The preparation and intra- and intermolecular addition reactions of acyclic N-acylimines: Application to the synthesis of (±)-sertraline

Article abstract of DOI:10.1021/jo010370l

Intramolecular endo-cyclization reactions of N-acyliminium ions have seen wide application for the synthesis of heterocyclic compounds. The corresponding exocyclic variant, which would provide 1-aminotetralin derivatives, for example, has little precedent. We have discovered that acyclic N-acylcarbamates can be readily reduced to the corresponding N-acylhemiaminal derivatives in high yield using DIBAL as the reducing agent. These intermediates are remarkably stable and, if desired, can be purified and stored. The acyclic N-acylhemiaminals undergo both intra- and intermolecular nucleophilic addition reactions mediated by strong Lewis acids, such as TiCl4. Diastereoselectivity, induced either by a substituent on the newly formed ring, or by utilizing a chiral ester on the carbamic acid, was disappointingly low. This methodology was successfully applied to the synthesis of the racemic form of the marketed antidepressant sertraline.

Full text of DOI:10.1021/jo010370l

6988
J . Org. Chem. 2001, 66, 6988-6993
Th e P r ep a r a tion a n d In tr a - a n d In ter m olecu la r Ad d ition
Rea ction s of Acyclic N-Acylim in es: Ap p lica tion to th e Syn th esis of
(()-Ser tr a lin e
Michael P. DeNinno,* Cynthia Eller, and J ohn B. Etienne
PGRD Groton Laboratories, Pfizer Inc., Groton, Connecticut 06340
michael_p_deninno@groton.pfizer.com
Received April 10, 2001
Intramolecular endo-cyclization reactions of N-acyliminium ions have seen wide application for
the synthesis of heterocyclic compounds. The corresponding exocyclic variant, which would provide
1-aminotetralin derivatives, for example, has little precedent. We have discovered that acyclic
N-acylcarbamates can be readily reduced to the corresponding N-acylhemiaminal derivatives in
high yield using DIBAL as the reducing agent. These intermediates are remarkably stable and, if
desired, can be purified and stored. The acyclic N-acylhemiaminals undergo both intra- and
intermolecular nucleophilic addition reactions mediated by strong Lewis acids, such as TiCl4.
Diastereoselectivity, induced either by a substituent on the newly formed ring, or by utilizing a
chiral ester on the carbamic acid, was disappointingly low. This methodology was successfully
applied to the synthesis of the racemic form of the marketed antidepressant sertraline.
Sch em e 1
In tr od u ction
Amino tetralins such as I are commonly found as a
substructure in compounds of biological interest and as
intermediates in the synthesis of natural products. This
functional motif is most often prepared from the corre-
sponding tetralones II (Scheme 1), which in turn are
products of intramolecular Friedel-Crafts acylation reac-
tions. Certain functionalized substrates are incompatible
with the strong acids and elevated temperatures often
required for Friedel-Crafts acylations. An alternate
strategy for the synthesis of I was envisioned (path B)
in which the amino tetralin is prepared in one step from
an acylimine such as IV. Although the intramolecular
endo cyclization of acylimines has been extensively
explored (e.g., to provide N-acyltetrahydroquinoline de-
rivatives),1 the exocyclic variant has little precedent.2
Herein, we report a novel method for the synthesis of
acyclic N-acylimine precursors (V) and the inter- and
intramolecular nucleophilic addition reactions thereof.
Resu lts a n d Discu ssion
tion of amino acids with lead tetraacetate,3 as well as
electrochemical oxidation.4 Newer methods for generating
acylimine precursors have also appeared.5 However, we
explored an alternate general approach, namely the
reduction of the acyl carbamates 2.6 Acyl carbamates
were chosen to avoid regiochemical issues in the reduc-
tion. In addition, the products (4) would contain a
The proposed synthetic sequence is outlined in Scheme
2. Literature methods for the preparation of acyclic
N-acylimine precursors, such as 3, include the degrada-
* To whom correspondence should be addressed. Tel: (860) 441-
5858. Fax: (860) 686-0620.
(1) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367. (b)
Speckamp, W. N.; Moolenaar, M. J . Tetrahedron 2000, 56, 3817.
(2) For examples of exocyclic imine ring closures, see: (a) Urban,
F. J . Tetrahedron Lett. 1988, 29, 5493. (b) Ben-Ishai, D.; Sataty, I.;
Peled, N.; Goldshare, R. Tetrahedron 1987, 43, 439. (c) Bosch, J .;
Bonjoch, J .; Diez, A.; Linares, A.; Moral, M.; Rubiralta, M. Tetrahedron
1985, 41, 1753. (d) Katritzky, A. R.; Rachwal, B.; Rachwal, S. J . Org.
Chem. 1995, 60, 3993. (e) Katritzky, A. R.; Rachwal, B.; Rachwal, S.;
Abboud, K. A. J . Org. Chem. 1996, 61, 3117. (f) Padwa, A.; Brodney,
M. A.; Marino, J . P., J r.; Sheehan, S. M. J . Org. Chem. 1997, 62, 78.
(g) Dinsmore, C. J .; Zartman, C. B.; Baginsky, W. F.; O’Neill, T. J .;
Koblan, K. S.; Chen, I.-W.; McLoughlin, D. A.; Olah, T. V.; Huff, J . R.
Organic Lett. 2000, 2, 3473.
(3) Corcoran, R. C.; Green, J . M. Tetrahedron Lett. 1990, 31, 6827.
(4) Shono, T.; Hamaguchi, H.; Matsumura, Y. J . Am. Chem. Soc.
1975, 97, 4264.
(5) (a) J ohnson, A. P.; Luke, R. W. A.; Boa, A. N. J . Chem. Soc.,
Perkin Trans. 1 1996, 895. (b) Veenstra, S. J .; Schmid, P. Tetrahedron
Lett. 1997, 38, 997. (c) Burgess, L. E.; Gross, E. K. M.; J urka, J .
Tetrahedron Lett. 1996, 37, 3255. (d) Mecozzi, T.; Petrini, M. J . Org.
Chem. 1999, 64, 8970. (e) Veenstra, S. J .; Schmid, P. Tetrahedron Lett.
1997, 38, 997. (f) Chao, W.; Weinreb, S. M. Tetrahedron Lett. 2000,
41, 9199.
(6) DeNinno, M. P.; Eller, C. Tetrahedron Lett. 1997, 38, 6545.
10.1021/jo010370l CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/21/2001

Addition Reactions of Acyclic N-Acylimines
J . Org. Chem., Vol. 66, No. 21, 2001 6989
Ta ble 1. Su r vey of Va r iou s Activa tor s for th e
Cycliza tion Rea ction
Sch em e 2
entry
activator (equiv)
T (°C)
yield (%)
a
b
c
d
e
f
g
h
i
Tf2O (1.0)
CSA (0.1)
0 f 25
25
25
<5
<5
<5
<5
12
55
15
25
80
TFA (2.0)
(iPrO)2TiCl2 (2.0)
TFA (2.0)
0 f 25
-78 f 0
-60
BF3OEt2 (2.0)
TiCl4 (0.5)
TiCl4 (1.0)
TiCl4 (1.5)
-78
-78
-78
carbamate-protected nitrogen that could undergo subse-
quent transformations. Although the reductive prepara-
tion of cyclic N-acylhemiaminals7 has been widely used,
the corresponding reaction in acyclic systems (e.g., 2 f
3) had not been previously reported.8 This lack of
literature precedent raised concerns about the stability
of such products and the viability of the approach.
Nonetheless, the directness of this sequence outweighed
these concerns and the route was investigated.
of fewer equivalents of TiCl4 resulted in a much slower
reaction and incomplete conversion of starting material.
A number of other substrates were investigated, and the
results are displayed in Table 2. Generally, the overall
yields for the reduction-cyclization sequence were very
good (>75%). The reaction times varied on the basis of
the reactivity of the aryl ring. For products 4e and 4f,
BF3‚OEt2 proved to give higher yields due to the precipi-
tation of a presumed catalyst-substrate complex when
TiCl4 was used. Exploring the formation of alternate ring
sizes proved interesting. The seven membered rings 4i
and 4j could be produced in moderate yields; however,
the five-membered ring 4h would not form even under
more forcing conditions. This result is in contrast with
intramolecular Friedel-Crafts acylation reactions in
which five-membered rings are quite readily prepared.11
The phenyl-substituted analogues 5a and 5b were
prepared and subjected to the standard two-step protocol
(Scheme 3) to explore the diastereoselectivity of the
cyclization reaction. The products (7) were isolated in
good yields as 1:1 mixtures of isomers. This lack of
selectivity was unexpected based on the literature reports
of similar ring closures.12 These results, combined with
the inability to form the five-membered ring, suggested
a possible nonobvious mechanism of ring closure. One
unlikely but easily tested mechanism involves the direct
displacement of a TiCl4-complexed hemiaminal, without
passing through an acylimine precursor. To rule out this
possibility, the 1:1 mixture of diastereomers 6a were
separated by silica gel chromatography and individually
subjected to the cyclization conditions. Both isomers
produced the same 1:1 mixture of products, ruling out
this pathway. The stability of the N-acylhemiaminals to
chromatography and lack of subsequent isomerization are
noteworthy. Another possible mechanism would involve
an initial ipso attack on the aromatic ring followed by
bond migration and rearomatization. Although we have
not seen direct evidence for this pathway in any of the
examples run thus far, additional experiments are planned
to directly address this question.
The acyl carbamates 2a and 2b were the first targets.
They could be readily prepared9 by reaction of methyl or
benzyl carbamate with phenyl butyryl chloride (1) in
toluene, and the products were isolated in high yield (90-
95%) as crystalline solids. Although many reducing
agents have been used successfully for the reduction of
cyclic imides,7 only DIBAL gave satisfactory results in
the present system. Moreover, excess reducing agent (2.2
equiv) was required to ensure complete consumption of
starting material, possibly due to the acidity of the imide
NH. Under these conditions, 2a and 2b reduced cleanly
at -78 °C in near-quantitative yield, thus removing the
need for purification. Our initial concern about the
stability of these products was unnecessary because the
colorless solids 3a and 3b were stable for months at room
temperature.10 The cyclization of compound 3a was now
examined. Unlike the related endocyclization reactions,
the choice of catalyst proved critical. The literature has
shown that a wide variety of protic and Lewis acids can
be effective in activating cyclic N-acylhemiaminals for the
addition of carbon based nucleophiles.1 In the present
case, only strong Lewis acids were successful (Table 1).
This difference may be attributed to the lower reactivity
of the presumed N-acylimine intermediates as compared
to the N-acyliminium ion intermediates in endocycliza-
tion reactions. From this survey, 1.5 equiv of TiCl4 at -78
°C was chosen as optimal cyclization conditions, affording
an 80% yield of product (4a ). Reaction of 3b under the
identical conditions furnished 4b in 78% yield. The use
(7) Hubert, J . C.; Wijnberg, J . B. P. A.; Speckamp, W. N. Tetrahedron
1975, 31, 1437.
(8) Concurrent with our earlier work,6 Fisher et al. reported on the
reduction of N-acyl dihydroisoquinolone derivatives: Fisher, M. J .;
Gunn, B. P.; Um, S.; J akubowski, J . A. Tetrahedron Lett. 1997, 38,
5747.
Several strategies were envisioned for the synthesis
of enantiomerically enriched products. One attractive
(9) See, for example: (a) Ben-Ishai, D.; Katchalski, E. J . Org. Chem.
1951, 16, 1025. (b) Atanassova, I. A.; Petrov, J . S.; Ognjanova, V. H.;
Mollov, N. M. Synth. Commun. 1990, 20, 2083. (c) Po¨pel, W.; Laban,
G.; Faust, G.; Dietz, G. Pharmazie 1980, 35, 266.
(10) An X-ray crystal structure of an analogue of 3a (compound 10)
did not lend any insight as to the reason for this stability (e.g.,
intramolecular hydrogen bonding).
(11) (a) Olah, G. Ed. Friedel-Crafts and Related Reactions; Inter-
science Publishers: New York, 1964, Vol. III. (b) Snyder, H. R.; Werber,
F. X. J . Am. Chem. Soc. 1950, 72, 2965.
(12) (a) Katritzky, A. R.; Rachwal, B.; Rachwal, S. J . Org. Chem.
1995, 60, 7631. (b) Kuznet, V. V.; Aliev, A. E.; Prostakov, N. S. Chem.
Heterocycl. Compd. (Engl. Trans.) 1994, 30, 64. (c) Talukdar, S.; Chen,
C.-T.; Fang, J .-M. J . Org. Chem. 2000, 65, 3148.

6990 J . Org. Chem., Vol. 66, No. 21, 2001
DeNinno et al.
Ta ble 2
Sch em e 3
a chiral auxiliary based approach was investigated. The
acyl carbamates 8 were prepared from three chiral
alcohols. After reduction and cyclization with BF3‚OEt2,
the products were analyzed by HPLC. The best result
was realized with the (1R,2S)-2-phenylcyclohexanol aux-
iliary (8c), which furnished the product with a disap-
pointing 40% de. Employing TiCl4 as catalyst led to
diminished diastereoselectivity (Table 3).
To expand the utility of this methodology, we examined
the intermolecular variant as well.14 The results are
summarized in Table 4. It was optimal to use a several-
fold excess of the nucleophile in the reactions and the
yields were generally good. Care must be taken with the
use of electron-rich nucleophiles (e.g., thiophene) to avoid
(13) For a recent example of a Ti-catalyzed enantioselective addition
of TMSCN to unactivated imines, see: Krueger, C. A.; Kuntz, K. W.;
Dzierba, C. D.; Wirschun, W. G.; Gleason, J . D.; Snapper, M. L.;
Hoveyda, A. H. J . Am. Chem. Soc. 1999, 121, 4284.
(14) (a) Zaugg, H. E. Synthesis 1984, 85. (b) Zaugg, H. E. Synthesis
1984, 181.
approach would be to use a chiral Lewis acid, a strategy
that has been successfully applied to numerous systems.13
Unfortunately, the generally less active chiral catalysts
are not strong enough to promote ring closure. Therefore,

Addition Reactions of Acyclic N-Acylimines
J . Org. Chem., Vol. 66, No. 21, 2001 6991
Ta ble 3
Sch em e 4
Ta ble 4. In ter m olecu la r Nu cleop h ilic Ad d ition
Rea ction s
ring. The desired cis product 15a could be readily
separated by column chromatography and was reduced
with LAH in THF. Isolation of the product as the
hydrochloride salt furnished pure (()-sertraline 16 in
95% yield, which was identical spectroscopically and
chromatographically to an authentic sample of (+)-
sertraline.16
A new and general method for the generation of acyclic
N-acylhemiaminals has been established. These remark-
ably stable intermediates are versatile precursors to
N-acylimines, which undergo inter- and intramolecular
nucleophilic addition reactions to furnish a number of
synthetically useful products. This methodology was
applied to the synthesis of (()-sertraline. Several unusual
results in this work have brought into question the
precise mechanism of the intramolecular exocyclization
reaction. Determination of this pathway remains an
active goal.
Exp er im en ta l Section
(4-P h en ylb u t yr yl)ca r b a m ic Acid Met h yl E st er (2a ).
Methyl carbamate (2.0 g, 0.0266 mol) was added to a solution
of 1 (2.5 g, 0.0137 mol) in dry toluene (5 mL) at room
temperature. The mixture was heated to 80 °C for 6 h, cooled,
diluted with ethyl acetate (75 mL), and washed with water
(2×) and brine (1×), dried, Na2SO4, filtered, and concentrated.
The product was crystallized from ethyl acetate/hexanes to
afford 2.85 g of 2a as a colorless solid (94% yield). Mp: 121.5-
a
The designated position represents the only isomer formed.
b
An additional 5% of the ortho isomer was produced.
1
122 °C. H NMR (400 MHz, CDCl3) δ: 7.5 (bs, 1H); 7.25 (m,
2H); 7.19 (m, 3H); 3.78 (s, 3H); 2.8 (m, 2H); 2.7 (m, 2H); 2.0
(m, 2H). Anal. Calcd for C12H15NO3: C, 65.14; H, 6.83; N, 6.33.
Found: C, 65.46; H, 6.99; N, 6.47.
reionization of the product and the addition of a second
equivalent of the nucleophile. In these cases, a short
reaction time (e.g., 15 min) was the key for obtaining
useful yields of the monoadducts.
We have applied the acyl imine cyclization methodol-
ogy to the synthesis of (()-sertraline. The acid 12,15
prepared for an earlier process route to the molecule, was
converted to the acyl carbamate 14 in 88% yield. Reduc-
tion with DIBAL and cyclization promoted by TiCl4
afforded a 2:1 mixture of cis (15a ) and trans (15b)
isomers in a combined 89% yield (Scheme 4). As expected,
the closure occurred exclusively on the unsubstituted aryl
(4-P h en ylbu tyr yl)ca r ba m ic Acid Ben zyl Ester (2b).
The procedure for the synthesis of the benzyl esters is the same
as for the methyl esters, except that chromatography is usually
required to separate the product from the excess benzyl
carbamate. Mp: 105-106 °C. MS: 298 (M + H)+. 1H NMR (400
MHz, CDCl3) δ: 7.4 (bs, 1H); 7.38-7.1 (m, 10H); 5.12 (s, 2H);
2.78 (t, 2H, J ) 7.3 Hz); 2.64 (t, 2H, 7.4 Hz); 1.95 (m, 2H).
Anal. Calcd for C18H19NO3: C, 72.71; H, 6.44; N, 4.71. Found:
C, 72.73; H, 6.47; N, 4.77.
(1,2,3,4-Tetr ah ydr on aph th alen -1-yl)car bam ic Acid Meth -
yl Ester (4a ). Step 1. A solution of diisobutylaluminum
(15) Quallich, G. J .; Williams, M. T.; Friedmann, R. C. J . Org. Chem.
1990, 55, 4971.
(16) An authentic sample of (+)-sertraline was kindly provided by
Dr. Willard Welch, Pfizer Inc., Groton, CT.

6992 J . Org. Chem., Vol. 66, No. 21, 2001
DeNinno et al.
hydride (1.5 M in toluene, 1.7 mL, 2.5 mmol) was added to a
stirred solution of compound 2a (250 mg, 1.13 mmol) in CH2-
Cl2 (5 mL) at -78 °C. After 1.5 h, the reaction was quenched
with methanol (0.5 mL), and the dry ice bath was removed.
Florisil (4 g) was added followed by saturated aqueous NaCl
(0.5 mL), and the mixture was diluted with ethyl acetate (10
mL). After the mixture was stirred for 15 min, MgSO4 was
added (4 g), and the mixture was stirred for 15 min. The
mixture was filtered through sintered-glass and the solids were
washed thoroughly with EtOAc. The filtrate was concentrated
in vacuo to provide the hemiaminal 3a as a colorless solid.
This product was used directly in the next reaction.1H NMR
(400 MHz, CDCl3) δ: 7.27 (m, 2H); 7.18 (m, 3H); 5.4 (bd, 1H);
5.19 (bs, 1H); 3.78 (m, 1H); 3.64 (s, 3H); 2.6 (m, 2H); 1.8-1.5
(m, 4H). MS: 206 (M - OH)+.
After 6 h, the mixture was cooled, diluted with EtOAc (30 mL),
washed with saturated aqueous NaHCO3 solution and brine,
dried (Na2SO4), filtered, and concentrated. The product was
purified by flash chromatography (20% EtOAc/hexanes) to
afford 1.85 g of 8c (93%) as a waxy solid. Mp: 72-74 °C. MS:
1
368 (M + H)+. H NMR (400 MHz, CDCl3) δ: 7.3 (m, 5H); 7.2
(m, 3H); 6.95 (m, 1H); 6.85 (m, 2H); 4.90 (m, 1H); 4.20 (d, 2H,
J ) 8.1 Hz); 3.02 (m, 2H); 2.2 (m, 1H); 1.95 (m, 2H); 1.9 (m,
1H); 1.6-1.3 (m, 5H). Anal. Calcd for C22H25NO4: C, 71.91;
H, 6.86; N, 3.81. Found: C, 71.63; H, 6.80; N, 3.97.
Ch r om a n -4-ylca r ba m ic Acid (-)-Men th yl Ester (9a ).
Compound 8b was reduced and cyclized (using BF3‚OEt2) as
described for compound 2a . The product was analyzed by chiral
HPLC (Chiralpak AD column, 10% EtOH/hexanes with 0.1%
DEA mobile phase) and shown to be a 1:1 mixture of diaster-
eomers. MS: 330 (M + H)+.
Step 2. The crude hemiaminal 3a (1.13 mmol) was dissolved
in CH2Cl2 (5 mL) and cooled to -78 °C. Titanium tetrachloride
(1 M solution in CH2Cl2, 1.7 mL, 1.7 mmol) was added and
the mixture stirred for 1 h. The cold reaction mixture was
poured into a stirred aqueous solution of NaHCO3. The mixture
was extracted with EtOAc (2×), the combined extracts were
washed with brine, dried (Na2SO4), and filtered, and the
filtrate was concentrated in vacuo. The product was purified
by flash chromatography (20% EtOAc/hexanes) to afford 186
mg of compound 4a (80%) as a colorless crystalline solid. Mp:
(1-P h en eth ylbu t-3-en yl)ca r ba m ic Acid Meth yl Ester
(11a ). Compound 2h (200 mg, 0.97 mmol) was reduced with
DIBAL as described previously for compound 2a . The crude
product was dissolved in CH2Cl2 (5 mL), and allyl trimethyl-
silane (0.5 mL, 2.9 mmol) was added. The mixture was cooled
to -78 °C and treated with TiCl4 (1.45 mL of a 1 M solution
in CH2Cl2, 1.45 mmol). After 1 h, the mixture was poured into
NaHCO3 solution and extracted with EtOAc (2×). The com-
bined organic extracts were washed with brine, dried (Na2-
SO4), filtered, and concentrated. Flash chromatography (15%
EtOAc/hexanes) afforded 154 mg (68%) of 11a as a colorless
1
76-77 °C. H NMR (400 MHz, CDCl3) δ: 7.27 (m, 4H); 4.90
(bs, 1H); 3.65 (s, 3H); 2.75 (m, 2H); 2.0 (m, 1H); 1.8 (m, 4H).
Anal. Calcd for C12H15NO2: C, 70.22; H, 7.37; N, 6.82. Found:
C, 70.61; H, 7.37; N, 6.88.
1
solid. Mp: 42-43 °C. MS: 234 (M + H)+. H NMR (400 MHz,
CDCl3) δ: 7.2 (m, 5H); 5.78 (m, 1H); 5.02 (m, 2H); 4.5 (bs, 1H);
3.74 (bs, 1H); 3.61 (s, 3H); 2.62 (m, 2H); 2.22 (m, 2H); 1.82-
1.6 (m, 2H). Anal. Calcd for C14H19NO2: C, 72.07; H, 8.21; N,
6.00. Found: C, 71.83; H, 7.99; N, 5.61.
(3,4-Diph en ylbu tyr yl)car bam ic Acid Meth yl Ester (5a).
Methyl carbamate (1.74 g, 23 mmol) was added to a solution
of 3,4-diphenylbutyryl chloride (2 g, 7.7 mmol, prepared from
the corresponding acid17 in toluene. The mixture was heated
at 80 °C for 6 h. The mixture was cooled, diluted with ethyl
acetate (75 mL), washed with water (2×) and brine (1×), dried
with Na2SO4, filtered, and concentrated. The product was
crystallized from ethyl acetate/hexanes to afford 1.8 g of
compound 5a as a colorless solid (80% yield). Mp: 100-101
[4-(3,4-Dich lor oph en yl)-4-ph en ylbu tyr yl]car bam ic Acid
Meth yl Ester (14). Oxalyl chloride (850 uL, 9.75 mmol) was
added to a solution of 4-(3,4-dichlorophenyl)-4-phenylbutyric
acid (2 g, 6.5 mmol) in CH2Cl2 (15 mL) at 0 °C. Two drops of
DMF were added, and the mixture was allowed to warm to
ambient temperature at which time vigorous evolution of gas
commenced. After 6 h, the mixture was concentrated in vacuo
and reconcentrated from toluene 2×. The residue was dissolved
in toluene (10 mL) and treated with methyl carbamate (2.4 g,
32.5 mmol). The mixture was heated at 100 °C for 8 h, cooled,
diluted with ethyl acetate, washed with water (2×) and brine,
dried (Na2SO4), filtered, and concentrated. The product was
crystallized from EtOAc/hexanes to afford 2 g of 14 (85%) as
a colorless solid. Mp: 140-141 °C. MS: 366 (M + H)+. 1H NMR
(400 MHz, CDCl3) δ: 7.4-7.2 (m, 7H); 7.14 (dd, 1H, J ) 2.1,
8.5 Hz); 3.97 (t, 1H, J ) 7.9 Hz); 3.73 (s, 3H); 2.72 (m, 2H);
2.39 (m, 2H). Anal. Calcd for C18H17Cl2NO3: C, 59.03; H, 4.68;
N, 3.82. Found: C, 59.32; H, 4.75; N, 3.82.
1
°C. MS: 298 (M + H)+. H NMR (400 MHz, CDCl3) δ 7.2 (m,
8H); 7.03 (m, 2H); 3.73 (s, 3H); 3.52 (m, 1H); 3.22 (dd, 1H, J )
8.7, 17 Hz); 3.02 (dd, 1H, J ) 6.3, 17 Hz); 2.95 (m, 2H). Anal.
Calcd for C18H19NO3: C, 72.71; H, 6.44; N, 4.71. Found: C,
72.76; H, 6.36; N, 4.60.
(3,4-Diph en ylbu tyr yl)car bam ic Acid Ben zyl Ester (5b).
Mp: 79-81 °C. MS: 374 (M + H)+. 1H NMR (400 MHz, CDCl3)
δ 7.39 (m, 4H); 7.2 (m, 9H); 7.02 (m, 2H); 5.12 (s, 2H); 3.5 (m,
1H); 3.22 (dd, 1H, J ) 8.5, 17 Hz); 3.03 (dd, 1H, J ) 6.2, 17
Hz); 2.92 (m, 2H). Anal. Calcd for C24H23NO3: C, 77.19; H,
6.21; N, 3.75. Found: C, 77.14; H, 6.14; N, 3.65.
(3-P h en yl-1,2,3,4-tetr a h yd r on a p h th a len -1-yl)ca r ba m -
ic Acid Meth yl Ester (7a ). Compound 5a was converted to
compound 7a by the general procedure described for compound
4a . The crude product was purified by flash chromatography
(5% EtOAc/hexanes) to afford an inseparable 1:1 mixture of
diastereomers in 76% yield. Anal. Calcd for C18H19NO2: C,
76.84; H, 6.81; N, 4.98. Found: C, 76.56; H, 6.98; N, 4.98.
(3-P h en yl-1,2,3,4-tetr a h yd r on a p h th a len -1-yl)ca r ba m -
ic Acid Ben zyl Ester (7b). Compound 5b was converted to
compound 7b by the general procedure described for compound
4a . The crude product was purified by flash chromatography
(10% EtOAc/hexanes) to afford an inseparable 1:1 mixture of
diastereomers in 80% yield. Anal. Calcd for C24H23NO2: C,
80.64; H, 6.49; N, 3.92. Found: C, 80.65; H, 6.53; N, 3.84.
(3-P h en oxyp r op ion yl)ca r ba m ic a cid (1R,2S)-2-P h en yl-
cycloh ex-1-yl Ester (8c). Carbamic acid (1R,2S)-2-phenyl-
cyclohex-1-yl ester18 (1.78 g, 8.1 mmol) was added to a solution
of 3-phenoxyproprionyl chloride (1.0 g, 5.4 mmol) in dry toluene
(5 mL), and the mixture was heated to reflux temperature.
[4-(3,4-Dich lor op h en yl)-1,2,3,4-tetr a h yd r on a p h th a len -
1-yl]ca r ba m ic Acid Meth yl Ester (15). DIBAL (2.0 mL of
a 1.5 M solution in toluene, 3 mmol) was added to a solution
of 14 (0.5 g, 1.37 mmol) in CH2Cl2 (10 mL) at -78 °C. After 2
h, the reaction was quenched with methanol (1 mL), and the
dry ice bath was removed. Florisil was added, and the mixture
was diluted with ethyl acetate (30 mL). Saturated NaCl
solution was added (1 mL) and the mixture stirred for 20 min.
The mixture was dried (MgSO4), filtered, and concentrated.
The crude product was dissolved in CH2Cl2 (10 mL) and
treated with TiCl4 (2.7 mL of a 1 M solution in CH2Cl2, 2.7
mmol) at -78 °C. After 1 h, the mixture was poured into
vigorously stirred aqueous NaHCO3 solution. The mixture was
extracted with ethyl acetate (2×), and the combined extracts
were washed with brine, dried (Na2SO4), filtered, and concen-
trated. Flash chromatography (20% EtOAc/hexanes) afforded
two products in a combined 87% overall yield.
High Rf Cis Isomer (15a ). Yield: 55%. Mp: 170.5-172 °C.
MS: 350 (M + H)+. 1H NMR (400 MHz, CDCl3) δ: 7.29 (m,
2H); 7.2 (m, 1H); 7.15 (m, 2H); 6.9 (d, 1H, J ) 8.1 Hz); 6.8 (d,
1H, J ) 8.1 Hz); 4.95 (m, 2H); 4.0 (m, 1H); 3.7 (s, 3H); 2.12
(m, 1H); 1.9 (m, 3H). Anal. Calcd for C18H17Cl2NO2: C, 61.73;
H, 4.89; N, 4.00. Found: C, 61.84; H, 5.03; N, 3.90.
(17) Vebrel, J .; Carrie, R. Bull. Soc. Chim. Fr. 1982, II-116.
(18) Whitesell, J . K.; Carpenter, J . F.; Yaser, H. K.; Machajewski,
T. J . Am. Chem. Soc. 1990, 112, 7653.
(19) Loev, B.; Kormendy, M. F. J . Org. Chem. 1963, 28, 3421.
(20) Remiszewski, S. W.; Yang, J .; Weinreb, S. M. Tetrahedron Lett.
1986, 1853.
Low Rf Trans Isomer (15b). Yield: 32%. Mp: 131-134 °C.
1
MS: 350 (M + H)+. H NMR (400 MHz, CDCl3) δ 7.41 (d, 1H,

Addition Reactions of Acyclic N-Acylimines
J . Org. Chem., Vol. 66, No. 21, 2001 6993
J ) 7.9 Hz); 7.36 (d, 1H, J ) 7.9 Hz); 7.22 (m, 1H); 7.18 (m,
2H); 6.88 (dd, 1H, J ) 2, 8.3 Hz); 6.80 (d, 1H, J ) 7.9 Hz);
5.02 (m, 1H); 4.91 (m, 1H); 4.1 (m, 1H); 3.70 (s, 3H); 2.2 (m,
2H); 1.85 (m, 1H); 1.75 (m, 1H). Anal. Calcd for C18H17Cl2-
NO2: C, 61.73; H, 4.89; N, 4.00. Found: C, 61.94; H, 4.95; N,
4.08.
of 16 were identical to those of an authentic sample of (+)-
sertraline. MS: 306 (M + H)+. 1H NMR (400 MHz, DMSO-d6)
δ: 9.22 (bs, 2H); 7.58 (m, 3H); 7.22 (m, 3H); 6.70 (d, 1H, J )
8.0 Hz); 4.39 (bs, 1H); 4.1 (m, 1H); 2.6 (s, 3H); 2.19 (m, 1H);
1.98 (m, 3H).
[4-(3,4-Dich lor op h en yl)-1,2,3,4-tetr a h yd r on a p h th a len -
1-yl]m eth yla m in e (16) ((()-Ser tr a lin e). LAH (22 mg, 0.57
mmol) was added to a solution of 15a (100 mg, 0.29 mmol) in
THF (3 mL) at rt. The mixture was heated at 70 °C for 1 h,
cooled, and quenched by the sequential addition of water (22
µL), 15% NaOH (22 µL), and water (66 µL). The mixture was
diluted with ether, dried with MgSO4, filtered, and concen-
trated. The residue was dissolved in ether and treated with a
solution of HCl in ether. The precipitate was filtered, washed
with ether, and dried to afford 94 mg (96%) of product as a
colorless solid. The chromatographic and spectral properties
Ack n ow led gm en t. The authors thank Dr. J on
Bordner and Ms. Debra DeCosta for the X-ray crystal
structure determination of compound 10 and Dr. Dan
Kung for helpful comments during the preparation of
this manuscript.
Su p p or tin g In for m a tion Ava ila ble: Spectral and ana-
lytical data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O010370L