Synthesis of cyclopropylpyrrolidines via reaction of N-allyl-N-propargylamides with a molybdenum carbene complex. Effect of substituents and reaction conditions

Article abstract of DOI:10.1021/jo9519930

Previous studies have demonstrated that group 6 carbene complexes react with α,ω-enynes to form vinylcyclopropane derivatives in good to excellent yield, and that the length and composition of the tether between the alkyne and the alkene often has a dramatic impact on the viability of this reaction pathway. The reactivity of allylpropargyl amine derivatives with pentacarbonyl(1-methoxypentylidene)molybdenum(0) (14a) was investigated in order to provide further insight into the steric and electronic factors controlling this reaction. Treatment of allylpropargyl amines with 14a failed to produce the desired cyclization products while treatment of allylpropargyl amides with 14a led to the expected cyclopropylpyrrolidine systems in good to excellent yields. Higher yields are obtained when the reaction is conducted in a sealed vial in the presence of atmospheric oxygen.

Full text of DOI:10.1021/jo9519930

2
268
J . Org. Chem. 1996, 61, 2268-2272
Articles
Syn th esis of Cyclop r op ylp yr r olid in es via Rea ction of
N-Allyl-N-p r op a r gyla m id es w ith a Molybd en u m Ca r ben e Com p lex.
Effect of Su bstitu en ts a n d Rea ction Con d ition s
Daniel F. Harvey* and Dina M. Sigano
Department of Chemistry & Biochemistry - 0358, University of CaliforniasSan Diego,
La J olla, California 92093-0358
Received November 9, 1995X
Previous studies have demonstrated that group 6 carbene complexes react with R,ω-enynes to form
vinylcyclopropane derivatives in good to excellent yield, and that the length and composition of
the tether between the alkyne and the alkene often has a dramatic impact on the viability of this
reaction pathway. The reactivity of allylpropargyl amine derivatives with pentacarbonyl(1-
methoxypentylidene)molybdenum(0) (14a ) was investigated in order to provide further insight into
the steric and electronic factors controlling this reaction. Treatment of allylpropargyl amines with
1
4a failed to produce the desired cyclization products while treatment of allylpropargyl amides
with 14a led to the expected cyclopropylpyrrolidine systems in good to excellent yields. Higher
yields are obtained when the reaction is conducted in a sealed vial in the presence of atmospheric
oxygen.
Studies of the reactivity of molybdenum and chromium
substituent it was envisioned that there might be sig-
nificant potential for the study of more subtle details of
the steric and electronic factors governing this process
with these substrates. Synthetically, the cyclopropylpyr-
rolidine system (4, X ) RN) produced in this reaction is
found in several biologically active natural product
frameworks, such as CC-1065 and the duocarmycins and
is also potentially convertible to a variety of other
nitrogen-containing polycyclic assemblies.
carbene complexes with 1,6- and 1,7-enynes (1) have
demonstrated that the length and composition of the
tether between the alkyne and the alkene and the nature
of the substituents on the alkene play critical roles in
determining the outcome of this cyclization reaction.1
Generally, molybdenum carbene complexes (2, M ) Mo)
react with these substrates to produce vinylcyclopropanes
,2
3
3
in good to excellent yield (see Scheme 1). Though the
enol ethers can generally be isolated, they are frequently
sensitive to hydrolysis and are often directly converted
to the corresponding ketone, 4. Substrates having an
unsubstituted alkane tether give vinylcyclopropanes
Shortly after the studies described herein were initi-
ated, two examples of related reactions of allylpropargyl
amine derivatives with chromium carbene complexes
were reported. In their studies of reactions of enynes
with chromium carbene complexes bound to a solid
support, Katz and Yang demonstrated that, following
adsorption on silica gel, amine 5 reacts with complex 6
to give, after enol ether hydrolysis, cyclopropane deriva-
tive 7 in 51% yield.2 Additionally, Mori and Watanuki
reported that allyl propargyl sulfonamides, such as 8,
readily react with chromium carbene complex 9 to give
cyclopropane derivative 10 in 91% overall yield after
conversion to the corresponding ketone.4
provided that an appropriate electron-withdrawing sub-
stituent is situated on the olefin.1
a,c
Alternatively, sub-
stituents appropriately situated on the tether can in-
crease the propensity for intramolecular cyclopropanation,
again leading to the formation of vinylcyclopropanes.1
Allyl propargyl ethers have also been found to participate
in this reaction (Scheme 1, X ) O).1 Successful cycliza-
tion of 1 (X ) O) was demonstrated to result from the
σ-electron-withdrawing ability of the ether oxygen.
In order to expand the scope of this reaction, we sought
to investigate the reactivity of allyl propargyl amine
derivatives (1, X ) RN) with group 6 Fischer carbene
complexes. Our motives for doing so were two-fold.
Mechanistically, since nitrogen can be bound to a third
a,i
a,i
Resu lts a n d Discu ssion
Su bstr a te P r ep a r a tion . Amine 5 was prepared in
two steps from allylamine. Initial treatment of an excess
(
6 equiv) of allylamine with benzyl bromide gave N-allyl-
X
5
Abstract published in Advance ACS Abstracts, March 1, 1996.
N-benzylamine in 92% yield. Subsequent exposure to
propargyl bromide in the presence of sodium hydride in
THF produced 5 in 60% yield (eq 3).6 Amine 11 was
prepared via reductive amination of 4-nitrobenzaldehyde
(1) (a) Harvey, D. F.; Lund, K. P.; Neil, D. A. J . Am. Chem. Soc.
1
992, 114, 8424-8434. (b) Katz, T. J .; Sivavec, T. M. J . Am. Chem.
Soc. 1985, 107, 737-738. (c) Wulff, W. D.; Kaesler, R. W. Organome-
tallics 1985, 4, 1461-1463. (d) McCallum, J . S.; Kunng, F. A.;
Gilbertson, S. R.; Wulff, W. D. Organometallics 1988, 7, 2346-2360.
(
e) Korkowski, P. F.; Hoye, T. R.; Rydberg, D. B. J . Am. Chem. Soc.
1
1
1
988, 110, 2676-2678. (f) Hoye, T. R.; Rehberg, G. M. Organometallics
989, 8, 2070-2071. (g) Hoye, T. R.; Rehberg, G. M. Organometallics
990, 9, 2014-3015. (h) Hoye, T. R.; Rehberg, G. M. J . Am. Chem.
(3) For recent reviews, see: (a) Boger, D. L. Advances in Heterocyclic
Natural Products Synthesis; Pearson, W. H., Ed.; J AI Press: Green-
wich, CT, 1992; vol. 2, pp 1-177. (b) Boger, D. L. Pure Appl. Chem.
1993, 65, 1123-1132. (c) Boger, D. L.; J ohnson, D. S. Proc. Natl. Acad.
Sci. U.S.A. 1995, 92, 3642-3649.
(4) Mori, M. Watanuki, S. J . Chem. Soc., Chem. Commun. 1992,
1082-1084.
Soc. 1990, 112, 2841-2842. (i) Harvey. D. F.; Lund, K. P.; Neil, D. A.
Tetrahedron Lett. 1991, 32, 6311-6314.
(2) Katz, T. J .; Yang, G. X. Q. Tetrahedron Lett. 1991, 32, 5895-
5
898.
0
022-3263/96/1961-2268$12.00/0 © 1996 American Chemical Society

Synthesis of Cyclopropylpyrrolidines
J . Org. Chem., Vol. 61, No. 7, 1996 2269
Sch em e 1
carbene complex does not occur, with oligomerization/
polymerization of the alkyne occurring instead.
The reactivity of amides 13a -c with complex 14a was
next investigated. Previous studies had demonstrated
that related cyclization reactions proceed well at reflux
in both THF and benzene.9 Treatment of 4-nitrobenz-
amide derivative 13a with 14a in THF at reflux under
nitrogen, followed by treatment with dilute hydrochloric
acid, produced cyclopropane 16 in 38% yield. Though the
starting material had been consumed, no other isolable
products were obtained. Under the same reaction condi-
tions, benzamide 13b produced 16b in 35% yield while
4
-methoxybenzamide derivative 13c gave 16c in 34%
yield.
with allylamine followed by alkylation with propargyl
bromide in the presence of sodium hydride in 33% overall
yield (eq 4).
In previous studies of the reactivity of allyl propargyl
ethers with molybdenum and chromium carbene com-
plexes, sealed vial conditions, wherein the solvent and
reaction components are heated in a closed container,
were found to give optimum results.1
a,i
The improved
yield under these conditions was thought to be primarily
due to reduction of the amount of volatile enyne substrate
lost during the reaction. Though evaporative loss of
substrate is not a problem with the higher molecular
weight amides 13a -c, improved product yields were
obtained with all three substrates under sealed vial
conditions. Thermolysis of 13a with complex 14a in THF
in a sealed vial at 100 °C gave, after acid-catalyzed enol
ether hydrolysis, cyclopropanation product 16a in 74%
yield. Likewise, complexes 13b and 13c produced cyclo-
propanation products 16b and 16c in 56% and 58% yield,
respectively.
Amides 13a -c were prepared by treatment of allyl
amine with the appropriate aroyl chloride 12a -c in
to give the corresponding N-allylamides.7 Sub-
2 2
CH Cl
sequent alkylation of the N-allylamides with propargyl
bromide in the presence of sodium hydride8 produced
N-allyl-N-propargylamides 13a -c in overall yields rang-
ing from 74 to 82%.
This dramatic improvement in isolated yield led us to
explore in more detail the effect of variations in the
reaction conditions. The reaction of 13a with complex
Ca r ben e Com p lex Cycliza tion Stu d ies. Although
1
4a to produce 16a was used as the standard reaction
5
reacted smoothly with 6 when bound to silica gel,2
in this study. The results are summarized in Table 1.
The reaction was performed with air and nitrogen
atmospheres under both sealed vial and atmospheric
pressure conditions. Sealed vial conditions allowed for
temperatures higher than reflux to be employed. While
attempting to ensure that temperature alone was not
responsible for the improved yield, 1,4-dioxane, which
was anticipated to function as a higher boiling surrogate
treatment of either 5 or 11 with molybdenum complex
4a or chromium complex 14b under a variety of solu-
1
tion-based reaction conditions did not lead to facile
formation of the desired cyclopropane derivative 15 or
the corresponding enol ether hydrolysis product. Though
amines 5 and 11 were consumed in this reaction, only a
complex mixture of nonisolable products was produced.
It appears that the carbene complex reacts with the
alkyne, presumably forming the desired vinylcarbene
complex intermediate. However, subsequent intramo-
lecular cyclopropanation of the in situ-generated vinyl-
(
7) Furniss, B. S.; Hannaford, A. J .; Smith, P. W. G.; Tatchell, A. R.
Vogel’s Textbook of Practical Organic Chemistry; Longman Scientific
Technical: Essex, England, 1989; p 709.
8) Related procedures for the preparation of dialkylamides have
&
(
previously been reported. See: Knapp, S.; Gibson, F. S. J . Org. Chem.
1992, 57, 4802-4809.
(9) (a) Harvey, D. F.; Brown, M. F. J . Am. Chem. Soc. 1990, 112,
7806-7807. (c) Harvey, D. F.; Brown, M. F. J . Org. Chem. 1992, 57,
5559-5561.
(
5) For a related procedure for the preparation of secondary amines,
see: Ben-Efraim, D. A. Tetrahedron 1973, 29, 4111-4125.
6) Amine 5 has been previously prepared by a different route. See
ref 2.
(

2
270 J . Org. Chem., Vol. 61, No. 7, 1996
Harvey and Sigano
Ta ble 1. Rea ction Con d ition s In vestiga ted for th e
Con ver sion of 13a a n d 14a to 16a
convert the reactive “Mo(CO)
nonreactive Mo(CO)
Tetrahydrofuran may also be responsible for modifying
” to the air stable, relatively
4
6
.
entry atmosphere
pressure
temp °C
solvent
THF
yield, %
4
the reactivity of the “Mo(CO) ”. Ligand exchange is quite
1
2
3
4
5
6
7
8
9
0
1
air
air
air
air
N2
N2
N2
air
air
N2
N2
sealed vial
sealed vial
sealed vial
sealed vial
sealed vial
sealed vial
sealed vial
atmospheric
atmospheric
atmospheric
atmospheric
100
67
74
72
57
21
50
<10
54
52
16
38
0
rapid with molybdenum(0) complexes11 and the formation
of mixed carbon monoxide/THF complexes, such as Mo-
THF
100
100
100
100
67
benzene
1,4-dioxane
THF
1,4-dioxane
THF
(
5 4 2 3 3
CO) (THF), Mo(CO) (THF) , and Mo(CO) (THF) , will
12
certainly occur when the reaction is performed in THF.
Though the THF ligands in these complexes are relatively
labile, they are probably less reactive than analogous
coordination complexes of 1,4-dioxane and η - and η -
benzene complexes. The η -benzene complex, (C
67
THF
2
4
100
67
1,4-dioxane
THF
1
1
6
6 6
H )Mo-
100
1,4-dioxane
(
CO) , which is anticipated to eventually be produced in
3
benzene via loss of an additional 1 equiv of carbon
of tetrahydrofuran, was employed in reactions 4, 6, 9, and
1. Under sealed vial conditions, carbon monoxide
2
monoxide, is entropically more stable than the η - and
1
4
η -benzene complexes but undergoes relatively rapid
produced during the reaction cannot escape from the
reaction flask. Reactions performed at atmospheric
pressure were carried out under a flow of the indicated
atmosphere so that carbon monoxide produced during the
reaction might be flushed from the reaction medium after
diffusion into the gas phase. All reactions were heated
for 1 h, at which time starting material appeared to be
completely consumed, based on analysis of the reaction
mixture by thin layer chromatography.
11
ligand substitution.
Oxygen may enhance the viability of the desired
4
reaction pathway by partially oxidizing the “Mo(CO) ”,
13
thus generating less reactive metal material. Material
of this type, though not characterized in these studies,
appears to precipitate from the reaction mixture during
14
the reaction. Partial oxidation of the metal center is
4
expected to reduce the ability of “Mo(CO) ” to react in a
deleterious fashion with either the substrate or the
desired product. Reactions involving chromium carbene
complexes are often treated with air after the reaction
has been completed in order to destroy remaining Cr(0)
Better yields were consistently obtained when air was
present than when a nitrogen atmosphere was employed
(1 vs 5; 4 vs 6; 8 vs 10; 9 vs 11). Under sealed vial
conditions, it was found that the thermolysis temperature
did not dramatically alter the outcome of the reaction (1
vs 2; 5 vs 7). Though anticipated to be of similar
coordination ability to THF, reactions carried out in 1,4-
dioxane were found to produce lower yields of 16a than
reactions performed in THF. Replacement of THF with
benzene also gave poorer results (1 vs 3). Open flask
conditions, in which carbon monoxide can dissipate from
the reaction, gave consistently lower yields than those
performed under sealed vial conditions in which carbon
monoxide would be contained in the reaction environment
14
material and facilitate isolation of the organic product.
In summary, cyclopropylpyrrolidines are readily pre-
pared via reaction of N-allyl-N-propargylbenzamide de-
rivatives with molybdenum carbene complexes while the
corresponding N-allyl-N-propargyl-N-benzylamine de-
rivatives fail to smoothly cyclize. Though we initially
anticipated that the electron-donating/electron-withdraw-
ing ability of substituents on the aromatic ring might
dramatically influence the outcome of this reaction, their
effect in the case of the benzamide derivatives was
relatively slight, with the 4-nitro derivative giving higher
yields of the desired product than the corresponding
unsubstituted or 4-methoxy-substituted derivatives. The
reaction proceeds best when carried out in a sealed vial
in the presence of air with THF as the solvent.
(2 vs 8; 4 vs 9).
The containment of carbon monoxide in the reaction
medium may enhance the outcome of the reaction in
several ways. The initial step in this and many other
group 6 carbene complex reaction pathways is thought
to be dissociation or displacement of carbon monoxide
from the carbene complex. As summarized in Scheme
Exp er im en ta l Section
Gen er a l Meth od s. 1H NMR and 13C NMR spectra were
recorded at either 300 MHz or 500 MHz. IR spectra were
recorded on a FT-IR spectrophotometer. Low resolution mass
spectra were recorded on a mass-selective detector (20 eV)
interfaced with a gas chromatograph. High resolution mass
spectra were performed at the University of California at
Riverside Mass Spectrometry Facility. Elemental analysis
were performed by Galbraith Laboratories, Inc. Column
chromatography was performed with florisil (100-200 mesh)
or silica gel (200-425 mesh). All reagents were obtained from
commercial suppliers and used as received unless otherwise
2
, alkyne coordination and insertion leads to vinylcarbene
intermediate, 18. Subsequent olefin coordination (19)
followed by addition and reductive elimination leads to
2
reaction is envisioned to be transiently coordinated to
either the product, the solvent, or both. Some of the “Mo-
0 and “Mo(CO)
4 4
”. The “Mo(CO) ” produced in this
(
CO)
from the reaction mixture. The additional equivalents
of CO necessary to convert “Mo(CO) ” to Mo(CO) are
4 6
” is converted to Mo(CO) , which can be recovered
4
6
obtained either by recoordination of the metal to the
carbon monoxide initially dissociated from the carbene
complex or by abstraction of carbon monoxide from
carbene complex 14a .
(11) For a recent discussion, see: Li, J .; Schreckenbach, G. Ziegler,
T. J . Am. Chem. Soc. 1995, 117, 486-494.
(12) (a) Werner, R. P. M.; Coffield, T. H. Chem. Ind. 1960, 936-
37. (b) Muetterties, E. L.; Bleeke, J . R.; Sievert, A. C. J . Organomet.
9
4
The presence of a reactive “Mo(CO) ” unit during the
Chem., 1979, 178, 197-216. (c) Hoff, C. D. J . Organomet. Chem. 1985,
82, 201-214. (d) Nolan, S. P.; Lopez de la Vega, R.; Hoff, C. D.
Organometallics 1986, 5, 2529-2537.
13) Less than stoichiometric quantities of oxygen are present in
reaction could adversely effect the desired reaction
pathway in a number of different ways. It could coordi-
nate to substrate 13, through the arene, alkyne, alkene,
or amide moiety, or react with the product 20, via the
strained cyclopropane ring.10 Carbon monoxide may
2
(
the reaction flask when “sealed vial” conditions are employed. Ap-
proximately 0.31 mmol of substrate and approximately 20 mL of
solvent are sealed in a reaction flask with a 25 mL capacity. Ap-
proximately 0.14 equiv of O
14) McGuire, M. A.; Hegedus, L. S. J . Am. Chem. Soc. 1982, 104,
5538-5540.
2
are present.
(
(10) Sarel, S. Acc. Chem. Res. 1978, 11, 204-211.

Synthesis of Cyclopropylpyrrolidines
J . Org. Chem., Vol. 61, No. 7, 1996 2271
Sch em e 2
indicated. Benzene and tetrahydrofuran were distilled from
potassium/benzophenone ketyl under a nitrogen atmosphere.
Diethyl ether was distilled from sodium/benzophenone ketyl
under a nitrogen atmosphere. 1,4-Dioxane was purified ac-
cording to a literature procedure. Disappearance of starting
material was monitored by thin layer chromatography.
N-Allyl-N-ben zyla m in e. Benzyl bromide (2.00 g, 11.7
mmol) was added dropwise to neat allylamine (5.26 mL, 70.2
mmol) at 0 °C. After 16 h at room temperature, the reaction
(80% in toluene, 779 µL, 6.99 mmol). After 36 h, the reaction
mixture was quenched with H
mL), dried over K CO
graphed on silica gel to give 11 (216 mg, 78%): H NMR (300
MHz, CDCl
2
O, extracted with Et
2
O (3 × 15
2
3
, concentrated in vacuo, and chromato-
1
1
5
3
) δ 2.27 (br s, 1 H), 3.18 (d, J ) 6.4 Hz, 2 H), 3.32
(s, 2 H), 3.74 (s, 2 H), 5.20 (d, J ) 10.1 Hz, 1 H), 5.29 (dd, J )
17.1, 1.5 Hz, 1 H), 5.84 (ddt, J ) 17.0, 6.5, 10.3 Hz, 1 H), 7.54
1
3
(d, J ) 8.3 Hz, 2 H), 8.54 (d, J ) 7.81 Hz, 2 H); C NMR (75
MHz, CDCl
3
) δ 41.5, 56.4, 56.6, 73.7, 77.7, 118.6, 123.5, 129.5,
was quenched with aqueous NaHCO
extracted with Et
Purification by silica gel chromatography gave N-allyl-N-
3
solution (10 mL),
CO
134.8, 146.5, 147.2; IR (neat) 3297, 3079, 1604, 1521, 1346,
-
1
+
2
O (3 × 10 mL), and dried over K
2
3
.
cm ; LRMS EI m/z 231 (7), 230 (M , 37), 229 (35), 203 (100),
191 (46), 136 (74), 94 (77), 78 (75), 41 (37). HRMS (EI) calcd
1
+
benzylamine (1.58 g, 92%) as a yellow oil: H NMR (300 MHz,
for C13
H
14
N
2
O
2
(M ) 230.1055, found 230.1055.
CDCl
.06 (dd, J ) 10.3, 0.8 Hz, 1 H), 5.14 (dd, J ) 17.4, 1.2 Hz, 1
H), 5.88 (ddt, J ) 17.4, 10.3, 5.9 Hz, 1 H), 7.17-7.27 (m, 5 H);
3
) δ 1.54 (s, 1 H), 3.23 (d, J ) 5.9 Hz, 2 H), 3.73 (s, 2 H),
Gen er a l P r oced u r e for t h e P r ep a r a t ion of N-Allyl-
a m id es. The benzoyl chloride was added dropwise to a
5
solution of allylamine in CH
aqueous NaOH was added and the reaction mixture was
extracted with CH Cl . The combined organics were dried over
CO and concentrated in vacuo.
N-Allyl-4-n itr oben za m id e.16 Following the general pro-
cedure, a solution of allylamine (404 µL, 5.39 mmol) in CH
Cl (5.0 mL) was treated with 4-nitrobenzoyl chloride (1.00 g,
2 2
Cl . After the specified time, 10%
1
3
C NMR (75 MHz, CDCl ) δ 51.7, 53.2, 115.9, 126.9, 128.1,
3
-
1
1
1
28.3, 136.8, 140.2; IR (neat) 1643 cm ; LRMS (EI) m/z (%)
2
2
+
47 (M , 16), 146 (36), 91 (100), 70 (17), 56 (39), 41 (16); HRMS
K
2
3
+
(EI) calcd for C10
H
13N (M ) 147.1048, found 147.1043.
N-Allyl-N-ben zyl-N-p r op a r gyla m in e (5). To a solution
2
-
of N-allyl-N-benzylamine (250 mg, 1.70 mmol) in THF (10 mL)
was added NaH (80% dispersion in mineral oil, 60.0 mg, 2.04
mmol). Propargyl bromide (80% in toluene) was then added
in 3 portions (182 µL per addition, 546 µL total, 5.95 mmol)
over an 8 h period. After 16 h, the reaction mixture was
2
5
9
.39 mmol). After 1.5 h, N-Allyl-4-nitrobenzamide (1.05 g,
5%) was obtained as a white solid: mp ) 119-120 °C; H
1
NMR (300 MHz, CDCl ) δ 4.11 (t, J ) 5.8 Hz, 2 H), 5.22 (d, J
)
1
8
1
3
2
3
10.6, 1 H), 5.27 (dd, J ) 17.2, 1.1 Hz, 1 H), 5.91 (ddt, J )
quenched with H
2
O, extracted with Et
2
O (3 × 15 mL), dried
6.7, 11.0, 5.6 Hz, 1 H), 6.40 (s, 1 H), 7.94 (d, J ) 8.7 Hz, 2 H),
over K CO , concentrated in vacuo, and chromatographed on
2
3
13
.28 (d, J ) 8.7 Hz, 2 H); C NMR (75 MHz, CDCl
3
) δ 42.7,
silica gel to give 5 (175 mg, 60%). Spectral data for 5 were in
17.4, 123.8, 128.2, 133.4, 140.0, 149.6, 165.3; IR (KBr) 3291,
2
agreeement with that previously reported.
-1
+
238, 1640 cm
06.0691, found 206.0697.
N-Allylben za m id e. Following the general procedure, at
°C allylamine (1.31 mL, 17.5 mmol) in CH Cl (5.0 mL) was
10 2 3
. HRMS (EI) calcd for C10H N O (M )
N-Allyl-N-(4-n itr oben zyl)a m in e. To a solution of 4-ni-
trobenzaldehyde (1.00 g, 6.62 mmol) in MeOH (20 mL) was
added allylamine (1.00 mL, 13.2 mmol). After 4 h, the reaction
0
2
2
3
mixture was cooled to 0 °C and NaBH CN (276 mg, 4.39 mmol)
treated with benzoyl chloride (2.03 mL, 17.5 mmol). After 1
h, N-allylbenzamide was purified by chromatography on silica
was added. The reaction mixture was slowly warmed to room
temperature and, after 24 h, sequentially quenched with 10%
aqueous HCl (10 mL) and brought to basic pH with 10%
aqueous NaOH (approximately 20 mL). The solution was
1
gel (2.45 g, 87%); H NMR (300 MHz, C
6
D
6
) δ 3.84 (t, J ) 5.7
Hz, 2 H), 4.90 (dd, J ) 10.3, 1.1 Hz, 1 H), 4.97 (dd, J ) 17.3,
.3 Hz, 1 H), 5.60-5.72 (m, 2 H containing 5.66 (ddt, J ) 16.3,
0.9, 5.5 Hz, 1 H)), 7.00-7.12 (m, 3 H), 7.62 (d, J ) 7.9 Hz, 2
H); C NMR (75 MHz, C
35.08, 135.14, 167.1; IR (KBr) 3309, 1642 cm
N-Allyl-4-m eth oxyben za m id e. Following the general
procedure, 4-methoxybenzoyl chloride (400 µL, 2.96 mmol) was
added to a solution of allylamine (244 µL, 3.25 mmol) in CH
Cl (5.0 mL). After 20 h, N-allyl-4-methoxybenzamide was
purified by chromatography on silica gel (513 mg, 91%): mp
1
1
extracted with CH
were dried over K
2
Cl
CO
2
(3 × 50 mL), and the combined organics
2
3
, concentrated in vacuo and chromato-
1
3
6 6
D ) δ 42.5, 115.7, 127.6, 128.5, 131.2,
graphed on silica gel to give N-Allyl-N-(4-nitrobenzyl)amine
532 mg, 42%) which was >98% pure by NMR and taken on
-
1
1
.
(
1
without further purification: H NMR (300 MHz, CDCl
3
) δ 1.75
(
)
(
8
5
1
5
br s, 1 H), 3.27 (d, J ) 6.0 Hz, 2 H), 3.90 (s, 2 H), 5.14 (dd, J
2
-
10.3, 1.0 Hz, 1 H), 5.20 (dd, J ) 17.4, 1.3 Hz, 1 H), 5.91
ddt, J ) 16.9, 10.3, 6.0 Hz, 1 H), 7.50 (d, J ) 8.5 Hz, 2 H),
2
.18 (d, J ) 8.6 Hz, 2 H); 1 C NMR (75 MHz, CDCl
3
3
) δ 51.7,
2.3, 116.5, 123.6, 128.6, 136.2, 148.1, 158.1; IR (neat) 3337,
1
)
44-47 °C; H NMR (300 MHz, C
6 6
D ) δ 3.20 (s, 3 H), 3.95
-1
+
(br t, J ) 5.6 Hz, 2 H), 4.93 (d, J ) 9.9 Hz, 1 H), 5.05 (dd, J )
604 cm ; LRMS (EI) m/z (%) 193 (6), 192 (M , 54), 136 (100),
6 (45), 41 (64).
1
7.0, 1.2 Hz, 1 H), 5.76 (ddt, J ) 16.6, 10.9, 5.5 Hz, 1 H), 6.44
(
br s, 1 H), 6.67 (d, J ) 8.7 Hz, 2 H), 7.80 (d, J ) 8.8 Hz, 2 H);
N-Allyl-N-(4-n itr oben zyl)-N-p r op a r gyla m in e (11). To
1
3
C NMR (75 MHz, C
6 6
D ) δ 42.6, 54.8, 113.8, 115.6, 127.5,
1
a solution of N-allyl-N-(4-nitrobenzyl)amine (224 mg, 1.17
mmol) in THF (10 mL) was added NaH (80% dispersion in
mineral oil, 38.5 mg, 1.28 mmol) followed by propargyl bromide
-
1
29.6, 135.4, 162.4, 167.1; IR (KBr) 3320, 3079, 1637 cm
;
(
16) This compound has been reported previously. See: (a) Agwada,
(
15) Perrin D. D., Armarego, W. L. F. Purification of Laboratory
V. C. J . Chem. Eng. Data 1984, 29, 231-235. (b) Agwada, V. C. Biomed.
Mass Spec. 1984, 11, 497-501.
Chemicals; Pergamon Press Ltd: Oxford, England, 1988, pp 164-165.

2
272 J . Org. Chem., Vol. 61, No. 7, 1996
Harvey and Sigano
+
LRMS EI m/z (%) 191 (M , 10), 135 (100), 107 (14), 92 (21), 77
(50.0 mg, 0.205 mmol) and 14a (103 mg, 0.307 mmol) in THF
gave 16a (49.0 mg, 74%): mp ) 73-75 °C; H NMR (500 MHz,
6 6
C D , rt, approximately a 1:1 mixture of amide rotamers) δ
+
1
(
24); HRMS (EI) calcd for C11
91.0935.
Gen er a l P r oced u r e for th e P r ep a r a tion of N-Allyl-N-
p r op a r gyla m id es (13a -c). To a solution of the N-allylben-
zamide in THF was added NaH (80% dispersion in mineral
oil) followed by propargyl bromide (80% in toluene). After 36
h, the reaction mixture was quenched with H
with Et O. The combined organics were dried over K
concentrated in vacuo, and chromatographed on silica gel to
give the N-allyl-N-propargylamide.
N-Allyl-N-p r op a r gyl-4-n itr oben za m id e (13a ). Follow-
ing the general procedure, N-allyl-4-nitrobenzamide (2.90 g,
H
13NO
2
(M ) 191.0946, found
1
0.14 (t, J ) 4.4 Hz, 1 H), 0.20-0.27 (m, 3 H), 0.76 (t, J ) 7.3
Hz, 3H), 0.80-0.88 (m, 5 H containing 0.83 (t, J ) 7.3 Hz, 3
H), 1.10 (sextet, J ) 7.3 Hz, 2 H), 1.17 (sextet, J ) 7.3 Hz, 2
H), 1.37 (pentet, J ) 7.3 Hz, 2 H), 1.45 (pentet, J ) 7.3 Hz, 2
H), 1.80 (d, J ) 17.6 Hz, 1 H), 1.84-1.93 (m, 6 H), 2.10 (d, J
) 17.6 Hz, 1 H), 2.82 (d, J ) 10.3 Hz, 1 H), 3.06 (d, J ) 10.3
Hz, 1 H) 3.18 (dd, J ) 10.3, 3.9 Hz, 1 H), 3.27 (d, J ) 11.7 Hz,
1 H), 3.31 (d, J ) 10.3 Hz, 1 H), 3.40 (dd, J ) 11.7, 3.9 Hz, 1
H), 4.23 (d, J ) 11.7 Hz, 1 H), 4.32 (d, J ) 11.7 Hz, 1 H), 6.99
2
O and extracted
3
CO ,
2
2
(
d, J ) 8.3 Hz, 2 H), 7.04 (d, J ) 8.3 Hz, 2 H), 7.65 (d, J ) 8.8
Hz, 2 H), 7.71 (d, J ) 8.3 Hz, 2 H); IR (neat) 1713, 1634, 1523
cm ; LRMS EI m/z (%) 330 (M , 6), 245 (35), 150 (100), 104
1
4.1 mmol) in THF (50 mL) was treated with NaH (80%
dispersion in mineral oil, 507 mg, 16.9 mmol) and propargyl
bromide (80% in toluene, 9.41 mL, 84.5 mmol) to give 13a (2.96
-
1
+
+
(
45); HRMS (CI, CH
found 331.1662. Anal. (C18
5â)-N-Ben zoyl-1â-(2-oxoh exa n yl)-3-a za bicyclo[3.1.0]-
4
) calcd for C18
H
23
N
2
O
4
(MH ) 331.1658,
1
22 2 4
H N O ) C, H, N.
g, 86%): mp ) 41-42 °C; H NMR (300 MHz, C
6
D
6
, 80 °C) δ
(
1
5
.91 (t, J ) 2.3 Hz, 1 H), 3.79 (br s, 4 H), 4.91-4.97 (m, 2 H),
h exa n e (16b). Following the general procedure, 13b (50.0
mg, 0.251 mmol) and 14a (127 mg, 0.380 mmol) were heated
in THF for 1 h to give 16b (40.1 mg, 56%): 1H NMR (300 MHz,
.42-5.55 (m, 1 H), 7.08 (d, J ) 8.5 Hz, 2 H), 7.71 (d, J ) 8.5
1
3
Hz, 2H); C NMR (75 MHz, C
6
D
6
, 70 °C) δ 49.2, 72.8, 78.8,
1
3
(
18.2, 123.6, 127.9, 132.5, 141.8, 148.8, 168.6; IR (neat) 3291,
081, 2120, 1643 cm-1; LRMS EI m/z (%) 243 (M - 1, 4), 205
+
C
6
D
6
, 80 °C) δ 0.25-0.34 (m, 2 H), 0.78 (t, J ) 7.3 Hz, 3 H),
0.96 (dt, J ) 7.8, 3.9 Hz, 1 H), 1.15 (sextet, J ) 7.3 Hz, 2 H),
.41 (pentet, J ) 7.3 Hz, 2 H), 1.98 (t, J ) 7.2 Hz, 2 H), 2.08
(s, 2 H), 3.25 (d, J ) 11.0 Hz, 1 H), 3.39 (dd, J ) 10.9, 3.6 Hz,
+
13), 203 (6), 150 (100). HRMS (EI) calcd for C13
H
12
N
2
O
3
(M )
1
2
44.0848, found 244.0848. Anal. (C13
N-Allyl-N-p r op a r gylben za m id e (13b). Following the
general procedure, a solution of N-allylbenzamide (2.46 g, 15.3
mmol) in THF (50 mL) was treated with NaH (550 mg, 80%
dispersion in mineral oil, 18.3 mmol) and propargyl bromide
H N O ) C, H, N.
12 2 3
1
7
1
H) 3.5-4.2 (very br s, 2 H), 7.06-7.08 (m, 3 H), 7.38-7.42
-
1
(m, 2 H); IR (neat) 1713, 1630 cm ; LRMS EI m/z (%) 285
+
+
(
2
M , 2), 105 (100); HRMS (CI, CH
86.1807, found 286.1816.
5â)-N -(4-M e t h o x y b e n z o y l)-1â-(2-o x o h e x a n y l)-3-
4 2
) calcd for C18H24NO (MH )
(
80% in toluene, 5.11 mL, 45.8 mmol) to give 13b (2.59 g, 85%).
Spectral data for 13b was in agreement with that previously
(
1
7
1
a za bicyclo[3.1.0]h exa n e (16c). Following the general pro-
cedure, 13c (50.0 mg, 0.218 mmol) and 14a (110 mg, 0.327
reported.
Hz, 1 H), 3.96 (br s, 4 H), 4.94 (d, J ) 9.3 Hz, 1 H), 4.98 (d, J
15.4 Hz, 1 H), 5.57 (ddt, J ) 16.6, 10.9, 5.5 Hz, 1 H), 7.04-
6 6
H NMR (300 MHz, C D , 70 °C) δ 1.92 (t, J ) 2.3
mmol) were heated in THF for 1 h to give 16c (36.5 mg, 58%):
)
1
.06 (m, 3 H), 7.38-7.41 (m, 2 H); 1 C NMR (75 MHz, C
3
6 6
H NMR (300 MHz, C D , 80 °C) δ 0.28-0.36 (m, 2 H), 0.79 (t,
7
7
1
D ,
6 6
J ) 7.3 Hz, 3 H), 0.94-1.01 (m, 1 H), 1.16 (sextet, J ) 7.4 Hz,
2 H), 1.42 (pentet, J ) 7.4 Hz, 2 H), 2.00 (t, J ) 7.3 Hz, 2 H),
2.11 (s, 2 H), 3.29 (d, J ) 11.0 Hz, 1 H), 3.33 (s, 3 H), 3.44 (dd,
J ) 11.0, 3.9 Hz, 1 H), 3.85 (very br s, 1 H), 4.05 (very br s, 1
H), 6.68 (d, J ) 8.5 Hz, 2 H), 7.43 (d, J ) 8.6 Hz, 2 H); IR
0 °C) δ 35.9, 49.2, 72.3, 79.6, 117.7, 127.4, 128.4, 129.7, 133.3,
-
1
36.7, 170.7; IR (neat) 3291, 3082, 1641 cm ; LRMS (EI) m/z
+
(
%) 198 (M , 16), 158 (18), 105 (100), 77 (86); HRMS (EI) calcd
+
for C13
2
H12NO (M - H) 198.0919; found 198.0922.
N-Allyl-N-p r op a r gyl-4-m eth oxyben za m id e (13c). Fol-
lowing the general procedure, N-allyl-4-methoxybenzamide
560 mg, 2.93 mmol) in THF (20 mL) was treated with NaH
80% dispersion in mineral oil, 104 mg, 3.52 mmol) and
-
1
+
(
(
3
neat) 1713, 1623, 1610 cm ; LRMS EI m/z 315 (M , 1), 230
+
7), 135 (100). HRMS (CI, CH
16.1913, found 316.1909.
4 3
) for C19H26NO (MH ) calcd
(
(
propargyl bromide (80% in toluene, 0.98 mL, 8.80 mmol) to
Ack n ow led gm en t. We are grateful for support from
1
give 13c (580 mg, 87%): H NMR (300 MHz, C
.89 (t, J ) 2.0 Hz, 1 H), 3.23 (s, 3 H), 4.01 (br s, 4 H), 4.97 (d,
J ) 11.0 Hz, 1 H), 5.02 (d, J ) 18.3 Hz, 1 H), 5.62 (ddt, J )
6 6
D , 70 °C) δ
the National Institutes of Health (Grant GM 39972) and
the Alfred P. Sloan Foundation. Fellowship support to
D.M.S. from the Graduate Assistance in Areas of
National Need (GAANN) Program of the Department
of Education, is gratefully acknowledged. The 500 MHz
NMR spectrometer was purchased with assistance from
the National Institutes of Health (RR04733) and the
National Science Foundation (CHE 8814866). Mass
spectra were obtained with the assistance of Dr. Richard
Kondrat and associates at the University of California
at Riverside Mass Spectroscopy Facility.
1
1
8
5
6.7, 11.0, 5.6 Hz, 1 H), 6.64 (d, J ) 8.6 Hz, 2 H), 7.45 (d, J )
13
.7 Hz, 2 H); C NMR (75 MHz, C
6 6
D , 70 °C) δ 36.2, 49.4,
4.9, 72.1, 79.9, 114.0, 117.6, 128.8, 129.5, 133.6, 161.5, 170.6;
-
1
+
IR (neat) 3290, 3078, 1633 cm ; LRMS EI m/z 228 (M - 1,
1
C
), 190 (2), 188 (3), 135 (100), 107 (8). HRMS (EI) calcd for
+
14
H
15NO
2
(M ) 229.1103, found 229.1105.
Gen er a l P r oced u r e for “Sea led Via l” Con d ition s (16a-
c). The N-allyl-N-propargylamide derivative and the carbene
complex were dissolved in THF (20.0 mL) in a 25 mL sealable
glass vial. The vial was then sealed with a rubber-lined screw
cap and Teflon tape. After heating at 100 °C behind a blast
shield, the reaction was cooled to room temperature and
treated with 10% aqueous HCl (2 mL) for 1 h. The reaction
mixture was then concentrated in vacuo and chromatographed
on silica gel to give the indicated product.
Su p p or tin g In for m a tion Ava ila ble: Copies of H and 13C
NMR spectra for N-allyl-N-benzylamine, 5, N-allyl-N-(4-ni-
trobenzyl)-amine, 11, N-allylbenzamide, N-allyl-4-methoxy-
1
1
benzamide, N-allyl-4-nitrobenzamide, 13a , 13b, 13c, and H
NMR for 16a , 16b, and 16c (23 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
(
5â)-N-(4-Nitr oben zoyl)-1â-(2-oxoh exan yl)-3-azabicyclo-
[
3.1.0]h exa n e (16a ). Following the general procedure, 13a
(17) This compound has been reported previously. See: Brown, S.
W.; Pauson, P. L. J . Chem. Soc., Perkin Trans. 1 1990, 1205-1209.
J O9519930