Palladium-catalysed synthesis of enantiopure 1,2,4,5-tetrahydro-1,4-benzodiazepin-3-(3H)-one derivatives

Article abstract of DOI:10.1055/s-2001-14606

A convenient procedure for the preparation of 1,2,4,5tetrahydro-1,4-benzodiazepin-3-(3H)-one derivatives (S)-2 from chiral α-substituted N-n-butyl-N-(o-iodobenzyl)glycinamides (S)-1 has been developed. Seven-membered ring formation occurs through an intramolecular N-arylation catalysed by palladium and bis(phosphine) ligands. The use of chelating bis(phosphines) allows to minimize or entirely suppress carbon-2 racemisation which occurs when a mono(phosphine) ligand is used.

Full text of DOI:10.1055/s-2001-14606

LETTER
803
Palladium-Catalysed Synthesis of Enantiopure 1,2,4,5-Tetrahydro-1,4-
benzodiazepin-3-(3H)-one Derivatives
Marta Catellani,a Claudio Catucci,b Giuseppe Celentano,c Raffaella Ferracciolib,*
aDipartimento di Chimica Organica e Industriale, Parco Area delle Scienze 17/A, I-43100 Parma, Italy
bCNR-Centro di Studio sulla Sintesi e Stereochimica di Speciali Sistemi Organici, Via Golgi 19, I-20133 Milano, Italy
cIstituto di Chimica Organica, Facoltà di Farmacia, Via Venezian 21, I-20133 Milano, Italy
Fax +39 (0)2 70636857; E-mail: rferra@icil64.cilea.it
Received 13 March 2001
moval of the N-Boc protecting group with trifluoroacetic
acid. The synthetic approach for ring construction is based
on the recently developed palladium-catalysed carbon-ni-
trogen bond formation methodology.1d,f After initial ex-
Abstract: A convenient procedure for the preparation of 1,2,4,5-
tetrahydro-1,4-benzodiazepin-3-(3H)-one derivatives (S)-2 from
chiral -substituted N-n-butyl-N-(o-iodobenzyl)glycinamides (S)-1
has been developed. Seven-membered ring formation occurs
through an intramolecular N-arylation catalysed by palladium and perimentation carried out with 1a (R1 = Me), we
bis(phosphine) ligands. The use of chelating bis(phosphines) allows
succeeded in obtaining 2a through seven-membered ring
to minimize or entirely suppress carbon-2 racemisation which oc-
formation with fair yields and excellent ee using
curs when a mono(phosphine) ligand is used.
Pd2(dba)3CHCl3 and bidentate phosphine ligands6 as a
catalyst, t-BuOK or Cs2CO3 as a base in toluene at 85 °C7
Key words: benzodiazepines, intramolecular N-arylations, palladi-
um, bis(phosphine) ligands, chirality
(Table, entries 1-6).
Table Palladium-Catalysed Cyclisation of 1 to 2a
Palladium-catalysed coupling chemistry leading to new
carbon-carbon, carbon-nitrogen and carbon-oxygen bond
formation from aryl halides and triflates is a powerful syn-
thetic method for the construction of carbocycles and het-
erocycles.1
In the framework of our synthetic activity in the field of
benzazepine and benzodiazepine derivatives2 we have be-
come interested in the synthesis of 2-substituted optically
active 1,2,4,5-tetrahydro-1,4-benzodiazepin-3(3H)-ones.
The 1,4-benzodiazepine nucleus bearing a C-2 chiral car-
bon with S-configuration is present in pharmacologically
active compounds.3,4 The synthetic procedures used to
build the seven-membered ring of the above mentioned
system are not without drawbacks such as low yields and
selectivities3 or carbon-2 racemisation.4
Here, we report the synthesis of model compounds of this
class, (S)-1,2,4,5-tetrahydro-1,4-benzodiazepin-3(3H)-
one derivatives 2 from the (S)-amides 1 as precursors
(Scheme 1).
aUnless otherwise indicated all reactions were run with
Pd2(dba)3CHCl3 (10 mol%) and chelating phosphine (molar ratio 1:1)
as catalyst and were not further optimised. bFor complete conversion
Scheme 1 1a R1 = Me; 1b R1 = Bn; 1c R1 = Ph; 1d R1 = CH2CO2Bn
of 1. cIsolated yield. dDetermined by chiral HPLC (Chiralcel OF; he-
xane/i-PrOH 8/2) on the isolated products. eThe reported results were
obtained with (R)-BINAP, unless otherwise noted. fAfter 8 h the 1/2
Compounds 15 are readily prepared by DCC coupling of ratio was about 3/7, by H NMR quantitative analysis of the crude.
1
gPd(Ph3)4 (10 mol%) was used as catalyst. hThe results in parentheses
N-n-butyl-N-(o-iodobenzyl)amine2c with the appropriate
N-tert-butoxycarbonyl-L-aminoacids and subsequent re-
were obtained with (S)-BINAP.
Synlett 2001 No. 6, 803–805 ISSN 0936-5214 © Thieme Stuttgart · New York

804
M. Catellani et al.
LETTER
BINAP and the less expensive bis(phosphines) DPPP, NAP as ligand turned out to be more effective than (R)-
DPPB, DPPF gave satisfactory results in terms of yield BINAP. It may be due to the fact that the two diastereoi-
and ee, while a small bite-angle phosphine like DPPE, al- someric amidopalladacycle intermediates undergo race-
beit preventing racemisation, gave compound 2a with low misation at different rates. The palladium-catalysed
yield and selectivity (entry 6).
cyclisation of 1d (R1 = CH2CO2Bn) led to the 1,4-benzo-
diazepine derivative 2d which is a key-intermediate in the
synthesis of pharmacologically active compounds.3,4 Ring
formation occurred with very high selectivity and enan-
tiopurity in the presence of BINAP as ligand and Cs2CO3
as a base (entry 13), while worse yield and ee were ob-
tained with DPPP (entry 14).
In the presence of a monodentate phosphine ligand8
(Ph3P) the cyclisation of 1a proceeded with partial race-
misation and compound 2a was obtained with low enanti-
omeric purity (entry 7). Since the (S)-precursor 1a did not
undergo base-catalysed racemisation9 after heating at
85 °C in toluene in the presence of t-BuOK, the erosion of
the enantiopurity must proceed through palladium-coordi- In conclusion, we have shown that 2-substituted optically
nated intermediates. Palladium-mediated racemisation of active 1,2,4,5-tetrahydro-1,4-benzodiazepin-3(3H)-ones
the coupled products obtained in the intermolecular can be synthesised through a stereospecific intramolecu-
N-arylation of enantiomerically pure -substituted amines lar palladium-catalysed N-arylation with bis(phosphine)
catalysed by palladium and mono(phosphine) ligand was ligands.
observed by Buchwald.10 The racemisation pathway is
triggered by -hydrogen elimination from a Pd-amido
Acknowledgement
complex leading to a Pd-coordinated imine intermedi-
ate.10
We thank National Research Council (CNR) and Ministero Univer-
sità e Ricerca Scientifica for financial support.
Intramolecular palladium-catalysed N-arylation of enanti-
omerically pure -substituted amines with mono(phos-
References and Notes
phine) ligands leading to small rings (five-membered) is
reported to proceed without loss of enantiopurity.10,11 Our
results show that the palladacyclic precursor of the seven-
membered ring displays a tendency to racemisation com-
parable to that occurring in intermolecular N-arylation. As
previously reported10 chelating bis(phosphine) ligands
suppress the racemisation pathway thus allowing the in-
termediate amidopalladacycle to undergo reductive C-N
coupling to compound 2a with retention of the stere-
ochemistry (Scheme 2, L2 = bidentate phosphines).
(1) For reviews, see: (a) de Meijere A.; Meyer F. Angew. Chem.
Int. Ed. Engl. 1994, 34, 2379. (b) Cabri W.; Candiani I. Acc.
Chem. Res. 1995, 28, 2. (c) Negishi E.; Copèret C.; Ma S.;
Liou S. Y.; Liu F. Chem. Rev. 1996, 96, 365. (d) Hartwig J. F.
Angew. Chem. Int. Ed. 1998, 37, 2046. (e) Larock R. C. J.
Organomet. Chem. 1999, 576, 111. (f) Yang B. H.; Buchwald
S. L. J. Organomet. Chem. 1999, 576, 125.
(2) (a) Bocelli G.; Catellani M.; Chiusoli G. P.; Cugini F.; Lasagni
B.; Neri Mari M. Inorg. Chim. Acta 1998, 270, 123. (b) Tietze
L. F.; Ferraccioli R. Synlett 1998, 145. (c) Bocelli G.;
Catellani M.; Cugini F.; Ferraccioli R. Tetrahedron Lett.
1999, 40, 2623.
(3) Miller W. H.; Ku T. W.; Ali F. E.; Bondinell W. E.; Calvo R.
R.; D. L. Davis; Erhard K. F.; Hall L. B.; Huffman W. F.;
Keenan R. M.; Kwon C.; Newlander K. A.; Ross S. T.;
Samanen J. M.; Takata D. T.; Yuan C. Tetrahedron Lett. 1995,
36, 9433.
(4) Hayes J. F. Synlett 1999, 865.
(5) Selected data for compounds 1:
(S)-1a: oil; [ ]D21 -7° (c = 2.2, CHCl3); IR (nujol) 3364, 1650
cm-1; 1H NMR (CDCl3-D2O) (1:1 rotameric mixture): 0.91
(t, 3H, J = 7.3 Hz), 1.2-1.36 (m, 5H), 1.52-1.61 (m, 2H), 3.07-
3.3 (m, 1.5H), 3.52-3.64 (m, 1H), 3.86 (quartet, 0.5 H, J = 6.7
Hz), 4.36-4.5 (m, 1.5H), 4.85 (d, 0.5H, J = 15.7 Hz), 6.9-7.1
(m, 2H), 7.26-7.4 (m, 1H), 7.8-7.87 (m, 1H); 13C NMR
(CDCl3): 13.7, 13.8 (CH3), 20.0, 20.1 (CH2), 21.9, 22.0
(CH3), 29.6, 31.2, 46.5, 46.8 (CH2), 46.9, 47.1 (CH), 53.3,
56.0 (CH2), 97.5, 98.9 (C), 126.5, 128.0, 128.5, 128.7,
128.9,129.3 (CH), 138.6 (C); 139.5, 139.8 (CH), 176.5, 179.9
(C); MS (EI): 360 (M+), 317, 217, 190.
Scheme 2
To further investigate the scope of this method we studied
the palladium-catalysed cyclisation of 1b-d, with DPPP
and BINAP as ligands. Ring formation from 1b (R1 = Bn)
proceeded in good yield and very high ee with both
ligands (entries 8-10). With the more sterically hindered
substrate 1c (R1 = Ph) the only ligand leading to satisfac-
tory yields was BINAP (entries 11, 12). However, with
t-BuOK as a base racemisation occurred to a large extent
(entry 11), the higher acidity of the proton involved
favouring base catalysis. Accordingly, when 1c and
t-BuOK were heated in toluene at 85 °C almost complete
racemisation of the substrate took place.9 Performing the
reaction in the presence of the less basic Cs2CO3, which
did not cause any racemisation of 1c, led to 2c with im-
proved ee (entry 12). As far as the ee is concerned, (S)-BI-
(S)-1b: oil; [ ]D21+24° (c = 0.3, CHCl3); IR (nujol) 3377,
3307, 1641 cm-1; 1H NMR (CDCl3-D2O, ca. 1:1 rotameric
mixture): 0.78-0.86 (m, 3H), 1.1-1.25 (m, 2H), 1.3-1.45 (m,
2H), 2.69-3.1 (m, 3.5H), 3.5-3.6 (m, 1H), 3.9-4.2 (m, 1.5H),
4.35 (d, 0.5H, J = 16 Hz), 4.7 (d, 0.5H, J = 16 Hz), 6.8-6.9 (m,
2H), 7.1-7.2 (m, 6H), 7.7-7.6 (m, 1H); 13C NMR (CDCl3):
13.7, 13.9 (CH3), 20.0, 20.2, 29.6, 31.1, 42.9, 43.0, 47.0
(CH2), 53.1, 53.5 (CH), 53.6, 56.0 (CH2), 97.3, 98.9 (C),
126.5, 126.8, 128.2, 128.5, 128.6, 128.8, 128.9, 129.3, 129.4
(CH), 137.6, 137.8, 138.6, 139.2 (C), 139.4, 139.7 (CH),
Synlett 2001, No. 6, 803–805 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
1,2,4,5-Tetrahydro-1,4-benzodiazepin-3-(3H)-one Derivatives
805
175.0, 175.4 (C); MS (EI): 437 (M+1), 345, 290, 217, 120.
6.47-6.5 (m, 1H), 6.59-6.64 (m, 1H), 6.89-6.92 (m 1H), 7.0-
7.1 (m, 1H); 13C NMR (CDCl3): 14.2, 17.7 (CH3), 20.4, 30.8,
47.6 (CH2), 50.3 (CH), 52.2 (CH2), 116.8, 118.0 (CH), 120.1
(C), 129.3, 129.7 (CH), 146.0, 171.1 (C); MS (EI): 232 (M+,
100); C14H20N2O: calcd. C 72.38, H 8.68, N 12.06; found C
72.65, H 8.51, N 12.17.
(S)-1c: oil; [ ]D21+45° (c = 0.53, CH2Cl2); IR (nujol) 3371,
3299, 1651 cm-1; 1H NMR (CDCl3-D2O, ca. 1:1 rotameric
mixture): 0.8-0.9 (m, 3H), 1.1-1.5 (m, 4H), 2.9-3.05 (m, 1H),
3.1-3.2 (m, 0.5H), 3.65-3.7 (m, 0.5H), 4.1 (d, 0.5H, J = 18
Hz), 4.4-4.5 (m, 1.5H), 4.75 (d, 0.5H, J = 16 Hz), 5.0 (s, 0.5
H), 6.9-7.0 (m, 2H), 7.15-7.43 (m, 6H), 7.76-7.8 (m, 1H); 13
NMR (CDCl3): 13.7, 13.8 (CH3), 20.0, 20.1, 29.4, 30.5,
C
(S)-2b: oil; [ ]D 109° (c = 0.17, CH2Cl2); IR (nujol) 3328,
21
1645 cm-1; 1H NMR (CDCl3-D2O): 0.85 (t, 3H, J = 7.3 Hz),
1.21-1.29 (m, 2H), 1.4-1.54 (m, 2H), 2.9 (dd, 1H, J = 14, 9
Hz), 3.35-3.62 (m, 3H), 3.78 (d, 1H, J = 16.5 Hz), 4.83 (dd,
1H, J = 9, 5.2 Hz), 5.3 (d, 1H, J = 16.5 Hz), 6.4-6.43 (m, 1H),
6.59-6.64 (m, 1H), 6.9-6.91 (m, 1H), 6.98-7.04 (m, 1H), 7.2-
7.35 (m, 5H); 13C NMR (CDCl3): 13.8 (CH3), 20.0, 30.4,
37.5, 47.5, 51.7 (CH2), 55.8 (CH), 116.8, 118.0 (CH), 120.2
(C), 126.7, 128.7, 128.9, 129.2, 129.3 (CH), 137.7, 145.5,
170.1 (C); MS (EI): 308 (M+), 217, 189, 118; C20H24N2O:
calcd. C 77.89, H 7.84, N 9.08; found C 78.04, H 7.64, N 9.20.
(S)-2c: oil; [ ]D21+8° (c = 0.21, CH2Cl2); IR (nujol) 3326,
1637 cm-1; 1H NMR (CDCl3-D2O): 0.79 (t, 3H, J = 7.3 Hz),
1.1-1.24 (m, 2H), 1.37-1.48 (m, 2H), 3.3-3.5 (m, 2H), 3.87 (d,
1H, J = 16.2Hz), 4.18 (d, 1H, J = 16.2 Hz), 5.3 (s, 1H), 6.56-
6.62 (m, 2H), 6.79-6.82 (m, 1H), 7.0-7.08 (m, 1H), 7.2-7.4 (m,
5H); 13C NMR (CDCl3): 13.8 (CH3), 20.0, 30.1, 47.8, 50.4
(CH2), 63.4, 116.6, 117.8 (CH), 120.1 (C), 125.8, 127.7,
128.8, 129.0, 129.2 (CH), 139.7, 144.9, 169.4 (C); MS (EI):
294 (M+), 195, 118; C19H22N2O: C 77.52, H 7.53, N 9.52;
46.7, 47.0, 53.6, 55.8 (CH2), 57.0, 57.2 (CH), 97.3, 98.7 (C),
126.6, 127.1, 127.2, 127.8, 128.0, 128.1, 128.4, 128.7, 128.9,
129.1, 129.2 (CH), 138.2, 139.2 (C), 139.4, 139.6 (CH),
141.1, 141.4, 173.0, 173.3 (C); MS (EI): 422 (M+), 317, 288,
246.
21
(S)-1d: oil; [ ]D 6° (c = 1.0, CH2Cl2); IR (nujol) 3362,
1730, 1626 cm-1; 1H NMR (CDCl3-D2O, ca. 1:1 rotameric
mixture): 0.89 (t 3H, J = 7.3 Hz), 1.25-1.34 (m, 2H), 1.47-
1.62 (m, 2H), 2.5-2.9 (m, 2H), 3.16-3.5 (m, 2H), 3.9 (br t,
0.5H, J = 6.7 Hz), 4.2 (br t, 0.5H, J = 6.6 Hz), 4.47-4.61 (m,
1.5H), 4.73 (d, 0.5H, J = 15.7 Hz), 5.1-5.18 (m, 2H), 6.9-7.0
(m, 1H), 7.1-7.12 (m, 1H), 7.24-7.36 (m, 6H), 7.8-7.86 (m,
1H); 13C NMR (CDCl3): 13.8, 13.9 (CH3), 20.0, 20.1, 29.5,
31.2, 40.7, 40.8, 46.7, 47.2 (CH2), 48.3, 48.6 (CH), 53.6, 56.2,
66.4, 66.6 (CH2), 97.7, 98.8 (C), 126.8, 128.1, 128.2, 128.3,
128.6, 128.7, 129.0, 129.3 (CH), 135.6, 138.6, 139.2 (C),
139.5, 139.8 (CH), 171.1, 171.2, 174.0, 174.2 (C); MS (EI):
495 (M+1), 217, 178.
(6) Bis(phosphine) ligands used: (R)- and (S)-2,2’-
bis(diphenylphosphino)-1,1’-binaphtyl [(R)- and (S)-BINAP],
1,2-bis(diphenylphosphino)ethane (DPPE), 1,3-
found C 77.73, H 7.68, N 9.60.
21
(S)-2d: oil; [ ]D
117° (c = 0.37, CH2Cl2); IR (nujol) 3309,
J = 7.3
1733, 1646 cm-1; 1H NMR (CDCl3-D2O): 0.84 t
bis(diphenylphosphino)propane (DPPP), 1,4-
bis(diphenylphosphino)butane (DPPB), 1,1’-bis(di
phenylphosphino)ferrocene (DPPF).
Hz), 1.18-1.29 (m, 2H), 1.42-1.52 (m, 2H), 2.69 (dd, 1H,
J = 16, 6.8 Hz), 3.04 (dd, 1H, J = 16, 6.6 Hz), 3.4-3.55 (m,
2H), 3.78 (d, 1H, J = 16 Hz), 5.0 (t, 1H, J = 6.7 Hz), 5.15 (d,
1H, J = 12 Hz), 5.18 (d, 1H, J = 12 Hz), 5.34 (d, 1H, J = 16
Hz), 6.5-6.54 (m, 1H), 6.64-6.69 (m, 1H), 6.90-6.94 (m, 1H),
7.04-7.09 (m, 1H), 7.3-7.4 (m, 5H); 13C NMR (CDCl3): 13.8
(CH3), 19.9, 30.4, 36.2, 47.4, 51.7 (CH2), 52.0 (CH), 66.7
(CH2), 117.5, 118.7 (CH), 120.6(C), 128.2, 128.3, 128.6,
129.0, 129.4 (CH), 135.7, 145.2, 169.4, 171.3 (C); MS (EI):
366 (M+), 275, 130, 118; C22H26N2O3: calcd. C 72.11, H 7.15,
N 7.64; found C 72.3, H 7.26, N 7.72.
(7) General procedure for the synthesis of (S)-1,2,4,5-
tetrahydro-1,4-benzodiazepin-3(3H)-ones 2. A Schlenk-
type flask was charged under nitrogen with Pd2(dba)3CHCl3
(13.4 mg, 0.013 mmol, 10 mol% Pd), bis(phosphine) ligand
(0.026 mmol) and toluene (10 mL) and the resulting mixture
was stirred at r.t. for 20 min. Then, the solution of compound
1 (0.26 mmol) in toluene (10 mL) and the desired base
(t-BuOK, 0.29 mmol, or Cs2CO3, 0.52 mmol) were added. The
mixture was heated under stirring at 85 °C until the starting
material completely disappeared as evidenced by TLC
(EtOAc/MeOH 9/1). The reaction mixture was cooled to r.t.
and partitioned between Et2O (16 mL) and water (10 mL). The
aqueous layer was extracted with Et2O (2 6 mL) and the
combined organic phase was dried over Na2SO4, filtered and
concentrated. Purification of the crude by flash
(8) The reaction of 1a with Pd2(dba)3/(o-tolyl)3P as a catalyst
gave poor conversion of the substrate.
(9) The enantiomeric purity of compounds 1 was determined by
chiral HPLC (Chiralcel OD, hexane/i-PrOH/diethylamine 70/
30/0.2).
(10) Wagaw S.; Rennels R. A.; Buchwald S. L. J. Am. Chem. Soc.
1997, 119, 8451.
chromatography on silicagel (petroleum ether/EtOAc 7/3)
afforded the title compounds.
(11) He F.; Foxman B. M.; Snider B. B. J. Am. Chem. Soc. 1998,
120, 6417.
21
(S)-2a: mp 79-80 °C (hexane); [ ]D 98° (c = 0.19, CH2Cl2);
IR (nujol) 3343, 1644 cm-1; 1H NMR (CDCl3-D2O): 0.87 (t,
3H, J = 7.3 Hz), 1.20-1.33 (m, 2H), 1.41 (d, 3H, J = 6.5 Hz),
1.46-1.55 (m, 2H), 3.45-3.5 (m, 2H), 3.76 (d, 1H, J = 16.4
Hz), 4.75 (quartet, 1H, J = 6.5 Hz), 5.36 (d, 1H, J = 16.4 Hz),
Article Identifier:
1437-2096,E;2001,0,06,0803,0805,ftx,en;G04501ST.pdf
Synlett 2001, No. 6, 803–805 ISSN 0936-5214 © Thieme Stuttgart · New York