Facile access to ring-fused aminals via direct α-amination of secondary amines with o-aminobenzaldehydes: Synthesis of vasicine, deoxyvasicine, deoxyvasicinone, mackinazolinone, and ruteacarpine

1730▌

FEATURE ARTICLE

feature article

Facile Access to Ring-Fused Aminals via Direct α-Amination of Secondary

Amines with o-Aminobenzaldehydes: Synthesis of Vasicine, Deoxyvasicine,

Deoxyvasicinone, Mackinazolinone, and Ruteacarpine

Ring-Fused Aminals from Secondary Amines and o-Aminobenzaldehydes

Matthew T. Richers,^aIndubhusan Deb,^aAlena Yu. Platonova,^a,bChen Zhang,^aDaniel Seidel*^a

a

Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA

Fax +1(732)4455312; E-mail: seidel@rutchem.rutgers.edu

b

Department of Organic Synthesis Technology, Ural Federal University, Yekaterinburg, 620002, Russian Federation

Received: 14.03.2013; Accepted after revision: 01.05.2013

Dedicated to Prof. Scott E. Denmark on the occasion of his 60^thbirthday

ported the Brønsted acid catalyzed formation of aminals

Abstract: Secondary amines undergo redox-neutral reactions with

related to 7 by employing a one-pot cascade strategy start-

aminobenzaldehydes under conventional and microwave heating to

ing form primary amines and tertiary o-aminobenzalde-

furnish polycyclic aminals via amine α-amination/N-alkylation.

This unique α-functionalization reaction proceeds without the in-

hydes. In addition to standard condensation based

volvement of transition metals or other additives. The resulting approaches to aminals,⁹a number of oxidative amine α-

aminations have also been reported.¹⁰

aminal products are precursors for various quinazolinone alkaloids

and their analogues.

Key words: C–H bond functionalization, redox isomerization,

aminals, quinazolinone alkaloids, Friedländer condensation

Pinnow (1895):

Me

N

Me

N

Me

Sn

Me

+

N

HCl

NH₂

NO₂

Introduction

1

2

3

The transformation of simple amines into value-added

building blocks via α-C–H bond functionalization re-

mains an active area of research.¹While the majority of

current approaches are oxidative in nature, redox-neutral²

methods offer an attractive alternative. Perhaps the earli-

est example of a nonoxidative α-functionalization of an

amine can be traced back to Pinnow who in 1895 reported

the unusual reaction outlined in Scheme 1.³Exposure of

nitroaniline 1 to reducing conditions provided benzimid-

azole 3 in addition to the expected diamine 2. Product 3

results from the functionalization of a methyl group, pre-

sumably via intramolecular H-transfer to an intermediate

nitroso compound.

Meth-Cohn (1967):

R

N

R

N

EtOH

Ox

N

H

4

5

Reinhoudt (1984):

CF₃

n-BuOH

heat, 5 d

Ar

H

N

66%

N

6

7

Reactions of this type in which a tertiary amine undergoes

functionalization in α-position were later classified under

the term tert-amino effect. Several reviews on this topic

have appeared.⁴Other classic examples of the tert-amino

effect that lead to amine α-amination are shown in

Scheme 1. Meth-Cohn et al. reported the acid-catalyzed

isomerization of imines 4 to dihydrobenzimidazoles 5,

species that readily air-oxidize to the corresponding benz-

imidazolium salts.⁵This interesting rearrangement is

thought to proceed via a 1,6-hydride transfer from an

amine α-C–H bond to an iminium ion. Reinhoudt and co-

workers, in addition to many other key contributions,⁶re-

ported the thermal rearrangement of imine 6 to aminal 7.^6b

This reactions involves a 1,5-hydride shift/ring closure se-

quence. Akiyama et al.⁷and our group⁸independently re-

Scheme 1 Examples of amine α-amination via C–H bond function-

alization

Our interest in the area of C–H functionalization was

sparked by an unexpected discovery. In the course of per-

forming Friedländer reactions¹¹to prepare a number of

quinolines, we observed the formation of an interesting

pyrrolidine-containing by-product. Specifically, the sup-

posedly innocent base pyrrolidine was found to undergo

an unexpected reaction with o-aminobenzaldehyde 8a to

form aminal 9a under mild conditions (Scheme 2). In this

process, an amine α-C–H bond is replaced by a C–N bond,

concomitant with a reductive N-alkylation of the

amine.^12–14Here we provide a full account of this process,

along with the application to the synthesis of several quin-

azolinone alkaloids.

SYNTHESIS 2013, 45, 1730–1748

Advanced online publication: 10.06.2013

0

3

9

-

7

8

1

4

3

7

-

2

1

0

X

DOI: 10.1055/s-0033-1338852; Art ID: SS-2013-C0210-FA

FEATURE ARTICLE

Ring-Fused Aminals from Secondary Amines and o-Aminobenzaldehydes

1731

Reaction Development

CHO

heat

Following our initial discovery, the condensation of pyr-

rolidine and o-aminobenzaldehydes was evaluated under

a range of conditions. Alcoholic solvents, in particular

ethanol, provided better results than solvents such as tolu-

ene, DMF, THF, and acetonitrile. An excess amount of

pyrrolidine proved beneficial to shorten reaction times

while the use of pyrrolidine as solvent led to inferior re-

N

+

N

– H₂O

H

NH₂

N

H

CN

8a

9a

Scheme 2 Serendipitously discovered redox-neutral formation of

aminals

Biographical Sketches█

Matthew T. Richers was Jersey. He is currently pur- search focuses on the facile

born in Scotch Plains, NJ suing a Ph.D. in organic synthesis

(USA) in 1987. In 2009, he chemistry at Rutgers Uni- containing

obtained his B.Sc. in chem- versity in the laboratory of compounds.

istry at The College of New Prof. Daniel Seidel. His re-

of

nitrogen-

heterocyclic

Indubhusan Deb was born dian Institute of Technology research group at Nanyang

in West Bengal (India). He Bombay and received his Technological University,

obtained his B.Sc. (Honors Ph.D. in 2008. He subse- Singapore, where his re-

in Chemistry) degree from quently moved to Rutgers search is focused on transi-

the University of Calcutta University where he carried tion-metal-catalyzed C–H

and his M.Sc. degree from out postdoctoral research bond functionalization for

Banaras Hindu University with Prof. Daniel Seidel. the synthesis of heterocy-

in 2002. He performed his Since 2011, he is pursuing cles.

graduate work with Prof. I. postdoctoral research in

N. N. Namboothiri at the In- Prof. Naohiko Yoshikai’s

Alena Yu. Platonova was Ph.D. research under the su- eration President Fellow.

born in Russia in 1987. She pervision of Prof. Yu. Yu. Her research interests are

received both her B.Sc. Morzherin. In 2011 Alena focused on the synthetic

(2008) and M.Sc. (2010) de- joined the group of Prof. chemistry of nitrogen-

grees from the Ural State Daniel Seidel at Rutgers containing heterocycles.

Technical University and is University for a ten-month

currently conducting her internship as a Russian Fed-

Chen Zhang was born in the Seidel group at Rutgers of Illinois at Urbana-Cham-

Fuzhou (P. R. of China) in University and received his paign. Chen is currently

1982. He received his B.Sc. Ph.D. in 2010. From 2010– conducting research in me-

degree from the University 2011, he performed his dicinal chemistry at Xizang

of Science and Technology postdoctoral research in the Haisco

Pharmaceutical

of China in 2005. In Sep- group of Prof. Scott E. Group Co., Ltd. in China.

tember of 2005, Chen joined Denmark at the University

Daniel Seidel was born in involved the development gers University in August

Mühlhausen,

Thüringen of new methods for the syn- 2005 and was promoted to

(Germany) and studied thesis of expanded porphy- Associate Professor with

chemistry at the Friedrich- rin analogues. From 2002– tenure in 2011. Research in

Schiller-Universität

Jena 2005, Daniel was an Ernst his group is focused on new

(Diplom 1998). His Ph.D. Schering Postdoctoral Fel- concepts for asymmetric ca-

research at the University of low in the group of Prof. talysis and synthetic meth-

Texas at Austin (1998– David A. Evans at Harvard odology.

2002) under the supervision University. He started his

of Prof. Jonathan L. Sessler independent career at Rut-

Synthesis 2013, 45, 1730–1748

1732

M. T. Richers et al.

FEATURE ARTICLE

X

CHO

EtOH (0.25 M)

reflux

N

+

R¹

N

H

Y

N

R²

Y

NH

R²

3 equiv

8

9

Ph

Br

Cl

N

H

Cl

N

Ph

N

H

Br

Cl

CN

9a, 95% (18 h)

9b, 92% (12 h)

9c, 92% (23 h)

9d, 84% (12 h)

9e, 57% (72 h)

MeO₂C

N

H

N

MeO₂C

N

H

N

H

Cl

Br

9f, 76% (18 h)

9g, 83% (36 h)

9h, 76% (24 h)

9i, 60% (24 h)

9j, 58% (48 h)

N

Et

N

H

N

H

N

H

OMe

9k, 73% (72 h)

9l, 81% (48 h)

9m, 94% (36 h)

9n, 91% (13 h)

9o, 84% (80 h)

Scheme 3 Reactions of pyrrolidine with various o-aminobenzaldehydes

sults. Under optimized reaction conditions, a range of reaction conditions (reflux in ethanol). However, a reac-

aminobenzaldehydes was allowed to react with three tion of piperidine and aminobenzaldehyde 8c performed

equivalents of pyrrolidine in ethanol under reflux in a sealed tube at 140 °C led to a reasonable conversion

(Scheme 3). Various aminobenzaldehydes with different to product. Even under these more forcing conditions,

substitution patterns and electronic properties proved to morpholine proved to be a poor substrate. Azepane

be suitable substrates, providing products in generally showed a higher reactivity than piperidine, and azocane

good yields. Electron-poor aminobenzaldehydes were was found to be reactive enough to undergo the reaction

found to be particularly reactive, whereas more electron- under the original reflux conditions. Cyclic amines with

rich substrates furnished products in good yields after benzylic α-C–H bonds such as tetrahydroisoquinoline

somewhat prolonged reaction times. Heterocyclic amino- (THIQ) were identified as highly reactive substrates, typ-

aldehydes gave ring-fused aminals in excellent yields. An ically providing good yields of aminal products. Notably,

ethyl substituent on the nitrogen atom of the aminobenz- shortly after our initial communication on these results,

aldehyde was tolerated.

Dang and Bai independently reported a related procedure

with o-phenylthio-o-aminopyrimidine aldehyde.¹⁵

The aminal formation was also explored with regard to

amines other than pyrrolidine (Scheme 4). Interestingly, Several of the aminal products were characterized by X-

piperidine gave very little conversion under the original ray crystallography (Figure 1). Interestingly, the pyrro-

R³

CHO

NH₂

R²

EtOH (0.25 M)

reflux

N

R³

+

R¹

N

R²

H

3 equiv

8

10

Br

N

O

N

H

Br

10a, 67% (48 h)

sealed tube, 140 °C

10b, 15% (48 h)

sealed tube, 140 °C

10c, 77% (24 h)

sealed tube, 140 °C

10d, 60% (12 h)

MeO₂C

Br

N

H

N

H

N

H

HN

Br

10e, 96% (16 h)

10f, 94% (48 h)

10g, 66% (72 h)

with 2.1 equiv of amine

10h, 80% (48 h)

with 2 equiv of amine

Scheme 4 Reactions of o-aminobenzaldehydes with various cyclic amines

Synthesis 2013, 45, 1730–1748

FEATURE ARTICLE

Ring-Fused Aminals from Secondary Amines and o-Aminobenzaldehydes

1733

Figure 1 Top and side views of the X-ray crystal structures of 9c (left) and 10a (right)

lidine-derived aminal 9c exhibits a bent structure whereas 14 to zwitterion 15. Interestingly, ethanol acts as a proton-

piperidine-based aminal 10a adopts a relatively planar shuttle in this instance (via 16). Ultimately, zwitterion 15

conformation.

collapses into product 9k. Support for this computational-

ly derived mechanism was obtained from various deuteri-

um-labeling studies and trapping of azaquinonemethide

and azomethine ylide intermediates (vide infra).

Reaction Mechanism

In collaboration with the Houk group, we have recently

performed a combined computational and experimental

study to delineate the mechanism of the aminal forma-

Reaction Optimization Under Microwave Conditions

tion.^12cDensity functional theory calculations revealed a Following our original publication,^12aPolshettiwar and

partially unexpected reaction pathway. Perhaps the most Varma reported the use of microwave irradiation to accel-

surprising finding is that simple iminium ions are most erate the formation of aminals from secondary amines and

likely not involved in the overall process. The lowest en- ortho-aminobenzaldehydes.¹⁶According to these authors,

ergy pathway for aminal formation is outlined in Scheme the reaction is best performed under solvent-free condi-

5, exemplified in the prototypical reaction of unsubstitut- tions with four equivalents of the cyclic amine. Specifical-

ed o-aminobenzaldehyde (8k) and pyrrolidine. In the first ly, reaction times between 40–60 minutes at 130 °C were

step, 8k and pyrrolidine react to form N,O-acetal 11. Rath- reported to give good yields of products. Surprisingly, the

er than fragmenting into an iminium ion as originally as- same reaction conditions are purportedly applicable to a

sumed, 11 undergoes elimination of water via a six- broad range of substrates, including cyclic amines such as

membered transition state with participation of the NH₂pyrrolidine, piperidine, and morpholine – substrates that

group to directly form ortho-azaquinonemethide 12. Nat- we had found to exhibit vastly different reactivities. In our

ural population analysis of 12 indicated a significant con- hands, the findings by Polshettiwar and Varma were

tribution from a zwitterionic resonance structure 13 with largely irreproducible. Our own efforts to identify effi-

a negative charge on the aniline nitrogen and an iminium cient microwave conditions are the subject of the follow-

ion at the heterocycle, restoring the aromaticity of the sys- ing discussion.

tem. The rate-determining step of the overall transforma-

tion is the rearrangement of azaquinonemethide 12/13 to

azomethine ylide 14 via 1,6-proton abstraction. The alter-

Morpholine, a substrate that was previously shown to ex-

hibit poor reactivity under conventional heating condi-

tions was selected for performance optimization under

native 1,6-hydride transfer process was ruled out. Another

microwave irradiation. Specifically, the reaction of ami-

proton transfer step follows, converting azomethine ylide

nobenzaldehyde 8c with morpholine to give aminal 10b

N

CHO

N

OH

H

+

N

– H₂O

NH

N

NH₂

H

8k

12

H

11

13

via:

N

EtOH

N

H

O

Et

N

H

9k

NH₂

14

N

H

N

H

15

H

15

16

Scheme 5 Mechanism of the aminal formation

Synthesis 2013, 45, 1730–1748

1734

M. T. Richers et al.

FEATURE ARTICLE

Br

N

n-BuOH (0.25 M)

8c

+

N

H

HN

μW (HE), 200 °C

30 min

reflux, 18 h

79%

HN

17a (2 equiv)

Br

17a (2 equiv)

91%

18

Br

N

n-BuOH (0.25 M)

8c

HN

8c

+

HN

N

H

μW (HE), 200 °C

30 min

reflux, 24 h

84%

Br

88%

17b (2 equiv)

OMe

19

OMe

Br

N

n-BuOH (0.25 M)

HN

OMe

N

OMe

μW (HE), 200 °C

1.5 h

reflux, 24 h

92%

H

Ph

Br

Ph

OMe

93%

17c (2 equiv)

OMe

20

Br

N

n-BuOH (0.25 M)

8c

+

HN

+

HN

N

H

reflux, 24 h

80%

μW (HE), 200 °C

H

Ph

HN

1 h

Ph

Br

Ph

87%

17d (2 equiv)

21

Scheme 7 Direct comparison of reflux vs microwave conditions for various amines

was investigated under a variety of conditions (Table 1). reactions that were performed under microwave irradia-

No reaction was observed when the reaction was conduct- tion.

ed with four equivalents of morpholine under neat condi-

The optimized microwave conditions were applicable to a

tions at 130 °C (Table 1, entry 1). This reaction was also

range of substrate combinations. For more reactive start-

performed in the presence of a silicon carbide heating el-

ing materials, microwave heating at 200 °C was suffi-

ement (HE) under otherwise identical conditions (entry

cient. As outlined in Scheme 6, drastic rate accelerations

2). While no change was observed in this instance, we

were observed for the reaction of pyrrolidine with amino-

benzaldehydes 8c and 8k. Products 9c and 9k were ob-

tained in excellent yields in only 10 or 30 minutes,

have found previously that the presence of a HE can dra-

matically impact the outcome of related reactions.¹³Typ-

ically, improved substrate conversions are observed in the

respectively. Applying the same reaction parameters to

presence of a HE even at the same bulk temperature. Cu-

the substantially less reactive piperidine in a reaction with

riously, Polshettiwar and Varma reported the formation of

8c resulted in the formation of aminal 10a in excellent

yield (reaction time 30 min). Combining piperidine with

the less reactive aminobenzaldehyde 8k required for the

10b in 65% yield under the conditions in entry 1, although

it is not clear whether or not a HE was used. Microwave

instrument calibration can certainly affect reaction out-

reaction to be performed at 250 °C in order to obtain rea-

comes and differences in yields are to be expected among

sonable yields of aminal 10i. The latter aminal was found

not to be readily accessible using standard reflux condi-

different instruments, even when the exact same settings

are used. However, we found that even when the title re-

tions. Good yields of aminal products could also be ob-

action was conducted under neat conditions at 200 °C for

tained for N-methyl- and N-phenylpiperazine, substrates

that previously failed to undergo the desired reactions.

one hour in the presence of a HE, the conversion remained

low and only 16% of aminal 10b was formed (entry 3). A

A range of other amines that had not previously been ex-

further increase in reaction temperature to 250 °C proved

plored in the aminal formation were also evaluated, in-

detrimental as decomposition was found to dominate un-

cluding sterically encumbered substrates. Shown in

der these conditions. As in conventional heating, the addi-

Scheme 7 is a side-by-side comparison for reactions con-

tion of alcoholic solvents led to superior results over the

ducted either at reflux or microwave heating in n-butanol.

Tetrahydrobenzoazepine 17a underwent the condensation

neat reaction conditions, a finding that is consistent with

the reaction mechanism and the role of solvent as a proton

cleanly to provide aminal 18 in high yield. Microwave

shuttle (see structure 16 in Scheme 5). Relatively drastic

heating proved superior not only in regard to reaction time

but also yield. The same observation was made for 1-sub-

stituted tetrahydroisoquinolines 17b and 17c and 1-phen-

yltetrahydro-β-carboline 17d. All corresponding aminal

reaction conditions were required to obtain a reasonable

amount of morpholine-containing aminal 10b. This prod-

uct was obtained in 49% yield following a reaction time

of 60 minutes at 270 °C. A HE was used in all subsequent

products were obtained in excellent yields.

Synthesis 2013, 45, 1730–1748

FEATURE ARTICLE

Ring-Fused Aminals from Secondary Amines and o-Aminobenzaldehydes

1735

of this reaction was essentially independent of the reaction

temperature and is very similar to what was observed in a

reaction of 8c and 2-methylpyrrolidine, conducted under

reflux in ethanol.^12aAs outlined previously in Scheme 4,

THIQ leads to exclusive functionalization of a benzylic

C–H bond when allowed to react with 8k under reflux in

ethanol. Aminal 10f was formed as the only product in ex-

cellent yield. Based on the different available α-C–H

bonds (benzylic vs aliphatic), this outcome is entirely ex-

pected. We were thus surprised to observe the formation

of small amounts of the regioisomeric product 24 when

the reaction was conducted under microwave irradiation.

At a temperature of 250 °C, a substantial amount of 24

was obtained (16%) although 10f was still formed as the

major product. Extension of the reaction time from 30

minutes to two hours led to the isolation of 24 as the major

product in 47% yield. In both cases, the combined yields

of 10f and 24 were essentially identical. These observa-

tions suggest that 10f is the kinetic product of this trans-

formation whereas 24 represents the thermodynamically

more stable aminal. Furthermore, there appears to be a

pathway for product isomerization. Computational results

are consistent with the experimental findings.^12cWhile the

pathway leading to the formation of 24 was calculated to

be higher in energy than that of 10f, the free energy of 24

is lower than that of 10f. Qualitatively similar observa-

tions were made in reactions of THIQ with 8c, although

product 10e dominates in all cases. While this outcome is

consistent with computational results (the difference in

free energy between 10e and 25 was found to be smaller

than that of 10f and 24), the reaction of THIQ with 8c

pyrrolidine (3 equiv)

R

CHO

NH₂

R

N

n-BuOH (0.25 M)

N

μW (HE), 200 °C

H

R

8c (R = Br)

8k (R = H)

9c (R = Br), 95%, 10 min

9k (R = H), 89%, 30 min

piperidine (3 equiv)

n-BuOH (0.25 M)

R

CHO

R

N

NH₂

N

μW (HE), 30 min

H

R

8c (R = Br)

8k (R = H)

10a (R = Br), 93%, 200 °C

10i (R = H), 67%, 250 °C

R

N

Br

n-BuOH

(0.25 M)

N

8c

+

N

R

μW (HE)

250 °C, 1 h

H

N

H

Br

3 equiv

10j (R = Ph), 73%

10k (R = Me), 59%

Scheme 6 Optimized microwave conditions for other substrates

Regioselectivity of the Aminal Formation

An interesting situation arises for nonsymmetrical amines

for which, at least in principle, different regioisomeric

products may be formed (Scheme 8). In a reaction of o-

aminobenzaldehyde (8k) and 2-methylpyrrolidine, con-

ducted at 180 °C under microwave irradiation, products

22 and 23 were obtained in a 2.4:1 ratio. This reflects a

preference for functionalization of a tertiary C–H bond

over a secondary C–H bond. This electronic effect appar-

ently outweighs any potential steric issues. The outcome

CHO

NH₂

n-BuOH (0.25 M)

μW (HE)

N

+

N

H

N

H

22

N

H

8k

3 equiv

23 (dr = 1:1)

180 °C, 1.5 h: 22/23 = 2.4:1, 76%

250 °C, 15 min: 22/23 = 2.6:1, 92%

CHO

NH₂

n-BuOH (0.25 M)

μW (HE), 250 °C

N

+

HN

N

H

2 equiv

24

10f

30 min:

2 h:

72%

38%

16%

47%

Br

CHO

Br

n-BuOH (0.25 M)

μW (HE)

N

+

HN

NH₂

N

H

N

H

2 equiv

Br

8c

10e

25

200 °C, 30 min: 10e/25 = 22:1, 94%

200 °C, 2 h: 10e/25 = 12:1, 92%

220 °C, 1 h: 10e/25 = 5:1, 83%

Br

CHO

NH₂

Br

n-BuOH (0.25 M)

N

+

μW (HE), 250 °C

N

H

N

30 min

H

Br

8c

Br

26, 64%

27, 15% (dr = 1:1)

2 equiv

Scheme 8 Regioselectivity of the aminal formation

Synthesis 2013, 45, 1730–1748

1736

M. T. Richers et al.

FEATURE ARTICLE

could not be performed at 250 °C as this resulted in sub- would have been the result of methyl group functionaliza-

stantial decomposition. A reaction of 8c with 2-methylpi- tion.

peridine led to the two expected regioisomeric products.

Reactions of Aminoketones

Interestingly, the preference for functionalization of the

Previous attempts to expand the substrate scope from ami-

tertiary C–H bond over a secondary C–H bond is more

nobenzaldehydes to related aminoketones had met with

pronounced than was seen for 2-methylpyrrolidine.

limited success. However, a reaction of aminobenzophe-

The impact of electronic factors on product distributions

none with pyrrolidine, conducted under microwave irradi-

was evaluated next (Scheme 9). Three different 2-arylpyr-

ation at 250 °C, gave the corresponding aminal (Scheme

rolidines were allowed to react with aminobenzaldehyde

10). Product 31 was isolated as a 1:1.5 mixture of diaste-

reomers in 53% yield, following a reaction time of one

hour. Aminoacetophenone also underwent the corre-

8k under identical conditions. The expected contra-steric

preference for benzylic C–H bond over aliphatic C–H

bond functionalization was observed in all instances.

sponding reaction, albeit less efficiently. In this case, in-

However, the electronics of the aryl ring exerted a marked

termediate enamine formation might prevent higher

influence on product distributions. Consistent with expec-

yields. Polshettiwar and Varma reported the unlikely for-

tations, an electron-donating group placed in the para-po-

mation of 32 in 45% yield (reaction performed under neat

sition of the aromatic ring led to an increase in benzylic

conditions in a microwave reactor, 60 min at 130 °C).¹⁶

product, whereas an electron-withdrawing group in the

Competing Side Reactions

same position resulted in a reduced ratio of benzylic to al-

iphatic functionalization. Notably, the overall product

yields were excellent in all cases.

Ph

O

A related study was performed for three different methyl-

benzylamines, substrates that were previously found to re-

sist aminal formation under reflux conditions. A clear

trend was again observed with regard to electronics: the

more electron-rich the substrate, the higher the yield of

aminal product. However, any conclusions drawn from

this should be considered tentative because aminal prod-

ucts 30a–c might differ in their propensity to hydrolyze,

potentially affecting product yields. Perhaps not surpris-

ingly, no trace amounts of products were observed that

n-BuOH (0.25 M)

N

Ph

+

N

H

μW (HE), 250 °C

N

H

NH₂

O

1 h

3 equiv

31, 53%, dr = 1:1.5

n-BuOH (0.25 M)

N

H

μW (HE), 250 °C

N

H

NH₂

1 h

3 equiv

32, 28%, dr = 1:1.4

Scheme 10 Aminal formation with aminoketones

Ar

Br

CHO

NH₂

n-BuOH (0.25 M)

N

+

Ar

N

H

μW (HE), 200 °C

N

30 min

Ar

H

Br

28

Br

8c

3 equiv

29 (dr = 1:1)

28a: 83%

28b: 64%

29a: 14%

Ar =

OMe

29b: 33%

29c: 37%

28c: 58%

CF₃

Br

Me

Br

CHO

NH₂

Me

N

n-BuOH (0.25 M)

N

H

+

N

H

μW (HE), 250 °C

R

30 min

Br

8c

R

3 equiv

Br

30

Br

Me

N

Br

N

H

N

H

Br

OMe

CF₃

30a, 41%

30b, 29%

30c, 20%

Scheme 9 Impact of electronic factors on the regioselectivity and yield of the aminal formation

Synthesis 2013, 45, 1730–1748

FEATURE ARTICLE

Ring-Fused Aminals from Secondary Amines and o-Aminobenzaldehydes

1737

In the course of our studies, we made additional observa- equivalents of pyrrolidine (200 °C, 30 min). Indeed, ami-

tions that outline the complexity of the overall process, in- nal 9k was obtained as a product, albeit in only 36% yield,

cluding potentially competing, undesired reaction establishing the reversibility of aminobenzaldehyde self-

pathways (Scheme 11). As expected for this particularly condensation.

challenging substrate combination, o-aminobenzaldehyde

(8k) and morpholine underwent aminal formation only re-

luctantly (Scheme 11). Even a reaction conducted at

250 °C for two hours gave 33 in only 12% yield. Interest-

Aminal Formation under Decarboxylative Conditions

As part of our initial study, we established that substitu-

tion of pyrrolidine for proline in a reaction with amino-

benzaldehyde 8c gave rise to the identical aminal product

ingly, in addition to 33, the unexpected product 34a was

9c although the reaction was less efficient than that with

observed in 38% yield. A simple switch from n-butanol to

pyrrolidine.^12aHowever, upon further optimization, effi-

toluene as the solvent and an increase in substrate concen-

tration allowed for the isolation of 34a in 70% yield. Re-

lated aminobenzaldehyde self-condensation products are

well known.¹⁷In particular, products in which the mor-

Br

N

n-BuOH (0.1 M)

8c

pholine subunit is replaced with simple alkoxy groups

+

COOH

N

H

reflux, 17 h

N

have been well characterized. In order to establish wheth-

er compounds such as 34a could intervene in other aminal

forming reactions, a solution of o-aminobenzaldehyde

(8k) in ethanol was exposed to one equivalent of pyrro-

lidine at room temperature for two days. No trace of ami-

nal 9k was observed under these conditions. However,

pyrrolidine-containing aminobenzaldehyde self-conden-

sation product 34b was obtained in 61% yield. Notably,

corresponding reactions conducted with piperidine or

morpholine at room temperature gave none of the trimeric

condensation products. In order to establish whether ami-

nobenzaldehyde self-condensation products can still par-

ticipate in aminal formation, 34a was exposed to 12

H

2.5 equiv

Br

9c, 85%

Br

N

n-BuOH (0.05 M)

8c

+

N

H

N

H

COOH

2.5 equiv

reflux, 19 h

Br

10a, 84%

CHO

NH₂

n-BuOH (0.05 M)

+

proline

2.5 equiv

N

reflux, 19 h

N

8m

H

9m, 85%

Scheme 12 Decarboxylative formation of aminals

H

NH

CHO

NH₂

O

n-BuOH (0.25 M)

N

+

H

O

N

μW (HE), 250 °C,

N

H

N

H

2 h

H

N

O

8k

3 equiv

33, 12%

34a, 38%

H

NH

CHO

NH₂

O

PhMe (0.5 M)

N

+

H

O

N

μW (HE), 250 °C,

N

H

N

H

20 min

H

N

O

8k

4 equiv

33, 6%

34a, 70%

H

NH

CHO

NH₂

EtOH (0.25 M)

r.t., 2 d

N

+

H

N

H

N

H

N

8k

1 equiv

9k (not observed)

34b, 61%

H

N

NH

n-BuOH (0.05 M)

N

+

H

N

μW (HE), 200 °C,

N

H

N

30 min

H

N

O

12 equiv

9k, 36%

34a

Scheme 11 Formation of aminobenzaldehyde self-condensation products

Synthesis 2013, 45, 1730–1748

1738

M. T. Richers et al.

FEATURE ARTICLE

upon decarboxylative condensation of an α-amino acid

Table 1 Optimization of Reaction Conditions for Morpholine, a Rel-

atively Unreactive Amine

with an aldehyde.^18,19

Br

CHO

NH₂

Driven by the notion that the decarboxylative formation of

aminals based on amino acids might enable control over

product regioselectivity, this approach was tested in the

formation of aminals that might otherwise be difficult to

prepare in regioselective fashion (Scheme 13). A reaction

of aminobenzaldehyde 8c and amino acid 35 led to the ex-

pected product 25, albeit in only 25% yield. In addition,

aminal 10e was isolated as the main product in 47% yield.

Apparently, isomerization of the initially formed azo-

methine ylide is competitive with the direct pathway lead-

ing to aminal 25, possibly involving intermediate

formation of THIQ that can engage 8c to form 10e. In con-

trast to what was seen for 35, the reactions of trans-4-hy-

O

N

solvent

+

O

N

H

μW

N

H

Br

8c

4 equiv

10b

Entry Solvent

(conc)

HE^a

Temp

(°C)

Time

(min)

Yield

(%)

1

2

–

no

130

200

250

130

200

250

270

45

60

45

60

NR

16

yes

no

3^b

4

traces^c

NR

6

droxyproline

and

trans-3-hydroxyproline

with

5

EtOH (2 M)

aminobenzaldehyde 8k were fully regioselective. Unfor-

tunately, the efficiency of these processes was poor and

the results shown in Scheme 13 represent the best yields

that could be obtained under a variety of conditions (in-

cluding reactions conducted under reflux). Our group^13h

and others²⁰have previously shown that trans-4-hydroxy-

proline forms N-alkylpyrroles when allowed to react with

aldehydes at elevated temperatures. This process becomes

competitive with aminal formation when the reaction is

conducted at higher temperatures.

6

n-BuOH (2 M)

yes

no

7

n-BuOH (0.5 M)

toluene (2 M)

8^b

9^b

10^b

11^b

12^d

13

14

n-BuOH (0.5 M)

n-BuOH (0.25 M)

yes

no

20

14

yes

21

Interception of Reactive Intermediates

29

Various studies were performed in an effort to obtain ex-

perimental evidence for the intermediacy of azomethine

ylides and o-azaquinonemethides.^18,21Since aldehydes are

known to be potent dipolarophiles, we speculated that

[3+2] cycloaddition products such as 38 may be isolated

under appropriate conditions (Scheme 14). We further

reasoned that a reduction in the amount of pyrrolidine in

combination with an increased reaction molarity might

render the [3+2] pathway competitive with aminal forma-

tion. Indeed, a reaction conducted with aminobenzalde-

hyde 8c and pyrrolidine in a 2:1 ratio and one molar

concentration resulted in the formation of aminal 9c in

74% yield, in addition to [3+2] cycloaddition product 38.

The latter was recovered as a single diastereomer in 18%

yield. The yield of 38 was increased to 27% at the expense

of aminal formation when the reaction was conducted in

toluene under otherwise identical conditions. It was sub-

sequently established that the [3+2] cycloaddition is re-

26

49

^aHE: Silicon carbide heating element.

^bThe reaction was incomplete.

^cDecomposition was observed.

^dWith 3 equiv of morpholine.

cient formation of 9c was achieved in 85% yield for a re-

action conducted under reflux in n-butanol at slightly

lower concentration (Scheme 12). These conditions were

applicable to other decarboxylative aminal formations

such as the reaction of 8c with pipecolic acid to give 10a

in 84% yield, and the reaction of 8m with proline to give

aminal 9m in 85% yield. The ability of α-amino acids with

a secondary amine to undergo the aminal formations is

perfectly consistent with the intermediacy of azomethine

ylides, as the latter species are known to be readily formed

HOOC

Br

CHO

NH₂

n-BuOH (0.1 M)

N

+

HN

reflux, 24 h

N

H

35 (2.5 equiv)

Br

8c

25, 25%

10e, 47%

HO

OH

8k (1 equiv)

n-BuOH (0.25 M)

N

OH

CO₂H

2.1 equiv

μW (HE), 150 °C

N

H

N

H

15 min

H

OH

2.1 equiv

36, 18% (dr = 1:1.2)

37, 11% (dr = 1:1.1)

Scheme 13 Regioselectivity in the decarboxylative aminal formation

Synthesis 2013, 45, 1730–1748

FEATURE ARTICLE

Ring-Fused Aminals from Secondary Amines and o-Aminobenzaldehydes

1739

versible under certain conditions. Exposure of 38 to five Support for the intermediacy of o-azaquinonemethides

equivalents of pyrrolidine for 10 minutes at 200 °C led to was obtained from a reaction of aminobenzaldehyde 44

the isolation of aminal 9c in 55% yield. Starting material and pyrrolidine, conducted under reflux in ethanol

38 was recovered in 42% yield.

(Scheme 15). The expected product 45 was obtained in

7% yield, in addition to 47 (7%), conjugate addition prod-

uct 48 (42%), aminal 49 (20%), and recovered starting

material 44 (9%). The formation of 45 is fully consistent

with an o-azaquinonemethide undergoing an endo-selec-

tive hetero-Diels–Alder reaction (via 46). Given the most-

ly zwitterionic nature of the o-azaquinonemethide, the

cycloaddition may not be fully concerted. Importantly, we

could show that 45 does not form via an alternate pathway

involving 47. Exposure of 47 to pyrrolidine under reflux

in ethanol did not result in the formation of any trace of 45

within 48 hours. An aza-Baylis–Hillman-type pathway

was ruled out on the basis that this would have to involve

an iminium ion, species that are unlikely to exist under

these conditions. An intramolecular Baylis–Hillman-type

pathway to the formation of 47 (conjugate addition of pyr-

rolidine to 44 with simultaneous attack of the aldehyde)

was ruled out since this would involve the unlikely forma-

tion of an intermediate with a ten-membered ring. More-

over, heating 44 by itself or in the presence of Hünig’s

base or N-methylpyrrolidine led to no reaction.

Other efforts were aimed at trapping an azomethine ylide

in an intramolecular process. In previous work on another

project, we have successfully demonstrated the formation

of azomethine ylide intermediates upon benzoic acid cat-

alyzed condensation of 3-pyrroline with aldehydes, a pro-

cess that ultimately leads to the formation of N-

alkylpyrroles.^13gSpecifically, a reaction of substituted sal-

icylaldehyde 39 and 3-pyrroline resulted in the formation

of [3+2] cycloaddition product 40 as a single diastereomer

in 53% yield (Scheme 14). Based on this precedent, we

prepared aminobenzaldehyde 41 bearing a pendant dipo-

larophile. Surprisingly, a reaction of 41 with pyrrolidine,

conducted under the typical aminal-forming conditions

gave neither aminal nor the expected cycloaddition prod-

uct 43. Instead, quinoline 42 was generated in 61% yield.

The formation of 42 most likely involves the initial isom-

erization of 41 to the corresponding enamine, presumably

by conjugate addition of pyrrolidine and subsequent elim-

ination. Alternatively, the requisite enamine could be

formed via a dienolate intermediate. No formation of 42

was observed when 41 was heated in the absence of pyr- In another attempt to capture an o-azaquinonemethide in-

rolidine.

termediate, we decided to evaluate an amine containing a

H

N

O

H₂N

NH₂

Br

CHO

NH₂

Br

solvent (1 M)

N

+

Br

N

H

μW (HE), 150 °C

N

H

30 min

Br

Br Br

8c

0.5 equiv

9c

38

EtOH:

PhMe:

74%

58%

18%

27%

H

N

O

Br

N

n-BuOH (0.125 M)

H₂N

NH₂

38

+

N

H

N

μW (HE), 200 °C

Br

H

10 min

Br

Br Br

38

5 equiv

9c, 55%

42% recovered

H

PhCOOH (20 mol%)

PhMe (0.5 M)

N

CHO

H

CO₂Et

+

N

H

μW (HE), 200 °C

H

O

CO₂Et

15 min

O

39

1.2 equiv

40, 53%

H

N

CHO

H

EtOH (0.25 M)

reflux, 14 h

CO₂Et

H

+

N

H

N

H

CO₂Et

N

H

41

3 equiv

42, 61%

43 (not observed)

Scheme 14 Attempted capture of azomethine ylide intermediates

Synthesis 2013, 45, 1730–1748

1740

M. T. Richers et al.

FEATURE ARTICLE

pendant dieneophile. However, a reaction of aminobenz- Synthesis of Quinazolinone Alkaloids

aldehyde 8c with pyrrolidine 50 did not give any of the de-

There are a sizable number of natural products that con-

sired cycloaddition product 53. Interestingly, in addition

to the expected aminal products 51 (15%) and 52 (3%),

the formation of aminal 54 (29%) and quinoline 55 (27%)

as the major products was observed. A plausible pathway

for the formation of 54 and 55 is outlined in Scheme 15.

Upon reaction of 8c with 50 to give the typical azomethine

ylide intermediate 56, the latter could undergo a transfor-

mation to dienamine 57, either by a concerted proton

transfer or a protonation/deprotonation event. Stepwise

hydrolysis of dienamine 57 via an intermediate such as 58

could result in enamine 59, a species that could subse-

quently cyclize to aminal 54. Importantly, the regioisomer

of 54 was not observed, ruling out any pathways that

would involve the formation of free 2-methylpyrrolidine.

Formation of quinoline 55 is readily explained by

Friedländer condensation of 8c with acetaldehyde, a by-

product from the hydrolysis of 58.

tain aminal substructures.²²Moreover, the ring-fused am-

inals obtained from aminobenzaldehydes and secondary

amines represent direct precursors of certain quinazoli-

none alkaloids and are thus ideally suited to generate ana-

logues of these biologically active species.^23,24Oxidation

of aminals to quinazolinones is readily accomplished un-

der reflux in acetone with potassium permanganate as the

oxidant (Scheme 16). Deoxyvasicinone, rutaecarpine,

mackinazolinone, and the unnatural analogue 60 could

thus be obtained in good yields via oxidation of the corre-

sponding aminals. Selective oxidation of aminals to ami-

dines without affecting the benzylic position was

achieved via iodine-promoted oxidation of deprotonated

precursors. This allowed for the synthesis of deoxyvasi-

cine and vasicine. A limitation of the two-step vasicine

synthesis is the poor yield obtained for the starting mate-

rial 37. As a potential solution to this shortcoming, we

CHO

NH

pyrrolidine (3 equiv)

N

EtOH (0.25 M)

N

CO₂Et

H

N

via:

CO₂Et

reflux, 48 h

CO₂Et

H

N

46

44

45, 7%

N

CO₂Et

CHO

N

CO₂Et

N

+

additional products:

CO₂Et

N

NH

47, 7%

48, 42%

49, 20%

Br

CHO

N

+

H

N

NH₂

N

H

Br

8c

EtOH (0.25 M)

reflux, 24 h

51, 15%

52, 3%

H

+

N

H

Br

N

53 (not observed)

N

H

+

N

H

50 (3 equiv)

Br

54, 29%

55, 27%

potential pathway for the formation of 54:

H

N

Br

H₂O

O

OH

+

H

NH₂

Br

NH₂

Br

56

57

58

59

Scheme 15 Attempts to capture azaquinonemethide intermediates

Synthesis 2013, 45, 1730–1748

FEATURE ARTICLE

Ring-Fused Aminals from Secondary Amines and o-Aminobenzaldehydes

1741

O

N

KMnO₄, acetone

reflux, 2 h

KMnO₄, acetone

N

reflux, 3 h

N

H

68%

87%

N

H

HN

N

HN

9k

deoxyvasicinone

10g

rutaecarpine

O

N

KMnO₄, acetone

reflux, 2 h

KMnO₄, acetone

reflux, 2 h

N

91%

76%

N

H

10i

N

H

mackinazolinone

10f

60

BuLi, I₂, THF, –78 °C

then Et₃N, r.t.

BuLi, I₂, Et₂O, –78 °C

then Et₃N, r.t.

N

85%

N

H

79%

N

H

9k

N

OH

deoxyvasicine

37

vasicine

Br

O

HO

8c (1 equiv)

n-BuOH (0.25 M)

i) KMnO₄, acetone, reflux, 2 h

ii) H₂, 10% Pd/C, MeOH, Et₃N

N

OH

N

OH

CO₂H

μW (HE), 150 °C

63%, two steps

N

H

30 min

Br

61, 50% (dr = 1:1.2)

N

62

2.1 equiv

Scheme 16 Synthesis of quinazolinone alkaloids and analogues

carried out in a CEM Discover reactor. Silicon carbide (SiC) pas-

sive heating elements were purchased from Anton Paar. Purification

of reaction products was carried out by flash column chromatogra-

phy using Sorbent Technologies Standard Grade silica gel (60 Å,

230–400 mesh). Analytical TLC was performed on EM Reagent

0.25 mm silica gel 60 F₂₅₄plates. Visualization was accomplished

with UV light or KMnO₄, and Dragendorff–Munier stains followed

by heating. Eluents for column chromatography and TLC were the

same as those used for determining the R_fvalues. Melting points

were recorded on a Thomas Hoover capillary melting point appara-

tus and are uncorrected. IR spectra were recorded on an ATI

Mattson Genesis Series FT-IR spectrophotometer. ¹H-NMR spectra

were recorded on a Varian VNMRS-500 MHz and are reported in

ppm using the solvent as an internal standard (CDCl₃at 7.26 ppm).

Standard abbreviations (besides app: apparent and com: complex)

found that the decarboxylative aminal formation of hy-

droxyprolines proceeds much more efficiently with ami-

nobenzaldehyde 8c than 8k. This finding was applied to

the synthesis of 62, a novel regioisomer of vasicinone. Re-

action of trans-4-hydroxyproline with 8c provided regio-

selective access to aminal 61 in 50% yield. Subsequent

oxidation with potassium permanganate, followed by re-

moval of the bromine substituents via hydrogenolysis pro-

vided 62 in 32% overall yield in just three steps from

commercially available materials.

Conclusion

Ring-fused aminals are readily available via condensation

of secondary amines with o-aminobenzaldehydes. These were used to denote signal multiplicities. Coupling constant(s) are

given in Hz. Proton-decoupled ¹³C NMR were recorded on a Varian

VNMRS-500 MHz and are reported in ppm using the solvent as an

internal standard (CDCl₃at 77.0 ppm). Mass spectra were recorded

on a Finnigan LCQ-DUO mass spectrometer. Optical rotations were

reactions feature simultaneous reductive N-alkylation and

oxidative α-amination, effectively rendering the process

redox-neutral. While many of the aminal-forming reac-

tions can be performed with conventional heating meth-

measured using a 1 mL cell with a 1 dm path length on a Jasco P-

2000 polarimeter at 589 nm and at 25 °C. Products 9a–o,^12a10a,^12a

10b,^12c10c–h,^12a10i,^25a22–24,^12c38,^12c39,40,^13g44,45,^12c47–49,^12c

54,^12a55,^25b60,^25cdeoxyvasicinone,^12brutaecarpine,^12amackinazo-

linone,^25ddeoxyvasicine,^25eand vasicine^25fwere previously report-

ed and their published characterization data matched our own in all

regards.

ods, microwave heating proved to be beneficial in all

cases and for some substrates it is required. The aminal

products are valuable precursors to various quinazolinone

alkaloids and their analogues. The reaction exhibits inter-

esting mechanistic features and o-azaquinonemethides

and azomethine ylides have been identified as reactive in-

termediates. The overall process adds to the growing

number of reactions that involve nonpericyclic reaction

pathways of azomethine ylides, an area that is expected to

experience further growth.

General Microwave Procedure

A 10 mL microwave reaction tube was charged with a 10 × 8 mm

SiC passive heating element, aminobenzaldehyde (1 mmol), n-

BuOH (0.25 M), and amine (3 equiv). The reaction tube was sealed

with a Teflon-lined snap cap, and heated in a microwave reactor

(Note: SiC passive heating elements must not be used in conjunc-

tion with stir bars because they may score glass and cause vessel

failure). After cooling with compressed air flow, the reaction mix-

ture was transferred to a round-bottom flask and the vessel was

rinsed with EtOAc (4 × 2 mL). The solvent was then removed in

Reagents and solvents were purchased from commercial sources

and were used as received unless otherwise stated. Toluene, THF,

Et₂O, and Et₃N were distilled prior to use. All secondary amines

were purified by distillation prior to use. Microwave reactions were

Synthesis 2013, 45, 1730–1748

1742

M. T. Richers et al.

FEATURE ARTICLE

vacuo and the residue was loaded onto a short column and purified

by silica gel chromatography.

¹³C NMR (125 MHz, CDCl₃): δ = 141.7, 139.5, 137.8, 132.2, 130.0,

129.1, 128.9, 128.4, 126.1, 123.3, 109.1, 108.9, 74.4, 54.3, 53.1,

35.2, 26.0.

General Reflux Procedure

MS-ESI: m/z = 409.0 [M + H]⁺.

A 10 mL round-bottom flask was charged with a magnetic stir bar,

aminobenzaldehyde (1 mmol), n-BuOH (4 mL), and amine (3

equiv). The resulting mixture was heated at reflux until the starting

material was consumed as determined by TLC. The solvent was

then removed in vacuo and the residue was loaded onto a short col-

umn and purified by silica gel chromatography.

Compound 19

Following the general microwave procedure, 19 was obtained from

8c (0.25 mmol) and 1-methyl-1,2,3,4-tetrahydroisoquinoline

(17b;^25h2 equiv) after 30 min at 200 °C in n-butanol (1 mL); yield:

90 mg (88%); tan solid; mp 121–123 °C; R_f= 0.14 (hexanes–

EtOAc, 93:7 v/v).

General Oxidation Procedure

A 10 mL round bottom flask was charged with a magnetic stir bar,

aminal (0.25 mmol), acetone (2.5 mL), and KMnO₄(5 equiv). The

resulting mixture was heated at reflux for 2 h. The solution was fil-

tered through a pad of Celite and the filtrate was washed with ace-

tone (20 mL). The solvent was removed in vacuo and the residue

was loaded onto a short column and purified by silica gel chroma-

tography.

IR (KBr): 3409, 2993, 2920, 2838, 1589, 1478, 1391, 1374, 1294,

1131, 1095, 1038, 933, 884, 753, 725, 700 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.57 (dd, J = 7.7, 1.6 Hz, 1 H),

7.46 (d, J = 2.2 Hz, 1 H), 7.38–7.25 (comp, 2 H), 7.17 (dd, J = 7.3,

1.8 Hz, 1 H), 7.12 (d, J = 1.5 Hz, 1 H), 4.63 (br s, 1 H), 4.55 (d, J =

17.0 Hz, 1 H), 3.72 (d, J = 17.0 Hz, 1 H), 3.17–3.06 (m, 1 H), 2.92

(app td, J = 10.9, 3.5 Hz, 1 H), 2.85–2.69 (comp, 2 H), 1.73 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 139.5, 137.6, 134.1, 132.2, 129.2,

128.6, 127.4, 126.7, 124.7, 120.5, 109.1, 107.9, 69.8, 51.2, 46.3,

29.6, 26.4.

Compound 10j

Following the general microwave procedure, 10j was obtained from

2-amino-3,5-dibromobenzaldehyde (8c; 1 mmol) and N-phenylpi-

perazine (3 equiv) after 1 h at 250 °C; yield: 307.5 mg (73%); tan

solid; mp 164–168 °C; R_f= 0.31 (hexanes–EtOAc, 85:15 v/v).

MS-ESI: m/z = 409.0 [M + H]⁺.

IR (KBr): 3317, 2952, 2925, 2830, 2785, 1599, 1491, 1458, 1325,

1267, 1250, 1214, 1145, 930, 844, 771, 757, 691, 608 cm^–1.

Compound 20

Following the general microwave procedure, 20 was obtained from

8c (0.25 mmol) and 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroiso-

quinoline (17c;²⁵ⁱ2 equiv) after 1.5 h at 200 °C in n-butanol (1 mL);

yield: 123 mg (93%); white solid; mp 73–76 °C; R_f= 0.29

(hexanes–EtOAc, 70:30 v/v).

¹H NMR (500 MHz, CDCl₃): δ = 7.43 (app dd, J = 2.3, 0.8 Hz, 1 H),

7.33–7.28 (comp, 2 H), 7.04 (d, J = 1.4 Hz, 1 H), 7.00–6.96 (comp,

2 H), 6.98 (app tt, J = 7.3, 1.1 Hz, 1 H), 4.31 (br s, 1 H), 4.19–4.08

(m, 1 H), 3.92 (d, J = 15.5 Hz, 1 H), 3.74 (d, J = 15.5 Hz, 1 H), 3.52

(dd, J = 11.7, 3.0 Hz, 1 H), 3.37–3.26 (comp, 2 H), 3.21 (dd, J =

11.8, 6.2 Hz, 1 H), 3.04 (ddd, J = 11.5, 6.3, 3.6 Hz, 1 H), 2.56 (ddd,

J = 11.0, 7.0, 3.6 Hz, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 150.8, 138.6, 132.6, 129.3, 128.8,

121.9, 120.5, 116.7, 109.6, 109.1, 68.0, 54.8, 53.6, 49.2, 49.1.

MS-ESI: m/z = 423.9 [M + H]⁺.

IR (KBr): 3412, 2931, 2831, 1609, 1589, 1515, 1472, 1290, 1251,

1233, 1168, 1140, 1021, 793, 754, 699 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.46 (dd, J = 2.3, 0.7 Hz, 1 H),

7.44–7.36 (comp, 2 H), 7.31–7.21 (comp, 3 H), 6.94 (d, J = 2.0 Hz,

1 H), 6.63 (s, 1 H), 6.20 (s, 1 H), 4.77 (br s, 1 H), 3.91–3.79 (comp,

4 H), 3.60 (s, 3 H), 3.45 (d, J = 16.9 Hz, 1 H), 3.30 (ddd, J = 16.0,

12.4, 6.1 Hz, 1 H), 3.01 (app td, J = 11.7, 3.6 Hz, 1 H), 2.82 (ddd,

J = 11.7, 6.1, 1.6 Hz, 1 H), 2.72 (ddd, J = 16.0, 3.7, 1.6 Hz, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 148.4, 147.7, 145.9, 137.6, 132.3,

132.2, 128.8, 128.3, 127.5, 127.4, 126.4, 121.4, 111.0, 110.7, 108.2,

108.1, 75.9, 56.0, 55.8, 51.7, 45.9, 29.3.

Compound 10k

Following the general microwave procedure, 10k was obtained

from 8c (1 mmol) and N-methylpiperazine (3 equiv) after 1 h at

250 °C; yield: 212.6 mg (59%); off-white solid; mp 116–119 °C; R_f

= 0.18 (EtOAc–MeOH, 90:10 v/v).

MS-ESI: m/z = 530.9 [M + H]⁺.

IR (KBr): 3389, 2933, 2842, 2897, 2516, 1594, 1475, 1346, 1323,

1285, 1143, 1079, 900, 856, 706 cm^–1.

Compound 21

Following the general microwave procedure, 21 was obtained from

8c (0.25 mmol) and 1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-

b]indole (17d;^25j2 equiv) after 1 h at 200 °C in n-butanol (1 mL);

yield: 111 mg (87%); oil; R_f= 0.35 (hexanes–EtOAc 70:30, v/v).

¹H NMR (500 MHz, CDCl₃): δ = 7.40 (d, J = 1.8 Hz, 1 H), 7.00 (s,

1 H), 4.27 (br s, 1 H), 4.12–3.75 (comp, 2 H), 3.68 (d, J = 15.1 Hz,

1 H), 2.91 (br s, 1 H), 2.78 (br s, 1 H), 2.67–2.36 (comp, 4 H), 2.34

(s, 3 H).

IR (KBr): 3398, 3056, 2903, 2841, 1589, 1463, 1298, 1171, 1106,

1028, 1016, 979, 932, 858, 743, 698 cm^–1.

¹³C NMR (125 MHz, CDCl₃): δ = 138.7, 132.5, 128.7, 122.1, 109.4,

108.9, 67.9, 59.1, 54.7, 54.7, 50.0, 45.8.

MS-ESI: m/z = 362.0 [M + H]⁺.

¹H NMR (500 MHz, CDCl₃): δ = 7.58 (app d, J = 7.7 Hz, 1 H), 7.55–

7.46 (comp, 3 H), 7.38–7.28 (comp, 4 H), 7.27–7.22 (comp, 2 H),

7.17 (app dtd, J = 20.1, 7.1, 1.2 Hz, 2 H), 6.99 (br s, 1 H), 4.93 (br

s, 1 H), 3.93 (d, J = 16.8 Hz, 1 H), 3.56 (d, J = 16.8 Hz, 1 H), 3.26–

3.05 (comp, 2 H), 3.03–2.92 (m, 1 H), 2.92–2.79 (m, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 142.9, 137.1, 136.5, 135.6, 132.5,

129.0, 128.8, 128.7, 128.4, 127.4, 126.7, 122.6, 121.9, 120.0, 119.1,

111.4, 109.3, 108.8, 73.3, 50.7, 46.8, 21.8.

Compound 18

Following the general microwave procedure, 18 was obtained from

8c (0.25 mmol) and 2,3,4,5-tetrahydro-1H-benzo[c]azepine (17a;^25g

2 equiv) after 30 min at 200 °C in n-butanol (1 mL); yield: 92.5 mg

(91%); tan solid; mp 124–127 °C; R_f= 0.40 (hexanes–EtOAc, 70:30

v/v).

MS-ESI: m/z = 510.0 [M + H]⁺.

IR (KBr): 3372, 2925, 2849, 1590, 1477, 1451, 1364, 1357, 1292,

1259, 1173, 1061, 946, 880, 749, 635 cm^–1.

Compound 25

¹H NMR (500 MHz, CDCl₃): δ = 7.45 (d, J = 2.2 Hz, 1 H), 7.33–

7.06 (comp, 4 H), 6.97 (d, J = 2.2 Hz, 1 H), 5.50 (d, J = 2.5 Hz, 1

H), 4.78 (br s, 1 H), 4.04 (d, J = 15.5 Hz, 1 H), 3.63 (d, J = 15.5 Hz,

1 H), 3.34 (ddd, J = 13.5, 7.3, 3.1 Hz, 1 H), 3.27–3.02 (comp, 2 H),

2.88 (ddd, J = 14.7, 9.3, 2.2 Hz, 1 H), 1.96–1.82 (m, 1 H), 1.82–1.68

(m, 1 H).

Following the general microwave procedure, 10e was obtained

from 8c (1 mmol) and 1,2,3,4-tetrahydroisoquinoline (2.0 mmol)

after 1 h at 220 °C in 69% yield as yellow solid and matches report-

ed spectroscopic data in all regards.^12cIn addition, the title com-

Synthesis 2013, 45, 1730–1748

FEATURE ARTICLE

Ring-Fused Aminals from Secondary Amines and o-Aminobenzaldehydes

1743

pound 25 was isolated as a pale yellow solid; yield: 54.2 mg (14%);

mp 135–138 °C; R_f= 0.20 (hexanes–EtOAc, 80:20 v/v).

¹³C NMR (125 MHz, CDCl₃): δ = 144.0, 138.2, 132.08, 129.1,

128.5, 127.5, 126.3, 121.0, 108.2, 107.7, 79.3, 50.2, 45.5, 43.4,

21.1.

IR (KBr): 3384, 3067, 2926, 1701, 1685, 1676, 1589, 1560, 1478,

1342, 1290, 1265, 1128, 1030, 855, 738 cm^–1.

MS-ESI: m/z = 409.0 [M + H]⁺.

¹H NMR (500 MHz, CDCl₃): δ = 7.40 (d, J = 2.0 Hz, 1 H), 7.21–

7.13 (comp, 3 H), 7.07–7.00 (comp, 2 H), 4.73–4.69 (m, 1 H), 4.29

(d, J = 16.2 Hz, 1 H), 4.24 (s, 1 H), 3.92 (d, J = 15.0 Hz, 1 H), 3.80

(d, J = 16.2 Hz, 1 H), 3.69 (d, J = 15.0 Hz, 1 H), 3.36 (dd, J = 17.0,

4.8 Hz, 1 H), 2.89 (dd, J = 17.0, 3.2 Hz, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 139.3, 133.4, 132.4, 129.9, 129.1,

128.8, 126.5, 126.4, 126.2, 121.6, 108.9, 108.8, 66.1, 54.7, 49.7,

34.5.

In addition, 29b was obtained as a white semi-solid in 33% yield

(1:1 mixture of diastereomers).

Compound 28c

Following the general microwave procedure, 28c was obtained

from 8c (0.25 mmol) and 2-(4-trifluoromethylphenyl)pyrrolidine^25k

(3 equiv) after 30 min at 200 °C in n-butanol (1 mL); yield: 69.3 mg

(58%); clear oil; R_f= 0.34 (hexanes–EtOAc, 90:10 v/v).

IR (KBr): 3414, 2955, 1593, 1475, 1406, 1325, 1164, 1126, 1071,

1017, 840 cm^–1.

MS-ESI: m/z = 395.0 [M + H]⁺.

¹H NMR (500 MHz, CDCl₃): δ = 7.61–7.57 (comp, 4 H), 7.45 (d,

J = 2.0 Hz, 1 H), 6.93 (s, 1 H), 4.77 (br s, 1 H), 3.73–3.53 (comp, 2

H), 3.20 (app td, J = 8.7, 3.3 Hz, 1 H), 2.86–2.67 (m, 1 H), 2.31–

2.15 (m, 1 H), 2.15–1.95 (comp, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 148.4, 137.8, 132.3, 129.9, 129.7,

129.2, 127.0, 125.6 (q, J_C,F= 3.6 Hz), 120.8, 108.4, 108.3, 79.1,

50.2, 45.4, 43.6, 21.2.

Compound 26

Following the general microwave procedure, 26 was obtained from

8c (0.25 mmol) and 2-methylpiperidine (2 equiv) after 30 min at

250 °C; yield: 58 mg (64%); tan semi-solid; R_f= 0.17 (hexanes–

EtOAc, 70:30 v/v).

IR (KBr): 3405, 2917, 2849, 1643, 1480, 1451, 1371, 1296, 1162,

1122, 858 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.41 (d, J = 2.1 Hz, 1 H), 7.03 (s,

1 H), 4.35 (d, J = 17.0 Hz, 1 H), 4.24 (br s, 1 H), 3.45 (d, J = 17.0

Hz, 1 H), 2.49–2.44 (comp, 2 H), 1.77–1.51 (comp, 6 H), 1.31 (s, 3

H).

MS-ESI: m/z = 477.0 [M + H]⁺.

In addition, 29c was obtained as a white semi-solid in 37% yield

(1:1 mixture of diastereomers).

¹³C NMR (125 MHz, CDCl₃): δ = 138.2, 132.1, 128.9, 120.5, 109.1,

Compound 30a

Following the general microwave procedure, 30a was obtained

from 8c (1 mmol) and N-methyl-p-methoxybenzylamine^25l(3

equiv) after 30 min at 250 °C; yield: 171.3 mg (41%); clear oil; R_f=

0.36 (hexanes–EtOAc–Et₃N, 69:30:1 v/v/v).

107.7, 77.2, 67.6, 51.0, 49.3, 38.0, 25.8, 20.3.

MS-ESI: m/z = 361.1 [M + H]⁺.

In addition, 27 was obtained as a white solid in 15% yield (1:1 mix-

ture of diastereomers).

IR (KBr): 3409, 2950, 2835, 1611, 1595, 1510, 1484, 1346, 1301,

1247, 1170, 1126, 1035, 957, 805 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.44 (d, J = 2.2 Hz, 1 H), 7.38–

7.33 (comp, 2 H), 6.99 (d, J = 2.3 Hz, 1 H), 6.94–6.88 (comp, 2 H),

4.90 (d, J = 2.2 Hz, 1 H), 4.75 (br s, 1 H), 3.81 (s, 3 H), 3.77 (d, J =

15.9 Hz, 1 H), 3.64 (d, J = 15.9 Hz, 1 H), 2.27 (s, 3 H).

Compound 28a

Following the general microwave procedure, 28a was obtained

from 8c (0.25 mmol) and 2-(4-methoxyphenyl)pyrrolidine^25k(3

equiv) after 30 min at 200 °C in n-butanol (1 mL); yield: 90.6 mg

(83%); clear oil; R_f= 0.23 (hexanes–EtOAc, 90:10 v/v).

IR (KBr): 2856, 2360, 2342, 1734, 1700, 1507, 1473, 1457, 1247,

1172, 830, 668 cm^–1.

¹³C NMR (125 MHz, CDCl₃): δ = 160.0, 139.0, 132.8, 132.6, 129.1,

128.8, 122.2, 114.2, 108.5, 108.4, 75.3, 55.6, 53.2, 40.2.

¹H NMR (500 MHz, CDCl₃): δ = 7.43 (d, J = 1.8 Hz, 1 H), 7.40–

7.31 (m, 2 H), 6.91 (s, 1 H), 6.88–6.81 (m, 2 H), 4.75 (br s, 1 H),

3.78 (s, 3 H), 3.68 (d, J = 17.0 Hz, 1 H), 3.56 (d, J = 17.0 Hz, 1 H),

3.16 (app td, J = 8.7, 3.1 Hz, 1 H), 2.77–2.68 (m, 1 H), 2.29–2.14

(m, 1 H), 2.13–1.95 (comp, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 159.2, 138.5, 136.1, 132.3, 129.3,

127.8, 121.3, 114.1, 108.4, 107.9, 79.3, 55.5, 50.2, 45.7, 43.4, 21.1.

MS-ESI: m/z = 412.9 [M + H]⁺.

Compound 30b

Following the general microwave procedure, 30b was obtained

from 8c (1 mmol) and N-methylbenzylamine (3 equiv) after 30 min

at 250 °C; yield: 109.5 mg (29%); light yellow solid; mp 108–112

°C; R_f= 0.38 (hexanes–EtOAc–Et₃N, 69:30:1 v/v/v).

IR (KBr): 3058, 2937, 1684, 1594, 1485, 1447, 1339, 1275, 1158,

1103, 1040, 1013, 983, 864, 742, 698 cm^–1.

MS-ESI: m/z = 438.9 [M + H]⁺.

¹H NMR (500 MHz, CDCl₃): δ = 7.48–7.41 (comp, 3 H), 7.41–7.31

(comp, 3 H), 7.00 (d, J = 1.0 Hz, 1 H), 5.01 (d, J = 2.3 Hz, 1 H), 4.79

(br s, 1 H), 3.77 (d, J = 15.9 Hz, 1 H), 3.65 (d, J = 15.9 Hz, 1 H),

2.32 (s, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 140.5, 138.6, 132.4, 129.0, 128.7,

128.5, 127.2, 121.8, 108.3, 108.2, 75.2, 52.5, 40.3.

In addition, 29a was obtained as a white semi-solid in 14% yield

(1:1 mixture of diastereomers).

Compound 28b

Following the general microwave procedure, 28b was obtained

from 8c (0.25 mmol) and 2-phenylpyrrolidine^25k(3 equiv) after 30

min at 200 °C in n-butanol (1 mL); yield: 64.9 mg (64%); clear oil;

R_f= 0.32 (hexanes–EtOAc, 90:10 v/v).

MS-ESI: m/z = 383.0 [M + H]⁺.

IR (KBr): 3410, 2954, 1593, 1475, 1445, 1285, 1178, 1149, 1121,

993, 756, 699 cm^–1.

Compound 30c

Following the general microwave procedure, 30c was obtained

from 8c (1 mmol) and N-methyl-p-trifluoromethylbenzylamine^25m

(3 equiv) after 30 min at 250 °C; yield: 89.9 mg (20%); clear oil;

R_f= 0.37 (hexanes–EtOAc–Et₃N, 69:30:1 v/v/v).

¹H NMR (500 MHz, CDCl₃): δ = 7.54–7.38 (comp, 3 H), 7.38–7.29

(comp, 2 H), 7.29–7.21 (m, 1 H), 6.91 (s, 1 H), 4.79 (br s, 1 H), 3.68

(d, J = 17.0 Hz, 1 H), 3.58 (d, J = 17.0 Hz, 1 H), 3.19 (app td, J =

8.7, 3.5 Hz, 1 H), 2.84–2.67 (m, 1 H), 2.31–2.20 (m, 1 H), 2.14–1.96

(comp, 3 H).

IR (KBr): 3399, 2945, 1618, 1595, 1486, 1411, 1325, 1273, 1161,

1125, 1125, 1067, 1014, 856, 823, 739 cm^–1.

Synthesis 2013, 45, 1730–1748

1744

M. T. Richers et al.

FEATURE ARTICLE

¹H NMR (500 MHz, CDCl₃): δ = 7.63 (d, J = 8.2 Hz, 2 H), 7.56 (d,

J = 8.2 Hz, 2 H), 7.47 (d, J = 2.3 Hz, 1 H), 7.00 (d, J = 2.3 Hz, 1 H),

5.09 (d, J = 2.1 Hz, 1 H), 4.84 (br s, 1 H), 3.71 (d, J = 16.3 Hz, 1 H),

3.58 (d, J = 16.3 Hz, 1 H), 2.37 (s, 3 H).

MS-ESI: m/z = 189.3 [M + H]⁺.

In addition, 34a was also isolated.

34a

¹³C NMR (125 MHz, CDCl₃): δ = 144.8, 137.9, 132.5, 130.6 (q,

Yield: 24.8 mg (38%); white solid; mp 251–253 °C; R_f= 0.19

(hexanes–EtOAc 70:30, v/v).

J_C,F= 31.4 Hz), 129.1, 127.6, 125.6 (q, J_C,F= 3.8 Hz), 123.9 (q,

J_C,F= 272.3 Hz), 121.6, 108.7, 108.5, 74.3, 51.4, 40.6.

MS-ESI: m/z = 451.1 [M + H]⁺.

IR (KBr): 3318, 2024, 2955, 2855, 2807, 1612, 1498, 1479, 1450,

1368, 1308, 1216, 1115, 1094, 1072, 1020, 963, 892, 871, 749 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.30–7.21 (comp, 4 H), 7.15–7.02

(comp, 3 H), 7.02–6.97 (m, 1 H), 6.94–6.81 (comp, 3 H), 6.71 (app

d, J = 8.0 Hz, 1 H), 5.82 (s, 1 H), 5.31 (d, J = 3.2 Hz, 1 H), 4.84 (br

s, 1 H), 4.54 (s, 1 H), 3.87–3.82 (comp, 4 H), 3.45–3.31 (m, 2 H),

2.84 (app dt, J = 11.6, 4.6 Hz, 2 H).

¹³C NMR (125 MHz, CDCl₃): δ = 146.3, 144.4, 140.7, 130.7, 129.1,

129.0, 128.8, 128.7, 128.5, 127.9, 125.3, 124.4, 124.2, 123.7, 123.3,

123.3, 120.00, 117.4, 84.8, 70.4, 67.7, 64.5, 50.5.

Compound 31

Following the general microwave procedure, 31 was obtained from

2-aminobenzophenone (0.5 mmol) and pyrrolidine (3 equiv) after 1

h at 250 °C; yield: 65.9 mg (53%) (1:1.5 mixture of diastereomers);

yellow semi-solid; R_f= 0.36 (hexanes–EtOAc, 70:30 v/v).

IR (KBr): 3219, 2956, 2871, 2368, 2602, 1473, 1364, 1300, 1248,

1152, 1089, 1029, 1007, 940, 923, 756, 703 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.39–7.27 (comp, 7 H), 7.24–7.19

(comp, 3 H), 7.08 (app td, J = 8.4, 1.6 Hz, 1 H), 7.02 (app td, J =

7.5, 1.5 Hz, 1 H), 6.91 (dd, J = 7.5, 1.6 Hz, 1 H), 6.73–6.60 (comp,

3 H), 6.58–6.53 (comp, 2 H), 4.92 (s, 1 H), 4.58 (s, 1 H), 4.37 (d, J =

4.3 Hz, 1 H), 4.11 (br s, 1 H), 3.89–3.84 (m, 1 H), 3.75 (br s, 1 H),

3.05 (app td, J = 8.5, 3.7 Hz, 1 H), 2.90 (app td, J = 8.9, 2.2 Hz, 1

H), 2.86–2.77 (m, 1 H), 2.24–2.12 (comp, 2 H), 2.10–1.85 (comp, 4

H), 1.85–1.72 (comp, 2 H), 1.66–1.58 (m, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 144.2, 143.6, 143.0, 129.6, 129.4,

128.8, 128.6, 128.3, 128.1, 127.6, 127.5, 127.1, 126.8, 126.6, 119.2,

118.6, 117.1, 116.6, 113.9, 104.7, 73.7, 69.9, 65.0, 61.0, 50.8, 50.0,

32.7, 30.4, 21.3, 20.0.

MS-ESI: m/z = 397.0 [M + H]⁺.

Compound 34b

A 10 mL round-bottom flask was charged with 2-aminobenzalde-

hyde (8k; 0.363 g, 3 mmol), absolute ethanol (4 mL), and pyrro-

lidine (0.083 mL, 1 mmol) and was stirred at r.t. for 2 days. After

this time, the solvent was removed in vacuo and the residue was pu-

rified by silica gel chromatography; yield: 232.5 mg (61%); light

yellow solid; mp 184–187 °C; R_f= 0.26 (hexanes–EtOAc, 70:30

v/v).

IR (KBr): 3375, 3050, 2967, 2800, 1734, 1610, 1572, 1494, 1480,

1447, 1369, 1334, 1305, 1243, 1218, 1128, 1070, 1007, 963, 952,

873, 792, 742 cm^–1.

MS-ESI: m/z = 251.1 [M + H]⁺.

¹H NMR (500 MHz, CDCl₃): δ = 7.31–7.18 (comp, 3 H), 7.14 (app

d, J = 7.7 Hz, 1 H), 7.11–7.00 (comp, 3 H), 7.00–6.93 (comp, 2 H),

6.92–6.80 (comp, 2 H), 6.71 (app d, J = 7.6 Hz, 1 H), 5.95 (s, 1 H),

5.29 (d, J = 1.8 Hz, 1 H), 4.85 (br s, 1 H), 4.50 (s, 1 H), 3.37–3.22

(m, 2 H), 2.95–2.78 (m, 2 H), 2.03–1.82 (comp, 4 H).

¹³C NMR (125 MHz, CDCl₃): δ = 145.9, 144.2, 140.8, 130.2, 129.4,

128.9, 128.5, 128.4, 128.3, 127.8, 127.8, 124.6, 124.2, 123.6, 123.5,

123.1 119.9, 117.4, 83.8, 70.8, 63.8, 51.2, 23.8.

Compound 32

Following the general microwave procedure, 32 was obtained from

2-aminoacetophenone (0.5 mmol) and pyrrolidine (3 equiv) after 1

h at 250 °C; yield: 25.9 mg (28%) (1:1.4 mixture of diastereomers);

tan oil; R_f= 0.25 (EtOAc–MeOH, 95:5 v/v).

IR (KBr): 3330, 2965, 2874, 1633, 1609, 1496, 1445, 1372, 1342,

1266, 1188, 1101, 1035, 938, 753 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.12–7.06 (m, 1 H), 7.06–6.93

(comp, 3 H), 6.79–6.71 (m, 1 H), 6.69–6.61 (m, 1 H), 6.58–6.54 (m,

1 H), 6.48–6.42 (m, 1 H), 4.70 (app t, J = 4.5 Hz, 1 H), 4.07–4.02

(m, 1 H), 3.96–3.90 (m, 1 H), 3.90–3.83 (m, 1 H), 3.64 (br s, 1 H),

3.13 (app td, J = 9.0, 4.3 Hz, 1 H), 2.97 (app td, J = 8.3, 4.3 Hz, 1

H), 2.72–2.61 (m, 1 H), 2.52–2.42 (m, 1 H), 2.20–1.80 (comp, 7 H),

1.75–1.63 (comp, 2 H), 1.52–147 (comp, 3 H), 1.46–1.42 (comp, 3

H).

MS-ESI: m/z = 381.0 [M + H]⁺.

Compound 36

Following the general microwave procedure, 36 was obtained from

2-aminobenzaldehyde (8k; 0.25 mmol) and trans-4-hydroxy-L-pro-

line (2.1 equiv) after 15 min at 150 °C in n-butanol (1 mL); yield:

8.4 mg (18%) (1:1.2 mixture of diastereomers); white solid; mp

126–129 °C; R_f= 0.17 (EtOAc–MeOH, 90:10 v/v).

¹³C NMR (125 MHz, CDCl₃): δ = 143.1, 141.6, 128.0, 127.0 (6),

127.0 (5), 126.1, 125.3, 122.6, 118.5, 117.0, 115.5, 113.8, 72.6,

64.2, 56.2, 52.4, 49.6, 47.9, 32.9, 31.2, 24.9, 21.0, 20.4, 19.1.

IR (KBr): 3284, 2922, 2806, 2361, 1610, 1491, 1379, 1267, 1152,

1091, 1018, 822, 746 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.07–6.92 (comp, 4 H), 6.77 (app

t, J = 7.6 Hz, 1 H), 6.70 (app t, J = 7.3 Hz, 1 H), 6.60 (app d, J = 7.8

Hz, 1 H), 6.51 (app d, J = 8.0 Hz, 1 H), 4.56 (br s, 1 H), 4.52–4.47

(m, 1 H), 4.47–4.40 (m, 1 H), 4.23–4.15 (comp, 2 H), 4.07 (d, J =

15.8 Hz, 1 H), 3.88 (d, J = 15.8 Hz, 1 H), 3.83 (d, J = 16.0 Hz, 1 H),

3.30 (dd, J = 9.7, 5.9 Hz, 1 H), 3.17 (dd, J = 10.4, 6.2 Hz, 1 H), 2.96

(app d, J = 10.4 Hz, 1 H), 2.73 (app d, J = 9.7 Hz, 1 H), 2.50–2.39

(comp, 2 H), 2.20–2.00 (comp, 3 H), 1.76 (app d, J = 13.8 Hz, 1 H).

MS-ESI: m/z = 189.1 [M + H]⁺.

Compound 33

Following the general microwave procedure, 33 was obtained from

2-aminobenzaldehyde (8k; 0.5 mmol) and morpholine (3 equiv) af-

ter 2 h at 250 °C; yield: 11.8 mg (12%); light yellow solid; mp 78–

81 °C; R_f= 0.36 (EtOAc–MeOH, 90:10 v/v).

IR (KBr): 3357, 2979, 2852, 1608, 1493, 1456, 1362, 1342, 1290,

1274, 1126, 1045, 1030, 930, 857, 743, 699 cm^–1.

¹³C NMR (125 MHz, CDCl₃): δ = 142.7, 142.6, 127.4, 127.3, 119.7,

119.3, 118.6, 118.4, 116.0, 114.7, 104.8, 103.0, 70.9, 70.8, 70.4,

69.9, 60.8, 59.6, 50.1, 49.3, 44.1, 43.3.

¹H NMR (500 MHz, CDCl₃): δ = 7.04 (app td, J = 7.8, 1.6 Hz, 1 H),

6.93 (app d, J = 7.5 Hz, 1 H), 6.72 (app td, J = 7.5, 1.2 Hz, 1 H), 6.58

(dd, J = 7.8, 1.1 Hz, 1 H), 4.11–3.73 (comp, 6 H), 3.70 (d, J = 15.3

Hz, 1 H), 3.58 (dd, J = 11.3, 5.5 Hz, 1 H), 3.06–2.87 (m, 1 H), 2.52–

2.32 (m, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 141.7, 127.4, 127.0, 119.0, 118.6,

115.3, 69.8, 67.2, 67.1, 55.1, 49.2.

MS-ESI: m/z = 191.2 [M + H]⁺.

Compound 37

Following the general microwave procedure, 37 was obtained from

2-aminobenzaldehyde (8k; 0.25 mmol) and trans-3-hydroxy-L-pro-

line (2.1 equiv) after 15 min at 150 °C in n-butanol (1 mL); yield:

Synthesis 2013, 45, 1730–1748

FEATURE ARTICLE

Ring-Fused Aminals from Secondary Amines and o-Aminobenzaldehydes

1745

5.2 mg (11%); (1:1.1 mixture of diastereomers); white solid; mp

128–130 °C; R_f= 0.21 (EtOAc–MeOH, 90:10 v/v).

¹H NMR (500 MHz, CDCl₃): δ = 8.84 (d, J = 2.2 Hz, 1 H), 8.08 (app

d, J = 8.3 Hz, 1 H), 8.07–8.05 (m, 1 H), 7.77 (app d, J = 8.3 Hz, 1

H), 7.68 (ddd, J = 8.3, 7.2, 1.1 Hz, 1 H), 7.52 (app t, J = 7.2 Hz, 1

H), 4.17 (q, J = 7.1 Hz, 2 H), 3.79 (s, 2 H), 1.25 (app td, J = 7.1, 0.4

Hz, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 170.6, 151.6, 147.2, 132.7, 129.2,

129.1, 127.8, 127.5, 127.0, 126.8, 61.2, 38.7, 14.2.

IR (KBr): 3271, 2924, 2841, 2784, 1609, 1493, 1451, 1378, 1303,

1263, 1151, 1132, 1087, 1037, 992, 843, 752 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.06 (app t, J = 7.7 Hz, 1 H), 7.04–

6.98 (m, 1 H), 6.99–6.91 (comp, 2 H), 6.75 (app t, J = 7.4 Hz, 1 H),

6.72–6.66 (comp, 2 H), 6.50 (app d, J = 8.0 Hz, 1 H), 4.35 (app dt,

J = 7.6, 3.8 Hz, 1 H), 4.27 (br s, 1 H), 4.21 (d, J = 16.2 Hz, 1 H),

4.09–4.05 (m, 1 H), 3.90 (d, J = 15.0 Hz, 1 H), 3.87–3.79 (comp, 3

H), 3.21 (app td, J = 9.3, 4.0 Hz, 1 H), 2.99 (app td, J = 9.0, 4.6 Hz,

1 H), 2.91 (app td, J = 9.2, 6.0 Hz, 1 H), 2.53–2.41 (comp, 2 H),

2.42–2.27 (comp, 2 H), 1.93–1.73 (comp, 3 H).

MS-ESI: m/z = 216.2 [M + H]⁺.

Compound 51

Following the general reflux procedure, 51 was obtained from 8c

(0.5 mmol) and 2-allylpyrrolidine (50)^25oafter heating for 24 h at re-

flux in absolute EtOH (2 mL). Products 51 and 52 were obtained to-

gether as an off-white solid in 15% and 3% yield, respectively. In

addition, 54 and 55 were obtained in 29% and 27% yield, respec-

tively.

¹³C NMR (125 MHz, CDCl₃): δ = 142.5, 142.4, 127.4 (2), 127.4 (0),

127.3, 127.2, 120.4, 118.8, 118.3, 114.6, 104.8, 104.3, 77.2, 76.9,

73.8, 71.6, 52.0, 49.3, 49.0, 48.5, 33.0, 32.0.

MS-ESI: m/z = 191.1 [M + H]⁺.

Data for 51

Yield: 27.9 mg (15%); mp 75–77 °C; R_f= 0.13 (hexanes–EtOAc,

90:10 v/v).

IR (KBr): 3414, 2889, 1593, 1490, 1341, 1109, 914, 863 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.38 (d, J = 2.1 Hz, 1 H), 6.99 (s,

1 H), 5.88–5.69 (m, 1 H), 5.22–4.97 (comp, 2 H), 4.78 (d, J = 4.1

Hz, 1 H), 4.33–4.11 (comp, 2 H), 3.78 (d, J = 17.1 Hz, 1 H), 2.89–

2.78 (m, 1 H), 2.56–2.43 (m, 1 H), 2.43–2.34 (m, 1 H), 2.28–1.95

(comp, 2 H), 1.83–1.54 (comp, 2 H).

¹³C NMR (125 MHz, CDCl₃): δ = 139.5, 135.3, 132.2, 128.8, 120.4,

116.8, 108.0, 107.5, 71.7, 57.6, 46.2, 38.8, 31.2, 27.8.

Compound 41

A 50 mL round-bottom flask was charged with NaH (0.077 g, 1.934

mmol), DMF (10 mL), and 18-crown-6 (0.025 mL, 0.117 mmol)

and cooled to 0 °C under N₂atmosphere. 2,2,2-Trifluoro-N-(2-for-

mylphenyl)acetamide²⁵ⁿ(0.4 g, 1.842 mmol) dissolved in DMF (5

mL) was added to the solution dropwise. The solution was stirred

for 20 min at r.t., then ethyl (E)-4-bromobut-2-enoate (0.381 mL,

2.211 mmol) dissolved in DMF (5 mL) was added dropwise. The

mixture was heated at 60 °C for 4 h. After this time, the solvent was

removed in vacuo and the residue was dissolved in CH₂Cl₂(20 mL).

The organic layer was washed with distilled H₂O (1 × 15 mL) and

brine (1 × 15 mL) and dried (Na₂SO₄). The solid was filtered off, the

solvent removed in vacuo and purified by silica gel chromatography

to give ethyl (E)-4-[2,2,2-trifluoro-N-(2-formylphenyl)acetami-

do]but-2-enoate; yield: 255.4 g (42%); R_f= 0.29 (hexanes–EtOAc,

80:20 v/v). A 10 mL round-bottom flask fitted with a magnetic stir

bar was charged with the above intermediate product (0.050 g,

0.152 mmol) and absolute EtOH (1.5 mL). To this stirred mixture,

aq 5% (w/v) NaHCO₃(1 mL) was added dropwise, resulting in the

formation of a precipitate. The resulting mixture was heated at re-

flux until a homogenous solution resulted. This solution was then

removed from its heat source and allowed to stir for 2 h. After this

time, brine (10 mL) was added to the solution and the product was

extracted with CH₂Cl₂(3 × 10 mL). The combined organic layers

were washed with brine (10 mL), dried (Na₂SO₄), filtered, and the

solvent was subsequently removed in vacuo. The crude mixture was

purified by silica gel chromatography; yield: 31.8 mg (90%);

yellow oil; R_f= 0.23 (hexanes–EtOAc 90:10 v/v).

MS-ESI: m/z = 373.2 [M + H]⁺.

Deoxyvasicine

To a 25 mL round-bottom flask was added compound 9k (0.174 g,

1.0 mmol) and THF (5 mL). The mixture was cooled to –78 °C un-

der N₂atmosphere in a dry ice/acetone bath and stirred for 5 min.

n-BuLi (2.5 M in hexanes, 0.42 mL, 1.05 equiv) was added to the

mixture and allowed to stir for 1 h. I₂(0.329 g, 1.3 mmol) dissolved

in THF (5 mL) was added to the solution dropwise and stirred for

30 min. Et₃N (0.418 mL, 3 mmol) was added to the solution, which

was then allowed to warm to r.t. and stirred for 30 min. The mixture

was then quenched with distilled H₂O (15 mL), extracted with EtO-

Ac (3 × 15 mL), and the solvent was removed in vacuo. The result-

ing residue was purified by silica gel chromatography with Et₃N–

MeOH–EtOAc (1:10:89) as the eluent. Deoxyvasicine was obtained

as a tan solid (146 mg, 85%) and matched reported spectroscopic

data in all regards.^25e

IR (KBr): 3334, 2981, 2747, 1717, 1659, 1580, 1520, 1432, 1276,

1180, 1041, 753 cm^–1.

Vasicine

To a 10 mL round-bottom flask was added compound 37 (0.014 g,

0.074 mmol) and Et₂O (1 mL). The mixture was cooled to –78 °C

under N₂atmosphere in a dry ice/acetone bath and stirred for 5 min.

BuLi (2.5 M in hexanes, 0.031 mL, 1.05 equiv) was added to the

mixture and was allowed to stir for 1 h. I₂(0.021 g, 0.081 mmol) dis-

solved in Et₂O (1 mL) was added dropwise and the mixture stirred

for 30 min. Et₃N (0.031 mL, 0.221 mmol) was then added to the so-

lution, which was then allowed to warm to r.t. and stir for 30 min.

The mixture was then quenched with distilled H₂O (5 mL), extract-

ed with EtOAc (3 × 5 mL), and the solvent was removed in vacuo.

The resulting residue was purified by silica gel chromatography

with Et₃N–MeOH–EtOAc (1:10:89) as the eluent. Vasicine was ob-

tained as a tan solid (10.9 mg, 79%) (R_f= 0.16 in i-PrNH₂–MeOH–

EtOAc, 2:10:88 v/v/v) and matches reported spectroscopic data in

all regards.^25f

¹H NMR (500 MHz, CDCl₃): δ = 9.84 (s, 1 H), 8.55 (br s, 1 H), 7.50

(dd, J = 7.7, 1.6 Hz, 1 H), 7.42–7.34 (m, 1 H), 7.00 (app dt, J = 15.7,

4.4 Hz, 1 H), 6.78–6.70 (m, 1 H), 6.58 (d, J = 8.5 Hz, 1 H), 5.99 (dt,

J = 15.7, 2.8 Hz, 1 H), 4.17 (q, J = 7.1 Hz, 2 H), 4.09–4.05 (m, 2 H),

1.26 (t, J = 7.1 Hz, 3 H).

¹³C NMR (125 MHz, CDCl₃): δ = 194.2, 166.0, 150.0, 143.9, 136.7,

135.9, 121.9, 118.7, 115.7, 110.9, 60.4, 43.2, 14.2.

MS-ESI: m/z = 234.0 [M + H]⁺.

Compound 42

A 10 mL round-bottom flask fitted with a magnetic stir bar was

charged with aminobenzaldehyde 41 (0.117 g, 0.5 mmol), absolute

EtOH (2 mL), and pyrrolidine (0.123 mL, 1.5 mmol). The resulting

mixture was heated at reflux for 14 h and the solvent was subse-

quently removed in vacuo. The crude mixture was purified by silica

gel chromatography; yield: 65.4 mg (61%); yellow oil; R_f= 0.19

(hexanes–EtOAc, 75:25 v/v).

Compound 61

Following the general microwave procedure, 61 was obtained from

8c (0.25 mmol) and trans-4-hydroxy-L-proline (2.1 equiv) after 30

min at 150 °C in n-butanol (1 mL); yield: 44.3 mg (50%) (1:1.2

IR (KBr): 3420, 3065, 2982, 2938, 1733, 1571, 1497, 1465, 1368,

1340, 1255, 1158, 1030, 908, 788, 753, 638, 616 cm^–1.

Synthesis 2013, 45, 1730–1748

1746

M. T. Richers et al.

FEATURE ARTICLE

mixture of diastereomers); tan solid; mp 122–125 °C; R_f= 0.19

(EtOAc–MeOH, 95:5 v/v).

(c) Tobisu, M.; Chatani, N. Angew. Chem. Int. Ed. 2006, 45,

1683. (d) Campos, K. R. Chem. Soc. Rev. 2007, 36, 1069.

(e) Murahashi, S.-I.; Zhang, D. Chem. Soc. Rev. 2008, 37,

1490. (f) Li, C.-J. Acc. Chem. Res. 2009, 42, 335. (g) Jazzar,

R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O.

Chem. Eur. J. 2010, 16, 2654. (h) Yoo, W.-J.; Li, C.-J. Top.

Curr. Chem. 2010, 292, 281. (i) Yeung, C. S.; Dong, V. M.

Chem. Rev. 2011, 111, 1215. (j) Sun, C.-L.; Li, B.-J.; Shi, Z.-

J. Chem. Rev. 2011, 111, 1293. (k) Liu, C.; Zhang, H.; Shi,

W.; Lei, A. W. Chem. Rev. 2011, 111, 1780. (l) Wendlandt,

A. E.; Suess, A. M.; Stahl, S. S. Angew. Chem. Int. Ed. 2011,

50, 11062. (m) Klussmann, M.; Jones, K. M. Synlett 2012,

23, 159. (n) Zhang, C.; Tang, C. H.; Jiao, N. Chem. Soc. Rev.

2012, 41, 3464. (o) Mitchell, E. A.; Peschiulli, A.; Lefevre,

N.; Meerpoel, L.; Maes, B. U. W. Chem. Eur. J. 2012, 18,

10092. (p) Pan, S. C. Beilstein J. Org. Chem. 2012, 8, 1374.

(2) (a) Burns, N. Z.; Baran, P. S.; Hoffmann, R. W. Angew.

Chem. Int. Ed. 2009, 48, 2854. (b) Newhouse, T.; Baran, P.

S.; Hoffmann, R. W. Chem. Soc. Rev. 2009, 38, 3010.

(3) (a) Pinnow, J. Ber. Dtsch. Chem. Ges. 1895, 28, 3039.

(b) See also: Ruiz, M. D. R.; Vasella, A. Helv. Chim. Acta

2011, 94, 785.

(4) (a) Meth-Cohn, O.; Suschitzky, H. Adv. Heterocycl. Chem.

1972, 14, 211. (b) Verboom, W.; Reinhoudt, D. N. Recl.

Trav. Chim. Pays-Bas 1990, 109, 311. (c) Meth-Cohn, O.

Adv. Heterocycl. Chem. 1996, 65, 1. (d) Quintela, J. M.

Recent Res. Dev. Org. Chem. 2003, 7, 259. (e) Matyus, P.;

Elias, O.; Tapolcsanyi, P.; Polonka-Balint, A.; Halasz-

Dajka, B. Synthesis 2006, 2625.

(5) (a) Meth-Cohn, O.; Naqui, M. A. Chem. Commun. 1967,

1157. (b) See also: Ryabukhin, S. V.; Plaskon, A. S.;

Volochnyuk, D. M.; Shivanyuk, A. N.; Tolmachev, A. A.

J. Org. Chem. 2007, 72, 7417. (c) See also: Che, X.; Zheng,

L.; Dang, Q.; Bai, X. Synlett 2008, 2373.

IR (KBr): 3302, 2940, 2819, 2360, 2342, 1596, 1483, 1375, 1285,

1258, 1152, 1023, 862, 683 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.43 (d, J = 2.1 Hz, 1 H), 7.39 (d,

J = 2.1 Hz, 1 H), 7.04 (s, 1 H), 7.01 (s, 1 H), 4.63 (dd, J = 5.4, 2.2

Hz, 1 H), 4.58–4.52 (m, 1 H), 4.52–4.45 (m, 1 H), 4.38 (br s, 1 H),

4.34–4.29 (m, 1 H), 4.22 (d, J = 16.6 Hz, 1 H), 4.17 (br s, 1 H), 4.07

(d, J = 15.7 Hz, 1 H), 3.84–3.72 (comp, 2 H), 3.22 (dd, J = 10.2, 6.4

Hz, 1 H), 3.07 (dd, J = 10.0, 5.6 Hz, 1 H), 2.83–2.73 (comp, 2 H),

2.48 (ddd, J = 13.7, 7.6, 5.1 Hz, 1 H), 2.23 (ddd, J = 14.0, 7.3, 2.3

Hz, 1 H), 2.15 (ddd, J = 14.0, 5.3, 2.8 Hz, 1 H), 1.88–1.79 (m, 1 H).

¹³C NMR (125 MHz, CDCl₃): δ = 139.1 (3), 139.1 (0), 132.5, 132.3,

129.1, 129.0, 122.0, 121.0, 109.9, 109.4, 108.6, 108.4, 70.9, 70.7,

70.5, 69.9, 60.0, 59.0, 49.4, 48.4, 44.5, 43.3.

MS-ESI: m/z = 349.2 [M + H]⁺.

Compound 62

To a 10 mL round-bottom flask was added 61 (0.05 g, 0.144 mmol),

acetone (4 mL), KMnO₄(0.068 g, 0.431 mmol). The solution was

heated at reflux for 2 h, after which time the solution was cooled to

r.t. and filtered through a pad of Celite. The filtrate was washed with

acetone (10 mL) and MeOH (10 mL), and the solvent was removed

in vacuo. The residue was purified by column chromatography, re-

sulting in the isolation of (R)-5,7-dibromo-2-hydroxy-2,3-dihydro-

pyrrolo[2,1-b]quinazolin-9(1H)-one as a tan solid; yield: 33.4 mg

(64%); R_f= 0.28 (EtOAc). To a 10 mL round-bottom flask was add-

ed the above intermediate product (0.0073 g, 0.02 mmol), MeOH (1

mL), 10% Pd/C (2.158 mg, 0.1 equiv), and Et₃N (8.48 μL, 3 equiv).

The atmosphere was evacuated and replaced with H₂gas using a

three-way glass adaptor. The mixture was stirred for 2 h and was

then filtered. The filtrate was washed with MeOH (15 mL) and the

solvent was removed in vacuo; yield: 4.01 mg (98%); white solid;

25

mp 168–171 °C; R_f= 0.16 (EtOAc–MeOH v/v); [α]_D–35.0 (c

(6) (a) Verboom, W.; Reinhoudt, D. N.; Visser, R.; Harkema, S.

J. Org. Chem. 1984, 49, 269. (b) Verboom, W.; Hamzink,

M. R. J.; Reinhoudt, D. N.; Visser, R. Tetrahedron Lett.

1984, 25, 4309. (c) Nijhuis, W. H. N.; Verboom, W.;

Reinhoudt, D. N.; Harkema, S. J. Am. Chem. Soc. 1987, 109,

3136. (d) Nijhuis, W. H. N.; Verboom, W.; Abu El-Fadl, A.;

Harkema, S.; Reinhoudt, D. N. J. Org. Chem. 1989, 54, 199.

(7) Mori, K.; Ohshima, Y.; Ehara, K.; Akiyama, T. Chem. Lett.

2009, 38, 524.

0.167, CHCl₃).

IR (KBr): 3395, 2917, 2849, 2357, 1682, 1633, 1607, 1454, 1392,

1277, 773 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 8.21 (app d, J = 8.0 Hz, 1 H), 7.75–

7.67 (m, 1 H), 7.61 (app d, J = 8.2 Hz, 1 H), 7.43 (app t, J = 7.5 Hz,

1 H), 4.87–4.77 (m, 1 H), 4.32 (app d, J = 13.2 Hz, 1 H), 4.21 (dd,

J = 13.2, 4.8 Hz, 1 H), 3.40 (dd, J = 17.5, 5.7 Hz, 1 H), 3.18 (app d,

J = 17.5 Hz, 1 H), 2.92 (br s, 1 H).

(8) Zhang, C.; Murarka, S.; Seidel, D. J. Org. Chem. 2009, 74,

419.

(9) Overview of aminal-forming reactions: Hiersemann, M. In

Comprehensive Organic Functional Group

¹³C NMR (125 MHz, CDCl₃): δ = 160.9, 157.5, 148.8, 134.3, 126.7,

126.5, 126.4, 120.5, 65.8, 55.2, 42.3.

MS-ESI: m/z = 203.0 [M + H]⁺.

Transformations II; Vol. 4; Katritzky, A. R.; Taylor, R. J. K.,

Eds.; Elsevier: Oxford, 2005, 411.

Acknowledgment

(10) Selected recent examples of oxidative amine α-aminations:

(a) Zhang, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Org. Lett. 2007, 9,

3813. (b) Liu, X. W.; Zhang, Y. M.; Wang, L.; Fu, H.; Jiang,

Y. Y.; Zhao, Y. F. J. Org. Chem. 2008, 73, 6207. (c) Xuan,

J.; Cheng, Y.; An, J.; Lu, L.-Q.; Zhang, X.-X.; Xiao, W.-J.

Chem. Commun. 2011, 47, 8337. (d) Mao, X. R.; Wu, Y. Z.;

Jiang, X. X.; Liu, X. H.; Cheng, Y. X.; Zhu, C. J. RSC Adv.

2012, 2, 6733. (e) Lao, Z. Q.; Zhong, W. H.; Lou, Q. H.; Li,

Z. J.; Meng, X. B. Org. Biomol. Chem. 2012, 10, 7869.

(f) Yan, Y. Z.; Zhang, Y. H.; Feng, C. T.; Zha, Z. G.; Wang,

Z. Y. Angew. Chem. Int. Ed. 2012, 51, 8077. (g) Xia, Q. Q.;

Chen, W. Z. J. Org. Chem. 2012, 77, 9366.

Financial support from the NIH–NIGMS (grant R01GM101389-

01) is gratefully acknowledged. Partial support (microwave

purchase) was provided by the National Science Foundation

through grant CHE-0911192. A.Y.P. gratefully acknowledges fi-

nancial support from the Russian Federation President Grant (order

N2057). D.S. is a fellow of the Alfred P. Sloan Foundation and the

recipient of an Amgen Young Investigator Award.

Supporting Information for this article is available online at

http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi

nnfomartit

(11) (a) Friedländer, P. Ber. Dtsch. Chem. Ges. 1882, 15, 2572.

(b) Marco-Contelles, J.; Perez-Mayoral, E.; Samadi, A.;

Carreiras, M. D.; Soriano, E. Chem. Rev. 2009, 109, 2652.

(12) (a) Zhang, C.; De , C. K.; Mal, R.; Seidel, D. J. Am. Chem.

Soc. 2008, 130, 416. (b) Zhang, C.; De , C. K.; Seidel, D.

Org. Synth. 2012, 89, 274. (c) Dieckmann, A.; Richers, M.

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Synthesis 2013, 45, 1730–1748

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Ring-Fused Aminals from Secondary Amines and o-Aminobenzaldehydes

1747

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Article Doi

Facile access to ring-fused aminals via direct α-amination of secondary amines with o-aminobenzaldehydes: Synthesis of vasicine, deoxyvasicine, deoxyvasicinone, mackinazolinone, and ruteacarpine

DOI: 10.1055/s-0033-1338852

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Article abstract of DOI:10.1055/s-0033-1338852

Full text of DOI:10.1055/s-0033-1338852

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