Regioselective synthesis of 2,3,4- or 2,3,5-trisubstituted pyrroles via [3,3] or [1,3] rearrangements of O-vinyl oximes

ARTICLE

pubs.acs.org/joc

Regioselective Synthesis of 2,3,4- or 2,3,5-Trisubstituted Pyrroles

via [3,3] or [1,3] Rearrangements of O-Vinyl Oximes

Heng-Yen Wang, Daniel S. Mueller, Rachna M. Sachwani, Rachel Kapadia, Hannah N. Londino, and

Laura L. Anderson*

Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, MC 111, Chicago, Illinois 60607, United States

S Supporting Information

b

ABSTRACT: The regioselective synthesis of 2,3,4- or 2,3,5-

trisubstituted pyrroles has been achieved via [3,3] and [1,3]

sigmatropic rearrangements of O-vinyl oximes, respectively.

Iridium-catalyzed isomerization of easily prepared O-allyl oxi-

mes enables rapid access to O-vinyl oximes. The regioselectivity

of pyrrole formation can be controlled by either the identity of

the R-substituent or through the addition of an amine base.

When enolization is favored, a [3,3] rearrangement followed by

a Paal-Knorr cyclization provides a 2,3,4-trisubstituted pyrrole; when enolization is disfavored, a [1,3] rearrangement occurs prior to

enolization to produce a 2,3,5-trisubstituted pyrrole after cyclization. Optimization and scope of the O-allyl oxime isomerization and

subsequent pyrrole formation are discussed and mechanistic pathways are proposed. Conditions are provided for selecting either the

[3,3] rearrangement or the [1,3] rearrangement product with β-ester O-allyl oxime substrates.

’ INTRODUCTION

Troﬁmov reaction is limited in scope and eﬃciency. The strongly

basic conditions limit functional group compatibility and the use

of substituted alkynes is rare and gives regioisomeric mixtures of

products in low yields (Scheme 1).²¹[1,3] Rearrangements of

isoxazoles have been used as precursors to aziridines and azo-

methine ylides (Scheme 1);^22,23however, to the best of our

knowledge, the [1,3] rearrangement of O-vinyl oximes has not

previously been reported as a method to access pyrrole precursors.

Recently, we developed a mild alkene isomerization method

for the facile preparation of O-vinyl oximes from easily accessible

O-allyl oximes.^24,25A catalytic mixture of [(cod)IrCl]₂(5 mol

%), AgOTf (10 mol %), and NaBH₄or LiAlH₄(10 mol %)

provided optimal results for this transformation in THF at 25 °C

(Scheme 2).^26ꢀ28The isomerization was shown to be tolerant of

a variety of acetophenone derivatives with both electron-donat-

ing and electron-withdrawing substituents on the aryl ring, as

well as alkyl, aryl, and ester substituents at the R-position. Only

E-oxime isomers were isolated as 2:1mixtures of Z/E vinyl

isomers in good yield. Dialkyl ketone-derived O-allyl oximes

were also tolerated under the isomerization conditions but

provided mixtures of oxime isomers as well as vinyl isomers.

Using our isomerization method, we have now broadened the

range of pyrroles that can be accessed using sigmatropic reactions

by developing single-ﬂask procedures for the direct conversion of

easily prepared O-allyl oximes to either 2,3,4- or 2,3,5-trisubsti-

tuted pyrroles via [3,3] or [1,3] rearrangements of O-vinyl oxime

intermediates, respectively. Here we report the scope of the

The regioselective synthesis of substituted pyrroles is an

important synthetic problem due to the prevalence of these

structures in biologically active compounds and new materials.^1,2

A variety of methods have been developed and evaluated for the

synthesis of substituted pyrroles³including the PaalꢀKnorr

reaction,⁴the PilotyꢀRobinson synthesis,⁵1,3-dipolar cycload-

ditions,⁶Hantzsch coupling reactions,⁷BuchwaldꢀHartwig cou-

pling reactions,⁸metal-catalyzed cyclization,⁹CꢀH bond

amination,¹⁰aza-Claisen rearrangements,¹¹and substitution of

the preformed heterocycle.^12ꢀ14Although many of these meth-

ods provide eﬃcient access to speciﬁc types of pyrroles, the

development of complementary access to two diﬀerent types of

substitution patterns from the same starting material with a

simple change in reaction conditions provides an appealing

alternative for eﬃcient library synthesis.

[3,3] Sigmatropic rearrangements, such as the Claisen and

Fisherꢀindole reactions, are powerful methods for forming new

carbonꢀcarbon bonds.¹⁵[1,3] Rearrangements are less often

observed for allyl vinyl ethers but have recently been studied and

applied to diastereoselective ring contractions.^16ꢀ18An under-

utilized example of a [3,3] rearrangement is the transformation of

O-vinyl oximes to pyrroles. Troﬁmov and co-workers have

shown that oximes can be added to acetylenes under strongly

basic conditions to form O-vinyl oximes that rearrange to 1,4-

imino carbonyl compounds and then participate in a PaalꢀKnorr

cyclization and condensation sequence.^19,20This transformation

is an intriguing alternative approach to the synthesis of pyrroles

because it uses the PaalꢀKnorr reaction sequence without requiring

the synthesis of 1,4-dicarbonyl compounds. Unfortunately, the

Received: January 13, 2011

Published: March 30, 2011

r

2011 American Chemical Society

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Scheme 1. Examples of [3,3] and [1,3] Rearrangements of

O-Vinyl Oximes

Scheme 4. Isomerization and Conversion of R-Cyano-Sub-

stituted O-Allyl Oximes to Pyrroles

^aRepresentative example.

^aNo byproducts were observed that corresponded to reduction of the

Scheme 2. Synthesis of O-Vinyl Oximes via Isomerization of

O-Allyl Oximes

ester substituent. ^bReactions were run at 50 °C.

provided the corresponding 2,3,4-trisubstituted pyrroles 3cꢀi in

good yield (Scheme 4).^29,30The conversion of R-cyano O-allyl

oximes to pyrroles at ambient temperature under the isomeriza-

tion conditions was in contrast to the isolation of the correspond-

ing O-vinyl oximes that occurred when unsubstituted, R-alkyl- or

R-aryl-substituted, and β-ester O-allyl oximes were subjected to

the same isomerization conditions.²⁴Both electron-rich- and

electron-poor aryl substituents were tolerated for the 3-cyano-

pyrrole synthesis and heating the reaction mixture to 50 °C

further expanded the scope of the transformation to include

other halide substituents and furanyl ketone-derived oximes

(1jꢀl).³¹The elevated reaction temperature also increased the

yield of the conversion of 1i to 3i. These data suggested that [3,3]

rearrangements and subsequent PaalꢀKnorr cyclizations are

particularly facile for R-cyano O-vinyl oximes and are tolerated

under the iridium-catalyzed isomerization conditions.³²The O-

vinyl oxime intermediates required in this reaction sequence

Scheme 3. This work—Regioselective Synthesis of Trisub-

stituted Pyrroles from O-Allyl Oximes

1

could not be isolated or purified but could be observed by H

NMR spectroscopy by taking aliquots of the reaction mixture at

25 °C at time points less than 18 h. The transformations shown in

Scheme 4 signified an expansion in the scope of the isomerization

method, showed that 3-cyano pyrroles could be efficiently

synthesized in two steps from commercially available starting

materials, and provided initial evidence that O-vinyl oximes could

be converted to pyrroles under mild conditions with appropriate

substitution patterns.

O-allyl oxime isomerization and pyrrole synthesis as well as the

factors that control the mechanistic pathway for pyrrole forma-

tion. The overall method provides a simple, regioselective, and

functional group tolerant synthesis of 2,5-disubstituted pyrroles

and 2,3,4- or 2,3,5-trisubstituted pyrroles in two- or three steps

from commercially available ketones and allyl hydroxylamine

(Scheme 3).

To determine if isolated O-vinyl oximes without cyano

substituents could be converted to pyrroles via an analogous

[3,3] rearrangement and PaalꢀKnorr cyclization, p-methoxy

acetophenone O-allyl oxime 2a was heated to 75 °C in THF

for 18 h. As shown in Table 1 (entry 1), 2,5-disubstituted pyrrole

4a was isolated from the reaction mixture and 4-methylpyrrole 3a

was not observed. The regiochemistry of the product was

’ RESULTS AND DISCUSSION

Regioselective Preparation of 2,3,4- and 2,3,5-Trisubsti-

tuted Pyrroles. While investigating the scope of our iridium-

catalyzed isomerization conditions for the conversion of O-allyl

oximes to O-vinyl oximes, the transformation was tested for

R-cyano O-allyl oximes 1cꢀi. Surprisingly, these isomerizations

1

assigned by a ¹Hꢀ H NOE experiment and was surprising due

to its complementary relationship to pyrroles 1cꢀl which were

generated from R-cyano O-allyl oximes (Scheme 4).^29,33The

synthesis of 4a from 2a was optimized and the thermal

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Table 1. Optimization of the Conversion of O-Vinyl Oximes

to 5-Methylpyrroles

Scheme 6. Single-Flask Process for the Conversion of O-Allyl

Oximes to 5-Methylpyrroles

entry

solvent

conc (M)

T (°C)

4a (%, yield)

1

2

3

4

5

6

7

8

9

THF

0.13

0.27

0.07

0.13

75

33

43

47

67

59

60

64

60

64

benzene

MeCN

dioxane

i-PrOAc

dioxane

75

the two potential sites for enolization for this substrate. Pyrrole

4v was isolated as a single isomer due to unfavorable steric

interactions that would arise from enolization at the neopentyl

position of 2v.

55

100

The diﬀerence in regioselectivity observed for the tandem,

iridium-catalyzed isomerization and pyrrole formation of

R-cyano O-allyl oximes (Scheme 4) and the metal-free, thermal

rearrangement and pyrrole formation observed for O-vinyl oxi-

mes lacking R-cyano substitution (Scheme 5) prompted an

investigation of the direct conversion of unsubstituted, R-alkyl-

or R-aryl-substituted, and β-ester O-allyl oximes to pyrroles in the

presence of the iridium-isomerization catalyst. As shown in

Scheme 6, when O-allyl oximes 1 were exposed to isomerization

conditions and heated to 75 °C, 2,3,5-trisubstituted pyrroles 4

were isolated from the corresponding reaction mixtures with

yields equal to the cumulative yield of the two-step procedure.^30,33

An advantage to the single ﬂask process was that it expanded the

scope of the isomerization reaction by facilitating the slow

isomerization of 1w and allowing the direct conversion of this

compound to pyrrole 4w. Comparison of the single ﬂask process

to the two-step procedure indicated that the presence of the

iridium catalyst was not responsible for the regioselective diﬀer-

ence between the pyrrole syntheses using R-cyano-substituted

O-allyl oximes (Scheme 4) and those using unsubstituted, R-alkyl

or R-aryl-substituted, and β-ester O-allyl oximes (Schemes 5 and 6).

Mechanistic Analysis of Substituent Effects on the

Regioselectivity of Pyrrole Formation. The formation of

2,3,5-trisubstituted pyrroles 4, from either O-vinyl oximes 2

(Scheme 5) or O-allyl oximes 1 (Scheme 6) cannot occur via a

[3,3] rearrangement and PaalꢀKnorr cyclization as proposed

for R-cyano substrates that provide 2,3,4-trisubstituted pyrroles 3

(Schemes 4 and 7).³⁵To better understand the origin of the

regioselectivity of this process and to propose a mechanism

for the synthesis of 4, the thermal transformation of O-vinyl

Scheme 5. Thermal Conversion of O-Vinyl Oximes to

5-Methylpyrroles

^aRegioselectivity ratio.

transformation was shown to provide 4a in good yield when run

in dioxane (Table 1, entry 4).³⁴The transformation was also

more eﬃcient at lower concentrations and the temperature of the

rearrangement seemed to only aﬀect reaction time and not

reaction eﬃciency (Table 1, entries 4, 6ꢀ9).

The conversion of O-vinyl oximes 2 to 5-methylpyrroles 4 was

further investigated for a variety of O-vinyl oximes using the

optimized conditions determined for 2a. As shown in Scheme 5,

the corresponding 2,5-disubstituted and 2,3,5-trisubstituted pyr-

roles 4b and 4mꢀv were isolated from these thermal transfor-

mations in moderate to good yield.^33,34The regiochemistry of

the products matched that of 4a, and the corresponding

4-methylpyrroles 3 were not observed.²⁹Both electron-donat-

ing- and electron-withdrawing groups were tolerated on the aryl

ring of the acetophenone-derived substrates and alkyl-, aryl- and

ester groups were tolerated at the R-position. Dialkyl O-vinyl

oxime 2u provided a chemoselective mixture of pyrroles due to

1

oxime 2s was monitored by H and ¹³C NMR spectroscopy

to observe potential reactive intermediates. Surprisingly, after

2.5 h of heating at 75 °C, 2s had undergone a [1,3] rearrange-

ment and complete conversion to aldehyde 5s (Scheme 8).

Continued heating and the addition of molecular sieves to the

reaction mixture led to the further conversion of aldehyde 5s to

pyrrole 4s. These observations suggested that pyrrole formation

was occurring via an initial [1,3] rearrangement followed by

tautomerization and cyclization by nucleophilic attack of the

enamine at the aldehyde (Scheme 7). In order to prove the

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Scheme 7. Proposed Mechanism for 4- and 5-Methylpyrrole

Formation via O-Vinyl Oxime [3,3] and [1,3]

Rearrangements

Table 2. Optimization of Basic Additives for the Formation

of Pyrrole 3b

entry

base

NEt₃

%, yield^a

3j:4j^b

1

2

3

4

5

6

7

8

9

58

88

72

69

64

62

18

14

30

50:50

86:14

84:16

50:50

66:33

50:50

66:33

25:75

DBU

DABCO

imidazole

DMAP

Cs₂CO₃

KO-t-Bu

KH

KHMDS

^aDetermined by H NMR spectroscopy with CH₂Br₂as a reference.

1

^bDetermined by ¹H NMR spectroscopy.

Scheme 9. Single-Flask, Regioselective Procedures for the

Synthesis of Pyrroles 3b and 4b

^aNaBH₄was used when R¹= CN. LiAlH₄was used when R¹= Me.

Scheme 8. Observation, Derivatization, and Isolation of an

O-Vinyl Oxime [1,3] Rearrangement Product

electron-withdrawing substituents at the R-position of the oxime.

β-Ester O-vinyl oxime 2b was chosen for this study due to the

intermediate acidity of this substrate in comparison to R-cyano-

substituted O-allyl oxime 1c and R-aryl-substituted O-vinyl oxime

2r.³⁷When a THF solution of 2b was heated in the presence of

triethylamine, a 1:1 mixture of 4-methylpyrrole 3b and 5-methyl-

pyrrole 4b was obtained (Table 2, entry 1). This mixture indicated a

change in mechanism based on reaction conditions and provided

access to the new regioisomer 3b. Following this initial result, several

amine bases were tested as additives for the transformation, and

DBU was identified as the optimal reagent for the selective

formation of 2,3,4-trisubstituted pyrrole 3b (entry 2). Carbonate,

tert-butoxide, hydride, and disilazane salts were also evaluated and

compared to DBU, but only poorly selective regioisomeric mixtures

of 3b and 4b were produced in low yield.³⁸

A single-ﬂask process incorporating the iridium-catalyzed

alkene isomerization and the use of DBU to control the regios-

electivity of pyrrole formation was shown to be viable for the

conversion of O-allyl oxime 1b to 4-methylpyrrole 3b

(Scheme 9). This procedure avoids the isolation of O-vinyl

oxime intermediate 2b and gives a higher overall yield of 3b

(86%) than the cumulative yield of the two-step process (51%).

The transformation of 1b to 3b is in contrast to the single-ﬂask

procedure for the conversion of 1b to 5-methylpyrrole 4b which

occurs under neutral conditions in signiﬁcantly lower yield.

Comparison of the reactions illustrated in Scheme 9 describes

identity of the aldehyde intermediate 5s, O-vinyl oxime 2s was

once again heated for 2.5 h at 75 °C and then treated with

LiAlH₄.³⁶After workup and purification, the corresponding

amino alcohol 6s was isolated as a diastereotopic mixture

(Scheme 8). A potential explanation for the deviation in the

sigmatropic rearrangement reactivity between transient R-cyano

O-vinyl oximes and the O-vinyl oxime substrates and intermedi-

ates shown in Schemes 5 and 6 is the potential for enolization.³⁷

When enolization is facile for O-vinyl oximes, as it is for R-cyano

substrates, the reaction proceeds via a [3,3] rearrangement and

PaalꢀKnorr cyclization to give 4-methylpyrroles 3; when en-

olization is less favored the [1,3] rearrangement is faster than

tautomerization and pyrrole formation occurs by attack of the

enamine on the tethered aldehyde (Scheme 7).

Effect of a Basic Additive on the Regioselectivity of Pyrrole

Formation. The apparent dependence of the regioselectivity of the

conversion of O-vinyl oximes to pyrroles on the enolizability of the

substrate prompted our investigation of basic reaction conditions to

promote the formation of 2,3,4-trisubstituted pyrroles with less

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Scheme 10. Scope of Isomerization and [3,3] Rearrange-

ment of β-Ester O-Allyl Oximes

Scheme 11. Observation of N,O-Acetal Intermediate from

[3,3] Rearrangement

Scheme 12. Eﬀect of DBU on the Regioisomeric Ratio of

3ll:4ll

how the regioselectivity of the pyrrole synthesis can be controlled

by the presence or the absence of DBU and how a single substrate

can be easily manipulated to selectively produce two diﬀerent

pyrrole regioisomers.

The scope of the β-ester O-allyl oxime isomerization and pyrrole

synthesis in the presence of DBU was investigated to determine the

tolerance of the method as well as the steric and electronic

substituent eﬀects on the regioselectivity of pyrrole formation

(Scheme 10). A variety of β-ester acetophenone derivatives were

tested, and halide, methoxy-, triﬂuoromethyl-, and alkyl groups

were shown to be tolerated at both the para- and meta-positions of

the aryl ring, providing exclusively 4-methylpyrroles 3xꢀkk in good

to excellent yield. In contrast, methyl substitution at the ortho-

position of the aryl group dramatically decreased the regioselec-

tivity of the transformation and provided a mixture of pyrroles 3hh

and 4hh. Destabilizing steric interactions involved in tautomeriza-

tion of the o-methyl O-vinyl oxime intermediate 2hh may be

responsible for decreasing the amount of product formed by the

proposed [3,3] rearrangement. Alkyl-substituted β-ketoester oxi-

mes 1iiꢀkk were also tolerated for the isomerization and pyrrole

formation sequence but similarly gave regioisomeric mixtures of

pyrroles. The decreased regioselectivity observed for these sub-

strates may be caused by a decreased electronic preference for

tautomerization due to lack of resonance stabilization. The pre-

ference for 4-methylpyrrole formation observed for cyclopropyl β-

ester O-allyl oxime 1ii is noteworthy but diﬃcult to explain. Overall,

the results illustrated in Scheme 10 support the proposed mechan-

istic and regioselectivity dependence of pyrrole formation on oxime

tautomerization and suggest that the use of DBU to favor [3,3]

rearrangement and 4-methylpyrrole formation for acetophenone-

derived β-ester O-allyl oximes is general.

starting material 2b and pyrrole 3b (Scheme 11). Additional

heating for 14 h resulted in the disappearance of the observed

intermediate and conversion to 3b. New methine resonances in

1

the H NMR spectrum between 4.5 and 6.0 ppm and carbon

resonances at 86.3 and 55.7 ppm suggested that the intermediate

was N,O-acetal 8b. These chemical shifts are analogous to NMR

data reported for similar cyclic N,O-acetals and do not match 2b

or 3b.³⁹Imino aldehyde 7b was eliminated as a potential structure

due to the lack of an aldehydic resonance in both the ¹H and ¹³

NMR spectra.

C

The generality of the use of DBU as an additive to favor the

[3,3] rearrangement of O-vinyl oximes over [1,3] rearrangement

was further tested for tert-butyl-substituted cyano O-allyl oxime

1ll and deoxybenzoin-derived substrate 1r. As illustrated in

Scheme 12a, when O-allyl oxime 1ll is subjected to the iri-

dium-catalyzed isomerization conditions under neutral condi-

tions a mixture of regioisomeric pyrroles 3ll:4ll (40:60) is

observed. This deviation in regioselectivity in comparison to

the other R-cyanoO-allyl oximesubstrates illustratedinScheme4

may be due to a decreased energetic preference for tautomeriza-

tion due to a lack of resonance stabilization in analogy to isomeric

mixtures obtained for β-ester oximes with alkyl substituents.

To facilitate tautomerization and favor the [3,3] rearrangement,

DBU was added to an isomerization reaction mixture with 1ll

(Scheme 12b). Although 4-methylpyrrole 3ll was not isolated

exclusively, the addition of DBU changed the ratio of 3ll:4ll from

40:60 in favor of 2,3,5-trisubstituted pyrrole 4ll to 80:20 in favor

of 2,3,4-trisubstituted pyrrole 3ll. The pK_alimits for the use of

DBU to favor enolization and the [3,3] rearrangement of O-vinyl

oximes were further evaluated with deoxybenzoin-derived

In order to observe the reactive intermediates involved in the

conversion of O-vinyl oxime 2b to 4-methylpyrrole 3b, the

1

transformation was monitored by H and ¹³C NMR spectros-

copy. After 6.5 h of heating a THF-d₈solution of 2b and DBU at

75 °C, a new major product was observed with a small amount of

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Scheme 13. Eﬀect of DBU on the Rearrangement and Cy-

clization of Deoxybenzoin-Derived Substrates

Scheme 15. Two-Step Procedure for the Synthesis of

4-Methylpyrrole 3mm

Scheme 14. Eﬀect of Aryl Substituents with Electron-With-

drawing Groups on the Ratio of 3:4

’ CONCLUSION

In summary, we have developed mild procedures for the

isomerization of easily accessible O-allyl oximes to O-vinyl

oximes and the eﬃcient transformation of O-vinyl oximes to

either 2,3,4- or 2,3,5-trisubstituted pyrroles. The regioselectivity

of pyrrole formation can be controlled by favoring or disfavoring

oxime tautomerization with substituent eﬀects and reaction

conditions. The use of electron-withdrawing substituents at the

R-position of the oxime and the addition of DBU to the reaction

mixture favor enolization, a [3,3] rearrangement of the O-vinyl

oxime intermediate, and formation of 2,3,4-trisubstituted pyr-

roles. In contrast, electron-donating or electronically neutral

substituents at the R-position of the oxime and the lack of an

amine base disfavor enolization, allowing a [1,3] rearrangement

of the O-vinyl oxime intermediate to occur prior to tautomeriza-

tion, cyclization, and elimination to provide 2,3,5-trisubstituted

pyrroles. These procedures provide a facile entry to an uncom-

mon synthetic intermediate and highlight the utility of O-vinyl

oximes with a simple, regiospeciﬁc, and functional group tolerant

preparation of either 2,3,4- or 2,3,5-trisubstituted pyrroles in two

steps from the same commercially available starting materials.

O-vinyl oxime 2r. When this substrate was heated in the absence

of DBU, only the 5-methylpyrrole 4r was observed (Scheme 5).

In contrast, when 2r was heated in the presence of DBU, a 80:20

mixture of the corresponding 4-methyl- and 5-methylpyrroles 3r

and 4r was isolated (Scheme 13a). The corresponding single-

ﬂask isomerization and pyrrole formation procedure was also

tested but provided a less selective product ratio in lower yield

(Scheme 13b). These results showed that the use of DBU to

favor the [3,3] rearrangement of O-vinyl oxime intermediates

was not limited to β-ester oxime substrates.

To further facilitate the regioselective preparation of diaryl

pyrroles such as 3r, deoxybenzoin-derived substrates with elec-

tron-withdrawing substituents on the R-aryl group were pre-

pared and evaluated. These substrates were chosen to test our

hypothesis that the amount of competing [1,3] rearrangement

product 4 could be suppressed if enolization was electronically

favored. When O-allyl oximes 1mmꢀoo were subjected to the

isomerization and pyrrole formation reaction conditions, the

4-methylpyrrole products 3mmꢀoo were isolated exclusively

(Scheme 14). These results further supported our mechanistic

proposal that the regioisomeric preference is determined by the

enolizability of the substrate. The moderate yields observed for

these transformations are due to an ineﬃcient alkene isomeriza-

tion as described by the analogous two-step procedure illustrated

in Scheme 15. β-Tetralone-derived O-allyl oxime 1pp was also

tested and similarly gave a single regioisomeric product, albeit

without increased acidity at R-position due to substitution.

’ EXPERIMENTAL SECTION

General Methods. ¹H NMR and ¹³C NMR spectra were recorded

at ambient temperature using 500 MHz spectrometers. The data are

reported as follows: chemical shift in ppm from internal tetramethylsi-

lane on the δ scale, multiplicity (br = broad, s = singlet, d = doublet, t =

triplet, q = quartet, m = multiplet), coupling constants (Hz), and

integration. High-resolution mass spectra were acquired on an LTQ

FT spectrometer and were obtained by peak matching. Melting points

are reported uncorrected. Analytical thin-layer chromatography was

performed on 0.25 mm extra hard silica gel plates with UV254

fluorescent indicator. Liquid chromatography was performed using

forced flow (flash chromatography) of the indicated solvent system on

60 Å (40 ꢀ 60 μm) mesh silica gel (SiO₂). All reactions were carried out

under an atmosphere of nitrogen in glassware that had been oven-dried.

Unless otherwise noted, all reagents were commercially obtained and,

where appropriate, purified prior to use. THF was dried by filtration

through alumina according to the procedure of Grubbs.⁴⁰Acetonitrile,

isopropyl acetate, benzene, dioxane, dichloroethane, DBU, and THF-d₈

were distilled over CaH₂and degassed prior to use in the glovebox.

Metal salts were stored in a nitrogen atmosphere drybox. O-Allyl oximes

1a, 1b, 1dꢀf, 1i, and 1mꢀw and O-vinyl oximes 2a,b and 2mꢀv were

prepared by previously reported procedures.²⁴

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General Procedure for the Synthesis of O-Allyl Oximes 1²⁵.

A 100 mL round-bottom flask (rbf) was charged with 1 equiv of

allylhydroxylamine hydrochloride salt, 1 equiv of NaOAc, and ∼40 mL

of MeOH. The resulting slurry was allowed to stir at 25 °C for 30 min. At

this time, 1 equiv of the corresponding ketone was added to the slurry

over a 5 min time period. Regardless of their physical state, ketones were

weighed into scintillation vials, mixed with 15 mL of MeOH, and added

as solutions with a syringe. The reaction mixtures were then allowed to

stir at 25 °C for 12ꢀ24 h or heated to 60 °C for 24 h. At this time, 30 mL

of water were added to the flask and a white precipitate appeared. The

mixture was then transferred to a separatory funnel and mixed with an

additional 20 mL of water and 40 mL of MTBE or CH₂Cl₂. The water

layer was extracted with 3 ꢁ 15 mL of MTBE or CH₂Cl₂and the organic

layer was extracted with 2 ꢁ 20 mL of water and 1 ꢁ 20 mL of brine. The

organic layers were then combined, dried over MgSO₄, and filtered.

Solvent was separated from the product under vacuum on a rotary

evaporator. Allyl oxime 1 was then transferred to a scintillation vial and

all remaining volatiles were removed on a high vacuum line. No further

purification of the products was required in most cases. For condensa-

tion reactions that did not go to completion, the remaining starting

material was separated by flash chromatography using a solvent gradient

of 2% TEA/hexanesꢀ10% EtOAc/2% TEA/hexanes.

þ H)^þ255.1497, found 255.1496. The ¹H NMR spectrum showed that

<10% of the product mixture was the Z-oxime isomer.

O-Allyl Oxime 1j. Allyl hydroxylamine hydrochloride (0.682 g, 6.22

mmol) was treated with NaOAc (0.562 g, 6.85 mmol) and 4-fluoro-

benzoylacetonitrile (1.02 g, 6.25 mmol). The reaction flask was then

attached to a reflux condenser and allowed to stir at 60 °C for 12 h. After

workup, 1j was isolated as a clear, colorless oil (1.06 g, 78%): ¹H NMR

(500 MHz, CDCl₃) δ 7.66ꢀ7.63 (m, 2H), 7.13ꢀ7.09 (m, 2H),

6.07ꢀ6.02 (m, 1H), 5.37 (dd, J = 17.0, 1.0 Hz, 1H), 5.27 (dd, J =

10.5, 1.0 Hz, 1H), 4.77 (d, J = 5.5 Hz, 2H), 3.80 (s, 2H); ¹³C NMR (125

MHz, CDCl₃) δ 163.9 (d, J_CꢀF= 248.8 Hz), 145.5, 133.4, 129.4, 128.2,

118.5, 116.1, 114.9, 76.1, 15.2; IR (thin film) 2930, 2257, 1602, 1511,

1417, 1233, 1161, 1022, 931, 835 cm^ꢀ1; HRMS (ESI) m/z calcd for

1

C₁₂H₁₂FN₂O (M þ H)^þ219.0934, found 219.0933. The H NMR

spectrum showed that <10% of the product mixture was the Z-oxime

isomer.

O-Allyl Oxime 1k. Allyl hydroxylamine hydrochloride (0.539 g, 4.92

mmol) was treated with NaOAc (0.412 g, 5.02 mmol) and 4-chlor-

obenzoylacetonitrile (0.818 g, 4.56 mmol). The reaction flask was then

attached to a reflux condenser and allowed to stir at 60 °C for 12 h. After

workup, 1k was isolated as a clear, colorless oil (0.843 g, 79%): ¹H NMR

(500 MHz, CDCl₃) δ 7.60ꢀ7.59 (m, 2H), 7.40ꢀ7.38 (m, 2H),

6.07ꢀ6.01 (m, 1H), 5.36 (dd, J = 20.0, 1.0 Hz, 1H), 5.29 (dd, J =

10.5, 1.0 Hz, 1H), 4.78 (d, J = 6.0 Hz, 2H), 3.79 (s, 2H); ¹³C NMR (125

MHz, CDCl₃) δ 163.9, 145.5, 133.3, 131.6, 129.1, 127.4, 118.6, 114.8,

76.2, 15.1; IR (thin film) 2950, 2250, 1600, 1490, 1412, 1327, 1092,

1009, 930, 829 cm^ꢀ1; HRMS (ESI) m/z calcd for C₁₂H₁₂ClN₂O (M þ

O-Allyl Oxime 1c. Allyl hydroxylamine hydrochloride (0.601 g, 5.49

mmol) was treated with NaOAc (0.675 g, 8.23 mmol) and benzoylace-

tonitrile (0.716 g, 4.93 mmol). The reaction flask was then attached to a

reflux condenser and allowed to stir at 60 °C for 12 h. After workup, 1c

was isolated as a clear, colorless oil (0.810 g, 82%): ¹H NMR (500 MHz,

CDCl₃) δ 7.67ꢀ7.65 (m, 2H), 7.39ꢀ7.36 (m, 3H), 6.09ꢀ7.06 (m, 1H),

5.38 (dd, J = 17.0, 1.0 Hz, 1H), 5.29 (dd, J = 10.5, 1.0 Hz, 1H), 4.79 (d, J

= 5.5 Hz, 2H), 3.81 (s, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 146.5,

133.5, 133.3, 130.2, 128.9, 126.2, 118.4, 115.0, 76.0, 15.3; IR (thin film)

1

H)^þ235.0638, found 235.0640. The H NMR spectrum showed that

<10% of the product mixture was the Z-oxime isomer.

O-Allyl Oxime Ether 1l. Allyl hydroxylamine hydrochloride (0.405 g,

3.70 mmol) was treated with NaOAc (0.334 g, 4.07 mmol) and

2-furoylacetonitrile (0.500 g, 3.70 mmol). The reaction flask was then

attached to a reflux condenser and allowed to stir at 60 °C for 12 h. After

workup and flash chromatography (2% TEA/hexanesꢀ5% EtOAc/2%

TEA/hexanes), 1l was isolated as a clear, colorless oil (0.530 g, 75%, E:Z

= 1:2): ¹H NMR of E-imine isomer (500 MHz, CDCl₃) δ 7.55ꢀ7.54

(m, 1H), 6.84ꢀ6.83 (m, 1H), 6.53ꢀ6.52 (m, 1H), 6.10ꢀ6.04 (m, 1H),

5.40 (dd, J = 17.5, 1.5 Hz, 1H), 5.30 (dd, J = 10.5, 1.5 Hz, 1H), 4.79 (m,

2H), 3.76 (s, 2H); ¹³C NMR of E-imine isomer (125 MHz, CDCl₃) δ

2926, 2252, 1604, 1445, 1415, 1341, 1020, 930, 759, 691, 532 cm^ꢀ1

;

HRMS (ESI) m/z calcd for C₁₂H₁₃N₂O (M þ H)^þ201.1028, found

1

201.1027. The H NMR spectrum showed that <10% of the product

mixture was the Z-oxime isomer.

O-Allyl Oxime 1g. Allyl hydroxylamine hydrochloride (0.539 g, 4.92

mmol) was treated with NaOAc (0.443 g, 5.28 mmol) and 3-trifluor-

omethylbenzoyl acetonitrile (0.868 g, 4.07 mmol). The reaction flask

was then attached to a reflux condenser and allowed to stir at 60 °C for

12 h. After workup and purification by flash chromatography (5%

EtOAc/2% TEA/hexanes), 1g was isolated as a clear, colorless oil

1

147.2, 144.6, 139.2, 133.2, 118.6, 114.7, 112.0, 111.1, 76.3, 14.6; H

NMR of Z-imine isomer (500 MHz, CDCl₃) δ 7.54ꢀ7.53 (m, 1H),

7.42ꢀ7.41 (m, 1H), 6.59ꢀ6.58 (m, 1H), 6.10ꢀ6.04 (m, 1H), 5.38 (dd, J

= 17.5, 1.5 Hz, 1H), 5.30 (dd, J = 10.5, 1.5 Hz, 1H), 4.79 (m, 2H), 3.73

(s, 2H); ¹³C NMR of Z-imine isomer (125 MHz, CDCl₃) δ 143.8, 143.4,

137.3, 133.5, 119.0, 118.4, 115.8, 112.7, 76.5, 20.9; IR (thin film) 2932,

2255, 1602, 1482, 1411, 1161, 999, 935, 896, 750 cm^ꢀ1; HRMS (ESI)

m/z calcd for C₁₀H₁₁N₂O₂(M þ H)^þ191.0822, found 191.0821.

O-Allyl Oxime 1x. Allylhydroxylamine hydrochloride (0.625 g, 5.70

mmol) was treated with NaOAc (0.468 g, 5.70 mmol) and ethyl (4-

fluorobenzoyl) acetate (1.00 g, 4.76 mmol). The reaction flask was then

attached to a reflux condenser and allowed to stir at 60 °C for 12 h. After

1

(1.02 g, 94%): H NMR (500 MHz, CDCl₃) δ 7.73 (s, 1H), 7.82 (d,

J = 7.5 Hz, 1H), 7.69 (d, J = 7.5 Hz, 1H), 7.56 (m, 1H), 6.08ꢀ6.02 (m,

1H), 5.39 (dd, J = 19.0, 1.0 Hz, 1H), 5.30 (dd, J = 10.5, 1.0 Hz, 1H), 4.82

(d, J = 6.0 Hz, 2H), 3.84 (s, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 145.4,

134.2, 133.3, 131.6 (d, J_CꢀF= 32.5 Hz), 129.6, 129.5, 126.9, 123.9 (q,

J_CꢀF= 270 Hz), 123.2, 119.0, 114.7, 76.6, 15.3; IR (thin film) 2900,

2251, 1616, 1424, 1304, 1278, 1125, 1021, 930, 800 cm^ꢀ1; HRMS (ESI)

m/z calcd for C₁₃H₁₂F₃N₂O (M þ H)^þ269.0902, found 269.0904. The

¹H NMR spectrum showed that <10% of the product mixture was the

Z-oxime isomer.

1

Allyl Oxime 1h. Allyl hydroxylamine hydrochloride (0.663 g,

6.05 mmol) was treated with NaOAc (0.745 g, 9.08 mmol) and

5,6,7,8-tetrahydro-2-napthoyl acetonitrile (1.09 g, 5.47 mmol). The

reaction flask was then attached to a reflux condenser and allowed to

stir at 60 °C for 12 h. After workup, 1h was isolated as a clear, colorless oil

workup, 1x was isolated as a clear colorless liquid (1.08 g, 86%): H

NMR (500 MHz, CDCl₃) δ 7.64ꢀ7.61 (m, 2H), 7.07ꢀ7.04 (m, 2H),

6.04ꢀ5.98 (m, 1H), 5.32 (dd, J = 17.5, 1.5 Hz, 1H), 5.22 (dd, J = 10.5,

1.5 Hz, 1H), 4.71 (d, J = 5.5 Hz, 2H), 4.15 (q, J = 7.0 Hz, 2H), 3.76 (s,

2H), 1.21 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 168.7,

163.5 (d, J_CꢀF= 247.5 Hz), 150.6, 134.0, 131.6, 128.2, 117.4, 115.6, 75.3,

61.2, 33.4, 14.1; IR (thin film) 3080, 2983, 2927, 2869, 1733, 1602, 1510,

1021, 922, 837 cm^ꢀ1; HRMS (ESI) m/z calcd for C₁₄H₁₇NO₃F (M þ

1

(1.17 g, 84%): H NMR (500 MHz, CDCl₃) δ 7.36ꢀ7.32 (m, 2H),

7.11ꢀ7.10 (m, 1H), 6.09ꢀ6.03 (m, 1H), 5.37 (d, J = 17.5 Hz, 1H), 5.27

(d, J = 10.5 Hz, 1H), 4.77 (d, J = 5.5 Hz, 2H), 3.78 (s, 2H), 2.80ꢀ2.78

(m, 4H), 1.81ꢀ1.80 (m, 4H); ¹³C NMR (125 MHz, CDCl₃) δ 146.7,

139.8, 137.8, 133.6, 130.4, 129.6, 126.8, 123.2, 118.2, 115.2, 75.9, 29.5,

29.3, 23.0, 22.9, 15.3; IR (thin film) 2926, 2859, 2250, 1650, 1424, 1330,

1021, 927, 852, 703 cm^ꢀ1; HRMS (ESI) m/z calcd for C₁₆H₁₉N₂O (M

1

H)^þ266.1192, found 266.1194. The H NMR spectrum showed that

<10% of the product mixture was the Z-oxime isomer.

O-Allyl Oxime 1y. Allylhydroxylamine hydrochloride (0.624 g, 5.70

mmol) was treated with NaOAc (0.468 g, 5.70 mmol) and methyl

4-chlorobenzoyl acetate (1.01 g, 4.75 mmol). The reaction flask was

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then attached to a reflux condenser and allowed to stir at 60 °C for 24 h.

After workup, 1y was isolated as a clear colorless liquid (1.15 g, 91%): ¹H

NMR (500 MHz, CDCl₃) δ 7.59ꢀ7.57 (m, 2H), 7.35ꢀ7.33 (m, 2H),

6.03ꢀ5.98 (m, 1H), 5.31 (dd, J = 17.5, 1.5 Hz, 1H), 5.22 (dd, J = 10.5,

61.1, 55.3, 33.4, 14.1; IR (thin film) 2979, 2934, 2871, 2837, 1731, 1608,

1247, 1173, 1023, 915, 833 cm^ꢀ1; HRMS (ESI) m/z calcd. for

C₁₅H₂₀NO₄(M þ H)^þ278.1392, found 278.1395. The ¹H NMR

spectrum showed that <10% of the product mixture was the Z-oxime

isomer.

1.5 Hz, 1H), 4.72 (d, J = 5.5 Hz, 2H), 3.77 (s, 2H), 3.68 (s, 3H); ¹³

C

O-Allyl Oxime 1dd. Allylhydroxylamine hydrochloride (0.394 g, 3.60

mmol) was treated with NaOAc (0.295 g, 3.60 mmol) and methyl

4-trifluoromethylbenzoyl acetate (0.738 g, 3.00 mmol). The reaction

flask was then attached to a reflux condenser and allowed to stir at 60 °C

for 24 h. After workup, 1dd was isolated as a clear colorless liquid (0.839

g, 93%): ¹H NMR (500 MHz, CDCl₃) δ 7.77ꢀ7.76 (m, 2H), 7.63ꢀ7.61

(m, 2H), 6.05ꢀ5.98 (m, 1H), 5.33 (dd, J = 17.0, 1.5 Hz, 1H), 5.24 (dd, J

= 10.5, 1.5 Hz, 1H), 4.74 (d, J = 5.5 Hz, 2H), 3.81 (s, 2H), 3.69 (s, 3H);

¹³C NMR (125 MHz, CDCl₃) δ 168.9, 150.1, 138.7, 133.8, 131.1 (q, J_FC

= 32.5 Hz), 126.5, 125.5, 123.9 (d, J_FC= 271.2 Hz), 117.7, 75.7, 52.3,

32.7; IR (thin film) 2994, 2956, 2926, 1740, 1606, 1256, 1163, 1010, 925,

844 cm^ꢀ1; HRMS (ESI) m/z calcd. for C₁₄H₁₅NO₃F₃(M þ H)^þ

302.1004, found 302.1001. The ¹H NMR spectrum showed that <10%

of the product mixture was the Z-oxime isomer.

NMR (125 MHz, CDCl₃) δ 169.1, 150.3, 135.5, 134.0, 133.7, 128.8,

127.5, 117.6, 75.5, 52.3, 32.8; IR (thin film) 3077, 2951, 2869, 1737,

1602, 1493, 1026, 921, 831, 706 cm^ꢀ1; HRMS (ESI) m/z calcd. for

1

C₁₃H₁₅NO₃Cl (M þ H)^þ268.0740, found 268.0740. The H NMR

spectrum showed that <10% of the product mixture was the Z-oxime

isomer.

O-Allyl Oxime 1z. Allylhydroxylamine hydrochloride (0.485 g, 4.43

mmol) was treated with NaOAc (0.363 g, 4.42 mmol) and ethyl

4-bromobenzoyl acetate (1.00 g, 3.69 mmol). The reaction flask was

then attached to a reflux condenser and allowed to stir at 60 °C for 24 h.

After workup, 1z was isolated as a clear colorless liquid (0.916 g, 76%):

¹H NMR (500 MHz, CDCl₃) δ 7.53ꢀ7.48 (m, 4H), 6.03ꢀ5.98 (m,

1H), 5.32 (dd, J = 17.5, 1.5 Hz, 1H), 5.22 (dd, J = 10.5, 1.5 Hz, 1H), 4.72

(d, J = 5.5 Hz, 2H), 4.14 (q, J = 7.5 Hz, 2H), 3.75 (s, 2H), 1.21 (t, J = 7.5

Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 168.6, 150.6, 134.3, 133.9,

131.7, 127.8, 123.7, 117.5, 75.5, 61.2, 33.1, 14.1; IR (thin film) 3080,

2981, 2930, 2869, 1733, 1602, 1488, 1021, 920, 829, 525 cm^ꢀ1; HRMS

(ESI) m/z calcd for C₁₄H₁₇NO₃Br (M þ H)^þ326.0392, found

326.0395. The ¹H NMR spectrum showed that <10% of the product mi-

xture was the Z-oxime isomer.

O-Allyl Oxime 1aa. Allylhydroxylamine hydrochloride (0.413 g, 3.77

mmol) was treated with NaOAc (0.309 g, 3.77 mmol) and ethyl

4-iodobenzoyl acetate (1.00 g, 3.14 mmol). The reaction flask was then

attached to a reflux condenser and allowed to stir at 60 °C for 24 h. After

workup, 1aa was isolated as a clear colorless liquid (0.874 g, 75%): ¹H

NMR (500 MHz, CDCl₃) δ 7.70ꢀ7.69 (m, 2H), 7.38ꢀ7.37 (m, 2H),

6.04ꢀ5.96 (m, 1H), 5.32 (dd, J = 17.5, 1.5 Hz, 1H), 5.22 (dd, J = 10.5,

1.5 Hz, 1H), 4.71 (d, J = 5.5 Hz, 2H), 4.13 (q, J = 7.0 Hz, 2H), 3.74 (s,

2H), 1.21 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 168.6,

150.7, 137.7, 134.9, 133.9, 127.9, 117.5, 95.6, 75.5, 61.2, 33.0, 14.1; IR

(thin film) 3079, 2980, 2931, 2869, 1731, 1601, 1486, 1020, 919, 826,

524 cm^ꢀ1; HRMS (ESI) m/z calcd for C₁₄H₁₇NO₃I (M þ H)^þ

374.0253, found 374.0257. The ¹H NMR spectrum showed that

<10% of the product mixture was the Z-oxime isomer.

O-Allyl Oxime 1ee. Allylhydroxylamine hydrochloride (0.637 g, 5.81

mmol) was treated with NaOAc (0.477 g, 5.81 mmol) and ethyl

3-methylbenzoyl acetate (1.00 g, 4.85 mmol). The reaction flask was

then attached to a reflux condenser and allowed to stir at 60 °C for 24 h.

After workup, 1ee was isolated as a clear colorless liquid (1.01 g, 80%):

¹H NMR (500 MHz, CDCl₃) δ 7.47 (s, 1H), 7.42ꢀ7.41 (m, 1H),

7.27ꢀ7.25 (m, 1H), 7.19ꢀ7.18 (m, 1H), 6.05ꢀ5.99 (m, 1H), 5.33 (dd, J

= 17.5, 1.5 Hz, 1H), 5.22 (dd, J = 10.5, 1.5 Hz, 1H), 4.72 (d, J = 5.5 Hz,

2H), 4.15 (q, J = 7.0 Hz, 2H), 3.77 (s, 2H), 2.37 (s, 3H), 1.22 (t, J = 7.0

Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 168.9, 151.8, 138.2, 135.4,

134.1, 130.2, 128.4, 126.9, 123.5, 117.3, 75.3, 61.1, 33.6, 21.5, 14.1; IR

(thin film) 2982, 2920, 2864, 1733, 1602, 1255, 1158, 1021, 926, 786,

692 cm^ꢀ1; HRMS (ESI) m/z calcd. for C₁₅H₂₀NO₃(M þ H)^þ

1

262.1443, found 262.1444. The H NMR spectrum showed that <10%

of the product mixture was the Z-oxime isomer.

O-Allyl Oxime 1ff. Allylhydroxylamine hydrochloride (0.580 g, 5.29

mmol) was treated with NaOAc (0.434 g, 5.29 mmol) and ethyl (3-

chlorobenzoyl) acetate (1.00 g, 4.42 mmol). The reaction flask was then

attached to a reflux condenser and allowed to stir at 60 °C for 24 h. After

1

workup, 1ff was isolated as a clear colorless liquid (1.13 g, 91%): H

O-Allyl Oxime 1bb. Allylhydroxylamine hydrochloride (0.637 g, 5.81

mmol) was treated with NaOAc (0.477 g, 5.81 mmol) and ethyl

4-methylbenzoyl acetate (1.00 g, 4.85 mmol). The reaction flask was

then attached to a reflux condenser and allowed to stir at 60 °C for 24 h.

After workup, 1bb was isolated as a clear colorless liquid (1.20 g, 95%):

¹H NMR (500 MHz, CDCl₃) δ 7.55ꢀ7.53 (m, 2H), 7.19ꢀ7.17 (m,

2H), 6.05ꢀ5.99 (m, 1H), 5.33 (dd, J = 17.5, 1.5 Hz, 1H), 5.22 (dd, J =

10.5, 1.5 Hz, 1H), 4.71 (d, J = 5.5 Hz, 2H), 4.14 (q, J = 7.0 Hz, 2H), 3.77

(s, 2H), 2.36 (s, 3H), 1.22 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz,

CDCl₃) δ 169.0, 151.5, 139.4, 134.2, 132.6, 129.2, 126.2, 117.2, 75.2,

61.1, 33.4, 21.3, 14.1; IR (thin film) 3082, 3031, 2982, 2922, 2869, 1734,

1614, 1157, 1022, 919, 817 cm^ꢀ1; HRMS (ESI) m/z calcd for

C₁₅H₂₀NO₃(M þ H)^þ262.1443, found 262.1441. The ¹H NMR

spectrum showed that <10% of the product mixture was the Z-oxime

isomer.

O-Allyl Oxime 1cc. Allylhydroxylamine hydrochloride (0.526 g, 4.80

mmol) was treated with NaOAc (0.393 g, 4.79 mmol) and ethyl 3-(4-

methoxyphenyl)-3-oxopropionate (0.889 g, 4.00 mmol). The reaction

flask was then attached to a reflux condenser and allowed to stir at 60 °C

for 24 h. After workup, 1cc was isolated as a clear colorless liquid (1.10 g,

99%): ¹H NMR (500 MHz, CDCl₃) δ 7.60ꢀ7.58 (m, 2H), 6.90ꢀ6.88

(m, 2H), 6.04ꢀ5.98 (m, 1H), 5.31 (dd, J = 17.5, 1.5 Hz, 1H), 5.21 (dd, J

= 10.5, 1.5 Hz, 1H), 4.70 (d, J = 5.5 Hz, 2H), 4.14 (q, J = 7.0 Hz, 2H),

3.82 (s, 3H), 3.75 (s, 2H), 1.21 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz,

CDCl₃) δ 169.0, 160.6, 151.1, 134.2, 128.0, 127.6, 117.2, 113.9, 75.1,

NMR (500 MHz, CDCl₃) δ 7.66 (s, 1H), 7.51ꢀ7.48 (m, 1H),

7.35ꢀ7.28 (m, 2H), 6.05ꢀ5.98 (m, 1H), 5.33 (dd, J = 17.5, 1.5 Hz,

1H), 5.22 (dd, J = 10.5, 1.5 Hz, 1H), 4.73 (d, J = 5.5 Hz, 2H), 4.15 (q, J =

7.0 Hz, 2H), 3.75 (s, 2H), 1.22 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz,

CDCl₃) δ 168.5, 150.4, 137.2, 134.6, 133.9, 129.8, 129.4, 126.4, 124.4,

117.6, 75.5, 61.2, 33.2, 14.1; IR (thin film) 3078, 2981, 2932, 2872, 1735,

1603, 1161, 1022, 922, 786, 684 cm^ꢀ1; HRMS (ESI) m/z calcd for

1

C₁₄H₁₇NO₃Cl (M þ H)^þ282.0897, found 282.0896. The H NMR

spectrum showed that <10% of the product mixture was the Z-oxime

isomer.

O-Allyl Oxime 1gg. Allylhydroxylamine hydrochloride (0.505 g, 4.61

mmol) was treated with NaOAc (0.378 g, 4.61 mmol) and ethyl (3-

trifluoromethylbenzoyl) acetate (1.00 g, 3.84 mmol). The reaction flask

was then attached to a reflux condenser and allowed to stir at 60 °C for

24 h. After workup, 1gg was isolated as a clear colorless liquid (1.04 g,

86%): ¹H NMR (500 MHz, CDCl₃) δ 7.92 (s, 1H), 7.82ꢀ7.81 (m, 1H),

7.63ꢀ7.61 (m, 1H), 7.51ꢀ7.48 (m, 1H), 6.05ꢀ5.99 (m, 1H), 5.33 (dd, J

= 17.5, 1.5 Hz, 1H), 5.23 (dd, J = 10.5, 1.5 Hz, 1H), 4.75 (d, J = 5.5 Hz,

2H), 4.15 (q, J = 7.0 Hz, 2H), 3.80 (s, 2H), 1.22 (t, J = 7.0 Hz, 3H); ¹³C

NMR (125 MHz, CDCl₃) δ 168.5, 150.3, 136.2, 133.8, 131.0 (q, J_FC

=

32.5 Hz), 129.5, 129.1, 125.9, 124.0 (d, J_FC= 271.2 Hz), 123.1, 117.7,

75.6, 61.3, 33.2, 14.0; IR (thin film) 2988, 2933, 2871, 1735, 1616, 1249,

1163, 1022, 923, 696 cm^ꢀ1; HRMS (ESI) m/z calcd for C₁₅H₁₇NO₃F₃

(M þ H)^þ316.1161, found 316.1160. The ¹H NMR spectrum showed

that <10% of the product mixture was the Z-oxime isomer.

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The Journal of Organic Chemistry

ARTICLE

O-Allyl Oxime 1hh. Allylhydroxylamine hydrochloride (0.637 g, 5.81

mmol) was treated with NaOAc (0.477 g, 5.81 mmol) and ethyl

2-methylbenzoyl acetate (1.00 g, 4.85 mmol). The reaction flask was

then attached to a reflux condenser and allowed to stir at 60 °C for 24 h.

After workup, 1hh was isolated as a clear colorless liquid (1.07 g, 84%):

¹H NMR (500 MHz, CDCl₃) δ 7.29ꢀ7.19 (m, 4H), 6.04ꢀ5.98 (m,

1H), 5.33 (dd, J = 17.0, 1.5 Hz, 1H), 5.23 (dd, J = 10.5, 1.5 Hz, 1H), 4.69

(d, J = 5.5 Hz, 2H), 4.11 (q, J = 7.0 Hz, 2H), 3.67 (s, 2H), 2.41 (s, 3H),

1.20 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 168.7, 153.1,

136.4, 135.7, 134.2, 130.8, 128.8, 128.6, 125.8, 117.3, 75.0, 61.0, 36.6,

20.2, 14.0; IR (thin film) 3068, 3030, 2980, 2927, 2870, 1735, 1601,

1156, 1019, 921, 757 cm^ꢀ1; HRMS (ESI) m/z calcd. for C₁₅H₂₀NO₃

(M þ H)^þ262.1443, found 262.1439. The ¹H NMR spectrum showed

that <10% of the product mixture was the Z-oxime isomer.

1164, 1023, 922 cm^ꢀ1; HRMS (ESI) m/z calcd for C₈H₁₄NO₃(M þ

H)^þ172.0974, found 172.0974.

O-Allyl Oxime 1ll. Allyl hydroxylamine hydrochloride (0.241 g, 2.20

mmol) was treated with NaOAc (0.246 g, 3.00 mmol) and 4,4-dimethyl-

3-oxopentanenitrile (0.257 g, 2.05 mmol). The reaction flask was then

attached to a reflux condenser and allowed to stir at 60 °C for 12 h. After

workup and flash chromatography (2% EtOAc/2% TEA/hexanes), 1ll

was isolated as a clear, colorless oil (0.305 g, 83%): ¹H NMR (500 MHz,

CDCl₃) δ 6.00ꢀ5.94 (m, 1H), 5.29 (dd, J = 17.0, 1.0 Hz, 1H), 5.18 (dd, J

= 10.5, 1.0 Hz, 1H), 4.60 (d, J = 6.0 Hz, 2H), 3.25 (s, 2H), 1.15 (s, 9H);

¹³C NMR (125 MHz, CDCl₃) δ 154.6, 133.8, 117.6, 115.5, 75.1, 37.3,

27.3, 13.4; IR (thin film) 2969, 2871, 2251, 1720, 1480, 1366, 1122,

1021, 924, 849 cm^ꢀ1; HRMS (ESI) m/z calcd for C₁₀H₁₇N₂O (M þ

1

H)^þ181.1341, found 181.1340. The H NMR spectrum showed that

<10% of the product mixture was the Z-oxime isomer.

O-Allyl Oxime 1ii. Allylhydroxylamine hydrochloride (0.842 g, 7.69

mmol) was treated with NaOAc (0.630 g, 7.68 mmol) and ethyl-3-

cyclopropyl-3-oxopropionate (1.00 g, 6.40 mmol). The reaction flask

was then attached to a reflux condenser and allowed to stir at 60 °C for

24 h. After workup, 1ii was isolated as a clear colorless liquid (1.22 g,

O-Allyl Oxime 1mm. Allyl hydroxylamine hydrochloride (0.082 g,

0.75 mmol) was treated with NaOAc (0.92 mg, 1.1 mmol) and ketone

9mm (0.198 g, 0.750 mmol). The reaction flask was then attached to a

reflux condenser and allowed to stir at 60 °C for 24 h. After workup and

flash chromatography (2% TEA/hexanesꢀ2% EtOAc/2%TEA/hexanes),

1mm was isolated as a clear, colorless oil (0.163 g, 68%, E:Z = 3:1): ¹H

NMR of E-imine isomer (500 MHz, CDCl₃) δ 7.98ꢀ7.94 (m, 2H),

7.66ꢀ7.64 (m, 2H), 7.35ꢀ7.28 (m, 5H), 6.08ꢀ6.00 (m, 1H), 5.32 (d, J

= 18.0 Hz, 1H), 5.24 (d, J = 10.5 Hz, 1H), 4.76 (d, J = 5.5 Hz, 2H), 4.22

(s, 2H); ¹³C NMR of E-imine isomer (125 MHz, CDCl₃) δ 155.4, 141.0,

135.3, 134.4, 134.2, 129.6, 128.9, 128.8, 128.2, 126.4, 117.8, 75.4, 32.9

(the CF₃resonance was not observed due to ¹⁹F splitting); ¹H NMR of

Z-imine isomer (500 MHz, CDCl₃) δ 7.98ꢀ7.94 (m, 2H), 7.66ꢀ7.64

(m, 2H), 7.35ꢀ7.28 (m, 5H), 6.08ꢀ6.00 (m, 1H), 5.32 (d, J = 18.0 Hz,

1

90%, E:Z = 5:1): H NMR of E-imine isomer (500 MHz, CDCl₃) δ

5.95ꢀ5.89 (m, 1H), 5.23 (dd, J = 17.0, 1.5 Hz, 1H), 5.15 (dd, J = 10.5,

1.5 Hz, 1H), 4.51 (d, J = 5.5 Hz, 2H), 4.13 (q, J = 7.0 Hz, 2H), 3.17 (s,

2H), 1.63ꢀ1.58 (m, 1H), 1.24 (t, J = 7.0 Hz, 3H), 0.75 (d, J = 1.0 Hz,

4H); ¹³C NMR of E-imine isomer (125 MHz, CDCl₃) δ 168.9, 154.6,

134.3, 116.9, 74.5, 60.9, 33.4, 14.6, 14.1, 5.0; ¹H NMR of Z-imine isomer

(500 MHz, CDCl₃) δ 6.03ꢀ5.96 (m, 1H), 5.29 (dd, J = 17.0, 1.5 Hz,

1H), 5.19 (dd, J = 10.5, 1.5 Hz, 1H), 4.59 (d, J = 5.5 Hz, 2H), 4.13 (q, J =

7.0 Hz, 2H), 2.90 (s, 2H), 2.34ꢀ2.28 (m, 1H), 1.24 (t, J = 7.0 Hz, 3H),

0.86 (d, J = 1.0 Hz, 2H), 0.70 (d, J = 1.0 Hz, 2H); ¹³C NMR of Z-imine

isomer (125 MHz, CDCl₃) δ 169.7, 155.4, 134.4, 117.1, 74.7, 61.1, 35.9,

14.1, 9.6, 5.1; IR (thin film) 3084, 3002, 2983, 2920, 2871, 1735, 1251,

1156, 1024, 922 cm^ꢀ1; HRMS (ESI) m/z calcd for C₁₁H₁₈NO₃(M þ

H)^þ212.1287, found 212.1286.

1H), 5.24 (d, J = 10.5 Hz, 1H), 4.63 (d, J = 5.5 Hz, 2H), 3.91 (s, 2H); ¹³

C

NMR of Z-imine isomer (125 MHz, CDCl₃) δ 155.4, 141.0, 135.3,

134.4, 134.2, 129.6, 128.9, 128.8, 128.2, 125.4, 117.2, 75.0, 41.5 (the CF₃

resonance was not observed due to ¹⁹F splitting); IR (thin film) 3067,

2920, 1681, 1616, 1321, 1109, 1066, 1017, 923, 692 cm^ꢀ1; HRMS (ESI)

m/z calcd. for C₁₈H₁₆F₃NO (MþH)^þ320.1262, found 320.1255.

Ketone 9 mm:⁴¹. Ketone 9 mm was prepared via a cross coupling

reaction between acetophenone and 4-trifluoromethyl iodobenzene.⁴²

In an inert atmosphere glovebox, a 25 mL round-bottom flask was

charged with Pd(dba)₂(0.045 g, 0.078 mmol) and dppf (0.052 g, 0.094

mmol). To the flask, 6 mL of THF were added and allowed to stir for 5

min before the addition of NaOt-Bu (0.211 g, 2.20 mmol). The

remaining solids were washed from the sides of the flask with 4 mL of

THF. The flask was then removed from the glovebox and placed under

an atmosphere of N₂with a needle. While stirring, 4-iodobenzotrifluor-

ide (0.271 g, 1.00 mmol) was added to the catalyst mixture, followed by

acetophenone (0.120 g, 1.00 mmol). The reaction flask was then

attached to a reflux condenser and the reaction mixture was heated to

75 °C for 2.5 h. The crude product was dry loaded on to silica and

purified by flash chromatography (2% TEA/hexanes ꢀ10% EtOAc/2%

TEA/hexanes) to afford 9mm as a white solid (0.229 g, 76%): ¹H NMR

(500 MHz, CDCl₃) δ 8.02ꢀ7.99 (m, 2H), 7.61ꢀ7.58 (m, 3H),

7.51ꢀ7.47 (m, 2H), 7.40ꢀ7.38 (m, 2H), 4.36 (s, 2H); ¹³C NMR

(125 MHz, CDCl₃) δ 196.7, 164.0, 137.4 (d, J_CꢀF= 271 Hz), 133.5,

130.0, 129.9, 129.2, 128.8, 128.5, 125.6, 45.1; IR (thin film) 3057, 2912,

1675, 1594, 1327, 1112, 994, 870, 754, 687 cm^ꢀ1; HRMS (ESI) m/z

calcd for C₁₅H₁₁OF₃(M þ H)^þ265.0840, found 265.0843; mp

130ꢀ132 °C.

O-Allyl Oxime 1jj. Allylhydroxylamine hydrochloride (0.526 g, 4.80

mmol) was treated with NaOAc (0.394 g, 4.80 mmol) and methyl

4-methyl-3-oxovalerate (0.623 g, 4.32 mmol). The reaction flask was

then attached to a reflux condenser and allowed to stir at 60 °C for 24 h.

After workup, 1jj was isolated as a clear colorless liquid (0.605 g, 70%, E:

Z = 3:1). ¹H NMR of E-imine isomer (500 MHz, CDCl₃) δ 5.96ꢀ5.88

(m, 1H), 5.23 (d, J = 17.0 Hz, 1H), 5.15 (d, J = 10.5 Hz, 1H), 4.51 (d, J =

5.5 Hz, 2H), 3.69 (s, 3H), 3.23 (s, 2H), 2.61ꢀ2.56 (m, 1H), 1.10 (d, J =

7.0 Hz, 6H); ¹³C NMR of E-imine isomer (125 MHz, CDCl₃) δ 169.6,

1

158.0, 134.3, 116.8, 74.4, 52.0, 33.7, 32.3, 19.6; H NMR of Z-imine

isomer (500 MHz, CDCl₃) δ 6.00ꢀ5.95 (m, 1H), 5.27 (d, J = 17.0 Hz,

1H), 5.20 (d, J = 10.5 Hz, 1H), 4.55 (d, J = 5.5 Hz, 2H), 3.70 (s, 3H),

3.35ꢀ3.30 (m, 1H), 3.17 (s, 2H), 1.06 (d, J = 7.0 Hz, 6H); ¹³C NMR of

Z-imine isomer (125 MHz, CDCl₃) δ 170.5, 159.2, 134.4, 117.0, 74.6,

52.1, 36.7, 72.4, 18.8; IR (thin film) 3018, 3002, 2968, 2933, 2871, 1739,

1259, 1160, 1028, 919 cm^ꢀ1; HRMS (ESI) m/z calcd for C₁₀H₁₈NO₃

(M þ H)^þ200.1287, found 200.1285.

O-Allyl Oxime 1kk. Allylhydroxylamine hydrochloride (0.606 g, 5.53

mmol) was treated with NaOAc (0.454 g, 5.53 mmol) and methyl

acetoacetate (0.581 g, 5.00 mmol). The reaction flask was then attached

to a reflux condenser and allowed to stir at 60 °C for 24 h. After workup,

1kk was isolated as a clear colorless liquid (0.674 g, 79%, E:Z = 1:1): ¹H

NMR of E-imine isomer (500 MHz, CDCl₃) δ 5.99ꢀ5.93 (m, 1H), 5.26

(dd, J = 17.5, 1.5 Hz, 1H), 5.18 (dd, J = 10.5, 1.5 Hz,1H), 4.56 (d, J = 5.5

Hz, 2H), 3.71 (s, 3H), 3.22 (s, 2H), 1.94 (s, 3H); ¹³C NMR of E-imine

isomer (125 MHz, CDCl₃) δ 170.1, 151.6, 134.3, 117.2, 74.6, 52.1, 41.2,

14.6; ¹H NMR of Z-imine isomer (500 MHz, CDCl₃) δ 5.99ꢀ5.93 (m,

1H), 5.28 (dd, J = 17.5, 1.5 Hz, 1H), 5.20 (dd, J = 10.5, 1.5 Hz, 1H), 4.54

(d, J = 5.5 Hz, 2H), 3.70 (s, 3H), 3.36 (s, 2H), 1.97 (s, 3H); ¹³C NMR of

Z-imine isomer (125 MHz, CDCl₃) δ 169.3, 150.5, 134.3, 117.0, 74.4,

41.2, 35.2, 20.6; IR (thin film) 3079, 2989, 2952, 2920, 2866, 1737, 1434,

O-Allyl Oxime Ether 1nn. Allyl hydroxylamine hydrochloride (0.61 g,

0.57 mmol) was treated with NaOAc (0.62 g, 0.76 mmol) and ketone

9nn (0.11 g, 0.50 mmol). The reaction flask was then attached to a reflux

condenser and allowed to stir at 60 °C for 24 h. After workup and flash

chromatography (2% TEA/hexanesꢀ5% EtOAc/2%TEA/hexanes),

1

1nn was isolated as a clear, colorless oil (0.11 g, 79%, E:Z = 3:1): H

NMR of E-imine isomer (500 MHz, CDCl₃) δ 7.62ꢀ7.60 (m, 2H),

3211

dx.doi.org/10.1021/jo200061b |J. Org. Chem. 2011, 76, 3203–3221

The Journal of Organic Chemistry

ARTICLE

7.55ꢀ7.52 (m, 2H), 7.35ꢀ7.28 (m, 5H), 6.05ꢀ5.99 (m, 1H), 5.30 (d, J

= 16.0 Hz, 1H), 5.23 (d, J = 11.5 Hz, 1H), 4.74 (d, J = 6.0 Hz, 2H), 4.21

(s, 2H); ¹³C NMR of E-imine isomer (125 MHz, CDCl₃) δ 117.8, 75.4,

32.9; ¹H NMR of Z-imine isomer (500 MHz, CDCl₃) δ 7.62ꢀ7.60 (m,

2H), 7.55ꢀ7.52 (m, 2H), 7.35ꢀ7.28 (m, 5H), 6.05ꢀ5.99 (m, 1H), 5.30

(d, J = 16.0 Hz, 1H), 5.23 (d, J = 11.5 Hz, 1H), 4.13 (d, J = 5.5 Hz, 2H),

3.91 (s, 2H); ¹³C NMR of Z-imine isomer (125 MHz, CDCl₃) δ 117.3,

75.1, 41.8; IR (thin film) 3060, 2923, 2865, 2227, 1607, 1502, 1444,

1020, 922, 694 cm^ꢀ1; HRMS (ESI) m/z calcd for C₁₈H₁₆N₂O (M þ

H)^þ277.1341, found 277.1345.

product was dry loaded on to silica and purified by flash chromatography

(2% TEA/hexanesꢀ10% EtOAc/2% TEA/hexanes) to afford 9oo as a

white solid (0.285 g, 53%): ¹H NMR (500 MHz, CDCl₃) δ 8.02ꢀ7.99

(m, 4H), 7.59ꢀ7.56 (m, 1H), 7.49ꢀ7.44 (m, 2H), 7.35ꢀ7.33 (m, 2H),

4.36 (q, J = 7.0 Hz, 2H), 4.35 (s, 2H), 1.38 (t, J = 7.0 Hz, 3H); ¹³C NMR

(125 MHz, CDCl₃) δ 196.8, 166.4, 139.7, 139.7, 136.4, 133.4, 129.9,

129.6, 129.2, 128.8, 128.6, 60.3, 45.4, 14.4; IR (thin film) 3053, 2982,

2884, 1707, 1683, 1610, 1449, 1104, 997, 755 cm^ꢀ1; HRMS (ESI) m/z

calcd. for C₁₇H₁₆O₃(M þ H)^þ269.1178, found 269.1178; mp

88ꢀ90 °C.

Ketone 9nn⁴³. Ketone 9nn was prepared via a cross-coupling reaction

between acetophenone and 4-cyano iodobenzene.⁴²In an inert atmo-

sphere glovebox, a 25 mL round-bottom flask was charged with Pd-

(dba)₂(0.087 g, 0.150 mmol) and dppf (0.099 g, 0.18 mmol). To the

flask, 6 mL of THF were added and allowed to stir for 5 min before the

addition of NaO-t-Bu (0.211 g, 2.20 mmol). The remaining solids were

washed from the sides of the flask with 4 mL of THF. The flask was then

removed from the glovebox and placed under an atmosphere of N₂with

a needle. While stirring, 4-iodobenzotrifluoride (0.462 g, 2.02 mmol)

was added to the catalyst mixture, followed by acetophenone (0.240 g,

2.0 mmol). The reaction flask was then attached to a reflux condenser

and the reaction mixture was heated to 75 °C for 2.5 h. The crude

product was dry loaded on to silica and purified by flash chromatography

(2% TEA/hexanesꢀ10% EtOAc/2% TEA/hexanes) to afford 9nn as a

white solid (0.238 g, 53%): ¹H NMR (500 MHz, CDCl₃) δ 8.01ꢀ7.99

(m, 2H), 7.63ꢀ7.59 (m, 3H), 7.51ꢀ7.48 (m, 2H), 7.38ꢀ7.36 (m, 2H),

4.36 (s, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 196.2, 140.0, 136.2, 133.7,

132.3, 130.6, 128.9, 128.5, 118.8, 111.0, 45.2, 166.4, 139.7, 139.7, 136.4,

133.4, 129.9, 129.6, 129.2, 128.8, 128.6, 60.3, 45.4, 14.4; IR (thin film)

3063, 2897, 2223, 1686, 1605, 1447, 1338, 1219, 999, 683 cm^ꢀ1; HRMS

(ESI) m/z calcd for C₁₅H₁₁NO (M þ H)^þ222.0919, found 222.0919.

O-Allyl Oxime 1oo. Allyl hydroxylamine hydrochloride (0.128 g, 1.17

mmol) was treated with NaOAc (0.131 g, 1.60 mmol) and ketone 9oo

(0.285 g, 1.06 mmol). The reaction flask was then attached to a reflux

condenser and allowed to stir at 60 °C for 24 h. After workup and flash

chromatography (2% TEA/hexanesꢀ5% EtOAc/2%TEA/hexanes),

1oo was isolated as a clear, colorless oil (0.271 g, 79%, E:Z = 3:1): ¹H

NMR of E-imine isomer (500 MHz, CDCl₃) δ 7.98ꢀ7.94 (m, 2H),

7.66ꢀ7.64 (m, 1H), 7.35ꢀ7.28 (m, 6H), 6.09ꢀ6.02 (m, 1H), 5.34 (dd, J

= 17.5, 1.5 Hz, 1H), 5.25 (dd, J = 10.5, 1.5 Hz, 1H), 4.78 (d, J = 5.5 Hz,

2H), 4.36 (q, J = 7.0 Hz, 2H), 4.24 (s, 2H), 1.38 (t, J = 7.0 Hz, 3H); ¹³C

NMR of E-imine isomer (125 MHz, CDCl₃) δ 166.5, 155.6, 142.2,

134.3, 133.5, 133.3, 130.2, 128.9, 126.2, 118.4, 115.0, 117.6, 75.3, 60.8,

32.9, 14.4; ¹H NMR of Z-imine isomer (500 MHz, CDCl₃) δ 7.98ꢀ7.94

(m, 2H), 7.66ꢀ7.64 (m, 1H), 7.35ꢀ7.28 (m, 6H), 6.09ꢀ6.02 (m, 1H),

5.34 (dd, J = 17.5, 1.5 Hz, 1H), 5.25 (dd, J = 10.5, 1.5 Hz, 1H), 4.65 (d, J

= 5.5 Hz, 2H), 4.36 (q, J = 7 Hz, 2H), 3.92 (s, 2H), 1.38 (t, J = 7 Hz, 3H);

¹³C NMR of Z-imine isomer (125 MHz, CDCl₃) δ 166.5, 155.6, 142.2,

134.5, 133.5, 133.3, 130.2, 128.9, 126.2, 118.4, 117.2, 75.0, 60.9, 41.8,

14.4; IR (thin film) 2980, 2919, 1714, 1611, 1415, 1272, 1102, 1020, 918,

693 cm^ꢀ1; HRMS (ESI) m/z calcd for C₂₀H₂₁NO₃(M þ H)^þ

324.1600, found 324.1599.

O-Allyl Oxime 1pp. Allylhydroxylamine hydrochloride (0.899 g, 8.21

mmol) was treated with NaOAc (0.673 g, 8.20 mmol) and β-tetralone

(1.00 g, 6.84 mmol). The reaction flask was then attached to a reflux

condenser and allowed to stir at 60 °C for 24 h. After workup and flash

chromatography (2% TEA/hexanes), 1pp was isolated as a light orange

liquid (1.25 g, 91%, E:Z = 1:1): ¹H NMR of E-imine isomer (500 MHz,

CDCl₃) δ 7.22ꢀ7.15 (m, 4H), 6.10ꢀ5.99 (m, 1H), 5.36 (dd, J = 17.0,

1.5 Hz, 1H), 5.22 (dd, J = 10.5, 1.5 Hz, 1H), 4.58 (d, J = 5.5 Hz, 2H), 3.54

(s, 2H), 2.85 (t, J = 7.0 Hz, 2H), 2.72 (t, J = 7.0 Hz, 2H); ¹³C NMR of E-

imine isomer (125 MHz, CDCl₃) δ 158.7, 138.4, 134.6, 133.4, 128.9,

1

127.6, 126.7, 126.6, 117.3, 74.6, 35.1, 29.1, 27.7; H NMR of Z-imine

isomer (500 MHz, CDCl₃) δ 7.22ꢀ7.15 (m, 4H), 6.10ꢀ5.99 (m, 1H),

5.32 (dd, J = 17.0, 1.5 Hz, 1H), 5.26 (dd, J = 10.5, 1.5 Hz, 1H), 4.64 (d, J

= 5.5 Hz, 2H), 3.83 (s, 2H), 2.91 (t, J = 7.0 Hz, 2H), 2.59 (t, J = 7.0 Hz,

2H); ¹³C NMR of Z-imine isomer (125 MHz, CDCl₃) δ 158.1, 137.1,

135.0, 134.7, 128.2, 127.3, 126.6, 126.2, 117.1, 74.5, 35.1, 29.4, 24.9; IR

(thin film) 3020, 2921, 2907, 2861, 2847, 1641, 1419, 1032, 912,

741 cm^ꢀ1; HRMS (ESI) m/z calcd for C₁₃H₁₆NO (M þ H)^þ

202.1232, found 202.1230.

General Procedure for the Synthesis of Pyrroles 3cꢀl

(Scheme 4). In an inert atmosphere drybox, a 20 mL scintillation

vial was charged with 0.5 equiv of [(cod)IrCl]₂, 1 equiv of AgOTf, 1

equiv of NaBH₄, and 3 mL of THF. This mixture was then allowed to

stir at 25 °C for 20 min. O-Allyl oxime 1 (10 equiv) was mixed with

2 mL of THF in a small vial. The oxime solution was then transferred

to the scintillation vial containing the 10 mol % iridium mixture. For

pyrroles 3cꢀi, the reaction mixture was then allowed to stir at 25 °C

for 24ꢀ48 h. For pyrroles 3iꢀl, the reaction mixture was then

transferred to a Teflon-sealed, conical vial and allowed to stir at

25 °C for 18 h. The vial was then removed from the glovebox and

heated to 50 °C for 24 h in an aluminum block. After the indicated

reaction times, an aliquot was removed from the reaction mixture and

checked by ¹H NMR spectroscopy to determine if the transformation

had gone to completion. The reaction mixture was then dry-loaded

on to silica gel and 3 was purified by flash chromatography (2% TEA/

hexanes ꢀ40% EtOAc/2% TEA/hexanes).

Pyrrole 3c⁴⁵. The catalyst mixture was prepared by mixing [(cod)-

IrCl]₂(0.0225 g, 0.0335 mmol), AgOTf (0.0168 g, 0.0654 mmol), and

NaBH₄(0.0025 g, 0.066 mmol) in THF for 15 min. Allyl oxime 1c

(0.122 g, 0.609 mmol) was then added to the catalyst mixture, and the

reaction mixture was allowed to stir for 48 h. After flash chromatography

(2% TEA/hexanes ꢀ40% EtOAc/2% TEA/hexanes), 3c was isolated as

a light yellow solid (0.092 g, 83%): ¹H NMR (500 MHz, CDCl₃) δ 8.70

(br s, 1H), 7.69ꢀ7.67 (m, 2H), 7.45ꢀ7.41 (m, 2H), 7.37ꢀ7.33 (m,

1H), 6.60 (m, 1H), 2.23 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 138.5,

130.1, 129.2, 128.5, 125.5, 124.2, 117.4, 116.8, 91.6, 10.7; IR (thin film)

3214, 3042, 2920, 2218, 1584, 1468, 1098, 763, 694, 623 cm^ꢀ1; HRMS

(ESI) m/z calcd for C₁₂H₁₁N₂(M þ H)^þ183.0922, found 183.0920;

mp 120ꢀ122 °C.

Ketone 9oo⁴⁴. Ketone 9oo was prepared via a cross-coupling reaction

between acetophenone and 4-(ethyl ester) iodobenzene.⁴²In an inert

atmosphere glovebox, a 25 mL round-bottom flask was charged with

Pd(dba)₂(0.0863 g, 0.150 mmol) and dppf (0.0998 g, 0.179 mmol). To

the flask, 6 mL of THF were added and allowed to stir for 5 min before

the addition of NaO-t-Bu (0.288 g, 3.00 mmol). The remaining solids

were washed from the sides of the flask with 4 mL of THF. The flask was

then removed from the glovebox and placed under an atmosphere of N₂

with a needle. While stirring, ethyl 4-iodobenzoate (0.553 g, 2.00 mmol)

was added to the catalyst mixture, followed by acetophenone (0.240 g,

2.0 mmol). The reaction flask was then attached to a reflux condenser,

and the reaction mixture was heated to 75 °C for 2.5 h. The crude

Pyrrole 3d:²⁴. The catalyst mixture was prepared by mixing [(cod)-

IrCl]₂(0.0225 g, 0.0335 mmol), AgOTf (0.0168 g, 0.0654 mmol), and

NaBH₄(0.0025 g, 0.066 mmol) in THF for 15 min. Allyl oxime 1d

(0.126 g, 0.588 mmol) was then added to the catalyst mixture, and the

complete reaction mixture was allowed to stir for 24 h. After flash

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ARTICLE

chromatography (2% TEA/hexanes ꢀ40% EtOAc/2% TEA/hexanes),

NaBH₄(0.0025 g, 0.066 mmol) in THF for 15 min. Allyl oxime ether 1i

(0.328 g, 1.27 mmol) was then added to the catalyst mixture, and the

complete reaction mixture was allowed to stir for 36 h. After flash

chromatography (2% TEA/hexanesꢀ40% EtOAc/2% TEA/hexanes),

1

3d was isolated as light yellow solid (0.0847 g, 73%): H NMR (500

MHz, CDCl₃) δ 8.75 (br s, 1H), 7.58ꢀ7.56 (m, 2H), 7.23ꢀ7.21 (m,

2H), 6.57 (s, 1H), 2.37 (s, 3H), 2.21 (s, 3H); ¹³C NMR (125 MHz,

CDCl₃) δ 138.8, 138.6, 129.9, 127.3, 125.4, 124.0, 117.7, 116.5, 91.0,

21.3, 10.7; IR (thin film) 3429, 3295, 3027, 2941, 2917, 2857, 2206,

1641, 1536, 820, 771 cm^ꢀ1; HRMS (ESI) m/z calcd for C₁₃H₁₃N₂(M þ

H)^þ197.1079, found 197.1076; mp 135ꢀ137 °C.

1

3i was isolated as light yellow solid (0.0916 g, 30%): H NMR (500

MHz, CDCl₃) δ 8.98 (br s, 1H), 8.07ꢀ8.05 (m, 2H), 7.76ꢀ7.74 (m,

2H), 6.67 (s, 1H), 3.93 (s, 3H), 2.23 (s, 3H); ¹³C NMR (125 MHz,

CDCl₃) δ 166.6, 136.8, 134.1, 130.5, 129.6, 125.1, 125.0, 117.9, 117.0,

92.9, 52.3, 10.7; IR (thin film) 3251, 3035, 2954, 2926, 2214, 1714, 1613,

1580, 1271, 857, 727 cm^ꢀ1; HRMS (ESI) m/z calcd for C₁₄H₁₃N₂O₂

(M þ H)^þ241.0977, found 241.0969; mp 198ꢀ200 °C.

Pyrrole 3e²⁴. The catalyst mixture was prepared by mixing

[(cod)IrCl]₂(0.0225 g, 0.0335 mmol), AgOTf (16.8 g, 0.0654 mmol),

and NaBH₄(0.0025 g, 0.066 mmol) in THF for 15 min. Allyl oxime 1e

(0.147 g, 0.638 mmol) was then added to the catalyst mixture, and the

complete reaction mixture was allowed to stir for 24 h. After flash chro-

matography (2% TEA/hexanesꢀ40% EtOAc/2% TEA/hexanes), 3e

was isolated as light yellow solid (0.101 g, 74%): ¹H NMR (500 MHz,

CDCl₃) δ 8.83 (br s, 1H), 7.61ꢀ7.59 (m, 2H), 6.93ꢀ6.91 (m, 2H), 6.54

(s, 1H), 3.82 (s, 3H), 2.19 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ

159.8, 138.9, 127.0, 123.7, 122.9, 117.9, 116.2, 114.6, 90.4, 55.4, 10.7; IR

(thin film) 3288, 3133, 3108, 2917, 2840, 2206, 1613, 1536, 1251, 820,

727 cm^ꢀ1; HRMS (ESI) m/z calcd for C₁₃H₁₃N₂O (M þ H)^þ

213.1028, found 213.1026; mp 114ꢀ116 °C.

Pyrrole 3i at 50 °C²⁴. The catalyst mixture was prepared by mixing

[(cod)IrCl]₂(0.0225 g, 0.0335 mmol), AgOTf (0.0168 g, 0.0654

mmol), and NaBH₄(0.0025 g, 0.066 mmol) in THF for 15 min. Allyl

oxime 1i (0.173 g, 0.671 mmol) was then added to the catalyst mixture

and the reaction was allowed to stir for 18 h at 25 °C and then 24 h at

50 °C. After flash chromatography (2% TEA/hexanesꢀ40% EtOAc/2%

TEA/hexanes), 3i was isolated as light yellow solid (0.134 g, 83%): ¹H

NMR (500 MHz, CDCl₃) δ 8.98 (br s, 1H), 8.07ꢀ8.05 (m, 2H),

7.76ꢀ7.74 (m, 2H), 6.67 (s, 1H), 3.93 (s, 3H), 2.23 (s, 3H); ¹³C NMR

(125 MHz, CDCl₃) δ 166.6, 136.8, 134.1, 130.5, 129.6, 125.1, 125.0,

117.9, 117.0, 92.9, 52.3, 10.7; IR (thin film) 3251, 3035, 2954, 2926,

2214, 1714, 1613, 1580, 1271, 857, 727 cm^ꢀ1; HRMS (ESI) m/z calcd

for C₁₄H₁₃N₂O₂(M þ H)^þ241.0977, found 241.0969; mp 198ꢀ200 °C.

Pyrrole 3j. The catalyst mixture was prepared by mixing [(cod)IrCl]₂

(0.0225 g, 0.0335 mmol), AgOTf (0.0168 g, 0.0654 mmol), and NaBH₄

(0.0025 g, 0.066 mmol) in THF for 15 min. Allyl oxime 1j (0.153 mg,

0.701 mmol) was then added to the catalyst mixture, and the reaction

was allowed to stir for 18 h at 25 °C and then 24 h at 50 °C. After flash

chromatography (2% TEA/hexanesꢀ40% EtOAc/2% TEA/hexanes),

Pyrrole 3f²⁴. The catalyst mixture was prepared by mixing [(cod)-

IrCl]₂(0.0225 g, 0.0335 mmol), AgOTf (0.0168 g, 0.0654 mmol), and

NaBH₄(0.0025 g, 0.066 mmol) in THF for 15 min. Allyl oxime ether 1f

(0.168 g, 0.602 mmol) was then added to the catalyst mixture, and the

complete reaction mixture was allowed to stir for 48 h. After flash

chromatography (2% TEA/hexanes ꢀ40% EtOAc/2% TEA/hexanes),

3f was isolated as light yellow solid (0.120 g, 76%): ¹H NMR (500 MHz,

CD₃OD) δ 7.64ꢀ7.62 (m, 2H), 7.60ꢀ7.58 (m, 2H), 6.68 (s, 1H), 2.18

1

(s, 3H) the NH peak did not appear in the H NMR spectrum; ¹³C

1

NMR (125 MHz, CD₃OD) δ 136.9, 131.8, 129.6, 126.8, 123.5, 121.5,

117.8, 117.1, 90.3, 9.2; IR (thin film) 3284, 3133, 2921, 2860, 2218,

1523, 824, 771, 706 cm^ꢀ1; HRMS (ESI) m/z calcd for C₁₂H₁₀N₂Br (M

þ H)^þ261.0027, found 261.0023; mp 212ꢀ215 °C.

3j was isolated as a light yellow solid (0.103 g, 74%): H NMR (500

MHz, CDCl₃) δ 8.70 (br s, 1H), 7.65ꢀ7.62 (m, 2H), 7.16ꢀ7.12 (m,

2H), 6.60 (m, 1H), 2.22 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 162.7

(d, J_CꢀF= 247.5 Hz),154.8, 136.7, 134.5, 129.0, 128.4, 126.1, 117.3, 75.1,

12.8; IR (thin film) 3262, 2929, 2850, 2208, 1606, 1528, 1495, 1229,

1092, 822, cm^ꢀ1; HRMS (ESI) m/z calcd for C₁₂H₁₀FN₂(M þ H)^þ

201.0828, found 201.0831; mp 124ꢀ126 °C.

Pyrrole 3g. The catalyst mixture was synthesized by mixing

[(cod)IrCl]₂(0.0225 g, 0.0335 mmol), AgOTf (16.8 g, 0.0654 mmol),

and NaBH₄(0.0025 g, 0.066 mmol) in THF for 15 min. Allyl oxime 1g

(0.180 g, 0.671 mmol) was then added to the catalyst mixture, and the

reaction mixture was allowed to stir for 36 h. After flash chromatography

(2% TEA/hexanesꢀ40% EtOAc/2% TEA/hexanes), 3g was isolated as

an light yellow solid (0.101 g, 60%): ¹H NMR (500 MHz, CDCl₃) δ 8.59

(br s, 1H), 7.96ꢀ7.94 (m, 1H), 7.81 (s, 1H), 7.63ꢀ7.57 (m, 2H), 6.67

(s, 1H), 2.25 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 136.5, 130.8,

130.0, 129.0, 125.1, 124.8, 121.9, 117.5, 116.6, 93.0, 10.7 (the CF₃and

aryl C-CF₃resonances were not observed due to ¹⁹F-splitting and low

solubility in CDCl₃); IR (thin film) 3265, 2930, 2222, 1587, 1522, 1469,

1314, 1168, 1109, 803 cm^ꢀ1; HRMS (ESI) m/z calcd. for C₁₃H₁₀N₂F₃

(M þ H)^þ251.0796, found 251.0797; mp 178ꢀ180 °C.

Pyrrole 3k. The catalyst mixture was synthesized by mixing [(cod)-

IrCl]₂(0.0225 g, 0.0335 mmol), AgOTf (0.0168 g, 0.0654 mmol), and

NaBH₄(0.0025 g, 0.066 mmol) in THF for 15 min. Allyl oxime 1k

(0.182 g, 0.777 mmol) was then added to the catalyst mixture, and the

reaction mixture was allowed to stir for 18 h and then heated at 50 °C for

24 h. After flash chromatography (2% TEA/hexanesꢀ40% EtOAc/2%

TEA/hexanes), 3k was isolated as a light yellow solid (0.136 g, 81%): ¹H

NMR (500 MHz, CDCl₃) δ 8.45 (br s, 1H), 7.62ꢀ7.58 (m, 2H),

7.42ꢀ7.40 (m, 2H), 6.62 (m, 1H), 2.23 (s, 3H);¹³C NMR (125 MHz,

CDCl₃) δ 137.2, 134.5, 129.5, 128.5, 127.1, 126.7, 124.5, 117.0, 92.2,

10.7; IR (thin film) 3252, 2917, 2852, 2215, 1646, 1457, 1083, 948, 820,

709 cm^ꢀ1; HRMS (ESI) m/z calcd. for C₁₂H₉ClN₂(M þ H)^þ

217.0533, found 217.0534; mp 177ꢀ179 °C.

Pyrrole 3h. The catalyst mixture was synthesized by mixing [(cod)-

IrCl]₂(0.0225 g, 0.0335 mmol), AgOTf (0.0168 g, 0.0654 mmol), and

NaBH₄(0.00225 g, 0.066 mmol) in THF for 15 min. Allyl oxime 1h

(0.122 g, 0.480 mmol) was then added to the catalyst mixture, and the

reaction mixture was allowed to stir for 36 h. After flash chromatography

(2% TEA/hexanesꢀ40% EtOAc/2% TEA/hexanes), 3h was isolated as

a light yellow solid (0.0895 g, 79%): ¹H NMR (500 MHz, CDCl₃) 8.37

(br s, 1H), 7.40ꢀ7.38 (m, 1H), 7.35 (s, 1H), 7.14ꢀ7.12 (m, 1H), 6.56

(s, 1H), 2.80ꢀ2.79 (m, 4H), 2.22 (s, 3H), 1.83ꢀ1.80 (m, 4H); ¹³C

NMR (125 MHz, CDCl₃) δ 138.9, 138.1, 138.0, 130.0, 127.3, 126.1,

124.1, 122.7, 117.3, 116.1, 91.3, 29.4, 29.3, 23.0 (2C, coincidental CH₂),

10.7; IR (thin film) 3268, 2917, 2852, 2217, 1736, 1580, 1467, 1106, 826,

713 cm^ꢀ1; HRMS (ESI) m/z calcd for C₁₆H₁₉N₂O (M þ H)^þ

237.1392, found 237.1391; mp 174ꢀ176 °C.

Pyrrole 3l. The catalyst mixture was synthesized by mixing [(cod)-

IrCl]₂(0.0225 g, 0.0335 mmol), AgOTf (0.0168 g, 0.0654 mmol), and

NaBH₄(0.0025 g, 0.066 mmol) in THF for 15 min. Allyl oxime 1l (0.129

g, 0.678 mmol) was then added to the catalyst mixture, and the reaction

mixture was allowed to stir at 25 °C for 18 h and then at 50 °C for 24 h.

After flash chromatography (2% TEA/hexanesꢀ40% EtOAc/2% TEA/

1

hexanes), 3l was isolated as a light yellow solid (0.0742 g, 64%): H

NMR (500 MHz, CDCl₃) δ 8.76 (br s, 1H), 7.40 (s, 1H), 6.91ꢀ6.90 (m,

1H), 6.54 (s, 1H), 6.50ꢀ6.49 (m, 1H), 2.20 (s, 3H); ¹³C NMR (125

MHz, CDCl₃) δ 144.8, 141.7, 130.2, 123.5, 116.5, 116.2, 112.1, 107.0,

90.0, 10.6; IR (thin film) 3265, 2925, 2214, 1614, 1561, 1441, 1092,

1017, 887, 733 cm^ꢀ1; HRMS (ESI) m/z calcd for C₁₀H₉N₂O (MþH)^þ

173.0715, found 173.0715; mp 102ꢀ104 °C.

Pyrrole 3i²⁴. The catalyst mixture was prepared by mixing [(cod)-

IrCl]₂(0.0225 g, 0.0335 mmol), AgOTf (0.0168 g, 0.0654 mmol), and

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ARTICLE

General Procedure for the Synthesis of Pyrroles 4a,b and

4mꢀv (Scheme 5). A 10 mL reaction flask with a Teflon stopper was

flushed with N₂and charged with 1 equiv of 2 dissolved in 4 mL of

dioxane (dried over CaH₂and isolated by vacuum transfer) and ∼15 4 Å

molecular sieves. The flask was then sealed and heated to 75 °C for 18 h.

The reaction mixture was then dry-loaded onto ∼2 mL of silica gel. The

crude product was purified by flash chromatography using a solvent

gradient (2% TEA/hexanesꢀ20% EtOAc/2% TEA/hexanes). The

fractions containing 3 were combined, and the solvent was removed

under vacuum using a rotary evaporator. The product was then

transferred to a scintillation vial and all remaining volatiles were removed

under high vacuum.

(m, 1H), 7.15ꢀ7.12 (m, 1H), 7.01ꢀ6.95 (m, 2H), 6.53 (s, 1H), 5.97 (s,

1H), 3.97 (s, 3H), 2.37 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 154.5,

128.4, 127.9, 126.2, 126.1, 121.4, 111.6, 106.8, 106.5, 55.7, 13.4 (one

quaternary carbon was not visible even with high signal-to-noise); IR

(thin film) 3450, 3104, 3064, 2958, 2917, 1589, 1507, 1231, 816,

743 cm^ꢀ1; HRMS (ESI) m/z calcd for C₁₂H₁₄NO (M þ H)^þ

188.1075, found 188.1078.

Pyrrole 4q⁴⁹. Vinyl oxime ether 2q (143 mg, 0.817 mmol) was

dissolved in dioxane with 4 Å molecular sieves and heated at 75 °C for 18

h. After workup and purification, 4q was isolated as a light yellow solid

1

(75.1 mg, 58%): H NMR (500 MHz, CDCl₃) δ 8.11 (br s, 1H),

7.46ꢀ7.44 (m, 2H), 7.38ꢀ7.34 (m, 2H), 7.21ꢀ7.17 (m, 1H), 6.43 (s,

1H), 5.98 (s, 1H), 2.35 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 133.0,

130.8, 129.1, 128.9, 125.7, 123.4, 108.0, 106.2, 13.2; IR (thin film) 3437,

3395, 3050, 2913, 2861, 1606, 1587, 1251, 893, 741 cm^ꢀ1; HRMS (ESI)

m/z calcd for C₁₁H₁₂N (M þ H)^þ158.0970, found 158.0968; mp

85ꢀ88 °C.

Pyrrole 4a⁴⁶. Vinyl oxime ether 2a (117 mg, 0.570 mmol) was dis-

solved in dioxane with 4 Å molecular sieves and heated at 75 °C for 18 h.

After workup and purification, 4a was isolated as a light yellow solid (68.3

mg, 64%): ¹H NMR (500 MHz, CDCl₃) δ 8.01 (br s, 1H), 7.37ꢀ7.35

(m, 2H), 6.90ꢀ6.89 (m, 2H), 6.28 (s, 1H), 5.93 (s, 1H), 3.82 (s, 3H),

2.35 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 157.9, 130.9, 128.4, 126.2,

124.8, 114.3, 107.7, 105.0, 55.4, 13.2; IR (thin film) 3437, 3395, 3050,

2920, 2835, 1616, 1590, 1245, 822, 764 cm^ꢀ1; HRMS (ESI) m/z calcd

for C₁₂H₁₄NO (M þ H)^þ188.1075, found 188.1079; mp 126ꢀ129 °C.

Pyrrole 4b⁴⁷. Vinyl oxime ether 2b (130 mg, 0.524 mmol) was disso-

lved in dioxane with 4 Å molecular sieves and heated at 75 °C for 24 h.

After workup and column chromatography, 4b was isolated as a light

yellow amphorous solid (72 mg, 60%): ¹H NMR (500 MHz, CDCl₃) δ

8.41 (br s, 1H), 7.56ꢀ7.54 (m, 2H), 7.37ꢀ7.30 (m, 3H), 6.38 (s, 1H),

4.16 (q, J = 7.0 Hz, 2H), 2.24 (s, 3H), 1.23 (t, J = 7.0 Hz, 3H); ¹³C NMR

(125 MHz, CDCl₃) δ 165.3, 136.1, 132.3, 128.9, 128.0, 127.9, 127.8,

112.0, 109.5, 59.6, 14.3, 12.7; IR (thin film) 3292, 3028, 2980, 2925,

1666, 1593, 1528, 1222, 814, 762 cm^ꢀ1; HRMS (ESI) m/z calcd for

C₁₄H₁₆NO₂(M þ H)^þ230.1181, found 230.1179.

Pyrrole 4r⁵⁰. Vinyl oxime ether 2r (145 mg, 0.579 mmol) was dis-

solved in dioxane with 4 Å molecular sieves and heated at 75 °C for 18 h.

After workup and column chromatography, 4r was isolated as a light

yellow amorphous solid (81.4 mg, 60%): ¹H NMR (500 MHz, CDCl₃)

δ 7.95 (br s, 1H), 7.38ꢀ7.18 (m, 10H), 6.12 (s, 1H), 2.37 (s, 3H); ¹³C

NMR (125 MHz, CDCl₃) δ 136.8, 133.6, 128.6, 128.5, 128.4, 128.3,

127.3, 126.9, 126.4, 125.6, 122.3, 109.0, 13.0; IR (thin film) 3414, 3056,

3020, 2916, 1596, 1499, 1076, 803, 744 cm^ꢀ1; HRMS (ESI) m/z calcd

for C₁₇H₁₆N (M þ H)^þ234.1283, found 234.1272.

Pyrrole 4s⁵¹. Vinyl oxime ether 2s (141 mg, 0.641 mmol) was disso-

lved in dioxane with 4 Å molecular sieves and heated at 75 °C for 18 h.

After workup and column chromatography, 4s was isolated as a light

yellow oil (78.2 mg, 61%): ¹H NMR (500 MHz, CDCl₃) δ 7.72 (br s,

1H), 7.33ꢀ7.31 (m, 2H), 6.95ꢀ6.93 (m, 2H), 5.82 (s, 1H), 3.84 (s, 3H),

2.29 (s, 3H), 2.20 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 157.7, 127.5,

126.8, 126.7, 126.7, 115.3, 114.1, 109.9, 55.3, 13.0, 12.3; IR (thin film)

3395, 3304, 2937, 2835, 1606, 1567, 1239, 819, 764 cm^ꢀ1; HRMS (ESI)

m/z calcd. for C₁₃H₁₆NO (M þ H)^þ202.1232, found 202.1240.

Pyrrole 4t⁵². Vinyl oxime ether 2t (197 mg, 1.120 mmol) was disso-

lved in dioxane with 4 Å molecular sieves and heated at 75 °C for 24 h.

After workup and column chromatography, 4t was isolated as a light

yellow solid (90.0 mg, 51%): ¹H NMR (500 MHz, CDCl₃) δ 8.89ꢀ8.74

(br s, 1H), 8.49ꢀ8.48 (m, 2H), 7.30ꢀ7.29 (m, 2H), 6.64 (s, 1H), 6.01

(s, 1H), 2.35 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 150.1, 139.6,

131.8, 127.7, 117.2, 109.6, 109.0, 13.3; IR (thin film) 3196, 3128, 2930,

2852, 1603, 1587, 819, 780 cm^ꢀ1; HRMS (ESI) m/z calcd for C₁₀H₁₁N₂

(M þ H)^þ159.0922, found 159.0915; mp 210ꢀ213 °C.

Pyrrole 4m. Vinyl oxime ether 2m (132 mg, 0.599 mmol) was disso-

ꢀ

lved in dioxane with 4 ÅÅ molecular sieves and heated at 75 °C for 18 h.

After workup and purification, 4m was isolated as a light yellow oil (51

mg, 42%): ¹H NMR (500 MHz, CDCl₃) δ 8.38 (bs, 1H), 7.83 (d, J = 9

Hz, 2H), 7.50 (d, J = 9 Hz, 2H), 6.63 (s, 1H), 6.04 (s, 1H), 2.37 (s, 3H);

¹³C NMR (125 MHz, CDCl₃) δ 144.9, 138.9, 132.6, 128.6, 124.8, 122.7,

110.6, 109.7, 13.5; IR (thin film) 3361, 2919, 1597, 1512, 1495, 1321,

1265, 1220, 1109, 1045, 850, 750 cm^ꢀ1; HRMS (ESI) m/z calcd for

C₁₁H₁₀N₂O₂(M þ H)^þ203.0821, found 203.0822.

Pyrrole 4n⁴⁸. Vinyl oxime ether 2n (227 mg, 0.897 mmol) was disso-

lved in dioxane with 4 Å molecular sieves and heated at 75 °C for 18 h.

After workup and purification, 4n was isolated as a light yellow solid (117

mg, 55%): ¹H NMR (500 MHz, CDCl₃) δ 8.07 (br s, 1H), 7.46ꢀ7.44

(m, 2H), 7.30ꢀ7.28 (m, 2H), 6.39 (s, 1H), 5.96 (s, 1H), 2.33 (s, 3H);

¹³C NMR (125 MHz, CDCl₃) δ 131.9, 129.7, 124.8, 119.0, 108.3, 106.8,

13.2 (two quaternary carbons were not visible even with high signal-to-

Pyrrole 4u (Minor). Vinyl oxime ether 2u (122 mg, 0.557 mmol) was

dissolved in dioxane with 4 Å molecular sieves and heated at 75 °C for 24

h. After workup and purification, 4u (minor) was isolated as a light

yellow oil (13 mg, 12%): ¹H NMR (500 MHz, CDCl₃) δ 7.47 (br s, 1H),

7.15ꢀ7.13 (m, 2H), 6.86ꢀ6.85 (m, 2H), 5.83 (s, 1H), 5.78 (s, 1H), 3.87

(s, 2H), 3.80 (s, 3H), 2.20 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ

158.2, 131.8, 129.8, 129.7, 126.9, 114.0, 106.3, 105.7, 55.3, 33.3, 13.1; IR

(thin film) 3365, 3055, 2994, 2966, 2935, 1600, 1508, 1262, 816,

731 cm^ꢀ1; HRMS (EI) m/z calcd for C₁₃H₁₅NO (M)^þ201.1154,

found 201.1156.

noise); IR (thin film) 3385, 2919, 2848, 1606, 1503, 827, 768, 662 cm^ꢀ1

;

HRMS (ESI) m/z calcd for C₁₁H₁₁NBr (M)^þ236.0075, found

236.0073; mp 102ꢀ105 °C.

Pyrrole 4o⁴⁸. Vinyl oxime ether 2o (130 mg, 0.535 mmol) was disso-

lved in dioxane with 4 Å molecular sieves and heated at 75 °C for 24 h.

After workup and purification, 4o was isolated as a light yellow solid

1

(55.5 mg, 46%): H NMR (500 MHz, CDCl₃) δ 8.18 (br s, 1H),

Pyrrole 4u (Major). Vinyl oxime ether 2u (122 mg, 0.557 mmol) was

dissolved in dioxane with 4 Å molecular sieves and heated at 75 °C for 24

h. After workup and column chromatography, 4u (major) was isolated

as a light yellow oil (38 mg, 34%): ¹H NMR (500 MHz, CDCl₃) δ 7.64

(br s, 1H), 7.36ꢀ7.34 (m, 2H), 6.96ꢀ6.94 (m, 2H), 5.99 (s, 1H), 3.85

(s, 3H), 2.36 (s, 3H), 2.28 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ

157.3, 130.0, 128.6, 125.7, 121.8, 120.6, 113.8, 106.3, 55.3, 12.9, 12.5; IR

(thin film) 3437, 3369, 3055, 2935, 2911, 2838, 1608, 1532, 1267, 832,

731 cm^ꢀ1; HRMS (ESI) m/z calcd for C₁₃H₁₆NO (M þ H)^þ202.1232,

found 202.1230.

7.58ꢀ7.56 (m, 2H), 7.50ꢀ7.48 (m, 2H), 6.52 (s, 1H), 6.00 (s, 1H), 2.36

(s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 136.1, 130.6, 129.3, 127.1 (q,

J_CꢀF= 33 Hz), 126.6 (q, J_CꢀF= 270 Hz), 125.9, 123.0, 108.6, 108.1,

13.2; IR (thin film) 3395, 1616, 1528, 1480, 1326, 1105, 832, 777 cm^ꢀ1

;

HRMS (ESI) m/z calcd. for C₁₂H₁₁NF₃(M þ H)^þ226.0844, found

226.0836; mp 130ꢀ132 °C.

Pyrrole 4p. Vinyl oxime ether 2p (95.5 mg, 0.465 mmol) was disso-

lved in dioxane with 4 Å molecular sieves and heated at 75 °C for 18 h.

After workup and purfication, 4p was isolated as a light yellow oil (49.3

mg, 57%): ¹H NMR (500 MHz, CDCl₃) δ 9.45 (br s, 1H), 7.65ꢀ7.64

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Pyrrole 4v. Vinyl oxime ether 2v (40.0 mg, 0.236 mmol) was

dissolved in dioxane with 4 Å molecular sieves and heated at 75 °C

for 24 h. After workup and column chromatography, 4v was isolated as a

light yellow oil (26 mg, 73%): ¹H NMR (500 MHz, CDCl₃) δ 7.50 (br s,

1H), 5.79ꢀ5.76 (m, 2H), 2.41 (s, 2H), 2.25 (s, 3H), 0.96 (s, 9H);

¹³C NMR (125 MHz, CDCl₃) δ 128.9, 125.8, 107.4, 105.7, 42.6, 31.6,

28.2, 13.1; IR (thin film) 3373, 1949, 2906, 2864, 1653, 1593, 1508,

1476, 1390, 1357, 1236, 1039 cm^ꢀ1; HRMS (ESI) m/z calcd for

C₁₀H₁₈N (M þ H)^þ152.1439, found 152.1432.

Pyrrole 4r⁵⁰. The catalyst mixture was prepared by mixing

[(cod)IrCl]₂(0.0225 g, 0.0335 mmol), AgOTf (0.0168 g, 0.654 mmol),

and NaBH₄(0.0025 g, 0.66 mmol) in THF for 15 min. Allyl oxime 1r

(0.138 g, 0.550 mmol) was then added to the catalyst mixture, and the

complete reaction mixture was allowed to stir for 24 h and then

transferred to a Teflon-sealed reaction flask and heated to 75 °C for

15 h. After flash chromatography (2% TEA/hexanesꢀ40% EtOAc/2%

TEA/hexanes), 4r was isolated as light yellow amphorous solid (0.052 g,

41%): ¹H NMR (500 MHz, CDCl₃) δ 7.95 (br s, 1H), 7.38ꢀ7.18 (m,

10H), 6.12 (s, 1H), 2.37 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 136.8,

133.6, 128.6, 128.5, 128.4, 128.3, 127.3, 126.9, 126.4, 125.6, 122.3, 109.0,

13.0; IR (thin film) 3414, 3056, 3020, 2916, 1596, 1499, 1076, 803,

744 cm^ꢀ1; HRMS (ESI) m/z calcd for C₁₇H₁₆N (M þ H)^þ234.1283,

found 234.1272.

General Procedure for the Synthesis of Pyrroles 4a, 4b,

4m, 4r, 4s, and 4w (Scheme 6). The general procedure used for the

preparation of 2 was used to prepare the reaction mixtures. After 24 h at

25 °C, the reaction mixtures were transferred to 10 mL Teflon-sealed

reaction flasks, charged with ∼15 4 Å molecular sieves, and heated to

75 °C for 15 h. The reaction mixtures were then transferred to

scintillation vials and dry-loaded on ∼3 mL of silica gel. The product

was then purified by flash chromatography as described in the general

procedure for the synthesis of 4a, 4b, and 4mꢀv (Scheme 5). The mass

balance for these transformations is assumed to be highly colored

polymeric pyrrole materials that were observed to remain coordinated

to the silica gel.

Pyrrole 4s⁵¹. The catalyst mixture was prepared by mixing [(cod)-

IrCl]₂(0.0225 g, 0.0335 mmol), AgOTf (0.0168 g, 0.0654 mmol), and

NaBH₄(0.0025 g, 0.066 mmol) in THF for 15 min. Allyl oxime ether 1s

(0.130 g, 0.594 mmol) was then added to the catalyst mixture, and the

complete reaction mixture was allowed to stir for 24 h and then

transferred to a Teflon-sealed reaction flask and heated to 75 °C for

15 h. After flash chromatography (2% TEA/hexanesꢀ40% EtOAc/2%

TEA/hexanes), 4s was isolated as light yellow oil (0.0478 g, 40%): ¹H

NMR (500 MHz, CDCl₃) δ 7.72 (br s, 1H), 7.33ꢀ7.31 (m, 2H),

6.95ꢀ6.93 (m, 2H), 5.82 (s, 1H), 3.84 (s, 3H), 2.29 (s, 3H), 2.20 (s,

3H); ¹³C NMR (125 MHz, CDCl₃) δ 157.7, 127.5, 126.8, 126.7, 126.7,

115.3, 114.1, 109.9, 55.3, 13.0, 12.3; IR (thin film) 3395, 3304, 2937,

2835, 1606, 1567, 1239, 819, 764 cm^ꢀ1; HRMS (ESI) m/z calcd for

C₁₃H₁₆NO (M þ H)^þ202.1232, found 202.1240.

Pyrrole 4a⁴⁶. The catalyst mixture was prepared by mixing [(cod)-

IrCl]₂(0.0225 g, 0.0335 mmol), AgOTf (0.0168 g, 0.0665 mmol), and

NaBH₄(0.0025 g, 0.066 mmol) in THF for 15 min. Allyl oxime 1a

(0.133 g, 0.649 mmol) was then added to the catalyst mixture, and the

complete reaction mixture was allowed to stir for 24 h and then

transferred to a Teflon-sealed reaction flask and heated to 75 °C for

15 h. After flash chromatography (2% TEA/hexanesꢀ40% EtOAc/2%

TEA/hexanes), 4a was isolated as light yellow solid (0.0562 g, 46%): ¹H

NMR (500 MHz, CDCl₃) δ 8.01 (br s, 1H), 7.37ꢀ7.35 (m, 2H),

6.90ꢀ6.89 (m, 2H), 6.28 (s, 1H), 5.93 (s, 1H), 3.82 (s, 3H), 2.35 (s,

3H); ¹³C NMR (125 MHz, CDCl₃) δ 157.9, 130.9, 128.4, 126.2, 124.8,

114.3, 107.7, 105.0, 55.4, 13.2; IR (thin film) 3437, 3395, 3050, 2920,

2835, 1616, 1590, 1245, 822, 764 cm^ꢀ1; HRMS (ESI) m/z calcd. for

C₁₂H₁₄NO (M þ H)^þ188.1075, found 188.1079; mp 126ꢀ129 °C.

Pyrrole 4b⁴⁷. The catalyst mixture was prepared by mixing

[(cod)IrCl]₂(0.0225 g, 0.0335 mmol), AgOTf (0.0168 g, 0.0654

mmol), and NaBH₄(0.0025 g, 0.066 mmol) in THF for 15 min. Allyl

oxime 1b (0.128 mg, 0.518 mmol) was then added to the catalyst

mixture, and the complete reaction mixture was allowed to stir for 24 h

and then transferred to a Teflon-sealed reaction flask and heated to

75 °C for 15 h. After flash chromatography (2% TEA/hexanesꢀ40%

EtOAc/2% TEA/hexanes), 4b was isolated as light yellow oil (0.0478 g,

40%): ¹H NMR (500 MHz, CDCl₃) δ 8.41 (br s, 1H), 7.56ꢀ7.54 (m,

2H), 7.37ꢀ7.30 (m, 3H), 6.38 (s, 1H), 4.16 (q, J = 7.0 Hz, 2H), 2.24 (s,

3H), 1.23 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 165.3,

136.1, 132.3, 128.9, 128.0, 127.9, 127.8, 112.0, 109.5, 59.6, 14.3, 12.7; IR

(thin film) 3292, 3028, 2980, 2925, 1666, 1593, 1528, 1222, 814,

762 cm^ꢀ1; HRMS (ESI) m/z calcd for C₁₄H₁₆NO₂(M þ H)^þ

230.1181, found 230.1179.

Pyrrole 4w⁵³. The catalyst mixture was prepared by mixing [(cod)-

IrCl]₂(0.0225 g, 0.0335 mmol), AgOTf (0.0168 g, 0.0654 mmol), and

NaBH₄(0.0025 g, 0.066 mmol) in THF for 15 min. Allyl oxime ether 1w

(0.120 g, 0.78 mmol) was then added to the catalyst mixture and the

complete reaction mixture was allowed to stir for 24 h and then

transferred to a Teflon-sealed reaction flask and heated to 75 °C for

15 h. After flash chromatography (2% TEA/hexanesꢀ40% EtOAc/2%

TEA/hexanes), 4w was isolated as light yellow oil (0.044 g, 42%): ¹H

NMR (500 MHz, CDCl₃) δ 7.40 (br s, 1H), 5.65 (s, 1H), 2.46ꢀ2.54 (m,

4H), 2.24 (s, 3H), 1.73ꢀ1.83 (m, 4H); ¹³C NMR (125 MHz, CDCl₃) δ

125.8, 125.4, 117.0, 105.1, 23.9, 23.6, 22.9, 22.7, 13.0; IR (thin film)

3294, 3206, 2926, 2855, 1632, 1443, 864 cm^ꢀ1; HRMS (EI) m/z calcd

for C₉H₁₄N (M þ H)^þ136.1, found 136.1.

General Procedure for the Synthesis of Pyrroles 3b, 3xꢀkk,

and 3mmꢀpp (Schemes 10 and 14). In an inert atmosphere

drybox, a 20 mL scintillation vial was charged with 0.5 equiv of [(cod)IrCl]₂,

1 equiv of AgOTf, 1 equiv of NaBH₄, and 3 mL of THF. This mixture was

then allowed to stir at 25 °C for 20 min. O-Allyl oxime 1 (10 equiv) was

mixed with 2 mL of THF in a small vial. The oxime solution was then

transferred to the scintillation vial containing the 10 mol % iridium

mixture, and DBU (10 equiv) was added after the substrate. The reaction

mixture was then transferred to a Teflon-sealed, conical vial and allowed

to stir at 25 °C for 1 h. The vial was then removed from the glovebox and

heated to 75 °C for 24 h in an aluminum block. The reaction mixture was

then dry-loaded on to silica gel and 3 was purified by flash chromatog-

raphy (2% TEA/hexanesꢀ40% EtOAc/2% TEA/hexanes).

Pyrrole 4m. The catalyst mixture was prepared by mixing [(cod)-

IrCl]₂(0.045 g, 0.067 mmol), AgOTf (0.034 g, 0.13 mmol), and NaBH₄

(0.005 g, 0.13 mmol) in THF for 15 min. Allyl oxime 1m (0.290 g, 1.32

mmol) was then added to the catalyst mixture, and the complete reaction

mixture was allowed to stir for 24 h and then transferred to a Teflon-

sealed reaction flask and heated to 75 °C for 15 h. After flash chro-

matography (2% TEA/hexanesꢀ40% EtOAc/2% TEA/hexanes), 4m

Pyrrole 3b⁵⁴. The catalyst mixture was prepared by mixing [(cod)-

IrCl]₂(0.0225 g, 0.0335 mmol), AgOTf (0.0168 g, 0.0654 mmol), and

NaBH₄(0.0025 g, 0.066 mmol) in THF for 15 min. Allyl oxime 1b

(0.165 g, 0.667 mmol) was then added to the catalyst mixture, followed

by DBU (0.145 g, 0.952 mmol). The reaction mixture was allowed to stir

for 1 h at 25 °C and then heated to 75 °C for 24 h. After flash

chromatography (2% TEA/hexanesꢀ40% EtOAc/2% TEA/hexanes),

3b was isolated as light yellow solid (0.132 g, 86%): ¹H NMR (500 MHz,

CDCl₃) δ 8.46 (br s, 1H), 7.43ꢀ7.40 (m, 2H), 7.04ꢀ7.01 (m, 2H),

6.50 (s, 1H), 4.14 (q, J = 7.0 Hz, 2H), 2.30 (s, 3H), 1.21 (t, J = 7.0 Hz,

1

was isolated as light yellow oil (0.107 g, 40%): H NMR (500 MHz,

CDCl₃) δ 8.38 (bs, 1H), 7.83 (d, J = 9 Hz, 2H), 7.50 (d, J = 9 Hz, 2H),

6.63 (s, 1H), 6.04 (s, 1H), 2.37 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ

144.9, 138.9, 132.6, 128.6, 124.8, 122.7, 110.6, 109.7, 13.5; IR (thin film)

3361, 2919, 1597, 1512, 1495, 1321, 1265, 1220, 1109, 1045, 850,

750 cm^ꢀ1; HRMS (ESI) m/z calcd for C₁₁H₁₀N₂O₂(M þ H)^þ

203.0821, found 203.0822.

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The Journal of Organic Chemistry

ARTICLE

3H); ¹³C NMR (125 MHz, CDCl₃) δ 166.0, 137.6, 133.1, 129.1, 128.9,

127.9, 122.5, 116.8, 111.3, 59.4, 14.1, 12.6; IR (thin film) 3301, 2981,

2925, 2857, 1670, 1432, 1284, 1137, 1081, 759 cm^ꢀ1; HRMS (ESI) m/z

calcd for C₁₄H₁₆NO₂(M þ H)^þ230.1181, found 230.1183; mp

90ꢀ92 °C.

MHz, CDCl₃) δ 8.38 (br s, 1H), 7.68ꢀ7.66 (m, 2H), 7.20ꢀ7.19 (m,

2H), 6.53 (s, 1H), 4.16 (q, J = 7.0 Hz, 2H), 2.29 (s, 3H), 1.21 (t, J = 7.0

Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 165.7, 137.1, 136.3, 132.4,

130.8, 122.8, 117.1, 111.7, 93.8, 59.6, 14.2, 12.7; IR (thin film) 3356,

3022, 2970, 2944, 1670, 1432, 1284, 1095, 861, 537 cm^ꢀ1; HRMS (ESI)

m/z calcd for C₁₄H₁₅NO₂I (M þ H)^þ356.0148, found 356.0148; mp

116ꢀ122 °C.

Pyrrole 3b from 2b:⁵⁴. O-Vinyl oxime 2b (0.127 g, 0.512 mmol) was

dissolved in 3 mL of THF and mixture with DBU (0.112 g, 0.952 mmol).

The reaction mixture was then transferred to a Teflon-sealed reaction

flask at allowed to heat at 75 °C for 24 h. After column chromatography,

Pyrrole 3bb. The catalyst mixture was prepared by mixing [(cod)-

IrCl]₂(0.0225 g, 0.0335 mmol), AgOTf (0.0168 g, 0.0654 mmol), and

NaBH₄(0.0025 g, 0.066 mmol) in THF for 15 min. Allyl oxime 1bb

(0.175 g, 0.670 mmol) was then added to the catalyst mixture followed

by DBU (0.145 g, 0.952 mmol). The reaction mixture was allowed to stir

for 1 h at 25 °C and then heated to 75 °C for 24 h. After flash

chromatography (2% TEA/hexanesꢀ40% EtOAc/2% TEA/hexanes),

1

3b was isolated as a light yellow solid (0.105 g, 89%): H NMR (500

MHz, CDCl₃) δ 8.46 (br s, 1H), 7.43ꢀ7.40 (m, 2H), 7.04ꢀ7.01 (m,

2H), 6.50 (s, 1H), 4.14 (q, J = 7.0 Hz, 2H), 2.30 (s, 3H), 1.21 (t, J = 7.0

Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 166.0, 137.6, 133.1, 129.1,

128.9, 127.9, 122.5, 116.8, 111.3, 59.4, 14.1, 12.6.

1

Pyrrole 3x. The catalyst mixture was prepared by mixing [(cod)IrCl]₂

(0.0225 g, 0.0335 mmol), AgOTf (0.0168 g, 0.0654 mmol), and NaBH₄

(0.0025 g, 0.066 mmol) in THF for 15 min. Allyl oxime 1x (0.177 g,

0.668 mmol) was then added to the catalyst mixture, followed by DBU

(0.145 g, 0.952 mmol). The reaction mixture was allowed to stir for 1 h at

25 °C and then heated to 75 °C for 24 h. After flash chromatography (2%

TEA/hexanesꢀ40% EtOAc/2% TEA/hexanes), 3x was isolated as light

yellow solid (0.139 g, 84%): ¹H NMR (500 MHz, CDCl₃) δ 8.46 (br s,

1H), 7.43ꢀ7.40 (m, 2H), 7.04ꢀ7.01 (m, 2H), 6.51 (s, 1H), 4.14 (q, J =

7.0 Hz, 2H), 2.29 (s, 3H), 1.21 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz,

CDCl₃) δ 165.8, 162.5 (d, J_CꢀF= 246.3 Hz), 136.7, 130.9, 129.1, 122.5,

116.7, 114.9, 111.3, 59.5, 14.2, 12.6; IR (thin film) 3300, 2985, 2926,

2920, 2858, 1665, 1443, 1277, 1082, 822 cm^ꢀ1; HRMS (ESI) m/z calcd

for C₁₄H₁₅NO₂F (M þ H)^þ248.1087, found 248.1091; mp 77ꢀ82 °C.

Pyrrole 3y. The catalyst mixture was prepared by mixing [(cod)IrCl]₂

(0.0225 g, 0.0335 mmol), AgOTf (0.0168 g, 0.0654 mmol), and NaBH₄

(0.0025 g, 0.066 mmol) in THF for 15 min. Allyl oxime 1y (0.178 g,

0.665 mmol) was then added to the catalyst mixture followed by DBU

(0.145 g, 0.952 mmol). The reaction mixture was allowed to stir for 1 h at

25 °C and then heated to 75 °C for 24 h. After flash chromatography (2%

TEA/hexanes ꢀ40% EtOAc/2% TEA/hexanes), 3y was isolated as light

yellow solid (0.130 g, 78%): ¹H NMR (500 MHz, CDCl₃) δ 8.31 (br s,

1H), 7.40ꢀ7.38 (m, 2H), 7.34ꢀ7.32 (m, 2H), 6.55 (s, 1H), 3.69 (s, 3H),

2.28 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 166.1, 136.4, 134.0, 131.4,

130.2, 128.3, 122.8, 117.0, 111.4, 50.7, 12.6; IR (thin film) 3316, 2980,

2944, 2920, 1660, 1442, 1284, 1081, 831, 715 cm^ꢀ1; HRMS (ESI) m/z

calcd for C₁₃H₁₃NO₂Cl (M þ H)^þ250.0635, found 250.0639; mp

118ꢀ122 °C.

3bb was isolated as light yellow solid (0.138 g, 85%): H NMR (500

MHz, CDCl₃) δ 8.26 (br s, 1H), 7.38ꢀ7.36 (m, 2H), 7.18ꢀ7.17 (m,

2H), 6.51 (s, 1H), 4.16 (q, J = 7.0 Hz, 2H), 2.38 (s, 3H), 2.30 (s, 3H),

1.21 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 165.9, 137.9,

137.8, 130.1, 128.9, 128.7, 122.4, 116.4, 111.1, 59.4, 21.3, 14.2, 12.7; IR

(thin film) 3314, 2988, 2952, 2926, 2900, 1665, 1443, 1291, 1082,

826 cm^ꢀ1; HRMS (ESI) m/z calcd for C₁₅H₁₈NO₂(M þ H)^þ

244.1338, found 244.1337; mp 85ꢀ90 °C.

Pyrrole 3cc. The catalyst mixture was prepared by mixing [(cod)-

IrCl]₂(0.0225 g, 0.0335 mmol), AgOTf (0.0168 g, 0.0654 mmol), and

NaBH₄(0.0025 g, 0.066 mmol) in THF for 15 min. Allyl oxime 1cc

(0.184 g, 0.663 mmol) was then added to the catalyst mixture followed

by DBU (0.145 g, 0.952 mmol). The reaction mixture was allowed to stir

for 1 h at 25 °C and then heated to 75 °C for 24 h. After flash chro-

matography (2% TEA/hexanesꢀ40% EtOAc/2% TEA/hexanes), 3cc

was isolated as light yellow solid (0.158 g, 92%): ¹H NMR (500 MHz,

CDCl₃) δ 8.47 (br s, 1H), 7.39ꢀ7.37 (m, 2H), 6.87ꢀ6.85 (m, 2H), 6.46

(s, 1H), 4.13 (q, J = 7.0 Hz, 2H), 3.82 (s, 3H), 2.29 (s, 3H), 1.20 (t, J =

7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 166.0, 159.4, 137.7, 130.3,

125.6, 122.3, 116.4, 113.4, 110.8, 59.4, 55.3, 14.2, 12.7; IR (thin film)

3309, 3014, 2982, 2945, 2839, 1663, 1440, 1237, 1137, 833 cm^ꢀ1

;

HRMS (ESI) m/z calcd for C₁₅H₁₈NO₃(M þ H)^þ260.1287, found

260.1287; mp 73ꢀ76 °C.

Pyrrole 3dd. The catalyst mixture was prepared by mixing [(cod)-

IrCl]₂(0.0225 g, 0.0335 mmol), AgOTf (0.0168 g, 0.0654 mmol), and

NaBH₄(0.0025 g, 0.066 mmol) in THF for 15 min. Allyl oxime 1dd

(0.200 g, 0.664 mmol) was then added to the catalyst mixture followed

by DBU (0.145 g, 0.952 mmol). The reaction mixture was allowed to stir

for 1 h at 25 °C and then heated to 75 °C for 24 h. After flash

chromatography (2% TEA/hexanesꢀ40% EtOAc/2% TEA/hexanes),

Pyrrole 3z. The catalyst mixture was prepared by mixing [(cod)IrCl]₂

(0.0225 g, 0.0335 mmol), AgOTf (0.0168 g, 0.0654 mmol), and NaBH₄

(0.0025 g, 0.066 mmol) in THF for 15 min. Allyl oxime 1z (0.217 g,

0.665 mmol) was then added to the catalyst mixture followed by DBU

(0.145 g, 0.952 mmol). The reaction mixture was allowed to stir for 1 h at

25 °C and then heated to 75 °C for 24 h. After flash chromatography (2%

TEA/hexanesꢀ40% EtOAc/2% TEA/hexanes), 3z was isolated as light

yellow solid (159 mg, 78%): ¹H NMR (500 MHz, CDCl₃) δ 8.33 (br s,

1H), 7.49ꢀ7.47 (m, 2H), 7.35ꢀ7.32 (m, 2H), 6.55 (s, 1H), 4.16 (q, J =

7.0 Hz, 2H), 2.29 (s, 3H), 1.21 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz,

CDCl₃) δ 165.7, 136.2, 131.9, 131.1, 130.6, 122.8, 122.1, 117.0, 111.7,

59.6, 14.2, 12.6; IR (thin film) 3297, 2985, 2923, 2858, 1674, 1443, 1284,

1076, 826, 520 cm^ꢀ1; HRMS (ESI) m/z calcd for C₁₄H₁₅NO₂Br (M þ

H)^þ308.0286, found 308.0288; mp 111ꢀ115 °C.

1

3dd was isolated as light yellow solid (154 mg, 82%): H NMR (500

MHz, CDCl₃) δ 8.55 (br s, 1H), 7.60ꢀ7.58 (m, 2H), 7.55ꢀ7.53 (m,

2H), 6.54 (s, 1H), 3.68 (s, 3H), 2.28 (s, 3H); ¹³C NMR (125 MHz,

CDCl₃) δ 166.2, 136.4, 135.9, 129.5 (d, J_CꢀF= 32.5 Hz), 129.2, 125.0,

124.1 (q, J_CꢀF= 270 Hz), 123.0, 117.7, 111.9, 50.8, 12.5; IR (thin film)

3286, 2992, 2959, 2920, 1655, 1615, 1445, 1156, 1086, 848 cm^ꢀ1

;

HRMS (ESI) m/z calcd for C₁₄H₁₃NO₂F₃(M þ H)^þ284.0898, found

284.0897; mp 134ꢀ137 °C.

Pyrrole 3ee. The catalyst mixture was prepared by mixing [(cod)-

IrCl]₂(22.5 mg, 0.0335 mmol), AgOTf (16.8 mg, 0.065 mmol), and

NaBH₄(2.5 mg, 0.066 mmol) in THF for 15 min. Allyl oxime 1ee (174

mg, 0.666 mmol) was then added to the catalyst mixture followed by

DBU (145 mg, 0.952 mmol). The reaction mixture was allowed to stir

for 1 h at 25 °C and then heated to 75 °C for 24 h. After flash

chromatography (2% TEA/hexanesꢀ40% EtOAc/2% TEA/hexanes),

3ee was isolated as light yellow oil (141 mg, 87%): ¹H NMR (500 MHz,

CDCl₃) δ 8.29 (br s, 1H), 7.26ꢀ7.23 (m, 3H), 7.15ꢀ7.13 (m, 1H), 6.46

(s, 1H), 4.13 (q, J = 7.0 Hz, 2H), 2.35 (s, 3H), 2.31 (s, 3H), 1.20 (t, J =

7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 166.1, 137.8, 137.4, 133.0,

129.7, 128.6, 127.9, 127.8, 126.2, 116.7, 111.1, 59.4, 21.4, 14.1, 12.6; IR

Pyrrole 3aa. The catalyst mixture was prepared by mixing [(cod)-

IrCl]₂(0.0225 g, 0.0335 mmol), AgOTf (0.0168 g, 0.0654 mmol), and

NaBH₄(0.0025 g, 0.066 mmol) in THF for 15 min. Allyl oxime 1aa

(0.248 g, 0.666 mmol) was then added to the catalyst mixture followed

by DBU (0.145 g, 0.952 mmol). The reaction mixture was allowed to stir

for 1 h at 25 °C and then heated to 75 °C for 24 h. After flash

chromatography (2% TEA/hexanesꢀ40% EtOAc/2% TEA/hexanes),

1

3aa was isolated as light yellow solid (0.179 g, 76%): H NMR (500

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(thin film) 3315, 3029, 2976, 2924, 2864, 1671, 1164, 1087, 781,

698 cm^ꢀ1; HRMS (ESI) m/z calcd for C₁₅H₁₈NO₂(M þ H)^þ

244.1338, found 244.1339.

g, 77%). The ratio of 3ii:4ii was 7:1, and the ratio was determined by the

relative ¹H integrations of the pyrrole methine resonances: ¹H NMR of

3ii (500 MHz, CDCl₃) δ 8.03 (br s, 1H), 6.29 (s, 1H), 4.28 (q, J = 7.5

Hz, 2H), 2.58ꢀ2.51 (m, 1H), 2.22 (s, 3H), 1.35 (t, J = 7.5 Hz, 3H), 0.95

(dd, J = 8.5, 1.5 Hz, 2H), 0.66 (dd, J = 5.5, 1.5 Hz, 2H); ¹³C NMR of 3ii

(125 MHz, CDCl₃) δ 166.5, 140.7, 121.8, 113.9, 111.8, 59.1, 14.5, 12.7,

9.1, 7.2; ¹H NMR of 4ii (500 MHz, CDCl₃) δ 7.94 (br s, 1H), 6.20 (s,

1H), 4.28 (q, J = 7.5 Hz, 2H),), 2.58ꢀ2.51 (m, 1H), 2.17 (s, 3H), 1.35 (t,

J = 7.5 Hz, 3H), 0.95 (dd, J = 8.5, 1.5 Hz, 2H), 0.66 (dd, J = 5.5, 1.5 Hz,

2H); ¹³C NMR of 4ii (125 MHz, CDCl₃) δ 165.9, 139.4, 125.2, 112.5,

107.9, 59.3, 14.5, 12.7, 8.5, 7.5; IR (thin film) 3326, 2982, 2956, 2907,

2861, 1665, 1445, 1242, 1076, 786 cm^ꢀ1; HRMS (ESI) m/z calcd for

C₁₁H₁₆NO₂(M þ H)^þ194.1179, found 194.1179.

Pyrrole 3ff⁵⁵. The catalyst mixture was prepared by mixing [(cod)-

IrCl]₂(0.0225 g, 0.0335 mmol), AgOTf (0.0168 g, 0.065 mmol), and

NaBH₄(0.0025 g, 0.066 mmol) in THF for 15 min. Allyl oxime 1ff

(0.189 g, 0.671 mmol) was then added to the catalyst mixture followed

by DBU (0.145 g, 0.952 mmol). The reaction mixture was allowed to stir

for 1 h at 25 °C and then heated to 75 °C for 24 h. After flash

chromatography (2% TEA/hexanesꢀ40% EtOAc/2% TEA/hexanes),

3ff was isolated as light yellow solid (0.144 g, 81%): ¹H NMR (500 MHz,

CDCl₃) δ 8.72 (br s, 1H), 7.43 (s, 1H), 7.31ꢀ7.24 (m, 3H), 6.49 (s,

1H), 4.12 (q, J = 7.0 Hz, 2H), 2.28 (s, 3H), 1.20 (t, J = 7.0 Hz, 3H); ¹³C

NMR (125 MHz, CDCl₃) δ 165.9, 135.8, 134.7, 133.7, 129.2, 129.1,

127.8, 127.2, 122.8, 117.4, 111.6, 59.6, 14.1, 12.6; IR (thin film) 3283,

2998, 2965, 2930, 2897, 1670, 1168, 10876, 774, 695 cm^ꢀ1; HRMS

(ESI) m/z calcd for C₁₄H₁₅NO₂Cl (M þ H)^þ264.0791, found

264.0791; mp 77ꢀ82 °C.

Pyrrole Mixture 3jj:4jj. The catalyst mixture was prepared by mixing

[(cod)IrCl]₂(22.5 mg, 0.0335 mmol), AgOTf (16.8 mg, 0.065 mmol),

and NaBH₄(2.5 mg, 0.066 mmol) in THF for 15 min. Allyl oxime ether

1jj (133 mg, 0.667 mmol) was then added to the catalyst mixture

followed by DBU (145 mg, 0.952 mmol). The reaction mixture was

allowed to stir for 1 h at 25 °C and then heated to 75 °C for 24 h. After

column chromatography, pyrrole mixture 3jj:4jj was isolated as light

yellow oil (53.2 mg, 44%). The ratio of 3jj:4jj was 2:3, and the ratio was

determined by the relative ¹H integrations of the pyrrole methine

Pyrrole 3gg. The catalyst mixture was prepared by mixing [(cod)-

IrCl]₂(0.0225 g, 0.0335 mmol), AgOTf (0.0168 g, 0.0654 mmol), and

NaBH₄(0.0025 g, 0.066 mmol) in THF for 15 min. Allyl oxime 3gg

(0.209 g, 0.663 mmol) was then added to the catalyst mixture followed

by DBU (0.145 g, 0.952 mmol). The reaction mixture was allowed to stir

for 1 h at 25 °C and then heated to 75 °C for 24 h. After flash chro-

matography (2% TEA/hexanesꢀ40% EtOAc/2% TEA/hexanes), 3gg

was isolated as light yellow solid (0.157 g, 80%): ¹H NMR (500 MHz,

CDCl₃) δ 8.60 (br s, 1H), 7.72 (s, 1H), 7.64ꢀ7.63 (m, 1H), 7.57ꢀ7.56

(m, 1H), 7.47ꢀ7.44 (m, 1H), 6.55 (s, 1H), 4.12 (q, J = 7.0 Hz, 2H), 2.29

(s, 3H), 1.15 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 165.7,

1

resonances: H NMR of pyrrole 3jj (500 MHz, CDCl₃) δ 8.18 (br s,

1H), 6.38 (s, 1H), 3.82ꢀ3.74 (m, 1H), 3.81 (s, 3H), 2.23 (s, 3H), 1.25

(d, J = 7.0 Hz, 3H); ¹³C NMR of pyrrole 3jj (125 MHz, CDCl₃) δ 166.6,

145.9, 121.4, 114.3, 109.7, 50.4, 26.3, 22.0, 12.7; ¹H NMR of pyrrole 4jj

(500 MHz, CDCl₃) δ 8.09 (br s, 1H), 6.18 (s, 1H), 3.82ꢀ3.74 (m, 1H),

3.77 (s, 3H), 2.21 (s, 3H), 1.25 (d, J = 7.0 Hz, 3H); ¹³C NMR of pyrrole

4jj (125 MHz, CDCl₃) δ 165.9, 144.5, 125.4, 109.7, 107.5, 50.6, 25.9,

22.1, 12.7; IR (thin film) 3339, 2970, 2954, 2932, 2874, 1671, 1620,

1448, 1240, 1082, 781 cm^ꢀ1; HRMS (ESI) m/z calcd for C₁₀H₁₆NO₂

(M þ H)^þ182.1181, found 182.1183.

135.6, 133.8, 132.4, 130.3 (d, J_CꢀF= 32.5 Hz), 128.4, 126.2 (q, J_CꢀF

=

270 Hz), 126.0, 124.5, 123.0, 117.4, 112.0, 59.6, 14.0, 12.5; IR (thin film)

3303, 2956, 2933, 2907, 1654, 1613, 1430, 1161, 1069, 700 cm^ꢀ1

;

HRMS (ESI) m/z calcd for C₁₅H₁₅NO₂F₃(M þ H)^þ298.1055, found

298.1055; mp 62ꢀ65 °C.

Pyrrole mixture 3kk⁵⁶:4kk⁵⁷. The catalyst mixture was prepared by

mixing [(cod)IrCl]₂(0.0225 g, 0.0335 mmol), AgOTf (0.0168 g, 0.0654

mmol), and NaBH₄(0.0025 g, 0.066 mmol) in THF for 15 min. Allyl

oxime 1kk (0.108 g, 0.633 mmol) was then added to the catalyst mixture

followed by DBU (0.145 g, 0.952 mmol). The reaction mixture was

allowed to stir for 1 h at 25 °C and then heated to 75 °C for 20 h. After

flash chromatography (2% TEA/hexanesꢀ40% EtOAc/2% TEA/

hexanes), pyrrole mixture 3kk:4kk was isolated as light yellow solid

(0.106 g, 54%). The ratio of 3kk:4kk was 2:1, and the ratio was

determined by the relative ¹H integrations of the pyrrole methine

Pyrrole Mixture 3hh:4hh. The catalyst mixture was prepared by

mixing [(cod)IrCl]₂(0.0225 g, 0.0335 mmol), AgOTf (0.0168 g, 0.0654

mmol), and NaBH₄(0.0025 g, 0.066 mmol) in THF for 15 min. Allyl

oxime 1hh (0.174 g, 0.666 mmol) was then added to the catalyst mixture

followed by DBU (0.145 g, 0.952 mmol). The reaction mixture was

allowed to stir for 1 h at 25 °C and then heated to 75 °C for 24 h. After

flash chromatography (2% TEA/hexanesꢀ40% EtOAc/2% TEA/

hexanes), pyrrole mixture 3hh:4hh was isolated as light yellow oil

(0.136 g, 84%). The ratio of 3hh:4hh was 5:3, and the ratio was

determined by the relative ¹H integrations of the pyrrole methine

1

resonances: H NMR of 3kk (500 MHz, CDCl₃) δ 8.29 (br s, 1H),

6.35 (s, 1H), 3.81 (s, 3H), 2.47 (s, 3H), 2.23 (s, 3H); ¹³C NMR of 3kk

(125 MHz, CDCl₃) δ 166.9, 136.1, 121.5, 114.4, 110.6, 50.5, 14.1, 12.6;

¹H NMR of 4kk (500 MHz, CDCl₃) δ 8.29 (br s, 1H), 6.18 (s, 1H), 3.78

(s, 3H), 2.47 (s, 3H), 2.18 (s, 3H); ¹³C NMR of 4kk (125 MHz, CDCl₃)

δ 166.4, 134.5, 125.8, 111.2, 107.4, 50.7, 13.1, 12.6; IR (thin film) 3298,

3020, 3002, 2922, 2853, 1665, 1444, 1222, 1088, 781 cm^ꢀ1; HRMS

(ESI) m/z calcd for C₈H₁₂NO₂(M þ H)^þ154.0868, found 154.0868;

mp 68ꢀ73 °C.

1

resonances: H NMR of 3hh (500 MHz, CDCl₃) δ 8.21 (br s, 1H),

7.29ꢀ7.16 (m, 4H), 6.51 (s, 1H), 4.00 (q, J = 7.0 Hz, 2H), 2.32 (s, 3H),

2.16 (s, 3H), 1.00 (t, J = 7.0 Hz, 3H); ¹³C NMR of 3hh (125 MHz,

CDCl₃) δ 165.6, 137.8, 133.6, 130.2, 129.7, 128.3, 127.2, 125.1, 121.6,

116.0, 112.4, 59.0, 19.9, 13.9, 12.4; ¹H NMR of 4hh (500 MHz, CDCl₃)

δ 8.21 (br s, 1H), 7.29ꢀ7.16 (m, 4H), 6.35 (s, 1H), 4.00 (q, J = 7.0 Hz,

2H), 2.25 (s, 3H), 2.20 (s, 3H), 1.08 (t, J = 7.0 Hz, 3H); ¹³C NMR of

4hh (125 MHz, CDCl₃) δ 165.0, 137.2, 135.5, 132.9, 130.2, 129.7,

128.3, 125.1, 121.6, 113.4, 108.0, 59.3, 19.9, 14.1, 12.7; IR (thin film)

Pyrrole 3mm. The catalyst mixture was prepared by mixing [(cod)-

IrCl]₂(0.0225 g, 0.0335 mmol), AgOTf (0.0168 g, 0.0654 mmol), and

NaBH₄(0.0025 g, 0.066 mmol) in THF for 15 min. Allyl oxime ether

1mm (0.213 g, 0.667 mmol) was then added to the catalyst mixture.

DBU (0.132 g, 0.873 mmol) was added to the complete reaction mixture

and the complete reaction mixture was allowed to stir at 25 °C for 1 h

and then heated to 75 °C for 24 h. After flash chromatography (2%

TEA/hexanesꢀ40% EtOAc/2% TEA/hexanes), 3mm was isolated as

light yellow solid (0.0858 g, 43%): ¹H NMR (500 MHz, CDCl₃) δ 8.14

(br s, 1H), 7.60ꢀ7.58 (m, 2H), 7.40ꢀ7.39 (m, 2H), 7.29ꢀ7.27 (m,

2H), 7.25ꢀ7.20 (m, 3H), 6.74 (s, 1H), 2.14 (s, 3H); ¹³C NMR (125

MHz, CDCl₃) δ 140.2, 132.9, 130.5, 129.5, 128.7, 127.8, 127.1, 126.7,

125.1, 124.6 (q, J_CꢀF= 270 Hz), 120.8, 119.5, 116.7, 11.0; IR (thin film)

3314, 3062, 3024, 2977, 2926, 1667, 1439, 1283, 1078, 759 cm^ꢀ1

;

HRMS (ESI) m/z calcd for C₁₅H₁₈NO₂(M þ H)^þ244.1338, found

244.1336.

Pyrrole Mixture 3ii:4ii. The catalyst mixture was prepared by mixing

[(cod)IrCl]₂(0.0225 g, 0.0335 mmol), AgOTf (0.0168 g, 0.0654

mmol), and NaBH₄(0.0025 g, 0.066 mmol) in THF for 15 min. Allyl

oxime 1ii (0.140 g, 0.663 mmol) was then added to the catalyst mixture

followed by DBU (0.145 g, 0.952 mmol). The reaction mixture was

allowed to stir for 1 h at 25 °C and then heated to 75 °C for 24 h. After

flash chromatography (2% TEA/hexanesꢀ40% EtOAc/2% TEA/

hexanes), pyrrole mixture 3ii:4ii was isolated as light yellow oil (0.099

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3401, 2949, 2926, 2864, 1698, 1616, 1322, 1164, 1066, 694 cm^ꢀ1

;

15 min. Allyl oxime 1aa (0.147 g, 0.816 mmol) was then added to the

catalyst mixture and the reaction mixture was allowed to stir at 25 °C for 18

h then at 50 °C for 24 h. After flash chromatography (2% TEA/hexanesꢀ

40% EtOAc/2% TEA/hexanes), 3aa:4aa was isolated as a light yellow oil

(0.0639 g, 49%). The ratio of 3aa:4aa was 2:3, and the ratio was determined

by the relative ¹H integrations of the pyrrole methine resonances: ¹H NMR

of 3aa (500 MHz, CDCl₃) δ8.38 (br s, 1H), 6.35 (s, 1H), 2.13 (s, 3H), 1.41

(s, 9H); ¹³C NMR of 3aa (125 MHz, CDCl₃) δ 149.0, 123.1, 117.9, 113.5,

89.3, 32.8, 29.6, 10.6; ¹HNMRof4aa (500 MHz, CDCl₃) δ8.38 (br s, 1H),

6.01 (s, 1H), 2.21 (s, 3H), 1.41 (s, 9H); ¹³C NMR of 4aa (125 MHz,

CDCl₃) δ 148.3, 126.1, 118.7, 109.8, 87.2, 32.8, 29.9, 12.5; IR (thin film)

3275, 2968, 2868, 2210, 1594, 1444, 1367, 1267, 804, 756 cm^ꢀ1; HRMS

(ESI) m/z calcd for C₁₀H₁₅N₂(M þ H)^þ163.1235, found 163.1234.

Pyrrole Mixture 3ll:4ll (3:1) Synthesized with DBU. The catalyst mix-

ture was synthesized by mixing [(cod)IrCl]₂(0.0230 g, 0.0343 mmol),

AgOTf (0.013 g, 0.051 mmol), and NaBH₄(0.0025 g, 0.065 mmol) in

THF for 15 min. Allyl oxime 1ll (0.142 g, 0.787 mmol) was then added

to the catalyst mixture followed by DBU (0.179 g, 1.18 mmol). The

reaction mixture was allowed to stir for 1 h at 25 °C and then heated to

50 °C for 18 h. After flash chromatography (2% TEA/hexanesꢀ40%

EtOAc/2% TEA/hexanes), 3ll:4ll was isolated as a light yellow oil

(0.0744 g, 58%). The ratio of 3ll:4ll was 3:1 and the ratio was

determined by the relative ¹H integrations of the pyrrole methine

HRMS (ESI) m/z calcd for C₁₈H₁₅NF₃(M þ H)^þ302.1157, found

302.1159; mp 72ꢀ75 °C.

Pyrrole 3nn. O-Vinyl oxime 2nn (0.109, 0.342 mmol) was treated

with DBU (0.078 mg, 0.51 mmol), and the reaction mixture was allowed

to stir for 18 h at 75 °C. After workup and column chromatography, 3nn

1

was isolated as a yellow solid (0.0847 g, 82%): H NMR (500 MHz,

CDCl₃) δ 8.14 (br s, 1H), 7.60ꢀ7.58 (m, 2H), 7.40ꢀ7.39 (m, 2H),

7.29ꢀ7.27 (m, 2H), 7.25ꢀ7.20 (m, 3H), 6.74 (s, 1H), 2.14 (s, 3H); ¹³C

NMR (125 MHz, CDCl₃) δ 140.2, 132.9, 130.5, 129.5, 128.7, 127.8,

127.1, 126.7, 125.1, 124.6 (q, J_CꢀF= 270 Hz), 120.8, 119.5, 116.7, 11.0;

IR (thin film) 3401, 2949, 2926, 2864, 1698, 1616, 1322, 1164, 1066,

694 cm^ꢀ1; HRMS (ESI) m/z calcd for C₁₈H₁₅NF₃(M þ H)^þ

302.1157, found 302.1159; mp 72ꢀ75 °C.

Pyrrole 3nn. The catalyst mixture was prepared by mixing [(cod)-

IrCl]₂(0.0135 g, 0.0201 mmol), AgOTf (0.0101 g, 0.0393 mmol), and

NaBH₄(0.0015 g, 0.040 mmol) in THF for 15 min. Allyl oxime ether

1nn (0.110 g, 0.398 mmol) was then added to the catalyst mixture. DBU

(0.079 g, 0.524 mmol) was added to the complete reaction mixture, and

the complete reaction mixture was allowed to stir at 25 °C for 1 h and

then heated to 75 °C for 24 h. After flash chromatography (2% TEA/

hexanesꢀ40% EtOAc/2% TEA/hexanes), 3nn was isolated as light

yellow solid (0.0465 g, 46%): ¹H NMR (500 MHz, CDCl₃) δ 8.16 (br s,

1H), 7.58ꢀ7.57 (m, 2H), 7.35ꢀ7.34 (m, 2H), 7.29ꢀ7.26 (m, 2H),

7.24ꢀ7.18 (m, 3H), 6.74 (s, 1H), 2.11 (s, 3H); ¹³C NMR (125 MHz,

CDCl₃) δ 141.6, 132.6, 132.0, 130.8, 129.9, 128.8, 127.3, 127.0, 120.3,

119.5, 119.3, 117.0, 109.2, 11.1; IR (thin film) 3332, 2973, 2929, 2893,

2861, 2227, 1603, 1174, 1002, 841 cm^ꢀ1; HRMS (ESI) m/z calcd. for

C₁₈H₁₅N₂(M þ H)^þ259.1235, found 259.1230; mp 185ꢀ188 °C.

Pyrrole 3oo. The catalyst mixture was prepared by mixing [(cod)-

IrCl]₂(0.0135 g, 0.0201 mmol), AgOTf (0.010.1 g, 0.0398 mmol), and

NaBH₄(0.0015 g, 0.040 mmol) in THF for 15 min. Allyl oxime ether

1oo (0.127 g, 0.390 mmol) was then added to the catalyst mixture. DBU

(0.079 g, 0.524 mmol) was added to the complete reaction mixture and

the complete reaction mixture was allowed to stir for 1 h at 25 °C and

then heated to 75 °C for 24 h. After flash chromatography (2% TEA/

hexanesꢀ40% EtOAc/2% TEA/hexanes), 3oo was isolated as light

orange oil (0.0684 g, 56%): ¹H NMR (500 MHz, CDCl₃) δ 8.23 (br s,

1H), 8.01ꢀ7.99 (m, 2H), 7.35ꢀ7.33 (m, 2H), 7.26ꢀ7.23 (m, 2H),

7.20ꢀ7.19 (m, 3H), 6.73 (s, 1H), 4.38 (q, J = 7.0 Hz, 2H), 2.12 (s, 3H),

1.40 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 170.0, 141.4,

133.0, 130.2, 129.5, 129.4, 128.7, 127.8, 127.1, 126.6, 121.2, 119.5, 116.7,

60.8, 11.4, 11.1; IR (thin film) 3336, 2983, 2915, 2877, 2848, 1737, 1607,

1372, 1044, 847 cm^ꢀ1; HRMS (ESI) m/z calcd for C₂₀H₂₀NO₂(M þ

H)^þ306.1494, found 306.1492.

1

resonances: H NMR of 3ll (500 MHz, CDCl₃) δ 8.38 (br s, 1H),

6.35 (s, 1H), 2.13 (s, 3H), 1.41 (s, 9H); ¹³C NMR of 3ll (125 MHz,

CDCl₃) δ 149.0, 123.1, 117.9, 113.5, 89.3, 32.8, 29.6, 10.6; ¹H NMR of

4ll (500 MHz, CDCl₃) δ 8.38 (br s, 1H), 6.01 (s, 1H), 2.21 (s, 3H), 1.41

(s, 9H); ¹³C NMR of 4ll (125 MHz, CDCl₃) δ 148.3, 126.1, 118.7,

109.8, 87.2, 32.8, 29.9, 12.5.

Pyrrole Mixture 3r:4r (5:3). The catalyst mixture was prepared by

mixing [(cod)IrCl]₂(0.0225 g, 0.0335 mmol), AgOTf (0.0168 g, 0.0654

mmol), and NaBH₄(0.0025 g, 0.066 mmol) in THF for 15 min. Allyl

oxime ether 1r (0.168 g, 0.668 mmol) was then added to the catalyst

mixture, followed by DBU (0.145 g, 0.952 mmol). The reaction mixture

was allowed to stir for 1 h at 25 °C and then heated to 75 °C for 24 h.

After flash chromatography (2% TEA/hexanesꢀ40% EtOAc/2% TEA/

hexanes), a mixture of 3r and 4r was isolated as light orange oil (0.062 g,

40%). The ratio of 3r:4r was 5:3 and the ratio was determined by the

relative ¹H integrations of the pyrrole methine resonances: ¹H NMR of

3r (500 MHz, CDCl₃) δ 8.07 (br s, 1H), 7.40ꢀ7.17 (m, 10H), 6.73 (s,

1H), 2.13 (s, 3H); ¹³C NMR of 3r (125 MHz, CDCl₃) δ 136.4, 133.4,

130.5, 128.6, 128.4, 128.3, 127.4, 126.9, 126.5, 126.3, 126.0, 116.4, 11.1;

¹H NMR of 4r (500 MHz, CDCl₃) δ 7.94 (br s, 1H), 7.40ꢀ7.17 (m,

10H), 6.14 (s, 1H), 2.37 (s, 3H); ¹³C NMR of 4r (125 MHz, CDCl₃) δ

137.0, 133.7, 128.7, 128.6, 128.3, 128.2, 127.4, 126.9, 126.3, 125.7, 122.3,

109.1, 13.1; IR (thin film) 3414, 3056, 3020, 2916, 2897, 1596, 1499,

1076, 803, 744 cm^ꢀ1; HRMS (ESI) m/z calcd for C₁₇H₁₆N (M þ H)^þ

234.1283, found 234.1278.

Pyrrole 3pp. The catalyst mixture was prepared by mixing [(cod)-

IrCl]₂(0.0225 g, 0.0335 mmol), AgOTf (0.0168 g, 0.0654 mmol), and

NaBH₄(0.0025 g, 0.066 mmol) in THF for 15 min. Allyl oxime ether

1pp (0.129 g, 0.642 mmol) was then added to the catalyst mixture. DBU

(0.132 g, 0.873 mmol) was added to the complete reaction mixture, and

the complete reaction mixture was allowed to stir for 1 h at 25 °C and

then heated to 75 °C for 24 h. After flash chromatography (2% TEA/

hexanesꢀ40% EtOAc/2% TEA/hexanes), 3pp was isolated as a yellow

Pyrrole Mixture 3r:4r (4:1) from 2r. O-Vinyl oxime 2r (0.0904 g,

0.360 mmol) was dissolved in 3 mL of THF and mixed with DBU

(0.0822 g, 0.540 mmol). The reaction mixture was then transferred to a

Teflon-sealed reaction flask at allowed to heat at 75 °C for 24 h. After

column chromatography, pyrrole mixture 3r:4r was isolated as a light

yellow oil (0.0493 g, 59%). The ratio of 3r:4r was 4:1 and the ratio was

determined by the relative ¹H integrations of the pyrrole methine

1

oil (0.0476 g, 41%): H NMR (500 MHz, CDCl₃) δ 7.72 (br s, 1H),

7.57ꢀ7.56 (m, 1H), 7.23ꢀ7.18 (m, 2H), 7.05ꢀ7.02 (m, 1H), 6.46 (s,

1H), 2.98 (t, J = 7.5 Hz, 2H), 2.77 (t, J = 7.5 Hz, 2H), 2.39 (s, 3H); ¹³

C

1

resonances. H NMR of 3r (500 MHz, CDCl₃) δ 8.07 (br s, 1H),

7.40ꢀ7.17 (m, 10H), 6.73 (s, 1H), 2.13 (s, 3H); ¹³C NMR of 3r (125

MHz, CDCl₃) δ 136.4, 133.4, 130.5, 128.6, 128.4, 128.3, 127.4, 126.9,

126.5, 126.3, 126.0, 116.4, 11.1; ¹H NMR of 4r (500 MHz, CDCl₃) δ

7.94 (br s, 1H), 7.40ꢀ7.17 (m, 10H), 6.14 (s, 1H), 2.37 (s, 3H); ¹³C

NMR of 4r (125 MHz, CDCl₃) δ 137.0, 133.7, 128.7, 128.6, 128.3,

128.2, 127.4, 126.9, 126.3, 125.7, 122.3, 109.1, 13.1.

NMR (125 MHz, CDCl₃) δ 134.6, 133.8, 130.2, 128.1, 126.7, 124.0,

122.1, 116.6, 115.9, 115.1, 30.4, 22.1, 13.0; IR (thin film) 3358, 3007,

2928, 2917, 2902, 2886, 1603, 1184, 1024, 745 cm^ꢀ1; HRMS (ESI) m/z

calcd for C₁₃H₁₄N (M þ H)^þ184.1126, found 184.1125.

Synthesis of Pyrrole Mixtures 3ll:4ll and 3rr:4rr (Schemes 12

and 13). Pyrrole Mixture 3aa:4aa (2:3). The catalyst mixture was

synthesized by mixing [(cod)IrCl]₂(0.0225 g, 0.0335 mmol), AgOTf

(0.0168 g, 0.0654 mmol), and NaBH₄(0.0025 g, 0.066 mmol) in THF for

Preparation of O-Vinyl Oxime 2mm. The catalyst mixture was

prepared by mixing [(cod)IrCl]₂(0.0164 g, 0.0244 mmol), AgOTf

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The Journal of Organic Chemistry

ARTICLE

(0.011 g, 0.043 mmol), and NaBH₄(0.0018 g, 0.047 mmol) in THF for

15 min. Allyl oxime ether 1mm (0.166 g, 0.520 mmol) was then added to

the catalyst mixture, and the reaction mixture was allowed to stir for 24 h.

After flash chromatography (2% TEA/hexanesꢀ2% EtOAc/2%

TEA/hexanes), 2mm was isolated as a light yellow oil (0.109 g, 65%):

¹H NMR of E-imine, Z-vinyl isomer (500 MHz, CDCl₃) δ 7.70ꢀ7.68

(m, 1H), 7.56ꢀ7.53 (m, 2H), 7.39ꢀ7.34 (m, 6H), 6.98 (m, 1H), 4.58

(q, J = 7.0 Hz, 1H), 4.30 (s, 2H), 1.62 (dd, J = 7.0, 1.5 Hz, 3H); ¹³C NMR

of E-imine, Z-vinyl isomer (125 MHz, CDCl₃) δ 157.1, 146.8, 140.5,

134.6, 129.9, 128.8, 128.7, 128.6, 128.2, 126.7, 125.6, 100.3, 33.2, 9.5. ¹H

NMR of E-imine, E-vinyl isomer (500 MHz, CDCl₃) δ 7.70ꢀ7.68 (m,

1H), 7.56ꢀ7.53 (m, 2H), 7.39ꢀ7.34 (m, 6H), 6.94 (m, 1H), 5.28 (q, J =

5.5 Hz, 1H), 4.26 (s, 2H), 1.67 (dd, J = 6.5, 1.5 Hz, 3H); ¹³C NMR of E-

imine, Z-vinyl isomer (125 MHz, CDCl₃) δ 157.1, 147.3, 140.5, 134.6,

129.9, 128.8, 128.7, 128.6, 128.2, 126.7, 125.6, 99.7, 33.0,12.3. ¹H NMR

of Z-imine, Z-vinyl isomer (500 MHz, CDCl₃) δ 7.70ꢀ7.68 (m, 1H),

7.56ꢀ7.53 (m, 2H), 7.39ꢀ7.34 (m, 6H), 6.86 (m, 1H), 4.48 (q, J = 6.5

Hz, 1H), 3.96 (s, 2H), 1.50 (dd, J = 7.0, 1.5 Hz, 3H); ¹³C NMR of Z-

imine, Z-vinyl isomer (125 MHz, CDCl₃) δ 156.9, 147.3, 140.5, 134.6,

129.9, 128.8, 128.7, 128.6, 128.2, 126.7, 125.6, 101.5, 41.2,12.3. The

Z-imine, E-vinyl isomer was difficult to distinguish from the other iso-

mers but specific resonances for the vinyl group were observed at 5.20

and 4.5 ppm.

1.17ꢀ1.05 (m, 3H), the OꢀH resonance was not observed. This

assignment was supported by a ¹³C NMR spectrum and comparison

to other similar compounds reported in the literature: ¹³C NMR (125

MHz, CDCl₃) δ 162.5, 154.1, 144.9, 131.5, 127.3, 126.1, 99.4, 86.3, 58.4,

55.4, 15.9, 13.5. The ¹³C NMR chemical shift observed for the N,O-

acetal carbon (86.3 ppm) and the sp²carbons of the dihydropyrrole

(99.4 ppm and 154.1 ppm) match other similar structures in the

literature and do not match 2b, 3b, 4b, 5b, or the expected resonances

for 7b.

’ ASSOCIATED CONTENT

S

Supporting Information. Experimental procedures, ex-

b

panded optimization tables, and compound characterization data.

This information is available free of charge via the Internet at http://

pubs.acs.org.

’ AUTHOR INFORMATION

Corresponding Author

*E-mail: lauralin@uic.edu.

’ ACKNOWLEDGMENT

Observation of [1,3] Rearrangement Product 5s and Isolation of

Amino Alcohol 6s. A 10 mL Teflon-sealed flask was charged with 2s

(0.1081 g, 0.493 mmol) and 4 mL of dioxane. The flask was then

stoppered and heated to 75 °C for 2.5 h. At this time, an aliquot was

removed from the flask and checked by ¹H NMR spectroscopy which

We thank Prof. Tom Driver (UIC) and Prof. Duncan War-

drop (UIC) for insightful discussions and chemicals and

Mr. Furong Sun (UIUC) for mass spectrometry data. We also

thank the ACS Petroleum Research Fund (50491-DNI) and the

University of Illinois at Chicago for funding.

1

showed that 2s had been completely converted into aldehyde 5s: H

NMR (500 MHz, CDCl₃) δ 9.78 (s, 1H), 7.79 (d, J = 9.0 Hz, 2H), 6.91

(d, J = 9.0 Hz, 2H), 2.71 (q, J = 7.5 Hz, 2H), 2.62 (q, J = 7.5 Hz, 1H), 1.39

(d, J = 7.0 Hz, 3H), 1.12 (t, J = 7.5 Hz, 3H). Compound 5s was not

isolated or purified. The crude solution of 5s was transferred to a 25 mL

round-bottom flask containing a slurry of LiAlH₄(0.039 g, 1.03 mmol)

in 10 mL of THF. The reaction mixture was then allowed to stir for 4 h.

At this time, the reaction mixture was diluted with 20 mL of MTBE and

slowly quenched with water. The reaction mixture was then extracted

with 3 ꢁ 20 mL of 1 M HCl_(aq), neutralized with 1 M NaOH_(aq), and

extracted with 3 ꢁ 15 mL of MTBE, and volatiles were removed under

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3294, 3191, 2959, 2929, 2871, 2834, 1610, 1510, 1245, 1035, 828 cm^ꢀ1

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Article Doi

Regioselective synthesis of 2,3,4- or 2,3,5-trisubstituted pyrroles via [3,3] or [1,3] rearrangements of O-vinyl oximes

DOI: 10.1021/jo200061b

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