Synthesis of hydrodipyrrins tailored for reactivity at the 1- and 9-positions

Tetrahedron 63 (2007) 37–55

Synthesis of hydrodipyrrins tailored for reactivity

at the 1- and 9-positions

*

Han-Je Kim, Dilek Kiper Dogutan, Marcin Ptaszek and Jonathan S. Lindsey

Department of Chemistry, North Carolina State University, Raleigh, NC 27695-8204, USA

Received 9 August 2006; revised 5 October 2006; accepted 9 October 2006

Available online 1 November 2006

Abstract—A collection of 33 hydrodipyrrins (9 targets, 21 intermediates, and 3 byproducts) has been prepared. The hydrodipyrrins

(dihydrodipyrrins, tetrahydrodipyrrins, and hexahydrodipyrrins) contain a pyrrole ring and a geminal-dimethyl substituted 1-pyrroline (or

pyrrolidine) ring. The a-substituents on the pyrrole ring (H, Br, CHO) and pyrroline ring (H, CH₃, CH(OR)₂, OMe, SMe) provide different

reactivity combinations (Nu^ꢀ, E⁺) and 0, 1, or 2 carbon atoms (which can give rise to the bridging meso-carbons in hydroporphyrins). Straight-

forward access to various hydrodipyrrins should facilitate development of syntheses of diverse hydroporphyrins.

1. Introduction

manipulate chlorins without incurring the enormous effort

required for the total synthesis.⁹

Hydroporphyrins perform a wide variety of essential func-

tions in living systems. Hydroporphyrins differ from porphy-

rins in having fewer p bonds along the perimeter of the

macrocycle. Representative hydroporphyrins are shown in

Chart 1. Chlorophylls a and b (chlorins) and bacteriochloro-

phylls a, b, and g (bacteriochlorins) serve as the principal

light-absorbing pigments in plant and bacterial photosyn-

thetic systems, respectively.¹Bonellin²and tolyporphins³

are examples of non-photosynthetic chlorin and bacterio-

chlorin macrocycles, respectively. Siroheme and heme d₁

(isobacteriochlorins) play an important role in the sulfur

and nitrogen metabolism of numerous microorganisms.⁴A

wide variety of other naturally occurring hydroporphyrins

(e.g., vitamin B₁₂⁵and F₄₃₀⁶) are known.

A middle approach, which we have pursued, is to develop de

novo syntheses of model hydroporphyrins that retain most of

the essential physicochemical properties of the natural

compounds yet have non-natural structural attributes that

facilitate synthesis and handling.^10–15A key structural

feature that we have employed is the use of a geminal-

dimethyl group in each reduced ring. The geminal-dimethyl

group locks in the reduction level of the resulting hydropor-

phyrin, thereby precluding adventitious oxidative reversion

to the porphyrin. Many naturally occurring hydroporphyrins

have a geminal dialkyl group in each reduced pyrroline ring

(e.g., bonellin, tolyporphin, siroheme, heme d₁, F₄₃₀, and

vitamin B₁₂). Although chlorophylls and bacteriochloro-

phylls lack the geminal dialkyl motif, synthetic analogues

that contain a geminal dialkyl group in the pyrroline ring

exhibit characteristic chlorin or bacteriochlorin features

and are quite stable compounds.^10–15

Fundamental chemical studies, biological investigations,

and materials chemistry applications require efﬁcient routes

for preparing the core hydroporphyrins. The simplest ap-

proach to chlorins, bacteriochlorins, and isobacteriochlorins

entails hydrogenation of the porphyrin.⁷The simplicity of

this approach is often offset by two problems: (1) reduction

in any of the four pyrrolic rings yields regioisomers if a dis-

tinct pattern of peripheral substituents is present, and (2) the

hydroporphyrin is susceptible to adventitious dehydrogena-

tion. By contrast, the most complex approach entails the

total synthesis of naturally occurring hydroporphyrins.⁸

Semisynthetic approaches also have been employed to

The de novo syntheses that we developed for chlorins, which

drew heavily on methods established in the total synthesis of

bonellin,^16,17are shown in Scheme 1. Each de novo synthe-

sis involves the convergent joining of an Eastern half and a

Western half. Two Western halves, a dihydrodipyrrin (1)¹⁰

and a tetrahydrodipyrrin (2),^12,18were each synthesized in

four to ﬁve steps from pyrrole-2-carboxaldehyde. Acid-

catalyzed condensation of

a bromo-dipyrromethane-

carbinol (Eastern half, 3a) and 1 or 2 followed by oxidative

cyclization afforded the meso-disubstituted zinc chlorin

4a. The cyclization yield reached up to 45% depending on

the presence of substituents in the components and the

choice of Western half.^10–13A related synthesis uses

Keywords: Hydrodipyrrin; 1-Pyrroline; Pyrrole; Hydroporphyrin.

* Corresponding author. Tel.: +1 9195156406; fax: +1 9195132830; e-mail:

jlindsey@ncsu.edu

doi:10.1016/j.tet.2006.10.027

38

H.-J. Kim et al. / Tetrahedron 63 (2007) 37–55

N

M

Chlorin

Bacteriochlorin

Isobacteriochlorin

CO₂H

O

CO₂H

CH₃

HO₂C

N

CO₂H

Fe

Mg

N

CO₂H

O

HO₂C

CO₂H

RO

O

Chlorophyll a

Bacteriochlorophyll a

Siroheme

CO₂H

O

HO₂C

R¹

NH

N

NH

N

Fe

HN

R²

O

CO₂H

R¹, R²= tetrahydropyrane

HO₂C

CO₂H

HO₂C

Heme d₁

Tolyporphin

Bonellin

Chart 1.

a formyl-containing Eastern half (3b) to give the fully un-

substituted zinc chlorin 4b.¹⁴

BC) were obtained as well as the ring-contracted analogue,

a tetradehydrocorrin (TDC).¹⁵

The de novo synthesis of bacteriochlorins is shown in

Scheme 2. A dihydrodipyrrin bearing an acetal moiety (5)

undergoes self-condensation under acidic conditions at

room temperature. Two bacteriochlorins (H-BC, MeO-

The strategy underlying each such ‘2+2’ route to hydro-

porphyrins depends on the nature of the substituents at the

a-positions of the hydrodipyrrins. In the chlorin synthe-

sis,^10–14the pyrrole unit and the a-methyl pyrroline unit of

Nu^-

NH

p-tol

E⁺

1

N

HO

Nu^-

HN

N

Mes

1. Condensation

+

Zn

OR

2. Oxidative

Cyclization

H

HN

NH

N

Br

E⁺

2

Chlorin (4a)

3a

Western half

Eastern Half

O

E⁺

H

NH

N

HN

E⁺

N

1. Condensation

+

Zn

2. Oxidative

Cyclization

Br

2

3b

Chlorin (4b)

Scheme 1.

H.-J. Kim et al. / Tetrahedron 63 (2007) 37–55

39

R

Nu^-

NH

Ar

NH

N

NH

N

Self-Condensation

+

2

BF₃·OEt₂, CH₃CN

HN

N

HN

Ar

O

E⁺

O

H-BC (R = H)

O

+

5

(Ar = p-tolyl)

MeO-BC (R = MeO)

TDC

Scheme 2.

the hydrodipyrrin (Western half) both functioned as nucleo-

philes, the two complementary sites on the Eastern half (bromo-

pyrrole, a-carbinol) functioned as electrophiles, and each

half contributed one bridging meso-carbon atom (Scheme

1). In the bacteriochlorin synthesis,¹⁵the pyrrole unit and

the a-acetal-pyrroline unit functioned as nucleophile and

electrophile, respectively, and the acetal provided the bridg-

ing meso-carbon atom (Scheme 2). In general, the develop-

ment of new 2+2 reactions for preparing hydroporphyrins

relies on access to hydrodipyrrins with suitable reactivity at

the a-position of the respective pyrrole or pyrroline unit.

(not shown). The number of a-carbon atoms, which poten-

tially confer bridging meso-carbon atoms upon hydro-

porphyrin formation, is two (A, B), one (C–E), or zero

(F). Most of the dihydrodipyrrins bear substituents at one

or both b-pyrrole positions as required for the synthesis of

naturally occurring hydroporphyrins.

Synthetic hydroporphyrins with few or no substituents could

serve as valuable benchmarks for understanding funda-

mental properties and reactivity. However, the syntheses of

such sparsely substituted hydroporphyrins have proved to

be more difﬁcult than those bearing a full complement of

pyrrole substituents, owing to the broader range of possible

side reactions of the unsubstituted hydrodipyrrin precursors.

A wide variety of dihydrodipyrrin species bearing diverse

a-substituents have been developed for the syntheses of nat-

urally occurring chlorins and isobacteriochlorins.^{16,17,19–29}

(By contrast, the tetrahydrodipyrrins prepared to date are

fewer in number and typically contain the same a-substitu-

ents as those of 2.^23,24,30) The representative collection of

dihydrodipyrrins (A–F) shown in Chart 2 illustrates the

substituents at the pyrroline and pyrrole a-positions that

have been employed to engender distinct nucleophilic or

electrophilic reactivity features. The reactivity includes an

electrophilic pyrrole (a-formyl: A,²⁷B,²⁷and D^{20,21,23–26}),

nucleophilic pyrrole (no a-substituent: C,¹⁷and E²⁷and F²⁷

upon decarboxylation), nucleophilic pyrroline (a-methyl,

which forms an enamine: A, C), and electrophilic pyrroline

via leaving groups (a-formyl: B, E; a-(thio)alkoxide: D, F;

or a-triﬂate: F) or via an a-unsubstituted pyrroline N-oxide²²

In this regard, the simple appearance of unsubstituted hydro-

dipyrrins can be deceptive, because the two different hetero-

cycles (pyrrole, 1-pyrroline) exhibit distinct reactivity

features.¹⁸A number of these differences are quite obvious:

the pyrrole in 1 or 2 is activated at three sites (7-, 8-, and 9-

position) for electrophilic substitution whereas the imine is

susceptible to reduction and addition; the pyrrole is a weak

acid whereas the pyrroline is a weak base. The coordination

ability of hydrodipyrrins can thwart a number of metal-medi-

ated reactions. Perhaps less obviously, tetrahydrodipyrrins

lacking b-pyrrole substituents (e.g., 2) can undergo irrevers-

ible intramolecular cyclization in the presence of acid, form-

ing a bicyclic, tropane-like structure.¹²Thus, the scope of

suitable synthetic methods for preparing and manipulating

synthetic hydrodipyrrins, particularly those lacking b-pyr-

role substituents, is somewhat constrained.

Nu^-/E⁺(2 α-carbons)

E⁺/E⁺(1 -carbon)

R⁵

R⁷

In this paper, we describe the synthesis of new hydrodipyr-

rins, chieﬂy tetrahydrodipyrrins, with a variety of groups

at the pyrrole and pyrroline a-positions. The emphasis on

tetrahydrodipyrrins stems from studies in chlorin chemis-

try¹²where unsubstituted tetrahydrodipyrrins (e.g., 2) were

found to have a substantially longer shelf-life than the corre-

sponding dihydrodipyrrins (e.g., 1). The hydrodipyrrins lack

b-pyrrole and meso-substituents. The availability of this set

of compounds should provide a valuable toolkit for investi-

gating the syntheses of a variety of hydroporphyrins.

R⁸

D

A

B

C

N

HN

N

HN

H₃C

CHO

MeX

CHO

X = O or S

E⁺/Nu^-(1 -carbon)

E⁺/E⁺(2 -carbons)

R⁷

R⁸

E

N

HN

N

HN

t

OHC

CHO

OHC

CO₂Bu

Nu^-/Nu^-(1 -carbon)

E⁺/Nu^-(0 -carbons)

R⁷

R

2. Results and discussion

2.1. Approach

R²

R⁸

F

N

HN

N

HN

t

H₃C

X

CO₂Bu

The target hydrodipyrrins are illustrated in Table 1. The

hydrodipyrrins in each class differ in the pattern of reactivity

(Nu^ꢀ/E⁺) and number of C₁synthons (0–2) attached at the

X = SMe or OTf

Chart 2.

40

H.-J. Kim et al. / Tetrahedron 63 (2007) 37–55

Table 1. Target hydrodipyrrins

8

2

X

Y

X

9

7

11

H

NH

N

NH

N

6

5

3

4

10

1

Y

dihydrodipyrrin

tetrahydrodipyrrin

hexahydrodipyrrin

Entry

a-Carbons

Reactivity type (substituent)

Pyrroline (-Y)

Pyrrole (-X)

I

II

III

IV

V

0

1

2

1

2

E⁺(H, OMe, SMe)

E⁺(CHO)

Nu^ꢀ(H)

E⁺(Br)

E⁺(CHO)

E⁺(Br)

Nu^ꢀ(CH₃)

VI

E⁺(CHO)

1- and 9-positions. While our chief focus centered on tetra-

hydrodipyrrins, we also examined dihydrodipyrrins and

hexahydrodipyrrins to a limited extent. The following sec-

tions describe the routes that afforded the target compounds,

protected analogues, and related derivatives.

deoxygenated N-Boc tetrahydrodipyrrin 6-Boc (16%). Two

routes were investigated to obtain 6 from the N-oxide

12-Boc, which differ in the order of deoxygenation and

cleavage of the Boc group. Removal of the Boc group

upon treatment with NaOMe afforded the N-oxide 13, which

proved to be slightly unstable. On the other hand, deoxygen-

ation of 12-Boc with Ti(0) gave 6-Boc (41% yield), which

upon subsequent treatment with NaOMe gave the target

compound 6 in 34% yield.

2.2. Synthesis of hydrodipyrrins

2.2.1. E^D/Nu^Lpyrroline–pyrrole units (0 a-carbons).

2.2.1.1. Imines. An initial target was an analogue of 2

lacking a methyl group at the a-position of the pyrroline

ring (6). Analogues of such ‘des-methyl’ species bearing

b-pyrrolic substituents were important precursors in Batters-

by’s synthesis of isobacteriochlorins.²²Thus, N-Boc-

pyrrole-2-carboxaldehyde (7-Boc)³¹was converted via the

intermediate nitrovinyl pyrrole 8-Boc to the nitroethylpyr-

role 9-Boc in either a two-step or one-ﬂask process (Scheme

3). The Michael addition of 9-Boc with 3-methyl-2-butenal

(10a) gave the nitropentanal-pyrrole 11-Boc (36% yield),

which upon cyclization in the presence of Zn and acetic

acid afforded the expected N-oxide (12-Boc, 39%) and the

2.2.1.2. Imidates. The electrophilicity of the a-pyrro-

line position can be altered by the introduction of a leaving

group. The synthesis of the corresponding tetrahydrodipyr-

rin-imidate (14) is shown in Scheme 4. The Michael addition

of 9¹⁸with methyl 3,3-dimethylacrylate (10b) was examined

under several conditions. The desired methyl nitropenta-

noate 16 was obtained upon reaction at 65 ^ꢁC via a solvent-

less synthesis with DBU (20% yield), with DBU in

acetonitrile (19% yield), or CsF in acetonitrile (11% yield).

On the other hand, the use of TBAF in acetonitrile at room

temperature gave 16 in 43% yield (see Section 4).

O

H

CH₃NO₂

NaOAc

NaBH₄

DMF

CH₃NH₂·HCl

CH₃OH

NBoc

NO₂

NBoc

10a

NBoc

CH₃OH

OHC

64%

52%

CsF, CH₃CN

55 °C

NO₂

9-Boc

NO₂

8-Boc

36%

7-Boc

O

H

one-flask reaction

(1) CH₃NO₂, NaOAc

CH₃NH₂·HCl, CH₃OH

11-Boc

(2) NaBH₄

Zn

61%

DMF/CH₃OH

AcOH/ethanol

0 °C

NaOMe

THF

TiCl₄, LiAlH₄,

Et₃N, THF

NaOMe

NH

N

NBoc

NH

NBoc

MeOH

THF/MeOH

34%

O

N

O

39%

41%

N

+

6

12-Boc (39%)

6-Boc (16%)

13

6-Boc

Scheme 3.

H.-J. Kim et al. / Tetrahedron 63 (2007) 37–55

41

Me₃OBF₄

Zn

DIEA

acid

NH

CH₃

NH

N

CH₂Cl₂

TBAF, THF, rt

O

EtOH

+

(R = H)

R

NO₂

N

NO₂

O

OCH₃

14 (50%)

10b

9

O

15 (10%)

R = H R = OH

O

17-OH

18%

10%

0%

17

43%

acid

9%

HCOONH₄

AcOH

16

30%

45%

HCOOH

Scheme 4.

The reductive cyclization of nitroester 16 also was carried

out under several conditions. Zn/HCO₂NH₄or Zn/

N-p-tosyl derivative7-Ts (a known compound³⁷butwith pre-

viously incomplete characterization data) in 86% yield. The

subsequent nitro-aldol condensation and reduction were ini-

tially performed in two steps via the intermediate nitrovinyl-

pyrrole 8-Ts to give N-p-tosyl nitroethylpyrrole 9-Ts. An

alternative two-step, one-ﬂask synthesis¹³proved to be sim-

pler and afforded a higher yield of 9-Ts (55% vs 28%). Mi-

chael addition of the latter with 10a in the presence of CsF

at 55 ^ꢁC gave the nitropentanal-pyrrole 11-Ts in 69% yield.

18

AcOH¹²afforded the mixture of lactam 17 (9% or 30%

yield) or hydroxamic acid 17-OH (18% or 10% yield),

respectively. The cleanest reaction and the highest yield

were obtained with Zn/HCO₂H³²in EtOH at room tempera-

ture, affording 17 in 45% yield. The reaction of 17 with

trimethyloxonium tetraﬂuoroborate in anhydrous CH₂Cl₂

containing N,N-diisopropylethylamine (DIEA) provided

the O-methylated product 14 in 50% yield (together with

the N-methyl lactam 15 in 10% yield).

Reductive cyclization of 11-Ts in the presence of Zn in

acetic acid and ethanol at 0 ^ꢁC afforded the N-oxide 12-Ts

in 45% yield. Deoxygenation of 12-Ts gave the N-protected

6-Ts in 47% yield. Dithiane addition³⁸to the imine of 6-Ts

gave two separable diastereomers (20aP-Ts, 20bP-Ts) in

29% overall yield. The p-tosyl group of each diastereomer

was removed using aqueous NaOH and 2-propanol. The

resulting 20aP and 20bP are protected derivatives of target

hexahydrodipyrrin-aldehyde 20. We note that 20 would

contain an a-aminoaldehyde, a motif prone to tautomeriza-

tion,³⁹but could provide a valuable precursor to bacterio-

chlorins if conditions are identiﬁed where condensation is

a competitive process.

2.2.1.3. Thioimidates. The greater reactivity of thio-

esters and thioimidates versus the oxygen analogues^23,33

toward nucleophilic substitution prompted the synthesis of

tetrahydrodipyrrin-thioimidates. Thus, treatment of lactam

17 with Lawesson’s reagent³⁴in toluene afforded thiolactam

18 in 43% yield. The attempted S-alkylation of 18 using

Meerwein’s salt gave multiple products, whereas methyl

iodide in the presence of silver(I) carbonate²⁴afforded the

expected S-methylsulfanyl product 19 in 49% yield (Scheme

5).

MeI

Lawesson's

reagent

2.2.2.2. Tetrahydrodipyrrin- and dihydrodipyrrin-

acetal. We examined the direct oxidation of the a-methyl

group in pyrroline 2 to afford aldehyde 21 using SeO₂,²⁷

but were unable to identify suitable conditions for this appar-

ently simple transformation. Given that the N-oxide in a pyr-

roline ring accelerates oxidative conversion of the a-methyl

group to the aldehyde,⁴⁰we turned to the pyrroline N-oxide.

Michael addition of 9-Ts with mesityl oxide (10c) gave

22-Ts, which upon reductive cyclization gave the tetra-

hydrodipyrrin N-oxide 23-Ts accompanied by the fully

deoxygenated 2-Ts (Scheme 7). Treatment of 23-Ts with

freshly prepared Ti(0)¹³afforded 2-Ts in 75% yield. Oxida-

tion of N-oxide 23-Ts with SeO₂gave the corresponding

aldehyde 24-Ts in 79% yield. Attempted deoxygenation of

both 2-Ts and 24-Ts failed to give 21-Ts.

Ag₂CO₃

NH

N

THF

49%

toluene

17

43%

S

18

19

Scheme 5.

In summary, tetrahydrodipyrrins 6, 14, and 19 contain no

a-carbons and meet the target criteria of E⁺/Nu^ꢀreactivity

at the 1- and 9-positions.

2.2.2. E^D/Nu^Lpyrroline–pyrrole units (1 a-carbon).

2.2.2.1. Hexahydrodipyrrin-dithiane. The synthesis of

the dithiane analogue (20P) of hexahydropyrrin-aldehyde 20

was initially attempted via 2-(2-nitroethyl)pyrrole (9) in the

same manner as for 2. However, the Michael addition of 9

with the aldehyde 10a gave multiple products. To suppress

the reactivity of 9 we turned to the p-tosyl protecting

group.^35–37The direct p-tosylation of nitroethylpyrrole 9 to

give 9-Ts was unsuccessful, requiring introduction of the

p-tosyl group at the outset of the synthesis (Scheme 6).

The failure of the direct deoxygenation of 24-Ts prompted

investigation of aldehyde protecting groups. Use of 1,3-pro-

panedithiol⁴¹gave compound 25-Ts, which was unstable

(e.g., decomposed after 24 h in CDCl₃). Attempts to deoxy-

genate 25-Ts were not successful, which can be attributed

to its instability. Use of neopentyl glycol^42,43gave N-oxide

27-Ts, which upon deoxygenation gave acetal 28-Ts in

92% yield. Although 28-Ts was stable, the subsequent

hydrolysis to give 21-Ts also was unsuccessful. Finally,

24-Ts was converted to the more labile dimethyl acetal

The reaction of pyrrole-2-carboxaldehyde (7) and p-tosyl

chloride under phase-transfer conditions afforded the

42

H.-J. Kim et al. / Tetrahedron 63 (2007) 37–55

O

NH

H

NH

10a

NO₂

X

NO₂

CsF, CH₃CN

55 °C

9

O

Two-step, one-flask route

H

TsCl, aq NaOH

Bu₄NHSO₄

CH₂Cl₂

(1) CH₃NO₂, NaOAc (2) NaBH₄

11

X

CH₃NH₂·HCl

CH₃OH

DMF/CH₃OH

55%

O

TsCl

CH₃NO₂

NaOAc

aq NaOH

Bu₄NHSO₄

CH₂Cl₂

NaBH₄

THF

NTs

NO₂

H

CH₃NH₂·HCl

10a

NTs

CH₃OH

NTs

NH

86%

31%

CsF, CH₃CN

55 °C

90%

OHC

NO₂

69%

O

H

11-Ts

8-Ts

7

7-Ts

9-Ts

TiCl₄

Zn

LiAlH₄

Et₃N

THF

aq NaOH

AcOH

ethanol

0 °C

2-propanol

reflux

dithiane

n-BuLi

NTs

N

NTs

NH

11-Ts

O

45%

47%

*

N

NH

*

NH

*

H

S

H

S

6-Ts

12-Ts

20aP-Ts (11%)

20bP-Ts (18%)

20aP (47%)

20bP (44%)

20aP-Ts

20bP-Ts

Scheme 6.

TiCl₄

TFA

LiAlH₄

Et₃N

THF

LiAlH₄

Et₃N

THF

H₂O

NTs

N

NTs

N

NTs

CH₂Cl₂

X

21-Ts

X

O

N

O

N

92%

S

O

42%

O

51%

S

O

S

BF₃⋅OEt₂

p-TsOH

neopentyl

glycol

28-Ts

25-Ts

26-Ts

27-Ts

HS

SH

Zn, AcOH

ethanol

0 °C

LaCl₃

MeOH

56%

NTs

NO₂

NTs

SeO₂

79%

29-Ts

O

N

O

N

O

N

O

H

O

23-Ts (57%)

+

24-Ts

TiCl₄, LiAlH₄

2-Ts (24%)

22-Ts

TiCl₄, LiAlH₄

Et₃N, THF

TiCl₄

84%

X

LiAlH₄

Et₃N

THF

Et₃N, THF

75%

73%

aq NaOH

TFA/H₂O

CH₂Cl₂

NTs

2-propanol

reflux

CsF

NTs

N

NH

N

SeO₂

CH₃CN

70 °C

X

43%

10c

N

O

9-Ts

H

O

2-Ts

21-Ts

21P-Ts

21P

Scheme 7.

H.-J. Kim et al. / Tetrahedron 63 (2007) 37–55

43

(29-Ts) using LaCl₃⁴⁴in methanol in 56% yield. Deoxygen-

ation gave 21P-Ts in 84% yield. Conversion of 21P-Ts to

21-Ts was attempted using established methods for acetal

hydrolysis [MoO₂(acac)₂in aqueous acetonitrile;⁴⁵TFA/

H₂O (3:1) in CH₂Cl₂^42,46] but to no avail. ¹H NMR spectros-

copy of the crude product obtained with aqueous TFA

showed that 21P-Ts had indeed reacted with water, but

with addition of water across the imine rather than hydro-

lysis of the acetal. In summary, all four approaches to the

N-p-tosyl protected target tetrahydrodipyrrin-carboxalde-

hyde 21-Ts failed. On the other hand, removal of the p-tosyl

protecting group in 21P-Ts upon basic treatment afforded

the target compound 21P, the dimethyl acetal of 21.

To compare the reactivity of the tetrahydrodipyrrin-acetal

(21P) with that of a dihydrodipyrrin-acetal (32P), we inves-

tigated the synthesis of the latter following the same method

employed in the synthesis of dihydrodipyrrin 1.¹⁰Jacobi

et al. described a related diformyl-dihydrodipyrrin (B, Chart

2),²⁷but given the difﬁculties we encountered in pursuit of

the 1-formyl-tetrahydrodipyrrin 21, we elected to prepare

an acetal-protected analogue. Thus, reductive cyclization

of 30 upon treatment with NaOMe followed by a buffered

solution of TiCl₃afforded 32P (Scheme 8). The yields in

both routes to 32P and 21P (protected derivatives of 32

and 21) were quite low, but sufﬁcient material was obtained

for subsequent exploratory studies. Such studies indicated

that the dihydrodipyrrin-acetal 32P was more reactive

than the tetrahydrodipyrrin-acetal 21P toward forming

the corresponding bacteriochlorin (lacking any b-pyrrole

substituents).⁴⁷

An approach to 21P without use of N-protection is shown in

Scheme 8. The Michael addition of 2-(2-nitroethyl)pyrrole

(9)¹⁸with a-keto acetal 10d¹⁵in the presence of CsF

afforded adduct 30 in 34% yield. Alternatively, Michael ad-

dition of acetal 10d with nitroethylpyrrole 9 in the presence

of DBU¹⁸under solventless conditions provided 30 in 53%

yield. Reductive cyclization of acetal 30 with Zn/HCO₂NH₄

in THF caused simultaneous reduction of the acetal to the

methyl group, affording tetrahydrodipyrrin 2 in 56% yield.

To our knowledge, the reduction of the a-acyl acetal, while

undesired, also is unprecedented under these conditions.

On the other hand, reductive cyclization of 30 in the

presence of Zn/acetic acid afforded (17% yield) the

N-oxide 31, which upon deoxygenation with Ti(0) gave the

tetrahydrodipyrrin-dimethyl acetal 21P, albeit in very low

yield.

2.2.2.3. Tetrahydrodipyrrin-carbinol. The N-oxide

aldehyde 24-Ts appeared to be a versatile intermediate given

the masked pyrrolic nitrogen, the ‘protected’ imine, and the

free formyl group. To explore conversion of the aldehyde to

the secondary carbinol, 24-Ts was treated with PhMgBr. The

resulting diastereomers 33a-Ts and 33b-Ts were separated

by column chromatography (34% total yield). The carbinols

33a-Ts and 33b-Ts were more stable than the corresponding

dipyrromethane-based carbinols prepared previously⁴⁸

(Scheme 9).

(1) PhMgBr

(2) NH₄Cl

NTs

O

N

O

N

*

OH

O

*

NH

Ph

H

O

+

33a-Ts (16%)

33b-Ts (18%)

O

24-Ts

NO₂

10d

9

Scheme 9.

CsF, CH₃CN, 70 °C, 34%

or

DBU, solventless, 53%

In summary, dihydrodipyrrin 32P, tetrahydrodipyrrin 21P,

and hexahydrodipyrrin 20aP/20bP each contains one

a-carbon and meet the target criteria of E⁺/Nu^ꢀreactivity

at the 1- and 9-positions.

Zn

AcOH

ethanol

0 °C

NH

HCO₂NH₄

THF

NH

N

2.2.3. E^D/E^Dpyrroline–pyrrole units (1 a-carbon). The

umpolung analogue of tetrahydrodipyrrin 2 (Nu^ꢀ/Nu^ꢀ)

requires conversion of both nucleophilic units (pyrrole and

methyl imine) to electrophilic units. In a previous chlorin

synthesis,^10–13an a-bromo-pyrrole in the Eastern half served

as a key electrophilic unit in the carbon–carbon bond-

forming cyclization process. Such an a-bromo-pyrrole and

an a-formyl-pyrroline are obvious choices for the two elec-

trophiles. However, direct conversion of the methyl imine to

the aldehyde (e.g., 2/21) was not viable, prompting exam-

ination of the N-oxide of tetrahydrodipyrrin 2 (i.e., 23) as

a surrogate for the corresponding conversion.

NO₂

O

17%

56%

N

O

2

O

31

30

TiCl₄, LiAlH₄

Et₃N, THF

(1) NaOMe/THF

(2) TiCl₃, pH 6

8%

14%

NH

N

O

N

O

Treatment of the N-oxide 23¹²with NBS in THF at ꢀ78 ^ꢁC

gave selective bromination at the a-pyrrole position, afford-

ing bromo N-oxide 34 in 79% yield. Oxidation of 34 with

SeO₂gave the aldehyde 35 in 43% yield (Scheme 10). It is

noteworthy that the opposite order of bromination and

O

21P

32P

Scheme 8.

44

H.-J. Kim et al. / Tetrahedron 63 (2007) 37–55

H

oxidation proved difﬁcult owing to the instability of the

pyrrole-N-oxide aldehyde. Compound 35 is the N-oxide

derivative that satisﬁes the desired E⁺/E⁺reactivity pattern

and contains one a-carbon.

O

H

O

NH

NO₂

Zn

POCl₃

DMF

NH₄Cl

THF/H₂O

(1:1)

O

NO₂

NH

N

CH₂Cl₂

Br

35%

45%

NBS

O

SeO₂

THF

NH

1,4-dioxane

O

-78 °C

79%

O

43%

N

O

30

Scheme 11.

36

37

H

23

34

35

38 bears the Nu^ꢀ/E⁺reactivity pattern at the 1- and 9-posi-

tions and bears one a-carbon.

Scheme 10.

2.2.4. E^D/E^Dpyrroline–pyrrole units (2 a-carbons). The

nitroacetal 30 was formylated under standard Vilsmeier con-

ditions to afford 36 in 35% yield. The reductive cyclization

of 36 in the presence of Zn/NH₄Cl¹⁸provided tetrahydro-

dipyrrin 37 in 45% yield (Scheme 11). A small amount

of a putative N-oxide analogue also was isolated. Compound

37 is the target compound with electrophilic units at both the

1- and 9-positions, and contains two a-carbons. Jacobi et al.

prepared a related diformyl-dihydrodipyrrin bearing substit-

uents at both b-pyrrole positions.²⁷

Br

NH

N

NH

N

NBS

83%

2

38

Scheme 12.

2.2.6. Nu^L/E^Dpyrroline–pyrrole units (2 a-carbons).

The tetrahydrodipyrrin bearing an a-pyrroline methyl group

and an a-pyrrole carboxaldehyde (39) was synthesized

according to the route displayed in Scheme 13. Vilsmeier

formylation of 22¹⁸afforded formyl-nitrohexanone 40 in

64% yield as well as a putative cyclic byproduct (40⁰) in

32% yield. Reductive cyclization of 40 using Zn/HCO₂NH₄

2.2.5. Nu^L/E^Dpyrroline–pyrrole units (1 a-carbon). The

conversion of the pyrrole unit from a nucleophilic to electro-

philic species can be accomplished by bromination. Thus,

bromination of tetrahydrodipyrrin 2 with NBS proceeded

selectively at the free a-pyrrole position, affording bromo-

tetrahydrodipyrrin 38 in 83% yield (Scheme 12). Compound

NH

22

NO₂

O

POCl₃

DMF, CH₂Cl₂

H

O

H

DMF, POCl₃

55%

O

NH

Zn/AcOH

EtOH

18%

Zn/HCOONH₄

THF

NH

N

NH

N

27%

O

NO₂

35%

H

N

O

2

41

39

O

40 (64%)

NH

+

CHO

N

H

O

NH

42

O₂N

40 (32%)

Scheme 13.

H.-J. Kim et al. / Tetrahedron 63 (2007) 37–55

45

in THF afforded 39 in 27% yield. It is interesting to note that

use of Zn/AcOH¹²caused reduction of the formyl group and

provided 9-methyl substituted N-oxide 41. An alternative

route to 39 entailed Vilsmeier formylation of 2, which

afforded 39 in 55% yield together with diformylated 42 in

35% yield. Compound 39 contains the Nu^ꢀ/E⁺reactivity

pattern at the 1- and 9-positions and contains two a-carbons.

2.08 mmol) was slowly added with stirring to dry THF

(6.0 mL) under argon at 0 ^ꢁC. The resulting yellow solution

was slowly treated with LiAlH₄(56.0 mg, 1.49 mmol). The

resulting black mixture was stirred at room temperature for

15 min. Triethylamine (TEA, 1.86 mL, 13.4 mmol) was

added. The black mixture was poured into a solution of

23-Ts (107 mg, 0.297 mmol) in dry THF (60 mL) at 0 ^ꢁC.

The mixture was stirred for 1 h in a water bath (w20 ^ꢁC),

and then water (40 mL) was added. The mixture was ﬁltered.

The ﬁltrate was extracted with CH₂Cl₂. The organic layer

was dried (Na₂SO₄) and concentrated. The resulting yellow

oil was puriﬁed by column chromatography (silica, ethyl

3. Outlook

Three synthetic approaches to hydrodipyrrins that have been

developed over the years include (1) stepwise synthesis be-

ginning with a pyrrole-2-carboxaldehyde and proceeding

via nitro-aldol condensation, reduction, Michael addition,

and metal-mediated reductive cyclization;^{16–18,20,22,23,30,49}

(2) convergent synthesis utilizing a Wittig reaction of a

pyrrole-derived phosphorus ylide and a thione;^21,24–26and

(3) palladium-mediated coupling of a halo-pyrrole with an

ethynyl compound followed by cyclization.^27–29,50The ﬁrst

method, while both the earliest and the most traditional of

the three routes, has been exploited herein to gain access

to a variety of hydrodipyrrin compounds.

1

acetate) to give a pale yellow oil (76 mg, 75%): H NMR

d 0.88 (s, 3H), 1.07 (s, 3H), 1.96–1.99 (m, 3H), 2.27 (AB,

²J¼17.0 Hz, 1H), 2.56 (AB, ²J¼17.0 Hz, 1H), 2.39 (s,

3H), 2.66 (ABX, ³J¼9.8 Hz, ²J¼16.2 Hz, 1H), 2.94

3

2

(ABX, J¼4.2 Hz, J¼16.2 Hz, 1H), 3.72–3.75 (m, 1H),

6.21–6.23 (m, 1H), 6.23–6.25 (m, 1H), 7.27 (d, J¼8.4 Hz,

2H), 7.28–7.29 (m, 1H), 7.65 (d, J¼8.4 Hz, 2H); ¹³C

NMR d 20.7, 21.8, 22.9, 27.3, 28.3, 42.4, 54.8, 78.2,

111.9, 113.7, 122.4, 127.0, 130.1, 134.3, 136.7, 144.9,

174.7; FABMS obsd 345.1649, calcd 345.1637 [(M+H)⁺,

M¼C₁₉H₂₄N₂O₂S]. Anal. Calcd for C₁₉H₂₄N₂O₂S: C,

66.25; H, 7.02; N, 8.13. Found: C, 65.93; H, 6.93; N, 8.00.

Each new hydrodipyrrin described herein contains one pyr-

role and one geminal-dimethyl substituted pyrroline (or pyr-

rolidine) unit. The a-pyrrole position is either unsubstituted

or bears a bromo or formyl substituent; the a-pyrroline posi-

tion is either unsubstituted or bears a methyl, formyl, acetal,

methoxy, or methylsulfanyl substituent; the a-pyrrolidine

substituent is a dithiane unit. Hydrodipyrrins bearing distinct

groups (methyl, acetal, methoxide, methylsulfanyl, no sub-

stituent) at the a-pyrroline position were obtained by

Michael addition of 2-(2-nitroethyl)pyrrolic compounds

with a,b-unsaturated carbonyl compounds (10a–d). The

availability of stable tetrahydrodipyrrins with diverse

1- and 9-substituents should facilitate a variety of studies

concerning the synthesis of hydroporphyrins.

4.3.2. 2,3,4,5-Tetrahydro-3,3-dimethyldipyrrin (6). Fol-

lowing a general procedure,¹¹a solution of 6-Boc

(299 mg, 1.08 mmol) in anhydrous THF (4.32 mL) under

argon at room temperature was treated with methanolic

NaOMe (1.50 mL, prepared by dissolving 373 mg of

NaOMe in 2.00 mL of MeOH). After 25 min, the reaction

was quenched by the addition of a mixture of hexanes and

water (20 mL, 1:1). The mixture was extracted with ethyl

acetate. The organic extract was washed (water and brine),

dried (Na₂SO₄), and chromatographed [alumina, hexanes/

ethyl acetate (3:1)] to give a pale yellow oil (64 mg, 34%):

IR 3380, 2958 cm^ꢀ1; ¹H NMR d 0.95 (s, 3H), 1.13 (s, 3H),

3

2

2.39–2.41 (m, 2H), 2.60 (ABX, J¼11.6 Hz, J¼14.8 Hz,

3

2

1H), 2.82 (ABX, J¼3.2 Hz, J¼14.8 Hz, 1H), 3.63–3.69

(m, 1H), 5.95–5.97 (m, 1H), 6.10–6.12 (m, 1H), 6.69–6.71

(m, 1H), 7.63–7.65 (m, 1H), 9.52–9.68 (br s, 1H); ¹³C

NMR d 23.0, 27.4, 28.0, 40.3, 52.5, 80.9, 105.5, 107.5,

116.7, 131.5, 166.7; EIMS obsd 176.1305, calcd 176.1313

(C₁₁H₁₆N₂).

4. Experimental

4.1. General

¹H NMR (400 MHz) and ¹³C NMR (100 MHz) spectra were

collected at room temperature in CDCl₃unless noted other-

wise. Melting points are uncorrected. Column chromato-

graphy was performed with ﬂash silica or alumina (80–200

mesh). The CHCl₃contained 0.8% ethanol. THF was dis-

tilled from sodium benzophenone ketyl as required.

CH₃CN was distilled from CaH₂and stored over powdered

molecular sieves. NBS was recrystallized (H₂O). Other

solvents were used as received.

4.3.3. N¹¹-tert-Butoxycarbonyl-3,3-dimethyl-2,3,4,5-

tetrahydrodipyrrin (6-Boc). Following a general proce-

dure,¹²TiCl₄(769 mL, 7.00 mmol) was slowly added with

stirring to dry THF (25.0 mL) under argon at 0 ^ꢁC. The re-

sulting yellow solution was slowly treated with LiAlH₄

(190 mg, 5.00 mmol). The resulting black mixture was

stirred at room temperature for 25 min. TEA (6.27 mL,

45.0 mmol) was added. The resulting black mixture was

stirred for 10 min at room temperature, and then cooled at

0 ^ꢁC. The black mixture was slowly poured into a solution

of 12-Boc (292 mg, 1.00 mmol) in dry THF (15.0 mL) at

0 ^ꢁC. The mixture was stirred for 1 h at room temperature,

and then water (10 mL) was added. The mixture was ﬁltered.

The ﬁltrate was extracted with CH₂Cl₂. The organic layer

was dried (Na₂SO₄), concentrated, and chromatographed

(silica, ethyl acetate) to give a pale yellow oil (112 mg,

4.2. Non-commercial compounds

Compounds 2,^12,187-Boc,³¹9,¹⁸10d,¹⁵22,¹⁸and 23¹²were

prepared according to literature procedures.

4.3. New synthetic compounds and procedures

4.3.1. 2,3,4,5-Tetrahydro-1,3,3-trimethyl-N¹¹-p-tosyldi-

pyrrin (2-Ts). Following a procedure for the deoxygenation

of N-oxides¹²with slight modiﬁcation, TiCl₄(229 mL,

1

41%): IR 2958, 1740, 1333, 1126 cm^ꢀ1; H NMR d 0.97

(s, 3H), 1.14 (s, 3H), 1.58 (s, 9H), 2.39–2.41 (m, 2H), 2.88

46

H.-J. Kim et al. / Tetrahedron 63 (2007) 37–55

(ABX, ³J¼10.4 Hz, ²J¼15.8 Hz, 1H), 3.15 (ABX, ³J¼

3.8 Hz, ²J¼15.8 Hz, 1H), 3.77–3.83 (m, 1H), 6.10–6.12

(m, 1H), 6.17–6.18 (m, 1H), 7.19–7.21 (m, 1H), 7.61–7.63

(m, 1H); ¹³C NMR d 23.0, 27.2, 28.3, 29.7, 40.7, 52.8,

78.6, 83.2, 110.4, 112.5, 121.1, 134.6, 149.8, 166.7; FABMS

obsd 277.1917, calcd 277.1916 [(M+H)⁺, M¼C₁₆H₂₄N₂O₂].

(562 mg, 64%): mp 123–124 ^ꢁC; IR 2965, 1748, 1504,

1

1368, 1331, 1123 cm^ꢀ1; H NMR d 1.65 (s, 9H), 6.29–

6.31 (m, 1H), 6.82–6.83 (m, 1H), 7.48 (d, J¼13.6 Hz, 1H),

7.53–7.54 (m, 1H), 8.76 (d, J¼13.6 Hz, 1H); ¹³C NMR

d 28.2, 86.1, 112.4, 118.1, 126.3, 127.7, 130.1, 135.2,

148.7; FABMS obsd 239.1035, calcd 239.1032 [(M+H)⁺,

M¼C₁₁H₁₄N₂O₄]. Anal. Calcd for C₁₁H₁₄N₂O₄: C, 55.46;

H, 5.92; N, 11.76. Found: C, 55.40; H, 6.01; N, 11.71.

4.3.4. 3,3-Dimethyl-2,3,4,5-tetrahydro-N¹¹-p-tosyldipyr-

rin (6-Ts). Following a procedure for the deoxygenation of

N-oxides¹²with slight modiﬁcation, TiCl₄(3.18 mL,

28.9 mmol) was slowly added with stirring to dry THF

(100 mL) under argon at 0 ^ꢁC. The resulting yellow solution

was slowly treated with LiAlH₄(784 mg, 20.7 mmol). The re-

sulting black mixture was stirred at room temperature for

15 min. TEA (25.9 mL, 186 mmol) was added. The black

mixture was poured into a solution of 12-Ts (1.43 g,

4.13 mmol) in dry THF (60 mL) at 0 ^ꢁC. The mixture was

stirred for 1 h in a water bath (w20 ^ꢁC), and then water

(40 mL) was added. The mixture was ﬁltered. The ﬁltrate

was extracted with CH₂Cl₂. The organic layer was dried

(Na₂SO₄), concentrated, and chromatographed (silica, ethyl

acetate) to give a pale yellow oil, which upon cooling gave

a white solid (635 mg, 47%): mp 80–82 ^ꢁC; ¹H NMR d 0.89

(s, 3H), 1.12 (s, 3H), 2.36–2.37 (m, 2H), 2.39 (s, 3H), 2.62

(ABX, ³J¼10.6 Hz, ²J¼16.2 Hz, 1H), 2.98 (ABX,

4.3.7. 2-(trans-2-Nitrovinyl)-N-p-tosylpyrrole (8-Ts). Fol-

lowing a general procedure,¹⁰a solution of 7-Ts (17.3 g,

69.4 mmol) in distilled methanol (300 mL) was treated

with nitromethane (11.2 mL, 208 mmol), sodium acetate

(6.26 g, 76.3 mmol), and methylamine hydrochloride

(5.15 g, 76.3 mmol). The mixture was stirred at room tem-

perature for 38 h under argon. The methanol was removed

in vacuo without heating to give a yellow solid. The solid

was dissolved in CH₂Cl₂(150 mL), and the resulting solu-

tion was washed with water. The organic extract was dried

(Mg₂SO₄), concentrated, and chromatographed (silica,

CH₂Cl₂) to give a yellow solid (18.3 g, 90%): mp 153–

154 ^ꢁC; ¹H NMR (300 MHz) d 2.42 (s, 3H), 6.39–6.41 (m,

1H), 6.81–6.83 (m, 1H), 7.33 (d, J¼8.1 Hz, 2H), 7.36 (d, J¼

13.5 Hz, 1H), 7.61–7.63 (m, 1H), 7.74 (d, J¼8.1 Hz, 2H),

8.51 (d, J¼13.5 Hz, 1H); ¹³C NMR d 21.6, 113.3, 118.6,

125.5, 126.9, 127.0, 128.3, 130.4, 135.0, 135.6, 146.1.

Anal. Calcd for C₁₃H₁₂N₂O₄S: C, 53.42; H, 4.14; N, 9.58.

Found: C, 53.44; H, 4.17; N, 9.53.

2

³J¼3.8 Hz, J¼16.2 Hz, 1H), 3.73–3.79 (m, 1H), 6.22–6.25

(m, 2H), 7.27 (d, J¼8.4 Hz, 2H), 7.28–7.31 (m, 1H), 7.56–

7.58 (m, 1H), 7.63 (d, J¼8.4 Hz, 2H); ¹³C NMR d 21.8,

23.0, 27.3, 28.3, 40.7, 52.7, 78.6, 112.0, 113.9, 122.6, 126.9,

130.2, 134.1, 136.8, 144.9, 166.9; FABMS obsd 331.1493,

calcd 331.1480 [(M+H)⁺, M¼C₁₈H₂₂N₂O₂S].

4.3.8. N-tert-Butoxycarbonyl-2-(2-nitroethyl)pyrrole (9-

Boc). Following a general procedure,¹¹a solution of 8-Boc

(490 mg, 2.06 mmol) in DMF/methanol (35.0 mL, 1:2) at

0 ^ꢁC was treated with sodium borohydride (117 mg,

3.09 mmol). The reaction mixture was stirred for 15 min.

Water (30 mL) was added followed by acetic acid (one

drop). The mixture was extracted with CH₂Cl₂. The organic

layer was dried (Na₂SO₄), concentrated, and chromato-

graphed [silica, hexanes/CH₂Cl₂(1:4)] to give a pale yellow

oil (258 mg, 52%): IR 2980, 1736 cm^ꢀ1; ¹H NMR d 1.60 (s,

9H), 3.57 (t, J¼7.0 Hz, 2H), 4.66 (t, J¼7.0 Hz, 2H), 6.05–

6.07 (m, 1H), 6.07–6.09 (m, 1H), 7.19–7.21 (m, 1H);

¹³C NMR d 27.1, 28.2, 75.0, 84.4, 110.5, 114.0, 122.2,

129.2, 149.5; FABMS obsd 240.1126, calcd 240.1110

(C₁₁H₁₆N₂O₄).

4.3.5. N-p-Tosylpyrrole-2-carboxaldehyde (7-Ts).³⁷Fol-

lowing a general procedure,³⁵a mixture of 7 (4.76 g,

50.0 mmol) and tetrabutylammonium hydrogen sulfate

(1.70 g, 5.00 mmol) was added to aqueous NaOH [9.00 g

(225 mmol) of NaOH in 30 mL of water]. The mixture

was stirred for 10 min. p-Toluenesulfonyl chloride (10.5 g,

55.0 mmol) in CH₂Cl₂(10 mL) was added rapidly. The reac-

tion mixture was stirred for 5 h, then water (200 mL) and

brine (100 mL) were added. The mixture was extracted

with CH₂Cl₂. The organic extract was dried (Na₂SO₄), con-

centrated, and chromatographed (silica, CH₂Cl₂) to give

a light pink solid (10.7 g, 86%): mp 94–95 ^ꢁC (lit.³⁷mp

1

94–96 ^ꢁC); H NMR d 2.42 (s, 3H), 6.39–6.41 (m, 1H),

7.15–7.16 (m, 1H), 7.32 (d, J¼8.6 Hz, 2H), 7.61–7.63 (m,

1H), 7.80 (d, J¼8.6 Hz, 2H), 9.98 (s, 1H); ¹³C NMR

d 21.9, 112.6, 124.6, 127.7, 129.6, 130.3, 133.7, 135.4,

146.2, 179.2. Anal. Calcd for C₁₂H₁₁NO₃S: C, 57.82; H,

4.45; N, 5.62. Found: C, 58.03; H, 4.62; N, 5.64.

4.3.9. One-ﬂask synthesis of N-tert-butoxycarbonyl-2-(2-

nitroethyl)pyrrole (9-Boc). Following a general proce-

dure,¹³a solution of 7-Boc (3.62 g, 18.5 mmol) in distilled

methanol (62.0 mL) was treated with nitromethane

(3.00 mL,

55.6 mmol),

sodium

acetate

(1.67 g,

20.4 mmol), and methylamine hydrochloride (1.37 g,

20.4 mmol). Stirring at room temperature for 16 h under ar-

gon afforded a yellow mixture. DMF (100 mL) and metha-

nol (138 mL) were added to the reaction mixture. Sodium

borohydride (910 mg, 24.1 mmol) was added rapidly at

0 ^ꢁC. The reaction mixture was stirred at room temperature

for 20 min. The mixture was neutralized with acetic acid

(w0.5 mL) and then concentrated. The resulting residue

was dissolved in CH₂Cl₂(100 mL) and washed with water.

The organic layer was dried (Na₂SO₄), concentrated, and

chromatographed [silica, hexanes/CHCl₃(1:4)] to give

a pale yellow oil (2.74 g, 61%). The characterization data

were identical with those from above.

4.3.6. N-tert-Butoxycarbonyl-2-(trans-2-nitrovinyl)pyr-

role (8-Boc). Following a general procedure,¹⁰a solution

of 7-Boc (772 mg, 3.70 mmol) in distilled methanol

(11.0 mL) was treated with nitromethane (599 mL,

11.1 mmol), sodium acetate (334 mg, 4.07 mmol), and me-

thylamine hydrochloride (275 mg, 4.07 mmol). The mixture

was stirred at room temperature for 21 h under argon. The

methanol was removed in vacuo without heating to give a

yellow solid. The solid was dissolved in CH₂Cl₂(100 mL),

and the resulting solution was washed with water. The

organic extract was dried (Na₂SO₄), concentrated, and

chromatographed (silica, CH₂Cl₂) to give a yellow solid

H.-J. Kim et al. / Tetrahedron 63 (2007) 37–55

47

4.3.10. 2-(2-Nitroethyl)-N-p-tosylpyrrole (9-Ts). Follow-

ing a general procedure,¹⁰a solution of 8-Ts (5.30 g,

18.1 mmol) in dry THF/methanol (180 mL, 19:1) at 0 ^ꢁC

was treated with sodium borohydride (1.71 g, 45.3 mmol)

in portions. The mixture was stirred for 50 min, neutralized

with acetic acid (w2 mL), and ﬁltered. The ﬁltrate was con-

centrated under reduced pressure. The residue was dissolved

in CH₂Cl₂(150 mL) and washed with water. The organic

layer was dried (Na₂SO₄), concentrated, and chromato-

graphed [silica, hexanes/CH₂Cl₂(3:7)] to give a light yellow

solid (1.64 g, 31%): mp 95–96 ^ꢁC; ¹H NMR d 2.42 (s, 3H),

3.41 (t, J¼6.8 Hz, 2H), 4.61 (t, J¼6.8 Hz, 2H), 6.09–6.11

(m, 1H), 6.21–6.23 (m, 1H), 7.30–7.32 (m, 1H), 7.32 (d,

J¼8.4 Hz, 2H), 7.65 (d, J¼8.4 Hz, 2H); ¹³C NMR d 21.6,

25.4, 74.4, 111.8, 114.7, 123.6, 126.5, 128.4, 130.2, 135.8,

145.3. Anal. Calcd for C₁₃H₁₄N₂O₄S: C, 53.05; H, 4.79;

N, 9.52. Found: C, 53.08; H, 4.82; N, 9.43.

to 100 ^ꢁC under vacuum for 1 h and then cooled to room

temperature under argon) was placed in a ﬂask under argon.

A mixture of 9-Ts (2.20 g, 7.47 mmol) and 3-methyl-2-bute-

nal (10a) (7.21 mL, 74.7 mmol, 10.0 mol equiv) in dry

acetonitrile (75 mL) was cannulated into the ﬂask containing

CsF. The mixture was heated at 55 ^ꢁC for 90 min, where-

upon the reaction was deemed to be complete by TLC.

The reaction mixture was ﬁltered through a pad of silica

(ethyl acetate). The ﬁltrate was concentrated and chromato-

graphed [silica, hexanes/ethyl acetate (3:1)] to give a pale

1

yellow oil (1.96 g, 69%): H NMR (300 MHz) d 1.22 (s,

3H), 1.27 (s, 3H), 2.43 (s, 3H), 2.40–2.60 (m, 2H), 3.23

(ABX, ³J¼2.2 Hz, ²J¼15.4 Hz, 1H), 3.34 (ABX, ³J¼

11.4 Hz, ²J¼15.4 Hz, 1H), 4.92 (ABX, ³J¼2.2 Hz, ³J¼

11.4 Hz, 1H), 6.02–6.06 (m, 1H), 6.17–6.20 (m, 1H),

7.26–7.28 (m, 1H), 7.32 (d, J¼8.0 Hz, 2H), 7.58 (d,

J¼8.0 Hz, 2H), 9.80–9.82 (m, 1H); ¹³C NMR d 21.9, 24.2,

24.5, 27.0, 36.9, 51.5, 95.6, 112.4, 115.7, 124.2, 126.5,

128.8, 130.5, 136.3, 145.6, 200.4. Anal. Calcd for

C₁₈H₂₂N₂O₅S: C, 57.13; H, 5.86; N, 7.40. Found: C,

57.12; H, 5.84; N, 7.20.

4.3.11. One-ﬂask synthesis of 2-(2-nitroethyl)-N-p-tosyl-

pyrrole (9-Ts). Following a general procedure,¹³a solution

of 7-Ts (10.9 g, 43.7 mmol) in distilled methanol (250 mL)

was treated with nitromethane (7.07 mL, 131 mmol), so-

dium acetate (4.30 g, 52.4 mmol), and methylamine hydro-

chloride (3.54 g, 52.4 mmol). Stirring at room temperature

for 40 h under argon afforded a yellow mixture. DMF

(200 mL) and methanol (250 mL) were added to the reaction

mixture. Sodium borohydride (1.98 g, 52.4 mmol) was

added rapidly at 0 ^ꢁC. The reaction mixture was stirred at

room temperature for 20 min, neutralized with acetic acid

(w2 mL), and concentrated. The mixture was dissolved in

CH₂Cl₂(100 mL) and washed with water. The organic layer

was dried (Na₂SO₄), concentrated, and chromatographed

[silica, CH₂Cl₂/hexanes (7:3)] to give a light yellow solid

(7.00 g, 55%). The characterization data were identical

with those from above.

4.3.14. N¹¹-tert-Butoxycarbonyl-2,3,4,5-tetrahydro-3,3-

dimethyldipyrrin N¹⁰-oxide (12-Boc). Following a general

procedure,¹²a vigorously stirred solution of 11-Boc

(364 mg, 1.12 mmol) in 5.50 mL of acetic acid and

5.50 mL of ethanol at 0 ^ꢁC was treated slowly with zinc

dust (1.83 g, 28.0 mmol) in small portions for 5 min. The

reaction mixture was stirred at 0 ^ꢁC for 15 min and then

ﬁltered through Celite. The ﬁltrate was concentrated under

high vacuum. The resulting residue was dissolved in

CH₂Cl₂(50 mL), affording a solution that was washed

with aqueous sodium carbonate (20%, 30 mL), dried

(Na₂SO₄), and concentrated. The resulting light brown oil

was puriﬁed by column chromatography [silica; CH₂Cl₂/

ethyl acetate/CH₂Cl₂/methanol (9:1)] to give a light brown

oil (6-Boc, 49 mg, 16%) and the title compound as a light

brown solid (127 mg, 39%). Data for the title compound:

4.3.12. 5-(N-tert-Butoxycarbonyl-2-pyrrolyl)-3,3-di-

methyl-4-nitro-1-pentanal (11-Boc). A mixture of 9-Boc

(2.50 g, 10.4 mmol) and 3-methyl-2-butenal (10a)

(10.0 mL, 104 mmol, 10.0 mol equiv) in dry acetonitrile

(10.4 mL) was treated with CsF (4.74 g, 31.2 mmol,

3.00 mol equiv, freshly dried under vacuum for 1 h and

purged with argon). The mixture was stirred at room temper-

ature for 2.5 h, whereupon the reaction was deemed to be

complete by TLC. The reaction mixture was ﬁltered through

alumina (w5 cm). The ﬁltrate was concentrated and chroma-

tographed [silica, hexanes/ethyl acetate (3:1)] to give a pale

yellow oil, which upon cooling gave a light brown solid

(1.22 g, 36%): mp 73–75 ^ꢁC; IR 2978, 1737, 1550, 1371,

mp 116–118 ^ꢁC; IR 3393, 2974, 1737, 1334, 1126 cm^ꢀ1

;

¹H NMR d 1.07 (s, 3H), 1.12 (s, 3H), 1.59 (s, 9H), 2.36–

3

2

2.39 (m, 2H), 3.22 (ABX, J¼9.6 Hz, J¼15.6 Hz, 1H),

3

2

3.72 (ABX, J¼5.2 Hz, J¼15.6 Hz, 1H), 4.05–4.10 (m,

1H), 6.07–6.11 (m, 2H), 6.84–6.86 (m, 1H), 7.19–7.21 (m,

1H); ¹³C NMR d 23.0, 26.5, 28.2, 28.3, 39.6, 42.6, 79.2,

83.9, 110.2, 113.6, 121.6, 131.3, 132.8, 149.6; FABMS

obsd 293.1875, calcd 293.1865 [(M+H)⁺, M¼C₁₆H₂₄N₂O₃].

4.3.15. 2,3,4,5-Tetrahydro-3,3-dimethyl-N¹¹-p-tosyldi-

pyrrin N¹⁰-oxide (12-Ts). Following a general procedure,¹²

a vigorously stirred solution of 11-Ts (1.94 g, 5.13 mmol) in

a solution of acetic acid (24.0 mL) and ethanol (24.0 mL) at

0 ^ꢁC was treated slowly with zinc dust (8.39 g, 128 mmol) in

small portions for 5 min. The reaction mixture was stirred at

0 ^ꢁC for 15 min. The mixture was ﬁltered through Celite.

The ﬁltrate was concentrated under high vacuum. The result-

ing oil was puriﬁed by column chromatography [silica,

CH₂Cl₂/ethyl acetate (1:1)/CH₂Cl₂/methanol (9:1)] to

1

1324, 1126 cm^ꢀ1; H NMR d 1.24 (s, 3H), 1.29 (s, 3H),

3

1.59 (s, 9H), 2.49–2.61 (m, 2H), 3.38 (ABX, J¼11.6 Hz,

²J¼15.2 Hz, 1H), 3.58 (ABX, ³J¼2.0 Hz, ²J¼15.2 Hz,

3

1H), 4.92 (ABX, J¼2.0 Hz, J¼11.6 Hz, 1H), 5.99–6.00

(m, 1H), 6.02–6.04 (m, 1H), 7.13–7.15 (m, 1H), 9.83–9.85

(m, 1H); ¹³C NMR d 24.1, 24.3, 28.1, 28.2, 36.8, 51.7,

84.2, 95.6, 110.5, 114.3, 122.1, 129.3, 149.5, 200.7; FABMS

obsd 325.1759, calcd 325.1763 [(M+H)⁺, M¼C₁₆H₂₄N₂O₅].

Anal. Calcd for C₁₆H₂₄N₂O₅: C, 59.24; H, 7.46; N, 8.64.

Found: C, 59.38; H, 7.46; N, 8.47.

1

afford a brown oil (796 mg, 45%): H NMR d 1.02 (s,

3H), 1.12 (s, 3H), 2.38–2.41 (m, 2H), 2.40 (s, 3H), 3.17

(ABX, ³J¼10.6 Hz, ²J¼16.2 Hz, 1H), 3.43 (ABX, ³J¼

3.8 Hz, ²J¼16.2 Hz, 1H), 4.05–4.11 (m, 1H), 6.09–6.11

(m, 1H), 6.20–6.23 (m, 1H), 6.84–6.87 (m, 1H), 7.29 (d,

J¼8.4 Hz, 2H), 7.30–7.33 (m, 1H), 7.68 (d, J¼8.4 Hz,

4.3.13. 3,3-Dimethyl-4-nitro-5-(N-p-tosyl-2-pyrrolyl)-1-

pentanal (11-Ts). Following a general procedure,¹³CsF

(3.40 g, 22.4 mmol, 3.00 mol equiv, freshly dried by heating

48

H.-J. Kim et al. / Tetrahedron 63 (2007) 37–55

2H); ¹³C NMR d 21.8, 23.3, 24.9, 29.0, 39.4, 42.7, 79.8,

111.8, 114.3, 123.2, 127.1, 130.3, 130.8, 133.3, 136.0,

145.3; FABMS obsd 347.1420, calcd 347.1429 [(M+H)⁺,

M¼C₁₈H₂₂N₂O₃S].

7.9 mmol, 5.0 mol equiv) was treated with DBU (0.70 mL,

4.7 mmol, 3.0 mol equiv). The reaction mixture was stirred

at 65 ^ꢁC for 16 h under argon. The crude reaction mixture

was diluted with ethyl acetate (20 mL) and washed with

water and brine. The organic layer was dried (Na₂SO₄)

and concentrated. Excess methyl 3,3-dimethylacrylate was

removed under high vacuum. The crude product was chro-

matographed [silica, hexanes/ethyl acetate (3:1)] to afford

4.3.16. 2,3,4,5-Tetrahydro-3,3-dimethyldipyrrin N¹⁰-

oxide (13). Following a general procedure,¹¹a solution of

12-Boc (413 mg, 1.41 mmol) in anhydrous THF (9.0 mL)

under argon at room temperature was treated with metha-

nolic NaOMe (1.40 mL of a solution prepared by dissolving

486 mg of NaOMe in 2.00 mL of MeOH). After 25 min, the

reaction was quenched by the addition of a mixture of hex-

anes and water (40 mL, 1:1). The mixture was extracted with

ethyl acetate. The organic extract was washed (water and

brine), dried (Na₂SO₄), and chromatographed (silica, ethyl

acetate) to give a light brown oil (106 mg, 39%): IR 3255,

1

a dark brown oil (80.0 mg, 20%): H NMR d 1.16 (s, 3H),

2

1.21 (s, 3H), 2.42 (s, 2H), 3.10 (ABX, ³J¼2.4 Hz, J¼

3

2

15.4 Hz, 1H), 3.37 (ABX, J¼11.6 Hz, J¼15.4 Hz, 1H),

3.72 (s, 3H), 4.94 (ABX, ³J¼11.6 Hz, ³J¼2.4 Hz, 1H),

5.96–6.02 (m, 1H), 6.10–6.11 (m, 1H), 6.67–6.68 (m, 1H),

8.02–8.22 (br s, 1H); ¹³C NMR d 24.0, 24.8, 27.2, 36.8,

43.8, 52.1, 96.0, 107.5, 108.9, 118.1, 126.0, 171.6; FABMS

obsd 255.1336, calcd 255.1345 [(M+H)⁺, M¼C₁₂H₁₈N₂O₄].

2962, 1590, 1236 cm^ꢀ^{1 1}H NMR d 1.15 (s, 3H), 1.22

;

(s, 3H), 2.29–2.48 (m, 2H), 2.99 (ABX, ³J¼3.0 Hz,

²J¼15.8 Hz, 1H), 3.07 (ABX, ³J¼7.4 Hz, ²J¼15.8 Hz,

1H), 3.85–3.89 (m, 1H), 5.93–5.96 (m, 1H), 6.05–6.09 (m,

1H), 6.70–6.72 (m, 1H), 6.93–6.95 (m, 1H), 10.30–10.46

(br s, 1H); ¹³C NMR d 23.0, 25.6, 27.8, 40.2, 42.6, 81.6,

106.5, 107.5, 117.8, 128.7, 135.5; EIMS obsd 192.1265,

calcd 192.1263 (C₁₁H₁₆N₂O).

4.3.19. Synthesis of 16 in acetonitrile with DBU. Follow-

ing a general procedure,¹⁸a mixture of 9 (4.2 g, 30 mmol)

and methyl 3,3-dimethylacrylate (10b, 37 mL, 300 mmol,

10 mol equiv) in CH₃CN (75 mL) was treated with DBU

(14 mL, 90 mmol, 3.0 mol equiv) under argon. The reaction

mixture was stirred at 65 ^ꢁC for 16 h under argon. The crude

reaction mixture was diluted with ethyl acetate (50 mL),

washed (water and brine), dried (Na₂SO₄), and concentrated.

Excess methyl 3,3-dimethylacrylate was removed under

high vacuum. The crude residue was chromatographed [sil-

ica, hexanes/ethyl acetate (3:1)] to afford a dark brown oil

(1.43 g, 19%). The data (¹H NMR, ¹³C NMR, and FABMS)

were consistent with those obtained from samples prepared

via the solventless method.

4.3.17. 2,3,4,5-Tetrahydro-1-methoxy-3,3-dimethyldi-

pyrrin (14). Following a general procedure,²³a mixture of

17 (0.129 g, 0.670 mmol) and trimethyloxonium tetraﬂuoro-

borate (0.109 g, 0.740 mmol) in CH₂Cl₂(2.2 mL) was

purged with argon for 10 min. A sample of N,N-diisopropyl-

ethylamine (DIEA, 0.130 mL, 0.740 mmol) was added. The

reaction mixture was stirred overnight at room temperature.

The reaction mixture was diluted with CH₂Cl₂(10 mL),

washed (water and brine), dried (Na₂SO₄), and concentrated

to afford a brown oil. The crude product was chromato-

graphed [silica, ethyl acetate] to afford a brown solid

(70 mg, 50%). A light pink byproduct also was isolated

and identiﬁed as 2,3,4,5-tetrahydro-3,3,10-trimethyldipyr-

rin-1(10H)-one (15) (14 mg, 10%). Data for 14: mp 85–

4.3.20. Synthesis of 16 in acetonitrile with CsF. Following a

general procedure,¹²CsF (9.11 g, 60.0 mmol, 3.0 mol equiv,

freshly dried by heating at 100 ^ꢁC under vacuum for 1 h and

then cooled to room temperature under argon) was placed in

a ﬂask. A mixture of 9 (2.80 g, 20.0 mmol) and methyl 3,3-

dimethylacrylate (10b, 25.0 mL, 200 mol, 10.0 mol equiv)

in CH₃CN (100 mL) was transferred by cannula to the ﬂask

containing CsF. The reaction mixture was stirred overnight

at 65 ^ꢁC under argon. The reaction mixture was diluted

with ethyl acetate (50 mL) and washed (water and brine),

dried (Na₂SO₄), and concentrated. Excess methyl 3,3-di-

methylacrylate was removed under high vacuum. The crude

product was chromatographed [silica, hexanes/ethyl acetate

(3:1)] to afford a dark brown oil (0.56 g, 11%). The data (¹H

NMR, ¹³C NMR, and FABMS) were consistent with those

obtained from samples prepared via the solventless method.

1

88 ^ꢁC; H NMR d 1.02 (s, 3H), 1.14 (s, 3H), 2.25 (AB,

2

²J¼16.4 Hz, 1H), 2.41 (AB, J¼16.4 Hz, 1H), 2.58 (ABX,

³J¼11.6 Hz, ²J¼14.8 Hz, 1H), 2.77 (ABX, ³J¼2.6 Hz, ²J¼

14.8 Hz, 1H), 3.57–3.61 (m, 1H), 3.96 (s, 3H), 5.91–5.96 (m,

1H), 6.10–6.12 (m, 1H), 6.69–6.76 (m, 1H), 9.67–9.95 (br s,

1H); ¹³C NMR d 23.2, 27.6, 28.8, 42.2, 46.7, 55.2, 75.3,

105.4, 107.6, 116.5, 132.0, 172.2; FABMS obsd 207.1498,

calcd 207.1497 [(M+H)⁺, M¼C₁₂H₁₈N₂O]. Data for 15:

1

mp 92–95 ^ꢁC; H NMR d 1.01 (s, 3H), 1.10 (s, 3H), 2.02

2

(AB, J¼16.2 Hz, 1H), 2.22 (AB, J¼16.2 Hz, 1H), 2.55

(s, 3H), 2.73 (ABX, ³J¼8.4 Hz, ²J¼14.8 Hz, 1H), 2.90

(ABX, ³J¼5.4 Hz, ²J¼14.8 Hz, 1H), 3.28 (ABX, ³J¼

4.3.21. Synthesis of 16 in THF with TBAF. Following

a general procedure²³with slight modiﬁcation, nitroethyl-

pyrrole 9 (4.20 g, 30.0 mmol) and powdered molecular

3

5.4 Hz, J¼8.4 Hz, 1H), 5.94–6.10 (m, 1H), 6.12–6.14 (m,

1H), 6.64–6.71 (m, 1H), 8.52–8.61 (br s, 1H); ¹³C NMR

d 23.0, 28.7, 29.1, 29.3, 37.1, 45.3, 70.4, 107.0, 109.1,

117.0, 128.1, 174.7; FABMS obsd 207.1498, calcd

207.1497 [(M+H)⁺, M¼C₁₂H₁₈N₂O]. Anal. Calcd for

C₁₂H₁₈N₂O: C, 69.87; H, 8.80; N, 13.58. Found: C, 69.93;

H, 8.86; N, 13.33.

sieves 4 A (100 g) were placed in a reaction ﬂask and purged

˚

with argon. Methyl 3,3-dimethylacrylate (10b, 37.0 mL,

300 mmol, 10.0 mol equiv) and TBAF (66.0 mL, 1 M in

THF, w66 mmol, 2.2 mol equiv) in THF (234 mL) were

added. The reaction mixture was stirred overnight at room

temperature under argon. The reaction mixture was then ﬁl-

tered through a column (silica, ethyl acetate). The ﬁltrate

was concentrated, dissolved in ethyl acetate, washed (water

and brine), dried (Na₂SO₄), and concentrated. Excess methyl

3,3-dimethylacrylate was removed under high vacuum.

Chromatography [silica, hexanes/ethyl acetate (3:1)]

4.3.18. Methyl 3,3-dimethyl-4-nitro-5-(2-pyrroyl)penta-

noate (16) via a solventless procedure with DBU. Follow-

ing a general procedure,¹⁸a mixture of 9 (0.220 g,

1.57 mmol) and methyl 3,3-dimethylacrylate (0.96 mL,

H.-J. Kim et al. / Tetrahedron 63 (2007) 37–55

49

afforded a brown oil (3.25 g, 43%). The data (¹H NMR, ¹³

NMR, and FABMS) were consistent with those obtained

from samples prepared via the solventless method.

C

(w20 mL). The ﬁltrate was neutralized with saturated aque-

ous NaHCO₃, washed (water and brine), dried (Na₂SO₄),

and concentrated. The crude product was chromatographed

[silica, hexanes/ethyl acetate/methanol (8:5:2)] to afford

white crystals (35 mg, 45%). The characterization data

4.3.22. 2,3,4,5-Tetrahydro-3,3-dimethyldipyrrin-1(10H)-

one (17) via Zn/HCO₂NH₄. Following a general proce-

dure,¹⁸a solution of 16 (0.153 g, 0.600 mmol) in ethanol

(1.2 mL) was treated with HCO₂NH₄(0.378 g, 6.00 mmol)

and zinc dust (0.589 g, 9.00 mmol). The mixture was stirred

overnight at room temperature. The crude reaction mixture

was diluted with ethyl acetate and ﬁltered. The ﬁlter cake

was washed with ethyl acetate. The ﬁltrate was washed (wa-

ter and brine), dried (Na₂SO₄), and concentrated to give a red

oil. Chromatography [silica, hexanes/ethyl acetate/methanol

(8:5:2)] afforded a brown solid (10 mg, 9%) and a byproduct

identiﬁed as 2,3,4,5-tetrahydro-1-hydroxy-3,3-dimethyldi-

pyrrin (17-OH) (23 mg, 18%). Data for 17: mp 92–94 ^ꢁC;

¹H NMR d 1.12 (s, 3H), 1.16 (s, 3H), 2.15–2.25 (m, 2H),

2.56 (ABX, ³J¼11.2 Hz, ²J¼14.4 Hz, 1H), 2.84 (ABX, ³J¼

2.8 Hz, ²J¼14.4 Hz, 1H), 3.48 (ABX, ³J¼2.8 Hz, ²J¼

11.2 Hz, 1H), 5.62–5.78 (br s, 1H), 5.94–6.20 (m, 1H),

6.14–6.16 (m, 1H), 6.69–6.71 (m, 1H), 8.10–8.25 (br s,

1H); ¹³C NMR d 22.9, 27.6, 29.3, 38.7, 46.3, 64.5, 106.7,

108.9, 117.7, 128.5, 177.2; FABMS obsd 193.1337, calcd

193.1341 [(M+H)⁺, M¼C₁₁H₁₆N₂O]. Data for 17-OH: mp

1

(mp, H NMR, ¹³C NMR, and FABMS) were consistent

with those obtained from samples prepared via reduction

with Zn/HCO₂NH₄.

4.3.25. 2,3,4,5-Tetrahydro-3,3-dimethyldipyrrin-1(10H)-

thione (18). Following a general procedure²⁴with slight

modiﬁcation, a mixture of 17 (0.0634 g, 0.330 mmol) and

Lawesson’s reagent (0.154 g, 0.382 mmol) in anhydrous

toluene (14 mL) was reﬂuxed overnight. The reaction mix-

ture was then concentrated and chromatographed [silica,

CH₂Cl₂/ethyl acetate (5:3)] to afford a white solid

1

(0.029 g, 43%): mp 105–108 ^ꢁC; H NMR d 1.09 (s, 3H),

3

2

1.24 (s, 3H), 2.63 (ABX, J¼11.4 Hz, J¼14.8 Hz, 1H),

2.74 (s, 2H), 2.84 (ABX, ³J¼3.3 Hz, ²J¼14.8 Hz, 1H),

3

3.75 (ABX, J¼3.3 Hz, J¼11.4 Hz, 1H), 5.98–6.04 (m,

1H), 6.15–6.18 (m, 1H), 6.71–6.73 (m, 1H), 7.50–7.62 (br

s, 1H), 8.02–8.18 (br s, 1H); ¹³C NMR d 22.4, 26.8, 28.2,

41.3, 58.4, 70.7, 107.0, 109.4, 118.0, 127.3, 204.9; FABMS

obsd 209.1103, calcd 209.1112 [(M+H)⁺, M¼C₁₁H₁₆N₂S].

1

120–122 ^ꢁC; H NMR d 1.13 (s, 3H), 1.20 (s, 3H), 1.81

4.3.26. 2,3,4,5-Tetrahydro-1-methylsulfanyl-3,3-di-

methyldipyrrin (19). Following a reported procedure,²⁴

a solution of 18 (0.023 g, 0.11 mmol) in THF (3 mL) was

treated ﬁrst with Ag₂CO₃(0.097 g, 0.35 mmol) and then

dropwise with MeI (22 mL, 0.35 mmol). The mixture was

stirred at 55 ^ꢁC for 4 h under argon. The reaction mixture

was washed (5% aqueous NaHCO₃, water, and brine), dried,

and concentrated. Chromatography [silica, hexanes/ethyl

acetate (1:1)] afforded a white solid (0.012 g, 49%): mp

2

(AB, J¼16.4 Hz, 1H), 1.96 (AB, J¼16.4 Hz, 1H), 2.96

(ABX, ³J¼3.7 Hz, ²J¼15.6 Hz, 1H), 3.11 (ABX, ³J¼

3.7 Hz, ²J¼15.6 Hz, 1H), 3.54–3.69 (m, 1H), 5.95–6.02

(m, 1H), 6.04–6.14 (m, 1H), 6.59–6.72 (m, 1H), 9.02–9.07

(br s, 1H) (the OH proton was not observed); ¹³C NMR

d 22.7, 26.5, 29.7, 35.1, 43.0, 69.9, 108.05, 108.09, 117.9,

126.9, 170.8; FABMS obsd 209.1291, calcd 209.1290

[(M+H)⁺, M¼C₁₁H₁₆N₂O₂].

1

112–115 ^ꢁC; H NMR d 0.98 (s, 3H), 1.15 (s, 3H), 2.41–

4.3.23. Synthesis of 17 via Zn/AcOH. Following a general

procedure,¹²a solution of 16 (0.255 g, 1.00 mmol) in etha-

nol (5.0 mL) was treated with AcOH (5.0 mL). The reaction

mixture changed immediately from dark brown to dark red.

Zinc dust (1.64 g, 25.0 mmol) was added in portions over

5 min. The resulting mixture was stirred overnight at room

temperature. The mixture was diluted with ethyl acetate

and ﬁltered. The ﬁltrate was neutralized with saturated aque-

ous NaHCO₃, washed (water and brine), dried, and concen-

trated. The resulting light brown crude mixture was

chromatographed [silica, hexanes/ethyl acetate/methanol

(8:5:2)]. The ﬁrst fraction contained the title compound,

which was isolated and concentrated to afford light brown

crystals (60 mg, 30%). The second fraction was isolated

(41 mg) and found to contain a mixture of 17 and 17-OH.

Further chromatography of the second fraction gave

17-OH as a red-brown solid (20 mg, 10%). The data for

2.45 (m, 1H), 2.50 (s, 3H), 2.51–2.54 (m, 1H), 2.59–2.66

(m, 1H), 2.77–2.82 (m, 1H), 3.67–3.71 (m, 1H), 5.95–5.99

(m, 1H), 6.12–6.14 (m, 1H), 6.72–6.73 (m, 1H), 9.76–9.84

(br s, 1H); ¹³C NMR d 13.8, 22.8, 27.1, 28.2, 43.0, 53.8,

80.3, 105.6, 107.7, 116.7, 131.8, 172.7; FABMS obsd

223.1263, calcd 223.1269 [(M+H)⁺, M¼C₁₂H₁₈N₂S].

4.3.27. 1-(1,3-Dithian-2-yl)-1,2,3,4-tetrahydro-3,3-di-

methyldipyrromethane (20aP). Following a general proce-

dure,³⁶a mixture of 20aP-Ts (86 mg, 0.19 mmol) in

2-propanol (1.3 mL) and 10 N aqueous NaOH (2.0 mL)

was stirred under reﬂux for 3 days. After cooling to room

temperature, the mixture was concentrated at reduced pres-

sure. The resulting residue was extracted with CH₂Cl₂.

The organic extract was dried (Na₂SO₄), concentrated, and

chromatographed (silica, ethyl acetate) to give a colorless

1

oil (27 mg, 47%): H NMR d 1.03 (s, 3H), 1.04 (s, 3H),

1

17 and 17-OH (mp, H NMR, ¹³C NMR, and FABMS)

1.69–1.83 (m, 2H), 1.85–1.92 (m, 1H), 2.10–2.16 (m, 1H),

2.20–2.31 (br s, 1H), 2.40–2.49 (m, 1H), 2.67–2.72 (m,

1H), 2.82–2.88 (m, 5H), 3.40–3.47 (m, 1H), 4.10 (d,

J¼7.2 Hz, 1H), 5.88–5.91 (m, 1H), 6.09–6.11 (m, 1H),

6.69–6.71 (m, 1H), 9.40–9.67 (br s, 1H); ¹³C NMR d 24.0,

26.4, 28.3, 30.0, 30.2, 30.3, 41.5, 44.1, 54.8, 59.6, 68.4,

105.5, 107.7, 116.7, 131.6; FABMS obsd 297.1462, calcd

297.1459 [(M+H)⁺, M¼C₁₅H₂₄N₂S₂].

were consistent with those obtained from samples prepared

via reduction with Zn/HCO₂NH₄.

4.3.24. Synthesis of 17 via Zn/HCO₂H. Following a general

procedure,³²a solution of 16 (0.101 g, 0.400 mmol) in etha-

nol (3.6 mL) was treated with formic acid (0.9 mL) and zinc

dust (0.65 g, 10 mmol). The resulting mixture was stirred

overnight at room temperature. The mixture was diluted

with ethyl acetate and then ﬁltered through a sintered glass

funnel. The ﬁltered material was washed with ethyl acetate

4.3.28. 1-(1,3-Dithian-2-yl)-1,2,3,4-tetrahydro-3,3-

dimethyldipyrromethane (20bP). Following a general

50

H.-J. Kim et al. / Tetrahedron 63 (2007) 37–55

procedure,³⁶a mixture of 20bP-Ts (210 mg, 0.466 mmol) in

2-propanol (3.00 mL) and 5 N aqueous NaOH (2.50 mL)

was stirred at reﬂux for 3 days. After cooling to room tem-

perature, the mixture was concentrated at reduced pressure.

The resulting residue was extracted with CH₂Cl₂. The or-

ganic extract was dried (Na₂SO₄), concentrated, and chro-

matographed (silica, ethyl acetate) to give a light brown

4.3.30. 1-(Dimethoxymethyl)-2,3,4,5-tetrahydro-3,3-di-

methyldipyrrin (21P). Following a general procedure,³⁶

a mixture of 21P-Ts (491 mg, 1.21 mmol) in 2-propanol

(12 mL) and 5 N aqueous NaOH (12 mL) was stirred under

reﬂux for 10 days. After cooling to room temperature, water

(50 mL) was added to the mixture. The mixture was

extracted with ethyl acetate. The organic extract was washed

with water, dried (Na₂SO₄), concentrated, and chromato-

graphed [silica, CH₂Cl₂/ethyl acetate (4:1)] to give a color-

1

solid (61 mg, 44%): mp 108–110 ^ꢁC; H NMR d 0.89 (s,

3H), 1.02 (s, 3H), 1.69 (ABX, ³J¼8.4 Hz, ²J¼12.8 Hz,

3

2

1

1H), 1.84 (ABX, J¼7.6 Hz, J¼12.8 Hz, 1H), 1.82–1.93

less oil (131 mg, 43%): H NMR d 0.96 (s, 3H), 1.12 (s,

3

2

(m, 1H), 2.04–2.17 (m, 2H), 2.41 (ABX, J¼10.4 Hz, J¼

15.4 Hz, 1H), 2.76 (ABX, ³J¼2.8 Hz, ²J¼15.4 Hz, 1H),

3H), 2.39–2.51 (m, 2H), 2.64 (ABX, ³J¼11.4 Hz, ²J¼

14.6 Hz, 1H), 2.83 (ABX, ³J¼3.2 Hz, ²J¼14.6 Hz, 1H),

3.43 (s, 3H), 3.44 (s, 3H), 3.70–3.76 (m, 1H), 4.81 (s, 1H),

5.93–5.97 (m, 1H), 6.09–6.12 (m, 1H), 6.69–6.73 (m, 1H),

9.53–9.63 (br s, 1H); ¹³C NMR d 22.9, 27.4, 28.1, 41.4,

48.8, 54.7, 54.8, 80.6, 103.1, 105.6, 107.6, 116.8, 131.4,

174.2; FABMS obsd 251.1753, calcd 251.1760 [(M+H)⁺,

M¼C₁₄H₂₂N₂O₂].

3

2.80–2.88 (m, 4H), 2.95 (ABX, J¼2.8 Hz, J¼10.4 Hz,

1H), 3.47–3.53 (m, 1H), 4.04 (d, J¼7.2 Hz, 1H), 5.90–

5.94 (m, 1H), 6.10–6.13 (m, 1H), 6.68–6.71 (m, 1H),

9.15–9.27 (br s, 1H); ¹³C NMR d 21.2, 25.8, 26.3, 28.2,

30.1, 42.4, 46.1, 55.0, 58.8, 67.4, 105.5, 108.1, 116.6,

130.7; FABMS obsd 297.1466, calcd 297.1459 [(M+H)⁺,

M¼C₁₅H₂₄N₂S₂].

4.3.31. 1-(Dimethoxymethyl)-2,3,4,5-tetrahydro-3,3-di-

methyldipyrrin (21P) from 31. Following a general proce-

dure,¹²a sample of TiCl₄(86 mL, 0.79 mmol) was slowly

added with stirring to dry THF (2.0 mL) under argon at

0 ^ꢁC. The resulting yellow solution was slowly treated

with LiAlH₄(20 mg, 0.53 mmol). The resulting black mix-

ture was stirred at room temperature for 15 min. TEA

(0.690 mL, 4.95 mmol) was added. The resulting black mix-

ture was stirred for 2 min at room temperature. The black

mixture was slowly poured into a solution of 31 (30 mg,

0.11 mmol) in dry THF (1.5 mL) at 0 ^ꢁC. The mixture was

stirred for 30 min at room temperature, and then water

(4 mL) was added. The resulting mixture was extracted

with CH₂Cl₂and ethyl acetate. The organic extract was

washed with water, dried (Na₂SO₄), and chromatographed

[silica, CH₂Cl₂/ethyl acetate (4:1)] to give a colorless oil

(2.2 mg, 8%). The characterization data were identical

with those described above.

4.3.29. 9-(1,3-Dithian-2-yl)-6,7,8,9-tetrahydro-7,7-di-

methyl-N¹⁰-p-tosyldipyrromethane (20P-Ts). Following

a procedure for organolithium addition to imines,³⁸a solu-

tion of 1,3-dithiane (919 mg, 7.64 mmol) in dry THF

(8 mL) at ꢀ20 ^ꢁC (salt ice bath) was treated with n-butyl

lithium (3.10 mL, 2.5 M in hexane, 7.64 mmol) followed

by stirring for 30 min at ꢀ20 ^ꢁC. The ﬂask was then cooled

to ꢀ78 ^ꢁC. A sample of 6-Ts (630 mg, 1.91 mmol) was

added, and the mixture was stirred for 1 h at ꢀ20 ^ꢁC. The

ﬂask was placed in a bath at ꢀ78 ^ꢁC and stirred for 5 min.

The reaction was quenched by the addition of saturated

aqueous NH₄Cl (20 mL). The mixture was extracted with

CH₂Cl₂. The organic extract was dried (Na₂SO₄) and con-

centrated. TLC analysis [silica, hexanes/ethyl acetate (9:1)]

showed two components with R_f¼0.67 (20aP-Ts, minor)

and R_f¼0.47 (20b-Ts, major). Column chromatography

[silica, hexanes/ethyl acetate (7:3)] afforded each isomer

as a light yellow oil. Each oil solidiﬁed upon cooling to

give a light brown solid (20aP-Ts, 98 mg, 11%; 20bP-Ts,

151 mg, 18%). Data for 20aP-Ts: mp 103–105 ^ꢁC; ¹H

4.3.32. 1-(Dimethoxymethyl)-2,3,4,5-tetrahydro-3,3-di-

methyl-N¹¹-p-tosyldipyrrin (21P-Ts). Following a general

procedure,¹²TiCl₄(1.22 mL, 11.1 mmol) was slowly added

with stirring to dry THF (30 mL) under argon at 0 ^ꢁC. The

resulting yellow solution was slowly treated with LiAlH₄

(280 mg, 7.39 mmol). The resulting black mixture was

stirred at room temperature for 15 min. TEA (9.66 mL,

69.3 mmol) was added. The resulting black mixture was

stirred for 2 min at room temperature. The black mixture

was slowly poured into a solution of 29-Ts (648 mg,

1.54 mmol) in dry THF (25 mL). The mixture was stirred

for 30 min at room temperature, and then water (30 mL)

was added. The mixture was extracted with CH₂Cl₂and

ethyl acetate. The organic extract was washed with water,

dried (Na₂SO₄), and chromatographed [silica, CH₂Cl₂/ethyl

acetate (4:1)] to give a colorless oil (525 mg, 84%): ¹H NMR

d 0.90 (s, 3H), 1.08 (s, 3H), 2.40 (s, 3H), 2.37–2.49 (m, 2H),

3

NMR d 0.97 (s, 3H), 1.02 (s, 3H), 1.59 (ABX, J¼8.0 Hz,

²J¼13.2 Hz, 1H), 1.79 (ABX, ³J¼8.4 Hz, ²J¼13.2 Hz,

1H), 1.84–1.93 (m, 2H), 2.03–2.08 (m, 1H), 2.40 (s, 3H),

2.48–2.55 (m, 1H), 2.77–2.95 (m, 6H), 3.21–3.27 (m, 1H),

3.90 (d, J¼8.4 Hz, 1H), 6.11–6.13 (m, 1H), 6.18–6.20 (m,

1H), 7.25–7.28 (m, 1H), 7.27 (d, J¼8.4 Hz, 2H), 7.60 (d,

J¼8.4 Hz, 2H); ¹³C NMR d 21.6, 24.5, 25.9, 27.7, 29.0,

29.3, 29.5, 39.1, 45.2, 53.2, 58.1, 66.2, 111.6, 113.5,

122.8, 126.5, 130.0, 133.9, 136.6, 144.7; FABMS obsd

451.1540, calcd 451.1548 [(M+H)⁺, M¼C₂₂H₃₀N₂O₂S₃].

Anal. Calcd for C₂₂H₃₀N₂O₂S₃: C, 58.63; H, 6.71; N, 6.22.

Found: C, 58.42; H, 6.75; N, 5.96. Data for 20bP-Ts: mp

1

126–128 ^ꢁC; H NMR d 0.90 (s, 3H), 1.00 (s, 3H), 1.65

(ABX, ³J¼8.6 Hz, ²J¼12.8 Hz, 1H), 1.77 (ABX, ³J¼

7.2 Hz, ²J¼12.8 Hz, 1H), 1.83–1.90 (m, 1H), 1.93–2.01

(br s, 1H), 2.03–2.10 (m, 1H), 2.39 (s, 3H), 2.39–2.46 (m,

1H), 2.71–2.86 (m, 5H), 3.02–3.05 (m, 1H), 3.42–3.48 (m,

1H), 3.90 (d, J¼7.2 Hz, 1H), 6.15–6.18 (m, 1H), 6.18–

6.21 (m, 1H), 7.25–7.27 (m, 1H), 7.27 (d, J¼8.4 Hz, 2H),

7.61 (d, J¼8.4 Hz, 2H); ¹³C NMR d 21.5, 21.6, 25.9, 26.0,

28.8, 29.3, 29.4, 41.2, 45.5, 54.2, 57.7, 64.8, 111.6, 113.1,

122.5, 126.6, 129.9, 133.7, 136.5, 144.7; FABMS obsd

451.1556, calcd 451.1548 [(M+H)⁺, M¼C₂₂H₃₀N₂O₂S₃].

3

2

3

2.72 (ABX, J¼9.6 Hz, J¼16.0 Hz, 1H), 2.98 (ABX, J¼

2

4.8 Hz, J¼16.0 Hz, 1H), 3.38 (s, 3H), 3.39 (s, 3H), 3.81–

3.85 (m, 1H), 4.79 (s, 1H), 6.21–6.24 (m, 2H), 7.27 (d, J¼

8.4 Hz, 2H), 7.29–7.31 (m, 1H), 7.65 (d, J¼8.4 Hz, 2H);

¹³C NMR d 21.8, 22.8, 27.3, 28.2, 41.8, 48.7, 54.8, 54.9,

78.3, 103.2, 111.9, 113.9, 122.6, 127.0, 130.2, 133.9,

136.7, 145.0, 174.2; FABMS obsd 405.1840, calcd

405.1848 [(M+H)⁺, M¼C₂₁H₂₈N₂O₄S]. Anal. Calcd for

H.-J. Kim et al. / Tetrahedron 63 (2007) 37–55

51

C₂₁H₂₈N₂O₄S: C, 62.35; H, 6.98; N, 6.93. Found: C, 62.20;

H, 7.00; N, 6.70.

2H), 3.06 (ABX, ³J¼9.2 Hz, ²J¼16.0 Hz, 1H), 3.43

3

2

(ABX, J¼4.4 Hz, J¼16.0 Hz, 1H), 4.38–4.43 (m, 1H),

6.13–6.15 (m, 1H), 6.23–6.25 (m, 1H), 7.31 (d, J¼8.4 Hz,

2H), 7.32–7.34 (m, 1H), 7.68 (d, J¼8.4 Hz, 2H), 10.13 (s,

1H); ¹³C NMR d 21.8, 22.6, 24.9, 27.5, 38.1, 39.8, 83.0,

112.0, 115.6, 123.7, 127.0, 129.8, 130.3, 136.0, 141.7,

145.4, 183.4. Anal. Calcd for C₁₉H₂₂N₂O₄S: C, 60.94; H,

5.92; N, 7.48. Found: C, 60.91; H, 5.85; N, 7.51.

4.3.33. 4,4-Dimethyl-5-nitro-6-(N-p-tosyl-2-pyrrolyl)-2-

hexanone (22-Ts). Following a general procedure,¹²CsF

(526 mg, 3.47 mmol, 3.00 mol equiv, freshly dried by heat-

ing to 100 ^ꢁC under vacuum for 1 h and then cooled to

room temperature under argon) was placed in a ﬂask under

argon. A mixture of 9-Ts (340 mg, 1.16 mmol) and mesityl

oxide (10c, 1.98 mL, 17.3 mmol, 15.0 mol equiv) in dry

acetonitrile (12 mL) was cannulated into the ﬂask containing

CsF. The mixture was heated at 70 ^ꢁC for 16 h, whereupon

the reaction was deemed to be complete by TLC. The reac-

tion mixture was ﬁltered through a bed of silica. The ﬁltrate

was concentrated and chromatographed [alumina, hexanes/

ethyl acetate (3:1)] to give a pale yellow oil, which upon

cooling (w ꢀ6 ^ꢁC) gave a pale yellow solid (330 mg,

73%): mp 92–93 ^ꢁC; ¹H NMR d 1.14 (s, 3H), 1.25 (s, 3H),

4.3.36. 2,3,4,5-Tetrahydro-3,3-dimethyl-1-(1,3-dithian-2-

yl)-N¹¹-p-tosyldipyrrin N¹⁰-oxide (25-Ts). Following

a general procedure,⁴¹a solution of 24-Ts (100 mg,

0.27 mmol) and 1,3-propanedithiol (32 mL, 0.32 mmol) in

CH₂Cl₂(2.0 mL) was treated with neat BF₃$OEt₂(140 mL,

˚

1.1 mmol) and powdered molecular sieves (4 A,

w200 mg). The mixture was stirred for 2 h at 0 ^ꢁC, warmed

to room temperature, and stirred for 40 h. Saturated aqueous

NaHCO₃(w2 mL) was added to the reaction mixture. The

mixture was extracted with CH₂Cl₂. The organic extract

was washed with water, dried (Na₂SO₄), and concentrated.

The resulting residue was chromatographed [silica,

CH₂Cl₂/ethyl acetate (4:1)] to give a pale yellow oil

2

2.14 (s, 3H), 2.42 (s, 3H), 2.43, 2.57 (AB, J¼17.4 Hz,

2H), 3.21 (ABX, ³J¼2.2 Hz, ²J¼16.0 Hz, 1H), 3.37

(ABX, ³J¼12.0 Hz, ²J¼16.0 Hz, 1H), 5.12 (ABX, ³J¼

2.2 Hz, ³J¼12.0 Hz, 1H), 6.02–6.03 (m, 1H), 6.16–6.18

(m, 1H), 7.24–7.26 (m, 1H), 7.32 (d, J¼8.4 Hz, 2H), 7.60

(d, J¼8.4 Hz, 2H); ¹³C NMR d 21.9, 23.8, 24.3, 26.7,

32.0, 36.9, 50.9, 94.2, 112.2, 114.8, 123.9, 126.6, 129.4,

130.4, 136.4, 145.4, 206.4. Anal. Calcd for C₁₉H₂₄N₂O₅S:

C, 58.15; H, 6.16; N, 7.14. Found: C, 58.21; H, 6.17; N, 7.10.

1

(52 mg, 42%): H NMR d 1.01 (s, 3H), 1.09 (s, 3H), 1.88–

2.00 (m, 1H), 2.11–2.18 (m, 1H), 2.39 (s, 3H), 2.53–2.56

(m, 2H), 2.85–2.92 (m, 2H), 2.99–3.10 (m, 3H), 3.42–3.48

(m, 1H), 4.13–4.17 (m, 1H), 5.66 (s, 1H), 6.11–6.13 (m,

1H), 6.20–6.22 (m, 1H), 7.29 (d, J¼8.4 Hz, 2H), 7.30–

7.32 (m, 1H), 7.70 (d, J¼8.4 Hz, 2H); ¹³C NMR d 21.8,

22.9, 24.8, 25.2, 28.2, 30.3, 37.7, 41.2, 43.0, 80.0, 111.8,

115.0. 123.2, 127.1, 130.3, 130.6, 135.9, 141.0, 145.3. The

limited stability of this compound prevented high-resolution

mass spectrometric analysis.

4.3.34. 2,3,4,5-Tetrahydro-1,3,3-trimethyl-N¹¹-p-tosyldi-

pyrrin N¹⁰-oxide (23-Ts). Following a general procedure,¹²

a vigorously stirred solution of 22-Ts (225 mg, 0.574 mmol)

in acetic acid (3.0 mL) and ethanol (3.0 mL) at 0 ^ꢁC was

treated slowly with zinc dust (932 mg, 14.3 mmol) in small

portions for 5 min. The reaction mixture was stirred at 0 ^ꢁC

for 15 min and then ﬁltered through Celite. The ﬁltrate

was concentrated under high vacuum. The resulting oil

was puriﬁed by column chromatography [silica, CH₂Cl₂/

ethyl acetate (1:1)/CH₂Cl₂/methanol (9:1)] to afford a

pale yellow oil (2-Ts, 47 mg, 24%) and the title compound

as a white solid (119 mg, 57%). Data for the title compound:

mp 123–125 ^ꢁC; ¹H NMR d 0.98 (s, 3H), 1.10 (s, 3H), 2.05–

2.06 (m, 3H), 2.39 (s, 3H), 2.39–2.41 (m, 2H), 3.15 (ABX,

³J¼10.4 Hz, ²J¼16.0 Hz, 1H), 3.49 (ABX, ³J¼3.4 Hz,

²J¼16.0 Hz, 1H), 4.08–4.12 (m, 1H), 6.08–6.09 (m, 1H),

6.20–6.22 (m, 1H), 7.29 (d, J¼8.2 Hz, 2H), 7.31–7.32

(m, 1H), 7.69 (d, J¼8.2 Hz, 2H); ¹³C NMR d 13.3, 21.8,

23.4, 25.0, 29.1, 36.8, 47.4, 79.6, 111.7, 114.2, 123.1,

127.1, 130.3, 131.1, 136.0, 143.2, 145.2. Anal. Calcd for

C₁₉H₂₄N₂O₃S: C, 63.31; H, 6.71; N, 7.77. Found: C,

63.27; H, 6.71; N, 7.70.

4.3.37. 2,3,4,5-Tetrahydro-3,3-dimethyl-1-(5,5-dimethyl-

1,3-dioxan-2-yl)-N¹¹-p-tosyldipyrrin N¹⁰-oxide (27-Ts).

Following a general procedure,⁴³a solution of 24-Ts

(224 mg, 0.600 mmol) and neopentyl glycol (81.0 mg,

0.78 mmol) in benzene (30.0 mL) was treated with p-

toluenesulfonic acid monohydrate (11.4 mg, 0.060 mmol).

The mixture was reﬂuxed for 2.5 h and then cooled. The re-

action mixture was washed with saturated aqueous NaHCO₃

and water. The organic layer was dried (Na₂SO₄), concen-

trated, and chromatographed [silica, CH₂Cl₂/ethyl acetate

(1:1)] to give a light brown solid (140 mg, 51%): mp 64–

1

65 ^ꢁC; H NMR d 0.75 (s, 3H), 1.00 (s, 3H), 1.09 (s, 3H),

1.21 (s, 3H), 2.39 (s, 3H), 2.54–2.56 (m, 2H), 3.10 (ABX, ³J¼

10.0 Hz, ²J¼16.0 Hz, 1H), 3.45 (ABX, ³J¼3.6 Hz, ²J¼

16.0 Hz, 1H), 3.56–3.61 (m, 2H), 3.63–3.69 (m, 2H), 4.15–

4.19 (m, 1H), 5.66 (s, 1H), 6.10–6.12 (m, 1H), 6.19–6.22

(m, 1H), 7.28 (d, J¼8.4 Hz, 2H), 7.30–7.32 (m, 1H), 7.69

(d, J¼8.4 Hz, 2H); ¹³C NMR d 21.8, 22.1, 23.1, 24.7, 28.5,

29.9, 30.6, 37.5, 41.4, 77.5, 80.9, 94.3, 111.7, 114.7, 123.2,

127.1, 130.3, 130.8, 136.1, 141.6, 145.2; FABMS obsd

461.2100, calcd 461.2110 [(M+H)⁺, M¼C₂₄H₃₂N₂O₅S].

4.3.35. 1-Formyl-2,3,4,5-tetrahydro-3,3-dimethyl-N¹¹-

p-tosyldipyrrin N¹⁰-oxide (24-Ts). Following a general

procedure,²⁷a solution of 23-Ts (590 mg, 1.64 mmol) in

1,4-dioxane (20.0 mL) was treated with SeO₂(272 mg,

2.46 mmol) under argon. The mixture was stirred for 2.5 h

at room temperature. The reaction mixture was treated

with saturated aqueous NaHCO₃(20 mL) and extracted

with CH₂Cl₂. The organic extract was washed with water,

dried (Na₂SO₄), and chromatographed [silica, CH₂Cl₂/ethyl

acetate (9:1)] to give a light brown solid (448 mg, 73%): mp

4.3.38. 1-(5,5-Dimethyl-1,3-dioxan-2-yl)-2,3,4,5-tetra-

hydro-3,3-dimethyl-N¹¹-p-tosyldipyrrin (28-Ts). Follow-

ing a general procedure,¹²TiCl₄(222 mL, 2.02 mmol) was

slowly added with stirring to dry THF (5.0 mL) under argon

at 0 ^ꢁC. The resulting yellow solution was slowly treated

with LiAlH₄(51.0 mg, 1.35 mmol). The resulting black

mixture was stirred at room temperature for 15 min. TEA

(1.78 mL, 12.8 mmol) was added. The resulting black

1

140–142 ^ꢁC; IR 2965, 1665, 1524, 1368 cm^ꢀ1; H NMR

d 1.06 (s, 3H), 1.10 (s, 3H), 2.41 (s, 3H), 2.57–2.59 (m,

52

H.-J. Kim et al. / Tetrahedron 63 (2007) 37–55

mixture was stirred for 2 min at room temperature. The black

mixture was slowly poured into a solution of 27-Ts (130 mg,

0.282 mmol) in dry THF (4.0 mL) at 0 ^ꢁC. The mixture was

stirred for 30 min at room temperature, and then water

(8.0 mL) was added. The reaction mixture was extracted

with CH₂Cl₂and ethyl acetate. The organic extract was

washed with water, dried (Na₂SO₄), and chromatographed

[silica, CH₂Cl₂/ethyl acetate (19:1)] to give a colorless oil

203.8; FABMS obsd 299.1605, calcd 299.1607. Anal. Calcd

for C₁₄H₂₂N₂O₅: C, 56.36; H, 7.43; N, 9.39. Found: C,

56.44; H, 7.57; N, 9.38.

4.3.41. Solventless synthesis of 30. Following a reported

procedure,¹⁸a sample of 9 (1.44 g, 10.0 mmol) was treated

with 10d (1.90 g, 12.0 mmol) and DBU (4.57 g,

30.0 mmol). The reaction mixture was stirred for 16 h and

then diluted with CH₂Cl₂. The mixture was washed with

water and brine. The organic layer was dried (Na₂SO₄),

concentrated, and chromatographed (silica, CH₂Cl₂) to

give a light brown oil, which solidiﬁed to a pale-brown solid

(1.75 g, 53%). The characterization data were identical as

those described above.

1

(116 mg, 92%): H NMR d 0.74 (s, 3H), 0.89 (s, 3H), 1.09

(s, 3H), 1.22 (s, 3H), 2.39 (s, 3H), 2.52–2.54 (m, 2H),

2.71 (ABX, ³J¼9.6 Hz, ²J¼16.0 Hz, 1H), 2.99 (ABX,

³J¼4.4 Hz, ²J¼16.0 Hz, 1H), 3.48–3.52 (m, 2H), 3.63–

3.68 (m, 2H), 3.79–3.84 (m, 1H), 5.04 (s, 1H), 6.20–6.22

(m, 1H), 6.22–6.24 (m, 1H), 7.26 (d, J¼8.4 Hz, 2H), 7.28–

7.29 (m, 1H), 7.64 (d, J¼8.4 Hz, 2H); ¹³C NMR d 21.8,

22.0, 22.7, 23.1, 27.1, 27.8, 30.5, 41.7, 48.6, 77.2, 78.3,

99.8, 111.8, 113.8, 122.4, 127.0, 130.1, 133.9, 136.6,

144.9, 173.8; FABMS obsd 445.2152, calcd 445.2161

[(M+H)⁺, M¼C₂₄H₃₂N₂O₄S].

4.3.42. 2,3,4,5-Tetrahydro-1-(dimethoxymethyl)-3,3-di-

methyldipyrrin N¹⁰-oxide (31). Following a general proce-

dure,¹²a vigorously stirred solution of 30 (60 mg, 0.20 mmol)

in acetic acid (1.0 mL) and ethanol (1.0 mL) at 0 ^ꢁC was

treated slowly with zinc dust (330 mg, 5.0 mmol) in small

portions for 5 min. The reaction mixture was stirred at

0 ^ꢁC for 15 min and ﬁltered through Celite. The ﬁltrate was

concentrated under high vacuum. The resulting oil was chro-

matographed [alumina, CH₂Cl₂/ethyl acetate (9:1)] to afford

a white solid (9.0 mg, 17%): mp 68–70 ^ꢁC; ¹H NMR d 1.11

(s, 3H), 1.21 (s, 3H), 2.47, 2.53 (AB, ²J¼17.8 Hz, 2H), 2.96

(ABX, ³J¼1.6 Hz, ²J¼15.8 Hz, 1H), 3.07 (ABX, ³J¼

4.3.39. 1-(Dimethoxymethyl)-2,3,4,5-tetrahydro-3,3-

dimethyl-N¹¹-p-tosyldipyrrin N¹⁰-oxide (29-Ts). Follow-

ing a general procedure,⁴⁴aldehyde 24-Ts (287 mg,

0.766 mmol) was dissolved in a methanolic solution of

LaCl₃$7H₂O (0.40 M, 1.9 mL). The resulting mixture was

treated with trimethyl orthoformate (758 mL, 6.93 mmol)

and stirred for 3 h at room temperature. The mixture was

poured into 5% aqueous NaHCO₃(16 mL). The mixture

was extracted with ethyl acetate. The organic extract was

dried (Na₂SO₄), concentrated, and chromatographed [silica,

CH₂Cl₂/ethyl acetate (4:1)] to afford a white solid (180 mg,

56%): mp 108–109 ^ꢁC; ¹H NMR d 1.01 (s, 3H), 1.09 (s, 3H),

2.39 (s, 3H), 2.47–2.49 (m, 2H), 3.06–3.13 (m, 1H), 3.47 (s,

6H), 3.46–3.51 (m, 1H), 4.18–4.22 (m, 1H), 5.48 (s, 1H),

6.10–6.12 (m, 1H), 6.20–6.22 (m, 1H), 7.29 (d, J¼8.4 Hz,

2H), 7.30–7.32 (m, 1H), 7.69 (d, J¼8.4 Hz, 2H); ¹³C

NMR d 21.8, 23.1, 24.8, 28.4, 37.7, 42.1, 55.4, 55.7, 80.7,

97.9, 111.8, 114.8. 123.3, 127.1, 130.3, 130.7, 136.0,

142.8, 145.3. Anal. Calcd for C₂₁H₂₈N₂O₅S: C, 59.98; H,

6.71; N, 6.66. Found: C, 59.82; H, 6.70; N, 6.50.

2

7.6 Hz, J¼15.8 Hz, 1H), 3.43 (s, 3H), 3.46 (s, 3H), 3.95

(ABX, ³J¼1.6 Hz, ²J¼7.6 Hz, 1H), 5.48 (s, 1H), 5.92–5.95

(m, 1H), 6.06–6.09 (m, 1H), 6.68–6.71 (m, 1H), 10.31–10.45

(br s, 1H); ¹³C NMR d 22.8, 25.5, 27.3, 38.4, 42.2, 55.3,

55.5, 82.9, 97.6, 106.4, 107.5, 117.8, 128.9, 145.1; FABMS

obsd 266.1630, calcd 266.1630 (M¼C₁₄H₂₂N₂O₃).

4.3.43. 2,3-Dihydro-1-(dimethoxymethyl)-3,3-dimethyl-

dipyrrin (32P). Following a general procedure,¹⁰a solution

of acetal 30 (149 mg, 0.500 mmol) in dry THF (5.0 mL) was

treated with sodium methoxide (135 mg, 2.50 mmol). The

resulting mixture was stirred at room temperature under

argon for 1 h to form the nitronate anion. TiCl₃(8.6 wt %

TiCl₃in 28 wt % HCl, 3.74 mL, 2.50 mmol, 5 mol equiv)

was placed in a ﬂask to which 20 mL of water was added.

Ammonium acetate (15.4 g, 200 mmol, 400 mol equiv)

was added to buffer the solution to pHw6 (pH meter), and

then 1.2 mL of THF was added. The nitronate anion in

THF was added to the buffered TiCl₃solution. The resulting

mixture was stirred at room temperature for 4.5 h. The reac-

tion mixture was extracted with ethyl acetate. The organic

layer was washed [aqueous NaHCO₃(10% w/v, 40 mL)

and water], dried, and concentrated under reduced pressure.

The resulting oil was puriﬁed by column chromatography

[alumina, packed in hexanes and eluted with hexanes/ethyl

4.3.40. 1,1-Dimethoxy-4,4-dimethyl-5-nitro-6-(2-pyr-

rolyl)-2-hexanone (30). Following a general procedure,¹²

CsF (8.97 g, 59.1 mmol, 3.00 mol equiv, freshly dried by

heating to 100 ^ꢁC under vacuum for 1 h and then cooled to

room temperature under argon) was placed in a ﬂask under

argon. A mixture of 9 (2.76 g, 19.7 mmol) and acetal 10d

(13.7 g, 86.6 mmol, 4.40 mol equiv) in 170 mL of dry aceto-

nitrile was cannulated into the ﬂask containing CsF. The

mixture was heated at 65 ^ꢁC for 14 h, whereupon the reac-

tion was deemed to be complete by TLC. The reaction mix-

ture was ﬁltered through a bed of alumina (ethyl acetate).

The ﬁltrate was concentrated and chromatographed [silica,

hexanes/ethyl acetate (3:1)] to afford a brown oil containing

some impurities. Chromatography (silica, CH₂Cl₂) gave

1

acetate (2:1)] to give a yellow oil (17 mg, 14%): H NMR

d 1.21 (s, 6H), 2.61 (s, 2H), 3.45 (s, 6H), 5.02 (s, 1H), 5.88

(s, 1H), 6.15–6.18 (m, 1H), 6.83–6.86 (m, 1H), 10.59–

10.70 (br s, 1H); ¹³C NMR d 29.3, 40.2, 48.3, 54.8, 103.0,

107.7, 108.7, 109.4, 119.6, 130.9, 159.5, 174.1; l_abs

(CH₂Cl₂) 341 nm. The limited stability of this compound

thwarted high-resolution mass spectrometric analysis.

1

a light brown solid (1.99 g, 34%): mp 74–75 ^ꢁC; H NMR

2

d 1.14 (s, 3H), 1.23 (s, 3H), 2.60, 2.72 (AB, J¼18.6 Hz,

2H), 3.03 (ABX, ³J¼2.4 Hz, ²J¼15.6 Hz, 1H), 3.36

3

2

(ABX, J¼11.8 Hz, J¼15.6 Hz, 1H), 3.43 (s, 3H), 3.44

3

(s, 3H), 4.36 (s, 1H), 5.15 (ABX, J¼2.4 Hz, J¼11.8 Hz,

1H), 5.97–5.99 (m, 1H), 6.08–6.11 (m, 1H), 6.65–6.67 (m,

1H), 8.00–8.13 (br s, 1H); ¹³C NMR d 24.4, 24.5, 26.9,

36.6, 45.3, 55.4, 95.0, 104.9, 107.5, 108.9, 117.9, 126.2,

4.3.44. 2,3,4,5-Tetrahydro-1-(a-hydroxy-a-phenyl-

methyl)-3,3-dimethyl-N¹¹-p-tosyldipyrrin N¹⁰-oxide

(33-Ts). A solution of 24-Ts (573 mg, 1.53 mmol) in dry

H.-J. Kim et al. / Tetrahedron 63 (2007) 37–55

53

THF (23.0 mL) at 0 ^ꢁC was treated with PhMgBr (1.84 mL,

1.0 M in THF, 1.84 mmol). The mixture was stirred for 1.5 h

at 0 ^ꢁC. The reaction was quenched by the addition of

H₂O/hexanes (20 mL). The reaction mixture was extracted

with ethyl acetate. The organic layer was washed with water

and brine. TLC analysis (silica, ethyl acetate) showed two

components with R_f¼0.65 (33a-Ts) and R_f¼0.49 (33b-

Ts). Column chromatography (silica, ethyl acetate) afforded

the two isomers as a light brown solid (33a-Ts, 113 mg,

16%) and a white solid (33b-Ts, 126 mg, 18%). Data for

and chromatographed [silica, hexanes/ethyl acetate (1:1)] to

give a light brown solid (13 mg, 43%): mp 115–117 ^ꢁC

(dec); H NMR d 1.09 (s, 3H), 1.27 (s, 3H), 2.60 (AB,

1

²J¼17.2 Hz, 1H), 2.66 (AB, J¼17.2 Hz, 1H), 2.84 (ABX,

2

3

2

³J¼2.2 Hz, J¼16.0 Hz, 1H), 3.08 (ABX, J¼8.2 Hz, J¼

16.0 Hz, 1H), 4.06–4.11 (m, 1H), 5.88–5.90 (m, 1H),

5.99–6.01 (m, 1H), 9.64–9.74 (br s, 1H), 10.20 (s, 1H);

¹³C NMR d 22.2, 25.2, 26.4, 38.9, 39.9, 85.4, 97.4, 108.7,

110.0, 129.8, 142.7, 183.1; FABMS obsd 299.0385, calcd

299.0395 [(M+H)⁺, M¼C₁₂H₁₅BrN₂O₂].

1

33a-Ts: mp 62–64 ^ꢁC; H NMR d 0.89 (s, 3H), 1.01 (s,

2

3H), 2.18, 2.32 (AB, J¼17.6 Hz, 2H), 2.40 (s, 3H), 3.07

4.3.47. 6-(5-Formylpyrrol-2-yl)-1,1-dimethoxy-4,4-

dimethyl-5-nitrohexan-2-one (36). A solution of 30

(0.289 g, 1.00 mmol) in CH₂Cl₂(2 mL) and DMF (1 mL)

was treated dropwise at 0 ^ꢁC with POCl₃(0.100 mL,

1.09 mmol). The resulting mixture was stirred at 0 ^ꢁC for

1 h, and then poured into ice-cooled 10% aqueous NaOH

(20 mL). The resulting mixture was stirred for 30 min, and

then extracted with CH₂Cl₂. The organic extract was washed

(water and brine), dried (Na₂SO₄), and concentrated. Chro-

matography (silica, CH₂Cl₂) afforded a yellow oil, which so-

lidiﬁed to a yellow solid (0.111 g, 35%): mp 103–104 ^ꢁC; ¹H

(ABX, ³J¼9.8 Hz, ²J¼15.8 Hz, 1H), 3.47 (ABX,

2

³J¼4.2 Hz, J¼15.8 Hz, 1H), 4.21–4.25 (m, 1H), 5.62 (s,

1H), 6.07–6.09 (m, 1H), 6.18–6.20 (m, 1H), 6.86–6.97 (br

s, 1H), 7.29 (d, J¼8.2 Hz, 2H), 7.29–7.31 (m, 1H), 7.32–

7.35 (m, 1H), 7.36–7.42 (m, 2H), 7.42–7.46 (m, 2H), 7.68

(d, J¼8.2 Hz, 2H); ¹³C NMR d 21.8, 22.7, 24.7, 28.1,

37.9, 44.0, 70.9, 80.3, 111.9, 114.9, 123.3, 126.5, 127.0,

128.5, 128.9, 130.3, 130.4, 135.9, 139.5, 145.3, 148.2;

FABMS obsd 453.1854, calcd 453.1848 (C₂₅H₂₈N₂O₄S).

Data for 33b-Ts: mp 156–158 ^ꢁC; ¹H NMR d 0.96 (s,

3H), 0.97 (s, 3H), 2.23–2.26 (m, 2H), 2.40 (s, 3H), 3.15

(ABX, ³J¼9.8 Hz, ²J¼16.0 Hz, 1H), 3.48 (ABX,

³J¼4.0 Hz, ²J¼16.0 Hz, 1H), 4.13–4.19 (m, 1H), 5.60–

5.62 (m, 1H), 6.09–6.11 (m, 1H), 6.20–6.22 (m, 1H),

7.01–7.03 (m, 1H), 7.30 (d, J¼8.6 Hz, 2H), 7.30–7.33

(m, 1H), 7.32–7.35 (m, 1H), 7.36–7.41 (m, 2H), 7.42–7.46

(m, 2H), 7.68 (d, J¼8.6 Hz, 2H); ¹³C NMR d 21.8, 22.9,

24.8, 28.3, 37.9, 44.2, 71.4, 80.7, 111.9, 114.8, 123.3,

126.6, 127.0, 128.6, 129.0, 130.3, 130.5, 136.0, 139.5,

145.4, 148.0; FABMS obsd 453.1859, calcd 453.1848

(C₂₅H₂₈N₂O₄S).

2

NMR d 1.16 (s, 3H), 1.26 (s, 3H), 2.64 (AB, J¼18.4 Hz,

2

3

1H), 2.72 (AB, J¼18.4 Hz, 1H), 3.16 (ABX, J¼2.4 Hz,

²J¼15.2 Hz, 1H), 3.42 (s, 3H), 3.43 (s, 3H), 3.45 (m, overlap-

ped, 1H), 4.35 (s, 1H), 5.23 (ABX, ³J¼2.4 Hz, ²J¼11.6 Hz,

1H), 6.10–6.11 (m, 1H), 6.86–6.88 (m, 1H), 6.38 (s, 1H),

10.42–10.46 (br s, 1H); ¹³C NMR d 24.2, 24.3, 27.1, 36.8,

45.0, 52.47, 52.51, 94.0, 105.0, 111.0, 122.9, 133.0, 136.8,

179.1, 203.6; FABMS obsd 327.1569, calcd 327.1556

[(M+H)⁺, M¼C₁₅H₂₂N₂O₆].

4.3.48. 9-Formyl-2,3-dihydro-1-(dimethoxymethyl)-3,3-

dimethyldipyrrin (37). Following a general procedure,¹⁸

a sample of 36 (32.6 mg, 0.100 mmol) in THF/H₂O (1 mL,

1:1) was treated with NH₄Cl (16.0 mg, 0.300 mmol) and

zinc dust (98.0 mg, 1.50 mmol). The resulting mixture was

stirred at room temperature for 1 h. Ethyl acetate (10 mL)

was added, and the resulting mixture was ﬁltered. The ﬁltrate

was washed (water and brine), dried (Na₂SO₄), and concen-

trated. Chromatography [silica, CH₂Cl₂/ethyl acetate (1:2)]

4.3.45. 9-Bromo-2,3,4,5-tetrahydro-1,3,3-trimethyl-

dipyrrin N¹⁰-oxide (34). Following a general procedure,¹⁰

a solution of 23 (413 mg, 2.00 mmol) in dry THF (20.0 mL)

was cooled to ꢀ78 ^ꢁC under argon. NBS (356 mg,

2.00 mmol) was added in two portions. The reaction mixture

was stirred for 1 h at ꢀ78 ^ꢁC. Hexanes (25 mL) and water

(25 mL) were added. The mixture was allowed to warm to

room temperature. The mixture was extracted with ethyl

acetate. The organic layer was dried (Na₂SO₄), concentrated

under vacuum without heat, and chromatographed (silica,

ethyl acetate) to give a white solid (453 mg, 79%): mp

124–125 ^ꢁC (dec); ¹H NMR d 1.09 (s, 3H), 1.19 (s,

3H), 2.07–2.08 (m, 3H), 2.32, 2.48 (AB, ²J¼17.6 Hz,

2H), 2.91 (ABX, ³J¼2.8 Hz, ²J¼15.6 Hz, 1H), 3.00

1

afforded a white solid (12.5 mg, 45%): mp 69–71 ^ꢁC; H

NMR d 1.09, (s, 3H), 1.20 (s, 3H), 2.44–2.56 (m, 2H),

2.98 (ABX, J¼3.2 Hz, J¼16.0 Hz, 1H), 3.14 (ABX, J¼

3

2

3

2

7.8 Hz, J¼16.0 Hz, 1H), 3.46 (s, 3H), 3.49 (s, 3H), 3.98–

4.00 (m, 1H), 5.50 (s, 1H), 6.07–6.08 (m, 1H), 6.81–6.82

(m, 1H), 9.42 (s, 1H), 11.36–11.44 (br s, 1H); ¹³C NMR

d 22.9, 25.7, 27.3, 29.9, 38.4, 41.9, 55.8, 56.1, 81.7, 110.4,

121.0, 133.2, 138.0, 145.5, 178.6; FABMS obsd 279.1696,

calcd 279.1709 [(M+H)⁺, M¼C₁₅H₂₂N₂O₃].

3

2

(ABX, J¼7.2 Hz, J¼15.6 Hz, 1H), 3.84–3.91 (m, 1H),

5.85–5.87 (m, 1H), 5.96–5.98 (m, 1H), 10.92–11.03 (br s,

1H); ¹³C NMR d 13.4, 23.0, 26.2, 27.8, 37.4, 47.2,

81.1, 96.8, 108.1, 109.4, 130.5, 146.3. Anal. Calcd for

C₁₂H₁₇BrN₂O: C, 50.54; H, 6.01; N, 9.82. Found: C,

50.48; H, 6.05; N, 9.65.

4.3.49. 9-Bromo-2,3,4,5-tetrahydro-1,3,3-trimethyl-

dipyrrin (38). Following a procedure for the a-bromination

of pyrroles,¹⁰a solution of 2 (95 mg, 0.50 mmol) in dry THF

(10 mL) was cooled to ꢀ78 ^ꢁC under argon. NBS (89 mg,

0.50 mmol) was added in two portions. The reaction mixture

was stirred for an additional 1 h at ꢀ78 ^ꢁC. Hexanes

(6.0 mL) and water (6.0 mL) were added, and the mixture

was allowed to warm to room temperature. The organic layer

was extracted with ethyl acetate, dried (MgSO₄), and con-

centrated under vacuum without heating. The resulting resi-

due was puriﬁed by gravity column chromatography (silica,

ethyl acetate) to give a white solid (112 mg, 83%): mp

4.3.46. 9-Bromo-1-formyl-2,3,4,5-tetrahydro-3,3-di-

methyldipyrrin N¹⁰-oxide (35). Following a general proce-

dure,²⁷a solution of 34 (29 mg, 0.10 mmol) in 1,4-dioxane

(1.0 mL) was treated with SeO₂(14 mg, 0.13 mmol) under

argon. The mixture was stirred for 2.5 h at room tempera-

ture. The reaction mixture was then treated with saturated

aqueous NaHCO₃(1.0 mL) and extracted with ethyl acetate.

The organic extract was washed with water, dried (Na₂SO₄),

54

H.-J. Kim et al. / Tetrahedron 63 (2007) 37–55

1

102–104 ^ꢁC (dec); H NMR d 0.92 (s, 3H), 1.11 (s, 3H),

2.04–2.06 (m, 3H), 2.26–2.41 (m, 2H), 2.49–2.57 (m, 1H),

2.69–2.71 (m, 1H), 3.55–3.62 (m, 1H), 5.85–5.87 (m, 1H),

5.98–6.00 (m, 1H), 9.84–10.00 (br s, 1H); ¹³C NMR

d 20.7, 23.0, 27.4, 28.3, 42.0, 54.5, 80.2, 95.7, 107.2,

109.4, 133.4, 175.0; FABMS obsd 269.0641, calcd

269.0653 [(M+H)⁺, M¼C₁₂H₁₇BrN₂].

Water (250 mL) was added, and the reaction mixture was ex-

tracted with CH₂Cl₂. The organic extract was washed (water

and brine), dried (Na₂SO₄), and concentrated. Chromato-

graphy [silica, hexanes/ethyl acetate (1:1)] afforded a yellow

solid (1.97 g, 64%). A light pink byproduct also was isolated

(0.090 g, 32%) and identiﬁed as 2,3,4-trihydro-4,4,6-

trimethyl-3-nitrocycloheptene[b]pyrrole (40⁰). Data for 40:

1

mp 105–107 ^ꢁC; H NMR d 1.13 (s, 3H), 1.28 (s, 3H),

2

4.3.50. 9-Formyl-2,3,4,5-tetrahydro-1,3,3-trimethyl-

dipyrrin (39) by reductive cyclization. Following a general

procedure,¹⁸a solution of 40 (0.226 g, 1.00 mmol) in THF

was treated with HCOONH₄(0.996 g, 15.8 mmol) and

zinc dust (0.981 g, 15.0 mmol). The resulting suspension

was stirred overnight at room temperature. The reaction

mixture was diluted with ethyl acetate and ﬁltered. The ﬁlter

cake was washed with ethyl acetate (w20 mL). The ﬁltrate

was washed (water and brine), dried (Na₂SO₄), and concen-

trated. The crude product (dark red) was chromatographed

[silica, ethyl acetate/methanol (10:1)] to afford a dark orange

solid (60 mg, 27%): mp 72–74 ^ꢁC; ¹H NMR d 0.93 (s, 3H),

1.12 (s, 3H), 2.04 (s, 3H), 2.30 (AB, ²J¼17.0 Hz, 1H), 2.39

(AB, ²J¼17.0 Hz, 1H), 2.62 (ABX, ³J¼11.2 Hz, ²J¼

15.2 Hz, 1H), 2.79 (ABX, ³J¼3.2 Hz, ²J¼15.2 Hz, 1H),

3.62–3.65 (m, 1H), 6.09–6.10 (m, 1H), 6.85–6.86 (m, 1H),

9.39 (s, 1H), 10.72–10.95 (br s, 1H); ¹³C NMR d 20.7,

23.1, 27.3, 28.3, 42.2, 54.6, 79.2, 109.9, 121.9, 132.5,

141.7, 175.3, 178.4; FABMS obsd 219.1491, calcd

219.1497 [(M+H)⁺, M¼C₁₃H₁₈N₂O].

2.15 (s, 3H), 2.43 (AB, J¼18.0 Hz, 1H), 2.62 (AB, J¼

18.0 Hz, 1H), 3.14 (ABX, ³J¼2.4 Hz, ²J¼15.4 Hz, 1H),

3.58 (ABX, ³J¼12.0 Hz, ²J¼15.4 Hz, 1H), 5.24 (ABX, ³J¼

2.4 Hz, ³J¼12.0 Hz, 1H), 6.11–6.14 (m, 1H), 6.87–6.88 (m,

1H), 9.39 (s, 1H), 10.20–10.32 (br s, 1H); ¹³C NMR d 24.1,

24.6, 27.0, 32.0, 37.1, 51.5, 93.7, 111.1, 123.1, 132.9, 136.8,

179.1, 206.9; FABMS obsd 267.1353, calcd 267.1345

[(M+H)⁺, M¼C₁₃H₁₈N₂O₄]. Data for 40⁰: mp 182–185 ^ꢁC;

¹H NMR d 1.20 (s, 3H), 1.23 (s, 3H), 2.06 (s, 3H), 3.42

(ABX, ³J¼3.8 Hz, ²J¼18.0 Hz, 1H), 3.74 (ABX, ³J¼

3.8 Hz, ²J¼17.2 Hz, 1H), 4.78 (ABX, ³J¼3.6 Hz, ³J¼

10.8 Hz, 1H), 5.36 (s, 1H), 6.92–6.93 (s, 1H), 9.42 (s, 1H),

10.12–10.23 (br s, 1H); ¹³C NMR d 23.0, 24.2, 29.0, 29.5,

29.8, 39.0, 89.4, 121.6, 123.6, 127.6, 131.4, 134.3, 179.3;

FABMS obsd 249.1226, calcd 249.1239 [(M+H)⁺,

M¼C₁₃H₁₆N₂O₃].

4.3.53. 2,3,4,5-Tetrahydro-1,3,3,9-tetramethyldipyrrin

N-oxide (41). Following a general procedure,¹²a vigorously

stirred solution of 40 (0.26 g, 1.0 mmol) in acetic acid

(5.0 mL) and ethanol (5.0 mL) was treated slowly with zinc

dust (1.64 g, 25.0 mmol) in small portions over 5 min at

0 ^ꢁC. The starting material was consumed in 2 h at 0 ^ꢁC.

The reaction mixture was ﬁltered. The ﬁlter cake was washed

with ethyl acetate (w20 mL). The ﬁltrate was neutralized

with aqueous NaHCO₃, washed (water and brine), dried

(Na₂SO₄), and concentrated. The resulting red oil was chro-

matographed [silica, hexanes/ethyl acetate/methanol (8:5:2)]

to afford a light brown solid (39.0 mg, 18%): mp 98–100 ^ꢁC;

¹H NMR d 1.11 (s, 3H), 1.18 (s, 3H), 2.04–2.05 (m, 3H), 2.22

(s, 3H), 2.29 (AB, ²J¼17.6 Hz, 1H), 2.43 (AB, ²J¼17.6 Hz,

1H), 2.91–3.01 (m, 2H), 3.84–3.86 (m, 1H), 5.66–5.71 (m,

1H), 5.77–5.79 (m, 1H), 10.10–10.24 (br s, 1H); ¹³C NMR

d 13.38, 13.41, 23.0, 26.1, 26.6, 28.0, 37.3, 47.2, 81.6,

105.0, 106.3, 127.6, 145.7; FABMS obsd 220.1562, calcd

220.1567 (C₁₃H₂₀N₂O).

4.3.51. Synthesis of 39 by Vilsmeier formylation. A solu-

tion of 2 (0.380 g, 2.00 mmol) in DMF (0.70 mL) and

CH₂Cl₂(16.0 mL) at 0 ^ꢁC under argon was treated dropwise

with POCl₃(0.229 mL, 2.50 mmol). The reaction mixture

was stirred at 0 ^ꢁC for 1 h and then brought to room temper-

ature. The reaction mixture was poured into 2.5 M NaOH

(10 mL) at 0 ^ꢁC. Water was added (250 mL), and the result-

ing mixture was extracted with CH₂Cl₂. The organic layer

was washed (water and brine), dried (Na₂SO₄), and concen-

trated. The crude product (red-brown) was chromatographed

[silica, ethyl acetate/methanol (10:1)] to afford a yellow

solid (0.24 g, 55%). A brownish yellow oil byproduct also

was obtained and identiﬁed as 1,11-diformyl-2,3-dihydro-

1,3,3-trimethyldipyrromethane (42, 0.17 g, 35%). The data

for the title compound (mp, ¹H NMR, ¹³C NMR, and

FABMS) were consistent with those obtained from samples

1

prepared via an earlier route. Data for 42: H NMR d 1.01

3

(s, 3H), 1.02 (s, 3H), 1.93 (s, 3H), 3.0 (ABX, J¼8.8 Hz,

Acknowledgements

²J¼15.6 Hz, 1H), 3.15 (ABX, ³J¼4.4 Hz, ²J¼15.6 Hz,

1H), 4.34–4.37 (m, 1H), 4.77 (s, 1H), 6.11–6.12 (m, 1H),

6.86–6.87 (m, 1H), 8.38 (s, 1H), 9.35 (s, 1H), 10.52–10.65

(br s, 1H); ¹³C NMR d 12.8, 22.4, 28.1, 30.6, 43.8,

66.0, 110.6, 120.9, 122.7, 132.3, 133.8, 140.0, 157.8,

178.5; FABMS obsd 247.1439, calcd 247.1447 [(M+H)⁺,

M¼C₁₄H₁₈N₂O₂].

This work was funded by the NIH (GM36238). We thank

Dr. Man Nyoung Kim for the synthesis of 38 and exploratory

studies on reactions of 9.

References and notes

4.3.52. 6-(5-Formyl-2-pyrrolyl)-4,4-dimethyl-5-nitro-

hexan-2-one (40). A solution of 22 (2.74 g, 11.5 mmol) in

DMF (3.7 mL) and CH₂Cl₂(85 mL) at 0 ^ꢁC under argon

was treated dropwise with POCl₃(1.25 mL, 13.6 mmol).

The reaction mixture changed from light brown to dark

red. The residue was stirred at 0 ^ꢁC for 1 h and then brought

to room temperature and stirred overnight. The reaction mix-

ture was poured into 2.5 M aqueous NaOH (60 mL) at 0 ^ꢁC.

1. (a) Vernon, L. P.; Seely, G. R. The Chlorophylls; Academic:

New York, NY, USA, 1966; (b) Chlorophylls; Scheer, H.,

Ed.; CRC: Boca Raton, FL, USA, 1991.

2. (a) Agius, L.; Ballantine, J. A.; Ferrito, V.; Jaccarini, V.;

Murray-Rust, P.; Pelter, A.; Psaila, A. F.; Schembri, P. J. Pure

Appl. Chem. 1979, 51, 1847–1864; (b) Helaja, J.; Montforts,

€

F.-P.; Kilpelainen, I.; Hynninen, P. H. J. Org. Chem. 1999,

64, 432–437.

H.-J. Kim et al. / Tetrahedron 63 (2007) 37–55

55

3. (a) Prinsep, M. R.; Caplan, F. R.; Moore, R. E.; Patterson,

G. M. L.; Smith, C. D. J. Am. Chem. Soc. 1992, 114, 385–

387; (b) Prinsep, M. R.; Patterson, G. M. L.; Larsen, L. K.;

Smith, C. D. Tetrahedron 1995, 51, 10523–10530.

4. (a) Crane, B. R.; Getzoff, E. D. Curr. Opin. Struct. Biol. 1996,

6, 744–756; (b) Nakayama, M.; Akashi, T.; Hase, T. J. Inorg.

Biochem. 2000, 82, 27–32.

5. (a) Chemistry; Dolphin, D., Ed.; B₁₂; Wiley-Interscience: New

York, NY, USA, 1982; Vol. 1; (b) Biochemistry and Medicine;

Dolphin, D., Ed.; B₁₂; Wiley-Interscience: New York, NY,

USA, 1982; Vol. 2; (c) Vitamin B₁₂and B₁₂-Proteins;

24. Arnott, D. M.; Harrison, P. J.; Henderson, G. B.; Sheng, Z.-C.;

Leeper, F. J.; Battersby, A. R. J. Chem. Soc., Perkin Trans. 1

1989, 265–278.

25. Battersby, A. R.; Block, M. H.; Fookes, C. J. R.; Harrison, P. J.;

Henderson, G. B.; Leeper, F. J. J. Chem. Soc., Perkin Trans. 1

1992, 2175–2187.

26. Battersby, A. R.; Block, M. H.; Leeper, F. J.; Zimmerman, S. C.

J. Chem. Soc., Perkin Trans. 1 1992, 2189–2195.

€

27. Jacobi, P. A.; Lanz, S.; Ghosh, I.; Leung, S. H.; Lower, F.;

Pippin, D. Org. Lett. 2001, 3, 831–834.

28. O’Neal, W. G.; Roberts, W. P.; Ghosh, I.; Jacobi, P. A. J. Org.

Chem. 2005, 70, 7243–7251.

29. O’Neal, W. G.; Roberts, W. P.; Ghosh, I.; Wang, H.; Jacobi,

P. A. J. Org. Chem. 2006, 71, 3472–3480.

€

Krautler, B., Arigoni, D., Golding, B. T., Eds.; Wiley-VCH:

Weinheim, 1998.

6. Ragsdale, S. W. The Porphyrin Handbook; Kadish, K. M.,

Smith, K. M., Guilard, R., Eds.; Academic: San Diego, CA,

2003; Vol. 11, pp 205–228.

30. Battersby, A. R.; Fookes, C. J. R.; Snow, R. J. J. Chem. Soc.,

Perkin Trans. 1 1984, 2725–2732.

7. (a) Dorough, G. D.; Miller, J. R. J. Am. Chem. Soc. 1952, 74,

6106–6108; (b) Dorough, G. D.; Huennekens, F. M. J. Am.

Chem. Soc. 1952, 74, 3974–3976; (c) Whitlock, H. W., Jr.;

Hanauer, R.; Oester, M. Y.; Bower, B. K. J. Am. Chem. Soc.

1969, 91, 7485–7489.

8. (a) Eschenmoser, A.; Wintner, C. E. Science 1977, 196, 1410–

1420; (b) Flitsch, W. Adv. Heterocycl. Chem. 1988, 43, 73–126;

(c) Woodward, R. B.; Ayer, W. A.; Beaton, J. M.; Bickelhaupt,

F.; Bonnett, R.; Buchschacher, P.; Closs, G. L.; Dutler, H.;

Hannah, J.; Hauck, F. P.; Ito, S.; Langemann, A.; Le Goff, E.;

Leimgruber, W.; Lwowski, W.; Sauer, J.; Valenta, Z.; Volz,

H. Tetrahedron 1990, 46, 7599–7659; (d) Montforts, F.-P.;

31. Tietze, L. F.; Kettschau, G.; Heitmann, K. Synthesis 1996,

851–857.

32. Cheruku, S. R.; Padmanilayam, M. P.; Vennerstrom, J. L.

Tetrahedron Lett. 2003, 44, 3701–3703.

33. Park, K.-H.; Marshall, W. J. J. Org. Chem. 2005, 70, 2075–2081.

34. Cava, M. P.; Levinson, M. I. Tetrahedron 1985, 41, 5061–5087.

35. Anderson, H. J.; Loader, C. E.; Xu, R. X.; Le, N.; Gogan,

N. J.; McDonald, R.; Edwards, L. G. Can. J. Chem. 1985,

63, 896–902.

36. Settambolo, R.; Lazzaroni, R.; Messeri, T.; Mazzetti, M.;

Salvadori, P. J. Org. Chem. 1993, 58, 7899–7902.

37. Abell, A. D.; Nabbs, B. K.; Battersby, A. R. J. Org. Chem.

1998, 63, 8163–8169.

€

Gerlach, B.; Hoper, F. Chem. Rev. 1994, 94, 327–347; (e)

Montforts, F.-P.; Glasenapp-Breiling, M. Prog. Heterocycl.

Chem. 1998, 10, 1–24; (f) Montforts, F.-P.; Glasenapp-

Breiling, M. Fortschr. Chem. Org. Naturst. 2002, 84, 1–51;

(g) Riether, D.; Mulzer, J. Eur. J. Org. Chem. 2003, 30–45.

9. Balaban, T. S.; Tamiaki, H.; Holzwarth, A. R. Top. Curr. Chem.

2005, 258, 1–38.

10. Strachan, J.-P.; O’Shea, D. F.; Balasubramanian, T.; Lindsey,

J. S. J. Org. Chem. 2000, 65, 3160–3172.

11. Balasubramanian, T.; Strachan, J. P.; Boyle, P. D.; Lindsey, J. S.

J. Org. Chem. 2000, 65, 7919–7929.

38. Hasegawa, M.; Taniyama, D.; Tomioka, K. Tetrahedron 2000,

56, 10153–10158.

39. (a) Jurczak, J.; Golebiowski, A. Chem. Rev. 1989, 89, 149–164;

(b) Gerspacher, M.; Rapoport, H. J. Org. Chem. 1991, 56,

3700–3706; (c) Reed, P. E.; Katzenellenbogen, J. A. J. Org.

Chem. 1991, 56, 2624–2634; (d) Lubell, W. D.; Jamison,

T. F.; Rapoport, H. J. Org. Chem. 1990, 55, 3511–3522; (e)

Myers, A. G.; Kung, D. W.; Zhong, B.; Movassaghi, M.;

Kwon, S. J. Am. Chem. Soc. 1999, 121, 8401–8402; (f)

Lubell, W. D.; Rapport, H. J. Am. Chem. Soc. 1987, 109,

236–239; (g) Bonini, B. F.; Comes-Franchini, M.; Fochi, M.;

Gawronski, J.; Mazzanti, G.; Ricci, A.; Varchi, G. Eur. J.

Org. Chem. 1999, 437–445.

12. Taniguchi, M.; Ra, D.; Mo, G.; Balasubramanian, T.; Lindsey,

J. S. J. Org. Chem. 2001, 66, 7342–7354.

13. Taniguchi, M.; Kim, H.-J.; Ra, D.; Schwartz, J. K.; Kirmaier,

C.; Hindin, E.; Diers, J. R.; Prathapan, S.; Bocian, D. F.;

Holten, D.; Lindsey, J. S. J. Org. Chem. 2002, 67, 7329–7342.

14. Laha, J. K.; Muthiah, C.; Taniguchi, M.; McDowell, B. E.;

Ptaszek, M.; Lindsey, J. S. J. Org. Chem. 2006, 71, 4092–4102.

15. Kim, H.-J.; Lindsey, J. S. J. Org. Chem. 2005, 70, 5475–5486.

16. Dutton, C. J.; Fookes, C. J. R.; Battersby, A. R. J. Chem. Soc.,

Chem. Commun. 1983, 1237–1238.

40. Black, D. St. C.; Strauch, R. J. Aust. J. Chem. 1988, 41, 183–

193.

´

41. Patrocınio, A. F.; Moran, P. J. S. J. Organomet. Chem. 2000,

603, 220–224.

42. Lindsey, J. S.; Brown, P. A.; Siesel, D. A. Tetrahedron 1989, 45,

4845–4866.

43. Nagata, T. Bull. Chem. Soc. Jpn. 1991, 64, 3005–3016.

44. Luche, J.-L.; Gemal, A. L. J. Chem. Soc., Chem. Commun.

1978, 976–977.

17. Battersby, A. R.; Dutton, C. J.; Fookes, C. J. R. J. Chem. Soc.,

Perkin Trans. 1 1988, 1569–1576.

18. Ptaszek, M.; Bhaumik, J.; Kim, H.-J.; Taniguchi, M.; Lindsey,

J. S. Org. Process Res. Dev. 2005, 9, 651–659.

45. Kantam, M. L.; Swapna, V.; Santhi, P. L. Synth. Commun.

1995, 25, 2529–2532.

19. Inhoffen, H. H.; Petrovicki, W.; Gossauer, A. Liebigs Ann.

Chem. 1973, 1067–1074.

46. Lindsey, J. S.; Prathapan, S.; Johnson, T. E.; Wagner, R. W.

Tetrahedron 1994, 50, 8941–8968.

20. Harrison, P. J.; Fookes, C. J. R.; Battersby, A. R. J. Chem. Soc.,

Chem. Commun. 1981, 797–799.

21. Arnott, D. M.; Battersby, A. R.; Harrison, P. J.; Henderson, G. B.;

Sheng, Z.-C. J. Chem. Soc., Chem. Commun. 1984, 525–526.

22. Battersby, A. R.; Reiter, L. A. J. Chem. Soc., Perkin Trans. 1

1984, 2743–2749.

47. Kim, H.-J. Ph.D. thesis, North Carolina State University, 2005.

48. (a) Lee, C.-H.; Li, F.; Iwamoto, K.; Dadok, J.; Bothner-By,

A. A.; Lindsey, J. S. Tetrahedron 1995, 51, 11645–11672; (b)

Rao, P. D.; Dhanalekshmi, S.; Littler, B. J.; Lindsey, J. S.

J. Org. Chem. 2000, 65, 7323–7344.

49. Battersby, A. R.; Dutton, C. J.; Fookes, C. J. R.; Turner, S. P. D.

J. Chem. Soc., Perkin Trans. 1 1988, 1557–1567.

50. Ghosh, I.; Jacobi, P. A. J. Org. Chem. 2002, 67, 9304–9309.

23. Harrison, P. J.; Sheng, Z.-C.; Fookes, C. J. R.; Battersby, A. R.

J. Chem. Soc., Perkin Trans. 1 1987, 1667–1678.

Article Doi

Synthesis of hydrodipyrrins tailored for reactivity at the 1- and 9-positions

DOI: 10.1016/j.tet.2006.10.027

Source and publish data:

Authors:

Article abstract of DOI:10.1016/j.tet.2006.10.027

Full text of DOI:10.1016/j.tet.2006.10.027

Products guided by the article

R&D Labs maybe for 922729-26-8

Relevant to this article

Hot Product