Stereoselective and catalytic access to β-enaminones: An entry to pyrimidines

DOI: 10.1021/jo301675g

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Journal of Organic Chemistry p. 9205 - 9220 (2012)

Update date:2022-08-04

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Authors:

Gayon, Eric

Szymczyk, Monika

Gérard, Hélène

Vrancken, Emmanuel

Campagne, Jean-Marc

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Article abstract of DOI:10.1021/jo301675g

We describe herein a highly stereoselective access to Cbz-protected β-enaminones 2 based on the NaOH catalyzed rearrangement of propargylic hydroxylamines 1. The synthetic potential of these β-enaminones is illustrated in an original synthesis of pyrimidi

Full text of DOI:10.1021/jo301675g

Article

pubs.acs.org/joc

Stereoselective and Catalytic Access to β‑Enaminones: An Entry to

Pyrimidines

Eric Gayon,^†Monika Szymczyk,^†Helene Gerard,*^,‡Emmanuel Vrancken,*^,†and Jean-Marc Campagne*^,†

^†Institut Charles Gerhardt UMR 5253 CNRS-UM2-UM1-ENSCM, 8 rue de l’Ecole Normale, 34296 Montpellier Cedex 5, France

^‡Laboratoire de Chimie Theo

France

rique, UMR 7616, UPMCUniversite

Paris 06, CNRS case 137, 4 Place Jussieu, 75262 Paris Cedex 05,

* Supporting Information

ABSTRACT: We describe herein a highly stereoselective

access to Cbz-protected β-enaminones 2 based on the NaOH

catalyzed rearrangement of propargylic hydroxylamines 1. The

synthetic potential of these β-enaminones is illustrated in an

original synthesis of pyrimidines.

Scheme 1. Synthesis of Pyrimidines

INTRODUCTION

■

β-Enaminones (vinylogous amides) are versatile compounds,¹

used for their pharmacological properties²and as building blocks

for heterocyclic³and natural product⁴syntheses. Since their

biological and chemical properties depend on the alkene

stereochemistry, stereoselective syntheses of β-enaminones are

thus highly desirable.⁵During initial experiments aimed at

developing an interrupted access to trisubstituted isoxazoles,⁶we

observed that a propargylic hydroxylamine (Ar = p-tol, R = n-Bu)

was able, under basic conditions, to rearrange to give the Cbz-

protected enaminone as a single (Z) diastereomer (eq 1, see

below for theoretical justiﬁcation):

of 2 into 2,4,6-trisubstituted pyrimidines is also reported

(Scheme 1, eq 2).

RESULTS AND DISCUSSION

■

The starting propargylic hydroxylamines 1 are easily obtained by

FeCl₃-catalyzed direct nucleophilic substitution of the prop-

argylic hydroxyl group by the commercially available Cbz-

NHOH under reaction conditions developed by Zhan (FeCl₃5

mol %, DCM, 60 °C, 1 h).¹⁰First, 1a was chosen as model

substrate and its isomerization under various basic conditions

was investigated (Table 1).

Puzzled by this stereoselective isomerization, we were keen to

investigate this transformation and to use the enaminones 2 as

building blocks for the synthesis of heterocyclic structures such as

pyrimidines. Pyrimidines are ubiquitous heterocyclic moieties

present in natural products, drugs and in functional materials.⁷

Eﬃcient strategies have been developed mainly on the basis of

N−C−N condensations, i.e., the addition of guanidines or

presynthetized amidines salts to 1,3-diketones or derivatives

thereof (such as ynones^7e) (Scheme 1, eq 1). The presence of a

nitrogen atom on enaminones 2 could be advantageous to

develop alternative synthetic strategies since it allows for

diﬀerentiation of the 2 nitrogen groups (which could, for

example, be useful for isotopic labeling strategies). Moreover,

such a cyclocondensation would use the readily commercially

available and stable class of carboxamides, which grants a more

convenient access to these heterocycles.⁸

Starting from the previously described conditions (4.0 equiv of

K₂CO₃in acetonitrile at 50 °C for 20 h),⁶the inﬂuence of the

base was ﬁrst tested: whereas no reaction is observed with NEt₃

(entry 2), the conversion is complete after 1 h using sodium

hydroxide (4 equiv), leading to 2a in 28% isolated yield along

with unidentiﬁed byproduct (entry 3). The (Z) geometry of the

double bond was assigned by ¹H NMR chemical shift correlation.

Indeed, the ¹H NMR shift of the proton attached to the nitrogen

atom of our enaminones 2 is in good agreement with previously

described (Z)-β-enaminones (δ_N−H: ca. 11 ppm).¹¹In sharp

contrast, in enecarbamates, which can be seen as analogs where

Herein, we describe the catalytic isomerization of readily

available propargylic hydroxylamines 1^9,10to (Z)-β-enaminones

2 and we propose a reaction pathway based on DFT calculations

for this unanticipated isomerization. The further transformation

Received: August 22, 2012

Published: September 24, 2012

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Table 1. Isomerization of Propargylic Hydroxylamine 1a

under Various Basic Conditions

Scheme 2. Scope of the Isomerization of Propargylic

Hydroxylamines: Inﬂuence of the Aryl Group at the

Propargylic Position

base

equiv

reaction time (h)

2a isolated yield (%)

K₂CO₃

NEt₃

NaOH

K₂CO₃

0.1

the carbonyl is not present, a lower shift is observed (δ_N−H: ca. 6

ppm).¹²This shielding eﬀect observed in the case of enaminones

is characteristic of the existence of a H bonding, which is in good

agreement with the proposed (Z) geometry. Moreover, the

structure of 2 was further conﬁrmed by nOesy experiments (see

Supporting Information for details).

Anticipating that an excess of base might be problematic, the

reaction was carried out with only 1 equiv of NaOH. Indeed, 2a

was isolated in 75% as a single (Z) isomer (entry 4). Considering

that the isomerization process should lead to an anionic product,

we assumed that a catalytic amount of base might be suﬃcient.

Thus, the use of 10 mol % of NaOH was ﬁnally attempted and,

gratifyingly, 2a was isolated in an improved 86% yield (entry 5).

In a control experiment (0.1 equiv of K₂CO₃in acetonitrile at 50

°C), compound 2a was isolated in 59% yield and the reaction

required 8 h for completion (entry 6). It is worth noting that the

presence of water is required to ensure good conversions (see the

mechanistic study for explanations and in particular about the

role of water). Consequently, our reactions are run in

nondistilled acetonitrile¹³and in an open-air ﬂask, which

makes this methodology quite practical.

General conditions: Propargylic hydroxylamine (0.2 mmol), NaOH

(0.02 mmol, 10 mol %), CH₃CN (2 mL, 0.1 M), 50 °C, 1 h. Isolated

yields.

We next studied the scope and limitations of this isomer-

ization. Using our optimized conditions (Scheme 2), the

inﬂuence of the aryl substituents at the propargylic position

was ﬁrst investigated. Starting from propargylic hydroxylamines

bearing electron-withdrawing or electron-donating groups, at the

para or meta position, Cbz-protected enaminones 2a−i were

obtained in good to excellent yields. Heteroaromatics, such as

thiophene, are also well tolerated in this reaction (2j). Some

limitations appear when using more hindered substrates:

compare for example 1-naphtyl vs 2-naphthyl moieties (2k and

2l) or o-Me vs o-F substituents (2m and 2n). Taken together,

these results show that the presence of a sterically hindered group

close to the propargylic position has a detrimental eﬀect on the

yield. Mechanistic implications of this observation are discussed

thereafter.

Moving to a TMS group, and under classical conditions, the

attempted enaminone 2o could not be observed. After some

optimization, and using 1 equiv of K₂CO₃at room temperature in

a methanol/water mixture, compound 4 could ﬁnally be isolated

in 68% yield (Scheme 3). Of note, this product is isolated as a

single Z isomer and results from a one-pot transformation

including three elemental steps: isomerization, desilylation and

Cbz deprotection. It is not clear when the Cbz deprotection

occurs in this sequence; nevertheless, knowing the stability of

acylsilane under hydrolysis conditions,¹⁴the formation of a

formyl group in the ﬁnal product indicates that the isomerization

step takes place after the TMS removal. Clearly, the presence of a

Scheme 3. Isomerization of a Propargylic Hydroxylamine

Substituted by a TMS Group at the Acetylenic Position

TMS at the acetylenic position inhibits the isomerization,

whereas terminal alkynes are suitable reagents for this trans-

formation.

Next, substrates bearing diﬀerent alkyl or aryl substituents on

the acetylenic position were tested. With Me and i-Pr alkyl

groups, the corresponding enaminones 2p,q were isolated in 75

and 63% yields, respectively (Scheme 4, eq 1 and 2). In contrast,

the expected enaminone 2r could only be observed as traces in

the crude material when a bulkier t-Butyl group stands at the

acetylenic position. Along with unreacted starting material 1r

(recovered in 46% yield), the major product was the imine 3r

isolated in 41% yield (Scheme 4, eq 3). With aryl groups (Ph and

p-Tol), the expected enaminones were obtained in 51% (2s) and

53% (2t) yields along with the corresponding imines 3s and 3t in

18 and 14% yields, respectively (Scheme 4, eq 4).

The detection of imines 3r−t provides some insight on the

reaction mechanism, which thus appears to be initiated by the β-

elimination of the OH group. This transformation is rare in

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(1) HO⁻elimination triggered by deprotonation at the

propargylic position to form the transient conjugated

imine 3u.

Scheme 4. Isomerization of Propargylic Hydroxylamines:

Inﬂuence of Alkyl or Phenyl Substituent at the Acetylenic

Position

(2) Addition of HO⁻to 3u yielding an allenol 5u′.

(3) Keto−enol tautomerization of 5u′ to conduct to

deprotonated enaminone 2u′.

(4) Proton exchange between the reactant 1u and the anionic

product 2u′.

Step one was found to be a syn elimination as, even though the

anti mechanism exhibits a low energy barrier (less than 0.5 kcal

mol⁻¹), it cannot take place in the deprotonated aminol form 1u′,

which is found to be preferred by 22.0 kcal mol⁻¹over the

structure leading to the anti process. Step two is associated with

the addition of the HO⁻at the position 4 of the imine 3u to yield

allenol 5u′, but no reprotonation of the amide is observed. As for

the starting aminol 1u, when including an explicit water molecule

in the modeled system, the most stable form is associated to a

delocalized organic anion and a water molecule. An anionic

structure is also predominant after the tautomerization, step 3, as

the protonation at the central carbon of allenol 5u′ and the

deprotonation of the OH group are simultaneous and mediated

through an H-bonded water molecule. Even though the

proposed reaction step already leads to the right Z/E isomer of

2u′, isomerization within this structure is easy, as rotation

between the Z and E isomers exhibit an energy barrier of only 5.7

kcal mol⁻¹. The last step of the reaction mechanism is a

reprotonation of 2u′ by the starting material (1u in Scheme 5) to

yield the ﬁnal product 2u, which is found to be exothermic by 1.3

kcal/mol⁻¹and thus fully equilibrated. The overall energy proﬁle

is reported in Figure 1.

literature,¹⁵and we were particularly puzzled that it could

proceed at relatively low temperature in basic conditions.

Moreover, the synthesis of β-enaminones from imines was not

documented. We thus decided to elucidate the mechanism of this

isomerization, and starting from the observation that imines were

formed in the reaction mixture, a mechanism model was sought

using a computational approach (DFT based; see Theoretical

Section for details). A complete catalytic path was found,

including the succession of steps described in Scheme 5.

Scheme 5. Computed Mechanism for the Isomerization

Process

Figure 1. Energy proﬁle (energies in italics are given in kcal/mol) of the

HO⁻catalyzed isomerization process. Numbers are introduced in

Scheme 5.

This reaction proﬁle is found to be in complete agreement with

experimental observations. The ﬁrst step of this reaction path is

supported by the lack of reactivity when a weak base such as NEt₃

(pK_a< 10) is used (see Table 1, entry 2). We also observed a

drastic drop of the conversion when the reaction is conducted in

strictly anhydrous conditions under argon atmosphere, which

conﬁrms the crucial role of water in the catalytic process.¹³In two

additional control experiments, we conﬁrmed this hypothesis by

submitting propargylic hydroxylamines 1v,w to our standard

conditions (Scheme 6, eq 1). As expected, no reaction occurs,

The full reaction sequence was found to take place in the

anionic, deprotonated form, in the presence of water. It is starting

from the deprotonated aminol 1u′ that is readily formed upon

geometry optimization when HO⁻is associated to 1u (no cation

is considered since ion pairs are supposed to exclusively exist as

solvent separated ion pairs (SSIP) in such a polar solvent; see

Theoretical Section). The following steps are observed, where

the deprotonated forms are noted with prime:

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Scheme 6. Complementary Experiments Performed to

Support the Mechanistic Model

Table 2. Energies of the Various Stereoisomers Relative to the

Most Stable One for Each Model

E-trans

E-cis

Z-trans

Z-cis

model A

model B

4.0

9.5

6.9

4.1

3.0

5.1

9.9

6.8

5.3

3.5

6.8

8.3

7.2

4.4

0.0

5.6

2u_solv

2u′

In kcal/mol⁻¹. The subscript “solv” stands for results in a continuum

model for the solvent.

model B) and stabilization by an H-bond (about 4 kcal/mol⁻¹),

the latest being weakened (by about 2.7 kcal/mol⁻¹) in presence

of a polar solvent. This double eﬀect sheds a new light on the

commonly accepted picture of stabilization by intramolecular H-

bonding.¹⁷

and the starting material is fully recovered. In this case, because of

the replacement of the aryl by an alkyl group in the propargylic

position, the propargylic proton is not acidic enough to allow the

ﬁrst deprotonation step. As evidence for the second step of our

proposed mechanism, the formation of imines is observed when

a sterically hindered t-Bu substituent stands in the acetylenic

position (Scheme 4, eq 3) or when the intermediate imine is fully

conjugated (Scheme 4, eq 4), i.e., when the 1,4 addition step is

disfavored. Moreover, when imine 3a¹⁶was subjected to a

stoichiometric amount of NaOH, the corresponding enaminone

2a was obtained in almost quantitative yield, which shows that

imine is a reaction intermediate (Scheme 6, eq 2).

To complete the theoretical study, the stereoselectivity of the

ﬁnal product was examined computationally through the relative

stability of the ﬁnal product 2u: indeed, the low isomerization

barrier between Z and E forms found in 2u′ associated with the

equilibrium of reprotonation of 2u′ to 2u let us conclude that

both isomers are in thermodynamic equilibrium in the ﬁnal

product. Geometry optimization was thus carried out on the

products, using increasing size models (see Figure 2): model A,

where only H-bond can stabilize the structure, model B where Ph

and Me substituent eﬀects are taken into account, and 2u, which

adds the C(O)OMe group at the nitrogen atom, with or without

the eﬀect of a continuous representation of the solvent. An

anionic model 2u′ deprotonated at the nitrogen and thus unable

to stabilize through H-bonding is also examined. Results are

given in Table 2. Whatever the model, a Z stereoisomer is

systematically favored over the E one and is evaluated to 6.8 kcal

mol⁻¹in the case of the model 2u (4.1 kcal/mol⁻¹in presence of

a continuum model of the solvent). In absence of substituent

eﬀects, and thus when only the H-bond is at stake, the preference

is only 4.0 kcal mol⁻¹, in good agreement with the results

published for similar species.¹⁷In absence of H-bonding, in the

anionic form, the preference for the Z form is maintained, with a

3.0 kcal mol⁻¹value. It is thus found that the preference for the Z

isomer is due both to substituent eﬀects (about 3 kcal/mol⁻¹,

steric hindrance of the Ph and Me in the E isomer, see Figure 2,

In the ﬁrst part of our work, we explored the isomerization of

propargylic hydroxylamine into β-enaminones and built a

plausible mechanism for this original transformation. We next

decided to explore the synthetic potential of the Cbz-protected

enaminones 2. We reasoned that enaminone could represent

interesting building block for the synthesis of heterocyclic

compounds such as pyrimidines. Indeed, the presence of a

geometrically deﬁned double bond as well as a nucleophilic

nitrogen and an electrophilic carbonyl groups should allow the

development of an alternative synthesis based on the use of a

complementary electrophile/nucleophile partner such as

carboxamide, in a classical ionic cyclocondensation process. To

test this hypothesis, the reactivity of enaminone 2a with

benzamide was screened under various conditions (Table 3).

Table 3. Formation of Pyrimidine 6 from Enaminone 2a and

Benzamide: Optimization Study

additives

(equiv)

conditions

product (isolated yield)

PTSA (0.1)

Dean−Stark,

reﬂux, 3 d

complex reaction mixture containing 6

and 7 in a 1:1 ratio

MeONa (1)

DBU (1)

sealed vial,

130 °C, 1 h

“

6 (30%) (6:8 in a 1:1 ratio is observed

in the crude material)

6 (14%) (7 is observed as the major

compound)

tBuOK (1)

tBuOK (1.5)

tBuOK (2)

“

6 (51%) (2a is recovered in 35% yield)

6 (76%)

6 (80%)

Figure 2. Models examined for relative stability of the Z and E isomers.

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Scheme 7. Attempts of Cyclocondensation Starting from Benzonitrile or Cbz-Deprotected 8

Scheme 8. Gram Scale Synthesis of Pyrimidine 6 from Propargylic Hydroxylamine 1a

Under acidic conditions (entry 1), the expected pyrimidine 6

was observed along with the hydrolysis product 7 (1:1 ratio along

with unidentiﬁed products). In contrast, in the presence of

MeONa (entry 2), pyrimidine 6 could be isolated in 30% yield.

This low yield results from the competitive formation of the Cbz

deprotected enaminone 8 (6 and 8 are in a 1:1 ratio in the crude

mixture). To avoid the competitive Cbz deprotection, the use of

bulkier bases such as DBU or t-BuOK was investigated. Whereas

deceptive results were observed with DBU (entry 3), the use of 1

equiv of t-BuOK led to 6 in 51% yield, along with unreacted

starting material 2a (35%) (entry 4). The amount of base is

crucial, and 2 equiv of t-BuOK appeared to be necessary to gain

full conversion and produce pyrimidine 6 in 80% yield (see

entries 5 and 6). Unfortunately, all tries to set up an eﬃcient one-

pot two-step access to pyrimidines from N-hydroxypropargyl-

amines 1 failed.¹⁸Indeed, the isolated yield was lowered

compared to the stepwise process due to the presence of

deprotected enaminone.

Attempt to use a nitrile as coupling partner gave unsatisfying

results: when enaminone 2a and benzonitrile were engaged in

the previously optimized reaction conditions, pyrimidine 6 and

deprotected enaminone 8 were obtained in 28 and 26% yield,

respectively (Scheme 7, eq 1). Of note, when 8 was treated with

benzamide, no trace of pyrimidine could be observed in the crude

mixture, which highlights (i) that 8 is not an intermediate in the

formation of 6 and (ii) the crucial role of the Cbz protecting

group for the reaction process (Scheme 7, eq 2). Consequently,

some insights into the mechanistic pathway can be brought

forward. These two remarks give some insights to the

mechanistic pathway of this transformation. If the exact course

of the nucleophilic attack steps remains unclear, it seems

reasonable to assume that the removal of the Cbz group should

occur during the aromatization step, as recently proposed by

Kuninobu and Takai for the formation of multisubstituted

pyridines.¹⁹

For practical reasons, these optimization studies have been

carried out on small scale (0.2 mmol), using sealed vials.

Consequently, these optimized conditions were next tried on a

larger scale, using classical glassware, and gratifyingly, pyrimidine

6 was isolated in 81% yield (3.05 mmol, 880 mg, Scheme 8).

With our optimized conditions (2.0 equiv of tBuOK in

reﬂuxing toluene), the scope and limitations of this pyrimidine

synthesis were surveyed. As illustrated in Scheme 9, diﬀerently

substituted enaminones lead, in the presence of carboxamides, to

the corresponding pyrimidines 6, 9−22 in moderate to good

yields. Starting from benzamide, pyrimidines 6, 9−16 were

obtained in 52−89% yields. Interestingly, the presence of

electron-donating groups at the meta or para position has a

positive inﬂuence on the yield. Nevertheless, halogen sub-

stituents are tolerated, and notably, the presence of a bromine

atom in compound 13 allows for further functionalization. The

nature of the alkyl substituent (primary or secondary) at the

carbonyl group (R²) has little inﬂuence (compounds 17, 18),

whereas a slight decrease in yield is observed when R²is a phenyl

group (54%, compound 19). The scope has been successfully

extended to heteroaromatic (20) and para-nitro and -bromo

substituted arenes (21 and 22, respectively).

2-Vinyl substituted pyrimidines are particularly interesting

substrates,²⁰usually obtained via cross-coupling reaction from

the corresponding 2-chloro pyrimidines. Starting from acryl-

amide, pyrimidines 23−25 have been obtained in 55, 51, and

46% yields, respectively (Scheme 10). Anticipating that these

pyrimidines could be sensitive to polymerization, the same

reactions were carried out in the presence of TEMPO (1 equiv)

as a radical inhibitor. Under these conditions, pyrimidines 23−25

were obtained in improved 72, 69, and 68% yields, respectively.

Finally, simple alkyl carboxamides, such as acetamide, can be

used as partners for this reaction, leading to 26 with a satisfying

72% isolated yield. Starting from formamide, the use of molecular

sieves proved to be detrimental, but in its absence, 4,6-

disubstituted pyrimidine 19 was ﬁnally obtained in 49% yield.

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Scheme 9. Synthesis of Pyrimidines from Aromatic and Heteroaromatic Carboxamides: Scope and Limitations

General conditions: vinylogous amide (0.2 mmol), amide (0.3 mmol, 1.5 equiv), t-BuOK (0.4 mmol, 2 equiv), 4 Å MS (70 mg), PhCH₃(2 mL, 0.1

M), 130 °C, 1 h.

novel access to pyrimidines with stable, commercially available

and inexpensive carboxylic amides.

CONCLUSIONS

■

In conclusion, we described a catalytic and stereoselective

isomerization of readily available propargylic hydroxylamines 1

leading β-enaminones 2 under simple and eﬃcient conditions

(NaOH 10 mol %, 1 h). This unanticipated transformation was

rationalized with the help of an intertwined theoretical/

experimental study that allows determining each step of the

catalytic pathway, i.e., β-elimination, 1,4-addition and tautome-

rization. The ﬁrst β-elimination step, which leads to the N−O

bond breaking, is of particular interest since it occurs via an

original water-assisted six-membered syn elimination process.

Moreover, the model generally admitted to explain the

preference for Z form of β-enaminone has been revisited, and

besides the internal stabilizing H-bonding, the substituents eﬀect

has been highlighted. The synthetic potential of Cbz-protected

β-enaminones 2 was illustrated through the development of a

THEORETICAL SECTION

■

Full geometry optimizations were systematically conducted with no

symmetry restraints using the Gaussian 09 program²¹within the

framework of the Density Functional Theory (DFT) using the

dispersion corrected B97D²²exchange-correlation functional (which

was shown to give good results on similar questions²³) and the 6-

31+G** basis set for all atoms. Frequencies were evaluated within the

harmonic approximation and the nature of all minima was ensured by

conﬁrming the presence of no imaginary frequency. A model system 1u

was examined, derived from 1i by replacing the Cbz C(O)OCH₂Ph

group by a simple C(O)OMe one, which is proposed to be a minor

modiﬁcation as (i) no major electronic eﬀect as conjugation is supposed

to be altered as non is expected for this group and (ii) the benzyl group is

ﬂexible enough to behave sterically like a methyl in this kind of

compound. Solvation was taken into account using an implicit solvation

model, and all geometry were fully optimized in presence of the

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was puriﬁed by ﬂash chromatography on silica gel to give the

corresponding β-enaminone.

Scheme 10. Synthesis of Pyrimidines from Various

Carboxamide Derivatives

Gram-Scale Procedure for the Obtention of (Z)-Benzyl (3-

oxo-1-phenylhept-1-en-1-yl)carbamate (2a). In a 250 mL-round-

bottom ﬂask equipped with a magnetic stirrer bar and a condenser, the

benzyl hydroxy(1-phenylhept-2-yn-1-yl)hept-2-yn-1-yl)carbamate 1a

(1770 mg, 5.25 mmol, 1 equiv), NaOH powder (22 mg, 0.55 mmol,

0.1 equiv) were added in acetonitrile (50 mL), and the mixture was

heated at 50 °C for 1 h. The reaction mixture was cooled and then

ﬁltered oﬀ through a silica gel pad and eluted with ethyl acetate, and the

ﬁltrate was concentrated. 1630 mg of the title compound 2a (4.83 mmol,

92% yield) and 70 mg of (E)-benzyl (1-phenylhept-2-yn-1-ylidene)-

carbamate 3a (0.21 mmol, 4% yield) were obtained after puriﬁcation by

ﬂash chromatography on silica gel (pentane/Et₂O 92/8).

General Procedure C for the Preparation of Pyrimidines (6,

9−22, 26, 27). In a 5 mL Wheaton reactor (screw top V-Vials with

open-top cap) equipped with a magnetic stirrer bar, the corresponding

vinylogous amide (0.2 mmol, 1 equiv), the corresponding amide (0.3

mmol, 1.5 equiv), 4 Å MS (70 mg) and potassium tert-butoxide (0.4

mmol, 2 equiv) were introduced by turn in toluene (2 mL), and the

mixture was heated at 130 °C for 1 h. The reaction mixture was then

ﬁltered oﬀ through a silica gel pad and eluted with ethyl acetate. The

ﬁltrate was concentrated, and the residue was puriﬁed by ﬂash

chromatography on silica gel to give the corresponding pyrimidine.

Gram-Scale Procedure for the Obtention of 4-Butyl-2,6-

diphenylpyrimidine (6). In an oven-dried 100 mL-round-bottom

ﬂask equipped with a magnetic stirrer bar and a condenser, the (Z)-

benzyl (3-oxo-1-phenylhept-1-en-1-yl)carbamate 2a (1280 mg, 3.80

mmol, 1 equiv), benzamide (740 mg, 6.10 mmol, 1.6 equiv), 4 Å MS

(1300 mg) and potassium tert-butoxide (908 mg, 8.mmol, 2.6 equiv)

toluene were introduced by turn, and the mixture was heated at reﬂux for

1 h under argon. The reaction mixture was cooled and then ﬁltered

through a silica gel pad and eluted with ethyl acetate, and the ﬁltrate was

concentrated. 880 mg of the title compound 6 (3.05 mmol, 81% yield)

were obtained after puriﬁcation by ﬂash chromatography on silica gel

(pentane/Et₂O 98/2).

General Procedure D for the Preparation of 2-Vinyl-

Substituted Pyrimidines (23−25). In a 5 mL Wheaton reactor

(screw top V-Vials with open-top cap) equipped with a magnetic stirrer

bar, the corresponding vinylogous amide (0.2 mmol, 1 equiv), the

corresponding amide (0.3 mmol, 1.5 equiv), 4 Å MS (70 mg), TEMPO

(0.2 mmol, 1 equiv) and potassium tert-butoxide (0.4 mmol, 2 equiv)

were introduced by turn in toluene (2 mL), and the mixture was heated

at 130 °C for 1 h. The reaction mixture was then ﬁltered oﬀ through a

silica gel pad and eluted with ethyl acetate. The ﬁltrate was concentrated,

and the residue was puriﬁed by ﬂash chromatography on silica gel to give

the corresponding pyrimidine.

Benzyl hydroxy(1-phenylhept-2-yn-1-yl)carbamate (1a). Ac-

cording to general procedure A (on 2 mmol scale) and starting from 1-

phenylhept-2-yn-1-ol and benzyl hydroxycarbamate, 626.0 mg of

compound 1a (1.855 mmol, 93% yield) were obtained as a pale yellow

solid after puriﬁcation by ﬂash chromatography on silica gel (pentane/

ethyl acetate 88/12): R_f(silica, pentane/ethyl acetate 9/1 = 0.25, UV/

PMA); mp 58−59 °C (Et₂O/pentane); ¹H NMR (400 MHz, CDCl₃) δ

(ppm) 0.92 (t, J = 7.3 Hz, 3H), 1.39−1.59 (m, 4H), 2.29 (dt, J = 2.2 Hz

and J = 7.1 Hz, 2H), 5.26 (s, 2H), 5.59 (brs, 1H), 6.13 (t, J = 2.1 Hz, 1H),

7.29−7.42 (m, 8H), 7.50−7.56 (m, 2H); ¹³C NMR (100 MHz, CDCl₃)

δ (ppm) 13.6, 18.5, 22.0, 30.6, 55.9, 68.4, 74.5, 87.1, 127.9, 128.1, 128.2,

128.4, 128.6, 135.6, 136.2, 157.1; IR (ATR, neat) ν (cm⁻¹) 3225, 2957,

2928, 2872, 2859, 2222, 1959, 1704, 1495, 1481, 1453, 1443, 1394,

1346, 1290, 1097, 1030, 959, 763, 743, 713, 694, 636, 608; MS (ESI+)

m/z 675 (15, [2M + H]⁺), 508 (45), 464 (100), 338 (50, [M + H]⁺), 320

(15), 261 (20); HRMS (ESI+) m/z 338.1742 calcd for C₂₁H₂₃NO₃+ H⁺

338.1756.

Reaction conducted with addition of TEMPO (0.2 mmol, 1 equiv).

Reaction carried out without 4 Å MS, and starting enaminone 2a was

recovered in 26% yield. General conditions: vinylogous amide (0.2

mmol), amide (0.3 mmol, 1.5 equiv), t-BuOK (0.4 mmol, 2 equiv), 4

Å MS (70 mg), PhCH₃(2 mL, 0.1 M), 130 °C, 1 h.

continuum. For these computations, the PCM model was used within

the default framework implemented in Gaussian 09,²⁴except for atomic

radii where the UFF values are used. The dielectric constant

implemented for DMSO (ε_R= 46.826) was used, a value slightly higher

than that for acetonitrile (ε_R= 35.688), in order to take into account the

presence of non-negligible amount of water in the reaction media. The

key intermediates were reoptimized in a model of acetonitrile in order to

conﬁrm the validity of this approach. Because of the high polarity of the

solvent, NaOH is considered as a fully dissociated ion pair, and no Na⁺

cation is included in the computational model.

EXPERIMENTAL SECTION

■

General Considerations. Unless otherwise stated, all commercial

materials were used without further puriﬁcation. Spherical 4 Å MS is

used when needed. Chromatography was carried out on silica gel 60 A

(35−70 mm). PMA stands for phosphomolybdic acid (ethanolic

solution) and is used as TLC stain. Solvents (acetonitrile, toluene and

methanol) were used without further puriﬁcation. H and ¹³C NMR

spectra were obtained on a 400 MHz NMR spectrometer and referenced

to CDCl₃. ¹⁹F NMR spectra are calibrated using C₆F₆as an external

standard. High resolution mass spectra (HRMS) were measured using

electrospray ionization and were acquired using a Q-TOF analyzer.

Propargylic alcohols have already been described and were easily

obtained by the addition of the corresponding alkynyl lithium reagent

(in anhydrous THF) to the corresponding aldehyde.^9c,25

General Procedure A for the Preparation of Propargylic

Hydroxylamines (1a−t). To a solution of the corresponding

propargylic alcohol (1 equiv) in dichloromethane (C = 0.1 M) was

added N-hydroxybenzenesulfonamide (1 equiv) and FeCl₃(5 mol %,

0.05 equiv), and the mixture was reﬂuxed for 90 min. After reaction

completion (TLC monitoring), the mixture was concentrated under

vacuum, and the crude material was puriﬁed by ﬂash chromatography on

silica gel to give the corresponding N-propargylic hydroxylamine.

General Procedure B for the Preparation of β-Enaminones

(2a−t). In a 5-mL Wheaton reactor, equipped with a magnetic stirrer

bar, the corresponding N-propargylic hydroxylamine (0.2 mmol, 1

equiv), and NaOH powder (0.02 mmol, 0.1 equiv) were added in

acetonitrile (2 mL) by turn, and the mixture was heated at 50 °C for 1 h.

Thus, the reaction mixture was ﬁltered oﬀ through a silica gel pad and

eluted with ethyl acetate, the ﬁltrate was concentrated, and the residue

Benzyl hydroxy(1-(p-tolyl)hept-2-yn-1-yl)carbamate (1b).

According to general procedure A (on 2 mmol scale) and starting

from 1-p-tolylhept-2-yn-1-ol and benzyl hydroxycarbamate, 659.5 mg of

compound 1b (1.876 mmol, 94% yield) were obtained as a viscous pale

yellow oil after puriﬁcation by ﬂash chromatography on silica gel

(pentane/ethyl acetate 88/12): R_f(silica, pentane/ethyl acetate 9/1 =

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0.25, UV/PMA); ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.92 (t, J = 7.2

Hz, 3H), 1.38−1.58 (m, 4H), 2.28 (dt, J = 2.1 Hz and J = 7.0 Hz, 2H),

2.34 (s, 3H), 5.25 (s, 2H), 5.55 (brs, 1H), 6.09 (t, J = 2.1 Hz, 1H), 7.15

(∼d, J = 8.0 Hz, 2H), 7.31−7.44 (m, 7H); ¹³C NMR (100 MHz, CDCl₃)

δ (ppm) 13.6, 18.5, 21.1, 22.0, 30.6, 55.6, 68.3, 74.7, 87.3, 127.9, 128.2,

128.4, 128.5, 129.1, 133.2, 135.6, 138.0, 157.1; IR (ATR, neat) ν (cm⁻¹)

3314, 3032, 2956, 2931, 2871, 2233, 1702, 1513, 1497, 1455, 1409,

1350, 1328, 1282, 1214, 1180, 1093, 797, 771, 751, 734, 695; MS (ESI+)

m/z 536 (15), 492 (15), 352 (10, [M + H]⁺), 334 (55), 216 (10), 185

(100); HRMS (ESI+) m/z 352.1910 calcd for C₂₂H₂₅NO₃+ H⁺

352.1913.

pentane/ethyl acetate 9/1 = 0.3, UV/PMA); H NMR (400 MHz,

CDCl₃) δ (ppm) 0.99 (t, J = 7.2 Hz, 3H), 1.45−1.67 (m, 4H), 2.36 (dt, J

= 2.0 Hz and J = 7.0 Hz, 2H), 5.26 (s, 2H), 6.23 (brs, 1H), 6.68 (brs,

1H), 7.31−7.52 (m, 8H), 7.58−7.70 (m, 6H); ¹³C NMR (100 MHz,

CDCl₃) δ (ppm) 13.5, 18.4, 21.9, 30.5, 55.4, 68.2, 74.7, 87.3, 126.9,

127.0, 127.3, 128.0, 128.2, 128.3, 128.4, 128.6, 135.4, 135.5, 140.5, 140.9,

157.2; IR (ATR, neat) ν (cm⁻¹) 3300, 2956, 2932, 2871, 1955, 1699,

1455, 1397, 1345, 1295, 1277, 1092, 1030, 797, 790, 777, 734, 695, 634;

MS (ESI+) m/z 414 (10, [M + H]⁺), 396 (25), 288 (15), 247 (100), 216

(10); HRMS (ESI+) m/z 414.2054 calcd for C₂₇H₂₇NO₃+ H⁺

414.2069.

Benzyl (1-(4-ﬂuorophenyl)hept-2-yn-1-yl)(hydroxy)-

carbamate (1c). According to general procedure A (on 0.5 mmol

scale) and starting from 1-(4-ﬂuorophenyl)hept-2-yn-1-ol and benzyl

hydroxycarbamate, 594.0 mg of compound 1c (1.671 mmol, 84% yield)

were obtained as a pale yellow oil after puriﬁcation by ﬂash

chromatography on silica gel (pentane/ethyl acetate 88/12): R_f(silica,

Benzyl hydroxy(1-(m-tolyl)hept-2-yn-1-yl)carbamate (1g).

According to general procedure A (on 1 mmol scale) and starting

from 1-m-tolylhept-2-yn-1-ol and benzyl hydroxycarbamate, 291.3 mg

of compound 1g (0.829 mmol, 83% yield) were obtained as a yellow oil

after puriﬁcation by ﬂash chromatography on silica gel (pentane/ethyl

acetate 88/12): R_f(silica, pentane/ethyl acetate 85/15 = 0.4, UV/

PMA); ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.94 (t, J = 7.2 Hz, 3H),

1.39−1.60 (m, 4H), 2.30 (dt, J = 2.1 Hz and J = 7.0 Hz, 2H), 2.35 (s,

3H), 5.25 (s, 2H), 5.92 (brs, 1H), 6.10 (brs, 1H), 7.13 (∼d, J = 7.3 Hz,

1H), 7.21−7.25 (m, 1H), 7.31−7.43 (m, 7H); ¹³C NMR (100 MHz,

CDCl₃) δ (ppm) 13.6, 18.5, 21.5, 22.0, 30.7, 55.8, 68.4, 74.8, 87.5, 125.1,

128.2, 128.3, 128.4, 128.6, 128.7, 129.0, 135.7, 136.3, 138.1, 157.2; IR

(ATR, neat) ν (cm⁻¹) 3302, 3033, 2956, 2931, 2871, 1702, 1455, 1404,

1350, 1281, 1092, 1029, 961, 753, 736, 719, 695; MS (ESI+) m/z 703 (5,

[2M + H]⁺), 536 (100), 519 (75), 492 (60), 459 (25), 369 (25), 352

(75, [M + H]⁺), 334 (80), 308 (60), 275 (75), 216 (25); HRMS (ESI+)

m/z 352.1909 calcd for C₂₂H₂₅NO₃+ H⁺352.1913.

Benzyl hydroxy(1-(3-methoxyphenyl)hept-2-yn-1-yl)-

carbamate (1h). According to general procedure A (on 2 mmol

scale) and starting from 1-(3-methoxyphenyl)hept-2-yn-1-ol and benzyl

hydroxycarbamate, 570.0 mg of compound 1h (1.551 mmol, 78% yield)

were obtained as an orange oil after puriﬁcation by ﬂash chromatog-

raphy on silica gel (pentane/ethyl acetate 85/15): R_f(silica, pentane/

ethyl acetate 85/15 = 0.3, UV/PMA); ¹H NMR (400 MHz, CDCl₃) δ

(ppm) 0.93 (t, J = 7.3 Hz, 3H), 1.39−1.60 (m, 4H), 2.29 (dt, J = 2.2 Hz

and J = 7.0 Hz, 2H), 3.76 (s, 3H), 5.23 (s, 2H), 6.11 (t, J = 2.1 Hz, 1H),

6.33 (brs, 1H), 6.84 (ddd, J = 0.7 Hz, J = 2.4 Hz and J = 8.1 Hz, 1H),

7.10−7.15 (m, 2H), 7.25 (t, J = 8.1 Hz, 1H), 7.30−7.41 (m, 5H); ¹³C

NMR (100 MHz, CDCl₃) δ (ppm) 13.5, 18.4, 21.9, 30.6, 55.1, 55.6,

68.3, 74.7, 87.3, 113.5, 113.8, 120.2, 128.1, 128.2, 128.5, 129.3, 135.6,

137.9, 157.1, 159.5; IR (ATR, neat) ν (cm⁻¹) 3305, 2957, 2933, 2872,

1703, 1601, 1586, 1489, 1454, 1433, 1404, 1350, 1279, 1223, 1159,

1093, 1043, 755, 737, 719, 695, 639; MS (ESI+) m/z 568 (50), 401

(100), 368 (15, [M + H]⁺), 350 (20), 291 (80), 201 (50); HRMS (ESI

+) m/z 368.1854 calcd for C₂₂H₂₅NO₄+ H⁺368.1862.

pentane/ethyl acetate 9/1 = 0.25, UV/PMA); H NMR (400 MHz,

CDCl₃) δ (ppm) 0.92 (t, J = 7.3 Hz, 3H), 1.39−1.58 (m, 4H), 2.28 (dt, J

= 2.1 Hz and J = 7.1 Hz, 2H), 5.23 (s, 2H), 6.03 (brs, 1H), 6.07 (brs,

1H), 7.01 (∼t, J = 8.7 Hz, 2H), 7.31−7.40 (m, 5H), 7.49 (∼dd, J = 5.4

Hz and J = 8.5 Hz, 2H). ¹⁹F NMR (376 MHz, CDCl₃) δ (ppm) −114.0;

¹³C NMR (100 MHz, CDCl₃) δ (ppm) 13.6, 18.4, 22.0, 30.6, 55.1, 68.4,

74.5, 87.7, 115.2 (d, J_ortho(C−F)= 21.7 Hz), 128.2, 128.4, 128.6, 129.8 (d,

J_meta(C−F)= 8.3 Hz), 132.1 (d, J_para(C−F)= 3.0 Hz), 135.5, 157.1, 162.5 (d,

J_ipso(C−F)= 246.7 Hz); IR (ATR, neat) ν (cm⁻¹) 3300, 2956, 2932, 2233,

1955, 1699, 1455, 1397, 1345, 1295, 1277, 1252, 1092, 1030, 797, 790,

777, 753, 734, 695, 634; MS (ESI+) m/z 523 (15), 356 (20, [M + H]⁺),

338 (100), 294 (25), 288 (10), 220 (40), 189 (90); HRMS (ESI+) m/z

356.1660 calcd for C₂₁H₂₂FNO₃+ H⁺356.1662.

Benzyl (1-(4-chlorophenyl)hept-2-yn-1-yl)(hydroxy)-

carbamate (1d). According to general procedure A (on 4 mmol

scale) and starting from 1-(4-chlorophenyl)hept-2-yn-1-ol and benzyl

hydroxycarbamate, 1.290 g of compound 1d (3.469 mmol, 87% yield)

were obtained as a viscous colorless oil after puriﬁcation by ﬂash

chromatography on silica gel (pentane/ethyl acetate 88/12): R_f(silica,

pentane/ethyl acetate 9/1 = 0.25, UV/PMA); H NMR (400 MHz,

CDCl₃) δ (ppm) 0.92 (t, J = 7.3 Hz, 3H), 1.37−1.58 (m, 4H), 2.28 (dt, J

= 2.1 Hz and J = 7.1 Hz, 2H), 5.23 (s, 2H), 5.97 (brs, 1H), 6.06 (brs,

1H), 7.30 (∼d, J = 8.5 Hz, 2H), 7.32−7.39 (m, 5H), 7.45 (∼d, J = 8.4 Hz,

2H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 13.6, 18.4, 22.0, 30.6, 55.2,

68.5, 74.2, 87.9, 128.2, 128.4, 128.5, 128.6, 129.4, 134.1, 134.9, 135.5,

157.2; IR (ATR, neat) ν (cm⁻¹) 3297, 2929, 1706, 1491, 1455, 1407,

1292, 1091, 1016, 797, 749, 697; MS (ESI+) m/z 532 (10), 372 (20, [M

+ H]⁺), 295 (10), 205 (100), 189 (20); HRMS (ESI+) m/z 372.1377

calcd for C₂₁H₂₂ClNO₃+ H⁺372.1366.

Benzyl (1-(4-bromophenyl)hept-2-yn-1-yl)(hydroxy)-

carbamate (1e). According to general procedure A (on 0.5 mmol

scale) and starting from 1-(4-bromophenyl)hept-2-yn-1-ol and benzyl

hydroxycarbamate, 177.9 mg of compound 1e (0.427 mmol, 86% yield)

were obtained as a viscous colorless oil after puriﬁcation by ﬂash

chromatography on silica gel (pentane/ethyl acetate 88/12): R_f(silica,

Benzyl (1-(3-bromophenyl)hept-2-yn-1-yl)(hydroxy)-

carbamate (1i). According to general procedure A (on 2 mmol

scale) and starting from 1-(3-bromophenyl)hept-2-yn-1-ol and benzyl

hydroxycarbamate, 526.5 mg of compound 1i (1.264 mmol, 64% yield)

were obtained as an colorless oil after puriﬁcation by ﬂash

chromatography on silica gel (pentane/ethyl acetate 9/1 → 85/15):

R_f(silica, pentane/ethyl acetate 85/15 = 0.4, UV/PMA); ¹H NMR (400

MHz, CDCl₃) δ (ppm) 0.93 (t, J = 7.3 Hz, 3H), 1.38−1.60 (m, 4H),

2.29 (dt, J = 2.2 Hz and J = 7.0 Hz, 2H), 5.26 (s, 2H), 5.67 (brs, 1H), 6.07

(t, J = 2.1 Hz, 1H), 7.19 (t, J = 7.9 Hz, 1H), 7.31−7.41 (m, 5H), 7.42−

7.47 (m, 2H), 7.70 (t, J = 1.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ

(ppm) 13.6, 18.4, 22.0, 30.6, 55.4, 68.6, 73.9, 88.3, 122.5, 126.6, 128.2,

128.5, 128.6, 129.9, 131.1, 131.3, 135.5, 138.6, 157.1; IR (ATR, neat) ν

(cm⁻¹) 3291, 3065, 2956, 2932, 2871, 1703, 1593, 1571, 1455, 1423,

1350, 1281, 1093, 745, 730, 695, 673, 633; MS (ESI+) m/z 418 (30, [M

+ H]⁺,⁸¹Br), 416 (30, [M + H]⁺,⁷⁹Br), 251 (98, ⁸¹Br), 249 (100, ⁷⁹Br);

HRMS (ESI+) m/z 416.0852 calcd for C₂₁H₂₂BrNO₃+ H⁺416.0861.

Benzyl hydroxy(1-(thiophen-2-yl)hept-2-yn-1-yl)carbamate

(1j). According to general procedure A (on 3 mmol scale) and starting

from 1-(thiophen-2-yl)hept-2-yn-1-ol and benzyl hydroxycarbamate,

886.0 mg of compound 1j (2.580 mmol, 86% yield) were obtained as a

yellow oil after puriﬁcation by ﬂash chromatography on silica gel

(pentane/ethyl acetate 9/1): R_f(silica, pentane/ethyl acetate 85/15 =

0.45, UV/PMA); ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.92 (t, J = 7.2

pentane/ethyl acetate 9/1 = 0.25, UV/PMA); H NMR (400 MHz,

CDCl₃) δ (ppm) 0.92 (t, J = 7.3 Hz, 3H), 1.37−1.57 (m, 4H), 2.28 (dt, J

= 2.2 Hz and J = 7.1 Hz, 2H), 5.24 (s, 2H), 5.75 (brs, 1H), 6.04 (brs,

1H),7.31−7.41 (m, 7H), 7.46 (∼d, J = 8.6 Hz, 2H); ¹³C NMR (100

MHz, CDCl₃) δ (ppm) 13.6, 18.4, 22.0, 30.6, 55.3, 68.5, 74.1, 88.0,

122.3, 128.2, 128.5, 128.6, 129.7, 131.5, 135.3, 135.4, 157.2; IR (ATR,

neat) ν (cm⁻¹) 3220, 2956, 2930, 2871, 2236, 1705, 1486, 1442, 1394,

1346, 1298, 1282, 1261, 1100, 1069, 1011, 954, 788, 745, 693, 672, 608;

MS (ESI+) m/z 418 (90, [M + H]⁺,⁸¹Br), 416 (90, [M + H]⁺,⁷⁹Br), 400

(98, ⁸¹Br), 398 (100, ⁷⁹Br), 374 (35, ⁸¹Br), 372 (35, ⁷⁹Br), 341 (30, ⁸¹Br),

339 (30, ⁷⁹Br); HRMS (ESI+) m/z 416.0852 calcd for C₂₁H₂₂BrNO₃+

H⁺416.0861.

Benzyl (1-([1,1′-biphenyl]-4-yl)hept-2-yn-1-yl)(hydroxy)-

carbamate (1f). According to general procedure A (on 1 mmol

scale) and starting from 1-(biphenyl-4-yl)hept-2-yn-1-ol and benzyl

hydroxycarbamate, 288.0 mg of compound 1f (0.696 mmol, 70% yield)

were obtained as a viscous pale yellow oil after puriﬁcation by ﬂash

chromatography on silica gel (pentane/ethyl acetate 9/1): R_f(silica,

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Hz, 3H), 1.38−1.58 (m, 4H), 2.27 (dt, J = 2.2 Hz and J = 7.0 Hz, 2H),

5.24 (s, 2H), 6.00 (brs, 1H), 6.28 (brs, 1H), 6.95 (dd, J = 3.5 Hz and J =

5.1 Hz, 1H), 7.16 (td, J = 1.1 Hz and J = 3.5 Hz, 1H), 7.26 (td, J = 1.2 Hz

and J = 5.2 Hz, 1H), 7.31−7.41 (m, 5H); ¹³C NMR (100 MHz, CDCl₃)

δ (ppm) 13.6, 18.4, 21.9, 30.5, 51.7, 68.5, 74.7, 86.7, 126.0, 126.6, 127.0,

128.2, 128.4, 128.5, 135.4, 139.8, 156.9; IR (ATR, neat) ν (cm⁻¹) 3307,

2955, 2928, 2869, 1646, 1444, 1395, 1345, 1296, 1254, 1092, 932, 912,

820, 756, 695; MS (ESI+) m/z 344 (10, [M + H]⁺), 319 (25), 295 (15),

214 (15), 177 (100); HRMS (ESI+) m/z 344.1339 calcd for

C₁₉H₂₁NO₃S + H⁺344.1320.

H₂and H₃), 2.27 (dt, J = 2.1 Hz and J = 7.1 Hz, 2H, H₄), 5.22 (brs, 2H,

H₁₅), 6.39 (brs, J = 2.1 Hz, 1H, H₇), 6.99−7.06 (m, 1H, H_Ar), 7.16 (dt, J

= 1.0 Hz and J = 7.6 Hz, 1H, H_Ar), 7.28−7.42 (m, 6H, H_Ar), 7.78 (dt, J =

1.8 Hz and J = 7.6 Hz, 1H, H_Ar). ¹⁹F NMR (376 MHz, CDCl₃) δ (ppm)

−117.4; ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 13.5, 18.4, 21.9, 30.6,

49.8 (d, ³J_(C−F)= 4.3 Hz), 68.4, 74.0, 87.4, 115.3 (d, J_ortho(C−F)= 21.3 Hz),

123.6 (d, ²J_(C−F)= 13.2 Hz), 123.8 (d, J = 3.6 Hz), 128.0, 128.2, 128.5,

130.2 (d, J = 8.4 Hz), 131.1 (d, J_para(C−F)= 2.9 Hz), 135.7, 157.1, 160.1

(d, J_ipso(C−F)= 249.4 Hz); IR (ATR, neat) ν (cm⁻¹) 3347, 2958, 2930,

2873, 1667, 1615, 1589, 1490, 1458, 1403, 1343, 1289, 1271, 1231,

1101, 1078, 952, 883, 753, 746, 698, 684, 626, 610; MS (ESI+) m/z 711

(35, [2M + H]⁺), 544 (25), 500 (90), 356 (50, [M + H]⁺), 189 (100);

HRMS (ESI+) m/z 356.1645 calcd for C₂₁H₂₂FNO₃+ H⁺356.1662.

Benzyl hydroxy(1-phenyl-3-(trimethylsilyl)prop-2-yn-1-yl)-

carbamate (1o). According to general procedure A (on 4 mmol

scale) and starting from 1-phenyl-3-(trimethylsilyl)prop-2-yn-1-ol and

benzyl hydroxycarbamate, 1.230 g of compound 1o (3.479 mmol, 87%

yield) were obtained as a colorless oil after puriﬁcation by ﬂash

chromatography on silica gel (pentane/ethyl acetate 85/15): R_f(silica,

Benzyl hydroxy(1-(naphthalen-2-yl)hept-2-yn-1-yl)-

carbamate (1k). According to general procedure A (on 2 mmol

scale) and starting from 1-(naphthalen-2-yl)hept-2-yn-1-ol and benzyl

hydroxycarbamate, 706.0 mg of compound 1k (1.822 mmol, 91% yield)

were obtained as an orange oil after puriﬁcation by ﬂash chromatog-

raphy on silica gel (pentane/ethyl acetate 9/1 → 85/15): R_f(silica,

pentane/ethyl acetate 85/15 = 0.4, UV/PMA); H NMR (400 MHz,

CDCl₃) δ (ppm) 0.95 (t, J = 7.3 Hz, 3H), 1.42−1.63 (m, 4H), 2.35 (dt, J

= 2.2 Hz and J = 7.0 Hz, 2H), 5.28 (s, 2H), 5.62 (brs, 1H), 6.28 (brs,

1H), 7.31−7.44 (m, 5H), 7.46−7.52 (m, 2H), 7.59 (dd, J = 1.8 Hz and J

= 8.5 Hz, 1H), 7.80−7.86 (m, 3H), 8.03 (brs, 1H); ¹³C NMR (100

MHz, CDCl₃) δ (ppm) 13.6, 18.5, 22.0, 30.7, 56.0, 68.5, 74.6, 87.9,

125.5, 126.2, 126.3, 127.3, 127.6, 128.1, 128.2, 128.4, 128.6, 133.1, 133.2,

133.7, 135.6, 157.2; IR (ATR, neat) ν (cm⁻¹) 3290, 3059, 2957, 2932,

2871, 1700, 1455, 1402, 1349, 1288, 1093, 808, 782, 739, 695; MS (ESI

+) m/z 608 (90), 564 (50), 388 (10, [M + H]⁺), 370 (30), 311 (100);

HRMS (ESI+) m/z 388.1919 calcd for C₂₅H₂₅NO₃+ H⁺388.1913.

Benzyl hydroxy(1-(naphthalen-1-yl)hept-2-yn-1-yl)-

carbamate (1l). According to general procedure A (on 1 mmol

scale) and starting from 1-(naphthalen-2-yl)hept-2-yn-1-ol and benzyl

hydroxycarbamate, 237.0 mg of compound 1l (0.613 mmol, 62% yield)

were obtained as a brown oil after puriﬁcation by ﬂash chromatography

on silica gel (pentane/ethyl acetate 9/1): R_f(silica, pentane/ethyl

pentane/ethyl acetate 85/15 = 0.3, UV/PMA); H NMR (400 MHz,

CDCl₃) δ (ppm) 0.22 (s, 9H), 5.25 (s, 2H), 5.73 (brs, 1H), 6.15 (s, 1H),

7.30−7.42 (m, 8H), 7.50−7.55 (m, 2H); ¹³C NMR (100 MHz, CDCl₃)

δ (ppm) −0.1, 56.1, 68.5, 91.9, 99.7, 128.0, 128.2, 128.3, 128.4, 128.5,

128.6, 135.4, 135.5, 156.9; IR (ATR, neat) ν (cm⁻¹) 3276, 3063, 3032,

2959, 1704, 1494, 1455, 1388, 1346, 1286, 1249, 1093, 1046, 1025, 838,

760, 751, 741, 693, 662, 604; MS (ESI+) m/z 707 (15, [2M + H]⁺), 540

(25), 354 (65, [M + H]⁺), 187 (100); HRMS (ESI+) m/z 354.1528

calcd for C₂₀H₂₃NO₃Si + H⁺354.1525.

Benzyl hydroxy(1-phenylbut-2-yn-1-yl)carbamate (1p). Ac-

cording to general procedure A (on 1 mmol scale) and starting from 1-

phenylbut-2-yn-1-ol and benzyl hydroxycarbamate, 232.2 mg of

compound 1p (0.786 mmol, 79% yield) were obtained as a pale yellow

oil after puriﬁcation by ﬂash chromatography on silica gel (pentane/

ethyl acetate 9/1 → 88/12): R_f(silica, pentane/ethyl acetate 8/2 = 0.4,

UV/PMA); ¹H NMR (400 MHz, CDCl₃) δ (ppm) 1.92 (d, J = 2.4 Hz,

3H), 5.24 (s, 2H), 5.99 (brs, 1H), 6.10 (q, J = 2.0 Hz, 1H), 7.28−7.41

(m, 8H), 7.50 − 7.55 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm)

3.7, 55.6, 68.4, 73.9, 82.9, 127.9, 128.1, 128.2, 128.4, 128.5, 135.6, 136.2,

157.1; IR (ATR, neat) ν (cm⁻¹) 3297, 3065, 3033, 2921, 2251, 1955,

1699, 1496, 1452, 1403, 1350, 1283, 1093, 907, 727, 707, 695; MS (ESI

+) m/z 591 (15, [2M + H]⁺), 424 (10), 380 (100), 296 (70, [M + H]⁺),

278 (90), 252 (15), 234 (50), 219 (40), 129 (20); HRMS (ESI+) m/z

296.1282 calcd for C₁₈H₁₇NO₃+ H⁺296.1287.

acetate 9/1 = 0.3, UV/PMA); H NMR (400 MHz, CDCl₃) δ (ppm)

0.95 (t, J = 7.3 Hz, 3H), 1.42−1.52 (m, 2H), 1.54−1.63 (m, 2H), 2.34

(dt, J = 2.0 Hz and J = 7.1 Hz, 2H), 5.23 (s, 2H), 5.73 (brs, 1H), 6.83

(brs, 1H), 7.32−7.43 (m, 5H), 7.44−7.52 (m, 3H), 7.81−7.87 (m, 2H),

8.02−8.08 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 13.6, 18.5,

22.0, 30.6, 53.3, 68.3, 74.7, 88.0, 123.0, 125.0, 125.7, 126.5, 127.9, 128.1,

128.3, 128.5, 128.7, 129.3, 130.6, 131.2, 133.7, 135.7, 157.0; IR (ATR,

neat) ν (cm⁻¹) 3297, 2956, 2931, 2871, 1948, 1703, 1455, 1398, 1347,

1296, 1278, 1095, 797, 790, 778, 754, 737, 696; MS (ESI+) m/z 608

(10), 388 (5, [M + H]⁺), 311 (20), 221 (100); HRMS (ESI+) m/z

388.1920 calcd for C₂₅H₂₅NO₃+ H⁺388.1913.

Benzyl hydroxy(4-methyl-1-phenylpent-2-yn-1-yl)-

carbamate (1q). According to general procedure A (on 0.5 mmol

scale) and starting from 4-methyl-1-phenylpent-2-yn-1-ol and benzyl

hydroxycarbamate, 140.8 mg of compound 1q (0.436 mmol, 88% yield)

were obtained as a pale yellow solid after puriﬁcation by ﬂash

chromatography on silica gel (pentane/ethyl acetate 9/1 → 88/12):

R_f(silica, pentane/ethyl acetate 9/1 = 0.25, UV/PMA); mp 78−79 °C

(Et₂O/pentane); ¹H NMR (400 MHz, CDCl₃) δ (ppm) 1.21 (d, J = 6.9

Hz, 3H), 1.22 (d, J = 6.9 Hz, 3H), 2.66 (septd, J = 2.0 Hz and J = 6.8 Hz,

1H), 5.26 (s, 2H), 5.60 (brs, 1H), 6.13 (d, J = 1.8 Hz, 1H), 7.28−7.42

(m, 8H), 7.50−7.55 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm)

20.6, 22.9, 55.7, 68.4, 73.7, 93.0, 127.9, 128.1, 128.2, 128.4, 128.5, 135.6,

136.2, 157.1; IR (ATR, neat) ν (cm⁻¹) 3300, 2967, 2927, 2877, 2255,

1967, 1888, 1754, 1655, 1495, 1448, 1415, 1349, 1288, 1099, 1030, 956,

883, 752, 739, 698, 634; MS (ESI+) m/z 647 (10, [2M + H]⁺), 491 (10),

480 (20), 436 (100), 324 (98, [M + H]⁺), 306 (25), 247 (25), 157 (20);

HRMS (ESI+) m/z 324.1592 calcd for C₂₀H₂₁NO₃+ H⁺324.1600.

Benzyl hydroxy(4,4-dimethyl-1-phenylpent-2-yn-1-yl)-

carbamate (1r). According to general procedure A (on 0.5 mmol

scale) and starting from 4,4-dimethyl-1-phenylpent-2-yn-1-ol and

benzyl hydroxycarbamate, 148.7 mg of compound 1r (0.441 mmol,

89% yield) were obtained as a pale yellow solid after puriﬁcation by ﬂash

chromatography on silica gel (pentane/ethyl acetate 88/12): R_f(silica,

pentane/ethyl acetate 9/1 = 0.25, UV/PMA); mp 100−102 °C (Et₂O/

pentane); ¹H NMR (400 MHz, CDCl₃) δ (ppm) 1.27 (s, 9H), 5.26 (s,

2H), 5.59 (brs, 1H), 6.12 (s, 1H), 7.28−7.42 (m, 8H), 7.50−7.54 (m,

2H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 27.6, 30.9, 55.7, 68.3, 72.9,

Benzyl hydroxy(1-(o-tolyl)hept-2-yn-1-yl)carbamate (1m).

According to general procedure A (on 1 mmol scale) and starting

from 1-o-tolylhept-2-yn-1-ol and benzyl hydroxycarbamate, 243.5 mg of

compound 1m (0.692 mmol, 70% yield) were obtained as a viscous

orange oil after puriﬁcation by ﬂash chromatography on silica gel

(pentane/ethyl acetate 88/12): R_f(silica, pentane/ethyl acetate 85/15 =

0.4, UV/PMA); ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.95 (t, J = 7.3

Hz, 3H), 1.40−1.60 (m, 4H), 2.30 (dt, J = 2.4 Hz and J = 7.2 Hz, 2H),

2.31 (s, 3H), 5.22 (s, 2H), 6.11 (brs, 1H), 6.22 (t, J = 2.0 Hz, 1H), 7.12−

7.16 (m, 1H), 7.20−7.25 (m, 2H), 7.33−7.41 (m, 5H), 7.81−7.85 (m,

1H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 13.5, 18.4, 18.8, 21.9, 30.6,

53.3, 68.1, 74.9, 87.2, 125.7, 128.0, 128.2, 128.3, 128.4, 129.6, 130.2,

134.1, 135.7, 136.3, 157.1; IR (ATR, neat) ν (cm⁻¹) 3263, 3034, 2960,

2868, 1675, 1655, 1487, 1463, 1455, 1410, 1346, 1296, 1259, 1093,

1079, 1016, 946, 797, 744, 729, 695, 629; MS (ESI+) m/z 536 (70), 519

(25), 492 (45), 459 (15), 369 (25), 352 (75, [M + H]⁺), 334 (20), 308

(50), 275 (100), 216 (30), 203 (30); HRMS (ESI+) m/z 352.1909 calcd

for C₂₂H₂₅NO₃+ H⁺352.1913.

Benzyl (1-(2-ﬂuorophenyl)hept-2-yn-1-yl)(hydroxy)-

carbamate (1n). According to general procedure A (on 2 mmol

scale) and starting from 1-(2-ﬂuorophenyl)hept-2-yn-1-ol and benzyl

hydroxycarbamate, 495.0 mg of compound 1n (1.393 mmol, 70% yield)

were obtained as a white semisolid after puriﬁcation by ﬂash

chromatography on silica gel (pentane/ethyl acetate 9/1 → 85/15):

R_f(silica, pentane/ethyl acetate 85/15 = 0.4, UV/PMA); ¹H NMR (400

MHz, CDCl₃) δ (ppm) 0.91 (t, J = 7.3 Hz, 3H, H₁), 1.36−1.58 (m, 4H,

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95.9, 127.9, 128.1, 128.2, 128.4, 128.6, 135.6, 136.3, 157.1; IR (ATR,

neat) ν (cm⁻¹) 3268, 2965, 2925, 2250, 1950, 1798, 1697, 1455, 1388,

1348, 1291, 1267, 1213, 1093, 1026, 910, 825, 741, 761, 693, 676, 627;

MS (ESI+) m/z 675 (5, [2M + H]⁺), 508 (35), 464 (20), 338 (100, [M +

H]⁺), 320 (20), 261 (25), 171 (15); HRMS (ESI+) m/z 338.1741 calcd

for C₂₁H₂₃NO₃+ H⁺338.1756.

Benzyl hydroxy(2-methyldec-5-yn-4-yl)carbamate (1w). An

anhydrous and purged with N₂10 mL round-bottom ﬂask equipped

with a magnetic stirrer bar was charged with dry THF (1 mL) and 1-

hexyne (0.23 mL, 2 mmol, 4 equiv), and the resulting solution was

cooled at −78 °C. n-Butyllithium (1.6 M in hexanes, 1.25 mL, 2 mmol, 4

equiv) was then added dropwise, and after 10 min, a solution of benzyl

hydroxy(3-methyl-1-(phenylsulfonyl)butyl)carbamate (189 mg, 0.5

mmol, 1 equiv) in dry THF (1 mL) was added via syringe. The

resulting mixture was stirred 30 min at −78 °C and then allowed to run

at 0 °C for 2 h. A saturated aqueous NH₄Cl (2 mL) was then added, and

the solution was allowed to reach room temperature. The reaction

mixture was then extracted with ethyl acetate (2 × 10 mL), and the

combined organic layers were washed with brine (5 mL), dried over

anhydrous MgSO₄and ﬁltered. After the removal of the solvent, the

crude mixture was puriﬁed by column chromatography (Pentane/Ethyl

acetate 95/5) to give 4 mg of the title compound 1w (0.013 mmol, 3%

yield) as a white solid after puriﬁcation by ﬂash chromatography on silica

gel (pentane/ethyl acetate 95/5): R_f(silica, pentane/ethyl acetate 85/15

= 0.7, UV/PMA); ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.86−0.94 (m,

9H), 1.32−1.77 (m, 7H), 2.17 (dt, J = 2.0 Hz and J = 7.0 Hz, 2H), 4.87

(tt, J = 2.0 Hz and J = 7.6 Hz, 1H), 5.22 (s, 2H), 5.59 (brs, 1H), 7.30−

7.42 (m, 5H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 13.6, 18.3, 21.9,

22.2, 22.3, 24.8, 30.7, 41.5, 50.9, 68.2, 73.4, 85.2, 128.1, 128.3, 128.5,

135.7, 157.3; IR (ATR, neat) ν (cm⁻¹) 3254, 2959, 2932, 2871, 1970,

1704, 1456, 1305, 1260, 1091, 1021, 798; MS (ESI+) m/z 635 (25, [2M

+ H]⁺), 608 (25), 410 (25), 359 (15), 324 (15), 318 (100, [M + H]⁺),

288 (65), 241 (20), 210 (35), 209 (25); HRMS (ESI+) m/z 318.2064

calcd for C₁₉H₂₇NO₃+ H⁺318.2069.

Benzyl (1,3-diphenylprop-2-yn-1-yl)(hydroxy)carbamate

(1s). According to general procedure A (on 1 mmol scale) and starting

from 1,3-diphenylprop-2-yn-1-ol and benzyl hydroxycarbamate, 259.7

mg of compound 1s (0.727 mmol, 73% yield) were obtained as a white

solid after puriﬁcation by ﬂash chromatography on silica gel (pentane/

ethyl acetate 88/12): R_f(silica, pentane/ethyl acetate 9/1 = 0.3, UV/

PMA); mp 115−117 °C (Et₂O/Pentane); ¹H NMR (400 MHz, CDCl₃)

δ (ppm) 5.28 (s, 2H), 5.73 (brs, 1H), 6.37 (s, 1H), 7.29−7.43 (m, 11H),

7.47−7.51 (m, 2H), 7.58−7.63 (m, 2H); ¹³C NMR (100 MHz, CDCl₃)

δ (ppm) 56.1, 68.5, 83.9, 86.6, 122.2, 128.0, 128.2, 128.3, 128.4, 128.5,

128.55, 128.6, 128.7, 131.9, 135.5, 135.7, 157.1; IR (ATR, neat) ν

(cm⁻¹) 3298, 3063, 3033, 2949, 2233, 1955, 1702, 1490, 1454, 1443,

1406, 1351, 1285, 1268, 1098, 1028, 756, 707, 692; MS (ESI+) m/z 732

(15), 548 (10), 504 (10), 375 (20), 358 (20, [M + H]⁺), 296 (10), 214

(10), 191 (100), 171 (15), 102 (25); HRMS (ESI+) m/z 358.1432 calcd

for C₂₃H₁₉NO₃+ H⁺358.1443.

Benzyl hydroxy(1-phenyl-3-(p-tolyl)prop-2-yn-1-yl)-

carbamate (1t). According to general procedure A (on 4 mmol

scale) and starting from 1-phenyl-3-(p-tolyl)prop-2-yn-1-ol and benzyl

hydroxycarbamate, 1.080 g of compound 1t (2.907 mmol, 73% yield)

were obtained as a yellow oil after puriﬁcation by ﬂash chromatography

on silica gel (pentane/ethyl acetate 85/15): R_f(silica, pentane/ethyl

acetate 85/15 = 0.3, UV/PMA); ¹H NMR (400 MHz, CDCl₃) δ (ppm)

2.36 (s, 3H) 5.27 (s, 2H), 5.88 (brs, 1H), 6.36 (s, 1H), 7.13 (d, J = 7.6

Hz, 2H), 7.31−7.43 (m, 10H), 7.13 (d, J = 6.4 Hz, 2H); ¹³C NMR (100

MHz, CDCl₃) δ (ppm) 21.5, 56.1, 68.5, 83.2, 86.7, 119.1, 128.0, 128.2,

128.4, 128.5, 128.6, 129.0, 131.8, 135.6, 135.9, 138.8, 157.1; IR (ATR,

neat) ν (cm⁻¹) 3287, 2921, 1698, 1509, 1452, 1404, 1265, 1094, 816,

731, 695; MS (ESI+) m/z 576 (25), 532 (10), 372 (50, [M + H]⁺), 354

(35), 288 (25), 221 (15), 209 (30), 205 (100); HRMS (ESI+) m/z

372.1609 calcd for C₂₄H₂₁NO₃+ H⁺372.1600.

(Z)-Benzyl (3-oxo-1-phenylhept-1-en-1-yl)carbamate (2a).

According to general procedure B (on 0.2 mmol scale) and starting

from benzyl hydroxy(1-phenylhept-2-yn-1-yl)hept-2-yn-1-yl)carbamate

1a, 57.3 mg of compound 2a (0.170 mmol, 86% yield) were obtained as

a pale yellow oil after puriﬁcation by ﬂash chromatography on silica gel

(pentane/Et₂O 92/8): R_f(silica, pentane/Et₂O 9/1 = 0.35, UV/

Vanillin); H NMR (400 MHz, CDCl₃) δ (ppm) 0.92 (t, J = 7.2 Hz,

3H), 1.29−1.41 (m, 2H), 1.55−1.67 (m, 2H), 2.47 (t, J = 7.0 Hz, 2H),

5.07 (s, 2H), 5.57 (s, 1H), 7.28−7.46 (m, 10H), 11.58 (brs, 1H, NH);

¹³C NMR (100 MHz, CDCl₃) δ (ppm) 13.9, 22.4, 26.9, 43.5, 67.4,

107.2, 127.5, 128.0, 128.3, 128.4, 128.5, 129.8, 135.5, 135.6, 152.8, 154.5,

202.6; IR (ATR, neat) ν (cm⁻¹) 2958, 2928, 2870, 1750, 1642, 1589,

1573, 1495, 1473, 1280, 1195, 1119, 1047, 765, 750, 694; MS (ESI+) m/

z 675 (5, [2M + H]⁺), 505 (10), 338 (100, [M + H]⁺), 320 (15), 294

(10); HRMS (ESI+) m/z 338.1747 calcd for C₂₁H₂₃NO₃+ H⁺

338.1756.

(E)-Benzyl (1-phenylhept-2-yn-1-ylidene)carbamate (3a). Ac-

cording to the gram-scale procedure for the preparation of (Z)-benzyl

(3-oxo-1-phenylhept-1-en-1-yl)carbamate 2a, 70 mg of compound 3a

(0.21 mmol, 4% yield) were isolated as a minor product: R_f(silica,

Pentane/Et₂O 9/1 = 0.45, UV/PMA); ¹H NMR (400 MHz, CDCl₃) δ

(ppm) 0.93 (t, J= 7.2 Hz, 3H), 1.38−1.60 (m, 4H), 2.36 (t, J= 7.2 Hz,

2H), 5.33 (s, 2H), 7.30−7.55 (m, 8H), 8.08 (∼d, J = 7.2 Hz, 2H); ¹³C

NMR (100 MHz, CDCl₃) δ (ppm) 13.5, 19.0, 21.9, 29.8, 68.2, 74.1,

103.4, 128.3, 128.4, 128.5, 132.4, 135.0, 135.6, 153.6, 163.1; IR (ATR,

neat) ν (cm⁻¹) 3066, 3033, 2972, 2929, 2868, 2218, 1724, 1597, 1571,

1450, 1318, 1295, 1258, 1203, 1176, 906, 690; MS (ESI+) m/z 320

(100, [M + H]⁺), 276 (30), 187 (15); HRMS (ESI+) m/z 320.1649

calcd for C₂₁H₂₁NO₂+ H⁺320.1651.

Benzyl hydroxy(4-phenylbut-3-yn-2-yl)carbamate (1v). A 100

mL round-bottom ﬂask charged with benzyl (tert-butyldimethylsilyl)-

oxycarbamate²⁶(1.27 g, 4.52 mmol, 1.1 equiv), THF (20 mL), PPh₃

(1.19 g, 4.52 mmol, 1.1 equiv) and DIAD (1.02 mL, 5.15 mmol, 1.25

equiv) was cooled to 0 °C, and a solution of 4-phenylbut-3-yn-2-ol (603

mg, 4.12 mmol, 1 equiv) in THF (15 mL) was added dropwise. Then,

the reaction was allowed to warm to ambient temperature and stirred for

2 h. Upon completion, the reaction was concentrated in vacuo and

puriﬁed by ﬂash chromatography on silica gel (Pentane/Et₂O 98/2),

which aﬀorded 1.01 g of benzyl (tert-butyldimethylsilyl)oxy(4-phenyl-

but-3-yn-2-yl)carbamate with the unseparable DIAD excess (∼20% by

¹H NMR). The product was used as such in the next step: R_f(silica,

Pentane/Et₂O 9/1 = 0.8, UV/PMA/KMnO₄).

To a solution of benzyl (tert-butyldimethylsilyl)oxy(4-phenylbut-3-

yn-2-yl)carbamate (1.01 g, 2.47 mmol) in dry THF (12.5 mL) was

added TBAF (1 M in THF, 2.5 mL, 2.5 mmol, 1.01 equiv) at 0 °C. After

5 min the mixture was quenched with saturated NH₄Cl solution (10

mL) and diluted with ether (20 mL). The organic layer was washed with

water (20 mL) and brine (20 mL), dried over MgSO₄, and evaporated,

and the crude was further puriﬁed by column chromatography on silica

(Pentane/Ethyl acetate 8/2) to give 619 mg of the title compound 1v

(2.09 mmol, 51% yield over 2 steps) as a white solid after puriﬁcation by

ﬂash chromatography on silica gel (pentane/ethyl acetate 85/15): R_f

(silica, pentane/ethyl acetate 8/2 = 0.3, UV/PMA); mp 90−91 °C

(Et₂O/pentane); ¹H NMR (400 MHz, CDCl₃) δ (ppm) 1.57 (d, J = 7.2

Hz, 3H, H₁), 5.15−5.25 (m, 3H, H₂and H₁₁), 6.82 (brs, 1H, H₃), 7.25−

7.44 (m, 10H, H_Ar); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 18.8, 48.2,

68.3, 83.5, 86.7, 122.4, 128.1, 128.0, 128.1, 128.2, 128.3, 128.5, 131.8,

135.6, 157.2; IR (ATR, neat) ν (cm⁻¹) 3279, 2985, 2939, 1954, 1698,

1489, 1454, 1443, 1402, 1353, 1289, 1114, 1068, 753, 690; MS (ESI+)

m/z 591 (30, [2M + H]⁺), 419 (25), 296 (100, [M + H]⁺), 252 (25), 234

(40), 193 (40); HRMS (ESI+) m/z 296.1276 calcd for C₁₈H₁₇NO₃+ H⁺

296.1287.

(Z)-Benzyl (3-oxo-1-(p-tolyl)hept-1-en-1-yl)carbamate (2b).

According to general procedure B (on 0.1 mmol scale) and starting

from benzyl (1-(p-tolyl)hept-2-yn-1-yl)(hydroxy)carbamate 1b, 27.7

mg of compound 2b (0.0788 mmol, 90% yield) were obtained as a pale

yellow oil after puriﬁcation by ﬂash chromatography on silica gel

(pentane/Et₂O 92/8): R_f(silica, pentane/Et₂O 9/1 = 0.35, UV/

Vanillin); H NMR (400 MHz, CDCl₃) δ (ppm) 0.92 (t, J = 7.2 Hz,

3H), 1.30−1.41 (m, 2H), 1.56−1.66 (m, 2H), 2.38 (s, 3H), 2.46 (t, J =

7.0 Hz, 2H), 5.08 (s, 2H), 5.57 (s, 1H), 7.19 (∼d, J = 8 Hz, 2H), 7.28−

7.37 (m, 7H), 11.58 (brs, 1H, NH); ¹³C NMR (100 MHz, CDCl₃) δ

(ppm) 13.9, 21.4, 22.4, 26.8, 43.4, 67.3, 106.8, 127.4, 128.2, 128.4, 128.7,

132.6, 135.5, 140.0, 152.8, 154.5, 202.4; IR (ATR, neat) ν (cm⁻¹) 3032,

2957, 2930, 2871, 1956, 1905, 1750, 1641, 1589, 1567, 1474, 1455,

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1286, 1195, 1136, 1047, 810, 764, 754, 696; MS (ESI+) m/z 703 (5, [2M

+ H]⁺), 352 (100, [M + H]⁺), 334 (55), 308 (10), 210 (10), 154 (10);

HRMS (ESI+) m/z 352.1913 calcd for C₂₂H₂₅NO₃+ H⁺352.1913.

(Z)-Benzyl (1-(4-ﬂuorophenyl)-3-oxohept-1-en-1-yl)-

carbamate (2c). According to general procedure B (on 0.2 mmol

scale) and starting from benzyl (1-(4-ﬂuorophenyl)hept-2-yn-1-yl)-

(hydroxy)carbamate 1c, 48.0 mg of compound 2c (0.135 mmol, 71%

yield) were obtained as a red oil after puriﬁcation by ﬂash

chromatography on silica gel (pentane/Et₂O 92/8): R_f(silica,

pentane/Et₂O 9/1 = 0.4, UV/Vanillin); ¹H NMR (400 MHz, CDCl₃)

δ (ppm) 0.93 (t, J = 7.2 Hz, 3H), 1.31−1.41 (m, 2H), 1.58−1.66 (m,

2H), 2.47 (t, J = 7.6 Hz, 2H), 5.08 (s, 2H), 5.54 (s, 1H), 7.19 (∼t, J = 8.4

Hz, 2H), 7.29−7.42 (m, 7H), 11.58 (brs, 1H, NH). ¹⁹F NMR (376

MHz, CDCl₃) δ (ppm) −110.6; ¹³C NMR (100 MHz, CDCl₃) δ (ppm)

13.9, 22.4, 26.8, 43.5, 67.3, 107.2, 115.2 (d, J_ortho(C−F)= 22.0 Hz), 128.3,

128.4, 128.6, 129.5 (d, J_meta(C−F)= 8.4 Hz), 131.5 (d, J_para(C−F)= 3.4 Hz),

135.4, 152.9, 153.3, 163.6 (d, J_ipso(C−F)= 249.9 Hz), 202.5; IR (ATR,

neat) ν (cm⁻¹) 2958, 2930, 2872, 1748, 1644, 1604, 1582, 1507, 1473,

1455, 1286, 1192, 1157, 1134, 1074, 1044, 839, 763, 731, 695; MS (ESI

+) m/z 356 (100, [M + H]⁺), 338 (15), 312 (20); HRMS (ESI+) m/z

356.1669 calcd for C₂₁H₂₂FNO₃+ H⁺356.1662.

(Z)-Benzyl (1-(4-chlorophenyl)-3-oxohept-1-en-1-yl)-

carbamate (2d). According to general procedure B (on 0.1 mmol

scale) and starting from benzyl (1-(4-chlorophenyl)hept-2-yn-1-yl)-

(hydroxy)carbamate 1d, 29.5 mg of compound 2d (0.794 mmol, 80%

yield) were obtained as a yellow oil after puriﬁcation by ﬂash

chromatography on silica gel (pentane/Et₂O 92/8): R_f(silica,

pentane/Et₂O 9/1 = 0.4, UV/Vanillin); ¹H NMR (400 MHz, CDCl₃)

δ (ppm) 0.92 (t, J = 7.3 Hz, 3H), 1.30−1.40 (m, 2H), 1.56−1.66 (m,

2H), 2.47 (t, J = 7.2 Hz, 2H), 5.07 (s, 2H), 5.54 (s, 1H), 7.28−7.38 (m,

9H), 11.54 (brs, 1H, NH); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 13.9,

22.4, 26.7, 43.5, 67.5, 107.2, 128.3, 128.4, 128.5, 128.8, 134.0, 135.3,

135.8, 152.8, 153.0, 202.5; IR (ATR, neat) ν (cm⁻¹) 3066, 3034, 2957,

2930, 2872, 1748, 1644, 1598, 1585, 1490, 1471, 1281, 1193, 1135,

1073, 1045, 1013, 908, 815, 729, 695; MS (ESI+) m/z 743 (5, [2M +

H]⁺), 372 (100, [M + H]⁺), 328 (15); HRMS (ESI+) m/z 372.1364

calcd for C₂₁H₂₂ClNO₃+ H⁺372.1366.

(Z)-Benzyl (1-(4-bromophenyl)-3-oxohept-1-en-1-yl)-

carbamate (2e). According to general procedure B (on 0.1 mmol

scale) and starting from benzyl (1-(4-bromophenyl)hept-2-yn-1-

yl)(hydroxy)carbamate 1e, 36.1 mg of compound 2e (0.867 mmol,

87% yield) were obtained as a red oil after puriﬁcation by ﬂash

chromatography on silica gel (pentane/Et₂O 92/8): R_f(silica, Pentane/

Et₂O 9/1 = 0.4, UV/Vanillin); ¹H NMR (400 MHz, CDCl₃) δ (ppm)

0.92 (t, J = 7.3 Hz, 3H), 1.29−1.40 (m, 2H), 1.54−1.65 (m, 2H), 2.47 (t,

J = 7.6 Hz, 2H), 5.07 (s, 2H), 5.53 (s, 1H), 7.26 (∼d, J = 8.4 Hz, 2H),

7.28−7.37 (m, 5H), 7.50 (∼d, J = 8.4 Hz, 2H), 11.53 (brs, 1H, NH); ¹³C

NMR (100 MHz, CDCl₃) δ (ppm) 13.9, 22.4, 26.8, 43.5, 67.6, 107.3,

124.2, 128.3, 128.4, 128.6, 129.1, 131.3, 134.5, 135.3, 152.8, 153.1,

202.5; IR (ATR, neat) ν (cm⁻¹) 3020, 2958, 2930, 2872, 1746, 1596,

1582, 1561, 1489, 1472, 1281, 1194, 1137, 1067, 1047, 1010, 746, 695,

666; MS (ESI+) m/z 418 (97, [M + H]⁺,⁸¹Br), 416 (100, [M +

H]⁺,⁷⁹Br); HRMS (ESI+) m/z 416.0844 calcd for C₂₁H₂₂BrNO₃+ H⁺

416.0861.

(Z)-Benzyl (1-([1,1′-biphenyl]-4-yl)-3-oxohept-1-en-1-yl)-

carbamate (2f). According to general procedure B (on 0.2 mmol

scale) and starting from benzyl (1-([1,1′-biphenyl]-4-yl)hept-2-yn-1-

yl)(hydroxy)carbamate 1f, 49.8 mg of compound 2f (0.120 mmol, 61%

yield) were obtained as a pale yellow oil after puriﬁcation by ﬂash

chromatography on silica gel (pentane/Et₂O 92/8): R_f(silica, pentane/

Et₂O 9/1 = 0.4, UV/Vanillin); ¹H NMR (400 MHz, CDCl₃) δ (ppm)

0.95 (t, J = 7.2 Hz, 3H), 1.32−1.44 (m, 2H), 1.58−1.70 (m, 2H), 2.50 (t,

J = 7.2 Hz, 2H), 5.11 (s, 2H), 5.65 (s, 1H), 7.30−7.41 (m, 6H), 7.44−

7.52 (m, 4H), 7.60−7.65 (m, 4H), 11.62 (brs, 1H, NH); ¹³C NMR (100

MHz, CDCl₃) δ (ppm) 13.9, 22.4, 26.8, 43.4, 67.4, 107.2, 126.7, 127.1,

127.6, 128.0, 128.2, 128.3, 128.5, 128.8, 134.4, 135.4, 140.3, 142.6, 152.9,

154.0, 202.4; IR (ATR, neat) ν (cm⁻¹) 3062, 3032, 2956, 2930, 2871,

1748, 1587, 1578, 1472, 1280, 1192, 1134, 1075, 1047, 908, 763, 752,

730, 694; MS (ESI+) m/z 414 (100, [M + H]⁺), 288 (10), 252 (10), 216

(25), 203 (5); HRMS (ESI+) m/z 414.2065 calcd for C₂₇H₂₇NO₃+ H⁺

414.2069.

(Z)-Benzyl (3-oxo-1-(m-tolyl)hept-1-en-1-yl)carbamate (2g).

According to general procedure B (on 0.4 mmol scale) and starting from

benzyl (1-(m-tolyl)hept-2-yn-1-yl)(hydroxy)carbamate 1g, 103.5 mg of

compound 2g (0.295 mmol, 74% yield) were obtained as a yellow oil

after puriﬁcation by ﬂash chromatography on silica gel (pentane/Et₂O

92/8): R_f(silica, pentane/Et₂O 9/1 = 0.4, UV/Vanillin); ¹H NMR (400

MHz, CDCl₃) δ (ppm) 0.91 (t, J = 7.3 Hz, 3H), 1.29−1.39 (m, 2H),

1.56−1.65 (m, 2H), 2.36 (s, 3H), 2.45 (t, J = 7.2 Hz, 2H), 5.06 (s, 2H),

5.55 (s, 1H), 7.16−7.36 (m, 9H), 11.56 (brs, 1H, NH); ¹³C NMR (100

MHz, CDCl₃) δ (ppm) 13.8, 21.3, 22.3, 26.7, 43.3, 67.3, 107.0, 124.6,

127.8, 127.9, 128.1, 128.2, 128.4, 130.5, 135.4, 135.5, 137.6, 152.7, 154.5,

202.4; IR (ATR, neat) ν (cm⁻¹) 3033, 2957, 2929, 2871, 1750, 1642,

1576, 1472, 1455, 1288, 1204, 1188, 1135, 1049, 786, 763, 754, 733, 695;

MS (ESI+) m/z 352 (100, [M + H]⁺), 308 (10); HRMS (ESI+) m/z

352.1929 calcd for C₂₂H₂₅NO₃+ H⁺352.1913.

(Z)-Benzyl (1-(3-methoxyphenyl)-3-oxohept-1-en-1-yl)-

carbamate (2h). According to general procedure B (on 0.4 mmol

scale) and starting from benzyl (1-(3-methoxyphenyl)hept-2-yn-1-

yl)(hydroxy)carbamate 1h, 96.5 mg of compound 2h (0.263 mmol, 66%

yield) were obtained as a pale yellow oil after puriﬁcation by ﬂash

chromatography on silica gel (pentane/Et₂O 92/8): R_f(silica, pentane/

Et₂O 9/1 = 0.3, UV/Vanillin); ¹H NMR (400 MHz, CDCl₃) δ (ppm)

0.94 (t, J = 7.2 Hz, 3H), 1.32−1.43 (m, 2H), 1.58−1.68 (m, 2H), 2.48 (t,

J = 7.2 Hz, 2H), 3.81 (s, 3H), 5.09 (s, 2H), 5.60 (s, 1H), 6.92−7.46 (m,

3H), 7.28−7.39 (m, 6H), 11.55 (brs, 1H, NH). ¹⁹F NMR (376 MHz,

CDCl₃) δ (ppm) −114.1; ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 13.8,

22.3, 26.7, 43.4, 55.2, 67.3, 107.0, 113.1, 115.1, 119.8, 128.2, 128.4,

128.9, 135.4, 136.9, 152.6, 154.0, 159.1, 202.4; IR (ATR, neat) ν (cm⁻¹)

3066, 3033, 2957, 2932, 1749, 1644, 1574, 1464, 1287, 1223, 1191,

1134, 1039, 880, 785, 755, 733, 695; MS (ESI+) m/z 368 (100, [M +

H]⁺), 324 (20); HRMS (ESI+) m/z 368.1855 calcd for C₂₂H₂₅NO₄+

H⁺368.1862.

(Z)-Benzyl (1-(3-bromophenyl)-3-oxohept-1-en-1-yl)-

carbamate (2i). According to general procedure B (on 0.4 mmol

scale) and starting from benzyl (1-(3-bromophenyl)hept-2-yn-1-

yl)(hydroxy)carbamate 1i, 86.0 mg of compound 2i (0.206 mmol,

52% yield) were obtained as a pale yellow oil after puriﬁcation by ﬂash

chromatography on silica gel (petroleum ether/Et₂O 92/8): R_f(silica,

pentane/Et₂O 9/1 = 0.4, UV/Vanillin); ¹H NMR (400 MHz, CDCl₃) δ

(ppm) 0.93 (t, J = 7.3 Hz, 3H), 1.31−1.42 (m, 2H), 1.57−1.68 (m, 2H),

2.48 (t, J = 7.2 Hz, 2H), 5.08 (s, 2H), 5.54 (s, 1H), 7.21−7.27 (m, 1H),

7.28−7.49 (m, 6H), 7.52−7.56 (m, 2H), 11.51 (brs, 1H, NH); ¹³C

NMR (100 MHz, CDCl₃) δ (ppm) 13.8, 22.3, 26.6, 43.4, 67.5, 107.4,

122.0, 126.2, 128.2, 128.3, 128.4, 129.3, 130.2, 132.5, 135.3, 137.6, 152.4,

152.6, 202.4; IR (ATR, neat) ν (cm⁻¹) 3065, 3034, 2957, 2930, 2871,

1748, 1582, 1600, 1558, 1479, 1463, 1280, 1192, 1131, 1046, 909, 785,

729, 694; MS (ESI+) m/z 418 (97, [M + H]⁺,⁸¹Br), 416 (100, [M +

H]⁺,⁷⁹Br), 148 (45); HRMS (ESI+) m/z 416.0860 calcd for

C₂₁H₂₂BrNO₃+ H⁺416.0861.

(Z)-Benzyl (3-oxo-1-(thiophen-2-yl)hept-1-en-1-yl)-

carbamate (2j). According to general procedure B (on 1 mmol

scale) and starting from benzyl hydroxy(1-(thiophen-2-yl)hept-2-yn-1-

yl)carbamate 1j, 155.0 mg of compound 2j (0.451 mmol, 45% yield)

were obtained as a red oil after puriﬁcation by ﬂash chromatography on

silica gel (petroleum ether/Et₂O 92/8): R_f(silica, Pentane/Et₂O 9/1 =

0.4, UV/Vanillin); ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.94 (t, J = 7.3

Hz, 3H), 1.32−1.42 (m, 2H), 1.58−1.67 (m, 2H), 2.48 (t, J = 7.6 Hz,

2H), 5.13 (s, 2H), 5.78 (s, 1H), 7.06 (dd, J = 3.7 Hz and J = 5.0 Hz, 1H),

7.33 (td, J = 1.2 Hz and J = 3.7 Hz, 1H), 7.34−7.38 (m, 5H), 7.42 (dd, J =

1.2 Hz and J = 5.0 Hz, 1H), 11.45 (brs, 1H, NH); ¹³C NMR (100 MHz,

CDCl₃) δ (ppm) 13.8, 22.3, 26.7, 43.4, 67.4, 107.2, 127.2, 128.0, 128.2,

128.3, 128.4, 129.2, 135.4, 136.5, 146.9, 152.8, 202.2; IR (ATR, neat) ν

(cm⁻¹) 2957, 2930, 1749, 1639, 1582, 1464, 1455, 1191, 1267, 1191,

1134, 1109, 694; MS (ESI+) m/z 344 (100, [M + H]⁺), 300 (30);

HRMS (ESI+) m/z 344.1313 calcd for C₁₉H₂₁NO₃S + H⁺344.1320.

(Z)-Benzyl (1-(naphthalen-2-yl)-3-oxohept-1-en-1-yl)-

carbamate (2k). According to general procedure B (on 0.4 mmol

scale) and starting from benzyl (1-(naphthalen-2-yl)hept-2-yn-1-

9215

dx.doi.org/10.1021/jo301675g | J. Org. Chem. 2012, 77, 9205−9220

The Journal of Organic Chemistry

Article

yl)(hydroxy)carbamate 1k, 87.1 mg of compound 2k (0.225 mmol, 58%

yield) were obtained as a pale yellow oil after puriﬁcation by ﬂash

chromatography on silica gel (petroleum ether/Et₂O 92/8): R_f(silica,

918, 773, 729, 692, 623, 611; MS (ESI+) m/z 260 (10), 148 (100, [M +

H]⁺); HRMS (ESI+) m/z 148.0746 calcd for C₉H₉NO + H⁺148.0762.

(Z)-Benzyl (3-oxo-1-phenylbut-1-en-1-yl)carbamate (2p). Ac-

cording to general procedure B (on 0.2 mmol scale) and starting from

benzyl (1-phenylbut-2-yn-1-yl)(hydroxy)carbamate 1p, 44.1 mg of

compound 2p (0.149 mmol, 75% yield) were obtained as a pale yellow

solid after puriﬁcation by ﬂash chromatography on silica gel (pentane/

Et₂O 92/8): R_f(silica, Pentane/Et₂O 9/1 = 0.35, UV/PMA/Vanillin);

mp 62−64 °C (Et₂O/pentane); ¹H NMR (400 MHz, CDCl₃) δ (ppm)

2.23 (s, 3H), 5.08 (s, 2H), 5.59 (s, 1H), 7.27−7.48 (m, 10H), 11.54 (brs,

1H, NH); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 30.8, 67.4, 107.4,

127.4, 127.9, 128.2, 128.3, 128.4, 129.8, 135.3, 135.4, 152.7, 154.5,

199.5; IR (ATR, neat) ν (cm⁻¹) 3033, 2949, 1752, 1639, 1605, 1587,

1570, 1494, 1467, 1454, 1357, 1290, 1206, 1170, 1114, 1046, 766, 747,

694; MS (ESI+) m/z 296 (100, [M + H]⁺), 252 (50), 162 (20); HRMS

(ESI+) m/z 296.1286 calcd for C₁₈H₁₇NO₃+ H⁺296.1287.

Pentane/Et₂O 9/1 = 0.4, UV/PMA/Vanillin); H NMR (400 MHz,

CDCl₃) δ (ppm) 0.98 (t, J = 7.6 Hz, 3H, H₁), 1.36−1.47 (m, 2H, H₂),

1.64−1.73 (m, 2H, H₃), 2.53 (t, J = 7.2 Hz, 2H, H₄), 5.11 (s, 2H, H₁₈),

5.72 (s, 1H, H₆), 7.28−7.36 (m, 5H, H_Ar), 7.48−7.58 (m, 3H, H_Ar),

7.81−7.95 (m, 4H, H_Ar), 11.71 (brs, 1H, NH); ¹³C NMR (100 MHz,

CDCl₃) δ (ppm) 13.8 (C₁), 22.3 (C₂), 26.7 (C₃), 43.4 (C₄), 67.4 (C₁₈),

107.4 (C₆), 125.1 (C_Ar), 126.4 (C_Ar), 126.7 (C_Ar), 126.9 (C_Ar), 127.3

(C_Ar), 127.7 (C_Ar), 128.1 (C_Ar), 128.2 (C_Ar), 128.3 (2C, C_Ar), 128.4 (2C,

C_Ar), 132.7 (C_q, C_Ar), 133.2 (C_q, C_Ar), 133.8 (C_q, C_Ar), 135.4 (C_q, C_Ar),

152.8 (C_q, C_Ar), 154.3 (C_q, C_Ar), 202.4 (C₅); IR (ATR, neat) ν (cm⁻¹)

3060, 2958, 2931, 2872, 1747, 1641, 1584, 1478, 1463, 1361, 1284,

1191, 1135, 1109, 1047, 906, 814, 726, 695, 646; MS (ESI+) m/z 388

(100, [M + H]⁺), 370 (20), 148 (20); HRMS (ESI+) m/z 388.1920

calcd for C₂₅H₂₅NO₃+ H⁺388.1913.

(Z)-Benzyl (4-methyl-3-oxo-1-phenylpent-1-en-1-yl)-

carbamate (2q). According to general procedure B (on 0.1 mmol

scale) and starting from benzyl (4-methyl-1-phenylpent-2-yn-1-yl)-

(hydroxy)carbamate 1q, 20.8 mg of compound 2q (0.064 mmol, 63%

yield) were obtained as a pale yellow oil after puriﬁcation by ﬂash

chromatography on silica gel (pentane/Et₂O 92/8): R_f(silica, Pentane/

(Z)-Benzyl (1-(naphthalen-1-yl)-3-oxohept-1-en-1-yl)-

carbamate (2l). According to general procedure B (on 0.2 mmol

scale) and starting from benzyl (1-(naphthalen-1-yl)hept-2-yn-1-

yl)(hydroxy)carbamate 1l, 18.5 mg of compound 2l (0.048 mmol,

29% yield) were obtained as a pale yellow oil after puriﬁcation by ﬂash

chromatography on silica gel (pentane/Et₂O 92/8): R_f(silica, Pentane/

Et₂O 9/1 = 0.4, UV/PMA/Vanillin); H NMR (400 MHz, CDCl₃) δ

(ppm) 1.15 (d, J = 7.2 Hz, 6H), 2.65 (sept., J = 7.2 Hz, 1H), 5.08 (s, 2H),

5.61 (s, 1H), 7.27−7.48 (m, 10H), 11.61 (brs, 1H, NH); ¹³C NMR (100

MHz, CDCl₃) δ (ppm) 17.7, 40.3, 66.4, 104.9, 126.5, 127.0, 127.2,

127.3, 127.5, 128.7, 135.5, 135.7, 151.8, 154.1, 205.1; IR (ATR, neat) ν

(cm⁻¹) 3065, 3034, 2969, 2872, 1749, 1639, 1604, 1587, 1573, 1495,

1462, 1286, 1194, 1174, 1129, 1069, 1048, 906, 726, 694; MS (ESI+) m/

z 647 (5, [2M + H]⁺), 324 (100, [M + H]⁺), 306 (50), 280 (45), 262

(10); HRMS (ESI+) m/z 324.1599 calcd for C₂₀H₂₁NO₃+ H⁺

324.1600.

(ppm) 0.93 (t, J = 7.2 Hz, 3H), 1.32−1.44 (m, 2H), 1.60−1.68 (m, 2H),

2.48 (t, J = 7.2 Hz, 2H), 4.92 (s, 2H), 5.59 (s, 1H), 7.15−7.21 (m, 2H),

7.27−7.32 (m, 3H), 7.40 (dd, J = 1.1 Hz and J = 7.1 Hz, 1H), 7.45−7.54

(m, 3H), 7.81−7.94 (m, 3H), 12.05 (brs, 1H, NH); ¹³C NMR (100

MHz, CDCl₃) δ (ppm) 13.9, 22.4, 26.8, 43.4, 67.3, 107.0, 124.4, 124.9,

125.3, 126.0, 126.7, 128.1, 128.2, 128.4, 128.5, 129.4, 131.0, 132.9, 133.7,

135.3, 152.0, 153.4, 202.9; IR (ATR, neat) ν (cm⁻¹) 3062, 2957, 2930,

2871, 1754, 1642, 1591, 1575, 1477, 1286, 1200, 1179, 1140, 1092, 801,

776, 697; MS (ESI+) m/z 388 (100, [M + H]⁺), 344 (10), 320 (15), 288

(25), 214 (10), 187 (10); HRMS (ESI+) m/z 388.1920 calcd for

C₂₅H₂₅NO₃+ H⁺388.1913.

(E)-Benzyl (4,4-dimethyl-1-phenylpent-2-yn-1-ylidene)-

carbamate (3r). According to general procedure B (on 0.2 mmol

scale) and starting from benzyl (4,4-dimethyl-1-phenylpent-2-yn-1-

yl)(hydroxy)carbamate 1r, 25.3 mg of compound 3r (0.079 mmol, 41%

yield) were obtained as a yellow oil after puriﬁcation by ﬂash

chromatography on silica gel (pentane/Et₂O 95/5): R_f(silica,

(Z)-Benzyl (1-(2-ﬂuorophenyl)-3-oxohept-1-en-1-yl)-

carbamate (2n). According to general procedure B (on 0.4 mmol

scale) and starting from benzyl (1-(2-ﬂuorophenyl)hept-2-yn-1-yl)-

(hydroxy)carbamate 1n, 119.9 mg of compound 2n (0.337 mmol, 84%

yield) were obtained as a yellow oil after puriﬁcation by ﬂash

chromatography on silica gel (pentane/Et₂O 92/8): R_f(silica,

Pentane/Et₂O 9/1 = 0.45, UV/PMA); H NMR (400 MHz, CDCl₃)

δ (ppm) 1.28 (s, 9H), 5.31 (s, 2H), 7.30−7.55 (m, 8H), 8.06 (∼d, J = 7.2

Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 28.3, 30.1, 68.3, 72.8,

110.7, 128.3, 128.35, 128.4, 128.5, 128.6, 132.4, 135.0, 135.5, 153.6,

163.0; IR (ATR, neat) ν (cm⁻¹) 3065, 3033, 2970, 2929, 2868, 2218,

1722, 1595, 1573, 1450, 1318, 1295, 1256, 1201, 1176, 905, 690.MS

(ESI+) m/z 320 (100, [M + H]⁺), 276 (5), 228 (10); HRMS (ESI+) m/

z 320.1638 calcd for C₂₁H₂₁NO₂+ H⁺320.1651.

Pentane/Et₂O 9/1 = 0.4, UV/PMA/Vanillin); H NMR (400 MHz,

CDCl₃) δ (ppm) 0.93 (t, J = 7.3 Hz, 3H), 1.31−1.42 (m, 2H), 1.57−1.67

(m, 2H), 2.47 (t, J = 7.2 Hz, 2H), 5.09 (s, 2H), 5.50 (s, 1H), 7.08 (∼t, J =

9.6 Hz, 1H), 7.18 (∼t, J = 7.5 Hz, 1H), 7.27−7.46 (m, 7H), 11.77 (brs,

1H, NH). ¹⁹F NMR (376 MHz, CDCl₃) δ (ppm) −114.1; ¹³C NMR

(100 MHz, CDCl₃) δ (ppm) 13.8, 22.3, 26.7, 43.4, 67.4, 106.9, 115.1 (d,

(Z)-Benzyl (3-oxo-1,3-diphenylprop-1-en-1-yl)carbamate

(2s) and (E)-Benzyl (1,3-diphenylprop-2-yn-1-ylidene)-

carbamate (3s). According to general procedure B (on 0.2 mmol

scale) and starting from benzyl (1,3-diphenylprop-2-yn-1-yl)(hydroxy)-

carbamate 1s, 36.3 mg of compound 2s as a viscous yellow oil (0.101

mmol, 51% yield) and 12.0 mg of compound 3s as a pale yellow oil

(0.035 mmol, 18% yield) were obtained. 2s, R_f(silica, Pentane/Et₂O 9/

1) = 0.45, UV/PMA/Vanillin), and 3s, R_f(silica, Pentane/Et₂O 9/1) =

0.4, UV/PMA), were separated by ﬂash chromatography on silica gel

(pentane/Et₂O 95/5). 2s: ¹H NMR (400 MHz, CDCl₃) δ (ppm) 5.11

(s, 2H), 6.29 (s, 1H), 7.28−7.58 (m, 13H), 7.93−7.98 (m, 2H), 12.01

(brs, 1H, NH); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 67.5, 103.8,

127.6, 127.8, 128.1, 128.3, 128.4, 128.5, 128.6, 129.9, 132.6, 135.4, 136.0,

138.6, 152.8, 156.8, 191.3; IR (ATR, neat) ν (cm⁻¹) 3063, 3032, 2923,

2851, 1749, 1722, 1621, 1586, 1567, 1496, 1469, 1319, 1291, 1171,

1126, 1045, 1020, 776, 750, 688; MS (ESI+) m/z 358 (100, [M + H]⁺),

340 (40), 314 (15), 288 (15); HRMS (ESI+) m/z 358.1447 calcd for

C₂₃H₁₉NO₃+ H⁺358.1443. 3s: ¹H NMR (400 MHz, CDCl₃) δ (ppm)

5.38 (s, 2H), 7.27−7.34 (m, 2H), 7.34−7.40 (m, 3H), 7.41−7.50 (m,

7H), 7.53−7.58 (m, 1H), 8.16−8.19 (m, 2H); ¹³C NMR (100 MHz,

CDCl₃) δ (ppm) 68.4, 81.7, 100.1, 120.3, 128.3, 128.4, 128.5, 128.7,

130.5, 132.6, 132.7, 134.9, 135.6, 153.3, 163.0; IR (ATR, neat) ν (cm⁻¹)

3083, 3060, 2215, 2192, 1711, 1589, 1566, 1490, 1446, 1330, 1255,

1239, 1195, 1172, 776, 752, 699, 690, 678, 605; MS (ESI+) m/z 679 (20,

J_ortho(C−F)= 22.0 Hz), 123.7 (d, J_meta(C−F)= 14.7 Hz), 123.9 (d, J_para(C−F)

3.5 Hz), 128.1, 128.2, 128.4, 129.3 (d, J_(C−F)= 2.9 Hz), 131.2 (d,

J_meta(C−F)= 8.3 Hz), 135.4, 149.0, 152.4, 159.7 (d, J_ipso(C−F)= 249.9 Hz),

202.5; IR (ATR, neat) ν (cm⁻¹) 3067, 3034, 2958, 2929, 2872, 1749,

1589, 1575, 1453, 1261, 1220, 1187, 113, 1100, 1046, 909, 752, 731, 695;

MS (ESI+) m/z 356 (100, [M + H]⁺), 336 (20), 312 (30), 288 (10);

HRMS (ESI+) m/z 356.1665 calcd for C₂₁H₂₂FNO₃+ H⁺356.1662.

(Z)-3-Amino-3-phenylacrylaldehyde (4). In 10 mL round-

bottom ﬂask equipped with a magnetic stirrer bar was added benzyl

hydroxy(1-phenyl-3-(trimethylsilyl)prop-2-yn-1-yl)carbamate 1o

(178.6 mg, 0.5 mmol, 1 equiv), methanol (3 mL), water (0.25 mL)

and potassium carbonate (69 mg, 0.5 mmol, 1 equiv), and the resulting

mixture was stirred at room temperature for 3 h. The reaction mixture

was then ﬁltered through a silica gel pad and eluted with ethyl acetate.

The ﬁltrate was concentrated, and the residue was puriﬁed by ﬂash

chromatography on silica gel (pentane/ethyl acetate 8/2 → 7/3, R_f

(silica, pentane/ethyl acetate 8/2 = 0.3, UV/Vanillin), to give 51.8 mg

(0.35 mmol, 68% yield) of the title compound 4 as a yellow semisolid:

¹H NMR (400 MHz, CDCl₃) δ (ppm) 5.40 (s, 1H), 5.78 (brs, 1H),

7.39−7.50 (m, 3H), 7.53−7.59 (m, 2H), 10.00 (brs, 1H); ¹³C NMR

(100 MHz, CDCl₃) δ (ppm) 95.5, 126.2, 128.9, 130.9, 136.2, 162.3,

188.1; IR (ATR, neat) ν (cm⁻¹) 3315, 3165, 3061, 2806, 2728, 1636,

1611, 1576, 1531, 1486, 1449, 1412, 1365, 1298, 1141, 1119, 1075, 996,

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[2M + H]⁺), 340 (100, [M + H]⁺), 169 (5); HRMS (ESI+) m/z

340.1333 calcd for C₂₃H₁₇NO₂+ H⁺340.1338.

14818, 1360, 820, 752, 695, 661; MS (ESI+) m/z 303 (100, [M + H]⁺);

HRMS (ESI+) m/z 303.1853 calcd for C₂₁H₂₂N₂+ H⁺303.1856.

4-Butyl-2-phenyl-6-(m-tolyl)pyrimidine (10). According to

general procedure C (on 0.2 mmol scale) and starting from (Z)-benzyl

(3-oxo-1-(m-tolyl)hept-1-en-1-yl)carbamate 2g and benzamide, 49.0

mg of compound 10 (0.162 mmol, 81% yield) were obtained as a pale

yellow oil after puriﬁcation by ﬂash chromatography on silica gel

(pentane/Et₂O 98/2): R_f(silica, pentane/Et₂O 95/5 = 0.9, UV/

(Z)-Benzyl (3-oxo-1-phenyl-3-(p-tolyl)prop-1-en-1-yl)-

carbamate (2t) and (E)-Benzyl (1-phenyl-3-(p-tolyl)prop-2-yn-

1-ylidene)carbamate (3t). According to general procedure B (on 0.2

mmol scale) and starting from benzyl (1-phenyl-3-(p-tolyl)prop-2-yn-1-

yl)(hydroxy)carbamate 1t, 39.2 mg of compound 2t as a pale yellow oil

(0.105 mmol, 53% yield) and 11.8 mg of compound 3t as a colorless oil

(0.033 mmol, 14% yield) were obtained. 2t, R_f(silica, Pentane/Et₂O 9/

1) = 0.45, UV/PMA/Vanillin), and 3t, R_f(silica, Pentane/Et₂O 9/1) =

0.4, UV/PMA), were separated by ﬂash chromatography on silica gel

(pentane/Et₂O 95/5). 2t: ¹H NMR (400 MHz, CDCl₃) δ (ppm) 2.41

(s, 3H), 5.11 (s, 2H), 6.28 (s, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.30−7.38

(m, 5H), 7.40−7.52 (m, 5H), 7.86 (d, J = 8.4 Hz, 2H), 12.03 (brs, 1H);

¹³C NMR (100 MHz, CDCl₃) δ (ppm) 21.6, 67.5, 103.8, 127.6, 127.9,

128.0, 128.3, 128.5, 129.3, 129.8, 135.5, 136.0, 136.1, 143.4, 152.8, 156.3,

191.0; IR (ATR, neat) ν (cm⁻¹) 3061, 3034, 2957, 1748, 1622, 1605,

1585, 1572, 1495, 1472, 1315, 1294, 1190, 1173, 1044, 805, 732, 694;

MS (ESI+) m/z 372 (100, [M + H]⁺), 354 (45); HRMS (ESI+) m/z

372.1599 calcd for C₂₄H₂₁NO₃+ H⁺372.1600. 3t: ¹H NMR (400 MHz,

CDCl₃) δ (ppm) 2.40 (s, 3H), 5.38 (s, 2H), 7.18(d, J = 8 Hz, 2H), 7.28−

7.36 (m, 5H), 7.44−7.50 (m, 4H), 7.52−7.57 (m, 1H), 8.15−8.19 (m,

2H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 21.7, 68.4, 81.5, 100.8,

117.2, 128.3, 128.4, 128.5, 128.6, 128.7, 129.3, 132.6, 135.0, 135.6, 141.2,

153.4, 163.0; IR (ATR, neat) ν (cm⁻¹) 3064, 3032, 2953, 2207, 2189,

1718, 1593, 1569, 1508, 1449, 1324, 1232, 1193, 1171, 1048, 814, 688;

MS (ESI+) m/z 354 (100, [M + H]⁺); HRMS (ESI+) m/z 354.1505

calcd for C₂₄H₁₉NO₂+ H⁺354.1494.

(Z)-1-Amino-1-phenylhept-1-en-3-one (7). In 10 mL round-

bottom ﬂask equipped with a magnetic stirrer bar was added (Z)-benzyl

(3-oxo-1-phenylhept-1-en-1-yl)carbamate 2a (67.5 mg, 0.2 mmol, 1

equiv), methanol (2 mL), palladium on carbon (wt. 10%, 23 mg, 0.02

mmol, 0.1 equiv), and the resulting mixture was stirred at room

temperature under hydrogen atmosphere for 30 min. The reaction

mixture was then ﬁltered through a silica gel pad and eluted with ethyl

acetate. The ﬁltrate was concentrated, and the residue was puriﬁed by

ﬂash chromatography on silica gel (pentane/ethyl acetate 8/2, R_f(silica,

pentane/ethyl acetate 8/2 = 0.25, UV/Ninhydrin)) to give 39.1 mg

(0.19 mmol, 97% yield) of the title compound 7 as a pale yellow oil: ¹H

NMR (400 MHz, CDCl₃) δ (ppm) 0.92 (t, J = 7.6 Hz, 3H), 1.36 (sext, J

= 7.6 Hz, 2H), 1.63 (pent, J = 7.6 Hz, 2H), 2.38 (t, J = 7.6 Hz, 2H), 5.25

(brs, 1H), 5.44 (s, 1H), 7.38−7.48 (m, 3H), 7.38−7.48 (m, 2H), 9.95

(brs, 1H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 13.9, 22.6, 28.0, 42.6,

94.7, 126.2, 128.8, 130.4, 137.4, 160.8, 200.7. The spectral data are

consistent with those of the literature.²⁷

Vanillin); H NMR (400 MHz, CDCl₃) δ (ppm) 1.01 (t, J = 7.4 Hz,

3H), 1.43−1.58 (m, 2H), 1.82−1.91 (m, 2H), 2.49 (s, 3H), 2.89 (t, J =

7.6 Hz, 2H), 7.33 (d, J = 7.6 Hz, 1H) 7.42 (t, J = 7.6 Hz, 1H), 7.45 (s,

1H), 7.48−7.56 (m, 3H), 8.00 (d, J = 7.6 Hz, 1H), 8.05 (brs, 1H), 8.62

(dd, J = 1.8 Hz and J = 7.9 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ

(ppm) 14.0, 21.5, 22.5, 31.0, 38.0, 113.5, 124.3, 127.8, 128.4, 128.7,

130.3, 131.3, 137.4, 138.3, 138.5, 163.9, 164.2, 171.5; IR (ATR, neat) ν

(cm⁻¹) 2955, 2926, 2870, 2859, 1587, 1569, 1532, 1367, 1173, 1027,

755, 692, 666, 639; MS (ESI+) m/z 303 (100, [M + H]⁺); HRMS (ESI

+) m/z 303.1861 calcd for C₂₁H₂₂N₂+ H⁺303.1861.

4-Butyl-6-(4-ﬂuorophenyl)-2-phenylpyrimidine (11). Accord-

ing to general procedure C (on 0.2 mmol scale) and starting from (Z)-

benzyl (1-(4-ﬂuorophenyl)-3-oxohept-1-en-1-yl)carbamate 2c and

benzamide, 41.0 mg of compound 11 (0.134 mmol, 67% yield) were

obtained as a pale yellow solid after puriﬁcation by ﬂash chromatography

on silica gel (pentane/Et₂O 98/2): R_f(silica, pentane/Et₂O 95/5 = 0.75,

UV/Vanillin); mp 78−79 °C (Et₂O/pentane); H NMR (400 MHz,

CDCl₃) δ (ppm) 1.00 (t, J = 7.2 Hz, 3H), 1.42−1.53 (m, 2H), 1.81−1.90

(m, 2H), 2.88 (t, J = 7.6 Hz, 2H), 7.21 (∼t, J = 8.8 Hz, 2H), 7.40 (s, 1H),

7.47−7.56 (m, 3H), 8.17−8.29 (m, 2H), 8.60 (dd, J = 2.4 Hz and J = 8.0

Hz, 2H). ¹⁹F NMR (376 MHz, CDCl₃) δ (ppm) −110.2; ¹³C NMR

(100 MHz, CDCl₃) δ (ppm) 13.9, 22.5, 31.0, 37.9, 113.0, 115.8 (d,

J_ortho(C−F)= 21.7 Hz), 128.3, 128.4, 129.2 (d, J_meta(C−F)= 8.7 Hz), 130.5,

133.5 (d, J_para(C−F)= 3.2 Hz), 138.9, 157.1, 162.5, 164.2, 164.4 (d,

J_ipso(C−F)= 250.9 Hz), 171.2; IR (ATR, neat) ν (cm⁻¹) 2957, 2929, 2870,

1603, 1586, 1573, 1527, 1509, 1416, 1360, 1231, 1219, 1163, 831, 751,

690, 663; MS (ESI+) m/z 307 (100, [M + H]⁺); HRMS (ESI+) m/z

307.1608 calcd for C₂₀H₁₉FN₂+ H⁺307.1611.

4-Butyl-6-(2-ﬂuorophenyl)-2-phenylpyrimidine (12). Accord-

ing to general procedure C (on 0.2 mmol scale) and starting from (Z)-

benzyl (1-(2-ﬂuorophenyl)-3-oxohept-1-en-1-yl)carbamate 2n and

benzamide, 39.1 mg of compound 12 (0.128 mmol, 64% yield) were

obtained as a viscous colorless oil after puriﬁcation by ﬂash

chromatography on silica gel (pentane/Et₂O 98/2): R_f(silica,

pentane/Et₂O 95/5 = 0.8, UV/Vanillin); ¹H NMR (400 MHz,

CDCl₃) δ (ppm) 1.00 (t, J = 7.2 Hz, 3H, H₁), 1.43−1.53 (m, 2H,

H₂), 1.81−1.90 (m, 2H, H₃), 2.90 (t, J = 7.6 Hz, 2H, H₄), 7.20 (ddd, J =

1.0 Hz, J = 8.3 Hz, J = 11.7 Hz, 1H, H_Ar), 7.34 (dt, J = 1.1 Hz and J = 7.6

Hz, 1H, H_Ar), 7.43−7.55 (m, 4H, H_Ar), 7.59 (d, J = 2.1 Hz, 1H, H_Ar),

8.36 (dt, J = 1.9 Hz and J = 7.8 Hz, 1H, H_Ar), 8.57−8.61 (m, 2H, H₁₆).

¹⁹F NMR (376 MHz, CDCl₃) δ (ppm) −114.8; ¹³C NMR (100 MHz,

CDCl₃) δ (ppm) 13.9, 22.5, 31.0, 37.9, 116.3 (d, J_ortho(C−F)= 22.9 Hz),

4-Butyl-2,6-diphenylpyrimidine (6). According to general

procedure C (on 0.1 mmol scale) and starting from (Z)-benzyl (3-

oxo-1-phenylhept-1-en-1-yl)carbamate 2a and benzamide, 23.0 mg of

compound 6 (0.797 mmol, 80% yield) were obtained as a white solid

after puriﬁcation by ﬂash chromatography on silica gel (pentane/Et₂O

98/2): R_f(silica, pentane/Et₂O 95/5 = 0.8, UV/Vanillin); H NMR

117.7 (d, J_meta(C−F)= 8.7 Hz), 124.6 (d, J_(C−F)= 3.5 Hz), 125.5 (d,

⁴J_(C−F)= 11.5 Hz), 128.3, 128.4, 130.4, 131.1 (d, J_para(C−F)= 2.5 Hz),

131.8 (d, J_meta(C−F)= 8.8 Hz), 138.1, 159.7 (d, J_(C−F)= 2.5 Hz), 161.4 (d,

J_ipso(C−F)= 251.9 Hz), 164.1, 171.6; IR (ATR, neat) ν (cm⁻¹) 3074, 3036,

2959, 2926, 2873, 2857, 1614, 1568, 1527, 1489, 1373, 1358, 1260,

1209, 872, 853, 773, 753, 734, 726, 694, 628; MS (ESI+) m/z 307 (100,

[M + H]⁺); HRMS (ESI+) m/z 307.1606 calcd for C₂₀H₁₉FN₂+ H⁺

307.1611.

4-(3-Bromophenyl)-6-butyl-2-phenylpyrimidine (13). Accord-

ing to general procedure C (on 0.2 mmol scale) and starting from (Z)-

benzyl (1-(3-bromophenyl)-3-oxohept-1-en-1-yl)carbamate 2i and

benzamide, 39.0 mg of compound 13 (0.106 mmol, 54% yield) were

obtained as a pale yellow oil after puriﬁcation by ﬂash chromatography

on silica gel (petroleum ether/Et₂O 97/3): R_f(silica, pentane/Et₂O 95/

5 = 0.8, UV/Vanillin); ¹H NMR (400 MHz, CDCl₃) δ (ppm) 1.01 (t, J =

7.6 Hz, 3H), 1.42−1.52 (m, 2H), 1.79−1.89 (m, 2H), 2.89 (t, J = 7.6 Hz,

2H), 7.35−7.66 (m, 6H), 8.09−8.15 (m, 1H), 8.31−8.40 (m, 1H),

8.50−8.75 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 13.9, 22.5,

30.9, 38.0, 113.4, 123.1, 125.7, 128.3, 128.4, 130.2, 130.3, 130.5, 133.4,

138.0, 139.5, 162.1, 164.3, 172.0; IR (ATR, neat) ν (cm⁻¹) 3066, 2957,

(400 MHz, CDCl₃) δ (ppm) 1.01 (t, J = 7.4 Hz, 3H), 1.43−1.54 (m,

2H), 1.82−1.91 (m, 2H), 2.90 (t, J = 7.4 Hz, 2H), 7.46 (s, 1H), 7.47−

7.57 (m, 6H), 8.21−8.26 (m, 2H), 8.63 (dd, J = 1.8 Hz and J = 7.8 Hz,

2H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 14.0, 22.5, 31.0, 37.9,

113.4, 127.2, 128.3, 128.4, 128.8, 130.4, 130.6, 137.4, 138.1, 163.7, 164.2,

171.6. The spectral data are consistent with those of the literature.²⁸

4-Butyl-2-phenyl-6-(p-tolyl)pyrimidine (9). According to gen-

eral procedure C (on 0.2 mmol scale) and starting from (Z)-benzyl (3-

oxo-1-(p-tolyl)hept-1-en-1-yl)carbamate 2b and benzamide, 53.4 mg of

compound 9 (0.177 mmol, 89% yield) were obtained as a pale yellow

solid after puriﬁcation by ﬂash chromatography on silica gel (pentane/

Et₂O 98/2): R_f(silica, pentane/Et₂O 95/5 = 0.8, UV/Vanillin); mp 61−

63 °C (Et₂O/Pentane); ¹H NMR (400 MHz, CDCl₃) δ (ppm) 1.01 (t, J

= 7.6 Hz, 3H), 1.44−1.54 (m, 2H), 1.82−1.91 (m, 2H), 2.45 (s, 3H),

2.88 (t, J = 7.6 Hz, 2H), 7.34 (d, J = 8 Hz, 2H) 7.43 (s, 1H), 7.47−7.56

(m, 3H), 8.14 (d, J = 8 Hz, 2H), 8.63 (dd, J = 1.7 Hz and J = 7.9 Hz, 2H);

¹³C NMR (100 MHz, CDCl₃) δ (ppm) 13.9, 21.4, 22.5, 31.0, 37.9,

113.0, 127.1, 128.3, 129.5, 130.3, 134.6, 138.4, 140.8, 163.6, 164.1,

171.4; IR (ATR, neat) ν (cm⁻¹) 2956, 2929, 1588, 1571, 1528, 1511,

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2928, 2859, 1587, 1563, 1531, 1367, 1115, 1069, 789, 756, 689, 660, 634;

MS (ESI+) m/z 369 (98, [M + H]⁺,⁸¹Br), 367 (100, [M + H]⁺,⁷⁹Br). 303

(15); HRMS (ESI+) m/z 367.0815 calcd for C₂₀H₁₉BrN₂+ H⁺

367.0810.

H₁and H_1′), 3.15 (sept., J = 6.8 Hz, 1H, H₂), 7.48 (s, 1H, H₄), 7.49−7.58

(m, 6H, H_Ar), 8.24 (dd, J = 2.0 Hz and J = 8.0 Hz, 2H, H₇), 8.66 (dd, J =

2.0 Hz and J = 8.0 Hz, 2H, H₁₂); ¹³C NMR (100 MHz, CDCl₃) δ (ppm)

21.9, 36.3, 111.5, 127.2, 128.4, 128.8, 130.3, 130.5, 137.6, 138.3, 163.9,

164.0, 176.3; IR (ATR, neat) ν (cm⁻¹) 2961, 2924, 2866, 1590, 1568,

1531, 1496, 1373, 756, 692, 633; MS (ESI+) m/z 275 (100, [M + H]⁺);

HRMS (ESI+) m/z 275.1551 calcd for C₁₉H₁₈N₂+ H⁺275.1548.

2,4,6-Triphenylpyrimidine (19). According to general procedure

C (on 0.1 mmol scale) and starting from (Z)-benzyl (3-oxo-1,3-

diphenylprop-1-en-1-yl)carbamate 2s and benzamide, 16.6 mg of

compound 19 (0.054 mmol, 54% yield) were obtained as a white

solid after puriﬁcation by ﬂash chromatography on silica gel (pentane/

4-Butyl-6-(3-methoxyphenyl)-2-phenylpyrimidine (14). Ac-

cording to general procedure C (on 0.2 mmol scale) and starting

from (Z)-benzyl (1-(3-methoxyphenyl)-3-oxohept-1-en-1-yl)-

carbamate 2h and benzamide, 38.9 mg of compound 14 (0.122 mmol,

62% yield) were obtained as a pale yellow oil after puriﬁcation by ﬂash

chromatography on silica gel (petroleum ether/Et₂O 97/3): R_f(silica,

pentane/Et₂O 95/5 = 0.6, UV/Vanillin); ¹H NMR (400 MHz, CDCl₃)

δ (ppm) 1.01 (t, J = 7.6 Hz, 3H), 1.43−1.54 (m, 2H), 1.82−1.91 (m,

2H), 2.89 (t, J = 7.6 Hz, 2H), 3.94 (s, 3H), 7.07 (dd, J = 2.5 Hz and J =

8.2 Hz, 1H), 7.42−7.47 (m, 2H), 7.48−7.56 (m, 3H), 7.77 (d, J = 7.7 Hz,

1H), 7.84 (brs, 1H), 8.60−8.65 (m, 2H); ¹³C NMR (100 MHz, CDCl₃)

δ (ppm) 13.9, 22.5, 30.9, 37.9, 55.4, 112.6, 113.5, 116.1, 119.5, 128.3,

128.4, 129.8, 130.4, 138.2, 138.9, 160.1, 163.4, 164.1, 171.6; IR (ATR,

neat) ν (cm⁻¹) 3066, 2955, 2930, 2870, 1587, 1568, 1531, 1463, 1368,

1253, 1045, 858, 756, 691, 673, 636; MS (ESI+) m/z 319 (100, [M +

H]⁺); HRMS (ESI+) m/z 319.1805 calcd for C₂₁H₂₂N₂O + H⁺

319.1810.

4-Butyl-6-(naphthalen-2-yl)-2-phenylpyrimidine (15). Accord-

ing to general procedure C (on 0.2 mmol scale) and starting from (Z)-

benzyl (1-(naphthalen-2-yl)-3-oxohept-1-en-1-yl)carbamate 2k and

benzamide, 38.2 mg of compound 15 (0.113 mmol, 57% yield) were

obtained as a yellow oil after puriﬁcation by ﬂash chromatography on

silica gel (petroleum ether/Et₂O 98/2): R_f(silica, pentane/Et₂O 95/5 =

0.8, UV/Vanillin); ¹H NMR (400 MHz, CDCl₃) δ (ppm) 1.04 (t, J = 7.6

Hz, 3H), 1.46−1.57 (m, 2H), 1.85−1.95 (m, 2H), 2.93 (t, J = 8.0 Hz,

2H), 7.50−7.62 (m, 6H), 7.89−8.05 (m, 3H), 8.35 (d, J = 8.4 Hz, 1H),

8.66−8.74 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 14.0, 22.5,

31.0, 38.0, 113.6, 124.2, 126.4, 127.1,127.2, 127.7, 128.3, 128.4, 128.5,

128.9, 130.4, 133.3, 134.5, 134.7, 138.3, 163.5, 164.3, 171.6; IR (ATR,

neat) ν (cm⁻¹) 3060, 2954, 2927, 2858, 1587, 1568, 1531, 1373; 1173,

854, 817, 758, 694, 656; MS (ESI+) m/z 339 (100, [M + H]⁺); HRMS

(ESI+) m/z 339.1861 calcd for C₂₄H₂₂N₂+ H⁺339.1861.

4-Butyl-2-phenyl-6-(thiophen-2-yl)pyrimidine (16). According

to general procedure C (on 0.2 mmol scale) and starting from (Z)-

benzyl (3-oxo-1-(thiophen-2-yl)hept-1-en-1-yl)carbamate 2j and ben-

zamide, 30.5 mg of compound 16 (0.104 mmol, 52% yield) were

obtained as a yellow oil after puriﬁcation by ﬂash chromatography on

silica gel (pentane/Et₂O 98/2): R_f(silica, pentane/Et₂O 95/5 = 0.7,

UV/Vanillin); ¹H NMR (400 MHz, CDCl₃) δ (ppm) 1.00 (t, J = 7.2 Hz,

3H), 1.42−1.52 (m, 2H), 1.79−1.88 (m, 2H), 2.85 (t, J = 8 Hz, 2H),

7.17 (dd, J = 3.9 Hz and J = 4.8 Hz, 1H), 7.30 (s, 1H), 7.44−7.56 (m,

4H), 7.82 (d, J = 3.2 Hz, 1H), 8.57 (dd, J = 1.9 Hz and J = 7.6 Hz, 2H);

¹³C NMR (100 MHz, CDCl₃) δ (ppm) 13.9, 22.5, 30.9, 37.8, 111.5,

126.8, 128.1, 128.3, 128.4, 129.5, 130.4, 137.8, 143.3, 158.7, 164.1,

171.4; IR (ATR, neat) ν (cm⁻¹) 2955, 2927, 2858, 1720, 1588, 1570,

1528, 1432, 1373, 1269, 1235, 1172, 1026, 856, 756, 694; MS (ESI+) m/

z 295 (100, [M + H]⁺); HRMS (ESI+) m/z 295.1261 calcd for

C₁₈H₁₈N₂S + H⁺295.1269.

Et₂O 98/2): R_f(silica, pentane/Et₂O 95/5 = 0.4, UV/Vanillin); H

NMR (400 MHz, CDCl₃) δ (ppm) 7.50−7.62 (m, 9H), 8.06 (s, 1H),

8.28−8.33 (dd, 1H, J = 1.6 Hz and J = 8.0 Hz, 4H), 8.28−8.33 (dd, 1H, J

= 2.0 Hz and J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm)

110.3, 127.3,128.4, 128.9, 130.6, 130.7, 137.5, 138.1, 164.5, 164.7. The

spectral data are consistent with those of the literature.³⁰

4-Butyl-6-phenyl-2-(thiophen-2-yl)pyrimidine (20). According

to general procedure C (on 0.2 mmol scale) and starting from (Z)-

benzyl (3-oxo-1-phenylhept-1-en-1-yl)carbamate 2a and 2-thiophene-

carboxamide, 36.2 mg of compound 20 (0.122 mmol, 60% yield) were

obtained as a pale yellow oil after puriﬁcation by ﬂash chromatography

on silica gel (pentane/Et₂O 98/2): R_f(silica, pentane/Et₂O 95/5 = 0.75,

UV/Vanillin); ¹H NMR (400 MHz, CDCl₃) δ (ppm) 1.00 (t, J = 7.6 Hz,

3H), 1.42−1.52 (m, 2H), 1.78−1.88 (m, 2H), 2.84 (t, J = 7.6 Hz, 2H),

7.17 (dd, J = 3.7 Hz and J = 5.0 Hz, 1H), 7.37 (s, 1H), 7.48 (dd, J = 1.2

Hz and J = 5.0 Hz, 1H), 7.50−7.56 (m, 3H), 8.14 (dd, J = 1.2 Hz and J =

3.6 Hz, 1H), 8.17−8.21 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ

(ppm) 13.9, 22.4, 30.8, 37.7, 112.8, 127.1, 128.0, 128.6, 128.8, 129.3,

130.6, 137.0, 144.2, 161.1, 163.6, 171.7. The spectral data are consistent

with those of the literature.³¹

4-Butyl-2-(4-nitrophenyl)-6-phenylpyrimidine (21). According

to general procedure C (on 0.2 mmol scale) and starting from (Z)-

benzyl (3-oxo-1-phenylhept-1-en-1-yl)carbamate 2a and 4-nitro-

benzamide, 54.6 mg of compound 21 (0.164 mmol, 82% yield) were

obtained as a yellow solid after puriﬁcation by ﬂash chromatography on

silica gel (pentane/Et₂O 97/3): R_f(silica, pentane/Et₂O 95/5 = 0.5,

UV/Vanillin); ¹H NMR (400 MHz, CDCl₃) δ (ppm) 1.01 (t, J = 7.2 Hz,

3H), 1.43−1.54 (m, 2H), 1.80−1.90 (m, 2H), 2.90 (t, J = 7.6 Hz, 2H),

7.52−7.58 (m, 4H), 8.18 − 8.22 (m, 2H), 8.33 (∼d, J = 8.8 Hz, 2H),8.77

(∼d, J = 9.2 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 13.9, 22.5,

30.9, 37.9, 114.4, 123.5, 127.2, 128.9, 129.2, 131.0, 136.8, 144.0, 149.1,

162.0, 164.0, 172.1; IR (ATR, neat) ν (cm⁻¹) 2953, 2926, 2869, 1577,

1520, 1463, 1420, 1353, 1336, 1223, 867, 857, 829, 773, 743, 690, 646;

MS (ESI+) m/z 386 (15), 334 (100, [M + H]⁺), 288 (10), 213 (10);

HRMS (ESI+) m/z 334.1536 calcd for C₂₀H₁₉N₃O₂+ H⁺334.1556.

2-(4-Bromophenyl)-4-butyl-6-phenylpyrimidine (22). Accord-

ing to general procedure C (on 0.2 mmol scale) and starting from (Z)-

benzyl (3-oxo-1-phenylhept-1-en-1-yl)carbamate 2a and 4-bromo-

benzamide, 56.7 mg of compound 22 (0.154 mmol, 78% yield) were

obtained as a pale yellow solid after puriﬁcation by ﬂash chromatography

on silica gel (pentane/Et₂O 98/2): R_f(silica, pentane/Et₂O 95/5 = 0.7,

4-Methyl-2,6-diphenylpyrimidine (17). According to general

procedure C (on 0.2 mmol scale) and starting from (Z)-benzyl (3-oxo-

1-phenylbut-1-en-1-yl)carbamate 2p and benzamide, 32.9 mg of

compound 17 (0.134 mmol, 77% yield) were obtained as a pale yellow

solid after puriﬁcation by ﬂash chromatography on silica gel (pentane/

UV/Vanillin); mp 88−90 °C (Et₂O/pentane); H NMR (400 MHz,

CDCl₃) δ (ppm) 1.00 (t, J = 7.6 Hz), 1.42−1.53 (m, 2H), 1.79−1.88 (m,

2H), 2.88 (t, J = 7.6 Hz, 2H), 7.46 (s, 1H), 7.50−7.56 (m, 3H), 7.63 (∼d,

J = 8.8 Hz, 2H), 8.18−8.22 (m, 2H), 8.49 (∼d, J = 8.8 Hz, 2H); ¹³C

NMR (100 MHz, CDCl₃) δ (ppm) 13.9, 22.5, 31.0, 37.9, 113.6, 125.1,

127.2, 128.8, 130.0, 130.7, 131.5, 137.1, 137.2, 163.3, 163.8, 171.7; IR

(ATR, neat) ν (cm⁻¹) 2956, 2924, 2857, 1588, 1564, 1530, 1363, 1169,

1069, 1010, 841, 767, 690, 639; MS (ESI+) m/z 369 (97, [M +

H]⁺,⁸¹Br), 367 (100, [M + H]⁺,⁷⁹Br). 288 (15), 275 (10); HRMS (ESI

+) m/z 367.0796 calcd for C₂₀H₁₉BrN₂+ H⁺367.0810.

Et₂O 96/4): R_f(silica, pentane/Et₂O 95/5 = 0.4, UV/Vanillin); H

NMR (400 MHz, CDCl₃) δ (ppm) 2.65 (s, 3H), 7.47 (s, 1H), 7.49−

7.57 (m, 6H), 8.20−8.25 (m, 2H), 8.58−8.64 (m, 2H); ¹³C NMR (100

MHz, CDCl₃) δ (ppm) 24.6, 114.0, 127.1, 128.3, 128.4, 128.8, 130.4,

130.6, 137.2, 138.1, 163.6, 164.2, 167.7. The spectral data are consistent

with those of the literature.²⁹

4-Isopropyl-2,6-diphenylpyrimidine (18). According to general

procedure C (on 0.2 mmol scale) and starting from (Z)-benzyl (4-

methyl-3-oxo-1-phenylpent-1-en-1-yl)carbamate 2q and benzamide,

39.2 mg of compound 18 (0.142 mmol, 71% yield) were obtained as

a pale yellow oil after puriﬁcation by ﬂash chromatography on silica gel

(pentane/Et₂O 98/2): R_f(silica, pentane/Et₂O 95/5 = 0.8, UV/

Vanillin); ¹H NMR (400 MHz, CDCl₃) δ (ppm) 1.44 (t, J = 6.8 Hz, 6H,

4-Butyl-6-phenyl-2-vinylpyrimidine (23). According to general

procedure D (on 0.1 mmol scale) and starting from (Z)-benzyl (3-oxo-

1-phenylhept-1-en-1-yl)carbamate 2a and acrylamide, 17.1 mg of

compound 23 (0.072 mmol, 72% yield) were obtained as a yellow oil

after puriﬁcation by ﬂash chromatography on silica gel (pentane/Et₂O

95/5): R_f(silica, pentane/Et₂O 9/1 = 0.6, UV/Vanillin); ¹H NMR (400

MHz, CDCl₃) δ (ppm) 0.97 (t, J = 7.4 Hz, 3H), 1.38−1.49 (m, 2H),

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1.73−1.83 (m, 2H), 2.81 (t, J = 7.6 Hz, 2H), 5.74 (dd, J = 1.9 Hz and J =

10.5 Hz, 1H), 6.75 (dd, J = 1.9 Hz and J = 17.3 Hz, 1H), 6.96 (dd, J =

10.5 Hz and J = 17.3 Hz, 1H), 7.40 (s, 1H), 7.47−7.53 (m, 3H), 8.09−

8.14 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 13.9, 22.5, 31.1,

37.8, 113.6, 123.5, 127.2, 128.8, 130.6, 137.0, 137.2, 163.8, 164.0, 171.3;

IR (ATR, neat) ν (cm⁻¹) 2956, 2926, 2857, 1573, 1531, 1420, 1371, 991,

940, 772, 690; MS (ESI+) m/z 239 (100, [M + H]⁺); HRMS (ESI+) m/

z 239.1537 calcd for C₁₆H₁₈N₂+ H⁺239.1548.

ASSOCIATED CONTENT

■

* Supporting Information

Table of atom coordinates and absolute energies, and NMR

spectra (¹H, ¹³C, ¹⁹F) for all products (1a−t, 1v,w, 2a−l, 2n,

2p,q, 2s,t, 4, 6, 7, 9−27). This material is available free of charge

via the Internet at http://pubs.acs.org.

4-Butyl-6-(4-ﬂuorophenyl)-2-vinylpyrimidine (24). According

to general procedure D (on 0.1 mmol scale) and starting from (Z)-

benzyl (1-(4-ﬂuorophenyl)-3-oxohept-1-en-1-yl)carbamate 2c and

acrylamide, 17.7 mg of compound 24 (0.069 mmol, 69% yield) were

obtained as a yellow oil after puriﬁcation by ﬂash chromatography on

silica gel (pentane/Et₂O 96/4): R_f(silica, pentane/Et₂O 9/1 = 0.7, UV/

Vanillin); ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.97 (t, J = 7.3 Hz, 3H,

H₁), 1.38−1.49 (m, 2H, H₂), 1.72−1.82 (m, 2H, H₃), 2.80 (t, J = 7.6 Hz,

2H, H₄), 5.74 (dd, J = 1.9 Hz and J = 10.4 Hz, 1H, H_14′), 6.73 (dd, J = 2.0

Hz and J = 17.3 Hz, 1H, H₁₄), 6.94 (dd, J = 10.4 Hz and J = 17.3 Hz, 1H,

H₁₃), 7.14−7.21 (m, 2H, H₁₀), 7.34 (s, 1H, H₆), 8.09−8.16 (m, 2H, H₉).

¹⁹F NMR (376 MHz, CDCl₃) δ (ppm) −110.1; ¹³C NMR (100 MHz,

CDCl₃) δ (ppm) 13.9, 22.5, 31.1, 37.8, 113.2, 115.8 (d, J_ortho(C−F)= 21.8

Hz), 123.6, 129.2 (d, J_meta(C−F)= 8.7 Hz, 2C), 133.3 (d, J_para(C−F)= 2.9

Hz), 136.9, 162.6, 164.0, 164.5 (d, J_ipso(C−F)= 250.9 Hz), 171.5; IR

(ATR, neat) ν (cm⁻¹) 2957, 2927, 2858, 1731, 1601, 1575, 1532, 1509,

1232, 1156, 837, 819; MS (ESI+) m/z 420 (15), 257 (100, [M + H]⁺);

HRMS (ESI+) m/z 257.1454 calcd for C₁₆H₁₇FN₂+ H⁺257.1454.

4-Methyl-6-phenyl-2-vinylpyrimidine (25). According to gen-

eral procedure D (on 0.1 mmol scale) and starting from (Z)-benzyl (3-

oxo-1-phenylbut-1-en-1-yl)carbamate 2p and acrylamide, 13.3 mg of

compound 25 (0.0678 mmol, 68% yield) were obtained as a yellow oil

after puriﬁcation by ﬂash chromatography on silica gel (pentane/Et₂O

AUTHOR INFORMATION

■

Corresponding Author

*E-mail: emmanuel.vrancken@enscm.fr; jean-marc.campagne@

enscm.fr; helene.gerard@upmc.fr.

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

Authors deeply acknowledge Dr. S. Rousseaux and Dr. B.

Liegault (ENSCM) for their help in the preparation of this

manuscript. We also thank MESR (E. G. Ph.D. grant) and the

ENSCM.

REFERENCES

■

(1) (a) Elassar, A. A.; El-Khair, A. A. Tetrahedron 2003, 59, 8463.

(b) Lee, D. H.; Park, S.; Cho, K.; Kim, Y.; Athar, T.; Lee, I. Tetrahedron

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88/12): R_f(silica, pentane/Et₂O 9/1 = 0.25, UV/Vanillin); H NMR

(3) For recent applications and refs cited: (a) Neumann, J. J.; Suri, M.;

Glorius, F. Ang. Chem. Int. Ed. 2010, 49, 7790. (b) Zhao, M.; Wang, F.;

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(b) Li, G.; Hsung, R. P.; Slafer, B. W.; Sagamanova, I. K. Org. Lett. 2012,

10, 4991. (c) Tsukanov, S. V.; Comins, D. L. Ang. Chem. Int. Ed. 2011,

50, 8626. (d) Caplan, J. F.; Zheng, R.; Blanchard, J. S.; Vederas, J. C. Org.

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R.; Cook, J. M. J. Nat. Prod. 2012, 75, 181.

(400 MHz, CDCl₃) δ (ppm) 2.59 (s, 3H), 5.75 (dd, J = 1.9 Hz and J =

10.5 Hz, 1H), 6.74 (dd, J = 1.9 Hz and J = 17.3 Hz, 1H), 6.95 (dd, J =

10.5 Hz and J = 17.3 Hz, 1H), 7.42 (s, 1H), 7.48−7.53 (m, 3H), 8.09−

8.14 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ (ppm) 24.2, 114.3, 123.8,

127.2, 128.9, 130.8, 136.7, 137.0, 163.9, 167.2; IR (ATR, neat) ν (cm⁻¹)

3034, 2924, 2853, 1574, 1535, 1441, 1354, 773, 690; MS (ESI+) m/z

197 (100, [M + H]⁺), 184 (5); HRMS (ESI+) m/z 197.1074 calcd for

C₁₃H₁₂N₂+ H⁺197.1079.

4-Butyl-2-methyl-6-phenylpyrimidine (26). According to gen-

eral procedure C (on 0.2 mmol scale) and starting from (Z)-benzyl (3-

oxo-1-phenylhept-1-en-1-yl)carbamate 2a and acetamide, 31.6 mg of

compound 26 (0.142 mmol, 71% yield) were obtained as a pale yellow

oil after puriﬁcation by ﬂash chromatography on silica gel (pentane/

Et₂O 85/15): R_f(silica, pentane/Et₂O 85/15 = 0.25, UV/Vanillin); ¹H

NMR (400 MHz, CDCl₃) δ (ppm) 0.96 (t, J = 7.6 Hz, 3H), 1.37−1.48

(m, 2H), 1.70−1.79 (m, 2H), 2.77 (t, J = 7.8 Hz, 2H), 2.78 (s, 3H), 7.35

(s, 1H), 7.46−7.52 (m, 3H), 8.02−8.08 (m, 2H); ¹³C NMR (100 MHz,

CDCl₃) δ (ppm) 13.9, 22.5, 26.2, 31.4, 37.9, 112.8, 127.2, 128.8, 130.5,

137.3, 164.1, 167.9, 171.3; IR (ATR, neat) ν (cm⁻¹) 2956, 2926, 2858,

1576, 1537, 1394, 1371, 754, 690; MS (ESI+) m/z 227 (100, [M + H]⁺);

HRMS (ESI+) m/z 227.1527 calcd for C₁₅H₁₈N₂+ H⁺227.1548.

4-Butyl-6-phenylpyrimidine (27). According to general proce-

dure C (on 0.2 mmol scale) in the absence of 4 Å MS and starting from

(Z)-benzyl (4-methyl-3-oxo-1-phenylpent-1-en-1-yl)carbamate 2i and

formamide, 20.7 mg of compound 27 (0.098 mmol, 49% yield) were

obtained as a yellow oil after puriﬁcation by ﬂash chromatography on

silica gel (pentane/Et₂O 95/5 → 9/1): R_f(silica, pentane/Et₂O 9/1 =

0.3, UV/Vanillin); ¹H NMR (400 MHz, CDCl₃) δ (ppm) 0.96 (t, J = 7.2

Hz, 3H), 1.37−1.48 (m, 2H), 1.73−1.82 (m, 2H), 2.82 (t, J = 7.6 Hz,

2H), 7.48−7.53 (m, 3H), 7.50 (s, 1H), 8.04−8.10 (m, 2H), 9.10 (s, 1H);

¹³C NMR (100 MHz, CDCl₃) δ (ppm) 13.9, 22.4, 31.1, 37.7, 115.9,

127.1, 128.9, 130.8, 136.8, 158.7, 163.9, 171.3; IR (ATR, neat) ν (cm⁻¹)

2956, 2927, 2859, 1588, 1578, 1526, 1465, 1442, 1374, 752, 690, 637;

MS (ESI+) m/z 583 (20, [2M + H]⁺), 292 (100, [M + H]⁺), 83 (5);

HRMS (ESI+) m/z 213.1377 calcd for C₁₄H₁₆N₂+ H⁺213.1392.

(5) For a recent stereoselective synthesis of Z-enaminones, see ref 1c.

(6) Gayon, E.; Quinonero, O.; Lemouzy, S.; Vrancken, E.; Campagne,

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(7) (a) Hill, M. D.; Movassaghi, M. Chem.Eur. J. 2008, 14, 6836.

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Muller, T. J. J. Synthesis 2003, 2815.

(8) The use of enaminones in the synthesis of pyrimidines has been

described, but the amino group is used as a leaving group: Schenone, P.;

Sansebastiano, L.; Mosti, L. J. Heterocycl. Chem. 1990, 27, 295.

(9) (a) Debleds, O.; Dal Zotto, C.; Vrancken, E.; Campagne, J.-M. Adv.

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9219

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The Journal of Organic Chemistry

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which a Karl Fischer titration shows the presence of 0.14% of water,

which corresponds to 0.61 equiv compared to the starting propargylic

hydroxylamine.

(14) Yoshida, J.-I.; Itoh, M.; Matsunaga, S.-I.; Isoe, S. J. Org. Chem.

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NaOH (10 mol%), CH₃CN, 50 °C, 1 h followed by the addition in the

reaction mixture of (2) t-BuOK (2 equiv), PhCONH₂(1.5 equiv), 4 Å

MS, 130 °C, 1 h (sealed tube). 6 was obtained in 23% yield, as compared

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dx.doi.org/10.1021/jo301675g | J. Org. Chem. 2012, 77, 9205−9220

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