Titanocene(III) chloride-mediated reductions of oxazines, hydroxamic acids, and N-hydroxy carbamates

Article abstract of DOI:10.1021/jo802184y

(Chemical Equation Presented) Titanocene(III) chloride (Cp ₂TiCl), generated in situ, reduces N-O bonds of various substrates in good to excellent yields (72-95%). Reactions may be performed with stoichiometric Cp₂TiCl or with cataly

Full text of DOI:10.1021/jo802184y

SCHEME 1. Syntheses of Carbocyclic Nucleosides from 3
Titanocene(III) Chloride-Mediated Reductions of
Oxazines, Hydroxamic Acids, and N-Hydroxy
Carbamates
Cara Cesario, Lawrence P. Tardibono, Jr., and
Marvin J. Miller*
Department of Chemistry and Biochemistry, UniVersity of
Notre Dame, 251 Nieuwland Science Hall,
Notre Dame, Indiana 46545
mmiller1@nd.edu
ReceiVed October 1, 2008
reagent has been used in reductive openings of epoxides,5
carbonyl-coupling reactions,6 and reduction of R,ꢀ-unsaturated
carbonyls,7 Cp2TiCl has not been investigated as a reagent for
the reduction of N-O bonds.
We selected several substrates containing N-O bonds,
including oxazines, N-hydroxyazetidinones, hydroxamic acids,
and N-hydroxycarbamates, as these compounds often serve as
key intermediates in the synthesis of carbocyclic nucleosides,8
ꢀ-lactam antibiotics,9 and benzodiazepines.10
Acylnitroso-derived hetero-Diels-Alder adducts 1 and 2,
generated from the reaction of a transient acylnitroso species
with cyclopentadiene and cyclohexadiene,11 respectively, are
synthetically important precursors to a variety of bioactive
molecules. For example, oxazine 1 may be reduced with
Mo(CO)6 to afford syn-1,4 aminocyclopentenol 3,12 a key
intermediate in the synthesis of noraristeromycin 4a8c and
carbocyclic uracil polyoxin C 4b8b (Scheme 1).
Titanocene(III) chloride (Cp2TiCl), generated in situ, reduces
N-O bonds of various substrates in good to excellent yields
(72-95%). Reactions may be performed with stoichiometric
Cp2TiCl or with catalytic Cp2TiCl.
In order to access diversified cyclopentene scaffolds, several
metal-mediated ring-opening strategies have been established
with key cycloadduct intermediate 1 to introduce different
functionalities as well as defined stereo- and regiochemistries.13-15
Reduction of N-O bonds with titanium(III) is a useful
transformation that has been applied to nitro groups,1 oximes,2
N-hydroxyazetidinones, hydroxamic acids, and N-hydroxycar-
bamates.3 Mechanistically, the reduction proceeds by single-
electron transfer and requires 2 equiv of the titanium(III) source
for each N-O bond. The preferred source of titanium(III) is
titanium trichloride, commercially available as a solution in
hydrochloric acid. Unfortunately, the concentration of tita-
nium(III) in solution is variable, and methods for determining
the concentration by titration are limited.4 Also, Ti(IV) salts
are formed in the reaction mixture, which often complicate the
workup. Additionally, the reaction conditions may not be
compatible with acid-sensitive functionalities.
(5) (a) RajanBabu, T. V.; Nugent, W. A. J. Am. Chem. Soc. 1994, 116, 986–
997. (b) Gansa¨uer, A.; Bluhm, H.; Pierobon, M. J. Am. Chem. Soc. 1998, 120,
12849–12859.
(6) (a) McMurry, J. E. Chem. ReV. 1989, 89, 1513–1524. (b) Furstner, A.;
Bogdanovic, B. Angew. Chem., Int. Ed. 1996, 35, 2442–2469.
(7) Moisan, L.; Hardouin, C.; Rousseau, B.; Doris, E. Tetrahedron Lett. 2002,
43, 2013–2015.
(8) (a) Kim, K.; Miller, M. J. Tetrahedron Lett. 2003, 44, 4571–4573. (b)
Li, F.; Brogan, J. B.; Gage, J. L.; Zhang, D.; Miller, M. J. J. Org. Chem. 2004,
69, 4538–4540. (c) Jiang, M. X.; Jin, B.; Gage, J. L.; Priour, A.; Savela, G.;
Miller, M. J. J. Org. Chem. 2006, 71, 4164–4169.
(9) (a) Woulfe, S. R.; Miller, M. J. Tetrahedron Lett. 1984, 25, 3293–3296.
(b) Woulfe, S. R.; Miller, M. J. J. Med. Chem. 1985, 28, 1447–1453. (c) Miller,
M. J. Acc. Chem. Res. 1986, 19, 49–56. (d) Boyd, D. B.; Eigenbrot, C.; Indelicato,
J. M.; Miller, M. J.; Pasini, C. E.; Woulfe, S. R. J. Med. Chem. 1987, 30, 528–
536. (e) Williams, M. A.; Miller, M. J. Tetrahedron Lett. 1990, 31, 1807–1810.
(f) Teng, M.; Gasparski, C. M.; Williams, M. A.; Miller, M. J. Bioorg. Med.
Chem. Lett. 1993, 3, 2431–2436. (g) Ghosh, M.; Miller, M. J. Tetrahedron 1996,
52, 4225–4238.
(10) Surman, M. D.; Mulvihill, M. J.; Miller, M. J. Org. Lett. 2002, 4, 139–
141.
(11) (a) Kirby, G. W. Chem. Soc. ReV 1977, 6, 1–24. (b) Vogt, P. F.; Miller,
M. J. Tetrahedron 1998, 54, 1317–1348.
Our continued interest in hydroxamic acids and the syntheses
of biologically relevant molecules from oxazine 1 and N-
hydroxyazetidinones led us to develop an improved and versatile
method for N-O bond reductions. We report herein the use of
an alternative source of titanium(III), titanocene monochloride
(Cp2TiCl), for the selective reduction of N-O bonds under mild
conditions and provides products in good to excellent yields.
Titanocene monochloride is readily generated in situ from
titanocene dichloride (Cp2TiCl2) and zinc dust. Although this
(12) Mulvihill, M. J.; Gage, J. L.; Miller, M. J. J. Org. Chem. 1998, 63,
3357–3363.
(1) (a) McMurry, J. E.; Melton, J. J. Org. Chem. 1973, 38, 4367–4373. (b)
McMurry, J. E. Acc. Chem. Res. 1974, 7, 281–286.
(2) Timms, G. H.; Wildsmith, E. Tetrahedron Lett. 1971, 12, 195–198.
(3) Mattingly, P. G.; Miller, M. J. J. Org. Chem. 1980, 45, 410–415.
(4) Citterio, A.; Cominelli, A.; Bonavoglia, F. Synthesis 1986, 308–309.
(13) Ring-opening of cycloadduct 1 with Pd(0), Cu(II), and Fe(III): (a)
Mulvihill, M. J.; Surman, M. D.; Miller, M. J. J. Org. Chem. 1998, 63, 4874–
4875. (b) Surman, M. D.; Miller, M. J. J. Org. Chem. 2001, 66, 2466–2469.
(14) Ring-opening of cycloadduct 1 with Grignard reagents: Surman, M. D.;
Mulvihill, M. J.; Miller, M. J. J. Org. Chem. 2002, 67, 4115–4121.
448 J. Org. Chem. 2009, 74, 448–451
10.1021/jo802184y CCC: $40.75 2009 American Chemical Society
Published on Web 11/17/2008

TABLE 1. Cp2TiCl-Mediated Reductions of Cycloadducts 5a-g
TABLE 2. Cp2TiCl-Mediated Reductions of Substrates 9a,b
entry
substrate
R
product
isolated yield (%)
entry cycloadduct
R
n
product isolated yield (%)
1
2
9a
9b
CH2Ph
OC(CH3)3
10a
10b
72
73
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
Ph
1
1
1
1
1
2
2
6a
6b
6c
6d
6e
6f
95
78
79
79
0
(R)-CH(OH)Ph
CH2Ph
OC(CH3)3
4-NO2Ph
CH2Ph
TABLE 3. Cp2TiCl-Mediated Reductions of Substrates 11a-c
86
77
5g
OC(CH3)3
6g
SCHEME 2. Proposed Mechanism for Cp2TiCl-Mediated
Reductions
isolated
yield (%)
entry
substrate
R
product
1
2
3
11a
11b
11c
H
Me
CH2Ph
12
12
12
80
no reaction
no reaction
TABLE 4. Cp2TiCl-Catalyzed Reductions of Selected Substrates
isolated yield
(%) catalytic
isolated yield
(%) stoich.
entry substrate conditions product
1
2
3
4
5
6
7
8
9
5c
5c
5d
5d
9a
Ba
Ca
Ba
Ca
Ba
Ca
Ca
Ba
Ca
6c
6c
6d
6d
10a
10a
10b
12
50 (7020
)
79
79
79
79
72
72
73
80
80
incomplete rxnb
In all cases, these metal-mediated ring openings furnish hy-
droxamic acids or N-hydroxycarbamates that may serve as
appropriate substrates for Cp2TiCl-mediated reductions.
A series of acylnitroso-derived hetero-Diels-Alder cycload-
ducts 1 and 2 were subjected to Cp2TiCl-mediated reduction
conditions (Table 1). Benzoyl-derived cycloadduct 5a was added
to a cooled solution of Cp2TiCl2 and zinc. The reaction was
complete within 45 min and syn-1,4 aminocyclopentenol 6a was
observed as the exclusive product in 95% yield. An identical
outcome was obtained for [2.2.1] bicyclic systems 5b-d
although in slightly decreased yield.
71
incomplete rxnb
48
43
44
9a
9b
11a
11a
no rxnc
no rxnc
12
a Procedure B: (i) Cp2TiCl2 (0.2 equiv), Mn (8 equiv),
2,4,6-trimethylpyridine (8 equiv), TMSCl (4 equiv); (ii) TBAF.
Procedure
C:
Cp2TiCl2
(0.2
equiv),
Mn
(8
equiv),
2,4,6-trimethylpyridinium HCl (2 equiv), 1,4-cyclohexadiene (4 equiv).
b Incomplete reaction after 18 h. c Unreactive toward catalytic Cp2TiCl.
Titanium(III) is known to reduce nitro groups;1 however, we
were interested to learn if the strained oxazine system could be
preferentially reduced in the presence of an aromatic nitro group.
Unfortunately, when nitro-containing cycloadduct 5e was
exposed to Cp2TiCl in solution, a complicated mixture resulted
and no desired product was observed.
presence of Pd(0) and the transient π-allyl species trapped with
acetic acid to provide 9a13 and 9b, respectively. When hydrox-
amate 9a was introduced to a solution of Cp2TiCl2 and zinc,
reduction occurred smoothly to afford amide 10a. Similarly,
N-hydroxycarbamate 9b was readily reduced to carbamate 10b.
Our group has previously reported the reduction of N-
hydroxyazetidinones with TiCl3.3 Therefore, we were not
surprised to find that N-hydroxyazetidinone 11a was reduced
to the corresponding azetidinone 12 with Cp2TiCl (Table 3).
Consistent with our group’s previous report,3 N-alkoxyazetidi-
none 11b and N-benzyloxyazetidinone 11c were unreactive
toward Ti(III)-reduction conditions.
We also investigated [2.2.2] cycloadducts 5f and 5g. syn-
1,4-Aminocyclohexenol products 6f and 6g were observed in
86% and 77% yields, respectively.
The Cp2TiCl-mediated reduction may proceed by the pro-
posed reaction mechanism (Scheme 2).16,17 Single-electron
transfer from Cp2TiCl to 1 cleaves the weak N-O bond and
generates radical intermediate 7. A second equivalent of Cp2TiCl
transfers an electron to the radical species to form reduced
product 8, which is protonated in the presence of MeOH/H2O
to reveal syn-1,4-aminocyclopentenol 3.
The successful reductions of oxazine systems 5a-g encour-
aged us to evaluate hydroxamic acid 9a and N-hydroxycarbam-
ate 9b as substrates for reduction with Cp2TiCl (Table 2). The
C-O bonds of cycloadducts 5c and 5d were cleaved in the
These observations demonstrated that Cp2TiCl-mediated
reductions of several N-O bond-containing substrates proceed
in good to excellent yields.
In order to regenerate Ti(III) from Ti(IV), 2,4,6-trimethylpy-
ridine and chlorotrimethylsilane may be used in the presence
of excess reductant (usually zinc or manganese metal).16 An
alternative method to regenerate Ti(III) from Ti(IV) requires
1,4-cyclohexadiene, 2,4,6-trimethylpyridinium hydrochloride,
and excess manganese powder.5b Several Cp2TiCl-catalyzed
reactions have been reported,5b,6b,17 and we decided to apply
these methods to reduce several types of N-O bonds (Table
4).
(15) Lee, W.; Kim, K.; Surman, M. D.; Miller, M. J. J. Org. Chem. 2003,
68, 139–149.
(16) Fu¨rstner, A.; Hupperts, A. J. Am. Chem. Soc. 1995, 117, 4468–4475.
(17) (a) Rajanbabu, T. V.; Nugent, W. A. J. Am. Chem. Soc. 1994, 116,
986–997. (b) Nugent, W. A.; RajanBabu, T. V. J. Am. Chem. Soc. 1988, 110,
8561–8562. (c) Gansa¨uer, A.; Pierobon, M.; Bluhm, H. Angew. Chem., Int. Ed.
1998, 37, 101–103. (d) Barrero, A. F.; Qu´ılez del Moral, J. F.; Sa´nchez, E. M.;
Arteaga, J. F. Eur. J. Org. Chem. 2006, 1627–1641.
J. Org. Chem. Vol. 74, No. 1, 2009 449

General Procedure B: Catalytic Cp2TiCl-Mediated Reduc-
tion of 5c,d and 9a. A clean, flame-dried, 25 mL round-bottom
flask equipped with a stir bar was evacuated and purged with Ar.
A degassed THF solution (3.7 mL) of Cp2TiCl2 (0.09 mmol) and
manganese powder (3.7 mmol) was stirred at rt under Ar for 15
min. Meanwhile, a clean, flame-dried, 10 mL round-bottom flask
was evacuated and purged with Ar. A degassed THF solution (1
mL) of substrate (0.46 mmol) and 2,4,6-trimethylpyridine (3.7
mmol) was prepared and then transferred to the Cp2TiCl2 reaction
mixture. Finally, chlorotrimethylsilane (1.9 mmol) was added to
the reaction mixture and the reaction proceeded under Ar for 2 h.
The reaction mixture was filtered through a Whatman glass
microfiber filter (type GF/F) to remove manganese salts. The filtrate
was partitioned between 10% w/v citric acid (5 mL) and EtOAc
(10 mL). The aqueous layer was extracted with EtOAc (3 × 10
mL). The combined organics were washed with brine (20 mL),
dried over Na2SO4, filtered, and concentrated to an oil. The resultant
crude material was dissolved in THF (2 mL) and charged with 1
M tetrabutylammonium fluoride in THF (1.86 mL, 1.86 mmol),
and the reaction was stirred at rt for 1 h. The reaction mixture was
concentrated to a slurry and partitioned between 1 M HCl (2 mL)
and EtOAc (5 mL). The aqueous layer was extracted with EtOAc
(4 × 5 mL). The combined organics were washed with brine (15
mL), dried over Na2SO4, filtered, and concentrated to an oil. The
resultant residue was purified by silica gel chromatography to afford
product.
In a typical reaction, a degassed THF solution of 20 mol %
of Cp2TiCl2 and excess manganese (8 equiv)18 was charged with
a degassed THF solution of substrate and 2,4,6-trimethylpyri-
dine, followed by introduction of chlorotrimethylsilane (TM-
SCl).19 Reduced amounts of Cp2TiCl2 (i.e., 5 and 10 mol %)
resulted in incomplete reactions after 18 h. Excess manganese
(8 equiv) with 20 mol % of Cp2TiCl provided the highest yields
and shortest reaction times. The Cp2TiCl-catalyzed reduction
of phenylacetyl cycloadduct 5c and Boc cycloadduct 5d were
complete within 2 h. The resultant silylated alcohols were easily
deprotected with tetrabutylammonium fluoride (TBAF) to afford
the corresponding alcohols 6c (50-70% yield)20 and 6d (71%
yield). Cp2TiCl-catalyzed reduction of Boc cycloadduct 5d was
performed on large scale (25 mmol), and an identical isolated
yield was obtained (71% yield). Hydroxamic acid 9a may be
directly reduced to amide 9b without exposure to TBAF.
Substrates 9a and 9b may be reduced to 10a (43% yield)
and 10b (44% yield), respectively, via a Cp2TiCl-catalyzed
reduction with 1,4-cyclohexadiene, 2,4,6-trimethylpyridinium
hydrochloride, and excess manganese powder. When cycload-
ducts 5c and 5d were exposed to identical Cp2TiCl-catalyzed
reduction conditions, incomplete reactions were observed after
20 h. N-Hydroxyazetidinone 11a was unreactive toward catalytic
amounts (20 mol %) of Cp2TiCl.
General Procedure C: Catalytic Cp2TiCl-Mediated Reduc-
tion of 9a and 9b. A clean, flame-dried, 25 mL round-bottom flask
equipped with a stir bar was evacuated and purged with Ar. A
degassed THF suspension (3.3 mL) of 2,4,6-trimethylpyridinium
hydrochloride (0.62 mmol) was charged with Cp2TiCl2 (0.06 mmol),
manganese powder (2.49 mmol), and substrate (0.31 mmol). 1,4-
Cyclohexadiene (1.24 mmol) was added to the reaction mixture,
and the reaction proceeded under Ar for 18 h. The reaction mixture
was filtered through a Whatman glass microfiber filter (type GF/F)
to remove manganese salts. The filtrate was partitioned between
10% w/v citric acid (5 mL) and EtOAc (10 mL). The aqueous layer
was extracted with EtOAc (3 × 10 mL). The combined organics
were washed with brine (20 mL), dried over Na2SO4, filtered, and
concentrated to an oil. The resultant residue was purified by silica
gel chromatography to afford product.
In conclusion, we have applied Cp2TiCl methodology to
reduce N-O bonds in diverse substrates, including oxazines,
N-hydroxyazetidinones, hydroxamic acids, and N-hydroxycar-
bamates. Reductions may be performed with stoichiometric
Cp2TiCl as well as catalytic Cp2TiCl. We intend to use this
methodology to synthesize biologically significant molecules
suchascarbocyclicnucleosideanaloguesandnovelbenzodiazepines.
Experimental Section
General Procedure A: Stoichiometric Cp2TiCl-Mediated
Reduction of 5a-g, 9a,b and 11a. A clean, flame-dried, 25 mL
round-bottom flask equipped with a stir bar was evacuated and
purged with Ar. A degassed THF solution (6.3 mL) of Cp2TiCl2
(1.24 mmol) and activated zinc (2.49 mmol) was stirred at rt under
Ar for 45 min. The reaction mixture changed color from dark red
to olive green. The reaction mixture was cooled to -30 °C and
charged with a MeOH solution (5 mL) of substrate (0.50 mmol)
dropwise over 3 min. The reaction mixture was stirred for 45 min
as the bath temperature was maintained between -10 and -30 °C.
The reaction mixture was warmed to rt and partitioned between
satd K2CO3 (5 mL) and EtOAc (20 mL). The organic layer was
removed via pipet and filtered through a Whatman glass microfiber
filter (type GF/F) to remove insoluble titanium salts. The aqueous
layer was extracted with EtOAc (4 × 20 mL), and the organic layer
was filtered through a Whatman glass microfiber filter (type GF/F)
after each extraction. The combined filtered organics were dried
over MgSO4 and again filtered through a Whatman glass microfiber
filter (type GF/F), and the filtrate was adsorbed on silica gel and
concentrated to solids. The adsorbed material was purified by silica
gel chromatography to afford the desired product.
(()-cis-(Z)-4-Hydroxycyclopent-2-enyl)benzamide 6a. Pre-
pared according to general procedure A. Crude material was purified
by silica gel chromatography (50-70% EtOAc/hexanes) to afford
the product as white solids (95%). An analytical sample was
recrystallized from EtOAc to provide a white powder from which
1
all data was obtained: mp ) 94-95 °C; H NMR (600 MHz,
CDCl3) δ 1.68 (ddd, 1H, J ) 14.2, 3.7, 3.7 Hz), 2.29 (d, 1H, J )
6.8 Hz), 2.83 (ddd, 1H, J ) 14.4, 8.2, 7.2 Hz), 4.78-4.82 (m, 1H),
4.93 (ddddd, 1H, J ) 7.2, 7.0, 3.7, 1.8, 0.7 Hz), 5.94 (ddd, 1H, J
) 5.4, 2.4, 1.0 Hz), 6.08 (ddd, 1H, J ) 5.6, 1.8, 1.8 Hz), 6.41 (d,
1H, J ) 7.0 Hz), 7.40-7.44 (m, 2H), 7.48-7.51 (m, 1H),
7.73-7.76 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 41.5, 54.6,
75.6, 127.1, 128.8, 131.8, 134.1, 134.6, 137.0, 167.2; IR (thin film,
cm-1) 3295, 2361, 1638, 1578, 1535, 1490; HRMS (FAB) m/z (M
+
+ H) calcd for C12H14NO2 204.1025, found 204.1009.
(R)-2-Hydroxy-N-((1R,4S)-4-hydroxycyclopent-2-enyl)-2-phe-
nylacetamide 6b. Prepared according to general procedure A. Crude
material was purified by silica gel chromatography (30-50%
EtOAc/hexanes) to afford the product as a tan gum (78%). An
analytical sample was recrystallized from EtOAc/hexanes to provide
a white powder from which all data was obtained: mp ) 120-121
(18) Cp2TiCl-catalyzed reactions were also conducted with zinc as the excess
reductant. However, starting materials were not completely consumed within
18 h.
(19) (a) Justicia, J.; Rosales, A.; Bun˜uel, E.; Oller-Lo´pez, J. L.; Valdivia,
N.; Ha¨ıdour, A.; Oltra, J. E.; Barrero, A. F.; Ca´rdenas, D. J.; Cuerva, J. M.
Chem.sEur. J. 2004, 10, 1778–1788. (b) Barrero, A. F.; Qu´ılez del Moral, J. F.;
Sa´nchez, E. M.; Arteaga, J. F. Org. Lett. 2006, 8, 669–672.
(20) Compound 6c was isolated in 70% yield when the reaction solids were
continuously extracted with a Soxhlet apparatus prior to workup. Continuous
extraction was accomplished with a 10% MeOH/CH2Cl2 solution (bath temper-
ature 60 °C) for 18 h to directly afford desilylated product 6c.
1
°C; H NMR (600 MHz, CDCl3) δ 1.56 (ddd, 1H, J ) 14.4, 3.8,
3.8 Hz), 2.73 (ddd, 1H, J ) 14.4, 8.4, 7.3 Hz), 2.80 (d, 1H, J )
7.5 Hz), 3.46 (d, 1H, J ) 7.5 Hz), 4.66 (ddddd, 1H, J ) 8.8, 7.8,
3.9, 2.9, 2.3 Hz), 4.71-4.74 (m, 1H), 5.77 (ddd, 1H, J ) 5.6, 2.3,
1.2 Hz), 6.01 (ddd, 1H, J ) 5.6, 2.0, 2.0 Hz), 6.43 (d, 1H, J ) 8.8
Hz), 7.33-7.40 (m, 5H); 13C NMR (150 MHz, CDCl3) δ 41.2, 54.4,
74.5, 75.5, 127.1, 129.0, 129.2, 133.4, 137.2, 139.5, 171.8; IR (thin
450 J. Org. Chem. Vol. 74, No. 1, 2009

film, cm-1) 3378, 1651, 1526; HRMS (FAB) m/z (M + H) calcd
J ) 10.1, 2.2, 0.6 Hz), 5.86 (ddd, 1H, J ) 10.1, 3.4, 1.9 Hz); 13C
NMR (150 MHz, CDCl3) δ 25.9, 28.6, 29.2, 46.0, 64.9, 79.7, 131.4,
132.4, 155.4; IR (thin film, cm-1) 3306, 2930, 2360, 1682, 1504;
HRMS (FAB) m/z (M + H) calcd for C11H20NO3+ 214.1443, found
214.1480.
+
for C13H16NO3 234.1130, found 234.1125.
(()-cis-(Z)-4-Hydroxycyclopent-2-enyl)-2-phenylacetamide 6c.
Prepared according to general procedures A and B. Crude material
was purified by silica gel chromatography (50-70% EtOAc/
hexanes) to afford the product as white solids (79% and 50%,
respectively). An analytical sample was recrystallized from EtOAc
to provide a white powder from which all data was obtained: mp
(()-cis-(Z)-4-(2-Phenylacetamido)cyclopent-2-enyl Acetate 10a.
Prepared according to general procedures A-C. Crude material was
purified by silica gel chromatography (50-70% EtOAc/hexanes)
to afford the product as white solids (72%, 48%, and 43%,
respectively). An analytical sample was recrystallized from EtOAc/
hexanes to provide a white powder from which all data was
1
) 118-119 °C; H NMR (600 MHz, CDCl3) δ 1.47 (ddd, 1H, J
) 14.2, 3.8, 3.8 Hz), 2.71 (ddd, 1H, J ) 13.4, 9.3, 7.3 Hz), 2.74
(d, 1H, J ) 7.5 Hz), 3.55 (s, 2H), 4.62 (dddd, 1H, J ) 7.3, 3.8, 1.9
Hz, 0.7 Hz), 4.68-4.71 (m, 1H), 5.59 (bs, 1H), 5.75 (ddd, 1H, J )
6.6, 2.2, 0.9 Hz), 5.98 (ddd, 1H, J ) 5.6, 1.9, 1.9 Hz, 7.23-7.26
(m, 2H), 7.28-7.31 (m, 1H), 7.34-7.37 (m, 2H); 13C NMR (150
MHz, CDCl3) δ 41.3, 44.2, 54.4, 75.5, 127.7, 129.3, 129.6, 133.7,
134.8, 136.9, 170.9; IR (thin film, cm-1) 3292, 1632, 1537; HRMS
1
obtained: mp ) 97-99 °C; H NMR (600 MHz, CDCl3) δ 1.40
(ddd, 1H, J ) 14.6, 4.0, 4.0 Hz), 1.96 (s, 3H), 2.76 (ddd, 1H, J )
14.6, 7.6, 7.6 Hz), 3.57 (s, 2H), 4.94-5.00 (m, 1H), 5.40 (bd, 1H,
J ) 6.5 Hz), 5.47-5.51 (m, 1H), 5.91-5.95 (m, 2H), 7.23-7.26
(m, 2H) 7.28-7.32 (m, 1H), 7.34-7.38 (m, 2H); 13C NMR (150
MHz, CDCl3) d 41.3, 44.2, 54.4, 75.5, 127.7, 129.3, 129.6, 133.7,
134.8, 136.9, 170.9; IR (thin film, cm-1) 3284, 3030, 1734, 1633,
1537, 1494, 1454; HRMS (FAB) m/z (M + H) calcd for
+
(FAB) m/z (M + H) calcd for C13H16NO2 218.1181, found
218.1182.
(()-cis-(Z)-4-Hydroxycyclohex-2-enyl)-2-phenylacetamide 6f.
Prepared according to general procedure A. Crude material was
purified by silica gel chromatography (70% EtOAc/hexanes) to
afford the product as a clear oil (70%): 1H NMR (600 MHz, CDCl3)
δ 1.55-1.61 (m, 2H), 1.72 (bs, 1H), 1.76-1.85 (m, 2H), 3.56 (s,
2H), 4.12-4.17 (m, 1H), 4.40-4.45 (m, 1H), 5.43 (d, 1H, J ) 6.5
Hz), 5.61 (ddd, 1H, J ) 10.0, 2.8, 0.6 Hz), 5.84 (ddd, 1H, J )
10.0, 3.7, 2.1 Hz), 7.23-7.25 (m, 2H), 7.27-7.31 (m, 1H),
7.33-7.36 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 25.3, 29.2,
44.1, 45.2, 64.4, 127.7, 129.3, 129.6, 130.9, 132.7, 134.9, 170.7;
IR (thin film, cm-1) 3282, 2929, 1648, 1542; HRMS (FAB) m/z
+
C15H17NO3 260.1287, found 260.1279.
Acknowledgment. We thank Prof. Brandon Ashfeld and Dr.
Jed Fisher for helpful discussions, Dr. Bill Boggess and Nonka
Sevova for mass spectroscopic analyses, and Dr. Jaroslav
Zajicek for NMR assistance. We acknowledge The University
of Notre Dame and the NIH (GM068012) for support of this
work.
Supporting Information Available: General methods and
experimental details for the preparation of 6d, 9b, 10b, and 12.
1H and 13C NMR spectra for compounds 6a-c, 6f-g, 9b, and
10a. Proposed catalytic cycles for Cp2TiCl-mediated N-O bond
reductions. This material is available free of charge via the
Internet at http://pubs.acs.org.
+
(M + H) calcd for C14H18NO2 232.1338, found 232.1356.
(()-cis-(Z)-tert-Butyl-4-hydroxycyclohex-2-enylcarbamate 6g.
Prepared according to general procedure A. Crude material was
purified by silica gel chromatography (50% EtOAc/hexanes) to
afford the product as a clear oil (86%): 1H NMR (600 MHz, CDCl3)
δ 1.44 (s, 9H), 1.65-1.72 (m, 2H), 1.79-1.89 (m, 2H), 4.07-4.13
(m, 1H), 4.14-4.19 (m, 1H), 4.57-4.64 (m, 1H), 5.74 (ddd, 1H,
JO802184Y
J. Org. Chem. Vol. 74, No. 1, 2009 451