Synthesis of complex fused polycyclic heterocycles utilizing IMDAF reactions of allylamino- or allyloxy-furyl(hetero)arenes

Tetrahedron 68 (2012) 1869e1885

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Tetrahedron

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Synthesis of complex fused polycyclic heterocycles utilizing IMDAF reactions

of allylamino- or allyloxy-furyl(hetero)arenes

,

Matthew L. Read ^a, Andreas Krapp ^b, Pedro O. Miranda ^a, Lise-Lotte Gundersen ^a

*

^aDepartment of Chemistry, University of Oslo, PO Box 1033, Blindern, N-0315 Oslo, Norway

^bCentre for Theoretical and Computational Chemistry, Department of Chemistry, University of Oslo, PO Box 1033, Blindern, N-0315 Oslo, Norway

a r t i c l e i n f o

a b s t r a c t

Article history:

Arenes and heteroarenes carrying a halogen and an amino- or hydroxy group have been converted to

allylamino- or allyloxy-furyl-(hetero)arenes. These compounds underwent IMDAF reactions to give

complex fused polycyclic heterocycles. The reactivity of the substrates was highly dependent on the

detailed substitution pattern, however cyclizations occurred with high stereoselectivity in most cases.

Experimental ﬁndings regarding reactivity and stereoselectivity were supported by calculations.

Received 16 September 2011

Received in revised form 15 December 2011

Accepted 29 December 2011

Available online 3 January 2012

Keywords:

Heterocycles

IMDAF reactions

Polycyclic compounds

Stereoselectivity

1. Introduction

Despite their aromaticity, furan derivatives may participate

as dienes in DielseAlder cycloadditions. The intramolecular

DielseAlder reaction on furans (IMDAF) is a versatile reaction

where two or more rings can be formed in a single step often

with high regio- and stereochemical control, and where the

oxanorbornene ring system initially formed, can easily be

converted into other cyclic structures.¹The IMDAF reaction is

often applied in synthesis directed toward natural products²

and numerous other polycyclic systems. There is a continuous

need for efﬁcient and selective protocols for the construction

of complex polycyclic heterocycles found as components in

natural products and other bioactive molecules. We have pre-

viously formed the tetrahydrodiazepinopurine heterocyclic

core in asmarines with ring closing metathesis as the key step,³

and studied cyclization processes leading to indolizines.⁴We

envisaged that the IMDAF reaction could be applied in the

construction in a variety of novel polycyclic heterocycles, and

we herein present our results from a study of reactivity and

diastereoselectivity in cyclizations between furans and allyl-

amines or allyl ethers both attached to an arene or heteroarene

as depicted in Fig. 1.

Fig. 1. An overview of the ring systems A and B constructed by IMDAF reactions.

2. Results and discussion

The furylbenzenes 3 and 4 for the IMDAF reaction leading to

type A adducts (Fig. 1) were synthesized as shown in Scheme 1. The

furyl group was introduced by a Pd-catalyzed coupling on the ha-

lides 1. The SuzukieMiyaura cross-coupling reaction of potassium

furyltriﬂuoroborate was found to be an efﬁcient way to synthesize

most furan derivatives described in this paper.⁵The products 2

were N- or O-allylated to give compounds 3. The allylation could be

€

achieved in the presence of Hunig’s base and a catalytic amount of

hydrochloric acid at 80 ^ꢀC, however under these conditions some of

the more reactive products also partly underwent the DielseAlder

reaction. In these cases the allylation was performed under milder

conditions employing an alkali metal hydride and a suitable crown

ether at ambient temperature. When NaH was found to react too

slowly or not at all, most likely due to the lack of acidity for the

proton in question, KH was used. The N,N-disubstituted anilines 4

were formed as a by-product in the synthesis of compounds 3 or by

further transformation of the mono-N-allylated anilines 3.

* Corresponding author. Tel.: þ47 228 57019; fax: þ47 228 55507; e-mail address:

l.l.gundersen@kjemi.uio.no (L.-L. Gundersen).

doi:10.1016/j.tet.2011.12.079

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M.L. Read et al. / Tetrahedron 68 (2012) 1869e1885

Scheme 1. (a) 2-FurylB(OH)₂or 2-furylBF₃K, Pd(OAc)₂, PPh₃, EtOH, 80 ^ꢀC; (b) 2-furylSnBu₃, Pd(PPh₃)₂Cl₂, DMF, 60e100 ^ꢀC; (c) allyl-Br, for detailed reaction conditions, see

Experimental section; (d) MeI, K₂CO₃, DMF; (e) (Boc)₂O, DMAP, K₂CO₃, THF; (f) formed as a by-product in the synthesis of 3.

Compounds 3 and 4 were heated in an inert solvent in order to

affect IMDAF cyclization (Scheme 2) and the results are summa-

rized in Table 1.

Computational details) showed that the barrier for the rearrange-

ment is higher (6 kcal/mol) than for the DielseAlder reaction. In-

terestingly, however, the product of the Claisen rearrangement is

more stable (9 kcal/mol) than the DielseAlder product. The cyclo-

addition product is thus the kinetically preferred product, whereas

the Claisen rearrangement product is the thermodynamically pre-

ferred one. The conversion in the reaction appeared to be ca. 75%,

but the isolated yield of the DielseAlder adduct 5b was reduced due

to low stability on both silica and alumina chromatography col-

umns. The same was observed for several other adducts 5 and 6.

A chloride ortho to the N-allyl substituent (compounds 3c and

3g) has a positive effect on the cyclization. In both cases a mixture

of compounds 5 and 6 was formed with the exo adducts 5 as the

major isomer. Introduction of substituents meta or para to the N-

allyl substituent (compounds 3def) did not result in compounds

with signiﬁcantly higher reactivity compared to the aniline de-

rivative 3a.

Scheme 2. (a) PhMe, 100 ^ꢀC; (b) xylene, 150 ^ꢀC.

N-Allyl(furyl)aniline 3a did not react at all in toluene at 100 ^ꢀC

for 24 h. Extended reaction time (7 days) or increased temperature

(150 ^ꢀC in xylene) did not have any positive effect on the reaction.

Also the phenol derivative 3b was unreactive at 100 ^ꢀC, but cycli-

zation was observed when the reaction was carried out at 150 ^ꢀC.

Only the exo isomer 5 was observed and isolated, and the stereo-

chemistry was determined by NOESY NMR spectroscopy (Fig. 2). No

Claisen rearrangement product 7 (Fig. 2) of this aryl allyl ether was

observed. Calculations at the DFT level (PBE/def2-SVP, see

Fig. 2. Important NOESY correlations for structure elucidation of the major isomer 5

and the numbering of the ring atoms in compounds 5, 6, 13, and 14. Potential Claisen

rearrangement product 7 from the allyloxybenzene 3b.

Table 1

IMDAF cyclization of compounds 3 and 4

Starting material

Y

R₁

R₂

R₃

Solvent

Temp (^ꢀC)

Ratio 5/6^a

Unreacted starting material (%)^a

Isolated yields 5 and 6 (%)

3a

3b

3c

3d

3e

3f

NH

O

NH

H

Cl

H

Cl

H

Cl

H

Cl

H

Cl

NO₂

H

Toluene

Xylene

Toluene

Xylene

Toluene

100

150

100

150

100

d

>99

23

d

>99:1

9:1

d

28, 5b

33, 5c and 6c

d

27

>99

22

<1

38

d

3f

6:1

9:1

10:3

7:1

7:3

d

13, 5f and 6f

88, 5g and 6g

d

3g

4a

4b

4c

4d

4e

NH

N-Allyl

N-Me

N-Boc

N-Allyl

^b5h and 6h

^b5i and 6i

H

d

NO₂

2

66, 5j and 24, 6j

d

4:1

<1

76, 5l and 6l

a

From ¹H NMR of the crude product.

Not isolated in pure form.

b

M.L. Read et al. / Tetrahedron 68 (2012) 1869e1885

1871

The N,N-dialkylated anilines 4aec and 4e were all prone to cy-

clization at 100 ^ꢀC, and in all cases the exo adducts 5 were the major

isomers, but the N-Boc derivative 4d did not react under the same

set of reaction conditions.

We then studied the IMDAF reaction on substrates where the

benzene ring in compounds 3 and 4 were exchanged with a pyri-

dine or pyrimidine ring. The syntheses of these starting materials

11 and 12, following the same strategy as for the synthesis of 3 and

4, are shown in Scheme 3. Compound 10c is not available by

a regioselective coupling on dichloropyridine 8a.⁶Instead this in-

termediate was synthesized by reduction of the nitropyridine 9.

Pyridine 11a did not react at all under standard conditions. In-

creased reaction time had no effect, and when the reaction was

attempted at higher temperatures, decomposition took place.

The results shown in Tables 1 and 2 show that in all cases ex-

amined the exo compounds 5 and 13 are the preferred di-

astereomers in the cyclization of the 2-furyl derivatives 3, 4, 11, and

12. This is consistent with former studies of IMDAF reactions on

simpler furans carrying an allylamino substituent in the 2-

position,⁷and in our cases the diastereoselective outcome is also

supported by theoretical calculations at the PBE/def2-SVP level of

theory. Fig. 3 illustrates the situation for the cyclization of allyl-

Scheme 3. (a) 2-FurylB(OH)₂, Pd(t-Bu₃P)₄, KF, dioxane,

(d) H₂, Raney-Ni, MeOH; (e) allyl-Br, for detailed reaction conditions, see Experimental section; (f) allyl halide or MeI, KH, 18-crown-6, toluene.

D

; (b) 2-furylSnBu₃, Pd(PPh₃)₂Cl₂or [(Furyl)₃]₄Pd DMF, 60 ^ꢀC; (c) PhBF₃K or 2-FurylBF₃K, Pd(OAc)₂, PPh₃, K₂CO₃, EtOH, 80 ^ꢀC;

Compounds 11 and 12 were heated in an inert solvent in order

to affect IMDAF cyclization (Scheme 4) and the results are sum-

marized in Table 2.

amine 3a; both the active conformation leading to cyclization, the

transition state and the product is higher in energy for the endo

compound.

Both a substituent on the allylic amine nitrogen in compounds 4

and 12, and a substituent ortho to the allylic side chain in all sub-

strates 3, 4, 11, and 12 appears to have a very positive inﬂuence on

reactivity in the cyclization. At least when it comes to the ortho

substituent the experimental results indicate that this effect is

steric rather than electronic. Effects of N-substituents on IMDAF

reactions of allylic amides have also been discussed before.⁸Our

theoretical studies revealed that the increased reactivity of ortho

substituted compounds is mainly due to a steric effect, which de-

stabilizes the minimum conformation of the reactant compared to

the active conformations. The transition states and the products are

not inﬂuenced signiﬁcantly by the ortho substituents. The same

effect is observed for the compounds bearing an additional N-

substituent. This is schematically shown in Fig. 4.

The activation barrier out of the active conformation

relatively constant as is the reaction energy out of the active con-

formation E_active. When looking, however, at the real activation

barrier

E^zfrom the minimum conformation the barrier becomes

D

E^z_activeis

D

Scheme 4. (a) Toluene, 100 ^ꢀC.

D

Table 2

IMDAF cyclization of compounds 11 and 12

Starting material

A

B

Y

Z

R

Ratio 13/14^a

Unreacted starting material (%)^a

Isolated yields 13 and 14 (%)

11a

11b

11c

11d

11e

11f

11g

11h

12a

12b

12c

12d

N

CH

N

CH

N

H

Cl

2-Fur

H

Allyl

Me

Allyl

d

>99

<1

25^c

>99

47

d

Cl

2-Fur

Ph

H

Cl

H

25:1^b

10:1

16:1

6:1

15:1

d

49, 13b and 14b

88, 13c and 14c

55, 13d

66, 13e and 14e

58, 13f and 14f

d

4:1

8:1

38, 13i and 10, 14i

80, 13j and 20, 14j

54, 13k and 14, 14k

78, 13l and 15, 14l

N

Cl

2-Fur

<1

13

<1

H

a

From ¹H NMR of the crude product.

From ¹H NMR of the isolated product.

Recovered starting material.

b

c

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M.L. Read et al. / Tetrahedron 68 (2012) 1869e1885

Table 3

Reaction energies

difference between the active and the minimum conformation of the reactant

for the endo and exo isomers formed from selected starting materials 3. For the exo

D

E, activation barriers for DielseAlder reaction

D

E^zand energy

E_conf

D

iso_zmer reaction energies

DE_activeand activation barriers for DielseAlder reaction

E_activerelative to the active conformer of the reactant is also shown. All energies at

D

the PBE/def2-SVP level, given in kcal/mol. See also Figs. 3 and 4 for illustration

Compound R¹exo

endo

DE

D

E^z

ꢁ4.4 23.8 7.1

Cl ꢁ10.8 17.4 1.4

DE_conf

D

E_active

D

E^z_active

DE

D

E^z

1.0 25.9 5.7

ꢁ5.8 19.2 0.0

DE_conf

3a

3c

H

ꢁ11.5

ꢁ12.4

16.7

16

Table 4

Reaction energies

difference between the active and the minimum conformation of the reactant

for the endo and exo isomers formed from selected starting materials 11. For the exo

D

E, activation barriers for DielseAlder reaction

D

E^zand energy

E_conf

D

iso_zmer reaction energies

DE_activeand activation barriers for DielseAlder reaction

E_activerelative to the active conformer of the reactant is also shown. All energies at

D

the PBE/def2-SVP level, given in kcal/mol. See also Figs. 3 and 4 for illustration

Compound A exo endo

B

Y

D

E

D

E^z

D

E_conf

D

E_active

D

E^z_active

D

E

D

E^z

5.3 29.3 9.6

DE_conf

11a

11b

11d

11e

11f

N CH H

N CH Cl

N N Cl

ꢁ1.6 26.8 8.8

ꢁ8.3 20.0 2.3

ꢁ7.4 20.5 1.8

ꢁ10.4 18.0

ꢁ10.6 17.3

ꢁ9.2 18.7

ꢁ10.6 18.1

ꢁ11.8 17.4

ꢁ1.6 22.4 3.0

ꢁ1.1 22.7 2.8

ꢁ4.3 20.0 0.8

1.3 26.0 6.9

N N 2-fur ꢁ10.6 18.1 0.0

Fig. 3. Schematic representation of the reaction mechanism of the IMDAF reaction for

compound 3a based on PBE/def2-SVP calculations (see text and Table 3 for details).

N N Ph

ꢁ5.8 23.4 6.0

coupling employing potassium triﬂuoro(2-furyl)borate, and N-

allylation was achieved when compounds 16a and 16b were reac-

ted with an allyl halide in the presence of alkali metal hydride and

a crown ether. N-Alkylation of purines normally results in the N-9

substituted isomer as the major product. Hence, purine 16c was

allylated in the presence of methylaquacobaloxime, which is

known to facilitate a selective reaction at N-7.^3,9

Compounds 17 were heated in toluene (Scheme 5, Table 5), and

the indole 17a was cyclized to the IMDAF product 18a, which was

isolated in 69% yield. The numbering system used in the in-

terpretation of the NMR spectra of compounds 18 is shown in

Scheme 5. Also the pyrrolopyrimidine 17b cyclized with complete

stereoselectivity to exo product 18b, but the conversion was mod-

erate under standard conditions. The purine 17c did not cyclize at

all after heating for 24 h at 100 ^ꢀC (toluene) or 24 h at 150 ^ꢀC (xy-

lene). It can be seen from the calculated energies presented in

Tables 3e5, that the ring nitrogen(s) in the starting materials de-

stabilize mainly the product and the transition state. Nevertheless,

several pyridines and pyrimidines 11 and 12 gave DielseAlder ad-

ducts in good yields (Table 2). In the case of the bicyclic system

(compounds 17), the overall reaction energy (Table 5) is less fa-

vorable compared to the monocyclic systems. This is probably again

a ring strain effect. Therefore, additional nitrogen atoms in the ring

led to overall unstable compounds. For the purine 17c the reaction

is thermodynamically unfavorable and will not take place. For the

reaction on the pyrrolopyrimidine 17b, only the exo isomer is

predicted to be stable, whereas for the indole 17a both isomers

should be isolable. However, we could only detect formation of the

exo isomer.

Finally we examined the possibility of carrying out the IMDAF

reaction on 3-furylarenes in order to form polycyclic products

containing a seven-membered ring. The 3-furylarene 19 was

formed from a Suzuki coupling on compound 1g and the amine was

mono- or diallylated to give the allylamines 20 or 22 depending on

the detailed reaction conditions (Scheme 6). Both compounds 20

and 22 cyclized to give IMDAF products 21 and 23. Compound 22

gave only the endo product 23 (structure shown) according to the

¹H NMR spectra of the crude product, and for compound 21 a 6:1

Fig. 4. Effect of the ortho substituents R₁in compounds 3 and 4 and Y in compounds 11

and 12sH in blue.

lower for sterically more demanding substituents. The reaction

energy

DE, however, increases. This means that sterically de-

manding substituents lead to a faster reaction and are subject to an

increased thermodynamic driving force. For the parent compound

3a the energy difference between the active conformation and the

minimum conformation is 8 kcal/mol (for exo). This means that at

100 ^ꢀC and assuming thermal equilibrium in the reaction mixture

the ratio between the populations of the two conformations is

0.00003, which explains the lack of reactivity for this substrate. In

the case of the more reactive ortho substituted substrate 3c, the

energy difference between the conformers is only 2 kcal/mol,

which means that the ratio of the two conformers at 100 ^ꢀC is 0.09.

Tables 3 and 4 summarize relative energies for selected reactions.

After seeing the dramatic effect on the N-substituent and the

‘ortho to N’-substituent on reactivity, we found it interesting to

study the cyclization of substrates where these two substituents are

combined to form an additional ring and hence we synthesized the

N-allyl-furyl(aza)indoles 17 and examined their reactivity in the

IMDAF reaction. The furyl group was introduced by a Suzuki-

M.L. Read et al. / Tetrahedron 68 (2012) 1869e1885

1873

Scheme 5. (a) 2-FurylBF₃K, Pd(OAc)₂, PPh₃, K₂CO₃, EtOH, 60e80 ^ꢀC; (b) allyl-Br, KH, 18-crown-6, toluene; (c) allyl-I, methylaquacobaloxime, K₂CO₃, MeCN; (d) toluene 100 ^ꢀC.

to the allylic side chain are shown to have very positive inﬂuence

Table 5

on reactivity in the cyclization. Our theoretical studies revealed

that the increased reactivity of ortho substituted compounds is

mainly due to a steric effect, which destabilizes the minimum

conformation of the reactant compared to the active conforma-

tions. The cyclizations occur with high stereoselectivity in most

cases; 2-furyl derivatives led mainly to exo adducts and 3-furyls to

the endo isomer. These ﬁndings were supported by calculations.

The DielseAlder adducts formed contain several functional groups

that may be manipulated further in syntheses of complex het-

erocyclic systems.

IMDAF cyclization of compounds 17; Experimental outcome and calculated energies

at PBE/def2-SVP in kcal/mol

A

B

Unreacted

starting

material

17 (%)^a

Isolated

yield 18 (%)

Energies compounds 18

exo endo

DE

D

E^z

D

E

D

E^z

CH

N

CH

N

CH

N

<1

56

>99

69, 18a

33, 18b

d, 18c

ꢁ6.8

ꢁ1.8

2.0

18.2

22.0

24.2

ꢁ2.7

3.2

6.7

21.2

25.5

28.0

a

From ¹H NMR of the crude product.

Scheme 6. (a) 3-FurylB(OH)₂, Pd(OAc)₂, PPh₃, EtOH, 85 ^ꢀC; (b) allyl-Br, NaH, 15-crown-5, toluene; (c) allyl-I, KH, 16-crown-8, toluene, 40 ^ꢀC; (d) toluene, 40 ^ꢀC.

endo/exo ratio was observed. Isomers 21a and 21b could be sepa-

rated and were isolated in 59 and 11% yields, respectively. In both

cases no unreacted starting material could be seen in the crude

product. Important NOESY correlations used in structure elucida-

tion of the endo adduct 23 are shown in Scheme 6. Calculations

showed the endo product 21a to be considerably more stable than

21b (by 30 kcal/mol). Furthermore the exo product 21b was found

to be thermodynamically unstable, whereas the endo product 21a

was predicted to be stable (by 6 kcal/mol).

In conclusion, we have shown that several complex polycyclic

heterocycles can be constructed with an IMDAF reaction on ally-

lamino- or allyloxy-furyl-(hetero)arenes as the key step. Both

a substituent on the allylic amine nitrogen and a substituent ortho

3. Experimental

3.1. General

¹H NMR spectra were recorded at 600 MHz on a Bruker AV 600

instrument, at 500 MHz on a Bruker DRX 500 instrument, at

400 MHz on a Bruker AVII 400 instrument, at 300 MHz on a Bruker

Avance DPX 300 instrument, or at 200 MHz on a Bruker Avance

DPX 200 instrument. The decoupled ¹³C NMR spectra were recor-

ded at 150, 125, 100, 75 or 50 MHz using the instruments men-

tioned above. Mass spectra under electron impact conditions were

recorded on a VG Prospec instrument at 70 eV ionizing voltage, and

are presented as m/z (% rel int.). Melting points were determined on

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M.L. Read et al. / Tetrahedron 68 (2012) 1869e1885

€

a Buchi Melting Point B-545 apparatus and are uncorrected. Dry

DMF, MeCN, and DMF were obtained from a solvent puriﬁcation

system, MB SPS-800 from MBraun, Garching, Germany. Toluene,

141.7 (C-1), 141.6 (C-5 in furyl), 128.4 (C-5), 126.9 (C-3), 123.0 (C-4),

117.9 (C-6), 117.3 (C-2), 111.4 (C-4 in furyl), 107.2 (C-3 in furyl); MS EI

m/z (rel %) 195/193 (36/100, M^þ), 166/164 (29/85), 158 (5), 130 (25);

HRMS (EI) calcd for C₁₀H₈ClNO: 193.0294. Found 193.02884.

€

xylene (isomeric mixture), and Hunig’s base were distilled from

CaH₂and dioxane from sodium/benzophenone. MeCN (HPLC

quality) was used without further puriﬁcation in the synthesis of

3b. All other reagents were commercially available and used as

received. Silica gel for ﬂash chromatography was purchased from

Merck, Darmstadt, Germany (Merck No. 09385). Compounds

available by literature methods: Methylaquacobaloxime,¹⁰2a,¹¹

8d,¹²9,⁶10b,⁶11d.¹³

3.1.5. 2-(2-Furyl)-4-nitroaniline (2f). The title compound was syn-

thesized from 2-iodo-4-nitroaniline (1f) (200 mg, 0.750 mmol) as

described for the synthesis of compound 2c above. The reaction

temperature was 100 ^ꢀC and reaction time 16 h. The product was

puriﬁed by ﬂash chromatography on silica gel eluting with CH₂Cl₂/

hexane (1:1); yield 125 mg (80%), mp 125e127 ^ꢀC, yellow solid. ¹H

NMR (CDCl₃, 200 MHz)

d

8.35 (d, J¼2.6 Hz, 1H, H-3), 7.98 (dd, J¼9.0,

3.1.1. 2-(2-Furyl)phenol (2b). A mixture of Pd(OAc)₂(51 mg,

0.23 mmol), PPh₃(300 mg, 1.15 mmol), 2-furylboronic acid (1.00 g,

8.80 mmol), K₂CO₃(1.25 g, 9.00 mmol), and 2-iodophenol (1b)

(1.00 g, 4.54 mmol) in EtOH (96%, 100 mL) were stirred under Ar for

16 h at 80 ^ꢀC. The solvent was removed in vacuo and the product

puriﬁed by ﬂash chromatography on silica gel eluting with CH₂Cl₂/

hexane (2:3); yield 672 mg, (93%) colorless oil. The spectroscopic

data were in good agreement with those reported before.¹⁴

2.6 Hz, 1H, H-5), 7.53 (d, J¼1.9 Hz, 1H, H-5 in furyl), 6.69 (m, 2H, H-3

in furyl and H-6), 6.54 (dd, J¼3.4, 1.9 Hz, 1H, H-4 in furyl), 5.17 (s,

2H, NH₂); ¹³C NMR (CDCl_3,75 MHz)

d 151.4 (C-2 in furyl), 148.9 (C-

1), 142.1 (C-5 in furyl), 138.9 (C-4), 124.8 (C-5), 124.1 (C-3), 115.4 (C-

6), 114.7 (C-2), 111.7 (C-4 in furyl), 107.8 (C-3 in furyl); MS EI m/z (rel

%) 204 (100, M^þ), 188 (2), 158 (16); HRMS (EI) calcd for C₁₀H₈N₂O₃:

204.0535. Found 204.0529.

3.1.6. 2-Chloro-6-(2-furyl)-4-nitroaniline (2g). The title compound

was synthesized from 2-bromo-6-chloro-4-nitroaniline (1g)

(1.00 g, 4.00 mmol) as described for the synthesis of compound 2d

above and puriﬁed by ﬂash chromatography on silica gel eluting

with CH₂Cl₂/hexane (3:7); yield 665 mg (70%), mp 180e182 ^ꢀC,

3.1.2. 2-Chloro-6-(2-furyl)aniline (2c). (2-Furyl)tributyltin (0.13 mL,

0.40 mmol) was added to a stirring solution of (Ph₃P)₂PdCl₂(15 mg,

0.020 mmol) and 2-chloro-6-iodoaniline (1c) (100 mg, 0.400 mmol)

in DMF (19 mL) and the mixture was stirred at 60 ^ꢀC under N₂for

16 h, and evaporated in vacuo. The residue was dissolved in satd KF

in THF (20 mL), stirred at ambient temperature for 16 h, and evap-

orated in vacuo. The residue was placed on top of a ﬂash chroma-

tography column and the product puriﬁed by ﬂash chromatography

on silica gel eluting with CH₂Cl₂/hexane (3:7); yield 70 mg (90%), mp

yellow solid. ¹H NMR (CDCl₃, 300 MHz)

d

8.27 (d, J¼2.5 Hz, 1H, H-

5), 8.16 (d, J¼2.5 Hz, 1H, H-3), 7.55 (br s, 1H, H-5 in furyl), 6.73 (d,

J¼3.4 Hz, 1H, H-3 in furyl), 6.56 (dd, J¼3.4, 1.8 Hz, 1H, H-4 in furyl),

5.66 (br s, 2H, NH₂); ¹³C NMR (CDCl₃, 75 MHz)

d 150.7 (C-2 in

furyl), 145.1 (C-1), 142.5 (C-5 in furyl), 138.1 (C-4), 124.4 (C-3),

122.2 (C-5), 119.2 (C-2), 115.3 (C-6), 111.9 (C-4 in furyl), 108.6 (C-3

in furyl); MS EI m/z (rel %) 240/238 (33/100, M^þ), 164 (25), 128

(21), 102 (15); HRMS (EI) calcd for C₁₀H₇N₂O₃Cl: 238.0145. Found

238.0146.

59e61 ^ꢀC, pale yellow crystals. ¹H NMR (CDCl₃, 300 MHz)

d 7.50 (dd,

J¼1.8, 0.7 Hz,1H, H-5 in furyl), 7.36 (dd, J¼7.9,1.5 Hz,1H, H-3 or H-5),

7.22 (dd, J¼7.9, 1.5 Hz, 1H, H-3 or H-5), 6.70 (t, J¼7.9 Hz, 1H, H-4),

6.60 (dd, J¼3.4, 0.7 Hz,1H, H-3 in furyl), 6.51 (dd, J¼3.4,1.8 Hz,1H, H-

4 in furyl), 4.81 (s, 2H, NH₂); ¹³C NMR (CDCl₃, 75 MHz)

d 152.8 (C-2 in

furyl),141.9 (C-5 in furyl),139.9 (C-1),128.9 (C-3 or C-5),126.4 (C-3 or

C-5), 120.7 (C-2), 118.4 (C-4), 117.5 (C-6), 111.7 (C-4 in furyl), 107.4 (C-

3 in furyl); MS EI m/z (rel %) 195/193 (32/100, M^þ), 166/164 (30/91),

71 (1); HRMS (EI) calcd for C₁₀H₈ClNO: 193.0294. Found 193.0292.

3.1.7. N-Allyl-2-(2-furyl)aniline (3a). Method A. HCl (2 drops, 37% in

water) was added to a mixture of 2-(2-furyl)aniline (2a) (400 mg,

2.52 mmol), allyl bromide (0.22 mL, 2.5 mmol), and (i-Pr)₂NEt

(0.44 mL, 2.5 mmol) and the resulting mixture was stirred at 80 ^ꢀC

for 3 h. Satd aq NaHCO₃(5 mL) was added and the mixture was

extracted with CH₂Cl₂(3ꢂ20 mL). The combined organic extracts

were dried (MgSO₂), evaporated and the product isolated by ﬂash

chromatography on silica gel eluting with EtOAc/hexane (1:19);

3.1.3. 5-Chloro-2-(2-furyl)aniline (2d). A mixture of Pd(OAc)₂

(25 mg, 0.11 mmol), PPh₃(110 mg, 0.420 mmol), potassium 2-

furyltriﬂuoroborate (420 mg, 2.40 mmol), K₂CO₃(450 mg,

3.26 mmol), and 5-chloro-2-iodoaniline (1d) (400 mg, 1.60 mmol)

in EtOH (96%, 100 mL) was stirred under Ar for 5 h at 80 ^ꢀC. The

solvent was removed in vacuo and the product puriﬁed by ﬂash

chromatography on silica gel eluting with CH₂Cl₂/hexane (1:4);

yield 360 mg (72%), yellow oil. ¹H NMR (CDCl₃, 300 MHz)

d 7.56 (d,

J¼1.8 Hz, 1H, H-5 in furyl), 7.52 (dd, J¼7.7, 1.6 Hz, 1H, H-3), 7.27 (m,

1H, H-5), 6.86e6.76 (m, 2H, H-4 and H-6), 6.64 (dd, J¼3.4, 0.7 Hz,

1H, H-3 in furyl), 6.57 (dd, J¼3.4, 1.8 Hz, 1H, H-4 in furyl), 6.05 (m,

1H, CH]), 5.42e5.23 (m, 3H, CH₂] and NH), 3.90 (m, 2H, NCH₂);

yield 245 mg (84%), yellow oil. ¹H NMR (CDCl₃, 300 MHz)

d 7.48 (d,

J¼1.8 Hz, 1H, H-5 in furyl), 7.35 (d, J¼7.9 Hz, 1H, H-3), 6.73 (m, 2H,

H-4 and H-6), 6.53 (dd, J¼3.4, 0.7 Hz, 1H, H-3 in furyl), 6.48 (dd,

J¼3.4, 1.8 Hz, 1H, H-4 in furyl), 4.30 (br s, 2H, NH₂); ¹³C NMR (CDCl₃,

¹³C NMR (CDCl₃, 75 MHz)

d 154.1 (C-2 in furyl), 145.1 (C-1), 141.7 (C-

5 in furyl), 135.7 (CH]), 129.6 (C-3), 128.6 (C-5), 117.4 (C-4), 116.5

(CH₂]), 116.4 (C-2), 112.0 (C-6), 111.8 (C-4 in furyl), 107.1 (C-3 in

furyl), 46.8 (NCH₂); MS EI m/z (rel %) 199 (100, M^þ), 172 (14), 143

(46), 130 (53); HRMS (EI) calcd for C₁₃H₁₃NO: 199.0997. Found

199.1004.

75 MHz) d 152.5 (C-2 in furyl), 144.2 (C-1), 141.4 (C-5 in furyl), 134.1

(C-5), 128.6 (C-3), 118.4 (C-4), 116.1 (C-6), 114.6 (C-2), 111.4 (C-4 in

furyl), 106.6 (C-3 in furyl); MS EI m/z (rel %) 195/193 (34/100, M^þ),

166/164 (27/81), 158 (5), 130 (23); HRMS (EI) calcd for C₁₀H₈ClNO:

193.0294. Found 193.0293.

Method B.

A solution of 2-(2-furyl)aniline (2a) (475 mg,

3.00 mmol) and 18-crown-6-ether (950 mg, 3.60 mmol) in dry

toluene (50 mL) at 0 ^ꢀC was treated with KH (700 mg, ca.

6.00 mmol, ca. 35% in mineral oil) and stirred for 10 min under Ar.

Allyl bromide (0.30 mL, 3.6 mmol) was added and the resulting

mixture was stirred at ambient temperature for 16 h. Water (10 mL)

was added and the mixture was extracted with EtOAc (3ꢂ50 mL).

The combined organic extracts were dried (MgSO₂), evaporated

and the products isolated by ﬂash chromatography on silica gel

eluting with CH₂Cl₂/hexane (1:4); yield 240 mg (40%) of N-allyl-2-

(2-furyl)aniline (3a) and 72 mg (10%) of N,N-diallyl-2-(2-furyl)an-

iline (4a), data below.

3.1.4. 4-Chloro-2-(2-furyl)aniline (2e). The title compound was

synthesized from 4-chloro-2-iodoanile (1e) (400 mg, 1.60 mmol) as

described for the synthesis of compound 2d above and puriﬁed by

ﬂash chromatography on silica gel eluting with CH₂Cl₂/hexane

(1:4); yield 245 mg (79%), yellow oil. ¹H NMR (CDCl₃, 300 MHz)

d

7.48 (d, J¼1.8 Hz, 1H, H-5 in furyl), 7.43 (d, J¼2.5 Hz, 1H, H-3), 7.02

(dd, 1H, J¼8.6, 2.5 Hz, H-5), 6.65 (d, 1H, J¼8.6 Hz, 1H, H-6), 6.57 (d,

J¼3.4 Hz, 1H, H-3 in furyl), 6.48 (dd, J¼3.4, 1.8 Hz, 1H, H-4 in furyl),

4.38 (br s, 2H, NH₂); ¹³C NMR (CDCl₃, 75 MHz)

d 152.0 (C-2 in furyl),

M.L. Read et al. / Tetrahedron 68 (2012) 1869e1885

1875

3.1.8. 2-[2-(Allyloxy)phenyl]furan (3b). A mixture of 2-(2-furyl)

phenol (2b) (750 mg, 4.70 mmol), allyl bromide (0.80 mL,

9.4 mmol), and K₂CO₃(1.30 g, 9.40 mmol) in MeCN (100 mL) was

stirred at ambient temperature for 48 h, concentrated in vacuo and

the product was puriﬁed by ﬂash chromatography on silica gel

eluting with CH₂Cl₂/hexane (1:9); yield 730 mg (78%), colorless oil.

206 (19), 192 (11), 177 (36), 166 (21); HRMS (EI) calcd for

₁₃H₁₂ClNO: 233.0607. Found 233.0603.

C

3.1.12. N-Allyl-2-(2-furyl)-4-nitroaniline (3f). NaH (20 mg, ca.

0.65 mmol, ca. 65% in mineral oil) was added to a stirring solution

of 2-(2-furyl)-4-nitroaniline (2f) (100 mg, 0.500 mmol) in dry THF

(20 mL) at 0 ^ꢀC under N₂and the resulting mixture was allowed to

warm to ambient temperature with stirring over 10 min. Allyl

bromide (0.04 mL, 0.6 mmol) and Bu₄NBr (160 mg, 0.500 mmol)

were added. The mixture was stirred at ambient temperature for

3 h, concentrated in vacuo and puriﬁed by ﬂash chromatography on

silica gel eluting with CH₂Cl₂/hexane (1:3) followed by CH₂Cl₂;

yield 50 mg (40%), yellow oil. N,N-Diallyl-2-(2-furyl)-4-nitroaniline

¹H NMR (CDCl₃, 300 MHz)

d

7.86 (dd, J¼7.8, 1.7 Hz, 1H, H-3), 7.46

(dd, J¼1.8, 0.7 Hz, 1H, H-5 in furyl), 7.25e7.14 (m, 1H, H-4),

7.07e6.88 (m, 3H, H-5 and H-6, H-3 in furyl), 6.49 (dd, J¼3.3, 1.8 Hz,

1H, H-4 in furyl), 6.14 (ddt, J¼17.2,10.6, 5.4 Hz,1H, CH]), 5.52e5.23

(m, 2H, CH₂]), 4.65 (dt, J¼5.4, 1.4 Hz, 2H, OCH₂); ¹³C NMR (CDCl₃,

75 MHz) d 154.5 (C-1), 150.4 (C-2 in furyl), 141.3 (C-5 in furyl), 133.4

(CH]), 128.1 (C-4), 126.3 (C-3), 121.1 (C-5 or C-6), 120.4 (C-2), 118.2

(CH₂]), 112.5 (C-5 or C-6), 111.9 (C-4 in furyl), 110.2 (C-3 in furyl),

69.5 (OCH₂). MS EI m/z (rel %) 200 (74, M^þ), 160 (48), 131 (100);

HRMS (EI) calcd for C₁₃H₁₂O₂: 200.0837. Found 200.0830.

43 mg (30%) was also isolated. ¹H NMR (CDCl₃, 300 MHz)

d 8.30 (d,

J¼2.5 Hz, 1H, H-3), 8.04 (dd, J¼9.2, 2.5 Hz, 1H, H-5), 7.52 (d,

J¼1.2 Hz, 1H, H-5 in furyl), 6.70e6.48 (m, 3H, H-3, H-4 in furyl and

H-6 in Ar), 6.17 (s, 1H, NH), 5.93 (ddt, J¼17.2, 10.2, 5.1 Hz, 1H, CH]),

5.37e5.16 (m, 2H, CH₂]), 3.99e3.86 (m, 2H, NCH₂); ¹³C NMR

3.1.9. N-Allyl-2-chloro-6-(2-furyl)aniline (3c). The title compound

was synthesized from 2-chloro-6-(2-furyl)aniline (2c) (120 mg,

0.620 mmol) and allyl bromide (0.07 mL, 0.72 mmol) at 35 ^ꢀC

otherwise as described for the synthesis of compound 3a (Method

B) above and puriﬁed by ﬂash chromatography on silica gel eluting

with EtOAc/CH₂Cl₂/hexane (1:3:15); yield 100 mg (69%), colorless

(CDCl₃, 75 MHz)

d 151.9 (C-2 in furyl), 149.9 (C-1), 142.6 (C-5 in

furyl), 138.1 (C-4), 133.6 (CH]), 125.9 (C-5), 124.6 (C-3), 117.6

(CH₂]), 115.4 (C-2), 112.1 (C-3 or C-4 in furyl), 110.6 (C-6), 108.5 (C-

3 or C-4 in furyl), 46.2 (NCH₂); MS EI m/z (rel %) 244 (100, M^þ), 207

(3), 198 (7), 188 (30); HRMS (EI) calcd for C₁₃H₁₂N₂O₃: 244.0848.

Found 244.0843.

oil. ¹H NMR (CDCl₃, 300 MHz)

d 7.50e7.40 (m, 2H, H-5 in furyl and

H-3 or H-5), 7.27 (dd, J¼7.9, 1.3 Hz, 1H, H-3 or H-5), 6.89 (m, 1H, H-

4), 6.77 (d, J¼3.2 Hz, 1H, H-3 in furyl), 6.48 (dd, J¼3.2, 1.8 Hz, 1H, H-

4 in furyl), 5.87 (m, 1H, CH]), 5.38e4.79 (m, 2H, CH₂]), 4.20 (br s,

1H, NH), 3.52 (d, J¼5.7 Hz, 2H, NCH₂); ¹³C NMR (CDCl₃, 50 MHz)

3.1.13. N-Allyl-2-chloro-6-(2-furyl)-4-nitroaniline (3g). NaH (125 mg,

ca. 3.36 mmol, ca. 65% in mineral oil) was added to a stirring solution

of 2-chloro-6-(2-furyl)-4-nitroaniline (2g) (800 mg, 3.36 mmol) in

dry THF (20 mL) at 0 ^ꢀC under N₂and the resulting mixture was

allowed to warm to ambient temperature with stirring over 10 min.

Allyl bromide (3.0 mL, 3.6 mmol) and Bu₄NBr (1.00 g, 3.36 mmol)

were added. The mixture was stirred at ambient temperature for 3 h,

concentrated in vacuo and puriﬁed by ﬂash chromatography on

silica gel eluting with EtOAc/CH₂Cl₂/hexane (1:3:15); yield 612 mg

d

151.8 (C-2 in furyl), 142.5 (C-1), 141.9 (C-5 in furyl), 136.1 (CH]),

129 (C-3 or C-5), 127.6 (C-3 or C-5), 127.2 (C-2 or C-6), 124.1 (C-2 or

C-6), 122.1 (C-4), 116.2 (CH₂]), 111.8 (C-4 in furyl), 108.9 (C-3 in

furyl), 50.1 (NCH₂); MS EI m/z (rel %) 235/233 (33/98, M^þ), 192 (19),

177 (100), 166 (36), 164 (96); HRMS (EI) calcd for C₁₃H₁₂ClNO:

233.0607. Found 233.0604.

(66%), yellow oil. ¹H NMR (CD₂Cl₂, 300 MHz)

d 8.18 (m, 2H, H-3 and

3.1.10. N-Allyl-5-chloro-2-(2-furyl)aniline (3d). The title compound

was synthesized from 5-chloro-2-(2-furyl)aniline (2d) (520 mg,

2.69 mmol) and allyl bromide (0.23 mL, 2.7 mmol) as described for

the synthesis of compound 3a (Method A) above and puriﬁed by

ﬂash chromatography on silica gel eluting with EtOAc/hexane

(1:9); yield 410 mg (65%), yellow oil. ¹H NMR (CDCl₃, 300 MHz)

H-5), 7.56 (br s, 1H, H-5 in furyl), 6.64 (d, J¼3.4 Hz, 1H, H-3 in furyl),

6.56 (dd, J¼3.4 and 1.8 Hz, 1H, H-4 in furyl), 5.82 (m, 1H, CH]),

5.32e5.10 (m, 3H, CH₂] and NH), 3.60 (m, 2H, NCH₂); ¹³C NMR

(CD₂Cl₂, 75 MHz)

d 150.4 (C-2 in furyl), 148.5 (C-1), 143.0 (C-5 in

furyl), 139.0 (C-4), 135.0 (CH]), 125.9 (C-3), 125.2 (C-5), 123.0 (C-2),

119.1 (C-6), 117.1 (CH₂]),112.1 (C-4 in furyl), 110.4 (C-3 in furyl), 48.7

(NCH₂); MS EI m/z (rel %) 280/278 (33/100, M^þ), 222 (74), 163 (81),

128 (68); HRMS (EI) calcd for C₁₃H₁₁N₂O₃Cl: 278.0458. Found

278.0455.

d

7.49 (m,1H, H-5 in furyl), 7.34 (d, J¼8.2 Hz,1H, H-3), 6.71e6.65 (m,

2H, H-4 and H-6), 6.54 (d, J¼3.3 Hz, 1H, H-3 in furyl), 6.50 (dd,

J¼3.3, 1.8 Hz, 1H, H-4 in furyl), 6.00e5.91 (m, 1H, CH]), 5.34e5.19

(m, 3H, CH₂] and NH), 3.80 (m, 2H, NCH₂); ¹³C NMR (CDCl₃,

75 MHz)

d

152.7 (C-2 in furyl), 145.5 (C-1), 141.4 (C-5 in furyl), 134.8

3.1.14. N,N-Diallyl-2-(2-furyl)aniline (4a). The title compound was

formed as a by-product in the synthesis of compound 3a (Method

(C-5), 134.4 (CH]), 128.8 (C-3), 116.7 (CH₂]), 116.4 (C-6), 114.4 (C-

2), 111.3 (C-4 in furyl), 111.3 (C-4) 106.8 (C-3 in furyl), 46.1 (NCH₂);

MS EI m/z (rel %) 235/233 (35/100, M^þ), 206 (17), 192 (8), 177 (39),

166 (13); HRMS (EI) calcd for C₁₃H₁₂ClNO: 233.0607. Found

233.0605.

B). Colorless oil. ¹H NMR (CDCl₃, 400 MHz)

d

7.82 (d, J¼7.7 Hz, 1H,

H-3), 7.48 (br s, 1H, H-5 in furyl), 7.23e7.10 (m, 4H, H-3 in furyl and

H-4, H-5 and H-6), 6.54e6.45 (m, 1H, H-4 in furyl), 5.81 (m, 2H, 2ꢂ

CH]), 5.14 (m, 4H, 2ꢂ CH₂]), 3.63 (d, J¼6.3 Hz, 4H, 2ꢂ NCH₂); ¹³

C

NMR (CDCl₃, 100 MHz)

d 152.0 (C-2 in furyl), 147.5 (C-1), 141.0 (C-5

3.1.11. N-Allyl-4-chloro-2-(2-furyl)aniline (3e). The title compound

was synthesized from 4-chloro-2-(2-furyl)aniline (2e) (520 mg,

2.59 mmol) and allyl bromide (0.23 mL, 2.6 mmol) as described for

the synthesis of compound 3a (Method A) above and puriﬁed by

ﬂash chromatography on silica gel eluting with EtOAc/hexane

(1:9); yield 385 mg (64%), yellow oil. ¹H NMR (CDCl₃, 300 MHz)

in furyl), 134.8 (2ꢂ CH]), 127.4 (C-4, C-5 or C-6), 127.2 (C-3), 126.4

(C-2), 123.5 (C-4, C-5 or C-6), 123.0 (C-4, C-5 or C-6), 117.7 (2ꢂ

CH₂]), 111.6 (C-4 in furyl), 109.0 (C-3 in furyl), 55.2 (2ꢂ NCH₂); MS

EI m/z (rel %) 239 (100, M^þ), 212 (28), 198 (14), 172 (4), 143 (29);

HRMS (EI) calcd for C₁₆H₁₇NO: 239.1310. Found 239.1307.

d

7.49 (br s, 1H, H-5 in furyl), 7.41 (d, J¼2.5 Hz, 1H, H-3), 7.10 (dd,

3.1.15. N,N-Diallyl-2-chloro-6-(2-furyl)aniline (4b). A solution of N-

allyl-2-chloro-6-(2-furyl)aniline (3c) (190 mg, 0.820 mmol) and 18-

crown-6-ether (430 mg, 1.60 mmol) in dry toluene (20 mL) at 0 ^ꢀC

was treated with KH (280 mg, ca. 2.40 mmol, ca. 35% in mineral oil)

and stirred for 10 min under Ar. Allyl iodide (0.15 mL, 1.6 mmol)

was added and the resulting mixture was stirred at ambient tem-

perature for 5 h. Water (10 mL) was added and the mixture was

extracted with EtOAc (3ꢂ20 mL). The combined organic extracts

J¼8.6, 2.5 Hz, 1H, H-5), 6.58 (d, J¼8.6 Hz, 1H, H-6), 6.57 (d, J¼3.4 Hz,

1H, H-3 in furyl), 6.50 (dd, J¼3.4, 1.8 Hz, 1H, H-4 in furyl), 6.01e5.89

(m, 1H, CH]), 5.31e5.17 (m, 3H, CH₂] and NH), 3.80 (m, 2H,

NCH₂); ¹³C NMR (CDCl₃, 75 MHz)

d 152.7 (C-2 in furyl), 143.5 (C-1),

142.3 (C-5 in furyl), 135.1 (CH]), 129.0 (C-3), 127.7 (C-5), 122.1 (C-

4), 117.7 (C-2), 117.7 (CH₂]), 113.3 (C-6), 111.8 (C-4 in furyl), 107.8

(C-3 in furyl), 46.8 (NCH₂); MS EI m/z (rel %) 235/233 (34/100, M^þ),

1876

M.L. Read et al. / Tetrahedron 68 (2012) 1869e1885

were dried (MgSO₂), evaporated and the products isolated by ﬂash

eluting with EtOAc/CH₂Cl₂/hexane (1:4:16); yield 100 mg (42%),

chromatography on silica gel eluting with CH₂Cl₂/hexane (1:9);

yellow oil. N-Allyl-2-chloro-6-(2-furyl)-4-nitroaniline (3g) (53 mg,

yield 135 mg (60%), colorless oil. ¹H NMR (CDCl₃, 300 MHz)

d

7.64

25%) was also isolated. ¹H NMR (CDCl₃, 200 MHz)

d 8.46 (d,

(dd, J¼7.8, 1.4 Hz, 1H, H-5), 7.46 (br s, 1H, H-5 in furyl), 7.29e7.20

(m, 1H, H-3), 7.09 (m, 1H, H-4), 7.01 (d, J¼3.3 Hz, 1H, H-3 in furyl),

6.48 (dd, J¼3.3, 1.8 Hz, 1H, H-4 in furyl), 5.83 (m, 2H, 2ꢂ CH]),

J¼2.8 Hz, 1H, H-3 or H-5), 8.10 (d, J¼2.8 Hz, 1H, H-3 or H-5), 7.53

(dd, J¼1.8, 0.7 Hz, 1H, H-5 in furyl), 6.97 (dd, J¼3.4, 0.7 Hz, 1H, H-3

in furyl), 6.53 (dd, J¼3.4, 1.8 Hz, 1H, H-4 in furyl), 5.79 (ddt, J¼16.7,

9.9, 6.7 Hz, 2H, 2ꢂ CH]), 5.25e4.97 (m, 4H, 2ꢂ CH₂]), 3.70 (d,

5.20e4.90 (m, 4H, 2ꢂ CH₂]), 3.70 (d, J¼6.7 Hz, 4H, 2ꢂ NCH₂); ¹³

C

NMR (CDCl₃, 75 MHz)

d

151.9 (C-2 in furyl), 143.6 (C-1), 141.9 (C-5 in

J¼6.7 Hz, 4H, 2ꢂ NCH₂); ¹³C NMR (CDCl₃, 75 MHz)

d 149.9 (C-2 in

furyl), 136.1 (2ꢂ CH]), 133.1 (C-2), 129.8 (C-3), 126.4 (C-4 or C-5),

126.1 (C-4 or C-5), 117.3 (2ꢂ CH₂]), 111.9 (C-4 in furyl), 110.2 (C-3 in

furyl), 100.2 (C-6), 55.8 (2ꢂ NCH₂); MS ESI m/z (rel %) 275/273 (33/

100, M^þ), 246 (32), 238 (20), 206 (26), 177 (24); HRMS (ESI) calcd

for C₁₆H₁₆ClNO: 273.0920. Found 273.0916.

furyl or C-6), 149.5 (C-2 in furyl or C-6), 144.3 (C-4), 143.0 (C-5 in

furyl), 135.6 (C-1), 134.8 (CH]), 132.1 (C-2), 124.6 (C-3 or C-5), 121.9

(C-3 or C-5), 118.5 (CH₂]), 112.3 (C-4 in furyl), 111.2 (C-3 in furyl),

55.3 (NCH₂); MS EI m/z (rel %) 320/318 (26/75, M^þ), 293/291 (11/

36), 277 (20), 41 (100); HRMS (EI) calcd for C₁₆H₁₅ClN₂O₃: 318.0771.

Found 318.0762.

3.1.16. N-Allyl-2-chloro-6-(2-furyl)-N-methyl-4-nitroaniline (4c). To

a

solution of N-allyl-2-chloro-6-(2-furyl)-4-nitroaniline (3g)

3.1.19. (ꢃ) (6aS,8S)-6a,7,8,10a-Tetrahydro-8,10a-epoxy-6H-benzo[c]

chromene (5b). A stirring solution of 2-[2-(allyloxy)phenyl]furan

(3b) (150 mg, 0.750 mmol) in dry xylene (15 mL) was heated at

150 ^ꢀC for 24 h under Ar, cooled to ambient temperature and

concentrated in vacuo. The product was puriﬁed by ﬂash chroma-

tography on silica gel eluting with CH₂Cl₂/hexane (1:9); yield

42 mg (28%), colorless oil, 35 mg (23%) starting material was re-

(410 mg, 1.47 mmol) in dry DMF (10 mL) were subsequently added

K₂CO₃(405 mg, 2.94 mmol) and methyl iodide (0.10 mL, 1.5 mmol).

The reaction mixture was stirred at ambient temperature for 18 h

under Ar and extracted with EtOAc (3ꢂ30 mL). The combined or-

ganic layers were washed with water (5ꢂ30 mL), dried (MgSO₄),

and evaporated in vacuo. The product was puriﬁed by ﬂash chro-

matography on silica gel eluting with hexane; yield 200 mg (46%),

covered. ¹H NMR (CDCl₃, 600 MHz)

d

7.48 (dd, J¼7.6, 1.4 Hz, 1H, H-

yellow oil. ¹H NMR (CDCl₃, 300 MHz)

d

8.40 (d, J¼2.7 Hz, 1H, H-5),

1), 7.37e7.28 (m,1H, H-3), 7.09e6.93 (m, 1H, H-2), 6.97 (d, J¼8.3 Hz,

1H, H-4), 6.58 (dd, J¼5.7, 1.6 Hz, 1H, H-9), 6.29 (d, J¼5.7 Hz, 1H, H-

10), 5.11e4.90 (m, 1H, H-8), 4.48 (dd, J¼10.7, 5.0 Hz, 1H, H-6_A), 3.77

(m, 1H, H-6_B), 2.05 (dddd, J¼10.7, 5.0, 3.7, 1.7 Hz, 1H, H-6a),

1.72e1.58 (m, 1H, H-7_A), 1.48 (dd, J¼11.5, 3.7 Hz, 1H, H-7_B); ¹³C NMR

8.10 (d, J¼2.7 Hz, 1H, H-3), 7.52 (br s, 1H, H-5 in furyl), 6.87 (d,

J¼3.4 Hz, 1H, H-3 in furyl), 6.52 (ddd, J¼3.4, 1.8 Hz, 1H, H-4 in furyl),

5.80 (m, 1H, CH]), 5.10 (m, 2H, CH₂]), 3.63 (d, J¼6.6 Hz, 2H,

NCH₂), 2.75 (s, 3H, CH₃); ¹³C NMR (CDCl₃, 75 MHz)

d 150.8 (C-1),

149.8 (C-2 in furyl), 143.8 (C-4), 142.8 (C-5 in furyl), 134.8 (CH]),

131.1 (C-2), 124.8 (C-6), 124.4 (C-3), 122.1 (C-5), 118.2 (CH₂]), 112.0

(C-4 in furyl), 110.8 (C-3 in furyl), 57.7 (NCH₂), 38.9 (CH₃); MS EI m/z

(rel %) 294/292 (34/100, M^þ), 236 (85), 223 (68), 177 (43); HRMS

(EI) calcd for C₁₄H₁₃N₂O₃Cl: 292.0615. Found 292.0607.

(CDCl₃, 150 MHz) d 156.4 (C-4a), 138.4 (C-9), 136.6 (C-10), 130.8 (C-

1), 130.2 (C-3), 121.0 (C-2), 120.1 (C-10b), 116.9 (C-4), 82.6 (C-10a),

77.9 (C-8), 69.9 (C-6), 33.9 (C-6a), 29.7 (C-7); MS EI m/z (rel %) 200

(88, M^þ), 158 (100), 131 (54), 115 (20), 77 (11); HRMS (EI) calcd for

C₁₃H₁₂O₂: 200.0837. Found 200.0833.

3.1.17. tert-Butyl-allyl[2-chloro-6-(2-furyl)-4-nitrophenyl]carbamate

(4d). To a solution of N-allyl-2-chloro-6-(2-furyl)-4-nitroaniline

(3g) (480 mg, 1.72 mmol) in dry THF (50 mL) were subsequently

added Boc₂O (380 mg, 1.72 mmol), K₂CO₃(475 mg, 3.44 mmol), and

DMAP (105 mg, 0.860 mmol). The reaction was stirred at ambient

temperature for 20 h under Ar, and extracted with EtOAc

(3ꢂ20 mL). The combined organic layers were washed with water

(5ꢂ30 mL), dried (MgSO₄), and evaporated in vacuo. The product

was puriﬁed by ﬂash chromatography on silica gel eluting with

EtOAc/CH₂Cl₂/hexane (1:4:7); yield 370 mg (57%), yellow oil. NMR

data for the major rotamer is reported. ¹H NMR (CDCl₃, 300 MHz)

3.1.20. (ꢃ) (6aS,8S)-4-Chloro-5,6,6a,7,8,10a-hexahydro-8,10a-epox-

yphenanthridine (5c). A stirring solution of N-allyl-2-chloro-6-(2-

furyl)aniline (3c) (300 mg, 1.30 mmol) in dry toluene (7 mL) was

heated at 100 ^ꢀC for 24 h under Ar, cooled to ambient temperature

and concentrated in vacuo. The product was puriﬁed by ﬂash

chromatography on silica gel eluting with EtOAc/CH₂Cl₂/hexane

(1:4:15); yield 100 mg (33%, ratio 5c/6c; 15:1), mp 98e100 ^ꢀC,

colorless solid. NMR data presented are for the major isomer 5c. ¹H

NMR (CDCl₃, 600 MHz)

d

7.33 (dd, J¼7.6, 1.7 Hz, 1H, H-1), 7.28 (br d,

J¼7.6 Hz, 1H, H-3), 6.72 (m, 1H, H-2), 6.56 (dd, J¼5.7, 1.6 Hz, 1H, H-

9), 6.25 (d, J¼5.7 Hz,1H, H-10), 5.00 (dd, J¼4.6, 1.6 Hz,1H, H-8), 4.82

(br s, 1H, NH), 3.60 (ddd, J¼11.3, 5.3, 3.8 Hz, 1H, H-6_A), 3.04e2.93

(m, 1H, H-6_B), 1.94e1.89 (m, 1H, H-6a), 1.69 (dd, J¼11.4, 7.6 Hz, 1H,

H-7_A), 1.54 (ddd, J¼11.4, 4.6, 3.0 Hz, 1H, H-7_B); ¹³C NMR (CDCl₃,

d

8.55 (d, J¼2.7 Hz, 1H, H-5), 8.15 (d, J¼2.7 Hz, 1H, H-3), 7.56 (dd,

J¼1.8, 0.5 Hz, 1H, H-5 in furyl), 6.72 (d, J¼3.5 Hz, 1H, H-3 in furyl),

6.53 (dd, J¼3.5, 1.8 Hz, 1H, H-4 in furyl), 5.74 (m, 1H, CH]), 4.94 (m,

2H, CH₂]), 4.30 (m, 1H, H_Ain NCH₂), 3.88 (m, 1H, H_Bin NCH₂), 1.28

150 MHz) d 143.0 (C-4a), 138.4 (C-9), 137.1 (C-10), 129.8 (C-1), 129.4

(s, 9H, t-Bu); ¹³C NMR (CDCl₃, 75 MHz)

d

153.2 (CO), 148.6 (C-2 in

(C-3), 120.1 (C-10b), 118.8 (C-4), 117.5 (C-2), 84.3 (C-10a), 77.7 (C-8),

46.1 (C-6), 33.8 (C-6a), 31.8 (C-7); MS EI m/z (rel %) 235/233 (35/100,

M^þ), 214 (77), 190 (94), 177 (27), 164 (35); HRMS (EI) calcd for

C₁₃H₁₂ClNO: 233.0607. Found 233.0607.

furyl), 146.7 (C-4), 143.7 (C-5 in furyl), 139.7 (C-1), 136.7 (C-6 and C-

2), 132.0 (CH]), 122.7 (C-5), 120.2 (C-3), 119.3 (CH₂]), 112.5 (C-4 in

furyl), 111.3 (C-3 in furyl), 81.3 (C in t-Bu), 50.7 (NCH₂), 27.9 (CH₃in

t-Bu); MS CI m/z (rel %) 381/379 (23/65, Mþ1), 351 (18), 325 (38),

323 (100), 281 (28), 279 (80).

3.1.21. (ꢃ)

(6aS,8S)-5,6,6a,7,8,10a-Hexahydro-2-nitro-8,10a-epox-

yphenanthridine (5f). A stirring solution of N-allyl-2-(2-furyl)-4-

nitroaniline (3f) (78 mg, 0.32 mmol) in dry xylene (10 mL) was

heated at 150 ^ꢀC for 24 h under Ar, cooled to ambient temperature

and concentrated in vacuo. The product was puriﬁed by ﬂash

chromatography on silica gel eluting with acetone/hexane (1:4);

yield 10 mg (13%, ratio 5f/6f; 14:1), yellow oil. NMR data presented

3.1.18. N,N-Diallyl-2-chloro-6-(2-furyl)-4-nitroaniline (4e). To a stir-

ring solution of 2-chloro-6-(2-furyl)-4-nitroaniline (2g) (175 mg,

0.750 mmol) in THF (20 mL) at 0 ^ꢀC, NaH (90 mg, ca. 2.3 mmol, ca.

60% in mineral oil) was added. The reaction mixture was allowed to

warm to ambient temperature over 10 min. Allyl bromide (0.18 mL,

0.80 mmol) was added, the reaction mixture was stirred at ambient

temperature for 16 h and evaporated in vacuo. The resulting solid

was dissolved in CHCl₃(50 mL) and the mixture subsequently

washed with water (3ꢂ50 mL), dried (MgSO₄), and evaporated in

vacuo. The product was puriﬁed by ﬂash chromatography on silica

are for the major isomer 5f. ¹H NMR (DMSO-d₆, 600 MHz)

d 8.03 (d,

J¼2.6 Hz,1H, H-1), 7.99 (dd, J¼9.1, 2.6 Hz,1H, H-3), 7.84 (d, J¼3.9 Hz,

1H, NH), 6.76 (d, J¼9.1 Hz, 1H, H-4), 6.66 (dd, J¼5.6, 1.6 Hz, 1H, H-9),

6.33 (d, J¼5.6 Hz, 1H, H-10), 4.97 (dd, J¼4.6, 1.6 Hz, 1H, H-8), 3.57

(dt, J¼12.0, 5.0 Hz,1H, H-6_A), 2.73 (t, J¼12.0 Hz,1H, H-6_B), 1.72e1.66

M.L. Read et al. / Tetrahedron 68 (2012) 1869e1885

1877

(m, 1H, H-6a), 1.58 (dd, J¼11.4, 7.5 Hz, 1H, H-7_A), 1.43 (ddd, J¼11.4,

4.6, 2.9 Hz, 1H, H-7_B); ¹³C NMR (DMSO-d₆, 150 MHz)

153.2 (C-4a),

(m, 1H, H-6_B), 1.90 (m, 1H, H-6a), 1.64 (dd, J¼11.6, 7.5 Hz, 1H, H-7_A),

1.47 (m, 1H, H-7_B); ¹³C NMR (CD₂Cl₂, 75 MHz)

152.4 (C-4a), 140.5

d

140.0 (C-9), 136.5 (C-10), 136.1 (C-2), 128.4 (C-1), 126.2 (C-3), 116.7

(C-10b), 114.2 (C-4), 83.8 (C-10a), 77.6 (C-8), 45.0 (C-6), 32.2 (C-6a

or C-7), 32.2 (C-6a or C-7); MS EI m/z (rel %) 244 (100, M^þ), 232 (31),

201 (69), 175 (28), 129 (13); HRMS (EI) calcd for C₁₃H₁₂N₂O₃:

244.0848. Found 244.0852.

(C-2), 138.9 (C-9), 136.1 (C-10), 126.9 (C-1), 126.7 (C-10b), 125.7 (C-

3), 125.2 (C-4), 84.4 (C-10a), 77.9 (C-8), 55.8 (C-6), 42.6 (CH₃), 30.9

(C-7), 30.3 (C-6a); MS EI m/z (rel %) 294/292 (34/100, M^þ), 275 (34),

265 (25), 263 (22), 249 (24), 236 (45); HRMS (EI) calcd for

C₁₄H₁₃N₂O₃Cl: 292.0615. Found 292.0614.

3.1.22. (ꢃ)

(6aS,8S)-2-Chloro-5,6,6a,7,8,10a-hexahydro-2-nitro-

3.1.24.2. (ꢃ) (6aR,8S)-2-Chloro-5,6,6a,7,8,10a-hexahydro-2-

nitro-5-methyl-8,10a-epoxyphenanthridine (6j). Yellow oil. ¹H NMR

8,10a-epoxyphenanthridine (5g). A stirring solution of N-allyl-2-

chloro-6-(2-furyl)-4-nitroaniline (3g) (90 mg, 0.33 mmol) in dry

toluene (5 mL) was heated at 100 ^ꢀC for 16 h under Ar, cooled to

ambient temperature and concentrated in vacuo. The product was

puriﬁed by ﬂash chromatography on silica gel eluting with EtOAc/

hexane (3:17); yield 80 mg (88%, ratio 5g/6g; 9:1), waxy yellow

solid. NMR data presented are for the major isomer 5g. ¹H NMR

(CD₂Cl₂, 300 MHz)

d

8.15 (d, J¼2.7 Hz, 1H, H-3), 8.02 (d, J¼2.7 Hz,

1H, H-1), 6.71 (dd, J¼5.6, 1.8 Hz, 1H, H-9), 5.98 (d, J¼5.6 Hz, 1H, H-

10), 5.15 (dd, J¼4.5, 1.8 Hz, 1H, H-8), 3.62 (dd, J¼11.2, 5.8 Hz, 1H, H-

6_A), 3.25 (s, 3H, CH₃), 2.59 (t, J¼11.2 Hz, 1H, H-6_B), 2.27 (m, 1H, H-

7_A), 2.08 (m, 1H, H-6a), 1.09 (dd, J¼11.3, 5.0 Hz, 1H, H-7_B); ¹³C NMR

(CD₂Cl₂, 75 MHz)

d 152.4 (C-4a), 139.7 (C-9), 138.5 (C-2), 134.4 (C-

(CD₂Cl₂, 300 MHz)

d

8.19 (br s, 2H, H-1 and H-3), 6.61 (dd, J¼5.7,

10), 128.9 (C-10a), 127.5 (C-3), 120.4 (C-4), 117.4 (C-1), 84.4 (C-10b),

80.4 (C-8), 56.6 (C-6), 43.1 (CH₃), 39.1 (C-6a), 30.6 (C-7); MS EI m/z

(rel %) 294/292 (33/100, M^þ), 275 (31), 265 (35), 263 (28), 236 (55),

223 (40); HRMS (EI) calcd for C₁₄H₁₃N₂O₃Cl: 292.0615. Found

292.0616.

1.7 Hz, 1H, H-9), 6.24 (d, J¼5.7 Hz, 1H, H-10), 5.65 (br s, 1H, NH),

5.00 (dd, J¼4.5, 1.7 Hz,1H, H-8), 3.70 (m, 1H, H-6_A), 3.03 (dd, J¼12.0,

0.5 Hz, 1H, H-6_B), 1.86 (m, 1H, H-6a), 1.68 (dd, J¼11.5, 7.4 Hz, 1H, H-

7_A), 1.55 (m, 1H, H-7_B); ¹³C NMR (CD₂Cl₂, 75 MHz)

d 148.3 (C-4a),

139.8 (C-9), 137.5 (C-2), 136.1 (C-10), 126.8 (C-1), 125.5 (C-3), 118.9

(C-10b), 118.1 (C-4), 84.0 (C-10a), 78.4 (C-8), 45.9 (C-6), 33.1 (C-6a),

32.3 (C-7); MS EI m/z (rel %) 280/278 (32/100, M^þ), 235 (56), 222

(41); HRMS (EI) calcd for C₁₃H₁₁N₂O₃Cl: 278.0458. Found 278.0466.

3.1.25. (ꢃ) (6aS,8S)-5-Allyl-4-chloro-5,6,6a,7,8,10a-hexahydro-2-

nitro-8,10a-epoxyphenanthridine (5l). A stirring solution of N,N-dia-

llyl-2-chloro-6-(2-furyl)-4-nitroaniline (4e) (620 mg, 1.95 mmol) in

dry toluene (10 mL) was heated at 100 ^ꢀC for 24 h under Ar, cooled to

ambient temperature and concentrated in vacuo. The residue was

dissolved in CH₂Cl₂(50 mL), washed with water (2ꢂ50 mL), dried

(MgSO₄), and evaporated in vacuo; yield 470 mg (76%, ratio 5l/6l;

4:1), yellow oil. NMR data presented are for the major isomer 5l. ¹H

3.1.23. (ꢃ) (6aS,8S)-5-Allyl-4-chloro-5,6,6a,7,8,10a-hexahydro-8,10a-

epoxyphenanthridine (5i). A stirring solution of N,N-diallyl-2-

chloro-6-(2-furyl)aniline (4b) (130 mg, 0.480 mmol) in dry tolu-

ene (10 mL) was heated at 100 ^ꢀC for 24 h under Ar, cooled to

ambient temperature and concentrated in vacuo. The residue was

dissolved in EtOAc (200 mL), washed with water (2ꢂ100 mL),

dried (MgSO₄), and evaporated in vacuo; crude yield 112 mg (ratio

of 5i, 6i and unconverted 4b: 7:1:5), colorless oil. Attempts to

purify by chromatography were not successful. NMR data pre-

sented are for the major isomer 5i. ¹H NMR (CDCl₃, 600 MHz)

NMR (CDCl₃, 500 MHz)

d

8.22 (q, J¼2.7 Hz, 2H, H-1 and H-3), 6.57

(dd, J¼5.7, 1.7 Hz, 1H, H-9), 6.21 (d, J¼5.7 Hz, 1H, H-10), 6.07e5.95

(m, 1H, CH]), 5.38e5.21 (m, 2H, CH₂]), 4.99 (dd, J¼4.5, 1.7 Hz, 1H,

H-8), 4.16 (ddd, J¼15.9, 3.9, 1.8 Hz, 1H, H_Ain NCH₂), 3.68 (dd, J¼15.9,

7.3 Hz, 1H, H_Bin NCH₂), 3.44 (dd, J¼13.6, 4.5 Hz, 1H, H-6_A), 2.83e2.74

(m, 1H, H-6_B), 1.84 (m, 1H, H-6a), 1.64 (dd, J¼11.5, 7.6 Hz, 1H, H-7_A),

1.46 (ddd, J¼11.6, 4.5, 3.2 Hz, 1H, H-7_B); ¹³C NMR (CDCl₃, 125 MHz)

d

7.41e7.35 (m, 1H, H-1 or H-3), 7.27 (dd, J¼8.0, 1.7 Hz, 1H, H-1 or

H-3), 6.99 (t, J¼7.7 Hz, 1H, H-2), 6.54 (dd, J¼5.7, 1.7 Hz, 1H, H-9),

6.27 (d, J¼5.7 Hz, 1H, H-10), 6.14e6.06 (m, 1H, CH]), 5.30 (ddd,

J¼13.7, 10.9, 0.9 Hz, 2H, CH₂]), 4.99 (dd, J¼4.5, 1.7 Hz, 1H, H-8),

3.98 (ddd, J¼15.3, 3.9, 1.9 Hz, 1H, H_Ain NCH₂), 3.55 (dd, J¼15.3,

7.9 Hz, 1H, H_Bin NCH₂), 3.44 (dd, J¼13.7, 4.3 Hz, 1H, H-6_A),

2.87e2.72 (m, 1H, H-6_B), 1.97 (ddd, J¼12.2, 7.6, 3.7 Hz, 1H, H-6a),

1.64 (dd, J¼11.4, 7.7 Hz, 1H, H-7_A), 1.45 (ddd, J¼11.4, 4.3, 3.5 Hz, 1H,

d 152.1 (C-4a), 140.7 (C-2 or C-4), 139.1 (C-9), 136.4 (C-10), 134.8

(CH]),127.5 (C-2 or C-4),127.3 (C-10b),126.9 (C-1 or C-3),125.9 (C-1

or C-3), 118.4 (CH₂]), 84.7 (C-10a), 78.1 (C-8), 56.6 (NCH₂), 51.5 (C-

6), 31.2 (C-7), 30.8 (C-6a); MS EI m/z (rel %) 320/318 (34/100, M^þ),

301 (35), 277 (11), 203 (22); HRMS (EI) calcd for C₁₆H₁₅ClN₂O₃:

318.0771. Found 318.0765.

H-7_B); ¹³C NMR (CDCl₃, 150 MHz)

d

146.5 (C-10b), 137.9 (C-9), 137.2

3.1.26. 2-(2-Furyl)pyridin-3-amine

(10a). Dry

KF

(150 mg,

(C-10), 136.0 (CH]), 135.9 (C-4a), 131.0 (C-1 or C-3), 129.4 (C-1 or

C-3), 128.5 (C-4), 122.5 (C-2), 117.3 (CH₂]), 84.8 (C-10a), 77.8 (C-

8), 56.2 (NCH₂), 50.4 (C-6), 31.0 (C-7), 29.2 (C-6a); MS EI m/z (rel %)

275/273 (33/100, M^þ), 246 (21), 238 (37), 232 (20); HRMS (EI)

calcd for C₁₆H₁₆NOCl: 273.0920. Found 273.0919.

2.57 mmol) and Pd(t-Bu₃P)₄(12 mg, 0.023 mmol) were added to

a solution of 3-amino-2-chloropyridine (8a) (100 mg, 0.780 mmol)

and 2-furylboronic acid (175 mg, 1.56 mmol) in dry dioxane. The

reaction mixture was heated at reﬂux for 18 h. After cooling, the

mixture was extracted with EtOAc (3ꢂ40 mL), the combined or-

ganic layers were washed with water (5ꢂ20 mL), dried (MgSO₄),

and evaporated in vacuo. The product was puriﬁed by ﬂash chro-

matography on silica gel eluting with EtOAc/hexane (1:2); yield

3.1.24. (ꢃ) (6aS,8S)-2-Chloro-5,6,6a,7,8,10a-hexahydro-2-nitro-5-

methyl-8,10a-epoxyphenanthridine (5j) and (ꢃ) (6aR,8S)-2-chloro-

5,6,6a,7,8,10a-hexahydro-2-nitro-5-methyl-8,10a-epoxyphenan-

thridine (6j). A stirring solution of N-allyl-2-chloro-6-(2-furyl)-N-

methyl-4-nitroaniline (4c) (150 mg, 0.512 mmol) in dry toluene

(10 mL) was heated at 100 ^ꢀC for 16 h under Ar, cooled to ambient

temperature and concentrated in vacuo. The products were sepa-

rated by ﬂash chromatography on silica gel eluting with EtOAc/

hexane (3:7); yield 100 mg (66%) 5j and 35 mg (24%) 6j.

110 mg (88%), yellow oil. ¹H NMR (CDCl₃, 300 MHz)

d 8.02 (s, 1H, H-

5), 7.50 (s, 1H, H-5 in furyl), 7.01e6.92 (m, 3H, H-3 in furyl, H-4 and

H-6), 6.51 (dd, J¼3.5, 1.8 Hz, 1H, H-4 in furyl), 4.62 (br s, 2H, NH₂);

¹³C NMR (CDCl₃, 75 MHz)

d 154.2 (C-2 in furyl), 141.8 (C-5 in furyl),

139.2 (C-3), 139.1 (C-6), 133.9 (C-2), 123.9 (C-5), 122.8 (C-4), 111.6

(C-4 in furyl), 108.8 (C-3 in furyl); MS EI m/z (rel %) 160 (100, M^þ),

131 (65), 104 (15); HRMS (EI) calcd for C₉H₈N₂O: 160.0637. Found

160.0632.

3.1.24.1. (ꢃ) (6aS,8S)-2-Chloro-5,6,6a,7,8,10a-hexahydro-2-nitro-

5-methyl-8,10a-epoxyphenanthridine (5j). Yellow oil. ¹H NMR

3.1.27. 2-Chloro-4-(2-furyl)pyridin-3-amine (10c). 2-Chloro-4-(2-

furyl)-3-nitropyridine (9) (330 mg, 1.47 mmol cont. ca. 10% of the

regioisomer 4-chloro-2-(2-furyl)-3-nitropyridine) and Raney

nickel (250 mg) were added to a ﬂask containing methanol (25 mL).

(CD₂Cl₂, 300 MHz)

d

8.20 (m, 2H, H-1 and H-3), 6.57 (dd, J¼5.7,

1.7 Hz, 1H, H-9), 6.20 (d, J¼5.7 Hz, 1H, H-10), 4.98 (dd, J¼4.5, 1.7 Hz,

1H, H-8), 3.34 (dd, J¼13.4, 4.5 Hz, 1H, H-6_A), 3.18 (s, 3H, CH₃), 2.96

1878

M.L. Read et al. / Tetrahedron 68 (2012) 1869e1885

The mixture was stirred under H₂-atm for 16 h at ambient tem-

perature, ﬁltered through a short plug of Celite, and evaporated in

vacuo. The product was puriﬁed by ﬂash chromatography on silica

gel eluting with EtOAc/CH₂Cl₂/hexane (1:3:6); yield 230 mg [81%,

cont. ca. 20% of the regioisomer 4-chloro-2-(2-furyl)pyridin-3-

amine], yellow oil. Data for the title compound are given. ¹H NMR

EI m/z (rel %) 197/195 (38/100, M^þ), 168 (19), 166 (49), 67 (3); HRMS

(EI) calcd for C₈H₆ClN₃O: 195.0199. Found 195.0197.

3.1.31. 2,4-Di(2-furyl)-pyrimidin-5-amine (10h). A mixture of

Pd(OAc)₂(20 mg, 0.070 mmol), PPh₃(80 mg, 0.30 mmol), potas-

sium (2-furyl)triﬂuoroborate (530 mg, 3.00 mmol), K₂CO₃(340 mg,

2.46 mmol), and 2,4-dichloropyrimidine-5-amine (8d) (200 mg,

1.20 mmol) in EtOH (50 mL, 96%) was stirred at 80 ^ꢀC for 16 h under

Ar, and evaporated in vacuo. The product was puriﬁed by ﬂash

chromatography on silica gel eluting with EtOAc/CH₂Cl₂/hexane

(1:5:5); yield 220 mg (80%), mp 173e175 ^ꢀC (dec), yellow solid. ¹H

(CDCl₃, 500 MHz)

d

7.77 (d, J¼5.1 Hz, 1H, H-6), 7.59 (d, J¼1.1 Hz, 1H,

H-5 in furyl), 7.29 (d, J¼5.1 Hz,1H, H-5), 6.81 (d, J¼3.4 Hz,1H, H-3 in

furyl), 6.57 (dd, J¼3.4, 1.8 Hz, 1H, H-4 in furyl), 4.93 (s, 2H, NH₂); ¹³

C

NMR (CDCl₃, 125 MHz)

d 150.9 (C-2 in furyl), 143.1 (C-5 in furyl),

139.2 (C-2 or C-3), 137.6 (C-6), 135.5 (C-2 or C-3), 122.8 (C-4), 120.0

(C-5), 112.1 (C-4 in furyl), 109.8 (C-3 in furyl); MS EI m/z (rel %) 196/

194 (33/100, M^þ), 167 (16), 165 (49), 129 (49); HRMS (EI) calcd for

C₉H₇ClN₂O: 194.0247. Found 194.0243.

NMR (CDCl₃, 300 MHz)

d

8.28 (s,1H, H-4), 7.62 (dd, J¼1.7, 0.8 Hz,1H,

H-5 in furyl), 7.53 (dd, J¼1.7, 0.8 Hz,1H, H-5 in furyl), 7.37 (dd, J¼3.5,

0.8 Hz, 1H, H-3 in furyl), 7.12 (dd, J¼3.5, 0.8 Hz, 1H, H-3 in furyl),

6.61 (dd, J¼3.5, 1.7 Hz, 1H, H-4 in furyl), 6.50 (dd, J¼3.5, 1.7 Hz, 1H,

3.1.28. 4,6-Di(2-furyl)-pyrimidin-5-amine (10e). The title com-

pound was formed as a by-product in the synthesis of compound

10d;⁶yield 200 mg (36%), mp 91e92 ^ꢀC, yellow solid. ¹H NMR

H-4 in furyl), 3.86 (br s, 2H, NH₂); ¹³C NMR (CDCl₃, 75 MHz)

d 153.3

(C-2 in furyl), 152.5 (C-2 in furyl), 148.7 (C-2, C-5, or C-6), 145.8 (C-

4), 144.0 (C-5 in furyl), 143.8 (C-5 in furyl), 139.1 (C-2, C-5, or C-6),

134.1 (C-2, C-5, or C-6), 112.8 (C-3 in furyl),112.4 (C-4 in furyl), 112.0

(C-4 in furyl), 110.4 (C-3 in furyl); MS EI m/z (rel %) 227 (100, M^þ),

198 (37), 171 (7), 114 (6), 78 (6); HRMS (EI) calcd for C₁₂H₉N₃O₂:

227.0695. Found 227.0694.

(CDCl₃, 300 MHz)

in furyl), 7.29 (dd, J¼5.5, 0.7 Hz, 2H, H-3 in furyl), 6.59 (dd, J¼3.5,1.7,

2H, H-4 in furyl), 5.73 (s, 2H, NH₂); ¹³C NMR (CDCl₃, 75 MHz)

153.2

d

8.54 (s, 1H, H-2), 7.61 (dd, J¼1.7, 0.7 Hz, 2H, H-5

d

(C-2 in furyl), 147.4 (C-2), 143.6 (C-5 in furyl), 140.4 (C-4), 132.3 (C-

5), 112.5 (C-3 in furyl), 112.1 (C-4 in furyl); MS EI m/z (rel %) 227

(100, M^þ), 198 (39), 170 (18), 78 (7); HRMS (EI) calcd for C₁₂H₉N₃O₂:

227.0695. Found 227.0699.

3.1.32. N-Allyl-2-(2-furyl)pyridin-3-amine (11a). A solution of 2-(2-

furyl)pyridine-3-amine (10a) (70 mg, 0.44 mmol) in THF (10 mL)

was treated with NaH (18 mg, ca. 0.44 mmol, ca. 65% in mineral oil)

and stirred at ambient temperature for 20 min under N₂. Allyl

bromide (0.2 mL, 2 mmol) and Bu₄NBr (283 mg, 0.878 mmol) were

added. The mixture was heated at 80 ^ꢀC for 12 h, and concentrated

in vacuo. The product was puriﬁed by ﬂash chromatography on

silica gel eluting with EtOAc/hexane (2:3); yield 60 mg (68%), yel-

3.1.29. 4-(2-Furyl)-6-phenyl-pyrimidin-5-amine (10f). A mixture of

Pd(OAc)₂(7 mg, 0.03 mmol), PPh₃(30 mg, 0.11 mmol), potassium

phenyltriﬂuoroborate (200 mg, 1.10 mmol), K₂CO₃(300 mg,

2.20 mmol), and 4-chloro-6-(2-furyl)pyrimidin-5-amine (10d)

(140 mg, 0.700 mmol) in EtOH (10 mL, 96%) was stirred at 60 ^ꢀC

for 1 h under Ar, before CH₂Cl₂(50 mL) was added to the re-

action mixture, and the resulting mixture subjected to dry ﬂash

chromatography on a short plug of silica. The column was

washed with acetone (50 mL) and the solution was evaporated in

vacuo. The product was puriﬁed by ﬂash chromatography on

silica gel eluting with EtOAc/CH₂Cl₂/hexane (1:5:5); yield

156 mg (94%), mp 122e125 ^ꢀC, yellow solid. ¹H NMR (CDCl₃,

low oil. ¹H NMR (CDCl₃, 300 MHz)

d

7.96 (dd, J¼4.4, 1.4 Hz, 1H, H-6),

7.60 (s, 1H, H-5 in furyl), 7.11e6.99 (m, 3H, H-5 and H-6, H-3 in

furyl), 6.60 (ddd, J¼3.5, 1.8 Hz, 1H, H-4 in furyl), 6.03 (m, 1H, CH]),

5.94 (br s, 1H, NH), 5.38e5.22 (m, 2H, CH₂]), 3.92 (m, 2H, NCH₂);

¹³C NMR (CDCl₃, 75 MHz)

d 155.6 (C-2 in furyl), 142.0 (C-5 in furyl),

141.1 (C-3), 137.7 (C-6), 135.1 (CH]), 135.4 (C-2), 123.7 (CH₂]),

111.9 (C-4 in furyl), 109.1 (C-3 in furyl), 45.9 (NCH₂); MS EI m/z (rel

%) 200 (100, M^þ), 171 (44), 131 (53); HRMS (EI) calcd for C₁₂H₁₂N₂O:

200.0950. Found 200.0942.

300 MHz)

d 8.66 (s, 1H, H-2), 7.77e7.67 (m, 2H, Ph), 7.62 (br s,

1H, H-5 in furyl), 7.57e7.40 (m, 3H, Ph), 7.30 (d, J¼3.4 Hz, 1H, H-3

in furyl), 6.61 (dd, J¼3.4, 1.7 Hz, 1H, H-4 in furyl), 4.85 (s, 2H,

NH₂); ¹³C NMR (CDCl₃, 75 MHz)

d

153.5 (C-2 in furyl), 153.2 (C-

3.1.33. N-Allyl-4-chloro-2-(2-furyl)pyridin-3-amine (11b). Method

4), 148.6 (C-2), 143.8 (C-5 in furyl), 139.4 (C-5 or C-6), 136.6 (C-1

in Ph), 133.8 (C-5 or C-6), 129.8 (C-3 or C-4 in Ph), 129.3 (C-3 or

C-4 in Ph), 128.6 (C-2 in Ph), 112.5 (C-3 or C-4 in furyl), 112.4 (C-3

or C-4 in furyl); MS EI m/z (rel %) 237 (100, M^þ), 236 (91), 208

(14), 104 (7), 77 (5); HRMS (EI) calcd for C₁₄H₁₁N₃O: 237.0902.

Found 237.0894.

A:

A

solution of 4-chloro-2-(2-furyl)pyridin-3-amine (10b)

(150 mg, 0.770 mmol) in THF (15 mL) at 0 ^ꢀC was treated with NaH

(35 mg, ca. 0.95 mmol, ca. 60% in mineral oil) and stirred at ambient

temperature for 20 min under N₂. Allyl bromide (0.07 mL,

0.8 mmol) was added and the mixture was heated at 80 ^ꢀC for 3 h,

and concentrated in vacuo. The residue was dissolved in CHCl₃

(50 mL), washed with water (3ꢂ50 mL), dried (MgSO₄), and evap-

orated in vacuo. The product was puriﬁed by ﬂash chromatography

on silica gel eluting with EtOAc; yield 45 mg (39%), yellow oil. (ꢃ)

(6aS,8S)-4-Chloro-5,6,6a,7,8,10a-hexahydro-8,10a-epoxybenzo[c]

[1,5]naphthyridine (13b) and isomer 14b; 28 mg (16%; 12:1 ratio)

were also isolated (data see below).

3.1.30. 2-Chloro-4-(2-furyl)-pyrimidin-5-amine (10g). Tri(2-furyl)

phosphine (36 mg, 0.16 mmol) and Pd₂(dba)₃(20 mg, 0.020 mmol)

were added to DMF (10 mL) under N₂at ambient temperature and

stirred for 10 min. Subsequently, 2,4-dichloropyrimidine-5-amine

(8d) (100 mg, 0.600 mmol) and (2-furyl)tributyltin (0.2 mL,

0.6 mmol) were added. The mixture was stirred at 60 ^ꢀC for 16 h,

and evaporated in vacuo. The residue was dissolved in satd KF in

THF (20 mL), stirred at ambient temperature for 16 h, and evapo-

rated in vacuo. The residue was placed on top of a ﬂash chroma-

tography column and the product was puriﬁed by ﬂash

chromatography on silica gel eluting with EtOAc/CH₂Cl₂/hexane

(5:8:12); yield 73 mg (61%), mp 169e170 ^ꢀC, yellow solid. ¹H NMR

Method B: A solution of 4-chloro-2-(2-furyl)pyridin-3-amine

(10b) (810 mg, 4.17 mmol) and 15-crown-5-ether (1.65 mL,

8.40 mmol) in dry toluene (100 mL) at 0 ^ꢀC was treated with NaH

(330 mg, ca. 8.40 mmol, ca. 60% in mineral oil) and stirred for

10 min under N₂. Allyl bromide (0.75 mL, 4.80 mmol) was added

and the mixture was stirred at 45 ^ꢀC for 16 h before water (50 mL)

was added. The resulting mixture was extracted with EtOAc

(3ꢂ50 mL), dried (MgSO₄), and concentrated in vacuo. The product

was puriﬁed by ﬂash chromatography on silica gel eluting with

EtOAc/CH₂Cl₂/hexane (1:3:6); yield 760 mg (78%), yellow oil. ¹H

(CDCl₃, 500 MHz)

d

8.08 (s, 1H, H-4), 7.61 (dd, J¼1.8, 0.7 Hz, 1H, H-5

in furyl), 7.31 (dd, J¼3.6, 0.7 Hz, 1H, H-3 in furyl), 6.59 (dd, J¼3.6,

1.8 Hz, 1H, H-4 in furyl), 4.71 (s, 2H, NH₂); ¹³C NMR (CDCl₃, 75 MHz)

d

152.4 (C-2 in furyl), 149.6 (C-2), 148.2 (C-4), 144.6 (C-5 in furyl),

NMR (CD₂Cl₂, 600 MHz)

1H, H-5 in furyl), 7.19 (d, J¼5.0 Hz,1H, H-5), 7.09 (d, J¼3.4 Hz, 1H, H-

d

8.08 (d, J¼5.0 Hz, 1H, H-6), 7.63e7.53 (m,

141.3 (C-6), 135.1 (C-1), 113.9 (C-3 in furyl), 112.8 (C-4 in furyl); MS

M.L. Read et al. / Tetrahedron 68 (2012) 1869e1885

1879

3 in furyl), 6.57 (dd, J¼3.4, 1.8 Hz,1H, H-4 in furyl), 5.91 (ddt, J¼16.3,

10.3, 5.9 Hz, 1H, CH]), 5.25e5.05 (m, 2H, CH₂]), 4.60 (s, 1H, NH),

eluting with CH₂Cl₂/EtOAc/hexane (4:1:5); yield 265 mg (41%),

colorless oil. ¹H NMR (400 MHz, CDCl₃)

8.82 (s, 1H, H-2), 7.66 (d,

d

3.72 (d, J¼6.1 Hz, 2H, NCH₂); ¹³C NMR (CD₂Cl₂, 150 MHz)

d

153.2 (C-

J¼1.8 Hz, 2H, H-5 in furyl), 7.42 (d, J¼3.5 Hz, 2H, H-3 in furyl), 6.64

2), 143.3 (C-5 in furyl), 142.7 (C-6), 142.3 (C-2), 139.7 (C-3), 136.3

(CH]), 124.1 (C-5), 117.9 (C-4), 116.7 (CH₂]), 112.2 (C-4 in furyl),

111.9 (C-3 in furyl), 50.7 (NCH₂); MS EI m/z (rel %) 236/234 (33/100,

M^þ), 217 (44), 205 (96), 193 (13), 178 (29), 165 (80); HRMS (EI) calcd

for C₁₂H₁₁ClN₂O: 234.0560. Found 234.0553.

(dd, J¼3.5, 1.8 Hz, 2H, H-4 in furyl), 5.99e5.75 (m, 1H, CH]),

5.31e5.00 (m, 3H, CH₂] and NH), 3.59 (d, J¼5.7 Hz, 2H, NCH₂); ¹³

C

NMR (100 MHz, CDCl₃)

d 151.7 (C-2 in furyl or C-2), 151.6 (C-2 in

furyl or C-2), 147.9 (C-4), 144.3 (C-5 in furyl), 135.4 (CH]), 134.5 (C-

5), 116.4 (CH₂]), 114.5 (C-3 in furyl), 112.3 (C-4 in furyl), 50.5

(NCH₂); MS EI m/z (rel %) 267 (100, M^þ), 240 (7), 211 (15); HRMS (EI)

calcd for C₁₅H₁₃N₃O₂: 267.1008. Found. 267.1012.

3.1.34. N-Allyl-2-chloro-4-(2-furyl)pyridin-3-amine

(11c). NaH

(150 mg, ca. 2.60 mmol, ca. 60% in mineral oil) was added to a so-

lution of 2-chloro-4-(2-furyl)pyridin-3-amine (10c) [230 mg, ca.

1.19 mmol, cont. ca. 20% of the regioisomer 4-chloro-2-(2-furyl)

pyridin-3-amine] and 15-crown-5-ether (0.5 mL, 3 mmol) in dry

toluene (40 mL) at ambient temperature, and the resulting mixture

was stirred under Ar for 10 min. Allyl bromide (0.13 mL, 1.4 mmol)

was added and the mixture was stirred for 16 h. Water (10 mL) was

added and the resulting mixture was extracted with EtOAc

(3ꢂ20 mL). The combined organic extracts were dried and con-

centrated in vacuo. The product was puriﬁed by ﬂash chromatog-

raphy on silica gel eluting with EtOAc/CH₂Cl₂/hexane (1:4:14);

3.1.37. N-Allyl-4-(2-furyl)-6-phenyl-pyrimidin-5-amine (11f). NaH

(30 mg, ca. 0.77 mmol, ca. 60% in mineral oil) was added to a solu-

tion of 4-(2-furyl)-6-phenyl-pyrimidin-5-amine (10f) (130 mg,

0.550 mmol) and 15-crown-5-ether (0.22 mL, 1.1 mmol) in dry

toluene (10 mL) at 0 ^ꢀC, and the resulting mixture was stirred under

N₂for 10 min. Allyl bromide (0.06 mL, 0.7 mmol) was added and

the mixture was stirred for 4 h at ambient temperature. Water

(10 mL) was added and the resulting mixture was extracted with

EtOAc (3ꢂ20 mL). The combined organic extracts were dried

(MgSO₄) and concentrated in vacuo. The product was puriﬁed by

ﬂash chromatography on silica gel eluting with EtOAc/CH₂Cl₂/

hexane (2:5:5); yield 90 mg (60%), yellow oil. ¹H NMR (CDCl₃,

yield 120 mg (43%), colorless oil. ¹H NMR (CDCl₃, 300 MHz)

d 7.89

(d, J¼5.1 Hz, 1H, H-6), 7.46 (dd, J¼1.8, 0.5 Hz, 1H, H-5 in furyl), 7.40

(d, J¼5.1 Hz, 1H, H-5), 6.98 (dd, J¼3.4, 0.5 Hz, 1H, C-3 in furyl), 6.47

(dd, J¼3.4, 1.8 Hz, 1H, H-4 in furyl), 5.82 (ddt, J¼16.9, 10.3, 5.8 Hz,

1H, CH]), 5.10 (m, 2H, CH₂]), 3.96 (br s, 1H, NH), 3.48 (dd, J¼6.7,

300 MHz) d 8.70 (s, 1H, H-2), 7.85e7.72 (m, 2H, H-2, H-6 in Ph), 7.57

(dd, J¼1.8, 0.8 Hz, 1H, H-5 in furyl), 7.46e7.32 (m, 3H, H-3 and H-4,

H-5 in Ph), 7.28 (dd, J¼3.5, 0.8 Hz, 1H, H-3 in furyl), 6.55 (dd, J¼3.5,

1.8 Hz, 1H, H-4 in furyl), 5.59 (ddt, J¼17.4, 10.0, 5.8 Hz, 1H, CH]),

5.8 Hz, 2H, NCH₂); ¹³C NMR (CDCl₃, 75 MHz)

d 149.5 (C-2 in furyl),

146.0 (C-4), 143.5 (C-5 in furyl), 142.1 (C-6), 137.7 (C-2), 135.7

(CH]), 131.3 (C-3), 121.1 (C-5), 117.0 (CH₂]), 112.6 (C-3 or C-4 in

furyl), 112.5 (C-3 or C-4 in furyl), 49.9 (NCH₂); MS EI m/z (rel %) 236/

234 (36/100, M^þ), 205 (29), 178 (54), 165 (45), 129 (42), 102 (19);

HRMS (EI) calcd for C₁₂H₁₁ClN₂O: 234.0560. Found 234.0556.

5.21e4.60 (m, 3H, CH₂] and NH), 3.25 (d, J¼5.8 Hz, 2H, NCH₂); ¹³

C

NMR (CDCl₃, 75 MHz) d 157.0 (C-6), 152.9 (C-2 in furyl), 150.6 (C-2),

145.0 (C-4), 144.3 (C-5 in furyl), 138.8 (C-1 in Ph), 136.9 (C-5), 135.7

(CH]), 129.8 (C-4 in Ph), 129.1 (C-3 in Ph), 128.6 (C-2 in Ph), 116.8

(CH₂]), 113.9 (C-3 in furyl), 112.7 (C-4 in furyl), 50.6 (NCH₂); MS EI

m/z (rel %) 277 (100, M^þ), 236 (6), 221 (10), 77 (10); HRMS (EI) calcd

for C₁₇H₁₅N₃O: 277.1215. Found 277.1211.

3.1.35. N-Allyl-4-chloro-6-(2-furyl)-pyrimidin-5-amine (11d). A so-

lution of 4-chloro-6-(2-furyl)-pyrimidin-5-amine (10d) (420 mg,

2.15 mmol) and 15-crown-5-ether (0.85 mL, 4.3 mmol) in dry tol-

uene (50 mL) at 0 ^ꢀC under Ar was treated with NaH (160 mg, ca.

4.30 mmol, ca. 60% in mineral oil) and stirred for 10 min. Allyl

bromine (0.17 mL, 1.9 mmol) was added and the reaction mixture

stirred for 30 min at 0 ^ꢀC and without cooling for a further 30 min.

Water (50 mL) was added, the mixture was extracted with EtOAc

(2ꢂ50 mL), the combined organic extracts were washed with satd

aq NaCl (50 mL), dried (MgSO₄), and concentrated in vacuo. The

product was puriﬁed by ﬂash chromatography on silica gel eluting

with EtOAc/CH₂Cl₂/hexane (2:3:16); yield 360 mg (71%), colorless

3.1.38. N-Allyl-2-chloro-4-(2-furyl)-pyrimidin-5-amine (11g). A so-

lution of 2-chloro-4-(2-furyl)-pyrimidin-5-amine (10g) (150 mg,

0.770 mmol) in THF (15 mL) at 0 ^ꢀC was treated with NaH (35 mg,

ca. 0.95 mmol, ca. 60% in mineral oil) and stirred at ambient tem-

perature for 10 min under N₂. Allyl bromide (0.07 mL, 0.8 mmol)

was added and the mixture was heated at 50 ^ꢀC for 2.5 h, and

concentrated in vacuo. The residue was dissolved in CHCl₃(50 mL),

washed with water (3ꢂ50 mL), dried (MgSO₄), and evaporated in

vacuo. The product was puriﬁed by ﬂash chromatography on silica

gel eluting with EtOAc/hexane (1:4); yield 42 mg (23%), yellow oil.

N,N-Diallyl-2-chloro-4-(2-furyl)pyrimidin-5-amine (12b) 58 mg

(55%) was also formed (data see below). ¹H NMR (CD₂Cl₂, 500 MHz)

oil. ¹H NMR (CDCl₃, 300 MHz)

d

8.51 (s, 1H, H-2), 7.63 (dd, J¼1.8,

0.7 Hz, 1H, H-5 in furyl), 7.36 (dd, J¼3.5, 0.7 Hz, 1H, H-3 in furyl),

6.60 (dd, J¼3.5, 1.8 Hz, 1H, H-4 in furyl), 6.05e5.85 (m, 1H, CH]),

5.18 (ddd, J¼13.7,11.5, 1.4 Hz, 2H, CH₂]), 4.22 (br s,1H, NH), 3.76 (d,

d

8.01 (s, 1H, H-6), 7.67 (dd, J¼1.8, 0.8 Hz, 1H, H-5 in furyl), 7.31 (dd,

J¼3.6, 0.8 Hz, 1H, H-3 in furyl), 6.64 (dd, J¼3.6, 1.8 Hz, 1H, H-4 in

furyl), 6.07e5.84 (m, 2H, NH and CH]), 5.37e5.18 (m, 2H, CH₂]),

J¼5.8 Hz, 2H, NCH₂); ¹³C NMR (CDCl₃, 75 MHz)

d 153.4 (C-4), 150.4

(C-2 in furyl), 150.4 (C-2), 146.0 (C-6), 144.7 (C-5 in furyl), 135.7 (C-

5), 134.9 (CH]), 117.2 (CH₂]), 115.3 (C-3 in furyl), 112.5 (C-4 in

furyl), 49.7 (NCH₂); MS EI m/z (rel %) 237/235 (34/100, M^þ), 208

(32), 194 (12), 179 (16), 168 (15); HRMS (EI) calcd for C₁₁H₁₀ClN₃O:

235.0512. Found. 235.0510.

4.00e3.78 (m, 2H, NCH₂); ¹³C NMR (CDCl₃, 125 MHz)

d 153.0 (C-2 in

furyl), 148.1 (C-4), 144.8 (C-5 in furyl), 143.7 (C-2), 141.4 (C-6), 136.4

(C-1), 134.2 (CH]), 117.1 (CH₂]), 113.7 (C-3 in furyl), 112.9 (C-4 in

furyl), 46.0 (NCH₂); MS EI m/z (rel %) 237/235 (33/100, M^þ), 208

(18), 208 (44), 144 (9); HRMS (EI) calcd for C₁₁H₁₀ClN₃O: 235.0512.

Found 235.0511.

3.1.36. N-Allyl-4,6-di(2-furyl)-pyrimidin-5-amine (11e). A solution

of 2,4-di(2-furyl)-pyrimidin-5-amine (10h) (540 mg, 2.40 mmol)

and 16-crown-8-ether (1.27 g, 4.80 mmol) in dry toluene (100 mL)

at 0 ^ꢀC under Ar was treated with KH (540 mg, ca. 4.80 mmol, ca.

35% in mineral oil) and stirred for 10 min. Allyl bromine (0.20 mL,

2.4 mmol) was added and the reaction mixture stirred for 90 min at

0 ^ꢀC. Water (50 mL) was added, the mixture was extracted with

EtOAc (2ꢂ50 mL), the combined organic extracts were washed with

satd aq NaCl (50 mL), dried (MgSO₄), and concentrated in vacuo.

The product was puriﬁed by ﬂash chromatography on silica gel

3.1.39. N-Allyl-2,4-di(2-furyl)-pyrimidin-5-amine (11h). A solution

of 2,4-di(2-furyl)pyrimidin-5-amine (10h) (55 mg, 0.24 mmol) and

18-crown-6-ether (126 mg, 0.480 mmol) in dry toluene (10 mL)

was treated with KH (40 mg, ca. 0.29 mmol, ca. 35% in mineral oil)

and stirred at ambient temperature for 10 min under Ar. Allyl

bromide (0.03 mL, 0.6 mmol) was added and the mixture was

stirred for 3 h. Water (10 mL) was added and the mixture was

extracted with EtOAc (3ꢂ20 mL). The combined organic extracts

were dried (MgSO₄) and concentrated in vacuo. The product was

1880

M.L. Read et al. / Tetrahedron 68 (2012) 1869e1885

puriﬁed by ﬂash chromatography on silica gel eluting with EtOAc/

CH₂Cl₂/hexane (1:4:4); yield 30 mg (47%), yellow wax. N,N-Diallyl-

2,4-di(2-furyl)pyrimidin-5-amine (12d) 30 mg (41%) was also iso-

d 154.4 (C-2 or C-6), 152.3 (C-4), 151.3 (C-2 or C-6), 148.8 (C-2 in

furyl), 145.7 (C-5 in furyl), 140.7 (C-5), 133.4 (CH]), 119.6 (CH₂]),

117.5 (C-3 in furyl), 112.6 (C-4 in furyl), 58.2 (NCH₂), 40.5 (CH₃); MS

EI m/z (rel %) 251/249 (22/67, M^þ), 234 (12), 222/220 (43/100), 208

(11), 182 (10), 179 (9); HRMS (EI) calcd for C₁₂H₁₂ClN₃O: 249.0669.

Found 249.0674.

lated (data, see below). ¹H NMR (CDCl₃, 300 MHz)

d 8.20 (s, 1H, H-

4), 7.60 (dd, J¼1.8, 0.8 Hz, 1H, H-5 in furyl), 7.52 (dd, J¼1.8, 0.8 Hz,

1H, H-5 in furyl), 7.37 (dd, J¼3.5, 0.8 Hz, 1H, H-3 in furyl), 7.06 (dd,

J¼3.4, 0.8 Hz, 1H, H-3 in furyl), 6.60 (dd, J¼3.5, 1.8 Hz, 1H, H-4 in

furyl), 6.49 (dd, J¼3.4, 1.8 Hz, 1H, H-4 in furyl), 5.95 (ddt, J¼17.2,

10.2, 5.1 Hz, 1H, CH]), 5.83 (br s, 1H, NH), 5.28 (m, 2H, CH₂]),

3.1.43. N,N-Diallyl-2,4-di(2-furyl)pyrimidin-5-amine (12d). A solu-

tion of 2,4-di(2-furyl)pyrimidin-5-amine (10h) (315 mg,

1.39 mmol) and 18-crown-6-ether (730 mg, 2.80 mmol) in dry

toluene (50 mL) was treated with KH (500 mg, ca. 4.20 mmol, ca.

35% in mineral oil) and stirred at ambient temperature for 10 min

under Ar. Allyl iodide (0.40 mL, 4.20 mmol) was added and the

mixture was stirred at 40 ^ꢀC for 3 h. Water (50 mL) was added and

the mixture was extracted with EtOAc (3ꢂ50 mL). The combined

organic extracts were washed with satd aq NaCl (50 mL), dried

(MgSO₄), and concentrated in vacuo. The product was puriﬁed by

ﬂash chromatography on silica gel eluting with EtOAc/CH₂Cl₂/

hexane (1:1:2); yield 332 mg (78%), mp 73e75 ^ꢀC, yellow solid. ¹H

3.99e3.89 (m, 2H, NCH₂); ¹³C NMR (CDCl₃, 75 MHz)

d 153.7 (C-2 in

furyl), 152.9 (C-2 in furyl), 147.7 (C-2 or C-6), 143.7 (C-5 in furyl),

143.5 (C-5 in furyl), 141.2 (C-4), 139.1 (C-2 or C-6), 135.1 (C-5), 134.0

(CH]), 117.3 (CH₂]), 112.7 (C-3 in furyl), 112.4 (C-4 in furyl), 111.9

(C-4 in furyl), 109.7 (C-3 in furyl), 45.7 (NCH₂); MS EI m/z (rel %) 267

(100, M^þ), 238 (9), 226 (26), 198 (34), 133 (5), 106 (15); HRMS (EI)

calcd for C₁₅H₁₃N₃O₂: 267.1008. Found 267.1007.

3.1.40. N,N-Diallyl-4-chloro-6-(2-furyl)-pyrimidin-5-amine (12a). A

solution of N-allyl-4-chloro-6-(2-furyl)-pyrimidin-5-amine (11d)

(250 mg, 1.30 mmol), allyl bromine (0.33 mL, 3.9 mmol), and 18-

crown-6-ether (410 mg, 1.55 mmol) in dry toluene (20 mL) was

treated with KH (300 mg, ca. 2.60 mmol, ca. 35% in mineral oil) and

stirred at ambient temperature for 5 h under Ar. Water (10 mL) was

added and the mixture was extracted with EtOAc (3ꢂ20 mL). The

combined organic extracts were dried (MgSO₄) and concentrated in

vacuo. The product was puriﬁed by ﬂash chromatographyon silica gel

eluting with EtOAc/hexane (1:9); yield 260 mg (72%), colorless oil.¹H

NMR (CDCl₃, 300 MHz)

d

8.41 (s,1H, H-4), 7.67 (dd, J¼1.7, 0.8 Hz,1H,

H-5 in furyl), 7.58 (dd, J¼1.7, 0.8 Hz,1H, H-5 in furyl), 7.55 (dd, J¼3.5,

0.7 Hz, 1H, H-3 in furyl), 7.28e7.21 (m, 1H, H-3 in furyl), 6.56 (dd,

J¼3.5, 1.8 Hz, 1H, H-4 in furyl), 6.52 (dd, J¼3.4, 1.8 Hz, 1H, H-4 in

furyl), 5.88e5.65 (m, 2H, 2ꢂ CH]), 5.14 (ddd, J¼6.6, 4.2, 1.0 Hz, 4H,

2ꢂ CH₂]), 3.68 (d, J¼6.4 Hz, 4H, 2ꢂ NCH₂); ¹³C NMR (CDCl₃,

75 MHz) d 152.7 (C-2 in furyl, C-2, or C-6), 152.6 (C-4), 152.4 (C-2 in

furyl, C-2, or C-6),150.2 (C-2 in furyl, C-2, or C-6),149.8 (C-2 in furyl,

C-2, or C-6), 145.1 (C-5 in furyl), 144.7 (C-5 in furyl), 137.7 (C-5),

133.5 (2ꢂ CH]), 119.4 (2ꢂ CH₂]), 116.6 (C-3 in furyl), 112.4 (C-3 in

furyl or C-4 in furyl), 112.3 (C-3 in furyl or C-4 in furyl), 112.2 (C-3 in

furyl or C-4 in furyl), 55.2 (2ꢂ NCH₂); MS EI m/z (rel %) 307 (100,

M^þ), 280 (9), 266 (18), 236 (37), 211 (13), 199 (14); HRMS (EI) calcd

for C₁₈H₁₇N₃O₂: 307.1321. Found 307.1321. The title compound was

also formed as a by-product in the synthesis of compound 11h.

NMR (CDCl₃, 400 MHz)

d

8.75 (s,1H, H-2), 7.69 (d, J¼1.8 Hz,1H, H-5 in

furyl), 7.63 (d, J¼3.5 Hz,1H, H-3 in furyl), 6.61 (dd, J¼3.5,1.8 Hz,1H, H-

4 in furyl), 5.82 (ddt, J¼16.9, 9.8, 6.9 Hz, 2H, 2ꢂ CH]), 5.11 (m, 4H, 2ꢂ

CH₂]), 3.76 (d, J¼6.9 Hz, 4H, 2ꢂ NCH₂); ¹³C NMR (CDCl₃, 100 MHz)

d

162.1 (C-4 or C-6),156.2 (C-4 or C-6),154.4 (C-2),149.3 (C-1 in furyl),

145.4 (C-5 in furyl), 136.4 (C-5), 134.2 (2ꢂ CH]), 118.8 (2ꢂ CH₂]),

118.0 (C-3 in furyl),112.5 (C-4 in furyl), 55.2 (2ꢂ NCH₂); MS EI m/z (rel

%) 277/275 (23/83 M^þ), 248 (36), 234 (57), 179 (11), 41 (100); HRMS

(EI) calcd for C₁₄H₁₄ClN₃O: 275.0825. Found 275.0828.

3.1.44. (ꢃ) (6aS,8S)-4-Chloro-5,6,6a,7,8,10a-hexahydro-8,10a-epox-

ybenzo[c][1,5]naphthyridine (13b). N-Allyl-4-chloro-(2-furyl)pyri-

dine-3-amine (11b) (85 mg, 0.36 mmol) was dissolved in dry

toluene (10 mL). The reaction mixture was heated at 100 ^ꢀC for 24 h

under Ar, allowed to cool to ambient temperature and concentrated

in vacuo. The product was puriﬁed by ﬂash chromatography on

silica gel eluting with EtOAc/CH₂Cl₂/hexane (2:3:3); yield 41 mg

(49%, ratio 13b/14b; 25:1), colorless wax. NMR data presented are

3.1.41. N,N-Diallyl-2-chloro-4-(2-furyl)-pyrimidin-5-amine

(12b). The title compound was formed as a by-product in the

synthesis of compound 11g. Yellow oil. ¹H NMR (CDCl₃, 300 MHz)

d

8.24 (s, 1H, H-2), 7.67 (dd, J¼1.7, 0.7 Hz, 1H, H-5 in furyl), 7.58 (dd,

J¼3.5, 0.7 Hz, 1H, H-3 in furyl), 6.58 (dd, J¼3.5, 1.7 Hz, 1H, H-4 in

furyl), 5.74 (ddt, J¼16.8, 10.4, 6.4 Hz, 2H, 2ꢂ CH]), 5.25e5.07 (m,

4H, 2ꢂ CH₂]), 3.65 (d, J¼6.4 Hz, 4H, 2ꢂ NCH₂); ¹³C NMR (CDCl₃,

for the major isomer 13b. ¹H NMR (CDCl₃, 500 MHz)

d 7.95 (d,

75 MHz)

d

155.3 (C-2), 154.9 (C-2 in furyl), 152.6 (C-2), 148.9 (C-6),

J¼5.0 Hz,1H, H-2), 7.15 (d, J¼5.0 Hz, 1H, H-3), 6.52 (dd, J¼5.7, 1.7 Hz,

1H, H-9), 6.35 (d, J¼5.7 Hz, 1H, H-10), 4.99 (dd, J¼4.5, 1.7 Hz, 1H, H-

8), 4.69 (s, 1H, NH), 3.56 (ddd, J¼11.4, 5.2, 4.0 Hz, 1H, H-6_A), 2.96 (m,

1H, H-6_B), 2.00e1.90 (m, 1H, H-6a), 1.68 (dd, J¼11.4, 7.6 Hz, 1H, H-

7_A), 1.52 (ddd, J¼11.4, 4.5, 3.2 Hz, 1H, H-7_B); ¹³C NMR (CDCl₃,

146.0 (C-5 in furyl), 138.8 (C-1), 133.2 (2ꢂ CH]), 120.1 (2ꢂ CH₂]),

118.0 (C-3 in furyl), 112.9 (C-4 in furyl), 55.1 (2ꢂ NCH₂); MS EI m/z

(rel %) 277/275 (34/98 M^þ), 246 (60), 179 (14), 41 (100); HRMS (EI)

calcd for C₁₄H₁₄ClN₃O: 275.0825. Found 275.0824.

125 MHz)

d 140.0 (C-4a), 139.4 (C-10b), 138.9 (C-2), 137.7 (C-9),

3.1.42. N-Allyl-2-chloro-4-(2-furyl)-N-methyl-pyrimidin-5-amine

(12c). A solution of N-allyl-2-chloro-4-(2-furyl)-pyrimidin-5-

amine (11g) (65 mg, 0.28 mmol) and 18-crown-6-ether (150 mg,

0.560 mmol) in dry toluene (10 mL) was treated with KH (64 mg,

ca. 0.56 mmol, ca. 35% in mineral oil) and stirred at ambient tem-

perature for 10 min under Ar. Methyl iodide (0.04 mL, 0.6 mmol)

was added and the mixture was stirred at 40 ^ꢀC for 30 min. Water

(10 mL) was added and the mixture was extracted with EtOAc

(3ꢂ20 mL). The combined organic extracts were dried (MgSO₄) and

concentrated in vacuo. The product was puriﬁed by ﬂash chroma-

tography on silica gel eluting with EtOAc/CH₂Cl₂/hexane (2:3:16);

136.1 (C-10), 127.4 (C-4), 124.0 (C-3), 85.2 (C-10a), 78.0 (C-8), 45.7

(C-6), 34.1 (C-6a), 32.2 (C-7); MS EI m/z (rel %) 236/234 (32/100

M^þ), 217 (8), 205 (20), 191 (47), 178 (29), 165 (28); HRMS (EI) calcd

for C₁₂H₁₁ClN₂O: 234.0560. Found 234.0558.

3.1.45. (ꢃ) (6aS,8S)-4-Chloro-6,6a,7,8,-tetrahydro-5H-8,10a-epox-

ybenzo[c][1,7]naphthyridine (13c). A stirring solution of N-allyl-2-

chloro-4-(2-furyl)pyridin-3-amine (11c) (120 mg, 0.510 mmol) in

dry toluene (20 mL) was heated at 100 ^ꢀC for 24 h under Ar, cooled

to ambient temperature and concentrated in vacuo. The product

was puriﬁed by ﬂash chromatography on silica gel eluting with

EtOAc/CH₂Cl₂/hexane (1:1:3); yield 105 mg (88%, ratio 13c/14c;

10:1), mp 156e159 ^ꢀC, colorless solid. NMR data presented are for

yield 52 mg (75%), colorless oil. ¹H NMR (CDCl₃, 300 MHz)

d 8.28 (s,

1H, H-4), 7.64 (dd, J¼1.8, 0.8 Hz, 1H, H-5 in furyl), 7.49 (dd, J¼3.5,

0.8 Hz, 1H, H-3 in furyl), 6.55 (dd, J¼3.5, 1.8 Hz, 1H, H-4 in furyl),

5.89e5.65 (m, 1H, CH]), 5.28e5.09 (m, 2H, CH₂]), 3.58 (d,

J¼6.4 Hz, 2H, NCH₂), 2.71 (s, 3H, CH₃); ¹³C NMR (CDCl₃, 75 MHz)

the major isomer 13c. ¹H NMR (CDCl₃, 600 MHz)

1H, H-2), 7.21 (d, J¼4.8 Hz,1H, H-1), 6.56 (dd, J¼5.7,1.6 Hz,1H, H-9),

6.18 (d, J¼5.7 Hz, 1H, H-10), 4.99 (dd, J¼4.5, 1.6 Hz, 1H, H-8), 4.84 (s,

d

7.75 (d, J¼4.8 Hz,

M.L. Read et al. / Tetrahedron 68 (2012) 1869e1885

1881

1H, NH), 3.59 (ddd, J¼11.6, 5.3, 4.1 Hz, 1H, H-6_A), 2.91 (m, 1H, H-6_B),

1.90e1.77 (m, 1H, H-6a), 1.66 (dd, J¼11.5, 7.6 Hz, 1H, H-7_A), 1.50

(ddd, J¼11.5, 4.5, 3.1 Hz, 1H, H-7_B); ¹³C NMR (CDCl₃, 150 MHz)

8), 46.2 (C-6), 34.6 (C-6a), 32.5 (C-7); MS EI m/z (rel %) 277 (100,

M^þ), 260 (15), 248 (38), 234 (59), 208 (13), 77 (9); HRMS (EI) calcd

for C₁₇H₁₅N₃O: 277.1215. Found 277.1210.

d

139.7 (C-4a), 139.1 (C-9), 136.8 (C-10b), 136.5 (C-2), 135.9 (C-10),

127.0 (C-4), 124.4 (C-1), 83.0 (C-10a), 78.0 (C-8), 45.7 (C-6), 33.4 (C-

6a), 31.6 (C-7); MS EI m/z (rel %) 236/234 (32/100 M^þ), 217 (8), 205

(20), 191 (47), 178 (29), 165 (28); HRMS (EI) calcd for C₁₂H₁₁ClN₂O:

234.0560. Found 234.0558.

3.1.49. (ꢃ) (6aS,8S)-5-Allyl-4-chloro-5,6,6a,7,8,10a-hexahydro-8,10a-

epoxypyrimido[5,4-c]isoquinoline (13i) and (ꢃ) (6aR,8S)-5-allyl-4-

chloro-5,6,6a,7,8,10a-hexahydro-8,10a-epoxypyrimido[5,4-c]isoquino-

line (14i). A stirring solution of N,N-diallyl-4-chloro-6-(2-furyl)-

pyrimidin-5-amine (12a) (250 mg, 0.900 mmol) in dry toluene

(60 mL) was heated at 100 ^ꢀC for 24 h under Ar, cooled to ambient

temperature and concentrated in vacuo. The product was puriﬁed by

ﬂash chromatography on silica gel eluting with EtOAc/hexane (3:2);

yield 95 mg (38%) of 13i, and 24 mg (10%) of 14i. Starting material

12a was recovered (44%).

3.1.46. (ꢃ) (6aS,8S)-4-Chloro-5,6,6a,7,8,10a-hexahydro-8,10a-epox-

ypyrimido[5,4-c]isoquinoline (13d). A stirring solution of N-allyl-4-

chloro-6-(2-furyl)-pyrimidin-5-amine (11d) (100 mg, 0.430 mmol)

in dry toluene (10 mL) was heated at 100 ^ꢀC for 16 h under Ar, cooled

to ambient temperature and concentrated in vacuo. The product was

puriﬁed by ﬂash chromatography on silica gel eluting with EtOAc/

hexane (2:3); yield 55 mg (55%, only isomer 13d), mp 156e159 ^ꢀC,

3.1.49.1. (ꢃ) (6aS,8S)-5-Allyl-4-chloro-5,6,6a,7,8,10a-hexahydro-

8,10a-epoxypyrimido[5,4-c]isoquinoline (13i). Mp 99e101 ^ꢀC, color-

colorless solid. ¹H NMR (CD₂Cl₂, 600 MHz)

d 8.36 (s, 1H, H-2), 6.55

(dd, J¼5.7, 1.7 Hz, 1H, H-9), 6.31 (d, J¼5.7 Hz, 1H, H-10), 5.01 (dd,

J¼4.5, 1.7 Hz, 1H, H-8), 4.80 (s, 1H, NH), 3.64 (ddd, J¼11.8, 5.3, 4.1 Hz,

1H, H-6_A), 2.94 (t, J¼11.8 Hz, 1H, H-6_B), 1.95e1.89 (m, 1H, H-6a), 1.71

(dd, J¼11.5, 7.6 Hz, 1H, H-7_A), 1.53 (ddd, J¼11.5, 4.5, 3.1 Hz, 1H, H-7_B);

lesssolid.¹HNMR (CDCl₃, 600 MHz)

d

8.60(s,1H, H-2), 6.56(dd,J¼5.8,

1.6 Hz, 1H, H-9), 6.35 (d, J¼5.8 Hz,1H, H-10), 5.98 (m, 1H, CH]), 5.29

(ddd, J¼13.7, 10.8, 0.8 Hz, 2H, CH₂]), 5.03 (dd, J¼4.1, 1.6 Hz,1H, H-8),

4.02 (dd, J¼15.7, 2.5 Hz, 1H, H_Ain NCH₂), 3.68 (dd, J¼15.7, 7.3 Hz, 1H,

H_BinNCH₂), 3.43(dd, J¼13.1, 4.5 Hz,1H, H-6_A), 2.80(m,1H, H-6_B),1.98

(ddd, J¼12.2, 7.6, 4.5 Hz,1H, H-6a), 1.68 (dd, J¼11.5, 7.6 Hz,1H, H-7_A),

¹³C NMR (CD₂Cl₂, 150 MHz)

d 146.3 (C-2), 145.2 (C-4), 144.9 (C-10b),

138.4 (C-9), 137.9 (C-4a), 135.4 (C-10), 84.2 (C-10a), 78.4 (C-8), 45.4

(C-6), 33.7 (C-6a), 31.9 (C-7); MS EI m/z (rel %) 235 (100, M^þ), 218

(25), 206 (47), 192 (60), 166 (20); HRMS (EI) calcd for C₁₁H₁₀ClN₃O:

235.0512. Found 235.0518.

1.53e1.43 (m, 1H, H-7_B); ¹³C NMR (CDCl₃,150 MHz)

d 153.3 (C-10b or

C-4), 152.9 (C-10b or C-4), 150.2 (C-2), 141.3 (C-4a), 138.0 (C-9), 135.2

(C-10), 134.4 (CH]), 118.1 (CH₂]), 84.3 (C-10a), 78.5 (C-8), 55.7

(NCH₂), 50.9 (C-6), 31.3 (C-7), 31.0 (C-6a); MS EI m/z (rel %) 277/275

(35/100, M^þ), 258 (25), 234 (25), 206 (26), 192 (22), 170 (11); HRMS

(EI) calcd for C₁₄H₁₄ClN₃O: 275.0825. Found 275.0819.

3.1.47. (ꢃ) (6aS,8S)-5,6,6a,7,8,10a-4-(2-Furyl)-hexahydro-8,10a-ep-

oxypyrimido[5,4-c]isoquinoline (13e). A stirring solution of N-allyl-

4,6-di(2-furyl)-pyrimidin-5-amine (11e) (265 mg, 0.990 mmol) in

dry toluene (80 mL) was heated at 100 ^ꢀC for 24 h under Ar, cooled

to ambient temperature and concentrated in vacuo. The product

was puriﬁed by ﬂash chromatography on silica gel eluting with

EtOAc/CH₂Cl₂(3:7); yield 174 mg (66%, ratio 13e/14e; 8:1) mp

167e172 ^ꢀC (dec), orange solid. NMR data presented are for the

3.1.49.2. (ꢃ) (6aR,8S)-5-Allyl-4-chloro-5,6,6a,7,8,10a-hexahydro-

8,10a-epoxypyrimido[5,4-c]isoquinoline (14i). Colorless oil. ¹H NMR

(CDCl₃, 600 MHz)

d

8.44 (s, 1H, H-2), 6.77 (dd, J¼5.6, 1.8 Hz, 1H, H-

9), 6.11 (d, J¼5.6 Hz, 1H, H-10), 5.92 (dddd, J¼17.3, 10.1, 7.3, 5.1 Hz,

1H, CH]), 5.35e5.15 (m, 3H, CH₂] and H-8), 4.29e4.10 (m, 1H, H_A

in NCH₂), 3.86 (dd, J¼15.6, 7.3 Hz, 1H, H_Bin NCH₂), 3.61 (dd, J¼11.0,

5.4 Hz, 1H, H-6_A), 2.48 (dd, J¼13.2, 11.0 Hz, 1H, H-6_B), 2.33 (ddd,

J¼11.3, 9.0, 4.6 Hz, 1H, H-7_A), 2.22 (ddd, J¼8.8, 7.7, 4.5 Hz, 1H, H-6a),

1.09 (dd, J¼11.3, 5.1 Hz, 1H, H-7_B); ¹³C NMR (CDCl₃, 150 MHz)

major isomer 13e. ¹H NMR (CDCl₃, 300 MHz)

d 8.59 (s,1H, H-2), 7.59

(dd, J¼1.8, 0.8 Hz,1H, H-5 in furyl), 7.27 (dd, J¼3.6, 0.8 Hz,1H, H-3 in

furyl), 6.58 (dd, J¼3.6, 1.8 Hz, 1H, H-4 in furyl), 6.53 (dd, J¼5.7,

1.7 Hz, 1H, H-9), 6.34 (d, J¼5.7 Hz, 1H, H-10), 6.00 (s, 1H, NH), 5.00

(dd, J¼4.4, 1.7 Hz, 1H, H-8), 3.60 (dd, J¼11.6, 5.1 Hz, 1H, H-6_A), 2.97

(t, J¼11.9 Hz, 1H, H-6_B), 2.00e1.86 (m, 1H, H-6a), 1.69 (dd, J¼11.4,

7.5 Hz, 1H, H-7_A), 1.53 (ddd, J¼11.5, 4.3, 3.2 Hz, 1H, H-7_B); ¹³C NMR

d

155.6 (C-10b), 148.1 (C-4), 148.0 (C-2), 139.9 (C-9), 137.4 (C-4a),

133.8 (CH]), 133.3 (C-10), 118.7 (CH₂]), 84.6 (C-10a), 80.8 (C-8),

57.0 (NCH₂), 53.0 (C-6), 38.7 (C-6a), 29.4 (C-6); MS EI m/z (rel %)

277/275 (33/100, M^þ) 248 (38), 240 (37), 234 (58), 206 (63); HRMS

(EI) calcd for C₁₄H₁₄ClN₃O: 275.0825. Found 275.0821.

(CDCl₃, 75 MHz) d 153.4 (C-2 in furyl),147.7 (C-2), 146.5 (C-10b or C-

4), 143.8 (C-5 in furyl), 139.4 (C-10b or C-4), 138.1 (C-4 in furyl),

136.6 (C-4a), 135.8 (C-10), 112.4 (C-3 in furyl), 112.4 (C-9), 84.6 (C-

10a), 78.3 (C-8), 45.6 (C-6), 33.7 (C-6a), 32.2 (C-7); MS EI m/z (rel %)

267 (100, M^þ), 250 (8), 238 (26), 224 (57), 210 (9), 198 (15); HRMS

(EI) calcd for C₁₅H₁₃N₃O₂: 267.1008. Found 267.1002.

3.1.50. (ꢃ) (6aS,8S)-5-Allyl-2-chloro-5,6,6a,7,8,10a-hexahydro-8,10a-

epoxypyrimido[5,4-c]isoquinoline (13j) and (ꢃ) (6aR,8S)-5-allyl-2-

chloro-5,6,6a,7,8,10a-hexahydro-8,10a-epoxypyrimido[5,4-c]isoquino-

line (14j). A stirring solution of N,N-diallyl-2-chloro-4-(2-furyl)-

pyrimidin-5-amine (12b) (58 mg, 0.20 mmol) in dry toluene (10 mL)

was heated at 100 ^ꢀC for 24 h under Ar, cooled to ambient temper-

ature and concentrated in vacuo. The product was puriﬁed by ﬂash

chromatography on silica gel eluting with EtOAc/hexane (1:1); yield

46 mg (80%) of 13j, and 12 mg (20%) of 14j.

3.1.48. (ꢃ) (6aS,8S)-5,6,6a,7,8,10a-Hexahydro-4-phenyl-8,10a-epox-

ypyrimido[5,4-c]isoquinoline (13f). A stirring solution of N-allyl-4-

(2-furyl)-6-phenyl-pyrimidin-5-amine (11f) (90 mg, 0.32 mmol) in

dry toluene (10 mL) was heated at 100 ^ꢀC for 16 h under Ar, cooled

to ambient temperature and concentrated in vacuo. The product

was puriﬁed by ﬂash chromatography on silica gel eluting with

EtOAc/CH₂Cl₂/hexane (2:5:5); yield 52 mg (58%, ratio 13f/14f;

22:1), yellow oil. NMR data presented are for the major isomer 13f.

3.1.50.1. (ꢃ) (6aS,8S)-5-Allyl-2-chloro-5,6,6a,7,8,10a-hexahydro-

8,10a-epoxypyrimido[5,4-c]isoquinoline (13j). Waxy yellow solid. ¹H

¹H NMR (CD₂Cl₂, 600 MHz)

d

8.65 (d, J¼4.7 Hz, 1H, H-2), 7.76e7.67

NMR (CD₂Cl₂, 500 MHz)

d

8.06 (s,1H, H-4), 6.53 (dd, J¼5.7,1.7 Hz,1H,

(m, 2H, H-2 in Ph), 7.56e7.45 (m, 3H, H-3 and H-4 in Ph), 6.64e6.50

(m, 1H, H-10), 6.38 (d, J¼5.7 Hz, 1H, H-9), 4.99 (dd, J¼4.5, 1.7 Hz, 1H,

H-8), 4.76 (s, 1H, NH), 3.47 (ddd, J¼11.5, 5.0, 4.2 Hz, 1H, H-6_A), 2.81

(t, J¼11.5 Hz, 1H, H-6_B), 1.99e1.89 (m, 1H, H-6a), 1.69 (dd, J¼11.4,

7.6 Hz, 1H, H-7_A), 1.50 (ddd, J¼11.4, 4.3, 3.3 Hz, 1H, H-7_B); ¹³C NMR

H-9), 6.30 (d, J¼5.7 Hz, 1H, H-10), 5.81 (ddt, J¼17.2, 10.3, 5.0 Hz, 1H,

CH]), 5.25e5.16 (m, 2H, CH₂]), 4.98 (dd, J¼4.5, 1.7 Hz, 1H, H-8),

4.10e3.82 (m, 2H, NCH₂), 3.37 (dd, J¼12.0, 5.3 Hz, 1H, H-6_A), 3.01 (t,

J¼12.1 Hz,1H, H-6_B), 1.98e1.86 (m, 1H, H-6a),1.68 (dd, J¼11.5, 7.5 Hz,

1H, H-7_A), 1.49 (ddd, J¼11.5, 4.5, 3.0 Hz, 1H, H-7_B); ¹³C NMR (CD₂Cl₂,

(CD₂Cl₂, 150 MHz)

d

151.8 (C-4), 148.6 (C-2), 145.6 (C-10b), 139.2 (C-

125 MHz) d 148.6 (C-10b),148.0 (C-2), 144.0 (C-4),140.5 (C-4a),138.5

4a), 138.1 (C-10), 136.7 (C-1 in Ph), 136.5 (C-9), 130.0 (C-3 or C-4 in

Ph), 129.5 (C-3 or C-4 in Ph), 128.7 (C-2 in Ph), 85.3 (C-10a), 78.7 (C-

(C-9), 135.8 (C-10), 131.9 (CH]), 117.9 (CH₂]), 84.4 (C-10a), 78.9 (C-

8), 53.8 (NCH₂or C-6), 53.5 (NCH₂or C-6), 33.7 (C-6a), 32.5 (C-7); MS

1882

M.L. Read et al. / Tetrahedron 68 (2012) 1869e1885

EI m/z (rel %) 277/275 (37/100, M^þ), 248 (21), 234 (42); HRMS (EI)

calcd for C₁₄H₁₄ClN₃O: 275.0825. Found 275.0828.

5.24e5.10 (m, 2H, CH₂]), 5.01 (dd, J¼5.3,1.7 Hz,1H, H-8), 4.13e3.76

(m, 2H, NCH₂), 3.33 (dd, J¼12.0, 4.4 Hz, 1H, H-6_A), 3.07 (t, J¼12.0 Hz,

1H, H-6_B), 2.04e1.84 (m,1H, H-6a),1.67 (dd, J¼11.4, 7.5 Hz,1H, H-7_A),

3.1.50.2. (ꢃ) (6aR,8S)-5-Allyl-2-chloro-5,6,6a,7,8,10a-hexahydro-

8,10a-epoxypyrimido[5,4-c]isoquinoline (14j). Yellow oil. ¹H NMR

1.55e1.40 (m, 1H, H-7_B); ¹³C NMR (CDCl₃, 75 MHz)

d 152.9 (C-2 in

furyl),148.1 (C-2),146.1 (C-4a),143.7 (C-5 in furyl),141.4 (C-4),139.2

(C-10b), 138.2 (C-9), 136.2 (C-10), 131.9 (CH]), 118.2 (CH₂]), 112.1

(C-4 in furyl),110.2 (C-3 in furyl), 84.7 (C-10a), 78.8 (C-8), 53.6 (NCH₂

or C-6), 53.3 (NCH₂or C-6), 34.0 (C-6a), 32.5 (C-7); MS EI m/z (rel %)

307 (100, M^þ), 280 (6), 277 (19), 238 (15), 224 (20); HRMS (EI) calcd

for C₁₈H₁₇N₃O₂: 307.1321. Found 307.1320.

(CD₂Cl₂, 500 MHz)

d

7.84 (s, 1H, H-4), 6.73 (dd, J¼5.6, 1.9 Hz, 1H, H-

9), 6.06 (d, J¼5.6 Hz, 1H, H-10), 5.80 (ddt, J¼17.2, 10.4, 4.6 Hz, 1H,

CH]), 5.29e5.08 (m, 3H, CH₂] and H-8), 4.00e3.79 (m, 2H, NCH₂),

3.49 (dd, J¼11.3, 5.2 Hz, 1H, H-6_A), 2.96e2.85 (m, 1H, H-6_B),

2.35e2.20 (m, 2H, H-6a and H-7_A), 1.11e0.97 (m, 1H, H-7_B); ¹³C

NMR (CDCl₃, 125 MHz)

d 151.5 (C-10b), 146.8 (C-2), 140.5 (C-4),

139.8 (C-9), 137.5 (C-4a), 133.6 (C-10), 131.1 (CH]), 116.8 (CH₂]),

84.4 (C-10a), 81.1 (C-8), 53.2 (C-6), 52.3 (NCH₂), 37.2 (C-6a), 29.7 (C-

7); MS EI m/z (rel %) 277/275 (35/100, M^þ), 248 (30), 234 (43);

HRMS (EI) calcd for C₁₄H₁₄ClN₃O: 275.0825. Found 275.0828.

3.1.52.2. (ꢃ) (6aR,8S)-5-Allyl-2-(2-furyl)-5,6,6a,7,8,10a-hexahy-

dro-8,10a-epoxypyrimido[5,4-c]isoquinoline (14l). Yellow oil. ¹H

NMR (CDCl₃, 400 MHz)

d

8.07 (s, 1H, H-2), 7.51 (dd, J¼1.8, 0.8 Hz, 1H,

H-5 in furyl), 7.14 (d, J¼3.4, 0.8 Hz, 1H, H-3 in furyl), 6.75 (dd, J¼5.6,

1.8 Hz, 1H, H-9), 6.48 (dd, J¼3.4, 1.8 Hz, 1H, H-4 in furyl), 6.15 (d,

J¼5.6 Hz, 1H, H-10), 5.83 (ddt, J¼17.2, 10.4, 4.8 Hz 1H, ]CH),

5.37e5.08(m, 3H, H-8 and ]CH₂), 4.09e3.82(m, 2H, NCH₂), 3.53(dd,

J¼11.0, 5.4 Hz, 1H, H-6), 2.96 (dd, J¼12.5,11.0 Hz,1H, H-6), 2.49e2.21

(m, 2H, H-6a and H-7), 1.06 (dd, J¼10.5, 4.3 Hz, 1H, H-7); ¹³C NMR

3.1.51. (ꢃ) (6aS,8S)-2-Chloro-5,6,6a,7,8,10a-hexahydro-5-methyl-

8,10a-epoxypyrimido[5,4-c]isoquinoline (13k) and (ꢃ) (6aR,8S)-2-

chloro-5,6,6a,7,8,10a-hexahydro-5-methyl-8,10a-epoxypyrimido

[5,4-c]isoquinoline (14k). A stirring solution of N-allyl-2-chloro-4-

(2-furyl)-N-methyl-pyrimidin-5-amine (12c) (50 mg, 0.20 mmol) in

dry toluene (10 mL) was heated at 100 ^ꢀC for 24 h under Ar, cooled to

ambient temperature and concentrated in vacuo. The product was

puriﬁed by ﬂash chromatography on silica gel eluting with EtOAc/

hexane (1:1); yield 27 mg (54%) of 13k, and 7 mg (14%) of 14k.

(CDCl₃,100 MHz)d152.6(C-2infuryl),148.9 (C-2orC-10b),146.8(C-2

or C-10b), 143.2 (C-5 in furyl), 139.3 (C-9), 138.1 (C-4), 135.9 (C-4a),

133.6 (C-10), 130.9 (]CH),117.1 (]CH₂),111.7 (C-4 in furyl),109.7(C-3

in furyl), 84.4 (C-10a), 80.8 (C-8), 53.0 (C-6), 52.0 (NCH₂), 37.2 (C-6a),

29.7 (C-7); MS EI m/z (rel %) 307 (100, M^þ), 280 (7), 278 (13), 238 (16),

224 (3); HRMS (EI) calcd for C₁₈H₁₇N₃O₂: 307.1321. Found 307.134.

3.1.51.1. (ꢃ) (6aS,8S)-2-Chloro-5,6,6a,7,8,10a-hexahydro-5-methyl-

8,10a-epoxypyrimido[5,4-c]isoquinoline (13k). Mp 160e162 ^ꢀC, color-

3.1.53. 7-(2-Furyl)-1H-indole (16a). A mixture of Pd(OAc)₂(12 mg,

less solid.¹H NMR(CDCl₃, 300 MHz)

d

8.06 (s,1H, H-4), 6.54 (dd, J¼5.8,

0.050 mmol),

PPh₃

(60 mg,

0.25 mmol),

potassium

2-

1.7 Hz,1H, H-9), 6.34 (d, J¼5.8 Hz,1H, H-10), 5.01 (dd, J¼4.5,1.7 Hz,1H,

H-8), 3.32 (dd, J¼11.7, 5.3 Hz,1H, H-6_A), 3.05e2.84 (m, 4H, CH₃and H-

6_B), 2.05e1.88 (m,1H, H-6a),1.69(dd, J¼11.5, 7.5 Hz,1H, H-7_A),1.51 (m,

furyltriﬂuoroborate (210 mg, 1.20 mmol), K₂CO₃(280 mg,

2.00 mmol), and 7-iodo-1H-indole (15a) (250 mg, 1.00 mmol) in

EtOH (20 mL, 96%) was stirred at 60 ^ꢀC for 4 h under Ar, and

evaporated in vacuo. The product was puriﬁed by ﬂash chroma-

tography on silica gel eluting with CH₂Cl₂/hexane (3:17); yield

1H, H-7_B); ¹³CNMR(CDCl₃, 75 MHz)

d148.8(C-2orC-4a),148.7(C-2or

C-4a), 143 (C-4), 141.2 (C-10b), 138.5 (C-9), 135.2 (C-10), 84 (C-10a),

78.6 (C-8), 55.0 (C-6), 38.6 (CH₃), 33.7 (C-6a), 32.2 (C-7); MS EI m/z (rel

%) 251/249 (35/100, M^þ), 248 (22), 220 (62), 206 (70), 180 (29); HRMS

(EI) calcd for C₁₂H₁₂ClN₃O: 249.0669. Found 249.0676.

145 mg (79%), colorless oil. ¹H NMR (CDCl₃, 300 MHz)

d 9.37 (s, 1H,

NH), 7.78 (d, J¼7.9 Hz, 1H, H-5 or H-6), 7.62 (d, J¼8.5 Hz, 2H, H-3 in

furyl and H-4 or H-6), 7.39e7.25 (m, 2H, H-2 and H-5), 6.86 (d,

J¼3.2 Hz, 1H, H-3 in furyl), 6.79e6.70 (m, 1H, H-3), 6.64 (dd, J¼3.2,

3.1.51.2. (ꢃ) (6aR,8S)-2-Chloro-5,6,6a,7,8,10a-hexahydro-5-

methyl-8,10a-epoxypyrimido[5,4-c]isoquinoline (14k). Waxy color-

1.8 Hz, 1H, H-4 in furyl); ¹³C NMR (CDCl₃, 75 MHz)

d 154.4 (C-2 in

furyl), 141.5 (C-5 in furyl), 131.6 (C-3a or C-7a), 129.2 (C-3a or C-7a),

124.8 (C-2 or C-5), 120.5 (C-4 or C-6), 120.0 (C-2 or C-5), 118.0 (C-4

or C-6), 114.7 (C-7), 111.8 (C-4 in furyl), 105.2 (C-3 in furyl), 102.6 (C-

3); MS EI m/z (rel %) 183 (100, M^þ), 154 (76), 127 (9), 92 (7), 77 (8);

HRMS (EI) calcd for C₁₂H₉NO: 183.0684. Found 183.0679.

less solid. ¹H NMR (CDCl₃, 300 MHz)

d 7.87 (s, 1H, H-4), 6.71 (dd,

J¼5.6, 1.9 Hz, 1H, H-9), 6.04 (d, J¼5.7 Hz, 1H, H-10), 5.19 (dd, J¼4.0,

1.7 Hz, 1H, H-8), 3.43 (dd, J¼11.2, 5.3 Hz, 1H, H-6_A), 3.07e2.82 (m,

4H, H-6_Band CH₃), 2.39e2.20 (m, 2H, H-6a and H-7_A), 1.02 (d,

J¼6.2 Hz, 1H, H-7_B); ¹³C NMR (CDCl₃, 75 MHz)

d 152.1 (C-10b), 147.3

(C-2), 139.7 (C-9), 139.1 (C-4), 137.9 (C-4a), 133.3 (C-10), 84.2 (C-

10a), 81.1 (C-8), 54.8 (C-6), 37.6 (CH₃), 37.2 (C-6a), 29.9 (C-7); MS EI

m/z (rel %) 251/249 (34/100, M^þ), 248 (16), 220 (62), 206 (74), 180

(29); HRMS (EI) calcd for C₁₂H₁₂ClN₃O: 249.0669. Found 249.0674.

3.1.54. 4-(2-Furyl)-5H-pyrrolo[3,2-d]pyrimidine (16b). A mixture of

Pd(OAc)₂(20 mg, 0.10 mmol), PPh₃(100 mg, 0.250 mmol), potas-

sium 2-furyltriﬂuoroborate (390 mg, 2.13 mmol), K₂CO₃(450 mg,

3.20 mmol), and 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (280 mg,

1.83 mmol) (15b) in EtOH (50 mL, 96%) was stirred at 80 ^ꢀC for 3 h

under Ar, and evaporated in vacuo. The product was puriﬁed by

ﬂash chromatography on silica gel eluting with acetone/hexane

(2:3); yield 260 mg (78%), mp 160e162 ^ꢀC, colorless solid. ¹H NMR

3.1.52. (ꢃ) (6aS,8S)-5-Allyl-2-(2-furyl)-5,6,6a,7,8,10a-hexahydro-

8,10a-epoxypyrimido[5,4-c]isoquinoline (13l) and (ꢃ) (6aR,8S)-5-

allyl-2-(2-furyl)-5,6,6a,7,8,10a-hexahydro-8,10a-epoxypyrimido

[5,4-c]isoquinoline (14l). A stirring solution of N,N-diallyl-2,4-di(2-

furyl)pyrimidin-5-amine (12d) (100 mg, 0.330 mmol) in dry toluene

(10 mL) was heated at 100 ^ꢀC for 24 h under Ar, cooled to ambient

temperature and concentrated in vacuo. The product was puriﬁed by

ﬂash chromatography on silica gel eluting with EtOAc/CH₂Cl₂/hexane

(2:5:5); yield 78 mg (78%) of 13l, and 15 mg (15%) of 14l.

(DMSO-d₆, 300 MHz) d 11.86 (s, 1H, NH), 8.80 (s, 1H, H-2), 8.04 (dd,

J¼1.8, 0.8 Hz, 1H, H-5 in furyl), 7.90 (d, J¼3.1 Hz, 1H, H-6), 7.47 (dd,

J¼3.5, 0.8 Hz, 1H, H-3 in furyl), 6.82 (dd, J¼3.5, 1.8 Hz, 1H, H-4 in

furyl), 6.67 (dd, J¼3.1, 1.7 Hz,1H, H-7); ¹³C NMR (DMSO-d₆, 75 MHz)

d

152.2 (C-2 in furyl or C-3a),152.0 (C-2 in furyl or C-3a),150.8 (C-2),

146.7 (C-5 in furyl), 138.9 (C-4), 135.0 (C-6), 121.4 (C-3b), 113.5 (C-4

in furyl), 113.2 (C-3 in furyl), 102.3 (C-7); MS EI m/z (rel %) 185 (100,

M^þ), 157 (27), 129 (9), 118 (7), 103 (6); HRMS (EI) calcd for

C₁₀H₇N₃O: 185.0589. Found 185.0589.

3.1.52.1. (ꢃ) (6aS,8S)-5-Allyl-2-(2-furyl)-5,6,6a,7,8,10a-hexahy-

dro-8,10a-epoxypyrimido[5,4-c]isoquinoline (13l). Mp 125e127 ^ꢀC,

colorless solid.¹H NMR (CDCl₃, 300 MHz)

d 8.21 (s,1H, H-4), 7.47 (dd,

J¼1.7, 0.8 Hz, 1H, H-5 in furyl), 7.07 (dd, J¼3.4, 0.8 Hz, 1H, H-3 in

furyl), 6.53 (dd, J¼5.7,1.7 Hz,1H, H-9), 6.44 (dd, J¼3.4,1.7 Hz,1H, H-4

in furyl), 6.39 (d, J¼5.7 Hz, 1H, H-10), 5.89e5.67 (m, 1H, CH]),

3.1.55. 6-(2-Furyl)-1H-purine (16c). A mixture of Pd(OAc)₂(30 mg,

0.15 mmol),

PPh₃

(120 mg,

0.46 mmol),

potassium

2-

furyltriﬂuoroborate (410 mg, 2.36 mmol), K₂CO₃(750 mg,

M.L. Read et al. / Tetrahedron 68 (2012) 1869e1885

1883

5.40 mmol), and 6-chloro-1H-purine (300 mg, 1.95 mmol) (15c) in

EtOH (50 mL, 96%) was stirred at 80 ^ꢀC for 16 h under N₂, and the

reaction mixture was, after cooling to ambient temperature, sub-

jected to dry ﬂash chromatography on a short plug of silica. The

column was washed with EtOH (100 mL) and the solution was

evaporated in vacuo. The residue was dissolved in a minimum of

EtOH and water was added until the product precipitated. The

product was isolated by ﬁltration, washed with cold hexane, and

dried; yield 340 mg (94%) off-white powder. The spectral data were

in good agreement with those reported before.¹⁵

After stirring in the dark for a total of 96 h, the mixture was

evaporated in vacuo and the residue transferred to a separatory

funnel using CHCl₃(100 mL) and aq NaOH (2 M, 200 mL). The

phases were separated and the aqueous phase was extracted with

CHCl₃(3ꢂ100 mL). The combined organic extracts were washed

with brine (100 mL), dried (MgSO₄), and evaporated in vacuo. The

product was puriﬁed by ﬂash chromatography on silica gel eluting

with acetone/hexane (1:9); yield 201 mg (37%), yellow oil. ¹H NMR

(CDCl₃, 300 MHz)

d 9.02 (s, 1H, H-2), 8.27 (s, 1H, H-8), 7.69 (dd,

J¼1.8, 0.8 Hz, 1H, H-5 in furyl), 7.38 (dd, J¼3.5, 0.8 Hz, 1H, H-3 in

furyl), 6.67 (dd, J¼3.5, 1.8 Hz, 1H, H-4 in furyl), 6.02e5.80 (m, 1H,

CH]), 5.20 (dt, J¼5.4, 1.5 Hz, 2H, CH₂]), 5.06 (ddd, J¼17.6, 13.8,

3.1.56. 1-Allyl-7-(2-furyl)-1H-indole (17a). A solution of 7-(2-

furyl)-1H-indole (16a) (130 mg, 0.750 mmol) and 18-crown-6-

ether (370 mg, 1.50 mmol) in dry toluene (10 mL) at 0 ^ꢀC was

treated with KH (103 mg, ca. 0.900 mmol, ca. 35% in mineral oil)

and stirred for 10 min under Ar, before allyl bromide (0.08 mL,

0.8 mmol) was added and the mixture was stirred at ambient

temperature for 3 h. Water (10 mL) was added and the mixture was

extracted with EtOAc (3ꢂ20 mL). The combined organic extracts

were dried (MgSO₄) and concentrated in vacuo. The product was

puriﬁed by ﬂash chromatography on silica gel eluting with EtOAc/

hexane (1:49); yield 74 mg (44%), colorless oil. ¹H NMR (CD₂Cl₂,

0.5 Hz, 2H, NCH₂); ¹³C NMR (CDCl₃, 75 MHz)

d 163.2 (C-4), 152.9 (C-

2), 151.2 (C-2 in furyl), 150.1 (C-8), 145.2 (C-3 in furyl), 141.6 (C-6),

132.7 (CH]), 120.9 (C-5), 118.7 (CH₂]), 114.8 (C-3 in furyl), 113.3

(C-4 in furyl), 51.3 (NCH₂); MS EI m/z (rel %) 226 (100, M^þ), 199 (6),

185 (7), 159 (2); HRMS (EI) calcd for C₁₂H₁₀N₄O: 226.0855. Found

226.0855.

3.1.59. (ꢃ) (7aS,9S)-7a,8,9,11a-Tetrahydro-9,11a-epoxy-7H-pyrrolo

[3,2,1-de]phenanthridine (18a). A stirring solution of 1-allyl-7-(2-

furyl)-1H-indole (17a) (160 mg, 0.72 mmol) in dry toluene

(50 mL) was heated at 100 ^ꢀC for 24 h under Ar, cooled to ambient

temperature and concentrated in vacuo. The product was puriﬁed

by ﬂash chromatography on silica gel eluting with acetone/CH₂Cl₂/

hexane (1:2:9); yield 110 mg (69%), colorless waxy material. ¹H

300 MHz)

d

7.70 (dd, J¼7.7, 1.4 Hz, 1H, H-6), 7.59 (dd, J¼1.9, 0.9 Hz,

1H, H-5 in furyl), 7.21 (dd, J¼7.3, 1.5 Hz, 1H, H-4 or H-5), 7.17e7.10

(m, 2H, H-2 and H-4 or H-5), 6.62 (d, J¼3.2 Hz, 1H, H-3), 6.58 (dd,

J¼3.2, 1.9 Hz, 1H, H-4 in furyl), 6.50 (dd, J¼3.2, 0.9 Hz, 1H, H-3 in

furyl), 5.80 (m, 1H, CH]), 5.02 (dd, J¼17.1, 1.5 Hz, 1H, H_Ain CH₂]),

4.81 (dd, J¼17.1, 1.5 Hz, 1H, H_Bin CH₂]), 4.45 (d, J¼5.5 Hz, 2H,

NMR (CD₂Cl₂, 300 MHz)

d

7.63 (d, J¼7.9 Hz, 1H, H-1 or H-3), 7.31 (d,

J¼7.1 Hz,1H, H-1 or H-3), 7.15 (m, 2H, H-4 or H-5 and H-2), 6.68 (dd,

J¼5.7, 1.7 Hz, 1H, H-10), 6.51 (d, J¼3.0 Hz, 1H, H-4 or H-5), 6.40 (d,

J¼5.7 Hz, 1H, H-11), 5.11 (dd, J¼4.5, 1.6 Hz, 1H, H-9), 4.45 (dd,

J¼12.0, 6.1 Hz, 1H, H-7_A), 3.67 (t, J¼11.8 Hz, 1H, H-7_B), 2.39e2.18 (m,

1H, H-7a), 1.77 (dd, J¼11.5, 7.5 Hz, 1H, H-8_A), 1.71e1.60 (m, 1H, H-

NCH₂); ¹³C NMR (CDCl₃, 75 MHz)

d 153.3 (C-2 in furyl), 142.4 (C-5 in

furyl), 135.2 (CH]), 134.4 (C-7a or C-3a), 130.9 (C-7a or C-3a), 130.5

(C-2), 125.6 (C-6), 122.6 (C-4 or C-5), 119.5 (C-4 or C-5), 116.6

(CH₂]),116.1 (C-7),111.9 (C-4 in furyl),109.7 (C-3 in furyl),102.6 (C-

3), 50.6 (NCH₂); MS EI m/z (rel %) 223 (100, M^þ), 206 (15), 194 (50),

154 (60), 127 (9); HRMS (EI) calcd for C₁₅H₁₃NO: 223.0997. Found

223.0992.

8_B); ¹³C NMR (CDCl₃, 75 MHz)

d 140.3 (C-10), 136.9 (C-11), 136.1 (C-

11b), 127.3 (C-2, C-4 or C-5), 121.5 (C-1 or C-3), 121.4 (C-1 or C-3),

120.4 (C-2, C-4 or C-5), 118.6 (C-3a), 101.7 (C-4 or C-5), 84.4 (C-11a),

80.7 (C-3a¹), 79.4 (C-9), 48.9 (C-7), 35.8 (C-7a), 32.8 (C-8); MS EI m/z

(rel %) 223 (100, M^þ), 206 (10), 194 (42), 180 (36), 167 (12), 154 (35);

HRMS (EI) calcd for C₁₅H₁₃NO: 223.0997. Found 223.0992.

3.1.57. 5-Allyl-4-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (17b). A so-

lution of 4-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (16b) (870 mg,

4.70 mmol) and 15-crown-5-ether (1.5 mL, 9.4 mmol) in dry ace-

tonitrile (100 mL) at ambient temperature was treated with NaH

(370 mg, ca.9.4 mmol, ca. 60% in oil) and stirred for 5 min under Ar

before allyl iodide (790 mg, 4.70 mmol) was added. The mixture

was stirred at ambient temperature for 1 h. Water was added

(50 mL), and the resulting mixture was extracted with Et₂O

(3ꢂ100 mL). The combined organic phases were washed with brine

(50 mL), dried (MgSO₄), and concentrated in vacuo. The product

was puriﬁed by ﬂash chromatography on silica gel eluting with

EtOAc/hexane (1:1); yield 520 mg (49%), colorless oil. ¹H NMR

3.1.60. (ꢃ) (7aS,9S)-7a,8,9,11a-Tetrahydro-9,11a-epoxy-7H-benzo[f]

pyrimido[4,5,6-hi]indolizine (18b). A stirring solution of 5-allyl-4-

(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (17b) (60 mg, 0.27 mmol) in

dry toluene (10 mL) was heated at 100 ^ꢀC for 24 h under Ar, cooled

to ambient temperature and concentrated in vacuo. The product

was puriﬁed by ﬂash chromatography on silica gel eluting with

acetone/hexane (1:1); yield 20 mg (33%), mp 200e202 ^ꢀC (dec),

colorless solid. ¹H NMR (CD₂Cl₂, 300 MHz)

d 9.02 (s, 1H, H-2), 7.52

(d, J¼3.0 Hz, 1H, H-5), 6.71 (dd, J¼5.8, 1.6 Hz, 1H, H-10), 6.65 (d,

J¼3.0 Hz, 1H, H-4), 6.51 (d, J¼5.8 Hz, 1H, H-11), 5.23 (dd, J¼4.4,

1.5 Hz, 1H, H-9), 4.53 (dd, J¼12.2, 6.3 Hz, 1H, H-7_A), 3.79 (m, 1H, H-

7_B), 2.59e2.35 (m, 1H, H-7a), 1.82 (m, 1H, H-8_A), 1.77e1.66 (m, 1H,

(CD₂Cl₂, 300 MHz)

d

8.87 (s, 1H, H-2), 7.69 (d, J¼0.9 Hz, 1H, H-5 in

furyl), 7.53 (d, J¼3.2 Hz, 1H, H-6), 7.18 (d, J¼3.4 Hz, 1H, H-3 in furyl),

6.71 (d, J¼3.2 Hz, 1H, H-7), 6.65 (dd, J¼3.4, 1.8 Hz, 1H, H-4 in furyl),

5.96e5.77 (m, 1H, CH]), 5.12e4.75 (m, 4H, CH₂] and NCH₂); ¹³C

H-8_B); ¹³C NMR (CDCl₃, 75 MHz)

d 152.8 (C-2), 149.7 (C-3a), 145.3

NMR (CD₂Cl₂, 75 MHz)

d

154.0 (C-3a), 152.0 (C-2 in furyl), 150.5 (C-

(C-11b), 140.2 (C-10), 134.8 (C-11), 133.8 (C-5), 127.8 (C-3a¹), 102.4

(C-4), 84.6 (C-11a), 80.6 (C-9), 48.9 (C-7), 37.9 (C-7a), 32.6 (C-8); MS

EI m/z (rel %) 225 (100, M^þ), 208 (29), 196 (56), 182 (12), 170 (10),

157 (12); HRMS (EI) calcd for C₁₃H₁₁N₃O: 225.0902. Found

225.0904.

2), 144.7 (C-5 in furyl), 140.1 (C-4), 137.8 (C-6), 134.4 (CH]), 124.1

(C-3b), 117.3 (CH₂]), 113.6 (C-3 in furyl), 112.8 (C-4 in furyl), 102.9

(C-7), 52.6 (NCH₂); MS EI m/z (rel %) 225 (100, M^þ), 208 (26), 196

(69), 170 (21), 157 (27); HRMS (EI) calcd for C₁₃H₁₁N₃O: 225.0902.

Found 225.0898.

3.1.61. 2-Chloro-6-(3-furyl)-4-nitroaniline (19). A mixture of

Pd(OAc)₂(24 mg, 0.10 mmol), PPh₃(130 mg, 0.500 mmol), 3-

furylboronic acid (270 mg, 2.40 mmol), K₂CO₃(800 mg,

5.97 mmol), and 2-bromo-6-chloro-4-nitroaniline (1g) (500 mg,

2.00 mmol) in EtOH (100 mL, 96%) was stirred at 85 ^ꢀC for 16 h

under Ar, and evaporated in vacuo. The product was puriﬁed by

ﬂash chromatography on silica gel eluting with CH₂Cl₂/hexane

(2:3); yield 385 mg (81%), yellow oil. ¹H NMR (CDCl₃, 600 MHz)

3.1.58. 7-Allyl-6-(2-furyl)-7H-purine (17c). 6-(2-Furyl)-9H-purine

(16c) (450 mg, 2.42 mmol) and methylaquacobaloxime (800 mg,

2.66 mmol) in dry MeCN (50 mL) was stirred at ambient temper-

ature under N₂for 5 min, before K₂CO₃(370 mg 2.66 mmol) was

added and the mixture was stirred for another 30 min. Allyl iodide

(0.50 mL, 4.8 mmol) was added and the mixture was stirred in the

dark. More allyl iodide (0.25 mmol) was added after 24 hand 48 h.

1884

M.L. Read et al. / Tetrahedron 68 (2012) 1869e1885

d

8.21 (d, J¼2.4 Hz, 1H, H-3), 8.03 (d, J¼2.4 Hz, 1H, H-5), 7.71 (s, 1H,

H-2 in furyl), 7.62 (s, 1H, H-5 in furyl), 6.75e6.49 (m, 1H, H-4 in

furyl), 5.01 (s, 2H, NH₂); ¹³C NMR (CDCl₃, 150 MHz)

146.8 (C-4),

(rel %) (30/100, M^þ), 249 (48), 232 (11), 203 (33); HRMS (EI) calcd

for C₁₃H₁₁ClN₂O₃: 278.0458. Found 278.0460.

d

144.4 (C-5 in furyl), 140.6 (C-2 in furyl), 138.4 (C-2), 124.7 (C-3),

124.4 (C-5), 121.3 (C-3 in furyl),118.2 (C-1 or C-6), 118.2 (C-1 or C-6),

110.3 (C-4 in furyl); MS EI m/z (rel %) 240/238 (33/100, M^þ), 221

(36), 192 (21); HRMS (EI) calcd for C₁₀H₇ClN₂O₃: 238.0145. Found

238.0139.

3.1.64. N,N-Diallyl-2-chloro-6-(3-furyl)-4-nitroaniline (22). A solu-

tion

of

2-chloro-6-(3-furyl)-4-nitroaniline

(19)

(160 mg,

0.670 mmol) and 16-crown-8-ether (350 mg, 1.34 mmol) in dry

toluene (100 mL) at ambient temperature under Ar was treated

with KH (300 mg, ca. 2.60 mmol, ca. 35% in mineral oil) and stirred

for 10 min. Allyl iodide (0.25 mL, 2.6 mmol) was added and the

reaction mixture stirred for 5 h at 40 ^ꢀC. Water (50 mL) was added,

the mixture was extracted with EtOAc (2ꢂ50 mL), the combined

organic extracts were washed with satd aq NaCl (50 mL), dried

(MgSO₄), and concentrated in vacuo. The product was puriﬁed by

ﬂash chromatography on silica gel eluting with CH₂Cl₂/hexane

(1:3); yield 160 mg (75%), yellow oil. ¹H NMR (CDCl₃, 400 MHz)

3.1.62. N-Allyl-2-chloro-6-(3-furyl)-4-nitroaniline (20). A solution

of 2-chloro-6-(3-furyl)-4-nitroaniline (19) (360 mg,1.50 mmol) and

15-crown-5-ether (0.60 mL, 3.0 mmol) in dry toluene (50 mL) at

0 ^ꢀC was treated with NaH (120 mg, ca. 3.0 mmol, ca. 60% in mineral

oil) and stirred for 10 min under Ar. Allyl bromide (0.19 mL,

2.3 mmol) was added and the mixture was stirred at ambient

temperature for 5 h before water (50 mL) was added. The resulting

mixture was extracted with EtOAc (2ꢂ50 mL), dried (MgSO₄), and

concentrated in vacuo. The product was puriﬁed by ﬂash chroma-

tography on silica gel eluting with CH₂Cl₂/hexane (1:1); yield

d

8.16 (d, J¼2.7 Hz, 1H, H-3 or H-5), 8.12 (d, J¼2.7 Hz, 1H, H-3 or H-

5), 7.89e7.84 (m, 1H, H-2 in furyl), 7.54 (d, J¼1.8 Hz, 1H, H-5 in

furyl), 6.73 (d, J¼2.3 Hz, 1H, H-4 in furyl), 5.79 (ddt, J¼16.9, 10.0,

6.8 Hz, 2H, CH]), 5.30e4.95 (m, 4H, CH₂]), 3.71 (d, J¼6.8 Hz, 4H,

115 mg (28%), yellow oil. ¹H NMR (CDCl₃, 600 MHz)

d

8.19 (d,

NCH₂); ¹³C NMR (CDCl₃, 100 MHz)

d 151.1 (C-1), 143.8 (C-4), 143.3

J¼2.6 Hz, 1H, H-3 or H-5), 8.00 (d, J¼2.6 Hz, 1H, H-3 or H-5),

7.70e7.63 (m, 1H, H-2 in furyl), 7.54 (d, J¼1.7 Hz, 1H, H-5 in furyl),

6.64 (dd, J¼1.7, 0.8 Hz, 1H, H-4 in furyl), 5.80e5.75 (m, 1H, CH]),

5.28e4.95 (m, 2H, CH₂]), 4.79 (s, 1H, NH), 3.80e3.44 (m, 2H,

(C-5 in furyl), 141.4 (C-2 in furyl), 134.5 (C-2 or C-3 in furyl), 134.3

(CH]), 134.0 (C-2 or C-3 in furyl), 124.8 (C-3 or C-5), 123.6 (C-3 or

C-5), 123.1 (C-6), 118.4 (CH₂]), 110.5 (C-4 in furyl), 55.1 (NCH₂); MS

EI m/z (rel %) 320/318 (26/80, M^þ), 291 (25), 283 (13), 277 (89), 251

(14), 41 (100); HRMS (EI) calcd for C₁₆H₁₅ClN₂O₃: 318.0771. Found

318.0768.

NCH₂); ¹³C NMR (CDCl₃, 150 MHz)

d 148.8 (C-1), 143.6 (C-5 in furyl),

140.6 (C-3 in furyl), 139.2 (C-4), 134.6 (CH]), 126.2 (C-3 or C-5),

124.5 (C-3 or C-5), 123.1 (C-3 in furyl), 122.7 (C-2 or C-6), 121.4 (C-2

or C-6), 117.0 (CH₂]), 110.9 (C-4 in furyl), 49.1 (NCH₂); MS EI m/z

(rel %) 280/278 (33/100, M^þ), 251 (36), 237 (13), 232 (14), 222 (8),

211 (7); HRMS (EI) calcd for C₁₃H₁₁ClN₂O₃: 278.0458. Found

278.0455.

3.1.65. (ꢃ) (3S,5S) 1-Allyl-11-chloro-2,3,4,5-tetrahydro-9-nitro-5,12-

epoxy-7,3-methano-1H-benzo[b]azonine (23). A stirring solution of

N,N-diallyl-2-chloro-6-(3-furyl)-4-nitroaniline

(22)

(77 mg,

0.27 mmol) in dry toluene (30 mL) was heated at 100 ^ꢀC for 24 h

under Ar, cooled to ambient temperature and concentrated in

vacuo. The product was puriﬁed by ﬂash chromatography on silica

gel eluting with CH₂Cl₂/hexane (3:7) followed by EtOAc/CH₂Cl₂/

hexane (1:7:12); yield 60 mg (86%), yellow oil. ¹H NMR (CDCl₃,

3.1.63. (ꢃ) (3S,5S)-11-Chloro-2,3,4,5-tetrahydro-9-nitro-5,12-epoxy-

7,3-methano-1H-benzo[b]azonine (21a) and (ꢃ) (3R,5S)-11-chloro-

2,3,4,5-tetrahydro-9-nitro-5,12-epoxy-7,3-methano-1H-benzo[b]azo-

nine (21b). A stirring solution of N-allyl-2-chloro-6-(3-furyl)-4-

nitroaniline (20) (90 mg, 0.32 mmol) in dry toluene (20 mL) was

heated at 100 ^ꢀC for 24 h under Ar, cooled to ambient temperature

and concentrated in vacuo. The product was puriﬁed by ﬂash

chromatography on silica gel eluting with EtOAc/CH₂Cl₂/hexane

(1:2:7) followed by EtOAc/CH₂Cl₂/hexane (1:4:5); yield 53 mg

(59%) of 21a, and 10 mg (11%) of 21b.

400 MHz)

d

8.15 (d, J¼2.7 Hz, 1H, H-10), 8.02 (d, J¼2.7 Hz, 1H, H-8),

6.28 (d, J¼1.0 Hz, 1H, H-6), 6.21e5.95 (m, 1H, CH]), 5.45e5.33 (m,

2H, CH₂]), 5.19 (d, J¼4.2 Hz, 1H, H-5), 5.04 (d, J¼5.0 Hz, 1H, H-12),

4.26e4.09 (m, 1H, NCH₂), 3.78 (dd, J¼15.2, 8.7 Hz, 1H, CH₂), 3.62

(dd, J¼14.7, 7.2 Hz,1H, H-2_A), 2.97 (ddd, J¼10.2, 5.3, 2.6 Hz,1H, H-3),

2.28 (dd, J¼14.7, 11.0 Hz, 1H, H-2_B), 2.12 (ddd, J¼11.6, 8.0, 4.3 Hz, 1H,

H-4_A), 1.04 (dd, J¼11.6, 2.0 Hz, 1H, H-4_B); ¹³C NMR (CDCl₃, 100 MHz)

d

150.7 (C-11a), 144.3 (C-7), 141.7 (C-9), 134.5 (CH]), 132.0 (C-7a),

3.1.63.1. (ꢃ) (3S,5S) 11-Chloro-2,3,4,5-tetrahydro-9-nitro-5,12-

epoxy-7,3-methano-1H-benzo[b]azonine (21a). Mp 220e221 ^ꢀC,

130.6 (C-6), 128.2 (C-11), 125.0 (C-10), 121.3 (C-8), 119.3 (CH₂]),

83.3 (C-12), 79.7 (C-5), 55.3 (NCH₂), 52.2 (C-2), 36.8 (C-3), 32.2 (C-

4); MS EI m/z (rel %) 320/318 (33/100, M^þ), 291 (23), 283 (12), 277

(100); HRMS (EI) calcd for C₁₆H₁₅ClN₂O₃: 318.0771. Found 318.0768.

yellow solid. ¹H NMR (CDCl₃, 600 MHz)

d

8.11 (d, J¼2.5 Hz, 1H, H-

10), 8.01 (d, J¼2.5 Hz, 1H, H-8), 6.22 (d, J¼1.0 Hz, 1H, H-6), 5.24 (s,

1H, NH), 5.22 (d, J¼5.2 Hz,1H, H-12), 5.15 (d, J¼4.2 Hz,1H, H-5) 3.70

(m, 1H, H-2_A), 2.97 (ddd, J¼10.5, 5.2, 2.0 Hz, 1H, H-3), 2.78e2.46 (m,

1H, H-2_B), 2.13 (ddd, J¼11.6, 7.9, 4.2 Hz, 1H, H-4_A), 1.07 (dd, J¼11.6,

3.2. Computational details

2.0 Hz, 1H, H-4_B); ¹³C NMR (CDCl₃, 150 MHz)

d

148.9 (C-11a), 143.4

All structures (minima and transition states) were fully opti-

mized at the gradient corrected density functional theory (DFT)

level using the exchange-correlation functional of Perdew, Burke,

and Ernzerhof¹⁶making use of the resolution of the identity ap-

proximation.¹⁷The basis sets that were used were the Wei-

gendeAhlrichs basis sets denoted def2-SVP and def2-TZVPP¹⁸and

the corresponding ﬁtting basis.¹⁹The inﬂuence of the basis set size

on the structures and relative energies for signiﬁcant steps in the

mechanism was tested and it was found that the inﬂuence was

minor. Therefore all structures presented were obtained using the

def2-SVP basis set in combination with the PBE functional (denoted

as PBE/def2-SVP). This methodology was also found to be reliable

for the given purpose in comparison to RI-MP2/def2-TZVPP for the

basic mechanism.²⁰Analytic Hessians were used to characterize the

nature of the stationary points on the potential energy surface.²¹All

energy, gradient, and hessian calculations were performed using

(C-7), 139.1 (C-9), 129.1 (C-5), 123.5 (C-10), 123.1 (C-11), 122.0 (C-8),

119.7 (C-7a), 82.8 (C-12), 79.5 (C-5), 50.5 (C-2), 39.0 (C-3), 32.4 (C-

4); MS EI m/z (rel %) 280/278 (31/100, M^þ), 249 (48), 232 (13), 203

(32) HRMS (EI) calcd for C₁₃H₁₁ClN₂O₃: 278.0458. Found 278.0463.

3.1.63.2. (ꢃ) (3R,5S)-11-Chloro-2,3,4,5-tetrahydro-9-nitro-5,12-

epoxy-7,3-methano-1H-benzo[b]azonine (21b). Yellow oil. ¹H NMR

(CDCl₃, 600 MHz)

d

8.28 (d, J¼2.6 Hz, 1H, H-8 or H-10), 8.18 (d,

J¼2.6 Hz, 1H, H-8 or H-10), 5.28 (s, 1H, NH), 4.69 (d, J¼5.2 Hz, 1H, H-

5), 4.67 (d, J¼5.2 Hz, 1H, H-6), 3.88e3.66 (m, 1H, H-2_A), 3.61 (s, 1H,

H-12), 3.32e3.11 (m, 1H, H-2_B), 2.98e2.79 (m, 1H, H-3), 2.20e1.87

(m, 1H, H-4_A), 1.42 (dd, J¼12.3, 3.4 Hz, 1H, H-4_B); ¹³C NMR (CDCl₃,

150 MHz)

d 150.6 (C-11a), 139.6 (C-9), 124.3 (C-8), 123.1 (C-10),

121.5 (C-7a or 11), 120.5 (C-7a or 11), 78.1 (C-6), 75.8 (C-5), 60.3 (C-

12), 59.0 (C-7), 49.2 (C-2), 43.0 (C-3), 31.8 (C-4); MS EI m/z 280/278

M.L. Read et al. / Tetrahedron 68 (2012) 1869e1885

1885

the Turbomole program package.²²All computations were per-

formed on the Stallo supercomputer located at the University of

Tromsø, Norway.

4. (a) Østby, O. B.; Dalhus, B.; Gundersen, L.-L.; Rise, F.; Bast, A.; Haenen, G. R. M.

M. Eur. J. Org. Chem. 2000, 9, 3763e3770.

5. See for instance: Molander, G. A.; Canturk, B. Angew. Chem., Int. Ed. 2009, 48,

9240e9261 and references sited therein.

6. Khoje, A. D.; Gundersen, L.-L. Tetrahedron Lett. 2011, 52, 523e525.

7. For a recent example, see for instance: Dadwal, M.; Kesharwani, M. K.; Danayak,

V.; Ganguly, B.; Mobin, S. M.; Muruganantham, R.; Namboothiri, I. N. N. Eur. J.

Org. Chem. 2008, 6106e6118 and references sited therein.

8. For a recent example, see for instance: Nakamura, M.; Takahashi, I.; Yamada, S.;

Dobashi, Y.; Kitagawa, O. Tetrahedron Lett. 2011, 52, 53e55 and references sited

therein.

9. Jahne, G.; Kroha, H.; Muller, A.; Helsberg, M.; Winkler, I.; Gross, G.; Scholl, T.

Angew. Chem., Int. Ed. Engl. 1994, 33, 562e563.

10. Schrauzer, G. N. Inorg. Synth. 1968, 11, 61e70.

Acknowledgements

The Norwegian Research Council is gratefully acknowledged for

a grant to POM (KOSK II, project number 177368) as well as for

partial ﬁnancing of the Bruker Avance instruments used in this

study. A.K. is grateful to NOTUR for providing generous computa-

tional resources and the Norwegian Research Council for their

Grant No.179568/V30 to the Centre of Theoretical and Computa-

tional Chemistry through their Centre of Excellence program.

€

11. Youn, S. W.; Bihn, J. H. Tetrahedron Lett. 2009, 50, 4598e4601.

12. Whittaker, N.; Jones, T. S. G. J. Chem. Soc. 1951, 1565e1570.

13. Read, M. L.; Brændvang, M.; Miranda, P. O.; Gundersen, L.-L. Bioorg. Med. Chem.

2010, 18, 3885e3897.

14. Nielsen, L. B.; Slamet, R.; Wege, D. Tetrahedron 2009, 65, 4569e4577.

15. Gundersen, L.-L.; Nissen-Meyer, J.; Spilsberg, B. J. Med. Chem. 2002, 45,

1383e1386.

References and notes

16. Perdew, P.; Burke, K.; Ernzerhof, M. Phys. Rev. Lett. 1996, 77, 3865e3868.

17. Eichkorn, K.; Treutler, O.; Oehm, H.; Haeser, M.; Ahlrichs, R. Chem. Phys. Lett.

1995, 242, 652e660.

1. See for instance: Kappe, C. O.; Murphree, S. S.; Padwa, A. Tetrahedron 1997, 53,

14179e14233 and references sited therein.

2. Selected recent examples: (a) Li, C.-C.; Liang, S.; Zhang, X.-H.; Xie, Z.-X.; Chen, J.-

H.; Wu, Y.-D.; Yang, Z. Org. Lett. 2005, 7, 3709e3712; (b) Wang, Q.; Padwa, A. Org.

Lett. 2006, 8, 601e604; (c) Lauchli, R.; Shea, K. J. Org. Lett. 2006, 8, 5287e5289; (d)

Sarang, P. S.; Yadav, A. A.; Patil, P. S.; Krishna, U. M.; Trivedi, G. K.; Salunkhe, M. M.

Synthesis 2007, 1091e1095; (e) Jung, M. E.; Min, S.-J. Tetrahedron 2007, 63,

3682e3701; (f) Bobeck, D. R.; France, S.; Leverett, C. A.; Sanchez-Cantalejo, F.;

Padwa, A. Tetrahedron Lett. 2009, 50, 3145e3147; (g) Zubkov, F. I.; Ershova, J. D.;

Zaytsev, V. P.; Obushak, M. D.; Matiychuck, V. S.; Sokolova, E. A.; Khrustalev, V. N.;

Varlamov, A. V. Tetrahedron Lett. 2010, 51, 6822e6824.

18. Weigend, F.; Ahlrichs, R. Phys. Chem. Chem. Phys. 2005, 7, 3297e3305.

19. Weigend, F. Phys. Chem. Chem. Phys. 2006, 8, 1057e1065.

€

20. (a) Weigend, F.; Haser, M. Theor. Chem. Acc. 1997, 97, 331e340; (b) Wei-

€

gend, F.; Haser, M.; Patzelt, H.; Ahlrichs, R. Chem. Phys. Lett. 1998, 294,

143e152.

21. Deglmann, P.; Furche, F.; Ahlrichs, R. Chem. Phys. Lett. 2002, 362, 511e518.

22. TURBOMOLE V6.2,

a development of University of Karlsruhe and For-

schungszentrum Karlsruhe GmbH, 1989e2007, TURBO MOLE GmbH; available

from: http://www.turbomole.com.

3. Vik, A.; Gundersen, L.-L. Tetrahedron Lett. 2007, 48, 1931e1934.

Article Doi

Synthesis of complex fused polycyclic heterocycles utilizing IMDAF reactions of allylamino- or allyloxy-furyl(hetero)arenes

DOI: 10.1016/j.tet.2011.12.079

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