Alkylthio unit as an α-pyrrole protecting group for use in dipyrromethane synthesis

Article abstract of DOI:10.1021/jo051806q

The synthesis of porphyrin precursors requires the successive introduction of substituents at the pyrrole α- and α′-positions (2- and 5-, respectively). An α-pyrrole substituent that serves as a temporary masking agent and is not deactivating would greatly facilitate such syntheses, particularly for β-(3,4)-unsubstituted pyrroles, but has heretofore not been available. A series of α-RS groups (R = Me, Et, n-decyl, Ph) have been investigated in this regard, including the determination of the kinetics of substitution at the pyrrolic 3-, 4-, and 5-positions and the application to dipyrromethane formation. The RS group was readily introduced into the pyrrole α-position by the reaction of 2-thiocyanatopyrrole (prepared from pyrrole, ammonium thiocyanate, and iodine) and the corresponding Grignard reagent RMgBr. Each 2-alkylthio group activated the pyrrole ring toward deuteration at the 3- or 5- (vs 4-) position. The dipyrromethane synthesis was carried out using a 2:1 ratio of 2-(RS)pyrrole/benzaldehyde with a catalytic amount of InCl₃ at room temperature in the absence of any solvent. The α-RS group was removed by hydrodesulfurization using Raney nickel or nickel complexes. This stoichiometric synthesis using the α-RS-protected pyrrole is in contrast to the traditional synthesis that employs an aldehyde and 25-100 mol equiv of pyrrole. Six meso-substituted dipyrromethanes were prepared by the reaction of 2-(n-decylthio)pyrrole/aldehyde/InCl₃ (2.2:1:0.2 ratio) followed by hydrodesulfurization. Other reactions of the 1,9-bis(RS)dipyrromethane include oxidation to give (i) the 1,9-bis(RS)dipyrrin or (ii) the 1,9-bis(RSO ₂)dipyrromethane, which underwent subsequent complexation with dibutyltin dichloride. In summary, under mild reaction conditions, the 2-alkylthio group is readily introduced to the pyrrole nucleus, directs electrophilic substitution to the 5-position, and is readily removed as required for elaboration of porphyrinic precursors.

Full text of DOI:10.1021/jo051806q

Alkylthio Unit as an r-Pyrrole Protecting Group for Use in
Dipyrromethane Synthesis
Patchanita Thamyongkit, Anil D. Bhise, Masahiko Taniguchi, and Jonathan S. Lindsey*
Department of Chemistry, North Carolina State UniVersity, Raleigh, North Carolina 27695-8204
jlindsey@ncsu.edu
ReceiVed August 26, 2005
The synthesis of porphyrin precursors requires the successive introduction of substituents at the pyrrole
R- and R′-positions (2- and 5-, respectively). An R-pyrrole substituent that serves as a temporary masking
agent and is not deactivating would greatly facilitate such syntheses, particularly forâ-(3,4)-unsubstituted
pyrroles, but has heretofore not been available. A series of R-RS groups (R ) Me, Et, n-decyl, Ph) have
been investigated in this regard, including the determination of the kinetics of substitution at the pyrrolic
3-, 4-, and 5-positions and the application to dipyrromethane formation. The RS group was readily
introduced into the pyrrole R-position by the reaction of 2-thiocyanatopyrrole (prepared from pyrrole,
ammonium thiocyanate, and iodine) and the corresponding Grignard reagent RMgBr. Each 2-alkylthio
group activated the pyrrole ring toward deuteration at the 3- or 5- (vs 4-) position. The dipyrromethane
synthesis was carried out using a 2:1 ratio of 2-(RS)pyrrole/benzaldehyde with a catalytic amount of
InCl3 at room temperature in the absence of any solvent. The R-RS group was removed by
hydrodesulfurization using Raney nickel or nickel complexes. This stoichiometric synthesis using the
R-RS-protected pyrrole is in contrast to the traditional synthesis that employs an aldehyde and 25-100
mol equiv of pyrrole. Six meso-substituted dipyrromethanes were prepared by the reaction of
2-(n-decylthio)pyrrole/aldehyde/InCl3 (2.2:1:0.2 ratio) followed by hydrodesulfurization. Other reactions
of the 1,9-bis(RS)dipyrromethane include oxidation to give (i) the 1,9-bis(RS)dipyrrin or (ii) the 1,9-
bis(RSO2)dipyrromethane, which underwent subsequent complexation with dibutyltin dichloride. In
summary, under mild reaction conditions, the 2-alkylthio group is readily introduced to the pyrrole nucleus,
directs electrophilic substitution to the 5-position, and is readily removed as required for elaboration of
porphyrinic precursors.
Introduction
nucleus (eq 1). Removal of the blocking carboxy moiety
typically requires treatment at high temperature with a strong
base, a strong acid, and/or a halogen reagent. Use of the halogen
reagent affords the 2-halopyrrolic species, which is converted
to the pyrrole with the open 2-position by catalytic hydrogena-
tion.1 In general, the use of a carboxylate (or other electron-
withdrawing group) to block the 2-position in a pyrrole lacking
substituents at the 3- and 4-positions (e.g., B, eq 2) is expected
to present three problems: (1) sluggish reaction, (2) diminished
selectivity for the direction of the incoming group to the
The synthesis of porphyrinic macrocycles and related com-
pounds requires the ability to carry out reactions at the pyrrolic
R- and R′-positions (2- and 5-positions, respectively). The
controlled introduction of a single substituent via electrophilic
substitution can necessitate the use of an R-blocking group,
particularly when the newly introduced substituent activates the
pyrrole to further substitution. In the synthesis of naturally
occurring porphyrins, which typically entails the use of 3,4-
disubstituted pyrroles (e.g., A), an ester (or carboxylic acid)
suffices to block the 2-position: substitution occurs at the
5-position, which contains the only open carbon in the pyrrolic
(1) Paine, J. B., III. In The Porphyrins; Dolphin, D. Ed.; Academic
Press: New York, 1978; Vol. I, pp 101-234.
10.1021/jo051806q CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/07/2006
J. Org. Chem. 2006, 71, 903-910
903

Thamyongkit et al.
SCHEME 1
5-position vs the 4-position, and (3) harsh conditions for removal
of the carboxylate group. To our knowledge, only one â-un-
substituted dipyrromethane has been prepared via this approach.2
On the other hand, the incoming group could be directed rapidly
to the 5-position with an R-blocking group that is not deactivat-
ing, but such a simple protective group for pyrroles has
heretofore not been developed.
The absence of a suitable R-blocking group for unsubstituted
pyrroles has substantially affected a number of synthetic
transformations. For example, the synthesis of â-unsubstituted
dipyrromethanes is typically carried out by reaction of an
aldehyde with excess pyrrole (up to 100 mol equiv), resulting
in 1, N-confused dipyrromethane (2), tripyrrane (3), and
oligomeric byproducts (Scheme 1). The presence of excess
pyrrole is required to trap the initially formed pyrrole-carbinol
and thereby suppress the competitive self-oligomerization of
the pyrrole-carbinol. Although considerable refinement has
gone into streamlining the conditions for carrying out this
reaction and purifying the product,3-5 the use of such a large
excess of pyrrole remains an inherent disadvantage. The
availability of an R-blocking group that is not deactivating would
enable the use of a stoichiometric amount of the protected
pyrrole (2 mol equiv) and the aldehyde. Thompson and
co-workers have recently reported a sulfonyl or 2,4-dinitrophe-
nylsulfinyl group for protecting the R-pyrrole position, but again,
both groups are deactivating.6
In this paper, we describe the use of the alkylthio unit as a
traceless R-pyrrole protecting group. We have screened acid
catalysts and characterized the kinetics of electrophilic aromatic
substitution of 2-substituted pyrroles. Our study includes the
development of a mild, solventless, and stoichiometric synthesis
of â-unsubstituted dipyrromethanes bearing different substituents
at the meso-position. Selective oxidation of the 1,9-bis(RS)-
dipyrromethanes at the dipyrromethane unit or the sulfur
moieties has been established. This work provides the foundation
for the use of the alkylthio unit in pyrrole and porphyrin
chemistry, masking the pyrrolic 2-position and activating the
pyrrolic unit toward electrophilic substitution at the 5-position.
For applications in the synthesis of porphyrinic precursors,
an ideal R-pyrrole protecting group would afford the following
features: (1) mask the R-carbon toward electrophilic aromatic
substitution, (2) direct electrophilic aromatic substitution to the
pyrrole 5-position without deactivation of the pyrrole ring, (3)
afford stability toward acidic conditions, (4) yield a crystalline
product, and (5) undergo traceless cleavage under nonacidic
conditions. In contemplating candidates for protection of the
R-pyrrolic position, we considered the alkylthio moiety. In this
regard, Muchowski and co-workers demonstrated that a 2-alky-
lthiopyrrole undergoes acylation selectively at the 5-position.7
Thioethers also have been employed as traceless linkers in solid-
phase chemistry.8
Results and Discussion
1. Syntheses of 2-(RS)pyrroles. We sought to prepare pyrrole
derivatives bearing a series of R-RS groups, where R ) methyl,
ethyl, n-decyl, and phenyl groups. Several routes have been
reported for the synthesis of 2-(RS)pyrroles lacking any other
substituents, though none has been used to prepare an extensive
set of homologues. The routes consist of (1) treatment of pyrrole
with a dialkyl disulfide in the presence of sulfuric acid,9 (2)
reaction of 2-thiocyanatopyrrole with a Grignard reagent,10,11
(3) cyclization of allyl isothiocyanate to give the pyrrole-2-
(2) (a) Setsune, J.-i.; Hashimoto, M. J. Chem. Soc., Chem. Commun.
1994, 657-658. (b) Setsune, J.-i.; Hashimoto, M.; Shiozawa, K.; Hayakawa,
J.-y.; Ochi, T.; Masuda, R. Tetrahedron 1998, 54, 1407-1424.
(3) Lee, C.-H.; Lindsey, J. S. Tetrahedron 1994, 50, 11427-11440.
(4) Littler, B. J.; Miller, M. A.; Hung, C.-H.; Wagner, R. W.; O’Shea,
D. F.; Boyle, P. D.; Lindsey, J. S. J. Org. Chem. 1999, 64, 1391-1396.
(5) Laha, J. K.; Dhanalekshmi, S.; Taniguchi, M.; Ambroise, A.; Lindsey,
J. S. Org. Process Res. DeV. 2003, 7, 799-812.
(6) Thompson, A.; Butler, R. J.; Grundy, M. N.; Laltoo, A. B. E.;
Robertson, K. N.; Cameron, T. S. J. Org. Chem. 2005, 70, 3753-3756.
(7) Franco, F.; Greenhouse, R.; Muchowski, J. M. J. Org. Chem. 1982,
47, 1682-1688.
(8) (a) Sucholeiki, I. Tetrahedron Lett. 1994, 35, 7307-7310. (b) Gayo,
L. M.; Suto, M. J. Tetrahedron Lett. 1997, 38, 211-214. (c) Krchna´k, V.;
Holladay, M. W. Chem. ReV. 2002, 102, 61-91. (d) Blaney, P.; Grigg, R.;
Sridharan V. Chem. ReV. 2002, 102, 2607-2624. (e) Rombouts, F. J. R.;
Fridkin, G.; Lubell, W. D. J. Comb. Chem. 2005, 7, 589-598.
(9) Takeuchi, H.; Hyama, T. Jpn. Kokai Tokkyo Koho 1996, JP 08245558.
(10) Campiani, G.; Nacci, V.; Bechelli, S.; Ciani, S. M.; Garofalo, A.;
Fiorini, I.; Wikstro¨m, H.; de Boer, P.; Liao, Y.; Tepper, P. G.; Cagnotto,
A.; Mennini, T. J. Med. Chem. 1998, 41, 3763-3772.
(11) Yadav, J. S.; Reddy, B. V. S.; Shubashree, S.; Sadashiv, K.
Tetrahedron Lett. 2004, 45, 2951-2954.
904 J. Org. Chem., Vol. 71, No. 3, 2006

Alkylthio Unit as an R-Pyrrole Protecting Group
TABLE 1. Rate Constants k of Deuteration of 2-Substituted
SCHEME 2
Pyrrolesa
rate constants k (× 104) in s-1
Hammett
(t1/2 in min)
substituent
constant
b
2-substituent
5-H
4-H
3-H
σm
-CH3
240 (0.04)
2.2 (48)
8.7 (13)
3.3 (34)
4.0 (28)
0.25 (460)
d
2.5 (45)
0.35 (310)
0.047 (2200)
0.049 (2300)
0.063 (1600)
110 (0.7)
0.35 (48)
8.8 (13)
2.8 (34)
3.7 (30)
-0.12
0.00
0.15
-Hc
-SCH3
-SCH2CH3
-S(CH2)9CH3
-SPh
0.18
0.015 (7000) 0.14 (780)
0.23
0.37
-COOH
d
d
a In neat CD3COOD with a pyrrole (87 mM, CD3COOD/pyrrole ) 200:
1) at 20 °C. See Supporting Information for details. b Reference 18. c Due
to molecular symmetry, 2-H and 3-H are equivalent to 5-H and 4-H,
respectively. d No significant change was observed after 2 days.
such groups on the reactivity of the 5-, 4-, and 3-positions on
the pyrrole ring toward electrophilic aromatic substitution. For
benchmarking purposes, other pyrroles examined include 2-me-
thylpyrrole, 2-carboxypyrrole, and pyrrole itself. A full descrip-
tion of experimental methods and data is available in the
Supporting Information.
The studies were carried out by performing the deuteration
of a given pyrrole in neat CD3COOD at 20 °C in an NMR tube
(eq 3) using 1,4-dichlorobenzene as an internal standard. The
thiolate followed by reaction with an alkyl halide,12 and (4)
alkylation of pyrrole with an alkylsulfanyl chloride.6,13 We
explored the first two methods. 2-(Methylthio)pyrrole (Me-4)
has been prepared by treatment of pyrrole with dimethyl
disulfide in sulfuric acid,9 but our attempts to extend this method
to the ethyl and n-decyl analogues afforded compounds Et-4
and Decyl-4 in low yield (Scheme 2). The phenyl analogue Ph-4
has been prepared by reaction of 2-thiocyanatopyrrole (5)11 with
phenylmagnesium bromide.10 2-Thiocyanatopyrrole (5), which
is readily prepared by reaction of pyrrole, ammonium thiocy-
anate, and iodine in methanol, proved to be a versatile substrate.
Thus, reaction of 5 with ethyl- or n-decylmagnesium bromide
afforded Et-4 or Decyl-4 in 67 or 92% yield, respectively.
2. Kinetic Study of Deuteration of Pyrroles Bearing
Different R-Substituents. The kinetics of deuterium exchange
on Me-4, Et-4, Ph-4, and Decyl-4 were examined to character-
ize the electronic effects of the various 2-substituents. The
electronic effects of pyrrolic substituents have been examined
by deuterium exchange, but no data are available for 2-RS sub-
stituents.14-17 Of particular concern was to assess the effect of
resonances corresponding to H5, H4, and H3 steadily diminished
in intensity over time. The kinetic data obtained obeyed the
first-order rate expression quite closely, affording rate constants
k (sec-1) and t1/2 (min) values for the various positions (Table
1). Two comparisons are noteworthy, the relative reactivity of
the 3-, 4-, and 5-positions for a given 2-(RS)pyrrole and the
overall reactivity of the 2-(RS)pyrrole vs the benchmark
pyrroles. For pyrrole itself, the R-(2-,5-) positions were six times
more reactive toward deuterium exchange vs the â-(3-,4-)
positions, which is comparable to the results of Bean’s study
of pyrrole in dilute acid, where the corresponding reactivity
difference was 1.6-fold.14
For a given 2-alkylthio-substituted pyrrole (Me-4, Et-4, and
Decyl-4), the reactivity toward deuterium exchange decreased
in the following order: 5-position ∼ 3-position > 4-position.
The presence of the 2-phenylthio group deactivates the pyrrole
ring; thus, deuterium exchange at all positions was very slow
for Ph-4. With pyrrole-2-carboxylic acid, no significant deu-
terium-hydrogen exchange was observed after two days, so
rate constants were not calculated.
To confirm that the observed deuterium exchange was not
confounded with any chemical reactions (e.g., pyrrole polym-
erization) under the acidic conditions, the reverse hydrogen-
deuterium exchange (dedeuteration) was examined. Thus, a
solution of deuterated Decyl-4 (>90% for D5 and D3 and >30%
for D4) in CD3COOD containing 1,3,5-tribromobenzene as an
internal standard was treated with CH3COOH (1 mL) for 24 h
at 20 °C. Integration of the resonances in the aromatic region
showed >98% conversion of deuterium to hydrogen in the
sample of Decyl-4. This experiment confirmed the integrity of
the 2-alkylthiopyrrole core structure under the acidic conditions.
(12) Klyba, L. V.; Bochkarev, V. N.; Brandsma, L.; Nedolya, N. A.;
Trofimov, B. A. Russ. J. Gen. Chem. 1999, 69, 1885-1890.
(13) (a) Leong, T. S.; Peach, M. E. J. Fluorine Chem. 1975, 5, 545-
558. (b) Haas, A.; Niemann, U. Chem. Ber. 1977, 110, 67-77. (c) Silvestri,
R.; Pagnozzi, E.; Stefancich, G.; Artico, M. Synth. Commun. 1994, 24,
2685-2695.
(14) Bean, G. P. J. Chem. Soc., Chem. Commun. 1971, 421.
(15) Muir, D. M.; Whiting, M. C. J. Chem. Soc., Perkin Trans. 2 1975,
1316-1320.
(16) Bean, G. P.; Wilkinson, T. J. J. Chem. Soc., Perkin Trans. 2 1978,
72-77.
(17) Gilow, H. M.; Hong, Y. H.; Millirons, P. L.; Snyder, R. C.; Casteel,
W. J., Jr. J. Heterocycl. Chem. 1986, 23, 1475-1480.
J. Org. Chem, Vol. 71, No. 3, 2006 905

Thamyongkit et al.
TABLE 2. Acid Screening Experiments for the Condensation of
2-(Methylthio)pyrrole (Me-4) and Benzaldehydea
product/N-confused
acid
TFA
byproduct ratiob
darknessc
3.3:1
6.1:1
5.9:1
3.4:1
4.4:1
brown
yellow
orange
orange
InCl3
MgBr2
d
Sc(OTf)3
Yb(OTf)3
light yellow
a Condensations (solventless) were performed with a 2:1:0.1 ratio of Me-
4/benzaldehyde/acid at room temperature for 1 h. b Only the peaks of Me-
1a (tR ) 19.3 min) and the putative N-confused byproduct (tR ) 19.6 min)
are considered; the peak assigned to 2-benzyl-5-(methylthio)pyrrole (tR
)
∼13.2 min) was observed in all cases but not taken into consideration.
c Relative darkening of the reaction mixture after quenching with base.d The
reaction time was 16 h.
FIGURE 1. Reactivity of 2-(RS)pyrroles for deuterium exchange
relative to exchange at the corresponding position of pyrrole. The value
given for each position is the ratio of two rate constants.
SCHEME 3
romethane (2), and 5,10-diphenyltripyrrane (3), as illustrated
in Scheme 1, when R ) phenyl. To assess the cleanliness of
the reaction yielding Me-1a, each fraction obtained from column
chromatography was analyzed by gas chromatography (GC),
gas chromatography mass spectrometry (GC-MS), and 1H
NMR spectroscopy. GC and GC-MS analyses showed two
dominant peaks (tR ) 19.3 and 19.6 min) that gave the same
molecule ion peak (m/z ) 312); the former was due to
dipyrromethane Me-1a, and the latter was due to a putative
N-confused dipyrromethane byproduct. A similar chromatogram
was observed in the condensation of pyrrole and benzaldehyde.5
No tripyrrane species were observed. This demonstrated the
stability of the methylthio protecting group toward the dipyr-
romethane-forming reaction conditions.
The effects of TFA or a mild Lewis acid (InCl3, MgBr2, Yb-
(OTf)3, or Sc(OTf)3) on the reaction course in the solventless
synthesis were examined. The cleanliness of the reaction was
determined quantitatively by the ratio of the dipyrromethane
Me-1a and the byproducts (detectable by GC analysis), and
qualitatively by the darkness of the reaction mixture.5 The
darkening of the reaction mixture signals the formation of the
materials that decrease the yield and complicate the purification
(such materials are difficult to quantitate by GC).5 The results
are summarized in Table 2. Considering all factors, InCl3
afforded the best results with dipyrromethane Me-1a and was
chosen as the catalyst for further studies.
Comparing the various 2-thiopyrroles with pyrrole, we note
that the presence of alkylthio substitution has the following
effect on each position toward deuterium exchange: (1) the
5-positions are slightly activated (1.5-4-fold), (2) the 4-positions
are deactivated (5-7-fold), and (3) the 3-positions are strongly
activated (8-25-fold). As expected, 2-methylpyrrole was strongly
activated toward deuterium exchange at the 3- and 5-positions
(>100 times) and at the 4-position (7 times).16 Thus, the
2-alkylthiopyrroles lie intermediate in reactivity between pyrrole
and 2-methylpyrrole. For ease of comparison, the relative
reactivity for deuterium exchange at a given position for the
various pyrroles compared to that of pyrrole itself is illustrated
in Figure 1. It is noteworthy that these results are at odds with
the expected electroneutrality or slight deactivation of alkylthio
groups predicted by the Hammett substituent constants.18
3. Synthesis of Dipyrromethanes. A. Condensation Yield-
ing 1,9-Bis(RS)dipyrromethanes. The condensation of Me-4
and benzaldehyde (0.25 M) was performed in CH2Cl2 containing
TFA (0.1 M) at room temperature, leading to dipyrromethane
Me-1a in 56% yield (Scheme 3). The same reaction in the
absence of CH2Cl2 (solventless) afforded Me-1a in 47% yield.
In both cases, only 2.2 mol equiv of Me-4 was employed, rather
than 25-100 mol equiv as in the one-flask synthesis of
dipyrromethanes from pyrrole and an aldehyde.
The conditions using InCl3 were applied with other 2-(RS)-
pyrroles in an effort to find substrates that afford an increase in
the ratio of dipyrromethane/N-confused byproduct and also limit
reliance on extensive chromatography for purification. The
reaction mixture obtained from Ph-4 contained Ph-1a and no
detectable quantity of N-confused byproduct, whereas that of
Decyl-4 gave Decyl-1a and the N-confused byproduct in g20:1
1
ratio. The H NMR analysis showed the remaining starting
material, Ph-4 or Decyl-4, in such reaction mixtures at the level
of ∼25 or ∼5%, respectively. Attempts to separate each
dipyrromethane, Ph-1a or Decyl-1a, by recrystallization of the
reaction mixture were unsuccessful. Purification by passage over
a short chromatographic column gave Ph-1a or Decyl-1a in 59
or 65% yield, respectively.
B. Hydrodesulfurization of 1,9-Bis(RS)dipyrromethanes.
Carbon-sulfur bond cleavage can be achieved using a variety
of metallic or organometallic reagents, of which Raney nickel
has been used the most frequently.19 Accordingly, removal of
The condensation of pyrrole and benzaldehyde typically
affords 5-phenyldipyrromethane (1), N-confused 5-phenyldipyr-
(19) (a) Pettit, G. R.; van Tamelen, E. E. Org. React. 1962, 12, 356-
529. (b) Hauptmann, H.; Walter, W. F. Chem. ReV. 1962, 62, 347-404.
(18) Hansch, C.; Leo, A.; Taft, R. W. Chem. ReV. 1991, 91, 165-195.
906 J. Org. Chem., Vol. 71, No. 3, 2006

Alkylthio Unit as an R-Pyrrole Protecting Group
TABLE 3. Synthesis of Dipyrromethanesa
SCHEME 4
the methylthio units from dipyrromethane Me-1a was carried
out by reduction with Raney nickel in refluxing EtOH. The
workup procedure requires filtration through a silica pad to
remove polar components and the remaining Raney nickel. The
deprotected product 1a was obtained in 97% yield. Application
of the same conditions to Ph-1a afforded an incomplete reaction
and the formation of several pyrrolic byproducts. This observa-
tion was consistent with Bru¨ckner’s report, wherein the forma-
tion of coupling byproducts occurred in the reductive desulfu-
rization of di-2-pyrrolylthione with Raney nickel.20 In the case
of Decyl-1a, Raney-nickel deprotection afforded 1a in 69%
yield. The use of other reagents (e.g., nickel boride generated
in situ from NiCl2 and NaBH4) did not afford better results.
a The condensations were carried out using a molar ratio of 2-(n-
decylthio)pyrrole/aldehyde/InCl3 of 2.2:1.0:0.2 for 16 h at room temperature
in the absence of any solvent. InCl3 was removed by precipitation with
hexanes. The crude product was hydrodesulfurized with Raney nickel at
room temperature. The solid dipyrromethane product was isolated by
precipitation. b TFA (0.23 mol equiv) was employed in place of InCl3; the
condensation was carried out for 1.75 h, and the condensation reaction
mixture was worked up by aqueous-organic extraction. c Column chro-
matography afforded the product as an oil. d The condensation was carried
out for 36 h.
tion of the aldehydes. Attempts to use molecular sieves to
remove the large quantity of water generated (∼1.8 M) were
unsuccessful (see Supporting Information). The application of
these conditions generally gave good results. However, the
swallowtail aldehyde 7-formyltridecane27 reacted sluggishly and
required 36 h for completion. Mesitaldehyde reacted smoothly
upon use of TFA instead of InCl3.
A simple method for the removal of InCl3 entails precipitation
upon addition of powdered NaOH,5 but traces of base deactivate
Raney nickel.28 To achieve a streamlined procedure for con-
densation/hydrodesulfurization, the crude dipyrromethane reac-
tion mixture was treated with hexanes, causing precipitation of
InCl3 while keeping the 1,9-bis(n-decylthio)dipyrromethane in
solution. The sole exception occurred in the synthesis of
dipyrromethane 1c where TFA catalysis was employed, where-
upon the reaction mixture was neutralized by 0.1 N aqueous
NaOH.
C. Scope of Application. The synthesis of dipyrromethanes
bearing diverse meso-substituents was examined using the
solventless synthesis with 2-(n-decylthio)pyrrole followed by
Raney-nickel mediated hydrodesulfurization of the resulting
dipyrromethane (Scheme 4). Each of the target dipyrromethanes
(1a,21 1b,22 1c,3 1d,23 1e,24 1f,25 and 1g26) is known, and 1a-
f 5 and 1g26 have been prepared recently by the solventless
synthesis method using pyrrole in large excess (typically 100
mol equiv).5 The solventless condensation herein was carried
out initially using a 2:1:0.1 ratio of Decyl-4/aldehyde/InCl3 at
1
room temperature for 2 h. However, H NMR analysis of the
reaction mixtures showed ∼5% incompletion; hence, the ratio
was increased to 2.2:1:0.2 and the reaction time was lengthened
to 16 h. This slight modification resulted in complete consump-
The resulting crude residue directly underwent hydrodesulfu-
rization with Raney-nickel slurry in THF at room temperature
for 1-2 h. The standard workup included removal of Raney
nickel by filtration followed by silica pad filtration or flash
column chromatography. The yield of each dipyrromethane
ranged from 38 to 66% (Table 3).
(20) Bru¨ckner, C.; Posakony, J. J.; Johnson, C. K.; Boyle, R. W.; James,
B. R.; Dolphin, D. J. Porphyrins Phthalocyanines 1998, 2, 455-465.
(21) Wilson, R. M.; Hengge, A. J. Org. Chem. 1987, 52, 2699-2707.
(22) Chong, R.; Clezy, P. S.; Liepa, A. J.; Nichol, A. W. Aust. J. Chem.
1969, 22, 229-238.
(23) Boyle, R. W.; Karunaratne, V.; Jasat, A.; Mar, E. K.; Dolphin, D.
Synlett 1994, 939-940.
4. Additional Transformations. A. Oxidation Processes.
Dipyrromethanes typically undergo oxidation to give the cor-
(24) Lee, C.-H.; Kim, J.-Y. Bull. Korean Chem. Soc. 1996, 17, 215-
217.
(25) Hammel, D.; Erk, P.; Schuler, B.; Heinze, J.; Mu¨llen, K. AdV. Mater.
1992, 4, 737-739.
(27) Kato, M.; Komoda, K.; Namera, A.; Sakai, Y.; Okada, S.; Yamada,
A.; Yokoyama, K.; Migita, E.; Minobe, Y.; Tani, T. Chem. Pharm. Bull.
1997, 45, 1767-1776.
(26) Thamyongkit, P.; Speckbacher, M.; Diers, J. R.; Kee, H. L.;
Kirmaier, C.; Holten, D.; Bocian, D. F.; Lindsey, J. S. J. Org. Chem. 2004,
69, 3700-3710.
(28) Grundmann, C.; Kober, E. J. Org. Chem. 1956, 21, 641-643.
J. Org. Chem, Vol. 71, No. 3, 2006 907

Thamyongkit et al.
SCHEME 5
responding dipyrrin, which can be a useful transformation in
the preparation of porphyrin precursors. The 1,9-bis(RS)-
dipyrromethanes differ from more simple dipyrromethanes
because they have two sites of reactivity toward oxidants, the
dipyrromethane motif and the two thioethers. Treatment of the
protected dipyrromethane Me-1a with DDQ gave the corre-
sponding dipyrrin Me-6a in 60% yield (eq 4). Treatment of
dipyrrin Me-6a with zinc acetate did not afford the correspond-
ing bis(dipyrrinato)zinc complex, unlike dipyrromethanes lack-
ing 1,9-substituents.29
Oxidation of the alkylthio group provides an alternative to
the use of Raney nickel for carbon-sulfur cleavage. Indeed, a
2-(methylthio)pyrrole was converted to the corresponding
sulfone using m-CPBA,6,30 and reductive desulfonation of
pyrrolic compounds has been achieved with Bu3SnH (photo-
chemically)30 or with Na(Hg) and Na2HPO4 in EtOH.31 We
found that 2-(n-decylthio)pyrrole (Decyl-4) was converted with
m-CPBA to the corresponding 2-(n-decylsulfonyl)pyrrole in 69%
yield. Thus, each crude dipyrromethane reaction mixture,
prepared by the condensation of benzaldehyde and Me-4, Ph-
4, or Decyl-4 via the solventless approach, was subjected to
oxidation with m-CPBA. In two cases examined in detail
(reaction of Ph-4 or Decyl-4), the corresponding bis(sulfone)
was isolated in ∼75% crude yield and at least 70% purity but
proved difficult to purify to homogeneity. To facilitate isolation
of the intermediate sulfone prior to desulfonation, we explored
the use of tin complexation,32 which afforded excellent results
with the structurally similar 1,9-diacyldipyrromethanes. Tin
complexation was carried out with Bu2SnCl2 in the presence of
TEA (Scheme 5). After filtration through a silica pad, Me-7a
or Decyl-7a was isolated as a viscous oil in 5 or 9% yield,
respectively. Ph-7a was obtained as platelike crystals in 21%
yield upon recrystallization. The low overall yields likely stem
from inefficient tin complexation. The X-ray crystal structure
of tin complex Ph-7a shows one O atom of each sulfonyl group
coordinated with the Sn atom, resulting in slight elongation of
the SdO bond (see Supporting Information). The superior yield
of Raney-nickel hydrodesulfurization made this the method of
choice for deprotection.
SCHEME 6
B. Stepwise Synthesis of Dipyrromethanes. The presence
of the 2-RS substituent opens the possibility of a stepwise
synthesis of dipyrromethanes. Thus, pyrrole Me-4 was acylated
by N,N-dimethylbenzamide in the presence of phosphorus
oxychloride following an established procedure7 to obtain
5-benzoyl-2-(methylthio)pyrrole (Me-8a) (Scheme 6). NaBH4
reduction of Me-8a led to the corresponding carbinol derivative.
Condensation of the carbinol derivative with a stoichiometric
amount of pyrrole Me-4 in the presence of InCl3 (0.1 equiv)
gave Me-1a in 45% yield. This route illustrates the potential
for exploitation of the 2-alkylthio group in stepwise syntheses
of pyrromethane compounds.
(29) Yu, L.; Muthukumaran, K.; Sazanovich, I. V.; Kirmaier, C.; Hindin,
E.; Diers, J. R.; Boyle, P. D.; Bocian, D. F.; Holten, D.; Lindsey, J. S.
Inorg. Chem. 2003, 42, 6629-6647.
(30) Antonio, Y.; de la Cruz, M. E.; Galeazzi, E.; Guzman, A.; Bray, B.
L.; Greenhouse, R.; Kurz, L. J.; Lustig, D. A.; Maddox, M. L.; Muchowski,
J. M. Can. J. Chem. 1994, 72, 15-22.
Outlook
(31) Pelkey, E. T.; Barden, T. C.; Gribble, G. W. Tetrahedron Lett. 1999,
40, 7615-7619.
The rational synthesis of porphyrins requires the ability to
prepare precursors such as dipyrromethanes in a controlled
(32) Tamaru, S.-I.; Yu, L.; Youngblood, W. J.; Muthukumaran, K.;
Taniguchi, M.; Lindsey, J. S. J. Org. Chem. 2004, 69, 765-777.
908 J. Org. Chem., Vol. 71, No. 3, 2006

Alkylthio Unit as an R-Pyrrole Protecting Group
Cl2. The organic phase was collected, dried (Na2SO4), and
concentrated. The crude mixture was passed through a silica column
(hexanes/ethyl acetate (8:1), 2.5 cm diameter × 18 cm in height).
Four fractions were obtained. The first fraction (yellow, Rf ) 0.50)
contained unknown pyrrole derivatives (by 1H NMR analysis). The
second fraction (colorless) consisted of unreacted Me-4 (Rf ) 0.45).
The third fraction (Rf ) 0.21) contained the product (Me-1a) in
the form of a viscous yellow oil (71 mg, 56%), which solidified
after 24 h at -15 °C. The last fraction had the same color and
retention (Rf ) 0.21) as that of the product, but 1H NMR, GC, and
GC-MS analyses indicated the presence of a mixture containing
an N-confused dipyrromethane. Characterization data for Me-1a:
manner. For â-substituted pyrroles, the R-carboxy group has
proved to be an effective masking agent, enabling introduction
of an R′-substituent. For â-unsubstituted pyrroles, which have
three sites open for reaction and are less electron rich than
typical â-substituted pyrroles, an R-masking agent that is not
deactivating is highly desirable. The studies reported herein have
established the relative activity of the 3-, 4-, and 5-positions in
a 2-(RS)-substituted pyrrole toward deuteration. In general, the
5-position of a 2-(alkylthio)-substituted pyrrole is ∼1.5-4 times
more reactive toward deuteration vs that of pyrrole itself. The
order of reactivity toward deuteration in a given 2-(RS)pyrrole
was 5-position ∼ 3-position > 4-position; however, upon acid-
catalyzed reaction with an aldehyde, the dominant product is
the desired dipyrromethane. The relative lack of reactivity at
the 3-position in this substitution process (vs deuteration) may
stem from steric hindrance of the bulky 2-alkylthio group. The
2-(n-decylthio) group was chosen for use in a study of
dipyrromethane formation. The ability to form dipyrromethanes
with the use of a stoichiometric quantity of the pyrrole
compound can be contrasted with the existing one-flask
synthesis of dipyrromethanes, which typically employs 25-100
mol equiv of pyrrole relative to the aldehyde. Taken together,
this work establishes the foundation for the use of the 2-alkylthio
group as a protecting group in pyrrole chemistry, including
introduction and removal under mild conditions and exploitation
for directing electrophilic substitution at the 5-position.
1
mp 90-91 °C; H NMR (THF-d8) δ 2.22 (s, 6H), 5.32 (s, 1H),
5.55-5.58 (m, 2H), 6.06-6.08 (m, 2H), 7.13-7.26 (m, 5H), 10.14
(br s, 2H); 13C NMR (THF-d8) δ 21.8, 45.5, 109.4, 115.1, 121.6,
127.2, 128.9, 129.4, 136.8, 143.7; FAB-MS obsd 314.0918, calcd
314.0911 (C17H18N2S2).
Solventless Synthesis. A mixture of benzaldehyde (85.2 mg,
0.802 mmol) and Me-4 (182 mg, 1.61 mmol, 2.0 equiv) was treated
with TFA (6.2 µL, 80 µmol, 0.1 equiv) at room temperature. After
15 min, the reaction mixture became viscous and the stirring was
very slow. Benzaldehyde was completely consumed within 1 h (by
TLC). Workup and purification as described above gave Me-1a
(0.12 g, 47%) with characterization data consistent with those
described above.
Stepwise Synthesis. A solution of pyrrole Me-8a (30.0 mg, 0.138
mmol) in THF/MeOH (3.0 mL, 10:1) was treated with NaBH4 (15.7
mg, 0.415 mmol) at room temperature for 20 min. The reaction
mixture was poured in a mixture of saturated aqueous NH4Cl (10
mL) and CH2Cl2 (10 mL). The organic phase was separated, washed
with water, dried (Na2SO4), and concentrated to dryness. A mixture
of the resulting residue and pyrrole Me-4 (15.6 mg, 0.138 mmol)
was dissolved in toluene (1.3 mL) and treated with InCl3 (30.5 mg,
0.139 mmol) at room temperature. After 30 min, the reaction
mixture was washed with 1 M aqueous NaOH. The organic layer
was dried (Na2SO4), concentrated, and chromatographed [silica,
hexanes/ethyl acetate (8:1)], affording a yellow oil (20 mg, 45%)
that solidified after 24 h at -15 °C. Characterization data were
consistent with those described above.
Experimental Section
Effect of R-Pyrrole Substituents: Kinetic Study of Deutera-
tion. A solution of CD3COOD (600 µL, 10.5 mmol) was added to
an R-substituted pyrrole (52 µmol) in an NMR tube at 20 °C.
1
Kinetic measurements were made by H NMR spectroscopy to at
least 90% exchange for the protons undergoing fast exchange and
to at least 60% exchange for those undergoing slow exchange (see
Supporting Information).
Acid Screening Experiment. All experiments were carried out
in the absence of a solvent. Each experiment employed benzalde-
hyde (42.6 mg, 401 µmol), Me-4 (91.0 mg, 804 µmol), and an
acid (40 µmol, 0.1 equiv relative to benzaldehyde) [TFA (3.1 µL),
InCl3 (8.9 mg), MgBr2 (7.4 mg), Yb(OTf)3 (25 mg) or Sc(OTf)3
(20 mg)]. The reaction was monitored by thin-layer chromatography
(TLC) analysis and stopped after the consumption of benzaldehyde
was complete. In each case, the reaction was quenched by adding
0.1 N aqueous NaOH and ethyl acetate after 1 h (with the exception
of the reaction using MgBr2, which took 16 h). After drying and
General Procedure for Dipyrromethane Synthesis Using an
n-Decylthio R-Pyrrole Protecting group, Exemplified for 5-Phe-
nyldipyrromethane (1a). A mixture of benzaldehyde (0.796 g, 7.50
mmol) and Decyl-4 (3.95 g, 16.5 mmol) in the absence of any
solvent was treated with InCl3 (0.332 g, 1.50 mmol) in a loosely
closed reaction vessel without deaeration. The heterogeneous
mixture was stirred magnetically at room temperature for 16 h. The
resulting violet mixture was treated with hexanes (5 mL), affording
a brownish mixture. The mixture was filtered through a sintered
glass funnel. The filtered material was washed with a small amount
of hexanes. The filtrate was concentrated to dryness, affording a
brown residue. The flask containing the crude brown residue was
placed on a balance. A solid portion of 30.0 g of wet Raney nickel
was removed from a Raney-nickel-THF slurry by a spatula and
added directly to the flask containing the brown residue. Reagent
grade THF (5.0 mL) was added to wash the inner walls of the flask.
The mixture was stirred at room temperature for 1 h. The mixture
was filtered through a sintered glass funnel to remove the Raney
nickel. The filtered material was washed with THF (∼150 mL).
The filtrate was concentrated to dryness. The resulting crude residue
was dissolved in a small quantity of hexanes/toluene (1:2) and
placed on top of a silica pad (3 cm diameter × 2 cm in height).
The silica pad was eluted with hexanes/toluene [(1:2), ∼200 mL].
The first fraction contained 2-benzyl-5-(methylthio)pyrrole, 2-(me-
thylthio)pyrrole, and unknown pyrrolic byproducts as determined
1
concentrating to dryness, each crude mixture was analyzed by H
1
NMR spectroscopy and GC. H NMR spectra showed compound
Me-1a as the main component and small peaks of the unreacted
2-(methylthio)pyrrole. A peak due to an N-confused byproduct
could not be clearly observed. Therefore, GC analysis was employed
to compare the yield and the cleanliness of the reaction, as described
in Table 1. The solution for the GC analysis was prepared by
diluting 5.0 mg of the crude mixture in 0.45 mL of THF.
1,9-Bis(methylthio)-5-phenyldipyrromethane (Me-1a). Several
conditions were investigated. The title compound was obtained both
under solution and under solventless conditions. The preferred
solventless condition was employed for the acid screening study.
Solution Synthesis. A mixture of benzaldehyde (42.6 mg, 401
µmol, 0.25 M) and Me-4 (100 mg, 884 µmol, 2.2 equiv) in CH2-
Cl2 (1.6 mL) was degassed for 5 min at room temperature. TFA
(12.0 µL, 156 µmol, 0.1 M) was added. The reaction was stopped
after 30 min, when the consumption of benzaldehyde was complete
(by TLC and 1H NMR spectroscopy). The violet reaction mixture
was treated with a mixture of 0.1 N aqueous NaOH and ethyl acetate
(10 mL, 1:1). The resulting orange mixture was extracted with CH2-
1
by GC analysis (and subsequent GC-MS analysis and H NMR
spectroscopy). The second fraction contained predominantly the
title compound accompanied by a trace amount of the byproducts.
The second fraction was concentrated to dryness. The resulting
yellowish solid was treated with hexanes (∼20 mL), and the slurry
J. Org. Chem, Vol. 71, No. 3, 2006 909

Thamyongkit et al.
was heated until the solvent refluxed. After a few minutes, the slurry
was filtered. The filtrate, which contained less polar byproducts
and only a small quantity of product, was discarded. The filtered
material (white) was washed with a small amount of hexanes and
then collected, affording a white solid (1.10 g, 66%): mp 98-99
commercial supplier, 1.91 mmol), and the mixture was stirred at
0 °C for 4 h. After warming to room temperature, the reaction
mixture was washed with saturated aqueous NaHCO3. The organic
phase was separated, washed with water, dried (Na2SO4), and
concentrated. Following a standard method,32 the crude mixture
was redissolved in CH2Cl2 (3 mL). TEA (0.265 mL, 1.91 mmol)
was added. The reaction mixture was treated with Bu2SnCl2 (193
mg, 0.635 mmol) for 30 min and then filtered through a silica pad
(CH2Cl2), affording a pale yellow viscous oil (25 mg, 5%): 1H
NMR (THF-d8) δ 0.70-0.77 (m, 6H), 0.86-1.21 (m, 4H), 1.28-
1.42 (m, 4H), 1.58-1.67 (m, 4H), 3.14 (s, 6H), 5.54 (s, 1H), 6.22
(d, J ) 3.2 Hz, 2H), 6.89 (d, J ) 3.2 Hz, 2H), 6.98-7.01 (m, 2H),
7.09-7.20 (m, 3H); 13C NMR (THF-d8) δ 13.84, 13.94, 26.6, 27.11,
27.14, 27.4, 28.0, 29.4, 45.9, 114.1, 116.4, 127.1, 128.6, 129.0,
132.6, 144.8, 145.9; FAB-MS obsd 611.1087, calcd 611.1060 [(M
+ H)+, M ) C25H34N2O4S2Sn].
1
°C (lit.21 100.2-101.1 °C); H NMR δ 5.49 (s, 1H), 5.92-5.98
(m, 2H), 6.15-6.22 (m, 2H), 6.65-6.75 (m, 2H), 7.22-7.36 (m,
5H), 7.94 (br s, 2H); 13C NMR δ 43.9, 107.2, 108.4, 117.2, 127.0,
128.4, 128.6, 132.5, 142.0. Anal. Calcd for C15H14N2: C, 81.05;
H, 6.35; N, 12.60. Found: C, 81.05; H, 6.44; N, 12.33.
1,9-Bis(methylthio)-5-phenyldipyrrin (Me-6a). Following a
standard procedure,29 a solution of Me-1a (20.0 mg, 63.6 µmol) in
THF (0.64 mL) was treated with DDQ (17.3 mg, 73.2 µmol) at
room temperature for 24 h. The mixture was concentrated and
chromatographed (hexanes/ethyl acetate (5:1) containing 1% TEA),
affording a yellow viscous solid (12 mg, 60%): 1H NMR (THF-
d8) δ 2.64 (s, 6H), 6.32 (d, J ) 4.4 Hz, 2H), 6.45 (d, J ) 4.4 Hz,
2H), 7.43 (s, 5H); 13C NMR (THF-d8) δ 16.0, 30.7, 119.0, 128.6,
128.9, 129.4, 131.7, 134.2, 138.0, 142.2, 151.8; FAB-MS obsd
313.0836, calcd 313.0833 [(M + H)+, M ) C17H16N2S2]; λabs 336,
474 nm.
Dibutyl[5,10-dihydro-1,9-bis(methylsulfonyl)-5-phenyldipyr-
rinato]tin(IV) (Me-7a). Following the solventless synthesis of Me-
1a described above, a mixture of benzaldehyde (85.2 mg, 0.802
mmol) and Me-4 (182 mg, 1.61 mmol) was treated with InCl3 (17.8
mg, 80.0 µmol) at room temperature. After 1 h, TLC showed the
reaction to be complete. The reaction mixture was diluted with ethyl
acetate and washed with 0.1 M aqueous NaOH. The organic phase
was separated, washed with water, dried (Na2SO4), and concentrated
to dryness. Following a published procedure,30 the residue was
dissolved in CH2Cl2 (15 mL) and cooled to 0 °C in an ice bath.
The solution was treated with m-CPBA (428 mg, 77% purity from
Acknowledgment. This research was supported by the NIH
(GM-36238). Mass spectra were obtained at the Mass Spec-
trometry Laboratory for Biotechnology at North Carolina State
University. Partial funding for the facility was obtained from
the North Carolina Biotechnology Center and the National
Science Foundation.
Supporting Information Available: Complete Experimental
Section, including procedures for kinetic experiments and extensive
kinetic data; procedures for the synthesis of all new compounds;
1
and H NMR and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JO051806Q
910 J. Org. Chem., Vol. 71, No. 3, 2006