Regioselective substituent effects upon the synthesis of dipyrrins from 2-formyl pyrroles

Article abstract of DOI:10.1139/cjc-2017-0662

The synthesis of symmetric α-free meso-H-dipyrrin hydrobromides from 5-H-2-formyl pyrroles was investigated. The self-condensation produces regioisomeric dipyrrins through adoption of two mechanistic pathways. The key difference between the two pathways lies in which position of the pyrrole directs nucleophilic attack. Through a systematic study involving various substituted and (or) isotopically labelled 5-H-2-formyl pyrroles, we herein provide evidence to suggest that not only do two mechanistic pathways exist, but the steric bulk of the substituent adjacent to the 5-unsubstituted position influences which pathway dominates.

Full text of DOI:10.1139/cjc-2017-0662

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ARTICLE
Regioselective substituent effects upon the synthesis of
dipyrrins from 2-formyl pyrroles
Michael H.R. Beh, Carlotta Figliola, Kate-Lyn A.R. Lund, Aleksandra K. Kajetanowicz, Ann E. Johnsen,
Elise M. Aronitz, and Alison Thompson
Abstract: The synthesis of symmetric ␣-free meso-H-dipyrrin hydrobromides from 5-H-2-formyl pyrroles was investigated. The
self-condensation produces regioisomeric dipyrrins through adoption of two mechanistic pathways. The key difference between
the two pathways lies in which position of the pyrrole directs nucleophilic attack. Through a systematic study involving various
substituted and (or) isotopically labelled 5-H-2-formyl pyrroles, we herein provide evidence to suggest that not only do two
mechanistic pathways exist, but the steric bulk of the substituent adjacent to the 5-unsubstituted position influences which
pathway dominates.
Key words: dipyrrins, pyrroles, steric effects, condensation, synthesis.
Résumé : Nous avons étudié la synthèse de bromhydrates de méso-H-dipyrrine symétriques non substituées à la position ␣ à
partir de 5-H-2-formylpyrroles. Ceux-ci subissent une autocondensation pour former des dipyrrines régio-isomériques par deux
voies mécanistiques différentes. La principale différence entre ces deux voies réside dans la position du pyrrole qui dirige
l’attaque nucléophile. Au moyen d’une étude systématique faisant appel à une série de 5-H-2-formylpyrroles substitués et/ou
marqués d’un isotope, nous faisons la démonstration non seulement qu’il existe deux voies mécanistiques, mais que
l’encombrement stérique du substituant adjacent à la position 5 non substituée a une incidence sur la voie privilégiée. [Traduit
par la Rédaction]
Mots-clés : dipyrrines, pyrroles, effets stériques, condensation, synthèse.
yields (60%–90%). Substituents such as alkyl, keto, alkanoate, and
conjugated esters were well tolerated. As well as being convenient
and efficient, this strategy complements existing literature meth-
ods by enabling the high-yielding synthesis of symmetric dipyr-
rins from pyrroles that bear electron withdrawing functional
groups.
When subjected to these reaction conditions, a 5-H-2-formyl
pyrrole (R1 = H in Scheme 1, top) produced both symmetric and
asymmetric regioisomers in a 9:1 ratio, respectively.18 The reac-
tion mechanism for formation of dipyrrins under these condi-
tions was presumed to proceed analogously to that for a fully
substituted 2-formyl pyrrole,17 whereby the carbonyl carbon atom
of one pyrrole undergoes nucleophilic attack by another to gen-
erate the requisite dipyrrin (Scheme 2). However, this does not
explain the presence of both asymmetric and symmetric prod-
ucts. We suspected that by virtue of the unsubstituted 5-position,
attack could originate from either the 2- or 5-position of 5-H-2-
formyl pyrroles. Thus, with two nucleophilic sites, two possible
regioisomeric dipyrrins could form (Scheme 1, bottom).
Introduction
Although historically used as a building block for porphyrins,1
in recent years the dipyrrinato unit2–6 (Fig. 1) has come to be
appreciated as a useful chromophore by which to invoke desirable
features such as energy transfer and storage.7,8 There are numer-
ous reports describing the use of dipyrrinato complexes in appli-
cations as diverse as biological stains or probes, light harvesters,
and anticancer agents.9 Of the dipyrrinato complexes, boron difluo-
ride complexes are the most thoroughly studied due to their high
thermal and photochemical stability, chemical robustness, high
fluorescence quantum yields, and tuneable fluorescence proper-
ties. These complexes are formally known as 4,4=-diflouro-4-bora-
diaza-s-indacenes and are commonly referred to as F-BODIPYs
(Fig. 1). Beyond the established utility of F-BODIPYs,11–14 the lumi-
nescence properties of these complexes, and those of other
metals,10–12 have fostered the use of this framework in dye-sensitized
solar cells and catalysts for hydrogenation and hydroamina-
tion,13–16 all pointing towards a promising future for this under-
developed ligand.
Based on a one-pot approach to transform 2-formyl pyrroles
into F-BODIPYs,17 we previously reported the efficient synthesis of
symmetric meso-H-dipyrrins from 2-formyl pyrroles in the pres-
ence of acid (Scheme 1, top).18 Using methanol as a solvent and
heating 2-formyl pyrroles at 70 °C for 1 h in the presence of excess
aqueous 48% hydrobromic acid, we produced the requisite sym-
metric dipyrrin hydrobromide salts in moderate-to-high isolated
Results and discussion
Curious as to the origin of this regioselectivity, the reaction
pathways for formation of ␣-free dipyrrins from 5-H-2-formyl pyr-
roles were investigated. Accordingly, several 5-H-2-formyl pyr-
roles bearing alkyl and isotopically labelled substituents at the
Received 25 October 2017. Accepted 19 December 2017.
M.H.R. Beh, C. Figliola, K.-L.A.R. Lund, A.K. Kajetanowicz, A.E. Johnsen, E.M. Aronitz, and A. Thompson. Department of Chemistry, Dalhousie
University, P.O. Box 15000, Halifax, NS B3H 4R2, Canada.
Corresponding author: Alison Thompson (email: Alison.Thompson@dal.ca).
This paper is part of a Special Issue to celebrate the 200th anniversary of Dalhousie University in Halifax, Nova Scotia, Canada.
Copyright remains with the author(s) or their institution(s). Permission for reuse (free in most cases) can be obtained from RightsLink.
Can. J. Chem. 00: 1–6 (0000) dx.doi.org/10.1139/cjc-2017-0662
Published at www.nrcresearchpress.com/cjc on 26 March 2018.

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Can. J. Chem. Vol. 00, 0000
Fig. 1. Dipyrrin (left) and F-BODIPY (right).
Table 1. meso-H-dipyrrin formation from alkyl substituted 5-H-2-for-
myl pyrrole 1.
R
R
R3
R3
R3
R3
R2
R2
N
N
N
HN
HBr, MeOH
70 C, 1 h
B
R2
R2
R2
R3
+
H
N
HBr
HN
N
HBr
HN
N
H
F
F
O
1
sym-2
asym-2
Scheme 1. meso-H-dipyrrin formation from 2-formyl pyrroles.
Entry
Pyrrole
R2
Et
Me
Me
Et
R3
Isolated yield (%)
Previous work
1
1a
1b
1c
1d
Me
Et
Me
Et
63 (9:1)a
0
0
75
R3
R3
R3
R2
2
3
4
HBr, MeOH
70 C, 1 h
R2
R2
N
HN
R1
N
HBr
asym-2 was the major isomer produced.
H
R1
R1
O
duced a polymeric tar (Table 1, entry 3), we evaluated whether
thermal (not acid-catalyzed) deformylation, and (or) condensa-
tion, of 1c occurred at the reaction temperature (70 °C). However,
despite heating a solution of 1c in MeOH at 70 °C for prolonged
periods of time, neither deformylation nor condensation oc-
curred. This indicated that protonation of 2-formyl pyrroles is
necessary for reaction to occur. Cognizant of this fact, the reaction
conditions were modified to enable isolation of dipyrrin rather
than allow subsequent reaction to lead to polymerization. Expo-
sure of a solution of 1c to HBr at 0 °C resulted in isolation of the
new acetal-containing dipyrrin 3 (Scheme 3, top). As the acetal
moiety of 3 is merely a protected formyl group formed under the
acidic methanolic reaction conditions, this result suggested that
nucleophilicity originated from the 5-position of pyrrole 1c. When
the reaction was repeated at 70 °C (vessel immersed into oil bath
held at 70 °C) and quenched after just 10 s, the new dipyrrin 4 was
isolated with no hint of the formation of 3 (Scheme 3, bottom).
The retention of the formyl functionality of 4 provides further
evidence for the nucleophilic role of the unsubstituted 5-position
of 1c. The small adjacent substituent (R2 = Me) would provide little
steric hindrance to the approach of the electrophile.
This work
R3
R3
R3
R2
R3
R2
R2
R2 R2
R3
N
HN
N
HBr
HN
N
HBr
H
O
Symmetric
Asymmetric
Scheme 2. Suggested pathway for the formation of symmetrical
dipyrrins from fully substituted 2-formyl pyrroles.
R
R
R
H+
5
2
N
N
N
H
H
H
O
OH
O
O
OH
Isolation of the ␣-acetal and ␣-formyl dipyrrins 3 and 4 from the
self-condensation of 1c indicated that attack from the unsubsti-
tuted 5-position of 5-H-2-formyl pyrroles was not only possible,
but also the only observed outcome when R2 = R3 = Me. We then
utilised the labeled 5-H-2-formyl pyrrole 1d*, bearing ethyl sub-
stituents at the 3- and 4-positions. As shown in Table 1, 1d reacts to
form dipyrrin; evidently, the presence of the R2 ethyl group adja-
cent to the unsubstituted 5-position results in a significant change
to reactivity (compare entries 2 and 3, where R2 = Me, with
entry 4). Our goal with the labelled pyrrole 1d* was to ascertain
whether nucleophilicity originated at the 2-position (to give the
symmetric dipyrrin, sym-2) or the unsubstituted 5-position (to
give the asymmetric dipyrrin, asym-2). Incorporation of a deute-
rium label within the ethyl substituent would serve to differenti-
ate the otherwise identical dipyrrin products.
The synthetic strategy for the preparation of the labelled 5-H-2-
formyl pyrrole 1d* began with Vilsmeier–Haack formylation of
pyrrole 519 (Scheme 4) with the intention of then effecting deu-
terative reduction of the acyl group. Surprisingly, the desired 5-H-
2-formyl pyrrole 6 was obtained in only 14% yield. The remainder
of the recovered material consisted of the two regioisomeric
alkynes 7 and 7= (Scheme 4).20 The position of the alkynyl group in
the major and minor isomer was assigned using two-dimensional
NMR spectroscopy.
R
R
R
R
dehydration
and
deformylation
NH HN
N
HN
3- and 4-positions were prepared, and their condensation prod-
ucts are reported herein.
With the hypothesis that nucleophilic attack could occur from
both the unsubstituted 5-position and the 2-formyl position of a
5-H-2-formyl pyrrole, we investigated four 5-H-2-formyl pyrroles
1a–1d with variation of methyl and ethyl substituents across R2
and R3. Upon exposure of the pyrroles to the reaction conditions
typically used for dipyrrin formation (HBr, MeOH, 70 °C, 1 h),
evidence of a steric influence emerged. Indeed, when R2 = Et
(Table 1, entries 1 and 4), dipyrrin formation was successful. On
the contrary, when using pyrroles bearing R2 = Me (entries 2 and
3), dipyrrin formation was not observed, and the reaction instead
produced an intractable tar. These results suggest that an ethyl
group provides sufficient steric bulk to hinder reaction at the
adjacent ␣-position (5-H) and, thus, prevent polymerization by
instead promoting the desired dipyrrin formation via reaction at
the position bearing the formyl group. In contrast, a methyl group
at R2 offers insufficient bulk to hinder reactivity at the adjacent
unsubstituted ␣-position and, thus, facilitates polymerization.
Furthermore, it appears that increasing steric bulk at R2 has a
more pronounced effect than at R3; note that when R2 is Me (1b
and 1c, entries 2 and 3), polymeric tars result no matter the nature
of R3.
The terminal alkynyl group could potentially be deuterated and
subsequently reduced to give the desired D1-labelled 5-H-2-formyl
pyrrole 1d* in two steps. However, treatment of 7 with nBuLi,
followed by quenching with D2O, resulted only in the degradation
of the starting material. Instead, the separated regioisomers 7 and
7= were each reduced using D2 gas to give 1d*(D4) and 1d=*(D4),
alongside the D3 analogues 1d*(D3) and 1d=*(D3), in a 1:0.6 and
1:0.7 ratio (Scheme 5). This was likely due to traces of HD in the D2
Given that exposure of 1c, and a labelled variant 1c* (see Sup-
porting Information), to our dipyrrin-formation conditions pro-
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Beh et al.
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the 2-formyl group and an ethyl group (R2 = Et) adjacent to the
unsubstituted 5-position. The ethyl group renders the adjacent
5-position somewhat sterically hindered and decreases the likeli-
hood of nucleophilic attack from the 5-position (Scheme 6,
Route 2), thus limiting asymmetric dipyrrin production. In this
way, we would expect nucleophilic attack from the 2-position of
1a to dominate (Scheme 6, Route 1), thus giving the symmetric
dipyrrin as the major product.
Scheme 3. Reaction of pyrrole 1c at 0 °C and at 70 °C.
1.35 equiv 48% HBr
N
HN
MeOH, 0 C, 40 min
HBr
H
3, 50%
O
O
NH
1c
O
Conclusion
1.35 equiv 48% HBr
In conclusion, the reaction pathway for formation of meso-H-
dipyrrins from 5-H-2-formyl pyrroles was investigated. We found
that nucleophilic attack can originate from the 2-position (bear-
ing the formyl group, Route 1) or from the unsubstituted
5-position (Route 2) of 5-H-2-formyl pyrroles, resulting in symmet-
ric or asymmetric regioisomers, respectively. Steric effects im-
parted by the substituents in the 4-position influence the course
of reactivity; the presence of bulkier groups adjacent to the un-
substituted 5-position promotes formation of the symmetric
dipyrrin akin to the case when 2,4,5-trisubstituted 2-formyl pyr-
roles are used.
N
HN
MeOH, 70 C, 10 s
HBr
CHO
4, 20%
Scheme 4. Formylation of 5.
1) POCl3, DMF
1,2-DCE
O
O
80 C, 1.5 h
N
H
5
N
H
N
H
N
2) NaOH
20 min,
H
O
O
O
6, 14%
7, 21%
7', 10%
Experimental
gas supply as a result of air permeation during the heavy water
electrolysis for the generation of D2 or the presence of trace
All chemicals were purchased and used as received unless oth-
erwise indicated. Moisture-sensitive reactions were performed in
oven-dried glassware and under a positive pressure of nitrogen.
Air- and moisture-sensitive compounds were introduced via sy-
ringe or cannula through a rubber septum. Flash chromatography
was performed using ultra-pure silica (230–400 mm). NMR spectra
were recorded using a 500 MHz spectrometer instrument using
CDCl3 as solvents and are reported in parts per million (ppm)
against solvent peaks referenced as follows: CDCl3 at 7.26 ppm for
21
water during reaction.22 The two mixtures were each submitted to
the acid-catalyzed condensation reaction, under typical condi-
tions, to afford the desired labelled ␣-free dipyrrins bearing 6–
8 deuterium labels (Scheme 5 shows the D6 and D8 variants). We
determined the ratio of products by comparing the integration for
two 1H signals common to both 2d* and 2d=*, located at ␦ 2.5 and
␦ 2.7, and how the presence of deuterium affected their respective
1
integration (see Supplementary data). The H NMR signals were
1
1H and at 77.16 ppm for 13C; CD2Cl2. at 5.31 ppm for H and at
assigned using two-dimensional methods and by comparing them
with the unlabelled analogue 2d. According to NMR spectroscopic
analysis (1H, 13C, HMBC, and HSQC) and based on the ratio of
(D4):(D3) for the product outcome corresponding to reaction of
1d* regioisomers, sym-2d* and asym-2d* were obtained in a 1:1
ratio. Likewise, reaction of 2d=* led to a 1:1 mixture of sym-2d=*
and asym-2d*, again with the expected (D4):(D3) isomeric ratio.
The production of both symmetric and asymmetric dipyrrins indi-
cates that the reaction can proceed via two pathways (Scheme 6),
with nucleophilicity originating at both the 5-unsubstituted and
2-formyl positions of 1d. Route 1 (Scheme 6, top) involves nucleophilic
attack from the 2-formyl position onto the formyl group of an-
other molecule. Subsequent loss of water and deformylation gives
the symmetric dipyrrin. Given the very high yields of dipyrrins
obtained when exposing tri-substituted pyrroles to these reaction
conditions (R1, R2, R3 ≠ H in Scheme 1),18 this pathway must oper-
ate efficiently. However, in the case of 5-unsubstituted pyrroles,
nucleophilicity at the unsubstituted 5-position of 5-H-2-formyl pyr-
roles becomes competitive (Scheme 6, Route 2). Notwithstanding
that the analysis of products resulting from the self-condensation
of 1d* or 1d=* is complicated by the presence of pyrroles contain-
ing D3 and D4 labels, it is clear that a mixture of both symmetric
and asymmetric dipyrrins form from 1d. In the self-condensation
of 1c (R2 = R3 = Me), dipyrrin formation presumably proceeds
through Route 2, and the asymmetric product is formed before
polymerization begins to dominate. However, when R2 = R3 = Et, a
1:1 ratio of symmetric and asymmetric products was observed,
thereby suggesting that the influence of increased steric bulk
decreased the nucleophilicity of the adjacent 5-position such that
both routes are equally preferred, and thus, an equal mixture of
dipyrrin isomers is obtained.
53.84 ppm for 13C. Coupling constants (J) are given in Hertz (Hz).
Mass spectra were obtained using TOF and LCQ Duo ion trap
instruments operating in ESI+/− mode, as indicated.
General procedure for the preparation of 2
HBr (48% aqueous solution, 0.5 mL) was added drop-wise to a
solution of 2-formyl pyrrole 1 (0.4 mmol) in MeOH (1 mL), and the
solution was slowly heated to 70 °C and stirred, monitoring visu-
ally and by TLC. If the mixture had not visibly polymerized (black
reaction mixture and intractable tar) and all starting material was
consumed, the reaction mixture was cooled to room temperature
and stored in the freezer for 19 h. If product formed, the precipi-
tate was isolated via filtration to provide dipyrrin 2 as a crystalline
solid.
1-Dimethoxymethyl-2,3,7,8-tetramethyl-5-H-4,6-dipyrrin
hydrobromide (3)
The title compound was synthesized following a modified liter-
ature procedure.18 Chilled (0 °C) aqueous HBr (48%, 50 ␮L) was
added to a solution of 1c (40.5 mg, 0.329 mmol) in methanol
(3.3 mL) at 0 °C. Red precipitate began to form after 5 min of
stirring. The reaction mixture was stirred for 1 h, and the solid was
collected via suction filtration, yielding the title compound as a
1
dark red solid (23 mg, 50%). M.p. 196–200 °C (decomp.); H NMR
(500 MHz; CDCl3) ␦ 13.56 (br s, 1H), 13.23 (br s, 1H), 7.66–7.64 (m,
1H), 7.27 (s, 1H), 6.05 (s, 1H), 3.55 (s, 6H), 2.30 (s, 3H), 2.28 (s, 3H), 2.14
(s, 3H), 2.07 (s, 3H); 13C{1H} NMR (126 MHz; CDCl3) ␦ 152.6, 144.5,
143.3, 142.1, 128.1, 126.8, 125.7, 124.7, 123.1, 99.9, 56.2, 10.4, 10.3,
10.1, 9.5; HRMS-ESI (m/z): [M + H]+ calcd for C16H23N2O2, 275.1754;
found, 275.1751.
Hailing back to the reaction of 1a (Table 1, entry 1), which
spurred our initial investigation, we believe that our findings help
support a rationale for the acquired 9:1 symmetric:asymmetric
product ratio. Pyrrole 1a has a methyl group (R3 = Me) adjacent to
1-Formyl-2,3,7,8-tetramethyl-5-H-4,6-dipyrrin hydrobromide (4)
The title compound was synthesized following a modified liter-
ature procedure.18 Aqueous HBr (48%, 50 ␮L) was added to a solu-
tion of 1c (37 mg, 0.300 mmol) in methanol (3 mL) at reflux
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Can. J. Chem. Vol. 00, 0000
Scheme 5. Synthesis of the labelled ␣-free dipyrrin 2d*.
N
H
N
H
O
O
7'
7
D2, Pd/C 10%
THF, rt, 19 h
D2, Pd/C 10%
THF, rt, 19 h
H
D
D
D
D
D
H
D
D
D
D
D
D
D
D
D
N
H
N
H
N
N
O
O
H
H
O
O
1d'*(D4)
1d'*(D3)
1d*(D4)
1d*(D3)
1:0.7 ratio
1:0.6 ratio
HBr, MeOH
HBr, MeOH
70 oC
70 oC
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
N
HBr
HN
N
HBr
HN
N
HBr
HN
N
HBr
HN
D
D
D
D
D
D
D
D
sym-2d*(D4)
asym-2d*(D4)
sym-2d'*(D4)
asym-2d*(D4)
1:1 ratio
1:1 ratio
D
D
D
D
H
D
H
D
D
D
H
H
D
D
D
D
H
D
H
H
D
H
D
D
N
HBr
HN
N
HBr
HN
N
HBr
HN
N
HBr
HN
D
D
D
D
D
D
D
D
1:1 ratio
sym-2d*(D3)
asym-2d*(D3)
sym-2d'*(D3)
asym-2d*(D3)
1:1 ratio
Scheme 6. Proposed mechanistic routes for formation of symmetric and asymmetric dipyrrins from 5-H-2-formyl pyrroles.
Symmetric
O
Route 1
OH
R3
R2
R3
R3
R3
R3
R3
R2
nucleophilicity
at the 2-position
dehydration
deformylation
R2
R2
R2
R2
NH HN
N
HN
N
N
H
H
R3
OH
R2
O
H+
N
H
O
R3
OH
R3
R2
R2
R3
R2
R3
R2
dehydration
deformylation
R2
R3
CHO
R2
R3
Route 2
nucleophilicity
at the 5-position
N
N
NH HN
N
HN
H
H
OH
O
Asymmetric
temperature. After 5–10 s, the mixture turned a dark red, and the
reaction vessel was immediately plunged into an ice bath (≤0 °C),
followed by addition of ether to dilute the mixture and assist in
rapid cooling. The resulting ethereal solution was concentrated in
vacuo, keeping the temperature below 25 °C, until a solid precip-
itate formed. The precipitate was collected via suction filtration
and washed with ether to yield the title compound (14 mg, 20%).
M.p. 185–189 °C (decomp); 1H NMR (300 MHz; CDCl3) ␦ 14.19 (br s,
1H), 13.64 (br s, 1H), 10.69 (s, 1H), 7.99–7.97 (m, 1H), 7.48 (s, 1H), 2.40
(s, 3H), 2.35 (s, 3H), 2.33 (s, 3H), 2.15 (s, 3H); 13C{1H} NMR (126 MHz;
CDCl3) ␦ 184.2, 149.8, 147.6, 142.4, 141.6, 131.9, 128.9, 127.8, 127.8,
125.2, 10.7, 10.3, 10.0, 9.7; HRMS-ESI (m/z): [M + H]+ calcd for
C14H17N2O1, 229.1335; found, 229.1340.
3-Acetyl-4-ethylpyrrole (5)
The title compound was synthesized following a modified liter-
ature procedure.23 A solution of 3-hexen-2-one (8.8 g, 90 mmol)
and TosMIC (17.8 g, 91.2 mmol) in a mixture of anhydrous DMSO/
Et2O (450 mL, 1:2) was slowly added to a well-stirred suspension of
sodium hydride (8 g, 200 mmol, 60% in oil) in anhydrous ether
(180 mL) via cannula transfer. After completion of the addition,
the mixture was stirred at room temperature for 1 h, then treated
with water to quench excess NaH, and thoroughly extracted with
ethyl acetate (4 × 350 mL). The combined organic extracts were
washed with brine (12 × 300 mL), dried over anhydrous Na2SO4,
and the solvent removed in vacuo to furnish a dark brown oil. The
oil was placed in a freezer overnight, producing a greasy solid that
was continually extracted with pentane for 26 h (Soxhlet) to yield
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Beh et al.
5
the desired product as a light brown solid after removal of the
solvent in vacuo (7.9 g, 63%). 1H NMR (300 MHz; CDCl3) ␦ 8.44 (br s,
1H), 7.37–7.36 (m, 1H), 6.59–6.57 (m, 1H), 2.80 (q, J = 7.4 Hz, 2H), 2.40
(s, 3H), 1.20 (t, J = 7.4 Hz, 3H), in accordance with literature.19
with MeOH three times. The combined washings were concen-
trated under reduced pressure and the crude mixture was purified
via column chromatography on SiO2 (hexanes:EtOAc, 70:30) to
give a pale yellow solid (0.13 g), containing both 1d=*(D4) and
1d=*(D3) in a 1:0.7 ratio. The following data correspond to the
deuterated compound 1d=*(D4). 1H NMR (CD2Cl2, 500 MHz) 9.58 (s,
1H), 9.34 (br s, 1H), 6.87 (d, 1H, J = 3.0 Hz), 2.46 (q, 2H, J = 7.6 Hz), 1.19
(t, 3H, J = 7.6 Hz), 1.15 (br s, 1H). Multiplet at 2.69–2.74 ppm is the
result of the CHD group of the deuterated compound cis-1d*(D4).
13C NMR (CD2Cl2, 125 MHz) 177.7, 137.1, 129.4, 127.7, 124.0, 18.0
(CH2), 17.2–16.3 (m, CHD2 and CD2), 14.9 (CH3). HRMS-ESI (m/z): [M +
Na]+ calcd for C9H9D4NNaO, 178.1140; found, 178.1138.
4-Acetyl-3-ethyl-2-formylpyrrole (6)
The title compound and alkynyl by-products were synthesized
following a modified literature procedure.20,24 POCl3 (2.04 mL,
21.9 mmol) was added, drop-wise, at 0 °C under N2 to DMF (16 mL).
The mixture was allowed to warm to room temperature and then
stirred for 15 min. This mixture was added drop-wise to a solution
of 3-acetyl-4-ethylpyrrole (5) (2.00 g, 14.6 mmol) in DCE (49 mL), at
0 °C under N2. The resulting mixture was heated to 80 °C and
stirred for an additional 80 min. Aqueous NaOH (2 M) was added to
the reaction until pH > 8 and the resulting emulsion was heated at
reflux temperature for 20 min. After cooling to room tempera-
ture, water (50 mL) was added, and the reaction mixture extracted
with EtOAc (3 × 50 mL). The combined organic fractions were
washed with brine (50 mL), dried over anhydrous Na2SO4, and
concentrated in vacuo. The crude mixture was purified via col-
umn chromatography on silica, eluting with an EtOAc/hexanes
gradient (20/80, 30/70) to afford the desired product 6 as a brown
solid (0.33 g, 14%), along with the two 4-alkynyl-2-formylpyrroles 7
(0.44, 21%) and 7= (0.22 g, 10%). 6: M.p. 119–123 °C; 1H NMR
(500 MHz; CDCl3) ␦ 10.03 (br s, 1H), 9.74 (s, 1H), 7.61–7.60 (m, 1H),
3.11 (q, J = 7.5 Hz, 2H), 2.44 (s, 3H), 1.26 (t, J = 7.5 Hz, 4H); 13C{1H}
NMR (126 MHz; CDCl3) ␦ 193.5, 179.1, 140.4, 130.7, 130.4, 125.0, 28.5,
17.9, 16.7; HRMS-ESI (m/z): [M + Na]+ calcd for C9H11NO2Na,
188.0682; found, 188.0680.
Dipyrrins sym-2d* and asym-2d* from 1d*
HBr (48% aqueous solution, 0.4 mL) was added drop-wise to a
solution of 1d*(D4) and cis-1d*(D3) (0.04 g, 0.26 mmol) in MeOH
(0.8 mL) and the solution was slowly heated to 70 °C and stirred for
5 min until complete consumption of the starting material ac-
cording to TLC analysis. The reaction mixture was cooled to room
temperature and stored in the freezer for 19 h. Filtration resulted
in isolation of the precipitate as a crystalline dark green solid
(22 mg) containing dypirrins sym-2d* and asym-2d* from alde-
hyde 1d*(D4) and 1d*(D3), both in a 1:1 ratio. The following data
correspond to sym-2d*(D4). 1H NMR (CDCl3, 500 MHz) 13.28 (br s,
2H), 7.74 (d, 2H, J = 3.0 Hz), 7.28 (br s, 1H), 2.72 (q, 4H, J = 7.6 Hz), 1.21
(t, 6H, J = 7.6 Hz), 1.18–1.17 (m, 1H). Multiplet at 2.48 ppm is the
result of the CH2 group of the asym-2d* from 1d*(D4) and 1d*(D3).
13C NMR (CDCl3, 125 MHz) 148.9, 141.7, 131.7, 127.4, 123.2, 18.2,
18.1–17.3 (m, CD2), 17.9, 16.7, 16.6–15.7 (m, CHD2), 14.3. Carbons at
17.9 and 14.3 ppm are the results of the CH3 (×2) and CH2 (×2),
respectively, of the asym-2d* from 1d*(D4) and 1d*(D3). HRMS-ESI
(m/z): [M – Br]+ calcd for C17H17D8N2, 265.2514; found, 265.2509.
3-Ethyl-4-ethynyl-2-formylpyrrole (7)
M.p. 80 °C (blackened), followed by melting at 119–120 °C;
1H NMR (500 MHz; CDCl3) ␦ 9.64 (s, 1H), 9.46 (br s, 1H), 7.23–7.22 (m,
1H), 3.10 (s, 1H), 2.85 (q, J = 7.6 Hz, 2H), 1.30 (t, J = 7.6 Hz, 3H); 13C{1H}
NMR (125 MHz; CDCl3) ␦ 177.9, 141.6, 129.6, 128.6, 106.8, 79.6, 76.3,
18.0, 16; HRMS-ESI (m/z): [M + Na]+ calcd for C9H9NONa, 170.0576;
found, 170.0575.
Dipyrrins sym-2d=* and asym-2d* from 1d=*
HBr (48% aqueous solution, 0.4 mL) was added drop-wise to a
solution of 1d=*(D4) and 1d=*(D3) (0.04 g, 0.26 mmol) in MeOH
(0.8 mL), and the solution was slowly heated to 70 °C and stirred
for 5 min until complete consumption of the starting material
according to TLC analysis. The reaction mixture was cooled to
room temperature and stored in the freezer for 19 h. Filtration
resulted in isolation of the precipitate as a crystalline dark green
solid (22 mg) containing dypirrins sym-2d=* and asym-2d* from
aldehyde 1d=*(D4) and 1d=*(D3), both in a 1:1 ratio. The following
data correspond to sym-2d=*. 1H NMR (CDCl3, 500 MHz) 13.28 (br s,
2H), 7.74 (d, 2H, J = 3.0 Hz), 7.28 (br s, 1H), 2.48 (q, 4H, J = 7.6 Hz), 1.21
(t, 6H, J = 7.6 Hz), 1.18–1.17 (m, 1H). Multiplet at 2.70 ppm is the
result of the CH2 group of the asym-2c* from 1d*(D4) and 1d=*(D3).
13C NMR (CDCl3, 125 MHz) 148.9, 141.7, 131.7, 127.4, 123.2, 18.1, 17.9,
17.3–18.1 (m, CD2), 16.6–15.7 (m, CHD2), 14.3. Carbons at 16.8 and
18.1 ppm are the results of the CH3 (×2) and CH2 (×2), respectively,
of the asym-2d* from 1d=*(D4) and 1d=*(D3). HRMS-ESI (m/z): [M –
Br]+ calcd for C17H17D8N2, 265.2514; found, 265.2509.
4-Ethyl-3-ethynyl-2-formylpyrrole (7=)
M.p. 95 °C (blackened), followed by melting at 104–105 °C;
1H NMR (500 MHz; CDCl3) ␦ 9.68 (s, 1H), 9.28 (br s, 1H), 6.86 (br s,
1H), 3.35 (s, 1H), 2.58 (q, J = 7.6 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H); 13C{1H}
NMR (125 MHz; CDCl3) ␦ 178.5, 134.2, 132.5, 123.3, 114.7, 83.8, 75.2,
18.8, 14.5; HRMS-ESI (m/z): [M + Na]+ calcd for C9H9NONa, 170.0576;
found, 170.0578.
Pyrroles 1d*(D3) and 1d*(D4)
A mixture of pyrrole 7 (0.30 g, 2.04 mmol) and Pd (10% on acti-
vated carbon, 30 mg, 10% w/w) in THF (25 mL) was stirred at room
temperature under deuterium atmosphere for 19 h. The reaction
mixture was filtered through Celite , which was then washed
®
with MeOH three times. The combined washings were concen-
trated under reduced pressure, and the crude mixture was puri-
fied via column chromatography on SiO2 (hexanes:EtOAc, 70:30)
to give a pale yellow solid (0.27 g), containing both 1d*(D4) and
1d*(D3) in a 1:0.6 ratio. The following data correspond to the deu-
terated compound 1d*(D4). 1H NMR (CD2Cl2, 500 MHz) 10.58 (br s,
1H), 9.62 (s, 1H), 6.85 (d, 1H, J = 3.0 Hz), 2.77 (q, 2H, J = 7.6 Hz), 1.24
(t, 3H, J = 7.6 Hz), 1.17 (br s, 1H). Multiplet at 2.43–2.44 ppm is the
Supplementary data
Supplementary data are available with the article through the
journal Web site at http://nrcresearchpress.com/doi/suppl/10.1139/
cjc-2017-0662.
Acknowledgements
result of the CHD group of the deuterated compound 1d*(D3). 13
C
This work was supported by the Natural Sciences and Engineering
Research Council of Canada (NSERC). We thank Dr. A.W.H. Speed
(Dalhousie) for access to D2 (g).
NMR (CD2Cl2, 125 MHz) 177.9, 138.0, 129.4, 127.5, 125.2, 13.9–14.7
(m, CHD2), 17.8–16.9 (m, CD2), 17.3 (CH2), 17.2 (CH3). HRMS-ESI
(m/z): [M + Na]+ calcd for C9H9D4NNaO, 178.1140; found, 178.1139.
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