Regio- and stereospecific uncatalyzed reactions of electron-rich arenes and olefins at organomolybdenum enantiomeric scaffolds

Article abstract of DOI:10.1021/om401087h

A novel uncatalyzed reaction between TpMo(CO)₂(5- trifluoroacetoxy-η³-5,6-dihydropyranyl/dihydropyridinyl) complexes and electron-rich arenes/olefins is reported. The reaction proceeds under mild reaction conditions so that a variety of functional groups are tolerated. Combined with a stereospecific annulative demetalation, the new reaction provides a rapid access to polycyclic alkaloid structures. The sequential protocol was used to prepare analogues of the antimalarial agent isofebrifugine.

Full text of DOI:10.1021/om401087h

Article
pubs.acs.org/Organometallics
Regio- and Stereospecific Uncatalyzed Reactions of Electron-Rich
Arenes and Olefins at Organomolybdenum Enantiomeric Scaffolds
Wenyong Chen,∥,† Kasinath Sana,†,¶ Yi Jiang,⊥,† Esmerelda V. S. Meyer,‡ Stacey Lapp,‡
Mary R. Galinski,‡,§ and Lanny S. Liebeskind*,†
†Sanford S. Atwood Chemistry Center, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States
‡Emory Vaccine Center at Yerkes National Primate Research Center, Emory University, Atlanta, Georgia 30329, United States
§Emory University School of Medicine, Department of Medicine, Division of Infectious Diseases, Emory University, Atlanta,
Georgia 30322, United States
S
* Supporting Information
ABSTRACT: A novel uncatalyzed reaction between TpMo(CO)2-
(5-trifluoroacetoxy-η3-5,6-dihydropyranyl/dihydropyridinyl) complexes
and electron-rich arenes/olefins is reported. The reaction proceeds
under mild reaction conditions so that a variety of functional groups are
tolerated. Combined with a stereospecific annulative demetalation, the
new reaction provides a rapid access to polycyclic alkaloid structures.
The sequential protocol was used to prepare analogues of the
antimalarial agent isofebrifugine.
latter disclosures demonstrate the direct reaction of charge neutral
TpMo(CO)2(5-oxo-η3-6H-pyranyl/pyridinyl) complexes, such as
1 and 2, and TpMo(CO)2(5-acetoxy-η3-5,6-dihydropyranyl/
pyridinyl) complexes, such as 3a and 4a, with preformed enolates
or alkoxide anions.3−5,9,10
INTRODUCTION
■
Readily available enantiopure, air- and moisture-stable TpMo(CO)2-
(5-oxo-η3-6H-pyranyl)and TpMo(CO)2(5-oxo-η3-6H-pyridinyl)
complexes, 1 and 2, and their derivatives are synthetically useful
scaffolds for the enantiocontrolled construction of substituted
heterocycles (Scheme 1; Tp = hydridotris(pyrazolyl)borato).1−24
Herein we report a new and synthetically versatile pathway
for the regio- and stereospecific functionalization of molybdenum-
based organometallic enantiomeric scaffoldsan uncata-
lyzed direct reaction between charge neutral TpMo(CO)2(5-
trifluoroacetoxy-η3-5,6-dihydropyranyl/pyridinyl) complexes,
3b and 4b, and electron-rich arenes and olefins (Scheme 1).
Simply by tuning the nucleofugality of the 5-position leaving
group, both 3 and 4 become competent electrophiles for high-
yield reactions with charge neutral π nucleophiles. The charge
neutral nature of the π nucleophile allows the presence of
internal functional groups that can be used for the rapid regio-
and stereospecific construction of functionalized polycyclic
motifs. Using this principle, the sequence of an uncatalyzed
reaction with π nucleophiles followed by annulative demetala-
tion was applied to a four-step synthesis of analogues of the
antimalarial natural product isofebrifugine. The reaction
proceeds under mild conditions in typical organic solvents at
room temperature without the addition of any activators, so
that a variety of sensitive functional groups are tolerated.
Scheme 1. Reaction with π-Nucleophiles Followed by an
Annulative Demetalation
The preparation of multigram quantities of high-enantiopurity
complexes is relatively straightforward.6,7 For carbon−carbon and
carbon−heteroatom bond constructions, both TpMo(CO)2-
stabilized cation1,2,6,8,11,14−20,23 and anion3−5,10 pathways have
been observed and applied in the enantiocontrolled synthesis of
natural products. The TpMo(CO)2-stabilized carbocations react
regio- and stereospecifically with a variety of sp3-, sp2-, and sp-
hybridized Grignard and lithium reagents.1,2,6,11,14−20 Comple-
menting the stabilized cation pathway, a TpMo(CO)2-mediated
nucleophilic functionalization pathway was also described. These
Received: November 8, 2013
Published: December 3, 2013
© 2013 American Chemical Society
7594
dx.doi.org/10.1021/om401087h | Organometallics 2013, 32, 7594−7611

Organometallics
Article
a
RESULTS AND DISCUSSION
Chart 1. Scope of the Reaction with Indoles
■
We initiated our study by examining the reaction of indole with
the racemic TpMo(CO)2(5-acetoxy-η3-5,6-dihydropyranyl)
complex 3a under a variety of reaction conditions (Table 1).
Table 1. Optimization of the C-Alkylation between Indole
a
and TpMo(CO)2(η3-dihydropyranyl) Complexes 3a,b
yield (%)
entry
1
substrate
conditions
NaH/THF
5
5′
3c
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
0
92
20
0
0
20
20
90
90
0
bc
,
2
3
4
5
6
7
8
9
NaH/THF/15-C-5
MeMgBr/THF
LiOtBu/THF
DBU/THF
DMSO
20
0
d
0
0
0
0
0
0
DMSO/NaH
DMSO/NaH/15-C-5
THF
0
86
89
0
0
b
0
0
73
78
86
0
a
The yield of purified product is reported; 1.2−1.5 equiv of indole
10
11
CH3CN
0
0
b
derivatives was used. A roughly 1:1 diastereomeric mixture at the
PhSO2-bearing center is formed. 97% ee Mo complex was used. 97% ee
Mo complex was used in the presence of MgO.
DMSO
0
0
c
d
a
The yield of purified product is reported. Conditions: entries 1−8, 3
equiv of indole was used; entries 9−11, 1.5 equiv of indole was used.
b
c
d
0.2 equiv 15-C-5 was added. 40% 3a was recovered. 80% 3a was
with 3b within minutes to form the C3-alkylation product 6b,
while the isomeric 3-methylindole reacted with 3b to provide
only the N-alkylation product 7. 1,3-Dimethylindole failed to
react with 3b under the same conditions. The dihydropyridinyl
complex system TpMo(CO)2(5-trifluoroacetoxy-η3-5,6-dihy-
dropyridinyl) (4b′) also showed a facile reaction with indole
to generate the C-3-substitution product 10. When the high-
enantiopurity dihydropyridinyl complex 4b′7 was used in the
reaction (97.5% ee), the product 10 was formed with only very
slight racemization (97.0% ee).2 Moreover, the addition of
MgO completely suppressed any racemization, presumably by
scavenging the TFA under the reaction conditions.2
2-Substituted indole derivatives bearing various tethered
functional groups were also suitable reaction partners. For
instance, 2-(1-methylindole)methanol reacted with the dihy-
dropyranyl complex 3b to generate 8 in 81% yield without
recourse to alcohol protecting groups (Chart 1, entry 3). The
reaction between the dihydropyridinyl TpMo(CO)2 complex
4b and various indoles bearing tethered sulfonyl, malonyl, and
nitro groups all took place in the absence of adverse events (see
9 and 11−13 in Chart 1).
In seeking to extend the reaction to π-electron nucleophiles
other than indoles, DMSO did not prove to be a suitable solvent.
However, a simple solvent switch to acetonitrile facilitated the
reaction of TpMo(CO)2(5-trifluoroacetoxy-η3-5,6-dihydropyranyl)
and TpMo(CO)2(5-trifluoroacetoxy-η3-5,6-dihydropyridinyl)-
complexes with electron-rich arenes and olefins (Table 2). For
example, 2-methylfuran yielded only 28% of product with
TpMo(CO)2(5-trifluoroacetoxy-η3-5,6-dihydropyridinyl) (4b) in
DMSO, while the same reaction in acetonitrile solely furnished
the desired 5-substitution product in 84% yield (entry 1).
recovered.
No reaction took place upon mixing the two substrates in THF.
Under basic reaction conditions in THF (NaH, NaH with 15-
crown-5-ether (15-C-5), MeMgBr, LiOtBu, or DBU) the
reaction was mostly unproductive, generating varying yields
of 3c, the product of hydrolysis of the acetoxy moiety, 5′, the
undesired product of indole N-alkylation, and only a low yield
(20%) of the desired product 5 when NaH was activated with
15-C-5. Complex 3a also did not react directly with indole in
DMSO at room temperature, although upon warming to 60 °C
the elimination product TpMo(CO)2(η3-pyranyl) was ob-
served. Reactions in DMSO in the presence of NaH or NaH
with 15-C-5 were likewise unproductive, only generating the
undesired product of indole N-alkylation 5′. In contrast to the
reactions of the acetoxy complex 3a, the more activated
TpMo(CO)2(5-trifluoroacetoxy-η3-5,6-dihydropyranyl) com-
plex 3b reacted easily with indole in THF, CH3CN, or
DMSO in the absence of base to afford the desired product of
C-alkylation of the indole in good yield (Table 1, entries 9−11).
The use of sulfonate esters, even better leaving groups than
trifluoroacetate, did not provide stable analogues of 3a,b and rather
led to known (η3-pyranyl)molybdenum complexes.7,12,20
Having observed a successful reaction of the trifluoroacetate
3b with indole, attention was then turned to determine the
scope of this process with respect to various substituted indoles
(Chart 1). The electron-rich 1-methylindole reacted with 3b in
DMSO at room temperature to furnish the C-3-alkylation
product 6a in 84% yield (see the Supporting Information for
details), while Cbz-protected indole failed to react with 3b
under the same reaction conditions. 2-Methylindole reacted
7595
dx.doi.org/10.1021/om401087h | Organometallics 2013, 32, 7594−7611

Organometallics
Article
1
Table 2. Scope of the Reaction with Electron-Rich Arenes
and Olefins
Scheme 2. H NMR Studies in d6-DMSO
a
decomposed to a complex mixture after standing overnight
(Scheme 3). However, indole was mixed with 3b in CD3CN,
1
Scheme 3. H NMR Studies in CD3CN
the reaction proceeded to generate product (40% conversion
after 30 min, 75% conversion after 2.5 h). In addition, in
comparison to the complete lack of reaction of 3b with
allyltrimethylsilane in d6-DMSO, in CD3CN the substitution
reaction proceeded uneventfully without the observable
intervention of intermediates 20a,b.
The observed reactivity differences can be understood
partially on the basis of the differential donicities of DMSO
and CH3CN.25 In order for a successful reaction to be
observed, both solvents must be able to support self-ionization
of 3b to the η4-diene cation A, which then reacts with π-
electron-rich substrates (Scheme 4). In strongly solvating
a
The yield of purified product is reported; 1.2−1.5 equiv of
b
nucleophile was used. Values in parentheses are yields using
DMSO as solvent.
Scheme 4. Proposed Mechanism for the Reaction in DMSO
versus CH3CN
N-Ethylaniline reacted with complex 3b to produce exclusively the
para-substituted product in 56% yield (entry 2), while no reaction
was observed using 4-methyl-N-ethylaniline, in which the para
position is blocked; no ortho-substitution product was detected
(entry 3). Although silyl enol ethers and allylsilanes showed no
reactivity toward molybdenum complex 3b in DMSO, both
substrate classes underwent facile reactions with 3b in acetonitrile
without requiring typical silane activators such as a fluoride source
or a Lewis acid (entries 4 and 6). Moreover, amine, diazo, and
malonate functional groups were all tolerated under the mild
reaction conditions, demonstrating the good functional group
compatibility of this system.
Intrigued by the different reactivities of the 5-trifluoroacetoxy
TpMo(CO)2 complex in DMSO and acetonitrile, an NMR
study with the complex TpMo(CO)2(5-trifluoroacetoxy-η3-5,6-
dihydropyranyl) (3b) was carried out in order to gain some
insight into the mechanism of this novel transformation. The
complex 3b when dissolved in d6-DMSO rearranged within
seconds to a mixture of the complexes 20a,b, which were thereafter
stable in solution even after 3 days (Scheme 2). Upon exposure
to indole, this mixture of rearranged products reacted very rapidly
(60 s) to afford the substitution product 5 quantitatively. In
contrast, the mixture of rearranged complexes 20a,b derived from
3b failed to react with allyltrimethylsilane in d6-DMSO.
DMSO we presume that the cation A is “stabilized” by solvent
trapping, giving B, which provides a cationic system with a
sufficient lifetime for the rearranged products 20a,b to be
formed and observed. Furthermore, interaction of the cation A
with strongly solvating DMSO to form B lowers not only the
effective concentration but also the reactivity of the active
cation A, allowing a productive reaction to be observed only
with the most potent of π-electron-rich nucleophiles, such as
indoles.26,27 In contrast, diminished solvent stabilization of the
cation A by the much weaker donor CH3CN presumably
generates a more reactive cation that, once generated, either
reacts with π-electron-rich nucleophiles when they are present
or rapidly decomposes to complex mixtures when they are not.
Solvent stabilization of the cationic intermediate also explains
the formation of 20a,b in d6-DMSO but not in CD3CN. It is
trace amounts of water in the d6-DMSO that leads to formation
of 20b (20a/20b ratio 5/1).
In comparison to dissolution in d6-DMSO, no rearrangement
of 3b occurred on dissolution in CD3CN; rather, 3b completely
7596
dx.doi.org/10.1021/om401087h | Organometallics 2013, 32, 7594−7611

Organometallics
Article
With conditions favoring the uncatalyzed reaction of π
nucleophiles with molybdenum complexes in hand, we
explored further development of the methodology in the
context of polycyclic indole synthesis28 (Table 3). Two
ring cis-fused to the piperidine ring (entry 3). In entry 4 the
pyranyl complex 9 underwent annulative demetalation to
furnish the single cyclization product 26 diastereoselectively in
excellent yield (entry 4). The stereochemistry of the product 26
was confirmed by an X-ray crystallographic study (see the
Supporting Information for details).
In contrast to the reactions shown in entries 2−4 (Table 3),
attempted annulative demetalation of the Cbz-protected
pyridinyl complex 12 failed to form the desired cyclization
product 27 (entry 5) under conditions identical with those
used to generate products 23, 25, and 26 in entries 2−4.
However, after N-deprotection of 12, the N-unprotected
pyridinyl complex 28 underwent nucleophilic oxidative ring
closure very slowly yet efficiently to form the six-membered
ring closure product 29 in 85% yield (entry 6).
Table 3. Oxidative Demetalation of Indole-Substituted
TpMo(CO)2 Complexes
Irrespective of the specific mechanistic details of the
nucleophilic oxidative demetalation pathway followed by
entries 2−4 and 6 of Table 3,5 we assume that maximum
orbital overlap favors a chairlike transition state for attack anti
to the molybdenum on the (η3-allyl)molybdenum moiety by
the incoming anion (or one-electron oxidized anion). Thus,
although TpMo(CO)2(5,6-dihydro-η-3,4,5-pyranyl)and TpMo-
(CO)2(5,6-dihydro-η-3,4,5-pyridinyl) complexes favor a ground
state conformation that orients substituents at the 2- and
6-positions axially,14 both the 5,6-dihydropyranyl and the
unprotected N−H 5,6-dihydropyridinyl molybdenum com-
plexes can presumably achieve effective concentrations of the
ring-flip conformations where the tether is situated equatorially
(Figure 1). As depicted in Figure 1, an equatorially oriented
a
b
The yield of purified product is reported. The reaction was run with
c
PDC/silica in CH2Cl2. The reaction was run with NaH open to air in
the presence of 0.2 equiv of Cu(2-ethylhexanoate)2.
Figure 1. Stereoelectronic influences on the demetalation.
demetalation protocols were examined. The 2-methylindole
adduct 6b was N-protected with Cbz, providing 21, which
participated in oxidative demetalation with pyridinium
dichromate to yield the unsaturated ketone 22 in a moderate
yield (entry 1). For the more synthetically interesting substrates
bearing tethered nucleophilic sources, a Cu(2-ethylhexanoate)2-
mediated annulative demetalation5 was employed to stereo-
selectively induce C−Nu bond formation between a terminus
of the (η3-allyl)molybdenum moiety and an internal
nucleophile. Entry 2 demonstrates a highly efficient C−O
bond forming annulative demetalation generating the indole
bis-pyran 23 from alcohol 8, while entries 3, 4, and 6 depict
effective and stereoselective generation of C−C bonds when
stabilized enolates are used as nucleophiles. For example, the
malonate anion of complex 24 (derived from molybdenum
complex 11 by protection of the indole NH with Cbz) was used
as the nucleophile to form product 25, bearing a five-membered
tether then places its distal functionality adjacent to the orbital
back lobe of the η3-allyl terminus, poised for a maximal orbital
overlap “axial” attack ring closure and product formation, after
spontaneous demetalation. This analysis also rationalizes the
formation of a single diastereomer of the ring closure product,
the isomer that orients the larger of the two electron-
withdrawing substituents that are attached to the attacking
carbon away from the (η3-allyl)molybdenum moiety.
In contrast, the equatorial conformation required for ring
closure of the N-Cbz protected dihydropyridinyl complex
experiences significant additional destabilization because of
A(1,3) strain between the carbamate and the equatorial
substituent.29,30 This added destabilization must make the
requisite equatorial conformer inaccessible in concentrations
sufficient to observe ring-closing reactions of the N-protected
pyridinylmolybdenum complex 12.
7597
dx.doi.org/10.1021/om401087h | Organometallics 2013, 32, 7594−7611

Organometallics
Article
Given the effective cyclization of N-protected dihydropyr-
idinyl substrates to generate five-membered ring closure
products (such as the N-Boc bearing 24 closing to 25 in this
paper or related N-Cbz bearing systems shown in an earlier
publication5), it appears that the greater ring closure rates for
five-membered vs six-membered cyclizations can compensate
for the conformational bias against cyclization in the N-protected
dihydropyridinyl systems.
3-(2-oxopropyl)-4(3H)-quinazolinone afforded 31 and 32, each
as a single diastereomer (addition anti to Mo) in good yields. A
nonstereoselective Luche reduction led to a mixture of two
separable diastereomeric alcohols in each case (Scheme 7), an
Scheme 7. Reactions with Silyl Enol Ether 30
Confirmation of the structural assignments made in this
paper rests on complete analyses made earlier5 and is further
supported through an X-ray crystal structure of the
demetalation product 26 (see the Supporting Information).
Application to a Concise Synthesis of Isofebrifugine
Analogues. The antimalarial alkaloids febrifugine and
isofebrifugine were isolated from the Chinese herb Chang
Shan (Dichroa febrifuga Lour).31 Because of their high
antimalarial activity, the two compounds have inspired a
number of total syntheses and formal syntheses.5,32−41
However, substantial toxicity, which was presumably associated
with in vivo oxidation of the quinazolinone ring and with the
generation of a reactive bioalkylating enone (Scheme 5) via a
intentional tactic used to provide diastereomers for bioassay.
The relative stereochemistry of alcohols 33, 33′, 34, and 34′
was assigned on the basis of 1D NOE NMR experiments of the
final deoxyisofebrifugine analogues 37, 37′, 38, and 38′. The
relative stereochemistry was further confirmed by the X-ray
crystal structure analysis of 34 and 35. In contrast to the Luche
reduction conditions, the use of NaBH4 led to a sluggish
reaction and resulted in a poor conversion to the alcohol. The
use of other reducing agents such as DIBAL and Li- and Na-
Selectride led to the reduction of the ketone accompanied by
substantial over-reduction of the quinazolinone ring.47,48
Following the annulative demetalation protocol,5 the
alcohols were transformed to the corresponding bicyclic
annulation products with excellent stereoselectivity (Table 4).
Scheme 5. Equilibration of Febrifugine and Isofebrifugine
retro-aza-Michael reaction, limited the potential efficacy of
febrifugine/isofebrifugine as a drug.42,43 Different strategies,
including replacing the piperidine with a pyrolidine, reposition-
ing the piperidine ring nitrogen,44 and studying the activities of
febrifugine metabolites45 and of an acetone adduct,46 have been
utilized to search for a solution to lower the toxicity. No
exploration of the structure−activity relationship (SAR) around
the piperidine ring has been reported to date.
Table 4. Annulative Demetalation of Isomers of Alcohols
The diastereomers of deoxyisofebrifugine are interesting
analogues of the natural product because the ether bond locks
the furan ring and prevents the formation of the bioalkylating
enone structure. To access the diastereomers of deoxyisofe-
brifugine, a highly convergent route was devised using a
π-nucleophile substitution−annulative demetalation sequence
(Scheme 6). Because the organometallic scaffold allows a
Scheme 6. Retrosynthetic Analysis of Deoxyisofebrifugine
a
The yield of the purified product is reported.
synthetic strategy to be equally applied in both the pyranyl and
pyridinyl systems, the tetrahydropyran analogues of deoxy-
isofebrifugine were also synthesized in order to evaluate their
antimalarial activity.
The reaction between the 5-trifluoroacetate scaffolds 3b
and 4b and electron-rich silyl enol ether 30 derived from
The structure of the product was confirmed by an X-ray
crystallographic study of 35 (see the Supporting Information
for details). This demetalative ring annulation protocol is
efficient for the construction of 2,3-fused bicyclic pyranyl and
pyridinyl derivatives, albeit only after fairly long reaction times
to reach completion (days). Finally, hydrogenation of the above
7598
dx.doi.org/10.1021/om401087h | Organometallics 2013, 32, 7594−7611

Organometallics
Article
TEA (165 mg, 1.62 mmol, 1.5 equiv) and TFAA (289 mg, 1.40 mmol,
1.3 equiv) at room temperature. The reaction mixture was stirred for
20 min and then loaded on the silica gel directly. Flash
chromatography in under 5 min with hexanes/EtOAc (3/1) afforded
( )-3b (547 mg, 0.95 mmol, 88%) as a yellow solid. TLC: Rf = 0.62
compounds delivered deoxyisofebrifugine analogues 37, 37′,
38, and 38′ (Table 5).
Table 5. Deoxyisofebrifugine Analogues
1
(3/1 hexanes/EtOAc). H NMR (400 MHz, CDCl3): δ 8.47 (d, J =
2.0 Hz, 1 H), 7.72 (d, J = 2.8 Hz, 1 H), 7.71 (d, J = 2.8 Hz, 1 H), 7.59
(d, J = 2.0 Hz, 1 H), 7.58 (d, J = 2.0 Hz, 1 H), 7.51 (d, J = 1.6 Hz, 1
H), 7.05 (dd, J = 4.4, 2.0 Hz, 1 H), 6.30 (t, J = 2.4 Hz, 1 H), 6.22
(t, J = 2.4 Hz, 1 H), 6.20 (t, J = 2.0 Hz, 1 H), 5.79 (ddd, J = 9.2, 6.0,
2.8 Hz, 1 H), 4.59 (dt, J = 7.6, 2.4 Hz, 1 H), 3.75 (dd, J = 10.8 Hz, 6.0
Hz, 1 H), 3.54 (dd, J = 8.0 Hz, 4.0 Hz, 1 H), 2.64 (dd, J = 11.6, 10.0
Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ 226.9, 224.0, 147.2, 146.8,
142.0, 141.8, 136.24, 136.21, 134.6, 134.5, 109.7, 106.1, 105.8 105.6,
73.5, 63.7, 62.8, 58.0.
( )-Dicarbonyl[hydridotris(1-pyrazolyl)borato][(η-2,3,4)-1-benzy-
loxycarbonyl-5-trifluoroacetoxy-5,6-dihydro-2H-pyridin-2-yl]molyb-
denum (( )-4b).
The double bond was also investigated as a functional group
handle to synthesize more highly elaborated deoxyisofebrifu-
gine analogues. The double bond of the annulation product 36′
was treated with catalytic osmium tetroxide in the presence of
N-methylmorpholine N-oxide, followed by hydrogenation to
give 40 as a single diastereomer (Scheme 8).
To a solution of ( )-TpMo(CO)2(syn-5-hydroxy-1-benzyloxycarbon-
yl-η3-5,6-dihydropyridinyl)5 (300 mg, 0.50 mmol, 1.0 equiv) in DCM
(3 mL) were added TEA (140 μL, 1.0 mmol, 2.0 equiv) and TFAA
(105 μL, 0.75 mmol, 1.5 equiv) at −15 °C. The reaction mixture was
stirred for 20 min and then loaded on the silica gel directly. Flash
chromatography in under 5 min with hexanes/EtOAc (3/1) afforded
( )-4b (310 mg, 0.44 mmol, 89%) as a yellow solid. TLC: Rf = 0.65
Scheme 8. Functionalization of the Double Bond of 36′
1
(3/1 hexanes/EtOAc). H NMR (a mixture of two rotamers) (600
MHz, CDCl3): δ 8.45 (d, J = 1.2 Hz, 0.3 H), 8.44 (d, J = 1.2 Hz, 0.7
H), 8.19 (d, J = 1.2 Hz, 1.0 H), 7.63 (d, J = 1.2 Hz, 1.0 H), 7.60 (s, 0.7
H), 7.58 (d, J = 2.4 Hz, 0.7 H), 7.56 (d, J = 2.4 Hz, 0.7 H), 7.54 (d, J =
2.4 Hz, 0.3 H), 7.51 (d, J = 2.4 Hz, 0.3 H), 7.47 (d, J = 2.4 Hz, 0.7 H),
7.45 (d, J = 2.4 Hz, 0.7 H), 7.44 (s, 0.3 H), 7.40−7.31 (m, 3 H), 7.15
(d, J = 6.0 Hz, 0.7 H), 6.90 (d, J = 6.0 Hz, 0.3 H), 6.25 (d, J = 1.8 Hz,
1.0 H), 6.22 (s, 0.7 H), 6.18−6.17 (m, 1 H), 5.91 (s, 0.3 H), 5.88−
5.5.85 (m, 1 H), 5.28 (d, J = 12.0 Hz, 0.7 H), 5.19 (s, 1 H), 5.18 (d, J =
12.0 Hz, 0.3 H), 4.58 (t, J = 8.4 Hz, 1.0 H), 3.75 (dd, J = 12.8 Hz, 7.2
Hz, 0.3 H), 3.71 (dd, J = 12.4 Hz, 7.2 Hz, 0.7 H), 3.51 (t, J = 7.2 Hz,
0.7 H), 3.42 (t, J = 7.2 Hz, 0.3 H), 2.23 (dd, J = 12.0 Hz, 9.0 Hz, 0.3
H), 2.14 (dd, J = 12.0 Hz, 9.0 Hz, 0.7 H). 13C NMR (150 MHz,
CDCl3): δ 228.2, 227.9, 223.9, 223.7, 157.4 (q, J = 43.9 Hz), 155.8,
155.4, 147.2, 147.0, 146.2, 145.2, 144.4, 144.0, 143.5, 141.1, 140.9,
136.3, 136.2, 136.1, 136.1, 134.9, 129.5, 129.2, 129.0, 128.9, 128.8,
128.6, 128.4, 128.3, 116.4 (q, J = 169 Hz), 113.4 (q, J = 169 Hz),
106.3, 106.1, 105.9, 105.8, 105.6, 105.5, 92.9, 91.7, 90.1, 89.0, 74.5,
74.3, 69.6, 69.1, 68.8, 68.4, 60.2, 60.1, 58.8, 58.3, 52.5, 51.8, 43.6, 43.5.
IR (cm−1): 2485 (w), 1948 (s), 1854 (s), 1780 (s), 1702 (s).
( )-Dicarbonyl[hydridotris(1-pyrazolyl)borato][(η-2,3,4)-1-tert-
butoxycarbonyl-5-oxo-5,6-dihydro-2H-pyridin-2-yl]molybdenum
(( )-2′).
None of the deoxyisofebrifugine analogues 37, 37′, 38, 38′,
and 40 demonstrated any significant in vitro antimalarial
activity (see the Supporting Information for details).
CONCLUSIONS
■
A novel uncatalyzed reaction of electron-rich arenes and olefins
with TpMo(CO)2(5-trifluoroacetoxy-η3-5,6-dihydropyranyl)-
and TpMo(CO)2(5-trifluoroacetoxy-η3-5,6-dihydropyridinyl)
complexes is reported. This reaction is sufficiently mild that it
can tolerate a variety of functional groups, including amines,
alcohols, esters, and diazo moieties. A subsequent nucleophilic,
oxidative annulative demetalation provides a rapid access to
piperidine- or pyran-embedding motifs, such as tetracyclic
indole alkaloid structures. The reaction sequence was applied to
a convergent synthesis of isofebrifugine analogues.
EXPERIMENTAL SECTION
■
All Tp molybdenum complexes decompose over 180−200 °C. Therefore,
melting points of the complexes are not useful and are not provided here.
Preparation of Substrates. ( )-Dicarbonyl[hydridotris-
(1-pyrazolyl)borato][(η-2,3,4)-5-trifluoroacetoxy-5,6-dihydro-2H-
pyran-2-yl]molybdenum (( )-3b).
To a solution of the complex 2 (500 mg, 0.88 mmol, 1.0 equiv) in
THF (25 mL) was added 10% Pd(OH)2/C (90 mg, 0.09 mmol, 0.1
equiv). The reaction mixture was stirred at room temperature under a
hydrogen balloon for 5 h. The mixture was filtered and then
concentrated to a solid. The unpurified solid was dissolved in DCM.
To the solution were added Boc2O (249 mg, 1.14 mmol, 1.3 equiv),
DMAP (11 mg, 0.09 mmol, 0.1 equiv), and triethylamine (138 mg,
1.32 mmol, 1.5 equiv). The mixture was stirred at room temperature
overnight and then poured into a separatory funnel containing EtOAc
(15 mL) and H2O (15 mL), and the layers were separated. The
To a solution of ( )-TpMo(CO)2(syn-5-hydroxy-η3-5,6-dihydropyr-
anyl)5 (500 mg, 1.08 mmol, 1.0 equiv) in DCM (25 mL) were added
7599
dx.doi.org/10.1021/om401087h | Organometallics 2013, 32, 7594−7611

Organometallics
Article
aqueous layer was extracted with EtOAc (2 × 5 mL), and the
combined organic layers were dried over Na2SO4, filtered, and
concentrated. Flash chromatography over silica gel with hexanes/
EtOAc (2/1) afforded the N-Boc protected complex ( )-TpMo-
(CO)2(5-oxo-η3-6H-pyridinyl) (2′; 434 mg, 0.77 mmol, 88%) as a
yellow solid. TLC: Rf = 0.28 (2/1 hexanes/EtOAc). 1H NMR (a
mixture of two rotamers) (400 MHz, CDCl3): δ 8.41 (d, J = 2.0 Hz,
0.3 H), 8.35 (d, J = 2.0 Hz, 0.7 H), 8.29 (d, J = 1.2 Hz, 0.7 H), 8.01 (d,
J = 1.6 Hz, 0.3 H), 7.77 (d, J = 1.6 Hz, 0.3 H), 7.69 (d, J = 1.4 Hz, 0.7
H), 7.65 (d, J = 2.0 Hz, 0.3 H), 7.58−7.62 (m, 1.7 H), 7.46−7.49 (m,
1.7 H), 7.32 (dd, J = 6.8 Hz, 2.0 Hz, 0.3 H), 6.27 (t, J = 1.6 Hz, 0.3 H),
6.17−6.24 (m, 2.7 H), 4.71−4.74 (m, 1 H), 3.99 (t, J = 6.0 Hz, 0.7 H),
3.94 (t, J = 6.0 Hz, 0.3 H), 3.38 (d, J = 20.0 Hz, 0.7 H), 3.36 (d, J =
20.0 Hz, 0.3 H), 3.20 (d, J = 20.4 Hz, 0.3 H), 3.17 (d, J = 20.0 Hz, 0.7
H), 1.57 (s, 2.7 H), 1.46 (s, 6.3 H). 13C NMR (100 MHz, CDCl3): δ
225.5, 223.0, 222.1, 193.8, 193.6, 153.5, 152.5, 147.3, 147.1, 144.5,
142.7, 141.9, 141.2, 136.5, 136.3, 136.2, 136.1, 134.7, 106.2, 106.0,
105.8, 105.7, 96.2, 93.2, 82.4, 82.0, 64.7, 64.1, 63.7, 62.9, 48.3, 47.5,
28.1, 27.9. IR (cm−1): 3420 (w), 2980 (w), 2482 (w), 1942 (s), 1845
(s), 1695 (s). HRMS (ESI): calcd for C21H25BMoN7O5 ([M + H]+),
564.1059; found, 564.1061.
(d, J = 2.0 Hz, 0.3 H), 7.58 (d, J = 2.0 Hz, 0.7 H), 7.47−7.49 (m, 1 H),
7.25 (dd, J = 6.4 Hz, 2.0 Hz, 0.7 H), 7.06 (dd, J = 5.6 Hz, 1.6 Hz, 0.3
H), 6.18−6.27 (m, 3 H), 5.86−5.91 (m, 1 H), 4.60 (d, J = 8.8 Hz, 0.3
H), 4.59 (d, J = 7.6 Hz, 0.7 H), 3.77 (dd, J = 12.8 Hz, 7.2 Hz, 0.3 H),
3.65 (dd, J = 12.4 Hz, 7.2 Hz, 0.7 H), 3.46 (t, J = 7.2 Hz, 0.7 H), 3.39
(t, J = 7.2 Hz, 0.3 H), 2.01−2.10 (m, 1 H), 1.59 (s, 3 H), 1.49 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ 228.5, 227.5, 224.0, 223.7, 157.2 (q,
J = 169.6 Hz), 154.4, 153.9, 147.0, 146.8, 144.2, 142.5, 141.2, 140.7,
136.3, 136.2, 136.1, 136.1, 134.5, 114.4 (q, J = 1138 Hz), 106.1, 105.9,
105.8, 105.6, 105.5, 94.8, 92.5, 82.1, 81.9, 77.3, 77.0, 76.7, 74.7, 74.5,
60.8, 59.5, 57.5, 57.0, 43.4, 42.6, 34.6, 34.5, 31.6, 29.0, 28.2, 28.0, 25.2,
22.6, 20.7, 14.1, 11.4.
Uncatalyzed Reactions with π-Nucleophiles. ( )-Dicarbonyl-
[hydridotris(1-pyrazolyl)borato][(η-3,4,5)-2-(3′-indolyl)-5,6-dihydro-
2H-pyran-3-yl]molybdenum (( )-5).
( )-Dicarbonyl[hydridotris(1-pyrazolyl)borato][(η-2,3,4)-1-tert-
butoxycarbonyl-5-trifluoroacetoxy-5,6-dihydro-2H-pyridin-2-yl]mo-
lybdenum (( )-4b′).
To a solution of ( )-3b (50 mg, 0.089 mmol, 1.0 equiv) in DMSO (4 mL)
was added indole (15.2 mg, 0.13 mmol, 1.5 equiv). The reaction
mixture was stirred at room temperature for 1 h and then quenched
with brine. The mixture was poured into a separatory funnel
containing EtOAc (5 mL), and the layers were separated. The
aqueous layer was extracted with EtOAc (2 × 5 mL), and the
combined organic layers were dried over Na2SO4, filtered, and
concentrated. Flash chromatography over silica gel with hexanes/
EtOAc (2.5/1) afforded ( )-5 (43 mg, 0.077 mmol, 86%) as an
To a solution of ( )-2′ (500 mg, 0.88 mmol, 1.0 equiv) in THF
(20 mL) was added DIBAL (1.0 M in hexane, 2.2 mL, 2.18 mmol,
2.5 equiv) at 0 °C. The reaction mixture was stirred at 0 °C for 20 min
and then quenched with potassium sodium tartrate tetrahydrate
(760 mg, 2.56 mmol, 3.0 equiv) and H2O (10 mL). The mixture was
poured into a separatory funnel containing EtOAc (15 mL), and the
layers were separated. The aqueous layer was extracted with EtOAc
(2 × 25 mL), and the combined organic layers were dried over
Na2SO4, filtered, and concentrated. Flash chromatography over silica
gel with hexanes/EtOAc (2/1) afforded ( )-TpMo(CO)2(syn-5-
hydroxy-1-tert-butoxycarbonyl-η3-5,6-dihydropyridinyl) (452 mg, 0.80
mmol, 91%) as an orange solid. TLC: Rf = 0.27 (2/1 hexanes/EtOAc).
1H NMR (a mixture of two rotamers) (400 MHz, CDCl3): δ 8.42 (d,
J = 1.2 Hz, 0.4 H), 8.40 (d, J = 1.2 Hz, 0.6 H), 8.18 (d, J = 1.2 Hz, 0.6
H), 7.96 (d, J = 1.2 Hz, 0.4 H), 7.82 (d, J = 0.8 Hz, 0.4 H), 7.77 (d, J =
1.2 Hz, 0.6 H), 7.62 (d, J = 2.0 Hz, 0.4 H), 7.56 (br s, 1.6 H), 7.46 (br
s, 1 H), 7.20 (d, J = 5.2 Hz, 0.6 H), 7.00 (d, J = 5.6 Hz, 0.4 H), 6.23
(br s, 0.4 H), 6.11−6.16 (m, 2.6 H), 4.67−4.79 (m, 2 H), 3.75 (dd, J =
12.0 Hz, 7.2 Hz, 0.4 H), 3.63 (dd, J = 12.4 Hz, 6.8 Hz, 0.6 H), 3.31 (t,
J = 6.8 Hz, 0.6 H), 3.25 (t, J = 6.8 Hz, 0.4 H), 1.75−1.85 (m, 1 H),
1.59 (s, 3.6 H), 1.47 (s, 5.4 H). 13C NMR (100 MHz, CDCl3): δ
232.7, 231.6, 224.1, 223.8, 154.6, 154.0, 146.6, 146.4, 143.8, 142.2,
141.1, 140.6, 136.0, 135.9, 135.82, 135.76, 134.3, 105.8, 105.7, 105.5,
105.4, 105.2, 94.4, 92.2, 81.5, 81.1, 69.5, 67.9, 67.8, 67.6, 57.2, 56.6,
47.4, 46.6, 28.1, 27.9, 27.4. IR (cm−1) 3420 (w), 2980 (w), 2482 (w),
1942 (s), 1845 (s), 1695 (s). HRMS (ESI): calcd for C21H26BMoN7O5
([M + Na]+), 588.1035; found, 588.1038.
1
orange solid. TLC: Rf = 0.45 (2/1 hexanes/EtOAc). H NMR (400
MHz, CDCl3): δ 8.69 (d, J = 2.4 Hz, 1 H), 8.17 (br s, 1 H), 7.83 (d,
J = 8.0 Hz, 1 H), 7.74 (d, J = 2.0 Hz, 1 H), 7.72 (d, J = 2.0 Hz, 1 H),
7.63 (d, J = 2.4 Hz, 1 H), 7.59 (d, J = 2.4 Hz, 1 H), 7.58 (d, J = 2.4 Hz,
1 H), 7.53 (d, J = 2.0 Hz, 1 H), 7.38 (d, J = 8.0 Hz, 1 H), 7.21 (t, J =
8.0 Hz, 1 H), 7.13 (t, J = 7.6 Hz, 1 H), 6.32 (t, J = 2.0 Hz, 1 H), 6.17(t,
J = 2.0 Hz, 1 H), 6.15 (t, J = 2.0 Hz, 1 H), 5.32 (d, J = 2.0 Hz, 1 H),
4.37 (dt, J = 6.8 Hz, 2.4 Hz, 1 H), 4.03−4.11 (m, 2 H), 3.88 (d, J =
12.0 Hz, 1 H), 3.62 (dd, J = 12.8 Hz, 2.4 Hz, 1 H). 13C NMR (100
MHz, CDCl3): δ 226.0, 225.8, 147.4, 141.9, 141.4, 136.6, 136.0, 135.9,
134.4, 127.1, 123.8, 122.5, 120.0, 119.9, 116.8, 111.0, 106.0, 105.3,
105.3, 69.8, 67.4, 65.4, 64.2, 57.5.IR (cm−1): 3300 (w), 2482 (w), 1938
(s), 1849 (s), 1505 (s). HRMS (ESI): calcd for C24H22BMoN7O3Na
([M + Na]+), 588.0823; found, 588.0829.
( )-Dicarbonyl[hydridotris(1-pyrazolyl)borato][(η-3,4,5)-2-(1′-in-
dolyl)-5,6-dihydro-2H-pyran-3-yl]molybdenum (( )-5′).
The N-substituted isomer ( )-5′ was formed when the reaction is
carried out in THF under basic conditions on the 5-acetoxymolybde-
num complex 3a: to a solution of ( )-3a5 (50 mg, 0.099 mmol,
1.0 equiv) in THF (4 mL) were added NaH (1.2 mg, 0.297 mmol,
3.0 equiv) and indole (38.0 mg, 0.297 mmol, 3.0 equiv). The reaction
mixture was stirred at room temperature for 2 h and then quenched
with saturated NH4Cl. The mixture was poured into a separatory
funnel containing EtOAc (5 mL), and the layers were separated. The
aqueous layer was extracted by EtOAc (2 × 5 mL), and the combined
organic layers were dried over Na2SO4, filtered, and concentrated.
Flash chromatography over silica gel with hexanes/EtOAc (20/1)
afforded ( )-5 (51.3 mg, 0.32 mmol, 92%) as an orange solid. TLC:
Rf = 0.65 (3/1 hexanes/EtOAc). 1H NMR (600 MHz, DMSO): δ 8.69
(d, J = 1.2 Hz, 1 H), 8.08 (d, J = 3.0 Hz, 1 H), 7.75 (s, 1 H), 7.73 (s, 1
H), 7.65 (d, J = 7.8 Hz, 1 H), 7.62 (d, J = 7.2 Hz, 1 H), 7.61 (d, J = 7.2
Then, to a solution of the reduction product( )-TpMo(CO)2(syn-
5-hydroxy-1-tert-butoxycarbonyl-η3-5,6-dihydropyridinyl) (452 mg,
0.80 mmol, 1.0 equiv) in DCM (15 mL) were added TEA (122 mg,
1.20 mmol, 1.5 equiv) and TFAA (218 mg, 1.04 mmol, 1.3 equiv) at
−15 °C. The reaction mixture was stirred for 20 min and then loaded
on the silica gel directly. Flash chromatography in under 5 min with
hexanes/EtOAc (3/1) afforded ( )-4b′ (490 mg, 0.74 mmol, 92%) as
1
a yellow solid. TLC: Rf = 0.63 (3/1 hexanes/EtOAc). H NMR (a
mixture of two rotamers) (400 MHz, CDCl3): δ 8.47 (d, J = 2.0 Hz,
0.3 H), 8.44 (d, J = 2.0 Hz, 0.7 H), 8.21 (d, J = 2.0 Hz, 0.7 H), 7.97 (d,
J = 2.0 Hz, 0.3 H), 7.69 (d, J = 1.6 Hz, 0.3 H), 7.66 (d, J = 2.4 Hz, 0.7
H), 7.63 (d, J = 2.0 Hz, 0.3 H), 7.59 (d, J = 2.0 Hz, 0.7 H), 7.58
7600
dx.doi.org/10.1021/om401087h | Organometallics 2013, 32, 7594−7611

Organometallics
Article
Hz, 1 H), 7.56 (s, 1 H), 7.55 (d, J = 9.0 Hz, 1 H), 7.23 (t, J = 7.2 Hz, 1
H), 7.15 (t, J = 7.2 Hz, 1 H), 6.59 (d, J = 7.2 Hz, 1 H), 6.36 (t, J =
3.0 Hz, 1 H), 6.22(t, J = 2.4 Hz, 1 H), 6.18 (t, J = 2.4 Hz, 1 H), 6.17 (s,
1 H), 4.30 (t, J = 7.2 Hz, 1 H), 4.26 (d, J = 7.2 Hz, 1 H), 4.18 (d, J =
7.2 Hz, 1 H), 3.90 (d, J = 13.2 Hz, 1 H), 3.66 (dd, J = 13.2 Hz, 1.8 Hz,
1 H). 13C NMR (100 MHz, DMSO): δ 225.5, 224.5, 147.4, 142.1,
141.3, 136.8, 136.2, 136.2, 134.6, 129.3, 125.5, 122.0, 120.7, 120.3,
110.6, 106.2, 105.6, 105.5, 101.8, 77.9, 66.4, 65.1, 63.9, 57.8. IR (cm−1):
3142 (w), 3053 (w), 2930 (w), 2486 (w), 1945 (s), 1861 (s).
( )-Dicarbonyl[hydridotris(1-pyrazolyl)borato][(η-3,4,5)-2-(1′-
methyl-3′-indolyl)-5,6-dihydro-2H-pyran-3-yl]molybdenum
(( )-6a).
141.9, 141.5, 135.9, 135.9, 135.2, 134.6, 134.4, 127.8, 121.1, 120.2, 119.7,
111.7, 110.3, 106.0, 105.3, 105.2, 71.2, 67.0, 66.5, 60.1, 12.7. IR (cm−1):
3347 (m), 2957 (w), 2482 (w), 1942 (s), 1853 (s), 1602 (m). HRMS
(FAB): calcd for C25H24BMoNaN7O3 ([M + Na]+), 602.0980; found,
602.0982.
( )-Dicarbonyl[hydridotris(1-pyrazolyl)borato][(η-3,4,5)-2-(3′-
methyl-1′-indolyl)-5,6-dihydro-2H-pyran-3-yl]molybdenum (( )-7).
To a solution of ( )-3b (50 mg, 0.089 mmol, 1.0 equiv) in DMSO
(4 mL) was added 3-methylindole (17.1 mg, 0.13 mmol, 1.5 equiv).
The reaction mixture was stirred at room temperature for 1 h and then
quenched with brine. The mixture was poured into a separatory funnel
containing EtOAc (5 mL), and the layers were separated. The aqueous
layer was extracted with EtOAc (2 × 5 mL), and the combined organic
layers were dried over Na2SO4, filtered, and concentrated. Flash
chromatography over silica gel with hexanes/EtOAc (20/1) afforded
( )-7 (40 mg, 0.075 mmol, 78%) as an orange solid. TLC: Rf = 0.61
To a solution of ( )-3b (50 mg, 0.089 mmol, 1.0 equiv) in DMSO
(4 mL) was added N-methylindole (17.1 mg, 0.13 mmol, 1.5 equiv).
The reaction mixture was stirred at room temperature for 1 h and then
quenched with brine. The mixture was poured into a separatory funnel
containing EtOAc (5 mL), and the layers were separated. The aqueous
layer was extracted with EtOAc (2 × 5 mL), and the combined organic
layers were dried over Na2SO4, filtered, and concentrated. Flash
chromatography over silica gel with hexanes/EtOAc (2.5/1) afforded
( )-6a (43 mg, 0.075 mmol, 84%) as an orange solid. TLC: Rf = 0.38
1
(6/1 hexanes/EtOAc). H NMR (400 MHz, DMSO): δ 8.65 (d, J =
2.4 Hz, 1 H), 8.19 (d, J = 2.0 Hz, 1 H), 8.09 (d, J = 2.0 Hz, 1 H), 8.00
(s, 1 H), 7.91 (d, J = 2.4 Hz, 1 H), 7.89 (d, J = 2.4 Hz, 1 H), 7.86 (d,
J = 2.0 Hz, 1 H), 7.53 (d, J = 2.0 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H),
7.16 (t, J = 8.0 Hz, 1 H), 7.08 (t, J = 8.0 Hz, 1 H), 6.50 (t, J = 2.0 Hz, 1
H), 6.33 (t, J = 2.0 Hz, 1 H), 6.26(t, J = 2.0 Hz, 1 H), 6.02 (d, J = 2.0
Hz, 1 H), 4.59 (d, J = 7.6 Hz, 1 H), 4.49 (d, J = 6.8 Hz, 1 H), 4.30
(t, J = 7.2 Hz, 1 H), 3.68 (d, J = 12.8 Hz, 1 H), 3.48 (dd, J = 12.4 Hz,
2.0 Hz, 1 H), 2.32 (s, 3 H). 13C NMR (100 MHz, DMSO): δ 226.2,
225.6, 147.0, 143.6, 142.3, 136.7, 136.7, 135.4, 129.4, 124.0, 121.5,
119.3, 118.7, 110.2, 109.5, 106.8, 106.0, 105.8, 77.3, 66.6, 65.8, 65.1,
57.5, 9.7. IR (cm−1): 2957 (w), 2482 (w), 1949 (s), 1864 (s), 1505
(w). HRMS (FAB): calcd for C25H25BMoN7O3 ([M + H]+),
580.1161; found, 580.1167.
1
(3/1 hexanes/EtOAc). H NMR (400 MHz, DMSO): δ 8.62 (d, J =
2.0 Hz, 1 H), 8.07 (d, J = 2.0 Hz, 1 H), 8.04 (d, J = 2.0 Hz, 1 H), 7.89
(d, J = 2.4 Hz, 1 H), 7.86 (d, J = 2.4 Hz, 1 H), 7.85 (d, J = 2.4 Hz, 1
H), 7.81 (s, 1 H), 7.56 (d, J = 7.6 Hz, 1 H), 7.45 (d, J = 8.4 Hz, 1 H),
7.18 (t, J = 7.2 Hz, 1 H), 7.05 (t, J = 8.0 Hz, 1 H), 6.49 (t, J = 2.0 Hz, 1
H), 6.30 (t, J = 2.0 Hz, 1 H), 6.26 (t, J = 2.0 Hz, 1 H), 5.11 (d, J = 2.4
Hz, 1 H), 4.58 (dt, J = 7.2 Hz, 2.4 Hz, 1 H), 4.39 (d, J = 6.4 Hz, 1 H),
4.00 (t, J = 7.2 Hz, 1 H), 3.84 (s, 3 H), 3.68 (d, J = 12.4 Hz, 1 H), 3.43
(dd, J = 12.0 Hz, 2.0 Hz, 1 H). 13C NMR (100 MHz, DMSO): δ
226.6, 226.2, 147.0, 142.9, 142.4, 137.1, 136.6, 135.3, 129.6, 127.2,
121.4, 118.9, 113.8, 109.8, 106.6, 105.8, 105.8, 70.2, 68.1, 64.8, 64.6,
56.9, 32.6. IR (cm−1): 2957 (w), 2922 (m), 2853 (w), 2482 (m), 1942
(s), 1849 (s). HRMS (FAB): calcd for C25H25BMoN7O3 ([M + H]+),
580.1161; found, 580.1167.
( )-Dicarbonyl[hydridotris(1-pyrazolyl)borato][(η-3,4,5)-2-(1′-
methyl-2′-hydroxymethyl-3′-indolyl)-5,6-dihydro-2H-pyran-3-yl]
molybdenum (( )-8).
( )-Dicarbonyl[hydridotris(1-pyrazolyl)borato][(η-3,4,5)-2-(2′-
methyl-3′-indolyl)-5,6-dihydro-2H-pyran-3-yl]molybdenum
(( )-6b).
To a solution of ( )-3b (50 mg, 0.089 mmol, 1.0 equiv) in DMSO
(4 mL) was added the indolyl alcohol, prepared as described in the
Supporting Information (20.9 mg, 0.13 mmol, 1.5 equiv). The reaction
mixture was stirred at room temperature for 1 h and then quenched with
brine. The mixture was poured into a separatory funnel containing EtOAc
(5 mL), and the layers were separated. The aqueous layer was extracted
with EtOAc (2 × 5 mL), and the combined organic layers were dried over
Na2SO4, filtered, and concentrated. Flash chromatography over silica gel
with hexanes/EtOAc (2.5/1) afforded ( )-8 (44 mg, 0.072 mmol, 81%)
as an orange solid. TLC: Rf = 0.38 (2/1 hexanes/EtOAc). 1H NMR (400
MHz, CDCl3)δ 8.67 (d, J = 2.0 Hz, 1 H), 8.58 (d, J = 8.4 Hz, 1 H), 7.78
(d, J = 1.6 Hz, 1 H), 7.72 (d, J = 2.0 Hz, 1 H), 7.61 (d, J = 2.0 Hz, 1 H),
7.59 (d, J = 2.0 Hz, 1 H), 7.55 (d, J = 2.0 Hz, 1 H), 7.38 (d, J = 8.4 Hz, 1
H), 7.28 (dt, J = 7.2 Hz, 1.2 Hz, 1 H), 7.16 (dt, J = 7.2 Hz, 1.2 Hz, 1 H),
6.34 (t, J = 2.0 Hz, 1 H), 6.22 (t, J = 2.0 Hz, 1 H), 6.13 (t, J = 2.0 Hz, 1
H), 5.34 (d, J = 2.0 Hz, 1 H), 4.92 (d, J = 14.0 Hz, 1 H), 4.86 (d, J = 13.2
Hz, 1 H), 4.56 (dt, J = 6.4 Hz, 2.4 Hz, 1 H), 4.31−4.37 (m, 2 H), 4.22
(dd, J = 12.4 Hz, 1.6 Hz, 1 H), 3.84 (s, 3 H), 3.74 (dd, J = 12.4 Hz, 1.6
Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ 226.8, 225.9, 147.4, 142.0,
141.4, 138.6, 137.0, 136.0, 134.4, 126.3, 121.9, 121.1, 119.6, 113.3, 109.5,
106.0, 105.4, 105.3, 71.1, 67.4, 67.3, 66.7, 60.1, 54.2, 29.7. IR (cm−1):
To a solution of ( )-3b (50 mg, 0.089 mmol, 1.0 equiv) in DMSO
(4 mL) was added 2-methylindole (17.1 mg, 0.13 mmol, 1.5 equiv).
The reaction mixture was stirred at room temperature for 1 h and then
quenched with brine. The mixture was poured into a separatory funnel
containing EtOAc (5 mL), and the layers were separated. The aqueous
layer was extracted with EtOAc (2 × 5 mL), and the combined organic
layers were dried over Na2SO4, filtered, and concentrated. Flash
chromatography over silica gel with hexanes/EtOAc (2.5/1) afforded
( )-6b (39 mg, 0.068 mmol, 76%) as an orange solid. TLC: Rf = 0.48
1
(2/1 hexanes/EtOAc). H NMR (400 MHz, CDCl3): δ 8.69 (d, J =
2.0 Hz, 1 H), 8.45 (d, J = 7.2 Hz, 1 H), 7.97 (br s, 1 H), 7.81 (d, J =
2.0 Hz, 1 H), 7.70 (d, J = 2.0 Hz, 1 H), 7.60 (d, J = 2.4 Hz, 1 H), 7.57
(d, J = 2.4 Hz, 1 H), 7.54 (d, J = 2.4 Hz, 1 H), 7.32 (d, J = 7.2 Hz, 1 H),
7.10−7.17 (m, 2 H), 6.34 (t, J = 2.4 Hz, 1 H), 6.22 (t, J = 2.4 Hz, 1 H),
6.12(t, J = 2.4 Hz, 1 H), 5.24 (d, J = 2.4 Hz, 1 H), 4.40−4.43 (m, 1 H),
4.32 (d, J = 5.6 Hz, 2 H), 4.30 (d, J = 12.0 Hz, 1 H), 3.80 (d, J = 12.0 Hz,
1 H), 2.56 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ 226.8, 225.8, 147.4,
7601
dx.doi.org/10.1021/om401087h | Organometallics 2013, 32, 7594−7611

Organometallics
Article
3377 (m), 3146 (w), 3053 (w), 2945 (w), 2482 (m), 1942 (s), 1845 (s),
1505 (m). HRMS (FAB): calcd for C26H27BMoN7O4 ([M + H]+),
610.1266; found, 610.1271.
( )-Dicarbonyl[hydridotris(1-pyrazolyl)borato][(η-3,4,5)-2-(2′-
(3″-methoxy-3″-oxo-2″-(phenylsulfonyl)propyl)-1′-methyl-1H-
indol-3′-yl)-5,6-dihydro-2H-pyran-3-yl]molybdenum (( )-9).
(8.8 mg, 0.22 mmol, 3 equiv) afforded (+)-10 (37 mg, 0.054 mmol, 74%,
97.5% ee).
Similar treatment of (+)-4b (50 mg, 0.072 mmol, 1.0 equiv, 97.5% ee)
in MeCN (4 mL) with indole (12.6 mg, 0.11 mmol, 1.5 equiv) afforded
(+)-10 (40 mg, 0.058 mmol, 74%, 97.5% ee). [α]D20 = +121.1° (c = 0.75,
CH2Cl2).
1
TLC: Rf = 0.28 (2/1 hexanes/EtOAc). H NMR (a mixture of two
rotamers) (400 MHz, CDCl3): δ 8.64 (d, J = 2.4 Hz, 0.5 H), 8.63
(d, J = 2.4 Hz, 0.5 H), 8.26 (d, J = 8.0 Hz, 0.5 H), 8.25 (s,0.5 H), 8.21
(s, 0.5 H), 7.81 (d, J = 2.0 Hz, 0.5 H), 7.79 (d, J = 2.0 Hz, 0.5 H), 7.73
(d, J = 8.0 Hz, 0.5 H), 7.72 (d, J = 2.4 Hz, 0.5 H), 7.69 (d, J = 2.0 Hz,
0.5 H), 7.60 (t, J = 2.4 Hz, 1 H), 7.57 (d, J = 2.0 Hz, 1 H), 7.53 (d, J =
2.0 Hz, 1 H), 7.51 (d, J = 2.0 Hz, 0.5 H), 7.26−7.39 (m, 6.5 H), 7.14−
7.23 (m, 1.5 H), 6.94 (t, J = 8.0 Hz, 0.5 H), 6.32 (m, 1 H), 6.21 (t, J =
2.0 Hz, 1 H), 6.12 (t, J = 2.0 Hz, 0.5 H), 6.11 (t, J = 2.0 Hz, 0.5 H),
5.87 (d, J = 2.8 Hz, 0.5 H), 5.78 (d, J = 2.8 Hz, 0.5 H), 5.15 (d, J =
12.4 Hz, 0.5 H), 5.12 (d, J = 12.0 Hz, 0.5 H), 5.02 (d, J = 12.0 Hz, 0.5
H), 4.98 (d, J = 12.0 Hz, 0.5 H), 4.51 (dt, J = 7.2 Hz, 2.8 Hz, 0.5 H),
4.41−4.46 (m, 1 H), 4.32−4.37 (m, 1 H), 4.26 (dd, J = 14.4 Hz, 2.8
Hz, 0.5 H), 4.00 (t, J = 7.2 Hz, 0.5 H), 3.94 (d, J = 7.2 Hz, 0.5 H), 3.71
(d, J = 10.0 Hz, 0.5 H),3.68 (d, J = 10.0 Hz, 0.5 H). 13C NMR (100
MHz, CDCl3): δ 225.8, 225.3, 225.3, 224.9, 154.7, 154.2, 147.3, 141.9,
141.7, 136.7, 136.6, 136.5, 136.2, 136.0, 134.4, 128.4, 128.2, 128.2, 127.9,
127.8, 127.6, 126.3, 126.0, 123.8, 122.9, 122.2, 122.1, 120.9, 120.1, 119.8,
119.6, 117.7, 117.5, 111.0, 106.0, 105.4, 105.3, 105.3, 105.3, 71.2, 70.8,
67.3, 67.1, 67.0, 64.1, 63.6, 47.3, 47.1, 39.4, 39.2. IR (cm−1): 3358 (m),
3123 (w), 3057 (w), 2482 (m), 1938 (s), 1857 (s), 1679 (s). HRMS
(FAB): calcd for C32H30BMoN8O4 ([M + H]+), 699.1532; found,
699.1550. HPLC: (DaicelChiralcelOD-RH column, isocratic solvent
system 65% CH3CN in H2O (without TFA), 1.0 mL/min, λ 254 nm):
(2R,3R)-(+)-10, t+ = 16.6 min; (2S,3S)-(−)-10, t− = 21.5 min.
To a solution of ( )-3b (175 mg, 0.31 mmol, 1.0 equiv) in DMSO
(5 mL) was added methyl 3-(1-methyl-1H-indol-2-yl)-2-
(phenylsulfonyl)propanoate, prepared as described in the Supporting
Information (165 mg, 0.47 mmol, 1.5 equiv). The reaction mixture
was stirred at room temperature for 1 h and then quenched with brine.
The mixture was poured into a separatory funnel containing EtOAc
(5 mL), and the layers were separated. The aqueous layer was
extracted with EtOAc (2 × 5 mL), and the combined organic layers
were dried over Na2SO4, filtered, and concentrated. Flash chromatography
over silica gel with hexanes/EtOAc (2.5/1) afforded ( )-9 (180 mg,
1
0.224 mmol, 73%) as an orange solid. H NMR (a mixture of two
diastereomers) (600 MHz, CDCl3): δ 8.68−8.65 (m, 1.5H), 8.44
(d, J = 7.8 Hz, 0.5H), 7.95 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 7.8 Hz,
1H), 7.78 (s, 0.5H), 7.76−7.75 (m, 1.5H), 7.68−7.66 (m, 1H), 7.59 (s,
1H), 7.58 (s, 1H), 7.55 (t, J = 1.8 Hz, 1H), 7.53−7.52 (m, 1H), 7.49
(t, J = 7.8 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H),
7.13 (t, J = 7.8 Hz, 1H), 6.33−6.31 (m, 1H), 6.21−6.19 (m, 1H),
6.09−6.08 (m, 1H), 5.18 (d, J = 1.8 Hz, 0.5H), 5.05 (d, J = 1.8 Hz,
0.5H), 4.73 (dd, J = 3.0, 11.4 Hz, 0.5H), 4.41−4.39 (m, 0.5H), 4.34−
4.32 (m, 1.5H), 4.28−4.26 (m, 2H), 4.17 (t, J = 7.2 Hz, 1H), 4.12 (dd,
J = 3.6, 12.6 Hz, 1.5H), 3.79 (s, 1.5H), 3.77 (s, 1.5H), 3.73 (dd, J =
3.0, 13.2 Hz, 1H), 3.69 (t, J = 5.4 Hz, 1H), 3.66−3.65 (m, 1H), 3.64−
3.63 (m, 0.5H), 3.59 (dd, J = 1.8, 13.2 Hz, 1H), 3.55 (s, 1.5H), 3.50 (s,
1.5H). 13C NMR (150 MHz, CDCl3): δ 227.0, 226.6, 226.5, 226.2,
166.0, 165.4, 147.6, 142.7, 142.4, 141.6, 141.5, 137.7, 137.6, 137.5,
137.2, 136.2, 136.1, 134.7, 134.6, 134.5, 133.4, 129.5, 129.4, 129.2,
126.9, 126.7, 122.0, 121.7, 121.1, 121.0, 114.4, 113.3, 109.8, 109.7,
106.2, 105.6, 105.5, 72.0, 71.6, 70.6, 70.2, 67.5, 67.3, 67.1, 66.6, 66.0,
60.6, 60.1, 53.6, 53.2, 30.2, 30.1, 22.4, 21.7. IR (cm−1): 2481 (w), 1938
(s), 1850 (s), 1741 (s). HRMS (FAB): calcd for C35H34BMoN7NaO7S
([M + Na]+), 828.1280; found, 828.1284.
( )-Dicarbonyl[hydridotris(1-pyrazolyl)borato][(η-3,4,5)-1-tert-
butoxycarbonyl-2-(2′-malonyl-3′-indolyl)-5,6-dihydro-2H-pyridin-
3-yl]molybdenum (( )-11).
To a solution of ( )-4b′ (50 mg, 0.076 mmol, 1.0 equiv) in DMSO
(4 mL) were added indolyl malonate49 (37.8 mg, 0.11 mmol, 1.5 equiv)
and MgO (8.8 mg, 0.22 mmol, 3.0 equiv). The reaction mixture was
stirred at room temperature for 1 h and then quenched with brine. The
mixture was poured into a separatory funnel containing EtOAc (5 mL),
and the layers were separated. The aqueous layer was extracted with
EtOAc (2 × 5 mL), and the combined organic layers were dried over
Na2SO4, filtered, and concentrated. Flash chromatography over silica gel
with hexanes/EtOAc (2.5/1) afforded ( )-11 (41 mg, 0.046 mmol, 61%)
(+)- and ( )-Dicarbonyl[hydridotris(1-pyrazolyl)borato][(η-3,4,5)-
1-benzyloxycarbonyl-2-(3′-indolyl)-5,6-dihydro-2H-pyridin-3-yl]mo-
lybdenum ((+)- and ( )-10).
1
as an orange solid. TLC: Rf = 0.26 (2/1 hexanes/EtOAc). H NMR
(a mixture of two rotamers) (400 MHz, CDCl3): δ 9.46 (s, 0.5 H), 9.35
(s, 0.5 H), 8.64 (d, J = 1.6 Hz, 1 H), 8.37 (d, J = 8.0 Hz, 0.5 H), 8.16 (d,
J = 8.0 Hz, 0.5 H), 7.88(br s, 1 H), 7.82 (d, J = 2.0 Hz, 0.5 H), 7.73 (d,
J = 2.0 Hz, 0.5 H), 7.58−7.60 (m, 1.5 H), 7.50−7.53 (m, 2.5 H), 7.41 (s,
0.5 H), 7.39 (s, 0.5 H), 7.17−7.22 (m, 1H), 7.12−7.16 (m, 1 H), 6.29−
6.31 (m, 1 H), 6.20−6.23 (m, 1 H), 6.03−6.05 (m, 1 H), 5.93 (s, 0.5 H),
5.58 (d, J = 2.0 Hz, 0.5 H), 5.52 (d, J = 2.8 Hz, 0.5 H), 5.38 (s, 0.5 H),
4.54−4.46 (m, 1 H), 4.45−4.50 (m, 1 H), 4.30−4.38 (m, 1 H), 4.27−4.31
(m, 1 H), 3.93−4.10 (m, 1 H), 1.56 (s, 4.5 H), 1.53 (s, 4.5 H), 1.46 (s, 4.5
H), 1.45 (s, 9 H), 1.36 (s, 4.5 H). 13C NMR (100 MHz, CDCl3): δ 226.3,
225.8, 225.2, 168.3, 167.7, 167.1, 166.1, 154.3, 153.8, 147.3, 147.3, 142.2,
142.1, 141.9, 141.8, 136.0, 136.0, 135.8, 134.3, 129.3, 128.8, 128.6, 128.5,
128.4, 128.3, 128.3, 127.0, 126.1, 125.6, 121.9, 121.6, 121.0, 119.6, 119.3,
116.9, 115.3, 111.4, 105.9, 105.8, 105.3, 105.1, 105.0, 83.2, 83.0, 82.5,
82.4, 80.3, 79.1, 70.9, 70.4, 67.0, 66.5, 66.0, 64.9, 50.8, 47.2, 46.0, 41.3,
41.0, 28.5, 28.3, 27.9, 27.9. IR (cm−1): 3358 (m), 3123 (w), 3057 (w),
To a solution of ( )-4b (50 mg, 0.072 mmol, 1.0 equiv) in DMSO (4 mL)
was added indole (12.6 mg, 0.11 mmol, 1.5 equiv). The reaction mixture
was stirred at room temperature for 1 h and then quenched with brine. The
mixture was poured into a separatory funnel containing EtOAc (5 mL), and
the layers were separated. The aqueous layer was extracted with EtOAc (2 ×
5 mL), and the combined organic layers were dried over Na2SO4, filtered,
and concentrated. Flash chromatography over silica gel with hexanes/EtOAc
(2.5/1) afforded ( )-10 (40 mg, 0.058 mmol, 80%) as an orange solid.
Similar treatment of (+)-4b (50 mg, 0.072 mmol, 1.0 equiv, 97.5% ee)
in DMSO (4 mL) with indole (12.6 mg, 0.11 mmol, 1.5 equiv) afforded
(+)-10 (40 mg, 0.058 mmol, 80%, 97% ee).
Similar treatment of (+)-4b (50 mg, 0.072 mmol, 1.0 equiv, 97.5% ee)
in DMSO (4 mL) with indole (12.6 mg, 0.11 mmol, 1.5 equiv) and MgO
7602
dx.doi.org/10.1021/om401087h | Organometallics 2013, 32, 7594−7611

Organometallics
Article
2482 (m), 1938 (s), 1857 (s), 1679 (s). HRMS (FAB): calcd for
C40H49BMoNaN8O8 ([M + Na]+), 901.2724; found, 901.2712.
( )-Dicarbonyl[hydridotris(1-pyrazolyl)borato][(η-3,4,5)-1-benzy-
loxycarbonyl-2-(2′-(3″-methoxy-3″-oxo-2″-(phenylsulfonyl)propyl)-
1′-methyl-1H-indol-3′-yl)-5,6-dihydro-2H-pyridin-3-yl]molybdenum
(( )-12).
described in the Supporting Information (22.4 mg, 0.11 mmol, 1.5
equiv), and MgO (8.8 mg, 0.22 mmol, 3.0 equiv). The reaction
mixture was stirred at room temperature for 1 h and then quenched
with brine. The mixture was poured into a separatory funnel
containing EtOAc (5 mL), and the layers were separated. The
aqueous layer was extracted with EtOAc (2 × 5 mL), and the
combined organic layers were dried over Na2SO4, filtered, and
concentrated. Flash chromatography over silica gel with hexanes/
EtOAc (2.5/1) afforded ( )-13 (41 mg, 0.046 mmol, 66%) as an orange
solid. TLC: Rf = 0.23 (2/1 hexanes/EtOAc). 1H NMR (major rotamer)
(400 MHz, CDCl3): δ 8.62 (d, J = 2.0 Hz, 1 H), 8.30 (d, J = 8.0 Hz, 1
H), 7.87 (d, J = 2.0 Hz, 1 H), 7.82 (d, J = 2.0 Hz, 1 H), 7.60 (d, J = 2.4
Hz, 1 H), 7.53 (d, J = 2.4 Hz, 1 H), 7.51 (d, J = 2.0 Hz, 1 H), 7.33 (d,
J = 8.0 Hz, 1 H), 7.26 (t, J = 7.2 Hz, 1 H), 6.30 (t, J = 2.0 Hz, 1 H), 6.23
(t, J = 2.0 Hz, 1 H), 6.08 (t, J = 2.0 Hz, 1 H), 5.58 (d, J = 2.8 Hz, 1 H),
4.96 (dt, J = 12.8 Hz, 6.8 Hz, 1 H), 4.64 (dt, J = 13.2 Hz, 6.4 Hz, 1 H),
4.47 (d, J = 4.4 Hz, 1 H), 4.22−4.35 (m, 3 H), 4.08 (t, J = 7.6 Hz, 1 H),
3.97 (d, J = 15.2 Hz, 1 H), 3.73 (s, 3 H), 3.62 (dt, J = 15.6 Hz, 6.8 Hz, 1
H), 1.37 (s, 9 H). 13C NMR (100 MHz, CDCl3)): δ 225.8, 225.7, 153.8,
147.4, 142.4, 141.6, 137.6, 136.0, 135.8, 134.3, 133.0, 125.6, 121.5, 120.9,
119.5, 115.1, 109.3, 105.9, 105.3, 79.4, 75.2, 71.4, 65.8, 65.4, 46.5, 41.5,
29.7, 28.3, 22.9. IR (cm−1): 2976 (w), 2930 (w), 2482 (w), 1942 (s),
1853 (s), 1679 (m). HRMS (FAB): calcd for C32H36BMoNaN9O6
([M + Na]+), 774.1828; found, 774.1835.
To a solution of ( )-4b (120 mg, 0.172 mmol, 1.0 equiv) in DMSO
(8 mL) was added methyl 3-(1-methyl-1H-indol-2-yl)-2-
(phenylsulfonyl)propanoate, prepared as described in the Supporting
Information (92 mg, 0.26 mmol, 1.5 equiv). The reaction mixture was
stirred at room temperature for 1 h and then quenched with brine.
The mixture was poured into a separatory funnel containing EtOAc
(5 mL), and the layers were separated. The aqueous layer was extracted
with EtOAc (2 × 5 mL), and the combined organic layers were dried
over Na2SO4, filtered, and concentrated. Flash chromatography over
silica gel with hexanes/EtOAc (2.5/1) afforded ( )-12 (102 mg, 0.108
mmol, 63%) as an orange solid. TLC: Rf = 0.22 (2/1 hexanes/EtOAc).
1H NMR (a mixture of two diastereomers) (600 MHz, CDCl3): δ 8.63
( )-Dicarbonyl[hydridotris(1-pyrazolyl)borato][(η-3,4,5)-1-benzy-
loxycarbonyl-2-(5′-methyl-2′-furanyl)-5,6-dihydro-2H-pyridin-3-yl]
molybdenum (( )-14).
(d, J = 1.2 Hz, 0.5 H), 8.61 (d, J = 1.2 Hz, 0.5 H), 8.34 (d, J = 7.8 Hz,
0.5 H), 8.31 (d, J = 7.8 Hz, 0.5 H), 8.23 (d, J = 1.8 Hz, 0.5 H), 8.19 (d,
J = 1.8 Hz, 0.5 H), 8.01 (d, J = 1.2 Hz, 0.5 H), 8.0 (d, J = 1.2 Hz, 0.5
H), 7.86 (d, J = 1.8 Hz, 0.5 H), 7.82 (d, J = 1.8 Hz, 0.5 H), 7.80 (d, J =
7.2 Hz, 1 H), 7.68 (d, J = 7.2 Hz, 0.5 H), 7.66 (d, J = 7.2 Hz, 0.5 H),
7.61 (d, J = 1.8 Hz, 1 H), 7.58 (d, J = 7.8 Hz, 0.5 H), 7.56 (d, J = 1.2
Hz, 1 H), 7.53 (s, 1H), 7.52 (d, J = 8.4 Hz, 0.5 H), 7.45 (d, J = 7.8 Hz,
0.5 H), 7.43 (d, J = 7.8 Hz, 0.5 H), 7.32−7.26 (m, 4 H), 7.22 (d, J =
7.8 Hz, 0.5 H), 7.20 (d, J = 7.8 Hz, 0.5 H), 7.05 (d, J = 7.2 Hz, 1 H),
6.31 (d, J = 1.8 Hz, 1 H), 6.24−6.22 (m, 1 H), 6.04 (t, J = 1.8 Hz, 0.5
H), 6.02 (t, J = 1.8 Hz, 0.5 H), 5.57 (d, J = 3.0 Hz, 0.5 H), 5.54 (d, J =
2.4 Hz, 1 H), 5.40 (d, J = 10.8 Hz, 0.5 H), 5.34 (d, J = 12.6 Hz, 0.5 H),
5.24 (d, J = 10.8 Hz, 0.5 H), 5.12 (d, J = 2.4 Hz, 0.5 H), 5.11 (s, 1 H),
5.08 (dd, J = 3.0, 12 Hz, 0.5 H), 4.87 (dd, J = 3.0, 12 Hz, 0.5 H), 4.81
(d, J = 12.6 Hz, 0.5 H), 4.75 (d, J = 12.6 Hz, 0.5 H), 4.51 (dd, J = 1.8,
7.2 Hz, 0.5 H), 4.43−4.40 (m, 1.5 H), 4.37 (br s, 0.5 H), 4.35 (br s, 0.5
H), 4.32 (dt, J = 2.4, 7.2 Hz, 0.5 H), 4.28 (dt, J = 2.4, 7.2 Hz, 0.5 H),
4.07−4.03 (m, 1.5 H), 3.98 (d, J = 13.8 Hz, 0.5 H), 3.71 (dd, J = 12.6,
15.0 Hz, 0.5 H), 3.65 (dd, J = 2.4, 15.0 Hz, 0.5 H), 3.60 (s, 1.5 H),
3.56 (s, 1.5 H), 3.50 (d, J = 6.6 Hz, 0.5 H), 3.42 (s, 1.5 H), 3.35 (s, 1.5
H), 2.80 (dd, J = 2.4, 15.0 Hz, 0.5 H). 13C NMR (150 MHz, CDCl3):
δ 227.0, 226.6, 225.0, 224.4, 166.4, 166.3, 155.4, 154.6, 147.6, 143.6,
141.3, 138.4, 137.2, 137.1, 136.9, 136.8, 136.3, 134.7, 134.6, 133.6, 132.4,
129.6, 129.4, 129.3, 128.6, 128.5, 128.1, 127.8, 127.7, 126.3, 126.1, 122.8,
122.5, 121.4, 121.3, 120.8, 120.6, 117.5, 116.6, 109.7, 109.5, 106.2, 105.7,
105.3, 105.2, 74.1, 73.9, 72.9, 72.5, 69.7, 69.2, 66.9, 66.7, 65.7, 65.4, 63.4,
56.3, 56.2, 53.3, 53.2, 47.9, 47.6, 42.3, 41.9, 22.7, 22.6. IR (cm−1): 1945
(s), 1858 (s), 1743 (s), 1692. HRMS (FAB): calcd for
C43H41BMoNaN8O8S ([M + Na]+), 961.181; found, 961.1803.
To a solution of ( )-4b (50 mg, 0.072 mmol, 1.0 equiv) in MeCN
(4 mL) was added 2-methylfuran (9.1 mg, 0.11 mmol, 1.5 equiv). The
reaction mixture was stirred at room temperature for 1 h and then
quenched with brine. The mixture was poured into a separatory funnel
containing EtOAc (5 mL), and the layers were separated. The aqueous
layer was extracted with EtOAc (2 × 5 mL), and the combined organic
layers were dried over Na2SO4, filtered, and concentrated. Flash
chromatography over silica gel with hexanes/EtOAc (2.5/1) afforded
( )-14 (40 mg, 0.060 mmol, 84%) as an orange solid. TLC: Rf = 0.34,
1
3/1 hexanes/EtOAc). H NMR (a mixture of two rotamers) (400 MHz,
CDCl3): δ 8.58 (br s, 1 H), 7.77 (d, J = 2.0 Hz, 0.4 H), 7.75 (br s, 1 H),
7.72 (d, J = 2.0 Hz, 0.6 H), 7.56−7.58 (m, 2 H), 7.51 (d, J = 2.0 Hz, 1 H),
7.27−7.34 (m, 5 H), 6.31 (t, J = 2.0 Hz, 1 H), 6.26 (d, J = 3.2 Hz, 0.4 H),
6.17−6.19 (m, 1 H), 6.14−6.16 (m, 1 H), 6.14 (d, J = 2.8 Hz, 0.6 H), 5.92
(d, J = 2.0 Hz, 0.4 H), 5.89 (d, J = 2.4 Hz, 0.6 H), 5.43 (d, J = 2.8 Hz, 0.4
H), 5.38 (d, J = 3.2 Hz, 0.6 H), 5.19 (d, J = 13.2 Hz, 0.6 H), 5.13 (d, J =
12.4 Hz, 0.4 H), 5.06 (d, J = 12.8 Hz, 0.4 H), 5.05 (d, J = 12.8 Hz, 0.6 H),
4.19−4.38 (m, 3 H), 3.87 (t, J = 7.2 Hz, 1 H), 3.75 (d, J = 13.2 Hz, 0.4 H),
3.67 (d, J = 13.2 Hz, 0.6 H), 2.31 (s, 1.2 H), 2.27 (s, 1.8 H). 13C NMR
(100 MHz, CDCl3): δ 225.7, 225.5, 225.3, 225.0, 154.8, 153.6, 153.6, 151.8,
151.7, 147.3, 141.9, 141.7, 136.9, 136.7, 136.0, 134.4, 128.3, 128.2, 127.9,
127.7, 127.6, 127.6, 107.6, 107.5, 106.2, 106.0, 106.0, 105.4, 105.3, 68.2,
68.0, 67.2, 67.0, 67.0, 64.0, 63.9, 48.9, 48.5, 39.8, 39.4, 13.8, 13.7. IR (cm−1):
3134 (w), 3030 (w), 2953 (w), 2837 (w), 2486 (m), 1945 (s), 1861 (s),
1698 (s). HRMS (FAB): calcd for C29H29BMoN7O5 ([M + H]+),
664.1372; found, 664.1377.
( )-Dicarbonyl[hydridotris(1-pyrazolyl)borato][(η-3,4,5)-1-tert-
butoxycarbonyl-2-(1′-methyl-2′-nitroethyl-3′-indolyl)-5,6-dihydro-
2H-pyridin-3-yl]molybdenum (( )-13).
( )-Dicarbonyl[hydridotris(1-pyrazolyl)borato][(η-3,4,5)-2-(4-eth-
ylaminophenyl)-5,6-dihydro-2H-pyran-3-yl]molybdenum (( )-15).
To a solution of ( )-4b′ (50 mg, 0.076 mmol, 1.0 equiv) in DMSO
(4 mL) were added methyl-2-(2-nitroethyl)-1H-indole, prepared as
To a solution of ( )-3b (50 mg, 0.089 mmol, 1.0 equiv) in MeCN
(4 mL) was added N-ethylaniline (25 mg, 0.18 mmol, 2 equiv). The
7603
dx.doi.org/10.1021/om401087h | Organometallics 2013, 32, 7594−7611

Organometallics
Article
reaction mixture was stirred at room temperature for 4 h and then
quenched with brine. The mixture was poured into a separatory funnel
containing EtOAc (5 mL), and the layers were separated. The aqueous
layer was extracted with EtOAc (2 × 5 mL), and the combined organic
layers were dried over Na2SO4, filtered, and concentrated. Flash
chromatography over silica gel with hexanes/EtOAc (2.5/1) afforded
( )-15 (28 mg, 0.050 mmol, 56%) as a yellow solid. TLC: Rf = 0.32
(2/1 hexanes/EtOAc).1H NMR (400 MHz, CDCl3): δ 8.68 (d, J = 1.9
Hz, 1H), 7.74 (d, J = 1.9 Hz, 1H), 7.70 (d, J = 1.9 Hz, 1H), 7.60 (d,
J = 2.2 Hz, 1H), 7.59 (d, J = 2.2 Hz, 1H), 7.57−7.53 (m, 2H), 6.65 (d,
J = 8.5 Hz, 2H), 6.33 (t, J = 2.2 Hz, 1H), 6.19 (t, J = 2.1 Hz, 1H), 6.15
(t, J = 2.1 Hz, 1H), 4.87 (d, J = 2.1 Hz, 1H), 4.23−4.17 (m, 1H),
4.17−4.10 (m, 2H), 3.97 (d, J = 12.5 Hz, 1H), 3.64 (d, J = 12.3 Hz,
2H), 3.19 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H). 13C NMR (101
MHz, CDCl3): δ 226.1, 225.6, 148.3, 147.4, 141.8, 141.4, 135.9, 134.3,
129.7, 129.0, 112.3, 105.9, 105.3, 105.2, 72.2, 69.8, 67.2, 64.5, 57.4,
38.4, 14.9. IR (cm−1): 2968 (w), 2868 (w), 2490 (w), 1942 (s), 1853
(s), 1598 (m). HRMS (ESI): calcd for C24H27N7O3BMo ([M + H]+),
570.1328; found, 570.1315.
(d, J = 2.4 Hz, 1 H), 6.30 (t, J = 2.0 Hz, 1 H), 6.17 (t, J = 2.4 Hz, 1 H),
4.41 (ddd, J = 7.2 Hz, 4.8 Hz, 2.0 Hz, 1 H), 4.24 (d, J = 12.8 Hz, 1 H),
4.14 (dt, J = 7.2 Hz, 2.4 Hz, 1 H), 4.08 (d, J = 7.2 Hz, 1 H), 3.86 (s, 3
H), 3.76 (d, J = 7.6 Hz, 1 H), 3.71 (dd, J = 12.8 Hz, 2.4 Hz, 1 H), 3.43
(dd, J = 14.4 Hz, 8.8 Hz, 1 H), 3.31 (dd, J = 14.8 Hz, 4.4 Hz, 1 H). 13C
NMR (100 MHz, CDCl3): δ 225.2, 225.2, 190.0, 161.8, 147.3, 141.9,
141.4, 135.9, 134.4, 105.9, 105.3, 70.7, 68.2, 67.0, 63.0, 57.9, 52.2, 46.5.
IR (cm−1): 3130 (w), 2957 (w), 2486 (m), 2138 (s), 1942 (s), 1853
(s), 1718 (s), 1648 (s). HRMS (FAB): calcd for C21H21BMoNaN8O6
([M + Na]+), 613.0623; found, 613.0633.
( )-Dicarbonyl[hydridotris(1-pyrazolyl)borato][(η-3,4,5)-2-allyl-
5,6-dihydro-2H-pyran-3-yl]molybdenum (( )-18).
To a solution of ( )-3b (50 mg, 0.089 mmol, 1.0 equiv) in MeCN
(4 mL) was added allyltrimethylsilane (14.8 mg, 0.13 mmol, 1.5 equiv).
The reaction mixture was stirred at room temperature for 1 h and then
quenched with brine. The mixture was poured into a separatory funnel
containing EtOAc (5 mL), and the layers were separated. The aqueous
layer was extracted with EtOAc (2 × 5 mL), and the combined organic
layers were dried over Na2SO4, filtered, and concentrated. Flash
chromatography over silica gel with hexanes/EtOAc (2.5/1) afforded
( )-18 (32 mg, 0.066 mmol, 74%) as an orange solid. TLC: Rf = 0.35
(6/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3)δ 8.63 (d, J = 2.0 Hz,
1 H), 7.70 (d, J = 2.0 Hz, 1 H), 7.68 (d, J = 2.0 Hz, 1 H), 7.57 (d, J = 2.0
Hz, 2 H), 7.52 (d, J = 2.4 Hz, 1 H), 6.31 (t, J = 2.4 Hz, 1 H), 6.17 (t, J =
2.0 Hz, 2 H), 5.93 (ddt, J = 16.8 Hz, 10.0 Hz, 7.2 Hz, 1 H), 5.16 (dd, J =
16.8 Hz, 2.0 Hz, 1 H), 5.10 (dd, J = 10.0 Hz, 0.8 Hz, 1 H), 4.16 (d, J =
12.4 Hz, 1 H), 4.07 (d, J = 6.8 Hz, 1 H), 4.06 (d, J = 6.8 Hz, 1 H), 3.90
(ddd, J = 8.0 Hz, 5.6 Hz, 2.0 Hz, 1 H), 3.78 (t, J = 7.2 Hz, 1 H), 3.72
(dd, J = 12.4 Hz, 1.6 Hz, 1 H), 2.60 (dt, J = 14.0 Hz, 7.2 Hz, 1 H), 2.50
(dt, J = 14.0 Hz, 6.0 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ 225.7,
225.3, 147.3, 141.6, 141.5, 135.9, 135.5, 134.3, 116.8, 105.9, 105.3, 71.1,
70.4, 67.4, 63.4, 57.6, 40.8. IR (cm−1): 3146 (w), 2926 (m), 2853 (w),
2482 (w), 1938 (s), 1845 (s), 1640 (w). HRMS (FAB): calcd for
C19H21BMoNaN6O3 ([M + Na]+), 513.0715; found, 513.0723.
( )-Dicarbonyl[hydridotris(1-pyrazolyl)borato][(η-3,4,5)-2-ace-
tonyl-5,6-dihydro-2H-pyran-3-yl]molybdenum (( )-16).
To a solution of ( )-3b (50 mg, 0.089 mmol, 1.0 equiv) in MeCN
(4 mL) was added 2-trimethyloxypropene (16.9 mg, 0.13 mmol, 1.5
equiv). The reaction mixture was stirred at room temperature for 1 h
and then quenched with brine. The mixture was poured into a
separatory funnel containing EtOAc (5 mL), and the layers were
separated. The aqueous layer was extracted with EtOAc (2 × 5 mL),
and the combined organic layers were dried over Na2SO4, filtered, and
concentrated. Flash chromatography over silica gel with hexanes/
EtOAc (2.5/1) afforded ( )-16 (36 mg, 0.071 mmol, 80%) as an
1
orange solid. TLC: Rf = 0.20 (2/1 hexanes/EtOAc). H NMR (400
MHz, CDCl3): δ 8.61 (d, J = 2.0 Hz, 1 H), 7.71 (d, J = 2.0 Hz, 1 H),
7.68 (d, J = 2.0 Hz, 1 H), 7.58 (br s, 2 H), 7.52 (d, J = 2.4 Hz, 1 H),
6.31 (t, J = 2.0 Hz, 1 H), 6.17−6.18 (m, 2 H), 4.35 (ddd, J = 7.6 Hz,
5.2 Hz, 2.0 Hz, 1 H), 4.14 (d, J = 12.8 Hz, 1 H), 4.06−4.12 (m, 2 H),
3.74 (t, J = 7.6 Hz, 1 H), 3.72 (dd, J = 12.4 Hz, 2.0 Hz, 1 H), 2.99 (dd,
J = 14.8 Hz, 8.0 Hz, 1 H), 2.83 (dd, J = 14.8 Hz, 5.2 Hz, 1 H). 13C
NMR (100 MHz, CDCl3): δ 225.3, 225.2, 207.0, 147.3, 141.8, 141.4,
136.0, 134.4, 106.0, 105.3, 70.5, 67.6, 66.8, 62.9, 57.8, 50.6, 30.2.IR
(cm−1): 2957 (m), 2856 (w), 2490 (w), 1948 (s), 1853 (s), 1714 (s),
1625 (s). HRMS (FAB): calcd for C19H21BMoNaN6O4 ([M + Na]+),
529.0675; found, 529.0664.
( )-Dicarbonyl[hydridotris(1-pyrazolyl)borato][(η-3,4,5)-2-(malo-
nylisobutenyl)-5,6-dihydro-2H-pyran-3-yl]molybdenum (( )-19).
To a solution of ( )-3b (50 mg, 0.089 mmol, 1.0 equiv) in MeCN
(4 mL) was added dimethyl 2-(2-((trimethylsilyl)methyl)allyl)-
malonate51 (33 mg, 0.13 mmol, 1.5 equiv). The reaction mixture
was stirred at room temperature for 1 h and then quenched with brine.
The mixture was poured into a separatory funnel containing EtOAc
(5 mL), and the layers were separated. The aqueous layer was
extracted with EtOAc (2 × 5 mL), and the combined organic layers
were dried over Na2SO4, filtered, and concentrated. Flash chromatog-
raphy over silica gel with hexanes/EtOAc (2.5/1) afforded ( )-19
(40 mg, 0.063 mmol, 71%) as an orange solid. TLC: Rf = 0.33 (3/1 hexanes/
( )-Dicarbonyl[hydridotris(1-pyrazolyl)borato][(η-3,4,5)-2-(diaz-
omethoxycarbonylacetonyl)-5,6-dihydro-2H-pyran-3-yl]molybde-
num (( )-17).
1
EtOAc). H NMR (400 MHz, CDCl3): δ 8.62 (d, J = 2.0 Hz, 1 H), 7.73
To a solution of ( )-3b (50 mg, 0.089 mmol, 1.0 equiv) in MeCN
(4 mL) was added tert-butyldimethylsilyloxyvinyldiazoacetate50 (33 mg,
0.13 mmol, 1.5 equiv). The reaction mixture was stirred at room
temperature for 1 h and then quenched with brine. The mixture was
poured into a separatory funnel containing EtOAc (5 mL), and the
layers were separated. The aqueous layer was extracted with EtOAc
(2 × 5 mL), and the combined organic layers were dried over Na2SO4,
filtered, and concentrated. Flash chromatography over silica gel with
hexanes/EtOAc (2.5/1) afforded ( )-7 (39 mg, 0.067 mmol, 77%) as
(d, J = 2.0 Hz, 1 H), 7.69 (d, J = 2.0 Hz, 1 H), 7.57 (d, J = 2.4 Hz, 2 H), 7.52
(d, J = 2.0 Hz, 1 H), 6.30 (t, J = 2.0 Hz, 1 H), 6.16−6.18 (m, 2 H), 4.98
(s, 1 H), 4.88 (s, 1 H), 4.15 (d, J = 12.4 Hz, 1 H), 4.06 (d, J = 7.2 Hz,
2 H), 4.00 (t, J = 7.2 Hz, 1 H), 3.78 (t, J = 7.6 Hz, 1 H), 3.74 (s, 6 H),
3,67−3.74 (m, 2 H), 2.74 (d, J = 7.6 Hz, 2 H), 2.58 (dd, J = 14.0 Hz,
8.4 Hz, 1 H), 2.45 (dd, J = 14.4 Hz, 4.8 Hz, 1 H). 13C NMR (100 MHz,
CDCl3): δ 225.5, 225.4, 169.4, 169.4, 147.3, 142.9, 141.8, 141.4, 135.9,
134.3, 113.7, 105.9, 105.3, 71.2, 69.2, 67.1, 63.2, 57.5, 52.6, 52.6, 50.4, 42.6,
34.8. IR (cm−1): 2957 (m), 2926 (m), 2482 (w), 1942 (s), 1853 (s), 1733
(s), 1648 (m). HRMS (FAB): calcd for C25H29BMoNaN6O7 ([M + Na]+),
657.1137; found, 657.1132.
1
an orange solid. TLC: Rf = 0.41 (2/1 hexanes/EtOAc). H NMR
(400 MHz, CDCl3): δ 8.61 (d, J = 1.6 Hz, 1 H), 7.73 (d, J = 2.0 Hz,
1 H), 7.68 (d, J = 2.0 Hz, 1 H), 7.57 (t, J = 1.6 Hz, 2 H), 7.51
7604
dx.doi.org/10.1021/om401087h | Organometallics 2013, 32, 7594−7611

Organometallics
Article
Oxidative Demetalations. ( )-Dicarbonyl[hydridotris(1-
pyrazolyl)borato][(η-3,4,5)-2-(1′-benzyloxycarbonyl-2′-methyl-3′-
indolyl)-5,6-dihydro-2H-pyran-3-yl]molybdenum (( )-21).
and copper 2-ethylhexanoate (5 mg, 0.014 mmol, 0.2 equiv). The reaction
mixture was stirred at room temperature under dry air for 3 days and then
quenched with brine. The mixture was poured into a separatory funnel
containing EtOAc (2 mL), and the layers were separated. The aqueous layer
was extracted with EtOAc (2 × 2 mL), and the combined organic layers
were dried over Na2SO4, filtered, and concentrated. Flash chromatography
over silica gel with hexanes/EtOAc (6/1) afforded ( )-23 (16 mg, 0.068
mmol, 95%) as a colorless oil. TLC: Rf = 0.36 (4/1 hexanes/EtOAc). 1H
NMR (400 MHz, CDCl3): δ 7.67 (d, J = 8.0 Hz, 1 H), 7.31 (d, J = 8.4 Hz,
1 H), 7.20 (dt, J = 8.4 Hz, 1.2 Hz, 1 H), 7.15 (dt, J = 8.0 Hz, 0.8 Hz, 1 H),
6.21 (dd, J = 10.4 Hz, 1.6 Hz, 1 H), 6.11 (ddt, J = 10.4 Hz, 4.0 Hz, 1.6 Hz,
1 H), 5.04 (d, J = 14.8 Hz, 1 H), 4.83 (dd, J = 14.8 Hz, 1.2 Hz, 1 H), 4.68
(s, 1 H), 4.32−4.43 (m, 2 H), 3.92 (dd, J = 4.4 Hz, 2.4 Hz, 1 H), 3.62 (s, 3
H). 13C NMR (100 MHz, CDCl3): δ 137.4, 135.7, 132.7, 126.5, 123.6,
121.7, 119.9, 118.4, 108.9, 106.8, 68.8, 67.4, 65.3, 62.6, 29.6. IR (cm−1):
3042 (w), 2926 (m), 2853 (m), 1471 (s). HRMS (ESI): calcd for
C15H16NO2 ([M + H]+), 242.1175; found, 242.1176.
To a solution of ( )-6b (110 mg, 0.19 mmol, 1.0 equiv) in THF (4 mL)
were added NaHMDS (1.0 M in THF, 0.38 mL, 0.38 mmol, 2 equiv) and
CbzCl (49 mg, 0.29 mmol, 1.5 equiv). The reaction mixture was stirred at
room temperature for 30 min and then quenched with brine. The mixture
was poured into a separatory funnel containing EtOAc (5 mL), and
the layers were separated. The aqueous layer was extracted with EtOAc
(2 × 5 mL), and the combined organic layers were dried over Na2SO4,
filtered, and concentrated. Flash chromatography over silica gel with
hexanes/EtOAc (2.5/1) afforded ( )-21 (95 mg, 0.13 mmol, 70%) as an
orange solid. TLC: Rf = 0.33 (2/1 hexanes/EtOAc). 1H NMR (400 MHz,
CDCl3): δ 8.66 (d, J = 2.0 Hz, 1H), 8.46−8.37 (m, 1H), 8.23−8.08 (m,
1H), 7.81 (d, J = 2.0 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 2.2 Hz,
1H), 7.57 (d, J = 2.2 Hz, 1H), 7.54 (d, J = 2.1 Hz, 1H), 7.52−7.48 (m,
2H), 7.45−7.35 (m, 3H), 7.30−7.23 (m, 2H), 6.33 (t, J = 2.2 Hz, 1H),
6.22 (t, J = 2.2 Hz, 1H), 6.11 (t, J = 2.2 Hz, 1H), 5.49 (s, 2H), 5.19 (d, J =
1.8 Hz, 1H), 4.50−4.37 (m, 3H), 4.34 (t, J = 6.8 Hz, 1H), 3.90−3.78 (m,
1H), 2.72 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 227.1, 226.3, 152.0,
147.4, 141.9, 141.3, 136.5, 136.0, 136.0, 134.9, 134.4, 128.8, 128.7, 128.7,
128.6, 123.5, 122.8, 120.4, 119.3, 115.4, 106.0, 105.4, 105.3, 71.4, 68.7, 68.5,
67.8, 66.8, 62.2, 14.3. IR (cm−1): 3150 (w), 3127 (w), 3049 (w), 2961 (w),
2856 (w), 2482 (m), 1942 (s), 1849 (s), 1733 (m). HRMS (ESI): calcd for
C33H30N7O5BMoNa ([M + Na]+), 736.1348; found, 736.1350.
( )-Dicarbonyl[hydridotris(1-pyrazolyl)borato][(η-3,4,5)-1-tert-
butoxycarbonyl-2-(2′-malonyl-3′-N-benzyloxycarbonylindolyl)-5,6-
dihydro-2H-pyridin-3-yl]molybdenum (( )-24).
To a solution of ( )-11 (50 mg, 0.051 mmol, 1.0 equiv) in THF
(4 mL) were added NaHMDS (1.0 M in THF, 0.10 mL, 0.10 mmol, 2
equiv) and CbzCl (14 mg, 0.092 mmol, 1.8 equiv). The reaction
mixture was stirred at room temperature for 30 min and then
quenched with brine. The mixture was poured into a separatory funnel
containing EtOAc (5 mL), and the layers were separated. The aqueous
layer was extracted with EtOAc (2 × 5 mL), and the combined organic
layers were dried over Na2SO4, filtered, and concentrated. Flash
chromatography over silica gel with hexanes/EtOAc (2.5/1) afforded
( )-24 (45 mg, 0.045 mmol, 88%) as an orange solid. TLC: Rf = 0.27
Benzyl 2-Methyl-3-(5-oxo-5,6-dihydro-2H-pyran-2-yl)-1H-indole-
1-carboxylate (( )-22).
1
(2/1 hexanes/EtOAc). H NMR (a mixture of two rotamers) (400
MHz, CDCl3): δ 8.59−8.61 (m, 1 H), 8.26 (dd, J = 8.8, 1.6 Hz, 0.7
H), 8.19 (dd, J = 8.8, 0.8 Hz, 0.7 H), 8.08 (d, J = 7.2 Hz, 0.3 H), 8.01
(d, J = 8.0 Hz, 0.3 H), 7.88 (d, J = 2.0 Hz, 0.7 H), 7.85 (d, J = 8.0 Hz,
0.3 H), 7.55−7.61 (m, 1 H), 7.46−7.54 (m, 4 H), 7.23−7.42 (m, 6 H),
6.32 (t, J = 2.4 Hz, 1 H), 6.21 (t, J = 2.0 Hz, 1 H), 6.10 (s, 0.7 H), 6.03
(t, J = 2.4 Hz, 1 H), 5.59 (d, J = 12.4 Hz, 0.7 H), 5.56 (d, J = 12.4 Hz,
0.3 H), 5.35−5.53 (m, 1.6 H), 5.21 (d, J = 12.4 Hz, 0.7 H), 4.47−4.54
(m, 1.3 H), 4.38 (dd, J = 15.2, 2.4 Hz, 1.0 H), 4.07−4.19 (m, 2.7 H),
4.00 (d, J = 15.6 Hz, 0.7 H), 3.89 (t, J = 6.8 Hz, 0.3 H), 1.47 (s, 2.7 H),
1.44 (s, 9 H), 1.38 (s, 6.3 H), 1.36 (s, 2.7 H), 1.35 (s, 6.3 H). 13C
NMR (101 MHz, CDCl3): δ 227.1, 226.8, 224.6, 224.1, 166.2, 165.9,
165.6, 165.3, 154.2, 153.9, 151.7, 151.6, 147.4, 142.4, 142.2, 141.4, 141.1,
140.8, 136.5, 136.1, 136.0, 135.9, 135.8, 135.5, 135.1, 134.4, 131.4, 129.7,
128.6, 128.5, 128.4, 128.3, 127.6, 127.5, 127.0, 125.5, 124.6, 124.0, 122.8,
122.5, 122.2, 121.1, 120.9, 120.4, 115.6, 115.3, 106.0, 105.3, 105.2, 105.1,
82.2, 82.1, 81.5, 81.4, 80.8, 79.5, 68.8, 68.4, 68.1, 67.9, 67.7, 66.5, 65.4, 64.8,
51.7, 51.2, 47.5, 46.8, 41.7, 41.1, 28.3, 28.0, 27.7. IR (cm−1): 3065 (w),
2961 (m), 2482 (w), 1945 (s), 1864 (s), 1741 (s). HRMS (ESI): calcd for
C48H55N8O10BMoNa ([M + Na]+), 1035.3091; found, 1035.3129.
6-Benzyl-1,5,5-tri-tert-butylpyrido[2′,3′:3,4]cyclopenta[1,2-b]-
indole-1,5,5,6(2H,4aH,10cH)-tetracarboxylate (( )-25).
To a solution of ( )-21 (50 mg, 0.07 mmol, 1.0 equiv) in CH2Cl2 (3 mL)
was added pyridinium dichromate (90 mg, 0.21 mmol, 3 equiv) and silica
(90 mg, 0.21 mmol, 3 equiv). The reaction mixture was stirred at room
temperature for 5 h, and then was passed through a plug of silica gel with
ethyl acetate as the eluent. The eluant was collected and concentrated for
further purification. Flash chromatography over silica gel with hexanes/
EtOAc (2.5/1) afforded ( )-22 (13 mg, 0.036 mmol, 52%) as a colorless
oil. TLC: Rf = 0.33 (2/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3):
δ 8.10 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.49 (dd, J = 7.8, 1.6
Hz, 1H), 7.46−7.35 (m, 3H), 7.25−7.17 (m, 1H), 7.11 (dd, J = 10.4, 1.8
Hz, 1H), 6.36 (dd, J = 10.4, 2.5 Hz, 1H), 5.63 (dd, J = 4.4, 2.1 Hz, 1H),
5.48 (s, 2H), 4.44 (d, J = 16.5 Hz, 1H), 4.33 (dd, J = 16.3, 2.1 Hz, 1H),
2.66 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 194.3, 151.8, 151.8, 136.2,
135.7, 134.8, 128.8, 128.6, 127.8, 127.7, 124.2, 123.2, 119.0, 115.8, 115.7,
72.4, 69.5, 68.9, 14.2. IR (cm−1): 3038 (w), 2968 (w), 2930 (w), 2856
(w), 1733 (s), 1698 (s). HRMS (ESI): calcd for C22H20NO4 ([M + H]+),
362.1387; found, 362.1383.
7-Methyl-4a,6,7,11c-tetrahydro-2H-pyrano[2′,3′:5,6]pyrano[3,4-
b]indole (( )-23).
To a solution of ( )-8 (44 mg, 0.072 mmol, 1.0 equiv) in DMSO
(4 mL) were added a 60% NaH suspension (4.3 mg, 0.11 mmol, 1.5 equiv)
7605
dx.doi.org/10.1021/om401087h | Organometallics 2013, 32, 7594−7611

Organometallics
Article
To a solution of ( )-24 (50 mg, 0.050 mmol, 1.0 equiv) in DMSO
(2 mL) were added a 60% NaH suspension (2.97 mg, 0.075 mmol, 1.5
equiv) and copper 2-ethylhexanoate (4 mg, 0.001 mmol, 0.2 equiv).
The reaction mixture was stirred at room temperature under dry air
overnight and then quenched with brine. The mixture was poured into
a separatory funnel containing EtOAc (2 mL), and the layers were
separated. The aqueous layer was extracted with EtOAc (2 × 2 mL),
and the combined organic layers were dried over Na2SO4, filtered, and
concentrated. Flash chromatography over silica gel with hexanes/
EtOAc (6/1) afforded ( )-25 (22 mg, 0.033 mmol, 67%) as a
filtered through a pad of Celite, and the filtrate was concentrated. Flash
chromatography over silica gel with 3−5% MeOH in CH2Cl2 afforded
( )-28 (60 mg, 0.075 mmol, 72%) as a yellow solid. TLC: Rf = 0.15
1
(9/1 CH2Cl2/MeOH). H NMR (a mixture of two diastereomers)
(600 MHz, CDCl3): δ 8.65 (s 1 H), 8.58 (d, J = 7.8 Hz, 0.6 H), 8.40
(d, J = 7.8 Hz, 0.4 H), 7.95 (d, J = 7.8 Hz, 0.4 H), 7.93 (d, J = 7.8 Hz,
1 H), 7.89 (d, J = 7.8 Hz, 0.6 H), 7.82 (s, 0.4 H), 7.81 (s, 0.6 H), 7.71
(t, J = 7.2 Hz, 0.4 H), 7.68 (s, 0.4 H), 7.60 (s, 1 H), 7.59 (s, 0.6 H),
7.57 (s, 0.4 H), 7.55 (t, J = 1.2 Hz, 1 H), 7.54 (d, J = 1.2 Hz, 1 H), 7.51
(t, J = 7.8 Hz, 0.6 H), 7.44−7.43 (m, 1 H), 7.23 (d, J = 7.8 Hz, 0.6 H),
7.17 (t, J = 7.2 Hz, 1 H), 6.33 (s, 1 H), 6.21 (d, J = 1.8 Hz, 1 H), 6.07
(s, 0.4 H), 6.05 (s, 0.6 H), 5.56 (d, J = 11.4 Hz, 0.4 H), 5.50 (d, J =
11.4 Hz, 0.6 H), 5.47 (d, J = 11.4 Hz, 0.4 H), 5.41 (d, J = 11.6 Hz, 0.6
H), 5.06 (dd, J = 2.4, 12.0 Hz, 0.6 H), 4.74 (dd, J = 3.6, 9.0 Hz, 0.4 H),
4.49 (br s, 0.4 H), 4.42 (br m, 0.6 H), 4.38 (d, J = 7.2 Hz, 0.6 H), 4.34
(d, J = 7.2 Hz, 0.4 H), 4.29 (t, J = 7.2 Hz, 0.6 H), 4.21 (t, J = 7.2 Hz,
0.4 H), 3.75 (dd, J = 4.2, 7.2 Hz, 1 H), 3.64 (d, J = 6.6 Hz, 0.6 H), 3.61
(d, J = 6.6 Hz, 0.4 H), 3.57 (s, 1.8 H), 3.55 (s, 1.2 H), 3.37 (s, 1.8 H),
3.34 (s, 1.2 H), 3.04 (d, J = 15.0 Hz, 0.4 H), 2.99 (d, J = 15.0 Hz, 0.6
H). 13C NMR (150 MHz, CDCl3): δ 227.4, 226.8, 226.4, 226.3, 166.3,
166.2, 147.6, 143.2, 142.4, 141.8, 141.4, 138.4, 138.2, 137.3, 137.1,
136.3, 134.7, 134.6, 129.5, 129.4, 126.9, 122.5, 121.6, 121.5, 120.5,
109.7, 106.2, 105.9, 105.6, 105.5, 105.3, 74.1, 74.0, 69.9, 69.6, 69.2,
56.3, 53.5, 53.2, 47.5, 41.4, 22.4, 22.1. IR (cm−1): 2929 (w), 1934 (s),
1845 (s), 1739 (s). HRMS (FAB): calcd for C35H35BMoNaN8O6S
([M + Na]+), 827.145; found, 827.1445.
1
colorless oil. TLC: Rf = 0.29 (2/1 hexanes/EtOAc). H NMR (400
MHz, CDCl3): δ 8.06 (br s, 1H), 7.47 (dd, J = 7.8, 1.6 Hz, 2H), 7.42−
7.29 (m, 4H), 7.29−7.25 (m, 1H), 7.24−7.17 (m, 1H), 6.08−5.93 (m,
1H), 5.86 (br s, 1H), 5.75−5.61 (m, 1H), 5.57−5.44 (m, 1H), 5.37−
5.24 (m, 1H), 4.40−4.04 (m, 2H), 3.33 (br s, 1H), 1.56 (s, 9H), 1.42
(s, 9H), 1.31 (s, 9H).13C NMR (101 MHz, CDCl3): δ 167.0, 165.9,
154.7, 150.3, 139.9, 135.2, 128.7, 128.6, 128.5, 127.9, 126.9, 126.1,
125.1, 124.5, 123.1, 119.3, 119.1, 116.2, 82.1, 68.6, 66.4, 52.4, 52.0,
38.4, 29.5, 28.5, 28.0, 27.9, 27.7, 22.6, 13.9, 11.8. IR (cm−1): 2976 (m),
2934 (w), 2872 (w), 1733 (s), 1698 (s). HRMS (ESI): calcd for
C37H45N2O8 ([M + H]+), 645.3170; found, 645.3163; calcd for
C37H44N2O8Na ([M + Na]+), 667.2990; found, 667.2978.
Methyl 7-Methyl-5-(phenylsulfonyl)-2,4a,5,6,7,11c-
hexahydropyrano[3,2-c]carbazole-5-carboxylate (( )-26).
Methyl 7-Methyl-5-(phenylsulfonyl)-2,4a,5,6,7,11c-hexahydro-
1H-pyrido[3,2-c]carbazole-5-carboxylate (( )-29).
To a solution of ( )-9 (50 mg, 0.062 mmol, 1.0 equiv) in DMSO
(4 mL) were added a 60% NaH suspension (3.74 mg, 0.094 mmol,
1.5 equiv) and copper 2-ethylhexanoate (34 mg, 0.094 mmol, 1.0 equiv).
The reaction mixture was stirred at room temperature under dry air
overnight and then quenched with brine. The mixture was poured into a
separatory funnel containing EtOAc (2 mL), and the layers were
separated. The aqueous layer was extracted with EtOAc (2 × 2 mL), and
the combined organic layers were dried over Na2SO4, filtered, and
concentrated. Flash chromatography over silica gel with hexanes/EtOAc
(6/1) afforded ( )-26 (24 mg, 0.056 mmol, 90%) as a white solid. TLC:
Rf = 0.36 (2/1 hexanes/EtOAc). Mp: 138−140 °C. 1H NMR (400 MHz,
CDCl3): δ 7.74 (dd, J = 8.0 Hz, 1.2 Hz, 2 H), 7.68 (d, J = 8.0 Hz, 1 H),
7.52 (t, J = 7.6 Hz, 1 H), 7.36 (t, J = 8.0 Hz, 2 H), 7.14−7.17 (m, 2 H),
7.10 (ddd, J = 7.8 Hz, 5.6 Hz, 3.2 Hz, 1 H), 5.86 (dq, J = 10.4 Hz, 2.8 Hz,
1 H), 5.68 (d, J = 9.6 Hz, 1 H), 5.62 (d, J = 4.8 Hz, 1 H), 4.11 (dq, J =
16.8 Hz, 2.8 Hz, 1 H), 3.94 (dq, J = 16.8 Hz, 2.8 Hz, 1 H), 3.80 (s, 3 H),
3.78−3.80 (m, 1 H), 3.43 (s, 3 H), 3.26 (s, 2 H). 13C NMR (100 MHz,
CDCl3): δ 167.5, 137.4, 136.4, 134.0, 132.7, 130.4, 129.5, 128.5, 126.0,
122.5, 121.6, 119.8, 118.9, 108.7, 107.0, 78.0, 68.0, 61.5, 53.5, 37.4, 29.2,
24.7. IR (cm−1): 3057 (w), 2930 (w), 2845 (w), 1737 (s). HRMS (ESI):
calcd for C24H24NO5S ([M + H]+), 438.1370; found, 438.1371.
To a solution of ( )-28 (59 mg, 0.062 mmol, 1.0 equiv) in DMSO
(4 mL) were added a 60% NaH suspension (3.7 mg, 0.094 mmol, 1.5
equiv) and copper 2-ethylhexanoate (34 mg, 0.094 mmol, 1.0 equiv).
The reaction mixture was stirred at room temperature under dry air
overnight and then quenched with brine. The mixture was poured into
a separatory funnel containing EtOAc (2 mL), and the layers were
separated. The aqueous layer was extracted with EtOAc (2 × 2 mL),
and the combined organic layers were dried over Na2SO4, filtered, and
concentrated. Flash chromatography over silica gel with hexanes/
EtOAc (6/1) afforded ( )-29 (23 mg, 0.053 mmol, 85%) as a white
1
solid. TLC: Rf = 0.36 (1/1 hexanes/EtOAc). Mp: 176−178 °C. H
NMR (400 MHz, CDCl3): δ 7.75 (d, J = 7.7 Hz, 1H), 7.68 (d, J = 7.7
Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 7.29−7.18 (m, 2H), 7.15−7.01 (m,
3H), 5.86−5.71 (m, 1H), 5.40 (d, J = 10.4 Hz, 1H), 5.01 (d, J = 4.9
Hz, 1H), 3.81 (s, 3H), 3.34 (s, 3H), 3.26−3.10 (m, 3H), 3.10−2.91
(m, 1H), 2.15 (broad s, 2H). 13C NMR (100 MHz, CDCl3): δ 168.24,
137.55, 136.98, 133.94, 132.23, 132.09, 129.60, 128.45, 126.38, 123.36,
121.43, 119.51, 119.34, 108.77, 108.28, 78.96, 53.66, 49.01, 48.99,
40.92, 38.81, 29.25, 29.22, 24.23. IR (cm−1): 3360 (s), 2922 (w), 1734
(s). HRMS (ESI): calcd for C24H25N2O4S ([M + H]+), 437.1530;
found, 437.1528.
( )-Dicarbonyl[hydridotris(1-pyrazolyl)borato][(η-3,4,5)-2-(2′-
(3″-methoxy-3″-oxo-2″-(phenylsulfonyl)propyl)-1′-methyl-1H-
indol-3″-yl)-5,6-dihydro-2H-pyridin-3-yl]molybdenum (( )-28).
Concise Synthesis of Isofebrifugin Analogues. ( )-Dicarbonyl-
[hydridotris(1-pyrazolyl)borato][(η-3,4,5)-2-(2′-oxo-3′-(4″-oxoqui-
nazolin-3″(3″H)-yl)propyl)-5,6-dihydro-2H-pyridin-3-yl]-
molybdenum (( )-31).
A portion of 10% Pd/C (100 mg) was added to a solution of ( )-12
(100 mg, 0.107 mmol) in MeOH/THF (3/1 v/v, 6 mL), and the
mixture was exposed to hydrogen at 250 psi for 48 h. The mixture was
To a solution of ( )-3b (650 mg, 1.15 mmol, 1.0 equiv) in MeCN (11
mL) was added 3-[2-(trimethylsilyloxy)allyl]-3H-quinazolin-4-one35
(950 mg, 3.45 mmol, 3.0 equiv). The reaction mixture was stirred at
7606
dx.doi.org/10.1021/om401087h | Organometallics 2013, 32, 7594−7611

Organometallics
Article
room temperature for 12 h and then quenched with brine. The
mixture was poured into a separatory funnel containing EtOAc
(25 mL), and the layers were separated. The aqueous layer was
extracted with EtOAc (2 × 25 mL), and the combined organic layers
were dried over Na2SO4, filtered, and concentrated. Flash chromatog-
raphy over silica gel with CH2Cl2/Et2O (3/1) afforded ( )-31 (530
mg, 0.817 mmol, 71%) as a yellow solid. TLC: Rf = 0.22 (1/1 CH2Cl2/
To a solution of ( )-31 (440 mg, 0.678 mmol, 1.0 equiv) in MeOH/
THF (1/1 v/v, 10 mL) at 0 °C were added CeCl3·7H2O (250 mg, 0.678
mmol, 1.0 equiv) and NaBH4 (32 mg, 0.846 mmol, 1.25 equiv). The
reaction mixture was stirred at room temperature for 12 h and then
quenched with saturated aqueous NH4Cl. The mixture was poured into
a separatory funnel containing EtOAc (25 mL), and the layers were
separated. The aqueous layer was extracted with EtOAc (2 × 25 mL),
and the combined organic layers were dried over Na2SO4, filtered, and
concentrated. Flash chromatography over silica gel first with toluene/
EtOAc (3/1) as eluent afforded ( )-33 (270 mg, 0.416 mmol, 61%) as
a yellow solid, and then elution with toluene/EtOAc (1/1) afforded
( )-33′ (130 mg, 0.2 mmol, 29%) as a yellow solid. The stereo-
chemistry was confirmed by an X-ray structure analysis of 35.
1
Et2O). H NMR (600 MHz, DMSO-d6): δ 8.55 (d, J = 1.8 Hz, 1H),
8.24 (s, 1H), 8.12 (d, J = 7.8 Hz, 1H), 8.02 (s, 2H), 7.85 (d, J = 1.8
Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.82 (s, 2H), 7.69 (d, J = 7.8 Hz, 1
H), 7.55 (t, J = 7.8 Hz, 1H), 6.44 (t, J = 1.8 Hz, 1H), 6.28−6.26 (m,
2H), 5.02 (d, J = 17.4 Hz, 1H), 4.98 (d, J = 17.4 Hz, 1H), 4.42 (d, J =
7.2 Hz, 2H), 4.24 (dd, J = 3.0, 8.4 Hz, 1H), 4.15 (d, J = 12.6 Hz, 1H),
3.66 (t, J = 7.2 Hz, 1H), 3.57 (d, J = 12.6 Hz, 1H), 3.11 (dd, J = 9.0,
13.2 Hz, 1H), 3.01 (dd, J = 4.8, 13.2 Hz, 1H). 13C NMR (150 MHz,
DMSO-d6): δ 226.9, 226.3, 202.8, 160.6, 148.8, 147.6, 143.2, 137.3,
136.0, 135.3, 127.9, 126.7, 122.1, 107.3, 106.5, 79.8, 71.3, 68.3, 67.8,
63.7, 57.8, 55.5, 46.4. IR (cm−1): 1940 (s), 1853 (s), 1677 (s), 1611
(m). HRMS (FAB): calcd for C27H26BMoN8O5 ([M + H]+),
651.1168; found, 651.1161.
( )-33. TLC: Rf = 0.18 (1/1 toluene/EtOAc). 1H NMR (600 MHz,
DMSO-d6): δ 8.57 (d, J = 1.8 Hz, 1H), 8.30 (s, 1H), 8.29 (s, 1H), 8.18
(d, J = 7.8 Hz, 1H), 7.99 (d, J = 1.2, Hz, 1H), 7.97 (d, J = 1.2, Hz, 1H),
7.81 (d, J = 1.8 Hz, 1H), 7.79 (s, 1H), 7.78 (dd, J = 1.2, 7.8 Hz, 1 H),
7.68 (d, J = 7.8 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 6.41 (t, J = 1.8 Hz,
1H), 6.25 (d, J = 1.8 Hz, 2H), 5.18 (br s, 1H), 4.35 (d, J = 2.4 Hz,
2H), 4.29 (dd, J = 2.4, 13.2 Hz, 1H), 4.09 (d, J = 12.6 Hz, 1H), 4.03 (t,
J = 6.6 Hz, 1H), 3.78 (dd, J = 9.0, 13.8 Hz, 1H), 3.66 (t, J = 6.6 Hz,
1H), 3.58 (d, J = 11.4 Hz, 1H), 1.99−1.92 (m, 2H). 13C NMR (150
MHz, DMSO-d6): δ 226.9, 226.8, 161.1, 149.5, 148.8, 147.6, 143.2,
143.0, 137.2, 135.8, 134.8, 127.8, 127.4, 126.8, 122.4, 107.2, 106.4,
79.9, 72.5, 68.7, 67.7, 66.6, 64.0, 57.8, 52.5, 41.1. IR (cm−1): 3393 (w),
1938 (s), 1851 (s), 1670 (m), 1611 (m). HRMS (FAB): calcd for
C27H28BMoN8O5 ([M + H]+), 653.1324; found, 653.1316.
( )-Dicarbonyl[hydridotris(1-pyrazolyl)borato][(η-3,4,5)-1-benzy-
loxycarbonyl-2-(2′-oxo-3′-(4″-oxoquinazolin-3″(3″H)-yl)propyl)-
5,6-dihydro-2H-pyridin-3-yl]molybdenum (( )-32).
( )-33′. TLC: Rf = 0.15 (1/1 toluene/EtOAc). 1H NMR (600 MHz,
DMSO-d6): δ 8.54 (s, 1H), 8.30 (s, 1H), 8.27 (s, 1H), 8.17 (d, J = 7.8 Hz,
1H), 8.02 (s, 1H), 8.0 (s, 1H), 7.84 (s, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.80
(s, 1 H), 7.67 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 6.43 (s, 1H),
6.25 (s, 2H), 5.18 (d, J = 6.0 Hz, 1H), 4.35 (d, J = 2.4 Hz, 2H), 4.19
(d, J = 13.8 Hz, 1H), 4.01−3.93 (m, 2H), 3.76 (dd, J = 8.4, 13.2 Hz, 1H),
3.63 (t, J = 7.2 Hz, 1H), 3.55 (d, J = 12.6 Hz, 1H), 1.84−1.79 (m, 2H).
13C NMR (150 MHz, DMSO-d6): δ 227.3, 226.4, 161.1, 149.5, 148.8,
147.6, 143.3, 143.0, 137.2, 135.9, 134.8, 127.8, 127.5, 126.8, 122.4, 107.3,
106.4, 79.9, 72.2, 69.5, 67.2, 66.0, 64.0, 57.4, 53.0, 40.7. IR (cm−1): 3394
(w), 1938 (s), 1853 (s), 1669 (m), 1610 (m). HRMS (FAB): calcd for
C27H28BMoN8O5 ([M + H]+), 653.1324; found, 653.1315.
( )-Dicarbonyl[hydridotris(1-pyrazolyl)borato][(η-3,4,5)-1-benzy-
loxycarbonyl-2-(2′-hydroxy-3′-(4″-oxoquinazolin-3″(3″H)-yl)-
propyl)-5,6-dihydro-2H-pyridin-3-yl]molybdenum (( )-34 and
( )-34′).
To a solution of ( )-4b (780 mg, 1.12 mmol, 1.0 equiv) in MeCN
(11 mL) was added 3-[2-(trimethylsilyloxy)allyl]-3H-quinazolin-4-one35
(920 mg, 3.36 mmol, 3.0 equiv). The reaction mixture was stirred at
room temperature for 12 h and then quenched with brine. The mix-
ture was poured into a separatory funnel containing EtOAc (25 mL),
and the layers were separated. The aqueous layer was extracted
with EtOAc (2 × 25 mL), and the combined organic layers were dried
over Na2SO4, filtered, and concentrated. Flash chromatography over
silica gel with CH2Cl2/Et2O (5/1) afforded ( )-32 (605 mg, 0.774
mmol, 69%) as a yellow solid. TLC: Rf = 0.28 (1/1 CH2Cl2/Et2O). 1H
NMR (a mixture of two rotamers) (600 MHz, CDCl3): δ 8.55 (s, 1H),
8.28 (d, J = 7.2 Hz, 0.7H), 8.25 (d, J = 7.2 Hz, 0.3H), 8.08 (s, 1H),
7.92 (d, J = 1.2 Hz, 0.3H), 7.86 (d, J = 1.2 Hz, 0.7H), 7.75 (t, J = 9.6
Hz, 1H), 7.74 (d, J = 1.2 Hz, 1H), 7.69 (d, J = 1.2 Hz, 1H), 7.58 (s,
1H), 7.56 (dd, J = 2.4, 6.0 Hz, 1H), 7.49 (d, J = 1.2 Hz, 1H), 7.47 (dd,
J = 2.4, 6.0 Hz, 1 H), 7.40 (d, J = 7.2 Hz, 0.5H), 7.36 (d, J = 7.2 Hz,
0.5H), 7.35−7.27 (m, 4H), 6.28 (s, 1H), 6.17 (s, 2H), 5.23 (d, J = 12.0
Hz, 0.3H), 5.17 (d, J = 17.4 Hz, 1H), 5.14 (d, J = 12.0 Hz, 0.7H), 5.07
(d, J = 12.0 Hz, 0.3H), 5.04 (d, J = 12.0 Hz, 0.7H), 5.01 (d, J = 17.4
Hz, 1H), 4.87 (ddd, J = 3.0, 4.2, 6.0 Hz, 1H), 4.57 (d, J = 9.0 Hz, 0.3
H), 4.46 (dd, J = 3.0, 6.0 Hz, 0.3H), 4.43−4.41 (m, 1.4H), 4.30 (dd,
J = 1.8, 4.8 Hz, 0.3H), 4.27 (dd, J = 2.4, 14.4 Hz, 0.3H), 4.24 (dd, J =
1.8, 4.8 Hz, 0.7H), 4.20 (dd, J = 2.4, 14.4 Hz, 0.7H), 3.72 (t, J = 7.2
Hz, 1H), 3.75 (d, J = 14.4 Hz, 0.7H), 3.58 (d, J = 14.4 Hz, 0.3H), 3.13
(dd, J = 4.8, 12.0 Hz, 1H), 2.93 (d, J = 6.0 Hz, 1H), 2.81 (dd, J = 8.4,
12.0 Hz, 1H). 13C NMR (150 MHz, CDCl3): δ 225.4, 225.3, 200.9,
200.4, 161.3, 155.5, 154.7, 148.5, 147.5, 147.3, 143.2, 142.6, 141.9, 141.7,
136.6, 136.4, 134.8, 134.7, 134.6, 128.8, 128.6, 128.4, 128.1, 127.9, 127.8,
127.6, 127.4, 126.9, 122.1, 106.0, 105.7, 77.0, 71.2, 67.7, 66.5, 63.2, 63.0,
54.9, 54.1, 49.4, 48.9, 48.6, 39.3, 39.1. IR (cm−1): 1947 (s), 1861 (s),
1681 (s), 1612 (m). HRMS (FAB): calcd for C35H33BMoN9O6 ([M +
H]+), 784.1695; found, 784.1701.
To a solution of ( )-32 (600 mg, 0.765 mmol, 1.0 equiv) in MeOH/
THF (1/1 v/v, 15 mL) at 0 °C were added CeCl3·7H2O (285 mg, 0.765
mmol, 1.0 equiv) and NaBH4 (36 mg, 0.955 mmol, 1.25 equiv). The
reaction mixture was stirred at room temperature for 12 h and then
quenched with saturated aqueous NH4Cl. The mixture was poured into
a separatory funnel containing EtOAc (25 mL), and the layers were
separated. The aqueous layer was extracted with EtOAc (2 × 25 mL),
and the combined organic layers were dried over Na2SO4, filtered, and
concentrated. Flash chromatography over silica gel first with CH2Cl/
Et2O (3/1) as eluent afforded ( )-34 (220 mg, 0.28 mmol, 37%) as a
yellow solid, and then elution with CH2Cl2/Et2O (1/1) afforded
( )-34′ (350 mg, 0.447 mmol, 58%) as a yellow solid. The stereo-
chemistry was confirmed by an X-ray structure analysis of 34.
( )-Dicarbonyl[hydridotris(1-pyrazolyl)borato][(η-3,4,5)-2-(2′-hy-
droxy-3′-(4″-oxoquinazolin-3″(3″H)-yl)propyl)-5,6-dihydro-2H-pyri-
din-3-yl]molybdenum (( )-33 and ( )-33′).
( )-34. TLC: Rf = 0.28 (1/1 CH2Cl2/Et2O). 1H NMR (a mixture of
two rotamers) (400 MHz, CDCl3): δ 8.51 (d, J = 1.2 Hz, 1H), 8.29 (d,
J = 8.4 Hz, 1H), 8.23 (s, 1H), 7.74 (d, J = 6.4 Hz, 1H), 7.73 (s, 1H),
7.71 (d, J = 1.6 Hz, 1H), 7.67 (d, J = 1.6 Hz, 1H), 7.56 (d, J = 2.8 Hz,
1H), 7.55 (d, J = 2.8 Hz, 1H), 7.51−7.47 (m, 2H), 7.27 (t, J = 7.2,
2H), 7.22 (t, J = 7.2 Hz, 2H), 7.08 (t, J = 7.2 Hz, 1H), 6.26 (t, J = 2.0
Hz, 1H), 6.17−6.16 (m, 2H), 5.03 (br s, 2H), 4.76 (br s, 1H), 4.60
7607
dx.doi.org/10.1021/om401087h | Organometallics 2013, 32, 7594−7611

Organometallics
Article
(d, J = 11.2 Hz, 1H), 4.42 (d, J = 11.2 Hz, 1H), 4.24−4.17 (m, 3H),
3.68 (t, J = 7.2 Hz, 1H), 3.61 (t, J = 8.8 Hz, 1H), 3.54 (d, J = 8.8 Hz,
1H), 1.92 (t, J = 11.6 Hz, 1H), 1.81 (t, J = 11.6 Hz, 1H). 13C NMR
(100 MHz, CDCl3): δ 225.5, 224.9, 161.5, 156.6, 148.5, 148.3, 147.5,
142.2, 141.7, 136.4, 136.3, 136.2, 134.7, 134.4, 128.5, 128.3, 128.1,
127.8, 127.2, 126.9, 122.3, 106.3, 105.7, 77.0, 72.3, 68.1, 66.9, 66.2,
63.2, 51.1, 47.8, 43.0, 38.9. IR (cm−1): 3392 (w), 1941 (s), 1855 (s),
1667 (s), 1609 (m). HRMS (FAB): calcd for C35H35BMoN9O6
([M + H]+), 786.1852; found, 786.1857.
under dry air for 2 days and then quenched with brine. The mixture
was poured into a separatory funnel containing EtOAc (5 mL), and
the layers were separated. The aqueous layer was extracted with EtOAc
(2 × 5 mL), and the combined organic layers were dried over Na2SO4,
filtered, and concentrated. Flash chromatography over silica gel with
CH2Cl2/Et2O (3/1) afforded ( )-35′ (21 mg, 0.074 mmol, 69%) as a
white solid. TLC: Rf = 0.35 (1/1 CH2Cl2/Et2O). Mp: 108−110 °C.
1H NMR (600 MHz, CDCl3): δ 8.28 (d, J = 7.8 Hz, 1H), 8.11 (s, 1H),
7.71 (t, J = 7.8 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.45 (t, J = 7.8 Hz,
1H), 6.05−5.98 (m, 2H), 4.41−4.38 (m, 1H), 4.30 (dd, J = 2.4, 13.8
Hz, 1H), 4.06 (dd, J = 7.8, 13.8 Hz, 1H), 3.99 (dd, J = 3.0, 5.4 Hz,
1H), 3.93 (s, 2H), 3.90 (dd, J = 1.2, 5.4 Hz, 1H), 2.46 (ddd, J = 5.4,
8.4, 13.8 Hz, 1H), 1.96 (dd, J = 3.0, 13.8 Hz, 1H). 13C NMR (150
MHz, CDCl3): δ 161.7, 148.3, 147.9 134.3, 131.2, 127.5, 127.1, 126.9,
122.8, 122.1 76.3, 75.8, 73.8, 64.4, 50.5, 36.6. IR (cm−1): 1671 (s),
1609 (s). HRMS (ESI): calcd for C16H16NaN2O3 ([M + Na]+),
307.1053; found, 307.1047.
1
( )-34′. TLC: Rf = 0.20 (1/1 CH2Cl2/Et2O). H NMR (a mixture
of two rotamers) (600 MHz, CDCl3): δ 8.53 (s, 1H), 8.38 (d, J = 7.8
Hz, 1H), 8.20 (s, 0.7H), 7.95 (s, 0.3H), 7.80 (d, J = 1.2 Hz, 1H), 7.70
(br s, 2H), 7.67 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 2.4 Hz, 0.7H), 7.56 (d,
J = 1.8 Hz, 1H), 7.54 (d, J = 1.8 Hz, 0.3H), 7.50 (d, J = 1.8 Hz, 0.7H),
7.49 (d, J = 1.8 Hz, 0.3H), 7.44 (t, J = 7.2 Hz, 1 H), 7.35 (d, J = 7.8
Hz, 0.5H), 7.32−7.28 (m, 3H), 7.23 (d, J = 7.8 Hz, 0.5H), 7.19 (t, J =
7.8 Hz, 0.7H), 7.11 (t, J = 7.8 Hz, 0.3H), 6.26 (s, 1H), 6.17 (s, 0.7H),
6.16 (s, 0.3H), 6.14 (s, 0.7H), 6.01 (s, 0.3H), 5.23 (d, J = 12.0 Hz,
0.3H), 5.10 (d, J = 12.6 Hz, 0.7H), 5.06 (d, J = 12.6 Hz, 0.7H), 4.98
(d, J = 12.6 Hz, 0.3H), 4.64−4.63 (br m, 0.3H), 4.57−4.56 (br m,
0.7H), 4.44 (br s, 1H), 4.39 (dd, J = 1.2, 12.0 Hz, 1H), 4.35 (dd, J =
4.2, 6.0 Hz, 1H), 4.26 (dd, J = 3.0, 13.8 Hz, 0.7H), 4.23−4.19 (m, 3H),
4.08 (dd, J = 3.0, 13.8 Hz, 0.3H), 3.83 (dd, J = 9.0, 13.8 Hz, 1H), 3.72
(t, J = 7.2 Hz, 0.7H), 3.67 (t, J = 7.2 Hz, 0.3H), 3.63 (d, J = 13.8 Hz,
0.7H), 3.57 (d, J = 13.8 Hz, 0.3H), 3.47 (br s, 0.3H), 2.35 (s, 0.7H),
2.13 (dt, J = 4.8, 13.8 Hz, 1H), 1.93 (ddd, J = 7.8, 12.6, 13.8, Hz, 1H).
13C NMR (100 MHz, CDCl3): δ 225.5, 225.1, 162.3, 155.9, 148.3,
( )-Benzyl 2-((4′-Oxoquinazolin-3′(3′H)-yl)methyl)-3,3a,5,7a-
tetrahydrofuro[3,2-b]pyridine-4(2H)-carboxylate (( )-36).
To a solution of ( )-34 (145 mg, 0.185 mmol, 1.0 equiv) in DMSO
(4 mL) at room temperature were added 60% NaH suspension
(15 mg, 0.37 mmol, 2.0 equiv) and copper 2-ethylhexanoate (130 mg,
0.37 mmol, 2.0 equiv). The reaction mixture was stirred at 65 °C
under dry air for 10 days and then quenched with brine. The mixture
was poured into a separatory funnel containing EtOAc (5 mL), and
the layers were separated. The aqueous layer was extracted with EtOAc
(2 × 5 mL), and the combined organic layers were dried over Na2SO4,
filtered, and concentrated. Flash chromatography over silica gel with
CH2Cl2/Et2O (2.5/1) afforded ( )-36 (47 mg, 0.112 mmol, 61%) as a
colorless oil. TLC: Rf = 0.35 (1/1 CH2Cl2/Et2O). 1H NMR (a mixture
of two rotamers) (600 MHz, CDCl3): δ 8.27 (d, J = 8.4 Hz, 1H), 8.11
(s, 1H), 7.74 (t, J = 8.4 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.48 (t, J =
8.4 Hz, 1H), 7.37−7.31 (m, 5H), 5.68 (dd, J = 1.8, 10.2 Hz, 1H), 5.49
(br m, 1H), 5.15 (d, J = 12.6 Hz, 1H), 5.12 (d, J = 12.6 Hz, 1H), 5.05
(br m, 1H), 4.43 (d, J = 7.2 Hz, 1H), 4.39 (br s, 1H), 4.26 (d, J = 13.8
Hz, 1H), 4.15 (br d, J = 13.2 Hz, 1H), 3.97 (br m, 1H), 3.46 (d, J =
18.6 Hz, 1H), 2.20 (br m, 1H), 1.66 (dd, J = 10.8, 18.6 Hz, 1H). 13C
NMR (150 MHz, CDCl3): δ 161.6, 155.4, 148.3, 147.8, 136.5, 134.5,
128.8, 128.4, 128.3, 127.7, 127.4, 126.9, 122.1, 76.0, 70.9, 67.7, 52.5,
50.3, 39.2. IR (cm−1): 1669 (s), 1609 (s). HRMS (ESI): calcd for
C24H23NaN3O4 ([M + Na]+), 440.1581; found, 440.1584.
148.0, 147.5, 142.3, 141.8, 136.6, 136.3, 134.6, 134.5, 128.8, 128.7,
128.6, 128.2, 128.1, 127.6, 127.3, 126.8, 122.1, 106.2, 105.6, 72.3, 69.4,
67.8, 66.5, 63.1, 52.7, 49.2, 43.0, 39.0. IR (cm−1): 3397 (w), 1941 (s),
1853 (s), 1670 (s), 1610 (m). HRMS (FAB): calcd for
C35H35BMoN9O6 ([M + H]+), 786.1852; found, 786.1843.
( )-3-((3′,3a′,5′,7a′-Tetrahydro-2′H-furo[3′,2′-b]pyran-2′-yl)-
methyl)quinazolin-4(3H)-one (( )-35).
To a solution of ( )-33 (70 mg, 0.107 mmol, 1.0 equiv) in DMSO (2
mL) at room temperature were added a 60% NaH suspension (9 mg,
0.214 mmol, 2.0 equiv) and copper 2-ethylhexanoate (75 mg, 0.214
mmol, 2.0 equiv). The reaction mixture was stirred at 65 °C under dry
air for 5 days and then quenched with brine. The mixture was poured
into a separatory funnel containing EtOAc (5 mL), and the layers were
separated. The aqueous layer was extracted with EtOAc (2 × 5 mL),
and the combined organic layers were dried over Na2SO4, filtered, and
concentrated. Flash chromatography over silica gel with CH2Cl2/Et2O
(3/1) afforded ( )-35 (23 mg, 0.081 mmol, 75%) as a white solid.
TLC: Rf = 0.32 (1/1 CH2Cl2/Et2O). Mp: 112−114 °C. 1H NMR (600
MHz, CDCl3): δ 8.28 (d, J = 7.8 Hz, 1H), 8.20 (s, 1H), 7.73 (t, J = 7.8
Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), 6.03
(dd, J = 3.6, 10.2 Hz, 1H), 5.93 (br d, J = 8.4 Hz, 1H), 4.63−4.59 (m,
1H), 4.23 (dd, J = 3.0, 13.8 Hz, 1H), 4.14 (dd, J = 5.4, 13.8 Hz, 1H),
4.12 (dd, J = 5.4, 13.8 Hz, 1H), 4.04−3.96 (m, 3H), 2.23 (dd, J = 5.4,
13.8 Hz, 1H), 1.81−1.76 (m, 1H). 13C NMR (150 MHz, CDCl3): δ
161.5, 148.2, 147.8, 134.5, 131.1, 127.6, 127.4, 127.0, 122.8, 122.2, 76.5,
76.2, 64.1, 48.7, 37.0. IR (cm−1): 1667 (s), 1608 (s). HRMS (ESI): calcd
for C16H16NaN2O3 ([M + Na]+), 307.1053; found, 307.1049.
( )-Benzyl 2-((4′-Oxoquinazolin-3′(3′H)-yl)methyl)-3,3a,5,7a-
tetrahydrofuro[3,2-b]pyridine-4(2H)-carboxylate (( )-36′).
To a solution of ( )-34′ (250 mg, 0.318 mmol, 1.0 equiv) in DMSO
(8 mL) at room temperature were added a 60% NaH suspension
(15 mg, 0.38 mmol, 1.2 equiv) and copper 2-ethylhexanoate (133 mg,
0.38 mmol, 1.2 equiv). The reaction mixture was stirred at 65 °C
under dry air for 2 days and then quenched with brine. The mixture
was poured into a separatory funnel containing EtOAc (5 mL), and
the layers were separated. The aqueous layer was extracted with EtOAc
(2 × 5 mL), and the combined organic layers were dried over Na2SO4,
filtered, and concentrated. Flash chromatography over silica gel with
CH2Cl2/Et2O (2.5/1) afforded ( )-36′ (95 mg, 0.227 mmol, 71%) as
( )-3-((3′,3a′,5′,7a′-Tetrahydro-2′H-furo[3′,2′-b]pyran-2′-yl)-
methyl)quinazolin-4(3H)-one (( )-35′).
1
a colorless oil. TLC: Rf = 0.35 (1/1 CH2Cl2/Et2O). H NMR (a
mixture of two rotamers) (400 MHz, CDCl3): δ 8.27 (dd, J = 1.2, 8.4
Hz, 1H), 8.10 (s, 1H), 7.73 (dt, J = 1.2, 8.4 Hz, 1H), 7.68 (dd, J = 1.2,
8.4 Hz, 1H), 7.46 (dt, J = 1.2, 8.4 Hz, 1H), 7.33−7.29 (m, 5H), 5.76
(br m, 1H), 5.56 (dd, J = 2.0, 6.4 Hz, 1H), 5.10 (br m, 2H), 4.83
(br m, 1H), 4.53 (br m, 1H), 4.34−4.33 (m, 2H), 4.16 (dd, J = 4.0,
To a solution of ( )-33′ (70 mg, 0.107 mmol, 1.0 equiv) in DMSO
(2 mL) at room temperature were added a 60% NaH suspension
(9 mg, 0.214 mmol, 2.0 equiv) and copper 2-ethylhexanoate (75 mg,
0.214 mmol, 2.0 equiv). The reaction mixture was stirred at 65 °C
7608
dx.doi.org/10.1021/om401087h | Organometallics 2013, 32, 7594−7611

Organometallics
Article
18.8 Hz, 1H), 3.76 (br m, 1H), 3.58 (br d, J = 18.4 Hz, 1H), 2.02−
1.91 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 161.4, 155.5, 148.4,
147.6, 136.5, 134.5, 128.8, 128.4, 128.2, 127.7, 127.4, 126.9, 122.2,
74.1, 71.9, 67.7, 51.5, 50.5, 39.2. IR (cm−1): 1672 (s), 1610 (s). HRMS
(ESI): calcd for C24H23NaN3O4 ([M + Na]+), 440.1581; found, 440.1576.
(s, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.45 (t, J =
7.8 Hz, 1H), 4.39 (d, J = 13.8 Hz, 1H), 4.30 (t, J = 9.0 Hz, 1H), 4.20
(dd, J = 5.4, 13.8 Hz, 1H), 3.71 (s, 1H), 3.18 (s, 1H), 2.82 (d, J = 12.0
Hz, 1H), 2.49 (t, J = 12.0 Hz, 1H), 2.27 (ddd, J = 5.4, 8.4, 13.8 Hz,
1H), 2.0 (d, J = 13.8 Hz, 1H) 1.66 (dd, J = 5.4, 13.8 Hz, 1H), 1.59 (dt,
J = 3.0, 13.2 Hz, 1H), 1.51 (dd, J = 3.0, 13.2 Hz, 1H), 1.39 (d, J = 13.2
Hz, 1H). 13C NMR (150 MHz, CDCl3): δ 161.6, 148.5, 148.3, 134.3,
127.6, 127.1, 126.9, 122.4, 75.4, 56.3, 51.2, 45.3, 37.6, 26.5, 21.5. IR
(cm−1): 2934 (w), 2854 (w), 1670 (s), 1610 (s). HRMS (ESI): calcd
for C16H20N3O2 ([M + H]+), 286.1550; found, 286.1556.
(
)-3-((Hexahydro-2′H-furo[3′,2′-b]pyran-2′-yl)methyl)-
quinazolin-4(3H)-one (( )-37).
( )-3-((Octahydrofuro[3′,2′-b]pyridin-2′-yl)methyl)quinazolin-
4(3H)-one (( )-38′).
A portion of 20% Pd(OH)2/C (5 mg) was added to a solution of
( )-35 (20 mg, 0.07 mmol, 1.0 equiv) in MeOH/THF (3/1 v/v, 2
mL), and the mixture was exposed to hydrogen at 250 psi for 1.5 h
with stirring. The mixture was filtered through a pad of Celite, and the
filtrate was concentrated. Flash chromatography over silica gel with 3%
MeOH in CH2Cl2 afforded ( )-37 (15 mg, 0.053 mmol, 72%) as a
white solid. TLC: Rf = 0.35 (5% MeOH in CH2Cl2). Mp: 130−132 °C.
1H NMR (600 MHz, CDCl3): δ 8.29 (d, J = 7.8 Hz, 1H), 8.22 (s, 1H),
7.76 (t, J = 7.8 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.49 (t, J = 7.8 Hz,
1H), 4.65 (dt, J = 3.0, 9.0 Hz, 1H), 4.22 (dd, J = 3.0, 13.8 Hz, 1H),
4.11 (dd, J = 6.6, 13.8 Hz, 1H), 3.92 (d, J = 2.4 Hz, 1H), 3.83 (dd, J =
1.8, 11.4 Hz, 1H), 3.76 (s, 1H), 3.31 (t, J = 11.4 Hz, 1H), 2.14 (dd, J =
6.6, 13.2 Hz, 1H), 2.04 (d, J = 13.2 Hz, 1H), 1.78−1.61 (m, 3H), 1.31
(dd, J = 1.8, 13.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 161.5,
148.3, 147.7, 134.5, 127.6, 127.4, 127.1, 122.2, 75.9, 66.5, 49.2, 37.5,
25.7, 20.2. IR (cm−1): 1669 (s), 1609 (s) 1473 (m). HRMS (ESI):
calcd for C16H18NaN2O3 ([M + Na]+), 309.1210; found, 309.1204.
A portion of 20% Pd(OH)2/C (8 mg) was added to a solution of
( )-36′ (30 mg, 0.072 mmol, 1.0 equiv) in MeOH/THF (3/1 v/v,
2 mL), and the mixture was exposed to hydrogen at 250 psi for 2.5 h
with stirring. The mixture was filtered through a pad of Celite, and the
filtrate was concentrated. Flash chromatography over neutral alumina
with 3% MeOH in CH2Cl2 afforded ( )-38′ (18 mg, 0.063 mmol,
89%) as a white solid. TLC: Rf = 0.23 (5% MeOH in CH2Cl2). Mp:
100−102 °C. 1H NMR (600 MHz, CDCl3): δ 8.29 (dd, J = 1.2, 7.8 Hz,
1H), 8.20 (s, 1H), 7.75 (dt, J = 1.2, 7.8 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H),
7.49 (t, J = 7.8 Hz, 1H), 4.64 (dt, J = 3.0, 9.0 Hz, 1H), 4.26 (dd, J = 3.0,
14.4 Hz, 1H), 3.98 (dd, J = 6.6, 13.8 Hz, 1H), 3.77 (t, J = 3.0 Hz, 1H),
3.23 (dd, J = 3.0, 4.0 Hz, 1H), 2.93 (d, J = 12.6 Hz, 1H), 2.51 (t, J = 10.8
Hz, 1H), 2.02 (d, J = 13.8 Hz, 1H), 1.96 (dd, J = 6.6, 13.8 Hz, 1H), 1.77
(ddd, J = 5.4, 8.4, 13.8 Hz, 1H), 1.62−1.52 (m, 2H), 1.38 (dd, J = 2.4,
13.2 Hz, 1H). 13C NMR (150 MHz, CDCl3): δ 161.6, 148.3, 147.7, 134.5,
127.7, 127.3, 127.0, 122.3, 75.9, 57.1, 49.6, 44.9, 37.5, 26.6, 21.1. IR
(cm−1): 2929 (w), 2850 (w), 1671 (s), 1611 (s). HRMS (ESI): calcd for
C16H20N3O2 ([M + H]+), 286.1550; found, 286.1554.
(
)-3-((Hexahydro-2′H-furo[3′,2′-b]pyran-2′-yl)methyl)-
quinazolin-4(3H)-one (( )-37′).
A portion of 20% Pd(OH)2/C (5 mg) was added to a solution of
( )-35′ (12 mg, 0.042 mmol, 1.0 equiv) in MeOH/THF (3/1 v/v,
1 mL), and the mixture was exposed to hydrogen at 250 psi for 2.5 h
with stirring. The mixture was filtered through a pad of Celite, and the
filtrate was concentrated. Flash chromatography over silica gel with 3%
MeOH in CH2Cl2 afforded ( )-37′ (9 mg, 0.031 mmol, 74%) as a
white solid. TLC: Rf = 0.41 (5% MeOH in CH2Cl2). Mp: 124−
126 °C. 1H NMR (600 MHz, CDCl3): δ 8.29 (d, J = 7.8 Hz, 1H), 8.18
(s, 1H), 7.72 (dt, J = 1.8, 7.8 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.46
(dt, J = 1.8, 7.8 Hz, 1H), 4.41−4.37 (m, 1H), 4.34 (dt, J = 3.0, 13.8 Hz,
1H), 4.07 (dd, J = 7.8, 13.8 Hz, 1H), 3.85 (dd, J = 1.8, 4.2 Hz, 1H), 3.72
(d, J = 1.8 Hz, 1H), 3.71 (d, J = 1.8 Hz, 1H), 3.28 (dt, J = 1.8, 11.4 Hz,
1H), 2.26 (ddd, J = 4.8, 10.2, 14.4 Hz, 1H), 2.07 (dd, J = 1.8, 14.4 Hz, 1H),
1.91−1.83 (m, 2H), 1.70 (dt, J = 4.8, 14.4 Hz, 1H) 1.36 (dd, J = 3.0, 14.4
Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 161.7, 148.4, 148.3, 134.3,
127.5, 127.2, 126.9, 122.4, 76.4, 75.4, 66.7, 51.2, 37.0, 25.1, 20.7. IR (cm−1):
1667 (s), 1611 (s) 1473 (m). HRMS (ESI): calcd for C16H18NaN2O3
([M + Na]+), 309.1210; found, 309.1205.
( )-Benzyl 6,7-Dihydroxy-2-((4′-oxoquinazolin-3′(3′H)-yl)-
methyl)hexahydrofuro[3′,2′-b]pyridine-4(2H)-carboxylate (( )-39).
To a solution of ( )-36′ (17 mg, 0.04 mmol, 1.0 equiv) in acetone/
water (9/1 v/v, 1 mL) at room temperature were added successively
N-methylmorpholine N-oxide (6 mg, 0.05 mmol, 1.25 equiv),
methanesulfonamide (5 mg, 0.05 mmol, 1.25 equiv), and OsO4
(4 wt % solution in water; 70 μL, 0.01 mmol, 0.25 equiv). The
reaction mixture was stirred at room temperature for 2 days and then
quenched with saturated aqueous NaHSO3. The mixture was poured
into a separatory funnel containing EtOAc (5 mL), and the layers were
separated. The aqueous layer was extracted with EtOAc (2 × 5 mL),
and the combined organic layers were dried over Na2SO4, filtered, and
concentrated. Flash chromatography over silica gel with 5% MeOH in
CH2Cl2 afforded ( )-39 (18 mg, 0.039 mmol, 92%) as a white solid.
TLC: Rf = 0.33 (5% MeOH in CH2Cl2). Mp: 80−82 °C. 1H NMR (a
mixture of two rotamers) (600 MHz, DMSO-d6): δ 8.30 (s, 1H), 8.15
(d, J = 8.4 Hz, 1H), 7.81 (t, J = 8.4 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H),
7.53 (t, J = 8.4 Hz, 1H), 7.36−7.29 (m, 5H), 5.04 (br m, 1H), 4.90 (br
s, 1H), 4.74 (br s, 1H), 4.69 (br m, 1H), 4.34 (br m, 1H), 4.18 (br d,
J = 12.0 Hz, 1H), 3.97 (dt, J = 2.4, 7.2 Hz, 2H), 3.83 (d, J = 13.8 Hz,
1H), 3.63 (br s, 1H), 3.37 (br s, 1H), 3.05 (br s, 1H), 2.12 (q, J = 10.8
Hz, 1H), 1.88 (t, J = 10.8 Hz, 1H). 13C NMR (150 MHz, DMSO-d6):
δ 161.0, 156.0, 149.4, 148.6, 137.6, 135.1, 129.1, 128.4, 128.1, 127.8,
127.7, 126.7, 122.2, 79.9, 77.7, 73.3, 69.8, 67.5, 66.9, 53.5, 51.0, 44.8,
30.0. IR (cm−1): 3395 (w), 1672 (s), 1610 (s). HRMS (ESI): calcd for
C24H25NaN3O6 ([M + Na]+), 474.1636; found, 474.1630.
( )-3-((Octahydrofuro[3′,2′-b]pyridin-2′-yl)methyl)quinazolin-
4(3H)-one (( )-38).
A portion of 20% Pd(OH)2/C (9 mg) was added to a solution of
( )-36 (35 mg, 0.084 mmol, 1.0 equiv) in MeOH/THF (3/1 v/v, 2
mL), and the mixture was exposed to hydrogen at 250 psi for 2.5 h
with stirring. The mixture was filtered through a pad of Celite, and the
filtrate was concentrated. Flash chromatography over neutral alumina
with 3% MeOH in CH2Cl2 afforded ( )-38 (20 mg, 0.07 mmol, 83%)
as a white solid. TLC: Rf = 0.25 (5% MeOH in CH2Cl2). Mp: 142−
144 °C. 1H NMR (600 MHz, CDCl3): δ 8.26 (d, J = 7.8 Hz, 1H), 8.22
7609
dx.doi.org/10.1021/om401087h | Organometallics 2013, 32, 7594−7611

Organometallics
Article
( )-3-((6′,7′-Dihydroxyoctahydrofuro[3′,2′-b]pyridin-2′-yl)-
methyl)quinazolin-4(3H)-one (( )-40).
(2) Coombs, T. C.; Huang, W.; Garnier-Amblard, E. C.; Liebeskind,
L. S. Organometallics 2010, 29, 5083−5097.
(3) Coombs, T. C.; Zhang, Y.; Garnier-Amblard, E. C.; Liebeskind, L.
S. J. Am. Chem. Soc. 2009, 131, 876−877.
(4) Cheng, B.; Liebeskind, L. S. Org. Lett. 2009, 11, 3682−3685.
(5) Chen, W.; Liebeskind, L. S. J. Am. Chem. Soc. 2009, 131, 12546−
12547.
(6) Garnier, E. C.; Liebeskind, L. S. J. Am. Chem. Soc. 2008, 130,
7449−7458.
A portion of 20% Pd(OH)2/C (5 mg) was added to a solution of
( )-39 (22 mg, 0.048 mmol, 1.0 equiv) in MeOH/THF (1/1 v/v,
1 mL), and the mixture was exposed to hydrogen at 50 psi for 3 h with
stirring. The mixture was filtered through a pad of Celite, and the
filtrate was concentrated. Flash chromatography over neutral alumina
with 10% MeOH in CH2Cl2 afforded ( )-40 (10 mg, 0.031 mmol,
63%) as a white solid. TLC: Rf = 0.2 (10% MeOH in CH2Cl2). Mp:
(7) Coombs, T. C.; Lee, M. D., IV.; Wong, H.; Armstrong, M.;
Cheng, B.; Chen, W.; Moretto, A. F.; Liebeskind, L. S. J. Org. Chem.
2008, 73, 882−888.
́
(8) Arrayas, R. G.; Yin, J.; Liebeskind, L. S. J. Am. Chem. Soc. 2007,
129, 1816−1825.
(9) Zhang, Y.; Liebeskind, L. S. J. Am. Chem. Soc. 2006, 128, 465−
1
472.
148−150 °C. H NMR (600 MHz, DMSO-d6): δ 8.31 (s, 1H), 8.15
(10) Zhang, Y.; Liebeskind, L. S. J. Am. Chem. Soc. 2005, 127,
(d, J = 8.4 Hz, 1H), 7.82 (t, J = 8.4 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H),
7.54 (t, J = 8.4 Hz, 1H), 4.61 (br s, 1H), 4.43−4.40 (m, 2H), 4.11 (dd,
J = 3.6, 13.8 Hz, 1H), 3.93 (dd, J = 7.8, 13.8 Hz, 2H), 3.76 (s, 1H),
3.69 (s, 1H), 3.41 (br d, J = 7.2 Hz, 1H), 3.27 (br s, 1H), 2.57 (t, J =
10.8 Hz, 1H), 2.43 (dd, J = 3.6, 12.0 Hz, 1H), 1.78 (dd, J = 6.6, 13.2
Hz, 1H), 1.66 (dd, J = 6.6, 13.2 Hz, 1H). 13C NMR (150 MHz,
DMSO-d6): δ 161.6, 148.0, 147.9, 134.6, 127.5, 127.4, 127.0, 122.1,
80.9, 75.3, 68.1, 66.3, 62.7, 60.8, 55.1, 49.8, 49.3, 31.9, 31.5, 25.0. IR
(cm−1): 3397 (w), 1671 (s), 1608 (s). HRMS (ESI): calcd for
C16H20N3O4 ([M + H]+), 318.1448; found, 318.1443.
11258−11259.
(11) Shu, C.; Liebeskind, L. S. J. Am. Chem. Soc. 2003, 125, 2878−
2879.
(12) Arrayas
9026−9027.
(13) Alcudia, A.; Arrayas
67, 5773−5778.
(14) Shu, C.; Alcudia, A.; Yin, J.; Liebeskind, L. S. J. Am. Chem. Soc.
2001, 123, 12477−12487.
(15) Arrayas
́
, R. G.; Liebeskind, L. S. J. Am. Chem. Soc. 2003, 125,
́
, R. G.; Liebeskind, L. S. J. Org. Chem. 2002,
́
, R. G.; Liebeskind, L. S. J. Am. Chem. Soc. 2001, 123,
ASSOCIATED CONTENT
* Supporting Information
6185−6186.
■
(16) Yin, J.; Llorente, I.; Villanueva, L. A.; Liebeskind, L. S. J. Am.
Chem. Soc. 2000, 122, 10458−10459.
S
Text, figures, tables, and CIF files giving additional
experimental procedures, synthesis and characterization data,
X-ray crystallographic study of 26, 34, and 35, biological assay
data, and 1H and 13C NMR spectra of all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(17) Moretto, A. F.; Liebeskind, L. S. J. Org. Chem. 2000, 65, 7445−
7455.
(18) Malinakova, H. C.; Liebeskind, L. S. Org. Lett. 2000, 2, 4083−
4086.
(19) Malinakova, H. C.; Liebeskind, L. S. Org. Lett. 2000, 2, 3909−
3911.
(20) Yin, J.; Liebeskind, L. S. J. Am. Chem. Soc. 1999, 121, 5811−
5812.
AUTHOR INFORMATION
■
(21) Ward, Y. D.; Villanueva, L. A.; Allred, G. D.; Liebeskind, L. S.
Organometallics 1996, 15, 4201−4210.
Corresponding Author
*E-mail for L.S.L.: chemll1@emory.edu.
(22) Ward, Y. D.; Villanueva, L. A.; Allred, G. D.; Liebeskind, L. S. J.
Am. Chem. Soc. 1996, 118, 897−898.
Present Addresses
∥Department of Chemistry, University of California, Berkeley,
CA 94720, United States.
(23) Villanueva, L. A.; Ward, Y. D.; Lachicotte, R.; Liebeskind, L. S.
Organometallics 1996, 15, 4190−4200.
(24) Ward, Y. D.; Villanueva, L. A.; Allred, G. D.; Payne, S. C.;
Semones, M. A.; Liebeskind, L. S. Organometallics 1995, 14, 4132−
4156.
(25) Reichardt, C.; Welton, T. Solvents and Solvent Effects in Organic
Chemistry, 4th ed.; Wiley-VCH: Weinheim, Germany, 2011.
(26) Lakhdar, S.; Westermaier, M.; Terrier, F.; Goumont, R.;
Boubaker, T.; Ofial, A. R.; May, H. J. Org. Chem. 2006, 71, 9088−
9095.
(27) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66−
77.
(28) Saxton, J. E. Indoles: The Monoterpenoid Indole Alkaloids in The
Chemistry of Heterocyclic Compounds; Wiley: New York, 1983; Vol. 25,
Part 4.
⊥Lilly China R&D Center, Eli Lilly and Company, 338 Jia Li
Lue Road, Shanghai 201203, People’s Republic of China.
¶Emory Institute of Drug Development, 954 Gatewood Road,
Atlanta, Georgia 30320.
Author Contributions
Authors Chen and Sana carried out the major portion of the
experimental work described in this manuscript. The manuscript
was written through contributions of all authors. All authors have
given approval to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(29) Johnson, F. Chem. Rev. 1968, 68, 375−413.
(30) Brown, J. D.; Foley, M. A.; Comins, D. L. J. Am. Chem. Soc.
1988, 110, 7445−7447.
■
This work was supported by Grant GM043107, awarded by the
National Institute of General Medical Sciences, DHHS. We
thank colleagues Dr. Kenneth Hardcastle and Dr. John Basca
for their skilled and efficient assistance with X-ray crystallog-
raphy.
(31) Koepfly, J. B.; Mead, J. F.; Brockman, J. A., Jr. J. Am. Chem. Soc.
1949, 71, 1048−1054.
(32) Kobayashi, S.; Ueno, M.; Suzuki, R.; Ishitani, H.; Kim, H.-S.;
Wataya, Y. J. Org. Chem. 1999, 64, 6833−6841.
(33) Takeuchi, Y.; Azuma, K.; Takahara, K.; Abe, H.; Harayama, T.
Chem. Commun. 2000, 1643−1644.
(34) Ooi, H.; Urushibara, A.; Esumi, T.; Iwabuchi, Y.; Hatakeyama, S.
Org. Lett. 2001, 3, 953−955.
REFERENCES
■
(1) Wong, H.; Garnier-Amblard, E. C.; Liebeskind, L. S. J. Am. Chem.
Soc. 2011, 133, 7517−7527.
7610
dx.doi.org/10.1021/om401087h | Organometallics 2013, 32, 7594−7611

Organometallics
Article
(35) Sugiura, M.; Hagio, H.; Hirabayashi, R.; Kobayashi, S. J. Am.
Chem. Soc. 2001, 123, 12510−12517.
(36) Takeuchi, Y.; Azuma, K.; Takakura, K.; Abe, H.; Kim, H.-S.;
Wataya, Y.; Harayama, T. Tetrahedron 2001, 57, 1213−1218.
(37) Huang, P.-Q.; Wei, B.-G.; Ruan, Y.-P. Synlett 2003, 1663−1667.
(38) Katoh, M.; Matsune, R.; Honda, T. Heterocycles 2006, 67, 189−
204.
(39) Bora, S.; Lozano, V. O.; Ver
2008, 1216−1218.
(40) Sudhakar, N.; Srinivasulu, G.; Rao, G. S.; Rao, B. V. Tetrahedron:
Asymmetry 2008, 19, 2153−2158.
́
onique, B.; Janine, C. Synlett 2008,
(41) Wee, A. G. H.; Fan, G.-J. Org. Lett. 2008, 10, 3869−3872.
(42) Zhu, S.; Meng, L.; Zhang, Q.; Wei, L. Bioorg. Med. Chem. Lett.
2006, 16, 1854−1858.
(43) Zhu, S.; Zhang, Q.; Gudise, C.; Wei, L.; Smith, E.; Zeng, Y.
Bioorg. Med. Chem. 2009, 17, 4496−4502.
(44) Takeuchi, Y.; Koike, M.; Azuma, K.; Nishioka, H.; Abe, H.; Kim,
H.-S.; Wataya, Y.; Harayama, T. Chem. Pharm. Bull. 2001, 49, 721−
725.
(45) Hirai, S.; Kikuchi, H.; Kim, H.-S.; Begum, K.; Wataya, Y.;
Tasaka, H.; Miyazawa, Y.; Yamamoto, K.; Oshima, Y. J. Med. Chem.
2003, 46, 4351−4359.
(46) Takaya, Y.; Tasaka, H.; Chiba, T.; Uwai, K.; Tanitsu, M.-a.; Kim,
H.-S.; Wataya, Y.; Miura, M.; Takeshita, M.; Oshima, Y. J. Med. Chem.
1999, 42, 3163−3166.
(47) Takeuchi, H.; Matsushita, Y.; Eguchi, S. J. Org. Chem. 1991, 56,
1535−1537.
(48) Shakhidoyatov, K. M.; Barakat, Y.; Levkovich, M. G.; Abdullaev,
N. D. Chem. Nat. Compd. 2007, 43, 429−436.
(49) Martin, C. L.; Overman, L. E.; Rohde, J. M. J. Am. Chem. Soc.
2008, 130, 7568−7569.
(50) Lian, Y.; Miller, L. C.; Born, S.; Sarpong, R.; Davies, H. M. L. J.
Am. Chem. Soc. 2010, 132, 12422−12425.
(51) Trost, B. M.; Chan, D. M. T. J. Am. Chem. Soc. 1983, 105,
2326−2335.
7611
dx.doi.org/10.1021/om401087h | Organometallics 2013, 32, 7594−7611