Synthesis and structural analysis of tetra- and pentacyclic lactams derived from regioisomeric tetrahydroisoquinoline diamines

Journal of Molecular Structure 983 (2010) 62–72

Contents lists available at ScienceDirect

Journal of Molecular Structure journal homepage: www.elsevier.com/locate/molstruc

Synthesis and structural analysis of tetra- and pentacyclic lactams derived from regioisomeric tetrahydroisoquinoline diamines Henri Kivelä a,⇑, Petri Tähtinen a, Olli Martiskainen a, Kalevi Pihlaja a,⇑⇑, László Lázár b, Edina Vigóczki b, Ferenc Fülöp b,c a b c

Department of Chemistry, Structural Chemistry Group, University of Turku, FI-20014 Turku, Finland Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary Research Group for Stereochemistry, Hungarian Academy of Sciences, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary

a r t i c l e

i n f o

Article history: Received 14 June 2010 Received in revised form 13 August 2010 Accepted 17 August 2010 Available online 21 August 2010 Keywords: Lactams Domino reactions Diastereoselectivity NMR spectroscopy Mass spectrometry

a b s t r a c t By means of the domino ring-closure reactions of 1-(aminomethyl)- and 3-(aminomethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline with acyclic and aromatic c- or d-oxo acids, angularly or linearly condensed tetra- and pentacyclic lactam derivatives were formed with moderate to excellent diastereoselectivities. NMR analysis indicated that the cis diastereomer (a) was the main or the only product in each case, depending on the nature of the starting oxo acid used. The angularly-condensed cis diastereomers were observed to populate two types of conformations in CDCl3 solution, the preferred conformation being determined by the substitution on the lactam ring. These conformers are related by ring inversion of the approximately half-chair-like tetrahydropyridine ring, combined with a pyramidal inversion of its nitrogen atom. For the other combinations of regio- and diastereochemistry, the preferred conformation was not strongly influenced by the lactam substitution within the subset. The linear and angular structural isomers gave fragment ions that were useful for distinguishing between isomers, but with diastereomers the differences were not so clear. Ó 2010 Elsevier B.V. All rights reserved.

1. Introduction The cyclocondensation of 1,2- and 1,3-amino alcohols, amino thiols or diamines (1) with c- and d-oxo acids or esters (2) is a well-established method for the preparation of 1,3-heterocyclefused c- or d-lactams with a nitrogen at the annelation (4) (Scheme 1) [1]. The reaction is classified as a domino process, since it presumably occurs in two steps: first a ring–chain tautomeric intermediate (3A–3B) is formed, the equilibrium of which gradually shifts towards the cyclic form 3B in consequence of the practically irreversible intramolecular N-acylation [2,3]. When the starting material contains asymmetric carbon(s), the stereochemical outcome of the lactam formation is controlled kinetically by the rates of N-acylation of the diastereomeric cyclic tautomers, the difference of which is usually sufficient to result in appreciably selective formation of the major isomer [4]. Because of the highly stereoselective availability and the extensive possibilities for further transformations, c- or d-lactam derivatives of chiral non-racemic amino alcohols (mainly phenylglycinol) are often applied as intermediates in various asymmetric processes which allow introduction of ⇑ Corresponding author. Tel.: +358 2 333 6754; fax: +358 2 333 6700. ⇑⇑ Corresponding author. Tel.: +358 2 333 6754; fax: +358 2 333 6700. E-mail addresses: hemiki@utu.fi (H. Kivelä), kpihlaja@utu.fi (K. Pihlaja). 0022-2860/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.molstruc.2010.08.031

the substituents at the different ring positions in a regio- and stereocontrolled manner [5,6]. We recently described the domino ring-closures of 1-(2-aminoethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline with c-oxo acids, whereby 8,13-diazaoestrone derivatives were obtained with 100% de values [7]. As a continuation of this work and in connection with our previous studies on the synthesis and structural analysis of tetrahydroisoquinoline-condensed saturated heterocycles [8], we now report on the reactions of regioisomeric tetrahydroisoquinoline 1,2-diamines with c- and d-oxo acids. Our aim was to investigate the effects of the regioisomeric structures, the substituents and the size of the lactam rings formed on the stereochemical outcome of the reactions, and the conformational and mass spectral behaviour of the tetra- and pentacyclic products.

2. Results and discussion 2.1. Synthesis 1-(Aminomethyl)- and 3-(aminomethyl)-substituted 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (7 and 10) were prepared in conventional two-step procedures, starting from the regioisomeric tetrahydroisoquinoline a-amino esters [9,10] (5 and 8). 5 and 8

H. Kivelä et al. / Journal of Molecular Structure 983 (2010) 62–72

R1OOC

1 NH2 R OOC + O XH R2

1

N XH 3A

2

R2

O

R1OOC NH

N

2 X R

2 X R 4

3B

1

X = O, S, NR; R = H, alkyl; R2 = H, alkyl, aryl Scheme 1. A general scheme for the preparation of 1,3-heterocycle-fused lactams.

were converted to the corresponding carboxamides 6 and 9, LiAlH4 reduction of which resulted in diamines 7 and 10 (Scheme 2). When tetrahydroisoquinoline diamines 7 and 10 were boiled in toluene with 4-oxopentanoic acid, 3-benzoylpropanoic acid, 5-oxohexanoic acid, 4-benzoylbutanoic acid, 2-formylbenzoic acid, 2-acetylbenzoic acid or 2-benzoylbenzoic acid, cyclocondensations generally took place within 2–10 h to furnish the corresponding tetra- and pentacyclic lactams 11–23 (Schemes 3 and 4). The reaction of 7 and 2-formylbenzoic acid led to a complex product mixture and all of our efforts to isolate its components failed. NMR spectra of the crude products 11–23 indicated that 12–14, 16, 17, 19 and 21 underwent cyclization with practically full diastereoselectivities (de 100%), affording compounds containing hydrogen at the annelation of the tetrahydroisoquinoline and imidazolidine rings (10b-H for 12; 11b-H for 13, 14 and 16; 5a-H for 17; 6a-H for 19; and 7a-H for 21) and substituent R in the cis position (a) as the only isomers. In the other cases, a mixture of the cis (a) and trans (b) diastereomers was obtained, which contained the cis isomer as the main component (de 30–90%). Both diastereomers of 11, 15, 18, 22 and 23 could be isolated by means of chromatographic separation. Assuming the reaction occurs via a ring–chain tautomeric intermediate as depicted in Scheme 1, the new stereocentre is formed upon the ring-closure of 3A into 3B, yielding cis-3B and trans-3B. These intermediates then undergo a second ring-closure which leads to the final lactams cis-4 and trans-4, respectively. Thus the cis-stereoselectivity can be explained either by a preferred formation of cis-3B in the tautomeric process or by its faster intramolecular N-acylation into products in comparison to trans-3B, or both. Based on the TLC analyses each domino ring-closure reaction proceeded practically to a complete conversion, without application of any extra acidic catalyst (maybe the acidity of the applied oxo acids was enough to cause some catalytic effect) or a water trap. Neither the starting diamines nor any side products could essentially be found in the crude ring-closed products. The yields in the manuscript are referring to diastereomerically pure and recrystallized products and their relatively low values originate only from the purification processes. The recrystallization

MeO

i

NH

MeO O 5

MeO MeO

OEt

O 6

O

MeO

NH

MeO 8

OEt

NH

i

MeO

ii

NH

MeO

NH2

7

NH2

O

MeO

NH

MeO

NH2 ii

9

MeO NH

MeO

NH2

10 Scheme 2. Reagents and conditions: (i) NH3, MeOH, r.t., 10 days, 76–84%; (ii) LiAlH4, THF, reflux, 3 h, 78–82%.

63

processes of the tetra- and pentacyclic products were not very effective and substantial amounts of compounds were lost during the recrystallizations. Also, the chromatographic separation of the diastereomers resulted in a considerable loss of the product(s) since only the separated pure diastereomers were taken into account when estimating the yield; the chromatographic fractions containing a mixture of diastereomers were disregarded. It should also be noted that in the ring-closure reactions, where two diastereomers were formed, the total yield is the sum of the yields of the two diastereomers.

3. Structure 3.1. NMR results The solution structures of compounds 11–23 were determined by 1H and 13C NMR spectroscopy in CDCl3 solution. The spectra were observed to be very sensitive to acidic contaminants, the presence of which led to severe exchange-broadening of the spectral lines due to protonation/deprotonation of the amine-type nitrogen in the tetrahydropyridine ring (Fig. 1). Particularly the acidic oxidation products present in aged chloroform [11] were enough to cause this line broadening, making it necessary either to use fresh or ampoule-stored solvent, or to neutralize the acidity (here, Na2CO3 treatment was applied). The 1H and 13C chemical shifts of the products 11–23 (Tables 1, 3, 4 and 6) could be assigned with the help of the standard 2D NMR correlation spectra (dqf-COSY, NOESY, multiplicity-edited HSQC and HMBC), except for an occasional ambiguity in the event of nearly isochronous chemical shifts. The bridgehead CH group (11 and 12: 10b, 13–16: 11b, 17 and 18: 5a, 19 and 20: 6a, 21–23: 7a) was readily identified in the multiplicity-edited HSQC spectra due to the opposite phase of its C,H-correlation signal with respect to the signals of the CH2 groups. Consequently, the ArCHCH2N (11– 16) or ArCH2CHCH2N (17–23) fragments could be assigned through COSY and HSQC. For the latter fragment, the CH2N methylene could be distinguished from that bound to the aromatic ring (e.g. C5H2 from C6H2 for 17a) on the basis of the deshielding effect of nitrogen on the carbon chemical shift, the NOE correlation between the ArCH2 and the aromatic CH proton (e.g. the NOEs 6-Hs/a M 7H for 17a), and the large negative coupling constant 2JH,H of the ArCH2 protons (cf. Table 5). The above-mentioned NOEs for 17– 23, and analogous NOEs for 11–16 (e.g. the NOEs 10-H M 11-Hs/a for 11a), also enabled the distinction between the two aromatic CH proton singlets of the dimethoxybenzene moiety (e.g. 7-H and 10-H for 11a). The NOE correlations of these protons could then be used to assign the two OCH3 proton singlets, whenever their chemical shifts were distinct enough (e.g. 10-H M 9-OCH3 for 11a), as well as the remaining CH2CH2N (11–16) or CH2N (17–23) fragments in the isoquinoline moiety (e.g. 6-Hs/a M 7-H for 11a). The latter type of fragment was also readily assigned by virtue of the doublet structure of its proton signals. Here, and later, the subscripts s and a refer to syn and anti positions relative to the bridgehead hydrogen at the B/C-ring fusion (e.g. 10b-H in case of 11a, cf. Figs. 2 and 3). The assignment of the (CH2)2–3 or (CH)4 spin system at the terminal lactam or benzene ring, respectively, required the neighbouring group of either end to be determined: for a lactam ring, the CH2 group bound to the carbonyl was identified via its large negative geminal H,H-coupling constant (between 16.2 and 18.5 Hz, cf. Tables 2 and 5), whilst the CH2 group at the other end could often be independently assigned through the NOE correlations with the substituent R. For a terminal benzene ring, 1H (15 and 16) or 4-H (21–23) could be assigned as a consequence of its being deshielded by the carbonyl and also being involved in an HMBC correlation with its carbon. The quaternary carbons were

64

H. Kivelä et al. / Journal of Molecular Structure 983 (2010) 62–72

MeO MeO

10

7

4

N R

MeO

N

11

ii

MeO

NH2

8

9

1

11

iii

H

MeO

8

9

5

N R

10

H

13

H

N

2

1

13b,14b O MeO

6 5

N R

4

N

MeO

2

13

O

15a,16a

+

3

4b

12

O

N R

MeO

+

3

N

12

11b 11

4

4a

7

N

MeO

6

13a,14a O MeO

H 11b,12b

O

7

N R

MeO

+

2

12

11b

10

3

3a

11a,12a

MeO NH

H

MeO

5

10b

9

i

MeO

6

7

8

N R H

N

1

14

15b, 16b

Compounds

R

Diastereomeric ratio in the crude product

11a : 11b 12a : 12b 13a : 13b 14a : 14b 15a : 15b 16a : 16b

Me Ph Me Ph Me Ph

95 : 5 ~100 : ~0 ~100 : ~0 ~100 : ~0 68 : 32 ~100 : ~0

O

Scheme 3. Reagents and conditions: (i) RCO(CH2)2COOH, toluene, reflux, 6 h, 2–36%; (ii) RCO(CH2)3COOH, toluene, reflux, 6 h, 37–42%; (iii) 2-RCOC6H4COOH, toluene, reflux, 2–3 h, 8–30%.

MeO

8

MeO

9

NH

MeO

NH2

ii

5 4

5a 12

N

N

10

i

MeO

H

6

7

11

12a

R

O 3

MeO

+

2

1

MeO

17a,18a

MeO MeO

9

10

8

H

7

6

10

N

10

MeO

11 12

H

8

9

MeO

1

3

+

N

N

MeO

2

6

N

O

R

14a

2

MeO

O 5 4

1

H N

N

O

R 19b,20b

R

21a – 23a

MeO

7

7a 14 13

4

13a

19a,20a

iii

O

5

N R

12

N 17b,18b

6a 13 11

H

+

3

Compounds

R

Diastereomeric ratio in the crude product

17a : 17b 18a : 18b 19a : 19b 20a : 20b 21a : 21b 22a : 22b 23a : 23b

Me Ph Me Ph H Me Ph

~100 : ~0 84 : 16 ~100 : ~0 91 : 9 ~100 : ~0 70 : 30 65 : 35

MeO

H N

N

O

R 21b – 23b

Scheme 4. Reagents and conditions: (i) R1CO(CH2)2COOH, toluene, reflux, 4–6 h, 8–28%; (ii) RCO(CH2)3COOH, toluene, reflux, 6–7 h, 25–38%; (iii) 2-RCOC6H4COOH, toluene, reflux, 4–12 h, 12–46%.

65

H. Kivelä et al. / Journal of Molecular Structure 983 (2010) 62–72

MeO MeO

N Ph H

MeO

H+

NH Ph

MeO

H

N

N

O

5.0

4.5

4.0

3.5

O

3.0

2.5

2.0

ppm

Fig. 1. The effect of solvent acidity on the aliphatic region of the 1H NMR spectrum of 16a (in CDCl3 at 298 K). Top: exchange-broadening of resonances due to acidic solvent decomposition products present in old CDCl3. Bottom: sharp resonances in neutral solution (neutralized with Na2CO3).

Table 1 Proton chemical shifts (in CDCl3 at 298 K, dH(TMS) = 0 ppm) of 11–16. Proton

11a

11b

12a

Proton

13a

14a

Proton

15a

15b

16a

2s 2a 3s 3a 5s 5a 6s 6a 7 8-OMe 9-OMe 10 10b 11s 11a R(Me) R(o-Ph) R(m-Ph) R(p-Ph)

2.83 2.47 2.06 2.20 2.69 2.94 2.81 2.99 6.61 3.83 3.81 6.43 4.28 3.70 3.49 1.38 – – –

2.42 2.73 2.09 1.93 2.89 3.12 2.75 2.96 6.63 3.85 3.84 6.49 3.82 4.37 2.93 1.44 – – –

2.79 2.54 2.24 2.72 2.93 2.60 2.99 2.83 6.60 3.83 3.76 6.43 4.06 3.54 3.54 – 7.50 7.38 7.31

2s 2a 3s 3a 4s 4a 6s 6a 7s 7a 8 9-OMe 10-OMe 11 11b 12s 12a R(Me) R(o-Ph) R(m-Ph) R(p-Ph)

2.52 2.37 1.94 1.98 2.09 1.62 2.76 3.01 2.85 3.04 6.63 3.85 3.84 6.52 4.14 4.02 3.57 1.31 – – –

2.48 2.39 1.44 1.79 2.31 2.07 3.02 2.82 2.99 2.85 6.59 3.82 3.76 6.39 3.82 3.88 3.62 – 7.37 7.37 7.31

1 2 3 4 6s 6a 7s 7a 8 9-OMe 10-OMe 11 11b 12s 12a R(Me) R(o-Ph) R(m-Ph) R(p-Ph)

7.80 7.52 7.63 7.57 2.41 1.99 2.87 2.49 6.56 3.83 3.87 6.56 5.06 3.78 3.61 1.81 – – –

7.84 7.50 7.61 7.53 2.86 3.51 2.75 3.06 6.64 3.85 3.85 6.50 3.95 4.64 3.27 1.67 – – –

7.82 7.46 7.48 7.30 2.49 2.02 3.03 2.53 6.60 3.83 3.78 6.42 4.57 3.60 3.65 – 7.77 7.36 7.31

Table 2 Proton–proton coupling constants (in CDCl3 at 298 K, in Hz) of 11–16. H,1H

a

1

11a

11b

12a

1

13a

14a

1

15a

15b

16a

2s,2a 2s,3s 2s,3a 2a,3s 2a,3a 3s,3a 5s,5a 5s,6s 5s,6a 5a,6s 5a,6a 6s,6a 10b,11s 10b,11a 11s,11a

17.0 9.4 10.5 2.3 10.1 12.6 10.7 4.8 10.2 2.8 6.7 16.1 7.7 9.6 10.0

16.6 9.0 1.7 11.5 8.1 12.2 11.6 4.5 10.0 3.1 6.2 15.8 5.8 9.2 10.6

17.3 10.1 7.7 4.4 10.2 13.8 10.2 4.9 4.8 8.8 4.2 15.9 8.3a 9.0a 9.5a

2s,2a 2s,3s 2s,3a 2a,3s 2a,3a 3s,3a 3s,4s 3s,4a 3a,4s 3a,4a 4s,4a 6s,6a 6s,7s 6s,7a 6a,7s 6a,7a 7s,7a 11b,12s 11b,12a 12s,12a

18.4 7.6 1.7 10.3 8.4 14.3 3.8 13.9 3.5 4.5 12.6 10.5 4.7 9.9 2.7 6.5 16.1 7.6 9.8 10.9

18.5 6.9 1.8 11.1 7.6 14.2 2.9 13.5 4.1 3.4 12.5 10.3 4.9 4.8 8.8 4.3 15.9 7.8 9.7 10.9

1,2 1,3 2,3 2,4 3,4 6s,6a 6s,7s 6s,7a 6a,7s 6a,7a 7s,7a 11b,12s 11b,12a 12s,12a

7.6 1.1 7.5 1.0 7.6 11.1 4.8 3.2 10.6 3.7 16.2 8.0 9.5 10.6

7.6 1.1 7.4 0.9 7.6 12.0 4.5 10.2 2.7 6.3 16.0 5.9 9.0 10.9

7.6 1.1 7.4 1.0 7.7 10.9 5.1 2.1 12.2 3.2 15.9 8.1 9.4 10.5

Uncertain due to signal overlap.

H,1H

H,1H

66

H. Kivelä et al. / Journal of Molecular Structure 983 (2010) 62–72

Table 3 Carbon chemical shifts (in CDCl3 at 298 K, dC(TMS) = 0 ppm) of 11–16. Carbon

11a

11b

12a

Carbon

13a

14a

Carbon

15a

15b

16a

1 2 3 3a 5 6 6a 7 8 8-OMe 9 9-OMe 10 10a 10b 11 R(Me) R(i-Ph) R(o-Ph) R(m-Ph) R(p-Ph)

176.99 33.44 33.33 84.72 41.75 29.02 125.60 111.62 147.85 55.90 147.42 55.95 107.79 128.19 61.23 46.56 18.42 – – – –

179.01 32.68 31.94 84.06 40.84 29.24 126.56 111.60 147.90 55.95a 147.55 56.01a 108.27 127.56 59.88 48.20 24.58 – – – –

177.61 33.02 30.50 91.75 41.08 28.93 125.38 111.11 147.79 55.86 147.59 55.90 108.62 126.83 60.74 47.23 – 142.71 125.45 128.45 127.77

1 2 3 4 4a 6 7 7a 8 9 9-OMe 10 10-OMe 11 11a 11b 12 R(Me) R(i-Ph) R(o-Ph) R(m-Ph) R(p-Ph)

169.12 30.14 17.51 33.87 78.61 42.31 29.15 125.69 111.64 147.91 56.01b 147.54 55.96b 108.15 128.09 56.55 48.76 17.93 – – – –

169.62 30.61 16.80 31.98 86.30 41.64 29.07 126.70 111.09 147.75 55.84 147.53 55.84 108.84 125.46 55.95 49.41 – 141.96 126.54 128.19 127.82

1 2 3 4 4a 4b 6 7 7a 8 9 9-OMe 10 10-OMe 11 11a 11b 12 14 14a R(Me) R(i-Ph) R(o-Ph) R(m-Ph) R(p-Ph)

124.34 129.59 132.49 123.00 146.23 89.62 42.98 28.70 125.46c 111.12 147.91 55.87 147.78 56.06 108.78 126.67c 63.06 46.81 171.78 133.76 23.49 – – – –

124.53 129.16 132.74 122.06 149.29 84.15 42.32 29.38 126.28d 111.57 147.88e 56.04f 147.62e 55.94f 108.09 128.20d 61.39 49.35 174.59 132.10 24.73 – – – –

124.52 129.63 132.66 124.48 145.68 94.74 42.43 29.01 126.70 111.37 148.04 56.08 147.89 56.15 109.13 125.80 63.79 46.68 172.36 133.39 – 140.84 126.04 129.00 128.49

a–f

Uncertain assignment, interchangeable with the chemical shift denoted by the same footnote letter.

Table 4 Proton chemical shifts (in CDCl3 at 298 K, dH(TMS) = 0 ppm) of 17–23.

a–c

Proton

17a

18a

18b

Proton

19a

20a

Proton

21a

22a

22b

23a

23b

1s 1a 2s 2a 5s 5a 5a 6s 6a 7 8-OMe 9-OMe 10 11s 11a R(Me) R(o-Ph) R(m-Ph) R(p-Ph)

2.02 2.18 2.79 2.52 3.47a 3.45a 3.21 2.92 2.73 6.61 3.85b 3.84b 6.58 3.63 3.80 1.35 – – –

2.65 2.58 2.71 2.56 3.77 3.64 2.91 2.90 2.80 6.55 3.81 3.81 6.53 3.15 3.89 – 7.30 7.42 7.34

2.41 2.54 2.43 2.63 4.33 2.97 2.94 2.85 2.71 6.58 3.84 3.83 6.57 3.97 3.97 – 7.52 7.37 7.31

1s 1a 2s 2a 3s 3a 6s 6a 6a 7s 7a 8 9-OMe 10-OMe 11 12s 12a R(Me) R(o-Ph) R(m-Ph) R(p-Ph)

2.12 1.58 1.89 1.95 2.51 2.37 3.70 3.52 3.10 2.97 2.70 6.62 3.85 3.85 6.58 3.68 3.81 1.25 – – –

2.91 1.77 1.42 1.82 2.33 2.40 4.05 3.65 2.74 2.94 2.74 6.55 3.82 3.82 6.53 3.17 3.88 – 7.21 7.41 7.33

1 2 3 4 7s 7a 7a 8s 8a 9 10-OMe 11-OMe 12 13s 13a R(H) R(Me) R(o-Ph) R(m-Ph) R(p-Ph)

7.60 7.59 7.53 7.83 3.76 3.55 3.30 2.97 2.81 6.59 3.84 3.85 6.61 3.82 4.29 4.83 – – – –

7.54 7.57 7.49 7.80 3.73 3.66 3.53 2.97 2.74 6.57 3.83c 3.82c 6.58 3.95 4.03 – 1.62 – – –

7.57 7.65 7.51 7.85 4.40 3.13 2.73 2.78 2.75 6.58 3.83 3.83 6.55 3.46 4.18 – 1.70 – – –

7.59 7.54 7.49 7.82 3.63 3.63 3.74 3.10 2.77 6.59 3.83 3.78 6.42 3.53 3.46 – – 7.70 7.38 7.32

7.27 7.59 7.55 7.92 4.40 2.97 2.99 2.84 2.90 6.65 3.87 3.84 6.57 3.59 4.26 – – 7.43 7.28 7.27

Uncertain assignment, interchangeable with the chemical shift denoted by the same footnote letter.

assigned on the basis of HMBC correlations and chemical shift. The exact 1H chemical shifts and coupling constants JH,H (Tables 1, 2, 4 and 5) were extracted by simulation and iteration of proton NMR spectra employing the PERCH NMR software (cf. Experimental). The compounds prepared contain two asymmetric carbons, one bearing hydrogen at the annelation of the tetrahydropyridine (B) and imidazolidine (C) rings, the other bearing substituent R at the annelation of the imidazolidine (C) and 5- or 6-membered lactam (D) rings. Thus, two diastereomers are possible in each case, with substituent R either cis (diastereomer a) or trans (b) with respect to the hydrogen at the first-mentioned asymmetric carbon. The cis diastereomers a could readily be identified because of the NOE correlation between the annelation-point CH proton (11a and 12a: 10b-H, 13a–16a: 11b-H, 17a and 18a: 5a-H, 19a and

20a: 6a-H, 21a–23a: 7a-H) and the proton(s) of substituent R (ortho-protons when of R = Ph). The 5a/6a-H proton in 18a and 20a is almost isochronous with one of the neighbouring ArCH2 protons, which obscures the interpretation of the observed NOE correlation, though the trans configuration for 18b can be deduced independently and used as indirect proof of the stereochemistry of 18a. Furthermore, the two vicinal coupling constants between the annelation proton and the protons of the adjacent CH2N group for 18a (7.4 and 7.7 Hz) and 20a (7.1 and 8.4 Hz) resemble those observed for the other a diastereomers more than they do for b (in the set a of compounds 17–23 both coupling constants are between 7.1–9.3 Hz whereas in the set b the coupling with the syn proton is 4.6–5.2 Hz and with the anti proton 9.5–10.1 Hz). The trans configurations of 11b and 15b could be verified from the

67

H. Kivelä et al. / Journal of Molecular Structure 983 (2010) 62–72 Table 5 Proton–proton coupling constants (in CDCl3 at 298 K, in Hz) of 17–23. H,1H

a

1

17a

18a

18b

1

H,1H

19a

20a

1

H,1H

21a

22a

22b

23a

23b

1s,1a 1s,2s 1s,2a 1a,2s 1a,2a 2s,2a 5s,5a 5s,5a 5a,5a 5a,6s 5a,6a 6s,6a 11s,11a

12.7 9.9 3.3 9.0 10.4 17.3 11.1a 7.6a 7.9a 3.7 11.0 15.2 13.5

12.4 9.1 2.3 10.2 9.6 17.0 10.9 7.4 7.7 4.0 9.9 15.3 13.5

12.0 8.2 13.2 0.7 7.1 16.2 10.9 5.2 9.5 3.2 10.6 15.2 13.9

1s,1a 1s,2s 1s,2a 1a,2s 1a,2a 2s,2a 2s,3s 2s,3a 2a,3s 2a,3a 3s,3a 6s,6a 6s,6a 6a,6a 6a,7s 6a,7a 7s,7a 12s,12a

12.7 3.7 3.6 14.1 4.2 14.2 7.1 11.0 1.7 8.0 18.2 11.7 7.7 8.1 3.8 10.7 15.3 13.4

13.3 3.5 3.4 13.6 4.1 14.2 8.0 9.8 1.8 8.6 18.3 11.7 7.1 8.4 4.2 10.9 16.1 13.4

1,2 1,3 2,3 2,4 3,4 7s,7a 7s,7a 7a,7a 7a,8s 7a,8a 8s,8a 13s,13a

7.5 1.3 7.2 1.1 7.6 10.4 7.1 9.3 3.8 11.1 15.4 13.4

7.6 0.9 7.5 1.1 7.6 11.0 7.7 7.8 3.7 10.8 15.2 13.3

7.6 0.9 7.4 1.1 7.6 11.1 4.6 9.5 3.5 10.3 15.1 13.5

7.7 0.9 7.4 1.1 7.6 13.7a 7.8a 8.5a 6.5 5.9 16.4 13.8

7.5 0.9 7.4 1.1 7.6 11.0 4.8 10.1 3.3 10.3 15.0 13.8

Uncertain due to signal overlap.

Table 6 Carbon chemical shifts (in CDCl3 at 298 K, dC(TMS) = 0 ppm) of 17–23.

a–g

Carbon

17a

18a

18b

Carbon

19a

20a

Carbon

21a

22a

22b

23a

23b

1 2 3 5 5a 6 6a 7 8 8-OMe 9 9-OMe 10 10a 11 12a R(Me) R(i-Ph) R(o-Ph) R(m-Ph) R(p-Ph)

32.19 32.82 177.68 46.85 58.30 34.96 125.67 111.87 147.66 55.95 147.50 55.95 109.61 125.74 46.78 84.08 16.95 – – – –

34.21 33.10 177.45 49.30 57.59 34.45 124.74a 111.55 147.63 55.93 147.51 55.93 109.56 125.51a 47.85 88.53 – 136.66 127.00 128.11 128.11

29.96 33.14 177.81 49.89 57.86 32.92 124.92 111.71 147.67 55.94 147.49 55.94 109.57 125.82 45.99 86.61 – 143.59 125.24 128.59 127.94

1 2 3 4 6 6a 7 7a 8 9 9-OMe 10 10-OMe 11 11a 12 13a R(Me) R(i-Ph) R(o-Ph) R(m-Ph) R(p-Ph)

34.66 17.72 30.57 168.46 48.81 53.64 34.76 125.49 111.81 147.70 55.96b 147.50 55.95b 109.60 125.49 47.09 77.74 16.11 – – – –

32.99 16.92 30.23 169.60 51.41 52.78 34.11 124.65 111.50 147.45 55.92 147.63 55.92 109.53 125.32 48.13 83.15 – 135.93 127.11 128.39 128.16

1 2 3 4 4a 5 7 7a 8 8a 9 10 10-OMe 11 11-OMe 12 12a 13 14a 14b R(Me) R(i-Ph) R(o-Ph) R(m-Ph) R(p-Ph)

123.01 132.17 129.86 124.68 133.69 173.41 48.43 64.22 33.50 125.08 111.61 147.87 55.93c 147.59 55.89c 109.54 124.56 51.72 82.02 143.67 – – – – –

121.40 132.27 129.44 124.85 132.14 173.22 47.34 60.93 35.20 125.28d 111.73 147.72 55.95e 147.52 55.93e 109.59 125.39d 47.70 84.03 148.43 14.65 – – – –

123.37 132.50 129.28 124.68 132.88 174.74 49.89 60.38 33.42 124.90 111.75 147.64f 55.93 147.45f 55.93 109.58 126.52 49.28 84.45 147.30 27.40 – – – –

123.90 132.42 129.44 124.59 133.14 172.50 46.65 59.73 31.37 123.92 111.23 147.94 55.94g 147.46 55.92g 109.63 125.66 47.15 91.69 146.81 – 138.65 126.47 128.61 128.32

125.06 132.71 129.46 124.50 133.26 174.93 49.44 60.67 33.56 125.21 111.81 147.66 55.94 147.43 55.94 109.60 126.58 50.33 87.50 147.36 – 142.29 126.93 128.20 128.09

Uncertain assignment, interchangeable with the chemical shift denoted by the same footnote letter.

observed NOE between R and 11-Ha (11b) or R and 12-Ha (15b) (while the syn protons 11/12-Hs displayed an NOE with 10b/11bH). Similarly, an NOE between R and 5-Ha for 18b, and between R and 7-Ha for 22b and 23b, implies a trans configuration for these derivatives. For 23b, the NOE alone was not conclusive in view of the overlap of the 7a-H and 7-Ha resonances, but the stereochemistry verified for its diastereomer 23a and the JH,H(7a,7a) and JH,H(7a,7s) values imply a trans isomer. The diastereotopic protons at the methylene groups of 11–23 could be assigned as participating in either a syn or an anti relationship with the bridgehead proton, on the basis of their observed NOE correlations with this proton or the proton(s) on substituent R, and by analysing the vicinal H,H-coupling constants. Furthermore, the NOEs and H,H-coupling constants could be used to deduce the preferred conformations of the compounds prepared (cf. Figs. 2 and 3 for representative examples, obtained by molecular

mechanics as described in the Section 5). The tetrahydropyridine ring (B) can be expected to assume a conformation close to a half-chair, with the CAC@CAC fragment approximately planar and the remaining N and C atoms lying above or below this plane. Thus, two half-chairs, CHN and NHC, are possible for this ring. Here, the superscript (subscript) indicates which out-of-plane atom is on the same (opposite) side of the plane as the bridgehead hydrogen. In the CHN conformation the bridgehead hydrogen is pseudoaxial, as is the syn hydrogen of the NCH2 group of the tetrahydropyridine ring, which places them close in space (cf. 11b-H and 6-Hs for 13a in Fig. 2). An NOE correlation between these hydrogens was observed for compounds 11a, 11b, 13a and 15b, and for both diastereomers of 17–23 (when applicable), though only barely so for 23a. This suggests a dominant CHN-like conformation for the tetrahydropyridine ring of these derivatives. The large observed values of JH,H(5s,6a) (11a and 11b), JH,H(6s,7a) (13a and 15b), JH,H(5a,6a)

68

H. Kivelä et al. / Journal of Molecular Structure 983 (2010) 62–72

Fig. 2. The conformations of selected angularly-condensed derivatives in CDCl3 at 298 K, as deduced by NMR spectroscopy. Top: the preferred (CHN) and unfavorable (NHC) conformations of 13a. Bottom: the dominant conformation of 15b.

Fig. 3. The dominant conformations of the linearly-condensed derivatives 19a and 18b in CDCl3 at 298 K, as deduced by NMR spectroscopy.

(17a and 18a/b), JH,H(6a,7a) (19a and 20a) and JH,H(7a,8a) (21a, 22a/ b and 23b) are consistent with the expected trans-diaxial relationship between these hydrogens in the CHN conformation. Again, 23a was an exception, suggesting a distorted conformation or conformational equilibrium for this derivative. In the alternative NHC tetrahydropyridine conformation of compounds 11–16, the anti hydrogen of the NCH2 methylene of ring B and the anti hydrogen of the CH2 group of ring C are spatially close to each other (e.g. 5-Ha and 11-Ha for 12a). The NOEs indicated this proximity in 12a, 14a, 15a and 16a, implying that their tetrahydropyridine conformation resembles NHC. The geometric constraints mean that the tetrahydropyridine ring must be approximately cis-fused to the imidazolidine ring in these compounds. In contrast, for the angularly-condensed derivatives which favour the CHN conformation, such as 13a, both cis and trans B/C-ring fusions are possible assuming a pyramidal nitrogen (being interconvertible via nitrogen inversion). Observed NOEs suggest preference for the latter (e.g. the NOEs observed between all pairs of CH3, 11b-H and 6-Hs in 13a and all pairs of 3-Hs, 5-Hs and 10b-H in 11b. Thus, the angularly-condensed derivatives with configuration a prefer an NHCtype conformation if R is phenyl or if they incorporate a benzene ring fused to the terminal lactam (12a, 14a, 15a, 16a). If R is methyl and the fused benzene ring is missing, these derivatives favour the C HN-type conformation (11a, 13a). The diastereomers b of the angularly-condensed compounds (11b, 15b), and also both diaste-

reomers of the linearly-condensed derivatives, likewise prefer this latter conformation. The terminal cyclohexane in 13a, 14a, 19a and 20a displays large vicinal H,H-coupling constants within the anti– syn–anti sequence of its protons (e.g. 3JH,H(2a,3s) and 3JH,H(3s,4a) for 13a and 14a), implying their trans-diaxial relationship. This is consistent with a chair or half-chair (with the amide group close to planar) conformation, with R in a (pseudo)axial position. 3.2. Mass spectrometric fragmentations The primary fragmentations of compounds 11–23 are based on ring cleavages occurring in ring B or ring C (Scheme 5 and Table 7). For all compounds, ring C splits into fragments a + 1 and a  1 (except 13a). Furthermore, 16, 18, 20a, 22 and 23 furnish small amounts of ion a. Most of the compounds give the complementary ion [Ma]+ (except 17, 19 and 20). Compounds 12, 14, 16, 18 and 23 also give the complementary ion [M(a + 1)]+ and compounds 15, 21, 22 and 23 even [M(a  1)]+. Ring C additionally splits into ion b, which contains one CH2 group more than ion a. Ion b is very abundant and in some cases even the parent ion for the angular compounds 11–16 in which the fusion between rings B and C occurs between positions N4 or N5 and C10b or C11b, respectively (Schemes 3 and 5). It is interesting that 17–23 (except 19 and 20) usually give a medium strong ion b1, which is always missing from compounds 11–16, except 15.

69

H. Kivelä et al. / Journal of Molecular Structure 983 (2010) 62–72 a

MeO

MeO b

a

16a

A

Ph

N

MeO

MeO

N O

B c

b

C N D Ph

O

N

E

23a,b

Scheme 5. The primary fragmentation routes for angularly (16a) and linearly (23a/ b) condensed compounds.

Another special feature for the linear compounds 17–23 in which the fusion of rings B and C occurs between N12, N13 or N14 and C5a– C7a, respectively (Schemes 4 and 5), is the formation of ions c and c + 1 via a double cleavage of ring B (Scheme 5). The ion c is usually relatively strong, and in a few cases it is the base peak of the spectra. The B/E and B2/E scans indicated that the parent ion for the ion C8H9O+ given only by these compounds was the ion c. All compounds also give the ion [MH]+, with an RA from 2% to 9% (Table 7). All compounds with R = CH3 (11, 13, 15, 17, 19 and

Table 7 Main fragments [m/z (RA%)] from the studied compounds under electron ionization. Compound

M+

[MH]+

[MR]+

[MCxH2x1O]+ +

a + 1a

aa

a  1a

ba

b1a

192(70) 192(75)

– 191(8)

190(6) 190(16)

205(100) 205(100)

–

+

11a 11b

302(5) 302(9)

301(5) 301(7)

[MCH3] 287(18) 287(16.5)

[MC3H5O] 245(4) 245(5)

12a

364(1)

363(2)

[MPh]+ 287(5)

[MC3H5O]+ 307(2)

192(15)

–

190(4)

205(100)

–

315(5)

[MCH3]+ 301(100)

–

192(9)

–

–

205(20)

–

377(9)

[MPh]+ 301(84)

–

192(10)

–

190(5)

205(100)

–

– –

192(11) 192(15)

– –

190(7) 190(7)

205(75) 205(68)

204(1) 204(1)

–

192(6)b

191(3)

190(6)

205(75)

–

13a 14a

316(4) 378(14)

15a 15b

350(41) 350(29)

349(3) 349(4)

[MCH3]+ 335(8) 335(4)

16a

412(36)

411(1)

[MPh]+ 335(2) +

17a

302(41)

+

315(6)

[MCH3] 287(100)

[MC4H7O] 245(5)

192(30)

–

190(14)

205(8)

204(5)

[MC3H5O]+ 307(5) 307(8)

192(6) 192(6)

191(4) 191(3)

190(12) 190(47)

205(11) 205(12.5)

204(6) 204(7)c

18a 18b

364(28) 364(35)

363(8) 363(10)

[MPh]+ 287(49) 287(41)

19a

316(4)

315(2)

[MCH3]+ 301(100)

[MC4H7O]+ 245(3)

–

–

190(3)

–

–

– –

192(4) –

191(10) –

190(10) 190(19)

– 205(4)

–c 204(16)c

20a 21a

378(8) 336(40)

377(2) 335(9)

[MPh]+ 301(100) –

22a 22b

350(56) 350(47)

349(9) 349(8)

[MCH3]+ 335(100) 335(62)

– –

192(28) 192(21)

– –

190(15) 190(15)

205(2) 205(3)

204(14) 204(11)

23a 23b

412(58) 412(50)

411(7) 411(7)

[MPh]+ 335(49) 335(41)

– –

192(7)b 192(6)b

191(2.5) 191(6)

190(33) 190(36)

205(16) 205(9)

204(34)c 204(20)c

Compound

Doubly-charged ions

c + 1: C10 H13 Oþ 2

 c: C10 H12 Oþ 2

[cC2H3O]+: C8H9O+

[Ma]+

[M(a + 1)]+

[M(a1)]+

11a 11b

–

–

–

–

C6H9NO+ 111(51) 111(38)

–

–

12a

–

–

–

–

C11H11NO+ 173(12.5)

C11H10NO+ 172(48)

–

13a

[MCH3]2+ 150.7(5)

–

C7H11NO+ 125(5.5)

–

–

–

C12H13NO+ 187(7)

C12H12NO+ 186(45)

–

– –

C10H10NO+ 160(3) 160(5)

14a

–

– –

– –

15a 15b

– –

– –

– –

– –

C10H9NO+ 159(100) 159(100)

16a

–

–

–

–

C15H11NO+ 221(37)

C15H10NO+ 220(100)

–

17a

–

165(12)

164(80.5)

121(6)

–

–

–

18a

M2+ 182(5)

121(5)

C11H11NO+ 173(14)

C11H10NO+ 172(43)

–

121(5)

C11H11NO+ 173(17)

C11H10NO+ 172(57)

–

18b

–

165(9) 165(9)

164(100) 164(100)

(continued on next page)

70

H. Kivelä et al. / Journal of Molecular Structure 983 (2010) 62–72

Table 7 (continued) Compound

Doubly-charged ions

c + 1: C10 H13 Oþ 2

 c: C10 H12 Oþ 2

[cC2H3O]+: C8H9O+

[Ma]+

[M(a + 1)]+

[M(a1)]+

19a

[MCH3]2+ 150.7(5)

165(7.5)

164(16)

121(2)

–

–

–

20a

[MPh]2+ 150.4(5)

165(6)

164(25)

121(3)

–

–

–

121(6)

C9H7NO+ 145(73)

–

C9H8NO+ 146(13)

21a

–

165(4)

164(100)

2+

+

a b c

C10H10NO+

C10H9NO

M 22a 22b

175(8) 175(6)

165(22) 165(12)

164(91.5) 164(38)

121(6) 121(4)

159(79) 159(100)

– –

160(4) 160(6)

23a 23b

206(10) 206(8)

165(31) 165(23)

164(97) 164(50)

121(6) 121(4)

C15H11NO+ 221(75) 221(69)

C15H10NO+ 220(100) 220(100)

C15H12NO+ 222(10) 222(7)

þ þ þ þ a + 1: C11H14NOþ 2 , a: C11 H13 NO2 , a1: C11H12NO2 , b: C12H15C11 H13 NO2 , b1: C12H14.NO2 (cf. Scheme 5). a + 2: 193 RA% 7 for each of 16a, 23a and 23b. b2: 203 RA% 5, 5, 6, 5 and 6 for 18b, 20a, 21a, 23a and 23b, respectively.

22) or Ph (12, 14, 16, 18a/b, 20 and 23a/b) usually furnish a relatively strong ion [MR]+, which in many cases is also the base peak of the spectrum. There are also doubly-charged ions, either M2+ (18a, 22a/b and 23a/b) or [MR]2+ (13, 19 and 20). The spectra of the pairs of diastereomers (15a/b, 18a/b, 22a/b and 23a/b) are very similar and it is not easy to distinguish them from each other on the basis of their EI mass spectra. However, in each pair there is at least one ion (Table 7) which reveals a significant difference between the diastereomers: for 11a/b it is the ion [Ma]+, for 15a/b the molecular ion, for 18a/b the ions a  1 and [M(a + 1)]+, for 22a/b the ions [MCH3]+ and [Ma]+, and for 23a/b the ions b, b1 and c. As concerns the other ions, the angular compounds 11–16 usually exhibit only a few, except for 14a, the lower mass fragments (m/z < 118) of which resemble those of 18a/b. Similarly, the lower mass fragments (m/z 6 146) of 15a/b and 22a/b resemble each other. A common feature for linear compounds 17–23 is the appearance of ions [MRc]+, where R is H for 21a, CH3 for 19a and 22a/b, and Ph for 17a, 18a/b and 23a/b.

4. Conclusions Our results demonstrate that regioisomeric tetrahydroisoquinoline 1,2-diamines were conveniently transformed to tetra- and pentacyclic lactams by domino cyclocondensations with acyclic or aromatic c- or d-oxo acids. The angularly-condensed lactams were generally formed with higher diastereoselectivity than that for the linearly-condensed counterparts. The NMR analyses proved that the main or the only diastereomer formed (depending on the starting oxo acid) was the cis isomer (a). The conformations of the products could be determined in CDCl3 solution by analysis of the NOE enhancements and the vicinal coupling constants JH,H. Of the four subsets of compounds defined by the four possible combinations of regio- (angular/linear fusion of the imidazolidine to the tetrahydroisoquinoline moiety) and diastereochemistry (cis/trans), the cis derivatives with angular ring fusion (11a–16a) displayed a clear conformational dependence on the nature of the substitution at the terminal lactam ring. In the case of aliphatic lactams and a methyl substituent, the preferred conformer was characterized by its tetrahydropyridine ring in a CHN conformation, whereas the other derivatives in this subset preferred the NHC conformation. The effect of substitution on the preferred conformation was observed to be smaller within the remaining three subsets of compounds, all of which could be characterized as CHN, with the possible exception of 23a. The EI mass spectra of the angular and

linear compounds were easy to differentiate, but the diastereomers displayed only minor differences.

5. Experimental 5.1. General Melting points were measured on a Kofler hot-plate microscope apparatus and are uncorrected. Column chromatography was performed with silica gel 60 (0.063–0.200). For routine thin-layer chromatography (TLC), silica gel 60 F254 plates (Merck, Germany) were used. Elemental analyses were performed with a Perkin–Elmer 2400 CHNS elemental analyser. Compounds 5 [9] and 8 [10] were prepared according to known procedures. 5.2. NMR spectra The NMR spectra were recorded in CDCl3, DMSO-d6 or D2O solutions on Bruker AVANCE DRX 400 and AVANCE 500 spectrometers. Chemical shifts are given in d (ppm) relative to TMS (CDCl3 and DMSO-d6) or to TSP (D2O) as internal standards. The spectra of the products were acquired without sample spinning at 298 K. The NMR experiments consisted of standard 1H NMR (using a 30° flip angle and a 5 s pulse repetition time), 13C NMR with broadband proton decoupling, dqf-COSY, 1D and 2D NOESY (with a mixing time of 0.3 s), multiplicity-edited HSQC (optimized for a one-bond coupling of 145 Hz and set to show CH and CH3 signals positive and CH2 signals negative), and HMBC (optimized for long-range couplings of 8 Hz with a low-pass J-filter optimized to remove signals due to one-bond coupling around 145 Hz) measurements. Proton chemical shifts and proton–proton coupling constants J were extracted by using the spectral simulation and analysis tool PER included in the PERCH NMR software package (version 2008.1) [12]. The initial guess for the NMR parameters was obtained from PERCH’s NMR predictor, which was first refined manually so that the calculated spectrum roughly resembled the observed one, and then solved iteratively by using the integraltransform and total line-shape-fitting modes of the software. The manual refinement and iterative fitting was repeated until good visual comparison was achieved for the match between the calculated and the observed spectra. The molecular structures displayed in Figs. 2 and 3 were obtained from a molecular mechanics optimization (with the MM+ force field) of starting structures which were prepared to have the features deduced from NMR spectroscopy, by using the HyperChem 7.0 software.

H. Kivelä et al. / Journal of Molecular Structure 983 (2010) 62–72

5.3. Mass spectral measurements The electron ionization mass spectra (Tables 7 and 8) were recorded on a VG ZABSpec mass spectrometer (VG Analytical, Division of Fisons, Manchester, UK) equipped with the Opus V3.3X program package (Fisons Instruments, Manchester, UK). The ionization energy used was 70 eV and the source temperature was 160 °C. The accelerating voltage was 8 kV and the trap current was 200 mA. Perfluorokerosene was used to calibrate the mass scale. A small amount of solid sample dissolved in MeOH was placed in a capillary tube and the solvent was evaporated off with hot air. Thereafter, the sample was introduced into the ionization chamber via the solid inlet. The fragmentation pathways were confirmed by linked scans at constant B/E or B2/E (first field-free region, FFR1) without collision gas. The low-resolution B/E and B2/E spectra were measured with a resolving power of 3000 (10% valley definition). The accurate masses were determined by voltage scanning with a resolving power of 6000–10,000. For the low-resolution spectra, consecutive scans selected from the stable and constant part of the total ion current chromatogram were averaged to obtain more reproducible abundances. For accurate masses and linked scans, P10 scans were averaged to minimize noise and to eliminate random peaks. General procedure for the preparation of 6,7-dimethoxy1,2,3,4-tetrahydroisoquinoline-1-carboxamide (6) and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (9): To a solution of amino ester 5 or 8 (5.31 g, 20 mmol) in MeOH (20 mL), 25% methanolic ammonia solution (50 mL) was added. The mixture was allowed to stand in a well-closed container at ambient temperature for 10 days, and the solvent was then evaporated off. The crystalline product was filtered off, washed with Et2O, dried and recrystallized from EtOH–DMF. 6: Yield: 3.60 g (76%). A yellowish-white solid: mp 211–212 °C. 1H NMR (400 MHz, DMSO-d6): d = 2.52–2.82 (m, 4H, 4-CH2, 3-CH2, NH), (dt, J = 5.2, 12.2 Hz, 1H, 3-CH2), 3.67 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 4.26 (s, 1H, 1-CH), 6.63 (s, 1H, C6H2), 6.92 (s, 1H, C6H2), 7.06 (br s, 1H, NH2), 7.40 (br s, 1H, NH2) ppm. 13C NMR (100 MHz, DMSO-d6): d = 29.3, 41.8, 56.4, 56.5, 60.1, 111.5, 113.1, 126.8, 128.5, 147.5, 148.4, 175.8 ppm. C12H16N2O3 (236.27): calcd. C 61.00, H 6.83, N 11.86; found C 60.72, H 6,49, N 11.65. 9: Yield: 3.97 g (84%). A white solid: mp 201–202 °C. 1H NMR (400 MHz, DMSO-d6): d = 2.49–2.53 (m, 1H, NH), 2.63 (dd, J = 10.1, 15.9 Hz, 1H), 2.79 (dd, J = 4.5, 15.9 Hz, 1H), 3.31 (dd, J = 4.6, 10.1 Hz, 1H), 3.69 (s, 3H, CH3O), 3.70 (s, 3H, CH3O), 3.76 (d, J = 16.2 Hz, 1H),

3.85 (d, J = 16.1 Hz, 1H), 6.61 (s, 1H, C6H2), 6.67 (s, 1H, C6H2), 7.03 (s, 1H, NH2), 7.31 (s, 1H, NH2) ppm. 13C NMR (100 MHz, DMSO-d6): d = 31.5, 47.4, 56.3, 56.4, 57.0, 110.3, 113.3, 126.9, 128.6, 147.9, 175.9 ppm. C12H16N2O3 (236.27): calcd. C 61.00, H 6.83, N 11.86; found C 61.25, H 6.74, N 11.60. General procedure for the preparation of 6,7-dimethoxy1,2,3,4-tetrahydroisoquinoline-1-methanamine (7) and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-methanamine (10): To a stirred and cooled suspension of LiAlH4 (1.14 g, 30 mmol) in dry THF (50 mL), carboxamide 6 or 9 (2.36 g, 10 mmol) was added in small portions. The mixture was stirred and refluxed for 3 h and then cooled, and the excess of LiAlH4 was decomposed by the addition of a mixture of water (2.5 mL) and THF (25 mL). The inorganic salts were filtered off and washed with EtOAc (3  50 mL). The combined organic filtrate and washings were dried (Na2SO4) and evaporated under reduced pressure to give the crude diamine as an oil, which was converted to the crystalline dihydrochloride salt by treatment of its solution in MeOH with an excess of 22% ethanolic HCl and Et2O. The crystalline dihydrochloride was filtered off, dried and recrystallized from MeOH–H2O–Et2O. 72HCl: Yield: 2.30 g (78%). Beige crystals: mp 266–268 °C (lit. [13] mp 265 °C). 1 H NMR (400 MHz, D2O): d = 3.19 (t, J = 6.5 Hz, 2H, 4-CH2), 3.62– 3.78 (m, 3H, 3-CH2, 10 -CH2), 3.84 (dd, J = 8.2, 14.8 Hz, 1H, 10 -CH2), 3.95 (br s, 6H, 2  OCH3), 7.00 (s, 1H, C6H2), 7.04 (s, 1H, C6H2) ppm. 13C NMR (100 MHz, D2O): d = 24.4, 39.3, 41.8, 53.0, 56.4, 56.6, 110.3, 112.8, 119.6, 125.8, 148.1, 149.4 ppm. C12H20Cl2N2O2 (295.21): calcd. C 48.42, H 6.83, N 9.49; found C 48.13, H 6.60, N 9.25. 102HCl: Yield: 2.42 g (82%). Beige crystals: mp 230–232 °C. 1H NMR (400 MHz, D2O): d = 3.10 (dd, J = 10.7, 17.0 Hz, 1H, 4-CH2), 3.32 (dd, J = 4.72, 17.1 Hz, 1H, 4-CH2), 3.51 (dd, J = 6.9, 13.8 Hz, 1H, 10 -CH2), 3.63 (dd, J = 6.1, 13.8 Hz, 1H, 10 -CH2), 3.88 (s, 3H, CH3O), 3.89 (s, 3H, CH3O), 4.00–4.09 (m, 1H, 3-CH), 4.50 (s, 2H, 1-CH2), 6.92 (s, 1H, C6H2), 6.97 (s, 1H, C6H2) ppm. 13C NMR (100 MHz, D2O): d = 28.8, 41.1, 45.0, 51.8, 56.3, 109.9, 112.3, 119.6, 122.5, 148.1, 148.6 ppm. C12H20Cl2N2O2 (295.21): calcd. C 48.42, H 6.83, N 9.49; found C 48.58, H 6.74, N 9.32. Pure diamine bases 7 and 10 were obtained from the above dihydrochlorides by alkaline treatment (10% NaOH), extraction (CH2Cl2) and evaporation under reduced pressure. The free bases were dried in a vacuum desiccator for 24 h before further transformations. General procedure for the preparation of tetra- and pentacyclic lactams 11–23: A mixture of diamine 7 or 10 (0.67 g, 3 mmol)

Table 8 Other ions [m/z (RA  5%)]. Compound 11a 11b 12a 13a 14a 15a 15b 16a 17a 18a 18b 19a 20a 21a 22a 22b 23a 23b

71

C5H9N+: 83(12); 55(21); 42(5) 83(20); 55(16); 42(12) C8H7N+: 117(16.5) [MH2CH3]+: 299(5); [MCH3O]+: 285(7) þ þ þ + + [MC2H5]+: 349(9); C16H17N2Oþ 3 : 285(8); 158(6.5); C8H7N +C9 H9 : 117(18); C7H5N +C8 H7 : 103(9); C7 H7 : 91(6); 77(4); 55(7) : 103(5); 90(4); 43(4) [M(b1)]+: 146(4); C9H8N+: 130(8.5); C8 Hþ 7 [M(b1)]+: 146(4); C9H8N+: 130(18.5); C8 Hþ 7 : 103(5); 90(4.5) þ C13 H9 : 165(17); 90(5) [MCH3c]+: 123(4); C5H9N+: 83(5), 55(10.5) þ C10H10NO+: 160(5); C10H10N+: 144(6); [MPhc]+: 123(2); C8H7N+: 117(21); C7H5O+: 105(5); C7H5N++C8 Hþ 7 : 103(6); C7 H7 : 91(8); 77(8) þ C10H10NO+: 160(3); C10H10N+: 144(6); [MPhc]+: 123(3); C8H7N+: 117(18); C7H5O+: 105(2); C7H5N++C8 Hþ 7 : 103(5); C7 H7 : 91(6); 77(6) [MCH3c]+: 137(5); 43(5) [MC2H5]+: 349(8); [MPhc]+: 137(4); C7H5O+: 105(31); 77(13); 57(5); 55(6); 43(6) [MHc]+: 171(5); 137(5); C8H7N+: 117(15); 90(10); 89(5); 43(8.5) [MCH3c]+: 171(14.5); [M(b1)]+: 146(6); C9H8N+: 130(18); C8 Hþ 7 : 103(7); 90(5); 77(6) [MCH3c]+: 171(9); [M(b1)]+: 146(4); C9H8N+: 130(15); C8 Hþ 7 : 103(5); 43(9) C14H11NO+: 209(8); C14H10NO+: 208(6); [MPhc]+: 171(10); C9H8N+: 130(5); C7 Hþ 7 : 91(10); 90(5); 77(8); 57(10.5) [MPhc]+: 171(8); 90(4); 77(5); 43(5)

72

H. Kivelä et al. / Journal of Molecular Structure 983 (2010) 62–72

and the corresponding c- or d-oxo acid (3 mmol) was refluxed in toluene (40 mL) until no more starting materials could be detected by TLC (2–10 h). The solvent was then evaporated off and the oily or crystalline residue (the NMR spectrum of which was applied for determination of the diastereomeric ratios) was purified by means of column chromatography to yield the less mobile cis (a) and the more mobile trans (b) diastereomers. In some cases (11a–14a, 16a and 21a), the chromatographic purification was followed by recrystallization. The NMR data of products are presented in Tables 1–6. 11: Eluent: EtOAc:MeOH = 4:1. 11a: Yield: 0.33 g (36%). Yellowish-white crystals, mp 175–177 °C (iPr2O–EtOAc). C17H22N2O3 (302.37): calcd. C 67.53, H 7.33, N 9.26; found C 67.44, H 7.21, N 9.18. HRMS: m/z calcd. for C17H22N2O3 302.1630; obsd. 302.1618. 11b: Yield: 16 mg (2%). A beige solid, mp 140–143 °C. HRMS: m/z calcd. for C17H22N2O3 302.1630; obsd. 302.1630. 12: Eluent: EtOAc:n-hexane = 5:2. 12a: Yield: 0.37 g (34%). A beige solid, mp 174–177 °C (iPr2O–EtOAc). C22H24N2O3 (364.44): calcd. C 72.50, H 6.64, N 7.69; found C 72.58, H 6.51, N 7.60. HRMS: m/z calcd. for C22H24N2O3 364.1742; obsd. 364.1762. 13: Eluent: EtOAc:MeOH = 7:3. 13a: Yield: 0.40 g (42%). A yellowish-white solid, mp 137–141 °C (iPr2O). C18H24N2O3 (316.39): calcd. C 68.33, H 7.65, N 8.85; found C 68.45, H 7.72, N 8.69. HRMS: m/z calcd. for C18H26N2O3 316.1787; obsd. 316.1777. 14: Eluent: EtOAc. 14a: Yield: 0.42 g (37%). A beige solid, mp 216–219 °C (iPr2O). C23H26N2O3 (378.46): calcd. C 72.99, H 6.92, N 7.40; found C 72.81, H 6.86, N 7.28. HRMS: m/z calcd. for C23H26N2O3 378.1943; obsd. 378.1936. 15: Eluent: EtOAc: n-hexane = 1:1. 15a: Yield: 0.28 g (27%). A pale-yellow solid, mp 185–189 °C. C21H22N2O3 (350.41): calcd. C 71.98, H 6.33, N 7.99; found C 71.88, H 6.27, N 7.92. HRMS: m/z calcd. for C21H22N2O3 350.1630; obsd. 350.1626. 15b: Yield: 0.08 g (8%). A yellow solid, mp 152–156 °C. C21H22N2O3 (350.41): calcd. C 71.98, H 6.33, N 7.99; found C 71.95, H 6.38, N 7.83. HRMS: m/z calcd. for C21H22N2O3 350.1630; obsd. 350.1631. 16: Eluent: EtOAc:MeOH = 1:1. 16a: Yield: 0.37 g (30%). Beige crystals, mp 200–203 °C (iPr2O–EtOAc). C26H24N2O3 (412.48): calcd. C 75.71, H 5.86, N 6.79; found C 75.56, H 5.69, N 6.64. HRMS: m/z calcd. for C26H24N2O3 412.1787; obsd. 412.1787. 17: Eluent: EtOAc. 17a: Yield: 0.20 g (22%). A pale-yellow solid, mp 143–148 °C. C17H22N2O3 (302.37): calcd. C 67.53, H 7.33, N 9.26; found C 67.40, H 7.23, N 9.09. HRMS: m/z calcd. for C17H22N2O3 302.1630; obsd. 302.1636. 18: Eluent: EtOAc:n-hexane = 6:1. 18a: Yield: 0.31 g (28%). A pale-yellow solid, mp 158–162 °C. C22H24N2O3 (364.44): calcd. C 72.50, H 6.64, N 7.69; found C 72.59, H 6.64, N 7.58. HRMS: m/z calcd. for C22H24N2O3 364.187; obsd. 364.1796. 18b: Yield: 0.09 g (8%). A yellow solid, mp 73–75 °C. C22H24N2O3 (364.44): calcd. C 72.50, H 6.64, N 7.69; found C 72.46, H 6.55, N 7.60. HRMS: m/z calcd. for C22H24N2O3 364.1787; obsd. 364.1792. 19: Eluent: EtOAc:MeOH = 20:1. 19a: Yield: 0.24 g (25%). A pale-yellow solid, mp 125–129 °C. C18H24N2O3 (316.39): calcd. C 68.33, H 7.65, N 8.85; found C 68.15, H 7.52, N 8.74. HRMS: m/z calcd. for C18H24N2O3 316.1787; obsd. 316.1778. 20: Eluent: EtOAc:n-hexane = 3:1. 20a: Yield: 0.43 g (38%). A yellow solid, mp 80–84 °C. C23H26N2O3 (378.46): calcd. C 72.99, H 6.92, N 7.40; found C 73.10, H 7.01, N 7.36. HRMS: m/z calcd. for C23H26N2O3 378.1943; obsd. 378.1935. 21: Eluent: EtOAc:MeOH = 10:1. 21a: Yield: 0.41 g (41%). Yellowish-white crystals, mp 175–177 °C (iPr2O–EtOAc). C20H20N2O3 (336.38): calcd. C 71.41, H 5.99, N 8.33; found C 71.36, H 5.78, N 8.21. HRMS: m/z calcd. for C20H20N2O3 336.1474; obsd. 336.1466. 22: Eluent: EtOAc:n-hexane = 1:1. 22a: Yield: 0.48 g (46%). A white solid, mp 183–187 °C. C21H22N2O3 (350.41): calcd. C 71.98, H 6.33, N 7.99; found C 72.08, H 6.15, N 7.84. HRMS: m/z calcd.

for C21H22N2O3 350.1630; obsd. 350.1620. 22b: Yield: 0.13 g (12%). A beige solid, mp 124–128 °C. C21H22N2O3 (350.41): calcd. C 71.98, H 6.33, N 7.99; found C 71.82, H 6.26, N 8.11. HRMS: m/ z calcd. for C21H22N2O3 350.1630; obsd. 350.1626. 23: Eluent: EtOAc:n-hexane = 2:3. 23a: Yield: 0.35 g (28%). A white solid, mp 171–174 °C. C26H24N2O3 (412.48): calcd. C 75.71, H 5.86, N 6.79; found C 75.62, H 5.94, N 6.71. HRMS: m/z calcd. for C26H24N2O3 412.1787; obsd. 412.1797. 23b: Yield: 0.21 g (17%). A pale-yellow solid, mp 75–79 °C. C26H24N2O3 (412.48): calcd. C 75.71, H 5.86, N 6.79; found C 75.57, H 5.80, N 6.68. HRMS: m/z calcd. for C26H24N2O3 412.1787; obsd. 412.1798. Acknowledgments E.V., L.L. and F.F. thank the Hungarian Scientific Research Foundation (Grant No. OTKA K 075433) for financial support. Some of the NMR spectra were recorded by Miss Heli Hartikainen, supervised by Dr. Petri Tähtinen, and some of the mass spectra by Technician Kirsti Wiinamäki. Their help is gratefully acknowledged. References [1] (a) A.I. Meyers, G.P. Brengel, Chem. Commun. (1997) 1; (b) F. Csende, G. Stájer, Heterocycles 53 (2000) 1379. [2] (a) A.I. Meyers, S.V. Downing, M.J. Weiser, J. Org. Chem. 66 (2001) 1413; (b) L. Lázár, F. Fülöp, Eur. J. Org. Chem. (2003) 3025. [3] (a) L.F. Tietze, Chem. Rev. 96 (1996) 115; (b) L.F. Tietze, G. Brasche, K.M. Gericke, Domino Reactions in Organic Synthesis, Wiley-VCH, Weinheim, 2006; (c) C.J. Chapman, C.G. Frost, Synthesis (2007) 1. [4] (a) A.R. Katritzky, H.-Y. He, A.K. Verma, Tetrahedron: Asymmetry 13 (2002) 933; (b) R. Deprez-Poulain, N. Willand, C. Boutillon, G. Nowogrocki, N. Azaroual, B. Deprez, Tetrahedron Lett. 45 (2004) 5287; (c) M. Penhoat, P. Bohn, G. Dupas, C. Papamicaël, F. Marsais, V. Levacher, Tetrahedron: Asymmetry 17 (2006) 281; (d) I. Kanizsai, Z. Szakonyi, R. Sillanpää, M. D’hooghe, N. De Kimpe, F. Fülöp, Tetrahedron: Asymmetry 17 (2006) 2857; (e) D.J. Edwards, D. House, H.M. Sheldrake, S.J. Stone, T.W. Wallace, Org. Biomol. Chem. 5 (2007) 2658; (f) R. Liu, Y. Wu, Q. Li, W. Liao, S.-H. Chen, G. Li, J.M. Betancort, D.T. Winn, D.A. Campbell, Tetrahedron 64 (2008) 4363. [5] For some recent examples of the transformations of the lactams derived from chiral non-racemic phenylglycinol, see: (a) M. Amat, O. Bassas, N. Llor, M. Cantó, M. Pérez, E. Molins, J. Bosch, Chem. Eur. J. 12 (2006) 7672; (b) C. Escolano, M. Amat, J. Bosch, Chem. Eur. J. 12 (2006) 8198; (c) M. Amat, R. Griera, R. Fabregat, J. Bosch, Tetrahedron: Asymmetry 19 (2008) 1233; (d) M. Amat, R. Fabregat, R. Griera, J. Bosch, J. Org. Chem. 74 (2009) 1794. [6] For some recent examples of the transformations of the lactams derived from chiral non-racemic amino alcohols (other than phenylglycinol), see: (a) M. Amat, M.M.M. Santos, A.M. Gómez, D. Jokic, E. Molins, J. Bosch, Org. Lett. 9 (2007) 2907; (b) M. Amat, M.M.M. Santos, O. Bassas, N. Llor, C. Escolano, A. Gómez-Esqué, E. Molins, S.M. Allin, V. McKee, J. Bosch, J. Org. Chem. 72 (2007) 5193; (c) S.M. Allin, S.N. Gaskell, M.R.J. Elsegood, W.P. Martin, J. Org. Chem. 73 (2008) 6448; (d) M. Amat, A. Gómez-Esqué, C. Escolano, M.M.M. Santos, E. Molins, J. Bosch, J. Org. Chem. 74 (2009) 1205. [7] L. Lázár, H. Kivelä, K. Pihlaja, F. Fülöp, Tetrahedron Lett. 45 (2004) 6199. [8] (a) I. Schuster, A. Koch, M. Heydenreich, E. Kleinpeter, E. Forró, L. Lázár, R. Sillanpää, F. Fülöp, Eur. J. Org. Chem. (2008) 1464; (b) I. Schuster, A. Koch, M. Heydenreich, E. Kleinpeter, L. Lázár, F. Fülöp, J. Mol. Struct. 888 (2008) 124; (c) M. Heydenreich, A. Koch, I. Szatmári, F. Fülöp, E. Kleinpeter, Tetrahedron 64 (2008) 7378; (d) E. Vigóczki, A. Hetényi, L. Lázár, F. Fülöp, ARKIVOC xii (2009) 8; (e) E. Kleinpeter, I. Szatmári, L. Lázár, A. Koch, M. Heydenreich, F. Fülöp, Tetrahedron 65 (2009) 8021. [9] Z. Zalán, T.A. Martinek, L. Lázár, R. Sillanpää, F. Fülöp, Tetrahedron 62 (2006) 2883. [10] R.T. Dean, H. Rapaport, J. Org. Chem. 43 (1978) 2115. [11] A.M. Clover, J. Am. Chem. Soc. 45 (1923) 3133. [12] See for example R. Laatikainen, M. Niemitz, U. Weber, J. Sundelin, T. Hassinen, J. Vepsäläinen, J. Magn. Reson., Ser. A 120 (1996) 1. . [13] (a) T. Yamazaki, Yakugaku Zasshi 79 (1959) 1003; (b) T. Yamazaki, Chem. Abstr. 54 (1960) 5678e.