Chemoselective intramolecular alkylation of the Blaise reaction intermediates: Tandem one-pot synthesis of exo -cyclic enaminoesters and their applications toward the synthesis of N -heterocyclic compounds

Article abstract of DOI:10.1021/jo201964a

The intramolecular alkylative reactivity and N/C selectivity of the various Blaise reaction intermediates, which are formed from the reaction of the Reformatsky reagents with ω-chloroalkyl nitriles, did not reach the synthetic potential as an entry to exo-cyclic enaminoesters. To circumvent this issue, various additives were investigated, among which the addition of NaHMDS dramatically enhanced the reactivity and N/C selectivity. This modification provided a highly efficient route for the synthesis of various N-fused heterocyclic compounds, as it requires only two steps from nitriles.

Full text of DOI:10.1021/jo201964a

Note
pubs.acs.org/joc
Chemoselective Intramolecular Alkylation of the Blaise Reaction
Intermediates: Tandem One-Pot Synthesis of exo-Cyclic
Enaminoesters and Their Applications toward the Synthesis of N-
Heterocyclic Compounds
Ju Hyun Kim,† Hyunik Shin,*,‡ and Sang-gi Lee*,†
†Department of Chemistry and Nano Science (BK21), Ewha Womans University, 125-750 Seoul, Korea
‡Chemical Development Division, LG Life Sciences, Ltd. R&D, Daejeon 305-380, Korea
S
* Supporting Information
ABSTRACT: The intramolecular alkylative reactivity and N/
C selectivity of the various Blaise reaction intermediates, which
are formed from the reaction of the Reformatsky reagents with
ω-chloroalkyl nitriles, did not reach the synthetic potential as
an entry to exo-cyclic enaminoesters. To circumvent this issue,
various additives were investigated, among which the addition
of NaHMDS dramatically enhanced the reactivity and N/C
selectivity. This modification provided a highly efficient route
for the synthesis of various N-fused heterocyclic compounds,
as it requires only two steps from nitriles.
pot synthesis of exo-cyclic enaminoesters from the readily
available chloroalkylnitriles through the chemoselective intra-
molecular N-alkylation of the Blaise reaction intermediate.
We recently envisioned that the Blaise reaction intermediates
(the enaminozincate intermediates),7 which are formed from
the reaction of a Reformatsky reagent with a nitrile, could be a
reactive aza-analogues of the zinc enolate of β-ketoesters, and
we were intrigued by the possible use of the intermediate as a
modular platform for tandem carbon−carbon and/or carbon−
nitrogen bond-forming reactions via chemoselective electro-
philic trapping reactions.8 In this respect, we anticipated that
chemoselective intramolecular N-alkylative trapping of the
Blaise reaction intermediates, formed from ω-haloalkylnitriles
and Reformatsky reagents, could be an efficient route for the
construction of the exo-cyclic enaminoester moiety. In this
regard, Kishi’s work is the only precedent, in which it has been
stated that “in situ alkylation of the initial adduct offers an
additional synthetic application for the Blaise reaction”.9
Although the intramolecular alkylative trapping concept has
been addressed, the reported successful results were on the
alkylation of zinc salt-free enaminoesters. Therefore, a more
detailed study on the intramolecular C- vs N-alkylation
selectivity of the divalent Blaise reaction intermediate and on
its reactivity has yet to be performed (Scheme 1). Herein, we
describe intramolecular alkylative reactivity profile of the Blaise
reaction intermediate and its modification, which led to highly
valuable chemoselective intramolecular N-alkylative trapping
he exo-cyclic enaminoesters are highly versatile inter-
Tmediates in the synthesis of N-heterocyclic fragments that
are embedded in many useful pharmaceuticals and natural
products.1 Synthetic approaches to exo-cyclic enaminoesters
mainly rely either on the use of existing N-heterocycles or on
construction of the N-heterocyclic moiety via intramolecular
ring closure reactions. Reaction of a thiolactam with a bromo
methyl ketone or ester followed by sulfur extrusion in the
presence of triphenylphosphine (Eschenmoser sulfide contrac-
tion)2 or condensation of organometallic reagents with lactams
or thiolactames are the most frequently employed approach for
the synthesis of exo-cyclic enaminoesters.3 Condensation
reactions of lactim ethers with active methylene compounds
have also been developed.4 In contrast to the former methods,
synthesis of exo-cyclic enaminoesters using ring closure
reactions has been reported in only a few cases. Carrie and
co-workers5a reported an approach utilizing the intramolecular
aza-Wittig reaction of ω-azido β-dicarbonyls, which were
prepared through lengthy steps of the γ-alkylation of β-
dicarbonyl dianions with α,ω-dihaloalkane compounds fol-
lowed by a nucleophilic substitution by sodium azide.5 Other
syntheses include, for example, intramolecular dehydrative
cyclization of ω-amino β-dicarbonyls, which are accessible from
the aziridine ring-opening with 1,3-dicarbonyl dianions,6a
reaction of N-Boc-protected γ-lactam with lithium enolate of
acetate or ketones,6b or lactone ring transformations.6c
However, these ring-closing strategies generally require multi-
step syntheses of the cyclization precursors, and thus, the
development of a new efficient method to construct exo-cyclic
enaminoester moiety from readily available compounds remains
a subject of significant interest. Herein, we report a general one-
Received: September 27, 2011
Published: January 9, 2012
© 2012 American Chemical Society
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Note
five-membered exo-enaminoesters 4ab in 46% yield as a
mixture of the (E)/(Z)-isomers, which could be separated by
silica column chromatography (entry 5, Table 1). Similarly,
from the tandem reaction with α-Ph substituted 3ac (n = 1, X =
Cl, R = Ph), the N-alkylated (Z)-4ac was formed as a major
product in 42% yield (entry 6, Table 1). However, alkylation of
the Blaise reaction intermediate 3cb (X = Cl, n = 2, R = Me)
with the α-Me substituent and the C4-tether length (n = 2) still
afforded the C-alkylated product. Thus, the cyclohexanone 6bb
(the initially formed imine was hydrolyzed during the workup)
was isolated in 45% yield along with small amount of N-
cyclized product 4bb (entry 7, Table 1). When the Blaise
reaction intermediate 3cc (X = Cl, n = 2, R = Ph) was used, the
N-cyclized 4bc and C-cyclized 6bc were formed in almost a 1:1
ratio (entry 8, Table 1). In general, the reactivity of the
unmodified Blaise reaction intermediate toward alkylation was
insufficiently high to efficiently accomplish the intramolecular
SN2 alkylation; in fact, it took prolonged reaction time at reflux.
To increase reactivity and chemoselectivity, we next
investigated the additive effect on this transformation. We
found that addition of sodium hexamethyldisilazide
(NaHMDS) dramatically increased not only the reactivity,
but also the chemoselectivity. After varying the amount of
NaHMDS (entries 1−4, Table 2), we found that addition of 3.5
equiv of NaHMDS to the Blaise reaction intermediate 3aa at 0
°C followed by reaction for 5 h at room temperature afforded a
93% yield of the N-cyclized exo-enaminoester 4aa (entry 4,
Table 2). Although the reason for the excess amounts (3.5
equiv) of NaHMDS and its exact role are not yet clear, it may
be associated with the proton exchange of its conjugate acid,
HMDS, with the deprotonated Blaise reaction intermediate,
which may have dianionic properties, and is probably more
basic than NaHMDS. Thus, shifting the equilibrium to the
deprotonated Blaise intermediate could be one of the limiting
factors of efficient intramolecular alkylations.10 The use of
LiHMDS did not change the chemoselectivity, but decreased
the yield of 4aa to 55% (entry 5, Table 2). Other
Scheme 1. Intramolecular Alkylative Trapping Reactions of
the Blaise Reaction Intermediate
reactions affording exo-cyclic enaminoesters, which can be used
toward the synthesis of N-heterocyclic compounds.
To investigate the reactivity and chemoselectivity of the
intramolecular alkylative trapping reactions, the Blaise reaction
intermediates 3 having different tether lengths and leaving
groups were prepared by reaction of nitrile 1 with a
Reformatsky reagent, generated in situ from α-bromoesters 2
(Table 1). The intrinsic reactivity of the Blaise reaction
intermediate toward intramolecular alkylations (entries 1−8,
Table 1) was investigated first, and we found that chemo-
selectivity was dependent on both tether length and the α-
substituent R. Thus, the Blaise reaction intermediates with no
α-substituents, 3aa (n = 1, R = H, X = Cl), 3ba (n = 1, R = H,
X = Br), 3ca (n = 2, R = H, X = Cl), and 3da (n = 2, R = H, X
= OMs), provided the corresponding C-cyclized cyclic
enaminoesters 5aa or 5ba as a major product (entries 1−4,
Table 1). In contrast, the Blaise intermediates 3ab (X = Cl, n =
1, R = Me) having α-Me substituent afforded the N-cyclized
t
organolithium, inorganic, and organic bases such as BuLi,
nBuLi, K2CO3, Na2CO3, 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU), diisopropylethylamine (DIEA), and triethylamine
were not as effective as NaHMDS (entries 6−12, Table 2).
a
Table 1. Chemoselectivity in Intramolecular N-Alkylation of the Blaise Reaction Intermediate 3
b
c
c
entry
1
2
3
time (h)
N-alkylation 4 (%)
C-alkylation 5 (or 6) (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1a
1a
1c
1c
2a
2a
2a
2a
2b
2c
2b
2c
3aa
3ba
3ca
3da
3ab
3ac
3cb
3cc
14
8
4aa (6)
4aa (−)
4ba (−)
4ba (−)
5aa (29)
5aa (40)
5ba (37)
5ba (62)
6ab (<5)
6ac (<5)
6bb (45)
6bc (25)
6
4
d
9
4ab (46)
8
4ac (42)
4bb (<5)
4bc (20)
7
8
a
Reaction conditions: 1 (3.82 mmol), 2 (4.97 mmol), Zn (7.65 mmol, preactivated with 6.5 mol % of methanesulfonic acid) in THF (1.5 mL) at
b
reflux temperature. Time for disappearance of the Blaise reaction intermediate, determined by GC after treatment the sample with saturated
aqueous NH4Cl solution. Isolated yield after chromatographic purification. A mixture of (E)- and (Z)-isomers.
c
d
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Note
a
Table 2. Intramolecular Alkylation of the Blaise Reaction Intermediate 3 in the Presence of Base
b
b
entry
1
2
3
base
N-alkylation 4 (%)
C-alkylation 5 (or 6) (%)
c
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1c
1c
1c
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2a
2b
2c
3aa
3aa
3aa
3aa
3aa
3aa
3aa
3aa
3aa
3aa
3aa
3aa
3aa
3ab
3ac
3ca
3cb
3cc
NaHMDS
NaHMDS
NaHMDS
NaHMDS
LiHMDS
tBuLi
4aa (−)
4aa (12)
4aa (24)
4aa (93)
4aa (55)
4aa (14)
4aa (28)
4aa (−)
4aa (−)
4aa (23)
4aa (>5)
4aa (7)
5aa (−)
5aa (17)
5aa (−)
5aa (−)
5aa (−)
5aa (>5)
5aa (>5)
5aa (−)
5aa (−)
5aa (>5)
5aa (>5)
5aa (−)
5aa (13)
6ab (>5)
6ac (>5)
5ba (42)
6bb (−)
6bc (−)
cd
,
2
3
4
5
6
7
8
9
e
nBuLi
K2CO3
Na2CO3
DBU
10
11
12
13
14
15
16
17
18
DIEA
Et3N
t-BuOK
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
4aa (68)
4ab (74)
4ac (71)
4ba (10)
4bb (72)
4bc (67)
a
Unless otherwise noted, the Blaise reaction intermediate 3 was prepared by reaction with 1 (3.82 mmol), 2 (4.97 mmol), Zn (7.65 mmol,
preactivated with 6.5 mol % of methanesulfonic acid) in THF (1.5 mL), and after addition of 3.5 equiv of base at 0 °C, the reaction was continued
b
c
d
for 5 h at room temperature. Isolated yield after chromatographic purification. Reaction with 1.0 equiv of base. Reaction was carried out at THF
e
reflux. Reaction with 2.0 equiv of base.
Under these reaction conditions, the unreacted Blaise reaction
intermediate 3aa could be isolated as ethyl 2-amino-6-chloro-2-
hexenoate. As we observed in Pd-catalyzed arylative intra-
molecular trapping of the Blaise reaction intermediate,11 t-
BuOK is reasonably effective for chemoslective intramolecular
alkylation of the Blaise reaction intermediate (entry 13, Table
2). In the same manner, the yields of 4ab and 4ac formation
also increased significantly in the presence of NaHMDS
(entries 14 and 15, Table 2). However, in the case of the α-
unsubstituted Blaise reaction intermediate 3ca (X = Cl, n = 2, R
Figure 1. Plausible transition state conformations for the observed
chemoselectivity in intramolecular alkylation of the Blaise reaction
intermediates.
= H) with a four-carbon tether length, although the N-
remained dominant when the tether length is n = 2,
selectivity was slightly improved, the C-alkylated compound
contributing to the formation of stable chair conformation C.
5ba was still formed as a major product (entry 16, Table 2). In
In contrast, the observed N-alkylative chemoselectivity in the
contrast, the α-substituted Blaise reaction intermediates 3cb (X
presence of NaHMDS could be attributed to the fact that
= Cl, n = 2, R = Me) and 3cc (X = Cl, n = 2, R = Ph) were
deprotonation of acidic N−H could generate the enamino
cyclized with high N-selectivity to afford the corresponding six-
anion D, in which the anion may be placed dominantly at
membered exo-enaminoesters 4bb with 67% (entry 17, Table
carbon atom to minimize the electronic repulsion with the N−
1) and 4bc with 72% yields (entry 18, Table 1). Noteworthy is
that in the presence of NaHMDS, all N-cyclized products have
(Z)-geometry, suggesting that the zinc bromide complex
persists during the cyclization process.
zinc bonding electrons generating an appropriate SN2 reaction
trajectory to afford the N-cyclized products 4aa−ac and 4bb,bc.
In the case of α-unsubstituted 3ca (X = Cl, n = 2, R = H) with a
four-carbon tether length, the stable chair conformation
remains dominant, affording the C-cyclized product 5ba as a
major product.
The synthetic utility of the chemoselective intramolecular N-
alkylative trapping reactions of the modified Blaise reaction
intermediate has been demonstrated by two-step synthesis of a
variety of N-heterocyclic compounds from nitriles (Scheme 2).
The chiral exo-cyclic enaminoester 4ad was synthesized in 76%
yield through the intramolecular alkylative trapping of the
Blaise reaction intermediate 3ea, formed from chiral O-
The chemoselectivity observed from the intramolecular
alkylation of the unmodified Blaise reaction intermediate may
have originated from stereoelectronic factors. For the α-
unsubstituted intermediates 3aa and 3ba (n = 1, R = H), the
intramolecular SN2 alkylation reaction may proceed via
conformation A (Figure 1), which is stereoelectronically
favorable for C-cyclization and affords 5aa as a major product.
In contrast, when R = Me or Ph, there is steric repulsion
between R and X in conformation A, and the N-cyclization
would be dominant via conformation B. The C-cyclization
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Scheme 2. Two-Step Syntheses of N-Hetrocyclic
Compounds via the N-Alkylative Trapping Reactions of the
Blaise Reaction Intermediates
EXPERIMENTAL SECTION
■
All reactions and manipulations were performed in a nitrogen
atmosphere using standard Schlenk techniques. Flasks were flame-
dried under a stream of nitrogen. Anhydrous solvents were distilled
prior to use (THF was distilled from sodium benzophenone ketyl). All
purchased reagents were used as received without further purification.
Anhydrous solvents were transferred by oven-dried syringe. The
chemical shifts were relative to TMS (as an internal reference) for 1H
24
NMR. Optical rotations data were reported as follows: [α]D
(concentration c = g/100 mL, solvent).
General Procedure for Intramolecular Alkylation of the
Blaise Reaction Intermediate. To a suspension of zinc dust (500
mg, 7.65 mmol) was added 6.5 mol % of methanesulfonic acid in THF
(1.5 mL), and the mixture was refluxed for 10 min. While maintaining
reflux, nitrile 1 (3.82 mmol) was added all at once, followed by ethyl 2-
bromoalkanoate 2 (4.97 mmol) added over 1 h using a syringe pump.
The reaction was continued until all of the Blaise reaction intermediate
had disappeared by GC, and then it was quenched by addition of
saturated aqueous NH4Cl and extracted with ethyl acetate (20 mL ×
3). The combined organic layer was dried over anhydrous sodium
sulfate, filtered, and concentrated under reduced pressure. Then, the
corresponding N-cyclized 4 and C-cyclized 5 (or 6) products were
separated using silica column chromatography to give the results in
Table 1. For the reactions in the presence of base additive: after
generation of the Blaise reaction intermediate as described above, the
reaction mixture was cooled to 0 °C. To this reaction mixture was
added a solution of sodium bis(trimethylsilyl)amide (1.0 M solution,
13.37 mmol) in THF. The reaction mixture was stirred for 5 h at room
temperature, quenched by the addition of saturated aqueous NH4Cl,
and extracted with ethyl acetate (20 mL × 3). The combined organic
layer was dried over anhydrous sodium sulfate, filtered, and
concentrated under reduced pressure. The residue was then purified
by column chromatography on silica gel to afford the corresponding
N-cyclized product 4 with the yields given in Table 2.
TBDMS-protected (3S)-4-chloro-3-hydroxybutyronitrile (1e),
which was prepared using commercial epichlorohydrin.12 The
Nenitzescu reaction of 4ad with 1,4-benzoquinone in the
presence of 20 mol % of ZnI2 afforded the N-fused indole 7 in
70% yield.13 Hydrogenation of the exo-double bond of (S)-4ad
in the presence of Pd−C catalyst provided (2S,4S)-8 in 97%
yield with >99% diastereoselectivity. The absolute stereo-
chemistry was determined, after conversion to N-Cbz-protected
pyrrolidine (N-CBz-8), by comparing the optical rotation with
Ethyl 2-(Pyrrolidin-2-ylidene)acetate (4aa). [C8H13NO2: 35150−
22−2]. Yield: 93% (552 mg, isolated from the reaction of entry 4 in
Table 2). Eluents: n-hexane/EtOAc = 7/1. White solid: mp = 60−61
°C; 1H NMR (250 MHz, CDCl3) δ 1.24 (t, J = 7.1 Hz, 3H), 1.97 (tt J
= 7.3, 7.3 Hz, 2H), 2.58 (t, J = 7.7 Hz, 2H), 3.52 (t, J = 6.9 Hz, 2H),
4.12 (q, J = 7.1 Hz, 2H); 4.52 (s, 1H), 7.93 (brs, 1H) ppm; 13C NMR
(63 MHz, CDCl3) δ 14.4, 21.7, 31.9, 46.7, 58.0, 76.2, 166.1, 170.3
ppm.
20
the reported (2R,4R)-N-Cbz-8 {[α]D = +13 (c = 1.02,
EtOAc)}.14 Optical rotation of the synthesized N-Cbz-8
24
exhibited levorotatory {[α]D = −11.8 (c = 10.0, EtOAc)},
indicating that the absolute stereochemistry of 8 is to be
(2S,4S)-configuration, which suggests that the hydrogenation
was proceeded anti-selectively as observed in the diastereose-
lective hydrogenation of ethyl (4-methoxypyrrolidin-2-ylidene)-
acetate.15 The 4-hydroxy homoprolines were used as the key
intermediates for the synthesis of sequence-selective DNA-
binding agents as potential antitumor drugs and antibiotics.16
Compared to the reported four-step synthesis of 8 starting from
4-hydroxy-2-pyrrolidinone, which was reportedly the shortest
synthetic procedure,17 our protocol is highly step-economical.
Biologically important indolizidine moiety18 could also be
synthesized from 4-chlorobutyronitriles 1a and 1e in an only
two-step procedure. Thus, the N-/C-bisalkylations of 4aa or
4ad with 1,3-dibromopropane or 1,4-dibromobutane afforded
the N-fused bicyclic compounds 9a−c with yields ranging from
67 to 96%.
Ethyl 2-(Pyrrolidin-2-ylidene)propanoate (4ab). [C9H15NO2:
96319−44−7]. Yield: 74% (479 mg, isolated from the reaction of
entry 14 in Table 2). Eluents: n-hexane/EtOAc = 7/1 to 3/1. (E)-
Isomer, pale yellowish liquid: 1H NMR (250 MHz, CDCl3) δ 1.30 (t, J
= 7.1 Hz, 3H), 1.62 (s, 3H), 2.00 (tt, J = 7.5, 7.5 Hz, 2H), 2.49−2.75
(m, 2H), 3.89 (tt, J = 7.4, 2.0 Hz, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.45
(brs, 1H) ppm; 13C NMR (63 MHz, CDCl3) δ 14.2, 23.5, 23.5, 33.5,
60.4, 62.1, 75.6, 173.1, 177.9e ppm. (Z)-Isomer (isolated from the
1
reaction of entry 5 in Table 1), white solid: mp = 62 °C; H NMR
(250 MHz, CDCl3) δ 1.27 (t, J = 7.1 Hz, 3H), 1.73 (s, 3H), 1.97 (tt, J
= 7.4, 7.4 Hz, 2H), 2.59 (t, J = 7.7 Hz, 2H), 3.50 (t, J = 6.9 Hz, 2H),
4.13 (q, J = 7.1 Hz, 2H), 8.02 (brs, 1H) ppm; 13C NMR (63 MHz,
CDCl3) δ 12.8, 14.7, 22.0, 31.2, 47.1, 58.6, 83.3, 163.9, 170.7 ppm.
Ethyl 2-Phenyl(pyrrolidin-2-ylidene)ethanoate (4ac). Yield: 71%
(628 mg, isolated from the reaction of entry 15 in Table 2). Eluents: n-
1
In conclusion, we have first disclosed the intramolecular
alkylative reactivity profile of the Blaise reaction intermediate
with a tethered leaving group, where the N/C cyclization was
determined mainly by the tethered length and substituent at the
C-2 position. To overcome its low reactivity and poor N/C
selectivity, we manipulated the Blaise reaction intermediate by
adding NaHMDS, which led to significant enhancement of
reactivity and N/C selectivity. This modification is sufficient
enough to use the current protocol as a general method for the
construction of N-heterocyclic exo-cyclic enaminoesters that are
embedded in many useful molecular structures.
hexane/EtOAc = 10/1 to 7/1. Colorless liquid: H NMR (250 MHz,
CDCl3) δ 1.16 (t, J = 7.1 Hz, 3H), 1.89 (tt, J = 7.3, 7.3 Hz, 2H), 2.43
(t, J = 7.6 Hz, 2H), 3.57 (td, J = 6.9, 0.6 Hz, 2H), 4.10 (q, J = 7.1 Hz,
2H), 7.15−7.20 (m, 3H), 7.24−7.31 (m, 2H), 8.50 (brs, 1H) ppm;
13C NMR (63 MHz, CDCl3) δ 14.7, 23.4, 32.4, 47.4, 59.0, 93.0, 125.7,
127.7, 131.7, 138.6, 165.5, 169.8 ppm. HRMS Calcd m/z for
C14H18NO2 [M + H]+: 232.1338. Found: 232.1334.
Ethyl 2-[4-(S)-tert-Butyl-dimethylsilanyloxypyrrolidin-2-ylidene]-
acetate (4ad). Yield: 76% (830 mg isolated from the reaction in
scheme 2). Eluents: n-hexane/EtOAc = 7/1. Colorless liquid: 1H
NMR (250 MHz, CDCl3) δ 0.06 (s, 6H), 0.86 (s, 9H), 1.24 (t, J = 7.1
Hz, 3H), 2.49 (dd, J = 16.6, 3.9 Hz, 1H), 2.74 (dd, J = 16.6, 6.3 Hz,
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Note
1H), 3.36 (dd, J = 10.4, 3.2 Hz, 1H), 3.65 (dd, J = 10.4, 5.6 Hz, 1H),
4.09 (q, J = 7.1 Hz, 2H), 4.45−4.49 (m, 1H), 4.51 (s, 1H), 7.78 (brs,
1H) ppm; 13C NMR (63 MHz, CDCl3) δ −4.8, −4.7, 14.8, 18.1, 25.8,
42.0, 55.6, 58.5, 69.2, 77.7, 164.4, 170.7 ppm. HRMS Calcd m/z for
C14H27NO3Si [M + H]+: 286.1838. Found: 286.1837.
to reflux, and then a solution of exo-cyclic enaminoester 4ad (300 mg,
1.05 mmol) in CH2Cl2 (2 mL) was added dropwise over 10 min. The
mixture was stirred at reflux for an additional 2 h. The reaction was
quenched at room temperature by addition of saturated aqueous
NH4Cl and extracted with ethyl acetate (20 mL × 3). The combined
organic layer was dried over anhydrous sodium sulfate, filtered, and
concentrated under reduced pressure. Purification by silica column
chromatography (n-hexane/EtOAc = 3/1) afforded 7 as a white solid
(277 mg, 70% yield). White solid: mp = 180−182 °C; 1H NMR (300
MHz, CDCl3) δ 0.11 (s, 6H), 0.90 (s, 9H), 1.40 (t, J = 7.1 Hz, 3H),
3.11 (dd, J = 17.8, 3.8 Hz, 1H), 3.48 (dd, J = 17.9, 6.9 Hz, 1H), 3.84
(dd, J = 10.7, 3.7 Hz, 1H), 4.18 (dd, J = 10.7, 6.3 Hz, 1H), 4.36 (q, J =
7.1 Hz, 2H), 5.02−5.05 (m, 1H), 6.81 (dd, J = 8.6, 2.2 Hz, 1H), 7.02
(d, J = 8.6 Hz, 1H), 7.59 (brs, 1H), 7.88 (d, J = 2.0 Hz, 1H) ppm; 13C
NMR (75 MHz, CDCl3) δ −4.8, −4.7, 14.6, 18.1, 25.8, 37.7, 53.8,
59.9, 74.1, 98.9, 106.3, 110.6, 111.4, 127.8, 131.7, 150.6, 152.6, 166.3
ppm. HRMS Calcd m/z for C20H30NO4Si [M + H]+: 376.1944.
Found: 376.1941.
Ethyl 2-(Piperidin-2-ylidene)acetate (4ba). [C9H15NO2: 25654−
24−4]. Yield: 10% (65 mg, isolated from the reaction of entry 16 in
Table 2). Eluents: n-hexane/EtOAc = 7/1. Pale yellow liquid: 1H
NMR (250 MHz, CDCl3) δ 1.25 (t, J = 7.1 Hz, 3H), 1.64−1.83 (m,
4H), 2.35 (t, J = 6.4 Hz, 2H), 3.29 (td, J = 5.8, 2.3 Hz, 2H), 4.08 (q, J
= 7.1 Hz, 2H), 4.36 (s, 1H), 8.73 (brs, 1H) ppm; 13C NMR (63 MHz,
CDCl3) δ 14.8, 20.1, 23.0, 29.3, 41.4. 58.3, 80.3, 162.9, 170.8 ppm.
Ethyl 2-(Piperidin-2-ylidene)propanoate (4bb). [C10H17NO2: (Z)-
96333−47−0]. Yield: 67% (470 mg, isolated from the reaction of
entry 17 in Table 2). Eluents: n-hexane/EtOAc = 7/1. Pale yellowish
liquid: 1H NMR (250 MHz, CDCl3) δ 1.27(t, J = 7.1 Hz, 3H), 1.71 (s,
3H), 1.65−1.78 (m, 4H), 2.37−2.45 (m, 2H), 3.24−3.32 (m, 2H),
4.11 (q, J = 7.1 Hz, 2H), 9.52 (brs, 1H) ppm; 13C NMR (63 MHz,
CDCl3) δ 11.4, 14.8, 20.4, 22.4, 26.7, 41.6, 58.55, 84.5, 160.0, 171.0
ppm.
Synthesis of Ethyl (2S,4S)-[4-tert-Butyldimethylsilanyloxy-
pyrrolidine-2-yl]acetate 8. [C14H29NO3Si: 612843−60−4]. To a
suspension of Pd/C (0.5 equiv, 10% Pd on charcoal) in ethanol (5
mL) was added exo-cyclic enaminoester 4ad (285.5 mg, 1.0 mmol).
The mixture was hydrogenated under H2 atmosphere (1 atm, balloon)
at room temperature for 48 h. The reaction mixture was filtered
through Celite and washed with ethanol, and then the filtrate was
concentrated in a vacuum to afford (2S,4S)-8 (285 mg, 97% yield) as
Ethyl 2-Phenyl(piperidin-2-ylidene)ethanoate (4bc). [C15H19NO2:
21743−54−3]. Yield: 72% (675 mg, isolated from the reaction of
1
entry 18 in Table 2). Eluents: n-hexane/diethylether = 6/1; H NMR
(300 MHz, CDCl3) δ 1.11 (t, J = 7.1 Hz, 3H), 1.55−1.61 (m, 2H),
1.70−1.76 (m, 2H), 2.12 (t, J = 6.5 Hz, 2H), 3.34−3.38 (m, 2H), 4.04
(q, J = 7.1 Hz, 2H), 7.11−7.13 (m, 2H), 7.17−7.22(m, 1H), 7.26−
7.31 (m, 2H), 9.72 (brs, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ
14.7, 20.0, 22.4, 27.9, 41.4, 58.7, 95.0, 125.8, 127.8, 132.4, 138.4, 161.2,
170.1 ppm.
24
1
pale yellow liquid: [α]D = +9.9 (c = 5.0, EtOH); H NMR (300
MHz, CDCl3) δ 0.03 (s, 6H), 0.86 (s, 9H), 1.24 (t, J = 7.1 Hz, 3H),
1.34−1.43 (m, 1H), 2.12−2.21 (m, 1H), 2.51 (dd, J = 15.6, 6.3 Hz,
1H), 2.60 (dd, J = 15.6, 7.6 Hz, 1H), 2.68(brs, 1H), 2.84−2.95 (m,
2H), 3.45 (tt, J = 7.3, 7.0, 1H), 4.12(q, J = 7.1 Hz, 2H), 4.29−4.35 (m,
1H) ppm; 13C NMR (75 MHz, CDCl3) δ −4.8, −4.7, 14.3, 18.1, 25.9,
41.1, 41.7, 54.5, 55.7, 60.4, 73.1, 172.1 ppm. The absolute
stereochemistry was determined, after conversion to the N-Cbz-8, by
comparison the optical rotation with the reported the reported
(2R,4R)-N-Cbz-8.14 (2S,4S)-N-Cbz-8, colorless liquid: [α]D24 = −11.8
Ethyl 2-Amino-1-cyclopentene-1-carboxylate (5aa). [C8H13NO2:
7149−18−0]. Yield: 29% (172 mg, isolated from the reaction of entry
1 in Table 1). Eluents: n-hexane/EtOAc = 7/1. White solid: mp = 48−
1
49 °C; H NMR (500 MHz, CDCl3) δ 1.27 (t, J = 7.0 Hz, 3H), 1.81
(tt, J = 7.5, 7.5 Hz, 2H), 2.48 (t, J = 7.5 Hz, 2H), 2.52 (t, J = 7.5 Hz,
2H), 4.15 (q, J = 7.0 Hz, 2H) ppm; 13C NMR (63 MHz, CDCl3) δ
14.55, 20.7, 29.4, 34.9, 58.5, 94.7, 162.0, 168.0 ppm.
1
Ethyl 2-Amino-1-cyclohexene-1-carboxylate (5ba). [C9H15NO2:
1128−00−3]. Yield: 46% (478 mg, isolated from the reaction of entry
16 in Table 2). Eluents: n-hexane/EtOAc = 7/1. Pale yellow solid: mp
= 60−62 °C; 1H NMR (500 MHz, CDCl3) δ 1.27 (t, J = 7.0 Hz, 3H),
1.59−1.64 (m, 4H), 2.20 (t, J = 6.0 Hz, 2H), 2.25 (t, J = 6.0 Hz, 2H),
4.13 (q, J = 7.0 Hz, 2H) ppm; 13C NMR (126 MHz, CDCl3) δ 14.6,
22.2, 23.2, 23.4, 30.5. 58.8, 92.1, 156.6, 170.5 ppm.
(c = 10.0, EtOAc); H NMR (300 MHz, CDCl3, 50 °C) δ 0.06 (s,
6H), 0.88 (s, 9H), 1.22 (t, J = 7.1 Hz, 3H), 1.87 (d, J = 13.5 Hz, 1H),
2.12−2.21 (m, 1H), 2.77−3.07 (m, 2H), 3.35 (d, J = 11.3 Hz, 1H),
3.50−3.60 (m, 1H), 4.07−4.12 (m, 2H), 4.24−4.39 (m, 2H), 5.14(s,
2H), 7.25−7.37 (m, 5H) ppm.
General Procedure for the Synthesis of N-Fused Bicyclic
Compounds 9a−9c. To a solution of exo-cyclic enaminoester 4aa
(310.4 mg, 2.0 mmol) in DMF (5 mL) was added NaH (120 mg, 3.5
mmol) at −30 °C. After stirring for 10 min, 1,3-dibromopropane (0.36
mL, 3.5 mmol) was added, and the reaction mixture was stirred at
same temperature for an additional 30 min. The reaction was
quenched by the addition of H2O and extracted with ethyl acetate (20
mL × 3), and the combined organic layer was dried over anhydrous
sodium sulfate, filtered, and concentrated under reduced pressure. The
residue was purified by silica column chromatography (n-hexane/
EtOAc = 5/1 to 3/1) to afford 9a as a viscous colorless liquid (297
mg, 76% yield).
Ethyl 1-Methyl-2-oxocyclopentanecarboxylate (6ab). [C9H14O3:
5453−88−3]. Yield: <5% (<10 mg, isolated from the reaction of entry
1
5 in Table 1). Eluents: n-hexane/EtOAc = 10/1. Colorless liquid: H
NMR (250 MHz, CDCl3) δ 1.25 (t, J = 7.1 Hz, 3H), 1.31 (s, 3H),
1.81−2.14 (m, 3H), 2.23−2.54 (m, 3H), 4.16 (q, J = 7.1 Hz, 2H)
ppm; 13C NMR (63 MHz, CDCl3) δ 14.0, 19.3, 19.5, 36.1, 37.6. 55.8,
61.2, 172.3, 215.9 ppm.
Ethyl 1-Methyl-2-oxocyclohexanecarboxylate (6bb). [C10H16O3:
5453−94−1]. Yield: 45% (317 mg, isolated from the reaction of entry
1
7 in Table 1). Eluents: n-hexane/EtOAc = 10/1. Colorless liquid: H
NMR (250 MHz, CDCl3) δ 1.26 (t, J = 7.1 Hz, 3H), 1.29 (s, 3H),
1.38−1.50 (m, 1H), 1.61−1.76 (m, 3H), 1.94−2.05 (m, 1H), 2.45−
2.55 (m, 3H), 4.20 (qd, J = 7.1 Hz, 1.3, 2H), 9.52 (brs, 1H) ppm; 13C
NMR (63 MHz, CDCl3) δ 14.1, 21.3, 22.7, 27.6, 38.3, 40.7, 57.2, 61.3,
173.1, 208.4 ppm.
Ethyl 2-Oxo-1-phenylcyclohexanecarboxylate (6bc). [C15H18O3:
55285−81−9]. Yield: 25% (236 mg, isolated from the reaction of
entry 8 in Table 1). Eluents: n-hexane/EtOAc = 7/1. Colorless liquid:
1H NMR (250 MHz, CDCl3) δ 1.23 (t, J = 7.1 Hz, 3H), 1.76−1.85
(m, 3H), 1.91−2.03 (m, 1H), 2.32−2.40 (m, 1H), 2.48−2.62 (m, 2H),
2.73−2.80 (m, 1H), 4.20 (qd, J = 7.1, 1.8 Hz, 2H), 7.21−7.25 (m,
2H), 7.28−7.29 (m, 3H) ppm; 13C NMR (63 MHz, CDCl3) δ 14.1,
22.3, 27.8, 35.4, 40.9, 61.7, 66.5, 136.9, 171.3, 206.7 ppm.
Synthesis of Ethyl 7-Hydroxy-2-tert-butyl-dimethyl-silany-
loxy-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylate 7. To a
solution of 1,4-benzoquinone (116 mg, 1.05 mmol) in CH2Cl2 (5 mL)
was added ZnI2 (67 mg, 0.21 mmol). The reaction mixture was heated
Ethyl 1,2,3,5,6,7-Hexahydroindolizine-8-carboxylate (9a).
[C11H17NO2: 90407−59−3]. Spectral data: 1H NMR (250 MHz,
CDCl3) δ 1.21 (t, J = 7.1 Hz, 3H), 1.74−1.93 (m, 4H), 2.31 (t, J = 6.3
Hz, 2H), 3.01 (t, J = 7.6 Hz, 2H), 3.11 (t, J = 5.7 Hz, 2H), 3.24 (t, J =
7.1 Hz, 2H), 4.06 (q, J = 7.1 Hz, 2H) ppm; 13C NMR (63 MHz,
CDCl3) δ 14.8, 21.0, 21.4, 21.6, 32.7, 45.0, 52.9, 58.4, 87.45, 159.2,
168.8 ppm.
Ethyl 2,3,5,6,7,8-Hexahydro-1H-pyrrolo[1,2-a]azepine-9-carboxy-
late (9b). Yield: 96% (402 mg). Eluents: n-hexane/EtOAc = 3/1 to 2/
1. Viscous colorless liquid: 1H NMR (250 MHz, CDCl3) δ 1.25 (t, J =
7.1 Hz, 3H), 1.62−1.75 (m, 4H), 1.89 (tt, J = 7.7, 7.7 Hz, 2H), 2.04−
2.15 (m, 2H), 2.17−2.27 (m, 2H), 2.46−2.53 (m, 2H), 3.81−3.86 (m,
2H), 4.17 (q, J = 7.1 Hz, 2H) ppm; 13C NMR (63 MHz, CDCl3) δ
14.1, 23.1, 24.9, 34.4, 34.8, 58.5, 60.5, 60.9, 174.7, 177.6 ppm. HRMS
Calcd m/z for C12H20NO2[M + H]+: 210.1494. Found: 210.1493.
Ethyl 2-tert-Butyl-dimethyl-silanyloxy-1,2,3,5,6,7-hexahydroindo-
lizine-8-carboxylate (9c). Yield: 67% (436 mg). Eluents: n-hexane/
1564
dx.doi.org/10.1021/jo201964a | J. Org. Chem. 2012, 77, 1560−1565

The Journal of Organic Chemistry
Note
1
EtOAc = 10/1 to 5/1. Viscous colorless liquid: H NMR (250 MHz,
CDCl3) δ 0.07 (d, J = 1.5 Hz, 6H), 0.88 (s, 6H), 1.25 (t, J = 7.1 Hz,
3H), 1.77−1.89 (m, 2H), 2.34 (t, J = 6.1 Hz, 2H), 2.98−3.18 (m, 4H),
3.27 (dd, J = 18.1, 6.9 Hz, 1H), 3.45 (dd, J = 10.0, 6.0 Hz, 1H), 4.10
(q, J = 7.1 Hz, 2H), 4.42−4.47 (m, 1H) ppm; 13C NMR (63 MHz,
CDCl3) δ −4.7, −4.6, 14.9, 18.2, 21.3, 21.5, 25.9, 42.9, 44.9, 58.6, 61.3,
68.3, 88.1, 157.3, 168.8 ppm. HRMS Calcd m/z for C17H32NO3Si [M
+ H]+: 326.2151. Found: 326.2153.
(12) Fraley, M. E.; Garbaccio, R. M.; Arrington, K. L.; Hoffman, W.
F.; Tasber, E. S.; Coleman, P. J.; Buser, C. A.; Walsh, E. S.; Hamilton,
K.; Fernandes, C.; Schaber, M. D.; Lobell, R. B.; Tao, W.; South, V. J.;
Yan, Y.; Kuo, L. C.; Prueksaritanont, T.; Shu, C.; Torrent, M.;
Heimbrook, D. C.; Kohl, N. E.; Huber, H. E.; Hartman, G. D. Bioorg.
Med. Chem. Lett. 2006, 16, 1775.
(13) Velezheva, V. S.; Kornienko, A. G; Topilin, S. V.; Turashev, A.
D.; Peregudov, A. S.; Brennan, P. J. J. Heterocycl. Chem. 2006, 43, 873.
(14) Zhao, X.; Hoesl, C. E.; Hoefner, G. C.; Wanner, K. T. Eur. J.
Org. Chem. 2005, 40, 231.
ASSOCIATED CONTENT
* Supporting Information
■
(15) Bellur, E.; Freifeld, I.; Bottcher, D.; Bornscheuer, U. T.; Lange,
̈
S
P. Tetrahedron 2006, 62, 7132.
Copies of 1H and 13C NMR spectra for 4, 5, 6, 7, 8, and 9. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(16) (a) Gregson, S. J.; Howard, P. W.; Corcoran, K. E.; Barcella, S.;
Yasin, M. M.; Hurst, A. A.; Jenkins, T. C.; Kelland, L. R.; Thurston, D.
E. Bioorg. Med. Chem. Lett. 2000, 10, 1845. (b) Kamal, A.; Reddy, G. S.
K.; Reddy, K. L.; Raghavan, S. Tetrahedron Lett. 2002, 43, 2103.
(c) Clerici, F.; Erba, E.; Pocar, D. Tetrahedron 2003, 59, 1667.
(17) Perron, J.; Joseph, B.; Merour, J.-Y. Tetrahedron Lett. 2003, 44,
6553.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: sanggi@ewha.ac.kr; hisin@lgls.com.
(18) Recent papers for the synthesis of indolizidines, see:
́
(a) Barluenga, J.; Mateos, C.; Aznar, F.; Valdes, C. Org. Lett. 2002,
ACKNOWLEDGMENTS
■
4, 1971. (b) Reddy, P. G.; Varghese, B.; Baskaran, S. Org. Lett. 2003, 5,
583. (c) Molander, G. A.; Pack, S. K. J. Org. Chem. 2003, 68, 9214.
(d) Lindsay, K. B.; Pyne, S. G. J. Org. Chem. 2002, 67, 7774. (e) Randl,
S.; Blechert, S. J. Org. Chem. 2003, 68, 8879. (f) Smith, A. B. III J. Org.
Chem. 2006, 71, 2547. (g) Back, T. G.; Parvez, M.; Zhai, H. J. Org.
Chem. 2003, 68, 9389. (h) Alcaide, B.; Almendros, P.; Alonso, J. M.;
Aly, M. F. Chem.Eur. J. 2003, 9, 3415. (i) Davis, F. A.; Yang, B. Org.
Lett. 2003, 5, 5011. (j) Zhu, W.; Dong, D.; Pu, X.; Ma, D. Org. Lett.
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This research was supported by the National Research
Foundation of Korea, funded by the Ministry of Education,
Science and Technology (NRF-20110002962 and NRF-
20110016344)
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