Oxidative Pictet-Spengler Cyclizations

Full text of DOI:10.1021/jo971705v

860
J . Org. Chem. 1998, 63, 860-863
Notes
Sch em e 1
Oxid a tive P ictet-Sp en gler Cycliza tion s
Hyun J in Kim,† Ung Chan Yoon,† Young-Shik J ung,‡
No Sang Park,‡ Ericka M. Cederstrom,§ and
Patrick S. Mariano*,§,|
Department of Chemistry, College of Natural Sciences,
Pusan National University, Pusan 609-735, Korea,
Division of Bioorganic Chemistry, Korea Research Institute
of Chemical Technology, P.O. Box 107, Yusong,
Taejon 305-606, Korea, and Department of Chemistry
and Biochemistry, University of Maryland,
Sch em e 2
Sch em e 3
College Park, Maryland 20742
Received September 12, 1997
The Pictet-Spengler reaction has stood as one of the
most useful synthetic methods to construct D3,4-aryl-fused
piperidine ring systems. The process is typically pro-
moted by acid-catalyzed condensation of an aryl ethyl-
amine with an aldehyde (Scheme 1). Intramolecular
capture of the intermediate iminium cation by the aryl
ring leads to generation of the piperidine ring system.
Although this process has been used effectively in a large
number of alkaloid syntheses2 and a number of variations
have been introduced to produce the iminium cation
intermediate,3 few studies have addressed issues associ-
ated with the intervention of N-acyliminium cation
intermediates and the preparation of ring systems smaller
(e.g., five-membered) or larger (e.g., seven- and eight-
membered) than piperidines.
Studies in our laboratory of photochemically induced
SET-reactions of tertiary R-silylamines and -amides5 and
related metal oxidation reactions6 have led to the devel-
opment of a new method to generate both N-alkyl- and
N-acyliminium cations. These efforts have demonstrated
that the silicon-substituted amine and amide substrates
undergo regioselective oxidative conversion to iminium
cations (Scheme 2). The high regiocontrol associated
with these processes is due to the more rapid rates of
tertiary aminium radical R-desilylation vs competitive
R-deprotonation.7 In a more recent effort, we have shown
how this oxidation process can be used effectively to
initiate Mannich cyclization reactions of R-silylamines
and -amides which possess tethered vinyl- and allylsilane
functionality. In this report, we describe the results of
a parallel study which has shown how the oxidative
protocol can be applied to promote both standard and
unique Pictet-Spengler cyclization reactions.
To gain preliminary information about the feasibility
of an oxidative Pictet-Spengler cyclization process, the
2-arylethyl R-silylamide 2a and related carbamate 2b
were prepared by N-silylmethylation and subjected to
ceric ammonium nitrate (CAN) oxidation (Scheme 3). The
oxidation reactions are conducted by using 2 equiv of
CAN in acetonitrile at 25 °C. In each case, workup
followed by chromatographic separation leads to isolation
of the respective tetrahydroisoquinoline products, 3a and
3b.
These results, which suggest that the oxidative protocol
is effective in promoting Pictet-Spengler cyclizations,
encouraged a further exploratory effort with variously
structured arylalkyl R-silyl substrates.8 Oxidation reac-
tions of the chain-shortened arylmethyl-amide 5a and
-carbamate 5b, while occurring with lower efficiencies as
a result of competitive iminium cation hydrolysis, do lead
to production of the corresponding isoindolines 6a and
† Pusan National University.
‡ Korea Research Institute of Chemical Technology.
§ University of Maryland.
| Current address: Department of Chemistry, University of New
Mexico, Albuquerque, NM 87131-1096.
(1) Pictet, A.; Spengler, T. Chem. Ber. 1911, 44, 2023. Decker, H.;
Becker, P. Liebigs Ann. Chem. 1913, 395, 342. Kametani, T. J .;
Fukumoto, K. Chem. Heterocycl. Compd. 1981, 38(1), 139.
(2) Stevens, R. V. In The Total Synthesis of Natural Products; Ap
Simon, J ., Ed.; J . Wiley and Sons: New York, 1977; Vol. 3, p 439.
Zangg, H. E. Synthesis 1984, 2, 85.
(3) Various methods have been introduced to promote iminium
cation formation in Pictet-Spengler cyclization pathways. Included
in this group are the oxidative Polonovsky and Hg(OAc)2 procedures,
R-cyano and R-carboxylic acid elimination processes, and enanimine
protonations. For a general, recent review of some of these methods,
see Overman, L. E.; Ricca, D. J . In Comprehensive Organic Synthesis;
Heathcock, C. H., Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford,
1991, Vol. 2, p 1007.
(4) Stokker, G. E. Tetrahedron Lett. 1996, 37, 5453.
(5) Yoon, U. C.; Mariano, P. S. Acc. Chem. Res., 1992, 25, 233. Xu,
W.; Zhang, X. M.; Mariano, P. S. J . Am. Chem. Soc., 1991, 113, 8863.
J oon, Y. T.; Lee, C. P.; Mariano, P. S. J . Am. Chem. Soc., 1991, 113,
8847.
(6) Zhang, X. M.; J ung, Y. S.; Mariano, P. S.; Fox, M. A.; Martin, P.
S.; Merkert, J . Tetrahedron Lett. 1993, 34, 5239.
(7) Zhang, X. M.; Yeh, S. R.; Hong, S.; Freccero, M.; Albini, A.;
Falvey, D. E.; Mariano, P. S. J . Am. Chem. Soc., 1997, 119, 5261.
(8) As is the case for the classical Pictet-Spengler reactions, lower
yields are observed for oxidative cyclizations with less electron rich
aryl-substituted systems.
S0022-3263(97)01705-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/22/1998

Notes
J . Org. Chem., Vol. 63, No. 3, 1998 861
Sch em e 4
Sch em e 5
Sch em e 6
Sch em e 7
Sch em e 8
Sch em e 9
tions. For example, the mild, nonacidic conditions re-
quired for the oxidative processes may be advantageous
when applied to systems that possess particularly acid
sensitive functionality. Of course, one limitation of the
oxidative protocol is that it is intolerant of functionality
(e.g., aldehydes) which are oxidatively unstable. Another
advantage of the CAN-procedure is that it does not
require the use of selective imide reduction to access
amidol precursors which is used in the more common,
acid-catalyzed route10 to N-acyliminium cations. On the
other hand, R-silylamides are the requisite starting
materials for the oxidative Pictet-Spengler protocol and
procedures which are available for their synthesis have
limitations. For example, approaches involving amide
anion or O-silylimidate N-alkylation depend on the
availability of R-halosilanes or related substrates and the
facility of their SN2-reactions. However, with the advent
of procedures for the synthesis of structurally complex
R-substituted R-silylamines11 and perhaps alternative
starting materials (e.g., R-amino carboxylates, unpub-
lished) the oxidative cyclization method may prove to be
generally applicable for the preparation of a wide range
of R-substituted aryl-fused piperidines.
6b (Scheme 4). Likewise, the process is not restricted to
systems that have the amide function exocyclic to the
forming N-heterocyclic ring. Accordingly, the silylamide
9, derived from arylacetic acid 7, cyclizes upon treatment
with CAN to form the 3-oxohydroisoquinoline 10 (Scheme
5).
Substances containing the â-carboline and tylophorine
types of polycyclic structures also can be prepared by use
of this oxidative process. The conversions of N-blocked
tryptamine derivative 12 to indolopiperidine 13 and
pyroglutamic acid derived9 pyrrolidinone 15 to phenan-
threnoindolizidine 16 (Scheme 7) exemplify the potential
(Schemes 6 and 7).
Finally, the reaction sequences depicted in Schemes 8
and 9 indicate that the oxidative Pictet-Spengler reac-
tion can be employed successfully in sequences targeted
at both benzo- and indolohydroazepines and -hydroazo-
cines.
The results presented above show that the oxidative
protocol can serve as a useful alternative to classical
methods for promoting Pictet-Spengler cyclization reac-
Exp er im en ta l Section
Gen er a l P r oced u r es. Unless otherwise noted, 1H NMR and
13C NMR spectra were recorded on CDCl3 solutions by using
(10) Speckamp, W. N. J . R. Netherlands Chem. Soc. 1981, 100, 345.
(11) Sieburth, S. M.; Somers, J . J .; O’Hare, H. K. Tetrahedron 1996,
52, 5669.
(9) Khim, S. K.; Cederstrom, E.; Ferri, D. C.; Mariano, P. S.
Tetrahedron 1996, 52, 3195.

862 J . Org. Chem., Vol. 63, No. 3, 1998
Notes
200.13, 400.13, or 500.14 MHz operational frequencies for 1H
observations and 50.32 and 100.62 MHz for 13C observations.
Chemical shifts are reported in parts per million relative to
CDCl3 (7.24 ppm for 1H NMR and 77.0 ppm for 13C NMR) as
the internal standard. 1H NMR coupling constant determina-
tions (J -values reported in Hz) and nuclei assignments were
aided by the use of homonuclear decoupling experiments. 13C
NMR resonance assignments were aided by use of the DEPT
technique to determine numbers of attached hydrogens. Infra-
red (IR) spectra were obtained on samples which were prepared
as neat liquids unless otherwise noted, and band assignments
-0.01 (B) and 0.09 (A) (s, 9H, TMS), 2.81(B) and 2.86 (A) (s,
2H, CH2TMS), 3.01 (A and B) (m, 2H, ArCH2), 3.55 (A and B)
(m, 2H, CH2N), 5.10 (A) and 5.15 (B) (OCH2Ar), 7.18 (A and B)
(m, 8H, Ar), 7.68 (A and B) (m, 1H, Ar), 8.01 (s, 1H, NH); 13C
NMR -1.06 (B) and -0.94 (A) (TMS) 23.9 (A) and 24.6 (A) (CH2-
TMS), 39.1 (B) and 39.7 (A) (ArCH2), 50.6 (A) and 51.1 (B)
(CH2N), 67.6 (B) and 67.7 (A) (OCH2Ar), 113.4, 128.0, 111.7,
119.2, 119.7, 119.8, 122.3, 122.5, 122.7, 128.2, 128.3, 128.4, 128.6,
129.0, 129.3, 136.8, 137.4 (Ar) 156.7 (CdO); IR 3416, 3319, 3090,
2908, 1699, 1448; EIMS 380 (M, 4), 289 (24), 234 (20), 206 (28),
130 (30); HRMS 380.1917, C22H28N2O2Si requires 380.1920.
A solution of 11 (2.50 g, 6.60 mmol) and sodium hydride (0.29
g, 6.60 mmol) in 30 mL of THF was stirred at reflux for 1.5 h
before adding benzene sulfonyl chloride (1.17 g, 6.60 mmol),
stirring at reflux for 1.5 h, cooling to 25 °C, and concentrating
in vacuo. The residue was triturated with CH2Cl2, and the
triturate was dried and concentrated in vacuo to give a residue
which was subjected to column chromatography (silica gel, 1:3
ethyl acetate-hexane) to yield 1.72 g (50%) of 12 (rotamer A:B
are in units of cm-1
. Mass spectrometric data determined by
use of either the electron impact (EIMS), chemical ionization
(CIMS), or fast atom bombardment (FAB) method are reported
as m/z (relative intensity), and high-resolution mass spectral
data (HRMS) are recorded as m/z. All new compounds were
obtained as oils in >90% purity (by 1H and 13C NMR analysis)
unless otherwise noted. Column chromatographic separations
were performed by using EM Type 60 silica gel (230-400 mesh),
Florisil (100-200 mesh), or Type F-20 Alumina (neutral, 80-
120 mesh). Preparative TLC was performed on 20 × 20 cm
plates coated with EM Type-60 GF-254 silica gel.
1
) 1.2:1) H NMR -0.01 (B) and 0.09 (A) (s, 3H, TMS), 2.68 (B)
and 2.78 (A) (s, 2H, CH2TMS), 2.93 (A and B) (m, 2H, ArCH2),
3.51 (A and B) (m, 2H, CH2N), 5.04 (A) and 5.16 (B) (s, 2H, OCH2-
Ar), 7.14 (A and B) (m, 1H, Ar), 7.40 (A and B) (m, 11H, Ar),
7.85 (A and B) (m, 2H, Ar), 8.02 (A and B) (m, 1H, Ar); 13C NMR
-1.16 (B) and -0.99 (A) (TMS), 23.7 (B) and 24.4 (A) (ArCH2),
39.4 (B) and 39.7 (A) (CH2TMS), 49.5 (A) and 50.1 (B) (CH2N),
67.7 (A and B) (OCH2Ar), 119.9 and 120.3, 114.2, 123.8, 125.3,
127.2, 128.6, 128.7, 129.0, 129.3, 129.4, 129.7, 129.9, 131.2 and
131.4, 135.8 and 137.3 and 138.7 (Ar), 156.3 (A) and 156.5 (B)
(CdO); IR 3090, 2953, 1693, 1464; EIMS 506 (M, 9), 429 (77),
270 (45), 233 (33), 206 (100); HRMS 506.1704, C27H30N2O4SiS
requires 506.1696.
A solution of 12 (0.23 g, 0.44 mmol) and CAN (0.49 g, 0.88
mmol) in 25 mL of anhydrous acetonitrile was stirred at 24 °C
for 6 h, diluted with CH2Cl2, and filtered. The filtrate was
washed with brine, dried, and concentrated in vacuo, giving a
residue which was subjected to column chromatography (silica
gel, 1:2 ethyl acetate-hexane) to give 168 mg (86%) of carbazole
13: (rotamer A:B ) 1:1) 1H NMR 2.72 (m, 2H, ArCH2), 3.79 (m,
2H, CH2N), 5.02 (s, 2H, ArCH2Ar), 5.22 (s, 2H, ArCH2N), 7.32
(m, 11H, Ar), 7.77 (m, 1H, Ar), 7.89 (m, 1H, Ar), 8.17 (m, 1H,
Ar). 13C NMR 21.6 and 22.1 (ArCH2), 41.0 (ArCH2N), 43.9
(CH2N) 68.0 (OCH2Ar),117.0 117.6 (ArCH2CH2N ArC7 quater-
nary), 114.1, 118.3, 123.5, 124.6, 126.2, 127.8, 128.0, 128.4, 129.2,
129.3, 133.7, 130.7, 131.2, 135.9, 136.4, 138.1 (Ar), 155.3 (CdO);
IR 3067, 2920, 1703, 1427; EIMS 446 (M, 1), 355 (100), 214 (34);
HRMS 446.1294, C25H22N2O4S requires 446.1256.
Rep r esen ta tive P r oced u r es. P r ep a r a tion a n d CAN-
P r om oted Cycliza tion of Ben zyl N-[2-(3,4-Dim eth oxyp h en -
yl)eth -1-yl]-N-[(tr im eth ylsilyl)m eth yl]ca r ba m a te (2b).
A
mixture of benzyl N-[2-(3,4-dimethoxyphenyl)eth-1-yl]carbamate
(1b)12 (5.00 g, 15.8 mmol) and sodium hydride (0.69 g, 15.8 mmol)
in 25 mL of THF was stirred at 0 °C for 1 h. (Trimethylsilyl-
)methyl iodide (4.00 g, 19.0 mmol) was added, and the mixture
was stirred at reflux for 19 h and concentrated in vacuo, giving
a residue which was triturated with CH2Cl2. The triturate was
dried and concentrated in vacuo to give a residue which was
subjected to column chromatography (silica gel, 1:3 ethyl acetate:
hexane) to yield 1.48 g (23%) of 2b: (rotamer A:B ) 1.3:1) 1H
NMR 0.01 (A) and 0.08 (B) (s, 9H, TMS), 2.80 (A and B) (m, 4H,
CH2TMS and ArCH2), 3.43 (A and B) (m, 2H, CH2N), 3.78 (A)
and 3.85 (B) (s, 6H, CH3O), 5.09 (A) and 5.11 (B) (s, 2H, CH2-
Ph), 6.70 (A and B) and 7.35 (A and B) (m, 8H, Ar and Ph); 13
C
NMR -1.06 (B) and -1.02 (A) (TMS), 34.5 (B) and 34.6 (A)
(ArCH2), 39.5 (B) and 39.6 (A) (TMS), 51.6 (A) and 52.1 (B)
(CH2N), 56.3 and 56.4 (A and B) (CH3O), 67.5 (A and B) (CH2-
Ar), 111.9, 112.6, 121.2, 128.4, 128.5, 128.6, 128.7, 128.8, 132.1,
137.5 and 137.6, 148.1, 149.5, 156.4 (Ar and Ph), 156.4 (CdO);
IR 3032, 2953, 1703, 1516; EIMS 401 (M, 5), 386 (34), 310 (72),
294 (36), 206 (71), 151 (42), 91 (100); HRMS 401.2009, C22H31
NO4Si requires 401.2022.
-
A solution of 2b (0.100 g, 0.258 mmol) and CAN (0.283 g, 0.515
mmol) in 10 mL of anhydrous acetonitrile was stirred at 25 °C
for 18 h, diluted with CH2Cl2, and filtered. The filtrate was
washed with brine, dried, and concentrated in vacuo, giving a
residue which was subjected to column chromatography (silica
gel, 1:2 ethyl acetate-hexane) to give 47 mg (60%) of tetrahy-
droisoquinoline 3b. 1H NMR 2.78 (t, J ) 5.5, 2H, (ArCH2), 3.72
(t, J ) 5.5, 2H, (CH2N), 3.86 (s, 6H, (CH3O), 4.58 (s, 2H,
(ArCH2N), 5.18 (s, 2H, OCH2Ar), 6.63(m, 2H, Ar), 7.36 (m, 5H,
Ar); 13C NMR 28.8 (ArCH2), 42.0 (CH2N), 45.9 (ArCH2N), 56.3
(CH3O), 67.5 (OCH2Ar), 109.7, 112.1, 125.2, 125.4, 126.7, 128.9,
128.4, 137.3, 148.1, 148.2 (Ar), 155.8 (CdO); IR 3080, 2935, 1632,
1518; EIMS 327 (M, 2), 236 (100), 91 (38); HRMS 327.1466,
C19H21NO4 requires 327.1471.
P r ep a r a tion a n d CAN-P r om oted Cycliza tion of [1-[(Tr i-
m e t h y ls ily l)m e t h y l]-2-o x o p y r r o lid in -5-y l][9-P h e n a n -
th r en yl]m eth yl Aceta te (15). A solution of phenanthrenyl
alcohol 148 (112 mg, 0.20 mmol), DMAP (11 mg, 0.09 mmol),
and acetic anhydride (0.20 mL, 0.22 g, 2.1 mmol) in pryridine
(3 mL) was stirred at 25 °C for 17 h, diluted with H2O, and
extracted with CH2Cl2. The extracts were washed with 5% HCl,
satd NaHCO3, and H2O, dried, and concentrated in vacuo to
provide a residue which was subjected to column chromatogra-
phy (Florisil, Et2O), yielding 83 mg (75%) of the acetate 15: 1H
NMR 0.01 (s, 9 H, Si(CH3)3), 1.75 (m, 1 H, CH2), 1.92 (m, 1 H,
CH2), 2.18 (m, 1 H, CH2), 2.16 (s, 3 H, CH3), 2.34 (m, 1 H, CH2),
2.41 and 3.35 (ABq, J ) 15.2, 2 H, SiCH2N), 4.23 (ddd, J ) 8.6,
6.6, and 2.4, 1 H, CH), 6.49 (d, J ) 6.6, 1 H, CHOAc), 7.65 (m,
4 H, Ar), 7.79 (s, 1 H, Ar H-10), 7.88 (dd, J ) 7.9 and 1.1, 1 H,
Ar), 8.20 (d, J ) 9.5, 1 H, Ar), 8.65 (d, J ) 8.2, 1 H, Ar H-4 or
H-5), 8.75 (dd, J ) 7.7 and 2.0, 1 H, Ar H-4 or H-5); 13C NMR
-1.3 (TMS), 21.3 (CH3CO), 22.9 (CH2), 29.4 (CH2), 34.6 (SiCH2N),
62.8(CH), 122.5, 123.6, 123.7, 126.6, 126.8, 126.99, 127.05, 127.4,
128.8, 129.4, 130.3, 130.7, 130.8, 132.0 (Ar), 169.6 (OCO), 174.5
(NCO); IR 3050, 2954, 1747, 1682; CIMS 421 (M+1, 1), 170 (100),
74 (30); HRMS 420.19875, C25H30O3NSi requires 420.19949.
A solution of 15 (38 mg, 0.091 mmol) and CAN (218 mg, 0.4
mmol) in 1.5 mL of anhydrous acetonitrile was stirred at 25 °C
for 18 h, diluted with satd NaHCO3, and extracted with CH2-
Cl2. The extracts were washed with brine, dried, and concen-
trated in vacuo to give a residue which was subjected to HPLC
(reverse phase C-18, Et2O to 4:1 Et2O-acetone) to provide 17
mg (54%) of indolizidine 16: 1H NMR 2.09 (m, 1 H, CH2), 2.05
(s, 3 H, CH3CO), 2.37 (m, 1 H, CH2), 2.52 (m, 2 H, CH2), 4.12
P r ep a r a tion a n d CAN-P r om oted Cycliza tion of Ben zyl
N-[(N-Ben zen esu lfon yl)-â-t r yt op h yl]-N-[(t r im et h ylsilyl)-
m eth yl]ca r ba m a te (12). A solution of tryptamine (1.50 g, 9.35
mmol), triethylamine (0.95 g, 9.35 mmol), and (trimethylsilyl-
)methyl iodide (2.67 g, 9.35 mmol) in 50 mL of CH2Cl2 was
stirred at reflux for 6 h, cooled, washed with H2O, dried, and
concentrated in vacuo. To a solution of the residue and triethy-
lamine (0.95 g, 9.35 mmol) in 50 mL of CH2Cl2 was added benzyl
chloroformate (2.13 g, 9.35 mmol) in 20 mL of CH2Cl2, and the
mixture was stirred for 2 h at 25 °C, washed with H2O, dried,
and concentrated in vacuo to give a residue which was subjected
to column chromatography (silica gel, 1:3 ethyl acetate-hexane)
1
to yield 2.52 g (71%) of 11: rotamers A and B, 1.8:1) H NMR
(12) Umino, N.; Iwakuma, T.; Itoh, N. Tetrahedron Lett. 1976, 10,
763.

Notes
J . Org. Chem., Vol. 63, No. 3, 1998 863
(ddd, J ) 8.6, 3.8, 2.1, 1 H, CH) 4.66 and 5.57 (ABq, J ) 18.0,
2 H, NCH2), 6.83 (d, J ) 2.1, 1 H, CHOAc), 7.67 (m, 4 H, Ar),
8.00 (d, J ) 8.0, 1 H, Ar), 8.08 (m, 1 H, Ar), 8.70 (d, J ) 8.6, 1
H, H-4, H-5 Ar); 13C NMR 20.0 (CH2), 21.0 (CH3CO), 30.3 (CH2),
40.9 (NCH2), 56.9 (CH), 66.0 (CHOAc), 123.1, 123.2, 123.3, 125,7,
126.8, 127.4, 127.8, 125.7, 128.5, 128.9. 129.7, 130.3, 130.5 (Ar),
171.1 (CON), 174.5 (OCO). IR 3030, 2974, 1732, 1686; EIMS 345
(M, 4), 285 (22), 284 (100), 229 (27); HRMS 345.13633, C22H19O3N
requires 345.13651.
P r ep a r a tion a n d CAN-P r om oted Cycliza tion of Ben zyl
N-[3-(3,4-Dim eth oxyp h en yl)p r op -1-yl]-N-[(tr im eth ylsilyl)-
m eth yl]ca r ba m a te (18a ). A solution of 3-(3,4-dimethoxyphen-
yl)prop-1-ylamine13 (1.85 g, 9.48 mmol) and iodo(methyltri-
methyl)silane (2.11 g, 9.85 mmol) in 15 mL of acetonitrile was
stirred at reflux for 12 h and concentrated in vacuo, and the
residue was dissolved in CH2Cl2, washed with water, dried, and
concentrated in vacuo to give 2.60 g (95%) of the secondary amine
17a which was used without further purification: 1H NMR 0.03
(s, 9H, TMS), 1.05 (s, 1H, NH), 1.79 (quin, J ) 7.5, 2H, CH2),
2.05 (s, 2H, CH2), 2.62 (m, 4H, (CH2)2), 3.84 (s, 3H, OCH3), 3.86
(s, 3H, OCH3), 6.761 (m, 3H, Ar); 13C NMR -2.6 (TMS), 31.2,
33.0, 40.0, 53.8, 55.6 (OCH3), 55.7 (OCH3), 111.0, 111.5, 119.9,
134.7, 146.9, 148.6; EIMS 281 (M, 1.8), 44 (100); HRMS
281.1811, C15H27NO2Si requires 281.1811.
To a solution of 17a (0.27 g, 0.96 mmol) and benzyl chloro-
formate (0.20 g, 1.17 mmol) in 20 mL of CH2Cl2 was added Et3N
(0.2 mL, 1.4 mmol), and the mixture was stirred for 1 h at 25
°C, washed with satd NaHCO3 and brine, dried, and concen-
trated in vacuo to give a residue which was subjected to column
chromatography (silica gel, 1:2 EtOAc-hexane) to give carbam-
ate 18a (0.37 g, 93%): (rotamer A:B ) 1:1) 1H NMR -0.01 and
0.06 (s, 9H, TMS), 1.87 (m, 2H, CH2), 2.55 (m, 2H, CH2), 2.79
(s, 2H, CH2TMS), 3.27 (m, 2H, CH2), 3.87 (s, 6H, OCH3), 5.13
(s, 2H, OCH2), 6.72 (m, 3H, Ar), 7.34 (s, 5H, Ar); 13C NMR -1.8
and -1.5, 29.0 and 29.5, 32.6 and 32.6, 37.9 and 38.8, 48.6 and
49.1, 55.7, 55.8, 66.8, 111.1, 111.5, 111.6, 119.9, 127.6, 127.7,
127.9, 128.1, 128.3, 128.3, 134.0, 134.3, 136.8, 137.1, 147.1, 148.7,
155.9 and 156.1 (CdO); EIMS 415 (M, 2.3), 400 (33), 308 (30),
165 (85), 73 (100); HRMS 415.2176, C23H33NO4Si requires
415.2179.
To a solution of 18a (0.369 g, 0.884 mmol) in 40 mL of
anhydrous acetonitrile was added CAN (0.980 g, 1.79 mmol),
and the mixture was stirred at 25 °C for 0.5 h, diluted with CH2-
Cl2, washed with satd NaHCO3 and water, dried, and concen-
trated in vacuo, giving a residue which was subjected to column
chromatography (silica gel, 1:2 EtOAc-hexane) to give tetrahy-
drobenzazepine 19a (0.214 g, 71%); mp 103-105 °C; (rotamer
A:B ) 2:1); 1H NMR 1.77 (m, 2H, CH2), 2.87 (m, 2H, CH2), 3.57,
3.83 (A) and 3.86 (B) (s, 6H, OCH3), 3.73 (m, 2H, CH2), 4.35 (A)
and 4.40 (B) (s, 2H, CH2), 5.02 (A) and 5.04 (B) (s, 2H, CH2),
6.54, 6.65 and 6.86 (A and B) (s, 2H, Ar), 7.29 (s, 5H, Ar); 13C
NMR (A) 28.1, 34.8, 50.9, 51.6, 55.6, 55.8, 67.1, 113.0, 113.2,
127.8, 127.9, 128.3, 130.6, 134.0, 136.6, 146.2, 147.4, 155.4
(CdO); (B) 28.7, 34.8, 50.3, 52.1, 55.7, 55.9, 66.8, 113.0, 113.2,
127.7, 127.9, 128.3, 130.4, 133.6, 136.7, 146.5, 147.5, 155.2
(CdO); EIMS 341 (M, 7), 250 (100), 206 (20), 91 (60); HRMS
341.1599, C20H23NO4 requires 341.1623.
Ack n ow led gm en t. Financial support provided by
KOSEF (965-0300-002-2, CBM Postech-1997, and Korea
Ministry of Education - BSR1-97-3408 for U.C.Y.),
Korea Ministry of Science and Technology (for Y.S.J .
and NSP), and the National Science Foundation (CHE-
9420889) and the National Institutes of Health (GM-
27251) for P.S.M.) is greatly acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and 1H NMR spectroscopic data for the new substances
described in this publication (48 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from ACS; see any current masthead page for ordering
information.
(13) Bremner, J . B.; Browne, E. J .; Davies, P. E.; Raston, C. L.;
White, A. H. Aust. J . Chem. 1980, 33, 1323.
J O971705V