Urea-induced acid amplification: A new approach for metal-free insertion chemistry

Article abstract of DOI:10.1002/chem.201403283

The enhanced catalytic activity of difluoroboronate ureas proved to be essential as an acidity amplifier to promote metal-free O-H and S-H insertion reactions of α-aryldiazoacetates in high yield. This methodology was found to be generally applicable to a

Full text of DOI:10.1002/chem.201403283

DOI: 10.1002/chem.201403283
Communication
&
Organocatalysis
Urea-Induced Acid Amplification: A New Approach for Metal-Free
Insertion Chemistry
Erica D. Couch, Tyler J. Auvil, and Anita E. Mattson*[a]
the nitrodiazoester through well-established hydrogen-bond
Abstract: The enhanced catalytic activity of difluoroboro-
recognition of the nitro group (A).
nate ureas proved to be essential as an acidity amplifier
Our success in developing reactions of urea-activated elec-
to promote metal-free OÀH and SÀH insertion reactions of
trophilic diazo compounds prompted us to question the ability
a-aryldiazoacetates in high yield. This methodology was
of urea catalysis to also control reactions of more basic diazo
found to be generally applicable to a broad substrate
compounds, such as aryldiazoacetates (Scheme 1, 3).[4] At the
scope and presents a conceptually new approach for or-
onset of our studies, we anticipated that ureas would be
ganocatalytic diazo insertion reactions. Mechanistic inves-
unable to affect the outcome of reactions of aryldiazoacetates;
tigations suggest that the reaction pathway involves
it was not obvious to us how a urea could enhance their reac-
a urea-induced protonation of the a-aryldiazoester.
tivity. Much to our surprise, urea catalysis proved to be an ex-
traordinary tool for select OÀH and SÀH insertion reactions of
aryldiazoacetates.
Diazo compounds have a rich history in organic synthesis.
Their allure can be attributed to the divergent reactivity that
arises from their inherent high-energy ground state and easily
accessed carbene-like reactivity.[1] Many strategies have been
employed to elicit and control the carbene-like reactivity of
diazos for heteroatom–hydrogen (X–H) insertion chemistry, the
vast majority of which rely on the decomposition to metal–car-
benoid intermediates.[2] Recently, our research group discov-
ered that urea catalysis (1) is a viable metal-free approach for
insertion and multicomponent coupling reactions of nitrodia-
zoesters (Scheme 1, 2).[3] In this process, it is reasonably sus-
pected that the urea catalyst amplifies the electrophilicity of
Early on, we were delighted to find that just 2.5 mol% of di-
flouroboronate urea 1a enabled the formation of a-acyloxy
ester 4a in an excellent 91% yield under mild reaction condi-
tions (Scheme 2).[9] Conventional urea and thioureas (1b and c)
were unable to catalyze the insertion event. Only select ureas
benefiting from both internal boron activation[10,11] and appro-
priate electron-withdrawing substitution patterns were found
to be active catalysts (1a, e–f). The lack of reactivity of control
catalyst 5 also suggested that the hydrogen-bonding urea
functionality is a necessary component of the catalyst struc-
ture, and simple Lewis acid catalysis at boron is unlikely.
Close consideration of our observations, taken along with
the recent, inventive investiga-
tions of urea/Brønsted acid co-
catalyst systems from the groups
of both Jacobsen and Seidel,[4]
led us to hypothesize that the
mechanism may likely not in-
volve urea activation of the
diazo
compound.
Instead,
a urea-catalyzed enhancement in
the organic acid’s acidity (B) is
proposed to promote the step-
wise insertion of aryldiazoace-
tates via an intermediate ion
pair (C).[5,6] Although many ex-
Scheme 1. Urea-catalyzed diazo reactivity amplification for XÀH insertions.
amples of urea/Brønsted acid co-
catalysis in 1,2-additions have
been described,[4,7] to the best of our knowledge, this concept
has not been applied to catalytic substrate acidification for X–
H insertions.[8] Herein, we report our initial success in the area
of urea-induced heteroatom acid amplification as an innovative
tactic for metal-free OÀH and SÀH insertion reactions.
With the optimal catalyst 1a in hand, the scope of the orga-
nocatalytic insertion reaction was examined. Methyl 4-
[a] E. D. Couch, Dr. T. J. Auvil, Prof. A. E. Mattson
Department of Chemistry and Biochemistry
The Ohio State University
100 W. 18th Ave, Columbus, OH, 43210 (USA)
E-mail: mattson@chemistry.ohio-state.edu
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403283.
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lyzed by BF3·OEt2,[13] were toler-
ated, providing only the S-
bound insertion adducts 6h and
i.
A
variety of a-aryldiazoace-
tates easily inserted into boro-
nate urea-activated OÀH and SÀ
H bonds. The efficiency of the in-
sertions was heavily dependent
on the diazo compounds’ aryl
substituents. As a general trend,
electron-donating groups sped
up the reaction, whereas elec-
tron-withdrawing
substituents
rendered the insertions more
sluggish. Ethyl phenyldiazoace-
tate (3b) rapidly inserted into
acetic acid in the presence of 1a
(Table 1, entry 1), whereas longer
reaction times and 508C reaction
temperatures were required to
insert into thiophenol’s SÀH
bond (entry 6). The introduction
of halogens onto the aryldiazo
compounds was tolerated. For
example, diazoester 3c inserted
into acetic acid providing 4m in
Scheme 2. Urea-catalyzed diazo OÀH insertion (see the Supporting Information for experimental details). Yields
1
are of isolated product. [a] Yield was determined by H NMR spectroscopy.
methoxyphenyldiazoacetate (3a) inserted readily into
a variety of acidic OÀH and SÀH bonds (Scheme 3).
Aliphatic carboxylic acids efficiently underwent inser-
tion to afford a-acyloxy esters 4a–c in the presence
of 2.5 mol% 1a at 238C in toluene (Scheme 3a). The
steric hindrance of the acid had little effect on the in-
sertions efficiency; even the sterically hindered pivalic
acid was a viable OÀH insertion partner. Electron-rich,
electron-poor, and sterically encumbered benzoic
acids underwent insertion giving rise to 4d–h in 53–
93% yield. Diazo compound 3a also inserted into the
OÀH bonds of a-amino acids, although we observed
no diastereoselectivity in the products (4i–k) under
the examined reaction conditions. Importantly, the N-
terminus of the amino acid required protection as
the tert-butyl carbamate in order for the insertion to
proceed. Mercaptans operated well in catalytic SÀH
insertion reaction under slightly different conditions
(Scheme 3b); utilizing 2.5 mol% of 1a, good yields of
the products 6 could be isolated after 12 h in a,a,a-
trifluorotoluene (PhCF3).[12] Thiophenols were efficient
substrates for SÀH bond insertion, irrespective of the
electronic nature of their substituents, providing the
insertion products 6a–e. Even alkyl thiols were ac-
commodated under the reaction conditions affording
Scheme 3. Substrate scope of the organocatalytic OÀH and SÀH insertions. All reactions
were performed at 0.5m with respect to 3a. [a] Reaction time 36 h. [b] Reaction time
SÀH insertion products 6 f and g in good yield. Thio-
acids, which are problematic in SÀH insertions cata- 72 h. [c] Reaction time 48 h.
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case.[16,17] The catalytic cycle would conclude with the diazoni-
um species in C reacting with the urea-stabilized anion (XÀ) to
generate the observed insertion products (4 or 6). The weak
interaction of 4 or 6 with difluoroboronate urea 1a would
then free the urea to re-enter the catalytic cycle.
Table 1. Aryldiazoacetate substrate scope.
Entry
1
4
Yield [%][a] Aryldiazoester
3
Entry
6
6
Yield [%][a]
More concrete insight into the proposed reaction pathway
was collected through the execution of strategically selected
experiments (Scheme 4b–d). We first attempted to trap a po-
tential donor/acceptor carbene intermediate through an intra-
molecular cyclopropanation of the olefin in the cinnamyl alco-
hol-derived a-aryldiazoacetate 3g (Scheme 4b).[18] When 3g
was subjected to the standard OÀH insertion reaction condi-
tions, we observed only formation of the a-acetoxyester 4q.
Importantly, when acetic acid was omitted from the reaction,
under otherwise identical reaction conditions, we observed no
reaction after 48 h at 238C. Moreover, when 3g was subjected
to high temperatures in PhCF3, reaction conditions known to
generate free carbenes from aryldiazoacetates,[19] 87% of exo-
(Æ)-7 was isolated as a single diastereomer. Collectively, this
data contends the formation of a free donor/acceptor carbene
intermediate under the optimal reaction conditions.
4l 66
4m 89
3b
6j 65[b,c]
2
3
3c
3d
3e
7
8
9
6k 81
4n 57[d]
6l 72[c]
4
5
4o 76
4p 50
6m 75[b]
3 f 10
6n 91
Further support of the proposed mechanism, depicted in
Scheme 4c, can be seen when the XÀH bond is not present
for HBD activation. For example, when triethylammonium ace-
tate or sodium benzoate were utilized under the optimal reac-
tion conditions, no reaction was observed. Similarly, when
sodium thiophenolate was added to the standard SÀH inser-
tion conditions, the expected product 6a was not formed in
any appreciable amount, demonstrating that the XÀH bond is
crucial for the insertion to occur. Confident that the reaction
was proceeding through an initial protonation event, we were
also curious if the catalyst could be involved in a direct proto-
nation of the a-aryldiazoester. To probe this question, the most
active diazo compound surveyed during our studies (3a) was
subjected to one equivalent of catalyst 1a in [D3]acetonitrile
for 24 h at 238C (Scheme 4d). Under these conditions, we
were unable to detect formation of 8, the product known to
form from deprotonation and isomerization of the urea cata-
[a] Yields are of isolated product [b] Reaction time 72 h. [c] Reaction temper-
ature 508C. [d] Reaction time 48 h. Reactions were performed at 0.5m with
respect to 3 (see the Supporting Information for elaborative experimental
details). The XÀH insertion conditions are identical to those shown in
Scheme 4 unless otherwise noted.
89% yield (entry 2). Similarly, 3c underwent insertion efficiently
into thiophenol to afford 6k (81%, entry 7). Halogens as the
sole substituent were also accepted; 3d underwent both OÀH
and SÀH insertion at room temperature, albeit longer reaction
times were required to provide 4n and 6l in 57 and 72%, re-
spectively (entries 3 and 8). As was expected, inductively do-
nating groups facilitated the insertion process; both acetic
acid and thiophenol underwent insertion by 3e more efficient-
ly than 3b, providing 10% higher yields in each of the studied
insertion reactions (entries 4 and 9). Unfortunately, the electron
poor a-aryldiazoester, methyl 4-(trifluoromethyl)phenyldiazoa-
cetate was inoperable in both insertion reactions, plausibly
due to its relatively poor basicity. The heteroaryl a-diazoester
3 f also operated well in the insertion reactions; insertion of 3 f
into acetic acid provided the a-acetoxyester 4p in 50% yield
(entry 5), whereas insertion into thiophenol occurred efficiently
providing 6n in 91% (entry 10).
Our working hypothesis of the catalytic cycle is depicted in
Scheme 4a. The process is thought to begin with coordination
of the difluoroboronate urea to the acidic heteroatom (XÀH),
forming complex B.[14,15] This complexation enables the amplifi-
cation of the acidity of the organic acid, which in the presence
of a Brønsted basic diazo compound, undergoes a proton
transfer through species D. The proton transfer, converting D
1
lyst, to any measureable extent by H NMR spectroscopy.[20,21]
In summary, we have discovered that difluoroboronate ureas
are unique metal-free catalysts for OÀH and SÀH insertion re-
actions of aryldiazoacetates. This innovative approach for diazo
insertion chemistry is believed to occur through hydrogen
bonding to suitable functionalities giving a urea-induced or-
ganic-acid enhancement. The reaction tolerates an assortment
of carboxylic acids and thiols, enabling the efficient prepara-
tion of a wide array of a-acyloxyesters and a-mercaptoesters
under mild reaction conditions. The utility of urea-induced or-
ganic acid amplification as a tool for metal-free, enantioselec-
tive insertion chemical technologies is of current interest in
our laboratory.
to C, may be rate determining in this process because it has Acknowledgements
been shown that a-aryldiazoacetate hydrolysis occurs through
The Ohio State University (OSU), Department of Chemistry and
a general acid-catalyzed A-SE2 mechanism, although additional
studies are required to provide tangible evidence in this
Biochemistry, and Donors of the American Chemical Society
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Keywords: acidity
·
diazo compounds
·
insertion
·
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Received: April 28, 2014
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COMMUNICATION
&
Organocatalysis
E. D. Couch, T. J. Auvil, A. E. Mattson*
&& – &&
Urea-Induced Acid Amplification: A
New Approach for Metal-Free
Insertion Chemistry
All amped up: Boronate ureas amplify
the acidity of protic heteroatoms for
metal-free, catalytic OÀH and SÀH inser-
tions by a-diazocarbonyls. The en-
hanced activity of difluoroboronate
ureas is essential for successful insertion
reactions; conventional (thio)ureas do
not catalyze the desired transforma-
tions. This new strategy for metal-free
insertions provides access to a broad
array of a-acyloxy esters and a-mercap-
toesters in high yield (see scheme).
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