Green and scalable aldehyde-catalyzed transition metal-free dehydrative N-alkylation of amides and amines with alcohols

Article abstract of DOI:10.1002/adsc.201200881

In contrast to the borrowing hydrogen-type N-alkylation reactions, in which alcohols were activated by transition metal-catalyzed anaerobic dehydrogenation, the addition of external aldehydes was accidentally found to be a simple and effective protocol for alcohol activation. This interesting finding subsequently led to an efficient and green, practical and scalable aldehyde-catalyzed transition metal-free dehydrative N-alkylation method for a variety of amides, amines, and alcohols. Mechanistic studies revealed that this reaction most possibly proceeds via a simple but interesting transition metal-free relay race mechanism. Copyright

Full text of DOI:10.1002/adsc.201200881

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DOI: 10.1002/adsc.201200881
Green and Scalable Aldehyde-Catalyzed Transition Metal-Free
Dehydrative N-Alkylation of Amides and Amines with Alcohols
Qing Xu,a,* Qiang Li,a Xiaogang Zhu,a and Jianhui Chena
a
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou, Zhejiang 325035, Peopleꢀs Republic of
China
Fax : (+86)-577-8668-9300; phone: (+86)-138-577-45327; e-mail: qing-xu@wzu.edu.cn
Received: September 30, 2012; Revised: October 15, 2012; Published online: January 7, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200881.
Abstract: In contrast to the borrowing hydrogen-
type N-alkylation reactions, in which alcohols were
activated by transition metal-catalyzed anaerobic
dehydrogenation, the addition of external aldehydes
was accidentally found to be a simple and effective
protocol for alcohol activation. This interesting
finding subsequently led to an efficient and green,
practical and scalable aldehyde-catalyzed transition
metal-free dehydrative N-alkylation method for
a variety of amides, amines, and alcohols. Mechanis-
tic studies revealed that this reaction most possibly
proceeds via a simple but interesting transition
metal-free relay race mechanism.
remain and many challenges have not yet been effec-
tively addressed in the existing methods. For example,
since the initial dehydrogenative alcohol activation to
aldehydes and hydridometal species is a thermody-
namically unfavourable process, preformed noble
metal complexes or addition of capricious ligands for
catalyst activation were usually required under inert
atmosphere protection, which is not only expensive,
not readily accessible and toxic, but can be severe
drawbacks of the methods, especially in pharmaceuti-
cal, biochemical and industrial applications. There-
fore, the development of efficient, economic, lowly
toxic, even transition metal-free processes is still an
urgent and challenging task in the field.
Keywords: alcohols; aldehyde catalysis; amides;
amines; N-alkylation; relay race mechanism; transi-
tion metal-free conditions
Although transition metal-free N-alkylation reac-
tions were already known[3d,10] before the emergence
of the metal-catalyzed reactions in 1981,[4] they re-
quire even harsher reaction conditions than the
metal-catalyzed methods,[3–8] such as very high tem-
perature (>2008C, even to 4008C), high pressure, the
use of large excess amounts of alcohols or amines,
Regarding the fundamental principles of a green strong basic conditions by using large amounts of
transformation,[1] advantageous synthetic methods bases, long reaction times, and suffer from the prob-
avoiding mutagenic and waste-producing reagents are lems of low yields and low selectivities of the prod-
of extraordinary interest in both academic and indus- ucts. To overcome these disadvantages, various transi-
trial work.[1,2] Recently, the transition metal-catalyzed tion metal-catalyzed methods were later reported.[3–8]
dehydrative N-alkylation of amines and amides using Consequently, there still remains much room for im-
alcohols as the greener alkylating reagents, namely provement over the known methods. A direct solution
the borrowing of hydrogen or hydrogen autotransfer to the problems seems vague; one of the best ways
methodology [Eq. (1)],[3–8] has become a useful way may be adopting the more economic and less toxic
to achieve versatile amine and amide derivatives, metal catalysts such as Cu and Fe,[6,7,11,12] or using re-
which are known as key moieties in pharmaceuticals, cyclable heterogeneous catalysts,[8] or by developing
bioactive molecules, and natural products.[3,9] How- more stable catalysts that can be used under less de-
ACHTUNGTRENNUNG
ever, despite the recent progresses, drawbacks still manding aerobic conditions.[7,12] However, many of
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Table 1. Screening and optimization of the reaction condi-
the reactions still have to use a large excess alcohols,
amines, or bases, and require high temperatures and
long reaction times.[6–8,11] Herein we report an advance
in the field by disclosing a green and efficient, practi-
cal and scalable aldehyde-catalyzed transition metal-
free dehydrative N-alkylation reaction of amides and
amines with alcohols [Eq. (2)].[13]
tions.[a]
Run
4a, K2CO3 (mol%)
T, t
3aa [%][b]
1
2
20, 20
20, 20
20, 20
10, 10
0, 10
10, 0
0, 0
10, 10
10, 10
1008C, 36 h
1208C, 16 h
1208C, 16 h
1208C, 16 h
1208C, 16 h
1208C, 16 h
1208C, 16 h
1358C, 17 h
1358C, 17 h
69 (57)
99 (99)
99 (99)
88 (80)
NR (NR)
NR (NR)
NR (NR)
99 (99)
3[c,d]
4
5[c]
6[c,e]
7[c]
8
9[c,d]
99 (99)
Recently, by employing the borrowing hydrogen
strategy, several transition metal-catalyzed N-alkyla-
tion methods, mainly benzylation reactions, were re-
ported for the synthesis of useful sulfonamide and
amine derivatives [Eq. (1)].[5–8] In contrast, we acci-
dentally found that air played a crucial role in a Rh-
catalyzed reaction,[12a] which subsequently led to the
discovery of an air-promoted metal-catalyzed aerobic
alkylation method and an interesting mechanism anal-
ogous to the relay race game.[12] We also proposed
that metal-catalyzed aerobic alcohol oxidation should
be a new way of alcohol activation/aldehyde genera-
tion,[12,14] which unfortunately it seems has not been
generally recognized by the field so far.[3–8,12,14] During
our further efforts to develop more preferable cata-
lysts, we accidentally noticed that the reaction of alco-
hols and sulfonamides could be driven to completion
by merely adding catalytic amounts of the intermedi-
ate aldehydes [Eq. (2), R2 =RSO2], which implied
[a]
The mixture of 1a (1.3 equiv.), 2a (3 mmol), 4a, and
K2CO3 (AR grade of 99.56% purity was used unless oth-
erwise noted) was sealed under N2 or air in a 20-mL
Schlenk tube and then heated. The reaction was then
monitored by TLC and/or GC-MS.
Conversions of 2a to 3aa are based on GC analysis. The
GC conversions obtained from the reactions under nitro-
gen are shown outside the parenthesis (those under air
are shown in the parenthesis). Usually none or <0.5%
5aa was detected by GC (3aa/5aa>99/1).
To avoid contamination of 1a by slight amounts of 4a, re-
distilled absolute 1a (100% purity) was used. NR: no re-
action.
Virgin glassware and stirring bar, absolute 1a and 4a, and
4N grade K2CO3 (99.992% purity) were used.
Traces 5aa derived from the added 4a and 2a were de-
tected.
[b]
[c]
[d]
[e]
that the lone aldehyde can catalyze the reaction effi- many metal-catalyzed or metal-free reactions,[16] and
ciently to completion without any transition metal cata- since there were no corresponding studies in the early
lysts![13] Thus, simply heating a solvent-free mixture of transition metal-free N-alkylation reactions,[3d,10]
benzyl alcohol 1a, benzenesulfonamide 2a, benzalde- whether transition metal catalysts are indeed not re-
hyde 4a (10–20 mol%), and K2CO3 (10–20 mol%) at quired in present reactions remains to be elucidated.
100–1358C could efficiently lead to high conversions As illustrated below, it can be demonstrated unequiv-
of 2a to product 3aa in high selectivities (Table 1). As ocally that the reaction is indeed transition metal-
shown, reactions with neither aldehyde nor base did free. Firstly, both the aldehyde and base were found
not occur at all (runs 5–7), and reactions using lesser to be essential. Their combination is so crucial that no
amounts of aldehyde and/or base were accordingly reaction occurred at all with neither of them (Table 1,
less efficient.[15] Worth noting is that the reactions runs 5–7). Accordingly, aldehyde and base loadings
conducted under air could also give equally good re- affected the reaction rates greatly (Table 1) so that
sults (yields in parenthesis) with those under nitrogen more amounts of them unexceptionally led to faster
(yield outside the parenthesis), showing that air does reactions and/or lower reaction temperatures (runs 1–
not affect the reaction at all. Therefore, inert atmos- 3) and vice versa.[15] Secondly, screening of the bases
phere protection can be avoided and operations and also revealed their key function in the reaction, in
conditions of the reaction can be simplified greatly by which K2CO3 was still found to be the best one re-
employing this new catalytic method.
garding efficiency, selectivity, economy and ease of
Since the influences of metal impurities in catalysts, handling.[15] Thirdly, control reactions using virgin
additives, or substrates and the determination of the glassware and stirring bar, 4N K2CO3 (99.992%
active catalytic species are currently key concerns in purity), and absolute benzyl alcohol 1a and benzalde-
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Green and Scalable Aldehyde-Catalyzed Transition Metal-Free Dehydrative N-Alkylation
hyde 4a (runs 3 and 9) also gave the same good re- cohols to give high yields of the target products under
sults as those with AR K2CO3 (runs 2 and 8),[17] both similar conditions by using NaOH or CsOH as the
under air and under nitrogen, revealing that the better alkali bases. The methodꢀs synthetic potential is
100 times purer 4N K2CO3 has the same catalytic ac- also exemplified by the efficient preparation of apyra-
tivity as the trace transiton metal-contaminated AR bactin 3ah (run 16),[9i] which used to be obtained from
K2CO3 in the same reaction. In addition, more control the corrosive, instable, and more expensive sulfonyl
reactions using 4N K2CO3 (10 mol%), 4-cholobenzal- chloride.
dehyde (4f) as the catalyst (10 mol%), and various
It should be mentioned that, during the extension
metal catalysts as the additives (1 mol%) in the reac- of the substrates, the base was again found to be cru-
tions of 4-cholobenzyl alcohol (1f) and 2a were also cial for the reactionꢀs efficiency as we have observed
carried out to investigate the influences of transition during the conditions screening. Thus, by carefully
metal catalysts on the reaction.[15] The results only re- screening the base effect and by using the best base
vealed that the metal catalysts were ineffective in pro- for each substrate, the reactions were very efficient
moting the aldehyde-catalyzed reactions, indicating and usually afforded high yields of the products. For
that the aldehyde alone is the best catalyst for the re- example, it was found that NaOH is the best base for
action. On the contrary, obvious retardance of the al- sulfinamides and heteroaromatic amines and CsOH
dehyde-catalyzed reactions and lower yields of the for aromatic amines. Although the reasons for these
product were observed when only catalytic amounts differences, the relationship between the basicity of
ꢀ
of 18-crown-6 was added as the additive [Eq. (3)], the bases and the acidity of the N H bonds, as well as
the choice of a right base for a given substrate remain
to be clarified, the above results revealed again that
the alkali cations played key roles in the reactions,
supporting again that the reactions are most possibly
transition metal-free. In contrast, as revealed by the
literature reports,[5–8] possibly because no base optimi-
zations were conducted in many of the metal-cata-
lyzed reactions, the metal catalysts would then play
a more significant role when the less effective bases
were used. On the contrary, in the present reactions,
by choosing the right base and using aldehydes as the
catalyst, the use of transition metal catalysts and inert
which should be attributed to the well-known strong atmosphere protection can be avoided, while still re-
complexation ability of 18-crown-6 with the potassium taining similarly high reaction efficiencies. This also
cation.[18] The addition of 18-crown-6 may result in reveals an advantage of the method over the metal-
a lower concentration of the free potassium cation in catalyzed reactions.
the reaction media, and consequently lower activity in
Moreover, products obtained by this new method
the reaction. The above results reflected clearly the are rather clean since small amounts of the organic
significant role of the alkali bases in promoting the re- impurities, mainly the slight excess of alcohols and al-
actions rather than the transition metal catalysts or dehydes, can be readily removed by vacuum distilla-
the metal impurities. Based on the above findings, the tion, rendering the method particularly promising for
possibilities of transition metal-catalyzed processes large-scale preparations at the lowest cost. Indeed,
due to metal contamination in the substrates, cata- several 50-mmol scale reactions of 1 and 2 readily af-
lysts, or bases can be eliminated.
forded good yields of pure 3 (72–77% isolated yields)
The optimized conditions were then applied to vari- by simply recrystallizing the crude products.[15] Al-
ous amides, amines and alcohols to extend the scope though substrate scope of the method remains to be
of the method by using corresponding aldehydes fully investigated, all the above results revealed its
(R1CHO, 4) as the catalysts (Table 2). As investigat- potential generality and broad utility in the green syn-
ed, various sulfonamides and benzylic alcohols, in- thesis of the amine and amide derivatives.
cluding the sterically more hindered ones (runs 4, 11,
All the above results also indicated that the mecha-
14, 16), heteroaromatic ones (runs 9, 17), aliphatic nism of the aldehyde-catalyzed N-alkylation reactions
sulfonamides (runs 18–20), and those with reactive should be interesting. Since no transition metal cata-
functional groups (runs 5–8, 13, 14, 16, 17, 20) gave lysts are involved, a new mechanism different to the
efficiently the target products in good to high yields. metal-catalyzed borrowing hydrogen process[3–8]
Similarly, sulfinamides (runs 21–23) and various should be responsible for the present reactions
hetero
important building blocks in pharmaceuticals and bio-
active molecules, also reacted efficiently with the al- condensation of amides/amines 2 with aldehydes 4 to
ACHTUNGTRENNUNG
aromatic and aromatic amines (runs 24–40), all (Scheme 1).[19]
Firstly, base was found to promote the dehydrative
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Table 2. Extension of the substrate scope.[a]
[a]
See the Supporting Information (Table S1) for detailed procedures and conditions. GC con-
versions of 2 to 3 are shown out of the parenthesis. Isolated yields based on 2 are shown in
the parenthesis. 3/5 ratios >99/1 as determined by GC.
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Green and Scalable Aldehyde-Catalyzed Transition Metal-Free Dehydrative N-Alkylation
cycled (step iii) to undergo a new condensation with 2
to finish the catalytic cycle. Interestingly, as shown in
Scheme 1, the process that the latter alcohol 1’ gives
its own hydrogen atoms to the preceding alcohol 1 (in
its imine form 5 via aldehyde 4) with itself being oxi-
dized to 4’, and will then (also in the imine form) re-
ceive new hydrogen atoms from an even later alcohol
in the next cycle is analogous to the relay race game,
resembling the passing on of the relay baton between
the runners.
Based on above findings and regarding that 4N
K2CO3 also showed the same high catalytic activity as
AR K2CO3 did in the reduction of imines 5 to prod-
ucts 3 by alcohols 1,[15] the transfer hydrogenation
step (Scheme 1, step ii) should be a transition metal-
Scheme 1. Proposed mechanism for the aldehyde-catalyzed
transition metal-free N-alkylation reaction.
afford the intermediate imines 5 (Scheme 1, step i),[15] free process, also. As documented in the literature
which is a classic organic reaction that can also occur that have long been known, conventional transition
without any additives.[20] In great contrast, base was metal-free Meerwein–Pondorf–Verley (MPV) reduc-
then found to be indispensible in the subsequent tion of aldehydes and ketones by alcohols or the Op-
transfer hydrogenation step (step ii). Thus, although penauer oxidation of alcohols by carbonyl compounds
no target reaction occurred at all without the base, is believed to proceed via six-membered cyclic transi-
the transfer hydrogenation of imines 5 by primary al- tion states [Scheme 2 (a), Y=O].[22] Although the
cohols 1 became very efficient even at lower tempera- exact process and the transition states in the present
tures (such as 1008C) once catalytic amounts of the transition metal-free transfer hydrogenation of imines
base were added, giving high yields of product 3.[15] In still remain to be clarified, since no transition metal
comparison, secondary alcohols were found to be in- catalysts are involved in the reactions, eliminating the
ferior reducing reagents in the reaction than the pri- possibilities of the hydridometal species participated
mary alcohols, giving low yields of the product under mechanisms, and that the cations of the main group
similar conditions.[21] More importantly, as measured metals MA (K, Na, or Cs) play key roles to facilitate
by NMR analysis, about 1 equiv. of the by-product al- the reactions, it may by analogy be assumed that the
dehyde 4 (in molar ratio to product 3) was also pro- present aldehyde-catalyzed transition metal-free N-al-
duced simultaneously [Eq. (4)],[15] implying that quan- kylation reactions most probably proceed via similar
titative amounts of 4 could be regenerated in the six-membered cyclic MPV-type transition states
transfer hydrogenation step, which should then be re- [Scheme 2, (b), Y=NR2].[23,24] To the best of our
knowledge, this may be the first example of mild, effi-
cient, and practical transfer hydrogenation of imines
by alcohols via the transition metal-free MPV-type
process.[3,22–25]
Besides, steps i+ii in Scheme 1 are similar to the
well-documented reductive amination reactions.[26]
Conventionally, carbonyl compounds were used as the
substrates and large excess amounts of the hazardous
gas hydrogen or waste-producing boron hydrides
Scheme 2. Possible transition states involved in the transition metal-free transfer hydrogenation reactions.
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were employed as the reducing reagents.[26] Different- the past.[3–8,10] The present results and conclusions not
ly, in the present method, by using alcohols 1 as the only support our previous studies,[12] but also indicate
reducing reagent, the starting aldehydes 4 can be that, by using the right base and simply adding small
readily regenerated in quantitative amounts amounts of aldehydes as the catalyst, the use of tran-
(Scheme 1, step ii) and will then circulate (step iii, 1= sition metal catalyst can be easily avoided. Since
1’, 4=4’) in the catalytic cycle until the whole reac- simple aldehyde-catalyzed reactions are still very rare
tion is completed. Therefore, only catalytic amounts up to date,[27] and due to the many obvious advantag-
of the corresponding aldehydes 4 should be required es, this aldehyde-catalyzed dehydrative alkylation
in the reaction, which is in good accordance with the method should be of potentially wide interest and
present aldehyde-catalyzed reactions. On the contrary, broad utility in many fields. Further extensions and
if a different aldehyde was added as the catalyst deeper mechanistic insights of the reactions are un-
(step iii, 1¼1’, 4¼4’), a mixture of products could be derway.
obtained as we have also observed in corresponding
control reactions.[15] These results not only revealed
the advantages of the present method over some of Experimental Section
the reductive amination reactions, but also strongly
support the proposed mechanism.
Typical Procedure for Aldehyde-Catalyzed N-
Moreover, the proposed mechanism (Scheme 1) Alkylation of Amides and Amines with Alcohols
also indicated that, like aldehydes, the intermediate
imines 5 that can give aldehydes 4 via transfer hydro-
genation and will then be regenerated in next conden-
K2CO3 (0.041 g, 0.3 mmol, 10 mol%), and absolute benzal-
The mixture of benzyl alcohol 1a (0.41 mL, 3.9 mmol,
1.3 equiv.), benzenesulfonamide 2a (0.471 g, 3.0 mmol),
sation step, should also be able to catalyze the reac-
tion. Similarly, oxidants that can oxidize the alcohols
to aldehydes (step iv) may also initiate the reaction
effectively under similar conditions (steps iv+i+ii+
iii). As shown in (Eq. (5)], the above hypothesis are
dehyde 4 (30 mL, 0.3 mmol, 10 mol%) in a 20-mL Schlenk
tube was sealed under air (or nitrogen) and then stirred at
1358C for 18 h. After completion of the reaction as was
monitored by TLC and/or GC-MS (>99% GC conversion),
the mixture was quenched with ethyl acetate and the crude
product purified by column chromatography using ethyl ace-
tate and petroleum ether (60–908C) (v/v 15/1) as eluent,
giving N-benzylbenzenesulfonamide 3aa; isolated yield:
0.675 g (91%).
Acknowledgements
We thank NNSFC (No. 20902070), SRF for ROCS of SEM,
ZJNSF (No. Y4100579), and ZJQJTP (No. QJD0902004)
for financial support. We also thank Prof. S. Ma (SIOC) for
helpful discussions.
indeed the cases as we have found out in the reactions
using catalytic amounts of imine 5aa, TEMPO
(2,2,6,6-tetramethyl-1-piperidinyloxyl), or PhIACTHNUTRGNEUNG(OAc)2
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gen source to reduce 5aa to 3aa instead of the primary
alcohols, but the reaction required a much higher tem-
perature and longer reaction time, and gave only low
yield of the product. See ref.[12f] for another example of
less efficient transfer hydrogenation reaction by using
a secondary alcohol as the reducing reagent.
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catalyzed reactions may also proceed via the MPV-O
mechanism without involving the hydridometal species.
See refs.[3c,22b]
[24] Although it was held that benzyl alcohol can reduce
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conditions (ref.[10]), it was a hypothesis only since no
corresponding reactions were investigated to verify the
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work, NaOH or CsOH that can be used in only catalyt-
ic amounts are found to be better bases than KOH in
the cases of aromatic amines, and they lead to higher
reaction efficiencies at much lower temperatures (see
the Supporting Information for details).
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