Rate constants for 5-exo secondary alkyl radical cyclizations onto hydrazones and oxime ethers via intramolecular competition experiments

Article abstract of DOI:10.1021/jo982017u

The kinetics for the 5-exo cyclizations of secondary radicals onto various imine acceptors (aryl-, alkyl-, and benzoylhydrazones, oxime ethers, etc.) have been determined. The rate constants have been established by competitive 'internal radical clock' type cyclizations on the basis of the known rate constants for alkene and N,N-diphenylhydrazone systems. In refluxing benzene (80 °C) the rate constants for these 5-exo cyclizations fall within the range of 16 x 10⁷ to 4 x 10⁷ s^-1 depending on the electron-withdrawing capacity of the imine acceptor (C=NR). The fastest rate constants were observed for the N-benzyoylhydrazone acceptor (cis, 1.2 x 10⁸ s^-1), a value that is very similar to rate constant determined previously for N,N-diphenylhydrazones (cis, 1.1 x 10⁸ s^-1). These rate constants are approximately 200 times faster than those for the corresponding 5-exo cyclization onto alkenes.

Full text of DOI:10.1021/jo982017u

6960
J . Org. Chem. 1999, 64, 6960-6968
Ra te Con sta n ts for 5-Exo Secon d a r y Alk yl Ra d ica l Cycliza tion s
on to Hyd r a zon es a n d Oxim e Eth er s via In tr a m olecu la r
Com p etition Exp er im en ts†
Poonam Tauh and Alex G. Fallis*
Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
Received October 6, 1998
The kinetics for the 5-exo cyclizations of secondary radicals onto various imine acceptors (aryl-,
alkyl-, and benzoylhydrazones, oxime ethers, etc.) have been determined. The rate constants have
been established by competitive “internal radical clock” type cyclizations on the basis of the known
rate constants for alkene and N,N-diphenylhydrazone systems. In refluxing benzene (80 °C) the
rate constants for these 5-exo cyclizations fall within the range of 16 × 107 to 4 × 107 s-1 depending
on the electron-withdrawing capacity of the imine acceptor (CdNR). The fastest rate constants
were observed for the N-benzyoylhydrazone acceptor (cis, 1.2 × 108 s-1), a value that is very similar
to rate constant determined previously for N,N-diphenylhydrazones (cis, 1.1 × 108 s-1). These rate
constants are approximately 200 times faster than those for the corresponding 5-exo cyclization
onto alkenes.
Sch em e 1. Ra d ica l Cycliza tion s on to
N,N-Dip h en ylh yd r a zon es
In tr od u ction
The interest in free radical reactions applied to syn-
thetic problems continues to advance, and these reactions
have been used successfully for a growing number of
synthetic targets.1 Further synthetic applications and
related mechanistic studies depend on a knowledge of the
rate constants for the various radical reactions. This
knowledge permits prediction of the radical kinetics and
hence control of the product distribution.2 In contrast to
the extensive studies of cyclizations onto alkenes and
carbonyl systems, it is only recently that imine acceptors
have received increased scrutiny.3 Earlier we reported
our results of a radical aza-Barbier type reaction in which
halohydrazones were cyclized directly, under either
n-Bu3SnH- or SmI2/HMPA-mediated conditions, to afford
cyclopentyl- or cyclohexylhydrazines (Scheme 1).4 The
related reaction with carbonylhydrazones provided access
to â-amino alcohols after hydrazine cleavage, with a high
level of diastereoselectivity. An extension of these studies
involved trapping of the initial radical with carbon
monoxide, prior to cyclization and reduction of the
resulting cyclopentanones. This sequence afforded an
alternative route to hydrazine alcohols.5 In contrast to
the extensive literature containing kinetic information
on free radical additions onto carbon-carbon double
bonds, there is less kinetic data for carbon-oxygen and
carbon-nitrogen double bonds. Thus an additional in-
vestigation established that, for 5- and 6-exo-hydrazone
ring closures, the rate constants for 5-exo cyclizations
onto N,N-diphenylhydrazones were 1.1 × 108 and 4.6 ×
107 s-1 at 80 °C for the cis and trans cyclopentylhydra-
zines, respectively.6
Limited data are available concerning the best accep-
tors in diverse imine systems in which two different
substitution patterns are present, and consequently their
relative rate constants are not as well established. To
help fill this void, we report the results of a comparative
study of 5-exo intramolecular additions onto CdN sys-
tems in different families. The relative rate constants
were established for the 5-exo cyclizations of secondary
radicals based on intramolecular competitive “internal
radical clock” experiments. These investigations estab-
lished that for many applications, the N,N-diphenylhy-
drazones are the most useful acceptors due to their
stability, ease of handling, homogeneous stereochemistry,
and relative rates. The rate constant for the 5-exo
cyclization onto N-benzoylhydrazones, determined below,
is similar. Due to its ease of hydrolysis, in some cases it
is synthetically more versatile.
† This paper is dedicated to Dr. Keith U. Ingold on the occasion of
his 70th birthday. Presented with respect and gratitude for his
contributions to physical organic chemistry.
(1) For reviews, see: (a) Giese, B. Radicals in Organic Synthesis:
Formation of Carbon-Carbon Bonds; Pergamon Press: New York,
1986. (b) Curran, D. P. Synthesis 1988, 417. (c) Curran, D. P. Synthesis
1988, 489. (d) J asperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev.
1991, 91, 1237. (e) Motherwell, W. B.; Crich, D. Free Radical Chain
Reactions in Organic Synthesis; Academic Press: London, 1992. (f)
Fossey, J .; Lefort, D.; Sorba, J . Free Radicals in Organic Chemistry;
J ohn Wiley & Sons: New York, 1995. (g) Curran, D. P.; Porter, N. A.;
Giese, B. Stereochemistry of Radical Reactions; VCH: New York, 1996.
(2) Newcomb, M. Tetrahedron 1993, 49, 1151.
A diverse family of oxime ethers and hydrazones were
selected for investigation. These systems represent syn-
thetically useful precursors. The oxime methyl ethers
1
allow facile detection by H NMR and can be converted
to the parent oxime with trimethylsilyliodide. In a related
fashion the benzyl oxime may be cleaved by hydrogenoly-
(3) Fallis, A. G.; Brinza, I. M. Tetrahedron 1997, 53, 17543.
(4) Sturino, C. F.; Fallis, A. G. J . Am. Chem. Soc. 1994, 116, 7447.
(5) Brinza, I. M.; Fallis, A. G. J . Org. Chem. 1996, 61, 3580.
(6) Sturino, C. F.; Fallis, A. G. J . Org. Chem. 1994, 59, 6514.
10.1021/jo982017u CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/25/1999

Rate Constants for Exo Alkyl Radical Cyclizations
J . Org. Chem., Vol. 64, No. 19, 1999 6961
Sch em e 2. Syn th esis of Br om o-bis-im in e
Su bstr a tesa
Sch em e 3. Com p etitive
N,N-Dip h en ylh yd r a zon e-Im in e Ra d ica l
Cycliza tion s
a
Key: (a) Br(CH2)4OTBDMS, Mg, THF, 0 °C, 60%; (b) PPh3‚Br2,
Et3N, CH2Cl2, 0 °C, 75%; (c) Bu4NF, THF, 0 °C, 80%; (d) DMSO,
Et3N, SO3‚Py, 21 °C, 75%; (e) H2NR, 21-80 °C, 60-80%.
sis. The N,N-dimethylhydrazone, in which the initial
nitrogen-centered radical is less stabilized, provides an
example for comparison with the N,N-diphenylhydrazone
and N-benzoylhydrazone cases. Kim and Cho9 have
demonstrated that N-sulfonylhydrazone systems are also
good acceptors, although the initial cyclization product
is prone to fragmentation.
Resu lts a n d Discu ssion
Syn th esis of In tr a m olecu la r Com p etition Su b-
str a tes. The required substrates were prepared as
outlined in Scheme 2. The N,N-hydrazone aldehyde 14
was condensed with the Grignard reagent, derived from
4-bromo-1-(tert-butyldimethylsilyloxy)butane, to afford
the secondary alcohol 2a (X ) OH). Treatment of the
alcohol with triphenylphosphine dibromide gave the
bromide 2b (X ) Br), and the silyl group was removed
to afford the primary alcohol 3. Of several oxidants
examined the sulfur trioxide-pyridine complex was the
only reagent that generated the aldehyde 4 cleanly
without concomitant decomposition products. This oxi-
dant was also required for the preparation of the alde-
hyde 1 from the corresponding primary alcohol. However,
if the synthetic order was reversed and the N,N-diphen-
ylhydrazone was installed later the sulfur trioxide-
pyridine reagent also caused extensive decomposition.
Exposure of 4 to the appropriate amino derivative af-
forded the desired bis-imine substrates 6-11 and 20
(Scheme 3).
Ta ble 1. Cis/Tr a n s Ra tios of Cyclop en ta n es
Cycliza tion Stu d ies a n d Refer en ce Com p ou n d s.
Treatment of compounds 6-11 individually, in refluxing
benzene with tributyltin hydride and azobis(isobutyroni-
(7) For representative examples, see: (a) Corey, E. J .; Pyne, S. G.
Tetrahedron Lett. 1983, 24, 2821. (b) Hart, D. J .; Seely, F. L. J . Am.
Chem. Soc. 1988, 110, 1631. (c) Bartlett, P. A.; McLaren, K. L.; Ting,
P. C. J . Am. Chem. Soc. 1988, 110, 1633. (d) Parker, K. A.; Spero, D.
M.; Van Epp, J . J . Org. Chem. 1988, 53, 4628. (e) Marco-Contelles, J .;
Pozuelo, C.; J imeno, M. L.; Martinez, L.; Martinez-Grau, A. J . Org.
Chem. 1992, 57, 2625. (f) Pattenden, G.; Schultz, D. J . Tetrahedron
Lett. 1993, 34, 6787. (g) Hollingworth, G. J .; Pattenden, G.; Schultz,
D. J . Aust. J . Chem. 1995, 48, 381. (h) Keck, G. E.; McHardy, S. F.;
Murry, J . A. J . Am. Chem. Soc. 1995, 117, 7289.
(8) (a) Kim, S.; Kee, I. S.; Lee, S. J . Am. Chem. Soc. 1991, 113, 9882.
(b) Kim, S.; Kee, I. S. Tetrahedron Lett. 1993, 34, 4213. (c) Lee, H.-Y.;
Kim, D.-Y.; Kim, S. J . Chem. Soc., Chem. Commun. 1996, 1539. (d)
Kim, S.; Cheong, J . H.; Yoon, K. S. Tetrahedron Lett. 1995, 36, 6069.
(e) Kim, S.; Yoon, K. S.; Kim, Y. S. Tetrahedron 1997, 53, 73. (f) Kim,
S.; J oe, G. H.; Do, J . Y. J . Am. Chem. Soc. 1993, 115, 3328. (g) Kim,
S.; Kim, Y.; Yoon, K. S. Tetrahedron Lett. 1997, 38, 2487.
trile) (AIBN), afforded the amino-substituted cyclopen-
tanes from 5-exo cyclization, including the cis/trans
isomeric pairs illustrated in Table 1. Under these tin
hydride conditions, uncyclized products from direct
quenching of the initial radical A were not detected
(Scheme 3). Thus these radicals were partitioned between
the 5-exo-N,N-diphenylhydrazone (radical B1) or 5-exo
imine (hydrazone or oxime, radical B2) cyclization path-
ways. Due to the potential for syn/anti isomerism, the
mixtures were complex, although in most cases the
anticipated signals for the cis and trans isomers could
be assigned by NMR spectroscopy. These assignments
(9) Kim, S.; Cho, J . R. Synlett 1992, 629.

6962 J . Org. Chem., Vol. 64, No. 19, 1999
Ta ble 2. Ra te Con sta n ts for 5-Exo-Cycliza tion s of Br om oim in es [80 °C, AlBN, n Bu 3Sn H]
Tauh and Fallis
cis
CdNR
trans
CdNR
entry
compound
product ratioa
kCdNR
cis/trans ratio
k
k
a
b
c
d
e
f
6 R ) OMe
12/16 4:1
13/17 2.5:1
14/18 3:1
15/19 1:1
1:0
4.0 × 107
6.4 × 107
5.3 × 107
1.6 × 108
<1.0 × 107
<1.0 × 107
1.6:1
1.7:1
2:1
2.4 × 107 s-1
4.0 × 107 s-1
3.5 × 107 s-1
1.2 × 108 s-1
1.5 × 107 s-1
2.4 × 107 s-1
1.8 × 107 s-1
0.4 × 108 s-1
7 R ) OBn
8 R ) NMe2
9 R ) NHCOPh
10 R ) NHSO2C6H4Meb
11 R ) NHSO2C6H2Me3
3.4:1
b
1:0
These ratios represent lower limits based on 1H NMR (500 MHz) analysis of the total product mixture. These data are estimates.
a
b
Sch em e 4. Syn th esis of Refer en ce Com p ou n d sa
Sch em e 5. Decom p osition P a th w a ys of
Ar ylsu lfon ylh yd r a zon es
bond with cyanoborohydride required for the aminocy-
clopentanes 34-38. Additional simplification of the
spectra was observed since the N,N-diphenylhydrazones
exist exclusively in the anti orientation.
Kin etic Resu lts. The product ratios for the competi-
tive 5-exo imine cyclizations are listed in Table 2, and
as mentioned above, the cis/trans ratios of the individual
products are summarized in Table 1. On the basis of the
data determined previously for the N,N-diphenylhydra-
zone cyclizations, the rate constants were determined and
tabulated.10 Accurate numbers for comparison could not
be obtained for the sulfonyl systems 10 and 11. The
values for 10 and 11 are estimates due to the instability
of the sulfonylhydrazinyl radical, resulting in the loss of
the sulfonyl group after cyclization as illustrated in
Scheme 5. As observed earlier,9 after cyclization, the
radical B2 expels the arylsulfonyl radical C to give the
azo compound D. Subsequent loss of nitrogen generates
the cyclopentanyl radical E, and ultimately a monosub-
stituted cyclopentane F is usually produced. However,
this compound was not detected, and the only products
isolated were the hydrazines from N,N-diphenylhydra-
zone addition. The competition between an N,N-diphenyl
and an N-aziridinylhydrazone as contained in 20 (Scheme
3) was also of interest, but the complex mixture derived
from this experiment did not afford reliable data even
when a selenide radical precursor was employed.
a
Key: (a) AIBN, n-Bu3SnH, C6H6, 80 °C, 98%; (b) Bu4NF, THF,
0 °C, 80%; (c) DMSO, Et3N, SO3‚Py, 21 °C, 75%; (d) H2NR, 40 °C,
∼70%; (e) I(CH2)4OTBDMS, LDA, HMPA, Me2Zn, -78 °C; (f)
NaCNBH3, p-TsOH, THF or NaBH4, MeOH.
were assisted by our earlier observations4 and current
data. This indicated that for the cis-cyclopentane hydra-
zine the carbon-bearing nitrogen resonated at δ ≈ 60 ppm
and at ∼65 ppm for the trans isomer. Similarly the
1
hydrogen attached to this carbon gave rise to a H NMR
signal in the range of δ ≈ 3.25-3.4 ppm for the cis
product and ∼3.0-3.1 ppm for the trans compound. This
shift differential of approximately 0.3 ppm was a consis-
tent pattern among the isomeric pairs. Additional con-
firmation was provided by the synthesis of authentic
samples or closely related models. The synthetic routes
to several of the aminocyclopentane products (12-15) or
cyclic relatives (represented by 21-38) are outlined in
Scheme 4. These model systems provided accurate spec-
tral details, in the various series, for the direct compari-
son of the synthetic and cyclized samples. Thus the NMR
assignments established the product ratios from the
expanded and integrated spectra. The synthetic se-
quences employed were similar to those described above
with the additional step involving reduction of the imine
In addition to our own research, the synthetic potential
of a variety of related acceptors has been investigated.
These include oxime ethers,7 N-aziridinylhydrazones,8
mesitylsulfonylhydrazones,9 â-allenic hydrazones,11 N,N-
(10) The 5-exo rate constants were determined using the N,N-
diphenylhydrazone rate constant (1.6 × 108 s-1, 80 °C) on the basis of
the following equation. Ka ) Kcis + Ktrans(diphenylhydrazone) is the known
total diphenylhydrazone cyclization rate constant, and Kb ) Kcis
+
Ktrans(oximes
hydrazones) is the unknown total cyclization rate constant
or other
for CdNR. Thus (Pa/Pb) is the product ratio, measured analytically
and Kb is determined from the equation -Kb ) Ka(Pa/Pb).
(11) (a) Bernard-Henriet, C. D.; Grimaldi, J . R.; Hatem, J . M.
Tetrahedron Lett. 1994, 35, 3699. (b) Marco-Contelles, J .; Balme, G.;
Bouyssi, D.; Destabel, C.; Bernard-Henriet, C. D.; Grimaldi, J .; Hatem,
J . M. J . Org. Chem. 1997, 62, 1202.

Rate Constants for Exo Alkyl Radical Cyclizations
J . Org. Chem., Vol. 64, No. 19, 1999 6963
Ch a r t 1. Ra te Con sta n ts for 5-exo Cycliza tion s to
Cyclop en ta n es
The increased cyclization rate of these imine systems
compared to simple alkenes is a consequence of the
polarization of the CdNR bonds and the increased
stability of the substituted nitrogen radicals B after
cyclization. Naturally, the nitrogen radical stability var-
ies with the attached groups. The second nitrogen present
in the hydrazones and the oxygen in oximes are likely
involved in a two-center, three-electron bond with the
developing radical on the nitrogen of the imine. This
three-electron bond will help stabilize the developing
nitrogen radical during cyclization. This is reflected in
the positive influence of the R2N and RO substituents
on the reaction exothermicity for of these radical cycliza-
tions compared to cyclizations onto alkenes. This may
explain why the 5- and 6-exo hydrazone cyclizations were
found to have lower activation barriers than the corre-
sponding alkene cyclizations. The activation barriers for
a secondary radical in 5-hexenyl-type 6-exo cyclizations
are 6.5 kcal/mol for the cis product and 7.4 kcal/mol for
the trans carbocycle. For comparison, the corresponding
values for 6-exo cyclizations onto N,N-diphenylhydra-
zones are 5.6 kcal/mol (cis) and 6.2 kcal/mol for the trans
product, lower than the values for the corresponding
carbocycles.6
These features are reflected in the data in Chart 1.
Thus diphenyl substituents on an alkene result in
approximately a 100-fold increase in the rate constant
(Chart 1, entries I and II). Similarily, the rate constants
for the diphenyl hydrazinyl radical (Chart 1, entry IV)
are greater than those for the dimethyl hydrazinyl case
(Chart 1, entry V), although the rate constants for the
N-benzoylhydrazone acceptor (Chart 1, entry VI) are
approximately equivalent to those for the N,N-diphenyl-
hydrazone. The oximes (Chart 1, entries VII-IX) and the
N,N-dimethylhydrazones have similar rate constants,
while the imine acceptor (Chart 1, entry IX, R ) Bn) has
the smallest rate constant and the N-aziridinylhydrazone
(Chart 1, entry X) has the largest rate constant.
Con clu sion
These investigations, employing intramolecular com-
petition experiments, have established the rate constants
for several 5-exo cyclizations onto CdN-R acceptors.
These 5-exo-hydrazone and 5-exo-oxime ether secondary
radical cyclizations have been shown to be relatively fast
reactions in a synthetically useful range. These results
establish that N,N-diphenylhydrazones and N-benzoyl-
hydrazones are superior radical acceptors compared to
the oxime ethers and N-sulfonylhydrazones. As noted
above these cyclizations proceed approximately 200 times
faster than the corresponding 5-exo alkene ring closures.
These data should facilitate the rational design of various
tandem cyclizations for the total synthesis of natural
products. Synthetic application of these results are
currently being explored.
diphenylhydrazones,3-5,12 and various imines.13 Some of
the rate constants from these investigations are also
tabulated in Chart 1 for comparison.
(12) (f) Bowman, W. R.; Stepheson, P. T.; Terett, N. K.; Young, A.
R. Tetrahedron Lett. 1994, 35, 6369. (b) Bowman, W. R.; Stepheson,
P. T.; Terett, N. K.; Young, A. R. Tetrahedron 1995, 51, 7959. (c) Clive,
D. L. J .; Zhang, J . J . Chem. Soc., Chem. Commun. 1997, 549. (d)
Grissom, J . W.; Klingberg, D.; Huang, D.; Slattery, B. J . J . Org. Chem.
1997, 62, 603.
Exp er im en ta l Section
Gen er a l. Melting points were determined in capillary tubes
with a Thomas-Hoover Unit-melt apparatus and are uncor-
rected. Infrared (IR) spectra were recorded on a Bomem
(13) (a) Tanner, D. D.; Rahimi, P. M. J . Org. Chem. 1979, 44, 1674.
(b) Han, O.; Frey, P. A. J . Am. Chem. Soc. 1990, 112, 8982. (c) Takano,
S.; Suzuki, M.; Kijima, A.; Ogasawara, K. Chemistry Lett. 1990, 315.
(d) Takano, S.; Suzuki, M.; Kijima, A.; Oasawara, K. Heterocycles 1994,
37, 149. (e) Tomaszewski, M. J .; Warkentin, J . Tetrahedron Lett. 1992,
33, 2123. (f) Tomaszewski, M. J .; Warkentin, J . J . Chem. Soc., Chem.
Commun. 1993, 966. (g) Tomaszewski, M. J .; Warkentin, J .; Werstiuk,
N. H. Aust. J . Chem. 1995, 48, 291. (h) Gioanola, M.; Leardini, R.;
Nanni, D.; Pareschi, P.; Zanardi, G. Tetrahedron 1995, 51, 2039.
(14) (a) Beckwith, A. L. J .; Easton, C. J .; Lawrence, T.; Saelis, A. K.
Aust. J . Chem. 1983, 36, 545. (b) Beckwith, A. L. J .; Schiesser, C, H.
Tetrahedron Lett. 1985, 26, 373.
(15) (a) Newcomb, M. Tetrahedron 1993, 49, 1151.
(16) (a) Lusztyk, J .; Maillard, B.; Deycard, S.; Lindsay, D. A.; Ingold,
K. U. J . Org. Chem. 1987, 52, 3509. (b) Lusztyk, J .; Kanabus-
Kaminska, J . M. In Handbook of Organic Photochemistry; Scaiano, J .
C., Ed.; CRC Press: Boca Raton, FL, 1989; Vol. II, p 177.

6964 J . Org. Chem., Vol. 64, No. 19, 1999
Tauh and Fallis
Michelson 100 FTIR spectrometer. Proton magnetic resonance
spectra (1H NMR) were measured at 200 MHz with a Varian
Gemini spectrometer and at 300 MHz with a Varian XL-300
spectrometer or at 500 MHz with a Bruker AMX500 spec-
trometer in deuteriochloroform unless otherwise stated. Car-
bon magnetic resonance spectra (13C NMR) were measured at
50 MHz (Varian Gemini), at 75 MHz (Varian XL-300), or at
125 MHz (Bruker). The residual CHCl3 signal was used as an
internal reference: CDCl3 1H, δ 7.24 ppm; 13C, δ 77.0 ppm.
Chemical shifts are reported in ppm downfield from trimeth-
ylsilane (δ scale). The multiplicity, coupling constants (hertz),
and number of protons are indicated in parentheses. Mass
spectra (MS) were determined on a V. G. micromass 7070 HS
instrument using an ionization energy of 70 eV. Elemental
analyses were conducted by M-H-W Laboratories, Phoenix,
AZ. The purity of all title compounds was judged to be >95%
4-Br om o-1-(ter t-bu tyld im eth ylsilyloxy)bu ta n e. TBDM-
SCl (148 mg, 0.979 mmol) was added to a solution of 4-bromo-
butanol (100 mg, 0.653 mmol), imidazole (89 mg, 1.307 mmol),
and 4-(dimethylamino)pyridine (40 mg, 0.326 mmol) in dry
CH2Cl2 (4 mL) at 0 °C. The solution was stirred overnight,
warmed to 21 °C, quenched with aqueous NH4Cl (2.5 mL), and
extracted with ether (3 × 10 mL). The combined organic
extracts were washed with aqueous NaCl (3 × 3 mL), dried,
filtered, concentrated, and chromatographed (pet ether) to
afford 140 mg (80%) of the silyl ether as a clear colorless oil:
IR (neat) 2994, 2858, 2361, 1468, 839, 776 cm-1; 1H NMR (200
MHz, CDCl3) δ 3.61 (t, J ) 6.0 Hz, 2H), 3.41 (t, J ) 6.7 Hz,
2H), 1.95-1.87 (m, 2H), 1.66-1.58 (m, 2H), 0.86 (s, 9H), 0.02
(s, 6H); 13C NMR (50 MHz, CDCl3) 62.1, 33.8, 31.2, 29.4, 25.9,
25.7, -5.3; HRMS calcd for C6H14BrOSi (M+-tert-butyl)
208.9998, found 209.0.
1
as determined by a combination of GC-MS, H NMR, and 13C
5-Hyd r oxy-9-(ter t-bu tyld im eth ylsilyloxy)n on a n a l-N,N-
d ip h en ylh yd r a zon e (2a ). Aldehyde 1 (425 mg, 1.5 mmol)
was disolved in dry THF (2 mL) in a two-necked flask, and
the resulting solution was cooled to 0 °C. The Grignard reagent
BrMg(CH2)4OTBDMS [prepared from the bromobutane above
(1.5 g, 5.6 mmol), and Mg (225 mg), in THF (2.5 mL, reflux)]
was added slowly at 0 °C, and the reaction was monitored by
TLC. The reaction was quenched with saturated aqueous NH4-
CI (15 mL), diluted with water and ethyl acetate (150 mL),
and extracted with ethyl acetate (3 × 50 mL). The combined
organic extracts were washed with saturated aqueous NaCl
(30 mL), dried, filtered, and concentrated, in vacuo. The
resultant oil was chromatographed (1:4, ether/pet ether) to
obtain 525 mg (60%) of 2 (X ) OH): IR (neat) 3396, 3061, 2906,
1592, 1479, 1302, 1210, 910, 744, 697 cm-1;1H NMR (200 MHz,
CDCl3) δ 7.39 7.21 (m, 4H), 7.14-7.06 (m, 6H), 6.54 (t, J )
5.2 Hz, 1H), 3.64-3.56 (m, 3H), 2.31-2.28 (m, 2H), 1.80 (br s,
1H), 1.62-1.45 (m, 10H), 0.90 (s, 9H), 0.06 (s, 6H); 13C (50
MHz, CDCl3) δ 144.3, 139.7, 129.6, 123.8, 122.3, 71.5, 63.1,
37.1, 36.9, 32.7, 32.6, 25.9, 23.0, 21.9, 18.3, 5.3; HRMS calcd
for C27H42N2O2Si (M+) 454.3096, found 454.3052.
NMR analyses.
Unless otherwise stated, all nonaqueous reactions were
performed under an atmosphere of nitrogen in flame-dried
glassware equipped with stir bar and a rubber septum.
Standard inert atmosphere techniques were used in handling
all air- and moisture-sensitive reagents. Reactions were
monitored by analytical thin-layer chromatography (TLC)
using commercial aluminum sheets precoated (0.2 mm layer
thickness) with silica gel 60 F254 (E. Merck). Product purifica-
tion by conventional and flash column chromatography was
performed using E. Merck silica gel 60 (70-230 or 230-400
mesh). Solutions in organic solvents were dried over anhydrous
magnesium sulfate and stripped of solvents with a Bu¨chi
rotatory evaporator connected to water aspirator. Trace sol-
vents were removed on a vacuum pump. All compounds were
stored at -15 °C in vials flushed with nitrogen.
Petroleum ether refers to a mixture of hydrocarbons with a
boiling range of 30-60 °C. Anhydrous diethyl ether (ether) and
anhydrous tetrahydrofuran (THF) were distilled from ben-
zophenone/sodium. Dry benzene, toluene, dichloromethane
(CH2Cl2), and triethylamine were distilled from calcium hy-
dride, and ethanol was distilled from magnesium ethoxide.
Flash chromatography was employed for purification. Com-
mercial starting materials were purchased from Aldrich
Chemical Co. unless otherwise indicated.
Gen er a l P r oced u r e for Ra d ica l Cycliza tion s. The hy-
drazone or oxime (1 equiv) was dissolved in dry benzene (0.007
M solution), nitrogen was bubbled through the solution for 30
min, and the solution was refluxed. Tributyltin hydride (1.2
equiv) and AIBN (0.34 equiv) were dissolved in dry benzene
(0.02 M solution), and the solution was purged with nitrogen
for 20 min. The latter solution was then added to the refluxing
hydrazone or oxime solution at a rate of 5.0 mL/h using a
syringe pump. After the addition of the tin hydride was
complete, the reaction mixture was refluxed for another 30
min before cooling to room temperature. The resulting solution
was concentrated and chromatographed on deactivated silica
gel (petroleum (pet) ether, to remove Bu3SnH and Bu3SnBr;
followed by 50% CH2Cl2/pet ether). All the fractions not
containing tin compounds were collected along with ap-
proximately 100 mL of additional eluent. 1H NMR analysis of
the “semicrude” mixture provided the ratio of the cyclized
products. Authentic samples of the anticipated products or
close representative products were prepared separately for
comparison.
4-Br om o-1-bu ta n ol. Borane-THF complex (1.25 mL of 1
M solution, 1.25 mmol) was added dropwise to bromobutyric
acid (210 mg, 1.25 mmol) in dry THF at -18 °C. The reaction
was stirred overnight and warmed to 21 °C. The reaction was
quenched with aqueous K2CO3 (1.5 mL) at 0 °C and extracted
with ether (3 × 50 mL). The combined organic extracts were
washed with saturated NH4C and concentrated. Chromatog-
raphy (4:1, hexane/ether) provided 161 mg (83%) of the bromo
alcohol: IR (neat) 3337, 2918, 1648, 1435, 1051 cm-1; 1H NMR
(200 MHz, CDCl3) δ 3.61(t, J ) 6.4 Hz, 1H), 3.40 (t, J ) 6.6
Hz, 2H), 2.80 (s, 1H), 1.93-1.83 (m, 2H), 1.71-1.61 (m, 2H);
13C NMR (50 MHz, CDCl3) 61.6, 33.7, 31.0, 29.1; HRMS calcd
for C4H7Br (M+ - H2O) 133.9731, found 133.9742.
5-Br om o-9-(ter t-b u t yld im et h ylsilyloxy)n on a n a l-N,N-
d ip h en ylh yd r a zon e (2b). Triethylamine (1.2 mL, 0.79 mmol)
was added to a cold solution (0 °C) of dry CH2Cl2 (8 mL)
containing triphenylphosphine (0.207 g, 0.79 mmol). Bromine
(45 mL, 0.79 mmol) was added dropwise until the reaction
mixture turned a faint yellow. The mixture was stirred at 0
°C for 10 min, and then the alcohol 2 (X ) H) (0.3 g, 0.66 mmol)
in dichloromethane (0.7 mL) was added dropwise. The reaction
mixture was stirred at 0 °C for 30 min and at 21 °C for 30
min and then quenched with saturated aqueous NaHCO3 (3
mL). The aqueous layer was extracted with ether (3 × 10 mL),
and the combined organic extracts were washed with brine,
dried, concentrated, and chromatographed (4:1, hexane/ether)
to afford 240 mg (75%) of 2 (X ) Br) as a clear colorless oil:
IR (neat) 2940, 2858, 2351, 1593, 1494, 749, 698 cm-1; 1H NMR
(200 MHz, CDCl3) 7.41-7.32 (m, 4H), 7.16-7.06 (m, 6H), 6.52
(t, J ) 5.17 Hz, 1H), 4.05 (m, 1H), 3.62 (t, J ) 5.86 Hz, 2H),
2.36-2.26 (m, 2H), 1.88-1.50 (m, 10H), 0.91 (s, 9H), 0.06 (s,
6H); 13C NMR (50 MHz, CDCl3) 144.1, 138.7, 129.6, 123.8,
122.2, 62.8, 58.0, 38.8, 38.4, 32.1, 31.9, 25.9, 24.8, 23.9, 18.2,
-5.2; HRMS calcd for C27H41N2SiBrO (M+) 516.2173, found
516.2221. Anal. Calcd for C27H41N2SiBrO: C, 62.95; H, 7.98;
N, 5.41. Found: C, 62.75; H, 7.83; N, 5.49.
5-Br om o-9-h yd r oxyn on a n a l-N,N-d ip h en ylh yd r a zon e
(3). Tetrabutylammonium fluoride (0.490 mL of 1 M solution
in THF, 0.49 mmol) was added to 2 (X ) Br) (210 mg, 0.41
mmol) in dry THF (3.5 mL), at 0 °C, and the resulting mixture
was stirred overnight. The reaction was quenched with water
(2 mL) and extracted with ether, and the combined organic
extracts were washed with saturated NaCl (2 × 10 mL), dried,
concentrated, and chromatographed (1:1 ether/hexanes) to
afford 130 mg (80%) of 3 as a faint yellow oil: IR (neat) 3360,
1
3060, 2916, 1592, 1210, 1091, 1062, 749, 689 cm-1; H NMR
(200 MHz, CDCl3) δ 7.39-7.32 (m, 4H), 7.14-7.03 (m, 6H),
6.50 (t, J ) 5.2 Hz, 1H), 4.07-4.01 (t, J ) 6.2 Hz, 1H), 3.65-
3.59 (t, J ) 6.0 Hz, 2H), 2.34-2.24 (m, 2H), 1.90-1.42 (m,
10H); 13C NMR (50 MHz, CDCl3) 144.1, 138.8, 129.6, 123.8,

Rate Constants for Exo Alkyl Radical Cyclizations
J . Org. Chem., Vol. 64, No. 19, 1999 6965
122.2, 62.5, 57.9, 38.8, 38.3, 31.9, 31.8, 24.8, 23.8; HRMS calcd
for C21H27N2OBr (M+) 402.1297, found 402.1293.
NMR (200 MHz, CDCl3) δ 10.10 (s, 1H), 7.80 (d, J ) 8.5 Hz,
2H), 7.60 (br s, 1H), 7.43 (t, J ) 7.4 Hz, 1H), 7.40-7.10 (m,
6H), 7.08-7.04 (m, 6H), 6.48 (t, J ) 5.16 Hz, 1H), 3.99-3.94
(m, 1H), 2.30-2.23 (m, 4H), 1.84-1.57 (m, 8H); 13C NMR (50
MHz, CDCl3) δ 164.4, 152.3, 144.2, 138.9, [133.1, 132.9 (syn,
anti)], 131.9, 129.7, [128.5, 128.4 (syn, anti)], [127.7, 127.5 (syn,
anti)], 123.9, 122.3, [57.7, 57.4 (syn, anti)], 38.5, [38.4, 38.3
(syn, anti)], 32.0, 31.9, [24.9, 24.6 (syn, anti)], 24.8; FAB
accurate mass calcd for C28H32N4OBr (M+ + 1) 519.17604,
found 519.2069.
5-Br om on on a n ed ia l-9-(N,N-d ip h en ylh yd r a zon e) (4). A
suspension of pyridine-sulfur trioxide complex (1.51 g, 3.23
mmol) in DMSO (3.6 mL) was added to the alcohol 3 (1.3 g,
3.23 mmol) and triethylamine (3.6 mL, 25.8 mmol) in DMSO
(5.6 mL) at 21 °C. The reaction was quenched with water and
extracted with ethyl acetate (3 × 50 mL). The combined
organic extracts were washed with brine (2 × 25 mL), dried,
concentrated, and chromatographed (4:1 hexanes/ether) to
yield 967 mg (75%) of 4 as a faint yellow oil: IR (neat) 3059,
2933, 1723, 1592, 1492, 1301, 1210, 1062 cm-1; 1H NMR (200
MHz, CDCl3 ) δ 9.73 (t, J ) 1.5 Hz, 1H), 7.39-7.24 (m, 4H),
7.2-7.03 (m, 6H), 6.49 (t, J ) 5.2 Hz, 1H), 4.05-4.02 (m, 1H),
2.48-2.24 (m, 4H), 1.90-1.60 (m, 8H); 13C NMR (50 MHz,
CDCl3) δ 201.7, 144.0, 138.6, 129.6, 123.8, 122.5, 57.1, 43.0,
38.3, 38.2, 31.8, 24.7, 20.1; HRMS calcd for C21H25N2OBr (M+)
400.1151, found 400.1161.
5-Br om on on a n ed ia l-[1-N-(p -t olu en esu lfon yl)h yd r a -
zon e]-9-N,N-d ip h en ylh yd r a zon e (10). p-Toluenesulfonyl-
hydrazine (134 mg, 0.625 mmol) and aldehyde 4 (200 mg, 0.50
mmol) were stirred in ethanol (1 mL) at 21 °C for 1 h. The
resulting solution was concentrated and chromatographed (2:5
ether/pet ether) to afford 170 mg of 10 (60%) as a faint yellow
oil: IR (neat) 3204, 2936, 1592, 1493, 1452, 1210, 1164, 1092,
1
902 cm-1; H NMR (500 MHz, CDCl3) δ 8.16 (br s, 1H), 7.84,
5-Br om on on a n ed ia l-(1-O-m eth yloxim e)-9-N,N-d ip h en -
ylh yd r a zon e (6). Methoxyamine hydrochloride (417 mg, 0.50
mmol) was added to a solution of the aldehyde 4 (200 mg, 0.50
mmol) at 0 °C, followed by addition of pyridine (42 µL, 0.52
mmol). The solution was stirred at this temperature until the
reaction was complete. The resulting solution was concentrated
and chromatographed (1:20, ether/pet ether) to yield 135 mg
(63%) of 6 as a clear colorless oil: IR (neat) 3060, 2933, 2351,
7.82 [d, (syn anti), J ) 8.3 Hz, J ) 8.2 Hz, 2H] 7.36-7.27 (m,
6H), 7.23-7.05 (m, 6H), 6.68 [t, J ) 5.2 Hz, (anti), (syn hidden
under 7.23-7.05), 1H], 6.50 (t, J ) 5.0 Hz, 1H), 3.95-3.92 (m,
1H), 2.19-2.39 (s, 3H), 2.30-2.24 (m, 2H), 2.19-2.12 (m, 2H),
1.82-1.50 (m, 8H); 13C NMR (125 MHz, CDCl3) δ [151.9, 150.8
(syn, anti)], 144.2, 144.1, 138.8, 135.2, 129.7, 129.6, [127.9,
127.8 (syn, anti)], 123.9, 122.3, [57.3, 57.0 (syn, anti)], [38.4,
38.3 (syn anti)], [38.2, 38.1 (syn anti)], 31.8, 31.5, [26.4, 24.7
(syn, anti)], [24.0, 23.8 (syn, anti)], 21.6; FAB accurate mass
calcd for C28H33N4O2SBr (M+ + 1) 569.1586, found: 569.1845.
5-Br om on on an edial-[1-N-(2,4,6-tr im eth ylben zen e)su lfo-
n ylh yd r a zon e]-9-N,N-d ip h en ylh yd r a zon e (11). 2,4,6-Tri-
methylbenzenesulfonyl hydrazine (67 mg, 0.312 mmol) and
aldehyde 4 (100 mg, 0.25 mmol) were stirred in ethanol (1 mL)
at 21 °C for 1 h. The resulting solution was concentrated and
chromatographed (2:5 ether/pet ether) to afford 67 mg of 11
(50%) as a faint yellow oil: IR (neat) 3267, 2937, 1597, 1494,
1453, 1371, 1210, 1153, 851, 749, 659 cm-1; 1H NMR (200 MHz,
CDCl3) δ 7.65 (s, 1H), 7.38-7.27 (m, 4H), 7.14-7.06 (m, 6H),
6.96-6.93 [overlapping s, 2H, (syn anti)], 6.63[t, J ) 5.2 Hz,
(anti), (syn hidden under, 7.14-7.06), 1H], 6.48 (t, J ) 5.2 Hz,
1H), 3.97-3.90 (m, 1H), 2.67-2.60 [overlapping s, 6H, (syn,
anti) ], 2.28-2.27 [overlapping s, 3H, (syn, anti)], 2.24-2.15
(m, 2H), 1.76-1.51 (m, 10H); 13C NMR (50 MHz, CDCl3) δ
[150.2, 149.0 (syn, anti)], 144.2, 142.8, [140.2, 140.1 (syn, anti)],
[138.7, 138.6 (syn, anti)], [132.3, 132.0 (syn, anti)], [131.9, 131.8
(syn, anti)], 129.9, 123.9, 122.3, [57.2, 56.8 (syn, anti)], [38.5,
38.4 (syn, anti)], [38.2, 38.0 (syn, anti)], 31.8, 31.4, [25.9, 24.8
(syn, anti)], [23.8, 23.7 (syn, anti)], [23.1, 23.0 (syn, anti)], 20.9;
FAB accurate mass calcd for C30H38N4O2BrS (M+ + 1) 597.1984,
found 597.1899.
1592, 1492, 1454, 1301, 1210, 1054, 883, 749, 698 cm-1 1H
;
NMR (200 MHz, CDCl3) δ 7.36-7.24 (m, 4H), 7.13-7.07 (m,
6H), 7.37, 6.61 [t, J ) 5.5 Hz, 1H (syn, anti)], 6.50 (t, J ) 5.1
Hz, 1H), 4.06-4.00 (m, 1H), 3.83, 3.80 [s, 3H (syn, anti)], 2.35-
2.17 (m, 4H), 1.88-1.59 (m, 8H); 13C NMR (50 MHz, CDCl3) δ
150.9, 150.0, 144.2, 138.7, 129.6, 123.9, 122.3, [61.6, 61.2 (syn,
anti)], 57.2, [38.6, 38.5 (syn, anti)], [38.4, 38.3 (syn, anti)], 31.9,
28.8, 24.8, 24.6, 24.2; HRMS calcd for C22H28N3OBr (M+)
429.1417, found 429.1433.
5-Br om on on a n ed ia l-(1-O-ben zyloxim e)-9-N,N-d ip h en -
ylh yd r a zon e (7). Benzyloxyamine hydrochloride (86 mg, 0.53
mmol) was added to a stirred solution of the aldehyde 4 (179
mg, 0.45 mmol) at 0 °C, followed by addition of pyridine (48
µL, 0.57 mmol). After completion of the reaction, the solution
was concentrated and chromatographed (1:20, ether/pet ether)
to afford 140 mg (62.2%) of 7 as faint yellow oil: IR (neat)
3031, 2933, 1592, 1453, 1301, 1210, 917, 748, 697 cm-1 1H
;
NMR (200 MHz, CDCl3) δ 7.44, 6.68 [t, (syn, J ) 6.1 Hz, anti,
J ) 5.5 Hz), 1H], 7.41-7.34 (m, 9H), 7.14-7.05 (m, 6H), 6.52
(dt, J ) 2.3 Hz, 5.2 Hz, 1H), 5.11, 5.05 [s, 2H, (syn, anti)],
4.04-4.01 (m, 1H), 2.41-2.24 (m, 4H), 1.86-1.59 (m, 8H); 13
C
NMR (50 MHz, CDCl3) δ [151.5, 150.6 (syn, anti)], 144.2, 138.8,
[138.0, 137.7 (syn, anti)], 129.7, [128.3, 128.2 (syn, anti)], 129.7,
[127.8, 127.7 (syn, anti)], 123.9, 122.3, [75.8, 75.5 (syn, anti)],
57.3, [38.6, 38.5 (syn, anti)], 38.2, 31.9, 28.8, [25.1, 24.8 (syn,
anti)], [24.5, 24.2 (syn, anti)]; HRMS calcd for C28H32N3OBr
(M+) 505.1729, found 505.1739.
cis- a n d tr a n s-4-[2-(N,N-Dip h en ylh yd r a zin o)cyclop en -
tyl]bu ta n a l(O-m eth yloxim e) (12). Methoxyamine hydro-
chloride (27 mg, 0.32 mmol) was added to the aldehyde 23 (65
mg, 0.20 mmol) in dry ethanol (1 mL) at 0 °C, followed by the
addition of pyridine (33 µL, 0.40 mmol). The solution was
stirred at 0 °C until the reaction was complete. The reaction
was concentrated and chromatographed (1:20, ether/pet ether)
to yield 52 mg (73.4%) of 12 as a clear colorless oil. Cis
isomer: IR (neat) 2918, 1590, 1494, 1279, 1053, 802, 749, 696
cm-1; 1H NMR (200 MHz, CDCl3) δ 7.35-7.23 (m, 4H), 7.16-
7.10 (m, 4H), 6.99-6.92 (m, 2H), 6.57 [t, J ) 5.5 Hz (anti, syn
hidden under 7.13-7.10), 1H], 3.92-3.87 (br s, 1H), 3.84, 3.77
[s, 3H, (syn, anti)], 3.27-3.25 (m, 1H), 2.28-2.12 (m, 2H),
1.86-1.30 (m, 11H); 13C NMR (50 MHz, CDCl3) δ [151.5, 150.5
(syn, anti)], 148.0, 129.0, 122.0, 120.2, 61.1, [59.1, 58.9 (syn,
anti)], [44.0, 43.9 (syn, anti)], [29.9, 29.7 (syn, anti)], [29.6, 29.5
(syn, anti)], [29.5, 29.4 (syn, anti)], [29.6, 29.5 (syn, anti)], [29.5,
29.4 (syn, anti)], [28.7, 28.4 (syn, anti)], [25.7, 25.6 (syn, anti)],
5-Br om on on a n ed ia l-(1-N,N-d im et h yl-9-N,N-d ip h en -
yld ih yd r a zon e) (8). N,N-Dimethylhydrazine (54 mg, 0.897
mmol) was added to the aldehyde 4 (120 mg, 0.299 mmol) in
dry CH2Cl2 (2 mL). The resulting solution was stirred over-
night at 40 °C. The solvent was concentrated and chromato-
graphed (2:5 ether/pet ether) to afford 100 mg (75%) of 8 as a
faint yellow oil: IR (neat) 2920, 2781, 1593, 1494, 1300, 1210,
749, 698 cm-1 1H NMR (200 MHz, CDCl3) δ 7.39-7.31 (m,
;
4H), 7.13-7.04 (m, 6H), 6.59 (t, J ) 5.42 Hz, 1H), 6.49 (t, J )
5.4 Hz, 1H), 4.05 (br q, J ) 6.05 Hz, 1H), 2.70 (s, 6H), 2.33-
2.19 (m, 4H), 1.90-1.59 (m, 8H); 13C NMR (50 MHz, CDCl3) δ
144.1, 138.7, 138.0, 129.6, 123.8, 122.2, 57.7, 43.2, 38.3, 38.3,
32.3, 31.9, 25.6, 24.8; HRMS calcd for
442.1733, found 442.1723.
C
23H31N4Br (M+)
5-Br om on on a n ed ia l-(1-N-Ben zoylh yd r a zon e)-9-N,N-
d ip h en ylh yd r a zon e (9). Benzoylhydrazine (106 mg, 0.78
mmol) and aldehyde 4 (250 mg, 0.625 mmol) were stirred in
dry toluene (6.6 mL) at 21 °C for 24 h. The resulting mixture
was concentrated and chromatographed (1:24, ether/CH2Cl2)
to yield 230 mg (71%) of 9 as a viscous oil, which was
crystallized from toluene/pet ether: mp 110-112 °C; IR (neat)
[22.2, 22.1 (syn, anti); HRMS calcd for C
22H29N3O (M+)
315.2319, found 351.2321. Trans isomer: 1H NMR (by differ-
ence) (500 MHz, CDCl3) δ 7.33-7.23 (m, 4H), 7.14-7.10 (m,
4H), 6.98-6.94 (m, 2H), 6.52 (t, J ) 5.5 Hz, 1H), 3.92-3.87
(br s, 1H), 3.82, 3.79 [s, 3H, (syn, anti)], 3.05-3.04 (m, 1H),
2.27-1.50 (m, 13 H).
cis- a n d tr a n s-4-[2-(N,N-Dip h en ylh yd r a zin o)cyclop en -
tyl]bu ta n a l(O-ben zyloxim e) (13). Benzyloxyamine hydro-
1
3221, 3052, 2935, 1736, 1648, 1492, 1210, 749, 698 cm-1; H

6966 J . Org. Chem., Vol. 64, No. 19, 1999
Tauh and Fallis
chloride (40 mg, 0.25 mmol) was added to a stirred solution of
the aldehyde 23 (50 mg, 0.15 mmol) at 0 °C, followed by the
addition of pyridine (28 µL, 0.34 mmol). The reaction was
concentrated and chromatographed (1:10, ether/pet ether) to
afford 51 mg (79.7%) of 13 as a faint yellow oil. Cis isomer:
IR (neat) 3030, 2933, 1590, 1495, 1454, 1283, 1029, 912, 814,
4H), 7.16-7.10 (m, 4H), 6.97 (t, J ) 6.9 Hz, 2H), 3.89 (br s,
1H), 3.58 (t, J ) 6.3 Hz, 2H), 3.31-3.27 (m, 1H), 1.88-1.70
(m, 4H), 1.69-1.25 (m, 9H), 0.90 (s, 9H), 0.05 (s, 6H); 13C NMR
(50 MHz, CDCl3) δ 148.0, 129.0, 121.9, 120.2, 63.1, 59.0, 44.3,
33.0, 29.9, 29.5, 28.8, 25.9, 25.1, 22.2, 18.3, 5.1. Trans
isomer: 1H NMR (by difference) (500 MHz, CDCl3) δ 7.25 (t,
J ) 7.8 Hz, 4H), 7.1 (d, J ) 8.2 Hz, 4H), 6.97 (t, J ) 7.2 Hz,
2H), 3.86 (br s, 1H), 3.55 (t, J ) 6.5 Hz, 2H), 3.06-3.02, (m,
1H), 2.13-1.2 (m, 13 H), 0.90 (s, 9H), 0.05 (s, 6H); 13C NMR
(50 MHz, CDCl3) 147.9, 128.9, 121.9, 120.1, 63.7, 63.1, 44.0,
34.4, 32.9, 31.4, 30.6, 25.9, 24.4, 23.6, 18.3, -5.1; HRMS calcd
for C27H42N2OSi (M+) 438.3068, found 438.3061. Anal. calcd
for C27H42N2OSi: C, 73.86; H, 9.67; N, 6.3. Found C, 73.68; H,
9.77; N, 6.48.
748, 697 cm-1 1H NMR (200 MHz, CDCl3) δ 7.45-7.21 (m,
;
9H), 7.16-6.93 (m, 6H), 6.63 [t, J ) 5.4 Hz (anti) (syn hidden
under 7.45-7.21), 1H], 5.09, 5.02 [s, 2H, (syn, anti)], 3.91 (br
s, 1H), 3.28-3.21 (m, 1H), 2.18-2.13 (m, 2H), 1.87-1.38 (m,
11H); 13C NMR (50 MHz, CDCl3) δ [152.1, 151.1 (syn, anti)],
[148.1, 148.0 (syn, anti)], 129.0, [128.3, 128.1 (syn, anti)],
[127.8, 127.7 (syn, anti)], [122.0, 121.9 (syn, anti)], [120.2, 120.0
(syn, anti)], [75.6, 75.5 (syn, anti)], [59.2, 58.9 (syn, anti)], [44.1,
43.9 (syn, anti)], [29.9, 29.7 (syn, anti)], [28.7, 28.4 (syn, anti)],
26.0, [25.5, 25.4 (syn, anti)], 22.2; HRMS calcd for C28H33N3O
(M+) 427.2625, found 427.2606. Trans isomer: 1H NMR (by
difference) (500 MHz, CDCl3) δ 7.42-7.21 (m, 9H), 7.13-7.05
(m, 4H), 7.07-6.91 (m, 2H), {6.62[ t, J ) 5.5 Hz cis], 6.58 [t,
J ) 5.62 Hz trans], 1H (syn) (anti hidden under 7.42-7.21)},
5.08-5.01 [s, 2H (syn, anti)], 3.85 (br s, 1H), 3.07-3.04 (m,
1H), 2.17-2.12 (m, 2H), 1.88-1.35 (m, 11H).
cis- a n d tr a n s-4-[2-(N,N-Dip h en ylh yd r a zin o)cyclop en -
tyl]bu ta n a l(N,N-d im eth ylh yd r a zon e) (14). N,N-Dimeth-
ylhydrazine (34 mg, 0.564 mmol) was added to a solution of
aldehyde 23 (50 mg, 0.153 mmol) in dry CH2Cl2 (1.5 mL). The
resulting solution was stirred overnight at 40 °C. The reaction
was concentrated and chromatographed (2:5 ether/pet ether)
to afford 45 mg (80%) of 14 as a faint yellow oil. Cis isomer:
IR (neat) 2909, 1591, 1482, 1029, 748, 696 cm-1; 1H NMR (200
MHz, CDCl3) δ 7.30-7.22 (m, 4H), 7.23-7.11 (m, 4H), 6.98-
6.91 (m, 2H), 6.66-6.65 (m, 1H), 3.99-3.98 (br s, 1H), 3.27-
3.23 (m, 1H), 2.68 (s, 6H), 2.24-2.16 (m, 2H), 1.85-1.39 (m,
11H); 13C NMR (50 MHz, CDCl3) δ 148.0, 138.9, 128.9, 121.8,
120.2, 58.8, 44.2, 43.4, 33.1, [29.9, 29.6 (syn, anti)], 29.5, 28.5,
26.5, 22.2; FAB accurate mass calcd for C23H33N4 (M+ + 1)
365.2706, found 365.3281. Anal. Calcd for C23H32N4: C, 75.78;
H, 8.84; N, 15.36. Found: C, 75.59; H, 8.90; N, 15.23. Trans
isomer: 1H NMR (by difference) (500 MHz, CDCl3) δ 7.35-
7.23 (m, 4H), 7.19-7.11 (m, 4H), 6.97-6.93 (m, 2H), 6.55 (t, J
) 5.5 Hz, 1H), 3.98-3.96 (br s, 1H), 3.05-3.03 (m, 1H), 2.67
(s, 6H), 2.20-2.17 (m, 2H), 2.16-1.34 (m, 11H);13C NMR (125
MHz, CDCl3) δ 148.1, 139.2, 128.7, 121.9, 120.3, 63.8, 43.9,
43.4, 34.1, 31.4, 30.7, 28.5, 26.4, 23.6.
cis- a n d tr a n s-2-(4-Hyd r oxybu tyl)-1-(N,N-d ip h en ylh y-
d r a zin o)cyclop en ta n e (22). Tetrabutylammonium fluoride
(1.12 mL of 1M soln. in THF, 1.12 mmol) was added to
compound 21 (408 mg, 0.931 mmol) in dry THF (7.5 mL) at 0
°C, and the resulting solution was stirred overnight. The
reaction was quenched with water (5 mL) and extracted with
ether. The combined organic extracts were washed with brine
(2 × 10 mL), concentrated, and chromatographed (1:2.5 ether/
pet ether) to afford 258 mg (86%) of 22 as a faint yellow oil.
Cis isomer: IR (neat) 3348, 2937, 2865, 1590, 1495, 1290, 1052,
748, 696 cm-1 1H NMR (200 MHz, CDCl3) δ 7.34-7.23 (m,
;
4H), 7.19-7.15 (m, 4H), 6.99-6.96 (m, 2H), 3.92 (br s, 1H),
3.58 (q, 1H), 3.30-3.26 (m, 1H), 1.91-1.30 (m, 13H); 13C NMR
(50 MHz, CDCl3) δ 148.0, 128.9, 121.8, 120.1, 62.5, 58.9, 44.2,
32.7, 29.8, 29.5, 28.6, 24.8, 22.2. Trans isomer: 1H NMR (by
difference) (500 MHz, CDCl3) δ 7.30-7.20 (m, 4H), 7.16-7.13
(m, 4H), 6.99-6.95 (m, 2H), 3.80 (br s, 1H), 3.55 (t, J ) 6.6
Hz, 2H), 3.08-3.07 (m, 1H), 1.89-1.76 (m, 3H), 1.65-1.28 (m,
10H); 13C NMR (50 MHz, CDCl3) 147.7, 128.8, 121.7, 120.0,
63.5, 62.4, 43.8, 34.2, 32.6, 31.3, 30.5, 24.2, 23.5; HRMS calcd
for C21H28N2O (M+) 324.2202, found 324.2219.
cis- a n d tr a n s-4-[2-(N,N-Dip h en ylh yd r a zin o)cyclop en -
tyl]bu ta n a l (23). A suspension of pyridine-sulfur trioxide
complex (380 mg, 0.81 mmol) in DMSO (3 mL) was added to
a solution of the alcohol 22 (258 mg, 0.79 mmol) and triethyl-
amine (0.90 mL, 6.45 mmol) in DMSO (5.6 mL) at 21 °C. The
reaction was quenched with water and extracted with ethyl
acetate (3 × 20 mL). The combined organic extracts were
washed with brine (2 × 10 mL), dried, and concentrated to
give 250 mg (97%) of 23 as a faint yellow oil. Compound 23
could not be further purified due to its instability on silica gel.
For 23: IR (neat) 2915, 2351, 1723, 1590, 1493, 1292, 749,
cis- a n d tr a n s-4-[2-(N,N-Dip h en ylh yd r a zin o)cyclop en -
tyl]bu ta n a l(N-ben zoylh yd r a zon e) (15). Benzoylhydrazine
(33.7 mg, 0.248 mmol) and aldehyde 23 (50 mg, 0.155 mmol)
were stirred in dry CH2Cl2 (1 mL) at 21 °C for 4 h. The reaction
was concentrated and chromatographed (1:24, ether/CH2Cl2)
to yield 55 mg (80%) of 15 as a viscous oil. Cis isomer: IR
(neat) 3226, 3052, 2937, 2865, 1648, 1586, 1494, 1289, 1075,
696 cm-1 1H NMR (200 MHz, CDCl3) δ 9.72 (s, 1H), 7.48-
;
6.92 (m, 10 H), 3.96 (br s, 1H), 3.35-3.21 (m, 1H), 2.48-2.39
(m, 2H), 1.99-1.45 (m, 11H).
cis- a n d tr a n s-4-[2-(N,N-Dip h en ylh yd r a zin o)cyclop en -
tyl]bu ta n a l[N-(p-tolu en esu lfon yl)-h yd r a zon e] (24). p-Tol-
uenesulfonylhydrazine (32 mg, 0.175 mmol) and aldehyde 23
(47 mg, 0.146 mmol) were stirred in ethanol (1 mL) at 21 °C
for 1 h. The reaction was concentrated and chromatographed
(2:5 ether/pet ether) to afford 45 mg (63.3%) of 24 as a faint
yellow viscous oil: IR (neat) 3207, 3092, 2914, 1591, 1479,
1320, 1165, 1059, 909, 813, 748, 684 cm-1; 1H NMR (500 MHz,
CDCl3) δ 7.84-7.75 (m, 2H), 7.29-7.22 (m, 6H), 7.15-7.08 (m,
4H), 7.07-6.94 (m, 3H), 6.63 [t, J ) 5.2 Hz (anti) (syn hidden
under 7.07-6.94), 1H], 3.74 (br s, 1H), [3.23-3.21 (m, cis),
2.99-2.96 (m, trans), 1H], 2.45-2.36 [overlapping s (cis, trans,
syn, anti), 3H], 2.21-2.10 (m, 2H), 1.91-1.25 (m, 11H). Cis
isomer 13C NMR (125 MHz, CDCl3) δ [152.7, 152.2 (syn, anti)],
148.1, 143.9, 135.3, 129.5, 129.0, 127.9, 122.0, 120.3, [59.4, 59.1
(syn, anti)], 44.1, [33.7, 32.3 (syn, anti)], 29.7, 29.6, [28.5, 28.3
(syn, anti)], 25.2, [22.1, 22.0 (syn, anti)], 21.5. Trans isomer:
13C NMR (125 MHz, CDCl3) δ [152.7, 151.2 (syn, anti)], 147.9,
143.9, 135.3, 129.6, 129.0, 128.0, 122.0, 120.1, 63.6, 43.7, 33.7,
31.3, 30.6, 29.6, [24.8, 24.7 (syn, anti)], 23.4, 21.5; HRMS calcd
for C28H34N4O2S (M+) 490.2405, found 490.2445.
1028, 909, 748, 696 cm-1 1H NMR (200 MHz, CDCl3) δ 9.1
;
(br s, 1H), 7.77-7.73 (m, 2H), 7.48-7.31 (m, 4H), 7.28-7.16
(m 4H), 7.12-7.02 (m, 4H), 6.99-6.90 (m, 2H), 3.80-3.79 (br
s, 1H), 3.28-3.25 (m, 1H), 2.31-2.27 (m, 2H), 1.88-1.35 (m,
11H); 13C NMR (50 MHz, CDCl3) δ 162.2, 152.2, 148.0, 148.0,
131.8, 129.0, 128.6, 127.3, 122.1, 120.3, 59.1, 44.1, 32.1, 29.6,
28.5, 28.5, 25.8, 22.1; HRMS calcd for C28H32N4O (M+) 440.2577,
found 440.2578. Trans isomer: 1H NMR (500 MHz, CDCl3)
(by difference), δ 8.96 (br s, 1H), 7.75-7.74 (m, 2H), 7.49-
7.39 (m, 4H), 7.27-7.22 (m, 4H), 7.19-7.09 (m, 4H), 6.97-
6.92 (m, 2H), 3.70 (br s, 1H), 3.07-3.05 (m, 1H), 2.48-2.34
(m, 2H), 1.86-1.40 (m, 11H); 13C NMR (125 MHz, CDCl3) δ
162.2, 152.2, 147.1, 147.1, 131.8, 129.0, 128.7, 127.2, 122.2,
120.2, 59.5, 44.1, 33.9, 31.2, 30.7, 30.6, 25.2, 23.4.
cis- a n d tr a n s-2-(4-ter t-Bu t yld im et h ylsilyloxyb u t yl)-
1-(N,N-d ip h en ylh yd r a zin o)cyclop en ta n e (21). Following
the general procedure for the radical cyclization tributyltin
hydride (0.390 mL, 1.45 mmol) and AIBN (53 mg, 0.33 mmol)
were added to the hydrazone 2 (X ) Br) (500 mg, 0.96 mmol)
in dry benzene (15.6 mL). The product mixture was chromato-
graphed (3:1 ether/pet ether) to obtain 424 mg (96%) of a 3:1
mixture of cis and trans 21 as a faint yellow oil. Cis isomer:
IR (neat) 3061, 2939, 2858, 1591, 1495, 1467, 1259, 1099, 838,
cis- a n d tr a n s-4-[2-(N,N-Dip h en ylh yd r a zin o)cyclop en -
t yl]b u t a n a l[N-(2,4,6-t r im et h ylb en zen esu lfon yl)h yd r a -
zon e] (25). 2,4,6-Trimethylbenzenesulfonylhydrazine (37 mg,
0.175 mmol) and aldehyde 23 (47 mg, 0.146 mmol) were stirred
in ethanol (1 mL) at 21 °C for 1 h. The reaction was
748, 695 cm-1 1H NMR, (200 MHz, CDCl3) δ 7.32 7.20(m,
;

Rate Constants for Exo Alkyl Radical Cyclizations
J . Org. Chem., Vol. 64, No. 19, 1999 6967
concentrated and chromatographed (2:5 ether/pet ether) to
mg, 926 mmol) in dry CH2Cl2 (1.5 mL). The resulting solution
was stirred overnight at 40 °C. The reaction was concentrated
and chromatographed (1:1 ether/pet ether) to afford 121 mg
(42%) of 29 as a faint yellow oil: IR (neat) 2943, 2858, 1654,
1468, 1387, 1253, 1100, 975, 840, 776; 1H NMR (500 MHz,
CDCl3) δ 3.51 (t, J ) 6.5 Hz, 2H), 2.47-2.41 (m, 1H), 2.38 (s,
6H), 2.35-2.20 (m, 2H), 1.88-1.61 (m, 3H), 1.55-1.17 (m, 7H),
0.80 (s, 9H), -0.04 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 177.3,
63.0, 46.9, 44.4, 33.0, 32.9, 30.2, 29.3, 25.8, 23.8, 22.7, 18.1,
-5.4; HRMS calcd for C17H36N2OSi (M+) 312.2598, found
312.2600.
2-[4-(ter t-Bu tyldim eth ylsilyloxy)bu tyl]cyclopen tan on e-
N-ben zoylh yd r a zon e (30). Benzoylhydrazine (122 mg, 0.88
mmol) and ketone 26 (200 mg, 0.74 mmol) were stirred in dry
toluene (8 mL) at 21 °C for 4 h. The reaction was concentrated
and chromatographed (1:24, ether/CH2Cl2) to yield 178 mg
(62%) of 30 as a viscous oil: IR (CCl4) 3180, 3069, 2913, 1657,
1577, 1463, 1383, 1254, 1102 cm-1; 1H NMR (500 MHz, CDCl3)
δ 8.58 (br s, 1H), 7.85-7.65 (m, 2H), 7.43-7.34 (m, 3H), 3.54
(m, 2H), 2.52-2.17 (m, 3H), 2.02-1.67 (m, 4H), 1.59-1.19 (m,
6H), 0.83 (s, 9H), 0.01 (s, 6H); 13C NMR (50 MHz, CDCl3) δ
169.9, 163.3, 133.5, [131.4, 131.2 (syn, anti)], [128.1, 128.0 (syn,
anti)], [127.3, 127.0 (syn, anti)], 62.9, 44.7, 32.7, 32.1, 30.6,
27.6, 25.8, 23.8, 22.4, 18.1, -0.05; HRMS calcd for C22H36N2O2-
Si (M+) 388.2547, found 388.2517.
2-[4-(ter t-Bu tyldim eth ylsilyloxy)bu tyl]cyclopen tan on e-
N-(p-tolu en esu lfon yl)h yd r a zon e (31). p-Toluenesulfonyl-
hydrazine (163 mg, 0.88 mmol) and ketone 26 (200 mg, 0.74
mmol) were stirred in ethanol (3 mL) at 21 °C for 1 h. The
resulting solution was concentrated and chromatographed (2:5
ether/pet ether) to afford 213 mg (66%) of 31 as a faint yellow
viscous oil: IR (neat) 3212, 2911, 1660, 1597, 1461, 1398, 1369,
1254, 1166, 1096, 924, 829, 776, 679 cm-1; 1H NMR (500 MHz,
CDCl3) δ 7.81 (d, J ) 6.9 Hz, 2H), 7.39 (br s, 1H), 7.26 (d, J )
10.9 Hz, 2H), 3.55-3.51 (m, 2H), 2.39 (s, 3H), 2.36-2.20 (m,
2H), 2.09-2.03 (m, 2H), 1.93-1.79 (m, 2H), 1.66-1.39 (m, 2H),
1.27-1.11 (m, 4H), 0.86 (s, 9H), 0.01 (s, 6H); 13C NMR (125
MHz, CDCl3) δ 169.9, 143.7, 135.9, 129.3, 128.0, 63.0, 44.7,
32.8, 31.6, 31.1, 28.0, 25.9, 23.5, 22.5, 21.5, 18.3, -5.2; HRMS
calcd for C18H29N2O3SSi (M+-t-Bu) 381.1669, found 381.1655.
afford 42 mg (55%) of 25 as a faint yellow oil: IR (neat) 3214,
1
2916, 1591, 1474, 1314, 1159, 1046, 852, 660 cm-1; H NMR
(500 MHz, CDCl3) δ 7.27-7.22 (m, 4H), 7.11-7.05 (m, 4H),
7.01-6.95 (m, 2H), 6.93-6.90 [overlapping s, 2H, (syn, anti)],
6.57 [t, J ) 5.3 Hz (anti), (syn hidden under 7.01-6.95), 1H],
3.82-3.74 (br s, 1H), [3.22-3.20 (m, cis), 2.98-2.96 (m, trans)
1H], 2.67-2.60 [overlapping s, 6H], 2.30-2.25 (s, 3H), 2.22-
2.08 (m, 2H), 1.88-1.70 (m, 4H), 1.67-1.66 (m, 3H), 1.59-
1.30 (m, 4H). Cis isomer: 13C NMR (125 MHz, CDCl3) δ 151.1,
148.1, 142.7, 140.6, 132.3, 131.8, 129.0, 122.1, 120.2, 59.2, 44.0,
[32.3, 32.2 (syn, anti)], 29.6, 29.5, 28.2, 25.1, 23.0, 22.0, 20.9.
Trans isomer: 13C NMR (125 MHz, CDCl3) δ 151.0, 147.9,
142.7, 140.0, 132.3, 131.8, 129.0, 122.0, 120.1, 63.6, 43.8, 33.7,
31.3, 30.6, 24.5, 23.4, 23.0, 22.0, 20.9; HRMS calcd for
C
30H38N4O2S (M+) 518.2717, found 518.2725.
2-(4-t er t -B u t y ld im e t h y ls ily lo x y b u t y l)c y c lo p e n t a -
n on e (26). n-Butyllithium (14.35 mL of 2.5 M solution, 35.8
mmol) was added dropwise to a cold solution (-78 °C) of
diisopropylamine (4.16 g, 41.11 mmol) in dry THF (42.6 mL).
This solution was stirred for 15 min, and then cyclopentanone
(2.7 g, 33.12 mmol) in THF (21.2 mL) was added and stirred
for a further 20 min. HMPA (27.73 mL, 163.8 mmol) was
added, followed by dimethyl zinc (16.3 mL of 1 M solution,
16.3 mmol) and ICH2CH2CH2CH2OTBDMS (2.6 g, 8.28 mmol)
as a solution in THF (32.2 mL). The reaction was stirred at
-78 °C for 4 h and then warmed to 21 °C. The reaction was
quenched with aqueous NH4Cl (50 mL) and extracted with
ether (3 × 150 mL). The combined organic extracts were
washed with brine (3 × 50 mL), dried, concentrated, and
chromatographed (6% ether/pet ether) to afford 1.34 g (60%)
of 26 as a clear colorless oil: IR (neat) 2942, 2859, 1740, 1465,
1360, 1253, 1152, 1100, 1006, 840, 776 cm-1 1H NMR (500
;
MHz, CDCl3) δ 3.57 (t, J ) 6.45 Hz, 2H), 2.29-2.16 (m, 2H),
2.10-1.94 (m, 3H), 1.78-1.72 (m, 2H), 1.54-1.50 (m, 3H),
1.45-1.31 (m, 2H), 1.26-1.20 (m, 1H), 0.85 (s, 9H), 0.01 (s,
6H); 13C NMR (125 MHz, CDCl3) δ 221.3, 62.9, 49.1, 38.1, 32.7,
29.5, 29.4, 25.9, 23.8, 20.7, 18.3, -5.3; HRMS calcd for
C
11H21O2Si (M+-t-Bu) 213.1312, found 213.1315. Anal. Calcd
for C15H30O2Si: C, 66.68; H, 11.17. Found: C, 66.65; H, 10.94.
2-[(4-ter t-Bu tyldim eth ylsilyloxy)bu tyl]cyclopen tan on e-
O-m eth yloxim e (27). Methoxyamine hydrochloride (102 mg,
1.22 mmol) was added to a solution of ketone 26 (300 mg, 1.11
mmol) in dry ethanol (5 mL) at 0 °C, followed by the addition
of pyridine (107 µL, 1.33 mmol), and the reaction was stirred
at 0 °C. The reaction was concentrated and chromatographed
(1:20, ether/pet ether) to yield 290 mg (87%) of 27 as a clear
colorless oil: IR (neat) 2942, 2859, 1486, 1387, 1361, 1253,
2-(4-Hydr oxybu tyl)cyclopen tan on e-O-m eth yloxim e (32).
Tetrabutylammonium fluoride (0.609 mL of 1 M solution in
THF, 0.609 mmol) was added to the oxime ether 27 (190 mg,
0.609 mmol) in dry THF (4.2 mL) at 0 °C, and the resulting
mixture was stirred overnight. The reaction was quenched
with water (2 mL) and extracted with ether. The combined
organic extracts were washed with brine (2 × 10 mL), dried,
concentrated, and chromatographed (2:3, ether/hexanes) to
afford 150 mg (80%) of 32 as a faint yellow oil: IR (neat) 3369,
1
1100, 1052, 1006, 841, 776 cm-1; H NMR (500 MHz, CDCl3)
δ 3.76 (s, 3H), 3.54 (t, J ) 6.4 Hz, 2H), 2.46-2.35 (m, 2H),
2.28-2.21 (m, 1H), 1.92-1.86 (m, 1H), 1.77-1.64 (m, 2H),
1.57-1.41 (m, 3H), 1.39-1.24 (m, 4H), 0.83 (s, 9H), -0.01 (s,
6H); 13C NMR (125 MHz, CDCl3) δ 167.9, [62.9, 62.8, (syn,
anti)], 61.1, [43.1, 39.7 (syn, anti)], 32.8, 32.3, 31.4, 27.5, 25.8,
23.9, 22.5, 18.2, -5.3; HRMS calcd for C16H33NO2Si (M+)
299.2282, found 299.2286.
1
2914, 2363, 1652, 1450, 1176, 1053, 873, 847 cm-1; H NMR
(200 MHz, CDCl3) δ 3.79-3.60 [overlapping s, 3H (syn, anti)],
3.56-3.44 (m, 2H), 3.06 (br s, 1H), 2.44-2.10 (m, 2H), 1.89-
1.10 (m, 11H); 13C NMR (50 MHz, CDCl3) δ 168.2, [62.0, 61.9
(syn, anti)], [42.9, 39.6 (syn, anti)], [32.3, 31.8 (syn, anti)], [31.2,
30.4 (syn, anti)], [30.7, 30.6 (syn, anti)], 27.4, 23.5, 22.7, 22.3;
HRMS calcd for C10H19NO2 (M+) 185.1416, found 185.1397.
2-[4-(ter t-Bu tyldim eth ylsilyloxy)bu tyl]cyclopen tan on e-
O-ben zyloxim e (28). Benzyloxyamine hydrochloride (150 mg,
0.937 mmol) was added to a stirred solution of ketone 26 (230
mg, 0.852 mmol) at 0 °C, followed by the addition of pyridine
(83 µL, 1.02 mmol). The reaction was worked up immediately
and chromatographed (1:10, ether/pet ether) to afford 275 mg
(86%) of 28 as a faint yellow oil: IR (neat) 2941, 2858, 2362,
1462, 1253, 1049, 1036, 839, 776, 697 cm-1; 1H NMR (500 MHz,
CDCl3) δ 7.36-7.23 (m, 5H), 5.07 (s, 2H), 3.5 (t, J ) 6.4 Hz,
2H), 2.57-2.34 (m, 3H), 1.97-1.70 (m, 3H), 1.62-1.45 (m, 3H),
1.39-1.29 (m, 4H), 0.89 (s, 9H), 0.04 (s, 6H); 13C NMR (125
MHz, CDCl3) δ 168.7, 130.4, 128.1, 127.9, 127.4, 75.4, [63.1,
62.9 (syn, anti)], [43.2, 40.1 (syn, anti)], [32.8, 32.7 (syn, anti)],
[32.7, 31.0 (syn, anti)], [31.5, 30.6 (syn, anti)], 28.0, 25.9, [23.8,
23.6 (syn, anti)], [23.0, 22.5 (syn, anti)], 18.3, -5.3; HRMS calcd
for C22H37NO2Si (M+) 375.2595, found 375.2586.
2-(4-Hydr oxybu tyl)cyclopen tan on e-O-ben zyloxim e (33).
Tetrabutylammonium fluoride (0.806 mL of 1 M solution in
THF, 0.806 mmol) was added to a solution of the oxime ether
28 (275 mg, 0.733 mmol) in dry THF (5 mL) at 0 °C, and the
resulting solution was stirred overnight. The reaction was
quenched with water (2 mL) and extracted with ether. The
combined organic extracts were washed with brine (2 × 10
mL), dried, concentrated, and chromatographed (1:1, ether/
pet ether) to afford 133 mg (87%) of 33 as a faint yellow oil.
IR (neat) 3365, 2936, 2863, 1496, 1454, 1365, 1037, 906, 737,
698 cm-1;1H NMR (500 MHz, CDCl3) δ 7.34-7.23 (m, 5H), 5.03
(s, 2H), [3.56 (t, J ) 6.4 Hz), 3.52 (t, J ) 6.5 Hz), 2H (syn,
anti)], 2.56-2.31 (m, 4H), 1.84-1.66 (m, 3H), 1.61-1.51 (m,
3H), 1.49-1.30 (m, 4H); 13C NMR (125 MHz, CDCl3) δ [169.0,
168.8 (syn, anti)], [138.3, 138.2 (syn, anti)], [128.2, 128.1 (syn
anti)], [127.9, 127.8 (syn, anti)], [127.5, 127.4 (syn, anti)], 75.4,
[65.7, 62.4 (syn, anti)], [41.1, 39.9 (syn, anti)], [32.5, 30.1 (syn,
anti)], [31.9, 30.6 (syn, anti)], [31.5, 30.6 (syn, anti)], 28.0, [23.5,
2-[4-(ter t-Bu tyldim eth ylsilyloxy)bu tyl]cyclopen tan on e-
N,N-d im eth ylh yd r a zon e (29). N,N-Dimethylhydrazine (77
µL, 1.02 mmol) was added to a solution of the ketone 26 (250

6968 J . Org. Chem., Vol. 64, No. 19, 1999
Tauh and Fallis
22.9 (syn, anti)], 22.5; HRMS calcd for C16H23NO2(M+) 261.1729,
found 261.1751.
3245, 2940, 2859, 1598, 1466, 1321, 1251, 1160, 1097, 838, 776
1
cm-1; H NMR (500 MHz, CDCl3) δ 7.77 (d, J ) 8.0 Hz, 2H),
cis- a n d tr a n s-2-[4-(t-Bu tyld im eth ylsilyloxy)bu tyl]-1-
(N,N-d im eth ylh yd r a zin o)cyclop en ta n e (34). A suspension
of sodium cyanoborohydride (12.6 mg, 0.199 mmol), the di-
methylhydrazone 29 (50 mg, 0.166 mmol) and a few milligrams
of Bromocresol Green in dry MeOH (1 mL) was stirred under
nitrogen. A solution of p-toluenesulfonic acid (190 mg, 1 mmol)
in MeOH (1 mL) was slowly added at 0 °C to maintain the pH
at 3.5. The reaction mixture was stirred at 0 °C for 1 h,
quenched with water, and extracted with ether (3 × 10 mL).
The combined organic extracts were washed with brine (2 ×
3 mL), dried, filtered, concentrated, and chromatographed (1:
1, ether/pet ether) to afford 25 mg (50%, 1:1.4 mixture of cis
and trans) of 34 as a faint yellow viscous oil: IR (neat) 3395,
7.27-7.26 (m, 2H), 3.58-3.52 (overlapping t, 2H), [3.12-3.11,
m (cis), 2.78-2.76, m (trans), 1H], [2.39, 2.36, overlapping s
(cis, trans), 3H], 1.73-1.01 (m, 13H), 0.85 (s, 9H), 0.01 (s, 6H).
Cis isomer 13C NMR (125 MHz, CDCl3) δ 143.8, 135.6, 129.4,
128.1, 63.1, 62.6, 43.3, 33.0, 30.7, 29.5, 28.6, 25.9, 24.9, 21.5,
21.3, 18.3, -5.3. Trans isomer 13C NMR (125 MHz, CDCl3) δ
143.7, 135.6, 129.2, 128.1, 63.3, 62.2, 43.8, 34.1, 33.0, 30.5, 29.2,
25.9, 24.3, 22.7, 21.3, 18.3, -5.3.
cis- a n d tr a n s-4-[2-(N-Meth oxyla m in o)cyclop en tyl]-1-
bu ta n ol (37). A suspension of sodium cyanoborohydride (76
mg, 1.216 mmol), the O-methyloxime 32 (150 mg, 0.811 mmol),
and a few milligrams of bromocresol green in methanol (5 mL)
was stirred under nitrogen. A solution of p-toluenesulfonic acid
(190 mg, 1 mmol) in methanol (1 mL) was slowly added at 21
°C to maintain the pH at 3.5. The reaction was stirred at 21
°C for 3 h, quenched with water, and extracted with ether (3
× 5 mL). The combined organic extracts were washed with
brine (2 × 5 mL), dried, filtered, concentrated, and chromato-
graphed (1:20, ether/pet ether) to afford 90 mg (60%, 1:2
mixture of cis and trans) of 37 as a clear colorless oil: IR (neat)
1
2909, 2361, 1464, 1253, 1100, 839 cm-1; H NMR (500 MHz,
CDCl3) δ 3.59-3.55 [overlapping t, 2H (cis, trans)], [3.22-3.20
(m, cis), 2.93-2.89 (m, trans), 1H], 1.87-1.20 (m, 13 H), 0.86
(s, 9H), 0.01 (s, 6H); 13C NMR (125 MHz, CDCl3) δ [64.0, 59.6
(cis, trans)], [63.2, 63.0 (cis, trans)], [47.6, 46.9 (cis, trans)],
[44.2, 43.4 (cis, trans)], [34.5, 33.5 (cis, trans)], [33.0, 31.3 (cis,
trans)], [32.1, 31.1 (cis, trans)], [29.5, 28.5 (cis, trans)], 25.9,
[24.8, 24.5 (cis, trans)], [22.5, 21.8 (cis, trans)], 18.2, -5.3; FAB
accurate mass calcd for C17H39N2OSi (M+ + 1) 315.2833, found
315.3075.
cis- a n d tr a n s-2-[4-(ter t-Bu tyld im eth ylsilyloxy)bu tyl]-
1-(N-ben zoylh yd r a zin o)cyclop en ta n e (35). Sodium boro-
hydride (40 mg, 1.12 mmol) was added to a solution of the
benzoylhydrazone 30 (220 mg, 0.563 mmol) in dry methanol
(4 mL), and the resulting mixture was stirred overnight at 21
°C. The reaction was quenched with acetone (3 mL) and
extracted with ether (3 × 25 mL). The combined organic
extracts were washed with brine, dried, concentrated, and
chromatographed (2% MeOH/CH2Cl2) to afford 124 mg (56%,
1:1.2 mixture of cis and trans) of 35 as a faint yellow oil: IR
(neat) 3277, 2911, 2352, 1638, 1577, 1457, 1253, 1097, 817
cm-1; 1H NMR (500 MHz, CDCl3) δ 7.75-7.71 (m, 2H), 7.49-
7.23 (m, 3H), [3.59, t, J ) 6.4 Hz (cis), 3.54, t, J ) 6.5 Hz
(trans), 2H], [3.51-3.43, m (cis), 3.17-3.10, m, (trans), 1H],
1.89-1.15 (m, 13H), [0.86, 0.85 overlapping s (cis, trans) 9H],
[0.25, 0.00 overlapping s (cis, trans), 6H]. Cis isomer 13C NMR
(125 MHz, CDCl3) δ 167.2, 133.0, 131.6, 128.5, 126.7, 63.3,
63.1, 43.9, 33.0, 30.3, 29.3, 29.1, 25.9, 24.9, 21.8, 15.1, -5.3.
Trans isomer: 13C NMR (125 MHz, CDCl3) δ 167.1, 132.9,
131.6, 128.5, 128.5, 67.3, 63.0, 44.2, 34.5, 32.9, 31.2, 31.0, 25.9,
24.4, 23.1, 15.1, -5.3; HRMS calcd for C22H38N2O2Si (M+)
390.2704, found 390.2685.
cis- a n d tr a n s-2-[4-(ter t-Bu tyld im eth ylsilyloxy)bu tyl]-
1-[N-(p-tolu en esu lfon ylh yd r a zin o)]cyclop en ta n e (36). A
suspension of sodium cyanoborohydride (34 mg, 0.545 mmol),
p-toluenesulfonylhydrazone 31 (200 mg, 0.448 mmol), and a
few milligrams of bromocresol green in dry THF (10 mL) was
stirred under nitrogen. A solution of p-toluenesulfonic acid (190
mg, 1.0 mmol) in THF (1 mL) was then slowly added at 0 °C
to maintain the pH at 3.5, indicated by the tan color of the
indicator. The reaction mixture was stirred at 21 °C for 18 h,
quenched with water, and extracted with ether (3 × 10 mL).
The combined organic extracts were washed with brine (2 ×
10 mL), dried, filtered, concentrated, and chromatographed (1:
1, ether/pet ether) to afford 100 mg (50%, 1.3:1.0 mixture of
cis and trans) of 36 as a faint yellow viscous oil: IR (neat)
1
3342, 2909, 1453, 1360, 1034, 833 cm-1; H NMR (500 MHz,
CDCl3) δ 3.58-3.55 [overlapping t (cis, trans), 2H], [3.47, 3.45
overlapping s (cis, trans), 3H] [3.36-3.35, 3.04-3.01 m (cis,
trans), 1H] 1.82-1.64 (m, 3H), 1.58-1.29 (m, 8H), 1.22-1.10
(m, 2H). Cis isomer 13C NMR (125 MHz, CDCl3) δ 67.3, 62.6,
61.9, 43.0, 34.5, 32.8, 31.4, 30.4, 24.7, 23.3. Trans isomer 13C
NMR (125 MHz, CDCl3) δ 62.9, 62.5, 61.6, 43.0, 32.7, 29.8,
29.4, 28.4, 24.7, 21.8; HRMS calcd for C10H21NO2 (M+) 187.1533,
found 187.1557.
cis- a n d tr a n s-4-[2-(N-Ben zyloxya m in o)cyclop en tyl]-
1-bu ta n ol (38). A suspension of sodium cyanoborohydride (32
mg, 0.509 mmol), the O-benzyloxime 33 (133 mg, 0.509 mmol),
and a few milligrams of bromocresol green in methanol (5 mL)
was stirred under nitrogen. A solution of p-toluenesulfonic acid
(190 mg, 1 mmol) in methanol (1 mL) was then slowly added
at 21 °C to maintain the pH at 3.5. The reaction was stirred
at 21 °C for 3 h, quenched with water, and extracted with ether
(3 × 5 mL). The combined organic extracts were washed with
brine (2 × 5 mL), dried, filtered, concentrated, and chromato-
graphed (1:20, ether/pet ether) to afford 90 mg (67%, 1:2
mixture of cis and trans) of 38 as a clear colorless oil: IR (neat)
1
3353, 2910, 2361, 1453, 1361, 1035, 742, 698 cm-1; H NMR
(500 MHz, CDCl3) δ 7.34-7.23 (m, 5H), [4.69, 4.67, s (cis,
trans), 2H], [3.60-3.56 overlapping s (cis, trans, syn, anti),
2H], [3.43-3.42 (m, cis), 3.12-3.09 (m, trans) 1H], 1.85-1.13
(m, 14H). Cis isomer: 13C NMR (125 MHz, CDCl3) δ 137.9,
128.3, 128.1, 127.6, 76.3, 67.5, 62.7, 43.0, 34.5, 32.8, 31.4, 30.6,
24.3, 23.4. Trans isomer 13C NMR (125 MHz, CDCl3) δ 137.9,
128.3, 128.2, 127.6, 75.4, 63.0, 62.6, 43.1, 34.5, 29.8, 29.5, 28.5,
24.7, 21.8; HRMS calcd for C16H25NO2 (M+) 263.1886, found
263.1861.
Ack n ow led gm en t. We are grateful to the Natural
Sciences and Engineering Research Council of Canada
for financial support of this research and S. Woo for
advice.
J O982017U