An acyl-Claisen/Paal-Knorr approach to fully substituted pyrroles

DOI: 10.1016/j.tet.2016.06.049

Source and publish data:

Tetrahedron p. 4676 - 4689 (2016)

Update date:2022-08-11

Topics:

Authors:

Dittrich, Nora

Jung, Eun-Kyung

Davidson, Samuel J.

Barker, David

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Article abstract of DOI:10.1016/j.tet.2016.06.049

The synthesis of fully substituted pyrroles using the Paal-Knorr reaction on acyl-Claisen derived 2,3-syn-disubstituted-1,4-diketones is reported. The use of the acyl-Claisen rearrangement allows the synthesis of wide variety of syn-substituted 1,4-diketones which are shown to be better substrates for pyrrole condensation than their corresponding anti isomers. When the reaction was performed open to air the use of nucleophilic amines in the pyrrole forming step leads to auto-oxidation of the 5-methyl group giving exclusively 5-formyl pyrroles.

Full text of DOI:10.1016/j.tet.2016.06.049

Accepted Manuscript

An acyl-Claisen/Paal-Knorr approach to fully substituted pyrroles

Nora Dittrich, Eun-Kyung Jung, Samuel J. Davidson, David Barker

PII:

S0040-4020(16)30571-3

10.1016/j.tet.2016.06.049

TET 27863

DOI:

Reference:

To appear in: Tetrahedron

Received Date: 18 April 2016

Revised Date: 9 June 2016

Accepted Date: 20 June 2016

Please cite this article as: Dittrich N, Jung E-K, Davidson SJ, Barker D, An acyl-Claisen/Paal-Knorr

approach to fully substituted pyrroles, Tetrahedron (2016), doi: 10.1016/j.tet.2016.06.049.

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Leave this area blank for abstract info.

An acyl-Claisen/Paal-Knorr approach to

fully substituted pyrroles

Nora Dittrich, Eun-Kyung Jung, Samuel J. Davidson, David Barker*

School of Chemical Sciences, University of Auckland, 23 Symonds St, Auckland, New Zealand

An acyl-Claisen/Paal-Knorr approach to fully substituted pyrroles.

Nora Dittrich, Eun-Kyung Jung, Samuel J. Davidson, David Barker^*

School of Chemical Sciences, University of Auckland, 23 Symonds St, Auckland, New Zealand

*Corresponding author. Tel.: +64-9-373-7599; fax: +64-64-373-7422; e-mail: d.barker@auckland.ac.nz

Abstract: The synthesis of fully substituted pyrroles using the Paal-Knorr reaction on acyl-Claisen derived 2,3-syn-

disubstituted-1,4-diketones is reported. The use of the acyl-Claisen rearrangement allows the synthesis of wide variety

of syn-substituted 1,4-diketones which are shown to be better substrates for pyrrole condensation than their

corresponding anti isomers. When the reaction was performed open to air the use of nucleophilic amines in the

pyrrole forming step leads to auto-oxidation of the 5-methyl group giving exclusively 5-formyl pyrroles.

Keywords: Pyrrole; Paal-Knorr; Acyl-Claisen; Oxidation

1. Introduction

The pyrrole ring features in a number of biologically active molecules with a wide range of pharmacological

activities. Compounds containing the pyrrole core have been found to possess antitumoral, antimalarial, antifungal,

antibacterial and anti-HIV activity and as such, they represent interesting lead compounds for drug development.^1–6

The pharmaceutical potential of pyrrolic compounds is exemplified by the HMG-CoA reductase inhibitor atorvastatin,

which has become one of the best-selling pharmaceutical products since its introduction to the global market in

1990.^7–9Pyrrolic compounds continue to enter the pharmaceutical market and include molecules such as the receptor

tyrosine kinase inhibitor sunitinib, approved in 2011 for the treatment of advanced neuroendocrine tumours of the

pancreas.^7,10,11Pyrroles also feature in a number of molecules presently undergoing preclinical trials such as lamellarin

D, which is being investigated for its anticancer activity (Figure 1).¹²

OMe

MeO

atorvastatin

sunitinib

lamellarin D

Figure 1: Pyrrolic pharmaceutical compounds

The synthesis of pyrroles can be achieved by a variety of reactions including the well documented Paal-Knorr

condensation, first reported in 1884.¹³Despite the successful synthesis of pyrroles through this reaction a major

limitation is introduced through the preparation of racemic diketone precursors for the condensation to form the

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pyrrole core. Although stereochemistry is lost in the condensation process, studies by Amarnath et al. have shown the

kinetics of the reaction are influenced by the stereochemistry of the starting material (Figure 2).¹⁴This is particularly

the case for diketones where the substituents at C-2 and C-3 are alkyl or aryl groups which do not facilitate the

deprotonation at these positions.

Figure 2: Mechanistic considerations for the Paal-Knorr condensation of anti versus syn-diketone precursors

1,4-Diketone precursors 1 with anti-aligned substituents at C-2 and C-3 adopt an intermediate state which brings these

substituents close together, thereby suffering unfavourable steric interactions and reducing the rate of cyclisation.

Alternatively, diketones in which these substituents are syn-aligned adopt an intermediate state which does not

experience these destabilising interactions and therefore condenses to form the pyrrole core occurs faster. With this in

mind we envisioned that a diastereoselective synthesis of syn-diketones would allow more efficient access to a range

of pyrrole compounds.

Our previous work on the acyl-Claisen rearrangement has shown this reaction to be a versatile method for the

synthesis of a precursor to these diketones with the desired syn-alignment of C2-C3 substituents.^15–19The reaction

involves the in situ generation of a ketene from an acid chloride, and the subsequent [3,3] sigmatropic rearrangement

of the ketene with an allylic amine yields syn-amides in >95% diastereomeric excess over the anti-products.^20–22We

therefore proposed that a synthetic route encompassing this reaction could be used to access syn-diketones and thus

the pyrrole core with high efficiency.

2. Results and Discussion

2.1 Synthesis of syn-disubstituted diketones.

We first chose to explore whether the use of syn-diketones 1 would indeed lead to higher yielding Paal-Knorr

condensations. To this end, two anti-diketones were synthesised along with their syn-counterparts with the aim of

evaluating the effect of stereochemistry on the reaction of these compounds in the Paal-Knorr reaction.

Our synthetic strategy towards syn-diketones 1 (Figure 3) involved the synthesis of a range of allylic morpholines and

the reaction of these with a variety of acid chlorides using the acyl-Claisen rearrangement. Additional structural

diversity could then be introduced by the addition of lithiates to yield ketone products. These would then be converted

to their dicarbonyl counterparts via the Wacker-Tsuji oxidation and the reaction of these diketones with commercially

available amines in the Paal-Knorr reaction would result in a series of pyrroles.

Figure 3: Synthetic strategy.

This short synthetic sequence would in principle allow access to a wide variety of highly substituted and structurally

diverse pyrroles with variability at all but the 5-position; bearing a methyl group following pyrrole formation. It was

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envisaged however that the benzylic nature of this functionality would render it emenable to late stage

transformations. To this end various aromatic and aliphatic reactants were selected in order to demonstrate the

substrate scope.

Syn-diketones 1a–b were prepared in six steps as depicted in Scheme 1. Firstly crotonaldehyde was reduced and the

resultant (E)-alcohol 2 was converted to the corresponding crotyl bromide, which underwent a nucleophilic

displacement to give morpholine 3. Acyl-Claisen rearrangement of amine 3 with propionyl chloride gave morpholine

amide 4a as a single diastereomer in excellent yield. Addition of two different aryl lithiates, gave ketone 5a–b, which

was then followed by a Wacker-Tsuji oxidation to afford the desired syn-diketones 1a–b.

b,c

R²

R¹

R²

R¹

syn-5a b

syn-4a

syn-1a b

Scheme 1: Synthesis of syn-diketones 1a–b. Reagents and conditions: a) LiAlH₄, Et₂O, 24 h, 70%; b) PBr₃, Et₂O, 0

°C, 24 h; c) morpholine, NEt₃, CH₂Cl₂, 0 °C to rt, 24 h, 48% over two steps; d) propionyl chloride, Pr₂NEt, AlCl₃,

CH₂Cl₂, 24 h; 82% e) ⁿBuLi, 4-bromoanisole or 3,4-methylenedioxybromobenzene, THF, -78 °C to rt, 24 h, 5a (R¹=

OMe, R²= H) 96%, 5b (R¹= R²= -OCH₂O-) 49%; f) PdCl₂, CuCl, DMF/H₂O (3:1), O₂, 24 h, 1a (R¹= OMe, R²= H)

91%, 1b (R¹= R²= -OCH₂O-) 28%.

The synthesis of the corresponding anti-diketones began with the Ireland-Claisen rearrangement of allylic ester 6

(Scheme 2) giving anti-acid 7 which was then coupled with moprholine to give anti-morpholine amide 4a. The

remainder of the synthesis was analogous to that of the syn-diketones, firstly preparing ketones anti-5a–b, followed by

a Wacker-Tsuji oxidation to install the second ketone functionality.

Scheme 2: Synthesis of anti-diketones 1a–b. Reagents and conditions: a) LDA, THF -78 °C, 2 h, 94%; b)

morpholine, DCC, DMAP, CH₂Cl₂,

0 °C to rt, 3

d, quant.; c) ⁿBuLi, 4-bromoanisole or 3,4-

methylenedioxybromobenzene, THF, -78 °C to rt, 24 h, anti-5a (R¹= OMe, R²= H) 50%, anti-5b (R¹= R²= -

OCH₂O-) 78%; d) PdCl₂, CuCl, DMF/H₂O (3:1), O₂, 24 h, anti-1a (R¹= OMe, R²= H) 49%, anti-1b (R¹= R²= -

OCH₂O-) 68%.

The syn and anti-diketones 1a–b were then condensed with benzylamine or 3-phenyl propylamine in the Paal-Knorr

reaction. As depicted in Table 1, the difference in reactivity for the starting materials was quite pronounced with the

syn-diketones resulting in cleaner reactions with higher yields of pyrroles.

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Table 1: Paal-Knorr condensation of syn and anti-diketones 1a–b.

Diketone

syn-1a

Amine

Product

Yield/Result

58%

3-phenylpropylamine

benzylamine

anti-1a

syn-1b

anti-1b

Complex mixture

52%

benzylamine

21%

These reactions not only highlighted the superior yields when using syn-diketones in the Paal-Knorr condensation

reaction, but unexpectedly resulted in the formation of the auto-oxidised pyrrole products 8a–b. Intrigued by the

isolation of these pyrrole aldehydes we decided to prepare other pyrroles to determine the generality of the oxidation

during pyrrole formation. Three allylic morpholines, crotyl 3, allyl 9 and cinnamyl morpholines 10 were chosen for

the acyl-Claisen rearrangement. The acid chlorides chosen for the acyl-Claisen rearrangement were all commercially

available, with the exception of 1,3-benzodioxole-5-propanoyl chloride which was prepared from the corresponding

acid. Thus, acid chlorides: propionyl chloride, phenylacetyl chloride, valeroyl chloride, acetyl chloride and 1,3-

benzodioxole-5-propanoyl chloride were reacted with morpholines 3,9–10 in the acyl-Claisen rearrangement using

previously reported conditions¹⁶yielding a range of syn-morpholine amides 4a–h (Table 2). Reactions were not

optimised if they gave sufficient material for further study.

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Table 2: Synthesis of 2,3-syn-morpholine amides 4a–h

Allylic

R¹

R²

Yield

Product

Morpholine

82%

86%

48%

nPr

Quant.

31%

67%

49%

14%

Either butyllithium or an aryl lithiate (prepared from their corresponding aryl bromides), were then added to the

morpholine amides 4a–h to afford ketones 5a–n in generally good to excellent yields. The synthesised ketones were

then converted to the corresponding diketones 1a-n using the Wacker-Tsuji oxidations using PdCl₂and CuCl in a

DMF/water mixture open to air (Table 3).

Table 3: Synthesis of ketones 5a–n and diketones 1a–n

R¹

R²

Yield ketone

5a 96%

R³

Yield diketone

1a 91%

4-OMe-Ph

5b 49%

5c 90%

3,4-OCH₂O-Ph

3,4-di-OMe-Ph

3,4,5-tri-OMe-Ph

4-OMe-Ph

1b 80%

1c 98%

5d 76%

5e 62%

1d 86%

1e 72%

ⁿbutyl

5f 73%

5g 88%

1f quant.

1g 55%

ⁿPr

4-OMe-Ph

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5h 28%

3,4-OCH₂O-Ph

1h 69%

4-OMe-Ph

5i 42%

1i 83%

3-OⁱPr-4-OMe-Ph

4-OMe-Ph

5j 75%

5k 99%

5m 83%

5n 79%

1j 76%

1k 77%

1m 54%

1n 96%

4-OMe-Ph

3,4-OCH₂O-Ph

The structurally diverse diketones 1a–n then underwent Paal-Knorr condensation reactions using a series of aliphatic

and aromatic amines. Reactions were generally performed open to air but selected reactions were performed under a

nitrogen atmosphere (see below). Reactions were carried until complete consumption of diketone (monitored by TLC)

and gave a range of pyrrole products 8a–ae (Table 4).

Table 4: Pyrroles synthesised via the Paal-Knorr condensation reaction of diketones 8a–ae.

Diketone

used

time

(h)

R¹

R²

R³

R⁴

R⁵

Yield

4-OMe-Ph

CHO

8a 58%

8b 52%

3,4-OCH₂O-

PhCH₂

4-OMe-Ph

8c 65%

4-OMe-Ph

PhCH₂

ⁿbutyl

CHO

8d 26%

8e 34%

8f 72%

3,4-OCH₂O-

CHO

8g 30%^a

3,4-OMe-Ph

8h 25%

8i 74%^a

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3,4-OMe-Ph

PhCH₂

CHO

8j 48%

8k 26%

3,4-OMe-Ph

CHO

3,4-OMe-Ph

CHO

8m 25%

3,4,5-OMe-

3-OTBDPS-4-

OMe-Ph

8n 13%

3,4,5-OMe-

3-OTBDPS-4-

OMe-Ph

8n 74%^b

4-OMe-Ph

8o 61%

PhCH₂

8p 39%^b

4-OMe-Ph

CHO

8q 43%

4-OMe-Ph

ⁿbutyl

CHO

8r 55%

8s 71%

8t 44%

ⁿbutyl

CHO

nPr

4-OMe-Ph

CHO

8u 30%

8v 24%

8w 15%

3,4-OCH₂O-

4-OMe-Ph

8x 29%

3-OⁱPr-4-

OMe-Ph

4-OMe-PhCH₂

4-OMe-Ph

8y 59%^b

8z 41%^b

3-OⁱPr-4-

OMe-Ph

3-OⁱPr-4-

OMe-Ph

PhCH₂

8aa 30%^b

8ab 30%

4-OMe-Ph

CHO

8ac 13%

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4-OMe-Ph

8ad 30%

8ae 82%^a

3,4-OCH₂O-

^aYield based on recovered starting material

^bReactions conducted under an atmosphere of nitrogen

Diketone precursors with substituents at both C-2 and C-3 (R²and R¹) produced pyrroles in higher yields as compared

to those with a hydrogen at either one of these positions. It is assumed that the presence of substituents at these

positions results in more rapid formation of a cyclic intermediate whilst compounds lacking in substituents have less

steric interactions to drive the formation of the cyclic intermediate.

Perhaps more unexpected was the result that the oxidation noted in the earlier Paal-Knorr reactions were also

observed in a number of pyrrole products shown in Table 4. A search of the available literature yielded very few

examples of auto-oxidation products in pyrrolic compounds. While the oxidation of pyrroles through photo-oxidation

reactions is more documented, this generally results in a mixture of products and demands UV irradiation in the

presence of an appropriate sensitiser.²³A report by Schmidt et al. detailed the auto-oxidation of the α-methyl group of

an N-vinyl-2,3-dimethylpyrrole by air, however the pyrrole aldehyde was formed as a minor product. In contrast to

this, our reaction conditions often afforded pyrrole aldehyde products exclusively, and in some cases very high yields.

We noted that the amine used appeared to determine the product of the condensation. The more nucleophilic amines

such as phenethylamine and 3-phenylpropylamine consistently gave pyrrole aldehydes (eg. 8a,e,q) with no unoxidised

pyrrole products isolated. In contrast, less nucleophilic amines such as aniline and anilines containing electron

withdrawing groups resulted in exclusively unoxidised (i.e. 5-methyl) pyrrole products. Anilines containing alkoxy

substituents generally gave mixtures of products where the oxidized pyrrole was the major product. It was discovered

that when the reactions of these electron-rich anilines were performed under a nitrogen atmosphere, the unoxidized

pyrroles predominated (e.g. 8n,z). The same reactivity was observed with benzylamine and α-methylbenzylamine,

where under air 5-formyl pyrroles (8b,d,j,k,u) were prepared, whilst under nitrogen unoxidized pyrroles (8p, aa) were

obtained.

We also observed that reactions leading to pyrrole aldehyde products required longer reaction times. We hypothesised

that the 5-methyl pyrroles may represent intermediates in the synthesis of the auto-oxidised formyl pyrrole products.

To test this purified 5-methyl pyrroles were stirred under the same conditions for pyrrole formation however this did

not result in any oxidation and gave only recovered starting material.

The absence of oxidation products being obtained from 5-methyl pyrroles allowed us to propose that the pyrrole

aldehyde products may form due to aerial oxidation of an enamine intermediate, formed by the reaction of the

diketone with a nucleophilic amine (Scheme 3). Whilst an enamine intermediate could be formed from all amines we

propose that when more nucleophilic amines are employed that the enamine has suitable reactivity to undergo reaction

with oxygen, whilst with less nucleophilic amines this reaction is reduced and elimination is preferred. Our

observation that reactions performed under a nitrogen atmosphere gave non-oxidized products is in agreement with

this proposed mechanism.

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R²

R³

R¹

R²

R¹

R²

H₂O

R³

R¹

R²

R¹

H⁺

-H₂O

R³

R = EDG

in air

OH₂

-H⁺

R¹

R²

R³

R²

R¹

R²

R³

-H₂O

O₂/ H⁺

R³

Dehydration

-2H₂O

-H⁺

R¹

CHO

R²

R³

R²

R³

R¹

Scheme 3: Proposed mechanism for the auto oxidation of pyrrole products in the Paal-Knorr reaction.

3. Conclusion

In conclusion a range of fully-substituted pyrroles have been prepared from 2,3-syn-disubstituted-1,4-diketones under

Paal-Knorr conditions. The use of 2,3-syn substituted diketones, obtained using an acyl-Claisen rearrangement, is

preferential to the corresponding anti-diketones or less substituted ketones and results in higher yields of pyrroles.

Reactions performed in air with electron rich amines or anilines resulted in oxidation of methyl group to give 5-formyl

pyrroles. This result fortuitously allows easy functionalisation of the 5-position of these fully substituted pyrroles,

with the other four positions easily modifiable based on the choice of the appropriate starting materials. This auto-

oxidation to a 5-formyl group may allow an alternative route to natural products such as lamellarin D which has an

ester group at the same position.

4. Experimental section

4.1 General Procedures

All reactions were carried out with oven-dried glassware and under a nitrogen atmosphere in dry, freshly distilled

solvents unless otherwise noted. Diisopropylethylamine was distilled from CaH₂and stored over activated 4Å

molecular sieves. Infrared (IR) spectra were recorded using a Perkin Elmer Spectrum1000 FT-IR spectrometer. NMR

spectra were recorded on a 300 MHz or 400 MHz spectrometer. Chemical shifts are reported relative to the solvent

peak of chloroform (δ 7.26 for H and δ 77.16 ± 0.06 for ¹³C). H NMR data is reported as position (δ), relative

integral, multiplicity (s, singletl; d, doublet; dd, doublet of doublets; ddd, doublet of doublet of doublets; dt, doublet of

triplets; t, triplet; td, triplet of doublets; tt, triplet of triplets; m, multiplet), coupling constant (J, Hz), and the

assignment of the atom. ¹³C NMR data are reported as position (δ) and assignment of the atom. NMR assignments

were performed using COSY, HSQC and HMBC experiments. High-resolution mass spectroscopy (HRMS) was

carried out by either chemical ionisation (CI) or electrospray ionization (ESI) on a MicroTOF-Q mass spectrometer.

Unless noted, chemical reagents were used as purchased.

4.2 Synthesis of compounds

4.2.1 General procedure: Acyl-Claisen rearrangement

To a stirred suspension of the Lewis acid (1 mmol) in CH₂Cl₂(5 mL), under an atmosphere of nitrogen at room

temperature, was added dropwise a solution of allyl/crotyl/cinnamyl morpholine (1 mmol) in CH₂Cl₂(5 mL) dropwise

and the resultant suspension stirred for 5 min. DIPEA (1.5 mmol) was added dropwise and the resultant suspension

was stirred for a further 15 min. A solution of acid chloride (1.2 mmol) in CH₂Cl₂(5 mL) was added dropwise and the

resultant suspension was stirred for 24 h. A solution of NaOH (1M, 15 mL) was added, the organic layer separated

and the aqueous phase further extracted with CH₂Cl₂(3 × 10 mL). The combined organic extracts were dried (MgSO₄)

and the solvent removed in vacuo. The crude product was purified by flash chromatography to yield the 2,3-syn

disubstituted amide product.

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4.2.1.1 (2R*, 3S*)-2,3-Dimethyl-1-morpholinopent-4-en-1-one syn-4a. Flash chromatography using 2:1 hexanes, ethyl

acetate to yield 5.0 g, 82% as a pale yellow oil. R_F(2:1 hexanes, ethyl acetate) = 0.16. δ_H(300 MHz; CDCl₃; Me₄Si)

1.03 (3H, d, J = 6.8 Hz, 3-CH₃), 1.10 (3H, d, J = 6.8 Hz, 2-CH₃)_,2.48 (1H, sext., J = 6.8 Hz, 3-H), 2.57 (1H, pent., J =

6.8 Hz, 2-H), 3.51–3.52 and 3.65-3.66 (8H, m, N(CH₂CH₂)₂O), 4.95–5.05 (2H, m, 5-H), 5.76 (1H, ddd, J = 7.2, 10.3,

17.4 Hz, 4-H). Spectroscopic data were in accordance with literature values.²⁰

4.2.1.2 (2S*, 3S*)-3-Methyl-1-morpholino-2-phenylpent-4-en-1-one 4b. Flash chromatography using 2:1 hexanes,

ethyl acetate to yield 1.6 g, 86% as a yellow solid. R_F(2:1 hexanes, ethyl acetate) = 0.33. MP: 65–70 °C. δ_H(400

MHz; CDCl₃; Me₄Si) 0.78 (3H, d, J = 6.9 Hz, 3-CH₃), 3.05–3.11 (1H, m, 3-H), 3.14–3.19, 3.47–3.70 (9H, m, 2-H,

N(CH₂CH₂)₂O), 5.01–5.12 (2H, m, 5-H), 5.81–5.90 (1H, m, 4-H), 7.23–7.34 (5H, m, Ar-H). δ_C(100 MHz; CDCl₃)

17.3 (3-CH₃), 40.1 (C-3), 42.4, 46.2 (N(CH₂CH₂)₂O), 54.2 (C-2), 66.4, 66.8 (N(CH₂CH₂)₂O), 114.0 (C-5), 127.1,

128.4, 128.7 (Ar-CH), 138.0 (Ar-C), 142.5 (C-4), 171.0 (C-1). IR: ν_max(film)/cm^-1; 2966, 2853, 1626, 1454, 754, 703.

m/z (ESI⁺) 282 (100%), 260 (60), 200 (20), 130 (40). HRMS (ESI⁺) found (MH⁺): 260.1650; C₁₆H₂₂NO₂requires

260.1645.

4.2.1.3 (2R*,3S*)-2-Propyl-3-methyl-1-morpholinopent-4-en-1-one 4c. Flash chromatography using 4:1 hexanes,

ethyl acetate to yield 84 mg, 48% as a pale yellow oil. R_F(2:1 hexanes, ethyl acetate) = 0.19. δ_H(300 MHz; CDCl)

0.90 (3H, t, J = 6.0 Hz, CH₂CH₂CH₃), 1.00 (3H, d, J = 6.0 Hz, 3-CH₃), 1.19–1.34 (2H, m, CH₂CH₂CH₃), 1.29–1.80

(2H, m, CH₂CH₂CH₃), 2.43–2.49 (1H, m, 3-H), 2.57–2.64 (1H, m, 2-H), 3.48–3.67 (8H, m, N(CH₂CH₂)₂O), 4.95–5.09

(2H, m, 5-H), 5.65–5.79 (1H, m, 4-H). δ_C(75 MHz; CDCl₃) 14.2 (CH₂CH₃), 16.8 (C-3), 21.0 (CH₂CH₃), 32.0

(CHCH₂), 40.3 (C-3), 42.0 (NCH₂), 45.8 (C-2), 46.4 (NCH₂), 66.8 and 67.2 (OCH₂), 114.0 (C-5), 142.0 (C-4), 173.8

(C-1); IR: ν_max(film)/cm^-1; 2961, 2860, 1636, 1435, 1266, 1222, 1116, 1034, 913, 845; m/z (ESI+) 248 (MNa+, 100

%); HRMS (ESI+): found (MH+): 226.1800 C₁₃H₂₄NO₂requires 226.1802.

4.2.1.4 (2R*, 3S*)-2-(Benzo[d][1′,3′]dioxol-5′-ylmethyl)-3-methyl-1-morpholinopent-4-en-1-one 4d. Flash

chromatography using 3:1 hexanes, ethyl acetate to yield 0.81 g, quant. as a yellow oil. R_F(2:1 hexanes, ethyl acetate)

= 0.28. δ_H(400 MHz; CDCl₃; Me₄Si) 1.13 (3H, d, J = 7.2 Hz, 3-CH₃), 2.55 (1H, pent., J = 7.2 Hz, 3-H), 2.68–2.75

(1H, m, 2-H), 2.78–2.85 (2H, m, 2-CH₂), 2.88–2.95 (1H, m, N(CH₂CH₂)₂O), 3.03–3.09 (1H, m, N(CH₂CH₂)₂O), 3.19–

3.25 (1H, m, N(CH₂CH₂)₂O), 3.32–3.39 (2H, m, N(CH₂CH₂)₂O), 3.41–3.47 (1H, m, N(CH₂CH₂)₂O), 3.55–3.60 (1H,

m, N(CH₂CH₂)₂O), 3.63–3.68 (1H, m, N(CH₂CH₂)₂O), 4.96–5.05 (2H, m, 5-H), 5.72–5.81 (1H, ddd, J = 7.6, 10.4,

17.6 Hz, 4-H), 5.90–5.92 (2H, m, 2′-H), 6.60 (1H, dd, J = 1.6, 7.8 Hz, 6′-H), 6.50 (1H, d, J = 1.6 Hz, 4′-H), 6.69 (1H,

d, J = 7.8 Hz, 7′-H). δ_C(100 MHz; CDCl₃) 17.2 (3-CH₃), 36.4 (2-CH₂), 40.2 (C-3), 41.9, 46.2 (N(CH₂CH₂)₂O), 49.0

(C-2), 66.4, 66.9 (N(CH₂CH₂)₂O), 100.8 (C-2′), 108.2 (C-7′), 109.5 (C-4′), 114.3 (C-5), 121.9 (C-6′), 133.8 (C-5′),

141.5 (C-4), 145.9 (C-7a′), 147.5 (C-3a′), 172.7 (C-1). IR: ν_max(film)/cm^-1; 2964, 2896, 2857, 1630, 1488, 1441, 1244,

1113, 1036, 926, 809. m/z (ESI⁺) 340 (MNa⁺, 100%), 207 (30). HRMS (ESI⁺) found (MNa⁺): 340.1518;

C₁₈H₂₃NNaO₄requires 340.1519.

4.2.1.5 3-Methyl-1-morpholinopent-4-en-1-one 4e. Flash chromatography using 2:1 hexanes, ethyl acetate to yield

0.39 g, 31% as a pale yellow oil. R_F= 0.17 (2:1 hexanes, ethyl acetate). δ_H(400 MHz; CDCl₃; Me₄Si) 1.08 (3H, d, J =

6.8 Hz, 3-CH₃), 2.24–2.40 (2H, m, 2-CH₂), 2.70–2.74 (1H, m, 3H), 3.48–3.69 (8H, m, O(CH₂CH₂)₂N), 4.95–5.04

(2H, m, 5-CH₂), 5.77–5.84 (1H, m, 4-H). δ_C(100 MHz; CDCl₃) 19.7 (3-CH₃), 34.3 (C-2), 39.4 (C-3), 41.9

(O(CH₂CH₂)₂N), 46.1 (O(CH₂CH₂)₂N), 66.6 (O(CH₂CH₂)₂N), 66.9 (O(CH₂CH₂)₂N), 113.1 (C-5), 142.9 (C-4), 170.3 (

C-1). IR: (film)/cm^-1; 3496, 2963, 2922, 1636, 1431, 1226, 1114, 911, 726. m/z (ESI⁺) 206 (MNa⁺, 100%). HRMS

(ESI+) Found (MNa⁺): 206.1160; C₁₀H₁₇NNaO₂requires 206.1151.

4.2.1.6 2-Methyl-1-morpholinopent-4-en-1-one 4f. Flash chromatography using 2:1 hexanes, ethyl acetate to yield

0.29 g, 67% as a yellow oil. R_F(2:1 hexanes, ethyl acetate) = 0.20. δ_H(400 MHz; CDCl₃; Me₄Si) 1.14 (3H, d, J = 6.8

Hz, 2-CH₃), 2.13-2.18 (1H, m, 3-H_A), 2.40–2.47 (1H, m, 3-H_B), 2.72 (1H, sext., J = 6.8 Hz, 2-H), 3.52–3.53, 3.63–

3.69 (8H, m, N(CH₂CH₂)₂O), 5.01–5.09 (2H, m, 5-H), 5.71–5.81 (1H, m, 4-H). Spectroscopic data were in accordance

with literature values.²⁰

4.2.1.7 1-Morpholino-2-phenylpent-4-en-1-one 4g. Flash chromatography using 2:1 hexanes, ethyl acetate to yield

0.29 g, 49% as a yellow oil. R_F(2:1 hexanes, ethyl acetate) = 0.80. δ_H(400 MHz; CDCl₃; Me₄Si) 2.42–2.49 (1H, m,

3-H_A), 2.83–2.90 (1H, m, 3-H_B), 3.09–3.75 (9H, m, 2-H, N(CH₂CH₂)₂O), 5.00–5.05 (2H, m, 5-H), 5.72–5.80 (1H, ddt,

J = 7.2, 10.0, 17.2 Hz, 4-H), 7.22–7.34 (5H, m, Ar-H). δ_C(75 MHz; CDCl₃) 39.0 (C-3), 42.4, 46.0 (N(CH₂CH₂)₂O),

48.9 (C-2), 66.3, 66.7 (N(CH₂CH₂)₂O), 116.5 (C-5), 127.1, 127.7, 128.9 (Ar-CH), 136.3 (C-4), 139.4 (Ar-C), 171.0

(C-1). IR: ν_max(film)/cm^-1; 2967, 2919, 1856, 1636, 1454, 1431, 1219, 1113, 751, 700. m/z (ESI⁺) 246 (MH⁺, 100),

268 (80). HRMS (ESI⁺) found (MH⁺): 246.1486; C₁₅H₂₀NO₂requires 246.1489.

4.2.1.8 (2R*, 3S*)-2-methyl-1-morpholino-3-phenylpent-4-en-1-one 4h. Flash chromatography using 3:1 hexanes,

ethyl acetate to yield 24 mg, 14% as a pale yellow solid. R_F(2:1 hexanes, ethyl acetate) = 0.29. MP: 75–78 °C. δ_H

(400 MHz; CDCl₃; Me₄Si) 0.83 (3H, d, J = 6.8 Hz, 2-CH₃), 2.98 (1H, dq, J = 6.8, 9.8 Hz, 2-H), 3.40–3.56 (9H, m,

ACCEPTED MANUSCRIPT

N(CH₂CH₂)₂O and 3-H), 4.89–4.98 (2H, m, 5-H), 5.93 (1H, ddd, J = 7.8, 10.5, 17.9 Hz, 4-H), 7.09–7.14 (3H, m, Ar-

CH), 7.20–7.23 (2H, m, Ar-CH). Spectroscopic data were in accordance with literature values.²⁰

4.2.2 General procedure: Lithiate addition of bromides to morpholine amides

A solution of bromide (1.2 mmol) in THF (15 mL) under an atmopshere of nitrogen, was precooled to -78 °C for 5

min. 1.6 M BuLi (2.4 mmol) was added dropwise, and the resultant solution was stirred at -78 °C for 5 minutes prior

to the addition of a solution of amide (1 mmol) in THF (15 mL) dropwise. The mixture was stirred for 24 h and

allowed to warm to room temperature over this time. Saturated aqueous NH₄Cl solution (20 mL) was added, the

organic layer separated and the aqueous phase further extracted with CH₂Cl₂(3 × 15 mL). The combined organic

extracts were dried (MgSO₄) and the solvent removed in vacuo. The crude product was purified by flash

chromatography to yield the ketone product. All ketones 5 have 2,3-syn stereochemistry except those formed using

amides anti-5a and anti-5b.

4.2.2.1 (2R*, 3S*)-1-(4′-Methoxyphenyl)-2,3-dimethylpent-4-en-1-one syn-5a. Using amide 4a. Flash chromatography

using 3:1 hexanes, ethyl actetate to yield 0.21 g, 96% as a colourless oil. R_F(2:1 hexanes, ethyl acetate) = 0.80. δ_H

(300 MHz; CDCl₃; Me₄Si) 0.99 (3H, d, J = 6.9 Hz, 3-CH₃), 1.13 (3H, d, J = 6.9 Hz, 2-CH₃), 2.64 (1H, sext., J = 6.9

Hz, 3-H), 3.41 (1H, pent., J = 6.9 Hz, 2-H), 3.87 (3H, s, OCH₃), 4.91–5.04 (2H, m, 5-H), 5.81 (1H, ddd, J = 7.1, 10.3,

17.3 Hz, 4-H), 6.94 (2H, d, J = 8.8 Hz, 3′′-H), 7.91 (2H, d, J = 8.8 Hz, 2′-H). Spectroscopic data were in accordance

with literature values.¹⁸

4.2.2.2 (2S*, 3S*)-1-(4′-Methoxyphenyl)-2,3-dimethylpent-4-en-1-one anti-5a. Using amide anti-4a. Flash

chromatography using 2:1 hexanes, ethyl acetate to yield 37 mg, 50% as a yellow oil. R_F(2:1 hexanes, ethyl acetate)

= 0.72. δ_H(400 MHz; CDCl₃; Me₄Si) 0.99 (3H, d, J = 6.8 Hz, 3-CH₃), 1.12 (3H, d, J = 6.8 Hz, 2-CH₃), 2.61 (1H,

sext., J = 6.8 Hz, 3-H), 3.29 (1H, pent., J = 6.8 Hz, 2-H), 3.87 (3H, s, OCH₃), 5.00–5.05 (2H, m, 5-H), 5.70 (1H, ddd,

J = 8.8, 10.0, 18.0 Hz, 4-H), 6.94 (2H, d, J = 8.8 Hz, 3′-H), 7.95 (2H, d, J = 8.8 Hz, 2′-H). δ_C(100 MHz; CDCl₃) 15.6

(2-CH₃), 19.0 (3-CH₃), 41.1 (C-3), 55.4 (C-2), 55.7 (OCH₃), 113.7 (C-3′), 114.8 (C-5), 130.5 (C-1′, C-2′), 141.3 (C-4),

163.4 (C-4′), 202.7 (C-1). IR: ν_max(film)/cm^-1; 2929, 2855, 1672, 1600, 1510, 1453, 1255, 1032. m/z (ESI⁺) 241

(MNa⁺, 100%). HRMS (ESI⁺) found (MNa⁺): 241.1203; C₁₄H₁₈NaO₂requires 241.1199.

4.2.2.3 (2R*, 3S*)-1-(Benzo[d][1′,3′]dioxol-5′-yl)-2,3-dimethylpent-4-en-1-one syn-5b. Using amide 4a. Columend

using 3:1 hexanes, ethyl acetate to yield 0.57 g, 49% as a yellow oil. R_F(2:1 hexanes, ethyl acetate) = 0.74. δ_H(400

MHz; CDCl₃; Me₄Si) 0.99 (3H, d, J = 6.8 Hz, 3-CH₃), 1.13 (3H, d, J = 7.2 Hz, 2-CH₃), 2.62 (1H, pent., J = 6.8 Hz, 3-

H), 3.36 (1H, pent., J = 6.8 Hz, 2-H), 4.91–5.02 (2H, m, 5-H), 5.79 (1H, ddd, J = 7.2, 10.4, 17.2 Hz 4-H), 6.03 (2H, s,

2′-H), 6.86 (1H, d, J = 8.4 Hz, 7′-H), 7.42 (1H, d, J = 1.6 Hz, 4′-H), 7.54 (1H, dd, J = 1.6, 8.4 Hz, 6′-H). δ_C(100

MHz; CDCl₃) 13.5 (2-CH₃), 15.6 (3-CH₃), 40.0 (C-3), 45.0 (C-2), 101.8 (C-2′), 107.8 (C-7′), 108.2 (C-4′), 112.3 (C-

5), 124.2 (C-6′), 131.9 (C-5′), 142.1 (C-4), 148.2 (C-3a′), 151.5 (C-7a′), 201.8 (C-1). IR: ν_max(neat)/cm^-1; 2972, 2896,

1671, 1605, 1502, 1472, 1438, 800. m/z (ESI⁺) 255 (MNa⁺, 100%). HRMS (ESI⁺) found (MNa⁺): 255.1006;

C₁₄H₁₆NaO₃requires 255.0992.

4.2.2.4 (2S*, 3S*)-1-(Benzo[d][1′,3′]dioxol-5′-yl)-2,3-dimethylpent-4-en-1-one anti-5b. Using amide anti-4a. Flash

chromatography using 2:1 hexanes, ethyl acetate to yield 0.11 g, 78% as a yellow oil. R_F(2:1 hexanes, ethyl acetate)

= 0.75. δ_H(400 MHz; CDCl₃; Me₄Si) 0.98 (3H, d, J = 6.8 Hz, 3-CH₃), 1.11 (3H, d, J = 6.8 Hz, 2-CH₃), 2.59 (1H,

sext., J = 6.8 Hz, 3-H), 3.24 (1H, pent., J = 6.8 Hz, 2-H), 5.00–5.05 (2H, m, 5-H), 5.69 (1H, ddd, J = 8.4, 9.6, 17.6 Hz,

4-H), 6.02 (2H, s, 2′–H), 6.84 (1H, d, J = 8.4 Hz, 7′-H), 7.44 (1H, d, J = 1.6 Hz, 4′-H), 7.56 (1H, dd, J = 1.6, 8.4 Hz,

6′-H). δ_C(100 MHz; CDCl₃) 15.6 (2-CH₃), 18.9 (3-CH₃), 41.1 (C-3), 45.2 (C-2), 101.7 (C-2′), 107.7 (C-7′), 108.0 (C-

4′), 114.8 (C-5), 124.2 (C-6′), 132.0 (C-5′), 141.1 (C-4), 148.2 (C-3a′), 151.6 (C-7a′), 202.1 (C-1). IR: ν_max(film)/cm^-1;

2969, 2929, 1670, 1438, 1243, 1037, 810, 741. m/z (ESI⁺) 255 (MNa⁺, 100%). HRMS (ESI⁺) found (MNa⁺):

255.1001; C₁₄H₁₆NaO₃requires 255.0992.

4.2.2.5 (2R*, 3S*)-1-(3′,4′-Dimethoxyphenyl)-2,3-dimethylpent-4-en-1-one 5c. Using amide 4a. Flash chromatography

using 19:1 hexanes, ethyl acetate to yield 0.61 g, 90% as a yellow oil. R_F(2:1 hexanes, ethyl acetate) = 0.57. δ_H(300

MHz; CDCl₃; Me₄Si) 1.01 (3H, d, J = 6.9 Hz, 2-CH₃), 1.14 (3H, d, J = 6.9 Hz, 3-CH₃), 2.65 (1H, sext., J = 6.9 Hz, 3-

H), 3.46 (1H, pent., J = 6.9 Hz, 2-H), 3.94 (3H, s, 3′-OCH₃), 3.95 (3H, s, 4′-OCH₃), 4.92–5.03 (2H, m, 5-H), 5.81 (1H,

ddd, J = 7.0, 10.1, 17.4 Hz, 4-H), 6.89 (1H, d, J = 8.4 Hz, 5′-H), 7.53 (1H, d, J = 1.8 Hz, 2′-H), 7.57 (1H, dd, J = 1.8,

8.4 Hz, 6′-H). Spectroscopic data were in accordance with literature values.^18,25

4.2.2.6 (2R*,3S*)-2,3-dimethyl-1-(3′,4′,5′-trimethoxyphenyl)pent-4-en-1-one 5d. Using amide 4a. Flash

chromatography using 9:1 hexanes, ethyl acetate to yield 0.45 g, 76% as a pale yellow oil. R_F= 0.71 (2:1, hexanes,

ethyl acetate). δ_H(300 MHz; CDCl₃; Me₄Si) 1.01 (3H, d, J = 6.8 Hz, 3-CH₃), 1.15 (3H, d, J = 6.8 Hz, 2-CH₃), 2.61–

2.72 (1H, m, 3-H), 3.36–3.45 (1H, m, 2-H), 3.92 (9H, s, 3′-OCH_3,4′-OCH₃), 4.93–5.05 (2H, m, 5-CH₂), 5.76–5.87

ACCEPTED MANUSCRIPT

(1H, m, 4-H), 7.20 (2H, s, 2′-H). δ_C(75 MHz; CDCl₃) 13.4 (2-CH₃), 15.6 (3-CH₃), 40.1 (C-3), 45.0 (C-2), 56.3 (3′-

OCH₃, 4′-OCH₃), 105.8 (C-2′), 114.0 (C-5), 132.2 (C-1′), 142.1 (C-4), 142.5 (C-4′), 153.1 (C-3′), 202.3 (C-1). IR:

(film)/cm^-1; 2976, 2983, 2854, 1674, 1583, 1456, 1413, 1323, 1127, 908, 730. m/z (ESI+) 301 (MNa⁺, 100%). HRMS

(ESI+) Found (MNa⁺): 301.1403; C₁₆H₂₂NaO₄requires 301.1410.

4.2.2.7 (2S*, 3S*)-1-(4′-Methoxyphenyl)-3-methyl-2-phenylpent-4-en-1-one 5e. Using amide 4b. Flash

chromatography using 9:1 hexanes, ethyl acetate to yield 34 mg, 62% as a yellow oil. R_F(2:1 hexanes, ethyl acetate)

= 0.72. δ_H(400 MHz; CDCl₃; Me₄Si) 0.84 (3H, d, J = 4.0 Hz, 3-CH₃), 3.15–3.23 (1H, m, 3-H), 3.81 (3H, s, OCH₃),

4.35 (1H, d, J = 10.2 Hz, 2-H), 4.92–5.09 (2H, m, 5-H), 5.83 (1H, ddd, J = 7.0, 10.4, 17.3 Hz, 4-H), 6.86 (2H, d, J =

8.9 Hz, 3′-H), 7.18–7.35 (5H, m, Ar-H), 7.95 (2H, d, J = 8.9 Hz, 2′-H). δ_C(100 MHz; CDCl₃) 17.7 (3-CH₃), 40.4 (C-

3), 55.4 (OCH₃), 58.9 (C-2), 113.7 (C-3′), 114.3 (C-5), 127.1, 128.7, 128.8 (Ar-CH, C-1′), 130.8 (C-2′), 138.0 (Ar-C),

142.2 (C-4), 163.3 (C-4′), 198.1 (C-1). IR: ν_max(film)/cm^-1; 2961, 1671, 1639, 1598, 1510, 1455, 1261, 1169, 1031,

746, 702. m/z (ESI⁺) 303 (MNa⁺, 100%), 281 (30). HRMS (ESI⁺) found (MNa⁺): 303.1360; C₁₉H₂₀NaO₂requires

303.1356.

4.2.2.8 (3S*, 4S*)-3-Methyl-4-phenylnon-1-en-5-one 5f. Using amide 4b. Flash chromatography using 2:1 hexanes,

ethyl acetate to yield 32 mg, 73% as a yellow oil. R_F(2:1 hexanes, ethyl acetate) = 0.89. δ_H(300 MHz; CDCl₃; Me₄Si)

0.75–0.81 (6H, m, 3-CH₃, 9-H), 1.07–1.26 (2H, m, 8-H), 1.38–1.50 (2H, m, 7-H), 2.31–2.42 (2H, m, 6-H), 2.96–3.06

(1H, m, 3-H), 3.48 (1H, d, J = 9.0 Hz, 4-H), 5.03 (2H, ddd, J = 7.4, 10.3, 17.4 Hz, 1-H), 5.72–5.84 (1H, m, 2-H),

7.20–7.33 (5H, m, Ar-H). δ_C(75 MHz; CDCl₃) 13.7 (C-9), 17.6 (3-CH₃), 22.0 (C-8), 25.4 (C-7), 39.5 (C-3), 42.9 (C-

6), 64.8 (C-4), 114.4 (C-1), 127.2, 128.7, 128.9 (Ar-CH), 137.2 (Ar-C), 141.9 (C-2), 209.8 (C-5). IR: ν_max(neat)/cm^-1;

2959, 2932, 2874, 1713, 1641, 1494, 1454, 915, 743. m/z (ESI⁺) 231 (MH⁺, 100%), 253 (20). HRMS (ESI⁺) found

(MH⁺): 231.1743; C₁₆H₂₃O requires 231.1743.

4.2.2.9 (2R*, 3S*)-1-(4′-Methoxyphenyl)-2-propyl-3-methylpent-4-en-1-one 5g. Using amide 4c. Flash

chromatography using 2:1 hexanes, ethyl acetate to yield 81 mg, 88% as a pale yellow oil. R_F(2:1 hexanes, ethyl

acetate) = 0.82. δ_H(400 MHz; CDCl₃) 0.92–1.01 (3H, m, 2-CH₂CH₂CH₃), 1.00 (3H, d, J = 6.9 Hz, 3-CH₃), 1.22–1.31

(4H, m, 2-CH₂CH₂CH₃), 2.62 (1H, q, J = 6.8 Hz, 2-H), 3.42 (1H, pent., J = 6.8 Hz, 3-H), 3.87 (3H, s, OCH₃), 4.91–

5.05 (2H, m, 5-H), 5.76–5.87 (1H, m, 4-H), 6.94 (2H, d, J = 8.9 Hz, 3′-H), 7.92 (2H, d, J = 8.9 Hz, 2′-H). δ_C(100

MHz; CDCl₃) 14.3 (CH₂CH₃), 16.3 (C-3), 21.1 (CH₂CH₃), 30.9 (CHCH₂), 40.1 (C-3), 50.4 (C-2), 55.4 (OCH₃), 113.9

(C-3), 114.0 (C-5), 129.4 (C-2), 131.3 (C-1'), 142.0 (C-4), 163.3 (C-4'), 201.2 (C-1). IR: ν_max(film)/cm^-1; 2958, 2933,

2874, 1671, 1638, 1509, 1462, 1250, 1172, 1032, 913; m/z (ESI+): 269 (MNa⁺, 100%); HRMS (ESI+) Found

(MNa⁺): 269.1508 C₁₆H₂₂NaO₂requires 269.1512.

4.2.2.10 (2R*, 3S*)-1-(Benzo[d][1′′,3′′]dioxol-5′′-yl)-2-(benzo[d][1′,3′]dioxol-5′-ylmethyl)-3-methylpent-4-en-1-one

5h. Using amide 4d. Flash chromatography using 9:1 hexanes, ethyl acetate to yield 0.12 g, 28% as an orange oil. R_F

(2:1 hexanes, ethyl acetate) = 0.63. δ_H(400 MHz; CDCl₃; Me₄Si) 1.04 (3H, d, J = 6.8 Hz, 3-CH₃), 2.60 (1H, pent., J =

6.8 Hz, 3-H), 2.71 (1H, dd, J = 3.7, 13.5 Hz, 2-CH_A), 3.04 (1H, dd, J = 10.4, 13.5 Hz, 2-CH_B), 3.56–3.60 (1H, m, 2-

H), 4.99–5.07 (2H, m, 5-H), 5.80–5.89 (3H, m, 4-H, 2′-H), 6.00 (2H, s, 2′′-H), 6.56–6.67 (3H, m, 4′-H, 6′-H, 7′-H),

6.76 (1H, d, J = 8.1 Hz, 7′′-H), 7.29 (1H, d, J = 1.6 Hz, 4′′-H), 7.35 (1H, dd, J = 1.6, 8.1 Hz, 6′′-H). δ_C(100 MHz;

CDCl₃) 16.1 (3-CH₃), 33.9 (2-CH₂), 40.2 (C-3), 53.2 (C-2), 100.6 (C-2′), 100.7 (C-2′′), 107.6, 107.7 (C-7′, C-7′′),

108.0 (C-4′′), 109.3 (C-4′), 114.6 (C-5), 121.8 (C-6′), 124.3 (C-6′′), 132.9 (C-5′′), 134.1 (C-5′), 141.2 (C-4), 145.6,

147.3 (C-7a′, C-3a′), 148.0 (C-3a′′), 151.4 (C-7a′′), 200.6 (C-1). IR: ν_max(film)/cm^-1; 2971, 2899, 1667, 1604, 1502,

1486, 1438, 1242, 1035, 925, 808, 733. m/z (ESI⁺) 375 (MNa⁺, 40%), 360 (100). HRMS (ESI⁺) found (MNa⁺):

375.1191; C₂₁H₂₀NaO₅requires 375.1203.

4.2.2.11 (2R*, 3S*)-2-(Benzo[d][1′,3′]dioxol-5′-ylmethyl)-1-(4′′-methoxyphenyl)-3-methylpent-4-en-1-one 5i. Using

amide 4d. Flash chromatography using 19:1 hexanes, ethyl acetate to yield 0.17 g, 42% as a yellow oil. R_F(2:1

hexanes, ethyl acetate) = 0.62. δ_H(400 MHz; CDCl₃; Me₄Si) 1.04 (3H, d, J = 7.0 Hz, 3-CH₃), 2.61 (1H, q, J = 7.0 Hz,

3-H), 2.71 (1H, dd, J = 3.6, 13.6 Hz, 2-CH_A), 3.06 (1H, dd, J = 10.0, 13.6 Hz, 2-CH_B), 3.62–3.67 (1H, m, 2-H), 3.83

(3H, s, OCH₃), 4.91–5.02 (2H, m, 5-H), 5.83–5.91 (3H, m, 4-H, 2′-H), 6.60–6.65 (3H, m, 4′-H, 6′-H, 7′-H), 6.86 (2H,

d, J = 8.9 Hz, 3′′-H), 7.78 (2H, d, J = 8.9 Hz, 2′′-H). δ_C(100 MHz; CDCl₃) 16.0 (3-CH₃), 33.6 (2-CH₂), 40.1 (C-3),

52.9 (C-2), 55.2 (OCH₃), 100.5 (C-2′), 107.9 (C-7′), 109.3 (C-4′), 113.5, 113.6 (C-3′′), 114.4 (C-5), 121.7 (C-6′),

130.3, 130.4 (C-2′′), 130.9 (C-1′′), 134.2 (C-5′), 141.3 (C-4), 145.5 (C-7a′), 147.3 (C-3a′), 163.1 (C-4′′), 200.9 (C-1).

IR: ν_max(film)/cm^-1; 2964, 2910, 2842, 1667, 1597, 1502, 1487, 1441, 1242, 1168, 1035, 919, 803, 732. m/z (ESI⁺)

360 (100), 361 (95). HRMS (ESI⁺) found (MNa⁺): 361.1407; C₂₁H₂₂NaO₄requires 361.1410.

4.2.2.12 1-(3′-isopropoxy-4′-methoxyphenyl)-3-methylpent-4-en-1-one 5j. Using amide 4e. Flash chromatography

using 19:1 hexanes, ethyl acetate to yield 0.32 g, 75% as a pale yellow oil. R_F= 0.80 (2:1 hexanes, ethyl acetate). δ_H

(400 MHz; CDCl₃; Me₄Si) 1.07 (3H, d, J = 6.8 Hz, 3-CH₃), 1.36 (6H, d, J = 6.0 Hz, 3′-OCH(CH₃)₂), 2.79–2.83 (1H,

m, 2-CH₂), 2.85–2.88 (1H, m, 3-H), 2.92–2.97 (1H, m, 2-CH₂), 3.89 (3H, s, 4′-OCH₃), 4.59–4.62 (1H, m, 3′-

CH(CH₃)₂), 4.92–5.02 (2H, m, 5-H), 5.79–5.86 (1H, m, 4-H), 6.86 (1H, d, J = 8.2 Hz, 5′-H) , 7.52 (1H, d, J = 2.0 Hz,

ACCEPTED MANUSCRIPT

2′-H), 7.54 (1H, dd, J = 8.2, 2.0 Hz, 6′-H). δ_C(100 MHz; CDCl₃) 19.8 (3-CH₃), 21.9 (3′-OCH(CH₃)₂), 33.9 (C-3), 44.7

(C-2), 56.0 (4′-OCH₃), 71.4 (3′-OCH(CH₃)₂), 110.6 (C-5′), 112.9 (C-5), 114.4 (C-2′), 122.8 (C-6′), 130.5 (C-1′), 143.4

(C-4), 147.2 (C-3′), 154.5 (C-4′), 197.9 (C-1). IR: (film)/cm-1; 2975, 1673, 1592, 1509, 1441, 1266, 1146, 1022, 911,

729. m/z (ESI+) 285 (MNa⁺, 100%). HRMS (ESI+) Found (MNa⁺): 285.1469; C₁₆H₂₂NaO₃requires 285.1461.

4.2.2.13 1-(4′-Methoxyphenyl)-2-methylpent-4-en-1-one 5k. Using amide 4f. Flash chromatography using 9:1 hexanes,

ethyl acetate to yield 55 mg, 99% as a yellow oil. R_F(2:1 hexanes, ethyl acetate) = 0.74. δ_H(400 MHz; CDCl₃; Me₄Si)

1.19 (3H, d, J = 7.2 Hz, 2-CH₃), 2.15–2.23 (1H, m, 3-H_A), 2.51–2.58 (1H, m, 3-H_B), 3.49 (1H, q, J = 7.2 Hz, 2-H),

3.86 (3H, s, OCH₃), 4.98–5.07 (2H, m, 5-H), 5.73–5.83 (1H, m, 4-H), 6.94 (2H, d, J = 8.8 Hz, 3′-H), 7.95 (2H, d, J =

8.8 Hz, 2′-H). Spectroscopic data were in accordance wih literature values.²⁵

4.2.2.14 1-(4′-Methoxyphenyl)-2-phenylpent-4-en-1-one 5m. Using amide 4g. Flash chromatography using 14:1

hexanes, ethyl acetate to yield 0.18 g, 83% as a colourless oil. R_F(2:1 hexanes, ethyl acetate) = 0.89. δ_H(400 MHz;

CDCl₃; Me₄Si) 2.55 (1H, pent., J = 7.2 Hz, 3-H_A), 2.95 (1H, pent., J = 7.2 Hz, 3-H_B), 3.70 (3H, s, OCH₃), 4.58 (1H, t,

J = 7.2 Hz, 2-H), 4.93–5.05 (2H, m, 5-H), 5.70–5.80 (1H, m, 4-H), 6.81 (2H, d, J = 8.9 Hz, 3′-H), 7.23–7.34 (5H, m,

Ar-H), 7.94 (2H, d, J = 8.9 Hz, 2′-H). δ_C(100 MHz; CDCl₃) 38.0 (C-3), 53.0 (C-2), 55.2 (OCH₃), 113.5 (C-3′), 116.4

(C-5), 126.8, 128.0, 128.7 (Ar-CH), 129.4 (C-1′), 130.8 (C-2′), 136.0 (C-4), 139.3 (Ar-C), 163.2 (C-4′), 197.6 (C-1).

IR: ν_max(film)/cm^-1; 3064, 2936, 2839, 1670, 1641, 1510, 1489, 1245, 1029, 824, 700. m/z (ESI⁺) 289 (MNa⁺, 100%).

HRMS (ESI⁺) found (MNa⁺): 289.1167; C₁₈H₁₈NaO₂requires 289.1199.

4.2.2.15 (2R*, 3S*)-1-(Benzo[d][1′,3′]dioxol-5′-yl)-2-methyl-3-phenylpent-4-en-1-one 5n. Using amide 4h. Flash

chromatography using 19:1 hexanes, ethyl acetate to yield 365 mg, 79% as a yellow oil. R_F(2:1 hexanes, ethyl

acetate) = 0.77. δ_H(300 MHz; CDCl₃; Me₄Si) 0.96 (3H, d, J = 6.6 Hz, 2-CH₃), 3.72–3.83 (2H, m, 2-H, 3-H), 4.89–

4.97 (2H, m, 5-H), 5.94 (1H, ddd, J = 6.9, 13.6, 17.1 Hz, 4-H), 6.03 (1H, d, J = 8.2 Hz, 5′-H), 6.61–6.63 (2H, m, 7′-

H), 7.22–7.35 (5H, m, Ar-H), 7.48 (1H, d, J = 1.6 Hz, 2′-H), 7.61 (1H, dd, J = 1.6, 8.2 Hz, 6′-H). δ_C(75 MHz; CDCl₃)

17.1 (2-CH₃), 44.7 (C-2), 52.8 (C-3), 101.8 (C-2′), 107.9 (C-7′), 108.1 (C-4′), 115.4 (C-5), 124.3 (C-6′), 126.6, 128.4,

128.6 (Ar-CH), 132.1 (C-5′), 139.8 (C-4), 141.7 (Ar-C), 148.3 (C-3a′), 151.7 (C-7a′), 201.6 (C-1). IR: ν_max(film)/cm^-1;

2977, 2860, 1622, 1241, 1110, 1033, 768, 735. The sample decomposed prior to mass spectrum acquisition.

4.2.3 General procedure: Wacker oxidation

To a solution of ketone (1 mmol) in DMF/H₂O (3:1, 100 mL) was added PdCl₂(0.5 mmol) and CuCl (1.3 mmol) and

the resultant suspension was stirred vigorously open to air. The mixture was filtered through a slurry of silica and

ethyl acetate and was washed with ethyl actetate (3 × 100 mL). The solvent was removed in vacuo, the residue was

diluted with ethyl acetate (30 mL) and water (30 mL) and the organic layer separated. The aqueous phase was further

extracted with ethyl acetate (3 × 30 mL) and the combined organic extracts were washed with water (3 × 30 mL),

dried (MgSO₄) and the solvent removed in vacuo. The crude product was purified by flash chromatography to yield

the diketone product. All diketones 1 have 2,3-syn stereochemistry except those formed using ketones anti-1a and

anti-1b.

4.2.3.1 (2R*, 3R*)-1-(4′-Methoxyphenyl)-2,3-dimethylpentane-1,4-dione syn-1a. Using alkene 5a. Flash

chromatography using 2:1 hexanes, ethyl acetate to yield 0.39 g, 91% as a brown-green oil. R_F(2:1 hexanes, ethyl

acetate) = 0.40. δ_H(400 MHz; CDCl₃; Me₄Si) 1.17 (6H, t, J = 7.1 Hz, 2-CH₃, 3-CH₃), 2.22 (3H, s, 5-CH₃), 3.07 (1H,

pent., J = 7.2 Hz, 3-H), 3.69 (1H, pent., J = 7.2 Hz, 2-H), 3.87 (3H, s, OCH₃), 6.90–6.96 (2H, m, 3′-H), 7.91–7.97

(2H, m, 2′-H). δ_C(100 MHz; CDCl₃) 13.9 (2-CH₃), 15.3 (3-CH₃), 29.0 (C-5), 42.7 (C-2), 48.8 (C-3), 55.4 (OCH₃),

113.7 (C-3′), 128.9 (C-1′), 130.6 (C-2′), 163.3 (C-4′), 202.6 (C-4), 212.3 (C-1). IR: ν_max(film)/cm^-1; 2973, 1669, 1598,

1510, 1257, 1167, 1028. m/z (ESI⁺) 257 (MNa⁺, 100%). HRMS (ESI⁺) found (MH⁺): 235.1324; C₁₄H₁₉O₃requires

235.1329.

4.2.3.2 (2S*, 3R*)-1-(4′-Methoxyphenyl)-2,3-dimethylpentane-1,4-dione anti-1a. Using alkene anti-5a. Flash

chromatography using 2:1 hexanes, ethyl acetate to yield 19 mg, 49% as a yellow oil. R_F(2:1 hexanes, ethyl acetate)

= 0.47. δ_H(300 MHz; CDCl₃; Me₄Si) 2.04 (3H, d, J = 6.9 Hz, 3-CH₃), 1.13 (3H, d, J = 6.9 Hz, 2-CH₃), 2.24 (3H, s, 5-

CH₃), 3.07 (1H, pent., J = 6.9 Hz, 3-H), 3.73 (1H, pent., J = 6.9 Hz, 2-H), 3.88 (3H, s, OCH₃), 6.95 (2H, d, J = 8.9 Hz,

3′-H), 7.98 (2H, d, J = 8.9 Hz, 2′-H). δ_C(75 MHz; CDCl₃) 16.0 (2-CH₃), 16.9 (3-CH₃), 30.4 (C-5), 42.3 (C-2), 49.4

(C-3), 55.5 (OCH₃), 113.9 (C-3′), 129.7 (C-1′), 130.7 (C-2′), 163.7 (C-4′), 201.7 (C-1), 212.1 (C-4). IR: ν_max(film)/cm^-

¹; 2972, 2935, 1710, 1669, 1599, 1259, 1169, 845. m/z (ESI⁺) 257 (MNa⁺, 100%). HRMS (ESI⁺) found (MNa⁺):

257.1150; C₁₄H₁₈NaO₃requires 257.1148.

4.2.3.3 (2R*, 3R*)-1-(Benzo[d][1′,3′]dioxol-5′-yl)-2,3-dimethylpentane-1,4-dione syn-1b. Using alkene 5b. Flash

chromatography using 19:1 hexanes, ethyl acetate to yield 0.40 g, 80% as a viscous colourless oil. R_F(2:1 hexanes,

ethyl acetate) = 0.50. δ_H(400 MHz; CDCl₃; Me₄Si) 1.15–1.19 (6H, m, 2-CH₃, 3-CH₃), 2.21 (3H, s, 5-H), 3.03–3.11

ACCEPTED MANUSCRIPT

(1H, m, 3-H), 3.60–3.67 (1H, m, 2-H), 6.03 (2H, s, 2′-H), 6.85 (1H, d, J = 8.2 Hz, 7′-H), 7.41 (1H, d, J = 1.6 Hz, 4′-

H), 7.58 (1H, dd, J = 1.6, 8.2 Hz, 6′-H). δ_C(100 MHz; CDCl₃) 13.9 (2-CH₃), 15.4 (3-CH₃), 28.9 (C-5), 42.9 (C-2),

49.0 (C-3), 101.7 (C-2′), 107.9 (C-7′), 108.3 (C-4′), 124.5 (C-6′), 130.7 (C-5′), 148.1 (C-3a′), 151.6 (C-7a′), 202.2 (C-

1), 212.2 (C-4). IR: ν_max(film)/cm^-1; 2975, 2917, 1705, 1659, 1601, 1498, 1444, 1250, 1101, 1035, 760, 738, 696. m/z

(ESI⁺) 271 (MNa⁺, 100%), 227 (10). HRMS (ESI⁺) found (MNa⁺): 271.0944; C₁₄H₁₆NaO₄requires 271.0941.

4.2.3.4 (2S*, 3R*)-1-(Benzo[d][1′,3′]dioxol-5′-yl)-2,3-dimethylpentane-1,4-dione anti-1b. Using alkene anti-5b. Flash

chromatography using 2:1 hexanes, ethyl acetate 78 mg, 68% as a yellow oil. R_F(2:1 hexanes, ethyl acetate) = 0.53.

δ_H(400 MHz; CDCl₃; Me₄Si) 1.04 (3H, d, J = 6.8 Hz, 3-CH₃), 1.12 (3H, d, J = 6.8 Hz, 2-CH₃), 2.23 (3H, s, 5-H), 3.06

(1H, pent., J = 6.8 Hz, 3-H), 3.69 (1H, pent., J = 6.8 Hz, 2-H), 6.05 (2H, s, 2′-H), 6.87 (1H, d, J = 8.4 Hz, 7′-H), 7.46

(1H, d, J = 2.0 Hz, 4′-H), 7.61 (1H, dd, J = 2.0 Hz, 8.4 Hz, 6′-H). δ_C(100 MHz; CDCl₃) 15.8 (3-CH₃), 16.9 (2-CH₃),

30.2 (C-5), 42.4 (C-2), 49.3 (C-3), 101.8 (C-2′), 107.8 (C-4′), 108.0 (C-7′), 124.6 (C-6′), 131.5 (C-5′), 148.3 (C-3a′),

151.9 (C-7a′), 201.2 (C-1), 211.8 (C-4). IR: ν_max(film)/cm^-1; 2924, 2854, 1710, 1669, 1607, 1504, 1480, 1439, 1243,

1036, 808, 756. m/z (ESI⁺) 271 (MNa⁺, 100%). HRMS (ESI⁺) found (MNa⁺): 271.0945; C₁₄H₁₆NaO₄requires

271.0954.

4.2.3.5 (2R*, 3R*)-1-(3′,4′-Dimethoxyphenyl)-2,3-dimethylpentane-1,4-dione 1c. Using alkene 5c. Flash

chromatography using 9:1 hexanes, ethyl acetate to yield 0.64 g, 98% as a pale yellow solid. R_F(2:1 hexanes, ethyl

acetate) = 0.30. MP: 61–64 °C. δ_H(300 MHz; CDCl₃; Me₄Si) 1.18 (3H, d, J = 7.2 Hz, 2-CH₃), 1.20 (3H, d, J = 7.3

Hz, 3-CH₃), 2.22 (3H, s, 5-H), 3.09 (1H, pent., J = 7.3 Hz, 3-H), 3.70 (1H, pent., J = 7.2 Hz, 2-H), 3.93 (3H, s, 3′-

OCH₃), 3.94 (3H, s, 4′-OCH₃), 6.90 (1H, d, J = 8.4 Hz, 5′-H), 7.50 (1H, d, J = 2.0 Hz, 2′-H), 7.63 (1H, dd, J = 2.0, 8.4

Hz, 6′-H). δ_C(75 MHz; CDCl₃) 13.9 (3-CH₃), 15.4 (2-CH₃), 28.9 (C-5), 42.6 (C-2), 48.9 (C-3), 55.8, 55.9 (3′-OCH₃,

4′-OCH₃), 110.0 (C-5′), 110.5 (C-2′), 122.8 (C-6′), 129.0 (C-1′), 149.0 (C-3′), 153.1 (C-4′), 202.6 (C-1), 212.2 (C-4).

IR: ν_max(film)/cm^-1; 2970, 2936, 2841, 1710, 1667, 1594, 1584, 1514, 1456, 1258, 1158, 766, 754. m/z (ESI⁺) 287

(MNa⁺, 100%), 265 (20). HRMS (ESI⁺) found (MNa⁺): 287.1245; C₁₅H₂₀NaO₄requires 287.1254.

4.2.3.6 (2R*,3R*)-2,3-dimethyl-1-(3′,4′,5′-trimethoxyphenyl)pentane-1,4-dione 1d. Using alkene 5d. Flash

chromatography using 2:1 hexanes, ethyl acetate to yield 0.16 g, 86% as a yellow oil. R_F= 0.29 (2:1 hexanes, ethyl

acetate). δ_H(500 MHz; CDCl₃; Me₄Si) 1.18 (3H, d, J = 7.2 Hz, 2-CH₃), 1.22 (3H, d, J = 7.2 Hz, 3-CH₃), 2.23 (3H, s,

5-CH₃), 3.08–3.11 (1H, m, 3-H), 3.66–3.69 (1H, m, 2-H), 3.91 (3H, s, 4′-OCH₃), 3.92 (6H, s, 3′-OCH₃), 7.22 (2H, s,

2′-H). δ_C(125 MHz; CDCl₃) 14.0 (3-CH₃), 15.5 (2-CH₃), 29.1 (5-CH₃), 42.9 (C-2), 49.1 (C-3), 56.1 (3′-OCH₃, 4′-

OCH₃), 105.9 (C-2′), 131.3 (C-1′), 142.5 (C-4′), 153.1 (C-3′), 203.1 (C-1), 212.3 (C-4). IR: (film)/cm-1; 2940, 2839,

1711, 1673, 1583, 1456, 1333, 1160, 1002, 908, 730. m/z (ESI+) 317 (MNa⁺, 100%). HRMS (ESI+) Found (MNa⁺):

317.1359; C₁₆H₂₂NaO₅requires 317.1359.

4.2.3.7 (2S*, 3R*)-1-(4′-Methoxyphenyl)-3-methyl-2-phenylpentane-1,4-dione 1e. Using alkene 5e. Flash

chromatography using 9:1 hexanes, ethyl acetate to yield 24 mg, 72% as a yellow oil. R_F(2:1 hexanes, ethyl acetate)

= 0.56. δ_H(400 MHz; CDCl₃; Me₄Si) 0.94 (3H, d, J = 7.2 Hz, 3-CH₃), 2.32 (3H, s, 5-H), 3.46 (1H, dq, J = 7.2, 10.8

Hz, 3-H), 3.78 (3H, s, OCH₃), 4.74 (1H, d, J = 10.8 Hz, 2-H), 6.81 (2H, d, J = 8.8 Hz, 3′-H), 7.27–7.29 (5H, m, Ar-H),

7.91 (2H, d, J = 8.8 Hz, 2′-H). δ_C(100 MHz; CDCl₃) 14.8 (3-CH₃), 29.2 (C-5), 49.9 (C-3), 55.3 (C-2), 56.5 (OCH₃),

113.6 (C-3′), 127.3, 128.7, 129.0 (Ar-CH), 129.3 (C-1′), 131.1 (C-2′), 137.5 (C-1′′), 163.2 (C-4′), 198.2 (C-1), 212.5

(C-4). IR: ν_max(film)/cm^-1; 2968, 2935, 2841, 1710, 1667, 1597, 1575, 1510, 1454, 1260, 1233, 1029, 743, 702. m/z

(ESI⁺) 319 (MNa⁺, 100%). HRMS (ESI⁺) found (MNa⁺): 319.1298; C₁₉H₂₀NaO₃requires 319.1305.

4.2.3.8 (3R*, 4S*)-3-Methyl-4-phenylnonane-2,5-dione 1f. Using alkene 5f. Flash chromatography using 2:1 hexanes,

ethyl acetate to yield 50 mg, quant. as a yellow oil. R_F(2:1 hexanes, ethyl acetate) = 0.81. δ_H(300 MHz; CDCl₃;

Me₄Si) 0.75–0.85 (6H, m, 3-CH₃, 9-H), 1.11–1.17 (2H, m, 8-H), 1.39–1.52 (2H, m, 7-H), 2.28 (3H, s, 1-H), 2.31–2.41

(2H, m, 6-H), 3.28–3.35 (1H, m, 3-H), 3.95 (1H, d, J = 12.0 Hz, 4-H), 7.15–7.33 (5H, m, Ar-H). δ_C(75 MHz; CDCl₃)

13.7 (3-CH₃), 14.6 (C-9), 22.0 (C-8), 25.6 (C-7), 29.0 (C-1), 41.3 (C-6), 48.6 (C-3), 61.4 (C-4), 127.5, 128.8, 129.0

(Ar-CH), 136.5 (Ar-C), 210.4 (C-5), 212.4 (C-2). IR: ν_max(neat)/cm^-1; 2959, 2933, 2874, 1707, 1494, 1454, 742. m/z

(ESI⁺) 269 (MNa⁺, 100%), 247 (60), 229 (20), 175 (40). HRMS (ESI⁺) found (MH⁺): 247.1691; C₁₆H₂₃O₂requires

247.1693.

4.2.3.9 (2R*, 3R*)-1-(4′-Methoxyphenyl)-3-methyl-2-propylpentane-1,4-dione 1g. Using alkene 5g. Flash

chromatography using 2:1 hexanes, ethyl acetate to yield 58 mg, 55% as a colourless oil. R_F(2:1 hexanes, ethyl

acetate) = 0.57. δ_H(300 MHz; CDCl₃; Me₄Si) 0.81 (3H, t, J = 7.2 Hz, 2-CH₂CH₂CH₃), 1.08–1.26 (2H, m, 2-

CH₂CH₂CH₃), 1.17 (3H, d, J = 7.3 Hz, 3-CH₃), 1.50–1.73 (2H, m, 2-CH₂CH₂CH₃), 2.18 (3H, s, 5-H), 3.07–3.17 (1H,

m, 2-H), 3.72 (1H, dq, J = 4.0, 8.1 Hz, 3-H), 3.86 (3H, s, OCH₃), 6.93 (2H, d, J = 8.8 Hz, 3′-H), 7.95 (2H, d, J = 8.8

Hz, 2′-H). δ_C(75 MHz; CDCl₃) 13.9 (3-CH₃), 14.4 (2-CH₂CH₂CH₃), 19.7 (2-CH₂CH₂CH₃), 29.1 (C-5), 31.6 (2-

CH₂CH₂CH₃), 47.3 (C-2), 47.6 (C-3), 55.4 (OCH₃), 113.7 (C-3′), 130.6 (C-2′, C-1′), 163.4 (C-4′), 202.7 (C-1), 212.0

(C-4). IR: ν_max(film)/cm^-1; 2959, 2935, 2874, 1711, 1668, 1598, 1574, 1509, 1461, 1167, 842, 771. m/z (ESI⁺) 285

(MNa⁺, 100%), 263 (40), 155 (40). HRMS (ESI⁺) found (MH⁺): 263.1640; C₁₆H₂₃O₃requires 263.1642.

ACCEPTED MANUSCRIPT

4.2.3.10 (2R*, 3R*)-1-(Benzo[d][1′′,3′′]dioxol-5′′-yl)-2-(benzo[d][1′,3′]dioxol-5′-ylmethyl)-3-methylpentane-1,4-dione

1h. Using alkene 5h. Flash chromatography using 9:1 hexanes, ethyl acetate to yield 84 mg, 69% as a yellow oil. R_F

(2:1 hexanes, ethyl acetate) = 0.47. δ_H(400 MHz; CDCl₃; Me₄Si) 1.23 (3H, d, J = 7.4 Hz, 3-CH₃), 2.17 (3H, s, 5-H),

2.81–2.90 (2H, m, 2-CH₂), 3.03 (1H, pent., J = 7.4 Hz, 3-H), 3.88–3.93 (1H, m, 2-H), 5.84 (2H, s, 2′′-H), 5.98 (2H, s,

2′-H), 6.48 (1H, dd, J = 1.2, 8.0 Hz, 6′-H), 6.53 (1H, d, J = 1.2 Hz, 4′-H), 6.59 (1H, J = 8.0 Hz, 7′-H), 6.74 (1H, d, J =

8.4 Hz, 7′′-H), 7.27 (1H, d, J = 1.6 Hz, 4′′-H), 7.36 (1H, dd, J = 1.6, 8.4 Hz, 6′′-H). δ_C(100 MHz; CDCl₃) 13.8 (3-

CH₃), 29.0 (C-5), 35.0 (2-CH₂), 48.0 (C-3), 49.8 (C-2), 100.7 (C-2′), 101.7 (C-2′′), 107.7 (C-7′), 108.0 and 108.1 (C-4′

and C-7′′), 109.4 (C-4′′), 122.0 (C-6′′), 124.5 (C-6′), 131.9 (C-5′), 132.2 (C-5′′), 145.9 (C-7a′), 147.3 (C-3a′), 147.9

(C-3a′′), 151.5 (C-7a′′), 201.3 (C-1), 211.3 (C-4). IR: ν_max(film)/cm^-1; 2900, 1708, 1666, 1502, 1487, 1439, 1243,

1034, 928, 808, 731. m/z (ESI⁺) 391 (MNa⁺, 100%), 227 (40). HRMS (ESI⁺) found (MNa⁺): 391.1144; C₂₁H₂₀NaO₆

requires 391.1152.

4.2.3.11 (2R*, 3R*)-2-(Benzo[d][1′,3′]dioxol-5′-ylmethyl)-1-(4′′-methoxyphenyl)-3-methylpentane-1,4-dione 1i. Using

alkene 5i. Flash chromatography using 9:1 hexanes, ethyl acetate to yield 0.14 g, 83% as a yellow oil. R_F(2:1

hexanes, ethyl acetate) = 0.59. δ_H(300 MHz; CDCl₃; Me₄Si) 1.22 (3H, d, J = 7.2 Hz, 3-CH₃), 2.16 (3H, s, 5-H), 2.79–

2.94 (2H, m, 2-CH₂), 3.03 (1H, pent., J = 7.2 Hz, 3-H), 3.79 (3H, s, OCH₃), 3.97 (1H, pent., J = 4.2 Hz, 2-H), 5.80

(2H, s, 2′-H), 6.48–6.64 (3H, m, 4′-H, 6′-H, 7′-H), 6.82 (2H, d, J = 8.6 Hz, 3′′-H), 7.78 (2H, d, J = 8.6 Hz, 2′′-H). δ_C

(75 MHz; CDCl₃) 13.6 (3-CH₃), 28.8 (C-5), 34.7 (2-CH₂), 47.8 (C-2), 49.5 (C-3), 55.2 (OCH₃), 100.5 (C-2′), 107.8

(C-7′), 109.3 (C-4′), 113.4 (C-3′′), 121.9 (C-6′), 129.9 (C-1′′), 130.4 (C-2′′), 132.3 (C-5′), 145.7, 147.2 (C-7a′, C-3a′),

163.1 (C-4′′), 201.4 (C-1), 211.2 (C-4). IR: ν_max(film)/cm^-1; 2975, 2935, 2896, 2842, 1708, 1667, 1598, 1504, 1488,

1442, 906, 724. m/z (ESI⁺) 377 (MNa⁺, 100%), 355 (20), 337 (15). HRMS (ESI⁺) found (MNa⁺): 377.1355;

C₂₁H₂₂NaO₅requires 377.1359.

4.2.3.12 1-(3′-isopropoxy-4′-methoxyphenyl)-3-methylpentane-1,4-dione 1j. Using alkene 5j. Flash chromatography

using 19:1 n-hexanes, ethyl acetate to yield 0.22 g, 76% as a yellow oil. R_F= 0.40 (2:1 hexanes, ethyl acetate). δ_H

(400 MHz; CDCl₃; Me₄Si) 1.17 (3H, d, J = 7.2 Hz, 3-CH₃), 1.35 (6H, d, J = 6.0 Hz, 3′-OCH(CH₃)₂), 2.28 (3H, s, 5-

CH₃), 2.86–2.91 (1H, m, 2-CH₂), 3.17–3.21 (1H, m, 3-H), 3.42–3.48 (1H, m, 2-CH₂), 3.89 (3H, s, 4′-OCH₃), 4.57–

4.60 (1H, m, 3′-OCH(CH₃)₂), 6.85 (1H, d, J = 8.4 Hz, 5′-H) , 7.49 (1H, d, J = 2.0 Hz, 2′-H), 7.56 (1H, dd, J = 8.4, 2.0

Hz, 6′-H). δ_C(100 MHz; CDCl₃) 16.7 (3-CH₃), 21.9 (3′-OCH(CH₃)₂), 28.8 (5-CH₃), 41.5 (C-2), 41.8 (C-3), 56.0 (4′-

OCH₃), 71.4 (3′-OCH(CH₃)₂), 110.6 (C-5′), 114.2 (C-2′), 123.0 (C-6′), 130.2 (C-1′), 147.2 (C-3′), 154.7 (C-4′), 197.9

(C-1), 211.7 (C-4). IR: (film)/cm-1; 3079, 2934, 2841, 1714, 1672, 1592, 1425, 1269, 1162, 1021, 961, 775. m/z

(ESI+) 301 (MNa⁺, 100%). HRMS (ESI+) Found (MNa⁺): 301.1420; C₁₆H₂₂NaO₄requires 301.1410.

4.2.3.13 1-(4′-Methoxyphenyl)-2-methylpentane-1,4-dione 1k. Using alkene 5k. Flash chromatography using 9:1

hexanes, ethyl acetate to yield 46 mg, 77% as a yellow oil. R_F(2:1 hexanes, ethyl acetate) = 0.48. δ_H(300 MHz;

CDCl₃; Me₄Si) 1.15 (3H, d, J = 7.2 Hz, 2-CH₃), 2.14 (3H, s, 5-H), 2.47–2.54 (1H, m, 3-H_A), 3.07–3.16 (1H, m, 3-H_B),

3.84 (3H, s, OCH₃), 3.86–3.94 (1H, m, 2-H), 6.92 (2H, d, J = 8.8 Hz, 3′-H), 7.95 (2H, d, J = 8.8 Hz, 2′-H).

Spectroscopic data were in accordance with literature values.²⁶

4.2.3.14 1-(4′-Methoxyphenyl)-2-phenylpentane-1,4-dione 1m. Using alkene 5m. Flash chromatography using 9:1

hexanes, ethyl acetate to yield 74 mg, 54% as a colourless oil. R_F(2:1 hexanes, ethyl acetate) = 0.68. δ_H(300 MHz;

CDCl₃; Me₄Si) 2.16 (3H, s, 5-H), 2.68 (1H, dd, J = 3.9, 17.7 Hz, 3-H_A), 3.57 (1H, dd, J = 9.9, 17.7 Hz, 3-H_B), 3.76

(3H, s, OCH₃), 5.06 (1H, dd, J = 3.9, 9.9 Hz, 2-H), 6.82 (2H, d, J = 9.0 Hz, 3′-H), 7.16–7.29 (5H, m, Ar-H), 7.93 (2H,

d, J = 9.0 Hz, 2′-H). Spectroscopic data were in accordance with literature values.²⁶

4.2.3.15 (2R*, 3S*)-1-(Benzo[d][1′,3′]dioxol-5′-yl)-2-methyl-3-phenylpentane-1,4-dione 1n. Using alkene 5n. Flash

chromatography using 9:1 hexanes, ethyl acetate to yield 66 mg, 96% as a pale yellow oil. R_F(2:1 hexanes, ethyl

acetate) = 0.69. δ_H(400 MHz; CDCl₃; Me₄Si) 0.91 (3H, d, J = 7.6 Hz, 2-CH₃), 2.07 (3H, s, 5-H), 4.02 (1H, dq, J =

7.6, 10.8 Hz, 2-H), 4.23 (1H, d, J = 10.8 Hz, 3-H), 6.03 (2H, s, 2′-H), 6.87 (1H, d, J = 8.3 Hz, 7′-H), 7.27–7.39 (5H,

m, Ar-H), 7.48 (1H, d, J = 1.6 Hz, 4′-H), 7.66 (1H, dd, J = 1.6, 8.3 Hz, 6′-H). δ_C(75 MHz; CDCl₃) 16.3 (2-CH₃), 29.2

(C-5), 43.4 (C-2), 62.3 (C-3), 101.7 (C-2′), 107.9 (C-7′), 108.3 (C-4′), 124.6 (C-6′), 127.7, 128.9, 129.0 (Ar-CH),

130.7 (C-5′), 136.5 (Ar-C), 148.1 (C-3a′), 151.7 (C-7a′), 202.1 (C-1), 207.9 (C-4). IR: ν_max(film)/cm^-1; 2975, 2911,

1705, 1659, 1602, 1499, 1444, 1250, 1101, 1035, 932, 760, 696. m/z (ESI⁺) 333 (MNa⁺, 100%). HRMS (ESI⁺) found

(MNa⁺): 333.1102; C₁₉H₁₈NaO₄requires 333.1097.

4.2.4 General procedure: Synthesis of pyrroles

To a solution of diketone (1 mmol) and NaOAc (1.1 mmol) in acetic acid (15 mL) was added dropwise amine (1.1

mmol) dropwise and the resultant mixture was stirred vigorously at 80 °C, open to air, for the time stated.

Alternatively the reaction was stirred under an atmosphere of nitrogen if specifically stated.The mixture was cooled to

room temperature and neutralized to pH 7 using NaOH solution. Ethyl acetate (15 mL) was added, the organic layer

separated and the aqueous phase further extracted with ethyl acetate (3 × 15 mL). The combined organic extracts were

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dried (MgSO₄) and the solvent removed in vacuo. The crude product was then purified by flash chromatography to

yield the pyrrole product.

4.2.4.1 5-(4′-Methoxyphenyl)-3,4-dimethyl-1-(3′′-phenylpropyl)-1H-pyrrole-2-carbaldehyde 8a. Using diketone 1a.

Flash chromatography using 2:1 hexanes, ethyl acetate to yield 86 mg, 58% as a viscous green-brown oil. R_F(2:1

hexanes, ethyl acetate) = 0.65. δ_H(300 MHz; CDCl₃; Me₄Si) 1.22–1.34 (2H, m, 2′′-H), 1.85 (3H, s, 3-CH₃), 2.30 (3H,

s, 4-CH₃), 2.46 (2H, t, J = 7.8 Hz, 3′′-H), 3.87 (3H, s, OCH₃), 4.20 (2H, t, J = 7.8 Hz, 1′′-H), 6.87–7.00 (3H, m, 3′-H,

Ar-H), 7.10–7.21 (4H, m, Ar-H), 7.96 (2H, dd, J = 1.9, 8.9 Hz, 2′-H), 9.72 (1H. s, CHO). δ_C(75 MHz; CDCl₃) 9.1,

9.2 (3-CH₃, 4-CH₃), 29.7 (C-2′′), 32.7 (C-3′′), 45.3 (C-1′′), 55.3 (OCH₃), 113.5 (C-3′), 122.1 (C-1′), 123.0 (C-4), 125.7

(C-2, C-3), 128.1, 128.2 (Ar-CH), 130.7 (C-2′), 131.7 (Ar-CH), 141.3 (Ar-C), 159.7 (C-4′, C-5), 177.1 (CHO). IR:

_max(film)/cm^-1; 2921, 2954, 2854, 1672, 1601, 1510, 1259, 1171, 1030. m/z (ESI⁺) 370 (MNa⁺, 100%), 348 (60).

HRMS (ESI⁺) found (MH⁺): 348.1970; C₂₃H₂₆NO₂requires 348.1958.

4.2.4.2 5-(Benzo[d][1′,3′]dioxol-5′-yl)-1-benzyl-3,4-dimethyl-1H-pyrrole-2-carbaldehyde 8b. Using diketone 1b.

Flash chromatography using 3:1 hexanes, ethyl acetate to yield 17 mg, 52% as a yellow oil. R_F(2:1 hexanes, ethyl

acetate) = 0.55. δ_H(400 MHz; CDCl₃; Me₄Si) 1.92 (3H, s, 3-CH₃), 2.33 (3H, s, 4-CH₃), 5.45 (2H, s, 1-CH₂), 5.99 (2H,

s, 2′-H), 6.64–6.66 (2H, m, 6′-H, 7′-H), 6.80–6.85 (3H, m, 4′-H, Ar-H), 7.16–7.23 (3H, m, Ar-H), 9.70 (1H, s, CHO).

δ_C(100 MHz; CDCl₃) 9.3 (4-CH₃), 9.4 (3-CH₃), 48.8 (1-CH₂), 101.3 (C-2′), 108.4 (C-4′), 110.4 (C-7′), 118.8 (C-3),

124.1 (C-5′), 124.2 (C-6′), 126.1, 126.9 (Ar-CH), 127.2 (C-5), 128.3 (Ar-CH), 133.7 (C-4), 139.0 (C-2), 141.0 (Ar-C),

147.7, 147.9 (C-7a′, C-3a′), 177.5 (CHO). IR: ν_max(film)/cm^-1; 2911, 1647, 1467, 1242, 1223, 1037, 822, 730. m/z

(ESI⁺) 356 (MNa+, 100%). HRMS (ESI⁺) found (MNa⁺): 356.1254; C₂₁H₁₉NNaO₃requires 356.1257.

4.2.4.3 4′′-(2-(4′-Methoxyphenyl)-3,4,5-trimethyl-1H-pyrrol-1-yl)benzenesulfonamide 8c. Using diketone 1a. Flash

chromatography using 4:1 hexanes, ethyl acetate to yield 51 mg, 65% as a yellow oil. R_F(2:1 hexanes, ethyl acetate)

= 0.22. δ_H(400 MHz; CDCl₃; Me₄Si) 2.04, 2.06, 2.08 (9H, s, 3-OCH₃, 4-OCH₃, 5-CH₃), 3.72 (3H, s, OCH₃), 5.18

(2H, s, NH₂), 6.72 (2H, d, J = 8.8 Hz, 3′-H), 6.91 (2H, d, J = 8.8 Hz, 2′-H), 7.12 (2H, d, J = 8.8 Hz, 2′′-H), 7.78 (2H,

d, J = 8.8 Hz, 3′′-H). δ_C(100 MHz; CDCl₃) 9.5 (4-CH₃), 10.0 (3-CH₃), 11.1 (5-CH₃), 55.0 (OCH₃), 113.5 (C-3′), 116.4

(C-4), 117.5 (C-3), 125.0 (C-1′), 125.3 (C-5), 126.9 (C-3′′), 128.7 (C-2′′), 129.2 (C-2), 131.3 (C-2′), 139.4 (C-1′′),

143.6 (C-4′′), 157.8 (C-4′). IR: ν_max(film)/cm^-1; 3296, 2961, 2925, 1597, 1500, 1457, 1250, 1027, 1162, 828. The

sample decomposed prior to mass spectrum acquisition.

4.2.4.4 1-Benzyl-5-(4′-methoxyphenyl)-3,4-dimethyl-1H-pyrrole-2-carbaldehyde 8d. Using diketone 1a. Flash

chromatography using 9:1 hexanes, ethyl acetate to yield 25 mg, 26% as a yellow oil. R_F(2:1 hexanes, ethyl acetate)

= 0.59. δ_H(400 MHz; CDCl₃; Me₄Si) 1.91 (3H, s, 3-CH₃), 2.33 (3H, s, 4-CH₃), 3.81 (3H, s, OCH₃), 5.44 (2H, s, 1-

CH₂), 6.83–6.86 (2H, m, Ar-H), 6.90 (2H, d, J = 8.8 Hz, 3′-H), 7.10 (2H, d, J = 8.8 Hz, 2′-H), 7.14–7.25 (3H, m, Ar-

H), 9.71 (1H, s, CHO). δ_C(100 MHz; CDCl₃) 9.3 (4-CH₃), 9.4 (3-CH₃), 48.8 (1-CH₂), 55.2 (OCH₃), 113.9 (C-3′),

118.8 (C-4), 122.8 (C-1′), 126.1, 126.8 (Ar-CH), 127.2 (C-2), 128.3 (Ar-CH), 131.4 (C-2′), 133.8 (C-3), 139.1 (Ar-C),

141.4 (C-5), 159.8 (C-4′), 177.4 (CHO). IR: ν_max(film)/cm^-1; 2934, 2837, 1642, 1610, 1455, 1246, 1028, 1176, 842,

789, 730, 697. m/z (ESI⁺) 342 (MNa⁺, 100%), 330 (50), 320 (20), 271 (10). HRMS (ESI⁺) found (MNa⁺): 342.1464;

C₂₁H₂₁NNaO₂requires 342.1465.

4.2.4.5 1-Butyl-5-(4′-methoxyphenyl)-3,4-dimethyl-1H-pyrrole-2-carbaldehyde 8e. Using diketone 1a. Flash

chromatography using 2:1 hexanes, ethyl acetate to yield 41 mg, 34% as a yellow oil. R_F(2:1 hexanes, ethyl acetate)

= 0.65. δ_H(400 MHz; CDCl₃; Me₄Si) 0.75 (3H, t, J = 8.0 Hz, 1-CH₂CH₂CH₂CH₃), 1.06–1.15 (2H, m, 1-

CH₂CH₂CH₂CH₃), 1.48–1.54 (2H, m, 1-CH₂CH₂CH₂CH₃), 1.86 (3H, s, 4-CH₃), 2.31 (3H, s, 3-CH₃), 3.87 (3H, s,

OCH₃), 4.13 (2H, t, J = 8.0 Hz, 1-CH₂CH₂CH₂CH₃), 6.99 (2H, d, J = 8.8 Hz, 3′-H), 7.20 (2H, d, J = 8.8 Hz, 2′-H),

9.73 (1H, s, CHO). δ_C(100 MHz; CDCl₃) 9.2, 9.3 (3-CH₃, 4-CH₃), 13.6 (1-CH₂CH₂CH₂CH₃), 19.7 (1-

CH₂CH₂CH₂CH₃), 33.7 (1-CH₂CH₂CH₂CH₃), 45.5 (1-CH₂CH₂CH₂CH₃), 55.3 (OCH₃), 114.0 (C-2′), 118.3 (C-1′),

131.4 (C-3′, C-4), 133.4 (C-2, C-3), 141.0 (C-5), 159.6 (C-4′), 177.1 (CHO). IR: ν_max(film)/cm^-1; 2957, 2925, 2861,

1639, 1613, 1511, 1246, 1176, 1028. m/z (ESI⁺) 286 (MH⁺, 90%), 274 (10), 257 (3), 227 (3), 217 (8). HRMS (ESI⁺)

found (MH⁺): 286.1803; C₁₈H₂₄NO₂requires 286.1802.

4.2.4.6 2-(4′-Methoxyphenyl)-3,4,5-trimethyl-1-phenyl-1H-pyrrole 8f. Using diketone 1a. Flash chromatography using

2:1 hexanes, ethyl acetate to yield 89 mg, 72% as a yellow oil. R_F(2:1 hexanes, ethyl acetate) = 0.32. δ_H(400 MHz;

CDCl₃; Me₄Si) 2.08 (9H, s, 3-CH₃, 4-CH₃, 5-CH₃), 3.73 (3H, s, OCH₃), 6.70 (2H, d, J = 8.7 Hz, 3′-H), 6.95 (2H, d, J =

8.7 Hz, 2′-H), 7.02–7.06 (2H, m, Ar-H), 7.22–7.26 (3H, m, Ar-H). δ_C(100 MHz; CDCl₃) 9.5, 10.1, 10.9 (3-CH₃, 4-

CH₃, 5-CH₃), 55.0 (OCH₃), 113.2 (C-3′), 113.5 (C-4), 116.1 (C-1′), 125.5 (C-3), 125.7 (C-5), 126.5, 128.5, 128.6 (Ar-

CH), 130.7 (C-2), 131.3 (C-2′), 139.7 (Ar-C), 157.6 (C-4′). IR: ν_max(film)/cm^-1; 2914, 1595, 1497, 1244, 1176, 1030.

m/z (ESI⁺) 292 (MH⁺, 100%), 290 (60). HRMS (ESI⁺) found (MH⁺): 292.1707; C₂₀H₂₂NO requires 292.1696.

4.2.4.7 5-(Benzo[d][1′,3′]dioxol-5′-yl)-1-(2′′,6′′-dimethoxyphenyl)-3,4-dimethyl-1H-pyrrole-2-carbaldehyde 8g. Using

diketone 1b. Flash chromatography using 2:1 hexanes, ethyl acetate to yield 15 mg, 30% b.r.s.m. as a yellow-green

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oil. R_F(2:1 hexanes, ethyl acetate) = 0.31. δ_H(400 MHz; CDCl₃; Me₄Si) 2.03 (3H, s, 4-CH₃), 2.43 (3H, s, 3-CH₃),

3.65 (6H, s, 2′′-OCH₃), 5.92 (2H, s, 2′-H), 6.55 (1H, t, J = 1.5 Hz, 4′-H), 6.60 (1H, d, J = 7.6 Hz, 7′-H), 6.68 (1H, dd, J

= 1.5, 7.6 Hz, 6′-H), 6.83 (3H, d, J = 1.6 Hz, 3′′-H, 4′′-H), 9.41 (1H, s, CHO). δ_C(100 MHz; CDCl₃) 9.5 (4-CH₃), 10.3

(3-CH₃), 55.7, 56.1 (2′′-OCH₃), 101.1 (C-2′), 107.9 (C-7′), 110.0 (C-4′), 114.8 (C-3′′), 116.1 (C-4′′), 119.4 (C-3),

123.9 (C-6′), 124.7 (C-5′), 126.8 (C-1′′), 129.0 (C-5), 130.9 (C-4), 138.8 (C-2), 147.2 (C-2′′), 150.0, 153.1 (C-7a′, C-

3a′), 179.5 (CHO). IR: ν_max(film)/cm^-1; 2921, 1651, 1507, 1463, 1242, 1225, 1036, 809, 729. m/z (ESI⁺) 402 (MNa⁺,

100%), 360 (90). HRMS (ESI⁺) found (MNa⁺): 402.1302; C₂₂H₂₁NNaO₅requires 402.1312.

4.2.4.8 2-(3′,4′-Dimethoxyphenyl)-3,4,5-trimethyl-1-phenyl-1H-pyrrole 8h. Using diketone 1c. Flash chromatography

using 14:1 hexanes, ethyl acetate to yield 15 mg, 25% as a yellow oil. R_F(2:1 hexanes, ethyl acetate) = 0.63. δ_H(400

MHz; CDCl₃; Me₄Si) 2.06 (6H, s, 2-CH₃, 3-CH₃), 2.12 (3H, s, 4-CH₃), 3.53 (3H, s, 4′-OCH₃), 3.83 (3H, s, 3′-OCH₃),

6.42 (1H, s, 5′-H), 6.69–6.75 (2H, m, 2′-H, 6′-H), 7.05–7.08 (1H, m, Ar-H), 7.22–7.30 (4H, m, Ar-H). δ_C(100 MHz;

CDCl₃) 9.5 (3-CH₃), 10.2 (4-CH₃), 10.9 (5-CH₃), 55.4 (3′-OCH₃), 55.7 (4′-OCH₃), 110.5 (C-2′), 113.6 (C-5′), 122.5

(C-6′), 115.2 (C-4), 116.2 (C-3), 125.7 (C-1′), 125.9 (C-5), 126.6, 128.5, 128.6 (Ar-CH), 129.4 (C-2), 139.7 (Ar-C),

147.0 (C-4′), 148.0 (C-3′). IR: ν_max(film)/cm^-1; 2926, 2855, 1597, 1501, 1251, 1139, 1026, 763, 699. m/z (ESI⁺) 344

(MNa⁺, 10%), 360 (100). HRMS (ESI⁺) found (MNa⁺): 344.1603; C₂₁H₂₃NNaO₂requires 344.1621.

4.2.4.9 4′′-(2-(3′,4′-Dimethoxyphenyl)-3,4,5-trimethyl-1H-pyrrol-1-yl)benzenesulfonamide 8i. Using diketone 1c.

Flash chromatography using 19:1 hexanes, ethyl acetate to yield 34 mg, 74% b.r.s.m. as a pink oil. R_F(2:1 hexanes,

ethyl acetate) = 0.14. δ_H(400 MHz; CDCl₃; Me₄Si) 2.07, 2.08, 2.10 (9H, s, 3-CH₃, 4-CH₃, 5-CH₃), 3.59 (3H, s, 3′-

OCH₃), 3.82 (3H, s, 4′-OCH₃), 4.95 (2H, s, NH₂), 6.44 (1H, d, J = 2.0 Hz, 2′-H), 6.62 (1H, dd, J = 2.0, 8.2 Hz, 6′-H),

6.73 (1H, d, J = 8.2 Hz, 5′-H), 7.17 (2H, d, J = 8.6 Hz, 2′′-H), 7.81 (2H, d, J = 8.6 Hz, 3′′-H). δ_C(100 MHz; CDCl₃)

9.5 (4-CH₃), 10.1 (3-CH₃), 11.1 (5-CH₃), 55.6, 55.7 (3′-OCH₃, 4′-OCH₃), 110.8 (C-2′), 113.5 (C-5′), 116.6 (C-4),

117.6 (C-3), 122.7 (C-6′), 125.3 and 125.4 (C-5, C-1′), 127.0 (C-3′′), 128.7 (C-2′′), 129.4 (C-2), 139.6 (C-1′′), 143.7

(C-4′′), 147.4 (C-4′), 148.2 (C-3′). IR: ν_max(film)/cm^-1; 3256, 2952, 2930, 2862, 1595, 1505, 1252, 1139, 1022, 1162,

836, 732. m/z (ESI⁺) 423 (MNa⁺, 100%), 400 (20). HRMS (ESI⁺) found (MNa⁺): 423.1355; C₂₁H₂₄N₂NaO₄S requires

423.1349.

4.2.4.10 1-Benzyl-5-(3′,4′-dimethoxyphenyl)-3,4-dimethyl-1H-pyrrole-2-carbaldehyde 8j. Using diketone 1c. Flash

chromatography using 4:1 hexanes, ethyl acetate to yield 24 mg, 48% as a yellow oil. R_F(2:1 hexanes, ethyl acetate)

= 0.65. δ_H(400 MHz; CDCl₃; Me₄Si) 1.94 (3H, s, 3-CH₃), 2.36 (3H, s, 4-CH₃), 3.55 (3H, s, 4′-OCH₃), 3.90 (3H, s, 3′-

OCH₃), 5.44 (2H, s, 1-CH₂), 6.54 (1H, d, J = 2.0 Hz, 2′-H), 6.78 (1H, dd, J = 2.0, 8.0 Hz, 6′-H), 6.88 (1H, d, J = 8.0

Hz, 5′-H), 7.16–7.27 (5H, m, Ar-H), 9.73 (1H, s, CHO). δ_C(100 MHz; CDCl₃) 9.3 (4-CH₃), 9.4 (3-CH₃), 49.1 (1-

CH₂), 55.5 (4′-OCH₃), 55.8 (3′-OCH₃), 110.9 (C-5′), 113.0 (C-2′), 118.8 (C-3), 122.8 (C-6′), 126.0, 128.2 (Ar-CH),

126.8 (C-1′), 127.2 (C-2), 128.4 (Ar-CH), 133.8 (C-4), 139.3 (Ar-C), 141.5 (C-5), 148.5 (C-4′), 149.2 (C-3′), 177.4

(CHO). IR: ν_max(film)/cm^-1; 2934, 2836, 1644, 1436, 1247, 1139, 814, 731, 698. m/z (ESI⁺) 372 (MNa⁺, 100%), 350

(80). HRMS (ESI⁺) found (MNa⁺): 372.1536; C₂₂H₂₃NNaO₃requires 372.1570.

4.2.4.11 (S)-5-(3′,4′-Dimethoxyphenyl)-3,4-dimethyl-1-(1-phenylethyl)-1H-pyrrole-2-carbaldehyde 8k. Using diketone

1c. Flash chromatography using 2:1 hexanes, ethyl acetate to yield 13 mg, 26% as a pink oil. R_F(2:1 hexanes, ethyl

acetate) = 0.65. α_D= +86 (c = 1.3, CHCl₃). δ_H(400 MHz; CDCl₃; Me₄Si) 1.76 (3H, d, J = 6.8 Hz, 1-CHCH₃), 1.87

(3H, s, 3-CH₃), 2.36 (3H, s, 4-CH₃), 3.63 (3H, s, 4′-OCH₃), 3.89–3.97 (4H, m, 3′-OCH₃, 1-CHCH₃), 6.85 (1H, d, J =

8.2 Hz, 5′-H), 6.99–7.07 (2H, m, 2′-H, 6′-H), 7.14–7.34 (5H, m, Ar-H), 9.63 (1H, s, CHO). δ_C(75 MHz; CDCl₃) 9.3

(4-CH₃), 9.9 (3-CH₃), 19.1 (1-CH(CH₃)Ar), 54.4 (1-CHCH₃), 55.0, 55.9 (3′-OCH₃, 4′-OCH₃), 110.9 (C-5′), 113.2 (C-

2′), 119.1 (C-3), 122.9 (C-6′), 124.1 (C-1′), 125.8, 126.7 (Ar-CH), 127.2 (C-4), 128.2 (Ar-CH), 133.6 (C-2), 141.1 (C-

5), 142.5 (Ar-C), 148.6 (C-4′), 149.2 (C-3′), 177.8 (CHO). IR: ν_max(film)/cm^-1; 2936, 2839, 1642, 1465, 1258, 1244,

1026, 1139, 766, 744, 698. m/z (ESI⁺) 386 (MNa⁺, 100%), 253 (20). HRMS (ESI⁺) found (MNa⁺): 386.1726;

C₂₃H₂₅NNaO₃requires 386.1727.

4.2.4.12 5-(3′,4′-Dimethoxyphenyl)-3,4-dimethyl-1-(3′′-phenylpropyl)-1H-pyrrole-2-carbaldehyde 8m. Using diketone

1c. Flash chromatography using 2:1 hexanes, ethyl acetate to yield 13 mg, 25% as a brown oil. R_F(2:1 hexanes, ethyl

acetate) = 0.80. δ_H(400 MHz; CDCl₃; Me₄Si) 1.85–1.89 (5H, m, 3-CH₃, 2′′-H), 2.31 (3H, s, 4-CH₃), 2.46 (2H, t, J =

8.0 Hz, 3′′-H), 3.83 (3H, s, 4′-OCH₃), 3.95 (3H, s, 3′-OCH₃), 4.20 (2H, t, J = 8.0 Hz, 1′′-H), 6.70 (1H, d, J = 1.6 Hz,

2′-H), 6.79 (1H, dd, J = 1.6, 8.0 Hz, 6′-H), 6.90 (1H, d, J = 8.4 Hz, 5′-H), 6.98–7.00 (2H, m, Ar-H), 7.11–7.19 (3H, m,

Ar-H), 9.73 (1H, s, CHO). δ_C(100 MHz; CDCl₃) 9.1 (4-CH₃), 9.3 (3-CH₃), 32.8 (C-2′′, C-3′′), 45.4 (C-1′′), 55.9 (3′-

OCH₃, 4′-OCH₃), 111.1 (C-5′), 113.0 (C-2′), 118.3 (C-3), 122.8 (C-6′), 123.3 (C-1′), 125.7 (Ar-CH), 126.9 (C-2),

128.1, 128.2 (Ar-CH), 133.6 (C-4), 141.0 (C-5), 141.2 (Ar-C), 148.8 (C-4′), 149.2 (C-3′), 177.2 (CHO). IR:

ν_max(film)/cm^-1; 2931, 2856, 1641, 1260, 1245, 1139, 1027, 751, 700. m/z (ESI⁺) 388 (100), 400 (MNa⁺, 80%). HRMS

(ESI⁺) found (MNa⁺): 400.1878; C₂₄H₂₇NNaO₃requires 400.1883.

4.2.4.13

1-(3′′-((tert-butyldiphenylsilyl)oxy)-4′′-methoxyphenyl)-3,4,5-trimethyl-2-(3′,4′,5′-trimethoxyphenyl)-1H-

pyrrole 8n. Using diketone 1d. Flash chromatography using 19:1 hexanes, ethyl acetate 0.16 g, 74% as a pale yellow

ACCEPTED MANUSCRIPT

oil. R_F= 0.77 (2:1 hexanes, ethyl acetate). δ_H(500 MHz; CDCl₃; Me₄Si) 1.03 (9H, s, SiC(CH₃)₃), 1.72 (3H, s, 4-CH₃),

1.99 (3H, s, 5-CH₃), 2.12 (3H, s, 3-CH₃), 3.51 (3H, s, 4′′-OCH₃), 3.63 (6H, s, 3′-OCH₃), 3.81 (3H, s, 4′-OCH₃), 6.23

(2H, s, 2′-H), 6.54 (1H, s, J = 2.0 Hz, 2′′-H), 6.55 (1H, dd, J = 6.2, 2.0 Hz, 6′′-H), 6.64 (1H, d, J = 6.2 Hz, 5′′-H),

7.31(4H, td, J = 7.2, 1.0 Hz, Ar-H), 7.38 (2H, tt, J = 7.2, 1.0 Hz, Ar-H), 7.62 (4H, d, J = 7.2 Hz, Ar-H). δ_C(125 MHz;

CDCl₃) 9.4 (5-CH₃), 10.3 (3-CH₃) 10.4 (4-CH₃), 19.7 (SiC(CH₃)₃), 26.5 (SiC(CH₃)₃), 55.5 (4′′-OCH₃), 55.9 (3′-

OCH₃), 60.8 (4′-OCH₃), 107.4 (C-2′), 111.5 (C-5′′), 114.5 (C-4), 115.9 (C-3), 120.7 (C-2′′), 121.8 (C-6′′), 126.7 (C-5),

127.6 (C-Ar), 128.7 (C-1′), 129.6 (C-1), 129.5 (C-2), 129.7 (C-Ar), 132.3 (C-1′′), 133.0 (C-Ar), 136.0 (C-4′), 144.8

(C-3′′), 149.8 (C-4′′), 152.6 (C-3′). IR: (film)/cm-1; 2927, 2369, 1736, 1579, 1466, 1269, 1127, 1014, 907, 731. m/z

(ESI+) 635 (MNa⁺, 100%). HRMS (ESI+) Found (MNa⁺): 658.2977; C₃₉H₄₅NNaO₅Si requires 658.2959.

4.2.4.14 2-(4′-Methoxyphenyl)-4,5-dimethyl-1,3-diphenyl-1H-pyrrole 8o. Using diketone 1e. Flash chromatography

using 19:1 hexanes, ethyl acetate to yield 39 mg, 61% as a yellow foam. R_F(2:1 hexanes, ethyl acetate) = 0.85. δ_H

(400 MHz; CDCl₃; Me₄Si) 2.12 (6H, s, 2-CH₃, 3-CH₃), 3.65 (3H, s, OCH₃), 6.54 (2H, d, J = 6.8 Hz, 3′-H), 6.79 (2H,

d, J = 6.8 Hz, 2′-H), 7.10–7.22 (10 H, m, Ar-H). δ_C(100 MHz; CDCl₃) 10.3 (4-CH₃), 11.0 (5-CH₃), 54.9 (OCH₃),

113.0 (C-3′), 114.1 (C-4), 122.9 (C-1′), 125.2 (C-5, Ar-CH), 126.4 (C-2), 126.9, 127.8, 128.6, 128.8 (Ar-CH), 129.8

(C-3), 130.5, 131.9 (Ar-CH), 136.5 (Ar-C), 139.3 (Ar-C), 157.6 (C-4′). IR: ν_max(film)/cm^-1; 2971, 2919, 1598, 1510,

1497, 1246, 1048, 835, 732, 699. m/z (ESI⁺) 376 (MNa⁺, 100%), 368 (15), 365 (20), 360 (25), 352 (85). HRMS

(ESI⁺) found (MNa⁺): 376.1672; C₂₅H₂₃NNaO requires 376.1675.

4.2.4.15 1-Benzyl-2-(4′-methoxyphenyl)-4,5-dimethyl-3-phenyl-1H-pyrrole 8p. Using diketone 1e. Flash

chromatography using 2:1 hexanes, ethyl acetate to yield 10 mg, 39% as a pink oil. R_F(2:1 hexanes, ethyl acetate) =

0.87. δ_H(400 MHz; CDCl₃; Me₄Si) 2.03 (6H, s, 4-CH₃and 5-CH₃), 3.66 (3H, s, OCH₃), 4.94 (2H, s, CH₂), 6.63 (2H,

d, J = 8.4 Hz, 3′-H), 6.88 (2H, d, J = 7.2 Hz, Ar-H), 6.94 (2H, d, J = 8.4 Hz, 2′-H), 7.03–7.17 (8H, m, Ar-H). δ_C(100

MHz; CDCl₃) 10.2 (4-CH₃), 10.4 (5-CH₃), 47.6 (CH₂Ar), 55.1 (OCH₃), 113.5 (C-3′), 113.7 (C-5), 122.4 (C-2), 124.9,

125.3, 125.4, 125.8, 126.8, 127.7, 128.6, 130.0, 130.3, 132.2 136.7, 139.3 (Ar-CH), 158.5 (C-4′). IR: ν_max(film)/cm^-1;

2927, 2857, 1647, 1510, 1454, 1247, 730, 699. m/z (ESI⁺) 382 (15), 354 (15), 332 (100), 354 (15), 368 (MH⁺, 10%).

HRMS (ESI⁺) found (MH⁺): 368.2019; C₂₆H₂₆NO requires 368.2009.

4.2.4.16 5-(4′-Methoxyphenyl)-3-methyl-1-phenethyl-4-phenyl-1H-pyrrole-2-carbaldehyde 8q. Using diketone 1e.

Flash chromatography using 4:1 hexanes, ethyl acetate to yield 22 mg, 43% as a dark orange oil. R_F(2:1 hexanes,

ethyl acetate) = 0.69. δ_H(400 MHz; CDCl₃; Me₄Si) 2.31 (3H, s, 3-CH₃), 2.83 (2H, t, J = 7.6 Hz, 1-CH₂CH₂Ar), 3.72

(3H, s, OCH₃), 4.34 (2H, t, J = 7.6 Hz, 1-CH₂CH₂Ar), 6.71 (2H, d, J = 8.8 Hz, 3′-H), 6.83 (2H, d, J = 8.8 Hz, 2′-H),

6.91–6.95 (5H, m, 1-CH₂CH₂Ar-H), 7.09–7.18 (5H, m, Ar-H), 9.82 (CHO). δ_C(100 MHz; CDCl₃) 9.8 (3-CH₃), 37.8

(1-CH₂CH₂Ar), 47.5 (1-CH₂CH₂Ar), 55.2 (OCH₃), 113.7 (C-3′), 122.6 (C-1′), 126.1, 126.4 (Ar-CH), 127.2 (C-3),

127.9, 128.4, 128.6, 128.9, 130.3 (Ar-CH), 131.8 (C-2′), 133.1 (C-2), 134.2 (C-4), 138.3 (1-CH₂CH₂Ar-C, Ar-C),

141.0 (C-5), 159.6 (C-4′), 177.8 (CHO). IR: ν_max(neat)/cm^-1; 2966, 2841, 1646, 1456, 1250, 1176, 703. m/z (ESI⁺) 418

(MNa⁺, 100%), 333 (60). HRMS (ESI⁺) found (MNa⁺): 418.1781; C₂₇H₂₅NNaO₂requires 418.1778.

4.2.4.17 5-(4′-Methoxyphenyl)-3-methyl-4-phenyl-1-(3′′-phenylpropyl)-1H-pyrrole-2-carbaldehyde 8r. Using diketone

1e. Flash chromatography using 9:1 hexanes, ethyl acetate to yield 26 mg, 55% as a viscous orange oil. R_F(2:1

hexanes, ethyl acetate) = 0.72. δ_H(400 MHz; CDCl₃; Me₄Si) 1.85–1.91 (2H, m, 2′′-H), 2.28 (3H, s, 3-CH₃), 2.36 (2H,

t, J = 8.0 Hz, 3′′-H), 3.73 (3H, s, OCH₃), 4.19 (2H, t, J = 7.6 Hz, 1′′-H), 6.71 (2H, d, J = 8.8 Hz, 3′-H), 6.93–7.17

(12H, m, 2′-H, Ar-H), 9.76 (1H, s, CHO). δ_C(100 MHz; CDCl₃) 9.8 (3-CH₃), 32.6 (C-2′′), 32.8 (C-3′′), 45.5 (C-1′′),

55.2 (OCH₃), 113.9 (C-3′), 122.7 (C-1′), 125.7, 126.1 (Ar-CH), 127.4 (C-3), 127.2, 128.1, 128.2, 130.3 (Ar-CH),

131.8 (C-2′), 132.2 (C-2), 132.8 (C-4), 134.2 (Ar-C), 140.6 (C-5), 141.2 (3′′-Ar-C), 159.6 (C-4′), 177.8 (CHO). IR:

ν_max(film)/cm^-1; 2961, 2854, 1645, 1455, 1248, 1174, 802, 789, 700. m/z (ESI⁺) 432 (MNa⁺, 100%), 281 (25). HRMS

(ESI⁺) found (MNa⁺): 432.1930; C₂₈H₂₇NNaO₂requires 432.1934.

4.2.4.18 2-Butyl-4,5-dimethyl-1,3-diphenyl-1H-pyrrole 8s. Using diketone 1f. Flash chromatography using 2:1

hexanes, ethyl acetate to yield 14 mg, 71% as a yellow oil. R_F(2:1 hexanes, ethyl acetate) = 0.63. δ_H(400 MHz;

CDCl₃; Me₄Si) 0.49 (3H, t, J = 7.6 Hz, 2-CH₂CH₂CH₂CH₃), 0.89 (2H, sext., J = 7.6 Hz, 2-CH₂CH₂CH₂CH₃), 1.02

(2H, pent., J = 7.6 Hz, 2-CH₂CH₂CH₂CH₃), 1.91 (3H, s, 5-CH₃), 1.95 (3H, s, 4-CH₃), 2.36 (2H, t, J = 7.6 Hz, 2-

CH₂CH₂CH₂CH₃), 7.14–7.40 (10H, m, Ar-H). δ_C(100 MHz; CDCl₃) 10.1 (4-CH₃), 10.7 (5-CH₃), 13.4 (2-

CH₂CH₂CH₂CH₃), 22.1 (2-CH₂CH₂CH₂CH₃), 24.5 (2-CH₂CH₂CH₂CH₃), 32.3 (2-CH₂CH₂CH₂CH₃), 122.8 (C-4),

122.0 (C-2), 124.7 (C-5), 125.4, 127.6, 127.9, 128.7, 128.9, 129.7 (Ar-CH), 130.1 (C-3), 137.1, 139.3 (Ar-C). IR:

ν_max(film)/cm^-1; 2957, 2859, 1598, 1497, 1260, 801, 755, 699. m/z (ESI⁺) 304 (MH⁺, 100%), 302 (90), 301 (80).

HRMS (ESI⁺) found (MH⁺): 304.2047; C₂₂H₂₆N requires 304.2060.

4.2.4.19 5-Butyl-3-methyl-4-phenyl-1-(3′′-phenylpropyl)-1H-pyrrole-2-carbaldehyde 8t. Using diketone 1f. Flash

chromatography using 9:1 hexanes, ethyl acetate to yield 32 mg, 44% as a yellow oil. R_F(2:1 hexanes, ethyl acetate)

= 0.66. δ_H(400 MHz; CDCl₃; Me₄Si) 0.73 (3H, t, J = 7.2 Hz, 5-CH₂CH₂CH₂CH₃), 1.11–1.16 (2H, m, 5-CH₂CH_2-

CH₂CH₃), 1.26–1.33 (2H, m, 5-CH₂CH₂CH₂CH₃), 2.03–2.09 (2H, m, 2′′-H), 2.25 (3H, s, 3-CH₃), 2.39 (2H, t, J = 8.0

ACCEPTED MANUSCRIPT

Hz, 5-CH₂CH₂CH₂CH₃), 2.72 (2H, t, J = 7.6 Hz, 3′′-H), 4.27 (2H, t, J = 8.0 Hz, 1′′-H), 7.16–7.40 (10H, m, Ar-H),

9.68 (1H, s, CHO). δ_C(100 MHz; CDCl₃) 9.5 (3-CH₃), 13.5 (5-CH₂CH₂CH₂CH₃), 22.5 (5-CH₂CH₂CH₂CH₃), 23.9 (5-

CH₂CH₂CH₂CH₃), 31.9 (5-CH₂CH₂CH₂CH₃), 32.9 (C-3′′), 33.1 (C-2′′), 44.9 (C-1′′), 124.8 (C-5), 126.0, 126.6, 128.3,

128.4, 130.2 (Ar-CH), 130.6 (C-3), 133.1 (C-4), 134.8 (Ar-C), 141.0 (C-2), 141.3 (3′′-Ar-C), 176.8 (CHO). IR:

_max(film)/cm^-1; 2958, 2862, 1709, 1644, 1496, 1454, 750, 701. m/z (ESI⁺) 360 (MNa⁺, 100%). HRMS (ESI⁺) found

(MH⁺): 360.2312; C₂₅H₃₀NO requires 360.2322.

4.2.4.20 (S)-5-(4'-Methoxyphenyl)-3-methyl-1-(1′′-phenylethyl)-4-propyl-1H-pyrrole-2-carbaldehyde 8u. Using

diketone 1g. Flash chromatography using 4:1 hexanes, ethyl acetate to yield 9 mg, 30% as a yellow oil. α_D= +17 (c =

1.3, CHCl₃). R_F(2:1 hexanes, ethyl acetate) = 0.85. δ_H(300 MHz; CDCl3; Me₄Si) 0.79 (3H, t, J = 7.6 Hz,

CH₂CH₂CH₃), 1.35 (2H, pent., J = 7.6 Hz, CH₂CH₂CH₃), 1.78 (3H, d, J = 7.1 Hz, 1-CH(CH₃)Ar), 2.20–2.25 (2H, m,

CH₂CH₂CH₃), 2.36 (3H, s, 3-CH₃), 3.82 (3H, s, 4′-OCH₃), 5.82 (1H, br s, 1-CH(CH₃)Ar), 6.86 (2H, d, J = 7.5 Hz, 3′-

H), 6.98–7.01 (2H, m, Ar-H), 7.17–7.25 (5H, m, 2′-H, Ar-H), 9.57 (1H, s, CHO). δ_C(75 MHz; CDCl₃) 10.1 (3-CH₃),

14.0 (CH₂CH₂CH₃), 19.7 (1-CH(CH₃)Ar), 24.0 (CH₂CH₂CH₃), 26.2 (CH₂CH₂CH₃), 54.1 (1-CH(CH₃)Ar), 55.3 (4′-

OCH₃), 133.8 (C-3′), 123.9 (C-1′, C-4), 125.7 (Ar-CH), 126.7 (Ar-CH, C-2), 128.2 (Ar-CH), 131.6 (C-2′, C-3), 142.3

(C-5, Ar-C), 159.7 (C-4′), 177.9 (CHO). IR: ν_max(film)/cm^-1; 2926, 2855, 1597, 1501, 1251, 1139, 1026, 763, 699.

m/z (ESI+) 384 (MNa⁺, 100 %), 365 (20). HRMS (ESI⁺): found (MNa⁺): 384.1946; C₂₄H₂₇NNaO₂requires 384.1934.

4.2.4.21 2-(Benzo[d][1′′,3′′]dioxol-5′′-yl)-3-(benzo[d][1′,3′]dioxol-5′-ylmethyl)-1-(4′′′-bromo-2′′′-fluorophenyl)-4,5-

dimethyl-1H-pyrrole 8v. Using diketone 1h. Flash chromatography using 14:1 hexanes, ethyl acetate to yield 14 mg,

24% as a colourless oil. R_F(2:1 hexanes, ethyl acetate) = 0.79. δ_H(400 MHz; CDCl₃; Me₄Si) 1.89 (3H, s, 4-CH₃),

1.98 (3H, s, 5-CH₃), 3.73 (2H, d, J = 5.1 Hz, 3-CH₂), 5.88, 5.90 (4H, s, 2′-H, 2′′-H), 6.49–6.51 (2H, m, 4′-H, 6′-H),

6.60–6.62 (2H, m, 6′′-H, 7′-H), 6.69–6.72 (2H, m, 4′′-H, 7′′-H), 6.93 (1H, t, J = 8.3 Hz, 3′′′-H), 7.19–7.22 (1H, m, 5′′′-

H), 7.28 (1H, dd, J = 2.1, 9.0 Hz, 6′′′-H). δ_C(100 MHz; CDCl₃) 9.6 (4-CH₃), 10.2 (5-CH₃), 30.4 (3-CH₂), 100.7, 100.9

(C-2′, C-2′′), 108.5 (C-4′′, C-7′′), 108.7 (C-7′), 110.2 (C-4′), 115.5 (C-4), 119.8, 119.9, 120.1 (C-6′′′, C-4′′′, C-3),

120.8 (C-6′′), 123.6 (C-6′), 126.2, 126.6, 127.0 (C-5, C-5′′, C-1′′′), 127.6 (C-5′′′), 130.9 (C-5′), 132.0 (C-3′′′), 136.0

(C-2), 145.3, 146.4, 147.2, 147.5 (C-7a′, C-3a′, C-7a′′, C-3a′′), 159.4 (C-2′′′). IR: ν_max(film)/cm^-1; 2895, 1499, 1485,

1443, 1229, 1040, 813, 734. m/z (ESI⁺) 544 (MNa⁺, 30%), 405 (100). HRMS (ESI⁺) found (MNa⁺): 544.0510;

C₂₇H₂₁BrFNNaO₄requires 544.0530.

4.2.4.22

4′′′-(2-(Benzo[d][1′′,3′′]dioxol-5′′-yl)-3-(benzo[d][1′,3′]dioxol-5′-ylmethyl)-4,5-dimethyl-1H-pyrrol-1-

yl)benzenesulfonamide 8w. Using diketone 1h. Flash chromatography using 14:1 hexanes, ethyl acetate to yield 8.2

mg, 15% as a colourless oil. R_F(2:1 hexanes, ethyl acetate) = 0.20. δ_H(400 MHz; CDCl₃; Me₄Si) 1.91 (3H, s, 4-CH₃),

2.07 (3H, s, 5-OCH₃), 3.74 (2H, s, 3-CH₂), 5.00 (2H, s, NH₂), 5.88, 5.90 (4H, s, 2′-H, 2′′-H), 6.45–6.48 (2H, m, 4′-H,

6′-H), 6.60–6.62 (2H, m, 6′′-H, 7′-H), 6.45–6.48 (2H, m, 4′′-H, 7′′-H), 7.19 (2H, d, J = 8.6 Hz, 2′′′-H), 7.84 (2H, d, J =

8.6 Hz, 3′′′-H). δ_C(100 MHz; CDCl₃) 9.7 (4-CH₃), 11.2 (5-CH₃), 30.4 (3-CH₂), 100.7, 100.9 (C-2′, C-2′′), 108.0 (C-

4′′, C-7′′), 108.1 (C-7′), 110.5 (C-4′), 116.3 (C-4), 120.8 (C-6′′), 124.0 (C-6′), 126.2 (C-3), 127.0 (C-5′′), 127.1 (C-3′′′),

128.6 (C-5), 128.7 (C-2′′′), 130.3 (C-5′), 135.8 (C-2), 139.5 (C-1′′′), 143.6 (C-4′′′), 145.4, 146.4, 147.3, 147.5 (C-7a′,

C-3a′, C-7a′′, C-3a′′). IR: ν_max(film)/cm^-1; 3377, 2920, 1501, 1486, 1442, 1247, 1165, 1038, 811, 731. The sample

decomposed prior to mass spectrum acquision.

4.2.4.23

4′′′-(3-(Benzo[d][1′,3′]dioxol-5′-ylmethyl)-2-(4′′-methoxyphenyl)-4,5-dimethyl-1H-pyrrol-1-

yl)benzenesulfonamide 8x. Using diketone 1i. Flash chromatography using 14:1 hexanes, ethyl acetate to yield 16 mg,

29% as a yellow oil. R_F(2:1 hexanes, ethyl acetate) = 0.20. δ_H(400 MHz; CDCl₃; Me₄Si) 1.92 (3H, s, 4-CH₃), 2.08

(3H, s, 5-CH₃), 3.72 (2H, s, 3-CH₂), 3.73 (3H, s, OCH₃), 4.92 (2H, s, NH₂), 5.90 (2H, s, 2′-H), 6.62–6.63 (2H, m, 6′-

H, 7′-H), 6.68–6.72 (3H, m, 3′′-H, 4′-H), 6.89 (2H, d, J = 8.8 Hz, 2′′-H), 7.17 (2H, d, J = 8.4 Hz, 2′′′-H), 7.81 (2H, d, J

= 8.4 Hz, 3′′′-H). δ_C(100 MHz; CDCl₃) 9.7 (4-CH₃), 11.0 (5-CH₃), 30.4 (3-CH₂), 55.1 (OCH₃), 100.7 (C-2′), 108.0

(C-4′), 108.7 (C-7′), 113.6 (C-3′′), 116.3 (C-4), 120.4 (C-3), 120.8 (C-6′), 124.8 (C-1′′), 125.7 (C-5), 127.0 (C-3′′′),

128.8 (C-2′′′), 130.4 (C-5′), 131.3 (C-2′′), 136.0 (C-2), 139.4 (C-4′′′), 143.6 (C-1′′′), 145.4, 147.5 (C-7a′, C-3a′), 158.2

(C-4′′). IR: ν_max(film)/cm^-1; 3267, 2917, 1596, 1499, 1487, 1245, 1162, 837, 730. m/z (ESI⁺) 513 (MNa⁺, 10%), 391

(100). HRMS (ESI⁺) found (MNa⁺): 513.1449; C₂₇H₂₆N₂NaO₅S requires 513.1455.

4.2.4.24 2-(3′-isopropoxy-4′-methoxyphenyl)-1-(4′′-methoxybenzyl)-4,5-dimethyl-1H-pyrrole 8y. Using diketone 1j.

Flash chromatography using 9:1 hexanes, ethyl acetate to yield 88 mg, 59% as a yellow oil. R_F= 0.81 (2:1 hexanes,

ethyl acetate). δ_H(500 MHz; CDCl₃; Me₄Si) 1.21 (6H, d, J = 6.2 Hz, CH(CH₃)₂), 2.07 (3H, s, 4-CH₃), 2.09 (3H, s, 5-

CH₃), 3.78 (3H, s, 4′′-OCH₃), 3.83 (3H, s, 4′-OCH₃), 4.14–4.19 (1H, m, CH(CH₃)₂), 5.02 (2H, s, 1-CH₂), 6.05 (1H, s,

3-CH), 6.77 (1H, s, J = 2.0 Hz, 2′-H), 6.80 (1H, d, J = 8.2 Hz, 5′-H), 6.82 (1H, dd, J = 2.0, 8.2 Hz, 6′-H), 6.83 (2H,

dd, J = 2.0, 10.4 Hz, 3′′-H), 6.88 (2H, dd, J = 2.0, 10.4 Hz, 2′′-H). δ_C(125 MHz; CDCl₃) 10.0 (4-CH₃), 11.3 (5-CH₃),

22.0 (3′-OCH(CH₃)₂), 47.2 (1-CH₂), 55.3 (4′′-OCH₃), 55.9 (4′-OCH₃), 70.9 (3′-OCH(CH₃)₂), 108.9 (C-3), 111.8 (C-

5′), 114.1 (C-3′′), 114.9 (C-4), 115.9 (C-2′), 121.2 (C-6′), 125.9 (C-5), 126.6 (C-1′), 126.8 (C-2′′), 131.6 (C-1′′), 133.2

(C-2), 146.9 (C-3′), 149.2 (C-4′), 158.6 (C-4′′). IR: (film)/cm-1; 2974, 1611, 1585, 1524, 1245, 1174, 1032, 959, 813,

787. m/z (ESI+) 402 (MNa⁺, 100%). HRMS (ESI+) Found (MNa⁺): 402.2027; C₂₄H₂₉NNaO₃requires 402.2040.

ACCEPTED MANUSCRIPT

4.2.4.25 2-(3′-isopropoxy-4′-methoxyphenyl)-1-(4′′-methoxyphenyl)-4,5-dimethyl-1H-pyrrole 8z. Using diketone 1j.

Flash chromatography using 9:1 hexanes, ethyl acetate to yield 53 mg, 41% as a yellow oil. R_F= 0.67 (2:1 hexanes,

ethyl acetate). δ_H(500 MHz; CDCl₃; Me₄Si) 1.16 (6H, d, J = 6.2 Hz, 3′-OCH(CH₃)₂), 2.02 (3H, s, 4-CH₃), 2.12 (3H, s,

5-CH₃), 3.78 (3H, s, 4′-OCH₃), 3.79 (3H, s, 4′′-OCH₃), 4.11–4.14 (1H, m, 3′-OCH(CH₃)₂), 6.16 (1H, s, 3-CH), 6.50

(1H, d, J = 2.0 Hz, 2′-H), 6.69 (1H, d, J = 8.2 Hz, 5′-H), 6.73 (1H, dd, J = 2.0, 8.2 Hz, 6′-H), 6.87 (2H, dd, J = 2.4, 8.8

Hz, 3′′-H), 7.07 (2H, d, J = 2.4, 8.8 Hz, 2′′-H). δ_C(125 MHz; CDCl₃) 10.8 (4-CH₃), 11.3 (5-CH₃), 22.0 (CH(CH₃)₂),

55.4 (4′-OCH₃), 55.9 (4′′-OCH₃), 71.0 (CH(CH₃)₂), 109.3 (C-3), 111.6 (C-5′), 114.1 (C-3′′), 115.0 (C-4), 115.7 (C-2′),

120.6 (C-6′), 126.5 (C-1′), 127.5 (C-5), 129.6 (C-2′′), 132.7 (C-1′′), 132.9 (C-2), 146.9 (C-3′), 149.2 (C-4′), 158.6 (C-

4′′). IR: (film)/cm-1; 2973, 1512, 1490, 1245, 1168, 1032, 998, 729. m/z (ESI+) 388 (MNa⁺, 100%). HRMS (ESI+)

Found (MNa⁺): 388.1870; C₂₃H₂₇NNaO₃requires 388.1883.

4.2.4.26 1-benzyl-5-(3′-isopropoxy-4′-methoxyphenyl)-2,3-dimethyl-1H-pyrrole 8aa. Using diketone 1j. Flash

chromatography using 9:1 hexanes, ethyl acetate 42 mg, 30% as a yellow oil. R_F= 0.83 (2:1 hexanes, ethyl acetate).

δ_H(500 MHz; CDCl₃; Me₄Si) 1.17 (6H, d, J = 6.1 Hz, 3′-OCH(CH₃)₂), 2.06 (3H, s, 3-CH₃), 2.10 (3H, s, 2-CH₃), 3.82

(3H, s, 4′-OCH₃), 4.08–4.13 (1H, m, 3′-OCH(CH₃)₂), 5.07 (2H, s, 1-CH₂), 6.06 (1H, s, 4-H), 6.73 (1H, d, J = 2.0 Hz,

2′-H), 6.79 (1H, d, J = 8.4 Hz, 5′-H), 6.83 (1H, dd, J = 2.0, 8.4 Hz, 6′-H), 6.97 (2H, dd, J = 1.0, 7.2 Hz, 2′′-H), 7.19

(1H, td, J = 1.0, 7.2 Hz, 4′′-H). δ_C(125 MHz; CDCl₃) 10.0 (3-CH₃), 11.3 (2-CH₃), 22.0 (3′-OCH(CH₃)₂), 47.8 (1-

CH₂), 56.0 (4′-OCH₃), 70.9 (3′-OCH(CH₃)₂), 108.9 (C-4), 111.9 (C-5′), 114.9 (C-3), 115.8 (C-2′), 121.1 (C-6′), 125.6

(C-2′′), 125.7 (C-2), 126.5 (C-1′), 126.8 (C-4′′), 128.7 (C-3′′), 133.2 (C-5), 139.5 (C-1′′), 146.9 (C-3′), 149.1 (C-4′).

IR: (film)/cm-1; 2923, 2855, 1605, 1525, 1494, 1246, 1137, 1029, 908, 730. m/z (ESI+) 372 (MNa⁺, 100%). HRMS

(ESI+) Found (MNa⁺): 372.1920; C₂₃H₂₇NNaO₂requires 372.1934.

4.2.4.27 2-(4′-Methoxyphenyl)-3,5-dimethyl-1-phenyl-1H-pyrrole 8ab. Using diketone 1k. Flash chromatography

using 14:1 hexanes, ethyl acetate to yield 11 mg, 30% as a pink oil. R_F(2:1 hexanes, ethyl acetate) = 0.83. δ_H(300

MHz; CDCl₃; Me₄Si) 2.12 (3H, s, 3-CH₃), 2.13 (3H, s, 5-CH₃), 3.74 (3H, s, OCH₃), 5.94 (1H, s, 4-H), 6.71 (2H, d, J =

8.8 Hz, 3′-H), 6.95 (2H, d, J = 8.8 Hz, 2′-H), 7.05–7.07 (2H, m, Ar-H), 7.23–7.24 (3H, m, Ar-H). δ_C(75 MHz;

CDCl₃) 11.9 (3-CH₃), 13.1 (5-CH₃), 55.1 (OCH₃), 109.3 (C-4), 113.2 (C-3′), 116.2 (C-3), 125.6 (C-1′), 126.8, 128.4,

128.6 (Ar-CH), 129.2 (C-5), 131.2 (C-2′), 131.4 (C-2), 139.5 (Ar-C), 157.6 (C-4′). IR: ν_max(film)/cm^-1; 2923, 2855,

1497, 1259, 1245, 1020, 798, 759, 732, 698. m/z (ESI⁺) 257 (100), 278 (MH⁺, 10%). HRMS (ESI⁺) found (MH⁺):

278.1504; C₁₉H₂₀NO requires 278.1539.

4.2.4.28 5-(4′-Methoxyphenyl)-4-methyl-1-(3′′-phenylpropyl)-1H-pyrrole-2-carbaldehyde 8ac. Using diketone 1k.

Flash chromatography using 9:1 hexanes, ethyl acetate to yield 5.0 mg, 13% as a purple oil. R_F(2:1 hexanes, ethyl

acetate) = 0.79. δ_H(300 MHz; CDCl₃; Me₄Si) 1.88 (2H, pent., J = 7.7 Hz, 2′′-H), 1.97 (3H, s, 4-CH₃), 2.45 (2H, t, J =

7.7 Hz, 3′′-H), 3.73 (3H, s, OCH₃), 4.21 (2H, t, J = 7.7 Hz, 1′′-H), 6.81 (1H, s, 3-H), 6.93 (2H, d, J = 8.8 Hz, 3′-H),

6.99 (1H, s, Ar-H), 7.12–7.21 (6H, m, Ar-H, 2′-H), 9.47 (1H, s, CHO). δ_C(75 MHz; CDCl₃) 11.5 (4-CH₃), 32.6 (C-

2′′), 32.7 (C-3′′), 45.6 (C-1′′), 55.3 (OCH₃), 114.1 (C-3′), 119.3 (C-3), 122.8 (C-1′), 125.7, 128.2, 128.4 (Ar-CH),

128.6, 128.8 (C-2, C-4), 131.3 (C-2′), 141.2 (C-5, Ar-C), 159.7 (C-4′), 178.6 (CHO). IR: ν_max(neat)/cm^-1; 3025, 2921,

2853, 1655, 1459, 1454, 1418, 1250, 1036, 1176, 748, 698. m/z (ESI⁺) 356 (MNa⁺, 100%), 352 (20), 301 (80), 245

(50). HRMS (ESI⁺) found (MNa⁺): 356.1620; C₂₂H₂₃NNaO₂requires 356.1621.

4.2.4.29 2-(4′-Methoxyphenyl)-5-methyl-1,3-diphenyl-1H-pyrrole 8ad. Using diketone 1m. Flash chromatography

using 9:1 hexanes, ethyl acetate to yield 13 mg, 30% as a yellow oil. R_F(2:1 hexanes, ethyl acetate) = 0.62. δ_H(400

MHz; CDCl₃; Me₄Si) 2.08 (3H, s, 5-CH₃), 3.65 (3H, s, OCH₃), 6.22 (1H, s, 4-H), 6.56 (2H, d, J = 8.8 Hz, 3′-H), 6.85

(2H, d, J = 8.8 Hz, 2′-H), 7.01–7.04 (4H, m, Ar-H), 7.10–7.23 (6H, m, Ar-H). δ_C(100 MHz; CDCl₃) 13.1 (5-CH₃),

55.0 (OCH₃), 107.6 (C-4), 113.3 (C-3′), 121.9 (C-3), 125.0 (Ar-CH), 125.4 (C-1′), 127.2, 128.0, 128.6, 128.7 (Ar-CH,

C-2′), 130.0 (C-2, C-5), 132.2 (C-4′). IR: ν_max(film)/cm^-1; 2933, 2964, 2855, 1599, 1508, 1250, 1031, 1175, 836, 761,

699. m/z (ESI⁺) 362 (MNa⁺, 10%), 360 (40), 319 (50), 298 (100). HRMS (ESI⁺) found (MNa⁺): 362.1511;

C₂₄H₂₁NNaO requires 362.1515.

4.2.4.30 4′′-(2-(Benzo[d][1′,3′]dioxol-5′-yl)-3,5-dimethyl-4-phenyl-1H-pyrrol-1-yl)benzenesulfonamide 8ae. Using

diketone 1n. Flash chromatography using 14:1 hexanes, ethyl acetate to yield 19 mg, 82% b.r.s.m. as a yellow oil. R_F

(2:1 hexanes, ethyl acetate) = 0.28. δ_H(400 MHz; CDCl₃; Me₄Si) 2.07 (3H, s, 3-CH₃), 2.14 (3H, s, 5-CH₃), 4.84 (2H,

br s, NH₂), 5.93 (2H, s, 2′-H), 6.53–6.57 (2H, m, 6′-H, 7′-H), 6.68 (1H, d, J = 8.0 Hz, 4′-H), 7.26–7.29 (2H, m, 2′′-H),

7.37–7.45 (5H, m, Ar-H), 7.88 (2H, d, J = 8.7 Hz, 3′′-H). δ_C(100 MHz; CDCl₃) 11.2 (3-CH₃), 12.3 (5-CH₃), 101.0 (C-

2′), 108.1 (C-4′), 110.6 (C-7′), 117.0 (C-3), 124.1 (C-6′), 126.0 (C-5′), 126.3 (Ar-CH and C-5), 127.2 (C-3′′), 128.2

(Ar-CH), 128.7 (C-2, C-2′′), 130.0 (Ar-CH), 130.1 (C-4), 135.9 (Ar-C), 139.8 (C-1′′), 143.4 (C-4′′), 146.2, 147.3 (C-

7a′, C-3a′). m/z (ESI^-) 445 (MH^-, 90%), 441 (100). HRMS (ESI^-) found (MH^-): 445.1190; C₂₅H₂₁N₂O₄S requires

445.1228.

ACCEPTED MANUSCRIPT

Acknowledgements.

Funding for this work was obtained from the Faculty Research Development Fund from the University of

Auckland (grant number 3626209).

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