Stereocontrolled synthesis of bicyclic ureas and sulfamides via Pd-catalyzed alkene carboamination reactions

Article abstract of DOI:10.1016/j.tet.2019.04.031

The synthesis of bicyclic ureas and sulfamides via palladium-catalyzed alkene carboamination reactions between aryl/alkenyl halides/triflates and alkenes bearing pendant cyclic sulfamides and ureas is described. The substrates for these reactions are gene

Full text of DOI:10.1016/j.tet.2019.04.031

Accepted Manuscript
Stereocontrolled synthesis of bicyclic ureas and sulfamides via Pd-catalyzed alkene
carboamination reactions
Nicholas R. Babij, Jordan R. Boothe, Grace M. McKenna, Ryan M. Fornwald, John P.
Wolfe
PII:
S0040-4020(19)30443-0
https://doi.org/10.1016/j.tet.2019.04.031
TET 30276
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 13 March 2019
Revised Date: 10 April 2019
Accepted Date: 12 April 2019
Please cite this article as: Babij NR, Boothe JR, McKenna GM, Fornwald RM, Wolfe JP,
Stereocontrolled synthesis of bicyclic ureas and sulfamides via Pd-catalyzed alkene carboamination
reactions, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.04.031.
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Stereocontrolled synthesis of bicyclic ureas
and sulfamides via Pd-catalyzed alkene
carboamination reactions
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Nicholas R. Babij, Jordan R. Boothe,† Grace M. McKenna,† Ryan M. Fornwald, and John P. Wolfe*
Department of Chemistry, University of Michigan, 930 N. University Ave., Ann Arbor, MI, 48109-1055, USA

1
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Tetrahedron
journal homepage: www.elsevier.com
Stereocontrolled synthesis of bicyclic ureas and sulfamides via Pd-catalyzed alkene
carboamination reactions
Nicholas R. Babij, Jordan R. Boothe,† Grace M. McKenna,† Ryan M. Fornwald, and John P. Wolfe
Department of Chemistry, University of Michigan, 930 N. University Ave., Ann Arbor, MI, 48109-1055, USA.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The synthesis of bicyclic ureas and sulfamides via palladium-catalyzed alkene carboamination
reactions between aryl/alkenyl halides/triflates and alkenes bearing pendant cyclic sulfamides
and ureas is described. The substrates for these reactions are generated in 3–5 steps from
commercially available materials, and products are obtained in good yield with up to >20:1
diastereoselectivity. The stereochemical outcome of the sulfamide alkene addition is consistent
with a mechanism involving anti-aminopalladation of the alkene, whereas the stereochemical
outcome of the urea alkene addition is consistent with a syn-aminopalladation mechanism.
Available online
Keywords:
Palladium
Alkenes
2009 Elsevier Ltd. All rights reserved
.
Heterocycles
Stereoselective
1. Introduction
tetraponerines (T-1, 3, 5, and 7) exhibit cis stereochemistry
between the C4a and C3 groups, whereas the even numbered
members of the family have trans C4a/C3 stereochemistry.
A number of interesting biologically active natural products
feature substituted polycyclic nitrogen heterocycle motifs.1 These
include tricyclic guanidines such as the batzelladine2 and
merobatzelladine alkaloids (e.g., merobatzelladine B)3 (Figure 1)
and the tetraponerine T1-T8 alkaloids.4 In many instances these
families of natural products contain members with differing
Many routes for the synthesis of polycyclic guanidines,
including the batzelladines and merobatzelladines, involve
construction of a bicyclic urea, which is then further elaborated to
the guanidine.5 Moreover, a 2-(alkylamino)pyrrolidine derivative,
that in principle could be accessed via reduction of a bicyclic
urea or sulfamide, was a key intermediate in a prior synthesis of
the tetraponerines.6 In addition to serving as useful synthetic
intermediates, substituted cyclic ureas and sulfamides act as
peptidomimetics7 that display a wide spectrum of biological
activity, such as antivirals8, HIV protease inhibitors9, and
hydroxysteroid dehydrogenase inhibitors10. As such, there has
been considerable interest in the development of methods for the
stereocontrolled synthesis of these structures.11
relative stereochemistry. For example, merobatzelladine
B
possesses a cis-relationship between the C4a hydrogen atom and
the C3 alkyl chain,3 whereas batzelladine K displays a trans-
relationship between these groups.2c Similarly, the odd numbered
We have previously reported a new approach to the
construction of cyclic ureas and sulfamides via Pd-catalyzed
alkene carboamination reactions12 between aryl/alkenyl
halide/triflate electrophiles and alkenes bearing pendant ureas13
or sulfamides (Scheme 1, eq 1).14 These transformations proceed
in generally good yields with high diastereoselectivities, as
illustrated by the Pd-catalyzed carboamination of urea 1 to afford
bicyclic urea 2 in 91% yield with >20:1 dr; this reaction was a
key step in the asymmetric synthesis of (–)-merobatzelladine B
(Scheme 1, eq 2).15 We have also described asymmetric
desymmetrization reactions of ureas derived from cis-2,5-
Fig 1. Polycyclic alkaloid natural products
———
† These two authors made equal contributions to this work
Corresponding author. e-mail: jpwolfe@umich.edu

2
Tetrahedron
ACCEPTED MANUSCRIPT
diallylpyrrolidine that afford products with high levels of
tolylbromide or E-1-decenylbromide.15 As shown in Table 1,
enantioselectivity; this latter method was applied to the synthesis
entries 1-2, these transformations afforded desired products 4a
and 4b in good yield with high diastereoselectivity. In order to
examine the scope of Pd-catalyzed coupling reactions of ureas
derived from cyclic amines, we treated 3a-b with a range of
different aryl halide electrophiles. Transformations of substrates
bearing electron-donating groups proceeded in high yield (entries
3-4 and 7), although lower yields were obtained with electron-
poor and/or ortho-substituted aryl bromides (entries 5-6). To
further illustrate the scope of this transformation, substrate 3b
bearing a methyl group at the internal alkene carbon was coupled
with 4-bromobiphenyl to afford 4g in excellent yield and dr,
although a higher reaction temperature (125 °C) was required
(entry 7). In contrast, substrates bearing 1,2-disubstituted alkenes
were unreactive. We also carried out the coupling of p-
methoxybenzyl protected substrate 3c with Z-1-bromobutene,
which we used as a model system in our studies leading up to the
synthesis of merobatzelladine B.15 As shown in eq 4, this
transformation provided the desired product 4i in 67% yield with
>20:1 dr. The coupling of PMP-protected substrate 3a with Z-1-
bromobutene led to a similar outcome, affording 4h in 58% yield
with >20:1 dr.
of an epimer of batzelladine K (Scheme 1, eq 3).16
Table 1
Pd-Catalyzed carboamination reactions of 2-allylpyrrolidinyl
ureasa
Scheme 1. Synthesis of cyclic ureas and sulfamides via Pd-
catalyzed alkene carboamination reactions
Although these transformations have demonstrated utility, as
illustrated through the syntheses shown in Scheme 1, the scope of
this approach to the construction of bicyclic ureas remains largely
unexplored.15 For example, no cases of formation of bicyclo
[4.4.0] ring systems have previously been described. Moreover,
the synthesis of 9-epi-batzelladine K also illustrates a significant
limitation of this method. We would have preferred to make the
naturally occurring isomer of batzelladine K, but we have
consistently observed complete substrate control in these
reactions; in all cases the products contain a cis-relationship
between the C3 alkyl group and the C4a hydrogen atom. These
transformations do not provide access to the diastereomeric
product with a trans relationship between the C3 alkyl/ C4a
hydrogen substituents, which would be needed to access
batzelladine K rather than its epimer.
entry urea
R
product yieldb
(%)
drc
1
2
3
4
3a
3a
3a
3a
p-MeC6H4
E-1-decenyl
p-PhC6H4
4a
4b
4c
4d
70
77
87
86
14:1
18:1
16:1
10:1
5
6
7
3a
3a
3b
o-F3CC6H4
p-O2NC6H4
p-PhC6H4
4e
4f
68
46
97
10:1
>20:1
15:1d
In this article we describe our studies on expanding the scope
of our previously reported strategy for the synthesis of bicyclic
ureas via Pd-catalyzed alkene carboamination reactions.15 This
includes studies on the reactivity of a variety of aryl and alkenyl
halide coupling partners, as well as preparation of both
bicyclo[4.3.0] and bicyclo[4.4.0] ring systems. We also describe
a method for the construction of bicyclic sulfamides analogous to
2,17 along with the corresponding bicyclo[4.4.0] congeners, but
that possess the opposite stereochemical relationship between the
C3 alkyl group and the C4a H atom as compared to the ureas.
Finally, we illustrate the conversion of these bicyclic products to
2-(alkylamino)pyrrolidine derivatives.
4g
aConditions: 1.0 equiv 3a or 3b, 2 equiv NaOtBu, 2 mol% Pd2(dba)3, 8 mol%
b
PCy3•HBF4, 2 equiv, ArBr, toluene (0.2 M), 110 ºC, 4–16 h. Isolated yields
(average of two or more experiments). cDiastereomeric ratio of the pure
isolated product. Diastereomeric ratios of isolated materials were identical to
d
those of crude products. The reaction was conducted in xylenes solvent (0.2
M) at 125 ºC.
In order to further explore the scope of the urea
carboamination reactions we prepared 2-allylpiperidinyl urea 5
and coupled it with Z-1-bromobutene using our standard reaction
conditions. This transformation provided the desired product 6a
in 69% yield, and 8:1 dr (eq 5), although the use of 5 equiv of
both the alkenyl bromide and the base, plus a slightly higher
catalyst loading, was necessary to obtain satisfactory results.
However, we were surprised to find these standard reaction
conditions were not effective for the coupling of PMP-protected
substrate 5 with aryl bromides.
2. Results and discussion.
2.1. Synthesis of bicyclic ureas via Pd-catalyzed alkene
carboamination reactions
During the course of model studies directed towards the
synthesis of (–)-merobatzelladine B, we briefly examined Pd-
catalyzed coupling reactions between 3a and either p-

3
undergoes syn-aminopalladation to provide 9,20 which
ACCEPTED MANUSCRIPT
undergoes C–C bond-forming reductive elimination to afford the
bicyclic urea product 4 or 6. The observed cis-relationship
between the angular hydrogen atom and the arylmethyl group in
the products derives from aminopalladation via a boat-like
transition state during the syn-aminopalladation of 8 to 9.15
Consequently, we examined the use of other bases and ligands
for coupling reactions of 5 with aryl bromides, and after some
optimization we found that use of Cs2CO3 as base, Pd(OAc)2 as
the palladium source, and Dpe-Phos as the ligand provided the
desired products in moderate yield (Table 2).18 The
stereochemical outcome of these reactions was analogous to that
for transformations of pyrrolidinyl ureas 3a-c. However,
chemical yields were generally lower than those obtained in
reactions of 3a-c due to incomplete consumption of starting
material. The origin of this difference in reactivity is not clear,
but could conceivably be due to differences in the conformational
flexibility of 5-membered vs. 6-membered rings. In both systems,
there is likely a ground state energy preference for pseudoaxial
orientation of the allyl group to minimize allylic strain
interactions with the urea moiety,19 which would position the
alkene fairly distant from the metal center in the key palladium
amido intermediate that undergoes syn-aminopalladation
(Scheme 2). However, due to the greater conformational
flexibility of 5-membered rings, the presumably reactive
conformation in which the allyl group is pseudoequatorial may
be more energetically accessible, leading to faster reaction rates
relative to the rate of catalyst deactivation.
Scheme 2. Catalytic cycle – syn-aminopalladation
While this method is useful for the stereocontrolled
construction of bicyclic ureas, the stereoselectivity is substrate
controlled. The conversion of 3 or 5 to bicyclic ureas with a cis-
relationship between the angular C4a hydrogen atom and the C3
arylmethyl group proceeds with generally high levels of
stereocontrol, but the syn-aminopalladation mechanism allows
for the selective formation of only the cis stereoisomer;
diastereomeric molecules bearing a trans-relationship between
the C4a angular hydrogen atom and the C3 arylmethyl group are
not accessible through this manifold.
Table 2
Pd-Catalyzed carboamination reactions of 2-allylpiperidinyl
ureasa
entry
R
product
6b
yieldb
(%)
35
drc
1
2
3
p-MeOC6H4
m-F3CC6H4
p-PhC(O)C6H4
15:1
15:1
10:1
Scheme 3. Catalytic cycle – anti-aminopalladation
6c
47
59
Although the syn-aminopalladation mechanism illustrated in
Scheme 2 provides selective access to only the cis stereoisomer,
we reasoned that it may be possible to access the trans
stereoisomer by inducing the transformations to proceed via an
alternative mechanistic pathway. As shown in Scheme 3, we
hypothesized that if the transformations could be made to
proceed via anti-aminopalladation of the alkene (following
oxidative addition and alkene coordination to Pd), the anti-
aminopalladation of Pd-alkene complex 11 would likely proceed
6d
aConditions: 1.0 equiv substrate, 2 equiv Cs2CO3, 4 mol% Pd(OAc)2, 6 mol%
Dpe-Phos 2 equiv, RBr, toluene (0.2 M), 110 ºC, 4–16 h. bIsolated yields
(average of two or more experiments). cDiastereomeric ratio of the pure
isolated product. Diastereomeric ratios of isolated materials were identical to
those of crude products.
2.2. Mechanism and stereochemistry
via
a chair-like transition state to afford 12. Reductive
Our prior studies on urea carboamination reactions suggest the
transformations described above likely proceed through the
mechanism illustrated in Scheme 2.12 The reactions are initiated
by oxidative addition of the aryl/alkenyl halide to Pd(0) to afford
intermediate 7, which reacts with the urea substrate 3 or 5 and
base to afford amido complex 8. The Pd-amido complex
elimination from 12 would then provide bicyclic urea product 13,
which contains a trans-relationship between the C4a hydrogen
atom and C3 arylmethyl group. In addition, although most of our
previously reported Pd-catalyzed alkene carboamination
reactions proceed via syn-aminopalladation,12 we have observed
that urea and sulfamide substrates can be induced to undergo

4
Tetrahedron
carboamination via anti-aminopalladation under appropriate
significant influence on diastereoselectivity,16 and we reasoned
ACCEPTED MANUSCRIPT
conditions. Specifically, factors that facilitate the formation of
cationic intermediate palladium complexes (such as use of aryl
triflates in place of aryl bromides, use of relatively polar solvents,
etc.) promote the anti-addition pathway.14 For example, treatment
of urea 14 with an aryl bromide in toluene afforded syn-addition
product 15 in 91 % yield and 7:1 dr using a Pd/Dpe-Phos
catalyst. In contrast, the Pd/RuPhos catalyzed coupling of 14
with phenyl triflate in benzotrifluoride solvent afforded anti-
addition product 16 in 80% yield and 10:1 dr (Scheme 4).14
this might also be the case for sulfamide substrates.
Table 3
Influence of protecting group on diastereoselectivitya
entry
sulfamide
19a
product
20a
yieldb
(%)
drc
6:1
3:1
3:1
1
2
3
80d
19b
20b
86
82
19c
20c
aConditions: 1.0 equiv substrate, 2 equiv LiOtBu, 4 mol% Pd(OAc)2, 10 mol%
C-Phos 2 equiv Ph–OTf, PhCF3 (0.2 M), 100 ºC, 16 h. bIsolated yields
(average of two or more experiments). cDiastereomeric ratio of the pure
isolated product. Diastereomeric ratios of isolated materials were identical to
those of crude products. dNMR yield with phenanthrene as an internal
standard.
Scheme 4. Syn- vs. anti-addition
To test this hypothesis, we examined the coupling of p-
nitrophenyl protected urea 17 with phenyl triflate using the
conditions optimized for anti-aminopalladation. As shown in eq
6, this transformation did lead to a change in product
stereochemistry, as 18 was produced as the major stereoisomer.
However, the diastereoselectivity of this transformation was low
(2:1 dr), and no increase in selectivity was observed despite
numerous changes to the reaction conditions, catalyst/ligand
system, and protecting group.
In order to test this hypothesis, 2-allylpyrrolidinyl sulfamide
substrates 19a-c were synthesized and coupled with phenyl
triflate using conditions we have previously shown to facilitate
anti-aminopalladation pathways (Table 3).14 We were gratified to
discover that substrate 19a, which contains an N-PMP group, did
react with significantly higher diastereoselectivity (6:1 dr) than
urea 17.22 In contrast, N-alkyl protecting groups provided the
desired products 20b-c in comparable yield, but with lower (3:1)
dr. Thus, the N-PMP group was selected for subsequent studies.
During the course of these studies, we observed inconsistent
results for the coupling of 19a with phenyl triflate, including
highly variable yields and impurity profiles. It was noted that
using anhydrous LiOtBu directly from the glove box led to
significant amounts of side products resulting from Heck
arylation and/or oxidative amination of the alkene, whereas using
LiOtBu stored on the bench under nitrogen led to an improved
reaction profile. We reasoned that the difference in reactivity
may be due to the bench-stored sample picking up small amounts
of water from the air, which would generate lithium hydroxide
and tert-butanol. After some experimentation, we found that
changing the solvent from benzotrifluoride to tert-butanol led to
significantly improved and reproducible yields, and greatly
diminished the formation of side products resulting from Heck
arylation or oxidative amination of the alkene.23 Under these
conditions, LiOtBu obtained directly from the glovebox and
LiOtBu stored on the bench gave comparable results.
2.3. Synthesis of bicyclic sulfamides via Pd-catalyzed alkene
carboamination reactions
We postulated that two factors might be the cause of the
modest diastereoselectivity observed for the coupling of 17 with
phenyl triflate: (1) the rates of syn- and anti-aminopalladation
may be comparable; and/or (2) the transition states/intermediates
leading to the two possible stereoisomers may be close in energy.
Both of these factors can be heavily influenced by the structural
and electronic features of the substrate. Many reports have
illustrated that slight changes to substrate structure can
dramatically influence the mechanism of aminopalladation
reactions and in turn, the ratio of products resulting from syn- or
anti-addition.14,21 We reasoned that employing a less nucleophilic
substrate, such as a sulfamide, might favor anti-aminopalladation
by decreasing the likelihood that the substrate would form the
Pd-N bond required to undergo syn-migratory insertion.20 We
also thought that changing the geometry of the substrate from the
trigonal planar carbonyl group to the tetrahedral sulfonyl group
With suitable reaction conditions in hand, we proceeded to
explore the scope of the bicyclic sulfamide-forming reactions. As
shown in Table 4, the transformations of 19a are effective with
both aryl and alkenyl triflate electrophiles, and provide products
20a and 20d-i in moderate to good yield with
diastereoselectivities in the range of 5–10:1 dr. Yields and
diastereoselectivities were comparable with both electron-rich
and electron-poor aryl triflates. However, reactions of alkenyl
triflates proceeded in slightly lower yield (entries 6–7). Reactions
of substrate 19d, which contains an allyl group at C5, proceeded
with slightly higher diastereoselectivities than were observed
with 19a (entries 8–9). Use of short reaction times (2 h) with
substrate 19d was necessary in order to avoid undesired
isomerization of the product’s allyl group to an internal alkene.
may
influence
the
stereodetermining
transition
states/intermediates leading to the two possible stereoisomers,
and consequently the selectivity of the desired transformation
could potentially be improved. Additionally, in prior studies on
Pd-catalyzed asymmetric desymmetrization reactions of ureas
derived from 2,5-diallylpyrrolidine, we observed that the nature
of the protecting group on the cyclizing nitrogen atom had a

5
The coupling of 19b with the alkenyl bromide Z-1-bromobutene
that for reductive elimination from 22a if strain in the transition
state for reductive elimination from 22 is significant.
ACCEPTED MANUSCRIPT
(entry 10) was achieved in modest yield and 5:1
diastereoselectivity when 2 equiv of LiOTf was added to the
reaction mixture, with slightly modified conditions (PhCF3 as
solvent and NaOtBu as base).24
Table 4
Pd-Catalyzed carboamination reactions of 2-allylpyrrolidinyl
sulfamidesa
Scheme 5. Control of stereoselectivity
We subsequently elected to explore the reactivity of 2-
allylpiperidine-derived sulfamides for the synthesis of
bicyclo[4.4.0] heterocyclic ring systems (Table 5). In contrast to
the reactions of urea derivatives, in which the pyrrolidinyl and
piperidinyl derived substrates had considerably different
reactivity, and required different reaction conditions, our standard
parameters were effective with both pyrrolidinyl (19a-d) and
piperidinyl sulfamides (23). The coupling of 23 with a range of
different aryl and alkenyl triflates provided products in
comparable yields, but slightly lower diastereoselectivities, than
were observed in reactions of 19a. The origin of the lower
diastereoselectivities is not clear, but the differences are also
relatively small (5–10:1 vs. 3–6:1). A range of electronic
properties of the aryl triflate were tolerated, and the
transformation was also effective with the heteroaryl bromide 2-
bromothiophene and the alkenyl bromide Z-1-bromobutene when
2 equiv of LiOTf was added to the reaction mixture (eq 7-8).
These latter two substrates are noteworthy, as the butenyl group
and the 2-thiophenyl group27 could conceivably be reduced to the
alkyl side chain present in batzelladine K and the tetraponerine
alkaloids.
entry sulfamide
R
product yieldb
(%)
drc
7:1
6:1
7:1
1
2
3
4
5
6
7
8
Ph
89
19a
19a
19a
19a
19a
19a
19a
19d
20a
20d
20e
20f
20g
20h
20i
p-tBuC6H4
p-MeOC6H4
p-PhC(O)C6H4
o-MeC6H4
1-cyclohexenyl
E-1-decenyl
Ph
78
70
61d
87
8:1
(5:1)
5:1
63d
45d
65e
6:1
10:1f,g
20:1
(12:1)
20j
9
p-MeOC6H4
63e
30h
>20:1
(13:1)
19d
20k
10
Z-1-bromobutene
5:1
19b
20l
aConditions: 1.0 equiv substrate, 2 equiv LiOtBu, 4 mol% Pd(OAc)2, 10 mol%
C-Phos 2 equiv, R–OTf, tBuOH (0.2 M), 82 ºC, 16 h. bIsolated yields
(average of two or more experiments). cDiastereomeric ratio of the pure
isolated product. Diastereomeric ratios of isolated materials were identical to
Table 5
Pd-Catalyzed carboamination reactions of 2-allylpiperidinyl
sulfamides a
d
those of crude products unless otherwise noted in parentheses. The reaction
e
was conducted with 3.0 equiv of LiOtBu and 3.0 equiv R-OTf. The reaction
time was 2 h. f1-Decenyl triflate was employed as 5:1 mixture of E:Z isomers.
gThe dr was determined following hydrogenation of 20j. The crude dr of 20j
could not be determined directly due to the presence of E/Z alkene
stereoisomers. However, we estimate the crude dr to be ca. 5-10:1. hThe
reaction was conducted in PhCF3 as solvent using NaOtBu as the base, with
2.0 equiv added LiOTf, and a reaction temperature of 100 °C.
entry
R
product
24a
yieldb
(%)
80
drc
5:1
5:1
4:1
4:1
5:1
The relatively high diastereoselectivities observed (5–13:1)
are both interesting and surprising, as other related alkene
carboamination reactions that proceed via anti-aminopalladation
typically provide low (ca 1-3:1) diastereoselectivity unless there
is a substituent at the allylic position of the alkene.24 The
relatively high selectivity observed in reactions of 19a-d may be
due to either thermodynamic or kinetic control. As shown in
Scheme 5, the aminopalladation step in the catalytic cycle is
likely reversible, especially since the cyclizing nitrogen atom is
relatively electron-poor.25 The reductive elimination step is most
likely not reversible, and there appear to be significant
unfavorable 1,3-diaxial interactions present in intermediates 21b
and 22b where the alkene or arylmethyl group is positioned in a
pseudoaxial position that are not present in intermediates 21a and
22a.26 So, if the rates of reductive elimination from 22a or 22b
are comparable, the relative equilibrium populations of 22a or
22b would dictate the outcome. Alternatively, the activation
energy for reductive elimination from 22b may be higher than
1
2
3
4
5
Ph
1-cyclohexenyl
p-tBuC6H4
o-MeC6H4
24b
85
71
83
87
24c
24d
24e
6
p-MeOC6H4
24f
76
3:1
aConditions: 1.0 equiv substrate, 2 equiv LiOtBu, 4 mol% Pd(OAc)2, 10 mol%
C-Phos 2 equiv, R–OTf, tBuOH (0.2 M), 82 ºC, 16 h. bIsolated yields
(average of two or more experiments). cDiastereomeric ratio of the pure

6
Tetrahedron
isolated product. Diastereomeric ratios of isolated materials were identical
proceed via anti-aminopalladation afford the trans-disubstituted
ACCEPTED MANUSCRIPT
to those of crude products.
products.
2.4. Elaboration of products
To further demonstrate the potential synthetic utility of the
transformations described above, we elected to examine
deprotection of products 24a and 4i (Scheme 6). After some
experimentation, we found that treatment of 24a with
concentrated HBr led to cleavage of the SO2 group, with
concomitant demethylation of the p-methoxyphenyl group.
Oxidation of the resulting product, in a one-pot process, with
ceric ammonium nitrate then removed the nascent p-
hydroxyphenyl group to provide diamine 25 in 75% yield (eq 9).
The PMB protecting group was cleaved from 4i by
hydrogenation, with concomitant reduction of the alkene, to
afford 26 in 92% yield (eq 10). The urea carbonyl was removed
to provide diamine 26 in 57% yield through reduction with
LiAlH4 and subsequent treatment with hydroxylamine (eq 11).
Scheme 7. Summary
4. Experimental section
4.1. General
All reactions were carried out under nitrogen atmosphere in
flame- or oven-dried glassware. All reagents were obtained from
commercial sources and were used as obtained unless otherwise
noted. Bis-(dibenzylidineacetone) dipalladium(0), palladium (II)
acetate, tricyclohexylphosphonium tetrafluoroborate, CPhos, and
Dpe-phos were purchased from Strem Chemical Co. and used
without further purification. Dichloromethane, toluene, and
tetrahydrofuran were purified using a GlassContour solvent
purification system. N-Boc-2-allylpyrrolidine,28 N-Boc-2-(2-
methallyl)pyrrolidine,29
N-Boc-2-allylpiperidine,28
E-1-
bromodecene,30 Z-1-bromobut-1-ene,31 19d,16 the oxooxazolidin
sulfonamides used to prepare 19a-c,14a and 1-decenyl triflate,14a
were synthesized according to published procedures. Aryl
triflates were either purchased from commercial sources, or
prepared according to the procedure of Frantz et. al.32
Benzotrifluoride was purified by distillation from P2O5, and
xylenes were purified by distillation from CaH2 prior to use.
Structural and stereochemical assignments were based on 2-D
COSY and NOESY experiments. Ratios of diastereomers were
Scheme 6. Elaboration of products
3. Conclusion
In conclusion, Pd-catalyzed alkene carboamination reactions
between ureas or sulfamides derived from 2-allylpyrrolidine or 2-
allylpiperidine are coupled with a range of aryl or alkenyl halides
or triflates to afford bicyclic ureas or sulfamides. As shown in
Scheme 7, the coupling of sulfamides with aryl/alkenyl triflates
affords bicyclic products with trans relative stereochemistry
between the C3 arylmethyl group and the angular C4a hydrogen
atom in good yield with moderate, but synthetically useful, levels
of diastereoselectivity. In contrast, the reactions of analogous
urea derivatives with aryl/alkenyl bromides affords bicyclic
products with cis relative stereochemistry, in moderate to good
yield, and with good diastereoselectivity. The change in the
stereochemical outcome of these transformations is due to a
change in reaction mechanism. Circumstances (conditions,
substrate structure) that lead to a syn-aminopalladation pathway
provide the cis-disubstituted products, whereas reactions that
1
determined by H NMR analysis. Yields refer to isolated yields
1
of compounds estimated to be ≥95% pure as determined by H
NMR analysis unless otherwise noted. The yields reported in the
experimental section describe the result of a single experiment,
whereas yields reported in Tables 1–2, and 4–5 are averages of
two or more experiments. Thus, the yields reported in the
experimental section may differ from those shown in Tables 1–2
and 4–5.
4.2. Preparation of starting materials

7
2.02–1.82 (m, 3 H), 1.78–1.73 (m, 1 H); 13C NMR (175 MHz,
4.2.1. General procedure 1:synthesis of urea
substrates
ACCEPTED MANUSCRIPT
CDCl3) δ 158.8, 156.6, 135.3, 131.9, 129.1, 117.1, 113.9, 56.8,
55.3, 46.0, 44.1, 38.8, 29.4, 23.6; IR (film) 3324, 1626 cm–1.
HRMS (ESI+ TOF) m/z [M + H]+: calcd for C16H22N2O2
275.1754; found 275.1747
A clean, flame-dried round bottom flask equipped with a stir
bar was cooled under a stream of nitrogen and charged with N-
Boc-2-allylpyrrolidine,28 N-Boc-2-(2-methallyl)pyrrolidine,29 or
N-Boc-2-allylpiperidine28 (1.0 equiv) and dichloromethane (0.2
M). The resulting solution was cooled to 0 ºC and trifluoroacetic
acid (10.0 equiv) was added. The reaction mixture was stirred
until judged as complete by thin layer chromatography (c.a. 4
hours), then diluted with water and quenched with ammonium
hydroxide until pH reached 12. The organic layer was reserved,
and the aqueous layer extracted with dichloromethane. The
organic extracts were combined, dried over anhydrous sodium
sulfate, and concentrated in vacuo. The resulting crude
intermediate was then carried on to the next step without any
additional purification.
4.2.1.4. (±)-2-Allyl-N-(4-methoxyphenyl)piperidine-
1-carboxamide 5
The title compound was prepared from N-Boc-2-
allylpiperidine (762 mg, 3.4 mmol) following General Procedure
1. This resulted in 355 mg (38% yield) of the title compound as a
1
pale yellow oil. H NMR (500 MHz, CDCl3) δ 7.23–7.17 (m, 2
H), 6.85–6.75 (m, 2 H), 6.32 (s, 1 H), 5.79 (ddt, J = 7.2, 10.1,
17.2 Hz, 1 H), 5.18–5.02 (m, 2 H), 4.29–4.21 (m, 1 H), 3.91 (dt, J
= 3.1, 13.4 Hz, 1 H), 3.76 (s, 3 H), 2.93 (td, J = 2.8, 13.1 Hz, 1
H), 2.52–2.47 (m, 1 H), 2.32–2.27 (m, 1 H), 1.71–1.52 (m, 5 H),
1.54–1.40 (m, 1 H); 13C NMR (126 MHz, CDCl3) δ 155.6, 135.4,
132.6, 122.2, 122.1, 117.3, 114.0, 55.5, 51.1, 39.3, 34.3, 27.9,
25.5, 18.8; IR (film) 2934.8, 1628.9, 1509.5, 1416.8 cm-1. HRMS
(ESI+ TOF) m/z: [M + H]+ calcd for C16H22N2O2 275.1761; found
275.1761.
The crude intermediate was re-dissolved in dichloromethane
(0.2M) and charged to a new clean, dry round bottom flask with a
stir bar. The appropriately substituted isocyanate (1.2 equiv) was
added slowly, and the resulting reaction stirred at 20 ºC until
judged as complete by TLC (ca. 4–14 hours). After concentration
in vacuo, the resulting residue was purified via flash column
chromatography on silica gel (20–40% ethyl acetate/hexanes
gradient).
4.2.1.5. (±)-2-Allyl-N-(4-nitrophenyl)pyrrolidine-
1-carboxamide 17
The title compound was prepared from N-Boc-2-
allylpyrrolidine (887 mg, 4.2 mmol) following General
Procedure 1. The chromatographed product material was diluted
with dichloromethane (35 mL) and washed with 1M HCl (2 x 15
mL) to remove any remaining 4-nitroanniline. This procedure
afforded 290 mg (25%) of the title compound as a yellow solid:
mp = 104–106 ºC. 1H NMR (700 MHz, CDCl3) δ 8.15 (d, J = 9.1
Hz, 2 H), 7.58 (d, J = 9.1 Hz, 2 H), 6.64 (s, 1 H), 5.84–5.78 (m, 1
H), 5.17–5.09 (m, 2 H), 4.09 (s, br, 1 H), 3.53–3.46 (m, 2 H),
2.56 (dt, J = 5.3, 12.4 Hz, 1 H), 2.25–2.18 (m, 1 H), 2.09–2.02
(m, 1 H), 2.04–1.94 (m, 2 H), 1.86–1.82 (m, 1 H); 13C NMR (175
MHz, CDCl3) δ 152.7, 145.4, 142.3, 134.7, 125.1, 118.0, 117.9,
57.5, 46.5, 38.5, 29.6, 23.7; IR (film) 3314, 1652, 1501, 1329
cm–1. HRMS (ESI+ TOF) m/z [M + H]+: calcd for C14H17N3O3
276.1343; found 276.1344.
4.2.1.1. (±)-2-Allyl-N-(4-
methoxyphenyl)pyrrolidine-1-carboxamide 3a
The title compound was prepared from N-Boc-2-
allylpyrrolidine (1.3 g, 6.1 mmol) following General Procedure 1.
This procedure afforded 997 mg (81% yield) of the title
compound as a yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.29 (d,
J = 9.5 Hz, 2 H), 6.83 (d, J = 9.0 Hz, 2 H), 6.07 (s, 1 H), 5.82
(ddt, J = 17.0, 10.0, 7.5 Hz, 1 H), 5.13-5.07 (m, 2 H), 4.07–4.04
(m, 1 H), 3.78 (s, 3 H), 3.45–3.42 (m, 2 H), 2.60–2.55 (m, 1 H),
2.22–2.16 (m, 1 H), 2.04–1.93 (m, 3 H), 1.83–1.79 (m, 1 H); 13C
NMR (125 MHz, CDCl3) δ 155.6, 154.3, 135.2, 132.2, 121.7,
117.4, 114.1, 57.2, 55.5, 46.3, 38.7, 29.5, 23.8; IR (film) 3306,
1639 cm-1. HRMS (ESI+ TOF) m/z [M + H]+: C15H20N2O2
261.1598; found 261.1599.
4.2.2. General procedure 2: synthesis of sulfamide
substrates
4.2.1.2. (±)-N-(4-Methoxyphenyl)-2-(2-
methylallyl)pyrrolidine-1-carboxamide 3b
A clean, flame-dried round bottom flask equipped with a stir
bar was cooled under a stream of nitrogen and charged with N-
Boc-2-allylpyrrolidine or N-Boc-2-allylpiperidine28 (1.0 equiv),
dichloromethane (0.2 M), and trifluoroacetic acid (1.0 M). The
reaction mixture was stirred until judged as complete by thin
layer chromatography (c.a. 4 hours), then diluted with water and
quenched with ammonium hydroxide until pH reached 12. The
organic layer was reserved, and the aqueous layer extracted with
dichloromethane . Organic extracts were combined, dried over
anhydrous sodium sulfate, and concentrated in vacuo. The
resulting crude intermediates were then carried on to the next
step without any additional purification.
The title compound was prepared from N-Boc-2-(2-
methallyl)pyrrolidine (663 mg, 2.9 mmol) following General
Procedure 1. This procedure afforded 186 mg (23% yield) of the
1
title compound as a yellow oil. H NMR (500 MHz, CDCl3) δ
7.31–7.27 (m, 2 H), 6.84–6.83 (m, 2 H), 6.11 (s, 1 H), 5.63–5.60
(m, 1 H), 5.46–5.44 (m, 1 H), 4.03–4.01 (m, 1 H), 3.78 (s, 3 H),
3.47–3.44 (m, 2 H), 2.55 (dd, J = 4.1, 13.6 Hz, 1 H), 2.23–2.03
(m, 1 H), 2.01–1.94 (m, 3 H), 1.79–1.67 (m, 1 H), 1.82 (s, 3 H);
13C NMR (126 MHz, CDCl3) δ 155.5, 154.4, 132.3, 126.6, 121.8,
121.7, 114.0, 57.6, 55.5, 46.3, 31.6, 29.9, 23.8, 13.1; IR (film)
2966.8, 1638.0, 1638.0, 1510.1 cm-1. HRMS (ESI+ TOF) m/z: [M
+ H]+ calcd for C16H22N2O2 275.1754; found 275.1760.
A separate clean, flame-dried round bottom flask was cooled
under a stream of nitrogen, and charged with the appropriate N-
protected-2-oxo-oxazolidanone-3-sulfonamide14a (1.2 equiv), 4-
dimethylaminopyridine (0.2 equiv), and a stir bar, and then was
evacuated and backfilled with nitrogen. Acetonitrile (0.12 M
based on added amine) was added, followed by triethylamine
(3.0 equiv), and then the reaction vessel was heated in an oil bath
to 75 ºC. After one hour at 75 ºC, the crude 2-allylpyrrolidine or
2-allylpiperidine from above was added, and the reaction mixture
stirred at 75 ºC overnight (approximately 16 hours). The mixture
was cooled to 20 ºC, solvent was removed in vacuo, and the
4.2.1.3. (±)-2-Allyl-N-(4-
methoxybenzyl)pyrrolidine-1-carboxamide 3c
The title compound was prepared from 4-methoxybenzyl
isocyanate (1.8 mL, 12.6 mmol) and N-Boc-2-allylpyrrolidine
(1.77 g, 8.4 mmol) via General Procedure 1. This procedure
afforded 862 mg (37%) of the title compound as a pale yellow
oil. 1H NMR (500 MHz, CDCl3) δ 7.25 (d, J = 8.0 Hz, 2 H), 6.90
(d, J = 8.5 Hz, 2 H), 5.78 (dddd, J = 6.6, 7.8, 10.2, 16.9 Hz, 1 H),
5.10–5.00 (m, 2 H), 4.43–4.30 (m, 3 H), 3.97 (m, 1 H), 3.80 (s, 3
H), 3.34–3.23 (m, 2 H), 2.54–2.49 (m, 1 H), 2.18–2.08 (m, 1 H),

8
Tetrahedron
ACCEPTED MANUSCRIPT
residue was partitioned between dichloromethane and 3M
ºC. 1H NMR (700 MHz, CDCl3) δ 7.19 (d, J = 8.4 Hz, 2 H), 6.85
hydrochloric acid (aq). The organic layer was reserved, and the
aqueous layer extracted with dichloromethane. Organic extracts
were combined, dried over anhydrous sodium sulfate, and
concentrated in vacuo, and the resulting residue purified via flash
column chromatography on silica gel (20–40% ethyl
acetate/hexanes gradient).
(d, J = 8.4 Hz, 2 H), 5.75–5.67 (m, 2 H), 5.07–5.02 (m, 4 H),
3.79 (s, 3 H), 3.79–3.74 (m, 2 H), 2.50 (dt, J = 5.5, 12.0 Hz, 2 H),
2.16 (dt, J = 8.3, 14.8 Hz, 2 H), 1.77–1.71 (m, 2 H), 1.68–1.62
(m, 2 H); 13C NMR (175 MHz, CDCl3) δ 157.2, 134.6, 130.0,
123.7, 117.5, 114.4, 61.6, 55.4, 40.4, 29.0; IR (film) 3268, 1508,
1247, 1151 cm–1. HRMS (ESI+ TOF) m/z: [M + H]+ calcd for
C17H24N2O3S, 337.1580; found 337.1580.
4.2.2.1. (±)-2-Allyl-N-(4-
methoxyphenyl)pyrrolidine-1-sulfonamide 19a
4.2.2.5. (±)-2-Allyl-N-(4-methoxyphenyl)piperidine-
1-sulfonamide 23
The title compound was prepared from N-Boc-2-
allylpyrrolidine (1.06 g, 5.0 mmol) following General Procedure
2. This procedure afforded 808 mg (68%) of the title compound
The title compound was prepared from N-Boc-2-
allylpiperidine (2.0 g, 8.9 mmol) following General Procedure 2.
This afforded 1.25 g (45% yield) of the title compound as a
1
as a pale yellow oil. H NMR (700 MHz, CDCl3) δ 7.18 (d, J =
1
9.1 Hz, 2 H), 6.85 (d, J = 9.1 Hz, 2 H), 6.30 (s, br, 1 H), 5.70–
5.61 (m, 1 H), 5.05–4.99 (m, 2 H), 3.79 (s, 3 H), 3.79–3.77 (m, 1
H), 3.36–3.27 (m, 2 H), 2.46–2.41 (m, 1 H), 2.12 (dt, J = 13.9,
8.5 Hz, 1 H), 1.86–1.73 (m, 3 H), 1.70–1.66 (m, 1 H); 13C NMR
(175 MHz, CDCl3) δ 157.2, 134.5, 130.1, 123.7, 117.5, 114.4,
60.3, 55.5, 49.1, 39.9, 30.1, 24.2; IR (film) 3267, 1327, 1245,
1146 cm–1. HRMS (ESI+ TOF) m/z: [M + H]+ calcd for
C14H20N2O3S 297.1267; found 297.1274.
yellow oil. H NMR (700 MHz, CDCl3) δ 7.12–7.07 (m, 2 H),
6.86–6.81 (m, 2 H), 6.15 (s, 1 H), 5.72–5.64 (m, 1 H), 5.06–4.99
(m, 2 H), 3.98–3.92 (m, 1 H), 3.78 (s, 3 H), 3.59 (dd, J = 4.5,
14.0 Hz, 1 H), 2.97 (td, J = 2.8, 13.3 Hz, 1 H), 2.41–2.30 (m, 2
H), 1.59–1.49 (m, 2 H), 1.50–1.37 (m, 2 H), 1.33–1.22 (m, 2 H);
13C NMR (176 MHz, CDCl3) δ 157.1, 135.0, 130.1, 123.3, 117.3,
114.4, 55.5, 53.5, 41.4, 34.1, 26.7, 24.9, 18.0; IR (film) 3271.5,
1509.0, 1246.2, 1142.1 cm-1. HRMS (ESI+ TOF) m/z: [M + H]+
calcd for C15H22N2O3S 311.1424; found 311.1422.
4.2.2.2. (±)-2-Allyl-N-benzylpyrrolidine-1-
sulfonamide 19b
4.3. Preparation of products
The title compound was prepared from N-benzyl-2-
oxooxazolidine-3-sulfonamide (2.1 g, 8.3 mmol) and N-Boc-2-
allylpyrrolidine (2.1 g, 10.0 mmol) in two steps following
General Procedure 2. This procedure afforded 1.22 g (52%) of
4.3.1. General procedure 3: Synthesis of bicyclic
pyrrolidinyl ureas
A clean, flame-dried Schlenk tube equipped with a stir bar
was cooled under a stream of nitrogen and charged with the urea
substrate, Pd2(dba)3, tricyclohexylphosphonium tetrafluoroborate,
sodium tert-butoxide, and aryl or alkenyl bromide. The tube was
purged with nitrogen and 2.5 mL toluene per 1 mmol substrate
was added via syringe. The reaction mixture was heated to 110
ºC with stirring until judged complete as determined by TLC
analysis. Subsequently, the crude reaction mixture was diluted
with ethyl acetate (2 mL) and quenched with saturated aqueous
ammonium chloride (3 mL). The organic layer was separated,
and the aqueous layer extracted with ethyl acetate (2 mL x 2).
The collected organic layers were then dried over anhydrous
sodium sulfate, decanted, and concentrated in vacuo and purified
by flash chromatography on silica gel using 20–60% ethyl
acetate/hexanes as the eluent unless otherwise noted.
º
1
the title compound as a pale-yellow solid: mp = 38–41 C. H
NMR (700 MHz, CDCl3) δ 7.30–7.20 (m, 5 H), 5.72–5.64 (m, 1
H), 5.03–4.96 (m, 2 H), 4.68 (s, br, 1 H), 4.15 (s, 2 H), 3.76 (ddt,
J = 3.9, 7.8, 9.0 Hz, 1 H), 3.31–3.24 (m, 1 H), 3.16 (ddd, J = 4.9,
6.6, 9.5 Hz, 1 H), 2.46 (dddt, J = 1.4, 4.0, 6.8, 13.7 Hz, 1 H),
2.18–2.10 (m, 1 H), 1.84–1.69 (m, 3 H), 1.68–1.61 (m, 1 H); 13C
NMR (175 MHz, CDCl3) δ 137.0, 134.6, 128.7, 127.9, 127.9,
117.5, 59.6, 49.0, 47.4, 40.1, 30.3, 24.3; IR (film) 3282, 1312,
1143 cm–1. HRMS (ESI+ TOF) m/z: [M + H]+ calcd for
C14H20N2O2S 281.1318; found 281.1325.
4.2.2.3. (±)-2-Allyl-N-(4-
methoxybenzyl)pyrrolidine-1-sulfonamide 19c
The title compound was prepared from N-(4-methoxybenzyl)-
2-oxooxazolidine-3-sulfonamide (2.4 g, 8.3 mmol) and N-Boc-2-
allylpyrrolidine (2.1 g, 10.0 mmol) following General Procedure
2. This procedure afforded 1.10 g (43%) of the title compound as
4.3.1.1. (±)-(3R*,4aR*)-2-(4-Methoxyphenyl)-3-(4-
methylbenzyl)hexahydropyrrolo[1,2-c]pyrimidin-
1(2H)-one 4a
º
1
a yellow solid: mp = 39–42 C. H NMR (700 MHz, CDCl3) δ
7.25 (d, J = 9.1 Hz, 2 H), 6.88 (d, J = 8.4 Hz, 2 H), 5.77 (ddt, J =
7.1, 10.2, 17.2 Hz, 1 H), 5.12–5.04 (m, 2 H), 4.16 (s, 2 H), 3.88–
3.79 (m, 1 H), 3.80 (s, 3 H), 3.37 (dt, J = 7.3, 9.9, Hz, 1 H), 3.25
(ddd, J = 5.1, 6.7, 9.7 Hz, 1 H), 2.56–2.53 (m, 1 H), 2.27–2.19
(m, 1 H), 1.95–1.79 (m, 3 H), 1.75–1.69 (m, 1 H); 13C NMR (175
MHz, CDCl3) δ 159.3, 134.7, 129.3, 129.0, 117.5, 114.1, 59.6,
55.3, 49.1, 47.0, 40.1, 30.3, 24.3; IR (film) 3289, 1302, 1247,
1144 cm–1. HRMS (ESI+ TOF) m/z: [M + H]+ calcd for
C15H22N2O3S 311.1424; Found 311.1416.
A flame-dried Schlenk tube was cooled under a stream of N2
and charged with Pd2(dba)3 (6.4 mg, 0.007 mmol), PCy3•HBF4
(10.3 mg, 0.028 mmol) and NaOtBu (50 mg, 0.52 mmol). The
flask was purged with N2, then a solution of 3a (83 mg, 0.35
mmol) in toluene (3.5 mL) was added via syringe and the
resulting mixture was stirred at rt for 5 min. 4-Bromotoluene (89
º
µL, 0.52 mmol) was added and the flask was heated to 110 C
and stirred overnight (ca. 14 h). The mixture was cooled to room
temperature and saturated aqueous NH4Cl (3 mL) and ethyl
acetate (3 mL) were added. The organic layer was filtered
through a plug of silica gel and the silica gel was washed with
ethyl acetate (10 mL). The filtrate was dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo. Analysis of
4.2.2.4. (±)-(2S*,5R*)-2,5-Diallyl-N-(4-
methoxyphenyl)pyrrolidine-1-sulfonamide 19d
1
the crude material by H NMR revealed the product had been
The title compound was prepared from N-(4-methoxyphenyl)-
formed as a 14:1 mixture of diastereomers. The crude material
was purified by flash chromatography on silica gel to afford 78
mg (70%) of the title compound as a pale yellow oil with 14:1 dr.
Data are for the major isomer. 1H NMR (500 MHz, CDCl3) δ
7.19 (d, J = 9.0 Hz, 2 H), 7.06 (d, J = 8.0 Hz, 2 H), 6.92–6.90 (m,
2-oxooxazolidine-3-sulfonamide (1.6 g, 5.9 mmol) and (±)-
(E,2R*,5S*)-tert-butyl
2-allyl-5-[3-
(trimethylsilyl)allyl]pyrrolidine-1-carboxylate (2.3 g, 7.1 mmol)
following General Procedure 2. This procedure afforded 1.46 g
(73%) of the title compound as an off-white solid: mp = 57–60

9
4 H), 3.96 (dt, J = 4.5, 11.5 Hz, 1 H), 3.82 (s, 3 H), 3.82–3.76 (m,
1 H), 3.60 (dt, J = 7.5, 11.5 Hz, 1 H), 3.55–3.51 (m, 1 H), 3.02
(dd, J = 3.8, 13.8 Hz, 1 H), 2.64 (dd, J = 11.0, 13.5 Hz, 1 H),
2.30 (s, 3 H), 2.13 (dt, J = 5.5, 12.0 Hz, 1 H), 2.05–1.95 (m, 2 H),
1.88–1.82 (m, 1 H), 1.54 (dt, J = 2.5, 12.5 Hz, 1 H) 1.50–1.44
(m, 1 H); 13C NMR (125 MHz, CDCl3) δ 157.5, 154.4, 135.9,
135.5, 134.8, 130.1, 129.2, 128.8, 114.2, 60.4, 55.4, 52.5, 46.1,
38.1, 33.8, 29.5, 23.4, 20.9; IR (film) 1640 cm-1. HRMS (ESI+
TOF) m/z: [M + H]+ calcd for C22H26N2O2, 351.2071; found
351.2071
The title compound was prepared from substrate 3a (41 mg,
ACCEPTED MANUSCRIPT
0.16 mmol), 1-bromo-3,4-methylenedioxybenzene (48 µL, 0.40
mmol), NaOtBu (40 mg, 0.42 mmol), Pd2(dba)3 (3.6 mg, 0.008
mmol), and PCy3•HBF4 (6.7 mg, 0.018 mmol) according to
General Procedure 3. This procedure afforded 48 mg (79%) of
the title compound as a pale brown foam. The compound was
1
obtained as a 10:1 mixture of diastereomers as judged by H
NMR analysis. Data are for the major isomer. H NMR (500
1
MHz, CDCl3) δ 7.20–7.14 (m, 2 H), 6.93–6.86 (m, 2 H), 6.69 (d,
J = 8.3 Hz, 1 H), 6.48 (dt, J = 2.0, 4.0 Hz, 2 H), 5.90 (s, 2 H),
3.97–3.89 (m, 1 H), 3.81 (s, 3 H), 3.79–3.71 (m, 1 H), 3.65–3.48
(m, 2 H), 2.96 (dd, J = 4.2, 13.7 Hz, 1 H), 2.59 (dd, J = 11.1, 13.7
Hz, 1 H), 2.20–1.75 (m, 4 H), 1.61–1.42 (m, 2 H); 13C NMR (126
MHz, CDCl3) δ 158.0, 154.8, 148.1, 146.5, 135.9, 132.1, 129.6,
122.4, 114.6, 109.6, 108.7, 101.3, 60.9, 55.8, 53.0, 46.6, 38.8,
34.3, 30.0, 23.9; IR (film) 2936.5, 1626.3, 1445.6, 1240.4 cm-1.
HRMS (ESI+ TOF) m/z: [M + H]+ calcd for C22H24N2O4
381.1809; found 381.1805.
4.3.1.2. (±)-(E,3R*,4aR*)-2-(4-Methoxyphenyl)-3-
(undec-2-en-1-yl)hexahydropyrrolo[1,2-
c]pyrimidin-1(2H)-one 4b
The title compound was prepared in a manner analogous to 4a
except using Pd2(dba)3 (6.4 mg, 0.007 mmol), PCy3•HBF4 (10.3
mg, 0.028 mmol) and NaOtBu (67 mg, 0.70 mmol), a solution of
3a (83 mg, 0.35 mmol) in toluene (3.5 mL), and a solution of
(E)-1-bromodec-1-ene (153 mg, 0.70 mmol) in toluene (1 mL).
4.3.1.5. (±)-(3R*,4aR*)-2-(4-Methoxyphenyl)-3-[2-
(trifluoromethyl)benzyl]hexahydropyrrolo[1,2-
c]pyrimidin-1(2H)-one 4e
1
Analysis of the crude material by H NMR revealed the product
had been formed as a 18:1 mixture of diastereomers. The crude
material was purified by flash chromatography on silica gel to
afford 98 mg (77%) of the title compound as a pale yellow oil
with 18:1 dr. Data are for the major isomer. 1H NMR (500 MHz,
CDCl3) δ 7.13 (d, J = 9.0 Hz, 2 H), 6.86 (d, J = 9.0 Hz, 2 H), 5.42
(dt, J = 7.5, 15.5 Hz, 1 H), 5.16 (dt, J = 7.0, 15.0 Hz, 1 H), 3.79
(s, 3 H), 3.76–3.73 (m, 1 H), 3.68–3.62 (m, 1 H), 3.58 (dt, J =
7.5, 11.5 Hz, 1 H), 3.50–3.46 (m, 1 H), 2.39 (dt, J = 5.0, 13.5 Hz,
1 H), 2.24 (ddt, J = 1.5, 2.0, 13.0 Hz, 1 H), 2.20–2.11 (m, 2 H),
2.00–1.91 (m, 3 H), 1.85–1.78 (m, 1 H), 1.62 (dt, J = 5.0, 12.3
Hz, 1 H), 1.49 (ddt, J = 7.5, 10.0, 12.0 Hz, 1 H), 1.30–1.23 (m,
12 H), 0.87 (t, J = 7.0 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ
157.5, 154.4, 135.7, 134.2, 129.3, 125.4, 114.1, 58.7, 55.4, 52.5,
46.0, 35.9, 33.9, 32.5, 31.8, 30.3, 29.4, 29.2, 29.1, 23.4, 22.6,
14.1 (one carbon signal is absent due to incidental equivalence);
IR (film) 1640 cm-1. HRMS (ESI+ TOF) m/z: [M + H]+ calcd for
C25H38N2O2 399.3006; found 399.3009
The title compound was prepared from substrate 3a (41 mg,
0.16 mmol), 2-bromobenzotrifluoride (55 µL, 0.40 mmol),
NaOtBu (41 mg, 0.42 mmol), Pd2(dba)3 (3.4 mg, 0.007 mmol),
and PCy3•HBF4 (5.6 mg, 0.015 mmol) according to General
Procedure 3. This procedure afforded 49 mg (78%) of the title
compound as a brown foam. The compound was obtained as a
1
>20:1 mixture of diastereomers as judged by H NMR analysis.
Data are for the major isomer. H NMR (700 MHz, CDCl3) δ
1
7.56 (d, J = 8.0 Hz, 1 H), 7.42–7.38 (m, 1 H), 7.28–7.21 (m, 1
H), 7.15–7.05 (m, 3 H), 6.85 (d, J = 8.3 Hz, 2 H), 4.15 (dd, J =
5.4, 10.6 Hz, 1 H), 3.82–3.78 (m, 1 H), 3.78 (s, 3 H), 3.62–3.51
(m, 2 H), 3.18–3.12 (m, 1 H), 3.04–2.96 (m, 1 H), 2.17–1.82 (m,
4 H), 1.62–1.57 (m, 1 H), 1.50–1.43 (m, 1 H); 13C NMR (176
MHz, CDCl3) δ 157.7 154.3, 136.6, 135.2, 131.7, 130.5, 129.2,
129.1 (q, J = 220 Hz), 126.6, 126.3, 114.5, 60.0, 55.3, 52.5, 46.1,
35.2, 33.8, 30.2, 23.4 (one carbon signal is absent due to
incidental equivalence); 19F NMR (377 MHz, CDCl3) δ –58.8; IR
(film) 2934.5, 1628.7, 1510.6, 1450.1, 1342.7 cm-1. HRMS (ESI+
TOF) m/z: [M + H]+ calcd for C22H23F3N2O2 405.1784; Found
405.1781.
4.3.1.3. (±)-(3R*,4aR*)-3-[(1,1'-biphenyl)-4-
ylmethyl] -2-(4-methoxyphenyl)hexahydropyrrolo
[1,2-c]pyrimidin-1(2H)-one 4c
The title compound was prepared from substrate 3a (53 mg,
0.20 mmol), 4-bromobiphenyl (95 mg, 0.41 mmol), NaOtBu (40
mg, 0.42 mmol), Pd2(dba)3 (3.4 mg, 0.007 mmol), and
PCy3•HBF4 (6.8 mg, 0.018 mmol) according to General
Procedure 3. This procedure afforded 64 mg (77%) of the title
compound as a brown foamy solid. The compound was obtained
as a 16:1 mixture of diastereomers as judged by 1H NMR
4.3.1.6. (±)-(3R*,4aR*)-2-(4-Methoxyphenyl)-3-(4-
nitrobenzyl)hexahydropyrrolo[1,2-c] pyrimidin-
1(2H)-one 4f
The title compound was prepared from substrate 3a (40 mg,
0.15 mmol), 1-bromo-4-nitrobenzene (83 mg, 0.41 mmol),
NaOtBu (40 mg, 0.42 mmol), Pd2(dba)3 (3.6 mg, 0.008 mmol),
and PCy3•HBF4 (5.6 mg, 0.015 mmol) according to General
Procedure 3. This procedure afforded 23 mg (39%) of the title
compound as a sticky brown solid. The compound was obtained
as a >20:1 mixture of diastereomers as judged by 1H NMR
1
analysis. Data are for the major isomer. H NMR (700 MHz,
CDCl3) δ 7.55 (d, J = 7.6 Hz, 2 H), 7.48 (d, J = 7.8 Hz, 2 H), 7.42
(t, J = 7.6 Hz, 2 H), 7.33 (t, J = 7.4 Hz, 1 H), 7.23 (d, J = 13.3
Hz, 2 H), 7.09 (d, J = 7.8 Hz, 2 H), 6.91 (d, J = 8.6 Hz, 2 H),
4.09–4.00 (m, 1 H), 3.81 (s, 3 H), 3.80–3.76 (m, 1H) 3.65–3.59
(m, 1 H), 3.59–3.49 (m, 1 H), 3.10 (dd, J = 4.2, 13.6 Hz, 1 H),
2.74 (dd, J = 11.0, 13.6 Hz, 1 H), 2.17–1.84 (m, 4 H), 1.63–1.45
(m, 2 H); 13C NMR (176 MHz, CDCl3) δ 157.7, 154.5, 140.7,
139.4, 137.1, 135.6, 129.4, 129.2, 128.8, 127.3, 127.0, 114.2,
60.5, 55.4, 52.7, 46.2, 38.4, 33.9, 29.8, 23.5 (one carbon signal is
absent due to incidental equivalence); IR (film) 2931.6, 2228.0,
1627.9, 1447.5 cm-1. HRMS (ESI+ TOF) m/z: [M + H]+ calcd for
C27H28N2O2 413.2224; found 413.2220.
1
analysis. Data are for the major isomer. H NMR (500 MHz,
CDCl3) δ 8.12 (d, J = 8.1 Hz, 2 H), 7.29–7.16 (m, 4 H), 6.91–
6.89 (m, 2 H), 4.10–4.07 (m, 1 H), 3.82 (s, 3 H), 3.81–3.75 (m, 1
H), 3.65–3.49 (m, 2 H), 3.17 (dd, J = 4.5, 13.6 Hz, 1 H), 2.85
(dd, J = 10.5, 13.7 Hz, 1 H), 2.18–2.15 (m, 1 H), 2.06–1.94 (m, 2
H), 1.93–1.83 (m, 1 H), 1.67–1.64 (m, 1 H), 1.51–1.44 (m, 1 H);
13C NMR (126 MHz, CDCl3) δ 157.9, 154.2 146.8, 145.7, 130.1
129.8, 129.1, 123.8, 114.3, 60.0, 55.5, 52.6, 46.2, 38.9, 33.9,
30.1, 23.4; IR (film) 2931.3, 1604.9, 1509.5, 1446.0 cm-1. HRMS
(ESI+ TOF) m/z: [M + H]+ calcd for C21H23N3O4 382.1761; found
382.1758.
4.3.1.4. (±)-(3R*,4aR*)-3-(Benzo[d][1,3]dioxol-5-
ylmethyl)-2-(4-methoxyphenyl)
hexahydropyrrolo[1,2-c]pyrimidin-1(2H)-one 4d

10
Tetrahedron
4.3.1.7. (±)-(3R*,4aR*)-3-[(1,1'-Biphenyl)-4-
= 12.3, 5.2 Hz, 1 H), 1.51 (tdd, J = 12.1, 10.0, 7.1 Hz, 1 H), 0.90
ACCEPTED MANUSCRIPT
(t, J = 7.5 Hz, 3 H); 13C NMR (175 MHz, CDCl3) δ 157.5, 154.4,
135.7, 134.5, 129.2, 124.2, 114.1, 58.7, 55.4, 52.6, 46.0, 33.9,
30.5, 30.4, 23.4, 20.7, 14.0; IR (film) 1638 cm–1. (ESI+ TOF)
m/z: [M + H]+ calcd for C19H26N2O2 315.2067; found 315.2070.
ylmethyl] -2-(4-methoxyphenyl)-3-
methylhexahydropyrrolo[1,2-c]pyrimidin-1(2H)-one
4g
The title compound was prepared from substrate 3b (42 mg,
0.15 mmol), 4-bromobiphenyl (89 mg, 0.38 mmol), NaOtBu (38
mg, 0.40 mmol), Pd2(dba)3 (3.1 mg, 0.006 mmol), and
PCy3•HBF4 (5.6 mg, 0.015 mmol) according to General
Procedure 3. This procedure afforded 64 mg (97%) of the title
compound as a brown solid, mp 73–74 ºC. The compound was
4.3.1.10. (±)-(Z,3R*,4aR*)-2-(4-methoxyphenyl)-3-
(pent-2-en-1-yl)octahydro-1H-pyrido[1,2-
c]pyrimidin-1-one 6a
The title compound was prepared from substrate 5 (55 mg, 0.2
mmol) and (Z)-1-bromobutene (500 µL, 1.0 mmol, 2.0 M
solution in toluene), NaOtBu (96 mg, 1.0 mmol), Pd2(dba)3 (5.5
mg, 0.006 mmol), and PCy3•HBF4 (9.0 mg, 0.024 mmol)
according to a modification of General Procedure 3. This
procedure afforded 45 mg (69%) of the title compound as a
brown oil. The compound was obtained as an 8:1 mixture of
1
obtained as a >20:1 mixture of diastereomers as judged by H
NMR analysis. Data are for the major isomer. H NMR (500
1
MHz, CDCl3) δ 7.54 (d, J = 7.7 Hz, 2 H), 7.48–7.42 (m, 2 H),
7.41–7.37 (m, 2 H), 7.31–7.27 (m, 1 H), 7.20–7.11 (m, 4 H), 6.88
(d, J = 8.3 Hz, 2 H), 3.95–3.91 (m, 1 H), 3.79 (s, 3 H), 3.64–3.58
(m, 1 H), 3.51 (t, J = 10.2 Hz, 1 H), 3.17 (d, J = 13.3 Hz, 1 H),
3.00 (d, J = 13.3 Hz, 1 H), 2.20–2.00 (m, 2 H), 1.99–1.97 (m, 1
H), 1.92–1.81 (m, 1 H), 1.50–1.43 (m, 1 H), 1.41–1.34 (m, 1 H),
1.00 (s, 3 H); 13C NMR (126 MHz, CDCl3) δ 158.5, 155.3, 140.6,
139.5, 136.4, 132.2, 131.0, 128.8, 127.3, 126.93, 126.88, 114.0,
59.3, 55.4, 52.6, 46.3, 43.8, 37.9, 34.0, 27.7, 23.2; IR (film)
2930.4, 1603.5, 1509.9, 1435.6 cm-1. HRMS (ESI+ TOF) m/z: [M
+ H]+ calcd for C28H30N2O2 427.2380; found 427.2376.
1
diastereomers as judged by H NMR analysis. Data are for the
major isomer. 1H NMR (700 MHz, CDCl3) δ 7.14 (d, J = 9.1 Hz,
2 H), 6.86 (d, J = 8.4 Hz, 2 H), 5.47–5.41 (m, 1 H), 5.17–5.14
(m, 1 H), 4.58 (d, J = 13.3 Hz, 1 H), 3.79 (s, 3 H), 3.59–3.55 (m,
1 H), 3.30 (dddd, J = 13.7, 11.0, 6.1, 3.6 Hz, 1 H), 2.57 (td, J =
12.7, 2.9 Hz, 1 H), 2.42–2.39 (m, 1 H), 2.27 (dt, J = 14.2, 9.4 Hz,
1 H), 2.04–1.93 (m, 3 H), 1.84 (d, J = 12.6 Hz, 1 H), 1.74–1.68
(m, 2 H), 1.50–1.35 (m, 2 H), 1.31–1.24 (m, 2 H), 0.93 (t, J = 7.7
Hz, 3 H); 13C NMR (175 MHz, CDCl3) δ 157.6, 155.0, 136.4,
134.5, 129.0, 124.1, 114.0, 57.1, 55.4, 50.8, 43.5, 33.6, 32.8,
30.9, 25.3, 24.0, 20.8, 14.1; IR (film) 1637 cm–1. (ESI+ TOF)
m/z: [M + H]+ calcd for C20H28N2O2 329.2224; found 329.2228.
4.3.1.8. (±)-(Z,3R*,4aR*)-2-(4-methoxybenzyl)-3-
(pent-2-en-1-yl)hexahydropyrrolo[1,2-c]pyrimidin-
1(2H)-one 4h
The title compound was prepared from substrate 3a (274 mg,
1.0 mmol) and (Z)-1-bromobutene (2.0 mL, 4.0 mmol, 2.0 M
solution in toluene), NaOtBu (384 mg, 4.0 mmol), Pd2(dba)3
(18.3 mg, 0.02 mmol), and PCy3•HBF4 (29.5 mg, 0.08 mmol)
according to a modification of General Procedure 3. This
procedure afforded 219 mg (67%) of the title compound as a
brown oil. The compound was obtained as a >20:1 mixture of
4.3.2. General procedure 4: synthesis of bicyclic
piperidinyl ureas
A clean, flame-dried Schlenk tube equipped with a stir bar
was cooled under a stream of nitrogen and charged with the urea
substrate, Pd(OAc)2, Dpe-Phos, Cs2CO3, and aryl bromide. The
tube was purged with nitrogen and 2.5 mL toluene per 1 mmol
substrate was added via syringe. The reaction mixture was heated
to 110 ºC with stirring until judged complete as determined by
TLC analysis. Subsequently, the crude reaction mixture was
diluted with ethyl acetate and quenched with saturated aqueous
ammonium chloride. The organic layer was separated, and the
aqueous layer extracted with ethyl acetate. The collected organic
layers were then dried over anhydrous sodium sulfate, decanted,
and concentrated in vacuo and purified by flash chromatography
on silica gel using 20–60% ethyl acetate/hexanes as the eluent
unless otherwise noted.
1
diastereomers as judged by H NMR analysis. Data are for the
major isomer. 1H NMR (700 MHz, CDCl3) δ 7.21 (d, J = 8.4 Hz,
2 H), 6.83 (d, J = 8.4 Hz, 2 H), 5.50–5.44 (m, 1 H), 5.23 – 5.17
(m, 1 H), 5.13 (d, J = 15.1 Hz, 1 H), 4.03 (d, J = 15.1 Hz, 1 H),
3.79 (s, 3 H), 3.60 (dt, J = 10.5, 6.0 Hz, 1 H), 3.58–3.54 (m, 1 H),
3.49 (dt, J = 9.1, 1.8 Hz, 1 H), 3.25–3.21 (m, 1 H), 2.38 (dd, J =
13.5, 6.7 Hz, 1 H), 2.19 (dt, J = 14.4, 9.4 Hz, 1 H), 2.09–1.94 (m,
5 H), 1.80 (ttd, J = 12.5, 9.6, 6.6 Hz, 1 H), 1.43 (qd, J = 11.9, 7.1
Hz, 1 H), 1.25 (td, J = 12.3, 5.0 Hz, 1 H), 0.95 (t, J = 7.5 Hz, 3
H); 13C NMR (175 MHz, CDCl3) δ 158.6, 155.0, 134.5, 131.3,
129.1, 124.5, 113.8, 55.2, 53.4, 52.6, 47.9, 46.1, 33.9, 30.6, 30.1,
23.5, 20.8, 14.2; IR (film) 1626 cm–1. (ESI+ TOF) m/z: [M + H]+
calcd for C20H28N2O2 329.2224; found 329.2221.
4.3.2.1. (±)-(3R*,4aR*)-3-(4-Methoxybenzyl)-2-(4-
methoxyphenyl)octahydro-1H-pyrido[1,2-
c]pyrimidin-1-one 6b
4.3.1.9. (±)-(Z,3R*,4aR*)-2-(4-methoxyphenyl)-3-
(pent-2-en-1-yl)hexahydropyrrolo[1,2-c]pyrimidin-
1(2H)-one 4i
The title compound was prepared from substrate 5 (45 mg,
0.16 mmol), 4-bromoanisole (50 µl, 0.40 mmol), Cs2CO3 (126
mg, 0.39 mmol), Pd(OAc)2 (1.7 mg, 0.008 mmol), and Dpe-Phos
(7.5 mg, 0.014 mmol) according to General Procedure 4. This
procedure afforded 23 mg (37%) of the title compound as a light
brown oil. The compound was obtained as a >20:1 mixture of
The title compound was prepared from substrate 3a (52 mg,
0.2 mmol) and (Z)-1-bromobutene (200 µL, 0.4 mmol, 2.0 M
solution in toluene), NaOtBu (38 mg, 0.40 mmol), Pd2(dba)3 (3.7
mg, 0.004 mmol), and PCy3•HBF4 (6.0 mg, 0.016 mmol)
according to General Procedure 3. This procedure afforded 36
mg (58%) of the title compound as a brown oil. The compound
was obtained as a >20:1 mixture of diastereomers as judged by
1
diastereomers as judged by H NMR analysis. Data are for the
major isomer. 1H NMR (500 MHz, CDCl3) δ 7.15 (d, J = 8.7 Hz,
2 H), 6.97 (d, J = 8.5 Hz, 2 H), 6.92–6.84 (m, 2 H), 6.80 (d, J =
8.4 Hz, 2 H), 4.66–4.57 (m, 1 H), 3.80 (s, 3 H), 3.80–3.77 (m,
1H), 3.77 (s, 3 H), 3.43–3.34 (m, 1 H), 3.08–2.99 (m, 1 H), 2.68–
2.56 (m, 2 H), 1.90–1.82 (m, 3 H), 1.73–1.69 (m, 2 H), 1.52–1.35
(m, 2 H), 1.25–1.16 (m, 1 H); 13C NMR (126 MHz, CDCl3) δ
158.2, 157.6, 154.9, 136.5, 130.1, 130.0, 129.0, 114.1, 114.0,
59.0, 55.4, 55.2, 50.7, 43.5, 38.4, 33.6, 32.1, 25.4, 24.0; IR (film)
1635.6, 1510.9, 1457.2, 1245.7 cm-1. HRMS (ESI+ TOF) m/z: [M
+ H]+ calcd for C23H28N2O3 381.2173; found 381.2170.
1
1H NMR analysis. Data are for the major isomer. H NMR (700
MHz, CDCl3) δ 7.14 (d, J = 8.4 Hz, 2 H), 6.87 (d, J = 9.1 Hz, 2
H), 5.47–5.40 (m, 1 H), 5.14–5.10 (m, 1 H), 3.80 (s, 3 H), 3.80–
3.74 (m, 1 H), 3.69–3.61 (m, 1 H), 3.58 (td, J = 10.6, 7.4 Hz, 1
H), 3.50 (ddd, J = 10.9, 8.8, 2.0 Hz, 1 H), 2.36–2.30 (m, 1 H),
2.30–2.26 (m, 1 H), 2.19 (ddd, J = 13.3, 3.5,1.4 Hz, 1 H), 2.16–
2.10 (m, 1 H), 2.01–1.92 (m, 3 H), 1.87–1.77 (m, 1 H), 1.64 (td, J

11
4.3.2.2. (±)-(3R*,4aR*)-2-(4-Methoxyphenyl)-3-[3-
(trifluoromethyl)benzyl]octahydro-1H-pyrido[1,2-
c]pyrimidin-1-one 6c
General procedure 5 was employed for the coupling of 7
ACCEPTED MANUSCRIPT
(55 mg, 0.2 mmol) and phenyl triflate (65 µL, 0.4 mmol), using a
catalyst composed of Pd(OAc)2 (1.8 mg, 0.008 mmol), and
RuPhos (9.3 mg, 0.02 mmol). This procedure afforded 66 mg
(94%) of the title compound as a yellow solid and as a 2:1
mixture of diastereomers as determined by 1H NMR analysis: mp
= 51–55 C. Data are for the major isomer. H NMR (700 MHz,
CDCl3) δ 8.26 (d, J = 9.1 Hz, 2 H), 7.56 (d, J = 8.4 Hz, 2 H),
7.29–7.23 (m, 3 H), 7.04 (d, J = 7.0 Hz, 2 H), 4.14 (tt, J = 3.9,
10.6 Hz, 1 H), 3.58–3.47 (m, 3 H), 2.85 (dd, J = 3.8, 13.5 Hz, 1
H), 2.32 (dd, J = 10.1, 13.4 Hz, 1 H), 2.26–1.46 (m, 6 H); 13C
NMR (175 MHz, CDCl3) δ 153.5, 147.5, 145.2, 137.0, 129.0,
128.7, 128.6, 126.7, 124.0, 58.2, 54.7, 46.0, 41.6, 35.0, 33.5,
23.0; IR (film) 1639, 1515, 1339 cm–1. HRMS (ESI+ TOF) m/z:
[M + H]+ calcd for C20H21N3O3 352.1656; found 352.1656.
The title compound was prepared from substrate 5 (48 mg,
0.17 mmol), 3-bromobenzotrifluoride (60 µl, 0.40 mmol),
Cs2CO3 (117 mg, 0.36 mmol), Pd(OAc)2 (1.4 mg, 0.006 mmol),
and Dpe-Phos (5.8 mg, 0.011 mmol) according to General
Procedure 4. This procedure afforded 36 mg (56%) of the title
compound as a viscous brown oil. The compound was obtained
as a >20:1 mixture of diastereomers as judged by 1H NMR
º
1
1
analysis. Data are for the major isomer. H NMR (700 MHz,
CDCl3) δ 7.49–7.47 (m, 1 H), 7.40–7.38 (m, 1 H), 7.29–7.22 (m,
2 H), 7.18–7.10 (m, 2 H), 6.95–6.84 (m, 2 H), 4.63 (dd, J = 1.9,
13.2 Hz, 1 H), 3.87 (dd, J = 3.3, 7.2 Hz, 1 H), 3.81 (s, 3 H), 3.42–
3.40 (m, 1 H), 3.16 (dd, J = 4.8, 13.6 Hz, 1 H), 2.81–2.76 (m, 1
H), 2.64–2.61 (m, 1 H), 1.98–1.81 (m, 3 H), 1.77–1.69 (m, 2 H),
1.49–1.45 (m, 2 H), 1.32–1.22 (m, 1 H); 13C NMR (176 MHz,
CDCl3) δ 157.8, 154.7, 139.0, 136.2, 132.5, 130.8 (q, 234 Hz),
129.1, 129.0, 125.5, 124.8, 123.5, 114.2, 58.6, 55.4, 50.7, 43.5,
39.2, 33.6, 32.4, 25.3, 24.0; 19F NMR (377 MHz, CDCl3) δ -62.6;
IR (film) 1635.7, 1511.3, 1444.6, 1331.5, 1233.5 cm-1. HRMS
(ESI+ TOF) m/z: [M + H]+ calcd for C25H25C3N2O3 419.1941;
found 419.1938.
4.3.3.2. (±)-(3S*,4aR*)-3-Benzyl-2-(4-
methoxyphenyl)hexahydro-2H-pyrrolo[1,2-
b][1,2,6]thiadiazine-1,1-dioxide 20a
General procedure 5 was employed for the coupling of 19a
(59 mg, 0.2 mmol) and phenyl triflate (65 µL, 0.4 mmol), using a
catalyst composed of Pd(OAc)2 (1.8 mg, 0.008 mmol), and
CPhos (8.7 mg, 0.02 mmol). This procedure provided an 80%
NMR yield (using phenanthrene as an internal standard) of the
title compound that was a 6:1 mixture of diastereomers as
4.3.2.3. (±)-(3R*,4aR*)-3-(4-Benzoylbenzyl)-2-(4-
methoxyphenyl)octahydro-1H-pyrido[1,2-
c]pyrimidin-1-one 6d
1
determined by H NMR analysis. Data for this compound are
provided below in entry 4.3.4.1.
4.3.3.3. (±)-(3S*,4aR*)-2,3-Dibenzylhexahydro-2H-
pyrrolo[1,2-b][1,2,6]thiadiazine-1,1-dioxide 20b
The title compound was prepared from substrate 5 (42 mg,
0.15 mmol), 4-bromobenzophenone (103.1 mg, 0.39 mmol),
Cs2CO3 (122 mg, 0.37 mmol), Pd(OAc)2 (1.4 mg, 0.006 mmol),
and Dpe-Phos (6.6 mg, 0.012 mmol) according to General
Procedure 4. This procedure afforded 43 mg (54%) of the title
compound as a viscous yellow oil. The compound was obtained
as a >20:1 mixture of diastereomers as judged by 1H NMR
General procedure 5 was employed for the coupling of 19b
(56 mg, 0.2 mmol) and phenyl triflate (65 µL, 0.4 mmol), using a
catalyst composed of Pd(OAc)2 (1.8 mg, 0.008 mmol), and
CPhos (8.7 mg, 0.02 mmol). This procedure afforded 61 mg
(86%) of the title compound as a white solid and as a 3:1 mixture
of diastereomers as determined by 1H NMR analysis: mp = 113–
1
analysis. Data are for the major isomer. H NMR (500 MHz,
CDCl3) δ 7.75 (d, J = 7.7 Hz, 2 H), 7.72–7.65 (m, 2 H), 7.57 (t, J
= 7.4 Hz, 1 H), 7.48–7.39 (m, 2 H), 7.22–7.08 (m, 4 H), 6.93–
6.83 (m, 2 H), 4.67–4.56 (m, 1 H), 3.91–3.83 (m, 1 H), 3.79 (s, 3
H), 3.42–3.39 (m, 1 H), 3.16 (dd, J = 4.7, 13.6 Hz, 1 H), 2.79
(dd, J = 10.3, 13.4 Hz, 1 H), 2.65–2.59 (m, 1 H), 1.93–1.81 (m, 3
H), 1.74–1.68 (m, 2 H), 1.52–1.37 (m, 2 H), 1.29–1.21 (m, 1 H);
13C NMR (126 MHz, CDCl3) δ 196.2, 157.7, 154.8, 143.0, 137.5,
136.3, 135.9, 132.4, 130.5, 129.9, 129.0, 128.9, 128.3, 114.2,
58.7, 55.4, 50.8, 43.5, 39.5, 33.6, 32.4, 25.3, 24.0; IR (film)
1633.8, 1603.6, 1510.0, 1443.5, 1276.0 cm-1. HRMS (ESI+ TOF)
m/z: [M + H]+ calcd for C29H30N2O3 455.2329; found 455.2324.
º
1
116 C. Data are for the major isomer. H NMR (700 MHz,
CDCl3) δ 7.42 (d, J = 7.0 Hz, 2 H), 7.34–7.18 (m, 6 H), 7.07 (d, J
= 7.0 Hz, 2 H), 4.59 (d, J = 16.2 Hz, 1 H), 4.15 (d, J = 16.1 Hz, 1
H), 4.15–4.09 (m, 1 H), 3.50–3.46 (m, 1 H), 3.26–3.21 (m, 2 H),
2.92 (dd, J = 4.6, 13.4 Hz, 1 H), 2.54 (dd, J = 10.5, 13.4 Hz, 1
H), 2.07–2.01 (m, 1 H), 1.98–1.90 (m, 1 H), 1.83–1.75 (m, 1 H),
1.71–1.49 (m, 3 H); 13C NMR (175 MHz, CDCl3) δ 138.5, 137.4,
129.2, 128.5, 128.4, 127.7, 127.2, 126.7, 61.6, 60.8, 49.6, 45.8,
40.6, 31.6, 30.7, 21.1; IR (film) 1333, 1155 cm–1. HRMS (ESI+
TOF) m/z: [M + H]+ calcd for C20H24N2O2S 357.1631; found
357.1632.
4.3.3. General procedure 5: synthesis of bicyclic
ureas and sulfamides from aryl triflates (for
reactions carried out in benzotrifluoride)
4.3.3.4. (±)-(3S*,4aR*)-3-Benzyl-2-(4-
methoxybenzyl)hexahydro-2H-pyrrolo[1,2-
b][1,2,6]thiadiazine-1,1-dioxide 20c
A test tube was charged with Pd(OAc)2 (0.04 equiv), a
phosphine ligand (0.1 equiv), and LiOtBu (2.0 equiv). The test
tube was purged with N2 then the appropriate aryl triflate (2.0
equiv) was added, followed by the appropriate substrate (1.0
equiv) in benzotrifluoride (0.2 M). The tube was heated to 100 ºC
and stirred overnight or until the starting material was completely
General procedure 5 was employed for the coupling of 19c
(62 mg, 0.2 mmol) and phenyl triflate (65 µL, 0.4 mmol), using a
catalyst composed of Pd(OAc)2 (1.8 mg, 0.008 mmol), and
CPhos (8.7 mg, 0.02 mmol). This procedure afforded 63 mg
(82%) of the title compound as a red-brown oil and as a 3:1
1
1
consumed as judged by H NMR analysis. The mixture was
mixture of diastereomers as determined by H NMR analysis.
1
cooled to room temperature and saturated aqueous NH4Cl (5
mL/mmol substrate) and dichloromethane (5 mL/mmol substrate)
were added. The layers were separated and the organic layer was
concentrated in vacuo. The crude material was purified by flash
chromatography on silica gel.
Data are for the major isomer. H NMR (700 MHz, CDCl3) δ
7.32 (d, J = 8.4 Hz, 2 H), 7.26–7.15 (m, 3 H), 7.08 (d, J = 7.0 Hz,
2 H), 6.85 (d, J = 8.4 Hz, 2 H), 4.51 (d, J = 15.9 Hz, 1 H), 4.08
(d, J = 16.1 Hz, 1 H), 4.11–4.03 (m, 1 H), 3.80 (s, 3 H), 3.48–
3.42 (m, 1 H), 3.27–3.21 (m, 2 H), 2.92 (dd, J = 13.3, 4.9 Hz, 1
H), 2.55 (dd, J = 13.4, 10.3 Hz, 1 H), 2.06–1.98 (m, 1 H), 1.96–
1.85 (m, 1 H), 1.82–1.76 (m, 1 H), 1.70–1.46 (m, 3 H); 13C NMR
(175 MHz, CDCl3) δ 158.8, 137.5, 130.4, 129.1, 129.1, 128.5,
4.3.3.1. (±)-(3S*,4aR*)-3-Benzyl-2-(4-
nitrophenyl)hexahydropyrrolo[1,2-c]pyrimidin-
1(2H)-one 18

12
Tetrahedron
126.6, 113.7, 61.3, 60.7, 55.2, 49.3, 45.9, 40.7, 31.6, 30.9,
52 mg (65%) of the title compound as a white solid and as a 7:1
ACCEPTED MANUSCRIPT
21.3; IR (film) 1332, 1245, 1155 cm–1. MS (ESI) 387.1725
(387.1737 calcd for C21H26N2O3S, M + H+).
mixture of diastereomers as determined by 1H NMR analysis: mp
º
1
= 48–51 C. Data are for the major isomer. H NMR (700 MHz,
CDCl3) δ 7.38 (d, J = 8.4 Hz, 2 H), 6.97 (d, J = 8.4 Hz, 2 H), 6.91
(d, J = 9.1 Hz, 2 H), 6.80 (d, J = 8.4 Hz, 2 H), 4.20–4.14 (m, 1
H), 3.85 (s, 3 H), 3.80 (s, 3 H), 3.80–3.73 (m, 1 H), 3.56–3.46
(m, 1 H), 3.37 (td, J = 5.7, 9.4 Hz, 1 H), 2.74 (dd, J = 4.4, 13.7
Hz, 1 H), 2.15–2.08 (m, 2 H), 2.04–1.91 (m, 2 H), 1.64–1.50 (m,
3 H); 13C NMR (175 MHz, CDCl3) δ 159.4, 158.3, 130.9, 130.4,
130.0, 129.3, 114.3, 113.9, 61.9, 60.3, 55.4, 55.2, 46.5, 39.5,
32.5, 31.3, 21.3; IR (film) 1507, 1338, 1247, 1158 cm–1. HRMS
(ESI+ TOF) m/z: [M + H]+ calcd for C21H26N2O4S 403.1686;
found 403.1679.
4.3.4. General procedure 6: synthesis of bicyclic
sufamides (for reactions carried out in tert-
butanol)
A test tube was charged with Pd(OAc)2 (0.04 equiv), a
phosphine ligand (0.1 equiv), and LiOtBu (2.0–3.0 equiv). The
test tube was purged with N2 then the appropriate aryl or alkenyl
triflate (2.0–3.0 equiv) was added, followed by the appropriate
substrate (1.0 equiv) in tert-butanol (0.1 M). The tube was heated
º
to 82 C and stirred overnight or until the starting material was
completely consumed as judged by 1H NMR analysis. The
mixture was cooled to room temperature and concentrated in
vacuo. The crude material was purified by flash chromatography
on silica gel.
4.3.4.4. (±)-(3S*,4aR*)-{4-{[2-(4-Methoxyphenyl)-
1,1-dioxidohexahydro-2H-pyrrolo[1,2-
b][1,2,6]thiadiazin-3-
yl]methyl}phenyl}(phenyl)methanone 20f
4.3.4.1. (±)-(3S*,4aR*)-3-Benzyl-2-(4-
methoxyphenyl)hexahydro-2H-pyrrolo[1,2-
b][1,2,6]thiadiazine-1,1-dioxide 20a
General procedure 6 was employed for the coupling of 19a
(59 mg, 0.2 mmol) and 4-benzoylphenyl triflate (132 mg, 0.4
mmol), using a catalyst composed of Pd(OAc)2 (1.8 mg, 0.008
mmol), and CPhos (8.7 mg, 0.02 mmol). The diastereoselectivity
of the reaction was judged to be 5:1 dr as determined by 1H NMR
analysis prior to flash chromatography. This procedure afforded
62 mg (65%) of the title compound as a white solid and as a 8:1
mixture of diastereomers as determined by 1H NMR analysis: mp
General procedure 6 was employed for the coupling of 19a
(59 mg, 0.2 mmol) and phenyl triflate (65 µL, 0.4 mmol), using a
catalyst composed of Pd(OAc)2 (1.8 mg, 0.008 mmol), and
CPhos (8.7 mg, 0.02 mmol). This procedure afforded 67 mg
(90%) of the title compound as a white solid and as a 7:1 mixture
1
º
1
of diastereomers as determined by H NMR analysis: mp = 45–
= 58–61 C. Data are for the major isomer. H NMR (700 MHz,
CDCl3) δ 7.78 (d, J = 7.7 Hz, 2 H), 7.72 (d, J = 8.4 Hz, 2 H), 7.59
(t, J = 7.5 Hz, 1 H), 7.49 (t, J = 7.6 Hz, 2 H), 7.38 (d, J = 8.8 Hz,
2 H), 7.18 (d, J = 7.9 Hz, 2 H), 6.91 (d, J = 8.7 Hz, 2 H), 4.33–
4.28 (m, 1 H), 3.79 (s, 3 H), 3.79–3.77 (m, 1 H), 3.54 (td, J = 5.7,
9.4 Hz, 1 H), 3.39 (td, J = 5.8, 9.3 Hz, 1 H), 2.87 (dd, J = 4.8,
13.7 Hz, 1 H), 2.33 (dd, J = 9.8, 13.7 Hz, 1 H), 2.19–2.12 (m, 1
H), 2.01–1.95 (m, 2 H), 1.68–1.62 (m, 3 H); 13C NMR (175
MHz, CDCl3) δ 196.2, 159.5, 142.4, 137.5, 136.1, 132.5, 130.9,
130.4, 130.2, 130.0, 129.0, 128.3, 114.4, 61.5, 60.1, 55.4, 46.5,
40.4, 32.9, 31.4, 21.3; IR (film) 1654, 1605, 1506, 1339, 1278,
1249, 1157 cm–1. HRMS (ESI+ TOF) m/z: [M + H]+ calcd for
C27H28N2O4S 477.1843; found 477.1847.
48 ºC. Data are for the major isomer. 1H NMR (700 MHz, CDCl3)
δ 7.39 (d, J = 8.4 Hz, 2 H), 7.29–7.20 (m, 3 H), 7.06 (d, J = 7.7
Hz, 2 H), 6.91 (d, J = 9.1 Hz, 2 H), 4.26–4.19 (m, 1 H), 3.80 (s, 3
H), 3.53 (td, J = 5.7, 9.5 Hz, 1 H), 3.38 (td, J = 5.8, 9.5 Hz, 1 H),
2.81 (dd, J = 4.4, 13.6 Hz, 1 H), 2.21–2.08 (m, 2 H), 2.07–1.91
(m, 3 H), 1.68–1.53 (m, 3 H); 13C NMR (175 MHz, CDCl3) δ
159.4, 137.4, 130.9, 130.4, 129.1, 128.6, 126.6, 114.3, 61.8, 60.2,
55.4, 46.5, 40.4, 32.6, 31.3, 21.3; IR (film) 1506, 1337, 1248,
1158 cm–1. HRMS (ESI+ TOF) m/z: [M + H]+ calcd for
C20H24N2O3S 373.1580; found 373.1589.
4.3.4.2. (±)-(3S*,4aR*)-3-[4-(tert-Butyl)benzyl] -2-
(4-methoxyphenyl)hexahydro-2H-pyrrolo[1,2-
b][1,2,6]thiadiazine-1,1-dioxide 20d
4.3.4.5. (±)-(3S*,4aR*)-2-(4-Methoxyphenyl)-3-(2-
methylbenzyl)hexahydro-2H-pyrrolo[1,2-
b][1,2,6]thiadiazine-1,1-dioxide 20g
General procedure 6 was employed for the coupling of 19a
(59 mg, 0.2 mmol) and 4-(tert-butyl)phenyl triflate (113 mg, 0.4
mmol), using a catalyst composed of Pd(OAc)2 (1.8 mg, 0.008
mmol), and CPhos (8.7 mg, 0.02 mmol). This procedure afforded
62 mg (72%) of the title compound as a white solid and as a 7:1
mixture of diastereomers as determined by 1H NMR analysis: mp
General procedure 6 was employed for the coupling of 19a
(59 mg, 0.2 mmol) and 2-tolyl triflate (96 mg, 0.4 mmol), using a
catalyst composed of Pd(OAc)2 (1.8 mg, 0.008 mmol), and
CPhos (8.7 mg, 0.02 mmol). This procedure afforded 65 mg
(84%) of the title compound as a white solid and as a 5:1 mixture
º
1
= 61–63 C. Data are for the major isomer. H NMR (700 MHz,
CDCl3) δ 7.39 (d, J = 9.1 Hz, 2 H), 7.27 (d, J = 7.7 Hz, 2 H), 6.98
(d, J = 8.4 Hz, 2 H), 6.90 (d, J = 9.1 Hz, 2 H), 4.25–4.19 (m, 1
H), 3.81 (s, 3 H), 3.80–3.76 (m, 1 H), 3.54–3.49 (m, 1 H), 3.41–
3.34 (m, 1 H), 2.77 (dd, J = 4.3, 13.7 Hz, 1 H), 2.14–2.09 (m, 2
H), 2.07–1.87 (m, 2 H), 1.70–1.52 (m, 3 H), 1.29 (s, 9 H); 13C
NMR (175 MHz, CDCl3) δ 159.4, 149.5, 134.2, 130.9, 130.4,
128.7, 125.4, 114.3, 61.8, 60.2, 55.4, 46.5, 39.9, 37.4, 34.4, 32.6,
31.3, 21.3; IR (film) 1506, 1338, 1247, 1158 cm–1. HRMS (ESI+
TOF) m/z: [M + H]+ calcd for C24H32N2O3S 429.2215; found
429.2215.
1
of diastereomers as determined by H NMR analysis: mp = 39–
43 ºC. Data are for the major isomer. 1H NMR (700 MHz, CDCl3)
δ 7.41 (d, J = 9.1 Hz, 2 H), 7.12–7.10 (m, 3 H), 7.05–7.02 (m, 1
H), 6.91 (d, J = 9.1 Hz, 2 H), 4.24–4.17 (m, 1 H), 3.82 (s, 3 H),
3.81–3.74 (m, 1 H), 3.55 (td, J = 5.7, 9.4 Hz, 1 H), 3.43–3.36 (m,
1 H), 2.75 (dd, J = 4.4, 13.8 Hz, 1 H), 2.22 (dd, J = 10.5, 13.8
Hz, 1 H), 2.18 (s, 3 H), 2.13 (ddt, J = 6.5, 9.6, 12.6 Hz, 1 H),
2.09–1.95 (m, 2 H), 1.67–1.60 (m, 3 H); 13C NMR (175 MHz,
CDCl3) δ 159.4, 136.3, 135.5, 130.9, 130.5, 130.4, 130.1, 126.8,
125.9, 114.3, 60.4, 60.2, 55.4, 46.5, 37.9, 32.7, 31.3, 21.3, 19.6;
IR (film) 1506, 1338, 1248, 1157 cm–1. HRMS (ESI+ TOF) m/z:
[M + H]+ calcd for C21H26N2O3S 387.1737; found 387.1745.
4.3.4.3. (±)-(3S*,4aR*)-3-(4-Methoxybenzyl)-2-(4-
methoxyphenyl)hexahydro-2H-pyrrolo[1,2-
b][1,2,6]thiadiazine-1,1-dioxide 20e
4.3.4.6. (±)-(3S*,4aR*)-3-(Cyclohex-1-en-1-
ylmethyl)-2-(4-methoxyphenyl)hexahydro-2H-
pyrrolo[1,2-b][1,2,6]thiadiazine-1,1-dioxide 20h
General procedure 6 was employed for the coupling of 19a
(59 mg, 0.2 mmol) and 4-methoxyphenyl triflate (72 µL, 0.4
mmol), using a catalyst composed of Pd(OAc)2 (1.8 mg, 0.008
mmol), and CPhos (8.7 mg, 0.02 mmol). This procedure afforded
General procedure 6 was employed for the coupling of 19a
(59 mg, 0.2 mmol) and 1-cyclohexenyl triflate (63 µL, 0.6

13
mmol), using a catalyst composed of Pd(OAc)2 (1.8 mg, 0.008
29.6, 29.4, 29.4, 29.3, 29.3, 25.4, 22.7, 21.2, 14.1; IR (film)
ACCEPTED MANUSCRIPT
mmol), and CPhos (8.7 mg, 0.02 mmol). This procedure afforded
55 mg (73%) of the title compound as a pale yellow oil and as a
6:1 mixture of diastereomers as determined by 1H NMR analysis.
1507, 1345, 1248, 1161 cm–1. HRMS (ESI+ TOF) m/z: [M + H]+
calcd for C24H40N2O3S 437.2832; found 437.2836.
4.3.5.2. (±)-(3S*,4aR*,7S*)-7-Allyl-3-benzyl-2-(4-
methoxyphenyl)hexahydro-2H-pyrrolo[1,2-
b][1,2,6]thiadiazine-1,1-dioxide 20j
1
Data are for the major isomer. H NMR (700 MHz, CDCl3) δ
7.32 (d, J = 8.4 Hz, 2 H), 6.87 (d, J = 9.1 Hz, 2 H), 5.33 (s, 1 H),
4.13–4.07 (m, 1 H), 3.87–3.82 (m, 1 H), 3.79 (s, 3 H), 3.51 (td, J
= 5.6, 9.4 Hz, 1 H), 3.36 (td, J = 5.8, 9.4 Hz, 1 H), 2.20 (ddt, J =
6.5, 9.7, 12.7 Hz, 1 H), 2.08–1.42 (m, 15 H); 13C NMR (175
MHz, CDCl3) δ 159.2, 133.1, 131.0, 130.4, 124.9, 114.0, 60.4,
58.5, 55.4, 46.4, 42.8, 33.0, 31.4, 28.2, 25.2, 22.8, 22.2, 21.3; IR
(film) 1506, 1337, 1248, 1156 cm–1. HRMS (ESI+ TOF) m/z: [M
+ H]+ calcd for C20H28N2O3S, 377.1893; found 377.1903.
General procedure 6 was employed for the coupling of 19d
(67 mg, 0.2 mmol) and phenyl triflate (65 µL, 0.4 mmol), using a
catalyst composed of Pd(OAc)2 (1.8 mg, 0.008 mmol), and
CPhos (8.7 mg, 0.02 mmol). The diastereoselectivity of the
1
reaction was judged to be 12:1 dr as determined by H NMR
analysis prior to flash chromatography. This procedure afforded
51 mg (62%) of the title compound as a pale yellow oil and as a
20:1 mixture of diastereomers as determined by 1H NMR
4.3.5. (±)-(E,3S*,4aR*)-2-(4-Methoxyphenyl)-3-
(undec-2-en-1-yl)-hexahydro-2H-pyrrolo[1,2-
b][1,2,6]thiadiazine-1,1-dioxide 20i
1
analysis. Data are for the major isomer. H NMR (700 MHz,
CDCl3) δ 7.40 (d, J = 8.4 Hz, 2 H), 7.26–7.19 (m, 3 H), 7.09 (d, J
= 7.0 Hz, 2 H), 6.88 (d, J = 9.1 Hz, 2 H), 5.78 (ddt, J = 7.1, 11.2,
15.8 Hz, 1 H), 5.10–5.04 (m, 2 H), 4.41 (tdd, J = 2.6, 5.3, 9.9 Hz,
1 H), 3.82 (s, 3 H), 3.77–3.72 (m, 1 H), 3.44 (tdd, J = 3.0, 5.0,
11.3 Hz, 1 H), 2.82 (dd, J = 5.3, 13.8 Hz, 1 H), 2.64–2.58 (m, 1
H), 2.37 (dt, J = 7.8, 14.0 Hz, 1 H), 2.11 (dd, J = 10.0, 13.8 Hz, 1
H), 2.01–1.94 (m, 1 H), 1.90 (ddt, J = 8.9, 10.2, 13.0 Hz, 1 H),
1.78–1.68 (m, 2 H), 1.68–1.53 (m, 2 H); 13C NMR (175 MHz,
CDCl3) δ 159.4, 137.3, 134.4, 131.4, 130.5, 129.1, 128.5, 126.7,
117.7, 114.0, 62.8, 61.7, 57.8, 55.4, 40.0, 39.8, 32.9, 30.5, 26.8;
IR (film) 1506, 1344, 1249, 1155 cm–1. HRMS (ESI+ TOF) m/z:
[M + H]+ calcd for C23H28N2O3S 413.1893; found 413.1895.
General procedure 6 was employed for the coupling of 19a
(15 mg, 0.05 mmol) and 1-decenyl triflate (29 µL, 0.15 mmol,
5:1 mixture of E/Z isomers), using a catalyst composed of
Pd(OAc)2 (0.45 mg, 0.002 mmol), and CPhos (2.2 mg, 0.005
mmol). The crude diastereoselectivity of the reaction could not
be precisely determined directly due to the formation of a
complex mixture of diastereomers and E/Z isomers. However, the
crude diastereoselectivity was estimated to be between 5:1 and
10:1 dr as determined by 1H NMR analysis prior to flash
chromatography. Following flash chromatography, this
procedure afforded 10 mg (46%) of the title compound as a pale
yellow oil and as a 10:1 mixture of diastereomers as determined
1
by H NMR analysis following hydrogenation of the olefin (see
4.3.5.3. (±)-(3S*,4aR*,7S*)-7-Allyl-3-(4-
methoxybenzyl)-2-(4-methoxyphenyl)hexahydro-2H-
pyrrolo[1,2-b][1,2,6]thiadiazine-1,1-dioxide 20k
1
below for details). Data are for the major isomer. H NMR (500
MHz, CDCl3) δ 7.34 (d, J = 9.0 Hz, 2 H), 6.88 (d, J = 9.1 Hz, 2
H), 5.46–5.41 (m, 1 H), 5.26–5.20 (m, 1 H), 4.01–3.90 (m, 2 H),
3.80 (s, 3 H), 3.52 (td, J = 6.0, 9.4 Hz, 1 H), 3.40 (td, J = 5.8, 9.4
Hz, 1 H), 2.20 (ddt, J = 6.7, 9.8, 12.8 Hz, 1 H), 2.10–1.91 (m, 3
H), 1.88–1.78 (m, 3 H), 1.73–1.54 (m, 2 H), 1.33–1.26 (m, 13 H),
0.88 (t, J = 7.0 Hz, 3 H); 13C NMR (175 MHz, CDCl3) δ 159.3,
133.3, 130.9, 130.2, 123.8, 114.2, 60.4, 60.0, 55.4, 46.6, 32.8,
31.9, 31.5, 31.4, 29.7, 29.4, 29.4, 29.3, 27.4, 22.7, 21.4, 14.1; IR
(film) 2922, 1507, 1349, 1248, 1161 cm–1. HRMS (ESI+ TOF)
m/z: [M + H]+ calcd for C24H38N2O3S 435.2676; found 435.2678.
General procedure 6 was employed for the coupling of 19d
(67 mg, 0.2 mmol) and 4-methoxyphenyl triflate (72 µL, 0.4
mmol), using a catalyst composed of Pd(OAc)2 (1.8 mg, 0.008
mmol), and CPhos (8.7 mg, 0.02 mmol). The diastereoselectivity
1
of the reaction was judged to be 13:1 dr as determined by H
NMR analysis prior to flash chromatography. This procedure
afforded 57 mg (64%) of the title compound as a white solid and
1
as a >20:1 mixture of diastereomers as determined by H NMR
analysis: mp = 44–46 ºC. Data are for the major isomer. 1H NMR
(700 MHz, CDCl3) δ 7.39 (d, J = 8.6 Hz, 2 H), 7.00 (d, J = 8.6
Hz, 2 H), 6.88 (d, J = 9.1 Hz, 2 H), 6.81 (d, J = 8.4 Hz, 2 H),
5.82–7.73 (m, 1 H), 5.10–5.04 (m, 2 H), 4.39–4.35 (m, 1 H), 3.82
(s, 3 H), 3.78 (s, 3 H), 3.77–3.72 (m, 1 H), 3.46–3.39 (m, 1 H),
2.76 (dd, J = 5.3, 13.9 Hz, 1 H), 2.61 (dd, J = 6.0, 14.4 Hz, 1 H),
2.37 (dt, J = 7.9, 15.0 Hz, 1 H), 2.04 (dd, J = 10.0, 13.9 Hz, 1 H),
4.3.5.1. (±)-(3S*,4aR*)-2-(4-Methoxyphenyl)-3-
undecylhexahydro-2H-pyrrolo[1,2-
b][1,2,6]thiadiazine-1,1-dioxide (reduction of 20i).
A flask equipped with a stirbar was charged with 20i (10 mg,
0.023 mmol) and methanol (2 mL). Pd/C (10 mg) was added to
the solution and the flask was capped with a rubber septum. The
flask was briefly flushed with hydrogen and then a hydrogen-
filled balloon attached to a needle (via an adaptor) was connected
to the flask through the septum. The mixture was stirred at rt
until the starting material had been consumed as judged by ESI+
MS analysis (ca. 1 hr). The crude product was then filtered
through a plug of celite to remove the Pd/C and washed with
methanol (5 mL). The crude material was concentrated in vacuo
and required no further purification. This procedure afforded 9
mg (90%) of the title compound as a clear colorless oil and as a
10:1 mixture of diastereomers as determined by 1H NMR
2.01–1.88 (m, 2 H), 1.78–1.68 (m, 2 H), 1.62–1.53 (m, 2 H); 13
C
NMR (175 MHz, CDCl3) δ 159.5, 158.4, 134.4, 131.5, 130.6,
130.0, 129.3, 117.7, 114.0, 113.9, 62.9, 61.9, 57.9, 55.4, 55.2,
39.8, 39.1, 32.9, 30.5, 26.8; IR (film) 1507, 1345, 1247, 1156
cm–1. HRMS (ESI+ TOF) m/z: [M + H]+ calcd for C24H30N2O4S
443.1999; found 443.1993.
4.3.5.4. (±)-(Z,3S*,4aR*)-2-Benzyl-3-(pent-2-en-1-
yl)hexahydro-2H-pyrrolo[1,2-b][1,2,6]thiadiazine-
1,1-dioxide 20l
1
A modified version of General Procedure 6 was employed for
the coupling of 19b (56 mg, 0.2 mmol) and (Z)-1-bromobutene
(400 µL, 0.8 mmol, 2.0 M solution in PhCF3), using NaOtBu (96
mg, 1.0 mmol), LiOTf (156 mg, 1.0 mmol), and a catalyst
composed of Pd(OAc)2 (1.8 mg, 0.008 mmol), and CPhos (8.7
analysis. Data are for the major isomer. H NMR (700 MHz,
CDCl3) δ 7.32 (d, J = 8.4 Hz, 2 H), 6.87 (d, J = 9.1 Hz, 2 H),
4.00–3.94 (m, 1 H), 3.88–3.78 (m, 1 H), 3.80 (s, 3 H), 3.50 (td, J
= 9.4, 5.6 Hz, 1 H), 3.35 (td, J = 9.4, 5.9 Hz, 1 H), 2.21 (ddt, J =
6.3, 9.6, 12.5 Hz, 1 H), 2.07–1.92 (m, 2 H), 1.81 (dt, J = 3.2,
13.9, Hz, 1 H), 1.73–1.57 (m, 2 H), 1.35–1.04 (m, 20 H), 0.88 (t,
J = 7.2 Hz, 3 H); 13C NMR (175 MHz, CDCl3) δ 159.2, 131.0,
130.4, 114.1, 60.7, 60.4, 55.4, 46.4, 33.4, 33.1, 31.9, 31.5, 29.6,
º
mg, 0.02 mmol). The reaction was heated to 100 C and stirred
overnight or until the starting material was completely consumed
as judged by 1H NMR analysis. The mixture was cooled to room

14
Tetrahedron
temperature and saturated aqueous NH4Cl (5 mL/mmol
General Procedure 6. This procedure afforded 80 mg (86%) of
ACCEPTED MANUSCRIPT
substrate) and dichloromethane (5 mL/mmol substrate) were
added. The layers were separated and concentrated in vacuo. The
crude material was purified by flash chromatography on silica
gel. This procedure afforded 20 mg (30%) of the title compound
as a pale yellow brown oil and as a 5:1 mixture of diastereomers
as determined by 1H NMR analysis. Data are for the major
the title compound as a sticky light brown foam. The compound
1
was obtained as a 4:1 mixture of diastereomers as judged by H
NMR analysis. Data are for the major isomer. H NMR (700
1
MHz, CDCl3) δ 7.41 (d, J = 8.4 Hz, 2 H), 7.31–7.26 (m, 2 H),
6.99 (d, J = 8.0 Hz, 2 H), 6.90 (d, J = 9.0 Hz, 2 H), 4.44–4.32 (m,
1 H), 3.81 (s, 3 H), 3.58–3.50 (m, 1 H), 3.48–3.44 (m, 1 H),
2.93–2.89 (m, 1 H), 2.75 (dd, J = 4.7, 13.7 Hz, 1 H), 2.08 (dd, J =
10.2, 13.7 Hz, 1 H), 1.84–1.64 (m, 6 H), 1.51–1.40 (m, 2 H), 1.29
(s, 9 H); 13C NMR (176 MHz, CDCl3) δ 159.4, 149.5, 134.0,
131.2, 129.1, 128.7, 125.4, 114.3, 66.2, 60.5, 57.1, 55.4, 44.3,
39.8, 34.4, 32.2, 31.9, 31.4, 25.0, 21.9 (one carbon signal is
absent due to incidental equivalence); IR (film) 1507.6, 1336.4,
1247.1, 1157.0 cm-1. HRMS (ESI+ TOF) m/z: [M + H]+
Calculated for C25H34N2O3S 443.2363; found 443.2364.
1
isomer. H NMR (700 MHz, CDCl3) δ 7.44–7.29 (m, 4 H), 7.24
(t, J = 7.4 Hz, 1 H), 5.41–5.37 (m, 1 H), 5.19–5.13 (m, 1 H), 4.50
(d, J = 16.2 Hz, 1 H), 4.11 (d, J = 16.2 Hz, 1 H), 3.90–3.85 (m, 1
H), 3.47 (td, J = 5.4, 9.0 Hz, 1 H), 3.40–3.31 (m, 1 H), 3.24 (td, J
= 6.1, 9.3 Hz, 1 H), 2.25–2.08 (m, 3 H), 1.95–1.80 (m, 5 H),
1.59–1.45 (m, 2 H), 0.88 (t, J = 7.7 Hz, 3 H); 13C NMR (175
MHz, CDCl3) δ 138.7, 134.7, 128.4, 127.6, 127.1, 123.9, 60.9,
60.6, 49.2, 45.9, 31.7, 31.6, 31.3, 21.0, 20.7, 13.9; IR (film)
1334, 1156 cm–1. HRMS (ESI+ TOF) m/z: [M + H]+ calcd for
C18H26N2O2S 335.1788; found 335.1793.
4.3.5.8. (±)-(3S*,4aR*)-2-(4-Methoxyphenyl)-3-(2-
methylbenzyl)octahydropyrido[1,2-
b][1,2,6]thiadiazine 1,1-dioxide 24d
4.3.5.5. (±)-(3S*,4aR*)-3-Benzyl-2-(4-
methoxyphenyl)octahydropyrido[1,2-
b][1,2,6]thiadiazine-1,1-dioxide 24a
The title compound was prepared from substrate 23 (57 mg,
0.18 mmol), 2-tolyl trifluoromethanesulfonate (96 µl, 0.40
mmol), LiOtBu (30 mg, 0.37 mmol), Pd(OAc)2 (2.3 mg, 0.010
mmol), and CPhos (7.7 mg, 0.018 mmol) according to General
Procedure 6. This procedure afforded 49 mg (67%) of the title
compound as a sticky off-white foam. The compound was
obtained as a 4:1 mixture of diastereomers as judged by 1H NMR
General procedure 6 was employed for the coupling of 23 (62
mg, 0.2 mmol) and phenyl triflate (65 µL, 0.4 mmol), using a
catalyst composed of Pd(OAc)2 (1.8 mg, 0.008 mmol), and
CPhos (8.7 mg, 0.02 mmol). This procedure afforded 65 mg
(84%) of the title compound as a white solid and as a 5:1 mixture
1
1
of diastereomers as determined by H NMR analysis: mp = 46–
analysis. Data are for the major isomer. H NMR (700 MHz,
49 ºC. Data are for the major isomer. 1H NMR (500 MHz, CDCl3)
δ 7.41 (d, J = 8.5 Hz, 2 H), 7.28–7.20 (m, 3 H), 7.07 (d, J = 7.5
Hz, 2 H), 6.91 (d, J = 9.0 Hz, 2 H), 4.41–4.37 (m, 1 H), 3.82 (s, 3
H), 3.59–3.43 (m, 2 H), 2.97–2.88 (m, 1 H), 2.79 (dd, J = 4.8,
13.6 Hz, 1 H), 2.13 (dd, J = 10.1, 13.7 Hz, 1 H), 1.89–1.65 (m, 4
H), 1.58–1.36 (m, 4 H); 13C NMR (175 MHz, CDCl3) δ 159.4,
137.2, 131.2, 130.0, 129.1, 128.5, 126.7, 114.2, 60.4, 57.1, 55.4,
44.3, 40.3, 32.1, 31.9, 24.9, 21.9; IR (film) 1507, 1338, 1250,
1156 cm–1. HRMS (ESI+ TOF) m/z: [M + H]+ calcd for
C21H26N2O3S 387.1737; found 387.1737.
CDCl3) δ 7.41 (d, J = 8.2 Hz, 2 H), 7.14–7.06 (m, 4 H), 6.95–
6.87 (m, 2 H), 4.41–4.36 (m, 1 H), 3.79 (s, 3 H), 3.59–3.47 (m, 2
H), 2.97–2.92 (m, 1 H), 2.72 (dd, J = 4.9, 14.0 Hz, 1 H), 2.19–
2.16 (m, 1 H), 2.16 (s, 3 H), 1.90 (dt, J = 12.1, 14.4 Hz, 1H),
1.73–1.64 (m, 5 H), 1.55–1.38 (m, 2 H); 13C NMR (176 MHz,
CDCl3) δ 159.5, 136.3, 135.4, 131.1, 130.5, 130.0, 128.6, 126.8,
126.0, 114.4, 59.1, 57.0, 55.4, 44.2, 37.6, 32.3, 31.8, 25.0, 21.8,
19.5; IR (film) 1606.1, 1506.1, 1463.5, 1338.8 cm-1. HRMS
(ESI+ TOF) m/z: [M + H]+ calcd for C22H28N2O3S 401.1893;
found 401.1891.
4.3.5.6. (±)-(3S*,4aR*)-3-(Cyclohex-1-en-1-
ylmethyl)-2-(4-methoxyphenyl)octahydropyrido[1,2-
b][1,2,6]thiadiazine 1,1-dioxide 24b
4.3.5.9. (±)-(3S*,4aR*)-3-(Benzo[d][1,3]dioxol-5-
ylmethyl)-2-(4-methoxyphenyl)octahydropyrido[1,2-
b][1,2,6]thiadiazine 1,1-dioxide 24e
The title compound was prepared from substrate 23 (62 mg,
0.20 mmol), cyclohex-1-en-1-yl trifluoromethanesulfonate (70
µl, 0.40 mmol), LiOtBu (35 mg, 0.44 mmol), Pd(OAc)2 (2.4 mg,
0.011 mmol), and CPhos (11.9 mg, 0.027 mmol) according to
General Procedure 6. This procedure afforded 60 mg (77%) of
the title compound as a sticky off-white foam. The compound
The title compound was prepared from substrate 23 (64 mg,
0.21 mmol), benzo[d][1,3]dioxol-5-yl trifluoromethanesulfonate
(100 µl, 0.40 mmol), LiOtBu (35 mg, 0.44 mmol), Pd(OAc)2 (2.2
mg, 0.010 mmol), and CPhos (10.0 mg, 0.023 mmol) according
to General Procedure 6. This procedure afforded 70 mg (79%) of
the title compound as a sticky white foam. The compound was
obtained as a 5:1 mixture of diastereomers as judged by 1H NMR
1
was obtained as a 2:1 mixture of diastereomers as judged by H
1
1
NMR analysis. Data are for the major isomer. H NMR (500
analysis. Data are for the major isomer. H NMR (500 MHz,
MHz, CDCl3) δ 7.36 (d, J = 8.3 Hz, 2 H), 6.86 (d, J = 8.4 Hz, 2
H), 5.32 (s, 1 H), 4.29–4.21 (m, 1 H), 3.79 (s, 3 H), 3.62–3.46
(m, 2 H), 2.91–2.85 (m, 1 H), 2.32–2.28 (m, 1 H), 2.20–2.16 (m,
1 H), 2.00–1.45 (m, 16 H); 13C NMR (176 MHz, CDCl3) δ 159.3,
132.9, 131.2, 130.0, 124.7, 114.0, 57.3, 57.1, 55.4, 44.4, 42.5,
32.9, 32.1, 28.3, 25.2, 25.0, 22.8, 22.3, 21.6; IR (film) 1505.6,
1441.8, 1337.8, 1246.8 cm-1. HRMS (ESI+ TOF) m/z: [M + H]+
calcd for C21H30N2O3S 391.2050; found 391.2049.
CDCl3) δ 7.47–7.34 (m, 2 H), 6.97–6.86 (m, 2 H), 6.71–6.66 (m,
1 H), 6.55 (s, 1 H), 6.53–6.47 (m, 1 H), 5.91 (s, 2 H), 4.31–4.28
(m, 1 H), 3.80 (s, 3 H), 3.52–3.48 (m, 2 H), 2.97–2.91 (m, 1 H),
2.69–2.66 (m, 1 H), 2.04 (dd, J = 10.1, 13.7 Hz, 1 H), 1.84–1.65
(m, 5 H), 1.54–1.40 (m, 3 H); 13C NMR (126 MHz, CDCl3) δ
159.4, 147.7, 146.3, 131.1, 130.0, 128.5, 122.1, 114.4, 109.3,
108.3, 101.0, 60.5, 57.0, 55.4, 44.3, 40.0, 32.1, 31.8, 24.8, 21.8;
IR (film) 1504.4, 1442.5, 1337.0, 1246.3 cm-1. HRMS (ESI+
TOF) m/z: [M + H]+ calcd for C22H26N2O5S 431.1635; found
431.1634.
4.3.5.7. (±)-(3S*,4aR*)-3-[4-(tert-Butyl)benzyl] -2-
(4-methoxyphenyl)octahydropyrido[1,2-
b][1,2,6]thiadiazine 1,1-dioxide 24c
4.3.5.10. (±)-(3S*,4aR*)-3-(4-Methoxybenzyl)-2-(4-
methoxyphenyl)octahydropyrido[1,2-
b][1,2,6]thiadiazine 1,1-dioxide 24f
The title compound was prepared from substrate 23 (65 mg,
0.21 mmol), 4-(tert-butyl)phenyl trifluoromethanesulfonate (112
µl, 0.40 mmol), LiOtBu (40 mg, 0.50 mmol), Pd(OAc)2 (1.8 mg,
0.008 mmol), and CPhos (7.4 mg, 0.017 mmol) according to
The title compound was prepared from substrate 23 (63 mg,
0.20 mmol), 4-methoxyphenyl trifluoromethanesulfonate (72 µl,

15
0.40 mmol), LiOtBu (30 mg, 0.37 mmol), Pd(OAc)2 (1.3 mg,
0.006 mmol), and CPhos (10.1 mg, 0.023 mmol) according to
General Procedure 6. This procedure afforded 58 mg (72%) of
the title compound as a sticky off-white foam. The compound
10.8 Hz, 1 H), 2.99 (ddd, J = 3.5, 8.4, 11.7 Hz, 1 H), 2.04 (dt,
ACCEPTED MANUSCRIPT
J = 6.0, 13.8 Hz, 1 H), 1.92–1.66 (m, 8 H), 1.62–1.45 (m, 3 H),
0.88 (t, J = 7.5 Hz, 3 H); 13C NMR (175 MHz, CDCl3) δ 159.3,
134.7, 131.1, 130.0, 123.5, 114.2, 59.5, 56.7, 55.4, 44.1, 32.1,
31.7, 31.4, 24.9, 21.5, 20.7, 13.9; IR (film) 1506, 1339, 1248,
1159 cm–1. HRMS (ESI+ TOF) m/z: [M + H]+ calcd for
C19H28N2O3S 365.1893; found365.1905.
1
was obtained as a 4:1 mixture of diastereomers as judged by H
1
NMR analysis. Data are for the major isomer. H NMR (700
MHz, CDCl3) δ 7.40 (d, J = 8.4 Hz, 2 H), 7.00–6.93 (m, 2 H),
6.93–6.86 (m, 2 H), 6.86–6.75 (m, 2 H), 4.38–4.30 (m, 1 H), 3.80
(s, 3 H), 3.76 (s, 3 H), 3.56–3.50 (m, 1 H), 3.49–3.42 (m, 1 H),
2.92–2.88 (m, 1 H), 2.71 (dd, J = 4.8, 13.8 Hz, 1 H), 2.10–2.03
(m, 1 H), 1.86–1.72 (m, 3 H), 1.72–1.64 (m 2 H), 1.56–1.39 (m,
3 H); 13C NMR (176 MHz, CDCl3) δ 159.4, 158.3, 131.2, 130.5,
130.0, 129.1, 114.3, 113.9, 60.5, 57.1, 55.4, 55.2, 44.3, 39.4,
32.2, 31.9, 25.0, 22.0; IR (film) 1506.8, 1442.4, 1338.2, 1338.2
cm-1. HRMS (ESI+ TOF) m/z: [M + H]+ calcd for C22H28N2O4S
417.1837; found 417.1843.
4.3.6. Elaboration of products
4.3.6.1. (±)-(S*,R*)-1-Phenyl-3-(pyrrolidin-2-
yl)propan-2-amine 25
The title compound was prepared via the following two-step
one-pot procedure. The first step was carried out according to the
published work by Snyder and Heckert.33 A flask equipped with
a stirbar and reflux condenser was charged with 24a (66 mg, 0.18
mmol). Hydrobromic acid (48%, 4 mL) was slowly added to the
O
flask and the reaction was heated to 120 C and stirred until the
4.3.5.11. (±)-(3R*,4aR*)-2-(4-Methoxyphenyl)-3-
(thiophen-2-ylmethyl)octahydropyrido
[1,2b][1,2,6]thiadiazine 1,1-dioxide 24g
starting material had been completely consumed (ca. 2 h) as
judged by MS ESI+ analysis (297.1 m/z, M + H+). The mixture
was cooled to rt, CH3CN (2 mL) was added, followed by a
solution of ceric ammonium nitrate (494 mg, 0.9 mmol) in H2O
A modified version of General Procedure 6 was employed for
the coupling of substrate 23 (62 mg, 0.20 mmol) and 2-
bromothiophene (40 µl, 0.41 mmol), using LiOtBu (30 mg, 0.37
mmol), lithium trifluoromethanesulfonate (64 mg, 0.41 mmol),
and a catalyst composed of Pd(OAc)2 (2.3 mg, 0.010 mmol), and
(2 mL) and then stirred overnight (ca.
8 hr) at rt.
Dichloromethane (8 mL) was added to the solution, the mixture
was transferred to a separatory funnel and the layers were
separated. The aqueous layer was carefully basified with NH4OH
to pH > 12 and extracted with CH2Cl2 (3 x 15 mL). The
combined organic layers were washed with Na2SO3 (1 x 10 mL)
and brine (1 x 10 mL). The organic layer was dried over
anhydrous sodium sulfate, filtered, and concentrated in vacuo.
This procedure afforded 27 mg (75%) of the title compound as a
yellow brown oil and as a 7:1 mixture of diastereomers as
determined by 1H NMR analysis. Data are for the major isomer.
1H NMR (500 MHz, CDCl3) δ 7.30 (t, J = 8.0 Hz, 2 H), 7.22 (t, J
= 8.0 Hz, 1 H), 7.17 (d, J = 7.5 Hz, 2 H), 3.37–3.33 (m, 1 H),
3.15–3.12 (m, 1 H), 3.06–2.97 (m, 2 H), 2.86 (s, br, 3 H), 2.79
(dd, J = 4.9, 13.3 Hz, 1 H), 2.54 (dd, J = 8.2, 13.3 Hz, 1 H),
2.02–1.97 (m, 1 H), 1.83–1.77 (m, 2 H), 1.70–1.66 (m, 1 H),
1.48–1.43 (m, 1 H), 1.37–1.32 (m, 1 H); 13C NMR (175 MHz,
CDCl3) δ 138.7, 129.3, 128.5, 126.4, 58.5, 52.4, 45.8, 45.7, 41.7,
32.1, 24.6; IR (film) 3360, 2929 cm–1. HRMS (ESI+ TOF) m/z:
[M + H]+ calcd for C13H20N2 205.1699; found 205.1700.
º
CPhos (8.4 mg, 0.019 mmol).The reaction was heated to 100 C
and stirred overnight or until the starting material was completely
1
consumed as judged by H NMR analysis. The mixture was
cooled to room temperature and saturated aqueous NH4Cl (5
mL/mmol substrate) and dichloromethane (5 mL/mmol substrate)
were added. The layers were separated and concentrated in
vacuo. The crude material was purified by flash chromatography
on silica gel. This procedure afforded 58 mg (74%) of the title
compound as a sticky light brown foam. The compound was
obtained as a 6:1 mixture of diastereomers as judged by 1H NMR
1
analysis. Data are for the major isomer. H NMR (700 MHz,
CDCl3) δ 7.40 (d, J = 8.5 Hz, 2 H), 7.19–7.13 (m, 1 H), 6.92–
6.88 (m, 3 H), 6.76–6.73 (m, 1 H), 4.45–4.33 (m, 1 H), 3.80 (s, 3
H), 3.56–3.46 (m, 2 H), 3.01–2.89 (m, 2 H), 2.45 (dd, J = 9.5,
14.9 Hz, 1 H), 1.74–1.64 (m, 8 H); 13C NMR (176 MHz, CDCl3)
δ 159.5, 139.1, 131.1, 127.0, 126.9, 126.1, 124.3, 114.3, 60.4,
56.8, 55.4, 44.2, 34.3, 32.0, 31.7, 24.9, 21.6; IR (film) 1505.5,
1441.0, 1338.2, 1248.7 cm-1. HRMS (ESI+ TOF) m/z: [M + H]+
calcd for C19H24N2O3S2 393.1301; found 393.1302.
4.3.6.2. (±)-(3R,4aR)-3-
Pentylhexahydropyrrolo[1,2-c]pyrimidin-1(2H)-one
26
4.3.5.12. (±)-(Z,3S*,4aR*)-2-(4-Methoxyphenyl)-3-
(pent-2-en-1-yl)octahydropyrido[1,2-
b][1,2,6]thiadiazine-1,1-dioxide 24h
A flame-dried flask was cooled under vacuum and charged
with 10% Pd/C (120 mg). The flask was capped with a rubber
septum, evacuated and backfilled with nitrogen. A solution of 4f
(66 mg, 0.2 mmol) in methanol (8 mL) was added to the flask via
a syringe, followed by acetic acid (0.2 mL). The flask was briefly
flushed with hydrogen and then a hydrogen-filled balloon
attached to a needle (via an adaptor) was connected to the flask
through the septum. The mixture was placed in an oil bath at 50
ºC and the reaction was stirred overnight (ca. 16 h). The crude
material was then filtered through a plug of celite to remove the
Pd/C and washed with methanol (5 mL). The crude material was
concentrated in vacuo and purified by flash chromatography on
silica gel to afford 38.5 mg (92%) of the title compound as a pale
yellow solid: mp = 63–66 ºC. 1H NMR (700 MHz, CDCl3) δ 4.79
(s, br, 1 H), 3.54–3.44 (m, 3 H), 3.39–3.32 (m, 1 H), 2.15–2.08
(m, 1 H), 1.97–1.92 (m, 2 H), 1.80–1.74 (m, 2 H), 1.54–1.25 (m,
9 H), 0.88 (t, J = 7.0 Hz, 3 H); 13C NMR (175 MHz, CDCl3) δ
155.3, 52.3, 50.0, 45.3, 36.8, 33.6, 32.2, 31.6, 25.7, 23.0, 22.6,
14.0; IR (film) 3214, 1650 cm–1. HRMS (ESI+ TOF) m/z: [M +
H]+ calcd for C12H22N2O 211.1805; found 211.1812.
A modified version of General Procedure 6 was employed for
the coupling of 23 (62 mg, 0.2 mmol) and (Z)-1-bromobutene
(400 µL, 0.8 mmol, 2.0 M solution in PhCF3), using NaOtBu (96
mg, 1.0 mmol), LiOTf (156 mg, 1.0 mmol) and a catalyst
composed of Pd(OAc)2 (1.8 mg, 0.008 mmol), and CPhos (8.7
º
mg, 0.02 mmol). The reaction was heated to 100 C and stirred
overnight or until the starting material was completely consumed
as judged by 1H NMR analysis. The mixture was cooled to room
temperature and saturated aqueous NH4Cl (5 mL/mmol substrate)
and dichloromethane (5 mL/mmol substrate) were added. The
layers were separated and concentrated in vacuo. The crude
material was purified by flash chromatography on silica gel. This
procedure afforded 60 mg (82%) of the title compound as a pale
yellow oil and as a 5:1 mixture of diastereomers as determined
1
1
by H NMR analysis. Data are for the major isomer. H NMR
(700 MHz, CDCl3) δ 7.38 (d, J = 8.4 Hz, 2 H), 6.88 (d, J = 9.1
Hz, 2 H), 5.51–5.40 (m, 1 H), 5.25–5.19 (m, 1 H), 4.13–4.06 (m,
1 H), 3.80 (s, 3 H), 3.67–3.62 (m, 1 H), 3.49 (ddd, J = 3.7, 6.6,

16
Tetrahedron
4.3.6.3. (±)-(Z,R,R)-N-(4-Methoxybenzyl)-1-
washed with CHCl3 (2 x 20 mL) and then the aqueous layer was
ACCEPTED MANUSCRIPT
(pyrrolidin-2-yl)hept-4-en-2-amine 27
carefully basified with Na2CO3 and extracted with CHCl3 (3 x 20
mL). The combined organic layers were dried with Na2SO4 and
This compound was prepared via a modification of a
published procedure by Trost.34 A flame-dried flask was cooled
under vacuum and charged with LAH (190 mg, 5.0 mmol). A
reflux condenser was attached to the flask and the apparatus was
evacuated and backfilled with nitrogen. Diethyl ether (4 mL) was
added, followed by a solution of 4i (66 mg, 0.2 mmol) in diethyl
ether (4 mL). The flask was placed in an oil bath and allowed to
reflux overnight (ca. 16 h). The reaction flask was allowed to
cool to rt and then the mixture was diluted with ether (10 mL).
The reaction flask was placed in an ice bath and quenched slowly
with water (2 mL). 1M NaOH (2 mL) was added, followed by
more water (2 mL) and the biphasic mixture was stirred
vigorously for 15 min. The mixture was decanted, dried with
Na2SO4, and concentrated in vacuo. The crude product appeared
concentrated in vacuo to afford 35 mg (57%) of the title
1
compound as a pale yellow oil. H NMR (700 MHz, CDCl3) δ
7.22 (d, J = 8.2 Hz, 2 H), 6.85 (d, J = 8.4 Hz, 2 H), 5.52–5.46 (m,
1 H), 5.33–5.30 (m, 1 H), 3.79 (s, 3 H), 3.75 (d, J = 12.8 Hz, 1
H), 3.69 (d, J = 12.8 Hz, 1 H), 3.17 (s, br, 1 H), 2.97–2.94 (m, 1
H), 2.85–2.80 (m, 1 H), 2.75–2.71 (m, 1 H), 2.28 (dt, J = 6.7,
13.9 Hz, 1 H), 2.22 (dt, J = 6.7, 14.1 Hz, 1 H), 2.1–2.06 (m, 2 H),
1.85 (td, J = 7.3, 12.6 Hz, 1 H), 1.73–1.66 (m, 2 H), 1.63–1.51
(m, 2 H), 1.25 (m, 1 H), 0.95 (t, J = 7.6 Hz, 3 H); 13C NMR (175
MHz, CDCl3) δ 158.6, 134.3, 129.3, 125.2, 113.8, 56.3, 55.3,
54.9, 50.5, 46.2, 39.8, 31.9, 31.8, 25.1, 20.8, 14.3 (one carbon
signal is absent due to incidental equivalence); IR (film) 3002,
1611, 1511, 1246 cm–1. HRMS (ESI+ TOF) m/z: [M + H]+ calcd
for C19H30N2O 303.2431; found 303.2427.
1
to by clean by H NMR and taken unto the next step without
further purification. A round bottom flask, equipped with a
stirbar was charged with the crude product and aqueous 0.01%
HCl (10 mL). H2NOH•HCl (69 mg, 1.0 mmol) was added and the
Acknowledgements
The authors thank the NIH-NIGMS (GM098314) for financial
support of this work.
º
reaction mixture was heated to 60 C in an oil bath and stirred
until the starting material had been consumed as judged by ESI+
MS analysis (ca. 60 min). The reaction was cooled to rt and
aqueous 1M HCl (20 mL) was added. The solution was then
Supplementary Material
Copies of 1H and 13C NMR spectra for all new compounds.
9.
a) Spaltenstein, A.; Almond, M. R.; Bock, W. J.; Cleary, D. G.;
Furfine, E. S.; Hazen, R. J.; Kazmierski, W. M.; Salituro, F. G.; Tung,
R. D.; Wright, L. L. Bioorg. Med. Chem .Lett. 2000, 10, 1159. b) De
Lucca, G. V.; Liang, J.; De Lucca, I. J. Med. Chem. 1999, 42, 135.
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17
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