Rhodium(III)-Catalyzed Synthesis of Spiropiperidine Derivatives via C-H Activation

Article abstract of DOI:10.1021/acs.joc.7b03252

Spiropiperidine derivatives, an important class of bioactive molecules, were synthesized under mild conditions by rhodium(III)-catalyzed intramolecular ArC-H activation. This reaction provides a novel route to highly substituted tricyclic spiropiperidines in good to excellent yields. Under acidic conditions the resulting enamines reacted with pendant amides to afford spiropiperidines derivatives possessing an original tetracyclic structure.

Full text of DOI:10.1021/acs.joc.7b03252

Subscriber access provided by READING UNIV
Article
Rhodium(III)-Catalyzed Synthesis of
Spiropiperidine Derivatives via C–H Activation
Augustin Peneau, Pascal Retailleau, Catherine Guillou, and Laurent Chabaud
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 01 Feb 2018
Downloaded from http://pubs.acs.org on February 1, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 18
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Rhodium(III)-Catalyzed Synthesis of Spiropiperidine Derivatives via
C–H Activation
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Augustin Peneau, Pascal Retailleau, Catherine Guillou,* and Laurent Chabaud*
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Univ Paris-Sud, Université Paris-Saclay, 1
av. de la Terrasse, 91198 Gif-sur-Yvette, France. Fax: (+33)- 1 69 07 72 47 (0); phone: (+33)-1 69 82 30 14.
laurent.chabaud@cnrs.fr, catherine.guillou@cnrs.fr
Supporting Information Placeholder
ABSTRACT: Spiropiperidine derivatives, an important class of bioactive molecules, were synthesized under mild condi-
tions by rhodium(III)-catalyzed intramolecular ArC–H activation. This reaction provides a novel route to highly substi-
tuted tricyclic spiropiperidines in good to excellent yields. Under acidic conditions the resulting enamines reacted with
pendant amides to afford spiropiperidines derivatives possessing an original tetracyclic structure.
INTRODUCTION
Figure 1. Some bioactive spiropiperidines developped by
Spirocycles are important scaffolds commonly embed-
ded in various natural products or synthetic congeners
with numerous biological properties.1 Among them, spi-
ropiperidines have attracted the attention of medicinal
chemists and have shown interesting biological activity
including human tryptase inhibitors 1,2 ghrelin receptor
inhibitors such as indane derivative3 2 and ibutamoren 3
(Figure 1).4
medicinal chemists.
Owing to the well-defined tridimensional structure of
these molecules and their ability to project functional
groups in a specific direction, spiropiperidines have been
considered by medicinal chemists as “privileged struc-
tures”.5 Accordingly, they are used to create focused
chemical libraries and to explore the chemical space dur-
ing structure-activity relationship studies.
Several strategies have been developed to access spi-
ropiperidine
derivatives
including
dialkylation
a,b
c
tions,6
intramolecular Fischer indole synthesis,6
Friedel–Crafts reaction,6d and Buchwald–Hartwig reaction
of amide.6e Other general and straightforward approaches
to synthesize aryl spiropiperidines 5 rely on cyclization of
aryl halides 4 under radical conditions7 or through a
Heck reaction (Scheme 1).7 However, these strategies
a
b
require the preparation of aromatic rings bearing an hal-
ogen atom, and usually performed under harsh reaction
conditions or in the presence of toxic reagents.
Scheme 1. Spiropiperidines synthesis from aryl hal-
ide by radical reaction or Pd(0)-catalyzed Heck reac-
tion
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 18
performed the reaction in the presence of Cu(OAc)2 (2
1
2
3
4
5
6
7
8
equiv.) as an external oxidant, but no improvement of the
yield was observed (Entry 5). It is not clear at this stage
why 11a (R = OMe) could be formed in more than 50%
yield even in the absence of external oxidant in degassed
solvents. It is possible that with this particular substrate,
the Rh(III)-catalyzed olefination occurs through a differ-
ent mechanism that the one proposed by Xia et al, involv-
ing a Rh(III)/Rh(I) catalytic cycle.13 Nevertheless, this
observation led us to consider another parameter, espe-
cially the nature of the nitrogen protecting group.
Recently, Rh(III)-catalyzed C–H bond activation reac-
tions have attracted tremendous interest due to their high
efficiency, functional-group tolerance and selectivity. So
far, Rh(III)-catalyzed C–H activation/intermolecular cou-
pling reactions with differents partners (alkenes, alkynes,
diazo compounds, etc.) have been most widely studied to
access a variety of heterocycles.8 By contrast, the intramo-
lecular variant has recieved much less attention, especial-
ly for substrates containing an olefin on the sidechain.9
Althought this approach provides a useful method for the
synthesis of spirocyclic compounds,9d-e,10 the reaction has
been limited to the synthesis of spirocarbocycles. Due to
the occurence of N-containing spiro heterocycles in bio-
active compounds, we became interest in the Rh(III)-
catalyzed C–H activation/spirocyclization of more sophis-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Optimisation of the Rh(III)-catalyzed spiro-
cyclization
ticated substrates
6 possessing an unsaturated N-
heterocycle (Scheme 2). Albeit the reaction appeared
challenging because of the potential catalyst inhibition by
both coordinating groups, it would led to N-containing
spiro heterocycles 7. We anticipated that further reaction
of the primary amide with the resulting enamine would
provide unprecedented heterocyclic compounds 8.11
Herein we describe the success of this approach.
Entry PG
Solvent
additives
CsOAc
Cpd (%)a
11a, 27b
11a, 53c
11a, 53
1
2
3
4
Bn 9a CH3CN
Bn 9a 1,2-DCE CsOAc
Bn 9a MeOH CsOAc
Scheme 2. Rh(III)-catalyzed spiropiperidine 7 syn-
thesis and tetracyclic derivatives 8
Bn 9a t-AmOH CsOAc
Cu(OAc)2,
11a, 55d
5
Bn 9a t-AmOH
11a, 56
e
AgSbF6
6
7
8
9
Ac 9b 1,2-DCE CsOAc
10b, 56
10b, 71
10b, 82
10c, 80
Ac 9b MeOH
CsOAc
Ac 9b t-AmOH CsOAc
Cbz 9c t-AmOH CsOAc
aIsolated yield. b16% of primary amide derived from 9a and
15 % of 9a were isolated. cRecovery of 38% of starting materi-
d
al 9a 14% of primary amide derived from 9a and 38 % of 9a
e
were isolated. 2 equiv. of Cu(OAc)2 and 5 mol % of AgSbF6
RESULTS & DISCUSSION
were used.
Our investigations initially focused on benzamide 9a
bearing a benzyl protecting group on the nitrogen atom
(Table 1). The reaction was first conducted in presence of
[RhCp*Cl2]2 (2.5 mol %) with 2 equivalents of CsOAc in
acetonitrile (C = 0.2 M) at 60°C. Interestingly, under these
conditions the tetracycle 11a was directly formed and
isolated in 27% yield,12 as well as with recovered starting
material (9a, 15%) and its corresponding primary amide
(16%) (Entry 1). No traces of enamine 10a were observed.
We noticed that the use of other solvents such as 1,2-DCE,
MeOH or t-AmOH slightly improved the isolated yield of
11a (53% to 55%) (Entries 2-4). However, the presence of
the N-OMe still on amide 11a indicates that the directing
group does not efficiently reoxidize the catalyst. We thus
We were delighted to see that an electron-withdrawing
group (9b, PG = Ac) has a dramatic effect on the course of
the reaction. Pleasingly, in the presence of [RhCp*Cl2]2
(2.5 mol %) and CsOAc (2 equiv.) in 1,2-DCE, the spirocy-
cle 10b resulting from the Heck-type reaction was ob-
tained in 56% yield, without any trace of 11b (R = H, PG =
Ac) (Entry 6). A rapid survey of solvents (entries 7-8),
showed that t-AmOH gave the best yield (82%, entry 8).
Interestingly, we also found that a CBz protecting group
on the nitrogen atom (i.e. 9c) was also tolerated and af-
forded the spirocyclic compound 10c in 80% yield (Entry
9), comparable to the N-acetyl 10b.
2
ACS Paragon Plus Environment

Page 3 of 18
The Journal of Organic Chemistry
Having established the optimal reaction conditions and
1
2
3
4
5
6
7
8
the appropriate protecting group, we then examined the
scope of the spirocyclization reaction (Table 2). We
showed that the reaction is compatible with several sub-
stituted aryl moities. For instance, substrates containing
electron-donating group on the aromatic ring such as a
methoxy 9d and dioxolane 9e reacted well to provide
10d-10e in excellent yields (83% and 70%, respectively).
Additionally, ortho substitution by a methyl group (i.e.
9f) led to sterically hindered amide 10f in 64%. Electron-
deficient p-fluoro 9g and p-nitro 9h substrates were also
converted into cyclic enamines 10g-h in 69% and 72%
yields, respectively.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
We next investigated the cyclization of substrates bear-
ing different linkers. Amide 9i reacted smoothly to pro-
duce the spirocyclic chromane 10i in 76% yield, while the
all-carbon tethered compound 9j delivered the indane
substructure 10j in 68% yield. Unfortunately, the mesyl-
ated aniline derivative 9k did not cyclize under these
reaction conditions.14
Interestingly, the regioisomeric N-acetyl piperidine 9l
led to the formation of the spiropiperidine 10l in 72%
yield. Furthermore, the related N-benzyl piperidine 9m
afforded the corresponding primary amide 10m in 91%
yield. This result contrasts with the cyclization of 9a that
gave N-OMe amide 11a in modest yield (Table 1, entry 4).
In the same manner, methylated analogue 10n was ob-
tained in excellent yield (82%) as a mixture of diastere-
omers (dr : 65/35). The cyclization can be extented to the
pyrrolidine derivative 9o bearing a Boc-protected nitro-
gen. In this case, the reaction afforded enamine 10o, that
could not be isolated in pure form due to partial cycliza-
tion into tetracycle 11o (See table 3).
Table 2. Rh(III)-catalyzed synthesis spiropiperidines
10a
c
aIsolated yield. bNo reaction. Compound 10o partially cy-
clizes during purification and was characterized as 11o after
treatment with TFA. dd.r.= 65/35.
The formation of the tetracyclic spiropiperidines was
then examined with enamines 10b-10j, 10o obtained by
Rh(III)-catalyzed CH activation. After screening several
conditions, we found that the spiropiperidine 10b under-
went smooth cyclization, with catalytic amount of TFA
(10 mol %), to give the tetracyclic derivative 11b in 72%
yield, as a single diastereomer (Table 3). Similarly, the
CBz protected enamine 10c efficiently afforded com-
pound 11c in 98%.
Substrates with electron-rich aromatic rings such as a
methoxy (10d) or dioxolane (10e) also gave compounds
11d-11e in nearly quantitative yield. We found that the
reaction of o-methyl substituted amide 10f with TFA did
not reach completion even after prolonged reaction time
or at higher temperature (50°C in 1,2 DCE). Consequently
compound 11f was isolated in 58% yield (brsm 99%). Oth-
er substrates 10g-h bearing electron-withdrawing groups
led to excellent isolated yields of polycyclic aminal 11g-h.
We also successfully transformed chromane and indane
derivatives 10i-j into the corresponding aminals 11i-j in
excellent 97% and 94% yields. Finally, we found that the
enamine of the unsaturated pyrrolidine 10o is more reac-
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
tive and partial cyclization to give 11o was observed dur-
Page 4 of 18
1
2
3
4
5
6
ing its purification over silica gel. Interestingly, treate-
ment of this mixture with 10 mol % of TFA led to isolation
of 11o in 97% yield over 2 steps, without deprotection of
the Boc group.
Table 3. Synthesis of spiropiperidine derivatives 11a
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. Mechanistic proposal
Initial formation of reactive rhodium(III) species
Cp*Rh(OAc)2 from rhodium precatalyst [Cp*RhCl2]2 was
achieved in the presence of CsOAc. The five-membered
rhodacycle A, generated through a reversible C–H activa-
tion
via
a
base-assisted
concerted
meta-
lation/deprotonation (CMD) pathway,15 underwent a syn
olefin insertion to afford the seven-membered ring inter-
mediate B. β-elimination then occured to provide C,
which led to compound 10, and regenerated the active
catalysis. Cyclisation of enamine 10 into tetracycle 11 was
achieved under acidic conditions either in the reaction
mixture (PG = Bn) or after subsequent treatment with
TFA (PG = Ac, Cbz).
CONCLUSION
In summary, we have developed
a rhodium(III)-
catalyzed synthesis of spiropiperidines by means of aryl
CH activation/intramolecular Heck-type reaction. We
found that the nature of the protecting group on the ni-
trogen atom has a critical influence on the reactivity. We
showed that an electron-withdrawing group on the nitro-
gen (Ac, Cbz) was required to provide complete selectivi-
ty for formation of the enamine. The conditions are mild
and the reaction is general with substrates having both
electron-donating and electron-withdrawing groups on
the aromatic ring. Different linkers and ring size of the N-
heterocycles (6 and 5 membered ring) are tolerated as
well. Finally, the tricyclic spiro enamines prepared by this
method were efficiently converted into tetracyclic N-
heterocycles. Evaluation of the biological activities of
these original structures is currently underway.
aIsolated yield. bYield brsm 99%. cIsolated yield over 2
steps.
To account for the formation of the spiropiperidine de-
rivatives 10 and 11, we postulate the proposed mechanism
depicted in figure 2.
EXPERIMENTAL SECTION
Melting points were measured in capillary tubes and were un-
corrected. Infrared spectra were recorded on a FT-IR spectrome-
ter. Proton (1H) and carbon (13C) NMR spectra were recorded on
300 and 500 MHz spectrometers (13C, 31P, 19F - probe or Dual 13 C
probe). Chemical shifts ( δ ) are reported in parts per million
(ppm) with reference to CDCl3 (1H: 7.26; 13C: 77.13). The following
4
ACS Paragon Plus Environment

Page 5 of 18
The Journal of Organic Chemistry
abbreviations are used for the proton spectra multiplicities: s:
then brine, dried with Na2SO4, and the solvent removed under
vacuum. The crude mixture was purified through silica gel to
afford the corresponding product.
singlet, d: doublet, t: triplet, q: quartet, quint: quintuplet, sept:
septuplet, m: multiplet, br: broad. Coupling constants ( J ) are
reported in Hertz (Hz). The multiplicity of carbons was given
using 2D spectra (HMQC and HMBC). The HRMS data were
measured on MALDI-TOF type of instrument for the high reso-
lution mass spectra (HRMS). Thin-layer chromatography were
performed on silica gel 60 F 254 on aluminum plates and visual-
ized under a UVP Mineralight UVLS-28 lamp (254 nm). Flash
chromatography was performed on silica gel 60 (230 − 400
mesh). All reagents were obtained from commercial suppliers
and were used as received.
1
2
3
4
5
6
7
8
Procedure E : Benzyl deprotection
N-benzyl amine (1 equiv.) was dissolved in 1,2 dichloroethane
(10 mL/mmol) and chilled to 4° C before 1-chloroethyl chlo-
roformate (ACE-Cl) (2 equiv.) was added. The reaction mixture
was stirred at 4° C. for 15 min and allowed to warm to rt before
heating to reflux for 24 h. The solution was concentrated and the
residue was dissolved in dry MeOH (10 mL/mmol). The heated
mixture was concentrated to give the title compound which was
purified through silica gel.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Procedure A: Alkylation
Procedure F: Amine acylation
A solution of phenol (1 equiv.), 4-(chloromethyl)pyridine hy-
drochloride (1.1 equiv.), K2CO3 (2.2 equiv.) in acetonitrile or DMF
(7 mL/mmol phenol), was heated at 60°C overnight. Water was
added and the aqueous layers were extracted with EtOAc (x 3).
The organic layers were combined, washed with brine, and dried
over Na2SO4. The solvent was removed under vacuum and the
crude mixture purified purified by flash column chromatog-
raphy.
To a solution of amine (1 equiv.), triethylamine (4 equiv.) and
catalytic amount of 4-dimethylaminopyridine in CH2Cl2 (14
mL/mmol amine) was added a solution of acetyl chloride (1.5
equiv.) in CH2Cl2 (1.1 mL/mmol AcCl). The reaction stirred at
room temperature for 1h then the reaction was quenched with
saturated NaHCO3. The aqueous layer was extracted with CH2Cl2
(x3), and the combined organic layers were washed with water
then brine, dried with Na2SO4, and the solvent removed under
vacuum. The crude mixture was purified through silica gel to
afford the corresponding product.
Procedure B : Pyridine dearomatization.
To a solution of pyridine derivative (1 equiv.) in acetone (5
mL/mmol) was added benzyl bromide (1.2 equiv.). The reaction
was stirred under reflux overnight. After cooling, the main part
of the acetone was evaporated under reduced pressure. Diiso-
propyl ether was added to the residue and after 1 hour of stirring
the suspension was collected by filtration. The compounds ob-
tained were pure enough and were used without further purifi-
cation in the next step.
In a cooling mixture (-5 °C) of pyridinium (1 equiv.) in metha-
nol (5 mL/mmol) was added portion wise sodium borohydride (2
equiv.). After the end of the addition, the reaction mixture was
stirred for 2 hours at room temperature. The main part of the
solvent was removed under reduced pressure and ethyl acetate
was added. The organic layer was washed with aqueous saturat-
ed NH4Cl, water, brine and dried over MgSO4. The solvent was
evaporated under reduced pressure and the crude product was
purified by flash column chromatography.
Procedure G: Heck-type reaction
A seal tube was charged with a stirbar, amide (1 equiv.),
[RhCp*Cl2]2 (0.025 equiv.) and CsOAc (2 equiv.). The tube was
purged three times by vacuum and argon, then tAmOH (0.2 M)
was added. The vial was sealed and stirred at the indicated tem-
perature for the indicated time. The reaction mixture was con-
centrated in vacuo. The crude residue was purified by column
chromatography to afford the corresponding spirocycle.
Procedure H: Cyclization
To a solution of primary amide (1 equiv.) in dichloromethane
(5 mL/mmol) was added a catalytic amount of TFA. The solution
was stirred at room temperature for 30 min, then the solvent was
removed under vacuo. The crude mixture was purified by col-
umn chromatography to afford the corresponding spirocycle.
Methyl 3-(pyridin-4-ylmethoxy)benzoate (S1). Prepared according
to procedure A from methyl 3-hydroxybenzoate (1.53 g, 10
mmol), 4-(chloromethyl)pyridine hydrochloride (1.80 g, 11
mmol), K2CO3 (2.68 g, 20 mmol) in acetonitrile (46 mL). The
solvent was removed under vacuum and the crude mixture
purified through silica gel (Hept. to Hept./EtOAc 6/4) to afford
the corresponding compound as a white solid (m = 1.58 g, 71%).
1H NMR (300 MHz, CDCl3) δ (ppm): 8.61 (dd, J = 4.3, 1.9 Hz, 2H),
7.66 (td, J =7.7, 1.5 Hz, 1H), 7.61 (dd, J = 2.7, 1.5 Hz, 1H), 7.38-7.31
(m, 3H), 7.15 (ddd, J = 8.2, 2.7, 1.1 Hz, 1H), 5.11 (s, 2H), 3.89 (s,
3H). 13C NMR (75 MHz, CDCl3) δ (ppm) 166.6 (Cq), 158.0 (Cq),
149.9 (CH), 145.7 (Cq), 131.6 (Cq), 129.6 (CH), 122.7 (CH), 121.4
(CH), 120.0 (CH), 114.9 (CH), 68.1 (CH2), 52.2 (CH3). IR υ (neat):
3085-2954, 1707, 1587, 1284 cm-1. MS (ESI, m/z): 244.1 (100)
[M+H]+. HMRS (ESI-TOF) m/z: [M+H]+ Calcd for C14H14NO3+:
244.0974. Found: 244.0974. m.p. = 48-50°C.
Procedure C: Amide synthesis
To a solution of ester (1 equiv.) in ethanol (5.9 mL/mmol) was
added a 3M solution of NaOH (3.5 mL/mmol) at room tempera-
ture. The mixture was stirred for 2 h, then HCl (2N) was added
at 0°C until pH = 2-3. The aqueous layer was extracted with
EtOAc and the solvent was evaporated under vacuum. The crude
mixture was used without purification.
Alternative procedure. To
a mixture of the ester in
THF/MeOH/H2O (v/v = 1/1/1, 8 mL/mmol) was added LiOH (8
equiv.) at room temperature. Same treatment as above.
To a solution of carboxylic acid (1 equiv.) in DMF (3
mL/mmol) was added successively, EDCI (1.1 equiv.), HOBT (1.1
equiv.) and the solution was stirred for 30 min. at room tempera-
ture. The amine (1.1 equiv.) was added then the mixture stirred
for an additional 10 min. iPr2NEt (2.3 equiv.) was added at 0°C,
then the mixture was stirred at overnight at RT. The reaction
mixture was diluted with brine and the aqueous layer extracted
with EtOAc (x3). The organic layer was washed with water then
dried over Na2SO4. The solvent was removed under vaccum. The
crude mixture was purified through silica gel to afford the corre-
sponding amide.
Methyl
3-((1-benzyl-1,2,3,6-tetrahydropyridin-4-
yl)methoxy)benzoate (S2). Prepared according to procedure B
from methyl 3-(pyridin-4-ylmethoxy)benzoate (189 mg, 0.777
mmol) in acetone (3.9 mL) and benzyl bromide (0.115 mL, 0.97
mmol). The crude pyridinium was used without purification.
Pyridinium (278 mg, 0.67 mmol) in methanol (3.9 mL) and
sodium borohydride (55.8 mg, 1.48 mmol). The crude product
was purified by flash column chromatography (Hept. to
Hept./EtOAc 6/4) to afford the title compound (m = 244 mg,
93%). 1H NMR (300 MHz, CDCl3) δ (ppm): 7.63 (ddd, J = 7.7, 1.3,
1.1 Hz, 1H), 7.57 (dd, J = 2.6, 1.5 Hz, 1H), 7.39-7.23 (m, 6H), 7.10
(ddd, J = 8.1, 2.4, 0.9 Hz, 1H), 5.80 (m, 1H), 4.45 (s, 2H), 3.91 (s,
3H), 3.61 (s, 2H), 3.04 (m, 2H), 2.64 (t, J = 5.7 Hz, 2H), 2.26 (m,
2H). 13C NMR (75 MHz, CDCl3) δ (ppm): 166.9 (Cq), 158.8 (Cq),
138.1 (Cq), 132.1 (Cq), 131.3 (Cq), 129.3 (CH), 129.1 (CH), 128.2
Procedure D: Cbz protection
To a solution of N-benzyl amine (1 equiv.) in CH2Cl2 (5
mL/mmol) was added KHCO3 (1 equiv.). Then a solution of
ClCO2Bn (4.5 equiv.) in CH2Cl2 (5 mL/mmol) was added drop-
wise at 0°C. The solution was stirred overnight at room tempera-
ture. The mixture was cooled to room temperature, then poured
into Na2CO3 1M. The aqueous layer was extracted with CH2Cl2
(x3), and the combined organic layers were washed with water
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 18
(CH), 127.1 (CH), 123.4 (CH), 122.0 (CH), 120.0 (CH), 115.0 (CH),
NMR (300 MHz, CDCl3) δ (ppm): 7.64 (ddd, J = 7.8, 1.3, 1Hz, 1H),
71.4 (CH2), 62.6 (CH2), 52.4 (CH2), 52.1 (CH3), 49.4 (CH2), 26.5
(CH2). IR υ (neat): 3062-2754, 1719, 1444, 1274, 1012 cm-1. MS (ESI,
m/z): 338.1 (100) [M+H+]. HRMS (ESI-TOF) m/z: [M+H]+ Calcd
for C21H24NO3 : 338.1756. Found: 338.1754.
3-((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-N-
7.56 (dd, J = 2.7, 1.5 Hz, 1H), 7.34 (dd, J = 8.3, 7.7 Hz, 1H), 7.10
(ddd, J = 8.0, 2.8, 1.0 Hz, 1H), 5.83 (brs, 1H), 4.48 (s, 2H), 4,11 (brs,
1H), 4.00 (brs, 1H), 3.91 (s, 3H), 3.73 (brs, 1H), 3.57 (brs, 1H), 2.34-
2.18 (brm, 2H), 2.12 (brs, 3H). 13C NMR (75 MHz, CDCl3) δ (ppm)
(2 rotamers) 169.3 (Cq), 166.8 (Cq), 158.5 (Cq), 131.8 (Cq), 131.5
(Cq), 129.4 (CH), 122.8 (CH), 122.3 (CH), 120.5 (CH), 120.0 (CH),
114.9 (CH), 71.2 (CH2), 70.9 (CH2), 52.2 (CH3), 45.2 (CH2), 43.0
(CH2), 41.4 (CH2), 37.9 (CH2), , 26.3 (CH2), 25.3 (CH2), 21.8 (CH3),
21.4 (CH3). IR υ (neat): 3022, 1719, 1642, 1278 cm-1. MS (ESI, m/z):
312.2 (100) [M+Na+]. HMRS (ESI-TOF) m/z: [M+Na]+ Calcd for
C16H19NO4Na+: 312.1206. Found: 312.1210.
1
2
3
4
5
6
7
8
+
methoxybenzamide (9a). Prepared according to procedure C
from methyl ester (128.9 mg, 0.382 mmol), NaOH 3M (1.3 mL),
EtOH (2.2 mL). The resulting crude carboxylic acid (0.382
mmol) was dissolved in DMF (1.2 mL) and reacted with EDCI
(80.5 mg, 0.42 mmol), HOBt (56.7 mg, 0.42 mmol),
MeONH2.HCl (35.1 mg, 0.42 mmol), and iPr2NEt (0.15 mL, 0.88
mmol). Purification over silica gel (Hept. to Hept./EtOAc 5/5 to
0/100) afforded the title compound as a yellow oil (m = 89.8 mg,
67% over 2 steps). 1H NMR (300 MHz, CDCl3) δ (ppm): 9.39 (brs,
1H), 7.35-7.23 (m, 8H), 7.03 (m, 1H), 5,75 (m, 1H), 4.40 (s, 2H),
3.85 (s, 3H), 3.59 (s, 2H), 3.01 (m, 2H), 2.62 (t, J = 5.7 Hz, 1H), 2.21
(m, 2H). 13C NMR (75 MHz, CDCl3) δ (ppm): 159.0 (Cq), 137.8
(Cq), 133.0 (Cq), 132.0 (Cq), 129.6 (CH), 129.2 (CH), 128.2 (CH),
127.1 (CH), 123.2 (CH), 119.0 (CH), 118.9 (CH), 71.4 (CH2), 64.4
(CH3), 62.6 (CH2), 52.3 (CH2), 49.4 (CH2), 26.4 (CH2). IR υ (neat):
3196, 3027-2805, 1646, 1579, 1234 cm-1. MS (ESI, m/z): 353.2 (100)
[M+H+]. HMRS (ESI-TOF) m/z: [M+H]+ Calcd for C21H25N2O3+:
353.1865. Found: 353.1871.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-((1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-N-
methoxybenzamide (9b). Prepared according to procedure C
from methyl ester (201 mg, 0.69 mmol), NaOH 3M (2.15 mL),
EtOH (4.1 mL). The resulting crude carboxylic acid (0.41 mmol)
was dissolved in DMF (1.2 mL) and reacted with EDCI (86.3 mg,
0.45 mmol), HOBt (60.8 mg, 0.45 mmol), MeONH2.HCl (37.6
mg, 0.45 mmol), and iPr2NEt (0.17 mL, 0.94 mmol). Purification
over silica gel (DCM to DCM/MeOH 95/5 to 80/20) afforded the
title compound as a white solid (m = 94.4 mg, 45% over 2 steps).
1H NMR (300 MHz, CDCl3) δ (ppm): (2 rotamers) 9.04 (brs, 1H),
7.36-7.24 (m, 3 H), 7.05 (ddd, J = 7.9, 2.8, 1.4 Hz, 1H), 5.82 (m, 1H
major rotamer), 5.79 (m, 1H minor rotamer), 4.46 (s, 2H), 4.10
(m, 1H major rotamer), 3.99 (m, 1H minor rotamer), 3.88 (s, 3H),
3.73 (t, J = 5.7 Hz, 1H minor rotamer), 3.57 (t, J = 5.7 Hz, 1H major
rotamer), 2.27 (m, 1H major rotamer), 2.20 (m, 1H minor rota-
4-benzyl-2-methoxy-3,4,5,6-tetrahydro-7H-3,6a-
methanobenzofuro[4,3-ef][1,3]diazonin-1(2H)-one (11a). Prepared
according to procedure D from amide (32 mg, 0.0908 mmol),
[RhCp*Cl2]2 (1.4 mg, 0.0023 mmol) and CsOAc (34.9 mg, 0.181
mmol) in tAmOH (0.45 mL) at 60°C overnight. The crude mix-
ture was purified over silica gel (Hept. to EtOAc) to afford a
mer) 2.13 (s, 3H, major rotamer), 2.10 (s, 3H, minor rotamer). 13
C
NMR (75 MHz, CDCl3) δ (ppm) (2 rotamers) 169.5 (Cq), 158.7
(Cq), 133.6 (Cq), 133.2 (Cq), 131.8 (Cq), 129.6 (CH), 122.5 (CH),
120.5 (CH), 119.3 (CH), 118.7 (CH), 113.1 (CH), 71.0 (CH2), 70.9
(CH2), 64.3 (CH3), 45.2 (CH2), 43.0 (CH2), 41.5 (CH2), 37.9 (CH2),
26.2 (CH2), 25.4 (CH2), 21.8 (CH3), 21.4 (CH3). IR υ (neat): 3022,
2835, 1719, 1642, 1278 cm-1. MS (ESI, m/z): 305.1 (100) [M+H+].
1
yellow oil (m = 17.5 mg, 55%). H NMR (300 MHz, CDCl3) δ
(ppm): 7.97 (dd, J = 8.1, 1.1 Hz, 1H), 7.39-7.22 (m, 6H), 6.96 (dd, J
= 7.9, 1.1 Hz, 1H), 5.05 (dd, J = 4.9, 2.4 Hz, 1H), 4.33 (d, J = 8.4 Hz,
1H), 4.21 (d, J = 14.0 Hz, 1H), 4.16 (d, J = 8.5 Hz, 1H), 3.70 (s, 3H),
3.69 (d, J = 14.0 Hz, 1H), 2.60 (ddd, J = 13.1, 4.1, 2.6 Hz, 1H), 2.43
(dd, J = 13.1, 4.8 Hz, 1H), 2.30 (ddd, J = 13.0, 11.3, 3.3 Hz, 1H), 2.14
(td, J = 13.1, 2.3 Hz, 1H), 1.88-1.69 (m, 2H). 13C NMR (75 MHz,
CDCl3) δ (ppm) 165.3 (Cq), 158.7 (Cq), 138.9 (Cq), 131.0 (Cq), 128.6
(CH), 128.2 (CH), 127.0 (CH), 123.8 (CH), 113.3 (CH), 82.9 (CH2),
77.7 (NCHN), 61.3 (CH3), 59.3 (CH2), 43.7 (Cq), 41.9 (CH2), 36.1
(CH2), 34.1 (CH2). IR υ (neat): 3005-2837, 1638, 1587, cm-1. MS
(ESI, m/z): 351.2 (100) [M+H+]. HMRS (ESI-TOF) m/z: [M+H]+
Calcd for C21H23N2O3+: 351.1703. Found: 351.1687. m.p. = 154-156
°C.
+
HMRS (ESI-TOF) m/z: [M+H]+ Calcd for C16H21N2O4 : 305.1501
Found: 305.1505.
1'-acetyl-2',3'-dihydro-1'H,2H-spiro[benzofuran-3,4'-pyridine]-4-
carboxamide (10b). Prepared according to procedure G from
amide (56 mg, 0.184 mmol), [RhCp*Cl2]2 (2.84 mg, 0.0046 mmol)
and CsOAc (70.6 mg, 0.368 mmol) in t-AmOH (0.92 mL) at 60°C
overnight. The crude mixture was purified over silica gel (Hept.
to EtOAc) to afford a white solid (m = 40.7 mg, 82%).1H NMR
(300 MHz, CDCl3) δ (ppm): (2 rotamers 60/40) 7.31 (d, J = 8.4 Hz,
1H, minor), 7.21 (t, J = 7.8 Hz, 1H, minor), 7.20 (t, J = 7.8 Hz, 1H,
major), 7.05 (d, J = 7.9 Hz, 1H, minor), 7.03 (t, J = 7.9 Hz, 1H,
major), 6.92 (t, J = 7.8 Hz, 1H, major), 6.91 (7.03 (t, J = 7.9 Hz, 1H,
minor), 6.75 (d, J = 8.5 Hz, 1H major + 1H minor), 6.09 (brs, 1H
minor), 5.98 (brs, 2H major + 1H minor), 5.01 (dd, J = 8.4, 1.8 Hz,
1H minor), 4.95 (dd, J = 8.3, 1.8 Hz, 1H major), 4.51 (ddd, J = 13.8,
4.3, 2.7 Hz, 1H major), 4.32 (d, J = 8.8 Hz, 1H major), 4.28 (d, J =
9.0 Hz, 1H minor), 4.22-4.14 (m, 1H major + 1H minor), 3.91 (ddd,
J = 12.7, 4.0, 3.1 Hz, 1H minor), 3.35 (ddd, J = 13.4, 12.5, 2.8 Hz, 1H
minor), 2.96 (ddd, J = 14.0, 13.4, 3.1 Hz, 1H minor), 2.75 (ddd, J =
13.8, 13.3, 4.3 Hz, 1H minor), 2.51 (ddt, J = 13.6, 4.5, 1.5 Hz, 1H
major), 2.20 (s, 3H major), 2.18 (s, 3H minor), 2.04-1.91 (m, 1H
major + 1H minor). 13C NMR (75 MHz, CDCl3) δ (ppm) (2 rota-
mers) 170.2 (Cq), 169.6 (Cq), 168.4 (Cq), 168.3 (Cq), 160.9 (Cq),
160.7 (Cq), 133.2 (Cq), 132.7 (Cq), 131.2 (Cq), 130.7 (Cq), 129.1 (CH),
129.0 (CH), 127.2 (CH), 126.0 (CH), 120.0 (CH), 119.8 (CH), 112.5
(CH), 112.3 (CH), 109.4 (CH), 108.9 (CH), 81.8 (CH2), 81.5 (CH2),
45.4 (Cq), 45.2 (Cq), 41.9 (CH2), 37.8 (CH2), 32.0 (CH2), 31.2
(CH2), 21.9 (CH3), 21.4 (CH3). IR υ (neat): 3358, 3209, 2974-2875,
1659, 1634, 1396 cm-1. MS (ESI, m/z): 273.1 (100) [M+H+]. HMRS
(ESI-TOF) m/z: [M+H]+ Calcd for C15H17N2O3+: 273.1240. Found:
273.1239. m.p. = 196-199 °C.
Methyl 3-((1,2,3,6-tetrahydropyridin-4-yl)methoxy)benzoate (S3).
Prepared according to procedure E from N-benzyl amine (137.3
mg, 0.407 mmol), 1,2 dichloroethane (4.1 mL), 1-chloroethyl
chloroformate (ACE-Cl) (0.088 mL, 0.814 mmol) then MeOH (4.1
mL). The mixture was concentrated to give the title compound
which was purified through silica gel (CH2Cl2 to CH2Cl2 /MeOH
1
95/5) to afford a beige solid (m = 99.6 mg, 99%). H NMR (300
MHz, CDCl3) δ (ppm): 9.87 (brs, 1H), 7.59 (ddd, J = 7.4, 1.1, 1.1 Hz,
1H), 7.47 (dd, J = 2.7, 1.5 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.02
(ddd, J = 8.3, 2.8, 1.0 Hz, 1H), 5.79 (brs, 1H), 4.43 (s, 2H), 3.85 (s,
3H), 3.69 (brm, 2H), 3.31 (brm, 2H), 2.51 (brm, 2H). 13C NMR (75
MHz, CDCl3) δ (ppm) 166.7 (Cq), 158.1 (Cq), 133.4 (Cq), 131.5 (Cq),
129.6 (CH), 122.6 (CH), 119.9 (CH), 116.7 (CH), 114.9 (CH), 70.1
(CH2), 52.2 (CH3), 41.2 (CH2), 40.4 (CH2), 22.2 (CH2). IR υ (neat):
3042, 2965-2644, 1716, 1583, 1451, 1287 cm-1. MS (ESI, m/z): 248.1
(100) [M+H+]. HMRS (ESI-TOF) m/z: [M+H]+ Calcd for
C14H18NO3+: 248.1287. Found: 248.1288. m.p. = 134-135 °C.
Methyl
3-((1-acetyl-1,2,3,6-tetrahydropyridin-4-
yl)methoxy)benzoate (S4). Prepared according to procedure F
from amine (183 mg, 0.740 mmol), triethylamine (0.41 mL, 2.9
mmol), 4-dimethylaminopyridine (cat.), CH2Cl2 (10.4 mL) and a
solution of acetyl chloride (0.078 ml, 1.11 mmol) in CH2Cl2 (1.3
mL). The crude mixture was purified over silica gel (DCM to
4-acetyl-3,4,5,6-tetrahydro-7H-3,6a-methanobenzofuro[4,3-
ef][1,3]diazonin-1(2H)-one (11b). Prepared according to procedure
H from amide (42.3 mg, 0.155 mmol), CH2Cl2 (0.77 mL) and TFA
1
DCM/MeOH (9/1)) to afford a yellow oil (m = 201 mg, 93%). H
6
ACS Paragon Plus Environment

Page 7 of 18
The Journal of Organic Chemistry
(87 µL, 0.0115 mmol). The crude mixture was purified over silica
(CH), 112.4 (CH), 112.3 (CH), 108.0 (CH), 107.3 (CH), 81.9 (CH2),
81.8 (CH2), 67.8 (CH2), 45.0 (Cq), 44.9 (Cq), 39.9 (CH2), 39.6
(CH2), 31.5 (CH2), 31.2 (CH2). IR υ (neat): 3335, 2932-2875, 1699,
1651, 1340 cm-1. MS (ESI, m/z): 365.1 (100) [M+H+]. HMRS (ESI-
TOF) m/z: [M+H]+ Calcd for C21H21N2O4 : 365.1490. Found:
365.1490. m.p. = 75-77 °C.
gel (CH2Cl2 to CH2Cl2 /MeOH 95/5) to afford a white solid (m =
1
2
3
4
5
6
7
8
1
30.4 mg, 72%). H NMR (300 MHz, CDCl3) δ (ppm): 7.91 (dd, J =
8.1, 0.8 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.02 (dd, J = 8.0, 0.9 Hz,
1H), 6.64 (d, J = 6.5 Hz, 1H), 6.22 (m, 1H), 4.33 (d, J = 8.5 Hz, 1H),
4.2 (d, J = 8.5 Hz, 1H), 3.63 (m, 1H), 3.13 (ddd, J = 14.3, 13.0, 2.8 Hz,
1H), 2.29-2.12 (m, 2H), 2.10 (s, 3H), 2.00 (m, 1H), 1.78 (dt, J = 13.1,
4.6 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ (ppm) 170.1 (Cq), 167.3
(Cq), 159.2 (Cq), 131.0 (Cq), 82.8 (CH2), 57.2 (CH), 44.7 (Cq), 37.9
(CH2), 35.7 (CH2), 32.7 (CH2), 21.8 (CH3). IR υ (neat): 2983, 1643,
1402, 1214 cm-1. MS (ESI, m/z): 273.1 (100) [M+H+]. HMRS (ESI-
+
Benzyl 1-oxo-2,3,5,6-tetrahydro-7H-3,6a-methanobenzofuro[4,3-
ef][1,3]diazonine-4(1H)-carboxylate (11c). Prepared according to
procedure H from amide (70 mg, 0.192 mmol), CH2Cl2 (0.96 mL)
and TFA (146 µL, 0.0192 mmol). The crude mixture was purified
over silica gel (CH2Cl2 to CH2Cl2 /MeOH 90/10) to afford color-
9
+
1
TOF) m/z: [M+H]+ Calcd for C15H17N2O3 : 273.1240. Found:
less oil (m = 69 mg, 98%). H NMR (300 MHz, CDCl3) δ (ppm):
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
273.1239. m.p. = 208-210 °C.
(2 rotamers : 64/36) : 8.21 (brs, 1H min.), 7.91 (d, J = 8.1 Hz, 1H),
7.62 (brs, 1H, maj.), 7.50-7.27 (m, 6H), 7.08 (d, J = 7.9 Hz, 1H),
5.93 (brm, 1H, maj.), 5.86 (brs, 1H, min.), 5.34-5.10 (m, 2H), 4.36
(d, J = 8.3 Hz, 1H), 4.22 (d, J = 8.5 Hz, 1H), 4.06 (brm, 1H), 2.84
(brm, 1H), 2.30-2.11 (brm, 2H), 1.98 (brm, 1H), 1.79 (ddd, J = 13.1,
12.6, 4.9 Hz, 1H). 13C NMR (75 MHz, CDCl3) rotamers δ (ppm)
169.2 (Cq), 168.7 (Cq), 160.6 (Cq), 160.1 (Cq), 159.3 (Cq), 135.6
(Cq), 129.2 (CH), 128.6 (CH), 128.4 (CH), 128.1 (CH), 114.9 (CH),
114.8 (CH), 82.8 (CH2), 68.4 (CH2), 68.1 (CH2), 60.6 (CH), 44.4
(Cq), 35.7 (CH2), 34.9 (CH2), 32.5 (CH2). IR υ (neat): 3287, 3010-
2872, 1695, 1645, 1586, 1398, 1293, 1211 cm-1. MS (ESI, m/z): 365.1
(100) [M+H+]. HMRS (ESI-TOF) m/z: [M+H]+ Calcd for
Benzyl
4-((3-(methoxycarbonyl)phenoxy)methyl)-3,6-
dihydropyridine-1(2H)-carboxylate (S5). Prepared according to
procedure D from N-benzyl amine (200 mg, 0.593 mmol) in
CH2Cl2 (2.9 mL), KHCO3 (59.4 mg, 0.593 mmol) and ClCO2Bn
(0.38 mL, 2.67 mmol) in CH2Cl2 (2.9 mL). The crude mixture was
over silica gel (Hept. to Hept./EtOAc 7/3) to afford a colorless oil
(m = 196 mg, 87%). 1H NMR (300 MHz, CDCl3) δ (ppm): 7.64 (td,
J = 7.6, 1.3 Hz, 1H), 7.56 (dd, J = 2.7, 1.5 Hz, 1H), 7.40-7.29 (m,
6H), 7.10 (dd, J = 8.2, 2.6 Hz, 1H), 5.80 (d, J = 14.5 Hz, 1H), 5.16 (s,
2H), 4.46 (s, 2H), 4.03 (s, 2H), 3.91 (s, 3H), 3.64 (t, J = 5.6 Hz,
2H), 2.23 (m, 2H). 13C NMR (75 MHz, CDCl3) δ (ppm) 166.8 (Cq),
158.5 (Cq), 136.7 (Cq), 132.4 and 132.2 (Cq), 131.4 (2xCq), 129.4
(CH), 128.4 (CH), 128.0 (CH), 127.9 (CH), 122.2 (CH), 121.4 (CH),
120.0 (CH), 114.9 (CH), 71.1 (CH2), 67.1 (CH2), 52.2 (CH3), 43.1
(CH2), 40.4 and 40.1 (CH2), 25.8 and 25.6 (CH2). IR υ (neat): 3032-
2950, 1699, 1430, 1275 cm-1. MS (ESI, m/z): 382.2 (100) [M+H+].
+
C21H21N2O4 : 365.1496. Found: 365.1497.
Methyl 4-methoxy-3-(pyridin-4-ylmethoxy)benzoate (S6). To a
solution of methyl 3-hydroxy-4-methoxybenzoate (300 mg, 1.65
mmol) in DMF (11.5 mL) was added NaH 60% (144.8 mg, 3.62
mmol) at 0°C. After stirring at 0°C for 30 min, 4-
(chloromethyl)pyridine hydrochloride (297 mg, 1.81 mmol) was
added and the reaction was stirred overnight at room tempera-
ture. Saturated NH4Cl was added, and the aqueous layer was
extracted with EtOAc (x3). The combined organic layers were
washed with water, then brine and dried over Na2SO4. The sol-
vent was removed under vacuum and the crude mixture purified
through silica gel (Hept. to Hept./EtOAc 5/5 to 3/7) to afford the
corresponding compound as a white solid (m = 331.6 mg, 74%).
1H NMR (300 MHz, CDCl3) δ (ppm): 8.62 (d, J = 5.6 Hz, 2H), 7.72
(dd, J = 8.6, 2.0 Hz, 1H), 7.54 (d, J = 2.1 Hz, 1H), 7.40 (dd, J = 5.2,
1.8 Hz, 2H), 6.93 (d, J = 8.5 Hz, 1H), 5.19 (s, 2H), 3.96 (s, 3H), 3.87
(s, 3H). 13C NMR (75 MHz, CDCl3) δ (ppm) 166.6 (Cq), 153.5 (Cq),
149.8 (CH), 147.1 (Cq), 146.0 (Cq), 124.5 (CH), 122.6 (Cq), 121.5
(CH), 114.4 (CH), 110.8 (CH), 69.1 (CH2), 56.0 (CH3), 52.0 (CH3).
IR υ (neat): 3061-2841, 1703, 1218 cm-1. MS (ESI, m/z): 274.1 (100)
+
HMRS (ESI-TOF) m/z: [M+H]+ Calcd for C22H24NO5 : 382.1654.
Found: 382.1659.
Benzyl
4-((3-(methoxycarbamoyl)phenoxy)methyl)-3,6-
dihydropyridine-1(2H)-carboxylate (9c). Prepared according to
procedure C from methyl ester (196 mg, 0.514 mmol) in a mix-
ture of THF/MeOH/H2O (v/v = 1/1/1, 15.3 mL), LiOH (98.4 mg,
4.11 mmol) at room temperature. The crude mixture was used
without purification. The carboxylic acid (0.514 mmol) was dis-
solved in DMF (1.54 mL) and reacted with EDCI (108.3 mg, 0.565
mmol), HOBt (76.3 mg, 0.565 mmol), MeONH2.HCl (47.2 mg,
0.565 mmol), and iPr2NEt (0.20 mL, 1.18 mmol). Purification over
silica gel (Hept. to Hept./EtOAc 5/5) afforded the title com-
pound as a colorless oil (m = 171.1 mg, 84% over 2 steps). 1H NMR
(300 MHz, CDCl3) δ (ppm): 9.46 (brs, 1H), 7.39-7.25 (m, 8H), 7.02
(m, 1H), 5.75 (brm, 1H), 5.13 (s, 2H), 4.42 (brs, 2H), 3.99 (brs, 2H),
3.85 (s, 3H), 3.6 (t, J = 5.7 Hz, 2H), 2.18 (m, 2H). 13C NMR (75
MHz, CDCl3) Due to rotamers some signals appears as pears δ
(ppm) 165.9 (Cq), 158.7 (Cq), 155.5 (Cq), 136.6 (Cq), 133.1 (Cq),
132.3 (Cq), 129.6 (CH), 128.4 (CH), 128.0 (CH), 127.8 (CH), 122.1
and 121.5 (CH), 119.2 (CH), 118.8 (CH), 113.1 (CH), 71.1 (CH2), 67.1
(CH2), 64.3 (CH3), 43.1 (CH2), 40.3 and 40.1 (CH2), 25.7 and 25.5
(CH2). IR υ (neat): 3212, 2935, 1697, 1665, 1428, 1232 cm-1. MS (ESI,
m/z): 397.2 (100) [M+H+]. HMRS (ESI-TOF) m/z: [M+H]+ Calcd
+
[M+H+]. HMRS (ESI-TOF) m/z: [M+H]+ Calcd for C15H16NO4 :
274.1074. Found: 274.1066. m.p. = 129-130 °C.
Methyl
3-((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-4-
methoxybenzoate (S7). Prepared according to procedure B from
methyl 4-methoxy-3-(pyridin-4-ylmethoxy)benzoate (365.1 mg,
1.36 mmol) in acetone (6.80 mL) and benzyl bromide (0.20 mL,
1.67 mmol). The crude pyridinium was used without purification.
The crude pyridinium was dissolved in methanol (6.8 mL) and
sodium borohydride (113.4 mg, 2.99 mmol) was added. The crude
product was purified by flash column chromatography (Hept. to
Hept./EtOAc 5/5) to afford the title compound as a beige solid
(m = 494 mg, 99%).1H NMR (300 MHz, CDCl3) δ (ppm): 7.67
(dd, J = 8.4, 2.0 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.41-7.26 (m, 5H),
6.88 (d, J = 8.5 Hz, 1H), 5.81 (m, 1H), 4.53 (s, 2H), 3.90 (s, 3H),
3.88 (s, 3H), 3.64 (brs, 2H), 3.03 (brs, 2H), 2.64 (t, J = 5.7 Hz, 2H),
2.27 (s, 2H). 13C NMR (75 MHz, CDCl3) δ (ppm): 166.8 (Cq), 153.5
(Cq), 147.8 (Cq), 132.0 (Cq), 129.2 (CH), 128.2 (CH), 127.1 (CH),
123.7 (CH), 123.4 (CH), 122.5 (Cq), 114.3 (CH), 110.6 (CH), 72.3
(CH2), 62.5 (CH2), 55.9 (CH3), 52.4 (CH2), 51.9 (CH3), 49.4 (CH2),
26.4 (CH2). IR υ (neat): 2940-2718, 1707, 1267, 1213, 1130 cm-1. MS
(ESI, m/z): 368.2 (100) [M+H+]. HMRS (ESI-TOF) m/z: [M+H]+
+
for C22H25N2O5 : 397.1763. Found: 397.1776.
Benzyl
4-carbamoyl-2',3'-dihydro-1'H,2H-spiro[benzofuran-3,4'-
pyridine]-1'-carboxylate (10c). Prepared according to procedure G
from amide (51.4 mg, 0.130 mmol), [RhCp*Cl2]2 (2.0 mg, 0.0032
mmol) and CsOAc (49.5 mg, 0.259 mmol) in tAmOH (0.65 mL)
at 60°C overnight. The crude mixture was purified over silica gel
(Hept. to Hept/EtOAc 5/5) to afford a white solid (m = 37.5 mg,
80%). 1H NMR (300 MHz, CDCl3) δ (ppm): (2 rotamers) 7.42-7.28
(m, 5H), 7.19 (t, J = 7.6 Hz, 1H), 7.08-6.95 (m, 2H), 6.90 (d, J = 7.8
Hz, 1H), 6.57 (brs, 1H), 6.16 (brs, 1H), 6.04 (brs, 1H), 5.98 (brs,
1H), 5.26-5.07 (m, 2H), 4.94 (d, J = 8.7 Hz, 1H), 4.84 (d, J = 8.2
Hz, 1H), 4.33-4.10 (m, 3H), 3.16 (m, 1H), 2.61 (m, 1H), 1.92 (dd, J =
13.1, 12.7 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ (ppm) (2 rotamers)
170.1 (Cq), 169.8 (Cq), 160.7 (Cq), 153.5 (Cq), 152.9 (Cq), 135.8
(Cq), 133.1 (Cq), 132.9 (Cq), 131.0 (Cq), 130.9 (Cq), 129.0 (CH),
128.5 (CH), 128.3 (CH), 128.1 (CH), 127.3 (CH), 126.5 (CH), 120.0
+
Calcd for C22H26NO4 : 368.1862. Found: 368.1847. m.p. = 110-112
°C.
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 18
Methyl
4-methoxy-3-((1,2,3,6-tetrahydropyridin-4-
8.5 Hz 1H, minor), 7.09 (d, J = 8.5 Hz 1H, minor), 7.06 (d, J = 8.9
yl)methoxy)benzoate (S8). Prepared according to procedure E
from N-benzyl amine (453.7 mg, 1.235 mmol), 1,2 dichloroethane
(12.3 mL), 1-chloroethyl chloroformate (ACE-Cl) (0.27 mL, 2.47
mmol) then MeOH (12.3 mL). The mixture was concentrated to
give the title compound as a beige solid which was used without
Hz, 1H, major), 6.82-6.63 (m, 2H), 6.27-5.70 (m, 2H, NH2), 4.97
(dd, J = 1.7, 8.3 Hz, 1H, minor), 4.89 (dd, J = 1.9, 8.4 Hz, 1H, ma-
jor), 4.49 (m, 1H), 4.31 (dd, J = 8.9, 10.9 Hz, 1H), 4.19 (ddd, J =
1.50, 5.30, 8.9 Hz, 1H), 3.96-3.77 (m, 1H), 3.84 (s, 3H), 3.30 (dt, J =
2.9, 12.7 Hz, 1H, minor), 2.90 (dt, J = 3.1, 13.7 Hz, 1H, major), 2.71
(dt, J = 4.4, 13.6 Hz, 1H, minor), 2.50 (dt, J = 4.5, 13.6 Hz, 1H,
major), 2.14 (s, 3H, major), 2.13 (s, 3H, minor), 1.98-1.84 (m, 1H).
13C NMR (75 MHz, CDCl3) δ (ppm) (2 rotamers): 169.7 (Cq), 169.2
(Cq), 168.5 (Cq), 146.9 (Cq), 132.6 (Cq), 127.0 (Cq), 125.9 (Cq),
125.0 (Cq), 124.5 (CH), 121.9 (CH), 121.6 (CH), 111.2 (CH), 111.1
(CH), 109.4 (CH), 109.0 (CH), 82.4 (CH2), 82.1 (CH2), 56.0 (CH3),
46.2 (Cq), 45.9 (Cq), 42.9 (CH2), 37.8 (CH2), 31.7 (CH2), 30.9
(CH2), 21.9 (CH3), 21.4 (CH3). IR υ (neat): 3344, 3159-2915, 1615,
1388, 1279 cm-1. MS (ESI, m/z): 303.3 (100) [M+H+]. HMRS (ESI-
1
2
3
4
5
6
7
8
1
purification (m = 339.0 mg, 99%). H NMR (300 MHz, CDCl3) δ
(ppm): 9.90 (brs, 1H), 7.69 (dd, J = 8.4, 1.9 Hz, 1H), 7.51 (d, J = 2.1
Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 5.87 (s, 1H), 4.53 (s, 2H), 3.90 (s,
3H), 3.87 (s, 3H), 3.73 (brs, 2H), 3.35 (brs, 2H), 2.59 (brs, 2H). 13
C
NMR (75 MHz, CDCl3) δ (ppm) 166.6 (Cq), 153.6 (Cq), 147.1 (Cq),
133.4 (Cq), 124.4 (CH), 122.6 (Cq), 116.9 (CH), 114.7 (CH), 110.8
(CH), 71.3 (CH2), 55.9 (CH3), 52.0 (CH3), 41.2 (CH2), 40.4 (CH2),
22.1 (CH2). IR υ (neat): 2937-2571, 1721, 1266, 1213 cm-1. MS (ESI,
m/z): 278.1 (100) [M+H+]. HMRS (ESI-TOF) m/z: [M+H]+ Calcd
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
+
for C15H20NO4 : 278.1392. Found: 278.1390. m.p. = 196-197 °C.
TOF) m/z: [M+H]+ Calcd for C16H19N2O2 : 303.1345. Found:
303.1339.
4-acetyl-9-methoxy-3,4,5,6-tetrahydro-7H-3,6a-
Methyl
3-((1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-4-
methoxybenzoate (S9). Prepared according to procedure F from
amine (339 mg, 1.23 mmol), triethylamine (0.79 mL, 5.85 mmol),
4-dimethylaminopyridine (cat.), CH2Cl2 (12.3 mL) and a solution
of acetyl chloride (0.15 mL, 2.19 mmol) in CH2Cl2 (2.4 mL). The
crude mixture was purified over silica gel (Hept./EtOAc 30/70 to
methanobenzofuro[4,3-ef][1,3]diazonin-1(2H)-one (11d). Prepared
according to procedure H from amide (31.6 mg, 0.104 mmol),
CH2Cl2 (0.7 mL) and TFA (79 µL, 0.0104 mmol). The crude mix-
ture was purified over silica gel (CH2Cl2 to CH2Cl2 /MeOH 90/10)
1
1
0/100) to afford a yellow solid (m = 297 mg, 75%). H NMR (300
to afford a yellow oil (m = 29.7 mg, 94%). H NMR (300 MHz,
MHz, CDCl3) δ (ppm): (2 rotamers) 7.60 (dd, J = 8.5, 2.0 Hz, 1H),
7.46 (t, J = 1.8 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 5.77 (m, 1H major),
5.73 (m, 1H minor), 4.45 (s, 2H), 4,01 (brm, 1H major), 3.90 (brm,
1H minor), 3.83 (s, 3H), 3.79 (s, 3H), 3.64 (t, J = 5.8 Hz, 1H mi-
nor), 3.48 (t, J = 5.8 Hz, 1H major), 2.22 (brm, 1H, major), 2.15
(brm, 1H minor), 2.04 (s, 3H major), 2.01 (s, 3H minor). 13C NMR
(75 MHz, CDCl3) δ (ppm) (2 rotamers) 169.0 (Cq), 168.9 (Cq),
166.4 (Cq), 153.3 (Cq), 147.3 (Cq), 133.4 (Cq), 131.6 (Cq), 123.8
(CH), 122.5 (CH), 122.3 (Cq), 120.4 (CH), 114.2 (CH), 114.0 (CH),
110.5 (CH), 71.9 (CH2), 71.5 (CH2), 55.7 (CH3), 51.7 (CH3), 44.9
(CH2), 42.7 (CH2), 41.2 (CH2), 37.6 (CH2), 26.0 (CH2), 25.2 (CH2),
21.6 (CH3), 21.2 (CH3). IR υ (neat): 3022-2839, 1707, 1620, 1209 cm-
1. MS (ESI, m/z): 320.1 (100) [M+H+]. HMRS (ESI-TOF) m/z:
CDCl3) δ (ppm): (2 rotamers, 80/20) 8.09 (brs, 1H, minor), 7.87
(d, J = 8.8 Hz, 1H, major+minor), 6.86 (d, J = 8.9 Hz, 1H, ma-
jor+minor), 6.83 (m, major), 6.60 (brs, 1H, NH), 6.16 (brm, 1H,
major), 5.46 (brs, 1H, minor), 4.46 (m, minor), 4.33 (d, J = 8.5 Hz,
1H), 4.18 (d, J = 8.5 Hz, 1H), 3.88 (s, 3H major+minor), 3.57 (m,
1H, major), 3.09 (td, J = 2.3, 13.6 Hz, 1H, major), 2.55 (td, J = 2.7,
13.9 Hz, 1H, minor), 2.29-1.89 (m, 3H), 2.05 (s, 3H), 1.72 (dt, J =
4.8, 13.2 Hz, 1H, major), 1.64 (dt, J = 4.6, 13.3 Hz, 1H, minor). 13C
NMR (75 MHz, CDCl3) δ (ppm): (2 rotamers) 170.3 (Cq), 167.6
(Cq), 148.4 (Cq), 146.6 (Cq), 132.1 (Cq), 126.6 (CH), 120.9 (Cq),
112.0 (CH), 83.4 (CH2), 62.9 (CH), 57.1 (CH2), 56.1 (CH2), 45.4
(Cq), 38.1 (CH2), 35.8 (CH2), 35.2 (CH2), 33.7 (CH2), 32.9 (CH2),
32.6 (CH2), 21.7 (CH3), 21.1 (CH3). IR υ (neat): 3405, 3028-2794,
1713, 1604, 1436, 1283, 1235, 1106, 908 cm-1. MS (ESI, m/z): 303.3
(100) [M+H+]. HMRS (ESI-TOF) m/z: [M+H]+ Calcd for
+
[M+H]+ Calcd for C17H22NO5 : 320.1498. Found: 320.1486. m.p. =
116-117 °C.
+
3-((1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-N,4-
dimethoxybenzamide (9d). Prepared according to procedure C
from methyl ester (297 mg, 0.93 mmol), LiOH (178.2 mg, 7.44
mmol), MeOH (3.7 mL) H2O (3.7 mL). The resulting crude car-
boxylic acid (0.93 mmol) was dissolved in DMF (2.8 mL) and
reacted with EDCI (158.8 mg, 1.02 mmol), HOBt (156.7 mg, 1.02
mmol), MeONH2.HCl (85.4 mg, 1.02 mmol), and iPr2NEt (0.37
mL, 2.11 mmol). Purification over silica gel (DCM to
DCM/MeOH 95/5) afforded the title compound as a white solid
C16H19N2O4 : 303.1345. Found: 303.1342.
Methyl 7-(pyridin-4-ylmethoxy)benzo[d][1,3]dioxole-5-carboxylate
(S10). Prepared according to procedure A from methyl 7-
hydroxybenzo[d][1,3]dioxole-5-carboxylate (368 mg, 1.87 mmol),
4-(chloromethyl)pyridine hydrochloride (338.4 mg, 2.06 mmol),
K2CO3 (570 mg, 4.13 mmol) in acetonitrile (9.4 mL). The solvent
was removed under vacuum and the crude mixture purified
through silica gel (Hept. to Hept./EtOAc 5/5) to afford the cor-
1
responding compound as a white solid (m = 420 mg, 78%). H
1
(m = 82.9 mg, 27% over 2 steps). H NMR (300 MHz, DMSO) δ
NMR (300 MHz, CDCl3) δ (ppm): 8.62 (d, J = 5.0 Hz, 2H), 7.36 (d,
J = 5.0 Hz, 2H), 7.35 (s, 1H), 7.23 (d, J = 1.4 Hz, 1H), 6.07 (s, 2H),
5.21 (s, 2H), 3.87 (s, 3H). 13C NMR (75 MHz, CDCl3) δ (ppm) 166.1
(Cq), 150.1 (CH), 149.0 (Cq), 145.4 (Cq), 141.8 (Cq), 139.8 (Cq),
124.5 (Cq), 121.5 (CH), 112.0 (CH), 104.5 (CH), 102.3 (CH2), 69.6
(CH2), 52.2 (CH3). IR υ (neat): 2954, 1720, 1709, 1432, 1104 cm-1.
MS (ESI, m/z): 288.1 (100) [M+H+]. HMRS (ESI-TOF) m/z:
(ppm): (2 rotamers) 7.40-7.35 (m, 2H), 7.03 (d, J = 8.0 Hz, 1H),
5.82 (m, 1H), 4.48 (s, 2H), 3.99 (m, 2H minor), 3.94 (m, 2H ma-
jor), 3.81 (s, 3H), 3.69 (s, 3H), 3.56 (t, J = 5.7 Hz, 2H minor), 3.52
(t, J = 5.8 Hz, 2H major), 2.21 (m, 2H major), 2.11 (m, 2H minor),
2.04 (s, 3H major), 2.00 (s, 3H minor). 13C NMR (75 MHz, CDCl3)
δ (ppm) 2 rotamers 168.5 (Cq), 168.4 (Cq), 151.9 (Cq), 147.3 (Cq),
132.7 (Cq), 132.3 (Cq), 124.2 (Cq), 121.9 (CH), 121.3 (CH), 120.6
(CH), 112.2 (CH), 111.3 (CH), 71.4 (CH2), 71.2 (CH2), 63.2 (CH3),
55.7 (CH3), 44.5 (CH2), 42.3 (CH2), 40.8 (CH2), 37.2 (CH2), 26.0
(CH2), 25.2 (CH2), 21.7 (CH3), 21.3 (CH3). IR υ (neat): 3172, 2966-
2853, 1663, 1602, 1267 cm-1. MS (ESI, m/z): 335.1 (100) [M+H+].
+
[M+H]+ Calcd for C15H14NO5 : 288.0872. Found: 288.0862. m.p. =
118-119°C.
Methyl
yl)methoxy)benzo[d][1,3]dioxole-5-carboxylate (S11). Prepared
according to procedure from methyl 7-(pyridin-4-
7-((1-benzyl-1,2,3,6-tetrahydropyridin-4-
B
+
HMRS (ESI-TOF) m/z: [M+H]+ Calcd for C17H23N2O5 : 335.1608
ylmethoxy)benzo[d][1,3]dioxole-5-carboxylate (425 mg, 1.48
mmol) in acetone (7.4 mL) and benzyl bromide (0.22 mL, 1.85
mmol). The crude pyridinium was used without purification.
Pyridinium (1.48 mmol) in methanol (14.8 mL) and sodium
borohydride (123.3 mg, 3.25 mmol). The crude product was puri-
fied by flash column chromatography (Hept. to Hept./EtOAc 8/2
to 5/5) to afford the title compound as a colorless oil (m = 483
Found: 335.1607. m.p. = 190-191 °C.
1'-acetyl-7-methoxy-2',3'-dihydro-1'H,2H-spiro[benzofuran-3,4'-
pyridine]-4-carboxamide (10d). Prepared according to procedure
G from amide (43 mg, 0.128 mmol), [RhCp*Cl2]2 (1.99 mg, 0.0032
mmol) and CsOAc (49 mg, 0.256 mmol) in t-AmOH (0.64 mL) at
60°C overnight. The crude mixture was purified over silica gel
(Hept. to EtOAc) to afford a colorless oil (m = 32.2 mg, 83%). 1H
NMR (300 MHz, CDCl3) δ (ppm): (2 rotamers 67/33) 7.28 (d, J =
1
mg, 86%). H NMR (300 MHz, CDCl3) δ (ppm): 7.37-7.27 (m,
6H), 7.19 (d, J = 1.5 Hz, 1H), 6.03 (s, 2H), 5.80 (s, 1H), 4.54 (s, 2H),
8
ACS Paragon Plus Environment

Page 9 of 18
The Journal of Organic Chemistry
3.87 (s, 3H), 3.59 (s, 2H), 3.02 (brs, 2H), 2.62 (t, J = 5.7 Hz, 2H),
2.26 (m, 2H). 13C NMR (75 MHz, CDCl3) δ (ppm) 166.3 (Cq), 148.7
349.1 (100) [M+H+]. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C17H21N2O6 : 349.1400 Found: 349.1396.
+
1
(Cq), 142.3 (Cq), 139.8 (Cq), 138.1 (Cq), 131.9 (Cq), 129.1 (CH), 128.2
(CH), 127.1 (CH), 124.2 (Cq), 124.0 (CH), 112.0 (CH), 103.8 (CH),
102.1 (CH2), 72.8 (CH2), 62.6 (CH2), 52.4 (CH2), 52.1 (CH3), 49.4
(CH2), 26.5 (CH2). IR υ (neat): 3059-2760, 1708, 1442, 1270, 1015
cm-1. MS (ESI, m/z): 382.1 (100) [M+H+]. HMRS (ESI-TOF) m/z:
1-acetyl-2,3-dihydro-1H,7'H-spiro[pyridine-4,6'-[1,3]dioxolo[4,5-
g]benzofuran]-5'-carboxamide (10e). Prepared according to pro-
cedure G from amide (35.0 mg, 0.1 mmol), [RhCp*Cl2]2 (1.5 mg,
0.0025 mmol) and CsOAc (38.6 mg, 0.2 mmol) in t-AmOH (0.5
mL) at 60°C overnight. The crude mixture was purified over
silica gel (Hept. to EtOAc) to afford a white solid (m = 22.1 mg,
2
3
4
5
6
7
+
[M+H]+ Calcd for C22H24NO5 : 382.1654. Found: 382.1645.
1
Methyl
7-((1,2,3,6-tetrahydropyridin-4-
70%). H NMR (300 MHz, DMSO) δ (ppm): (2 rotamers) 7.56
yl)methoxy)benzo[d][1,3]dioxole-5-carboxylate (S12). Prepared
according to procedure E from N-benzyl amine (420.5 mg, 1.1
mmol), 1,2 dichloroethane (11 mL), 1-chloroethyl chloroformate
(ACE-Cl) (0.24 mL, 2.2 mmol) then MeOH (11 mL). The mixture
was concentrated to give the title compound which was purified
through silica gel (CH2Cl2 to CH2Cl2 /MeOH 95/5) to afford a
(brs, 1H), 7.25 (brs, 1H), 7.12 (d, J = 8.3 Hz, 1H min.), 6.85 (d, J =
8.3 Hz, 1H maj.), 6.58 (s, 1H maj.), 6.55 (s, 1H, min.), 6.04 (s, 1H),
6.01 (s, 1H), 4.86 (dd, J = 8.5, 1.7 Hz, 1H, min.), 4.77 (dd, J = 8.2,
1.6 Hz, 1H, maj.), 4.46 (dd, J = 8.9, 7.9 Hz, 1H maj.+min.), 4.29
(ddd, J = 13.6, 3.4, 2.8 Hz, 1H, maj.), 4.09 (m, 1H, maj.+min.), 3.92
(ddd, J = 12.9, 3.9, 3.7 Hz, 1H, min.), 3.39 (ddd, J = 13.7, 13.4, 3.0
Hz, 1H, min.), 2.93 (ddd, J = 13.7, 13.4, 3.0 Hz, 1H, maj.), 2.55
(ddd, J = 13.7, 13.4, 3.2 Hz, 1H), 2.43 (ddd, J = 13.7, 13.4, 3.2 Hz,
1H), 2.12 (s, 3H, min.), 2.10 (s, 3H maj.), 1.81 (m, 1H, maj.), 1.77 (m,
1H, min.). 13C NMR (75 MHz, DMSO) δ (ppm) (2 rotamers) 168.4
(Cq), 167.7 (Cq), 148.2 (Cq), 142.1 (Cq), 130.8 (Cq), 128.0 (Cq),
127.7 (CH), 127.5 (Cq), 127.3 (Cq), 124.7 (CH), 108.6 (CH), 108.0
(CH), 101.8 (CH2), 100.9 (CH), 100.8 (CH), 82.0 (CH2), 44.9 (Cq),
44.6 (Cq), 41.0 (CH2), 37.3 (CH2), 31.0 (CH2), 30.6 (CH2), 21.8
(CH3), 21.2 (CH3). IR υ (neat): 3356, 3176, 2970-2872, 1667, 1628,
1417 cm-1. MS (ESI, m/z): 317.1 (100) [M+H+]. HRMS (ESI-TOF)
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
beige solid (m = 310.4 mg, 96%). H NMR (300 MHz, CDCl3) δ
(ppm): 9.93 (brs, 1H), 7.29 (d, J = 1.6 Hz, 1H), 7.21 (d, J = 1.4 Hz,
1H), 6.04 (s, 2H), 5.84 (m, 1H), 4.58 (s, 2H), 3.87 (s, 3H), 3.74 (m,
2H), 3.35 (m, 2H), 2.58 (m, 2H). 13C NMR (75 MHz, CDCl3) δ
(ppm) 166.1 (Cq), 149.0 (Cq), 141.5 (Cq), 139.8 (Cq), 133.3 (Cq),
124.5 (Cq), 117.1 (CH), 112.4 (CH), 104.4 (CH), 102.3 (CH2), 71.7
(CH2), 52.2 (CH3), 41.1 (CH2), 40.4 (CH2), 22.1 (CH2). IR υ (neat):
2938, 2896-2657, 1703, 1435, 1260 cm-1. MS (ESI, m/z): 292.1 (100)
+
[M+H+]. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H18NO5 :
292.1185. Found: 292.1191. m.p. = 210-211 °C.
+
Methyl
7-((1-acetyl-1,2,3,6-tetrahydropyridin-4-
m/z: [M+H]+ Calcd for C16H17N2O5 : 317.1137. Found: 317.1136.
m.p. = 215-216 °C.
5-acetyl-4,5,6,7-tetrahydro-2H-2a,6-
yl)methoxy)benzo[d][1,3]dioxole-5-carboxylate (S13). Prepared
according to procedure F from amine (200 mg, 0.686 mmol),
triethylamine (0.39 mL, 2.81 mmol), 4-dimethylaminopyridine
(cat.), CH2Cl2 (6.8 mL) and a solution of acetyl chloride (0.073
ml, 1.03 mmol) in CH2Cl2 (1.1 mL). The crude mixture was puri-
fied over silica gel (DCM to DCM/MeOH 95/5) to afford a yellow
methano[1,3]dioxolo[4',5':6,7]benzofuro[4,3-ef][1,3]diazonin-
8(3H)-one (11e). Prepared according to procedure H from amide
(22.3 mg, 0.07 mmol), CH2Cl2 (0.35 mL) and TFA (53 µL, 0.007
mmol). The crude mixture was purified over silica gel (DCM to
DCM/MeOH (95/5)) to afford a white solid (m = 20.9 mg, 94%).
1H NMR (300 MHz, CDCl3) δ (ppm): 7.44 (s, 1H), 6.59 (d, J = 6.8
Hz, 1H), 6.18 (m, 1H), 6.03 (dd, J = 10.6, 1.4 Hz, 2H), 4.38 (d, J =
8.4 Hz, 1H), 4.25 (d, J = 8.4 Hz, 1H), 3.63 (m, 1H), 3.12 (ddd, J =
14.1, 12.9, 2.9 Hz, 1H), 2.18 (m, 1H), 2.12 (m, 1H), 2.09 (s, 3H), 1.99
(m, 1H), 1.76 (dt, J = 13.3, 4.7 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ
(ppm) 170.1 (Cq), 166.7 (Cq), 150.0 (Cq), 140.4 (Cq), 134.2 (Cq),
128.8 (Cq), 122.4 (Cq), 104.6 (CH), 102.4 (CH2), 84.4 (CH2), 56.9
(CH3), 45.0 (Cq), 38.0 (CH2), 35.8 (CH2), 32.3 (CH2), 21.8 (CH3).
IR υ (neat): 3224, 3086-2872, 1625, 1615, 1418, 1288 cm-1. MS (ESI,
m/z): 317.1 (100) [M+H+]. HRMS (ESI-TOF) m/z: [M+H]+ Calcd
1
oil (m = 204.8 mg, 89%). H NMR (300 MHz, CDCl3) δ (ppm): 2
rotamers 7.29 (s, 1H), 7.18 (s, 1H), 6.03 (s, 2H), 5.82 (brs, 1H,
major), 5.78 (brs, 1H, minor), 4.54 (brs, 2H), 4.08 (brs, 2H, ma-
jor), 3.97 (brs, 2H, minor), 3.85 (s, 3H), 3.71 (t, J = 6.0 Hz, 1H,
minor), 3.54 (t, J = 5.8 Hz, 1H, major), 2.28 (brs, 2H, major), 2.21
(brs, 2H, minor), 2.11 (s, 3H, major), 2.08 (s, 3H, minor). 13C NMR
(75 MHz, CDCl3) δ (ppm) (2 rotamers) 169.2 (Cq), 169.1 (Cq),
166.1 (Cq), 148.8 (Cq), 141.8 (Cq), 139.7 (Cq), 133.4 (Cq), 131.5 (Cq),
124.2 (Cq), 123.2 (CH), 120.9 (CH), 112.0 (CH), 111.9 (CH), 104.0
(CH), 102.1 (CH2), 72.5 (CH2), 72.2 (CH2), 52.0 (CH3), 45.1 (CH2),
42.9 (CH2), 41.3 (CH2), 37.7 (CH2), 26.2 (CH2), 25.3 (CH2), 21.8
(CH3), 21.3 (CH3). IR υ (neat): 300-2839, 1710, 1626, 1429, 1325 cm-
1. MS (ESI, m/z): 334.1 (100) [M+H+]. HMRS (ESI-TOF) m/z:
+
for C16H17N2O5 : 317.1137. Found: 317.1134. m.p. = 272-273 °C.
Methyl 2-methyl-5-(pyridin-4-ylmethoxy)benzoate (S14). Prepared
+
[M+H]+ Calcd for C17H20NO6 : 334.1291. Found: 334.1275. m.p. =
according to procedure
A
from methyl 5-hydroxy-2-
100-101°C.
methylbenzoate (200 mg, 1.1 mmol), 4-(chloromethyl)pyridine
hydrochloride (198 mg, 1.21 mmol), K2CO3 (334 mg, 2.41 mmol) in
DMF (7.7 mL). The solvent was removed under vacuum and the
crude mixture purified through silica gel (Hept. to Hept./EtOAc
5/5) to afford the corresponding compound (m = 261.7 mg, 93%).
1H NMR (300 MHz, CDCl3) δ (ppm): 8.62 (m, 2H), 7.51 (d, J = 2.9
Hz, 1H), 7.37 (m, 2H), 7.16 (d, J = 8.5 Hz, 1H), 7.01 (dd, J = 8.4, 2.9
Hz, 1H), 5.10 (s, 2H), 3.89 (s, 3H), 2.52 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ (ppm) 167.5 (Cq), 155.8 (Cq), 149.8 (CH), 145.8 (Cq),
132.9 (Cq), 132.7 (CH), 130.2 (Cq), 121.3 (CH), 118.8 (CH), 116.1
(CH), 68.2 (CH2), 51.8 (CH3), 20.7 (CH3). IR υ (neat): 3091-2836,
1720, 1286, 1213 cm-1. MS (ESI, m/z): 258.1 (100) [M+H+]. HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C15H16NO3+: 258.1125. Found:
258.1113. m.p. = 40-42°C.
7-((1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-N-
methoxybenzo[d][1,3]dioxole-5-carboxamide (9e). Prepared ac-
cording to procedure C from methyl ester (202 mg, 0.606 mmol),
LiOH (38.2 mg, 0.909 mmol), MeOH (2.9 mL) H2O (0.9 mL).
The resulting crude carboxylic acid (0.606 mmol) was dissolved
in DMF (1.8 mL) and reacted with EDCI (127.9 mg, 0.667 mmol),
HOBt (90.1 mg, 0.667 mmol), MeONH2.HCl (55.7 mg, 0.667
mmol), and iPr2NEt (0.24 mL, 1.39 mmol). Purification over silica
gel (DCM to DCM/MeOH 95/5) afforded the title compound as a
1
white foam (m = 149 mg, 70% over 2 steps). H NMR (300 MHz,
CDCl3) δ (ppm): (2 rotamers 54/46) 10.4 (brs, 1H), 7.11 (s, 1H),
6.96 (d, J = 1.5 Hz, 1H), 5.97 (s, 3H), 5.75 (m, 1H), 4.50 (s, 2H),
4.03 (m, 2H major), 3.94 (m, 1H minor), 3.80 (s, 3H), 3.66 (t, J =
5.8 Hz, 1H minor), 3.52 (t, J = 5.7 Hz, 1H major), 2.24 (m, 1H
major), 2.14 (m, 1H minor) 2.08 (s, 3H, major), 2.05 (s, 3H, mi-
nor). 13C NMR (75 MHz, CDCl3) δ (ppm) 169.5 (Cq), 165.2 (Cq),
149.0 (Cq), 142.2 (Cq), 138.8 (Cq), 133.5 (Cq), 131.7 (Cq), 126.0
(Cq), 123.0 (CH), 121.0 (CH), 109.9 (CH), 102.1 (CH2), 101.5 (CH),
72.6 (CH2), 72.3 (CH2), 64.3 (CH3), 45.2 (CH2), 43.0 (CH2), 41.5
(CH2), 37.9 (CH2), 26.2 (CH2), 25.4 (CH2), 21.8 (CH3), 21.4 (CH3).
IR υ (neat): 3175, 2932-2897, 1605, 1427, 1083 cm-1. MS (ESI, m/z):
Methyl
5-((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-2-
methylbenzoate (S15). Prepared according to procedure B from
methyl 2-methyl-5-(pyridin-4-ylmethoxy)benzoate (218.5 mg,
0.849 mmol) in acetone (4.2 mL) and benzyl bromide (0.126 mL,
1.06 mmol). The crude pyridinium was used without purifica-
tion. Pyridinium (0.849 mmol) in methanol (8.5 mL) and sodi-
um borohydride (70.7 mg, 1.86 mmol). The crude product was
purified by flash column chromatography (Hept. to
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 18
Hept./EtOAc 5/5 to 0/100) to afford the title compound as a
yellow oil (m = 146.2 mg, 49%). H NMR (300 MHz, CDCl3) δ
113.6 (CH), 71.0 (CH2), 64.1 (CH3), 45.1 (CH2), 42.9 (CH2), 41.3
1
(CH2), 37.8 (CH2), 26.1 (CH2), 25.3 (CH2), 21.5 (CH3), 21.1 (CH3),
18.5 (CH3). IR υ (neat): 3439, 3164, 2930, 1606, 1438, 1233 cm-1. MS
(ESI, m/z): 319.2 (100) [M+H+]. HRMS (ESI-TOF) m/z: [M+H]+
1
2
3
4
5
6
7
8
(ppm): 7.47 (d, J = 2.8 Hz, 1H), 7.39-7.25 (m, 5H), 7.13 (d, J = 8.5
Hz, 1H), 6.96 (dd, J = 8.5, 3.1 Hz, 1H), 5.79 (brs, 1H), 4.41 (s, 2H),
3.88 (s, 3H), 3.61 (s, 2H), 3.04 (brs, 2H), 2.65 (t, J = 5.6 Hz, 2H),
2.52 (s, 3H), 2.25 (brs, 2H). 13C NMR (75 MHz, CDCl3) δ (ppm):
167.8 (Cq), 156.5 (Cq), 137.9 (Cq), 132.5 (CH), 132.2 (Cq), 132.1
(Cq), 129.2 (CH), 128.2 (CH), 127.1 (CH), 123.1 (CH), 118.9 (CH),
116.1 (CH), 71.4 (CH2), 62.5 (CH2), 52.3 (CH2), 51.8 (CH3), 49.4
(CH2), 26.4 (CH2), 20.8 (CH3). IR υ (neat): 2924, 1721, 1498, 1211
cm-1. MS (ESI, m/z): 352.2 (100) [M+H+]. HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C22H26NO3+: 352.1913. Found: 352.1913.
+
Calcd for C17H23N2O4 : 319.1658 Found: 319.1669.
1'-acetyl-5-methyl-2',3'-dihydro-1'H,2H-spiro[benzofuran-3,4'-
pyridine]-4-carboxamide (10f). Prepared according to procedure
G from amide (36.9 mg, 0.116 mmol), [RhCp*Cl2]2 (1.8 mg, 0.0029
mmol) and CsOAc (44.3 mg, 0.231 mmol) in t-AmOH (0.58 mL)
at 60°C overnight. The crude mixture was purified over silica gel
(Hept. to EtOAc) to afford a white solid (m = 21.1 mg, 64%).1H
NMR (300 MHz, CDCl3) δ (ppm): (2 rotamers 60/40) 7.33 (d, J =
8.6 Hz, 1H min.), 7.01 (d, J = 8.3 Hz, 1H maj.), 6.81-6.70 (m, 2H,
maj.+min.), 6.50 (brs, 1H min.), 5.98 (brs, 1H maj.), 5.78 (brs, 1H
min.), 5.75 (brs, 1H maj.), 5.05 (d, J = 8.5 Hz, 1H min.), 4.99 (d, J =
8.5 Hz, 1H maj.), 4.48 (td, J = 13.9, 3.2 Hz, 1H maj.), 4.25 (t, J = 9.1
Hz, 2H maj.), 4.16 (t, J = 8.7 Hz, 2H min.), 3.88 (m, 1H min.), 3.35
(dt, J = 12.9, 2.2 Hz, 1H min.), 2.95 (dt, J = 13.7, 2.9 Hz, 1H maj.),
2.43 (dt, J = 13.5, 3.6 Hz, 1H), 2.30 (s, 3H major), 2.19 (s, 3H mi-
nor), 2.16 (s, 3H), 2.05-1.93 (m, 1H, maj.+min.). 13C NMR (75 MHz,
DMSO) δ (ppm) (2 rotamers) 168.8 (Cq), 167.7 (Cq), 157.6 (Cq),
135.8 (Cq), 135.5 (Cq), 129.8 (CH), 128.8 (Cq), 127.7 (CH), 125.5
(CH), 124.6 (CH), 109.1 (CH), 108.5 (CH), 80.4 (CH2), 44.7 (Cq),
44.5 (Cq), 40.9 (CH2), 37.1 (CH2), 31.3 (CH2), 31.1 (CH2), 21.7
(CH3), 21.2 (CH3), 17.8 (CH3). IR υ (neat): 3367, 3175-2877, 1664,
1630, 1348, 969 cm-1. MS (ESI, m/z): 309.1 (100) [M+Na+]. HRMS
(ESI-TOF) m/z: [M+Na]+ Calcd for C16H18N2O3Na+: 309.1215.
Found: 309.1219. m.p. = 234-235°C.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methyl
2-methyl-5-((1,2,3,6-tetrahydropyridin-4-
yl)methoxy)benzoate (S16). Prepared according to procedure E
from N-benzyl amine (146.2 mg, 0.416 mmol), 1,2 dichloroethane
(4.2 mL), 1-chloroethyl chloroformate (ACE-Cl) (0.09 mL, 0.832
mmol) then MeOH (4.2 mL). The mixture was concentrated to
give the title compound which was purified through silica gel
(CH2Cl2 to CH2Cl2 /MeOH 90/10) to afford a beige solid (m = 93.1
1
mg, 86%). H NMR (300 MHz, CDCl3) δ (ppm): 7.46 (brs, 1H),
7.40 (d, J = 2.9 Hz, 1H), 7.12 (d, J = 8.5 Hz, 1H), 6.92 (dd, J = 8.4,
2.5 Hz, 1H), 5.81 (brs, 1H), 4.42 (s, 2H), 3.86 (s, 3H), 3.73 (brs,
2H), 3.34 (t, J = 6.0 Hz, 2H), 2.52 (m, 2H), 2.48 (s, 3H). 13C NMR
(75 MHz, CDCl3) δ (ppm) 167.6 (Cq), 155.9 (Cq), 133.4 (Cq), 132.8
(Cq), 132.7 (CH), 130.2 (Cq), 118.8 (CH), 116.8 (CH), 116.1 (CH),
70.3 (CH2), 51.8 (CH3), 41.3 (CH2), 40.5 (CH2), 22.3 (CH2), 20.7
(CH3). IR υ (neat): 3423, 3043, 2959-2714, 1730; 1719, 1282 cm-1. MS
(ESI, m/z): 261.1 (100) [M+H+]. HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C15H20NO3+: 262.1443. Found: 262.1448. m.p. = 144-146
°C.
4-acetyl-11-methyl-3,4,5,6-tetrahydro-7H-3,6a-
methanobenzofuro[4,3-ef][1,3]diazonin-1(2H)-one (11f). Prepared
according to procedure H from amide (16.6 mg, 0.0579 mmol),
CH2Cl2 (0.5 mL) and TFA (44 µL, 0.058 mmol). The crude mix-
ture was purified over silica gel (DCM to DCM/MeOH (95/5)) to
afford a white solid (m = 9.7 mg, 58%) with recovered starting
material (m = 6.9 mg, 42%). 1H NMR (300 MHz, CDCl3) δ (ppm):
7.14 (d, J = 8.2 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.28 (brs 1H), 6.15
(m, 1H), 4.27 (d, J = 8.4 Hz, 1H), 4.16 (d, J = 8.4 Hz, 1H), 3.63 (m,
1H), 3.20 (ddd, J = 14.2, 12.9, 2.9 Hz, 1H), 2.63 (s, 3H), 2.21 (m, 1H),
2.11 (s, 3H), 2.09-2.00 (m, 2H), 1.77 (dt, J = 13.4, 4.8 Hz, 1H). 13C
NMR (75 MHz, CDCl3) δ (ppm) 170.0 (Cq), 169.8 (Cq), 157.4 (Cq),
135.9 (Cq), 133.7 (CH), 131.5 (Cq), 127.9 (Cq), 113.4 (CH), 83.1
(CH2), 57.5 (CH), 45.2 (Cq), 38.1 (CH2), 36.3 (CH2), 32.9 (CH2),
24.4 (CH3), 21.8 (CH3). IR υ (neat): 3286, 3194-2853, 1667, 1639
cm-1. MS (ESI, m/z): 287.1 (100) [M+H+]. HRMS (ESI-TOF) m/z:
Methyl
5-((1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-2-
methylbenzoate (S17). Prepared according to procedure F from
amine (96.6 mg, 0.367 mmol), triethylamine (0.20 mL, 1.51
mmol), 4-dimethylaminopyridine (cat.), CH2Cl2 (3.8 mL) and a
solution of acetyl chloride (0.04 mL, 0.55 mmol) in CH2Cl2 (0.63
mL). The crude mixture was purified over silica gel (Hept. to
1
Hept./EtOAc 30/70) to afford a yellow oil (m = 80 mg, 72%). H
NMR (300 MHz, CDCl3) δ (ppm) (2 rotamers) : 7.44 (d, J = 2.8
Hz, 1H), 7.14 (d, J = 8.5 Hz, 1H), 6.95 (dd, J = 8.5, 2.7 Hz, 1H), 5.83
(brs, 1H, maj.), 5.78 (brs, 1H, min.), 4.43 (s, 2H), 4,10 (brm, 1H,
maj.), 3.99 (brs, 1H, min.), 3.88 (s, 3H), 3.73 (t, J = 5.2 Hz, 1H,
min.), 3.56 (t, J = 5.2 Hz, 1H, maj.), 2.51 (s, 3H), 2.27 (brm, 1H,
maj.), 2.21 (brm, 1H, min.), 2.13 (brs, 3H, maj.), 2.10 (brs, 3H,
min.). 13C NMR (75 MHz, CDCl3) δ (ppm) (2 rotamers) 169.3
(Cq), 167.8 (Cq), 156.3 (Cq), 132.7 (CH), 132.5 (Cq), 130.2 (Cq),
122.6 (CH), 120.3 (CH), 118.9 (CH), 116.1 (CH), 71.2 (CH2), 70.9
(CH2), 51.9 (CH3), 45.1 (CH2), 43.0 (CH2), 41.5 (CH2), 37.9 (CH2),
26.3 (CH2), 25.5 (CH2), 21.8 (CH3), 21.4 (CH3), 20.8 (CH3). IR υ
(neat): 3100-2850, 1720, 1636, 1434, 1281, 1239 cm-1. MS (ESI, m/z):
304.1 (100) [M+H+]. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
+
[M+H]+ Calcd for C16H19N2O3 : 287.1396. Found: 287.1384. m.p. =
210-211 °C.
Methyl 4-fluoro-3-(pyridin-4-ylmethoxy)benzoate (S18). Prepared
according to procedure A methyl 4-fluoro-3-hydroxybenzoate
(166 mg, 0.976 mmol), 4-(chloromethyl)pyridine hydrochloride
(176 mg, 1.07 mmol), K2CO3 (297 mg, 2.15 mmol) in DMF (6.8
mL). The solvent was removed under vacuum and the crude
mixture purified through silica gel (Hept. to Hept./EtOAc 5/5) to
+
C17H22NO4 : 304.1549. Found: 304.1554.
5-((1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-N-methoxy-2-
methylbenzamide (9f). Prepared according to procedure C from
methyl ester (102.1 mg, 0.336 mmol), LiOH (64.5 mg, 2.69
mmol), MeOH (3.36 mL) and water (3.36 mL). The resulting
crude carboxylic acid (0.336 mmol) was dissolved in DMF (1.0
mL) and reacted with EDCI (70.8 mg, 0.37 mmol), HOBt (50.0
mg, 0.37 mmol), MeONH2.HCl (28.1 mg, 0.336 mmol), and
iPr2NEt (0.14 mL, 0.773 mmol). Purification over silica gel (DCM
to DCM/MeOH 95/5) afforded the title compound as a colorless
oil (m = 73.9 mg, 69% over 2 steps). 1H NMR (300 MHz, CDCl3) δ
(ppm): (2 rotamers) 9.52 (brs, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.87-
6.78 (m, 2H), 5.72 (m, 1H), 4.35 (s, 2H), 3.99 (m, 1H major), 3.93
(m, 1H minor), 3.82 (s, 3H), 3.33 (t, J = 5.9 Hz, 1H minor), 3.50 (t,
J = 5.9 Hz, 1H major), 2.31 (s, 3H), 2.20 (m, 1H major), 2.12 (m, 1H
minor), 2.04 (s, 3H, major), 2.02 (s, 3H, minor). 13C NMR (75
MHz, CDCl3) δ (ppm) 169.4 (Cq), 167.1 (Cq), 156.1 (Cq), 133.6
(Cq), 131.7 (CH), 128.7 (Cq), 122.1 (CH), 120.3 (CH), 116.6 (CH),
1
afford a white solid (m = 235.9 mg, 92%). H NMR (300 MHz,
CDCl3) δ (ppm): 8.64 (d, J = 5.2 Hz, 2H), 7.72-7.65 (m, 1H), 7.68
(d, J = 7.3 Hz, 1H), 7.39 (d, J = 5.1 Hz, 2H), 7.17 (dd, J = 10.6, 8.7
Hz, 1H), 5.20 (s, 2H), 3.90 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
(ppm) 165.8 (Cq), 155.5 (Cq, d, JCF = 255 Hz), 150.0 (CH), 146.0
(Cq, d, JCF = 11.1 Hz) 145.0 (Cq), 126.6 (Cq, d, JCF = 4.1 Hz), 124.0
(CH, d, JCF = 7.7 Hz), 121.3 (CH), 116.4 (CH), 116.1 (CH), 69.2
(CH2), 52.3 (CH3). IR υ (neat): 3085-2956, 1719, 1294 cm-1. MS
(ESI, m/z): 262.1 (100) [M+H+]. HMRS (ESI-TOF) m/z: [M+H]+
+
Calcd for C14H12FNO3 : 262.0879. Found: 262.0891. m.p. = 104-106
°C.
Methyl
3-((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-4-
fluorobenzoate (S19). Prepared according to procedure B from
methyl 4-fluoro-3-(pyridin-4-ylmethoxy)benzoate (234 mg, 0.89
mmol) in acetone (4.45 mL) and benzyl bromide (0.13 mL, 1.12
mmol). The crude pyridinium was used without purification.
10
ACS Paragon Plus Environment

Page 11 of 18
The Journal of Organic Chemistry
Pyridinium (327 mg, 0.75 mmol) in methanol (7.5 mL) and sodi-
2H major), 3.98 (m, 2H minor), 3.84 (s, 3H), 3.69 (t, J = 5.7 Hz,
2H minor), 3.56 (t, J = 5.8 Hz, 2H major), 2.27 (m, 2H major), 2.18
(m, 2H minor) 2.11 (s, 3H, major), 2.08 (s, 3H, minor). 13C NMR
(75 MHz, CDCl3) δ (ppm) 169.6 (Cq), 169.5 (Cq), 165.1 (Cq), 154.9
(Cq, d, JCF = 255 Hz), 146.6 (Cq, d, JCF = 11.0 Hz), 133.2 (Cq), 131.5
(Cq), 128.7 (Cq), 128.3 (Cq), 123.1 (CH), 121.0 (CH), 120.4 (CH, d,
JCF = 7.5 Hz), 120.3 (CH, d, JCF = 7.5 Hz), 116.2 (CH), 116.0 (CH),
114.7 (CH), 72.3 (CH2), 72.0 (CH2), 64.2 (CH3), 45.2 (CH2), 43.0
(CH2), 41.4 (CH2), 37.9 (CH2), 26.2 (CH2), 25.3 (CH2), 21.8 (CH3),
21.3 (CH3). IR υ (neat): 3176, 2972-2936, 1605 cm-1. MS (ESI, m/z):
323.1 (100) [M+H+]. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
um borohydride (63 mg, 1.66 mmol). The crude product was
purified by flash column chromatography (Hept. to
Hept./EtOAc 7/3) to afford the title compound as a colorless oil
1
2
3
4
5
6
7
8
1
(m = 217 mg, 68%). H NMR (300 MHz, CDCl3) δ (ppm): 7.66-
7.57 (m, 2H), 7.35-7.19 (m, 5H), 7.07 (dd, J = 10.7, 8.7 Hz, 1H),
5.80 (brs, 1H), 4.49 (s, 2H), 3.86 (s, 3H), 3.57 (s, 2H), 3.00 (brm,
2H), 2.61 (t, J = 5.7 Hz, 2H), 2.24 (brm, 2H).13C NMR (75 MHz,
CDCl3) δ (ppm): 165.9 (Cq), 155.6 (Cq, d, JCF = 254 Hz), 146.5 (Cq,
d, JCF = 11.0 Hz), 138.0 (Cq), 131.4 (Cq), 128.9 (CH), 128.0 (CH),
126.9 (CH), 126.2 (Cq, d, JCF = 3.6 Hz), 123.0 (CH, d, JCF = 8.1 Hz),
116.1 (CH, d, JCF = 3.4 Hz), 115.8 (CH, d, JCF = 19.1 Hz), 72.4 (CH2),
62.4 (CH2), 52.2 (CH2), 52.0 (CH3), 49.2 (CH2), 26.3 (CH2). IR υ
(neat): 2800, 1719, 1511, 1290 cm-1. MS (ESI, m/z): 356.1 (100)
[M+H+]. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C21H23FNO3+:
356.1656. Found: 356.1648.
9
+
C16H20FN2O4 : 323.1407 Found: 323.1418. m.p. = 141-143 °C.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1'-acetyl-7-fluoro-2',3'-dihydro-1'H,2H-spiro[benzofuran-3,4'-
pyridine]-4-carboxamide (10g). Prepared according to procedure
G from amide (44.1 mg, 0.136 mmol), [RhCp*Cl2]2 (2.1 mg, 0.0034
mmol) and CsOAc (52.5 mg, 0.274 mmol) in t-AmOH (0.68 mL)
at 60°C overnight. The crude mixture was purified over silica gel
(Hept. to EtOAc) to afford a white solid (m = 27.1 mg, 69%).1H
NMR (300 MHz, acetone d6) δ (ppm): (2 rotamers) 7.29 (d, J =
8.4 Hz, 1H, min.), 7.13 (brs, 1H), 7.12-7.00 (m, 2H), 6.91 (d, J = 8.3
Hz, 1H maj.), 6.73 (brs, 1H), 4.97 (dd, J = 8.5, 1.9 Hz, 1H min.),
4.89 (dd, J = 8.3, 1.9 Hz, 1H maj.), 4.47 (dt, J = 13.9, 3.6 Hz, 1H,
maj.), 4.26 (dd, J = 5.5, 1.3 Hz, 1H, maj.), 4.23 (dd, J = 5.5, 1.3 Hz,
1H, min.), 4.04 (dt, J = 12.2, 3.6 Hz, 1H, min.), 3.49 (dt, J = 13.1, 3.0
Hz, 1H, min.), 2.97 (dt, J = 13.7, 3.0 Hz, 1H, maj.), 2.76 (dt, J = 13.2,
4.2 Hz, 1H, min.), 2.64 (dt, J = 13.2, 4.2 Hz, 1H, maj.), 2.18 (s, 3H
maj.), 2.17 (s, 3H min.), 1.98 (m, 1H, maj.), 1.93 (m, 1H, min.). 13C
NMR (75 MHz, DMSO) δ (ppm) (2 rotamers) 168.3 (Cq), 167.7
(Cq), 147.3 (Cq, d, JCF = 245.0 Hz), 147.2 (Cq, d, JCF = 245.0 Hz),
146.4 (Cq, d, JCF = 11.1 Hz), 134.9 (Cq), 134.6 (Cq), 131.1 (Cq), 130.9
(Cq), 128.0 (CH), 125.0 (CH), 120.8 (CH, d, JCF = 6.0 Hz), 120.6
(CH, d, JCF = 6.0 Hz), 115.5 (CH), 115.2 (CH), 107.9 (CH), 107.4
(CH), 81.8 (CH2), 45.6 (Cq), 45.3 (Cq), 40.9 (CH2), 37.1 (CH2), 31.0
(CH2), 30.7 (CH2), 21.8 (CH3), 21.2 (CH3). IR υ (neat): 3370, 3212,
2931-2881, 1660, 1638, 1621 cm-1. MS (ESI, m/z): 291.1 (100)
[M+H+]. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H16N2O3F+:
291.1145. Found: 291.1141. m.p. = 203-204°C.
Methyl
4-fluoro-3-((1,2,3,6-tetrahydropyridin-4-
yl)methoxy)benzoate (S20). Prepared according to procedure E
from N-benzyl amine (217 mg, 0.61 mmol), 1,2 dichloroethane
(6.1 mL), 1-chloroethyl chloroformate (ACE-Cl) (0.13 mL, 1.22
mmol) then MeOH (6.1 mL). The mixture was concentrated to
give the title compound which was used without purification (m
= 168.5 mg, 99%). 1H NMR (300 MHz, CDCl3) δ (ppm): 9.95 (brs,
1H), 7.67 (ddd, J = 6.2, 2.3, 2.0 Hz, 1H), 7.62 (dd, J = 8.1, 1.8 Hz,
1H), 7.12 (dd, J = 10.6, 8.4 Hz, 1H), 5.89 (brs, 1H), 4.56 (s, 2H),
3.90 (s, 3H), 3.76 (brm, 2H), 3.37 (brm, 2H), 2.60 (brm, 2H). 13C
NMR (75 MHz, CDCl3) δ (ppm) 165.9 (Cq), 155.8 (Cq, d, JCF = 256
Hz), 146.1 (Cq, d, JCF = 11.0 Hz), 132.9 (Cq), 126.0 (Cq), 123.9 (CH,
d, JCF = 8.5 Hz), 117.3 (CH), 116.5 (CH, d, JCF = 3.2 Hz), 116.1 (CH),
71.4 (CH2), 52.3 (CH3), 41.1 (CH2), 40.4 (CH2), 22.1 (CH2). IR υ
(neat): 3408, 2947-2671, 1708, 1287 cm-1. MS (ESI, m/z): 266.1
(100) [M+H+]. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C14H17NO3F+: 266.1192. Found: 266.1197. m.p. = 180-182 °C.
Methyl
3-((1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-4-
fluorobenzoate (S21). Prepared according to procedure F from
amine (165 mg, 0.622 mmol), triethylamine (0.36 mL, 2.55
mmol), 4-dimethylaminopyridine (cat.), CH2Cl2 (6.2 mL) and a
solution of acetyl chloride (0.066 ml, 0.933 mmol) in CH2Cl2 (1.0
mL). The crude mixture was purified over silica gel (DCM to
DCM/MeOH 95/5) to afford a yellow oil (m = 147.7 mg, 77%). 1H
NMR (300 MHz, CDCl3) δ (ppm): (2 rotamers) 7.66-7.58 (m, 2H),
7.10 (dd, J = 10.5, 9.0 Hz, 1H), 5.85 (brm, 1H, major), 5.81 (brm,
1H, minor), 4.52 (s, 2H), 4.09 (brs, 2H, major), 3.98 (brs, 2H,
minor), 3.89 (s, 3H), 3.72 (t, J = 5.9 Hz, 2H, minor), 3.56 (t, J = 5.8
Hz, 2H, major), 2.29 (brm, 2H, major), 2.22 (brm, 2H, minor),
2.12 (s, 3H, major), 2.08 (s, 3H, minor). 13C NMR (75 MHz, CDCl3)
δ (ppm) (2 rotamers) 169.3 (Cq), 169.2 (Cq), 166.0 (Cq), 155.8 (Cq,
d, JCF = 255 Hz), 146.4 (Cq, d, JCF = 11.5 Hz), 133.2 (Cq), 131.3 (Cq),
126.5 (Cq), 123.5 (CH, d, JCF = 8.5 Hz), 123.4 (CH, d, JCF = 8.5 Hz),
121.0 (CH), 116.5 (CH, d, JCF = 3.5 Hz), 116.4 (CH, d, JCF = 3.5 Hz),
116.2 (CH), 116.0 (CH), 72.4 (CH2), 72.2 (CH2), 52.2 (CH3), 45.1
(CH2), 42.9 (CH2), 41.4 (CH2), 37.8 (CH2), 26.2 (CH2), 25.4 (CH2),
21.8 (CH3), 21.4 (CH3). IR υ (neat): 3072-2849, 1722, 1633, 1283 cm-
1. MS (ESI, m/z): 308.1 (100) [M+H+]. HRMS (ESI-TOF) m/z:
4-acetyl-9-fluoro-3,4,5,6-tetrahydro-7H-3,6a-
methanobenzofuro[4,3-ef][1,3]diazonin-1(2H)-one (11g) Prepared
according to procedure H from amide (27.1 mg, 0.093 mmol),
CH2Cl2 (0.47 mL) and TFA (71 µL, 0.0093 mmol). The crude
mixture was purified over silica gel (DCM to DCM/MeOH
1
(95/5)) to afford a white solid (m = 27 mg, 99%). H NMR (300
MHz, DMSO) δ (ppm) (2 rotamers) : 8.68 (d, J = 6.1 Hz, 1H maj.),
8.35 (d, J = 6.7 Hz, 1H min.), 7.73 (dd, J = 8.9, 4.5 Hz, 1H,
maj.+min.), 7.26 (dd, J = 10.4, 8.9 Hz, 1H, maj.+min.), 6.04 (brm,
1H, min.), 5.47 (brm, 1H, maj.), 4.50 (d, J = 8.6 Hz, 1H,
maj.+min.), 4.31 (d, J = 8.2 Hz, 1H, maj.+min.), 4.27 (m, 1H, maj.),
3.70 (m, 1H min.), 2.85 (m, 1H min.), 2.36-2.19 (m, 1H), 2.22 (s, 3H
maj.), 2.17-2.05 (m, 2H), 2.04 (s, 3H min.), 1.93-1.60 (m, 2H,
maj.+min.). 13C NMR (75 MHz, DMSO) δ (ppm) 168.0 (Cq), 165.2
(Cq), 149.0 (Cq, d, JCF = 249.0 Hz), 144.6 (Cq, d, JCF = 13.9 Hz),
136.2 (Cq, d, JCF = 13.9 Hz), 125.0 (CH), 124.8 (CH, d, JCF = 6.5 Hz),
116.1 (CH, d, JCF = 17.4 Hz), 83.7 (CH2), 61.7 (CH), 45.1 (Cq), 45.0
(Cq), 37.1 (CH2), 35.1 (CH2), 34.3 (CH2), 32.6 (CH2), 31.7 (CH2),
21.6 (CH3), 21.1 (CH3). IR υ (neat): 3198, 3077-2877, 1727, 1615, 1597
cm-1. MS (ESI, m/z): 291.1 (100) [M+H+]. HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C15H16N2O3F+: 291.1145. Found: 291.1150. m.p. =
203-207 °C.
+
[M+H]+ Calcd for C16H19FNO4 : 308.1298. Found: 308.1295. m.p. =
110-111 °C (decomp.).
3-((1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-4-fluoro-N-
methoxybenzamide (9g). Prepared according to procedure C
from methyl ester (147 mg, 0.69 mmol), LiOH (30 mg, 0.717
mmol), MeOH (2.4 mL) H2O (0.76 mL). The resulting crude
carboxylic acid (0.69 mmol) was dissolved in DMF (1.4 mL) and
reacted with EDCI (100.8 mg, 0.526 mmol), HOBt (71.1 mg, 0.526
mmol), MeONH2.HCl (44 mg, 0.526 mmol), and iPr2NEt (0.19
mL, 1.1 mmol). Purification over silica gel (DCM to DCM/MeOH
95/5) afforded the title compound as a yellow oil (m = 95.8 mg,
Methyl 4-nitro-3-(pyridin-4-ylmethoxy)benzoate (S22). Pre-
pared according to procedure A from methyl 3-hydroxy-4-
nitrobenzoate (305.3 mg, 1.55 mmol), 4-(chloromethyl)pyridine
hydrochloride (279 mg, 1.7 mmol), K2CO3 (470 mg, 3.4 mmol) in
DMF (10.8 mL), The solvent was removed under vacuum and the
crude mixture purified through silica gel (Hept. to Hept./EtOAc
1
1
62% over 2 steps). H NMR (300 MHz, CDCl3) δ (ppm): (2 rota-
7/3) to afford a beige solid (m = 330.8 mg, 74%). H NMR (300
mers) 10.1 (brs, 1H), 7.49 (dd, J = 7.9, 2.3 Hz, 1H), 7.33 (m, 1H),
7.07 (dd, J = 10.6, 8.4 Hz, 1H), 5.80 (s, 1H), 4.50 (s, 2H), 4.07 (m,
MHz, CDCl3) δ (ppm): 8.67 (d, J = 5.0 Hz, 1H), 7.92 (d, J = 8.2 Hz,
1H), 7.80-7.73 (m, 2H), 7.45 (d, J = 5.0 Hz, 1H), 5.31 (s, 2H), 3.97
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 18
(s, 3H). 13C NMR (75 MHz, CDCl3) δ (ppm) 164.9 (Cq), 150.8 (Cq),
with EDCI (171.6 mg, 0.895 mmol), HOBt (120.9 mg, 0.895
150.1 (CH), 144.1 (Cq), 135.0 (Cq), 125.7 (CH), 122.3 (CH), 121.1
(CH), 115.6 (CH), 69.3 (CH2), 52.9(CH3). IR υ (neat): 3085-2958,
1719, 1293 cm-1. MS (ESI, m/z): 289.1 (100) [M+H+]. HMRS (ESI-
TOF) m/z: [M+H]+ Calcd for C14H12N2O5 : 289.0824. Found:
289.0835. m.p. = 167-169 °C.
mmol), MeONH2.HCl (68 mg, 0.814 mmol), and iPr2NEt (0.33
mL, 1.87 mmol). Purification over silica gel (Hept to EtOAc)
afforded the title compound as a white foam (m = 148.4 mg, 52%
1
2
3
4
5
6
7
8
+
1
over 2 steps). H NMR (300 MHz, CDCl3) δ (ppm) (2 rotamers,
55/45) 10.68 (brs, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.59 (s, 1H), 7.45 (d,
J = 8.6 Hz, 1H), 5.88 (s, 1H, min.), 5.84 (s, 1H, maj.), 4.59 (s, 2H),
4.07 (brm, 2H, maj.), 4.01 (brm, 2H, min.), 3.88 (s, 3H), 3.71 (t, J =
6.5 Hz, 2H, min.), 3.59 (t, J = 5.7 Hz, 2H, maj.), 2.30 (brm, 2H,
maj.), 2.16 (brm, 2H, min.) 2.12 (s, 3H, maj.), 2.10 (s, 3H, min.). 13C
NMR (75 MHz, CDCl3) (2 rotamers) δ (ppm) 169.8 (Cq), 162.7
(Cq), 151.5 (Cq), 141.5 (Cq), 136.9 (Cq), 132.3 (Cq), 131.0 (Cq), 125.5
(CH), 123.2 (CH), 120.9 (CH), 119.1 (CH), 119.0 (CH), 114.0 (CH),
72.4 (CH2), 71.9 (CH2), 64.1 (CH3), 45.2 (CH2), 43.0 (CH2), 41.5
(CH2), 38.0 (CH2), 26.0 (CH2), 25.2 (CH2), 21.7 (CH3), 21.3 (CH3).
IR υ (neat): 3176, 2936, 1605, 1588, 1241 cm-1. MS (ESI, m/z): 350.1
(100) [M+H+]. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
Methyl 3-((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-4-
nitrobenzoate (S23). Prepared according to procedure B from
methyl 4-nitro-3-(pyridin-4-ylmethoxy)benzoate (251 mg, 0.87
mmol) in acetone (4.35 mL) and benzyl bromide (0.12 mL, 1.08
mmol). The crude pyridinium was used without purification.
Pyridinium (330 mg, 0.71 mmol) in methanol (7.1 mL) and sodi-
um borohydride (59.8 mg, 1.58 mmol). The crude product was
purified by flash column chromatography (Hept. to
Hept./EtOAc 7/3) to afford the title compound as a yellow oil (m
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
= 223 mg, 67%). H NMR (300 MHz, CDCl3) δ (ppm): 7.81 (d, J =
8.4 Hz, 1H), 7.73 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 5.85 (brs, 1H),
4.59 (s, 2H), 3.95 (s, 3H), 3.57 (brs, 2H), 3.60 (s, 2H), 3.03 (brs,
2H), 2.65 (t, J = 5.8 Hz, 2H), 2.25 (3, 2H). 13C NMR (75 MHz,
CDCl3) δ (ppm): 165.1 (Cq), 151.4 (Cq), 142.5 (Cq), 138.0 (Cq), 134.6
(Cq), 130.7 (Cq), 129.0 (CH), 128.1 (CH), 127.0 (CH), 125.2 (CH),
124.3 (CH), 121.3 (CH), 115.7 (CH), 72.7 (CH2), 62.5 (CH2), 52.7
(CH3), 52.3 (CH2), 49.2 (CH2), 26.1 (CH2). IR υ (neat): 2758, 1719,
1521, 1292 cm-1. MS (ESI, m/z): 383.1 (100) [M+H+]. HRMS (ESI-
+
C16H20N3O6 : 350.1352 Found: 350.1339.
1'-acetyl-7-nitro-2',3'-dihydro-1'H,2H-spiro[benzofuran-3,4'-
pyridine]-4-carboxamide (10h). Prepared according to procedure
G from amide (39 mg, 0.111 mmol), [RhCp*Cl2]2 (1.7 mg, 0.0027
mmol) and CsOAc (42. mg, 0.222 mmol) in t-AmOH (0.55 mL)
at 60°C overnight. The crude mixture was purified over silica gel
(DCM to DCM/MeOH : 97/3) to afford a yellow solid (m = 25.3
mg, 72%).1H NMR (300 MHz, DMSO) δ (ppm): (2 rotamers,
60/40) 7.98 (d, J = 8.5 Hz, 1H, maj.), 7.94 (brs, 2H, maj.), 7.71
(brs, 2H, min.), 7.22 (d, J = 8.4 Hz, 1H, min.), 7.03 (d, J = 8.4 Hz,
1H, min.), 7.01 (d, J = 8.4 Hz, 1H, min.), 6.97 (d, J = 8.4 Hz, 1H,
min.), 4.98 (dd, J = 8.4, 1.7 Hz, 1H, min.) 4.89 (dd, J = 8.3, 1.7 Hz,
1H, maj.), 4.72 (t, J = 8.9 Hz, 2H, maj.+min.), 4.34 (d, J = 10.0 Hz,
2H, maj.+min.), 4.31 (m, 1H, maj.), 3.97 (m, 1H, min.), 3.43 (dt, J =
13.1, 2.9 Hz, 1H, min.), 2.98 (dt, J = 13.5, 3.0 Hz, 1H, maj.), 2.45 (m,
1H, min.), 2.34 (dt, J = 13.3, 4.7 Hz, 1H, maj.), 1.93 (m, 2H,
maj.+min.). 13C NMR (75 MHz, DMSO) δ (ppm) (2 rotamers)
167.8 (Cq), 167.6 (Cq), 154.9 (Cq), 140.8 (Cq) 140.6 (Cq), 135.1
(Cq), 134.9 (Cq), 132.5 (Cq), 128.6 (CH), 125.6 (CH), 124.2 (CH),
120.0 (CH), 119.9 (CH), 107.0 (CH), 106.4 (CH), 82.6 (CH2), 44.5
(Cq), 44.3 (Cq), 40.7 (CH2), 37.0 (CH2), 31.3 (CH2), 31.0 (CH2), 21.7
(CH3), 21.2 (CH3). IR υ (neat): 3359, 3166, 2927-2853, 1678, 1669,
1630 cm-1. MS (ESI, m/z): 318.1 (100) [M+H+]. HRMS (ESI-TOF)
+
TOF) m/z: [M+H]+ Calcd for C21H23N2O5 : 383.1607. Found:
383.1588.
Methyl
4-nitro-3-((1,2,3,6-tetrahydropyridin-4-
yl)methoxy)benzoate (S24). Prepared according to procedure E
from N-benzyl amine (286 mg, 0.748 mmol), 1,2 dichloroethane
(7.5 mL), 1-chloroethyl chloroformate (ACE-Cl) (0.16 mL, 1.5
mmol) then MeOH (7.5 mL). The mixture was concentrated to
give the title compound which was purified through silica gel
(CH2Cl2 to CH2Cl2 /MeOH 95/5) to afford a beige solid (m = 218.0
1
mg, 99%). H NMR (300 MHz, MeOD) δ (ppm): 7.93-7.84 (m,
2H), 7.74 (dd, J = 8.4, 1.8 Hz, 1H), 6.00 (m, 1H), 4.78 (s, 2H), 3.95
(s, 3H), 3.74 (m, 2H), 3.39 (t, J = 6.2 Hz, 2H), 2.52 (m, 2H). 13C
NMR (75 MHz, MeOD) δ (ppm) 166.7 (Cq), 152.2 (Cq), 136.3 (Cq),
133.8 (Cq), 126.4 (CH), 123.2 (CH), 119.4 (CH), 117.0 (CH), 72.9
(CH2), 53.5 (CH3), 43.0 (CH2), 41.9 (CH2), 23.4 (CH2). IR υ (neat):
3648, 2928-2560, 1720, 1527, 1291, 1248 cm-1. MS (ESI, m/z): 293.1
(100) [M+H+]. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
+
m/z: [M+H]+ Calcd for C15H16N3O5 : 318.1084. Found: 318.1090.
+
C14H17N2O5 : 293.1137. Found: 293.1150. m.p. = 163-165 °C.
m.p. = 250-254 °C.
4-acetyl-9-nitro-3,4,5,6-tetrahydro-7H-3,6a-
Methyl
3-((1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-4-
nitrobenzoate (S25). Prepared according to procedure F from
amine (240 mg, 0.82 mmol), triethylamine (0.45 mL, 3.36 mmol),
4-dimethylaminopyridine (cat.), CH2Cl2 (8.5 mL) and a solution
of acetyl chloride (0.087 mL, 1.23 mmol) in CH2Cl2 (1.4 mL). The
crude mixture was purified over silica gel (Hept. to Hept./EtOAc
methanobenzofuro[4,3-ef][1,3]diazonin-1(2H)-one (11h). Prepared
according to procedure H from amide (14.7 mg, 0.046 mmol),
CH2Cl2 (0.23 mL) and TFA (35 µL, 0.0046 mmol). The crude
mixture was purified over silica gel (DCM to DCM/MeOH
(95/5)) to afford a yellow solid (m = 14.0 mg, 95%). 1H NMR (300
MHz, CDCl3) (2 rotamers) δ (ppm): 8.98 (d, J = 6.1 Hz, 1H, maj.),
8.70 (d, J = 6.6 Hz, 1H, maj.), 8.03 (d, J = 9.0 Hz, 1H), 7.85 (d, J =
9.0 Hz, 1H), 6.08 (m, 1H, min.), 5.53 (m, 1H, maj.), 4.67 (d, J = 8.6
Hz, 1H, maj.), 4.66 (d, J = 8.6 Hz, 1H, min.), 4.45 (d, J = 8.6 Hz,
1H, maj.), 4.42 (d, J = 8.6 Hz, 1H, min.), 4.30 (m, 1H, maj.), 3.78-
3.54 (m, 1H, min.), 2.83 (m, 1H, min.), 2.39-2.25 (m, 2H), 2.23 (s,
3H, maj.), 2.18 (m, 2H), 2.06 (s, 3H, min.), 1.90 (m, 1H, min.),
1.84-1.71 (m, 2H). 13C NMR (75 MHz, DMSO) (2 rotamers) δ
(ppm) 168.1 (Cq), 164.4 (Cq), 154.1 (Cq), 137.5 (Cq), 134.0 (Cq),
133.9 (Cq), 123.5 (CH), 123.2 (CH), 84.3 (CH2), 61.6 (CH), 56.0
(CH), 44.3 (Cq), 44.2 (Cq), 36.6 (CH2), 35.0 (CH2), 34.2 (CH2),
32.2 (CH2), 31.3 (CH2), 31.2 (CH2), 21.6 (CH3), 21.1 (CH3). IR υ
(neat): 3244, 3098-2940, 1646, 1603, 1203 cm-1. MS (ESI, m/z):
318.1 (100) [M+H+]. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
1
20/80) to afford a white solid (m = 220 mg, 80%). H NMR (300
MHz, CDCl3) δ (ppm): (2 rotamers) 7.80 (dd, J = 8.2, 3.7 Hz, 1H),
7.69 (d, J = 1.5 Hz, 1H), 7.66 (dd, J = 8.2, 1.6 Hz, 1H), 5.86 (brs,
1H), 4.59 (s, 2H), 4,08 (brm, 1H, maj.), 3.98 (brm, 1H, min.), 3.92
(s, 3H), 3.70 (t, J = 5.7 Hz, 1H, min.), 3.55 (t, J = 5.8 Hz, 1H, maj.),
2.27 (brm, 1H, maj.), 2.18 (brm, 1H, min.), 2.10 (s, 3H, maj.), 2.07
(s, 3H, min.). 13C NMR (75 MHz, CDCl3) δ (ppm) (2 rotamers)
169.3 (Cq), 169.2 (Cq), 164.9 (Cq), 151.1 (Cq), 142.4 (Cq), 134.7
(Cq), 132.2 (Cq), 130.6 (Cq), 125.3 (CH), 125.2 (CH), 123.7 (CH),
121.6 (CH), 121.0 (CH), 115.7 (CH), 115.6 (CH), 71.4 (CH2), 71.8
(CH2), 52.7 (CH3), 45.1 (CH2), 42.8 (CH2), 41.3 (CH2), 37.7 (CH2),
26.0 (CH2), 25.2 (CH2), 21.7 (CH3), 21.3 (CH3). IR υ (neat): 3100-
2850, 1720, 1636, 1281 cm-1. MS (ESI, m/z): 335.1 (100) [M+H+].
+
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H19N2O6 : 335.1238.
+
Found: 335.1236. m.p. = 118-120 °C.
C15H16N3O5 : 318.1074. Found: 318.1090. m.p. = 249-250 °C (de-
3-((1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-N-methoxy-4-
nitrobenzamide (9h). Prepared according to procedure C from
methyl ester (272.2 mg, 0.814 mmol), LiOH (156 mg, 6.51 mmol),
MeOH (8.1 mL) H2O (8.1 mL). The resulting crude carboxylic
acid (0.814 mmol) was dissolved in DMF (2.44 mL) and reacted
comp.).
Methyl
3-(2-(1-benzyl-1,2,3,6-tetrahydropyridin-4-
yl)ethoxy)benzoate (S26). To a solution of alcohol16 (101.7 mg,
0.468 mmol) in CH2Cl2 (4.7 mL) was added Et3N (0.13 mL, 0.938
mmol), and DMAP (cat.) at RT. MsCl (0.054 mL, 0.7 mmol) was
12
ACS Paragon Plus Environment

Page 13 of 18
The Journal of Organic Chemistry
added at 0°C and the reaction mixture was stirred overnight at
3-(2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)ethoxy)-N-
RT. The reaction was quenched with saturated NaHCO3. The
aqueous layer was extracted with EtOAc and the combined
organic were dried on Na2SO4 and solvent was removed under
reduced pressure. The crude mixture was used without further
purification.
methoxybenzamide (9i). Prepared according to procedure C from
methyl ester (102.2 mg, 0.337 mmol), LiOH (63.7 mg, 2.69
mmol), MeOH (3.3 mL) and water (3.3 mL). The resulting crude
carboxylic acid was dissolved in DMF (1.0 mL) and reacted with
EDCI (71.2 mg, 0.371 mmol), HOBt (50.2 mg, 0.371 mmol),
MeONH2.HCl (31.1 mg, 0.371 mmol), and iPr2NEt (0.14 mL, 0.778
mmol). Purification over silica gel (DCM to DCM/MeOH 98/2)
afforded the title compound as a colorless oil (m = 87.0 mg, 81%
1
2
3
4
5
6
7
8
To a solution of phenol (71.3 mg, 0.469 mmol) in DMF (2.3
mL) was added NaH (60%, 11.2 mg, 0.469 mmol) at 0°C. The
mixture was stirred at 0°C for 15 min, then a solution of the
crude mesylate (0.468 mmol) in DMF (2.3 mL) was added drop-
wise at 0°C. After stirring overnight at RT, the reaction was
quenched with saturated NaCl. The aqueous layer was extracted
with EtOAc and the combined organic were dried on Na2SO4
and solvent was removed under reduced pressure. The crude
mixture was purified over silica gel (Hept. to Hept./EtOAc 5/5)
to afford a colorless oil (m = 87.5 mg, 53% over 2 steps). 1H NMR
(300 MHz, CDCl3) δ (ppm): 7.62 (td, J = 7.6, 1.5 Hz, 1H), 7.54 (dd,
J = 2.7, 1.5 Hz, 1H), 7.39-7.24 (m, 6H), 7.08 (ddd, J = 8.3, 2.8, 1.0
Hz, 1H), 5.51 (tt, J = 3.2, 1.6 Hz, 1H), 4.09 (t, J = 6.9 Hz, 2H), 3.91
(s, 3H), 3.60 (s, 2H), 3.01 (brs, 2H), 2.60 (t, J = 5.8 Hz, 2H), 2.48
(t, J = 7.1 Hz, 2H), 2.19 (brm, 2H). 13C NMR (75 MHz, CDCl3) δ
(ppm): 167.0 (Cq), 158.8 (Cq), 137.9 (Cq), 132.9 (Cq), 131.4 (Cq),
129.4 (CH), 129.3 (CH), 128.2 (CH), 127.1 (CH), 121.9 (CH), 121.1
(CH), 120.0 (CH), 114.7 (CH), 66.7 (CH2), 62.6 (CH2), 52.7 (CH2),
52.1 (CH3), 49.7 (CH2), 36.3 (CH2), 29.4 (CH2). IR υ (neat): 2897-
2798, 1719, 1444, 1275 cm-1. MS (ESI, m/z): 352.2 (100) [M+H+].
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H26NO3+: 352.1913.
Found: 352.1908.
Methyl 3-(2-(1,2,3,6-tetrahydropyridin-4-yl)ethoxy)benzoate (S27).
Prepared according to procedure E from N-benzyl amine (84.9
mg, 0.241 mmol), 1,2 dichloroethane (2.4 mL), 1-chloroethyl
chloroformate (ACE-Cl) (0.05 mL, 0.48 mmol) then MeOH (2.4
mL). The mixture was concentrated to give the title compound
which was purified through silica gel (CH2Cl2 to CH2Cl2 /MeOH
90/10) to afford an orange oil (m = 50.7 mg, 80%). 1H NMR (300
MHz, CDCl3) δ (ppm): 9.79 (brs, 1H), 7.61 (ddd, J = 7.6, 1.5, 1.2
Hz, 1H), 7.50 (dd, J = 2.6, 1.6 Hz, 1H), 7.31 (t, J = 7.9 Hz, 1H), 7.06
(ddd, J = 8.1, 2.7, 0.8 Hz, 1H), 5.51 (s, 1H), 4.09 (t, J = 6.3 Hz, 2H),
3.88 (s, 3H), 3.66 (brs, 2H), 3.28 (t, J = 6.0 Hz, 2H), 2.56-2.43 (m,
4H). 13C NMR (75 MHz, CDCl3) δ (ppm) 166.8 (Cq), 158.4 (Cq),
134.5 (Cq), 131.4 (Cq), 129.4 (CH), 122.2 (CH), 119.9 (CH), 115.4
(CH), 114.6 (CH), 65.8 (CH2), 52.1 (CH3), 41.3 (CH2), 40.5 (CH2),
36.1 (CH2), 25.0 (CH2). IR υ (neat): 3282, 2933-2765, 1713, 1444 cm-
1. MS (ESI, m/z): 262.1 (100) [M+H+]. HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C15H20NO3+: 262.1443. Found: 262.1436.
1
over 2 steps). H NMR (300 MHz, CDCl3) δ (ppm): (2 rotamers)
9.92 (brs, 1H), 7.37-7.25 (m, 3H), 7.01 (td, J = 7.3, 2.2 Hz, 1H), 5.49
(m, 1H), 4.07 (t, J = 6.5 Hz, 2H), 4.01 (brs, 1H), 3.92 (brs, 1H), 3.87
(s, 3H), 3.65 (t, J = 5.8 Hz, 1H), 3.51 (t, J = 5.8 Hz, 1H), 2.48 (m,
2H), 2.18 (m, 1H), 2.11 (m, 1H), 2.09 (s, 3H, major), 2.07 (s, 3H,
minor). 13C NMR (75 MHz, CDCl3) δ (ppm) (2 rotamers) 169.7
(Cq), 169.3 (Cq), 165.9 (Cq), 158.8 (Cq), 134.6 (Cq), 133.3 (Cq),
132.7 (Cq), 129.5 (CH), 120.5 (CH), 119.2 (CH), 118.9 (CH), 118.6
(CH), 112.9 (CH), 66.3 (CH2), 64.3 (CH3), 45.4 (CH2), 43.2 (CH2),
41.6 (CH2), 38.2 (CH2), 36.4 (CH2), 29.1 (CH2), 28.3 (CH2), 21.7
(CH3), 21.3 (CH3). IR υ (neat): 3190, 2933, 1614, 1580, 1428, 1237 cm-
1. MS (ESI, m/z): 319.2 (100) [M+H+]. HRMS (ESI-TOF) m/z:
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
[M+H]+ Calcd for C17H23N2O4 : 319.1652 found: 319.1657.
1'-acetyl-2',3'-dihydro-1'H-spiro[chromane-4,4'-pyridine]-5-
carboxamide (10i). Prepared according to procedure G from
amide (24.1 mg, 0.079 mmol), [RhCp*Cl2]2 (1.2 mg, 0.0019 mmol)
and CsOAc (30.4 mg, 0.158 mmol) in t-AmOH (0.4 mL) at 60°C
overnight. The crude mixture was purified over silica gel (CH2Cl2
to CH2Cl2 /MeOH 90/10) to afford a white solid (m = 17.3 mg,
1
76%). H NMR (300 MHz, methanol d4) δ (ppm): (2 rotamers,
75/25) 7.17 (d, J = 8.3 Hz, 1H, minor), 7.13 (t, J = 15.4 Hz, 1H ma-
jor), 6.82 (m, 2H major+minor), 6.76 (d, J = 8.3 Hz, 1H, major),
5.08 (dd, J = 1.9, 8.6 Hz, 1H, minor), 5.00 (dd, J = 2.0, 8.3 Hz, 1H,
major), 4.37-4.14 (m, 3H), 3.89-3.77 (m, 1H, major), 3.54 (dt, J =
3.2, 12.9 Hz, 1H, minor), 3.09 (dt, J = 3.1, 13.5 Hz, 1H, major), 3.00
(dt, J = 4.6 Hz, 13.5 Hz, 1H, minor), 2.88 (dt, J = 4.4, 13.6 Hz, 1H,
major), 2.21 (s, 3H, major), 2.19 (s, 3H, minor), 2.11-2.00 (m, 2H,
minor), 1.98-1.90 (m, 2H, major). 13C NMR (75 MHz, methanol
d4) δ (ppm) (2 rotamers) 170.6 (Cq), 156.0 (Cq), 128.8 (CH), 128.0
(CH), 125.8 (CH), 125.4 (CH). 121.7 (CH), 119.7 (CH), 119.6 (CH),
117.8 (CH), 117.5 (CH), 62.1 (CH2), 62.0 (CH2), 41.7 (CH2). 37.7
(CH2), 35.3 (CH2), 35.2 (CH2), 34.9 (CH2), 33.5 (CH2), 33.4 (CH2),
21.8 (CH3), 21.4 (CH3). IR υ (neat): 3349, 2925, 2542, 1630,1422,
1394, 1294, 1230, 1070 cm-1. MS (ESI, m/z): 287.1 (100) [M+H+].
+
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H19N2O3 : 287.1390.
Found: 287.1393.
Methyl
3-(2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-
6-acetyl-2,3,5,6,7,8-hexahydro-3a,7-methanochromeno[5,4-
ef][1,3]diazonin-9(4H)-one (11i). Prepared according to procedure
H from amide (17.3 mg, 0.06 mmol), CH2Cl2 (0.35 mL) and TFA
(46 µL, 0.006 mmol). The crude mixture was purified over silica
gel (DCM to DCM/MeOH (95/5)) to afford a white solid (m =
yl)ethoxy)benzoate (S28). Prepared according to procedure F
from amine (50.7 mg, 0.194 mmol), triethylamine (0.108 mL,
0.776 mmol), 4-dimethylaminopyridine (cat.), CH2Cl2 (1.9 mL)
and a solution of acetyl chloride (0.021 mL, 0.29 mmol) in
CH2Cl2 (0.32 mL). The crude mixture was purified over silica gel
(DCM to DCM/MeOH 95/5) to afford a yellow oil (m = 38 mg,
1
16.9 mg, 97%). H NMR (300 MHz, CDCl3) δ (ppm) (2 rotamers,
85/15): 8.16 (dd, J = 2.1, 8.6 Hz, 1H, minor), 8.12 (dd, J = 1.6, 7.9
Hz, 1H, major), 7.26 (t, J = 8.1 Hz, 1H), 7.10 (dd, J = 1.7, 8.4 Hz, 1H,
minor), 7.06 (dd, J = 1.5, 8.0 Hz, 1H, major), 6.92 (brs, 1H), 5.96
(dd, J = 4.6, 5.1 Hz, 1H, major), 5.45 (t, J = 5.0 Hz, 1H, minor),
4.42-4.21 (m, 2H), 3.62-3.48 (m, 1H), 3.43-3.29 (m, 1H), 4.21-4.04
(m, 2H, minor), 2.34 (s, 3H, minor), 2.25-1.99 (m, 3H, major +
minor), 2.17 (s, 3H, major), 1.91-1.67 (m, 2H, major + minor). 13C
NMR (75 MHz, CDCl3) δ (ppm) 171.3 (Cq), 170.1 (Cq), 169.7 (Cq),
168.9 (Cq), 153.4 (Cq), 153.2 (Cq), 132.2 (Cq), 129.1 (Cq), 127.9
(CH), 127.8 (CH), 127.2 (CH), 127.1 (CH), 122.9 (CH), 122.0 (CH),
61.4 (CH), 61.1 (CH), 56.5 (CH2), 38.1 (CH2), 37.9 (CH2), 37.6
(CH2), 37.3 (CH2), 36.5 (CH2), 36.2 (CH2), 35.9 (CH2), 35.1 (CH2),
33.6 (CH2), 32.0 (Cq), 21.6 (CH3), 21.0 (CH3). IR υ (neat): 3228,
3035 - 2868, 1625, 1685, 1423, 1302 cm-1. MS (ESI, m/z): 287.1 (100)
[M+H+]. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H19N2O3+:
287.1396. Found: 287.1398.
1
64%). H NMR (300 MHz, CDCl3) δ (ppm) (2 rotamers : 55/45) :
7.62 (td, J = 7.5, 1.4 Hz, 1H), 7.53 (dd, J = 2.7, 1.5 Hz, 1H), 7.32 (t, J
= 8.0 Hz, 1H), 7.07 (d, J = 8.2, 2.8, 1.1 Hz, 1H), 5.54 (m, 1H, maj.),
5.49 (m, 1H, min.), 4.09 (dt, J = 6.7, 2.0 Hz, 2H), 4.04 (m, 2H,
maj.), 3,92 (m, 2H, min.), 3.90 (s, 3H), 3.68 (t, J = 5.7 Hz, 2H,
min.), 3.52 (t, J = 5.7 Hz, 2H, maj.), 2.51 (m, 2H), 2.24-2.12 (brm,
2H), 2.10 (s, 3H, maj.), 2.08 (s, 3H, min.). 13C NMR (75 MHz,
CDCl3) δ (ppm) (2 rotamers) 169.3 (Cq), 169.1 (Cq), 166.9 (Cq),
158.7 (Cq), 134.6 (Cq), 132.6 (Cq), 131.4 (Cq), 129.4 (CH), 122.0
(CH), 120.6 (CH), 119.9 (CH), 118.9 (CH), 114.6 (CH), 66.5 (CH2),
66.3 (CH2), 52.1 (CH3), 45.4 (CH2), 43.2 (CH2), 41.6 (CH2), 38.1
(CH2), 36.5 (CH2), 29.2 (CH2), 28.3 (CH2), 21.8 (CH3), 21.4 (CH3).
IR υ (neat): 2949-2841, 1718, 1637, 1429, 1275, 1223 cm-1. MS (ESI,
m/z): 304.1 (100) [M+H+]. HRMS (ESI-TOF) m/z: [M+H]+ Calcd
+
for C17H22NO4 : 304.1549. Found: 304.1536.
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 18
Methyl 3-(2-(pyridin-4-yl)ethyl)benzoate (S29). To a solution of
(3-(methoxycarbonyl)benzyl)triphenylphosphonium bromide
Methyl 3-(2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)ethyl)benzoate
(S32). Prepared according to procedure F from amine (255 mg,
1
(700mg, 1.70 mmol, 1 eq) in dry THF (7 mL) cooled at 0°C in an
ice-bath, was added in one portion t-BuOK (230 mg, 2.05 mmol,
1.2 eq). After stirring 30 min at this temperature, 4-
pyridinecarboxaldehyde (176 μL, 1.87 mmL, 1.1 eq) was added.
The reaction mixture was allowed to reach room temperature
and stirred at this temperature for 1 hour. After cooling with an
ice-bath, the reaction mixture was quenched with saturated
NH4Cl then extracted with EtOAc. The combined organic layers
were dried on MgSO4 and the solvent was removed under re-
duced pressure. The crude mixture was purified through silica
gel (Hept. to Hept./EtOAc 4/6) to afford the title compound as a
light yellow oil (350 mg, 86% yield, mixture of Z/E diasterom-
ers).
1.04 mmol), triethylamine (0.58 mL, 4.15 mmol), 4-
dimethylaminopyridine (cat.), CH2Cl2 (14 mL) and a solution of
acetyl chloride (0.11 mL, 1.56 mmol) in CH2Cl2 (1.7 mL). The
crude mixture was purified over silica gel (Hept. to EtOAc) to
afford a yellow oil (m = 172 mg, 55%). 1H NMR (300 MHz, CDCl3)
δ (ppm) (2 rotamers, 50/50) : 7.91-7.83 (m, 2H, major+minor),
7.39-7.33 (m, 2H, major+minor), 5.43 (t, J = 3.2 Hz, 1H major),
5.34 (t, J = 3.0 Hz, 1H major), 4.01 (brs, 1H), 3.92 (s, 3H), 3.89 (brs,
1H), 3.68 (t, J = 5.8 Hz, 1H), 3.51 (t, J = 5.8 Hz, 1H), 2.78 (t, J = 7.7
Hz, 2H), 2.34 (m, 2H), 2.12 (m, 2H), 2.11 (s, 3H), 2.08 (s, 3H). 13C
NMR (75 MHz, CDCl3) δ (ppm) (2 rotamers) 169.4 (Cq), 169.2
(Cq), 167.2 (Cq), 142.0 (Cq), 137.1 (Cq), 135.1 (Cq), 133.0 (CH), 130.2
(Cq), 129.4 (CH), 128.4 (CH), 127.3 (CH), 119.1 (CH), 117.6 (CH),
52.0 (CH3), 45.4 (CH2), 43.2 (CH2), 41.6 (CH2), 38.7 (CH2), 38.6
(CH2), 38.2 (CH2), 33.8 (CH2), 33.6 (CH2), 29.0 (CH2), 28.1 (CH2),
21.8 (CH3), 21.5 (CH3). IR υ (neat): 2922, 1718, 1641, 1432, 1284, 1201
cm-1. MS (ESI, m/z): 288.1 (100) [M+H+]. HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C17H21NO3Na+: 310.1414. Found: 310.1416.
3-(2-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)ethyl)-N-
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To a solution of methyl 3-(2-(pyridin-4-yl)vinyl)benzoate (350
mg, 1.46 mmol, 1 eq) in anhydrous ethanol (20 mL) was added
Pd/C (10% loading, 150 mg, 10% eq). The flask was purged with
hydrogen and maintained under a hydrogen atmosphere for 2
hours. The reaction mixture was then filtered on a pad of celite®.
The organic layer was reduced under vacuum to give the titled
1
compound as colorless oil. H NMR (300 MHz, CDCl3) δ (ppm):
methoxybenzamide (9j). Prepared according to procedure C from
methyl ester (172 mg, 0.599 mmol), 3N NaOH (2.1 mL), EtOH
(3.5 mL). The resulting crude carboxylic acid (0.336 mmol) was
dissolved in DMF (1.5 mL) and reacted with EDCI.HCl (88 mg,
0.571 mmol), HOBt (88 mg, 0.571 mmol), MeONH2.HCl (48 mg,
0.571 mmol), and iPr2NEt (0.21 mL, 1,19 mmol). Purification over
silica gel (CH2Cl2 to CH2Cl2 /MeOH 90/10) afforded the title
8.50 (d, J = 5.9 Hz, 2H), 7.9 (dd, J = 1.8, 7.1 Hz, 2H), 7.35 (m, 2H),
7.09 (d, J = 5.9 Hz, 2H), 3.93 (s, 3H), 2.98 (m, 2H). 13C NMR (75
MHz, CDCl3) δ (ppm): 167.1 (Cq), 150 (Cq), 149.8 (CH), 140.9
(Cq), 133.1 (CH), 130.4 (Cq), 129.5 (CH), 128.6 (CH), 127.6 (CH),
123.9 (CH), 52.13 (CH3), 36.8 (CH2), 36.3 (CH2). IR υ (neat): 2950,
1716, 1600, 1434, 1282, 1199, 1107 cm-1. MS (ESI, m/z): 341.1 (100)
+
1
[M+H+]. HMRS (ESI-TOF) m/z: [M+H]+ Calcd for C15H16NO2 :
compound as a colorless oil (m = 129 mg, 71% over 2 steps). H
242.1176. Found: 242.1179.
NMR (300 MHz, CDCl3) δ (ppm): (2 rotamers, 50/50) 9.15 (brs,
1H), 7.64-7.50 (m, 2H), 7.40-7.30 (m, 2H), 5.39 (brs, 1H), 5.34
(brs, 1H), 4.01 (brs, 1H), 3.90 (s, 3H), 3.88 (brs, 1H), 3.67 (t, J = 5.9
Hz, 1H), 3.52 (t, J = 5.8 Hz, 1H), 2.77 (dt, J = 1.6, 7.9 Hz, 2H), 2.33
(m, 2H), 2.12 (s, 3H), 2.09 (m, 2H), 2.07 (s, 3H) 13C NMR (75 MHz,
CDCl3) δ (ppm) (presence of rotamers) 169.8 (Cq), 166.5 (Cq),
142.2 (Cq), 137.1 (Cq), 135.2 (Cq), 132.1 (CH), 132.0 (CH), 128.5
(CH), 127.3 (CH), 124.6 (CH), 119.0 (CH), 117.6 (CH), 64.3 (CH3),
45.4 (CH2), 43.3 (CH2), 41.7 (CH2), 38.6 (CH2), 38.5 (CH2), 38.4
(CH2), 33.8 (CH2), 33.7 (CH2), 29.0 (CH2), 28.0 (CH2), 21.7 (CH3),
21.4 (CH3). IR υ (neat): 3439, 3164, 2930, 1606, 1438, 1233 cm-1. MS
(ESI, m/z): 303.4 (100) [M+H+]. HRMS (ESI-TOF) m/z: [M+H]+
Methyl
3-(2-(1-benzyl-1,2,3,6-tetrahydropyridin-4-
yl)ethyl)benzoate (S30). Prepared according to procedure B from
methyl 3-(2-(pyridin-4-yl)ethyl)benzoate (310 mg, 1.52 mmol) in
acetone (7.8 mL) and benzyl bromide (0.182 mL, 1.59 mmol). The
crude pyridinium was used without purification. Pyridinium
(1.52 mmol) in methanol (9.8 mL) and sodium borohydride (115
mg, 3.04 mmol). The crude product was purified by flash column
chromatography (Hept. to Hept./EtOAc 4/6) to afford the title
compound as a yellow oil (m = 353 mg, 69% over 2 steps). The oil
turned to purple readily and was used in the next step immedi-
ately. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.81-7.71 (m, 2H), 7.35-
7.10 (m, 7H), 5.50 (brs, 1H), 3.87 (s, 3H), 3.61 (s, 2H), 2.99 (brs,
2H), 2.80 (m, 2H), 2.65 (t, J = 5.7 Hz, 2H), 2.25 (m, 2H). 13C NMR
(75 MHz, CDCl3) δ (ppm): 167.3 (Cq), 142.6 (Cq), 138.4 (Cq), 135.5
(CH), 133.1 (Cq), 133.0 (CH), 130.1 (Cq), 129.5 (CH), 129.4 (CH),
129.4 (CH), 129.2 (CH), 128.4 (CH), 128.3 (CH), 128.2 (CH), 128.1
(CH), 128.0 (CH), 127.1 (CH), 127.0 (CH), 119.6 (CH), 62.7 (CH2),
52.9 (CH2), 52.0 (CH3), 49.8 (CH2), 38.6 (CH2), 33.8 (CH2), 29.3
(CH2). IR υ (neat): 3027-2751, 1719, 1281, 1199 cm-1. MS (ESI, m/z):
336.2 (100) [M+H+]. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
+
Calcd for C17H23N2O4 : 319.1658 Found: 319.1669.
1'-acetyl-2,2',3,3'-tetrahydro-1'H-spiro[indene-1,4'-pyridine]-7-
carboxamide (10j). Prepared according to procedure G from
amide (30 mg, 0.095 mmol), [RhCp*Cl2]2 (1.5 mg, 0.0025 mmol)
and CsOAc (36.5 mg, 0.190 mmol) in t-AmOH (0.48 mL) at 60°C
overnight. The crude mixture was purified over silica gel (CH2Cl2
to CH2Cl2 /MeOH 90/10) to afford a colorless oil (m = 17.9 mg,
68%) .1H NMR (300 MHz, CDCl3) δ (ppm): (2 rotamers, 65/35)
7.27-7.11 (m, 4H), 6.57 (d, J = 8.3 Hz, 1H, major), 6.48 (brs, 1H,
NH minor), 5.90 (brs, 1H, NH major+minor), 5.72 (brs, 1H, NH
major), 4.98 (dd, J = 1.9, 8.6 Hz, 1H, minor), 4.89 (dd, J = 1.9, 8.4
Hz, 1H, major), 4.43 (ddd, J = 2.7, 4.3, 13.5 Hz, 1H major), 3.82
(dtd, J = 1.9, 4.1, 11.3 Hz, 1H, minor), 3.37 (td, J = 2.9, 12.7 Hz, 1H,
minor), 3.05-2.73 (m, 2H major+minor), 2.61 (dt, J = 4.4, 13.3 Hz,
1H, minor), 2.36 (ddd, J = 4.5, 13.2, 13.7 Hz, 1H, major), 2.13 (s, 3H,
major), 2.11 (s, 3H, minor), 2.07-1.88 (m, 2H major+minor), 1.81-
1.70 (m, 1H major+minor). 13C NMR (75 MHz, CDCl3) δ (ppm) (2
rotamers): 171.8 (Cq), 171.4 (Cq), 168.3 (Cq), 168.2 (Cq), 146.0
(Cq), 145.3 (Cq), 145.1 (Cq), 127.3 (CH), 127.1 (CH), 126.6 (CH),
126.4 (CH), 125.8 (CH), 125.5 (CH), 125.4 (CH), 123.7 (CH), 114.7
(CH), 114.1 (CH), 47.2 (Cq), 47.0 (Cq), 42.7 (CH2), 40.9 (CH2),
40.5 (CH2), 38.6 (CH2), 31.3 (CH2), 30.5 (CH2), 29.6 (CH2), 29.5
(CH2), 21.9 (CH3), 21.5 (CH3). IR υ (neat): 3370, 3212, 2931-2881,
1660, 1638, 1621 cm-1. MS (ESI, m/z): 271.3 (100) [M+H+]. HRMS
+
C22H26NO2 : 336.1958. Found: 336.1964.
Methyl 3-(2-(1,2,3,6-tetrahydropyridin-4-yl)ethyl)benzoate (S31).
Prepared according to procedure E from N-benzyl amine (348
mg, 1.04 mmol), 1,2 dichloroethane (5 mL), 1-chloroethyl chlo-
roformate (ACE-Cl) (0.22 mL, 2.07 mmol) then MeOH (10.4 mL).
The mixture was concentrated to give the title compound which
was purified through silica gel (CH2Cl2 to CH2Cl2 /MeOH 90/10)
1
to afford colorless oil (m = 255 mg, 99%). H NMR (300 MHz,
CDCl3) δ (ppm): 9.82 (brs, 1H), 7.90-7.85 (m, 2H), 7.38-7.35 (m,
2H), 5.40 (brs, 1H), 3.93 (s, 3H), 3.64 (brs, 2H), 5.38 (m, 2H), 2.81
(dd, J = 7.68, 9.23 Hz, 2H), 2.48-2.33 (m, 4H). 13C NMR (75 MHz,
CDCl3) δ (ppm) 167.1 (Cq), 141.4 (Cq), 139.6 (Cq), 133.0 (CH), 130.3
(Cq), 129.3 (CH), 128.6 (CH), 127.5 (CH), 114.0 (CH), 52.1 (CH3),
41.3 (CH2), 40.6 (CH2), 38.4 (CH2), 33.3 (CH2), 25.0 (CH2). IR υ
(neat): 3417, 2949, 2800, 2650, 1716, 1445, 1285, 1201 cm-1. MS (ESI,
m/z): 246.1 (100) [M+H+]. HRMS (ESI-TOF) m/z: [M+H]+ Calcd
+
(ESI-TOF) m/z: [M+H]+ Calcd for C16H19N2O2 : 271.1447. Found:
+
for C15H20NO2 : 246.1489. Found: 246.1494.
271.1443.
14
ACS Paragon Plus Environment

Page 15 of 18
The Journal of Organic Chemistry
4-acetyl-3,4,5,6,7,8-hexahydro-3,6a-methanoindeno[7,1-
Cl) (0.15 mL, 1.39 mmol) then MeOH (6.9 mL). The mixture was
concentrated to give the title compound which was purified
through silica gel (CH2Cl2 to CH2Cl2 /MeOH 90/10) to afford a
ef][1,3]diazonin-1(2H)-one (11j). Prepared according to procedure
H from amide (22.1 mg, 0.082 mmol), CH2Cl2 (0.7 mL) and TFA
(63 µL, 0.008 mmol). The crude mixture was purified over silica
gel (DCM to DCM/MeOH (95/5)) to afford a colorless oil (m =
1
2
3
4
5
6
7
8
1
beige foam (m = 225 mg, 99%). H NMR (300 MHz, CDCl3) δ
(ppm): 9.76 (brs, 1H), 8.01 (td, J = 7.5, 1.5 Hz, 1H), 7.94 (dd, J =
2.2, 1.6 Hz, 1H), 7.56 (m, 1H), 7.50 (m, 1H), 5.49 (s, 1H), 4.29 (s,
2H), 3.94 (s, 3H), 3.54 (brs, 2H), 3.20 (t, J = 5.9 Hz, 2H), 2.94 (s,
3H), 2.53 (brm, 2H). 13C NMR (75 MHz, CDCl3) δ (ppm) 165.9
(Cq), 139.0 (Cq), 133.7 (CH), 132.7 (Cq), 131.8 (Cq), 129.9 (CH),
129.4 (CH), 128.2 (CH), 118.6 (CH), 55.8 (CH2), 52.4 (CH3), 41.0
(CH2), 40.3 (CH2), 37.7 (CH3), 22.5 (CH2). IR υ (neat): 3416, 2931-
2642, 1717, 1333, 1149 cm-1. MS (ESI, m/z): 325.1 (100) [M+H+].
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H21N2O4S+: 325.1222.
found: 325.1229.
1
20.9 mg, 94%). H NMR (300 MHz, CDCl3) δ (ppm) (2 rotamers,
80/20): 8.22 (d, J = 7.9 Hz, 1H), 7.38-7.32 (m, 1H), 7.26 (t, J = 7.61
Hz, 1H), 6.62 (brm, 1H), 6.12-6.05 (m, 1H, major), 5.36 (brm, 1H,
minor), 4.46-4.35 (m, 1H, minor), 3.51 (dd, J = 4.1, 14.2 Hz, 1H,
major), 3.12-2.93 (m, 2H), 2.88-2.76 (m, 1H), 2.47 (dt, J = 2.9, 13.9
Hz, 1H, minor), 2.21 (s, 3H minor), 2.24-2.07 (m, 2H), 2.03 (s, 3H
major), 2.01-1.85 (m, 2H), 1.82-1.72 (m, 1H), 1.63 (dt, J = 4.3, 13.1
Hz, 1H). 13C NMR (75 MHz, CDCl3) δ (ppm) (2 rotamers): 170.2
(Cq), 168.2 (Cq), 146.5 (Cq), 143.6 (Cq), 130.8 (CH), 129.5 (Cq),
129.3 (CH), 128.7 (Cq), 127.5 (CH), 62.9 (CH), 57.1 (CH), 46.9
(Cq), 41.9 (CH2), 38.5 (CH2), 37.6 (CH2), 36.4 (CH2), 35.2 (CH2),
34.5 (CH2), 33.2 (CH2), 29.6 (CH2), 21.8 (CH3), 21.3 (CH3). IR υ
(neat): 3224, 3086-2872, 1625, 1615, 1418, 1288 cm-1. MS (ESI, m/z):
271.3 (100) [M+H+]. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methyl
3-(N-((1-acetyl-1,2,3,6-tetrahydropyridin-4-
yl)methyl)methylsulfonamido)benzoate (S36). Prepared accord-
ing to procedure F from amine (125.7 mg, 0.387 mmol), triethyl-
amine (0.22 mL, 1.55 mmol), 4-dimethylaminopyridine (cat.),
CH2Cl2 (3.8 mL) and a solution of acetyl chloride (0.041 mL, 0.581
mmol) in CH2Cl2 (0.64 mL). The crude mixture was purified over
silica gel (DCM to DCM/MeOH 95/5) to afford a yellow oil (m =
111.4 mg, 78%). 1H NMR (300 MHz, CDCl3) δ (ppm) (2 rotamers) :
7.97 (td, J = 7.4, 1.7 Hz, 1H), 7.91 (m, 1H), 7.55-7.40 (m, 2H), 5.46
(brs, 1H), 4.26 (s, 2H), 3,90 (s, 3H), 3.86 (brs, 1H, maj.), 3.78 (brs,
1H, min.), 3.55 (t, J = 5.7 Hz, 1H min.), 3.39 (t, J = 5.7 Hz, 1H maj.),
2.89 (s,3H), 2.20 (brm, 1H, maj.), 2.10 (brm, 1H, min.), 2.04 (s, 3H,
maj.), 1.98 (s, 3H min.). 13C NMR (75 MHz, CDCl3) δ (ppm) (2
rotamers) 169.2 (Cq), 169.1 (Cq), 165.9 (Cq), 139.2 (Cq), 138.9 (Cq),
133.3 (CH), 133.2 (CH), 132.7 (Cq), 131.5 (Cq), 130.7 (Cq), 129.5
(CH), 129.1 (CH), 129.0 (CH), 128.3 (CH), 128.2 (CH), 124.2 (CH),
122.1 (CH), 55.8 (CH2), 55.6 (CH2), 52.3 (CH3), 45.0 (CH2), 42.8
(CH2), 41.3 (CH2), 37.7 (CH2), 37.4 (CH3), 37.3 (CH3), 26.5 (CH2),
25.8 (CH2), 21.7 (CH3), 21.3 (CH3). IR υ (neat): 3009-2845, 1720,
1630, 1434, 1338, 1283, 1151 cm-1. MS (ESI, m/z): 367.4 (100)
[M+H+]. HMRS (ESI-TOF) m/z: [M+H]+ Calcd for C17H22N2O5S+:
367.1328. found: 367.1343.
+
C16H19N2O2 : 271.1447. Found: 271.1444.
Methyl
3-(N-(pyridin-4-ylmethyl)methylsulfonamido)benzoate
(S33). To a solution of methyl 3-(methylsulfonamido)benzoate
(723 mg, 3.15 mmol) in DMF (22 mL) was added NaH 60% (278
mg, 6.94 mmol) at 0°C. After stirring at 0°C for 30 min, 4-
(chloromethyl)pyridine hydrochloride (569 mg, 3.47 mmol) was
added and the reaction was stirred overnight at room tempera-
ture. Saturated NaHCO3 was added, and the aqueous layer was
extracted with EtOAc (x3). The combined organic layers were
washed with water, then brine and dried over Na2SO4. The sol-
vent was removed under vacuum and the crude mixture purified
through silica gel (Hept. to EtOAc) to afford the corresponding
1
compound as a white solid (m = 335 mg, 33%). H NMR (300
MHz, CDCl3) δ (ppm): 8.49 (d, J = 5.4 Hz, 2H), 7.96 (t, J = 1.8 Hz,
1H), 7.92 (td, J = 7.5, 1.6 Hz, 1H), 7.48 (ddd, J = 8.0, 2.3, 1.1 Hz,
1H), 7.39 (t, J = 7.8 Hz, 1H), 7.21 (d, J = 5.5 Hz, 2H), 4.88 (s, 2H),
3.87 (s, 3H), 2.96 (s, 3H). 13C NMR (75 MHz, CDCl3) δ (ppm) 165.7
(Cq), 149.9 (CH), 145.0 (Cq), 139.0 (Cq), 133.4 (CH), 131.7 (Cq),
129.7 (CH), 129.2 (CH), 128.1 (CH), 122.8 (CH), 53.5 (CH2), 52.3
(CH3), 37.8 (CH3). IR υ (neat): 3034-2913, 1727, 1333, 1287 cm-1. MS
(ESI, m/z): 321.1 (100) [M+H+]. HMRS (ESI-TOF) m/z: [M+H]+
Calcd for C15H16N2O4S+: 321.0909. found: 321.0909. m.p. = 130-133
°C.
3-(N-((1-acetyl-1,2,3,6-tetrahydropyridin-4-
yl)methyl)methylsulfonamido)-N-methoxybenzamide (9k). Pre-
pared according to procedure C from methyl ester (195.9 mg,
0.535 mmol), LiOH (101.1 mg, 4.28 mmol), MeOH (5.3 mL) and
water (5.3 mL). The resulting crude carboxylic acid (0.525 mmol)
was dissolved in DMF (1.6 mL) and reacted with EDCI (110.6 mg,
0.577 mmol), HOBt (77.9 mg, 0.577 mmol), MeONH2.HCl (43.8
mg, 0.525 mmol), and iPr2NEt (0.21 mL, 1.21 mmol). Purification
over silica gel (DCM to DCM/MeOH 98/2 to 95/5) afforded the
title compound as a white foam (m = 126.6 mg, 63% over 2
steps). 1H NMR (300 MHz, CDCl3) δ (ppm) (2 rotamers : 59/41) :
10.63 (brs, 1H, min.), 10.54 (brs, 1H, maj.), 7.78-7.68 (m, 2H),
7.47-7.34 (m, 2H), 5.44 (m, 1H), 4.23 (s, 2H), 3.83 (brs, 2H, maj.),
3.80 (s, 3H), 3.77 (brs, 2H, min.), 3.51 (t, J = 5.7 Hz, 2H, min.),
3.40 (t, J = 5.6 Hz, 2H, maj.), 2.87 (s, 3H), 2.18 (brm, 2H, maj.),
2.07 (brm, 2H, min.), 2.01 (s, 3H, maj.), 1.95 (s, 3H, min.). 13C
NMR (75 MHz, CDCl3) δ (ppm) (2 rotamers) 169.8 (Cq), 169.6
(Cq), 164.9 (Cq), 139.2 (Cq), 139.1 (Cq), 133.4 (Cq), 132.7 (Cq), 132.0
(CH), 131.8 (CH), 129.6 (CH), 126.6 (CH), 124.0 (CH), 122.3 (CH),
63.2 (CH3), 55.7 (CH2), 55.6 (CH2), 45.1 (CH2), 43.0 (CH2), 41.4
(CH2), 38.0 (CH2), 37.5 (CH3), 37.4 (CH3), 26.6 (CH2), 25.7 (CH2),
21.7 (CH3), 21.3 (CH3). IR υ (neat): 3197, 2930, 1613, 1331, 1150 cm-1.
MS (ESI, m/z): 404.1 (100) [M+Na+]. HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C17H23N3O5SNa+: 404.1256. found: 404.1255.
Methyl
yl)methyl)methylsulfonamido)benzoate (S34). Prepared accord-
ing to procedure from methyl 3-(N-(pyridin-4-
3-(N-((1-benzyl-1,2,3,6-tetrahydropyridin-4-
B
ylmethyl)methylsulfonamido)benzoate (335 mg, 1.04 mmol) in
acetone (5.2 mL) and benzyl bromide (0.13 mL, 1.09 mmol). The
crude pyridinium was used without purification. Pyridinium
(1.04 mmol) in methanol (10.4 mL) and sodium borohydride
(86.6 mg, 2.29 mmol). The crude product was purified by flash
column chromatography (Hept. to Hept./EtOAc 5/5) to afford
the title compound as a dark orange oil (m = 288 mg, 67% over 2
1
steps). H NMR (300 MHz, CDCl3) δ (ppm): 7.98 (dt, J = 7.6, 1.7
Hz, 1H), 7.94 (t, J = 2.0 Hz, 1H), 7.53 (dt, J = 7.6, 1.9 Hz, 1H), 7.45
(t, J = 7.8 Hz, 1H), 7.32-7.17 (m, 5H), 5.45 (brs, 1H), 4.23 (s, 2H),
3.91 (s, 3H), 3.49 (s, 2H), 2.90 (s, 3H), 2.82 (brs, 2H), 2.49 (t, J =
5.8 Hz, 2H), 2.16 (m, 2H). 13C NMR (75 MHz, CDCl3) δ (ppm):
166.0 (Cq), 139.3 (Cq), 137.8 (Cq), 133.5 (CH), 131.3 (Cq), 130.8
(Cq), 129.3 (CH), 129.0 (CH), 128.8 (CH), 128.5 (CH), 128.1 (CH),
127.0 (CH), 124.9 (CH), 62.0 (CH2), 55.8 (CH2), 52.3 (CH3), 52.1
(CH2), 49.2 (CH2), 37.5 (CH3), 26.5 (CH2). IR υ (neat): 3027-2753,
1721, 1443, 1150 cm-1. MS (ESI, m/z): 415.1 (100) [M+H+]. HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C22H27N2O4S+: 415.1692. found:
415.1707.
Methyl
yl)methoxy)benzoate (S37). Prepared according to procedure E
from methyl 3-((1-benzyl-1,2,5,6-tetrahydropyridin-3-
3-((1-acetyl-1,2,5,6-tetrahydropyridin-3-
yl)methoxy)benzoate S39 (170 mg, 0.503 mmol), 1,2 dichloro-
ethane (5 mL), 1-chloroethyl chloroformate (ACE-Cl) (0.10 mL,
1.00 mmol) then MeOH (10 mL). The mixture was concentrated
to give the free amine, which was used in the next step without
purification. The title compound was prepared according to
Methyl
3-(N-((1,2,3,6-tetrahydropyridin-4-
yl)methyl)methylsulfonamido)benzoate (S35). Prepared accord-
ing to procedure E from N-benzyl amine (288 mg, 0.695 mmol),
1,2 dichloroethane (6.9 mL), 1-chloroethyl chloroformate (ACE-
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 18
procedure F from amine (123 mg, 0.503 mmol), triethylamine
Methyl
3-((1-benzyl-1,2,5,6-tetrahydropyridin-3-
(0.28 mL, 2.01 mmol), 4-dimethylaminopyridine (cat.), CH2Cl2 (7
mL) and a solution of acetyl chloride (0.05 mL, 0.75 mmol) in
CH2Cl2 (1 mL). The crude mixture was purified over silica gel
(Hept. to EtOAc) to afford a colorless oil (m = 130 mg, 88% yield
over two steps). 1H NMR (300 MHz, CDCl3) δ (ppm) (2 rotamers,
55/45): 7.70-7.63 (m, 1H), 7.61-7.56 (m, 1H), 7.41-7.31 (m, 1H), 7.15-
7.08 (m, 1H), 6.07 (brs, 1H, minor), 5.99 (brs, 1H, major), 4.53
(brs, 2H, minor), 4.50 (brs, 2H, major), 4.18 (dt, J = 1.8, 2.6 Hz,
1H), 4.05 (td, J = 2.1, 2.8 Hz, 1H), 3.93 (s, 3H, minor), 3.92 (s, 3H,
major), 3.70 (t, J = 5.8 Hz, 1H), 3.54 (t, J = 5.8 Hz, 1H), 2.32-2.18
(m, 2H), 2.15 (s, 3H, major), 2.13 (s, 3H, minor). 13C NMR (75
MHz, CDCl3) δ (ppm): 169.6 (Cq), 169.3 (Cq), 166.8 (Cq), 166.7
(Cq), 158.5 (Cq), 158.3 (Cq), 131.9 (Cq), 131.5 (Cq), 131.4 (Cq), 130.6
(Cq), 129.5 (CH), 129.4 (CH), 126.3 (CH), 123.5 (CH), 122.4 (CH),
122.3 (CH), 120.1 (CH), 120.0 (CH), 119.9 (CH), 114.9 (CH), 70.3
(CH2), 70.2 (CH2), 52.2 (CH3), 52.1 (CH3), 46.0 (CH2), 42.9 (CH2),
42.4 (CH2), 37.9 (CH2), 25.4 (CH2), 24.5 (CH2), 21.9 (CH3), 21.5
(CH3). IR υ (neat): 3020, 1721, 1643, 1281 cm-1. MS (ESI, m/z): 312.2
(100) [M+Na+]. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C16H19NO4Na+: 312.1206. Found: 312.1209.
yl)methoxy)benzoate (S38). Prepared according to procedure A
from methyl 5-hydroxy-2-methylbenzoate (67 mg, 0.44 mmol),
1-benzyl-5-(chloromethyl)-1,2,3,6-tetrahydropyridine hydrochlo-
ride17 (113 mg, 0.437 mmol), K2CO3 (150 mg, 1.08 mmol) in DMF
(3 mL). The solvent was removed under vacuum and the crude
mixture purified through silica gel (Hept. to Hept./EtOAc 5/5) to
1
2
3
4
5
6
7
8
1
afford a colorless oil (m = 96 mg, 65%). H NMR (300 MHz,
CDCl3) δ (ppm): 7.64 (dt, J = 2.3, 7.6 Hz, 1H), 7.57 (dd, J = 1.53, 2.6
Hz, 1H), 7.41-7.24 (m, 6H), 7.10 (dd, J = 2.81, 8.19 Hz, 1H), 5.92
(brs, 1H), 4.45 (s, 2H), 3.92 (s, 3H), 3.65 (s, 2H), 3.10 (q, J = 2.3 Hz,
2H), 2.60 (t, J = 5.7 Hz, 2H), 2.29-2.20 (m, 2H). 13C NMR (75
MHz, CDCl3) δ (ppm): 166.9 (Cq), 158.7 (Cq), 138.1 (Cq), 133.2
(Cq), 131.4 (Cq), 129.5 (CH), 129.3 (CH), 128.3 (CH), 127.1 (CH),
124.5 (CH), 122.1 (CH), 120.1 (CH), 115.0 (CH), 70.9 (CH2), 62.6
(CH2), 53.3 (CH3), 52.1 (CH2), 49.3 (CH2), 25.7 (CH2). IR υ (neat):
3058-2749, 1722, 1464, 1273, 1022 cm-1. MS (ESI, m/z): 338.4 (100)
[M+H+]. HMRS (ESI-TOF) m/z: [M+H]+ Calcd for C21H24NO3+:
338.1751. Found: 338.1753.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-((1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)methoxy)-N-
methoxybenzamide (9m). Prepared according to procedure C
from methyl ester (264 mg, 0.782 mmol), LiOH (37 mg, 1.56
mmol), THF/Water (1/1, 6 mL). The resulting crude carboxylic
acid (0.782 mmol) was dissolved in DMF (8 mL) and reacted
with EDCI.HCl (165 mg, 0.860 mmol), HOBt (116 mg, 0.860
mmol), MeONH2.HCl (72 mg, 0.860 mmol), and iPr2NEt (0.31
mL, 1.8 mmol). Purification over silica gel (CH2Cl2 to CH2Cl2
/MeOH 90/10) afforded the title compound as a colorless oil (m
= 275 mg, 80% over 2 steps). 1H NMR (300 MHz, CDCl3) δ (ppm):
9.17 (brs, 1H), 7.40-7.24 (m, 8H), 7.04 (td, J = 2.33, 7.08 Hz, 1H),
5.88 (brs, 1H), 4.41 (s, 2H), 3.88 (s, 3H), 3.64 (s, 2H), 3.07 (q, J =
2.3 Hz, 2H), 2.59 (t, J = 5.74 Hz, 2H), 2.27-2.17 (m, 2H). 13C NMR
(75 MHz, CDCl3) δ (ppm): 159.0 (Cq), 137.9 (Cq), 133.1 (Cq), 132.0
(Cq), 129.7 (CH), 129.3 (CH), 128.3 (CH), 127.2 (CH), 124.5 (CH),
119.1 (CH), 119.0 (CH), 113.2 (CH), 70.9 (CH2), 64.4 (CH3), 62.6
(CH2), 53.2 (CH2), 49.3 (CH2), 25.6 (CH2). IR υ (neat): 3196, 3028-
2803, 1641, 1583, 1233 cm-1. MS (ESI, m/z): 353.2 (100) [M+H+].
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C21H25N2O3+: 353.1865.
Found: 353.1870.
1'-benzyl-1',6'-dihydro-2H,2'H-spiro[benzofuran-3,3'-pyridine]-4-
carboxamide (10m). Prepared according to procedure G from
amide (29 mg, 0.083 mmol), [RhCp*Cl2]2 (1.3 mg, 0.0020 mmol)
and CsOAc (31 mg, 0.165 mmol) in t-AmOH (0.41 mL) at 60°C
overnight. The crude mixture was purified over silica gel (CH2Cl2
to CH2Cl2 /MeOH 90/10) to afford a colorless oil (m = 23.8 mg,
91%) .1H NMR (300 MHz, CDCl3) δ (ppm): 7.76 (brs, 1H, NH),
7.35-7.15 (m, 7H), 6.90 (dd, J = 1.77, 7.4 Hz, 1H), 5.96 (td, J = 3.3,
9.8 Hz, 1H), 5.86 (brs, 1H, NH), 5.72 (td, J = 2.1, 9.9 Hz, 1H), 4.55
(d, J = 8.9 Hz, 1H), 4.19 (d, J = 8.6 Hz, 1H), 3.69 (d, J = 12.8 Hz,
1H), 3.53 (d, J = 13.0 Hz, 1H), 3.15-2.90 (m, 3H), 2.74 (d, J = 11.3 Hz,
1H). 13C NMR (75 MHz, CDCl3) δ (ppm): 169.8 (Cq), 160.8 (Cq),
137.3 (Cq), 133.7 (Cq), 129.1 (Cq), 128.4 (CH), 127.5 (CH), 126.7
(CH), 121.1 (CH), 112.5 (CH), 81.9 (CH2), 62.4 (CH2), 59.9 (CH2),
52.1 (CH2), 49.5 (Cq). IR υ (neat): 3189, 3017-2812, 1635, 1562, 1228
cm-1. MS (ESI, m/z): 319.4 (100) [M+H+]. HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C21H22N2ONa+: 341.1624. Found: 341.1625.
3-((1-benzyl-6-methyl-1,2,5,6-tetrahydropyridin-3-yl)methoxy)-N-
methoxybenzamide (9n). To a solution of (1-benzyl-6-methyl-
1,2,5,6-tetrahydropyridin-3-yl)methanol (640 mg, 2.95 mmol) in
THF (15 mL), were added methyl 3-hydroxybenzoate (448 mg,
2.95 mmol, 1 eq) and triphenylphosphine (1.08 g, 4.13 mmol, 1.4
eq). Diethyl azodicarboxylate (0.68 mmL, 4.13 mmol, 1.4 eq) was
added dropwise and the reaction mixture was stirred overnight
at room temperature. EtOAc was added and the organic layer
was washed with water, brine and dried over Na2SO4 then re-
duced under vacuum. The crude product was purified by flash
chromatography (Hept. to hept./EtOAc 5/5) to give a colorless
3-((1-acetyl-1,2,5,6-tetrahydropyridin-3-yl)methoxy)-N-
methoxybenzamide (9l). Prepared according to procedure C from
methyl ester (121 mg, 0.418 mmol), LiOH (40 mg, 1.67 mmol),
THF/Water (1/1, 4 mL). The resulting crude carboxylic acid
(0.418 mmol) was dissolved in DMF (3 mL) and reacted with
EDCI.HCl (88 mg, 0.460 mmol), HOBt (62 mg, 0.460 mmol),
MeONH2.HCl (38 mg, 0.460 mmol), and iPr2NEt (0.17 mL, 0.96
mmol). Purification over silica gel (CH2Cl2 to CH2Cl2 /MeOH
90/10) afforded the title compound as colorless oil (m = 91 mg,
72% yield over 2 steps). 1H NMR (300 MHz, CDCl3) δ (ppm) (2
rotamers, 60/40): 10.61 (brs, 1H, NH, major), 10.47 (brs, 1H, NH,
minor), 7.36-7.25 (m, 2H), 7.24-7.16 (m, 1H), 6.99-6.87 (m, 1H),
5.92 (brs, 1H, minor), 5.83 (brs, 1H, major), 4.39 (brs, 2H, minor),
4.34 (brs, 2H, major), 4.01 (brs, 2H, major), 3.91 (brs, 2H, minor),
3.77 (s, 3H, major), 3.76 (s, 3H, minor), 3.56 (t, J = 5.6 Hz, 2H,
minor), 3.43 (t, J = 5.8 Hz, 2H, major), 2.20-2.06 (m, 2H), 2.03 (s,
3H, major), 3.00 (s, 3H, minor). 13C NMR (75 MHz, CDCl3) δ
(ppm): 169.7 (Cq), 169.6 (Cq), 165.8 (Cq), 158.5 (Cq), 158.4 (Cq),
133.4 (Cq), 131.9 (Cq), 130.6 (Cq), 129.6 (CH), 129.5 (CH), 126.1
(CH), 123.7 (CH), 120.0 (CH), 119.7 (CH), 118.9 (CH), 118.7 (CH),
113.4 (CH), 113.2 (CH), 70.3 (CH2), 70.2 (CH2), 64.1 (CH3), 46.1
(CH2), 43.1 (CH2), 42.3 (CH2), 39.9 (CH2), 25.3 (CH2), 24.5 (CH2),
21.9 (CH3), 21.4 (CH3). IR υ (neat): 3021, 2837, 1719, 1645, 1285 cm-1.
MS (ESI, m/z): 305.1 (100) [M+H+]. HRMS (ESI-TOF) m/z:
+
[M+H]+ Calcd for C16H21N2O4 : 305.1501 Found: 305.1502.
1'-acetyl-1',6'-dihydro-2H,2'H-spiro[benzofuran-3,3'-pyridine]-4-
carboxamide (10l). Prepared according to procedure G from
amide (33 mg, 0.108 mmol), [RhCp*Cl2]2 (3.3 mg, 0.0054 mmol)
and CsOAc (41 mg, 0.216 mmol) in t-AmOH (0.54 mL) at 60°C
overnight. The crude mixture was purified over silica gel (CH2Cl2
to CH2Cl2 /MeOH 90/10) to afford a colorless oil (m = 21.2 mg,
72% yield) .1H NMR (300 MHz, MeOD) δ (ppm) (2 rotamers,
70/30): 7.31-7.23 (m, 1H), 7.05 (dd, J = 7.6, 8.5 Hz, 1H), 6.94 (dd, J
= 8.1, 10.1 Hz, 1H), 5.98-5.79 (m, 2H), 4.62 (brm, 1H, minor), 4.54
(td, J = 1.5, 12.8 Hz, 1H), 4.44-4.31 (m, 1H), 4.21 (dd, J = 3.7, 17.9
Hz, 1H, major), 4.09-3.91 (m, 2H), 3.77 (d, J = 13.2 Hz, 1H, minor),
3.53 (dt, J = 4.0, 19.0 Hz, 1H, minor), 3.44 (dd, J = 2.1, 12.6 Hz, 1H,
major), 2.16 (s, 3H, major), 2.15 (s, 3H, minor). 13C NMR (75 MHz,
methanol D4) δ (ppm): (2 rotamers) 172.9 (Cq), 172.8 (Cq), 172.6
(Cq), 172.3 (Cq), 162.7 (Cq), 162.5 (Cq), 135.5 (Cq), 135.4 (Cq), 130.7
(CH), 130.6 (CH), 129.2 (Cq), 129.1 (Cq), 129.0 (CH), 127.8 (CH),
127.2 (CH), 126.6 (CH), 121.1 (CH), 120.9 (CH), 113.2 (CH), 113.1
(CH), 79.9 (CH2), 79.3 (CH2), 50.8 (CH2), 50.3 (Cq), 50.2 (Cq),
46.3 (CH2), 46.2 (CH2), 42.5 (CH2), 21.6 (CH3), 21.4 (CH3). IR υ
(neat): 3337, 3195, 1777, 1664, 1619, 1439, 11468 cm-1. MS (ESI,
m/z): 273.1 (100) [M+H+]. HRMS (ESI-TOF) m/z: [M+H]+ Calcd
for C15H17N2O3+: 273.1239 Found: 273.1241.
16
ACS Paragon Plus Environment

Page 17 of 18
The Journal of Organic Chemistry
oil (m = 798 mg, 79%, contamined with about 5% of inseparable
residual DEAD).
mg, 0.960 mmol), THF/Water (1/1.6 mL). The resulting crude
carboxylic acid (0.240 mmol) was dissolved in DMF (3 mL) and
reacted with EDCI.HCl (50 mg, 0.264 mmol), HOBt (36 mg,
0.264 mmol), MeONH2.HCl (22 mg, 0.264 mmol), and iPr2NEt
(0.05 mL, 0.552 mmol). Purification over silica gel (CH2Cl2 to
CH2Cl2 /MeOH 90/10) afforded the title compound as colorless
1
2
3
4
5
6
7
8
The amide was prepared according to procedure C from me-
thyl ester (297 mg, 0.845 mmol), LiOH (81 mg, 3.38 mmol),
THF/Water (1/1, 8 mL). The resulting crude carboxylic acid
(0.845 mmol) was dissolved in DMF (6 mL) and reacted with
EDCI.HCl (178 mg, 0.930 mmol), HOBt (125 mg, 0.930 mmol),
MeONH2.HCl (77 mg, 0.930 mmol), and iPr2NEt (0.34 mL, 1.94
mmol). Purification over silica gel (CH2Cl2 to CH2Cl2 /MeOH
90/10) afforded the title compound as colorless oil (m = 236 mg,
77% yield over 2 steps). 1H NMR (300 MHz, CDCl3) δ (ppm) 8.77
(brs, 1H, NH), 7.33-7.12 (m, 8H), 6.94 (td, J = 2.1, 7.7 Hz, 1H), 5.76
(brs, 1H), 4.32 (brs, 2H), 3.80 (s, 3H), 3.71 (d, J = 13.2 Hz, 1H), 3.45
(d, J = 13.2 Hz, 1H), 2.99 (m, 2H), 2.93-2.83 (m, 1H), 2.30 (m, 1H),
1.87 (m, 1H), 1.03 (d, J = 6.5 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ
(ppm): 158.9 (Cq), 131.2 (Cq), 129.7 (CH), 129.1 (CH), 128.3 (CH),
127.0 (CH), 123.5 (CH), 119.0 (CH), 113.3 (CH), 70.8 (CH2), 64.5
(CH3), 57.4 (CH2), 50.9 (CH), 49.2 (CH2), 32.0 (CH2), 14.9 (CH3).
IR υ (neat): 3192, 2966, 2931, 1649, 1580, 1482, 1290, 1237 cm-1. MS
(ESI, m/z): 367.5 (100) [M+H+]. HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C22H27N2O3+: 367.2022 Found: 367.2024.
1
oil (m = 29 mg, 39% yield over 2 steps). H NMR (300 MHz,
CDCl3) δ (ppm) (2 rotamers, 55/45): 9.88 (brs, 1H, NH), 9.73 (brs,
1H, NH), 7.41-7.26 (m, 3H), 7.04 (t, J = 8.2 Hz, 1H), 5.81 (brs, 1H,
major), 5.77 (brs, 1H, minor), 4.61 (s, 2H), 4.16 (s, 2H), 4.14 (s,
2H), 3.86 (s, 3H), 1.48 (s, 9H). 13C NMR (75 MHz, CDCl3) δ
(ppm): (presence of rotamers) 166.0 (Cq), 158.6 (Cq), 158.5 (Cq),
154.4 (Cq), 154.3 (Cq), 135.1 (Cq), 135.0 (Cq), 133.4 (Cq), 129.7
(CH), 123.3 (CH), 122.9 (CH), 120.7 (CH), 119.6 (CH), 119.5 (CH),
119.2 (CH), 119.0 (CH), 118.7 (CH), 113.1 (CH), 111.9 (CH), 79.7 (Cq),
65.0 (CH2), 64.4 (CH3), 63.8 (CH2), 53.4 (CH2), 53.3 (CH2), 53.1
(CH2), 52.9 (CH2), 28.5 (CH3), 27.9 (CH3). IR υ (neat): 3015, 2812,
1754, 1622, 1381 cm-1. MS (ESI, m/z): 349.4 (100) [M+H+]. HRMS
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
(ESI-TOF) m/z: [M+H]+ Calcd for C18H25N2O5 : 349.1763 Found:
349.1767.
Tert-butyl 4-carbamoyl-2H-spiro[benzofuran-3,3'-pyrrole]-1'(2'H)-
carboxylate (10o). Prepared according to procedure G from
amide (22 mg, 0.063 mmol), [RhCp*Cl2]2 (1.0 mg, 0.0016 mmol)
and CsOAc (24 mg, 0.126 mmol) in t-AmOH (0.31 mL) at 60°C
overnight. The crude mixture was purified over silica gel (CH2Cl2
to CH2Cl2 /MeOH 90/10) to afford a colorless oil (m = 19.4 mg,
97% yield). This product partially cyclizes in the NMR tube and
was engaged in the next step without further characterisation.
Tert-butyl 1-oxo-2,3-dihydro-1H,6H-3,5a-methanobenzofuro[3,4-
ef][1,3]diazocine-4(5H)-carboxylate (11o). Prepared according to
procedure H from amide (19.4 mg, 0.063 mmol), CH2Cl2 (0.35
mL) and TFA (48 µL, 0.006 mmol). The crude mixture was fil-
tered over a pad of basic alumina and eluted with MeOH to
afford a white solid (m = 19.3 mg, 99% yield). 1H NMR (300 MHz,
CDCl3) δ (ppm) (2 rotamers, 55/45): 8.32 (d, J = 6.2 Hz, 1H, NH),
7.80 (t, J = 8.1 Hz, 1H), 7.70 (d, J = 6.2 Hz, 1H, NH), 7.27-7.18 (m,
1H), 6.98 (dd, J = 5.7, 8.0 Hz, 1H), 5.28-5.12 (m, 1H), 4.51 (t, J = 8.9
Hz, 1H), 4.40 (d, J = 9.3 Hz, 1H), 3.79 (d, J = 9.8 Hz, 1H, major),
3.71 (d, J = 9.7 Hz, 1H, minor), 3.35 (dd, J = 7.0, 10.1 Hz, 1H), 2.55-
2.39 (m, 1H), 2.34-2.23 (m, 1H), 1.41 (s, 9H, major), 1.35 (s, 9H,
minor). 13C NMR (75 MHz, CDCl3) δ (ppm): 168.5 (Cq), 167.6
(Cq), 158.6 (Cq), 158.6 (Cq), 153.6 (Cq), 153.1 (Cq), 132.5 (Cq), 132.3
(Cq), 129.5 (CH), 129.3 (CH), 127.0 (Cq), 126.4 (Cq), 124.5 (CH),
124.5 (CH), 115.0 (CH), 114.5 (CH), 81.7 (Cq), 81.1 (Cq), 76.9 (Cq),
76.8 (Cq), 76.8 (CH), 76.9 (CH), 65.6 (CH2), 65.5 (CH2), 60.3
(CH2), 60.1 (CH2), 52.2 (Cq), 51.3 (Cq), 37.1 (CH2), 36.7 (CH2), 28.3
(CH3). IR υ (neat): 3017, 2788, 1712, 1654, 1421, 1380 cm-1. MS (ESI,
m/z): 317.4 (100) [M+H+]. HRMS (ESI-TOF) m/z: [M+H]+ Calcd
1'-benzyl-6'-methyl-1',6'-dihydro-2H,2'H-spiro[benzofuran-3,3'-
pyridine]-4-carboxamide (10n). Prepared according to procedure
G from amide (30.5 mg, 0.083 mmol), [RhCp*Cl2]2 (1.3 mg, 0.002
mmol) and CsOAc (32 mg, 0.166 mmol) in t-AmOH (0.41 mL) at
60°C overnight. The crude mixture was purified over silica gel
(CH2Cl2 to CH2Cl2 /MeOH 90/10) to afford a colorless oil (m =
1
20.3 mg, 82% yield, dr : 65/35). H NMR (300 MHz, CDCl3) δ
(ppm) (major diastereomer): 7.27-7.12 (m, 5H), 7.09 (t, J = 7.8 Hz,
1H), 7.01 (d, J = 7.5 Hz, 1H), 6.75 (d, J = 7.9 Hz, 1H), 4.95 (brs, 1H,
NH), 5.72 (dd, J = 2.4, 9.8 Hz, 1H), 5.65 (d, J = 10.7 Hz, 1H), 5.64
(brs, 1H, NH), 4.45 (d, J = 8.7 Hz, 1H), 4.07 (d, J = 8.8 Hz, 1H),
3.98 (d, J = 13.5 Hz, 1H), 3.18 (d, J = 13.5 Hz, 1H), 3.11-3.04 (m, 1H),
2.84 (d, J = 11.4 Hz, 1H), 2.67 (d, J = 11.4 Hz, 1H), 1.19 (d, J = 6.6 Hz,
3H). 13C NMR (75 MHz, CDCl3) δ (ppm): 169.7 (Cq), 161.2 (Cq),
138.7 (Cq), 134.6 (CH), 133.2 (Cq), 129.2 (CH), 129.0 (CH), 128.8
(CH), 128.4 (CH), 127.1 (CH), 126.6 (CH), 120.4 (CH), 112.6 (CH),
81.4 (CH2), 58.0 (CH2), 56.4 (CH2), 54.6 (CH), 49.3 (Cq), 18.8
(CH3). IR υ (neat): 3085, 2943, 2711, 1643, 1581, 1477, 1353, 1212 cm-1.
MS (ESI, m/z): 335.2 (100) [M+H+]. HRMS (ESI-TOF) m/z:
+
[M+H]+ Calcd for C21H23N2O2 : 335.1760 Found: 335.1767.
Tert-butyl 3-((3-(methoxycarbonyl)phenoxy)methyl)-2,5-dihydro-
1H-pyrrole-1-carboxylate (S40). To a solution of methyl 3-
hydroxybenzoate (179 mg, 1.18 mmol) in DMF (3 mL) cooled with
an ice-bath, was added NaH 60% (57 mg, 1.42 mmol, 1.2 eq).
After 15 min of stirring at this temperature, a solution of tert-
butyl
3-(chloromethyl)-2,5-dihydro-1H-pyrrole-1-carboxylate18
(258 mg, 1.18 mmol, 1 eq) in DMF (2 mL) was added dropwise.
The reaction mixture was allowed to reach room temperature
and after 2 hours stirring, was quenched with saturated NH4Cl.
The aqueous layer was extracted with EtOAc (x3), and the com-
bined organic layers were washed with water then brine, dried
with Na2SO4, and the solvent removed under vacuum. The crude
mixture was purified through silica gel (Hept. to Hept/EtOAc
7/4) to afford a yellow oil (m = 404 mg, 97% yield). 1H NMR (300
MHz, CDCl3) δ (ppm): 7.66 (dd, J = 1.6, 7.5 Hz, 1H), 7.60-7.55 (m,
1H), 7.35 (t, J = 7.9 Hz, 1H), 7.11 (dd, J = 2.7, 7.7 Hz, 1H), 5.82
(brm, 1H), 4.64 (brs, 2H), 4.26-4.11 (m, 4H), 3.92 (s, 3H), 1.49 (s,
9H). 13C NMR (75 MHz, CDCl3) δ (ppm): 166.8 (Cq), 158.3 (Cq),
154.3 (Cq), 135.1 (Cq), 131.5 (Cq), 129.5 (CH), 123.4 (CH), 122.9
(CH), 122.4 (CH), 121.1 (CH), 120.3 (CH), 120.1 (CH), 120.0 (CH),
116.4 (CH), 114.7 (CH), 79.6 (Cq), 65.0 (CH2), 53.3 (CH2), 53.1
(CH2), 52.2 (CH3), 28.5 (CH3). IR υ (neat): 3015, 2812, 1754, 1622,
1381 cm-1. MS (ESI, m/z): 334.4 (100) [M+H+]. HRMS (ESI-TOF)
+
for C17H21N2O4 : 317.1501 Found: 317.1498.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Copies of 1H, 13C NMR and crystallographic data (PDF)
AUTHOR INFORMATION
Corresponding Author
+
m/z: [M+H]+ Calcd for C18H24NO5 : 334.1654 Found: 334.1657.
* E-Mail: laurent.chabaud@cnrs.fr
* E-Mail : catherine.guillou@cnrs.fr
Author Contribution
Tert-butyl
3-((3-(methoxycarbamoyl)phenoxy)methyl)-2,5-
dihydro-1H-pyrrole-1-carboxylate (9o). Prepared according to
procedure C from methyl ester (80 mg, 0.240 mmol), LiOH (23
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 18
The manuscript was written through contributions of all
1
2
3
authors. / All authors have given approval to the final version
of the manuscript.
Notes
4
5
6
7
8
9
Y.; Park, C.-M. Angew. Chem., Int. Ed. 2012, 51, 9372. g) Zhang, X.;
The authors declare no competing financial interest.
Li, Y.; Shi, H.; Zhang, L.; Zhang, S.; Xu, X.; Liu, Q. Chem. Com-
mun. 2014, 50, 7306. h) Tao, P.; Jia, Y. Chem. Commun. 2014, 50,
7367. i) Tao, P.; Chena, Z. Jia, Y. Chem. Commun. 2016, 52, 11300.
j) Krieger, J.-P.; Lesuisse, D.; Ricci, G.; Perrin, M.-A.; Meyer, C.
Cossy, J. Org. Lett. 2017, 19, 2706. k) Song, L.; Tian, G.; He, Y.;
Van der Eycken, E. V. Chem. Commun. 2017, 53, 12394.
ACKNOWLEDGMENT
This work was supported by CNRS and ICSN. We thank
Albane Decerf and Quentin Tricart for technical assistance
with preparing starting materials.
10
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For recent examples of spirocycles synthesis using Rh(III)-
catalyzed CH-activation see : a) Zhou, T. ; Li, L.; Li, B.; Song, H. ;
B. Wang, Org. Lett. 2015, 17, 4204. b) Zheng, J.; Li, P.; Gu, M.;
Lin, A.; Yao, H. Org. Lett. 2017, 19, 2829. and references 10d-e.
11 For an example of a related brigded structure see : Mohacsi,
E. J. Heterocyclic Chem. 1986, 23, 1897.
REFERENCES
12 The structure of 11a was confirmed by X-ray crystallography
(see supporting informations) : CCDC1573425.
1 (a) Rios, R. Chem. Soc. Rev. 2012, 41, 1060. (b) Kotha, S.; Deb,
A.; Lahiri, K.; Manivannan, E. Synthesis 2009, 165. (c) D’yakonov,
V. A.; Trapeznikova, O. A.; de Meijere, A. ; Dzhemilev, U. M.
Chem. Rev. 2014, 114, 5775. (d) Smith, L. K.; Baxendale, I. R. Org.
Biomol. Chem., 2015, 13, 9907.
13
Xu, L.; Zhu, Q.; Huang, G.; Cheng, B.; Xia, Y. J. Org. Chem.
2012, 77, 3017.
14
Other catalysts ([RhCp*(MeCN)3](SbF6)2], CoCp*(CO)I2) or
at higher temperature (100 °C instead of 60°C) led to the recov-
ery of starting material or extensive degradation.
2 Costanzo, M. J.; Yabut, S. C.; Zhang, H.-C.; K. B. White, K. B.;
de Garavilla, L. ; Wang, Y.; Minor, L. K.; Tounge, B. A.; Barnakov,
A. N.; Lewandowski, F.; et al., Bioorg. Med. Chem. Lett. 2008, 18,
2114.
15
(a) Stuart, D.R.; Alsabeh, P.; Kuhn, M. ; Fagnou, K. J. Am.
Chem. Soc. 2010, 132, 18326. (b) Li, L. ; Brennessel, W.W.; Jones,
W. D. Organometallics 2009, 28, 3492.
16
3
Castro, P.; Jose, L.; Dinnell, K.; Elliott, J. M.; Hollingworth,
Moulin, A.; Ryan, J.; Martinez, J.; Fehrentz, J.-A.
G. J.; Shaw, D. E.; Swain, C. J. Patent: US2003/236250 A1, 2003 ;
ChemMedChem 2007, 2, 1242.
4
Page 27.
Dean, D. C.; Nargund, R. P.; Pong, S.-S.; Chaung, L.-Y. P.;
17
Husson, H-P.; Bettiol, J.-L.; Grierson, D.S.; Castells, J.; Reig,
Griffin, P.; Melillo, D. G.; Ellsworth, R. L.; Van Der Ploeg, L. H.;
I.; Diez, A.; Rubiralta, M. Heterocycles, 1990, 31, 173.
Patchett, A. A.; Smith, R. G. J. Med. Chem. 1996, 39, 1767.
18
5
Pearson, W. H. ; Dietz, A. L. ; Aponick, A. Eur. J. Org.
(a) Zheng, Y.; Tice, C. M.; Singh, S. B. Bioorg. Med. Chem.
Chem., 2008, 4264.
Lett. 2014, 24, 3673. (b) Welsch, M. E.; Snyder, S. A.; Stockwell, B.
R. Curr. Opin. Chem. Biol. 2010, 14, 347.
6
(a) Xie, J.-S.; Huang, C. Q.; Fang, Y.-Y.; Zhu, Y.-F.; Tetrahe-
dron 2004, 60, 4875. (b) Ye, L.; Tian, Y.; Li, Z.; Jin, H.; Zhu, Z.;
Wan, S.; Zhang, J.; Yu, P.; Zhang, J.; Wu, S. Eur. J. Med. Chem.
2012, 50, 370. (c) Qiao, J. X.; Wang, T. C.; Ruel, R.; Thibeault, C.;
L’Heureux, A.; Schumacher, W. A.; Spronk, S. A.; Hiebert, S.;
Bouthillier, G.; Lloyd, J. et al., J. Med. Chem. 2013, 56, 9275. (d)
He, S.; Ye, Z.; Dobbelaar, P. H.; Sebhat, I. K.; Guo, L.; Liu, J.; Jian,
T.; Lai, Y.; Franklin, C. L.; Bakshi, R. K. et al., Bioorg. Med. Chem.
Lett. 2010, 20, 2106. (e) Bignan, G. C.; Battista, K.; Connolly, P. J.;
Orsini, M. J.; Liu, J.; Middleton, S. A.; Reitz, A. B. Bioorg. Med.
Chem. Lett. 2005, 15, 5022.
7
(a) Chen, M.-H.; Abraham, J. A.; Tetrahedron Lett. 1996, 30,
5233. (b) LeFlemme, N.; Stoit, A. R.; Borghese, A. Tetrahedron
Lett. 2012, 53, 2432.
8
For selected reviews on RhIII catalysis in C–H activation: a)
Satoh, T.; Miura, M. Chem. Eur. J. 2010, 16, 11212. (b) Oberg, K.
M.; Rovis, T. in Asymmetric Synthesis II (Eds.: M. Christmann, S.
Bräse), Wiley-VCH Verlag GmbH & Co. KGaA, 2012, pp. 303. (c)
Patureau, F. W.; Wencel-Delord, J.; Glorius, F. Aldrichimica Acta
2012, 45, 31. (d) Kuhl, N.; Schroder, N.; Glorius, F. Adv. Synth.
Catal. 2014, 356, 1443. (e) Song, G.; Li, X. Acc. Chem. Res. 2015,
48, 1007. (f) Mo, J.; Wang, L.; Liu, Y.; Cui, X. Synthesis 2015, 47,
439. (g) Das, R.; Kumar, G. S.; Kapur, M. Eur. J. Org. Chem. 2017,
37, 5439.
9 For examples of intramolecular reaction with alkenes. a) Da-
vis, T. A.; Hyster, T. K.; Rovis, T. Angew. Chem. Int. Ed. 2013, 52,
14181. b) Shi, Z.; Boultadakis-Arapinis, M.; Koester, D. C.; Glorius,
F. Chem. Commun. 2014, 50, 2650. c) Ye, B.; Donets, P. A.;
Cramer, N. Angew. Chem. Int. Ed. 2014, 53, 507. d) Davis, T.;
Wang, C.; Rovis, T. Synlett 2015, 26, 1520. e) Chabaud, L.; Raynal,
Q.; Barre, E.; Guillou, C. Adv. Synth. Catal. 2015, 357, 3880. For
examples of intramolecular reaction with alkynes : f) Xu, X.; Liu,
18
ACS Paragon Plus Environment