Skeletal diversification via heteroatom linkage control: Preparation of bicyclic and spirocyclic scaffolds from N-substituted homopropargyl alcohols

Article abstract of DOI:10.1021/jo400077m

The discovery and application of a new branching pathway synthesis strategy that rapidly produces skeletally diverse scaffolds is described. Two different scaffold types, one a bicyclic iodo-vinylidene tertiary amine/tertiary alcohol and the other, a spirocyclic 3-furanone, are each obtained using a two-step sequence featuring a common first step. Both scaffold types lead to intermediates that can be orthogonally diversified using the same final components. One of the scaffold types was obtained in sufficiently high yield that it was immediately used to produce a 97-compound library.

Full text of DOI:10.1021/jo400077m

Article
pubs.acs.org/joc
Skeletal Diversification via Heteroatom Linkage Control: Preparation
of Bicyclic and Spirocyclic Scaffolds from N‑Substituted
Homopropargyl Alcohols
Thomas O. Painter,† Jonathon R. Bunn,† Frank J. Schoenen,‡ Justin T. Douglas,†,§ Victor W. Day,§
and Conrad Santini*,†
†Center for Chemical Methodologies and Library Development and ‡Specialized Chemistry Center, The University of Kansas, 2034
Becker Drive, Lawrence, Kansas 66047, United States
§The University of Kansas Molecular Structures Group, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045, United States
S
* Supporting Information
ABSTRACT: The discovery and application of a new
branching pathway synthesis strategy that rapidly produces
skeletally diverse scaffolds is described. Two different scaffold
types, one a bicyclic iodo-vinylidene tertiary amine/tertiary
alcohol and the other, a spirocyclic 3-furanone, are each
obtained using a two-step sequence featuring a common first
step. Both scaffold types lead to intermediates that can be
orthogonally diversified using the same final components. One
of the scaffold types was obtained in sufficiently high yield that
it was immediately used to produce a 97-compound library.
structural complexity with rigidity. Substituents can be moved
around the scaffold in discrete, predictable increments thus
enabling the controlled exploration of the surrounding space.3
These and other characteristics of spirocycles have been
exploited in recent reports.4 Surveying the number of highly
saturated spirocycles derived from diversifiable ketones like 4-
piperidone with the corresponding ones derived from 3-
piperidone revealed that the latter structural class contained
comparatively few members. We therefore initiated studies to
discover a methodology that affords rapid access to spirocyclic
scaffolds from 3-piperidone.
As part of a larger spirocycle synthesis effort, we started by
noting the precedents of Larock and others who used
electrophilic iodoetherification for the efficient preparation of
benzofurans from o-alkyne-substituted anisoles.5 We sought to
use iodoetherification to obtain spirocycles bearing a
dihydrofuran that is not fused to an aromatic ring. We
imagined that treatment of homopropargyl tertiary alcohol 3
with iodine monochloride (ICl) would affect electrophilic
cyclization to afford the previously unreported spirocyclic β-
iodo-enol ether 4 with possible concomitant loss of the Boc
group (Scheme 1). Loss of the protecting group would facilitate
isolation of 4 as it could be extracted into 0.1 N HCl and
lyophilized to afford its salt. This substrate would be ready for
orthogonal diversification via the unprotected amine and the
vinyl iodide.
INTRODUCTION
■
In recent years, high-throughput organic synthesis has gained
an increasingly prominent role for lead generation in the service
of drug discovery. The accelerated creation of innovative
compound collections with high degrees of structural diversity
is now seen as a necessary component of the larger biomedical
research landscape. Coupled with increasingly efficient high
throughput screening and assay models that seek to be more
relevant to biological reality the impetus for developing
versatile methods to create chemical diversity continues to
increase. Skeletal diversification represents one of the most
versatile concepts in high throughput organic synthesis.1 One
manifestation of this concept is the derivation of profoundly
different molecular scaffolds from a common precursor by
employing different reagents, sometimes referred to as the
“branching pathway” strategy.2
Our laboratory’s mission involves the development of
innovative chemistry with the goal of using it to produce
unique compound libraries by high-throughput synthesis.
Deriving more than one scaffold from the same substrate is
clearly advantageous in terms of both compound diversity and
productivity. This report deals with the preparation of two
distinct families of scaffolds so derived.
RESULTS AND DISCUSSION
■
Our interest in exploring chemical space by creating structural
diversity led us to survey the literature to find under-
represented compound types. One such substructure search
centered on diversifiable spirocycles. Spirocyclic scaffolds offer
an opportunity to create chemical diversity by combining
Received: January 31, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo400077m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 1. Synthesis of Bicyclo[3.2.1]-β-iodo Enamines from Homopropargyl Tertiary Alcohols Derived from N-Boc-3-
piperidone
Synthesis of compound 3 was envisioned as a two-step
sequence starting from N-Boc-3-piperidone 1. Addition of
lithiated 1-TMS-1-propyne to 1 using TMEDA as additive
afforded 2 in poor to modest yields that diminished on larger
scale.6 Modification of the organolithium with CeCl3 gave 2 in a
range of yields that was higher.7 Basic hydrolysis of 2 afforded
the cyclization precursor 3 in generally excellent yields and
purity. A more direct method using 1, propargyl bromide, and
Zn/Cu couple with sonication afforded 3 accompanied by a
minor amount of its inseparable allene isomer (not shown).8
The allene byproduct did not introduce any apparent
complications in the subsequent steps. Treatment of 3 with
ICl afforded, not the anticipated 4, but the bicyclic [3.2.1] β-
iodo-enamine HCl salt 5a after extraction and lyophilization. β-
Iodo-enamine HCl salt 5a was accompanied by a minor
amount (∼10 A% by HPLC) of a diiodo species which could be
separated by pHPLC. Compound 5a was elaborated to the
more complex derivative 10{10,1} as described below (Scheme
4). X-ray crystallography of 10{10,1} confirmed the depicted
bicyclic core structure of its precursor 5a. The presence of the
diiodo species did not affect subsequent steps. Enamine 5a was
stable and could be handled using standard techniques
presumably because the bridgehead position of the nitrogen
precludes interaction between it and the olefin.
hydroxyl.10 In addition, β-iodoenamines contained within a
bicyclic structure have been previously reported.11 We were
curious about whether removing the possibility of participation
by the piperidine nitrogen would lead to the desired cyclization.
To test this hypothesis, we prepared tertiary alcohols 6 and 8
from 1-Boc-4-piperidone and 1-PhSO2-3-piperidone, respec-
tively (Scheme 3). In the case of 6 we predicted that nitrogen
Scheme 3. Attempted Iodoetherification of Homopropargyl
Tertiary Alcohols
would be unable to participate due to distance and/or
unfavorable conformation. In the case of 8, we expected the
protecting group to survive the reaction conditions and prevent
nitrogen unmasking. This would demonstrate that the loss of
the Boc group is required for iodoamination to occur. In the
event, treatment of 6 and 8 with ICl gave only complex
mixtures with no detectable formation of 7 or 9.
The conversion of 3 to 5a is envisioned as proceeding via an
unsaturated iodonium intermediate Int1 (Scheme 2). Instead
of the iodonium being attacked by the free tertiary alcohol via a
5-endo cyclization (path a) and leading to 4 it is captured by
the nitrogen via a 5-exo mechanism (path b, Int2).9 This latter
mode of cyclization is precedented for unsubstituted terminal
alkynes although not in the presence of a well-positioned free
We then performed the originally desired spirocyclization
using the precedent of Zhang (Scheme 4).12 Thus, exposure of
3 to catalytic Au(PPh3)(NTf2) in the presence of a substituted
pyridine N-oxide as co-oxidant under acidic conditions gave the
spirocyclic 3-furanone 11.13 Moving further, we prepared a pair
of potential final library compounds featuring the same
peripheral substituents. Salt 5a was neutralized, and the free
amine 5b was treated with p-Cl-benzoyl chloride/TEA in the
presence of DMAP. This method afforded the intermediate
ester (not shown) which was subjected to Suzuki coupling to
give the orthogonally diversified derivative 10{10,1}, confirmed
by X-ray crystallography (see the Supporting Information,
Figure S1). Moving in the other direction, spirocycle 11 was
converted to its enol triflate 12.14 Enol triflate 12 was subjected
to Suzuki coupling followed by deprotection and amide
coupling with p-Cl-benzoyl chloride/TEA/DMAP. This
alternate sequence gave the skeletally divergent derivative 13.
We deferred further optimizing the spirocycle route and
instead elected to first use the [3.2.1] scaffold 5 for library
production. Compounds like 10, having both the bridgehead
ester and an exoarylenamine, are previously unreported and so
we used this serendipitous discovery to prepare a novel
compound library. A 14 × 10 diversity component library of
Scheme 2. Alternative Mechanisms for Cyclization of the
Iodonium Derived from 3
B
dx.doi.org/10.1021/jo400077m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 4. Skeletal Diversification Including Introduction of Peripheral Substituents
Figure 1. Components for the proposed 140-member library from scaffold 5.
140 members was designed (Figure 1). As a matter of routine,
component subsets were used to validate the methodology and
the synthesis platform. Components A6 and B9 were poor
performers and thus removed. The remaining 117 compounds
were prepared using miniblocks.
Some of the compounds were obtained by an alternative
sequence as shown in Scheme 5. Treatment of free amine 5b
with Boc2/TEA in the presence of DMAP gave the O-protected
vinyl iodide 14. At this stage, any diiodo species present could
be readily removed by silica gel chromatography. Suzuki
coupling, deprotection, and acylation gave the library
compounds.
Table 1 shows the isolated yields of the compounds. Of the
117 compounds proposed, 97 were obtained in our target
purities of ≥90%.
Finally, we explored the limits of the both the iodoamination
and spirocyclization. For this purpose, we employed homo-
propargyl alcohols 16a and 16b (Scheme 6). Both of these
C
dx.doi.org/10.1021/jo400077m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 5. Alternate Sequence for Library Compounds
Table 1. Yields of Library Compounds 10 after Reversed-Phase Preparative Mass Directed Fractionation (MDF)
boronic acids
a
B1
B2
B3
B4
B5
B6
B7
B8
B10
acid chlorides
A1
30
37
11
41
34
19
36
35
13
32
27
16
10
34
33
13
40
35
19
25
13
32
6
14
18
10
23
15
9
31
39
14
41
34
23
14
28
38
24
26
14
43
42
19
A2
A3
A4
32
29
13
7
41
35
17
46
41
14
A5
A7
A8
A9
4
35
28
31
32
30
1
26
23
22
42
1
4
28
32
27
36
4
20
21
31
42
A10
A11
A12
A13
A14
34
21
28
43
14
31
19
34
31
23
15
10
26
30
23
37
47
32
26
20
50
a
Compounds incorporating B6 were reprocessed by normal-phase preparative TLC after MDF to attain 90% purity by HPLC.
Scheme 6. Skeletal Diversification of Lower Homologues of 3
substrates were obtained from the precursor ketones 15a and
15b by the action of propargyl bromide and Zn/Cu couple.
Treatment of 16a with ICl afforded no detectable 17a. In
contrast, 16b gave the corresponding bicyclic [2.2.1] amine 17b
in reduced yield. We surmise that the diminished yields
obtained in these systems largely arise from increased ring
strain.
Using catalytic Au(PPh3)(NTf2), both 16a and 16b were
successfully employed in spirocyclization. Thus both substrates
afforded spiro-3-furanones 18a and 18b.13 These products were
D
dx.doi.org/10.1021/jo400077m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
funnel over 25 m. The final reaction mixture was stirred for 2 h, and
then satd aq NH4Cl (1 L) was added. The cold bath was removed and
the reaction mixture warmed to rt overnight. The mixture was diluted
with 1 M HCl (500 mL) and MTBE (800 mL). The mixture was
drawn in portions from the flask by suction through a polypropylene
tube and filtered through Celite to remove flocculent salts. The two-
phase filtrate was returned to the reaction flask and partitioned by
siphoning the aqueous via a suction tube. The combined organics were
dried over MgSO4, filtered, and concentrated under vacuum using a
continuous-feed rotovapor. The crude material (59.00 g) was
chromatographed on silica gel (15 to 30% EtOAc in hexanes) to
afford the product as a white waxy solid (24.30 g, 38%). A yield of 58%
was obtained using 1.350 g (6.760 mmol) of N-Boc-3-piperidone (1):
1H NMR (DMSO-d6, 400 MHz 85 °C) δ 4.15 (s, 1H), 3.46 (m, 1H),
3.38 (d, J = 13.1 Hz, 1H), 3.16 (d, J = 13.1 Hz, 1H), 3.05 (m, 1H),
2.37 (d, J = 17.1 Hz, 1H), 2.32 (d, J = 17.1 Hz, 1H), 1.69 (m, 2H),
1.55 (m, 1H), 1.42 (s, 9H), 1.37 (m, 1H), 0.14 (s, 9H); 13C NMR
(DMSO-d6, 100 MHz, 85 °C) δ 153.9, 103.9, 86.1, 77.9, 67.7, 52.2,
42.8, 34.3, 30.3, 27.7, 20.6, −0.39; IR 3426, 2954, 2176, 1669 cm−1;
HRMS (ESI-TOF) m/z calcd for (M + H−Boc)+ (C11H22NOSi)+
212.1471, found 212.1492.
advanced to the enol triflates 19a and 19b by LDA-promoted
enolization and trapping on oxygen.
CONCLUSION
■
We have developed a divergent synthetic strategy that, from N-
Boc-3-piperidone, rapidly affords two profoundly different
scaffolds, exemplified by compounds 5 and 12, each of which
was shown to be orthogonally diversifiable using the same
diversity components. The previously unreported scaffold 5 was
formed via an unanticipated iodoamination reaction. Com-
pound 5 was used to produce an innovative 97 member library.
Work continues to further optimize the preparation and use of
spirocyclic scaffold 12 with the goal of using it for production of
other libraries of compounds.
EXPERIMENTAL SECTION
■
General Methods. All air- and moisture-sensitive reactions were
carried out in flame- or oven-dried glassware under argon atmosphere
using standard gastight syringes, cannula, and septa. Stirring was
achieved with oven-dried, magnetic stir bars. CH2Cl2 was purified by
passage through a purification system employing activated Al2O3. Flash
column chromatography was performed with SiO2 from Sorbent
Technology (30930M-25, silica gel 60A, 40−63 μm) or by using an
automated chromatography instrument with an appropriately sized
column. Thin-layer chromatography was performed on silica gel
60F254 plates (EM-5717). Deuterated solvents were purchased from
commercial sources. 1H and 13C NMR spectra were recorded on
instruments operating at 400 or 500 MHz and 100 or 125 MHz
respectively. High-resolution mass spectrometry (HRMS) spectra were
obtained on a spectrometer operating on ESI. Library synthesis was
carried out on a mini-block platform in 17 × 100 mm tubes with
parallel evaporation. Automated preparative reversed-phase HPLC
purification was performed using a mass-directed fractionation system
with UV-DAD detection and a quadrapole spectrometer using a C18
column (19 × 150 mm, 5 μm, w/19 × 10 mm guard column). Samples
were diluted in DMSO and purified utilizing an elution of water
(modified to pH 9.8 through addition of NH4OH) and CH3CN, with
a gradient increasing by 20% in CH3CN over 4 min at a flow rate of 20
mL/min. The starting and ending points of the corresponding
preparative CH3CN/water gradient, triggering thresholds, and UV
wavelength were selected on the basis of the HPLC analysis of each
crude sample. Analytical analysis of each sample after purification
employed an HPLC system with UV and mass detection using an ESI-
TOF mass spectrometer. The analytical method utilized a Waters
Aquity BEH C18 column (2.1 × 50 mm, 1.7 μm) eluting with a linear
gradient of 95% water (modified to pH 9.8 through addition of
NH4OH) to 100% CH3CN at 0.6 mL/min flow rate where purity was
determined using UV peak area at 214 nm. Melting points were
determined using an automated apparatus with digital imaging
capability. Alkyllithiums were titrated using N-benzylbenzamide.15
tert-Butyl 3-Hydroxy-3-(3-(trimethylsilyl)prop-2-yn-1-yl)-
piperidine-1-carboxylate (2). Using a procedure similar to that of
Imamoto,7 a three-necked, 5 L flask equipped with an overhead stirrer
and nitrogen inlet was purged with nitrogen for 40 min. Anhydrous
cerium(III) chloride (100.0g, 405.6 mmol) pellets were added to the
flask and suspended in anhydrous THF (810 mL). The mixture was
stirred for 20 h at 120 rpm under nitrogen resulting in a thick white
suspension. A second, 3 L, three-necked flask equipped with an
overhead stirrer, nitrogen inlet, and addition funnel was purged with
nitrogen for 40 min. 1-(Trimethylsilyl)-1-propyne (45.52 g, 405.6
mmol) was added to this flask and dissolved in THF (810 mL). This
solution was cooled to −78 °C, and n-BuLi (181.0 mL of a 2.24 M
solution in hexanes, 405.6 mmol) was added via the addition funnel
over 15 m. This solution was stirred for 1 h. The initial CeCl3 mixture
was cooled to −78 °C, and the solution from the second three-necked
flask was added to it via cannula over 1.5 h. The new combined
mixture was stirred for 1 h, and a solution of N-Boc-3-piperidone 1
(40.40 g, 202.8 mmol) in THF (290 mL) was added via addition
tert-Butyl 4-Hydroxy-4-(3-(trimethylsilyl)prop-2-yn-1-yl)-
piperidine-1-carboxylate (20). Following the procedure for the
synthesis of compound 2, N-Boc-4-piperidone (1.000 g, 5.020 mmol)
was reacted with cerium trichloride (3.710 g, 15.06 mmol), n-
butyllithium (6.350 mL of a 2.37 M solution in hexanes, 15.06 mmol),
and 1-(trimethylsilyl)-1-propyne (1.700 g, 15.15 mmol) to afford the
product 20 (0.966 g, 62%) as a white granular solid: mp = 98.8−102.4
°C; 1H NMR (DMSO-d6, 400 MHz, 85 °C) δ 4.28 (s, 1H), 3.78−3.58
(m, 2H), 3.09 (td, J = 13.2, 2.9 Hz, 2H), 2.42−2.32 (m, 2H), 1.62 (td,
J = 12.7, 4.7 Hz, 2H), 1.52−1.37 (m, 11H), 0.14 (s, 9H); 13C NMR
(DMSO-d6, 100 MHz, 85 °C) δ 153.6, 104.3, 86.0, 77.9, 67.6, 34.9,
33.7, 27.7, 27.6, −0.4; IR 3428, 2960, 2175, 1664 cm−1; HRMS (ESI-
TOF) m/z calcd for (M + M + H)+ (C32H59N2O6Si2)+ 623.3912,
found 623.3908.
tert-Butyl 3-Hydroxy-3-(prop-2-yn-1-yl)piperidine-1-carbox-
ylate (3). To a 3-L, three-necked flask equipped with an overhead
stirrer were added tert-butyl 3-hydroxy-3-(3-(trimethylsilyl)prop-2-yn-
1-yl)piperidine-1-carboxylate (2) (24.30 g, 78.01 mmol), methanol
(780 mL), and K2CO3 (12.90 g). The mixture was stirred at rt for 2.5
h, drawn from the flask via suction, concentrated under vacuum,
redissolved in MTBE (300 mL), and adsorbed onto silica gel (80 g) by
evaporation. The dried silica gel was put over Celite in a fritted funnel
and eluted with MTBE (1500 mL). The filtrate was concentrated
under vacuum to give the product (16.70 g, 89%) as a granular white
solid which was used without further purification: mp = 63.6−67.0 °C;
1H NMR (DMSO-d6, 400 MHz, 85 °C) δ 4.22 (s, 1H), 3.39 (m, 1H),
3.32 (d, J = 13.1 Hz, 1H), 3.22 (d, J = 13.1 Hz, 1H), 3.13 (m, 1H),
2.62 (t, J = 2.5 Hz, 1H), 2.30 (m, 2H), 1.78−1.62 (m, 2H), 1.55 (m,
1H), 1.41 (s, 9H), 1.36 (m, 1H); 13C NMR (DMSO-d6, 100 MHz, 85
°C) δ 153.9, 80.6, 78.0, 72.0, 67.6, 52.2, 42.8, 34.2, 28.8, 27.7, 20.7; IR
3427, 2934, 2119, 1670 cm−1; HRMS (ESI-TOF) m/z calcd for (M +
NH4)+ (C13H25N2O3)+ 257.1865, found 257.1877.
tert-Butyl 4-Hydroxy-4-(prop-2-yn-1-yl)piperidine-1-carbox-
ylate (6). Using the above K2CO3 hydrolysis procedure for compound
3, tert-butyl 4-hydroxy-4-(3-(trimethylsilyl)prop-2-yn-1-yl)piperidine-
1-carboxylate (20) (0.913 g, 2.93 mmol) was reacted with K2CO3
(0.486g, 3.520 mmol). The crude material was chromatographed on
silica gel (5 to 30% EtOAc in hexanes) to afford the product 6 (0.530
1
g, 76%) as a powdered white solid: mp = 41.9−45.1 °C; H NMR
(DMSO-d6, 400 MHz, 85 °C) δ 4.29 (s, 1H), 3.67 (dt, J = 13.0, 3.6
Hz, 2H), 3.11 (m, 2H), 2.62 (t, J = 2.5 Hz, 1H), 2.32 (d, J = 2.5 Hz,
2H), 1.59 (m, 2H), 1.50 (m, 2H), 1.42 (s, 9H); 13C NMR (DMSO-d6,
100 MHz, 85 °C) δ 153.7, 80.9, 78.0, 72.0, 67.4, 35.0, 32.2, 27.7; IR
E
dx.doi.org/10.1021/jo400077m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3418, 2934, 2119, 1662 cm−1; HRMS (ESI-TOF) m/z calcd for (M +
H)+ (C13H22NO3)+ 240.1600, found 240.1587.
tert-Butyl 3-Hydroxy-3-(prop-2-yn-1-yl)piperidine-1-carbox-
ylate (3). Compound 3 was prepared directly from N-Boc-3-
piperidone (1). (CAUTION: This reaction can be accompanied by
a vigorous exotherm and should be properly cooled and vented.)
Using a procedure modified from that of Wang,8 to a solution of N-
Boc-3-piperidone (10.13 g, 50.80 mmol) and propargyl bromide (8.49
mL of an 80 wt % solution in toluene, 76.00 mmol) in THF (10.2 mL)
at 0 °C was added Zn/Cu couple (4.550 g, 55.90 mmol). The mixture
was sonicated for 10 min and then diluted with sat’ aq NH4Cl and
ethyl acetate. (On a scale >1 g of ketone filtration of the mixture
through paper at this point facilitates isolation.) The layers were
separated, and the aqueous layer was extracted with ethyl acetate (3×).
The combined organic layers were dried over MgSO4, filtered, and
concentrated under vacuum. The crude material was chromatographed
on silica gel (5−30% EtOAc in hexanes) to afford the product (7.100
g, 58%) as a white solid. The product contains an inseparable but small
(E)-7-(Iodomethylene)-1-azabicyclo[3.2.1]octan-5-ol (HCl
Salt) (5a). To a 5 L, three-necked flask equipped with an overhead
stirrer were added tert-butyl 3-hydroxy-3-(prop-2-yn-1-yl)piperidine-1-
carboxylate (3) (16.70 g, 69.78 mmol) and dichloromethane (DCM,
700 mL). To this was added a solution of iodine monochloride (34.00
g, 209.3 mmol) in DCM (700 mL) over 30 min via addition funnel.
The reaction mixture was stirred for 22 h, quenched with satd aq
Na2SO3 (1000 mL), and made basic (pH paper checking) with satd aq
NaHCO3 (1000 mL). The aqueous layer was removed via siphon and
the organic layer washed in this fashion with deionized water (300 mL
× 2). Approximately 250 mL of deionized water was added to the
organic layer and the mixture acidified to pH 2 with 1 M HCl as
determined by pH meter. The layers were separated, and the aqueous
layer was lyophilized to afford the amine salt 5a (15.80 g, ∼75%) as a
yellow powder which was used without further purification. In all
cases, and as determined by LC−MS, the product contains the diiodo
species 21a as a 10 area % impurity: mp (HCl salt 5a as mixture with
21a) = 175.7−177.4 °C dec. The two products could be separated via
reversed-phase HPLC as their free bases. The stationary phase was a
Waters Sunfire C18-OBD 5 μM 30 × 150 mm column. The mobile
phase was an CH3CN/water (0.02% TFA) gradient starting at 0%
CH3CN and ending at 100% CH3CN over 13 min. Both products
were obtained as viscous brown oils. Remaining data provided for free
base 5b: 1H NMR (CDCl3, 500 MHz) δ 6.96 (t, J = 2.5 Hz, 1H), 3.55
(d, J = 10.2 Hz, 1H), 3.35 (dd, J = 12.4, 4.8 Hz, 1H), 3.25−3.11 (m,
2H), 2.66 (d, J = 18.0 Hz, 1H), 2.61 (dd, J = 18.0, 2.7 Hz, 1H), 2.08−
1.85 (m, 4H); 13C NMR (CDCl3, 125 MHz) δ 145.1, 75.0, 73.2, 62.8,
55.6, 43.3, 35.2, 18.1; HRMS (ESI-TOF) m/z calcd for (C8H13INO)+
(M + H)+ 266.0042, found 266.0054. Data provided for free base 21b:
1H NMR (DMSO-d6, 500 MHz) δ 3.20 (dd, J = 12.8, 5.7 Hz, 1H),
1
amount of the allene isomer (∼10:1, alkyne/allene as observed by H
NMR). This causes no perceivable issues in subsequent reactions.
Spectral data is reported above.
1-(Phenylsulfonyl)-3-(prop-2-yn-1-yl)piperidin-3-ol (8). Using
the above Zn/Cu/propargyl bromide procedure for compound 3, N-
benzensulfonyl-3-piperidone (1.024 g, 4.280 mmol) was reacted with
propargyl bromide (0.715 mL, 6.420 mmol) and Zn/Cu couple (0.383
g, 4.710 mmol) under sonication for 50 min to afford the product 8
(0.610 g, 51%) as a viscous, orange oil. The product contains an
inseparable, but small amount of the allene isomer (∼8.3:1, alkyne/
1
1
allene as observed by H NMR): H NMR (DMSO-d6, 400 MHz, 85
°C) δ 7.75 (m, 2H), 7.66 (m, 3H), 3.04 (m, 1H), 2.95 (d, J = 11.6 Hz,
1H), 2.87 (d, J = 11.5 Hz, 1H), 2.80 (m, 1H), 2.63 (t, J = 2.6 Hz, 1H),
2.41 (dd, J = 16.9, 2.6 Hz, 1H), 2.34 (dd, J = 16.9, 2.6 Hz, 1H), 1.79
(m, 1H), 1.61 (m, 1H), 1.56−1.43 (m, 2H); 13C NMR (DMSO-d6,
100 MHz, 85 °C) δ 136.4, 132.3, 128.7, 126.7, 80.2, 72.3, 67.4, 54.0,
45.3, 33.4, 28.8, 20.5; IR 3497, 2940, 2115, 1446, 1334 cm−1; HRMS
(ESI-TOF) m/z calcd for (C14H18NO3S)+ (M + H)+, 280.1007 found
280.1021.
2.99 (d, J = 10.0 Hz, 1H), 2.85 (d, J = 9.5 Hz, 1H), 2.70 (m, 1H),
2.44−2.35 (m, 2H), 2.19 (d, J = 16.8 Hz, 1H), 1.69−1.54 (m, 3H),
1.47 (m, 1H); 13C NMR (DMSO-d6, 125 MHz) δ 155.7, 75.9, 65.2,
52.0, 48.8, 35.9, 20.5, 10.1; HRMS (ESI-TOF) m/z calcd for (M +
H)+ (C8H12I2NO)+ 391.9008, found 391.9029.
tert-Butyl 3-Hydroxy-3-(prop-2-yn-1-yl)azetidine-1-carboxy-
late (16a). Using the above Zn/Cu/propargyl bromide procedure for
compound 3, N-Boc-3-azetidinone (1.673 g, 9.77 mmol) was reacted
with propargyl bromide (1.633 mL, 14.66 mmol) and Zn/Cu couple
(0.875 g, 10.75 mmol) under sonication for 30 min to afford the
product 16a (1.674 g, 81%) as a white solid. The product contains an
inseparable but small amount of the allene isomer (∼8.3:1, alkyne/
(E)-2-(Iodomethylene)-1-azabicyclo[2.2.1]heptan-4-ol (HCl
Salt) (17b). Following the above procedure for compound 5a, tert-
butyl 3-hydroxy-3-(prop-2-yn-1-yl)pyrrolidine-1-carboxylate (16b)
(0.530 g, 2.353 mmol) was reacted with iodine monochloride (1.146
g, 7.060 mmol) to afford 17b (0.217 g, 32%) as a yellow powder: mp =
1
155.9−159.1 °C dec; H NMR (DMSO-d6, 400 MHz) δ 12.63 (s,
1H), 6.97 (s, 1H), 6.41 (s, 1H), 3.72 (td, J = 11.1, 6.2 Hz, 1H), 3.34−
3.22 (m, 2H), 3.19 (d, J = 8.1 Hz, 1H), 2.48 (m, 2H), 1.99 (m, 2H);
13C NMR (DMSO-d6, 100 MHz) δ 146.7, 78.4, 74.6, 60.5, 54.4, 42.5,
1
allene as observed by H NMR. This causes no perceivable issues in
1
subsequent reactions): mp = 83.8−90.0 °C; H NMR (CDCl3, 400
31.3; IR 3247, 2824, 2503, 1356 cm−1; HRMS (ESI-TOF) m/z calcd
MHz) δ 3.92 (d, J = 9.6 Hz, 2H), 3.87 (d, J = 9.6 Hz, 2H), 3.53 (s,
1H), 2.62 (d, J = 2.6 Hz, 2H), 2.06 (t, J = 2.6 Hz, 1H), 1.42 (s, 9H);
13C NMR (CDCl3, 100 MHz) δ 156.4, 79.9, 79.0, 71.1, 68.9, 61.0,
for (M + H)+ (C7H11INO)+ 251.9885, found 251.9906.
(E)-7-(Iodomethylene)-1-azabicyclo[3.2.1]octan-5-ol (5b) by
Neutralization of 5a. A solution of salt 5a (5.008 g, 16.61 mmol) in
water (150 mL) was made basic to pH > 7 (pH paper) using satd aq
sodium bicarbonate. The solution was extracted into ethyl acetate
(×6), and the combined organic layers were dried over MgSO4,
filtered, and concentrated under vacuum to give the free base as a
viscous, brown oil (3.900 g, 89%).
(E)-7-Benzylidene-1-azabicyclo[3.2.1]octan-5-yl 4-Chloro-
benzoate (10{10,1}). To a solution of (E)-7-(iodomethylene)-1-
azabicyclo[3.2.1]octan-5-ol (5b) (0.064 mg, 0.242 mmol), triethyl-
amine (0.200 mL, 1.45 mmol), and dimethylaminopyridine (0.015 g,
0.121 mmol) in CH3CN (1.00 mL) was added 4-chlorobenzoyl
chloride (0.16 mL, 1.21 mmol). The reaction mixture was heated to 50
°C for 22 h. The reaction mixture was diluted with diethyl ether,
filtered through Celite, and concentrated under vacuum. The crude
residue was chromatographed on silica gel (15 to 30% EtOAc in
hexanes) to give the purified intermediate (E)-7-(iodomethylene)-1-
azabicyclo[3.2.1]octan-5-yl 4-chlorobenzoate (0.078 g, 79%). This was
taken directly on to the next step.
29.4, 28.3; IR 3384, 2977, 1669 cm−1; HRMS (ESI-TOF) m/z calcd
for (C11H18NO3)+ (M + H)+ 212.1287, found 212.1287.
tert-Butyl 3-Hydroxy-3-(prop-2-yn-1-yl)pyrrolidine-1-car-
boxylate (16b). Using the above Zn/Cu/propargyl bromide
procedure for compound 3, N-Boc-3-pyrrolidinone (15b) (4.062 g,
21.93 mmol) was reacted with propargyl bromide (3.660 mL, 32.90
mmol) and Zn/Cu couple (1.964 g, 24.12 mmol) under sonication for
45 min to afford the product 16b (2.535 g, 51%) as a white solid. The
product contains an inseparable, but small amount of the allene isomer
(∼8:1, alkyne/allene as observed by 1H NMR. This causes no
1
perceivable issues in subsequent reactions): mp = 75.3−79.8 °C; H
NMR (DMSO-d6, 500 MHz, 90 °C) δ 4.54 (s, 1H), 3.45−3.36 (m,
2H), 3.32 (m, 1H), 3.27 (d, J = 11.2 Hz, 1H), 2.54 (s, 1H), 2.49 (m,
2H), 1.96 (m, 1H), 1.84 (m, 1H), 1.44 (s, 9H); 13C NMR (DMSO-d6,
125 MHz, 90 °C) δ 153.2, 80.6, 77.5, 76.2, 70.9, 56.1, 43.9, 35.9, 28.0,
27.6; IR 3379, 2978, 2109, 1658 cm−1; HRMS (ESI-TOF) m/z calcd
for (M + H)+ (C12H20NO3)+ 226.1443, found 226.1452.
F
dx.doi.org/10.1021/jo400077m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
A solution of (E)-7-(iodomethylene)-1-azabicyclo[3.2.1]octan-5-yl
4-chlorobenzoate (0.046 g, 0.110 mmol), cesium carbonate (0.22 mL
of a 2 M aqueous solution, 0.440 mmol), phenylboronic acid (0.015 g,
0.120 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.008 g,
0.007 mmol) in DMF (1.10 mL) was heated to 90 °C for 90 min. The
reaction mixture was diluted with EtOAc and filtered through a 1 g
silica gel solid-phase extraction column (SPE). The filtrate was
concentrated under vacuum and the residue chromatographed on
reversed-phase C18 (10 to 100% CH3CN in water) to give the
product 10{10,1} (0.026 mg, 68%) as a brown solid: 1H NMR
(CDCl3, 500 MHz) δ 7.97 (m, 2H), 7.43 (m, 2H), 7.38−7.31 (m,
4H), 7.21 (m, 1H), 6.34 (t, J = 2.3 Hz, 1H), 3.49 (dt, J = 16.8, 2.1 Hz,
1H), 3.29 (dd, J = 10.7, 2.1 Hz, 1H), 3.21 (dd, J = 10.7, 3.2 Hz, 1H),
3.16 (dd, J = 13.4, 6.0 Hz, 1H), 3.12−2.99 (m, 2H), 2.39 (m, 1H),
2.22 (tdd, J = 12.4, 5.8, 1.3 Hz, 1H), 2.02 (m, 1H), 1.68 (m, 1H); 13C
NMR (CDCl3, 125 MHz) δ 164.8, 149.5, 139.5, 136.6, 131.0, 128.9,
128.7, 128.5, 127.8, 126.2, 117.1, 84.1, 62.7, 58.1, 42.2, 33.2, 21.5; IR
2942, 1718 cm−1; HRMS (ESI-TOF) m/z calcd for (M + H)+
(C21H21ClNO2)+ 354.1261, found 354.1254.
11 (0.511 g, 52%) as a colorless oil: H NMR (DMSO-d6, 500 MHz,
90 °C) δ 4.02 (d, J = 17.0 Hz, 1H), 3.96 (d, J = 17.0 Hz, 1H), 3.51−
3.39 (m, 2H), 3.38−3.23 (m, 2H), 2.38 (d, J = 18.2 Hz, 1H), 2.34 (d, J
= 18.1 Hz, 1H), 1.89−1.69 (m, 3H), 1.49−1.36 (m, 1H), 1.44 (s, 9H);
13C NMR (CDCl3, 125 MHz, 90 °C) δ 212.7, 153.5, 78.5, 78.2, 68.7,
50.0, 44.6, 42.6, 34.1, 27.4, 21.0; IR 2936, 1760, 1687 cm−1; HRMS
(ESI-TOF) m/z calcd for (M−Boc + H)+ (C8H14NO2)+ 156.1025,
found 156.1053.
tert-Butyl 7-Oxo-5-oxa-2-azaspiro[3.4]octane-2-carboxylate
(18a). Following the above procedure for compound 11, tert-butyl 3-
hydroxy-3-(prop-2-yn-1-yl)azetidine-1-carboxylate (16a) (1.138 g,
5.39 mmol) was reacted with 3,5-dichloropyridine N-oxide (1.767 g,
10.77 mmol), methanesulfonic acid (0.419 mL, 6.460 mmol), and
triphenylphosphinegold(I) bis(trifluoromethanesulfonyl)imidate
(0.199 g, 0.269 mmol) to afford the product 18a (0.606 g, 50%) as
1
a granular white solid: mp = 70.6−80.5 °C; H NMR (CDCl3, 400
MHz) δ 4.10 (d, J = 9.4 Hz, 2H), 4.00−3.97 (t, J = 5.9 Hz, 4H), 2.70
(s, 2H), 1.43 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 212.2, 156.1,
80.0, 77.3, 70.8, 61.0, 45.5, 28.2; IR 2978, 1765, 1694 cm−1; HRMS
(ESI-TOF) m/z calcd for (C11H16NO4)− (M−H)−, 226.1085 found
226.1062.
tert-Butyl 3-Oxo-1-oxa-7-azaspiro[4.4]nonane-7-carboxylate
(18b). Following the above procedure for compound 11, tert-butyl 3-
hydroxy-3-(prop-2-yn-1-yl)pyrrolidine-1-carboxylate (16b) (2.470 g,
10.96 mmol) was reacted with 3,5-dichloropyridine N-oxide (3.600 g,
21.93 mmol), methanesulfonic acid (0.854 mL, 13.16 mmol), and
triphenylphosphinegold(I) bis(trifluoromethanesulfonyl)imidate
(0.405 g, 0.548 mmol) to afford the product 18b (1.653 g, 63%) as
(E)-tert-Butyl (7-(Iodomethylene)-1-azabicyclo[3.2.1]octan-
5-yl)carbonate (14) and tert-Butyl (7-(Diiodomethylene)-1-
azabicyclo[3.2.1]octan-5-yl)carbonate (22). To a solution of the
alcohol mixture 5b (3.538 g, 13.35 mmol) and 21b (579 mg, 1.48
mmol) in DCM (62 mL) were added N,N-dimethylaminopyridine
(DMAP, 0.379 g, 3.110 mmol), triethylamine (TEA, 4.330 mL, 31.10
mmol), and di-tert-butyl dicarbonate (Boc2O, 4.070 g, 18.64 mmol).
The reaction mixture was stirred for 3 h and then diluted with water
and DCM, and the layers were separated. The aqueous layer was
extracted with DCM (2×), and the combined organic layers were
washed with 10% aqueous citric acid (1×) and brine (1×), dried over
MgSO4, filtered, and concentrated under vacuum. The crude material
was chromatographed on silica gel (5 to 30% EtOAc in hexanes) to
give the separated final products: (E)-tert-butyl (7-(iodomethylene)-
1-azabicyclo[3.2.1]octan-5-yl)carbonate (14) as a light brown
powder (4.131 g, 11.31 mmol) and tert-butyl (7-(diiodomethy-
lene)-1-azabicyclo[3.2.1]octan-5-yl)carbonate (22) as a granular
brown solid (0.393 g, 0.80 mmol). Overall amount: 12.11 mmol, 82%.
Monoiodide 14: mp = 61.1−64.8 °C; 1H NMR (CDCl3, 400 MHz) δ
5.89 (m, 1H), 3.14 (dd, J = 11.0, 2.3 Hz, 1H), 3.10 (dd, J = 11.0, 3.0
Hz, 1H), 3.07−2.94 (m, 2H), 2.84 (td, J = 13.1, 4.5 Hz, 1H), 2.56
(ddd, J = 17.2, 2.5, 1.9 Hz, 1H), 2.31−2.21 (m, 1H), 2.05 (tdd, J =
12.3, 5.9, 1.6 Hz, 1H), 1.86 (m, 1H), 1.64 (m, 1H), 1.47 (s, 9H); 13C
NMR (CDCl3, 100 MHz) δ 158.1, 151.9, 83.4, 82.3, 64.9, 64.3, 57.7,
45.0, 32.9, 27.7, 21.5; IR 2940, 1738 cm−1; HRMS (ESI-TOF) m/z
calcd for (C13H21INO3)+ (M + H)+ 366.0566, found 366.0596.
Diiodide 22: mp = 98.2−137.7 °C (slowly decomposes over reported
range); 1H NMR (CDCl3, 400 MHz) δ 3.45−3.32 (m, 1H), 3.27−2.96
(m, 3H), 2.69 (m, 1H), 2.60 (dd, J = 17.2, 1.6 Hz, 1H), 2.28 (dd, J =
11.2, 1.6 Hz, 1H), 2.05 (m, 1H), 1.73 (m, 2H), 1.47 (s, 9H); 13C
NMR (CDCl3, 100 MHz) δ 159.5, 151.7, 85.2, 82.4, 64.4, 52.5, 47.4,
32.6, 27.7, 22.1, 0.6; IR 2977, 1737 cm−1; HRMS (ESI-TOF) m/z
calcd for (C13H20I2NO3)+ (M + H)+ 491.9533, found 491.9532.
tert-Butyl 3-Oxo-1-oxa-7-azaspiro[4.5]decane-7-carboxylate
(11). Using the method of Zhang,12 to a solution of tert-butyl 3-
hydroxy-3-(prop-2-yn-1-yl)piperidine-1-carboxylate (3) (0.927 g,
3.870 mmol) in DCE (31.0 mL) were added 3,5-dichloropyridine
N-oxide (1.270 g, 7.750 mmol) and methanesulfonic acid (0.302 mL,
4.650 mmol). In a separate flask, triphenylphosphinegold(I) bis-
(trifluoromethanesulfonyl)imidate (0.143 g, 0.194 mmol, 5 mol %)
was weighed in a glovebox. The gold catalyst was placed under argon,
removed from the glovebox and dissolved in DCE (46.50 mL). The
contents of the first reaction flask were added to the gold catalyst-
containing flask via cannula and the reaction mixture stirred for 4 h.
The reaction mixture was concentrated under vacuum and chromato-
graphed on silica gel (5 to 30% EtOAc in hexanes) to give the product
1
a granular pale yellow solid: mp = 70.8−76.2 °C; H NMR (DMSO-
d6, 500 MHz, 90 °C) δ 4.01 (m, 2H), 3.54 (d, J = 11.7 Hz, 1H), 3.48−
3.40 (m, 2H), 3.36 (d, J = 11.7 Hz, 1H), 2.66 (d, J = 18.1 Hz, 1H),
2.57 (d, J = 18.1 Hz, 1H), 2.19−2.08 (m, 1H), 1.99 (m, 1H), 1.45 (s,
9H); 13C NMR (DMSO-d6, 125 MHz, 90 °C) δ 212.4, 153.1, 85.8,
77.9, 69.2, 54.6, 43.8, 42.9, 34.8, 27.6; IR 2975, 1762, 1688 cm−1;
HRMS (ESI-TOF) m/z calcd for (M + H)+ (C12H20NO4)+ 242.1392,
found 242.1374.
tert-Butyl 3-(((Trifluoromethyl)sulfonyl)oxy)-1-oxa-7-
azaspiro[4.5]dec-2-ene-7-carboxylate (12). To a solution of
diisopropylamine (0.373 mL, 2.660 mmol) in THF (8.87 mL) at
−78 °C was added n-butyllithium (1.142 mL of a 2.330 M solution in
hexanes). The reaction mixture was warmed to 0 °C, stirred for 30
min, and then cooled to −78 °C. A solution of tert-butyl 3-oxo-1-oxa-
7-azaspiro[4.5]decane-7-carboxylate (11) (0.227 g, 0.887 mmol) in
THF (4.44 mL) was then added via cannula and the mixture stirred for
30 min. A solution of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethyl-
sulfonyl)methanesulfonamide (0.634 g, 1.775 mmol) in THF (7.10
mL) was then added via cannula and the solution allowed to warm to
rt and stirred overnight for 18 h. The reaction mixture was quenched
with satd aq NH4Cl and diluted with water and MTBE, and the layers
were separated. The aqueous layer was extracted with MTBE (3×),
and the combined organic layers were dried over MgSO4, filtered
through a pad of silica gel, and concentrated under vacuum. The crude
residue was chromatographed on reversed-phase C18 (0 to 100%
CH3CN in pH 9.4 ammonia/water) to give the product 12 (0.196 g,
57%) as an orange/brown oil: 1H NMR (DMSO-d6, 500 MHz, 85 °C)
δ 6.09 (t, J = 1.9 Hz, 1H), 4.64 (m, 2H), 3.43−3.36 (m, 2H), 3.37 (d, J
= 13.3 Hz, 1H), 3.23 (m, 1H), 1.82 (m, 1H), 1.73 (m, 2H), 1.52 (m,
1H), 1.43 (s, 9H); 13C NMR (CDCl3, 125 MHz, 85 °C) δ 153.5,
144.2, 117.8, 117.6 (q, JC−F = 322.12 Hz), 85.1, 78.2, 67.7, 50.7, 42.3,
33.9, 27.4, 20.7; IR 2938, 1692 cm−1; HRMS (ESI-TOF) m/z calcd for
(M−Boc + H)+ (C9H13F3NO4S)+ 288.0517, found 288.0532.
tert-Butyl 7-(((Trifluoromethyl)sulfonyl)oxy)-5-oxa-2-
azaspiro[3.4]oct-6-ene-2-carboxylate (19a). Following the above
procedure for compound 12, tert-butyl 7-oxo-5-oxa-2-azaspiro[3.4]-
octane-2-carboxylate (18a) (0.125 g, 0.550 mmol) was reacted with
LDA (0.231 mL, 1.650 mmol of diisopropylamine with 0.743 mL,
1.650 mmol of a 2.220 M solution of butyllithium in hexanes) and N-
(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)-
methanesulfonamide (Comins’ reagent, 0.432 g, 1.100 mmol) in place
of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methane-
G
dx.doi.org/10.1021/jo400077m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
sulfonamide. The reaction was quenched with 5 M aqueous NH4OH
saturated with NH4Cl and washed again (1×) with this solution after
dilution with MTBE. The workup then proceeded as for compound
12. Chromatography on silica gel (0−25% EtOAc in hexanes) afforded
the product 19a (0.075 g, 38%) as a granular off-white solid: mp =
46.2−52.5 °C; 1H NMR (CDCl3, 400 MHz) δ 5.98 (s, 1H), 4.66 (d, J
= 2.1 Hz, 2H), 4.20−4.09 (m, 2H), 4.07−3.96 (m, 2H), 1.43 (s, 9H);
13C NMR (CDCl3, 100 MHz) δ 156.0, 145.8, 118.4 (q, JC−F = 321.1
48 (8 × 6) members. Stock solutions were prepared to accommodate
52 members in order to provide for potential handling losses.
Step 1. Stock solutions were prepared as follows: (1) (E)-7-
(Iodomethylene)-1-azabicyclo[3.2.1]octan-5-ol (5b): 4.461 g (16.83
mmol) in acetonitrile (CH3CN, 58.40 mL, 0.288 M). (2) TEA (8.320
mL, 59.69 mmol) and DMAP (572.0 mg, 4.322 mmol) in CH3CN
(7.800 mL). To each of 48 17 × 100 mm tubes equipped with stirring
bars on two 24-place mini-block platforms on stirring plates were
added 1.000 mL of stock solution 1 (0.288 mmol amine), 0.320 mL of
stock solution 2 (1.150 mmol TEA and 0.090 mmol DMAP), and the
appropriate volume of each neat acid chloride (0.864 mmol, eight acid
chlorides were used six times each in this first step). The reactor blocks
were heated to 50 °C, as judged by thermocouple inserted into each
block, for 22 h. Each reaction mixture was then diluted with MTBE
(10 mL) and filtered into new 17 × 100 mm reaction tubes through a
1 g silica gel SPE using a mini-block filtration platform. The filtrates
were concentrated in parallel using a parallelpersonal evaporator. The
crude material was taken on to the final step.
Step 2. Using the same mini-block setup described above, to each
reaction tube were added dimethylformamide (2.900 mL), cesium
carbonate (0.580 mL of a 2 M solution in water, 1.15 mmol), the
appropriate amount of each bornic acid (0.320 mmol), and
tetrakis(triphenylphosphine)palladium(0) (20.00 mg, 0.017 mmol,
added using the mini-block powder dispenser). The reactor blocks
were heated to 90 °C, as judged by a thermocouple inserted into each
block, for 90 min. Each reaction mixture was then diluted with ethyl
acetate (7 mL) and filtered through 1 g of silica gel SPE tubes into bar-
coded 16 × 100 mm screw cap tubes. The filtrates were concentrated
under vacuum using a parallel evaporator and the crude products
purified using high-throughput MDF as described in the general
procedures section above.
Hz), 114.4, 83.8, 80.0, 70.2, 62.0, 28.3; IR 2978, 1702, 1667 cm−1;
HRMS (ESI-TOF) m/z calcd for (C24H33F6N2O12S2)+ (M + M + H)+
719.1379, found 719.1380.
tert-Butyl 3-(((Trifluoromethyl)sulfonyl)oxy)-1-oxa-7-
azaspiro[4.4]non-2-ene-7-carboxylate (19b). Following the
above procedure for compound 12, tert-butyl 3-oxo-1-oxa-7-
azaspiro[4.4]nonane-7-carboxylate (18b) (0.186 g, 0.771 mmol) was
reacted with LDA (0.324 mL, 2.313 mmol of diisopropylamine with
1.042 mL, 2.313 mmol of a 2.220 M solution of butyllithium in
hexanes) and 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)-
methanesulfonamide (0.551 g, 1.542 mmol). In this case, chromatog-
raphy on silica gel (0 to 25% EtOAc in hexanes) afforded the product
19b (0.112 g, 39%) as an orange/brown oil: 1H NMR (DMSO-d6, 500
MHz, 90 °C) δ 6.15 (s, 1H), 4.65 (m, 2H), 3.48 (m, 1H), 3.45−3.34
(m, 3H), 2.11 (dt, J = 13.0, 9.1 Hz, 1H), 2.02 (ddd, J = 13.0, 7.1, 3.1
Hz, 1H), 1.45 (s, 9H); 13C NMR (DMSO-d6, 125 MHz, 90 °C) δ
152.9, 144.1, 122.3, 117.6 (q, JC−F = 321.7 Hz), 92.3, 77.9, 67.8, 54.5,
43.7, 35.4, 27.5; IR 2979, 1693, 1671 cm−1; HRMS (ESI-TOF) m/z
calcd for (M + H)+ (C13H19F3NO6S)+ 374.0885, found 374.0901.
(4-Chlorophenyl)(3-phenyl-1-oxa-7-azaspiro[4.5]dec-2-en-7-
yl)methanone (13). A solution of tert-butyl 3-(((trifluoromethyl)-
sulfonyl)oxy)-1-oxa-7-azaspiro[4.5]dec-2-ene-7-carboxylate (12)
(0.044 g, 0.113 mmol), phenylboronic acid (0.015 g, 0.125 mmol),
and Cs2CO3 (0.227 mL of a 2 M aqueous solution, 0.453 mmol) in
DMF (1.11 mL) was purged with argon for 5 min. Tetrakis-
(triphenylphosphine)palladium(0) (0.008 g, 0.007 mmol) was added
and the reaction mixture heated to 90 °C for 110 min. The reaction
mixture was cooled and diluted with ethyl acetate and water, and the
layers were separated. The aqueous layer was extracted with ethyl
acetate (3×), and the combined organic layers were washed with brine
(1×), dried over MgSO4, filtered, and concentrated under vacuum.
The crude material was chromatographed on silica gel (0 to 10%
EtOAc in hexanes) to give the intermediate arylated product, tert-butyl
3-phenyl-1-oxa-7-azaspiro[4.5]dec-2-ene-7-carboxylate (0.018 mg,
51%) as a yellow oil. This was taken directly to the next step.
To a solution of tert-butyl 3-phenyl-1-oxa-7-azaspiro[4.5]dec-2-ene-
7-carboxylate (0.018 g, 0.057 mmol) in DCM (0.300 mL) was added
activated 4 Å molecular sieves and trifluoroacetic acid (TFA, 0.300
mL). After 5 min, the reaction mixture was filtered, and the filtrate was
diluted with toluene and concentrated under vacuum (flushed) three
times to remove TFA. The residue was then dissolved in DCM (1.000
mL). To this solution were added TEA (0.020 mL, 0.143 mmol),
DMAP (∼1 mg, ∼0.006 mmol), and 4-chlorobenzoyl chloride (0.011
mL, 0.086 mmol). The reaction mixture was stirred for 2 h at rt,
concentrated under vacuum, and directly chromatographed on silica
gel (20 to 40% EtOAc in hexanes) to give the product 13 (0.016 g,
78%) as a white, amorphous solid: 1H NMR (DMSO-d6, 500 MHz, 90
°C) δ 7.53−7.24 (m, 9H), 6.30 (s, 1H), 4.95 (dd, J = 12.6, 1.8 Hz,
1H), 4.81 (d, J = 12.6 Hz, 1H), 3.82 (m, 1H), 3.54 (d, J = 13.2 Hz,
1H), 3.44 (d, J = 13.2 Hz, 1H), 3.23 (m, 1H), 1.88−1.84 (m, 3H),
1.67 (m, 1H); 13C NMR (CDCl3, 125 MHz, 90 °C) δ 168.0, 138.6,
135.0, 133.3, 131.5, 128.1, 127.8, 127.6, 127.5, 125.2, 124.8, 87.6, 72.7,
52.4, 43.0, 34.0, 21.0; IR 2941, 1628 cm−1; HRMS (ESI-TOF) m/z
calcd for (M + H)+ (C21H21ClNO2)+ 354.1261, found 354.1254.
General Procedure for Library Synthesis, Route 2. The
following describes the synthesis of a subset of the library consisting of
eighteen (9 × 2) members. Stock solutions were prepared in a 10%
excess to provide for potential handling losses.
Step 1. Stock solutions were prepared as follows: (1) (E)-tert-butyl
(7-(iodomethylene)-1-azabicyclo[3.2.1]octan-5-yl)carbonate (21)
(2.530 g, 6.930 mmol) in DMF (69.30 mL, 0.100 M). Using the
same mini-block setup described above to each reaction tube was
added 3.5 mL of stock solution 1 (0.350 mmol of 21), cesium
carbonate (0.700 mL of a 2 M solution in water, 1.400 mmol), the
appropriate boronic acid (0.385 mmol, nine boronic acids were used
twice each in this first step), and tetrakis(triphenylphosphine)-
palladium(0) (24.00 mg, 0.021 mmol, added using the mini-block
powder dispenser). The reactor blocks were heated to 90 °C, as
judged by thermocouple inserted into each block, for 3 h. Each
reaction mixture was then diluted with ethyl acetate (8 mL) and
filtered into new 17 × 100 mm reaction tubes through a 1 g silica gel
SPE using a mini-block filtration platform. The filtrates were
concentrated in parallel using a parallel evaporator.
Step 2. A stock solution of 1:1 DCM/TFA (1.80 mL) was added to
each of the 18 reaction tubes. The mixtures were stirred for 30 min
and then toluene (4.000 mL) was added to each reaction. After
removal of the solvent on the parallel personal evaporator, another
4.00 mL of toluene was added to each and once again removed under
vacuum in the same manner.
Step 3. A stock solution of TEA and DMAP was prepared: (1) TEA
(6.80 mL, 48.79 mmol) and DMAP (260.0 mg, 2.128 mmol) in
CH3CN (35.00 mL). To each reaction tube was added 1.750 mL of
CH3CN, 2.100 mL of stock solution 1, and the appropriate acid
chloride (1.050 mmol). The reactor blocks were either heated to 50
°C, as judged by thermocouple (A8, isoxazole derived acid chloride)
for 3 h, or kept at room temperature (A14, mesyl chloride) for 1 h. In
General Procedure for Library Synthesis, Route 1. The
following describes the synthesis of a subset of the library consisting of
H
dx.doi.org/10.1021/jo400077m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
the case of A8, each reaction mixture was diluted with MTBE (5 mL),
while the A14 mixtures were diluted with 1:1, DCM:CH3CN (5 mL).
All reaction mixtures were filtered through 1 g silica gel SPE tubes into
bar-coded 16 × 100 mm screw cap tubes. The filtrates were
concentrated under vacuum using a parallel evaporator and the
crude products purified using high-throughput MDF as described in
the general procedures section above.
1H); 13C NMR (DMSO-d6, 125 MHz) δ 159.2, 155.4, 152.2, 138.9,
133.3, 130.3, 127.1, 126.0, 125.8, 114.7, 109.9, 85.5, 61.4, 57.5, 41.6,
32.5, 21.3; IR 2946, 1731, 1279 cm−1; HRMS (ESI-TOF) m/z calcd
for (M + H)+ (C18H18ClN2O3)+ 345.1000, found 345.0998.
(E)-7-(4-Cyanobenzylidene)-1-azabicyclo[3.2.1]octan-5-yl
1
pivalate (10{7,10}): H NMR (DMSO-d6, 500 MHz) δ 7.78 (d, J =
8.4 Hz, 2H), 7.47 (d, J = 8.4, 2H), 6.29 (t, J = 2.0 Hz, 1H), 3.24 (dt, J
= 17.0, 1.9 Hz, 1H), 3.10 (dd, J = 10.6, 2.3 Hz, 1H), 3.02−2.88 (m,
4H), 2.08 (m, 1H), 2.00 (dt, J = 12.2, 5.6 Hz, 1H), 1.77 (m, 1H), 1.54
(m, 1H), 1.14 (s, 9H); 13C NMR (DMSO-d6, 125 MHz) δ 176.9,
155.5, 141.7, 132.4, 128.1, 119.2, 114.7, 107.8, 82.5, 61.8, 57.7, 42.5,
38.5, 32.3, 26.9, 21.2; IR 2961, 2224, 1726 cm−1; HRMS (ESI-TOF)
m/z calcd for (M + H)+ (C20H25N2O2)+ 325.1911, found 325.1887.
(E)-7-(4-Cyanobenzylidene)-1-azabicyclo[3.2.1]octan-5-yl 4-
chlorobenzoate (10{10,10}): 1H NMR (DMSO-d6, 500 MHz) δ
7.97 (d, J = 8.7 Hz, 2H), 7.79 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.7 Hz,
2H), 7.49(d, J = 8.4 Hz, 2H), 6.32 (s, 1H), 3.34 (m, 1H), 3.24 (dd, J =
10.6, 2.2 Hz, 1H), 3.16 (d, J = 17.7 Hz, 1H), 3.08 (dd, J = 10.6, 2.8 Hz,
1H), 3.05−3.02 (m, 2H), 2.25−2.15 (m, 2H), 1.84 (m, 1H), 1.59 (m,
1H); 13C NMR (DMSO-d6, 125 MHz) δ 164.2, 155.3, 141.7, 138.4,
132.4, 131.2, 129.0, 128.9, 128.1, 119.2, 114.7, 107.9, 84.0, 61.7, 57.7,
42.5, 32.5, 21.3; IR 2946, 2223, 1717 cm−1; HRMS (ESI-TOF) m/z
calcd for (M + H)+ (C22H20ClN2O2)+ 379.1208, found 379.1209.
(E)-7-(Pyridin-4-ylmethylene)-1-azabicyclo[3.2.1]octan-5-yl
(E)-7-Benzylidene-1-azabicyclo[3.2.1]octan-5-yl 4-chloro-
benzoate (10{10,1}): 1H NMR (CDCl3, 500 MHz) δ 7.97 (m,
2H), 7.43 (m, 2H), 7.38−7.31 (m, 4H), 7.21 (m, 1H), 6.34 (t, J = 2.3
Hz, 1H), 3.49 (dt, J = 16.8, 2.1 Hz, 1H), 3.29 (dd, J = 10.7, 2.1 Hz,
1H), 3.21 (dd, J = 10.7, 3.2 Hz, 1H), 3.16 (dd, J = 13.4, 6.0 Hz, 1H),
3.12−2.99 (m, 2H), 2.39 (m, 1H), 2.22 (tdd, J = 12.4, 5.8, 1.3 Hz,
1H), 2.02 (m, 1H), 1.68 (m, 1H); 13C NMR (CDCl3, 125 MHz) δ
164.8, 149.5, 139.5, 136.6, 131.0, 128.9, 128.7, 128.5, 127.8, 126.2,
117.1, 84.1, 62.7, 58.1, 42.2, 33.2, 21.5; IR 2942, 1718 cm−1; HRMS
(ESI-TOF) m/z calcd for (M + H)+ (C21H21ClNO2)+ 354.1261, found
354.1254. Crystal structure CIF available (Supporting Information).
(E)-7-(4-Cyanobenzylidene)-1-azabicyclo[3.2.1]octan-5-yl
furan-2-carboxylate (10{2,10}): 1H NMR (DMSO-d6, 500 MHz) δ
7.98 (dd, J = 1.7, 0.8 Hz, 1H), 7.78 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 8.5
Hz, 2H), 7.31 (dd, J = 3.5, 0.8 Hz, 1H), 6.70 (dd, J = 3.5, 1.7 Hz, 1H),
6.31 (s, 1H), 3.32 (d, J = 17.0 Hz, 1H), 3.21 (dd, J = 10.6, 2.3 Hz, 1H),
3.11 (d, 17.0 Hz, 1H), 3.05−3.00 (m, 3H), 2.21 (m, 1H), 2.14 (m,
1H), 1.83 (m, 1H), 1.59 (m, 1H); 13C NMR (DMSO-d6, 125 MHz) δ
157.1, 155.2, 147.7, 143.9, 141.7, 132.3, 128.1, 119.2, 118.8, 114.7,
112.4, 107.9, 83.9, 61.7, 57.7, 42.5, 32.6, 21.3; IR 2946, 2223, 1721,
1603, 1301 cm−1; HRMS (ESI-TOF) m/z calcd for (M + H)+
(C20H19N2O3)+ 335.1390, found 335.1369.
(E)-7-(3-Chlorobenzylidene)-1-azabicyclo[3.2.1]octan-5-yl
cyclopentanecarboxylate (10{5,7}): 1H NMR (DMSO-d6, 500
MHz) δ 7.36 (t, J = 7.9 Hz, 1H), 7.32 (t, J = 1.7 Hz, 1H), 7.26 (d, J =
7.9 Hz, 1H), 7.22 (ddd, J = 7.9, 2.1, 0.9 Hz, 1H), 6.18 (t, J = 2.1 Hz,
1H), 3.20 (dt, J = 16.9, 1.9 Hz, 1H), 3.06 (dd, J = 10.6, 2.3 Hz, 1H),
2.96−2.84 (m, 4H), 2.72 (m, 1H), 2.09 (m, 1H), 2.00 (dt, J = 11.9, 6.0
Hz, 1H), 1.84−1.50 (m, 10H); 13C NMR (DMSO-d6, 125 MHz) δ
175.1, 152.9, 139.0, 133.2, 130.3, 127.0, 125.9, 125.6, 114.4, 82.6, 61.8,
57.6, 43.3, 42.1, 32.5, 29.5, 29.4, 25.4, 21.1; IR 2947, 1730, 1662 cm−1;
HRMS (ESI-TOF) m/z calcd for (M + H)+ (C20H25ClNO2)+
346.1568, found 346.1550.
1
4-chlorobenzoate (10{10,4}): H NMR (DMSO-d6, 500 MHz) δ
8.49 (d, J = 6.2 Hz, 2H), 7.97 (d, J = 8.7 Hz, 2H), 7.61 (d, J = 8.7 Hz,
2H), 7.28 (d, J = 6.2 Hz, 2H), 6.21 (s, 1H), 3.37 (dd, J = 16.6, 1.9 Hz,
1H), 3.25 (dd, J = 10.6, 2.3 Hz, 1H), 3.17 (d, J = 17.0 Hz, 1H), 3.08
(dd, J = 10.6, 2.8 Hz, 1H), 3.05−3.03 (m, 2H), 2.22 (m, 1H), 2.19 (dt,
J = 11.7, 5.6 Hz, 1H), 1.85 (m, 1H), 1.59 (m, 1H); 13C NMR
(DMSO-d6, 125 MHz) δ 164.2, 156.5, 149.7, 144.0, 138.4, 131.2,
129.0, 128.9, 122.0, 113.6, 83.9, 61.7, 57.8, 42.5, 32.5, 21.3; IR 2944,
1719 cm−1; HRMS (ESI-TOF) m/z calcd for (M + H)+
(C20H20ClN2O2)+ 355.1208, found 355.1197.
(E)-7-(4-Chlorobenzylidene)-1-azabicyclo[3.2.1]octan-5-yl 3-
fluorobenzoate (10{12,2}): 1H NMR (DMSO-d6, 500 MHz) δ 7.81
(dt, J = 7.6, 1.2 Hz, 1H), 7.70 (ddd, J = 9.5, 2.6, 1.6 Hz, 1H), 7.59
(ddd, J = 13.9, 8.2, 5.8 Hz, 1H), 7.53 (ddt, J = 8.7, 2.6, 1.2 Hz, 1H),
7.39 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H) 6.22 (t, J = 2.1 Hz,
1H), 3.30 (m, 1H), 3.22 (dd, J = 10.6, 2.2 Hz, 1H), 3.08 − 3.04 (m,
2H), 3.00−2.95 (m, 2H), 2.25−2.15 (m, 2H), 1.89−1.81 (m, 1H),
(E)-7-(4-Methoxybenzylidene)-1-azabicyclo[3.2.1]octan-5-yl
1
1.61−1.57 (m, 1H); 13C NMR (DMSO-d6, 125 MHz) δ 163.9 (JCF
=
4-fluorobenzoate (10{11,3}): H NMR (DMSO-d6, 500 MHz) δ
8.03 (m, 2H), 7.36 (t, J = 9.8 Hz, 2H), 7.25 (d, J = 8.8 Hz, 2H), 6.92
(d, J = 8.8 Hz, 2H), 6.16 (t, J = 2.0 Hz, 1H), 3.74 (s, 3H), 3.28 (d, J =
16.7 Hz, 1H), 3.19 (dd, J = 10.6, 2.1 Hz, 1H), 3.03−2.95 (m, 4H),
2.24 (m, 1H), 2.16 (dt, J = 12.0, 5.8 Hz, 1H), 1.85 (m, 1H), 1.58 (m,
1H); 13C NMR (DMSO-d6, 125 MHz) δ 165.2 (d, JC−F = 249.9 Hz),
164.1, 157.5, 148.3, 132.2 (d, JC−F = 9.5 Hz), 129.3, 128.7, 126.8 (d,
JC−F = 2.8 Hz), 115.9 (d, JC−F = 21.9 Hz), 114.0, 84.0, 61.9, 57.5, 55.1,
41.9, 32.8, 21.3; IR 2941, 1718, 1280 cm−1; HRMS (ESI-TOF) m/z
calcd for (M + H)+ (C22H23FNO3)+ 368.1656, found 368.1629.
(E)-7-(3-(Dimethylamino)benzylidene)-1-azabicyclo[3.2.1]-
octan-5-yl furan-2-carboxylate (10{2,6}): 1H NMR (DMSO-d6,
500 MHz) δ 7.97 (dd, J = 1.8, 0.9 Hz, 1H), 7.31 (dd, J = 3.6, 0.9 Hz,
1H), 7.14 (t, J = 7.9 Hz, 1H), 6.69 (dd, J = 3.6, 1.8 Hz, 1H), 6.64 (d, J
= 7.9 Hz, 1H), 6.61 (m, 1H), 6.57 (dd, J = 8.1, 2.2, 1H), 6.15 (t, J =
2.0, 1H), 3.29 (d, J = 16.7 Hz, 1H), 3.16 (dd, J = 10.6, 2.2 Hz, 1H),
3.01−2.94 (m, 4H), 2.88 (s, 6H), 2.22 (m, 1H), 2.14 (dt, J = 12.2, 6.0
Hz, 1H), 1.84 (m, 1H), 1.58 (m, 1H); 13C NMR (DMSO-d6, 125
MHz) δ 157.1, 150.6, 149.9, 147.7, 144.0, 137.2, 128.9, 118.7, 116.7,
115.6, 112.4, 112.0, 110.5, 84.0, 61.8, 57.5, 42.1, 40.2, 32.8, 21.3; IR
2943, 1714, 1298 cm−1; HRMS (ESI-TOF) m/z calcd for (M + H)+
(C21H25N2O3)+ 353.1860, found 353.1866.
2.5 Hz), 162.0 (d, JCF = 243.8 Hz), 151.7, 135.7, 132.5 (d, JCF = 7.5
Hz), 131.0 (d, JCF = 7.5 Hz); 130.3, 129.2, 128.4, 125.5 (d, JCF = 6.3
Hz), 120.5 (d, JCF = 21.1 Hz), 115.9 (d, JCF = 22.9 Hz), 114.6, 84.2,
61.7, 57.6, 42.0, 32.6, 21.3; IR 2944, 1720 cm−1; HRMS (ESI-TOF)
m/z calcd for (M + H)+ (C21H20ClFNO2)+ 372.1167, found 372.1146.
(E)-7-(3-Methoxybenzylidene)-1-azabicyclo[3.2.1]octan-5-yl
acetate (10{13,5}): 1H NMR (DMSO-d6, 500 MHz) δ 7.24 (t, J = 7.8
Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.82 (m, 1H), 6.76 (m, 1H), 6.15 (t
J = 2.2 Hz), 3.75 (s, 3H), 3.20 (dt, J = 16.8, 2.0 Hz, 1H), 3.04 (dd, J =
10.6, 2.3 Hz, 1H), 2.96−2.90 (m, 2H), 2.89−2.82 (m, 2H), 2.16−2.10
(m, 1H), 2.06−1.96 (m, 1H), 2.00 (s, 3H), 1.83−1.71 (m, 1H), 1.58−
1.48 (m, 1H); 13C NMR (DMSO-d6, 125 MHz) δ 169.8, 159.3, 151.3,
138.1, 129.4, 119.9, 115.5, 113.1, 111.4, 82.8, 61.9, 57.5, 55.0, 42.1,
32.6, 21.4, 21.2; IR 2942, 1735 cm−1; HRMS (ESI-TOF) m/z calcd for
(M + H)+ (C17H22NO3)+ 288.1600, found 288.1593.
(E)-7-(Pyridin-3-ylmethylene)-1-azabicyclo[3.2.1]octan-5-yl
1
4-fluorobenzoate (10{11,8}): H NMR (DMSO-d6, 500 MHz) δ
8.53 (d, J = 2.1 Hz, 1H), 8.37 (dd, J = 4.7, 1.5 Hz, 1H), 8.08−8.00 (m,
2H), 7.74 (dt, J = 8.0, 1.8 Hz, 1H), 7.36 (m, 3H), 6.24 (t, J = 2.0 Hz,
1H), 3.33 (m, 1H), 3.24 (dd, J = 10.6, 2.2 Hz, 1H), 3.15−2.99 (m,
4H), 2.28−2.13 (m, 2H), 1.95−1.76 (m, 1H), 1.67−1.52 (m, 1H); 13C
NMR (DMSO-d6, 125 MHz) δ 166.2, 165.2 (d, JCF = 251.5 Hz),
164.1, 153.3, 148.8, 146.7, 133.9, 132.2 (d, JCF = 9.6 Hz), 126.7 (d, JCF
= 2.8 Hz), 123.5, 115.9 (d, JCF = 22.1 Hz), 112.2, 83.8, 61.8, 57.6, 42.1,
32.6, 21.2; IR 2947, 1717 cm−1; HRMS (ESI-TOF) m/z calcd for (M
+ H)+ (C20H20FN2O2)+ 339.1509, found 339.1483.
(E)-7-(3-Chlorobenzylidene)-1-azabicyclo[3.2.1]octan-5-yl
isoxazole-5-carboxylate (10{8,7}): 1H NMR (DMSO-d6, 500
MHz) δ 8.85 (d, J = 1.9 Hz, 1H), 7.39−7.35 (m, 2H), 7.30−7.28
(m, 2H), 7.25 (ddd, J = 7.9, 2.0, 0.9 Hz, 1H), 6.24 (t, J = 2.1 Hz, 1H),
3.31 (dt, J = 16.9, 1.9 Hz, 1H), 3.21 (dd, J = 10.6, 2.2 Hz, 1H), 3.14 (d,
J = 16.9 Hz, 1H), 3.06 (dd, J = 10.6, 3.0 Hz, 1H), 3.00−2.99 (m, 2H),
2.23 (m, 1H), 2.18 (dt, J = 11.8, 6.0 Hz, 1H), 1.86 (m, 1H), 1.59 (m,
(E)-7-Benzylidene-1-azabicyclo[3.2.1]octan-5-yl acetate
1
(10{13,1}): H NMR (DMSO-d6, 500 MHz) δ 7.36−7.31 (m, 2H),
I
dx.doi.org/10.1021/jo400077m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
7.29 (m, 2H), 7.21−7.14 (m, 1H), 6.18 (t, J = 2.2 Hz, 1H), 3.20 (dt, J
= 16.8, 2.1 Hz, 1H), 3.04 (dd, J = 10.6, 2.3 Hz, 1H), 2.97−2.81 (m,
4H), 2.18−2.10 (m, 1H), 2.06−1.96 (m, 1H), 2.00 (s, 3H), 1.84−1.70
(m, 1H), 1.53 (m, 1H); 13C NMR (DMSO-d6, 125 MHz) δ 169.8,
150.9, 136.7, 128.5, 127.5, 125.9, 115.6, 82.8, 61.9, 57.5, 42.0, 32.6,
21.4, 21.2; IR 2942, 1735 cm−1; HRMS (ESI-TOF) m/z calcd for (M
+ H)+ (C16H19NO2)+ 258.1494, found 258.1464.
41.9, 35.9, 32.7, 21.2, 18.0, 13.4; IR 2958, 1733 cm−1; HRMS (ESI-
TOF) m/z calcd for (M + H)+ (C19H26NO3)+ 316.1913, found
316.1898.
(E)-7-(Pyridin-4-ylmethylene)-1-azabicyclo[3.2.1]octan-5-yl
cyclohexanecarboxylate (10{4,4}): 1H NMR (DMSO-d6, 500
MHz) δ 8.47 (dd, J = 4.6, 1.6 Hz, 2H), 7.24 (dd, J = 4.7, 1.5 Hz,
2H), 6.17 (t, J = 2.0 Hz, 1H), 3.25 (dt, J = 17.0, 2.0 Hz, 1H), 3.09 (dd,
J = 10.7, 2.4 Hz, 1H), 3.03−2.84 (m, 4H), 2.27 (tt, J = 10.7, 3.6 Hz,
1H), 2.15−2.04 (m, 1H), 2.04−1.96 (m, 1H), 1.86−1.69 (m, 3H),
1.66 (m, 2H), 1.55 (m, 2H), 1.43−1.08 (m, 5H); 13C NMR (DMSO-
d6, 125 MHz) δ 174.4, 156.7, 149.7, 144.0, 122.0, 113.5, 82.4, 61.8,
57.7, 42.6, 42.4, 32.4, 28.6, 28.5, 25.3, 24.8, 24.7, 21.2; IR 2932, 1731
cm−1; HRMS (ESI-TOF) m/z calcd for (M + H)+ (C20H27N2O2)+
327.2073, found 327.2058.
(E)-7-(3-Methoxybenzylidene)-1-azabicyclo[3.2.1]octan-5-yl
cyclopentanecarboxylate (10{5,5}): 1H NMR (DMSO-d6, 500
MHz) δ 7.25 (t, J = 7.9 Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), 6.82 (m,
1H), 6.76 (m, 1H), 6.15 (t, J = 2.1 Hz, 1H), 3.74 (s, 3H), 3.22−3.19
(m, 1H), 3.05 (dd, J = 10.6, 2.2 Hz, 1H), 3.00−2.77 (m, 4H), 2.77−
2.65 (m, 1H), 2.10 (m, 1H), 1.99 (m, 1H), 1.87−1.73 (m, 3H), 1.73−
1.63 (m, 2H), 1.63−1.45 (m, 5H); 13C NMR (DMSO-d6, 125 MHz) δ
175.2, 159.3, 151.3, 138.1, 129.5, 119.8, 115.6, 113.3, 111.3, 82.6, 61.9,
57.6, 55.0, 43.3, 42.2, 32.5, 29.5, 29.4, 25.4, 21.1; IR 2947, 1729 cm−1;
HRMS (ESI-TOF) m/z calcd for (M + H)+ (C21H28NO3)+ 342.2069,
found 342.2054.
(E)-7-(4-Chlorobenzylidene)-1-azabicyclo[3.2.1]octan-5-yl
pivalate (10{7,2}): 1H NMR (DMSO-d6, 500 MHz) δ 7.46−7.35 (m,
2H), 7.35−7.25 (m, 2H), 6.19 (t, J = 2.1 Hz, 1H), 3.19 (m, 1H), 3.07
(dd, J = 10.6, 2.2 Hz, 1H), 3.02−2.89 (m, 2H), 2.86 (dd, J = 10.6, 3.1
Hz, 1H), 2.80 (d, J = 16.9 Hz, 1H), 2.08 (m, 1H), 2.00 (m, 1H), 1.77
(m, 1H), 1.53 (m, 1H), 1.14 (s, 9H); 13C NMR (DMSO-d6, 125
MHz) δ 176.9, 151.9, 135.7, 130.2, 129.1, 128.4, 114.5, 82.5, 61.8,
57.5, 42.0, 38.5, 32.3, 26.9, 21.1; IR 2957, 1727 cm−1; HRMS (ESI-
TOF) m/z calcd for (M + H)+ (C19H25ClNO2)+ 334.1574, found
334.1571.
(E)-7-(Pyridin-3-ylmethylene)-1-azabicyclo[3.2.1]octan-5-yl
1
4-chlorobenzoate (10{10,8}): H NMR (DMSO-d6, 500 MHz) δ
8.53 (d, J = 2.1 Hz, 1H), 8.37 (dd, J = 4.7, 1.5 Hz, 1H), 7.99−7.95 (m,
2H), 7.74 (dt, J = 8.0, 1.8 Hz, 1H), 7.64−7.59 (m, 2H), 7.37 (dd, J =
7.9, 4.7 Hz, 1H), 6.24 (s, 1H), 3.38−3.29 (m, 1H), 3.24 (dd, J = 10.6,
2.2 Hz, 1H), 3.15−2.99 (m, 4H), 2.28−2.14 (m, 2H), 1.94−1.80 (m,
1H), 1.65−1.56 (m, 1H); 13C NMR (DMSO-d6, 125 MHz) δ 164.2,
153.2, 148.8, 146.7, 138.4, 133.9, 132.6, 131.2, 128.9, 123.5, 112.3,
84.0, 61.8, 57.6, 42.1, 32.6, 21.2; IR 2944, 1718 cm−1; HRMS (ESI-
TOF) m/z calcd for (M + H)+ (C20H20ClN2O2)+ 355.1213, found
355.1216.
(E)-7-(3-Chlorobenzylidene)-1-azabicyclo[3.2.1]octan-5-yl
cyclohexanecarboxylate (10{4,7}): 1H NMR (DMSO-d6, 500
MHz) δ 7.36 (t, J = 7.9 Hz, 1H), 7.32 (t, J = 1.7 Hz, 1H), 7.26 (d,
J = 7.9 Hz, 1H), 7.23 (ddd, J = 7.9, 2.1, 0.9 Hz, 1H), 6.19 (t, J = 2.1
Hz, 1H), 3.20 (dd, J = 10.3, 8.4 Hz, 1H), 3.07 (dd, J = 10.7, 2.2 Hz,
1H), 2.99−2.80 (m, 4H), 2.27 (tt, J = 10.7, 3.6 Hz, 1H), 2.08 (dd, J =
10.3, 5.6 Hz, 1H), 2.00 (td, J = 12.0, 6.1 Hz, 1H), 1.86−1.70 (m, 3H),
1.70−1.61 (m, 2H), 1.55 (m, 2H), 1.41−1.12 (m, 5H); 13C NMR
(DMSO-d6, 125 MHz) δ 174.4, 152.9, 139.0, 133.2, 130.3, 127.0,
125.9, 125.6, 114.4, 82.5, 61.8, 57.6, 42.5, 42.1, 32.5, 28.6, 28.5, 25.3,
24.8, 24.7, 21.1; IR 2934, 1731 cm−1; HRMS (ESI-TOF) m/z calcd for
(M + H)+ (C21H27ClNO2)+ 360.1730, found 360.1711.
(E)-7-Benzylidene-1-azabicyclo[3.2.1]octan-5-yl nicotinate
1
(10{9,1}): H NMR (DMSO-d6, 500 MHz) δ 9.11 (dd, J = 2.2, 0.7
Hz, 1H), 8.82 (dd, J = 4.8, 1.8 Hz, 1H), 8.34−8.28 (m, 1H), 7.60−
7.56 (m, 1H), 7.38−7.32 (m, 4H), 7.19 (m, 1H), 6.23 (t, J = 2.2 Hz,
1H), 3.36−3.31 (m, 1H), 3.23 (dd, J = 10.6, 2.2 Hz, 1H), 3.14−3.04
(m, 2H), 3.04−2.97 (m, 2H), 2.30−2.16 (m, 2H), 1.86 (m, 1H), 1.61
(m, 1H); 13C NMR (DMSO-d6, 125 MHz) δ 164.0, 153.7, 150.7,
150.2, 137.0, 136.7, 128.5, 127.5, 126.1, 126.0, 123.9, 115.7, 84.3, 61.7,
57.5, 42.0, 32.69, 21.28; IR 2943, 1718 cm−1; HRMS (ESI-TOF) m/z
calcd for (M + H)+ (C20H21N2O2)+ 321.1603, found 321.1580.
(E)-7-(4-Methoxybenzylidene)-1-azabicyclo[3.2.1]octan-5-yl
(E)-7-(3-Methoxybenzylidene)-1-azabicyclo[3.2.1]octan-5-yl
pivalate (10{7,5}): 1H NMR (DMSO-d6, 500 MHz) δ 7.26 (t, J = 7.9
Hz, 1H), 6.88 (d, J = 7.9 Hz, 1H), 6.82 (m, 1H), 6.77 (m, 1H), 6.16 (t,
J = 2.1 Hz, 1H), 3.75 (s, 3H), 3.21 (m, 1H), 3.06 (dd, J = 10.6, 2.2 Hz,
1H), 2.93 (m, 2H), 2.85 (dd, J = 10.6, 3.1 Hz, 1H), 2.79 (d, J = 16.8
Hz, 1H), 2.09 (m, 1H), 1.99 (m, 1H), 1.77 (m, 1H), 1.53 (m, 1H),
1.14 (s, 9H); 13C NMR (DMSO-d6, 125 MHz) δ 176.9, 159.3, 151.2,
138.1, 129.5, 119.8, 115.6, 113.4, 111.2, 82.5, 61.8, 57.5, 55.0, 42.1,
38.5, 32.4, 26.9, 21.1; IR 2957, 1726 cm−1; HRMS (ESI-TOF) m/z
calcd for (M + H)+ (C20H28NO3)+ 330.2069, found 330.2070.
(E)-7-(Pyridin-3-ylmethylene)-1-azabicyclo[3.2.1]octan-5-yl
1
benzoate (10{1,3}): H NMR (DMSO-d6, 500 MHz) δ 8.00−7.94
(m, 2H), 7.70−7.63 (m, 1H), 7.56−7.50 (m, 2H), 7.25 (d, J = 8.8 Hz,
2H), 6.95−6.89 (m, 2H), 6.16 (t, J = 2.0 Hz, 1H), 3.75 (s, 3H), 3.29
(d, J = 16.7 Hz, 1H), 3.20 (dd, J = 10.5, 2.0 Hz, 1H), 3.07−2.92 (m,
4H), 2.29−2.21 (m, 1H), 2.16 (m, 1H), 1.91−1.78 (m, 1H), 1.58 (m,
1H); 13C NMR (DMSO-d6, 125 MHz) δ 165.0, 157.5, 148.4, 133.4,
130.2, 129.3, 128.7, 128.7, 115.2, 114.0, 83.8, 61.9, 57.5, 55.1, 41.9,
32.8, 21.3 (one overlap peak in aromatic region); IR 2939, 1714 cm−1;
HRMS (ESI-TOF) m/z calcd for (M + H)+ (C22H24NO3)+ 350.1756,
found 350.1738.
1
benzoate (10{1,8}): H NMR (DMSO-d6, 500 MHz) δ 8.53 (d, J =
2.1 Hz, 1H), 8.37 (dd, J = 4.7, 1.5 Hz, 1H), 7.97 (m, 2H), 7.74 (dt, J =
8.0, 1.8 Hz, 1H), 7.66 (m, 1H), 7.53 (m, 2H), 7.36 (dd, J = 8.0, 4.7 Hz,
1H), 6.24 (t, J = 2.0 Hz, 1H), 3.39−3.30 (m, 1H), 3.24 (dd, J = 10.6,
2.2 Hz, 1H), 3.16−2.95 (m, 4H), 2.32−2.12 (m, 2H), 1.87 (m, 1H),
1.60 (m, 1H); 13C NMR (DMSO-d6, 125 MHz) δ 165.0, 153.4, 148.8,
146.7, 133.8, 133.4, 132.6, 130.1, 129.3, 128.7, 123.5, 112.2, 83.7, 61.9,
57.6, 42.2, 32.6, 21.3; IR 2945, 1716 cm−1; HRMS (ESI-TOF) m/z
calcd for (M + H)+ (C20H21N2O2)+ 321.1603, found 321.1608.
(E)-7-(4-Chlorobenzylidene)-1-azabicyclo[3.2.1]octan-5-yl
butyrate (10{3,2}): 1H NMR (DMSO-d6, 500 MHz) δ 7.38 (m, 2H),
7.30 (m, 2H), 6.18 (t, J = 2.1 Hz, 1H), 3.19 (dt, J = 16.8, 2.2 Hz, 1H),
3.06 (dd, J = 10.6, 2.2 Hz, 1H), 3.01−2.76 (m, 4H), 2.26 (t, J = 7.3 Hz,
2H), 2.32 (m, 1H), 2.01 (m, 1H), 1.77 (m, 1H), 1.61−1.47 (m, 3H),
0.88 (t, J = 7.4 Hz, 3H); 13C NMR (DMSO-d6, 125 MHz) δ 172.2,
152.0, 135.7, 130.2, 129.1, 128.4, 114.5, 82.7, 61.9, 57.5, 42.1, 35.9,
32.6, 21.2, 18.0, 13.4; IR 2939, 1732 cm−1; HRMS (ESI-TOF) m/z
calcd for (M + H)+ (C18H23ClNO2)+ 320.1417, found 320.1422.
(E)-7-(3-(Dimethylamino)benzylidene)-1-azabicyclo[3.2.1]-
octan-5-yl 3-fluorobenzoate (10{12,6}): 1H NMR (DMSO-d6, 500
MHz) δ 7.81 (dt, J = 7.6, 1.2 Hz, 1H), 7.71 (ddd, J = 9.5, 2.5, 1.5 Hz,
1H), 7.59 (m, 1H), 7.53 (m, 1H), 7.15 (t, J = 7.9 Hz, 1H), 6.66 (d, J =
7.7 Hz, 1H), 6.62 (m, 1H), 6.58 (dd, J = 8.1, 2.3 Hz, 1H), 6.17 (t, J =
2.0 Hz, 1H), 3.32 (m, 1H), 3.21 (dd, J = 10.6, 2.1 Hz, 1H), 3.10−2.93
(E)-7-(Pyridin-4-ylmethylene)-1-azabicyclo[3.2.1]octan-5-yl
1
furan-2-carboxylate (10{2,4}): H NMR (DMSO-d6, 500 MHz) δ
8.48 (dd, J = 4.6, 1.6 Hz, 2H), 7.98 (dd, J = 1.6, 0.8 Hz, 1H), 7.32 (dd,
J = 3.5, 0.8 Hz, 1H), 7.27 (dd, J = 4.6, 1.6 Hz, 2H), 6.70 (dd, J = 3.5,
1.6 Hz, 1H), 6.20 (t, J = 2.0 Hz, 1H), 3.39−3.31 (m, 1H), 3.21 (dd, J =
10.6, 2.3 Hz, 1H), 3.12 (d, J = 17.6 Hz, 1H), 3.04 (m, 3H), 2.25−2.10
(m, 2H), 1.90−1.74 (m, 1H), 1.60−1.56 (m, 1H); 13C NMR (DMSO-
d6, 125 MHz) δ 157.1, 156.4, 149.7, 147.7, 143.9, 122.0, 118.8, 113.6,
112.4, 83.9, 61.7, 57.7, 42.5, 32.6, 21.3 (one overlap in aromatic
region); IR 2945, 1718 cm−1; HRMS (ESI-TOF) m/z calcd for (M +
H)+ (C18H19N2O3)+ 311.1396, found 311.1377.
(E)-7-(4-Methoxybenzylidene)-1-azabicyclo[3.2.1]octan-5-yl
1
butyrate (10{3,3}): H NMR (DMSO-d6, 500 MHz) δ 7.22 (d, J =
8.8 Hz, 2H), 6.96−6.84 (m, 2H), 6.12 (t, J = 2.1 Hz, 1H), 3.74 (s,
3H), 3.22−3.10 (m, 1H), 3.03 (dd, J = 10.6, 2.1 Hz, 1H), 2.96−2.81
(m, 3H), 2.77 (m, 1H), 2.26 (t, J = 7.3 Hz, 2H), 2.17−2.08 (m, 1H),
2.00 (td, J = 12.0, 5.7 Hz, 1H), 1.86−1.67 (m, 1H), 1.60−1.45 (m,
3H), 0.88 (t, J = 7.4 Hz, 3H); 13C NMR (DMSO-d6, 125 MHz) δ
172.2, 157.5, 148.5, 129.3, 128.7, 115.1, 114.0, 82.8, 62.0, 57.4, 55.1,
J
dx.doi.org/10.1021/jo400077m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(m, 4H), 2.89 (s, 6H), 2.31−2.11 (m, 2H), 1.86 (m, 1H), 1.59 (m,
1H); 13C NMR (DMSO-d6, 125 MHz) δ 163.9 (d, JCF = 3.0 Hz),
162.0 (d, JCF = 245.0 Hz), 150.6, 149.9, 137.2, 132.5 (d, JCF = 7.3 Hz),
(3) For recent reviews on spirocycle synthesis, see: (a) Kotha, S.;
Deb, A. C.; Lahiri, K.; Manivannan, E. Synthesis 2009, 2, 165−193.
(b) Rosenberg, S.; Leino, R. Synthesis 2009, 16, 2651−2673. (c) Kang,
F.-A.; Sui, Z. Tetrahedron Lett. 2011, 52 (32), 4204−4206. (d) Rios, R.
Chem. Soc. Rev. 2012, 41 (3), 1060−1074.
131.0 (d, JCF = 8.0 Hz), 128.9, 125.5 (d, JCF = 2.7 Hz), 120.4 (d, JCF
=
21.2 Hz), 116.7, 115.9 (d, JCF = 22.9 Hz), 115.5, 112.1, 110.5, 84.2,
61.7, 57.5, 42.0, 40.2, 32.6, 21.3; IR 2943, 1718 cm−1; HRMS (ESI-
TOF) m/z calcd for (M + H)+ (C23H26FN2O2)+ 381.1978, found
381.1954.
(4) For selected recent examples of spirocycle syntheses, see:
(a) Badillo, J. J.; Arevalo, G. E.; Fettinger, J. C.; Franz, A. K. Org. Lett.
2011, 13 (3), 418−421. (b) Dohi, T.; Nakae, T.; Ishikado, Y.; Kato,
D.; Kita, Y. Org. Biomol. Chem. 2011, 9 (20), 6899−6902. (c) Li, D.-B.;
Rogers-Evans, M.; Carreira, E. M. Org. Lett. 2011, 13 (22), 6134−
6136. (d) Burkhard, J. A.; Guerot, C.; Knust, H.; Carreira, E. M. Org.
Lett. 2012, 14 (1), 66−69. (e) Liu, T.-L.; He, Z.-L.; Tao, H.-Y.; Wang,
C.-J. Chem.Eur. J. 2012, 18 (26), 8042−8046.
ASSOCIATED CONTENT
* Supporting Information
X-ray structure of compound 10{10,1}, details about library
■
S
1
compound yield trend data for individual components, and H
(5) (a) Yao, T.; Yue, D.; Larock, R. C. J. Comb. Chem. 2005, 7 (6),
809−812. (b) Yao, T.; Yue, D.; Larock, R. C. J. Org. Chem. 2005, 70
(24), 9985−9989. (c) Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem.
2005, 70 (25), 10292−10296. (d) Cho, C.-H.; Neuenswander, B.;
Lushington, G. H.; Larock, R. C. J. Comb. Chem. 2008, 10 (6), 941−
947. (e) Okitsu, T.; Nakazawa, D.; Taniguchi, R.; Wada, A. Org. Lett.
2008, 10 (21), 4967−4970. (f) Godoi, B.; Schumacher, R. F.; Zeni, G.
Chem. Rev. 2011, 111 (4), 2937−2980.
and 13C NMR spectral data for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: csantini@ku.edu.
■
(6) Wenkert, E.; Bookser, B. C.; Arrhenius, T. S. J. Am. Chem. Soc.
1992, 114 (2), 644−54.
(7) Imamoto, T.; Kusumoto, T.; Tawarayama, Y.; Sugiura, Y.; Mita,
T.; Hatanaka, Y.; Yokoyama, M. J. Org. Chem. 1984, 49 (21), 3904−
12.
(8) Ma, X.; Wang, J.-X.; Li, S.; Wang, K.-H.; Huang, D. Tetrahedron
2009, 65 (42), 8683−8689.
(9) (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 18, 734−6.
(b) Baldwin, J. E.; Cutting, J.; Dupont, W.; Kruse, L.; Silberman, L.;
Thomas, R. C. J. Chem. Soc., Chem. Commun. 1976, 18, 736−8.
(10) Zhang, X.; Zhou, Y.; Wang, H.; Guo, D.; Ye, D.; Xu, Y.; Jiang,
H.; Liu, H. Adv. Synth. Catal. 2011, 353 (9), 1429−1437.
(11) Horvath, L.; Petz, A.; Kollar, L. Lett. Org. Chem. 2010, 7 (1),
54−60.
(12) Ye, L.; Cui, L.; Zhang, G.; Zhang, L. J. Am. Chem. Soc. 2010, 132
(10), 3258−3259.
(13) The syntheses of compounds 11 and 18b were previously
reported via a three-step route: Moskalenko, A. I.; Belopukhov, S. L.;
Ivlev, A. A.; Boev, V. I. Russ. J. Org. Chem. 2011, 47 (7), 1073−1077.
An online search for compound 18a returns a commercial supplier but
not a published description of its preparation.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge the assistance of Prof. Jeff Aube,
■
́
CMLD Center Director, and Prof. Ryan Altman for kindly
reviewing this manuscript. We acknowledge Mr. Patrick
Porubsky, KU-CMLD Purification Chemist and Compound
Curator, as well as Mr. Jared Downard, who carried out the
pTLC final purification of library compounds indicated in
Table 1. Financial support for the KU-CMLD was provided
under NIGMS Grant No. 5P50GM069663. Support for the
KU-NMR Center (J.T.D.) was provided under Grant No. NIH
1S10RR024664-01. Support for the KU-X-ray facility (V.W.D.)
was provided under NSF-MRI Grant no. CHE-0923449.
REFERENCES
■
(1) For selected recent examples of skeletal diversification, see:
(a) Nielsen, T. E.; Schreiber, S. L. Angew. Chem., Int. Ed. 2008, 47 (1),
48−56. (b) Kelly, A. R.; Wei, J.; Kesavan, S.; Marie, J.-C.; Windmon,
N.; Young, D. W.; Marcaurelle, L. A. Org. Lett. 2009, 11 (11), 2257−
2260. (c) Medeiros, M. R.; Narayan, R. S.; McDougal, N. T.; Schaus,
S. E.; Porco, J. A., Jr. Org. Lett. 2010, 12 (14), 3222−3225.
(d) Dandapani, S.; Lowe, J. T.; Comer, E.; Marcaurelle, L. A. J. Org.
Chem. 2011, 76 (19), 8042−8048. (e) Painter, T. O.; Wang, L.;
Majumder, S.; Xie, X.-Q.; Brummond, K. M. ACS Comb. Sci. 2011, 13
(2), 166−174. (f) Samarakoon, T. B.; Loh, J. K.; Rolfe, A.; Le, L. S.;
Yoon, S. Y.; Lushington, G. H.; Hanson, P. R. Org. Lett. 2011, 13 (19),
5148−5151. (g) Attanasi, O. A.; Bartoccini, S.; Favi, G.; Giorgi, G.;
Perrulli, F. R.; Santeusanio, S. J. Org. Chem. 2012, 77 (2), 1161−1167.
(h) Loh, J. K.; Yoon, S. Y.; Samarakoon, T. B.; Rolfe, A.; Porubsky, P.;
Neuenswander, B.; Lushington, G. H.; Hanson, P. R. Beilstein J. Org.
Chem. 2012, 8, 1293−1302.
(14) Tang, F.; Moeller, K. D. Tetrahedron 2009, 65 (52), 10863−
10875.
(15) Burchat, A. F.; Chong, J. M.; Nielsen, N. J. Organomet. Chem.
1997, 542, 281−283.
(2) For selected recent examples, see: (a) Kumagai, N.; Muncipinto,
G.; Schreiber, S. L. Angew. Chem., Int. Ed. 2006, 45 (22), 3635−3638.
(b) Wyatt, E. E.; Fergus, S.; Galloway, W. R. J. D.; Bender, A.; Fox, D.
J.; Plowright, A. T.; Jessiman, A. S.; Welch, M.; Spring, D. R. Chem.
Commun. 2006, 31, 3296−3298. (c) Sunderhaus, J. D.; Dockendorff,
C.; Martin, S. F. Org. Lett. 2007, 9 (21), 4223−4226. (d) Muncipinto,
G.; Kaya, T.; Wilson, J. A.; Kumagai, N.; Clemons, P. A.; Schreiber, S.
L. Org. Lett. 2010, 12 (22), 5230−5233. (e) Pizzirani, D.; Kaya, T.;
Clemons, P. A.; Schreiber, S. L. Org. Lett. 2010, 12 (12), 2822−2825.
(f) Murrison, S.; Maurya, S. K.; Einzinger, C.; McKeever-Abbas, B.;
Warriner, S.; Nelson, A. Eur. J. Org. Chem. 2011, 12, 2354−2359.
(g) O’Connor, C. J.; Beckmann, H. S. G.; Spring, D. R. Chem. Soc. Rev.
2012, 41 (12), 4444−4456.
K
dx.doi.org/10.1021/jo400077m | J. Org. Chem. XXXX, XXX, XXX−XXX