Intramolecular reactions of benzylic azides with ketones: Competition between Schmidt and Mannich pathways

Article abstract of DOI:10.1021/jo001367p

The Lewis acid-promoted reactions of benzylic azides with ketones can proceed by two major pathways. The azido-Schmidt reaction involves simple addition of azide to the ketone followed by rearrangement and ring expansion. In addition, benzylic azides can undergo prior rearrangement to afford iminium ions that can subsequently participate in a Mannich reaction. A series of ketones containing an α CH₂(CH₂)_nCH(N₃)Ph substituent (n = 1-3) was prepared to investigate the dependence of products on ketone ring size and tether length. For all ketones examined, good yields of bicyclic lactams arising from intramolecular Schmidt reaction were obtained when a four-carbon linker was used (n = 1 in the above formulation), but Mannich products predominated for the longer tethers examined (n = 2, 3).

Full text of DOI:10.1021/jo001367p

886
J . Org. Chem. 2001, 66, 886-889
In tr a m olecu la r Rea ction s of Ben zylic Azid es w ith Keton es:
Com p etition betw een Sch m id t a n d Ma n n ich P a th w a ys
Aaron Wrobleski and J effrey Aube´*
Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045-2506
jaube@ukans.edu
Received September 15, 2000
The Lewis acid-promoted reactions of benzylic azides with ketones can proceed by two major
pathways. The azido-Schmidt reaction involves simple addition of azide to the ketone followed by
rearrangement and ring expansion. In addition, benzylic azides can undergo prior rearrangement
to afford iminium ions that can subsequently participate in a Mannich reaction. A series of ketones
containing an R CH2(CH2)nCH(N3)Ph substituent (n ) 1-3) was prepared to investigate the
dependence of products on ketone ring size and tether length. For all ketones examined, good yields
of bicyclic lactams arising from intramolecular Schmidt reaction were obtained when a four-carbon
linker was used (n ) 1 in the above formulation), but Mannich products predominated for the
longer tethers examined (n ) 2, 3).
The intramolecular Schmidt reaction of ketones and
alkyl azides1 is a broadly useful process that has emerged
as a valuable tool for alkaloid synthesis.2 In contrast, the
intermolecular reaction of unfunctionalized alkyl azides
is much less facile and is subject to severe limitations
with respect to usable ketone substrates (Figure 1a).3 For
example, only four- and six-membered rings react effi-
ciently under normal circumstances, and even moderate
steric hindrance near the carbonyl can effectively shut
down the addition of azide to the carbonyl group. We have
recently reported that, when benzyl azide is used as the
nucleophile, an alternative pathway involving rearrange-
ment of the azide to an N-phenyliminium species can
occur, followed by trapping by the enol form of the ketone
in a variation of the Mannich reaction (Figure 1b).3b,4
Similar rearrangements of benzylic azides or (trimeth-
ylsilyl)methyl azide have been reported by Pearson5 and
Kuwajima,6 respectively. In general, these azido-Mannich
reactions intervene in cases in which the Schmidt process
is rendered unfavorable.
F igu r e 1. (a) Azido-Schmidt reaction of an alkyl azide with
cyclohexanone. (b) Acid-promoted rearrangement of benzyl
azide followed by Mannich reaction with cyclohexanone.
lactam from the substrate shown in eq 1 (this would have
provided the ring system of lycorane alkaloids).7 In this
instance, only loss of N2 to afford nitrile, but neither a
Schmidt nor Mannich process, was observed.
In our continuing investigations of the intramolecular
Schmidt reaction in organic synthesis, we have consid-
ered carrying out the reaction with substrates in which
the azide group is on a benzylic carbon. An early
indication that such substrates might prove problematic
was evident in the attempted formation of a bridged
Corresponding author: Tel 1.785.864.4496; Fax 1.785.864.5326.
(1) (a) Aube´, J .; Milligan, G. L. J . Am. Chem. Soc. 1991, 113, 8965-
8966. (b) Milligan, G. L.; Mossman, C. J .; Aube´, J . J . Am. Chem. Soc.
1995, 117, 10449-10459. (c) Mossman, C. J .; Aube´, J . Tetrahedron
1995, 52, 3403-3408.
(2) (a) Le Dre´au, M.-A.; Desmae¨le, D.; Dumas, F.; d'Angelo, J . J .
Org. Chem. 1993, 58, 2933-2935. (b) Aube´, J .; Rafferty, P. S.; Milligan,
G. L. Heterocycles 1993, 35, 1141-1147. (c) Wendt, J . A.; Aube´, J .
Tetrahedron Lett. 1996, 37, 1531-1534. (d) Iyengar, R.; Schildknegt,
K.; Aube´, J . Org. Lett. 2000, 2, 1625-1627.
(3) (a) Aube´, J .; Milligan, G. L.; Mossman, C. J . J . Org. Chem. 1992,
57, 1635-1637. (b) Desai, P.; Schildknegt, K.; Agrios, K. A.; Mossman,
C.; Milligan, G. L.; Aube´, J . J . Am. Chem. Soc. 2000, 122, 7226-7232.
(c) Desai, P.; Aube´, J . Org. Lett. 2000, 2, 1657-1659.
(4) Schildknegt, K.; Agrios, K. A.; Aube´, J . Tetrahedron Lett. 1998,
39, 7687-7690.
(5) Pearson, W. H.; Fang, W.-k. Isr. J . Chem. 1997, 37, 39-46.
(6) Tanino, K.; Takahashi, M.; Murayama, K.; Kuwajima, I. J . Org.
Chem. 1992, 57, 7009-7010.
The rational use of the intramolecular Schmidt reac-
tion of ketones with benzylic azide nucleophiles in
complex synthesis would require the delineation of which
substrates are amenable to this process. In this paper,
we report the results of a study designed to examine the
competition between the intramolecular Schmidt and
Mannich pathways. To accomplish this, we prepared a
series of benzylic azides connected to ketones by tethers
(7) Morton, M. A. MS Thesis Applications of the Intramolecular
Schmidt Reaction Toward the Total Synthesis of (()-Crinane; Univer-
sity of Kansas: Lawrence, KS, 1996.
10.1021/jo001367p CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/05/2001

Intramolecular Reactions of Benzylic Azides with Ketones
J . Org. Chem., Vol. 66, No. 3, 2001 887
Ta ble 1. Lew is-a cid Med ia ted Rea ction s of Hyd r oxy
Sch em e 1
Azid es 1-6
product
entry
azide
n
m
conditions
A (%)
B (%)
1
2
3
4
5
6
7
8
9
1
1
2
2
3
3
4
5
6
1
1
1
1
2
2
2
3
3
1
1
2
2
1
2
2
2
2
TiCl4
TfOH
TfOH
TiCl4
TfOH
TiCl4
TfOH
TfOH
TfOH
10 (50)
10 (60)
11 (52)
11 (81)
a
b
a
a
a
a
a
a
a
12 (46)
b
13 (55)
14 (36)
15 (31)
Notes: Yields are not optimized and reflect purified product.
This product was not observed. Starting material decomposed.
a
b
containing from four to six carbon atoms and subjected
them to prototypical protic and Lewis acid conditions.
Previous work1 has established that cyclic ketones con-
taining a three-carbon spacer between the carbonyl and
azide do not undergo the azido-Schmidt reaction and
were therefore not included in this study.
Sch em e 2
Resu lts a n d Discu ssion
The substrates required for this study were prepared
via the straightforward methods shown in Scheme 1.
After alkylation of the appropriate dimethylhydrazone
and hydrolysis, the benzylic azide group was installed
by successive bromination and azide displacement, gen-
erally without detailed characterization of the bromide
intermediate. Cyclic keto azides 1-6 were prepared and
examined as a 1:1 mixture of diastereomers. Acyclic
congeners 7-9 were synthesized in an analogous fashion
(not shown). The yields of the syntheses were acceptable
(22-75% overall) and readily afforded several hundred
milligrams of each required compound.
Our previous experience in the intermolecular series
indicated that, in general, Lewis acid treatment gave the
highest yields of Schmidt insertion products whereas
strong protic conditions, particularly triflic acid (TfOH),
seemed best for the azido-Mannich reactions.3b (It is
possible that TiCl4 does not promote the Mannich reac-
tion because of competing enolization of the ketone.)
Furthermore, intramolecular Schmidt reactions of sub-
strates in which the carbonyl and azide components are
separated by four carbon atoms proceed well under a
variety of protic and Lewis acid conditions, whereas those
containing a five-carbon tether require treatment with
TiCl4.1 Accordingly, both triflic acid and TiCl4 conditions
were tried for most substrates. The results of experiments
carried out with substrates containing cyclic ketones are
indicated in Table 1.
The overall trends can be summarized along the lines
depicted for the substituted cyclopentanones shown in
Scheme 2. The only cases in which the Schmidt pathway
prevailed were in examples containing the optimal four-
carbon tether (n ) 1). Thus, the attack of azide onto
carbonyl activated by either Lewis or protic acids is fast
enough to afford an azidohydrin intermediate that can
then go on to bicyclic lactam. Interestingly, the same
products were observed throughout when either TfOH
or TiCl4 were used, with only modest yield differences
being observed between the two conditions.
Schmidt reactions of substrates with the two-carbon
longer tether lengths examined would require formation
of a seven- or eight-membered azidohydrin ring. The fact
that only Mannich products were obtained suggests that
the slower formation of such rings gives the phenyl group
time to take part in C f N migration, affording the
iminium species shown. This migration is by far more
efficient when TfOH is used to trigger the reaction,
although some Schmidt product was previously observed
in intermolecular reactions carried out under these
conditions.3b Intramolecular attack of the enol on this
species readily affords the spirobicyclic products in mod-
est yield. In each case, only spirocyclic products were
observed, although bridged adducts could have reason-
ably resulted from the reaction of the alternative enol
with the iminium ion. It is worth noting that the
corresponding reaction of the azide where n ) 1 could
have also proceeded to afford bridged adducts (or prod-
ucts resulting from decomposition of iminium ion), but
this route was not taken. In either case, it is possible that
the formation of the more stable enol form of the ketone
directed the regiochemistry of the Mannich reactions.

888 J . Org. Chem., Vol. 66, No. 3, 2001
Wrobleski and Aube´
Sch em e 3
to note that in no case was addition of the alternative
enol to the iminium ion observed, although in this case
such a reaction would result in a product containing an
endocyclic ketone but without the steric stigma of pro-
ducing a bicyclic product. In addition, a previously
unobserved reaction pathway leading to known9 elimina-
tion product 18 was observed in the reaction of ketone 8
in this instance only.
In conclusion, the intramolecular reactions of ketones
and benzylic azides follow the same overall guidelines
as previously reported for the intermolecular examples.3b
Thus, only optimal intramolecular Schmidt reactions (i.e.,
those in which the initial azidohydrin formation occurs
to give a six-membered ring) can successfully compete
with phenyl group migration and lead to insertion. In
cases that would require the formation of awkward-sized
azidohydrins, only phenyl migration is observed. Once
formed, the iminium ions react smoothly, if nonstereo-
selectively, to afford spirocyclic Mannich adducts that
may have some synthetic utility.
Overall, it appears that the kinetic competency of the
Schmidt reaction pathway, or lack thereof, determined
the product distribution for all of these examples.
Exp er im en ta l Section
Gen er a l In for m a tion . General protocols have been pub-
lished.10 The following phenylalkyl-substituted ketones are
known compounds: 2-(3′-phenylprop-1′-yl)cyclopentanone,11
2-(3′-phenylprop-1′-yl)cyclohexanone,12 6-phenyl-2-hexanone,13
and 7-phenyl-2-heptanone.14 Additional new compounds may
be found in the Supporting Information.
In both reaction types, approximately equimolar mix-
tures of stereoisomeric products were observed, but for
different reasons. The intramolecular Schmidt reaction
products merely reflected the 1:1 mixture of keto azides
that went into the reaction. In the intramolecular Man-
nich cases, the achiral enol intermediate could have
afforded a single stereoisomeric Mannich adduct, but
both isomers were obtained in comparable (1.0-1.2:1)
amounts. The stereochemistry of each isomer was ten-
tatively assigned through reasoning based on several
spectroscopic and chromatographic trends throughout the
series. In each case, the isomer that had the higher Rf
value (silica gel, EtOAc/hexane) had both a lower field
chemical shift for the NH proton in CDCl3 (∆δ 0.53-0.69
ppm) and a higher field shift for the proton on the carbon
containing the phenylamino group (∆δ 0.34-0.87 ppm).
One example is given below, with the rest of the relevant
data available in the Experimental Section. These ob-
servations are consistent with the higher Rf (and pre-
sumably less polar) compound enjoying a greater degree
of intramolecular hydrogen bonding as shown for 12a
below.8 This isomer is therefore assigned as having the
carbonyl group and the phenylamino substituent in a cis
disposition. In addition, the proton adjacent to the
phenylamino group in the more polar isomer is deshield-
ed due to close proximity to the carbonyl group (e.g., 12b).
Gen er a l P r oced u r e for th e Alk yla tion of Hyd r a zon es.
To a solution of hydrazone (1.5 mmol) in THF (20 mL) at 0 °C
was added n-BuLi (1.65 mmol, 2.5 M in hexanes). The
resulting cloudy solution was stirred for 30 min and subse-
quently quenched by dropwise addition of alkyl iodide (1.5
mmol) in THF (5 mL). This clear solution was allowed to slowly
warm to 25 °C and then stirred for 8 h. To the reaction was
then added 2 N H2SO4 (6 mL), and stirring was continued for
1 h. The mixture was concentrated in vacuo and the aqueous
layer extracted with diethyl ether. The combined organic layers
were washed with saturated NaHCO3, brine, dried over
anhydrous Na2SO4, and concentrated to yield a dark brown
oil. Chromatography (0-20% EtOAc/hexanes) afforded alky-
lated ketone (0.75-1.4 mmol) as a clear, colorless oil.
8-P h en yl-2-octa n on e: 1H NMR (400 MHz, CDCl3) δ 1.30-
1.35 (m, 4H), 1.53-1.63 (m, 4H), 2.13 (s, 3H), 2.41 (t, J ) 7.5
Hz, 2H), 2.60 (t, J ) 7.6 Hz, 2H), 7.16-7.29 (m, 5H); 13C (100.6
MHz, CDCl3) δ 23.7, 28.9, 29.0, 29.8, 31.2, 35.8, 43.7, 125.5,
128.2, 128.3, 142.6, 209.2; IR (neat) 1715 cm-1; MS (CI) m/e
205 (M+ + 1); HRMS calcd for C14H21O (M + H): 205.1592,
found 205.1595.
2-(4′-P h en ylbu tyl)cyclop en ta n on e: 1H NMR (400 MHz,
CDCl3) δ 1.26-2.33 (complex, 13H), 2.61 (t, J ) 7.2 Hz, 2H),
7.16-7.29 (m, 5H); 13C (100.6 MHz, CDCl3) δ 20.7, 27.2, 29.4,
29.5, 31.4, 35.7, 38.1, 49.1, 125.6, 128.2, 128.3, 142.5, 221.6;
IR (neat) 1735 cm-1; MS (CI) m/e 217 (M+ + 1); HRMS calcd
for C15H21O (M + H): 217.1592, found 217.1596.
Gen er a l P r oced u r e for Ben zylic Br om in a tion /Azid a -
tion of Alk yla ted Keton es. To a solution of ketone (0.63
mmol) in CCl4 (10 mL) was added NBS (0.69 mmol). The
resulting solution was heated at reflux until TLC indicated
An analogous acyclic series was briefly examined, with
essentially the same results (Scheme 3). Using either
protic acids or TiCl4, the shorter four-carbon tether gave
exclusively intramolecular Schmidt product whereas the
two longer tethers preferentially undergo the rearrange-
ment/Mannich reaction sequence. Again, it is interesting
(9) Liedtke, R. J .; Gerrard, A. F.; Diekman, J .; Djerassi, C. J . Org.
Chem. 1972, 37, 776-788.
(10) Gracias, V.; Frank, K. E.; Milligan, G. L.; Aube´, J . Tetrahedron
1997, 53, 16241-16252.
(11) Shono, T.; Kise, N.; Fujimoto, T.; Tominaga, N.; Morita, H. J .
Org. Chem. 1992, 57, 7175-7187.
(12) Muratake, H.; Natsume, M. Tetrahedron Lett. 1997, 38, 7581-
7582.
(13) Yasuda, M.; Hayashi, K.; Katoh, Y.; Shibata, I.; Baba, A. J . Am.
Chem. Soc. 1998, 120, 715-721.
(14) Ozaki, S.; Matsushita, H.; Ohmori, H. J . Chem. Soc., Perkin
Trans. 1 1993, 649-651.
(8) For a discussion of the effect of intramolecular hydrogen bonding
on chemical shift, see: Asakura, T.; Toaka, K.; Demura, M.; William-
son, M. P. J . Biomol. NMR 1995, 6, 227-236.

Intramolecular Reactions of Benzylic Azides with Ketones
J . Org. Chem., Vol. 66, No. 3, 2001 889
the absence of ketone at which time the reaction was cooled
to 25 °C and diluted with water. The layers were separated,
and the aqueous layer was extracted with CH2Cl2. The
combined organic layers were washed with brine, dried over
anhydrous Na2SO4, and concentrated in vacuo to yield a light
brown/yellow oil (0.54-0.63 mmol). In general, the bromides
were not characterized but rather directly carried on in the
next step. However, in a few cases formation of the bromide
was confirmed by H NMR. For example, the H spectrum of
2-(3′-bromo-3′-phenylpropyl)cyclohexanone showed a new sig-
nal at δ 4.90 ppm (t, 1H) for the benzylic proton. The
corresponding benzylic protons of the hydrocarbon had a signal
at δ 2.60 ppm (t, 2H). To a solution of bromide (0.54 mmol) in
THF (20 mL) at 25 °C was added TMSN3 (0.81 mmol) dropwise
followed by dropwise addition of TBAF (0.81 mmol, 1.0 M in
THF). The mixture was stirred at 25 °C for 24 h and then
concentrated in vacuo to yield a thick, brown oil. Chromatog-
raphy (3% EtOAc/hexanes) afforded azide (0.27-0.45 mmol)
as a clear, light yellow oil.
126.5, 128.2, 128.4, 143.2, 143.7, 168.9, 169.2; IR (neat) 1655
cm-1; MS (CI) m/e 216 (M+ + 1); HRMS calcd for C14H18NO
(M + H): 216.1388, found 216.1385.
1-Acetyl-2-p h en ylp yr r olid in e (16): 1H NMR (400 MHz,
CDCl3) δ 1.84 (s, 2H), 1.86-1.95 (m, 3H), 2.15 (s, 1H), 2.23-
2.57 (m, 1H), 3.58-3.77 (m, 2H), 4.91 (m, 1H), 5.22 (dd, J )
1.7, 6.1 Hz, 1H), 7.13-7.36 (m, 5H); 13C (100.6 MHz, CDCl3) δ
21.8, 22.5, 22.7, 23.6, 34.0, 36.2, 46.9, 48.3, 60.1, 62.2, 125.30,
125.34, 126.5, 127.2, 128.3, 128.7, 142.8, 143.1, 169.2, 170.2;
IR (neat) 1660 cm-1; MS (CI) m/e 190 (M+ + 1); HRMS calcd
for C12H16NO (M + H): 190.1232, found 190.1236.
1
1
Gen er a l P r oced u r e for TfOH-P r om oted In tr a m olecu -
la r Sch m id t Rea ction of Azid es. To a solution of azide (0.21
mmol) in CH2Cl2 (7 mL) at 0 °C was added TfOH (0.27 mmol)
over a 10 min period. The resulting light, clear yellow solution
was allowed to stir at 0 °C for ca. 15 min. The mixture was
then quenched with saturated NaHCO3 and diluted with water
and CH2Cl2. The layers were separated, and the aqueous layer
was extracted with CH2Cl2. The combined organic layers were
washed with brine, dried over anhydrous sodium sulfate, and
concentrated in vacuo to afford a yellow oil. Chromatography
(20-60% EtOAc/hexanes) afforded both diastereomers of lac-
tam as a light yellow oil (see Table 1 and Scheme 3 for yields).
Gen er a l P r oced u r e for TfOH-P r om oted In tr a m olecu -
la r Ma n n ich Rea ction of Azid es. The procedure used was
similar to the above except that 2 equiv of TfOH were used in
place of TiCl4 for ca. 4 h reaction time. Chromatography (0-
3% EtOAc/hexanes) allowed for individual isolation of both
diastereomers of Mannich product as clear, colorless oils (see
Table 1 and Scheme 3 for yields).
2-(3′-Azid o-3′-p h en ylp r op yl)cyclop en t a n on e (1): 1H
NMR (400 MHz, CDCl3) δ 1.19-2.39 (complex, 12H), 4.41 (dt,
J ) 3.1, 6.6 Hz, 1H), 7.25-7.39 (m, 5H); 13C (100.6 MHz,
CDCl3) δ 20.66, 20.67, 26.4, 26.6, 29.55, 29.63, 34.0, 34.3, 38.0,
48.6, 48.7, 66.36, 66.42, 126.8, 126.9, 128.3, 128.8, 139.4, 139.5,
220.6, 220.7; IR (neat) 2110, 1745 cm-1; MS (CI) m/e 244
(M+ + 1), 201; HRMS calcd for C14H18N3O (M + H): 244.1450,
found 244.1440.
2-(4′-Azido-4′-ph en ylbu tyl)cyclopen tan on e (3): 1H NMR
(400 MHz, CDCl3) δ 1.26-2.35 (complex, 14H), 4.44 (dt, J )
1.8, 7.9 Hz, 1H), 7.30-7.40 (m, 5H); 13C (100.6 MHz, CDCl3) δ
20.6, 24.2, 24.3, 29.1, 29.2, 29.48, 29.49, 36.07, 36.11, 38.02,
38.04, 48.9, 49.0, 66.09, 66.11, 126.76, 126.81, 128.17, 128.21,
cis-6-(P h en yla m in o)sp ir o[4.4]n on a n -1-on e (12a ): 1H
NMR (400 MHz, CDCl3) δ 1.52-2.24 (complex, 12H), 3.77 (t,
J ) 6.3 Hz, 1H), 4.15 (br s, 1H), 6.58 (m, 2H), 6.66 (m, 1H),
7.13 (m, 2H); 13C (100.6 MHz, CDCl3) δ 19.8, 22.2, 33.0, 35.5,
37.7, 38.9, 58.6, 62.1, 113.4, 117.2, 129.2, 147.6, 223.2; IR (neat)
3410, 1725 cm-1; MS (CI) m/e 230 (M+ + 1); HRMS calcd for
128.7, 139.6, 139.7, 221.09, 221.11; IR (neat) 2110, 1740 cm-1
;
MS (CI) m/e 258 (M+ + 1), 215; HRMS calcd for C15H20N3O
(M + H): 258.1606, found 258.1615.
6-Azid o-6-p h en yl-2-h exa n on e (7): 1H NMR (400 MHz,
CDCl3) δ 1.52-1.84 (m, 4H), 2.10 (s, 3H), 2.43 (t, J ) 7.4 Hz,
2H), 4.41 (t, J ) 6.4 Hz, 1H), 7.26-7.39 (m, 5H); 13C (100.6
MHz, CDCl3) δ 20.4, 29.8, 35.4, 42.9, 66.1, 126.8, 128.2, 128.7,
139.4, 208.1; IR (neat) 2120, 1725 cm-1; MS (CI) m/e 218
(M+ + 1), 175; HRMS calcd for C12H16N3O (M + H): 218.1293,
found 218.1286.
C
15H19NO: 229.1467, found 229.1466.
tr a n s-6-(P h en yla m in o)sp ir o[4.4]n on a n -1-on e (12b): 1H
NMR (400 MHz, CDCl3) δ 1.41-2.31 (complex, 12H), 3.62 (br
s, 1H), 4.14 (dd, J ) 2.0, 7.4 Hz, 1H), 6.48 (m, 2H), 6.64 (m,
1H), 7.11 (m, 2H); 13C (100.6 MHz, CDCl3) δ 19.6, 21.7, 31.7,
34.5, 37.84, 37.86, 58.5, 59.3, 113.0, 117.2, 129.3, 147.2, 224.1;
IR (neat) 3400, 1720 cm-1; MS (CI) m/e 230 (M+ + 1); HRMS
calcd for C15H19NO: 229.1467, found 229.1465.
7-Azid o-7-p h en yl-2-h ep ta n on e (8): 1H NMR (400 MHz,
CDCl3) δ 1.25-1.40 (m, 3H), 1.55-1.61 (m, 3H), 1.73-1.89 (m,
2H), 2.12 (s, 3H), 2.42 (t, J ) 7.3 Hz, 2H), 4.41 (t, J ) 6.7 Hz,
1H), 7.26-7.38 (m, 5H); 13C (100.6 MHz, CDCl3) δ 23.2, 25.7,
29.8, 35.9, 43.3, 66.1, 128.2, 128.3, 128.7, 139.6, 208.6; IR (neat)
2100, 1710 cm-1; MS (CI) m/e 232 (M+ + 1), 189; HRMS calcd
for C13H18N3O (M + H): 232.1450, found 232.1458.
Gen er a l P r oced u r e for TiCl4-P r om oted In tr a m olecu -
la r Sch m id t Rea ction of Azid es. To a solution of azide (0.18
mmol) in CH2Cl2 (4 mL) at 0 °C was added TiCl4 (0.46 mmol)
over a 10 min period. The resulting solution was allowed to
stir at 0 °C for ca. 15 min. The reaction was then quenched
with saturated NaHCO3 and diluted with water and CH2Cl2.
The layers were separated, and the aqueous layer was
extracted with CH2Cl2. The combined organic layers were
washed with brine, dried over anhydrous sodium sulfate, and
concentrated in vacuo to afford both diastereomers of lactam
as a light brown oil (see Table 1 and Scheme 3 for yields).
1-Aza -9-p h en ylbicyclo[4.3.0]n on a n -2-on e (10): 1H NMR
(400 MHz, CDCl3) δ 1.24-2.46 (complex, 10H), 3.55-3.63 (m,
0.5H), 3.71-3.79 (m, 0.5H), 5.11-5.16 (m, 1H), 7.11-7.32 (m,
5H); 13C (100.6 MHz, CDCl3) δ 20.8, 21.3, 28.7, 29.5, 30.1, 31.2,
31.5, 32.9, 33.0, 33.4, 60.0, 60.2, 60.4, 125. 3, 125.4, 126.4,
1-(P h en yla m in o)-2-a cetylcyclop en ta n e (17): 1H NMR
(400 MHz, CDCl3) δ 1.46-1.57 (m, 1H), 1.70-1.84 (m, 3H),
1.97-2.06 (m, 1H), 2.10-2.17 (m, 1H), 2.18 (s, 3H), 2.77-2.83
(m, 1H), 3.65 (br s, 1H), 4.12 (q, J ) 5.6 Hz, 1H), 6.56 (d, J )
7.7 Hz, 2H), 6.70 (t, J ) 7.3 Hz, 1H), 7.14-7.17 (m, 2H); 13C
(100.6 MHz, CDCl3) δ 24.0, 28.6, 29.5, 33.9, 56.8, 59.1, 113.4,
117.6, 129.3, 147.3, 210.4; IR (neat) 3420, 1710 cm-1; MS (CI)
m/e 204 (M+ + 1); HRMS calcd for C13H18NO (M + H):
203.1388, found 204.1378.
Ack n ow led gm en t. Support of this research by the
National Institutes of Health (GM-49093) is gratefully
acknowledged. We thank one of the referees for making
some interesting mechanistic suggestions.
Su p p or tin g In for m a tion Ava ila ble: Additional com-
pound characterizations and copies of 1H and 13C NMR spectra
of new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O001367P