Intramolecular and intermolecular Schmidt reactions of alkyl azides with aldehydes

Article abstract of DOI:10.1016/j.tet.2007.05.079

Despite recent advances in the use of alkyl azides in ring expansion reactions of ketones, there has been little work done on the corresponding chemistry of aldehydes. In the present study, the Lewis acid-promoted reactions of alkyl azides with aldehydes

Full text of DOI:10.1016/j.tet.2007.05.079

Tetrahedron 63 (2007) 9007–9015
Intramolecular and intermolecular Schmidt reactions of alkyl
azides with aldehydes
*
ꢀ
Huey-Lih Lee and Jeffrey Aube
Department of Medicinal Chemistry, 1251 Wescoe Hall Drive, Room 4070 Malott Hall, University of Kansas, Lawrence,
KS 66045-7582, United States
Received 27 January 2007; revised 28 April 2007; accepted 22 May 2007
Available online 26 May 2007
Abstract—Despite recent advances in the use of alkyl azides in ring expansion reactions of ketones, there has been little work done on the
corresponding chemistry of aldehydes. In the present study, the Lewis acid-promoted reactions of alkyl azides with aldehydes were studied in
both intermolecular and intramolecular contexts. The intramolecular reactions of azidoalkyl aldehydes in which the azide and carbonyl groups
were separated by 2–5 carbons were examined. Although the examples having the shortest tether failed (3-azidopropanals), each of the other
systems gave good yields of either NH-substituted lactams (resulting from hydride migration in the initially formed azidohydrin adduct) or
formamides (alkyl migration). The product formed was dependent on the chain length of the starting azido aldehyde. The intermolecular re-
actions were less efficient, requiring TiCl4 promotion for even moderate yields, and in each case gave mixtures of products resulting from
hydride and alkyl migration.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
intramolecular reactions of one g-azido aldehyde and one
d-azido aldehyde, the latter using a variety of protic and
Lewis acid conditions.8d
The amide bond is one of the most important linkages in
chemistry. Although majority of the amide bonds are formed
by the condensation of an amine and a carboxylic acid equiv-
alent, alternative approaches to amide synthesis are of con-
tinuing interest.1 In particular, aldehydes are attractive
precursors to amides due to their ready availability and reac-
tivity. A number of ways of accomplishing this conversion
have been reported.2,3
Lewis
acid
O
O
O
R2
R1 N3
+
or
R1
N
R1
H
N
H
R2
H
R2
Scheme 1.
In the work described herein, we reinvestigated the reactions
of azides with aldehydes to determine whether this poten-
tially useful transformation could be realized using modern
Lewis acid conditions. In the intermolecular framework, we
focused both on possible Lewis acids and on the issue of al-
kyl group versus hydride migration in the Schmidt reaction
step. It has been amply established that the intramolecular
reactions of azides with ketones are much more facile than
their intermolecular counterparts.8 Accordingly, we began
the present study by examining the intramolecular reactions
of u-azido alkyl aldehydes in greater detail than previously
reported,8d again focusing on the matter of regioselectivity.
Another way of preparing amides is through rearrangement.4
In this regard, the Schmidt reaction has long been known to
provide amides from aldehydes or ketones, with nitriles as
commonly observed side products when aldehydes are
used as the carbonyl component.5 Although the Schmidt re-
action classically uses hydrazoic acid as a nitrogen source, it
is now known that alkyl azides can be used in Schmidt
chemistry as well.6,7
Our own work in this area has focused on the acid-promoted
reactions of alkyl azide with ketones.8 In contrast, only a few
examples of useful azide/aldehyde reactions to afford am-
ides have been reported (Scheme 1). In 1950s, Boyer and
co-workers showed that certain aromatic aldehydes could re-
act with azides to afford amides under the influence of
H2SO4, albeit in poor yield.9 Much later, we reported the
2. Intramolecular reactions
A series of azidoalkyl aldehydes containing a 2–5 carbon
chain connecting the two functional group were prepared
for examination under protic (TFA) and Lewis acid (TiCl4)
conditions. Electronically neutral substituents were added
Keywords: Schmidt reaction; Alkyl azide; Aldehyde.
* Corresponding author. E-mail: jaube@ku.edu
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.079

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H.-L. Lee, J. Aube / Tetrahedron 63 (2007) 9007–9015
9008
Table 1. Synthesis of azidoalkyl aldehydes
R
R
OEt
LDA, RBr
DIBAL-H
–78 °C
( )n
X
OEt
H
( )n
( )n
N3
N3
O
O
O
X = Br
NaN3
DMF
2a–f
3a–f
1a–c, X = N3
Entry
Compd
n
1 (yield, %)
Compd
R
2 (yield, %)
Compd
3 (yield, %)
1
2
3
4
5
6
1a
1a
1b
1b
1c
1c
1
1
2
2
3
3
96
96
99
99
99
99
2a
2b
2c
2d
2e
2f
Allyl
Benzyl
Allyl
Benzyl
Allyl
Benzyl
84
79
44
65
83
54
3a
3b
3c
3d
3e
3f
59
41
66
83
81
78
Table 2. Intramolecular reactions of azides with aldehydes
a to the aldehyde to facilitate product isolation and identifi-
cation. Except for the case of b-azidoalkyl aldehyde (3g),
which was prepared via the Michael addition of hydrazoic
acid to acrylaldehyde (Table 1),10 the azidoalkyl aldehydes
were synthesized from commercially available bromoalkyl
esters. Thus, the bromide was first displaced by sodium
azide, followed by a-alkylation of the ester11 and reduction
using DIBAL–H.12 As suggested by precedent,12 the azides
typically survived the conditions required for the reduction
of the ester group.
R2
R1
R2 R1
( )n
( )n
( )n
acid
H
+
H
N
N3
O
R2
R1
N
O
H
O
3a-g
4c-f
5a-b
Entry Compd
n
R1
R2
Acid
Product (yield, %)
4
5
1
2
3
4
5
6
7
8
3g
3g
3a
3a
3b
3b
3c
3c
3d
3d
3e
3e
3f
0
0
1
1
1
1
2
2
2
2
3
3
3
3
H
H
C6H13 TFA
C6H13 TiCl4
—
—
—
—
—
—
60
—
—
63
90
77
94
—
—
—
—
—
—
—
—
Treatment of the azido aldehydes 3a–g with acid can in
principle afford two kinds of products, depending on the
mechanism. First, azide adds to the aldehyde to form an
azidohydrin intermediate, which can lead to formamide
4 or lactam 5 by carbon–carbon bond migration or 1,2-
hydride shift (followed by tautomerization), respectively
(Scheme 2).
Allyl
Allyl
Benzyl
Benzyl
Allyl
Allyl
Benzyl
Benzyl
Allyl
Allyl
Benzyl
Benzyl
H
H
H
H
H
H
H
H
H
H
H
H
TFA
TiCl4
TFA
TiCl4
TFA
TiCl4 96
TFA 68
TiCl4 85
TFA 53
TiCl4 41
TFA 71
TiCl4 49
9
10
11
12
13
14
( )n
N
alkyl
migration
3f
H
R
R
O
R
In general, these results can be rationalized by strain consid-
erations (Scheme 3). The lack of b-lactam formation (entries
1 and 2) is ascribed to the nonformation of a necessary four-
membered cyclic azidohydrin intermediate from the b-azido
aldehyde. In contrast, a g-azidoalkyl aldehyde readily forms
a five-membered cyclic azidohydrin that can in principle
lead to migration of either an endocyclic bond (affording
formamide 4) or hydride (affording lactam 5). Two of the
stereoisomeric possibilities for this intermediate are shown
where X¼H (protic acid promotion) or complexed TiCl4
(two epimers at the aminol carbon are also possible but in
this case do not affect the regiochemical outcome of the
Schmidt reaction). Assuming antiperiplanar migration in
the azidohydrin (darkened bonds indicate the bond antiperi-
planar to the N+2 leaving group), either alkyl or hydride
migration is possible on stereoelectronic grounds, but it
appears in the present case that developing strain in the
four-membered azetidine product disfavors alkyl migration
and so valerolactam is exclusively formed (entries 3–6).
OH
H
( )n
formamide (4)
H
( )n
N3
N
N2
O
R
( )n
3a–g
O
N
n = 0–3
hydride
migration
H
lactam (5)
Scheme 2.
When the azido aldehydes were exposed to either protic or
Lewis acid at room temperature, gas evolution was observed
and products isolated following workup as summarized in
Table 2. A successful Schmidt reaction of b-azido aldehyde
would in principle afford a b-lactam; however, no tractable
products were detected upon protic or Lewis acid treatment
of 3g (entries 1 and 2). Increasing tether length by one car-
bon led to the exclusive formation of lactam 5a or 5b in
good yields (entries 3–6), while further increase in chain
length switched the product profile such that only form-
amides were observed (entries 7–14). In general, all of these
reactions were efficient, although higher yields were usually
observed when TiCl4 was used. In addition, the yields
obtained in this study were generally improved over the two
examples we reported previously.8d
In the larger ring sizes, ring strain is less of consideration (en-
tries 7–14). Of four possible azidohydrins, antiperiplanar
alkyl migration from either A or C affords the formamide
products that are solely observed in these series. It is not clear
if the reason for this is (1) intrinsic preference for or greater

´
H.-L. Lee, J. Aube / Tetrahedron 63 (2007) 9007–9015
9009
β
-Azidoalkyl aldehyde
Scheme 4. As above, it was expected that an acid-activated
aldehyde would react with the alkyl azide to form an azido-
hydrin intermediate that would ultimately afford either
formamide resulting from alkyl migration or simple amide
resulting from hydride migration/tautomerization.
Hex
Hex
N2
Hex
HN
N3
N
OH
O
H
O
azidohydrin does
not form
not observed
hydride
O
γ-Azidoalkyl aldehydes
migration
R2
H
alkyl
migration
N
H
R1
R
N2
R
N
N
H
OH
R1
disfavored
by strain
XO
H
O
R2
amide (6)
N3
O
R2 N3
+
N
H
H
R1
R
not observed
N2
alkyl
migration
H
O
H
hydride
H
R2
migration
O
R
N
H
R
N
N
R1
XO
O
H
N2
formamide (7)
δ-Azidoalkyl aldehydes
Scheme 4.
R
R
N
N
H
Although low yields of amides had been reported to result
from treatment of aromatic aldehydes with H2SO4,9 we
had hoped to achieve superior results using Lewis acid pro-
motion. To this end, a variety of Lewis acid conditions were
initially tried for reaction of n-hexyl azide with either hepta-
nal or phenylacetaldehyde (SnBr4, BF3$OEt2, Ti(O-i-Pr)3,
Sc(OTf)3, CF3SO3H, and 1 N HCl). Unfortunately, none of
these conditions provided useful quantities of amide. Only
two acid promoters, TFA and TiCl4, provided sufficient
yields of products so that they were further examined with
a series of reactants (Table 3). In general, the reactions pro-
ceeded best when TiCl4 was used to promote them.
H
O
not observed
H
O
H
H
R
R
N2
N
N
XO
N2
B
XO
A
N3
R
H
H
O
OX
OX
R
R
N2
N
N
H
H
N2
Benzyl azide gave the lowest yields among those examined
in these reactions (entries 1–6). This was not surprising as
D
C
cannot react
Table 3. Intermolecular reactions of alkyl azides with aldehydes
R
R1
N
H
H
X = H or [TiCl4]–
R2
H
acid
17-19 h
R2
N
R1
H
+
+
N3
R1
H
N
O
R2
7a-i
O
O
O
Scheme 3.
6a-i
Entry R1
R2
Acid Compds
6 and 7
Yield, %a
+
reactivity of A or C (equatorial N2 ) versus B or D (axial
N2 ), (2) greater migratory aptitude of an alkyl group over
6
7
+
1
2
3
4
5
6
Ph
Ph
Ph
Ph
Ph
Ph
PhCH2
PhCH2
n-Hex
n-Hex
Ph(CH3)CH TFA
Ph(CH3)CH TiCl4
PhCH2
PhCH2
n-Hex
n-Hex
Ph(CH3)CH TFA
Ph(CH3)CH TiCl4
TFA
a
a
b
b
c
c
d
d
e
e
f
Trace Trace
21 10
Trace Trace
16 10
a hydride, or (3) preferred formation of C or D (axial OX,
conceivably preferred due to the anomeric effect in C) over
A or B (equatorial OX) coupled with the lack of a mechanism
for hydride migration from D (oxaziridines or products there-
from have never been observed in the azido-Schmidt reac-
tion8). Although not shown, similar considerations apply
for the 3-azido aldehyde series. The relatively modest yields
in this series suggest that either cyclization or orbital
alignment for the migration step is less ideal for the seven-
membered azidohydrin intermediate. In none of the cases ex-
amined were products of intermolecular reactions identified.
TiCl4
TFA
TiCl4
Trace Trace
33b
16
22
9
11b
16
19
9
7
8
9
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
CH3(CH2)3CH2 PhCH2
CH3(CH2)3CH2 PhCH2
CH3(CH2)3CH2 n-Hex
CH3(CH2)3CH2 n-Hex
TFA
TiCl4
TFA
TiCl4
10
11
12
13
14
15
16
17
18
45
13
20
19
29
28
37
23
35
39
5
f
30
13
26
12
26
8
TFA
g
g
h
h
i
TiCl4
TFA
TiCl4
CH3(CH2)3CH2 Ph(CH3)CH TFA
CH3(CH2)3CH2 Ph(CH3)CH TiCl4
3. Intermolecular reactions
i
27
a
We sought to expand the reaction to its intermolecular vari-
ant using different aldehydes and alkyl azides as depicted in
Isolated products, unless otherwise noted.
Inseparable mixture. Yields estimated from 1H NMR.
b

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H.-L. Lee, J. Aube / Tetrahedron 63 (2007) 9007–9015
9010
benzylic azides are known to decompose under acidic condi-
tions.13 In contrast, use of azidoethylbenzene or azidohex-
ane afforded increased yields. Although the combined
yields of products were in some cases reasonable (i.e., en-
tries 10, 12, 14, 16, and 18), selectivities of products result-
ing from hydride and alkyl migration were low throughout.
This suggests that the intrinsic migratory preference for
alkyl and hydride is comparable in this system, which in
turn suggests that the considerably better selectivities noted
for the intramolecular examples in Table 2 could well arise
from the stereoelectronic effects imposed in those reactions.
The temperature was decreased to ꢀ78 ꢁC and the azido es-
ter 1 (1.00 equiv) was added. After 30 min of stirring, allyl
bromide (1.10 equiv) was added into the reaction mixture.
Then, the temperature was allowed to slowly increase to
room temperature over 3.5 h before the reaction mixture
was diluted with Et2O (50 mL) and water (20 mL). The or-
ganic layer was separated and the aqueous layer was ex-
tracted with Et2O (3ꢂ10 mL). The combined organic
layers were washed with brine (1ꢂ30 mL), dried (NaSO4),
and concentrated to give the crude product, which was puri-
fied by flash chromatography to afford the azido ester 2.
5.2.1. Ethyl 2-(20-azidoethyl)pent-4-enoate (2a). Com-
pound 2a (1.25 g, 84%) was isolated after chromatography
(5% EtOAc/hexanes) as a pale yellow oil. Rf¼0.50 (30%
4. Summary
1
The intramolecular reaction of azides and aldehydes, like the
version using azidoketone substrates, is a useful tool for
the synthesis of nitrogenous heterocycles. In those reactions,
the product profile was shown to entirely depend on the
length of the tether between the azide and aldehyde. Al-
though in some cases the intermolecular reaction of azides
and aldehydes proceeds with useful efficiency, especially
in the presence of TiCl4, the lack of regiochemical control
in the migration step is a drawback.
EtOAc/hexanes). H NMR (400 MHz, CDCl3) d 5.73 (m,
1H), 5.07 (m, 2H), 4.16 (q, J¼7.2 Hz, 2H), 3.32 (m, 2H),
2.56 (m, 1H), 2.63 (m, 1H), 2.41 (m, 1H), 1.93 (m, 1H),
1.75 (m, 1H), 1.27 (t, J¼3.9 Hz, 3H); 13C NMR
(100.6 MHz, CDCl3) d 174.6, 134.7, 117.4, 60.6, 49.4,
42.3, 36.4, 30.5, 14.3; IR (NaCl) 3000, 2100, 1740; MS
(ES+) m/z 198.2 (M++H); HRMS calcd for C9H16N3O2
(M++H) 198.1242, found 198.1516.
5.2.2. Ethyl 4-azido-2-benzylbutanoate (2b). Compound
2b (1.62 g, 79%) was isolated after chromatography (10%
EtOAc/hexanes) as a pale yellow oil. Rf¼0.50 (30%
5. Experimental section
5.1. General
1
EtOAc/hexanes). H NMR (400 MHz, CDCl3) d 7.15 (m,
5H), 4.07 (q, J¼7.12 Hz, 2H), 3.30 (m, 2H), 2.95 (m, 1H),
2.75 (m, 2H), 1.94 (m, 1H), 1.75 (m, 1H), 1.55 (t,
J¼7.12 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) d 174.7,
138.5, 130.1, 128.9, 128.5, 126.6, 60.6, 49.5, 44.8, 38.5,
30.8, 14.1; IR (NaCl) 3100, 3000, 2100, 1730; MS (ES+)
m/z 248.2 (M++H); HRMS calcd for C13H18N3O2 (M++H)
248.1399, found 248.1682.
Unless otherwise stated, all reactions were performed under
an argon atmosphere in flame-dried glassware. All chroma-
tography was performed using Sorbent Technologies silica
gel (230–400 mesh) with the indicated solvent mixtures.
Infrared spectra were recorded on a Perkin–Elmer 1420
spectrometer or a Nicolet Fourier transform infrared spec-
trometer and are expressed in wavenumbers (cmꢀ1). Proton
nuclear magnetic resonance (1H NMR) and carbon nuclear
magnetic resonance (13C NMR) spectra were recorded in
deuterochloroform using a Bruker AV-400 spectrometer.
Chemical shifts are reported in parts per million (ppm) and
are referenced to the centerline of deuterochloroform (d
5.2.3. Ethyl 2-(30-azidopropyl)pent-4-enoate (2c). Com-
pound 2c (0.38 g, 44%) was isolated after chromatography
(10% EtOAc/hexanes) as a pale yellow oil. Rf¼0.50 (30%
1
EtOAc/hexanes). H NMR (400 MHz, CDCl3) d 5.75 (m,
1H), 5.06 (m, 2H), 4.16 (q, J¼7.1 Hz, 2H), 3.29 (t, J¼
6.5 Hz, 2H), 2.41 (m, 2H), 2.26 (m, 1H), 1.60 (m, 4H), 1.28
(t, J¼7.1 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) d 175.1,
135.1, 117.1, 60.4,51.2,44.8, 36.5,28.7,26.7,14.3;IR(NaCl)
2020, 1660; MS (ES+) m/z 184.1 (M+ꢀ2N+H); HRMS calcd
for C10H18NO2 (M+ꢀ2N+H) 184.1338, found 184.1337.
1
7.24 ppm H NMR, 77.0 ppm 13C NMR). Coupling con-
stants (J values) are given in hertz (Hz). Low-resolution
mass spectra were obtained using a Ribermag R10-10 quad-
rupole instrument. High-resolution mass spectra (HRMS)
were obtained using a VG Analytical ZAG double focusing
spectrometer.
5.2.4. Ethyl 5-azido-2-benzylpentanoate (2d). Compound
2d (0.69 g, 65%) was isolated after chromatography (10%
EtOAc/hexanes) as a pale yellow oil. Rf¼0.50 (30%
Tetrahydrofuran, dichloromethane, and ether (when used as
reaction solvents) were purchased from Fisher Scientific and
purified using an Innovative Technologies solvent purifica-
tion system. All other reagents were commercially available
and were used without further purification. The azido esters
1a–c were prepared according to a modified procedure of
Khoukhi and co-workers.11,14
1
EtOAc/hexanes). H NMR (400 MHz, CDCl3) d 7.23 (m,
5H), 4.09 (q, J¼7.1 Hz, 2H), 3.27 (t, J¼6.6 Hz, 2H), 2.97
(m, 1H), 2.76 (dd, J¼6.8, 6.7 Hz, 1H), 2.68 (m, 1H), 1.65
(m, 4H), 1.18 (t, J¼7.2 Hz, 3H); 13C NMR (100.6 MHz,
CDCl3) d 175.1, 139.0, 128.9, 128.4, 126.4, 60.4, 51.2,
47.2, 38.6, 29.0, 26.7, 14.2; IR (NaCl) 2000, 1680, 1450;
MS (ES+) m/z 262.2 (M++H); HRMS calcd for
C14H20N3O2 (M++H) 262.1555, found 262.1553.
5.2. General procedure for the synthesis of azido
esters 2a–f
5.2.5. Ethyl 2-allyl-6-azidohexanoate (2e). Compound 2e
(0.50 g, 83%) was isolated after chromatography (10%
EtOAc/hexanes) as a pale yellow oil. Rf¼0.50 (30%
Diisopropylamine (1.30 equiv) was dissolved in THF
(50 mL) at 0 ꢁC, followed by the addition of n-butyllithium
(1.10 equiv). The mixture was allowed to stir for 40 min.
1
EtOAc/hexanes). H NMR (400 MHz, CDCl3) d 5.66 (m,

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H.-L. Lee, J. Aube / Tetrahedron 63 (2007) 9007–9015
9011
1H), 4.96 (m, 2H), 4.07 (q, J¼4.9 Hz, 2H), 3.19 (t,
J¼6.8 Hz, 2H), 2.33 (m, 2H), 2.16 (m, 1H), 1.51 (m, 4H),
1.32 (m, 2H), 1.19 (t, J¼4.9 Hz, 3H); 13C NMR
(100.6 MHz, CDCl3) d 175.1, 135.3, 116.7, 60.1, 51.1,
45.0, 36.4, 31.1, 28.7, 34.4, 14.2; IR (NaCl) 2950, 2060,
1710; MS (ES+) m/z 200.2 (M+ꢀ2N+3H); HRMS calcd
for C11H22NO2 (M+ꢀ2N+3H) 200.1650, found 200.1644.
13C NMR (100.6 MHz, CDCl3) d 204.0, 134.4, 117.7,
51.3, 50.7, 33.1, 26.3, 25.3; IR (NaCl) 2880, 2010, 1660,
1600; MS (ES+) m/z 140.1 (M+ꢀ2N+H); HRMS calcd for
C8H14NO (M+ꢀ2N+H) 140.1075, found 140.1078.
5.3.4. 5-Azido-2-benzylpentanal (3d). Compound 3d
(0.54 g, 83%) was isolated as a pale yellow oil. Rf¼0.50
(30% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3)
d 9.71 (d, J¼2.2 Hz, 1H), 7.26 (m, 5H), 3.28 (t, J¼6.5 Hz,
2H), 3.04 (q, J¼7.2, 6.7 Hz, 1H), 2.76 (dd, J¼7.2, 6.7 Hz,
1H), 2.68 (m, 1H), 1.65 (m, 4H); 13C NMR (100.6 MHz,
CDCl3) d 203.9, 138.3, 128.9, 128.7, 126.6, 52.9, 51.3,
35.2, 26.4, 25.5; IR (NaCl) 3000, 2010, 1700, 1650; MS
(ES+) m/z 217.1 (M+); HRMS calcd for C12H15N3O (M+)
217.1215, found 217.1056.
5.2.6. Ethyl 6-azido-2-benzylhexanoate (2f). Compound 2f
(0.80 g, 54%) was isolated after chromatography (20%
EtOAc/hexanes) as a pale yellow oil. Rf¼0.60 (50%
1
EtOAc/hexanes). H NMR (400 MHz, CDCl3) d 7.21 (m,
5H), 4.06 (q, J¼7.1 Hz, 2H), 3.17 (t, J¼6.8 Hz, 2H), 2.95
(m, 1H), 2.70 (m, 2H), 1.67 (m, 1H), 1.51 (m, 3H), 1.35
(m, 2H), 1.13 (t, J¼7.1 Hz, 3H); 13C NMR (100.6 MHz,
CDCl3) d 175.1, 139.3, 128.9, 128.3, 126.3, 60.1, 51.1,
47.4, 38.6, 31.5, 28.7, 24.5, 14.2; IR (NaCl) 2880, 2020,
1700; MS (ES+) m/z 298.2 (M++Na); HRMS calcd for
C15H21N3O2Na (M++Na) 298.1531, found 298.1532.
5.3.5. 2-Allyl-6-azidohexanal (3e). Compound 3e (97 mg,
81%) was isolated as a pale yellow oil. Rf¼0.50 (30%
1
EtOAc/hexanes). H NMR (400 MHz, CDCl3) d 9.57 (d,
J¼2.2 Hz, 1H), 5.69 (m, 1H), 5.04 (m, 2H), 3.23 (t, J¼
6.8 Hz, 2H), 2.35 (m, 2H), 2.23 (m, 1H), 1.59 (m, 3H),
1.40 (m, 3H); 13C NMR (100.6 MHz, CDCl3) d 204.3,
134.7, 117.3, 51.1, 50.9, 32.9, 29.0, 27.6, 24.0; IR (NaCl)
2850, 2040, 1680; MS (ES+) m/z 154.1 (M+ꢀ2N+H);
HRMS calcd for C9H16NO (M+ꢀ2N+H) 154.1232, found
154.1236.
5.3. General procedure for the synthesis of azido alde-
hydes 3a–f
DIBAL–H (1.08 equiv) was slowly added to a solution of the
azido ester 2 (1.00 equiv) in anhydrous Et2O (10.0 mL) at
ꢀ70 ꢁC. The reaction mixture was stirred for 1 h and
quenched with MeOH (0.50 mL) followed by the addition
of saturated aqueous potassium sodium tartrate solution
(10 mL). The reaction mixture was then passed through
a thin layer of Celite. After the separation of organic layer,
the aqueous layer was extracted with Et2O (3ꢂ5 mL).
The combined organic layers were washed with brine
(1ꢂ30 mL), dried (NaSO4), and concentrated to give the
crude product, which was purified by flash chromatography
to afford the azido ester 3.
5.3.6. 6-Azido-2-benzylhexanal (3f). Compound 3f (0.52 g,
78%) was isolated as a pale yellow oil. Rf¼0.50 (30%
1
EtOAc/hexanes). H NMR (400 MHz, CDCl3) d 9.66 (d,
J¼2.1 Hz, 1H), 7.24 (m, 5H), 3.21 (t, J¼6.7 Hz, 2H), 3.00
(dd, J¼7.0, 6.9 Hz, 1H), 2.73 (dd, J¼7.0, 6.9 Hz, 1H),
2.62 (m, 1H), 1.67 (m, 1H), 1.38 (m, 5H); 13C NMR
(100.6 MHz, CDCl3) d 204.1, 138.8, 138.2, 129.3, 129.0,
128.8, 128.6, 128.4, 127.6, 126.8, 126.5, 53.2, 51.1, 35.0,
28.8, 27.9, 24.1; IR (NaCl) 2960, 2020, 1680, 1660; MS
(ES+) m/z 204.1 (M+); HRMS calcd for C13H18NO
(M+ꢀ2N+H) 204.1388, found 204.1389.
5.3.1. 2-(20-Azidoethyl)pent-4-enal (3a). Compound 3a
(0.32 g, 41%) was isolated after chromatography (20%
EtOAc/hexanes) as a pale yellow oil. Rf¼0.40 (20%
1
EtOAc/hexanes). H NMR (400 MHz, CDCl3) d 9.68 (d,
5.3.7. 3-Azidononanal (3g). To a solution of NaN3 (1.46 g,
22.5 mmol) in aqueous acetic acid (21.6 mmol in 2.0 mL of
H2O) was added nonenal (1.20 mL, 7.23 mmol) at 0 ꢁC. Af-
ter 1 h of consistent stirring, the reaction mixture was diluted
with Et2O (20 mL) before washing with NaHCO3 (3ꢂ5 mL)
and brine (10 mL). The organic layer was dried (NaSO4) and
concentrated to give the crude product, which was purified
by flash chromatography (2% EtOAc/hexanes) to afford 3g
(1.14 g, 87%). Rf¼0.30 (10% EtOAc/hexanes) as a pale yel-
J¼1.5 Hz, 1H), 5.74 (m, 1H), 5.13 (m, 2H), 3.35 (m, 2H),
2.50 (m, 2H), 2.28 (m, 1H), 1.97 (m, 1H), 1.71 (m, 1H);
13C NMR (100.6 MHz, CDCl3) d 203.1, 134.1, 118.1,
49.1, 48.3, 32.9, 27.3; IR (NaCl) 2960, 2140, 1730; MS
(ES+) m/z 126.1 (M+ꢀ2N+H); HRMS calcd for C7H12NO
(M+ꢀ2N+H) 126.0919, found 126.0911.
5.3.2. 4-Azido-2-benzylbutanal (3b). Compound 3b
(0.73 g, 59%) was isolated after chromatography (5%
EtOAc/hexanes) as a pale yellow oil. Rf¼0.35 (20%
1
low oil. H NMR (400 MHz, CDCl3) d 9.78 (m, 1H), 3.87
(m, 1H), 2.62 (m, 2H), 1.41 (m, 10H), 0.88 (m, 3H); 13C
NMR (100.6 MHz, CDCl3) d 199.9, 57.4, 48.6, 34.9, 32.0,
29.3, 26.2, 22.9, 14.4; IR (NaCl) 2115, 1731; MS (FAB+)
m/z 184 (M++H).
1
EtOAc/hexanes). H NMR (400 MHz, CDCl3) d 9.73 (d,
J¼1.5 Hz, 1H), 7.27 (m, 5H), 3.32 (m, 2H), 3.06 (dd,
J¼5.5, 7.0 Hz, 1H), 2.77 (m, 2H), 1.96 (m, 1H), 1.70 (m,
1H); 13C NMR (100.6 MHz, CDCl3) d 203.1, 137.9, 128.9,
128.8, 126.8, 50.5, 49.1, 35.1, 27.6; IR (NaCl) 2960, 2120,
1740; MS (ES+) m/z 178.1 (M+ꢀ2N+3H); HRMS calcd
for C11H16NO (M+ꢀ2N+3H) 178.1232, found 178.1227.
5.3.3. 2-(30-Azidopropyl)pent-4-enal (3c). Compound 3c
(0.25 g, 66%) was isolated as a pale yellow oil. Rf¼0.60
(30% EtOAc/hexanes). 1H NMR (400 MHz, CDCl3)
d 9.66 (s, 1H), 5.76 (m, 1H), 5.13 (m, 2H), 3.33 (t,
J¼6.0 Hz, 2H), 2.47 (m, 2H), 2.29 (m, 1H), 1.68 (m, 4H);
5.4. General procedures for intramolecular Schmidt
reactions using TiCl4 and TFA
TiCl4 procedure: The azido aldehyde (1.0 equiv) was acti-
vated by TiCl4 (1.3 equiv) in CH2Cl2 (2.0 mL) at room tem-
perature. After 17–19 h of stirring, the mixturewas quenched
with saturated NaHCO3 and diluted with CH2Cl2. The layers
were separated and the aqueous layer was extracted with
CH2Cl2 (3ꢂ5 mL). The combined organic layers were

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H.-L. Lee, J. Aube / Tetrahedron 63 (2007) 9007–9015
9012
washed with brine, dried (NaSO4), and concentrated to give
crude product, which was purified by chromatography.
5.4.5. 2-Allylpiperidine-1-carbaldehyde (4e). Compound
4e (35 mg, 41% with TiCl4 and 45 mg, 53% with TFA)
was isolated as rotamers in a 1:1 ratio after chromatography
(40% EtOAc/hexanes) as a pale yellow oil. Rf¼0.15 (50%
EtOAc/hexanes). IR (NaCl) 3000, 2860, 1620; MS (ES+)
m/z 154.1 (M++H); HRMS calcd for C9H16NO (M++H)
154.1232, found 154.1230. Rotamer 1: 1H NMR (400 MHz,
CDCl3) d 8.00 (s, 1H), 5.66 (m, 1H), 5.05 (m, 2H), 4.21
(dd, J¼3.4, 9.6 Hz, 1H), 3.60 (m, 1H), 2.70 (t, J¼3.0,
10.4 Hz, 1H), 2.52 (m, 1H), 2.27 (m, 1H), 1.69 (m, 5H),
1.39 (m, 1H); 13C NMR (100.6 MHz, CDCl3) d 161.3, 134.9,
TFA procedure: The azido aldehyde was dissolved in TFA
(1.0 mL) at room temperature and quenched after 17–19 h of
stirring. Workup as described above afforded crude product,
which was purified by chromatography.
5.4.1. 3-Allylpyrrolidin-2-one (5a). Compound 5a (81 mg,
90% with TiCl4 and 57 mg, 63% with TFA) was afforded
after chromatography (75% EtOAc/hexanes) as a pale yellow
1
1
oil. Rf¼0.20 (100% EtOAc). H NMR (400 MHz, CDCl3)
118.2, 54.5, 42.5, 34.9, 29.4, 26.3, 19.9. Rotamer 2: H
d 7.33 (s, 1H), 5.75 (m, 1H), 5.07 (m, 2H), 3.31 (m, 2H),
2.55 (m, 1H), 2.46 (m, 1H), 2.20 (m, 2H), 1.81 (m, 1H);
13C NMR (100.6 MHz, CDCl3) d 180.3, 135.6, 116.8,
40.6, 40.5, 35.0, 26.6; IR (NaCl) 3000, 1710, 1660; MS
(ES+) m/z 126.1 (M++H); HRMS calcd for C7H12NO
(M++H) 126.0919, found 126.0917.
NMR (400 MHz, CDCl3) d 8.00 (s, 1H), 5.66 (m, 1H),
5.05 (m, 2H), 4.60 (q, J¼6.4 Hz, 1H), 3.36 (dd, J¼4.2,
9.2 Hz, 1H), 3.14 (t, J¼2.8, 10.5 Hz, 1H), 2.41 (m, 1H), 2.27
(m, 1H), 1.69 (m, 5H), 1.39 (m, 1H); 13C NMR (100.6 MHz,
CDCl3) d 161.2, 134.1, 117.1, 46.8, 36.3, 34.1, 27.1, 25.0, 19.5.
5.4.6. 2-Benzylpiperidine-1-carbaldehyde (4f). Com-
pound 4f (43 mg, 49% with TiCl4 and 62 mg, 71% with
TFA) was isolated as rotamers in a 3:2 ratio after chromato-
graphy (40% EtOAc/hexanes) as a pale yellow oil. Rf¼0.20
(50% EtOAc/hexanes). IR (NaCl) 2880, 1620; MS (ES+) m/z
226.1 (M++Na); HRMS calcd for C13H17NONa (M++Na)
226.1208, found 226.1204. Major rotamer: 1H NMR
(400 MHz, CDCl3) d 7.64 (s, 1H), 7.23 (m, 5H), 4.29 (dd,
J¼4.3, 9.2 Hz, 1H), 3.76 (m, 1H), 3.07 (q, J¼4.3 Hz, 1H),
2.85 (m, 2H), 1.69 (m, 6H); 13C NMR (100.6 MHz,
CDCl3) d 161.2, 138.2, 138.0, 129.2, 129.0, 128.8, 126.8,
5.4.2. 3-Benzylpyrrolidin-2-one (5b). Compound 5b
(89 mg, 94% with TiCl4 and 100 mg, 77% with TFA) was
afforded after chromatography (70% EtOAc/hexanes) as
a pale yellow oil. Rf¼0.20 (100% EtOAc). 1H NMR
(400 MHz, CDCl3) d 7.47 (s, 1H), 7.30 (m, 5H), 3.23 (m,
3H), 2.65 (m, 2H), 2.09 (m, 1H), 1.80 (m, 1H); 13C NMR
(100.6 MHz, CDCl3) d 180.2, 139.6, 129.0, 128.8, 128.5,
126.3, 43.0, 40.5, 36.7, 21.1; IR (NaCl) 3240, 3020, 1660;
MS (ES+) m/z 176.1 (M++H); HRMS calcd for C11H14NO
(M++H) 176.1075, found 176.1071.
1
56.6, 42.7, 37.0, 29.5, 26.4, 20.0. Minor rotamer: H NMR
5.4.3. 2-Allylpyrrolidine-1-carbaldehyde (4c). Compound
4c (80 mg, 96% with TiCl4 and 50 mg, 60% with TFA) was
isolated as a mixture of rotamers in a 6:4 ratio after chroma-
tography (50% EtOAc/hexanes) as a pale yellow oil.
Rf¼0.10 (50% EtOAc/hexanes). IR (NaCl) 2900, 1620;
MS (ES+) m/z 140.1 (M++H); HRMS calcd for C8H14NO
(M++H) 140.1075, found 140.1070. Major rotamer: 1H
NMR (400 MHz, CDCl3) d 8.26 (s, 1H), 5.76 (m, 1H),
5.09 (m, 2H), 3.55 (m, 1H), 3.84 (m, 1H), 3.39 (m, 1H),
2.28 (m, 2H), 1.90 (m, 3H), 1.77 (m, 1H); 13C NMR
(100.6 MHz, CDCl3) d 161.1, 134.3, 118.7, 57.1, 46.7,
40.5, 30.2, 23.7. Minor rotamer: 1H NMR (400 MHz,
CDCl3) d 8.26 (s, 1H), 5.76 (m, 1H), 5.09 (m, 2H), 3.84
(m, 1H), 3.55 (m, 1H), 3.39 (m, 1H), 2.28 (m, 2H), 1.90
(m, 3H), 1.77 (m, 1H); 13C NMR (100.6 MHz, CDCl3)
d 161.0, 133.6, 117.6, 54.7, 43.5, 37.5, 29.5, 22.4.
(400 MHz, CDCl3) d 7.98 (s, 1H), 7.23 (m, 5H), 4.81 (q,
J¼7.2 Hz, 1H), 3.43 (dd, J¼4.9, 8.4 Hz, 1H), 3.28 (t,
J¼2.7, 10.3 Hz, 1H), 2.85 (m, 2H), 1.69 (m, 6H); 13C
NMR (100.6 MHz, CDCl3) d 161.2, 138.2, 138.0, 129.2,
129.0, 128.5, 126.4, 48.6, 36.3, 35.7, 26.1, 25.1, 19.5.
5.5. General procedures for intermolecular Schmidt
reactions using TiCl4 and TFA
TiCl4 procedure: The aldehyde (1.0 equiv) was activated
by TiCl4 (1.3 equiv) in CH2Cl2 (2.0 mL) at room tempera-
ture, followed by slow addition of alkyl azide (1.1 equiv).
After 17–19 h of consistent stirring, the mixture was
quenched with saturated NaHCO3 and diluted with CH2Cl2.
The layers were separated and the aqueous layer was
extracted with CH2Cl2 (3ꢂ5 mL). The combined organic
layers were washed with brine, dried (NaSO4), and concen-
trated to give the crude product, which was purified by flash
chromatography.
5.4.4. 2-Benzylpyrrolidine-1-carbaldehyde (4d). Com-
pound 4d (74 mg, 85% with TiCl4 and 59 mg, 68% with
TFA) was isolated as rotamers in a 2:1 ratio after chromato-
graphy (50% EtOAc/hexanes) as a pale yellow oil. Rf¼0.10
(50% EtOAc/hexanes). IR (NaCl) 2950, 1650, 750, 690; MS
(ES+) m/z 190.1 (M++H); HRMS calcd for C12H16NO
(M++H) 190.1232, found 190.1227. Major rotamer: 1H
NMR (400 MHz, CDCl3) d 7.87 (s, 1H), 7.22 (m, 5H),
4.02 (m, 1H), 3.52 (m, 1H), 3.40 (m, 1H), 2.74 (m, 2H),
1.85 (m, 4H); 13C NMR (100.6 MHz, CDCl3) d 161.1,
137.5, 129.6, 129.4, 128.8, 128.4, 126.8, 56.5, 46.8, 38.7,
TFA procedure: The aldehyde was reacted with the alkyl
azide in TFA (1.0 mL) at room temperature and quenched
after 17–19 h of stirring. Workup as described above gave
crude product, which was purified by flash chromatography.
5.5.1. N-Benzyl-2-phenylacetamide (6a) and N,N-dibenz-
ylformamide (7a). Compounds 6a (40 mg, 21%) and 7a
(20 mg, 10%) were isolated after chromatography (20%
EtOAc/hexanes) as pale yellow oils. Compound 6a:
Rf¼0.35 (50% EtOAc/hexanes). 1H NMR (400 MHz,
CDCl3) d 7.30 (m, 10H), 5.90 (s, 1H), 4.43 (d, J¼5.8 Hz,
2H), 3.64 (s, 2H); 13C NMR (100.6 MHz, CDCl3) d 171.0,
138.2, 134.9, 129.5, 129.1, 128.7, 127.5, 127.4, 127.4,
1
30.3, 22.3; Minor rotamer: H NMR (400 MHz, CDCl3)
d 8.30 (s, 1H), 7.22 (m, 5H), 4.24 (m, 1H), 3.52 (m, 1H),
3.30 (m, 1H), 2.74 (m, 2H), 1.85 (m, 4H); 13C NMR
(100.6 MHz, CDCl3) d 161.1, 138.3, 129.6, 129.4, 128.8,
128.4, 126.3, 59.1, 43.4, 42.4, 29.2, 23.5.

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9013
60.4, 43.8, 43.6; IR (NaCl) 3320, 3100, 1660, 1070; MS
(ES+) m/z 226.1 (M++H); HRMS calcd for C15H16NO
(M++H) 226.1232, found 226.1245. Compound 7a:
Rf¼0.30 (50% EtOAc/hexanes). 1H NMR (400 MHz,
CDCl3) d 8.45 (s, 1H), 7.31 (m, 10H), 4.44 (s, 2H), 4.29
(s, 2H); 13C NMR (100.6 MHz, CDCl3) d 162.9, 136.0,
135.6, 129.0, 128.7, 128.5, 128.2, 127.7, 127.7, 50.3, 44.7;
IR (NaCl) 3080, 2980, 1680, 1210; MS (ES+) m/z 226.1
(M++H); HRMS calcd for C15H16NO (M++H) 226.1232,
found 226.1245.
CDCl3) d 7.23 (m, 8H), 7.01 (m, 2H), 5.37 (s, 1H), 3.52 (s,
2H), 3.44 (q, J¼6.8 Hz, 2H), 2.71 (t, J¼6.8 Hz, 2H); 13C
NMR (100.6 MHz, CDCl3) d 170.9, 138.7, 134.8, 129.5,
129.0, 128.7, 128.6, 127.3, 126.4, 43.9, 40.7, 35.5; IR
(NaCl) 3260, 3000, 1620; MS (ES+) m/z 240.1 (M++H);
HRMS calcd for C16H18NO (M++H) 240.1388, found
240.1380. Compound 7d: Rf¼0.15 (25% EtOAc/hexanes).
IR (NaCl) 3000, 1650; MS (ES+) m/z 240.1 (M++H);
HRMS calcd for C16H18NO (M++H) 240.1388, found
1
240.1377. Rotamer 1: H NMR (400 MHz, CDCl3) d 8.26
(s, 1H), 7.18 (m, 10H), 4.55 (s, 2H), 3.44 (t, J¼7.4 Hz,
2H), 2.78 (m, 2H); 13C NMR (100.6 MHz, CDCl3)
d 162.9, 138.8, 136.4, 129.9, 129.2, 128.9, 128.7, 128.3,
5.5.2. N-Benzylheptanamide (6b) and N-benzyl-N-hexyl-
formamide (7b). Compounds 6b (30 mg, 16%) and 7b
(20 mg, 10%, rotamers in a 5:6 ratio) were isolated after
chromatography (30% EtOAc/hexanes) as pale yellow oils.
1
127.7, 126.9, 126.5, 51.9, 45.5, 35.1. Rotamer 2: H NMR
(400 MHz, CDCl3) d 7.96 (s, 1H), 7.18 (m, 10H), 4.22 (s,
2H), 3.37 (t, J¼7.0 Hz, 2H), 2.78 (m, 2H); 13C NMR
(100.6 MHz, CDCl3) d 162.8, 137.8, 136.1, 129.4, 129.1,
128.8, 128.6, 128.1, 127.6, 126.9, 126.5, 48.4, 43.9, 33.5.
1
Compound 6b: Rf¼0.30 (50% EtOAc/hexanes). H NMR
(400 MHz, CDCl3) d 7.33 (m, 5H), 5.88 (s, 1H), 4.44 (d,
J¼5.7 Hz, 2H), 2.22 (t, J¼7.4 Hz, 2H), 1.66 (t, J¼7.1 Hz,
2H), 1.32 (m, 6H), 0.896 (t, J¼6.8 Hz, 3H); 13C NMR
(100.6 MHz, CDCl3) d 173.1, 138.5, 128.7, 127.8, 127.5,
43.6, 36.8, 31.5, 29.0, 25.8, 22.5, 14.0; IR (NaCl) 3320,
3100, 1700, 1200; MS (ES+) m/z 220.2 (M++H); HRMS
calcd for C14H22NO (M++H) 220.1701, found 220.1703.
Compound 7b: Rf¼0.45 (50% EtOAc/hexanes). IR (NaCl)
3000, 2960, 2900, 1680; MS (ES+) m/z 220.2 (M++H);
HRMS calcd for C14H22NO (M++H) 220.1701, found
5.5.5. N-Phenethylheptanamide (6e) and N-hexyl-N-phen-
ethylformamide (7e). Compounds 6e (77 mg, 45% with
TiCl4 and 16 mg, 9% with TFA) and 7e (68 mg, 39% with
TiCl4 and 16 mg, 9% with TFA, rotamers in a 5:4 ratio)
were isolated after chromatography (20% EtOAc/hexanes)
as pale yellow oils. Compound 6e: Rf¼0.10 (25% EtOAc/
hexanes). 1H NMR (400 MHz, CDCl3) d 7.26 (m, 5H),
5.74 (s, 1H), 3.52 (m, 2H), 2.82 (t, J¼7.0 Hz, 2H), 2.13 (t,
J¼7.4 Hz, 2H), 1.60 (m, 2H), 1.31 (m, 6H), 0.89 (t,
J¼6.4 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) d 173.3,
139.0, 128.8, 128.6, 126.5, 40.5, 36.8, 35.7, 31.6, 29.0,
25.7, 22.5, 14.2, 14.0; IR (NaCl) 3350, 2880, 1620; MS
(ES+) m/z 234.2 (M++H); HRMS calcd for C15H24NO
(M++H) 234.1858, found 234.1843. Compound 7e:
Rf¼0.20 (25% EtOAc/hexanes). IR (NaCl) 2880, 1650,
1620; MS (ES+) m/z 234.2 (M++H); HRMS calcd for
C15H24NO (M++H) 234.1858, found 234.1847. Major ro-
1
220.1694. Rotamer 1: H NMR (400 MHz, CDCl3) d 8.30
(s, 1H), 7.31 (m, 5H), 4.41 (s, 2H), 3.24 (t, J¼7.5 Hz, 2H),
1.50 (m, 2H), 1.27 (m, 6H), 0.89 (q, J¼6.7 Hz, 3H); 13C
NMR (100.6 MHz, CDCl3) d 162.9, 136.3, 128.9, 128.6,
128.2, 128.1, 127.5, 51.2, 45.2, 31.5, 28.1, 26.8, 26.1,
1
14.0. Rotamer 2: H NMR (400 MHz, CDCl3) d 8.21 (s,
1H), 7.31 (m, 5H), 4.55 (s, 2H), 3.14 (t, J¼7.1 Hz, 2H),
1.50 (m, 2H), 1.27 (m, 6H), 0.89 (q, J¼6.7 Hz, 3H); 13C
NMR (100.6 MHz, CDCl3) d 162.8, 136.3, 128.9, 128.6,
128.2, 128.1, 127.5, 46.8, 42.0, 31.3, 28.1, 26.5, 22.5, 14.0.
1
tamer: H NMR (400 MHz, CDCl3) d 8.07 (s, 1H), 7.24
5.5.3. N-Benzyl-2-phenylpropanamide (6c) and N-benz-
yl-N-(10-phenylethyl)-formamide (7c). Compounds 6c15
and 7c (86 mg, 44%) were isolated as inseparable product
in mixture a 1:3 ratio after chromatography (20% EtOAc/
hexanes) as pale yellow oils. Compound 7c: exists as an
inseparable mixture in a 1:3 ratio of rotamers. Rf¼0.15
(25% EtOAc/hexanes). IR (NaCl) 3320, 3100, 1660; MS
(ES+) m/z 240.1 (M++Na); HRMS calcd for C16H17NONa
(M++Na) 262.1208, found 262.1204. Major rotamer: 1H
NMR (400 MHz, CDCl3) d 8.54 (s, 1H), 7.15 (m, 10H), 4.40
(m, 2H), 4.07 (m, 1H), 1.54 (m, 3H); 13C NMR
(100.6 MHz, CDCl3) d 163.6, 141.4, 139.7, 138.4, 137.7,
128.9, 128.6, 128.5, 128.0, 127.8, 127.7, 127.3, 126.8,
56.7, 48.3, 20.2. Minor rotamer: 1H NMR (400 MHz,
CDCl3) d 8.31 (d, J¼10.6 Hz, 1H), 7.15 (m, 10H), 4.40 (m,
2H), 3.61 (m, 1H), 1.54 (m, 3H); 13C NMR (100.6 MHz,
CDCl3) d 162.5, 140.4, 139.7, 138.4, 137.5, 128.7, 128.6,
128.5, 128.0, 127.8, 127.7, 127.3, 126.8, 50.6, 45.3, 17.0.
(m, 5H), 3.53 (t, J¼7.6 Hz, 2H), 3.11 (t, J¼7.2 Hz, 2H),
2.86 (m, 2H), 1.50 (m, 2H), 1.33 (m, 6H), 0.91 (m, 3H);
13C NMR (100.6 MHz, CDCl3) d 162.9, 138.8, 137.8,
128.8, 128.7, 128.5, 126.8, 49.1, 44.2, 35.5, 31.5, 28.6,
26.6, 22.6, 14.0. Minor rotamer: 1H NMR (400 MHz,
CDCl3) d 7.85 (s, 1H), 7.24 (m, 5H), 3.46 (t, J¼7.2 Hz,
2H), 3.34 (t, J¼7.6 Hz, 2H), 2.86 (m, 2H), 1.50 (m, 2H),
1.33 (m, 6H), 0.91 (m, 3H); 13C NMR (100.6 MHz,
CDCl3) d 162.8, 138.8, 137.8, 128.8, 128.6, 128.5, 126.5,
48.0, 42.4, 33.7, 31.3, 27.3, 26.1, 22.5, 14.0.
5.5.6. N-Phenethyl-2-phenylpropanamide (6f) and N-
phenethyl-N-(10-phenylethyl)-formamide (7f). Com-
pounds 6f (38 mg, 20% with TiCl4 and 24 mg, 13% with
TFA) and 7f (57 mg, 30% with TiCl4 and 9 mg, 5% with
TFA, rotamers in a 2:1 ratio) were isolated as pale yellow
oil after chromatography (20% EtOAc/hexanes). Compound
1
6f: Rf¼0.15 (25% EtOAc/hexanes). H NMR (400 MHz,
CDCl3) d 7.22 (m, 8H), 6.99 (d, J¼6.3 Hz, 2H), 5.39 (s,
1H), 3.48 (m, 2H), 3.38 (m, 1H), 2.69 (t, J¼1.6, 5.1 Hz,
2H), 1.49 (d, J¼7.2 Hz, 3H); 13C NMR (100.6 MHz,
CDCl3) d 174.1, 141.3, 138.8, 128.9, 128.7, 128.5, 127.7,
127.2, 126.4, 47.1, 40.7, 35.5, 18.3; IR (NaCl) 3320, 3000,
1650, 1550; MS (ES+) m/z 254.1 (M++H); HRMS calcd
for C17H20NO (M++H) 254.1545, found 254.1533. Com-
pound 7f: Rf¼0.10 (25% EtOAc/hexanes). IR (NaCl) 3000,
5.5.4. N-Phenethyl-2-phenylacetamide (6d) and N-benz-
yl-N-phenethyl-formamide (7d). Compounds 6d (40 mg,
22% with TiCl4 and 28 mg, 16% with TFA) and 7d
(33 mg, 19% with TiCl4 and 28 mg, 16% with TFA, rotamers
in a 1:1 ratio) were isolated after chromatography (30%
EtOAc/hexanes) as pale yellow oils. Compound 6d:
Rf¼0.10 (25% EtOAc/hexanes). 1H NMR (400 MHz,

´
H.-L. Lee, J. Aube / Tetrahedron 63 (2007) 9007–9015
9014
2860, 1620; MS (ES+) m/z 254.2 (M++H); HRMS calcd for
(M++H) 234.1858, found 234.1847. Compound 7i:
Rf¼0.30 (25% EtOAc/hexanes). IR (NaCl) 3500, 2980,
1670; MS (ES+) m/z 234.2 (M++H); HRMS calcd for
C15H24NO (M++H) 234.1858, found 234.1847. Major ro-
C17H20NO (M++H) 254.1545, found 254.1537. Major ro-
tamer: H NMR (400 MHz, CDCl3) d 8.39 (s, 1H), 7.25
1
(m, 10H), 4.67 (q, J¼7.0 Hz, 1H), 3.23 (m, 2H), 2.79 (m,
1H), 2.56 (m, 1H), 1.59 (dd, J¼2.2, 5.0 Hz, 3H); 13C
NMR (100.6 MHz, CDCl3) d 163.1, 141.3, 140.1, 138.9,
128.9, 128.7, 128.5, 128.3, 128.0, 127.8, 127.2, 126.7,
126.4, 51.1, 49.8, 44.2, 34.5, 16.8. Minor rotamer: 1H
NMR (400 MHz, CDCl3) d 8.02 (s, 1H), 7.25 (m, 10H),
5.79 (q, J¼7.2 Hz, 1H), 3.36 (m, 2H), 2.69 (t, J¼1.3,
5.3 Hz, 1H), 2.42 (m, 1H), 1.49 (d, J¼7.2 Hz, 3H); 13C
NMR (100.6 MHz, CDCl3) d 162.5, 140.2, 139.1, 138.0,
128.8, 128.7, 128.5, 128.3, 128.0, 127.8, 127.2, 126.7,
126.4, 51.1, 46.0, 37.9, 19.3, 16.8.
1
tamer: H NMR (400 MHz, CDCl3) d 8.36 (s, 1H), 7.30
(m, 5H), 4.72 (q, J¼7.1 Hz, 1H), 3.10 (t, J¼2.0, 5.0 Hz,
2H), 1.67 (d, J¼7.1 Hz, 3H), 1.42 (m, 2H), 1.20 (m, 6H),
0.85 (m, 3H); 13C NMR (100.6 MHz, CDCl3) d 163.2,
140.5, 128.8, 128.4, 127.6, 127.5, 126.8, 56.8, 44.6, 31.4,
29.4, 26.8, 22.5, 19.6, 14.0. Minor rotamer: 1H NMR
(400 MHz, CDCl3) d 8.19 (s, 1H), 7.30 (m, 5H), 5.73 (q,
J¼7.2 Hz, 1H), 3.00 (m, 2H), 1.57 (d, J¼7.2 Hz, 3H), 1.42
(m, 2H), 1.20 (m, 6H), 0.85 (m, 3H); 13C NMR
(100.6 MHz, CDCl3) d 162.4, 140.2, 128.7, 127.8, 127.5,
127.2, 126.8, 49.8, 44.6, 31.2, 28.3, 26.4, 22.4, 16.8, 13.9.
5.5.7. N-Hexyl-2-phenylacetamide (6g) and N-benzyl-N-
hexylformamide (7g). Compounds 6g (51 mg, 29% with
TiCl4 and 32 mg, 19% with TFA) and 7g (45 mg, 26%
with TiCl4 and 22 mg, 13% with TFA rotamers in a 1:1 ratio)
were isolated after chromatography (20–25% EtOAc/hex-
anes) as pale yellow oils. Compound 6g: Rf¼0.50 (50%
Compounds 6i and 7i were also obtained using TFA (62 mg,
31%). The compounds were not separated in this experiment
(6i/7i¼1:3 by NMR).
1
EtOAc/hexanes). H NMR (400 MHz, CDCl3) d 7.31 (m,
Acknowledgements
5H), 5.39 (s, 1H), 3.58 (s, 2H), 3.21 (q, J¼6.9 Hz, 2H),
1.42 (t, J¼7.0 Hz, 2H), 1.25 (m, 6H), 0.87 (t, J¼6.8 Hz,
3H); 13C NMR (100.6 MHz, CDCl3) d 170.8, 135.1, 129.5,
129.0, 127.3, 43.9, 39.7, 31.4, 29.4, 26.4, 22.5, 14.0; IR
(NaCl) 3300, 2980, 1640; MS (ES+) m/z 220.2 (M++H);
HRMS calcd for C14H22NO (M++H) 220.1701, found
220.1692.
We thank the National Institute of General Medical Sciences
(GM-49093) for financial support and Erik Fenster for assis-
tance in preparing the manuscript.
References and notes
5.5.8. Hexylheptanamide (6h) and N,N-dihexylform-
amide (7h). Compounds 6h (68 mg, 37% with TiCl4 and
51 mg, 28% with TFA) and 7h (48 mg, 26% with TiCl4
and 22 mg, 12% with TFA) were isolated after chromato-
graphy (20% EtOAc/hexanes) as pale yellow oils. Com-
pound 6h: Rf¼0.50 (50% EtOAc/hexanes). 1H NMR
(400 MHz, CDCl3) d 5.66 (s, 1H), 3.22 (q, J¼6.9 Hz, 2H),
2.15 (t, J¼7.5 Hz, 2H), 1.60 (q, J¼6.5 Hz, 2H), 1.48 (q, J¼
6.2 Hz, 2H), 1.32 (s, 12H), 0.88 (t, J¼5.0 Hz, 6H); 13C NMR
(100.6 MHz, CDCl3) d 173.1, 39.5, 36.9, 31.6, 31.5, 29.6,
29.0, 26.6, 25.8, 22.5, 22.5, 14.0, 14.0; IR (NaCl) 3300,
2960, 1650; MS (ES+) m/z 214.2 (M++H); HRMS calcd for
C13H28NO (M++H) 214.2171, found 214.2161. Compound
1. For recent reviews on chemical methods for amide synthesis,
see: (a) Albericio, F. Curr. Opin. Chem. Biol. 2004, 8, 211–
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1
7h: Rf¼0.25 (50% EtOAc/hexanes). H NMR (400 MHz,
CDCl3) d 8.03 (s, 1H), 3.28 (t, J¼6.4 Hz, 2H), 3.18 (t,
J¼6.9 Hz, 2H), 1.52 (s, 4H), 1.29 (s, 12H), 0.89 (m, 6H);
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31.4, 28.6, 27.3, 26.6, 26.1, 22.6, 22.5, 14.0, 14.0; IR
(NaCl) 2980, 1660; MS (ES+) m/z 214.2 (M++H); HRMS
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were isolated as pale yellow oils after chromatography
(20% EtOAc/hexanes). Compound 6i: Rf¼0.35 (25%
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EtOAc/hexanes). H NMR (400 MHz, CDCl3) d 7.37 (m,
5H), 5.51 (s, 1H), 3.56 (q, J¼7.2 Hz, 1H), 3.18 (m, 2H),
1.53 (d, J¼7.2 Hz, 3H), 1.40 (m, 2H), 1.24 (m, 6H), 0.86
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