Degradative rearrangements of N-(t-butyloxycarbonyl)-O-methanesulfonyl- hydroxamic acids: A novel, reagent-based alternative to the Lossen rearrangement

Full text of DOI:10.1021/jo981498e

10040
J . Org. Chem. 1998, 63, 10040-10044
Sch em e 1
Degr a d a tive Rea r r a n gem en ts of
N-(t-Bu tyloxyca r bon yl)-O-m eth a n esu lfon yl-
h yd r oxa m ic Acid s: A Novel, Rea gen t-Ba sed
Alter n a tive to th e Lossen Rea r r a n gem en t1
J effrey A. Stafford,* Stephen S. Gonzales,
David G. Barrett, Edward M. Suh, and Paul L. Feldman
Glaxo Wellcome Research, Five Moore Drive,
Research Triangle Park, North Carolina 27709
Received J uly 28, 1998
the hydroxamic acid results in dimerization (Scheme 1b).5
In this paper, we describe the development and applica-
tion of a modified Lossen rearrangement.
During the course of our research efforts, we required
a multigram conversion of cyclopentenyl carboxylic acid
1 to the corresponding amine 2 (eq 1). Application of the
Curtius rearrangement2 on laboratory microscale satis-
factorily delivered the desired product. However, due to
the scale on which we needed to operate the Curtius
reaction and the safety hazard3 associated with the in-
volvement of low molecular-weight acyl azides, we con-
sidered an alternative means for this transformation. The
oxidative and relatively harsh conditions required for the
Hofmann rearrangement2 represent a liability to its
application as well.
To overcome the dimerization associated with the class-
ical Lossen rearrangement, it would be desirable to ini-
tiate the rearrangement on the “activated hydroxamate”
(Scheme 1) only after the hydroxamic acid is completely
consumed. Therefore, we considered that a protected form
of the activated hydroxamate could harbor a latent
Lossen rearrangement substrate that would undergo
spontaneous rearrangement in the event of deprotection.
We recently described a method that was envisaged to
be applicable to the above hypothesis, namely the re-
moval of tert-butyloxycarbonyl (BOC) protecting groups
from amides and carbamates using mild Lewis acid ca-
talysis.6 By this method, BOC deprotection of a protected
and suitably activated hydroxamate would, in principle,
initiate the rearrangement sequence, undisturbed by the
presence of any interfering hydroxamic acid, providing
stepwise control of the Lossen rearrangement.7
Commercially available tert-butyl-N-hydroxycarbamate
(3) was converted to the methanesulfonyloxycarbamate
4 in 77% yield (Scheme 2). Reagent 4 is routinely
prepared in batches >20 g in weight and recrystallized
from diisopropyl ether.8 The coupling of 4 to an activated
carboxylic acid derivative of 1 was investigated in
considerable detail. The diminished basicity conferred on
the nitrogen atom in 4 by the attached tert-butyloxycar-
bonyl and methanesulfonyloxy groups compromises the
reactivity of 4 for many amine-acid coupling procedures.
Nevertheless, coupling of 4 with acid chloride 59 in DMF
provided the N-acylated derivative 6 in 73% yield fol-
lowing purification by flash chromatography. We found
that the relatively low reactivity of 4 is overcome by using
The Lossen rearrangement (Scheme 1), in which hy-
droxamic acids are O-activated to create a suitable
leaving group for subsequent rearrangement, also be-
longs to the category of named, classical carboxyl deg-
radation reactions that provide useful isocyanate inter-
mediates from carboxylic acid derivatives.2 We became
interested in the use of the Lossen rearrangement due
to its apparent simplicity and relatively mild conditions.
In our hands, however, attempts to effect the Lossen
rearrangement on the hydroxamic acid of 1 failed to
provide us with the desired amine, but rather afforded
complex mixtures. A survey of the chemical literature
reveals that the Lossen rearrangement receives little
attention as a general and practical synthetic method.
The reasons for its limited use appear to be two-fold: the
relative unavailability of hydroxamic acids and the
competing formation of self-condensation byproducts as
a result of unfavorable reaction kinetics.4 Specifically, the
rate-limiting step is the activation of the hydroxamic acid
(Scheme 1a); the consequence of these kinetics is ac-
cumulation of isocyanate before complete consumption
of the hydroxamic acid. Trapping of the isocyanate by
(5) (a) Stolberg, M. A.; Tweit, R. C.; Steinberg, G. M.; Wagner-
J auregg, T. J . Am. Chem. Soc. 1955, 77, 765. (b) Hurd, C. D.; Bauer,
L. J . Am. Chem. Soc. 1954, 76, 2791. (c) Pihuleac, J .; Bauer, L.
Synthesis 1989, 61.
(6) Stafford, J . A.; Brackeen, M. F.; Karanewsky, D. S.; Valvano,
N. L. Tetrahedron Lett. 1993, 34, 7873.
(7) Alternative strategies to provide stepwise control of the Lossen
rearrangement have been reported: (a) Miller, M. J .; Loudon, G. M.
J . Am. Chem. Soc. 1975, 97, 5295. (b) King, F. D.; Pike, S.; Walton, D.
R. M. J . Chem. Soc., Chem. Commun. 1978, 351.
* To whom correspondence should be addressed. E-mail: jas24960@
glaxowellcome.com.
(1) Part of this work was presented by SSG at the Southeast
Regional Meeting of the American Chemical Society, Greenville, SC,
Nov 1996.
(8) While reagent 4 can be readily manipulated on the benchtop in
open air, it is recommended that 4 be stored under nitrogen at 4 °C.
When stored in this manner, 4 is stable and can be used for several
months. (CAUTION: Formation of hazardous peroxides of diisopropyl
ether has been reported. For a review on controlling the hazards
associated with peroxidized ethers see: J ackson, H. L. et al. J . Chem.
Educ. 1970, 47, A175.)
(9) Activation and coupling of 1 via formation of a mixed anhydride
also provides good yields of 6. This method was applied for the
synthesis of 9 and 11 (vide infra). Attempts at carbodiimide-based
coupling procedures (e.g., EDC) were unsuccessful.
(2) For
a recent review on carboxyl degradation reactions see:
Shioiri, T. In Comprehensive Organic Synthesis; Trost, B. M., Ed.;
Pergamon: Oxford, 1991; Vol. 6, p 795, and references therein.
(3) (a) Landgrebe, J . A. Chem. Eng. News 1981, 59, 47. (b) Middleton,
W. J . J . Org. Chem. 1984, 49, 4541.
(4) (a) Hoare, D. G.; Olson, A.; Koshland, D. E., J r. J . Am. Chem.
Soc. 1968, 90, 1638. (b) Bauer, L.; Exner, O. Angew. Chem., Int. Ed.
Engl. 1974, 13, 376.
10.1021/jo981498e CCC: $15.00 © 1998 American Chemical Society
Published on Web 12/04/1998

Notes
J . Org. Chem., Vol. 63, No. 26, 1998 10041
Sch em e 2
Sch em e 3
Ta ble 1. Mod ified Lossen Rea r r a n gm en t of
Hyd r oxa m a te Der iva tive 6a
(entries 3 and 4). Complete removal of base from the
reaction mixture also resulted in lower yields (entry 5).
The options of using allyl alcohol or 2-trimethylsilyl-
ethanol (entries 6 and 8) introduce additional flexibility
to carbamate-deprotection strategies.11 A dramatic sol-
vent effect was noted. Thus, in less polar solvents (i.e.,
DME and toluene) little or no formation of 7a was
observed (entries 9 and 10).
Lewis
acid
temp yieldb
solvent (°C)
entry
base
alcohol
(%)
1
2
3
4
5
6
7
8
9
Zn(OTf)2 2,6-DTBP PhCH2OH
Zn(OTf)2 2,6-DTBP PhCH2OH
CH3CN 85
CH3CN 50
CH3CN 85
CH3CN 85
CH3CN 85
82
-
Zn(OTf)2 Et3N
Zn(OTf)2 pyridine PhCH2OH
Zn(OTf)2 PhCH2OH
PhCH2OH
54
55
35
76c
19
46d
47
-
-
Zn(OTf)2 2,6-DTBP CH2dCHCH2OH CH3CN 85
Zn(OTf)2 2,6-DTBP (CH3)3COH CH3CN 85
Zn(OTf)2 2,6-DTBP TMSCH2CH2OH CH3CN 85
Zn(OTf)2 2,6-DTBP PhCH2OH DME 85
Interestingly, the rearrangement can be effected in
equally good yield by thermolysis12 when the Lewis acid
is omitted (entry 11). This observation is in contrast to
our earlier work in which simple thermolysis at 85 °C
showed no effect on BOC deprotection from amides and
carbamates.6 After this finding, the Lewis acid was
omitted from the reaction vessel. The omission of the
Lewis acid prompted a reinvestigation into whether 2,6-
DTBP is the preferred base for this transformation.
Pyridine and 2,6-lutidine were both examined, but the
yields were consistently lower with these bases. Further
investigation to define the optimized conditions for rear-
rangement of 9 in the absence of zinc triflate paralleled
the findings observed for hydroxamate 6 in the presence
of zinc triflate. Finally, the observation that the rear-
rangement proceeds at 85 °C without zinc triflate led us
to consider stronger Lewis acids that may indeed catalyze
the process at lower temperatures (e.g., 0 °C). The use of
TMSOTf and TiCl4 failed to initiate the rearrangement
at or below room temperature, and these efforts were
discontinued.
10 Zn(OTf)2 2,6-DTBP PhCH2OH
toluene 85
CH3CN 85
11
-
2,6-DTBP PhCH2OH
78
a
All rearrangements were conducted according to the general
b
procedure described in the Experimental Section. Yields refer
to isolated, pure products having proper spectral and/or analytical
d
data. c Compound 7b in Experimental Section. Compound 7c
in Experimental Section.
DMF as the reaction solvent for the coupling of 4, and
by this practice we routinely obtained 6 in good yield.10
The N-acyl-hydroxamate products such as 6 described
herein are air stable, conveniently handled compounds
possessing excellent shelf stability at room temperature.
Treatment of 6 with zinc triflate, benzyl alcohol, and
2,6-di-tert-butylpyridine (2,6-DTBP) in acetonitrile at 85
°C effected the desired rearrangement to the CBz-
protected amine 7a in 82% isolated yield. The rearrange-
ment of 6 to 7a represents a novel method for the overall
conversion of a carboxylic acid to a protected amine. By
comparison to the classical Lossen rearrangement, use
of reagent 4 circumvents preparation of the requisite
hydroxamic acid and allows direct use of a more readily
available carboxylic acid. The conditions for the rear-
rangement of 6 were examined, and several points are
noteworthy (Table 1). A lowering of the reaction temper-
ature fails to effect the rearrangement, and starting
material is recovered (entry 2). 2,6-DTBP was chosen as
the base to scavenge methanesulfonic acid because we
believed that its steric hindrance would also serve to
inhibit coordination to the Lewis acid. The use of tri-
ethylamine or pyridine resulted in lower yields of 7a
To assess the scope and generality of the present
method, we investigated its application to the degradative
rearrangement of other carboxylic acids (Scheme 3).
Reagent 4 can be coupled to a variety of activated car-
boxylic acids. Coupling between 4 and the mixed anhy-
dride derived from hydrocinnamic acid (8) provided
compound 9 in 82% yield. Similarly, 4 couples to the
mixed anhydride of (R)-(-)-2-phenylpropionic acid (10)
(11) The alloc- and teoc-protected amines derived from these experi-
ments, compounds 7b and 7c, respectively, are described in the
Experimental Section.
(12) (a) Wasserman, H. H.; Berger, G. D. Tetrahedron 1983, 39,
2459. (b) Tian, X.; Hudlicky, T.; Ko¨nigsberger, K. J . Am. Chem. Soc.
1995, 117, 3643. (c) Rawal, V. H.; Cava, M. P. Tetrahedron Lett. 1985,
26, 6141.
(10) The use of methylene chloride or THF for the coupling of 4 to
activated carboxylic acid derivatives resulted in significantly dimin-
ished yields of coupled product.

10042 J . Org. Chem., Vol. 63, No. 26, 1998
Notes
Sch em e 4
Sch em e 5
In summary, we have described the novel rearrange-
ment of an activated, N-acyl-hydroxamate to a protected
amine in good yield. During the course of defining the
conditions for this rearrangement we found that Lewis
acids are not required to mediate this process. In this
regard, the present method differs from our earlier work,6
wherein the Lewis acid played a key role in facilitating
mild BOC deprotection. The underlying basis for this
difference remains unclear.
A noteworthy feature of the present rearrangement is
found in the stable rearrangement precursor. The novel
N-acyl-hydroxamates are conveniently prepared, stored,
and handled. The two-step, reagent-based sequence (i.e.,
coupling between reagent 4 and a carboxylic acid, fol-
lowed by rearrangement) is easily adapted to large-scale
preparations, making this “modified Lossen” reaction an
attractive alternative to the Curtius rearrangment and
similar rearrangements.
and the sterically demanding 1-adamantanecarbonyl
chloride (12) to provide protected hydroxamates 11 and
13, respectively.
The rearrangements of 9, 11, and 13 are illustrated in
Scheme 4. Thermolysis of 9 in acetonitrile in the presence
of 2,6-DTBP and an alcohol provided the desired car-
bamates 14a -c in good yields.13 Rearrangement of the
enantiopure hydroxamate 11 provided the CBz-protected
(R)-(+)-R-methylbenzylamine 15 in 69% yield. The enan-
tiopurity of 15 was determined to be 99% (98% ee),
establishing that this rearrangement, like other degrada-
tions (e.g., the Curtius rearrangement), proceeds with
retention of the configuration of the migrating group.14
The adamantyl hydroxamate 13 underwent rearrange-
ment under identical conditions, providing benzyl car-
bamate 16 in 53% yield.
Exp er im en ta l Section 16
The mechanism of the Lossen rearrangement is thought
to be similar to the related and more commonly used
Curtius, Schmidt, and Hofmann rearrangements, al-
though the exact nature of the transient intermediates
in all of these processes remains unclear.15 To probe
whether an isocyanate is the initial product of the current
method, the following experiments were performed
(Scheme 5). When rearrangement of 9 in the absence of
a trapping nucleophile was judged complete by TLC
analysis, allyl alcohol was added to the reaction mixture;
after workup and flash chromatography we obtained a
62% yield of carbamate 14b. Likewise, expanding the
scope of this process to include products other than
carbamates, the isocyanate arising from the rearrange-
ment of 6 was intercepted by benzylamine to afford an
80% yield of urea 17. Additionally, adamantyl hydrox-
amate 13 was heated in acetonitrile at 85 °C for 17 h,
filtered, and evaporated to a solid. IR analysis of this solid
showed a strong and sharp absorbance at 2256 cm-1, a
stretching frequency that is highly characteristic of an
isocyanate.
N-ter t-Bu t yloxyca r b on yl-O-m et h a n esu lfon ylh yd r oxyl-
a m in e (4). To a stirring solution of tert-butyl-N-hydroxycar-
bamate (3) (26.6 g, 0.2 mol) in CH2Cl2 (500 mL) at 0 °C was
added pyridine (17.4 g, 0.22 mol). After 10 min, methanesulfonyl
chloride (25.1 g, 0.22 mol) was added dropwise via an addition
funnel. The reaction was allowed to stand for 3 days at 4 °C
(refrigerator) and was then poured into water (200 mL). The
layers were separated, and the organic layer was washed with
water (100 mL), 1 M H3PO4 (100 mL), and brine (100 mL). The
organic layer was dried (MgSO4), filtered, and concentrated in
vacuo to a solid. Recrystallization from diisopropyl ether/hexanes
afforded 4 as a colorless solid (32.6 g, 77%, two crops). Mp: 83-
1
85 °C. H NMR (DMSO-d6, 400 MHz): δ 11.35 (s, 1), 3.19 (s, 3),
1.41 (s, 9). 13C NMR (CDCl3, 100 MHz): δ 154.8, 84.6, 36.1, 27.9.
(16) All starting materials were obtained from commercial suppliers
and used without further purification. All reactions involving oxygen-
or moisture-sensitive compounds were performed under a dry N2
atmosphere. All reactions and chromatography fractions were analyzed
by thin-layer chromatography on 2.5 × 7.5 cm silica gel plates (250-
µm SiO2 thickness) and visualized with UV light and/or KMnO4 dip
(Feldman, P. L.; Rapoport, H. J . Org. Chem. 1986, 51, 3882). Flash
column chromatography was carried out using Merck silica gel 60
(230-400 mesh). Evaporation of solvents was accomplished with a
rotary evaporator. 1H NMR and 13C NMR spectra were measured using
either a Varian Unity Plus 300 or a Varian Unity Plus 400 spectrom-
eter. Chemical shifts are expressed in ppm downfield from the internal
standard, tetramethylsilane. Apparent multiplicities are designated
as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; or
b, broad. J values are reported in Hertz. IR spectra were recorded on
a Nicolet 510 FT-IR spectrometer. Mass spectra were taken in positive-
ion mode by atmospheric pressure chemical ionization (APCI). Melting
points were determined on a Laboratory Devices Mel-Temp III and
are uncorrected. Elemental analyses were performed by Atlantic
Microlab (Norcross, GA).
(13) For comparison purposes the rearrangement of 9 in the pres-
ence of zinc triflate and benzyl alcohol provided 14a in 69% yield.
(14) Analyzed by comparison with a racemic sample using super-
critical fluid chromatography in a Chiralcel OJ column (mobile phase:
5% methanol and 95% CO2; flow rate: 2.0 mL/min; monitored at 255
nM).
(15) March, J . Advanced Organic Chemistry, J ohn Wiley & Sons:
New York, 1985; Chapter 18, pp 982-987.

Notes
J . Org. Chem., Vol. 63, No. 26, 1998 10043
Anal. Calcd for C6H13NO5S: C, 34.12; H, 6.20; N, 6.63. Found:
C, 34.16; H, 6.25; N, 6.62.
brine (100 mL), dried (MgSO4), filtered, and concentrated in
vacuo to give a white solid. This solid was triturated with
hexanes/ether (6:1) to provide 9 (8.97 g, 87%), possessing the
spectral identity of that described above.
N-(t-Bu t yloxyca r b on yl)-N-(m et h a n esu lfon yloxy)cyclo-
p en t-3-en ylca r boxa m id e (6). To a cooled (0 °C), stirring
solution of 3-cyclopentene carboxylic acid (1)17 (1.12 g, 10.0
mmol) in CH2Cl2 (20 mL) was added, dropwise, oxalyl chloride
(1.33 g, 10.5 mmol), followed by one drop of DMF. The resulting
solution was stirred at ambient temperature until gas evolution
ceased (ca. 3 h). The volume of CH2Cl2 was reduced by concen-
tration in vacuo to provide a concentrated solution of acid
chloride 5, which was used immediately.
To a cooled (0 °C), stirring solution of 4 (1.89 g, 9.0 mmol) in
DMF (30 mL) were added triethylamine (1.21 g, 12 mmol) and
4-(dimethylamino)pyridine (DMAP) (0.09 g, 0.74 mmol). This
solution was then treated with the solution of 5 described above.
The resulting mixture was stirred at ambient temperature for
1 h and then diluted with water (60 mL). The solution was
extracted with ether (4 × 40 mL), and the combined ether
extracts were washed with water (2 × 30 mL), 1 M H3PO4 (40
mL), and brine (50 mL). The resulting organic layer was dried
(MgSO4), filtered, and concentrated in vacuo to give an orange
oil. Flash chromatography (4:1 hexanes/ethyl acetate) afforded
6 as a colorless solid (2.00 g, 73%). Mp: 62-65 °C (hexanes). 1H
NMR (CDCl3, 400 MHz): δ 5.66 (s, 2), 4.05 (quint, 1, J ) 7.7),
3.33 (s, 3), 2.73 (bd, 4), 1.58 (s, 9). 13C NMR (CDCl3, 100 MHz):
δ 173.3, 149.5, 128.6, 86.7, 42.6, 40.3, 36.6, 27.7. Anal. Calcd
for C12H19NO6S: C, 47.20; H, 6.27; N, 4.59. Found: C, 47.23; H,
6.21; N, 4.58.
Gen er a l P r oced u r e for th e Cou p lin g of 4 to a Mixed
An h yd r id e. N-(t-Bu tyloxyca r bon yl)-N-(m eth a n esu lfon yl-
oxy)-3-p h en ylp r op ion a m id e (9). To a solution of 3-phenyl-
propionic acid (8) (750 mg, 5.0 mmol) in DMF (10 mL), stirring
at 0 °C, was added N-methylmorpholine (NMM) (510 mg, 5.0
mmol). The solution was stirred for 5 min, and then isobutyl
chloroformate (690 mg, 5.1 mmol) was added dropwise. The
mixture was stirred for 30 min at 0 °C and then added to a
solution of N-(t-butyloxycarbonyl)-O-methanesulfonylhydroxyl-
amine (1.0 g, 4.8 mmol) and 4-(dimethylamino)pyridine (DMAP)
(60 mg, 0.5 mmol) in DMF (3 mL) at 0 °C. The ice bath was
removed, and the mixture was stirred for 16 h at room temper-
ature. The mixture was then partitioned between ether (50 mL)
and water (100 mL). The aqueous layer was extracted with ether
(3 × 20 mL), and the combined organic layers were washed with
water (2 × 50 mL), 1 M H3PO4 (50 mL), and brine (50 mL). The
organic layer was dried (MgSO4), filtered, and concentrated in
vacuo to a solid that was triturated with 8:1 hexanes/ether to
give 9 as a colorless solid (1.36 g, 82%). Mp: 85-87 °C. 1H NMR
(CDCl3, 300 MHz): δ 7.32-7.21 (m, 5), 3.29 (s, 3), 3.21 (bt, 2),
3.00 (t, 2, J ) 7.6), 1.56 (s, 9), 13C NMR (CDCl3, 100 MHz): δ
169.8, 149.6, 140.1, 128.5, 128.4, 126.4, 86.8, 40.3, 38.7, 30.4,
28.0, 27.7. Anal. Calcd for C15H21NO6S: C, 52.47; H, 6.16; N,
4.08. Found: C, 52.53; H, 6.22; N, 4.10.
(R)-N-(t-Bu tyloxyca r bon yl)-N-(m eth a n esu lfon yloxy)-2-
p h en ylp r op ion a m id e (11). (R)-(-)-2-phenylpropionic acid was
coupled to compound 4 according to the general procedure for
mixed anhydride coupling to give, after flash chromatography
(10% ethyl acetate/hexane), the product (1.15 g, 50%) as a clear
oil. 1H NMR (CDCl3, 400 MHz): δ 7.34-7.25 (m, 5), 4.85 (bq,
1), 3.28 (bs, 3), 1.53 (d, 3, J ) 7), 1.49 (s, 9). 13C NMR (CDCl3,
100 MHz): δ 172.1, 149.3, 139.5, 128.5, 127.8, 127.3, 86.7, 45.4,
39.9, 27.5, 19.4. Anal. Calcd for C15H21NO6S: C, 52.47; H, 6.16;
N, 4.08. Found: C, 52.72; H, 6.21; N, 4.03.
N-(t-Bu tyloxyca r bon yl)-N-(m eth a n esu lfon yloxy)-1-a d a -
m a n ta n eca r boxa m id e (13). 1-Adamantanecarbonyl chloride
(4.16 g, 21 mmol) was treated according to the general procedure
for acid chloride coupling to give, after flash chromatography
(10% ethyl acetate/hexane), the product (3.2 g, 43%) as a white
1
solid. Mp: 108-110 °C. H NMR (CDCl3, 400 MHz): δ 3.22, (s,
3), 2.08 (m, 6), 2.05 (br s, 3), 1.73 (s, 6), 1.57 (s, 9). 13C NMR
(CDCl3, 100 MHz): δ 181.0, 151.6, 86.6, 45.7, 38.2, 38.06, 36.2,
28.0, 27.9. Anal. Calcd for C17H27NO6S: C, 54.67; H, 7.29; N,
3.75. Found: C, 54.79; H, 7.31; N, 3.82.
Gen er a l P r oced u r e for th e Mod ified Lossen Rea r r a n ge-
m en t w ith Lew is Acid . N-(Ben zyloxyca r bon yl)cyclop en t-
3-en yla m in e (7a ). To a solution of 6 (610 mg, 2.0 mmol) in
CH3CN (10 mL) were added benzyl alcohol (238 mg, 2.2 mmol),
2,6-di-t-butylpyridine (382 mg, 2.0 mmol), and zinc triflate (72
mg, 0.2 mmol). The mixture was heated with stirring to 85 °C
for 16 h and then cooled to room temperature. It was then diluted
with ethyl acetate (50 mL) and washed with water (50 mL), 1
M H3PO4 (50 mL), and brine (50 mL). The combined aqueous
layers were back-extracted with ethyl acetate (2 × 50 mL), and
the combined organic layers were dried (MgSO4), filtered, and
concentrated in vacuo. Flash chromatography (4:1 hexanes/ethyl
acetate) afforded 7a as a colorless solid (352 mg, 81%). Mp: 50-
1
52 °C. H NMR (DMSO-d6, 400 MHz): δ 7.42-7.25 (m, 5), 5.63
(s, 2), 4.97 (s, 2), 4.08 (m, 1), 2.53 (dd, 2, J ) 8.2, 14.8), 2.13 (dd,
2, J ) 5.2, 14.7). 13C NMR (CDCl3, 100 MHz): δ 155.8, 136.5,
128.7, 128.4, 128.0, 127.9, 66.4, 50.5, 40.2. Anal. Calcd for C13H15
-
NO2: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.83; H, 6.97; N,
6.47.
N-(Allyloxyca r bon yl)cyclop en t-3-en yla m in e (7b). Com-
pound 6 (610 mg, 2 mmol) was treated according to the general
procedure above using allyl alcohol (2.2 mmol) in place of benzyl
alcohol to yield 7b as a colorless oil (253 mg, 76%). 1H NMR
(CDCl3, 400 MHz): δ 5.93 (m, 1), 5.69 (overlapping dd, 2, J )
8.3), 5.30 (d, 1, J ) 17.3), 5.21 (d, 1, J ) 10.3), 4.88 (bs, 1), 4.56
(bd, 2, J ) 4.6), 4.35 (bd, 1, J ) 3.3), 2.74 (dd, 2, J ) 7.5, 15.6),
2.20 (dd, 2, J ) 3.8, 15.2). 13C NMR (CDCl3, 100 MHz): δ 155.8,
132.9, 128.7, 117.5, 65.3, 50.5, 40.2. Anal. Calcd for C9H13NO2:
C, 64.65; H, 7.84; N, 8.38. Found: C, 64.37; H, 7.76; N, 8.33.
N -(Tr im e t h ylsilyle t h oxyca r b on yl)cyclop e n t -3-e n yl-
a m in e (7c). Compound 6 (323 mg, 1.1 mmol) was treated
according to the general procedure above using 2-trimethylsi-
lylethanol (1 mmol) in place of benzyl alcohol to yield 7c as a
1
colorless solid (104 mg, 46%). Mp: 45-46 °C. H NMR (CDCl3,
300 MHz): δ 5.69 (overlapping dd, 2, J ) 8.3), 4.75 (bs, 1), 4.33
(bs, 1), 4.14 (t, 2, J ) 8.3), 2.73 (dd, 2, J ) 7.6, 15.5), 2.19 (dd,
2, J ) 3.9, 15.2), 0.97 (t, 2, J ) 8.3), 0.04 (s, 9). 13C NMR (CDCl3,
100 MHz): δ 156.3, 128.7, 62.8, 50.4, 40.3, 17.7, -1.5. Anal.
Calcd for C11H21NO2Si: C, 58.11; H, 9.31; N, 6.16. Found: C,
58.12; H, 9.38; N, 6.07.
1-(Ben zyloxyca r bon yl)p h en eth yla m in e (14a ). Compound
9 (686 mg, 2 mmol) was treated according to the general
procedure above to yield 14a as a colorless solid (350 mg, 69%).
Mp: 55-57 °C. 1H NMR (CDCl3, 400 MHz): δ 7.34-7.17 (m,
10), 5.10 (s, 2), 4.74 (bs, 1), 3.47 (dd, 2, J ) 6.6, 13.0), 2.82 (t, 2,
J ) 6.8). 13C NMR (CDCl3, 100 MHz): δ 156.2, 138.6, 136.5,
128.7, 128.5, 128.4, 128.3, 128.0, 126.4, 66.6, 42.1, 36.0. Anal.
Calcd for C16H17NO2: C, 75.27; H, 6.71; N, 5.49. Found: C, 75.19;
H, 6.71; N, 5.49.
Gen er a l P r oced u r e for Cou p lin g of 4 to Acid Ch lor id es.
N-(t-Bu tyloxyca r bon yl)-N-(m eth a n esu lfon yloxy)-3-p h en yl-
p r op ion a m id e (9). To a solution of compound 4 (6.33 g, 30
mmol) stirring in DMF (120 mL) at 0 °C was added, in order,
triethylamine (3.33 g, 33 mmol), 4-(dimethylamino)pyridine (366
mg, 3 mmol), and hydrocinnamoyl chloride (5.29 g, 31.5 mmol).
The mixture was stirred for 5 min at 0 °C and then allowed to
warm to room temperature, being stirred 1 h longer. The mixture
was partitioned between ether and water (300 mL each), the
layers were separated, and the aqueous layer was extracted with
diethyl ether (3 × 120 mL). The combined organic layers were
washed with water (2 × 100 mL), 1 M H3PO4 (100 mL), and
Gen er a l P r oced u r e for th e Th er m olytic Degr a d a tion of
th e Hyd r oxa m a tes. N-(Ben zyloxyca r bon yl)cyclop en t-3-
en yla m in e (7a ). To a solution of 6 (305 mg, 1.0 mmol) in CH3-
CN (5 mL) were added benzyl alcohol (1.1 mmol) and 2,6-di-
tert-butylpyridine (1.0 mmol). The mixture was heated with
stirring to 85 °C for 22 h and then cooled to room temperature.
It was then diluted with ethyl acetate (50 mL) and washed with
water (50 mL), 1 M H3PO4 (50 mL), and brine (50 mL). The
combined aqueous layers were back-extracted with ethyl acetate
(2 × 50 mL), and the combined organic layers were dried
(MgSO4), filtered, and concentrated in vacuo. Flash chromatog-
raphy (4:1 hexanes/ethyl acetate) afforded 7a as a colorless solid
(168 mg, 78%). Spectral data for this compound were identical
to those described above.
(17) Schmid, G. H.; Wolkoff, A. W. J . Org. Chem. 1967, 32, 254.

10044 J . Org. Chem., Vol. 63, No. 26, 1998
Notes
1
1-(Ben zyloxyca r bon yl)p h en eth yla m in e (14a ). Compound
9 (343 mg, 1 mmol) and benzyl alcohol (1.1 mmol) were treated
according to the general procedure for thermolytic rearrange-
ment, to provide, after flash chromatography (4:1 ethyl acetate/
hexane), 14a as a colorless solid (198 mg, 78%). Spectral data
for this compound were identical to those described above.
1-(Allyloxyca r bon yl)p h en eth yla m in e (14b). Compound 9
(343 mg, 1 mmol) and allyl alcohol (64 mg, 1.1 mmol) were
treated according to the general procedure for thermolytic
rearrangement to give, after flash chromatography (10% ethyl
acetate/hexane), 14b as a white solid (160 mg, 78%). 1H NMR
(CDCl3, 400 MHz): δ 7.33-7.19 (m, 5), 5.96-5.88 (m, 1), 5.29
(d, 1, J ) 17.2), 5.20 (d, 1, J ) 10.4), 4.72 (bs, 1), 4.56 (d, 2, J )
5.3), 3.46 (q, 2, J ) 6.6, 13.1), 2.82 (t, 2, J ) 7). 13C NMR (CDCl3,
100 MHz): δ. Anal. Calcd for C12H15NO2: C, 70.22; H, 7.37; N,
6.82. Found: C, 69.95; H, 7.33; N, 6.85.
1-(Tr im eth ylsilyleth oxyca r bon yl)p h en eth yla m in e (14c).
Compound 9 (686 mg, 2 mmol) and 2-(trimethylsilyl)ethanol (260
mg, 2.2 mmol) were treated according to the general procedure
for thermolytic rearrangement to give, after flash chromatog-
raphy (10% ethyl acetate/hexane), 14c as a clear-oil compound
(284 mg, 54%). 1H NMR (CDCl3, 400 MHz): δ 7.33-7.18 (m, 5),
4.62 (bs, 1), 4.15 (t, 2, J ) 8.6), 3.43 (q, 2, J ) 6.5, 13), 2.81 (t,
2, J ) 7), 0.96 (t, 2, J ) 8.6), 0.03 (s, 9). 13C NMR (CDCl3, 100
MHz): δ 158.2, 140.3, 130.3, 127.9, 64.4, 43.6, 37.7, 19.2, 1.5.
Anal. Calcd for C14H23NO2Si: C, 63.35; H, 8.73; N, 5.28. Found:
C, 63.13; H, 8.66; N, 5.29.
°C. H NMR (CDCl3, 400 MHz): δ 7.38-7.28 (m, 5), 5.04 (br s,
2), 4.62 (br s, 1), 2.08 (m, 3), 1.94 (d, 6, J ) 2.2), 1.67 (s, 6). 13C
NMR (CDCl3, 100 MHz): δ 136.8, 128.5, 128.1, 128.0, 65.9, 50.7,
41.8, 36.5, 36.3, 29.4. Anal. Calcd for C18H23NO2: C, 75.76; H,
8.12; N, 4.91. Found: C, 75.92; H, 8.20; N, 4.91.
Step w ise Rea r r a n gem en t a n d Tr a p p in g of N-Acyl-h y-
d r oxa m a te. 1-(Allyloxyca r bon yl)-p h en eth yla m in e (14b). To
solution of compound 9 (686 mg, 2 mmol) in acetonitrile (10 mL)
was added 2,6-di-tert-butylpyridine (382 mg, 2 mmol). The
mixture was heated to 85 °C. After 8 h, thin-layer chromatog-
raphy indicated that starting material was still present. After
24 h, the rearrangement was judged to be complete by TLC
analysis. Allyl alcohol (582 mg, 10 mmol) was added to the
mixture, which was then stirred at 85 °C for an additional 2 h.
The reaction was worked up as previously described and purified
via flash chromatography to afford 14b (253 mg, 62%), whose
spectral characteristics were identical to those described above.
N-(3-Cyclop en ten yl)-N-(p h en ylm eth yl)u r ea (17). Com-
pound 6 (305 mg, 1.0 mmol), 2,6-di-tert-butylpyridine (224 µL,
1 mmol), and zinc trifluoromethanesulfonate (364 mg, 0.1 mmol)
were dissolved in acetonitrile (10 mL), and the solution was
heated to reflux with stirring. The reaction was monitored by
TLC (4:1 hexane/ethyl acetate) for disappearance of 6, and after
6 h, formation of the isocyanate was judged complete. Ben-
zylamine (120 µL, 1.1 mmol) was then added in one portion, and
the reaction was stirred for 20 min. The reaction was allowed
to cool to room temperature and was concentrated to an oil. Flash
chromatography (4:1 to 1:1 hexane/ethyl acetate) afforded 17 as
a colorless solid (172 mg, 80%). Mp: 133-134 °C. Low resolution
MS (CI): m/e 217.2 (MH+), 238.9 (M + Na+), 151.1. 1H NMR
(CDCl3, 400 MHz): δ 7.32-7.22 (m, 5), 5.65 (m, 2), 4.33 (m, 3),
2.69 (dd, 2, J ) 7.5, 15.2), 2.13 (dd, 2, J ) 3.7, 15). 13C NMR
(CDCl3, 100 MHz): δ 157.8, 139.0, 128.8, 128.6, 127.5, 127.4,
50.0, 44.6, 40.6. Anal. Calcd for C13H16N2O: C, 72.19; H, 7.46;
N, 12.95. Found: C, 72.08; H, 7.44; N, 13.00.
(R)-(+)-1-(Ben zyloxycar bon yl)-r-m eth ylben zylam in e (15).
Compound 11 (686 mg, 2 mmol) and benzyl alcohol (238 mg,
2.2 mmol) were treated according to the general procedure for
thermolytic rearrangement to give, after flash chromatography
(20% ethyl acetate/hexane), 15 as a white solid (353 mg, 69%).
1H NMR (CDCl3, 400 MHz): δ 7.34-7.24 (m, 10), 5.08 (ABq, 2,
J ) 25.3, 12.3) 5.04 (br m, 1), 4.86 (br m, 1), 1.48 (d, 3, J ) 6.6).
13C NMR (CDCl3, 100 MHz): δ 155.5, 143.4, 136.4, 128.6, 128.5,
128.1, 127.3, 125.9, 77.2, 66.7, 50.7, 22.5. Anal. Calcd for C16H17
-
NO2: C, 75.27; H, 6.71; N, 5.49. Found: C, 75.12; H, 6.81; N,
5.48.
Ack n ow led gm en t. The authors thank Manon Vil-
leneuve and Lan Nguyen for HPLC analysis of the
enantiomeric purity of 15 and Dr. Susan M. Daluge for
many helpful discussions.
1-(Ben zyloxyca r bon yl)-1-a d a m a n ta n a m in e (16). Com-
pound 13 (746 mg, 2 mmol) and benzyl alcohol (238 mg, 2.2
mmol) were treated according to the general procedure for
rearrangement to give, after flash chromatography (10% ethyl
acetate/hexane), 16 as a white solid (302 mg, 53%). Mp: 34-36
J O981498E