 2 Design of an oxidative formylation reaction
and significant substrate decomposition (entry 1). Alter- Further improvements in yield were observed with the ad-
natively, triethylsilane (1 equiv) resulted in a significant dition of molecular sieves (entry 6), lowering of the tem-
increase of yield of 6 to 49%, albeit still with accompany- perature to –15 °C (entry 7), and dilution of the reaction
ing palladium black formation and a relatively complex medium (entry 8). Finally, optimal conditions were
product mixture (entry 2).
achieved through the use of a slight excess of palladium
reagent (1.05 equiv) and by presaturating the solvent with
carbon monoxide (entry 9). Under these conditions, the
oxidative formylation product 6 was produced in 78%
yield (as its ethylene acetal 6¢) as a >20:1 mixture of syn/
anti isomers. To the best of our knowledge, this represents
the first report of oxidative formylation of an alkenyl
amine derivative.
On the other hand, triphenylsilane provided a comparable
yield (43%) of 6 to triethylsilane but suppressed palladi-
um black formation and proved to be more reproducible
(entry 3). The use of additional equivalents of the silane
increased the yield significantly (entries 4 and 5), presum-
ably by helping to outcompete acid chloride formation,
which tended to be the major side product in this process.
Biographical Sketches
Lisa Ambrosini was born summer research at The Lambert. Her graduate stud-
in New Brunswick, New Memorial Sloan-Kettering ies have been focused on the
Jersey in 1983. She received Cancer Center with Derek development of new meth-
her B.S. degree in biochem- Tan. In 2006 she began her ods to enable multicatalytic
istry at Providence College graduate studies under the reactions.
in 2006. She also conducted mentorship
of
Tristan
Tim Cernak was born in der the supervision of Jim oping carbonylation reac-
Montreal, Québec in 1980. Gleason. From 2007 to tions as a platform for
He received a B.Sc. in 2002 2009, Tim worked with multicatalysis. In 2009, he
from Okanagan University Tristan Lambert at Colum- joined the Medicinal Chem-
College and a Ph.D. in 2007 bia University as a FQRNT istry team at Merck in
from McGill University un- Postdoctoral Fellow devel- Rahway, New Jersey.
Tristan Lambert was born and moved with MacMillan assistant
professor
at
in Madison, Wisconsin in to Caltech in 2000 where he Columbia University. His
1976 and received his B.S. received his Ph.D. in 2004. research group is interested
from the University of From 2004–2006 he was an in the development of new
Wisconsin at Platteville in NIH postdoctoral fellow multicatalytic processes and
1998. That year he began with Samuel Danishefsky at the design of reaction meth-
graduate studies with David the
Memorial
Sloan- ods using aromatic ions.
MacMillan at the University Kettering Cancer Center.
of California at Berkeley, Since 2006 he has been an
Synthesis 2010, No. 5, 870–881 © Thieme Stuttgart · New York

872
L. M. Ambrosini et al.
FEATURE ARTICLE
Table 1 Optimization Screen for Oxidative Formylation
Table 2 Substrate Scope for Intramolecular Oxidative Formylationa
i) PdCl2(PhCN)2
O
CO, 4 Å MS
i) PdCl2(PhCN)2 (1 equiv)
CO, PhCF3, 1 h
O
R
X
iPr
iPr
H
R
H
X
NH
Ts
N
ii) hydride source
–15 °C, PhCF3
ii) Ph3SiH
Ts
X = OH, NHTs
oxidative
formylation
5
6
Entry Substrate
Product
Yieldb drc
(%)
Entry Hydride source
(equiv)
Additive
Temp Molarity Yielda
(°C)
(%)
21
49
43
55
59
65
70
71
78c
1
2
3
4
5
6
7
8
9b
Bu3SnH (1)
Et3SiH (1)
Ph3SiH (1)
Ph3SiH (2)
Ph3SiH (3)
Ph3SiH (3)
Ph3SiH (3)
Ph3SiH (3)
Ph3SiH (3)
–
0
0.12
0.12
0.12
0.12
0.12
0.12
0.12
0.05
0.05
O
O
1
77
>20:1
>20:1
18:1
Me
NH
Ts
–
0
Me
H
H
N
Ts
–
0
2
3
4
81
66
74
–
0
Ph
NH
Ts
Ph
N
Ts
–
0
O
4 Å MS
4 Å MS
4 Å MS
4 Å MS
0
MeO2C
NH
Ts
MeO2C
H
N
Ts
–15
–15
–15
CHO
NTs
NHTs
a Yields determined by 1H NMR analysis using Bn2O as an internal
standard. The dr was >20:1 syn/anti in all cases.
b PdCl2(PhCN)2 (1.05 equiv) was used and the solvent was saturated
with CO before reaction.
H
5
6
66
63
>20:1
>20:1
NH
Ts
N
Ts
H
CHO
O
c The isolated yield for this reaction for 6 as its ethylene acetal 6¢ was
also 78%.
NH
Ts
N
H
An examination of the substrate scope of this reaction is
shown in Table 2. Both a-alkyl and a-aryl amino sub-
strates were found to participate efficiently in this process
(entries 1 and 2). In addition, use of an a-amino ester sub-
strate led to the generation of a proline ester derivative
(entry 3). Substitution in the b-position was also well tol-
erated (entry 4). Notably, oxidative formylation of an in-
ternal olefin proved possible, as with the production of the
bicyclic aldehyde shown in entry 5. We found cyclization
to form piperidine adducts to be more difficult, although
N-tosylhex-5-en-1-amine was employed with reasonable
success (entry 6).
Ts
H
H
H
O
7
8
70
72
OH
O
H
H
H
O
Bn
Bn
Bn
Bn
–
OH
H
O
a Reactions were performed using the optimal conditions described in
the text.
b Determined on the 1,3-dioxolane derivatives as isolated and purified
products.
Alcohol substrates present an additional challenge due to
the potential for carbonylative dimerization (acylation of
the starting material by the acylpalladium intermediate).
Nevertheless, we found that certain substrates were viable
in this process. Thus the cyclohexenol substrate shown in
entry 7 led to the formation of an octahydrochromenyl al-
dehyde in good yield. In addition, a tertiary alcohol sub-
strate reacted efficiently to produce the tetrahydrofuranyl
aldehyde shown in entry 8.
c Determined by 1H NMR analysis on crude reaction mixtures.
i) oxidative formylation
CO2Et
iPr
iPr
N
NH
Ts
ii)
Ts
CO2Et
Ph3P
72% yield
>20:1 syn/anti
3:1 E/Z
5
7
Equation 1
As a demonstration of the utility of this oxidative formy-
lation reaction for one-pot, multi-transformation synthe-
sis, we conducted the following experiment. Thus
alkenylamine 5 was subjected to oxidative formylation
followed by addition to the reaction mixture of ethyl
(triphenylphosphoranylidene)carboxylate, which pro-
duced the a,b-unsaturated ester 7 in 72% yield as a single
observable diastereomer (Equation 1).
We were also interested in employing aldehyde products
of oxidative formylation as substrates for in situ nucleo-
philic addition reactions. However, when alcohol 8 was
subjected to our standard oxidative formylation condi-
tions and then treated with diethylzinc, we were surprised
to observe ketone 9 (67% yield, >20:1 syn/anti) and none
of the expected secondary alcohol (Equation 2).
Synthesis 2010, No. 5, 870–881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Oxidative Formylation and Ketonylation
873
H
H
H
which is remarkable given that an equivalent of HCl is
produced during acylpalladium formation. Other organo-
metallic partners also proved viable for the production of
the phenyl ketone product 16, including phenylzinc chlo-
ride (entry 6) and tributyl(phenyl)stannane (entry 7). No-
tably, use of 1.5 equivalents of stannane resulted in the
same yield as 3 equivalents (entries 7 and 8), and reason-
able efficiency was still observed using only 1.1 equiva-
lents (entry 9). A Grignard reagent provided the expected
product, albeit with diminished yield (entry 10), while
i) "oxidative formylation"
standard conditions
O
ii) Et2Zn
OH
O
Et
H
H
(see Figure 3)
8
9
ketone!
67% yield
>20:1 syn/anti
Equation 2
In an effort to understand how ketone 9 arose from this se- phenyllithium and phenylboronic acid proved to be poor
quence, we independently prepared aldehyde 13 and sub- participants in this process (entries 11 and 12).
jected it to diethylzinc under a range of conditions,
Next we conducted experiments to probe the substrate
attempting to mimic those present in the reaction shown in
scope for this oxidative ketonylation reaction (Table 4).
Equation 2 (Scheme 3). Under no circumstances, howev-
Thus both ethyl and methyl ketones could be accessed in
er, was any nucleophilic addition product observed, sug-
gesting that the reaction of diethylzinc to form 9 must
have occurred prior to reductive elimination of the puta-
tive acylpalladium hydride intermediate 12.
Table 3 Oxidative Ketonylation Using Various Organometallic Re-
agentsa
i) PdCl2(PhCN)2
O
CO, 4 Å MS
This finding was interesting, given that when methanol
was added to the same intermediate, aldehyde 13 was gen-
erated without production of methyl ester 11, which is
produced if no hydride source is added (Semmelhack car-
bonylation). Thus we believe that acylpalladium hydride
intermediate 12 is formed but does not undergo reductive
elimination until workup, and that addition of diethylzinc
to intermediate 12 results in production of an acylpalladi-
um alkyl intermediate 14 that undergoes reductive elimi-
nation in complete preference to the corresponding
hydride reductive elimination.
iPr
iPr
PhCF3, 30 min
–15 °C
NH
Ts
N
R
Ts
5
ii) RM
Entry RM
Equiv Product
Yieldb (%)
1
2
3
4
5
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
3.0
1.5
95
94
93
90
88
O
1.0
0.6
0.5
iPr
Et
N
Ts
15
6
7
8
PhZnCl
PhSnBu3
PhSnBu3
PhSnBu3
PhMgBr
PhLi
1.1
3.0
1.5
1.1
2.2
2.2
85
92
92
79
64
Given our goal of generating ketone products via oxida-
tive carbonylation, we decided to investigate the same
general reaction without the addition of silane (Table 3).
Remarkably, when the acylpalladium intermediate pro-
duced from alkenylamine 5 was treated with three equiv-
alents of diethylzinc, the ethyl ketone product 15 was
produced in 95% yield as a single observable diastereo-
mer (entry 1). Furthermore, we found that the equivalents
O
9
iPr
Ph
N
10
11
12
Ts
16
<15
35
PhB(OH)2 2.0
a Reactions conditions: substrate, PdCl2(PhCN)2 (1.05 equiv), 4 Å
MS, PhCF3 (0.075 M), CO, stirring, –15 °C, 30 min. Indicated orga-
of the zinc reagent could be reduced to as low as 0.5 with- nometallic reagent was then added and stirred at –15 °C for 20 min.
b Isolated yield.
out substantial detriment to product yield (entries 2–5),
product
intermediate
H
H
PdCl2(PhCN)2
CO
O
O
O
MeOH
8
Cl
L
Semmelhack
carbonylation
O
H
11
OMe
O
Pd
Pd
Pd
H
H
H
H
H
H
H
L
10
Ph3SiH
O
MeOH
H
L
oxidative
formylation
O
H
13
H
O
H
H
H
H
L
Et2Zn
12
Et2Zn
(11 not observed)
X
O
O
Et
L
O
oxidative
ketonylation
O
H
9
Et
H
H
L
14
Scheme 3 Studies to determine fate of acylpalladium intermediates
Synthesis 2010, No. 5, 870–881 © Thieme Stuttgart · New York

874
L. M. Ambrosini et al.
FEATURE ARTICLE
high yield using commercially available dialkylzinc re- generation of furanyl ketone products in high yield (en-
agents (entries 1–3). A benzylic amine substrate was also tries 7 and 9). It should be noted that furans and unactivat-
a productive reactant, leading to a phenyl ketone product ed benzenes (entries 4, 7, and 9) were not accessible using
with the use of commercially available phenylzinc chlo- our previously reported multicatalytic chlorocarbonyla-
ride (entry 4). Notably, use of tributyl(vinyl)stannane tion/Friedel–Crafts methodology, making the present
gave rise to an a,b-unsaturated ketone (entry 5), a synthet- technology a useful complement to that procedure.1a As
ically versatile structural motif. Alternatively, allyltribu- observed before, cyclization to piperidine adducts was
tylstannane furnished the corresponding b,g-unsaturated possible, though less efficient (entry 8). On the other
ketone, albeit with somewhat diminished yield (entry 6). hand, alcohol substrates could be employed with high ef-
On the other hand, tributyl(furan-2-yl)stannane led to the
Table 4 Substrate Scope Studies for Oxidative Ketonylationa
i) PdCl2(PhCN)2
O
CO, 4 Å MS
R
X
R
R
X
–15 °C, PhCF3
ii) RM
X = OH, NHTs
oxidative
ketonylation
Entry
1
Substrate
RM (equiv)
Product
Yieldb (%)
90
drc
O
O
O
O
O
Et2Zn
(0.6)
>20:1
iPr
NH
iPr
iPr
Me
Ph
iPr
Et
N
Ts
Ts
Me2Zn
(0.6)
2
3
4
5
6
82
76
79
94
58
>20:1
>20:1
16:1
iPr
Me
Ph
iPr
iPr
NH
Ts
Me
Me
Ph
N
Ts
Me2Zn
(0.6)
NH
Ts
N
Ts
PhZnCl
(1.1)
NH
Ts
N
Ts
SnBu3
>20:1
18:1
NH
Ts
N
(1.3)
Ts
O
SnBu3
SnBu3
NH
Ts
iPr
N
(1.5)
Ts
O
O
7
8
9
84
>20:1
O
iPr
iPr
NH
Ts
N
Ts
(1.3)
O
Et2Zn
(0.6)
63 (82d)
93
–
–
N
Et
NHTs
OH
Ts
O
O
Bn
Bn
SnBu3
Bn
Bn
O
O
(1.3)
H
OH
Et2Zn
(0.6)
O
10
72
>20:1
O
Et
H
H
a Reaction conditions: substrate, PdCl2(PhCN)2 (1.05 equiv), 4 Å MS, PhCF3 (0.075 M), CO, stirring, –15 °C, 30 min. Indicated organometallic
reagent was then added and stirred at –15 °C for 20 min.
b Isolated yield.
c Diastereomeric ratios were determined by 1H NMR analysis on crude reaction mixtures.
d Based on recovered starting material.
Synthesis 2010, No. 5, 870–881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Oxidative Formylation and Ketonylation
875
in PhCF3 (filtered through silica gel before use) cooled to –15 °C
was added. The mixture was stirred until completion of the reaction
(10–60 min). 0.45 M Ph3SiH in PhCF3 (3 equiv) cooled to –15 °C
was added quickly and the mixture was stirred for 10 min. Ethylene
glycol (5 equiv) was added and the mixture was warmed to 23 °C.
After 3 h, the mixture was filtered through a plug of celite and con-
centrated in vacuo. The product was purified by flash chromatogra-
phy (silica gel or alumina).
ficiency, as with the tertiary and secondary alcohols
shown in entries 9 and 10.
To demonstrate the ability of this oxidative ketonylation
procedure to facilitate one-pot, multi-transformation pro-
cesses, we subjected the alkenylamine substrate 5 to our
standard conditions, using tributyl(vinyl)stannane as the
organometallic reagent (Equation 3). Subsequent addition
of cyclopentadiene to the resultant vinyl ketone then in-
duced a Diels–Alder reaction to produce the complex ke-
tone 17 in 89% yield.
Oxidative Ketonylation; General Procedure
An oven-dried round-bottom flask with a magnetic stir bar was
charged with PdCl2(PhCN)2 (1.05 equiv) and flame-dried, ground 4
Å MS (500 mg/mmol of substrate). The flask was evacuated and
backfilled with CO via balloon (3 ×) and PhCF3 (8.5 mL/mmol) was
added. The soln was cooled to –15 °C in a salt–ice bath and CO was
bubbled through the soln for 30 min. A 0.24 M soln of the substrate
in PhCF3 (filtered through silica gel before use) cooled to –15 °C
was added. The mixture was stirred until completion of reaction
(10–60 min). The required organometallic reagent at the indicated
amount was then added at –15 °C and the mixture was stirred at this
temperature for 20 min. The mixture was filtered through a plug of
celite and concentrated in vacuo. The product was purified by flash
chromatography (silica gel or alumina).
i)
oxidative
ketonylation
O
SnBu3
iPr
iPr
N
NH
Ts
5
Ts
ii)
17
one pot
89% yield
>20:1 syn/anti
(55:45 endo/exo)
Troubleshooting
Equation 3
This reaction is sensitive to the saturation of the reaction solvent by
CO. For best reproducibility, reactions are run in larger reactions
vessels (25-mL and 50-mL round bottom flasks for 0.1–0.2 mmol
reactions) to increase the surface area for CO absorption. After al-
lowing the PdCl2(PhCN)2 to dissolve in the solvent and then cooling
the reaction, bubble CO through the mixture before addition of the
substrate to ensure maximum CO solubility. Finally, the solns of
both the substrate and silane must be cooled to the reaction temper-
ature before very quick additions to the reaction vessel. The best re-
sults have been obtained using PdCl2(PhCN)2 synthesized from
PdCl2 purchased from Strem.
In conclusion, we have developed the first examples of
oxidative carbonylation reactions that generate aldehyde
and ketone products. These transformations provide new
synthetic tools with which to access these important het-
erocyclic architectures without the need for redox manip-
ulations. Further development of this chemistry to achieve
catalytic use of palladium represents an intriguing goal
that we are currently contemplating.8
1-Phenyl-N-tosylpent-4-en-1-amine (Table 2, Entry 2, Sub-
strate)
All reactions were performed using base-washed, oven-dried glass-
ware under an atmosphere of argon (dried by passage through
Drierite) or CO. Reagents and solvents were transferred under ar-
gon by syringe. Organic solns were concentrated under reduced
pressure using a Buchi rotary evaporator. PhCF3 purchased from
Aldrich was distilled from K2CO3, degassed by freeze-pump-thaw
method and stored under an atmosphere of CO. Et2O, THF, and
CH2Cl2 were dried using a J. C. Meyer solvent purification system.
PdCl2(PhCN)2 was prepared according to a known procedure9 from
PdCl2 purchased from Strem or Aldrich and PhCN purchased from
TCI America. All other reagents were used as received unless spec-
ified. Flash column chromatography was performed employing 32–
63 mm silica gel (Dynamic Adsorbents Inc) or basic alumina (Fluka,
pH 9.5). TLC was performed on silica gel 60 F254 plates (EMD).
1H and 13C NMR were recorded in CDCl3 on Bruker DRX-300 and
DRX-400 as noted, and are internally referenced to the residual sol-
vent peak. Data for 13C NMR are reported in terms of chemical shift.
IR spectra were recorded on a Nicolet Avatar 370 DTGS (Thermo)
using NaCl salt plates.. LR-MS were acquired on a JEOL JMS-LC-
mate liquid chromatography mass spectrometer system using AP-
CI+ ionization technique.
A soln of 1-phenylpent-4-en-1-amine10 (0.41 g, 2.5 mmol, 1.0
equiv), Et3N (0.70 mL, 5.0 mmol, 2.0 equiv), and DMAP (30.5 mg,
0.25 mmol, 0.1 equiv) in CH2Cl2 (8 mL) was cooled to 0 °C. A soln
of TsCl (572 mg, 3.0 mmol, 1.2 equiv) in CH2Cl2 (2 mL) was slowly
added to the mixture, which was then stirred at r.t. overnight. The
mixture was diluted with CH2Cl2 (10 mL), washed with 1 M HCl (1
× 10 mL), H2O (1 × 10 mL), and brine (1 × 10 mL), dried (anhyd
Na2SO4), and concentrated in vacuo. Column chromatography (sil-
ica gel, 5% EtOAc–hexanes) gave the title compound (459 mg,
58%) as a white solid.
IR: 3280, 3070, 3035, 2930, 2854, 1449, 1337, 1155, 1099, 924,
812, 708, 659 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.53 (d, J = 8.4 Hz, 2 H, Ar-H),
7.16–7.14 (m, 3 H, Ar-H), 7.11 (d, J = 8.4 Hz, 2 H, Ar-H), 7.01–
6.98 (m, 2 H, Ar-H), 5.77–5.64 (m, 1 H, CH=CH2), 4.97–4.90 (m,
3 H, TsNH, CH=CH2), 4.33–4.26 (m, 1 H, PhCH), 2.35 (s, 3 H,
ArCH3), 2.03–1.72 (m, 4 H, CH2CH2).
13C NMR (75 MHz, CDCl3): d = 143.1, 140.8, 137.8, 137.3, 129.4,
128.6, 127.6, 127.2, 126.6, 115.7, 58.0, 36.8, 30.1, 21.6.
LR-MS (APCI+): m/z [M + H]+ calcd for C18H22NO2S: 316.4;
found: 316.1.
Oxidative Formylation; General Procedure A
An oven-dried round-bottom flask with a magnetic stir bar was
charged with PdCl2(PhCN)2 (1.05 equiv) and flame-dried, ground 4
Å MS (500 mg/mmol of substrate). The flask was evacuated and
backfilled with CO via balloon (3 ×) and PhCF3 (9.2 mL/mmol) was
added. The soln was cooled to –15 °C in a salt–ice bath and CO was
bubbled through the soln for 30 min. A 0.24 M soln of the substrate
Methyl 2-(Tosylamino)hex-5-enoate (Table 2, Entry 3, Sub-
strate)
A soln of N-(diphenylmethylene)glycine methyl ester11 (447 mg,
1.76 mmol, 1.0 equiv) in DMF (3 mL) was added to a 0 °C suspen-
sion of 60% NaH (74 mg, 1.85 mmol, 1.05 equiv) in DMF (10 mL).
Synthesis 2010, No. 5, 870–881 © Thieme Stuttgart · New York

876
L. M. Ambrosini et al.
FEATURE ARTICLE
The mixture was stirred for 30 min at 0 °C, NaI (26 mg, 0.176
mmol, 0.1 equiv) and 4-bromobut-1-ene (0.36 mL, 3.53 mmol, 2.0
equiv) were added. The mixture was stirred at 50 °C for 90 min. The
mixture was cooled and diluted with Et2O (30 mL) and washed with
H2O (5 × 20 mL) and brine (1 × 20 mL). The organic layer was dried
(anhyd Na2SO4) and concentrated in vacuo. The crude product was
then stirred overnight in a mixture of 1 M HCl (5 mL) and Et2O (5
mL) at 23 °C. The layers were then separated and Na2CO3 was add-
ed to the aqueous layer until it reached pH 9. The aqueous layer was
then extracted with 5% MeOH–CH2Cl2 (5 × 10 mL) and then the or-
ganic layer was washed with brine (1 × 20 mL). The soln was dried
(anhyd Na2SO4) and concentrated in vacuo to give crude product
that was used directly in the next reaction. A soln of the amino ester,
Et3N (0.29 mL, 1.64 mmol, 2.0 equiv), and DMAP (10 mg, 0.082
mmol, 0.1 equiv) in CH2Cl2 (3 mL) was cooled to 0 °C. A soln of
TsCl (187 mg, 0.98 mmol, 1.2 equiv) in CH2Cl2 (1 mL) was slowly
added to the mixture, which then stirred at r.t. for 6 h. The mixture
was diluted with CH2Cl2 (5 mL), washed with H2O (1 × 5 mL) and
brine (1 × 5 mL), dried (anhyd Na2SO4), and concentrated in vacuo.
Column chromatography (silica gel, gradient 10–20% EtOAc–
hexanes) gave the title compound (241 mg, 46% over 3 steps) as a
white solid.
LR-MS (APCI+): m/z [M + H]+ calcd for C14H19O3S: 267.4; found:
267.0.
The tosylate synthesized above (2.0 g, 7.5 mmol, 1.0 equiv), K2CO3
(2.07 g, 15.0 mmol, 2.0 equiv), and TsNH2 (1.93 g, 11.3 mmol, 1.5
equiv) in acetone (10 mL) were heated to reflux overnight. The mix-
ture was then concentrated and diluted with EtOAc (30 mL), then
washed with H2O (1 × 20 mL) and brine (1 × 20 mL), dried (anhyd
Na2SO4), and concentrated in vacuo. Column chromatography (sil-
ica gel, gradient 5–10% EtOAc–hexanes) gave the title compound
(1.21 g, 56%) as a colorless oil.
IR: 3278, 2935, 2843, 1422, 1317, 1161, 1087, 752, 665 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.75 (d, J = 8.1 Hz, 2 H, Ar-H),
7.31 (d, J = 7.8 Hz, 2 H, Ar-H), 5.72–5.70 (m, 1 H, CH=CH), 5.57–
5.54 (m, 1 H, CH=CH), 4.40 (t, J = 5.7 Hz, 1 H, TsNH), 2.97 (q,
J = 7.2 Hz, 2 H, TsNHCH2), 2.67–2.61(m, 1 H, CH), 2.43 (s, 3 H,
ArCH3), 2.33–2.20 (m, 2 H, CH=CHCH2), 2.04–1.92 (m, 1 H,
CH2), 1.63–1.51 (m, 1 H, CH2), 1.50–1.41 (m, 1 H, CH2), 1.38–1.28
(m, 1 H, CH2).
13C NMR (75 MHz, CDCl3): d = 143.5, 137.7, 137.1, 133.9, 131.4,
129.8, 127.2, 42.9, 42.0, 35.8, 32.0, 29.6, 21.6.
LR-MS (APCI+): m/z [M + H]+ calcd for C14H20NO2S: 266.4;
found: 266.0.
IR: 3273, 2951, 2917, 1742, 1637, 1595, 1435, 1330, 1169, 1092,
812, 652 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.71 (d, J = 8.1 Hz, 2 H, Ar-H),
7.28 (d, J = 8.4 Hz, 2 H, Ar-H), 5.77–5.64 (m, 1 H, CH=CH2), 5.24
(d, J = 9.3 Hz, 1 H, TsNH), 5.01–4.96 (m, 2 H, CH=CH2), 3.95–
3.88 (m, 1 H, TsNHCH), 3.48 (s, 3 H, OCH3), 2.40 (s, 3 H, CH3),
2.10 (q, J = 7.5 Hz, 2 H, CH2), 1.86–1.63 (m, 2 H, CH2).
13C NMR (75 MHz, CDCl3): d = 172.2, 143.7, 136.8, 136.6, 129.7,
127.4, 116.1, 55.2, 52.5, 32.6, 29.1, 21.6.
2-Benzyl-1-phenylhex-5-en-2-ol (Table 2, Entry 8, Substrate)
To soln of methyl pent-4-enoate (0.60 g, 5.3 mmol, 1.0 equiv) in
THF (49 mL) cooled to –78 °C, 2.0 M BnMgCl in Et2O (6.6 mL,
13.3 mmol, 2.5 equiv) was slowly added. The mixture was warmed
to 23 °C and stirred for 2 h. The reaction was quenched at 0 °C with
sat. NH4Cl soln (30 mL). The layers were separated and the aqueous
layer was extracted with Et2O (3 × 20 mL). The organic layer was
then washed with brine (1 × 20 mL), dried (anhyd Na2SO4), and
concentrated in vacuo. Column chromatography (silica gel, 5%
EtOAc–hexanes) gave the title compound (0.80 g, 59%) as a pale
yellow oil.
LR-MS (APCI+): m/z [M + H]+ calcd for C14H20NO4S: 298.4;
found: 298.2.
2-(Cyclopent-2-enyl)-N-tosylethanamine (Table 2, Entry 5,
Substrate)
IR: 3568, 3470, 3061, 3025, 2923, 1637, 1606, 1499, 1446, 1370,
1268, 1085, 1036, 903, 756, 725, 698 cm–1.
To a suspension of LiAlH4 (1.51 g, 39.8 mmol, 2.5 equiv) in THF
(80 mL) cooled to 0 °C, a soln of cyclopent-2-eneacetic acid (1.66
g, 14.8 mmol, 1.0 equiv) in THF (16 mL) was slowly added. The
mixture was heated to reflux for 3 h and then cooled to 0 °C. The
mixture was diluted with Et2O (100 mL) and then H2O (2 mL), 1 M
NaOH (2 mL), and H2O (4 mL) were added sequentially. The mix-
ture was stirred for 1 h and then filtered over a short silica plug,
dried (anhyd Na2SO4), and concentrated in vacuo to yield 2-(cyclo-
pent-2-enyl)ethanol as a colorless oil (1.66 g, 93%). A soln of the
alcohol, Et3N (4.1 mL, 29.6 mmol, 2.0 equiv), and DMAP (90 mg,
0.74 mmol, 0.05 equiv) in CH2Cl2 (44 mL) was cooled to 0 °C. A
soln of TsCl (3.39 g, 17.8 mmol, 1.2 equiv) in CH2Cl2 (12 mL) was
slowly added to the mixture, which was stirred at r.t. overnight. The
mixture was diluted with CH2Cl2 (40 mL), washed with H2O (1 ×
40 mL) and brine (1 × 40 mL), dried (anhyd Na2SO4), and concen-
trated in vacuo. Column chromatography (silica gel, gradient 5–
10% EtOAc–hexanes) gave 3-[2-(tosyloxy)ethyl]cyclopentene
(3.51 mg, 89%) as a colorless oil.
1H NMR (300 MHz, CDCl3): d = 7.40–7.28 (m, 10 H, Ar-H), 5.90–
5.77 (m, 1 H, CH=CH2), 5.11–4.98 (m, 2 H, CH=CH2), 2.88 (s, 4 H,
PhCH2), 2.36–2.28 (m, 2 H, CH2), 1.55–1.49 (m, 2 H, CH2), 1.46 (s,
1 H, OH).
13C NMR (75 MHz, CDCl3): d = 138.6, 137.3, 130.8, 128.3, 126.6,
114.6, 74.2, 45.6, 37.4, 28.4.
LR-MS (APCI+): m/z [M + H]+ calcd for C19H23O: 267.4; found:
267.2.
syn-2-[(1,3-Dioxolan-2-yl)methyl]-5-isopropyl-1-tosylpyrroli-
dine (6¢)
Following general procedure A using 2-methyl-N-tosylhept-6-en-3-
amine1a (5, 40.0 mg, 0.142 mmol, 1.0 equiv), PdCl2(PhCN)2 (56.4
mg, 0.147 mmol, 1.05 equiv), 4 Å MS (70 mg), Ph3SiH (111 mg,
0.426 mmol, 3.0 equiv), and ethylene glycol (40 mL, 0.71 mmol, 5.0
equiv) and flash chromatography (silica gel, gradient 1–5% EtOAc–
hexanes) gave 6¢ (39.1 mg, 78%) as a white solid.
IR: 3056, 2924, 2854, 1609, 1372, 1176, 1099, 952, 903, 812, 652
cm–1.
IR: 2958, 2867, 1602, 1330, 1148, 1085, 1036, 994, 819, 658 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.72 (d, J = 8.4 Hz, 2 H, Ar-H),
7.29 (d, J = 8.4 Hz, 2 H, Ar-H), 4.95 [t, J = 5.1 Hz, 1 H,
CH2CH(OR)2], 3.99–3.90 (m, 2 H, OCH2), 3.90–3.84 (m, 2 H,
OCH2), 3.79–3.74 (m, 1 H, TsNCH), 3.40 (q, J = 6.9 Hz, 1 H,
TsNCH), 2.41 (s, 3 H, ArCH3), 2.29 [dt, J = 4.8, 13.8 Hz, 1 H,
CH2CH(OR)2], 2.10–1.99 (m, 1 H, Me2CH), 1.78–1.67 [m, 1 H,
CH2CH(OR)2], 1.65–1.55 (m, 2 H, CH2), 1.52–1.42 (m, 1 H, CH2),
1.35–1.24 (m, 1 H, CH2), 0.96 (d, J = 6.9 Hz, 3 H, CH3), 0.90 (d,
J = 6.7 Hz, 3 H, CH3).
1H NMR (300 MHz, CDCl3): d = 7.79 (d, J = 8.1 Hz, 2 H, Ar-H),
7.34 (d, J = 8.1 Hz, 2 H, Ar-H), 5.72–5.69 (m, 1 H, CH=CH), 5.56–
5.53 (m, 1 H, CH=CH), 4.07 (t, J = 6.0 Hz, 2 H, CH2OTs), 2.73–
2.66 (m, 1 H, CH), 2.45 (s, 3 H, ArCH3), 2.37–2.16 (m, 2 H,
CH=CHCH2), 2.04–1.92 (m, 1 H, CH2), 1.82–1.70 (m, 1 H, CH2),
1.67–1.56 (m, 1 H, CH2), 1.38–1.27 (m, 1 H, CH2).
13C NMR (75 MHz, CDCl3): d = 144.8, 133.6, 133.4, 131.5, 130.0,
128.0, 69.7, 41.9, 35.0, 32.0, 29.6, 21.7.
Synthesis 2010, No. 5, 870–881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Oxidative Formylation and Ketonylation
877
13C NMR (75 MHz, CDCl3): d = 143.3, 135.1, 129.7, 127.8, 102.6,
67.3, 64.9, 64.7, 58.1, 41.1, 31.7, 30.3, 25.5, 21.6 20.2, 17.5.
3 H, ArCH3), 2.35 [dt, 1 H, CH2CH(OR)2], 1.99–1.65 [m, 5 H,
CH2CH(OR)2, CH2CH2].
LR-MS (APCI+): m/z [M + H]+ calcd for C18H28NO4S: 354.2;
found: 354.0.
13C NMR (75 MHz, CDCl3): d = 172.7, 143.9, 135.2, 129.9, 127.8,
102.5, 65.0, 64.8, 61.7, 58.3, 52.7, 39.9, 31.1, 29.5, 21.7.
LR-MS (APCI+): m/z [M + H]+ calcd for C17H24NO6S: 370.1;
found: 370.2.
syn-2-[(1,3-Dioxolan-2-yl)methyl]-5-methyl-1-tosylpyrrolidine
(Table 2, Entry 1, Product)
Following general procedure A using N-tosylhex-5-en-2-amine12
(40.0 mg, 0.158 mmol, 1.0 equiv), PdCl2(PhCN)2 (63.6 mg, 0.166
mmol, 1.05 equiv), 4 Å MS (79 mg), Ph3SiH (123 mg, 0.474 mmol,
3.0 equiv), and ethylene glycol (44 mL, 0.79 mmol, 5.0 equiv) and
flash chromatography (alumina, gradient 5–20% EtOAc–hexanes)
gave the title compound (39.5 mg, 77%) as a white solid.
3-[(1,3-Dioxolan-2-yl)methyl]-2-tosyl-2-azaspiro[4.5]decane
(Table 2, Entry 4, Product)
Following general procedure A using N-tosyl(1-allylcyclohex-
yl)methylamine5b (40.0 mg, 0.130 mmol, 1.0 equiv), PdCl2(PhCN)2
(52.4 mg, 0.137 mmol, 1.05 equiv), 4 Å MS (65 mg), Ph3SiH (102
mg, 0.390 mmol, 3.0 equiv), and ethylene glycol (36 mL, 0.65
mmol, 5.0 equiv) and flash chromatography (silica gel, gradient 5–
20% EtOAc–hexanes) gave the title compound (36.7 mg, 74%) as a
colorless oil.
IR: 2968, 2922, 2871, 1604, 1340, 1157, 1099, 1036, 664 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.73 (d, J = 8.1 Hz, 2 H, Ar-H),
7.29 (d, J = 8.1 Hz, 2 H, Ar-H), 4.98 [t, J = 4.8 Hz, 1 H,
CH2CH(OR)2], 4.00–3.90 (m, 2 H, OCH2CH2O), 3.88–3.81 (m, 2
H, OCH2CH2O), 3.79–3.74 (m, 1 H, TsNCH), 3.70–3.75 (m, 1 H,
TsNCH), 2.42 (s, 3 H, ArCH3), 2.32 [dt, J = 5.1, 13.8 Hz, 1 H,
CH2CH(OR)2], 1.85–1.76 [m, 1 H, CH2CH(OR)2], 1.73–1.45 (m, 4
H, CH2), 1.33 (d, J = 6.3 Hz, 3 H, CH3).
IR: 2924, 2847, 1595, 1449, 1337, 1162, 1085, 1043, 938, 819, 659
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.73 (d, J = 8.4 Hz, 2 H, Ar-H),
7.30 (d, J = 8.1 Hz, 2 H, Ar-H), 4.91 [dd, J = 4.2, 5.7 Hz, 1 H,
CH2CH(OR)2], 3.99–3.89 (m, 2 H, OCH2CH2O), 3.85–3.81 (m, 2
H, OCH2CH2O), 3.66–3.58 (m, 1 H, TsNCH), 3.24 (d, 1 H,
13C NMR (75 MHz, CDCl3): d = 143.3, 135.1, 129.7, 127.7, 102.6,
64.9, 64.8, 58.3, 57.5, 41.4, 32.2, 20.4, 23.7, 21.6.
TsNCH2), 3.10 (d, 1 H, TsNCH2), 2.68–2.61 [m, 1 H,
CH2CH(OR)2], 2.41 (s, 3 H, ArCH3), 1.94–1.80 [m, 2 H,
CH2CH(OR)2, CH2], 1.56–1.50 (m, 1 H, CH2), 1.42–1.13 (m, 8 H,
CH2), 0.80–0.73 (m, 1 H, CH2), 0.64–0.60 (m, 1 H, CH2).
LR-MS (APCI+): m/z [M + H]+ calcd for C16H24NO4S: 326.1;
found: 326.2.
syn-2-[(1,3-Dioxolan-2-yl)methyl]-5-phenyl-1-tosylpyrrolidine
(Table 2, Entry 2, Product)
13C NMR (75 MHz, CDCl3): d = 143.3, 134.9, 129.6, 127.7, 102.8,
64.9, 58.6, 56.0, 45.2, 41.4, 41.0, 36.6, 34.3, 26.0, 23.8, 23.0, 21.7.
Following general procedure A using 1-phenyl-N-tosylpent-4-en-1-
amine (40.0 mg, 0.127 mmol, 1.0 equiv), PdCl2(PhCN)2 (51.1 mg,
0.133 mmol, 1.05 equiv), 4 Å MS (64 mg), Ph3SiH (99.2 mg, 0.381
mmol, 3.0 equiv), and ethylene glycol (35 mL, 0.64 mmol, 5.0
equiv) and flash chromatography (silica gel, gradient 5–20%
EtOAc–hexanes) gave the title compound (39.7 mg, 81%) as a
white solid.
LR-MS (APCI+): m/z [M + H]+ calcd for C20H30NO4S: 380.2;
found: 380.3.
syn-6-(1,3-Dioxolan-2-yl)-1-tosyloctahydrocyclopenta[b]pyr-
role (Table 2, Entry 5, Product)
Following general procedure A using 2-(cyclopent-2-enyl)-N-to-
sylethanamine (35.0 mg, 0.132 mmol, 1.0 equiv), PdCl2(PhCN)2
(60.7 mg, 0.158 mmol, 1.2 equiv), 4 Å MS (66 mg), Ph3SiH (103
mg, 0.396 mmol, 3.0 equiv), and ethylene glycol (37 mL, 0.66
mmol, 5.0 equiv) and flash chromatography (alumina, gradient 2–
15% EtOAc–hexanes) gave the title compound (29.4 mg, 66%) as a
white solid.
IR: 2970, 2883, 1600, 1487, 1439, 1335, 1152, 1087, 1035, 743,
665 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.72 (d, J = 8.1 Hz, 2 H, Ar-H),
7.37–7.20 (m, 7 H, Ar-H), 5.00 [t, J = 5.1 Hz, 1 H, CH2CH(OR)2],
4.71 (t, J = 6.6 Hz, 1 H, TsNCHPh), 4.02–3.92 (m, 3 H,
OCH2CH2O, TsNCH), 3.88–3.84 (m, 2 H, OCH2CH2O), 2.53 [dt,
J = 4.8, 13.8 Hz, 1 H, CH2CH(OR)2], 2.43 (s, 3 H, ArCH3), 1.97–
1.84 [m, 3 H, CH2CH(OR)2, CH2], 1.69 (q, J = 6.3 Hz, 2 H, CH2).
13C NMR (75 MHz, CDCl3): d = 143.5, 142.7, 135.1, 129.7, 128.5,
127.9, 127.1, 126.3, 102.7, 65.0, 64.8, 64.7, 58.6, 40.9, 34.4, 30.6,
21.7.
IR: 2952, 2865, 1591, 1343, 1152, 1109, 1026, 813, 652 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.76 (d, J = 8.4 Hz, 2 H, Ar-H),
7.32 (d, J = 8.1 Hz, 2 H, Ar-H), 5.08 [d, J = 3.6 Hz, 1 H,
CH2CH(OR)2], 4.04–3.84 (m, 4 H, OCH2CH2O), 3.77 (dd, 1 H,
NTsCH), 3.50–3.42 (m, 1 H, TsNCH2), 3.13–3.05 (m, 1 H,
TsNCH2), 2.66–2.61 [m, 1 H, CHCH(OR)2], 2.50–2.42 (m, 1 H,
CH2), 2.42 (s, 3 H, ArCH3), 1.89–1.73 (m, 2 H, CH2), 1.69–1.41 (m,
4 H, CH2, CH).
13C NMR (75 MHz, CDCl3): d = 143.4, 134.3, 129.7, 128.0, 104.9,
66.5, 65.3, 65.1, 50.1, 49.4, 44.3, 30.6, 30.4, 24.8, 21.7.
LR-MS (APCI+): m/z [M + H]+ calcd for C17H24NO4S: 338.1;
found: 338.9.
LR-MS (APCI+): m/z [M + H]+ calcd for C21H26NO4S: 388.2;
found: 388.0.
Methyl syn-5-[(1,3-Dioxolan-2-yl)methyl]-1-tosylpyrrolidine-2-
carboxylate (Table 2, Entry 3, Product)
Following general procedure A using methyl 2-(tosylamino)hex-5-
enoate (40.0 mg, 0.135 mmol, 1.0 equiv), PdCl2(PhCN)2 (54.2 mg,
0.141 mmol, 1.05 equiv), 4 Å MS (68 mg), Ph3SiH (105 mg, 0.405
mmol, 3.0 equiv), and ethylene glycol (41 mL, 0.68 mmol, 5.0
equiv) and chromatography (silica gel, gradient 10–30% EtOAc–
hexanes) gave the title compound (32.7 mg, 66%) as a pale yellow
oil.
2-[(1,3-Dioxolan-2-yl)methyl]-1-tosylpiperidine (Table 2, Entry
6, Product)
Following general procedure A using N-tosylhex-5-en-1-amine12
(40.0 mg, 0.158 mmol, 1.0 equiv), PdCl2(PhCN)2 (63.6 mg, 0.166
mmol, 1.05 equiv), 4 Å MS (79 mg), Ph3SiH (123 mg, 0.474 mmol,
3.0 equiv), and ethylene glycol (44 mL, 0.79 mmol, 5.0 equiv) and
flash chromatography (silica gel, gradient 5–20% EtOAc–hexanes)
gave 2-[(1,3-dioxolan-2-yl)methyl]-1-tosylpiperidine (32.4 mg,
63%) as a white solid. This example suffers from a significant yield
of acid chloride that was not able to be circumvented. The acid chlo-
IR: 2951, 2881, 1763, 1595, 1344, 1197, 1155, 1015, 812, 666 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.75 (d, J = 8.4 Hz, 2 H, Ar-H),
7.31 (d, J = 8.1 Hz, 2 H, Ar-H), 4.96 [t, J = 4.8 Hz, 1 H,
CH2CH(OR)2], 4.23 (t, J = 6.0 Hz, 1 H, TsNCHCO2CH3), 3.97–
3.81 (m, 5 H, OCH2CH2O, TsNCH), 3.74 (s, 3 H, CO2CH3), 2.42 (s,
Synthesis 2010, No. 5, 870–881 © Thieme Stuttgart · New York

878
L. M. Ambrosini et al.
FEATURE ARTICLE
ride is isolated as 2-hydroxyethyl 2-(1-tosylpiperidin-2-yl)etha-
noate (12.4 mg, 23%) as a white solid.
LR-MS (APCI+): m/z [M + H]+ calcd for C22H27O3: 339.5; found:
339.1.
2-[(1,3-Dioxolan-2-yl)methyl]-1-tosylpiperidine
Ethyl 4-(syn-5-Isopropyl-1-tosylpyrrolidin-2-yl)but-2-enoate
(7)
IR: 2928, 2888, 1598, 1334, 1151, 1094, 922, 818 cm–1.
Following general procedure A using 2-methyl-N-tosylhept-6-en-3-
amine1a (5, 40.0 mg, 0.142 mmol, 1 equiv), PdCl2(PhCN)2 (56.4 mg,
0.147 mmol, 1.05 equiv), 4 Å MS (70 mg), and Ph3SiH (111 mg,
0.426 mmol, 3.0 equiv), but instead of ethylene glycol,
Ph3P=CHCO2Et (148 mg, 0.426 mmol, 3.0 equiv) was added and
the mixture was stirred at r.t. for 12 h. This modified procedure was
followed by flash chromatography (silica gel, gradient 1–5%
EtOAc–hexanes) to yield 7 (39.0 mg, 72%) as a white solid; ratio
E/Z 3:1.
1H NMR (300 MHz, CDCl3): d = 7.73 (d, J = 8.4 Hz, 2 H, Ar-H),
7.27 (d, J = 8.1 Hz, 2 H, Ar-H), 4.86–4.82 [m, 1 H, CH2CH(OR)2],
4.36–4.27 (m, 1 H, TsNCH), 3.98–3.90 (m, 2 H, OCH2CH2O),
3.88–3.78 (m, 3 H, OCH2CH2O, NTsCH2), 3.03–2.93 (m, 1 H,
TsNCH2), 2.42 (s, 3 H, ArCH3), 2.02–1.94 [m, 1 H, CH2CH(OR)2],
1.81–1.74 [m, 1 H, CH2CH(OR)2], 1.72–1.48 (m, 5 H, CH2), 1.30–
1.26 (m, 1 H, CH2).
13C NMR (75 MHz, CDCl3): d = 142.9, 138.9, 129.7, 127.2, 102.7,
65.0, 64.9, 49.6, 40.9, 34.2, 28.3, 24.7, 21.6, 18.6.
LR-MS (APCI+): m/z [M + H]+ calcd for C16H24NO4S: 326.1;
found: 326.2.
E-Isomer (major product)
IR: 2951, 2868, 1714, 1665, 1477, 1344, 1253, 1162, 1085, 1029,
994, 812, 666 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.71 (d, J = 8.4 Hz, 2 H, Ar-H),
7.31 (d, J = 8.1 Hz, 2 H, Ar-H), 6.94–6.84 (m, 1 H, CH=CHCO2Et),
5.90–5.86 (m, 1 H, CH=CHCO2Et), 4.16 (q, J = 7.2 Hz, 2 H,
CO2CH2CH3), 3.71–3.62 (m, 1 H, NTsCH), 3.41 (q, J = 5.1 Hz, 1
H, NTsCH), 2.83–2.75 (m, 1 H, CH2CH=CH), 2.43 (s, 3 H, ArCH3),
2.48–2.35 (m, 1 H, CH2CH=CH), 2.06–1.95 (m, 1 H, Me2CH),
1.66–1.58 (m, 1 H, CH2), 1.51 (q, J = 7.2 Hz, 2 H, CH2), 1.31–1.20
(m, 1 H, CH2), 1.29 (t, J = 7.2 Hz, 3 H, CO2CH2CH3), 0.99 (d,
J = 6.9 Hz, 3 H, CH3), 0.91 (d, J = 6.6 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 166.4, 144.8, 143.6, 134.8, 129.8,
127.8, 124.0, 67.7, 60.5, 39.7, 31.5, 29.3, 25.5, 21.7, 20.2, 17.8,
14.4.
LR-MS (APCI+): m/z [M + H]+ calcd for C20H30NO4S: 380.5;
found: 381.1.
2-Hydroxyethyl 2-(1-Tosylpiperidin-2-yl)ethanoate
1H NMR (300 MHz, CDCl3): d = 7.72 (d, J = 8.4 Hz, 2 H, Ar-H),
7.29 (d, J = 8.4 Hz, 2 H, Ar-H), 4.66–4.60 (m, 1 H, TsNCH), 4.33–
4.14 (m, 2 H, CO2CH2CH2), 3.88–3.72 (m, 3 H, CH2OH, NTsCH2),
3.12–3.03 (m, 1 H, TsNCH2), 2.83–2.70 (m, 2 H, CH2CO2, OH),
2.50 (dd, J = 14.4, 6.3 Hz, 1 H, CH2CO2), 2.42 (s, 3 H, ArCH3),
1.58–1.37 (m, 5 H, CH2), 1.14–1.08 (m, 1 H, CH2).
trans-2-[(1,3-Dioxolan-2-yl)methyl]octahydro-2H-chromene
(Table 2, Entry 7, Product)
Following
general
procedure
A
using
syn-2-(but-3-
enyl)cyclohexanol13 (30.0 mg, 0.195 mmol, 1.0 equiv), PdCl2(Ph-
CN)2 (78.5 mg, 0.205 mmol, 1.05 equiv), 4 Å MS (98 mg), Ph3SiH
(152 mg, 0.585 mmol, 3.0 equiv), and ethylene glycol (54 mL, 0.98
mmol, 5.0 equiv) and flash chromatography (silica gel, gradient
benzene to 2% EtOAc–benzene) gave the title compound (31.0 mg,
70%) as a colorless liquid.
Z-Isomer (minor product)
IR: 2959, 2919, 2870, 1717, 1334, 1156, 1090, 1032, 743, 663 cm–1.
IR: 2926, 2852, 1448, 1404, 1139, 1104, 1035, 943 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.73 (d, J = 8.1 Hz, 2 H, Ar-H),
7.31 (d, J = 8.1 Hz, 2 H, Ar-H), 6.46–6.37 (m, 1 H, CH=CHCO2Et),
5.90–5.86 (m, 1 H, CH=CHCO2Et), 4.17 (q, J = 6.9 Hz, 2 H,
CO2CH2CH3), 3.83–3.72 (m, 1 H, NTsCH), 3.42 (q, J = 6.6 Hz, 1
H, NTsCH), 3.14–3.03 (m, 1 H, CH2CH=CH), 2.94–2.83 (m, 1 H,
CH2CH=CH), 2.43 (s, 3 H, ArCH3), 2.15–2.03 (m, 1 H, Me2CH),
1.74–1.62 (m, 1 H, CH2), 1.57–1.46 (m, 1 H, CH2), 1.43–1.31 (m, 1
H, CH2), 1.29 (t, J = 7.2 Hz, 3 H, CO2CH2CH3), 1.31–1.18 (m, 1 H,
CH2), 0.97 (d, J = 6.9 Hz, 3 H, CH3), 0.91 (d, J = 6.6 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 166.5, 146.1, 143.5, 135.1, 129.8,
127.9, 121.5, 67.7, 61.0, 60.1, 35.5, 31.7, 29.5, 25.5, 21.7, 20.3,
17.4, 14.4.
LR-MS (APCI+): m/z [M + H]+ calcd for C20H30NO4S: 380.5;
found: 380.1.
1H NMR (300 MHz, CDCl3): d = 5.04 [dd, J = 3.6, 6.6 Hz, 1 H,
CH2CH(OR)2], 3.98–3.90 (m, 2 H, OCH2CH2O), 3.86–3.82 (m, 2
H, OCH2CH2O), 3.58–3.49 (m, 1 H, OCH), 2.96–2.89 (m, 1 H,
OCH), 1.99–1.86 [m, 2 H, CH2CH(OR)2, CH2], 1.76–1.57 [m, 6 H,
CH2CH(OR)2, CH2, CH), 1.43–1.07 (m, 6 H, CH2), 1.00–0.88 (m, 1
H, CH2).
13C NMR (75 MHz, CDCl3): d = 102.4, 82.0, 74.4, 64.9, 64.8, 41.8,
41.1, 32.8, 32.7, 31.9, 31.0, 26.0, 25.2.
LR-MS (APCI+): m/z [M + H]+ calcd for C13H23O3: 227.2; found:
227.1.
2-[(5,5-Dibenzyltetrahydrofuran-2-yl)methyl]-1,3-dioxolane
(Table 2, Entry 8, Product)
Following general procedure A using 2-benzyl-1-phenylhex-5-en-
2-ol (35.0 mg, 0.132 mmol, 1.0 equiv), PdCl2(PhCN)2 (53.2 mg,
0.139 mmol, 1.05 equiv), 4 Å MS (66 mg), Ph3SiH (103 mg, 0.396
mmol, 3.0 equiv), and ethylene glycol (37 mL, 0.66 mmol, 5.0
equiv) and flash chromatography (silica gel, gradient CH2Cl2–hex-
anes 1:1 to 2:1) gave the title compound (31.8 mg, 72%) as a color-
less liquid.
( )-1-(Octahydro-2H-chromen-2-yl)butan-2-one (9)
Following general procedure A: using syn-2-(but-3-
enyl)cyclohexanol13 (30.0 mg, 0.195 mmol, 1.0 equiv), PdCl2(Ph-
CN)2 (78.5 mg, 0.205 mmol, 1.05 equiv), 4 Å MS (98 mg), Ph3SiH
(152 mg, 0.585 mmol, 3.0 equiv), but instead of ethylene glycol, 1.0
M Et2Zn in THF (0.59 mL, 0.585 mmol, 3.0 equiv) was added at
–15 °C. The mixture stirred at –15 °C for 20 min and then quenched
with sat. NH4Cl soln (0.5 mL). The mixture was filtered through a
celite plug using EtOAc, dried (anhyd Na2SO4), and concentrated in
vacuo. This modified procedure was followed by flash chromatog-
raphy (silica gel, gradient hexanes to 2% EtOAc–hexanes) to yield
9 (27.3 mg, 67%) as a colorless liquid.
IR: 3070, 3021, 2914, 2870, 1495, 1450, 1085, 1032, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.31–7.23 (m, 10 H, Ar-H), 4.95
[dd, J = 4.2, 6.3 Hz, 1 H, CH2CH(OR)2], 3.99–3.95 (m, 2 H,
OCH2CH2O), 3.92–3.83 (m, 3 H, OCH2CH2O, OCH), 2.95–2.71
(m, 4 H, PhCH2), 1.92–1.79 (m, 3 H, CH2, CH2), 1.63–1.54 (m, 2 H,
CH2), 0.95–0.82 (m, 1 H, CH2).
Following general procedure B: syn-2-(but-3-enyl)cyclohexanol7
(20.0 mg, 0.130 mmol, 1.0 equiv), PdCl2(PhCN)2 (52.3 mg, 0.137
mmol, 1.05 equiv), 4 Å MS (65 mg), and 1.0 M Et2Zn in hexanes
13C NMR (75 MHz, CDCl3): d = 138.4, 138.2, 131.1, 130.9, 128.0,
127.8, 126.3, 102.9, 85.4, 75.7, 64.8, 46.8, 46.6, 40.0, 33.1, 32.4.
Synthesis 2010, No. 5, 870–881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Oxidative Formylation and Ketonylation
879
(78 mL, 0.078 mmol, 0.6 equiv) followed by flash chromatography
(silica gel, gradient 1–2% EtOAc–hexanes) yielded the title com-
pound as a colorless oil (19.7 mg, 72%). Spectra same as described
above.
1-(syn-5-Isopropyl-1-tosylpyrrolidin-2-yl)propan-2-one (Table
4, Entry 2)
Following general procedure B using 2-methyl-N-tosylhept-6-en-3-
amine1a (5, 20.0 mg, 0.071 mmol, 1.0 equiv), PdCl2(PhCN)2 (28.6
mg, 0.075 mmol, 1.05 equiv), 4 Å MS (36 mg), and 1.0 M Me2Zn
in heptane (43 mL, 0.043 mmol, 0.6 equiv) and flash chromatogra-
phy (silica gel, gradient 7–10% EtOAc–hexanes) gave the title com-
pound (18.8 mg, 82%) as a colorless oil.
IR: 2932, 2856, 1708, 1446, 1357, 1103, 1072 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.81–3.74 (m, 1 H, OCH), 2.92–
2.89 (m, 1 H, OCH), 2.66 [dd, J = 15.6, 7.5 Hz, 1 H, CH2C(O)CH2],
2.52–2.34 [m, 3 H, CH2C(O)CH2], 1.82–1.55 (m, 6 H, CH, CH2),
1.35–1.08 (m, 6 H, CH, CH2), 1.01 (t, J = 7.2 Hz, 3 H, CH3), 1.04–
0.86 (m, 1 H, CH2).
13C NMR (75 MHz, CDCl3): d = 210.3, 82.1, 74.3, 49.3, 41.7, 37.2,
32.7, 32.4, 31.8, 30.8, 25.9, 25.2, 7.74.
IR: 2965, 2868, 1714, 1337, 1155, 1085, 1008, 812, 680 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.70 (d, J = 8.4 Hz, 2 H, Ar-H),
7.31 (d, J = 8.1 Hz, 2 H, Ar-H), 3.97–3.88 (m, 1 H, TsNCH), 3.40–
3.34 (m, 1 H, TsNCH), 3.26 [dd, J = 17.7, 3.3 Hz, 1 H, CH2C(O)],
2.60 [dd, J = 17.7, 9.9 Hz, 1 H, CH2C(O)], 2.42 (s, 3 H, ArCH3),
2.16 (s, 3 H, CH3), 2.07–1.95 (m, 1 H, Me2CH), 1.81–1.70 (m, 1 H,
CH2), 1.63–1.54 (m, 1 H, CH2), 1.46–1.35 (m, 1 H, CH2), 1.28–1.16
(m, 1 H, CH2), 0.98 (d, J = 6.9 Hz, 3 H, CH3), 0.91 (d, J = 6.9 Hz, 3
H, CH3).
13C NMR (75 MHz, CDCl3): d = 207.1, 143.6, 134.5, 129.8, 127.8,
67.4, 57.4, 51.4, 31.7, 30.8, 30.6, 25.5, 21.6, 20.2, 17.7.
LR-MS (APCI+): m/z [M]+ calcd for C17H26NO3S: 324.5; found:
323.9.
LR-MS (APCI+): m/z [M + H]+ calcd for C13H23O2: 211.3; found:
211.0.
1-(syn-5-Isopropyl-1-tosylpyrrolidin-2-yl)butan-2-one (15)
Following general procedure B using 2-methyl-N-tosylhept-6-en-3-
amine1a (5, 20.0 mg, 0.071 mmol, 1.0 equiv), PdCl2(PhCN)2 (28.6
mg, 0.075 mmol, 1.05 equiv), 4 Å MS (36 mg), and 1.0 M Et2Zn in
hexanes (43 mL, 0.043 mmol, 0.6 equiv) and flash chromatography
(silica gel, gradient 7–10% EtOAc–hexanes) gave 15 (21.7 mg,
90%) as a colorless oil.
1-(syn-5-Methyl-1-tosylpyrrolidin-2-yl)propan-2-one (Table 4,
Entry 3)
IR: 2958, 2875, 1707, 1602, 1470, 1330, 1162, 1092, 994, 819, 666
cm–1.
Following general procedure B using N-tosylhex-5-en-2-amine12
(25.0 mg, 0.099 mmol, 1.0 equiv), PdCl2(PhCN)2 (39.7 mg, 0.166
mmol, 1.05 equiv), 4 Å MS (50 mg), and 1.0 M Me2Zn in heptane
(60 mL, 0.059 mmol, 0.6 equiv) and flash chromatography (silica
gel, gradient 7–10% EtOAc–hexanes) gave the title compound
(22.1 mg, 76%) as a white solid.
1H NMR (300 MHz, CDCl3): d = 7.71 (d, J = 8.1 Hz, 2 H, Ar-H),
7.31 (d, J = 8.1 Hz, 2 H, Ar-H), 3.99–3.89 (m, 1 H, TsNCH), 3.40–
3.34 (m, 1 H, TsNCH), 3.22 [dd, J = 17.4, 3.3 Hz, 1 H, CH2C(O)],
2.62–2.36 [m, 3 H, CH2C(O), CH2C(O)], 2.44 (s, 3 H, ArCH3),
2.07–1.95 [m, 1 H, (CH3)2CH], 1.81–1.70 (m, 1 H, CH2), 1.64–1.54
(m, 1 H, CH2), 1.47–1.36 (m, 1 H, CH2), 1.27–1.18 (m, 1 H, CH2),
1.06 (t, J = 7.5 Hz, 3 H, CH2CH3), 0.99 (d, J = 6.9 Hz, 3 H, CH3),
0.91 (d, J = 6.9 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 209.9, 143.6, 134.6, 129.9, 127.9,
67.5, 57.6, 50.2, 36.7, 31.8, 30.9, 25.5, 21.7, 20.3, 17.8.
LR-MS (APCI+): m/z [M]+ calcd for C18H28NO3S: 338.5; found:
337.9.
IR: 2979, 2917, 2889, 1707, 1344, 1148, 1092, 987, 826, 666 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.71 (d, J = 8.4 Hz, 2 H, Ar-H),
7.31 (d, J = 8.0 Hz, 2 H, Ar-H), 3.94–3.87 (m, 1 H, TsNCH), 3.68–
3.61 (m, 1 H, TsNCH), 3.29 [dd, J = 17.6, 3.6 Hz, 1 H, CH2C(O)],
2.66 [dd, J = 17.6, 9.6 Hz, 1 H, CH2C(O)], 2.42 (s, 3 H, ArCH3),
2.17 (s, 3 H, CH3), 1.82–1.73 (m, 1 H, CH2), 1.56–1.38 (m, 3 H,
CH2CH2), 1.32 (d, J = 6.4 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 207.2, 143.6, 134.4, 129.8, 127.7,
2-(syn-5-Isopropyl-1-tosylpyrrolidin-2-yl)-1-phenylethanone
(16)
Following general procedure B using 2-methyl-N-tosylhept-6-en-3-
amine1a (5, 20.0 mg, 0.071 mmol, 1.0 equiv), PdCl2(PhCN)2 (28.6
mg, 0.075 mmol, 1.05 equiv), 4 Å MS (36 mg), and 0.5 M PhZnCl
in THF (160 mL, 0.078 mmol, 1.1 equiv) and flash chromatography
(silica gel, benzene) gave 16 (23.3 mg, 85%) as a white solid.
57.6, 57.5, 51.7, 31.8, 30.7, 30.6, 23.5, 21.6.
LR-MS (APCI+): m/z [M + H]+ calcd for C15H22NO3S: 296.4;
found: 295.9.
1-Phenyl-2-(syn-5-phenyl-1-tosylpyrrolidin-2-yl)ethanone
(Table 4, Entry 4)
Following general procedure B using 1-phenyl-N-tosylpent-4-en-1-
amine (20.0 mg, 0.063 mmol, 1.0 equiv), PdCl2(PhCN)2 (25.5 mg,
0.067 mmol, 1.05 equiv), 4 Å MS (32 mg), and 0.5 M PhZnCl in
THF (140 mL, 0.069 mmol, 1.1 equiv) and flash chromatography
(silica gel, benzene) gave the title compound (20.9 mg, 79%) as a
white solid.
IR: 2951, 2975, 1686, 1588, 1449, 1344, 1211, 1162, 1092, 1001,
666 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.00 (d, J = 7.5 Hz, 2 H, Ar-H),
7.72 (d, J = 8.1 Hz, 2 H, Ar-H), 7.62–7.47 (m, 3 H, Ar-H), 7.36–
7.30 (m, 2 H, Ar-H), 4.17–4.13 (m, 1 H, TsNCH), 3.88 (dd,
J = 17.1, 3.0 Hz, 1 H, TsNCH), 3.42 [q, J = 7.2 Hz, 1 H, CH2C(O)],
3.07 [dd, J = 17.1, 10.5 Hz, 1 H, CH2C(O)], 2.43 (s, 3 H, ArCH3),
2.14–2.02 (m, 1 H, Me2CH), 1.85–1.70 (m, 1 H, CH2), 1.60–1.47
(m, 2 H, CH2), 1.32–1.20 (m, 1 H, CH2), 1.02 (d, J = 6.9 Hz, 3 H,
CH3), 0.96 (d, J = 6.6 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 198.6, 143.6, 136.7, 134.6, 133.5,
129.9, 128.8, 128.3, 127.8, 67.5, 58.3, 46.9, 31.7, 30.6, 25.5, 21.7,
20.3, 17.6.
LR-MS (APCI+): m/z [M]+ calcd for C22H28NO3S: 386.5; found:
385.9.
IR: 3070, 2937, 2868, 1679, 1595, 1351, 1169, 1085, 666 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.03 (dd, J = 8.1, 1.2 Hz, 2 H, Ar-
H), 7.76 (d, J = 8.1 Hz, 2 H, Ar-H), 7.62–7.25 (m, 10 H, Ar-H), 4.73
(t, J = 5.1 Hz, 1 H, TsNCH), 4.36–4.27 (m, 1 H, TsNCH), 4.10 [dd,
J = 16.8, 3.0 Hz, 1 H, CH2C(O)], 3.24 [dd, J = 17.1, 10.5 Hz, 1 H,
CH2C(O)], 2.45 (s, 3 H, ArCH3), 2.05–1.75 (m, 3 H, CH2CH2),
1.61–1.50 (m, 1 H, CH2).
13C NMR (75 MHz, CDCl3): d = 198.5, 143.9, 142.5, 136.7, 134.4,
133.6, 130.0, 128.9, 128.6, 128.3, 127.9, 127.3, 126.3, 64.7, 58.7,
46.6, 34.0, 30.8, 21.7.
LR-MS (APCI+): m/z [M]+ calcd for C25H26NO3S: 420.5; found:
419.8.
Synthesis 2010, No. 5, 870–881 © Thieme Stuttgart · New York

880
L. M. Ambrosini et al.
FEATURE ARTICLE
1-(syn-5-Isopropyl-1-tosylpyrrolidin-2-yl)but-3-en-2-one
(Table 4, Entry 5)
1 H, CH2), 1.00 (d, J = 6.9 Hz, 3 H, CH3), 0.94 (d, J = 6.6 Hz, 3 H,
CH3).
Following general procedure B using 2-methyl-N-tosylhept-6-en-3-
amine1a (5, 20.0 mg, 0.071 mmol, 1.0 equiv), PdCl2(PhCN)2 (28.6
mg, 0.075 mmol, 1.05 equiv), 4 Å MS (36 mg), and tributyl(vi-
nyl)stannane (27 mL, 0.092 mmol, 1.3 equiv) and flash chromatog-
raphy (silica gel, gradient 7–10% EtOAc–hexanes) gave the title
compound (22.4 mg, 94%) as a colorless oil.
13C NMR (75 MHz, CDCl3): d = 187.3, 152.6, 146.8, 143.6, 134.5,
129.9, 127.8, 118.0, 112.5, 67.5, 58.1, 46.4, 31.7, 30.4, 25.4, 21.7,
20.2, 17.7.
LR-MS (APCI+): m/z [M]+ calcd for C20H26NO4S: 376.5; found:
375.9.
IR: 2972, 2930, 2868, 1672, 1602, 1337, 1155, 1092, 994, 812, 666
cm–1.
1-(1-Tosylpiperidin-2-yl)butan-2-one (Table 4, Entry 8)
Following general procedure B, N-tosylhex-5-en-1-amine12 (20.0
mg, 0.079 mmol, 1.0 equiv), PdCl2(PhCN)2 (31.8 mg, 0.083 mmol,
1.05 equiv), 4 Å MS (40 mg), and 1.0 M Et2Zn in hexanes (47 mL,
0.047 mmol, 0.6 equiv) and flash chromatography (silica gel, gradi-
ent 10–15% EtOAc–hexanes) gave the title compound (15.3 mg,
63%) as a colorless oil; starting material (4.9 mg, 0.019 mmol) re-
covered giving an 82% yield of product based on recovered starting
material.
1H NMR (300 MHz, CDCl3): d = 7.71 (d, J = 8.4 Hz, 2 H, Ar-H),
7.31 (d, J = 8.1 Hz, 2 H, Ar-H), 6.33–6.30 (m, 2 H, CH=CH2), 5.91
(dd, J = 7.5, 3.9 Hz, 1 H, CH=CH2), 4.02–3.93 (m, 1 H, TsNCH),
3.46 [dd, J = 17.1, 3.3 Hz, 1 H, CH2C(O)], 3.41–3.35 (m, 1 H,
TsNCH), 2.74 [dd, J = 17.1, 10.5 Hz, 1 H, CH2C(O)], 2.43 (s, 3 H,
ArCH3), 2.09–1.98 (m, 1 H, Me2CH), 1.80–1.69 (m, 1 H, CH2),
1.66–1.50 (m, 1 H, CH2), 1.49–1.17 (m, 2 H, CH2), 0.99 (d, J = 6.9
Hz, 3 H, CH3), 0.92 (d, J = 6.6 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 199.1, 143.6, 136.7, 134.4, 129.8,
129.1, 127.8, 67.4, 57.9, 47.4, 31.7, 30.6, 28.0, 27.0, 25.4, 21.6,
20.2, 17.7, 13.7.
LR-MS (APCI+): m/z [M]+ calcd for C18H26NO3S: 336.5; found:
335.9.
IR: 2930, 2868, 1707, 1330, 1155, 1099, 917, 826, 666 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.69 (d, J = 8.4 Hz, 2 H, Ar-H),
7.27 (d, J = 9.0 Hz, 2 H, Ar-H), 4.52–4.49 (m, 1 H, TsNCH), 3.80–
3.75 (m, 1 H, NTsCH2), 2.98–2.89 (m, 1 H, TsNCH2), 2.76 [dd,
J = 16.2, 9.3 Hz, 1 H, CH2C(O)], 2.56 [dd, J = 16.2, 4.8 Hz, 1 H,
CH2C(O)], 2.41 (s, 3 H, ArCH3), 2.41–2.35 [m, 2 H, CH2C(O)],
1.62–1.25 (m, 6 H, CH2), 1.01 (t, J = 7.2 Hz, 3 H, CH3).
1-(syn-5-Isopropyl-1-tosylpyrrolidin-2-yl)pent-4-en-2-one
(Table 4, Entry 6)
13C NMR (75 MHz, CDCl3): d = 208.9, 143.3, 138.2, 129.8, 127.2,
49.0, 42.7, 41.4, 36.5, 27.9, 24.8, 21.7, 18.5, 7.77.
Following general procedure B using 2-methyl-N-tosylhept-6-en-3-
amine1a (5, 20.0 mg, 0.071 mmol, 1.0 equiv), PdCl2(PhCN)2 (28.6
mg, 0.075 mmol, 1.05 equiv), 4 Å MS (36 mg), and allyltributyl-
stannane (33 mL, 0.107 mmol, 1.5 equiv) and flash chromatography
(silica gel, gradient 2–7% EtOAc–hexanes) yielded the title com-
pound (14.3 mg, 58%) as a colorless oil.
LR-MS (APCI+): m/z [M + H]+ calcd for C16H24NO3S: 310.4;
found: 309.9.
2-(5,5-Dibenzyltetrahydrofuran-2-yl)-1-(furan-2-yl)ethanone
(Table 4, Entry 9)
Following general procedure B using 2-benzyl-1-phenylhex-5-en-
2-ol (20.0 mg, 0.075 mmol, 1.0 equiv), PdCl2(PhCN)2 (30.2 mg,
0.079 mmol, 1.05 equiv), 4 Å MS (38 mg), and tributyl(furan-2-
yl)stannane (31 mL, 0.098 mmol, 1.3 equiv) and flash chromatogra-
phy (silica gel, gradient 5–7% EtOAc–hexanes) gave the title com-
pound (25.2 mg, 93%) as a white solid.
IR: 2958, 2868, 1721, 1344, 1162, 1085, 994, 819, 659 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.70 (d, J = 8.4 Hz, 2 H, Ar-H),
7.31 (d, J = 8.1 Hz, 2 H, Ar-H), 5.98–5.84 (m, 1 H, CH=CH2), 5.22–
5.13 (m, 2 H, CH=CH2), 3.97–3.88 (m, 1 H, TsNCH), 3.40–3.34 (m,
1 H, TsNCH), 3.26 [dd, J = 17.7, 3.6 Hz, 1 H, CH2C(O)], 3.22–3.18
(m, 2 H, CH2CH=CH2), 2.62 [dd, J = 17.7, 9.9 Hz, 1 H, CH2C(O)],
2.43 (s, 3 H, ArCH3), 2.06–1.95 (m, 1 H, Me2CH), 1.81–1.70 (m, 1
H, CH2), 1.63–1.54 (m, 1 H, CH2), 1.46–1.35 (m, 1 H, CH2), 1.27–
1.15 (m, 1 H, CH2), 0.99 (d, J = 6.9 Hz, 3 H, CH3), 0.91 (d, J = 6.6
Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 207.1, 143.6, 134.5, 130.3, 129.8,
127.9, 127.8, 119.3, 67.4, 57.4, 50.1, 48.3, 31.8, 30.9, 25.5, 21.7,
20.2, 17.8.
LR-MS (APCI+): m/z [M]+ calcd for C19H28NO3S: 350.5; found:
349.9.
IR: 3028, 2924, 1665, 1567, 1470, 1078, 1015, 757, 701 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.71 (s, 1 H, Ar-H), 7.31–7.22 (m,
10 H, Ar-H), 7.14 (d, J = 3.3 Hz, 1 H, Ar-H), 6.56–6.55 (m, 1 H, Ar-
H), 4.21–4.12 (m, 1 H, OCH), 3.05–2.70 [m, 5 H, PhCH2,
CH2C(O)], 2.56 [dd, J = 15.3, 6.6 Hz, 1 H, CH2C(O)], 1.86–1.82
(m, 2 H, CH2), 1.68–1.58 (m, 1 H, CH2), 0.93–0.80 (m, 1 H, CH2).
13C NMR (75 MHz, CDCl3): d = 187.4, 153.0, 146.5, 138.2, 131.2,
131.0, 128.1, 127.8, 126.3, 117.5, 112.3, 85.8, 75.5, 46.9, 46.6,
44.7, 32.8, 32.1.
LR-MS (APCI+): m/z [M + H]+ calcd for C24H25O3: 361.5; found:
360.9.
1-(Furan-2-yl)-2-(syn-5-isopropyl-1-tosylpyrrolidin-2-yl)eth-
anone (Table 4, Entry 7)
1-(Bicyclo[2.2.1]hept-5-en-2-yl)-2-(syn-5-isopropyl-1-tosylpyr-
rolidin-2-yl)ethanone (17)
Following general procedure B using 2-methyl-N-tosylhept-6-en-3-
amine1a (5, 20.0 mg, 0.071 mmol, 1.0 equiv), PdCl2(PhCN)2 (28.6
mg, 0.075 mmol, 1.05 equiv), 4 Å MS (36 mg), and tributyl(furan-
2-yl)stannane (29 mL, 0.092 mmol, 1.3 equiv) and flash chromatog-
raphy (silica gel, 7–10% EtOAc–hexanes) gave the title compound
(22.5 mg, 84%) as a white solid.
Following general procedure B using 2-methyl-N-tosylhept-6-en-3-
amine1a (5, 20.0 mg, 0.071 mmol, 1.0 equiv), PdCl2(PhCN)2 (28.6
mg, 0.075 mmol, 1.05 equiv), 4 Å MS (36 mg), and tributyl(vi-
nyl)stannane (27 mL, 0.092 mmol, 1.3 equiv). Cyclopentadiene (17
mL, 0.213 mmol, 3.0 equiv) was added and the mixture stirred at
–15 °C for 3 h. The mixture was then filtered through celite and pu-
rified by chromatography (silica gel, 5% EtOAc–hexanes) to yield
17 (25.5 mg, 89%) as a colorless oil; ratio endo/exo 55:45.
IR: 2958, 2868, 1686, 1470, 1351, 1155, 1092, 673 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.72 (d, J = 8.4 Hz, 2 H, Ar-H),
7.61 (d, J = 1.2 Hz, 1 H, Ar-H), 7.33–7.30 (m, 3 H, Ar-H), 6.57–
6.55 (m, 1 H, Ar-H), 4.11–4.02 (m, 1 H, TsNCH), 3.64 [dd,
J = 16.2, 3.3 Hz, 1 H, CH2C(O)], 3.44–3.37 (m, 1 H, TsNCH), 3.07
[dd, J = 16.2, 10.5 Hz, 1 H, CH2C(O)], 2.43 (s, 3 H, ArCH3), 2.12–
2.00 (m, 1 H, Me2CH), 1.77–1.54 (m, 3 H, CH2CH2), 1.32–1.19 (m,
IR: 2958, 2868, 1700, 1344, 1162, 1092, 994, 805, 666 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.70 (d, J = 8.4 Hz, 2 H, Ar-H),
7.30 (d, J = 8.1 Hz, 2 H, Ar-H), 6.17–6.14 (m, 1 H, CH=CH), 5.94–
5.91 (m, 1 H, CH=CH; one diastereomer), 5.78–5.75 (m, 1 H,
Synthesis 2010, No. 5, 870–881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Oxidative Formylation and Ketonylation
881
CH=CH; one diastereomer), 3.97–3.84 (m, 1 H, TsNCH), 3.41–
3.33 (m, 1 H, TsNCH), 3.29 (br s, 1 H, CHCHCH), 3.23 (br s, 1 H,
CHCHCH), 3.08–2.96 [m, 1 H, CH2C(O)], 2.90 [br s, 1 H,
CHC(O)], 2.66–2.55 [m, 1 H, CH2C(O)], 2.42 (s, 3 H, ArCH3),
2.06–1.95 (m, 1 H, Me2CH), 1.79–1.53 (m, 3 H, CH2), 1.52–1.16
(m, 5 H, CH2), 1.01–0.89 (m, 7 H, CH2, CH3).
13C NMR (75 MHz, CDCl3): d = 209.6, 209.3, 143.5, 138.3, 137.8,
134.6, 131.8, 131.0, 129.8, 127.9, 67.4, 57.8, 57.6, 52.4, 51.9, 50.2,
50.1, 49.9, 49.8, 46.2, 42.9, 42.8, 31.8, 31.7, 31.0, 30.9, 28.0, 27.6,
27.5, 27.0, 25.5, 21.7, 20.3, 17.8, 17.7, 13.8.
Chem. Soc. 1984, 106, 1496. (c) Semmelhack, M. F.;
Zhang, N. J. Org. Chem. 1989, 54, 4483. (d) Semmelhack,
M. F.; Kim, C.; Zhang, N.; Bodurow, C.; Sanner, M.;
Dobler, W.; Meier, M. Pure Appl. Chem. 1990, 62, 2035.
(e) McCormick, M.; Monohan, M. III; Soria, J.; Goldsmith,
D.; Liotta, D. J. Org. Chem. 1989, 54, 4485. (f) White, J.
D.; Hong, J.; Robarge, L. A. Tetrahedron Lett. 1999, 40,
1463. (g) Holmes, C. P.; Bartlett, P. A. J. Org. Chem. 1989,
54, 98.
(5) (a) Hegedus, L. S.; Allen, G. F.; Olsen, D. J. J. Am. Chem.
Soc. 1980, 102, 3583. (b) Hegedus, L. S.; McKearin, J. M.
J. Am. Chem. Soc. 1982, 104, 2444. (c) Hegedus, L. S.;
Winton, P. M.; Varaprath, S. J. Org. Chem. 1981, 46, 2215.
(6) For selected examples, see: (a) Semmelhack, M. F.; Epa, W.
R.; Cheung, A. W.-H.; Gu, Y.; Kim, C.; Zhang, N.; Lew, W.
J. Am. Chem. Soc. 1994, 116, 7455. (b) Babjak, M.;
Kapitán, P.; Gracza, T. Tetrahedron 2005, 61, 2471.
(c) White, J. D.; Kranemann, C. L.; Kuntiyong, P. Org. Lett.
1999, 3, 4003. (d) White, J. D.; Kuntiyong, P.; Lee, T. H.
Org. Lett. 2006, 8, 6039. (e) White, J. D.; Kuntiyong, P.;
Lee, T. H. Org. Lett. 2006, 8, 6043. (f) Hornberger, K. R.;
Hamblett, C. L.; Leighton, J. L. J. Am. Chem. Soc. 2000,
122, 12894.
(7) (a) Beccalli, E. D.; Broggini, G.; Martinelli, M.;
Sottocornola, S. Chem. Rev. 2007, 107, 5318. (b) Schmalz,
H.-G.; Geis, O. In Handbook of Organopalladium
Chemistry for Organic Synthesis, Vol. 2; Negishi, E., Ed.;
John Wiley: New York, 2002, 2377.
(8) Probe experiments using standard co-oxidants including
copper(II) salts, benzoquinone, and PhI(OAc)2 have not
been productive.
LR-MS (APCI+): m/z [M]+ calcd for C23H31NO3S: 402.6; found:
401.6.
Acknowledgment
T.A.C. thanks FQRNT for a post-doctoral fellowship. T.H.L. is
grateful for an Abbott Young Investigator Award.
References
(1) (a) Cernak, T. A.; Lambert, T. H. J. Am. Chem. Soc. 2009,
131, 3124. (b) Kelly, B. D.; Allen, J. M.; Tundel, R. E.;
Lambert, T. H. Org. Lett. 2009, 11, 1381.
(2) For selected recent reviews on multicatalysis, see:
(a) Ajamian, A.; Gleason, J. L. Angew. Chem. Int. Ed. 2004,
43, 3754; Angew. Chem. 2004, 116, 3842. (b) Lee, J. M.;
Na, Y.; Han, H.; Chang, S. Chem. Soc. Rev. 2004, 33, 302.
(c) Wasilke, J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C.
Chem. Rev. 2005, 105, 1001. (d) Enders, D.; Grondal, C.;
Hüttl, M. R. M. Angew. Chem. Int. Ed. 2007, 46, 1570;
Angew. Chem. 2007, 119, 1590. (e) Chapman, C. J.; Frost,
C. G. Synthesis 2007, 1. (f) Walji, A. M.; MacMillan, D. W.
C. Synlett 2007, 1477.
(3) For recent examples, see: (a) Edwards, M. G.; Kenworthy,
M. N.; Kitson, R. R. A.; Scott, M. S.; Taylor, R. J. K. Angew.
Chem. Int. Ed. 2008, 47, 1935; Angew. Chem. 2008, 120,
1961. (b) Millemaggi, A.; Perry, A.; Whitwood, A. C.;
Taylor, R. J. K. Eur. J. Org. Chem. 2009, 2947; and
references cited therein.
(9) Anderson, G. K.; Lin, M.; Sen, A.; Gretz, E. In Inorganic
Syntheses, Vol. 28; Angelici, R. J., Ed.; John Wiley & Sons:
Chichester, 1990, 60.
(10) Gribkov, D. V.; Hulttzsch, K. C.; Hampel, F. J. Am. Chem.
Soc. 2006, 128, 3748.
(11) Pintér, ; Haberhauer, G. Eur. J. Org. Chem. 2008, 14, 2375.
(12) Marcotullio, M. C.; Campagna, V.; Sternativo, S.;
Costantino, F.; Curini, M. Synthesis 2006, 2760.
(13) Hon, Y.-S.; Liu, Y.-W.; Hsieh, C.-H. Tetrahedron 2004, 60,
4837.
(4) (a) Semmelhack, M. F.; Zhask, A. J. Am. Chem. Soc. 1983,
105, 2034. (b) Semmelhack, M. F.; Bodurow, C. J. Am.
Synthesis 2010, No. 5, 870–881 © Thieme Stuttgart · New York