Synthesis of 4,4′-disubstituted azepines via ring-closing metathesis reaction and asymmetric arylation of lactones

Article abstract of DOI:10.1055/s-2006-926433

The syntheses of the title compounds were accomplished via an original sequence of reactions including the ring-closing metathesis of ω-dienes by using the second-generation Grubbs' catalyst. The chiral diene precursors are available in racemic or optical

Full text of DOI:10.1055/s-2006-926433

PAPER
1437
Synthesis of 4,4¢-Disubstituted Azepines via Ring-Closing Metathesis Reaction
and Asymmetric Arylation of Lactones
S
ynthesis of 4,4
a
¢
-Disubstitute
d
Hexahyr
e
nes nt Delhaye, Alain Merschaert,* Khalid Diker, Ioannis N. Houpis*1
Chemical Product Research and Development, Lilly Development Centre, rue Granbonpré 11, 1348 Mont-St-Guibert, Belgium
Fax +32(10)476315; E-mail: merschaert_alain@lilly.com; E-mail: yhoupis@prdbe.jnj.com
Received 8 December 2005
R2
R1
Abstract: The syntheses of the title compounds were accomplished
via an original sequence of reactions including the ring-closing
metathesis of w-dienes by using the second-generation Grubbs’ cat-
alyst. The chiral diene precursors are available in racemic or opti-
cally enriched form from the corresponding a,a¢-disubstituted
lactones derivatives
NH
1
Figure 2
Key words: heterocycles, ring closure, metathesis, butyrolactone,
arylation
heteroatom thus precluding any possibility of using the
latter as an ancillary directing functionality.
A number of syntheses of azepines are reported in the lit-
erature; however, to our knowledge there are relatively
few examples of chiral non-racemic syntheses of com-
pounds bearing our desired functionality. Until recently,
the most common approach to these azepines derivatives
involved a Beckman rearrangement strategy of oxime
derivatives3 that already contain the chiral center. An in-
tersecting approach, in which the azepine ring was in-
stalled by photochemical rearrangement of chiral
oxaziridine derivatives, has been developed by the Aube
group.4
Azepines and their chiral non-racemic tetrahydro and
hexahydro derivatives have found extensive use in the
pharmaceutical industry as they represent the pharma-
cophore in a number of drug candidates (Figure l).2
HCl
HO
N
N
HO
HBr
Eptazocine hydrobromide
Analgesic opioid, mixed opioid
agonist/antagonist
Meptazinol hydrochloride
Analgesic, non-opioid
In the last decade, ring-closing metathesis strategies for
the synthesis of small or medium-sized carbocycles and
heterocycles have became popular.5 In our work,6 we
sought to utilize such strategy in combination with a cata-
lytic asymmetric arylation methodology that was detailed
recently.7 The retrosynthetic analysis (Scheme 1) intro-
duces a double bond into the hexahydroazepine ring af-
fording a tetrahydroazepine retron for the ring-closing
metathesis (RCM) transformation that in turn affords a
suitable w-diene. Such a diene can be prepared from a bis-
homoallylic alcohol that itself can be derived from an a-
substituted-g-butyrolactone.
N
O
HCl
N
N
OH
HO
OH
O
HO
O
N
O
OH
O
O
Cl
N
Azelastine hydrochloride
Antihistaminique, antipsoriatic
Balanol
Antineoplastic,
Protein Kinase C inhibitor
In this paper, we demonstrate the viability of this route, by
first focusing on racemic substrates and then expanding
Figure 1
In connection with such a project in our laboratories we
had to synthesize hexahydroazepine derivatives 1
(Figure 2) containing a chiral quaternary center at the 4-
position.
R2
R2
R1
[H]
RCM
R2
R1
NH
N-Cbz
R1
N-Cbz
Apart from the general difficulty in installing a quaternary
chiral center, the substitution pattern in 1 presented the ad-
ditional challenge that the chiral center was remote to the
R2
O
R2
R1
R1
O
OH
SYNTHESIS 2006, No. 9, pp 1437–1442
Advanced online publication: 11.04.2006
x
x
.
x
x
.2
0
0
6
Scheme 1 Retrosynthetic analysis
DOI: 10.1055/s-2006-926433; Art ID: Z24005SS
© Georg Thieme Verlag Stuttgart · New York

1438
L. Delhaye et al.
PAPER
Scheme 2 Synthesis of 4,4¢-disubstituted hexahydroazepines from a,a¢-disubstituted lactones
the chemistry to select non-racemic compounds prepared Chemoselective reduction of the lactones 3a–f to the lac-
from a,a¢-disubstituted lactones (Scheme 2, Table 1).
tols 4a–f was accomplished by reaction with diisobutyl-
aluminum hydride10 at –78 °C, in a mixture of
dichloromethane and toluene. The products 4 were ob-
tained after careful quench with methanol (0.25 mL/mmol
of DIBAL-H) and water (0.38 mL/mmol DIBAL-H). The
resulting precipitate was filtered through Celite and the
product was isolated by evaporation and used directly in
the next step. Under these conditions of temperature and
solvents, no over-reduction was observed even with 1.2
equivalents of diisobutylaluminum hydride and good
yields of the lactol were obtained.11
Lactones 3a and 3f are commercially available and the
synthesis of 3b8and 3c9 was readily performed according
to literature procedures. Compounds 3d and 3e were pre-
pared in optically enriched form by Ni-catalyzed aryla-
tion.7 Specifically, deprotonation at ambient temperature
by sodium hexamethyldisilazide, formation of the corre-
sponding Zn-species with zinc bromide followed by reac-
tion with chlorobenzene and Ni(COD)2/(R)-BINAP as the
catalyst (5 mol% and 8.5 mol% respectively) afforded 3d
and 3e. The enantiomeric excess (90% ee) was established
by the methods described in the literature.7
Table 1 Compounds Prepared and Corresponding Isolated Yields
R1
R2
Lactols 4
Alcohols 5
w-Dienes 7
Cbz-dienes 8
Tetrahy-
droazepines 9
(%)c
Hexahy-
droazepines 1
(%)e
(%)a
(%)c
(%)c
(%)c
Me
Et
H
4ab
5ab
7ab
8ab
9a (75)d
9b (77)d
9c (75)d
9d (83)d
9e (88)d
9f (68)d
1a (100)
1b (90)
1c (85)
1d (96)
1e (73)
1f (100)
Me
H
4bb
5bb
7bb
8bb
Ph
Ph
Ph
Ph
4c (99)
4d (84)
4e (62)
4f (86)
5c (98)
5d (97)
5e (90)
5f (92)
7c (65)
7d (90)
7e (91)
7f (81)
8c (83)
8d (75)
8e (74)
8f (84)
Me
OEt
Ph
a Crude yield after filtration on Celite.
b Not purified due to volatility issue.
c After quick flash chromatography on silica gel.
d Unstable, significant degradation of the retention sample observed after storage for a few days at r.t.
e Isolated as acetate salt, then converted to the free base for characterization.
Synthesis 2006, No. 9, 1437–1442 © Thieme Stuttgart · New York

PAPER
Synthesis of 4,4¢-Disubstituted Hexahydroazepines
1439
The lactols 4a–f were treated with 2.6 equivalents of substituted diaryl derivatives and will report on this in due
triphenylphosphonium bromide and 2.4 equivalents of po- time.
tassium tert-butoxide in tetrahydrofuran at ambient tem-
perature to give the desired bis-homoallylic alcohols 5a–f
in 90–98% yield after extractive work-up and silica gel
filtration.12 It is worth noting that both the ratio of base to
phosphonium salt and the resulting ylide to substrate ratio
were crucial for the success of this reaction. For example,
in an attempt to reduce the phosphorus by-products, we
utilized 2 equivalents of base and 1.1 equivalents of phos-
phonium salt but found that there no reaction took place
under these conditions. Other ratios produced mixed re-
sults with reduced overall yields and formation of several
by-products.
The nucleophilic substitution13 of activated 5a–f initially
posed the usual problems of over-alkylation when active
derivatives such as the triflate were used. On the other
hand, when Boc-allyl amine was deprotonated and reacted
with the mesylate 6, attack on sulfur was observed to give
N-Boc, N-methyl sulfonyl allyl amine. To our surprise, re-
action of 6a–f in neat allylamine resulted in good to high
yields of the desired products 7a–f, with no over-alkyla-
tion. The same result could be achieved with methanol as
the solvent and ten equivalents of allylamine. Extractive
work-up afforded the product without any need for further
purification.
1H NMR and 13C NMR spectra were recorded in CDCl3 on a Bruker
Avance 400 spectrometer. HRMS data were obtained by time-of-
flight technique on a hybrid quadrupole time-of-flight mass spec-
trometer (QTOF Ultima Waters). For compounds 3d and 3e, the
solvent was degassed by argon bubbling for 3 h. In all other cases,
chemicals were used as received.
The following compounds gave analytical data that were consistent
with the literature: 4c (1H NMR and 13C NMR),17a 4f,17b 5c (1H
NMR),18a 5f (1H NMR),18b and 1f (1H NMR).19b
3-Ethoxy-3-phenyltetrahydrofuran-2-one (3e)
An oven-dried, resealable 100-mL Schlenk flask containing a mag-
netic stirbar was allowed to cool to r.t. and then was charged with
(S)-BINAP (813 mg, 1.3 mmol). The flask was sealed, evacuated
and backfilled with argon. From a freshly prepared stock solution of
Ni(COD)2 (0.05 M, toluene), 15.4 mL (0.77 mmol) was added by
syringe while purging with argon. The flask was sealed and heated
to 60 °C for 5 min during which time the solution turned dark red.
The reaction vessel was removed from the oil bath, and to it were
sequentially added 3-ethoxy-tetrahydrofuran-2-one (1.8 g, 13.8
mmol), NaHMDS (0.6 M in toluene; 26.5 mL, 15.9 mmol), and a
solution of ZnBr2 (0.15 M in THF; 15.4 mL, 2.3 mmol). The mix-
ture was then stirred for 5 min at r.t. 1-Chlorobenzene (1.56 mL,
15.3 mmol) was added by syringe. The flask was sealed and heated
to 60 °C for 48 h, after which complete conversion had been accom-
plished, as judged by TLC. The reaction mixture was allowed to
cool to r.t. and was then filtered through a pad of silica gel (30 g)
eluting with EtOAc. The eluate was concentrated under reduced
pressure, followed by chromatography of the residue (~2 g) on sili-
ca gel (100 g) (EtOAc–heptane 1:9). Fraction at Rf = 0.65 was col-
lected and concentrated, affording 3e in 30% yield (850 mg, 4.12
mmol)
Exposure of 7 to a variety of RCM catalysts and condi-
tions failed to afford the desired product, presumably due
to the coordination of the free nitrogen to the Ru center.14
Thus 7a–f were protected as the Cbz derivatives 8a–f by
treatment with benzyl chloroformate in tetrahydrofuran at
10 °C in the presence of triethylamine in 84–90% yield.
1H NMR (250 MHz, CDCl3): d = 1.27 (t, 3 H), 2.52 (m, 1 H), 2.65
(m, 1 H), 3.36 (m, 1 H), 3.58 (m, 1 H), 4.24 (m, 1 H), 4.44 (m, 1 H),
7.44 (m, 5 H).
13C NMR (67.5 MHz, CDCl3): d = 15.80, 39.66, 61.46, 65.42,
81.30, 126.92, 128.93, 129.09, 137.47, 174.74.
Despite the protection, treatment of 8a–f with first-gener-
ation Grubbs catalyst15 resulted in low conversion and the
formation of polymeric materials. We speculated that the
steric hindrance due to the adjacent quaternary center was
responsible for the deceleration of the RCM pathway.
Fortunately, exposure of 8a–f to the second-generation
imidazolinium carbene derived catalyst16 (1 mol%) in
dichloroethane at 80 °C (Scheme 2) gave complete con-
Lactols 4a–f; General Procedure
To a magnetically stirred solution of lactone 3 (82 mmol) in CH2Cl2
(290 mL) cooled at –70 °C was dropwise added 1.5 M DIBAL-H in
toluene (65 mL, 97 mmol) in 30 min. After 30 min post-stirring,
versions. Although we are gratified that the transforma- MeOH (25mL) was added in one portion and the mixture was
warmed to r.t. within 5 min in the water bath. H2O (37.5 mL) was
tion required low catalyst loadings, one drawback of this
added and the resulting gel was vigorously stirred. After 15 min, the
reaction is that it must be run at 0.01 M concentration to
mixture was filtered on Celite® (15 min under 0.2 bar). Mother li-
quors were evaporated to dryness to give the tetrahydrofuran-2-ols
4a–f (yield: 84–99%).
avoid polymerization side-reactions. Concentration of the
solvent and quick filtration through silica gel gave good
yields of the desired cyclized products 9a–f. However,
surprisingly these tetrahydroazepine derivatives seemed
to be unstable at room temperature. Compounds 9a–f
were thus directly converted to the hexahydroazepines
1a–f by hydrogenation over Pd/C in good overall yields.
4a, 4b
Because of the high volatility of the product, this reaction was run
with DIBAL-H in CH2Cl2 in order to remove the solvent without
losing too much product.
In conclusion we have been able to effect a general syn-
4d
thesis of 4-mono- or disubstituted hexahydroazepines in 1H NMR (250 MHz, CDCl3, 2 diastereomeric pairs): d = 1.21–1.31
(2 × s, 1 H), 1.50 (br s, 1 H), 1.95, 2.15, 2.30, 2.50 (4 × m, 4 H), 3.78,
4.00, 4.10 (3 × m, 2 H), 5.31–5.32 (2 × s, 1 H), 7.10 (m, 5 H).
13C NMR (67.5 MHz, CDCl3): d = 27.15, 33.52, 49.8–51.6, 66.74,
103.28, 125.9–128.5 (3 × C), 144.8–146.
good overall yields from readily available a-mono- or dis-
ubstituted lactones. Some disubstituted derivatives could
be obtained in optically active form with known method-
ology. We are currently attempting to expand the scope to
Synthesis 2006, No. 9, 1437–1442 © Thieme Stuttgart · New York

1440
4e
L. Delhaye et al.
PAPER
13C NMR (67.5 MHz, CDCl3): d = 25.60, 41.42, 43.89, 45.78,
52.92, 112.27, 116.17, 126.32, 126.85, 128.57, 137.71, 147.06,
147.48.
1H NMR (250 MHz, CDCl3, 2 diastereomers): d = 1.15 (m, 3 H),
1.59 (br s, 1 H), 2.46 (m, 2 H), 3.16–3.38 (2 × m, 2 H), 3.99–4.17
(2 × m, 2 H), 4.37–5.21 (2 × d, 1 H), 7.40 (m, 5 H).
HRMS: m/z calcd for C15H21N: 216.1752; found: 216.1748.
13C NMR (67.5 MHz, CDCl3): d = 15.91, 32.67, 59.93, 65.95,
84.90, 102.92, 127.11, 128.58, 128.92, 139.10.
7e
1H NMR (250 MHz, CDCl3): d = 1.12 (t, 3 H), 2.11 (m, 2 H), 2.46
(m, 2 H), 3.09 (m, 2 H), 3.24 (m, 2 H), 4.90–5.30 (m, 4 H), 5.82 (m,
2 H), 7.30 (m, 5 H).
13C NMR (67.5 MHz, CDCl3): d = 15.98, 36.95, 44.77, 52.89,
58.36, 81.04, 115.17, 116.15, 126.85–128.70 (5 × C), 137.08,
142.33, 143.89.
Bis-homoallylic Alcohols 5a–f; General Procedure
Solid t-BuOK (110 mmol) was added to the suspension of triphen-
ylmethylposphonium bromide (120 mmol) in anhyd THF (100 mL),
and the mixture was cooled with an ice bath. After 15 min post-stir-
ring, tetrahydrofuran-2-ol 4 (46 mmol) was added and the mixture
was allowed to stir overnight. H2O (100 mL) was added to the mix-
ture. The aqueous layer was extracted with toluene (100 mL). The
organic layers were pooled and washed with brine, dried on MgSO4
and evaporated to dryness. The residue was filtered on silica gel
(400 g) with EtOAc–n-heptane (2:8 → 4:6). The penten-1-ols 5
were so-isolated in 90–98% yield. 5a and 5b were not isolated be-
cause of their high volatility, but were engaged directly in the next
step.
HRMS: m/z calcd for C16H23NO: 246.1858; found: 246.1846.
7f
1H NMR (250 MHz, CDCl3): d = 2.41 (s, 4 H), 3.07 (d, 2 H), 4.76
(dd, 1 H), 4.97 (m, 2 H), 5.12 (dd, 1 H), 5.75 (m, 1 H), 6.48 (dd, 1
H), 7.18 (m, 10 H).
13C NMR (67.5 MHz, CDCl3): d = 38.84, 45.73, 52.53, 114.69,
116.91, 126.00–128.00 (10 × C), 136.00, 144.68, 146.85 (2 × C);
quaternary benzylic carbon was not detected because of very weak
signal.
5d
1H NMR (250 MHz): d = 1.34 (s, 3 H), 2.01 (m, 2 H), 3.53 (m, 2 H),
5.05 (m, 2 H), 5.97 (m, 1 H), 7.23 (m, 5 H).
HRMS: m/z calcd for C20H23N: 278.1909; found: 278.1898.
13C NMR (62.9 MHz, CDCl3): d = 25.70, 43.59, 43.75, 60.36,
112.46, 126.51, 126.78, 128.69, 146.97, 147.27.
Cbz-Protected w-Dienes 8a–f; General Procedure
Benzyl chloroformate (27 mmol) was added to the solution of w-di-
ene 7 (12.4 mmol) in THF (40 mL) and Et3N (25 mmol) at 7–15 °C.
The mixture was allowed to stir at 25 °C during 30 min. H2O (20
mL) was added. The aqueous layer was extracted with toluene (20
mL). The organic layers were pooled, washed with brine, dried on
MgSO4 and evaporated to dryness. The residue (5.1 g) was filtered
on silica gel with EtOAc–n-heptane (2:8). The pure fractions of
Cbz-dienes 8 were isolated in 75–84% yield.
5e
1H NMR (250 MHz, CDCl3): d = 1.15 (t, 3 H), 2.11 (t, 2 H), 2.90
(br s, 1 H), 3.26 (m, 2 H), 3.60 (m, 2 H), 5.27 (dd, 2 H), 5.93 (dd, 1
H), 7.34 (m, 5 H).
13C NMR (67.5 MHz, CDCl3): d = 14.53, 38.84, 57.76, 58.48,
81.68, 114.90, 125.63, 126.22, 127.20, 139.26, 141.47.
w-Dienes 7a–f; General Procedure
8a
Mesyl chloride (16.5 mmol) was added to the solution of penten-1-
ol 5 (15 mmol) in CH2Cl2 (36 mL) and Et3N (33 mmol) at 10–15 °C.
The mixture was allowed to stir at 25 °C for the next 2.5 h. H2O (10
mL) was added to the mixture. The organic layer was dried on
MgSO4 and evaporated to dryness to yield the mesylate 6. It was re-
dissolved in MeOH (50 mL) and allylamine (150 mmol) was added.
The solution was heated at 75 °C during 50 h. After cooling to r.t.
toluene (50 mL) and H2O (50 mL) were added. The aqueous layer
was extracted with toluene (50 mL). The organic layers were
pooled, dried on MgSO4 and evaporated to dryness. The residue was
filtered on silica gel (40 g), eluting first with EtOAc–n-heptane
(4:6) to remove the non-polar impurities and remaining starting ma-
terial, and then with a 25% CH2Cl2–MeOH–NH3 (90:10:1) mixture
to get the w-dienes 7 (yield: 65–91%). 7a and 7b were not isolated
because of their high volatility, but were engaged directly in the
next step.
1H NMR (250 MHz, CDCl3): d = 0.99 (br s, 3 H), 1.55 (br s, 2 H),
2.05 (br s, 1 H), 3.23 (br s, 2 H), 3.88 (br s, 2 H), 4.94 (br s, 2 H),
5.14 (br s, 4 H), 5.65 (br s, 2 H), 7.35 (br s, 5 H).
13C NMR (67.5 MHz, CDCl3): d = 20.62, 34.93, 35.98, 45.50,
50.05, 67.37, 113.48, 116.94, 128.15, 128.24, 128.80, 134.35,
137.45, 144.12, 156.43.
HRMS: m/z calcd for C17H23NO2: 274.1807; found: 274.1801.
8b
1H NMR (250 MHz, CDCl3): d = 0.80 (br s, 3 H), 0.95 (br m, 3 H),
1.30 (br s, 2 H), 1.56 (br s, 2 H), 3.19 (br s, 2 H), 3.89 (br s, 2 H),
4.98 (br m, 2 H), 5.15 (br s, 4 H), 5.75 (br m, 2 H), 7.37 (br s, 5 H).
13C NMR (67.5 MHz, CDCl3): d = 22.43, 33.53, 39.07, 50.29,
67.38, 112.54, 117.19, 128.24–128.78 (5 × C), 134.42, 137.32,
146.54, 151.75.
7c
HRMS: m/z calcd for C19H27NO2: 302.2120; found: 302.2119.
1H NMR (250 MHz, CDCl3): d = 1.84 (m, 2 H), 2.51 (m, 2 H), 3.12
(d, 2 H), 3.26 (m, 1 H), 5.00 (m, 4 H), 5.85 (m, 2 H), 7.20 (m, 5 H).
13C NMR (67.5 MHz, CDCl3): d = 35.75, 47.69, 48.16, 52.66,
114.59, 116.44, 126.69, 127.92, 128.90, 136.89, 142.34, 144.33.
8c
1H NMR (250 MHz, CDCl3): d = 1.90 (br s, 2 H), 3.10 (br s + m, 2
H + 1 H), 3.75 (br s, 2 H), 4.80–5.10 (br m, 4 H), 5.05 (s, 2 H), 5.60
(br m, 1 H), 5.90 (br s, 1 H), 7.25 (m, 10 H).
HRMS: m/z calcd for C14H19N: 202.1596; found: 202.1588.
13C NMR (67.5 MHz, CDCl3): d = 33.91, 45.45–46.25, 47.86,
50.36, 67.45, 114.82, 117.35, 126.80–128.95 (10 × C), 134.24,
137.28, 141.93, 143.82, 156.39.
7d
1H NMR (250 MHz, CDCl3): d = 1.25 (s, 3 H), 1.83 (m, 2 H), 2.33
(m, 2 H), 3.02 (m, 2 H), 4.98 (m, 4 H), 5.75 (m, 1 H), 5.88 (dd, 1 H),
7.20 (m, 5 H).
HRMS: m/z calcd for C22H25NO2: 336.1964; found: 336.1957.
Synthesis 2006, No. 9, 1437–1442 © Thieme Stuttgart · New York

PAPER
Synthesis of 4,4¢-Disubstituted Hexahydroazepines
1441
8d
13C NMR (67.5 MHz, CDCl3): d = 8.51, 22.72, 26.33, 35.02, 38.75,
1H NMR (250 MHz, CDCl3): d = 1.30 (br m, 3 H), 1.95 (br s, 2 H),
3.00 (br s, 2 H), 3.80 (br s, 2 H), 4.80–5.20 (br s, 4 H), 5.05 (s, 2 H),
5.60 (br s, 1 H), 5.90 (br m, 1 H), 7.25 (m, 10 H).
35.74, 39.07, 42.48, 48.52.
HRMS: m/z calcd for C14H19N: 142.1596; found: 142.1591.
13C NMR (67.5 MHz, CDCl3): d = 25.52, 39.16, 43.32, 43.59,
50.44, 53.84, 67.54, 112.60, 117.55, 126.43–128.85 (10 × C),
134.22, 137.23, 146.40, 166.30.
1c
1H NMR data were consistent with the literature data.19a
13C NMR (67.5 MHz, CDCl3): d = 30.06, 35.51, 40.10, 46.22,
48.16, 49.19, 126.14, 127.03, 128.79, 149.48.
HRMS: m/z calcd for C23H27NO2: 350.2120; found: 350.2115.
HRMS: m/z calcd for C12H17N: 176.1439; found: 176.1432.
8e
1H NMR (250 MHz, CDCl3): d = 1.20 (br m, 3 H), 2.20 (br s, 2 H),
3.00 (br s, 2 H), 3.30 (br m, 2 H), 3.80 (br s, 2 H), 4.90–5.40 (br m,
4 H), 5.10 (s, 2 H), 5.80 (br m, 2 H), 7.30 (m, 10 H).
1d
1H NMR (250 MHz, CDCl3): d = 1.26 (s, 3 H), 1.50–1.90 (m, 4 H),
2.00–2.30 (m, 3 H), 2.75–3.00 (m, 3 H), 7.10–7.50 (m, 5 H).
13C NMR (67.5 MHz, CDCl3): d = 15.92, 34.42, 42.53, 50.63,
58.08, 67.54, 80.22, 115.00, 117.0, 126.00–128.00 (10 × C),
134.23, 137.00, 142.36, 143.00, 166.50.
13C NMR (67.5 MHz, CDCl3): d = 27.02, 3.23, 40.25, 41.40, 44.55,
45.12, 49.83, 125.79, 126.32, 128.65, 150.27.
HRMS: m/z calcd for C13H19N: 190.1596; found: 190.1593.
HRMS: m/z calcd for C24H29NO3: 380.2140; found: 380.2137.
1e
8f
1H NMR (250 MHz, CDCl3): d = 0.90–4.50 (non-resolved multip-
1H NMR (250 MHz, CDCl3): d = 2.42 (br s, 2 H), 2.95 (br s, 2 H),
4.72 (br s, 2 H), 4.65–5.35 (m, 4 H), 5.05 (s, 2 H), 5.60 (br s, 1 H),
6.30 (br s, 1 H), 7.20 (m, 15 H).
lets summing to 15 H), 7.26 (m, 5 H).
13C NMR (67.5 MHz, CDCl3): d = 15.94, 22.12, 37.40, 41.34,
41.72, 47.57, 57.89, 79.79, 126.10, 127.63, 128.71, 146.76.
13C NMR (150 MHz, CDCl3): d = 29.68–30.87, 36.60, 43.19–44.26,
50.13–52.42, 67.29, 114.20, 120.12, 124.00–128.50 (15 × C),
133.66, 143.85, 146.0 (2 × C), 156.00.
HRMS: m/z calcd for C14H21NO: 220.1701; found: 220.1703.
HRMS: m/z calcd for C28H29NO2: 412.2277; found: 412.2281.
Acknowledgment
We thank Pieter Delbeke and Laurent Leclerq (Lilly Development
Centre) for their support in spectroscopy (NMR and MS).
Tetrahydroazepines 9a–f; General Procedure
Grubbs’ 2nd generation catalyst (0.026 mmol) was added to a solu-
tion of Cbz-diene 8 (2.6 mmol) in anhyd DCE (100 mL) under N2.
The solution was warmed to reflux (82 °C) during 5 h. The solvent
was removed under vacuum and the residue was quickly filtered on
silica gel with EtOAc–n-heptane (1:9 → 2:8) to yield the tetrahy-
droazepines 9 in 68–88%.
References
(1) Current address: J&J PRD, Turnhoutseweg 30, 2340 Beerse,
Belgium.
(2) A search in the mddr-3d Isis database produced >1000 hits
of azepine derivatives in various stages of development.
(3) (a) Sainsbury, M.; Mahon, M. F.; Williams, C. S.
Tetrahedron 1991, 47, 4195. (b) Sainsbury, M.; Williams,
C. S. Tetrahedron Lett. 1990, 31, 2763.
9b
1H NMR (250 MHz, CDCl3): d = 0.90 (m, 3 H), 1.03 (m, 3 H), 1.44
(m, 2 H), 1.67 (m, 1 H), 1.91 (m, 1 H), 3.70 (m, 2 H), 4.04 (m, 2 H),
5.21 (s, 2 H), 5.46 (br d, 1 H), 5.69 (m, 1 H), 7.41 (m, 5 H).
(4) Aube, J.; Wang, Y.; Hammond, M.; Tanol, M.; Takusagawa,
F.; Velde, D. V. J. Am. Chem. Soc. 1990, 112, 4879.
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104, 2199. (b) McReynolds, M. D.; Dougherty, J. M.;
Hanson, P. R. Chem. Rev. 2004, 104, 2239. For specific
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HRMS: m/z calcd for C17H23NO2: 274.1807; found: 274.1812.
9d
HRMS: m/z calcd for C21H23NO2: 322.1807; found: 322.1805.
Hexahydrazepines 1a–f; General Procedure
Tetrahydrazepine 9 (0.35 mmol) was dissolved in AcOH (3.5 mL).
Pd/C (5%) was added and the suspension was hydrogenated under
50 psi H2 at 20 °C overnight. The catalyst was filtered off and the
mother liquors were evaporated to dryness after several additions of
toluene (azeotrope: AcOH–toluene). Acetate salt of hexahy-
droazepines 1 were obtained as oils (73–100%). A sample was free-
based and purified on silica gel for characterization.
(6) With the exception of compounds 9 (unstable), all isolated
compounds in this work gave satisfactory 1H and 13C NMR
spectra and HRMS or favorable comparison with the
literature data.
(7) Spielvogel, D. L.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 3500.
1a
1H NMR data were consistent with the literature data.19a
(8) Canney, D. J. J. Med. Chem. 1991, 34, 1460.
(9) Rosen, J. D.; Nelson, T. D.; Huffman, M. A.; McNamara, J.
M. Tetrahedron Lett. 2003, 44, 365.
(10) Schmitt, A.; Reißig, H. U. Chem. Ber. 1995, 28, 871.
(11) Compounds 4a and 4b and their subsequent derivatives are
volatile and were not isolated. Overall yields are reported for
9a and 9b.
13C NMR (67.5 MHz, CDCl3): d = 8.51, 22.71, 26.32, 35.02, 35.66,
38.74, 39.06, 42.47, 48.51.
HRMS: m/z calcd for C9H19N: 142.1596; found: 142.1591.
1b
1H NMR (250 MHz, CDCl3): d = 0.88 (m, 6 H), 1.28 (m, 2 H), 1.30–
1.75 (m, 6 H), 3.04 (m, 4 H), 4.80 (br s, 1 H).
(12) Wittig olefination of lactols bearing two a,a¢ substituents has
not been commonly reported. There has been a report
Synthesis 2006, No. 9, 1437–1442 © Thieme Stuttgart · New York

1442
L. Delhaye et al.
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(16) Tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-
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Synthesis 2006, No. 9, 1437–1442 © Thieme Stuttgart · New York