Aza- and carbo-[3+3] annulations of exo-cyclic vinylogous amides and urethanes. Synthesis of tetrahydroindolizidines and an unexpected formation of hexahydroquinolines

Article abstract of DOI:10.1016/j.tet.2007.09.089

[3+3] Annulations of exo-cyclic vinylogous amides and urethanes with vinyl iminium salts are described here. We observed an intriguing dichotomy in their reaction pathways. For pyrrolidine- and azepane-based vinylogous amides or urethanes, aza-[3+3] annul

Full text of DOI:10.1016/j.tet.2007.09.089

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 883e893
www.elsevier.com/locate/tet
Aza- and carbo-[3þ3] annulations of exo-cyclic vinylogous amides
and urethanes. Synthesis of tetrahydroindolizidines and an
unexpected formation of hexahydroquinolines
Sunil K. Ghosh, Grant S. Buchanan, Quincy A. Long, Yonggang Wei, Ziyad F. Al-Rashid,
*
Heather M. Sklenicka, Richard P. Hsung
Division of Pharmaceutical Sciences and Department of Chemistry, University of Wisconsin, 777 Highland Avenue, Rennebohm Hall, Madison, WI 53705, USA
Received 22 June 2007; accepted 26 September 2007
Available online 24 October 2007
Abstract
[3þ3] Annulations of exo-cyclic vinylogous amides and urethanes with vinyl iminium salts are described here. We observed an intriguing
dichotomy in their reaction pathways. For pyrrolidine- and azepane-based vinylogous amides or urethanes, aza-[3þ3] annulation would
dominate to give tetrahydroindolizidines, whereas, unexpectedly, for piperidine-based vinylogous amides or urethanes, carbo-[3þ3] annulation
was the pathway, leading to hexahydroquinolines. The origin for such a contrast is likely associated with a switch in the initial reaction pathway
between C-1,2-addition and C-1,4-addition.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Aza-[3þ3] annulation; Carbo-[3þ3] annulation; Vinylogous amides; Quinolines; Tetrahydroindolizidines
O
O
X
1. Introduction
C-terminus
chirality
Knoevenagel
Condensation
AcO
NR2
H
X
X
+
HN
P
Aza-[3þ3] annulation or formal cycloaddition reaction has
emerged as a formidable strategy in the synthesis of alka-
loids.1e5 Specifically, our intermolecular aza-[3þ3] annulation5
involves a Knoevenagel-type condensation of vinyl iminium
ions 1 with vinylogous amides or urethanes 2 followed by
a 6p-electron electrocyclic ring-closure of 1-azatrienes 36,7 en
route to 1,2-dihydropyridines 4 (Scheme 1). This annulation
process provides a unique opportunity to develop approaches
toward a stereoselective ring-closure of 1-azatrienes, which
had represented a real challenge in such pericyclic processes.6,8
Efforts in developing such a torquoselective9 reaction have
been largely overlooked. An elegant exception would be
Tanaka and Katsumura’s electrocyclic ring-closure using chi-
ral amines.10 In our own work, we employed either chiral
iminium ions 1 with a preexisting stereogenic center in the
X =O, NCH3 or CH2
n = 0 or 1
P: = protecting gp
n
n
X
R*
N
R*
P
3: 1-azatrienes
1
2
torquoselective
pericyclic ring-closure
aza-[3 + 3]
O
O
annulation
O
O
R
N
R
N
H
X
+
X
Aux*
Aux*
6
5: 1-azatrienes
n
n
R*
N
X
R*
N
X
Aux* = chiral auxiliary: Stereoselective
6π -electron electrocyclic ring-closure
with selectivity up to 96 : 4
H
H
P
P
selectivity up to 92 : 8
4a 4b
Scheme 1. An aza-[3þ3] annulation.
b-substituent,11 or 1-azatrienes 5 containing a chiral N-auxil-
iary12,13 (see the box in Scheme 1) en route to 1,2-dihydropyr-
idines 4 or 1-azadecalins 6.
* Corresponding author.
E-mail address: rphsung@pharmacy.wisc.edu (R.P. Hsung).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.09.089

884
S.K. Ghosh et al. / Tetrahedron 64 (2008) 883e893
O
O
O
X
NR2
chiral amine salts
an intramolecular
aza-[3 + 3]
cat asy aza-[3 + 3]
up to 62% ee
H
H
R
S
H
N
N
[reference 15]
N
R1
R1
R1
n
n
(R)-8
(S)-8
7
n
Prevalent Structural Motifs in Nitrogen Alkaloids
N
N
N
N
N
9:
a
b
c
d
e
Scheme 2. An intramolecular aza-[3þ3] annulation.
Although by a very different mechanism,13 we have exerted
(Fig. 1).19 On the other hand, intermolecular annulations of
exo-cyclic vinylogous amides 12 (or vinylogous urethanes
13) with vinyl iminium ion 14 did not give any desired quino-
lizidine nucleus 15, thereby thwarting our efforts in the syn-
thesis of members of the quinolizidine and indolizidine
families of alkaloids.20 Instead, we identified another product,
and we report here our findings in the synthesis of tetra-
hydroindolizidines accompanied with an unexpected forma-
tion of hexahydroquinolines via a carbo-[3þ3] annulation.
much efforts in the last few years in developing both a dia-
stereoselective14 and an amine salt-catalyzed asymmetric15
intramolecular aza-[3þ3] annulation reaction employing
vinylogous amides tethered with a,b-unsaturated iminium
salts 7 (Scheme 2). This annulation provides a powerful syn-
thetic strategy to construct nitrogen heterocycles 8 that can
lead to a range of prevalent structural motifs among alkaloids.
We have already successfully applied this strategy toward
total syntheses of several alkaloids such as (þ)-gephyro-
toxin,14 (ꢀ)-tangutorine,16 (þ)/(ꢁ)-deplancheine,17 and
(ꢁ)-cylindricine C,18 and most recently, five members of the
azaphenalene alkaloid family (see Fig. 1).19
Despite our understanding of this annulation reaction, we
encountered a rather intriguing and unexpected outcome dur-
ing our efforts in achieving total syntheses of azaphenalene al-
kaloids. As shown in Scheme 3, we found that intramolecular
aza-[3þ3] annulations of exo-cyclic vinylogous amides such
as 10 would proceed effectively (Scheme 3) to give the key
aza-tricycle 11 that would subsequently serve as a common
intermediate en route to the five azaphenalene alkaloids
O
O X NR2
R1
R1
intramol
N
aza-[3 + 3]
N
NH
azaphenalenes
10
11
exo-cyclic vinylogous
amides or urethanes
quinolizidine
nucleus
O
O
O
intermolecular
X NR2
H
aza-[3 + 3]
W
Me
OEt
or
+
W = Me or OEt
R1
N
NH
NH
R1
12
13
14
15: Not Found
Scheme 3. An aza-[3þ3] pathway to azaphenalenes and quinolizidines.
H
H
H
H
H
H
N
N
N
H
N
H
H
N
2. Results and discussions
OH
( )-tangutorine
(+)/(-)-deplancheine
HO
2.1. An unexpected formation of hexahydroquinolines
(+)-gephyrotoxin
azaphenalenes
Preparations of exo-cyclic vinylogous amides 12 and 13 are
shown in Scheme 4. The synthesis commenced with either 1,3-
H
H
H
HO
H
O
H
H
N
pentanedione 16a or ethyl acetoacetate 16b and followed
21
N
H
Carrie’s protocol that features Weiler’s dianion22 addition
N
H
´
O
C6H13
( )-precoccinelline
( )-coccinelline
to 1-bromo-2-chloro-propane, azide substitution, and an intra-
molecular aza-Wittig of azides 18a or 18b. The Z-geometry in
12 and 13 was confirmed via NOE experiments.21
Unsuspectingly, with exo-cyclic vinylogous amides 12 and
13 in hand, we attempted their aza-[3þ3] annulation reactions
using vinyl iminium salts 20aec generated from their corre-
sponding enals 19aec under standard conditions5,11e15
(Scheme 5). To our surprise, no desired aza-[3þ3] annulation
(-)-cylindricine C
O
N
H
N
N
H
H
H
H
H
H
H
H
( )-convergine
myrrhine
( )-hippodamine
Figure 1. Alkaloids synthesized via intramolecular aza-[3þ3].

S.K. Ghosh et al. / Tetrahedron 64 (2008) 883e893
885
°
one being de-conjugated, and an ensuing C-1,2-addition to
the iminium salt in a Mannich manner would give E. A
sequence of elimination of the secondary amine in E and
tautomerization would then afford the observed
hexahydroquinolines.
1.1 equiv NaH at 0 C, THF, 1 h
O
O
O
O
and then 1.05 equiv n-BuLi, 10 min
R
R
Cl
and then 1.0 equiv Br
Cl
16a: R = Me
16b: R = OEt
17a: R = Me
17b: R = OEt
°
°
- 50 C to - 30 C, 18 h
NaN3, NaI
DMSO
O
O
50 °C, 18 h
nOe
nOe
1.0 equiv PPh3
Et2O, rt, 15 h
X
X
R1
R2N
R1
R2N
R1
Me
OEt
NH
C-1,4-add or R2N
Michael add
O
O
Z
Z
or
NH
W
W
R
N3
W
W = Me or OEt
18a: R = Me: 41% overall
18b: R =OEt: 36% overall
N
O
N
O
N
O
H
H
12: 66%
13: 89%
H
X
A
B
C
Scheme 4. Syntheses of exo-cyclic vinylogous amide and urethane.
carbo-[3 + 3]
deconjugative
tautomerization
R1
products 15 were formed, and instead, we isolated hexahydro-
quinolines 21aec and 22b,c in good yields.
R2N
R1
X
R2N
R1
elimination and
tautomerization
C-1,2
W
W
W
We also employed chiral enal 23 in an attempt to detect
possible diastereoselectivity. However, while the reaction of
chiral enal 23 with 12 led to the isomeric hexahydroquinolines
24 and 25 in good yield, the selectivity was found to be low,
and consequently, the relative stereochemistry was not as-
signed. It is also noteworthy that using more polar solvents
such as DMF or EtOH, we still obtained hexahydroquinoline
22 in good yields.
Mannich
N
O
N
O
H
N
O
H
F
X
H
E
D
Scheme 6. A proposed pathway for the hexahydroquinoline formation.
What we have encountered here for the very first time in
our own work with aza-[3þ3] annulations is the competing
carbo-[3þ3] annulation pathway.23,24 This finding invokes
some unique historical perspectives as shown in Figure 2.
Prelog25 in 1949 found that instead of the expected Robinson
annulation pathway, a carbo-[3þ3] cyclization had occurred to
give the bicyclo[5.3.1]undecenone. In 1950, and more relevant
to the current study, Stork26 reported the addition of the Stork
enamine to acrolein, leading to bicyclo[3.3.1]octanone via
a carbo-[3þ3] cyclization. These reactions all share a similar
pathway: 1,4-addition followed by 1,2-addition.
2.2. A carbo-[3þ3] annulation pathway
A plausible mechanism for the formation of these unex-
pected hexahydroquinolines is initiated through a C-1,4-addi-
tion of the vinylogous amide in a Michael fashion to the
iminium salt to give intermediate B (Scheme 6). Tautomeriza-
tion of B could lead to intermediates C and D with the latter
1.4 equiv
O
1.4 equiv
AcO
O
AcO
COW
NR2
N
H
H
W
H
EtOAc/toluene [2 : 3]
Na2SO4, 95-100
3-4 h
N
R1
NH
C
R1
R1
°
20a: R1 = Me
20b: R1 = n-Pr
20c: R1 = Ph
19a: R1 = Me
19b: R1 = n-Pr
19c: R1 = Ph
12 or 13
15: W= Me or OEt
From 12:
From 13:
n-Pr
Me
n-Pr
Ph
Ph
OEt
OEt
N
O
N
O
N
O
N
O
N
O
H
H
H
H
H
21a: 50%
21b: 64%
21c: 90%
22b: 84%
DMF: 76%
EtOH: 75%
22c: 81%
1.4 equiv
AcO
O
N
H
H
H
O
O
H
N
H
N
H
O
O
reacting with 12
EtOAc/toluene [2 : 3]
Na2SO4, 95-100 °C
3-4 h
H
Me
O
O
O
O
Me
24
25
23
84%; ratio: 1.8 : 1
Scheme 5. Unexpected formation of hexahydroquinolines.

886
S.K. Ghosh et al. / Tetrahedron 64 (2008) 883e893
carbo-[3 + 3]
aza-[3 + 3]
O
R1
X
R2N
versus
R1
R1
X NR2
COW
W
W
W
N
N
O
NH
R1
H
N
O
W = Me or OEt
H
carbo-[3 + 3]
O
O
Prelog
1949
N
O
Stork, 1956
N
Me
O
O
X
Me3N
O
OR
Figure 2. Aza-[3þ3] versus carbo-[3þ3] annluation.
tetrahydroindole synthesis
AcO NR2
Despite the fact that this can be a very useful reaction for
R1
O
O
constructing highly substituted cyclohexane derivatives to
compliment the DielseAlder strategy, much of the earlier
work focused on the synthesis of bridged bicyclic systems
with an interest in accessing anti-Bredt’s olefins.23,27 While
there has been a surging interest (especially in the synthesis
of garsubellin A) given the array of elegant accounts that ap-
peared recently,28 most efforts are still exerted on the synthesis
of bridged bicyclic systems.
carbo-[3 + 3]
W
OMe
Me
or
+
H
N
O
NH
NH
H
R1
W = OMe or Me
Not Found
30
31
20
Figure 3. A possible synthesis of tetrahydroindoles.
However, as shown in Table 1, reactions of 30 and 31 with
achiral enals 19aec (entries 1e4), or chiral enals 23 and 33e
35 (entries 5e9), led to the respective aza-[3þ3] annulation
products: tetrahydroindolizidines 36e40. Even when we
employed azepane-based exo-cyclic vinylogous urethane
32,21,31 we obtained the aza-annulation products 41 and 42
in good yields (entries 10 and 11).
2.3. Syntheses of quinolines
One immediate application of this carbo-[3þ3] annulation
is in the synthesis of quinolines, which would also be in accord
with the theme of this Symposium-in-Print. As shown in
Scheme 7, treatment of hexahydroquinolines 21b and 22b
with 3.0 equiv of DDQ at rt led to quinoline 26 and 27 in
50% and 83% yields, respectively. With less DDQ used, we
were able to isolate the respective tetrahydroquinolines 28
and 29, although there was no apparent selectivity over the
extent of aromatization.
2.5. C-1,2 versus C-1,4-addition
These two contrasting reaction pathways intrigued us. Al-
though we do not have any definitive understanding at this
point, one possible cause for is that they mechanistically differ
in the very initial step. As shown in Scheme 8, for the pyrro-
lidine-based exo-cyclic vinylogous amide (left), there appears
to be a preference for C-1,2-addition, whereas for piperidine-
based exo-cyclic vinylogous amide (right), the preference is
C-1,4-addition.
Specifically, for the pyrrolidine-based vinylogous amide
G-1, it may react through conformer G-2 because the internal
hydrogen-bonding in G-1 is not as perfectly aligned or tight as
in piperidine-based exo-cyclic vinylogous amide J-1. Thus,
the conformational equilibrium does not shift away from
G-2 or at least not completely, thereby freeing the carbonyl
group to participate in hydrogen-bonding with protons of the
vinyl iminium salt (in green). This external hydrogen-bonding
n-Pr
R
n-Pr
R
3.0 equiv DDQ, CH2Cl2, rt, 1 h
N
O
N
O
H
21b: R = Me
22b: R = OEt
26: R = Me [50%]
27: R = OEt [83%]
n-Pr
n-Pr
n-Pr
1.0 equiv DDQ
CH2Cl2, rt, 1 h
R
R
R
+
N
O
N
O
N
O
H
H
21b: R = Me
22b: R = OEt
26: [20%]
27: [22%]
28: R = Me [20%]
29: R = OEt [37%]
Scheme 7. DDQ aromatization in the quinoline synthesis.
interaction can in fact provide
w14.7 Kcal molꢁ1 3
a
stabilization of
.
2.4. A contrasting reaction pathway
With this hydrogen-bonding network in place, C-1,2-addi-
tion (red arrow) would be better aligned stereoelectronically
than C-1,4-addition (dotted blue arrow), thereby leading to
1-azatriene H after b-elimination and subsequently completing
the aza-annulation pathway via a pericyclic ring-closure. It is
noteworthy that the theoretical observation of this external hy-
drogen-bonding network likely provides a major rationale for
When we directed our attention to pyrrolidine-based exo-
cyclic vinylogous urethane 3021,29 and vinylogous amide
31,21,30 we were fully intending on preparing a series of tetra-
hydroindoles via the same carbo-[3þ3] annulation (Fig. 3).
We were not prepared for additional surprises.

S.K. Ghosh et al. / Tetrahedron 64 (2008) 883e893
887
Table 1
Aza-[3þ3] annulations of exo-cyclic vinylogous amides
Ratiob
a
Entry
Amides
Aldehydes
Aza-[3+3] products
Yield (
)
ROC
O
O
R
H
N
R1
R1
NH
36a: R = OMe; R 1 = Me
36b: R = OMe; R 1 = n-Pr
36c: R = OMe; R 1 = Ph
36d: R = Me; R 1 = n-Pr
1
2
3
4
30c
30
30
31d
19a: R1 = Me
19b: R1 = n-Pr
19c: R1 = Ph
19b: R1 = n-Pr
O
51
70
75
73
—
—
—
—
O
MeO2C
H
OMe
O
N
O
O
H
NH
37
5
6
30
30
23
56
50
1.5:1
1.3:1
O
O
MeO2C
OAc
H
OAc
N
H
38
33
OAc OAc
OAc OAc
ROC
O
N
H
H
39a: R = OMe
39b: R = Me
MeO2C
7
8
30
31
34
34
10
7
≥20:1
≥20:1
O
H
N
H
9
30
35
33
53
2.2:1e
—
40
41
EtO2C
EtO2C
N
Ph
10
32f
19c
O
OEt
NH
O
O
N
H
42
11
32
23
62
1.2 : 1
a
Isolated yields.
b
c
d
e
Ratio determined using 1H NMR, and unless noted otherwise, the relative stereochemistry was not assigned.
See Refs. 21 and 29 for the preparation of 30.
See Refs. 21 and 30 for the preparation of 31.
The ratio was found in crude 1H NMR but the minor isomer appeared to isomerize to the major isomer during purification. The major isomer shown here was
assigned using NOE experiment and the final ratio was 13.8:1.
f
See Refs. 21 and 31 for the preparation of 32.
the high level of regioselectivity found in most of our annula-
tion work5a,32 involving vinyl iminium salts, especially when
comparing with protocols in which vinyl iminium salts are
generated in situ or not employed.33,34
On the other hand, for piperidine-based exo-cyclic vinylo-
gous amide, conformer J-1 dominates due to the strong internal
hydrogen-bonding (in green), which precludes the carbonyl
group in J-1 from participating in the related external hydro-
gen-bonding network. With both options of C-1,2- and C-1,4-
additions being available, C-1,4-addition (solid blue arrow)
could take precedent based on the ‘hard-and-soft’ concept.
This would allow the piperidine-based exo-cyclic vinylogous
amide (or urethane) to follow the carbo-annulation pathway.
In addition, although all of these mechanistic steps are re-
versible, our calculations using B3LYP/6-31G* [SpartanÔ]
suggest (Fig. 4) that the observed dichotomy of these two
reaction pathways cannot be attributed as a result of thermo-
dynamic equilibration. For all three cases, pyrrolidine-, piper-
idine-, and azepane-based vinylogous amides or urethanes, the
respective carbo-annulation products are thermodynamically
more favored than their corresponding aza-annulation prod-
ucts, although in a relatively lesser extent for both the

888
S.K. Ghosh et al. / Tetrahedron 64 (2008) 883e893
R1
internal H-bond
X
N
R1
O
X
N
H
NH
H
N
N
H
O
N
O
O
H
H
G-1
G-2: external H-bond
J-1: tight internal H-bond
C-1,4-add or Michael
J-2
C-1,2-add or Mannich
R1
N
R1
N
H
N
H
H
N
O
H
X
O
H
X
K
-elimination
tautoemrization
pip-H
aza-[3 + 3]
C-[3 + 3]
R1
X
O
N
R1
O
pericyclic
C-1,2 add
ring-closure
N
R1
I: 1-azatriene
N
L
O
H
N
O
N
R1
H
Scheme 8. C-1,2 addition versus C-1,4-addition.
O
4. Experimental section
O
4.1. General
versus
versus
N
N
N
O
NH
O
H
Mc: carbo-[3 + 3]
Ma: aza-[3 + 3] Nc: carbo-[3 + 3]
Na: aza-[3 + 3]
All reactions were performed in flame-dried glassware un-
der a nitrogen atmosphere. Solvents were distilled prior to use.
Reagents were used as purchased (Aldrich, Acros), except
where noted. Chromatographic separations were performed
ΔE = 2.54 Kcal mol-1 in favor of Mc
ΔE = 12.0 Kcal mol-1 in favor of Nc
O
EtO
OEt
using Bodman 60 A SiO2. 1H and 13C NMR spectra were
˚
versus
N
NH
O
obtained on Varian VI-300, VI-400, and VI-500 spectrometers
using CDCl3 (except where noted) with TMS or residual
CHCl3 in the solvent as standard. Melting points were deter-
mined using a Laboratory Devices MEL-TEMP and are un-
corrected/calibrated. Infrared spectra were obtained using
NaCl plates on a Bruker Equinox 55/S FTIR Spectrophoto-
meter, and relative intensities are expressed qualitatively as
s (strong), m (medium), and w (weak). TLC analysis was per-
Oc: carbo-[3 + 3]
Oa: aza-[3 + 3]
-1
ΔE = 1.38 Kcal mol in favor of Oc
Figure 4. Energetic differences in the annulation products.
pyrrolidine-based vinylogous amide and azepane-based vinyl-
ogous urethane.
˚
formed using Aldrich 254 nm polyester-backed plates (60 A,
250 mm) and visualized using UV and a suitable chemical
stain.
3. Conclusion
Low-resolution mass spectra were obtained using an Agi-
lent-1100-HPLC/MSD and can be either APCI or ESI, or an
IonSpec HiRes-MALDI FT-Mass Spectrometer. High-resolu-
tion mass spectral analyses were performed at University of
Wisconsin Mass Spectrometry Laboratories. All spectral data
obtained for new compounds are reported.
We have described here [3þ3] annulations of exo-cyclic vi-
nylogous amides and urethanes with vinyl iminium salts and
observed an intriguing dichotomy in their reaction pathways.
For pyrrolidine- and azepane-based vinylogous amide or ure-
thanes, aza-[3þ3] annulation dominates to give tetrahydroin-
dolizidines, whereas the piperidine-based vinylogous amide
or urethane underwent an unexpected carbo-[3þ3] annulation
to afford hexahydroquinolines. The origin for such a contrast
is not clear at this moment, although we suspect it is asso-
ciated with an initial preference for either C-1,2-addition or
C-1,4-addition. This work provides a useful approach toward
either total syntheses of the indolizidine family of natural
products or functionalized quinolines.
4.2. General procedure for all annulations
To a solution of an enal (1.40 mmol, 1.40 equiv) in EtOAc/
toluene (3.5 to 5 mL with a ratio of 2:3) in a sealed tube were
added Na2SO4 (400.0 mg), piperidinium acetate (1.40 mmol,
1.40 equiv), and the respective vinylogous amide
(1.00 mmol) sequentially. After stirring at rt for 1 min, the

S.K. Ghosh et al. / Tetrahedron 64 (2008) 883e893
889
mixture was heated at 95e100 ꢂC for 3e4 h. The reaction
130.5, 152.6, 170.9; IR (neat) cmꢁ1 2956brm, 2864brm,
1630s, 1578s, 1243s; mass spectrum (APCI): m/e (% relative
intensity) 250 (100) (MþH)þ; m/e (ESI) calcd for
C15H24NO2 250.1807, found 250.1807.
1
progress was monitored using TLC analysis and/or crude H
NMR. When the starting material completely disappeared,
the reaction mixture was cooled and the excess amine salt
was filtered off through a small cotton plug (or CeliteÔ),
and the excess solvent was evaporated under reduced pressure.
The crude residue was purified by flash silica gel column chro-
matography (gradient eluent: EtOAc in hexanes) to provide
the corresponding annulation product.
4.2.5. Carbo-[3þ3] annulation product 22c
Rf¼0.28 (10% EtOAc/hexanes); 1H NMR (400 MHz,
CDCl3) d 1.12 (t, 3H, J¼7.0 Hz), 1.77e1.93 (m, 2H), 2.39e
2.45 (m, 3H), 2.76e2.83 (m, 1H), 3.40e3.44 (m, 2H),
3.95e4.12 (m, 3H), 5.77 (d, 1H, J¼5.6 Hz), 7.14e7.24 (m,
5H), 9.42 (s, 1H); 13C NMR (100 MHz, CDCl3) d 14.8,
23.3, 29.0, 32.4, 36.2, 41.9, 58.8, 88.1, 125.9, 127.6, 128.0,
129.8, 130.0, 146.9, 153.8, 170.9; IR (neat) cmꢁ1 2945brm,
2860brm, 1630s, 1584s, 1273s; mass spectrum (APCI): m/e
(% relative intensity) 284 (100) (MþH)þ; m/e (ESI) calcd
for C18H22NO2 284.1654, found 284.1642.
4.2.1. Carbo-[3þ3] annulation product 21a
Rf¼0.10 (30% EtOAc/hexane); 1H NMR (400 MHz,
CDCl3) d 0.96 (d, 3H, J¼6.8 Hz), 1.66e1.75 (m, 1H), 1.84
(ddd, 1H, J¼4.3, 8.8, 21.8 Hz), 1.94 (s, 1H), 2.05 (dd, 1H,
J¼6.5, 17.4 Hz), 2.10 (s, 3H), 2.29e2.48 (m, 2H), 2.72 (p,
1H, J¼7.0 Hz), 3.32 (ddd, 2H, J¼2.7, 3.8, 6.8 Hz), 5.87 (d,
1H, J¼6.5 Hz), 11.86 (s, 1H); 13C NMR (100 MHz, CDCl3)
d 20.6, 22.7, 26.6, 27.7, 28.5, 31.9, 41.5, 102.7, 128.5,
131.9, 154.0, 193.6; IR (neat) cmꢁ1 2951brm, 2860brm,
1569s, 1550s, 1480m, 1450m, 1364m, 1348m, 1252s; mass
spectrum (APCI): m/e (% relative intensity) 192 (100)
(MþH)þ, 150 (5), 140 (10); m/e (ESI) calcd for C12H17NO
191.1310, found 191.1309.
4.2.6. Chiral carbo-[3þ3] annulation products 24 and 25
(characterized as an inseparable mixture)
Rf¼0.16 (50% EtOAc/hexane); 1H NMR (500 MHz,
CDCl3) d major diastereomer: 1.30 (s, 3H), 1.39 (s, 3H),
1.69e1.90 (m, 2H), 2.13e2.18 (m, 1H), 2.23 (s, 3H), 2.33e
2.45 (m, 3H), 2.86 (t, 1H, J¼7.5 Hz), 3.30e3.37 (m, 2H),
3.59 (t, 1H, J¼7.5 Hz), 3.91e3.97 (m, 1H), 4.06e4.11 (m,
1H), 5.91 (d, 1H, J¼6.0 Hz), 12.1 (s, 1H, NH); minor diaste-
reomer ( partial listing due to unresolved overlapping reso-
nances): 1.31 (s, 3H), 1.69e1.90 (m, 3H), 2.20 (s, 3H),
2.33e2.45 (m, 3H), 2.53e2.58 (m, 1H), 2.77 (t, 1H, J¼
7.5 Hz), 3.30e3.37 (m, 2H), 3.65 (dd, 1H, J¼5.5, 8.5 Hz),
3.82 (dd, 1H, J¼5.5, 8.5 Hz), 3.95e3.97 (m, 1H), 5.97 (d,
1H, J¼5.5 Hz); IR (film): cmꢁ1 2934brw, 1662w, 1609m,
1571s, 1554s; mass spectrum (APCI): m/e (% relative inten-
sity) 278 (100) (MþH)þ, 236 (10), 140 (20), 101 (10); m/e
(ESI) calcd for C16H24NO3 278.1756, found 278.1762.
4.2.2. Carbo-[3þ3] annulation product 21b
Rf¼0.26 (30% EtOAc/hexanes); 1H NMR (500 MHz,
CDCl3) d 0.89 (t, 3H, J¼7.2 Hz), 1.13e1.20 (m, 2H), 1.28e
1.32 (m, 1H), 1.38e1.45 (m, 1H), 1.67e1.74 (m, 1H),
1.80e1.85 (m, 1H), 2.09 (s, 3H), 2.19e2.41 (m, 4H), 2.50e
2.54 (m, 1H), 3.32 (dd, 2H, J¼4.0, 7.0 Hz), 5.85 (d, 1H,
J¼6.0 Hz), 11.90 (s, 1H); 13C NMR (125 MHz, CDCl3)
d 14.4, 21.0, 22.8, 26.7, 28.4, 28.6, 32.7, 36.6, 41.6, 102.7,
129.0, 132.2, 154.4, 193.6; IR (neat) cmꢁ1 2955brm,
2869brm, 1569s, 1543s, 1257s; mass spectrum (APCI): m/e
(% relative intensity) 220 (100) (MþH)þ; m/e (ESI) calcd
for C14H22NO 220.1701, found 220.1703.
4.3. General procedure for the DDQ aromatization
4.2.3. Carbo-[3þ3] annulation product 21c
Rf¼0.36 (50% EtOAc/hexanes); 1H NMR (500 MHz,
CDCl3) d 1.82e1.84 (m, 1H), 1.88e1.98 (m, 1H), 1.97 (s,
3H), 2.41e2.53 (m, 3H), 2.84e2.91 (m, 1H), 3.48e3.50 (m,
2H), 3.99 (d, 1H, J¼8.0 Hz), 5.80 (d, 1H, J¼5.5 Hz), 7.19e
7.31 (m, 5H), 12.06 (s, 1H); 13C NMR (125 MHz, CDCl3)
d 22.9, 27.2, 28.5, 33.4, 38.5, 41.8, 99.1, 126.3, 127.8,
128.3, 128.4, 129.8, 131.1, 145.7, 155.4; IR (neat) cmꢁ1
2940brm, 2859brm, 1670s, 1577s, 1552, 1273s; mass spec-
trum (APCI): m/e (% relative intensity) 254 (100) (MþH)þ;
m/e (ESI) calcd for C17H20NO 254.1545, found 254.1534.
To a solution of 21b (30.0 mg, 0.136 mmol) in CH2Cl2
(3 mL) was added DDQ (93.0 mg, 0.40 mmol, 3.00 equiv).
The reaction mixture was stirred at rt for 1 h and the reaction
progress was monitored using TLC analysis. When the starting
material completely disappeared, the reaction mixture was
concentrated under reduced pressure. The crude residue was
purified by flash silica gel column chromatography (gradient
eluent: 0e25% EtOAc in hexanes) to provide the desired quino-
line 26 (14.5 mg, 50%).
4.3.1. Quinoline 26
4.2.4. Carbo-[3þ3] annulation product 22b
Rf¼0.39 (20% EtOAc/hexanes); 1H NMR (500 MHz,
CDCl3) d 0.98 (t, 3H, J¼7.5 Hz), 1.69e1.74 (m, 2H), 2.68e
2.71 (m, 2H), 2.72 (s, 3H), 7.37 (dd, 1H, J¼4.5, 8.5 Hz),
7.41 (d, 1H, J¼8.5 Hz), 7.75 (d, 1H, J¼8.5 Hz), 8.11 (dd,
1H, J¼2.0, 8.5 Hz), 8.86 (dd, 1H, J¼1.5, 4.0 Hz); 13C NMR
(100 MHz, CDCl3) d 14.4, 25.0, 33.9, 35.7, 121.0, 126.5,
128.2, 128.8, 135.8, 139.5, 140.3, 145.8, 150.4, 207.8; IR
(neat) cmꢁ1 2961m, 2871m, 1705s, 1572m; mass spectrum
Rf¼0.29 (10% EtOAc/hexanes); 1H NMR (500 MHz,
CDCl3) d 0.87 (t, 3H, J¼7.0 Hz), 1.16e1.35 (m, 7H), 1.68e
1.76 (m, 1H), 1.81e1.87 (m, 1H), 2.16 (dd, 1H, J¼6.0,
16.5 Hz), 2.29e2.42 (m, 3H), 2.72 (q, 1H, J¼5.0 Hz), 3.29e
3.34 (m, 2H), 4.06e4.15 (m, 2H), 5.81 (d, 1H, J¼6.0 Hz),
9.17 (s, 1H); 13C NMR (125 MHz, CDCl3) d 14.4, 14.8,
20.7, 23.3, 28.3, 29.0, 29.9, 36.3, 41.8, 58.6, 90.7, 128.9,

890
S.K. Ghosh et al. / Tetrahedron 64 (2008) 883e893
(APCI): m/e (% relative intensity) 214 (100) (MþH)þ; m/e
1.94 (m, 2H), 2.87 (ddd, 1H, J¼9.2, 18.0, 36.0 Hz), 3.25
(ddd, 1H, J¼4.4, 8.8, 18.0 Hz), 3.25 (q, 1H, J¼7.2 Hz),
3.30e3.34 (m, 1H), 3.49 (ddd, 1H, J¼4.0, 8.4, 12.0 Hz),
3.61 (s, 3H), 4.87 (dd, 1H, J¼5.6, 7.6 Hz), 5.95 (d, 1H, J¼
7.6 Hz); 13C NMR (125 MHz, CDCl3) d 14.5, 18.1, 22.0,
32.0, 33.2, 41.2, 50.5, 51.2, 94.2, 108.9, 126.0, 155.6, 169.4;
IR (neat) cmꢁ1 2951brm, 2869brm, 1673s, 1578s, 1194s;
mass spectrum (APCI): m/e (% relative intensity) 222 (100)
(MþH)þ; m/e (ESI) calcd for C13H20NO2 222.1494, found
222.1504.
(ESI) calcd for C14H15NONa 236.1051, found 236.1053.
4.3.2. Quinoline 27
Rf¼0.11 (10% EtOAc/hexane); 1H NMR (400 MHz,
CDCl3) d 1.01 (t, 3H, J¼7.2 Hz), 1.46 (t, 3H, J¼7.2 Hz),
1.72e1.81 (m, 2H), 2.78 (dt, 2H, J¼6.0, 7.6 Hz), 4.59 (q,
2H, J¼7.2 Hz), 7.38 (dd, 1H, J¼4.0, 8.0 Hz), 7.40 (d, 1H, J¼
8.8 Hz), 7.79 (d, 1H, J¼8.4 Hz), 8.11 (dd, 1H, J¼2.0, 8.4 Hz),
8.93 (dd, 1H, J¼2.0, 4.0 Hz); 13C NMR (100 MHz, CDCl3)
d 14.3, 14.6, 24.6, 36.3, 61.6, 121.1, 126.5, 128.3, 128.7,
133.1, 135.8, 140.9, 145.7, 151.1, 169.7; IR (film) cmꢁ1
:
4.4.3. Aza-[3þ3] annulation product 36c
2962brw, 2872w, 1725s, 1613w, 1569w, 1499w, 1459brw,
1370w, 1265s; mass spectrum (APCI): m/e (% relative inten-
sity) 244 (100) (MþH)þ, 198 (20), 101 (5); m/e (ESI) calcd
for C15H18NO2 244.1338, found 244.1349.
Rf¼0.35 (20% EtOAc/hexanes); 1H NMR (500 MHz,
CDCl3) d 2.02e2.11 (m, 2H), 3.10 (dt, 1H, J¼9.0, 18.0 Hz),
3.28 (ddd, 1H, J¼5.0, 9.0, 18 Hz), 3.45 (q, 1H, J¼8.0 Hz),
3.62 (s, 3H), 3.65 (ddd, 1H, J¼4.5, 9.0, 9.0 Hz), 4.64 (d,
1H, J¼5.5 Hz), 5.08 (dd, 1H, J¼5.0, 7.5 Hz), 6.12 (d, 1H, J¼
5.5 Hz), 7.20e7.23 (m, 1H), 7.29e7.35 (m, 4H); 13C NMR
(125 MHz, CDCl3) d 21.9, 32.2, 40.2, 50.7, 51.4, 94.6,
109.6, 125.1, 126.3, 127.7, 128.5, 148.9, 154.9, 169.1; IR
(neat) cmꢁ1 2940brm, 2852brm, 1676s, 1595s, 1273s,
1106s; mass spectrum (APCI): m/e (% relative intensity) 256
(100) (MþH)þ, 178 (25); m/e (ESI) calcd for C16H17NO2Na
278.1157, found 278.1165.
4.3.3. Tetrahydroquinoline 28
Rf¼0.50 (20% EtOAc/hexanes); 1H NMR (400 MHz,
CDCl3) d 0.92 (t, 3H, J¼7.2 Hz), 1.55e1.61 (m, 2H), 1.84e
1.90 (m, 2H), 2.48 (s, 3H), 2.52e2.56 (m, 2H), 2.72 (t, 2H, J¼
5.6 Hz), 3.27 (t, 2H, J¼3.6 Hz), 5.30 (br s, 1H), 6.43 (d, 1H,
J¼7.6 Hz), 6.88 (d, 1H, J¼3.6 Hz); mass spectrum (APCI):
m/e (% relative intensity) 218 (100) (MþH)þ; m/e (ESI) calcd
for C14H20NO 218.1545, found 218.1554.
4.4.4. Aza-[3þ3] annulation product 36d
4.3.4. Tetrahydroquinoline 29
Rf¼0.33 (20% EtOAc/hexane); 1H NMR (400 MHz,
CDCl3) d 0.88 (t, 3H, J¼7.2 Hz), 1.19e1.41 (m, 4H), 1.92e
2.07 (m, 2H), 2.19 (s, 3H), 2.95 (dt, 1H, J¼8.8, 18.0 Hz),
3.19 (ddd, 1H, J¼4.0, 8.0, 18.0 Hz), 3.33 (dt, 1H, J¼8.0,
8.8 Hz), 3.37e3.42 (m, 1H), 3.59 (ddd, 1H, J¼4.0, 8.0,
9.6 Hz), 5.06 (dd, 1H, J¼6.0, 8.0 Hz), 6.03 (d, 1H, J¼
8.0 Hz); 13C NMR (100 MHz, CDCl3) d 14.4, 18.1, 21.9,
28.5, 32.9, 33.9, 41.7, 51.1, 105.4, 110.0, 125.9, 155.3,
196.6; IR (film) cmꢁ12953m, 2869m, 2360w, 1659m,
1613m, 1530s, 1395m; mass spectrum (APCI): m/e (% relative
intensity) 206 (100) (MþH)þ; m/e (EI) calcd for C13H20NO
206.1545, found 206.1549.
Rf¼0.29 (10% EtOAc/hexanes); 1H NMR (500 MHz,
CDCl3) d 0.94 (t, 3H, J¼7.5 Hz), 1.39 (t, 3H, J¼7.0 Hz),
1.55e1.61 (m, 2H), 1.88 (dt, 2H, J¼5.0, 6.5 Hz), 2.68 (m,
2H), 2.74 (t, 2H, J¼6.0 Hz), 3.35 (t, 2H, J¼6.0 Hz), 4.35 (q,
2H, J¼7.0 Hz), 6.38 (d, 1H, J¼7.5 Hz), 6.89 (d, 1H, J¼
7.5 Hz); IR (film) cmꢁ1 2957m, 2929m, 1725w, 1679m,
1599w, 1582w, 1507m; mass spectrum (APCI): m/e (% rela-
tive intensity) 248.2 (100) (MþH)þ, 202 (65), 101 (5); m/e
(ESI) calcd for C15H22NO2 248.1651, found 248.1658.
4.4. General procedure
See Section 4.2.
4.4.5. Aza-[3þ3] annulation product 37 (characterized as
a mixture)
4.4.1. Aza-[3þ3] annulation product 36a
Rf¼0.42 (50% EtOAc/hexane); 1H NMR (500 MHz,
CDCl3) d major diastereomer: 1.33 (s, 3H), 1.41 (s, 3H),
1.88e2.05 (m, 2H), 2.95 (dt, 1H, J¼9.0 Hz), 3.14 (ddd, 1H,
J¼3.5, 8.5, 18.0 Hz), 3.33e3.36 (m, 1H), 3.57 (dt, 1H, J¼
3.5, 8.5 Hz), 3.68 (s, 3H), 3.82 (dd, 1H, J¼6.5, 8.0 Hz),
3.86e3.90 (m, 2H), 4.18 (dt, 1H, J¼2.5, 4.5 Hz), 4.96 (dd,
1H, J¼2.0, 5.5 Hz), 6.19 (d, 1H, J¼8.0 Hz); minor diastereo-
mer ( partial listing due to unresolved overlapping reso-
nances): 1.40 (s, 3H), 1.88e2.05 (m, 2H), 2.91e2.98 (m,
1H), 3.15e3.23 (m, 1H), 3.31e3.38 (m, 1H), 3.60e3.65 (m,
2H), 3.95e4.00 (m, 2H), 4.12e4.14 (m, 1H), 5.01 (dd, 1H, J¼
6.0, 7.5 Hz), 6.14 (d, 1H, J¼7.0 Hz). 13C NMR (125 MHz,
CDCl3) d from a small sample of resolved major isomer:
21.8, 25.3, 26.4, 32.2, 36.6, 50.8, 51.2, 66.1, 78.8, 90.1,
94.9, 104.5, 108.8, 128.1, 157.1; IR (film) cmꢁ1 2984m,
2949w, 1671brs, 1578s, 1414s, 1370s, 1251s; mass spectrum
Rf¼0.27 (20% EtOAc/hexane); 1H NMR (400 MHz, CDCl3)
d 0.99 (d, 3H, J¼6.4 Hz), 1.88e2.00 (m, 2H), 2.92 (dt, 1H,
J¼9.1, 18.1 Hz), 3.10 (ddd, 1H, J¼4.5, 8.6, 18.1 Hz), 3.29 (q,
1H, J¼9.1 Hz), 3.36 (p, 1H, J¼6.4 Hz), 3.52 (ddd, 1H, J¼4.1,
8.0, 9.1 Hz), 3.65 (s, 3H), 4.88 (dd, 1H, J¼5.5, 7.6 Hz), 5.92
(d, 1H, J¼7.6 Hz); 13C NMR (100 MHz, CDCl3) d 21.8, 25.0,
28.5, 32.0, 50.5, 51.1, 95.4, 110.6, 125.2, 155.1, 169.2; IR
(neat) cmꢁ1 2947brm, 2862brm, 1672s, 1578s, 1256s, 1219s,
1094s; mass spectrum (APCI): m/e (% relative intensity) 194
(100) (MþH)þ, 162 (15); m/e (ESI) calcd for C11H16NO2
194.1181, found 194.1188.
4.4.2. Aza-[3þ3] annulation product 36b
Rf¼0.22 (10% EtOAc/hexanes); 1H NMR (400 MHz,
CDCl3) d 8.25 (t, 3H, J¼7.2 Hz), 1.17e1.32 (m, 4H), 1.83e

S.K. Ghosh et al. / Tetrahedron 64 (2008) 883e893
891
(APCI): m/e (% relative intensity) 280 (30) (MþH)þ, 248
(100), 222 (90), 178 (25); m/e (ESI) calcd for C15H21NO4Na
302.1368, found 302.1375.
4.4.9. Aza-[3þ3] annulation product 40
Rf¼0.30 (25% EtOAc/hexanes); [a]2D5 ꢁ95.2 (c 2.05,
1
CH2Cl2); H NMR (500 MHz, CDCl3) d major diastereomer:
0.87 (s, 3H), 1.10 (d, 1H, J¼9.5 Hz), 1.28 (s, 3H), 1.86 (m,
1H), 2.04 (ddd, 1H, J¼2.5, 6.0, 13.0 Hz), 2.08 (m, 1H), 2.14
(dddd, 1H, J¼2.0, 4.0, 6.0, 6.0 Hz), 2.36 (ddddd, 1H, J¼0.5,
2.5, 4.0, 9.5, 13.5 Hz), 2.63 (dd, 1H, J¼5.5, 5.5 Hz), 2.68
(ddddd, 1H, J¼0.5, 2.0, 6.5, 6.5, 10.0 Hz), 2.90 (ddd, 1H,
J¼9.5, 11.0, 18.5 Hz), 2.98 (ddd, 1H, J¼7.0, 9.5, 11.0 Hz),
3.27 (ddd, 1H, J¼2.0, 10.0, 18.5 Hz), 3.52 (ddd, 1H, J¼1.5,
8.5, 9.5 Hz), 3.68 (s, 3H), 4.18 (ddd, 1H, J¼2.0, 6.0,
9.0 Hz), 6.13 (d, 1H, J¼2.0 Hz); minor diastereomer: 2.26
(m, 1H), 2.53 (dd, 1H, J¼5.5, 5.5 Hz), 3.43 (ddd, 1H, J¼
2.0, 8.5, 10.0 Hz), 3.67 (s, 3H), 4.43 (ddd, 1H, J¼2.5, 8.5,
8.5 Hz), 6.02 (d, 1H, J¼2.5 Hz); 13C NMR (100 MHz,
CDCl3) d 21.0, 24.0, 27.2, 32.6, 33.2, 37.5, 39.8, 42.3, 50.6,
50.7, 50.8, 51.8, 95.5, 116.9, 129.6, 163.8, 167.4; IR (neat)
cmꢁ1 2979w, 2944w, 1732w, 1683s, 1562s, 1435m, 1273s,
1174s, 1116s, 1071s, 910w; mass spectrum (APCI): m/e (%
relative intensity) 274 (100) (Mþ1)þ, 242 (10); (MALDI)
mass spectrum (APCI): m/e (% relative intensity) 274 (100)
(Mþ1)þ, 242 (10); m/e (MALDI) calcd for C17H24NO2
(MþHþ) 274.1802, found 274.1800 and [(MþHþ)ꢁH2]
272.1626.
4.4.6. Aza-[3þ3] annulation product 38 (characterized as
a mixture)
Rf¼0.19 (50% EtOAc/hexane); 1H NMR (500 MHz,
CDCl3) d major diastereomer ( partial listing due to unre-
solved overlapping resonances): 2.83e2.89 (m, 1H), 2.99e
3.03 (m, 1H), 3.09e3.15 (m, 1H), 3.66 (s, 3H), 3.83e3.88
(m, 1H), 4.10e4.20 (m, 2H), 4.35 (dd, 1H, J¼2.0, 12.5 Hz),
4.84 (dd, 1H, J¼5.5, 7.5 Hz), 5.06 (dd, 1H, J¼4.0, 7.0 Hz),
5.27e5.32 (m, 1H), 6.18 (d, 1H, J¼7.5 Hz); minor diastereo-
mer: 1.95e1.97 (m, 1H), 2.00 (s, 3H), 2.03 (s, 3H), 2.05 (s,
3H), 2.08e2.1 (m, 1H), 2.94 (dt, 1H, J¼9.0, 18 Hz), 3.09e
3.15 (m, 1H), 3.37 (dd, 1H, J¼8.0, 17.0 Hz), 3.63e3.66 (m,
1H), 3.69 (s, 3H), 3.85e3.87 (m, 1H), 4.10e4.16 (m, 1H),
4.47 (dd, 1H, J¼2.5, 12.0 Hz), 4.93 (dd, 1H, J¼6.0, 7.5 Hz),
4.98 (dd, 1H, J¼5.0, 7.0 Hz), 5.33 (ddd, 1H, J¼2.5, 5.0,
7.5 Hz), 6.21 (d, 1H, J¼7.5 Hz); IR (film) cmꢁ1 2950brw,
1742s, 1676m, 1579m, 1435m, 1371m, 1264s; mass spectrum
(APCI): m/e (% relative intensity) 396 (100) (MþH)þ, 336
(20), 194 (5), 101 (10); m/e (ESI) calcd for C19H25NO8Na
418.1478, found 418.1480.
4.4.10. Aza-[3þ3] annulation product 41
Rf¼0.32 (10% EtOAc/hexanes); 1H NMR (400 MHz,
CDCl3) d 1.37 (t, 3H, J¼7.2 Hz), 1.62e1.88 (m, 6H), 2.92
(dd, 1H, J¼8.4, 14.4 Hz), 3.41e3.61 (m, 3H), 3.97e4.02
(m, 2H), 4.57 (d, 1H, J¼6.0 Hz), 4.92 (dd, 1H, J¼5.6,
7.6 Hz), 5.94 (d, 1H, J¼7.6 Hz), 7.15e7.18 (m, 1H), 7.24e
7.29 (m, 4H); 13C NMR (100 MHz, CDCl3) d 14.1, 26.5,
27.9, 28.9, 39.9, 52.7, 59.1, 98.3, 107.0, 125.8, 127.2, 128.0,
129.9, 149.0, 155.0, 168.9; IR (neat) cmꢁ1 2927m, 2853brm,
1676s, 1561s, 1186s; mass spectrum (APCI): m/e (% relative
intensity) 298 (100) (MþH)þ; m/e (ESI) calcd for
C19H24NO2 298.1807, found 298.1812.
4.4.7. Aza-[3þ3] annulation product 39a
Rf¼0.45 (20% EtOAc/hexane); [a]2D5 ꢁ303.0 (c 0.55,
1
CHCl3); H NMR (400 MHz, CDCl3) d major diastereomer:
1.55e1.69 (m, 1H), 1.72e1.77 (m, 1H), 1.82 (s, 3H), 1.85e
1.87 (m, 1H), 1.91 (dddd, 2H, J¼8.0 Hz), 2.08e2.21 (m,
2H), 2.28e2.33 (dq, 1H, J¼2.8, 13.2 Hz), 2.43 (s, 1H), 2.88
(dt, 1H, J¼8.0, 17.6 Hz), 3.08 (dt, 1H, J¼7.2, 18.0 Hz), 3.24
(q, 1H, J¼8.0 Hz), 3.41 (dt, 1H, J¼6.8, 9.2 Hz), 3.55 (dd,
1H, J¼3.2, 12.0 Hz), 3.65 (s, 3H), 5.01 (d, 2H, J¼6.8 Hz),
5.65 (s, 1H); 13C NMR (100 MHz, CDCl3) d 21.5, 22.8,
28.6, 31.4, 32.1, 33.8, 39.0, 40.5, 50.3, 50.9, 91.7, 111.3,
117.0, 125.3, 146.8, 155.3, 169.5; IR (film) cmꢁ1 2361w,
1709s, 1580w, 1422w, 1360m; mass spectrum (APCI): m/e
(% relative intensity) 274 (100) (MþH)þ; m/e (EI) calcd for
C17H23NO2 273.1729, found 273.1728.
4.4.11. Aza-[3þ3] annulation product 42 (characterized as
a mixture)
Rf¼0.48 (50% EtOAc/hexane); 1H NMR (500 MHz,
CDCl3) d major diastereomer: 1.25e1.29 (m, 3H), 1.32 (s,
3H), 1.39 (s, 3H), 1.51e1.78 (m, 6H), 2.73 (dd, 1H, J¼8.5,
14.5 Hz), 3.39e3.56 (m, 3H), 3.78 (dd, 1H, J¼6.5, 7.5 Hz),
3.85 (dd, 1H, J¼5.0, 6.0 Hz), 3.89 (dd, 1H, J¼6.5, 8.0 Hz),
4.08 (m, 1H), 4.14 (q, 2H, J¼7.0 Hz), 4.81 (dd, 1H, J¼6.0,
7.5 Hz), 6.07 (d, 1H, J¼7.5 Hz); minor diastereomer ( partial
listing due to unresolved overlapping resonances): 1.51e1.78
(m, 6H), 2.70e2.76 (m, 1H), 3.30 (dd, 1H, J¼6.0, 10.0 Hz),
3.39e3.56 (m, 1H), 3.87e3.90 (m, 1H), 4.92 (t, 1H,
J¼7.0 Hz), 6.05 (d, 1H, J¼7.5 Hz); 13C NMR (125 MHz,
CDCl3) d from a small sample of resolved major isomer:
14.6, 25.5, 26.5, 26.7, 28.2, 28.9, 29.1, 36.5, 52.6, 59.6,
66.1, 79.2, 94.4, 102.0, 108.7, 133.1, 157.1, 169.1; IR (film)
cmꢁ1: 2983w, 2931m, 1675s, 1552s, 1188s; mass spectrum
(APCI): m/e (% relative intensity) 322 (100) (MþH)þ, 276
4.4.8. Aza-[3þ3] annulation product 39b
Rf¼0.30 (30% EtOAc/hexane); [a]2D5 ꢁ449.0 (c 0.080,
1
CHCl3); H NMR (400 MHz, CDCl3) d major diastereomer:
1.59e1.76 (m, 2H), 1.84 (s, 3H), 1.92e2.02 (m, 3H), 2.11e
2.29 (m, 6H), 2.43 (s, 1H), 2.89 (dt, 1H, J¼8.8, 17.6 Hz),
3.11 (dt, 1H, J¼6.8, 17.6 Hz), 3.30 (dt, 1H, J¼8.0, 9.2 Hz),
3.48 (dt, 1H, J¼6.4, 9.2 Hz), 3.65 (dd, 1H, J¼3.6,
12.0 Hz), 5.02 (d, 2H, J¼10.0 Hz), 5.70 (s, 1H); 13C NMR
(100 MHz, CDCl3) d 21.6, 23.1, 28.9, 29.0, 31.8, 33.1, 34.7,
39.4, 40.6, 50.9, 104.2, 111.4, 116.9, 127.0, 147.1, 154.8,
195.6; IR (film) cmꢁ1 2932w, 2360w, 1688m, 1639w, 1540s,
1437m, 1417m, 1276s, 1225m; mass spectrum (APCI): m/e
(% relative intensity) 258 (100) (MþH)þ; m/e (EI) calcd for
C17H23NO 257.1780, found 257.1774.

892
S.K. Ghosh et al. / Tetrahedron 64 (2008) 883e893
2001, 66, 3099; (c) Tanaka, K.; Kobayashi, T.; Mori, H.; Katsumura, S.
J. Org. Chem. 2004, 69, 5906.
(100), 264 (50), 220 (5), 101 (10); m/e (ESI) calcd for
C18H27NO4Na 344.1838, found 344.1852.
11. Sydorenko, N.; Hsung, R. P.; Vera, E. L. Org. Lett. 2006, 8, 2611.
12. Wei, L.-L.; Hsung, R. P.; Xiong, H.; Mulder, J. A.; Nkansah, N. T. Org.
Lett. 1999, 1, 2145.
Acknowledgements
13. Sklenicka, H. M.; Hsung, R. P.; McLaughlin, M. J.; Wei, L.-L.; Gerasyuto,
A. I.; Brennessel, W. W. J. Am. Chem. Soc. 2002, 124, 10435.
14. Wei, L.-L.; Sklenicka, H. M.; Gerasyuto, A. I.; Hsung, R. P. Angew.
Chem., Int. Ed. 2001, 40, 1516.
Authors thank the NIH [NS38049], NIH [AI57153-05], and
UW-Madison for funding.
15. Gerasyuto, A. I.; Hsung, R. P.; Sydorenko, N.; Slafer, B. W. J. Org. Chem.
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