NHC-Catalyzed intramolecular redox amidation for the synthesis of functionalized lactams

Article abstract of DOI:10.1021/ol102536s

A very efficient NHC-catalyzed lactamization reaction is reported. For most cases, the ring expansion reaction proceeds to cleanly furnish five- and six-membered N-Ts and N-Bn lactams, without the need for further purification. Evidence is presented suggesting a dual role for the stoichiometric base: (1) deprotonation of the triazolium precatalyst and (2) activation of the nitrogen leaving group through hydrogen bonding.

Full text of DOI:10.1021/ol102536s

ORGANIC
LETTERS
2010
Vol. 12, No. 24
5708-5711
NHC-Catalyzed Intramolecular Redox
Amidation for the Synthesis of
Functionalized Lactams
Karen Thai,† Li Wang,† Travis Dudding,‡ Franc¸ois Bilodeau,§ and Michel Gravel*,†
Department of Chemistry, UniVersity of Saskatchewan, 110 Science Place, Saskatoon,
SK S7N 5C9, Canada, Department of Chemistry, Brock UniVersity, St. Catharines, ON
L2S 3A1 Canada, and Boehringer Ingelheim (Canada) Ltd. Research and
DeVelopment, 2100 rue Cunard, LaVal, QC, H7S 2G5, Canada
michel.graVel@usask.ca
Received October 19, 2010
ABSTRACT
A very efficient NHC-catalyzed lactamization reaction is reported. For most cases, the ring expansion reaction proceeds to cleanly furnish five-
and six-membered N-Ts and N-Bn lactams, without the need for further purification. Evidence is presented suggesting a dual role for the
stoichiometric base: (1) deprotonation of the triazolium precatalyst and (2) activation of the nitrogen leaving group through hydrogen bonding.
The applications of N-heterocyclic carbenes (NHC) as
organocatalysts have been intensively investigated in the past
decade.1 An attractive feature of these NHCs is their ability
to effect the umpolung (inversion of reactivity) of aldehydes.
In recent years, various NHC-catalyzed formal redox trans-
formations of aldehydes bearing R-reducible functionalities
have been reported.2
form succinimide derivatives (Scheme 1a). In subsequent
work, Rovis et al. reported the formation of a ꢀ-amino amide
from the ring opening of an N-Ts aziridine in the presence
of an amine and a nucleophilic cocatalyst (Scheme 1b).2k
Other aldehydes bearing good leaving groups at the R
position were also shown to lead to amides, again in the
Following our NHC-catalyzed ring-expansion reaction of
oxacycloalkane-2-carboxaldehydes to furnish lactones,2n we
explored the extension of this methodology to the synthesis
of functionalized lactams, which represent a ubiquitous
structural feature of many alkaloid natural products and drug
candidates. Earlier work by Alcaide et al.2f,j and You et al.2i
demonstrated the ring expansion of strained ꢀ-lactams to
(2) Selected examples: (a) Chow, K. Y.-K.; Bode, J. W. J. Am. Chem.
Soc. 2004, 126, 8126–8127. (b) Reynolds, N. T.; Read de Alaniz, J.; Rovis,
T. J. Am. Chem. Soc. 2004, 126, 9518–9519. (c) Chan, A.; Scheidt, K. A.
Org. Lett. 2005, 7, 905–908. (d) Sohn, S. S.; Bode, J. W. Org. Lett. 2005,
7, 3873–3876. (e) Reynolds, N. T.; Rovis, T. J. Am. Chem. Soc. 2005, 127,
16406–16407. (f) Alcaide, B.; Almendros, P.; Cabrero, G.; Ruiz, M. P.
Org. Lett. 2005, 7, 3981–3984. (g) Zeitler, K. Org. Lett. 2006, 8, 637–640.
(h) Sohn, S. S.; Bode, J. W. Angew. Chem., Int. Ed. 2006, 45, 6021–6024.
(i) Li, G.-Q.; Li, Y.; Dai, L.-X.; You, S.-L. Org. Lett. 2007, 9, 3519–3521.
(j) Alcaide, B.; Almendros, P.; Cabrero, G.; Ruiz, M. P. Chem. Commun.
2007, 4788–4790. (k) Vora, H. U.; Rovis, T. J. Am. Chem. Soc. 2007, 129,
13796–13797. (l) Bode, J. W.; Sohn, S. S. J. Am. Chem. Soc. 2007, 129,
13798–13799. (m) Phillips, E. M.; Wadamoto, M.; Roth, H. S.; Ott, A. W.;
Scheidt, K. A. Org. Lett. 2009, 11, 105–108. (n) Wang, L.; Thai, K.; Gravel,
M. Org. Lett. 2009, 11, 891–893. (o) Li, G.-Q.; Dai, L.-X.; You, S.-L.
Org. Lett. 2009, 11, 1623–1625. (p) Yamaki, Y.; Shigenaga, A.; Li, J.;
Shimohigashi, Y.; Otaka, A. J. Org. Chem. 2009, 74, 3278–3285. (q)
Kawanaka, Y.; Phillips, E. M.; Scheidt, K. A. J. Am. Chem. Soc. 2009,
131, 18028–18029. (r) Ling, K. B., Smith, A. D. Chem. Commun. 2011,
DOI: 10.1039/c0cc02456b.
† University of Saskatchewan.
‡ Brock University.
§ Boehringer Ingelheim (Canada) Ltd. Research and Development.
(1) For selected reviews on NHC-catalyzed reactions, see: (a) Enders,
D.; Niemeier, O.; Henseler, A. Chem. ReV. 2007, 107, 5606–5655. (b)
Marion, N.; D´ıez-Gonza´lez, S.; Nolan, S. P. Angew. Chem., Int. Ed. 2007,
46, 2988–3000. (c) Nair, V.; Vellalath, S.; Babu, B. P. Chem. Soc. ReV.
2008, 37, 2691–2698. (d) Moore, J. L.; Rovis, T. Top. Curr. Chem. 2010,
291, 77–144.
10.1021/ol102536s  2010 American Chemical Society
Published on Web 11/16/2010

Tautomerization to form the activated carboxylate III fol-
lowed by intramolecular amide bond formation would furnish
the desired lactam and regenerate the NHC catalyst.4
A brief screen of azolium salts (not shown) rapidly
identified triazolium precatalyst 1 as the most promising
candidate. Initially, DBU was used to generate the NHC
catalyst, but it was also found to slowly cause decomposition
of the model N-Ts prolinal (2). The problem could be avoided
by portionwise addition of the base in substoichiometric
amounts to afford complete conversion after one day (Table
1, entry 1). A screen of bases was then conducted to increase
Scheme 1. NHC-Catalyzed Amide Formation
Table 1. Reaction Optimizationa
b
entry substrate
base
DBU
KHMDS
iPr2NEt
Cs2CO3
DMAP
imidazole
pyridine
iPr2NEt
iPr2NEt
iPr2NEt
pKa
time (h) conv (%)c
1d
2e
3
2
2
2
2
2
2
2
2
3
4
16.6 (-)
25.8 (-)
12.5 (10.8)
-(10.3)
11.2 (9.7)
-(7.0)
24
24
2
5
4
>95
<5
>95
>95
80
presence of a nucleophilic additive (Scheme 1c).2k,l Encour-
aged by our earlier success with strain-free oxygen-containing
substrates,2n we set out to find a reaction manifold that would
give access to a variety of lactams while obviating the need
for strained R-amino aldehydes (Scheme 1d). In the event,
we not only succeeded in defining appropriate conditions
and nitrogen activating groups for this transformation but
also found that simple unactiVated amines represent ideal
substrates. Moreover, our results suggest hydrogen bonding
plays an important role in the catalytic cycle.
4
5
6
7
24
24
5
24
7 d
<5
<5
>95
>95
80
5.5 (5.2)
8f
9f
10f
a The base (1 equiv) was added to the aldehyde (1 equiv) and precatalyst
1 (20 mol %) in CH2Cl2 (0.5 M of aldehyde). b pKa of the conjugate acid
in THF;5 values in H2O6 are given in parentheses. The values for Et3N are
given in entry 7. c Conversion determined by 1H NMR analysis of the crude
reaction mixture. d DBU was added in two portions (0.32 equiv). e Catalyst
was preformed by adding KHMDS (16 mol %) to the precatalyst 1 (20
mol %) in CH2Cl2 (0.5 M), and then aldehyde 2 (1 equiv) was added. f 10
mol % 1 was used. KHMDS ) potassium bis(trimethylsilyl)amide, DBU
) 1,8-diazabicycloundec-7-ene, DMAP ) 4-dimethylaminopyridine.
In line with our proposed mechanism for lactone
formation,2n we envisioned that the reaction would proceed
through the formation of a Breslow intermediate3 (I) poised
for ring opening to generate intermediate II (Scheme 2). The
the reaction rate and to make the procedure more convenient.
Thus, bases of varying strength were screened using N-Ts
prolinal (2) as the model substrate (Table 1). No reaction
was observed when the strong base KHMDS was used to
preform the carbene catalyst (entry 2). Whereas the use of
iPr2NEt, Cs2CO3, or 4-dimethylaminopyridine provided the
desired transformation, iPr2NEt proved to be superior (entries
3-5). However, weak bases such as imidazole and pyridine
returned the starting material (entries 6 and 7). Lowering
the catalyst loading to 10 mol % still resulted in a clean and
rapid reaction (entry 8). The influence of the electron-
withdrawing group on the efficiency of the reaction was
Scheme 2. Proposed Mechanism for Lactam Formation
(3) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719–3726.
(4) An intermediate related to III was proposed in homoenolate additions
to sulfonimines: (a) He, M.; Bode, J. W. Org. Lett. 2005, 7, 3131–3134.
(b) Nair, V.; Varghese, V.; Babu, B. P.; Sinu, C. R.; Suresh, E. Org. Biomol.
Chem. 2010, 8, 761–764.
nature of the electron-withdrawing group would be a defining
factor in facilitating the ring-opening step of the reaction.
Org. Lett., Vol. 12, No. 24, 2010
5709

investigated next. Amide 3 and carbamate 4 were both found
to require much longer reaction times (entries 9 and 10) than
sulfonamide 2.
Table 2. Scope of the Reaction
The observation that strong or weak bases do not provide
an effective conversion while intermediate ones are remark-
ably efficient is noteworthy.2d Presumably, the role of the
base in this reaction is 2-fold: (1) to generate the carbene
catalyst and (2) to activate the sulfonamide leaving group
through hydrogen bonding via its conjugate acid (Figure 1).7
Figure 1. Proposed mode of hydrogen bonding activation.
Thus, the base needs to be strong enough to deprotonate the
triazolium precatalyst but weak enough for its conjugate acid
to participate in hydrogen bonding catalysis.8
The synthesis of functionalized N-Ts lactams was then
investigated with the optimized conditions (Table 2). The
model substrate 2 furnished the desired lactam in high yield
(entry 1). Prolinal derivatives with substituents at the 3, 4,
or 5 position were efficiently converted to the corresponding
lactams (entries 2-4). Surprisingly, substrate 11 resulted in
a lower yield and the presence of numerous side products
(entry 5). The sluggish reaction rates of aldehydes 8, 10,
and 11 were initially thought to be a result of the relative
configuration of the substituents; however, aliquots taken
from the reaction mixture indicated that the reactivity of each
diastereomer is similar (entries 2, 4, and 5). The reason
behind the inefficient transformation of 11 could be that of
functional group incompatibility (vide infra).
Intrigued by the postulated hydrogen bonding effect of
the conjugate acid, we then examined the importance of the
electron-withdrawing group. If the nitrogen-containing func-
tional group is indeed activated through hydrogen bonding,
the electron-withdrawing group may not be necessary at all.
If this hypothesis holds true, simple amines should form
stronger hydrogen bonds than sulfonamides, making them
a Unless otherwise noted, all reactions were performed using racemic
susbtrate (see Supporting Information for details). b Yield of isolated, pure
product. c Enantiomerically enriched substrate (>99% ee) was used.
viable leaving groups. To our delight, the reaction with
N-benzyl prolinal 16 quickly furnished the desired lactam
in quantitative yield following a simple filtration of the crude
reaction mixture through a short pad of silica (Table 3, entry
1). In contrast to previously reported NHC-catalyzed redox
amidation reactions using aliphatic amines, no nucleophilic
cocatalyst or additive is required for this methodology.2k,l
Presumably, the tethered secondary amine released during
the catalytic cycle rapidly undergoes lactamization before
any side reaction or inhibition can take place.
Intrigued with the result obtained with the N-alkyl
substrate, we investigated the scope and limitations of the
reaction (Table 3). The use of substituents bearing silyl
protecting groups is well tolerated, furnishing the desired
lactam in high yield (entry 2). As was also observed for N-Ts
substrate 11, the 5-benzyloxymethyl substituent in 18 resulted
in a sluggish reaction and the formation of unidentified side
products (entry 3). In contrast, the allyl substituent at the
same position is well tolerated (entry 4). Thus, benzyl ethers
do not appear to be compatible with these reaction conditions,
although the reason for this incompatibility is not clear at
the moment. Interestingly, both cis and trans diastereomers
of substrates with a substituent at position 5 were consumed
at similar rates (entries 3 and 4). Whereas the attempted
formation of seven-membered lactam 27 only provided a
(5) (a) Fraser, R. R.; Mansour, T. S.; Savard, S. J. Org. Chem. 1985,
50, 3232–3234. (b) Rodima, T.; Kaljurand, I.; Pihl, A.; Ma¨emets, V.; Leito,
I.; Koppel, I. A. J. Org. Chem. 2002, 67, 1873–1881.
(6) (a) Perrin, D. D. Dissociation Constants of Organic Bases in Aqueous
Solution; Butterworths: London, 1965. (b) Smith, M. B.; March, J. March’s
AdVanced Organic Chemistry; Wiley: NY, 2007.
(7) For computational evidence of hydrogen bonding activation of
substrates in an NHC-catalyzed reaction, see: (a) Dudding, T.; Houk, K. N.
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5770–5775. For other examples
of catalytic hydrogen bonding or Lewis acid activation of substrates in NHC-
promoted umpolung reactions, see: (b) Mennen, S. M.; Blank, J. T.; Tran-
Dube´, M. B.; Imbriglio, J. E.; Miller, S. J. Chem. Commun. 2005, 195–
197. (c) Mattson, A. E.; Zuhl, A. M.; Reynolds, T. E.; Scheidt, K. A. J. Am.
Chem. Soc. 2006, 128, 4932–4933. (d) O’Toole, S. E.; Connon, S. J. Org.
Biomol. Chem. 2009, 7, 3584–3593. (e) Cardinal-David, B.; Raup, D. E. A.;
Scheidt, K. A. J. Am. Chem. Soc. 2010, 132, 5345–5347. (f) Raup, D. E. A.;
Cardinal-David, B.; Holte, D.; Scheidt, K. A. Nature Chem. 2010, 2, 766–
771.
(8) For a discussion of hydrogen bonding in sulfonamides, see: Ads-
mond, D. A.; Grant, D. J. W. J. Pharm. Sci. 2001, 90, 2058–2077.
5710
Org. Lett., Vol. 12, No. 24, 2010

the proposal that hydrogen bonding is involved in the ring-
opening step of the reaction.
Table 3. Scope of the Reaction
When considering the reaction with the N-benzyl sub-
strates, we reasoned that the tertiary amine substrate could
itself act as the base instead of iPr2NEt. To test this
hypothesis, the model substrate 16 was subjected to the
lactamization conditions in the absence of iPr2NEt (Scheme
3). Interestingly, the reaction proceeded to completion,
Scheme 3
.
NHC-Catalyzed Lactamization in the Absence of an
External Base
although the rate of the reaction suffered significantly
compared to the reaction performed in the presence of
iPr2NEt (20 h vs 30 min, respectively). It is not clear at this
point whether the basicity of the substrate (and thus the
acidity of its conjugate acid) relative to that of iPr2NEt can
alone explain the dramatic difference in reaction rates.
In summary, we developed an efficient intramolecular
redox lactamization reaction catalyzed by a triazolium-
derived carbene. Both N-Ts and N-Bn substrates efficiently
furnish the desired lactams in high yield. In addition to its
role in the in situ generation of the carbene catalyst, the
tertiary amine base is postulated to act as a hydrogen bonding
cocatalyst to facilitate the ring-opening step. Nonetheless, a
different mode of acceleration by the base can not be
excluded at this point. Further investigations into the
mechanism of this reaction are underway, including the exact
role of iPr2NEt and the nature of the hydrogen bonding
interaction.
a Unless otherwise noted, all reactions were performed using racemic
substrates (see Supporting Information for details). b Yield of isolated, pure
product. c Enantiomerically enriched substrate (>99% ee) was used.
trace of the desired product, five-membered lactam 26 was
obtained with great efficiency. Of note, the rate of the
reactivity of azetidine substrate 20 was found to be similar
to that of prolinal model substrate 16 despite the increased
strain in the former.
To further investigate the dual role of the base, substrate
16 was subjected to the conditions of Table 3 using DBU
instead of iPr2NEt.9 The observed reaction was appreciably
slower compared to the one using iPr2NEt (<20% vs >98%
conversion after 30 min).10 These results are consistent with
Acknowledgment. We thank Boehringer Ingelheim
(Canada) Ltd. for an Industrial Cooperative Research Schol-
arship in Synthetic Organic Chemistry (to K.T.), the Natural
Sciences and Engineering Research Council of Canada, the
Canada Foundation for Innovation, and the University of
Saskatchewan for financial support.
Supporting Information Available: Experimental pro-
cedures, characterization data, and NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(9) We thank a reviewer for this suggestion.
(10) Slow decomposition of the aldehyde was observed in the presence
of DBU; therefore, the stated conversion (formation of lactam product with
respect to remaining aldehyde substrate) is an approximate value determined
1
by H NMR.
OL102536S
Org. Lett., Vol. 12, No. 24, 2010
5711