Intramolecular Diels-Alder chemistry of 4-vinylimidazoles

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PAPER

Intramolecular Diels–Alder chemistry of 4-vinylimidazoles†

Yong He, Pasupathy Krishnamoorthy, Heather M. Lima, Yingzhong Chen, Haiyan Wu, Rasapalli Sivappa,‡

H. V. Rasika Dias* and Carl J. Lovely*

Received 1st September 2010, Accepted 13th December 2010

DOI: 10.1039/c0ob00657b

An investigation of 4-vinylimidazoles as diene components in the intramolecular Diels–Alder reaction

is described. In the course of these studies several parameters affecting the cycloaddition were evaluated

including the nature of the imidazole protecting group, the type of dienophile and the linking group.

These investigations established that amino linkers were generally more effective than either ethers or

esters. In most cases, the cycloadditions were highly stereoselective, resulting in the formation of

products derived from an anti transition state. The polysubstituted tetrahydrobenzimidazole core of the

pyrrole-imidazole alkaloid ageliferin can be constructed through the use of pseudo dimeric

4-vinylimidazoles.

Our group has been interested for some time in the development

of new synthetic methods for the elaboration of simple imidazoles

into more complex derivatives.¹The primary motivation for this

effort has been to apply these methods in the total synthesis of

imidazole-containing alkaloids, in particular for approaches to

the oroidin family of pyrrole-imidazole marine alkaloids^1,2and

the Leucetta family of aminoimidazole alkaloids (Fig. 1).^3,4We

also anticipated these efforts would provide useful methods in a

general sense for the construction of polysubstituted imidazoles. In

connection with an approach to the originally reported structure of

palau’amine (2)⁵and related congeners,^5–7we have developed the

intermolecular Diels–Alder (DA) reaction of 4-vinylimidazoles⁸

and subsequent oxidative functionalization⁹of these adducts

to construct the DEF-ring fragment based on a biosynthetic

proposal.⁵An obvious and important extension of the initial

cycloaddition chemistry was its application in an intramolecular

variant.¹⁰Although we perceived that this reaction may be valuable

in its own right for the construction of polycyclic imidazole

derivatives,¹¹we were particularly interested in determining its

utility in the context of approaches to several pyrrole-imidazole

alkaloids, e.g., ageliferin (3),^12,13axinellamine A (4),^14,15massadine

(5),^16,17and the recently-revised structures of the palau’amine

family,^18,19e.g., 6 as a means to enforce, inter alia, the correct

regiochemistry (“head-to-head”) of the building blocks. In general

Fig. 1 Structures of some oroidin alkaloids.

Department of Chemistry and Biochemistry, The University of Texas at

Arlington, Arlington, Texas, USA. E-mail: lovely@uta.edu, dias@uta.edu;

Fax: +1 817-272-3808; Tel: +1 817-272-5446; +1 817-272-3813

terms, the intramolecular variant of the DA reaction is well known,

† Electronic supplementary information (ESI) available: Experimental

and widely used in synthetic approaches to natural products,²⁰

procedures and characterization data for new compounds not described

in the main manuscript. Plots of X-ray structures for compounds

20a, 62, and 68. CCDC reference numbers 791657–791659. For ESI

and crystallographic data in CIF or other electronic format see DOI:

10.1039/c0ob00657b

‡ Current address: Department of Chemistry and Biochemistry, University

of Massachusetts Dartmouth, North Dartmouth, MA02747–2300, USA.

however at the outset of this study, there were few examples

of vinylimidazoles as 4p-components in the DA reaction.²¹Sim-

ilarly, there were only limited examples of intramolecular DA

(IMDA) reactions involving imidazoles.²²Wuonola and Smallheer

have reported one example of an IMDA reaction involving the

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imidazole moiety as a diene, although the imidazole fragment was

not found in the product due to a retro DA reaction leading to the

expulsion of HCN.²²Snyder and co-workers have examined several

2-aminoimidazole derivatives as 2p-components in intramolecular

variants of inverse electron demand DA reactions, which provided

efﬁcient access to a variety of fused heterocyclic systems.²³As

a result of the paucity of reports,²⁴the general parameters to

successfully execute this reaction had to be ascertained prior to

application of this chemistry in total synthesis efforts. For example,

the nature of the imidazole nitrogen protecting group and the

range of dienophile substituents needed to be established, along

with the identiﬁcation of suitable linking moieties.²⁵Further, as

was found in the intermolecular variant, there is the possibility of

the formation of two possible products, the initial adduct cf. 8 and

the aromatized adduct 9 (Fig. 2);⁸raising the question of whether

this can be controlled by the substrate structural features (e.g.,

the N-protecting group, the nature of the dienophile etc.) or the

reaction conditions. Finally, issues pertaining to stereocontrol in

these DA reactions and the utility of the cycloadducts for further

elaboration towards natural product targets, such as those depicted

in Fig. 1 needed to be determined.

Scheme 1

Fig. 2 Overview of the current study.

turn suggested that there most likely were unfavorable steric

interactions between the bulky trityl protecting group and the

terminal substituent. An X-ray crystal structure (see the ESI†)

obtained on 20a strongly supports this notion, as there is very

little free space between the trityl moiety and H8. The fact that

the allyl substrate 14a did not engage in a DA reaction was

not difﬁcult to rationalize, based on (presumably) unfavorable

electronic factors, the acrylate substrate 16a was somewhat more

difﬁcult to understand considering we knew that intermolecular

DA reactions occur with electron deﬁcient dienophiles, including

Results and discussion

Urocanic acid (10) serves as a convenient starting material for

this investigation as this unsaturated imidazole derivative is

commercially available, or can be readily prepared from histidine.²⁶

Conversion of 10 to the corresponding methyl ester 11 via a simple

Fischer esteriﬁcation protocol can be conveniently accomplished

on large scales using Pirrung’s modiﬁcation of the original Wunack

procedure (Scheme 1).²⁷Initial experiments were conducted using

a trityl-protecting group on nitrogen as compounds 12a and

13a were not only described in the literature, but the protection

occurs selectively at the least hindered nitrogen atom, providing

the 4-vinylimidazole derivative 12a efﬁciently (Scheme 1), thus

permitting direct comparison with the previously reported in-

termolecular studies.^28,29Reduction of ester 12a with DIBAL-

H gave the corresponding allyl alcohol 13a (Scheme 1).³⁰With

quantities of the allyl alcohol in hand, a variety of simple ethers

and esters 14a–19a were prepared via standard methods,³¹and

subjected to DA reactions under thermal activation. In most

cases, the heating bath temperature was increased (temperature

range 60–180 ^◦C) until cycloaddition was observed or alternatively

decomposition occurred. As can be seen from Table 1, only two of

the six substrates, the propargylic derivative 18a (145 ^◦C, PhH,

26 h) and the propiolate derivative 19a (140 ^◦C, PhH, 24 h),

engaged in the cycloaddition reaction forming dihydrobenzimi-

dazoles 20a (and the aromatized derivative) and 21a, respectively.

The remaining substrates underwent decomposition on extended

heating at 150 ^◦C (typically through loss of the trityl moiety).

In the absence of other information, we concluded from these

results that terminal substituents were not tolerated, which in

Table 1 Cyclization products and yields from intramolecular DA reac-

tions of alkynyl substrates

PG =

Substrate

Product

Tr/%

Bn/%

DMAS/%

10^a(34)^b

76

b

65 (1)^b

c

18

19

20

21

a

30

a

0^c

b

30

c

^aStructure was conﬁrmed by X-ray crystallography. ^bYield in parenthesis

corresponds to the oxidized product. ^cThe propiolate derivative was not

stable to chromatographic puriﬁcation, and attempts to cyclize the crude

product derived from the acylation of the alcohol were unsuccessful.

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methyl acrylate, although the intrinsic regioselectivity of this

reaction is in the opposite sense (see Scheme 3 below).⁸Initially,

guided by the notion that steric factors due to the bulky nature of

the trityl protecting group were playing a dominant role, we turned

our attention to the preparation and evaluation of substrates with

smaller imidazole protecting groups.

By the time these initial results with the Tr-systems were

in hand, our experience in imidazole chemistry had evolved

substantially, and thus we were able to prepare selectively two other

4-vinylimidazole derivatives from urocanic acid (10) containing

smaller,⁸and more robust, protecting groups, with complemen-

tary electronic properties; the electron rich benzyl group and

the electron withdrawing dimethylaminosulfonyl (Me₂NSO₂–,

DMAS) group leading to the preparation of alcohols 13b and

13c, respectively (Scheme 1). Similar series of dienes 14b–19b and

14c–19c were prepared from each alcohol ranging from simple

unactivated oleﬁns to electron deﬁcient oleﬁns, and each diene

was subjected to a DA reaction under thermal activation. In

addition to the systems depicted in Scheme 1 and in Table 1,

we were eager to push our chemistry towards natural product

applications and so the pseudo dimeric substrate 22 (Scheme 2)

was prepared and evaluated in the DA reaction. Essentially the

same pattern of results was observed for these new derivatives 14b–

19b and 14c–19c as for the Tr-protected series 14a–19a with only

the acetylenic substrates undergoing cycloaddition. In addition

ester 22 failed to undergo cycloaddition to produce the expected

lactone 23 (Scheme 2).

Scheme 3

h) compared to the reactions with N-phenylmaleimide, and (2)

the reaction was regioselective, placing the carboxymethyl moiety

proximal to the imidazole (Scheme 3, 24→25).⁸Similar results

were obtained with 24 and acrylonitrile (Scheme 3, 24→26).

In other words, mono activated dienophiles are substantially

less reactive in this chemistry and they react with the opposite

regiochemistry to that enforced by intramolecularity in the present

study. Clearly, the entropic gain from the intramolecularity of

the reaction with these O-linked substrates was not sufﬁcient to

overcome the intrinsic and unfavorable reactivity and electronic

factors.

It is known in the literature that attainment of the transition

state in cycloadditions with substrates related to 16a–c and 17a–

c is accompanied by a twisting of the C–C bond between the

oleﬁn and carbonyl unit, which reduces the effectiveness of the

conjugation between the p-bonds and thus raises the activation

energy of the process.³³Taking this factor into account suggested

that the use of doubly activated dienophiles may provide substrates

that would engage more readily in an intramolecular reaction.³⁴

Accordingly, the fumarates 27b–c, the acetylpropenoates 30b–c,

and the phenylpropiolates 32b–c were prepared by condensing the

half acid chloride or the corresponding acid (activated in situ with

DCC) with the two allylic alcohols 13b and 13c (Table 2).³⁵Both fu-

marate derivatives participated in an intramolecular DA reaction

in benzene at 145 ^◦C (bath temperature), providing cycloadducts,

Table 2 Intramolecular DA reactions of bis-activated substrates

Product

Scheme 2

PG = Bn

(%)

PG =

DMAS (%)

Entry

R

Only the propargyl substrates 18a–c, and in the cases of the

Tr- and DMAS-derivatives, the propiolate systems 19a and c

successfully participate in the cycloaddition chemistry. These

results clearly demonstrate that steric interactions between the

nitrogen protecting group and the terminal dienophile substituent

are not the primary (or perhaps even the major) cause for these

cycloaddition reactions to fail, as presumably the Bn and DMAS

groups can largely avoid unfavorable non-bonded interactions

by rotating the majority of their steric bulk out of the way of

an approaching dienophile. Again, for unactivated systems (allyl

and cinnamyl), the failure still could be rationalized, at least

qualitatively, in terms of mismatched HOMO–LUMO energies,

whereas the activated systems (acryloyl³²and cinnamoyl) were a

little more puzzling to understand from this perspective. Around

this time, results were emerging from parallel studies in the

intermolecular reaction, which provided a possible clue to the

cause of the failure of these systems to react in a general

sense. For example, when the Bn-protected vinylimidazole 24 was

reacted with methyl acrylate (Scheme 3) two notable observations

were made: (1) the reaction was signiﬁcantly slower (days vs.

70

b

20^a

c

1

27

29

59

b

68

c

2

3

30

32

31

33

85

b

65

c

^a51% of unreacted starting material was recovered.

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in modest to good yield. In the case of the Bn-protected derivative

27b, all of the spectroscopic data were consistent with formation

of an all trans substituted adduct 29b. Similarly with the DMAS-

protected derivative, the spectroscopic data was consistent with the

formation of a cycloadduct with the same all trans conﬁguration.

However, X-ray crystallographic analysis of this cycloadduct,§

performed to conﬁrm the relative stereochemistry, revealed a

surprise; although the stereochemistry was determined to be all

trans as expected, the nitrogen protecting group had migrated

to the less sterically congested nitrogen (28, Scheme 4).³⁶This

type of migration has been observed previously with the DMAS

group on an imidazole system.³⁷Subsequently it was found that

by conducting the reaction at lower temperatures, the migration

could be avoided and the expected cycloadduct 29c was obtained in

relatively low yield (entry 1, Table 2), although it should be noted

that the migration started to occur on extended reaction times.

We also evaluated the corresponding unsaturated keto ester

derivatives 30b and 30c, which were being considered as substrates

for approaches to several of the oroidin dimers.¹³We found that

these substrates also participated in the cycloaddition reactions

providing 31b and 31c, respectively, although the efﬁciencies were

still relatively modest. Similarly, the phenylpropiolate derivatives

32b and 32c were prepared and subjected to the IMDA reaction,

leading in both cases to a successful cycloaddition, providing 33b

and 33c in reasonable yields.

be achieved, therefore structural features in the cyclization pre-

cursor that increase the population of the reactive conformation

should lead to an increase in the cycloaddition rate.³⁸It is well-

known that substituted amines and amides can behave in this

manner, and so the next logical step was to prepare and evaluate

such substrates.

Initially, the N-tosyl protected derivatives 36 and 37 were

prepared via a Mitsunobu reaction of the corresponding N-tosyl

allyl amine 34³⁹and N-tosyl propargyl amine 35⁴⁰with allylic

alcohol 13c. This route was successful only for the DMAS-

protected series (Scheme 5). It was found that the Bn-protected

series did not participate in Mitsunobu reactions cleanly, in fact

under these reaction conditions S_N2¢ products were formed as the

major product in addition to the desired product, and these two

adducts often proved difﬁcult to separate chromatographically,

leading to very poor yields. In subsequent studies it was found

that the S_N2¢ pathway could be circumvented through the use

of reductive amination (see Scheme 6 below) or by Pd-catalyzed

p–allyl nucleophilic substitution,⁴¹but this was not determined

until much later in the investigation, and thus the Bn-derivatives

corresponding to 36 and 37 were not prepared. However, when

the two sulfonyl urea substrates 36 and 37 were subjected to the

DA reaction at elevated temperature, we were delighted to observe

that cycloaddition occurred providing the expected cycloadducts,

albeit in relatively moderate efﬁciency and under harsh reaction

conditions (Scheme 5) leading to the formation of 39 (and 38)

and 40 (and 41). Presumably, the high reaction temperatures

result in some decomposition leading to modest yields. In the

case of the allyl substrate 36, both the initial adduct 38 and

aromatized adducts 39 were obtained, each as inseparable 1 : 1

mixtures of stereoisomers. The propargyl substrate 37 led to the

formation of two cycloadducts; the expected aromatized adduct

40, along with a very small amount of the oxidized adduct 41.

The key observation from these experiments was the fact that

even the non-activated allyl system 36 underwent cycloaddition

in contrast to the corresponding ethers 14a–c, suggesting that

conformational issues do in fact play a major role in the facility of

these cycloadditions. Extrapolating these ﬁndings suggested that

combining more activated dienophiles with an amino linker should

further facilitate the cycloaddition, and therefore we turned our

attention to the preparation of related amides.

Scheme 4

Despite the fact that these cyclizations can be considered

successful, based on the relatively modest efﬁciencies in some cases,

we suspected that in addition to electronic effects, conformational

issues were playing a signiﬁcant role. Speciﬁcally, in order for

cycloaddition to occur, an appropriate reactive conformation must

Our initial investigations were conducted with the DMAS series,

in part due to the accessibility of the requisite substrates, as the

S_N2¢ problems discussed above initially precluded the use of the

corresponding Bn-protected system.

§ The X-ray structures and CIFs were reported in the preliminary account

of this work (see ref. 10) and have been deposited at the Cambridge

Crystallographic Data Center (compound 28 = CCDC 222234; compound

60 = CCDC 222235).

Scheme 5

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Scheme 6

It was found that the N-alkyl phthalimide 42 was readily

obtained through a Mitsunobu reaction of the allylic alcohol 13c

with phthalimide, although later it was determined that a more

traditional Gabriel-type of reaction with K-phthalimide via the

allyl chloride was more efﬁcient (Scheme 6). Hydrazinolysis of

42 to 43, conversion to the imine with benzaldehyde and then

reduction with NaBH₄provided the corresponding benzylamine

44a. Subsequently an improved second generation route was

developed whereby the same benzylamine 44a can be obtained

via oxidation of the allylic alcohol 13c to aldehyde 50a, and

reductive amination with benzylamine affords 44a (Scheme 6).

Critically, this new route also permitted the construction of

the corresponding Bn-protected substrates 53a and 53b (see

below). With 44a in hand, the preparation of the corresponding

fumaramide 45, cinnamide 46, acrylamide 47, and urocanamide

48 (Table 3) was easily accomplished via treatment with the

appropriate acid chlorides (45–47) or the activated carboxylic acid

(48). That these substrates were more reactive was immediately

evident during the preparation of 45, as it was found that some

cycloaddition occurred during the process of preparation and

work-up. Subsequent thermal activation of the puriﬁed amide at

68 ^◦C provided the anticipated initial adduct 59 in an excellent

95% yield as a single stereoisomer (no other isomer detected

the ester and amido moiety. It is also of note that under these

mild reaction conditions, migration of the DMAS group was

not observed. Similarly, the cinnamide derivative 46 underwent

cycloaddition, providing a separable mixture of the initial adduct

61 and the aromatized congener 62. Unlike with the fumaramide

45, we were unable to ﬁnd conditions which led to the exclusive

production of the initial cycloadduct 61. Access to the initial

adduct would be useful as it permits oxidative functionalization

of the oleﬁn and ultimately would serve as a handle for the

introduction of heteroatoms in targets such as palau’amine (6),

axinellamine A (4) and massadine (5). The aromatized adduct 62

provided good quality crystals, which were evaluated by X-ray

crystallography (see the ESI†), indicating that the relative stereo-

chemistry was all trans. As expected, the acrylamide derivative 47

was much less reactive, but a cycloadduct 63 could be obtained

in low yield and in this case as a nearly equimolar mixture of

stereoisomers.

Most gratifyingly, the “dimeric” substrate 48 also undergoes

cycloaddition in good yield (82% combined), but surprisingly

two cycloadducts were obtained in these experiments. Initially,

we suspected that these adducts were cis and trans stereoisomers,

presumably at the ring junction, however proving this was difﬁcult

as we had some trouble in separating the two adducts. Eventually,

however, preparative TLC permitted their separation and char-

acterization. Extensive NMR analysis indicated that rather than

being stereoisomers, these cycloadducts were in fact constitutional

isomers, in which the major isomer was the normal (and expected)

DA adduct 64, and the minor isomer 65 results from an inverse

electron demand DA reaction through the alternate pairing of the

vinylimidazoles (48→75 + 76→64 + 65, Scheme 7). Interestingly,

both cycloadducts had the same all trans relative stereochemistry

(determined from the magnitudes of the appropriate vicinal

coupling constants), and thus both cycloadducts, in principle,

could be employed en route to the ageliferin group of natural

products.

1

by H NMR spectroscopy of the crude reaction mixture). After

the initial preparation, where cycloaddition occurred during the

work-up, it was decided to subject the crude reaction mixture

to the conditions employed above. In this case the cycloaddition

occurred readily; however, the initial adduct 59 was only obtained

in 10% yield, the major product was in fact the aromatized adduct

60, again obtained as a single stereoisomer. Presumably traces

of either acid or base remaining from the preparation of the

substrate catalyze the aromatization process.⁸This aromatized

cycloadduct was highly crystalline, providing material suitable

for an X-ray crystal structure determination,§ which conﬁrmed

that the ring junction was trans, as was the relationship between

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Table 3 Intramolecular DA products from amide-containing substrates

Substrate (yield/%)^a/conditions^b

PG

R¢

R

Initial adduct (%)

Aromatized product (%)

45 (92)^c

DMAS

CO₂Et

Bn

59

95^d

10^e

60^f

—

80

PhH, 68 ^◦C, 12 h

PhH, 68 ^◦C, 10 h

46 (82)

DMAS

Ph

Bn

61

27

62^f

32

51

PhH, 130 ^◦C, 25 h

PhH, 130 ^◦C, 45 h

47 (41)

DMAS

H

Bn

63

PhH, 145 ^◦C, 60 h

21 (3 : 2)^g

48 (78)

DMAS

Bn

64

50

56

65

32

43

PhH, 95 ^◦C, 70 h

PhH, 135 ^◦C, 25 h

h

49

DMAS

BOC

PhH, 95 ^◦C, 14 days

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Table 3 (Contd.)

Substrate (yield/%)^a/conditions^b

PG

R¢

R

Initial adduct (%)

Aromatized product (%)

54 (75)

DMAS

Ph

Bzh

66

38

67

52

PhH, 95 ^◦C, 44 h

55 (98)

DMAS

Bzh

68^f

56

53

60

69

39

42

30

PhH, 95 ^◦C, 46 h

MeOH, 95 ^◦C, 42 h

CH₂Cl₂, 95 ^◦C, 72 h

56 (28)

Bn

H

Bn

70

PhMe, 145 ^◦C, 98 h

71 (3 : 2)^g

57 (80)

Bn

71

31

72

35

PhH, 130 ^◦C, 36 h

58 (80)

Bn

Bzh

73

45

74

45

PhH, 95 ^◦C, 30 h

^aYields correspond to the acylation of the allylic amines to produce DA substrates. For details of their preparation see Experimental and the ESI.†

^bConditions correspond to those employed in the DA cycloaddition. ^cIn addition, 5% of initial cycloadduct. ^dThe substrate was puriﬁed by column

chromatography prior to cycloaddition. ^eThe crude substrate was used in the cycloaddition. ^fThe structure was conﬁrmed by X-ray crystallography.

^gThe stereochemistry of the major adduct was not determined. ^hCycloaddition occurred, but a complex mixture of products was obtained from which

no characterizable products were isolated.

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Scheme 7

In an attempt to improve the cycloaddition selectivity both in

terms of isolation of the initial adduct, chemoselectivity (normal

versus inverse electron demand DA) and ease of subsequent

elaboration, we became interested in the use of other substituents

on the linking amino group with an aim of lowering the reaction

temperature and potentially increasing selectivity. In particular,

the use of bulky N-substituents has been shown to be beneﬁcial

in accelerating sluggish cycloaddition reactions by increasing the

“reactive conformer” concentration,⁴²therefore derivatives were

prepared which contained either a N-BOC moiety 49 or a N-

benzhydryl moiety, 54 and 55, via standard chemistry. These

substrates were then subjected to DA reactions. In the case of

the N-BOC system 49, a very slow reaction took place, with

only approximately 40% conversion (estimated by ¹H NMR

spectroscopy of the crude reaction mixture) after 14 days at 95 ^◦C,

increasing the temperature did not lead to an appreciable im-

provement in the situation. A fairly complex mixture of products

was obtained containing what appear to be several cycloadducts

judging from the complexity of the NMR spectrum, presumably

the normal and inverse products and their corresponding initial

adducts. Unfortunately, attempted puriﬁcation of these products

to rigorously establish their identity was not successful. On

the other hand, substrates containing the benzhydryl group 54

and 55 underwent cycloaddition at a somewhat increased rate

and reasonable temperatures. Fortuitously, with the DMAS-

protected pseudo dimeric system 55, it was found that the

major product 68 crystallized out selectively from the partially

concentrated reaction mixture and provided crystals suitable for

X-ray crystallography (see the ESI†). This analysis not only

conﬁrmed the connectivity of the major adduct, but the all

trans stereochemistry, which, as indicated above, was required

in several of the natural products targeted in this program.

Attempts were made to improve the selectivities by conducting

the reaction in different solvents, but this only led to incremental

improvements. Although the formation of constitutional isomers

was not considered to be fatal to this approach to several natural

product targets, e.g., ageliferin, the situation was exacerbated by

our inability to elaborate the lactam moiety under sufﬁciently mild

conditions that did not lead to deprotection of the imidazoles or

decomposition.

Therefore we looked at the preparation of the corresponding

Bn-protected derivative, which we hoped may display improved

selectivities in the cycloaddition due to the different electronic

properties conferred on the imidazoles and, as the protecting

groups are more robust, would permit the elaboration of the

amide. Unfortunately, however, when either the N_amide-benzyl 57

or N_amide-benzhydryl 58 substituted derivatives were subjected

to cycloaddition, an inseparable, essentially 1 : 1 mixture, of the

two isomers 71 and 72 was obtained in 66% yield, and 73

and 74 in 90% yield. For characterization purposes and to

demonstrate that these two cycloadducts were in fact regioisomeric

rather than stereoisomers, the lactam moiety was reduced with

LiAlH₄, leading to the formation of single compounds (77 and

78, respectively, Scheme 8) in both the benzyl series and the

benzyhydryl series.

Scheme 8

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A common trend observed among these doubly activated

derivatives is that they all proceed to give the all trans isomer (irre-

spective of the connectivity in the cases where competitive inverse

electron demand DA reaction occurred), whereas the acrylamide

derivatives provide mixtures of cis and trans cycloadducts. The

putative transition states for these trans selective cycloadditions

place the terminal substituents in an anti orientation¶ (79→81,

Scheme 9), i.e., tucked under the imidazole moiety of the diene,

and thus there is a possibility of stabilizing secondary orbital or

p/p-interactions.⁴³However, since many of these reactions occur

at elevated temperature it is highly likely that the stereochemistry

in these cycloadditions is a result of steric interactions, as in the

alternate transition state leading to the cis fused product there

appears to be a steric clash between the imidazole protecting group

and the dienophile substituent (80→82, Scheme 9). In the case of

the acrylamide derivatives this steric interaction is absent, and

there are no other apparent secondary stabilizing interactions and

therefore both cis and trans cycloadducts are more or less equally

feasible.

are now investigating second generation systems and employing

this chemistry in a number of approaches to imidazole-containing

natural products and we will report our endeavors in due course.

Experimental

General considerations

All reactions were conducted in oven-dried glassware under an

inert atmosphere of either nitrogen or argon. All reaction solvents

were dried prior to use, either by standard methods or using

alumina columns. NMR spectra were recorded in CDCl₃solutions

at 500 MHz for ¹H NMR or 125 MHz for ¹³C NMR unless

indicated otherwise. Experimental descriptions are provided for

the DMAS-containing series, the remaining Tr- and Bn-derivatives

are described in the ESI.†

General procedure A for alkylation (and some acylation) reactions

(GP-A). A THF (5 mL) solution of alcohol (0.50 mmol) was

cooled in an ice bath for 20 min. NaH (34 mg, 60% suspension in

mineral oil, ~0.85 mmol) was added to the ﬂask in two portions,

and the ﬂask was purged with nitrogen after the addition was

completed. The solution was held in the ice bath for 1 h. The neat

alkyl halide (0.50 mmol) was then added via syringe dropwise.

The ice bath was removed after 10 min and the reaction ﬂask was

allowed warm up to room temperature.⁴⁴Tetrabutylammonium

iodide (50 mg, 0.13 mmol) was added and stirring was continued

until the reaction was deemed complete by TLC analysis (12–36

h). Water (5 mL) was added to quench the reaction with the ﬂask in

an ice bath. After the mixture was stirred for 20 min, the aqueous

layer was extracted with EtOAc (3 ¥ 5 mL). The combined organic

layer was washed with water (2 ¥ 6 mL) then dried (MgSO₄)

and concentrated. The EtOAc solution was concentrated and the

residue was puriﬁed by ﬂash column chromatography.

Scheme 9

General procedure B for N-acylation reactions with acid chlorides

(GP-B). The appropriate acyl chloride (1.05 mmol) in CH₂Cl₂(1

mL) was added dropwise to a mixture of the amine (1.00 mmol)

and sodium bicarbonate (101 mg, 1.20 mmol) in CH₂Cl₂(3 mL) at

0 ^◦C. After the completion of addition, the reaction was allowed to

warm up to room temperature and stirred for several hours until

completion (TLC). The reaction mixture was diluted with CH₂Cl₂

(5 mL), washed with water (2 ¥ 5 mL), brine, dried (Na₂SO₄) and

concentrated. Puriﬁcation of the crude sample by chromatography

gave the corresponding N-acylated product.

A second trend that emerges is that the initial adduct is

only observed with the certain substrates in the DMAS series

(e.g., 49→63), this observation is consistent with the intermolec-

ular variants where lower reaction temperatures and electron

withdrawing N-substituents favor the formation of stable initial

adducts.⁸Thus at lower reaction temperatures at which the

fumaramide, and to a lesser extent the cinnamide derivatives react,

the re-aromatization pathway is less favorable, this is augmented

by the N-sulfamoyl moiety reducing the electron density on

the N1 of imidazole, which in turn reduces the driving force

for rearomatization. For other analogs, either a higher reaction

temperature is employed which facilitates aromatization, or the

N1-substituent is electron rich, favoring aromatization.

In summary, we have investigated the preparation and in-

tramolecular DA chemistry of several 4-vinylimidazole derivatives.

In general, we have found that nitrogen-linked systems engage

in cycloaddition with better efﬁciencies than the corresponding

oxygen-linked systems. It was found, however, that propiolate,

aryl-substituted propiolate, and bis activated derivatives linked via

an ester do participate in cycloaddition. Based on this study, we

General procedure C for EDCI coupling reactions (GP-C). The

alcohol or amine (1.00 mmol), EDCI (287 mg, 1.50 mmol) and acid

(1.50 mmol) were dissolved in anhydrous CH₂Cl₂(10 mL). The

solution was cooled to 0 ^◦C and DMAP (183 mg, 1.50 mmol) was

added in one portion. The solution was allowed to warm to room

temperature and stirred overnight. On completion of the reaction

(TLC), the reaction mixture was diluted with CH₂Cl₂, washed

with water (3 ¥ 5 mL), brine, dried (Na₂SO₄) and concentrated.

The residue was puriﬁed by chromatography to afford the pure

ester or amide.

General procedure D for DCC coupling reactions (GP-D).

Allylic alcohol (2.0 mmol), DMAP (10 mg) and acid (3.0 mmol)

were dissolved in CH₂Cl₂(3 mL). The solution was cooled to

-78 ^◦C and DCC (500 mg, 2.4 mmol) in CH₂Cl₂(1.5 mL)

¶ Syn and anti denote the orientation of the terminal dienophile sub-

stituent relative to the diene and used to avoid confusion with endo and

exo, using terms suggested by Ciganek (see ref. 20).

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was added by cannula. The solution was allowed to warm to

room temperature over a period of 3–4 h. On completion of the

reaction (TLC), the reaction mixture was ﬁltered through Celite

and washed with CH₂Cl₂. The combined ﬁltrates were evaporated

under vacuum and the residue puriﬁed by chromatography to

afford the pure ester.

5,7-Dihydro-1-dimethylsulfamoyl-1H-furo[3,4-f ]benzimidazole.

Only NMR data is available for this compound: H NMR: d =

8.22 (s, 1H), 7.69 (s, 1H), 7.61 (s, 1H), 5.20 (s, 4H), 2.90 (s, 6H);

¹³C NMR: d = 143.7, 142.1, 137.4, 136.3, 131.6, 113.1, 105.3, 73.2,

73.1, 38.4.

1

3,7,7a,8-Tetrahydro-3-dimethylsulfamoyl-5H-furo[3,4-f ]benz-

imidazol-5-one (21c). Compound 21c was prepared from the

Diels–Alder reaction of compound 19c (391 mg, 1.38 mmol) in

benzene. Flash chromatography (EtOAc)_◦afforded 21c (117 mg,

General procedure for thermal Diels–Alder reactions. The

Diels–Alder substrate was dissolved in the appropriate solvent

(usually benzene) to prepare a ~0.1 M solution in a thick-walled

pressure tube with a Teﬂon screw-cap. The solution was degassed

by bubbling N₂or Ar gas through it for a few minutes and then

the tube was sealed. The mixture was heated at the indicated

temperature and the reaction was monitored by TLC or ¹H NMR

spectroscopy of the crude reaction mixture. On completion of the

reaction, the solvent was removed by rotary evaporation followed

by puriﬁcation of the residue by chromatography to afford the

cycloadducts.

1

30%) as colorless solid: mp: 171.5–172.0 C; H NMR: d = 7.87

(s, 1H), 7.56 (d, 1H, J = 3.7 Hz), 4.75 (dd, 1H, J = 8.8, 8.8 Hz),

4.04 (dd, 1H, J = 9.2, 8.8 Hz), 3.52 (ddddd, 1H, J = 17.2, 9.5, 9.2,

8.8, 3.7 Hz), 3.11 (dd, 1H, J = 9.5, 17.2 Hz), 2.86 (s, 6H), 2.65 (dd,

1H, J = 17.2, 17.2 Hz); ¹³C NMR: d = 168.8, 143.6, 139.1, 126.2,

125.4, 121.2, 72.0, 38.3, 36.3, 26.9; IR (KBr, cm^-1): 3123, 2924,

1748, 1638, 1393, 1187, 1044, 968, 727, 598, 567; EIMS (m/z):

65, 89, 108, 177, 283 (M⁺), 284 (100%, M⁺+ 1); Anal. Calcd for

C₁₁H₁₃N₃O₄S: C, 46.63; H, 4.63; N, 14.83. Found: C, 47.01; H,

4.89; N, 14.46.

1-Dimethylsulfamoyl-4-[(1E)-3-(prop-2-ynyloxy)prop-1-enyl]-

1H-imidazole (18c). Compound 18c was prepared by GP-A

from 13c⁴⁵(464 mg, 2.01 mmol) and propargyl bromide. Flash

chromatography (EtOAc–hexane, 4 : 1) afforded 18c (326 mg, 60%)

as a pale yellow liquid: ¹H NMR: d = 7.79 (s, 1H), 7.09 (s, 1H), 6.46

(m, 2H), 4.18 (d, J = 4.0 Hz, 2H), 4.15 (d, J = 2.6 Hz, 2H), 2.80 (s,

6H), 2.42 (t, J = 2.6 Hz, 1H);¹³C NMR: d = 141.03, 137.0, 127.0,

123.0, 114.5, 79.7, 74.7, 69.6, 57.2, 8.3; IR (CHCl₃, cm^-1): 3290,

3133, 2854, 2115, 1669, 1479, 1419, 1394, 1264, 1176, 1085, 1008,

966, 730, 601; EIMS (m/z): 270 (100%, M⁺+ 1), 214, 161, 125,

108; Anal. Calcd for C₁₁H₁₅N₃O₃S: C, 49.06; H, 5.61; N, 15.60.

Found: C, 49.16; H, 5.82; N, 15.51.

Ethyl

(2E)-3-(1-dimethylsulfamoyl-1H-imidazol-4-yl)-2-pro-

penyl (2E)-2-butenedioate (27c). Compound 27c was prepared

by GP-C from 13c (463 mg, 2.00 mmol) and the half ethyl ester

of fumaric acid. Chromatography (Et₂O–hexane: 85/15) afforded

27c (695 m_◦g, 97%) as a colorless oil which solidiﬁed on standing.

mp: 61–62 C. ¹H NMR: d = 7.84 (d, J = 1.4 Hz, 1H), 7.15 (d, J =

1.4 Hz, 1H), 6.86 (s, 2H), 6.52 (m, 2H), 4.83 (dd, J = 2.3, 2.3 Hz,

2H), 4.24 (q, J = 6.9 Hz, 2H), 2.85 (s, 6H), 1.30 (t, J = 6.9 Hz,

3H); ¹³C NMR: d = 165.0, 164.8, 140.5, 137.1, 134.2, 133.3, 124.3,

115.0, 65.3, 61.5, 38.3, 14.2; IR (KBr, cm^-1): 3138, 2984, 2942,

1731, 1715, 1480, 1420, 1394, 1308, 1178, 1225, 1079, 1007, 970,

729, 603; EI-MS (m/z): 357 (M⁺, 10%), 229 (100%). Anal. Calcd

for C₁₄H₁₉N₃O₆S: C, 47.05; H, 5.36; N, 11.76. Found: C, 46.98; H,

5.19; N, 11.40.

(2E)-3-(1-Dimethylsulfamoyl-1H -imidazol-4-yl)prop-2-enyl

propynoate (19c). Compound 19c was prepared by GP-C from

13c⁴⁵(347 mg, 1.50 mmol) and propiolic acid. Flash chromatogra-

phy (EtOAc–hexane, 4 : 1) afforded product 19c (331 mg, 79%) as

colorless solid: mp: 67.0–67.5 ^◦C; ¹H NMR: d = 7.83 (s, 1H), 7.16

(s, 1H), 6.55 (d, J = 15.8 Hz, 1H), 6.50 (dt, J = 15.8, 4.8 Hz, 1H),

4.82 (d, J = 4.8 Hz, 2H), 2.90 (s, 1H), 2.85 (s, 6H); ¹³C NMR: d =

152.5, 140.4, 137.1, 125.1, 123.5, 115.2, 75.1, 74.6, 66.2, 38.3; IR

(KBr, cm^-1): 3274, 2119, 1714, 1392, 1221, 1175, 1077, 1008, 966,

728, 598; EIMS (m/z): 65, 71, 98, 108, 125, 153, 214 (100%), 284

(M⁺); Anal. Calcd for C₁₁H₁₃N₃O₄S: C, 46.63; H, 4.63; N, 14.83.

Found: C, 46.76; H, 4.94; N, 14.45.

Ethyl (4S*,4aR*,7aS*)-1-dimethylsulfamoyl-5-oxo-4,4a,7a,8-

tetrahydro-1H-furo-[3,4-f ]benzimidazole-4-carboxylate

(28).

Compound 28 was prepared by the general Diels–Alder reaction

procedure from 27c (300 mg, 0.84 mmol) in benzene at 160 ^◦C

for 4 days. Chromatographic puriﬁcation of the crude residue

(EtOAc) _◦provided 28 (60 mg, 20%) as a colorless solid. mp:

180–181 C. ¹H NMR: d = 7.82 (s, 1H), 4.56 (dd, J = 8.8, 6.4 Hz,

1H), 4.36 (dq, J = 7.1, 3.6 Hz, 1H), 4.31 (dq, J = 7.1, 3.6 Hz, 1H),

4.10 (dd, J = 10.3, 8.8 Hz, 1H), 3.80 (d, J = 10.8 Hz, 1H), 3.20

(dd, J = 11.2, 10.4 Hz, 1H), 3.07 (dd, J = 13.3, 10.8 Hz, 1H), 2.90

(s, 6H), 2.69–2.66 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H); ¹³C NMR:

d = 174.1, 170.9, 138.0, 137.0, 125.5, 71.1, 62.1, 44.7, 42.3, 38.7,

38.2, 24.6, 14.3; IR (KBr, cm^-1): 2982, 1782, 1734, 1469, 1390,

1178, 1150, 1091, 992, 720, 588; EI-MS (m/z): 358.7 (M⁺+1, 5%),

356.5 (M⁺, 45%), 283.5 (100%), 106.9 (65%). Anal. Calcd for

C₁₄H₁₉N₃O₆S: C, 47.05; H, 5.36; N, 11.76. Found: C, 47.14; H,

5.57; N, 11.89.

4,4a,5,7-Tetrahydro-1-dimethylsulfamoyl-1H-furo[3,4-f ]benz-

imidazole (20c). Compound 20c was prepared from the Diels–

Alder reaction of compound 18c (277 mg, 1.03 mmol) in benzene.

Flash chromatography (EtOAc) afforded_◦product 21c (181 mg,

1

65%) as colorless solid: mp: 171.0–171.5 C; H NMR: d = 7.70

(s, 1H), 6.43 (d, J = 2.6 Hz, 1H), 4.59 (dd, J = 15.0, 1.5 Hz, 1H),

4.42 (d, J = 15.0 Hz, 1H), 4.33 (dd, J = 8.1, 7.7 Hz, 1H), 3.53 (dd,

J = 10.3, 8.4 Hz, 1H), 3.28 (m, 1H), 2.93 (dd, J = 15.8, 9.2 Hz,

1H), 2.82 (s, 6H), 2.53 (dd, J = 16.3, 16.3 Hz, 1H); ¹³C NMR: d =

143.7, 138.0, 135.9, 127.2, 105.5, 73.9, 69.4, 42.1, 38.3, 25.2; IR

(KBr, cm^-1): 3104, 2860, 1382, 1169, 1122, 1040, 962, 912, 726,

593; EIMS (m/z): 270 (100%, M⁺+ 1), 269 (M⁺),202, 163, 131, 65;

Anal. Calcd for C₁₁H₁₅N₃O₃S: C, 49.06; H, 5.61; N, 15.60. Found:

C, 49.11; H, 5.82; N, 15.57. In addition a very small quantity

(1.4 mg, ~1%) of the oxidized cycloadduct was obtained

Ethyl (4aS*,7aR*,8S*)-1-dimethylsulfamoyl-7-oxo-4,4a,7a,8-

tetrahydro-1H-furo[3,4-f ]benzimidazole-8-carboxylate

(29c).

Compound 29c was prepared by the general Diels–Alder reaction

procedure from 27c (197 mg, 0.55 mmol) in benzene at 135 ^◦C for

72 h. Flash chromatography (EtOAc–hexane, 80/20) provided the

unreacted starting material 27c (100 mg, 51%) and the cycloadduct

29c (40 mg, 20%) as a colorless solid. mp: 135–136 ^◦C. ¹H NMR:

2694 | Org. Biomol. Chem., 2011, 9, 2685–2701

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d = 7.86 (s, 1H), 4.53 (dd, J = 8.8, 6.9 Hz, 1H), 4.28 (dq, J = 7.2,

3.6 Hz, 1H), 4.23 (dq, J = 7.2, 3.6 Hz, 1H), 4.06 (dd, J = 10.7,

8.8 Hz, 1H), 3.94 (d, J = 10.6 Hz, 1H), 2.90 (m, 1H), 2.88 (s, 6H),

2.82 (dd, J = 13.6, 10.6 Hz, 1H), 2.71 (ddd, J = 15.1, 11.2, 2.8 Hz,

1H), 2.62 (m, 1H), 1.32 (t, J = 7.2 Hz, 3H); ¹³C NMR: d = 173.4,

171.1, 141.1, 139.1, 123.3, 70.8, 60.2, 46.7, 41.1, 39.6, 38.2, 27.5,

14.0; IR (KBr, cm^-1): 2984, 2933, 1783, 1732, 1474, 1392, 1233,

1186, 1149, 1082, 1011, 760, 595; EI-MS (m/z): 357 (M⁺, 100%),

283. Anal. Calcd for C₁₄H₁₉N₃O₆S: C, 47.05; H, 5.36; N, 11.76.

Found: C, 47.09; H, 5.30; N, 11.53.

130.9, 128.7, 124.8, 124.0, 119.6, 115.1, 86.7, 80.5, 65.9, 38.3; IR

(NaCl disk, cm^-1): 3138, 2934, 2221, 1708, 1489, 1393, 1286, 1173,

1077, 966, 728, 599; HRMS (ESI) calcd for C₁₇H₁₈N₃O₄S (M+H)⁺

360.1013; found 360.1034; calcd for C₁₇H₁₇N₃O₄SNa (M+Na)⁺

382.0832, found 382.0835.

3,7,7a,8-Tetrahydro-3-dimethylsulfamoyl-4-phenyl-5H-furo[3,4-

f ]benzimidazol-5-one (33c). The substrate 32c (1.00 g, 2.77

mmol) was dissolved in benzene (150 mL) in a pressure tube and

bubbled with N₂for 5 min. The tube was then sealed and heated to

130 ^◦C for 48 h. The solvent was removed under reduced pressure

and the resulting solid was washed repeatedly with CH₂Cl₂to

afford the product 33c (0.73 g, 73%) as an off-white solid. mp:

(2E)-3-(1-Dimethylsulfamoyl-1H-imidazol-4-yl)-2-propenyl (E)-

3-acetylpropenoate (30c). To a solution of (E)-3-acetylpropenoic

acid (518 mg, 4.54 mmol) and alcohol 13c (700 mg, 3.03 mmol)

in CH₂Cl₂(40 mL), DCC (937 mg, 4.54 mmol) and DMAP

(37 mg) were added and stirred for 30 h at room temperature.

The precipitated N,N-dicyclohexylurea was removed by ﬁltration

and the ﬁltrate was washed with EtOAc. The organic layer was

concentrated and to the resulting residue was added EtOAc (50

mL). The insoluble N,N-dicyclohexylurea obtained was removed

by ﬁltration. The EtOAc layer was washed with saturated aqueous

NaHCO₃solution (10 mL), dried (Na₂SO₄), ﬁltered, and concen-

trated. Column chromatography (EtOAc–hexane, 1 : 1) afforded

◦

1

180–184 C; H NMR (300 MHz, DMSO-d₆): d = 8.17 (s, 1H),

7.20–7.28 (m, 5H), 4.60 (t, J = 8.7 Hz, 1H), 4.00 (t, J = 8.7 Hz,

1H), 3.55–3.70 (m, 1H), 2.95 (dd, J = 15.9, 16.5 Hz, 1H), 2.70 (t,

J = 17.1 Hz, 1H), 2.58 (s, 6H); ¹³C NMR (300 MHz, DMSO-d₆):

d = 167.6, 146.9, 142.9, 139.1, 133.3, 130.7, 130.3, 128.8, 127.4,

121.0, 70.2, 37.9, 37.2, 27.5; IR (KBr, cm^-1): 3105, 2966, 2900,

1737, 1619, 1447, 1378, 1263, 1168, 1103, 1070, 1028, 1004, 980,

762, 726, 590, 564; HRMS (ESI) calcd for C₁₇H₁₈N₃O₄S (M+H)⁺

360.1013, found 360.1011.

◦

N -Allyl-N -[(2E)-3-(1-dimethylsulfamoyl-1H-imidazol-4-yl)-

prop-2-enyl]-N-tosylamine (36). Allyl tosyl amine 34³⁹(2.11 g,

10.0 mmol) and PPh₃(3.90 g, 15.0 mmol) was dissolved in

THF (70 mL). The allylic alcohol 13c (1.16 g, 5.00 mmol) was

added followed by DEAD (1.9 mL, 12.3 mmol). The mixture was

stirred at room temperature for 2 h. The solvent was removed

by rotary evaporation and the residue was subjected to column

chromatography (EtOAc–hexane, 3 : 2) to give product 36 (1.12 g,

1

30c as a white solid (580 mg, 59%). mp: 105–107 C; H NMR

(300 MHz): d = 7.84 (s, 1H), 7.16 (s, 1H), 7.04 (d, J = 16.2 Hz,

1H), 6.67 (d, J = 15.9, 1H) 6.54 (s, 2H), 4.86 (s, 2H), 2.86 (s, 6H),

2.36 (s, 3H); ¹³C NMR (75 MHz): d = 197.6, 165.2, 140.4, 140.3,

137.1, 131.2, 124.5, 124.2, 115.0, 65.4, 38.2, 28.2; IR (neat, cm^-1): =

2927, 1715, 1674, 1542, 1479. HRMS (ESI): calcd for C₁₃H₁₈N₃O₅S

(M+H)⁺328.0962, found 328.0971.

1

(4aS*,7aR*,8S*)-8-Acetyl-1-dimethylsulfamoyl-7-oxo-4,4a,7a,

8-tetrahydro-1H-furo[3,4-f ]benzimidazole (31c). Compound 31c

was prepared by the general Diels–Alder reaction procedure

from 30c (200 mg, 0.610 mmol) at 135 ^◦C for 86 h in benzene.

Chromatography (CHCl₃–MeOH, 24 : 1) provided 31c (135 mg,

68%) as a white solid. mp: 84–86 ^◦C; ¹H NMR (C₆D₆+ CDCl₃):

d = 7.54 (s, 1H), 3.93 (d, J = 10.6 Hz, 1H), 3.58 (dd, J = 8.7,

6.9, Hz, 1H), 3.02 (dd, J = 11.0, 8.7 Hz, 1H), 2.67 (s, 3H), 2.33

(dd, J = 15.1, 4.6 Hz, 1H), 2.02 (ddd, J = 15.7, 11.3, 2.8 Hz, 1H),

1.99 (dd, J = 13.8, 10.6 Hz, 1H), 2.16 (s, 6H), 1.65 (m, 1H) ¹³C

NMR (75 MHz): d = 208.6, 174.5, 140.8, 138.0, 125.2, 71.1, 47.6,

46.4, 40.3, 38.3, 32.5, 27.3; IR (neat, cm^-1): = 2924, 1774, 1716 and

1473; HRMS (ESI): calcd for C₁₃H₁₇N₃O₅SNa (M+Na)⁺350.0781,

found 350.0806.

53%) as a sticky colorless solid: H NMR: d = 7.78 (s, 1H), 7.67

(d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 7.06 (s, 1H), 6.31 (d,

J = 15.8 Hz, 1H), 6.19 (dt, J = 15.8, 5.9 Hz, 1H), 5.57 (m, 1H),

5.12 (d, J = 6.2 Hz, 1H), 5.09 (s, 1H), 3.89 (d, J = 5.9 Hz, 2H),

3.79 (d, J = 6.2 Hz, 2H), 2.81 (s, 6H), 2.37 (s, 3H); ¹³C NMR: d =

143.4, 140.8, 137.4, 136.9, 132.7, 129.8, 127.3, 125.8, 123.9, 119.3,

114.4, 49.8, 48.4, 38.3, 21.6; IR (CHCl₃, cm^-1): 3313, 2984, 1731,

1393, 1339, 1225, 1176, 1159, 1080, 967, 729, 600; EIMS (m/z):

425 (M⁺), 269, 243, 214 (100%), 177, 157, 139, 125, 108, 65; Anal.

Calcd for C₁₈H₂₄N₄O₄S₂: C, 50.92; H, 5.70; N, 13.20. Found: C,

50.90; H, 6.06; N, 12.87.

N -[(2E)-3-(1-Dimethylsulfamoyl-1H -imidazol-4-yl)prop-2-

enyl]-N-prop-2-ynyl-N-tosylamine (37). N-Propargyl toluene-

sulfonamide 35⁴⁶(419 mg, 2.00 mmol) and PPh₃(781 mg, 3.00

mmol) was dissolved in THF (14 mL). The allylic alcohol 13c

(231 mg, 1.00 mmol) was added followed by DIAD (0.5 ml, 2.5

mmol). The mixture was stirred at room temperature for 2 h.

The solvent was removed by rotary evaporation and the residue

was subjected to column chromatography (EtOAc–hexane, 3 : 2)

to give compound 37 (329 mg, 78%) as a sticky colorless solid: mp:

110–112 ^◦C; ¹H NMR: d = 7.81 (s, 1H), 7.33 (d, J = 8.1 Hz, 2H),

7.29 (d, J = 8.1 Hz, 2H), 7.11 (s, 1H), 6.47 (d, J = 15.8 Hz, 1H),

6.31 (dt, J = 15.8, 6.6 Hz, 1H), 4.11 (d, J = 2.4 Hz, 2H), 3.96 (d, J =

(2E)-3-(1-Dimethylsulfamoyl-1H-imidazol-4-yl)prop-2-enyl 3-

phenylpropynoate (32c). The allylic alcohol 13c (2.55 g, 11.0

mmol), phenyl propiolic acid (2.43 g, 16.6 mmol) and DMAP

(0.055 g, 0.45 mmol) were dissolved in CH₂Cl₂(35 mL), and

◦

the mixture was cooled to -78 C under N₂. DCC (2.77 g, 13.4

mmol) dissolved in CH₂Cl₂(10 mL) was added dropwise. The

solution was allowed to warm to rt and stir overnight. The solids

were ﬁltered through Celite and washed with CH₂Cl₂. The ﬁltrate

was concentrated under reduced pressure and puriﬁed by column

chromatography (EtOAc–hexane,_◦2 : 3) to afford 32c (3.43 g, 83%)

6.6 Hz, 2H), 2.85 (s, 6H), 2.41 (s, 3H), 2.02 (t, J = 2.4 Hz, 1H); ¹³

C

1

as an off-white solid. mp: 83–85 C; H NMR: d = 7.84 (s, 1H),

NMR: d = 143.7, 140.7, 137.0, 136.0, 129.6, 127.9, 124.85, 124.80,

114.7, 76.6, 74.0, 48.0, 38.3, 36.0, 21.6; IR (CHCl₃, cm^-1): 3245,

3040, 2990, 1753, 1697, 1534, 1392, 1260, 1161, 1075, 966, 899,

729, 659, 598; EIMS (m/z): 423 (M⁺), 316, 214, 177, 153 (100%),

7.58 (d, J = 8.3 Hz, 2H), 7.45 (t, J = 7.4 Hz, 1H), 7.37 (t, J =

6.9 Hz, 2H), 7.16 (s, 1H), 6.57 (s, 2H), 4.88 (d, J = 3.2 Hz, 2H),

2.85 (s, 6H); ¹³C NMR (75 MHz): d = 153.8, 140.5, 137.1, 133.1,

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125, 108, 65; Anal. Calcd for C₁₈H₂₂N₄O₄S₂: C, 51.17; H, 5.25; N,

13.26. Found: C, 51.39; H, 5.57; N, 12.94.

C₁₈H₂₀N₄O₄S₂: C, 51.41; H, 4.79; N, 13.32. Found: C, 51.70; H,

5.16; N, 13.12.

1-Dimethylsulfamoyl-6-tosyl-1,4,4a,5,6,7,7a,8-octahydroimi-

dazo[4,5-f ]isoindole (39) and 1-dimethylsulfamoyl-6-tosyl-1,4a,

4-[(1E)-3-Chloroprop-1-enyl]-1-dimethylsulfamoyl-1H-imida-

zole. Allylic alcohol 13c (231 mg, 1.00 mmol) was dissolved in

CH₂Cl₂(6 mL). The mixture was cooled to 0 ^◦C and thionyl

chloride (0.08 mL, 1.1 mmol) was added. The mixture was allowed

to warm up to room temperature and stirred for 2 h. The organic

solvent was removed by distillation under reduced pressure and the

residue was dissolved in EtOAc (10 mL). The solution was washed

with saturated NaHCO₃aqueous solution and the organic solvent

was dried over MgSO₄and concentrated under reduced pressure

to afford the chloride (250 mg, 100%) as a colorless solid. mp:

76.0–76.5 ^◦C. ¹H NMR: d = 7.80 (s, 1H), 7.13 (s, 1H), 6.53 (dt, J =

15.4, 6.6 Hz, 1H), 6.47 (d, J = 15.4 Hz, 1H), 4.18 (d, J = 6.2 Hz,

2H), 2.81 (s, 6H); ¹³C NMR: d = 140.3, 137.1, 126.6, 124.2, 115.1,

45.0, 38.2; IR (KBr, cm^-1): 3137, 2936, 1486, 1382, 1265, 1167,

1088, 1012, 951, 803, 738, 603, 515; EIMS (m/z): 250 (55%, M⁺),

228, 214, 97, 73, 65, 55 (100%). Anal. Calcd for C₈H₁₂ClN₃O₂S:

C, 38.48; H, 4.84; N, 16.83. Found: C, 38.63; H, 5.07; N, 16.47.

5,6,7,7a,8,8a-octahydroimidazo[4,5-f ]isoindole

(38). Com-

pounds 38 and 39 were obtained from the Diels–Alder reaction

of compound 36 (566 mg, 1.33 mmol) in benzene at 160 ^◦C. Flash

chromatography (EtOAc) afforded 39 (308 mg, 54%), as a

colorless solid as a 1 : 1 mixture of two diastereomers (trans and

cis), and 38 (45 mg, 8%):

◦

1

Data for compound 39: mp: 125–126 C; H NMR: d = 7.68–

7.76 (m, 3H), 7.28–7.34 (m, 2H), 3.72 (dd, J = 9.5, 6.6 Hz, 1H), 3.46

(ddd, J = 9.5, 6.6, 3.7 Hz, 1H), 2.55–3.20 (m, 10H), 2.24–2.50 (m,

7H), 1.92 (m, 1H),; ¹³C NMR: d = 143.72, 143.66, 137.4, 137.23,

137.17, 135.7, 134.4, 134.3, 129.9, 127,4, 127.3, 124.7, 122.6, 52.48,

54.41, 52.37, 51.8, 41.2, 41.1, 38.15, 38.12, 35.8, 35.7, 29.8, 27.4,

25.2, 23.6, 21.8, 21.6; IR (KBr, cm^-1): 3025, 2946, 1716, 1598, 1472,

1390, 1340, 1164, 967, 759, 665, 591, 549; EIMS (m/z): 425 (M⁺),

307, 279, 201, 180, 153 (100%), 125, 108, 89, 74, 65; Anal. Calcd

for C₁₈H₂₄N₄O₄S₂: C, 50.92; H, 5.70; N, 13.20. Found: C, 50.86;

H, 5.94; N, 13.02.

4-[(1E)-3-Phthalimidoylprop-1-enyl]-1-dimethylsulfamoyl-1H-

imidazole (42). The chloride (350 mg, 1.40 mmol) was dissolved

in dry DMF (3 mL) at room temperature, potassium phthalimide

(623 mg, 3.36 mmol) in dry DMF (7 mL) was added dropwise. The

mixture was stirred at room temperature overnight then the DMF

was removed by vacuum distillation. The residue was subjected to

chromatography (Et_◦OAc) to give 42 (505 mg, 100%) as a colorless

Data for compound 38: this compound is quite sensitive to

1

column chromatography (EtOAc),ꢀ only H NMR and IR data

are available for this compound: ¹H NMR: d = 8.27 (s, 1H), 7.70

(d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 6.59 (d, J = 5.1 Hz,

1H), 4.75 (d, J = 9.2 Hz, 1H), 3.87 (m, 1H), 3.48 (dd, J = 9.5,

9.2 Hz, 1H), 3.30 (dd, J = 10.3, 6.2, Hz, 1H), 3.21 (d, J = 10.3 Hz,

1H), 3.05 (dd, J = 9.2, 9.5 Hz, 1H), 2.82 (s, 6H), 2.44 (s, 3H), 2.34

(m, 1H), 1.96 (ddd, J = 12.8, 5.1, 4.8 Hz, 1H), 1.50 (dd, J = 23.1,

12.8 Hz, 1H); IR (CHCl₃, cm^-1): 3280, 3022, 2924, 2887, 1691,

1516, 1457, 1337, 1155, 1092, 959, 757, 710, 669, 592, 549.

1

solid. mp: 180–181 C. H NMR: d = 7.84 (dd, J = 5.1, 2.9 Hz,

2H), 7.79 (s, 1H), 7.71 (dd, J = 5.1, 2.9 Hz, 2H), 7.09 (s, 1H), 6.51–

6.44 (m, 2H), 4.43 (d, J = 4.2 Hz, 2H), 2.82 (s, 6H); ¹³C NMR: d =

168.0, 140.7, 136.9, 134.1, 132.2, 124.8, 123.5, 123.4, 114.6, 39.3,

38.3; IR (KBr, cm^-1): 3132, 1773, 1708, 1482, 1388, 1262, 1171,

1075, 955, 723, 603; EI-MS (m/z): 361 (20%, M⁺), 181, 165, 148,

125, 111, 101 (100%). Anal. Calcd for C₁₆H₁₆N₄O₄S: C, 53.32; H,

4.47; N, 15.55. Found: C, 53.09; H, 4.71; N, 15.22.

1-Dimethylsulfamoyl-6-tosyl-1,4,4a,5,6,7-hexahydroimidazo-

[4,5-f ]isoindole (40) and 1-dimethylsulfamoyl-6-tosyl-1,5,6,7-

tetrahydroimidazo[4,5-f ]isoindole (41). These compounds were

prepared from the Diels–Alder reaction of compound 37 (329 mg,

0.78 mmol) in benzene at 160 ^◦C. Flash chromatography (EtOAc)

afforded 40 (124 mg, 38%) and 41 (27 mg, 8%) as colorless solids:

Data for compound 40: mp: 172–173 ^◦C; ¹H NMR: d = 7.72 (d,

J = 8.1 Hz, 2H), 7.66 (s, 1H), 7.35 (d, J = 8.1 Hz, 2H), 6.43 (s, 1H),

4.23 (d, J = 15.8 Hz, 1H), 3.95 (dd, J = 8.6, 8.6 Hz, 1H), 3.78 (d,

J = 15.8 Hz, 1H), 3.25 (m, 1H), 2.90 (dd, J = 15.8, 9.2 Hz, 1H),

2.81 (s, 6H), 2.77 (m, 1H), 2.44 (m, 1H), 2.43 (s, 3H), ¹³C NMR:

d = 144.1, 138.9, 137.8, 136.1, 132.5, 129.9, 127.9, 126.3, 108.3,

53.8, 50.5, 40.6, 38.3, 26.3, 21.7; IR (KBr, cm^-1): 3125, 3025, 2945,

2852, 1598, 1558, 1454, 1391, 1346, 1165, 1094, 1049, 965, 816,

755, 726, 665, 594, 550, 497; EIMS (m/z): 423 (M⁺), 316, 279, 180,

157 (100%),139, 125, 108, 93, 65; Anal. Calcd for C₁₈H₂₂N₄O₄S₂:

C, 51.17; H, 5.25; N, 13.26. Found: C, 51._◦31; H, 5.46; N, 12.91.

(2E)-3-(1-Dimethylsulfamoyl-1H-imidazol-4-yl)prop-2-en-1-

amine (43). Compound 42 (505 mg, 1.4 mmol) was dissolved

in absolute ethanol (14 mL) at room temperature and hydrazine

monohydrate (0.4 mL, 7 mmol) was added and the mixture was

heated at reﬂux for 3 h, then cooled to room temperature. The

precipitated solid was removed by ﬁltration and the resulting solid

was washed with ethanol. The ethanolic solutions were combined

and concentrated. CH₂Cl₂(15 mL) was added to the residue and

the precipitate formed was removed by ﬁltration and this process

was repeated one more time. The solvent was removed to provide

crude amine47 as a brown oil (290 mg, 90%) whichwas notpuriﬁed

1

further and was used directly in for the next step: H NMR: d =

7.82 (s, 1H), 7.07 (s, 1H), 6.56 (dt, J = 15.7, 5.7 Hz, 1H), 6.36 (d,

J = 15.7 Hz, 1H), 3.46 (d, J = 5.7 Hz, 2H), 2.84 (s, 6H), 1.44 (brs,

2H); ¹³C NMR: d = 141.5, 136.9, 133.2, 119.5, 113.7, 43.9, 38.3;

IR (neat, cm^-1): 3300, 2922, 1477, 1389, 1174, 1080, 964, 728, 600;

EI-MS (m/z): 230 (26%, M⁺), 213, 121 (100%), 94.

1

Data for compound 41: mp: 184–185 C; H NMR: d = 8.18

(s, 1H), 7.78 (d, 2H, J = 8.1 Hz), 7.62 (s, 1H), 7.57 (s, 1H), 7.31

(d, 2H, J = 8.1 Hz), 4.70 (br s, 4H), 2.89 (s, 6H), 2.39 (s, 3H); ¹³

C

NMR: d = 144.0, 143.8, 142.4, 134.0, 133.5, 133.1, 131.7, 130.0,

127.8, 115.0, 107.1, 53.5, 53.3, 38.4, 21.6; IR (KBr, cm^-1): 2925,

1700, 1597, 1497, 1453, 1392, 1344, 1165, 1096, 967, 759, 667,

591, 549; EIMS (m/z): 152, 108, 91, 64 (100%); Anal. Calcd for

(2E)-3-(1-Dimethylsulfamoyl-1H-imidazol-4-yl)propenal (50a).

General Procedure for MnO₂Oxidation: The alcohol 13c (200 mg,

0.86 mmol) was dissolved in dry CH₂Cl₂(6 mL), then MnO₂

(216 mg, 85% activated from Aldrich, 2.59 mmol) was added and

the resulting mixture was stirred at room temperature overnight,

or under reﬂux for 6 h, until TLC analysis indicated complete

ꢀ These initial adducts tend to aromatize on puriﬁcation by silica-gel

chromatography.

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consumption of starting material. The reaction mixture was

ﬁltered and washed thoroughly with CH₂Cl₂. The combined

ﬁltrates were washed with brine and concentrated to provide the

aldehyde (181 mg, 92%) as a beige_◦solid, which was used without

the aqueous layer was extracted with CH₂Cl₂(3¥). The combined

organics were dried (Na₂SO₄), concentrated and dried to afford

44b (158 mg, 95%) as a colorless solid.

Method B: Aldehyde 50a (60 mg, 0.26 mmol) and diphenyl-

methylamine (53 mg, 0.05 mL, 0.29 mmol) were dissolved in

anhydrous MeOH (1.3 mL) at room temperature and stirred for

3 h, then NaBH₄(20 mg, 0.52 mmol) was added in one portion

and stirred for an additional 5 h. Following the same work-up

procedures as in Method A, the pure product 44b (99 mg, 96%)

was obta_◦ined after trituration with ether as a colorless solid. mp:

124–125 C. ¹H NMR: d = 7.84 (s, 1H), 7.43–7.41 (m, 4H), 7.32–

7.28 (m, 4H), 7.22–7.19 (m, 2H), 7.09 (s, 1H), 6.58 (dt, J = 15.6,

6.0 Hz, 1H), 6.41 (dt, J = 15.6, 1.4 Hz, 1H), 4.92 (s, 1H), 3.37

(dd, J = 6.0, 1.4 Hz, 2H), 2.84 (s, 6H), 1.73 (brs, 1H); ¹³C NMR:

d = 144.0, 141.6, 136.9, 130.6, 128.6, 127.4, 127.1, 121.2, 113.7,

66.5, 49.3, 38.3; IR (KBr, cm^-1): 1454, 1418, 1390, 1175, 1077, 966;

EI-MS (m/z): 396.8 (M⁺, 15%), 166.1 (100%), 228.2 (77%), 287.6

(32%). Anal. Calcd for C₂₁H₂₄N₄O₂S: C, 63.61; H, 6.10; N, 14.13.

Found: C, 63.42; H, 6.14; N, 13.84.

1

further puriﬁcation. mp: 143–145 C. H NMR: d = 9.67 (d, J =

7.8 Hz, 1H), 7.93 (s, 1H), 7.50 (s, 1H), 7.33 (d, J = 15.6 Hz, 1H), 6.88

(dd, J = 15.6, 7.8 Hz, 1H), 2.91 (s, 6H); ¹³C NMR: d = 193.3, 141.7,

139.1, 137.9, 129.7, 119.6, 38.3; IR (neat, cm^-1): 3121, 2961, 1673,

1386, 1174, 1085, 1007, 972, 859, 776, 739, 609; ESI-MS (m/z),

positive mode: 413 (100%), 252 (M+Na⁺, 10%), 230 (M+H⁺, 3%);

negative mode: 264 (M+Cl^-, 54%), 257 (100%), 228 ([M - H]^-,

53%). Anal. Calcd for C₈H₁₁N₃O₃S: C, 41.91; H, 4.84; N, 18.33.

Found: C, 41.82; H, 4.47; N, 18.35.

N-Benzyl-N-[(2E)-3-(1-dimethylsulfamoyl-1H-imidazol-4-yl)-

2-propenyl]amine (44a). Method A: Benzaldehyde (484 mg, 4.56

mmol) was added to a solution of allylamine 43 (1.00 g, 4.34 mmol)

in anhydrous ethanol (40 mL) and stirred at room temperature for

◦

2 h. The reaction was then cooled to 0 C and NaBH₄(330 mg,

8.72 mmol) was added. After stirring for several hours at room

temperature, the reaction was quenched carefully with H₂O and

extracted with CH₂Cl₂(3¥). The combined organics were dried

(Na₂SO₄) and concentrated to afford 44a (1.28 g, 92%) as a beige

oil, which was used in the next step without further puriﬁcation.

Method B: aldehyde 50a (56 mg, 0.24 mmol), molecular sieves

(E,E)-4-[[3-(1-Dimethylsulfamoyl-1H-imidazol-4-yl)-2-pro-

penyl]benzylamino]-4-oxo-2-butenoic acid, ethyl ester (45). Com-

pound 45 was prepared by procedure GP-B from 44a (320 mg, 1.00

mmol) and fumaric acid chloride ethyl ester⁴⁷(171 mg, 1.05 mmol).

Chromatography (EtOAc–hexane, 3 : 1) afforded 45 (410 mg, 92%)

as an oil and the Diels–Alder adduct 59 (22 mg, 5%) as a colorless

˚

(4 A, 132 mg) and benzylamine (31 mg, 0.032 mL, 0.29 mmol) were

dissolved in anhydrous MeOH (1.5 mL) at room temperature and

stirred for 3 h, then NaBH₄(14 mg, 0.37 mmol) was added in one

portion and stirred for an additional 5 h. The reaction mixture

was diluted with CH₂Cl₂, ﬁltered through Celite, and rinsed with

a small amount of CH₂Cl₂. Sat. NH₄Cl was added and the organic

layer was separated, washed with H₂O (2¥), brine, dried (Na₂SO₄)

and concentrated to provide the pure amine 44a (74 mg, 95%) as

a be_◦ige solid, which was used directly in the next step. mp: 141–

1

waxy solid. H NMR of a 60 : 40 mixture of two rotamers: d =

7.83, 7.82 (s, total 1H), 7.40–7.24 (m, 5H), 7.23–7.21, 7.18–7.16

(m, total 1H), 7.103, 7.096 (s, total 1H), 6.90, 6.87 (d, J = 12.4,

12.4 Hz, total 1H), 6.44–6.37 (m, 1H), 6.37–6.29 (m, 1H), 4.69,

4.63 (s, total 2H), 4.25–4.16 (m, 2H), 4.06 (d, J = 3.9 Hz, 2H), 2.87,

2.84 (s, total 6H), 1.29 (t, J = 7.3 Hz, 3H); ¹³C NMR of a 60 : 40

mixture of two rotamers: d = 165.75, 165.66, 165.24, 165.11, 140.9,

140.4, 137.1, 136.9, 136.80, 136.3, 136.1, 133.7, 132.3, 129.1, 128.9,

128.8, 128.4, 127.9, 127.8, 126.7, 125.5, 123.6, 122.4, 114.8, 114.4,

61.3, 48.8, 48.4, 47.2, 47.0, 38.32, 38.27, 14.2; IR (neat, cm^-1):

3056, 3028, 2980, 2941, 1721, 1698, 1654, 1627, 1556, 1420, 1391,

1287, 1175, 1079, 969, 763, 599; EI-MS (m/z): 446 (100%, M⁺),

293, 52. Anal. Calcd for C₂₁H₂₆N₄O₅S·1/2H₂O: C, 55.37; H, 5.97;

N, 12.30. Found: C, 55.73; H, 5.65; N, 12.31.

1

143 C H NMR: d = 7.82 (s, 1H), 7.34–7.30 (m, 4H), 7.25–7.23

(m, 1H), 7.08 (s, 1H), 6.54 (dt, J = 15.6, 6.0 Hz, 1H), 6.42 (dt, J =

15.6, 0.9 Hz, 1H), 3.83 (s, 2H), 3.43 (dd, J = 6.0, 0.9 Hz, 2H), 2.84

(s, 6H), 1.94 (brs, 1H); ¹³C NMR: d = 141.5, 140.2, 136.9, 130.3,

128.5, 128.3, 127.1, 121.6, 113.8, 53.2, 50.7, 38.3; IR (neat, cm^-1):

3153, 3056, 2944, 2847, 1653, 1639, 1457, 1390, 1262, 1175, 1078,

998, 966, 727, 599; EI-MS (m/z): 320 (16%, M⁺), 211 (100%), 90.

N-Benzhydryl-N-((2E)-3-(1-dimethylsulfamoyl-1H-imidazol-4-

yl)-2-propenyl) amine (44b). Method A: A mixture of allyl amine

43 (100 mg, 0.43 mmol) and benzophenone imine (73 mL, 0.43

mmol) in CH₂Cl₂(2 mL) was stirred at room temperature

overnight. The solvent was then completely removed under

vacuum to provide the pure imine intermediate (170 mg, 100%)

which was directly used in the next step without puriﬁcation. Data

for the imine intermediate: mp: 136–137 C. H NMR: d = 7.83

(s, 1H), 7.67–7.64 (m, 2H), 7.48–7.32 (m, 6H), 7.20–7.17 (m, 2H),

7.09 (s, 1H), 6.65 (dt, J = 15.6, 5.5 Hz, 1H), 6.44 (dt, J = 15.6,

1.8 Hz, 1H), 4.19 (dd, J = 5.5, 1.8 Hz, 2H), 2.84 (s, 6H); ¹³C NMR:

d = 169.4, 141.9, 139.8, 136.8, 136.6, 130.4, 130.2, 128.63, 128.60,

128.2, 127.7, 120.4, 113.6, 55.2, 38.3; IR (KBr, cm^-1): 1659, 1392,

1175, 1078, 966; EI-MS (m/z): 179.1 (20%), 285.5 (100%), 394.5

(M⁺, 21%). The crude imine from the previous step was suspended

in anhydrous MeOH (4 mL) at 0 ^◦C, and then NaBH₄(40 mg, 1.05

mmol) was added in one portion. Then the reaction mixture was

stirred at room temperature for 3 h. H₂O (10 mL) was added, and

(E,E)-N-Benzyl-N-[3-(1-dimethylsulfamoyl-1H-imidazol-4-yl)-

2-propenyl]-3-phenyl-2-propenamide (46). Compound 46 was

prepared by procedure GP-B from 44a (250 mg, 0.78 mmol)

and cinnamoyl chloride (136 mg, 0.82 mmol). Chromatography

(EtOAc–hexane, 3 : 1) afforded 46 (287 mg, 82%) as a colorless

solid. mp: 129–130 ^◦C. ¹H NMR of a 57 : 43 mixture of two

rotamers: d = 7.85, 7.83 (s, total 1H), 7.79, 7.71 (d, J = 16.0,

16.0 Hz, total 1H), 7.51–7.50, 7.44–7.43 (m, total 2H), 7.38–7.23

(m, 8H), 7.11, 7.09 (s, total 1H), 6.88, 6.84 (d, J = 5.3, 5.0 Hz, total

1H), 6.52–6.43 (m, 1H), 6.36 (dd, J = 16.0, 3.4 Hz, 1H), 4.75, 4.71

(s, total 2H), 4.25, 4.15 (d, J = 5.7, 3.7 Hz, total 1H), 2.85, 2.84

(s, total 6H); ¹³C NMR of a 57 : 43 mixture of two rotamers: d =

167.14, 167.08, 143.82, 143.78, 141.1, 140.6, 137.5, 137.2, 137.1,

137.02, 136.96, 136.90, 135.3, 135.2, 129.8, 129.1, 128.9, 128.7,

128.4, 128.0, 127.9, 127.6, 126.6, 126.4, 126.1, 123.0, 121.8, 117.3,

114.7, 114.6, 114.2, 114.1, 50.6, 49.1, 48.3, 47.6, 38.31, 38.27; IR

(KBr, cm^-1): 3121, 2926, 1650, 1609, 1458, 1419, 1392, 1175, 1078,

967, 729, 598; EI-MS (m/z): 450 (17%, M⁺), 342 (100%), 90. Anal.

◦

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Calcd for C₂₄H₂₆N₄O₃S: C, 63.98; H, 5.82; N, 12.44. Found: C,

63.93; H, 5.73; N, 12.28.

total 1H), 6.84, 6.51 (s, total 1H), 6.10–5.83 (m, total 2H), 4.29,

4.19 (s, total 2H), 2.80 (s, 6H); ¹³C NMR of a 65 : 35 mixture of

two rotamers: d = 167.7, 167.3, 143.9, 143.1, 141.4, 140.7, 139.3,

136.8, 136.7, 135.3, 129.8, 129.2, 129.0, 128.9, 128.6, 128.1, 127.9,

127.6, 127.2, 122.4, 121.7, 118.5, 118.2, 114.1, 113.7, 65.5, 61.6,

47.1, 38.2; IR (KBr, cm^-1): 3028, 1648, 1605, 1455, 1392, 1175,

1077, 966; EI-MS (m/z): 526.3 (M⁺, 25%), 418.4 (100%); HRMS

(ESI) calcd for C₁₇H₁₉N₂O₃S (M+H)⁺527.2111, found 527.2127.

(E)-N-Benzyl-N-[3-(1-dimethylsulfamoyl-1H-imidazol-4-yl)-2-

propenyl]propenamide (47). To the allyl amine 44b (300 mg, 0.936

m_◦mol) and triethylamine (127 mg, 1.40 mmol) in dry CH₂Cl₂at

0 C was added acryloyl chloride (170 mg, 1.70 mmol) dropwise

and stirred at room temperature for 3 h, after which water was

added and the organic layer was separated. The aqueous layer was

extracted with CH₂Cl₂and the combined organic layers were dried

over anhydrous Na₂SO₄, ﬁltered and concentrated under reduced

pressure. The solution was concentrated and the residue was

puriﬁed by ﬂash chromatography (hexane–EtOAc, 4 : 1), yielding

47 as a white solid (40% yield, 140 mg). mp: 86–88 ^◦C. ¹H NMR

(300 MHz) of 56 : 44 mixture of two rotamers: d = 7.83, 7.82 (s,

total 1H), 7.38–7.17 (m, 5H), 7.09 (s, 1H), 6.63–6.52 (m, 1H),

6.48–6.38 (m, 2H), 6.36–6.27 (m, 1H), 5.71 (td, J = 9.9, 2.1 Hz,

1H), 4.69, 4.61 (s, 2H), 4.19, 4.04 (d, J = 5.4 Hz, 3.9 Hz, total 2H),

2.86, 2.84 (s, total 6H); ¹³C NMR (75 MHz): d = 141.0, 140.5,

137.3, 137.0, 136.8, 136.7, 129.0, 128.7, 128.3, 127.8, 127.6, 127.5,

126.5, 126.1, 125.9, 123.1, 121.9, 114.5, 114.1, 50.3, 48.8, 48.2,

47.3, 38.2; IR (neat, cm^-1) = 2927, 1647, 1612, 1450, 1421; HRMS

(ESI): calcd for C₁₈H₂₃N₄O₃S (M+H)⁺375.1485, found 375.1485.

(E,E)-N -Benzhydryl-3-(1-dimethylsulfamoyl-1H-imidazol-4-

yl)-N -[3-(1-dimethyl-sulfamoyl-1H -imidazol-4-yl)-2-propenyl]-

2-propenamide (55). 55 was prepared from amine 44b (2.50 g,

6.31 mmol) and acid (2.32 g, 9.46 mmol) according to GP-D. The

crude sample was puriﬁed through a short plug of SiO₂(EtOAc–

MeOH, 4 : 0.15) to provide the_◦title compound (3.87 g, 98%) as

1

a colorless solid. mp: 151–152 C. H NMR of a 65 : 35 mixture

of two rotamers: d = 7.83, 7.81 (s, total 1H), 7.70 (s, 1H), 7.61,

7.56 (d, J = 14.9, 14.7 Hz, total 1H), 7.38–7.20 (m, total 11H),

7.18, 6.88 (s, total 1H), 6.83, 6.61 (s, total 1H), 5.96–5.91 (m, 1H),

5.84–5.79 (m, 1H), 4.26, 4.15 (d, J = 4.2, 4.6 Hz, total 2H), 2.83 (s,

6H), 2.78 (s, 6H); ¹³C NMR of a 65 : 35 mixture of two rotamers:

d = 167.3, 167.1, 141.4, 140.8, 140.2, 140.0, 139.4, 139.2, 137.4,

136.7, 133.3,133.0, 129.1, 128.7, 128.5, 128.0, 127.6, 127.1, 127.0,

122.0, 121.8, 122.0, 121.8, 119.4, 119.0, 118.3, 114.1, 113.6, 65.1,

61.7, 47.1, 46.8, 38.3, 38.2; IR (KBr, cm^-1): 3137, 2928, 1654, 1610,

1392, 1264, 1175, 1077, 966, 728, 597; EI-MS (m/z): 624.2 (M⁺+1,

28%), 593.5 (15%), 514.6 (34%), 430.0 (100%), 228.2 (83%). Anal.

Calcd for C₂₉H₃₃N₇O₅S₂·H₂O: C, 54.27; H, 5.50; N, 15.28. Found:

C, 54.01; H, 5.17; N, 14.73.

(E,E)-N-Benzyl-3-(1-dimethylsulfamoyl-1H-imidazol-4-yl)-N-

[3-(1-dimethyl-sulfamoyl-1H -imidazol-4-yl)-2-propenyl]-2-pro-

penamide (48). Following GP-D using benzylamine 51a (320 mg,

1.00 mmol) and the imidazolyl acid (368 mg, 1.50 mmol) afforded

the corresponding amide 48 (427 mg, 78%) as a colorless soli_◦d after

ﬂash chromatography (EtOAc–MeOH, 9 : 1). mp: 131–132 C. ¹H

NMR of a 59 : 41 mixture of two rotamers: d = 7.86, 7.83 (s, total

1H), 7.824, 7.819 (s, total 1H), 7.64, 7.61 (d, J = 5.7, 5.7 Hz, total

1H), 7.36–7.27 (m, 5H), 7.22–7.21, 7.17–7.14 (m, total 2H), 7.09,

7.07 (s, total 1H), 6.48–6.41 (m, 1H), 6.35–6.32 (m, 1H), 4.73, 4.71

(s, total 2H), 4.21, 4.15 (d, J = 5.7, 4.1 Hz, total 2H), 2.87, 2.863,

2.860, 2.84 (s, total 12H); ¹³C NMR of a 59 : 41 the mixture of

two rotamers: d = 166.9, 166.8, 141.1, 140.8, 140.1, 140.0, 137.50,

137.47, 137.0, 136.9, 136.7, 133.3, 133.2, 129.0, 128.7, 128.3, 127.8,

127.5, 126.8, 126.2, 123.0, 121.9, 118.5, 118.4, 118.33, 118.30,

114.5, 114.1, 60.5, 50.4, 48.9, 48.2, 47.2, 38.3; IR (KBr, cm^-1): 3126,

2926, 1655, 1611, 1460, 1420, 1391, 1263, 1175, 1078, 1007, 967,

729, 598; EI-MS (m/z): 439 (32%, M⁺), 90 (100%). Anal. Calcd

for C₂₃H₂₉N₇O₅S₂·1/2H₂O: C, 49.63; H, 5.43; N, 17.61. Found: C,

49.58; H, 5.39; N, 17.24.

(3aS*,4S*,4aR*,7aS*)-6-Benzyl-3-dimethylsulfamoyl-3a,4a,

5,6,7,7a-hexahydro-5-oxo-5H-imidazo[4,5-f ]isoindole-4-carboxy-

lic acid, ethyl ester (59). Compound 59 was prepared by the

general Diels–Ald_◦er reaction procedure from puriﬁed 45 (60 mg,

0.13 mmol) at 68 C in benzene for 12 h. Flash chromatography

(hexane–EtOAc, 15 : 85) afforded the product 59 (57 mg, 95%) as a

colorless solid. mp: 64–66 ^◦C. ¹H NMR: d = 7.52 (s, 1H), 7.34–7.27

(m, 3H), 7.23–7.21 (m, 2H), 6.03 (dd, J = 3.7, 3.7 Hz, 1H), 4.49

(d, J = 14.7 Hz, 1H), 4.45 (ddd, J = 9.0, 3.7, 1.6 Hz, 1H), 4.42 (d,

J = 14.7 Hz, 1H), 4.16 (dq, J = 7.1, 3.7 Hz, 1H), 4.12 (dq, J = 7.1,

3.7 Hz, 1H), 3.63 (dd, J = 9.0, 8.2 Hz, 1H), 3.45 (dd, J = 9.5, 6.6 Hz,

1H), 3.26 (dd, J = 9.9, 9.5 Hz, 1H), 2.91 (s, 6H), 2.35 (m, 1H), 2.30

(dd, J = 12.6, 8.2 Hz, 1H), 1.25 (t, J = 7.1 Hz, 3H); ¹³C NMR: d =

171.5, 153.9, 153.6, 136.3, 128.9, 128.2, 127.9, 111.6, 61.5, 58.6,

48.2, 47.9, 47.0, 40.4, 39.3, 38.1, 14.2; IR (KBr, cm^-1): 3053, 3013,

2987, 2939, 1731, 1696, 1556, 1377, 1258, 1157, 970, 719, 595;

EI-MS (m/z): 446 (51%, M⁺), 338, 293 (100%), 265. Anal. Calcd

for C₂₁H₂₆N₄O₅S·1/2H₂O: C, 55.37; H, 5.97; N, 12.30. Found: C,

55.81; H, 5.77; N, 12.34.

(E,E)-N-Benzhydryl-N-[3-(1-dimethylsulfamoyl-1H-imidazol-

4-yl)-2-propenyl]-3-phenyl-2-propenamide (54). To amine 44b

(312 mg, 0.79 mmol) in anhydrous THF (6 mL) at 0 ^◦C was added

NaH (60% oil dispersion, 42 mg, 1.06 mmol) and stirred at 0 ^◦C

for 30 min. Cinnamoyl chloride (181 mg, 1.06 mmol) in THF (1.5

mL) was added to the above anion solution at 0 ^◦C dropwise. Then

the reaction mixture was allowed to warm up to room temperature

and stirred overnight. After being quenched carefully with a small

amount of water, the reaction mixture was diluted with CH₂Cl₂,

washed with H₂O (2¥), brine, dried (Na₂SO₄) and concentrated.

The crude oil was puriﬁed by chromatography (hexane–EtOAc,

3 : 1) to afford the title product as a colorless solid (312 mg, 75%).

(4S*,4aR*,7aS*)-6-Benzyl-3-dimethylsulfamoyl-4a,5,6,7,7a,8-

hexahydro-5-oxo-5H-imidazo[4,5-f ]isoindole-4-carboxylic acid,

ethyl ester (60). Compound 60 was prepared by the general

Diels–Alder reaction procedure from the crude sample 45 (180 mg,

0.56 mmol) at 68 ^◦C in benzene for 10 h. Chromatography

(hexane–EtOAc: 20/80) afforded the initial adduct 59 (18 mg,

10%) and the aromatized product 60 (144 mg, 80%) as a colorless

◦

1

mp: 88–89 C. H NMR of the 65 : 35 mixture of two rotamers:

d = 7.82, 7.70 (d, J = 15.4, 15.6 Hz, total 1H), 7.73 (s, 1H), 7.52–

7.48, 7.38–7.24 (m, total 15H), 6.92, 6.80 (d, J = 15.4, 15.6 Hz,

solid. mp: 155–156 C. H NMR (benzene-d6): d = 7.70 (s, 1H),

7.06–6.98 (m, 5H), 4.43 (dq, J = 7.1, 3.6 Hz, 1H), 4.30 (d, J =

14.7 Hz, 1H), 4.24 (dq, J = 7.1, 3.6 Hz, 1H), 3.93 (d, J = 10.8 Hz,

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1H), 3.91 (d, J = 14.7 Hz, 1H), 2.57 (dd, J = 12.9, 10.8 Hz, 1H),

2.39 (m, 1H), 2.35 (dd, J = 9.4, 7.1 Hz, 1H), 2.10 (m, 1H), 2.09

(s, 6H), 2.04 (dd, J = 9.6, 9.4 Hz, 1H), 1.37 (m, 1H), 1.27 (t, J =

7.1 Hz, 3H); ¹³C NMR: d = 171.9, 141.9, 139.1, 136.2, 128.9,

128.3, 127.9, 123.5, 61.8, 49.5, 49.4, 46.7, 42.0, 38.2, 37.4, 28.5,

14.1; IR (KBr, cm^-1): 3132, 3056, 3028, 2982, 2933, 1731, 1698,

1474, 1421, 1392, 1329, 1275, 1251, 1186, 1028, 967, 762, 730,

579; EI-MS (m/z): 446 (16%, M⁺), 203, 107 (100%). Anal. Calcd

for C₂₁H₂₆N₄O₅S·1/2H₂O: C, 55.37; H, 5.97; N, 12.30. Found: C,

55.44; H, 5.77; N, 12.41.

29.9, 28.1, 26.2, 23.1, 19.6; IR (neat, cm^-1): = 2924, 1687, 1443,

1389; HRMS (ESI): calcd for C₁₈H₂₃N₄O₃S (M+H)⁺375.1485,

found 375.1485.

(4S*,4aR*,7aS*)-6-Benzyl-3-dimethylsulfamoyl-4-(1-dimethyl-

sulfamoyl-1H-imidazol-4-yl)-4a,5,6,7,7a,8-hexahydro-5-oxo-5H-

imidazo[4,5-f ]isoindole (64) and (4S*,4aR*,7aS*)-6-benzyl-3-

dimethylsulfamoyl-4-(1-dimethylsulfamoyl-1H-imidazol-4-yl)-4a,

5,6,7,7a,8-hexahydro-7-oxo-5H-imidazo[4,5-f ]isoindole

(65).

Compounds 64 and 65 were prepared by the general Diels–Alder

reaction procedure from 48 (62 mg, 0.11 mmol) at 95 ^◦C in

benzene for 72 h. Puriﬁcation by preparative TLC (CHCl₃–

MeOH, 95 : 5) afforded adduct 64 (31 mg, 50%) and adduct 65

(20 mg, 32%).

(3aS*,4S*,4aR*,7aS*)-6-Benzyl-3-dimethylsulfamoyl-3a,4a,5,

6,7,7a-hexahydro-5-oxo-4-phenyl-5H-imidazo[4,5-f ]isoindole (61)

and (4S*,4aR*,7aS*)-6-benzyl-3-dimethylsulfamoyl-4a,5,6,7,7a,8-

hexahydro-5-oxo-4-phenyl-5H-imidazo[4,5-f ]

isoindole

(62).

◦

1

Data for 64: A colorless solid mp: 174.5–175 C. H NMR

(benzene-d6): d = 7.80 (s, 1H), 7.74 (s, 1H), 7.58 (s, 1H), 7.12–6.98

(m, 5H), 4.48 (d, J = 10.5 Hz, 1H), 4.35 (d, J = 14.9 Hz, 1H),

3.89 (d, J = 14.9 Hz, 1H), 2.83 (dd, J = 12.8, 10.5 Hz, 1H), 2.55

(dd, J = 14.6, 3.8 Hz, 1H), 2.40–2.32 (m, 2H), 2.29 (s, 6H), 2.12

(dd, J = 9.7, 9.7 Hz, 1H), 1.95 (s, 6H), 1.48 (m, 1H); ¹³C NMR

(CDCl₃): d = 173.2, 142.5, 141.0, 138.3, 136.4, 135.9, 128.9, 128.1,

127.8, 127.4, 117.2, 50.3, 48.9, 46.6, 38.5, 38.4, 37.8, 34.5, 28.6;

IR (KBr, cm^-1): 2928, 1693, 1389, 1274, 1175, 1076, 964, 725, 600;

EI-MS (m/z): 547 (M⁺, 5%), 152, 107, 90 (100%). Anal. Calcd for

C₂₃H₂₉N₇O₅S₂·H₂O: C, 48.84; H, 5.52; N, 17.33. Found: C, 48.75;

H, 5.32; N, 17.12.

Data for 65: A colorless solid. mp: 177.5–178.5 C. H NMR:

d = 7.76 (d, J = 1.4 Hz, 1H), 7.73 (s, 1H), 7.33–7.27 (m, 3H),

7.22–7.20 (m, 2H), 6.93 (d, J = 1.4 Hz, 1H), 4.59 (d, J = 14.9 Hz,

1H), 4.33 (d, J = 14.9 Hz, 1H), 4.06 (d, J = 10.1 Hz, 1H), 3.19–3.17

(m, 2H), 3.15 (ddd, J = 16.0, 4.7, 1.4 Hz, 1H), 2.87–2.83 (m, 1H),

2.833 (s, 6H), 2.827 (s, 6H), 2.57 (ddd, J = 12.8, 11.5, 4.7 Hz, 1H),

2.49–2.43 (m, 1H); ¹³C NMR: d = 173.4, 143.4, 141.7, 137.5, 136.4,

136.3, 128.9, 128.3, 127.8, 127.2, 114.7, 49.4, 46.9, 46.2, 44.7, 38.2,

26.1; IR (KBr, cm^-1): 3113, 2927, 1692, 1390, 1268, 1175, 1075,

965, 729, 599, 584; EI-MS (m/z): 547 (40%, M⁺⁾, 440, 406, 357,

151 (100%).

Compounds 61 and 62 were prepared by the general Diels–Alder

reaction procedure from 46 (200 mg, 0.44 mmol) at 130 ^◦C

in benzene for 45 h. Chromatography (EtOAc–hexane, 85 : 15)

afforded the initial adduct 61 (54 mg, 27%) and the aromatized

adduct 62 (102 mg, 51%).

Data for 61: A colorless solid. mp: 163–164 ^◦C. ¹H NMR: d =

7.49 (s, 1H), 7.33–7.15 (m, 8H), 7.08–7.06 (m, 2H), 6.11 (dd, J =

3.9, 3.7 Hz, 1H), 4.73 (ddd, J = 9.5, 3.7, 2.3 Hz, 1H), 4.48 (d, J =

14.9 Hz, 1H), 4.37 (d, J = 14.9 Hz, 1H), 3.88 (dd, J = 9.5, 8.7 Hz,

1H), 3.47 (dd, J = 9.4, 6.9 Hz, 1H), 3.21 (dd, J = 10.3, 9.4 Hz,

1H), 2.46 (m, 1H), 2.39 (s, 6H), 2.13 (dd, J = 13.1, 8.7 Hz, 1H); ¹³

C

NMR: d = 172.8, 154.9, 154.7, 142.0, 136.5, 128.9, 128.7, 128.4,

128.2, 127.8, 127.1, 112.1, 60.4, 54.2, 48.2, 46.9, 40.3, 39.8, 37.0;

IR (KBr, cm^-1): 3061, 3039, 2928, 2861, 1689, 1551, 1360, 1157,

1076, 971, 702, 591; EI-MS (m/z): 450 (100%, M⁺), 342. Anal.

Calcd for C₂₄H₂₆N₄O₃S: C, 63.98; H, 5.82; N, 12.44. Found: C,

64.06; H, 5.88; N, 12.38.

◦

1

◦

1

Data for 62: A colorless solid. mp: 177.0–177.5 C. H NMR:

d = 7.85 (s, 1H), 7.38–7.21 (m, 7H), 7.20–7.16 (m, 3H), 4.53 (d,

J = 10.1 Hz, 1H), 4.48 (d, J = 14.7 Hz, 1H), 4.31 (d, J = 14.7 Hz,

1H), 3.27 (dd, J = 9.4, 7.3 Hz, 1H), 3.00 (dd, J = 10.1, 9.4 Hz,

1H), 2.85 (dd, J = 14.9, 4.1 Hz, 1H), 2.69 (ddd, J = 14.9, 11.9,

1.8 Hz, 1H), 2.49 (dd, J = 12.8, 10.1 Hz, 1H), 2.39–2.31 (m, 1H),

2.36 (s, 6H); ¹³C NMR: d = 173.2, 143.1, 141.3, 139.4, 136.5, 128.9,

128.8, 128.3, 127.7, 127.1, 54.6, 48.8, 46.6, 40.8, 39.3, 37.1, 28.8; IR

(KBr, cm^-1): 3057, 3027, 2919, 2851, 1693, 1420, 1387, 1144, 970,

757, 726, 699, 587; EI-MS (m/z): 450 (32%, M⁺), 342 (100%), 90.

Anal. Calcd for C₂₄H₂₆N₄O₃S: C, 63.98; H, 5.82; N, 12.44. Found:

C, 64.18; H, 5.93; N, 12.27.

(3aS*,4S*,4aR*,7aS*)-6-Benzhydryl-3-dimethylsulfamoyl-3a,

4a,5,6,7,7a-hexahydro-5-oxo-4-phenyl-5H-imidazo[4,5-f ]isoindole

(66) and (4S*,4aR*,7aS*)-6-benzhydryl-3-dimethylsulfamoyl-4a,

5,6,7,7a,8-hexahydro-5-oxo-4-phenyl-5H -imidazo[4,5-f ]iso-

indole (67). Compounds 66 and 67 were prepared by the general

Diels–Alder reaction procedure from 54 (66 mg, 0.12 mmol) at

◦

(4aR*/S*,7aS*)-6-Benzyl-3-dimethylsulfamoyl-4a,5,6,7,7a,8-

hexahydro-5-oxo-5H-imidazo[4,5-f ]isoindole (63). Compound

63 was prepared by the general Diels–Alder reaction procedure

from 47 (75.0 mg, 0.20 mmol) at 145 ^◦C in benzene for 60 h.

The solution was concentrated and the residue was puriﬁed by

ﬂash chromatography (EtOAc–methanol, 49 : 1), yielding 63 as

an inseparable mixture of cis and trans isomer_◦s (ratio = 3 : 2) as a

95 C for 44 h. Chromatography (hexane–EtOAc, 1 : 4) afforded

the initial adduct 66 (25 mg, 38%) and the aromatized adduct 67

(34 mg, 52%).

1

Data for the initial cycloadduct 66: A colorless semi-solid. H

NMR: d = 7.50 (s, 1H), 7.39–7.22 (m, 8H), 7.07–7.05 (m, 2H),

6.53 (s, 1H), 6.10 (dd, J = 3.9, 3.9 Hz, 1H), 4.77 (ddd, J = 9.3,

3.9, 2.3 Hz, 1H), 3.92 (dd, J = 9.3, 8.6 Hz, 1H), 3.56 (dd, J = 9.8,

6.6 Hz, 1H), 3.06 (dd, J = 10.1, 9.8 Hz, 1H), 2.54 (m, 1H), 2.40

(s, 6H), 2.14 (dd, J = 13.1, 8.6 Hz, 1H); ¹³C NMR: d = 172.8,

154.9, 154.8, 141.9, 138.9, 138.6, 129.1, 128.8, 128.7, 128.3, 127.9,

127.8, 127.7, 127.1, 111.9, 60.5, 58.6, 54.3, 46.2, 40.3, 39.9, 37.0; IR

(KBr, cm^-1): 1694, 1553, 1495, 1455, 1400, 1361, 1158,1076; EI-MS

(m/z): 526.4 (M⁺, 79%), 438.7 (78%), 413.9 (100%). Anal. Calcd

for C₃₀H₃₀N₄O₃S·1/2H₂O: C, 67.27; H, 5.83; N, 10.46. Found: C,

67.37; H, 5.54; N, 10.45.

1

white solid (16 mg, 21% yield). mp: 105–107 C; H NMR (300

MHz): d = 7.97, 7.94 (s, total 1H), 7.51–7.43 (m, 3H), 7.41–7.37

(m, 2H), 4.64, 4.63 (d, J = 8.7 and 9.6 Hz, total 2H), 3.61, 3.53

(dd, m, J = 9.6, 4.8 Hz, total 2H), 3.26 (t, J = 9.6 Hz, 1H), 3.09,

3.07 (2xs, total 6H), 2.97 (m, 2H), 2.84 (m, 1H), 2.71–2.57 (m,

1H), 2.48–2.37 (m, 1H); ¹³C NMR (75 MHz): d = 174.6, 174.0,

139.1, 137.7, 137.2, 136.6, 136.3, 129.0, 128.4, 128.3, 128.0, 127.9,

125.2, 123.4, 52.0, 50.3, 47.4, 46.9, 45.3, 41.2, 38.4, 38.3, 30.8,

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Data for aromatized cycloadduct 67: A colorless solid. mp: 171–

172. ¹H NMR: d = 7.86 (s, 1H), 7.35–7.27 (m, 10H), 7.19–7.17 (m,

1H), 7.14–7.12 (m, 4H), 6.51 (s, 1H), 4.59 (d, J = 10.1 Hz, 1H), 3.39

(dd, J = 9.6, 6.4 Hz, 1H), 2.89–2.83 (m, 2H), 2.68 (ddd, J = 15.1,

10.8, 2.5 Hz, 1H), 2.52 (dd, J = 13.1, 10.1 Hz, 1H), 2.49–2.45 (m,

1H), 2.36 (s, 6H); ¹³C NMR: d = 173.3, 143.1, 141.3, 139.4, 138.9,

138.7, 129.2, 128.9, 128.7, 128.3, 127.9, 127.7, 127.5, 127.1, 58.4,

54.7, 47.0, 40.8, 39.5, 37.1, 29.8, 28.7; IR (KBr, cm^-1): 2923, 2853,

1694, 1411, 1390, 1271, 1244, 1179, 1145, 970; EI-MS (m/z): 526.3

(M⁺, 100%), 166.2 (25%). Anal. Calcd for C₃₀H₃₀N₄O₃S·1/2H₂O:

C, 67.27; H, 5.83; N, 10.46. Found: C, 67.70; H, 5.65; N,

10.54.

Acknowledgements

We are grateful to the Robert A. Welch Foundation (Y-1362 (CJL)

and Y-1289 (HVRD)), National Institutes of Health (GM065503)

and the NSF (CHE-0234811, CHE-9601771) for supporting our

efforts in this area.

Notes and references

1 Y. He, H. Du, R. Sivappa and C. J. Lovely, Synlett, 2006, 965.

2 H. Hoffmann and T. Lindel, Synthesis, 2003, 1753; S. M. Weinreb, Nat.

Prod. Rep., 2007, 24, 931; B. Forte, B. Malgesini, C. Piutti, F. Quartieri,

A. Scolaro and G. Papeo, Mar. Drugs, 2009, 7, 705.

3 J. D. Sullivan, R. L. Giles and R. E. Looper, Curr. Bioact. Comp,

2009, 5, 39; P. B. Koswatta and C. J. Lovely, Nat. Prod. Rep., 2011,

DOI: 10.1039/c0np00001a.

4 P. B. Koswatta, R. Sivappa, H. V. R. Dias and C. J. Lovely, Org. Lett.,

2008, 10, 5055; P. B. Koswatta and C. J. Lovely, Tetrahedron Lett., 2009,

50, 4998; P. B. Koswatta, R. Sivappa, H. V. R. Dias and C. J. Lovely,

Synthesis, 2009, 2970; P. B. Koswatta and C. J. Lovely, Tetrahedron

Lett., 2010, 51, 164; P. B. Koswatta and C. J. Lovely, Chem. Commun.,

2010, 46, 2148.

5 R. B. Kinnel, H. P. Gehrken and P. J. Scheuer, J. Am. Chem. Soc., 1993,

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(4S*,4aR*,7aS*)-6-Benzhydryl-3-dimethylsulfamoyl-4-(1-dim-

ethylsulfamoyl-1H-imidazol-4-yl)-4a,5,6,7,7a,8-hexahydro-5-oxo-

5H-imidazo[4,5-f ]isoindole

(68)

and

(4S*,4aR*,7aS*)-6-

benzhydryl-3-dimethylsulfamoyl-4-(1-dimethylsulfamoyl-1H-imi-

dazol-4-yl)-4a,5,6,7,7a,8-hexahydro-7-oxo-5H-imidazo[4,5-f ]-

isoindole (69). Compounds 68 and 69 were prepared by the

general Diels–Alder reaction procedure from 55. On a small

scale: 55 (62 mg, 0.1 mmol) was heated in benzene (1.0 mL) at

95 ^◦C for 42 h. Chromatography (EtOAc–MeOH, 4 : 0.5) afforded

the normal Diels–Alder adduct 68 (35 mg, 56%) and the inverse

electron demand adduct 69 (24 mg, 39%). On a larger scale: 55

(1.25 g, 2.00 mmol) was heated in benzene (20.0 mL) at 95 ^◦C for

51 h. The solution was then cooled to room temperature and the

resulting white precipitate was collected and rinsed with a small

amount of benzene (2¥) to afford the pure 68 (579 mg, 46%).

The benzene rinsings were combined with the previous benzene

ﬁltrate and concentrated under vacuum to afford an oily product

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5771.

1

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(~700 mg), which H NMR indicated contained mainly 69 with

some impurities and a trace amount of 72. The crude oil was

then passed through a short plug of SiO₂(EtOAc–MeOH, 5 : 1)

to afford pure 69 (424 mg, 34%).

11 L. De Luca, Curr. Med. Chem., 2006, 13, 1.

Data for adduct 68: A colorless solid. mp: 149–150 ^◦C. ¹H NMR

(benzene-d6): d = 7.81 (s, 1H), 7.72 (s, 1H), 7.55 (s, 1H), 7.19–7.00

(m, 8H), 6.99–6.92 (m, 2H), 6.72 (s, 1H), 4.52 (d, J = 10.5 Hz,

1H), 2.94 (dd, J = 13.1, 10.5 Hz, 1H), 2.75 (dd, J = 9.6, 7.1 Hz,

1H), 2.52 (dd, J = 15.0, 4.2 Hz, 1H), 2.33 (dd, J = 10.1, 9.6 Hz,

1H), 2.29–2.26 (m, 1H), 2.28 (s, 6H), 1.96 (s, 6H), 1.67 (m, 1H);¹³C

NMR: d = 173.2, 142.4, 141.0, 138.9, 138.7, 138.2, 136.0, 129.1,

128.71, 128.68, 127.9, 127.8, 127.6, 127.4, 117.2, 58.4, 50.4, 47.1,

38.7, 38.3, 37.8, 34.5, 28.5; IR (KBr, cm^-1): 2929, 1686, 1474,

1416, 1388, 1272, 1175, 1075, 964; EI-MS (m/z): 623.6 (M⁺, 43%),

430.1 (74%), 82.8 (100%). Anal. Calcd for C₂₉H₃₃N₇O₅S₂·1/2H₂O:

C, 55.05; H, 5.42; N, 15.50. Found: C, 54.87; H, 5.03; N,

15.20.

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Data for adduct 69: A colorless solid. mp: 167–169 ^◦C. ¹H NMR

(benzene-d6): d = 7.62 (s, 1H), 7.60 (s, 1H), 7.14–7.07 (m, 7H),

7.03–6.96 (m, 3H), 6.95 (s, 1H), 6.80 (s, 1H), 3.88 (d, J = 10.1 Hz,

1H), 3.44 (dd, J = 9.6, 6.9 Hz, 1H), 3.40 (dd, J = 11.2, 4.8 Hz, 1H),

2.98 (dd, J = 9.9, 9.9 Hz, 1H), 2.94 (m, 1H), 2.58 (m, 1H), 2.21

(s, 6H), 2.09 (ddd, J = 12.3, 12.0, 5.0 Hz, 1H), 1.99 (s, 6H); ¹³C

NMR: d = 173.6, 143.2, 141.5, 138.4, 137.4, 136.4, 129.3, 128.8,

128.7, 128.0, 127.7, 127.5, 127.2, 114.9, 58.53, 58.48, 47.0, 45.9,

44.9, 38.3, 38.1, 26.0; IR (KBr, cm^-1): 2922, 1689, 1475, 1417,

1390, 1266, 1175, 1077, 965; EI-MS (m/z): 624.1 (M⁺+1, 74%),

516.8 (34%), 166.7 (100%), 150.7 (61%); HRMS (ESI) calcd for

C₂₈H₃₄N₇O₅S₂(M+H)⁺624.2057, found 624.2086.

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28 This study was conducted in parallel with the intermolecular study,

and we had experienced some initial success with trityl-protected

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Intramolecular Diels-Alder chemistry of 4-vinylimidazoles

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