A Schmidt route to 1-azabicyclo[x.y.0]alkanes: A comparison of carbocation stabilizing groups

Article abstract of DOI:10.1016/S0040-4020(01)00353-2

The intramolecular Schmidt reactions of tertiary alkyl, tertiary benzylic, tertiary propargylic, and tertiary allylic carbocations with tethered azides are reported. Using product analysis and deuterium labeling studies, the role of cation rearrangement p

Full text of DOI:10.1016/S0040-4020(01)00353-2

TETRAHEDRON
Pergamon
Tetrahedron 57 62001) 5081±5089
A Schmidt route to 1-azabicyclo[x.y.0]alkanes: a comparison of
carbocation stabilizing groups
²
William H. Pearsonp and Rajesh Walavalkar
Department of Chemistry, University of Michigan, 930 N. University, Ann Arbor, Michigan, MI 48109-1055, USA
Dedicated to Professor Barry M. Trost on the occasion of his 60th birthday
Received 31 January 2001; revised 6 March 2001; accepted 12 March 2001
AbstractÐThe intramolecular Schmidt reactions of tertiary alkyl, tertiary benzylic, tertiary propargylic, and tertiary allylic carbocations
with tethered azides are reported. Using product analysis and deuterium labeling studies, the role of cation rearrangement prior to Schmidt
reaction is reported. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
the tether length between the azide and the cation affect the
outcome of the cyclization? For example, a longer tether
length may slow the initial cyclization enough to allow
rearrangement or decomposition of the cation. Herein we
report studies on these factors.3 A key ®nding is that cation
rearrangment prior to cyclization may be expressed to vary-
ing degrees depending on the nature of the cation stabilizing
group R and the length of the tether between the azide and
the cation.
As part of our program on the Schmidt reaction of aliphatic
azides with carbocations,1,2 we wished to further explore the
use of this chemistry for the generation of indolizidines,
quinolizidines, and other 1-azabicyclo[x.y.0]alkanes 61).
One possible Schmidt route to such heterocycles would be
the intramolecular capture of an azide with a carbocation to
produce a fused-bicyclic aminodiazonium ion 6e.g., 4!3,
Scheme 1). Rearrangement of 3 to the iminium ion 2
followed by reaction with a nucleophile should produce
the target azabicycles 1. Several concerns arise. First, how
stabilized must the carbocation 4 be to allow this chemistry?
Second, will the carbocation rearrange prior to cyclization,
perhaps affording other Schmidt products? Third, how does
2. Results and discussion
A representative selection of carbocation precursors 6±10,
16, and 18 were synthesized as shown in Scheme 2, where
the group R was chosen to be alkyl, aryl, alkenyl, and
propargyl. Should the initially formed cation cyclize
successfully with the pendant azide, a six-membered ring
aminodiazonium ion would result in each case except for 16,
which was designed to test for the ability to form a seven-
membered ring aminodiazonium ion intermediate. The
addition of organomagnesium and organolithium reagents
to the azido ketones 53 and 17 was best accomplished with
the assistance of CeCl3.4 The addition of phenylmagnesium
bromide to the azido ketone 15 did not require the cerium
method. The azido alcohols 6, 7, 10, 16, and 18 were
obtained as single diastereomers, whereas 8 and 9 were
each accompanied by a minor diastereomer, presumably
involving addition of the organometallic from the face of
the carbonyl group syn to the azidoalkyl side chain.
Scheme 1. Target structure and Schmidt strategy.
Keywords: Schmidt reaction; carbocation; azide; aminodiazonium ion;
indolizidine; quinolizidine.
The Schmidt reactions of the carbocation precursors 6±10,
16, 18, and the alkene 19, derived from elimination of 7, are
shown in Table 1. Ionization of the alcohols to the carboca-
tions was performed with either stannic chloride or tri¯ic
acid, whereas cation formation from the alkene 19 required
p
Corresponding author. Tel.: 11-734-763-5837; fax: 11-401-712-6599;
e-mail: wpearson@umich.edu
²
Present address: Libenn Aroma, Inc., 1800 Bloomsbury Avenue, Asbury
Park, New Jersey, USA.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020601)00353-2

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W. H. Pearson, R. Walavalkar / Tetrahedron 57 02001) 5081±5089
the bridgehead nitrogen atom. When the nucleophile used is
hydride, this pathway would produce the products found in
entries 2, 3, 5, and 6 in Table 1, and possibly the hetero-
cycles 20 and 23 in entries 1 and 4, but it would not explain
the products 21, 24, and 25 found in these last two entries. A
likely reason is that rearrangement of the cation 4 to the
cation 31 occurs prior to cyclization in some cases. Cycliza-
tion of 31 to the spirocyclic aminodiazonium ion 32
followed by rearrangement pathways a, b, and c would
produce the iminium ions 33, 34, and 35, respectively,
and thus the heterocycles 36, 37, and 38 after reduction. A
comparison of 1 with 36 reveals that the group R is adjacent
to the bridgehead nitrogen atom in both cases, but the posi-
tion of the nucleophile is different, i.e., the iminium ions 2
and 33 are regioisomeric. When hydride is used to reduce
these iminium ions, the same products would be formed, but
they would be distinguishable if a different nucleophile were
to be used 6vide infra). The heterocycle 37 is consistent with
the formation of 21 and 24 in entries 1 and 4, and the
heterocycle 38 is consistent with the formation of 25 in
entry 4, clearly indicating that at least some cation
rearrangement occurred in these two entries. The hetero-
cycles 20, 22, 23, 26, and 27 formed in entries 1±6 could
be derived from either the initial cation 4 or the rearranged
cation 31, or a combination of both. For the rearranged
cation 31 to be involved in entries 2, 3, 5, and 6, a regio-
selective migration of bond a in 32 would have to be
operational, which seems unlikely based on the results of
entries 1 and 4, which appear to involve non-regioselective
rearrangement. Finally, it is unclear whether the expected
heterocycles 20 and 23 in entries 1 and 4 are the result of the
non-rearranged pathway 6via 3) or the rearranged pathway
6via migration of bond a in 32). To answer these questions,
we have examined the use of deuteride rather than hydride
in the reduction step, which should allow discrimination of
these various pathways.
Cation precursors 6, 7, and 16 were subjected to Schmidt
rearrangement and reduction with sodium borodeuteride
6Table 2). Yields were not optimized. Entry 1 produced
the deuterated indolizidines 20-d and 21-d, each with
deuterium at the bridgehead position, clearly a result of
cation rearrangement 6cf. 4!!31!!36/37 in Scheme
3). Hence, none of the expected indolizidine 20 is derived
from the non-rearranged cation 4. In contrast, entry 2 shows
that the Schmidt reaction of 7 led to 22-d, where deuterium
was found at the benzylic position only, indicating that this
indolizidine was derived solely from the non-rearranged
cation 4 6Scheme 3). Thus, the greater stability of the
benzylic cation derived from 7 allows cyclization to 3 to
compete effectively with rearrangement to 31. In entry 1,
rearrangement of the tertiary cation 4 to the alternative
tertiary cation 31 is likely to be fast and reversible, pro-
ducing roughly equal amounts of these two cations 6i.e.,
Keqˆca. 1), but the relative rate of cyclization of 31 is
expected to be faster than that of 4, since a ®ve-membered
ring is formed in the former case versus a six-membered
ring in the latter case 6i.e., k2.k1); hence products from the
rearranged cation are formed exclusively. In entry 2, there
are two likely scenarios. First, cyclization of 4 to 3 might
occur faster than 4 rearranges to 31. Second, the rearrange-
ment of 4 to 31 may be fast relative to cyclization, but 3 is
selectively formed.15 For this pathway to be operational, k1
Scheme 2. Synthesis of cation precursors.
protic acid. In all cases, the resultant iminium ions 6see 2 in
Scheme 1) were reduced with a hydride reagent 6NaBH4 or
BH3zMe2S) to afford the heterocycles shown. Successful
Schmidt reactions were observed where alkyl, aryl, and
propargyl groups were present at the site of carbocation
generation, whereas only decomposition was observed in
attempted Schmidt reactions of the alkenyl systems 9 and
10 6entry 7). The failure of the alkenyl systems may be a
result of intramolecular cycloaddition of the azides onto the
allylic cation intermediates.5 In general, the cation stabiliz-
ing group R was found adjacent to the bridgehead nitrogen
atom in the 1-azabicyclo[x.y.0]alkane products, as expected
6Scheme 1). However, the products shown in entries 1 and 4
included azabicycles that did not have this connectivity 6i.e.,
21, 24, and 25).
To rationalize the results in Table 1, a mechanistic scheme
is proposed in Scheme 3. Formation of the carbocation 4
from the precursors 29 or 30 followed by cyclization should
give the fused-bicyclic aminodiazonium ion 3, as desired.
Bond migration as shown should give the iminium ion 2 and
thus the azabicycle 1, where the R group is found adjacent to

W. H. Pearson, R. Walavalkar / Tetrahedron 57 02001) 5081±5089
5083
Table 1. Schmidt reactions
a
Isolated, puri®ed yields unless otherwise noted.
b From Ref. 3.
Improved yield over Ref. 3.
c
d From 7 by elimination 6MsCl, triethylamine) in 67% yield.
e
Yield after separation 613% of 22, 7% of 23, and 16% of 24).
Reduced to 20 6indolizidine 209D) with H2, Pd/C in 80% yield.
f
g Extensive decomposition observed under several protic and Lewis acidic conditions.
would need to be larger, or at least comparable, to k2, since
Keq is expected to be very small due to the greater stability of
4. That is, six-membered ring formation would need to be
faster or at least comparable in rate to ®ve-membered ring
formation, which is possible but not common. To uncover
any rearrangement that may be happening when RˆPh in
Scheme 3, we studied a longer azide tether, which should
slow the cyclization of 4 to 3 because it would involve the
formation of a seven-membered ring aminodiazonium ion.
Entry 3shows the results of that study. Cyclization of 16
gave four products, one derived from the non-rearranged
pathway 6i.e., 23A-d), and three derived from rearrange-
ment of the carbocation prior to Schmidt reaction 6i.e.,
23B-d, 24-d, and 25-d). Products from the rearranged cation
pathway predominate by a 69:31 ratio. Hence, adding one
methylene group to the tether 6cf. 7 vs 16) slows the rate of
Schmidt cyclization enough to allow rearrangement of the
tertiary benzylic carbocation 4 6Scheme 3, RˆPh, mˆ1,
nˆ2) to the less-stabilized cation 31. A likely scenario is
that an equilibrium between 4 and 31 is rapidly achieved,

5084
W. H. Pearson, R. Walavalkar / Tetrahedron 57 02001) 5081±5089
Scheme 3. Mechanistic rationale.
probably favoring the more stabilized cation 4 6i.e., Keq is
small), but the difference in relative rates of cyclization of
these two cations 6i.e., seven- vs six-membered amino-
diazonium ion formation; k1,k2) is suf®cient to allow a
predominance of products derived from the rearranged
cation 31. Overall, entries 1 and 3in Table 2 are likely to
embody the Curtin±Hammett principle, while entry 2
involves a kinetically-controlled cyclization of the initially
formed cation. However, it is not possible to rule out a
mechanism for entry 2 wherein rearrangement occurs, but
an unusually large rate constant k1 leads to `unrearranged'
products only.15 Entries 5 and 6 in Table 1, which involve
propargyl cations, are presumed to proceed without cation
rearrangement, by analogy to the cyclization of the benzylic
Table 2. Deuterium labeling studies
a
From Ref. 3.
23A-d and 23B-d could not be separated.
b

W. H. Pearson, R. Walavalkar / Tetrahedron 57 02001) 5081±5089
5085
alcohol 7, but again, rearrangement cannot be ruled out as a
non-productive process.
H), 1.37±2.15 6m, 16 H), 0.91 6t, Jˆ7 Hz, 3H); 13C NMR
6CDCl3, 90 MHz, JMOD) d 86.9 62), 81.36 2), 78.1 62),
51.8 62), 50.4 61), 42.1 62), 30.8 62), 29.2 62), 28.8 62),
27.6 62), 21.9 62), 20.6 62), 18.4 62), 13.5 61); IR 6neat)
3418 6br, m), 2233 6w), 2095 6s) cm21; MS 6CI, NH3) m/z
6rel. int.) 267 [6M1NH4)1, 1.3], 249 [6M1NH42H2O)1,
3.1], 222 610.9), 204 6100.0); HRMS calcd for
C14H23N3ONH4 267.2185 [6M1NH4)1], found 267.2187.
3. Conclusion
Schmidt reactions involving azido cations such as 4
6Schemes 1 and 3, mˆnˆ1 or mˆ2, nˆ1) may lead to
1-azabicyclo[5.3.0]decanes or 1-azabicyclo[4.3.0]nonanes
6indolizidines) without the formation of products derived
from cation rearrangement, as long as the initially-formed
carbocation is stabilized at the level of tertiary benzylic or
tertiary propargylic. A simple tertiary carbocation is not
stabilized enough to prevent the involvement of cation
rearrangement, producing regioisomeric indolizidines
6e.g., 20/21, entry 1, Table 1). A longer tether connecting
the azide to the carbocation site slows the Schmidt reaction
suf®ciently that cation rearrangement can occur prior to
cyclization, even if the cation is a tertiary benzylic one,
allowing a majority of product formation by a rearranged
spirocyclic aminodiazonium ion 6e.g. 32, Scheme 3), produ-
cing regioisomeric 1-azabicyclo[4.4.0]decanes 6quinolizi-
dines; e.g., 23/24, Tables 1 and 2). These studies provide
guidelines for synthetic design when 1-azabicyclo-
[x.y.0]alkanes are targeted using this Schmidt reaction
variant.
1
Data for 8E: Rfˆ0.4 615% ethyl acetate/hexane); H NMR
6CDCl3, 360 MHz) d 3.30 6t, Jˆ7 Hz, 2 H), 2.20 6t,
Jˆ6.8 Hz, 2 H), 1.41±1.97 6m, 16 H), 0.91 6t, Jˆ7 Hz, 3
H); 13C NMR 6CDCl3, 90 MHz, JMOD) d 84.2 62), 83.1
62), 75.5 62), 51.7 62), 50.9 61), 42.4 62), 30.8 62), 29.0
62), 27.7 62), 25.9 62), 21.9 62), 21.2 62), 18.36 2), 13.5
61); IR 6neat) 3542 6br, m), 2358 6w), 2095 6s) cm21; MS
6CI, NH3) m/z 6rel. int.) 267 [6M1NH4)1, 3.4], 249
[6M1NH42H2O)1, 4.6], 225 66.3), 224 66.2), 222 613.7),
204 6100.0); HRMS calcd for C14H23N3ONH4 267.2185
[6M1NH4)1], found 267.2182.
4.3. .1R*,2R*)-2-.3-Azidopropyl)-1-vinylcyclopentan-1-
ol .9Z) and .1R*,2S*)-2-.3-azidopropyl)-1-vinylcyclo-
pentan-1-ol .9E)
Vinyl magnesium bromide 67.5 mL of a 1.0 M solution in
THF, 7.5 mmol) was added to a cold 62788C) solution of
anhydrous CeCl3 6from 2.79 g of CeCl3z7H2O, 7.5 mmol)4
in THF 625 mL). After 1 h, a solution of 2-63-azidopropyl)-
6
4. Experimental
cyclopentanone 65) 60.84 g, 5.0 mmol) was added. After
2 h, the reaction was quenched with 10% aqueous acetic
acid, and the resulting mixture was extracted 3£ with
ether. The combined organic extracts were washed with
saturated aqueous NaHCO3 and brine, then dried 6K2CO3)
and concentrated. Chromatography 63±9% ethyl acetate/
hexane gradient) afforded 0.6 g 671%) of 9Z, Rfˆ0.24
610% ethyl acetate/hexane), and 86 mg 69%) of 157,
Rfˆ0.19 610% ethyl acetate/hexane). The relative con-
®guration of the major diastereomer was assigned based
4.1. .1R*,2R*)-1-Hexyl-2-.3-azidopropyl)cyclopentan-1-
ol .6) and .1R*,2R*)-1-phenyl-2-.3-azidopropyl)cyclo-
pentan-1-ol .7)
See Pearson et al.3 for the synthesis of these two azido
alcohols.
4.2. .1R*,2R*)-1-.1-Hexynyl)-2-.3-azidopropyl)cyclo-
pentan-1-ol .8Z) and .1R*,2S*)-1-.1-hexynyl)-2-.3-
azidopropyl)cyclopentan-1-ol .8E)
1
on literature precedent.3,7 Data for 9Z: H NMR 6CDCl3,
360 MHz) d 5.87 6dd, Jˆ17, 10.7 Hz, 1 H), 5.28 6dd,
Jˆ17, 1.3Hz, 1 H), 5.10 6dd, Jˆ10.7, 1.3Hz, 1 H), 3.25
6t, Jˆ6.8 Hz, 2 H), 1.75±2.0 6m, 3H), 1.40±1.75 6m, 7 H),
1.15±1.25 6m, 2 H); 13C NMR 6CDCl3, 90 MHz) d 143.8,
112.4, 82.7, 51.7, 48.7, 40.9, 29.7, 27.9, 25.2, 21.4; IR 6neat)
3478 6br, m), 2096 6s) cm21; MS 6CI, NH3) m/z 6rel. int.) 213
[6M1NH4)1, 3.2], 195 69.7), 168 68.7), 152 65.5), 151
626.2), 150 6100.0); HRMS calcd for C10H17N3ONH4
n-Butyllithium 65.0 mL of a 2.0 M solution in hexane,
10.0 mmol) was added to a cold 62308C) solution of
1-hexyne 60.82 g, 1.2 mL, 10.0 mmol) in THF 614 mL).
After 30 min, the solution was cooled to 2788C and trans-
ferred via cannula to a cold 62788C) solution of anhydrous
CeCl3 6from 3.73 g of CeCl3z7H2O, 10.0 mmol) in THF
614 mL).4 After 1 h, a solution of 2-63-azidopropyl)cyclo-
pentanone 65)3,6 60.84 g, 5.0 mmol) in THF 68.3mL) was
added. After 2 h, the reaction was quenched by adding 50%
aqueous THF. Saturated aqueous KH2PO4 was added, and
the resulting mixture was extracted 3£ with ether. The
combined organic extracts were washed with saturated
aqueous NaHCO3 and brine, then dried 6K2CO3), and
concentrated to provide 1.22 g 698%) of 8Z and 8E as a
2:1 mixture of diastereomers as determined by 13C NMR.
Based upon literature precedent,3,7 the major diastereomer
was assigned as 8Z where the hydroxy group is cis to the
3-azidopropyl group. For characterization, partial separa-
tion of diastereomers was achieved by radial chromato-
graphy 65±8% ethyl acetate/hexane gradient). Data for 8Z:
Rfˆ0.5 615% ethyl acetate/hexane); 1H NMR 6CDCl3,
360 MHz) d 3.28 6t, Jˆ7 Hz, 2 H), 2.24 6t, Jˆ6.8 Hz, 2
1
213.1715 [6M1NH4)1], found 213.1727. Data for 9E: H
NMR 6CDCl3, 360 MHz) d 5.95 6dd, Jˆ17, 10.7 Hz, 1 H),
5.25 6dd, Jˆ17, 1.3Hz, 1 H), 5.12 6dd, Jˆ10.7, 1.3Hz, 1
H), 3.22 6m, 2 H), 2.0 6m, 1 H), 1.4±1.9 6m, 9 H), 1.2±1.3
6m, 1 H), 1.0±1.1 6m, 1 H); 13C NMR 6CDCl3, 90 MHz,) d
143.8, 112.4, 82.7, 51.7, 48.7, 40.9, 29.7, 27.9, 25.2,
21.4; MS 6CI, NH3) m/z 6rel. int.) 195 [6M1NH42H2O)1,
7.5], 168 69.2), 154 62.4), 152 68.8), 151 615.0), 150
6100.0); HRMS calcd for C10H15N3NH4 195.1610
[6M1NH42H2O)1], found 195.1608.
4.4. .1R*,2R*)-2-.3-Azidopropyl)-1-.1-hexenyl)cyclo-
pentan-1-ol .10)
n-Butyllithium 62.5 mL of a 2.0 M solution in hexane,
5.0 mmol) was added to a cold 62788C) solution of

5086
W. H. Pearson, R. Walavalkar / Tetrahedron 57 02001) 5081±5089
1-iodo-1-hexene3 61.05 g, 5.0 mmol) in ether 67.5 mL).
After 30 min, the solution was transferred via cannula to a
cold 62788C) solution of anhydrous CeCl3 6from 1.86 g of
CeCl3z7H2O, 5.0 mmol)4 in THF 67 mL). After 1 h, a solu-
tion of 2-63-azidopropyl)cyclopentanone 65)3,6 60.42 g,
2.5 mmol) in THF 64.2 mL) was added. After 2 h, the reac-
tion was quenched by adding 50% aqueous THF. Saturated
aqueous KH2PO4 was added, and the resulting mixture was
extracted 3£ with ether. The combined organic extracts
were washed with saturated aqueous NaHCO3 and brine,
then dried 6K2CO3), and concentrated. Chromatography
60±6% ethyl acetate/hexane gradient) afforded 0.19 g
631%) of the title compound as a colorless oil and as a single
diastereomer whose relative con®guration was assigned
based on literature precedent.3,7 Rfˆ0.2 65% ethyl acetate/
compound as a colorless liquid, Rfˆ0.365% ethyl acetate/
hexane): 1H NMR 6CDCl3, 360 MHz) d 4.20 6q, Jˆ7 Hz, 2
H), 3.49 6dt, Jˆ6.2, 2.1 Hz, 2 H), 2.46 6m, 3H), 1.90±2.20
6m, 2 H), 1.55±1.85 6m, 6 H), 1.40±1.50 6m, 1 H), 1.25 6t,
Jˆ7 Hz, 3H); 13C NMR 6CDCl3, 90 MHz, JMOD) d 207.7
62), 171.8 62), 61.36 2), 60.36 2), 45.0 62), 41.0 62), 36.2
62), 32.2 62), 27.6 62), 27.5 62), 14.1 61); IR 6neat) 1731
6s), 1707 6s) cm21; MS 6CI, NH3) m/z 6rel. int.) 264
[6M1NH4)1, 33.4], 247 [6M1H)1, 100.0], 218 65.1), 211
613.2); HRMS calcd for C12H1935ClO3H 247.1101
[6M1H)1], found 247.1098.
4.7. 2-.4-Bromobutyl)cyclopentanone
Hydrogen bromide 61.13g, 2.4 mL of a 47±49% aqueous
solution, 14.0 mmol) was added to the ketoester 13 62.77 g,
10.0 mmol) at room temperature, and the resulting mixture
was heated at re¯ux for 4 h, and then cooled to room
temperature. Water was added, and the resulting mixture
was extracted 3£ with ethyl acetate. The combined organic
extracts were washed with 10% Na2CO3 and brine, then
dried 6MgSO4), and concentrated. Chromatography 62±
10% ethyl acetate/hexane gradient) gave 1.26 g 657%) of
the title compound as a pale yellow oil, Rfˆ0.2 610%
1
hexane): H NMR 6CDCl3, 360 MHz) d 5.68 6td, Jˆ15.1,
6.7 Hz, 1 H), 5.48 6d, Jˆ15.1 Hz, 1 H), 3.24 6t, Jˆ6.9 Hz, 2
H), 2.06 6q, Jˆ6.9 Hz, 2 H), 1.10±1.95 6m, 16 H), 0.91 6t,
Jˆ7 Hz, 3H); 13C NMR 6CDCl3, 90 MHz, JMOD) d 135.3
61), 128.7 61), 82.2 62), 51.7 62), 48.9 61), 41.1 62), 32.0
62), 31.6 62), 29.6 62), 28.0 62), 25.36 2), 22.2 62), 21.3
62), 13.9 61); MS 6CI, NH3) m/z 6rel. int.) 224
[6M2N21H)1, 8.3], 208 613.2), 207 628.0), 206 6100.0);
HRMS calcd for C14H25NOH 224.2014 [6M2N21H)1],
found 224.2003.
1
ethyl acetate/hexane): H NMR 6CDCl3, 360 MHz) d 3.35
6t, Jˆ6.9 Hz, 2 H), 2.15±2.35 6m, 2 H), 1.90±2.18 6m, 3 H),
1.65±1.85 6m, 4 H), 1.38±1.50 6m, 2 H), 1.15±1.30 6m, 1
H); 13C NMR 6CDCl3, 90 MHz) d 220.6, 48.6, 37.8, 33.3,
32.4, 29.3, 28.5, 25.8, 20.4; IR 6neat) 1732 6s) cm21; MS
6CI, NH3) m/z 6rel. int.) 185 [6M1NH4)1, 100.0], 221 61.1),
219 61.2), 136 650.2); HRMS calcd for C9H1579BrONH4
236.0650 [6M1NH4)1], found 236.0642.
4.5. 2-.4-Bromobutyl)-2-carbomethoxycyclopentanone
.13)
A solution of 2-carbomethoxycyclopentanone 60.71 g,
5.0 mmol) in THF 62.5 mL) was added to a cold 608C) solu-
tion of potassium tert-butoxide 60.62 g, 5.25 mmol) in THF
615.7 mL). The mixture was stirred for 30 min, and then 1,4-
dibromobutane 61.35 g, 0.75 mL, 6.25 mmol) was added in
a dropwise fashion. After 2 h, the mixture was warmed to
room temperature for 48 h, and water was added. The result-
ing mixture was extracted 3£ with ethyl acetate, and the
combined organic extracts were washed with water and
brine, then dried 6MgSO4), and concentrated. Chromato-
graphy 65±20% ethyl acetate/hexane gradient) afforded
0.69 g 650%) of the title compound as a colorless liquid,
Rfˆ0.7 633% ethyl acetate/hexane): 1H NMR 6CDCl3,
300 MHz) d 3.71 6s, 3 H), 3.40 6t, Jˆ6.5 Hz, 2 H), 2.30±
2.65 6m, 4 H), 1.90±2.09 6m, 4 H), 1.32±1.75 6m, 4 H); 13C
NMR 6CDCl3, 75 MHz) d 214.7, 171.3, 60.3, 52.6, 37.9,
33.8, 33.2, 32.7, 32.5, 23.4, 19.6; IR 6neat) 1770 6s), 1731
6s) cm21; MS 6CI, NH3) m/z 6rel. int.) 277 [6M1H)1, 38.9],
264 69.7), 26369.0), 197 66.6); HRMS calcd for
C11H1779BrO3H 277.0439 [6M1H)1], found 277.0415.
4.8. 2-.4-Azidobutyl)cyclopentanone .15)
Sodium azide 61.40 g, 21.5 mmol) was added to a solution
of the 2-64-bromobutyl)cyclopentanone 61.26 g, 5.4 mmol)
in DMSO 610.7 mL). After 12 h, water was added and the
resulting mixture was extracted 3£ with ethyl acetate. The
combined organic extracts were washed with brine, dried
6MgSO4), and concentrated. Chromatography 62±13% ethyl
acetate/hexane gradient) provided 0.78 g 680%) of the title
compound as a colorless oil, Rfˆ0.4 610% ethyl acetate/
1
hexane): H NMR 6CDCl3, 360 MHz) d 3.28 6t, Jˆ6.5 Hz,
2 H), 2.25±2.45 6m, 2 H), 2.10 6q, Jˆ7.7 Hz, 1 H), 1.90±2.1
6m, 2 H), 1.74±1.88 6m, 2 H), 1.45±1.65 6m, 5 H), 1.18±
1.35 6m, 1 H); 13C NMR 6CDCl3, 90 MHz, JMOD) d 208.5
62), 51.1 62), 48.9 61), 38.0 62), 29.4 62), 29.1 62), 28.7
62), 24.6 62), 20.6 62); IR 6neat) 2094 6s), 1732 6s) cm21
;
MS 6CI, NH3) m/z 6rel. int.) 182 [6M1H)1, 67.8], 154
6100.0), 152 613.0), 151 610.3); HRMS calcd for
C9H15N3OH 182.1293[6M 1H)1], found 182.1293.
4.6. 2-.3-Chloropropyl)-2-carboethoxycyclohexanone
.14)
A
solution of 2-carboethoxycyclohexanone 68.51 g,
4.9. 2-.3-Azidopropyl)cyclohexanone .17)
50.0 mmol) in THF 625 mL) was added to a cold 608C)
solution of potassium tert-butoxide 65.90 g, 50.0 mmol) in
THF 675 mL). The mixture was stirred for 30 min, and then
1-chloro-3-iodopropane 612.8 g, 62.5 mmol) was added in a
dropwise fashion. After 48 h, water was added and the
mixture was extracted 3£ with ethyl acetate. The combined
organic extracts were washed with water and brine, then
dried 6MgSO4) and concentrated. Chromatography 62%
ethyl acetate/hexane) afforded 8.56 g 669%) of the title
Hydrogen bromide 62.28 g, 4.8 mL of a 47±49% aqueous
solution, 28.2 mmol) was added to the ketoester 14 64.96 g,
20.1 mmol) at room temperature and the resulting mixture
was heated at re¯ux for 2.5 h and then cooled to room
temperature. Water was added, and the resulting mixture
was extracted 3£ with ethyl acetate. The combined organic
extracts were washed with 10% Na2CO3 and brine 620 mL),
then dried 6MgSO4), and concentrated. The residue was

W. H. Pearson, R. Walavalkar / Tetrahedron 57 02001) 5081±5089
5087
taken up in DMSO 615 mL), and sodium azide 61.71 g,
26.3mmol) was added. After stirring overnight at 40 8C,
water was added and the mixture was extracted 3£ with
ethyl acetate. The combined organic extracts were washed
with brine 640 mL), dried 6MgSO4), and concentrated. Chro-
matography 62±5% ethyl acetate/hexane gradient) gave
0.98 g 627%) of the title compound as a pale yellow liquid,
Rfˆ0.3610% ethyl acetate/hexane): 1H NMR 6CDCl3,
360 MHz) d 3.25 6dt, Jˆ6.2, 3.7 Hz, 2 H), 2.25±2.45 6m,
3H), 2.0±2.2 6m, 2 H), 1.75±1.95 6m, 2 H), 1.50±1.75 6m, 4
H), 1.40 6m, 1 H), 1.20±1.35 6m, 1 H); 13C NMR 6CDCl3,
90 MHz, JMOD) d 212.6 62), 51.5 62), 50.2 61), 42.0 62),
34.1 62), 27.9 62), 26.7 62), 26.5 62), 24.9 62); IR 6neat)
2095 6s), 1714 6s) cm21; MS 6CI, NH3) m/z 6rel. int.) 199
[6M1NH4)1, 21.5], 155 614.7), 154 6100.0); HRMS calcd
for C9H15N3ONH4 199.1559 [6M1NH4)1], found 199.1559.
literature precedent.3,7 Rfˆ0.1 610% ethyl acetate/hexane);
1H NMR 6CDCl3, 360 MHz) d 3.27 6app q, Jˆ6.5 Hz, 2 H),
2.236t, Jˆ6.8 Hz, 2 H), 1.81±2.01 6m, 3H), 1.35±1.80 6m,
10 H), 1.10±1.35 6m, 5 H), 0.9 6t, Jˆ7 Hz, 3H); 13C NMR
6CDCl3, 75 MHz) d 86.9, 81.2, 72.8, 51.9, 47.7, 41.9, 31.0,
29.5, 27.9, 27.1, 25.6, 24.2, 22.0, 18.4, 13.6; IR 6neat) 3426
6br, m), 2095 6s) cm21; MS 6CI, NH3) m/z 6rel. int.) 281
[6M1NH4)1, 1.5], 263 65.1), 236 63.9), 220 66.8), 219
624.4), 218 6100.0); HRMS calcd for C15H25N3ONH4
281.2341 [6M1NH4)1], found 281.2332.
4.12. 5-.3-Azidopropyl)-1-phenylcyclopent-1-ene .19)
A solution of azido alcohol 73 61.00 g, 4.1 mmol) in
dichloromethane 612 mL) was cooled to 2508C, and
triethylamine 60.83g, 1.1 mL, 8.2 mmol) and methanesul-
fonyl chloride 60.70 g, 0.47 mL, 6.1 mmol) were added
sequentially. After 15 min, the mixture was warmed to
08C for 2.5 h, and then water 66 mL) was added. The result-
ing mixture was extracted 3£ with dichloromethane and the
combined organic extracts were washed with brine, dried
6MgSO4), and concentrated. Chromatography 60±2% ethyl
acetate/hexane gradient) gave 0.62 g 667%) of the title
compound as a colorless liquid, Rfˆ0.8 65% ethyl acetate/
hexane): 1H NMR 6CDCl3, 360 MHz) d 7.30±7.41 6m, 4 H),
7.22±7.26 6m, 1 H), 6.08 6dd, Jˆ4.8, 2.1 Hz, 1 H), 3.21 6m,
2 H), 2.50 6m, 2 H), 2.20 6m, 1 H), 1.75 6m, 1 H), 1.55±1.69
6m, 4 H), 1.36m, 1 H); 13C NMR 6CDCl3, 90 MHz, JMOD)
d 146.1 62), 136.3 62), 128.4 61), 126.9 61), 126.8 61),
126.1 61), 51.6 62), 44.5 61), 31.5 62), 30.5 62), 29.5 62),
26.7 62); IR 6neat) 2094 6s) cm21; MS 6CI, NH3) m/z 6rel.
int.) 245 [6M1NH4)1, 6.2], 228 [6M1H)1, 1.1], 200
6100.0); HRMS calcd for C14H17N3H 228.1501 [6M1H)1],
found 228.1496.
4.10. .1R*,2S*)-1-Phenyl-2-.4-azidobutyl)cyclopentan-1-
ol .16)
Phenylmagnesium bromide 65.0 mL, 3.0 M in THF,
15.0 mmol) was added to a solution of the azido ketone
15 61.81 g, 10.0 mmol) in THF 650 mL) at 2788C. After
20 min, the solution was warmed to 08C for 30 min, and
then to room temperature for 2 h. The reaction was
quenched with saturated aqueous NH4Cl and extracted 3£
with ethyl acetate. The combined organic layers were
washed with brine, dried 6MgSO4), and concentrated. Chro-
matography 61±5% ethyl acetate/hexane gradient) afforded
1.77 g 669%) of the title compound as a single diastereomer
whose relative con®guration was assigned as depicted based
on literature precedent.3,7 Rfˆ0.3610% ethyl acetate/
1
hexane): H NMR 6CDCl3, 360 MHz) d 7.46 6d, Jˆ7 Hz,
2 H), 7.45 6t, Jˆ7 Hz, 2 H), 7.35 6d, Jˆ7 Hz, 1 H), 3.16 6t,
Jˆ6.4 Hz, 2 H), 2.0±2.2 6m, 3H), 1.7±2.0 6m, 3H), 1.16±
1.70 6m, 6 H); 13C NMR 6CDCl3, 90 MHz, JMOD) d 145.9
62), 128.1 61), 126.5 61), 124.9 61), 84.0 62), 51.36 2),
51.0 61), 43.7 62), 29.7 62), 29.0 62), 27.5 62), 25.7 62),
21.7 62); IR 6neat) 3478 6br, m), 2096 6s) cm21; MS 6CI,
NH3) m/z 6rel. int.) 277 [6M1NH4)1, 6.5], 259
[6M1NH42H2O)1, 4.8], 242 65.4), 232 615.7), 216 612.0),
215 685.1), 214 6100.0); HRMS calcd for C15H21N3ONH4
277.2028 [6M1NH4)1], found 277.2019.
4.13. .5R*,8aR*)-5-Hexylindolizidine .indolizidine 209D,
20) and .8R*,8aR*)-8-hexylindolizidine .21)
See Pearson et al.3 for the synthesis of these two indolizi-
dines.
4.14. .5R*,8aS*)-5-Phenylindolizidine .22)3
4.11. .1R*,2R*)-1-.1-Hexynyl)-2-.3-azidopropyl)cyclo-
hexan-1-ol .18)
From alkene 19: Tri¯uoromethanesulfonic acid 60.23g,
0.13mL, 1.5 mmol) was added to a cool 615 8C) solution
of alkene 19 60.23g, 1.0 mmol) in benzene 610.0 mL).
After 5 min, the mixture was cooled to 08C, and a cold
608C) solution of sodium borohydride 60.23g, 6.0 mmol)
in 3mL of dry methanol was carefully added. After
10 min, the solution was warmed to room temperature for
24 h, then cooled to 08C, and 15% NaOH was added. The
resulting mixture was extracted 3£ with ethyl acetate and
the combined organic phases were washed with brine, then
dried 6K2CO3) and concentrated. Chromatography 62±25%
ethyl acetate/hexane gradient, basic alumina activity I)
afforded 0.16 g 657%) of the title compound. All spectral
data matched the literature values.3 From azido alcohol 7
0improved procedure): Repetition of the literature pro-
cedure3 using SnCl4 rather than tri¯uoromethanesulfonic
acid resulted in an improved isolated yield of 63% of the
title compound.
n-Butyllithium 65.0 mL of a 2.0 M solution in hexane,
10.0 mmol) was added to a cold 62308C) solution of
1-hexyne 60.82 g, 1.2 mL, 10.0 mmol) in THF 614 mL).
After 30 min, the solution was cooled to 2788C and trans-
ferred via cannula to a cold 62788C) solution of anhydrous
CeCl3 6from 3.73 g of CeCl3z7H2O, 10.0 mmol)4 in THF
614 mL). After 1 h, a solution of azido ketone 17 60.91 g,
5.0 mmol) in THF 68.3mL) was added. After 2 h, the reac-
tion was quenched by adding 50% aqueous THF. Saturated
aqueous KH2PO4 was added, and the resulting mixture was
extracted 3£ with ether. The combined organic extracts
were washed with saturated aqueous NaHCO3 and brine,
then dried 6K2CO3) and concentrated. Chromatography
62±15% ethyl acetate/hexane gradient) afforded 1.05 g
680%) of the title compound as a single diastereomer,
whose relative con®guration was assigned based on

5088
W. H. Pearson, R. Walavalkar / Tetrahedron 57 02001) 5081±5089
4.15. .4R*,9aR*)-4-Phenylquinolizidine .23), .1R*,9aS*)-
1-phenylquinolizidine .24), and .1R*,2R*)-2-phenyl-1-
.1-pyrrolidino)cyclopentane .25)
mixture was extracted 3£ with dichloromethane and the
combined organic extracts were washed with brine, dried
6K2CO3), and concentrated. Chromatography 62±10% ethyl
acetate/hexane gradient) provided 0.12 g 660%) of the title
compound as a colorless oil and as a single diastereomer,
Rfˆ0.3610% ethyl acetate/hexane); 1H NMR 6CDCl3,
300 MHz) d 3.44 6t, Jˆ8.6 Hz, 1 H), 2.736bd, Jˆ10.7 Hz,
1 H), 2.16 6m, 2 H), 2.05 6m, 1 H), 1.25±1.89 6m, 15 H),
0.89 6t, Jˆ7 Hz, 3H); 13C NMR 6CDCl3, 90 MHz) d 82.9,
80.6, 64.1, 54.9, 53.2, 33.3, 31.3, 30.9, 29.7, 24.3, 22.7,
20.1, 18.4, 14.8; IR 6neat) 2933 6s), 2930 6s), 2857 6s),
2782 6m), 2361 6w), 1456 6m), 1378 6m), 1362 6m), 1304
6m) cm21; MS 6EI, 70 eV) m/z 6rel. int.) 206 [6M1H)1,
20.1], 205 6M1, 69.2), 204 679.5), 176 670.2), 163674.5),
162 6100.0), 154 684.2), 124 644.3), 120 659.8), 41 657.3);
HRMS calcd for C14H23NH 206.1909 [6M1H)1], found
206.1913. Catalytic hydrogenation 6hydrogen, Pd/C) gave
indolizidine 209D 620)3 in 80% yield.
Tri¯uoromethanesulfonic acid 60.29 g, 170 mL, 2.0 mmol)
was added to a cool 6158C) solution of alcohol 16 60.25 g,
1.0 mmol) in benzene 610 mL). After 5 min, the solution
was cooled to 08C, and treated with borane±dimethyl sul®de
complex 63.0 mL of a 2.0 M solution in THF, 6.0 mmol).
After 5 min at 08C and 14 h at room temperature, the
mixture was cooled to 08C and water was added. After
1 h, the mixture was diluted with 15% NaOH and extracted
3£ with ethyl acetate. The combined organic extracts were
washed with brine, dried 6K2CO3), and concentrated. Chro-
matography on deactivated silica gel9 60±10% ethyl acetate/
hexane gradient) gave 28 mg 613%) of 23 whose spectral
properties matched those reported in the literature,10 Rfˆ0.7
65% ethyl acetate/hexane, deactivated silica plate), 15 mg
67%) of 24, Rfˆ0.365% ethyl acetate/hexane, deactivated
silica plate), and 33 mg 616%) of 25, Rfˆ0.1 65% ethyl
acetate/hexane, deactivated silica plate). The relative
con®guration of 24 was assigned by analogy to C68)-
substituted indolizidines 6cf. 21).3 The relative con®guration
of 25 was assigned by comparison to reduction products
of analogous iminium ions.11,12 Data for 23: 1H NMR
6CDCl3, 360 MHz) d 7.20±7.30 6m, 5 H), 2.89 6dd, Jˆ11,
3Hz, 1 H), 2.62 6d, Jˆ11 Hz, 1 H), 1.91 6t, Jˆ9.7 Hz, 1 H),
1.46±1.85 6m, 7 H), 1.25±1.45 6m, 6 H); 13C NMR 6CDCl3,
90 MHz, JMOD) d 145.6 62), 128.2 61), 127.5 61), 126.6
61), 70.5 61), 63.4 61), 53.7 62), 36.6 62), 33.9 62), 33.8
62), 26.2 62), 24.9 62), 24.8 62); IR 6neat) 2785 6s), 2750
6m) cm21; MS 6EI, 70 eV) m/z 6rel. int.) 215 6M1, 34.8), 214
637.9), 172 628.0), 138 6100.0); HRMS calcd for C15H21N
4.17. .2R*,7S*)-2-.1-Hexynyl)-1-azabicyclo[5.3.0]-
decane .27)
Stannic chloride 60.8 mL of a 1.0 M solution in dichloro-
methane, 0.8 mmol) was added to a cold 62788C) solution
of 18 60.14 g, 0.5 mmol) in dichloromethane 622 mL). After
10 min, a cold 608C) solution of sodium borohydride
60.12 g, 3.2 mmol) in methanol 63 mL) was added. After
5 min, the reaction mixture was warmed to 08C for
30 min, and then to room temperature for 20 h. It was
then cooled to 08C, and quenched with saturated aqueous
NaHCO3. The resulting mixture was extracted 3£ with
dichloromethane, and the combined organic extracts were
washed with brine, then dried 6K2CO3) and concentrated.
Chromatography 63±15% ethyl acetate/hexane gradient)
provided 53mg 644%) of the title compound as a colorless
oil, as a single diasteromer. The relative con®guration was
assigned based on the stereoelectronic model proposed for
reduction of analogous iminium ions.10,13,14 Rfˆ0.3615%
1
215.1674, found 215.1665. Data for 24: H NMR 6CDCl3,
300 MHz) d 7.10±7.40 6m, 5 H), 3.22 6dt, Jˆ7.9, 3.7 Hz, 1
H), 2.64 6q, Jˆ7.9 Hz, 1 H), 2.35 6m, 4 H), 2.15 6m, 1 H),
1.4±2.0 6m, 9 H); 13C NMR 6CDCl3, 90 MHz, JMOD) d
145.6 62), 129.0 61), 127.7 61), 125.6 61), 71.36 1),
53.8 62), 48.8 61), 36.6 62), 33.2 62), 30.8 62), 29.7
62), 23.4 62), 22.4 62); IR 6CDCl3) 2785 6m) cm21; MS
6EI, 70 eV) m/z 6rel. int.) 215 6M1, 15.6), 115 65.2), 111
612.7), 110 6100.0); HRMS calcd for C15H21N 215.1674,
1
ethyl acetate/hexane): H NMR 6CDCl3, 300 MHz) d 3.49
6dt, Jˆ9.7, 3.2 Hz, 1 H), 3.11 6bs, 1 H), 2.58 6q, Jˆ8 Hz, 1
H), 2.49 6q, Jˆ8 Hz, 1 H), 2.18 6t, Jˆ6.4 Hz, 2 H), 1.3±2.0
6m, 6 H), 0.9 6t, Jˆ7 Hz, 3H); 13C NMR 6CDCl3, 90 MHz,
JMOD) d 82.7 62), 82.5 62), 61.9 61), 57.1 61), 56.9 62),
36.1 62), 35.1 62), 34.0 62), 30.9 62), 26.7 62), 24.1 62),
22.8 62), 22.0 62), 18.5 62), 13.6 61); IR 6neat) 2780 6m),
2244 6w) cm21; MS 6EI, 70 eV) m/z 6rel. int.) 219 6M1,
55.1), 190 651.8), 177 625.9), 176 6100.0); HRMS calcd
for C15H25N 219.1987, found 219.1982.
1
found 215.1665. Data for 25: H NMR 6CDCl3, 360 MHz)
d 7.60 6d, Jˆ6.9 Hz, 2 H), 7.27 6t, Jˆ6.9 Hz, 2 H), 7.18 6t,
Jˆ6.9 Hz, 1 H), 2.8±3.0 6m, 2 H), 2.2±2.3 6bs, 1 H), 2.1 6m,
2 H), 1.05±1.95 6m, 11 H); 13C NMR 6CDCl3, 90 MHz) d
144.4, 130.0, 127.6, 125.6, 65.0, 57.3, 45.6, 29.7, 25.08,
25.07, 21.3; IR 6neat) 2934 6s), 2756 6m), 1491 6m), 1443
6m) cm21; MS 6EI, 70 eV) m/z 6rel. int.) 215 6M1, 33.7), 214
614.9), 123 620.1), 111 657.9), 110 623.8), 104 617.3), 98
670.5), 91 619.0), 836100.0); HRMS calcd for C 15H21N
215.1674, found 215.1669.
4.18. .5R*,8aS*)-5-Phenyl-5-deuterioindolizidine .22-d)
Tri¯uoromethanesulfonic acid 61.13g, 0.67 mL, 7.5 mmol)
was added to a cool 6158C) solution of 73 60.73g, 3.0 mmol)
in benzene 630.0 mL). After 5 min, the mixture was cooled
to 08C, and a cold 608C) solution of NaBD4 60.75 g,
18.0 mmol) in methanol-d 69.0 mL) was carefully added.
After 10 min, the solution was warmed to room temperature
for 24 h, then cooled to 08C, and 15% NaOH was added. The
resulting mixture was extracted 3£ with ethyl acetate and
the combined organic phases were washed with brine, then
dried 6K2CO3), and concentrated. Chromatography 62±25%
ethyl acetate/hexane gradient, basic alumina activity I)
afforded 0.30 g 650%) of the title compound as an oil. The
4.16. .5R*,8aS*)-5-.1-Hexynyl)indolizidine .26)
Stannic chloride 61.5 mL, 1.0 M in dichloromethane,
1.5 mmol) was added to a cold 62788C) solution of 8Z
and 8E 60.25 g, 1.0 mmol, 2:1 mixture of diastereomers)
in dichloromethane 640 mL). After 10 min, a cold 608C)
solution of sodium borohydride 60.23g, 6.0 mmol) in
methanol 64 mL) was added, and the mixture was warmed
to room temperature for 20 h. It was then cooled to 08C, and
quenched with saturated aqueous NaHCO3. The resulting

W. H. Pearson, R. Walavalkar / Tetrahedron 57 02001) 5081±5089
5089
position of the deuterium label was determined by 13C NMR
spectroscopy, wherein the signal at d 69.8 for the benzylic
carbon at the C-5 position was completely absent. Data for
22-d: Rfˆ0.47 610% methanol/chloroform on silica gel); 1H
NMR 6CDCl3, 360 MHz) d 7.22±7.35 6m, 5 H), 2.74 6bs, 1
H), 1.3±2.0 6m, 12 H); 13C NMR 6CDCl3, 90 MHz, JMOD)
d 144.7 62), 128.1 61), 127.4 61), 126.8 61), 65.1 61), 52.6
62), 35.4 62), 30.8 62), 30.5 62), 25.2 62), 20.36 2); IR
6neat) 2781 6s), cm21; MS 6EI, 70 eV) m/z 6rel int) 202 6M1,
68.6), 201 659.7), 200 627.8), 125 6100.0); HRMS calcd. for
C14H18DN 202.1580, found 202.1580.
117 612.1), 112 624.0), 111 6100.0); HRMS calcd for
C15H20DN 216.1737, found 216.1742. Data for 25-d: H
1
NMR 6CDCl3, 360 MHz) d 7.58 6d, Jˆ6.9 Hz, 2 H), 7.27
6t, Jˆ6.9 Hz, 2 H), 7.18 6t, Jˆ6.9 Hz, 1 H), 2.8±3.0 6m, 2
H), 2.1±2.2 6bs, 1 H), 1.1±1.9 6m, 12 H); 13C NMR 6CDCl3,
90 MHz) d 144.4, 130.0, 127.6, 125.6, 57.3, 45.6, 29.7,
25.08, 25.07, 21.3; IR 6CDCl3) 1601 6m), 1418 6m) cm21
;
MS 6EI, 70 eV) m/z 6rel. int.) 216 6M1, 100.0), 215 636.9),
112 671.4), 111 632.5), 41 628.6); HRMS calcd for
C15H20DN 216.1737, found 216.1732.
Acknowledgements
4.19. .4S*,9aS*)-4-Phenyl-4-deuterioquinolizidine .23A-
d), .4S*,9aS*)-4-phenyl-9a-deuterioquinolizidine .23B-
d), .1R*,10S*)-1-phenyl-10-deuterioquinolizidine .24-d),
and .1R*,2R*)-2-phenyl-1-.1-pyrrolidino)-1-
deuteriocyclopentane .25-d)
We thank the National Institutes of Health 6GM-35572) for
®nancial support of this research.
References
Tri¯uoromethanesulfonic acid 60.36 g, 0.2 mL, 2.4 mmol)
was added to a cool 6158C) solution of alcohol 25 60.31 g,
1.2 mmol) in benzene 612 mL). After 5 min, the reaction
mixture was cooled to 08C, and a cold solution of NaBD4
60.30 g, 7.2 mmol) in methanol-d 63.5 mL) was added. After
10 min at 08C and 24 h at room temperature, the mixture
was cooled to 08C, and 15% NaOH was added. The resulting
mixture was extracted 3£ with ethyl acetate, and the
combined organic extracts were washed with brine, then
dried 6K2CO3), and concentrated. Chromatography on deac-
tivated silica gel9 60±10% ethyl acetate/hexane gradient)
afforded 24 mg 610%) of a 3.5:1 mixture [2H NMR:
6CDCl3 external standard, 360 MHz) d 2.89 6bs, 0.99 D),
1.90 6bs, 0.28 D)] of 23A-d and 23B-d, Rfˆ0.7 65% ethyl
acetate/hexane, deactivated silica plate), 12 mg 65%) of
24-d, Rfˆ0.365% ethyl acetate/hexane, deactivated silica
plate), and 25 mg 610%) of 25-d, Rfˆ0.1 65% ethyl acetate/
hexane, deactivated silica plate). The % deuterium incor-
poration was estimated to be 90% by comparision of the
mass spectra of 23 and 23-d. The position of the deuterium
label for the mixture of 23A-d and 23B-d was determined by
deuterium 62H) NMR. The signal at d 2.89 6bs, 1.01 D)
corresponds to the deuterium label at the benzylic carbon
and the signal at d 1.90 6bs, 0.27 D) corresponds to the
deuterium label at the bridgehead position. The position of
the deuterium label for 24-d and 25-d was assigned spectro-
scopically: In the 13C NMR spectrum of 24-d the signal at d
71.3for the bridgehead carbon was completely absent and in
the 13C NMR spectrum of 25-d the signal at d 65.0 for the
carbon next to nitrogen was completely absent. Data for
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Â
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9. Deactivated silica gel was prepared by adding 20% by weight
of hexamethyldisilazane to a suspension of ¯ash silica gel in
hexane. After wet-packing the chromatography column, the
silica gel was washed successively with ethyl acetate, 50%
ethyl acetate/hexane, and hexane.
1
23A-d and 23B-d: H NMR 6CDCl3, 360 MHz) d 7.20±
7.40 6m, 5 H), 2.89 6dd, Jˆ11, 3Hz, 0.2 H), 2.62 6d,
Jˆ11 Hz, 1 H), 1.91 6t, Jˆ9.7 Hz, 1 H), 1.46±1.85 6m, 7
H), 1.25±1.45 6m, 6 H); 13C NMR 6CDCl3, 90 MHz, JMOD)
d 145.6 62), 128.2 61), 127.5 61), 126.6 61), 70.5 61), 63.4
61), 53.7 62), 36.6 62), 33.9 62), 33.8 62), 26.2 62), 24.9
62), 24.8 62); IR 6neat) 2779 6s), 1445 6m) cm21; MS 6EI,
70 eV) m/z 6rel. int.) 216 6M1, 60.7), 215 648.3), 139
6100.0); HRMS calcd for C15H20DN 216.1737, found
10. Bohlmann, F. Chem. Ber. 1958, 91, 2157±2167.
11. Smith, M. B.; Shroff, H. N. Heterocycles 1985, 2229±2235.
12. Bohlmann, F.; Schumann, D.; Arndt, C. Tetrahedron Lett.
1965, 2705±2711.
13. Stevens, R. V. Acc. Chem. Res. 1984, 17, 289±296.
14. Polniaszek, R. P.; Belmont, S. E. J. Org. Chem. 1990, 55,
4688±4693.
1
215.1741. Data for 24-d: H NMR 6CDCl3, 300 MHz) d
7.10±7.40 6m, 5 H), 3.22 6bs, 1 H), 2.2±2.4 6m, 4 H), 2.15
15. We thank a referee for providing thoughtful comments on this
issue.
6m, 1 H), 1.4±1.9 6m, 9 H); 13C NMR 6CDCl3, 90 MHz) d
145.6, 129.0, 127.7, 125.6, 53.7, 48.7, 36.6, 33.2, 30.8, 29.7,
21
23.4, 22.4; IR 6neat) 27736m), 14936m), 1452 6m) cm
;
MS 6EI, 70 eV) m/z 6rel. int.) 216 6M1, 47.4), 215 610.4),